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Synthesis method of cefprozil

A technology of cefprozil and synthesis method, which is applied in fermentation and other directions, can solve the problems of many impurities, long reaction cycle of cefprozil, low yield, etc., and achieve the effects of high purity, shortened synthesis cycle, and high product yield

Inactive Publication Date: 2015-11-18
ZHEJIANG DONGYING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] For the above-mentioned technical characteristics of the prior art, the purpose of this invention is to provide a kind of synthetic method of cefprozil, to solve the long reaction cycle of enzymatic synthesis of cefprozil in the prior art, many impurities, low technical problems of yield

Method used

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  • Synthesis method of cefprozil

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Take 15g of mother nucleus 7-APRA, add 150ml of purified water and dissolve it with 6mol / L ammonia water, take 13.75g of L-p-hydroxyphenylglycine methyl ester, dissolve it with 6mol / L hydrochloric acid, add it to the mother nucleus 7-APRA solution, add penicillinyl Lyase IPA-750. Stirring was started, and the reaction started for 5 minutes. Before cefprozil was precipitated in the reaction solution, 0.67% (w / v) cefprozil seed crystals (purity greater than 99%) were added at one time. The synthetic pH is 6.5 and the temperature is 15°C.

[0050] After reacting for 2 hours, take samples for HPLC detection. At this time, the residue of mother nucleus 7-APRA is 0.88 mg / ml, and the conversion rate of mother nucleus 7-APRA is 99.1%. Use a sieve to separate penicillin acylase and cefprozil suspension for synthesis, cephalosporin The weight of cefprozil obtained after refining the propylene suspension was 18.54 g, the weight yield was 123.6%, and the purity was 99.51%.

Embodiment 2

[0052] Take 15g of mother nucleus 7-APRA and add 150ml of purified water to dissolve it with 6mol / L ammonia water, then add penicillin acylase PGA-450. Take 13.75g of L-p-hydroxyphenylglycine ethyl ester, dissolve it with 6mol / L hydrochloric acid, and slowly add it dropwise into the mother nucleus 7-APRA solution system. 30 minutes after the dropwise reaction started, before cefprozil was precipitated in the reaction solution, 0.67% (w / v) cefprozil seed crystals (purity greater than 99%) were added in one go. The synthetic pH is 6.5 and the temperature is 15°C.

[0053] After reacting for 2 hours, take samples for HPLC detection. At this time, the residue of mother nucleus 7-APRA is 0.52 mg / ml, and the conversion rate of mother nucleus 7-APRA is 99.5%. Use a screen to separate penicillin acylase and cefprozil suspension for synthesis, cephalosporin The weight of cefprozil obtained after refining the propylene suspension was 18.73 g, the weight yield was 124.9%, and the purity...

Embodiment 3

[0055] Take 15g of the mother nucleus 7-APRA, add 150ml of purified water, dissolve it with 6mol / L ammonia water, and add penicillin acylase for synthesis. Take 13.75g of L-p-hydroxyphenylglycine ethyl ester, dissolve it with 6mol / L hydrochloric acid, and slowly add it dropwise into the mother nucleus 7-APRA solution system. 0-30 minutes after the start of the reaction, 2% (w / v) cefprozil was added in 3 times as a seed crystal (purity greater than 99%). The synthetic pH is 6.0, and the temperature is 20°C.

[0056] After reacting for 2 hours, take samples for HPLC detection. At this time, the residue of mother nucleus 7-APRA is 0.48 mg / ml, and the conversion rate of mother nucleus 7-APRA is 99.5%. Use a sieve to separate penicillin acylase and cefprozil suspension for synthesis, cephalosporin The weight of cefprozil obtained after refining the propylene suspension was 18.70 g, the weight yield was 124.7%, and the purity was 99.58%.

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Abstract

The invention relates to a synthesis method of cefprozil. The synthesis method comprises the following steps: under the existence of an enzyme, enabling parent nucleus 7-APRA and a D-4-hydroxyphenylglycine ester derivative to react with each other, and before the precipitation of cefprozil, adding cefprozil, with the purity greater than 99%, taken as a seed crystal, into a reaction system. According to the invention, the reaction efficiency is improved, the synthesis period is shortened, the conversion rate of 7-APRA is increased, and the purity of the obtained cefprozil is improved; the method is an enzymatic method, and the enzymatic catalysis is only required, water is taken as a solvent, and any organic solvent is not required during the reaction process, so that the environment friendliness is achieved, the route is simple, the product yield is high, and the purity is high.

Description

technical field [0001] The invention relates to the field of cefprozil synthesis, in particular to a method for biologically synthesizing cefprozil and cefprozil synthesized by the method. Background technique [0002] Cefprozil (cefprozil) chemical name: the product is (6R,7R)-7-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3- [(Z)-Prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate, a second-generation oral cephalosporin antibiotic. Cefprozil is a second-generation cephalosporin antibiotic with a broad-spectrum antibacterial effect. Blood bacteria etc. also have inhibitory effect. The bactericidal mechanism is to hinder the synthesis of bacterial cell walls, which is safe and has extremely low adverse reactions. [0003] [0004] cefprozil [0005] At present, there are chemical and enzymatic methods for the production of cefprozil at home and abroad, and the chemical method is mainly used to synthesize cefprozil in China. The chemic...

Claims

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Application Information

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IPC IPC(8): C12P35/04
Inventor 刘忠乐侯仲轲王宗利吕秋波潘伯安孟仲建邱家军
Owner ZHEJIANG DONGYING PHARMA
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