WO2019011287A1 - Preparation method for imidazoisoindole derivative - Google Patents

Preparation method for imidazoisoindole derivative Download PDF

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WO2019011287A1
WO2019011287A1 PCT/CN2018/095371 CN2018095371W WO2019011287A1 WO 2019011287 A1 WO2019011287 A1 WO 2019011287A1 CN 2018095371 W CN2018095371 W CN 2018095371W WO 2019011287 A1 WO2019011287 A1 WO 2019011287A1
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group
compound
formula
preparation
alkyl
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PCT/CN2018/095371
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French (fr)
Chinese (zh)
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邵启云
徐超
张浩宇
尤凌峰
冯君
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201880004456.1A priority Critical patent/CN109983020A/en
Publication of WO2019011287A1 publication Critical patent/WO2019011287A1/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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine and relates to a preparation method of an imidazoisoindole derivative.
  • Indoleamine-pyrrole-2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds.
  • the alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket.
  • IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan.
  • Fast enzyme which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein.
  • IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack.
  • Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
  • IDO inhibitors have good application prospects in the pharmaceutical industry as drugs.
  • WO2016169421 discloses a new class of IDO inhibitors whose compounds have the structure shown in formula (I).
  • This class of compounds shows excellent IDO inhibition.
  • the synthesis method of the compound is mainly prepared by reacting a halophenylpyrazole with piperidinyl imidazolium.
  • the method has the disadvantages of complicated operation, high cost, low yield, and difficulty in amplifying production.
  • the invention provides a process for the preparation of a compound of formula I, which comprises the step of reacting a compound of formula II with a compound of formula III.
  • R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl and heteroaryl;
  • R 2 is selected from -CH 2 -CH 2 -OR 3 , preferably hydrogen;
  • R 3 is selected from hydrogen or a hydroxy protecting group
  • One of X and Y is a leaving group, and the other is selected from -BF 3 K, -BR a R b , -Sn(R c ) m or -Zn-X',
  • the leaving group is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, - SR, -SO 2 R;
  • R a and R b are independently selected from -OH, alkyl, alkoxy or optionally substituted C 1 -C 6 mono and diol, or R a and R b are taken together to form a ring, and R c is independently selected from a C 1 -C 6 alkyl group, X' is selected from -Cl, -Br, -I, and R is a C 1 -C 6 alkyl group;
  • n is an integer of 0, 1, 2, 3 or 4
  • m is an integer of 0, 1, 2, 3 or 4.
  • the leaving group is preferably Cl, Br, I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy;
  • X is a leaving group; in certain embodiments, Y is a leaving group.
  • X is a leaving group and Y is selected from the group consisting of BF 3 K and BR a R b ; in certain embodiments, Y is a leaving group and X is selected from the group consisting of BF 3 K and BR a R b .
  • the BR a R b wherein R a and R b are independently selected from -OH, alkyl, alkoxy, or BR a R b is a pinacol boronate frequency, i.e.,
  • the compound of Formula II and the compound of Formula III are preferably subjected to a coupling reaction in the presence of a catalyst, which may include PdL p , PdCl 2 L p , Pd(OAc) 2 L p , Pd 2 (dba) 3 L p , Pd(II) L p , Pd(0), NiCl 2 L p , Ni(COD) 2 L p , NiCl 2 (NEt 3 ) 2 or NiCl 2 (bipy)
  • L is a phosphine-containing ligand or an N-heterocyclic carbene ligand
  • the phosphine-containing ligand may be PPh 3 , dppf, PCy 3 , tBu 3 P, P(OMe) 3 , dppe or dppb, p independent An integer selected from 0, 1, 2, 3 or 4.
  • the catalyst may be Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 , NiCl 2 (dppf), NiCl 2 (PPh 3 ) 2 , Ni ⁇ P(OMe) 3 ⁇ 2 Cl 2 , NiCl 2 (PCy 3 ) 2 , NiCl 2 (dppe), NiCl 2 (dppb), NiCl 2 (NEt 3 2 ) NiCl 2 (bipy), NiCl 2 ⁇ 6H 2 O, NiCl 2 , or Ni(COD) 2 , preferably Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 ,
  • the reaction is carried out in the presence of a basic material, wherein the basic substance is preferably Li 2 CO 3 , Na 2 CO 3 , Ba(OH) 2 , K 3 PO 4 , Cs 2 CO 3 , K 2 or more of CO 3 , TlOH, KF, CsF, Bu 4 NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, wherein R is independently selected from C 1 ⁇ C 6 alkyl.
  • NaOR, KOR or TlOR can be, for example, NaOMe, NaOEt, KOtBu or TlOEt.
  • the alkaline substance is more preferably one or more of Na 2 CO 3 or K 2 CO 3 .
  • the solvent of the reaction may be a conventional solvent, and may be, for example, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide, dimethyl ether, isopropanol.
  • the reaction temperature may be from 60 ° C to 150 ° C.
  • the compound of formula (I) in the present invention contains a chiral carbon atom, and the structure of the aforementioned unspecified configuration represents any possibility including, but not limited to, a racemate or an isomer thereof, when obtained by the reaction.
  • the compound of the formula (I) is in the form of a racemate, the isomer form can be further obtained by means of resolution or the like.
