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Method for obtaining S-(-)-amlodipine in splitting manner

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: 2010-02-24
JIANGXI SHIMEI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Method for obtaining S-(-)-amlodipine in splitting manner
  • Method for obtaining S-(-)-amlodipine in splitting manner
  • Method for obtaining S-(-)-amlodipine in splitting manner

Examples

Experimental program
Comparison scheme
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 obtaining S-(-)-amlodipine in a splitting manner. The method comprises the following steps: dissolving racemic amlodipine and D-tartaric acid into a mixed cosolvent containg dimethylsulfoxide and urea to carry out a complex reaction, carrying out alkaline treatment, solvent-out crystallization and the like on the S-(-)-amlodipine, the D-tartaric acid and the urea complexes solid sedimentation obtained after the complex reaction is finished, and then obtaining S-(-)-amlodipine pure crystal. The method introduces the other chiral auxiliary reagent-urea in the prior dimethylsulfoxide solution, thus the racemic amlodipine can better react with a splitting agent D-tartaric acid in the cosolvent containing the dimethylsulfoxide and urea, the reaction time islargely shortened, and the reaction does not have special requirements on the water content of the used solvent; the enantiomeric purity of the obtained levamlodipine is over than 99% and the rate ofrecovery is over than 80%. The method can be applied to preparing the intermediate of other chiral medicaments basically meeting the standard of the medical industry, is simple and provides a betterprospect for the preparation of various agents by the amlodipine single enantiomer.

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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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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