WO2022199378A1 - Synthetic method of bempedoic acid active pharmaceutical ingredient - Google Patents

Synthetic method of bempedoic acid active pharmaceutical ingredient Download PDF

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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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compound
solvent
synthetic method
alkali metal
sodium
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PCT/CN2022/079806
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Chinese (zh)
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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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    • 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.

Abstract

The present invention provides a synthetic method of a bempedoic acid active pharmaceutical ingredient. The synthetic method comprises: subjecting an organozinc reagent (a compound 1) and aldehyde (a compound 2) to an addition reaction in an aprotic solvent to generate a compound 3, hydrolyzing the compound 3 under alkaline conditions, and then performing acidification to obtain bempedoic acid. The reaction formula is as shown in the drawing, wherein R is C1-C12 straight-chain or branched-chain alkyl, preferably, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, and isopentyl, and more preferably, R is methyl or ethyl. Compared with the prior art, the technical solution of the present invention has the advantages of high product purity, high yield, easy purification, etc. The use of the organozinc reagent in preparation of bempedoic acid can greatly reduce reaction by-products and improve the product yield and purity, and the reaction route has low cost and is convenient for industrialization.

Description

贝派度酸原料药的合成方法The synthetic method of beipedox acid raw material medicine 技术领域technical field
本发明涉及有机合成领域，具体而言，涉及一种贝派度酸原料药的合成方法。The invention relates to the field of organic synthesis, in particular, to a method for synthesizing a bepidoxic acid crude drug.
背景技术Background technique
贝派度酸是一种小分子三磷酸腺苷-柠檬酸裂解酶抑制剂，相对于现有的他汀类药物，其耐受性较好，且与他汀类药物联用可用于控制低密度脂蛋白胆固醇的升高，其结构式如下：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:
Figure PCTCN2022079806-appb-000001
Figure PCTCN2022079806-appb-000001
专利申请CN111825546A公开了贝派度酸的合成路线，如下所示：Patent application CN111825546A discloses the synthetic route of beipedox acid, as follows:
Figure PCTCN2022079806-appb-000002
Figure PCTCN2022079806-appb-000002
该路线采用氰化合物或酯类化合物作为原料，在碱催化下，与2,5-二溴戊烷反应得到式(Ⅱ)化合物；式(Ⅱ)化合物与镁形成格氏试剂，再与HCOOR发生反应得到式(Ⅲ)化合物；式(Ⅲ)化合物经碱水解并酸化得到贝派度酸。该路线中式(Ⅱ)化合物与镁形成格氏试剂，再与HCOOR发生反应得到式(Ⅲ)化合物，因式(Ⅱ)化合物中含有-COOR或-CN，其会与格式试剂反应，因此反应收率低，产品纯化困难，而作为医药原料药，其质量标准高，杂质含量≤0.10％。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 beipedox acid. In this route, the compound of formula (II) forms a Grignard reagent with magnesium, and then reacts with HCOOR to obtain the compound of formula (III). Because 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%.
此外，专利WO2004067489，CN111170855A，CN111285760A公开的路线存在成本高，不易于产业化的问题。In addition, the routes disclosed in patents WO2004067489, CN111170855A, and CN111285760A have problems of high cost and difficulty in industrialization.
鉴于上述问题的存在，有必要提供一种收率高，产品便于纯化，纯度高且成本低和易于产业化的贝派度酸原料药的合成方法。In view of the existence of the above-mentioned problems, it is necessary to provide a method for synthesizing the raw material of beipedox with high yield, easy purification of the product, high purity, low cost and easy industrialization.
发明内容SUMMARY OF THE INVENTION
本发明的主要目的在于提供一种贝派度酸原料药的合成方法，以解决现有的贝派度酸的合成方法存在收率低、纯度低、成本高的问题。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.
为了实现上述目的，本发明提供了一种贝派度酸原料药的合成方法，包括以下步骤：有机锌试剂(化合物1)和醛(化合物2)在非质子性溶剂中发生加成反应，生成化合物 3，化合物3再在碱性条件下水解然后经酸化得到贝派度酸。反应式如下所示：In order to achieve the above purpose, 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 beipedox acid. The reaction formula is as follows:
Figure PCTCN2022079806-appb-000003
Figure PCTCN2022079806-appb-000003
其中，R为C 1～C 12的直链或支链烷基，优选地，R为甲基、乙基、正丙基、异丙基、正丁基、正戊基、异戊基；更优选地，R为甲基或乙基。 wherein, 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.