  • the compound of Formula I is preferably selected from the following structure:
  • R 3 has the same definition as described above;
  • the compound of formula II is preferably derived from the following structure:
  • the compound of formula III is preferably derived from the following structure:
  • Y and R 3 are the same as described above.
  • the compound of Formula I is preferably selected from the following structure:
  • Another aspect of the invention provides a process for the preparation of a compound of formula Ia, or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula I according to the process of the invention, said method further Including a step of chiral resolution of the compound of formula I, the chiral resolution method is preferably chemical resolution, membrane resolution, chromatographic resolution or capillary electrophoresis resolution,
  • R 1 , R 2 and n are the same as described above.
  • the compound of Formula Ia can be any organic compound.
  • the compound of Formula Ia can be any organic compound.
  • R 3 when R 3 is hydrogen or a hydroxy protecting group, the reaction can proceed smoothly and to obtain the desired product.
  • R 3 is a hydroxy protecting group, a small amount of dehydroxyethyl impurity is easily formed during the process of removing the protecting group, and the impurity has certain pharmacological toxicity, which will have certain influence on the preparation of the compound Ib; when R 3 is In the case of hydrogen, no generation of dehydroxyethyl impurities was detected during the reaction.
  • the preparation method of the imidazoisoindole derivative of the invention has the advantages of safe and simple operation, safer reaction reagent, milder reaction condition, lower cost, suitable for industrial production, and better reaction effects. It has technology and significant social and economic benefits. Among them, the yield of the coupling reaction of the compound II and the compound III is greatly improved, the purity of the product is higher than that of the prior art, the subsequent reaction is easier, the post-treatment operation is reduced, and the industrial scale-up production is more suitable.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, carbonyl group.
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, preferably a 6 to 10 membered aryl group, Phenyl and naphthyl are more preferred, and phenyl is most preferred.
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 6 to 10 yuan.
  • the heteroaryl group is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carbonyl group, a -carboxylic acid or a carboxylic acid ester.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycl
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O)n ( Wherein n is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups.
  • Alkoxy means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and an alkane group.
  • the hydroxy protecting group is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts).
  • the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C 1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C 1-6 alkoxy substituted C a 1-6 alkyl or phenyl substituted C 1-6 alkyl group, most preferably a C 1-4 alkoxy substituted C 1-4 alkyl group, for example: methyl, tert-butyl,
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • reaction solution was cooled to room temperature, 400 mL of water was added, and the mixture was stirred at room temperature for 30 min, filtered, and the filter cake was rinsed with water, and the filter cake was collected, dissolved with 1.2 L of methanol, concentrated hydrochloric acid (40 mL), stirred for 30 min, and concentrated to remove methanol.

Abstract

The present invention relates to a preparation method for an imidazoisoindole derivative. In particular, the present invention relates to a preparation method for an imidazoisoindole derivative as shown in formula I, comprising the step of reacting a compound as shown in formula II with a compound as shown in formula III. The yield of the preparation method of the present invention is greatly improved compared with the prior art, and the purity of the product is also higher such that the subsequent reaction is easier and the post-treatment operations are reduced. The preparation method is more suitable for industrial scale-up productions.

Description

一种咪唑并异吲哚类衍生物的制备方法Preparation method of imidazoisoindole derivatives 技术领域Technical field
本发明属于医药领域，涉及一种咪唑并异吲哚类衍生物的制备方法。The invention belongs to the field of medicine and relates to a preparation method of an imidazoisoindole derivative.
背景技术Background technique
吲哚胺-吡咯-2,3-双加氧酶(Indoleamine-pyrrole-2,3-dioxygenase，IDO)是一种含铁血红素单体蛋白，由403个氨基酸残基组成，包括两个折叠的α-螺旋结构域，大结构域包含催化口袋，底物可在催化口袋内与IDO发生疏水等作用。IDO是催化色氨酸转化为甲酰犬尿氨酸的酶，广泛分布在人和其他哺乳动物(兔、鼠)除肝脏以外的组织中，是肝脏以外唯一可催化色氨酸分解代谢的限速酶，而色氨酸是细胞维持活化和增殖所必需的氨基酸，也是构成蛋白质不可缺少的重要成分。目前大量研究表明IDO在白血病细胞中较高表达，使局部T细胞增殖受抑，抑制T-细胞介导的免疫反应，使T-细胞活化信号转导受阻，从而介导肿瘤细胞逃逸免疫***的攻击。已经发现大多数人类肿瘤组成性地表达IDO。因此，IDO是一个具潜力的癌症免疫治疗的靶标。Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds. The alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket. IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan. Fast enzyme, which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein. A large number of studies have shown that IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack. Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
IDO抑制剂作为药物在医药行业具有良好的应用前景。WO2016169421公开了一类新的IDO抑制剂，其化合物结构如式(I)所示，IDO inhibitors have good application prospects in the pharmaceutical industry as drugs. WO2016169421 discloses a new class of IDO inhibitors whose compounds have the structure shown in formula (I).
Figure PCTCN2018095371-appb-000001
Figure PCTCN2018095371-appb-000001
该类化合物显示出了优异的IDO抑制作用。目前该类化合物的合成方法主要是由卤代苯基吡唑与哌啶基咪唑并异吲哚反应制得。该方法存在操作复杂，成本高，收率低，不易于放大生产等缺点。This class of compounds shows excellent IDO inhibition. At present, the synthesis method of the compound is mainly prepared by reacting a halophenylpyrazole with piperidinyl imidazolium. The method has the disadvantages of complicated operation, high cost, low yield, and difficulty in amplifying production.
