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Method for synthesizing cefprozil through green enzymatic method

A technology of cefprozil and enzymatic synthesis, applied in the field of medicine, can solve the problems of unreachable industrial production, long reaction time, low yield, etc., and achieve remarkable economic effect, strong selectivity, high yield and purity

Inactive Publication Date: 2016-12-14
GUANGZHOU BAIYUNSHAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sun Baihu (Tianjin University master's thesis, 2012) and CN104928340 reported a method for enzymatically synthesizing cefprozil, but these methods still have problems such as long reaction time and low yield, and cannot meet the requirements of industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Check whether the equipment and materials are ready, add 260 mL of phosphate buffer solution with a pH of 7.5, 20 g of 7-APRA, and 14.5 g of D-p-hydroxyphenylglycine amide at a pH of 5 to the enzyme reactor;

[0031] (2) Add 15 g of penicillin acylase SIPA-III to the solution obtained in step (1). During the reaction, use 6N hydrochloric acid to maintain the reaction pH at 6.8-7.0, and the reaction temperature is 18°C. After the reaction started, samples were taken every 30 minutes for inspection, and the reaction was stopped when the concentration of APRA was less than 0.3% (w / w), and the enzyme and the reaction solution were separated with a sieve.

[0032] (3) Adjust the pH value of the obtained mixed solution to 1.0-1.1 with a mass fraction of 20% sulfuric acid, suction filter, and adjust the pH value of the obtained filtrate to 5.5-5.6 with 3 mol / L sodium hydroxide solution at 15°C. Cultivate crystals at 5°C After 30 minutes, suction filtration, washing, and dr...

Embodiment 2

[0034] (1) Check whether the equipment and materials are ready, add 260 mL of phosphate buffer with a pH of 7.5, 20 g of 7-APRA hydrochloride to the enzyme reactor, and add 18.3 g of D-p-hydroxyphenylglycine methyl at a pH of 7 ester;

[0035] (2) Add 15 g of immobilized penicillin G acylase II to the solution obtained in step (1). During the reaction, use 6N hydrochloric acid to maintain the reaction pH at 6.8-7.0, and the reaction temperature is 15°C. After the reaction started, samples were taken every 30 minutes for inspection, and the reaction was stopped when the concentration of APRA was less than 0.3% (w / w), and the enzyme and the reaction solution were separated with a sieve.

[0036] (3) Adjust the pH of the obtained mixed solution to 1.0-1.1 with a mass fraction of 20% sulfuric acid, filter with suction, and adjust the pH value of the obtained filtrate to 5.5-5.6 with 3mol / L sodium hydroxide solution at 15°C. Cultivate crystals at 5°C for 30 Minutes later, suction ...

Embodiment 3

[0038](1) Check whether the equipment and materials are ready, add 260L of phosphate buffer solution with a pH of 7.5, 60kg of 7-APRA to the enzyme reactor, and add 54.9kg of D-p-hydroxyphenylglycine methyl ester at a pH of 7.5;

[0039] (2) Add 45 kg of penicillin acylase IPA-IIP to the solution obtained in step (1). During the reaction, use 6N hydrochloric acid to maintain the reaction pH at 6.8-7.0, and the reaction temperature is 18°C. At the beginning of the reaction, samples were taken every 30 minutes for inspection. When the concentration of APRA was less than 0.3% (w / w), the reaction was stopped, and the enzyme and the reaction solution were separated with a sieve.

[0040] (3) Adjust the pH of the obtained mixed solution to 1.0-1.1 with a mass fraction of 20% sulfuric acid, filter with suction, and adjust the pH value of the obtained filtrate to 5.5-5.6 with 3mol / L sodium hydroxide solution at 15°C. Cultivate crystals at 5°C for 30 Minutes later, suction filtration, ...

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Abstract

The invention relates to a method for synthesizing cefprozil through a green enzymatic method. The method includes following steps: S1, adding parent nucleus 7-APRA or hydrochloride thereof into a buffer solution, and adding D-para hydroxybenzene glycinate derivative and / or D-para hydroxybenzene glycine amide under the condition that pH is 5-8; S2, adding cefprozil synthetase into the S1, reacting at temperature of 15-30 DEG C and pH of 6.5-7.8 for 1-3h, separating out separation liquid after reaction finishes, and immobilizing cefprozil synthetase to obtain a cefprozil crude product; S3, subjecting the crude product obtained in the S2 to acidolysis dissolved clarification, filtering and re-crystallizing to obtain cefprozil. Raw materials are cheap and easy to obtain, reaction is simple, hydrolysis activity of penicillin acylase can be effectively inhibited, and production cost is low; compared with conventional chemical synthesis methods, the method is simple and convenient to operate and low in cost, synthesis period is shortened, production efficiency is improved, total yield is high, controllability is high, and needs on industrial production are met.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing cefprozil by a green enzymatic method. Background technique [0002] The chemical name of Cefprozil is (6R,7R)-7-[(R)-2-amino-2-(p-hydroxy-phenyl)acetamido]-8-oxo-3-propene-5-sulfur Hetero-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-hydrate is a second-generation non-ester oral cephalosporin broad-spectrum antibacterial developed by Bristol-Myers Squibb It is also the first oral cephalosporin antibiotic approved by the FDA for the treatment of otitis media and sinusitis in children. Its antibacterial mechanism is similar to other cephalosporin antibiotics, and it has strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and anaerobic bacteria, and its antibacterial activity against Gram-positive bacteria is prominent. Cefprozil can be used clinically for mild and moderate infections caused by sensitive ba...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/04
CPCC12P35/04
Inventor 罗春李庆范玉珍何星垚韩贵良
Owner GUANGZHOU BAIYUNSHAN PHARM CO LTD
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