Preparation method of pregabalin

A pregabalin and organic solvent technology, applied in the field of preparation of pregabalin, can solve the problems of expensive catalyst, high synthesis cost, low enantioselectivity, etc., and achieve simple operation, easy industrial production, and easy-to-obtain raw materials Effect

Active Publication Date: 2013-05-01
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The selected catalyst of this method is expensive and has poor stability, thereby increasing the synthetic cost of (S)-pregabalin
WO2008009897A1 uses quinine asymmetric catalysis to prepare (S)-pregabalin, but its enantioselectivity is low, and it is still necessary to obtain intermediates with high optical purity and (S)-pregabalin by resolution

Method used

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  • Preparation method of pregabalin

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Experimental program
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Effect test

Embodiment 1

[0038] Under nitrogen protection, 3-isobutylglutaric anhydride (1.70 g, 10 mmol), methyl tert-butyl ether (10 mL), (1R,2S)-1-(3,5-bis(trifluoromethane phenylsulfonyl)-N,N-dimethyl-1-(4-nitrophenyl)-3-(triphenylmethoxy)-2-propanamine (1.51 g, 2 mmol) in dry in the reaction vial. After stirring at room temperature for 10 minutes, it was cooled to 20 °C, and benzyl mercaptan (1.49 g, 12 mmol) was added dropwise, followed by TLC until the anhydride completely disappeared. The solvent was recovered under reduced pressure, the residue was dissolved in dichloromethane (10 mL), and extracted with saturated sodium carbonate solution (2×10 mL). The combined extracts were acidified to pH 1.0 with 2 N HCl and extracted with ethyl acetate (3×15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain a colorless oil (2.80 g, 95%). [α] D 20 = +1.17 ( c =12, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ = 0...

Embodiment 2

[0040] Under nitrogen protection, 3-isobutylglutaric anhydride (1.70 g, 10 mmol), toluene (10 mL), (1S,2S)-2-(dimethylamino)-1-(4-nitrophenyl )-3-(trityloxy)propanol (0.96 g, 2 mmol) was placed in a dry reaction flask. After stirring at room temperature for 10 minutes, it was cooled to 0 °C, and benzyl mercaptan (1.49 g, 12 mmol) was added dropwise, followed by TLC until the anhydride completely disappeared. The solvent was recovered under reduced pressure, the residue was dissolved in dichloromethane (10 mL), and extracted with saturated sodium carbonate solution (2×10 mL). The combined extracts were acidified to pH 1.0 with 2 N HCl and extracted with ethyl acetate (3×15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain a colorless oil (2.79 g, 94%). [α] D 20 = +1.19 ( c =12, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ = 0.77-0.83 (m, 6 H), 1.14 (t, J = 6.8 Hz, 2 H), 1.50 (sep, J ...

Embodiment 3

[0042] Under nitrogen protection, 3-isobutylglutaric anhydride (1.70 g, 10 mmol), methyl tert-butyl ether (10 mL), (1R,2S)-1-(3,5-bis(trifluoromethane Base) benzenesulfonyl)-N,N-methyl-1-(4-nitrophenyl)-3-(triphenylmethoxy)-2-propanamine (1.51 g, 2 mmol) placed in a dry in the reaction vial. After stirring at room temperature for 10 minutes, it was cooled to -20°C, and benzyl mercaptan (1.49 g, 12 mmol) was added dropwise, followed by TLC until the anhydride completely disappeared. The solvent was recovered under reduced pressure, the residue was dissolved in dichloromethane (10 mL), and extracted with saturated sodium carbonate solution (2×10 mL). The combined extracts were acidified to pH 1.0 with 2 N HCl and extracted with ethyl acetate (3×15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain a colorless oil (2.82 g, 96%). [α] D 20 = +1.18 ( c =12, CHCl 3 ); 1 H NMR (400 MHz, CD...

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Abstract

The invention provides a synthetic method of pregabalin. The method comprises the following steps that (R)-3-(2-(benzyl sulfydryl)-2-ethyl)-5-methylhexanoic acid is synthesized from 3-isobutyl glutaric anhydride in carbinol; then, through base catalysis, (S)-S-phenyl 3-((benzyloxycarbonylamino group) methyl)-5-methylhexanol thioester is synthesized; next, hydrolysis is carried out, (S)-S-phenyl 3-((benzyloxycarbonylamino group) methyl)-5-methylhexanol is synthesized; and finally, hydrogenation is carried out, and the pregabalin is prepared. The material has the advantages that raw materials are easy to obtain, the operation is simple and convenient, the reaction condition is mild, and the industrial production is easy.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of pregabalin. Background technique [0002] Pregabalin (Pregabalin, 1), the chemical name is (S)-3-aminomethyl-5-methylhexanoic acid, is a new type of γ-aminobutyric acid (GABA) receptor antagonist developed by Pfizer. In July 2004, it was approved by the European Union for the treatment of partial seizures in adult patients for the first time, under the trade name Lyrica. In June 2005, it was approved by the US 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 pain, and its clinical application has been further expanded. [0003] The anticonvulsant effect of ...

Claims

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Application Information

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IPC IPC(8): C07C229/08C07C227/20
CPCY02P20/582
Inventor 陈芬儿杨鸿均熊方均李杰
Owner FUDAN UNIV
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