WO2023246677A1 - Indole-phenylpiperidine compound, method for preparing same, and use thereof - Google Patents

Indole-phenylpiperidine compound, method for preparing same, and use thereof Download PDF

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Publication number
WO2023246677A1
WO2023246677A1 PCT/CN2023/100967 CN2023100967W WO2023246677A1 WO 2023246677 A1 WO2023246677 A1 WO 2023246677A1 CN 2023100967 W CN2023100967 W CN 2023100967W WO 2023246677 A1 WO2023246677 A1 WO 2023246677A1
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methyl
mmol
phenyl
methoxycarbonyl
reaction
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PCT/CN2023/100967
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French (fr)
Chinese (zh)
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吴俊军
陆银锁
白阳
肖瑛
王刘林
段振芳
杨闯
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深圳信立泰药业股份有限公司
惠州信立泰药业有限公司
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Publication of WO2023246677A1 publication Critical patent/WO2023246677A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • MN membranous nephropathy
  • C3G C3 glomerulonephritis
  • AMD age-related macular degeneration
  • GA geographic atrophy
  • aHUS atypical hemolytic uremic syndrome
  • HUS hemolytic uremic syndrome
  • NMO neuromyelitis
  • liver inflammation inflammatory bowel disease
  • dermatomyositis and amyotrophic lateral sclerosis
  • myasthenia gravis MG
  • respiratory diseases and cardiovascular diseases include membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), liver inflammation, inflammatory bowel disease, dermatomyositis and amyotrophic lateral sclerosis , myasthenia grav
  • WO2022028527A1 and CN104603127B disclose small molecule compounds as complement factor B inhibitors, and methods of using them to treat a variety of specific diseases or conditions.
  • this application provides a compound represented by general formula (I), or its isomer, or its racemate, or its pharmaceutically acceptable salt, as well as its preparation method and application.
  • this application provides a compound represented by general formula (I), or an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof:
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound described in any one of the above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease condition, the disease being a disease related to a complement factor B inhibitor,
  • the condition is selected from conditions such as PNH.
  • the present invention is implemented through the following technical solutions:
  • n 0, 1 or 2;
  • R 1 is selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, said The substituent is selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, and the substituent can be one or more;
  • R 2 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, the substituent is hydroxyl, halogen, and the substituent can be one or more;
  • R 3 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, the substituent is hydroxyl, halogen, and the substituent can be one or more;
  • R 4 and R 5 are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the substituent is selected from hydroxyl, halogen , C3-6 heterocycloalkyl, -(CH 2 ) m -C(O)OH, m is 0, 1 or 2, and the substituent can be one or more;
  • R 6 is independently selected from hydrogen and alkyl
  • R 7 is independently selected from hydrogen or hydroxyl
  • Ring A is independently selected from aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more R 8 if the valency allows, wherein R 8 is independently selected from hydrogen, cyano , sulfone group, halogen, substituted or unsubstituted C 1-6 alkyl group, substituted or unsubstituted C 3-6 cycloalkyl group, substituted or unsubstituted C 1-6 alkoxy group, substituted or unsubstituted C 3-6 ring Oxyalkyl, substituted or unsubstituted C 3-6 cycloalkoxy, wherein the substituent is selected from halogen, C 1-6 alkoxy, cyano, C 3-6 cycloalkyl, the substituent can be one or more indivual.
  • the C 1-6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, Secondary hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl;
  • the C 1-6 alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy Oxygen, sec-pentyloxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentyloxy, 1,2-dimethylpropyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, 1-ethylbutoxy;
  • the C 3-6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the C 3-6 epoxyalkyl group refers to one or more carbon atoms on the cycloalkane being replaced by an oxygen atom. replace.
  • the aryl group is selected from a five-membered ring, a six-membered ring, a seven-membered ring, an eight-membered ring, a nine-membered ring, and a ten-membered ring, and the aryl group is a single ring or a bicyclic ring;
  • the heteroaryl group means that more than one carbon atom on the aromatic ring is substituted by a heteroatom.
  • the A ring is selected from benzene ring
  • the C 3-6 heterocycloalkyl group is selected from
  • the A ring substituted by R 8 is selected from
  • R 1 is selected from methoxy and cyclopropyl
  • R 3 is selected from hydrogen
  • R 4 is selected from
  • R 5 is selected from hydrogen
  • R 6 is selected from hydrogen
  • R 7 is selected from hydrogen or hydroxyl
  • the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from:
  • the pharmaceutically acceptable salt refers to the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt and a pharmaceutically acceptable acid. or base preparation.
  • At least one hydrogen atom of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, is replaced by an isotope deuterium.
  • the present invention further provides the pharmaceutical use of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, its use in the preparation of medicaments for the treatment of diseases. It is a disease related to complement factor B inhibitors, specifically selected from diseases such as proteinuria.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention prepared from a compound having specific substituents found in the present invention and a pharmaceutically acceptable acid or base.
  • the compounds provided by the invention also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention.
  • prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, the atropisomer, and racemic and other mixtures thereof, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • the atoms of the compound molecules of the present invention are isotopes, and isotope derivatization can usually extend the half-life, reduce the clearance rate, stabilize metabolism, and improve in vivo activity. Also included is an embodiment in which at least one atom is replaced by an atom with the same atomic number (number of protons) and a different mass number (sum of protons and neutrons).
  • isotopes included in the compound of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H, 3 H, 13 C, 14 C, and 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl.
  • radioactive isotopes that emit radiation as they decay such as 3 H or 14 C, may be used in pharmaceutical preparations or in the anatomical examination of compounds in the body. Stable isotopes do not decay or change with their amount, nor are they radioactive, making them safe to use.
  • the isotope can be converted according to general methods by substituting reagents containing the corresponding isotope for the reagents used in the synthesis.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes such as deuterium ( 2H ), iodine-125 ( 125I ) or C-14 ( 14C ). All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the preparation method of the isotope derivative usually includes: phase transfer catalysis method.
  • phase transfer catalysts eg, tetraalkylammonium salts, NBu 4 HSO 4 .
  • the use of a phase transfer catalyst to exchange the methylene proton of the diphenylmethane compound results in a lower ratio of the methylene protons with a deuterated silane (e.g. triethyldeuterated silane) in the presence of an acid (e.g. methanesulfonic acid) or with a Lewis acid such as trichloro Aluminum is reduced by deuterated sodium borate to introduce higher deuterium.
  • a deuterated silane e.g. triethyldeuterated silane
  • an acid e.g. methanesulfonic acid
  • Lewis acid such as trichloro Aluminum
  • the term "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect.
  • the "effective amount” of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • Figure 2 is a crystal parameter diagram of the crystal structure of intermediate I
  • Figure 4 is the XRPD pattern of the crystal structure of Intermediate I.
  • compound 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester 5.0 g, 15 mmol
  • acetic acid HOAc, 100 ml
  • zinc powder Zn, 3.0 g, 45 mmol
  • Step D Synthesis of (S)-6-(4-cyanophenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step E Synthesis of (S)-4-(1-((benzyloxy)carbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-2-yl)benzoic acid
  • Step G Synthesis of methyl 4-((2S)-4-phenylpiperidin-2-yl)benzoate
  • Step H Synthesis of 5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step I Synthesis of 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step J Synthesis of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-phenylpiperidin-1-yl)methyl)-7- Methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1( 2H)-Carboxylic acid benzyl ester
  • (S)-2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester (1.3 g, 3.68 mmol), 1,1,1-trifluoro- N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.2 g, 6.02 mmol) was dissolved in tetrahydrofuran (THF, 20 ml), and cooled to -60°C in a cryogenic bath. Lithium bistrimethylsilylamide (LiHMDS, 6 ml, 6 mmol) was added, stirred for 30 minutes, raised to room temperature, and stirred for 1 hour.
  • LiHMDS Lithium bistrimethylsilylamide
  • reaction solution was poured into water (100 ml), extracted with ethyl acetate (50 ml x 3 times), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step B Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H) -Benzyl carboxylate
  • Step D Synthesis of 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step F Synthesis of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-2-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
  • Step A Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-thiazol-2-yl)piperidin-2-yl benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-(1-((benzyloxy)carbonyl)-6-(4-(methoxycarbonyl)phenyl)-1,2,3,6-tetrahydropyridin-4-yl ) boric acid
  • Step C Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Benzyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester
  • Step C Synthesis of methyl 4-((2S)-4-(thiophen-3-yl)piperidin-2-yl)benzoate
  • compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester 200 mg, 0.5 mmol
  • 5-bromoisothiazole 100 mg, 0.6 mmol
  • potassium phosphate (K 3 PO 4 , 215 mg, 1.0 mmol) were added 1,4-dioxane (10 ml), under nitrogen protection, raise the temperature to 95°C and react for 24 hours.
  • Step D Synthesis of 4-(((2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-4-(isothiazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidine-1-carboxylic acid benzyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1( 2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of methyl 4-((2S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate
  • Step C Synthesis of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1-methyl-1H-pyrazol-3-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1-methyl-1H-pyra Azol-5-yl)piperidin-2-yl)benzoic acid
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(thiophen-2-yl)piperidin-2-yl)benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-hydroxy-4-(thiophen-3-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-4-((4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl) -5-Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step D Synthesis of Compounds 14A and 14B
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
  • compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester 400 mg, 0.84 mmol
  • 3-bromo-2-methylthiophene 178 mg, 1.01 mmol
  • [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride 62 mg, 0.83 mmol
  • potassium carbonate (231 mg, 1.68 mmol) were added to 1,4-dioxane (10 ml), add water (5 ml), and under nitrogen protection, heat to 90°C and react for 5 hours.
  • Step B Synthesis of (S)-4-(4-(2-methylthiophen-3-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1 -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1 -methyl)-7-methyl-1H-indole-1-carboxylic acid
  • compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine- 1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, crude product) was dissolved in methanol (10 ml), and potassium carbonate (235 mg) was added , 1.7 mmol), heated to 70°C for 3 hours, added water (2 ml) and continued the reaction for 3 hours.
  • Step A Synthesis of (S)-2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester
  • Step D Synthesis of (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl) )methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step E Synthesis of compound (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1- (methyl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid
  • compound (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1- (methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester 80 mg, 0.11 mmol, crude product
  • methanol 5 ml
  • Potassium 165 mg, 1.2 mmol
  • water (2 ml) was added to continue the reaction for 2 hours.
  • Step A Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
  • Step B Synthesis of (S)-4-(4-(5-methylthiophen-3-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)piperidine-1 -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step D Synthesis of Compounds 17A and 17B
  • Step A Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)-3,6-dihydropyridine-1(2H)- Benzyl carboxylate
  • Step B Synthesis of (S)-4-(4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)piperidine- 1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-methylisothiazole-5 -yl)piperidin-2-yl)benzoic acid
  • Step A Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
  • Step B Synthesis of (S)-4-(4-(2-methylthiazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)piperidine-1 -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine -1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazole-4- (yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step D Synthesis of Compounds 20A and 20B
  • step D of Example 3 the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 38 mg of diastereomer 20A with absolute configuration (yield: 15%) and 120 mg of diastereoisomer 20A with absolute configuration.
  • Enantiomer 20B yield: 48%).
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1-ethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step D Synthesis of Compounds 21A and 21B
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine- 1(2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl) )piperidin-1-yl)methyl)-7-methyl -1H-indole-1-carboxylic acid tert-butyl ester
  • step D of Example 3 the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 23 mg of diastereomer 22A with absolute configuration (yield: 7%) and 217 mg of diastereoisomer 22A with absolute configuration.
  • Enantiomer 22B yield: 66%).
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine- 1(2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl) )piperidin-1-yl)methyl)-7-methyl -1H-indole-1-carboxylic acid tert-butyl ester
  • step D of Example 3 the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 30 mg of diastereoisomer 23A with absolute configuration (yield: 11%) and 140 mg of diastereoisomer 23A with absolute configuration.
  • Enantiomer 23B yield: 50%).
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.0 g, 2.1 mmol), 4-bromo-1-(2-methoxyethyl)-1H - Pyrazole (648.3 mg, 3.1 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (307 mg, 0.4 mmol), potassium phosphate (912 mg, 4.2 mmol) mol) was added to 1,4-dioxane (30 ml) and water (6 ml), and the temperature was raised to 95°C under nitrogen protection for 12 hours.
  • Step B Synthesis of (S)-4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H- Pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1( 2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl benzoic acid methyl ester
  • Step C Synthesis of 5-cyclopropyl-4-((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidine -1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of 4-bromo-1-(deuterated methyl)-1H-pyrazole
  • Step B Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(deuteratedmethyl)-1H-pyrazol-4-yl)-3,6-di Hydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step C Synthesis of (S)-4-(4-(1-(deuterated methyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step D Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(deuteratedmethyl)-1H-pyrazole- 4-yl)piperidin-1-yl))methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro Pyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-4-((4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine- 1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro Pyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step D Synthesis of (S)-4-((4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine- 1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step B Synthesis of (S)-4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6- Dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step C Synthesis of (S)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step D Synthesis of (S)-4-((4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piper ((ridin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
  • Step B Synthesis of (S)-4-(4-(1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)piperidine-1- (methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step D Compounds 30A and 30B
  • 1,2-dihydro-3H-pyrazol-3-one (3.00 g, 35.7 mmol) was dissolved in acetonitrile (30 ml), and 1,2-dibromoethane (20.21 g, 107.1 mmol) was added. mol) and potassium carbonate (14.78 g, 107.1 mmol), and the temperature was raised to 80°C to react overnight.
  • Step B Synthesis of 7-bromo-2,3-dihydropyrazole[5,1-b]oxazole
  • Step C Synthesis of (S)-4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)-6-(4-(methoxycarbonyl)phenyl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step D Synthesis of (S)-4-(4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)piperidin-2-yl)benzoate methyl ester
  • Step E Synthesis of (S)-4-(4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)-2-(4-(methoxycarbonyl)phenyl) Piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H )-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1-methyl-1H-imidazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl(phenyl))-4-(1-methyl-1H-imidazol-4-yl)piperidine- 1-yl)methyl)-7-methyl-1H-indole-1-carboxylate tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-3,6 -Dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(1-methyl-1H-1,2,3-tri Azol-4-yl)piperidin-1)-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-6-methyl-3′,6′-dihydro-[2,4′-bipyridyl]-1′( 2′H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(6-methylpyridin-2-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(6-methylpyridin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-5-methyl-3′,6′-dihydro-[2,4′-bipyridyl]-1′( 2′H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(5-methylpyridin-2-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(5-methylpyridin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)-3,6-dihydropyridine-1(2H)- Benzyl carboxylate
  • Step B Synthesis of (S)-4-(4-(4-methylpyridin-2-yl)piperidin-2-ylbenzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(pyridazin-3-yl)piperidin-2-yl)benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(pyrimidin-4-yl)piperidin-2-yl)benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
  • Step D Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl methyl)-7-methyl-1H-indole-1-carboxylic acid
  • Step A Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid
  • Step D Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl )-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step E Compounds 39A and 39B
  • the crystal structure of intermediate I was successfully determined by the MicroED method.
  • the crystal structure belongs to the orthorhombic crystal system and the P212121 (No. 19) space group.
  • the z′ of the system is 1, and the asymmetric unit of the crystal is composed of 1 API molecule.
  • the absolute configuration of Intermediate I is determined as follows, as shown in Figure 1.
  • the crystal parameter diagram of the crystal structure of Intermediate I is shown in Figure 2.
  • the atomic coordinates and isotropic displacement parameter diagram of the crystal structure of Intermediate I are shown in Figure 1.
  • the XRPD pattern of the crystal structure of Intermediate I is shown in Figure 4:
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(pyrimidin-2-yl)piperidin-2-yl)benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
  • Step A Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H) -Benzyl carboxylate
  • Step B Synthesis of (S)-4-(4-(pyridin-3-yl)piperidin-2-yl)benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(pyridin-4-yl)piperidin-2-yl)benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-4-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(pyrimidin-5-yl)piperidin-2-yl)benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylate tert-butyl ester
  • Step A Synthesis of (S)-4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3 , 6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-4-(4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-2-(4-(methoxycarbonyl)phenyl) )piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-methoxy-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridyl]-1( 2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(6-methoxypyridin-2-yl)piperidin-2-yl)benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(6-methoxypyridin-2-yl)piperidine-1 -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
  • Step B Synthesis of methyl 4-((2S)-4-(5-methylthiophen-2-yl)piperidin-2-yl)benzoate
  • Step C Synthesis of 5-methoxy-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)piperidin-1-yl) )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-4-(3,6-dichloropyridazin-4-yl)-6-(4-methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)- Benzyl carboxylate
  • Step B Synthesis of (S)-4-(4-(pyridazin-4-yl)piperidin-2-yl)benzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-4-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)-3,6-dihydropyridine-1( 2H)-Carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(5-trifluoromethyl)thiophen-2-yl)piperidin-2-yl benzoate methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)piper (Din-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-6-(4-(2H-tetrazol-5yl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H) -Benzyl carboxylate
  • Step C Synthesis of (S)-2-(2-(4-(2H-tetrazol-5yl)phenylpiperidin-4-ylpyrazine)
  • Step D Synthesis of (S)-5-methoxy-4-(2-4-(2H-tetrazol-5yl)phenyl-4-(pyrazin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step E Compounds 49A and 49B
  • Step A Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
  • Step B Synthesis of (S)-4-(4-(5-fluoropyridin-2-yl)piperidin-2-ylbenzoic acid methyl ester
  • Step C Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • reaction solution was poured into an ice-cold saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (10 ml ⁇ 3 times), the organic phases were combined, dried and spin-dried, and the resulting residue was purified by silica gel column chromatography (eluent : n-hexane) to obtain 1.7 g of colorless liquid 4-bromo-2-(difluoromethyl)thiophene (yield: 76.9%).
  • Step B Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid benzyl ester
  • Step C Synthesis of (S)-4-(4-(5-(difluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate methyl ester
  • Step D Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
  • Step A Synthesis of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
  • Step B Synthesis of (S)-4-(4-(2-pyrazinyl)piperidin-2-yl)benzonitrile
  • Step C Synthesis of (S)-2-(4-cyanophenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-2-(4-(N-hydroxyaminoimidazolyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester

Abstract

The present application relates to the technical field of chemical drugs, and particularly, to a compound represented by general formula (I), a racemate thereof, an isomer thereof or a pharmaceutically acceptable salt thereof as a complement factor B inhibitor, and a method for treating various specific diseases or symptoms using same.

Description

一种吲哚-苯基哌啶化合物及其制备方法与应用An indole-phenylpiperidine compound and its preparation method and application 技术领域Technical field
本发明属于化学药物技术领域，涉及一种吲哚-苯基哌啶化合物，或其异构体、或其消旋体、或其可药用的盐，及其制备方法与应用。作为补体B因子抑制剂，以及使用其治疗多种特定疾病或病状的方法。The invention belongs to the technical field of chemical drugs and relates to an indole-phenylpiperidine compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, as well as its preparation method and application. As inhibitors of complement factor B, and methods of using them to treat a variety of specific diseases or conditions.
背景技术Background technique
补体是免疫***中一类可溶性模式识别分子，可以行使多种效应功能。目前已知的补体激活途径主要包括3条：经典途径、凝集素途径、旁路途径。补体B因子(Complement factor B，CFB)是一种胰蛋白酶样的丝氨酸蛋白酶，以潜在的酶原形式在人体血液中循环。旁路途径是一种镁-依赖性级联，其通过C3在某些易感表面(例如酵母菌和细菌的细胞壁多糖，和某些生物高分子材料)上的沉积和活化而激活。Complement is a type of soluble pattern recognition molecule in the immune system that can perform a variety of effector functions. There are currently three known complement activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Complement factor B (CFB) is a trypsin-like serine protease that circulates in human blood as a potential zymogen. The alternative pathway is a magnesium-dependent cascade that is activated through the deposition and activation of C3 on certain susceptible surfaces, such as cell wall polysaccharides of yeasts and bacteria, and certain biopolymer materials.
PNH是一种罕见的、危及生命的血液疾病，特征是补体驱动的溶血、血栓形成和骨髓功能受损，导致贫血、疲劳和其他衰弱症状，这些症状会严重影响患者的生活质量。尽管使用当前的抗C5标准护理疗法进行治疗，很大一部分PNH患者仍然贫血，并依赖输血。PNH is a rare, life-threatening hematologic disorder characterized by complement-driven hemolysis, thrombosis, and impaired bone marrow function, resulting in anemia, fatigue, and other debilitating symptoms that can severely impact patients' quality of life. Despite treatment with current anti-C5 standard-of-care therapies, a large proportion of PNH patients remain anemic and transfusion dependent.
与补体级联相关的其它疾病还包括膜性肾病(MN)、C3肾小球肾炎(C3G)、年龄相关性黄斑变性(AMD)、地图状萎缩(GA)、非典型溶血***综合征(aHUS)、溶血***综合征(HUS)、血液透析并发症、溶血性贫血或血液透析、神经脊髓炎(NMO)、肝脏类炎症、炎症性肠病、皮肌炎和肌萎缩性侧索硬化、重症肌无力(MG)、呼吸***疾病和心血管等疾病。Other diseases associated with the complement cascade include membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome ( aHUS), hemolytic uremic syndrome (HUS), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), liver inflammation, inflammatory bowel disease, dermatomyositis and amyotrophic lateral sclerosis , myasthenia gravis (MG), respiratory diseases and cardiovascular diseases.
炎症和免疫性相关的疾病具有多样性、难治愈的特点；PNH疾病上市的药物仅有依库珠单抗，但是由于价格，给患者带来了沉重的负担；同时，许多患者经用依库珠单抗治疗后仍然出现贫血现象，并且许多患者依然需要持续的输血；此外，在用药方式上依库珠单抗需要静脉注射。而一些疾病截至目前并没有特效的治疗药物，比如IgAN等。在这些领域有尚未满足的临床需求，需要开发新的小分子药物用于医学治疗。Inflammatory and immune-related diseases are diverse and difficult to cure; the only drug on the market for PNH disease is eculizumab, but due to its price, it brings a heavy burden to patients; at the same time, many patients often take eculizumab. Anemia still occurs after Tizumab treatment, and many patients still require continuous blood transfusions; in addition, Eculizumab requires intravenous injection. There are currently no specific treatments for some diseases, such as IgAN. There are unmet clinical needs in these areas that require the development of new small molecule drugs for medical treatment.
现有技术例如：WO2022028527A1和CN104603127B公开了作为补体B因子抑制剂小分子化合物，以及使用其治疗多种特定疾病或病状的方法。Prior art, for example: WO2022028527A1 and CN104603127B disclose small molecule compounds as complement factor B inhibitors, and methods of using them to treat a variety of specific diseases or conditions.
发明内容Contents of the invention
鉴于现有技术存在的问题，本申请提供一种通式(I)所示的化合物，或其异构体、或其消旋体、或其可药用的盐，及其制备方法与应用。作为补体B因子小分子抑制剂，以及使用其治疗多种特定疾病或病状的方法。In view of the problems existing in the prior art, this application provides a compound represented by general formula (I), or its isomer, or its racemate, or its pharmaceutically acceptable salt, as well as its preparation method and application. As small molecule inhibitors of complement factor B, and methods of using them to treat a variety of specific diseases or conditions.
第一方面，本申请提供一种通式(I)所示的化合物，或其异构体、或其消旋体、或其可药用的盐：
In the first aspect, this application provides a compound represented by general formula (I), or an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof:
第二方面，本发明还提供一种药物组合物，其包含治疗有效量的上述任一项所述的化合物或其药物可接受的盐和药物可接受的载体。In a second aspect, the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound described in any one of the above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
第三方面，本发明还提供一种治疗有效量的上述所述的化合物或其药物可接受的盐在制备用于治疗病况的药物中的用途，所述疾病是补体B因子抑制剂相关疾病，具体地，所述病况选自PNH等病症。In a third aspect, the present invention also provides the use of a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease condition, the disease being a disease related to a complement factor B inhibitor, In particular, the condition is selected from conditions such as PNH.
具体地，本发明通过以下技术方案来实现：Specifically, the present invention is implemented through the following technical solutions:
一种通式(I)所示的化合物，或其异构体、或其消旋体、或其可药用的盐，包括：
A compound represented by general formula (I), or its isomer, or its racemate, or its pharmaceutically acceptable salt, including:
其中，n是0、1或2；Where, n is 0, 1 or 2;
R1选自氢、卤素、羟基、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的C3-6环烷基，所述取代基选自卤素、羟基、氨基、C1-6烷基、C1-6烷氧基，取代基可以是一个或多个；R 1 is selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, said The substituent is selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, and the substituent can be one or more;
R2选自氢、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基，所述取代基为羟基、卤素，取代基可以是一个或多个；R 2 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, the substituent is hydroxyl, halogen, and the substituent can be one or more;
R3选自氢、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基，所述取代基为羟基、卤素，取代基可以是一个或多个；R 3 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, the substituent is hydroxyl, halogen, and the substituent can be one or more;
R4、R5独立地选自氢、取代或未取代的C1-6烷基、取代或未取代的芳基、或取代或未取代的杂芳基，所述取代基选自羟基、卤素、C3-6的杂环烷基，-(CH2)m-C(O)OH，m是0、1或2，取代基可以是一个或多个； R 4 and R 5 are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the substituent is selected from hydroxyl, halogen , C3-6 heterocycloalkyl, -(CH 2 ) m -C(O)OH, m is 0, 1 or 2, and the substituent can be one or more;
R6独立地选自氢、烷基；R 6 is independently selected from hydrogen and alkyl;
R7独立地选自氢或羟基；R 7 is independently selected from hydrogen or hydroxyl;
A环独立选自芳基或杂芳基，其中所述芳基及杂芳基在化合价容许的情况下任选经一个或多个R8取代，其中，R8独立地选自氢、氰基、砜基、卤素、取代或未取代C1-6烷基、取代或未取代C3-6环烷基、取代或未取代C1-6烷氧基、取代或未取代C3-6环氧烷基，取代或未取代C3-6环烷氧基，其中取代基选自卤素、C1-6烷氧基、氰基、C3-6环烷基，取代基可以是一个或多个。Ring A is independently selected from aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more R 8 if the valency allows, wherein R 8 is independently selected from hydrogen, cyano , sulfone group, halogen, substituted or unsubstituted C 1-6 alkyl group, substituted or unsubstituted C 3-6 cycloalkyl group, substituted or unsubstituted C 1-6 alkoxy group, substituted or unsubstituted C 3-6 ring Oxyalkyl, substituted or unsubstituted C 3-6 cycloalkoxy, wherein the substituent is selected from halogen, C 1-6 alkoxy, cyano, C 3-6 cycloalkyl, the substituent can be one or more indivual.
作为本发明的一种优选技术方案，所述C1-6的烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、仲戊基、1-乙基丙基、2-甲基丁基、叔戊基、1，2-二甲基丙基、异戊基、新戊基、正己基、异己基、仲己基、叔己基、新己基、2-甲基戊基、1，2-二甲基丁基、1-乙基丁基；As a preferred technical solution of the present invention, the C 1-6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, Secondary hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl;
所述C1-6烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、仲戊氧基、1-乙基丙氧基、2-甲基丁氧基、叔戊氧基、1，2-二甲基丙氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、仲己氧基、叔己氧基、新己氧基、2-甲基戊氧基、1，2-二甲基丁氧基、1-乙基丁氧基；The C 1-6 alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy Oxygen, sec-pentyloxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentyloxy, 1,2-dimethylpropyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, 1-ethylbutoxy;
所述C3-6的环烷基选自环丙基、环丁基、环戊基、环己基，所述C3-6的环氧烷基是指环烷上一个以上的碳原子被氧原子取代。The C 3-6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The C 3-6 epoxyalkyl group refers to one or more carbon atoms on the cycloalkane being replaced by an oxygen atom. replace.
所述C3-6环烷氧基是其中x是1、2、3或4，为连接键。The C 3-6 cycloalkoxy group is where x is 1, 2, 3 or 4, is the connection key.
作为本发明的一种优选技术方案，所述芳基选自五元环、六元环、七元环、八元环、九元环、十元环，所述芳基为单环或者双环；所述杂芳基是指芳环上一个以上的碳原子被杂原子取代。As a preferred technical solution of the present invention, the aryl group is selected from a five-membered ring, a six-membered ring, a seven-membered ring, an eight-membered ring, a nine-membered ring, and a ten-membered ring, and the aryl group is a single ring or a bicyclic ring; The heteroaryl group means that more than one carbon atom on the aromatic ring is substituted by a heteroatom.
作为本发明的一种优选技术方案，所述卤素选自氟、氯、溴、碘。As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine.
作为本发明的一种优选技术方案，杂原子选自氮、氧、硫，所述杂原子为一个或者多个。As a preferred technical solution of the present invention, the heteroatom is selected from nitrogen, oxygen, and sulfur, and the number of heteroatoms is one or more.
作为本发明的一种优选技术方案，其中，所述A环选自苯环、 所述C3-6的杂环烷基选自 As a preferred technical solution of the present invention, the A ring is selected from benzene ring, The C 3-6 heterocycloalkyl group is selected from
作为本发明的一种优选技术方案，其中，R8取代的A环选自 As a preferred technical solution of the present invention, the A ring substituted by R 8 is selected from
R1选自甲氧基、环丙基；R 1 is selected from methoxy and cyclopropyl;
R2选自甲基；R 2 is selected from methyl;
R3选自氢；R 3 is selected from hydrogen;
R4选自 R 4 is selected from
R5选自氢；R 5 is selected from hydrogen;
R6选自氢；R 6 is selected from hydrogen;
R7选自氢或羟基；R 7 is selected from hydrogen or hydroxyl;
为连接键。 is the connection key.
作为本发明的一种优选技术方案，所述的化合物，或其异构体、或其消旋体、或其可药用的盐，选自：



As a preferred technical solution of the present invention, the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, is selected from:



作为本发明的一种优选技术方案，所述药学上可接受的盐是指所述化合物，或其异构体、或其消旋体、或其可药用的盐与药学上可接受的酸或碱制备。As a preferred technical solution of the present invention, the pharmaceutically acceptable salt refers to the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt and a pharmaceutically acceptable acid. or base preparation.
作为本发明的一种优选技术方案，所述化合物，或其异构体、或其消旋体、或其可药用的盐的一个以上的氢原子上被同位素氘取代。As a preferred technical solution of the present invention, at least one hydrogen atom of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, is replaced by an isotope deuterium.
本发明进一步提供了一种药物组合物，其特征在于，包含治疗有效量的所述化合物，或其异构体、或其消旋体、或其可药用的盐和药物可接受的载体。The present invention further provides a pharmaceutical composition, which is characterized in that it contains a therapeutically effective amount of the compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
本发明进一步提供了所述化合物，或其异构体、或其消旋体、或其可药用的盐的医药用途，具体地，在制备用于治疗疾病的药物中的用途，所述疾病为补体B因子抑制剂相关疾病，具体选自蛋白尿等病症。The present invention further provides the pharmaceutical use of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, its use in the preparation of medicaments for the treatment of diseases. It is a disease related to complement factor B inhibitors, specifically selected from diseases such as proteinuria.
为清楚起见，本文定义了在化合物的描述中所使用的通用术语。For the sake of clarity, common terms used in the description of compounds are defined herein.
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与药学上可接受的酸或碱制备。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having specific substituents found in the present invention and a pharmaceutically acceptable acid or base.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。 In addition to salt forms, the compounds provided by the invention also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention. In addition, prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，阻转异构体，及其外消旋混合物和其他混合物，所述混合物例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, the atropisomer, and racemic and other mixtures thereof, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体，以及D和L异构体，阻转异构体等。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers, as well as D and L isomers, atropisomers, etc., can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
本发明化合物分子的原子是同位素，通过同位素衍生化通常可以延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。并且，包括一个实施方案，其中至少一个原子被具有相同原子数(质子数)和不同质量数(质子和中子和)的原子取代。本发明化合物中包括的同位素的实例包括氢原子、碳原子、氮原子、氧原子、磷原子、硫原子、氟原子、氯原子，其分别包括2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl。特别的是，随其衰退而发射辐射的放射性同位素例如3H或14C可用于药物制剂或者体内化合物的局部解剖学检验。稳定的同位素既不随其量衰减或变化，也不具有放射性，因此其可以安全使用。当构成本发明化合物分子的原子是同位素时，通过用包含相应同位素的试剂替代合成中所用的试剂，可以根据通用方法转化同位素。The atoms of the compound molecules of the present invention are isotopes, and isotope derivatization can usually extend the half-life, reduce the clearance rate, stabilize metabolism, and improve in vivo activity. Also included is an embodiment in which at least one atom is replaced by an atom with the same atomic number (number of protons) and a different mass number (sum of protons and neutrons). Examples of isotopes included in the compound of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H, 3 H, 13 C, 14 C, and 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C, may be used in pharmaceutical preparations or in the anatomical examination of compounds in the body. Stable isotopes do not decay or change with their amount, nor are they radioactive, making them safe to use. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotope can be converted according to general methods by substituting reagents containing the corresponding isotope for the reagents used in the synthesis.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(2H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes such as deuterium ( 2H ), iodine-125 ( 125I ) or C-14 ( 14C ). All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
进一步地，本发明的化合物一个或多个氢原子上被同位素氘(2H)取代，本发明化合物氘代后，具有延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。Furthermore, one or more hydrogen atoms of the compound of the present invention are replaced by the isotope deuterium (2H). After deuteration of the compound of the present invention, it has the effects of extending the half-life, reducing the clearance rate, stabilizing metabolism and improving in vivo activity.
所述同位素衍生物的制备方法通常包括：相转移催化方法。例如，优选的氘化方法采用相转移催化剂(例如，四烷基铵盐，NBu4HSO4)。使用相转移催化剂交换二苯基甲烷化合物的亚甲基质子，导致比在酸(例如，甲磺酸)存在下用氘化硅烷(例如三乙基氘化甲硅烷)或用路易斯酸如三氯化铝采用氘化硼酸钠还原而引入较高的氘。The preparation method of the isotope derivative usually includes: phase transfer catalysis method. For example, preferred deuteration methods employ phase transfer catalysts (eg, tetraalkylammonium salts, NBu 4 HSO 4 ). The use of a phase transfer catalyst to exchange the methylene proton of the diphenylmethane compound results in a lower ratio of the methylene protons with a deuterated silane (e.g. triethyldeuterated silane) in the presence of an acid (e.g. methanesulfonic acid) or with a Lewis acid such as trichloro Aluminum is reduced by deuterated sodium borate to introduce higher deuterium.
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质，代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington：The Science and Practice of Pharmacy，21st Ed.，Lippincott，Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any preparation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil , vegetables and minerals, cream base, lotion base, ointment base, etc. These matrices include suspending agents, viscosifiers, transdermal penetration enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicine. For additional information on vectors, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。The term "excipient" generally refers to a carrier, diluent and/or medium required for formulating an effective pharmaceutical composition.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease or condition.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or condition may but need not occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not occur.
表示连接键，表示不同构型的混合物，“abs”表示绝对构型。 Represents the connection key, Indicates a mixture of different configurations, and "abs" indicates the absolute configuration.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
附图说明Description of the drawings
图1为中间体I的晶体结构示意图；Figure 1 is a schematic diagram of the crystal structure of intermediate I;
图2为中间体I晶体结构的晶体参数图；Figure 2 is a crystal parameter diagram of the crystal structure of intermediate I;
图3为中间体I晶体结构的原子坐标及各项同性位移参数图；Figure 3 is a diagram of the atomic coordinates and isotropic displacement parameters of the crystal structure of intermediate I;
图4为中间体I晶体结构的XRPD图。Figure 4 is the XRPD pattern of the crystal structure of Intermediate I.
具体实施方式 Detailed ways
下面结合实施例对本申请作进一步详细的描述，但本申请的实施方式不限于此。The present application will be described in further detail below with reference to examples, but the implementation of the present application is not limited thereto.
THF四氢呋喃、Zn锌、HOAc醋酸、Dioxane 1，4-二氧六环、NaOH氢氧化钠、i-PrOH异丙醇、r.t.室温、K3PO4磷酸钾、SOCl2氯化亚砜、MeOH甲醇、DCM二氯甲烷、DMAP4-二甲氨基吡啶、DCE 1，2-二氯乙烷、K2CO3碳酸钾、NaBH4硼氢化钠、DMF N，N-二甲基甲酰胺、EA/EtOAc乙酸乙酯、Acetone丙酮、NaIO4高碘酸钠、Py吡啶、HBr氢溴酸、H2氢气。THF tetrahydrofuran, Zn zinc, HOAc acetic acid, Dioxane 1,4-dioxane, NaOH sodium hydroxide, i-PrOH isopropanol, rt room temperature, K 3 PO 4 potassium phosphate, SOCl2 thionyl chloride, MeOH methanol, DCM dichloromethane, DMAP4-dimethylaminopyridine, DCE 1,2-dichloroethane, K2CO3 potassium carbonate, NaBH4 sodium borohydride, DMF N,N-dimethylformamide, EA/EtOAc ethyl acetate Ester, Acetone, NaIO4, Pypyridine, HBr hydrobromide, H2 hydrogen gas.
实施例1合成化合物1A和1B
Example 1 Synthesis of Compounds 1A and 1B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成2-(4-氰基苯基)-4-氧代-3，4-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向4-溴苄腈(36.7克，201.5毫摩尔)的四氢呋喃(180毫升)溶液中滴入异丙基氯化镁氯化锂复合物(i-PrMgCl.LiCl)溶液(1.3M in THF，155毫升)，滴毕搅拌2小时。-5到-10℃下，向溶有4-甲氧基吡啶(20克，183毫摩尔)的四氢呋喃(THF，100毫升)中，依次滴加上述反应液、氯甲酸苄酯(CbzCl，27毫升，192毫摩尔)，滴毕，于0℃搅拌1.5小时，升至室温搅拌16小时。To a solution of 4-bromobenzonitrile (36.7 g, 201.5 mmol) in tetrahydrofuran (180 ml) at room temperature was added dropwise a solution of isopropyl magnesium chloride lithium chloride complex (i-PrMgCl.LiCl) (1.3 M in THF, 155 ml), stir for 2 hours after the drops are completed. At -5 to -10°C, to tetrahydrofuran (THF, 100 ml) dissolved in 4-methoxypyridine (20 g, 183 mmol), the above reaction solution and benzyl chloroformate (CbzCl, 27 ml, 192 mmol), after completion of dropping, stir at 0°C for 1.5 hours, then rise to room temperature and stir for 16 hours.
反应结束，加5M HCl(40毫升)水溶液猝灭，室温搅拌0.5小时。减压浓缩，乙酸乙酯萃取(50毫升×3次)，饱和碳酸氢钠水溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/3)，得到21克淡黄色固体2-(4-氰基苯基)-4-氧代-3，4-二氢吡啶-1(2H)-羧酸苄酯(收率：34％)。LC-MS：RT＝1.98min，[M+H]+＝333.14。When the reaction was completed, 5M HCl (40 ml) aqueous solution was added to quench the reaction, and the mixture was stirred at room temperature for 0.5 hours. Concentrate under reduced pressure, extract with ethyl acetate (50 ml × 3 times), wash with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, and dry over anhydrous sodium sulfate. concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/3), and 21 g of light yellow solid 2-(4-cyanophenyl)-4-oxo-3 was obtained. 4-Dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 34%). LC-MS: RT=1.98min, [M+H] + =333.14.
步骤B：合成(S)-2-(4-氰基苯基)-4-氧代哌啶-1-羧酸苄酯Step B: Synthesis of (S)-2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester
室温下，化合物2-(4-氰基苯基)-4-氧代-3，4-二氢吡啶-1(2H)-羧酸苄酯(5.0克，15毫摩尔)加入醋酸(HOAc，100毫升)中，加热至100℃，分批次加入锌粉(Zn，3.0克，45毫摩尔)反应过夜。At room temperature, compound 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (5.0 g, 15 mmol) was added with acetic acid (HOAc, 100 ml), heated to 100°C, added zinc powder (Zn, 3.0 g, 45 mmol) in batches and reacted overnight.
反应结束，降至室温，乙酸乙酯(50毫升)稀释，过滤，滤液用水洗涤，饱和碳酸氢钠中和，饱和食盐水洗涤，干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到3.0克浅黄色固体2-(4-氰基苯基)-4-氧代哌啶-1-羧酸苄酯(收率59％)。通过手性SFC、使用AS-H柱与55％在CO2中的(含有5mM NH4OH的MeOH)拆分得到1.3克白色固体(S)-2-(4-氰基苯基)-4-氧代哌啶-1-羧酸苄酯。After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), filtered, the filtrate was washed with water, neutralized with saturated sodium bicarbonate, washed with saturated brine, dried, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). 3.0 g of light yellow solid benzyl 2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylate was obtained (yield 59%). By chiral SFC, use AS-H column resolution with 55% (MeOH containing 5mM NH4OH ) in CO2 gave 1.3 g of white solid (S)-2-(4-cyanophenyl)-4-oxopiperidine- 1-Carboxylic acid benzyl ester.
步骤C：合成(S)-6-(4-氰基苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step C: Synthesis of (S)-6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
室温下，将(S)-2-(4-氰基苯基)-4-氧代哌啶-1-羧酸苄酯(200毫克，0.60毫摩尔)，1，1，1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(PhN(Tf)2，320毫克，0.90毫摩尔)溶于四氢呋喃(THF，10毫升)中，降至-60℃。加入双三甲基硅基胺基锂(LiHMDS，1.8毫升，1.8毫摩尔)，搅拌0.5小时，升至室温反应1小时。(S)-2-(4-Cyanophenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester (200 mg, 0.60 mmol), 1,1,1-trifluoro- N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (PhN(Tf)2, 320 mg, 0.90 mmol) was dissolved in tetrahydrofuran (THF, 10 ml) and cooled to -60°C . Lithium bistrimethylsilylamide (LiHMDS, 1.8 ml, 1.8 mmol) was added, stirred for 0.5 hours, and allowed to react at room temperature for 1 hour.
反应结束，将反应液倒入水(40毫升)中，乙酸乙酯萃取(50毫升×3次)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)。得到190毫克黄色油状(S)-6-(4-氰基苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率68％)。At the end of the reaction, the reaction solution was poured into water (40 ml), extracted with ethyl acetate (50 ml x 3 times), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). Obtained 190 mg of (S)-6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)- as a yellow oil Benzyl carboxylate (yield 68%).
步骤D：合成(S)-6-(4-氰基苯基)-4-苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯Step D: Synthesis of (S)-6-(4-cyanophenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，将化合物(S)-6-(4-氰基苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(190毫克，0.41毫摩尔)，苯硼酸(100毫克，0.82毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，30毫克，0.04毫摩尔)，磷酸钾(K3PO4，180毫克，0.82毫摩尔)加入1，4-二氧六环(10毫升)中，氮气保护下，升温至90℃反应过夜。At room temperature, compound (S)-6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)- Benzyl carboxylate (190 mg, 0.41 mmol), phenylboronic acid (100 mg, 0.82 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf) Cl 2 , 30 mg, 0.04 mmol), potassium phosphate (K 3 PO 4 , 180 mg, 0.82 mmol) were added to 1,4-dioxane (10 ml), and under nitrogen protection, the temperature was raised to 90°C for reaction. overnight.
反应结束，加入乙酸乙酯(30毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸 乙酯＝4/1)。得到230毫克浅黄色油状(S)-6-(4-氰基苯基)-4-苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯。LC-MS：RT＝2.28min，[M+H]+＝395.14。At the end of the reaction, add ethyl acetate (30 ml) to dilute, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/acetic acid Ethyl ester=4/1). 230 mg of (S)-6-(4-cyanophenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester were obtained as a light yellow oil. LC-MS: RT=2.28min, [M+H] + =395.14.
步骤E：合成(S)-4-(1-((苄氧基)羰基)-4-苯基-1，2，5，6-四氢吡啶-2-基)苯甲酸Step E: Synthesis of (S)-4-(1-((benzyloxy)carbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-2-yl)benzoic acid
室温下，将化合物(S)-6-(4-氰基苯基)-4-苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯(230毫克，0.58毫摩尔)溶于异丙醇(i-PrOH，10毫升)中，加入水(10毫升)和氢氧化钠(NaOH，120毫克，2.92毫摩尔)，加热至100℃反应过夜。Compound (S)-6-(4-cyanophenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (230 mg, 0.58 mmol) was added to the solution at room temperature. Dissolve in isopropanol (i-PrOH, 10 ml), add water (10 ml) and sodium hydroxide (NaOH, 120 mg, 2.92 mmol), heat to 100°C and react overnight.
反应结束，加入水(30毫升)稀释，6N盐酸水溶液调节pH＝5-6，乙酸乙酯萃取(20毫升×3次)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到250毫克黄色油状(S)-4-(1-((苄氧基)羰基)-4-苯基-1，2，5，6-四氢吡啶-2-基)苯甲酸(粗品)。LC-MS：RT＝2.13min，[M+H]+＝412.17。At the end of the reaction, add water (30 ml) to dilute, adjust the pH to 5-6 with 6N hydrochloric acid aqueous solution, extract with ethyl acetate (20 ml × 3 times), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. concentrate. 250 mg of (S)-4-(1-((benzyloxy)carbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-2-yl)benzoic acid (crude product) were obtained as a yellow oil. LC-MS: RT=2.13min, [M+H] + =412.17.
步骤F：合成(S)-6-(4-(甲氧基羰基)苯基)-4-苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯Step F: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，将化合物(S)-4-(1-((苄氧基)羰基)-4-苯基-1，2，5，6-四氢吡啶-2-基)苯甲酸(230毫克，0.55毫摩尔)溶于甲醇(MeOH，10毫升)中，加入氯化亚砜(SOCl2，330毫克，2.78毫摩尔)，加热至80℃反应3小时。Compound (S)-4-(1-((benzyloxy)carbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-2-yl)benzoic acid (230 mg, 0.55 mmol) was dissolved in methanol (MeOH, 10 ml), added thionyl chloride (SOCl 2 , 330 mg, 2.78 mmol), and heated to 80°C for 3 hours.
反应完成，加入乙酸乙酯(30毫升)稀释，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)。得到120毫克浅黄色油状(S)-6-(4-(甲氧基羰基)苯基)-4-苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯(粗品)。LC-MS：RT＝2.30min，[M+H]+＝428.21。After the reaction was completed, add ethyl acetate (30 ml) to dilute, wash with water and saturated brine in sequence, dry over anhydrous sodium sulfate, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1). Obtained 120 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (crude product) as a light yellow oil . LC-MS: RT=2.30min, [M+H] + =428.21.
步骤G：合成4-((2S)-4-苯基哌啶-2-基)苯甲酸甲酯Step G: Synthesis of methyl 4-((2S)-4-phenylpiperidin-2-yl)benzoate
室温下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯(100毫克，0.23毫摩尔)溶于甲醇(MeOH，10毫升)，用6N盐酸调节pH＝5-6，加入甲酸铵(HCOONH4，300毫克，4.68毫摩尔)和钯/碳(Pd/C，50毫克)，加热至80℃，反应2小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (100 mg, 0.23 mmol) was dissolved in methanol (MeOH, 10 ml), adjusted to pH=5-6 with 6N hydrochloric acid, and ammonium formate (HCOONH 4 , 300 mg, 4.68 mmol) and palladium/carbon (Pd/C, 50 mg) were added. , heated to 80°C and reacted for 2 hours.
反应结束，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10/1)。得到50毫克浅黄色油状4-((2S)-4-苯基哌啶-2-基)苯甲酸甲酯(收率60％)。LC-MS：RT＝1.68min，[M+H]+＝296.19。At the end of the reaction, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1). 50 mg of methyl 4-((2S)-4-phenylpiperidin-2-yl)benzoate was obtained as a light yellow oil (yield 60%). LC-MS: RT=1.68min, [M+H] + =296.19.
步骤H：合成5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step H: Synthesis of 5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将5-甲氧基-7-甲基-1H-吲哚(10.0克，62.0毫摩尔)，二碳酸二叔丁酯(Boc2O，16.2克，74.4毫摩尔)，4-二甲氨基吡啶(DMAP，9.1克，74.4毫摩尔)溶于二氯甲烷(DCM，100毫升)中反应1小时。At room temperature, 5-methoxy-7-methyl-1H-indole (10.0 g, 62.0 mmol), di-tert-butyl dicarbonate (Boc 2 O, 16.2 g, 74.4 mmol), 4-dicarbonate were mixed. Methylaminopyridine (DMAP, 9.1 g, 74.4 mmol) was dissolved in dichloromethane (DCM, 100 ml) and reacted for 1 hour.
反应结束，加入水，二氯甲烷(30毫升×4次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/10)，得到15.6克淡黄色固体5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：96.0％)。LC-MS：RT＝2.21min，[M+H]+＝262.20。After the reaction was completed, water was added and extracted with dichloromethane (30 ml x 4 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/10) to obtain 15.6 g of light yellow solid 5-methoxy-7-methyl-1H-indole-1- Tert-butyl carboxylate (yield: 96.0%). LC-MS: RT=2.21 min, [M+H] + =262.20.
步骤I：合成4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step I: Synthesis of 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
0℃下，向含有N-甲基-N-苯基甲酰胺(5.2克，38.7毫摩尔)的二氯甲烷(80毫升)中缓慢加入草酰氯(COCl2，4.9克，38.7毫摩尔)，升至室温反应12小时。降至-10℃下，加入溶有5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(7.8克，29.8毫摩尔)的二氯甲烷(DCM，30毫升)溶液，升温至0℃反应1小时，并于室温反应3小时。To dichloromethane (80 ml) containing N-methyl-N-phenylformamide (5.2 g, 38.7 mmol) was slowly added oxalyl chloride (COCl 2 , 4.9 g, 38.7 mmol) at 0°C. Warm up to room temperature and react for 12 hours. Lower to -10°C, add 5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (7.8 g, 29.8 mmol) dissolved in dichloromethane (DCM, 30 ml) ) solution, raise the temperature to 0°C for 1 hour, and react at room temperature for 3 hours.
反应结束，冰浴下加入饱和碳酸氢钠水溶液(150毫升)，用二氯甲烷(50毫升×3次)萃取，合并有机相，饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/20)，得到5.5克白色固体4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：63.8％)。LC-MS：RT＝2.25min，[M+H]+＝290.21。At the end of the reaction, add saturated aqueous sodium bicarbonate solution (150 ml) in an ice bath, extract with dichloromethane (50 ml × 3 times), combine the organic phases, wash with saturated brine (50 ml), dry over anhydrous sodium sulfate, and filter. ,concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/20) to obtain 5.5 g of white solid 4-formyl-5-methoxy-7-methyl-1H-indole. Indole-1-carboxylic acid tert-butyl ester (yield: 63.8%). LC-MS: RT=2.25min, [M+H] + =290.21.
步骤J：合成5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-苯基哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step J: Synthesis of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-phenylpiperidin-1-yl)methyl)-7- Methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将化合物4-((2S)-4-苯基哌啶-2-基)苯甲酸甲酯(50毫克，0.17毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(98毫克，0.34毫摩尔)溶于1，2-二氯乙烷(DCE，10毫升)，加入三乙酰氧基硼氢化钠(NaBH(OAc)3，180毫克，0.85毫摩尔)搅拌过夜。Compound 4-((2S)-4-phenylpiperidin-2-yl)benzoate methyl ester (50 mg, 0.17 mmol) and 4-formyl-5-methoxy-7-methyl were mixed at room temperature. Tert-butyl-1H-indole-1-carboxylate (98 mg, 0.34 mmol) was dissolved in 1,2-dichloroethane (DCE, 10 ml), and sodium triacetoxyborohydride (NaBH ( OAc) 3 , 180 mg, 0.85 mmol) and stirred overnight.
反应结束后，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到68毫克黄色油状5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-苯基哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率62％)。LC-MS：RT＝1.96min，[M+H]+＝569.30。After the reaction was completed, methanol was added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 68 mg of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-phenylpiperidin-1-yl)methyl)-7 as a yellow oil -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 62%). LC-MS: RT=1.96min, [M+H] + =569.30.
步骤K：合成化合物1A和1BStep K: Synthesis of Compounds 1A and 1B
室温下，将化合物5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-苯基哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(65毫克，0.11毫摩尔)溶于甲醇(MeOH，10毫升)，加入碳酸钾(K2CO3，160毫克，1.1毫摩尔)，加热至70℃反应过夜，加入水(5毫升)继续反应2小时。At room temperature, compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-phenylpiperidin-1-yl)methyl)-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (65 mg, 0.11 mmol) was dissolved in methanol (MeOH, 10 ml), and potassium carbonate (K 2 CO 3 , 160 mg, 1.1 mmol) was added , heated to 70°C for overnight reaction, and water (5 ml) was added to continue the reaction for 2 hours.
反应完成，加入10％柠檬酸的水溶液调节pH至中性，用二氯甲烷(10毫升×4次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩，用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝5/1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到2毫克绝对构型的非对映异构体1A(收率：3.8％)和7.3毫克绝对构型的非对映异构体1B(收率：14％)。After the reaction is completed, add 10% citric acid aqueous solution to adjust the pH to neutral, extract with dichloromethane (10 ml × 4 times), combine the organic phases, wash with saturated brine (20 ml), dry over anhydrous sodium sulfate, and filter. Concentrate and purify with silica gel column chromatography (eluent: ethyl acetate/methanol = 5/1) to obtain the crude product. The diastereoisomers are separated by using chiral HPLC (Agilent prep C18). 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution was used for elution and separation to obtain 2 mg of absolute configuration diastereomer 1A (yield: 3.8%) and 7.3 mg of absolute configuration diastereomer 1A. Enantiomer 1B (yield: 14%).
化合物1A：HPLC：RT＝8.5min，LC-MS：RT＝1.77min，[M+H]+＝455.25。Compound 1A: HPLC: RT=8.5min, LC-MS: RT=1.77min, [M+H] + =455.25.
化合物1B：HPLC：RT＝9.7min，LC-MS：RT＝1.77min，[M+H]+＝455.28。Compound 1B: HPLC: RT=9.7min, LC-MS: RT=1.77min, [M+H] + =455.28.
实施例2合成化合物2A和2B
Example 2 Synthesis of Compounds 2A and 2B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1( 2H)-Carboxylic acid benzyl ester
室温下，将(S)-2-(4-氰基苯基)-4-氧代哌啶-1-羧酸苄酯(1.3克，3.68毫摩尔)，1，1，1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(2.2克，6.02毫摩尔)溶于四氢呋喃(THF，20毫升)中，低温槽冷却至-60℃。加入双三甲基硅基胺基锂(LiHMDS，6毫升，6毫摩尔)，搅拌30分钟，升至室温，搅拌1小时。At room temperature, (S)-2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester (1.3 g, 3.68 mmol), 1,1,1-trifluoro- N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.2 g, 6.02 mmol) was dissolved in tetrahydrofuran (THF, 20 ml), and cooled to -60°C in a cryogenic bath. Lithium bistrimethylsilylamide (LiHMDS, 6 ml, 6 mmol) was added, stirred for 30 minutes, raised to room temperature, and stirred for 1 hour.
反应结束，将反应液倒入水(100毫升)中，乙酸乙酯萃取(50毫升×3次)，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)。得到1.4克浅黄色油状(S)-6-(4-(甲氧基羰基)苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率79％)。At the end of the reaction, the reaction solution was poured into water (100 ml), extracted with ethyl acetate (50 ml x 3 times), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). Obtained 1.4 g of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- as a light yellow oil 1(2H)-carboxylic acid benzyl ester (yield 79%).
步骤B：合成(S)-6′-(4-(甲氧基羰基)苯基)-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯Step B: Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H) -Benzyl carboxylate
氮气保护下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.4毫摩尔)，2-吡啶硼酸(348毫克，2.8毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，102毫克，0.14毫摩尔)，磷酸钾(K3PO4，594毫克，2.8毫摩尔)加入1，4-二氧六环(30毫升)中，升至105℃反应24小时。Under nitrogen protection, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- 1(2H)-Carboxylic acid benzyl ester (700 mg, 1.4 mmol), 2-pyridineboronic acid (348 mg, 2.8 mmol), [1,1′-bis(diphenylphosphine)ferrocene]dichloro Palladium (Pd(dppf)Cl 2 , 102 mg, 0.14 mmol) and potassium phosphate (K 3 PO 4 , 594 mg, 2.8 mmol) were added to 1,4-dioxane (30 ml), and the mixture was raised to React at 105°C for 24 hours.
反应完成，降至室温加入乙酸乙酯(30毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到210毫克黄色油状(S)-6′-(4-(甲氧基羰基)苯基)-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯(收率35％)。LC-MS：RT＝2.13min，[M+H]+＝429.20。After the reaction was completed, the mixture was cooled to room temperature and diluted with ethyl acetate (30 ml), filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 210 mg of (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H ) - benzyl carboxylate (yield 35%). LC-MS: RT=2.13min, [M+H] + =429.20.
步骤C：合成4-((2S)-4-(吡啶-2-基)哌啶-2-基)苯甲酸甲酯Step C: Synthesis of methyl 4-((2S)-4-(pyridin-2-yl)piperidin-2-yl)benzoate
室温下，将化合物(S)-6′-(4-(甲氧基羰基)苯基)-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯(180毫克，0.42毫摩尔)溶于甲醇(MeOH，10毫升)中，用6N盐酸调节pH＝4-5，加入甲酸铵(HCOONH4，265毫克，4.2毫摩尔)和钯/碳(Pd/C，50毫克)，加热至80℃反应2小时。At room temperature, compound (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H )-Benzyl carboxylate (180 mg, 0.42 mmol) was dissolved in methanol (MeOH, 10 ml), adjusted to pH=4-5 with 6N hydrochloric acid, and ammonium formate (HCOONH 4 , 265 mg, 4.2 mmol) and Palladium/carbon (Pd/C, 50 mg), heated to 80°C for 2 hours.
反应完成，过滤，滤液加入碳酸钠，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10/1)。得到150毫克浅黄色固体4-((2S)-4-(吡啶-2-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.49min，[M+H]+＝297.19。After the reaction is completed, filter, add sodium carbonate to the filtrate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1). 150 mg of methyl 4-((2S)-4-(pyridin-2-yl)piperidin-2-yl)benzoate were obtained as a pale yellow solid. LC-MS: RT=1.49min, [M+H] + =297.19.
步骤D：合成4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
冰浴条件下，向含有4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(1.0克，3.4毫摩尔)的甲醇(MeOH，20毫升)中，缓慢加入硼氢化钠(NaBH4，257.2毫克，6.8毫摩尔)，室温反应1小时。To the solution containing 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (1.0 g, 3.4 mmol) in methanol (MeOH, 20 ml) under ice bath conditions ), slowly add sodium borohydride (NaBH 4 , 257.2 mg, 6.8 mmol), and react at room temperature for 1 hour.
反应结束，冰浴条件下，用饱和氯化铵水溶液(45毫升)淬灭，乙酸乙酯(20毫升×4次)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)，得到830.0毫克白色固体4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率84％)。LC-MS：RT＝1.95min，[M-18+H]+＝174.18。At the end of the reaction, quench with saturated ammonium chloride aqueous solution (45 ml) under ice bath conditions, extract with ethyl acetate (20 ml x 4 times), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 830.0 mg of white solid 4-(hydroxymethyl)-5-methoxy-7-methyl- 1H-indole-1-carboxylic acid tert-butyl ester (yield 84%). LC-MS: RT=1.95min, [M-18+H] + =174.18.
步骤E：合成4-(氯甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step E: Synthesis of 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物4-(羟甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(250毫克，0.86毫摩尔)溶于二氯甲烷(DCM，6毫升)中，冰水浴冷却，加入(氯亚甲基)二甲基氯化铵(181毫克，1.46毫摩尔)，升至室温反应1小时。Compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (250 mg, 0.86 mmol) was dissolved in dichloromethane (DCM, 6 ml), cooled in an ice-water bath, added (chloromethylene)dimethylammonium chloride (181 mg, 1.46 mmol), raised to room temperature and reacted for 1 hour.
反应完成，冰水浴冷却，加入5％碳酸氢钠淬灭，二氯甲烷(20毫升×3次)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到200毫克棕色油状4-(氯甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯粗品，直接用于下一步反应。After the reaction is completed, cool in an ice-water bath, add 5% sodium bicarbonate to quench, extract with dichloromethane (20 ml × 3 times), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. 200 mg of brown oily 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester crude product was obtained, which was directly used in the next reaction.
步骤F：合成5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step F: Synthesis of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-2-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
室温下，将化合物4-((2S)-4-(吡啶-2-基)哌啶-2-基)苯甲酸甲酯(80毫克，0.27毫摩尔)和4-(氯甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(167毫克，0.54毫摩尔)溶于N，N-二甲基甲酰胺(DMF，6毫升)中，加入碳酸钠(Na2CO3，85毫克，0.81毫摩尔)搅拌过夜。 Compound 4-((2S)-4-(pyridin-2-yl)piperidin-2-yl)benzoate methyl ester (80 mg, 0.27 mmol) and 4-(chloromethyl)-5 were mixed at room temperature. -Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (167 mg, 0.54 mmol) was dissolved in N,N-dimethylformamide (DMF, 6 ml) and added Sodium carbonate (Na 2 CO 3 , 85 mg, 0.81 mmol) was stirred overnight.
反应完成，加水淬灭，乙酸乙酯(20毫升×4次)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10/1)。得到145毫克深黄色油状5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率56％)。LC-MS：RT＝1.86min，[M+H]+＝570.25。When the reaction is completed, add water to quench, extract with ethyl acetate (20 ml × 4 times), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1). Obtained 145 mg of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-2-yl)piperidin-1-yl) as a dark yellow oil )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 56%). LC-MS: RT=1.86min, [M+H] + =570.25.
步骤G：合成化合物2A和2BStep G: Synthesis of Compounds 2A and 2B
室温下，将化合物5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(145毫克，0.15毫摩尔)溶于甲醇(MeOH，5毫升)中，加入碳酸钾(K2CO3，211毫克，1.5毫摩尔)，加热至70℃搅拌过夜，加入水(1毫升)继续反应2小时。At room temperature, compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-2-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (145 mg, 0.15 mmol) was dissolved in methanol (MeOH, 5 ml), and potassium carbonate (K 2 CO 3 , 211 mg, 1.5 mmol), heated to 70°C and stirred overnight, then added water (1 ml) and continued the reaction for 2 hours.
反应完成，加入10％柠檬酸的水溶液调节pH至中性，用二氯甲烷(10毫升×4次)萃取，合并有机相，饱和食盐水(20毫升)洗涤无水硫酸钠干燥，过滤，浓缩，用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝1/1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到2.9毫克绝对构型的非对映异构体2A(收率：2.5％)和8.7毫克绝对构型的非对映异构体2B(收率：7.5％)。After the reaction is completed, add 10% citric acid aqueous solution to adjust the pH to neutral, extract with dichloromethane (10 ml x 4 times), combine the organic phases, wash with saturated brine (20 ml), dry over anhydrous sodium sulfate, filter and concentrate. , purified by silica gel column chromatography (eluent: ethyl acetate/methanol = 1/1) to obtain the crude product, and completed the separation of diastereoisomers by using chiral HPLC (Agilent prep C18), using 25 %CH 3 CN (+0.05% NH 3 ·H 2 O) solution was used for elution and separation to obtain 2.9 mg of absolute configuration diastereomer 2A (yield: 2.5%) and 8.7 mg of absolute configuration diastereomer 2A. Enantiomer 2B (yield: 7.5%).
化合物2A：HPLC：RT＝7.5min，LC-MS：RT＝1.62min，[M+H]+＝456.19。Compound 2A: HPLC: RT=7.5min, LC-MS: RT=1.62min, [M+H] + =456.19.
化合物2B：HPLC：RT＝10.2min，LC-MS：RT＝1.62min，[M+H]+＝456.22。Compound 2B: HPLC: RT=10.2min, LC-MS: RT=1.62min, [M+H] + =456.22.
实施例3合成化合物3A和3B
Example 3 Synthesis of Compounds 3A and 3B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-((4-甲氧基羰基)苯基)-4-(噻唑-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.42毫摩尔)的二氧六环(10毫升)中，加入2-溴噻唑(104毫克，0.63毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，61毫克，0.08毫摩尔)和磷酸钾(K3PO4，182毫克，0.84毫摩尔)，水(2毫升)，置换氮气，升温到90℃反应5小时。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.42 mmol) in dioxane (10 ml), 2-bromothiazole (104 mg , 0.63 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 61 mg, 0.08 mmol) and potassium phosphate (K 3 PO 4 , 182 mg, 0.84 mmol), water (2 ml), replaced with nitrogen, heated to 90°C and reacted for 5 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到120毫克淡黄色油状液体(S)-6-((4-甲氧基羰基)苯基)-4-(噻唑-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：66％)。LC-MS：RT＝2.16min，[M+H]+＝435.23。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 120 mg of light yellow oily liquid (S)-6-((4-methoxycarbonyl)phenyl) -4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 66%). LC-MS: RT=2.16min, [M+H] + =435.23.
步骤B：合成(S)-4-(4-噻唑-2-基)哌啶-2-基苯甲酸甲酯Step B: Synthesis of (S)-4-(4-thiazol-2-yl)piperidin-2-yl benzoic acid methyl ester
室温下，将(S)-6-((4-甲氧基羰基)苯基)-4-(噻唑-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(100毫克，0.24毫摩尔)溶于乙酸乙酯溶液(EA，10毫升)中，加入钯碳(Pd/C，20毫克)，置换氢气，升温到60℃反应过夜。At room temperature, (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (100 mg, 0.24 mmol) was dissolved in ethyl acetate solution (EA, 10 ml), palladium on carbon (Pd/C, 20 mg) was added, replaced with hydrogen, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到55毫克淡黄色油状液体(S)-4-(4-噻唑-2-基)哌啶-2-基苯甲酸甲酯(收率：66％)。LC-MS：RT＝1.65min，[M+H]+＝303.19。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 55 mg of light yellow oily liquid (S)-4-(4-thiazol-2-yl)piperidin-2-yl benzoic acid methyl ester (yield: 66% ). LC-MS: RT=1.65min, [M+H] + =303.19.
步骤C：合成(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(噻唑-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-噻唑-2-基)哌啶-2-基苯甲酸甲酯(55毫克，0.18毫摩尔)的1，2-二氯乙烷(DCE，5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(79毫克，0.27毫摩尔)和三乙酰氧基硼氢化钠(NaBH(OAc)3，76毫克，0.36毫摩尔)，升温到40℃反应过夜。Into 1,2-dichloroethane (DCE, 5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (79 mg, 0.27 mmol) and sodium triacetoxyborohydride (NaBH(OAc) 3 , 76 mg, 0.36 mmol), the temperature was raised to 40°C and the reaction was carried out overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到44毫克白色固体(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(噻唑-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：42％)。LC-MS：RT＝1.97min，[M+H]+＝576.27。At the end of the reaction, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 44 mg of white solid (S)-5-methoxy. -4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1- Tert-butyl carboxylate (yield: 42%). LC-MS: RT=1.97min, [M+H] + =576.27.
步骤D：合成化合物3A和3B Step D: Synthesis of Compounds 3A and 3B
室温下，向(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(噻唑-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(44毫克，0.08毫摩尔)的甲醇(MeOH，5毫升)溶液中，加碳酸钾(K2CO3，42毫克，0.30毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)piperidin-1-yl)methyl) at room temperature -To a solution of 7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (44 mg, 0.08 mmol) in methanol (MeOH, 5 ml), add potassium carbonate (K 2 CO 3 , 42 mg, 0.30 mmol), heated to 70°C for 5 hours, added water (1 ml) and continued the reaction for 4 hours.
反应完成，加入10％柠檬酸的水溶液调节pH至中性，用二氯甲烷(10毫升×4次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到9毫克绝对构型的非对映异构体3A(收率：24％)和15毫克绝对构型的非对映异构体3B(收率：41％)。After the reaction is completed, add 10% citric acid aqueous solution to adjust the pH to neutral, extract with dichloromethane (10 ml × 4 times), combine the organic phases, wash with saturated brine (20 ml), dry over anhydrous sodium sulfate, and filter. Concentrate, and the resulting residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain a crude product. The resolution of the diastereoisomers is completed by using chiral HPLC (Agilent prep C18). 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution was used for elution and separation to obtain 9 mg of absolute configuration diastereomer 3A (yield: 24%) and 15 mg of absolute configuration diastereomer 3A. Diastereomer 3B (yield: 41%).
化合物3A：HPLC：RT＝10.1min，LC-MS：RT＝1.66min，[M+H]+＝462.24。Compound 3A: HPLC: RT=10.1 min, LC-MS: RT=1.66 min, [M+H] + =462.24.
化合物3B：HPLC：RT＝14.2min，LC-MS：RT＝1.66min，[M+H]+＝462.22。Compound 3B: HPLC: RT=14.2min, LC-MS: RT=1.66min, [M+H] + =462.22.
实施例4Example 4
合成4-((2S)-1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(1H-吡唑-1-基)哌啶-2-基)苯甲酸
Synthesis of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1H-pyrazol-1-yl)piperidine -2-yl)benzoic acid
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温氮气保护下，将化合物(S)-6-(4-氰基苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(500毫克，1.0毫摩尔)，联硼酸频哪醇酯(760毫克，3.0毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，150毫克，0.2毫摩尔)，乙酸钾(KOAc，400毫克，4.0毫摩尔)加入1，4-二氧六环(15毫升)中，升温至105℃反应24小时。Under nitrogen protection at room temperature, compound (S)-6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H )-Benzyl carboxylate (500 mg, 1.0 mmol), pinacol diboronate (760 mg, 3.0 mmol), [1,1′-bis(diphenylphosphine)ferrocene] dichloride Palladium (Pd(dppf)Cl 2 , 150 mg, 0.2 mmol), potassium acetate (KOAc, 400 mg, 4.0 mmol) were added to 1,4-dioxane (15 ml), and the temperature was raised to 105°C for reaction 24 Hour.
反应完成，加入乙酸乙酯(30毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝10/1)。得到400毫克黄色油状(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率80％)。LC-MS：RT＝2.30min，[M+H]+＝478.17。1H NMR(400MHz，CDCl3)δ8.04-7.86(m，2H)，7.55-7.22(m，7H)，5.77-5.48(m，1H)，5.29-5.03(m，2H，)，4.54-4.28(m，1H)，3.98-3.85(m，3H)，3.58-3.47(m，1H)，3.03-2.65(m，2H)，2.40-2.22(m，1H)，1.29-1.26(m，12H)After the reaction was completed, ethyl acetate (30 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1). Obtained 400 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane as yellow oil) Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield 80%). LC-MS: RT=2.30min, [M+H] + =478.17. 1 H NMR (400MHz, CDCl 3 ) δ 8.04-7.86 (m, 2H), 7.55-7.22 (m, 7H), 5.77-5.48 (m, 1H), 5.29-5.03 (m, 2H,), 4.54- 4.28(m, 1H), 3.98-3.85(m, 3H), 3.58-3.47(m, 1H), 3.03-2.65(m, 2H), 2.40-2.22(m, 1H), 1.29-1.26(m, 12H )
步骤B：合成(S)-(1-((苄氧基)羰基)-6-(4-(甲氧基羰基)苯基)-1，2，3，6-四氢吡啶-4-基)硼酸Step B: Synthesis of (S)-(1-((benzyloxy)carbonyl)-6-(4-(methoxycarbonyl)phenyl)-1,2,3,6-tetrahydropyridin-4-yl ) boric acid
室温下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(400毫克，0.84毫摩尔)溶于丙酮(10毫升)中，依次加入水(10毫升)，乙酸铵(NH4OAc，200毫克，2.52毫摩尔)，高碘酸钠(NaIO4，540毫克，2.52毫摩尔)反应过夜。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (400 mg, 0.84 mmol) was dissolved in acetone (10 ml), and water (10 ml) and acetic acid were added successively. Ammonium (NH 4 OAc, 200 mg, 2.52 mmol) and sodium periodate (NaIO 4 , 540 mg, 2.52 mmol) were reacted overnight.
反应完成，加入水(50毫升)稀释，乙酸乙酯萃取(20毫升×3次)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到310毫克黄色油状(S)-(1-((苄氧基)羰基)-6-(4-(甲氧基羰基)苯基)-1，2，3，6-四氢吡啶-4-基)硼酸(收率93％)。LC-MS：RT＝1.95min，[M+H]+＝396.14。After the reaction is completed, add water (50 ml) to dilute, extract with ethyl acetate (20 ml x 3 times), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. 310 mg of (S)-(1-((benzyloxy)carbonyl)-6-(4-(methoxycarbonyl)phenyl)-1,2,3,6-tetrahydropyridine-4- were obtained as a yellow oil) base) boric acid (yield 93%). LC-MS: RT=1.95min, [M+H] + =396.14.
步骤C：合成(S)-6-(4-(甲氧羰基)苯基)-4-(1H-吡唑-1-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step C: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Benzyl ester
室温下，将化合物(S)-(1-((苄氧基)羰基)-6-(4-(甲氧基羰基)苯基)-1，2，3，6-四氢吡啶-4-基)硼酸(260毫克，0.66毫摩尔)，醋酸铜(360毫克，1.97毫摩尔)，吡唑(135毫克，1.97毫摩尔)溶于二氯甲烷(DCM，10毫升)中，加入吡啶(Py，1毫升)反应48小时。At room temperature, compound (S)-(1-((benzyloxy)carbonyl)-6-(4-(methoxycarbonyl)phenyl)-1,2,3,6-tetrahydropyridine-4- (260 mg, 0.66 mmol), copper acetate (360 mg, 1.97 mmol), and pyrazole (135 mg, 1.97 mmol) were dissolved in dichloromethane (DCM, 10 ml), and pyridine (Py , 1 ml) react for 48 hours.
反应完成，加入乙酸乙酯(30毫升)稀释，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)。得到180毫克浅黄色胶状(S)-6-(4-(甲氧羰基)苯基)-4-(1H-吡唑-1-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率65％)。LC-MS：RT＝2.14min，[M+H]+＝418.16。After the reaction was completed, ethyl acetate (30 ml) was added to dilute, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1). Obtained 180 mg of light yellow gummy (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)-3,6-dihydropyridine-1(2H) - Benzyl carboxylate (yield 65%). LC-MS: RT=2.14min, [M+H] + =418.16.
步骤D：合成4-((2S)-4-(1H-吡唑-1-基)哌啶-2-基)苯甲酸甲酯Step D: Synthesis of methyl 4-((2S)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoate
室温氢气保护下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(1H-吡唑-1-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(150毫克，0.36毫摩尔)溶于甲醇(MeOH，10毫升)中，用6N盐酸调节pH＝2，加入钯/碳(Pd/C，50毫克)反应10小时。Under the protection of hydrogen at room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)-3,6-dihydropyridine-1(2H) - Benzyl carboxylate (150 mg, 0.36 mmol) was dissolved in methanol (MeOH, 10 ml), adjusted to pH=2 with 6N hydrochloric acid, and palladium/carbon (Pd/C, 50 mg) was added to react for 10 hours.
反应完成，过滤，浓缩，加入乙酸乙酯和水稀释，加入氨水调节pH大于13，乙酸乙酯萃取(20毫升×3次)， 合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩。得到95毫克浅黄色油状4-((2S)-4-(1H-吡唑-1-基)哌啶-2-基)苯甲酸甲酯(收率90％)。LC-MS：RT＝1.56min，[M+H]+＝286.15。After the reaction is completed, filter and concentrate, add ethyl acetate and water to dilute, add ammonia water to adjust the pH to greater than 13, and extract with ethyl acetate (20 ml × 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 95 mg of methyl 4-((2S)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoate was obtained as a light yellow oil (yield 90%). LC-MS: RT=1.56min, [M+H] + =286.15.
步骤E：合成5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-1-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step E: Synthesis of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)piperidine-1- (methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将化合物4-((2S)-4-(1H-吡唑-1-基)哌啶-2-基)苯甲酸甲酯(90毫克，0.32毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(183毫克，0.64毫摩尔)溶于1，2-二氯乙烷(DCE，6毫升)中，加入三乙酰氧基硼氢化钠(NaBH(OAc)3，334毫克，1.58毫摩尔)反应过夜。Compound 4-((2S)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoate methyl ester (90 mg, 0.32 mmol) and 4-formyl-5 were mixed at room temperature. -Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (183 mg, 0.64 mmol) was dissolved in 1,2-dichloroethane (DCE, 6 ml), and Tris Sodium acetoxyborohydride (NaBH(OAc) 3 , 334 mg, 1.58 mmol) was reacted overnight.
反应完成，加入甲醇溶解至澄清，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)。得到86毫克黄色油状5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-1-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率48％)。LC-MS：RT＝1.86min，[M+H]+＝559.24。When the reaction is completed, add methanol to dissolve until clear and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1). Obtained 86 mg of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)piperidine-1 as a yellow oil) -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 48%). LC-MS: RT=1.86min, [M+H] + =559.24.
步骤F：合成4-((2S)-1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(1H-吡唑-1-基)哌啶-2-基)苯甲酸Step F: Synthesis of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1H-pyrazol-1-yl) )piperidin-2-yl)benzoic acid
室温下，将化合物5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-1-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(86毫克，0.15毫摩尔)溶于甲醇(MeOH，5毫升)中，加入碳酸钾(K2CO3，213毫克，1.5毫摩尔)，加热至70℃搅拌过夜，加入水(1毫升)继续反应2小时。At room temperature, compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)piperidine-1 -(methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (86 mg, 0.15 mmol) was dissolved in methanol (MeOH, 5 ml), and potassium carbonate (K 2 CO 3 , 213 mg, 1.5 mmol), heated to 70°C and stirred overnight, added water (1 ml) and continued the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理方法分离得到40.4毫克的4-((2S)-1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(1H-吡唑-1-基)哌啶-2-基)苯甲酸。LC-MS：RT＝1.63min，[M+H]+＝445.18。The reaction was completed, and 40.4 mg of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)) was isolated using the purification method in step D of Example 3. Methyl)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoic acid. LC-MS: RT=1.63min, [M+H] + =445.18.
实施例5Example 5
合成4-((2S)-1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(噻吩-3-基)哌啶-2-基)苯甲酸
Synthesis of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(thiophen-3-yl)piperidine-2- benzoic acid
合成路线：
synthetic route:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温氮气保护下，将化合物(S)-6-(4-氰基苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(940毫克，1.88毫摩尔)，3-噻吩硼酸(482毫克，3.76毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，137毫克，0.188毫摩尔)，磷酸钾(K3PO4，1.2克，5.65毫摩尔)加入1，4-二氧六环(15毫升)中，升温至95℃反应24小时。Under nitrogen protection at room temperature, compound (S)-6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H )-Benzyl carboxylate (940 mg, 1.88 mmol), 3-thiopheneboronic acid (482 mg, 3.76 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride ( Pd(dppf)Cl 2 , 137 mg, 0.188 mmol), potassium phosphate (K 3 PO 4 , 1.2 g, 5.65 mmol) were added to 1,4-dioxane (15 ml), and the temperature was raised to 95°C for reaction. 24 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)。得到610毫克黄色半固体(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率74％)。LC-MS：RT＝2.27min，[M+H]+＝434.28。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). Obtained 610 mg of yellow semi-solid (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Benzyl ester (yield 74%). LC-MS: RT=2.27min, [M+H] + =434.28.
步骤B：合成(2S)-2-(4-(甲氧羰基)苯基)-4-(噻吩-3-基)哌啶-1-羧酸苄酯Step B: Synthesis of (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester
室温下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(300毫克，0.69毫摩尔)溶于甲醇(MeOH，10毫升)中，用6N盐酸调节pH＝2，加入甲酸铵(HCOONH4，692毫克，13.84毫摩尔)和钯/碳(Pd/C，100毫克)，加热至75℃反应3小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl The ester (300 mg, 0.69 mmol) was dissolved in methanol (MeOH, 10 ml), adjusted to pH=2 with 6N hydrochloric acid, and ammonium formate (HCOONH 4 , 692 mg, 13.84 mmol) and palladium/carbon (Pd/C , 100 mg), heated to 75°C for 3 hours.
反应完成，过滤，浓缩。加入乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。得到200毫克浅黄色油状(2S)-2-(4-(甲氧羰基)苯基)-4-(噻吩-3-基)哌啶-1-羧酸苄酯(收率66％)。LC-MS：RT＝2.27min，[M+H]+＝436.12。The reaction is completed, filtered and concentrated. Add ethyl acetate to dilute, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. 200 mg of (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester was obtained as a light yellow oil (yield 66%). LC-MS: RT=2.27min, [M+H] + =436.12.
步骤C：合成4-((2S)-4-(噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step C: Synthesis of methyl 4-((2S)-4-(thiophen-3-yl)piperidin-2-yl)benzoate
室温下，将化合物(2S)-2-(4-(甲氧羰基)苯基)-4-(噻吩-3-基)哌啶-1-羧酸苄酯(150毫克，0.34毫摩尔)溶于乙酸乙酯(EA，5毫升)中，冰水浴冷却，加入33％氢溴酸/醋酸溶液(HBr/HOAc，2毫升)，升至室温反应2小时。Compound (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester (150 mg, 0.34 mmol) was dissolved at room temperature. To ethyl acetate (EA, 5 ml), cool in an ice-water bath, add 33% hydrobromic acid/acetic acid solution (HBr/HOAc, 2 ml), and raise to room temperature for 2 hours.
反应完成，加甲醇淬灭，氨水调节至碱性，减压浓缩去除大部分甲醇。所得残余物用乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得到100毫克棕色固体4-((2S)-4-(噻吩-3-基)哌啶-2-基)苯甲酸甲酯(收率72％)。LC-MS：RT＝1.65min，[M+H]+＝302.14。When the reaction is completed, methanol is added to quench the reaction, ammonia water is adjusted to alkalinity, and most of the methanol is removed by concentration under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=10/1). 100 mg of methyl 4-((2S)-4-(thiophen-3-yl)piperidin-2-yl)benzoate were obtained as a brown solid (yield 72%). LC-MS: RT=1.65min, [M+H] + =302.14.
步骤D：合成5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯 Step D: Synthesis of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
室温下，将化合物4-((2S)-4-(噻吩-3-基)哌啶-2-基)苯甲酸甲酯(100毫克，0.33毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(192毫克，0.66毫摩尔)溶于1，2-二氯乙烷(DCE，10毫升)中，加入三乙酰氧基硼氢化钠(NaBH(OAc)3，352毫克，1.66毫摩尔)反应过夜。Compound 4-((2S)-4-(thiophen-3-yl)piperidin-2-yl)benzoate methyl ester (100 mg, 0.33 mmol) and 4-formyl-5-methoxy were mixed at room temperature. Tert-butyl-7-methyl-1H-indole-1-carboxylate (192 mg, 0.66 mmol) was dissolved in 1,2-dichloroethane (DCE, 10 ml), and triacetoxy was added Sodium borohydride (NaBH(OAc) 3 , 352 mg, 1.66 mmol) was reacted overnight.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到210毫克黄色油状5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯粗品。LC-MS：RT＝1.95min，[M+H]+＝575.24。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). 210 mg of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl) were obtained as a yellow oil Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester crude product. LC-MS: RT=1.95min, [M+H] + =575.24.
步骤E：合成4-((2S)-1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(噻吩-3-基)哌啶-2-基)苯甲酸Step E: Synthesis of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(thiophen-3-yl)piperidine -2-yl)benzoic acid
室温下，将化合物5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(210毫克，0.146毫摩尔，纯度40％)溶于甲醇(MeOH，5毫升)中，加入碳酸钾(K2CO3，202毫克，1.46毫摩尔)，加热至70℃搅拌过夜，加入水(2毫升)继续反应2小时。At room temperature, compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (210 mg, 0.146 mmol, purity 40%) was dissolved in methanol (MeOH, 5 ml), and potassium carbonate (K 2 CO 3 , 202 mg, 1.46 mmol), heated to 70°C and stirred overnight, added water (2 ml) and continued the reaction for 2 hours.
反应完成，采用实施例3步骤D中纯化处理方法处理后得到47.8毫克的4-((2S)-1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(噻吩-3-基)哌啶-2-基)苯甲酸。LC-MS：RT＝1.69min，[M+H]+＝461.15。The reaction was completed, and 47.8 mg of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)) was obtained after adopting the purification treatment method in step D of Example 3. Methyl)-4-(thiophen-3-yl)piperidin-2-yl)benzoic acid. LC-MS: RT=1.69min, [M+H] + =461.15.
实施例6合成化合物6A和6B
Example 6 Synthesis of Compounds 6A and 6B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-4-(异噻唑-5-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-4-(isothiazol-5-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.5毫摩尔)，5-溴异噻唑(100毫克，0.6毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，37毫克，0.05毫摩尔)，磷酸钾(K3PO4，215毫克，1.0毫摩尔)加入1，4-二氧六环(10毫升)中，氮气保护下，升温至95℃反应24小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (200 mg, 0.5 mmol), 5-bromoisothiazole (100 mg, 0.6 mmol), [1, 1′-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 37 mg, 0.05 mmol), potassium phosphate (K 3 PO 4 , 215 mg, 1.0 mmol) were added 1,4-dioxane (10 ml), under nitrogen protection, raise the temperature to 95°C and react for 24 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到170毫克黄色油状(S)-4-(异噻唑-5-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率77％)。LC-MS：RT＝2.16min，[M+H]+＝435.12。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 170 mg of (S)-4-(isothiazol-5-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid as a yellow oil Benzyl ester (yield 77%). LC-MS: RT=2.16min, [M+H] + =435.12.
步骤B：合成(2S)-4-(异噻唑-5-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯Step B: Synthesis of (2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester
室温下，将化合物(S)-4-(异噻唑-5-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(170毫克，0.39毫摩尔)溶于乙酸乙酯(EA，10毫升)中，加入钯/碳(Pd/C，100毫克)，氢气氛围下加热至60℃，反应过夜。At room temperature, compound (S)-4-(isothiazol-5-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid The benzyl ester (170 mg, 0.39 mmol) was dissolved in ethyl acetate (EA, 10 ml), palladium/carbon (Pd/C, 100 mg) was added, heated to 60°C under a hydrogen atmosphere, and the reaction was carried out overnight.
反应完成，过滤，浓缩。得到150毫克浅黄色胶状(2S)-4-(异噻唑-5-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝2.12min，[M+H]+＝437.07。The reaction is completed, filtered and concentrated. Obtained 150 mg of light yellow gummy (2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (crude product), no It needs to be purified and used directly in the next reaction. LC-MS: RT=2.12min, [M+H] + =437.07.
步骤C：4-((2S)-4-(异噻唑-5-基)哌啶-2-基)苯甲酸甲酯Step C: Methyl 4-((2S)-4-(isothiazol-5-yl)piperidin-2-yl)benzoate
室温下，将化合物(2S)-4-(异噻唑-5-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯(150毫克，0.34毫摩尔)溶于乙酸乙酯(EtOAc，5毫升)中，冰水浴冷却，加入33％氢溴酸/醋酸溶液(HBr/HOAc，0.6毫升)，升温至室温搅拌2小时。At room temperature, compound (2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (150 mg, 0.34 mmol ) was dissolved in ethyl acetate (EtOAc, 5 ml), cooled in an ice-water bath, added 33% hydrobromic acid/acetic acid solution (HBr/HOAc, 0.6 ml), heated to room temperature and stirred for 2 hours.
反应完成，用甲醇淬灭，氨水调节至碱性，浓缩。所得残余物用乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得到50毫克黄色胶状4-((2S)-4-(异噻唑-5-基)哌啶-2-基)苯甲酸甲酯(收率48％)。LC-MS：RT＝1.58min，[M+H]+＝303.10。When the reaction is completed, it is quenched with methanol, adjusted to alkaline with ammonia water, and concentrated. The obtained residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=10/1). 50 mg of methyl 4-((2S)-4-(isothiazol-5-yl)piperidin-2-yl)benzoate was obtained as a yellow gum (yield 48%). LC-MS: RT=1.58min, [M+H] + =303.10.
步骤D：合成4-(((2S)-4-(异噻唑-5-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of 4-(((2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将化合物4-((2S)-4-(异噻唑-5-基)哌啶-2-基)苯甲酸甲酯(50毫克，0.16毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(96毫克，0.33毫摩尔)溶于1，2-二氯乙烷(DCE，5毫升)中，搅拌1小时，加入三乙酰氧基硼氢化钠(NaBH(OAc)3，175毫克，0.83毫摩尔)反应过夜。 Compound 4-((2S)-4-(isothiazol-5-yl)piperidin-2-yl)benzoate methyl ester (50 mg, 0.16 mmol) and 4-formyl-5-methyl were mixed at room temperature. Oxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (96 mg, 0.33 mmol) was dissolved in 1,2-dichloroethane (DCE, 5 ml) and stirred for 1 hour. Sodium triacetoxyborohydride (NaBH(OAc) 3 , 175 mg, 0.83 mmol) was added and allowed to react overnight.
反应完成，加入甲醇溶解至澄清，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)。得到160毫克黄色油状4-(((2S)-4-(异噻唑-5-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(粗品)，直接用于下一步反应。LC-MS：RT＝1.90min，[M+H]+＝576.18。When the reaction is completed, add methanol to dissolve until clear and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1). Obtained 160 mg of 4-(((2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5 as a yellow oil -Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (crude product) was directly used in the next reaction. LC-MS: RT=1.90min, [M+H] + =576.18.
步骤E：合成化合物6A和6BStep E: Synthesis of Compounds 6A and 6B
室温下，将化合物4-(((2S)-4-(异噻唑-5-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(160毫克，0.16毫摩尔，粗品)溶于甲醇(MeOH，10毫升)中，加入碳酸钾(K2CO3，384毫克，2.7毫摩尔)，加热至70℃搅拌过夜，加入水(2毫升)继续反应2小时。At room temperature, compound 4-(((2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5 -Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (160 mg, 0.16 mmol, crude product) was dissolved in methanol (MeOH, 10 mL), and potassium carbonate (K 2 CO 3 , 384 mg, 2.7 mmol), heated to 70°C and stirred overnight, added water (2 ml) and continued the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到4毫克绝对构型的非对映异构体6A(收率：3.1％)和13.5毫克绝对构型的非对映异构体6B(收率：8.0％)。The reaction was completed, and the purification treatment and chiral resolution method in step D of Example 3 were used to separate and obtain 4 mg of diastereomer 6A with absolute configuration (yield: 3.1%) and 13.5 mg of diastereoisomer 6A with absolute configuration. Enantiomer 6B (yield: 8.0%).
化合物6A：HPLC：RT＝14.8min，LC-MS：RT＝1.66min，[M+H]+＝462.14。Compound 6A: HPLC: RT=14.8 min, LC-MS: RT=1.66 min, [M+H] + =462.14.
化合物6B：HPLC：RT＝16.7min，LC-MS：RT＝1.66min，[M+H]+＝462.12。Compound 6B: HPLC: RT=16.7min, LC-MS: RT=1.66min, [M+H] + =462.12.
实施例7合成化合物7A和7B
Example 7 Synthesis of Compounds 7A and 7B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-4-(异噻唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-4-(isothiazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.5毫摩尔)，4-溴异噻唑(100毫克，0.6毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，37毫克，0.05毫摩尔)，磷酸钾(K3PO4，215毫克，1.0毫摩尔)加入1，4-二氧六环(10毫升)中，氮气保护下升温至95℃反应24小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (200 mg, 0.5 mmol), 4-bromoisothiazole (100 mg, 0.6 mmol), [1, 1′-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 37 mg, 0.05 mmol), potassium phosphate (K 3 PO 4 , 215 mg, 1.0 mmol) were added 1,4-dioxane (10 ml), heated to 95°C under nitrogen protection, and reacted for 24 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到100毫克黄色油状(S)-4-(异噻唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率55％)。LC-MS：RT＝2.16min，[M+H]+＝435.12。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 100 mg of (S)-4-(isothiazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid as a yellow oil Benzyl ester (yield 55%). LC-MS: RT=2.16min, [M+H] + =435.12.
步骤B：合成(2S)-4-(异噻唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯Step B: Synthesis of (2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester
氢气保护下，将化合物(S)-4-(异噻唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(100毫克，0.23毫摩尔)溶于乙酸乙酯(10毫升)，加入钯/碳(100毫克)，加热至60℃过夜。Under hydrogen protection, compound (S)-4-(isothiazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic Benzyl acid ester (100 mg, 0.23 mmol) was dissolved in ethyl acetate (10 ml), palladium/carbon (100 mg) was added, and the mixture was heated to 60°C overnight.
反应完成，过滤，浓缩。得到100毫克黄色胶状(2S)-4-(异噻唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝2.13min，[M+H]+＝437.08。The reaction is completed, filtered and concentrated. Obtain 100 mg of (2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (crude product) as a yellow gum, no need Purified and used directly in the next reaction. LC-MS: RT=2.13min, [M+H] + =437.08.
步骤C：4-((2S)-4-(异噻唑-4-基)哌啶-2-基)苯甲酸甲酯Step C: Methyl 4-((2S)-4-(isothiazol-4-yl)piperidin-2-yl)benzoate
冰水浴冷却下，将化合物(2S)-4-(异噻唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯(100毫克，0.23毫摩尔)溶于乙酸乙酯(EtOAc，5毫升)中，加入33％氢溴酸/醋酸溶液(HBr/HOAc，0.6毫升)，升至室温搅拌2小时。Under cooling in an ice water bath, compound (2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (100 mg, 0.23 mmol) was dissolved in ethyl acetate (EtOAc, 5 ml), 33% hydrobromic acid/acetic acid solution (HBr/HOAc, 0.6 ml) was added, and the mixture was raised to room temperature and stirred for 2 hours.
反应完成，用甲醇淬灭，氨水调节至碱性，浓缩。所得残余物用乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得到60毫克黄色胶状4-((2S)-4-(异噻唑-4-基)哌啶-2-基)苯甲酸甲酯(收率86％)。LC-MS：RT＝1.58min，[M+H]+＝303.10。When the reaction is completed, it is quenched with methanol, adjusted to alkaline with ammonia water, and concentrated. The obtained residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=10/1). 60 mg of methyl 4-((2S)-4-(isothiazol-4-yl)piperidin-2-yl)benzoate was obtained as a yellow gum (yield 86%). LC-MS: RT=1.58min, [M+H] + =303.10.
步骤D：合成4-(((2S)-4-(异噻唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of 4-(((2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将化合物4-((2S)-4-(异噻唑-4-基)哌啶-2-基)苯甲酸甲酯(60毫克，0.2毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(115毫克，0.4毫摩尔)溶于1，2-二氯乙烷(DCE，5毫升)中，加入三乙酰氧基硼氢化钠(NaBH(OAc)3，210毫克，1.0毫摩尔)反应过夜。Compound 4-((2S)-4-(isothiazol-4-yl)piperidin-2-yl)benzoate methyl ester (60 mg, 0.2 mmol) and 4-formyl-5-methyl were mixed at room temperature. Oxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (115 mg, 0.4 mmol) was dissolved in 1,2-dichloroethane (DCE, 5 ml), and triacetoxy was added Sodium borohydride (NaBH(OAc) 3 , 210 mg, 1.0 mmol) was reacted overnight.
反应完成，加入甲醇溶解至澄清，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)。得到210毫克黄色油状4-(((2S)-4-(异噻唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(粗品，纯度30％)，直接用于下一步反应。LC-MS：RT＝1.88min，[M+H]+＝576.17。 When the reaction is completed, add methanol to dissolve until clear and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1). Obtained 210 mg of 4-(((2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5 as a yellow oil -Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (crude product, purity 30%), was used directly for the next reaction. LC-MS: RT=1.88min, [M+H] + =576.17.
步骤E：合成化合物7A和7BStep E: Synthesis of Compounds 7A and 7B
室温下，将化合物4-(((2S)-4-(异噻唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(210毫克，0.11毫摩尔，粗品)溶于甲醇(MeOH，5毫升)中，加入碳酸钾(K2CO3，150毫克，1.1毫摩尔)，加热至70℃搅拌过夜，加入水(2毫升)继续反应2小时。At room temperature, compound 4-(((2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5 -Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (210 mg, 0.11 mmol, crude) was dissolved in methanol (MeOH, 5 mL), and potassium carbonate (K 2 CO 3 , 150 mg, 1.1 mmol), heated to 70°C and stirred overnight, added water (2 ml) and continued the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到6毫克绝对构型的非对映异构体7A(收率：3.5％)和12.4毫克绝对构型的非对映异构体7B(收率：7.4％)。The reaction was completed, and the purification treatment and chiral resolution method in step D of Example 3 were used to separate and obtain 6 mg of diastereomer 7A with absolute configuration (yield: 3.5%) and 12.4 mg of diastereoisomer 7A with absolute configuration. Enantiomer 7B (yield: 7.4%).
化合物7A：HPLC：RT＝11.2min，LC-MS：RT＝1.69min，[M+H]+＝462.15。Compound 7A: HPLC: RT=11.2 min, LC-MS: RT=1.69 min, [M+H] + =462.15.
化合物7B：HPLC：RT＝13.8min，LC-MS：RT＝1.69min，[M+H]+＝462.12。Compound 7B: HPLC: RT=13.8 min, LC-MS: RT=1.69 min, [M+H] + =462.12.
实施例8合成化合物8A和8B
Example 8 Synthesis of Compounds 8A and 8B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
氮气保护下，将含有(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200.0毫克，0.42毫摩尔)、4-溴噻唑(103.7豪克，0.62毫摩尔)、[1，1′-双(三苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2，61.0毫克，0.08毫摩尔)和磷酸钾(K3PO4，182.0毫克，0.84毫摩尔)的1，4-二氧六环与水的混合溶液(12毫升，1，4-二氧六环∶水＝5∶1)，加热至95℃反应12小时。Under nitrogen protection, the mixture containing (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle Pentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (200.0 mg, 0.42 mmol), 4-bromothiazole (103.7 mg, 0.62 mmol), [1 , 1′-bis(triphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 61.0 mg, 0.08 mmol) and potassium phosphate (K 3 PO 4 , 182.0 mg, 0.84 mmol) ) of a mixed solution of 1,4-dioxane and water (12 ml, 1,4-dioxane:water=5:1), heated to 95°C for 12 hours.
反应结束，加水，用乙酸乙酯(20毫升×4次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)，得到57.0毫克淡黄色固体(S)-6-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：31.2％)。LC-MS：RT＝2.11min，[M+H]+＝435.08。After the reaction was completed, water was added, extracted with ethyl acetate (20 ml x 4 times), the organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 3/1) to obtain 57.0 mg of light yellow solid (S)-6-(4-(methoxycarbonyl)phenyl) -4-(thiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 31.2%). LC-MS: RT=2.11 min, [M+H] + =435.08.
步骤B：合成(2S)-2-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)哌啶-1-羧酸苄酯Step B: Synthesis of (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidine-1-carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(57.0毫克，0.13毫摩尔)的乙酸乙酯(EtOAc，10毫升)中，加入钯碳(30毫克)，置换氢气，氢气保护下，升温至60℃反应12小时。At room temperature, to benzyl containing (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate To the ester (57.0 mg, 0.13 mmol) in ethyl acetate (EtOAc, 10 ml), add palladium carbon (30 mg), replace the hydrogen, and under the protection of hydrogen, heat to 60°C and react for 12 hours.
反应结束，冷却至室温，过滤，浓缩至干，得到57.0毫克淡黄色固体(2S)-2-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)哌啶-1-羧酸苄酯(收率：100％)。LC-MS：RT＝2.09min，[M+H]+＝437.09。The reaction was completed, cooled to room temperature, filtered, and concentrated to dryness to obtain 57.0 mg of light yellow solid (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidine- 1-Carboxylic acid benzyl ester (yield: 100%). LC-MS: RT=2.09min, [M+H] + =437.09.
步骤C：合成(S)-4-(4-(噻唑-4-基)哌啶-2-基)苯甲酸甲酯Step C: Synthesis of (S)-4-(4-(thiazol-4-yl)piperidin-2-yl)benzoic acid methyl ester
冰浴条件下，向含有(2S)-2-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)哌啶-1-羧酸苄酯(57.0毫克，0.13毫摩尔)的乙酸乙酯(EtOAc，5.0毫升)中，滴加氢溴酸的醋酸溶液(0.3毫升，氢溴酸的浓度为30％)，升至室温反应2小时。To a solution containing (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidine-1-carboxylic acid benzyl ester (57.0 mg, 0.13 mg) under ice bath conditions mole) of ethyl acetate (EtOAc, 5.0 ml), a solution of hydrobromic acid in acetic acid (0.3 ml, the concentration of hydrobromic acid is 30%) was added dropwise, and the mixture was raised to room temperature for 2 hours.
反应结束，冰浴条件下，饱和碳酸氢钠水溶液淬灭，乙酸乙酯(20毫升×4次)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)，得到28.0毫克淡黄色油状液体(S)-4-(4-(噻唑-4-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.61min，[M+H]+＝303.09。At the end of the reaction, quench the saturated sodium bicarbonate aqueous solution under ice bath conditions, extract with ethyl acetate (20 ml × 4 times), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/2) to obtain 28.0 mg of light yellow oily liquid (S)-4-(4-(thiazol-4-yl)piperazine). Methyl benzoate. LC-MS: RT=1.61 min, [M+H] + =303.09.
步骤D：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
氮气保护下，将(S)-4-(4-(噻唑-4-基)哌啶-2-基)苯甲酸甲酯(28.0毫克，0.09毫摩尔)，4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(65.0毫克，0.22毫摩尔)溶于1，2-二氯乙烷(DCE，3.0毫升)中，升温至40℃反应1小时，加入三乙酰氧基硼氢化钠(NaBH(OAc)3，57.2毫克，0.27毫摩尔)继续反应12小时。Under nitrogen protection, (S)-4-(4-(thiazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (28.0 mg, 0.09 mmol), 4-formyl-5-methoxy Tert-butyl-7-methyl-1H-indole-1-carboxylate (65.0 mg, 0.22 mmol) was dissolved in 1,2-dichloroethane (DCE, 3.0 ml), and the temperature was raised to 40°C for reaction. After 1 hour, sodium triacetoxyborohydride (NaBH(OAc) 3 , 57.2 mg, 0.27 mmol) was added and the reaction continued for 12 hours.
反应结束，加入甲醇，旋干拌样，硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)，得到34.0毫克黄色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：66.6％)。LC-MS：RT＝1.91min，[M+H]+＝576.19。After the reaction was completed, methanol was added, the mixture was rotated to dryness, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/2) to obtain 34.0 mg of yellow solid (S)-5-methoxy-4- ((2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxy Tert-butyl acid ester (yield: 66.6%). LC-MS: RT=1.91min, [M+H] + =576.19.
步骤E：合成化合物8A和8BStep E: Synthesis of Compounds 8A and 8B
室温下，向含有(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(噻唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(44.0毫克，0.06毫摩尔)的甲醇溶液(MeOH，5.0毫升)加入碳酸钾(K2CO3，33.1毫克，0.24毫摩尔)，升温 至70℃反应5小时，加入水(1.0毫升)继续反应12小时。To a compound containing (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidin-1-yl) To a solution of tert-butyl methyl)-7-methyl-1H-indole-1-carboxylate (44.0 mg, 0.06 mmol) in methanol (MeOH, 5.0 mL) was added potassium carbonate (K 2 CO 3 , 33.1 mg, 0.24 mmol), heating React at 70°C for 5 hours, add water (1.0 ml) and continue the reaction for 12 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到10.0毫克绝对构型的非对映异构体8A(收率：28.4％)和15.0毫克绝对构型的非对映异构体8B(收率：44.1％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 10.0 mg of diastereomer 8A with absolute configuration (yield: 28.4%) and 15.0 mg of diastereoisomer 8A with absolute configuration. Enantiomer 8B (yield: 44.1%).
化合物8A：HPLC：RT＝12.2min，LC-MS：RT＝1.66min，[M+H]+＝462.16。Compound 8A: HPLC: RT=12.2min, LC-MS: RT=1.66min, [M+H] + =462.16.
化合物8B：HPLC：RT＝14.5min，LC-MS：RT＝1.66min，[M+H]+＝462.16。Compound 8B: HPLC: RT=14.5min, LC-MS: RT=1.66min, [M+H] + =462.16.
实施例9合成化合物9A和9B
Example 9 Synthesis of Compounds 9A and 9B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-((4-甲氧基羰基)苯基)-4-(噻唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.42毫摩尔)的二氧六环(10毫升)中，加入5-溴噻唑(104毫克，0.63毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，61毫克，0.08毫摩尔)和磷酸钾(K3PO4，182毫克，0.84毫摩尔)，加入水(2毫升)，置换氮气，升温到90℃反应5小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (200 mg, 0.42 mmol) in dioxane (10 ml), 5-bromothiazole (104 mg, 0.63 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 61 mg, 0.08 mmol) and potassium phosphate (K 3 PO 4 , 182 mg, 0.84 mmol), add water (2 ml), replace nitrogen, and heat to 90°C for 5 hours.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/5)得到160毫克淡黄色油状液体(S)-6-((4-甲氧基羰基)苯基)-4-(噻唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：88％)。LC-MS：RT＝2.12min，[M+H]+＝435.25。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/5) to obtain 160 mg of light yellow oily liquid (S)-6-((4-methoxycarbonyl)phenyl) -4-(thiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 88%). LC-MS: RT=2.12min, [M+H] + =435.25.
步骤B：合成(S)-2-(4-甲氧基羰基)苯基)-4-(噻唑-5-基)哌啶-1-羧酸苄酯Step B: Synthesis of (S)-2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidine-1-carboxylic acid benzyl ester
室温下，将(S)-6-((4-甲氧基羰基)苯基)-4-(噻唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(150毫克，0.35毫摩尔)溶于甲醇溶液(MeOH，10毫升)中，加入钯碳(Pd/C，30毫克)，置换氢气继续反应0.5小时。At room temperature, (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (150 mg, 0.35 mmol) was dissolved in methanol solution (MeOH, 10 ml), palladium on carbon (Pd/C, 30 mg) was added, and hydrogen was replaced to continue the reaction for 0.5 hours.
反应结束，过滤，甲醇洗涤，浓缩得到110毫克淡黄色油状液体(S)-2-((4-甲氧基羰基)苯基)-4-(噻唑-5-基)哌啶-1-羧酸苄酯。LC-MS：RT＝2.13min，[M+H]+＝437.19。The reaction was completed, filtered, washed with methanol, and concentrated to obtain 110 mg of light yellow oily liquid (S)-2-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidine-1-carboxylic Benzyl acid ester. LC-MS: RT=2.13min, [M+H] + =437.19.
步骤C：合成(S)-4-(4-噻唑-5-基)哌啶-2-基苯甲酸甲酯Step C: Synthesis of (S)-4-(4-thiazol-5-yl)piperidin-2-yl benzoic acid methyl ester
冰浴下，将(S)-2-((4-甲氧基羰基)苯基)-4-(噻唑-5-基)哌啶-1-羧酸苄酯(110毫克，0.25毫摩尔)溶于乙酸乙酯溶液(6毫升)中，加入氢溴酸的醋酸溶液(HBr/AcOH，0.4毫升)，升温到室温反应2小时。Under ice bath, (S)-2-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidine-1-carboxylic acid benzyl ester (110 mg, 0.25 mmol) Dissolve in ethyl acetate solution (6 ml), add hydrobromic acid in acetic acid solution (HBr/AcOH, 0.4 ml), warm to room temperature and react for 2 hours.
反应结束，氨水淬灭，调节pH大约在5左右，乙酸乙酯萃取，干燥，过滤，浓缩得到95毫克淡黄色油状液体(S)-4-(4-噻唑-5-基)哌啶-2-基苯甲酸甲酯。LC-MS：RT＝1.67min，[M+H]+＝303.21。At the end of the reaction, the ammonia solution was quenched, the pH was adjusted to about 5, extracted with ethyl acetate, dried, filtered, and concentrated to obtain 95 mg of light yellow oily liquid (S)-4-(4-thiazol-5-yl)piperidine-2. -Methyl benzoate. LC-MS: RT=1.67min, [M+H] + =303.21.
步骤D：合成(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(噻唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-噻唑-5-基)哌啶-2-基苯甲酸甲酯(60毫克，0.20毫摩尔)的二氯乙烷(DCE，5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(86毫克，0.30毫摩尔)和三乙酰氧基硼氢化钠(NaBH(OAc)3，76毫克，0.36毫摩尔)，升温至40℃反应过夜。(S)-4-(4-thiazol-5-yl)piperidin-2-ylbenzoic acid methyl ester (60 mg, 0.20 mmol) in dichloroethane (DCE, 5 mL) at room temperature. , add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (86 mg, 0.30 mmol) and sodium triacetoxyborohydride (NaBH(OAc )3, 76 mg, 0.36 mmol), heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到25毫克白色固体(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(噻唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：21％)。LC-MS：RT＝1.98min，[M+H]+＝576.27。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 25 mg of white solid (S)-5-methoxy- 4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxy Tert-butyl acid ester (yield: 21%). LC-MS: RT=1.98min, [M+H] + =576.27.
步骤E：合成化合物9A和9BStep E: Synthesis of Compounds 9A and 9B
室温下，向(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(噻唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(25毫克，0.04毫摩尔)的甲醇(5毫升)溶液中，加碳酸钾(K2CO3，24毫克，0.17毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidin-1-yl)methyl) at room temperature -To a solution of 7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (25 mg, 0.04 mmol) in methanol (5 ml), add potassium carbonate (K 2 CO 3 , 24 mg, 0.17 mmol) ), heated to 70°C for 5 hours, added water (1 ml) and continued the reaction for 4 hours.
反应完成，采用实施例3步骤D中纯化处理和手性拆分方法分离得到5毫克绝对构型的非对映异构体9A(收率：26％)和10毫克绝对构型的非对映异构体9B(收率：52％)。The reaction was completed, and 5 mg of the absolute configuration of diastereomer 9A (yield: 26%) and 10 mg of the absolute configuration of the diastereomer were separated using the purification treatment and chiral resolution method in step D of Example 3. Isomer 9B (yield: 52%).
化合物9A：HPLC：RT＝12.2min，LC-MS：RT＝1.71min，[M+H]+＝462.26。 Compound 9A: HPLC: RT=12.2 min, LC-MS: RT=1.71 min, [M+H] + =462.26.
化合物9B：HPLC：RT＝14.6min，LC-MS：RT＝1.71min，[M+H]+＝462.28。Compound 9B: HPLC: RT=14.6min, LC-MS: RT=1.71min, [M+H] + =462.28.
实施例10合成化合物10A和10B
Example 10 Synthesis of Compounds 10A and 10B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1( 2H)-Carboxylic acid benzyl ester
氮气保护下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.0克，2.09毫摩尔)，4-溴-1-甲基-1H-吡唑(675毫克，4.18毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，154毫克，0.21毫摩尔)，磷酸钾(K3PO4，890毫克，4.18毫摩尔)加入1，4-二氧六环(15毫升)，水(2毫升)中，升温至95℃反应24小时。Under nitrogen protection, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle Pentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.0 g, 2.09 mmol), 4-bromo-1-methyl-1H-pyrazole (675 mg , 4.18 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 154 mg, 0.21 mmol), potassium phosphate (K 3 PO 4 , 890 mg, 4.18 mmol) was added to 1,4-dioxane (15 ml) and water (2 ml), and the temperature was raised to 95°C and reacted for 24 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到570毫克深黄色固体(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率63％)。LC-MS：RT＝2.05min，[M+H]+＝432.23。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 570 mg of dark yellow solid (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine- 1(2H)-carboxylic acid benzyl ester (yield 63%). LC-MS: RT=2.05min, [M+H] + =432.23.
步骤B：合成4-((2S)-4-(1-甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of methyl 4-((2S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate
氢气保护下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(520毫克，1.21毫摩尔)溶于乙酸乙酯(EtOAc，25毫升)，加入钯/碳(130毫克)，室温反应5小时。Under hydrogen protection, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine- 1(2H)-Benzylcarboxylate (520 mg, 1.21 mmol) was dissolved in ethyl acetate (EtOAc, 25 ml), palladium/carbon (130 mg) was added, and the reaction was carried out at room temperature for 5 hours.
反应完成，过滤，浓缩。得到390毫克黄色油状4-((2S)-4-(1-甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝1.50min，[M+H]+＝300.21。The reaction is completed, filtered and concentrated. 390 mg of 4-((2S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (crude product) was obtained as a yellow oil. No purification was required and it was used directly. react in the next step. LC-MS: RT=1.50min, [M+H] + =300.21.
步骤C：合成5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将化合物4-((2S)-4-(1-甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(390毫克，1.3毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(754毫克，2.6毫摩尔)溶于1，2-二氯乙烷(DCE，20毫升)中，加入三乙酰氧基硼氢化钠(NaBH(OAc)3，159毫克，0.75毫摩尔)反应过夜。Compound 4-((2S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester (390 mg, 1.3 mmol) and 4 -formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (754 mg, 2.6 mmol) dissolved in 1,2-dichloroethane (DCE, 20 mL ), add sodium triacetoxyborohydride (NaBH(OAc) 3 , 159 mg, 0.75 mmol) and react overnight.
反应完成，加入甲醇溶解至澄清，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到480毫克浅黄色胶状5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率64％)，直接用于下一步反应。LC-MS：RT＝1.88min，[M+H]+＝573.34。When the reaction is completed, add methanol to dissolve until clear and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 480 mg of light yellow gummy 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazole-4) -(yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 64%) was directly used in the next reaction. LC-MS: RT=1.88min, [M+H] + =573.34.
步骤D：合成化合物10A和10BStep D: Synthesis of Compounds 10A and 10B
室温下，将化合物5-甲氧基-4-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(40毫克，0.07毫摩尔，粗品)溶于甲醇(MeOH，5毫升)中，加入碳酸钾(K2CO3，100毫克，0.7毫摩尔)，加热至70℃搅拌过夜，加入水(2毫升)继续反应2小时。At room temperature, the compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl) )piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol, crude) was dissolved in methanol (MeOH, 5 mL), Add potassium carbonate (K 2 CO 3 , 100 mg, 0.7 mmol), heat to 70°C and stir overnight, add water (2 ml) and continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到1.2毫克绝对构型的非对映异构体10A(收率：3.8％)和2.1毫克绝对构型的非对映异构体10B(收率：6.5％)。The reaction was completed, and 1.2 mg of diastereoisomer 10A with absolute configuration and 2.1 mg of diastereomer 10A with absolute configuration were isolated using the purification treatment and chiral resolution method in step D of Example 3 (yield: 3.8%). Enantiomer 10B (yield: 6.5%).
化合物10A：HPLC：RT＝7.0min，LC-MS：RT＝1.65min，[M+H]+＝459.29。Compound 10A: HPLC: RT=7.0 min, LC-MS: RT=1.65 min, [M+H] + =459.29.
化合物10B：HPLC：RT＝10.4min，LC-MS：RT＝1.65min，[M+H]+＝459.27。Compound 10B: HPLC: RT=10.4min, LC-MS: RT=1.65min, [M+H] + =459.27.
实施例11合成化合物11A和11B
Example 11 Synthesis of Compounds 11A and 11B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.42毫摩尔)的二氧六环(10毫升)中，加入3-溴-1-甲基吡唑(101毫克，0.63毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl2，61毫克，0.08毫摩尔)和磷酸钾(K3PO4，182毫克，0.84毫摩尔)，加入水(2毫升)，置换氮气，升温到90℃反应5小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (200 mg, 0.42 mmol) in dioxane (10 ml) was added 3-bromo-1-methyl Pyrazole (101 mg, 0.63 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 61 mg, 0.08 mmol) and potassium phosphate (K 3 PO 4 , 182 mg, 0.84 mmol), add water (2 ml), replace with nitrogen, raise the temperature to 90°C and react for 5 hours.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/5)得到165毫克淡黄色油状液体(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：90％)。LC-MS：RT＝2.12min，[M+H]+＝432.25。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/5) to obtain 165 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl) -4-(1-Methyl-1H-pyrazol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 90%). LC-MS: RT=2.12min, [M+H] + =432.25.
步骤B：合成(S)-4-(4-(1-甲基-1H-吡唑-3-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-methyl-1H-pyrazol-3-yl)piperidin-2-yl)benzoate methyl ester
室温下，将(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(165毫克，0.38毫摩尔)溶于乙酸乙酯溶液(10毫升)中，加入钯碳(30毫克)，置换氢气，升温到60℃反应过夜。At room temperature, (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)-3,6-dihydropyridine-1 (2H)-Benzylcarboxylate (165 mg, 0.38 mmol) was dissolved in ethyl acetate solution (10 ml), palladium on carbon (30 mg) was added, replaced with hydrogen, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩得到110毫克无色油状液体(S)-4-(4-(1-甲基-1H-吡唑-3-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.60min，[M+H]+＝300.19。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 110 mg of colorless oily liquid (S)-4-(4-(1-methyl-1H-pyrazol-3-yl)piperidin-2-yl)benzene. Methyl formate. LC-MS: RT=1.60min, [M+H] + =300.19.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-(1-甲基-1H-吡唑-3-基)哌啶-2-基)苯甲酸甲酯(50毫克，0.17毫摩尔)的二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(72毫克，0.25毫摩尔)和三乙酰氧基硼氢化钠(50毫克，0.24毫摩尔)，升温至40℃反应过夜。To a solution containing (S)-4-(4-(1-methyl-1H-pyrazol-3-yl)piperidin-2-yl)benzoic acid methyl ester (50 mg, 0.17 mmol) was added to the solution at room temperature. To ethyl chloride (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (72 mg, 0.25 mmol) and triacetoxy Sodium borohydride (50 mg, 0.24 mmol) was heated to 40°C and allowed to react overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到45毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：46％)。LC-MS：RT＝1.90min，[M+H]+＝573.35。After the reaction is completed, a small amount of methanol is added and the solvent is directly rotated to dryness. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 45 mg of white solid (S)-5-methoxy. -4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-7- Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 46%). LC-MS: RT=1.90min, [M+H] + =573.35.
步骤D：合成化合物11A和11BStep D: Synthesis of Compounds 11A and 11B
