Method for preparing high-purity bendamustine hydrochloride

Abstract

The invention provides a method for preparing high-purity bendamustine hydrochloride. The method comprises the following steps of: (1) completely dissolving oily or colloidal 4-{5-[bis-(2-ethoxyl)amino]-1-methyl-2 benzimidazole}ethyl butyrate in 0.1 to 0.5g / ml solution of C1 to C4 alkyl acetate, wherein the dissolution temperature is 0 to 40 DEG C; (2) adding C5 to C8 hydrocarbons into the solution obtained in the step (1) dropwise, stirring the mixed solution at the temperature of between 10 DEG C below zero and 40 DEG C for crystallization, filtering the mixed solution to obtain solids of 4-{5-[bis-(2-ethoxyl)amino]-1-methyl-2 benzimidazole}ethyl butyrate; (3) performing chlorination on the solids of 4-{5-[bis-(2-ethoxyl)amino]-1-methyl-2 benzimidazole}ethyl butyrate obtained in the step 2 and thionyl chloride, performing hydrolysis by using concentrated hydrochloric acid to obtain salts, and purifying the salts to obtain the crude products of bendamustine hydrochloride; and (4) refining the crude products of bendamustine hydrochloride obtained in the step 3 by using water to obtain the finished products of bendamustine hydrochloride. The purity of the products prepared by the method of the invention is over 99.5 percent, and the content of single impurity is below 0.1 percent; and the method has the advantages of high yield, high product stability and suitability for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of high-purity bendamustine hydrochloride, which belongs to the technical field of pharmaceutical production. Background technique [0002] Bendamustine hydrochloride, the chemical name is [1-methyl-2-(4'-butanoyl)-5-N,N'-di-(2'-chloroethyl)]-1H-benzo Imidazole hydrochloride, the structural formula is: [0003] [0004] Bendamustine hydrochloride was first developed in the early 1960s by Ozegowski and colleagues at the Institute for Microbiological Experiments in Jena, Germany. The purpose of the synthesis is to link an alkylated nitrogen mustard (a non-functional alkylating agent) to a purine and an amino acid. The major advantage of the newly synthesized compound over chlorambucil is its water solubility. Anger et al. published initial clinical results of the successful use of bendamustine in patients with plasmacytoma. Bendamustine was produced under the trade name Cytostasan by the pharmaceutical...

AI Technical Summary

Problems solved by technology

[0011] The chemical name of the intermediate 7 in the above reaction process is: ethyl 4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-2benzimidazole} butyrate, and the intermediate 7 reported in the literature is all It exists in the form of oil or jelly, which not only has low purity and poor stability, but cannot meet the necessary storage stability. During the storage process, it will inevitably lead to a decrease in purity, an increase in the content of similar substances, and a deepening of the color; Benzene hydrochloride obtained by chlorination and hydrolysis of ethyl 4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-2benzimidazole}butyrate in colloidal form The yield of damustine is extremely low, and the purity of the finished product can barely reach 99% after multiple recrystallization methods, but it is very difficult to continue to improve its purity on this basis, especially to control a single impurity below 0.1% It is impossible to achieve, it is difficult to meet the quality requirements of injection raw materials, and it also fails to reach the relevant technical requirements of the European Union's quality research technical guidelines ICH, which makes the research and development of bendamustine hydrochloride injection stagnant, making bendamustine hydrochloride Tin raw materials cannot be exported to European and American countries

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