进一步地，非质子性溶剂为醚类、卤代烃、苯、甲苯组成的组中的一种或多种。Further, the aprotic solvent is one or more of the group consisting of ethers, halogenated hydrocarbons, benzene, and toluene.
进一步地，非质子性溶剂为四氢呋喃、1,4-二氧六环、二氯甲烷、苯、甲苯组成的组中的一种或多种。Further, the aprotic solvent is one or more selected from the group consisting of tetrahydrofuran, 1,4-dioxane, dichloromethane, benzene, and toluene.
进一步地，碱选自碱金属化合物或碱金属化合物的水溶液，碱金属化合物选自氢氧化物、醇钠、醇钾或碱金属的碳酸盐中的一种或多种，优选地，碱金属化合物选自氢氧化锂、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、碳酸锂、碳酸钠和碳酸钾组成的组中的一种或多种；优选地，碱金属化合物选自氢氧化锂、氢氧化钠、氢氧化钾；优选地，化合物3与碱的摩尔比为1:(2～6)。Further, the base is selected from an alkali metal compound or an aqueous solution of an alkali metal compound, and 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).
进一步地，有机锌试剂(化合物1)经由以异丁酸烷基酯和1，5-二溴戊烷为起始原料，在一定温度下，溶剂存在条件下缩合得到7-溴-2,2-二甲基庚酸烷基酯；该化合物在惰性溶剂中，催化剂存在条件下和锌粉作用制得有机锌试剂。反应式如下所示：Further, 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:
Figure PCTCN2022079806-appb-000004
Figure PCTCN2022079806-appb-000004
进一步地，温度为室温～70℃，溶剂为四氢呋喃、二氯甲烷、三氯甲烷、乙腈、苯和甲苯组成的组中的一种或多种；惰性溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、醚类、卤代烃、苯、甲苯、二甲苯组成的组中的一种或多种；催化剂为碘(I 2)、碘化亚铜(CuI)。 Further, the temperature is room temperature～70 ℃, and 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 One or more of the group consisting of , N,N-dimethylacetamide, ethers, halogenated hydrocarbons, benzene, toluene, and xylene; the catalyst is iodine (I 2 ), cuprous iodide (CuI) .
进一步地，醛(化合物3)经由以异丁酸酸烷基酯和1-溴戊烯为起始原料，在一定温度下，溶剂存在条件下缩合得到7-乙烯基-2,2-二甲基庚酸烷基酯；将该化合物与臭氧反应，先生成过氧化物，直接将其还原为醛。还原可用催化氢化、锌、碘化钠、磷化氢类化合物、亚磷酸、甲硫醚等方法。反应式如下所示：Further, 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:
Figure PCTCN2022079806-appb-000005
Figure PCTCN2022079806-appb-000005
应用本发明的技术方案，相对于现有技术，具有产品纯度高，收率高，便于纯化，成本低和易于产业化等优点。利用有机锌试剂制备贝派度酸，可大幅减少反应副产物，提高产品收率和纯度。Compared with the prior art, 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.
具体实施方式Detailed ways
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。It should be noted that the embodiments in the present application and the features of the embodiments may be combined with each other in the case of no conflict. The present invention will be described in detail below with reference to the embodiments.
正如背景技术所描述的，现有的贝派度酸的合成方法存在收率低，纯度低，成本高和不易于产业化的问题。为了解决上述技术问题，本申请提供了一种贝派度酸原料药的合成方法，该合成方法包括：有机锌试剂(化合物1)和醛(化合物2)在非质子性溶剂中发生加成反应，生成化合物3，化合物3再在碱性条件下水解然后经酸化得到贝派度酸。反应式如下所示：As described in the background art, the existing synthetic methods of bepidulic acid have the problems of low yield, low purity, high cost and difficulty in industrialization. In order to solve the above-mentioned technical problems, 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:
Figure PCTCN2022079806-appb-000006
Figure PCTCN2022079806-appb-000006
其中，R为C 1～C 12的直链或支链烷基，优选地，R为甲基、乙基、正丙基、异丙基、正丁基、正戊基、异戊基；更优选地，R为甲基或乙基。 wherein, 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.
与格式试剂相比，有机锌试剂不易与酸、酮、酯等基团反应，减少副产物的产生，提高产品纯度和收率。Compared with Grignard reagents, 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.
