Industrial production method for Daclatasvir key intermediate

A technology of daclatasvir and production method, applied in the field of biochemical industry, can solve the problems of many steps, long synthesis route, low yield and the like

Inactive Publication Date: 2019-03-22
GENCHEM & GENPHARM CHANGZHOU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The present invention is mainly aimed at the existing 5,5'-[1,1'-biphenyl]-4,4'-diylbis[2-(2S)-2-pyrrolidinyl-1H-imidazole] tetrasalt In the salt production process, the product synthesis route is long, there are many steps, the post-treatment is cumbersome, and the yield is low. A series of problems such as 5,5'-[1,1'-biphenyl]-4, 4'-diylbis[2-(2S)-2-pyrrolidinyl-1H-imidazole]tetrahydrochloride industrial one-pot continuous production method

Method used

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  • Industrial production method for Daclatasvir key intermediate
  • Industrial production method for Daclatasvir key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Synthesis of compound 1

[0027] (1) Under the protection of nitrogen, suck 400kg of methylene chloride into the 1000L reactor, add 80kg of raw material biphenyl (molecular weight 154.2, 519mol) under stirring, stir to dissolve and cool down;

[0028] (2) Cool the reaction system to below 0°C, add 208 kg of anhydrous aluminum chloride (molecular weight 133.3, 1560 mol) in batches, the reaction has obvious exotherm during the addition process, and control the temperature of the reaction system;

[0029] (3) Under the condition of controlling the reaction temperature of the system at 0°C, slowly add 176 kg of chloroacetyl chloride (molecular weight 112.9, 1560 mol) dropwise;

[0030] (4) After the dropwise addition is completed, the reaction system is slowly warmed up to 25°C, and the reaction temperature is maintained, and the liquid phase is controlled until the end of the reaction;

[0031] (5) After the reaction finishes, the reaction solution is directly concentrate...

Embodiment 2

[0048] Synthesis of compound 1

[0049] (1) Under the protection of nitrogen, pump 1000kg of dichloromethane into the 2000L reactor, add 80kg of raw material biphenyl (molecular weight 154.2, 519mol) under stirring, stir to dissolve and cool down;

[0050] (2) Cool the reaction system to below 0°C, add 145 kg of anhydrous aluminum chloride (molecular weight 133.3, 1090 mol) in batches, the reaction has obvious exotherm during the addition process, and control the temperature of the reaction system;

[0051] (3) Under the condition of controlling the reaction temperature of the system at 0°C, slowly add 123 kg of chloroacetyl chloride (molecular weight 112.9, 1090 mol) dropwise;

[0052] (4) After the dropwise addition is completed, the reaction system is slowly warmed up to 25°C, and the reaction temperature is maintained, and the liquid phase is controlled until the end of the reaction;

[0053] (5) After the reaction finishes, the reaction solution is directly concentrated ...

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Abstract

The invention relates to the technical field of biochemical engineering and specifically relates to an industrial production method for a Daclatasvir key intermediate 5,5'-[1,1'-biphenyl]-4,4'-diyl di[2-(2S)-2-pyrrolidyl-1H-imidazole]terthydrochloride. The 5,5'-[1,1'-biphenyl]-4,4'-diyl di[2-(2S)-2-pyrrolidyl-1H-imidazole]terthydrochloride is prepared according to a one-pot method. Compared with aconventional process, the industrial production method for the Daclatasvir key intermediate 5,5'-[1,1'-biphenyl]-4,4'-diyl di[2-(2S)-2-pyrrolidyl-1H-imidazole]terthydrochloride is capable of efficiently and stably producing high-quality 5,5'-[1,1'-biphenyl]-4,4'-diyl di[2-(2S)-2-pyrrolidyl-1H-imidazole]terthydrochloride, the purity of the intermediate is greater than 99%, and the content of unknown single impurities is smaller than 0.3%.

Description

technical field [0001] The invention relates to the field of biochemical technology, in particular to the key intermediate of daclatasvir 5,5'-[1,1'-biphenyl]-4,4'-diylbis[2-(2S)-2-pyrrole Alkyl-1H-imidazole]tetrahydrochloride industrial production method. Background technique [0002] 5,5'-[1,1'-Biphenyl]-4,4'-Diylbis[2-(2S)-2-pyrrolidinyl-1H-imidazole]tetrahydrochloride, daclatasvir intermediate body. English name: 1H-IMidazole,5,5'-[1,1'-biphenyl]-4,4'-diylbis[2-(2S)-2-pyrrolidinyl-,hydrochloride(1:4). CAS number: 1009119-83-8. [0003] 5,5'-[1,1'-biphenyl]-4,4'-diylbis[2-(2S)-2-pyrrolidinyl-1H-imidazole]tetrahydrochloride is a synthetic daclatasvir key intermediates. Daclatasvir (Daklinza) is an oral hepatitis C virus (HCV) NS5A inhibitor developed by Bristol-Myers Squibb (BMS). After the European Union approved its combination with other antiviral drugs for the treatment of genotype 1-4 chronic hepatitis C adult patients in 2014, the US FDA approved its combinatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 王玉琴陈连方孟硕
Owner GENCHEM & GENPHARM CHANGZHOU CO LTD
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