Preparation method of midbody 7-chloroquinaldine

An intermediate, the technology of chloroquine, which is applied in the field of preparation of 7-chloroquinaldine, can solve the problems of no solution for product separation and purification, and no practical application value, so as to achieve a safe and reliable reaction process and suppress a large number of isomers Produce, reduce the effect of reaction conditions

Inactive Publication Date: 2009-02-18
中国科学院嘉兴应用化学工程中心
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] People such as Ganesabaskaran Sivaprasad, Rengasamy Rajesh and ParamasivanT.perumal also use m-chloroaniline and crotonaldehyde to synthesize 7-chloroquinaldine under microwave conditions in Tetrahedron Letters 47 (2006) 1783-1785, and the yield of this method has improved, but There is no practical application value, and there is no solution to the separation and purification of products

Method used

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  • Preparation method of midbody 7-chloroquinaldine
  • Preparation method of midbody 7-chloroquinaldine
  • Preparation method of midbody 7-chloroquinaldine

Examples

Experimental program
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Effect test

Embodiment 1

[0029] The preparation of m-chloroaniline hydrobromide:

[0030] In 1000 milliliters of four-necked flasks with mechanical stirring, thermometer, condensing tube, dropping funnel, add hydrobromic acid (500 grams, 40%, 2.5mol, commercially available industrial grade), cooling with water bath, start to drop m-chlorine 292 grams of aniline, 99%, 2.273mol, commercially available industrial grade), the control temperature is not more than 50 degrees, and the dropwise addition time is about 30 minutes. After cooling to room temperature, begin to filter to obtain m-chloroaniline hydrobromide, and dry to obtain 454 grams, content 99%, yield 95%.

[0031] In 2000 milliliters of four-necked flasks with mechanical stirring, thermometer, condenser, dropping funnel, add the hydrobromide (211g, 1mol) of m-chloroaniline, 1000 milliliters of methyl alcohol, 300 milliliters of o-nitrotoluene, heat up and reflux, Add dropwise crotonaldehyde (trans commercially available 85g, 98%, 1.2mol) for a...

Embodiment 2

[0034] In a 2000 ml four-necked flask with mechanical stirring, a thermometer, a condenser, and a dropping funnel, add the hydrobromide (211g, 1mol) of m-chloroaniline, 1000 ml of methanol, 300 ml of toluene, and 100 ml of o-nitrotoluene , warming up to reflux, dropwise adding crotonaldehyde (trans-commercially available 85g, 98%, 1.2mol) for about 20 minutes, refluxed for 40 minutes, cooled to 15-25 degrees, white solids were precipitated, filtered, methanol 2×200 Milliliter washing, 201 grams of 7-chloroquinaldine hydrobromide was obtained, the content was 99.6%, and the yield was 77.0%. 201 grams (0.77mol) of hydrobromide was added in 410 milliliters of 10% sodium carbonate solution, stirred for 30 minutes, and filtered to obtain 136.8 grams of white solid 7-chloroquinaldine, with a content of 99.5% and a yield of 100 %, filter the mother liquor and add 2000 milliliters of water, separate 390 milliliters of the organic layer for the next reaction, and the water layer is dir...

Embodiment 3

[0036] In a 2000 ml four-neck flask with mechanical stirring, a thermometer, a condenser tube, and a dropping funnel, add the hydrobromide (211g, 1mol) of m-chloroaniline, 1000 ml of methanol, 200 ml of toluene, and 200 ml of o-nitrotoluene , warming up to reflux, dropwise adding crotonaldehyde (trans-commercially available 85g, 98%, 1.2mol) for about 20 minutes, refluxed for 40 minutes, cooled to 15-25 degrees, white solids were precipitated, filtered, methanol 2×200 Milliliter washing, 7-chloroquinaldine hydrobromide 198 grams, content 99.6%, yield 76.3.0%. 198 grams (0.76mol) of hydrobromide was added in 410 milliliters of 10% sodium carbonate solution, stirred for 30 minutes, filtered to obtain 135 grams of white solid 7-chloroquinaldine, content 99.4%, yield 100 %, filter the mother liquor and add 2000 milliliters of water, separate 385 milliliters of the organic layer for the next reaction, the water layer is directly recovered by methanol distillation.

[0037]In 2000 ...

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Abstract

The present invention provides a preparation method of medicine intermediate 7-chlorine quinaldine. M-chloroaniline salt of inorganic acid and crotonaldehyde have a closed loop reaction in mixed solvent of alcohol and arene to prepare the salt of 7-chlorine quinaldine; alkaline is added for neutralization; and the 7-chlorine quinaldine can be prepared. The present invention has the advantages that the production of a large quantity of isomers is inhibited, the operation is simple, the production period is obviously shortened, no large amount of acid, alkaline or expensive solvent is used in the post-processing, and the product is more conducive to the environmental protection; a large amount of energy is saved; simultaneously, the reaction conditions are simplified, the reaction process is safer and more reliable, the quality and yield rate of the product are ensured, and the present invention is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, more specifically to a preparation method of 7-chloroquinaldine. Background technique [0002] 7-Chloroquinaldine has another name called 7-chloro-2-methylquinoline, as an important intermediate for the synthesis of Montelukast sodium (Montelu-kast) and leukotriene receptor antagonist MK-0679, its synthetic method is prepared attention. [0003] In U.S. Patents US5126456 and US5066806, people such as Zhiguo Song and Emmerich Pastorek use m-chloroaniline and crotonaldehyde to react under acidic conditions to obtain 7-chloro-2-methylquinoline, wherein tetrachloro-p-benzoquinone is used as Oxidant, use zinc chloride, tartaric acid, etc. to complex with the product to separate from the isomer 5-chloro-2-methylquinoline. Tetrachloro-p-benzoquinone and tartaric acid are very expensive, and the post-treatment process is quite cumbersome. Complexation and filtration are required to obtain th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18
Inventor 张振明吴长江张建荣左勇章
Owner 中国科学院嘉兴应用化学工程中心
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