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A preparation method of a high -purity injection for cephalosporin sodium

A technology for cefotetan disodium and injection, which is applied in the production and purification process of high-purity injection drug compounds, and the field of preparation of cefotetan disodium, which can solve the problems of affecting product quality and easy breakage, so as to avoid The effect of quality risk, reaction thoroughness, reaction efficiency and conversion rate improvement

Active Publication Date: 2019-09-17
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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  • A preparation method of a high -purity injection for cephalosporin sodium
  • A preparation method of a high -purity injection for cephalosporin sodium
  • A preparation method of a high -purity injection for cephalosporin sodium

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preparation example Construction

[0034] A kind of preparation method of high-purity cefotetan disodium for injection of the present invention, its specific implementation steps are as follows:

[0035]a. Under the protection of nitrogen, the reaction raw 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 dichloromethane as a solvent, cooled to -25~-40°C, added pyridine as a catalyst, and then added dichloromethane solution of acylating agent, stirred evenly and acylated 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, separate the dichloromethane phase, add pu...

Embodiment 1

[0042] a. Under the protection of nitrogen, dissolve the reaction material 7-MAC in the solvent methylene chloride, cool down to -38°C, add pyridine as a catalyst, and then add the methylene chloride solution of acylating agent chloroacetyl chloride, stir evenly and carry out 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 dichloromethane phase is separated again. phase and separate the dichloromethane phase, add anhydrous magnesium sulfate to the dichloromethane phase that has been separated again, stir well and filter, remove the filter residue, and add n-butanol, dichloromethane, Ethyl acetate and tetrahydrofuran were used...

Embodiment 2～5

[0049] The steps of the preparation method adopted in Examples 2 to 5 are the same as those in the above-mentioned Example 1, but the different process parameters or selected different types of compounds are shown in Table 1 below. Wherein, in step a, "temperature I" represents the temperature reached by cooling after 7-MAC is dissolved in solvent methylene chloride; "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 adding ice water; "pH-2" represents the pH value of the solution before static phase separation; "pH-3" represents the pH value of ...

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Abstract

The invention discloses a preparation method of high-purity cefotetan disodium for injection, which belongs to the field of production and purification process of cephalosporin antibiotics. The main raw materials are 7‑MAC, acylating agent and isothiazole monosodium salt. After the acylation reaction, hydrolysis reaction and condensation reaction, the active alumina chromatography column is used to purify and remove impurities, and then after steps such as decolorization, salt formation and refining, cefotetan disodium is finally obtained; the present invention can overcome organic solvents Residue and no quality risk caused by resin crushing, better product quality and lower impurity content, and lower cost, simple operation, energy saving and environmental protection, 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 injection drug compounds. Background technique [0002] Cefotetan disodium is a broad-spectrum antibiotic of the cephalosporin class, its effect is similar to that of the third-generation cephalosporins, and its effect on Gram-negative bacteria is stronger than that of the first and second-generation cephalosporins. Infections caused by sensitive strains have a better effect on enzyme-producing Gram-negative bacteria and anaerobic bacteria. Cefotetan disodium was first developed by Yamanouchi Pharmaceutical Co., Ltd. in Japan, and was launched in Japan in the 1980s. Later, AstraZeneca of Sweden was authorized to be launched in countries other than Japan. The internationally registered trade names are Cefotan and Apatef. In 2007, Cefotet...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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