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Preparation method of pregabalin intermediate

A technology of pregabalin and intermediates, applied in the field of organic synthesis, can solve the problems of difficult industrialization, long reaction route and high cost, and achieve the effects of reducing production process, shortening steps and mild conditions

Active Publication Date: 2021-03-19
内蒙古永太化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second step of sodium hydroxide hydrolysis of 3-isobutylglutaric acid imine also needs to be heated to complete, and the post-treatment is relatively complicated
But the reaction route is long, and the product needs to go through column chromatography, and the purification process is complicated, which is not conducive to industrial production
[0015] That is to say, the current process of synthesizing pregabalin by chemical method generally has problems such as complicated process, high cost, heavy pollution, and great difficulty in industrialization.

Method used

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  • Preparation method of pregabalin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] A kind of preparation method of pregabalin intermediate, it comprises the steps:

[0055] Preparation of S1 intermediate 3-isobutylglutarimide

[0056]

[0057] 249g of 70% cyanoacetic acid aqueous solution is cooled to below 10°C, and 300g of 30% lye is slowly added dropwise to control the internal temperature below 15°C. 86 g of isovaleraldehyde was slowly added dropwise. Insulated and stirred for 8h. Control the internal temperature not higher than 35°C, and slowly add 400g of concentrated sulfuric acid dropwise. Stir at 20-30°C for 0.5 hour, then at 60°C for 4 hours. The temperature was lowered to 20-30°C, and 300g of toluene was extracted twice. The organic phase was concentrated to obtain 158.0 g of crude 3-isobutylglutarimide, with a yield of 93.5% and a purity of 99.1%.

[0058] Such as Figure 1-2 Shown, is the intermediate 3-isobutylglutarimide 1 HNMR and 13 CNMR spectrum. It can be seen from the analysis that the detection result is consistent wit...

Embodiment 2

[0064] A kind of preparation method of pregabalin intermediate, it comprises the steps:

[0065] Preparation of S1 intermediate 3-isobutylglutarimide

[0066] 249g of 70% cyanoacetic acid aqueous solution, cool down to below 10°C, slowly add 300g of 30% lye, control the internal temperature below 15°C; slowly add 86g of isovaleraldehyde, keep stirring for 20h, control the internal temperature not higher than At 35°C, 400g of concentrated sulfuric acid was slowly added dropwise. Stir at 20-30°C for 0.5 hour, then at 60°C for 4 hours. The temperature was lowered to 20-30° C., and 300 g of toluene was extracted twice; the organic phase was concentrated to obtain 154.1 g of crude 3-isobutylglutarimide, with a yield of 91.2% and a purity of 98.8%. Preparation of S2 3-(carbamoylmethyl)-5-methylhexanoic acid

[0067] Add 170g of crude 3-isobutylglutarimide and 60g of sodium hydroxide to 500g of water, slowly raise the temperature to 100°C, stir for 4-6h, cool to 10-20°C, slowly ad...

Embodiment 3

[0069] A kind of preparation method of pregabalin intermediate, it comprises the steps:

[0070] Preparation of S1 intermediate 3-isobutylglutarimide

[0071] 249g of 70% cyanoacetic acid aqueous solution is cooled to below 10°C, and 300g of 30% lye is slowly added dropwise to control the internal temperature below 15°C. 53 g of isovaleraldehyde was slowly added dropwise. Insulated and stirred for 8h. Control the internal temperature not higher than 35°C, and slowly add 400g of concentrated sulfuric acid dropwise. Stir at 20-30°C for 0.5 hour, then at 60°C for 4 hours. The temperature was lowered to 20-30°C, and 300g of toluene was extracted twice. The organic phase was concentrated to obtain 93.0 g of crude 3-isobutylglutarimide, with a yield of 89.3% and a purity of 95.5%.

[0072] Preparation of S2 3-(carbamoylmethyl)-5-methylhexanoic acid

[0073] Add 170g of crude 3-isobutylglutarimide and 36g of LiOH to 500g of water, slowly raise the temperature to 50-60°C, stir f...

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Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a pregabalin intermediate. The method comprises the following steps: by taking cyanoacetic acid and isovaleraldehyde as raw materials, carrying out condensation and hydrolysis reaction to obtain imide in an intermediate, and further carrying out alkaline hydrolysis to obtain the intermediate3-(carbamylmethyl)-5-methylcaproic acid. The preparation method of the pregabalin intermediate has the advantages of easily available raw materials, mild reaction conditions, high safety factor, strong operability, simple process, easy realization of industrialization, high product purity and stable quality.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of a pregabalin intermediate. Background technique [0002] Pregabalin, chemical name (3S)-3-aminomethyl-5-methylhexanoic acid (3S-3-aminomethy-5-methylhexanoic acid), CAS number: 148553-50-8; molecular formula C 8 h 17 NO 2 ;Molecular weight: 159.23. It is a novel aminobutyric acid (GABA) receptor antagonist developed by Pfizer. In July 2004, it was first approved by the European Union for the treatment of partial seizures in adult patients, and the trade name is Lyrica. In June 2005, it was approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States. In March 2006, it added indications for the treatment of generalized anxiety disorder and social anxiety disorder. In 2009, it was approved for the treatment of spinal cord injury, trauma, and multiple sclerosis. syndrome, diabetic nerve pain and herpes zoster nerve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/10C07C231/24C07C233/05C07D211/88C07C253/30C07C255/19
CPCC07C231/10C07C231/24C07D211/88C07C253/30C07C255/19C07C233/05
Inventor 孔佳辉杨建平周怀林夏海建
Owner 内蒙古永太化学有限公司
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