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Method for synthetizing 7-amino-3-vinyl-cephalosporin ring-4-carboxylic acid

A synthetic method and vinyl technology, applied in the field of medicine and chemical industry, can solve the problems of inapplicability to industrial production, high cost, and large environment of reagent toxicity, and achieve the goal of improving product yield and quality, low production cost, and improving product conversion rate Effect

Inactive Publication Date: 2014-10-01
GUANGDONG LIGUO PHARMACY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the existing synthetic technology has the following technical defects: (1) The synthetic route is long, the production cost is high, and the raw materials are not sufficiently sourced, etc., which are not suitable for industrial production; (2) The reagents used are highly toxic and easy to cause environmental damage Pollution, but also a threat to the health of the operator; (3) The purity of the synthesized product is not high
The technical scheme of the invention has a long synthetic route, high production cost, insufficient sources of raw materials, etc., and is not suitable for industrial production. At the same time, the conversion rate of the synthetic product is low

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] (1) Synthesis of 7-phenylacetamido-3-vinyl-4-cephalosporanic acid p-methoxybenzyl ester (GVNE) part:

[0041]Add 160ml of acetone and 40ml of dimethylacetamide to the reaction flask, add 30g of 7-phenylacetamido-3-chloromethyl-4-cephanoic acid p-methoxybenzyl ester (GCLE) under slow stirring, 28.5g of three Phenylphosphine, after the reaction is completed, add 7.8g of potassium iodide and 45ml of 37% formaldehyde, maintain 12°C, and stir slowly for 1 hour; after the reaction, add 40.0ml of 1mol / L sodium hydroxide solution, raise the temperature, and maintain the solution temperature at Stir and react at 33°C for 30 minutes; add 5% sulfuric acid aqueous solution to neutralize, stir, and let stand; extract and separate the liquid, save the organic phase, and distill under reduced pressure. Stir at this temperature for 1 hour; filter with suction, and dry the material in vacuum until the water content is less than 0.5%, to obtain about 27.0 g of p-methoxybenzyl 7-phenyl...

Embodiment 2

[0045] (1) Synthesis of 7-phenylacetamido-3-vinyl-4-cephalosporanic acid p-methoxybenzyl ester (GVNE) part:

[0046] Add 160ml of acetone and 40ml of dimethylacetamide to the reaction flask, add 30g of 7-phenylacetamido-3-chloromethyl-4-cephanoic acid p-methoxybenzyl ester (GCLE) under slow stirring, 28.5g of three Phenylphosphine, after the reaction, add 7.8g of potassium iodide and 45ml of 37% formaldehyde, maintain 10°C, and slowly stir the reaction for 1 hour; after the reaction, add 40.0ml of 1mol / L sodium hydroxide solution, raise the temperature, and maintain the solution temperature at Stir and react at 34°C for 30 minutes; add 5% sulfuric acid aqueous solution to neutralize, stir, and let stand; extract and separate the liquid, save the organic phase, and distill under reduced pressure. Stir at this temperature for 1 hour; filter with suction, and dry the material in vacuum until the water content is less than 0.5%, to obtain about 27.0 g of p-methoxybenzyl 7-pheny...

Embodiment 3

[0050] (1) Synthesis of 7-phenylacetamido-3-vinyl-4-cephalosporanic acid p-methoxybenzyl ester (GVNE) part:

[0051] Add 160ml of acetone and 40ml of dimethylacetamide to the reaction flask, add 30g of 7-phenylacetamido-3-chloromethyl-4-cephanoic acid p-methoxybenzyl ester (GCLE) under slow stirring, 28.5g of three Phenylphosphine, after the reaction, add 7.8g of potassium iodide and 45ml of 37% formaldehyde, maintain 10°C, and slowly stir the reaction for 1 hour; after the reaction, add 40.0ml of 1mol / L sodium hydroxide solution, raise the temperature, and maintain the solution temperature at Stir and react at 35°C for 30 minutes; add 5% sulfuric acid aqueous solution to neutralize, stir, and let stand; extract and separate the liquid, save the organic phase, and distill under reduced pressure. Stir at this temperature for 1 hour; filter with suction, and dry the material in vacuum until the water content is less than 0.5%, to obtain about 27.0 g of p-methoxybenzyl 7-pheny...

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Abstract

The invention discloses a method for synthetizing 7-amino-3-vinyl-cephalosporin ring-4-carboxylic acid. According to the technical scheme, the method comprises the following steps: reacting 7-phenylacetamido-3-chloromethyl-4-cephalosporanic acid p-methoxy benzyl ester (GCLE) serving as a raw material with triphenylphosphine under the action of strong alkali to generate 7-phenylacetamido-3-vinyl-4-cephalosporanic acid p-methoxy benzyl ester (GVNE), carrying out hydrolysis reaction on the GVNE in a phenol solution to remove the carboxyl protecting group, adjusting the PH to alkaline without separating, and adding immobilized penicillin acylase to carry out enzymolysis reaction to remove the carboxyl protecting group to obtain the 7-amino-3-vinyl-4-cephalosporanic acid. The method has the advantages that the product conversion ratio is high; the extracting solvent is low in toxicity and easy to recycle; the reaction temperature is moderate and easy to control; moreover, the immobilized penicillin acylase can be recycled; the production cost is low; the environmental pollution is little; and the harm to the health of operators is hardly caused.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a method for synthesizing 7-amino-3-vinyl-3-cephalosporin-4-carboxylic acid. Background technique [0002] 7-AVCA (7-amino-3-vinyl-3-cephalosporin-4-carboxylic acid) is a key intermediate for the synthesis of the third-generation cephalosporin cefixime. At present, there are many synthetic routes for 7-AVCA, mainly based on Cephalosporin C (DAC), 7-ACA, penicillin G potassium salt, GCLE, etc. are used as starting materials, synthesized by chemical cleavage, after esterification, oxidation, ring expansion, reduction, witting reaction, deamination and carboxyl protecting group and other steps to synthesize 7-AVCA. [0003] However, the existing synthetic technology has the following technical defects: (1) The synthetic route is long, the production cost is high, and the raw materials are not sufficiently sourced, etc., which are not suitable for industrial ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/02C07D501/18C07D501/04C07D501/12
CPCY02P20/55
Inventor 许伟龙曾建江黄雪枚
Owner GUANGDONG LIGUO PHARMACY
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