Preparation method for pregabalin

A pregabalin, reactive technology, applied in chemical instruments and methods, cyanide reaction preparation, preparation of organic compounds, etc., can solve the problems of difficult source of raw materials, low total yield of pregabalin, low product purity, etc. , to achieve the effect of ensuring 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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  • Preparation method for pregabalin
  • Preparation method for pregabalin
  • Preparation method for pregabalin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] In the reaction vessel, put isovaleraldehyde, 0.8% niobium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), the DMF and pyridine mixed solvent of 2 volumes (in the form of 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.

[0027] 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 wat...

Embodiment 2

[0032] In the reaction vessel, put isovaleraldehyde, 4% niobium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), DMF and pyridine mixed solvent of 10 volumes (in the amount of isovaler 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.

[0033]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 ...

Embodiment 3

[0038] In the reaction vessel, put isovaleraldehyde, 2.4% niobium tetrachloride (the total mass of isovaleraldehyde and diethyl malonate is 100%), DMF and pyridine mixed solvent of 6 volumes (in the amount of isovaler 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.

[0039] 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 r...

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Abstract

The invention discloses a preparation method for pregabalin. The preparation method comprises the following steps: step 1, performing an addition elimination reaction on isovaleraldehyde and diethyl malonate in a solvent comprising DMF and pyridine by using niobium tetrachloride as a catalyst at the temperature of 5-10 DEG C; step 2, performing Michael addition on a product obtained in the step 1 in an alkaline alcohol solvent; step 3, performing a hydrogenation reaction on a product obtained in the step 2 and hydrogen by using raney nickel as a catalyst; step 4, performing a hydration reaction on a product obtained in the step 3 under the condition of hydrochloric acid; step 5, performing chiral resolution on a product obtained in the step 4 in a mixed solvent comprising alcohol and water by using L-tartaric acid as a resolving agent. According to the preparation method, inexpensive and readily-available isovaleraldehyde is used as a raw material, and pregabalin is obtained through the addition elimination reaction, the Michael addition reaction, the hydrogenation reaction, the hydration reaction and chiral resolution. The reaction route is simple, and the yield of each reaction is relatively high, so that the total yield and the purity of the final product of pregabalin are ensured.

Description

technical field [0001] The invention relates to the technical field of pregabalin, in particular to a method for preparing pregabalin. Background technique [0002] Pregabalin, whose chemical name is (S)-3-aminomethyl-5-methylhexanoic acid, is a novel aminobutyric acid (GABA) receptor antagonist developed by Pfizer. 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 Its clinical application has been further expanded, and it has become one of the best-selling drugs in the world. Its structure is shown in formula ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/08C07C227/34
Inventor 张卫东
Owner TAICANG YUNTONG BIOCHEM ENG
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