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A kind of Montelukast sodium side chain intermediate and preparation method thereof

A technology of reaction time and solid acid catalyst, applied in the field of medicinal chemistry, to achieve the effects of avoiding poor selectivity, cheap and easy-to-obtain raw materials, and ingenious route design

Active Publication Date: 2017-08-08
LUNAN BETTER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although some methods are known for the preparation of montelukast and its key intermediates, however, none of these methods are particularly suitable for large-scale industrial production

Method used

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  • A kind of Montelukast sodium side chain intermediate and preparation method thereof
  • A kind of Montelukast sodium side chain intermediate and preparation method thereof
  • A kind of Montelukast sodium side chain intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: Preparation of 6-bromomethyl-5,7-dioxaspiro[2.5]octane

[0038] In the reaction flask, add 102.1g (1.00mol) of 1,1-cyclopropyldimethanol, 177.5g (1.05mol) of 2-bromo-1,1-dimethoxyethane, SO 4 2- / TiO 2 1.5g, 500ml tetrahydrofuran, stirred at 45-55℃ for 5-8 hours, after the reaction, filter to remove SO 4 2- / TiO 2 (recyclable), recovered THF and collected the components at 38-45°C (0.10mmHg) by vacuum distillation to obtain 190.5g of colorless liquid with a yield of 92.0% and a purity (GC detection) of 98.96%; 1 H-NMR ((500MHz, CDCl3) δ: 0.36 (4H, m), 4.16 (4H, S), 3.34 (d, 2H, J = 4.3Hz), 5.32 (t, lH, J = 4.1Hz); HRMS (C 7 h 11 BrO 2 ), calculated: 205.9942 / 207.9922, measured: 205.9894 / 207.9889.

Embodiment 2

[0039] Embodiment 2: Preparation of 6-bromomethyl-5,7-dioxaspiro[2.5]octane

[0040] In the reaction flask, add 102.1g (1.00mol) of 1,1-cyclopropyldimethanol, 186g (1.1mol) of 2-bromo-1,1-dimethoxyethane, 1.86g of perfluorosulfonic acid resin, 500ml of tetrahydrofuran, stirred and reacted at 45-55°C for 5-8 hours, after the reaction, filtered to remove the perfluorosulfonic acid resin, recovered THF and collected the components at 38-45°C (0.10mmHg) by vacuum distillation to obtain a colorless liquid 185g, yield 89.4%, purity (GC detection) 98.75%.

Embodiment 3

[0041] Example 3: Preparation of 6-bromomethyl-5,7-dioxaspiro[2.5]octane

[0042] In the reaction flask, add 102.1g (1.00mol) of 1,1-cyclopropyldimethanol, 203g (1.2mol) of 2-bromo-1,1-dimethoxyethane, SO 4 2- / ZrO 2 3.5g, 560ml tetrahydrofuran, stirred at 45-55°C for 5-8 hours, after the reaction, filter to remove SO 4 2- / ZrO 2 (recyclable), recovered THF and collected the components at 38-45° C. (0.10 mmHg) by distillation under reduced pressure to obtain 188 g of colorless liquid with a yield of 90.9% and a purity (GC detection) of 98.89%.

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Abstract

The invention belongs to the field of medical chemistry, and particularly relates to a montelukast side chain intermediate and a preparing method thereof. A provided intermediate compound is 6-halogenated methyl-5,7-dioxaspiro[2,5] octane, wherein 1,1-cyclopropyl dimethyl carbinol serving as a starting material and 2-halogeno-1,1-dimethoxyethane are subjected to a transacetalation reaction under solid acid catalysis to obtain 6-halogenated methyl-5,7-dioxaspiro[2,5] octane, the intermediate is treated with organic alkali and then hydrolyzed with a water solution containing acetic acid to obtain monoacetylated protected diol. The problems that monoacetylated protected diol is poor in selectivity, and diol loss is serious are solved, the availability of the raw materials is improved, and the montelukast side chain intermediate can be synthesized economically and conveniently.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a side chain intermediate of montelukast sodium and a preparation method thereof. Background technique [0002] Montelukast Sodium (Montelukast Sodium) is a new type of highly selective LTD4 receptor antagonist. It is an anti-asthma, anti-inflammatory and anti-allergic drug with high efficiency, low toxicity and good safety. It has been widely used in the world pharmaceutical market in recent years. Sales are among the best. Its chemical name is: 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinoline) vinyl]phenyl-3-[2-(1- Hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane sodium acetate, the structural formula is as follows: [0003] [0004] Through the retrosynthetic analysis of montelukast sodium, it can be seen that the key intermediate of synthetic montelukast sodium has 1-(mercaptomethyl) cyclopropyl acetic acid or its derivatives of side chain part and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/08C07C319/02C07C323/55
CPCC07C67/24C07C67/287C07C253/14C07C253/30C07C319/02C07C335/32C07D319/08C07C69/16C07C69/63C07C255/31C07C323/55
Inventor 张贵民王增学马庆文
Owner LUNAN BETTER PHARMA