WO2022126942A1 - Procédé de synthèse d'un chlorhydrate d'amine chiral contenant du cyclopropyle - Google Patents

Procédé de synthèse d'un chlorhydrate d'amine chiral contenant du cyclopropyle Download PDF

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Publication number
WO2022126942A1
WO2022126942A1 PCT/CN2021/086610 CN2021086610W WO2022126942A1 WO 2022126942 A1 WO2022126942 A1 WO 2022126942A1 CN 2021086610 W CN2021086610 W CN 2021086610W WO 2022126942 A1 WO2022126942 A1 WO 2022126942A1
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WIPO (PCT)
Prior art keywords
compound
solution
cyclopropyl
amine hydrochloride
chiral amine
Prior art date
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PCT/CN2021/086610
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English (en)
Chinese (zh)
Inventor
冯宇
钱伟
党军奎
黄兴
仲晨昊
王植鹏
李缪斌
高莉燕
许燕萍
卞吉顺
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诚达药业股份有限公司
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Application filed by 诚达药业股份有限公司 filed Critical 诚达药业股份有限公司
Priority to AU2021404731A priority Critical patent/AU2021404731B2/en
Publication of WO2022126942A1 publication Critical patent/WO2022126942A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the invention relates to the technical field of synthesis of pharmaceutical intermediates and organic chemical intermediates, and relates to a synthesis method of a cyclopropyl-containing chiral amine hydrochloride.
  • Cyclopropyl-containing chiral amines are an important class of pharmaceutical intermediates and are widely used. For example, it has been reported in the literature that they can be used to synthesize corticotropin-releasing factor-1 (CRF1) receptor antagonists (J.Med.Chem .2009,52,4173), the literature also reported that it was used to synthesize quinazoline drugs for the treatment of cancer (ACS Med.Chem.Lett.2018,9,9,941–946), and patents reported that it could be used for Synthetic Cathepsin S inhibitors are used for the treatment of autoimmunity and related disorders (WO2011109470), and another patent reports that it can be synthesized to modulate Ras activity agents for the treatment of cancer (WO2018212774). In a word, cyclopropyl-containing chiral amines are currently widely used in the field of pharmaceutical synthesis, and their synthesis processes have great development value.
  • CCF1 corticotropin-releasing factor-1
  • the existing synthetic routes all have shortcomings, such as long steps, the need to use expensive reagents, involving inflammable and explosive and other dangerous reagents or production processes, requiring special production equipment, serious environmental pollution and other problems, which are not conducive to Large-scale industrial production. Therefore, there is a need for a method for preparing a cyclopropyl chiral amine with simple reaction, low cost and easy industrial production.
  • the technical problem to be solved by the present invention is to develop a method for synthesizing a cyclopropyl-containing chiral amine hydrochloride, which is easy to obtain from raw materials, has high yield, good quality, and is easy to operate and suitable for industrial production.
  • Cyclopropanecarboxaldehyde (compound (I)) is the starting material and is condensed with (R)-1-phenethylamine to obtain compound (II), followed by alkylation with the corresponding Grignard reagent to prepare compound (III) of general formula, and then Hydrogenation and debenzylation protection can obtain the compound (IV) of the general formula, and then split into a salt to prepare the product of the general formula (V).
  • a synthetic method containing cyclopropyl chiral amine hydrochloride comprising the following synthetic steps:
  • Step 1) Compound (I) cyclopropanecarbaldehyde is used as starting material, and it is condensed with (R)-1-phenethylamine to obtain compound (II), and compound (I) and (R)-1-phenethylamine are in a solvent
  • the reaction is carried out at a reaction temperature of 50-110° C., and the compound (II) or its solution is obtained after post-treatment, and the solvent is tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, dichloromethane Any one or more of the methane, the cyclopropanecarboxaldehyde and (R)-1-phenethylamine mol ratio is 1:1 ⁇ 3;
  • Step 2 The compound (II) solution is reacted with a Grignard reagent solution at -50 to 100° C., and post-processing is performed to prepare the general formula compound (III) or its solution.
  • the molar ratio of the compound (II) to the Grignard reagent is 1 : 1 to 10;
  • Step 3 Under the catalysis of a catalyst, the solution of the compound (III) of the general formula is reacted at 0-100° C. under a hydrogen atmosphere of 0-10 MPa, and the compound of the general formula (IV) or its solution is obtained by post-treatment;
