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Method for producing S-(-)-amlodipine besylate

A kind of technology of levamlodipine besylate and production method, which is applied in the field of drug synthesis, can solve the problems of high price, high production cost, high production cost, etc., achieve the effect of good yield and crystal form, and good industrial application prospect

Active Publication Date: 2012-06-27
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But these two raw materials are more expensive and the production cost is high
[0007] In 2009, the patented production method of levamlodipine besylate (CN 100591670C) invented by Mu Zhengyi of Nanchang Hongyi Technology Co., Ltd. Using N,N-dimethylformamide (DMF) as a chiral auxiliary agent and L-tartaric acid as a resolving agent for resolution, according to my own experiments, the optical purity of the obtained levamlodipine besylate can only reach Reaching 85%, the effect is very poor, and the number of steps is long, and the production cost is high

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  • Method for producing S-(-)-amlodipine besylate
  • Method for producing S-(-)-amlodipine besylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Preparation of levamlodipine besylate

[0027] Step 1) Preparation of S-(-)-amlodipine-L-tartrate from (R,S)-amlodipine

[0028] Mix 1050ml of N,N-dimethylformamide and 150ml of water evenly, filter and set aside to obtain 1L resolution aid solution. Weigh 100g of racemic amlodipine and dissolve in 900ml of the above mixed solution, filter to remove insoluble impurities, add the filtrate to a clean 2L three-neck flask and stir at room temperature for 30 minutes. Weigh 18.4g L-tartaric acid and dissolve it in 300ml resolution solution, filter and add dropwise into the reaction solution, and stir at room temperature for 50 minutes. Add a small amount of S-(-)-amlodipine-L-tartrate seed crystals, and continue stirring for 4 hours to crystallize. Filtrate under reduced pressure to obtain a white solid, wash with 150 ml of cold acetone, and dry under pressure for 10 hours to obtain 50.4 g of S-(-)-amlodipine-L-tartrate.

[0029] Mp: 135-138 ℃, MS (Cl): (M+H)...

Embodiment 2

[0033] Example 2 Preparation of levamlodipine besylate

[0034] Step 1) Preparation of S-(-)-amlodipine-L-tartrate from (R,S)-amlodipine

[0035]Mix 600ml of N,N-dimethylformamide and 600ml of water evenly, filter and set aside to obtain 1L resolution aid solution. Weigh 100g of racemic amlodipine and dissolve in 900ml of the above mixed solution, filter to remove insoluble impurities, add the filtrate to a clean 2L three-neck flask and stir at room temperature for 30 minutes. Weigh 36.65g L-tartaric acid and dissolve it in 300ml resolution solution, filter and add dropwise to the reaction solution, and stir at room temperature for 50 minutes. Add a small amount of S-(-)-amlodipine-L-tartrate seed crystals, and continue stirring for 4 hours to crystallize. Filtrate under reduced pressure to obtain a white solid, wash with 150 ml of cold acetone, and dry under pressure for 10 hours to obtain 40.8 g of S-(-)-amlodipine-L-tartrate.

[0036] Mp: 135-138 ℃, MS (Cl): (M+H) / z:...

Embodiment 3

[0040] Example 3 Preparation of levamlodipine besylate

[0041] Step 1) Preparation of S-(-)-amlodipine-L-tartrate from (R,S)-amlodipine

[0042] Mix 1090ml of N,N-dimethylformamide and 109ml of water evenly, filter and set aside to obtain 1L resolution aid solution. Weigh 100g of racemic amlodipine and dissolve in 900ml of the above mixed solution, filter to remove insoluble impurities, add the filtrate to a clean 2L three-neck flask and stir at room temperature for 30 minutes. Weigh 7.33g L-tartaric acid and dissolve it in 300ml resolution solution, filter and add dropwise to the reaction solution, and stir at room temperature for 50 minutes. Add a small amount of S-(-)-amlodipine-L-tartrate seed crystals, and continue stirring for 4 hours to crystallize. Filtrate under reduced pressure to obtain a white solid, wash with 150 ml of cold acetone, and dry under pressure for 10 hours to obtain 53.6 g of S-(-)-amlodipine-L-tartrate.

[0043] Mp: 135-138 ℃, MS (Cl): (M+H) / z...

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Abstract

The invention provides a method for producing S-(-)-amlodipine besylate. The method comprises the following steps: 1, reacting R,S-amlodipine with the structural formula represented by formula I and a resolving agent which are treated as raw materials in a mixed solution of water and an organic solvent to obtain an intermediate 1; and 2, directly reacting the intermediate 1 with benzenesulfonic acid in the mixed solution of water and the organic solvent to obtain the S-(-)-amlodipine besylate, wherein the resolving agent in step 1 is selected from L-tartrate or D-tartrate. The method of the invention, which adopts cheap tartrate as the resolving agent and certain proportions of water and the organic solvent as chiral assistants, allows the optical purity of the obtained S-(-)-amlodipine besylate to reach 99.9%, the S-(-)-amlodipine besylate to be obtained by directly reacting the intermediate 1 with benzenesulfonic acid without hydrolysis, and the yield and the crystal form to be verygood, so the method has a good industrial application prospect.

Description

technical field [0001] The invention relates to a production method of levamlodipine besylate, which belongs to the technical field of medicine synthesis. Background technique [0002] The invention provides a production method for resolving racemic amlodipine to obtain S-(-)-amlodipine and levamlodipine besylate. [0003] Levoamlodipine (S-(-)-amlodipine) is the third-generation dihydropyridine calcium antagonist preparation developed by Pfizer. It was first launched in the UK in 1990, and then successively in Europe, the United States, and Japan. It has been approved in my country. 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 contractility, long-acting, low incidence of side effects, and not causing reflex tachycardia. Compared with levamlodipine, its dextroisomer (R-(+)-amlodipine) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
Inventor 胡玉玺路显峰冯建鹏居斌林毅阳祝传宝马立金陆良喆
Owner JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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