Refining method of daclatasvir hydrochloride

A technology of daclatasvir hydrochloride and refining method, which is applied in the field of medicine and can solve the problems of difficult scale-up production, difficult removal, low yield, etc.

Active Publication Date: 2019-02-05
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its shortcoming is that after the crude product is dissolved in methanol, part of the methanol needs to be concentrated, which is not conducive to operation, difficult to scale up production, and low yield
Because there are 4 chiral centers in daclatasvir hydrochloride, there will inevitably be isomer impurities in the crude product, and it is difficult to remove. The purity of the product prepared by this method is not high, and the impurities, especially isomer impurities, etc. poor removal

Method used

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  • Refining method of daclatasvir hydrochloride
  • Refining method of daclatasvir hydrochloride
  • Refining method of daclatasvir hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 10 g of crude daclatasvir hydrochloride was dissolved in 45 ml of methanol and stirred at 60°C until dissolved. Add 0.4g of activated carbon, stir at 60°C for 30 minutes, filter while it is hot, add a mixed solvent of 50ml of acetone and 50ml of isopropanol dropwise to crystallize the filtrate when it is heated to 60°C, and crystallize at 20-30°C for 2 hours after the addition is completed, filter , and the filter cake was vacuum-dried at 50° C. to obtain 8.7 g of off-white solid, with a yield of 87%, a chromatographic purity of 99.87%, a maximum heterogeneity of 0.07%, and an isomer of 0.05%.

Embodiment 2

[0033] 10 g of crude daclatasvir hydrochloride was dissolved in 50 ml of methanol and stirred at 58°C until dissolved. Add 0.8g of activated carbon, stir at 65°C for 30 minutes, filter while it is hot, add a mixed solvent of 50ml of acetone and 50ml of isopropanol dropwise to crystallize the filtrate when the temperature is raised to 60°C, and crystallize at 20-30°C for 2 hours after the addition is completed, filter , and the filter cake was vacuum-dried at 50° C. to obtain 8.6 g of a white solid, with a yield of 86%, a chromatographic purity of 99.70%, a maximum heterogeneity of 0.07%, and an isomer of 0.07%.

Embodiment 3

[0035] 10 g of crude daclatasvir hydrochloride was dissolved in 60 ml of methanol and stirred at 55°C until dissolved. Add 0.4g of activated carbon, stir at 65°C for 30 minutes, filter while it is hot, add a mixed solvent of 50ml of isopropanol and 50ml of acetone to crystallize the filtrate when it is heated up to 60°C, and crystallize at 20-30°C for 2 hours after the addition is complete, and filter , and the filter cake was vacuum-dried at 50° C. to obtain 8.5 g of white solid, with a yield of 85%, a chromatographic purity of 99.87%, and a maximum single heterogeneity of 0.07%. Isomers: none.

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Abstract

The invention discloses a refining method of daclatasvir hydrochloride. The refining method comprises the following steps: (1) adding a daclatasvir hydrochloride crude product into methanol and dissolving at 55 to 65 DEG C; (2) adding activated carbon and de-coloring at 55 to 65 DEG C; (3) filtering and raising the temperature of filtrate to 55 to 65 DEG C; dropwise adding a mixed solvent of a water-soluble aprotic solvent A and a proton solvent B and crystallizing; after dropwise adding, and cooling to 20 to 30 DEG C, stirring and crystallizing for 2 h; (4) filtering a mixture obtained by stirring and crystallizing in step (3); drying a filter cake in vacuum to obtain the high-purity daclatasvir hydrochloride. The method disclosed by the invention can be used for effectively removing impurities in the daclatasvir hydrochloride crude product and the purity of a product reaches 99.5 percent or more; the content of isomer impurities and other single impurities is not greater than 0.1 percent and the refining yield is not lower than 85 percent; furthermore, the refining method disclosed by the invention has a simple technological process and industrial production is easy to realize bythe technology.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a method for refining high-purity daclatasvir hydrochloride. Background technique [0002] Daclatasvir hydrochloride is a selective hepatitis C virus (HCV) nonstructural protein 5a replication complex inhibitor with high specificity for multiple HCV genotypes / subtypes and low toxicity to host cells. [0003] Daclatasvir hydrochloride was developed by Bristol-Myers Squibb, and was approved by the European Union at the end of 2014. It is used in combination with other drugs for the treatment of adults with genotype 1, 2, 3, and 4 chronic hepatitis C (HCV) infection. Daclatasvir hydrochloride is currently on the market in the United Kingdom, Japan and the United States, and its clinical treatment effect is that the average cure rate reaches 95%, and the cure rate for adults with genotype 1 chronic hepatitis C infection is even close to 100%. On April 28, 2017, the State Food and Drug Administr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 鲍鹤龄徐浩宇蔡伟刘景龙申新程钱斌董志奎曹兵朱晶
Owner YANGTZE RIVER PHARM GRP CO LTD
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