上述合成方法中采用的非质子性溶剂可以采用本领域常用的种类。在一种优选的实施例中，溶剂包括但不限于醚类、卤代烃、苯、甲苯组成的组中的一种或多种。综合成本因素考虑，优选四氢呋喃、1,4-二氧六环、二氯甲烷、苯、甲苯组成的组中的一种或多种。The aprotic solvent used in the above-mentioned synthesis method can adopt the kind commonly used in the art. In a preferred embodiment, the solvent includes, but is not limited to, one or more of the group consisting of ethers, halogenated hydrocarbons, benzene, and toluene. Considering the overall cost factor, one or more of the group consisting of tetrahydrofuran, 1,4-dioxane, dichloromethane, benzene, and toluene are preferred.
上述合成方法中碱为碱金属化合物或碱金属化合物的水溶液，碱金属化合物可以选用本领域常用的种类。优选地，碱金属化合物包括但不限于氢氧化物、醇钠、醇钾或碱金属的碳酸盐中的一种或多种，优选地，碱金属化合物选自氢氧化锂、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、碳酸锂、碳酸钠和碳酸钾组成的组中的一种或多种；更优选地，碱金属化合 物选自氢氧化锂、氢氧化钠、氢氧化钾；优选地，化合物3与碱的摩尔比为1:(2～6)。In the above synthesis method, 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. Preferably, 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; Preferably, the molar ratio of compound 3 to the base is 1:(2-6).
在一种优选的实施例中，化合物1和化合物2的摩尔比为1：(1.0～1.5)。优选地，化合物1和化合物2的摩尔比为1：(1.0～1.3)。化合物1和化合物2的摩尔比包括但不限于上述范围，而将其限定在上述范围内有利于提高化合物3的纯度。In a preferred embodiment, the molar ratio of compound 1 and compound 2 is 1:(1.0-1.5). Preferably, 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.
上述合成方法中有机锌试剂(化合物1)经由以异丁酸烷基酯和1，5-二溴戊烷为起始原料，在一定温度下，溶剂存在条件下缩合得到7-溴-2,2-二甲基庚酸烷基酯；该化合物在惰性溶剂中，催化剂存在条件下和锌粉作用制得有机锌试剂。反应式如下所示：In the above-mentioned synthetic method, 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:
Figure PCTCN2022079806-appb-000007
Figure PCTCN2022079806-appb-000007
在一种优选的实施例中，温度为室温～70℃，温度包括但不限于上述范围，而将其限定在上述范围内有利于进一步提高有机锌试剂(化合物1)的收率。所述的溶剂可以采用本领域常用的种类。在一种优选的实施例中，溶剂包括但不限于四氢呋喃、二氯甲烷、三氯甲烷、乙腈、苯和甲苯组成的组中的一种或多种。所述惰性溶剂可以采用本领域常用的种类。在一种优选的实施例中，溶剂包括但不限于N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、醚类、卤代烃、苯、甲苯、二甲苯组成的组中的一种或多种；所述催化剂可以采用本领域常用的种类，催化剂包括但不限于催化剂为碘(I 2)、碘化亚铜(CuI)。 In a preferred embodiment, 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. In a preferred embodiment, 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. In a preferred embodiment, 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. One or more of the catalysts; 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).
上述合成方法中醛(化合物2)经由以异丁酸酸烷基酯和1-溴戊烯为起始原料，在一定温度下，溶剂存在条件下缩合得到7-乙烯基-2,2-二甲基庚酸烷基酯；将该化合物与臭氧反应，先生成过氧化物，直接将其还原为醛。还原可用催化氢化、锌、碘化钠、磷化氢类化合物、亚磷酸、甲硫醚等方法。反应式如下所示：In the above-mentioned synthetic method, 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:
Figure PCTCN2022079806-appb-000008
Figure PCTCN2022079806-appb-000008
以下结合具体实施例对本申请作进一步详细描述，这些实施例不能理解为限制本申请所要求保护的范围。The present application will be described in further detail below with reference to specific embodiments, which should not be construed as limiting the scope of protection claimed by the present application.
