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Preparation method for asymmetrical synthesis of pregabalin

A pregabalin and asymmetric technology is applied in the preparation field of asymmetric synthesis of pregabalin, can solve the problems of low yield, long synthesis route of pregabalin, need to split, etc., achieves few steps, novel synthesis route, The effect of mild reaction conditions

Active Publication Date: 2016-07-13
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In order to solve the problems of long synthetic route of pregabalin, low yield in the production process, and the need for resolution in the preparation process, the present invention provides an asymmetric synthetic route with few synthetic steps, high yield and no need for chiral resolution

Method used

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  • Preparation method for asymmetrical synthesis of pregabalin
  • Preparation method for asymmetrical synthesis of pregabalin
  • Preparation method for asymmetrical synthesis of pregabalin

Examples

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Embodiment 1

[0040] 1. Catalytic asymmetric alcoholysis

[0041] Take a 100mL three-necked flask, add 3-isobutylglutaric anhydride (1.70g, 0.01mol), bromide (S)-2-(3(3,5-bis(trifluoro Methyl)phenyl)thioureido)-N,N,4-trimethyl-N-(4-nitrobenzyl)pentan-1-ammonium (630mg, 1.0mmol), and 50mL THF was added to dissolve the solid, Benzylthiol (1.50g, 0.012mol) was added under stirring at -10°C, reacted for 16h, the solvent was removed under reduced pressure, and purified by column chromatography to obtain 2.80g of thiol ester with a yield of 95% and an ee value of 94%.

[0042] 2. Synthesis of benzyloxycarbamide methyl thiol ester

[0043] Take a 100mL three-necked flask, dissolve thiol ester (2.80g, 9.5mmol) in dry toluene at 25°C, add triethylamine (0.97g, 9.6mmol) and diphenylphosphoryl azide (2.64g, 9.6mmol), stirred for 15min, then slowly raised the temperature to 85°C, when no bubbles emerged from the system, slowly added benzyl alcohol (1.08g, 10.0mmol) and stirred and refluxed for 12h. ...

Embodiment 2

[0049] 1. Catalytic asymmetric alcoholysis

[0050] Take a 100mL three-necked flask, add 3-isobutylglutaric anhydride (1.70g, 0.01mol), chloride (S)-2-(3(3,5-bis(trifluoro Methyl)phenyl)thioureido)-N,N,4-trimethyl-N-(4-nitrobenzyl)pentan-1-ammonium (590mg, 1.0mmol), and added 50mL methyl tert-butyl Dissolve the solid in base ether, add benzyl mercaptan (1.50g, 0.012mol) under stirring at -10°C, react for 16h, remove the solvent under reduced pressure, and purify by column chromatography to obtain 2.84g of thiol ester with a yield of 96% and an ee value 95%.

[0051] 2. Synthesis of benzyloxycarbamide methyl thiol ester

[0052] Take a 50mL three-necked flask, dissolve thiol ester (1.42g, 4.8mmol) in dry toluene at 25°C, add triethylamine (0.49g, 4.8mmol) and diphenylphosphoryl azide (1.324g, 4.8mmol), stirred for 15min, then slowly raised the temperature to 85°C, when no bubbles emerged from the system, slowly added benzyl alcohol (0.54g, 5.0mmol) and stirred and refluxed f...

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Abstract

The invention discloses a preparation method for asymmetric synthesis of pregabalin.The preparation method includes: using 3-isobutylglutaric anhydride as a starting raw material; under catalytic action of chiral thiourea ammonium salt, enabling the starting raw material to be in asymmetric alcoholysis with mercaptan to generate mercaptide; enabling mercaptide to react with diphenylphosphoryl azide and benzyl alcohol sequentially to generate benzyloxy carbonyl methyl mercaptide; obtaining pregabalin through hydrolysis and hydrogenation reduction.The synthetic method is adopted to synthesize pregabalin, asymmetric catalysis is adopted to synthesize a key intermediate, a chemical resolution reagent is not used, total yield is greater than 50%, and ee value is greater than 94%.The preparation method has the advantages of novel synthesis path, few steps, mild reaction condition and the like.

Description

technical field [0001] The invention relates to the field of chemical synthesis, more specifically, to a preparation method for asymmetrically synthesizing pregabalin. Background technique [0002] Pregabalin (CAS: 148553-50-8) is a gamma-aminobutyric acid (GABA) analogue, similar in structure and action to gabapentin, with antiepileptic, analgesic and anxiolytic activities. The mechanism of antiepileptic action of this drug is not clear. In laboratory studies, the drug has anticonvulsant activity on various epilepsy models; the activity spectrum of animal models is similar to that of gabapentin, but the activity is 3 to 10 times that of gabapentin. [0003] The drug was applied for registration by Pfizer in 2003, and the FDA approved it for listing in December, 2004, and the preparation is a capsule. This variety is widely used in the treatment of epilepsy, neuropathic pain and anxiety disorders, generalized anxiety disorder, diabetic peripheral neuropathy, post-herpetic ...

Claims

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Application Information

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IPC IPC(8): C07C227/34C07C227/18C07C229/08C07B57/00
CPCC07B57/00C07B2200/07C07C227/18C07C227/34C07C269/06C07C327/30C07C327/32C07C229/08C07C271/54
Inventor 蓝温龙
Owner SHENZHEN HUAXIAN PHARMA TECH CO LTD
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