WO2023130334A1 - Procédé de préparation d'un composé chromène-4-one et intermédiaire de celui-ci - Google Patents

Procédé de préparation d'un composé chromène-4-one et intermédiaire de celui-ci Download PDF

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WO2023130334A1
WO2023130334A1 PCT/CN2022/070607 CN2022070607W WO2023130334A1 WO 2023130334 A1 WO2023130334 A1 WO 2023130334A1 CN 2022070607 W CN2022070607 W CN 2022070607W WO 2023130334 A1 WO2023130334 A1 WO 2023130334A1
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compound
reaction
combination
ethanol
preparation
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PCT/CN2022/070607
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English (en)
Chinese (zh)
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郭振荣
唐恕一
李学飞
陈志宏
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同润生物医药(上海)有限公司
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Priority to PCT/CN2022/070607 priority Critical patent/WO2023130334A1/fr
Publication of WO2023130334A1 publication Critical patent/WO2023130334A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to the field of drug synthesis, in particular to a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- Preparation methods of 4-ketones and intermediates thereof.
  • Phosphoinositide-3 kinases belong to a class of intracellular lipid kinases that phosphorylate the 3-hydroxyl of the inositol ring of phosphoinositide lipids (PI), thereby generating lipid second messengers. It has been reported in the art that targeted inhibitors of the phosphoinositide-3-kinase (PI3K) pathway can be used as immunomodulators.
  • Patent document WO2011055215A2 discloses a novel benzopyran kinase regulator.
  • patent document WO2014195888A1 further studies and discloses an inhibitor (S)-2-(1-( 9H-Purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one.
  • the present invention on the basis of the existing literature, to (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H -Chromene-4-ketone carries out further research, has obtained technical scheme of the present invention.
  • the present invention provides a novel preparation of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one Compared with the methods disclosed in existing documents, the present invention reduces the reaction steps, thereby improving the purity and yield of the reaction and reducing production costs.
  • the present invention provides the following technical solutions:
  • a compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one (formula (I))
  • the preparation method is characterized in that, comprises the following steps:
  • X represents halogen, preferably Cl, Br, more preferably Br;
  • Y represents a leaving group, preferably a halogen, more preferably Cl or Br.
  • the catalytic hydrogenation reaction of the step (I) is carried out under the condition of palladium as a catalyst and hydrogen.
  • the palladium catalyst is selected from any one of Pd/C, Pd(OH) 2 /C or a combination thereof.
  • reaction solvent of the step (I) is any one of methanol, ethanol, tetrahydrofuran, dioxane, DMSO, acetone, butanol or a combination thereof.
  • reaction condition of described step (II) is carried out under alkaline condition.
  • the alkaline condition is an inorganic base or an organic base, preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, N,N-di Any one or combination of isopropylethylamine (DIPEA), sodium tert-butyl, sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine, DMAP, morpholine, N-methylmorpholine, More preferred is triethylamine.
  • DIPEA isopropylethylamine
  • DIPEA isopropylethylamine
  • sodium tert-butyl sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine
  • DMAP morpholine
  • N-methylmorpholine More preferred is triethylamine.
  • reaction solvent in the described step (II) is any of water, methanol, ethanol, tetrahydrofuran, dioxane, DMSO, acetone, butanol, tert-butanol, ether one or a combination thereof.
  • the present invention also provides a preparation method of compound 2, which is characterized in that it comprises the following steps:
  • the reaction condition of the hydrogenation catalytic reaction is that in the presence of an organic solvent, palladium is used as a catalyst, and the catalytic hydrogenation reaction is carried out by hydrogen under high pressure;
  • X represents a halogen, preferably Cl or bromine, more preferably Br .
  • said palladium catalyst is selected from any one of Pd/C, Pd(OH) 2 /C or a combination thereof
  • the organic solvent is selected from any one of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, DMSO or a combination thereof.
  • the high pressure reaction is 0.5-1MPa.
  • the present invention also provides a preparation method of Compound 1, which is characterized in that it comprises the following steps:
  • Compound 4 and compound 5 are prepared by reacting in an organic solvent under alkaline/condensing agent conditions to obtain compound 1;
  • X represents halogen, preferably Cl or bromine, more preferably Br.
  • the alkaline condition is an inorganic base or an organic base, preferably Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, N,N-di Any one of isopropylethylamine (DIPEA), tert-butyl sodium, sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine, DMAP, morpholine, N-methylmorpholine, or a combination thereof .
  • DIPEA isopropylethylamine
  • tert-butyl sodium sodium ethoxide, sodium methoxide, triethylamine, diethylamine, pyridine
  • DMAP morpholine
  • N-methylmorpholine or a combination thereof .