实施例17-溴-2,2-二甲基庚酸乙酯的制备Example 17 Preparation of ethyl bromo-2,2-dimethylheptanoate
在500mL单口瓶中加入二异丙胺21g(0.208mol),四氢呋喃50mL,在氮气保护下，降温至0℃，滴加正丁基锂(0.208mol)，滴加完后搅拌10～20min,然后再滴加20g异丁酸乙酯 (0.172mol),43.5g 5-二溴戊烷(0.189mol)，反应过夜，TLC检测反应完全，向反应液中加水/乙酸乙酯萃取，无水硫酸钠干燥，得到53g淡青色液体。将液体蒸馏得到产物41g。收率90％，纯度97％。Add 21 g (0.208 mol) of diisopropylamine and 50 mL of tetrahydrofuran to a 500 mL single-necked bottle, under nitrogen protection, cool down to 0 °C, add n-butyllithium (0.208 mol) dropwise, stir for 10 to 20 min after the dropwise addition, and then add Add dropwise 20g ethyl isobutyrate (0.172mol), 43.5g 5-dibromopentane (0.189mol), react overnight, TLC detects that the reaction is complete, add water/ethyl acetate to the reaction solution for extraction, and dry over anhydrous sodium sulfate , 53g of light blue liquid was obtained. The liquid was distilled to obtain 41 g of the product. The yield is 90% and the purity is 97%.
实施例27-溴锌-2,2-二甲基庚酸乙酯的制备Example 27 Preparation of ethyl bromozinc-2,2-dimethylheptanoate
向反应器中加入锌粉15mmol，通氮气除氧，在氮气保护下，加入碘0.5mmol和8mL无水DMA，常温下搅拌2～3min后加入7-溴-2,2-二甲基庚酸乙酯10mmol和8mL无水DMA，然后升温至80℃下搅拌3h，停止反应并于室温下静置至溶液澄清。Add 15 mmol of zinc powder to the reactor, pass nitrogen to remove oxygen, under nitrogen protection, add 0.5 mmol of iodine and 8 mL of anhydrous DMA, stir at room temperature for 2-3 min, and then add 7-bromo-2,2-dimethylheptanoic acid 10 mmol of ethyl ester and 8 mL of anhydrous DMA were then heated to 80 °C and stirred for 3 h, the reaction was stopped and the solution was allowed to stand at room temperature until the solution was clear.
实施例37-乙烯基-2,2-二甲基庚酸乙酯Example 37-ethyl vinyl-2,2-dimethylheptanoate
在500mL单口瓶中加入二异丙胺21g(0.208mol),四氢呋喃50mL,在氮气保护下降温至0℃，滴加0.208mol正丁基锂，滴加完后搅拌10～20min,然后再滴加20g异丁酸乙酯(0.172mol),33.5g 1-溴戊烯，反应过夜，TLC检测反应完全，向反应液中加水/乙酸乙酯萃取，无水硫酸钠干燥，得到34.3g无色液体。收率94％。Add 21 g (0.208 mol) of diisopropylamine and 50 mL of tetrahydrofuran to a 500 mL single-necked bottle, and under nitrogen protection, the temperature is lowered to 0 °C, and 0.208 mol of n-butyllithium is added dropwise. Ethyl isobutyrate (0.172mol), 33.5g of 1-bromopentene, reacted overnight, TLC detected that the reaction was complete, added water/ethyl acetate to the reaction solution for extraction, and dried over anhydrous sodium sulfate to obtain 34.3g of colorless liquid. Yield 94%.
实施例48-氧代-2,2-二甲基辛酸乙酯Example 48-ethyl oxo-2,2-dimethyloctanoate
在-78℃条件下，向500mL单口瓶中加入100mL二氯甲烷，7-乙烯基-2,2-二甲基庚酸乙酯，向溶液中通入臭氧，待反应完全后通入氮气除去臭氧，然后添加60mL的二甲基硫醚。将混合物放置过夜，用硫酸钠干燥。在低真空下除去溶剂和DMS，得到8-氧代-2,2-二甲基辛酸乙酯。用饱和的氯化钠溶液洗涤，并经过无水硫酸钠干燥，然后在硅胶色谱柱上纯化，洗脱剂为己烷/乙酸乙酯9:1。得到38.3g的8-氧代-2,2-二甲基辛酸乙酯，收率90％。At -78°C, add 100 mL of dichloromethane and 7-vinyl-2,2-dimethylheptanoic acid ethyl ester to a 500 mL single-necked bottle, pass ozone into the solution, and pass nitrogen to remove after the reaction is complete. ozone, then 60 mL of dimethyl sulfide was added. The mixture was left overnight and dried over sodium sulfate. The solvent and DMS were removed under low vacuum to give ethyl 8-oxo-2,2-dimethyloctanoate. It was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified on a silica gel column, eluent hexane/ethyl acetate 9:1. 38.3 g of ethyl 8-oxo-2,2-dimethyloctanoate were obtained with a yield of 90%.
