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Process for preparation of chiral amlodipine salts

A kind of amlodipine salt, amlodipine technology, applied in the field of preparation of chiral amlodipine salt, can solve the problem of low yield of split salt

Inactive Publication Date: 2006-12-20
COUNCIL OF SCI & IND RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] 3. Apply a small amount of resolution reagent, so that the separated resolution salt yield is low

Method used

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  • Process for preparation of chiral amlodipine salts
  • Process for preparation of chiral amlodipine salts
  • Process for preparation of chiral amlodipine salts

Examples

Experimental program
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Effect test

Embodiment 1

[0047]Example 1: Preparation of R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate from RS amlodipine

[0048] To a stirred solution of 10.50 g (0.0256 mole) RS amlodipine in 30 ml DMSO was added a solution of 1.93 g (0.0128 moles, 0.5 equivalent (eq.)) L(+) tartaric acid in 30 ml DMSO. Within 5-10 minutes, solids began to separate from the clear solution. The reaction was stirred for 3 hours and the solid was filtered off, washed with acetone and dried to afford 6.66 g (46.2%) of R(+) amlodipine hemi L(+) tartrate monoDMSO solvate. Melting point (mp.) 160-162°C, determined by chiral HPLC to be 95.2%d.e. M. Kremser.].

Embodiment 2

[0049] Example 2: Preparation of R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate from RS amlodipine

[0050] To a stirred solution of 100 g (0.245 mole) RS amlodipine in 300 ml DMSO was added a solution of 9.2 g (0.06 mole, 0.25 equivalent (eq.)) L(+) tartaric acid in 300 ml DMSO. Within 5-10 minutes, solids began to separate from the clear solution. The reaction was stirred for 3 hours and the solid was filtered off, washed with acetone and dried to yield 52.3 g (36.2%) of R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate. Melting point (mp.) 160-162°C, 98.2% d.e. by chiral HPLC.

Embodiment 3

[0051] Example 3: Preparation of R(+) amlodipine hemi-L(+) tartrate monoDMSO solvate from RS amlodipine

[0052] To a stirred solution of 100 g (0.245 mole) RS amlodipine in 150 ml DMSO was added a solution of 9.2 g (0.06 mole, 0.25 equivalent (eq.)) L(+) tartaric acid in 100 ml DMSO. Within 5-10 minutes, solids began to separate from the clear solution. The reaction was stirred for 3 hours and the solid was filtered off, washed with acetone and dried to yield 58.6 g (40.5%) of R(+) amlodipine hemi L(+) tartrate monoDMSO solvate. Melting point (mp.) 160-162°C, 96.8% d.e. by chiral HPLC.

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Abstract

A process for the preparation of pharmaceutically acceptable salts of chiral Amlodipine namely S(-) Amlodipine and R(+) Amlodipine without isolation of the chiral free base wherein the product has optical purity ranging between 96-99% is described in the present invention. The process comprises resolving RS amlodipine base using L(+) or D(-) tartaric acid followed by reaction of the separated tartrate salt with an organic acid to obtain the salt corresponding to the acid used in ee ranging from 96-99%.

Description

field of invention [0001] The present invention relates to an improved process for the preparation of chiral amlodipine salts. More particularly, the present invention relates to the preparation of S(-) amlodipine having the structure of formula (1) and R(+) ammonia having the structure of formula (2) as shown below in the presence of dimethylsulfoxide Pharmaceutically acceptable salts of lodipine, and methods for their direct conversion into besylate salts without isolation of the free base, wherein R=benzenesulfonic acid, succinic acid, maleic acid, oxalic acid, p-toluenesulfonic acid acid. [0002] [0003] Formula-1 Formula-2 Background of the invention [0004] Among all the above-mentioned S(-) amlodipine salts, S(-) amlodipine besylate (4-S)-2-{[(2-aminoethyl)oxy]methyl}-4-(2 -Chlorophenyl)6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate is of commercial importance as a potent long-acting calcium channel blocker. [0005] R(+) aml...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90C07B57/00
CPCC07B2200/07C07D211/90A61K31/4422
Inventor 罗希尼·拉梅什·乔希拉梅什·安娜·乔希尼勒什·巴普罗·卡拉达穆昆·凯沙夫·古扎尔
Owner COUNCIL OF SCI & IND RES
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