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Process for producing 7-amino-3-[(1-methyl pyrrolidine) methyl]-3- cephalosporin-4-carboxylic dihydrochloride

A technology of methyltetrahydropyrrole and carboxylic acid dihydrochloride, applied in the synthesis of cephalosporin antibiotic intermediates, 7-amino-3-[methyl]-3-cephalosporin-4-carboxylic acid di-salt In the field of salt synthesis, it can solve problems affecting product yield and quality, poor product color and quality, long reaction time, etc., and achieve the effect of long reaction time, many side reactions, and fast reaction speed

Inactive Publication Date: 2009-05-13
河北九派制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this patent application, hexamethyldisilazane (HMDS) is used to protect 7-ACA under reflux in trifluorotrichloroethane (or cycloalkane, methylene chloride, carbon tetrachloride, chloroform, etc.) Amino and carboxyl groups, long reaction time, many side reactions, poor product color and quality, affecting the yield and quality of the final product

Method used

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  • Process for producing 7-amino-3-[(1-methyl pyrrolidine) methyl]-3- cephalosporin-4-carboxylic dihydrochloride
  • Process for producing 7-amino-3-[(1-methyl pyrrolidine) methyl]-3- cephalosporin-4-carboxylic dihydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1: A. After adding 30g imidazole, 54g trimethylchlorosilane (TMSC1) and 40g0.147mol of 7-ACA in a container with 250ml dichloromethane solvent successively, under stirring state at 20~25°C Carrying out the reaction, the above reaction is carried out for 2 to 3 hours and then filtered, and the generated imidazole hydrochloride which affects the subsequent layering and crystallization is removed by filtration, so as to facilitate the subsequent reaction;

[0022] B. The filtrate in the previous step is a silanized 7-ACA dichloromethane solution. When the filtrate is cooled to 10-15°C, add 50ml of 0.183mol iodotrimethylsilane (TMSI) dropwise, and then stir for 15-20 minutes. The reaction is carried out under the condition of 15-20 ℃ heat preservation, and the end point of the reaction can be tracked by HPLC;

[0023] C. When the reaction of step B is carried out after 3 hours, use HPLC to detect that when the 7-ACA residue is less than 1%, the reaction ends, and th...

Embodiment 2

[0032] A. Add 30g of imidazole, 54g of trimethylchlorosilane (TMSC1) and 40g of 0.147mol 7-ACA in sequence in a container containing 250ml of dichloromethane solvent, and then react at 20-25°C under stirring. After the reaction is carried out for 2 to 3 hours, filter, and filter and remove the generated imidazole hydrochloride that affects the subsequent layering and crystallization, so as to facilitate the subsequent reaction;

[0033] B. When the above filtered filtrate is cooled to 10-15°C, add 50ml of 0.183mol iodotrimethylsilane (TMSI) solution dropwise, then stir for 15-20 minutes and then carry out the reaction at 15-20°C while keeping warm. Use HPLC to track the end point of the reaction;

[0034] C. When the reaction in the above step is carried out for 3 hours, use HPLC to detect that when the 7-ACA iodide is complete, that is, the 7-ACA residue is less than 1%, then the reaction ends, and then the reaction feed liquid is distilled at 101Kp to distill out the reactio...

Embodiment 3

[0043] A. Add 25g of imidazole, 48g of trimethylchlorosilane (TMSC1) and 40g of 0.147mol 7-ACA in sequence in a container containing 250ml of dichloromethane solvent, and then react at 20-25°C under stirring. After the reaction is carried out for 2 to 3 hours, filter, and filter and remove the generated imidazole hydrochloride that affects the subsequent layering and crystallization, so as to facilitate the subsequent reaction;

[0044] B. When the above filtered filtrate is cooled to 10-15°C, add 50ml of 0.183mol iodotrimethylsilane (TMSI) solution dropwise, then stir for 15-20 minutes and then carry out the reaction at 15-20°C while keeping warm. Use HPLC to track the end point of the reaction;

[0045] C. When the reaction of step B is carried out after 3 hours, use HPLC to detect that when the 7-ACA iodide is complete, that is, the 7-ACA residue is less than 1%, the reaction ends. After the reaction ends, the reaction feed liquid is distilled at 101Kp to distill Excessive...

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Abstract

The invention discloses a method for preparing 7-amino-3-[(1-methylpyrro-lidinio)methyl]-3-cephem-4-carboxylic acid dihydrochloride, which comprises the following steps: imidazole, trimethylchlorosilane and 7-ACA react in a methylene dichloride solvent at a temperature of between 10 and 30 DEG C, and then are filtered; the temperature is reduced, and TMSI is dripped to react; THF is added into the mixture after methylene dichloride is distilled from a reaction feed liquid, and a N-methylpyrrolidine solution is dripped and stirred at a temperature of between 30 DEG C below zero and 25 DEG C below zero to react; methanol is dripped after the reaction, and then concentrated hydrochloric acid or hydriodic acid is dripped to hydrolyze; a hydrolysate is added with the methylene dichloride, and an aqueous phase is obtained through the separation; a yellow aqueous solution is obtained after the aqueous phase is decolored; and then acetone is added into the mixture to be filtered, washed and dried to obtain a 7-MPCA product. The methylene dichloride is distilled, so as to effectively improve the utilization rate of equipment, and the method can improve 30 percent of the utilization rate of the equipment compared with a process that the methylene dichloride is not distilled; and imidazole hydrochloride generated by the reaction which affects the subsequent layering and crystallization is filtered, which is favorable for the reaction, and ensures that the yield can reach 100 percent and the purity of a liquid phase is more than 99 percent.

Description

technical field [0001] The present invention relates to the field of pharmaceutical intermediates, in particular to a synthetic method of cephalosporin antibiotic intermediates, namely 7-amino-3-[(1-methyltetrahydropyrrole)methyl]-3-cephalosporin-4- Synthetic method of carboxylic acid dihydrochloride. Background technique [0002] Cefepime hydrochloride is the fourth-generation cephalosporin for injection, developed by Bristol-Myers Squibb (Bristol-Myers Squibb), and has been used for the treatment of various bacterial infectious diseases since it was first launched in Sweden in 1993. Cefepime has a broad antibacterial spectrum. It not only maintains a good antibacterial effect on Gram-negative bacteria, but also has strong anti-staphylococcal activity, strong antibacterial effect, high stability to β-lactamase, and drug resistance. It has good acceptability, so it is a promising antibiotic, and its intermediate 7-amino-3-[(1-methyltetrahydropyrrole) methyl]-3-cephalosporin...

Claims

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Application Information

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IPC IPC(8): C07D501/18
Inventor 张辑钟建西张晓光邱玉敏李培鸿张青坡
Owner 河北九派制药股份有限公司
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