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Preparation method of N-formyl cefotaxime

A formyl head, cefotaxime acid technology, applied in the field of biological and pharmaceutical raw materials and intermediates, can solve the problems of unfavorable impurity research, etc., achieve the effect of simple and easy to control, improve product purity, and low product purity

Pending Publication Date: 2022-05-13
河北合佳创新医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Aiming at the fact that there is no synthesis and preparation method of N-formyl cefotaxime at present, which is not conducive to the related research on impurities, the present invention provides a synthesis method of high-purity target product N-formyl cefotaxime, which is used for drug research and methods learning development

Method used

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  • Preparation method of N-formyl cefotaxime
  • Preparation method of N-formyl cefotaxime
  • Preparation method of N-formyl cefotaxime

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Example 1: After successively adding 45g of acetic anhydride and 30g of anhydrous formic acid into a 1L dry and clean four-necked bottle, the temperature was raised to 25-35°C, and after stirring for 30 minutes, the temperature was lowered to 15°C, and 75g was added in 5 times After cefotaxime acid, the temperature rises to 35-40°C, when the reactants start to agglomerate and form a group, add 0.15g of zinc oxide and continue stirring for 30 minutes;

[0031] After the reaction, add 750mL of purified water, white crystals begin to precipitate, adjust the pH of the system to 3.0 with 15% ammonia solution, cool to 10-15°C and filter, then wash with 150mL of purified water, dry at 55°C, - Dry at 0.090Mpa for 5-10 hours until the water content is less than 2.5% to obtain the target product of white powder N-formyl cefotaxime, the mass yield of the target product is 80.2%, and the product purity (HPLC) is 97.9%.

[0032] Structural analysis of the target product obtained abo...

Embodiment 2

[0038] Example 2: After successively adding 60 g of acetic anhydride and 30 g of anhydrous formic acid into a 2L dry and clean four-neck flask, the temperature was raised to 25-35°C, kept stirring for 30 minutes and then cooled to 15°C, and then 90g of cefotaxime was added in 3 times After the hydroxamic acid, the temperature rises to 35-40°C, and when the reactants start to agglomerate, add 0.10g of zinc oxide, and continue stirring for 30 minutes;

[0039] After the reaction, add 1100mL of purified water, white crystals begin to precipitate, use 20% ammonia solution to adjust the pH of the system to 2.5, cool to 10-15°C, filter, then wash with 200mL of purified water, dry at 55°C, - Dry at 0.090Mpa for 5-10 hours until the water content is less than 2.5% to obtain the target product of white powder N-formyl cefotaxime, the mass yield of the target product is 76%, and the product purity (HPLC) is 98.6%.

Embodiment 3

[0040] Example 3: After successively adding 96g of acetic anhydride and 30g of anhydrous formic acid into a 2L dry and clean four-necked flask, the temperature was raised to 25-35°C, and after stirring for 30 minutes, the temperature was lowered to 15°C, and 105g of cephalosporin was added in 3 times After thioxamic acid, the temperature rises to 35-40°C, when the reactants start to agglomerate, add 0.32g of manganese oxide, and continue to stir and react for 30 minutes;

[0041] After the reaction, add 1380mL of purified water, white crystals start to precipitate, use 18% ammonia solution to adjust the pH of the system to 3.5, cool to 10-15°C and filter, then wash with 300mL of purified water, dry at 55°C, - Dry at 0.090Mpa for 5-10 hours until the water content is less than 2.5% to obtain the target product of white powder N-formyl cefotaxime, the mass yield of the target product is 78%, and the product purity (HPLC) is 97.3%.

[0042] At present, the technical solution of t...

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Abstract

The invention discloses a preparation method of N-formyl cefotaxime, which is characterized by comprising the following steps: adding anhydrous formic acid into acetic anhydride, controlling the temperature at 25-35 DEG C, reacting for 30 minutes, cooling to 15 DEG C, adding cefotaxime acid in batches, heating to 35-40 DEG C, adding a metal catalyst to continue reacting when reactants start to agglomerate, reacting for 30 minutes, adding purified water, and reacting for 30 minutes to obtain N-formyl cefotaxime. And adjusting the pH value when white crystals are separated out, filtering and washing when the temperature is reduced to 10-15 DEG C, and drying at the temperature of 50-60 DEG C and the pressure of-0.085--0.095 Mpa until the water content is less than 2.5% to obtain a target product. According to the method, multi-step synthesis by taking 7-ACA as a raw material is not needed, the production cost is effectively reduced, the reaction steps are simple, the steps of phase inversion purification, carbon decoloration and the like are not needed, the operation is simple and easy to control, the weight yield can reach 80%, and the highest product purity can reach 98.6%. The method fills the blank of N-formyl cefotaxime impurities prepared by chemical synthesis, and has important theoretical significance and practical application value for improving the quality of cefotaxime sodium and reducing the clinical medication risk.

Description

technical field [0001] The invention relates to biological and pharmaceutical raw materials and intermediates, more specifically, to a synthesis and preparation method of N-formyl cefotaxime, a key known impurity in the quality research of cefotaxime sodium. Background technique [0002] Cefotaxime sodium (cefotaxime sodium) is a third-generation semi-synthetic cephalosporin, its chemical name is (6R,7R-3-[(acetyloxy)methyl]-7-[(2-amino-4-thiazole Base)-(methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, the drug is produced by Germany Hoechst Jointly developed with French Roussel Company, it was successfully developed in 1977 and launched in 1980. Its powder injection product is named Claforan, which has the characteristics of broad spectrum, high efficiency, enzyme resistance, and small toxic and side effects. It is clinically used in various sensitive bacterial infections Treatment. [0003] With the continuous improvement o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/04C07D501/12C07D501/34
CPCC07D501/04C07D501/12C07D501/34
Inventor 程广业祁振海雷影赵玲玉刘亮亮张海燕杨欣
Owner 河北合佳创新医药科技有限公司
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