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Montelukast sodium intermediate compound

A technology for montelukast sodium and its compounds, which is applied in the field of intermediate compounds of montelukast sodium, can solve the problems of troublesome post-processing, harsh operating conditions, and low purity, and achieve easy storage, good stability, and high yield Effect

Active Publication Date: 2020-11-20
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The reaction described in this route is carried out in the presence of ionic liquid, but the ionic liquid is very easy to absorb water, so that the operating conditions of the reaction are harsh, and the post-treatment is also troublesome; in addition, the ionic liquid is expensive, so this method is not suitable for industrial production.
[0012] The technical route disclosed in CN105294556A all uses diphenoxyphosphoryl chloride as an electrophile to react with chiral alcoholic hydroxyl to prepare the intermediate of montelukast, and diphenoxyphosphoryl chloride is used as the protecting group of chiral alcoholic hydroxyl , the atomic economic benefit is poor, and there are many "three wastes". This technology is not conducive to industrial production.
[0014] CN106831863A discloses a disubstituted oxyphosphoryl chloride compound and a method for preparing montelukast acid with it. The oily disubstituted oxyphosphoryl chloride compound prepared by the contriver according to the disclosed method has relatively low purity; The montelukast acid prepared from the oily disubstituted oxyphosphoryl chloride compound is also an oil, and the purity is relatively low by HPLC analysis
[0015] Although montelukast sodium has been approved for production for a long time, the production process is not yet mature enough, especially in the current situation where environmental protection pressure is high, it is of great significance to develop a green environmental protection process

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: Preparation of Montelukast Sodium Intermediate Compound II

[0051] Under nitrogen protection, in a 1000mL there-necked flask with mechanical stirring, add 45.8g 2-(2-(3-(2-(7-chloro-2-quinolyl)-vinylphenyl)-3-hydroxypropane Base) phenyl)-2-propanol (compound III), 550mL tetrahydrofuran, 25.8g N,N-diisopropylethylamine, stirring and cooling to -10~-5°C, adding 22.9g o- The mixed solution of phenylenedioxyphosphoryl chloride and 70 mL of tetrahydrofuran was added dropwise, and stirred at -10 to -5°C for 3 to 4 hours; slowly warmed to room temperature, and the reaction progress was detected by TLC. After the reaction is completed, filter, wash the filter cake with 30mL tetrahydrofuran, evaporate the filtrate to remove the solvent under reduced pressure, add 100mL purified water and 300mL ethyl acetate to the residue, mix well and separate the liquids, and the organic layer is successively washed with 100mL 5% sodium bicarbonate aqueous solution , 100 mL of sa...

Embodiment 2

[0054] Embodiment 2: Preparation of Montelukast Sodium Intermediate Compound II

[0055] Under nitrogen protection, in a 1000mL there-necked flask with mechanical stirring, add 45.8g 2-(2-(3-(2-(7-chloro-2-quinolyl)-vinylphenyl)-3-hydroxypropane Base) phenyl)-2-propanol (compound III), 458mL acetonitrile, 18.2g triethylamine, stirring to cool down to -15~-10℃, dropwise adding 21.0g phthalic dioxyphosphoryl chloride and 70mL The tetrahydrofuran mixed solution, after the dropwise addition, was stirred and reacted at -15 to -10°C for 3 to 4 hours; it was slowly raised to room temperature, and the reaction progress was detected by TLC. After the reaction is completed, filter, wash the filter cake with 20 mL of tetrahydrofuran, evaporate the filtrate to remove the solvent under reduced pressure, add 100 mL of purified water and 300 mL of ethyl acetate to the residue, mix well and separate the liquids, and use 100 mL of 5% sodium bicarbonate aqueous solution, 100 mL of saturated br...

Embodiment 3

[0057] Embodiment 3: Preparation of Montelukast Sodium Intermediate Compound II

[0058] Under nitrogen protection, in a 1000mL three-necked flask with mechanical stirring, add 45.8g (0.1mol) 2-(2-(3-(2-(7-chloro-2-quinolyl)-vinylphenyl)- 3-hydroxypropyl)phenyl)-2-propanol (compound III), 640mL tetrahydrofuran, 26.9g DMAP, stirring and cooling down to -10~-5°C, adding 26.7g of phthalic dioxyphosphoryl chloride dropwise under stirring Mix the solution with 80mL of tetrahydrofuran, after the dropwise addition is completed, stir and react at -10 to -5°C for 3 to 4 hours; slowly rise to room temperature, and detect the reaction progress by TLC. After the reaction is completed, filter, wash the filter cake with 35mL tetrahydrofuran, evaporate the filtrate to remove the solvent under reduced pressure, add 100mL purified water and 300mL ethyl acetate to the residue, mix well and separate the liquids, and the organic layer is sequentially washed with 100mL 5% sodium bicarbonate aqueou...

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Abstract

The invention provides a novel montelukast sodium intermediate compound and a preparation method thereof. The intermediate compound is good in stability and convenient to store; the intermediate compound serves as a starting material of montelukast sodium, the synthesized montelukast sodium is high in yield and good in purity; and the structural formula of the intermediate compound is shown in thespecification,

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to a montelukast sodium intermediate compound. Background technique [0002] Montelukast sodium was developed by Merck of the United States and approved by the FDA of the United States in 1998. It was first launched in Finland and Mexico in February 1998, and then successively launched in Canada and the United States. Montelukast sodium is a selective leukotriene D4 receptor antagonist, which can selectively combine with leukotriene in the airway, block the action of allergic mediators, improve respiratory inflammation, and make the airway unobstructed. , low toxicity, good safety anti-asthma anti-inflammatory and anti-allergic drugs. The chemical name of montelukast sodium is: 1-(((1-(R–(3-(2-(7-chloro-2-quinolyl)-vinyl)-phenyl)-3-(2 -Hydroxyl-1-methylethyl)-phenyl)propyl)mercapto)methyl)cyclopropyl sodium acetate, structure as shown in formula I: [0003] [0004] The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6574C07D215/18
CPCC07F9/65742C07D215/18Y02P20/55
Inventor 白文钦朱姚亮
Owner LUNAN PHARMA GROUP CORPORATION
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