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Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof

A compound and mixture technology, applied in the field of montelukast sodium new intermediate, synthesis of montelukast sodium, can solve the problems of complex and harsh conditions, many by-products, unsuitable for large-scale production, etc.

Active Publication Date: 2012-04-25
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Some of the synthetic methods of the above-mentioned intermediates need to use precious palladium metal reagents, which increases the production cost; some require multiple Grignard reactions, complex and harsh conditions, strict control, and many by-products; Not suitable for long-term storage problems, not suitable for mass production
[0010] In the prior art, about another important intermediate of montelukast, 2-(2-3-(3-2(7-chloro-2-quinolyl)-vinyl)phenyl)-3-oxopropane There are few reports on the synthetic method of base) phenyl) propanol, and this intermediate can obtain the required chiral mother nucleus selectively under the effect of chiral reducing agent, so this intermediate has wide application prospect

Method used

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  • Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof
  • Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof
  • Montelukast sodium intermediate and method for synthesizing montelukast sodium thereof

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Experimental program
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Effect test

Embodiment 1

[0097] Embodiment 1: [2-[1-methyl-1-(tetrahydropyran-2-oxyl group) ethyl] phenyl]-methanol synthesis

[0098] Step 1: In an ice bath at -15°C, add 50 grams of phthalide and 200 milliliters of tetrahydrofuran to a 2000 milliliter three-necked round-bottomed flask, protect it with nitrogen, and then slowly add 400 milliliters of CH 3 The tetrahydrofuran solution of MgCl (2.0 mol / liter), dripped within 2 hours, then slowly warmed up to room temperature, and after 4 hours, the reaction solution was poured into a flask with 500 ml of saturated ammonium chloride ice-water solution, stirred, and dissolved in acetic acid Ethyl ester (4 × 200 ml) was extracted, the ethyl acetate layers were combined, washed with 10% brine (3 × 200 ml), dried by adding magnesium sulfate, the solvent was spun to dryness, and vacuum dried for 4 hours to obtain 57 g of white waxy solid , yield 92.0%. 1 H NMR (400MHz, CDCl 3 ): δ1.59 (s, 6H), 4.52 (s, 2H), 4.71 (s, 2H), 7.27-7.17 (m, 4H).

[0099] The seco...

Embodiment 2

[0102] Embodiment 2: the synthesis of [2-[1-methyl-1-(methoxy) ethyl] phenyl]-methanol

[0103] The first step: the same as the first step in embodiment 1.

[0104] The second step: dissolve 55 grams of the waxy solid obtained in the first step in 115 milliliters of dichloromethane, add 100 milliliters of triethylamine, 0.4 grams of 4-dimethylaminopyridine, and slowly drop into the dissolved 62.5 grams of tert-butyldimethylchlorosilane in 50 milliliters of dichloromethane were reacted for 4 hours. After the reaction was completed, 200 milliliters of saturated sodium bicarbonate solution was added, the layers were separated, and the water layer was washed with dichloromethane (2×150 milliliters) ), the dichloromethane layers were combined, washed with saturated brine (3×200 ml), dried by adding magnesium sulfate, and the solvent was spun to dryness to obtain an oil, which was directly used in the next step.

[0105] The third step: at room temperature, take part of 28 grams of...

Embodiment 3

[0107] Example 3: 1-[3-[2-(7-chloro-2-quinolyl)-vinyl]phenyl]-3-[2-(1-hydroxyl-1-methyl)ethylphenyl Synthesis of ]-propan-1-one (compound of formula III)

[0108] Take 3.09 grams of 1-[3-[2-(7-chloro-2-quinolyl)vinylphenyl]-ethanol, dissolve it in 20 ml of toluene, and add [2-[1-methyl-1-( Tetrahydropyran-2-oxygen) ethyl] phenyl]-methanol 3.0 grams, potassium hydroxide 1.2 grams, reflux for 6 hours, after reaction, add 100 milliliters of saturated NH4Cl solution, with ethyl acetate (3 * 40 ml), combined the ethyl acetate layers, washed with saturated brine, dried over magnesium sulfate, and evaporated to dryness to obtain an oil. Dissolve the oil in 20 ml of dichloromethane, add 4.2 g of Dess-Martin oxidant at room temperature, react for 4 hours, filter through diatomaceous earth, spin to dry the solvent, add 20 ml of methanol, add 0.75 g of p-tolylidine sulfonate Acetate, reacted at room temperature for 10 hours, evaporated methanol to dryness, added 30 ml of water, extract...

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PUM

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Abstract

The invention relates to a chemical synthesis drug technology, especially relates to a novel technology for synthesizing montelukast sodium, the invention also relates to a novel intermediate of the synthesized montelukast sodium. The method has the advantages of cheap raw material and easy acquisition, short synthesis route and simple operation, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a new intermediate of montelukast sodium and a method for synthesizing montelukast sodium using the intermediate. Background technique [0002] The chemical name of Montelukast Sodium is: [R-(E)]-1-[[[1-[3-[2-[7-chloro-2-quinoline]vinyl]phenyl ]-3-[2-(1-Hydroxy-1-methylethyl)phenyl]propyl]sulfur]methyl]cyclopropaneacetic acid monosodium salt, its structural formula is as follows: [0003] [0004] Montelukast sodium is a leukotriene receptor antagonist, which can inhibit the biosynthesis of leukotrienes, and can be used as an antiasthma agent and antiallergic agent in medicine. This compound is disclosed for the first time in CN1061407A patent by Canada McFrost Company, and the preparation method of this compound described in this patent is 2-(2-(3(R)-(3-(2-(7-chloro- 2-quinolyl)-vinyl)phenyl)-3-(hydroxyl)propyl)phenyl)propanol is reacted with 1-(mercaptomethyl)-cyclopropane ac...

Claims

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Application Information

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IPC IPC(8): C07D309/12C07D215/18C07C43/178C07C41/26
CPCY02P20/55
Inventor 罗海荣顾荣领李江马静柴健朱国荣蔡青峰
Owner ZHEJIANG HISUN PHARMA CO LTD
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