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A kind of recrystallization method of the 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: 2020-07-31
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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  • A kind of recrystallization method of the key intermediate of hepatitis C virus drug velpatasvir
  • A kind of recrystallization method of the key intermediate of hepatitis C virus drug velpatasvir

Examples

Experimental program
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Effect test

Embodiment 1

[0025] In a 5000ml dry reaction bottle equipped with a reflux condenser and a stirring device, put 600ml of N-methylpyrrolidone and 1400ml of acetone, and put in 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H - 200 grams of benzo[D]naphtho[2,3-B]pyran-8(9H)-one crude product, vacuum nitrogen replacement, heat up to 55-60 ° C, keep stirring for 2 hours, until completely dissolved . Cooling and stirring for crystallization: speed 75-80rpm, about 40-50 minutes, lower the temperature to 25-30°C, keep stirring for 1 hour, continue for about 40-50 minutes, cool down to 5-10°C, keep stirring for 2-3 hours , filtered wet solid product, vacuum-dried at 40-50° C. to obtain 182.3 g of a 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, 1246ml of acetone was recovered, and the recovery rate of acetone was 89%.

Embodiment 2

[0027] In a 5000ml dry reaction bottle equipped with a reflux condenser and a stirring device, put 500ml of N-methylpyrrolidone and 1500ml of tetrahydrofuran, and put in 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H - Benzo[D]naphtho[2,3-B]pyran-8(9H)-one crude product 200g, vacuum nitrogen replacement, heat up to 60-65℃, keep stirring for 2 hours, until completely dissolved . Cooling and stirring for crystallization: speed 75-80rpm, about 40-50 minutes, lower the temperature to 25-30°C, keep stirring for 1 hour, continue for about 40-50 minutes, cool down to 0-5°C, keep stirring for 2-3 hours , filtered, and vacuum-dried at 40-50° C. to obtain 178.9 g of a 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 1385 ml of tetrahydrofuran was recovered, and the recovery rate of tetrahydrofuran was 92.3%.

Embodiment 3

[0029] In the 5000ml drying reaction bottle equipped with a reflux condenser and a stirring device, drop into N,N-dimethylacetamide 500ml and methylene chloride 1500ml, drop into 9-bromo-3-(2-bromoacetyl)-10, 11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one crude product 200g, vacuum nitrogen replacement, heating to 35-40°C, keep stirring for 2 hours until completely dissolved. Cooling and stirring for crystallization: speed 60-65rpm, about 40-50 minutes, lower the temperature to 20-25°C, keep stirring for 1 hour, continue for about 40-50 minutes, cool down to 0-5°C, keep stirring for 2-3 hours , filtered, and vacuum-dried at 30-40° C. to obtain 183.3 g of a light 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 1215 ml of dichloromethane was recovered, and the recovery rate of dichloromethane 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 recrystallization method of a key intermediate of velpatasvir, a hepatitis C virus medicine, and belongs to the field of medicinal chemistry. Background technique [0002] Hepatitis C virus is a serious threat to human health. According to the latest data from WHO, about 71 million people worldwide are infected with hepatitis C virus, and there are about 7.6 million people infected with hepatitis C virus in China. From 2012 to 2016, the number of cases of hepatitis C in China Gaining momentum, from 201,600 to 206,800. Velpatasvir belongs to the protease NS5A inhibitor drug, which is a pan-genotype hepatitis C virus treatment specific drug developed by Gilead, and 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 interme...

Claims

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Application Information

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Patent Type & Authority Patents(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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