Novel method for synthesizing anti-hepatitis C virus novel medicine daclatasvir

A synthetic method, daclatasvir technology, applied in organic chemistry, peptides, etc., can solve the problems of many synthesis steps and high synthesis cost, and achieve the effect of short synthesis cycle, low production cost and few steps

Inactive Publication Date: 2016-04-06
上海步越化工科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above three synthetic methods have their own advantages, but there are many synthetic steps and high synthetic costs.

Method used

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  • Novel method for synthesizing anti-hepatitis C virus novel medicine daclatasvir
  • Novel method for synthesizing anti-hepatitis C virus novel medicine daclatasvir
  • Novel method for synthesizing anti-hepatitis C virus novel medicine daclatasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 , 4,4'-two (N-(methoxycarbonyl)-L-valyl-L-proline ester acetyl) biphenyl (14) synthesis

[0034] Add 4,4'-bis(2-bromoacetyl)biphenyl (20g, 50mmol), N-(methoxycarbonyl)-L-valyl-L-proline (29g, 105mmol) into a 500mL three-necked flask ) and acetonitrile (200mL), the reaction solution was a suspension, then cooled to 10°C, and the reaction acid-binding agent diisopropylethylamine (DIPEA) (3.7g, 105mmol) (3.7g, 105mmol) was added dropwise under control of the temperature in the range of 10-20°C, and After the addition is completed, the temperature is controlled in the range of 25-30° C. and stirred for 3-5 hours, and the condensation reaction is completed.

[0035] The reaction solution was concentrated to dryness under reduced pressure, extracted with toluene solution (200 mL), and then washed twice with saturated sodium chloride solution (100 mL). The toluene solution was concentrated to obtain an oily foamy solid (37.5 g), yield 96%.

Embodiment 2

[0036] Example 2 , 4,4'-two (N-(methoxycarbonyl)-L-valyl-L-proline ester acetyl) biphenyl (14) synthesis

[0037] Add 4,4'-bis(2-bromoacetyl)biphenyl (20g, 50mmol), N-(methoxycarbonyl)-L-valyl-L-proline (29g, 105mmol) into a 500mL three-necked flask ) and acetonitrile (200mL), the reaction solution was a suspension, then the temperature was raised to 40°C, and the reaction acid-binding agent diisopropylethylamine (DIPEA) (13.7g, 105mmol) (13.7g, 105mmol) was added dropwise under control of the temperature in the range of 40-50°C. After the addition is completed, the temperature is controlled in the range of 40-50° C. and stirred for 1-2 hours, and the condensation reaction is completed.

[0038] The reaction solution was concentrated to dryness under reduced pressure, extracted with toluene solution (200 mL), and then washed twice with saturated sodium chloride solution (100 mL). The toluene solution was concentrated to obtain an oily foamy solid (35.1 g), yield 90%.

Embodiment 3

[0039] Example 3 , 4,4'-two (N-(methoxycarbonyl)-L-valyl-L-proline ester acetyl) biphenyl (14) synthesis

[0040] Add 4,4'-bis(2-bromoacetyl)biphenyl (20g, 50mmol), N-(methoxycarbonyl)-L-valyl-L-proline (29g, 105mmol) into a 500mL three-necked flask ) and acetonitrile (200mL), the reaction solution was a suspension, then cooled to 10°C, and the reaction acid-binding agent diisopropylethylamine DIPEA (13.7g, 105mmol) was added dropwise under control of the temperature in the range of 10-15°C, and the addition was completed , control the temperature in the range of 10-15°C and stir for 8-10 hours, and the condensation reaction is completed.

[0041] The reaction solution was concentrated to dryness under reduced pressure, extracted with toluene solution (200 mL), and then washed twice with saturated sodium chloride solution (100 mL). The toluene solution was concentrated to obtain an oily foamy solid (36.2 g), yield 93%.

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Abstract

The invention provides a novel method for synthesizing anti-hepatitis C virus novel medicine daclatasvir. 4,4'-di(2-bromoacetyl) biphenyl serve as a raw material and first undergoes the condensation reaction with N-(methoxycarbonyl)-L-valyl-L-proline to obtain 4,4'-di(N-(methoxycarbonyl)-L-valyl-L-proline ester acetyl) biphenyl, and 4,4'-di(N-(methoxycarbonyl)-L-valyl-L-proline ester acetyl) biphenyl undergoes ring closing reaction with ammonium acetate to synthesize hepatitis C virus (HCV) NS5A inhibitor daclatasvir through two-step reaction. The novel method for synthesizing anti-hepatitis C virus novel medicine daclatasvir has the advantages that the reaction and separation and purification steps are fewer, the synthetic cycle is short and the production cost is low; and the method has wide prospect of large scale industrial application.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a new synthesis method of a new anti-hepatitis C drug daclatasvir. Background technique [0002] At present, the standard antiviral treatment for hepatitis C in China is pegylated interferon combined with ribavirin, and the cure rate is 50% to 70%. However, interferon is an indirect effect, which can easily cause flu-like symptoms, hematopenia, and mental disorders. , autoimmune diseases, kidney damage and other side effects, some patients are highly resistant. [0003] Daclatasvir (DAKLINZA) is a newest hepatitis C virus (HCV) NS5A inhibitor invented by Bristol-Myers Squibb. It is used in combination with other anti-hepatitis C drugs (including sofosbuvir), and it is effective against 1, 2, 3 1. The cure rate of type 4 hepatitis C is 89% to 100%, and it is suitable for the treatment of chronic HCV genotype 3 infection using Sofosbuvir. [0004] Patents such as WO2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07K5/062
CPCC07D403/14C07K5/06052
Inventor 周盛峰冯志勇
Owner 上海步越化工科技有限公司
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