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Method for preparing amlodipine

A technology of amlodipine and ground level meter, which is applied in the field of medicine and chemical industry, can solve the problems of high boiling point, easy explosion, disproportionation reaction, etc., and achieve the effects of good solvent stability, low cost and low toxicity

Active Publication Date: 2009-09-30
北京天衡药物研究院有限公司
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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 obtain amlodipine enantiomers by directly resolving amlodipine. The disadvantages are The solvent dimethyl sulfoxide has a high boiling point of 189°C. During the production process, it is easy to cause the problem that the solvent is not easy to recover. Moreover, due to the violent disproportionation reaction of dimethyl sulfoxide during the heating recovery process, it will cause explosion and be dangerous for industrial production. sex big
Methyl ethyl sulfoxide is not a common solvent in industry and has no industrial source. In this patent, it is prepared by oxidation of methyl ethyl sulfide through hydrogen peroxide. In the process of distilling the reaction mixture to obtain the product, it is easy to explode

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] ①. Preparation of S-(-)-amlodipine-semi-L-(+)-tartrate-DMF solvate

[0057] R, S-amlodipine 50g (0.12mol), add DMF 150ml, stir to dissolve at 30°C, add dropwise a solution of L-(+)-tartaric acid 9g (0.06mol) (molar ratio 1:0.5) / DMF 240ml while stirring , after the dropwise addition, keep stirring at 30°C for 5 hours, stir at room temperature overnight, a large amount of solid precipitates, filter, wash the filter cake with a small amount of DMF, drain, add 150ml of DMF to the solid, stir for 1 hour at 30°C in a water bath, and Continue to stir overnight, filter, and wash the filter cake with a small amount of DMF, suck dry, dry, and weigh to obtain 42.2 g of S-(-)-amlodipine-half-L-(+)-tartrate-DMF solvate. Yield: 124.1% (based on S-(-)-amlodipine, the same below). Melting point: 123-128°C, ee value measurement result is 74.6%.

[0058] ②, the preparation of S-(-)-amlodipine

[0059] Add 100 ml of 1 mol / L sodium hydroxide aqueous solution to 10 g of S-(-)-amlodipine-...

Embodiment 2

[0062] ①. Preparation of S-(-)-amlodipine-semi-L-(+)-tartrate-DMF solvate

[0063] R, S-amlodipine 50g (0.12mol), add DMF150ml, stir to dissolve at 30°C, add L-(+)-tartaric acid 4.5g (0.03mol) (molar ratio 1:0.25) / DMF 120ml dropwise under stirring After the dropwise addition of the solution, keep stirring at 30°C for 5 hours, then stir overnight at room temperature, a large amount of solids precipitate out, filter, wash the filter cake with a small amount of DMF, drain, add 150ml of DMF to the solids, and stir for 1 hour at 30°C in a water bath. Stirring was continued at room temperature overnight, filtered, the filter cake was washed with a small amount of DMF, sucked dry, dried, and weighed to obtain 32.8 g of S-(-)-amlodipine-semi-L-(+)-tartrate-DMF solvate. Yield: 96.4%. Melting point: 125-129°C, ee value measurement result is 94.4%.

[0064] ②, the preparation of S-(-)-amlodipine

[0065] The method is the same as in Example 1, and vacuum-dried to obtain 6.7g. Yield 9...

Embodiment 3

[0067] ①. Preparation of S-(-)-amlodipine-semi-L-(+)-tartrate-DMF solvate

[0068] R, S-amlodipine 50g (0.12mol), add DMF150ml, stir to dissolve at 40°C, add L-(+)-tartaric acid 4.5g (0.03mol) (molar ratio 1:0.25) / DMF 120ml dropwise under stirring Solution, after the dropwise addition was completed, kept stirring at 40°C for 3 hours, and stirred at room temperature overnight, a large amount of solids precipitated, filtered, and the filter cake was washed with a small amount of DMF, then drained, and the solids were added to 150ml of DMF, and stirred for 1 hour at 40°C in a water bath. Stirring was continued at room temperature overnight, filtered, the filter cake was washed with a small amount of DMF, drained, dried, and weighed to obtain 32g (yield: 94.1%), melting point: 126-129°C, ee value measurement result was 95.9%.

[0069] ②, the preparation of S-(-)-amlodipine

[0070] The method is the same as in Example 1 to obtain 6.8g. (Yield 92.6%). The ee value measurement resu...

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Abstract

The present invention relates to a method for preparing a novel S-(-)-amlodipine, and especially to a novel method for preparing S-(-)-amlodipine through the resolution of racemic amlodipine. The N,N-dimethylformamide (DMF) is used as a dissolvent. The L-(+)-tartaric acid is used as a resolving agent. Not only can the excellent resolving effect be obtained, but also the cost is low and safety is excellent.

Description

technical field [0001] The present invention relates to a new preparation method of S-(-)-amlodipine, in particular to a new method for preparing S-(-)-amlodipine by splitting racemic amlodipine, which belongs to medicine chemical industry. Background technique [0002] Amlodipine is a calcium antagonist clinically used in the treatment of hypertension and stable angina. According to Arrowsmiith, J.E.; etal.J.Med.chem (1956) 29; 1696-1702 report, its pharmacologically active main ingredient is S-(-)-amlodipine, and its calcium ion antagonistic activity is about R-(+) -1000 times of amlodipine, 2 times of racemate; Young, J.W., WO93 / 10779 reported that using S-(-)-amlodipine can reduce acral edema, headache and dizziness compared to using racemic amlodipine and other side effects. Therefore, the use of S-(-)-amlodipine to treat hypertension and stable angina pectoris has a good market prospect. The chemical structural formula of amlodipine is as follows: [0003] [0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90C07B57/00A61K31/4422A61P9/12A61P9/10
Inventor 赵兴凯杨文斌
Owner 北京天衡药物研究院有限公司
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