Preparation method of 5-amino-2-methyl quinoline

A technology of methylquinoline and amino group, applied in the field of synthesis of 5-amino-2-methylquinoline, can solve the problems of difficulty, high production cost, low high-temperature cyclization yield and the like

Inactive Publication Date: 2011-03-09
ZHEJIANG QIMING BIOCHEM TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One of the biggest disadvantages of this process: high temperature ring closure yield is not high (EP2005 / 012531 yield 50%) high temperature production industrial production cost is too high, the second disadvantage: two isomers are obtained simultaneously in the nitration stage: 5-nitro -2-methylquinoline and 8-nitro-2-methylquinoline, in which 5-nitro-2-methylquinoline is an oil and 8-nitro-2-methylquinoline is a solid
Therefore, it is difficult to obtain high-purity 5-nitro-2-methylquinoline, and the yield of the method is also low, and the yield reported in EP2005 / 012531 is only 30%.
Therefore, this synthetic method brings great difficulty to realize industrialized production

Method used

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  • Preparation method of 5-amino-2-methyl quinoline

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 50g of o-chloroaniline, 130.5g of n-butanol, 120g of concentrated hydrochloric acid, 96.3g of chlorobenzoquinone into a 1L reaction bottle, stir mechanically, and heat the oil bath to 90-95°C; mix 33g of crotonaldehyde and 33g of n-butanol evenly , Added dropwise to the reaction flask, heated to reflux for 1h after dropping. Cool down to 80°C, add 53.4g zinc chloride solid in batches, then add 240g isopropyl ether, and reflux for 1h. Sampling analysis, the reaction is complete. Cool to 0°C, keep stirring for 1 h, filter, and collect 83.1 g of solid product. HPLC detection purity ≥ 99%, yield 99% (based on o-chloroaniline).

Embodiment 2

[0028] According to Example 1, 240 g of tetrahydrofuran was used instead of isopropyl ether as a solvent, and 83.4 g of 8-chloro-2-methylquinoline hydrochloride was obtained under the same operation. The purity by HPLC was 98.8%, and the yield was 99.3%.

Embodiment 3

[0030] According to Example 1, the consumption of chloranil was reduced by half, and 48.2 g was cast instead. Other conditions remained unchanged, and finally the product 8-chloro-2-methylquinoline hydrochloride was 53g, the purity was 95%, and the yield was 60%.

[0031] The second step: the preparation of 8-chloro-5-nitro-2-methylquinoline

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Abstract

The invention relates to a preparation method of pharmaceutical intermediate 5-amino-2-methyl quinoline. The method is as follows: cyclizing o-chloroaniline and crotonaldehyde under the action of Lewis acid to obtain chinoline rings, carrying out 5-site nitrification on the chinoline rings, reducing by iron powder, and carrying out hydrogenation reduction by 5% palladium carbon to finally obtain the target compound 5-amino-2-methyl quinoline with high purity. The preparation method has the advantages of simple process, mild reaction conditions, low cost and simple post treatment and is applicable to industrial production, and the obtained products have high yield, high purity and stable quality, therefore 5-amino-2-methyl quinoline completely conforms to the using requirement when serving as pharmaceutical intermediate.

Description

technical field [0001] The invention is a synthesis method of 5-amino-2-methylquinoline, which is an important pharmaceutical intermediate. Background technique [0002] 5-amino-2-methylquinoline is an important pharmaceutical intermediate. In the prior art, domestic and foreign literature reports mainly use aniline as a raw material, and then synthesize a quinoline ring with ethyl acetoacetate at a high temperature of 250°C, and then obtain 5-nitro-2-methylquinoline through nitration, and finally in the catalytic The target product 5-amino-2-methylquinoline was obtained under hydrogenation. One of the biggest disadvantages of this process: high temperature ring closure yield is not high (EP2005 / 012531 yield 50%) high temperature production industrial production cost is too high, the second disadvantage: two isomers are obtained simultaneously in the nitration stage: 5-nitro -2-methylquinoline and 8-nitro-2-methylquinoline, wherein 5-nitro-2-methylquinoline is an oil and 8...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/38
Inventor 张牧群肖方亮卢扬锡
Owner ZHEJIANG QIMING BIOCHEM TECH
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