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Synthesis method of diflunisal drug intermediate 2,4-difluoroaniline

A technology of difluorophenyl salicylic acid and difluoroaniline, applied in chemical instruments and methods, preparation of organic compounds, preparation of amino compounds, etc., to achieve the effect of increasing the reaction yield and improving the reaction yield

Inactive Publication Date: 2016-10-12
CHENGDU QIANYE LONGHUA PETROLEUM ENG TECH CONSULTING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Wang Qiuling (Wang Qiuling, Fu Limin. Synthesis of 2,4-difluoroaniline [J]. Organic Fluorine Industry, 1991, 02:25-29.) with 2,4-difluoronitrobenzene as raw material, in ammonium chloride Iron powder is used as reducing agent in the aqueous solution to carry out reflux reaction to synthesize 2,4-difluoroaniline. Although the reaction is relatively simple, the reaction yield of this synthesis method is only 87.8%. Therefore, in order to improve the reaction yield, there are It is necessary to propose a new synthetic method

Method used

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  • Synthesis method of diflunisal drug intermediate 2,4-difluoroaniline

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] A kind of synthetic method of difluorophenyl salicylic acid medicine intermediate 2,4-difluoroaniline, comprises the steps:

[0020] A, in the reaction vessel that agitator, thermometer, reflux condenser, dropping funnel are installed, add molybdenum powder 0.53mol, mass fraction is 50% 2,6-dimethoxyphenol solution 300ml, control stirring speed at 270rpm, add 0.32mol of 2,4-difluoronitrobenzene, increase the temperature of the solution to 56°C, and reflux for 5h;

[0021] B, steam distillation for 120min, the distillate is extracted with a trifluoroacetic acid solution with a mass fraction of 63%, the extract is washed with diammonium hydrogen citrate solution, dehydrated with anhydrous potassium carbonate dehydrating agent, distilled under reduced pressure at 1.9kPa, and collected The fraction at 55°C yielded 39.58 g of 2,4-difluoroaniline, with a yield of 96%.

Embodiment 2

[0023] A kind of synthetic method of difluorophenyl salicylic acid medicine intermediate 2,4-difluoroaniline, comprises the steps:

[0024] A, in the reaction vessel that agitator, thermometer, reflux condenser, dropping funnel are installed, add molybdenum powder 0.53mol, mass fraction is 50% 2,6-dimethoxyphenol solution 300ml, control stirring speed at 250rpm, add 0.32mol of 2,4-difluoronitrobenzene, increase the temperature of the solution to 53°C, and reflux for 4h;

[0025] B, steam distillation 110min, the distillate is extracted with the trifluoroacetic acid solution of 60% by mass fraction, the extract is washed with potassium sulfate solution, dehydrated with anhydrous magnesium sulfate dehydrating agent, 2.1kPa vacuum distillation, collect 53 ℃ The distillate obtained 38.89 g of 2,4-difluoroaniline, with a yield of 94%.

Embodiment 3

[0027] A kind of synthetic method of difluorophenyl salicylic acid medicine intermediate 2,4-difluoroaniline, comprises the steps:

[0028] A, in the reaction vessel that agitator, thermometer, reflux condenser, dropping funnel are installed, add molybdenum powder 0.53mol, mass fraction is 45% 2,6-dimethoxyphenol solution 300ml, control stirring speed at 230rpm, add 0.32mol of 2,4-difluoronitrobenzene, increase the temperature of the solution to 50°C, and reflux for 3h;

[0029] B, steam distillation for 90min, the distillate is extracted with a trifluoroacetic acid solution with a mass fraction of 60%, the extract is washed with diammonium hydrogen citrate solution, dehydrated with anhydrous potassium carbonate dehydrating agent, distilled under reduced pressure at 1.8kPa, and collected The fraction at 50°C yielded 38.92 g of 2,4-difluoroaniline, with a yield of 94%.

[0030]

Response time h

Reaction yield%

Example 1

5.5

96

Example 2

...

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Abstract

The invention discloses a synthesis method of a diflunisal drug intermediate 2,4-difluoroaniline. The method comprises the following steps: adding 2,4-difluoronitrobenzene and molybdenum powder to a 2,6-dimethoxyphenol solution, heating the obtained solution to 50-56DEG C, refluxing the solution for 3-5h, carrying out water vapor distillation, carrying out trifluoroacetic acid solution extraction, washing the obtained extract with a salt solution, dewatering the washed extract with a dewatering agent, carrying out reduced pressure distillation, and collecting a 50-55DEG C fraction to obtain 2,4-difluoroaniline. The reaction yield of the above reaction can reach 94% or above, and is obviously higher than that in the background technologies. The invention also provides a new synthesis route. The new synthesis route lays a good foundation for further increasing the reaction yield.

Description

technical field [0001] The invention relates to a method for preparing a pharmaceutical intermediate, which belongs to the field of organic synthesis, and in particular to a method for synthesizing 2,4-difluoroaniline, a drug intermediate of difluoroben salicylic acid. Background technique [0002] 2,4-Difluoroaniline is an intermediate in organic synthesis, and it is used in the synthesis of difluben salicylic acid and polyfluxalic acid in medicine. Flubenyl salicylic acid is a carboxylic acid non-steroidal anti-inflammatory drug. This new derivative of salicylic acid does not contain the acetyl group of aspirin but contains difluorophenyl group, so the side effects of anti-platelet are small, and the gastrointestinal tract reaction It is mild, and the action time can be maintained for 8-12 hours. It is the most promising variety among salicylic acid drugs. At present, m-phenylenediamine is mostly used in the pharmaceutical industry through diazotization, replacement, nitr...

Claims

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Application Information

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IPC IPC(8): C07C209/36C07C211/52
CPCC07C209/365C07C211/52
Inventor 关艮安
Owner CHENGDU QIANYE LONGHUA PETROLEUM ENG TECH CONSULTING
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