A kind of synthetic method of velpatasvir intermediate a

A technology of velpatasvir and synthesis method, which is applied in the field of medicine, can solve the problems of restricting industrial application, harsh reaction conditions, and high synthesis cost, and achieve good application prospects and market potential, mild reaction conditions, and high synthesis efficiency.

Active Publication Date: 2020-08-28
ZHEJIANG YONGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the existing technology has different problems such as high synthesis cost, low yield, and harsh reaction conditions, which is not conducive to increasing the output of velpatasvir, and is not conducive to the control and treatment of hepatitis C due to the high price.
For example, in the method reported in patent WO2013 / 075029, the cost of compound B is too high, and expensive vinyl potassium trifluoroborate is used, which leads to high cost and is not conducive to industrial production
[0007] Another example is that the patent US2015 / 0361073 also reports a synthetic method using 2-bromo-5-iodobenzyl alcohol (compound I) as a raw material, but in this method, the palladium-catalyzed ring-closing reaction yield of compound N is low, thereby This restricts the industrial application of this method
[0008] Another example is that CN107311852A reports a synthetic method of velpatasvir intermediate A, which uses a new synthetic route and intermediate, but it is still a linear synthetic method with many steps, which affects the final yield

Method used

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  • A kind of synthetic method of velpatasvir intermediate a
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  • A kind of synthetic method of velpatasvir intermediate a

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: Synthesis of Compound II.

[0065] Under nitrogen protection, 37.4 g of compound I, 25.0 g of triethylamine and 400 mL of dichloromethane were added to a 1 L reaction flask. After cooling down to 0°C, 18.0 g of acetyl chloride was added dropwise. After the dropwise addition was completed, the reaction solution was raised to 25° C. and stirred for 2 hours.

[0066] TLC detects that the reaction is complete, and 6.0g of AlCl in the reaction bottle 3 , the temperature was raised to 55° C., 16.5 g of acetyl chloride was slowly added dropwise, and after the dropwise addition was completed, the reaction was refluxed for 4 hours. 200 mL of water was added to the reaction bottle, and after stirring for 0.5 hours, liquid separation was carried out to obtain an organic phase. The organic phase was washed once with 200 mL of saturated brine, concentrated to dryness at 50°C under reduced pressure, and slurried in 100 mL of ethyl acetate overnight to obtain 47.6 g of c...

Embodiment 2

[0068] Example 2: Synthesis of compound II.

[0069] Under nitrogen protection, 37.4 g of compound 4 and 25.0 g of triethylamine were added to a 1 L reaction flask. After cooling down to 0°C, 22.0 g of acetic anhydride was added dropwise. After the dropwise addition, the reaction liquid was raised to 35° C., and stirred for 2 hours.

[0070] TLC detects that the reaction is completed, and 6gAlCl is added to the reaction bottle 3 , the temperature was raised to 70° C., and 24.0 g of acetic anhydride was slowly added dropwise, and reacted for 4 hours after the dropwise addition was completed. 200 mL of water was added to the reaction bottle, and after stirring for 0.5 hours, liquid separation was carried out to obtain an organic phase. The organic phase was washed once with 200 mL of saturated brine, concentrated to dryness at 50°C under reduced pressure, and slurried in 100 mL of ethyl acetate overnight to obtain 44.7 g of compound II as a pale yellow oil, with a gross yield...

Embodiment 3

[0072] Example 3: Compound IV is obtained by protecting the carbonyl group of compound III.

[0073] In a 1L reaction flask, add 56.0g of compound III (X is Br), 15.0g of ethylene glycol, and 300ml of petroleum ether, dehydrate under reflux for 6 hours, evaporate the solvent under reduced pressure, and obtain 63.2g of a solid, which is compound IV.

[0074] MS: C 12 h 12 BrFO 2 (M+H) + :288.00.

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Abstract

The invention relates to the technical field of medicine, in particular to a synthesis method of a velpatasvir intermediate A. Proper reactants are selected for synthesis of the velpatasvir intermediate A, a linear synthesis mode is changed into a convergence synthesis mode, and the method is mild in reaction condition, simple in step, high in synthesis efficiency, environmentally friendly and beneficial to industrial production and has good application prospects and market potentials. Besides, the invention also provides an intermediate compound for synthesizing the velpatasvir intermediate A.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a method for synthesizing velpatasvir intermediate A. Background technique [0002] Hepatitis C virus (HCV) is a hepatitis virus that is widespread worldwide. It is estimated that about 185 million people in the world are infected with chronic hepatitis C virus. At present, there are about 3.5 million new cases in the world every year, and about 350,000 patients die from hepatitis C every year. The mortality rate related to HCV infection will continue to increase in the next 20 years , has caused great harm to the health and life of patients, and has become a serious social and public health problem. [0003] In June 2016, the U.S. FDA approved the compound drug Epclusa (the third generation of Gilead, also known as the third generation of Gilead, Ekolusa), which is a combination of sofosbuvir and velpatasvir. It is a compound drug for all genotypes 1-6 HCV infection, in which...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/78C07F5/02
CPCC07D311/78C07F5/02
Inventor 甘立新金逸中张峰杨建平
Owner ZHEJIANG YONGTAI PHARMA
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