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Method of preparing montelukast and intermediates used therein

一种化合物、溶剂的技术，应用在化学仪器和方法、有机化合物/氢化物/配位配合物催化剂、呼吸系统疾病等方向，能够解决不稳定正丁基锂、易爆水分和空气、不适合大规模生产等问题

Inactive Publication Date: 2009-10-14
HANMI SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, the synthesis of compounds of formula (B') requires the use of n-butyllithium which is very explosive and unstable to moisture and air
Therefore, the method described in the reaction scheme is not suitable for large-scale production

Method used

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  • Method of preparing montelukast and intermediates used therein
  • Method of preparing montelukast and intermediates used therein
  • Method of preparing montelukast and intermediates used therein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl)-3-diphenylphosphate oxypropane Base)phenyl)-2-propanol (2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-diphenylphosphate oxypropyl)phenyl )-2-propanol) preparation

[0053]20g 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl)-3-hydroxypropyl)phenyl)-2- Propanol was dissolved in 240 ml of a mixture of dichloromethane and toluene (2:1), and 7.31 ml (1.2 equivalents) of triethylamine was slowly added thereto. To the resulting mixture, 13.6 ml of diphenyl chlorophosphate and 1.06 g of 4-dimethylaminopyridine were successively added dropwise. After about 1 hour, the completion of the reaction was confirmed by thin layer chromatography (TLC). The reaction mixture was treated with 100 ml of dichloromethane and 200 ml of distilled water. Shaking, the organic layer was separated and dried over sodium sulfate, then the solvent was removed under reduced pressure. The residue thus obtained was diss...

Embodiment 2

[0056] Example 2: 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl)-3-(2-(1-hydroxyl-1 - Preparation of methyl ethyl) phenyl) propyl) thio) methyl) cyclopropyl acetic acid

[0057] At 0-5°C, slowly add 12.7g of 1-(mercaptomethyl)cyclopropylacetic acid dissolved in 90ml of dimethylformamide into 6.26g of 60% sodium hydride dissolved in 90ml of dimethylformamide solution. To the resulting mixture was slowly added dropwise the 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinone) obtained in Example 1 dissolved in 30 g of dimethylformamide phenyl)vinyl)phenyl)-3-diphenylphosphate oxypropyl)phenyl)-2-propanol. After the temperature was slowly raised to room temperature, the reaction was carried out for 18-20 hours. Then, the reaction mixture was neutralized with saturated aqueous ammonium chloride, and treated with ethyl acetate and distilled water. Shaking, the organic layer was separated and dried over sodium sulfate, then the solvent was removed under reduced pressure. The residue thus...

Embodiment 3

[0059] Example 3: 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl)-3-(2-(1-hydroxyl-1 - Preparation of methyl ethyl) phenyl) propyl) thio) methyl) cyclopropyl acetic acid sodium salt

[0060] Step 1: 1-(((1-(R)-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl)-3-(2-(1-hydroxy-1- Preparation of methyl ethyl) phenyl) propyl) thio) methyl) cyclopropyl acetate

[0061] At a temperature of 0-5°C, 2.1 g of methyl 1-(acetylthiomethyl)cyclopropylacetate dissolved in 35 ml of dimethylformamide was slowly added to 0.71 g of 60% sodium hydride dissolved in 35ml solution in dimethylformamide. At a temperature of 0-5°C, 7.73 g of 2-(2-(3-(S)-(3- (2-(7-Chloro-2-quinolyl)vinyl)phenyl)-3-diphenylphosphateoxypropyl)phenyl)-2-propanol. After about 1 hour, the reaction mixture was treated with ethyl acetate and distilled water. Shake, separate the organic layer and dry over sodium sulfate, then remove the solvent under reduced pressure to afford 5.68 g (84.5%) of the title compound as a yellow li...

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PUM

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Abstract

The present invention relates to a method for preparing montelukast, an inhibitor against leukotrienes, and an intermediate used therein. According to the inventive method, high-purity montelukast or its sodium salt can be prepared in a high yield.

Description

field of invention [0001] The present invention relates to improved processes for the preparation of montelukast and intermediates used therein. Background of the invention [0002] Leukotrienes are produced by arachidonic acid in the body, which constitute a group of local functional hormones. The main leukotrienes include leukotrienes B4 (LTB4), C4 (LTC4), D4 (LTD4) and E4 ( LTE4). The biosynthesis of leukotrienes involves the production of an epoxide called leukotriene A4 (LTA4) from arachidonic acid by the action of 5-lipoxygenase, which is then converted by a series of enzymatic steps into various Leukotrienes (see Leukotrienes and lipoxygenases, edited by J. Rokach, Elsevier, Amsterdam, 1989). [0003] Recently, it has been known that montelukast or a pharmaceutically acceptable salt thereof is useful as an anti-leukotriene antagonist and also as an anti-leukotriene biosynthesis inhibitor. The sodium salt of montelukast is commercially available from Merck under the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18A61P11/06
CPCC07D215/18A61P11/06A61P35/00A61K31/47B01J31/02
Inventor 李宽淳长永佶李在宪朴哲玄朴珢珠刘在浩
Owner HANMI SCI CO LTD
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