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WO2022199378A1 - Procédé de synthèse d'un principe actif pharmaceutique d'acide bempédoïque - Google Patents

Procédé de synthèse d'un principe actif pharmaceutique d'acide bempédoïque Download PDF

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Publication number
WO2022199378A1
WO2022199378A1 PCT/CN2022/079806 CN2022079806W WO2022199378A1 WO 2022199378 A1 WO2022199378 A1 WO 2022199378A1 CN 2022079806 W CN2022079806 W CN 2022079806W WO 2022199378 A1 WO2022199378 A1 WO 2022199378A1
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Prior art keywords
compound
solvent
synthetic method
alkali metal
sodium
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PCT/CN2022/079806
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English (en)
Chinese (zh)
Inventor
阮晶
严恭超
阮晓娜
张薇
张鑫鑫
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上海鼎雅药物化学科技有限公司
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Publication of WO2022199378A1 publication Critical patent/WO2022199378A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/285—Polyhydroxy dicarboxylic acids having five or more carbon atoms, e.g. saccharic acids

Definitions

  • the invention relates to the field of organic synthesis, in particular, to a method for synthesizing a bepidoxic acid crude drug.
  • Bepidoic acid is a small molecule adenosine triphosphate-citrate lyase inhibitor. Compared with existing statins, its tolerance is better, and it can be used in combination with statins to control the level of low-density lipoprotein cholesterol. rise, its structural formula is as follows:
  • Patent application CN111825546A discloses the synthetic route of beipedox acid, as follows:
  • This route uses cyanide compounds or ester compounds as raw materials, and reacts with 2,5-dibromopentane under alkali catalysis to obtain the compound of formula (II); the compound of formula (II) forms a Grignard reagent with magnesium, and then reacts with HCOOR
  • the compound of formula (III) is obtained by the reaction; the compound of formula (III) is hydrolyzed with base and acidified to obtain crizpedox acid.
  • the compound of formula (II) forms a Grignard reagent with magnesium, and then reacts with HCOOR to obtain the compound of formula (III).
  • the compound of formula (II) contains -COOR or -CN, it will react with the Grignard reagent, so the reaction yields The rate is low, the product purification is difficult, and as a pharmaceutical raw material, its quality standard is high, and the impurity content is less than or equal to 0.10%.
  • the main purpose of the present invention is to provide a method for synthesizing beipedox crude drug, so as to solve the problems of low yield, low purity and high cost in the existing synthesis method of beipedox.
  • the present invention provides a method for synthesizing a bepidoxic acid raw material drug, which comprises the following steps: an addition reaction occurs between an organozinc reagent (compound 1) and an aldehyde (compound 2) in an aprotic solvent to generate Compound 3, compound 3 is then hydrolyzed under alkaline conditions and then acidified to obtain crizpedox acid.
  • the reaction formula is as follows:
  • R is a C 1 -C 12 straight or branched chain alkyl group, preferably, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, isoamyl; more Preferably, R is methyl or ethyl.
  • the aprotic solvent is one or more of the group consisting of ethers, halogenated hydrocarbons, benzene, and toluene.
  • the aprotic solvent is one or more selected from the group consisting of tetrahydrofuran, 1,4-dioxane, dichloromethane, benzene, and toluene.
  • the base is selected from an alkali metal compound or an aqueous solution of an alkali metal compound
  • the alkali metal compound is selected from one or more of hydroxides, sodium alkoxides, potassium alkoxides or alkali metal carbonates, preferably, an alkali metal
  • the compound is selected from one or more of the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, lithium carbonate, sodium carbonate and potassium carbonate; preferably, the alkali metal compound is selected from hydroxide Lithium, sodium hydroxide, potassium hydroxide; preferably, the molar ratio of compound 3 to the base is 1:(2-6).
  • the organic zinc reagent (compound 1) is condensed to obtain 7-bromo-2,2 at a certain temperature and in the presence of a solvent by using alkyl isobutyrate and 1,5-dibromopentane as starting materials.
  • - Alkyl dimethyl heptanoate this compound reacts with zinc powder in the presence of a catalyst in an inert solvent to prepare an organozinc reagent.
  • the reaction formula is as follows:
  • the temperature is room temperature ⁇ 70 °C
  • the solvent is one or more of the group consisting of tetrahydrofuran, dichloromethane, chloroform, acetonitrile, benzene and toluene
  • the inert solvent is N,N-dimethylformamide
  • the catalyst is iodine (I 2 ), cuprous iodide (CuI) .
  • the aldehyde (compound 3) is condensed to obtain 7-vinyl-2,2-dimethylform by using alkyl isobutyrate and 1-bromopentene as starting materials at a certain temperature and in the presence of a solvent Alkyl heptanoate; reacts this compound with ozone to generate peroxides, which are directly reduced to aldehydes.
  • the reduction can be carried out by catalytic hydrogenation, zinc, sodium iodide, phosphine compounds, phosphorous acid, methyl sulfide and other methods.
  • the reaction formula is as follows:
  • the application of the technical solution of the present invention has the advantages of high product purity, high yield, convenient purification, low cost and easy industrialization.
  • the use of organozinc reagents to prepare bepidulic acid can greatly reduce reaction by-products and improve product yield and purity.
  • the existing synthetic methods of bepidulic acid have the problems of low yield, low purity, high cost and difficulty in industrialization.
  • the present application provides a method for synthesizing a raw material of bepidolic acid, which comprises: an addition reaction of an organozinc reagent (compound 1) and an aldehyde (compound 2) in an aprotic solvent , to generate compound 3, which is hydrolyzed under alkaline conditions and then acidified to obtain beipedox acid.
