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Preparation method of high-purity cefotetan disodium for injection

A technology for cefotetan disodium and injection, which is applied in purification process, preparation of cefotetan disodium, and production of high-purity pharmaceutical compounds for injection, can solve problems such as easy breakage, affect product quality, etc., achieve reaction Thorough, avoid quality risk, easy to operate effect

Active Publication Date: 2017-09-08
NORTH CHINA PHARMA HEBEI HUAMIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Patent CN200610084416 provides a method for preparing cefotetan acid without using an organic solvent. After separating the crude product with tautomer content, it is purified through a resin chromatography column. However, since the resin is a high-molecular substance, It is prone to breakage in the process of industrial production, which affects product quality

Method used

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  • Preparation method of high-purity cefotetan disodium for injection
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  • Preparation method of high-purity cefotetan disodium for injection

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preparation example Construction

[0034] The method for preparing high-purity cefotetan disodium for injection of the present invention has the following specific implementation steps:

[0035] a. Under the protection of nitrogen, the reaction material 7-MAC (chemical name 7β-amino-7α-methoxy-3-(1-methyl-1H-tetrazole-5-thiomethyl)-3-cephalosporin Diphenylmethyl ene-4-carboxylate) was dissolved in the solvent dichloromethane, the temperature was reduced to -25~-40℃, pyridine was added as a catalyst, and the dichloromethane solution of the acylating agent was added, stirred uniformly and acylated For the reaction, the reaction temperature is controlled at -20 to -40°C, and the reaction time is 15 to 45 minutes; the acylating agent is any one or a mixture of chloroacetyl chloride or bromoacetyl bromide.

[0036] b. Adjust the pH of the solution after the reaction in step a to below 1.0 with dilute sulfuric acid or dilute hydrochloric acid. After the solution is allowed to stand for phase separation, the dichloromethan...

Embodiment 1

[0042] a. Under the protection of nitrogen, dissolve the reaction raw material 7-MAC in the solvent dichloromethane, reduce the temperature to -38°C, add pyridine as a catalyst, and then add the dichloromethane solution of the acylating agent chloroacetyl chloride, stir well and proceed. For acylation reaction, the reaction temperature is controlled at -35°C, and the reaction time is 30 minutes;

[0043] b. Adjust the pH of the solution after the reaction in step a to 0.5 with dilute sulfuric acid or dilute hydrochloric acid. After the solution is allowed to stand for phase separation, the dichloromethane phase is separated, and purified water is added to the dichloromethane phase, and the solution is allowed to stand again Phase and separate the dichloromethane phase, add anhydrous magnesium sulfate to the dichloromethane phase separated again, stir well, filter, remove the filter residue, add equal mass mixed n-butanol, dichloromethane, Ethyl acetate and tetrahydrofuran are use...

Embodiment 2～5

[0049] The steps of the preparation method used in Examples 2 to 5 are the same as those in the foregoing Example 1, and the different process parameters or the selected different types of compounds are shown in Table 1 below. Among them, "temperature I" in step a represents the temperature reached by 7-MAC after being dissolved in dichloromethane; "temperature II" represents the temperature during the acylation reaction; "time A" represents the time of the acylation reaction; step b Among them, "pH-1" represents the pH value of the solution after the reaction in step a is adjusted with dilute sulfuric acid or dilute hydrochloric acid; "Temperature III" represents the temperature reached after adding the catalyst; "Time B" represents the time of the hydrolysis reaction; In step c, "temperature IV" represents the temperature after ice water is added; "pH-2" represents the pH value of the solution before the phase separation; "pH-3" represents the pH value of the condensation reac...

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Abstract

The invention discloses a preparation method of high-purity cefotetan disodium for injection, belonging to the process fields of production and purification of cephalosporin antibiotics. The preparation method comprises the steps of carrying out acylation reaction, hydrolysis reaction and condensation reaction on the main raw materials including 7-MAC, an acylating agent and isothiazole mono-sodium salt, carrying out purification and impurity removal by virtue of an activated alumina chromatographic column, and carrying out the steps of decoloration, salt formation, refining and the like, so as to prepare cefotetan disodium. According to the preparation method, the quality risks caused by residual solvent residues and resin-free crushing can be overcome, the product quality is relatively good, and the impurity content is relatively low; and furthermore, the preparation method is relatively low in cost, simple in operation, saving in energy, environmentally friendly and suitable for industrial production.

Description

Technical field [0001] The invention relates to the production and preparation of cephalosporin antibiotics, in particular to a preparation method of cefotetan disodium, which belongs to the production and purification process of high-purity pharmaceutical compounds for injection. Background technique [0002] Cefotetan disodium is a broad-spectrum antibiotic of cephalosporins. Its effect is similar to that of the third-generation cephalosporins. It has stronger effects on Gram-negative bacteria than the first and second-generation cephalosporins. It is used to treat specific bacteria Infections caused by sensitive strains have a good effect on enzyme-producing gram-negative bacteria and anaerobic bacteria. Cefotetan disodium was first developed by Japan's Yamanouchi Pharmaceutical Co., Ltd., and it was listed in Japan in the 1980s. After that, AstraZeneca was authorized to sell in countries other than Japan. The internationally registered trade names are Cefotan and Apatef. In ...

Claims

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Application Information

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IPC IPC(8): C07D501/57C07D501/06C07D501/12
Inventor 贾全张锁庆魏宝军马亚松田洪年胡少华张立斌张文胜魏阔杨梦德张映雪孙玉双
Owner NORTH CHINA PHARMA HEBEI HUAMIN PHARMA
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