  • Step 4) Compound (IV) of general formula or its solution, after adding a resolving agent and a solvent for resolution, then post-processing is converted into hydrochloride to prepare compound (V) of general formula, and the resolution is (S) - any one or more of mandelic acid, (S)-acetyl mandelic acid, L-dibenzoyl tartaric acid, L-tartaric acid, and the solvent is methanol, ethanol, isopropanol, n-propanol, n- Any one or more of butanol, isobutanol, tert-butanol, and water, and the molar ratio of the compound (IV) to the resolving agent is 0:0.5 to 10;
  • step 1) the molar ratio of cyclopropanecarboxaldehyde and (R)-1-phenethylamine is 1:1 to 1.5, the solvent is toluene, the reaction temperature is 80 to 110 ° C, and the reaction preparation compound ( II).
  • step 1) compound (II) or a solution is prepared by post-treatment, and the next step is carried out.
  • the reaction temperature is -20 to 60° C.
  • the molar ratio of compound (II) to Grignard reagent is 1:1 to 1.5.
  • the Grignard reagent is methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, vinylmagnesium chloride, vinylmagnesium bromide, ethynylmagnesium chloride, ethynylmagnesium bromide
  • step 2) the compound of general formula (III) or a solution is prepared by post-treatment, and the next step is carried out.
  • the reaction temperature is 30-60° C.
  • the hydrogen pressure is 0.5-1 Mpa.
  • the catalyst is any one or more of palladium carbon, rhodium carbon, platinum carbon and platinum oxide.
  • the catalyst is palladium carbon.
  • the resolving agent is (S)-mandelic acid
  • the molar ratio of the general formula compound (IV) and the resolving agent is 0:0.8 ⁇ 1.5
  • the solvent is isopropanol
  • the route of the invention is relatively simple, the raw materials used are all commercially available commercial materials, and the raw materials are relatively cheap, without complicated special operations, and suitable for industrial production; it is the synthesis preparation of cyclopropyl-containing chiral amine hydrochloride A new synthetic protocol is provided.
  • the compound (III-1) solution was put into the autoclave, 5g of 5% Pd/C was added, replaced with hydrogen, the pressure was adjusted to 0.5MPa, the reaction was performed for 4h, vented and discharged, and filtered to obtain the solution of compound (IV-1), Enter the next reaction.
  • the NMR data of the compound are as follows: 1 H NMR (400MHz, D 2 O): ⁇ 2.07(m, 1H), ⁇ 1.44(m, 2H), ⁇ 0.68(t, 3H), ⁇ 0.67(m, 1H) ), ⁇ 0.33(m, 2H), ⁇ 0.03(m, 2H); 13 C NMR (400MHz, D 2 O): ⁇ 56.6, ⁇ 24.0, ⁇ 10.6, ⁇ 6.9, ⁇ 1.5 .
  • the compound (III-2) solution was put into the autoclave, 3g of 5% Pd/C was added, replaced with hydrogen, the pressure was adjusted to 1.0MPa, the reaction was performed for 4h, the material was vented, filtered, and the filtrate was the solution of compound (IV-2) , into the next reaction.
  • the NMR data of the compound are as follows: 1 H NMR (400MHz, D 2 O): ⁇ 5.81(m, 1H), ⁇ 5.28(m, 2H), ⁇ 3.03(m, 1H), ⁇ 0.95(m, 1H) ), ⁇ 0.43 (m, 4H); 13 C NMR (400 MHz, D 2 O): ⁇ 132.5, ⁇ 119.4, ⁇ 58.3, ⁇ 12.8, ⁇ 3.3, ⁇ 2.6.
  • the compound (III-3) solution was put into the autoclave, 10g of 5% Pd/C was added, replaced with hydrogen, the pressure was adjusted to 1.0MPa, the reaction was performed for 2h, the material was vented and discharged, filtered, and the filtrate was the solution of compound (IV-3) , into the next reaction.
  • the NMR data of the compound are as follows: 1 HNMR (400MHz, D 2 O): ⁇ 2.0(m, 1H), ⁇ 1.74(m, 1H), ⁇ 0.74(d, 6H), ⁇ 0.67(m, 1H) , ⁇ 0.23 (m, 4H); 13 C NMR (400 MHz, D 2 O): ⁇ 61.2, ⁇ 29.5, ⁇ 15.7, ⁇ 9.0, ⁇ 3.0.
  • the NMR data of the compound are as follows: 1 H NMR (400MHz, D 2 O): ⁇ 3.79(m, 1H), ⁇ 2.85(s, 1H), ⁇ 1.14(m, 1H), ⁇ 0.51(m, 4H) ); 13 C NMR (400 MHz, D 2 O): ⁇ 74.7, ⁇ 74.2, ⁇ 44.7, ⁇ 10.6, ⁇ 1.6.
  • the compound (III-5) solution was put into the autoclave, 2g of 5% Pd/C was added, replaced with hydrogen, the pressure was adjusted to 0.2MPa, the reaction was performed for 10h, the material was vented, filtered, and the filtrate was the solution of compound (IV-5) , into the next reaction.
  • the NMR data of the compound are as follows: 1 HNMR (400MHz, D 2 O): ⁇ 2.1(m, 1H), ⁇ 1.54(m, 2H), ⁇ 1.32(m, 2H), ⁇ 1.27(m, 2H) , ⁇ 0.74(t, 3H), ⁇ 0.67(m, 1H), ⁇ 0.28(m, 4H); 13 C NMR (400MHz, D 2 O): ⁇ 59.8, ⁇ 30.5, ⁇ 27.7 , ⁇ 22.5, ⁇ 15.7, ⁇ 12.8, ⁇ 2.8.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention se rapporte au domaine de la synthèse et de la préparation des intermédiaires médicaux. L'invention concerne un procédé de synthèse d'un intermédiaire médical de chlorhydrate d'amine chirale contenant du cyclopropyle. Selon la présente invention, un composé (I) cycloprogyl déhyde est utilisé en tant que matière première de départ, et un produit cible de chlorhydrate d'amine chirale est obtenu par condensation, alkylation, débenzylation, résolution chirale et réactions de salification. Le procédé de synthèse de l'intermédiaire médical de chlorhydrate d'amine chirale contenant du cyclopropyle selon la présente invention présente des caractéristiques d'un faible coût et d'un fonctionnement simple.
PCT/CN2021/086610 2020-12-18 2021-04-12 Procédé de synthèse d'un chlorhydrate d'amine chiral contenant du cyclopropyle WO2022126942A1 (fr)

