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Method for preparing Montelukast sodium

A technology of montelukast sodium and sodium salt, applied in the direction of organic chemistry, can solve the problem that styrene impurities cannot be removed well, and achieve the effect of good impurity removal effect and simple process conditions

Inactive Publication Date: 2014-10-29
MUDANJIANG HENGYUAN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] U.S. Merck disclosed the complete industrial synthesis method of montelukast sodium in the patent publication No. 1139429, but its technology has defects in controlling several impurities of montelukast sodium, wherein the sulfoxide impurity (U.S. Pharmacopoeia impurity a), disulfide impurity (USP impurity c and d), styrene impurity (USP impurity f) cannot be removed well, and with the gradual expansion of the international market of montelukast sodium in recent years, the product The improvement of quality has become a problem that must be solved

Method used

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  • Method for preparing Montelukast sodium
  • Method for preparing Montelukast sodium
  • Method for preparing Montelukast sodium

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preparation example Construction

[0027] A preparation method of montelukast sodium of the following formula I, comprising:

[0028]

[0029] I

[0030] A. Preparation of the disodium salt of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid: the carboxyl and mercapto groups in the compound of formula II are converted into active disodium salt to obtain the compound of formula III.

[0031]

[0032] II III

[0033] The step A is to dissolve the compound of formula II in tetrahydrofuran or toluene or a C3-C5 solvent, cool down to -40-0°C, add alkaline sodium, and react at -40-0°C for 0.5-10 hours to obtain the compound of formula II Disodium salt of the compound.

[0034] The alkaline sodium is sodium hydroxide ethanol solution or sodium methylate solution.

[0035] The compound of formula II is preferably dissolved in tetrahydrofuran, the reaction temperature is preferably -10-0°C, the alkaline sodium is preferably sodium methoxide solution, and the reaction time is preferably 0....

Embodiment 1

[0052] Example 1: Add 20g (0.137mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200ml of tetrahydrofuran to a 500ml three-necked flask, stir and dissolve, then cool down to -10°C, add 30g of sodium methoxide, -10 Insulate at ~0°C for 3 hours and set aside for later use.

Embodiment 2

[0053] Example 2: Add 20g (0.137mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200ml of toluene to a 500ml there-necked flask, stir and dissolve, then cool down to -10°C, add 30g of sodium methoxide, -10 Insulate at ~0°C for 3 hours and set aside for later use.

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Abstract

The invention provides a method for preparing and purifying Montelukast sodium. The method comprises the following steps: A. preparing a disodium salt of 2-[1-(mercapto methyl) cyclopropyl] acetic acid; B. preparing an Montelukast free acid; C. preparing an Montelukast di-n-propylamine salt; D. preparing an Montelukast dicyclohexylamine salt; E. converting the Montelukast dicyclohexylamine salt into an Montelukast sodium salt. The synthesis method is simple in process conditions, good in impurity removal effect and small in risk factor, the sulfoxide impurity is less than 0.1%, other impurities are less than 0.05%, and even a certain impurity cannot be detected, and the purity of the Montelukast sodium is larger than 99.8%. All impurities of the Montelukast sodium can be effectively controlled to be less than 0.05%.

Description

technical field [0001] The invention relates to a preparation method of montelukast sodium for further purification. Background technique [0002] Montelukast sodium is a new generation of selective leukotriene receptor antagonist developed by Merck for many years. It is currently the best drug in the world for the treatment of asthma and allergic rhinitis. Sales growth of more than 10%. [0003] The chemical name of Montelukast sodium is (+)-1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolyl)-ethylene Base]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfur]methyl]cyclopropane sodium acetate, its structural formula is as follows: [0004] [0005] I [0006] U.S. Merck disclosed the complete industrial synthesis method of montelukast sodium in the patent publication No. 1139429, but its technology has defects in controlling several impurities of montelukast sodium, wherein the sulfoxide impurity (U.S. Pharmacopoeia impurity a), disulfide impurity...

Claims

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Application Information

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IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 张永文彭士军
Owner MUDANJIANG HENGYUAN PHARMA CO LTD
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