Enzymatic synthesis method of cefaclor

A technology for cefaclor and enzymatic synthesis, which is applied in the field of pharmaceutical and chemical production, can solve the problems of few reuses of enzymes and insufficient purity of cefaclor, and achieves the advantages of inhibiting the pH drop of the system, inhibiting the cleavage reaction and short reaction time. Effect

Active Publication Date: 2020-07-10
TIANJIN UNIV +1
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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 ...

Method used

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  • Enzymatic synthesis method of cefaclor

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Effect test

Embodiment 1

[0041] A method for enzymatically synthesizing cefaclor:

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

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

[0044] The addition metho...

Embodiment 2

[0052] A method for enzymatically synthesizing cefaclor:

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

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

[0055] Step 2, the above...

Embodiment 3

[0061] A method for enzymatically synthesizing cefaclor:

[0062] Step 1. At 10°C, add 60.0 g of 7-amino-3-chloro-cephemic acid and 500 mL of mixed solvent to the reaction flask, adjust the pH to 8.1-8.3 with refined ammonia water with a mass concentration of 15 wt%, and add immobilized penicillin 25g of acylase, add 22g of D-phenylglycine methyl ester hydrochloride and 29g of D-phenylglycine methyl ester side chain mixture, react at 25°C for 80min, separate the reaction solution after the reaction and synthesize it with immobilized cefaclor Enzyme, cefaclor crude product was obtained; the immobilized penicillin acylase was washed with 90mL of the above mixed solution for 3 times, and the washing liquid was mixed with the separated cefaclor crude product to obtain a cefaclor crude product suspension;

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

[0064]...

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Abstract

The invention provides an enzymatic synthesis method of cefaclor. The enzymatic synthesis method of the cefaclor comprises the following steps: adding 7-amino-3-chloro cephalosporanic acid into a mixed solvent, adjusting a pH value to be 8.1-8.3, adding an immobilized cefaclor synthetase, adding D-p-phenylglycine methyl ester hydrochloride and methyl (R)-aminophenylacetate, carrying out an enzymatic synthesis reaction, separating out reaction liquid and the immobilized cefaclor synthetase after the reaction is completed to obtain a crude product of the cefaclor, and conducting recrystallization to obtain a cefaclor product, wherein the mixed solvent comprises methanol, glutaraldehyde and a soluble phosphate. According to the provided production method, a pH value of the reaction process does not need to be controlled, the number of times of recycling of the recoverable synthetase in the reaction is significantly increased, the purity of the produced cefaclor product can reach 99% or above, the bulk density can reach 6.2 g/mL or above, the number of times of recycling of the recoverable synthetase can reach 200, the production technology is simplified, the production cost is reduced, and the enzymatic synthesis method of the cefaclor is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical and chemical production, in particular to a method for enzymatically synthesizing cefaclor. Background technique [0002] Cefaclor is a second-generation oral cephalosporin antibiotic drug developed by Eli Lilly and Company of the United States. It has a strong killing effect on a variety of Gram-positive bacteria and Gram-negative bacteria. , good chemical stability and good clinical safety, it is now widely used in the field of treatment of bacterial infections, and has been the world's largest sales of oral cephalosporin antibiotics for many years. [0003] At present, the reported method of synthesizing cefaclor mainly adopts the chemical synthesis method, basically all synthesized with 7-amino-3-chloro-3-cephem-4-acid (7-ACCA) as the key intermediate , which mainly has the problems of complicated process, high cost, heavy pollution, high solvent residue and low yield. With the contin...

Claims

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Application Information

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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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