A method for enzymatically synthesizing cefaclor

A technology for cefaclor and enzymatic synthesis, which is applied in the field of pharmaceutical and chemical production, and can solve the problems of low enzyme reuse times and insufficient cefaclor purity.

Active Publication Date: 2022-05-24
TIANJIN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Aiming at the problem that the purity of cefaclor is not high enough and the number of times of enzyme reuse is low in the existing bio-enzyme synthesis of cefaclor, the present invention provides a method for enzymatically synthesizing cefaclor

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  • A method for enzymatically synthesizing cefaclor

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Embodiment 1

[0041] A method for enzymatic synthesis of cefaclor:

[0042]Step 1. At 10°C, add 60.0 g of 7-amino-3-chloro-cephem acid and 450 mL of mixed solvent to the reaction flask, adjust the pH to 8.1-8.3 with purified ammonia with a mass concentration of 18 wt%, and add immobilized penicillin Acylase 30g, add the side chain mixture of 19g D-p-phenylglycine methyl ester hydrochloride and 31.5g D-phenylglycine methyl ester, react at 20°C for 100min, after the reaction is completed, separate the reaction solution and immobilized cefaclor Synthesize enzyme to obtain the crude cefaclor; wash the immobilized penicillin acylase with 90 mL of the above mixed solution for 3 times, and mix the washing solution with the separated crude cefaclor to obtain the cefaclor crude suspension;

[0043] Wherein, the mixed solvent includes the following components by mass percentage: methanol 3%, glutaraldehyde 0.5%, disodium hydrogen phosphate 0.3%, water 96.2%;

[0044] The way of adding the side chain...

Embodiment 2

[0052] A method for enzymatic synthesis of cefaclor:

[0053] Step 1. At 10°C, add 60.0 g of 7-amino-3-chloro-cephem acid and 550 mL of mixed solvent to the reaction flask, adjust the pH to 8.1-8.3 with purified ammonia with a mass concentration of 20 wt%, and add immobilized penicillin Acylase 15g, add the side chain mixture of 20.2g D-p-phenylglycine methyl ester hydrochloride and 30.6g D-phenylglycine methyl ester at one time, react at 15°C for 150min, after the reaction is completed, separate the reaction solution and fix Cefaclor synthase was synthesized to obtain crude cefaclor; the immobilized penicillin acylase was washed three times with 90 mL of the above mixed solution, and the washing solution was mixed with the separated crude cefaclor to obtain a suspension of cefaclor crude ;

[0054] Wherein, the mixed solvent includes the following components by mass percentage: methanol 0.5%, glutaraldehyde 0.8%, disodium hydrogen phosphate 1%, water 97.7%;

[0055] Step 2,...

Embodiment 3

[0061] A method for enzymatic synthesis of cefaclor:

[0062] Step 1. At 10°C, add 60.0 g of 7-amino-3-chloro-cephelenic acid and 500 mL of mixed solvent to the reaction flask, adjust the pH to 8.1-8.3 with purified ammonia with a mass concentration of 15 wt%, and add immobilized penicillin Acylase 25g, add the side chain mixture of 22g D-p-phenylglycine methyl ester hydrochloride and 29g D-phenylglycine methyl ester, at 25 ° C, react for 80min, after the reaction is completed, separate the reaction solution and immobilize cefaclor to synthesize Enzyme to obtain crude cefaclor; wash the immobilized penicillin acylase with 90 mL of the above mixed solution for 3 times, and mix the washings with the separated crude cefaclor to obtain a suspension of cefaclor crude;

[0063] Wherein, the mixed solvent includes the following components by mass percentage: methanol 10%, glutaraldehyde 1%, disodium hydrogen phosphate 0.1%, water 88.9%;

[0064] The way of adding the side chain mixt...

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Abstract

The invention provides a method for enzymatically synthesizing cefaclor, comprising the following steps: adding 7-amino-3-chloro-cephemic acid to a mixed solvent, adjusting the pH to 8.1-8.3, and adding immobilized cefaclor synthase , adding D-p-phenylglycine methyl ester hydrochloride and D-phenylglycine methyl ester to carry out the enzyme-catalyzed synthesis reaction. After the reaction, the reaction solution and immobilized cefaclor synthetase were separated to obtain cefaclor crude product and recrystallized , to obtain the cefaclor product; wherein, the mixed solvent includes methanol, glutaraldehyde and soluble phosphate. The preparation method provided by the invention does not need to control the pH value of the reaction process, and significantly improves the number of recycling enzymes recovered in the reaction, and the purity of the prepared cefaclor product can reach more than 99%, and the bulk density can reach 6.2g More than / mL, the recycled enzyme can be used up to 200 times, which simplifies the production process, reduces the production cost, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical production, in particular to a method for synthesizing cefaclor by an enzymatic method. Background technique [0002] Cefaclor is a second-generation oral cephalosporin antibiotic drug developed by Eli Lilly, USA. It has the advantages of good chemical stability and good clinical safety. It is now widely used in the treatment of bacterial infections, and has been the top global sales of oral cephalosporin antibiotics for many years. [0003] At present, the reported methods for synthesizing cefaclor are mainly chemical synthesis methods, which are basically synthesized with 7-amino-3-chloro-3-cephem-4-acid (7-ACCA) as the key intermediate. , it mainly has the problems of complex process, high cost, large pollution, high solvent residue and low yield. With the continuous progress of biotechnology, the technology of synthesizing cefaclor catalyzed by biological enzymes has also dev...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P35/04C07D501/59C07D501/12
CPCC12P35/04C07D501/59C07D501/12
Inventor 张锁庆龚俊波刘荣亮胡利敏杨梦德张立斌魏阔贾全魏宝军田洪年胡少华
Owner TIANJIN UNIV
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