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Method for preparing 7-chloroquinaldine by utilizing phase-transfer reaction

A technology of phase transfer and phase transfer catalysts, applied in chemical instruments and methods, organic compound/hydride/coordination complex catalysts, organic chemistry, etc., can solve problems such as low reaction yield and difficult impurity purification, and achieve reduction Polymerization side reaction, the effect of mild reaction process

Inactive Publication Date: 2010-02-03
SHANGHAI YIMIN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention proposes a method for preparing the key raw material 7-chloroquinaldine of the anti-asthma drug Montelukast Sodium (Montelukast Sodium) through a phase transfer catalytic reaction, using a two-phase solvent system to complete the synthesis reaction under strong Lewis acid catalysis conditions , can greatly reduce the polymerization side reaction of crotonaldehyde, and solve the problem of low reaction yield caused by too many side reactions and difficult purification caused by too many impurities

Method used

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  • Method for preparing 7-chloroquinaldine by utilizing phase-transfer reaction
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  • Method for preparing 7-chloroquinaldine by utilizing phase-transfer reaction

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Experimental program
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Effect test

Embodiment 1

[0040] Step 1, m-chloroaniline is dissolved in organic solvent

[0041] Dissolve 192 g (1500 mmol) of m-chloroaniline in 250 ml of 2-ethylhexanol and 150 ml of toluene, and stir evenly.

[0042] Step 2, synthesis reaction

[0043] A 2000 ml four-necked glass flask equipped with mechanical stirring, a thermometer, a spherical reflux condenser, and a dropping funnel, successively added 600 ml of 31% mass fraction (5800 mmol) of industrial grade hydrochloric acid and 10 g of alkylphenol polyoxyethylene ether to the flask. OP-10, 2.5 grams of benzyltriethylamine chloride, 185 grams (750 mmol) of tetrachloro-p-benzoquinone, 12 grams (72 mmol) of potassium iodide, 8.2 grams (32 mmol) of iodine, 1.2 grams (10 mmol) of p-dimethylaminopyridine ( DMAP). Then add the already prepared m-chloroaniline solution dropwise into the flask through the dropping funnel under stirring at room temperature within 15 minutes. Due to the exotherm of the neutralization reaction, the temperature of th...

Embodiment 2

[0047] Step 1, m-chloroaniline is dissolved in organic solvent

[0048] Dissolve 192 g (1500 mmol) m-chloroaniline in 250 ml C 4 ~C 9 Mix low-carbon alcohol and 150 ml of sec-butanol, and stir evenly.

[0049] Step 2, synthesis reaction

[0050] A 2000 ml four-necked glass flask equipped with mechanical stirring, a thermometer, a spherical reflux condenser, and a dropping funnel, successively added 600 ml of 31% mass fraction (5800 mmol) of industrial grade hydrochloric acid and 10 g of alkylphenol polyoxyethylene ether to the flask. OP-10, 86 grams (627 mmol) o-nitrotoluene, 1.2 grams (10 mmol) p-dimethylaminopyridine (DMAP). Then add the already prepared m-chloroaniline solution dropwise into the flask through the dropping funnel under stirring at room temperature within 15 minutes. Due to the exotherm of the neutralization reaction, the temperature of the reaction solution naturally rose to 50-60°C, and white m-chloroaniline hydrochloride was precipitated. The reaction...

Embodiment 3

[0054] Step 1, m-chloroaniline is dissolved in organic solvent

[0055] Dissolve 192 grams (1500 mmol) of m-chloroaniline in 250 milliliters of secondary octanol and 150 milliliters of refined fusel oil, and stir evenly.

[0056] Step 2, synthesis reaction

[0057] A 2000 ml four-necked glass flask equipped with mechanical stirring, a thermometer, a spherical reflux condenser, and a dropping funnel, successively added 600 ml of 31% mass fraction (5800 mmol) of industrial grade hydrochloric acid and 10 g of alkylphenol polyoxyethylene ether to the flask. OP-10, 100 grams (635 mmol) m-nitrochlorobenzene, 12 grams (72 mmol) potassium iodide, 8.2 grams (32 mmol) iodine. Then add the already prepared m-chloroaniline solution dropwise into the flask through the dropping funnel under stirring at room temperature within 15 minutes. Due to the exotherm of the neutralization reaction, the temperature of the reaction solution naturally rose to 50-60°C, and white m-chloroaniline hydroch...

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Abstract

The invention relates to a method for preparing 7-chloroquinaldine by utilizing a phase-transfer reaction. The method comprises the following steps: (1), dissolving m-chloroaniline to organic solvent;(2), carrying out a synthesis reaction: adding a phase-transfer catalyst and an oxidant to a diluted acid aqueous solution; stirring and dipping the m-chloroaniline solution obtained in the step (1)to the prepared diluted acid solution; heating to be 98-103 DEG C; fully stirring, dipping crotonic aldehyde, keeping temperature and stirring after dipping; and (3), purifying reaction products. Theinvention finishes the synthesis reaction by adopting a two-phase solvent system under a catalytic condition of strong Lewis acid, effectively reduces side reactions, lowers the purification difficulties, improves the yield and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, more specifically, to a method for preparing 7-chloroquinaldine through a phase transfer reaction, which is suitable for industrial production. Background technique [0002] 7-Chloroquinaldine, chemical name 2-methyl-7-chloroquinaldine, English name 7-Chloroquinaldine, CASNo.: 4965-33-7, its chemical structural formula is: [0003] [0004] 7-Chloroquinaldine is a synthetic anti-asthma drug Montelukast, selective leukotriene D 4 An important intermediate of the receptor antagonist MK-0679. 7-Chloroquinaldine belongs to quinoline compounds, and the synthesis of 7-chloroquinaldine generally adopts m-chloroaniline and crotonaldehyde (Crotonaldehyde) to carry out through the Skraup-Doebner-Von Miller reaction, but due to many side reactions, the reaction product The composition is complex, and to obtain the target main product must go through multi-step and complicated sep...

Claims

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Application Information

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IPC IPC(8): C07D215/18B01J31/06B01J31/02B01J27/138
Inventor 虞人杰周琦
Owner SHANGHAI YIMIN CHEM
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