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A kind of purification method of bendamustine hydrochloride

A technology of bendamustine hydrochloride and a purification method, which is applied in the field of purification of bendamustine hydrochloride, can solve the problems of poor product purity, difficulty in satisfying a single impurity, and inability to effectively remove impurities, etc., to achieve product The effect of good quality, short cycle and simple process

Active Publication Date: 2022-04-05
南京力成药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the experiment, we found that bendamustine hydrochloride is easy to accelerate the degradation of HP1 and HP2 under high temperature conditions in aqueous solution, but cannot effectively remove impurities. 0.1% requirement

Method used

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  • A kind of purification method of bendamustine hydrochloride
  • A kind of purification method of bendamustine hydrochloride
  • A kind of purification method of bendamustine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Place 15.0 g of 5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazole-2-butyric acid methyl ester in a three-necked reaction flask, add 150 mL of dichloromethane, drop 13.3g of thionyl chloride, and reacted at 20-30°C for 7 hours. Then add 75mL of concentrated hydrochloric acid dropwise, stir and separate at room temperature, retain the upper aqueous phase and raise the temperature to 60-70°C to continue the reaction for 12-18 hours, distill off the aqueous hydrochloric acid solution under reduced pressure, add 75mL of water and cool to 15-25°C to precipitate a solid. Add 2N NaOH aqueous solution dropwise to adjust the pH of the system to 1-2, then cool in an ice-water bath to 0-5°C, filter, rinse the filter cake with pre-cooled isopropanol and dry at 35°C for 8-12 hours to obtain 14.9g of hydrochloric acid Bendamustine crude.

Embodiment 2

[0046] Place 15.0 g of 5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazole-2-butyric acid methyl ester in a three-necked reaction flask, add 75 mL of dichloromethane, drop 16.0 g of thionyl chloride, and reacted at 20-30° C. for 7 hours. Then add 75mL of concentrated hydrochloric acid dropwise, stir and separate at room temperature, retain the upper aqueous phase and raise the temperature to 60-70°C to continue the reaction for 12-18 hours, distill off the aqueous hydrochloric acid solution under reduced pressure, add 75mL of water and cool to 15-25°C to precipitate a solid. Add 2N NaOH aqueous solution dropwise to adjust the pH of the system to 1-2, then cool in an ice-water bath to 0-5°C, filter, rinse the filter cake with pre-cooled isopropanol and dry at 35°C for 8-12 hours to obtain 15.5g of hydrochloric acid Bendamustine crude.

Embodiment 3

[0048]Put 6.4g of bendamustine hydrochloride crude product (containing HP1: 0.20%) in a three-necked reaction flask, add 32mL of 6mol / L hydrochloric acid aqueous solution, the temperature of the solution is 20-30°C, add 0.64g of activated carbon, stir and decolorize 2-3 hours, filter to remove activated carbon. Collect the mother liquor and add 10% Na dropwise 2 CO 3 The aqueous solution adjusts the pH of the system to 1-2, and then cools in an ice-water bath to 0-5°C for recrystallization. After filtering, the filter cake was rinsed with pre-cooled acetone and dried at 35° C. for 16 hours to obtain 5.9 g of bendamustine hydrochloride. Yield of bendamustine hydrochloride: 92%; HPLC purity: 99.94%, HP1: not detected, single impurity: 0.06%, see attached figure 1 .

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Abstract

The present invention relates to a purification method of bendamustine hydrochloride. The method comprises the following steps: (1) adding hydrochloric acid aqueous solution to the crude product of bendamustine hydrochloride, stirring and dissolving, and then adding activated carbon for decolorization; (2) adding Adding an inorganic alkali solution to the solution obtained in step (1) to adjust the pH of the solution to 1-4, then cooling, recrystallizing, and filtering to obtain a filter cake; (3) washing and drying the filter cake obtained in step (2) to obtain Bendamustine hydrochloride. By adopting the purification method of the present invention, the crude product of bendamustine hydrochloride can be obtained at low temperature and normal temperature to obtain high-purity bendamustine hydrochloride, avoiding the generation of new impurities under high temperature conditions, the product purity is above 99.8%, and all single impurities The content is all lower than 0.10%. The method has simple process, short cycle, a refining yield of more than 90%, good product quality, can meet preparation requirements, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of purification of pharmaceutical compounds, in particular to a purification method of bendamustine hydrochloride. Background technique [0002] Bendamustine hydrochloride (Bendamustine hydrochloride) was first developed in the early 1860s by Ozegowski and his colleagues at the Microbiological Experiment Association in Jena, Germany. Its chemical name is 5-4-[5-[double (2 -Chloroethyl)amino]-1-methylbenzimidazol-2-yl]butyric acid hydrochloride, the structural formula is 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 company Jena from 197...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/16
CPCC07D235/16
Inventor 李正奇
Owner 南京力成药业有限公司
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