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Preparation method of cefepime hydrochloride with reduced content of genotoxic impurity 2-mercaptobenzothiazole

A technology of cefepime hydrochloride and cefepime hydrochloride, which is applied in the field of preparation of cefepime hydrochloride, can solve the problems of drug safety threats, strong toxicity, and economic losses of pharmaceutical factories

Active Publication Date: 2020-12-11
GUANGZHOU HC PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because of its strong toxicity, it poses a strong threat to the safety of medication. In recent years, more and more medical accidents have occurred due to traces of genotoxic impurities found in marketed drugs. FDA In the case of forced recall, the pharmaceutical factory caused huge economic losses

Method used

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  • Preparation method of cefepime hydrochloride with reduced content of genotoxic impurity 2-mercaptobenzothiazole
  • Preparation method of cefepime hydrochloride with reduced content of genotoxic impurity 2-mercaptobenzothiazole
  • Preparation method of cefepime hydrochloride with reduced content of genotoxic impurity 2-mercaptobenzothiazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 10g of cefepime side chain compound into 40ml of dichloromethane, add 8.3ml of triethylamine, stir and react for half an hour, add 9.46g of AE active ester to the solution, stir and react for 2 hours at 25-28°C; then, the reaction Pour the liquid into 200ml water, extract, stand and stratify, add 5wt% dilute hydrochloric acid to the obtained water phase, adjust the pH of the water phase to 2.4-2.5, add 20ml×2 toluene to the water phase for extraction twice, and separate the water phase; Add 1g of activated carbon to the water phase, stir and decolorize at room temperature for 20 minutes, filter, wash the activated carbon layer with 10ml of water, and combine the water phases; add 5wt% dilute hydrochloric acid to the combined water phase after decolorization to adjust the pH of the water phase to 1.0-1.1, and then slowly 105ml of acetone was added dropwise, and a large amount of white precipitate was precipitated to obtain 14.4g of cefepime hydrochloride with a molar ...

Embodiment 2

[0045] Add 10g of cefepime side chain compound into 60ml of dichloromethane, add 10ml of triethylamine, stir and react for half an hour, add 10.5g of AE active ester to the solution, stir and react for 2 hours at 25-28°C; then, the reaction solution Pour it into 240ml of water, carry out extraction, let it stand for stratification, add 12wt% dilute hydrochloric acid to the obtained water phase, adjust the pH of the water phase to 2.0-2.1, add 24ml×2 xylene to the water phase for extraction twice, and separate the water phase; Add 2g of activated carbon to the water phase, stir at room temperature for 20 minutes to decolorize, filter, wash the activated carbon layer with 20ml of water, and combine the water phase; add 12wt% dilute hydrochloric acid to the water phase after decolorization to adjust the pH of the water phase=1.4-1.5, and then slowly 260ml isopropanol was added dropwise, and a large amount of white precipitates were separated out to obtain cefepime hydrochloride 14...

reference example 1

[0047] Dissolve 8g of cefepime side chain compound in 40ml of dichloromethane, add 10ml of triethylamine, stir and react for half an hour, add 7.4g of AE active ester to the solution, stir and react for 2 hours at 28°C; then, pour the reaction solution into 200ml of water, extract, stand for stratification, add 5wt% dilute hydrochloric acid to the obtained water phase, adjust the pH of the water phase to about 1.15, add 20ml of ethyl acetate to the water phase, extract, stand for stratification, and separate the water phase Add 1g of activated carbon to the water phase, stir and decolorize at room temperature for 20 minutes, filter, wash the activated carbon layer with 10ml water, and merge the water phase; slowly add 100ml of acetone dropwise to the combined water phase after decolorization, and a large amount of white precipitates are separated out to obtain cephalosporin hydrochloride Piroxime 11.0g, molar yield 83%, product purity 99.2%, 2-mercaptobenzothiazole content 14mm...

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a preparation method of cefepime hydrochloride. The preparation method comprises the steps: in a dichloromethane solvent, in the presence of triethylamine, carrying out acylation reaction on a cefepime side chain compound and AE active ester; after the reaction, adding water into the reaction liquid, and extracting to obtaina water phase; adding hydrochloric acid into the water phase to adjust the pH value of the water phase to 2.0-2.5, then adding a water-insoluble organic solvent, extracting, standing for layering, and separating out the water phase; adjusting the pH value of the water phase to 1.0-1.5 with hydrochloric acid after activated carbon decoloration, and adding a crystallization solvent to obtain cefepime hydrochloride. According to the cefepime hydrochloride prepared by the preparation method disclosed by the invention, the content of a genotoxic impurity 2-mercaptobenzothiazole in the cefepime hydrochloride is reduced to 1-5 mmp, even 1-3 mmp, so that the safety of a cefepime hydrochloride medicine is improved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a preparation method of cefepime hydrochloride, in particular to a preparation method of cefepime hydrochloride with reduced genotoxic impurity 2-mercaptobenzothiazole content. Background technique [0002] Cefepime is a fourth-generation cephalosporin developed by Bristol-Myers Squibb. It was first used clinically in Sweden in 1993, and was subsequently marketed in Europe, the United States, Japan and other countries. Bristol-Myers Squibb took the lead in introducing cefepime for injection (trade name "Masiping", Maxipime) into China in 1998, and obtained administrative protection for drugs in China in August 1999. Because the drug is stable to β-lactamase, it has a wider antibacterial spectrum than the antibiotics currently used clinically. It has played a good clinical role in the treatment of lower respiratory tract, skin and bone tissue, urinary system, gynecology and abdom...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/06C07D501/12C07D501/46
CPCC07D501/06C07D501/12C07D501/46
Inventor 林立东冯彩云
Owner GUANGZHOU HC PHARM CO LTD
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