Preparation method of cefotetan disodium

A technology for cefotetan disodium and cefotetan acid, which is applied in the field of preparation of cefotetan disodium, can solve the problems of low product purity, poor appearance quality, complicated process and the like, and achieves high product yield, stable medicinal properties, simple craftsmanship

Inactive Publication Date: 2018-01-05
JIANGSU HI STONE PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The existing synthetic method of cefotetan disodium has defects such as complex process, low product purity, poor appearance quality and low yield

Method used

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  • Preparation method of cefotetan disodium
  • Preparation method of cefotetan disodium
  • Preparation method of cefotetan disodium

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preparation example Construction

[0030] The invention discloses a preparation method of cefotetan disodium, using 7-amino-7-methoxy-3-1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem- 4-diphenylmethyl carboxylate (7-MAC) was used as the starting material, and bromoacetyl bromide was subjected to amidation reaction at low temperature to obtain 7-bromoacetamide-7-methoxy-3-(1-methyl Base-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylate diphenylmethyl ester (intermediate 1), the product of this step is directly subjected to the next step reaction without isolation to obtain the product 7-bromoethyl Amide-7-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid (intermediate 2), and finally with 4-carboxy-3 -Hydroxy-5-mercaptoisothiazole trisodium (CHMT) was reacted to obtain cefotetan acid, and the acid was converted to sodium salt, and then sterile filtered, freeze-dried and pulverized to obtain cefotetan disodium sterile powder.

[0031] The reaction formula is as follows:

[0032]

[0033...

Embodiment 1

[0049] Add 60~80L ethyl acetate, 3.5~4kg 7-amino-7-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem- 4-Diphenylmethyl carboxylate, stirred to dissolve, cooled in ice-water bath to -5~0℃, then added 900~1000g N,N-dimethylaniline, then added dropwise 1.8~2.5kg bromoacetyl bromide,- Under constant temperature conditions of 5-0°C, stir at a stirring rate of 50-80r / min to carry out amidation reaction for 15-30min; then add ice water and ethyl acetate mixed at a volume ratio of 1:3-5 to the reaction liquid The ester was shaken to separate the organic layer, and the organic layer was washed with 0.2-0.5 mol / L hydrochloric acid solution for more than 3 times, then dried with sodium sulfate, filtered, and the filtrate was distilled under reduced pressure at 50°C to remove the organic solvent to obtain the first intermediate 7-Bromoacetamide-7-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester;

[0050] Add 40-50L of dichloromethane and 4-...

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Abstract

The invention discloses a preparation method of cefotetan disodium, comprising the following steps: (1) preparing a first intermediate; (2) separating by extraction; (3) preparing a second intermediate; (4) separating by crystallization; (5) preparing a cefotetan acid crude product; (6) purifying cefotetan acid; and (7) preparing cefotetan disodium. The preparation method of cefotetan disodium hasthe following advantages: the process is simple; reaction condition is mild; controllability of the reaction process is excellent; product yield is high; and the cefotetan disodium obtained has highpurity, low impurity content, good appearance quality and stable drug properties, and has a wide application prospect in clinic.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a preparation method of cefotetan disodium. Background technique [0002] Infectious disease is the most common clinical disease, involving almost all clinical specialties, and it is also one of the most common causes of patient death. According to the report of the World Health Organization in 1997, the number of deaths from infectious diseases was as high as 33.3% of the total number of deaths from various causes. In China, the main diseases that endanger people's health are still infectious diseases caused by various pathogenic bacteria, and they are also the main cause of disability and death. [0003] Cephalosporin antibiotics are one of the main drugs for the effective treatment of infectious diseases. Cefotetan disodium is a semi-synthetic broad-spectrum cephalosporin, which is similar to the third-generation cephalosporins. It has a strong bactericidal ...

Claims

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Application Information

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IPC IPC(8): C07D501/57C07D501/12C07D501/04
Inventor 王多平卫耿虎史加桂芦丽欢
Owner JIANGSU HI STONE PHARMA
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