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AU2021404731A AU2021404731B2 (en) 2020-12-18 2021-04-12 Synthesis method for cyclopropyl-containing chiral amine hydrochloride

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CN202011504634.2 2020-12-18
CN202011504634.2A CN112552184B (zh) 2020-12-18 2020-12-18 一种含环丙基手性胺盐酸盐的合成方法

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CN112552184B (zh) * 2020-12-18 2022-05-10 诚达药业股份有限公司 一种含环丙基手性胺盐酸盐的合成方法

Citations (4)

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CN1989097A (zh) * 2004-07-22 2007-06-27 帝斯曼知识产权资产管理有限公司 用于制备非对映异构体富集的化合物的方法
CN110520406A (zh) * 2017-04-06 2019-11-29 勃林格殷格翰国际有限公司 环丙基烷基胺及其制备方法
WO2020079145A1 (fr) * 2018-10-18 2020-04-23 Boehringer Ingelheim International Gmbh Synthèse évolutive de 1-cyclopropylalkyl-1-amines optiquement actives
CN112552184A (zh) * 2020-12-18 2021-03-26 诚达药业股份有限公司 一种含环丙基手性胺盐酸盐的合成方法

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US7932256B2 (en) * 2008-07-31 2011-04-26 Bristol-Myers Squibb Company (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile: a pyrazinone modulator of corticotropin-releasing factor receptor activity
CN105017082B (zh) * 2015-07-31 2017-09-19 上海皓元医药股份有限公司 一种心衰药Entresto 关键中间体(R)‑叔丁基 (1‑([1,1`‑联苯]‑4‑基)‑3‑羟基丙烷‑2‑基)氨基甲酸酯的制备方法
CN105237406A (zh) * 2015-10-14 2016-01-13 湖南华腾制药有限公司 (r)-(-)-1-甲基-3-苯丙胺的合成方法
CN106831538B (zh) * 2017-01-22 2019-06-25 苏州楚凯药业有限公司 托法替尼中间体的制备方法

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
CN1989097A (zh) * 2004-07-22 2007-06-27 帝斯曼知识产权资产管理有限公司 用于制备非对映异构体富集的化合物的方法
CN110520406A (zh) * 2017-04-06 2019-11-29 勃林格殷格翰国际有限公司 环丙基烷基胺及其制备方法
WO2020079145A1 (fr) * 2018-10-18 2020-04-23 Boehringer Ingelheim International Gmbh Synthèse évolutive de 1-cyclopropylalkyl-1-amines optiquement actives
CN112552184A (zh) * 2020-12-18 2021-03-26 诚达药业股份有限公司 一种含环丙基手性胺盐酸盐的合成方法

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CN112552184A (zh) 2021-03-26
CN112552184B (zh) 2022-05-10
AU2021404731A1 (en) 2022-07-28
AU2021404731B2 (en) 2023-03-30

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