室温下，向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(45毫克，0.08毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(44毫克，0.31毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(1-methyl-1H-pyrazol-3-yl) at room temperature To a solution of piperidin-1-ylmethyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (45 mg, 0.08 mmol) in methanol (5 ml) was added potassium carbonate (44 mg , 0.31 mmol), heated to 70°C for 5 hours, added water (1 ml) and continued the reaction for 4 hours.
反应完成，采用实施例3步骤D的纯化处理和手性拆分方法分离得到5毫克绝对构型的非对映异构体11A(收率：14％)和25毫克绝对构型的非对映异构体11B(收率：69％)。The reaction was completed, and the purification process and chiral resolution method of step D of Example 3 were used to separate and obtain 5 mg of the absolute configuration of diastereomer 11A (yield: 14%) and 25 mg of the absolute configuration of the diastereomer. Isomer 11B (Yield: 69%).
化合物11A：HPLC：RT＝11.0min，LC-MS：RT＝1.65min，[M+H]+＝459.22。Compound 11A: HPLC: RT=11.0 min, LC-MS: RT=1.65 min, [M+H] + =459.22.
化合物11B：HPLC：RT＝14.4min，LC-MS：RT＝1.65min，[M+H]+＝459.26。Compound 11B: HPLC: RT=14.4min, LC-MS: RT=1.65min, [M+H] + =459.26.
实施例12Example 12
合成(S)-4-(1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(1-甲基-1H-吡唑-5-基)哌啶-2-基)苯甲酸
Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1-methyl-1H-pyrazole-5 -yl)piperidin-2-yl)benzoic acid
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯 Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.42毫摩尔)的二氧六环(10毫升)中，加入5-溴-1-甲基吡唑(101毫克，0.63毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(61毫克，0.08毫摩尔)和磷酸钾(182毫克，0.84毫摩尔)，加入水(2毫升)，置换氮气后，升温到90℃反应5小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (200 mg, 0.42 mmol) in dioxane (10 ml) was added 5-bromo-1-methyl Pyrazole (101 mg, 0.63 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (61 mg, 0.08 mmol) and potassium phosphate (182 mg, 0.84 mmol) ), add water (2 ml), replace nitrogen, and raise the temperature to 90°C to react for 5 hours.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/5)得到120毫克淡黄色油状液体(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：66％)。LC-MS：RT＝2.15min，[M+H]+＝432.25。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/5) to obtain 120 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl) -4-(1-Methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 66%). LC-MS: RT=2.15min, [M+H] + =432.25.
步骤B：合成(S)-4-(4-(1-甲基-1H-吡唑-5-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoate methyl ester
室温下，将(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(120毫克，0.28毫摩尔)溶于乙酸乙酯溶液(10毫升)中，加入钯碳(30毫克)，置换氢气后，升温到60℃反应过夜。At room temperature, (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1 (2H)-Benzylcarboxylate (120 mg, 0.28 mmol) was dissolved in ethyl acetate solution (10 ml), palladium on carbon (30 mg) was added, and after replacing hydrogen, the temperature was raised to 60°C and the reaction was carried out overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩得到75毫克无色油状液体(S)-4-(4-(1-甲基-1H-吡唑-5-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.60min，[M+H]+＝300.19。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 75 mg of colorless oily liquid (S)-4-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl) Methyl benzoate. LC-MS: RT=1.60min, [M+H]+=300.19.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-(1-甲基-1H-吡唑-5-基)哌啶-2-基)苯甲酸甲酯(50毫克，0.17毫摩尔)的二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(72毫克，0.25毫摩尔)和三乙酰氧基硼氢化钠(50毫克，0.24毫摩尔)，升温至40℃反应过夜。To a solution containing (S)-4-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoic acid methyl ester (50 mg, 0.17 mmol) was added to the solution at room temperature. To ethyl chloride (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (72 mg, 0.25 mmol) and triacetoxy Sodium borohydride (50 mg, 0.24 mmol) was heated to 40°C and allowed to react overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到40毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：41％)。LC-MS：RT＝1.93min，[M+H]+＝573.35。After the reaction is completed, a small amount of methanol is added and the solvent is directly rotated to dryness. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 40 mg of white solid (S)-5-methoxy. -4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-7- Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 41%). LC-MS: RT=1.93min, [M+H] + =573.35.
步骤D：合成(S)-4-(1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(1-甲基-1H-吡唑-5-基)哌啶-2-基)苯甲酸Step D: Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1-methyl-1H-pyra Azol-5-yl)piperidin-2-yl)benzoic acid
室温下，向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(40毫克，0.07毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(39毫克，0.28毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(1-methyl-1H-pyrazol-5-yl) at room temperature To a solution of piperidin-1-ylmethyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol) in methanol (5 ml) was added potassium carbonate (39 mg , 0.28 mmol), heated to 70°C for 5 hours, added water (1 ml) and continued the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理方法分离得到23毫克的(S)-4-(1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(1-甲基-1H-吡唑-5-基)哌啶-2-基)苯甲酸(收率：72％)。LC-MS：RT＝1.62min，[M+H]+＝459.26。1H NMR(400MHz，DMSO-d6)δ10.82(s，1H)，7.83(d，J＝8.4Hz，2H)，7.42(d，J＝7.7Hz，2H)，7.25(t，J＝2.8Hz，1H)，7.22(d，J＝1.9Hz，1H)，6.66(s，1H)，6.44(t，J＝2.5Hz，1H)，6.00(d，J＝1.9Hz，1H)，3.74(d，J＝8.1Hz，6H)，3.60(d，J＝11.7Hz，1H)，3.31-3.17(m，3H)，2.94-2.80(m，2H)，2.42(s，3H)，2.22-2.10(m，1H)，1.86(d，J＝12.7Hz，1H)，1.79-1.65(m，2H)，1.48-1.33(m，1H).The reaction was completed, and 23 mg of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl) was isolated using the purification treatment method in step D of Example 3) Methyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoic acid (Yield: 72%). LC-MS: RT=1.62min, [M+H] + =459.26. 1H NMR (400MHz, DMSO-d6) δ 10.82 (s, 1H), 7.83 (d, J=8.4Hz, 2H), 7.42 ( d, J=7.7Hz, 2H), 7.25 (t, J=2.8Hz, 1H), 7.22 (d, J=1.9Hz, 1H), 6.66 (s, 1H), 6.44 (t, J=2.5Hz, 1H), 6.00 (d, J=1.9Hz, 1H), 3.74 (d, J=8.1Hz, 6H), 3.60 (d, J=11.7Hz, 1H), 3.31-3.17 (m, 3H), 2.94- 2.80 (m, 2H), 2.42 (s, 3H), 2.22-2.10 (m, 1H), 1.86 (d, J=12.7Hz, 1H), 1.79-1.65 (m, 2H), 1.48-1.33 (m, 1H).
实施例13A和13BExamples 13A and 13B
合成化合物13A和13B
Synthesis of Compounds 13A and 13B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(940毫克，1.88毫摩尔)，2-噻吩硼酸(482毫克，3.76毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(137毫克，0.188毫摩尔)，磷酸钾(1.2克，5.65毫摩尔)加入1，4-二氧六环(15毫升)，氮气保护下，升温至90℃反应12小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1 (2H)-Benzylcarboxylate (940 mg, 1.88 mmol), 2-thiopheneboronic acid (482 mg, 3.76 mmol), [1,1′-bis(diphenylphosphine)ferrocene] dichloride Palladium (137 mg, 0.188 mmol) and potassium phosphate (1.2 g, 5.65 mmol) were added to 1,4-dioxane (15 ml). Under nitrogen protection, the temperature was raised to 90°C and the reaction was carried out for 12 hours.
反应完成，加入乙酸乙酯(30毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到402毫克黄色半固体状(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯 (收率47.6％)。LC-MS：RT＝2.20min，[M+H]+＝434.19。After the reaction was completed, ethyl acetate (30 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 402 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxy as a yellow semi-solid Benzyl acid ester (Yield 47.6%). LC-MS: RT=2.20min, [M+H] + =434.19.
步骤B：合成(S)-4-(4-(噻吩-2-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(thiophen-2-yl)piperidin-2-yl)benzoic acid methyl ester
室温下，将(S)-6-(4-甲氧基羰基)苯基)-4-(噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(400毫克，0.41毫摩尔)溶于乙酸乙酯(15毫升)中，加入钯碳(60毫克)，置换氢气，升温至60℃反应过夜。At room temperature, (S)-6-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester ( 400 mg, 0.41 mmol) was dissolved in ethyl acetate (15 ml), palladium on carbon (60 mg) was added, replaced with hydrogen, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到80毫克无色油状液体(S)-4-(4-(噻吩-2-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.70min，[M+H]+＝302.20。After the reaction was completed, it was filtered, washed with ethyl acetate, and concentrated to obtain 80 mg of (S)-4-(4-(thiophen-2-yl)piperidin-2-yl)benzoate methyl ester as a colorless oily liquid. LC-MS: RT=1.70min, [M+H] + =302.20.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
室温下，向含有(S)-4-(4-(噻吩-2-基)哌啶-2-基)苯甲酸甲酯(80毫克，0.27毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(118毫克，0.41毫摩尔)和三乙酰氧基硼氢化钠(115毫克，0.54毫摩尔)，升温至40℃反应过夜。To (S)-4-(4-(thiophen-2-yl)piperidin-2-yl)benzoic acid methyl ester (80 mg, 0.27 mmol) was added to 1,2-dichloroethane ( 5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (118 mg, 0.41 mmol) and sodium triacetoxyborohydride (115 mg, 0.54 mmol), heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到68毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：44％)。LC-MS：RT＝1.95min，[M+H]+＝575.24。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to obtain 68 mg of white solid (S)-5-methoxy- 4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1 - tert-butyl carboxylate (yield: 44%). LC-MS: RT=1.95min, [M+H] + =575.24.
步骤D：合成化合物13A和13BStep D: Synthesis of Compounds 13A and 13B
室温下，向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(68毫克，0.12毫摩尔)的甲醇(5毫升)中，加入碳酸钾(82.8毫克，0.6毫摩尔)，升温至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidin-1-yl)methyl at room temperature tert-butyl)-7-methyl-1H-indole-1-carboxylate (68 mg, 0.12 mmol) in methanol (5 ml), add potassium carbonate (82.8 mg, 0.6 mmol), and heat to React at 70°C for 5 hours, add water (1 ml) and continue the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到6毫克绝对构型的非对映异构体13A(收率：14％)和15毫克绝对构型的非对映异构体13B(收率：36％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 6 mg of diastereomer 13A with absolute configuration (yield: 14%) and 15 mg of diastereoisomer 13A with absolute configuration. Enantiomer 13B (yield: 36%).
化合物13A：HPLC：RT＝11.7min，LC-MS：RT＝1.66min，[M+H]+＝423.24。Compound 13A: HPLC: RT=11.7min, LC-MS: RT=1.66min, [M+H] + =423.24.
化合物13B：HPLC：RT＝14.9min，LC-MS：RT＝1.24min，[M+H]+＝423.24。Compound 13B: HPLC: RT=14.9 min, LC-MS: RT=1.24 min, [M+H] + =423.24.
实施例14A和14BExamples 14A and 14B
合成化合物14A和14B
Synthesis of Compounds 14A and 14B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(940毫克，1.88毫摩尔)，3-噻吩硼酸(482毫克，3.76毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(137毫克，0.188毫摩尔)，磷酸钾(1.2克，5.65毫摩尔)加入1，4-二氧六环(15毫升)中，氮气保护下升温至90℃反应14小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1 (2H)-Benzylcarboxylate (940 mg, 1.88 mmol), 3-thiopheneboronic acid (482 mg, 3.76 mmol), [1,1′-bis(diphenylphosphine)ferrocene] dichloride Palladium (137 mg, 0.188 mmol) and potassium phosphate (1.2 g, 5.65 mmol) were added to 1,4-dioxane (15 ml), and the temperature was raised to 90°C under nitrogen protection for 14 hours.
反应完成，加入乙酸乙酯(30毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到610毫克黄色半固体状(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率74％)。LC-MS：RT＝2.27min，[M+H]+＝434.08。After the reaction was completed, ethyl acetate (30 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 610 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxy as a yellow semi-solid Benzyl acid ester (yield 74%). LC-MS: RT=2.27min, [M+H] + =434.08.
步骤B：合成(S)-4-(4-羟基-4-(噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-hydroxy-4-(thiophen-3-yl)piperidin-2-yl)benzoate methyl ester
室温下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(170毫克，0.39毫摩尔)溶于乙酸乙酯(5毫升)中，冰水浴冷却，加入HBr/HOAc溶液(2毫升)，于室温反应1小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl The ester (170 mg, 0.39 mmol) was dissolved in ethyl acetate (5 ml), cooled in an ice-water bath, HBr/HOAc solution (2 ml) was added, and the reaction was carried out at room temperature for 1 hour.
反应完成，冰水浴冷却，加冰块淬灭，氨水调pH＝12-13，乙酸乙酯(20毫升×3次)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10/1)。得到85毫克浅黄色油状(S)-4-(4-羟基-4-(噻吩-3-基)哌啶-2-基)苯甲酸甲酯(收率72％)。LC-MS：RT＝1.58min，[M+H]+＝318.12。1H NMR(400MHz，CDCl3)δ8.02(d，J＝8.0Hz，2H)，7.52(d，J＝8.0Hz，2H)，7.33-7.30(m，1H)，7.26-7.22(m，1H)，7.19-7.16(m，1H)，4.32-4.27(m，1H)，3.92(s，3H)，3.39-3.32(m，1H)，3.21-3.16(m，1H)，2.23-2.15(m，1H)，2.01-1.90(m，4H). After the reaction is completed, cool it in an ice-water bath, add ice cubes to quench, adjust the pH to 12-13 with ammonia water, extract with ethyl acetate (20 ml × 3 times), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1). 85 mg of (S)-4-(4-hydroxy-4-(thiophen-3-yl)piperidin-2-yl)benzoate methyl ester was obtained as a light yellow oil (yield 72%). LC-MS: RT=1.58min, [M+H] + =318.12. 1 H NMR (400MHz, CDCl 3 ) δ8.02 (d, J=8.0Hz, 2H), 7.52 (d, J=8.0Hz, 2H), 7.33-7.30 (m, 1H), 7.26-7.22 (m, 1H), 7.19-7.16(m, 1H), 4.32-4.27(m, 1H), 3.92(s, 3H), 3.39-3.32(m, 1H), 3.21-3.16(m, 1H), 2.23-2.15( m, 1H), 2.01-1.90 (m, 4H).
步骤C：合成(S)-4-((4-羟基-2-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-4-((4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl) -5-Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-羟基-4-(噻吩-3-基)哌啶-2-基)苯甲酸甲酯(85毫克，0.268毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(155毫克，0.536毫摩尔)反应4小时，加入三乙酰氧基硼氢化钠(284毫克，1.34毫摩尔)反应过夜。To 1,2-dimethyl (S)-4-(4-hydroxy-4-(thiophen-3-yl)piperidin-2-yl)benzoate (85 mg, 0.268 mmol) was added to the solution at room temperature. To ethyl chloride (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (155 mg, 0.536 mmol) and react for 4 hours. Sodium triacetoxyborohydride (284 mg, 1.34 mmol) was added and the reaction was carried out overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到55毫克黄色油状(S)-4-((4-羟基-2-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：34％)。LC-MS：RT＝1.89min，[M+H]+＝591.17。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 55 mg of yellow oily (S)-4-((4- Hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H- Indole-1-carboxylic acid tert-butyl ester (yield: 34%). LC-MS: RT=1.89min, [M+H] + =591.17.
步骤D：合成化合物14A和14BStep D: Synthesis of Compounds 14A and 14B
室温下，向(S)-4-((4-羟基-2-(4-(甲氧基羰基)苯基)-4-(噻吩-3-基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(55毫克，0.09毫摩尔)的甲醇(5毫升)中，加入碳酸钾(130毫克，0.9毫摩尔)，升温至70℃反应过夜，加水(2毫升)继续反应2小时。To (S)-4-((4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl) at room temperature To -5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (55 mg, 0.09 mmol) in methanol (5 ml), add potassium carbonate (130 mg, 0.9 mmol) ), raise the temperature to 70°C and react overnight, add water (2 ml) and continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到16.4毫克绝对构型的非对映异构体14A(收率：37％)和3.9毫克绝对构型的非对映异构体14B(收率：8.8％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 16.4 mg of diastereoisomer 14A with absolute configuration (yield: 37%) and 3.9 mg of diastereoisomer 14A with absolute configuration. Enantiomer 14B (yield: 8.8%).
化合物14A：HPLC：RT＝14.3min，LC-MS：RT＝1.66min，[M+H]+＝477.17。Compound 14A: HPLC: RT=14.3min, LC-MS: RT=1.66min, [M+H] + =477.17.
化合物14B：HPLC：RT＝15.2min，LC-MS：RT＝1.66min，[M+H]+＝477.17。Compound 14B: HPLC: RT=15.2min, LC-MS: RT=1.66min, [M+H] + =477.17.
实施例15Example 15
合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸
Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(2-甲基噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
室温下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(400毫克，0.84毫摩尔)，3-溴-2-甲基噻吩(178毫克，1.01毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(62毫克，0.83毫摩尔)，碳酸钾(231毫克，1.68毫摩尔)加入1，4-二氧六环(10毫升)中，加入水(5毫升)，氮气保护下，升温至90℃反应5小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (400 mg, 0.84 mmol), 3-bromo-2-methylthiophene (178 mg, 1.01 mmol) , [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (62 mg, 0.83 mmol), potassium carbonate (231 mg, 1.68 mmol) were added to 1,4-dioxane (10 ml), add water (5 ml), and under nitrogen protection, heat to 90°C and react for 5 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到208毫克黄色油状(S)-6-(4-(甲氧羰基)苯基)-4-(2-甲基噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率43％)。LC-MS：RT＝2.29min，[M+H]+＝448.25。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 208 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)- as a yellow oil Benzyl carboxylate (yield 43%). LC-MS: RT=2.29min, [M+H] + =448.25.
步骤B：合成(S)-4-(4-(2-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(2-methylthiophen-3-yl)piperidin-2-yl)benzoate methyl ester
室温下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(2-甲基噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(110毫克，0.25毫摩尔)溶于乙酸乙酯(10毫升)中，加入钯/碳(50毫克)，氢气氛围下加热至60℃，反应过夜。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)- Benzyl carboxylate (110 mg, 0.25 mmol) was dissolved in ethyl acetate (10 ml), palladium/carbon (50 mg) was added, heated to 60°C under a hydrogen atmosphere, and the reaction was carried out overnight.
反应完成，过滤，浓缩。得到60毫克浅黄色胶状(S)-4-(4-(2-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝1.73min，[M+H]+＝316.18。The reaction is completed, filtered and concentrated. 60 mg of (S)-4-(4-(2-methylthiophen-3-yl)piperidin-2-yl)benzoic acid methyl ester (crude product) was obtained as a light yellow gum. No purification was required and it was used directly in the following step. One step reaction. LC-MS: RT=1.73min, [M+H] + =316.18.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1 -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将化合物(S)-4-(4-(2-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯(60毫克，0.15毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(132毫克，0.45毫摩尔)溶于1，2-二氯乙烷(5毫升)中搅拌6小时，加入三乙酰氧基硼氢化钠(161毫克，0.76毫摩尔)反应过夜。Compound (S)-4-(4-(2-methylthiophen-3-yl)piperidin-2-yl)benzoate methyl ester (60 mg, 0.15 mmol) and 4-formyl- 5-Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (132 mg, 0.45 mmol) was dissolved in 1,2-dichloroethane (5 ml) and stirred for 6 hours. Sodium triacetoxyborohydride (161 mg, 0.76 mmol) was added and the reaction was carried out overnight.
反应完成，加入甲醇，浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到100毫克黄色油状(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(粗品)，直接用于下一步反应。LC-MS：RT＝2.05min，[M+H]+＝589.29。After the reaction was completed, methanol was added, concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 3/1). Obtained 100 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-) as a yellow oil 1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (crude product) was directly used in the next reaction. LC-MS: RT=2.05min, [M+H] + =589.29.
步骤D：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1 -methyl)-7-methyl-1H-indole-1-carboxylic acid
室温下，将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(100毫克，0.16毫摩尔，粗品)溶于甲醇(10毫升)中，加入碳酸钾(235毫克，1.7毫摩尔)，加热至70℃反应3小时，加入水(2毫升)继续反应3小时。 At room temperature, compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine- 1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, crude product) was dissolved in methanol (10 ml), and potassium carbonate (235 mg) was added , 1.7 mmol), heated to 70°C for 3 hours, added water (2 ml) and continued the reaction for 3 hours.
反应完成，采用实施例3步骤D中的纯化处理方法分离得到1.3毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸(收率：1.1％)。The reaction was completed, and 1.3 mg of white solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4 was isolated using the purification method in step D of Example 3. -(2-methylthiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid (yield: 1.1%).
化合物15：HPLC：RT＝3.554min，LC-MS：RT＝1.78min，[M+H]+＝475.25。Compound 15: HPLC: RT=3.554min, LC-MS: RT=1.78min, [M+H] + =475.25.
实施例16Example 16
合成化合物(S)-4-((4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸
Synthetic compound (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-2-(4-(甲氧羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-羧酸苄酯Step A: Synthesis of (S)-2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(2-甲基噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.45毫摩尔)溶于乙酸乙酯(15毫升)中，加入钯/碳(50毫克)，氢气氛围下加热至60℃反应5小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl The ester (200 mg, 0.45 mmol) was dissolved in ethyl acetate (15 ml), palladium/carbon (50 mg) was added, and the reaction was heated to 60°C under a hydrogen atmosphere for 5 hours.
反应完成，过滤，浓缩。得到190毫克浅黄色胶状(S)-2-(4-(甲氧羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-羧酸苄酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝2.29min，[M+H]+＝450.25。The reaction is completed, filtered and concentrated. Obtained 190 mg of light yellow gummy (S)-2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylic acid benzyl ester (crude product) , no purification is required and can be used directly in the next reaction. LC-MS: RT=2.29min, [M+H] + =450.25.
步骤B：合成(S)-4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯Step B: Synthesis of (S)-4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester
室温下，将化合物(S)-2-(4-(甲氧羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-羧酸苄酯(100毫克，0.22毫摩尔)溶于N，N-二甲基甲酰胺(5毫升)中，加入NBS(40毫克)反应过夜。Compound (S)-2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylic acid benzyl ester (100 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 ml), NBS (40 mg) was added and the reaction was carried out overnight.
反应完成，加入至水(30毫升)中，乙酸乙酯(15毫升×3次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝9/1)，得到80毫克黄色胶状(S)-4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯(收率68％)。After the reaction was completed, add to water (30 ml), extract with ethyl acetate (15 ml x 3 times), combine the organic phases, wash with saturated brine (20 ml), dry over anhydrous sodium sulfate, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 9/1) to obtain 80 mg of yellow gummy (S)-4-(5-bromo-2-methylthiophene-3). -(yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (yield 68%).
步骤C：(S)-4-(4-(5-溴-2-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step C: (S)-Methyl 4-(4-(5-bromo-2-methylthiophen-3-yl)piperidin-2-yl)benzoate
将化合物(S)-4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯(80毫克，0.15毫摩尔)溶于乙酸乙酯(5毫升)中，冰水浴冷却，加入33％氢溴酸/醋酸溶液(0.6毫升)，升至室温反应2小时。Compound (S)-4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (80 mg , 0.15 mmol) was dissolved in ethyl acetate (5 ml), cooled in an ice-water bath, added 33% hydrobromic acid/acetic acid solution (0.6 ml), and raised to room temperature for 2 hours.
反应完成，加水淬灭，氨水调节至碱性，浓缩，所得残余物用乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得到30毫克黄色胶状(S)-4-(4-(5-溴-2-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯(收率50％)。LC-MS：RT＝1.77min，[M+H]+＝394.05。After the reaction is completed, add water to quench, adjust ammonia to alkalinity, and concentrate. The resulting residue is diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=10/1). 30 mg of (S)-4-(4-(5-bromo-2-methylthiophen-3-yl)piperidin-2-yl)benzoate methyl ester was obtained as a yellow gum (yield 50%). LC-MS: RT=1.77min, [M+H] + =394.05.
步骤D：合成(S)-4-((4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl) )methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将化合物(S)-4-(4-(5-溴-2-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯(30毫克，0.076毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(88毫克，0.3毫摩尔)溶于1，2-二氯乙烷(5毫升)中反应过夜，加入三乙酰氧基硼氢化钠(80毫克，0.38毫摩尔)反应3小时。Compound (S)-4-(4-(5-bromo-2-methylthiophen-3-yl)piperidin-2-yl)benzoate methyl ester (30 mg, 0.076 mmol) and 4 -Formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (88 mg, 0.3 mmol) was dissolved in 1,2-dichloroethane (5 ml) The reaction was carried out overnight, and sodium triacetoxyborohydride (80 mg, 0.38 mmol) was added and the reaction was carried out for 3 hours.
反应完成，加入甲醇，浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)。得到80毫克黄色油状(S)-4-((4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(粗品)，直接用于下一步反应。LC-MS：RT＝2.05min，[M+H]+＝669.05。After the reaction was completed, methanol was added and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1). Obtained 80 mg of (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-) as a yellow oil (methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (crude product) was directly used in the next reaction. LC-MS: RT=2.05min, [M+H] + =669.05.
步骤E：合成化合物(S)-4-((4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸Step E: Synthesis of compound (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1- (methyl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid
室温下，将化合物(S)-4-((4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(80毫克，0.11毫摩尔，粗品)溶于甲醇(5毫升)中，加入碳酸钾(165毫克，1.2毫摩尔)，加热至70℃反应过夜，加入水(2毫升)继续反应2小时。At room temperature, compound (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1- (methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (80 mg, 0.11 mmol, crude product) was dissolved in methanol (5 ml), and carbonic acid was added Potassium (165 mg, 1.2 mmol) was heated to 70°C to react overnight, and water (2 ml) was added to continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理方法分离得到6.1毫克白色固体(S)-4-((4-(5-溴-2-甲基噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸(收率：9％)。The reaction was completed, and 6.1 mg of white solid (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4) was isolated using the purification method in step D of Example 3 -(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid (yield: 9%).
化合物16：HPLC：RT＝11.2min，LC-MS：RT＝1.84min，[M+H]+＝553.17。 Compound 16: HPLC: RT=11.2 min, LC-MS: RT=1.84 min, [M+H] + =553.17.
实施例17A和17BExamples 17A and 17B
合成化合物17A和17B
Synthesis of Compounds 17A and 17B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-甲氧基羰基)苯基)-4-(5-甲基噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(300毫克，0.63毫摩尔)的1，4-二氧六环(10毫升)中，加入5-甲基-3-溴噻吩(110毫克，0.94毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(92毫克，0.13毫摩尔)和磷酸钾(273毫克，1.26毫摩尔)，水(2毫升)，置换氮气，升温到90℃反应5小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (300 mg, 0.63 mmol) in 1,4-dioxane (10 ml) was added 5-methyl -3-bromothiophene (110 mg, 0.94 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (92 mg, 0.13 mmol) and potassium phosphate (273 mg, 1.26 mmol), water (2 ml), replaced with nitrogen, heated to 90°C and reacted for 5 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/5)得到200毫克淡黄色油状液体(S)-6-(4-甲氧基羰基)苯基)-4-(5-甲基噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：71％)。LC-MS：RT＝2.22min，[M+H]+＝448.21。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to obtain 200 mg of light yellow oily liquid (S)-6-(4-methoxycarbonyl)phenyl)- 4-(5-Methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 71%). LC-MS: RT=2.22min, [M+H] + =448.21.
步骤B：合成(S)-4-(4-(5-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(5-methylthiophen-3-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6-(4-甲氧基羰基)苯基)-4-(5-甲基噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.41毫摩尔)溶于乙酸乙酯(15毫升)中，加入钯碳(70毫克)，置换氢气，升温到60℃反应过夜。(S)-6-(4-Methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate benzyl ester (200 mg, 0.41 mmol) was dissolved in ethyl acetate (15 ml), palladium on carbon (70 mg) was added, replaced with hydrogen, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到50毫克无色油状液体(S)-4-(4-(5-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.67min，[M+H]+＝316.21。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 50 mg of colorless oily liquid (S)-4-(4-(5-methylthiophen-3-yl)piperidin-2-yl)benzoic acid methyl ester. . LC-MS: RT=1.67min, [M+H] + =316.21.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)piperidine-1 -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-甲基噻吩-3-基)哌啶-2-基)苯甲酸甲酯(50毫克，0.16毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(69毫克，0.24毫摩尔)和三乙酰氧基硼氢化钠(67毫克，0.32毫摩尔)，升温至40℃反应过夜。To (S)-4-(4-(5-methylthiophen-3-yl)piperidin-2-yl)benzoic acid methyl ester (50 mg, 0.16 mmol) in 1,2-dichloroethane (5 ml), 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (69 mg, 0.24 mmol) and triacetoxyhydroborate were added Sodium (67 mg, 0.32 mmol) was heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到50毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：53％)。LC-MS：RT＝2.03min，[M+H]+＝589.33。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to obtain 50 mg of white solid (S)-5-methoxy- 4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H- Indole-1-carboxylic acid tert-butyl ester (yield: 53%). LC-MS: RT=2.03min, [M+H] + =589.33.
步骤D：合成化合物17A和17BStep D: Synthesis of Compounds 17A and 17B
向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-甲基噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(50毫克，0.09毫摩尔)的甲醇(5毫升)中，加碳酸钾(47毫克，0.34毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol) in methanol (5 ml), add potassium carbonate (47 mg, 0.34 mmol), and heat React to 70°C for 5 hours, add water (1 ml) and continue the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到6毫克绝对构型的非对映异构体17A(收率：14％)和15毫克绝对构型的非对映异构体17B(收率：36％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 6 mg of diastereomer 17A with absolute configuration (yield: 14%) and 15 mg of diastereoisomer 17A with absolute configuration. Enantiomer 17B (yield: 36%).
化合物17A：HPLC：RT＝10.7min，LC-MS：RT＝1.79min，[M+H]+＝475.29。1H NMR(400MHz，DMSO-d6)δ10.80(s，1H)，7.81(d，J＝7.8Hz，2H)，7.40(d，J＝7.8Hz，2H)，7.24(t，J＝2.7Hz，1H)，7.01(d，J＝1.5Hz，1H)，6.79(s，1H)，6.63(s，1H)，6.48(dd，J＝3.0，1.7Hz，1H)，3.68(s，3H)，3.61(d，J＝11.9Hz，1H)，3.45-3.41(m，1H)，3.25(s，1H)，2.96(t，J＝4.5Hz，1H)，2.60-2.54(m，1H)，2.43(d，J＝14.9Hz，6H)，2.23-1.98(m，3H)，1.92-1.89(m，1H)，1.79-1.73(m，1H).Compound 17A: HPLC: RT=10.7min, LC-MS: RT=1.79min, [M+H] + =475.29. 1 H NMR (400MHz, DMSO-d 6 ) δ10.80 (s, 1H), 7.81 (d, J=7.8Hz, 2H), 7.40 (d, J=7.8Hz, 2H), 7.24 (t, J= 2.7Hz, 1H), 7.01 (d, J=1.5Hz, 1H), 6.79 (s, 1H), 6.63 (s, 1H), 6.48 (dd, J=3.0, 1.7Hz, 1H), 3.68 (s, 3H), 3.61 (d, J=11.9Hz, 1H), 3.45-3.41 (m, 1H), 3.25 (s, 1H), 2.96 (t, J=4.5Hz, 1H), 2.60-2.54 (m, 1H ), 2.43 (d, J=14.9Hz, 6H), 2.23-1.98 (m, 3H), 1.92-1.89 (m, 1H), 1.79-1.73 (m, 1H).
化合物17B：HPLC：RT＝15.9min，LC-MS：RT＝1.79min，[M+H]+＝475.31。1H NMR(400MHz，DMSO-d6)δ10.83(d，J＝2.4Hz，1H)，7.88(d，J＝7.9Hz，2H)，7.49(d，J＝7.8Hz，2H)，7.25(t，J＝2.8Hz，1H)，6.84(d，J＝1.4Hz，1H)，6.72(s，1H)，6.65(s，1H)，6.47(t，J＝2.5Hz，1H)，3.72(s，3H)，3.60(d，J＝11.8Hz，1H)，3.22(dd，J＝14.3，10.3Hz，2H)，2.85(dt，J＝11.7，3.4Hz，1H)，2.68(td，J＝10.4，8.8，6.1Hz，1H)，2.39(d，J＝25.5Hz，6H)，2.15-2.04(m，1H)，1.92-1.83(m，1H)，1.80-1.62(m，2H)，1.48-1.38(m，1H). Compound 17B: HPLC: RT=15.9min, LC-MS: RT=1.79min, [M+H] + =475.31. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.83 (d, J = 2.4Hz, 1H), 7.88 (d, J = 7.9Hz, 2H), 7.49 (d, J = 7.8Hz, 2H), 7.25 (t, J=2.8Hz, 1H), 6.84 (d, J=1.4Hz, 1H), 6.72 (s, 1H), 6.65 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 3.72 (s, 3H), 3.60 (d, J=11.8Hz, 1H), 3.22 (dd, J=14.3, 10.3Hz, 2H), 2.85 (dt, J=11.7, 3.4Hz, 1H), 2.68 (td, J=10.4, 8.8, 6.1Hz, 1H), 2.39 (d, J=25.5Hz, 6H), 2.15-2.04 (m, 1H), 1.92-1.83 (m, 1H), 1.80-1.62 (m, 2H) ,1.48-1.38(m,1H).
实施例18Example 18
合成(S)-4-(1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(3-甲基异噻唑-5-基)哌啶-2-基)苯甲酸
Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-methylisothiazol-5-yl) Piperidin-2-yl)benzoic acid
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-甲氧基羰基)苯基)-4-(3-甲基异噻唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)-3,6-dihydropyridine-1(2H)- Benzyl carboxylate
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.42毫摩尔)的1，4-二氧六环(10毫升)中，加入3-甲基-5-溴异噻唑(113毫克，0.63毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(61毫克，0.08毫摩尔)和磷酸钾(182毫克，0.84毫摩尔)，水(2毫升)，置换氮气，升温到90℃反应5小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (200 mg, 0.42 mmol) in 1,4-dioxane (10 ml) was added 3-methyl -5-bromoisothiazole (113 mg, 0.63 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (61 mg, 0.08 mmol) and potassium phosphate (182 mg , 0.84 mmol), water (2 ml), replaced with nitrogen, heated to 90°C and reacted for 5 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到110毫克淡黄色油状液体(S)-6-(4-甲氧基羰基)苯基)-4-(3-甲基异噻唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：61％)。LC-MS：RT＝2.13min，[M+H]+＝449.21。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 110 mg of light yellow oily liquid (S)-6-(4-methoxycarbonyl)phenyl)- 4-(3-Methylisothiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 61%). LC-MS: RT=2.13min, [M+H] + =449.21.
步骤B：合成(S)-4-(4-(3-甲基异噻唑-5-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6-(4-甲氧基羰基)苯基)-4-(3-甲基异噻唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(110毫克，0.25毫摩尔)溶于乙酸乙酯-(10毫升)中，加入钯碳(50毫克)，-置换氢气-，升温到60℃反应过夜。(S)-6-(4-Methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl The ester (110 mg, 0.25 mmol) was dissolved in ethyl acetate (10 ml), palladium on carbon (50 mg) was added, -replacing hydrogen -, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到31毫克无色油状液体(S)-4-(4-(3-甲基异噻唑-5-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.67min，[M+H]+＝317.19。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 31 mg of colorless oily liquid (S)-4-(4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoic acid methyl ester. LC-MS: RT=1.67min, [M+H] + =317.19.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(3-甲基异噻唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)piperidine- 1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(3-甲基异噻唑-5-基)哌啶-2-基)苯甲酸甲酯(31毫克，0.10毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(43毫克，0.15毫摩尔)和三乙酰氧基硼氢化钠(42毫克，0.2毫摩尔)，升温至40℃反应过夜。To 1,2-dichloroethyl containing (S)-4-(4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoate (31 mg, 0.10 mmol) To alkane (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (43 mg, 0.15 mmol) and triacetoxyboron Sodium hydride (42 mg, 0.2 mmol) was heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到18毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(3-甲基异噻唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：31％)。LC-MS：RT＝1.95min，[M+H]+＝590.33。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 18 mg of white solid (S)-5-methoxy- 4-((2-(4-(methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H - Indole-1-carboxylic acid tert-butyl ester (yield: 31%). LC-MS: RT=1.95min, [M+H] + =590.33.
步骤D：合成(S)-4-(1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(3-甲基异噻唑-5-基)哌啶-2-基)苯甲酸Step D: Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-methylisothiazole-5 -yl)piperidin-2-yl)benzoic acid
向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(3-甲基异噻唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(18毫克，0.03毫摩尔)的甲醇(5毫升)中，加碳酸钾(17毫克，0.12毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (18 mg, 0.03 mmol) in methanol (5 ml), add potassium carbonate (17 mg, 0.12 mmol), Heat to 70°C and react for 5 hours, add water (1 ml) and continue the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理方法分离得到5毫克白色固体(S)-4-(1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(3-甲基异噻唑-5-基)哌啶-2-基)苯甲酸(收率：35％)。LC-MS：RT＝1.70min，[M+H]+＝476.21。The reaction was completed, and 5 mg of white solid (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl) was isolated using the purification method in step D of Example 3 )methyl)-4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoic acid (yield: 35%). LC-MS: RT=1.70min, [M+H] + =476.21.
实施例19A和19BExamples 19A and 19B
合成化合物19A和19B
Synthesis of Compounds 19A and 19B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-甲氧基羰基)苯基)-4-(2-甲基噻唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(200毫克，0.42毫摩尔)的1，4-二氧六环(10毫升)中，加入2-甲基-4-溴噻唑(113毫克，0.63毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(61毫克，0.08毫摩尔)和磷酸钾(182毫克，0.84毫摩尔)，水(2毫升)，置换氮气，升温到90℃反应5小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (200 mg, 0.42 mmol) in 1,4-dioxane (10 ml) was added -4-bromothiazole (113 mg, 0.63 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (61 mg, 0.08 mmol) and potassium phosphate (182 mg, 0.84 mmol), water (2 ml), replaced with nitrogen, heated to 90°C and reacted for 5 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到140毫克淡黄色油状液体(S)-6-(4-甲氧基羰基)苯基)-4-(2-甲基噻唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：74％)。LC-MS：RT＝2.10min，[M+H]+＝449.21。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 140 mg of light yellow oily liquid (S)-6-(4-methoxycarbonyl)phenyl)- 4-(2-Methylthiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 74%). LC-MS: RT=2.10min, [M+H] + =449.21.
步骤B：合成(S)-4-(4-(2-甲基噻唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(2-methylthiazol-4-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6-(4-甲氧基羰基)苯基)-4-(2-甲基噻唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(120毫克，0.27毫摩尔)溶于乙酸乙酯10毫升)中，加入钯碳(50毫克)，置换氢气，升温到60℃反应过夜。(S)-6-(4-Methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate benzyl ester (120 mg, 0.27 mmol) was dissolved in ethyl acetate (10 ml), palladium on carbon (50 mg) was added, replaced with hydrogen, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩，得到90毫克淡黄色油状液体(S)-4-(4-(2-甲基噻唑-4-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.63min，[M+H]+＝317.17。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 90 mg of light yellow oily liquid (S)-4-(4-(2-methylthiazol-4-yl)piperidin-2-yl)benzoic acid methyl ester. LC-MS: RT=1.63min, [M+H] + =317.17.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)piperidine-1 -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-(2-甲基噻唑-4-基)哌啶-2-基)苯甲酸甲酯(90毫克，0.28毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(123毫克，0.43毫摩尔)和三乙酰氧基硼氢化钠(118毫克，0.56毫摩尔)，升温至40℃反应过夜。To 1,2-bis(S)-4-(4-(2-methylthiazol-4-yl)piperidin-2-yl)benzoate (90 mg, 0.28 mmol) was added to the solution at room temperature. To ethyl chloride (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (123 mg, 0.43 mmol) and triacetoxy Sodium borohydride (118 mg, 0.56 mmol) was heated to 40°C and allowed to react overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到45毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：42％)。LC-MS：RT＝1.91min，[M+H]+＝589.31。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 45 mg of white solid (S)-5-methoxy- 4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H- Indole-1-carboxylic acid tert-butyl ester (yield: 42%). LC-MS: RT=1.91min, [M+H] + =589.31.
步骤D：合成化合物19A和19BStep D: Synthesis of Compounds 19A and 19B
室温下，向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(2-甲基噻唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(45毫克，0.08毫摩尔)的甲醇(5毫升)中，加碳酸钾(42毫克，0.31毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(2-methylthiazol-4-yl)piperidine-1 at room temperature -(methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (45 mg, 0.08 mmol) in methanol (5 ml), add potassium carbonate (42 mg, 0.31 mmol) ), heated to 70°C for 5 hours, added water (1 ml) and continued the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到5.8毫克绝对构型的非对映异构体19A(收率：15％)和17.3毫克绝对构型的非对映异构体19B(收率：46％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 5.8 mg of diastereomer 19A with absolute configuration (yield: 15%) and 17.3 mg of diastereoisomer 19A with absolute configuration. Enantiomer 19B (yield: 46%).
化合物19A：HPLC：RT＝13.6min，LC-MS：RT＝1.72min，[M+H]+＝476.23。Compound 19A: HPLC: RT=13.6min, LC-MS: RT=1.72min, [M+H] + =476.23.
化合物19B：HPLC：RT＝18.5min，LC-MS：RT＝1.72min，[M+H]+＝476.22。Compound 19B: HPLC: RT=18.5min, LC-MS: RT=1.72min, [M+H] + =476.22.
实施例20A和20BExamples 20A and 20B
合成化合物20A和20B
Synthesis of Compounds 20A and 20B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-二氟甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine -1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.47毫摩尔)的1，4-二氧六环(20毫升)中，加入4-溴-1-二氟甲基吡唑(433毫克，2.20毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(214毫克，0.29毫摩尔)，磷酸钾(637毫克，2.93毫摩尔)，水(4毫升)，置换氮气，升温到90℃反应过夜。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (700 mg, 1.47 mmol) in 1,4-dioxane (20 ml) was added 4-bromo- 1-Difluoromethylpyrazole (433 mg, 2.20 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (214 mg, 0.29 mmol), potassium phosphate ( 637 mg, 2.93 mmol), water (4 ml), replaced with nitrogen, heated to 90°C and reacted overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶5)得到450毫克淡黄色油状液体(S)-6-(4-(甲氧基羰基)苯基)-4-(1-二氟甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸 苄酯(收率：65％)。LC-MS：RT＝2.17min，[M+H]+＝468.23。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:5) to obtain 450 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl) -4-(1-Difluoromethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Benzyl ester (yield: 65%). LC-MS: RT=2.17min, [M+H] + =468.23.
步骤B：合成(S)-4-(4-(1-二氟甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
室温下，将(S)-6-(4-(甲氧基羰基)苯基)-4-(1-二氟甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(450毫克，0.96毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯碳(200毫克)，置换氢气，室温反应3个小时。At room temperature, (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine -1(2H)-Benzylcarboxylate (450 mg, 0.96 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (200 mg) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 3 hours.
反应结束后过滤，用乙酸乙酯洗涤，液相直接减压浓缩得到330毫克无色油状液体(S)-4-(4-(1-二氟甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.68min，[M+H]+＝336.21。After the reaction, it was filtered, washed with ethyl acetate, and the liquid phase was directly concentrated under reduced pressure to obtain 330 mg of colorless oily liquid (S)-4-(4-(1-difluoromethyl-1H-pyrazol-4-yl) Piperidin-2-yl)benzoic acid methyl ester. LC-MS: RT=1.68min, [M+H] + =336.21.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-二氟甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazole-4- (yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-(1-二氟甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(330毫克，0.98毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(427毫克，1.48毫摩尔)和三乙酰氧基硼氢化钠(848毫克，4.00毫摩尔)，升温至40℃反应过夜。To a solution containing (S)-4-(4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (330 mg, 0.98 mmol) at room temperature To 1,2-dichloroethane (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (427 mg, 1.48 mg mol) and sodium triacetoxyborohydride (848 mg, 4.00 mmol), and the temperature was raised to 40°C and the reaction was carried out overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶1)得到310毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-二氟甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：52％)。LC-MS：RT＝1.97min，[M+H]+＝608.34After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 310 mg of white solid (S)-5-methoxy- 4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 52%). LC-MS: RT=1.97min, [M+H] + =608.34
步骤D：合成化合物20A和20BStep D: Synthesis of Compounds 20A and 20B
室温下，向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-二氟甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(310毫克，0.51毫摩尔)的甲醇(15毫升)中，加入碳酸钾(284毫克，2.04毫摩尔)，加热至70℃反应5小时，加水(3毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(1-difluoromethyl-1H-pyrazole-4- To tert-butyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (310 mg, 0.51 mmol) in methanol (15 ml), potassium carbonate ( 284 mg, 2.04 mmol), heated to 70°C for 5 hours, added water (3 ml) and continued the reaction for 4 hours.
反应结束，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到38毫克绝对构型的非对映异构体20A(收率：15％)和120毫克绝对构型的非对映异构体20B(收率：48％)。At the end of the reaction, the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 38 mg of diastereomer 20A with absolute configuration (yield: 15%) and 120 mg of diastereoisomer 20A with absolute configuration. Enantiomer 20B (yield: 48%).
化合物20A：HPLC：RT＝8.5min，LC-MS：RT＝1.63min，[M+H]+＝495.27。1H NMR(400MHz，DMSO-d6)δ10.80(s，1H)，8.16(s，1H)，7.84-7.77(m，3H)，7.40(d，J＝7.8Hz，2H)，7.24(t，J＝2.7Hz，1H)，6.63(s，1H)，6.48(dd，J＝3.1，1.7Hz，1H)，3.68(s，3H)，3.58(d，J＝11.9Hz，1H)，3.19(d，J＝11.9Hz，1H)，3.03(s，1H)，2.56(dd，J＝9.7，6.0Hz，1H)，2.52(s，2H)，2.41(s，3H)，2.17-2.02(m，3H)，1.90-1.75(m，2H).Compound 20A: HPLC: RT=8.5 min, LC-MS: RT=1.63 min, [M+H] + =495.27. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 8.16 (s, 1H), 7.84-7.77 (m, 3H), 7.40 (d, J=7.8Hz, 2H), 7.24 ( t, J=2.7Hz, 1H), 6.63 (s, 1H), 6.48 (dd, J=3.1, 1.7Hz, 1H), 3.68 (s, 3H), 3.58 (d, J=11.9Hz, 1H), 3.19 (d, J=11.9Hz, 1H), 3.03 (s, 1H), 2.56 (dd, J=9.7, 6.0Hz, 1H), 2.52 (s, 2H), 2.41 (s, 3H), 2.17-2.02 (m, 3H), 1.90-1.75 (m, 2H).
化合物20B：HPLC：RT＝13.6min，LC-MS：RT＝1.63min，[M+H]+＝495.27。1H NMR(400MHz，DMSO-d6)δ10.85(t，J＝2.2Hz，1H)，8.00(s，1H)，7.88(d，J＝7.9Hz，2H)，7.68(d，J＝7.1Hz，2H)，7.54-7.45(m，2H)，7.25(t，J＝2.8Hz，1H)，6.66(s，1H)，6.47(t，J＝2.5Hz，1H)，3.72(s，3H)，3.60(d，J＝11.8Hz，2H)，3.23(dd，J＝15.8，10.1Hz，2H)，2.85(dt，J＝11.7，3.3Hz，1H)，2.73-2.63(m，1H)，2.43(s，3H)，2.15-2.06(m，1H)，1.95(d，J＝12.6Hz，1H)，1.79(d，J＝13.0Hz，1H)，1.66(q，J＝12.2Hz，1H)，1.50-1.35(m，1H).Compound 20B: HPLC: RT=13.6min, LC-MS: RT=1.63min, [M+H] + =495.27. 1 H NMR (400MHz, DMSO-d 6 ) δ10.85 (t, J=2.2Hz, 1H), 8.00 (s, 1H), 7.88 (d, J=7.9Hz, 2H), 7.68 (d, J= 7.1Hz, 2H), 7.54-7.45 (m, 2H), 7.25 (t, J=2.8Hz, 1H), 6.66 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 3.72 (s, 3H), 3.60 (d, J=11.8Hz, 2H), 3.23 (dd, J=15.8, 10.1Hz, 2H), 2.85 (dt, J=11.7, 3.3Hz, 1H), 2.73-2.63 (m, 1H ), 2.43 (s, 3H), 2.15-2.06 (m, 1H), 1.95 (d, J = 12.6Hz, 1H), 1.79 (d, J = 13.0Hz, 1H), 1.66 (q, J = 12.2Hz , 1H), 1.50-1.35(m, 1H).
实施例21A和21BExamples 21A and 21B
合成化合物21A和21B
Synthesis of Compounds 21A and 21B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-乙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1克，2.10毫摩尔)的1，4-二氧六环(20毫升)中，加入4-溴-1-乙基吡唑(546毫克，3.14毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(306毫克，0.42毫摩尔)，磷酸钾(910毫克，4.19毫摩尔)和水(4毫升)，置换氮气，升温至90℃反应过夜。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1 g, 2.10 mmol) in 1,4-dioxane (20 ml) was added 4-bromo- 1-Ethylpyrazole (546 mg, 3.14 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (306 mg, 0.42 mmol), potassium phosphate (910 mg , 4.19 mmol) and water (4 ml), replaced with nitrogen, heated to 90°C and reacted overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/5)得到550毫克淡黄色油状液体(S)-6-(4-(甲氧基羰基)苯基)-4-(1-乙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：59％)。LC-MS：RT＝2.20min，[M+H]+＝446.25。 At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/5) to obtain 550 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl) -4-(1-ethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 59%). LC-MS: RT=2.20min, [M+H] + =446.25.
步骤B：合成(S)-4-(4-(1-乙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-ethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
室温下，将(S)-6-(4-(甲氧基羰基)苯基)-4-(1-乙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(550毫克，1.23毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯碳(105毫克)，置换氢气，升温到60℃反应3小时。At room temperature, (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1 (2H)-Benzylcarboxylate (550 mg, 1.23 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (105 mg) was added, replaced with hydrogen, and the temperature was raised to 60°C for 3 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到450毫克无色油状液体(S)-4-(4-(1-乙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.65min，[M+H]+＝314.23。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 450 mg of colorless oily liquid (S)-4-(4-(1-ethyl-1H-pyrazol-4-yl)piperidin-2-yl) Methyl benzoate. LC-MS: RT=1.65min, [M+H] + =314.23.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-乙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-(1-乙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(450毫克，1.42毫摩尔)的1，2-二氯乙烷(10毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(617毫克，2.14毫摩尔)和三乙酰氧基硼氢化钠(602毫克，2.84毫摩尔)，升温至40℃反应过夜。To 1 containing (S)-methyl 4-(4-(1-ethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (450 mg, 1.42 mmol) at room temperature , to 2-dichloroethane (10 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (617 mg, 2.14 mmol) and sodium triacetoxyborohydride (602 mg, 2.84 mmol), and heated to 40°C to react overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到410毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-乙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：46％)。LC-MS：RT＝2.00min，[M+H]+＝587.37。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 410 mg of white solid (S)-5-methoxy- 4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl Tert-butyl-1H-indole-1-carboxylate (yield: 46%). LC-MS: RT=2.00min, [M+H] + =587.37.
步骤D：合成化合物21A和21BStep D: Synthesis of Compounds 21A and 21B
室温下，向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-乙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(350毫克，0.59毫摩尔)的甲醇(15毫升)中，加入碳酸钾(330毫克，2.38毫摩尔)，加热至70℃反应5小时，加水(3毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl) at room temperature To piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (350 mg, 0.59 mmol) in methanol (15 ml), potassium carbonate (330 mg , 2.38 mmol), heated to 70°C for 5 hours, added water (3 ml) and continued the reaction for 4 hours.
反应完成后，采用实施例3步骤D中的纯化处理方法和手性拆分方法分离得到19毫克绝对构型的非对映异构体21A(收率：7％)和198毫克绝对构型的非对映异构体21B(收率：70％)。After the reaction was completed, the purification treatment method and chiral resolution method in step D of Example 3 were used to separate and obtain 19 mg of absolute configuration diastereomer 21A (yield: 7%) and 198 mg of absolute configuration diastereomer 21A. Diastereomer 21B (yield: 70%).
化合物21A：HPLC：RT＝12.4min，LC-MS：RT＝1.70min，[M+H]+＝473.33。Compound 21A: HPLC: RT=12.4min, LC-MS: RT=1.70min, [M+H] + =473.33.
化合物21B：HPLC：RT＝16.7min，LC-MS：RT＝1.70min，[M+H]+＝473.34。Compound 21B: HPLC: RT=16.7min, LC-MS: RT=1.70min, [M+H] + =473.34.
实施例22A和22BExamples 22A and 22B
合成化合物22A和22B
Synthesis of Compounds 22A and 22B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-异丙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine- 1(2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1克，2.10毫摩尔)的1，4-二氧六环(20毫升)中，加入4-溴-1-异丙基吡唑(546毫克，3.14毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(306毫克，0.42毫摩尔)，磷酸钾(910毫克，4.19毫摩尔)，加水(4毫升)，置换氮气，升温到90℃反应过夜。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1 g, 2.10 mmol) in 1,4-dioxane (20 ml) was added 4-bromo- 1-isopropylpyrazole (546 mg, 3.14 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (306 mg, 0.42 mmol), potassium phosphate (910 mg, 4.19 mmol), add water (4 ml), replace nitrogen, heat to 90°C and react overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶5)得到570毫克淡黄色油状液体(S)-6-(4-(甲氧基羰基)苯基)-4-(1-异丙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：59％)。LC-MS：RT＝2.15min，[M+H]+＝460.27。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:5) to obtain 570 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl) -4-(1-isopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 59%). LC-MS: RT=2.15min, [M+H] + =460.27.
步骤B：合成(S)-4-(4-(1-异丙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
室温下，将(S)-6-(4-(甲氧基羰基)苯基)-4-(1-异丙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(570毫克，1.24毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯碳(200毫克)，置换氢气，室温反应3小时。At room temperature, (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine- 1(2H)-Benzylcarboxylate (570 mg, 1.24 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (200 mg) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 3 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到330毫克无色油状液体(S)-4-(4-(1-异丙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.64min，[M+H]+＝328.23。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 330 mg of colorless oily liquid (S)-4-(4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-2-yl). ) methyl benzoate. LC-MS: RT=1.64min, [M+H] + =328.23.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-异丙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基 -1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl) )piperidin-1-yl)methyl)-7-methyl -1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-(1-异丙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(330毫克，1.01毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(438毫克，1.51毫摩尔)和三乙酰氧基硼氢化钠(856毫克，4.04毫摩尔)，升温至40℃反应过夜。To a solution containing (S)-4-(4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester (330 mg, 1.01 mmol) at room temperature To 1,2-dichloroethane (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (438 mg, 1.51 mmol ) and sodium triacetoxyborohydride (856 mg, 4.04 mmol), raise the temperature to 40°C and react overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶1)得到400毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-异丙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：46％)。LC-MS：RT＝1.97min，[M+H]+＝601.37After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 400 mg of white solid (S)-5-methoxy- 4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7- Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 46%). LC-MS: RT=1.97min, [M+H] + =601.37
步骤D：合成化合物22A和22BStep D: Synthesis of Compounds 22A and 22B
室温下，向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-异丙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(400毫克，0.67毫摩尔)的甲醇(15毫升)中，加入碳酸钾(371毫克，2.67毫摩尔)，加热至70℃反应5小时，加水(3毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(1-isopropyl-1H-pyrazol-4-yl) at room temperature ) piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (400 mg, 0.67 mmol) in methanol (15 ml), add potassium carbonate (371 mg, 2.67 mmol), heated to 70°C for 5 hours, added water (3 ml) and continued the reaction for 4 hours.
反应结束，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到23毫克绝对构型的非对映异构体22A(收率：7％)和217毫克绝对构型的非对映异构体22B(收率：66％)。At the end of the reaction, the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 23 mg of diastereomer 22A with absolute configuration (yield: 7%) and 217 mg of diastereoisomer 22A with absolute configuration. Enantiomer 22B (yield: 66%).
化合物22A：HPLC：RT＝9.2min，LC-MS：RT＝1.65min，[M+H]+＝487.24。1H NMR(400MHz，DMSO-d6)δ10.79(s，1H)，7.80(d，J＝8.1Hz，2H)，7.64(s，1H)，7.39(d，J＝7.8Hz，2H)，7.35(s，1H)，7.24(t，J＝2.7Hz，1H)，6.63(s，1H)，6.49(dd，J＝3.1，1.7Hz，1H)，4.49(p，J＝6.6Hz，1H)，3.68(s，3H)，3.58(d，J＝11.9Hz，1H)，3.39(d，J＝4.5Hz，2H)，3.20(d，J＝12.0Hz，1H)，2.98(d，J＝4.5Hz，1H)，2.41(s，3H)，2.19-2.10(m，1H)，2.05-1.98(m，2H)，1.81-1.73(m，2H)，1.44(d，J＝6.7Hz，6H).Compound 22A: HPLC: RT=9.2min, LC-MS: RT=1.65min, [M+H] + =487.24. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 7.80 (d, J = 8.1Hz, 2H), 7.64 (s, 1H), 7.39 (d, J = 7.8Hz, 2H) , 7.35 (s, 1H), 7.24 (t, J = 2.7Hz, 1H), 6.63 (s, 1H), 6.49 (dd, J = 3.1, 1.7Hz, 1H), 4.49 (p, J = 6.6Hz, 1H), 3.68 (s, 3H), 3.58 (d, J=11.9Hz, 1H), 3.39 (d, J=4.5Hz, 2H), 3.20 (d, J=12.0Hz, 1H), 2.98 (d, J=4.5Hz, 1H), 2.41 (s, 3H), 2.19-2.10 (m, 1H), 2.05-1.98 (m, 2H), 1.81-1.73 (m, 2H), 1.44 (d, J=6.7Hz , 6H).
化合物22B：HPLC：RT＝15.6min，LC-MS：RT＝1.65min，[M+H]+＝487.24。1H NMR(400MHz，DMSO-d6)δ10.84(t，J＝2.3Hz，1H)，7.93-7.85(m，2H)，7.53(d，J＝11.1Hz，3H)，7.29-7.19(m，2H)，6.66(s，1H)，6.48(dd，J＝3.1，1.9Hz，1H)，4.36(p，J＝6.6Hz，1H)，3.72(s，3H)，3.60(d，J＝11.8Hz，1H)，3.23(dd，J＝18.1，10.1Hz，2H)，2.84(dt，J＝11.9，3.3Hz，1H)，2.67-2.56(m，1H)，2.42(s，3H)，2.16-2.05(m，1H)，1.95-1.87(m，1H)，1.80-1.72(m，1H)，1.61(q，J＝12.2Hz，1H)，1.45-1.25(m，7H).Compound 22B: HPLC: RT=15.6min, LC-MS: RT=1.65min, [M+H] + =487.24. 1 H NMR (400MHz, DMSO-d 6 ) δ10.84 (t, J=2.3Hz, 1H), 7.93-7.85 (m, 2H), 7.53 (d, J=11.1Hz, 3H), 7.29-7.19 ( m, 2H), 6.66 (s, 1H), 6.48 (dd, J=3.1, 1.9Hz, 1H), 4.36 (p, J=6.6Hz, 1H), 3.72 (s, 3H), 3.60 (d, J =11.8Hz, 1H), 3.23 (dd, J = 18.1, 10.1Hz, 2H), 2.84 (dt, J = 11.9, 3.3Hz, 1H), 2.67-2.56 (m, 1H), 2.42 (s, 3H) , 2.16-2.05(m, 1H), 1.95-1.87(m, 1H), 1.80-1.72(m, 1H), 1.61(q, J=12.2Hz, 1H), 1.45-1.25(m, 7H).
实施例23A和23BExamples 23A and 23B
合成化合物23A和23B
Synthesis of Compounds 23A and 23B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-环丙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine- 1(2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(900毫克，1.89毫摩尔)的1，4-二氧六环(20毫升)中，加入4-溴-1-环丙基吡唑(534毫克，2.83毫摩尔)、[1，1′-双(二苯基膦)二茂铁]二氯化钯(276毫克，0.38毫摩尔)、磷酸钾(821毫克，3.78毫摩尔)和水(4毫升)，置换氮气，升温到90℃反应过夜。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (900 mg, 1.89 mmol) in 1,4-dioxane (20 ml) was added 4-bromo- 1-cyclopropylpyrazole (534 mg, 2.83 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (276 mg, 0.38 mmol), potassium phosphate (821 mg, 3.78 mmol) and water (4 ml), replaced with nitrogen, heated to 90°C and reacted overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶5)得到700毫克淡黄色油状液体(S)-6-(4-(甲氧基羰基)苯基)-4-(1-环丙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：81％)。LC-MS：RT＝2.18min，[M+H]+＝458.26。The reaction was completed, filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:5) to obtain 700 mg of light yellow oily liquid (S)-6- (4-(Methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester ( Yield: 81%). LC-MS: RT=2.18min, [M+H] + =458.26.
步骤B：合成(S)-4-(4-(1-环丙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
室温下，将(S)-6-(4-(甲氧基羰基)苯基)-4-(1-环丙基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.53毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯碳(200毫克)，置换氢气，室温反应3小时。At room temperature, (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine- 1(2H)-Benzylcarboxylate (700 mg, 1.53 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (200 mg) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 3 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到500毫克无色油状液体(S)-4-(4-(1-环丙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.63min，[M+H]+＝326.23。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 500 mg of colorless oily liquid (S)-4-(4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-2-yl). ) methyl benzoate. LC-MS: RT=1.63min, [M+H] + =326.23.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-环丙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基 -1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl) )piperidin-1-yl)methyl)-7-methyl -1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有(S)-4-(4-(1-环丙基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(550毫克，1.53毫摩尔)的1，2-二氯乙烷(10毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(665毫克，2.30毫摩尔)和三乙酰氧基硼氢化钠(661毫克，3.12毫摩尔)，升温至40℃反应过夜。To a solution containing (S)-4-(4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester (550 mg, 1.53 mmol) at room temperature To 1,2-dichloroethane (10 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (665 mg, 2.30 mmol ) and sodium triacetoxyborohydride (661 mg, 3.12 mmol), raise the temperature to 40°C and react overnight.
反应结束，加入甲醇，浓缩至干，用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶1)得到350毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-环丙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：38％)。LC-MS：RT＝1.98min，[M+H]+＝599.36。After the reaction was completed, methanol was added, concentrated to dryness, and purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 350 mg of white solid (S)-5-methoxy-4-( (2-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl- 1H-indole-1-carboxylic acid tert-butyl ester (yield: 38%). LC-MS: RT=1.98min, [M+H] + =599.36.
步骤D：合成化合物23A和23BStep D: Synthesis of Compounds 23A and 23B
室温下，向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-环丙基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(350毫克，0.58毫摩尔)的甲醇(15毫升)中，加入碳酸钾(325毫克，2.34毫摩尔)，加热至70℃反应5小时，加水(3毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(1-cyclopropyl-1H-pyrazol-4-yl) at room temperature ) piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (350 mg, 0.58 mmol) in methanol (15 ml), add potassium carbonate (325 mg, 2.34 mmol), heated to 70°C for 5 hours, added water (3 ml) and continued the reaction for 4 hours.
反应结束，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到30毫克绝对构型的非对映异构体23A(收率：11％)和140毫克绝对构型的非对映异构体23B(收率：50％)。At the end of the reaction, the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 30 mg of diastereoisomer 23A with absolute configuration (yield: 11%) and 140 mg of diastereoisomer 23A with absolute configuration. Enantiomer 23B (yield: 50%).
化合物23A：HPLC：RT＝9.7min，LC-MS：RT＝1.65min，[M+H]+＝485.34。1H NMR(400MHz，DMSO-d6)δ10.79(s，1H)，7.81(d，J＝7.8Hz，2H)，7.68(s，1H)，7.39(d，J＝7.8Hz，2H)，7.33(s，1H)，7.24(t，J＝2.7Hz，1H)，6.63(s，1H)，6.48(t，J＝2.3Hz，1H)，3.73(dt，J＝7.4，3.6Hz，1H)，3.68(s，3H)，3.57(d，J＝12.0Hz，1H)，3.19(d，J＝11.9Hz，1H)，2.95(t，J＝4.2Hz，1H)，2.55(s，2H)，2.41(s，3H)，2.13(d，J＝9.5Hz，1H)，2.04-1.96(m，2H)，1.79-1.72(m，2H)，1.11-1.02(m，2H)，0.97-0.93(m，2H).Compound 23A: HPLC: RT=9.7min, LC-MS: RT=1.65min, [M+H] + =485.34. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 7.81 (d, J = 7.8Hz, 2H), 7.68 (s, 1H), 7.39 (d, J = 7.8Hz, 2H) , 7.33 (s, 1H), 7.24 (t, J = 2.7Hz, 1H), 6.63 (s, 1H), 6.48 (t, J = 2.3Hz, 1H), 3.73 (dt, J = 7.4, 3.6Hz, 1H), 3.68 (s, 3H), 3.57 (d, J = 12.0Hz, 1H), 3.19 (d, J = 11.9Hz, 1H), 2.95 (t, J = 4.2Hz, 1H), 2.55 (s, 2H), 2.41 (s, 3H), 2.13 (d, J=9.5Hz, 1H), 2.04-1.96 (m, 2H), 1.79-1.72 (m, 2H), 1.11-1.02 (m, 2H), 0.97 -0.93(m,2H).
化合物23B：HPLC：RT＝14.3min，LC-MS：RT＝1.65min，[M+H]+＝485.34。1H NMR(400MHz，DMSO-d6)δ10.83(t，J＝2.3Hz，1H)，7.93(d，J＝7.9Hz，2H)，7.58(d，J＝7.8Hz，2H)，7.53(s，1H)，7.30-7.20(m，2H)，6.66(s，1H)，6.47(t，J＝2.5Hz，1H)，3.72(s，3H)，3.59(d，J＝3.9Hz，1H)，3.30-3.17(m，3H)，2.83(dt，J＝11.6，3.3Hz，1H)，2.59(td，J＝10.2，8.3，6.0Hz，1H)，2.17-2.02(m，1H)，1.95-1.86(m，1H)，1.74(d，J＝12.4Hz，1H)，1.59(q，J＝12.2Hz，1H)，1.42-1.30(m，1H)，0.99-0.90(m，2H)，0.87-0.82(m，2H).Compound 23B: HPLC: RT=14.3min, LC-MS: RT=1.65min, [M+H] + =485.34. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.83 (t, J=2.3Hz, 1H), 7.93 (d, J=7.9Hz, 2H), 7.58 (d, J=7.8Hz, 2H), 7.53 (s, 1H), 7.30-7.20 (m, 2H), 6.66 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 3.72 (s, 3H), 3.59 (d, J=3.9Hz, 1H), 3.30-3.17 (m, 3H), 2.83 (dt, J=11.6, 3.3Hz, 1H), 2.59 (td, J=10.2, 8.3, 6.0Hz, 1H), 2.17-2.02 (m, 1H) , 1.95-1.86 (m, 1H), 1.74 (d, J=12.4Hz, 1H), 1.59 (q, J=12.2Hz, 1H), 1.42-1.30 (m, 1H), 0.99-0.90 (m, 2H ), 0.87-0.82(m, 2H).
实施例24A和24BExamples 24A and 24B
合成化合物24A和24B
Synthesis of Compounds 24A and 24B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.0克，2.1毫摩尔)，4-溴-1-(2-甲氧基乙基)-1H-吡唑(648.3毫克，3.1毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(307毫克，0.4毫摩尔)，磷酸钾(912毫克，4.2毫摩尔)加入1，4-二氧六环(30毫升)和水(6毫升)中，氮气保护下升温至95℃反应12小时。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.0 g, 2.1 mmol), 4-bromo-1-(2-methoxyethyl)-1H - Pyrazole (648.3 mg, 3.1 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (307 mg, 0.4 mmol), potassium phosphate (912 mg, 4.2 mmol) mol) was added to 1,4-dioxane (30 ml) and water (6 ml), and the temperature was raised to 95°C under nitrogen protection for 12 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到532毫克黄色油状(S)-6-(4-(甲氧基羰基)苯基)-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率53.3％)。LC-MS：RT＝2.05min，[M+H]+＝476.25。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 532 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3 as a yellow oil , 6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield 53.3%). LC-MS: RT=2.05min, [M+H] + =476.25.
步骤B：合成(S)-4-(4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
室温下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(532毫克，1.12毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯/碳(600毫克)，氢气氛围下室温反应过夜。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3 , 6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (532 mg, 1.12 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (600 mg) was added, and the reaction was carried out at room temperature overnight under a hydrogen atmosphere. .
反应完成，过滤，浓缩。得到300毫克浅黄色油状物(S)-4-(4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)哌啶-2-基)苯甲 酸甲酯(粗品)，直接用于下一步反应。LC-MS：RT＝1.56min，[M+H]+＝344.25。The reaction is completed, filtered and concentrated. Obtained 300 mg of light yellow oil (S)-4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzyl Acid methyl ester (crude product) was directly used in the next reaction. LC-MS: RT=1.56min, [M+H] + =344.25.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H- Pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将化合物(S)-4-(4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(300毫克，0.87毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(502毫克，1.74毫摩尔)溶于1，2-二氯乙烷(5毫升)中，室温搅拌1小时，加入三乙酰氧基硼氢化钠(553.1毫克，2.61毫摩尔)，升温至40℃反应过夜。At room temperature, compound (S)-4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (300 mg , 0.87 mmol) and 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (502 mg, 1.74 mmol) were dissolved in 1,2-dichloro into ethane (5 ml), stirred at room temperature for 1 hour, added sodium triacetoxyborohydride (553.1 mg, 2.61 mmol), raised the temperature to 40°C and reacted overnight.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)。得到350毫克棕色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率65.3％)。LC-MS：RT＝1.89min，[M+H]+＝617.41。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1). Obtained 350 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H) -pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 65.3%). LC-MS: RT=1.89min, [M+H] + =617.41.
步骤D：合成化合物24A和24BStep D: Synthesis of Compounds 24A and 24B
室温下，将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)哌啶-1-基))甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(350毫克，0.56毫摩尔)溶于甲醇(10毫升)中，加入碳酸钾(313毫克，2.2毫摩尔)，加热至70℃反应过夜，加入水(2毫升)继续反应2小时。At room temperature, compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H -pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (350 mg, 0.56 mmol) was dissolved in methanol (10 ml), add potassium carbonate (313 mg, 2.2 mmol), heat to 70°C and react overnight, add water (2 ml) and continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到22毫克绝对构型的非对映异构体24A(收率：7.8％)和118毫克绝对构型的非对映异构体24B(收率：41.9％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 22 mg of diastereomer 24A with absolute configuration (yield: 7.8%) and 118 mg of diastereoisomer 24A with absolute configuration. Enantiomer 24B (yield: 41.9%).
化合物24A：HPLC：RT＝3.214min，LC-MS：RT＝1.63min，[M+H]+＝503.35。Compound 24A: HPLC: RT=3.214 min, LC-MS: RT=1.63 min, [M+H] + =503.35.
1H NMR(400MHz，DMSO-d6)δ10.81(s，1H)，7.81(d，J＝7.8Hz，2H)，7.63(s，1H)，7.42-7.34(m，3H)，7.24(t，J＝2.7Hz，1H)，6.63(s，1H)，6.47(dd，J＝3.0，1.8Hz，1H)，4.32-4.23(m，2H)，3.76-3.65(m，5H)，3.57(d，J＝11.9Hz，1H)，3.26(s，3H)，3.17(d，J＝11.9Hz，1H)，2.98(d，J＝5.7Hz，1H)，2.55(s，2H)，2.41(s，3H)，2.15(dt，J＝12.3，7.2Hz，1H)，2.05-1.93(m，2H)，1.77(d，J＝5.0Hz，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 7.81 (d, J = 7.8Hz, 2H), 7.63 (s, 1H), 7.42-7.34 (m, 3H), 7.24 ( t, J=2.7Hz, 1H), 6.63 (s, 1H), 6.47 (dd, J=3.0, 1.8Hz, 1H), 4.32-4.23 (m, 2H), 3.76-3.65 (m, 5H), 3.57 (d, J=11.9Hz, 1H), 3.26 (s, 3H), 3.17 (d, J=11.9Hz, 1H), 2.98 (d, J=5.7Hz, 1H), 2.55 (s, 2H), 2.41 (s, 3H), 2.15 (dt, J=12.3, 7.2Hz, 1H), 2.05-1.93 (m, 2H), 1.77 (d, J=5.0Hz, 2H).
化合物24B：HPLC：RT＝3.217min，LC-MS：RT＝1.63min，[M+H]+＝503.35Compound 24B: HPLC: RT=3.217min, LC-MS: RT=1.63min, [M+H] + =503.35
1H NMR(400MHz，DMSO-d6)δ10.81(t，J＝2.3Hz，1H)，7.83(d，J＝7.8Hz，2H)，7.47-7.38(m，3H)，7.27-7.20(m，2H)，6.64(s，1H)，6.47(dd，J＝3.1，1.9Hz，1H)，4.11(t，J＝5.4Hz，2H)，3.71(s，3H)，3.64-3.54(m，3H)，3.20(t，J＝5.6Hz，1H)，3.17(s，4H)，2.85-2.77(m，1H)，2.62-2.56(m，1H)2.41(s，3H)，2.07(t，J＝11.9Hz，1H)，1.88(d，J＝12.6Hz，1H)，1.82-1.70(m，1H)，1.59(q，J＝12.2Hz，1H)，1.42-1.28(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (t, J=2.3Hz, 1H), 7.83 (d, J=7.8Hz, 2H), 7.47-7.38 (m, 3H), 7.27-7.20 ( m, 2H), 6.64 (s, 1H), 6.47 (dd, J=3.1, 1.9Hz, 1H), 4.11 (t, J=5.4Hz, 2H), 3.71 (s, 3H), 3.64-3.54 (m , 3H), 3.20 (t, J=5.6Hz, 1H), 3.17 (s, 4H), 2.85-2.77 (m, 1H), 2.62-2.56 (m, 1H) 2.41 (s, 3H), 2.07 (t , J=11.9Hz, 1H), 1.88 (d, J=12.6Hz, 1H), 1.82-1.70 (m, 1H), 1.59 (q, J=12.2Hz, 1H), 1.42-1.28 (m, 1H) .
实施例25A和25BExamples 25A and 25B
合成化合物25A和25B
Synthesis of Compounds 25A and 25B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1( 2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1克，2.1毫摩尔)的1，4-二氧六环(10毫升)中，加入4-溴-1-甲基-1H-吡唑(514毫克，3.15毫摩尔)、[1，1′-双(二苯基膦)二茂铁]二氯化钯(154毫克，0.21毫摩尔)、磷酸钾(1.11克，5.25毫摩尔)和水(2毫升)，置换氮气，升温到90℃反应过夜。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl -2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.1 mmol) in 1,4-dioxane (10 ml) was added 4-bromo -1-Methyl-1H-pyrazole (514 mg, 3.15 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (154 mg, 0.21 mmol), phosphoric acid Potassium (1.11 g, 5.25 mmol) and water (2 ml) were replaced with nitrogen, and the temperature was raised to 90°C to react overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)得到560毫克淡黄色油状液体(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：62％)。LC-MS：RT＝2.04min，[M+H]+＝432.22。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 560 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl)- 4-(1-Methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 62%). LC-MS: RT=2.04min, [M+H] + =432.22.
步骤B：合成(S)-4-(1-甲基-1H-吡唑-4-基)哌啶-2-基苯甲酸甲酯Step B: Synthesis of (S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl benzoic acid methyl ester
室温下，将(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(560毫克，1.30毫摩尔)溶于乙酸乙酯(10毫升)中，加入钯碳(50毫克)，置换氢气，室温反应4小时。 At room temperature, (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1( 2H)-Benzyl carboxylate (560 mg, 1.30 mmol) was dissolved in ethyl acetate (10 ml), palladium on carbon (50 mg) was added, replaced with hydrogen, and the reaction was carried out at room temperature for 4 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到350毫克淡黄色油状液体(S)-4-(1-甲基-1H-吡唑-4-基)哌啶-2-基苯甲酸甲酯(收率：90％)。LC-MS：RT＝1.52min，[M+H]+＝300.23。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 350 mg of light yellow oily liquid (S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl benzoic acid methyl ester. (Yield: 90%). LC-MS: RT=1.52min, [M+H] + =300.23.
步骤C：合成5-环丙基-4-((2S)-2-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of 5-cyclopropyl-4-((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidine -1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(1-甲基-1H-吡唑-4-基)哌啶-2-基苯甲酸甲酯(200毫克，0.67毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(215毫克，1.01毫摩尔)和三乙酰氧基硼氢化钠(284毫克，1.34毫摩尔)，升温至40℃反应过夜。To 1,2-dichloroethane contained (S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-ylbenzoic acid methyl ester (200 mg, 0.67 mmol) (5 mL), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (215 mg, 1.01 mmol) and triacetoxyborohydride Sodium (284 mg, 1.34 mmol) was heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到95毫克淡黄色油状物5-环丙基-4-((2S)-2-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：24％)。LC-MS：RT＝1.91min，[M+H]+＝583.38。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 95 mg of light yellow oily substance 5-cyclopropyl-4- ((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl Tert-butyl-1H-indole-1-carboxylate (yield: 24%). LC-MS: RT=1.91min, [M+H] + =583.38.
步骤D：合成化合物25A和25BStep D: Synthesis of Compounds 25A and 25B
向5-环6基-4-((2S)-2-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(95毫克，0.16毫摩尔)的甲醇(5毫升)中，加入碳酸钾(88毫克，0.64毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To 5-cyclo6yl-4-((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidine-1- To methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (95 mg, 0.16 mmol) in methanol (5 ml), potassium carbonate (88 mg, 0.64 mmol) was added , heated to 70°C for 5 hours, added water (1 ml) and continued the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到12.3毫克绝对构型的非对映异构体25A(收率：16％)和30.9毫克绝对构型的非对映异构体25B(收率：41％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 12.3 mg of diastereomer 25A with absolute configuration (yield: 16%) and 30.9 mg of diastereoisomer 25A with absolute configuration. Enantiomer 25B (yield: 41%).
化合物25A：HPLC：RT＝3.285min，LC-MS：RT＝1.66min，[M+H]+＝469.30。Compound 25A: HPLC: RT=3.285 min, LC-MS: RT=1.66 min, [M+H] + =469.30.
化合物25B：HPLC：RT＝3.303min，LC-MS：RT＝1.66min，[M+H]+＝469.30。1H NMR(400MHz，DMSO-d6)δ10.83(s，1H)，7.82-7.75(m，2H)，7.45(s，1H)，7.35(d，J＝7.7Hz，2H)，7.23(s，1H)，7.22(d，J＝2.7Hz，1H)，6.55(dd，J＝3.1，1.7Hz，1H)，6.43(s，1H)，3.81(d，J＝12.0Hz，1H)，3.72(s，3H)，3.27(d，J＝11.9Hz，2H)，3.21(dd，J＝11.2，2.7Hz，1H)，2.79-2.72(m，1H)，2.65-2.55(m，1H)，2.35(s，3H)，2.25-2.17(m，1H)，2.15-2.05(m，1H)，1.88(d，J＝12.8Hz，1H)，1.72-1.62(m，1H)，1.37(dd，J＝12.6，3.4Hz，1H)，0.84-0.75(m，1H)，0.72-0.64(m，1H)，0.60-0.52(m，1H)，0.19-0.11(m，1H)。Compound 25B: HPLC: RT=3.303 min, LC-MS: RT=1.66 min, [M+H] + =469.30. 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 7.82-7.75 (m, 2H), 7.45 (s, 1H), 7.35 (d, J=7.7Hz, 2H), 7.23 (s , 1H), 7.22 (d, J=2.7Hz, 1H), 6.55 (dd, J=3.1, 1.7Hz, 1H), 6.43 (s, 1H), 3.81 (d, J=12.0Hz, 1H), 3.72 (s, 3H), 3.27 (d, J = 11.9Hz, 2H), 3.21 (dd, J = 11.2, 2.7Hz, 1H), 2.79-2.72 (m, 1H), 2.65-2.55 (m, 1H), 2.35(s, 3H), 2.25-2.17(m, 1H), 2.15-2.05(m, 1H), 1.88(d, J=12.8Hz, 1H), 1.72-1.62(m, 1H), 1.37(dd, J=12.6, 3.4Hz, 1H), 0.84-0.75 (m, 1H), 0.72-0.64 (m, 1H), 0.60-0.52 (m, 1H), 0.19-0.11 (m, 1H).
实施例26A和26BExamples 26A and 26B
合成化合物26A和26B
Synthesis of Compounds 26A and 26B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成4-溴-1-(氘代甲基)-1H-吡唑Step A: Synthesis of 4-bromo-1-(deuterated methyl)-1H-pyrazole
将化合物4-溴-1H-吡唑(1.0克，6.8毫摩尔)，氘代碘甲烷(1.1克，7.53毫摩尔)溶于N，N-二甲基甲酰胺(10毫升)中，降至0℃，加入氢化钠(324毫克，8.1毫摩尔)，升至室温反应12小时。Compound 4-bromo-1H-pyrazole (1.0 g, 6.8 mmol), deuterated methyl iodide (1.1 g, 7.53 mmol) were dissolved in N, N-dimethylformamide (10 ml) and reduced to At 0°C, add sodium hydride (324 mg, 8.1 mmol), raise to room temperature and react for 12 hours.
反应完成，加入冰水淬灭，乙酸乙酯(20毫升×3次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝10/1)。得到530毫克黄色油状4-溴-1-(氘代甲基)-1H-吡唑(收率48.1％)。LC-MS：RT＝1.66min，[M+H]+＝164.04。When the reaction is completed, add ice water to quench, extract with ethyl acetate (20 ml × 3 times), combine the organic phases, wash with saturated brine (20 ml), dry over anhydrous sodium sulfate, filter and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1). 530 mg of 4-bromo-1-(deuterated methyl)-1H-pyrazole were obtained as a yellow oil (yield 48.1%). LC-MS: RT=1.66min, [M+H] + =164.04.
步骤B：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-(氘代甲基)-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step B: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(deuteratedmethyl)-1H-pyrazol-4-yl)-3,6-di Hydropyridine-1(2H)-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(900毫克，1.89毫摩尔)，4-溴-1-(氘代甲基)-1H-吡唑(463毫克，2.8毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(276毫克，0.38毫摩尔)，磷酸钾(820毫克，3.8毫摩尔)加入1，4-二氧六环(20毫升)和水(4毫升)，氮气保护下，升温至95℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Benzyl)-3,6-dihydropyridine-1(2H)-carboxylate (900 mg, 1.89 mmol), 4-bromo-1-(deuterated methyl)-1H-pyrazole (463 mg , 2.8 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (276 mg, 0.38 mmol), potassium phosphate (820 mg, 3.8 mmol) were added to 1,4 - Dioxane (20 ml) and water (4 ml) were heated to 95°C for 12 hours under nitrogen protection.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到400毫克黄色油状(S)-6-(4-(甲氧基羰基)苯基)-4-(1-(氘代甲基)-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率48.7％)。LC-MS：RT＝2.04min，[M+H]+＝435.28。 After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). 400 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(deuteratedmethyl)-1H-pyrazol-4-yl)-3,6- were obtained as a yellow oil Dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield 48.7%). LC-MS: RT=2.04min, [M+H] + =435.28.
步骤C：合成(S)-4-(4-(1-(氘代甲基)-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step C: Synthesis of (S)-4-(4-(1-(deuterated methyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(1-(氘代甲基)-1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(400毫克，0.92毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯/碳(400毫克)，氢气氛围下室温反应过夜。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(deuteratedmethyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine -1(2H)-Benzylcarboxylate (400 mg, 0.92 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (400 mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere overnight.
反应完成，过滤，浓缩。得到250毫克浅黄色油状物(S)-4-(4-(1-(氘代甲基)-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝1.54min，[M+H]+＝303.24。The reaction is completed, filtered and concentrated. Obtained 250 mg of light yellow oily substance (S)-4-(4-(1-(deuterated methyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (crude product), No purification is required and it can be used directly in the next reaction. LC-MS: RT=1.54min, [M+H] + =303.24.
步骤D：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-(氘代甲基)-1H-吡唑-4-基)哌啶-1-基))甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(deuteratedmethyl)-1H-pyrazole- 4-yl)piperidin-1-yl))methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物(S)-4-(4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(250毫克，0.82毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(578毫克，2.0毫摩尔)溶于1，2-二氯乙烷(5毫升)，室温搅拌1小时，加入三乙酰氧基硼氢化钠(343.3毫克，1.64毫摩尔)，升温至40℃继续反应过夜。Compound (S)-4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (250 mg, 0.82 mg mol) and 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (578 mg, 2.0 mmol) were dissolved in 1,2-dichloroethane ( 5 ml), stir at room temperature for 1 hour, add sodium triacetoxyborohydride (343.3 mg, 1.64 mmol), raise the temperature to 40°C and continue the reaction overnight.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)。得到280毫克棕色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-(氘代甲基)-1H-吡唑-4-基)哌啶-1-基))甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率59.3％)。LC-MS：RT＝1.88min，[M+H]+＝576.42。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2). Obtained 280 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(deuteratedmethyl)-1H-pyrazole) -4-yl)piperidin-1-yl))methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 59.3%). LC-MS: RT=1.88min, [M+H] + =576.42.
步骤E：合成化合物26A和26BStep E: Synthesis of Compounds 26A and 26B
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)哌啶-1-基))甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(280毫克，0.48毫摩尔)溶于甲醇(12毫升)，加入碳酸钾(268.7毫克，1.9毫摩尔)，加热至70℃反应过夜，加入水(2毫升)继续反应2小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazole) -4-yl)piperidin-1-yl))methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (280 mg, 0.48 mmol) was dissolved in methanol (12 ml), Add potassium carbonate (268.7 mg, 1.9 mmol), heat to 70°C and react overnight, add water (2 ml) and continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到25毫克绝对构型的非对映异构体26A(收率：11.3％)和160毫克绝对构型的非对映异构体26B(收率：72.3％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 25 mg of diastereomer 26A with absolute configuration (yield: 11.3%) and 160 mg of diastereoisomer 26A with absolute configuration. Enantiomer 26B (yield: 72.3%).
化合物26A：HPLC：RT＝3.160min，LC-MS：RT＝1.61min，[M+H]+＝462.30。Compound 26A: HPLC: RT=3.160 min, LC-MS: RT=1.61 min, [M+H] + =462.30.
1H NMR(400MHz，DMSO-d6)δ10.79(s，1H)，7.80(d，J＝7.9Hz，2H)，7.60(s，1H)，7.38(d，J＝7.7Hz，2H)，7.32(s，1H)，7.23(t，J＝2.7Hz，1H)，6.62(s，1H)，6.50-6.44(m，1H)，3.67(s，3H)，3.56(d，J＝11.9Hz，1H)，3.16(d，J＝11.9Hz，1H)，3.00-2.94(m，1H)，2.55(s，2H)，2.40(s，3H)，2.13(dt，J＝12.0，7.2Hz，1H)，1.98(td，J＝13.9，12.1，6.8Hz，2H)，1.75(p，J＝3.9Hz，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 7.80 (d, J = 7.9Hz, 2H), 7.60 (s, 1H), 7.38 (d, J = 7.7Hz, 2H) , 7.32 (s, 1H), 7.23 (t, J=2.7Hz, 1H), 6.62 (s, 1H), 6.50-6.44 (m, 1H), 3.67 (s, 3H), 3.56 (d, J=11.9 Hz, 1H), 3.16 (d, J=11.9Hz, 1H), 3.00-2.94 (m, 1H), 2.55 (s, 2H), 2.40 (s, 3H), 2.13 (dt, J=12.0, 7.2Hz , 1H), 1.98 (td, J=13.9, 12.1, 6.8Hz, 2H), 1.75 (p, J=3.9Hz, 2H).
化合物26B：HPLC：RT＝3.190min，LC-MS：RT＝1.61min，[M+H]+＝462.30。Compound 26B: HPLC: RT=3.190 min, LC-MS: RT=1.61 min, [M+H] + =462.30.
1H NMR(400MHz，DMSO-d6)δ10.83(t，J＝2.3Hz，1H)，7.82(d，J＝7.8Hz，2H)，7.45-7.36(m，3H)，7.26-7.20(m，2H)，6.64(s，1H)，6.46(dd，J＝3.1，1.9Hz，1H)，3.71(s，3H)，3.58(d，J＝11.8Hz，1H)，3.18(dd，J＝11.4，2.9Hz，2H)，2.81(dt，J＝11.6，3.3Hz，1H)，2.65-2.52(m，1H)，2.41(s，3H)，2.07(dd，J＝13.2，10.7Hz，1H)，1.88(d，J＝12.7Hz，1H)，1.73(dd，J＝14.2，4.5Hz，1H)，1.60(q，J＝12.2Hz，1H)，1.42-1.29(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.83 (t, J=2.3Hz, 1H), 7.82 (d, J=7.8Hz, 2H), 7.45-7.36 (m, 3H), 7.26-7.20 ( m, 2H), 6.64 (s, 1H), 6.46 (dd, J=3.1, 1.9Hz, 1H), 3.71 (s, 3H), 3.58 (d, J=11.8Hz, 1H), 3.18 (dd, J =11.4, 2.9Hz, 2H), 2.81 (dt, J = 11.6, 3.3Hz, 1H), 2.65-2.52 (m, 1H), 2.41 (s, 3H), 2.07 (dd, J = 13.2, 10.7Hz, 1H), 1.88 (d, J=12.7Hz, 1H), 1.73 (dd, J=14.2, 4.5Hz, 1H), 1.60 (q, J=12.2Hz, 1H), 1.42-1.29 (m, 1H).
