Method for preparing intermediate in process of preparing bendamustine hydrochloride

A technology for the preparation of bendamustine hydrochloride, which is applied in the field of preparation of intermediates, and can solve the problems of low yield and insufficient purity of intermediates

Active Publication Date: 2012-07-11
武汉长联来福制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the yield of the method disclosed in Reference Document 3 is not high, and the purity of the resulting intermediate is not high enough

Method used

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  • Method for preparing intermediate in process of preparing bendamustine hydrochloride
  • Method for preparing intermediate in process of preparing bendamustine hydrochloride
  • Method for preparing intermediate in process of preparing bendamustine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The preparation method of the intermediate in the bendamustine hydrochloride preparation process, the method comprises the steps:

[0039] (1) Put 7.7g of [1-methyl-2-(4'-butyric acid ethyl)-5-amino]-1H-benzimidazole, 23.1g of chloroacetic acid and 20ml of tetrahydrofuran into a 250ml three-necked flask, and Stir in the bath until the solid dissolves, add 154ml of 1mol / L borane tetrahydrofuran solution dropwise, adjust the dropping speed, control the internal temperature below 25°C, and stir overnight at room temperature after the drop is completed; after the reaction is completed, concentrate the reaction solution, add 50ml tetrahydrofuran and stir to dissolve , Na in ice bath 2 CO 3 Adjust the solution to neutral, continue to stir, and solids precipitate out, filter, wash the filter cake with water, and drain to obtain the crude product;

[0040] (2) Dissolve the crude product in 30ml of methanol, add 10ml of water, stir in ice water, a solid precipitates, filter, w...

Embodiment 2

[0043] The preparation method of the intermediate in the bendamustine hydrochloride preparation process, the method comprises the steps:

[0044] (1) Put [1-methyl-2-(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole 7.7g, chloroacetic acid 13.9g and solvent THF 20ml into a 250ml three-necked flask, Stir in a cold water bath until the solid dissolves, add 3.0g of sodium borohydride in batches, control the internal temperature below 25°C, and stir overnight at room temperature after the addition is complete; Na 2 CO 3 Adjust the solution to neutral, continue to stir, and solids precipitate out, filter, wash the filter cake with water, and drain to obtain the crude product;

[0045] (2) Dissolve the crude product in 30ml of methanol, add 10ml of water, stir in ice water, a solid precipitates, filter, wash with water, and dry under reduced pressure at 45°C to obtain 8.31g of off-white solid. The off-white solid is [1-methyl-2-(4'-ethyl butyrate)-5-N,N'-bis(2'-chloroethyl)]-1H-...

Embodiment 3

[0048] The preparation method of the intermediate in the bendamustine hydrochloride preparation process, the method comprises the steps:

[0049] (1) Put 7.3g of [1-methyl-2-(4'-butyric acid methyl)-5-amino]-1H-benzimidazole, 41.6g of chloroacetic acid and 20ml of solvent tetrahydrofuran into a 250ml three-necked flask, Stir in a cold water bath until the solid dissolves, add 3.3g of lithium aluminum tetrahydrogen in batches, control the internal temperature below 25°C, and stir overnight at room temperature after the addition is complete; use Na 2 CO 3 Adjust the solution to neutral, continue to stir, and solids precipitate out, filter, wash the filter cake with water, and drain to obtain the crude product;

[0050] (2) Dissolve the crude product in 28ml of methanol, add 14ml of water, stir in ice water, a solid precipitates, filter, wash with water, and dry under reduced pressure at 45°C to obtain 8.31g of off-white solid. The off-white solid is [1-methyl-2-(4'-butyric ac...

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Abstract

The invention provides a method for preparing an intermediate in the process of preparing bendamustine hydrochloride. The prepared intermediate is [1-methyl-2-(4'-ethyl butyrate)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole or [1-methyl-2-(4'-methyl butyrate)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole. The method comprises the following steps of: (1) putting a compound shown as a formula I into a reactor, adding an organic solvent for dissolving, adding a reducing agent into the reactor, reacting at the temperature of lower than 25 DEG C, regulating the pH value until a solution is neutral, and filtering, washing and drying a solid precipitate to obtain a crude product; and (2) dissolving the crude product in a mixture of methanol and water, stirring in ice water to precipitate a solid, and filtering, washing and drying the solid precipitate to obtain a target product. The yield is over 74 percent, the prepared key intermediate has the purity of over 99.5 percent, the content of a single impurity is less than 0.1 percent, and the method has the advantages of high yield and high product stability and is easy to operate and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of an intermediate in the preparation process of bendamustine hydrochloride. Background technique [0002] Bendamustine hydrochloride (bendamustine hydrochloride) is an alkylation antineoplastic drug developed by Merckle Company, which was launched in Germany in October 2003 under the trade name Ribomustine. It is clinically used for single or combined treatment of breast cancer, chronic lymphocytic leukemia, non-Hodgkin's lymphoma (stage II-IV), Hodgkin's disease, and plasmacytoma. Clinical application shows that its single treatment or combined treatment of breast cancer has definite curative effect, can significantly reduce the recurrence rate and mortality, and has small adverse reactions and good safety. [0003] There are many synthetic routes of bendamustine hydrochloride. "Chinese Journal of New Drugs" (volume 16, issue 23, 2007, pages 1960-1961, referred to as reference document 1 in the present ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/16
Inventor 苏江涛郭文胜廖佳
Owner 武汉长联来福制药股份有限公司
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