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Method for synthesizing Pregabalin

A technology of pregabalin and synthesis method, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of difficult source of raw materials, low total yield of pregabalin, low product purity, etc. Guaranteed total yield and purity, simple reaction route and high yield

Inactive Publication Date: 2015-11-18
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
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Effect test

Embodiment 1

[0028] In the reaction vessel, put isovaleraldehyde, 0.8% titanium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), 2 volumes of pyridine, THF mixed solvent (in cyclohexane The volume of the ketone 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 recrystall...

Embodiment 2

[0034] In the reaction vessel, put isovaleraldehyde, 4% titanium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), 10 volumes of pyridine, THF mixed solvent (in the amount of isovaleraldehyde The volume of aldehyde 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...

Embodiment 3

[0040] In the reaction vessel, put isovaleraldehyde, 2.4% titanium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), 6 volumes of pyridine, THF mixed solvent (in the amount of isovaleraldehyde The volume of aldehyde 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,...

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Abstract

The invention discloses a method for synthesizing Pregabalin. The synthesis method comprises the following steps: 1, enabling isovaleraldehyde and diethyl malonate to be subjected to addition elimination reaction in a solvent composed of pyridine and THF at the temperature of 5-10 DEG C by taking titanium tetrachloride as a catalyst; 2, enabling the product obtained in the step 1 to be subjected to Michael addition in an alcohol solvent of alkali; 3, enabling the product obtained in the step 2 and hydrogen to be subjected to hydrogenation reaction by taking Pd as a catalyst; 4, enabling the product obtained in the step 3 to be subjected to hydrolysis reaction under the hydrochloric acid condition; 5, enabling the product obtained in the step 4 to be subjected to chiral resolution in a mixed solvent of alcohol and water by taking L-aspartic acid as a resolving agent. According to the invention, the low-price isovaleraldehyde easy to obtain is used as the raw material, and is subjected to addition elimination, Michael addition, hydrogenation reaction, hydrolysis and chiral resolution, so as to obtain the Pregabalin. The reaction route is simple, and the yield of the reaction in each step is relatively high, so that the total yield and purity of the final Pregabalin are guaranteed.

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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