发明内容Summary of the invention
为了克服现有技术的不足，本发明的目的在于提供一种新的咪唑并异吲哚类衍生物的制备方法。In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a novel process for the preparation of imidazoisoindole derivatives.
本发明一方面提供了如式I所示化合物的制备方法，包括将式II所示化合物与式III所示化合物反应的步骤。In one aspect, the invention provides a process for the preparation of a compound of formula I, which comprises the step of reacting a compound of formula II with a compound of formula III.
Figure PCTCN2018095371-appb-000002
Figure PCTCN2018095371-appb-000002
其中，R 1相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基和杂芳基； Wherein R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl and heteroaryl;
R 2选自-CH 2-CH 2-OR 3，优选氢； R 2 is selected from -CH 2 -CH 2 -OR 3 , preferably hydrogen;
R 3选自氢或羟基保护基； R 3 is selected from hydrogen or a hydroxy protecting group;
X和Y中一个为离去基团，另一个选自-BF 3K、-BR aR b、-Sn(R c) m或-Zn-X’， One of X and Y is a leaving group, and the other is selected from -BF 3 K, -BR a R b , -Sn(R c ) m or -Zn-X',
其中所述离去基团选自-Cl、-Br、-I、-F、三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基、乙酰氧基或磷酸酯基、-SR，-SO 2R； Wherein the leaving group is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, - SR, -SO 2 R;
R a和R b独立地选自-OH、烷基、烷氧基或任意取代的C 1～C 6一元和二元醇，或R a和R b在一起成环，R c独立地选自C 1～C 6烷基，X’选自-Cl、-Br、-I，R为C 1～C 6烷基； R a and R b are independently selected from -OH, alkyl, alkoxy or optionally substituted C 1 -C 6 mono and diol, or R a and R b are taken together to form a ring, and R c is independently selected from a C 1 -C 6 alkyl group, X' is selected from -Cl, -Br, -I, and R is a C 1 -C 6 alkyl group;
n为0、1、2、3或4的整数，m为0、1、2、3或4的整数。n is an integer of 0, 1, 2, 3 or 4, and m is an integer of 0, 1, 2, 3 or 4.
其中所述离去基团优选Cl、Br、I、三氟甲磺酰氧基、甲磺酰氧基或苯磺酰氧基；Wherein the leaving group is preferably Cl, Br, I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy;
在某些实施方式中，X为离去基团；在某些实施方式中，Y为离去基团。In certain embodiments, X is a leaving group; in certain embodiments, Y is a leaving group.
在某些实施方式中，X为离去基团，Y选自BF 3K和BR aR b；在某些实施方式中，Y为离去基团，X选自BF 3K和BR aR b。 In certain embodiments, X is a leaving group and Y is selected from the group consisting of BF 3 K and BR a R b ; in certain embodiments, Y is a leaving group and X is selected from the group consisting of BF 3 K and BR a R b .
在某些实施方式中，所述BR aR b中R a和R b独立地选自-OH、烷基、烷氧基，或BR aR b为频哪醇硼酸酯，即
Figure PCTCN2018095371-appb-000003
In certain embodiments, the BR a R b wherein R a and R b are independently selected from -OH, alkyl, alkoxy, or BR a R b is a pinacol boronate frequency, i.e.,
Figure PCTCN2018095371-appb-000003
在某些实施方式中，所述式II所示化合物与式III所示化合物优选在催化剂的存在下进行偶联反应，所述的催化剂可以包括PdL p、PdCl 2L p、Pd(OAc) 2L p、Pd 2(dba) 3L p、Pd(II)L p、Pd(0)、NiCl 2L p、Ni(COD) 2L p、NiCl 2(NEt 3) 2或NiCl 2(bipy)，其中L为含膦配体或N-杂环卡宾配体，所述含膦配体可以是PPh 3、dppf、PCy 3、tBu 3P、P(OMe) 3、dppe或dppb，p独立的选自0、1、2、3或4的整数。 In certain embodiments, the compound of Formula II and the compound of Formula III are preferably subjected to a coupling reaction in the presence of a catalyst, which may include PdL p , PdCl 2 L p , Pd(OAc) 2 L p , Pd 2 (dba) 3 L p , Pd(II) L p , Pd(0), NiCl 2 L p , Ni(COD) 2 L p , NiCl 2 (NEt 3 ) 2 or NiCl 2 (bipy) Wherein L is a phosphine-containing ligand or an N-heterocyclic carbene ligand, and the phosphine-containing ligand may be PPh 3 , dppf, PCy 3 , tBu 3 P, P(OMe) 3 , dppe or dppb, p independent An integer selected from 0, 1, 2, 3 or 4.