实施例27A和27BExamples 27A and 27B
合成化合物27A和27B
Synthesis of Compounds 27A and 27B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-4-(1，3-二甲基-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro Pyridine-1(2H)-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.0克，2.1毫摩尔)，4-溴-1，3-二甲基-1H-吡唑(550毫克，3.1毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(307毫克，0.4毫摩尔)，磷酸钾(912毫克，4.2毫摩尔)加入1，4-二氧六环(30毫升)和水(6毫升)，氮气保护下升温至95℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Benzyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 2.1 mmol), 4-bromo-1,3-dimethyl-1H-pyrazole (550 mg, 3.1 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (307 mg, 0.4 mmol), potassium phosphate (912 mg, 4.2 mmol) were added to 1,4- Dioxane (30 ml) and water (6 ml) were heated to 95°C under nitrogen protection for 12 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到400毫克黄色油状(S)-4-(1，3-二甲基-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率42.8％)。LC-MS：RT＝2.05min，[M+H]+＝446.27。 After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 400 mg of (S)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-di as a yellow oil Hydropyridine-1(2H)-carboxylic acid benzyl ester (yield 42.8%). LC-MS: RT=2.05min, [M+H] + =446.27.
步骤B：合成(S)-4-(4-(1，3-二甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
将化合物(S)-4-(1，3-二甲基-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(400毫克，0.9毫摩尔)溶于乙酸乙酯(20毫升)，加入钯/碳(400毫克)，氢气氛围下室温反应过夜。Compound (S)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine- 1(2H)-Benzylcarboxylate (400 mg, 0.9 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (400 mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere overnight.
反应完成，过滤，浓缩。得到270毫克浅黄色油状物(S)-4-(4-(1，3-二甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝1.54min，[M+H]+＝314.24。The reaction is completed, filtered and concentrated. 270 mg of light yellow oily substance (S)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (crude product) was obtained. It needs to be purified and used directly in the next reaction. LC-MS: RT=1.54min, [M+H] + =314.24.
步骤C：合成(S)-4-((4-(1，3-二甲基-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-4-((4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine- 1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物(S)-4-(4-(1，3-二甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(270毫克，0.86毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(500毫克，1.72毫摩尔)溶于1，2-二氯乙烷(5毫升)，室温搅拌1小时，加入三乙酰氧基硼氢化钠(546.8毫克，2.58毫摩尔)，升温至40℃反应过夜。Compound (S)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (270 mg, 0.86 mmol) and 4 -Formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (500 mg, 1.72 mmol) was dissolved in 1,2-dichloroethane (5 ml), Stir at room temperature for 1 hour, add sodium triacetoxyborohydride (546.8 mg, 2.58 mmol), raise the temperature to 40°C and react overnight.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到290毫克棕色固体(S)-4-((4-(1，3-二甲基-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率57.5％)。LC-MS：RT＝1.89min，[M+H]+＝587.41。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 290 mg of brown solid (S)-4-((4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine -1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 57.5%). LC-MS: RT=1.89min, [M+H] + =587.41.
步骤D：合成化合物27A和27BStep D: Synthesis of Compounds 27A and 27B
将化合物(S)-4-((4-(1，3-二甲基-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(290毫克，0.5毫摩尔)溶于甲醇(10毫升)，加入碳酸钾(276毫克，2.0毫摩尔)，加热至70℃反应过夜，加入水(2毫升)继续反应2小时。Compound (S)-4-((4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1- Methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (290 mg, 0.5 mmol) was dissolved in methanol (10 ml), and potassium carbonate (276 mg, 2.0 mmol), heated to 70°C for overnight reaction, and water (2 ml) was added to continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到20毫克绝对构型的非对映异构体27A(收率：8.4％)和100毫克绝对构型的非对映异构体27B(收率：42.3％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 20 mg of diastereomer 27A with absolute configuration (yield: 8.4%) and 100 mg of diastereoisomer 27A with absolute configuration. Enantiomer 27B (yield: 42.3%).
化合物27A：HPLC：RT＝13.1min，LC-MS：RT＝1.63min，[M+H]+＝473.30。Compound 27A: HPLC: RT=13.1 min, LC-MS: RT=1.63 min, [M+H] + =473.30.
1H NMR(400MHz，DMSO-d6)δ10.80(s，1H)，7.79(d，J＝7.9Hz，2H)，7.66(s，1H)，7.41(d，J＝7.8Hz，2H)，7.24(t，J＝2.7Hz，1H)，6.63(s，1H)，6.51(dd，J＝3.0，1.8Hz，1H)，3.78(s，3H)，3.69(s，3H)，3.66(d，J＝11.9Hz，1H)，3.53(dd，J＝10.1，3.1Hz，1H)，2.89(d，J＝4.8Hz，1H)，2.61-2.53(m，2H)，2.41(s，3H)，2.21(t，J＝10.9Hz，1H)，2.02(s，4H)，1.85(d，J＝13.5Hz，1H)，1.70(s，1H)，1.60(d，J＝13.1Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 7.79 (d, J = 7.9Hz, 2H), 7.66 (s, 1H), 7.41 (d, J = 7.8Hz, 2H) , 7.24 (t, J=2.7Hz, 1H), 6.63 (s, 1H), 6.51 (dd, J=3.0, 1.8Hz, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.66 ( d, J=11.9Hz, 1H), 3.53 (dd, J=10.1, 3.1Hz, 1H), 2.89 (d, J=4.8Hz, 1H), 2.61-2.53 (m, 2H), 2.41 (s, 3H ), 2.21 (t, J=10.9Hz, 1H), 2.02 (s, 4H), 1.85 (d, J=13.5Hz, 1H), 1.70 (s, 1H), 1.60 (d, J=13.1Hz, 1H ).
化合物27B：HPLC：RT＝13.58min，LC-MS：RT＝1.63min，[M+H]+＝473.30。Compound 27B: HPLC: RT=13.58 min, LC-MS: RT=1.63 min, [M+H] + =473.30.
1H NMR(400MHz，DMSO-d6)δ10.82(t，J＝2.3Hz，1H)，7.84(d，J＝7.9Hz，2H)，7.44(d，J＝7.7Hz，2H)，7.31(s，1H)，7.24(t，J＝2.8Hz，1H)，6.64(s，1H)，6.46(dd，J＝3.1，1.9Hz，1H)，3.71(s，3H)，3.62(s，4H)，3.25-3.15(m，3H)，2.85-2.77(m，1H)，2.41(s，3H)，2.14-2.07(m，1H)，2.05(s，3H)，1.82-1.73(m，1H)，1.64(dd，J＝12.0，6.2Hz，1H)，1.57(d，J＝12.2Hz，1H)，1.39-1.25(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.82 (t, J = 2.3Hz, 1H), 7.84 (d, J = 7.9Hz, 2H), 7.44 (d, J = 7.7Hz, 2H), 7.31 (s, 1H), 7.24 (t, J=2.8Hz, 1H), 6.64 (s, 1H), 6.46 (dd, J=3.1, 1.9Hz, 1H), 3.71 (s, 3H), 3.62 (s, 4H), 3.25-3.15(m, 3H), 2.85-2.77(m, 1H), 2.41(s, 3H), 2.14-2.07(m, 1H), 2.05(s, 3H), 1.82-1.73(m, 1H), 1.64 (dd, J=12.0, 6.2Hz, 1H), 1.57 (d, J=12.2Hz, 1H), 1.39-1.25 (m, 1H).
实施例28A和28BExamples 28A and 28B
合成化合物28A和28B
Synthesis of Compounds 28A and 28B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-4-(1，5-二甲基-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro Pyridine-1(2H)-carboxylic acid benzyl ester
将含有(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.0克，2.09毫摩尔)、4-溴-1，5-二甲基-1H-吡唑(550.0豪克，3.14毫摩尔)、[1，1′-双(三苯基膦基)二茂铁]二氯化钯(154.0毫克，0.21毫摩尔)和磷酸钾(890.0毫克，4.19毫摩尔)的1，4-二氧六环与水的混合溶液(35毫升，1，4-二氧六环∶水＝6∶1)中，在氮气保护下，加热至90℃反应12小时。Will contain (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.0 g, 2.09 mmol), 4-bromo-1,5-dimethyl-1H-pyrazole (550.0 mg , 3.14 mmol), [1,1′-bis(triphenylphosphino)ferrocene]palladium dichloride (154.0 mg, 0.21 mmol) and potassium phosphate (890.0 mg, 4.19 mmol) In a mixed solution of 4-dioxane and water (35 ml, 1,4-dioxane:water = 6:1), under nitrogen protection, heat to 90°C for 12 hours.
反应结束，加入水，用乙酸乙酯(20毫升×4次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)，得到500毫克黄色胶状(S)-4-(1，5-二甲基-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：54％)。LC-MS：RT＝2.05min，[M+H]+＝446.23。 After the reaction was completed, water was added, extracted with ethyl acetate (20 ml x 4 times), the organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 500 mg of (S)-4-(1,5-dimethyl-1H-pyridine) as a yellow gum. Azol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 54%). LC-MS: RT=2.05min, [M+H] + =446.23.
步骤B：合成(S)-4-(4-(1，5-二甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
室温下，向含有(S)-4-(1，5-二甲基-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(500毫克，1.12毫摩尔)的乙酸乙酯((20毫升)中，加入钯碳(150毫克)，置换氢气三次，氢气保护下，室温反应8小时。To a compound containing (S)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-di Hydropyridine-1(2H)-carboxylic acid benzyl ester (500 mg, 1.12 mmol) in ethyl acetate ((20 ml), add palladium carbon (150 mg), replace hydrogen three times, under hydrogen protection, react at room temperature 8 Hour.
反应结束，抽滤，滤液旋干，得到350毫克黄棕色油状(S)-4-(4-(1，5-二甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(收率：100％)。LC-MS：RT＝1.55min，[M+H]+＝314.25。At the end of the reaction, filter with suction and spin the filtrate to dryness to obtain 350 mg of yellow-brown oily (S)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl) Methyl benzoate (yield: 100%). LC-MS: RT=1.55min, [M+H] + =314.25.
步骤D：合成(S)-4-((4-(1，5-二甲基-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-4-((4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine- 1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将(S)-4-(4-(1，5-二甲基-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(350.0毫克，1.12毫摩尔)，4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(650.0毫克，2.24毫摩尔)溶于1，2-二氯乙烷(15毫升)中，室温反应过夜，加入三乙酰氧基硼氢化钠(710毫克，3.35毫摩尔)反应5小时。(S)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (350.0 mg, 1.12 mmol), 4- Formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (650.0 mg, 2.24 mmol) was dissolved in 1,2-dichloroethane (15 ml). React at room temperature overnight, add sodium triacetoxyborohydride (710 mg, 3.35 mmol) and react for 5 hours.
反应结束，加入甲醇，旋干拌样，硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)，得到390.0毫克黄色胶状(S)-4-((4-(1，5-二甲基-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：59％)。LC-MS：RT＝1.88min，[M+H]+＝587.42。After the reaction was completed, methanol was added, the mixture was spin-dried, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2) to obtain 390.0 mg of yellow gummy (S)-4-((4-( 1,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 59%). LC-MS: RT=1.88min, [M+H] + =587.42.
步骤E：合成化合物28A和28BStep E: Synthesis of Compounds 28A and 28B
室温下，向含有(S)-4-((4-(1，5-二甲基-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(390毫克，0.665毫摩尔)的甲醇(15.0毫升)中，加入碳酸钾(919毫克，6.65毫摩尔)，升温至70℃反应过夜，加入水(5.0毫升)继续反应2小时。At room temperature, the solution containing (S)-4-((4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine To -1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (390 mg, 0.665 mmol) in methanol (15.0 ml), add carbonic acid Potassium (919 mg, 6.65 mmol) was heated to 70°C to react overnight, and water (5.0 ml) was added to continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到31毫克绝对构型的非对映异构体28A(收率：9.8％)和135.8毫克绝对构型的非对映异构体28B(收率：43.2％)。The reaction was completed, and 31 mg of diastereoisomer 28A with absolute configuration and 135.8 mg of diastereoisomer 28A with absolute configuration were isolated using the purification treatment and chiral resolution method in step D of Example 3 (yield: 9.8%). Enantiomer 28B (yield: 43.2%).
化合物28A：HPLC：RT＝12.2min，LC-MS：RT＝1.63min，[M+H]+＝473.29。1H NMR(400MHz，DMSO-d6)δ10.81(s，1H)，7.79(d，J＝8.0Hz，2H)，7.45(s，1H)，7.40(d，J＝8.0Hz，2H)，7.27-7.23(m，1H)，6.65(s，1H)，6.51-6.47(m，1H)，3.75-3.64(m，7H)，3.59-3.53(m，1H)，3.39-3.34(m，1H)，2.92-2.85(m，1H)，2.65-2.57(m，1H)，2.42(s，3H)，2.35-2.25(m，1H)，2.12(s，3H)，2.07-1.97(m，1H)，1.93-1.85(m，1H)，1.75-1.59(m，2H).Compound 28A: HPLC: RT=12.2 min, LC-MS: RT=1.63 min, [M+H] + =473.29. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 7.79 (d, J = 8.0Hz, 2H), 7.45 (s, 1H), 7.40 (d, J = 8.0Hz, 2H) , 7.27-7.23(m, 1H), 6.65(s, 1H), 6.51-6.47(m, 1H), 3.75-3.64(m, 7H), 3.59-3.53(m, 1H), 3.39-3.34(m, 1H), 2.92-2.85(m, 1H), 2.65-2.57(m, 1H), 2.42(s, 3H), 2.35-2.25(m, 1H), 2.12(s, 3H), 2.07-1.97(m, 1H), 1.93-1.85(m, 1H), 1.75-1.59(m, 2H).
化合物28B：HPLC：RT＝14.5min，LC-MS：RT＝1.63min，[M+H]+＝473.29。1H NMR(400MHz，DMSO-d6)δ10.83(s，1H)，7.90(d，J＝8.0Hz，2H)，7.54(d，J＝8.0Hz，2H)，7.27-7.23(m，1H)，7.13(s，1H)，6.65(s，1H)，6.48-6.45(m，1H)，3.72(s，3H)，3.64(s，3H)，3.62-3.56(m，1H)，3.30-3.24(m，1H)，3.23-3.17(m，1H)，2.87-2.79(m，1H)，2.59-2.53(m，1H)，2.42(s，3H)，2.15(s，3H)，2.13-2.07(m，1H)，1.77-1.55(m，3H)，1.48-1.36(m，1H).Compound 28B: HPLC: RT=14.5min, LC-MS: RT=1.63min, [M+H] + =473.29. 1 H NMR (400MHz, DMSO-d 6 ) δ10.83 (s, 1H), 7.90 (d, J=8.0Hz, 2H), 7.54 (d, J=8.0Hz, 2H), 7.27-7.23 (m, 1H), 7.13(s, 1H), 6.65(s, 1H), 6.48-6.45(m, 1H), 3.72(s, 3H), 3.64(s, 3H), 3.62-3.56(m, 1H), 3.30 -3.24(m, 1H), 3.23-3.17(m, 1H), 2.87-2.79(m, 1H), 2.59-2.53(m, 1H), 2.42(s, 3H), 2.15(s, 3H), 2.13 -2.07(m, 1H), 1.77-1.55(m, 3H), 1.48-1.36(m, 1H).
实施例29A和29BExamples 29A and 29B
合成化合物29A和29B
Synthesis of Compounds 29A and 29B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成4-溴-1-(2-氟乙基)-1H-吡唑Step A: Synthesis of 4-bromo-1-(2-fluoroethyl)-1H-pyrazole
室温下，向含有4-溴-1H-吡唑(2.0克，13.61毫摩尔)的N，N-二甲基甲酰胺(30毫升)中，加入4-甲基苯磺酸2-氟乙酯(4.5克，20.41毫摩尔)，碳酸铯(6.7克，20.41毫摩尔)，氮气保护下，加热至100℃反应过夜。To 4-bromo-1H-pyrazole (2.0 g, 13.61 mmol) in N,N-dimethylformamide (30 mL) was added 2-fluoroethyl 4-methylbenzenesulfonate at room temperature. (4.5 g, 20.41 mmol), cesium carbonate (6.7 g, 20.41 mmol), under nitrogen protection, heated to 100°C for overnight reaction.
反应结束，加入水，用乙酸乙酯(20毫升×4次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)，得到1.3克无色油状4-溴-1-(2-氟乙基)-1H-吡唑(收率：49％)。LC-MS：RT＝1.74min，[M+H]+＝193.04。After the reaction was completed, water was added, extracted with ethyl acetate (20 ml x 4 times), the organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 3/1) to obtain 1.3 g of 4-bromo-1-(2-fluoroethyl)-1H-pyrazole as a colorless oil. (Yield: 49%). LC-MS: RT=1.74min, [M+H] + =193.04.
步骤B：合成(S)-4-(1-(2-氟乙基)-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step B: Synthesis of (S)-4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6- Dihydropyridine-1(2H)-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄 酯(1.0克，2.09毫摩尔)，4-溴-1-(2-氟乙基)-1H-吡唑(605毫克，3.13毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(154毫克，0.21毫摩尔)，磷酸钾(890毫克，4.18毫摩尔)加入1，4-二氧六环(30毫升)中，加入水(6毫升)，氮气保护下升温至90℃反应过夜。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl Ester (1.0 g, 2.09 mmol), 4-bromo-1-(2-fluoroethyl)-1H-pyrazole (605 mg, 3.13 mmol), [1,1′-bis(diphenylphosphine) Ferrocene] palladium dichloride (154 mg, 0.21 mmol), potassium phosphate (890 mg, 4.18 mmol) were added to 1,4-dioxane (30 ml), water (6 ml), nitrogen The temperature was raised to 90°C for overnight reaction under protection.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)得到670毫克淡黄色胶状液体(S)-4-(1-(2-氟乙基)-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：69％)。LC-MS：RT＝2.05min，[M+H]+＝464.30。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/2) to obtain 670 mg of light yellow colloidal liquid (S)-4-(1-(2-fluoroethyl)- 1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 69%). LC-MS: RT=2.05min, [M+H] + =464.30.
步骤C：合成(S)-4-(4-(1-(2-氟乙基)-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step C: Synthesis of (S)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
将(S)-4-(1-(2-氟乙基)-1H-吡唑-4-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(670毫克，1.45毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯碳(300毫克)，置换氢气，室温反应4小时。(S)-4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine -1(2H)-Benzylcarboxylate (670 mg, 1.45 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (300 mg) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 4 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到450毫克淡黄色油状液体(S)-4-(4-(1-(2-氟乙基)-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(收率：93％)。LC-MS：RT＝1.54min，[M+H]+＝332.24。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 450 mg of light yellow oily liquid (S)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)piperidine -2-yl)benzoic acid methyl ester (yield: 93%). LC-MS: RT=1.54min, [M+H] + =332.24.
步骤D：合成(S)-4-((4-(1-(2-氟乙基)-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-4-((4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piper ((ridin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，将(S)-4-(4-(1-(2-氟乙基)-1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(450毫克，1.36毫摩尔)溶解于1，2-二氯乙烷(20毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(784毫克，2.72毫摩尔)反应过夜，加入三乙酰氧基硼氢化钠(863毫克，4.07毫摩尔)反应5小时。(S)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (450 mg, 1.36 mg) at room temperature. mol) was dissolved in 1,2-dichloroethane (20 ml), and 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (784 mg , 2.72 mmol) reacted overnight, then added sodium triacetoxyborohydride (863 mg, 4.07 mmol) and reacted for 5 hours.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到550毫克浅黄色胶状(S)-4-((4-(1-(2-氟乙基)-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：67％)。LC-MS：RT＝1.84min，[M+H]+＝605.40。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 550 mg of light yellow gummy (S)-4-((( 4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 67%). LC-MS: RT=1.84min, [M+H] + =605.40.
步骤E：合成化合物29A和29BStep E: Synthesis of Compounds 29A and 29B
向(S)-4-((4-(1-(2-氟乙基)-1H-吡唑-4-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(550毫克，0.91毫摩尔)的甲醇(20毫升)中，加入碳酸钾(1.26克，9.1毫摩尔)，加热至70℃反应过夜，加水(5毫升)继续反应3小时。To (S)-4-((4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1 -(methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (550 mg, 0.91 mmol) in methanol (20 ml), add potassium carbonate ( 1.26 g, 9.1 mmol), heated to 70°C and reacted overnight, added water (5 ml) and continued the reaction for 3 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到46.3毫克绝对构型的非对映异构体29A(收率：10.3％)和257.3毫克绝对构型的非对映异构体29B(收率：57.6％)。The reaction was completed, and the purification treatment and chiral resolution method in step D of Example 3 were used to separate and obtain 46.3 mg of diastereomer 29A with absolute configuration (yield: 10.3%) and 257.3 mg of diastereoisomer 29A with absolute configuration. Enantiomer 29B (yield: 57.6%).
化合物29A：HPLC：RT＝12.2min，LC-MS：RT＝1.61min，[M+H]+＝491.42。1H NMR(400MHz，DMSO-d6)δ10.81(s，1H)，7.81(d，J＝8.0Hz，2H)，7.69(s，1H)，7.44-7.34(m，3H)，7.26-7.20(m，1H)，6.63(s，1H)，6.50-6.46(m，1H)，4.88-4.82(m，1H)，4.76-4.70(m，1H)，4.50-4.45(m，1H)，4.43-4.38(m，1H)，3.68(s，3H)，3.61-3.54(m，1H)，3.40-3.38(m，1H)，3.21-3.13(m，1H)，3.03-2.95(m，1H)，2.59-2.53(m，1H)，2.41(s，3H)，2.21-2.10(m，1H)，2.08-1.95(m，2H)，1.83-1.72(m，2H).Compound 29A: HPLC: RT=12.2 min, LC-MS: RT=1.61 min, [M+H] + =491.42. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 7.81 (d, J=8.0Hz, 2H), 7.69 (s, 1H), 7.44-7.34 (m, 3H), 7.26- 7.20 (m, 1H), 6.63 (s, 1H), 6.50-6.46 (m, 1H), 4.88-4.82 (m, 1H), 4.76-4.70 (m, 1H), 4.50-4.45 (m, 1H), 4.43-4.38(m, 1H), 3.68(s, 3H), 3.61-3.54(m, 1H), 3.40-3.38(m, 1H), 3.21-3.13(m, 1H), 3.03-2.95(m, 1H ), 2.59-2.53(m, 1H), 2.41(s, 3H), 2.21-2.10(m, 1H), 2.08-1.95(m, 2H), 1.83-1.72(m, 2H).
化合物29B：HPLC：RT＝14.6min，LC-MS：RT＝1.61min，[M+H]+＝491.42。1H NMR(400MHz，DMSO-d6)δ10.84(s，1H)，7.89(d，J＝8.0Hz，2H)，7.58-7.44(m，3H)，7.32(s，1H)，7.27-7.22(m，1H)，6.66(s，1H)，6.51-6.44(m，1H)，4.78-4.72(m，1H)，4.67-4.60(m，1H)，4.36-4.31(m，1H)，4.29-4.23(m，1H)，3.72(s，3H)，3.62-3.57(m，1H)，3.28-3.16(m，2H)，2.87-2.80(m，1H)，2.68-2.57(m，1H)，2.42(s，3H)，2.14-2.03(m，1H)，1.97-1.87(m，1H)，1.81-1.72(m，1H)，1.67-1.55(m，1H)，1.45-1.31(m，1H).Compound 29B: HPLC: RT=14.6 min, LC-MS: RT=1.61 min, [M+H] + =491.42. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 7.89 (d, J=8.0Hz, 2H), 7.58-7.44 (m, 3H), 7.32 (s, 1H), 7.27- 7.22(m, 1H), 6.66(s, 1H), 6.51-6.44(m, 1H), 4.78-4.72(m, 1H), 4.67-4.60(m, 1H), 4.36-4.31(m, 1H), 4.29-4.23(m, 1H), 3.72(s, 3H), 3.62-3.57(m, 1H), 3.28-3.16(m, 2H), 2.87-2.80(m, 1H), 2.68-2.57(m, 1H ), 2.42(s, 3H), 2.14-2.03(m, 1H), 1.97-1.87(m, 1H), 1.81-1.72(m, 1H), 1.67-1.55(m, 1H), 1.45-1.31(m ,1H).
实施例30A和30BExamples 30A and 30B
合成化合物30A和30B
Synthetic Compounds 30A and 30B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.5克，3.14毫摩尔)的1，4-二氧六环(25毫升)中，加入4-溴-1H-吡唑-1-羧酸叔丁酯(1.16克，4.71毫摩尔)、 [1，1′-双(二苯基膦)二茂铁]二氯化钯(460毫克，0.63毫摩尔)、磷酸钾(1.37克、6.28毫摩尔)和水(4毫升)，置换氮气，升温到95℃反应过夜。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.5 g, 3.14 mmol) in 1,4-dioxane (25 ml) was added 4-bromo- 1H-pyrazole-1-carboxylic acid tert-butyl ester (1.16 g, 4.71 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (460 mg, 0.63 mmol), potassium phosphate (1.37 g, 6.28 mmol) and water (4 ml), replaced with nitrogen, The temperature was raised to 95°C and the reaction was carried out overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶5)得到800毫克淡黄色油状液体(S)-6-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：61％)。LC-MS：RT＝1.98min，[M+H]+＝418.23。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:5) to obtain 800 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl) -4-(1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 61%). LC-MS: RT=1.98min, [M+H] + =418.23.
步骤B：合成(S)-4-(4-(1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1H-pyrazol-4-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800毫克，1.92毫摩尔)溶于乙酸乙酯-(20毫升)中，加入钯碳(300毫克)，置换氢气，室温反应3小时。(S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate benzyl ester (800 mg, 1.92 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (300 mg) was added, replaced with hydrogen, and reacted at room temperature for 3 hours.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到550毫克无色油状液体(S)-4-(4-(1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯。LC-MS：RT＝1.61min，[M+H]+＝286.23。After the reaction was completed, it was filtered, washed with ethyl acetate, and concentrated to obtain 550 mg of colorless oily liquid (S)-4-(4-(1H-pyrazol-4-yl)piperidin-2-yl)benzoic acid methyl ester. LC-MS: RT=1.61min, [M+H] + =286.23.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)piperidine-1- (methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(1H-吡唑-4-基)哌啶-2-基)苯甲酸甲酯(400毫克，0.96毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(416毫克，1.44毫摩尔)和三乙酰氧基硼氢化钠(815毫克，3.84毫摩尔)，升温至40℃反应过夜。To a solution containing (S)-4-(4-(1H-pyrazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (400 mg, 0.96 mmol) in 1,2-dichloroethane ( 5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (416 mg, 1.44 mmol) and sodium triacetoxyborohydride (815 mg, 3.84 mmol), heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶1)得到400毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：75％)。LC-MS：RT＝1.85min，[M+H]+＝559.34After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 400 mg of white solid (S)-5-methoxy- 4-((2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indino Indole-1-carboxylic acid tert-butyl ester (yield: 75%). LC-MS: RT=1.85min, [M+H] + =559.34
步骤D：化合物30A和30BStep D: Compounds 30A and 30B
向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1H-吡唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(200毫克，0.36毫摩尔)的甲醇(10毫升)中，加入碳酸钾(200毫克，1.43毫摩尔)，加热至70℃反应5小时，加水(2毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)piperidin-1-yl)methyl (200 mg, 0.36 mmol) in methanol (10 ml), add potassium carbonate (200 mg, 1.43 mmol), and heat to React at 70°C for 5 hours, add water (2 ml) and continue the reaction for 4 hours.
反应结束，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到5毫克绝对构型的非对映异构体30A(收率：3％)和80毫克绝对构型的非对映异构体30B(收率：50％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 5 mg of diastereoisomer 30A with absolute configuration (yield: 3%) and 80 mg of diastereoisomer 30A with absolute configuration. Enantiomer 30B (yield: 50%).
化合物30A：HPLC：RT＝10.1min，LC-MS：RT＝1.63min，[M+H]+＝445.27。Compound 30A: HPLC: RT=10.1 min, LC-MS: RT=1.63 min, [M+H] + =445.27.
化合物30B：HPLC：RT＝15.6min，LC-MS：RT＝1.63min，[M+H]+＝445.27。1H NMR(400MHz，DMSO-d6)δ10.80(t，J＝2.3Hz，1H)，7.83(d，J＝7.8Hz，2H)，7.40(d，J＝8.5Hz，4H)，7.24(t，J＝2.7Hz，1H)，6.65(s，1H)，6.48(dd，J＝3.2，1.7Hz，1H)，3.72(s，3H)，3.60(d，J＝11.9Hz，1H)，3.20(dd，J＝11.5，3.2Hz，2H)，2.88-2.78(m，1H)，2.64(td，J＝12.1，6.2Hz，1H)，2.42(s，3H)，2.09(dd，J＝13.2，10.7Hz，1H)，1.91(d，J＝12.8Hz，1H)，1.75(d，J＝12.8Hz，1H)，1.63(q，J＝12.1Hz，1H)，1.45-1.33(m，1H).Compound 30B: HPLC: RT=15.6min, LC-MS: RT=1.63min, [M+H] + =445.27. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.80 (t, J=2.3Hz, 1H), 7.83 (d, J=7.8Hz, 2H), 7.40 (d, J=8.5Hz, 4H), 7.24 (t, J=2.7Hz, 1H), 6.65 (s, 1H), 6.48 (dd, J=3.2, 1.7Hz, 1H), 3.72 (s, 3H), 3.60 (d, J=11.9Hz, 1H) , 3.20 (dd, J=11.5, 3.2Hz, 2H), 2.88-2.78 (m, 1H), 2.64 (td, J=12.1, 6.2Hz, 1H), 2.42 (s, 3H), 2.09 (dd, J =13.2, 10.7Hz, 1H), 1.91 (d, J = 12.8Hz, 1H), 1.75 (d, J = 12.8Hz, 1H), 1.63 (q, J = 12.1Hz, 1H), 1.45-1.33 (m ,1H).
实施例31A和31BExamples 31A and 31B
合成化合物31A和31B
Synthesis of Compounds 31A and 31B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成2，3-二氢吡唑[5，1-b]噁唑Step A: Synthesis of 2,3-dihydropyrazole[5,1-b]oxazole
室温下，1，2-二氢-3H-吡唑-3-酮(3.00克，35.7毫摩尔)溶于乙腈(30毫升)中，加入1，2-二溴乙烷(20.21克，107.1毫摩尔)和碳酸钾(14.78克，107.1毫摩尔)，升温至80℃反应过夜。At room temperature, 1,2-dihydro-3H-pyrazol-3-one (3.00 g, 35.7 mmol) was dissolved in acetonitrile (30 ml), and 1,2-dibromoethane (20.21 g, 107.1 mmol) was added. mol) and potassium carbonate (14.78 g, 107.1 mmol), and the temperature was raised to 80°C to react overnight.
反应完成，过滤，浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到800毫克淡黄色油状物2，3-二氢吡唑[5，1-b]噁唑(收率：20％)。LC-MS：RT＝0.72min，[M+H]+＝111.13。The reaction was completed, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 800 mg of light yellow oily substance 2,3-dihydropyrazole [5,1 -b]oxazole (yield: 20%). LC-MS: RT=0.72min, [M+H] + =111.13.
步骤B：合成7-溴-2，3-二氢吡唑[5，1-b]噁唑 Step B: Synthesis of 7-bromo-2,3-dihydropyrazole[5,1-b]oxazole
零摄氏度下，向含有2，3-二氢吡唑[5，1-b]噁唑(1克，9.08毫摩尔)的乙腈(10毫升)中，加入N-溴代丁二酰亚胺(1.78克，9.99毫摩尔)，升至室温反应2小时。To acetonitrile (10 ml) containing 2,3-dihydropyrazole[5,1-b]oxazole (1 g, 9.08 mmol) at zero degrees Celsius was added N-bromosuccinimide ( 1.78 g, 9.99 mmol), raised to room temperature and reacted for 2 hours.
反应完成，过滤，浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到1.4克白色固体2，3-二氢吡唑[5，1-b]噁唑(收率：82％)。LC-MS：RT＝1.66min，[M+H]+＝189.04/191.00。The reaction was completed, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 1.4 g of white solid 2,3-dihydropyrazole [5,1-b ]oxazole (yield: 82%). LC-MS: RT=1.66min, [M+H] + =189.04/191.00.
步骤C：合成(S)-4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)-6-(4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step C: Synthesis of (S)-4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)-6-(4-(methoxycarbonyl)phenyl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800毫克，1.68毫摩尔)的1，4-二氧六环(10毫升)中，加入7-溴-2，3-二氢吡唑[5，1-b]噁唑(476毫克，2.52毫摩尔)、[1，1′-双(二苯基膦)二茂铁]二氯化钯(124毫克，0.17毫摩尔)、磷酸钾(892毫克，4.20毫摩尔)和水(2毫升)，置换氮气，升温到90℃反应过夜。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl -2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.68 mmol) in 1,4-dioxane (10 ml) was added 7-bromo -2,3-dihydropyrazole[5,1-b]oxazole (476 mg, 2.52 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (124 mg, 0.17 mmol), potassium phosphate (892 mg, 4.20 mmol) and water (2 ml), replaced with nitrogen, heated to 90°C and reacted overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)得到230毫克淡黄色油状液体(S)-4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)-6-(4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：30％)。LC-MS：RT＝2.02min，[M+H]+＝460.23。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 4/1) to obtain 230 mg of light yellow oily liquid (S)-4-(2,3-dihydropyrazole [5, 1-b]oxazol-7-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 30%) . LC-MS: RT=2.02min, [M+H] + =460.23.
步骤D：合成(S)-4-(4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)哌啶-2-基)苯甲酸甲酯Step D: Synthesis of (S)-4-(4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)piperidin-2-yl)benzoate methyl ester
将(S)-4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)-6-(4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(230毫克，0.50毫摩尔)溶于乙酸乙酯(10毫升)中，加入钯碳(100毫克)，置换氢气，升温到50℃反应3小时。(S)-4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-di Hydropyridine-1(2H)-carboxylic acid benzyl ester (230 mg, 0.50 mmol) was dissolved in ethyl acetate (10 ml), palladium carbon (100 mg) was added, replaced with hydrogen, and the temperature was raised to 50°C for 3 hours.
反应结束，过滤，用乙酸乙酯洗涤，浓缩，得到110毫克淡黄色油状液体(S)-4-(4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)哌啶-2-基)苯甲酸甲酯(收率：68％)。LC-MS：RT＝1.54min，[M+H]+＝328.21。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 110 mg of light yellow oily liquid (S)-4-(4-(2,3-dihydropyrazole[5,1-b]oxazole-7- (yl)piperidin-2-yl)benzoic acid methyl ester (yield: 68%). LC-MS: RT=1.54min, [M+H] + =328.21.
步骤E：合成(S)-4-(4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸酯叔丁酯Step E: Synthesis of (S)-4-(4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)-2-(4-(methoxycarbonyl)phenyl) Piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate tert-butyl ester
向含有(S)-4-(4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)哌啶-2-基)苯甲酸甲酯(110毫克，0.34毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(246毫克，0.85毫摩尔)，三乙酰氧基硼氢化钠(144毫克，0.68毫摩尔)，升温至40℃反应过夜。To a solution containing (S)-4-(4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)piperidin-2-yl)benzoate (110 mg, 0.34 mmol) of 1,2-dichloroethane (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (246 mg , 0.85 mmol), sodium triacetoxyborohydride (144 mg, 0.68 mmol), heat to 40°C and react overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到100毫克淡黄色油状物(S)-4-(4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸酯叔丁酯(收率：50％)。LC-MS：RT＝1.86min，[M+H]+＝601.36。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 100 mg of light yellow oily substance (S)-4-(4- (2,3-dihydropyrazol[5,1-b]oxazol-7-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- Methoxy-7-methyl-1H-indole-1-carboxylate tert-butyl ester (yield: 50%). LC-MS: RT=1.86min, [M+H] + =601.36.
步骤F：合成化合物31A和31BStep F: Synthesis of Compounds 31A and 31B
向(S)-4-(4-(2，3-二氢吡唑[5，1-b]噁唑-7-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸酯叔丁酯(100毫克，0.17毫摩尔)的甲醇(5毫升)中，加入碳酸钾(94毫克，0.68毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-4-(4-(2,3-dihydropyrazole[5,1-b]oxazol-7-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine- To 1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate tert-butyl ester (100 mg, 0.17 mmol) in methanol (5 ml), carbonic acid was added Potassium (94 mg, 0.68 mmol) was heated to 70°C for 5 hours, and water (1 ml) was added to continue the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到9.5毫克绝对构型的非对映异构体31A(收率：11％)和26.9毫克绝对构型的非对映异构体31B(收率：32％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 9.5 mg of diastereomer 31A with absolute configuration (yield: 11%) and 26.9 mg of diastereoisomer 31A with absolute configuration. Enantiomer 31B (yield: 32%).
化合物31A：HPLC：RT＝3.171min，LC-MS：RT＝1.65min，[M+H]+＝487.29。Compound 31A: HPLC: RT=3.171 min, LC-MS: RT=1.65 min, [M+H] + =487.29.
化合物31B：HPLC：RT＝3.174min，LC-MS：RT＝1.65min，[M+H]+＝487.29。1H NMR(400MHz，DMSO-d6)δ10.80(t，J＝2.3Hz，1H)，7.87(d，J＝7.9Hz，2H)，7.49(d，J＝7.7Hz，2H)，7.24(t，J＝2.8Hz，1H)，7.12(s，1H)，6.64(s，1H)，6.47(t，J＝2.5Hz，1H)，4.96(t，2H)，4.13(t，J＝7.9Hz，2H)，3.71(s，3H)，3.57(d，J＝11.9Hz，1H)，3.25-3.14(m，3H)，2.80(dt，J＝11.8，3.4Hz，1H)，2.41(s，3H)，2.05(dd，J＝13.3，10.7Hz，1H)，1.90-1.81(m，1H)，1.73-1.52(m，2H)，1.46-1.31(m，1H)。Compound 31B: HPLC: RT=3.174min, LC-MS: RT=1.65min, [M+H] + =487.29. 1 H NMR (400MHz, DMSO-d6) δ10.80 (t, J=2.3Hz, 1H), 7.87 (d, J=7.9Hz, 2H), 7.49 (d, J=7.7Hz, 2H), 7.24 ( t, J=2.8Hz, 1H), 7.12 (s, 1H), 6.64 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 4.96 (t, 2H), 4.13 (t, J=7.9 Hz, 2H), 3.71 (s, 3H), 3.57 (d, J=11.9Hz, 1H), 3.25-3.14 (m, 3H), 2.80 (dt, J=11.8, 3.4Hz, 1H), 2.41 (s , 3H), 2.05 (dd, J=13.3, 10.7Hz, 1H), 1.90-1.81 (m, 1H), 1.73-1.52 (m, 2H), 1.46-1.31 (m, 1H).
实施例32A和32BExamples 32A and 32B
合成化合物32A和32B
Synthesis of Compounds 32A and 32B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-咪唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H )-carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800毫克，1.68毫摩尔)的1，4-二氧六环(10毫升)中，加入4-溴-1-甲基-1H-咪唑(411毫克，2.52毫摩尔)、[1，1′-双(二苯基膦)二茂铁]二氯化钯(124毫克，0.17毫摩尔)、磷酸钾(892毫克，4.2毫摩尔)和水(2毫升)，置换氮气，升温到90℃反应2小时。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl -2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.68 mmol) in 1,4-dioxane (10 ml) was added 4-bromo -1-Methyl-1H-imidazole (411 mg, 2.52 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (124 mg, 0.17 mmol), potassium phosphate (892 mg, 4.2 mmol) and water (2 ml), replaced with nitrogen, heated to 90°C and reacted for 2 hours.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到250毫克淡黄色油状液体(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-咪唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：42％)。LC-MS：RT＝1.70min，[M+H]+＝432.24。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 250 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl)-4 -(1-Methyl-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 42%). LC-MS: RT=1.70min, [M+H] + =432.24.
步骤B：合成(S)-4-(4-(1-甲基-1H-咪唑-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-methyl-1H-imidazol-4-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-咪唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(250毫克，0.58毫摩尔)溶于乙酸乙酯溶液(10毫升)中，加入钯碳(130毫克)，置换氢气，升温到50℃反应4小时。(S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic Dissolve benzyl acid ester (250 mg, 0.58 mmol) in ethyl acetate solution (10 ml), add palladium carbon (130 mg), replace hydrogen, and heat to 50°C for 4 hours.
反应结束，过滤，用乙酸乙酯洗涤，浓缩，得到130毫克淡黄色油状液体(S)-4-(4-(1-甲基-1H-咪唑-4-基)哌啶-2-基)苯甲酸甲酯(收率：74％)。LC-MS：RT＝0.26min，[M+H]+＝300.25。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 130 mg of light yellow oily liquid (S)-4-(4-(1-methyl-1H-imidazol-4-yl)piperidin-2-yl) Methyl benzoate (yield: 74%). LC-MS: RT=0.26min, [M+H] + =300.25.
步骤C：合成(S)-5-甲氧基-4-(2-(4-(甲氧羰基(苯基)-4-(1-甲基-1H-咪唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸酯叔丁酯Step C: Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl(phenyl))-4-(1-methyl-1H-imidazol-4-yl)piperidine- 1-yl)methyl)-7-methyl-1H-indole-1-carboxylate tert-butyl ester
向含有(S)-4-(4-(1-甲基-1H-咪唑-4-基)哌啶-2-基)苯甲酸甲酯(130毫克，0.43毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(312毫克，1.08毫摩尔)和三乙酰氧基硼氢化钠(182毫克，0.86毫摩尔)，升温至40℃反应过夜。To 1,2-bis containing (S)-4-(4-(1-methyl-1H-imidazol-4-yl)piperidin-2-yl)benzoate (130 mg, 0.43 mmol) To ethyl chloride (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (312 mg, 1.08 mmol) and triacetoxy Sodium borohydride (182 mg, 0.86 mmol) was heated to 40°C and allowed to react overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到86毫克淡黄色油状物(S)-5-甲氧基-4-(2-(4-(甲氧羰基(苯基)-4-(1-甲基-1H-咪唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸酯叔丁酯(收率：35％)。LC-MS：RT＝1.73min，[M+H]+＝573.34。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 86 mg of light yellow oily substance (S)-5-methoxy. -4-(2-(4-(methoxycarbonyl(phenyl)-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)methyl)-7-methyl- 1H-indole-1-carboxylate tert-butyl ester (yield: 35%). LC-MS: RT=1.73min, [M+H] + =573.34.
步骤D：合成化合物32A和32BStep D: Synthesis of Compounds 32A and 32B
向(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(1-甲基-1H-咪唑-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸酯叔丁酯(86毫克，0.15毫摩尔)的甲醇(5毫升)中，加入碳酸钾(83毫克，0.60毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylate tert-butyl ester (86 mg, 0.15 mmol) in methanol (5 ml), add potassium carbonate (83 mg, 0.60 mmol) , heated to 70°C for 5 hours, added water (1 ml) and continued the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到10毫克绝对构型的非对映异构体32A(收率：15％)和17毫克绝对构型的非对映异构体32B(收率：25％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 10 mg of diastereoisomer 32A with absolute configuration (yield: 15%) and 17 mg of diastereoisomer 32A with absolute configuration. Enantiomer 32B (yield: 25%).
化合物32A：HPLC：RT＝0.988min，LC-MS：RT＝1.66min，[M+H]+＝462.24。Compound 32A: HPLC: RT=0.988 min, LC-MS: RT=1.66 min, [M+H] + =462.24.
化合物32B：HPLC：RT＝0.672min，LC-MS：RT＝1.66min，[M+H]+＝455.22。Compound 32B: HPLC: RT=0.672min, LC-MS: RT=1.66min, [M+H] + =455.22.
实施例33A和33BExamples 33A and 33B
合成化合物33A和33B
Synthesis of Compounds 33A and 33B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-1，2，3-***-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-3,6 -Dihydropyridine-1(2H)-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(750毫克，1.57毫摩尔)，4-溴-1-甲基-1H-1，2，3-***(381.4毫克，2.35毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(229.5毫克，0.3毫摩尔)，磷酸钾(682毫克，3.1毫摩尔)加入1，4-二氧六环(25毫升)和水(5毫升)混合液中，氮气保护下升温至95℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (750 mg, 1.57 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole ( 381.4 mg, 2.35 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (229.5 mg, 0.3 mmol), potassium phosphate (682 mg, 3.1 mmol) were added to 1 , in a mixture of 4-dioxane (25 ml) and water (5 ml), the temperature was raised to 95°C under nitrogen protection for 12 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸 乙酯＝1/1)。得到470毫克(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-1，2，3-***-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率53.3％)。LC-MS：RT＝1.97min，[M+H]+＝433.24。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/acetic acid Ethyl ester=1/1). Obtained 470 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-3,6- Dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield 53.3%). LC-MS: RT=1.97min, [M+H] + =433.24.
步骤B：合成(S)-4-(4-(1-甲基-1H-1，2，3-***-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-2-yl)benzoate methyl ester
室温下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-1，2，3-***-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(420毫克，0.97毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯/碳(420毫克)，氢气氛围下反应过夜。At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester (420 mg, 0.97 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (420 mg) was added, and the reaction was carried out overnight under a hydrogen atmosphere.
反应完成，过滤，浓缩。得到300毫克浅黄色油状物(S)-4-(4-(1-甲基-1H-1，2，3-***-4-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝1.49min，[M+H]+＝301.22。The reaction is completed, filtered and concentrated. Obtained 300 mg of light yellow oily substance (S)-4-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (crude product ), no purification is required, and it can be used directly in the next reaction. LC-MS: RT=1.49min, [M+H] + =301.22.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-1，2，3-***-4-基)哌啶-1)-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(1-methyl-1H-1,2,3-tri Azol-4-yl)piperidin-1)-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物((S)-4-(4-(1-甲基-1H-1，2，3-***-4-基)哌啶-2-基)苯甲酸甲酯(300毫克，1.0毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(578毫克，2.0毫摩尔)溶于1，2-二氯乙烷(5毫升)中，室温搅拌1小时，加入三乙酰氧基硼氢化钠(635.8毫克，3.0毫摩尔)，升温至40℃反应过夜。Compound ((S)-4-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-2-yl)benzoate (300 mg, 1.0 mg mol) and 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (578 mg, 2.0 mmol) were dissolved in 1,2-dichloroethane ( 5 ml), stir at room temperature for 1 hour, add sodium triacetoxyborohydride (635.8 mg, 3.0 mmol), raise the temperature to 40°C and react overnight.
反应完成，加入甲醇溶，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到387毫克棕色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-1，2，3-***-4-基)哌啶-1)-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率67.5％)。LC-MS：RT＝1.84min，[M+H]+＝574.34。When the reaction is completed, add methanol to dissolve and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 387 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3- Triazol-4-yl)piperidin-1)-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 67.5%). LC-MS: RT=1.84min, [M+H] + =574.34.
步骤D：合成化合物33A和33BStep D: Synthesis of Compounds 33A and 33B
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-1，2，3-***-4-基)哌啶-1)-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(387毫克，0.67毫摩尔)溶于甲醇(15毫升)中，加入碳酸钾(372.8毫克，2.7毫摩尔)，加热至70℃反应过夜，加入水(2毫升)继续反应2小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(1-methyl-1H-1,2,3-triazole- 4-yl)piperidin-1)-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (387 mg, 0.67 mmol) was dissolved in methanol (15 ml). Add potassium carbonate (372.8 mg, 2.7 mmol), heat to 70°C and react overnight, add water (2 ml) and continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到10毫克绝对构型的非对映异构体33A(收率：3.2％)和102毫克绝对构型的非对映异构体33B(收率：33.1％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 10 mg of diastereoisomer 33A with absolute configuration (yield: 3.2%) and 102 mg of diastereoisomer 33A with absolute configuration. Enantiomer 33B (yield: 33.1%).
化合物33A：HPLC：RT＝3.055min，LC-MS：RT＝1.61min，[M+H]+＝460.27。Compound 33A: HPLC: RT=3.055min, LC-MS: RT=1.61min, [M+H] + =460.27.
化合物33B：HPLC：RT＝2.961min，LC-MS：RT＝1.61min，[M+H]+＝460.27。Compound 33B: HPLC: RT=2.961 min, LC-MS: RT=1.61 min, [M+H] + =460.27.
1H NMR(400MHz，DMSO-d6)δ10.82(d，J＝2.7Hz，1H)，7.86-7.80(m，2H)，7.79(s，1H)，7.41(d，J＝7.7Hz，2H)，7.24(t，J＝2.7Hz，1H)，6.65(s，1H)，6.48(dd，J＝3.1，1.8Hz，1H)，3.93(s，3H)，3.72(s，3H)，3.60(d，J＝11.8Hz，1H)，3.27-3.17(m，2H)，2.89-2.77(m，2H)，2.42(s，3H)，2.11(dd，J＝13.2，10.7Hz，1H)，1.99-1.90(m，1H)，1.81(d，J＝12.9Hz，1H)，1.71(q，J＝12.3Hz，1H)，1.52-1.38(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.82 (d, J = 2.7Hz, 1H), 7.86-7.80 (m, 2H), 7.79 (s, 1H), 7.41 (d, J = 7.7Hz, 2H), 7.24 (t, J=2.7Hz, 1H), 6.65 (s, 1H), 6.48 (dd, J=3.1, 1.8Hz, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.60 (d, J=11.8Hz, 1H), 3.27-3.17 (m, 2H), 2.89-2.77 (m, 2H), 2.42 (s, 3H), 2.11 (dd, J=13.2, 10.7Hz, 1H) , 1.99-1.90 (m, 1H), 1.81 (d, J=12.9Hz, 1H), 1.71 (q, J=12.3Hz, 1H), 1.52-1.38 (m, 1H).
实施例34A和34BExamples 34A and 34B
合成化合物34A和34B
Synthesis of Compounds 34A and 34B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6′-(4-(甲氧羰基)苯基)-6-甲基-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯Step A: Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-6-methyl-3′,6′-dihydro-[2,4′-bipyridyl]-1′( 2′H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800毫克，1.68毫摩尔)的1，4-二氧六环(10毫升)中，加入2-溴-6-甲基吡啶(433毫克，2.52毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(124毫克，0.17毫摩尔)，磷酸钾(892毫克，4.2毫摩尔)，水(2毫升)，置换氮气，升温到90℃反应过夜。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.68 mmol) in 1,4-dioxane (10 ml) was added 2-bromo -6-methylpyridine (433 mg, 2.52 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (124 mg, 0.17 mmol), potassium phosphate (892 mg , 4.2 mmol), water (2 ml), replace nitrogen, heat to 90°C and react overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)得到120毫克淡黄色油状液体(S)-6′-(4-(甲氧羰基)苯基)-6-甲基-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯(收率：58％)。LC-MS：RT＝2.09min，[M+H]+＝443.24。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 4/1) to obtain 120 mg of light yellow oily liquid (S)-6'-(4-(methoxycarbonyl)phenyl) -6-Methyl-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid benzyl ester (yield: 58%). LC-MS: RT=2.09min, [M+H] + =443.24.
步骤B：合成(S)-4-(4-(6-甲基吡啶-2-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(6-methylpyridin-2-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6′-(4-(甲氧羰基)苯基)-6-甲基-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯(430毫克，0.97毫摩尔)溶于乙酸 乙酯(10毫升)中，加入钯碳(250毫克)，置换氢气，室温反应过夜。(S)-6′-(4-(methoxycarbonyl)phenyl)-6-methyl-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H )-Benzyl carboxylate (430 mg, 0.97 mmol) dissolved in acetic acid To ethyl ester (10 ml), add palladium on carbon (250 mg), replace the hydrogen gas, and react at room temperature overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到150毫克淡黄色油状液体(S)-4-(4-(6-甲基吡啶-2-基)哌啶-2-基)苯甲酸甲酯(收率：49％)。LC-MS：RT＝1.41min，[M+H]+＝311.23。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 150 mg of light yellow oily liquid (S)-4-(4-(6-methylpyridin-2-yl) )piperidin-2-yl)benzoic acid methyl ester (yield: 49%). LC-MS: RT=1.41min, [M+H] + =311.23.
步骤C：合成(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(6-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(6-methylpyridin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(6-甲基吡啶-2-基)哌啶-2-基)苯甲酸甲酯(150毫克，0.48毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(347毫克，1.2毫摩尔)，三乙酰氧基硼氢化钠(203毫克，0.96毫摩尔)，升温至40℃反应过夜。To (S)-4-(4-(6-methylpyridin-2-yl)piperidin-2-yl)benzoic acid methyl ester (150 mg, 0.48 mmol) in 1,2-dichloroethane (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (347 mg, 1.2 mmol), triacetoxy hydroboration Sodium (203 mg, 0.96 mmol) was heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)得到120毫克淡黄色油状物(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(6-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：44％)。LC-MS：RT＝1.98min，[M+H]+＝584.37。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 120 mg of light yellow oily substance (S)-5-methoxy. Base-4-(2-(4-(methoxycarbonyl)phenyl)-4-(6-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H- Indole-1-carboxylic acid tert-butyl ester (yield: 44%). LC-MS: RT=1.98min, [M+H] + =584.37.
步骤D：合成化合物34A和34BStep D: Synthesis of Compounds 34A and 34B
向(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(6-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(120毫克，0.21毫摩尔)的甲醇(5毫升)中，加入碳酸钾(116毫克，0.84毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(6-methylpyridin-2-yl)piperidin-1-yl)methyl )-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (120 mg, 0.21 mmol) in methanol (5 ml), add potassium carbonate (116 mg, 0.84 mmol), and heat to 70 The reaction was carried out at ℃ for 5 hours, and water (1 ml) was added to continue the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到23.8毫克绝对构型的非对映异构体34A(收率：24％)和30.2毫克绝对构型的非对映异构体34B(收率：31％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 23.8 mg of diastereomer 34A with absolute configuration (yield: 24%) and 30.2 mg of diastereoisomer 34A with absolute configuration. Enantiomer 34B (yield: 31%).
化合物34A：HPLC：RT＝0.971min，LC-MS：RT＝1.57min，[M+H]+＝470.30。1H NMR(400MHz，DMSO-d6)δ10.81(s，1H)，7.88(d，J＝7.9Hz，2H)，7.58-7.49(m，3H)，7.26(t，J＝2.8Hz，1H)，7.01(t，J＝8.0Hz，2H)，6.66(s，1H)，6.50(dd，J＝3.1，1.9Hz，1H)，3.72(s，3H)，3.61(d，J＝11.9Hz，1H)，3.32-3.19(m，2H)，2.93-2.86(m，1H)，2.85-2.75(m，1H)，2.42(s，3H)，2.39(s，3H)，2.18-2.08(m，1H)，1.91-1.76(m，2H)，1.75-1.68(m，1H)，1.67-1.56(m，1H)。Compound 34A: HPLC: RT=0.971 min, LC-MS: RT=1.57 min, [M+H] + =470.30. 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.88 (d, J=7.9Hz, 2H), 7.58-7.49 (m, 3H), 7.26 (t, J=2.8Hz, 1H ), 7.01 (t, J=8.0Hz, 2H), 6.66 (s, 1H), 6.50 (dd, J=3.1, 1.9Hz, 1H), 3.72 (s, 3H), 3.61 (d, J=11.9Hz , 1H), 3.32-3.19(m, 2H), 2.93-2.86(m, 1H), 2.85-2.75(m, 1H), 2.42(s, 3H), 2.39(s, 3H), 2.18-2.08(m , 1H), 1.91-1.76 (m, 2H), 1.75-1.68 (m, 1H), 1.67-1.56 (m, 1H).
化合物34B：HPLC：RT＝2.239min，LC-MS：RT＝1.57min，[M+H]+＝470.30。1H NMR(400MHz，DMSO-d6)δ10.80(s，1H)，7.93(d，J＝8.1Hz，2H)，7.69-7.60(m，3H)，7.25(t，J＝2.8Hz，1H)，7.20(d，J＝7.8Hz，1H)，7.08(d，J＝7.6Hz，1H)，6.64(s，1H)，6.47(dd，J＝3.1，1.9Hz，1H)，3.75-3.70(m，1H)，3.69(s，3H)，3.40-3.32(m，2H)，3.06-2.99(m，1H)，2.69-2.58(m，1H)，2.49(s，1H)，2.41(s，3H)，2.29-2.19(m，1H)，2.19-2.10(m，1H)，2.10-1.98(m，1H)，1.81-1.71(m，1H)。Compound 34B: HPLC: RT=2.239 min, LC-MS: RT=1.57 min, [M+H] + =470.30. 1 H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 7.93 (d, J=8.1Hz, 2H), 7.69-7.60 (m, 3H), 7.25 (t, J=2.8Hz, 1H ), 7.20 (d, J=7.8Hz, 1H), 7.08 (d, J=7.6Hz, 1H), 6.64 (s, 1H), 6.47 (dd, J=3.1, 1.9Hz, 1H), 3.75-3.70 (m, 1H), 3.69 (s, 3H), 3.40-3.32 (m, 2H), 3.06-2.99 (m, 1H), 2.69-2.58 (m, 1H), 2.49 (s, 1H), 2.41 (s , 3H), 2.29-2.19(m, 1H), 2.19-2.10(m, 1H), 2.10-1.98(m, 1H), 1.81-1.71(m, 1H).
实施例35A和35BExamples 35A and 35B
合成化合物35A和35B
Synthesis of Compounds 35A and 35B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6′-(4-(甲氧羰基)苯基)-5-甲基-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯Step A: Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-5-methyl-3′,6′-dihydro-[2,4′-bipyridyl]-1′( 2′H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800毫克，1.68毫摩尔)的1，4-二氧六环(10毫升)中，加入2-溴-5-甲基吡啶(433毫克，2.52毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(124毫克，0.17毫摩尔)，磷酸钾(892毫克，4.2毫摩尔)，水(2毫升)，置换氮气，升温到90℃反应过夜。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.68 mmol) in 1,4-dioxane (10 ml) was added 2-bromo -5-methylpyridine (433 mg, 2.52 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (124 mg, 0.17 mmol), potassium phosphate (892 mg , 4.2 mmol), water (2 ml), replace nitrogen, heat to 90°C and react overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到600毫克淡黄色油状液体(S)-6′-(4-(甲氧羰基)苯基)-5-甲基-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯(收率：85％)。LC-MS：RT＝2.11min，[M+H]+＝443.24。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 600 mg of light yellow oily liquid (S)-6'-(4-(methoxycarbonyl)phenyl) -5-Methyl-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid benzyl ester (yield: 85%). LC-MS: RT=2.11 min, [M+H] + =443.24.
步骤B：合成(S)-4-(4-(5-甲基吡啶-2-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(5-methylpyridin-2-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6′-(4-(甲氧羰基)苯基)-5-甲基-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-羧酸苄酯(600毫克，1.36毫摩尔)溶于乙酸 乙酯(10毫升)中，加入钯碳(300毫克)，置换氢气，室温反应过夜。(S)-6′-(4-(methoxycarbonyl)phenyl)-5-methyl-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H )-Benzyl carboxylate (600 mg, 1.36 mmol) dissolved in acetic acid To ethyl ester (10 ml), add palladium on carbon (300 mg), replace the hydrogen gas, and react at room temperature overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到180毫克淡黄色油状液体(S)-4-(4-(5-甲基吡啶-2-基)哌啶-2-基)苯甲酸甲酯(收率：43％)。LC-MS：RT＝1.50min，[M+H]+＝311.23。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 180 mg of light yellow oily liquid (S)-4-(4-(5-methylpyridin-2-yl) )piperidin-2-yl)benzoic acid methyl ester (yield: 43%). LC-MS: RT=1.50min, [M+H] + =311.23.
步骤C：合成(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(5-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(5-methylpyridin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-甲基吡啶-2-基)哌啶-2-基)苯甲酸甲酯(180毫克，0.58毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(419毫克，1.45毫摩尔)和三乙酰氧基硼氢化钠(246毫克，1.16毫摩尔)，升温至40℃反应过夜。To (S)-4-(4-(5-methylpyridin-2-yl)piperidin-2-yl)benzoic acid methyl ester (180 mg, 0.58 mmol) in 1,2-dichloroethane (5 mL), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (419 mg, 1.45 mmol) and triacetoxyborohydride Sodium (246 mg, 1.16 mmol) was heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)得到250毫克淡黄色油状物(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(5-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：74％)。LC-MS：RT＝1.89min，[M+H]+＝584.41。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 250 mg of light yellow oily substance (S)-5-methoxy. Base-4-(2-(4-(methoxycarbonyl)phenyl)-4-(5-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H- Indole-1-carboxylic acid tert-butyl ester (yield: 74%). LC-MS: RT=1.89min, [M+H] + =584.41.
步骤D：合成化合物35A和35BStep D: Synthesis of Compounds 35A and 35B
向(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(5-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(250毫克，0.43毫摩尔)的甲醇(5毫升)中，加碳酸钾(237毫克，1.72毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(5-methylpyridin-2-yl)piperidin-1-yl)methyl )-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (250 mg, 0.43 mmol) in methanol (5 ml), add potassium carbonate (237 mg, 1.72 mmol), and heat to 70 The reaction was carried out at ℃ for 5 hours, and water (1 ml) was added to continue the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到23毫克绝对构型的非对映异构体35A(收率：11％)和144毫克绝对构型的非对映异构体35B(收率：53％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 23 mg of diastereomer 35A with absolute configuration (yield: 11%) and 144 mg of diastereoisomer 35A with absolute configuration. Enantiomer 35B (yield: 53%).
化合物35A：HPLC：RT＝3.038min，LC-MS：RT＝1.72min，[M+H]+＝470.31。1H NMR(400MHz，DMSO-d6)δ10.79(s，1H)，8.42(d，J＝2.3Hz，1H)，7.79(d，J＝7.9Hz，2H)，7.57(dd，J＝8.1，2.4Hz，1H)，7.36(d，J＝7.8Hz，2H)，7.31(d，J＝8.0Hz，1H)，7.24(t，J＝2.8Hz，1H)，6.62(s，1H)，6.46(dd，J＝3.0，1.8Hz，1H)，3.66(s，3H)，3.63(d，J＝11.9Hz，1H)，3.46(dt，J＝9.8，4.6Hz，1H)，3.23(d，J＝11.9Hz，2H)，3.07(t，J＝4.7Hz，1H)，2.62-2.55(m，1H)，2.41(s，3H)，2.37(s，1H)，2.30(s，3H)，2.19-2.13(m，1H)，2.13-2.00(m，1H)，1.80-1.70(m，1H)。Compound 35A: HPLC: RT=3.038 min, LC-MS: RT=1.72 min, [M+H] + =470.31. 1 H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 8.42 (d, J=2.3Hz, 1H), 7.79 (d, J=7.9Hz, 2H), 7.57 (dd, J=8.1 , 2.4Hz, 1H), 7.36 (d, J=7.8Hz, 2H), 7.31 (d, J=8.0Hz, 1H), 7.24 (t, J=2.8Hz, 1H), 6.62 (s, 1H), 6.46 (dd, J=3.0, 1.8Hz, 1H), 3.66 (s, 3H), 3.63 (d, J=11.9Hz, 1H), 3.46 (dt, J=9.8, 4.6Hz, 1H), 3.23 (d , J=11.9Hz, 2H), 3.07 (t, J=4.7Hz, 1H), 2.62-2.55 (m, 1H), 2.41 (s, 3H), 2.37 (s, 1H), 2.30 (s, 3H) , 2.19-2.13(m, 1H), 2.13-2.00(m, 1H), 1.80-1.70(m, 1H).
化合物35B：HPLC：RT＝0.974min，LC-MS：RT＝1.72min，[M+H]+＝470.31。1H NMR(400MHz，DMSO-d6)δ10.82(s，1H)，8.27(d，J＝2.3Hz，1H)，7.86(d，J＝8.2Hz，2H)，7.51-7.43(m，3H)，7.25(t，J＝2.8Hz，1H)，7.14(d，J＝8.0Hz，1H)，6.65(s，1H)，6.50(dd，J＝3.1，1.9Hz，1H)，3.72(s，3H)，3.61(d，J＝11.9Hz，1H)，3.31-3.19(m，2H)，2.91-2.78(m，2H)，2.42(s，3H)，2.21(s，3H)，2.18-2.08(m，1H)，1.89-1.80(m，2H)，1.74-1.67(m，1H)，1.65-1.55(m，1H)。Compound 35B: HPLC: RT=0.974min, LC-MS: RT=1.72min, [M+H] + =470.31. 1 H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 8.27 (d, J=2.3Hz, 1H), 7.86 (d, J=8.2Hz, 2H), 7.51-7.43 (m, 3H ), 7.25 (t, J=2.8Hz, 1H), 7.14 (d, J=8.0Hz, 1H), 6.65 (s, 1H), 6.50 (dd, J=3.1, 1.9Hz, 1H), 3.72 (s , 3H), 3.61 (d, J=11.9Hz, 1H), 3.31-3.19 (m, 2H), 2.91-2.78 (m, 2H), 2.42 (s, 3H), 2.21 (s, 3H), 2.18- 2.08 (m, 1H), 1.89-1.80 (m, 2H), 1.74-1.67 (m, 1H), 1.65-1.55 (m, 1H).
实施例36A和36BExamples 36A and 36B
合成化合物36A和36B
Synthesis of Compounds 36A and 36B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-((4-甲氧基羰基)苯基)-4-(4-甲基吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)-3,6-dihydropyridine-1(2H)- Benzyl carboxylate
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1000毫克，2.09毫摩尔)的1，4-二氧六环(30毫升)中，加入2-溴-4-甲基吡啶(541毫克，3.14毫摩尔)、[1，1′-双(二苯基膦)二茂铁]二氯化钯(152毫克，0.21毫摩尔)、磷酸钾(1100毫克，5.24毫摩尔)和水(6毫升)，置换氮气，升温到90℃反应5小时。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl -2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1000 mg, 2.09 mmol) in 1,4-dioxane (30 ml) was added 2-bromo -4-methylpyridine (541 mg, 3.14 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (152 mg, 0.21 mmol), potassium phosphate (1100 mg , 5.24 mmol) and water (6 ml), replaced with nitrogen, heated to 90°C and reacted for 5 hours.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝8/1)得到470毫克淡黄色油状液体(S)-6-((4-甲氧基羰基)苯基)-4-(4-甲基吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：51％)。LC-MS：RT＝1.97min，[M+H]+＝443.23。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 8/1) to obtain 470 mg of light yellow oily liquid (S)-6-((4-methoxycarbonyl)phenyl) -4-(4-methylpyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 51%). LC-MS: RT=1.97min, [M+H] + =443.23.
步骤B：合成(S)-4-(4-(4-甲基吡啶-2-基)哌啶-2-基苯甲酸甲酯 Step B: Synthesis of (S)-4-(4-(4-methylpyridin-2-yl)piperidin-2-ylbenzoic acid methyl ester
将(S)-6-((4-甲氧基羰基)苯基)-4-(4-甲基吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(470毫克，1.06毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯碳(47毫克)，置换氢气，升温到60℃反应过夜。(S)-6-((4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl The ester (470 mg, 1.06 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (47 mg) was added, hydrogen was replaced, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩，得到290毫克淡黄色油状液体(S)-4-(4-(4-甲基吡啶-2-基)哌啶-2-基苯甲酸甲酯(收率：88％)。LC-MS：RT＝1.47min，[M+H]+＝311.23。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 290 mg of light yellow oily liquid (S)-4-(4-(4-methylpyridin-2-yl)piperidin-2-yl benzoic acid methyl ester) (Yield: 88%). LC-MS: RT = 1.47 min, [M+H] + = 311.23.
步骤C：合成(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(4-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(4-甲基吡啶-2-基)哌啶-2-基苯甲酸甲酯(290毫克，0.93毫摩尔)的1，2-二氯乙烷(20毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(405毫克，1.40毫摩尔)和三乙酰氧基硼氢化钠(396毫克，1.87毫摩尔)，升温至40℃反应过夜。To a solution containing (S)-4-(4-(4-methylpyridin-2-yl)piperidin-2-ylbenzoic acid methyl ester (290 mg, 0.93 mmol) in 1,2-dichloroethane ( 20 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (405 mg, 1.40 mmol) and sodium triacetoxyborohydride (396 mg, 1.87 mmol), heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)得到240毫克白色固体(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(4-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：44％)。LC-MS：RT＝1.91min，[M+H]+＝584.38。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 240 mg of white solid (S)-5-methoxy- 4-(2-(4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole -1-tert-butylcarboxylate (yield: 44%). LC-MS: RT=1.91min, [M+H] + =584.38.
步骤D：合成化合物36A和36BStep D: Synthesis of Compounds 36A and 36B
向(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(4-甲基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(240毫克，0.41毫摩尔)的甲醇(15毫升)中，加入碳酸钾(568毫克，4.10毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)piperidin-1-yl)methyl )-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (240 mg, 0.41 mmol) in methanol (15 ml), add potassium carbonate (568 mg, 4.10 mmol), and heat to 70 The reaction was carried out at ℃ for 5 hours, and water (1 ml) was added to continue the reaction for 4 hours.
反应完成，抽滤，甲醇淋洗，浓缩，采用实施例3步骤D中的手性拆分方法分离得到26毫克绝对构型的非对映异构体36A(收率：13％)和153毫克绝对构型的非对映异构体36B(收率：79％)。The reaction was completed, filtered with suction, rinsed with methanol, concentrated, and separated using the chiral resolution method in step D of Example 3 to obtain 26 mg of absolute configuration diastereomer 36A (yield: 13%) and 153 mg. Absolute configuration of diastereomer 36B (yield: 79%).
化合物36A：HPLC：RT＝1.875min，LC-MS：RT＝1.54min，[M+H]+＝470.34。1H NMR(400MHz，DMSO-d6)δ10.80(d，J＝2.5Hz，1H)，8.44(d，J＝5.0Hz，1H)，7.81(d，J＝7.8Hz，2H)，7.39(d，J＝8.0Hz，2H)，7.24(dd，J＝6.3，3.6Hz，2H)，7.06(d，J＝5.0Hz，1H)，6.64(s，1H)，6.49(t，J＝2.3Hz，1H)，3.68(s，3H)，3.54(dd，J＝9.2，3.3Hz，1H)，3.40-3.30(s，2H)，3.06(t，J＝4.9Hz，1H)，2.64-2.58(m，1H)，2.42(s，3H)，2.34(s，3H)，2.28-2.13(m，3H)，2.07(ddd，J＝13.8，9.1，4.9Hz，1H)，1.80-1.69(m，1H).Compound 36A: HPLC: RT=1.875 min, LC-MS: RT=1.54 min, [M+H] + =470.34. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.80 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.0 Hz, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.39 (d, J=8.0Hz, 2H), 7.24 (dd, J=6.3, 3.6Hz, 2H), 7.06 (d, J=5.0Hz, 1H), 6.64 (s, 1H), 6.49 (t, J= 2.3Hz, 1H), 3.68 (s, 3H), 3.54 (dd, J=9.2, 3.3Hz, 1H), 3.40-3.30 (s, 2H), 3.06 (t, J=4.9Hz, 1H), 2.64- 2.58 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 2.28-2.13 (m, 3H), 2.07 (ddd, J=13.8, 9.1, 4.9Hz, 1H), 1.80-1.69 ( m, 1H).
化合物36B：HPLC：RT＝0.968min，LC-MS：RT＝1.54min，[M+H]+＝470.34。1H NMR(400MHz，DMSO-d6)δ10.84(s，1H)，8.29(d，J＝5.0Hz，1H)，7.84(d，J＝7.8Hz，2H)，7.43(d，J＝7.7Hz，2H)，7.26(t，J＝2.8Hz，1H)，7.09(s，1H)，6.98(d，J＝5.0Hz，1H)，6.66(s，1H)，6.52(t，J＝2.5Hz，1H)，3.73(s，3H)，3.63(d，J＝11.9Hz，1H)，3.28-3.20(m，3H)，2.93-2.75(m，2H)，2.43(s，3H)，2.25(s，3H)，2.18-2.07(m，1H)，1.88(q，J＝10.6，8.2Hz，2H)，1.72(d，J＝12.4Hz，1H)，1.61(qd，J＝12.2，3.6Hz，1H).Compound 36B: HPLC: RT=0.968 min, LC-MS: RT=1.54 min, [M+H] + =470.34. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 8.29 (d, J = 5.0Hz, 1H), 7.84 (d, J = 7.8Hz, 2H), 7.43 (d, J = 7.7Hz, 2H), 7.26 (t, J=2.8Hz, 1H), 7.09 (s, 1H), 6.98 (d, J=5.0Hz, 1H), 6.66 (s, 1H), 6.52 (t, J= 2.5Hz, 1H), 3.73 (s, 3H), 3.63 (d, J=11.9Hz, 1H), 3.28-3.20 (m, 3H), 2.93-2.75 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 2.18-2.07 (m, 1H), 1.88 (q, J=10.6, 8.2Hz, 2H), 1.72 (d, J=12.4Hz, 1H), 1.61 (qd, J=12.2, 3.6Hz, 1H).
实施例37A和37BExamples 37A and 37B
合成化合物37A和37B
Synthesis of Compounds 37A and 37B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(哒嗪-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(0.8克，1.68毫摩尔)，3-溴哒嗪(675毫克，4.18毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(123毫克，0.168毫摩尔)，磷酸钾(713毫克，3.36毫摩尔)加入1，4-二氧六环(20毫升)和水(4毫升)混合液中，氮气保护下，升温至80℃反应过夜。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (0.8 g, 1.68 mmol), 3-bromopyridazine (675 mg, 4.18 mmol), [1,1′- Bis(diphenylphosphine)ferrocene]palladium dichloride (123 mg, 0.168 mmol), potassium phosphate (713 mg, 3.36 mmol) were added to 1,4-dioxane (20 ml) and water ( 4 ml) mixed solution, under nitrogen protection, raise the temperature to 80°C and react overnight.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)。得到560毫克棕色胶状(S)-6-(4-(甲氧羰基)苯基)-4-(哒嗪-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率77％)。LC-MS：RT＝1.98min，[M+H]+＝430.22。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2). Obtained 560 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid as a brown gum Benzyl ester (yield 77%). LC-MS: RT=1.98min, [M+H] + =430.22.
步骤B：合成(S)-4-(4-(哒嗪-3-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(pyridazin-3-yl)piperidin-2-yl)benzoic acid methyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(哒嗪-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(560毫克，1.3毫摩尔)溶于乙 酸乙酯(20毫升)中，加入钯/碳(280毫克)，氢气保护下室温反应过夜。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (560 mg, 1.3 mmol) dissolved in B To ethyl acid ester (20 ml), add palladium/carbon (280 mg), and react at room temperature overnight under hydrogen protection.
反应完成，过滤，浓缩。得到350毫克黄色油状(S)-4-(4-(哒嗪-3-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝1.49min，[M+H]+＝298.26。The reaction is completed, filtered and concentrated. 350 mg of (S)-4-(4-(pyridazin-3-yl)piperidin-2-yl)benzoic acid methyl ester (crude product) was obtained as a yellow oil. No purification was required and it was directly used in the next reaction. LC-MS: RT=1.49min, [M+H] + =298.26.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(哒嗪-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物(S)-4-(4-(哒嗪-3-基)哌啶-2-基)苯甲酸甲酯(350毫克，1.18毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(681毫克，2.35毫摩尔)溶于1，2-二氯乙烷(20毫升)中，室温搅拌过夜，加入三乙酰氧基硼氢化钠(750毫克，3.53毫摩尔)反应4小时。Compound (S)-4-(4-(pyridazin-3-yl)piperidin-2-yl)benzoate methyl ester (350 mg, 1.18 mmol) and 4-formyl-5-methoxy- 7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (681 mg, 2.35 mmol) was dissolved in 1,2-dichloroethane (20 ml), stirred at room temperature overnight, and added triacetoxy Sodium borohydride (750 mg, 3.53 mmol) was reacted for 4 hours.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/3)。得到430毫克浅黄色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(哒嗪-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率64％)。LC-MS：RT＝1.86min，[M+H]+＝571.40。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/3). 430 mg of light yellow solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(pyridazin-3-yl)piperidine-1- was obtained (methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 64%). LC-MS: RT=1.86min, [M+H] + =571.40.
步骤D：合成化合物37A和37BStep D: Synthesis of Compounds 37A and 37B
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(哒嗪-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(430毫克，0.75毫摩尔)溶于甲醇(20毫升)中，加入碳酸钾(1.04克，7.5毫摩尔)，加热至70℃反应过夜，加入水(5毫升)继续反应4小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)piperidin-1-yl)methyl )-7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (430 mg, 0.75 mmol) was dissolved in methanol (20 ml), potassium carbonate (1.04 g, 7.5 mmol) was added, and heated to The reaction was carried out at 70°C overnight, and water (5 ml) was added to continue the reaction for 4 hours.
反应完成，浓缩，用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到39.4毫克绝对构型的非对映异构体37A(收率：8.6％)和170.8毫克绝对构型的非对映异构体37B(收率：37.3％)。The reaction was completed, concentrated, and purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain a crude product. The resolution of the diastereoisomers was completed by using chiral HPLC (Agilent prep C18). 39.4 mg of absolute diastereomer 37A (yield: 8.6%) and 170.8 mg of absolute diastereomer 37A were obtained by elution with 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution. Diastereomer 37B (yield: 37.3%).
化合物37A：HPLC：RT＝7.0min，LC-MS：RT＝1.59min，[M+H]+＝457.30。(MeOH，Rudolph Autopol I比旋仪)。1H NMR(400MHz，DMSO-d6)δ10.82(s，1H)，9.13(d，J＝8.0Hz，1H)，7.82(d，J＝8.0Hz，2H)，7.76-7.70(m，1H)，7.69-7.63(m，1H)，7.40(d，J＝8.0Hz，2H)，7.27-7.23(m，1H)，6.64(s，1H)，6.50-6.45(m，1H)，3.71-3.63(m，4H)，3.56-3.49(m，1H)，3.29-3.22(m，2H)，2.69-2.61(m，1H)，2.48-2.39(m，4H)，2.27-2.12(m，3H)，1.90-1.79(m，1H).Compound 37A: HPLC: RT=7.0 min, LC-MS: RT=1.59 min, [M+H] + =457.30. (MeOH, Rudolph Autopol I spinometer). 1 H NMR (400MHz, DMSO-d 6 ) δ10.82 (s, 1H), 9.13 (d, J=8.0Hz, 1H), 7.82 (d, J=8.0Hz, 2H), 7.76-7.70 (m, 1H), 7.69-7.63 (m, 1H), 7.40 (d, J=8.0Hz, 2H), 7.27-7.23 (m, 1H), 6.64 (s, 1H), 6.50-6.45 (m, 1H), 3.71 -3.63(m, 4H), 3.56-3.49(m, 1H), 3.29-3.22(m, 2H), 2.69-2.61(m, 1H), 2.48-2.39(m, 4H), 2.27-2.12(m, 3H), 1.90-1.79(m, 1H).
化合物37B：HPLC：RT＝10.4min，LC-MS：RT＝1.59min，[M+H]+＝457.30。(MeOH，Rudolph Autopol I比旋仪)。1H NMR(400MHz，DMSO-d6)δ10.85(s，1H)，9.05(d，J＝8.0Hz，1H)，7.91(d，J＝8.0Hz，2H)，7.66-7.49(m，4H)，7.29-7.29(m，1H)，6.67(s，1H)，6.54-6.47(m，1H)，3.74(s，3H)，3.68-3.60(m，1H)，3.40-3.32(m，1H)，3.29-3.21(m，1H)，3.16-3.05(m，1H)，2.97-2.89(m，1H)，2.43(s，3H)，2.26-2.15(m，1H)，2.00-1.90(m，2H)，1.85-1.78(m，1H)，1.76-1.64(m，1H)Compound 37B: HPLC: RT=10.4min, LC-MS: RT=1.59min, [M+H] + =457.30. (MeOH, Rudolph Autopol I spinometer). 1 H NMR (400MHz, DMSO-d 6 ) δ10.85 (s, 1H), 9.05 (d, J=8.0Hz, 1H), 7.91 (d, J=8.0Hz, 2H), 7.66-7.49 (m, 4H), 7.29-7.29(m, 1H), 6.67(s, 1H), 6.54-6.47(m, 1H), 3.74(s, 3H), 3.68-3.60(m, 1H), 3.40-3.32(m, 1H), 3.29-3.21(m, 1H), 3.16-3.05(m, 1H), 2.97-2.89(m, 1H), 2.43(s, 3H), 2.26-2.15(m, 1H), 2.00-1.90( m, 2H), 1.85-1.78 (m, 1H), 1.76-1.64 (m, 1H)
实施例38Example 38
合成化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸
Synthetic compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(嘧啶-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(0.8克，1.68毫摩尔)，4-氯嘧啶盐酸盐(380毫克，2.52毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(123毫克，0.168毫摩尔)，碳酸氢钠(283毫克，3.36毫摩尔)加入1，4-二氧六环(20毫升)和水(5毫升)中，氮气保护下80℃反应过夜。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (0.8 g, 1.68 mmol), 4-chloropyrimidine hydrochloride (380 mg, 2.52 mmol), [1,1 '-Bis(diphenylphosphine)ferrocene]palladium dichloride (123 mg, 0.168 mmol), sodium bicarbonate (283 mg, 3.36 mmol) were added to 1,4-dioxane (20 ml) and water (5 ml), and reacted overnight at 80°C under nitrogen protection.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)。得到450毫克浅黄色油状(S)-6-(4-(甲氧羰基)苯基)-4-(嘧啶-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率62％)。LC-MS：RT＝2.06min，[M+H]+＝430.19。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2). Obtained 450 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl as a light yellow oil Ester (yield 62%). LC-MS: RT=2.06min, [M+H] + =430.19.
步骤B：合成(S)-4-(4-(嘧啶-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(pyrimidin-4-yl)piperidin-2-yl)benzoic acid methyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(嘧啶-4-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(450毫克，1.05毫摩尔)溶于乙酸乙酯(20毫升)，加入钯/碳(230毫克)，氢气保护下室温反应过夜。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (450 mg , 1.05 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (230 mg) was added, and the reaction was carried out at room temperature overnight under hydrogen protection.
反应完成，过滤，浓缩。得到300毫克黄色油状(S)-4-(4-(嘧啶-4-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝1.53min，[M+H]+＝298.19。The reaction is completed, filtered and concentrated. 300 mg of (S)-4-(4-(pyrimidin-4-yl)piperidin-2-yl)benzoic acid methyl ester (crude product) was obtained as a yellow oil. No purification was required and it was directly used in the next reaction. LC-MS: RT=1.53min, [M+H] + =298.19.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯 Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
将化合物(S)-4-(4-(嘧啶-4-基)哌啶-2-基)苯甲酸甲酯(300毫克，1.01毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(584毫克，2.02毫摩尔)溶于1，2-二氯乙烷(20毫升)，室温搅拌过夜，加入三乙酰氧基硼氢化钠(642毫克，3.53毫摩尔)反应4小时。Compound (S)-4-(4-(pyrimidin-4-yl)piperidin-2-yl)benzoate methyl ester (300 mg, 1.01 mmol) and 4-formyl-5-methoxy-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (584 mg, 2.02 mmol) was dissolved in 1,2-dichloroethane (20 ml), stirred at room temperature overnight, and triacetoxyboration was added. Sodium (642 mg, 3.53 mmol) was reacted for 4 hours.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/9)。得到500毫克浅黄色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率87％)。LC-MS：RT＝1.86min，[M+H]+＝571.34。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/9). 500 mg of light yellow solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(pyrimidin-4-yl)piperidin-1-yl was obtained )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 87%). LC-MS: RT=1.86min, [M+H] + =571.34.
步骤D：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl methyl)-7-methyl-1H-indole-1-carboxylic acid
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(500毫克，0.87毫摩尔)溶于甲醇(20毫升)，加入碳酸钾(1.21克，8.7毫摩尔)，加热至70℃反应过夜，加入水(5毫升)继续反应4小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (500 mg, 0.87 mmol) was dissolved in methanol (20 ml), potassium carbonate (1.21 g, 8.7 mmol) was added, and heated to 70°C The reaction was allowed to proceed overnight, and water (5 ml) was added to continue the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理方法分离得到238.9毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸(收率：59.6％)。The reaction was completed, and 238.9 mg of white solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4) was isolated using the purification method in step D of Example 3. -(pyrimidin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid (yield: 59.6%).
化合物38：HPLC：RT＝7.0min，LC-MS：RT＝1.59min，[M+H]+＝457.30。1H NMR(400MHz，DMSO-d6)δ10.86(s，1H)，9.05(d，J＝8.0Hz，1H)，8.64(d，J＝8.0Hz，1H)，7.85(d，J＝8.0Hz，2H)，7.49-7.35(m，3H)，7.28-7.23(m，1H)，6.66(s，1H)，6.53-6.47(m，1H)，3.73(s，3H)，3.66-3.59(m，1H)，3.29-3.20(m，2H)，2.94-2.83(m，2H)，2.43(s，3H)，2.19-2.10(m，1H)，1.94-1.72(m，3H)，1.68-1.55(m，1H).Compound 38: HPLC: RT=7.0 min, LC-MS: RT=1.59 min, [M+H] + =457.30. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 9.05 (d, J = 8.0Hz, 1H), 8.64 (d, J = 8.0Hz, 1H), 7.85 (d, J = 8.0Hz, 2H), 7.49-7.35(m, 3H), 7.28-7.23(m, 1H), 6.66(s, 1H), 6.53-6.47(m, 1H), 3.73(s, 3H), 3.66-3.59 (m, 1H), 3.29-3.20 (m, 2H), 2.94-2.83 (m, 2H), 2.43 (s, 3H), 2.19-2.10 (m, 1H), 1.94-1.72 (m, 3H), 1.68 -1.55(m,1H).
实施例39A和39BExamples 39A and 39B
合成化合物39A和39B
Synthesis of Compounds 39A and 39B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-((4-甲氧基羰基)苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.47毫摩尔)的1，4-二氧六环(15毫升)中，加入2-溴吡嗪(348毫克，2.20毫摩尔)、[1，1′-双(二苯基膦)二茂铁]二氯化钯(214毫克，0.29毫摩尔)、磷酸钾(634毫克，2.92毫摩尔)和水(3毫升)，置换氮气，升温到95℃反应5小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (700 mg, 1.47 mmol) in 1,4-dioxane (15 ml) was added 2-bromopyridine Azine (348 mg, 2.20 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (214 mg, 0.29 mmol), potassium phosphate (634 mg, 2.92 mmol) and water (3 ml), replaced with nitrogen, raised the temperature to 95°C and reacted for 5 hours.
反应结束，过滤，用乙酸乙酯洗涤，压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶5)得到380毫克淡黄色油状液体(S)-6-((4-甲氧基羰基)苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：60％)。LC-MS：RT＝2.10min，[M+H]+＝430.25。At the end of the reaction, filter, wash with ethyl acetate, and concentrate under pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:5) to obtain 380 mg of light yellow oily liquid (S)-6-((4-methoxycarbonyl)phenyl) -4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 60%). LC-MS: RT=2.10min, [M+H] + =430.25.
步骤B：合成(S)-2-(4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸Step B: Synthesis of (S)-2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid
将(S)-6-((4-甲氧基羰基)苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(380毫克，0.89毫摩尔)溶于乙酸乙酯(10毫升)中，加入钯碳(150毫克)，置换氢气，室温反应3小时。(S)-6-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (380 mg, 0.89 mmol) was dissolved in ethyl acetate (10 ml), palladium on carbon (150 mg) was added, replaced with hydrogen, and reacted at room temperature for 3 hours.
反应结束，过滤，甲醇洗涤，浓缩，得到310毫克淡黄色油状液体(S)-2-((4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸。LC-MS：RT＝2.13min，[M+H]+＝297.19。The reaction was completed, filtered, washed with methanol, and concentrated to obtain 310 mg of light yellow oily liquid (S)-2-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1 -carboxylic acid. LC-MS: RT=2.13min, [M+H] + =297.19.
步骤D：合成(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl )-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-2-((4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸(310毫克，1.04毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(452毫克，1.57毫摩尔)，三乙酰氧基硼氢化钠(881毫克，4.16毫摩尔)，升温至40℃反应过夜。 To 1,2 containing (S)-2-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid (310 mg, 1.04 mmol) -To dichloroethane (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (452 mg, 1.57 mmol), tris Sodium acetoxyborohydride (881 mg, 4.16 mmol), heated to 40°C and reacted overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶1)得到178毫克白色固体(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：30％)。LC-MS：RT＝2.02min，[M+H]+＝571.34。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 178 mg of white solid (S)-5-methoxy- 4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1- Tert-butyl carboxylate (yield: 30%). LC-MS: RT=2.02min, [M+H] + =571.34.
步骤E：化合物39A和39BStep E: Compounds 39A and 39B
向(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(178毫克，0.31毫摩尔)的甲醇(15毫升)中，加入碳酸钾(174毫克，1.25毫摩尔)，加热至70℃反应5小时，加水(3毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (178 mg, 0.31 mmol) in methanol (15 ml), add potassium carbonate (174 mg, 1.25 mmol), heat to 70°C for reaction 5 hour, add water (3 ml) and continue the reaction for 4 hours.
反应结束，浓缩，用硅胶柱层析纯化(洗脱剂：二氯甲烷∶甲醇＝10∶1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到19毫克绝对构型的非对映异构体39A(收率：13％)和71毫克绝对构型的非对映异构体39B(收率：50％)。The reaction was completed, concentrated, and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain a crude product. The resolution of the diastereoisomers was completed by using chiral HPLC (Agilent prep C18). 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution was used for elution and separation to obtain 19 mg of absolute configuration diastereomer 39A (yield: 13%) and 71 mg of absolute configuration diastereomer 39A. Diastereomer 39B (yield: 50%).
化合物39A：HPLC：RT＝9.6min，LC-MS：RT＝1.62min，[M+H]+＝457.26。(MeOH，Rudolph Autopol I比旋仪)。1H NMR(400MHz，DMSO-d6)δ10.86(s，1H)，8.72(d，J＝1.8Hz，1H)，8.67(dd，J＝2.4，1.8Hz，1H)，8.50(d，J＝2.4Hz，1H)，7.82(d，J＝7.8Hz，2H)，7.40(d，J＝7.8Hz，2H)，7.25(t，J＝2.8Hz，1H)，6.63(s，1H)，6.47(t，J＝2.5Hz，1H)，3.67(s，3H)，3.69-3.65(m，1H)，3.51(dd，J＝9.6，3.3Hz，1H)，3.31-3.23(m，2H)，2.67-2.59(m，1H)，2.44-2.39(m，1H)，2.41(s，3H)，2.21-2.08(m，3H)，1.85-1.75(m，1H).Compound 39A: HPLC: RT=9.6min, LC-MS: RT=1.62min, [M+H] + =457.26. (MeOH, Rudolph Autopol I spinometer). 1H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 8.72 (d, J＝1.8Hz, 1H), 8.67 (dd, J＝2.4, 1.8Hz, 1H), 8.50 (d, J＝ 2.4Hz, 1H), 7.82 (d, J=7.8Hz, 2H), 7.40 (d, J=7.8Hz, 2H), 7.25 (t, J=2.8Hz, 1H), 6.63 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 3.67 (s, 3H), 3.69-3.65 (m, 1H), 3.51 (dd, J=9.6, 3.3Hz, 1H), 3.31-3.23 (m, 2H), 2.67-2.59(m, 1H), 2.44-2.39(m, 1H), 2.41(s, 3H), 2.21-2.08(m, 3H), 1.85-1.75(m, 1H).
化合物39B：HPLC：RT＝13.5min，LC-MS：RT＝1.62min，[M+H]+＝457.26。1H NMR(400MHz，DMSO-d6)δ10.83(t，J＝2.4Hz，1H)，8.59(d，J＝1.5Hz，1H)，8.54-8.49(m，1H)，8.44(d，J＝2.5Hz，1H)，7.83(d，J＝7.9Hz，2H)，7.43(d，J＝7.7Hz，2H)，7.26(t，J＝2.7Hz，1H)，6.66(s，1H)，6.50(dd，J＝3.0，1.8Hz，1H)，3.73(s，3H)，3.62(d，J＝11.9Hz，1H)，3.25(dd，J＝12.0，8.4Hz，2H)，3.02-2.86(m，2H)，2.43(s，3H)，2.21-2.10(m，1H)，1.98-1.86(m，2H)，1.81-1.61(m，2H).Compound 39B: HPLC: RT=13.5min, LC-MS: RT=1.62min, [M+H] + =457.26. 1 H NMR (400MHz, DMSO-d 6 ) δ10.83 (t, J=2.4Hz, 1H), 8.59 (d, J=1.5Hz, 1H), 8.54-8.49 (m, 1H), 8.44 (d, J=2.5Hz, 1H), 7.83 (d, J=7.9Hz, 2H), 7.43 (d, J=7.7Hz, 2H), 7.26 (t, J=2.7Hz, 1H), 6.66 (s, 1H) , 6.50 (dd, J=3.0, 1.8Hz, 1H), 3.73 (s, 3H), 3.62 (d, J=11.9Hz, 1H), 3.25 (dd, J=12.0, 8.4Hz, 2H), 3.02- 2.86(m, 2H), 2.43(s, 3H), 2.21-2.10(m, 1H), 1.98-1.86(m, 2H), 1.81-1.61(m, 2H).
通过使用的手性HPLC(Agilent prep C18)来完成(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到107毫克绝对构型中间体I(收率：18％)和178毫克绝对构型的中间体II(收率：30％)。Completion of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl) by using chiral HPLC (Agilent prep C18) Resolution of diastereoisomers of piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester with 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution was eluted and separated to obtain 107 mg of absolute configuration intermediate I (yield: 18%) and 178 mg of absolute configuration intermediate II (yield: 30%).
中间体I的绝对构型的确证：Confirmation of the absolute configuration of intermediate I:
通过MicroED方法成功测定了中间体I的晶体结构，该晶体结构属于正交晶系，P212121(No.19)空间群。MicroED测得的晶胞常数为α＝24，β＝24，γ＝24.，晶胞体积 体系的z′为1，晶体的非对称单元由1个API分子组成。确定了中间体I的绝对构型如下所示，具体如图1所示，中间体I晶体结构的晶体参数图如图2所示，中间体I晶体结构的原子坐标及各项同性位移参数图如图3所示，中间体I晶体结构的XRPD图如图4所示：The crystal structure of intermediate I was successfully determined by the MicroED method. The crystal structure belongs to the orthorhombic crystal system and the P212121 (No. 19) space group. The unit cell constant measured by MicroED is α=24, β=24, γ=24., unit cell volume The z′ of the system is 1, and the asymmetric unit of the crystal is composed of 1 API molecule. The absolute configuration of Intermediate I is determined as follows, as shown in Figure 1. The crystal parameter diagram of the crystal structure of Intermediate I is shown in Figure 2. The atomic coordinates and isotropic displacement parameter diagram of the crystal structure of Intermediate I are shown in Figure 1. As shown in Figure 3, the XRPD pattern of the crystal structure of Intermediate I is shown in Figure 4:
因此，中间体II的结构为 Therefore, the structure of intermediate II is
向中间体I5-甲氧基-4-(((2S，4S)-(2-(4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(80毫克，0.14毫摩尔)的甲醇(15毫升)中，加入碳酸钾(193毫克，1.4毫摩尔)，加热至70℃反应5小时，加水(3毫升)继续反应4小时。反应结束，浓缩，用硅胶柱层析纯化(洗脱剂：二氯甲烷∶甲醇＝10∶1)得到29毫克4-((2S，4S)-1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(吡嗪-2-基)哌啶-2-基)苯甲酸，核磁数据同39A(收率：45％)。To intermediate I5-methoxy-4-(((2S,4S)-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) in methanol (15 ml), add potassium carbonate (193 mg, 1.4 mmol), Heat to 70°C and react for 5 hours, add water (3 ml) and continue the reaction for 4 hours. The reaction was completed, concentrated, and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain 29 mg of 4-((2S, 4S)-1-((5-methoxy-7- Methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid, NMR data are the same as 39A (yield: 45%).
向中间体II 5-甲氧基-4-(((2S，4R)-(2-(4-甲氧基羰基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(160毫克，0.28毫摩尔)的甲醇(15毫升)中，加入碳酸钾(386毫克，2.8毫摩尔)，加热至70℃反应5小时，加水(3毫升)继续反应4小时。反应结束，浓缩，用硅胶柱层析纯化(洗脱剂：二氯甲烷∶甲醇＝10∶1)得到69毫克4-((2S，4R)-1-((5-甲氧基-7-甲基-1H-吲哚-4-基)甲基)-4-(吡嗪-2-基)哌啶-2-基)苯甲酸，核磁数据同39B(收率：54％)。
To intermediate II 5-methoxy-4-(((2S,4R)-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1- To methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (160 mg, 0.28 mmol) in methanol (15 ml), potassium carbonate (386 mg, 2.8 mmol) was added , heated to 70°C for 5 hours, added water (3 ml) and continued the reaction for 4 hours. The reaction was completed, concentrated, and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain 69 mg of 4-((2S, 4R)-1-((5-methoxy-7- Methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid, NMR data are the same as 39B (yield: 54%).
所以，化合物39A和39B分别为：
Therefore, compounds 39A and 39B are respectively:
实施例40A和40BExamples 40A and 40B
合成化合物40A和40B
Synthetic Compounds 40A and 40B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(嘧啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800毫克，1.7毫摩尔)，2-溴嘧啶(333.9毫克，2.5毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(244.1毫克，0.33毫摩尔)，磷酸钾(725.6毫克，3.3毫摩尔)加入1，4-二氧六环(30毫升)和水(6毫升)，氮气保护下，升温至95℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (800 mg, 1.7 mmol), 2-bromopyrimidine (333.9 mg, 2.5 mmol), [1,1'-bis (Diphenylphosphine)ferrocene]palladium dichloride (244.1 mg, 0.33 mmol), potassium phosphate (725.6 mg, 3.3 mmol) were added to 1,4-dioxane (30 ml) and water (6 ml), under nitrogen protection, raise the temperature to 95°C and react for 12 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到600毫克黄色油状(S)-6-(4-(甲氧基羰基)苯基)-4-(嘧啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率83.7％)。LC-MS：RT＝2.10min，[M+H]+＝430.21。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 600 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl as a yellow oil Ester (yield 83.7%). LC-MS: RT=2.10min, [M+H] + =430.21.
