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Preparation method of montelukast sodium

A technology of montelukast sodium and hexylamine salt, which is applied in the field of preparation of montelukast sodium salt, can solve the problems of low impurity removal efficiency and complicated operation, and achieve high product purity, simple operation and high yield Effect

Inactive Publication Date: 2014-02-12
ZHEJIANG CHARIOTEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method involves a large amount of extraction and washing solvents, the operation is complicated and the removal efficiency is very low
[0007] As the market has higher and higher quality requirements for raw materials (API), simply complying with the Pharmacopoeia standards is not enough to meet the requirements, and there is an urgent need to develop a method suitable for industrial production of high-quality montelukast sodium salt

Method used

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  • Preparation method of montelukast sodium
  • Preparation method of montelukast sodium
  • Preparation method of montelukast sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Put 20g (0.034 moles) of montelukast acid into a 500ml three-necked bottle, add 200ml of toluene, replace with nitrogen twice, add 7.45ml (0.0374 moles) of dicyclohexylamine, stir until the material solution is clear, add seed crystals, and keep at 25°C Stir for 24 hours, and filter to obtain 30 g of montelukast dicyclohexylamine salt wet material.

[0031] Add the above-mentioned montelukast dicyclohexylamine salt into 200ml ethyl acetate, replace with nitrogen twice, add 100ml of 2.5% glacial acetic acid aqueous solution, stir for 30 minutes, let stand, and separate to remove the water layer; wash the organic phase once with 100ml of water, separate Remove the water layer. Dry the organic phase with magnesium sulfate, filter, and evaporate the solvent; add 200ml of toluene, stir evenly, replace with nitrogen twice, add 5.11ml of di-n-propylamine (0.0374 moles), stir until the material solution is clear, add seed crystals, and stir at 25°C 24h. Filter and dry. 20 g ...

Embodiment 2

[0034] Put 20g (0.034 moles) of montelukast acid into a 500ml three-necked bottle, add 100ml of acetone, replace nitrogen twice, add 10.15ml (0.051 moles) of dicyclohexylamine, stir until the material solution is clear, add seed crystals, and heat at 35°C Stir for 20 hours, and filter to obtain 30 g of montelukast dicyclohexylamine salt wet material.

[0035] Add the above-mentioned montelukast dicyclohexylamine salt into 200ml of ethyl acetate, replace with nitrogen twice, add 100ml of 0.5M tartaric acid aqueous solution, stir for 30 minutes, let stand, and separate to remove the water layer; wash the organic phase once with 100ml of water, separate Remove the water layer. Dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the solvent; add 200ml of toluene, stir evenly, replace with nitrogen twice, add 5.11ml (0.0374 moles) of di-n-propylamine, stir until the material liquid is dissolved, add seed crystals, 20 Stir at ℃ for 20h. After filtering and d...

Embodiment 3

[0038] Put 20g (0.034 moles) of montelukast acid into a 500ml three-necked bottle, add 200ml of toluene, replace with nitrogen twice, add 7.45ml (0.0374 moles) of dicyclohexylamine, stir until the material solution is clear, add seed crystals, and keep at 25°C Stir for 24 hours, and filter to obtain 30 g of montelukast dicyclohexylamine salt wet material.

[0039]Add the above-mentioned montelukast dicyclohexylamine salt into 200ml of dichloromethane, replace with nitrogen twice, add 100ml of 2.5% glacial acetic acid aqueous solution, stir for 30 minutes, let stand, and separate to remove the water layer; wash the organic phase once with 100ml of water, separate Remove the water layer. Dry the organic phase with magnesium sulfate, filter, and evaporate the solvent; add 200ml of toluene, stir evenly, replace with nitrogen twice, add 5.11ml of di-n-propylamine (0.0374 moles), stir until the material solution is clear, add seed crystals, and stir at 25°C 24h. Filter and dry. 2...

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Abstract

The invention discloses a preparation method of a montelukast sodium, and the preparation method comprises the following steps: step A, transforming a montelukast free acid into a montelukast dicyclohexylamine salt; step B, transforming the montelukast dicyclohexylamine salt into a montelukast di-n-propylamine salt; step C, transforming the montelukast di-n-propylamine salt into a montelukast sodium salt. The preparation method of the montelukast sodium salt disclosed by the invention has the advantages of simplicity in operation, high yield, high product purity and the like.

Description

(1) Technical field [0001] The invention relates to a preparation method of montelukast sodium salt. (2) Background technology [0002] The chemical name of Montelukast Sodium is: 1-(((1-(R)-(3-(2-(7-chloro-2-quinolinyl)phenyl)-3-(2 -(1-Hydroxy-1-methylethyl)phenyl)thio))methyl)sodium cyclopropylacetate, the structural formula is as follows: [0003] [0004] The compound can be used to treat respiratory diseases such as asthma and allergic rhinitis. Merck's patent US5565473 discloses the chemical structural formula of montelukast and its preparation method. The prepared montelukast oil is purified by column chromatography, dissolved in water as a sodium salt and freeze-dried, because the intermediate And the final product all need column purification and yield is low, so this preparation method is not suitable for large-scale production. The above defects are also mentioned in its process patent CN1046712C, and a method for purifying and preparing montelukast sodium t...

Claims

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Application Information

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IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 张飞飞蒲通范一陈恬王乃星杨建明
Owner ZHEJIANG CHARIOTEER PHARMA
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