  • the organic solvent is selected from any of dichloromethane, carbon tetrachloride, chloroform, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, DMF, acetone one or a combination thereof.
  • the condensing agent is selected from any one of HATU, HBTU, TBTU, TATU, HOBt, DCC, EDCI, DMAP or a combination thereof.
  • X represents halogen, preferably Cl or bromine, more preferably Br.
  • the catalyst for the reaction is AlCl 3 .
  • organic solvent is preferably dichloromethane, carbon tetrachloride, chloroform, methyl alcohol, ethanol, isopropanol, tetrahydrofuran, Any one or combination of dioxane, DMF, acetone.
  • the preparation method of compound 5 comprises the following steps:
  • the base is selected from Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH any one or combination of them.
  • reaction solvent in step (i) is selected from any one of H 2 O, methanol, ethanol, tetrahydrofuran, dioxane or a combination thereof.
  • the base is selected from Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH Any one or combination thereof, preferably NaOH.
  • reaction solvent in step (ii) is selected from any one of H 2 O, methanol, ethanol, tetrahydrofuran, dioxane or a combination thereof.
  • X represents halogen, preferably Cl or bromine, more preferably Br.
  • Step 1) Add m-fluorophenylacetic acid (200g, 1.0eq.), DMF (2.4g, 0.012W), dichloromethane (750mL, 3.5V) into the reaction flask, replace with nitrogen 3 times; cool down and stir to -10 °C, SOCl2 (200.8 g, 1.3 eq.) was added dropwise at -10 °C. After the dropwise addition, the temperature was raised to 20° C., and kept stirring for 3 hours; the sample was controlled by HPLC (methanol quenching); after the reaction was completed, it was concentrated at 30° C. until no liquid flowed out. Add dichloromethane (600mL, 3V) and continue to concentrate until no liquid flows out to obtain m-fluorophenylacetyl chloride;
  • Step 2) Add m-fluorophenylacetyl chloride (1.0eq.), p-bromoanisole (315.6g, 1.3eq.), dichloromethane (750mL, 3.5V) into the reaction flask.
  • Step 1) Add m-fluorophenylacetic acid (200g, 1.0eq.), DMF (2.4g, 0.012W), dichloromethane (300mL, 1.5V) into the reaction flask, replace with nitrogen 3 times; cool down and stir to 20°C , add (COCl) 2 (181g, 1.1eq.) dropwise at 20°C; after the dropwise addition, keep stirring at 20-25°C for 12h; control HPLC during sampling (methanol quenching); step 2): m-fluorobenzene Add acetyl chloride (1.0eq.), p-bromoanisole (315.6g, 1.3eq.), dichloromethane (1250mL, 6.5V) into the reaction flask, cool and stir to 0°C; add AlCl 3 (225g , 1.3eq.), and control the reaction temperature at 0-10°C; after the addition, the temperature was raised to 40°C, and after 15 hours of heat preservation and stirring, the sample was controlled
  • Embodiment 2 N the preparation of N-dibenzyl aminobutyric acid (compound 5)
  • Step 1) Take KOH (108.9g, 1.94mol, 2.0eq.), K 2 CO 3 (268.05g, 1.94mol, 2.0eq.) and water (1L, 10V) into the reactor. At 25°C, 2-aminobutyric acid (100 g, 0.97 mol, 1.0 eq.) was added, and the temperature was raised to 90°C.
  • Step 2) Take the crude intermediate 1, heat up to 80°C, and add KOH aqueous solution (108.9g, 1.94mol, 2.0eq; 1080mL, 10.8V water) dropwise. After raising the temperature to 80°C, keep it warm for 12 hours, and take a sample to control it; precipitation at 75°C until there are basically no fractions, and the crude product of intermediate 2 is obtained as a yellow oily liquid;
  • KOH aqueous solution 108.9g, 1.94mol, 2.0eq; 1080mL, 10.8V water
  • Step 4) Take the crude compound 5 and add ethanol (1080mL, 3V), beat at room temperature (25°C) for 2h, filter, and wash with ethanol (50mL) to obtain 213.34g of compound 5 as a white solid with a purity of 96.17%. Take 213.34g of compound 5 product with a purity of 96.17%, add ethanol (600mL, 3V), beat at room temperature (25°C) for 2h, filter, and wash with ethanol (50mL) to obtain 193.01g of compound 5 product as a white solid, yield It is 70.24% and the purity is 98.58%.
  • Step 1) Take NaOH (77.57g, 1.94mol, 2.0eq.), K2CO3 (268.05g, 1.94mol, 2.0eq.) and water (1L, 10V) into the reactor. After cooling down to 25°C, 2-aminobutyric acid (100g, 0.97mol, 1.0eq.) was added, and the temperature was raised to 80°C. After that, benzyl bromide (855.8g, 5.09mol, 3.1eq.) was added dropwise, and after 10h of heat preservation at 80°C, the sample was taken for control; after cooling down to room temperature, it was allowed to stand still, and the upper organic layer was separated to obtain the crude intermediate 1, which was yellow oily liquid.
  • NaOH aqueous solution NaOH 154.21g, 3.86mol, 4.0eq; water 720mL, 7.2V
  • Step 4) Concentrate the above DCM layer solution to 336g, then add absolute ethanol (230mL, 2.3V) and n-heptane (230mL, 2.3V), heat up to 70°C to dissolve, and cool down to room temperature to precipitate fine granular compounds 5. Beat for 2 hours at room temperature, then lower to 0°C and stir for 1 hour. After filtration, the filter cake was washed with n-heptane (250 mL), and dried to obtain 189 g of compound 5 as a white solid with a yield of 65.50% and a purity of 99.4%.
  • the obtained yellow solid was added into (30 mL, 0.5V) tetrahydrofuran and (60 mL, 1V) MTBE and stirred at 50°C under reflux for 0.5h-1h. Cool down to room temperature, and add (240mL, 4V) n-heptane dropwise, and continue stirring for 1h-2h.
  • the yellow solid obtained by filtration was sampled for HPLC control, and the mother liquor was sampled; Compound 2 was obtained as 26.1 g of orange solid in a vacuum oven at 60° C. (16 h), with a yield of 81.3% and a purity of 99.34%.

