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Process for the preparation of [S(-) amlodipine - L (+)- hemitartarate]

Inactive Publication Date: 2003-09-18
COUNCIL OF SCI & IND RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] Accordingly, the invention provides a new and efficient process for the preparation of [S(-)amlodipine-L(+)hemi tartarte] in good yield with high enantiomeric purity by reacting RS amlodipine base with L(+) tartaric acid in an organic solvent at a temperature ranging from 20-35.degree. C. for a period ranging from 16 to 24 hours, separating by filtration solid [R(+)amlodipine-L(+)-hemi taratarte], seeding the filtrate to obtain solid [S(-) amlodipin-L(+)-hemi taratarte], filtering and recrystallising the solid, basifying to obtain S(-) amlodipine.

Problems solved by technology

1. The use of unnatural tartaric acid for the separation of S(-)amlodipine
2. The use of costlier camphanic acid or 2-methoxy-2-phenylethanol as a resolving agents.

Method used

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  • Process for the preparation of [S(-) amlodipine - L (+)- hemitartarate]

Examples

Experimental program
Comparison scheme
Effect test

example-2

[0018] RS Amlodipine L(+)tartarate mono DMSO Solvate from RS Amlodipine

[0019] The procedure as described in example 1 was repeated and the reaction was kept overnight. The solid filtered and dried to yeidl 14 gm, 97.9% RS Amlodipien L(+) tartarate mono DMSO solvate. Mp 148.5-151.degree. C. (c=1 MeOH) 3.3% de by chiral HPLC.

example-3

[0020] S(-)Amlodipine hemi L(+)tartarate monohydrate from S(-) Amlodipine-hemi-L-(+)tartarate monohydrate DMSO Solvate--Methanol as Solvent.

[0021] 50 gms of S(-) Amlodipine-hemi-L(+)-tartarate mohohydrate DMSO solvate was dissolved in 250 ml refluxing methanol (30 min). The solution was kept overnight at room temperature (25-28.degree. C.) with stirring. The solid was collected by filtration, washed with 100 ml methanol and dried at 50.degree. C. in vacuo (2 hrs till constant wt.) to give 35 gm (80%). S(-)Amlodipine-hemi-L(+)-tartarate monohydrate. Mp 171-172.degree. C.=114.1 (c=1, MeOH); 90% de chiral HPLC.

example-4

[0022] S(-)Amlodipine hemi L(+)-tartarte mohohydrate from S(-) Amlodipine-hemi-L-(+)tartarate monohydrate DMSO Solvate--Ethanol as Solvent.

[0023] The procedure was followed as mentioned in example 3 was using ethanol (150 ml) instead of methanol. The solid obtained was collected by filtration, washed with 50 ml cold ethanol and dried at 50.degree. C. in vacuo (2 hrs till constant wt.) to give 30 gms (68%). S(-)Amlodipine hemi L(+)tartarate monohydrate mp 172.5-174.degree. C.=17.44 (C=1, MeOH), 97% de chiral HPLC.

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Abstract

The present invention relates to a process for the preparation of [S(-)amlodipine-L(+)-hemi taratarte] from RS amlodipine base using L(+) tartaric acid in the presence of dimethyl sulfoxide.

Description

[0001] The present invention relates to a process for the preparation of [S(-)amlodipine-L(+)-hemi taratarte] from RS amlodipine base using L(+) tartaric acid in the presence of dimethyl sulfoxide.[0002] Amlodipine and its salts are long acting calcium channel blockers and are useful for the treatment of cardiovascular disorders. Racemic Amlodipine is currently being used as its besylate in the treatment of hypertension and angina. The preparation of racemic compound is described in European patent 0089167. Amlodipine is racemic compound and has chiral center at 4 position of the dihydropyridine ring.[0003] It has also been reported that the R(+) isomer is a potent inhibitor of smooth muscle cell migration (PCT / EP-94 / 02697). The S(-) isomer is having calcium channel blocker activity while the R(+) isomers has little or no calcium channel blocking activity.[0004] Prior art for the preparation of R and S enantiomers of amlodipine are a) resolution of amlodipine azide ester with optica...

Claims

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Application Information

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IPC IPC(8): A61K31/455C07D211/82
CPCC07D211/90
Inventor JOSHI, ROHINI RAMESHJOSHI, RAMESH ANNAGURJAB, M. K
Owner COUNCIL OF SCI & IND RES
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