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Preparation method of 4-chloro-2,5-difluorobenzoic acid

A technology of difluorobenzoic acid and difluorobromobenzene, which is applied in the field of preparation of fluorine-containing organic acids, can solve problems such as difficulty in preparation and purification, low purity of difluorobenzoic acid, and limited application

Inactive Publication Date: 2009-03-11
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
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Problems solved by technology

The disadvantage of this method is: 4-chloro-2,5-difluoroacetophenone (starting material) is difficult to prepare and purify (isomers formed during chlorination are difficult to separate), making 4-chloro-2,5 - The purity of difluorobenzoic acid (target substance) is not high, which limits its further application

Method used

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  • Preparation method of 4-chloro-2,5-difluorobenzoic acid

Examples

Experimental program
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Effect test

Embodiment

[0021] A. Bromination

[0022] Add 399g of water and 510g of concentrated sulfuric acid (T≤60°C) into a 5L three-neck flask equipped with a spherical condenser, thermometer, and electric stirrer, and then add 90g (0.638mol) of p-fluoronitrobenzene, and control the temperature at 38-43 °C, 112 g (0.67 mol) of potassium bromate was added in batches, and the reaction time was about 12 hours. During the feeding process, follow up and measure the sample. When p-nitrofluorobenzene ≤ 2%, and the product content is above 98%, stop the reaction, cool, add 500g of water, cool to below 40°C, let stand for stratification, and wash the lower layer with water. Wash with weak alkali until neutral. Distilled under reduced pressure to obtain 110 g of 3-bromo-4-fluoronitrobenzene with a yield of 78.7% and a content of 98%. Melting point: 57~59℃, 1 H NMR (CDCl 3 ) δ (ppm): 7.29 to 8.46 (m, 3H).

[0023] B. Hydrogenation reduction

[0024] Add 600 mL of methanol, 200 g (0.913 mol) of 3-brom...

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Abstract

The invention relates to a preparation method for 4-chloro-2,5-difluorobenzoic acid. The preparation method comprises the following steps that: p-fluoronitroben-zene is used as a starting material and is subjected to bromization to obtain 3-bromo,4-fluoro-nitrobenzene; the 3-bromo,4-fluoro-nitrobenzene is reduced to obtain 3-bromo,4-fluoro-aniline; the 3-bromo,4-fluoro-aniline is chlorized to obtain 3-bromo,4-fluoro,6-chloro-aniline; the 3-bromo,4-fluoro,6-chloro-aniline is subjected to diazotization and then fluorized to obtain 4-chloro-2,5-difluorobromobenzene; and the 4-chloro-2,5-difluorobromobenzene is made into a bromobenzene grignard reagent and then is added into carbon dioxide to obtain a target substance after acidification. The preparation method prepares the 4-chloro-2,5-difluorobenzoic acid with high purity (more than 98 percent) through a easy large scale of commercial preparation method and lays a foundation for commercial application of the 4-chloro-2,5-difluorobenzoic acid.

Description

technical field [0001] The invention relates to a preparation method of fluorine-containing organic acid, in particular to a preparation method of 4-chloro-2,5-difluorobenzoic acid. Background technique [0002] 4-Chloro-2,5-difluorobenzoic acid is a widely used pharmaceutical intermediate. For example, WO 2006040966 reports that the compound can be used to synthesize an enhancer of insulin secretion; WO 2005079300 reports that it can be used as a raw material for the synthesis of protein kinase inhibitors; and WO 9962890 reports that it can be used as an intermediate for the synthesis of anticancer drugs. [0003] However, there are few reports about the preparation method of 4-chloro-2,5-difluorobenzoic acid. WO 9012780 reports the use of 4-chloro-2,5-difluoroacetophenone as a starting material to obtain 4-chloro-2,5-difluorobenzoic acid through oxidation (using hypohalite as an oxidizing agent). The disadvantage of this method is: 4-chloro-2,5-difluoroacetophenone (star...

Claims

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Application Information

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IPC IPC(8): C07C63/70C07C51/15
Inventor 钱旭红陈卫东曹松唐秀红
Owner EAST CHINA UNIV OF SCI & TECH
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