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Method for synthesizing cefprozil by enzymic method

A technology for cefprozil and enzymatic synthesis, applied in the field of medicine, can solve the problems of long reaction period, low yield, and many impurities of cefprozil, and achieve the effects of reducing the use of solvent, high yield and high purity

Inactive Publication Date: 2018-04-06
福安药业集团重庆博圣制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] 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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  • Method for synthesizing cefprozil by enzymic method
  • Method for synthesizing cefprozil by enzymic method
  • Method for synthesizing cefprozil by enzymic method

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Add 40g (0.1665mol) of 7-APRA, 34g (0.1876mol) of side chains into 120g of purified water, add 28g of PGA synthase, keep the temperature at 5-10°C for 5 hours, and monitor by HPLC until 7-APRA≤3.0% After the reaction, use a 100-mesh sieve to separate the enzyme, coarse powder, and clear liquid. Add the coarse powder to the clear liquid and adjust the pH value to 1.0 with hydrochloric acid to dissolve the clear liquid. Then add 600g N, N-dimethylformamide and control the temperature. Adjust the pH value to 5.0-6.5 with ammonia water at 15-20°C to crystallize, stir for 30 minutes, cool down to 5-10°C to grow crystals for 30 minutes, filter, and then dry at 40-45°C to obtain 73.1g of cefprozil-DMF complex, yield 95.3%, purity ≥ 98.4%, light yellow.

[0032] Add 73.1g (0.1578mol) of cefprozil DMF complex to 150g of purified water, control the temperature at 10-20°C and stir for 30 minutes, then filter, add the filtered wet powder to 100g of purified water, control the tempe...

Embodiment 2

[0034] Add 40g (0.1665mol) of 7-APRA, 34g (0.1876mol) of side chains to 160g of purified water, add 28g of PGA synthetase, keep the temperature at 5-10°C for 5 hours, and monitor by HPLC until 7-APRA≤3.0% After the reaction, use a 100-mesh sieve to separate the enzyme, coarse powder, and clear liquid. Add the coarse powder to the clear liquid and adjust the pH value to about 1.0 with hydrochloric acid to dissolve the clear liquid, then add 600g N,N-dimethylformamide, Add 1g of activated carbon for injection to decolorize and filter, control the temperature at 15-20°C and use ammonia water to adjust the pH value to 5.0-6.5 to crystallize, stir for 30 minutes, cool down to 5-10°C to grow crystals for 30 minutes, filter, and then dry at 40-45°C to obtain 74.8g of cefprozil-DMF complex, yield 97.5%, purity ≥ 99.1%, pale yellow.

[0035] Add 74.8g (0.1615mol) of cefprozil DMF complex to 180g of purified water, control the temperature at 10-20°C and stir for 30 minutes, then filter,...

Embodiment 3

[0037]Add 43.8g (0.1665mol) of 7-APRA, 90.53g (0.4995mol) of side chains into 200g of purified water, add 28g of PGA synthetase, keep the temperature at 5-10°C for 5 hours, and monitor by HPLC until 7-APRA≤ 3.0%; after the reaction is over, use a 100-mesh screen to separate the enzyme, coarse powder, and clear liquid. Add the coarse powder to the clear liquid and adjust the pH value to about 1.0 with hydrochloric acid to dissolve the clear liquid, and then add 1000g N,N-dimethyl formazan For amides, add 2g of activated carbon for injection to decolorize and filter, then control the temperature at 15-20°C and use ammonia water to adjust the pH value to 5.0-6.5 to crystallize, stir for 30 minutes, cool down to 5-10°C to grow crystals for 30 minutes, filter, and then at 40-45°C Dried to obtain 76.5 g of cefprozil-DMF complex with a yield of 99.75%, a purity of ≥99.9%, and a light yellow color.

[0038] Add 76.5g (0.1652mol) of cefprozil DMF complex into 300g of purified water, co...

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Abstract

The invention relates to a method for synthesizing cefprozil by an enzymic method. The method is characterized in that 7-APRA and a D-hydroxy phenylglycine derivative are added in water for being stirred and mixed, PGA synthetase is added for a reaction, after the reaction is finished, enzyme, coarse powder and clear liquid are separated, coarse powder is added in clear liquid, a pH value is adjusted, N,N-dimethyl formamide is added, temperature is controlled at the temperature of 15-20 DEG C, the pH value is adjusted to 5.0-6.5 and crystallization is carried out, the materials are stirred, then cooled to 5-10 DEG C and crystal growing is carried out, filtering is performed, the material is dried at the temperature of 40-45 DEG C to obtain a cefprozil DMF complex, the cefprozil DMF complexis added in water, the temperature is controlled at 10-20 DEG C, the material is stirred for crystal transformation, and then filtered, wet powder is added in water, the temperature is controlled at10-20 DEG C, the pH value is adjusted to 4.5-5.5 and crystallization is carried out, and the material is filtered, washed, and dried to obtain a cefprozil finished product. The method has the advantages that the reaction time is short, the generated impurities are less, the method is benefit for separating and purifying, usage of a solvent is reduced, safety and environmental protection pressure can be reduced, product yield is high, and purity is high.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for enzymatically synthesizing cefprozil. Background technique [0002] Cefprozil (cefprozil), the chemical name 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 is a second-generation oral cephalosporin antibiotic, The structural formula is shown in formula I. Cefprozil is a second-generation cephalosporin antibiotic with a broad-spectrum antibacterial effect against G + , G - Bacteria and anaerobic bacteria have strong antibacterial activity, against G + Bacterial activity is particularly prominent. Cefprozil is used as a monohydrate, which has a strong effect on suppurative pneumonia, Streptococcus agalactiae, Staphylococcus aureus sensitive to methicillin, and has inhibitory effect on Haemophilus influenzae. The bactericidal mechanism is to hinder t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/04
CPCC12P35/04
Inventor 张闯洪荣川袁明华罗开伟徐飞刘中权
Owner 福安药业集团重庆博圣制药有限公司
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