Process for the enantioselective preparation of pregabalin

An enantioselective, pregabalin technology, applied in the field of enantioselective preparation-pregabalin or its salts, can solve problems such as high cost of catalyst systems

Inactive Publication Date: 2010-09-29
LAB DEL DR ESTEVE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although this method directly provides (S)-pregabalin in high enantiomeric purity, it has several drawbacks due to the higher cost of the catalyst system and the synthesis of chiral expensive starting materials

Method used

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  • Process for the enantioselective preparation of pregabalin
  • Process for the enantioselective preparation of pregabalin
  • Process for the enantioselective preparation of pregabalin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] 1.1 Synthesis of (R)-2,2-dimethyl-1,3-dioxolane-4-aldehyde

[0092]

[0093] NaIO 4 (16g, 74.8mmol) added (1S,2S)-1,2-bis((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2 -diol (20g, 76.2mmol) in 9:1 THF-H 2 In a stirred solution in O (280 mL), the resulting mixture was stirred for 4 h. The resulting precipitate was filtered off and most of the THF was evaporated under reduced pressure. Water (20 mL) was then added, and the aqueous solution was extracted with dichloromethane (6 x 50 mL). Combined organic extracts in MgSO 4 ((R)-2,2-Dimethyl-1,3-dioxolane-4-carbaldehyde (16.8 g, 85% yield), which was used without further purification In the next steps.

[0094] · 1 H-NMR (250MHz, CDCl 3 )

[0095] 1.4(s, 3H), 1.5(s, 3H), 4.1(m, 2H), 4.4(m, 1H), 9.7(d, 3 J H-H = 2Hz, 1H).

[0096] IR (film): 3417, 2985, 1735, 1372, 1064cm -1 .

[0097] ·Appearance: Colorless oil.

[0098] 1.2 Synthesis of (E)-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate

[0099]

[01...

Embodiment 2

[0165] 2.1 Synthesis of (S)-1-benzyl-4-((S)-2,2-dimethyl-1,3-dioxolane-4-yl)pyrrolidin 2-one

[0166]

[0167] Sodium hydride (60%, 0.24 g, 6.0 mmol) in paraffin oil was added to (S)-4-((S)-2,2-dimethyl-1,3-dioxolane on an ice bath -4-yl)pyrrolidin-2-one (1.0 g, 5.4 mmol) in a stirred solution of anhydrous THF (75 mL). The mixture was stirred at 0°C for 30 min, and benzyl bromide (0.7 mL, 5.7 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for another 3 h. The solvent was evaporated under vacuum, and the residue was poured into EtOAc (100 mL), washed several times with water. Organic phase in MgSO 4 Dry and remove the solvent. The residue (0.8g) was in Chromatography on silica gel with EtOAc-hexane (2:3) as eluent afforded pure (S)-1-benzyl 4-((S)-2,2-dimethyl-1,3- Dioxolan-4-yl)pyrrolidin-2-one (0.9 g, 60% yield).

[0168] · 1 H-NMR (250MHz, CDCl 3 )

[0169] 1.3(s, 3H), 1.4(s, 3H), 2.2(m, 1H), 2.5(m, 2H), 3.3(m...

Embodiment 3

[0219] 3.1 (S)-tert-butyl 4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxopyrrolidine-1-carboxylate synthesis

[0220]

[0221] To (S)-4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)pyrrolidin-2-one (500 mg, 2.7 mmol) in dichloromethane ( To a stirred solution in 25 mL), triethylamine (0.4 mL, 2.9 mmol), 4-dimethylaminopyridine (330 mg, 2.7 mmol) and Boc anhydride (1.2 mL, 5.4 mmol) were added successively. The light protected mixture was stirred at room temperature for 12 h. The solvent was evaporated under vacuum and the residue was Chromatography on silica gel using EtOAc-hexane (1:2) as eluent gave pure (S)-tert-butyl 4-((S)-2,2-dimethyl-1,3- Dioxolane4-yl) 2-oxopyrrolidine-1-carboxylate (770 mg, 100% yield), could be crystallized in EtOAc / pentane.

[0222] Characterization:

[0223] · 1 H-NMR (250MHz, CDCl 3 )

[0224] 1.4(s, 3H), 1.5(s, 3H), 1.6(s, 9H), 2.3(m, 1H), 2.4(m, 1H), 2.6(m, 1H), 3.7(m, 2H), 3.9 (dd, 3 J H-H = 6Hz, 3 J H-H = 10.5 Hz, 1H), 4.1 (m, 2H).

[02...

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Abstract

The invention provides a new enantioselective process for the preparation of (S) -pregabalin, or a pharmaceutical acceptable addition acid salt comprising: acid hydrolysis of the dioxolan ring of a chiral compound of general formula (I) to obtain compound of general formula (II); oxidation of compound (II) to obtain a compound of general formula (III) and transforming compound (III) into compound of general formula (IV); subjecting compound (IV) to basic hydrolysis to obtain a compound of general formula (V) which is reduced to obtain enantiomerically pure S-pregabalin. The invention also provides new chiral intermediates involved in the process.

Description

field of invention [0001] The present invention relates to a method for enantioselectively preparing (S)-pregabalin (pregabalin) or a salt thereof, especially a pharmaceutically acceptable salt. Chirality was introduced at the beginning of the process using D-mannitol bisacetonide to obtain the starting compound (S)-4-((S)-2,2-dimethyl-1,3 -dioxolan-4-yl)pyrrolidin-2-one, optionally protected with an amine protecting group, and maintained during the process. The invention also relates to novel chiral intermediates involved in this process. Background of the invention [0002] (S)-Pregabalin, also known as (S)-3-(aminomethyl)-5-methylhexanoic acid, as Gabapentin for the treatment of epilepsy, pain, anxiety and social phobia, A follower compound was developed. Both (S)-pregabalin and gabapentin are analogs of 4-aminobutyric acid (GABA), a neurotransmitter thought to play a major inhibitory role in the central nervous system (CNS). (S)-Pregabalin was approved in the United...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/20C07C229/14C07D491/056C07D207/273C07C229/08C07D207/27C07D207/267C07C227/16C07C227/18
CPCC07D317/20C07D207/267C07C227/32C07D207/273C07C227/22C07D207/27C07D491/056C07C229/08
Inventor 罗莎·M·奥图尼奥桑德拉·伊斯昆亚度海尔姆特·海因里希·布希曼安东尼·托伦斯·乔夫莫尼卡·加西亚·洛佩斯
Owner LAB DEL DR ESTEVE SA
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