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Method for preparing S-(-)-amlodipine

A kind of technology of amlodipine and tetrahydrofuran, applied in the direction of organic chemistry method, chemical instrument and method, organic racemization and the like, can solve the problems of high toxicity, difficult recovery, environmental pollution and the like

Inactive Publication Date: 2008-07-02
钟南平
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, both solvents have high boiling points. The boiling point of N,N-dimethylacetamide is 164-166°C, and the boiling point of dimethyl sulfoxide is 189°C. They are not easy to recycle. Large-scale production of S-(-)-ammonia chloride Flat ground, easy to cause environmental pollution
N,N-Dimethylacetamide is a second-class solvent with high toxicity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Preparation of S-(-)-amlodipine

[0020] Dissolve 10 grams of (R, S)-amlodipine (0.0244 moles) in 40 ml of tetrahydrofuran, add 1.84 grams of D-(-)-tartaric acid (0.0122 moles) in 80 ml of tetrahydrofuran solution, and react at 13-16 ° C for about A solid precipitated out in 10 minutes, was filtered, washed with a small amount of tetrahydrofuran, and dried in vacuo at 50°C overnight. The obtained solid solvate was recrystallized from methanol to obtain 4.1 g of the solid solvate.

[0021] Add 4g of the above solvate to 40ml of dichloromethane, add dropwise 15ml of 2N sodium hydroxide solution, and stir for 30 minutes. After separation, the dichloromethane layer is washed twice with water (40ml / time), separated, and the dichloromethane layer is washed with an appropriate amount of no Sodium carbonate water was dried overnight, filtered, dichloromethane was distilled off, n-hexane was added to stir and crystallize, and the filtered solid was vacuum-dried at 50° C. overnig...

Embodiment 2

[0023] Dissolve 10 grams of (R, S)-amlodipine (0.0244 moles) in 40 ml of tetrahydrofuran, add 1.84 grams of D-(-)-tartaric acid (0.0122 moles) in about 2 ml of water and 80 ml of tetrahydrofuran solution, and the other operations are the same Example 1. Obtain 2.0 g of white solid S-(-)-amlodipine (theoretical yield 40%) m.p.108-110°C, [α] D 20 +32.1° (C=1, methanol), optical purity 99.2% (enantiomeric excess by chiral HPLC).

Embodiment 3

[0025] The solvent tetrahydrofuran is replaced by a mixed solvent, and the content of the co-solvent is represented by V 助 % indicates that its value is V 助 / (V 助 +V 四氢呋喃 ). Experiment adopts the method for embodiment 2, prepares S-(-)-amlodipine, and experimental result sees the following table:

[0026] Solvent name

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PUM

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Abstract

The invention relates to an economical and effective method used for preparing S-(-)-amlodipine by taking tetrahydrofuran as solvent and D-tartaric acid as resolution agent to resolve racemic amlodiphine.

Description

field of invention [0001] The invention relates to an economical and effective method for preparing S-(-)-amlodipine by resolving racemic amlodipine by using tetrahydrofuran as a solvent and D-tartaric acid as a resolving agent. Background of the invention [0002] Racemic amlodipine and its salts are long-acting calcium ion channel blockers and can be used to treat angina pectoris, hypertension and congestive heart failure. There is a chiral carbon in the molecular structure of amlodipine, and racemic amlodipine is composed of two enantiomers of equal quantity, namely S-(-)-amlodipine and R-(+)-amlodipine. ArrowsmithJ.Med.Chem (1986) 29, 1696-1702 study shows that the calcium channel blocking effect of racemic amlodipine is mainly produced by S-(-)-amlodipine, Young.J.W, WO93 / 10779 patent shows that alone Using S-(-)-amlodipine to treat angina pectoris and hypertension can reduce side effects such as acral edema, headache and dizziness caused by racemic amlodipine. [000...

Claims

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Application Information

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IPC IPC(8): C07D211/90C07B57/00
Inventor 钟南平王慧丽
Owner 钟南平
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