步骤B：合成(S)-4-(4-(嘧啶-2-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(pyrimidin-2-yl)piperidin-2-yl)benzoic acid methyl ester
氢气氛围下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(嘧啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(600毫克，1.4毫摩尔)溶于乙酸乙酯(20毫升)，加入钯/碳(600毫克)，室温反应过夜。Under a hydrogen atmosphere, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Benzyl ester (600 mg, 1.4 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (600 mg) was added, and the reaction was carried out at room temperature overnight.
反应完成，过滤，浓缩。得到370毫克浅黄色油状物(S)-4-(4-(嘧啶-2-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝1.52min，[M+H]+＝298.22。The reaction is completed, filtered and concentrated. 370 mg of light yellow oily substance (S)-4-(4-(pyrimidin-2-yl)piperidin-2-yl)benzoic acid methyl ester (crude product) was obtained. No purification was required and it was directly used in the next reaction. LC-MS: RT=1.52min, [M+H] + =298.22.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
将化合物(S)-4-(4-(嘧啶-2-基)哌啶-2-基)苯甲酸甲酯(370毫克，1.2毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(717.6毫克，2.4毫摩尔)溶于1，2-二氯乙烷(7毫升)中，室温搅拌1小时，加入三乙酰氧基硼氢化钠(762.9毫克，3.6毫摩尔)，升温至40℃反应过夜。Compound (S)-4-(4-(pyrimidin-2-yl)piperidin-2-yl)benzoate methyl ester (370 mg, 1.2 mmol) and 4-formyl-5-methoxy-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (717.6 mg, 2.4 mmol) was dissolved in 1,2-dichloroethane (7 ml), stirred at room temperature for 1 hour, and added triacetoxy Sodium borohydride (762.9 mg, 3.6 mmol) was heated to 40°C and reacted overnight.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)。得到330毫克棕色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率48.2％)。LC-MS：RT＝1.84min，[M+H]+＝571.36。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1). 330 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)piperidin-1-yl) were obtained Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 48.2%). LC-MS: RT=1.84min, [M+H] + =571.36.
步骤D：合成化合物40A和40BStep D: Synthesis of Compounds 40A and 40B
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(嘧啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(330毫克，0.57毫摩尔)溶于甲醇(10毫升)，加入碳酸钾(317毫克，2.3毫摩尔)，加热至70℃反应过夜，加入水(2毫升)继续反应2小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (330 mg, 0.57 mmol) was dissolved in methanol (10 ml), potassium carbonate (317 mg, 2.3 mmol) was added, and heated to 70°C The reaction was carried out overnight, water (2 ml) was added and the reaction was continued for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到2.4毫克绝对构型的非对映异构体40A(收率：0.9％)和47毫克绝对构型的非对映异构体40B(收率：18.1％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 2.4 mg of diastereomer 40A with absolute configuration (yield: 0.9%) and 47 mg of diastereoisomer 40A with absolute configuration. Enantiomer 40B (yield: 18.1%).
化合物40A：HPLC：RT＝11.2min，LC-MS：RT＝1.61min，[M+H]+＝457.23。Compound 40A: HPLC: RT=11.2 min, LC-MS: RT=1.61 min, [M+H] + =457.23.
化合物40B：HPLC：RT＝13.8min，LC-MS：RT＝1.61min，[M+H]+＝457.23。Compound 40B: HPLC: RT=13.8 min, LC-MS: RT=1.61 min, [M+H] + =457.23.
1H NMR(400MHz，DMSO-d6)δ10.81(t，J＝2.3Hz，1H)，8.69(d，J＝4.9Hz，2H)，7.85-7.77(m，2H)，7.41(d，J＝7.7Hz，2H)，7.32-7.25(m，1H)，7.25(d，J＝2.7Hz，1H)，6.65(s，1H)，6.51(dd，J＝3.1，1.8Hz，1H)，3.72(s，3H)， 3.68-3.58(m，1H)，3.28-3.22(m，2H)，3.04-2.94(m，1H)，2.92-2.85(m，1H)，2.42(s，3H)，2.13(dd，J＝13.1，10.6Hz，1H)，1.94(q，J＝12.4Hz，2H)，1.84(d，J＝14.3Hz，1H)，1.71-1.58(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (t, J=2.3Hz, 1H), 8.69 (d, J=4.9Hz, 2H), 7.85-7.77 (m, 2H), 7.41 (d, J=7.7Hz, 2H), 7.32-7.25 (m, 1H), 7.25 (d, J=2.7Hz, 1H), 6.65 (s, 1H), 6.51 (dd, J=3.1, 1.8Hz, 1H), 3.72(s,3H), 3.68-3.58(m, 1H), 3.28-3.22(m, 2H), 3.04-2.94(m, 1H), 2.92-2.85(m, 1H), 2.42(s, 3H), 2.13(dd, J=13.1 , 10.6Hz, 1H), 1.94 (q, J=12.4Hz, 2H), 1.84 (d, J=14.3Hz, 1H), 1.71-1.58 (m, 1H).
实施例41A和41BExamples 41A and 41B
合成化合物41A和41B
Synthesis of Compounds 41A and 41B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6′-(4-(甲氧基羰基)苯基)-3′，6′-二氢-[3，4′-联吡啶]-1′(2′H)-羧酸苄酯Step A: Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H) -Benzyl carboxylate
氮气保护下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800毫克，1.67毫摩尔)，3-溴吡啶(395.0毫克，2.5毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(244.1毫克，0.33毫摩尔)，磷酸钾(725毫克，3.3毫摩尔)加入1，4-二氧六环(30毫升)和水(6毫升)，升温至95℃反应12小时。Under nitrogen protection, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle Pentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (800 mg, 1.67 mmol), 3-bromopyridine (395.0 mg, 2.5 mmol), [1, 1′-Bis(diphenylphosphine)ferrocene]palladium dichloride (244.1 mg, 0.33 mmol), potassium phosphate (725 mg, 3.3 mmol) were added to 1,4-dioxane (30 ml) and water (6 ml), and the temperature was raised to 95°C for 12 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到550毫克黄色油状物(S)-6′-(4-(甲氧基羰基)苯基)-3′，6′-二氢-[3，4′-联吡啶]-1′(2′H)-羧酸苄酯(收率76.9％)。LC-MS：RT＝1.91min，[M+H]+＝429.22。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 550 mg of yellow oil (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′ H)-carboxylic acid benzyl ester (yield 76.9%). LC-MS: RT=1.91min, [M+H] + =429.22.
步骤B：合成(S)-4-(4-(吡啶-3-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(pyridin-3-yl)piperidin-2-yl)benzoic acid methyl ester
氢气氛围下，将化合物(S)-6′-(4-(甲氧基羰基)苯基)-3′，6′-二氢-[3，4′-联吡啶]-1′(2′H)-羧酸苄酯(550毫克，1.28毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯/碳(600毫克)，室温反应过夜。Under a hydrogen atmosphere, compound (S)-6'-(4-(methoxycarbonyl)phenyl)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2' H)-carboxylic acid benzyl ester (550 mg, 1.28 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (600 mg) was added, and the reaction was carried out at room temperature overnight.
反应完成，过滤，浓缩。得到360毫克浅黄色油状物(S)-4-(4-(吡啶-3-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝0.49min，[M+H]+＝297.24。The reaction is completed, filtered and concentrated. 360 mg of light yellow oily substance (S)-4-(4-(pyridin-3-yl)piperidin-2-yl)benzoic acid methyl ester (crude product) was obtained. No purification was required and it was directly used in the next reaction. LC-MS: RT=0.49min, [M+H] + =297.24.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(吡啶-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
将化合物(S)-4-(4-(吡啶-3-基)哌啶-2-基)苯甲酸甲酯(360毫克，1.2毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(693毫克，2.4毫摩尔)溶于1，2-二氯乙烷(7毫升)中，室温搅拌1小时，加入三乙酰氧基硼氢化钠(762.9毫克，3.6毫摩尔)，升温至40℃反应过夜。Compound (S)-4-(4-(pyridin-3-yl)piperidin-2-yl)benzoate methyl ester (360 mg, 1.2 mmol) and 4-formyl-5-methoxy-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (693 mg, 2.4 mmol) was dissolved in 1,2-dichloroethane (7 ml), stirred at room temperature for 1 hour, and added triacetoxy Sodium borohydride (762.9 mg, 3.6 mmol) was heated to 40°C and reacted overnight.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)。得到560毫克棕色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(吡啶-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率81.9％)。LC-MS：RT＝1.82min，[M+H]+＝570.37。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2). 560 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl) were obtained Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 81.9%). LC-MS: RT=1.82min, [M+H] + =570.37.
步骤D：合成化合物41A和41BStep D: Synthesis of Compounds 41A and 41B
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(吡啶-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(560毫克，0.98毫摩尔)溶于甲醇(10毫升)，加入碳酸钾(543毫克，3.93毫摩尔)，加热至70℃反应过夜，加入水(2毫升)继续反应2小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (560 mg, 0.98 mmol) was dissolved in methanol (10 ml), potassium carbonate (543 mg, 3.93 mmol) was added, and heated to 70°C The reaction was carried out overnight, water (2 ml) was added and the reaction was continued for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到55毫克绝对构型的非对映异构体41A(收率：12.3％)和270毫克绝对构型的非对映异构体41B(收率：60.5％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 55 mg of diastereomer 41A with absolute configuration (yield: 12.3%) and 270 mg of diastereoisomer 41A with absolute configuration. Enantiomer 41B (yield: 60.5%).
化合物41A：HPLC：RT＝0.895min，LC-MS：RT＝1.50min，[M+H]+＝456.30。Compound 41A: HPLC: RT=0.895 min, LC-MS: RT=1.50 min, [M+H] + =456.30.
1H NMR(400MHz，DMSO-d6)δ10.83(d，J＝2.7Hz，1H)，8.58(d，J＝2.4Hz，1H)，8.43(dd，J＝4.7，1.6Hz，1H)，7.80(d，J＝7.9Hz，3H)，7.43-7.34(m，3H)，7.25(t，J＝2.7Hz，1H)，6.65(s，1H)，6.49(dd，J＝3.1，1.8Hz，1H)，3.75(d，J＝12.0Hz，1H)，3.69(s，3H)，3.58(dd，J＝8.4，3.6Hz，1H)，3.45(d，J＝12.0Hz，1H)，3.06(t，J＝5.3Hz，1H)，2.71-2.62(m，1H)，2.42(s，3H)，2.28(d，J＝11.3Hz，2H)，2.14(ddd，J＝13.5，8.3，4.8Hz，1H)，2.05-1.97(m，1H)，1.75(td，J＝9.3，4.5Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.83 (d, J = 2.7Hz, 1H), 8.58 (d, J = 2.4Hz, 1H), 8.43 (dd, J = 4.7, 1.6Hz, 1H) , 7.80 (d, J=7.9Hz, 3H), 7.43-7.34 (m, 3H), 7.25 (t, J=2.7Hz, 1H), 6.65 (s, 1H), 6.49 (dd, J=3.1, 1.8 Hz, 1H), 3.75 (d, J=12.0Hz, 1H), 3.69 (s, 3H), 3.58 (dd, J=8.4, 3.6Hz, 1H), 3.45 (d, J=12.0Hz, 1H), 3.06 (t, J=5.3Hz, 1H), 2.71-2.62 (m, 1H), 2.42 (s, 3H), 2.28 (d, J=11.3Hz, 2H), 2.14 (ddd, J=13.5, 8.3, 4.8Hz, 1H), 2.05-1.97 (m, 1H), 1.75 (td, J=9.3, 4.5Hz, 1H).
化合物41B：HPLC：RT＝0.800min，LC-MS：RT＝1.50min，[M+H]+＝456.30。Compound 41B: HPLC: RT=0.800min, LC-MS: RT=1.50min, [M+H] + =456.30.
1H NMR(400MHz，DMSO-d6)δ10.85(t，J＝2.3Hz，1H)，8.46(d，J＝2.3Hz，1H)，8.36(dd，J＝4.7，1.6Hz，1H)，7.88-7.82(m，2H)，7.66(dt，J＝8.0，2.0Hz，1H)，7.46(d，J＝7.7Hz，2H)，7.30-7.22(m，2H)，6.65(s，1H)，6.47(dd，J＝ 3.1，1.9Hz，1H)，3.72(s，3H)，3.62(d，J＝11.8Hz，1H)，3.29-3.25(m，1H)，3.23(d，J＝6.0Hz，1H)，2.89(dt，J＝11.8，3.3Hz，1H)，2.76(s，1H)，2.42(s，3H)，2.21-2.10(m，1H)，1.80(t，J＝9.7Hz，2H)，1.68(d，J＝12.1Hz，1H)，1.57(qd，J＝12.4，3.5Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.85 (t, J=2.3Hz, 1H), 8.46 (d, J=2.3Hz, 1H), 8.36 (dd, J=4.7, 1.6Hz, 1H) , 7.88-7.82 (m, 2H), 7.66 (dt, J=8.0, 2.0Hz, 1H), 7.46 (d, J=7.7Hz, 2H), 7.30-7.22 (m, 2H), 6.65 (s, 1H ), 6.47 (dd, J＝ 3.1, 1.9Hz, 1H), 3.72 (s, 3H), 3.62 (d, J=11.8Hz, 1H), 3.29-3.25 (m, 1H), 3.23 (d, J=6.0Hz, 1H), 2.89 ( dt, J=11.8, 3.3Hz, 1H), 2.76 (s, 1H), 2.42 (s, 3H), 2.21-2.10 (m, 1H), 1.80 (t, J=9.7Hz, 2H), 1.68 (d , J=12.1Hz, 1H), 1.57 (qd, J=12.4, 3.5Hz, 1H).
实施例42A和42BExamples 42A and 42B
合成化合物42A和42B
Synthesis of Compounds 42A and 42B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-3，6-二氢-[4，4′-联吡啶]-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-carboxylic acid benzyl ester
氮气保护下，将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(650毫克，1.45毫摩尔)，4-溴吡啶(343.3毫克，2.1毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(211.9毫克，0.29毫摩尔)，磷酸钾(630毫克，2.9毫摩尔)加入1，4-二氧六环(20毫升)和水(4毫升)，升温至95℃反应12小时。Under nitrogen protection, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle Pentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (650 mg, 1.45 mmol), 4-bromopyridine (343.3 mg, 2.1 mmol), [1, 1′-Bis(diphenylphosphine)ferrocene]palladium dichloride (211.9 mg, 0.29 mmol), potassium phosphate (630 mg, 2.9 mmol) were added to 1,4-dioxane (20 ml) and water (4 ml), and the temperature was raised to 95°C for 12 hours.
反应完成，加入乙酸乙酯(50毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)。得到390毫克黄色油状物(S)-6-(4-(甲氧基羰基)苯基)-3，6-二氢-[4，4′-联吡啶]-1(2H)-羧酸苄酯(收率62.8％)。LC-MS：RT＝1.81min，[M+H]+＝429.22。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1). Obtained 390 mg of yellow oil (S)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-carboxylic acid benzyl Ester (yield 62.8%). LC-MS: RT=1.81 min, [M+H] + =429.22.
步骤B：合成(S)-4-(4-(吡啶-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(pyridin-4-yl)piperidin-2-yl)benzoic acid methyl ester
氢气氛围下，将化合物(S)-6-(4-(甲氧基羰基)苯基)-3，6-二氢-[4，4′-联吡啶]-1(2H)-羧酸苄酯(390毫克，0.91毫摩尔)溶于乙酸乙酯(20毫升)中，加入钯/碳(400毫克)，室温反应过夜。Under a hydrogen atmosphere, compound (S)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-carboxylic acid benzyl The ester (390 mg, 0.91 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (400 mg) was added, and the reaction was carried out at room temperature overnight.
反应完成，过滤，浓缩。得到230毫克浅黄色油状物(S)-4-(4-(吡啶-4-基)哌啶-2-基)苯甲酸甲酯(粗品)，不需要纯化，直接用于下一步反应。LC-MS：RT＝0.494min，[M+H]+＝297.23。The reaction is completed, filtered and concentrated. 230 mg of light yellow oily substance (S)-4-(4-(pyridin-4-yl)piperidin-2-yl)benzoic acid methyl ester (crude product) was obtained. No purification was required and it was directly used in the next reaction. LC-MS: RT=0.494min, [M+H] + =297.23.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(吡啶-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-4-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate
将化合物(S)-4-(4-(吡啶-4-基)哌啶-2-基)苯甲酸甲酯(230毫克，0.77毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(450毫克，1.55毫摩尔)溶于1，2-二氯乙烷(5毫升)，室温搅拌1小时，加入三乙酰氧基硼氢化钠(490毫克，2.3毫摩尔)，升温至40℃反应过夜。Compound (S)-4-(4-(pyridin-4-yl)piperidin-2-yl)benzoate methyl ester (230 mg, 0.77 mmol) and 4-formyl-5-methoxy-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (450 mg, 1.55 mmol) was dissolved in 1,2-dichloroethane (5 ml), stirred at room temperature for 1 hour, and triacetoxyboron was added Sodium hydride (490 mg, 2.3 mmol) was heated to 40°C and reacted overnight.
反应完成，加入甲醇，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/2)。得到320毫克棕色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(吡啶-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率72.9％)。LC-MS：RT＝1.79min，[M+H]+＝570.33。When the reaction is completed, methanol is added and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/2). Obtained 320 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 72.9%). LC-MS: RT=1.79min, [M+H] + =570.33.
步骤D：合成化合物42A和42BStep D: Synthesis of Compounds 42A and 42B
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(吡啶-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(320毫克，0.56毫摩尔)溶于甲醇(15毫升)中，加入碳酸钾(310毫克，2.24毫摩尔)，加热至70℃反应过夜，加入水(2毫升)继续反应2小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-4-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (320 mg, 0.56 mmol) was dissolved in methanol (15 ml), potassium carbonate (310 mg, 2.24 mmol) was added, and heated to 70 The reaction was carried out overnight at ℃, and water (2 ml) was added to continue the reaction for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到40毫克绝对构型的非对映异构体42A(收率：15.6％)和170毫克绝对构型的非对映异构体42B(收率：66.7％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 40 mg of diastereoisomer 42A with absolute configuration (yield: 15.6%) and 170 mg of diastereoisomer 42A with absolute configuration. Enantiomer 42B (yield: 66.7%).
化合物42A：HPLC：RT＝0.993min，LC-MS：RT＝1.50min，[M+H]+＝456.29。Compound 42A: HPLC: RT=0.993 min, LC-MS: RT=1.50 min, [M+H] + =456.29.
1H NMR(400MHz，DMSO-d6)δ10.82(s，1H)，8.56-8.50(m，2H)，7.80(d，J＝7.9Hz，2H)，7.43-7.36(m，4H)，7.25(t，J＝2.7Hz，1H)，6.64(s，1H)，6.48(dd，J＝3.0，1.7Hz，1H)，3.68(s，3H)，3.49(dd，J＝8.6，3.3Hz，1H)，3.37(s，2H)，3.02(t，J＝5.1Hz，1H)，2.64(dd，J＝11.6，6.3Hz，1H)，2.41(s，3H)，2.27(d，J＝14.2Hz，1H)，2.22-2.07(m，2H)，2.02(d，J＝13.4Hz，1H)，1.77(td，J＝9.6，9.1，5.0Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 8.56-8.50 (m, 2H), 7.80 (d, J=7.9Hz, 2H), 7.43-7.36 (m, 4H), 7.25 (t, J=2.7Hz, 1H), 6.64 (s, 1H), 6.48 (dd, J=3.0, 1.7Hz, 1H), 3.68 (s, 3H), 3.49 (dd, J=8.6, 3.3Hz , 1H), 3.37 (s, 2H), 3.02 (t, J=5.1Hz, 1H), 2.64 (dd, J=11.6, 6.3Hz, 1H), 2.41 (s, 3H), 2.27 (d, J= 14.2Hz, 1H), 2.22-2.07 (m, 2H), 2.02 (d, J=13.4Hz, 1H), 1.77 (td, J=9.6, 9.1, 5.0Hz, 1H).
化合物42B：HPLC：RT＝0.786min，LC-MS：RT＝1.50min，[M+H]+＝456.29。Compound 42B: HPLC: RT=0.786min, LC-MS: RT=1.50min, [M+H] + =456.29.
1H NMR(400MHz，DMSO-d6)δ10.85(t，J＝2.4Hz，1H)，8.448.38(m，2H)，7.85(d，J＝7.9Hz，2H)，7.45(d，J＝7.7Hz，2H)，7.28-7.22(m，3H)，6.65(s，1H)，6.46(dd，J＝3.0，1.9Hz，1H)，3.72(s，3H)，3.61(d，J＝11.8Hz，1H)， 3.28-3.20(m，2H)，2.89(dt，J＝11.8，3.3Hz，1H)，2.74(tt，J＝12.0，3.8Hz，1H)，2.42(s，3H)，2.14(td，J＝11.9，2.3Hz，1H)，1.88-1.65(m，3H)，1.54(qd，J＝12.4，3.5Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.85 (t, J = 2.4Hz, 1H), 8.448.38 (m, 2H), 7.85 (d, J = 7.9Hz, 2H), 7.45 (d, J=7.7Hz, 2H), 7.28-7.22 (m, 3H), 6.65 (s, 1H), 6.46 (dd, J=3.0, 1.9Hz, 1H), 3.72 (s, 3H), 3.61 (d, J =11.8Hz, 1H), 3.28-3.20 (m, 2H), 2.89 (dt, J=11.8, 3.3Hz, 1H), 2.74 (tt, J=12.0, 3.8Hz, 1H), 2.42 (s, 3H), 2.14 (td, J= 11.9, 2.3Hz, 1H), 1.88-1.65 (m, 3H), 1.54 (qd, J=12.4, 3.5Hz, 1H).
实施例43A和43BExamples 43A and 43B
合成化合物43A和43B
Synthesis of Compounds 43A and 43B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(嘧啶-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(400毫克，0.84毫摩尔)的1，4-二氧六环(5毫升)中，加入5-溴嘧啶(200毫克，1.26毫摩尔)、[1，1′-双(二苯基膦)二茂铁]二氯化钯(61毫克，0.08毫摩尔)、磷酸钾(446毫克，2.10毫摩尔)和水(1毫升)，置换氮气，升温到90℃反应过夜。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 0.84 mmol) in 1,4-dioxane (5 ml) was added 5-bromo Pyrimidine (200 mg, 1.26 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (61 mg, 0.08 mmol), potassium phosphate (446 mg, 2.10 mmol) and water (1 ml), replaced with nitrogen, heated to 90°C and reacted overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)得到150毫克淡黄色油状液体(S)-6-(4-(甲氧羰基)苯基)-4-(嘧啶-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：42％)。LC-MS：RT＝1.97min，[M+H]+＝430.22。At the end of the reaction, filter, wash with ethyl acetate and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 4/1) to obtain 150 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl)- 4-(pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 42%). LC-MS: RT=1.97min, [M+H] + =430.22.
步骤B：合成(S)-4-(4-(嘧啶-5-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(pyrimidin-5-yl)piperidin-2-yl)benzoic acid methyl ester
将(S)-6-(4-(甲氧羰基)苯基)-4-(嘧啶-5-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(250毫克，0.58毫摩尔)溶于乙酸乙酯溶液(10毫升)中，加入钯碳(100毫克)，置换氢气，升温到60℃反应过夜。(S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate benzyl ester (250 mg, 0.58 mmol) was dissolved in ethyl acetate solution (10 ml), palladium on carbon (100 mg) was added, hydrogen was replaced, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，用乙酸乙酯洗涤，浓缩，得到100毫克淡黄色油状液体(S)-4-(4-(嘧啶-5-基)哌啶-2-基)苯甲酸甲酯(收率：59％)。LC-MS：RT＝1.49min，[M+H]+＝298.22。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 100 mg of light yellow oily liquid (S)-4-(4-(pyrimidin-5-yl)piperidin-2-yl)benzoic acid methyl ester (yield :59%). LC-MS: RT=1.49min, [M+H] + =298.22.
步骤C：合成(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(嘧啶-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸酯叔丁酯Step C: Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylate tert-butyl ester
向含有(S)-4-(4-(嘧啶-5-基)哌啶-2-基)苯甲酸甲酯(100毫克，0.34毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(246毫克，0.85毫摩尔)和三乙酰氧基硼氢化钠(144毫克，0.68毫摩尔)，升温至40℃反应过夜。To (S)-4-(4-(pyrimidin-5-yl)piperidin-2-yl)benzoate methyl ester (100 mg, 0.34 mmol) in 1,2-dichloroethane (5 mL) , add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (246 mg, 0.85 mmol) and sodium triacetoxyborohydride (144 mg , 0.68 mmol), the temperature was raised to 40°C and the reaction was carried out overnight.
反应结束，加入甲醇，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到145毫克淡黄色油状物(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(嘧啶-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸酯叔丁酯(收率：74％)。LC-MS：RT＝1.84min，[M+H]+＝571.31。After the reaction was completed, methanol was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 145 mg of light yellow oily substance (S)-5-methoxy. Base-4-(2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1 - Carboxylic acid ester tert-butyl ester (yield: 74%). LC-MS: RT=1.84min, [M+H] + =571.31.
步骤D：合成化合物43A和43BStep D: Synthesis of Compounds 43A and 43B
向(S)-5-甲氧基-4-(2-(4-(甲氧羰基)苯基)-4-(嘧啶-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸酯叔丁酯(145毫克，0.25毫摩尔)的甲醇(5毫升)中加入碳酸钾(138毫克，1.00毫摩尔)，加热至70℃反应5小时，加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)piperidin-1-yl)methyl)-7- Add potassium carbonate (138 mg, 1.00 mmol) to methanol (5 ml) of methyl-1H-indole-1-carboxylate tert-butyl ester (145 mg, 0.25 mmol), and heat to 70°C for 5 hours. , add water (1 ml) and continue the reaction for 4 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到16.8毫克绝对构型的非对映异构体43A(收率：15％)和56.4毫克绝对构型的非对映异构体43B(收率：49％)。The reaction was completed, and the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 16.8 mg of diastereomer 43A with absolute configuration (yield: 15%) and 56.4 mg of diastereoisomer 43A with absolute configuration. Enantiomer 43B (yield: 49%).
化合物43A：HPLC：RT＝12.8min，LC-MS：RT＝1.59min，[M+H]+＝457.29。Compound 43A: HPLC: RT=12.8 min, LC-MS: RT=1.59 min, [M+H] + =457.29.
化合物43B：HPLC：RT＝13.4min，LC-MS：RT＝1.59min，[M+H]+＝457.29。1H NMR(400MHz，DMSO-d6)δ10.81(s，1H)，8.99(s，1H)，8.71(s，2H)，7.83(d，J＝7.9Hz，2H)，7.43(d，J＝7.7Hz，2H)，7.24(t，J＝2.7Hz，1H)，6.65(s，1H)，6.45(dd，J＝3.1，1.7Hz，1H)，3.72(s，3H)，3.61(d，J＝11.8Hz，1H)，3.28-3.23(m，2H)，3.21(d，J＝11.7Hz，1H)，2.93-2.86(m，1H)，2.42(s，3H)，2.20-2.10(m，1H)，1.85(t，J＝8.9Hz，2H)，1.71(d，J＝12.3Hz，1H)，1.62(dd，J＝12.3，3.6Hz，1H)。Compound 43B: HPLC: RT=13.4min, LC-MS: RT=1.59min, [M+H] + =457.29. 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 8.99 (s, 1H), 8.71 (s, 2H), 7.83 (d, J=7.9Hz, 2H), 7.43 (d, J =7.7Hz, 2H), 7.24 (t, J = 2.7Hz, 1H), 6.65 (s, 1H), 6.45 (dd, J = 3.1, 1.7Hz, 1H), 3.72 (s, 3H), 3.61 (d , J＝11.8Hz, 1H), 3.28-3.23(m, 2H), 3.21(d, J＝11.7Hz, 1H), 2.93-2.86(m, 1H), 2.42(s, 3H), 2.20-2.10( m, 1H), 1.85 (t, J=8.9Hz, 2H), 1.71 (d, J=12.3Hz, 1H), 1.62 (dd, J=12.3, 3.6Hz, 1H).
实施例44A和44B
Examples 44A and 44B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)-6-(4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3 , 6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-(甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1克，2.09毫摩尔)的二氧六环(10毫升)中，加入2-溴-6，7-二氢-5H-吡咯并[1，2-a]咪唑(587毫克，3.14毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(154毫克，0.21毫摩尔)和磷酸钾(1.11克，5.23毫摩尔)，然后加入水(2毫升)，反应置换氮气后，升温到90℃反应5小时。At room temperature, the solution containing (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.09 mmol) in dioxane (10 ml) was added 2-bromo-6,7 -Dihydro-5H-pyrrolo[1,2-a]imidazole (587 mg, 3.14 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (154 mg, 0.21 mmol) and potassium phosphate (1.11 g, 5.23 mmol), and then add water (2 ml). After replacing nitrogen, the temperature was raised to 90°C for 5 hours.
反应结束后过滤，用乙酸乙酯洗涤，有机相直接减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)得到540毫克淡黄色油状液体(S)-4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)-6-(4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：57％)。LCMS：RT＝1.77min，[M+H]+＝458.29。After the reaction, it was filtered, washed with ethyl acetate, and the organic phase was directly concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 2/1) to obtain 540 mg of light yellow oily liquid (S)-4-(6,7-dihydro-5H-pyrrole [ 1,2-a]imidazol-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (Yield: 57% ). LCMS: RT=1.77min, [M+H] + =458.29.
步骤B：合成(S)-4-(4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)piperidin-2-yl)benzoate methyl ester
将(S)-4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)-6-(4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(540毫克，1.18毫摩尔)溶于乙酸乙酯溶液(20毫升)中，加入钯碳(300毫克)，反应置换氢气后，升温到50℃反应2小时。(S)-4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6- Dihydropyridine-1(2H)-carboxylic acid benzyl ester (540 mg, 1.18 mmol) was dissolved in ethyl acetate solution (20 ml), palladium on carbon (300 mg) was added, and after the reaction displaced hydrogen, the temperature was raised to 50°C. Reaction takes 2 hours.
反应结束后过滤，用乙酸乙酯洗涤，有机相直接减压浓缩得到240毫克淡黄色油状液体(S)-4-(4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)哌啶-2-基)苯甲酸甲酯(收率：63％)。LCMS：RT＝0.26min，[M+H]+＝326.30。After the reaction, it was filtered, washed with ethyl acetate, and the organic phase was directly concentrated under reduced pressure to obtain 240 mg of light yellow oily liquid (S)-4-(4-(6,7-dihydro-5H-pyrrole [1,2-a ]imidazol-2-yl)piperidin-2-yl)benzoic acid methyl ester (yield: 63%). LCMS: RT = 0.26 min, [M+H] + = 326.30.
步骤C：合成(S)-4-(4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-4-(4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-2-(4-(methoxycarbonyl)phenyl) )piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)哌啶-2-基)苯甲酸甲酯(240毫克，0.74毫摩尔)的1，2-二氯乙烷(10毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(535毫克，1.85毫摩尔)和三乙酰氧基硼氢化钠(314毫克，1.48毫摩尔)，40℃反应过夜。To a solution containing (S)-4-(4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)piperidin-2-yl)benzoate (240 mg, 0.74 mmol) of 1,2-dichloroethane (10 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (535 mg, 1.85 mmol) and sodium triacetoxyborohydride (314 mg, 1.48 mmol), react overnight at 40°C.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到158毫克淡黄色油状液体(S)-4-(4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：35％)。LCMS：RT＝1.70min，[M+H]+＝599.34。After the reaction was completed, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 158 mg of light yellow oily liquid (S)-4-(4 -(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)- 5-Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 35%). LCMS: RT=1.70min, [M+H] + =599.34.
步骤D：合成化合物44A和44BStep D: Synthesis of Compounds 44A and 44B
向(S)-4-(4-(6，7-二氢-5H-吡咯[1，2-a]咪唑-2-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(158毫克，0.26毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(144毫克，1.04毫摩尔)，且将该溶液加热至70℃，持续5小时。再加水(1毫升)在70℃继续加热4小时。To (S)-4-(4-(6,7-dihydro-5H-pyrrole[1,2-a]imidazol-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine To a solution of -1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (158 mg, 0.26 mmol) in methanol (5 ml) was added carbonic acid Potassium (144 mg, 1.04 mmol) and the solution was heated to 70°C for 5 hours. Add water (1 ml) and continue heating at 70°C for 4 hours.
反应完成后，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到4.4毫克绝对构型的非对映异构体44A(收率：3％)和8.7毫克绝对构型的非对映异构体44B(收率：7％)。After the reaction was completed, the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 4.4 mg of diastereoisomer 44A with absolute configuration (yield: 3%) and 8.7 mg of diastereoisomer 44A with absolute configuration. Enantiomer 44B (yield: 7%).
化合物44A：HPLC：RT＝3.707min，LCMS：RT＝1.52min，[M+H]+＝485.31。Compound 44A: HPLC: RT=3.707 min, LCMS: RT=1.52 min, [M+H] + =485.31.
化合物44B：HPLC：RT＝3.995min，LCMS：RT＝1.52min，[M+H]+＝485.31。Compound 44B: HPLC: RT=3.995 min, LCMS: RT=1.52 min, [M+H] + =485.31.
1H NMR(400MHz，DMSO-d6)δ10.80(s，1H)，7.81(d，J＝7.8Hz，2H)，7.38(d，J＝7.7Hz，2H)，7.23(t，J＝2.7Hz，1H)，6.68(s，1H)，6.64(s，1H)，6.47(t，J＝2.4Hz，1H)，3.80(t，J＝7.0Hz，2H)，3.71(s，3H)，3.58(d，J＝11.9Hz，1H)，3.22-3.14(m，2H)，2.81(dt，J＝11.7，3.4Hz，1H)，2.65-2.58(m，2H)，2.58-2.52(m，1H)，2.46-2.35(m，5H)，2.05(t，J＝11.9Hz，1H)，1.89(d，J＝12.7Hz，1H)，1.74(d，J＝12.7Hz，1H)，1.64(q，J＝12.3Hz，1H)，1.45-1.31(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.80 (s, 1H), 7.81 (d, J=7.8Hz, 2H), 7.38 (d, J=7.7Hz, 2H), 7.23 (t, J= 2.7Hz, 1H), 6.68 (s, 1H), 6.64 (s, 1H), 6.47 (t, J=2.4Hz, 1H), 3.80 (t, J=7.0Hz, 2H), 3.71 (s, 3H) , 3.58 (d, J = 11.9Hz, 1H), 3.22-3.14 (m, 2H), 2.81 (dt, J = 11.7, 3.4Hz, 1H), 2.65-2.58 (m, 2H), 2.58-2.52 (m , 1H), 2.46-2.35 (m, 5H), 2.05 (t, J=11.9Hz, 1H), 1.89 (d, J=12.7Hz, 1H), 1.74 (d, J=12.7Hz, 1H), 1.64 (q, J=12.3Hz, 1H), 1.45-1.31 (m, 1H).
实施例45
Example 45
化合物45的合成路线如下：
The synthetic route of compound 45 is as follows:
步骤A：合成(S)-6-甲氧基-6′-(4-(甲氧羰基)苯基)-3′，6′-二氢-[2，4′-联吡啶]-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-methoxy-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridyl]-1( 2H)-Carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700.0毫克，1.46毫摩尔)，2-溴-6-甲氧基吡啶(258.4毫克，2.2毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(213.4毫克，0.29毫摩尔)，磷酸钾(634.4毫克，2.92毫摩尔)加入1，4-二氧六环(20毫升)和水(4毫升)，氮气保护下95℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Benzyl)-3,6-dihydropyridine-1(2H)-carboxylate (700.0 mg, 1.46 mmol), 2-bromo-6-methoxypyridine (258.4 mg, 2.2 mmol), [ 1,1′-Bis(diphenylphosphine)ferrocene]palladium dichloride (213.4 mg, 0.29 mmol), potassium phosphate (634.4 mg, 2.92 mmol) were added to 1,4-dioxane (20 ml) and water (4 ml), react at 95°C for 12 hours under nitrogen protection.
反应完成后，加入乙酸乙酯(50毫升)稀释，过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)。得到500.0毫克深黄色固体(S)-6-甲氧基-6′-(4-(甲氧羰基)苯基)-3′，6′-二氢-[2，4′-联吡啶]-1(2H)-羧酸苄酯(收率74.7％)。LCMS：RT＝2.29min，[M+H]+＝459.24。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). 500.0 mg of dark yellow solid (S)-6-methoxy-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridyl]- was obtained 1(2H)-carboxylic acid benzyl ester (yield 74.7%). LCMS: RT = 2.29 min, [M+H] + = 459.24.
步骤B：合成(S)-4-(4-(6-甲氧基吡啶-2-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(6-methoxypyridin-2-yl)piperidin-2-yl)benzoate methyl ester
将化合物(S)-6-甲氧基-6′-(4-(甲氧羰基)苯基)-3′，6′-二氢-[2，4′-联吡啶]-1(2H)-羧酸苄酯(500毫克，1.1毫摩尔)溶于乙酸乙酯(20毫升)，加入钯/碳(500毫克)，氢气保护下室温反应12小时。Compound (S)-6-methoxy-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridyl]-1(2H) - Benzyl carboxylate (500 mg, 1.1 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (500 mg) was added, and the reaction was carried out at room temperature under hydrogen protection for 12 hours.
反应完成后，抽滤，减压浓缩。得到340毫克黄色油状(S)-4-(4-(6-甲氧基吡啶-2-基)哌啶-2-基)苯甲酸甲酯，不需要纯化，直接用于下一步反应。LCMS：RT＝1.65min，[M+H]+＝327.26。After the reaction was completed, it was filtered with suction and concentrated under reduced pressure. 340 mg of (S)-4-(4-(6-methoxypyridin-2-yl)piperidin-2-yl)benzoic acid methyl ester was obtained as a yellow oil. No purification was required and it was directly used in the next reaction. LCMS: RT=1.65min, [M+H] + =327.26.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(6-甲氧基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(6-methoxypyridin-2-yl)piperidine-1 -(yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物(S)-4-(4-(6-甲氧基吡啶-2-基)哌啶-2-基)苯甲酸甲酯(340.0毫克，1.0毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(578.0毫克，2.0毫摩尔)溶于1，2-二氯乙烷(7毫升)，室温搅拌12小时，然后缓慢加入三乙酰氧基硼氢化钠(635.8毫克，3.0毫摩尔)，40℃反应4小时。Compound (S)-4-(4-(6-methoxypyridin-2-yl)piperidin-2-yl)benzoate methyl ester (340.0 mg, 1.0 mmol) and 4-formyl-5- Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (578.0 mg, 2.0 mmol) was dissolved in 1,2-dichloroethane (7 ml), stirred at room temperature for 12 hours, and then Slowly add sodium triacetoxyborohydride (635.8 mg, 3.0 mmol), and react at 40°C for 4 hours.
反应完成后，加入甲醇溶解至澄清，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)。得到300毫克浅黄色固体(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(6-甲氧基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率50.0％)。LCMS：RT＝1.95min，[M+H]+＝600.34。After the reaction is completed, add methanol to dissolve until clear, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). 300 mg of light yellow solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl))-4-(6-methoxypyridin-2-yl)piperidine was obtained -1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 50.0%). LCMS: RT = 1.95 min, [M+H] + = 600.34.
步骤D：合成化合物45Step D: Synthesis of Compound 45
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(6-甲氧基吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(300毫克，0.5毫摩尔)溶于甲醇(20毫升)，加入碳酸钾(276.0毫克，2.0毫摩尔)，加热至70℃搅拌过夜。再加入水(1毫升)，70℃反应12小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(6-methoxypyridin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (300 mg, 0.5 mmol) was dissolved in methanol (20 ml), and potassium carbonate (276.0 mg, 2.0 mmol) was added. Heat to 70°C and stir overnight. Then add water (1 ml) and react at 70°C for 12 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到25.0毫克绝对构型的非对映异构体45(收率：10.3％)。The reaction was completed, and 25.0 mg of the absolute configuration of diastereomer 45 was isolated using the purification treatment and chiral resolution method in step D of Example 3 (yield: 10.3%).
化合物45：HPLC：RT＝3.489min，LCMS：RT＝1.70min，[M+H]+＝486.27.Compound 45: HPLC: RT=3.489min, LCMS: RT=1.70min, [M+H] + =486.27.
1H NMR(400MHz，DMSO-d6)δ10.82(d，J＝2.7Hz，1H)，7.82(d，J＝7.8Hz，2H)，7.60-7.52(m，1H)，7.41(d，J＝7.6Hz，2H)，7.25(t，J＝2.8Hz，1H)，6.81(d，J＝7.3Hz，1H)，6.65(s，1H)，6.57(d，J＝8.2Hz，1H)，6.46(dd，J＝3.1，1.8Hz，1H)，3.79(s，3H)，3.72(s，3H)，3.61(d，J＝11.8Hz，1H)，3.28-3.17(m，2H)，2.92-2.85(m，1H)，2.82-2.71(m，1H)，2.42(s，3H)，2.18-2.07(m，1H)，1.84(dt，J＝24.2，13.2Hz，2H)，1.74(d，J＝12.9Hz，1H)，1.69-1.55(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.82 (d, J = 2.7Hz, 1H), 7.82 (d, J = 7.8Hz, 2H), 7.60-7.52 (m, 1H), 7.41 (d, J=7.6Hz, 2H), 7.25 (t, J=2.8Hz, 1H), 6.81 (d, J=7.3Hz, 1H), 6.65 (s, 1H), 6.57 (d, J=8.2Hz, 1H) , 6.46 (dd, J=3.1, 1.8Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.61 (d, J=11.8Hz, 1H), 3.28-3.17 (m, 2H), 2.92-2.85(m, 1H), 2.82-2.71(m, 1H), 2.42(s, 3H), 2.18-2.07(m, 1H), 1.84(dt, J=24.2, 13.2Hz, 2H), 1.74( d, J=12.9Hz, 1H), 1.69-1.55 (m, 1H).
化合物46A和46B
Compounds 46A and 46B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-(4-(甲氧羰基)苯基)-4-(5-甲基噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800.0毫克，1.67毫摩尔)，2-溴-5-甲基噻吩(445.0毫克，2.5毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(244.0毫克，0.33毫摩尔)，磷酸钾(725.0毫克，3.34毫摩尔)加入1，4-二氧六环(20毫升)，水(4毫升)。氮气保护下95℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (800.0 mg, 1.67 mmol), 2-bromo-5-methylthiophene (445.0 mg, 2.5 mmol), [1 , 1'-bis(diphenylphosphine)ferrocene]palladium dichloride (244.0 mg, 0.33 mmol), potassium phosphate (725.0 mg, 3.34 mmol) was added to 1,4-dioxane (20 ml ), water (4 ml). React at 95°C for 12 hours under nitrogen protection.
反应完成后，加入乙酸乙酯(50毫升)稀释，过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)。得到390.0毫克深黄色固体(S)-6-(4-(甲氧羰基)苯基)-4-(5-甲基噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率52.2％)。LCMS：RT＝2.30min，[M+H]+＝448.22。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). Obtained 390.0 mg of dark yellow solid (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)-3,6-dihydropyridine-1(2H) - Benzyl carboxylate (yield 52.2%). LCMS: RT=2.30min, [M+H] + =448.22.
步骤B：合成4-((2S)-4-(5-甲基噻吩-2-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of methyl 4-((2S)-4-(5-methylthiophen-2-yl)piperidin-2-yl)benzoate
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(5-甲基噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(390.0毫克，0.87毫摩尔)溶于乙酸乙酯(25毫升)，加入钯/碳(390毫克)，氢气保护下60℃反应36小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl The ester (390.0 mg, 0.87 mmol) was dissolved in ethyl acetate (25 ml), palladium/carbon (390 mg) was added, and the reaction was carried out at 60°C for 36 hours under hydrogen protection.
反应完成后，过滤，减压浓缩。得到210.0毫克黄色油状4-((2S)-4-(5-甲基噻吩-2-基)哌啶-2-基)苯甲酸甲酯，不需要纯化，直接用于下一步反应。LCMS：RT＝1.73min，[M+H]+＝316.19。After the reaction is completed, filter and concentrate under reduced pressure. 210.0 mg of methyl 4-((2S)-4-(5-methylthiophen-2-yl)piperidin-2-yl)benzoate was obtained as a yellow oil. No purification was required and it was directly used in the next reaction. LCMS: RT = 1.73 min, [M+H] + = 316.19.
步骤C：合成5-甲氧基-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(5-甲基噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of 5-methoxy-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)piperidin-1-yl) )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物4-((2S)-4-(5-甲基噻吩-2-基)哌啶-2-基)苯甲酸甲酯(210.0毫克，0.66毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(381.4毫克，1.32毫摩尔)溶于1，2-二氯乙烷(6毫升)，室温搅拌12小时，然后缓慢加入三乙酰氧基硼氢化钠(420毫克，1.98毫摩尔)，40℃反应4小时。Compound 4-((2S)-4-(5-methylthiophen-2-yl)piperidin-2-yl)benzoate methyl ester (210.0 mg, 0.66 mmol) and 4-formyl-5-methyl Oxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (381.4 mg, 1.32 mmol) was dissolved in 1,2-dichloroethane (6 ml), stirred at room temperature for 12 hours, then slowly Add sodium triacetoxyborohydride (420 mg, 1.98 mmol) and react at 40°C for 4 hours.
反应完成后，加入甲醇溶解至澄清，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)。得到240毫克浅黄色胶状5-甲氧基-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(5-甲基噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率61.7％)。LCMS：RT＝1.97min，[M+H]+＝589.33。After the reaction is completed, add methanol to dissolve until clear, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1). Obtained 240 mg of 5-methoxy-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)piperidine-) as a light yellow gum 1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 61.7%). LCMS: RT = 1.97 min, [M+H] + = 589.33.
步骤D：合成化合物46A和46BStep D: Synthesis of Compounds 46A and 46B
将化合物5-甲氧基-(((2S)-2-(4-(甲氧基羰基)苯基)-4-(5-甲基噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(240毫克，0.53毫摩尔)溶于甲醇(5毫升)，加入碳酸钾(292.5毫克，2.1毫摩尔)，加热至70℃搅拌过夜。再加入水(2毫升)，70℃反应2小时。Compound 5-methoxy-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)piperidin-1-yl)methyl tert-butyl)-7-methyl-1H-indole-1-carboxylate (240 mg, 0.53 mmol) was dissolved in methanol (5 ml), potassium carbonate (292.5 mg, 2.1 mmol) was added, and heated to Stir overnight at 70°C. Then add water (2 ml) and react at 70°C for 2 hours.
反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到25.0毫克绝对构型的非对映异构体46A(收率：10.0％)和35.0毫克绝对构型的非对映异构体46B(收率：13.9％)。The reaction was completed, and the purification treatment and chiral resolution method in step D of Example 3 were used to separate and obtain 25.0 mg of diastereomer 46A with absolute configuration (yield: 10.0%) and 35.0 mg of diastereoisomer 46A with absolute configuration. Enantiomer 46B (yield: 13.9%).
化合物46A：HPLC：RT＝3.587min，LCMS：RT＝1.75min，[M+H]+＝475.26。Compound 46A: HPLC: RT=3.587 min, LCMS: RT=1.75 min, [M+H] + =475.26.
化合物46B：HPLC：RT＝3.590min，LCMS：RT＝1.75min，[M+H]+＝475.26。Compound 46B: HPLC: RT=3.590min, LCMS: RT=1.75min, [M+H] + =475.26.
1H NMR(400MHz，DMSO-d6)δ10.82(d，J＝2.9Hz，1H)，7.88(d，J＝7.9Hz，2H)，7.50(d，J＝7.7Hz，2H)，7.25(t，J＝2.8Hz，1H)，6.65(s，1H)，6.59(d，J＝3.5Hz，1H)，6.55(d，J＝3.6Hz，1H)，6.45(t，J＝2.5Hz，1H)，3.71(s，3H)，3.57(d，J＝11.8Hz，1H)，3.27(dd，J＝11.1，2.7Hz，1H)，3.20(d，J＝11.8Hz，1H)，2.95-2.79(m，2H)，2.41(s，3H)，2.33(s，3H)，2.11(t，J＝11.8Hz，1H)，1.98-1.86(m，1H)，1.80(d，J＝12.7Hz，1H)，1.66(q，J＝12.1Hz，1H)，1.44(tt，J＝13.7，7.0Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.82 (d, J = 2.9 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 7.7 Hz, 2H), 7.25 (t, J=2.8Hz, 1H), 6.65 (s, 1H), 6.59 (d, J=3.5Hz, 1H), 6.55 (d, J=3.6Hz, 1H), 6.45 (t, J=2.5Hz , 1H), 3.71 (s, 3H), 3.57 (d, J=11.8Hz, 1H), 3.27 (dd, J=11.1, 2.7Hz, 1H), 3.20 (d, J=11.8Hz, 1H), 2.95 -2.79 (m, 2H), 2.41 (s, 3H), 2.33 (s, 3H), 2.11 (t, J=11.8Hz, 1H), 1.98-1.86 (m, 1H), 1.80 (d, J=12.7 Hz, 1H), 1.66 (q, J=12.1Hz, 1H), 1.44 (tt, J=13.7, 7.0Hz, 1H).
实施例47
Example 47
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-4-(3，6-二氯哒嗪-4-基)-6-(4-甲氧羰基)苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-4-(3,6-dichloropyridazin-4-yl)-6-(4-methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)- Benzyl carboxylate
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.47毫摩尔)，4-溴-3，6-二氯哒嗪(335毫克，1.47毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(108毫克，0.147毫摩尔)，碳酸氢钠(247毫克，2.94毫摩尔)加入1，4-二氧六环(20毫升)，再加入5毫升水，氮气保护下80℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Benzyl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 1.47 mmol), 4-bromo-3,6-dichloropyridazine (335 mg, 1.47 mmol) , [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (108 mg, 0.147 mmol), sodium bicarbonate (247 mg, 2.94 mmol) were added to 1,4-dioxane ring (20 ml), then add 5 ml of water, and react at 80°C for 12 hours under nitrogen protection.
反应完成后，加入乙酸乙酯(50毫升)稀释，过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到500毫克黄色油状(S)-4-(3，6-二氯哒嗪-4-基)-6-(4-甲氧羰基)苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率68％)。LCMS：RT＝2.16min，[M+H]+＝498.17。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 500 mg of (S)-4-(3,6-dichloropyridazin-4-yl)-6-(4-methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H) as a yellow oil - Benzyl carboxylate (yield 68%). LCMS: RT=2.16min, [M+H] + =498.17.
步骤B：合成(S)-4-(4-(哒嗪-4-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(pyridazin-4-yl)piperidin-2-yl)benzoic acid methyl ester
将化合物(S)-4-(3，6-二氯哒嗪-4-基)-6-(4-甲氧羰基)苯基-3，6-二氢吡啶-1(2H)-羧酸苄酯(110毫克，0.25毫摩尔)溶于异丙醇(20毫升)/乙酸乙酯(2毫升)，加入钯/碳(200毫克)，碳酸氢钠(168毫克，2毫摩尔)，氢气氛围下室温反应5小时。Compound (S)-4-(3,6-dichloropyridazin-4-yl)-6-(4-methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid Benzyl ester (110 mg, 0.25 mmol) was dissolved in isopropyl alcohol (20 ml)/ethyl acetate (2 ml), palladium on carbon (200 mg), sodium bicarbonate (168 mg, 2 mmol), and hydrogen were added The reaction was carried out at room temperature for 5 hours.
反应完成后，过滤，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10/1)得到150毫克黄色胶状(S)-4-(4-(哒嗪-4-基)哌啶-2-基)苯甲酸甲酯(收率63％)。LCMS：RT＝1.49min，[M+H]+＝298.22。After the reaction is completed, filter and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1) to obtain 150 mg of (S)-4-(4-(pyridazin-4-yl)piperidine-) as a yellow gum. 2-yl)benzoic acid methyl ester (yield 63%). LCMS: RT = 1.49 min, [M+H] + = 298.22.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(哒嗪-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-4-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物(S)-4-(4-(哒嗪-4-基)哌啶-2-基)苯甲酸甲酯(150毫克，0.5毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(292毫克，1.0毫摩尔)溶于1，2-二氯乙烷(8毫升)，室温搅拌4小时。然后加入三乙酰氧基硼氢化钠(320毫克，1.5毫摩尔)，继续反应过夜。Compound (S)-4-(4-(pyridazin-4-yl)piperidin-2-yl)benzoate methyl ester (150 mg, 0.5 mmol) and 4-formyl-5-methoxy- 7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (292 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (8 ml), and stirred at room temperature for 4 hours. Then sodium triacetoxyborohydride (320 mg, 1.5 mmol) was added and the reaction was continued overnight.
反应完成后，加入甲醇溶解至澄清，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到240毫克黄色油状(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(哒嗪-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率83％)。LCMS：RT＝1.81min，[M+H]+＝571.35。After the reaction is completed, add methanol to dissolve until clear, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 240 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-4-yl)piperidin-1-yl) as a yellow oil )methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 83%). LCMS: RT = 1.81 min, [M+H] + = 571.35.
步骤D：合成化合物47Step D: Synthesis of Compound 47
将化合物(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(哒嗪-4-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(240毫克，0.42毫摩尔)溶于甲醇(10毫升)，加入碳酸钾(580毫克，4.2毫摩尔)，加热至60℃搅拌过夜。再加入水(2毫升)，60℃反应4小时。Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-4-yl)piperidin-1-yl)methyl )-7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (240 mg, 0.42 mmol) was dissolved in methanol (10 ml), potassium carbonate (580 mg, 4.2 mmol) was added, and heated to 60 °C and stir overnight. Then add water (2 ml) and react at 60°C for 4 hours.
反应完成后，在真空下浓缩该溶液且采用实施例3步骤D中的纯化处理和手性拆分方法分离得到162.8毫克绝对构型的非对映异构体47(收率：84％)After the reaction was completed, the solution was concentrated under vacuum and 162.8 mg of the absolute configuration of diastereomer 47 was isolated using the purification treatment and chiral resolution method in step D of Example 3 (yield: 84%)
化合物47：HPLC：RT＝3.554min，LCMS：RT＝1.57min，[M+H]+＝475.28。Compound 47: HPLC: RT=3.554min, LCMS: RT=1.57min, [M+H] + =475.28.
1H NMR(400MHz，DMSO-d6)δ10.85(s，1H)，9.18(s，1H)，9.05(d，J＝8.0Hz，2H)，7.84(d，J＝8.0Hz，2H)，7.60-7.53(m，1H)，7.44(d，J＝8.0Hz，2H)，7.28-7.22(m，1H)，6.66(s，1H)，6.48-6.43(m，1H)，3.73(s，3H)，3.64-3.58(m，1H)，3.30-3.17(m，2H)，2.94-2.76(m，2H)，2.43(s，3H)，2.21-2.11(m，1H)，1.91-1.68(m，3H)，1.63-1.51(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.85 (s, 1H), 9.18 (s, 1H), 9.05 (d, J = 8.0Hz, 2H), 7.84 (d, J = 8.0Hz, 2H) , 7.60-7.53(m, 1H), 7.44(d, J=8.0Hz, 2H), 7.28-7.22(m, 1H), 6.66(s, 1H), 6.48-6.43(m, 1H), 3.73(s , 3H), 3.64-3.58(m, 1H), 3.30-3.17(m, 2H), 2.94-2.76(m, 2H), 2.43(s, 3H), 2.21-2.11(m, 1H), 1.91-1.68 (m, 3H), 1.63-1.51 (m, 1H).
实施例48A和48B
Examples 48A and 48B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-6-((4-甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)-3,6-dihydropyridine-1( 2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.47毫摩尔)的二氧六环(10毫升)中，加入2-溴-5-(三氟甲基)噻吩(374毫克，1.62毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(110毫克，0.15毫摩尔)和磷酸钾(624毫克，2.94毫摩尔)，然后加入水(2毫升)，反应置换氮气后，升温到95℃反应过夜。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane -2-yl)-3,6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester (700 mg, 1.47 mmol) in dioxane (10 ml) was added 2-bromo-5-( Trifluoromethyl)thiophene (374 mg, 1.62 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (110 mg, 0.15 mmol) and potassium phosphate (624 mg , 2.94 mmol), and then add water (2 ml). After the reaction is replaced with nitrogen, the temperature is raised to 95°C and the reaction is carried out overnight.
反应结束后过滤，用乙酸乙酯洗涤，有机相直接减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷 /乙酸乙酯＝3/1)得到306毫克淡黄色油状液体(S)-6-((4-甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：41％)。LCMS：RT＝2.29min，[M+H]+＝502.21。After the reaction, it was filtered, washed with ethyl acetate, and the organic phase was directly concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane /ethyl acetate=3/1) to obtain 306 mg of light yellow oily liquid (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl )-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 41%). LCMS: RT = 2.29 min, [M+H] + = 502.21.
步骤B：合成(S)-4-(4-(5-三氟甲基)噻吩-2-基)哌啶-2-基苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(5-trifluoromethyl)thiophen-2-yl)piperidin-2-yl benzoate methyl ester
将(S)-6-((4-甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(306毫克，0.61毫摩尔)溶于乙酸乙酯溶液(20毫升)中，加入钯碳(300毫克)，反应置换氢气后，升温到50℃反应6小时。(S)-6-((4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- Benzyl carboxylate (306 mg, 0.61 mmol) was dissolved in ethyl acetate solution (20 ml), palladium on carbon (300 mg) was added, and after the reaction replaced hydrogen, the temperature was raised to 50°C for 6 hours.
反应结束后过滤，用乙酸乙酯洗涤，有机相直接减压浓缩得到200毫克淡黄色油状液体(S)-4-(4-(5-三氟甲基)噻吩-2-基)哌啶-2-基苯甲酸甲酯(收率：89％)。LCMS：RT＝0.26min，[M+H]+＝326.30。After the reaction, it was filtered, washed with ethyl acetate, and the organic phase was directly concentrated under reduced pressure to obtain 200 mg of light yellow oily liquid (S)-4-(4-(5-trifluoromethyl)thiophen-2-yl)piperidine- 2-ylbenzoic acid methyl ester (yield: 89%). LCMS: RT = 0.26 min, [M+H] + = 326.30.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)piper (Din-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-三氟甲基)噻吩-2-基)哌啶-2-基苯甲酸甲酯(200毫克，0.74毫摩尔)的1，2-二氯乙烷(10毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(390毫克，1.35毫摩尔)和三乙酰氧基硼氢化钠(229毫克，1.08毫摩尔)，40℃反应过夜。To 1,2-dichlorocontaining (S)-4-(4-(5-trifluoromethyl)thiophen-2-yl)piperidin-2-ylbenzoate methyl ester (200 mg, 0.74 mmol) To ethane (10 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (390 mg, 1.35 mmol) and triacetoxy Sodium borohydride (229 mg, 1.08 mmol), react at 40°C overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到187毫克淡黄色油状液体(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：54％)。LCMS：RT＝2.04min，[M+H]+＝643.29。After the reaction was completed, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol = 10/1) to obtain 187 mg of light yellow oily liquid (S)-5-methoxy. Base-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)piperidin-1-yl)methyl)-7- Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 54%). LCMS: RT = 2.04 min, [M+H] + = 643.29.
步骤D：合成化合物48A和48BStep D: Synthesis of Compounds 48A and 48B
向(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(187毫克，0.29毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(160毫克，1.16毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)piperidine-1 To a solution of -methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (187 mg, 0.29 mmol) in methanol (5 ml), potassium carbonate (160 mg, 1.16 mmol) was added ), heated to 70°C and reacted for 5 hours, then added water (1 ml) and continued the reaction for 4 hours.
反应完成后，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到17.2毫克绝对构型的非对映异构体48A(收率：3％)和4.8毫克绝对构型的非对映异构体48B(收率：7％)。After the reaction was completed, the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 17.2 mg of diastereoisomer 48A with absolute configuration (yield: 3%) and 4.8 mg of diastereoisomer 48A with absolute configuration. Enantiomer 48B (yield: 7%).
化合物48A：HPLC：RT＝3.663min，LCMS：RT＝1.82min，[M+H]+＝529.23。Compound 48A: HPLC: RT=3.663 min, LCMS: RT=1.82 min, [M+H] + =529.23.
化合物48B：HPLC：RT＝3.672min，LCMS：RT＝1.82min，[M+H]+＝529.23。Compound 48B: HPLC: RT=3.672 min, LCMS: RT=1.82 min, [M+H] + =529.23.
实施例49A和49B
Examples 49A and 49B
化合物49A和49B的合成路线如下：
The synthetic routes of compounds 49A and 49B are as follows:
步骤A：合成(S)-6-(4-氰基苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-氰基苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(3克，6.74毫摩尔)的二氧六环(20毫升)中，加入2-溴吡嗪(1.60克，10.11毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(740毫克，1.01毫摩尔)和磷酸钾(3.93克，13.48毫摩尔)，然后加入水(4毫升)，反应置换氮气后，升温到95摄氏度反应5小时。At room temperature, to a compound containing (S)-6-(4-cyanophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (3 g, 6.74 mmol) in dioxane (20 ml), 2-bromopyrazine (1.60 g, 10.11 mmol) was added mol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (740 mg, 1.01 mmol) and potassium phosphate (3.93 g, 13.48 mmol), then water (4 ml ), after the reaction replaces nitrogen, the temperature is raised to 95 degrees Celsius and reacted for 5 hours.
反应结束后过滤，用乙酸乙酯洗涤，液相直接减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶5)得到2.5克淡黄色油状液体(S)-6-(4-氰基苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：93％)。LCMS：RT＝2.06min，[M+H]+＝397.21。After the reaction, it was filtered, washed with ethyl acetate, and the liquid phase was directly concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:5) to obtain 2.5 g of light yellow oily liquid (S)-6-(4-cyanophenyl)-4-( Pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 93%). LCMS: RT=2.06min, [M+H] + =397.21.
步骤B：合成(S)-6-(4-(2H-四氮唑-5基)苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step B: Synthesis of (S)-6-(4-(2H-tetrazol-5yl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H) -Benzyl carboxylate
室温下，向含有(S)-6-(4-氰基苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(2.20克，5.54毫摩尔)的N，N-二甲基甲酰胺(15毫升)中，加入三甲基硅基叠氮(1.30克，11.08毫摩尔)和2M的四丁基氟化铵(1.1毫升)，氮气保护后升温到80摄氏度反应。At room temperature, the solution containing (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (2.20 g, 5.54 mmol) of N,N-dimethylformamide (15 ml), trimethylsilyl azide (1.30 g, 11.08 mmol) and 2 M tetrabutylammonium fluoride (1.1 ml ), and then the temperature is raised to 80 degrees Celsius for reaction after nitrogen protection.
反应结束后用水淬灭，用乙酸乙酯萃取，有机相干燥后直接减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶3)得到900毫克淡黄色油状液体(S)-6-(4-(2H-四氮唑-5基)苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：37％)。LCMS：RT＝1.90min，[M+H]+＝440.27。After the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:3) to obtain 900 mg of light yellow oily liquid (S)-6-(4-(2H-tetrazole-5yl) )phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 37%). LCMS: RT = 1.90 min, [M+H] + = 440.27.
步骤C：合成(S)-2-(2-(4-(2H-四氮唑-5基)苯基哌啶-4-基吡嗪 Step C: Synthesis of (S)-2-(2-(4-(2H-tetrazol-5yl)phenylpiperidin-4-ylpyrazine)
将(S)-6-(4-(2H-四氮唑-5基)苯基-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(900毫克，2.05毫摩尔)溶于乙酸乙酯溶液(10毫升)和甲醇(20毫升)的混合溶剂中，加入钯碳(450毫克)，反应置换氢气后，室温反应0.5小时。(S)-6-(4-(2H - tetrazol-5yl)phenyl-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl The ester (900 mg, 2.05 mmol) was dissolved in a mixed solvent of ethyl acetate solution (10 ml) and methanol (20 ml). Palladium on carbon (450 mg) was added. After the reaction replaced hydrogen, the reaction was carried out at room temperature for 0.5 hours.
反应结束后过滤，用甲醇洗涤，液相直接减压浓缩得到750毫克淡黄色油状液体(S)-2-(2-(4-(2H-四氮唑-5基)苯基哌啶-4-基吡嗪。LCMS：RT＝1.60min，[M+H]+＝308.19。After the reaction, it was filtered, washed with methanol, and the liquid phase was directly concentrated under reduced pressure to obtain 750 mg of light yellow oily liquid (S)-2-(2-(4-(2H-tetrazol-5yl)phenylpiperidine-4) -pyrazine. LCMS: RT=1.60min, [M+H] + =308.19.
步骤D：合成(S)-5-甲氧基-4-(2-4-(2H-四氮唑-5基)苯基-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-5-methoxy-4-(2-4-(2H-tetrazol-5yl)phenyl-4-(pyrazin-2-yl)piperidin-1-yl )Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-2-(2-(4-(2H-四氮唑-5基)苯基哌啶-4-基吡嗪(350毫克，1.14毫摩尔)的甲醇(10毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(494毫克，1.71毫摩尔)和氰基硼氢化钠(350毫克)，40摄氏度反应过夜。To (S)-2-(2-(4-(2H-tetrazol-5yl)phenylpiperidin-4-ylpyrazine) (350 mg, 1.14 mmol) in methanol (10 mL), Add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (494 mg, 1.71 mmol) and sodium cyanoborohydride (350 mg), 40°C Reaction was allowed to take place overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯∶正己烷＝1∶1)得到230毫克白色固体(S)-5-甲氧基-4-(2-4-(2H-四氮唑-5基)苯基-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：35％)。LCMS：RT＝1.82min，[M+H]+＝581.32。After the reaction was completed, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) to obtain 230 mg of white solid (S)-5-methoxy. -4-(2-4-(2H-tetrazol-5yl)phenyl-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole Indole-1-carboxylic acid tert-butyl ester (yield: 35%). LCMS: RT = 1.82 min, [M+H] + = 581.32.
步骤E：化合物49A和49BStep E: Compounds 49A and 49B
向(S)-5-甲氧基-4-(2-4-(2H-四氮唑-5基)苯基-4-(吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(230毫克，0.40毫摩尔)的甲醇(15毫升)和(3毫升)水溶液中加氢氧化钠(64毫克，1.59毫摩尔)，且将该溶液加热至80摄氏度，持续3小时。在真空下浓缩该溶液且用采用实施例3步骤D中的纯化处理和手性拆分方法分离得到5毫克绝对构型的非对映异构体49A和5毫克绝对构型的非对映异构体49B。To (S)-5-methoxy-4-(2-4-(2H-tetrazol-5yl)phenyl-4-(pyrazin-2-yl)piperidin-1-yl)methyl )-7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (230 mg, 0.40 mmol) in methanol (15 ml) and (3 ml) water was added with sodium hydroxide (64 mg, 1.59 mmol) mol) and the solution was heated to 80 degrees Celsius for 3 hours. The solution was concentrated under vacuum and separated using the purification treatment and chiral resolution method in step D of Example 3 to obtain 5 mg of diastereomer 49A in absolute configuration and 5 mg of diastereomer 49A in absolute configuration. Conform 49B.
化合物49A：HPLC：RT＝9.8min，LCMS：RT＝1.63min，[M+H]+＝481.27。Compound 49A: HPLC: RT=9.8 min, LCMS: RT=1.63 min, [M+H] + =481.27.
化合物49B：HPLC：RT＝11.5min，LCMS：RT＝1.63min，[M+H]+＝481.27。Compound 49B: HPLC: RT=11.5 min, LCMS: RT=1.63 min, [M+H] + =481.27.
实施例50
Example 50
化合物50的合成路线如下：
The synthetic route of compound 50 is as follows:
步骤A：合成(S)-6-((4-甲氧基羰基)苯基)-4-(5-氟吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxy Benzyl acid ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.47毫摩尔)的二氧六环(30毫升)中，加入2-溴-5-氟吡啶(387毫克，2.20毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(106毫克，0.15毫摩尔)和磷酸钾(778毫克，3.67毫摩尔)，然后加入水(6毫升)，反应置换氮气后，升温到90℃反应5小时。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 1.47 mmol) in dioxane (30 ml) was added 2-bromo-5-fluoro Pyridine (387 mg, 2.20 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (106 mg, 0.15 mmol), and potassium phosphate (778 mg, 3.67 mmol) , then add water (6 ml), and after the reaction replaces nitrogen, the temperature is raised to 90°C for 5 hours.
反应结束后过滤，用乙酸乙酯洗涤，有机相直接减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝6/1)得到330毫克淡黄色油状液体(S)-6-((4-甲氧基羰基)苯基)-4-(5-氟吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：50％)。LCMS：RT＝2.18min，[M+H]+＝447.22。After the reaction, it was filtered, washed with ethyl acetate, and the organic phase was directly concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 6/1) to obtain 330 mg of light yellow oily liquid (S)-6-((4-methoxycarbonyl)phenyl) -4-(5-fluoropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 50%). LCMS: RT = 2.18 min, [M+H] + = 447.22.
步骤B：合成(S)-4-(4-(5-氟吡啶-2-基)哌啶-2-基苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(5-fluoropyridin-2-yl)piperidin-2-ylbenzoic acid methyl ester
将(S)-6-((4-甲氧基羰基)苯基)-4-(5-氟吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(330毫克，0.74毫摩尔)溶于乙酸乙酯溶液(15毫升)中，加入钯碳(33毫克)，反应置换氢气后，升温到60℃反应过夜。(S)-6-((4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate benzyl ester (330 mg, 0.74 mmol) was dissolved in ethyl acetate solution (15 ml), palladium on carbon (33 mg) was added, and after the reaction replaced hydrogen, the temperature was raised to 60°C and the reaction was carried out overnight.
反应结束后过滤，用乙酸乙酯洗涤，有机相直接减压浓缩得到215毫克无色油状液体(S)-4-(4-(5-氟吡啶-2-基)哌啶-2-基苯甲酸甲酯(收率：92％)。LCMS：RT＝1.59min，[M+H]+＝315.22。After the reaction, it was filtered, washed with ethyl acetate, and the organic phase was directly concentrated under reduced pressure to obtain 215 mg of colorless oily liquid (S)-4-(4-(5-fluoropyridin-2-yl)piperidin-2-ylbenzene). Methyl formate (yield: 92%). LCMS: RT = 1.59 min, [M+H] + = 315.22.
步骤C：合成(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(5-氟吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-氟吡啶-2-基)哌啶-2-基苯甲酸甲酯(215毫克，0.68毫摩尔)的1，2-二氯乙烷(15毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(495毫克，1.71毫摩尔)和三乙酰氧基硼氢化钠(580毫克，2.74毫摩尔)，40℃反应过夜。To 1,2-dichloroethane (15 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (495 mg, 1.71 mmol) and sodium triacetoxyborohydride ( 580 mg, 2.74 mmol), react at 40°C overnight.
反应结束，加入少量甲醇，直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到270毫克黄色油状(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(5-氟吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：69％)。LCMS：RT＝1.95min，[M+H]+＝588.35。After the reaction was completed, a small amount of methanol was added, and the solvent was directly spun to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 270 mg of yellow oily (S)-5-methoxy. Base-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole Indole-1-carboxylic acid tert-butyl ester (yield: 69%). LCMS: RT=1.95min, [M+H] + =588.35.
步骤D：合成化合物50 Step D: Synthesis of Compound 50
向(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(5-氟吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(277毫克，0.47毫摩尔)的甲醇(15毫升)溶液中加碳酸钾(651毫克，4.71毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)piperidin-1-yl)methyl) -To a solution of tert-butyl 7-methyl-1H-indole-1-carboxylate (277 mg, 0.47 mmol) in methanol (15 ml), add potassium carbonate (651 mg, 4.71 mmol) and heat to 70°C The reaction was continued for 5 hours, and water (1 ml) was added to continue the reaction for 4 hours.
反应完成后，硅藻土抽滤，滤饼甲醇洗，滤液浓缩后采用实施例3步骤D中的手性拆分方法分离得到147毫克绝对构型的非对映异构体50(收率：66％)After the reaction is completed, the diatomaceous earth is suction filtered, and the filter cake is washed with methanol. After the filtrate is concentrated, the chiral separation method in step D of Example 3 is used to separate and obtain 147 mg of the absolute configuration of diastereomer 50 (yield: 66%)
化合物50：HPLC：RT＝3.35min，LCMS：RT＝1.66min，[M+H]+＝474.27。Compound 50: HPLC: RT=3.35min, LCMS: RT=1.66min, [M+H] + =474.27.
1H NMR(400MHz，DMSO-d6)δ10.85(t，J＝2.3Hz，1H)，8.43(d，J＝3.0Hz，1H)，7.92(d，J＝7.9Hz，2H)，7.59(ddt，J＝8.6，5.8，2.9Hz，3H)，7.35(dd，J＝8.7，4.5Hz，1H)，7.27(t，J＝2.8Hz，1H)，6.66(s，1H)，6.49(t，J＝2.5Hz，1H)，3.73(s，3H)，3.33(dd，J＝10.2，3.8Hz，2H)，3.24(d，J＝11.8Hz，2H)，2.90(dd，J＝9.7，5.9Hz，2H)，2.42(s，3H)，2.20-2.10(m，1H)，1.93-1.80(m，2H)，1.77-1.70(m，1H)，1.62(tt，J＝13.9，6.9Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.85 (t, J=2.3Hz, 1H), 8.43 (d, J=3.0Hz, 1H), 7.92 (d, J=7.9Hz, 2H), 7.59 (ddt, J=8.6, 5.8, 2.9Hz, 3H), 7.35 (dd, J=8.7, 4.5Hz, 1H), 7.27 (t, J=2.8Hz, 1H), 6.66 (s, 1H), 6.49( t, J=2.5Hz, 1H), 3.73 (s, 3H), 3.33 (dd, J=10.2, 3.8Hz, 2H), 3.24 (d, J=11.8Hz, 2H), 2.90 (dd, J=9.7 , 5.9Hz, 2H), 2.42 (s, 3H), 2.20-2.10 (m, 1H), 1.93-1.80 (m, 2H), 1.77-1.70 (m, 1H), 1.62 (tt, J=13.9, 6.9 Hz, 1H).
实施例51
Example 51
化合物51合成路线如下：
The synthetic route of compound 51 is as follows:
步骤A：合成4-溴-2-(二氟甲基)噻吩Step A: Synthesis of 4-bromo-2-(difluoromethyl)thiophene
冰浴下，向含有4-溴噻吩-2-甲醛(2.0克，10.4毫摩尔)的二氯甲烷(30毫升)中，加入二乙胺基三氟化硫(4.19克，13.1毫摩尔)，滴加完毕后升温到40℃反应12小时。Under ice bath, to dichloromethane (30 ml) containing 4-bromothiophene-2-carbaldehyde (2.0 g, 10.4 mmol), diethylamine sulfur trifluoride (4.19 g, 13.1 mmol) was added. After the dropwise addition is completed, the temperature is raised to 40°C and reacted for 12 hours.
反应结束后将反应液倒入冰的饱和碳酸氢钠水溶液中，用二氯甲烷(10毫升×3次)萃取，有机相合并干燥旋干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷)得到1.7克无色液体4-溴-2-(二氟甲基)噻吩(收率：76.9％)。After the reaction, the reaction solution was poured into an ice-cold saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (10 ml × 3 times), the organic phases were combined, dried and spin-dried, and the resulting residue was purified by silica gel column chromatography (eluent : n-hexane) to obtain 1.7 g of colorless liquid 4-bromo-2-(difluoromethyl)thiophene (yield: 76.9%).
步骤B：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(5-(二氟甲基)噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step B: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1 (2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.2克，2.51毫摩尔)的二氧六环(20毫升)中，加入4-溴-2-(二氟甲基)噻吩(809.4毫克，3.8毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(365.5毫克，0.5毫摩尔)和磷酸钾(1.1克，5.0毫摩尔)，然后加入水(4毫升)，反应置换氮气后，升温到95℃反应12小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.2 g, 2.51 mmol) in dioxane (20 ml), 4-bromo-2-(dihydropyridine-1(2H)-carboxylate Fluoromethyl)thiophene (809.4 mg, 3.8 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (365.5 mg, 0.5 mmol) and potassium phosphate (1.1 g, 5.0 mmol), then add water (4 ml), and after replacing nitrogen, the temperature is raised to 95°C and reacted for 12 hours.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到700毫克淡黄色油状液体(S)-6-(4-(甲氧基羰基)苯基)-4-(5-(二氟甲基)噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：57.7％)。LCMS：RT＝2.21min，[M+H]+＝484.20。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 700 mg of light yellow oily liquid (S)-6-(4-(methoxycarbonyl)phenyl) -4-(5-(Difluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 57.7%). LCMS: RT = 2.21 min, [M+H] + = 484.20.
步骤C：合成(S)-4-(4-(5-(二氟甲基)噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step C: Synthesis of (S)-4-(4-(5-(difluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6-(4-(甲氧基羰基)苯基)-4-(5-(二氟甲基)噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.4毫摩尔)溶于乙酸乙酯溶液(25毫升)中，加入钯碳(600毫克)，反应置换氢气后，升温到60℃反应24小时。(S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H) - Benzyl carboxylate (700 mg, 1.4 mmol) was dissolved in ethyl acetate solution (25 ml), palladium on carbon (600 mg) was added, and after the reaction replaced hydrogen, the temperature was raised to 60°C and reacted for 24 hours.
反应结束后过滤，用乙酸乙酯洗涤，液相直接减压浓缩得到300毫克无色油状液体(S)-4-(4-(5-(二氟甲基)噻吩-3-基)哌啶-2-基)苯甲酸甲酯。LCMS：RT＝1.70min，[M+H]+＝352.14。After the reaction, it was filtered, washed with ethyl acetate, and the liquid phase was directly concentrated under reduced pressure to obtain 300 mg of colorless oily liquid (S)-4-(4-(5-(difluoromethyl)thiophen-3-yl)piperidine -2-yl) methyl benzoate. LCMS: RT=1.70min, [M+H] + =352.14.
步骤D：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-(二氟甲基)噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)) Piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-(二氟甲基)噻吩-3-基)哌啶-2-基)苯甲酸甲酯(300毫克，0.86毫摩尔)的二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(495毫克，1.71毫摩尔)，室温搅拌12小时，然后缓慢加入三乙酰氧基硼氢化钠(546.8毫克，2.58毫摩尔)，40℃反应4小时。To (S)-4-(4-(5-(difluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate (300 mg, 0.86 mmol) was added to dichloroethane (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (495 mg, 1.71 mmol), stir at room temperature for 12 hours, and then Slowly add sodium triacetoxyborohydride (546.8 mg, 2.58 mmol), and react at 40°C for 4 hours.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝9/1)得到200毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-(二氟甲基)噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：41％)。LCMS：RT＝1.95min，[M+H]+＝625.31。After the reaction is completed, a small amount of methanol is added and the solvent is directly rotated to dryness. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 9/1) to obtain 200 mg of white solid (S)-5-methoxy. -4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)piperidin-1-yl)methyl)-7- Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 41%). LCMS: RT=1.95min, [M+H] + =625.31.
步骤E：合成化合物51 Step E: Synthesis of Compound 51
向(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(1-甲基-1H-吡唑-5-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(40毫克，0.07毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(39毫克，0.28毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidine- To a solution of 1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol) in methanol (5 ml) was added potassium carbonate (39 mg, 0.28 mmol). mol), heated to 70°C and reacted for 5 hours, then added water (1 ml) and continued the reaction for 4 hours.
反应完成，浓缩旋干，加入二氯甲烷/甲醇＝10/1的混合溶剂20毫升，抽滤，滤液旋干，得到粗品，采用实施例3步骤D中的手性拆分方法分离得到75.0绝对构型的非对映异构体51(收率：50.0％)。After the reaction is completed, concentrate and spin to dryness, add 20 ml of a mixed solvent of methylene chloride/methanol = 10/1, filter with suction, and spin the filtrate to dryness to obtain a crude product. Use the chiral separation method in step D of Example 3 to separate and obtain 75.0 absolute Configuration of diastereomer 51 (yield: 50.0%).
化合物51：HPLC：RT＝3.86min，LCMS：RT＝1.75min，[M+H]+＝511.24.Compound 51: HPLC: RT=3.86min, LCMS: RT=1.75min, [M+H] + =511.24.
1H-NMR(400MHz，DMSO-d6)δ10.82(t，J＝2.3Hz，1H)，7.82(d，J＝7.9Hz，2H)，7.45-7.37(m，4H)，7.3-7.05(m，2H)，6.65(s，1H)，6.49-6.43(m，1H)，3.71(s，3H)，3.59(d，J＝11.8Hz，1H)，3.26-3.16(m，2H)，2.88-2.73(m，2H)，2.41(s，3H)，2.10(dd，J＝13.0，10.5Hz，1H)，1.91(d，J＝12.7Hz，1H)，1.81-1.63(m，2H)，1.52-1.38(m，1H). 1 H-NMR (400MHz, DMSO-d 6 ) δ10.82 (t, J=2.3Hz, 1H), 7.82 (d, J=7.9Hz, 2H), 7.45-7.37 (m, 4H), 7.3-7.05 (m, 2H), 6.65 (s, 1H), 6.49-6.43 (m, 1H), 3.71 (s, 3H), 3.59 (d, J=11.8Hz, 1H), 3.26-3.16 (m, 2H), 2.88-2.73 (m, 2H), 2.41 (s, 3H), 2.10 (dd, J=13.0, 10.5Hz, 1H), 1.91 (d, J=12.7Hz, 1H), 1.81-1.63 (m, 2H) ,1.52-1.38(m,1H).
实施例52A和52B
Examples 52A and 52B
化合物52A和52B合成路线如下：
The synthetic routes of compounds 52A and 52B are as follows:
步骤A：合成(S)-6-(4-氰基苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-氰基苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(2.0克，4.5毫摩尔)的二氧六环(20毫升)中，加入2-溴吡嗪(1.06克，6.75毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(493.4毫克，0.67毫摩尔)和磷酸钾(1.95克，9毫摩尔)，然后加入水(4毫升)，反应置换氮气后，升温到95℃反应12小时。At room temperature, to a compound containing (S)-6-(4-cyanophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (2.0 g, 4.5 mmol) in dioxane (20 ml), 2-bromopyrazine (1.06 g, 6.75 mmol) was added mol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (493.4 mg, 0.67 mmol) and potassium phosphate (1.95 g, 9 mmol), then water (4 ml ), after the reaction replaces nitrogen, the temperature is raised to 95°C and reacted for 12 hours.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到1.3克棕色油状液体(S)-6-(4-氰基苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：72.9％)。LCMS：RT＝2.04min，[M+H]+＝397.21。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 1.3 g of brown oily liquid (S)-6-(4-cyanophenyl)-4-(pyridine). Azin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 72.9%). LCMS: RT=2.04min, [M+H] + =397.21.
步骤B：合成(S)-4-(4-(2-吡嗪基)哌啶-2-基)苯甲腈Step B: Synthesis of (S)-4-(4-(2-pyrazinyl)piperidin-2-yl)benzonitrile
将(S)-6-(4-氰基苯基)-4-(吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.3克，3.3毫摩尔)溶于乙酸乙酯溶液(25毫升)中，加入钯碳(650毫克)，反应置换氢气后，室温反应过夜。(S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.3 g, 3.3 mg mol) was dissolved in ethyl acetate solution (25 ml), palladium on carbon (650 mg) was added, and the reaction was carried out to replace hydrogen, and the reaction was carried out at room temperature overnight.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩得到740毫克淡黄色油状液体(S)-4-(4-(2-吡嗪基)哌啶-2-基)苯甲腈(收率：84.9％)。LCMS：RT＝1.47min，[M+H]+＝265.21。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure to obtain 740 mg of light yellow oily liquid (S)-4-(4-(2-pyrazinyl)piperidin-2-yl)benzonitrile (yield :84.9%). LCMS: RT = 1.47 min, [M+H] + = 265.21.
步骤C：合成(S)-2-(4-氰基苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯Step C: Synthesis of (S)-2-(4-cyanophenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester
将(S)-4-(4-(2-吡嗪基)哌啶-2-基)苯甲腈(740毫克，2.8毫摩尔)，二碳酸二叔丁酯(916.6毫克，4.2毫摩尔)，三乙胺(566.4毫克，5.6毫摩尔)溶于二氯甲烷(15毫升)中，加入4-二甲氨基吡啶(17.1毫克，0.14毫摩尔)，室温反应过夜。(S)-4-(4-(2-pyrazinyl)piperidin-2-yl)benzonitrile (740 mg, 2.8 mmol), di-tert-butyl dicarbonate (916.6 mg, 4.2 mmol) , triethylamine (566.4 mg, 5.6 mmol) was dissolved in dichloromethane (15 ml), 4-dimethylaminopyridine (17.1 mg, 0.14 mmol) was added, and the reaction was carried out at room temperature overnight.
反应结束后过滤，旋干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)得到400毫克棕色油状液体(S)-2-(4-氰基苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯(收率：39.2％)。LCMS：RT＝1.98min，[M-100+H]+＝265.20。After the reaction is completed, filter and spin to dryness. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 400 mg of brown oily liquid (S)-2-(4-cyano). Phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (yield: 39.2%). LCMS: RT = 1.98 min, [M-100+H] + = 265.20.
步骤D：合成(S)-2-(4-(N-羟基氨基咪唑基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯Step D: Synthesis of (S)-2-(4-(N-hydroxyaminoimidazolyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester
将(S)-2-(4-氰基苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯(400毫克，1.1毫摩尔)，羟胺盐酸盐(114.6毫克，1.65毫摩尔)，N，N-二异丙基乙胺(355.4毫克，2.75毫摩尔)溶于甲醇(20毫升)中，75℃反应过夜。(S)-2-(4-Cyanophenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.1 mmol), hydroxylamine hydrochloride ( 114.6 mg, 1.65 mmol), N,N-diisopropylethylamine (355.4 mg, 2.75 mmol) was dissolved in methanol (20 ml), and the reaction was carried out at 75°C overnight.
反应结束后，旋干，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到290毫克棕色油状液体(S)-2-(4-(N-羟基氨基咪唑基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯(收率：66.5％)。LCMS：RT＝1.63min，[M+H]+＝398.28。After the reaction was completed, spin to dryness, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 290 mg of brown oily liquid (S)-2-(4-(N-hydroxyl) Aminoimidazolyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (yield: 66.5%). LCMS: RT = 1.63 min, [M+H] + = 398.28.
步骤E：合成(S)-2-(4-(5-氧代-4，5-二氢-1，2，4-噁二唑-3-基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯Step E: Synthesis of (S)-2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazine- 2-yl)piperidine-1-carboxylic acid tert-butyl ester
将(S)-2-(4-(N-羟基氨基咪唑基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯(250毫克，0.63毫摩尔)，吡啶(99.6毫克，1.26毫摩尔)溶于四氢呋喃(10毫升)中，0℃加入三氯甲基碳酸酯(74.7毫克，0.252毫摩尔)，反应1小时后，升温至60℃反应过夜。(S)-2-(4-(N-Hydroxyaminoimidazolyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.63 mmol) , Pyridine (99.6 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 ml), trichloromethyl carbonate (74.7 mg, 0.252 mmol) was added at 0°C, and after reacting for 1 hour, the temperature was raised to 60°C and the reaction was carried out overnight.
反应结束后，旋干，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到140毫克棕色油状液体(S)-2-(4-(5-氧代-4，5-二氢-1，2，4-噁二唑-3-基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯(收率：68.9％)。LCMS：RT＝ 1.89min，[M+H]+＝324.24。After the reaction was completed, spin to dryness, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 140 mg of brown oily liquid (S)-2-(4-(5-oxo) Tert-butyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate (yield :68.9%). LCMS：RT＝ 1.89min, [M+H] + =324.24.
步骤F：合成(S)-3-(4-(4-(2-吡嗪基)哌啶-2-基)苯基)-1，2，4-噁二唑-5(4H)-酮Step F: Synthesis of (S)-3-(4-(4-(2-pyrazinyl)piperidin-2-yl)phenyl)-1,2,4-oxadiazole-5(4H)-one
将(S)-2-(4-(5-氧代-4，5-二氢-1，2，4-噁二唑-3-基)苯基)-4-(吡嗪-2-基)哌啶-1-羧酸叔丁酯(140毫克，0.33毫摩尔)溶于盐酸二氧六环溶液(4摩尔每升，5毫升)中，室温反应1小时。(S)-2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazin-2-yl ) Piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.33 mmol) was dissolved in dioxane hydrochloride solution (4 moles per liter, 5 ml), and reacted at room temperature for 1 hour.
反应结束后旋干，加入碳酸钾溶液调pH为9，旋干，加入5毫升甲醇，过滤，滤液旋干，得到109毫克白色固体(S)-3-(4-(4-(2-吡嗪基)哌啶-2-基)苯基)-1，2，4-噁二唑-5(4H)-酮。LCMS：RT＝1.49min，[M+H]+＝324.21。After the reaction is completed, spin to dryness, add potassium carbonate solution to adjust the pH to 9, spin to dryness, add 5 ml of methanol, filter, and spin the filtrate to dryness to obtain 109 mg of white solid (S)-3-(4-(4-(2-pyridine) Azinyl)piperidin-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one. LCMS: RT = 1.49 min, [M+H] + = 324.21.
步骤G：合成(S)-5-甲氧基-7-甲基-4-((2-(4-(5-氧代-4，5-二氢-1，2，4-噁二唑-3-基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-1H-吲哚-1-羧酸叔丁酯Step G: Synthesis of (S)-5-methoxy-7-methyl-4-((2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole) -3-yl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-1H-indole-1-carboxylic acid tert-butyl ester
将(S)-3-(4-(4-(2-吡嗪基)哌啶-2-基)苯基)-1，2，4-噁二唑-5(4H)-酮(109毫克，0.33毫摩尔)，4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(190.7毫克，0.66毫摩尔)溶于二氯乙烷(4毫升)中，室温搅拌12小时，然后缓慢加入三乙酰氧基硼氢化钠(209.8毫克，0.99毫摩尔)，40℃反应4小时。(S)-3-(4-(4-(2-pyrazinyl)piperidin-2-yl)phenyl)-1,2,4-oxadiazole-5(4H)-one (109 mg , 0.33 mmol), 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (190.7 mg, 0.66 mmol) was dissolved in dichloroethane (4 ml), stir at room temperature for 12 hours, then slowly add sodium triacetoxyborohydride (209.8 mg, 0.99 mmol), and react at 40°C for 4 hours.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到160毫克黄色油状物粗品(S)-5-甲氧基-7-甲基-4-((2-(4-(5-氧代-4，5-二氢-1，2，4-噁二唑-3-基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-1H-吲哚-1-羧酸叔丁酯。LCMS：RT＝1.82min，[M+H]+＝597.37。After the reaction is completed, a small amount of methanol is added and the solvent is directly rotated to dryness. The resulting residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 160 mg of crude yellow oily product (S)-5-methoxy. Base-7-methyl-4-((2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-( Pyrazin-2-yl)piperidin-1-yl)methyl)-1H-indole-1-carboxylic acid tert-butyl ester. LCMS: RT = 1.82 min, [M+H] + = 597.37.
步骤H：合成化合物52A和52BStep H: Synthesis of Compounds 52A and 52B
向(S)-5-甲氧基-7-甲基-4-((2-(4-(5-氧代-4，5-二氢-1，2，4-恶二唑-3-基)苯基)-4-(吡嗪-2-基)哌啶-1-基)甲基)-1H-吲哚-1-羧酸叔丁酯(160毫克，0.26毫摩尔)的甲醇(10毫升)溶液中加碳酸钾(148毫克，1.08毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。To (S)-5-methoxy-7-methyl-4-((2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3- tert-butyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-1H-indole-1-carboxylate (160 mg, 0.26 mmol) in methanol ( Add potassium carbonate (148 mg, 1.08 mmol) to the solution (10 ml), heat to 70°C and react for 5 hours, then add water (1 ml) and continue the reaction for 4 hours.
反应完成，浓缩旋干，加入二氯甲烷/甲醇＝10/1的混合溶剂10毫升，抽滤，滤液旋干，得到粗品，采用实施例3步骤D中的手性拆分方法分离得到3.3毫克绝对构型的非对映异构体52A(收率：2.5％)和13.8毫克绝对构型的非对映异构体52B(收率：10.6％)。After the reaction is completed, concentrate and spin to dryness, add 10 ml of a mixed solvent of dichloromethane/methanol = 10/1, filter with suction, and spin the filtrate to dryness to obtain a crude product. Use the chiral separation method in step D of Example 3 to isolate and obtain 3.3 mg. Absolute configuration of diastereomer 52A (yield: 2.5%) and 13.8 mg of absolute configuration of diastereomer 52B (yield: 10.6%).
化合物52A：HPLC：RT＝3.226min，LCMS：RT＝1.66min，[M+H]+＝497.29.Compound 52A: HPLC: RT=3.226min, LCMS: RT=1.66min, [M+H] + =497.29.
1H NMR(400MHz，DMSO-d6)δ10.83(s，1H)，8.73(d，J＝1.5Hz，1H)，8.71-8.65(m，1H)，8.52(d，J＝2.6Hz，1H)，7.80(d，J＝8.0Hz，2H)，7.62(d，J＝8.0Hz，2H)，7.26(t，J＝2.8Hz，1H)，6.65(s，1H)，6.45(t，J＝2.5Hz，1H)，3.74-3.61(m，5H)，3.26-3.20(m，3H)，2.42(s，3H)，2.32-2.29(m，1H)，2.19(d，J＝15.3Hz，3H)，1.83(s，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 8.73 (d, J = 1.5Hz, 1H), 8.71-8.65 (m, 1H), 8.52 (d, J = 2.6Hz, 1H), 7.80 (d, J=8.0Hz, 2H), 7.62 (d, J=8.0Hz, 2H), 7.26 (t, J=2.8Hz, 1H), 6.65 (s, 1H), 6.45 (t, J=2.5Hz, 1H), 3.74-3.61 (m, 5H), 3.26-3.20 (m, 3H), 2.42 (s, 3H), 2.32-2.29 (m, 1H), 2.19 (d, J=15.3Hz , 3H), 1.83 (s, 1H).
化合物52B：HPLC：RT＝3.153min，LCMS：RT＝1.66min，[M+H]+＝497.29。Compound 52B: HPLC: RT=3.153 min, LCMS: RT=1.66 min, [M+H] + =497.29.
实施例53A和53B
Examples 53A and 53B
化合物53A和53B的合成路线如下：
The synthetic routes of compounds 53A and 53B are as follows:
步骤A：合成(S)-6-((4-甲氧基羰基)苯基)-4-(5-氯吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxy benzyl acid ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(500毫克，1.05毫摩尔)的二氧六环(15毫升)中，加入2-碘-5-氯吡啶(376毫克，1.57毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(76毫克，0.10毫摩尔)和磷酸钾(556毫克，2.62毫摩尔)，然后加入水(3毫升)，反应置换氮气后，升温到90℃反应5小时。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.05 mmol) in dioxane (15 ml) was added 2-iodo-5-chloro Pyridine (376 mg, 1.57 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (76 mg, 0.10 mmol), and potassium phosphate (556 mg, 2.62 mmol) , then add water (3 ml), and after the reaction replaces nitrogen, the temperature is raised to 90°C for 5 hours.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到258毫克淡黄色油状液体(S)-6-((4-甲氧基羰基)苯基)-4-(5-氯吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：53％)。LCMS：RT＝2.25min，[M+H]+＝463.19。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 258 mg of light yellow oily liquid (S)-6-((4-methoxycarbonyl)phenyl) -4-(5-chloropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 53%). LCMS: RT=2.25min, [M+H] + =463.19.
步骤B：合成(S)-4-(4-(5-氯吡啶-2-基)哌啶-2-基苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(5-chloropyridin-2-yl)piperidin-2-ylbenzoic acid methyl ester
将(S)-6-((4-甲氧基羰基)苯基)-4-(5-氯吡啶-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(258毫克，0.56毫摩尔)溶于乙酸乙酯溶液(15毫升)中，加入威尔金森催化剂(25毫克)，反应置换氢气后，升温到60℃反应过夜。 (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (258 mg, 0.56 mmol) was dissolved in ethyl acetate solution (15 ml), Wilkinson catalyst (25 mg) was added, and after the reaction replaced hydrogen, the temperature was raised to 60°C and the reaction was carried out overnight.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩得到130毫克淡黄色油状液体(S)-4-(4-(5-氯吡啶-2-基)哌啶-2-基苯甲酸甲酯(收率：88％)。LCMS：RT＝1.65min，[M+H]+＝331.19。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure to obtain 130 mg of light yellow oily liquid (S)-4-(4-(5-chloropyridin-2-yl)piperidin-2-yl benzoic acid methyl ester. (Yield: 88%). LCMS: RT = 1.65 min, [M+H] + = 331.19.
步骤C：合成(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(5-氯吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)piperidin-1-yl) Methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-氯吡啶-2-基)哌啶-2-基苯甲酸甲酯(130毫克，0.39毫摩尔)的1，2-二氯乙烷(20毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(284毫克，0.98毫摩尔)和三乙酰氧基硼氢化钠(333毫克，1.57毫摩尔)，40℃反应过夜。To 1,2-dichloroethane (20 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (284 mg, 0.98 mmol) and sodium triacetoxyborohydride ( 333 mg, 1.57 mmol), react at 40°C overnight.
反应结束，加入少量甲醇，直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝6/1)得到87毫克淡黄色固体(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(5-氯吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：36％)。LCMS：RT＝2.00min，[M+H]+＝604.34。After the reaction was completed, a small amount of methanol was added, and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 6/1) to obtain 87 mg of light yellow solid (S)-5-methyl. Oxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H- Indole-1-carboxylic acid tert-butyl ester (yield: 36%). LCMS: RT=2.00min, [M+H] + =604.34.
