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Method for synthesizing pregabalin

A synthesis method and technology of pregabalin, applied in the field of pregabalin, can solve the problems of low total yield of pregabalin, difficult source of raw materials, low product purity, etc., achieve simple reaction route, ensure total yield and purity , the effect of high yield

Inactive Publication Date: 2015-11-25
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
  • Method for synthesizing pregabalin
  • Method for synthesizing pregabalin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] In the reaction vessel, put isovaleraldehyde, 0.8% vanadium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), 2 volumes of DMSO and carbon tetrachloride mixed solvent ( The volume of cyclohexanone is 1), and the mixture is cooled to -5°C. Then add 1.05% of diethyl malonate (based on the amount of isovaleraldehyde as 1), keep the temperature at 5°C, let it react for 12h under constant stirring, filter, distill, and wash with ether to obtain 2-carboxyethyl Base-5-methyl-2-hexenoic acid ethyl ester, this was named compound A.

[0029] Put the above-mentioned compound A and ethanol with a mass of 3 (based on the mass of compound A as 1) in a high-pressure reactor, adjust the temperature to 20° C., and slowly drop in HCN with a mass of 1.02 (according to the mass of compound A) The mass is 1 meter). After reacting for 4 hours, the temperature was lowered to 10°C and the solid was filtered out. The solid was washed twice with water, and recry...

Embodiment 2

[0034] In the reaction vessel, put isovaleraldehyde, 4% vanadium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), 10 volumes of DMSO and carbon tetrachloride mixed solvent ( The volume of isovaleraldehyde is 1), and the mixture is cooled to 10°C. Then add 1.14 mass of diethyl malonate (based on the mass of isovaleraldehyde as 1), keep the temperature at 10°C, react for 6 hours under constant stirring, filter, distill, and wash with ether to obtain 1,1- Diethyl cyclohexyl allenoate, this was named compound A.

[0035]Put the above-mentioned compound A and methanol with a mass of 10 (based on the mass of compound A as 1) in a high-pressure reactor, adjust the temperature to 35 ° C, and slowly drop in HCN with a mass of 1.08 (calculated as the mass of compound A) The mass is 1 meter). After reacting for 2 hours, the temperature was lowered to 10°C and the solid was filtered out. The solid was washed twice with water, and recrystallized using a m...

Embodiment 3

[0040] In the reaction vessel, put isovaleraldehyde, 2.4% vanadium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), 6 volumes of DMSO and carbon tetrachloride mixed solvent ( The volume of isovaleraldehyde is 1), and the mixture is cooled to 7°C. Then add 1.095 mass of diethyl malonate (based on the mass of isovaleraldehyde as 1), keep the temperature at 7°C, react for 9 hours under constant stirring, filter, distill, and wash with ether to obtain 2-carboxyethyl Base-5-methyl-2-hexenoic acid ethyl ester, this was named compound A.

[0041] Put the above-mentioned compound A and ethanol with a mass of 6 (based on the mass of compound A as 1) in a high-pressure reactor, adjust the temperature to 28 ° C, and slowly drop in HCN with a mass of 1.06 (calculated as the mass of compound A) The mass is 1 meter). After reacting for 3 h, the temperature was lowered to 10° C. and the solid was filtered out. The solid was washed twice with water, and recr...

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Abstract

The invention discloses a synthesis method of pregabalin. The synthesis method comprises the following steps: carrying out addition elimination reaction on isovaleraldehyde and diethyl malonate in a solvent composed of DMSO (dimethyl sulfoxide) and carbon tetrachloride by using vanadium tetrachloride as a catalyst; carrying out Michael addition on the product obtained in the first step in an alkaline alcohol solvent; carrying out hydrogenation reaction on the product obtained in the second step with hydrogen gas by using a carbon-supported Pd catalyst; carrying out hydrolysis reaction on the product obtained in the third step in hydrochloric acid; and carrying out chiral resolution on the product obtained in the fourth step in an alcohol-water mixed solvent by using L-malic acid as a resolving agent. The cheap and accessible isovaleraldehyde used as the raw material is subjected to addition elimination, Michael addition, hydrogenation reaction, hydrolysis and chiral resolution to obtain the pregabalin. The method has the advantages of simple reaction route and higher yield of each step, thereby ensuring the total yield and purity of the final pregabalin.

Description

technical field [0001] The invention relates to the technical field of pregabalin, in particular to a method for synthesizing pregabalin. Background technique [0002] Pregabalin (Pregbalin), the chemical name is (S)-3-aminomethyl-5-methylhexanoic acid, which is developed by Pfizer company. [0003] A novel gamma-aminobutyric acid (GABA) receptor antagonist. In July 2004, it was first approved by the European Union under the trade name Lyrica for the treatment of partial epileptic seizures in adult patients. In June 2005, it was approved by the U.S. Food and Drug Administration (FDA) to go on the market in the United States. In March 2006, new indications were 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 shingles Rash nerve pain, making it clinical [0004] The application has been further expanded and it has become...

Claims

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Application Information

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IPC IPC(8): C07C229/08C07C227/34
Inventor 张卫东
Owner TAICANG YUNTONG BIOCHEM ENG
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