Method for splitting Amlodipine

A technology of amlodipine and methylpyrrolidone, which is applied in the direction of organic chemistry, can solve the problems of high price of deuterated dimethyl sulfoxide and lack of industrial application prospects, and achieves cheap and easy-to-obtain reagents, simple methods, and split The effect of high yield

Active Publication Date: 2007-02-21
YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, deuterated dimethyl sulfoxide (DMSO-d 6 ) is very expensive, and deuterated reagents are very toxic, and are prohibited from being used in the pharmaceutical industry, so they do not have any industrial application prospects

Method used

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  • Method for splitting Amlodipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1 is prepared by (R, S)-amlodipine (S)-(-)-amlodipine-semi-D-tartaric acid-single-N-methylpyrrolidone complex and (R)-(+)- Amlodipine-Semi-D-Tartrate-Mono-N-Methylpyrrolidone Complex

[0020] In a 250 ml egg-shaped bottle, 57 g of (R,S)-amlodipine was dissolved in 200 ml of N-methylpyrrolidone. A solution of 10.5 grams of D-tartaric acid dissolved in 200 milliliters of N-methylpyrrolidone was added dropwise into the reaction system, and left to react at room temperature for 1 hour. Add a small amount of (S)-(-)-amlodipine-hemi-D-tartrate as a seed crystal, and continue static crystallization at room temperature for 12 hours. Filter under reduced pressure, wash the obtained white solid with 50 ml of acetone, and dry under reduced pressure in vacuo for 10 hours. 26 g (80% of theory) of (S)-(-)-amlodipine-hemi-D-tartaric acid-mono-N-methylpyrrolidone complex were obtained.

[0021] Compound 3-30

[0022] Molecular formula: C 27 h 38 o 7 ClN 3 o 9

[00...

Embodiment 2

[0039] Example 2 Preparation of (R)-(+)-amlodipine-semi-L-tartaric acid-single-N-methylpyrrolidone complex and (S)-(-)-by (R, S)-amlodipine Amlodipine-Semi-L-Tartrate-Mono-N-Methylpyrrolidone Complex

[0040] In a 250 ml egg-shaped bottle, 11.84 g of (R,S)-amlodipine was dissolved in 50 ml of N-methylpyrrolidone. A solution of 4.2 g of L-tartaric acid dissolved in 40 ml of N-methylpyrrolidone was added dropwise into the reaction system, and stirred at room temperature for 5 hours. A small amount of (R)-(+)-amlodipine-hemi-L-tartrate was added as a seed crystal, and stirring and crystallization were continued at room temperature for 12 hours. Filter under reduced pressure, wash the obtained white solid with 50 ml of acetone, and dry under reduced pressure in vacuo for 10 hours. This gave 4.62 g (70% of theory) of (R)-(+)-amlodipine-semi-L-tartaric acid-mono-N-methylpyrrolidone complex.

[0041] Compound 3-30

[0042] Molecular formula: C 27 h 38 o 7 ClN 3 o 9

[0043]...

Embodiment 3

[0057] Example 3 Preparation of (S)-(-)-amlodipine (alkaline hydrolysis) by (S)-(-)-amlodipine-half-D-tartaric acid-mono-N-methylpyrrolidone complex

[0058] 5 g of (S)-(-)-amlodipine-semi-D-tartaric acid-mono-N-methylpyrrolidone complex were stirred with 15 ml of 2N aqueous sodium hydroxide solution and 15 ml of dichloromethane for 40 minutes. Oil and water were separated, the organic layer was washed twice with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, replaced with petroleum ether and stirred to crystallize to obtain a white solid, filtered under reduced pressure, and dried in vacuo to obtain 3.2 g of (S)-(-)-amlodipine ( 88% of theoretical yield).

[0059] Molecular formula: C 20 h 25 o 7 ClN 2 o 5

[0060] m.p.110-111℃

[0061] [α] D =-31.8° (c=1.25, MeOH)

[0062] Optical purity 99.7% d.e. (chiral HPLC)

[0063] 1 H NMR (300Hz, CDCl 3 )δ: 7.96(s, 1H), 7.31(d, 1H, J=7.8Hz), 7.15(d, 1H, J=7.8Hz), 7.06(t, 1H, J=7.5Hz), 6.97...

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Abstract

This invention discloses a method for resolving amlodipine. The method uses tartaric acid as the chiral reagent, and N-methylpyrrolidone as the chiral aid. The method has such advantages as high resolving rate, high product optic purity and simple process, and is suitable for mass production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry. Specifically relate to the resolution method of amlodipine. Background technique [0002] The present invention provides a method for the resolution of a pair of S-(-)-amlodipine and R-(+)-amlodipine enantiomers of racemic amlodipine. [0003] Levoamlodipine (S-(-)-amlodipine) is the third-generation dihydropyridine calcium antagonist developed by Pfizer Company. Approved for import. Its antihypertensive effect is very good, and it also has a good curative effect on diseases such as angina pectoris and heart failure. Compared with common calcium antagonists, it has the advantages of not affecting myocardial contraction rate, long-acting, low incidence of side effects, and not causing reflex tachycardia. [0004] Compared with levamlodipine, its dextroisomer (R-(+)-amlodipine) lacks calcium channel blocking activity, but it is a potent inhibitor of smooth muscle cell motility. It ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
Inventor 王涛林国强甘益民周庆武邱雪飞
Owner YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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