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Method for re-crystallizing key intermediate of hepatitis C virus drug velpatasvir

A technology of hepatitis C virus and velpatasvir, applied in the field of medicinal chemistry, can solve the problems of difficult impurity removal, poor solubility of intermediates and by-products, etc., and achieve the effect of high purity and high yield

Active Publication Date: 2018-12-18
SULI PHARMA TECH JIANGYIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] As the key intermediate of velpatasvir, the purity and impurities directly affect the purity and impurities of velpatasvir raw materials, but polybrominated by-products are inevitably generated during its synthesis, and the intermediates and by-products The solubility of the products is relatively poor, and it is difficult to remove impurities. Therefore, it is necessary to explore a suitable recrystallization method to improve its purity.
[0006] Synthetic method of 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one , there are 4 related patent reports, namely: WO2013075029, US20140178336, US20130309196, CN105712969A, but there are few reports on the method of recrystallization refining and purification

Method used

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  • Method for re-crystallizing key intermediate of hepatitis C virus drug velpatasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In a 5000ml dry reaction flask equipped with a reflux condenser and a stirring device, put in 600ml of N-methylpyrrolidone and 1400ml of acetone, and put in 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H -Benzo[D]naphtho[2,3-B]pyran-8(9H)-ketone crude product 200g, evacuated and replaced with nitrogen, heated to 55-60℃, kept at the temperature and stirred for 2 hours until completely dissolved . Cooling and stirring for crystallization: rotate speed 75-80rpm, about 40-50 minutes, reduce the temperature to 25-30℃, keep stirring for 1 hour, continue for about 40-50 minutes, cool to 5-10℃, keep stirring for 2-3 hours , The filtered wet solid product was vacuum dried at 40-50°C to obtain 182.3 g of light yellow solid with a purity of 99.4% and a yield of 91.2%. The mother liquor was sorted under normal pressure at 75°C, and 1246ml of acetone was recovered. The recovery rate of acetone was 89%.

Embodiment 2

[0027] In a 5000ml dry reaction flask equipped with a reflux condenser and a stirring device, add 500ml of N-methylpyrrolidone and 1500ml of tetrahydrofuran, and add 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H -Benzo[D]naphtho[2,3-B]pyran-8(9H)-ketone crude product 200g, evacuated and replaced with nitrogen, heated to 60-65°C, kept warm and stirred for 2 hours, until completely dissolved . Cooling and stirring for crystallization: rotate speed 75-80rpm, about 40-50 minutes, reduce the temperature to 25-30°C, keep stirring for 1 hour, continue for about 40-50 minutes, cool to 0-5°C, keep stirring for 2-3 hours , Filtered and dried under vacuum at 40-50°C to obtain 178.9 g of light yellow solid with a purity of 99.6% and a yield of 89.5%. The mother liquor was sorted under normal pressure at 75°C, and 1385ml of tetrahydrofuran was recovered. The recovery rate of tetrahydrofuran was 92.3%.

Embodiment 3

[0029] In a 5000ml dry reaction flask equipped with a reflux condenser and a stirring device, add 500ml of N,N-dimethylacetamide and 1500ml of dichloromethane, and add 9-bromo-3-(2-bromoacetyl)-10, 11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one crude product 200 grams, vacuumed and replaced with nitrogen, heated to 35-40°C, kept stirring for 2 Hours, to completely dissolve. Cooling and stirring for crystallization: Rotate speed 60-65rpm, about 40-50 minutes, reduce the temperature to 20-25°C, keep stirring for 1 hour, continue for about 40-50 minutes, cool to 0-5°C, keep stirring for 2-3 hours , Filtered and dried under vacuum at 30-40°C to obtain 183.3 g of pale yellow solid with a purity of 99.6% and a yield of 91.7%. The mother liquor was sorted under normal pressure at 45°C, and 1,215ml of methylene chloride was recovered, and the methylene chloride recovery rate was 81%.

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Abstract

The invention provides a method for re-crystallizing a key intermediate of a hepatitis C virus drug velpatasvir. Highly pure 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one is obtained, and parts of organic solvents can be recovered, so the method is economical and environmentally friendly. The method concretely includes the following steps: dissolving crude 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one in a mixed solvent containing a high-solubility organic solvent A and a low-solubility organic solvent B under a 35-70 DEG Cheating condition, precipitating crystals by a gradient cooling technology, centrifuging the obtained system, carrying out vacuum drying on the obtained wet solid at 30-70 DEG C, and performing normalpressure distillation on the obtained centrifugal mother liquor to recover the solvent B.

Description

Technical field [0001] The invention relates to a method for recrystallization of a key intermediate of the hepatitis C virus drug virpatavir, and belongs to the field of medicinal chemistry. Background technique [0002] Hepatitis C virus seriously harms human health. According to the latest WHO data, about 71 million people worldwide are infected with hepatitis C virus, and about 7.6 million people are infected with hepatitis C virus in China. From 2012 to 2016, the number of cases of hepatitis C in China is high. Increased momentum from 201,600 to 206,800. Vipatavir is a protease NS5A inhibitor. It is a pan-genotype hepatitis C virus treatment specific drug developed by Gilead. It has been widely used in the treatment of hepatitis C patients. [0003] 9-Bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one, molecular formula: C19H14Br2O3 , The structural formula is as follows: [0004] [0005] As the key core intermediate of vepatavir, purity and impur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/78C07D491/052
CPCC07D311/78C07D491/052
Inventor 墙广灿汪静莉
Owner SULI PHARMA TECH JIANGYIN
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