例如，所述催化剂可以是Pd(PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2、钯碳、Pd(OAc) 2、PCy 3/Pd 2(dba) 3、NiCl 2(dppf)、NiCl 2(PPh 3) 2、Ni{P(OMe) 3} 2Cl 2、NiCl 2(PCy 3) 2、NiCl 2(dppe)，NiCl 2(dppb)，NiCl 2(NEt 3) 2、NiCl 2(bipy)、NiCl 2·6H 2O、NiCl 2，或Ni(COD) 2，优选Pd(PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2、钯碳、Pd(OAc) 2、 PCy 3/Pd 2(dba) 3，更优选Pd(PPh 3) 2Cl 2。 For example, the catalyst may be Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 , NiCl 2 (dppf), NiCl 2 (PPh 3 ) 2 , Ni{P(OMe) 3 } 2 Cl 2 , NiCl 2 (PCy 3 ) 2 , NiCl 2 (dppe), NiCl 2 (dppb), NiCl 2 (NEt 3 2 ) NiCl 2 (bipy), NiCl 2 ·6H 2 O, NiCl 2 , or Ni(COD) 2 , preferably Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 , more preferably Pd(PPh 3 ) 2 Cl 2 .
在某些实施方式中，所述反应在碱性物质存在下反应，其中碱性物质优选Li 2CO 3、Na 2CO 3,Ba(OH) 2、K 3PO 4、Cs 2CO 3、K 2CO 3、TlOH、KF、CsF、Bu 4NF、LiOH、NaOH、KOH、三乙胺、DIPEA、DABCO、NaOR、KOR、TlOR中的一种或多种，其中R独立地选自C 1～C 6烷基。其中NaOR、KOR或TlOR例如可以是NaOMe，NaOEt，KOtBu或TlOEt。所述碱性物质更优选Na 2CO 3或K 2CO 3中的一种或多种。 In certain embodiments, the reaction is carried out in the presence of a basic material, wherein the basic substance is preferably Li 2 CO 3 , Na 2 CO 3 , Ba(OH) 2 , K 3 PO 4 , Cs 2 CO 3 , K 2 or more of CO 3 , TlOH, KF, CsF, Bu 4 NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, wherein R is independently selected from C 1 ～ C 6 alkyl. Wherein NaOR, KOR or TlOR can be, for example, NaOMe, NaOEt, KOtBu or TlOEt. The alkaline substance is more preferably one or more of Na 2 CO 3 or K 2 CO 3 .
所述反应的溶剂可以是常规溶剂，例如可以是二甲基甲酰胺、1-甲基-2-吡咯烷酮、四氢呋喃、二氧六环、甲苯、二甲亚砜、二甲基醚、异丙醇、乙醇、水中的一种或多种，优选二甲基甲酰胺、二甲基醚、二氧六环、水中的一种或多种。反应温度可以是60℃～150℃。The solvent of the reaction may be a conventional solvent, and may be, for example, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide, dimethyl ether, isopropanol. One or more of ethanol, water, and water, preferably one or more of dimethylformamide, dimethyl ether, dioxane, and water. The reaction temperature may be from 60 ° C to 150 ° C.
应该理解，本发明中式(I)化合物中含有手性碳原子，前述未指明构型的结构代表了任何的可能性，包括但不限于消旋体或者其中任意的异构体，当反应得到的式(I)化合物为消旋体形式时，可以进一步使用拆分等手段得到异构体形式。It should be understood that the compound of formula (I) in the present invention contains a chiral carbon atom, and the structure of the aforementioned unspecified configuration represents any possibility including, but not limited to, a racemate or an isomer thereof, when obtained by the reaction. When the compound of the formula (I) is in the form of a racemate, the isomer form can be further obtained by means of resolution or the like.
在某些实施方式中，所述式I化合物优选自以下结构：In certain embodiments, the compound of Formula I is preferably selected from the following structure:
Figure PCTCN2018095371-appb-000004
Figure PCTCN2018095371-appb-000004
其中，R 3的定义与前述相同； Wherein R 3 has the same definition as described above;
所述式II化合物优选自以下结构：The compound of formula II is preferably derived from the following structure:
Figure PCTCN2018095371-appb-000005
Figure PCTCN2018095371-appb-000005
其中，X的定义与前述相同；Wherein, the definition of X is the same as described above;
所述式III化合物优选自以下结构：The compound of formula III is preferably derived from the following structure:
Figure PCTCN2018095371-appb-000006
Figure PCTCN2018095371-appb-000006
其中，Y、R 3的定义与前述相同。 Among them, the definitions of Y and R 3 are the same as described above.
在某些实施方式中，所述式I化合物优选自以下结构：In certain embodiments, the compound of Formula I is preferably selected from the following structure:
Figure PCTCN2018095371-appb-000007
Figure PCTCN2018095371-appb-000007
本发明另一方面提供了一种如式Ia所示的化合物或其药学上可接受的盐的制备方法，包括根据本发明所述的方法制备如式I所示化合物的步骤，所述方法还包括手性拆分式I所示化合物的步骤，所述手性拆分的方法优选化学拆分、膜拆分、色谱拆分或毛细管电泳拆分，Another aspect of the invention provides a process for the preparation of a compound of formula Ia, or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula I according to the process of the invention, said method further Including a step of chiral resolution of the compound of formula I, the chiral resolution method is preferably chemical resolution, membrane resolution, chromatographic resolution or capillary electrophoresis resolution,
Figure PCTCN2018095371-appb-000008
Figure PCTCN2018095371-appb-000008
其中，R 1、R 2、n的定义与前述相同。 Here, the definitions of R 1 , R 2 and n are the same as described above.
