Improved method of synthesizing 4-chlorine-1hydrogen-quinoline-2-ketone-3-carboxylic methyl ester by isatoic anhydride

A technology of methyl carboxylate and isatoic anhydride, which is applied in the field of chemical synthesis, can solve the problems of large consumption of organic solvents, and achieve the effects of less solvent residue, high yield, and simple purification process

Inactive Publication Date: 2017-07-21
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The intermediate of this method is easy to react with water to generate by-products in the post-treatment process, and the consumption of organic solvents in the post-treatment is large

Method used

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  • Improved method of synthesizing 4-chlorine-1hydrogen-quinoline-2-ketone-3-carboxylic methyl ester by isatoic anhydride

Examples

Experimental program
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Effect test

Embodiment 1

[0012] Embodiment 1: Preparation of 4-hydroxyl-1 hydrogen-quinolin-2-one-3-carboxylic acid methyl ester

[0013] Dissolve NaH (60%) (0.80g, 20.0mmoL) in 30mL DMF in a 50mL three-neck flask equipped with magnetic stirring, and add dimethyl malonate (2.43 g, 18.2mmoL) dropwise at -10°C, After dropping, the temperature was raised to room temperature. Stir at room temperature for 20min, add isatoic anhydride (3.00g, 18.2mmoL) to the above mixture at one time, stop heating and stirring after reacting at 110°C for 1h, cool to room temperature and collect the solid by suction filtration. Dissolve the solid in 15mL water, acidify with hydrochloric acid at low temperature to pH ≈ 4, a large amount of white solid is produced, filter the filter cake obtained by suction and dry to obtain methyl 4-hydroxy-1hydro-quinolin-2-one-3-carboxylate Pure ester (3.73g, 92.5% yield).

Embodiment 2

[0014] Embodiment 2: Preparation of 4-hydroxyl-1 hydrogen-quinolin-2-one-3-carboxylic acid methyl ester

[0015] Dissolve NaH (60%) (8.00 g, 0.200 moL) in 300 mL of DMF in a 500 mL three-neck flask equipped with mechanical stirring, and add dimethyl malonate (24.3 g, 0.182 moL) dropwise at -10 °C, After dropping, the temperature was raised to room temperature. Stir at room temperature for 20min, add isatoic anhydride (30.0g, 0.182moL) to the above mixture at one time, stop heating and stirring after reacting at 110°C for 1h, cool to room temperature and collect the solid by suction filtration. Dissolve the solid in 110mL of water, acidify with hydrochloric acid at low temperature to pH ≈ 4, a large amount of white solid is produced, filter the filter cake obtained by suction and dry to obtain methyl 4-hydroxy-1hydro-quinolin-2-one-3-carboxylate Pure ester (38.3 g, 96% yield).

Embodiment 3

[0016] Embodiment 3: Preparation of 4-hydroxyl-1 hydrogen-quinolin-2-one-3-carboxylic acid methyl ester

[0017] The feeding amount and feeding method are the same as in Example 2. The post-treatment method adopts the previously reported method. The reaction solution is cooled to room temperature, poured into 2L of ice water, and hydrochloric acid is added at a low temperature. Only a small amount of solids are produced when acidifying to pH ≈ 4. , when acidified to pH ≈ 2, a large amount of solids were produced, and 28.2 g of the product was obtained after suction filtration, washing and drying, with a yield of 70%.

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Abstract

The invention discloses an improved method of synthesizing 4-chlorine-1hydrogen-quinoline-2-ketone-3-carboxylic methyl ester by isatoic anhydride. The method includes: improving aftertreatment mode of 4-chlorine-1hydrogen-quinoline-2-ketone-3-carboxylic methyl ester and high-yield one-pot process synthesis in the subsequent process. The improved method has the advantages that isatoic anhydride is purified by means of filtering first and acidifying second after reacting with dimethyl malonate in DMF, so that consumption of water and hydrochloric acid is reduced obviously, and generation of wastewater is reduced; compared with treatment modes mentioned in existing reports, an improved treatment mode has the advantages of high yield and zero solvent residue. Synthesis of 4-chlorine-1hydrogen-quinoline-2-ketone-3-carboxylic methyl ester through a 4-chlorine-1hydrogen-quinoline-2-ketone-3-carboxylic methyl ester one-pot process has the advantages of being free of water participation in the process of synthesis, simple to operate, free of organic solvent consumption in the subsequent process and high in yield. Compared with conventional synthesis methods, the method is simple to operate, low in cost and low in wastewater discharge and has important actual application value in the field of chemical industry production.

Description

technical field [0001] The present invention relates to the technical field of chemical synthesis, in particular to an improved method for synthesizing 4-chloro-1 hydrogen-quinolin-2-one-3-carboxylic acid methyl ester from isatoic anhydride, especially the post-reaction treatment method The improvement and the use of 4-hydroxy-1 hydrogen-quinolin-2-one-3-carboxylate methyl ester to synthesize the target product in one pot. Background technique [0002] 4-Chloro-1H-quinolin-2-one-3-carboxylate is an important chemical and pharmaceutical intermediate, especially 4-Chloro-1H-quinolin-2-one-3-carboxylate Important synthetic raw materials. Studies on pharmacological properties have shown that the carboxyl or ester-based compounds are very likely to have analgesic effects, and therefore make 4-chloro-1 hydrogen-quinolin-2-one-3-carboxylic acid methyl ester and 4-chloro-1 hydrogen-quinolin Lin-2-one-3-carboxylic acids are playing an increasingly important role in the field of dru...

Claims

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Application Information

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IPC IPC(8): C07D215/54
CPCC07D215/54
Inventor 刘晓磊杨涛孙国新张燕汉吉勋崔玉
Owner UNIV OF JINAN
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