Preparation method of cefepime hydrochloride

Abstract

The invention discloses a preparation method of cefepime hydrochloride, comprising the following steps of: reacting oxalyl chloride with 2-methoxyimino-2-(2-aminothiazole-4-yl) acetic acid hydrochloride to obtain a midbody I, i.e. 2-methoxyimino-2-(2-aminothiazole-4-yl) acetyl chloride hydrochloride; mixing silanized 7-aminoce-phalosporanic acid and silanized N-methylpyrrolidine, and reacting to obtain a midbody II, i.e. hydriodic acidification (6R, 7R)-7-amino-3-[(1-methyl-1-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic betaine, in the presence of trimethyl idodine silicon hydride, isopropanol and an aqueous solution of hydrogen iodide; dissolving the midbody II into dichloromethane, sequentially adding trimethylchlorosilane and hexamethyldisilazane for reaction, and then adding the midbody I and triethylamine to react to prepare the cefepime hydrochloride. The cefepime hydrochloride prepared by the method has the advantages of uniform crystal form, good flowability and simple process and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of cefepime hydrochloride. Background technique [0002] Cefepime hydrochloride, whose trade name is Maspin, was developed by Boomer-Squibb Company and launched in Switzerland in 1993; in 1998, Shanghai Bristol-Myers Squibb Company introduced it and sold it in my country. The chemical name of cefepime hydrochloride is: 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-glyoxylamide]-2-carboxy-8-oxo- 5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolium salt, 72-(Z)-(O-methyloxime) Dihydrochloride monohydrate; the structural formula is: [0003] [0004] Cefepime hydrochloride is the fourth-generation cephalosporin for injection, which is based on the molecular structure of the third-generation cephalosporin, and introduces c-3 at the c-3 position of the 7-aminocephalosporanic acid (7-ACA) nucleus 'Quaternary amino substituent compounds. Com...

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Problems solved by technology

However, the cefepime hydrochloride synthesized by the prior art generally has the defects of inhomogeneous crystal form, poor fluidity and high content of related substances. Meanwhile, in the existing synthetic method of cefepime hydrochloride, the reaction conditions are harsh, the raw materials are not easy to obtain, and the process Complexity, low yield, low product purity, and the solvent used in the reaction is highly toxic, cannot be recycled, pollutes the environment, and costs high

[0006] Chinese patent application CN200810022542.3 discloses a method for synthesizing the antibiotic cefepime hydrochloride. The method uses strong acid and alkali, and the equipment is easy to corrode, thereby shortening the service life of the production equipment and making the product mixed with insoluble particles , resulting in indicators such as the clarity and heavy metals of cefepime hydrochloride preparations not meeting the requirements of the Chinese Pharmacopoeia

In this method, p-toluenesulfonyl chloride is used as a catalyst, which affects the final product yield and quality. In addition, the by-product isomers produced in the reaction process are not removed, resulting in high content of related substances and cephalosporin polymers in the final product.

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