在某些实施方式中，式Ia所示的化合物可以是In certain embodiments, the compound of Formula Ia can be
Figure PCTCN2018095371-appb-000009
Figure PCTCN2018095371-appb-000009
在某些实施方式中，当R 3为氢或羟基保护基时，反应都可顺利进行并得到目标产物。当R 3为羟基保护基时，脱除保护基的过程中容易生成微量的脱羟乙基杂质，该杂质存在一定的药理毒性，这将对化合物Ib制成药物产生一定影响；当R 3为氢时，反应过程中未检测到脱羟乙基杂质的产生。 In certain embodiments, when R 3 is hydrogen or a hydroxy protecting group, the reaction can proceed smoothly and to obtain the desired product. When R 3 is a hydroxy protecting group, a small amount of dehydroxyethyl impurity is easily formed during the process of removing the protecting group, and the impurity has certain pharmacological toxicity, which will have certain influence on the preparation of the compound Ib; when R 3 is In the case of hydrogen, no generation of dehydroxyethyl impurities was detected during the reaction.
本发明所述的咪唑并异吲哚类衍生物的制备方法具有操作安全、简单，使用的反应试剂更加安全，反应条件更加温和，成本更低，适合工业化生产等特点，反应效果均优于现有技术，具有显著的社会效益和经济效益。其中，化合物II与化合物III偶联反应的产率大大提高，相比现有技术产物纯度更高，更易于后续反应，减少了后处理操作，也更加适合工业放大生产。The preparation method of the imidazoisoindole derivative of the invention has the advantages of safe and simple operation, safer reaction reagent, milder reaction condition, lower cost, suitable for industrial production, and better reaction effects. It has technology and significant social and economic benefits. Among them, the yield of the coupling reaction of the compound II and the compound III is greatly improved, the purity of the product is higher than that of the prior art, the subsequent reaction is easier, the post-treatment operation is reduced, and the industrial scale-up production is more suitable.
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基或戊基等。更优选的是含有1至6个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基、戊基、庚基等。烷基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷氧基、卤素、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、羰基。"Alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, carbonyl group.
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元的芳基，更优选苯基和萘基，最优选苯基。芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie ring that shares a pair of adjacent carbon atoms) groups having a conjugated π-electron system, preferably a 6 to 10 membered aryl group, Phenyl and naphthyl are more preferred, and phenyl is most preferred. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane. Base amino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Sulfur based.
“杂芳基”指包含1至4个杂原子，5至14个环原子的杂芳族体系，其中杂原子包括氧、硫和氮。优选为6至10元。杂芳基优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羰基、-羧酸或羧酸酯。"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 6 to 10 yuan. The heteroaryl group is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carbonyl group, a -carboxylic acid or a carboxylic acid ester.
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)n(其中n是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1～4个是杂原子，更优选环烷基环包含3至10个环原子。单环环烷基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环环烷基包括螺环、稠环和桥环的杂环基。"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O)n ( Wherein n is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups.
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基)，其中烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自为烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羰基、羧酸或羧酸酯。“羟基”指-OH基团。"Alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and an alkane group. Thio group, alkylamino group, halogen, thiol, hydroxyl group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide A heterocyclic alkylthio group, a carbonyl group, a carboxylic acid or a carboxylic acid ester. "Hydroxy" refers to an -OH group.
“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基(MOM)，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或 C 6-10芳基氧基)羰基。 "Hydroxy protecting group" is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts). As an example, preferably, the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C 1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C 1-6 alkoxy substituted C a 1-6 alkyl or phenyl substituted C 1-6 alkyl group, most preferably a C 1-4 alkoxy substituted C 1-4 alkyl group, for example: methyl, tert-butyl, allyl, benzyl , methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; may be (C 1-10 alkyl or aryl) acyl, for example: formyl, acetyl , benzoyl, etc.; may be (C 1-6 alkyl or C 6-10 aryl)sulfonyl; may also be (C 1-6 alkoxy or C 6-10 aryloxy)carbonyl.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .
具体实施方式Detailed ways
以下将结合具体实例详细地解释本发明，使得本专业技术人员更全面地理解本发明具体实例仅用于说明本发明的技术方案，并不以任何方式限定本发明。The invention will be explained in detail below with reference to specific examples, which are to be understood by those skilled in the art.
实施例1Example 1
Figure PCTCN2018095371-appb-000010
Figure PCTCN2018095371-appb-000010
第一步first step
将化合物a(177g，0.495mol，根据WO2016169421公开方法制备)溶于1.5L二氯甲烷中，加入300mL 1,4-二氧六环，冰水浴冷却下，滴加浓盐酸(412mL，4.95mol)，升至室温，搅拌反应2小时。反应结束后，向反应液中加入600mL水，萃取分离水相。将氢氧化钠(215g，5.38mol)溶于215mL水中，缓慢滴入上述水相，调节至pH值8～9，水相用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品b 144.8g，产品不经纯化直接进行下一步反应。Compound a (177 g, 0.495 mol, prepared according to the method disclosed in WO2016169421) was dissolved in 1.5 L of dichloromethane, 300 mL of 1,4-dioxane was added, and the mixture was cooled with ice water, and concentrated hydrochloric acid (412 mL, 4.95 mol) was added dropwise. The temperature was raised to room temperature and the reaction was stirred for 2 hours. After completion of the reaction, 600 mL of water was added to the reaction mixture to extract and separate the aqueous phase. Sodium hydroxide (215 g, 5.38 mol) was dissolved in 215 mL of water, and the aqueous phase was slowly added dropwise to adjust to pH 8-9. The aqueous phase was extracted with dichloromethane. The filtrate was concentrated under reduced pressure to give a crude material (144.8 g).
