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Preparation method of 7-alpha amino 7-methoxy-3-methyltetrazolium thiomethyl cephalosporanic acid benzyl ester

A kind of technology of methyl tetrazolium thiomethyl cephalosporanic acid benzyl ester and methoxy group, which is applied in the field of preparation of 7-alpha amino 7-methoxy-3-methyltetrazolium thiomethyl cephalosporanic acid benzyl ester , which can solve the problems of unable to meet the requirements of 7-MAC light transmittance and difficult to meet the requirements of downstream products, and achieve the effect of less impurity precipitation, complete crystallization and slow crystallization speed.

Inactive Publication Date: 2011-12-07
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, the light transmittance of 7-MAC prepared by the existing process is 60% to 70%, which is difficult to meet the requirements of downstream products, and also cannot meet the requirements of some domestic and foreign pharmaceutical companies for higher light transmittance of 7-MAC

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] 1. Preparation of methoxylating reagent aluminum salt

[0020] a. Add 10kg of aluminum trichloride to 125kg of methanol, heat up to 25°C, and react under stirring;

[0021] b. After the above reaction for 40 minutes, add 16.5kg of sodium bicarbonate to adjust the pH of the reaction solution to 7.5-8.5, then continue the reaction at 20-25°C for 30 minutes under stirring to prepare the methoxylating reagent aluminum salt solution ,spare;

[0022] 2. Preparation of 7-MAC

[0023] a. Add 55kg of 7-thiamine-3-methyltetrazolium thiomethyl cephalosporanic acid benzyl ester to 1000kg of dichloromethane, stir at -5~5°C for 15 minutes, then add 30kg of triphenylphosphine , and then react under stirring;

[0024] b. After the above reaction for 20-30 minutes, add the prepared aluminum methoxylate solution, and then continue the reaction at 2-5°C under stirring;

[0025] c. When the residue of benzyl 7-thiamine-3-methyltetrazolium thiomethyl cephalosporanate in the above reacti...

Embodiment 2

[0028] 1. Preparation of methoxylating reagent aluminum salt

[0029] a. Add 18kg of aluminum trichloride to 150kg of methanol, heat up to 35°C, and react under stirring;

[0030] b. After the above reaction for 20 minutes, add 16.5kg of sodium bicarbonate to adjust the pH of the reaction solution to 7.5-8.5, then continue the reaction at 20-25°C for 25 minutes under stirring to prepare the methoxylating reagent aluminum salt solution ,spare;

[0031] 2. Preparation of 7-MAC:

[0032] a. Add 40kg of 7-thiamine-3-methyltetrazolium thiomethyl cephalosporanic acid benzyl ester to 1500kg of dichloromethane, stir at -5~5°C for 15 minutes, then add 35kg of triphenylphosphine , and then react under stirring;

[0033] b. After the above reaction for 20-30 minutes, add the prepared methoxylating reagent aluminum salt solution, and then continue the reaction at 2-5°C under stirring;

[0034] c. When the residue of benzyl 7-thiamine-3-methyltetrazolium thiomethyl cephalosporanate in ...

Embodiment 3

[0036] Embodiment 3: The difference between this embodiment and Embodiment 1 is that 600 kg of methanol is used instead of 650 kg of methanol.

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Abstract

The invention discloses a preparation process of 7-MAC which can effectively improve the light transmittance of the product. Aluminum trichloride is added to methanol, and after the temperature is raised, the reaction is carried out in a stirring state to prepare the aluminum salt of the methoxylation reagent; Add 7-thiamine-3-methyltetrazolium thiomethyl cephalosporanic acid benzyl ester to methyl chloride, add triphenylphosphine after stirring, and then add methoxylated aluminum salt solution to continue the reaction, when the residual < At 0.5%, washing, decolorizing, concentrating, filtering to obtain wet product, and then drying at low temperature gradient to obtain finished product. The invention can timely and effectively control the crystallization state of the product, slow down the crystallization speed, and has high product purity, and can ensure that the light transmittance of the final product reaches more than 85%, which is 60-70% higher than that of the 7-MAC prepared by the prior art. % level; compared with the prior art, the light transmittance of the 7-MAC of the present invention only decreased by about 10%; under normal storage conditions, the light transmittance of the 7-MAC prepared by the existing process decreased by about 18% compared with that of the present invention. Significantly decreased, making up for the defect of quality reduction in storage and transportation.

Description

technical field [0001] The invention relates to an important intermediate in the synthetic process of antibiotics such as cefmetazole sodium, cefminox sodium and cefotetan, that is, benzyl 7-αamino 7-methoxy-3-methyltetrazolium thiomethyl cephalosporanate The preparation method of ester (abbreviated 7-MAC). Background technique [0002] At present, many manufacturers at home and abroad that produce 7-αamino 7-methoxy-3-methyltetrazolium thiomethyl cephalosporanic acid benzyl ester, that is, 7-MAC, have increased their attention to product quality indicators, especially with the With the country's stricter supervision on the quality of cephalosporin antibiotics, various pharmaceutical manufacturers continue to improve the quality standards of various antibiotic intermediates. 7-MAC is used as a variety of important second-generation cephalosporins such as cefmetazole sodium and cefminox Sodium, cefotetan and other important intermediates, the improvement of the quality of 7-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/18C07D501/04
Inventor 张晓光祁振海刘星刘洁邢彦召张青坡
Owner 河北九派制药股份有限公司
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