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Method for synthesizing pregabalin with isobutyl butanedinitrile as intermediate

A technology of isobutylsuccinonitrile and pregabalin, which is applied in the field of pregabalin, can solve the problems of difficult sources of raw materials, low total yield of pregabalin, and low product purity, so as to ensure the total yield and purity , simple reaction route and high yield

Inactive Publication Date: 2016-04-06
TAICANG YUNTONG BIOCHEM ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material source that this method adopts is difficult, and the total yield of pregabalin is not high, and the purity of product is lower

Method used

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  • Method for synthesizing pregabalin with isobutyl butanedinitrile as intermediate
  • Method for synthesizing pregabalin with isobutyl butanedinitrile as intermediate
  • Method for synthesizing pregabalin with isobutyl butanedinitrile as intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Put isovaleraldehyde, piperazine with a mass of 0.3 (based on the mass of ethyl cyanoacetate as 1), and 5 cyclohexane (based on the total mass of isovaleraldehyde and ethyl cyanoacetate) in the reaction vessel. 1g), the temperature of this mixture is controlled to 70°C. Then add 1.1 ethyl cyanoacetate (based on isovaleraldehyde as 1), keep the temperature at 70°C, and react for 8h under constant stirring. After the reaction is completed, the cyclohexane is removed by evaporation. Then add water and repeat extraction several times, and combine the organic phases. Dry over anhydrous magnesium sulfate overnight, remove the anhydrous magnesium sulfate by suction filtration, and distill the filtrate under reduced pressure to obtain a pale yellow oily liquid called 5-methyl-2-cyano-2-hexenoic acid ethyl ester, which is named compound A .

[0027] Put the above compound A and ethanol with a mass of 3 into the reaction vessel, adjust the temperature to 20℃, and slowly drop in 1...

Embodiment 2

[0032] Put isovaleraldehyde, piperazine with a mass of 0.6 (based on the mass of ethyl cyanoacetate as 1), and 20ml cyclohexane (based on the total mass of isovaleraldehyde and ethyl cyanoacetate) in the reaction vessel. 1g), the temperature of this mixture is controlled to 80°C. Then add 1.2 ethyl cyanoacetate (based on isovaleraldehyde as 1), keep the temperature at 80°C, and react for 4 hours under constant stirring. After the reaction is completed, the cyclohexane is removed by evaporation. Then add water and repeat extraction several times, and combine the organic phases. Dry over anhydrous magnesium sulfate overnight, remove the anhydrous magnesium sulfate by suction filtration, and distill the filtrate under reduced pressure to obtain a pale yellow oily liquid called 5-methyl-2-cyano-2-hexenoic acid ethyl ester, which is named compound A .

[0033] Put the above-mentioned compound A and ethanol with a mass of 3 in the reaction vessel, adjust the temperature to 35°C, and...

Embodiment 3

[0038] Put isovaleraldehyde, piperazine with a mass of 0.45 (based on the mass of ethyl cyanoacetate as 1), 12ml cyclohexane (based on the total mass of isovaleraldehyde and ethyl cyanoacetate) in the reaction vessel 1g), the temperature of this mixture is controlled to 75°C. Then add ethyl cyanoacetate with a mass of 1.15 (based on the mass of isovaleraldehyde as 1), keep the temperature at 75° C., and allow it to react for 6 hours under constant stirring. After the reaction is completed, the cyclohexane is removed by evaporation. Then add water and repeat extraction several times, and combine the organic phases. Dry over anhydrous magnesium sulfate overnight, remove the anhydrous magnesium sulfate by suction filtration, and distill the filtrate under reduced pressure to obtain a pale yellow oily liquid called 5-methyl-2-cyano-2-hexenoic acid ethyl ester, which is named compound A .

[0039] Put the above compound A and ethanol with a mass of 3 into the reaction vessel, adjus...

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Abstract

The invention discloses a method for synthesizing pregabalin with isobutyl butanedinitrile as the intermediate. The method includes the steps of conducting the Knoevenagel condensation reaction on isovaleraldehyde and ethyl cyanoacetate in cyclohexane solvent with piperazine as the catalyst, conducting Michael addition on the product obtained in the first step and cyanic acid in alkaline alcohol solvent, conducting the decarboxylic reaction on the product obtained in the second step in isopropanol solvent under the heating condition to obtain the isobutyl butanedinitrile solvent, conducting hydrolysis on the intermediate under catalysis of cyanide hydratase AtNiTl, and conducting catalytic hydrogenation with raney nickel as the catalyst. According to the method, isoamyl aldehyde and ethyl cyanoacetate which are low in price and easy to obtain are used as raw materials, and the isobutyl butanedinitrile intermediate is obtained through the Knoevenagel condensation reaction, Michael addition and the decarboxylic reaction. The intermediate is then catalyzed, hydrolyzed and reduced through cyanide hydratase AtNiTl, and pregabalin is obtained. The reaction route is simple, the yield of each step of reaction is high, and therefore the final total recovery and purity of pregabalin are ensured.

Description

Technical field [0001] The present invention relates to the technical field of pregabalin, in particular to a method for synthesizing pregabalin by using isobutyl succinonitrile as an intermediate. Background technique [0002] Pregbalin, whose chemical name is (S)-3-aminomethyl-5-methylhexanoic acid, is a new gamma-aminobutyric acid (GABA) receptor antagonist developed by Pfizer. In July 2004, it was first approved by the European Union to be marketed under the trade name Lyrica for the treatment of some epileptic seizures in adult patients. In June 2005, it was approved by the US Food and Drug Administration (FDA) for listing in the United States. In March 2006, a new indication was added for the treatment of generalized anxiety disorder and social anxiety disorder. In 2009, it was approved for the treatment of spinal cord injury, trauma, multiple sclerosis, diabetic nerve pain and band scars. Eruptive nerve pain has further expanded its clinical application and has become on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/00C07C227/04C07C229/08
CPCC07B2200/07C07C227/04C12P13/005C07C229/08
Inventor 张卫东
Owner TAICANG YUNTONG BIOCHEM ENG
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