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A method for splitting and obtaining s-(-)-amlodipine

A technology of amlodipine and dichloromethane, which is applied in the field of optical separation to obtain S--amlodipine, can solve problems such as pollution, surplus, and difficulty in reaching clinical medical standards, and achieve simple preparation process and shortened reaction time Effect

Active Publication Date: 2011-12-28
JIANGXI SHIMEI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the high boiling point of above-mentioned these solvents is difficult for reclaiming, and above-mentioned solvents such as dimethylacetamide are second-class solvents, and its toxicity is big, easily causes serious pollution in the production process, and after separation process, most of them may remain, very Difficult to meet clinical medical standards

Method used

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  • A method for splitting and obtaining s-(-)-amlodipine
  • A method for splitting and obtaining s-(-)-amlodipine
  • A method for splitting and obtaining s-(-)-amlodipine

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Dissolve 1.0 g of racemic amlodipine in 10 mL of dimethyl sulfoxide, then add it to 10 mL of dimethyl sulfoxide solution containing 0.1847 g of D-tartaric acid, and finally, add 3 mL of urea with a concentration of 0.0247 g / mL aqueous solution. Heat up to 50°C and stir, after 5-10min precipitation appears, adjust to 10°C after half an hour and continue to stir for 16h, after the reaction is completed, put the reaction system in the refrigerator for 10h, filter, rinse with methanol and recrystallize, then vacuum dry After 4 hours, 0.4894 g of a white solid was obtained, with a yield of 97.88%. The e.e% was 92.8% when detected by a chiral chromatographic column.

[0040] Add 0.4894g of the above-mentioned solvate after drying, add 40mL of dichloromethane, 30mL of 2N sodium hydroxide solution, stir and react for 30 minutes, let it stand, separate the organic layer, add an appropriate amount of anhydrous sodium carbonate to dry, filter, and use a small amount of dichloro W...

Embodiment 2

[0042] Dissolve 10.0 g of racemic amlodipine in 150 mL of dimethyl sulfoxide, then add it to 150 mL of dimethyl sulfoxide containing 0.923 g of D-tartaric acid, and finally add 30 mL of 0.01 g / mL Aqueous urea solution. Heat up to 50°C and stir. After 5-10 minutes, precipitation appears and continue to stir for half an hour. Then adjust to 40°C and continue to stir for 3 hours. After the reaction, place in the refrigerator for 10 hours, vacuum filter, and rinse with dimethyl sulfoxide for recrystallization Afterwards, vacuum-dried for 4 hours to obtain 4.271 g of a white solid with a yield of 85.42%. The e.e% was 94.3% when detected by a chiral chromatographic column.

[0043]Add 3.871 g of the above-mentioned solvate after drying, add 155 mL of dichloromethane, 310 mL of 2N sodium hydroxide solution, stir and react for 30 minutes, let it stand, separate the organic layer, add an appropriate amount of anhydrous sodium carbonate to dry, filter, and use a small amount of dichloro...

Embodiment 3

[0045] Dissolve 10.0 g of racemic amlodipine in 50 mL of dimethyl sulfoxide, then add it to 50 mL of dimethyl sulfoxide solution containing 3.7 g of D-tartaric acid, and finally add 60.7 mL of it to a concentration of 0.0247 g / mL urea aqueous solution. Heat to 50°C and stir, 5-10 minutes later precipitation appears, adjust to 60°C after half an hour and continue to stir for 24 hours, place in the refrigerator for 10 hours, centrifuge to obtain a precipitate, rinse with the original co-solvent for recrystallization, and vacuum dry for 4 hours to obtain a white solid 4.318g, the yield is 86.36%, detected by chiral chromatography column, e.e% is 96.2%.

[0046] Add 4.318 grams of the above-mentioned solvate after drying, add 43.2 mL of dichloromethane, 43.2 mL of 2N sodium hydroxide solution, stir for 30 minutes, let stand, separate the organic layer, add an appropriate amount of anhydrous sodium carbonate to dry, filter, and use a small amount of The filter cake was washed with...

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Abstract

The invention relates to a method for splitting and obtaining S-(-)-amlodipine, in which racemic amlodipine and D-tartaric acid are dissolved in a mixed co-solvent of dimethyl sulfoxide and urea for a complex reaction, and the reaction is completed to obtain The solid precipitation of the S-(-)-amlodipine D-urea tartrate complex is followed by alkali treatment, eluent crystallization and other processes to obtain pure crystals of S-(-)-amlodipine. The present invention introduces another kind of chiral auxiliary agent-urea in the traditional dimethyl sulfoxide solvent, so that racemic amlodipine can be better mixed with the resolving agent in the auxiliary solvent mixed with dimethyl sulfoxide and urea. D-tartaric acid is reacted, and the reaction time is greatly shortened, and there is no special requirement on the moisture content of the solvent used; the obtained levamlodipine enantiomer has a purity of more than 99%, and a recovery rate of more than 80%, which can be used to prepare other The intermediate of the chiral drug basically meets the standard of the medical industry, the preparation process is simple, and it also opens up a good prospect for the preparation of amlodipine single enantiomer into various dosage forms.

Description

technical field [0001] The invention relates to a method for obtaining S-(-)-amlodipine by optical resolution, which belongs to the downstream separation field of medicinal chemistry. Background technique [0002] Amlodipine (Amlodipine), trade name Norvasc, is a kind of calcium antagonist developed and listed by Pfizer Company of the United States, because of its remarkable curative effect, gentle onset of effect, long drug effect time (with 24h long-acting effect) and patient's It is well tolerated and widely used clinically. As a third-generation calcium antagonist, amlodipine effectively overcomes the shortcomings of the second-generation calcium antagonists, such as unstable blood pressure reduction and large adverse reactions, and has been recognized as a safe and effective drug by the US FDA. [0003] The chemical structure of amlodipine is shown below: [0004] [0005] Amlodipine [0006] Since its molecular structure contains a chiral carbon atom, it has a pa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90C07B57/00
Inventor 卢定强党安旺凌岫泉涂清波
Owner JIANGXI SHIMEI PHARM CO LTD
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