步骤D：合成化合物53A和53BStep D: Synthesis of Compounds 53A and 53B
向(S)-5-甲氧基-4-(2-(4-甲氧基羰基)苯基)-4-(5-氯吡啶-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(87毫克，0.14毫摩尔)的甲醇(10毫升)溶液中加碳酸钾(199毫克，1.40毫摩尔)，加热至70℃反应5小时，再加水(0.3毫升)继续反应4小时。To (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)piperidin-1-yl)methyl) -To a solution of tert-butyl 7-methyl-1H-indole-1-carboxylate (87 mg, 0.14 mmol) in methanol (10 ml), add potassium carbonate (199 mg, 1.40 mmol) and heat to 70°C The reaction was continued for 5 hours, and water (0.3 ml) was added to continue the reaction for 4 hours.
反应完成后，硅藻土抽滤，滤饼甲醇洗，滤液浓缩后，采用实施例3步骤D中的手性拆分方法分离得到13.8毫克绝对构型的非对映异构体53A(收率：19％)和2.2毫克绝对构型的非对映异构体53B(收率：3％)。After the reaction was completed, diatomaceous earth was suctioned and filtered, and the filter cake was washed with methanol. After the filtrate was concentrated, the chiral separation method in step D of Example 3 was used to separate and obtain 13.8 mg of the absolute configuration of diastereomer 53A (yield : 19%) and 2.2 mg of the absolute configuration of diastereomer 53B (yield: 3%).
化合物53A：HPLC：RT＝3.563min，LCMS：RT＝1.75min，[M+H]+＝490.21。(MeOH，Rudolph Autopol I比旋仪)。Compound 53A: HPLC: RT=3.563min, LCMS: RT=1.75min, [M+H] + =490.21. (MeOH, Rudolph Autopol I spinometer).
1HNMR(400MHz，DMSO-d6)δ10.84(s，1H)，8.65(s，1H)，7.95(d，J＝7.9Hz，2H)，7.89(dd，J＝8.5，2.6Hz，1H)，7.65(d，J＝7.9Hz，2H)，7.49(d，J＝8.5Hz，1H)，7.26(d，J＝2.8Hz，1H)，6.65(s，1H)，6.46(t，J＝2.4Hz，1H)，3.69(m，4H)，3.67(s，1H)，3.62(dd，J＝9.1，3.3Hz，2H)，3.34(d，J＝11.9Hz，3H)，3.12(t，J＝4.9Hz，2H)，2.63(dt，J＝12.5，4.4Hz，1H)，2.27-2.03(m，3H)，1.77(tt，J＝10.1，4.8Hz，1H).化合物53B：HPLC：RT＝3.455min，LCMS：RT＝1.73min，[M+H]+＝490.25。 1 HNMR (400MHz, DMSO-d 6 ) δ10.84 (s, 1H), 8.65 (s, 1H), 7.95 (d, J=7.9Hz, 2H), 7.89 (dd, J=8.5, 2.6Hz, 1H ), 7.65 (d, J=7.9Hz, 2H), 7.49 (d, J=8.5Hz, 1H), 7.26 (d, J=2.8Hz, 1H), 6.65 (s, 1H), 6.46 (t, J =2.4Hz, 1H), 3.69 (m, 4H), 3.67 (s, 1H), 3.62 (dd, J = 9.1, 3.3Hz, 2H), 3.34 (d, J = 11.9Hz, 3H), 3.12 (t , J=4.9Hz, 2H), 2.63 (dt, J=12.5, 4.4Hz, 1H), 2.27-2.03 (m, 3H), 1.77 (tt, J=10.1, 4.8Hz, 1H). Compound 53B: HPLC : RT=3.455min, LCMS: RT=1.73min, [M+H] + =490.25.
实施例54
Example 54
化合物54的合成路线如下：
The synthetic route of compound 54 is as follows:
步骤A：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(940毫克，1.88毫摩尔)，2-噻吩硼酸(482毫克，3.76毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(137毫克，0.188毫摩尔)，磷酸钾(1.2克，5.65毫摩尔)加入1，4-二氧六环(15毫升)，氮气保护下90℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H) - Benzyl carboxylate (940 mg, 1.88 mmol), 2-thiopheneboronic acid (482 mg, 3.76 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (137 mg, 0.188 mmol), potassium phosphate (1.2 g, 5.65 mmol) was added to 1,4-dioxane (15 ml), and the reaction was carried out at 90°C for 12 hours under nitrogen protection.
反应完成后，加入乙酸乙酯(30毫升)稀释，过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到402毫克黄色半固体状(S)-6-(4-(甲氧基羰基)苯基)-4-(噻吩-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率47.6％)。LCMS：RT＝2.20min，[M+H]+＝434.19。After the reaction was completed, ethyl acetate (30 ml) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 402 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxy as a yellow semi-solid Acid benzyl ester (yield 47.6%). LCMS: RT = 2.20 min, [M+H] + = 434.19.
步骤B：合成(S)-4-(噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯Step B: Synthesis of (S)-4-(thiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester
将(S)-4-(噻吩-2-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(400毫克，0.94毫摩尔)溶于乙酸乙酯溶液(15毫升)中，加入钯碳(60毫克)，反应置换氢气后，升温到60℃反应过夜。(S)-4-(thiophen-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (400 mg , 0.94 mmol) was dissolved in ethyl acetate solution (15 ml), palladium on carbon (60 mg) was added, and after the reaction replaced hydrogen, the temperature was raised to 60°C and the reaction was carried out overnight.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩得到355毫克无色油状液体(S)-4-(噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯(收率86.6％)。LCMS：RT＝2.15min，[M+H]+＝436.21。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure to obtain 355 mg of colorless oily liquid (S)-4-(thiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridine. Benzyl carboxylate (yield 86.6%). LCMS: RT=2.15min, [M+H] + =436.21.
步骤C：合成(S)-4-(5-氯噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯Step C: Synthesis of (S)-4-(5-chlorothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester
将(S)-4-(噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯(355毫克，0.82毫摩尔)溶于15mL乙酸/N，N-二甲基甲酰胺溶液(1∶2)中，加入N-氯代丁二酰亚胺(110毫克，0.82毫摩尔)，室温反应1小时。 Dissolve (S)-4-(thiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester (355 mg, 0.82 mmol) in 15 mL acetic acid/N, N -To the dimethylformamide solution (1:2), add N-chlorosuccinimide (110 mg, 0.82 mmol) and react at room temperature for 1 hour.
反应完成后，用冰块淬灭反应，乙酸乙酯(20毫升×3次)萃取，合并有机相，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝5/1)。得到302毫克浅黄色油状(S)-4-(5-氯噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯(收率79％)。LCMS：RT＝2.32min，[M+H]+＝470.21。After the reaction was completed, the reaction was quenched with ice cubes, extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=5/1). 302 mg of (S)-4-(5-chlorothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester was obtained as a light yellow oil (yield 79%). LCMS: RT = 2.32 min, [M+H] + = 470.21.
步骤D：合成(S)-4-(4-(5-氯噻吩-2-基)哌啶-2-基)苯甲酸甲酯Step D: Synthesis of (S)-4-(4-(5-chlorothiophen-2-yl)piperidin-2-yl)benzoate methyl ester
将化合物(S)-4-(5-氯噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯(300毫克，0.64毫摩尔)溶于乙酸乙酯(5毫升)，冰水浴冷却，加入33％氢溴酸/醋酸溶液(2毫升)，室温反应1小时。Compound (S)-4-(5-chlorothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester (300 mg, 0.64 mmol) was dissolved in ethyl acetate ester (5 ml), cooled in an ice-water bath, added 33% hydrobromic acid/acetic acid solution (2 ml), and reacted at room temperature for 1 hour.
反应完成后，冰水浴冷却，用冰块淬灭反应，再用氨水调节pH＝12-13，乙酸乙酯(20毫升×3次)萃取，合并有机相，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10/1)。得到112毫克浅黄色油状(S)-4-(4-(5-氯噻吩-2-基)哌啶-2-基)苯甲酸甲酯(收率52％)。LCMS：RT＝1.72min，[M+H]+＝336.13。After the reaction is completed, cool it in an ice-water bath, quench the reaction with ice cubes, then adjust the pH to 12-13 with ammonia water, extract with ethyl acetate (20 ml × 3 times), combine the organic phases, and then dry with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1). 112 mg of (S)-4-(4-(5-chlorothiophen-2-yl)piperidin-2-yl)benzoic acid methyl ester was obtained as a light yellow oil (yield 52%). LCMS: RT = 1.72 min, [M+H] + = 336.13.
步骤E：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-氯噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step E: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothiophen-2-yl)piperidine-1- (methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-氯噻吩-2-基)哌啶-2-基)苯甲酸甲酯(110毫克，0.33毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(142毫克，0.49毫摩尔)和三乙酰氧基硼氢化钠(174毫克，0.82毫摩尔)，40℃反应过夜。To a solution containing (S)-methyl 4-(4-(5-chlorothiophen-2-yl)piperidin-2-yl)benzoate (110 mg, 0.33 mmol) in 1,2-dichloroethane ( 5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (142 mg, 0.49 mmol) and sodium triacetoxyborohydride (174 mg, 0.82 mmol), react at 40°C overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到109毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-氯噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：54％)。LCMS：RT＝2.04min，[M+H]+＝609.26。After the reaction is completed, a small amount of methanol is added and the solvent is directly rotated to dryness. The resulting residue is purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to obtain 109 mg of white solid (S)-5-methoxy. -4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H- Indole-1-carboxylic acid tert-butyl ester (yield: 54%). LCMS: RT=2.04min, [M+H] + =609.26.
步骤F：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-氯噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸Step F: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothiophen-2-yl)piperidine-1- (methyl)-7-methyl-1H-indole-1-carboxylic acid
(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-氯噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(100毫克，0.16毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(227毫克，1.6毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。(S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothiophen-2-yl)piperidin-1-yl)methyl )-7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) in methanol (5 ml) was added with potassium carbonate (227 mg, 1.6 mmol), and heated to 70 The reaction was carried out at ℃ for 5 hours, and water (1 ml) was added to continue the reaction for 4 hours.
反应完成后，采用实施例3步骤D中的纯化处理方法分离得到13毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-氯噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸(收率：16.4％)。After the reaction was completed, 13 mg of white solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)- 4-(5-chlorothiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid (yield: 16.4%).
化合物54：HPLC：RT＝4.98min，LCMS：RT＝1.79min，[M+H]+＝495.17。Compound 54: HPLC: RT=4.98 min, LCMS: RT=1.79 min, [M+H] + =495.17.
实施例55A和55B
Examples 55A and 55B
化合物55A和55B合成路线如下：
The synthetic routes of compounds 55A and 55B are as follows:
步骤A：合成(S)-2-(4-甲氧羰基)苯基)-4-(噻吩-2-基)哌啶-1-羧酸苄酯Step A: Synthesis of (S)-2-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidine-1-carboxylic acid benzyl ester
0℃下，向含有(S)-2-(4-甲氧羰基)苯基)-4-(噻吩-2-基)哌啶-1-羧酸苄酯(300毫克，0.69毫摩尔)的乙腈(10毫升)溶液中加入N-溴代丁二酰亚胺(123毫克，0.69毫摩尔)，0℃左右反应4小时。To a solution containing (S)-2-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidine-1-carboxylic acid benzyl ester (300 mg, 0.69 mmol) at 0°C Add N-bromosuccinimide (123 mg, 0.69 mmol) to the acetonitrile (10 ml) solution, and react at about 0°C for 4 hours.
反应结束后，直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到159毫克淡黄色油状液体(S)-2-(4-甲氧羰基)苯基)-4-(噻吩-2-基)哌啶-1-羧酸苄酯(收率：45％)。LCMS：RT＝2.32min，[M+H]+＝514.10/516.06。After the reaction, the solvent was directly spun to dryness, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 159 mg of light yellow oily liquid (S)-2-(4- Methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidine-1-carboxylic acid benzyl ester (yield: 45%). LCMS: RT=2.32min, [M+H] + =514.10/516.06.
步骤B：合成(S)-4-(4-(5-溴噻吩-2-基)哌啶-2-甲基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(5-bromothiophen-2-yl)piperidine-2-methyl)benzoate methyl ester
0℃下，向含有(S)-2-(4-甲氧羰基)苯基)-4-(噻吩-2-基)哌啶-1-羧酸苄酯的乙酸乙酯(10毫升)溶液中加入33％氢溴酸/醋酸溶液(0.5毫升)，升至室温反应2小时。To a solution of (S)-2-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidine-1-carboxylic acid benzyl ester in ethyl acetate (10 ml) at 0°C Add 33% hydrobromic acid/acetic acid solution (0.5 ml) and raise to room temperature for 2 hours.
反应结束后，加入氨水调节pH至中性，直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：100％乙酸乙酯)得到23毫克淡黄色油状物(S)-4-(4-(5-溴噻吩-2-基)哌啶-2-甲基)苯甲酸甲酯(收率：22％)。LCMS：RT＝1.73min，[M+H]+＝380.08/382.10。 After the reaction was completed, ammonia was added to adjust the pH to neutral, and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: 100% ethyl acetate) to obtain 23 mg of light yellow oily substance (S)-4- (4-(5-bromothiophen-2-yl)piperidine-2-methyl)benzoate methyl ester (yield: 22%). LCMS: RT=1.73min, [M+H] + =380.08/382.10.
步骤C：合成(S)-4-((4-(5-溴噻吩-2-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-4-((4-(5-bromothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5 -Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-溴噻吩-2-基)哌啶-2-甲基)苯甲酸甲酯(52毫克，0.14毫摩尔)的1，2-二氯乙烷(10毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(101毫克，0.35毫摩尔)和三乙酰氧基硼氢化钠(59毫克，0.28毫摩尔)，40℃反应过夜。To (S)-4-(4-(5-bromothiophen-2-yl)piperidine-2-methyl)benzoate methyl ester (52 mg, 0.14 mmol) in 1,2-dichloroethane (10 mL), 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (101 mg, 0.35 mmol) and triacetoxyhydroborate were added Sodium (59 mg, 0.28 mmol), react at 40°C overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到52毫克淡黄色油状液体(S)-4-((4-(5-溴噻吩-2-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：57％)。LCMS：RT＝2.02min，[M+H]+＝653.20。After the reaction was completed, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 52 mg of light yellow oily liquid (S)-4-( (4-(5-bromothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H - Indole-1-carboxylic acid tert-butyl ester (yield: 57%). LCMS: RT = 2.02 min, [M+H] + = 653.20.
步骤D：合成化合物55A和55BStep D: Synthesis of Compounds 55A and 55B
向(S)-4-((4-(5-溴噻吩-2-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(52毫克，0.08毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(44毫克，0.32毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。To (S)-4-((4-(5-bromothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy To a solution of tert-butyl-7-methyl-1H-indole-1-carboxylate (52 mg, 0.08 mmol) in methanol (5 ml), potassium carbonate (44 mg, 0.32 mmol) was added and heated to 70 The reaction was carried out at ℃ for 5 hours, and water (1 ml) was added to continue the reaction for 4 hours.
反应完成后，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到17.2毫克绝对构型的非对映异构体55A(收率：1.6％)和4.8毫克绝对构型的非对映异构体55B(收率：3％)。After the reaction was completed, the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 17.2 mg of diastereoisomer 55A with absolute configuration (yield: 1.6%) and 4.8 mg of diastereoisomer 55A with absolute configuration. Enantiomer 55B (yield: 3%).
化合物55A：HPLC：RT＝3.663min，LCMS：RT＝1.84min，[M+H]+＝539.16/541.16。Compound 55A: HPLC: RT=3.663min, LCMS: RT=1.84min, [M+H] + =539.16/541.16.
化合物55B：HPLC：RT＝3.665min，LCMS：RT＝1.84min，[M+H]+＝539.16/541.16。Compound 55B: HPLC: RT=3.665min, LCMS: RT=1.84min, [M+H] + =539.16/541.16.
实施例56A和56B
Examples 56A and 56B
化合物56A和56B合成路线如下：
The synthetic routes of compounds 56A and 56B are as follows:
步骤A：合成(S)-2-(4-(甲氧羰基)苯基)-4-(噻吩-3-基)哌啶-1-羧酸苄酯Step A: Synthesis of (S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.5克，3.46毫摩尔)溶于乙酸乙酯(40毫升)，加入钯/碳(600毫克)，氢气氛围下加热至60℃，反应过夜、过滤，再加入钯/碳(600毫克)，继续反应过夜。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.5 g , 3.46 mmol) was dissolved in ethyl acetate (40 ml), added palladium/carbon (600 mg), heated to 60°C under a hydrogen atmosphere, reacted overnight, filtered, then added palladium/carbon (600 mg), and continued the reaction overnight .
反应完成后，过滤，减压浓缩。得到780毫克浅黄色胶状(S)-2-(4-(甲氧羰基)苯基)-4-(噻吩-3-基)哌啶-1-羧酸苄酯(粗品)，不需要纯化，直接用于下一步反应。LCMS：RT＝2.21min，[M+H]+＝436.21。After the reaction is completed, filter and concentrate under reduced pressure. Obtained 780 mg of (S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester (crude product) as a light yellow gum, no purification required , used directly for the next reaction. LCMS: RT = 2.21 min, [M+H] + = 436.21.
步骤B：合成(S)-4-(2-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯Step B: Synthesis of (S)-4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester
将化合物(S)-2-(4-(甲氧羰基)苯基)-4-(2-甲基噻吩-3-基)哌啶-1-羧酸苄酯(630毫克，1.45毫摩尔)溶于N，N-二甲基甲酰胺(20毫升)，加入醋酸(4毫升)，冰水浴冷却，加入NCS(193毫克，1.45毫摩尔)，室温反应过夜。Compound (S)-2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylic acid benzyl ester (630 mg, 1.45 mmol) Dissolve in N,N-dimethylformamide (20 ml), add acetic acid (4 ml), cool in an ice-water bath, add NCS (193 mg, 1.45 mmol), and react at room temperature overnight.
反应完成后，反应液倒入100毫升水中，用乙酸乙酯(25毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝9/1)，得到450毫克黄色胶状(S)-4-(2-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯(收率64％)。LCMS：RT＝2.31min，[M+H]+＝470.16。After the reaction is completed, the reaction solution is poured into 100 ml of water, extracted with ethyl acetate (25 ml × 3 times), and the organic phases are combined. The organic phase is first washed with saturated brine (20 ml), and then dried over anhydrous sodium sulfate. Finally, concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 9/1) to obtain 450 mg of yellow gummy (S)-4-(2-chlorothiophen-3-yl)-2 -(4-(Methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (yield 64%). LCMS: RT = 2.31 min, [M+H] + = 470.16.
1H NMR(400MHz，CDCl3)δ7.99(d，J＝8.0Hz，2H)，7.42-7.28(m，5H)，7.18-7.09(m，2H)，7.05(d，J＝5.2Hz，1H)，6.76(d，J＝5.2Hz，1H)，5.13-5.05(m，2H)，4.24-4.16(m，1H)，3.94(s，3H)，3.65-3.55(m，1H)，3.25-3.13(m，1H)，2.37-2.25(m，1H)，2.22-2.13(m，1H)，2.09-1.94(m，2H)，1.72-1.58(m，2H) 1 H NMR (400MHz, CDCl 3 ) δ7.99 (d, J=8.0Hz, 2H), 7.42-7.28 (m, 5H), 7.18-7.09 (m, 2H), 7.05 (d, J=5.2Hz, 1H), 6.76 (d, J=5.2Hz, 1H), 5.13-5.05 (m, 2H), 4.24-4.16 (m, 1H), 3.94 (s, 3H), 3.65-3.55 (m, 1H), 3.25 -3.13(m, 1H), 2.37-2.25(m, 1H), 2.22-2.13(m, 1H), 2.09-1.94(m, 2H), 1.72-1.58(m, 2H)
步骤C：(S)-4-(4-(2-氯噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step C: (S)-Methyl 4-(4-(2-chlorothiophen-3-yl)piperidin-2-yl)benzoate
将化合物(S)-4-(2-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-羧酸苄酯(450毫克，0.96毫摩尔)溶于乙酸乙酯(10毫升)，冰水浴冷却，加入33％氢溴酸/醋酸溶液(1毫升)，室温搅拌2小时。Compound (S)-4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (450 mg, 0.96 mmol) Dissolve in ethyl acetate (10 ml), cool in an ice-water bath, add 33% hydrobromic acid/acetic acid solution (1 ml), and stir at room temperature for 2 hours.
反应完成后，用水淬灭反应，氨水调节至碱性，乙酸乙酯(15毫升×3次)萃取，饱和食盐水洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得到180毫克黄色胶状(S)-4-(4-(2-氯噻吩-3-基)哌啶-2-基)苯甲酸甲酯(收率55％)。LCMS：RT＝1.67min，[M+H]+＝336.15。After the reaction was completed, the reaction was quenched with water, adjusted to alkaline with ammonia water, extracted with ethyl acetate (15 ml × 3 times), washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=10/1). 180 mg of (S)-4-(4-(2-chlorothiophen-3-yl)piperidin-2-yl)benzoic acid methyl ester was obtained as a yellow gum (yield 55%). LCMS: RT = 1.67 min, [M+H] + = 336.15.
步骤D：合成(S)-4-((4-(2-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1- 羧酸叔丁酯Step D: Synthesis of (S)-4-((4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)- 5-methoxy-7-methyl-1H-indole-1- tert-butyl carboxylate
将化合物(S)-4-(4-(2-氯噻吩-3-基)哌啶-2-基)苯甲酸甲酯(180毫克，0.54毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(310毫克，1.08毫摩尔)溶于1，2-二氯乙烷(15毫升)，室温反应过夜。再加入三乙酰氧基硼氢化钠(340毫克，1.61毫摩尔)，反应4小时。Compound (S)-4-(4-(2-chlorothiophen-3-yl)piperidin-2-yl)benzoate methyl ester (180 mg, 0.54 mmol) and 4-formyl-5-methoxy Tert-butyl-7-methyl-1H-indole-1-carboxylate (310 mg, 1.08 mmol) was dissolved in 1,2-dichloroethane (15 ml), and the reaction was carried out at room temperature overnight. Then add sodium triacetoxyborohydride (340 mg, 1.61 mmol) and react for 4 hours.
反应完成后，加入甲醇溶解至澄清，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)。得到610毫克黄色油状(S)-4-((4-(2-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(粗品)，直接用于下一步反应。LCMS：RT＝1.97min，[M+H]+＝609.28。After the reaction is completed, add methanol to dissolve until clear, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1). Obtained 610 mg of (S)-4-((4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl) as a yellow oil -5-Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (crude product) was directly used in the next reaction. LCMS: RT = 1.97 min, [M+H] + = 609.28.
步骤E：合成化合物56A和56BStep E: Synthesis of Compounds 56A and 56B
将化合物(S)-4-((4-(2-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(610毫克，0.3毫摩尔，粗品)溶于甲醇(20毫升)，加入碳酸钾(415毫克，3毫摩尔)，加热至60℃搅拌过夜。再加入水(5毫升)，继续反应5小时。Compound (S)-4-((4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (610 mg, 0.3 mmol, crude product) was dissolved in methanol (20 ml), and potassium carbonate (415 mg, 3 mmol) was added , heated to 60°C and stirred overnight. Then add water (5 ml) and continue the reaction for 5 hours.
反应完成后，在真空下浓缩该溶液且采用实施例3步骤D中的纯化处理和手性拆分方法分离得到2.0毫克绝对构型的非对映异构体56A和42.8毫克绝对构型的非对映异构体56B(收率：29％)。After the reaction was completed, the solution was concentrated under vacuum and the purification treatment and chiral resolution method in step D of Example 3 were used to separate and obtain 2.0 mg of absolute configuration diastereomer 56A and 42.8 mg of absolute configuration diastereomer 56A. Enantiomer 56B (yield: 29%).
化合物56A：HPLC：RT＝10.2min，LCMS：RT＝1.77min，[M+H]+＝495.17。Compound 56A: HPLC: RT=10.2 min, LCMS: RT=1.77 min, [M+H] + =495.17.
化合物56B：HPLC：RT＝11.6min，LCMS：RT＝1.77min，[M+H]+＝495.17。Compound 56B: HPLC: RT=11.6 min, LCMS: RT=1.77 min, [M+H] + =495.17.
1H NMR(400MHz，DMSO-d6)δ10.83(s，1H)，7.98(d，J＝8.0Hz，2H)，7.71(d，J＝8.0Hz，2H)，7.36(d，J＝4.0Hz，1H)，7.28-7.24(m，1H)，7.02(d，J＝4.0Hz，1H)，6.67(s，1H)，6.49-6.44(m，1H)，3.73(s，3H)，3.63-3.56(m，1H)，3.25-3.19(m，2H)，2.95-2.84(m，2H)，2.43(s，3H)，2.21-2.11(m，1H)，1.82-1.70(m，2H)，1.65-1.49(m，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.83 (s, 1H), 7.98 (d, J=8.0Hz, 2H), 7.71 (d, J=8.0Hz, 2H), 7.36 (d, J= 4.0Hz, 1H), 7.28-7.24 (m, 1H), 7.02 (d, J=4.0Hz, 1H), 6.67 (s, 1H), 6.49-6.44 (m, 1H), 3.73 (s, 3H), 3.63-3.56(m, 1H), 3.25-3.19(m, 2H), 2.95-2.84(m, 2H), 2.43(s, 3H), 2.21-2.11(m, 1H), 1.82-1.70(m, 2H ), 1.65-1.49(m, 2H).
实施例57
Example 57
化合物57的合成路线如下：
The synthetic route of compound 57 is as follows:
步骤A：合成4-溴-2-(二氟甲基)噻吩Step A: Synthesis of 4-bromo-2-(difluoromethyl)thiophene
冰浴下，向含有5-氯吡嗪-2-甲醛(2.0克，14.0毫摩尔)的二氯甲烷(30毫升)中，加入二乙胺基三氟化硫(5.6克，35毫摩尔)，滴加完毕后室温反应12小时。To dichloromethane (30 ml) containing 5-chloropyrazine-2-carbaldehyde (2.0 g, 14.0 mmol), diethylamine sulfur trifluoride (5.6 g, 35 mmol) was added in an ice bath. , react at room temperature for 12 hours after the dropwise addition is completed.
反应结束后将反应液导入冰的饱和碳酸氢钠水溶液中，用二氯甲烷(10毫升×3次)萃取，有机相合并干燥旋干，所得残余物用硅胶柱层析纯化，正己烷过柱得到520毫克无色液体2-氯-5-(二氟甲基)吡嗪(收率：23％)。After the reaction, the reaction solution was introduced into an ice-cold saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10 ml × 3 times), the organic phases were combined, dried and spin-dried. The resulting residue was purified by silica gel column chromatography, and n-hexane was passed through the column. 520 mg of colorless liquid 2-chloro-5-(difluoromethyl)pyrazine was obtained (yield: 23%).
步骤B：合成(S)-6-(4-(甲氧基羰基)苯基)-4-(5-(二氟甲基)吡嗪-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step B: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)pyrazin-2-yl)-3,6-dihydropyridine- 1(2H)-Carboxylic acid benzyl ester
室温下，向含有(S)-6-(4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(700毫克，1.46毫摩尔)的二氧六环(10毫升)中，加入2-氯-5-(二氟甲基)吡嗪(356.3毫克，2.19毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(213.0毫克，0.29毫摩尔)和磷酸钾(634.4毫克，2.92毫摩尔)，然后加入水(2毫升)，反应置换氮气后，升温到95℃反应12小时。At room temperature, to a compound containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- To 2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (700 mg, 1.46 mmol) in dioxane (10 ml), 2-chloro-5-(dihydropyridine-1(2H)-carboxylate Fluoromethyl)pyrazine (356.3 mg, 2.19 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (213.0 mg, 0.29 mmol) and potassium phosphate (634.4 mg , 2.92 mmol), then add water (2 ml), and after replacing nitrogen, the temperature is raised to 95°C and reacted for 12 hours.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)得到350毫克淡黄色油状液体(S)-4-(5-(二氟甲基)吡嗪-2-基)-6-(4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：50.1％)。LCMS：RT＝2.14min，[M+H]+＝484.20。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 4/1) to obtain 350 mg of light yellow oily liquid (S)-4-(5-(difluoromethyl)pyrazine- 2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 50.1%). LCMS: RT = 2.14 min, [M+H] + = 484.20.
步骤C：合成(S)-4-(4-(5-(二氟甲基)吡嗪-2-基)哌啶-2-基)苯甲酸甲酯Step C: Synthesis of (S)-4-(4-(5-(difluoromethyl)pyrazin-2-yl)piperidin-2-yl)benzoate methyl ester
将(S)-4-(5-(二氟甲基)吡嗪-2-基)-6-(4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(350毫克，0.73毫摩尔)溶于乙酸乙酯溶液(20毫升)中，加入钯碳(400毫克)，反应置换氢气后，室温反应24小时。(S)-4-(5-(difluoromethyl)pyrazin-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H) - Benzyl carboxylate (350 mg, 0.73 mmol) was dissolved in ethyl acetate solution (20 ml), palladium on carbon (400 mg) was added, and the reaction was carried out to replace hydrogen, and the reaction was carried out at room temperature for 24 hours.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩得到200毫克无色油状液体(S)-4-(4-(5-(二氟甲基)吡嗪-2-基)哌啶-2-基)苯甲酸甲酯(收率：79.0％)。LCMS：RT＝1.59min，[M+H]+＝348.21。After the reaction, filter, wash with ethyl acetate and concentrate under reduced pressure to obtain 200 mg of colorless oily liquid (S)-4-(4-(5-(difluoromethyl)pyrazin-2-yl)piperidine-2 -yl) methyl benzoate (yield: 79.0%). LCMS: RT = 1.59 min, [M+H] + = 348.21.
步骤D：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-(二氟甲基)吡嗪-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯 Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)pyrazin-2-yl) )piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-(二氟甲基)吡嗪-2-基)哌啶-2-基)苯甲酸甲酯(200毫克，0.57毫摩尔)的二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(330毫克，1.14毫摩尔)，室温搅拌12小时，然后缓慢加入三乙酰氧基硼氢化钠(360.8毫克，1.71毫摩尔)，40℃反应4小时。To (S)-4-(4-(5-(difluoromethyl)pyrazin-2-yl)piperidin-2-yl)benzoate methyl ester (200 mg, 0.57 mmol) was added to dichloroethyl (5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (330 mg, 1.14 mmol), and stir at room temperature for 12 hours. Then sodium triacetoxyborohydride (360.8 mg, 1.71 mmol) was slowly added, and the reaction was carried out at 40°C for 4 hours.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)得到228毫克白色固体(S)-4-((4-(5-(二氟甲基)吡嗪-2-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：64.5％)。LCMS：RT＝1.93min，[M+H]+＝621.36。After the reaction was completed, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 4/1) to obtain 228 mg of white solid (S)-4-((4 -(5-(difluoromethyl)pyrazin-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7- Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 64.5%). LCMS: RT = 1.93 min, [M+H] + = 621.36.
步骤E：合成化合物57Step E: Synthesis of Compound 57
向(S)-4-((4-(5-(二氟甲基)吡嗪-2-基)-2-(4-(甲氧羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(228毫克，0.36毫摩尔)的甲醇(10毫升)溶液中加碳酸钾(198.7毫克，1.44毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。反应完成，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到80.0毫克绝对构型的非对映异构体57(收率：50.0％)。To (S)-4-((4-(5-(difluoromethyl)pyrazin-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl )-5-Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (228 mg, 0.36 mmol) in methanol (10 ml) was added with potassium carbonate (198.7 mg, 1.44 mg mol), heated to 70°C and reacted for 5 hours, then added water (1 ml) and continued the reaction for 4 hours. The reaction was completed, and 80.0 mg of the absolute configuration of diastereomer 57 was isolated using the purification treatment and chiral resolution method in step D of Example 3 (yield: 50.0%).
化合物57：HPLC：RT＝3.355min，LCMS：RT＝1.66min，[M+H]+＝507.27.Compound 57: HPLC: RT=3.355min, LCMS: RT=1.66min, [M+H] + =507.27.
1H NMR(400MHz，DMSO-d6)δ10.84(d，J＝2.4Hz，1H)，8.83(s，1H)，8.73(d，J＝1.4Hz，1H)，7.83(d，J＝7.9Hz，2H)，7.43(d，J＝7.7Hz，2H)，7.26(t，J＝2.8Hz，1H)，7.19-6.92(t，J＝54Hz，1H)，6.66(s，1H)，6.52-6.46(m，1H)，3.73(s，3H)，3.62(d，J＝11.9Hz，1H)，3.30-3.24(m，2H)，3.08(d，J＝8.3Hz，1H)，2.94-2.86(m，1H)，2.42(s，3H)，2.22-2.11(m，1H)，1.98-1.89(m，2H)，1.79(d，J＝12.4Hz，1H)，1.74-1.60(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.84 (d, J = 2.4Hz, 1H), 8.83 (s, 1H), 8.73 (d, J = 1.4Hz, 1H), 7.83 (d, J = 7.9Hz, 2H), 7.43 (d, J=7.7Hz, 2H), 7.26 (t, J=2.8Hz, 1H), 7.19-6.92 (t, J=54Hz, 1H), 6.66 (s, 1H), 6.52-6.46 (m, 1H), 3.73 (s, 3H), 3.62 (d, J=11.9Hz, 1H), 3.30-3.24 (m, 2H), 3.08 (d, J=8.3Hz, 1H), 2.94 -2.86 (m, 1H), 2.42 (s, 3H), 2.22-2.11 (m, 1H), 1.98-1.89 (m, 2H), 1.79 (d, J=12.4Hz, 1H), 1.74-1.60 (m ,1H).
实施例58
Example 58
化合物58的合成路线如下：
The synthetic route of compound 58 is as follows:
步骤A：合成(S)-6-(4-甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H )-carboxylic acid benzyl ester
室温下，向含有(S)-6-((4-甲氧基羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.0克，2.09毫摩尔)的二氧六环(10毫升)中，加入4-溴-2-(三氟甲基)噻吩(580毫克，2.51毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(153毫克，0.21毫摩尔)和磷酸钾(1.11克，5.23毫摩尔)，然后加入水(2毫升)，反应置换氮气后，升温到95℃反应过夜。At room temperature, the solution containing (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane To benzyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 2.09 mmol) in dioxane (10 ml) was added 4-bromo-2-( Trifluoromethyl)thiophene (580 mg, 2.51 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (153 mg, 0.21 mmol) and potassium phosphate (1.11 g , 5.23 mmol), and then add water (2 ml). After the reaction replaces nitrogen, the temperature is raised to 95°C and the reaction is carried out overnight.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝7/1)得到640毫克(S)-6-(4-甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：61％)。LCMS：RT＝2.30min，[M+H]+＝502.20。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 7/1) to obtain 640 mg of (S)-6-(4-methoxycarbonyl)phenyl)-4-(5- (Trifluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 61%). LCMS: RT=2.30min, [M+H] + =502.20.
步骤B：合成(S)-4-(4-(5-(三氟甲基)噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate methyl ester
将(S)-6-(4-甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-3-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(640毫克，1.28毫摩尔)溶于乙酸乙酯溶液(20毫升)中，加入钯碳(300毫克)，反应置换氢气后，升温到50℃反应过夜。(S)-6-(4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic Dissolve benzyl acid ester (640 mg, 1.28 mmol) in ethyl acetate solution (20 ml), add palladium on carbon (300 mg), react to replace hydrogen, then heat to 50°C and react overnight.
反应结束后过滤，用乙酸乙酯洗涤，有机相直接减压浓缩得到410毫克淡黄色油状液体(S)-4-(4-(5-(三氟甲基)噻吩-3-基)哌啶-2-基)苯甲酸甲酯(收率：88％)。LCMS：RT＝1.73min，[M+H]+＝370.19。After the reaction, it was filtered, washed with ethyl acetate, and the organic phase was directly concentrated under reduced pressure to obtain 410 mg of light yellow oily liquid (S)-4-(4-(5-(trifluoromethyl)thiophen-3-yl)piperidine -2-yl)benzoic acid methyl ester (yield: 88%). LCMS: RT = 1.73 min, [M+H] + = 370.19.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)piper (Din-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-(三氟甲基)噻吩-3-基)哌啶-2-基)苯甲酸甲酯(410毫克，1.11毫摩尔)的1，2-二氯乙烷(10毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(390毫克，1.35毫摩尔)和三乙酰氧基硼氢化钠(229毫克，1.08毫摩尔)，40℃反应过夜。To 1,2-containing (S)-4-(4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate (410 mg, 1.11 mmol) To dichloroethane (10 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (390 mg, 1.35 mmol) and triacetyl Sodium oxyborohydride (229 mg, 1.08 mmol), react at 40°C overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)得到270毫克淡黄色油状液体(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：54％)。LCMS：RT＝1.98min，[M+H]+＝643.31。After the reaction was completed, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 4/1) to obtain 270 mg of light yellow oily liquid (S)-5-methyl. Oxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-1-yl)methyl)-7 -Methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 54%). LCMS: RT = 1.98 min, [M+H] + = 643.31.
步骤D：合成化合物58Step D: Synthesis of Compound 58
向(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(5-(三氟甲基)噻吩-3-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(270毫克，0.42毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(232毫克，1.68毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)piperidine-1 To a solution of -methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (270 mg, 0.42 mmol) in methanol (5 ml), potassium carbonate (232 mg, 1.68 mmol) was added ), heated to 70°C and reacted for 5 hours, then added water (1 ml) and continued the reaction for 4 hours.
反应完成后，加入10％柠檬酸的水溶液调节pH至中性，用二氯甲烷(10毫升×4次)萃取，合并有机相，有机相 先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，在真空下浓缩该溶液且用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到13.9毫克非对映异构体58(收率：1.5％)。After the reaction is completed, add 10% citric acid aqueous solution to adjust the pH to neutral, extract with dichloromethane (10 ml × 4 times), combine the organic phases, and First wash with saturated brine (20 ml), and then dry with anhydrous sodium sulfate. The solution is concentrated under vacuum and purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain a crude product. The resolution of diastereoisomers was completed by using chiral HPLC (Agilent prep C18), and 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution was used for elution and separation to obtain 13.9 mg of diastereoisomers. Enantiomer 58 (yield: 1.5%).
化合物58：HPLC：RT＝3.663min，LCMS：RT＝1.83min，[M+H]+＝529.24。Compound 58: HPLC: RT=3.663 min, LCMS: RT=1.83 min, [M+H] + =529.24.
实施例59A和59B
Examples 59A and 59B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-2-(4-(甲氧羰基)苯基)-4-(甲氧亚氨基)哌啶-1-羧酸苄酯Step A: Synthesis of (S)-2-(4-(methoxycarbonyl)phenyl)-4-(methoxyimino)piperidine-1-carboxylic acid benzyl ester
将(S)-2-(4-氰基苯基)-4-氧代哌啶-1-羧酸苄酯(500毫克，1.36毫摩尔)溶于甲醇溶液(10毫升)中，加入甲氧基胺盐酸盐(277毫克，2.72毫摩尔)和吡啶(215毫克，2.72毫摩尔)，室温反应过夜。Dissolve (S)-2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester (500 mg, 1.36 mmol) in methanol solution (10 ml), add methoxy Amine hydrochloride (277 mg, 2.72 mmol) and pyridine (215 mg, 2.72 mmol) were reacted at room temperature overnight.
反应结束后直接减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到510毫克白色固体(S)-2-(4-(甲氧羰基)苯基)-4-(甲氧亚氨基)哌啶-1-羧酸苄酯(收率：95％)。LCMS：RT＝2.07min，[M+H]+＝397.23。After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 510 mg of white solid (S)-2-(4-(methoxy) Carbonyl)phenyl)-4-(methoxyimino)piperidine-1-carboxylic acid benzyl ester (yield: 95%). LCMS: RT = 2.07 min, [M+H] + = 397.23.
步骤B：合成(S)-4-(4-甲氧基亚氨基)哌啶-2-基)苯甲酸甲酯Step B: Synthesis of (S)-4-(4-methoxyimino)piperidin-2-yl)benzoic acid methyl ester
将(S)-2-(4-(甲氧羰基)苯基)-4-(甲氧亚氨基)哌啶-1-羧酸苄酯(510毫克，1.29毫摩尔)溶于乙酸乙酯溶液(20毫升)中，加入钯碳(250毫克)，反应置换氢气后，室温反应3小时。Dissolve (S)-2-(4-(methoxycarbonyl)phenyl)-4-(methoxyimino)piperidine-1-carboxylic acid benzyl ester (510 mg, 1.29 mmol) in ethyl acetate solution (20 ml), add palladium on carbon (250 mg), react to replace hydrogen, and react at room temperature for 3 hours.
反应结束后过滤，用乙酸乙酯洗涤后减压浓缩得到320毫克淡黄色油状液体(S)-4-(4-甲氧基亚氨基)哌啶-2-基)苯甲酸甲酯(收率：95％)。LCMS：RT＝1.50min，[M+H]+＝263.19。After the reaction, it was filtered, washed with ethyl acetate and concentrated under reduced pressure to obtain 320 mg of light yellow oily liquid (S)-4-(4-methoxyimino)piperidin-2-yl)benzoic acid methyl ester (yield :95%). LCMS: RT=1.50min, [M+H] + =263.19.
步骤C：合成(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(甲氧亚氨基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(methoxyimino)piperidin-1-yl)methyl) -7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-甲氧基亚氨基)哌啶-2-基)苯甲酸甲酯(100毫克，0.38毫摩尔)的1，2-二氯乙烷(10毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(220毫克，0.76毫摩尔)和三乙酰氧基硼氢化钠(161毫克，0.76毫摩尔)，40℃反应过夜。To (S)-methyl 4-(4-methoxyimino)piperidin-2-yl)benzoate (100 mg, 0.38 mmol) in 1,2-dichloroethane (10 mL) , add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (220 mg, 0.76 mmol) and sodium triacetoxyborohydride (161 mg, 0.76 mmol), react at 40°C overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/2)得到118毫克淡黄色油状液体(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(甲氧亚氨基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：58％)。LCMS：RT＝1.98min，[M+H]+＝536.32。After the reaction was completed, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/2) to obtain 118 mg of light yellow oily liquid (S)-5-methyl. Oxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(methoxyimino)piperidin-1-yl)methyl)-7-methyl-1H-indole- 1-tert-butylcarboxylate (yield: 58%). LCMS: RT = 1.98 min, [M+H] + = 536.32.
步骤D：合成化合物59A和59BStep D: Synthesis of Compounds 59A and 59B
向(S)-5-甲氧基-4-((2-(4-(甲氧羰基)苯基)-4-(甲氧亚氨基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(118毫克，0.22毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(121毫克，0.88毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。To (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(methoxyimino)piperidin-1-yl)methyl)-7- Add potassium carbonate (121 mg, 0.88 mmol) to a solution of methyl-1H-indole-1-carboxylic acid tert-butyl ester (118 mg, 0.22 mmol) in methanol (5 ml), and heat to 70°C for 5 hours. , add water (1 ml) and continue the reaction for 4 hours.
反应完成后，加入10％柠檬酸的水溶液调节pH至中性，用二氯甲烷(10毫升×4次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，在真空下浓缩该溶液且用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到14毫克绝对构型的非对映异构体59A(收率：15％)和18毫克绝对构型的非对映异构体59B(收率：19％)。After the reaction is completed, add 10% citric acid aqueous solution to adjust the pH to neutral, extract with dichloromethane (10 ml × 4 times), combine the organic phases, wash the organic phase with saturated brine (20 ml), and then wash with Dried over sodium sulfate, the solution was concentrated under vacuum and purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain the crude product, which was completed by using chiral HPLC (Agilent prep C18). For the resolution of enantiomers, 14 mg of absolute configuration diastereomer 59A was obtained by elution with 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution (yield: 15 %) and 18 mg of the absolute configuration of diastereomer 59B (yield: 19%).
化合物59A：HPLC：RT＝3.201min，LCMS：RT＝1.66min，[M+H]+＝422.26。Compound 59A: HPLC: RT=3.201 min, LCMS: RT=1.66 min, [M+H] + =422.26.
1H NMR(400MHz，DMSO-d6)δ10.88(s，1H)，7.84(d，2H)，7.41(d，J＝8.0Hz，2H)，7.24(t，J＝2.8Hz，1H)，6.65(s，1H)，6.47-6.41(m，1H)，3.71(s，3H)，3.70(s，3H)，3.57(d，J＝11.9Hz，1H)，3.31-3.23(m，1H)，3.18(d，J＝11.9Hz，1H)，2.88(d，J＝14.2Hz，2H)，2.43(s，1H)，2.41(s，3H)，2.27(d，J＝13.8Hz，1H)，2.06-1.96(m，1H)，1.92-1.80(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 7.84 (d, 2H), 7.41 (d, J = 8.0Hz, 2H), 7.24 (t, J = 2.8Hz, 1H) , 6.65 (s, 1H), 6.47-6.41 (m, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.57 (d, J=11.9Hz, 1H), 3.31-3.23 (m, 1H ), 3.18 (d, J = 11.9Hz, 1H), 2.88 (d, J = 14.2Hz, 2H), 2.43 (s, 1H), 2.41 (s, 3H), 2.27 (d, J = 13.8Hz, 1H ), 2.06-1.96(m, 1H), 1.92-1.80(m, 1H).
化合物59B：HPLC：RT＝3.173min，LCMS：RT＝1.66min，[M+H]+＝422.26。Compound 59B: HPLC: RT=3.173 min, LCMS: RT=1.66 min, [M+H] + =422.26.
实施例60
Example 60
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成((S)-4-(4-(叔丁氧羰基氨基)噻吩-3-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of ((S)-4-(4-(tert-butoxycarbonylamino)thiophen-3-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine -1(2H)-carboxylic acid benzyl ester
将含有(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.0克，2.09毫摩尔)、(4-溴噻吩-3-基)氨基甲酸叔丁酯(700.0豪克，2.51毫摩尔)、[1，1′-双(三苯基膦基)二茂铁]二氯化钯(154.0毫克，0.21毫摩尔)和磷酸钾(890.0毫克，4.19毫摩尔)的1，4-二氧六环与水的混合溶液(25毫升，1，4-二氧六环∶水＝4∶1)在氮气保护下，加热至90℃反应12小时。Will contain (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -(yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.0 g, 2.09 mmol), (4-bromothiophen-3-yl)carbamic acid tert-butyl ester (700.0 mg, 2.51 mmol), [1,1′-bis(triphenylphosphino)ferrocene]palladium dichloride (154.0 mg, 0.21 mmol) and potassium phosphate (890.0 mg, 4.19 mmol) of 1,4 - A mixed solution of dioxane and water (25 ml, 1,4-dioxane:water=4:1) was heated to 90°C for 12 hours under nitrogen protection.
反应结束后，混合液中加入水，用乙酸乙酯(20毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝1/1)，得到1.0克黄色胶状((S)-4-(4-(叔丁氧羰基氨基)噻吩-3-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率：86％)。LCMS：RT＝2.27min，[M+H-100]+＝449.19。After the reaction, water was added to the mixture, extracted with ethyl acetate (20 ml Pressure concentration. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1) to obtain 1.0 g of yellow gummy ((S)-4-(4-(tert-butoxycarbonylamino)thiophene) -3-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 86%). LCMS: RT= 2.27min, [M+H-100] + = 449.19.
步骤B：合成((S)-4-(4-(叔丁氧羰基氨基)噻吩-3-基)-6-(4-(甲氧羰基苯基))吡啶-1-羧酸苄酯Step B: Synthesis of ((S)-4-(4-(tert-butoxycarbonylamino)thiophen-3-yl)-6-(4-(methoxycarbonylphenyl))pyridine-1-carboxylic acid benzyl ester
室温下，向含有((S)-4-(4-(叔丁氧羰基氨基)噻吩-3-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(1.0克，1.82毫摩尔)的乙酸乙酯(20毫升)中，加入钯碳(1克)，置换氢气三次，接着在氢气氛围下，60℃反应12小时。过滤，加入钯碳(1克)，继续反应过夜。At room temperature, to To ethyl acetate (20 ml) of pyridine-1(2H)-carboxylic acid benzyl ester (1.0 g, 1.82 mmol), add palladium carbon (1 g), replace the hydrogen three times, and then react at 60°C under a hydrogen atmosphere. 12 hours. Filter, add palladium on carbon (1 g), and continue the reaction overnight.
反应结束后，冷却至室温，抽滤，滤液旋干，得到520毫克黄棕色油状((S)-4-(4-(叔丁氧羰基氨基)噻吩-3-基)-6-(4-(甲氧基羰基)苯基)吡啶-1-羧酸苄酯(粗品)。LCMS：RT＝2.25min，[M+H-100]+＝451.20。After the reaction is completed, cool to room temperature, filter with suction, and spin the filtrate to dryness to obtain 520 mg of yellow-brown oily ((S)-4-(4-(tert-butoxycarbonylamino)thiophen-3-yl)-6-(4- (Methoxycarbonyl)phenyl)pyridine-1-carboxylic acid benzyl ester (crude). LCMS: RT = 2.25 min, [M+H-100] + = 451.20.
步骤C：合成((S)-4-(4-((叔丁氧羰基氨基)-5-氯噻吩-3-基)-2-(4-(甲氧羰基苯基))哌啶-1-羧酸苄酯Step C: Synthesis of ((S)-4-(4-((tert-butoxycarbonylamino)-5-chlorothiophen-3-yl)-2-(4-(methoxycarbonylphenyl))piperidine-1 -Benzyl carboxylate
室温下，((S)-4-(4-(叔丁氧羰基氨基)噻吩-3-基)-6-(4-(甲氧基羰基)苯基)吡啶-1-羧酸苄酯(0.5克，0.86毫摩尔)溶解在N，N-二甲基甲酰胺(10毫升)，加入醋酸(1毫升)，冰水浴冷却，加入NCS(116毫克，0.86毫摩尔)，室温反应过夜。((S)-4-(4-(tert-butoxycarbonylamino)thiophen-3-yl)-6-(4-(methoxycarbonyl)phenyl)pyridine-1-carboxylic acid benzyl ester ( 0.5 g, 0.86 mmol) was dissolved in N,N-dimethylformamide (10 ml), acetic acid (1 ml) was added, cooled in an ice-water bath, NCS (116 mg, 0.86 mmol) was added, and the reaction was carried out at room temperature overnight.
反应完成后，反应液倒入50毫升水中，用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)，得到280毫克黄棕色油状((S)-4-(4-((叔丁氧羰基氨基)-5-氯噻吩-3-基)-2-(4-(甲氧羰基苯基))哌啶-1-羧酸苄酯(收率48％)。LCMS：RT＝2.24min，[M+H]+＝585.22。After the reaction is completed, the reaction solution is poured into 50 ml of water, extracted with ethyl acetate (20 ml × 3 times), and the organic phases are combined. The organic phase is first washed with saturated brine (20 ml), and then dried over anhydrous sodium sulfate. Finally, concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to obtain 280 mg of ((S)-4-(4-((tert-butoxycarbonylamino)) as a yellow-brown oil) -5-Chlorothiophen-3-yl)-2-(4-(methoxycarbonylphenyl))piperidine-1-carboxylic acid benzyl ester (yield 48%). LCMS: RT=2.24min, [M+ H] + =585.22.
步骤D：合成(S)-4-(4-氨基-5-氯噻吩-3-基)-2-(4-(甲氧羰基苯基)哌啶-1-羧酸苄酯Step D: Synthesis of (S)-4-(4-amino-5-chlorothiophen-3-yl)-2-(4-(methoxycarbonylphenyl)piperidine-1-carboxylic acid benzyl ester
室温下，((S)-4-(4-((叔丁氧羰基氨基)-5-氯噻吩-3-基)-2-(4-(甲氧羰基苯基))哌啶-1-羧酸苄酯(0.28克，0.48毫摩尔)溶解在乙酸乙酯(10毫升)，加入4M盐酸-二氧六环(5毫升)，室温反应2小时。((S)-4-(4-((tert-butoxycarbonylamino)-5-chlorothiophen-3-yl)-2-(4-(methoxycarbonylphenyl))piperidine-1- at room temperature Benzyl carboxylate (0.28 g, 0.48 mmol) was dissolved in ethyl acetate (10 ml), 4M hydrochloric acid-dioxane (5 ml) was added, and the reaction was carried out at room temperature for 2 hours.
反应完成后，加水稀释，氨水调节至碱性，乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩得200毫克黄色胶状(S)-4-(4-氨基-5-氯噻吩-3-基)-2-(4-(甲氧羰基苯基)哌啶-1-羧酸苄酯(收率88％)。LCMS：RT＝2.20min，[M+H]+＝485.18。After the reaction is completed, add water to dilute, adjust ammonia to alkaline, extract with ethyl acetate (20 ml × 3 times), combine the organic phases, wash the organic phase with saturated brine (20 ml), and then dry with anhydrous sodium sulfate. Finally, concentrate under reduced pressure to obtain 200 mg of yellow gummy (S)-4-(4-amino-5-chlorothiophen-3-yl)-2-(4-(methoxycarbonylphenyl)piperidine-1-carboxylic acid) Benzyl ester (yield 88%). LCMS: RT=2.20min, [M+H] + =485.18.
步骤E：合成(S)-4-(4-(5-氯噻吩-3-基)哌啶-2-基)苯甲酸甲酯Step E: Synthesis of (S)-4-(4-(5-chlorothiophen-3-yl)piperidin-2-yl)benzoate methyl ester
(S)-4-(4-氨基-5-氯噻吩-3-基)-2-(4-(甲氧羰基苯基)哌啶-1-羧酸苄酯(0.1克，0.21毫摩尔)溶解在二氧六环(10毫升)，加入浓硫酸(0.5毫升)，冰水浴冷却，加入NaNO2(20毫克，0.25毫摩尔)，室温反应0.5小时。然后加热至90℃反应1小时。(S)-4-(4-Amino-5-chlorothiophen-3-yl)-2-(4-(methoxycarbonylphenyl)piperidine-1-carboxylic acid benzyl ester (0.1 g, 0.21 mmol) Dissolve in dioxane (10 ml), add concentrated sulfuric acid (0.5 ml), cool in an ice water bath, add NaNO 2 (20 mg, 0.25 mmol), react at room temperature for 0.5 hours. Then heat to 90°C for 1 hour.
反应完成后，加水稀释，氨水调节至碱性，乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，最后减压浓缩得80毫克棕色胶状(S)-4-(4-氨基-5-氯噻吩-3-基)-2-(4-(甲氧羰基苯基)哌啶-1-羧酸苄酯(粗品)。直接用于下一步反应。LCMS：RT＝1.67min，[M+H]+＝336.23。After the reaction is completed, add water to dilute, adjust ammonia to alkaline, extract with ethyl acetate (20 ml × 3 times), combine the organic phases, wash the organic phase with saturated brine (20 ml), and then dry with anhydrous sodium sulfate. Finally, concentrate under reduced pressure to obtain 80 mg of brown gummy (S)-4-(4-amino-5-chlorothiophen-3-yl)-2-(4-(methoxycarbonylphenyl)piperidine-1-carboxylic acid) Benzyl ester (crude product). Used directly for the next reaction. LCMS: RT=1.67min, [M+H] + =336.23.
1H NMR(400MHz，CDCl3)δ8.02(d，J＝8.0Hz，2H)，7.49(d，J＝8.0Hz，2H)，6.84(s，1H)，6.76(s，1H)，3.93(s，3H)，3.86-3.82(m，1H)，3.39-3.28(m，1H)，3.01-2.92(m，1H)，2.86-2.77(m，1H)，2.09-1.94(m，2H)，1.72-1.58(m，2H) 1 H NMR (400MHz, CDCl 3 ) δ8.02 (d, J=8.0Hz, 2H), 7.49 (d, J=8.0Hz, 2H), 6.84 (s, 1H), 6.76 (s, 1H), 3.93 (s, 3H), 3.86-3.82 (m, 1H), 3.39-3.28 (m, 1H), 3.01-2.92 (m, 1H), 2.86-2.77 (m, 1H), 2.09-1.94 (m, 2H) ,1.72-1.58(m,2H)
步骤F：合成合成(S)-4-((4-(5-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯 Step F: Synthesis of (S)-4-((4-(5-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl) -5-Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
将化合物(S)-4-(4-(5-氯噻吩-3-基)哌啶-2-基)苯甲酸甲酯(70毫克，0.21毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(120毫克，0.42毫摩尔)溶于1，2-二氯乙烷(10毫升)，室温反应过夜。再加入三乙酰氧基硼氢化钠(130毫克，0.63毫摩尔)，反应5小时。Compound (S)-4-(4-(5-chlorothiophen-3-yl)piperidin-2-yl)benzoate methyl ester (70 mg, 0.21 mmol) and 4-formyl-5-methoxy Tert-butyl-7-methyl-1H-indole-1-carboxylate (120 mg, 0.42 mmol) was dissolved in 1,2-dichloroethane (10 ml), and the reaction was carried out at room temperature overnight. Then add sodium triacetoxyborohydride (130 mg, 0.63 mmol) and react for 5 hours.
反应完成后，加入甲醇溶解至澄清，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)。得到500毫克黄色油状(S)-4-((4-(5-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(粗品)，直接用于下一步反应。LCMS：RT＝2.09min，[M+H]+＝609.23。After the reaction is completed, add methanol to dissolve until clear, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1). Obtained 500 mg of (S)-4-((4-(5-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl) as a yellow oil -5-Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (crude product) was directly used in the next reaction. LCMS: RT = 2.09 min, [M+H] + = 609.23.
步骤G：合成化合物60Step G: Synthesis of Compound 60
将化合物(S)-4-((4-(5-氯噻吩-3-基)-2-(4-(甲氧基羰基)苯基)哌啶-1-基)甲基)-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(500毫克，0.3毫摩尔)溶于甲醇(20毫升)，加入碳酸钾(1毫克，7.2毫摩尔)，加热至60℃搅拌过夜。再加入水(5毫升)，60℃反应5小时。Compound (S)-4-((4-(5-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5- Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (500 mg, 0.3 mmol) was dissolved in methanol (20 ml), potassium carbonate (1 mg, 7.2 mmol) was added, and heated Stir overnight at 60°C. Then add water (5 ml) and react at 60°C for 5 hours.
反应完成后，在真空下浓缩该溶液且用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到19.7毫克绝对构型的非对映异构体60(收率：19％)。After the reaction was completed, the solution was concentrated under vacuum and purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain a crude product, which was completed by using chiral HPLC (Agilent prep C18). For the resolution of enantiomers, 19.7 mg of the absolute configuration of diastereomer 60 was obtained by elution with 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution (yield: 19% ).
化合物60：HPLC：RT＝11.2min，LCMS：RT＝1.80min，[M+H]+＝495.22。Compound 60: HPLC: RT=11.2 min, LCMS: RT=1.80 min, [M+H] + =495.22.
1H NMR(400MHz，DMSO-d6)δ10.83(s，1H)，7.96(d，J＝8.0Hz，2H)，7.66(d，J＝8.0Hz，2H)，7.28-7.23(m，1H)，7.1-7.04(m，2H)，6.66(s，1H)，6.48-6.42(m，1H)，3.72(s，3H)，3.62-3.54(m，1H)，3.24-3.18(m，2H)，2.91-2.81(m，1H)，2.77-2.67(m，1H)，2.42(s，3H)，2.17-2.07(m，1H)，1.95-1.88(m，1H)，1.80-1.72(m，1H)，1.70-1.59(m，1H)，1.49-1.36(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.83 (s, 1H), 7.96 (d, J=8.0Hz, 2H), 7.66 (d, J=8.0Hz, 2H), 7.28-7.23 (m, 1H), 7.1-7.04(m, 2H), 6.66(s, 1H), 6.48-6.42(m, 1H), 3.72(s, 3H), 3.62-3.54(m, 1H), 3.24-3.18(m, 2H), 2.91-2.81(m, 1H), 2.77-2.67(m, 1H), 2.42(s, 3H), 2.17-2.07(m, 1H), 1.95-1.88(m, 1H), 1.80-1.72( m, 1H), 1.70-1.59 (m, 1H), 1.49-1.36 (m, 1H).
实施例61
Example 61
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-4-甲氧基羰基苯基哌嗪-1-甲酸苄酯Step A: Synthesis of (S)-4-methoxycarbonylphenylpiperazine-1-carboxylic acid benzyl ester
冰浴下，向4-甲氧基羰基苯基哌嗪-1-甲酸苄酯(3克，6.6毫摩尔)的乙酸乙酯溶液(15毫升)中加入盐酸二氧六环溶液(10毫升)，将混合物在室温下搅拌2小时。To a solution of 4-methoxycarbonylphenylpiperazine-1-carboxylic acid benzyl ester (3 g, 6.6 mmol) in ethyl acetate (15 ml) was added dioxane hydrochloride solution (10 ml) under an ice bath. , and the mixture was stirred at room temperature for 2 hours.
反应完成，浓缩至干，得到2.29克白色固体(S)-4-甲氧基羰基苯基哌嗪-1-甲酸苄酯(收率：98％)。LCMS：RT＝1.61min，[M+H]+＝355.22。The reaction was completed and concentrated to dryness to obtain 2.29 g of white solid (S)-4-methoxycarbonylphenylpiperazine-1-carboxylic acid benzyl ester (yield: 98%). LCMS: RT = 1.61 min, [M+H] + = 355.22.
步骤B：合成(S)-5-氯吡啶-2-基-2-2-(4-甲氧基羰基苯基)哌嗪-1-甲酸苄酯Step B: Synthesis of (S)-5-chloropyridin-2-yl-2-2-(4-methoxycarbonylphenyl)piperazine-1-carboxylic acid benzyl ester
室温下，将化合物(S)-4-甲氧基羰基苯基哌嗪-1-甲酸苄酯(2.29克，6.4毫摩尔)，2-溴-5-氯吡啶(1.2克，6.4毫摩尔)，4，5-双二苯基膦-9，9-二甲基氧杂蒽二氯化钯(0.05克，0.064毫摩尔)，叔丁醇钠(0.68克，7.04毫摩尔)加入2-甲基四氢呋喃(30毫升)中，氮气保护下，75℃下反应2小时。At room temperature, compound (S)-4-methoxycarbonylphenylpiperazine-1-carboxylic acid benzyl ester (2.29 g, 6.4 mmol), 2-bromo-5-chloropyridine (1.2 g, 6.4 mmol) , 4,5-bisdiphenylphosphine-9,9-dimethylxanthene palladium dichloride (0.05 g, 0.064 mmol), sodium tert-butoxide (0.68 g, 7.04 mmol) were added to 2-methyl In tetrahydrofuran (30 ml), react under nitrogen protection at 75°C for 2 hours.
反应完成，过滤，乙酸乙酯萃取(50毫升×3次)，有机层用饱和氯化钠洗涤两次，无水硫酸钠干燥。过滤所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到有机相直接减压浓缩得到316毫克淡黄色油状液体(S)-5-氯吡啶-2-基-2-2-(4-甲氧基羰基苯基)哌嗪-1-甲酸苄酯(收率：10.5％)。LCMS：RT＝2.20min，[M+H]+＝466.20。After the reaction was completed, it was filtered and extracted with ethyl acetate (50 ml × 3 times). The organic layer was washed twice with saturated sodium chloride and dried over anhydrous sodium sulfate. The residue obtained by filtration was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain the organic phase, which was directly concentrated under reduced pressure to obtain 316 mg of light yellow oily liquid (S)-5-chloropyridine-2. -Benzyl-2-2-(4-methoxycarbonylphenyl)piperazine-1-carboxylate (yield: 10.5%). LCMS: RT = 2.20 min, [M+H] + = 466.20.
步骤C：合成(S)-4-(5-氯吡啶-2-基)哌嗪-2-基苯甲酸甲酯Step C: Synthesis of (S)-4-(5-chloropyridin-2-yl)piperazin-2-yl benzoic acid methyl ester
向(S)-5-氯吡啶-2-基-2-2-(4-甲氧基羰基苯基)哌嗪-1-甲酸苄酯(316毫克，0.68毫摩尔)的乙酸乙酯溶液(5毫升)中，依次加入异丙醇(1毫升)和钯碳(30毫克)，置换氢气后室温反应2小时。To a solution of (S)-5-chloropyridin-2-yl-2-2-(4-methoxycarbonylphenyl)piperazine-1-carboxylic acid benzyl ester (316 mg, 0.68 mmol) in ethyl acetate ( 5 ml), add isopropyl alcohol (1 ml) and palladium on carbon (30 mg) in sequence, replace the hydrogen gas, and react at room temperature for 2 hours.
反应完成，过滤，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到147毫克黄色油状物(S)-4-(5-氯吡啶-2-基)哌嗪-2-基苯甲酸甲酯(收率：65.4％)。LCMS：RT＝1.72min，[M+H]+＝332.14。The reaction was completed, filtered, and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 147 mg of yellow oil (S)-4-(5-chloropyridine). -2-yl)piperazin-2-ylbenzoic acid methyl ester (yield: 65.4%). LCMS: RT = 1.72 min, [M+H] + = 332.14.
步骤D：合成(S)-4-(4-(5-氯吡啶-2-基)-2-(4-甲氧基羰基苯基)哌嗪-1-甲基)甲基叔丁基-5-甲氧基-7-甲基吲哚-1-羧酸酯 Step D: Synthesis of (S)-4-(4-(5-chloropyridin-2-yl)-2-(4-methoxycarbonylphenyl)piperazine-1-methyl)methyltert-butyl- 5-Methoxy-7-methylindole-1-carboxylate
室温下，向含有化合物(S)-4-(5-氯吡啶-2-基)哌嗪-2-基苯甲酸甲酯(147毫克，0.44毫摩尔)的1，2-二氯甲烷(5毫升)溶液中加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-甲酸叔丁酯(321毫克，1.11毫摩尔)，室温搅拌过夜，次日加入三乙酰氧基硼氢化钠(188毫克，0.89毫摩尔)，升温至40℃下反应过夜。The compound (S)-4-(5-chloropyridin-2-yl)piperazin-2-ylbenzoic acid methyl ester (147 mg, 0.44 mmol) was added to 1,2-dichloromethane (5 ml) solution, add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (321 mg, 1.11 mmol), stir at room temperature overnight, and add triacetyl the next day Sodium oxyborohydride (188 mg, 0.89 mmol) was heated to 40°C and allowed to react overnight.
反应结束，加入甲醇(0.5毫升)，浓缩至干，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/2)得到73毫克(S)-4-(4-(5-氯吡啶-2-基)-2-(4-甲氧基羰基苯基)哌嗪-1-甲基)甲基叔丁基-5-甲氧基-7-甲基吲哚-1-羧酸酯(收率：27％)。LCMS：RT＝2.16min，[M+H]+＝605.30。After the reaction was completed, methanol (0.5 ml) was added and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/2) to obtain 73 mg of (S)-4-(4 -(5-chloropyridin-2-yl)-2-(4-methoxycarbonylphenyl)piperazine-1-methyl)methyltert-butyl-5-methoxy-7-methylindole -1-carboxylic acid ester (yield: 27%). LCMS: RT = 2.16 min, [M+H] + = 605.30.
步骤E：合成(S)-4-4-5-氯吡啶-2-基-1-(5-甲氧基-7-甲基-4-吲哚基甲基)哌嗪-2-基苯甲酸Step E: Synthesis of (S)-4-4-5-chloropyridin-2-yl-1-(5-methoxy-7-methyl-4-indolylmethyl)piperazin-2-ylbenzene Formic acid
室温下，向(S)-4-(4-(5-氯吡啶-2-基)-2-(4-甲氧基羰基苯基)哌嗪-1-甲基)甲基叔丁基-5-甲氧基-7-甲基吲哚-1-羧酸酯(73毫克，0.121毫摩尔)的甲醇(5毫升)中加入水(1毫升)，碳酸钾(166毫克，1.21毫摩尔)，升温至70℃反应过夜。To (S)-4-(4-(5-chloropyridin-2-yl)-2-(4-methoxycarbonylphenyl)piperazine-1-methyl)methyltert-butyl- To 5-methoxy-7-methylindole-1-carboxylate (73 mg, 0.121 mmol) in methanol (5 ml) was added water (1 ml) and potassium carbonate (166 mg, 1.21 mmol). , raise the temperature to 70°C and react overnight.
反应完成，在真空下浓缩该溶液且采用实施例3步骤D中的纯化处理和手性拆分方法分离得到33.8毫克白色固体(S)-4-4-5-氯吡啶-2-基-1-(5-甲氧基-7-甲基-4-吲哚基甲基)哌嗪-2-基苯甲酸。After the reaction was completed, the solution was concentrated under vacuum and 33.8 mg of white solid (S)-4-4-5-chloropyridin-2-yl-1 was isolated using the purification treatment and chiral resolution method in step D of Example 3. -(5-Methoxy-7-methyl-4-indolylmethyl)piperazin-2-ylbenzoic acid.
化合物61：HPLC：RT＝3.58min，LCMS：RT＝1.66min，[M+H]+＝491.22。Compound 61: HPLC: RT=3.58 min, LCMS: RT=1.66 min, [M+H] + =491.22.
1H NMR(400MHz，DMSO-d6)δ10.86(d，J＝2.4Hz，1H)，8.08(d，J＝2.7Hz，1H)，7.97(d，J＝7.9Hz，2H)，7.64(d，J＝7.9Hz，2H)，7.56(dd，J＝9.1，2.7Hz，1H)，7.27(t，J＝2.8Hz，1H)，6.88(d，J＝9.1Hz，1H)，6.68(s，1H)，6.45(dd，J＝3.1，1.9Hz，1H)，4.17(d，J＝12.8Hz，1H)，4.10(d，J＝12.6Hz，1H)，3.73(s，3H)，3.64(d，J＝11.8Hz，1H)，2.91-2.72(m，3H)，2.44(s，3H)，2.24-2.14(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.86 (d, J = 2.4Hz, 1H), 8.08 (d, J = 2.7Hz, 1H), 7.97 (d, J = 7.9Hz, 2H), 7.64 (d, J=7.9Hz, 2H), 7.56 (dd, J=9.1, 2.7Hz, 1H), 7.27 (t, J=2.8Hz, 1H), 6.88 (d, J=9.1Hz, 1H), 6.68 (s, 1H), 6.45 (dd, J=3.1, 1.9Hz, 1H), 4.17 (d, J=12.8Hz, 1H), 4.10 (d, J=12.6Hz, 1H), 3.73 (s, 3H) , 3.64 (d, J=11.8Hz, 1H), 2.91-2.72 (m, 3H), 2.44 (s, 3H), 2.24-2.14 (m, 1H).
实施例62A和62B
Examples 62A and 62B
化合物62A和62B的合成路线如下：
The synthetic routes of compounds 62A and 62B are as follows:
步骤A：合成2-溴-4-二氟甲基噻吩Step A: Synthesis of 2-bromo-4-difluoromethylthiophene
将化合物5-溴噻吩-3-甲醛(2.0克，10.5毫摩尔)溶于二氯甲烷中(40毫升)，0℃下缓慢滴加二乙胺基三氟化硫(4.2毫升，31.5毫摩尔)，滴毕反应体系缓慢升至室温反应3小时。Compound 5-bromothiophene-3-carbaldehyde (2.0 g, 10.5 mmol) was dissolved in dichloromethane (40 ml), and diethylamine sulfur trifluoride (4.2 ml, 31.5 mmol) was slowly added dropwise at 0°C. ), the reaction system was slowly raised to room temperature after dripping and reacted for 3 hours.
TLC检测原料反应完全，加入饱和碳酸氢钠水溶液(40毫升)淬灭反应，二氯甲烷萃取，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝4/1)。得到1.3克黄色油状物2-溴-4-二氟甲基噻吩(收率58.6％)。TLC detected that the raw material reaction was complete, added saturated aqueous sodium bicarbonate solution (40 ml) to quench the reaction, extracted with dichloromethane, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). 1.3 g of yellow oily substance 2-bromo-4-difluoromethylthiophene was obtained (yield 58.6%).
步骤B：合成(S)-4-(4-二氟甲基)噻吩-2-基-6-甲氧基羰基苯基-3，6-二氢吡啶-1-羧酸苄酯Step B: Synthesis of (S)-4-(4-difluoromethyl)thiophen-2-yl-6-methoxycarbonylphenyl-3,6-dihydropyridine-1-carboxylate benzyl ester
将化合物(S)-6-(4-(甲氧羰基)苯基)-4-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(800毫克，1.67毫摩尔)，2-溴-4-二氟甲基噻吩(390毫克，1.84毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(124毫克，0.17毫摩尔)，磷酸钾(709毫克，3.34毫摩尔)加入1，4-二氧六环(20毫升)，氮气保护下95℃反应24小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Benzyl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.67 mmol), 2-bromo-4-difluoromethylthiophene (390 mg, 1.84 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (124 mg, 0.17 mmol), potassium phosphate (709 mg, 3.34 mmol) were added to 1,4-dioxane ( 20 ml), react at 95°C for 24 hours under nitrogen protection.
反应完成后，加入乙酸乙酯(50毫升)稀释，过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到550毫克黄色油状(S)-4-(4-二氟甲基)噻吩-2-基-6-甲氧基羰基苯基-3，6-二氢吡啶-1-羧酸苄酯(收率68％)。LCMS：RT＝2.21min，[M-H]-＝482.13。After the reaction was completed, ethyl acetate (50 ml) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 550 mg of (S)-4-(4-difluoromethyl)thiophen-2-yl-6-methoxycarbonylphenyl-3,6-dihydropyridine-1-carboxylic acid benzyl ester (S) as a yellow oil. rate 68%). LCMS: RT = 2.21 min, [MH] - = 482.13.
步骤C：合成(S)-4-(4-二氟甲基)噻吩-2-基-2-(4-甲氧基羰基苯基)哌啶-1-羧酸苄酯Step C: Synthesis of (S)-4-(4-difluoromethyl)thiophen-2-yl-2-(4-methoxycarbonylphenyl)piperidine-1-carboxylate benzyl ester
将化合物(S)-4-(4-二氟甲基)噻吩-2-基-6-甲氧基羰基苯基-3，6-二氢吡啶-1-羧酸苄酯(550毫克，1.14毫摩尔)溶于乙酸乙酯(20毫升)，加入钯/碳(200毫克)，氢气氛围下加热至60℃，反应过夜。Compound (S)-4-(4-difluoromethyl)thiophen-2-yl-6-methoxycarbonylphenyl-3,6-dihydropyridine-1-carboxylic acid benzyl ester (550 mg, 1.14 mmol) was dissolved in ethyl acetate (20 ml), palladium/carbon (200 mg) was added, heated to 60°C under a hydrogen atmosphere, and reacted overnight.
反应完成后，过滤，减压浓缩。得到303毫克浅黄色胶状(S)-4-(4-二氟甲基)噻吩-2-基-2-(4-甲氧基羰基苯基)哌啶-1-羧酸苄酯(粗品)，不需要纯化，直接用于下一步反应。LCMS：RT＝2.15min，[M-H]-＝484.11。After the reaction is completed, filter and concentrate under reduced pressure. Obtained 303 mg of light yellow gummy (S)-4-(4-difluoromethyl)thiophen-2-yl-2-(4-methoxycarbonylphenyl)piperidine-1-carboxylic acid benzyl ester (crude product ), no purification is required, and it can be used directly in the next reaction. LCMS: RT = 2.15 min, [MH] - = 484.11.
步骤D：(S)-4-(4-二氟甲基)噻吩-2-基哌啶苯甲酸甲酯Step D: (S)-4-(4-Difluoromethyl)thiophen-2-ylpiperidine benzoate methyl ester
将化合物4-(4-二氟甲基)噻吩-2-基-2-(4-甲氧基羰基苯基)哌啶-1-羧酸苄酯(303毫克，0.63毫摩尔)溶于乙酸乙酯(10毫升)，冰水浴冷却，加入33％氢溴酸/醋酸溶液(1.2毫升)，室温搅拌2小时。 Compound 4-(4-difluoromethyl)thiophen-2-yl-2-(4-methoxycarbonylphenyl)piperidine-1-carboxylate benzyl ester (303 mg, 0.63 mmol) was dissolved in acetic acid ethyl ester (10 ml), cooled in an ice-water bath, added 33% hydrobromic acid/acetic acid solution (1.2 ml), and stirred at room temperature for 2 hours.
反应完成后，用甲醇淬灭反应，氨水调节至碱性，减压浓缩去除大部分甲醇。所得残余物用乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)。得到152毫克黄色胶状(S)-4-(4-二氟甲基)噻吩-2-基哌啶苯甲酸甲酯(收率69％)。LCMS：RT＝1.73min，[M+H]+＝352.17。After the reaction is completed, the reaction is quenched with methanol, ammonia water is adjusted to alkalinity, and most of the methanol is removed by concentration under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=10/1). 152 mg of (S)-4-(4-difluoromethyl)thiophen-2-ylpiperidine benzoate methyl ester was obtained as a yellow gum (yield 69%). LCMS: RT = 1.73 min, [M+H] + = 352.17.
步骤E：合成4-(2S)-4-(4-二氟甲基)噻吩-2-基-2-2-(4-甲氧基羰基苯基)哌啶-1-甲基)-5-甲氧基-7-甲基吲哚-1-甲酸叔丁酯Step E: Synthesis of 4-(2S)-4-(4-difluoromethyl)thiophen-2-yl-2-2-(4-methoxycarbonylphenyl)piperidine-1-methyl)-5 -Methoxy-7-methylindole-1-carboxylic acid tert-butyl ester
将化合物(S)-4-(4-二氟甲基)噻吩-2-基哌啶苯甲酸甲酯(152毫克，0.43毫摩尔)和4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(372.8毫克，1.29毫摩尔)溶于1，2-二氯乙烷(20毫升)，室温搅拌1小时。然后加入三乙酰氧基硼氢化钠(455.8毫克，2.15毫摩尔)继续反应过夜。Compound (S)-4-(4-difluoromethyl)thiophen-2-ylpiperidine benzoate methyl ester (152 mg, 0.43 mmol) and 4-formyl-5-methoxy-7-methyl tert-butyl-1H-indole-1-carboxylate (372.8 mg, 1.29 mmol) was dissolved in 1,2-dichloroethane (20 ml), and stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (455.8 mg, 2.15 mmol) was added and the reaction continued overnight.
反应完成后，加入甲醇溶解至澄清，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝2/1)。得到185毫克黄色油状4-(2S)-4-(4-二氟甲基)噻吩-2-基-2-2-(4-甲氧基羰基苯基)哌啶-1-甲基)-5-甲氧基-7-甲基吲哚-1-甲酸叔丁酯(粗品)，直接用于下一步反应。LCMS：RT＝1.88min，[M+H]+＝625.18。After the reaction is completed, add methanol to dissolve until clear, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1). 185 mg of 4-(2S)-4-(4-difluoromethyl)thiophen-2-yl-2-2-(4-methoxycarbonylphenyl)piperidine-1-methyl)- were obtained as a yellow oil. 5-Methoxy-7-methylindole-1-carboxylic acid tert-butyl ester (crude product) was directly used in the next reaction. LCMS: RT = 1.88 min, [M+H] + = 625.18.
步骤F：合成化合物62A和62BStep F: Synthesis of Compounds 62A and 62B
将化合物4-(2S)-4-(4-二氟甲基)噻吩-2-基-2-2-(4-甲氧基羰基苯基)哌啶-1-甲基)-5-甲氧基-7-甲基吲哚-1-甲酸叔丁酯(185毫克，0.30毫摩尔，粗品)溶于甲醇(10毫升)，加入碳酸钾(165毫克，1.2毫摩尔)，加热至70℃搅拌过夜。再加入水(2毫升)，70℃反应2小时。Compound 4-(2S)-4-(4-difluoromethyl)thiophen-2-yl-2-2-(4-methoxycarbonylphenyl)piperidine-1-methyl)-5-methyl Oxy-7-methylindole-1-carboxylic acid tert-butyl ester (185 mg, 0.30 mmol, crude product) was dissolved in methanol (10 ml), potassium carbonate (165 mg, 1.2 mmol) was added, and heated to 70°C Stir overnight. Then add water (2 ml) and react at 70°C for 2 hours.
反应完成后，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到9.2毫克绝对构型的非对映异构体62A(收率：6.0％)和11.0毫克绝对构型的非对映异构体62B(收率：7.2％)。After the reaction was completed, the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 9.2 mg of diastereoisomer 62A with absolute configuration (yield: 6.0%) and 11.0 mg of diastereoisomer 62A with absolute configuration. Enantiomer 62B (yield: 7.2%).
化合物62A：HPLC：RT＝15.8min，LCMS：RT＝1.79min，[M+H]+＝511.12。Compound 62A: HPLC: RT=15.8 min, LCMS: RT=1.79 min, [M+H] + =511.12.
化合物62B：HPLC：RT＝17.3min，LCMS：RT＝1.79min，[M+H]+＝511.12。Compound 62B: HPLC: RT=17.3min, LCMS: RT=1.79min, [M+H] + =511.12.
实施例63
Example 63
化合物63的合成路线如下：
The synthetic route of compound 63 is as follows:
步骤A：合成4-溴-2-二氟甲基噻唑Step A: Synthesis of 4-bromo-2-difluoromethylthiazole
冰浴下，向4-溴噻唑-2-甲醛(1克，5.2毫摩尔)的二氯甲烷(20毫升)中加入三乙胺基三氟化硫(2.099克，13摩尔)，室温下反应过夜。Under ice bath, add triethylamine sulfur trifluoride (2.099 g, 13 mol) to 4-bromothiazole-2-carbaldehyde (1 g, 5.2 mmol) in dichloromethane (20 ml), and react at room temperature. overnight.
反应完成，用饱和碳酸氢钠(20毫升)水溶液淬灭反应，混合液用乙酸乙酯萃取(50毫升×3次)，有机相用饱和氯化钠(50毫升)溶液洗涤，无水硫酸钠干燥，过滤，浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝20/1)，得到619毫克淡黄色油状液体4-溴-2-二氟甲基噻唑(收率：56％)。The reaction was completed. The reaction was quenched with saturated aqueous sodium bicarbonate (20 ml) solution. The mixture was extracted with ethyl acetate (50 ml × 3 times). The organic phase was washed with saturated sodium chloride (50 ml) solution and anhydrous sodium sulfate. Dry, filter, and concentrate, and the resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 20/1) to obtain 619 mg of 4-bromo-2-difluoromethylthiazole as a light yellow oily liquid. (Yield: 56%).
步骤B：合成(S)-4-2-二氟甲基噻唑-4-基-6-甲氧基羰基苯基-3，6-二氢吡啶-1-羧酸苄酯Step B: Synthesis of (S)-4-2-difluoromethylthiazol-4-yl-6-methoxycarbonylphenyl-3,6-dihydropyridine-1-carboxylic acid benzyl ester
室温下，将化合物(S)-4-(4-甲氧基羰基苯基)苄基-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1羧酸酯(920毫克，1.9毫摩尔)，4-溴-2-二氟甲基噻唑(619毫克，2.89毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(278毫克，0.38毫摩尔)，磷酸钾(826毫克，3.8毫摩尔)，水(4毫升)加入二氧六环(20毫升)，氮气保护下，升温至至95℃反应过夜。At room temperature, compound (S)-4-(4-methoxycarbonylphenyl)benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane -2-yl)-3,6-dihydropyridine-1carboxylate (920 mg, 1.9 mmol), 4-bromo-2-difluoromethylthiazole (619 mg, 2.89 mmol), [1, 1′-Bis(diphenylphosphine)ferrocene]palladium dichloride (278 mg, 0.38 mmol), potassium phosphate (826 mg, 3.8 mmol), water (4 ml) were added to dioxane (20 ml), under nitrogen protection, raise the temperature to 95°C and react overnight.
反应完成，加入乙酸乙酯(30毫升)稀释，过滤，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)。得到423毫克黄色油状液体(S)-4-2-二氟甲基噻唑-4-基-6-甲氧基羰基苯基-3，6-二氢吡啶-1-羧酸苄酯(收率45.3％)。LC-MS：RT＝2.20min，[M+H]+＝434.19。After the reaction was completed, ethyl acetate (30 ml) was added to dilute, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1). Obtained 423 mg of yellow oily liquid (S)-4-2-difluoromethylthiazol-4-yl-6-methoxycarbonylphenyl-3,6-dihydropyridine-1-carboxylic acid benzyl ester (yield 45.3%). LC-MS: RT=2.20min, [M+H] + =434.19.
步骤C：合成(S)-4-(2-二氟甲基)噻唑-4-基苄酯-2-(4-甲氧基羰基苯基)哌啶-1-羧酸酯Step C: Synthesis of (S)-4-(2-difluoromethyl)thiazol-4-ylbenzyl ester-2-(4-methoxycarbonylphenyl)piperidine-1-carboxylate
室温下，将(S)-4-2-二氟甲基噻唑-4-基-6-甲氧基羰基苯基-3，6-二氢吡啶-1-羧酸苄酯(423毫克，0.87毫摩尔)溶于乙酸乙酯(5毫升)中，加入钯碳(50毫克)，置换氢气，升温至60℃反应过夜。 (S)-4-2-Difluoromethylthiazol-4-yl-6-methoxycarbonylphenyl-3,6-dihydropyridine-1-carboxylic acid benzyl ester (423 mg, 0.87 mmol) was dissolved in ethyl acetate (5 ml), palladium on carbon (50 mg) was added, replaced with hydrogen, and the temperature was raised to 60°C to react overnight.
反应结束，过滤，乙酸乙酯洗涤，浓缩，得到301毫克黄色油状物(S)-4-(2-二氟甲基)噻唑-4-基苄酯-2-(4-甲氧基羰基苯基)哌啶-1-羧酸酯。(收率98％)。LCMS：RT＝1.69min，[M+H]+＝353.14。The reaction was completed, filtered, washed with ethyl acetate, and concentrated to obtain 301 mg of yellow oil (S)-4-(2-difluoromethyl)thiazol-4-ylbenzyl ester-2-(4-methoxycarbonylbenzene) base)piperidine-1-carboxylate. (Yield 98%). LCMS: RT = 1.69 min, [M+H] + = 353.14.
步骤D：合成(S)-4-(4-(2-二氟甲基)噻唑-4-基哌啶-2-基苯甲酸甲酯Step D: Synthesis of (S)-4-(4-(2-difluoromethyl)thiazol-4-ylpiperidin-2-ylbenzoic acid methyl ester
冰浴下，将化合物(S)-4-(2-二氟甲基)噻唑-4-基苄酯-2-(4-甲氧基羰基苯基)哌啶-1-羧酸酯(301毫克，0.62毫摩尔)溶于乙酸乙酯(10毫升)中，加入33％氢溴酸/醋酸溶液(0.5毫升)，转移至室温下反应一小时。Under ice bath, compound (S)-4-(2-difluoromethyl)thiazol-4-ylbenzyl ester-2-(4-methoxycarbonylphenyl)piperidine-1-carboxylate (301 mg, 0.62 mmol) was dissolved in ethyl acetate (10 ml), 33% hydrobromic acid/acetic acid solution (0.5 ml) was added, and the mixture was transferred to room temperature for reaction for one hour.
反应完成，加入乙酸乙酯(10毫升)稀释，加入氨水调节PH＝8，乙酸乙酯萃取(50毫升×3次)，无水硫酸钠干燥，浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝25/2)，得到115毫克淡黄色油状液体(S)-4-(4-(2-二氟甲基)噻唑-4-基哌啶-2-基苯甲酸甲酯(收率：53％)。LCMS：RT＝1.65min，[M+H]+＝353.14。After the reaction is completed, add ethyl acetate (10 ml) to dilute, add ammonia water to adjust pH = 8, extract with ethyl acetate (50 ml × 3 times), dry over anhydrous sodium sulfate, and concentrate. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=25/2) to obtain 115 mg of (S)-4-(4-(2-difluoromethyl)thiazole as a light yellow oily liquid). -4-ylpiperidin-2-ylbenzoic acid methyl ester (yield: 53%). LCMS: RT = 1.65 min, [M+H] + = 353.14.
步骤E：合成(S)-4-(4-(2-二氟甲基)噻唑-4-基-2-(4-甲氧基羰基苯基)哌啶-1-甲基)-5-甲氧基-7-甲基-1H-吲哚-1-甲酸叔丁酯Step E: Synthesis of (S)-4-(4-(2-difluoromethyl)thiazol-4-yl-2-(4-methoxycarbonylphenyl)piperidine-1-methyl)-5- Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
室温下，向含有化合物(S)-4-(4-(2-二氟甲基)噻唑-4-基哌啶-2-基苯甲酸甲酯(115毫克，0.33毫摩尔)的1，2-二氯甲烷(10毫升)中加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-甲酸叔丁酯(236毫克，0.82毫摩尔)，和三乙酰氧基硼氢化钠(138毫克，0.66毫摩尔)，升温至40℃下反应过夜。To 1,2 containing compound (S)-4-(4-(2-difluoromethyl)thiazol-4-ylpiperidin-2-ylbenzoate methyl ester (115 mg, 0.33 mmol) at room temperature -To dichloromethane (10 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (236 mg, 0.82 mmol), and triacetoxy Sodium borohydride (138 mg, 0.66 mmol) was heated to 40°C and allowed to react overnight.
反应结束，加入甲醇(0.5毫升)，浓缩至干，所得残余用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝5/1)得到62毫克(S)-4-(4-(2-二氟甲基)噻唑-4-基-2-(4-甲氧基羰基苯基)哌啶-1-甲基)-5-甲氧基-7-甲基-1H-吲哚-1-甲酸叔丁酯(收率：30％)。LCMS：RT＝1.98min，[M+H]+＝626.31。After the reaction was completed, methanol (0.5 ml) was added and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5/1) to obtain 62 mg of (S)-4-(4- (2-Difluoromethyl)thiazol-4-yl-2-(4-methoxycarbonylphenyl)piperidine-1-methyl)-5-methoxy-7-methyl-1H-indole -1-tert-butyl formate (yield: 30%). LCMS: RT = 1.98 min, [M+H] + = 626.31.
步骤F：合成化合物63Step F: Synthesis of Compound 63
室温下，向化合物(S)-4-(4-(2-二氟甲基)噻唑-4-基-2-(4-甲氧基羰基苯基)哌啶-1-甲基)-5-甲氧基-7-甲基-1H-吲哚-1-甲酸叔丁酯(62毫克，0.1毫摩尔)的甲醇(5毫升)中，加入水(1毫升)，加入碳酸钾(138毫克，1毫摩尔)，升温至60℃，反应4小时。To compound (S)-4-(4-(2-difluoromethyl)thiazol-4-yl-2-(4-methoxycarbonylphenyl)piperidine-1-methyl)-5 at room temperature -Methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (62 mg, 0.1 mmol) in methanol (5 ml), add water (1 ml), add potassium carbonate (138 mg , 1 mmol), raise the temperature to 60°C, and react for 4 hours.
反应完成后，加入10％柠檬酸的水溶液调节pH至中性，用二氯甲烷(10毫升×升次)萃取，合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，在真空下浓缩该溶液且用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到粗品，通过使用的手性HPLC(Agilent prep C18)来完成非对映异构体的拆分，用25％CH3CN(+0.05％NH3·H2O)溶液进行洗脱分离得到25.7毫克绝对构型的非对映异构体63(收率：51％)After the reaction is completed, add 10% citric acid aqueous solution to adjust the pH to neutral, extract with dichloromethane (10 ml × liters), combine the organic phases, wash the organic phase with saturated brine (20 ml), and then wash with Dried over sodium sulfate, the solution was concentrated under vacuum and purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain the crude product, which was completed by using chiral HPLC (Agilent prep C18). The enantiomers were separated by elution with 25% CH 3 CN (+0.05% NH 3 ·H 2 O) solution to obtain 25.7 mg of the absolute configuration of diastereomer 63 (yield: 51 %)
化合物63：HPLC：RT＝3.48min，LCMS：RT＝1.73min，[M+H]+＝512.25。Compound 63: HPLC: RT=3.48 min, LCMS: RT=1.73 min, [M+H] + =512.25.
1H NMR(400MHz，DMSO-d6)δ10.84(d，J＝2.7Hz，1H)，7.98(d，J＝8.2Hz，2H)，7.71(d，J＝7.8Hz，2H)，7.64(s，1H)，7.27(dd，J＝4.9，2.1Hz，1H)，6.67(s，1H)，6.50(t，J＝2.5Hz，1H)，3.73(s，3H)，3.60(d，J＝12.0Hz，1H)，3.01(d，J＝12.1Hz，1H)，2.89(d，J＝11.4Hz，1H)，2.68(s，1H)，2.43(s，3H)，2.17(t，J＝11.9Hz，1H)，2.04(d，J＝12.6Hz，1H)，1.88(d，J＝12.3Hz，1H)，1.73(s，1H)，1.56(d，J＝11.0Hz，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.84 (d, J = 2.7Hz, 1H), 7.98 (d, J = 8.2Hz, 2H), 7.71 (d, J = 7.8Hz, 2H), 7.64 (s, 1H), 7.27 (dd, J=4.9, 2.1Hz, 1H), 6.67 (s, 1H), 6.50 (t, J=2.5Hz, 1H), 3.73 (s, 3H), 3.60 (d, J=12.0Hz, 1H), 3.01 (d, J=12.1Hz, 1H), 2.89 (d, J=11.4Hz, 1H), 2.68 (s, 1H), 2.43 (s, 3H), 2.17 (t, J=11.9Hz, 1H), 2.04 (d, J=12.6Hz, 1H), 1.88 (d, J=12.3Hz, 1H), 1.73 (s, 1H), 1.56 (d, J=11.0Hz, 1H) .
实施例64A和64B
Examples 64A and 64B
具体合成路线如下：
The specific synthesis route is as follows:
步骤A：合成(S)-4-(5-氟噻吩-2-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯Step A: Synthesis of (S)-4-(5-fluorothiophen-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxy benzyl acid ester
将化合物(S)-6-(4-(甲氧基羰基)苯基)-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(940毫克，1.88毫摩尔)，5-氟-2-噻吩硼酸(548毫克，3.76毫摩尔)，[1，1′-双(二苯基膦)二茂铁]二氯化钯(137毫克，0.188毫摩尔)，磷酸钾(1.2克，5.65毫摩尔)加入1，4-二氧六环(15毫升)，氮气保护下90℃反应12小时。Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H) - Benzyl carboxylate (940 mg, 1.88 mmol), 5-fluoro-2-thiopheneboronic acid (548 mg, 3.76 mmol), [1,1′-bis(diphenylphosphine)ferrocene]dichlor Palladium (137 mg, 0.188 mmol) and potassium phosphate (1.2 g, 5.65 mmol) were added to 1,4-dioxane (15 ml), and the reaction was carried out at 90°C for 12 hours under nitrogen protection.
反应完成后，加入乙酸乙酯(30毫升)稀释，过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：正己烷/乙酸乙酯＝3/1)。得到425毫克黄色半固体状(S)-4-(5-氟噻吩-2-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(收率46.1％)。LCMS：RT＝2.34min，[M+H]+＝452.21。After the reaction was completed, ethyl acetate (30 ml) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). Obtained 425 mg of (S)-4-(5-fluorothiophen-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H) as a yellow semi-solid )-benzyl carboxylate (yield 46.1%). LCMS: RT=2.34min, [M+H] + =452.21.
步骤B：合成(S)-4-(5-氟噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯Step B: Synthesis of (S)-4-(5-fluorothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester
将(S)-4-(5-氟噻吩-2-基)-6-(4-(甲氧基羰基)苯基)-3，6-二氢吡啶-1(2H)-羧酸苄酯(425毫克，0.94毫摩尔)溶于乙酸乙酯溶液(15毫升)中，加入钯碳(60毫克)，反应置换氢气后，升温到60℃反应过夜。 (S)-4-(5-fluorothiophen-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (425 mg, 0.94 mmol) was dissolved in ethyl acetate solution (15 ml), palladium on carbon (60 mg) was added, and after the reaction replaced hydrogen, the temperature was raised to 60°C and the reaction was carried out overnight.
反应结束后过滤，用乙酸乙酯洗涤，液相直接减压浓缩得到380毫克无色油状液体(S)-4-(5-氟噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯(收率89.4％)。LCMS：RT＝2.25min，[M+H]+＝454.19。After the reaction, it was filtered, washed with ethyl acetate, and the liquid phase was directly concentrated under reduced pressure to obtain 380 mg of colorless oily liquid (S)-4-(5-fluorothiophen-2-yl)-2-(4-(methoxy) Carbonyl)phenyl)pyridinecarboxylic acid benzyl ester (yield 89.4%). LCMS: RT=2.25min, [M+H] + =454.19.
步骤C：合成(S)-4-(4-(5-氟噻吩-2-基)哌啶-2-基)苯甲酸甲酯Step C: Synthesis of (S)-4-(4-(5-fluorothien-2-yl)piperidin-2-yl)benzoate methyl ester
将化合物(S)-4-(5-氟噻吩-2-基)-2-(4-(甲氧基羰基)苯基)吡啶羧酸苄酯(380毫克，0.84毫摩尔)溶于乙酸乙酯(5毫升)，冰水浴冷却，加入33％氢溴酸/醋酸溶液(0.5毫升)，室温反应1小时。Compound (S)-4-(5-fluorothien-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester (380 mg, 0.84 mmol) was dissolved in ethyl acetate ester (5 ml), cooled in an ice-water bath, added 33% hydrobromic acid/acetic acid solution (0.5 ml), and reacted at room temperature for 1 hour.
反应完成后，冰水浴冷却，用冰块淬灭反应，再用氨水调节pH＝12-13，乙酸乙酯(20毫升×3次)萃取，合并有机相，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10/1)。得到178毫克浅黄色油状(S)-4-(4-(5-氟噻吩-2-基)哌啶-2-基)苯甲酸甲酯(收率64％)。LCMS：RT＝1.70min，[M+H]+＝320.18。After the reaction is completed, cool it in an ice-water bath, quench the reaction with ice cubes, then adjust the pH to 12-13 with ammonia water, extract with ethyl acetate (20 ml × 3 times), combine the organic phases, and then dry with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1). 178 mg of (S)-4-(4-(5-fluorothien-2-yl)piperidin-2-yl)benzoic acid methyl ester was obtained as a light yellow oil (yield 64%). LCMS: RT=1.70min, [M+H] + =320.18.
步骤D：合成(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-氟噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-fluorothiophen-2-yl)piperidine-1- (methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester
向含有(S)-4-(4-(5-氟噻吩-2-基)哌啶-2-基)苯甲酸甲酯(170毫克，0.53毫摩尔)的1，2-二氯乙烷(5毫升)中，加入4-甲酰基-5-甲氧基-7-甲基-1H-吲哚-1-羧酸叔丁酯(231毫克，0.80毫摩尔)和三乙酰氧基硼氢化钠(224毫克，1.06毫摩尔)，40℃反应过夜。To a solution containing (S)-4-(4-(5-fluorothien-2-yl)piperidin-2-yl)benzoate methyl ester (170 mg, 0.53 mmol) in 1,2-dichloroethane ( 5 ml), add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (231 mg, 0.80 mmol) and sodium triacetoxyborohydride (224 mg, 1.06 mmol), react at 40°C overnight.
反应结束，加入少量甲醇直接旋干溶剂，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝1/1)得到161毫克白色固体(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-氟噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(收率：51.4％)。LCMS：RT＝2.00min，[M+H]+＝593.28。After the reaction was completed, a small amount of methanol was added and the solvent was directly rotated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to obtain 161 mg of white solid (S)-5-methoxy. -4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-fluorothien-2-yl)piperidin-1-yl)methyl)-7-methyl-1H- Indole-1-carboxylic acid tert-butyl ester (yield: 51.4%). LCMS: RT=2.00min, [M+H] + =593.28.
步骤E：合成化合物64A和64BStep E: Synthesis of Compounds 64A and 64B
(S)-5-甲氧基-4-((2-(4-(甲氧基羰基)苯基)-4-(5-氟噻吩-2-基)哌啶-1-基)甲基)-7-甲基-1H-吲哚-1-羧酸叔丁酯(160毫克，0.27毫摩尔)的甲醇(5毫升)溶液中加碳酸钾(372.6毫克，2.7毫摩尔)，加热至70℃反应5小时，再加水(1毫升)继续反应4小时。(S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-fluorothien-2-yl)piperidin-1-yl)methyl )-7-Methyl-1H-indole-1-carboxylic acid tert-butyl ester (160 mg, 0.27 mmol) in methanol (5 ml) was added with potassium carbonate (372.6 mg, 2.7 mmol), and heated to 70 The reaction was carried out at ℃ for 5 hours, and water (1 ml) was added to continue the reaction for 4 hours.
反应完成后，采用实施例3步骤D中的纯化处理和手性拆分方法分离得到21毫克绝对构型的非对映异构体64A(收率：16.3％)和23毫克绝对构型的非对映异构体64B(收率：17.8％)。After the reaction was completed, the purification process and chiral resolution method in step D of Example 3 were used to separate and obtain 21 mg of diastereoisomer 64A with absolute configuration (yield: 16.3%) and 23 mg of diastereoisomer 64A with absolute configuration. Enantiomer 64B (yield: 17.8%).
化合物64A：HPLC：RT＝11.9min，LCMS：RT＝1.72min，[M+H]+＝479.24.Compound 64A: HPLC: RT=11.9min, LCMS: RT=1.72min, [M+H] + =479.24.
1H NMR(400MHz，DMSO-d6)δ10.83(s，1H)，7.83(d，J＝7.8Hz，2H)，7.39(d，J＝7.8Hz，2H)，7.25(t，J＝2.7Hz，1H)，6.69-6.58(m，3H)，6.45(t，J＝2.4Hz，1H)，3.69(s，3H)，3.21(d，J＝11.9Hz，2H)，2.59(dt，J＝13.6，4.6Hz，1H)，2.42(s，3H)，2.22(dt，J＝12.9，6.9Hz，1H)，2.02(d，J＝13.8Hz，1H)，1.83(q，J＝4.8，3.8Hz，2H). 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 7.83 (d, J=7.8Hz, 2H), 7.39 (d, J=7.8Hz, 2H), 7.25 (t, J=2.7 Hz, 1H), 6.69-6.58 (m, 3H), 6.45 (t, J=2.4Hz, 1H), 3.69 (s, 3H), 3.21 (d, J=11.9Hz, 2H), 2.59 (dt, J =13.6, 4.6Hz, 1H), 2.42 (s, 3H), 2.22 (dt, J = 12.9, 6.9Hz, 1H), 2.02 (d, J = 13.8Hz, 1H), 1.83 (q, J = 4.8, 3.8Hz, 2H).
化合物64B：HPLC：RT＝16.9min，LCMS：RT＝1.72min，[M+H]+＝479.24.Compound 64B: HPLC: RT=16.9min, LCMS: RT=1.72min, [M+H] + =479.24.
1H NMR(400MHz，DMSO-d6)δ10.83(s，1H)，7.91(d，J＝7.9Hz，2H)，7.54(d，J＝7.8Hz，2H)，7.26(t，J＝2.8Hz，1H)，6.66(s，1H)，6.52(t，J＝3.7Hz，1H)，6.50-6.42(m，2H)，3.72(s，3H)，3.58(d，J＝11.8Hz，1H)，3.25-3.16(m，2H)，2.91-2.81(m，2H)，2.42(s，3H)，2.12(t，J＝11.9Hz，1H)，2.01-1.91(m，1H)，1.82(d，J＝12.5Hz，1H)，1.64(q，J＝12.1Hz，1H)，1.47-1.37(m，1H).
 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 7.91 (d, J=7.9Hz, 2H), 7.54 (d, J=7.8Hz, 2H), 7.26 (t, J=2.8 Hz, 1H), 6.66 (s, 1H), 6.52 (t, J=3.7Hz, 1H), 6.50-6.42 (m, 2H), 3.72 (s, 3H), 3.58 (d, J=11.8Hz, 1H ), 3.25-3.16(m, 2H), 2.91-2.81(m, 2H), 2.42(s, 3H), 2.12(t, J=11.9Hz, 1H), 2.01-1.91(m, 1H), 1.82( d, J=12.5Hz, 1H), 1.64 (q, J=12.1Hz, 1H), 1.47-1.37 (m, 1H).
实施例65补体***旁路途径抑制活性测试Example 65 Complement system alternative pathway inhibitory activity test
采用商品化试剂盒(COMPLAP330 RUO，Svar life science)评价化合物对人血清补体旁路途经的抑制作用。受试化合物起始测试浓度为10μM，3倍梯度稀释，设置8个浓度点，单孔检测。Using commercial test kits ( COMPLAP330 RUO, Svar life science) evaluates the inhibitory effect of compounds on the human serum complement alternative pathway. The initial test concentration of the test compound was 10 μM, 3-fold gradient dilution, 8 concentration points were set, and single-well detection was performed.
受试化合物采用DMSO稀释成720倍终浓度的梯度浓度溶液，取0.5μL的化合物溶液加入340μL Diluent中，再加入20μL人血清混匀，取100μL混合液加入至预包被的反应板中；取20μL阴性对照或阳性对照液加入340μL Diluent和0.5μL DMSO混匀，各取100μL混合液分别加入反应板作为阴性对照孔或阳性对照孔。37℃孵育60分钟后，弃去孔中液体，每孔加入300μL洗涤液洗涤3次。每孔加入100μL Conjugate，室温孵育30分钟，弃去孔中液体，加入300μL洗涤液洗涤3次。然后每孔加入100μL底物，室温下孵育15分钟。使用酶标仪(FLUOstar Omega，BMG LRBTECH)检测，读取OD405值，测试结果见表1。The test compound is diluted with DMSO into a gradient concentration solution of 720 times the final concentration. Add 0.5 μL of the compound solution to 340 μL of Diluent, then add 20 μL of human serum and mix well. Add 100 μL of the mixed solution to the pre-coated reaction plate; take Add 340 μL Diluent and 0.5 μL DMSO to 20 μL of negative control or positive control solution and mix well. Take 100 μL of each mixed solution and add it to the reaction plate as a negative control well or a positive control well. After incubation at 37°C for 60 minutes, the liquid in the wells was discarded, and 300 μL of washing solution was added to each well for washing three times. Add 100 μL Conjugate to each well and incubate at room temperature for 30 minutes. Discard the liquid in the well and add 300 μL washing solution to wash three times. Then add 100 μL of substrate to each well and incubate at room temperature for 15 minutes. Use a microplate reader (FLUOstar Omega, BMG LRBTECH) to detect and read the OD405 value. The test results are shown in Table 1.
表1：


