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Method for preparing optically active amlodipine tosilate

A technology of p-toluenesulfonate and p-toluenesulfonic acid, which is applied in the field of preparation of amlodipine salt, can solve problems such as pollution, toxicity of deuterated reagents, and difficulty in recycling, so as to reduce production costs, prevent environmental pollution, and solvent toxicity small effect

Inactive Publication Date: 2010-02-17
NANJING UNIV
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  • Abstract
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  • Application Information

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Problems solved by technology

[0010] Then some improved technologies of industrial application were reported successively: in 1994, Pfizer Research and Development Company invented the method (WO95 / 25722) for splitting levoamlodipine with tartaric acid, and the optical purity of the product reached 99%, and the yield was also very high. High, but the limitation of this method is to use dimethyl sulfoxide as a solvent, and only levorotatory amlodipine can be obtained, and the boiling point and melting point of dimethyl sulfoxide are relatively high, and it will solidify below 18 ° C, thus giving production great inconvenience
In 2003, Zhang Xitian invented the resolution method (CN1100038C) utilizing tartaric acid as a resolution reagent and deuterated dimethyl sulfoxide as a solvent, which can simultaneously obtain two isomers of amlodipine, but the The price of deuterated dimethyl sulfoxide is very expensive, and the deuterated reagent is very toxic, and its use is prohibited in the pharmaceutical industry, so it has no industrial application prospects
The patent (WO 03 / 035623) of Sepracor company has described a kind of with D or L-tartaric acid as resolving agent, with N, N-dimethylacetamide is the method for solvent resolution amlodipine, but N, N- Dimethylacetamide (DMAC) has a boiling point of 164-166°C. It is difficult to recover due to its high boiling point. Moreover, DMAC is a second-class solvent with high toxicity and is likely to cause serious pollution during the production process.
In 2003, Shijiazhuang Pharmaceutical Group Ouyi Pharmaceutical Co., Ltd. invented tartaric acid as a resolution reagent and 2-butanone as a solvent, but 2-butanone is irritating to eyes, nose, throat and mucous membranes
In 2005, the patent (CN 1915674A) invented by Yangzijiang Pharmaceutical Group Shanghai Haini Pharmaceutical Co., Ltd. used N-methylpyrrolidone as a solvent for resolution to obtain R, S-amlodipine, but N-methylpyrrolidone is harmful to the skin. Stimulating effect, and its chronic effect can cause dysfunction of the central nervous system, causing lesions of respiratory organs, kidneys, and vascular system

Method used

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  • Method for preparing optically active amlodipine tosilate
  • Method for preparing optically active amlodipine tosilate
  • Method for preparing optically active amlodipine tosilate

Examples

Experimental program
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Effect test

example 1

[0026] Example 1: Preparation of S-(-)-amlodipine-semi-di-p-methylbenzoyl-D-tartrate from (R,S)-amlodipine

[0027] 0.13g O, O'-di-p-methylbenzoyl-D-tartaric acid (0.25 molar equivalent) and 0.50g amlodipine were dissolved in 10mL of isopropanol; Stir for 10 to 15 minutes, add O, O'-di-p-toluyl-D-tartaric acid isopropanol solution to the above solution under stirring, continue stirring for 10 minutes, stop heating, and continue stirring for 2 Hour, no white precipitate is generated, and the solution is clear and transparent. Add 0.02g O, O'-di-p-toluyl-D-amlodipine tartrate salt as a seed crystal, and a white precipitate is produced rapidly; continue to stir for 3 hours, Filtered, dried, weighed 0.37g, vacuum dried for 3 hours and weighed to obtain a gross weight of 0.36g (the actual weight was 0.34g, that is, the gross weight minus the mass of the 0.02g seed crystal) and the yield was 85% (theoretical yield was 0.4g). m.p.: 123-127°C. Found values: C: 59.81%, H: 5.86%, N: 4...

