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Synthesis method of cefepime hydrochloride

A technology of cefepime hydrochloride and a synthesis method, which is applied in the synthesis field of cefepime hydrochloride, can solve problems such as troublesome processing and reduced yield, and achieve the effects of low reagent cost, simple processing and high yield

Inactive Publication Date: 2021-06-25
刀鹏
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of these two methods is the use of polyhalogenated hydrocarbon solvents that are strictly prohibited by environmental protection.
[0008] According to the method of patent CN 107201391, it avoids the formation of isomers well, but it needs to remove two protecting groups in two steps, which makes the processing troublesome and the yield decreases

Method used

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  • Synthesis method of cefepime hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 1) Control the temperature at 25°C, add 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid benzhydryl hydrochloride into 100ml of tetrahydrofuran, stir to dissolve, drop into 9.66 g of di-tert-butyl dicarbonate was stirred under temperature control for 3 hours, then extracted with water and dichloromethane to obtain a dichloromethane solution of the Boc protected product.

[0025] 2) Add 3.77 g of N-methylpyrrolidine to the dichloromethane solution of the Boc-protected product at 25°C, and stir under temperature control for 3 hours. After the reaction is completed, the solvent is spin-dried, and the crude product is stirred with diethyl ether, crystallized and filtered to obtain the inner salt compound.

[0026] 3) At 0°C, the internal salt product obtained in step 2 was stirred in 50ml methanol and 3M HCl to remove the carboxyl and amino protecting groups. After the reaction was completed, continue to add 50ml methanol, stir and f...

Embodiment 2

[0029] 1) Control the temperature at 25°C, add 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid benzhydryl hydrochloride into 100ml of tetrahydrofuran, stir to dissolve, drop into 9.66 g of di-tert-butyl dicarbonate was stirred under temperature control for 3 hours, then extracted with water and dichloromethane to obtain a dichloromethane solution of the Boc protected product.

[0030] 2) Add 3.77 g of N-methylpyrrolidine to the dichloromethane solution of the Boc-protected product at 25°C, and stir under temperature control for 3 hours. After the reaction is completed, the solvent is spin-dried, and the crude product is stirred with diethyl ether, crystallized and filtered to obtain the inner salt compound.

[0031] 3) At -10°C, stir the internal salt product obtained in step 2 in 50ml methanol and 3M HCl to remove the carboxyl and amino protecting groups. After the reaction is completed, continue to add 50ml methanol, stir and filter ...

Embodiment 3

[0034] 1) Control the temperature at 25°C, add 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephalosporin-4-carboxylic acid benzhydryl hydrochloride into 100ml of tetrahydrofuran, stir to dissolve, drop into 9.66 g of di-tert-butyl dicarbonate was stirred under temperature control for 3 hours, then extracted with water and dichloromethane to obtain a dichloromethane solution of the Boc protected product.

[0035] 2) Add 3.77 g of N-methylpyrrolidine to the dichloromethane solution of the Boc-protected product at 25°C, and stir under temperature control for 3 hours. After the reaction is completed, the solvent is spin-dried, and the crude product is stirred with diethyl ether, crystallized and filtered to obtain the inner salt compound.

[0036] 3) At 10°C, stir the internal salt product obtained in step 2 in 50ml methanol and 3M HCl to remove the carboxyl and amino protecting groups. After the reaction is completed, continue to add 50ml methanol, stir and filter t...

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Abstract

The invention relates to a synthesis method of cefepime hydrochloride, which comprises the following steps: by taking 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride as a raw material, protecting amino by using di-tert-butyl dicarbonate ester, reacting with N-methylpyrrolidine, and removing 4-site and 7-site protecting groups by using acid to obtain an intermediate 7-amino-3-(1-methyltetrahydropyrrole)methyl)-3-cephem-4-carboxylic acid hydrochloride (7-ACP); and then carrying out an acylation reaction with aminothiazide sulfhydryl benzothiazole active ester (AE-active ester) to obtain the product. The route has the advantages of simple reaction treatment, harsh reaction conditions, less isomer generation, high yield, high purity and simple process, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of synthesis of cephalosporin raw materials, in particular to a synthesis method of cefepime hydrochloride. Background technique [0002] Cefepime hydrochloride is the fourth generation of cephalosporin antibiotics for injection, which was developed and marketed in 1993 by Boomer-Squibb Company of the United States. Compared with the commonly used third-generation cephalosporins, it has a wider antibacterial spectrum, stronger effect on Gram-positive bacteria, and more stable to lactamase. In this paper, the synthesis process of cefepime hydrochloride was studied. The structure of cefepime hydrochloride is [0003] [0004] In the exploration of different routes for the synthesis of cefepime hydrochloride, the predecessors all encountered the problem of 2,3-position isomerism when the three-position side chain is connected. Its isomerization mechanism has been studied: since N-methylpyrrolidine (NMP) has both nu...

Claims

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Application Information

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IPC IPC(8): C07D501/46C07D501/04C07D501/06C07D501/12
CPCC07D501/06C07D501/46Y02P20/55
Inventor 刀鹏
Owner 刀鹏
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