实施例5贝派度酸Example 5 Bepidoic acid
在500mL单口瓶中加入四氢呋喃150mL，0.1mol(20.0g)8-氧代-2,2-二甲基辛酸乙酯，在氮气保护下降温至5℃以下，滴加0.11mol(36.36g)7-溴锌-2,2-二甲基庚酸乙酯，反应2h，TLC检测反应完全，向反应液中加1M的盐酸和100mL乙酸乙酯，分离有机相，有机相用盐水洗涤，然后用无水硫酸镁干燥。除去溶剂，得到化合物3，然后再向化合物3中加入100mL的乙醇，6mol氢氧化钠20mL，室温反应完全，加入去离子水50mL，用1M的盐酸调pH至2-3，在0-5℃搅拌1h析晶，过滤，真空干燥，得到32.7g的贝派度酸，收率95％，纯度99.93％。Add 150 mL of tetrahydrofuran and 0.1 mol (20.0 g) of 8-oxo-2,2-dimethyloctanoic acid ethyl ester to a 500 mL single-necked bottle, and under nitrogen protection, the temperature is below 5 °C, and 0.11 mol (36.36 g) of 7 -Bromozinc-2,2-dimethylheptanoic acid ethyl ester, reacted for 2h, TLC detected that the reaction was complete, 1M hydrochloric acid and 100mL ethyl acetate were added to the reaction solution, the organic phase was separated, the organic phase was washed with brine, and then Dry over anhydrous magnesium sulfate. Remove the solvent to obtain compound 3, and then add 100 mL of ethanol and 20 mL of 6mol sodium hydroxide to compound 3. The reaction is complete at room temperature, add 50 mL of deionized water, and adjust the pH to 2-3 with 1M hydrochloric acid. It was stirred for 1 hour for crystallization, filtered, and dried in vacuo to obtain 32.7 g of bepidulic acid with a yield of 95% and a purity of 99.93%.
1H-NMR(400MHz,CDCl 3)4.13-4.12(m,1H),1.45-1.42(m,4H),1.27-1.24(m,16H),1.06(s,12H). 1 H-NMR (400 MHz, CDCl 3 ) 4.13-4.12 (m, 1H), 1.45-1.42 (m, 4H), 1.27-1.24 (m, 16H), 1.06 (s, 12H).
M/Z＝343.2(M-H) -。 M/Z=343.2 (MH) − .
对比例1Comparative Example 1
根据文献CN111825546A的合成方法制备贝派度酸，总收率74％，纯度99.0％。According to the synthetic method of document CN111825546A, beipedox acid was prepared, the total yield was 74%, and the purity was 99.0%.
从对比实施例的结果可以看出：采用现有技术合成贝派度酸收率低于本申请的收率，且贝派度酸的纯度不符合医药原料药的标准，无法用作药物用途。As can be seen from the results of the comparative examples: 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.
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：采用本申请提供的合成方法能够大大提高贝派度酸原料药的收率，纯度，合成路线成本低，易于产业化。From the above description, it can be seen that the above-mentioned embodiments of the present invention have achieved the following technical effects: 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 beipedoxic acid. industrialization.
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (7)

  1. 一种贝派度酸原料药的合成方法，包括以下步骤：A method for synthesizing beipedox crude drug, comprising the following steps:
    有机锌试剂(化合物1)和醛(化合物2)在非质子性溶剂中发生加成反应，生成化合物3，化合物3再在碱性条件下水解然后经酸化得到贝派度酸；反应式如下所示：Organozinc reagent (compound 1) and aldehyde (compound 2) undergo an addition reaction 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 Show:
    Figure PCTCN2022079806-appb-100001
    Figure PCTCN2022079806-appb-100001
    其中，R为C 1～C 12的直链或支链烷基，优选地，R为甲基、乙基、正丙基、异丙基、正丁基、正戊基、异戊基；更优选地，R为甲基或乙基。 wherein, 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.
  2. 如权利要求1所示的合成方法，其特征在于，所述非质子性溶剂为醚类、卤代烃、苯、甲苯组成的组中的一种或多种；更优选地，所述的非质子性溶剂为四氢呋喃、1,4-二氧六环、二氯甲烷、苯、甲苯组成的组中的一种或多种。The synthetic method as claimed in claim 1, wherein the aprotic solvent is one or more selected from the group consisting of ethers, halogenated hydrocarbons, benzene, and toluene; more preferably, the non-protic solvent is The protic solvent is one or more selected from the group consisting of tetrahydrofuran, 1,4-dioxane, dichloromethane, benzene, and toluene.
