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Novel process

An enantiomeric, enriched technology, applied in the field of γ-amino acids such as enantiomerically enriched-pregabalin, which can solve problems such as expensive resolving agents

Inactive Publication Date: 2011-06-08
GENERICS UK LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, (S)-mandelic acid used in excess (1.7eq.) is an expensive resolving agent

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Example 1: Resolution of racemic pregabalin using L-tartaric acid by the method described in Scheme 2 (2)

[0169] Preparation of (S)-pregabalin (L)-tartrate (4):

[0170] A mixture of racemic 3-aminoethyl-5-methylhexanoic acid (2) (100 g), L-tartaric acid (94.3 g), n-butanol (1.01) and water (200 ml) was stirred at 25-30°C to obtain a clear solution. The clear solution was then filtered, cooled to 8-10°C, and stirred at 8-10°C for 4 hours. The solid obtained was filtered off and dried under vacuum at 40-45°C. Yield: 90 g (93% mol, 46% w / w). Enantiomeric purity: 99.0% S-isomer (as determined by chiral HPLC). Chemical purity: 99.64% (as determined by HPLC). No lactam impurity was observed by HPLC.

[0171] Recrystallization of (S)-pregabalin (L)-tartrate (4):

[0172] (S)-Pregabalin (L)-tartrate (4) (90 g) was added to n-butanol (450 ml) and water (90 ml) and stirred at 20-30° C. to obtain a clear solution. The clear solution was filtered, cooled to 10-15°C, a...

Embodiment 2

[0177] Example 2: Resolution of racemic pregabalin by L-tartaric acid by the method described in Scheme 3 (2)

[0178] Preparation of pregabalin (L)-tartrate (5):

[0179] A mixture of racemic 3-aminoethyl-5-methylhexanoic acid (2) (100 g), L-tartaric acid (94.3 g), n-butanol (1.01) and water (100 ml) was stirred at 20-25°C to obtain a clear solution. The clear solution was then filtered, cooled to 0-5°C, and stirred at 0-5°C for 4 hours. The solid obtained was filtered off and dried under vacuum at 40-45°C. Yield: 184.5 g (95% mole and w / w). Enantiomeric purity: 48% (S)-pregabalin (L)-tartrate and 52% (R)-pregabalin (L)-tartrate (as determined by chiral HPLC). Chemical purity: 99.91% (as determined by HPLC). No lactam impurity was observed by HPLC.

[0180] Preparation of (S)-pregabalin (L)-tartrate (4) by fractional crystallization:

[0181] Pregabalin (L)-tartrate (5) (184.5g) was added to n-butanol (1845ml) and water (369ml) and stirred at 20-30°C to obtain a cl...

Embodiment 3

[0186] Example 3: Resolution of racemic pregabalin (2) by a method similar to that described in Scheme 2 but using O,O'-di-p-toluoyl-(D)-tartaric acid

[0187] (S)-Pregabalin O, the preparation of O'-di-p-toluoyl-(D)-tartrate (6):

[0188] Stir racemic 3-aminoethyl-5-methylhexanoic acid (2) (100 g), O, O'-di-p-toluoyl-(D)-tartaric acid (126 g), tert-butyl A mixture of alcohol (1.01) and water (200ml) to obtain a clear solution. The clear solution was then filtered, cooled to 0-5°C, and stirred at 0-5°C for 4 hours. The solid obtained was filtered off and dried under vacuum at 40-45°C. Yield: 168 g (98% mole, 49% w / w). Enantiomeric purity: 96.0% S-isomer (as determined by chiral HPLC). Chemical purity: 99.50% (as determined by HPLC). No lactam impurity was observed by HPLC.

[0189] Recrystallization of (S)-pregabalin O.O'-di-p-toluoyl-(D)-tartrate (6):

[0190] (S)-Pregabalin O, O'-di-p-toluoyl-(D)-tartrate (6) (168g) was added in tert-butanol (1680ml) and water (33...

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Abstract

The present invention relates to a novel process of preparing an enantiomerically enriched Gamma-amino acid, such as enantiomerically enriched (S)-pregabalin.

Description

technical field [0001] The present invention relates to a novel process for the preparation of enantiomerically enriched [gamma]-amino acids such as enantiomerically enriched (S)-pregabalin. Background technique [0002] Many gamma-amino acids, such as (S)-pregabalin (1), are used as anticonvulsants. [0003] [0004] (S)-Pregabalin(1) Racemic Pregabalin(2) [0005] (S)-Pregabalin (1) is related to the endogenous inhibitory neurotransmitter γ-amino-butyric acid (GABA) involved in the regulation of brain neuronal activity. (S)-Pregabalin (1) exhibits anti-seizure activity and is also considered useful in the treatment of pain, physiological disorders associated with psychomotor stimulants, inflammation, gastrointestinal injury, among other conditions , alcoholism, insomnia, fibromyalgia, and various mental disorders, including mania and bipolar disorder. [0006] Various literature articles and patent applications have disclosed synthetic routes to racemic γ-amino acids...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/34C07C229/08
CPCC07C227/34A61P1/00A61P21/00A61P25/04A61P25/20A61P25/24A61P29/00A61P39/02C07C229/08
Inventor 维纳亚克·戈雷德巴希什·达塔马赫什库马·加达卡尔基兰·波克哈尔卡尔维拉杰·曼卡尔斯奈哈·瓦夫哈尔
Owner GENERICS UK LTD
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