Resolution method of optically active amlodipine

A kind of amlodipine and peaceful technology, applied in the splitting field of optically active amlodipine, can solve the problems of long reaction time, increased equipment cost, unsuitable for large-scale production and the like, and achieves the effect of shortening the reaction time

Active Publication Date: 2008-11-26
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pfizer's WO95 / 25722 patent provides a method with D or L-tartaric acid as a resolving agent and dimethyl sulfoxide as a solvent to directly split amlodipine to obtain amlodipine enantiomers. The disadvantages are The reaction time is long, and overnight reaction is required, and the water content of the solvent is strictly required. When the water content of dimethyl sulfoxide is 0.25% in Example 11, the product E value is 96.8%, and when the water content is 0.5%, The E value of the product is 87.7%, which shows that the water content in dimethyl sulfoxide has a great influence on the E value of the product. It is necessary to control the water content in the solvent system, and to strictly control the water content in the production process, first of all Control the water content of the starting material. The removal of water content in dimethyl sulfoxide is complicated and can only be realized under rectification conditions, resulting in cumbersome process steps and increased equipment costs. It is not suitable for large-scale production

Method used

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  • Resolution method of optically active amlodipine

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Experimental program
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Effect test

Embodiment 1

[0023] The preparation of embodiment one methyl ethyl sulfoxide

[0024] 1. Take four 1000ml reaction bottles (with thermometers and condenser tubes), first add 350ml of acetone, 2mol of methyl ethyl ether, put the reaction bottle in an ice bath, add 1.98mol of hydrogen peroxide (concentration is 31%) dropwise, and the temperature should be controlled at Below 40°C, keep warm at 25-35°C for 6 hours after the addition, and remove excess methyl ethyl sulfide, acetone and water under vacuum at 60°C to obtain 176 grams of product with a water content of 5.2% and a yield of 91%. . Gas chromatography purity 99.2%.

[0025] 2. Take 80 grams of the above product (water content 5.2%), add 60 grams of calcium oxide, heat up to 70 degrees, dry for 5 hours, filter after cooling down to room temperature, filter the filtrate under reduced pressure, and vacuum distill to obtain 62 grams of fractions. It is 81%, moisture content is 0.4%, gas chromatography purity is 99.3%.

Embodiment 2

[0026] The preparation of embodiment two (S)-(-)-amlodipine

[0027] 5 grams (0.012mol) of amlodipine is dissolved in 40ml water content and is in the methyl ethyl sulfoxide (made by embodiment 1) of 0.4%, add and dissolve 1.0 grams (0.006mol) D-(-)-tartaric acid 40ml of methyl ethyl sulfoxide solution with a water content of 0.5%, stirred at room temperature for 1 hour, precipitated, filtered, washed with 15ml of acetone, and vacuumed at 50°C for 4 hours to obtain (S)-(-)-amlodipine, D- (-)-tartrate, methyl ethyl sulfoxide three-component solvate 2.40 grams.

[0028] Add 2.40 g of the above-mentioned solvate after drying, add 35 ml of dichloromethane, 18 ml of 2N sodium hydroxide solution, stir and react 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 dichloro Wash the filter cake with methane, concentrate the filtrate under reduced pressure, add an appropriate amount of ...

Embodiment 3

[0029] The preparation of embodiment three (S)-(-)-amlodipine

[0030] Using undried methyl ethyl sulfoxide in Example 1, with a water content of 5.2%, the others are the same as in Example 2, to obtain (S)-(-)-amlodipine, D-(-)-tartrate, methyl ethyl sulfoxide three 2.35 g of solvate composed of components, and finally 1.49 g of (S)-(-)-amlodipine was obtained. The enantiomeric excess value (ee) determined by chiral column HPLC was 98.5%, and the total yield was 59.6%.

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Abstract

The present invention relates to chemical method of resolving despinner Amlodipine into (S)-(-)-Amlodipine and (R)-(+)-Amlodipine. The resolving agent is L-tartaric acid or D-tartaric acid; and the solvent is methyl ethyl sulfoxide or mixed solvent containing methyl ethyl sulfoxide. The present invention has greatly shortened reaction period and no special requirement on the water content in the solvent, and is especially suitable for large scale production.

Description

technical field [0001] The invention relates to a chemical method for splitting (S)-(-)-amlodipine and (R)-(+)-amlodipine from racemic amlodipine. technical background [0002] Amlodipine is a calcium antagonist clinically used in the treatment of hypertension and stable angina. Amlodipine clinically used at present is mainly a racemate, according to Arrowsmiith, J.E.; etal.J.Med.Chem (1986) 29; 1696-1702 report, its main pharmacological activity is (S)-(-)- Amlodipine, its calcium ion antagonistic activity is about 1000 times that of (R)-(+)-amlodipine, 2 times that of the racemate; Young, J.W., WO93 / 10779 reports the use of (S)-(-)- Compared with the use of racemic amlodipine, amlodipine can reduce side effects such as acral edema, headache, and dizziness. Therefore, the use of (S)-(-)-amlodipine to treat hypertension and stable angina pectoris has a good market prospect. The other enantiomer (R)-(+)-amlodipine has activity in the treatment of atherosclerosis. [0003]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
Inventor 王金戌张宏武杨秋生孙京国陈玉洁
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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