  • the reaction formula is as follows:
  • R is a C 1 -C 12 straight or branched chain alkyl group, preferably, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, isoamyl; more Preferably, R is methyl or ethyl.
  • organozinc reagents are not easy to react with groups such as acids, ketones, esters, etc., reducing the production of by-products and improving product purity and yield.
  • the aprotic solvent used in the above-mentioned synthesis method can adopt the kind commonly used in the art.
  • the solvent includes, but is not limited to, one or more of the group consisting of ethers, halogenated hydrocarbons, benzene, and toluene.
  • the solvent includes, but is not limited to, one or more of the group consisting of ethers, halogenated hydrocarbons, benzene, and toluene.
  • the solvent includes, but is not limited to, one or more of the group consisting of ethers, halogenated hydrocarbons, benzene, and toluene.
  • the group consisting of tetrahydrofuran, 1,4-dioxane, dichloromethane, benzene, and toluene are preferred.
  • the base is an alkali metal compound or an aqueous solution of an alkali metal compound, and the alkali metal compound can be selected from the types commonly used in the art.
  • the alkali metal compound includes but is not limited to one or more of hydroxide, sodium alkoxide, potassium alkoxide or alkali metal carbonate, preferably, the alkali metal compound is selected from lithium hydroxide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium methoxide, sodium ethoxide, lithium carbonate, sodium carbonate and potassium carbonate; more preferably, the alkali metal compound is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide;
  • the molar ratio of compound 3 to the base is 1:(2-6).
  • the molar ratio of compound 1 and compound 2 is 1:(1.0-1.5).
  • the molar ratio of compound 1 and compound 2 is 1:(1.0-1.3).
  • the molar ratio of compound 1 and compound 2 includes but is not limited to the above range, and limiting it to the above range is beneficial to improve the purity of compound 3.
  • the organic zinc reagent (compound 1) is obtained by taking alkyl isobutyrate and 1,5-dibromopentane as starting raw materials, and at a certain temperature, condensed in the presence of a solvent to obtain 7-bromo-2, Alkyl 2-dimethylheptanoate; the compound is in the presence of a catalyst in an inert solvent to react with zinc powder to prepare an organozinc reagent.
  • the reaction formula is as follows:
  • the temperature is from room temperature to 70°C, and the temperature includes but is not limited to the above range, and limiting it within the above range is conducive to further improving the yield of the organozinc reagent (compound 1).
  • the solvent can be the one commonly used in the art.
  • the solvent includes, but is not limited to, one or more of the group consisting of tetrahydrofuran, dichloromethane, chloroform, acetonitrile, benzene and toluene.
  • the inert solvent can be a kind commonly used in this field.
  • the solvent includes but is not limited to the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, ethers, halogenated hydrocarbons, benzene, toluene, and xylene.
  • the catalysts can be those commonly used in the art, and the catalysts include, but are not limited to, iodine (I 2 ) and cuprous iodide (CuI).
  • aldehyde (compound 2) is condensed to obtain 7-vinyl-2,2-diol by taking alkyl isobutyrate and 1-bromopentene as starting materials, at a certain temperature and in the presence of a solvent.
  • Alkyl methyl heptanoate reacts this compound with ozone to generate peroxides, which are directly reduced to aldehydes.
  • the reduction can be carried out by catalytic hydrogenation, zinc, sodium iodide, phosphine compounds, phosphorous acid, methyl sulfide and other methods.
  • the reaction formula is as follows:
  • the yield of synthesizing beipedox acid using the prior art is lower than the yield of the present application, and the purity of bepidoic acid does not meet the standard of pharmaceutical raw materials, so it cannot be used for medicinal purposes.
  • the use of the synthetic method provided by the application can greatly improve the yield, purity, and synthetic route cost of the raw material of Anlagenpedoxic acid. industrialization.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de synthèse d'un principe actif pharmaceutique d'acide bempédoïque. Le procédé de synthèse consiste à : soumettre un réactif d'organozinc (un composé 1) et de l'aldéhyde (un composé 2) à une réaction d'addition dans un solvant aprotique pour générer un composé 3, hydrolyser le composé 3 dans des conditions alcalines, puis réaliser une acidification pour obtenir de l'acide bempédoïque. La formule de réaction est telle que représentée dans le dessin, R étant un alkyle à chaîne droite ou à chaîne ramifiée en C1-C12, préférentiellement, R étant du méthyle, de l'éthyle, du n-propyle, de l'isopropyle, du n-butyle, du n-pentyle et de l'isopentyle, et plus préférentiellement, R étant du méthyle ou de l'éthyle. Par comparaison avec l'état de la technique, la solution technique de la présente invention présente les avantages d'une pureté de produit élevée, d'un rendement élevé, d'une purification simple, etc. L'utilisation du réactif d'organozinc dans la préparation de l'acide bempédoïque peut considérablement réduire les sous-produits de réaction et améliorer le rendement et la pureté du produit, et la voie de réaction présente un faible coût et est appropriée pour l'industrialisation.
PCT/CN2022/079806 2021-03-20 2022-03-08 Procédé de synthèse d'un principe actif pharmaceutique d'acide bempédoïque WO2022199378A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110298843.4 2021-03-20
CN202110298843.4A CN115108904A (zh) 2021-03-20 2021-03-20 贝派度酸原料药的合成方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115974689A (zh) * 2022-12-29 2023-04-18 华中农业大学 一种氚标记截短侧耳素及其合成方法
CN116836141A (zh) * 2023-07-19 2023-10-03 上海绿智创领医药科技有限公司 新的贝派度酸中间体及其制备方法和应用其合成贝派度酸的方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116120163B (zh) * 2022-12-30 2024-05-28 安徽艾立德制药有限公司 一种贝派地酸的合成方法及其中间体

