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A method for enzymatically synthesizing cefprozil

A technology of cefprozil and enzymatic synthesis, which is applied in the field of medicine, can solve the problems of high cost and large pollution, and achieve the effect of convenient addition of raw materials, high purity, and suitable for industrial production

Active Publication Date: 2019-01-11
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 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

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 30g 7-APCA, 27g D-p-hydroxyphenylglycine methyl ester in a 500mL three-necked flask, add 300mL purified water, 24g penicillin acylase for synthesis, control the temperature at 18~22°C, stir the reaction, and measure 7 by HPLC after 3 hours. -APCA residues should be less than 1.5mg / mL. After passing the test, a 100-mesh sieve is used to separate the penicillin acylase and cefprozil crude product mixture. The cefprozil crude product mixture is filtered to obtain the cefprozil crude product and the filtrate. Wash and remove the penicillin acylase to obtain the enzyme reaction mother liquor, add the obtained enzyme reaction mother liquor and cefprozil crude product into a 2000mL four-neck flask, control the temperature at 5~10°C, add hydrochloric acid solution dropwise until the solution is clear, pH=0.4~0.6, Add 1400mL DMF, stir, adjust the pH value with ammonia water, add seed crystals, grow the crystals until the pH value is 5.8~6.2, control the crystal growth tempera...

Embodiment 2

[0029] Add 30g of 7-APCA, 28g of D-p-hydroxyphenylglycine ethyl ester in a 500mL three-necked flask, add 300mL of purified water, 36g of penicillin acylase for synthesis, control the temperature at 15~20°C, stir the reaction, and measure 7 by HPLC after 3 hours. -APCA residues 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. Wash and remove the penicillin acylase to obtain the enzyme reaction mother liquor, add the obtained mother liquor and crude cefprozil into a 2000mL four-neck flask, control the temperature at 5~10℃, add hydrochloric acid solution dropwise until the solution is clear, pH=0.4~0.6, add 1300mL DMF, stirring, adjusting the pH value with ammonia water, adding seed crystals, growing the crystals until the pH value is 6.0~6.4, controlling the crystal growth temperatu...

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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PUM

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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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Patent Type & Authority Patents(China)
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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