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Preparation method for 3-deacetyl-7-aminocephalosporanic acid

A technology of aminocephalosporanic acid and deacetylation, which is applied in the field of medicine, can solve the problems of reduced product yield and content, reduced service life, and increased side reactions, and achieves the effects of lower temperature, lower production costs, and less side effects

Active Publication Date: 2015-04-01
华北制药河北莱欣药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the two-enzyme one-step method uses two biological enzymes under the same medium condition, but because the properties of the two biological enzymes are different, and the activity of the biological enzyme itself is greatly affected by the medium environment, so the two enzymes are used under the same condition Use will reduce the rate of enzymatic hydrolysis, resulting in increased side reactions and increased impurities, resulting in a decrease in the yield and content of the product at the same time; moreover, biological enzymes survive in a non-optimal environment for a long time, and their service life is also greatly reduced

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] A, use high performance liquid chromatography to monitor the potency of concentrated solution, cephalosporin C sodium salt feed liquid is concentrated to 30000ug / ml; Measure 1000ml, adjust pH to 6.5 with 3mol / L ammonia water, obtain raw material liquid; Then The raw material solution is added to a lysis tank equipped with 100 g of immobilized CPC acylase (unit enzyme activity is 100 u / g), the stirring is started, and the pH of the lysate is adjusted to 8.30 with 3 mol / L ammonia water at 13° C. to 18° C. The reaction is over;

[0044] B. Add the lysate obtained in step A into a cleavage tank equipped with 20.0 g of immobilized deacetylesterase (unit enzyme activity is 400 u / g), start stirring, and use 6 mol / L ammonia water at 13°C to 18°C Adjust the pH of the lysate to 7.40, and the reaction is completed to obtain the final lysate;

[0045] C. Transfer the final lysate obtained in step B to a crystallization tank, lower the temperature to 5°C-10°C, add hydrochloric acid...

Embodiment 2

[0048] A, use high performance liquid chromatography to monitor the potency of concentrated solution, cephalosporin C sodium salt feed liquid is concentrated to 31000ug / ml; Measure 1000ml, adjust pH to 6.7 with 3mol / L ammonia water, obtain raw material liquid; Then The raw material solution is added to a lysis tank equipped with 100 g of immobilized CPC acylase (unit enzyme activity is 100 u / g), the stirring is started, and the pH of the lysate is adjusted to 8.40 with 3 mol / L ammonia water at 13°C to 18°C. The reaction is over;

[0049] B. Add the lysate obtained in step A into a cleavage tank equipped with 20.0 g of immobilized deacetylesterase (unit enzyme activity is 400 u / g), start stirring, and use 6 mol / L ammonia water at 13°C to 18°C Adjust the pH of the lysate to 7.60, and the reaction is completed to obtain the final lysate;

[0050] C. Transfer the final lysate obtained in step B to a crystallization tank, lower the temperature to 5°C to 10°C, and add hydrochloric ...

Embodiment 3

[0053] A, use high performance liquid chromatography to monitor the potency of concentrated solution, cephalosporin C sodium salt feed liquid is concentrated to 32000ug / ml, measure 1000ml, adjust pH to 7.0 with 3mol / L ammonia water, obtain raw material liquid; Then The raw material solution is added to a lysis tank equipped with 100 g of immobilized CPC acylase (unit enzyme activity is 100 u / g), the stirring is started, and the pH of the lysis solution is adjusted to 8.50 with 3 mol / L ammonia water at 13°C to 18°C. The reaction is over;

[0054] B. Add the lysate obtained in step A into a cleavage tank equipped with 20.0 g of immobilized deacetylesterase (unit enzyme activity is 400 u / g), start stirring, and use 6 mol / L ammonia water at 13°C to 18°C Adjust the pH of the lysate to 7.80, and the reaction is completed to obtain the final lysate;

[0055] C. Transfer the final lysate obtained in step B to a crystallization tank, lower the temperature to 8°C, and add hydrochloric ...

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Abstract

The invention discloses a preparation method for 3-deacetyl-7-aminocephalosporanic acid (ACA), and belongs to the technical field of medicines. The preparation method adopts a two-enzyme two-step method and comprises the following steps: concentrating cephalosporin C (CPC) sodium salt liquid for acid modulation, performing catalytic cracking through immobilized CPC acylase and immobilized deacetyl esterase in sequence, and finally performing acid modulation and crystallization to obtain D-7-ACA. According to the preparation method, the preparation process is simple to carry out, a D-7-ACA product is high in purity and high in reaction yield, the immobilized CPC acylase and the immobilized deacetyl esterase can be repeatedly utilized, the service life of the immobilized CPC acylase reaches up to 600-700 batches, the service life of the immobilized deacetyl esterase reaches up to 800-1,000 batches, and the production cost is greatly reduced; the method is of great significance on industrialized enlarged production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of 3-deacetyl-7-aminocephalosporanic acid, which belongs to the technical field of medicine. Background technique [0002] 3-Deacetyl-7-aminocephalosporanic acid, referred to as D-7-ACA, is a pharmaceutical intermediate for the production of cephalosporin antibiotics, and can be used to synthesize cefixime, cefuroxime, cefpirome, and cefoca A series of cephalosporin antibiotics such as pinate, cefdinir, and ceftazidime. Compared with 7-ACA (7-aminocephalosporanic acid) and 7-ADCA (7-amino-3-desacetoxycephalosporanic acid), the hydroxyl group at position 3 in the D-7-ACA structure has a higher Reactivity is conducive to the synthesis of new cephalosporin products, can simplify the production process route, and has the advantages of simple modification, easy purification, good product quality, and low production cost, and the demand cont...

Claims

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Application Information

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IPC IPC(8): C12P35/06C12P35/02
Inventor 侯红杰韦卫军王梦谭程俊山王刚胡斌李建强于佩恩
Owner 华北制药河北莱欣药业有限公司
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