其中，A#表示＜200nM，B#表示大于200nM小于500nM，C#表示大于500nM。Table 1:


Among them, A # means <200nM, B # means greater than 200nM and less than 500nM, and C # means greater than 500nM.
由表1的实验结果可知，与对比例1A和1B相比，本发明化合物对补体***旁路具有较好的抑制活性。It can be seen from the experimental results in Table 1 that compared with Comparative Examples 1A and 1B, the compounds of the present invention have better inhibitory activity on the complement system alternative pathway.
实施例66药代动力学实验Example 66 Pharmacokinetic Experiment
(1)实验材料(1) Experimental materials
SD大鼠：雄性，180-250g，购于北京维通利华实验动物技术有限公司。SD rats: male, 180-250g, purchased from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd.
试剂：DMSO(二甲亚砜)，PEG-400(聚乙二醇400)，生理盐水，肝素，乙腈，甲酸，***(内标)均为市售可得。Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.
仪器：赛默飞LC-MS(U300 UPLC，TSQ QUANTUMN ULTRA三重四级杆质谱)。Instrument: Thermo Fisher LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).
(2)实验方法(2) Experimental methods
称取化合物溶于DMSO-PEG-400-生理盐水(5∶60∶35，v/v/v)体系中，大鼠静脉或灌胃给药后，于15min、30min、1h、2h、5h、7h、24h(iv组加采5min)采集静脉血200μL于EDTA-K2抗凝EP管中，12000rpm离心2min，取血浆-80℃冻存待测。精密称取一定量供试品用DMSO溶解至2mg/mL，作为储备液。准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL，加入空白血浆180μL，涡旋混匀，配制成相当于血浆浓度为1、3、5、10、30、100、300、1000、3000ng/mL的血浆样品，每一浓度进行双样本分析，建立标准曲线。取30μL血浆(静脉给药5min、15min、30min血浆稀释10倍)，加入内标***(50ng/mL)的乙腈溶液200μL，涡旋混匀后，加入100μL纯化水，再次涡旋混匀，4000rpm离心5min，取上清LC-MS分析。LC-MS检测条件如下：Weigh the compound and dissolve it in the DMSO-PEG-400-physiological saline (5:60:35, v/v/v) system. After intravenous or intragastric administration to rats, the compounds are administered at 15min, 30min, 1h, 2h, 5h, Collect 200 μL of venous blood in EDTA-K2 anticoagulant EP tubes at 7h and 24h (5 min for the IV group), centrifuge at 12000 rpm for 2 min, and freeze the plasma at -80°C for testing. Precisely weigh a certain amount of the test sample and dissolve it in DMSO to 2 mg/mL as a stock solution. Accurately draw an appropriate amount of compound stock solution and add acetonitrile to dilute it to prepare a standard series of solutions. Accurately draw 20 μL of each of the above standard series solutions, add 180 μL of blank plasma, vortex and mix, and prepare plasma samples equivalent to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000ng/mL. Analyze two samples at one concentration to establish a standard curve. Take 30 μL of plasma (the plasma is diluted 10 times at 5, 15, and 30 minutes after intravenous administration), add 200 μL of the acetonitrile solution of the internal standard propranolol (50 ng/mL), vortex to mix, then add 100 μL of purified water, and vortex again. Homogenize, centrifuge at 4000 rpm for 5 min, and take the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:
色谱柱：赛默飞HYPERSIL GOLD C-18 UPLC柱，100*2.1mm，1.7μm。Chromatographic column: Thermo Fisher HYPERSIL GOLD C-18 UPLC column, 100*2.1mm, 1.7μm.
流动相：水(0.1％甲酸)-乙腈按下表进行梯度洗脱如下表2。Mobile phase: water (0.1% formic acid)-acetonitrile. Gradient elution is performed as shown in Table 2.
表2
Table 2
(3)数据处理(3)Data processing
LC-MS检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数，结果见表3。After detecting the blood drug concentration by LC-MS, WinNonlin 6.1 software and non-compartmental model method were used to calculate the pharmacokinetic parameters. The results are shown in Table 3.
表3：本发明化合物的大鼠药代动力学参数(PO给药)
Table 3: Rat pharmacokinetic parameters of the compounds of the present invention (PO administration)
由表3的实验结果可知，本发明的化合物的大鼠PK与对比例1A和1B的化合物相比，具有更高的口服暴露量和生物利用度。It can be seen from the experimental results in Table 3 that the rat PK of the compound of the present invention has higher oral exposure and bioavailability than the compounds of Comparative Examples 1A and 1B.
实施例67化合物的酶诱导试验研究 Enzyme induction test study of the compound of Example 67
(1)实验材料与仪器(1) Experimental materials and instruments
材料：Williams’Medium E(without phenol red)购于西格玛奥德里奇贸易有限公司；Williams′Medium E、人重组胰岛素、GlutaMAX和HEPES购于Life Technologies；Isotonic Percoll购于General Electric；Fetal bovine serum购于Coming；***市售可得；CellTiter-FluorTM Cell Viability Assay kit购于Promega；Taqman Gene Expression Assay probe(20×，CYP3A4，FAM labeled)和Taqman Gene Expression Assay probe(20×，ACTB，VIC labeled)购于AB(Applied biosystems)；人原代肝细胞，购于BioIVT。Materials: Williams' Medium E (without phenol red) was purchased from Sigma-Aldrich Trading Co., Ltd.; Williams' Medium E, human recombinant insulin, GlutaMAX and HEPES were purchased from Life Technologies; Isotonic Percoll was purchased from General Electric; Fetal bovine serum was purchased from Coming; dexamethasone is commercially available; CellTiter-Fluor TM Cell Viability Assay kit was purchased from Promega; Taqman Gene Expression Assay probe (20×, CYP3A4, FAM labeled) and Taqman Gene Expression Assay probe (20×, ACTB, VIC labeled ) were purchased from AB (Applied biosystems); human primary hepatocytes were purchased from BioIVT.
仪器：AB Sciex5500+。Instrument: AB Sciex5500+.
(2)试验设计(2) Experimental design
精密称取受试物(实施例39A、实施例53A与对比例2)、阳性诱导剂、阴性诱导剂、内标，配成相应浓度储备液。准备好细胞复苏液和孵育液；CellTiter-FluorTM细胞活力试验的检测试剂盒、mRNA提取、反转录和荧光定量PCR的相关试剂和耗材。Precisely weigh the test substance (Example 39A, Example 53A and Comparative Example 2), positive inducer, negative inducer, and internal standard to prepare a corresponding concentration stock solution. Prepare cell recovery solution and incubation solution; CellTiter-Fluor TM cell viability test detection kit, mRNA extraction, reverse transcription and fluorescence quantitative PCR related reagents and consumables.
将冻存的人原代肝细胞复苏，按一定密度接种于合适的细胞培养板上进行单层细胞培养以达到细胞生长要求。The cryopreserved human primary hepatocytes are revived and seeded on appropriate cell culture plates at a certain density for monolayer cell culture to meet cell growth requirements.
在相应孔中加入用孵育液新鲜配制并预热好的含阳性/阴性诱导剂或受试物不同浓度的给药溶液，连续孵育3天并每天换液，每个化合物或浓度两复孔平行操作。Add freshly prepared and preheated dosing solutions containing positive/negative inducers or test substances at different concentrations into the corresponding wells, incubate continuously for 3 days and change the medium every day. Each compound or concentration has two duplicate wells in parallel. operate.
酶活测试则加入相应底物孵育一定时间，采用LC-MS/MS进行半定量分析。CellTiter-FluorTM细胞活力检测试剂盒用于检测细胞内蛋白酶活性。For enzyme activity testing, the corresponding substrate is added and incubated for a certain period of time, and LC-MS/MS is used for semi-quantitative analysis. CellTiter-Fluor TM cell viability detection kit is used to detect intracellular protease activity.
mRNA的提取、反转录和荧光定量PCR的操作根据相关试剂盒说明书进行实验。The extraction, reverse transcription and fluorescence quantitative PCR of mRNA were carried out according to the instructions of the relevant kits.
(3)试验结果(3)Test results
实施例39A、实施例53A以及对比例2对CYP3A4的mRNA水平的诱导作用试验结果见下表4。The test results of the induction effect of Example 39A, Example 53A and Comparative Example 2 on the mRNA level of CYP3A4 are shown in Table 4 below.
表4实验结果
Table 4 Experimental results
由表4的实验结果可知，本申请的化合物39A和53A与对比例2相比降低诱导风险。It can be seen from the experimental results in Table 4 that the compounds 39A and 53A of the present application reduce the risk of induction compared with Comparative Example 2.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。 The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, etc. may be made without departing from the spirit and principles of the present invention. All simplifications should be equivalent substitutions, and are all included in the protection scope of the present invention.

