Method for synthesizing cefprozil through enzymatic method

A technology for cefprozil and enzymatic synthesis, which is applied in the field of medicine, can solve problems such as high cost and large pollution, and achieve the effects of convenient addition of raw materials, high purity, and simple and easy preparation method.

Active Publication Date: 2016-03-02
苏州盛达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many ways to synthesize cefprozil, but before this century, they were all chemical synthesis methods. The preparation process used many raw materials and auxiliary materials, and a larg

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 30g of 7-APCA, 27g of D-p-hydroxyphenylglycine methyl ester into a 500mL three-necked flask, add 300mL of purified water, 24g of penicillin acylase for synthesis, control the temperature at 18~22°C, stir the reaction, and measure 7-APCA by HPLC after 3 hours Residue should be less than 1.5mg / mL. After passing the test, use a 100-mesh sieve to separate to obtain a mixture of penicillin acylase and cefprozil crude product. The crude cefprozil mixture is filtered to obtain cefprozil crude product and filtrate, and the filtrate is removed by repeated washing. After penicillin acylase, the enzyme reaction mother liquor was obtained, and the obtained enzyme reaction mother liquor and cefprozil crude product were added into a 2000mL four-neck flask, the temperature was controlled at 5~10°C, hydrochloric acid solution was added dropwise until the solution was clear, pH=0.4~0.6, and 1400mL DMF was added , stir, adjust the pH value with ammonia water, add seed crystals, grow t...

Embodiment 2

[0029] Add 30g of 7-APCA, 28g of D-p-hydroxyphenylglycine ethyl ester into a 500mL three-necked flask, add 300mL of purified water, and 36g of penicillin acylase for synthesis, control the temperature at 15~20°C, stir the reaction, and measure 7-APCA by HPLC after 3 hours The residue should be less than 1.5mg / mL. After passing the test, use a 120-mesh screen to separate to obtain a mixture of penicillin acylase and cefprozil crude product. The crude product mixture of cefprozil is filtered to obtain crude cefprozil and filtrate, and the filtrate is removed by repeated washing. After penicillin acylase, the enzyme reaction mother liquor was obtained, and the obtained mother liquor and cefprozil crude product were added into a 2000mL four-neck flask, the temperature was controlled at 5~10°C, and hydrochloric acid solution was added dropwise until the solution was clear, pH=0.4~0.6, and 1300mL DMF was added, and stirred , adjust the pH value with ammonia water, add seed crystals, ...

Embodiment 3

[0032] The reaction conditions are basically the same as those in Example 1, except that the penicillin acylase recovered in Example 1 is used to adjust the pH to 7.0-7.8 with ammonia water, and the reaction temperature is controlled at 15-25°C for activation. The molar yield of the cefprozil finished product of the present embodiment is 78%, the purity is 99.5%, and the appearance is white.

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Abstract

The invention relates to a method for synthesizing cefprozil through an enzymatic method. According to the method, a cefprozil parent nucleus, D-para hydroxybenzene glycine methyl ester and/or D-para hydroxybenzene glycine ethyl ester, water and penicillin acylase react at the temperature of 10 DEG C-25 DEG C to obtain a crude cefprozil product and enzyme reaction mother liquor, the temperature is controlled to be 0 DEG C-15 DEG C, a pH value is controlled to be 0.2-0.8, N,N-dimethyl formamide is added, the mixture is stirred uniformly, a seed crystal is added for crystal growing, the pH value is adjusted to be 5.5-6.5, and the temperature is controlled to be 10 DEG C-30 DEG C to obtain a cefprozil N,N-dimethyl formamide compound; the temperature is controlled to be 0 DEG C-25 DEG C, water and the cefprozil N,N-dimethyl formamide compound are added into a reactor, the mixture is stirred for crystal transformation for 1-4.5 h, and then filtering, washing, swabbing-off and drying are carried out to obtain a finished cefprozil product. The cefprozil is high in product yield and high in purity, appearance is white, the preparing method is simple and easy to implement, the condition is mild, and the method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for enzymatically synthesizing cefprozil. Background technique [0002] Cefprozil is a third-generation oral broad-spectrum cephalosporin antibiotic, which was developed by Bristol-Myers Company of the United States and the Tokyo Research Institute, and was approved by the FDA in December 1992. There are many ways to synthesize cefprozil, but before this century, they were all chemical synthesis methods. The preparation process used many raw materials and auxiliary materials, and a large amount of solvents such as dichloromethane and acetone were used. The reaction conditions were also relatively harsh, often requiring -50 Low temperature below ℃, high cost and heavy pollution. After entering the 21st century, with the development of biotechnology and the breakthrough of enzyme gene modification technology, the use of biosynthesis technology to replace trad...

Claims

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Application Information

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IPC IPC(8): C12P35/04
CPCC12P35/04
Inventor 周自金罗新祖钱志勇汪飞强刘要武张波钟建西张群芳
Owner 苏州盛达药业有限公司
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