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A kind of synthetic method of daclatasvir starting material

A daclatasvir and synthetic method technology, applied in the field of industrial synthesis of intermediate raw materials, can solve the problems of harsh reaction conditions, complex process routes, unfavorable industrialization, etc., and achieve less by-products, simple process, and easy operation Effect

Active Publication Date: 2020-12-15
CHANGZHOU YINSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the process methods have complex process routes, cumbersome operations, harsh reaction conditions, and high raw material costs, which are not conducive to industrialization

Method used

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  • A kind of synthetic method of daclatasvir starting material
  • A kind of synthetic method of daclatasvir starting material
  • A kind of synthetic method of daclatasvir starting material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The synthesis method of the daclatasvir starting material of this embodiment comprises the following steps:

[0022] Add 27.8g of 2,4'-dibromoacetophenone, 21.6g of L-BOC-proline, 27.6g of potassium carbonate, and 300g of toluene into a 500mL reaction flask, stir mechanically, raise the temperature in a water bath, and control the temperature React at 28°C for 8 hours, take a sample for detection, after the reaction is over, add water to quench, stir for 20 minutes, stand to separate layers, collect the upper toluene layer, discard the lower water layer, add 1L of pure water to the toluene layer again, and stir After 20 minutes, the layers were left to stand, and the upper toluene layer was collected. The temperature of the toluene layer was raised to reflux, and the reflux was kept for 60 minutes after water separation. The reflux was stopped, and the reaction solution was collected for the next reaction.

[0023] Ammonium acetate was added to the above reaction soluti...

Embodiment 2

[0028] The synthesis method of the daclatasvir starting material of this embodiment comprises the following steps:

[0029] Add 27.8g of 2,4'-dibromoacetophenone, 22g of L-BOC-proline, 28g of potassium carbonate, and 280g of toluene into a 500mL reaction flask, stir mechanically, raise the temperature in a water bath, and control the temperature at 30 ℃, react for 7 hours, take a sample for detection, after the reaction is completed, add water to quench, stir for 18 minutes, let stand to separate layers, collect the upper toluene layer, discard the lower water layer, add 1L of pure water to the toluene layer again, and stir for 18 minutes Finally, let stand to separate layers, collect the upper toluene layer, heat up the toluene layer to reflux, keep the reflux and divide water for 45 minutes, then stop the reflux, and collect the reaction solution to be used in the next reaction.

[0030] Ammonium acetate was added to the above reaction solution, heated to reflux and stirred ...

Embodiment 3

[0032] The synthesis method of the daclatasvir starting material of this embodiment comprises the following steps:

[0033] Add 27.8g of 2,4'-dibromoacetophenone, 21.6g of L-BOC-proline, 27.6g of potassium carbonate, and 350g of toluene into a 500mL reaction flask, stir mechanically, raise the temperature in a water bath, and control the temperature React at 25°C for 9 hours, take a sample for testing, after the reaction is over, add water to quench, stir for 15 minutes, let stand to separate layers, collect the upper toluene layer, discard the lower water layer, add 1L of pure water to the toluene layer again, stir After 15 minutes, the layers were left to stand, and the upper toluene layer was collected. The temperature of the toluene layer was raised to reflux, and the reflux was maintained for 30 minutes after water separation. The reflux was stopped, and the reaction solution was collected for the next reaction.

[0034] Ammonium acetate was added to the above reaction so...

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Abstract

The present invention relates to a kind of synthetic method of daclatasvir starting material, 2,4'-dibromoacetophenone shown in formula I, L-BOC-proline shown in formula II, potassium carbonate and Toluene is reacted to form an intermediate product shown in formula III, and the intermediate product shown in formula III is reacted with ammonium acetate to form a compound shown in formula IV. The method for synthesizing the daclatasvir starting material of the invention has simple reaction route and low cost of raw materials, and is suitable for industrial production.

Description

technical field [0001] The invention relates to an industrial synthesis method for preparing intermediate raw materials of daclatasvir, belonging to the technical field of chemical synthesis. Background technique [0002] Hepatitis C is the abbreviation of hepatitis C virus, which is an infectious disease caused by hepatitis C virus (HCV) inflammation and necrosis of the liver, which is extremely harmful to human health and life. Daclatasvir (Daclatasvir) is a hepatitis C virus (HCV) NS5A inhibitor developed by Bristol-Myers Squibb, suitable for the treatment of chronic HCV genotype 3 infection, combined with other drugs, for 1, 2, 3, 4 genotypes of chronic hepatitis C (HCV) in the treatment of adults infected. The cure rate is over 95%. The structural formula of Daclatasvir is as follows: [0003] [0004] At present, there are many existing processes for synthesizing daclatasvir. International patents WO2009020825, WO2012048421, and Chinese patents CN106256825A and C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04C07D403/14
CPCC07D403/04
Inventor 陶鑫韩加齐史鹤峰季翔罗安贸
Owner CHANGZHOU YINSHENG PHARMA
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