Velpatasvir intermediate as well as preparation method and application thereof

A reaction and time technology, applied in chemical instruments and methods, bulk chemical production, organic chemistry, etc., can solve problems such as high production costs, failure to meet API standards, and unsuitability for industrial production.

Active Publication Date: 2018-01-12
上海云晟研新生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to overcome the preparation method of Velpatasvir (Velpatasvir or GS5816) in the prior art, the control of chiral isomers in the reaction process is difficult, the obtained product has poor chiral purity, and cannot reach the raw material Drug standard, low total yield, high production cost, not suitable for industrial production and other defects, but provides velpatasvir intermediates, preparation methods and applications

Method used

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  • Velpatasvir intermediate as well as preparation method and application thereof
  • Velpatasvir intermediate as well as preparation method and application thereof
  • Velpatasvir intermediate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1: Preparation of compound 10 (L is Br, P is tert-butoxycarbonyl, namely Boc)

[0219]

[0220] Compound 11 (2kg, 3.18mol, 1eq) was dissolved in methanol, and a mass concentration of 37% concentrated hydrochloric acid (1.33L, 5eq) was added (the mass concentration refers to the percentage of the mass of hydrogen chloride in the total mass of the hydrochloric acid solution), heated Reflux (60°C~65°C), react for 2-6 hours, TLC shows complete reaction, drop to room temperature, add methyl tert-butyl ether slowly, after the dropwise addition, stir at 0-10°C for 2-5 hours, filter , the solid was suspended in dichloromethane, saturated sodium bicarbonate was added, stirred for 1 hour, filtered, the organic phase was washed with water and saturated sodium chloride successively, concentrated to dryness, and 1.52kg of compound 10 was obtained, the yield was 90.0%, and the HPLC purity was 98.23% .

Embodiment 2

[0221] The preparation of embodiment 2 compound 14 (P is Boc)

[0222]

[0223] Compound 25 (1.96kg, 5.29mol, 1.0eq) and compound 24 (1.37kg, 1.05eq) were dissolved in N, N-dimethylformamide (DMF), potassium carbonate (730.8g, 1.05eq) was added, nitrogen Vacuum replaced three times, heated to 20-40°C and stirred for 3 hours. TLC showed complete reaction of compound 25. Reduce to 5-10°C, add water dropwise, stir at 5-10°C for 2-3 hours, filter, wash the filter cake with water, and dry to obtain 2.85kg of compound 14 with a yield of 98.0% and an HPLC purity of 98.56%.

Embodiment 3

[0224] Preparation of Example 3 Compound 13 (P is Boc, i.e. tert-butoxycarbonyl)

[0225]

[0226] Compound 14 (2.85kg, 5.18mol, 1eq) was dissolved in isopropyl acetate, added isopropyl acetate / hydrogen chloride (1.33L, 5eq), heated to reflux (60°C-65°C), reacted for 2-6 hours, TLC Show complete reaction, lower to room temperature, slowly add methyl tert-butyl ether dropwise, stir at 0-10°C for 2-5 hours after dropwise addition, filter, suspend the solid in dichloromethane, add saturated sodium bicarbonate, stir After filtering for 1 hour, the organic phase was washed with water and saturated sodium chloride successively, and concentrated to dryness to obtain 2.21 kg of compound 13 with a yield of 95.0% and a purity of 98.86% by HPLC.

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Abstract

The invention discloses a velpatasvir intermediate as well as a preparation method and application thereof. The preparation method of a velpatasvir intermediate compound 4 provided by the invention comprises the following steps that under the protection of protection gas, in the organic solvent, a compound 5 and an oxidizing agent take oxidation reaction to obtain a compound 4. The velpatasvir isprepared from the intermediate compound 4; the reaction conditions are mild; the operation is simple and safe; specific purification equipment is not needed; the column chromatography separation operation in the aftertreatment process is avoided; the chiral isomer is easy to control; the yield is high; the chemical and optical purity of the velpatasvir prepared from the intermediate compound 4 isgreater than 99.50 percent; all impurities are smaller than 0.10 percent; the raw material medicine standard can be reached; the cost is low; the preparation method is suitable for industrial production. The formula is shown in the description.

Description

technical field [0001] The invention relates to a velpatasvir intermediate, a preparation method and an application. Background technique [0002] In June 2016, the FDA approved another blockbuster anti-hepatitis C drug from Gilead Sciences, Epclusa (Sofosbuvir 400mg+Velpatasvir 100mg), the first anti-hepatitis C drug for the treatment of major genotypes 1-6. Known as the third-generation anti-hepatitis C blockbuster drug after Sofosbuvir and Harvoni. [0003] In October 2016, Gilead Sciences announced the results of 4 global Phase III clinical studies, Sofosbuvir, Velpatasvir (Velpatasvir and Voxilaprevir) three-in-one tablet has a significant curative effect on patients with genotype 1-6 HCV infection . The new anti-hepatitis C drug with Velpatasvir as a compound was approved by the FDA in July 2017. The drug name is Vosevi. Vosevi will soon become a star drug in the field of anti-hepatitis C, with a broad market prospect. [0004] The US20150361073 preparation patent o...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07D491/052Y02P20/55
Inventor 应述欢皮红军公绪栋于冲冲
Owner 上海云晟研新生物科技有限公司
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