Method for purifying cefozopran hydrochloride

Abstract

The invention discloses a method for purifying cefozopran hydrochloride, and the method sequentially comprises the following steps: (1) mixing a cefozopran hydrochloride crude product and monobasic alkali in a molar ratio of 1: (2.1-3.0) to generate a cefozopran salt solution; (2) filtering out solid impurities from the cefozopran salt solution, adding hydrochloric acid to adjust the pH value to be neutral, and adding water to precipitate a cefozopran solid; (3) reacting the separated cefozopran solid with hydrochloric acid to prepare a primary refined cefozopran hydrochloride product; (4) carrying out vacuum drying on the primary cefozopran hydrochloride refined product to obtain the cefozopran hydrochloride refined product. According to the principle that the water solubility of the cefozopran is poor, the crude cefozopran hydrochloride is alkalized and then separated out, the residual amount of organic matter is reduced, excessive water is removed through vacuum drying, and the purer refined cefozopran hydrochloride is obtained.

Description

technical field [0001] The invention relates to the technical field of preparation of cefozopran hydrochloride, in particular to a purification method of cefozopran hydrochloride. Background technique [0002] Cefozolam hydrochloride, its chemical name is: [[(6R,7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methanol Oxyiminoacetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]imidazo[1,2 -b] Pyridazinium hydroxide inner salt monohydrochloride, molecular formula: C19H17N9O5S2. HCl, molecular weight: 551.99, structural formula: [0003] [0004] Cefazolam hydrochloride is the fourth-generation cephalosporin for injection developed by Takeda Pharmaceutical Co., Ltd. in Japan. At present, it has been widely used in the treatment of various infectious diseases including neonatal infection in Japan as the drug of choice in the early stage of out-of-hospital infection. . [0005] In the preparation process of cefazolam hydrochloride, from the intermedia...

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Problems solved by technology

[0005] In the preparation process of cefazolam hydrochloride, from the intermediate (6R, 7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- Methoxyiminoacetamido]-3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl-8-oxo-5-thio-1-nitrogen Heterobicyclo[4.2.0]octyl-2-enyl-2-carboxylic acid (hereinafter referred to as cefazolam) to (6R,7R)-7-[(Z)-2-(5-amino-1,2 , 4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl During the synthesis of -8-oxo-5-thio-1-azabicyclo[4.2.0]octyl-2-enyl-2-carboxylic acid monohydrochloride (hereinafter referred to as cefzoram hydrochloride) , it is easy to produce excessive moisture

[0006] In addition, in the preparation process of cefozopran hydrochloride, the phenomenon that the product dissolves and remains beyond the standard due to the generation of solvation will also occur. One or several kinds are solvents, dissolve to obtain cefozopran hydrochloride solution, and then carry out (about 500 times) crystallization, filtration, Washing, obtain cefozopran hydrochloride, in this method, not only solvent consumption is too large, and production cost is high, and there is the phenomenon that solvent is not easy to remove

If the solvent is removed by heating, for acetone, the verification proves that vacuum drying at 80°C is required to remove it, but because cefozopran hydrochloride is very unstable, experiments have proved that cefozopran hydrochloride will decompose when it is dried in vacuum above 40°C. The color deepens and the purity decreases; it is very difficult to remove these solvents. After obtaining the solvated cefazolam hydrochloride, supercritical technology is used to remove residual solvents. This method is complicated in process and high in supercritical costs. The application cannot meet the demand; in addition, this patent also discloses the use of HCl gas to pass into the organic solvent suspension of ceftozolam to obtain ceftozolam hydrochloride, but the moisture in ceftozolam is difficult to strictly control during the preparation process. Therefore, it is not easy to obtain cefzoram hydrochloride products with qualified moisture content

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