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Method of resolving amlodipine racemate

A technology for amlodipine and racemization, which is applied in the field of resolution of amlodipine racemate, and can solve problems such as being unsuitable for the routine production of enantiomer amlodipine

Inactive Publication Date: 2005-04-20
SEPACOR INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the use of DMSO makes Spargo's method unsuitable for the large-scale (kilogram) routine production of enantiomer amlodipine

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: S-(-)-Amlodipine D-hemitartrate DMAC monosolvate

[0038] To a stirred suspension of arolodipine besylate (200 g, 0.353 mol) in methyl tert-butyl ether (1.3 L) was added aqueous sodium hydroxide (1 N, 530 mL). The reaction mixture was stirred for 20-30 minutes before the aqueous and organic layers were allowed to separate. After removing the aqueous layer, water (220 mL) was added to the organic layer and the mixture was stirred for 20 minutes. The aqueous layer was removed again and the organic layer was concentrated to about one third of its original volume by vacuum distillation. The organic layer was collected and concentrated to approximately one third of its original volume by distillation. The concentrate was then mixed with N,N-dimethylacetamide (DMAC, 650 mL) and further concentrated by vacuum distillation until the temperature of the concentrate rose by 10-15°C. The concentrate was allowed to equilibrate to room temperature and pressure and then ...

Embodiment 2

[0039] Embodiment 2: S-(-)-amlodipine free base

[0040] To a stirred suspension of S-(-)-amlodipine D-hemitartrate DMAC monosolvate (81.1 g, 0.142 mol) in methyl tert-butyl ether (960 mL) was added aqueous sodium hydroxide (1N, 220ml). The reaction mixture was stirred for 20-30 minutes before the aqueous and organic layers were allowed to separate. After removing the aqueous layer, water (220 mL) was added to the organic layer and the mixture was stirred for 20 minutes. The aqueous layer was removed again and the organic layer was concentrated to about one third of its original volume by vacuum distillation. After allowing the concentrate to equilibrate to room temperature and pressure, heptane (320 mL) was added and the resulting slurry was stirred for 1-2 hours. The slurry was filtered and the remaining crystalline solid was washed with heptane (500 mL). The crystals were dried under vacuum at 40-50°C for 8-16 hours to obtain S-(-)-amlodipine free base (49.10 g, 85% yie...

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Abstract

The present invention relates to a process for the resolution of racemic amlodipine into enantiomerically enriched components by precipitation with tartaric acid in the presence of a non-aqueous solvent such as N,N'-dimethylacetamide. The molar ratio of tartaric acid:amlodipine is preferably less than 0.25:1.0 and greater than 0.75:1.0.

Description

field of invention [0001] Amlodipine is a long-acting dihydropyridine-type inhibitor of low calcium channels used in the treatment of hypertension and coronary insufficiency. Amlodipine contains an asymmetric carbon. The calcium channel blocking activity is mainly due to the S-(-) amlodipine enantiomer. The present invention relates to a process for the resolution of racemic amlodipine into its R-(+) and S-(-) enantiomers by precipitation with tartaric acid. Background of the invention [0002] U.S. Patent No. 4,572,909 to Campbell et al. describes the racemate amlodipine (3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorobenzene base)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate) and its activity as a calcium channel inhibitor. Arrowsmith et al., J.Med.Chem., (1986) 29, 1696-1702 describe the determination of the calcium antagonist activity of the enantiomers of amlodipine against calcium-induced potassium-depolarizing contraction of the rat aorta in vitro assay res...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4422A61P9/10A61P9/12C07D211/90
CPCC07D211/90A61P9/10A61P9/12C07D213/46
Inventor C·H·塞纳纳亚克G·J·塔诺里H·S·威尔金逊R·P·巴卡勒A·A·兹罗塔K·萨兰特斯
Owner SEPACOR INC
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