第二步Second step
将粗品b(144.8g，563mmol)溶于2L乙醇中，依次加入化合物c(94.6g，844mmol)和10％Pd/C 14.5g，升温至75℃，通空气，搅拌反应28小时。反应结束后，过滤除去Pd/C，滤饼用甲醇淋洗，将滤液减压浓缩，真空干燥，得到化合物d 94.4g，产率：48％。The crude b (144.8 g, 563 mmol) was dissolved in 2 L of ethanol, and then compound c (94.6 g, 844 mmol) and 10% Pd/C 14.5 g were sequentially added, and the mixture was heated to 75 ° C, and the mixture was stirred for 28 hours. After completion of the reaction, Pd/C was removed by filtration, and the filter cake was rinsed with methanol, and the filtrate was concentrated under reduced pressure and dried in vacuo to give compound d 94.4 g.
第三步third step
将化合物d(94.4g，0.27mol)溶于1.2L二氯甲烷中。降温至0℃，加入吡啶(106.8g，1.35mol)，再滴加Tf 2O(99g，0.351mol)。升温至室温，搅拌反应1小时。反应结束后，反应液中加入100mL水，用1M盐酸调节pH值至2，静置分层，分离有机相，水相用二氯甲烷萃取，合并有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，所得残余物柱层析(洗脱剂：DCM:MeOH＝10:1)，得到化合物e 73g，产率：56.1％。 Compound d (94.4 g, 0.27 mol) was dissolved in 1.2 L of dichloromethane. The temperature was lowered to 0 ° C, pyridine (106.8 g, 1.35 mol) was added, and Tf 2 O (99 g, 0.351 mol) was added dropwise. The temperature was raised to room temperature, and the reaction was stirred for 1 hour. After the reaction was completed, 100 mL of water was added to the reaction mixture, and the pH was adjusted to 2 with 1M hydrochloric acid. The mixture was separated and separated, and the organic phase was separated. The aqueous phase was extracted with dichloromethane. The organic phase was combined, dried over anhydrous magnesium sulfate and filtered. The organic layer was concentrated under reduced pressure. EtOAcjjjjjjj
实施例2Example 2
Figure PCTCN2018095371-appb-000011
Figure PCTCN2018095371-appb-000011
第一步first step
将化合物e(73g，0.15mol)和化合物f(74.1g，0.23mol，采用“Journal of Medicinal Chemistry,2012,55(18),8091-8109”制备而得)溶于1.1L 1,4-二氧六环和水(V:V＝5:1)的混合溶剂中，依次加入碳酸钠(47.7g，450mmol)和Pd(PPh 3) 2Cl 2(15.8g，22.5mmol)，氩气保护下升温至回流，搅拌反应17小时。反应结束后，反应液冷却至室温，过滤除去催化剂固体，滤液减压浓缩，残余物中加入300mL水，用二氯甲烷萃取，合并有机相，无水硫酸镁干燥，减压浓缩，所得残余物柱层析(洗脱剂：DCM:MeOH＝50:1～20:1)，得到浅棕色固体化合物g 48g，产率：60.7％，HPLC纯度88.1％。 Compound e (73 g, 0.15 mol) and compound f (74.1 g, 0.23 mol, prepared by "Journal of Medicinal Chemistry, 2012, 55 (18), 8091-8109") were dissolved in 1.1 L 1,4-two Sodium carbonate (47.7 g, 450 mmol) and Pd(PPh 3 ) 2 Cl 2 (15.8 g, 22.5 mmol) were sequentially added to a mixed solvent of oxetane and water (V: V = 5:1) under argon atmosphere. The temperature was raised to reflux and the reaction was stirred for 17 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the residue was evaporated to dryness. Column chromatography (eluent: DCM: MeOH = 50:1 to 20:1) afforded pale brown solid compound g 48 g, yield: 60.7%, HPLC purity 88.1%.
第二步Second step
将化合物g(36g，68.27mmol)溶于400mL甲醇，加入浓盐酸(12mL，136.55mmol)，升温至40℃，搅拌反应2小时。反应液减压浓缩，加入二氯甲烷200mL，加入150mL饱和碳酸钾溶液，搅拌，过滤，滤饼用少量二氯甲烷淋洗，正己烷淋洗，收集滤饼真空干燥，得到浅棕色固体化合物h 20.8g，产率：69％，HPLC纯度92％。The compound g (36 g, 68.27 mmol) was dissolved in 400 mL of methanol, and concentrated hydrochloric acid (12 mL, 136.55 mmol) was added, and the mixture was warmed to 40 ° C, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure. dichloromethane (200 mL) was added, and 150 mL of saturated potassium carbonate solution was added, and the mixture was stirred and filtered. The filter cake was rinsed with a small amount of dichloromethane and rinsed with n-hexane. 20.8 g, yield: 69%, HPLC purity 92%.
