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A kind of preparation method of montelukast

A technology of mercaptomethyl and cyclopropyl acetic acid, applied in the field of medicine, can solve the problems of difficult recycling, potential safety hazards, and high equipment requirements, and achieve the effects of easy recycling, easy separation and purification, and low equipment requirements.

Active Publication Date: 2018-06-19
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the above-mentioned methods, there are high requirements on equipment or potential safety hazards, and a large amount of organic solvents are used in the whole synthesis preparation and product purification, and it is difficult to recycle them.

Method used

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  • A kind of preparation method of montelukast
  • A kind of preparation method of montelukast
  • A kind of preparation method of montelukast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] (1) Add 11g (0.275mol) of sodium hydroxide to 60ml of purified water, stir and cool down to 0-10°C, add 16.0g (0.11mol) of 1-(mercaptomethyl)-cyclopropylacetic acid and stir for 3 hours to obtain 1 -(mercaptomethyl)-cyclopropylacetic acid dianion disodium solution;

[0036] (2) Add 50g (0.11mol) of quinoline diols to 500ml of purified water, add 5.7g (0.14mol) of sodium hydroxide and 1.8g (0.0055mol) of tetrabutylammonium bromide at a temperature of 10-30°C Stir for 0.5h, then add p-toluenesulfonyl chloride 23g (0.12mol) to react for 2h at a temperature of 0-5°C;

[0037] (3) Control the temperature of the solution in step (2) to 0-5° C. and add 1-(mercaptomethyl)cyclopropylacetic acid dianion disodium solution within 1 hour to continue the reaction for 10 hours to obtain an aqueous solution of montelukast;

[0038] (4) Raise the temperature to 10-20°C, extract the impurities 3 times with 150ml*3 ethyl acetate, adjust the pH of the aqueous phase to 8-9 with 50% acetic ...

Embodiment 2

[0042] (1) Add 12g (0.30mol) of sodium hydroxide to 62ml of purified water, stir and cool down to 0-10°C, add 16.0g (0.11mol) of 1-(mercaptomethyl)-cyclopropylacetic acid and stir for 3 hours to obtain 1 -(mercaptomethyl)-cyclopropylacetic acid dianion disodium solution;

[0043] (2) Add 50g (0.11mol) of quinoline diols to 500ml of purified water, add 5.7g (0.14mol) of sodium hydroxide and 1.8g (0.0055mol) of tetrabutylammonium bromide at a temperature of 10-30°C Stir for 0.5h, then add p-toluenesulfonyl chloride 23g (0.12mol) to react for 2h at a temperature of 0-5°C;

[0044] (3) Control the temperature of the solution in step (2) to 5-10° C. and add 1-(mercaptomethyl)cyclopropylacetic acid dianion disodium solution within 1 hour to continue the reaction for 10 hours to obtain an aqueous solution of montelukast;

[0045] (4) Raise the temperature to 10-20°C, extract impurities 3 times with 150ml*3 ethyl acetate, adjust pH=8-8.5 with 50% acetic acid for the water phase, extr...

Embodiment 3

[0047] (1) Add 10g (0.25mol) of sodium hydroxide to 58ml of purified water, stir and cool down to 0-10°C, add 16.0g (0.11mol) of 1-(mercaptomethyl)-cyclopropylacetic acid, and stir for 3 hours to obtain 1-(Mercaptomethyl)-cyclopropylacetic acid dianion disodium solution;

[0048] (2) Add 50g (0.11mol) of quinoline diols to 500ml of purified water, add 7.8g (0.14mol) of potassium hydroxide and 1.8g (0.0055mol) of tetrabutylammonium bromide at a temperature of 10-30°C Stir for 0.5h, then add p-toluenesulfonyl chloride 23g (0.12mol) to react for 2h at a temperature of 0-5°C;

[0049] (3) Control the temperature of the solution in step (2) to 0-5°C, add 1-(mercaptomethyl)cyclopropylacetic acid dianion disodium solution within 1 hour and continue the reaction for 10 hours to obtain an aqueous solution of montelukast;

[0050] (4) Raise the temperature to 10-20°C, extract the impurities 3 times with 150ml*3 ethyl acetate, adjust the pH=8-9 with 50% acetic acid in the water phase, a...

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Abstract

The invention discloses a preparation method of montelukast. An inorganic base solution is cooled to 0-10 DEG C, 1-(mercaptomethyl)-cyclopropaneacetic acid is added, and a stirred reaction is performed to obtain a 1-(mercaptomethyl)-cyclopropaneacetic acid dianion base solution; a quinolinediol compound is dissolved into water, and inorganic base and a phase transfer catalyst are added for stirring and even mixing; after the mixture is cooled to 0-10 DEG C, paratoluensulfonyl chloride is added for a reaction to obtain a tosylate compound solution, and then the tosylate compound solution is added into the 1-(mercaptomethyl)-cyclopropaneacetic acid dianion base solution for a stirred reaction to obtain a water solution of montelukast; then the montelukast solid is obtained through post-treatment. The method is simple in technology, mild in reaction condition, economical, environmentally friendly and high in yield and makes industrialized production easy.

Description

technical field [0001] The invention relates to a preparation method of montelukast, which belongs to the technical field of medicine. Background technique [0002] Montelukast sodium (trade name: Singulair) was developed by Merck & Co. of the United States. It was first launched in Finland and Mexico in February 1998. It was officially launched in 1999 with the approval of the State Food and Drug Administration of China. Montelukast sodium is an oral leukotriene receptor antagonist, which can specifically inhibit cysteinyl leukotriene receptors in the airway, thereby improving airway inflammation and effectively controlling asthma symptoms. in the treatment of allergic rhinitis. [0003] Montelukast sodium, chemical name: (+)-1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)-vinyl] Phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfur]methyl]cyclopropaneacetic acid monosodium salt, molecular formula: C 35 h 35 ClNNaO 3 S, molecular weight: 608.18, structural formula:...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 周先国杨庆坤吴柯张兆珍董廷华高大龙江海平周学文杨波勇
Owner 山东安信制药有限公司