Method for preparing S-(-)-Benzoylthio-2-methylpropanoic acid compound

A technology of benzoyl mercapto and methylpropionic acid, which is applied in the field of synthesis of zofenopril intermediates, can solve the problems of high price of thiobenzoic acid, large environmental pollution, and low total yield, and achieve high yield High, cheap raw materials, less side effects

Inactive Publication Date: 2019-04-19
ZHEJIANG HUAHAI PHARMA CO LTD +2
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Problems solved by technology

[0006] So far, there are following two methods about the method for preparing S-(-)-benzoylmercapto-2-methylpropionic acid: 1. Thiobenzoic acid is first added with 2-methacrylic acid, and then resolved Obtain S-(-)-benzoyl mercapto-2-methyl propionic acid, this method raw material thiobenzoic acid is expensive, and side reaction is many in preparation process, and environmental pollution is big; Acrylic acid addition, then hydrolysis, condensation with benzoyl chloride, and finally S-(-)-benzoylmercapto-2-methylpropionic acid is obtained through resolution. There are many side reactions in the hydrolysis process of this method, and the total yield Low

Method used

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  • Method for preparing S-(-)-Benzoylthio-2-methylpropanoic acid compound

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example 1

[0021] Under the protection of nitrogen, add 21.5g of sodium hydroxide, 90mL of drinking water and 0.4g of zinc powder to the three-necked flask successively, cool down to 0°C, and slowly add 20g of S-(-)-3-acetylmercapto-2-methylpropionic acid dropwise , insulation reaction 3h. After the reaction, the pH was adjusted to 9.0 with concentrated hydrochloric acid. Control the feed liquid temperature to be 15°C, add dropwise 20g of benzoyl chloride and 36mL of 4mol / L sodium hydroxide aqueous solution. After the reaction, use concentrated hydrochloric acid to adjust the pH to 2.0, add 80 mL of ethyl acetate for extraction, and add 120 mL of n-heptane to the ethyl acetate layer, stir and crystallize for 4 hours, filter, and dry to obtain 19.4 g of S-(- )-benzoylmercapto-2-methylpropionic acid, yield: 71.9%, HPLC: purity: 99.90%, optical purity: 99.2%.

example 2

[0023] Under the protection of nitrogen, add 21.5g of sodium hydroxide, 90mL of drinking water and 0.2g of aluminum powder to the three-necked flask successively, cool down to 0°C, and slowly add 20g of S-(-)-3-acetylmercapto-2-methylpropionic acid dropwise , insulation reaction 3h. After the reaction, the pH was adjusted to 9.0 with concentrated hydrochloric acid. Control the feed liquid temperature to 15°C, add dropwise 22g p-toluoyl chloride and 36mL 4mol / L sodium hydroxide aqueous solution. After the reaction was finished, use concentrated hydrochloric acid to adjust the pH to 2.0, add 80 mL of ethyl acetate for extraction, and after layering, add 120 mL of n-heptane to the ethyl acetate layer, stir and crystallize for 4 hours, filter, and dry to obtain 19.2 g of S-(- )-benzoylmercapto-2-methylpropionic acid, yield: 66.7%, HPLC: purity: 99.0%, optical purity: 99.0%.

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Abstract

The invention discloses a method for preparing a S-(-)-Benzoylthio-2-methylpropanoic acid compound. S-(-)-3-acetylthio-2-methylpropionic acid as a raw material shown in the formula II is hydrolyzed ina reacting solvent to obtain S-(-)-3-mercapto-2-methylpropionic acid shown in hte formula III, and the S-(-)-3-mercapto-2-methylpropionic acid and benzoyl chloride are subjected to condensation to obtain the S-(-)-Benzoylthio-2-methylpropanoic acid shown in the formula I. The preparation method is easy in operation, the raw materials and accessory materials are low in cost and easy to obtain, thereaction conditions are mild, the yield is high, and the quality is high. (The formula is shown in the description.).

Description

technical field [0001] The invention relates to a synthetic method for preparing zofenopril intermediate. Background technique [0002] Zofenopril is an angiotensin-converting enzyme inhibitor containing a sulfhydryl group, which has a good effect on the treatment of hypertension, heart failure and acute myocardial infarction. Its structural formula is as follows: [0003] [0004] S-(-)-benzoylmercapto-2-methylpropionic acid is an important intermediate of zofenopril, and its structural formula is as shown in formula I: [0005] [0006] So far, there are following two methods about the method for preparing S-(-)-benzoylmercapto-2-methylpropionic acid: 1. Thiobenzoic acid is first added with 2-methacrylic acid, and then resolved Obtain S-(-)-benzoyl mercapto-2-methyl propionic acid, this method raw material thiobenzoic acid is expensive, and side reaction is many in preparation process, and environmental pollution is big; Acrylic acid addition, then hydrolysis, cond...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C327/32
CPCC07C319/02C07C327/32C07C323/52C07B2200/07
Inventor 张剑黄文锋金磊韩铮郑国喜
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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