Abstract

Procédé de préparation d'un inhibiteur de (S)-2-(1-(9H-purine-6-ylamino) propyle)-3-(3-fluorophényle)-4H-chromène-4-one PI3K δ/γ et d'un intermédiaire de celui-ci. Par comparaison avec un procédé des l'état de la technique, ce procédé réduit le processus de réaction, peut augmenter le rendement de réaction et la pureté du produit, et facilite la production industrielle.
PCT/CN2022/070607 2022-01-07 2022-01-07 Procédé de préparation d'un composé chromène-4-one et intermédiaire de celui-ci WO2023130334A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/CN2022/070607 WO2023130334A1 (fr) 2022-01-07 2022-01-07 Procédé de préparation d'un composé chromène-4-one et intermédiaire de celui-ci

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PCT/CN2022/070607 WO2023130334A1 (fr) 2022-01-07 2022-01-07 Procédé de préparation d'un composé chromène-4-one et intermédiaire de celui-ci

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102812013A (zh) * 2009-11-05 2012-12-05 理森制药股份公司 新型苯并吡喃激酶调节剂
CN103946213A (zh) * 2011-11-25 2014-07-23 霍夫曼-拉罗奇有限公司 作为组织蛋白酶抑制剂的新吡咯烷衍生物
CN104507922A (zh) * 2012-05-04 2015-04-08 理森制药股份公司 用于制备光学纯的并且任选地经取代的2-(1-羟基-烷基)-色烯-4-酮衍生物的新型方法以及其在制备药物中的用途
CN105358560A (zh) * 2013-06-07 2016-02-24 理森制药股份公司 双重选择性PI3δ和γ激酶抑制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102812013A (zh) * 2009-11-05 2012-12-05 理森制药股份公司 新型苯并吡喃激酶调节剂
CN103946213A (zh) * 2011-11-25 2014-07-23 霍夫曼-拉罗奇有限公司 作为组织蛋白酶抑制剂的新吡咯烷衍生物
CN104507922A (zh) * 2012-05-04 2015-04-08 理森制药股份公司 用于制备光学纯的并且任选地经取代的2-(1-羟基-烷基)-色烯-4-酮衍生物的新型方法以及其在制备药物中的用途
CN105358560A (zh) * 2013-06-07 2016-02-24 理森制药股份公司 双重选择性PI3δ和γ激酶抑制剂

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