  3. 如权利要求1所示的合成方法，其特征在于，所述的碱选自碱金属化合物或碱金属化合物的水溶液，碱金属化合物选自氢氧化物、醇钠、醇钾或碱金属的碳酸盐中的一种或多种，优选地，碱金属化合物选自氢氧化锂、氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、碳酸锂、碳酸钠和碳酸钾组成的组中的一种或多种；优选地，碱金属化合物选自氢氧化锂、氢氧化钠、氢氧化钾；优选地，化合物3与碱的摩尔比为1:(2～6)。The synthetic method as claimed in claim 1, wherein the alkali is selected from an aqueous solution of an alkali metal compound or an alkali metal compound, and the alkali metal compound is selected from a hydroxide, a sodium alkoxide, a potassium alkoxide or an alkali metal carbonic acid One or more of the salts, preferably, the alkali metal compound is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, lithium carbonate, sodium carbonate and potassium carbonate or more; preferably, the alkali metal compound is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide; preferably, the molar ratio of compound 3 to the base is 1:(2-6).
  4. 如权利要求1所示的合成方法，其特征在于，化合物1和化合物2的摩尔比为1：(1.0～1.5)；优选地，化合物1和化合物2的摩尔比为1：(1.0～1.3)。The synthesis method according to claim 1, wherein the molar ratio of compound 1 and compound 2 is 1:(1.0-1.5); preferably, the molar ratio of compound 1 and compound 2 is 1:(1.0-1.3) .
  5. 如权利要求1所示的合成方法，其特征在于，所述有机锌试剂(化合物1)经由以异丁酸烷基酯和1，5-二溴戊烷为起始原料，在一定温度下，溶剂存在条件下缩合得到7-溴-2,2-二甲基庚酸烷基酯；该化合物在惰性溶剂中，催化剂存在条件下和锌粉作用制得有机锌试剂；反应式如下所示：The synthetic method as claimed in claim 1, wherein the organozinc reagent (compound 1) takes alkyl isobutyrate and 1,5-dibromopentane as starting materials, and at a certain temperature, Condensation in the presence of a solvent obtains alkyl 7-bromo-2,2-dimethylheptanoate; the compound is reacted with zinc powder in an inert solvent in the presence of a catalyst to obtain an organozinc reagent; the reaction formula is as follows:
    Figure PCTCN2022079806-appb-100002
    Figure PCTCN2022079806-appb-100002
  6. 如权利要求5所示的合成方法，其特征在于，所述温度为室温～70℃，溶剂为四氢呋喃、二氯甲烷、三氯甲烷、乙腈、苯和甲苯组成的组中的一种或多种；惰性溶剂为N,N-二 甲基甲酰胺、N,N-二甲基乙酰胺、醚类、卤代烃、苯、甲苯、二甲苯组成的组中的一种或多种；催化剂为碘(I 2)、碘化亚铜(CuI)。 The synthetic method as claimed in claim 5, wherein the temperature is from room temperature to 70°C, and the solvent is one or more selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, acetonitrile, benzene and toluene ; The inert solvent is one or more of the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, ethers, halogenated hydrocarbons, benzene, toluene and xylene; the catalyst is Iodine (I 2 ), cuprous iodide (CuI).
  7. 如权利要求1所示的合成方法，其特征在于，所述醛(化合物3)经由以异丁酸酸烷基酯和1-溴戊烯为起始原料，在一定温度下，溶剂存在条件下缩合得到7-乙烯基-2,2-二甲基庚酸烷基酯；将该化合物与臭氧反应，先生成过氧化物，直接将其还原为醛；还原可用催化氢化、锌、碘化钠、磷化氢类化合物、亚磷酸、甲硫醚等方法；反应式如下所示：The synthetic method as claimed in claim 1, wherein the aldehyde (compound 3) takes alkyl isobutyrate and 1-bromopentene as starting materials, at a certain temperature, in the presence of a solvent Condensation to obtain 7-vinyl-2,2-dimethylheptanoic acid alkyl ester; react this compound with ozone to first generate peroxide, which is directly reduced to aldehyde; reduction can be achieved by catalytic hydrogenation, zinc, sodium iodide , phosphine compounds, phosphorous acid, methyl sulfide and other methods; the reaction formula is as follows:
    Figure PCTCN2022079806-appb-100003
    Figure PCTCN2022079806-appb-100003
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