实施例3Example 3
Figure PCTCN2018095371-appb-000012
Figure PCTCN2018095371-appb-000012
将化合物e(73g，152mmol)和化合物i(72.2g，304mmol，按照CN105189461A公开的方法制备)溶于1500mL 1,4-二氧六环和水(V:V＝5:1)的混合溶剂中，依次加入碳酸钠(48.3g，456mmol)和Pd(dppf)Cl 2(11.1g，15.2mmol)，氩气保护下升温至回流，搅拌反应3小时。反应结束后，反应液冷却至室温，加入400mL水，室温搅拌30min，过滤，滤饼用水淋洗，收集滤饼，用1.2L甲醇分散，加入浓盐酸(40mL)，搅拌30min，浓缩除去甲醇，加入2L水，搅拌30min，过滤，固体用水淋洗，合并水相，用乙酸乙酯反萃(600mL×2)，收集水相，用饱和NaHCO 3溶液调pH至碱性，析出固体，过滤得固体，水洗，真空干燥，得化合物h 41.8g，产率62％，化学纯度：94.4％。 Compound e (73 g, 152 mmol) and compound i (72.2 g, 304 mmol, prepared according to the method disclosed in CN 105189461 A) were dissolved in a mixed solvent of 1500 mL of 1,4-dioxane and water (V:V=5:1). Sodium carbonate (48.3 g, 456 mmol) and Pd(dppf)Cl 2 (11.1 g, 15.2 mmol) were successively added, and the mixture was warmed to reflux under argon atmosphere, and the reaction was stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 400 mL of water was added, and the mixture was stirred at room temperature for 30 min, filtered, and the filter cake was rinsed with water, and the filter cake was collected, dissolved with 1.2 L of methanol, concentrated hydrochloric acid (40 mL), stirred for 30 min, and concentrated to remove methanol. 2L of water, stirred for 30min, filtered, the solid was rinsed with water, the aqueous phase was combined, extracted with ethyl acetate (600mL × 2), the aqueous phase was collected, the pH was adjusted to basic with saturated NaHCO 3 solution, solids were precipitated and filtered. The solid was washed with water and dried in vacuo to give 4j,j,j,
实施例4Example 4
将化合物h 11.59g进行手性制备(分离条件：手性制备柱Superchiral S-AS(Chiralway),2cm I.D.*25cm Length,5um；流动相：CO2/MeOH/DEA＝60/40/0.05(v/v)，流速：50mL/min)，收集目标组分，减压浓缩，得到化合物Ib 4.49g，光学纯度：99.6％。Chiral preparation of compound h 11.59 g (isolation conditions: chiral preparative column Superchiral S-AS (Chiralway), 2 cm ID * 25 cm Length, 5 um; mobile phase: CO 2 / MeOH / DEA = 60 / 40 / 0.05 (v / v), flow rate: 50 mL/min), the target component was collected, and concentrated under reduced pressure to give Compound Ib 4.49 g, optical purity: 99.6%.
由于已根据其特殊的实施方案描述了本发明，某些修饰和等价变化对于精通此领域的技术人员是显而易见的且包括在本发明的范围内。Since the present invention has been described in terms of its specific embodiments, certain modifications and equivalents are obvious to those skilled in the art and are included within the scope of the invention.

Claims (10)

  1. 一种如式I所示化合物的制备方法，包括将式II所示化合物与式III所示化合物反应的步骤，A process for the preparation of a compound of formula I, which comprises the step of reacting a compound of formula II with a compound of formula III,
    Figure PCTCN2018095371-appb-100001
    Figure PCTCN2018095371-appb-100001
    其中，R 1相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基和杂芳基； Wherein R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl and heteroaryl;
    R 2选自-CH 2-CH 2-OR 3； R 2 is selected from -CH 2 -CH 2 -OR 3 ;
    R 3选自氢或羟基保护基，优选氢； R 3 is selected from hydrogen or a hydroxy protecting group, preferably hydrogen;
    X和Y中一个为离去基团，另一个选自-BF 3K、-BR aR b、-Sn(R c) m或-Zn-X’， One of X and Y is a leaving group, and the other is selected from -BF 3 K, -BR a R b , -Sn(R c ) m or -Zn-X',
    其中所述离去基团选自-Cl、-Br、-I、-F、三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基、乙酰氧基或磷酸酯基、-SR，-SO 2R； Wherein the leaving group is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, - SR, -SO 2 R;
    R a和R b独立地选自-OH、烷基、烷氧基或任意取代的C 1～C 6一元和二元醇，或R a和R b在一起成环，R c独立地选自C 1～C 6烷基，X’选自-Cl、-Br、-I，R为C 1～C 6烷基； R a and R b are independently selected from -OH, alkyl, alkoxy or optionally substituted C 1 -C 6 mono and diol, or R a and R b are taken together to form a ring, and R c is independently selected from a C 1 -C 6 alkyl group, X' is selected from -Cl, -Br, -I, and R is a C 1 -C 6 alkyl group;
    n为0、1、2、3或4的整数，m为0、1、2、3或4的整数。n is an integer of 0, 1, 2, 3 or 4, and m is an integer of 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的制备方法，其特征在于，所述反应在催化剂的存在下进行，所述的催化剂优选自PdL p、PdCl 2L p、Pd(OAc) 2L p、Pd 2(dba) 3L p、Pd(II)L p、Pd(0)、NiCl 2L p、Ni(COD) 2L p、NiCl 2(NEt 3) 2或NiCl 2(bipy)， The process according to claim 1, wherein the reaction is carried out in the presence of a catalyst, preferably from PdL p , PdCl 2 L p , Pd(OAc) 2 L p , Pd 2 (dba) 3 L p , Pd(II) L p , Pd(0), NiCl 2 L p , Ni(COD) 2 L p , NiCl 2 (NEt 3 ) 2 or NiCl 2 (bipy),
    其中L为含膦配体或N-杂环卡宾配体，所述含膦配体优选自PPh 3、dppf、PCy 3、tBu 3P、P(OMe) 3、dppe或dppb， Wherein L is a phosphine-containing ligand or an N-heterocyclic carbene ligand, preferably from PPh 3 , dppf, PCy 3 , tBu 3 P, P(OMe) 3 , dppe or dppb,
    p独立的选自0、1、2、3或4的整数，p independent of an integer selected from 0, 1, 2, 3 or 4,
    所述的催化剂更优选Pd(PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2、钯碳、Pd(OAc) 2、PCy 3/Pd 2(dba) 3，最优选Pd(PPh 3) 2Cl 2。 More preferably, the catalyst is Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , palladium carbon, Pd(OAc) 2 , PCy 3 /Pd 2 (dba) 3 , most preferably Pd(PPh 3 ) 2 Cl 2 .