Claims (10)

  1. 一种通式(I)所示的化合物，或其异构体、或其消旋体、或其可药用的盐，其特征在于：
    A compound represented by general formula (I), or an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized by:
    其中，n是0、1或2；Where, n is 0, 1 or 2;
    R1选自氢、卤素、羟基、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的C3-6环烷基，所述取代基选自卤素、羟基、氨基、C1-6烷基、C1-6烷氧基，取代基可以是一个或多个；R 1 is selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, said The substituent is selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, and the substituent can be one or more;
    R2选自氢、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基，所述取代基为羟基、卤素，取代基可以是一个或多个；R 2 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, the substituent is hydroxyl, halogen, and the substituent can be one or more;
    R3选自氢、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基，所述取代基为羟基、卤素，取代基可以是一个或多个；R 3 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, the substituent is hydroxyl, halogen, and the substituent can be one or more;
    R4、R5独立地选自氢、取代或未取代的C1-6烷基、取代或未取代的芳基、或取代或未取代的杂芳基，所述取代基选自羟基、卤素、C3-6的杂环烷基，-(CH2)m-C(O)OH，m是0、1或2，取代基可以是一个或多个；R 4 and R 5 are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the substituent is selected from hydroxyl, halogen , C 3-6 heterocycloalkyl, -(CH 2 ) m -C(O)OH, m is 0, 1 or 2, and the substituent can be one or more;
    R6独立地选自氢、烷基；R 6 is independently selected from hydrogen and alkyl;
    R7选自氢或者羟基；R 7 is selected from hydrogen or hydroxyl;
    A环独立选自芳基或杂芳基，其中所述芳基及杂芳基在化合价容许的情况下任选经一个或多个R8取代，其中，R8独立地选自氢、氰基、砜基、卤素、取代或未取代C1-6烷基、取代或未取代C3-6环烷基、取代或未取代C1-6烷氧基、取代或未取代C3-6环氧烷基，取代或未取代C3-6环烷氧基，其中，所述取代基选自卤素、C1-6烷氧基、氰基、C3-6环烷基，取代基可以是一个或多个。Ring A is independently selected from aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more R 8 if the valency allows, wherein R 8 is independently selected from hydrogen, cyano , sulfone group, halogen, substituted or unsubstituted C 1-6 alkyl group, substituted or unsubstituted C 3-6 cycloalkyl group, substituted or unsubstituted C 1-6 alkoxy group, substituted or unsubstituted C 3-6 ring Oxyalkyl, substituted or unsubstituted C 3-6 cycloalkoxy, wherein the substituent is selected from halogen, C 1-6 alkoxy, cyano, C 3-6 cycloalkyl, the substituent can be one or more.
  2. 根据权利要求1所述的化合物，或其异构体、或其消旋体、或其可药用的盐，其特征在于，The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that,
    所述C1-6的烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、仲戊基、1-乙基丙基、2-甲基丁基、叔戊基、1,2-二甲基丙基、异戊基、新戊基、正己基、异己基、仲己基、叔己基、新己基、2-甲基戊基、1,2-二甲基丁基、1-乙基丁基；The C 1-6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1- Ethylpropyl, 2-methylbutyl, tert-amyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2 -Methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl;
    所述C1-6烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、仲戊氧基、1-乙基丙氧基、2-甲基丁氧基、叔戊氧基、1,2-二甲基丙氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、仲己氧基、叔己氧基、新己氧基、2-甲基戊氧基、1,2-二甲基丁氧基、1-乙基丁氧基；The C 1-6 alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy Oxygen, sec-pentyloxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentyloxy, 1,2-dimethylpropyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, 1-ethylbutoxy;
    所述C3-6的环烷基选自环丙基、环丁基、环戊基、环己基，所述C3-6的环氧烷基是指环烷上一个以上的碳原子被氧原子取代；The C 3-6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The C 3-6 epoxyalkyl group refers to one or more carbon atoms on the cycloalkane being replaced by an oxygen atom. replace;
    所述C3-6环烷氧基是其中x是1、2、3或4，为连接键。The C 3-6 cycloalkoxy group is where x is 1, 2, 3 or 4, is the connection key.
  3. 根据权利要求1所述的化合物，或其异构体、或其消旋体、或其可药用的盐，其特征在于，所述芳基选自五元环、六元环、七元环、八元环、九元环、十元环，所述芳基为单环或者双环；所述杂芳基是指芳环上一个以上的碳原子被杂原子取代。The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that the aryl group is selected from a five-membered ring, a six-membered ring, a seven-membered ring , eight-membered ring, nine-membered ring, ten-membered ring, the aryl group is a single ring or a bicyclic ring; the heteroaryl group means that more than one carbon atom on the aromatic ring is replaced by a heteroatom.
  4. 根据权利要求1所述的化合物，或其异构体、或其消旋体、或其可药用的盐，其特征在于，所述卤素选自氟、氯、溴、碘。The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that the halogen is selected from fluorine, chlorine, bromine, and iodine.
  5. 根据权利要求1所述的化合物，或其异构体、或其消旋体、或其可药用的盐，其特征在于，杂原子选自氮、氧、硫，所述杂原子为一个或者多个。The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that the heteroatom is selected from nitrogen, oxygen, and sulfur, and the heteroatom is one or Multiple.
  6. 根据权利要求1所述的化合物，或其异构体、或其消旋体、或其可药用的盐，其特征在于，The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that,
    其中，所述A环选自苯环、 所述C3-6的杂环烷基选自 Wherein, the A ring is selected from benzene ring, The C 3-6 heterocycloalkyl group is selected from
  7. 根据权利要求1所述的化合物，或其异构体、或其消旋体、或其可药用的盐，其特征在于，The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that,
    其中，R8取代的A环选自 Among them, the A ring substituted by R 8 is selected from
    R1选自甲氧基、环丙基；R 1 is selected from methoxy and cyclopropyl;
    R2选自甲基；R 2 is selected from methyl;
    R3选自氢；R 3 is selected from hydrogen;
    R4选自 R 4 is selected from
    R5选自氢；R 5 is selected from hydrogen;
    R6选自氢；R 6 is selected from hydrogen;
    R7选自氢或羟基；R 7 is selected from hydrogen or hydroxyl;
    为连接键。 is the connection key.
  8. 根据权利要求1所述的化合物，或其异构体、或其消旋体、或其可药用的盐，其特征在于，选自：




    The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that it is selected from:




  9. 一种药物组合物，其特征在于，包含治疗有效量的权利要求1-8任一项所述化合物，或其异构体、或其消旋体、或其可药用的盐和药物可接受的载体。A pharmaceutical composition, characterized in that it contains a therapeutically effective amount of the compound described in any one of claims 1 to 8, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. Carrier.
  10. 权利要求1-8任一项所述化合物，或其异构体、或其消旋体、或其可药用的盐的医药用途，具体地，在制备用于治疗疾病的药物中的用途，所述疾病为补体B因子抑制剂相关疾病，具体选自蛋白尿等病症。 The pharmaceutical use of the compound of any one of claims 1 to 8, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, its use in the preparation of drugs for treating diseases, The disease is a disease related to complement factor B inhibitors, specifically selected from diseases such as proteinuria.
PCT/CN2023/100967 2022-06-20 2023-06-19 Indole-phenylpiperidine compound, method for preparing same, and use thereof WO2023246677A1 (en)

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