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Preparation method of high-purity ethyl 4-chloro-3-hydroxybutyrate

A technology of ethyl hydroxybutyrate and ethyl chloroacetoacetate, which is applied in the field of preparation of high-purity ethyl 4-chloro-3-hydroxybutyrate, can solve the problems of many impurities and low purity, so as to improve the purity and reduce the Concentration temperature, the effect of reducing the generation of impurities

Inactive Publication Date: 2018-08-07
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Ethyl 4-chloro-3-hydroxybutyrate is an intermediate of the drug oxiracetam for the treatment of senile dementia. Due to the new drug registration requirements in my country, the impurities of the drug intermediate must also be studied to study the whereabouts of the impurities and their impact on the finished product. According to The existing preparation method of ethyl 4-chloro-3-hydroxybutyrate has many impurities and low purity, the highest being only 84.9%

Method used

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  • Preparation method of high-purity ethyl 4-chloro-3-hydroxybutyrate
  • Preparation method of high-purity ethyl 4-chloro-3-hydroxybutyrate

Examples

Experimental program
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Embodiment 1

[0029] Add 50g of ethyl 4-chloroacetoacetate and 300ml of absolute ethanol into a 1L reaction flask, and cool down to -10°C. Add 3.0 g of sodium borohydride several times, and control the temperature at -10 to -5°C. After the addition, react at -10 to -5°C for 1 hour. After the reaction, add 10 g of anhydrous sodium sulfate, adjust the pH to neutral with glacial acetic acid, about 4 ml, and stir for 10 minutes.

[0030] Suction filtration to remove salt, the filtrate was concentrated under reduced pressure until no distillate was evaporated, and the temperature was lowered to 25-30°C. Add 200ml of dichloromethane and stir for 10 minutes, wash with 40*2ml of purified water twice, add 20g of anhydrous sodium sulfate to the organic phase and dry for 2 hours. Dichloromethane was distilled off by concentration to obtain crude 4-chloro-3-hydroxybutyric acid ethyl ester. Continue vacuum distillation to obtain the fine product of ethyl 4-chloro-3-hydroxybutyrate with a purity of 99...

Embodiment 2

[0032] Add 50g of ethyl 4-chloroacetoacetate and 300ml of absolute ethanol into a 1L reaction flask, and cool down to -10°C. Add 4.5 g of sodium borohydride several times, and control the temperature at -10 to -5°C. After the addition, react at -10 to -5°C for 1 hour. After the reaction, add 10 g of anhydrous sodium sulfate, adjust the pH to neutral with glacial acetic acid, about 4 ml, and stir for 10 minutes.

[0033] Suction filtration to remove salt, the filtrate was concentrated under reduced pressure until no distillate was evaporated, and the temperature was lowered to 25-30°C. Add 200ml of dichloromethane and stir for 10 minutes, wash with 40*2ml of purified water twice, add 20g of anhydrous sodium sulfate to the organic phase and dry for 2 hours. Dichloromethane was distilled off by concentration to obtain crude 4-chloro-3-hydroxybutyric acid ethyl ester. Continue vacuum distillation to obtain the fine product of ethyl 4-chloro-3-hydroxybutyrate with a purity of 99...

Embodiment 3

[0035] Add 50g of ethyl 4-chloroacetoacetate and 300ml of absolute ethanol into a 1L reaction flask, and cool down to -10°C. Add 7.8 g of sodium borohydride several times, and control the temperature at -10 to -5°C. After the addition, react at -10 to -5°C for 1 hour. After the reaction, add 10 g of anhydrous sodium sulfate, adjust the pH to neutral with glacial acetic acid, about 4 ml, and stir for 10 minutes.

[0036] Suction filtration to remove salt, the filtrate was concentrated under reduced pressure until no distillate was evaporated, and the temperature was lowered to 25-30°C. Add 200ml of dichloromethane and stir for 10 minutes, wash with 40*2ml of purified water twice, add 20g of anhydrous sodium sulfate to the organic phase and dry for 2 hours. Dichloromethane was distilled off by concentration to obtain crude 4-chloro-3-hydroxybutyric acid ethyl ester. Continue vacuum distillation to obtain the fine product of ethyl 4-chloro-3-hydroxybutyrate with a purity of 99...

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Abstract

The invention belongs to the field of drug preparation and particularly relates to a preparation method of high-purity ethyl 4-chloro-3-hydroxybutyrate. Ethyl 4-chloroacetoacetate is used as a raw material to carry out reacting with ethanol as a solvent and sodium borohydride as a reducing agent; the reacted liquid is dewatered, neutralizing with glacial acetic acid is performed until neutrality,filtering is performed to remove salts, vacuum concentration is performed, a solvent is added to carry out dissolving, washing with water is carried out to remove salts, concentrating is performed, and vacuum distillation is performed to obtain the high-purity ethyl 4-chloro-3-hydroxybutyrate. The ethyl 4-chloro-3-hydroxybutyrate is an intermediate of oxiracetam, a drug to treat senile dementia; as registration of new medicines in China requires research on impurities of pharmaceutical intermediates, namely research on impurity whereabouts and influence of impurities on products, the existingpreparation method of ethyl 4-chloro-3-hydroxybutyrate causes many impurities and low purity, only 84.9%; the preparation method has a reasonable ratio of materials, has good simplicity and low cost,and enables the purity to reach 99.5% and above and the yield to reach 90% and above, and the prepared samples may meet the requirements for medicine registration.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a preparation method of high-purity ethyl 4-chloro-3-hydroxybutyrate. Background technique [0002] Ethyl 4-chloro-3-hydroxybutyrate is an intermediate of oxiracetam, a drug for the treatment of senile dementia. Due to the new drug registration requirements in my country, the impurities of the drug intermediate must also be studied to study the whereabouts of impurities and their impact on the finished product. According to The existing preparation method of ethyl 4-chloro-3-hydroxybutyrate has many impurities and low purity, the highest being only 84.9%. Contents of the invention [0003] Aiming at the deficiencies in the prior art, the purpose of the present invention is to provide a preparation method of high-purity 4-chloro-3-hydroxybutyric acid ethyl ester, the ratio of raw materials is reasonable, the process is simple, the cost is low, the purity reaches mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/31C07C67/48C07C69/675
CPCC07C67/31C07C67/48C07C69/675
Inventor 贺新恒郑忠辉蒋涛郭统山贺维昊蒋泽宇
Owner SHANDONG XINHUA PHARMA CO LTD
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