  3. 根据权利要求1所述的制备方法，其特征在于，所述反应在碱性物质存在下进行反应，其中碱性物质优选Li 2CO 3、Na 2CO 3、Ba(OH) 2、K 3PO 4、Cs 2CO 3、K 2CO 3、TlOH、KF、CsF、Bu 4NF、LiOH、NaOH、KOH、三乙胺、DIPEA、DABCO、NaOR、 KOR、TlOR中的一种或多种，其中R独立地选自C 1～C 6烷基，所述碱性物质更优选Na 2CO 3或K 2CO 3中的一种或多种。 The production method according to claim 1, wherein the reaction is carried out in the presence of a basic substance, wherein the basic substance is preferably Li 2 CO 3 , Na 2 CO 3 , Ba(OH) 2 , K 3 PO 4 , one or more of Cs 2 CO 3 , K 2 CO 3 , TlOH, KF, CsF, Bu 4 NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, wherein R is independently selected from a C 1 -C 6 alkyl group, and the basic substance is more preferably one or more of Na 2 CO 3 or K 2 CO 3 .
  4. 根据权利要求1所述的制备方法，其特征在于，所述反应的溶剂为二甲基甲酰胺、1-甲基-2-吡咯烷酮、四氢呋喃、二氧六环、甲苯、二甲亚砜、二甲基醚、异丙醇、乙醇、水中的一种或多种，优选二甲基甲酰胺、二甲基醚、二氧六环、水中的一种或多种。The preparation method according to claim 1, wherein the solvent for the reaction is dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethyl sulfoxide, and the like. One or more of methyl ether, isopropanol, ethanol, and water, preferably one or more of dimethylformamide, dimethyl ether, dioxane, and water.
  5. 根据权利要求1所述的制备方法，其特征在于，X为离去基团，Y选自-BF 3K或-BR aR b，其中所述离去基团选自-Cl、-Br、-I、三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基，所述BR aR b优选R a和R b独立地选自-OH、烷基、烷氧基，或BR aR b为频哪醇硼酸酯。 The preparation method according to claim 1, wherein X is a leaving group, and Y is selected from -BF 3 K or -BR a R b , wherein the leaving group is selected from -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, said BR a R b preferably R a and R b are independently selected from -OH, alkyl, alkoxy, or BR a R b is a pinacol borate.
  6. 根据权利要求1所述的制备方法，其特征在于，所述式I化合物为The method according to claim 1, wherein the compound of the formula I is
    Figure PCTCN2018095371-appb-100002
    Figure PCTCN2018095371-appb-100002
  7. 根据权利要求1所述的制备方法，其特征在于，所述式II化合物为The method according to claim 1, wherein the compound of the formula II is
    Figure PCTCN2018095371-appb-100003
    Figure PCTCN2018095371-appb-100003
  8. 一种如式Ia所示的化合物或其药学上可接受的盐的制备方法，包括根据权利要求1-7任意一项的方法制备如式I所示化合物的步骤，所述方法还包括手性拆分式I所示化合物的步骤，所述手性拆分的方法优选化学拆分、膜拆分、色谱拆分或毛细管电泳拆分，A process for the preparation of a compound of formula Ia, or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula I according to the process of any of claims 1-7, said method further comprising chirality a step of isolating the compound of formula I, which is preferably chemical resolution, membrane resolution, chromatographic resolution or capillary electrophoresis resolution,
    Figure PCTCN2018095371-appb-100004
    Figure PCTCN2018095371-appb-100004
    其中，R 1、R 2、n的定义如权利要求1所述。 Wherein R 1 , R 2 , and n are as defined in claim 1.
  9. 根据权利要求8所述的制备方法，其特征在于，所述式Ia化合物为The method according to claim 8, wherein the compound of the formula Ia is
    Figure PCTCN2018095371-appb-100005
    Figure PCTCN2018095371-appb-100005
  10. 根据权利要求1至5任意一项所述的制备方法，其特征在于，所述式I化合物为The preparation method according to any one of claims 1 to 5, wherein the compound of the formula I is
    Figure PCTCN2018095371-appb-100006
    Figure PCTCN2018095371-appb-100006
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