Method for synthesizing bendamustine hydrochloride intermediate

A technology of bendamustine hydrochloride and a synthesis method, which is applied in the field of chemical synthesis, can solve the problems of low selectivity of reduction, a large amount of sodium sulfide waste water, environmental pollution and the like, and achieves the advantages of shortening production cycle, short route and reducing cost. Effect

Inactive Publication Date: 2018-08-03
WUJIANG XINKAI MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] This route is a four-step reaction. The main defect of this route is that in the second step reaction, sodium sulfide is used to selectively reduce nitro groups to amino groups, and a large amount of sodium sulfide wastewater will be produced in the post-treatment, which will pollute the environment more seriously, and the choice of reduction The yield is not high, and the yield of patent CN101948436 is 73.5%.
There is also the problem of low yield in the route, and the total yield is 44%-55%

Method used

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  • Method for synthesizing bendamustine hydrochloride intermediate
  • Method for synthesizing bendamustine hydrochloride intermediate
  • Method for synthesizing bendamustine hydrochloride intermediate

Examples

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Embodiment 1

[0018] Take 51.6g of 2-chloro-5-nitroaniline into a three-neck flask, add 500ml of toluene, add 36g of glutaric anhydride at room temperature, heat to 80°C for 3 hours, cool to room temperature, filter, and filter cake at 70°C After drying, 145 g of a yellow solid intermediate was obtained, with a yield of 95%.

[0019] Add intermediate 1 obtained above into 150ml of 40% methylamine aqueous solution, heat to 50°C for 3 hours, cool to room temperature, adjust pH to 4-5 with 2N hydrochloric acid, precipitate a yellow solid, stir for 1 hour, filter, filter The cake was rinsed with toluene and dried at 70°C to obtain 40.5 g of yellow solid intermediate 2 with a yield of 91.7%.

[0020] Put the intermediate 2 prepared above into a three-necked flask, add 365ml of absolute ethanol, add 12ml of 98% concentrated sulfuric acid dropwise under stirring, heat to 80°C and reflux for 3h after the dropwise addition, cool to 45-50°C, pour the reaction solution into In saturated aqueous potas...

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Abstract

The invention discloses a method for synthesizing a bendamustine hydrochloride intermediate. The method comprises the following steps: performing an acylation reaction on 2-chloro-5-nitroaniline usedas a raw material and glutaric anhydride to obtain an intermediate 1, performing a substitution reaction on the intermediate 1 in an aqueous solution of methylamine to prepare an intermediate 2, and performing cyclization and esterification reactions on the intermediate 2 and ethanol in the presence of sulfuric acid to obtain the target product ethyl 1-methyl-5-nitro-1H-benzimidazole-2-butyrate. The method has the characteristics of simple synthesis route, high yield and less wastewater.

Description

technical field [0001] The invention relates to a synthesis method of a bendamustine hydrochloride intermediate, belonging to the technical field of chemical synthesis. Background technique [0002] 1-Methyl-5-nitro-1H-benzimidazole-2-butyric acid ethyl ester is an important intermediate of bendamustine hydrochloride. Bendamustine hydrochloride is a bifunctional alkylating agent with antitumor effects. In 2003, it was launched in Germany under the trade name Ribomustine for the treatment of breast cancer and chronic lymphocytic leukemia. The trade name of bendamustine hydrochloride listed in the United States was Treanda, which was applied for by Cephalon and passed the priority approval process. Received FDA approval. In March 2008, the FDA first approved bendamustine hydrochloride for the treatment of chronic lymphocytic leukemia (CLL). In October of the same year, the FDA approved the second indication of the drug, that is, during the treatment of rituximab (rituximab,...

Claims

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Application Information

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IPC IPC(8): C07D235/16
CPCC07D235/16
Inventor 魏海洋徐成浩皱培欢
Owner WUJIANG XINKAI MEDICAL TECH
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