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Synthetic method of antibiotic cefixime

A technology of cefixime and synthetic method, applied in the direction of antibacterial drugs, organic chemistry, etc., can solve problems such as unfavorable continuity, large-scale industrial production, expensive tetrahydrofuran, harsh reaction conditions, etc., to shorten the production cycle and simplify Effects on manipulation, yield enhancement and purity

Inactive Publication Date: 2009-01-07
国药集团致君(苏州)制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the existing synthetic method, tetrahydrofuran is usually used as a solvent for the acylation reaction of 7-AVCA and MICA active ester. Since tetrahydrofuran is expensive and difficult to recycle, the product cost is high and the quality of the obtained product is not high.
The reaction conditions are harsh and the reaction time is long, which is not conducive to continuous and large-scale industrial production

Method used

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  • Synthetic method of antibiotic cefixime
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] In a 1000L reactor, add 500L acetone, 50kgAVCA, 75kgMICA-active ester, 50L methanol, add 25kg triethylamine dropwise at 5°C for about 1.5h (hour), and keep the reaction at 5°C for 4h (hour), Sampling (intermediate less than 0.3%).

[0017] After the reaction is over, acetone and methanol are recovered by distillation under reduced pressure at 40°C. The recovered acetone and methanol can be used directly. After steaming, add 400L of pure water and 400L of ethyl acetate to cool down to 10°C. The water phase was extracted twice by adding 200L ethyl acetate to the water phase, and the water phase was collected and filtered to remove insoluble matter.

[0018] Add 8 kg of activated carbon to the water phase, stir for 30 min, filter, then wash the filter cake with 200 L of pure water, and combine the filtrate and washing liquid.

[0019] Add 200L of acetone to the water phase and lower the temperature to below -10°C, add 80L of 30% sodium hydroxide at one time, stir for 5min...

Embodiment 2

[0022] In a 1000L reactor, add 500L acetone, 50kgAVCA, 90kgMICA-active ester, 50L pure water, add 25kg triethylamine dropwise at 10 degrees for about 2.5 hours, keep warm at 5 degrees for 4 hours, and take samples (intermediate less than 0.3 %).

[0023] After the reaction is over, acetone is recovered by distillation under reduced pressure at 45°C. The recovered ketone can be used directly. After steaming, add 500L of pure water and 400L of ethyl acetate to cool down to 10°C, keep the layers for 30 minutes, collect the water phase, water The phase was extracted twice by adding 200L ethyl acetate, and the aqueous phase was collected and filtered to remove insoluble matter.

[0024] Add 3 kg of activated carbon to the water phase, stir for 30 min, filter, then wash the filter cake with 200 L of pure water, and combine the filtrate and washing liquid.

[0025] Add 200L of acetone to the water phase and lower the temperature to below -5°C, add 100L of 20% sodium hydroxide at one...

Embodiment 3

[0028] The weight ratio of 7-AVCA and MICA active ester is that 1: 1.5 is mixed and placed in the mixed solvent that the volume ratio of acetone and methanol is 1: 30 and the volume ratio of pure water water is 1: 30, with sodium hydroxide or Potassium hydroxide adjusts the pH value to 7.0, dissolves and undergoes an acylation reaction at a temperature of -20°C to obtain a cefixime intermediate A solution; the obtained cefixime intermediate A solution is extracted with ethyl acetate solvent, and after extraction In the water phase obtained, add 0.1% activated carbon of 7-AVCA charging capacity in water phase and carry out decolouring, then add 0.1% EDTA of 7-AVCA charging capacity, obtain cefixime intermediate A aqueous solution; The weight ratio is 1:1,

[0029] When the acylation reaction is over, acetone and methanol are recovered by distillation under reduced pressure at 40°C. The recovered acetone and methanol can be used directly. After steaming, add 3 times the amount o...

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Abstract

The invention relates to a synthesis method of cefixime that is bacteriophage. 7-azyl-3-vinyl cephalosporanic acid (7-AVCA) is used as starting material to react with MICA active ester first, and an intermediate MECEF of cefixime is obtained through separation; the intermediate MECEF is directly hydrolyzed to generate a cefixime product without separation; the condensation and the hydrolyzation in a synthesis route of the cefixime product is combined into one. The synthesis method has the advantages that the technologcial conditions are simple, the operation is convenient, the product yield is high, the product quality is stable, and the method is suitable for the large-scale industrialized production; two-step reactions are combined into one, an intermediate A is not needed to be separated, the operation is simplified, and the production period is shortened; the yield can reach 200 to 212 percent; the purity quotient is more than 99 percent; the curative effect of the product is increased. Expensive tetrahydrofuran which is used in the reaction is replaced by low-cost acetone, the problem that tetrahydrofuran is mixed with the other reaction solvent and cannot be recycled and reused is solved, the wastewater discharge is reduced, the manufacture cost is lowered, and the competitive ability of the product is increased.

Description

technical field [0001] The invention relates to a method for synthesizing the third-generation cephalosporin antibiotic cefixime, and belongs to the technical field of medicine preparation. Background technique [0002] Cefixime (Cefixime) was first developed by Fujisawa Pharmaceutical Co., Ltd., Japan, and was launched in 1987 as a cephem antibiotic. As the first orally effective third-generation cephalosporin, cefixime acts by inhibiting the synthesis of bacterial cell walls. Cefixime has good antibacterial activity against Gram-positive bacteria and Gram-negative bacilli. Compared with existing oral β-lactam antibiotics, it has especially enhanced activity against Gram-negative bacteria. [0003] Cefixime chemical name: (6R,7R)-7-[(2Z)-(2-aminothiazol-4-yl)[(carboxymethoxy)imino]acetamido]-3-vinyl- 8-Oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The structure is as follows: [0004] [0005] The synthetic method of cefepime, according to the classific...

Claims

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Application Information

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IPC IPC(8): C07D501/22A61P31/04
Inventor 史利军孙元强陈德华
Owner 国药集团致君(苏州)制药有限公司
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