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Method for preparing bendamustine hydrochloride

A technology of hydrochloric acid and concentrated hydrochloric acid, which is applied in the field of preparation of bendamustine hydrochloride, can solve the problems of accumulation, low refining yield, cumbersome operation, etc., and achieve the effects of short production cycle, high refining efficiency and high stability

Active Publication Date: 2020-02-07
LIANYUNGANG RUNZHONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

WO2009120386 discloses that a refined solvent is ethanol / water (v / v=97 / 3), but because the heating temperature in the experiment is too high, bendamustine will undergo esterification reaction with the alcohol solvent, resulting in impurities of the esterified product , affecting the quality of finished products, and this impurity will be difficult to remove
The final refining method of CN101691359 is to mix and heat the crude product with tetrahydrofuran (70°C), and then slowly add water until the solid dissolves; however, due to the low boiling point of tetrahydrofuran (66°C), it is easy to bump when it is heated to reflux and then added dropwise. The operation is cumbersome; due to the degradation of bendamustine hydrochloride in the solution, the refining yield is low; and tetrahydrofuran has hepatotoxicity and accumulation, which will cause varying degrees of impact on operators and the environment

Method used

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  • Method for preparing bendamustine hydrochloride
  • Method for preparing bendamustine hydrochloride
  • Method for preparing bendamustine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Dissolve 100 g of the crude product of bendamustine hydrochloride in 300 g of concentrated hydrochloric acid (mass fraction is 37%, concentration is about 12 mol / L), the dissolution temperature is 25°C, dissolve in 15 min, filter while it is hot, add 2.1 L to pre-cool to 10 ℃ purified water, cooled and crystallized, filtered and dried to obtain bendamustine hydrochloride white crystals with a yield of 82%. Using the area normalization method, the HPLC purity detection results are shown in the table below, the purity of bendamustine is 99.79%, and the maximum simple impurity content is 0.048%.

[0024] components HP1 NP1 Bendamustine Hydrochloride Bendamustine hydrochloride methyl ester Bendamustine hydrochloride ethyl ester content 0.028％ 0.022％ 99.79％ 0.021％ 0.048％

Embodiment 2

[0026] Dissolve 100 g of the crude product of bendamustine hydrochloride in 100 g of concentrated hydrochloric acid (mass fraction is 37%, the concentration is about 12 mol / L), the dissolution temperature is 40 ° C, 25 min to dissolve, filter while it is hot, add 900 mL to pre-cool to 10 ° C Cool and crystallize in purified water, filter and dry to obtain bendamustine hydrochloride white crystals with a yield of 89.4%. Using the area normalization method, the HPLC purity detection results are shown in the following table, the purity of bendamustine is 99.86%, and the maximum simple impurity content is 0.044%.

[0027] components HP1 NP1 Bendamustine Hydrochloride Bendamustine hydrochloride methyl ester Bendamustine hydrochloride ethyl ester content 0.042％ 0.008％ 99.86％ 0.044％ /

Embodiment 3

[0029] Dissolve 100 g of the crude product of bendamustine hydrochloride in 150 g of concentrated hydrochloric acid (mass fraction is 37%, concentration is about 12 mol / L), dissolve at a temperature of 30°C, dissolve in 20 minutes, filter while hot, add 700mL to pre-cool to 10°C Cool and crystallize in purified water, filter and dry to obtain bendamustine hydrochloride white crystals with a yield of 91.6%. Using the area normalization method, the HPLC purity detection results are shown in the following table, the purity of bendamustine is 99.92%, and the maximum simple impurity content is 0.029%.

[0030] components HP1 NP1 Bendamustine Hydrochloride Bendamustine hydrochloride methyl ester Bendamustine hydrochloride ethyl ester content 0.025％ / 99.92％ / 0.029％

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Abstract

The invention belongs to the field of drug synthesis and particularly relates to a method for preparing bendamustine hydrochloride. According to the preparation method, concentrated hydrochloric acidis adopted as a refining solvent, thus, the bendamustine hydrochloride can be rapidly dissolved in the concentrated hydrochloric acid at the temperature of 20 DEG C to 45 DEG C, and the production cycle is short; the method is applicable to enlarged-scale industrial production, the refining efficiency is high, the yield is high, the reproducibility is good, and the obtained bendamustine hydrochloride is high in stability; and proven by high-temperature, high-humidity, accelerated and long-term tests, related substances and content thereof are free of obvious changes, the content of each singleimpurity is lower than 0.1%, and particularly, an impurity, i.e., a bendamustine dimer is undetectable, so that the bendamustine hydrochloride meets the technical requirements of ICH European Union (EU) quality research technique governing principles on limit of impurities.

Description

technical field [0001] The application belongs to the field of drug synthesis and relates to a preparation method of bendamustine hydrochloride. Background technique [0002] Bendamustine hydrochloride is a bifunctional alkylating agent, which can lead to the cross-linking of DNA single and double strands through alkylation, disrupting the function of DNA and the synthesis of DNA, so that DNA and protein, as well as protein Cross-linking with proteins, thus exerting anti-tumor effect and anti-metabolism effect, has shown good curative effect in various hematological tumors and solid tumors. On March 20, 2008, bendamustine hydrochloride developed by Cephalon was approved by the US FDA for the treatment of chronic lymphocytic leukemia (CLL), with the trade name Treanda; on October 31 of the same year, the drug was approved for inert Treatment of B-cell non-Hodgkin's lymphoma (NHL). [0003] The chemical name of bendamustine hydrochloride: 4-[5-[bis(2-chloroethyl)amino]-1-met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/16
CPCC07D235/16
Inventor 贺绍杰伯兆柏程进荣苏旭邹西赢
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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