Preparation method of midbody 7-chloroquinaldine

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

A kind of preparation method of medicine intermediate 7-chloroquinaldine technical field The invention relates to the field of pharmaceutical intermediates, more specifically to a preparation method of 7-chloroquinaldine. Background technique 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. In U.S. Patent Nos. 5,126,456 and 5,066,806, ZhiguoSong, Emmerich Pastorek and others use m-chloroaniline and crotonaldehyde to react under acidic conditions to obtain 7-chloro-2-methylquinoline, wherein tetrachloro-p-benzoquinone is used as an 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. Com...

AI Technical Summary

Problems solved by technology

In U.S. Patent Nos. 5,126,456 and 5,066,806, ZhiguoSong, Emmerich Pastorek and others use m-chloroaniline and crotonaldehyde to react under acidic conditions to obtain 7-chloro-2-methylquinoline, wherein tetrachloro-p-benzoquinone is used as an 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, filtration, the complex of the product is obtained, the product is separated from the complex, crystallized, filtered, and finally the product is obtained. Suitable for industrial production operations

In the Hungarian patent HU200401607, Salamon Zoltán Debrecen et al obtained 7-chloro-2-methylquinoline through the cyclization of m-chloroaniline and ethyl acetoacetate, N,N-dimethylformamide, chlorination, hydrolysis and decarboxylation. There are many reaction steps, the total yield is less than 25%, and the cost of raw materials is high

Document Chemical&PharmaceuticalBulletin, 34 (2), 463-70; In 1986, people such as MachikoOno adopts paraldehyde and m-chloroaniline to react and can obtain 7-chloroquinaldine (yield 34%) and 5-chloroquinaldine (yield 3.78%), but because this mixture is difficult to separate, cause can not obtain the higher 7-chloroquinaldine of purity

In document J.HeterocyclicChem.30,17(1993), people such as ZhiguoSong use m-chloroaniline and the reaction of crotonaldehyde and use p-chlorobenzoquinone as oxidant to improve the yield of product 7-chloro-2-methylquinoline by 81% , has also given the purification method of using tetrahydrofuran as a solvent and complexing with zinc chloride, but the process is cumbersome and the cost is higher

GanesabaskaranSivaprasad, people such as RengasamyRajeshandParamasivanT.perumal also use m-chloroaniline and crotonaldehyde to synthesize 7-chloroquinaldine under microwave conditions in TetrahedronLetters47 (2006) 1783-1785, and this method yield has improved, but has no practical application value, and There is no solution to the separation and purification of products

Images