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Compounding method of midbody required in compounding of montelukast sodium

A technology for the synthesis of montelukast sodium and its synthesis method, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of high production equipment requirements and high prices, and achieve the effect of simple raw materials, mild conditions, and easy availability of raw materials

Inactive Publication Date: 2012-08-01
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main problem is that acetic anhydride is needed for condensation, the price is high, and acetic acid is needed for the oxidation of bromide to aldehyde, which requires high production equipment

Method used

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  • Compounding method of midbody required in compounding of montelukast sodium
  • Compounding method of midbody required in compounding of montelukast sodium
  • Compounding method of midbody required in compounding of montelukast sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0038] 250mL three-necked bottle, equipped with a reflux condenser, a mechanical stirring paddle, and nitrogen protection. At room temperature, add 40 mL of 3N hydrochloric acid and 40 mL of ethanol to the bottle, and stir. Add 10.4 mL of m-chloroaniline and stir to form a white slurry. Heat the oil bath to 85-100°C, add 10.32 mL of crotonaldehyde dropwise, the system turns into a yellow turbid liquid, and reflux for 2 hours. Cool to room temperature, extract twice with 40 mL of petroleum ether, and discard the organic phase. The obtained aqueous phase was put into a 250mL three-neck flask equipped with a stirring paddle and a reflux condenser, stirred at a high speed at room temperature, and 13.6g of zinc chloride was added. The oil bath was heated to 120° C. and refluxed for half an hour. Keep stirring at a high speed, cool to room temperature, a precipitate appears, and the mother liquor is nearly colorless and transparent. The mother liquor was discarded, and the obtai...

Embodiment 2

[0041]250mL three-neck bottle, install the reflux water separation device. At room temperature, add 30 g of m-toluenesulfonic acid, 5 g of p-toluenesulfonic acid (or 2.16 g of concentrated sulfuric acid), 40 mL of ethanol, and 90 mL of benzene into the bottle, and stir to form a colorless and clear liquid. Heat the oil bath to 120°C, reflux and separate water for about 16 hours. Cool to room temperature, distill off benzene and excess ethanol to obtain brown viscous turbid liquid, add 100mL of ethyl acetate to dissolve, wash with 30mL of water, 30mL of saturated sodium bicarbonate solution, 30mL of saturated sodium chloride solution, and separate The ethyl acetate phase was dried over anhydrous sodium sulfate, and the solvent was spun off to obtain a yellow clear viscous liquid. Distilled under reduced pressure to obtain compound 6 as a colorless clear viscous liquid with a special smell, with a yield of 86%.

[0042] 1 H NMR (CDCl 3 ) δ (ppm): 1.40 ~ 1.44 (t, 3H); 2.43 (s...

Embodiment 3

[0044] 250mL three-necked bottle, install a reflux condenser. At room temperature, 8.2 g of compound (6), 160 mL of carbon tetrachloride, and 9 g of NBS were added to the bottle, and stirred evenly to form a light yellow suspension. Heat the oil bath to 80°C for reflux. After reflux, use a 200W light bulb to irradiate at a distance of 2 cm from the reaction bottle. At the same time, lower the temperature of the oil bath to keep the reaction system gently refluxed for 16 hours. Sampling TLC showed disappearance of starting material with an apparent spot of new material. Turn off light and cool to room temperature. Filter out the precipitate with diatomaceous earth, and wash the obtained clear water with 50 mL*2 of water and 50 mL of saturated sodium chloride solution in sequence. The organic phase after liquid separation was dried with anhydrous sodium sulfate, distilled under reduced pressure, and the solvent was recovered to obtain a yellow-brown oily liquid. Distilled und...

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Abstract

The invention provides a compounding method of an important midbody (E)-3-(2-(7-Cl-2- quinolyl)) vinyl-benzoate required in compounding of montelukast sodium. Raw materials of the method are simple to obtain, and the method is suitable for large scale production. A product is the important midbody in compounding of the montelukast sodium which is an anti-asthmatic agent.

Description

technical field [0001] The invention belongs to the synthesis of pharmaceutical intermediates, in particular to an intermediate (E)-3-(2-(7-chloro-2-quinolyl)vinylbenzyl) of an anti-asthma drug montelukast sodium Method for the synthesis of acid esters. Background technique [0002] Montelukast sodium, the chemical name is [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)vinyl]phenyl ]-3-[2-(1-Hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropyl sodium acetate is a drug developed and produced by Merck, commercial product Named "Singulair", it was launched in Europe and America in 1998 and in China in 2002. The compound is a highly selective cysteinyl leukotriene receptor antagonist, which can effectively treat asthma without obvious side effects. [0003] There are many reports on the synthesis of montelukast sodium (US4851409, EP480717, US5565473, WO 2006 / 021974A1, WO2008035086, WO9518107, etc.). Wherein (E) 3-(2-(7-chloro-2-quinolyl) vinyl benzoate is used as an inte...

Claims

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Application Information

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IPC IPC(8): C07D215/18
Inventor 张亚竹张钧康马闻颖高婷轶叶正清赵刚
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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