example 2

[0028] Example 2: Preparation of S-(-)-amlodipine p-toluenesulfonate from S-(-)-amlodipine-semi-di-p-toluene-D-tartrate

[0029] The S-(-)-amlodipine-semi-di-p-toluoyl-D-tartrate 0.34g solid prepared in Example 1 was placed in a 100mL conical flask, and 10mL of dichloromethane and 10mL of Sodium hydroxide solution (2mol / L). Stir at room temperature for 1.5 hours. Transfer the mixed liquid to a separatory funnel, let it stand, separate the layers, wash the aqueous layer twice with dichloromethane, 10mL each time, combine the organic layer, wash the organic layer twice with water, 10mL each time, and then saturated with 10mL Wash once with salt water, the organic layer becomes clear and transparent, separate the liquid into a dry Erlenmeyer flask; add anhydrous sodium sulfate and dry for 30 minutes; filter, wash anhydrous sodium sulfate with dichloromethane; spin dry dichloromethane to obtain a yellow viscous, then add 0.2g p-toluenesulfonic acid and 20mL water, a white solid wi...

example 3

[0030] Example 3: Preparation of R-(+)-amlodipine p-toluenesulfonate

[0031] Spin the mother liquor in Example 1 to dryness, add 10mL of dichloromethane and 10mL of sodium hydroxide solution (2mol / L); stir at room temperature for 1.5 hours; transfer the mixed liquid to a separatory funnel, let it stand, separate liquid, water layer was washed twice with dichloromethane, 10 mL each time, the organic layers were combined, the organic layer was washed twice with water, 10 mL each time, and then washed once with 10 mL saturated brine, the organic layer became clear and transparent, and the liquid was separated to dryness. Add anhydrous sodium sulfate to dry for 30 minutes, filter, wash anhydrous sodium sulfate with dichloromethane; spin dry dichloromethane to obtain a yellow sticky substance; add 0.2g p-toluenesulfonic acid and 20mL water, After 10 minutes, a white solid will precipitate out, N 2 Heated under protection until the solids were completely dissolved, then cooled at ...

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Abstract

The invention discloses a method for preparing optically active amlodipine tosilate. The method comprises the following steps: reacting (R, S)-amlodipine with 0,0'-dimethyl-p benzoyl-D-tartaric acid which is a resolving agent in an isopropanol solvent; crystallizing and filtering a reaction product to obtain optically active S-(-)-amlodipine-semi-dimethyl-p benzoyl-D-tartrate or a solvate thereofand collecting a mother liquor; then treating the obtained optically active S-(-)-amlodipine-semi-dimethyl-p benzoyl-D-tartrate or the solvate thereof with alkali; reacting the tartrate or the solvatethereof treated with alkali with para-toluenesulfonic acid to obtain optically active S-(-)-amlodipine tosilate; and finally, concentrating the mother liquor obtained after filtering to be dry and reacting the dry mother liquor with para-toluenesulfonic acid to obtain R-(+)-amlodipine tosilate. The invention is suitable for industrial production, has less environmental pollution and can reduce the production cost.

Description

technical field [0001] The invention relates to a method for preparing amlodipine salt, in particular to a method for preparing optically active amlodipine p-toluenesulfonate. Background technique [0002] Amlodipine is a well-known long-acting calcium ion channel inhibitor, which can be effectively used in the treatment of cardiovascular diseases, such as angina pectoris, hypertension, congestive heart failure, coronary heart disease and so on. The structural formula of amlodipine is: [0003] [0004] Amlodipine has a chiral center, and racemic amlodipine is composed of equal amounts of R-(+)-amlodipine and S-(-)-amlodipine; its pharmacological activity and its three-dimensional conformation and salt Compared with racemic amlodipine, S-(-)-amlodipine has more potent pharmacological activity; R-(+)-amlodipine has also been shown to prevent and treat arterial Atherosclerosis, is a potent inhibitor of smooth muscle migration; thus a method for resolving the racemate into...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 王杰纪宪勇张婧
Owner NANJING UNIV
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