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Synthesizing method of velpatasvir

A velpatasvir and synthetic method technology, which is applied in the field of new method synthesis of the new hepatitis C virus drug velpatasvir and its series of intermediates, can solve the problem of not being suitable for industrial scale-up production, shortening reaction steps, and long reaction routes and other problems, to achieve the effect of suitability for industrialized production, low cost and high total yield

Active Publication Date: 2018-07-13
ZHEJIANG YONGTAI PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The synthesis methods disclosed in the prior art generally have the disadvantages that the reaction route is too long, the total yield is low, and it is not suitable for industrial scale-up production. Therefore, using new synthetic raw materials and shortening the reaction steps has important technical value and economic benefits

Method used

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  • Synthesizing method of velpatasvir
  • Synthesizing method of velpatasvir
  • Synthesizing method of velpatasvir

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Example 1 Preparation of Intermediate III

[0042] Take compound I (28.5g, 100mmol), 1-Cl-2-ethoxyethylene (16.0g, 150mmol), palladium acetate (1.00g, 4.5mmol), 1,3-bis(diphenylphosphine) propane ( 4.23g, 10.2mmol), potassium carbonate (20.7g, 150mmol) in 200ml of 60% THF aqueous solution, stir evenly, reflux for 2.5h, the reaction is complete, cool to room temperature, slowly add 37% concentrated hydrochloric acid 24ml, drip and stir. After the reaction was completed for 3 hours, ethyl acetate was added and extracted twice with 100 ml each time. The organic layers were combined and washed with 10% potassium carbonate aqueous solution once. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound III (31.2 g, 95.4%), add 90 ml of methanol and reflux at 65° C. for 10 min, slowly cool to room temperature and crystallize for 1 h, and filter to obtain compound III (30.1 g, 91.3%).

[0043] Compound III: MS(E...

Embodiment 2

[0044] Example 2 Preparation of Intermediate IV

[0045] Take compound III (19.6g, 60mmol), pyridinium tribromide (43.4g, 136mmol) and dissolve it in 150ml of 9:1 dichloromethane / methanol, under nitrogen protection, heat to 35℃, stir and react for 50min. The reaction is complete. The solution was cooled to 10°C, filtered to obtain Intermediate IV, 100ml methanol was added and refluxed at 65°C for 15min, slowly cooled to room temperature to crystallize for 2h, filtered, the filter cake was washed with 10ml methanol, and dried at 40°C to obtain Intermediate IV (20.7g, 85%).

Embodiment 3

[0046] Example 3 Synthesis of Compound VI

[0047] Compound IV (20.3 g, 50 mmol), compound V (17.2 g, 60 mmol), potassium carbonate 5.5 g, and tetrahydrofuran 150 ml were sequentially added to the reaction flask, and then reacted at 30-35° C. for 16 hours. LC monitored the disappearance of raw material IV. Add 300ml ethyl acetate, 200ml water, stir for 10min, separate the organic phase, extract the aqueous phase with ethyl acetate 100ml*3 times, combine the organic phases, dry with sodium sulfate, and concentrate to obtain compound VI (27.5g, yield 90.0%) ).

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Abstract

The invention relates to a synthesizing method of velpatasvir. The synthesizing method has the advantages that the novel raw materials and novel intermediates are adopted, the number of reaction stepsis reduced, the usage amount of onium salt is reduced, the defects of longer reaction route, lower total yield rate and unsuitability to industrial production amplification in the synthesizing methodof the prior art are overcome, and the production cost is effectively reduced.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical engineering, and particularly relates to a new method for synthesizing a new hepatitis C virus drug, vepatavir and its series intermediates. Background technique [0002] Hepatitis C virus infection seriously harms human health and is one of the main causes of hepatitis after blood transfusion. At present, the world's hepatitis C infection rate is 3%, and it is estimated that between 170 million and 200 million people are infected with hepatitis virus C (HCV), and about 3.5 million people are newly infected each year. [0003] At present, research on NS5A as an antiviral target has become a hot spot in the field of anti-HCV. Vipatavir (CAS:1377049-84-7), as a new type NS5A hepatitis C specific drug developed by Gilead, has a broad market prospect. [0004] The synthetic methods disclosed in the prior art generally have the defects that the reaction route is too long, the total yield is low, and is no...

Claims

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Application Information

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IPC IPC(8): C07D491/052C07D311/80C07D311/78
CPCC07D311/78C07D311/80C07D491/052
Inventor 何匡周国斌向科张雷刚
Owner ZHEJIANG YONGTAI PHARMA
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