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WO2004067489A2 (fr) * 2003-01-23 2004-08-12 Esperion Therapeutics, Inc. Composes hydroxyles et compositions de regulation du cholesterol et utilisations associees
WO2011053892A1 (fr) * 2009-10-31 2011-05-05 Martek Biosciences Corporation Synthèse et utilisation d'acides gras polyinsaturés à très longue chaîne (vlc-pufa) oméga-3 et oméga-6
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EP3666750A1 (fr) * 2018-12-10 2020-06-17 Sandoz AG Forme cristalline d'acide bempédoïque
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CN112479856A (zh) * 2021-01-18 2021-03-12 南京工业大学 一种贝派地酸的合成方法

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WO2004067489A2 (fr) * 2003-01-23 2004-08-12 Esperion Therapeutics, Inc. Composes hydroxyles et compositions de regulation du cholesterol et utilisations associees
WO2011053892A1 (fr) * 2009-10-31 2011-05-05 Martek Biosciences Corporation Synthèse et utilisation d'acides gras polyinsaturés à très longue chaîne (vlc-pufa) oméga-3 et oméga-6
EP3666750A1 (fr) * 2018-12-10 2020-06-17 Sandoz AG Forme cristalline d'acide bempédoïque
WO2020141419A2 (fr) * 2018-12-31 2020-07-09 Lupin Limited Nouveaux sels et formes polymorphes d'acide bempedoïque
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CN111825546A (zh) * 2020-07-11 2020-10-27 合肥市梓熤科技贸易有限公司 一种贝派地酸的合成方法
CN112479856A (zh) * 2021-01-18 2021-03-12 南京工业大学 一种贝派地酸的合成方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115974689A (zh) * 2022-12-29 2023-04-18 华中农业大学 一种氚标记截短侧耳素及其合成方法
CN116836141A (zh) * 2023-07-19 2023-10-03 上海绿智创领医药科技有限公司 新的贝派度酸中间体及其制备方法和应用其合成贝派度酸的方法

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