Synthetic method of medical intermediate 2, 4-difluorobenzoic acid

A technology of difluorobenzoic acid and a synthesis method, which is applied in the field of synthesis of a pharmaceutical intermediate 2,4-difluorobenzoic acid, can solve the problems of complicated steps, difficult operation, low product yield and the like, and achieves low equipment requirements and stable performance. The effect of good performance and simple process

Inactive Publication Date: 2018-04-24
SUZHOU GAIDE FINE MATERIALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] 2,4-Difluorobenzoic acid is an important intermediate of the antifungal drug fluconazole. Its current synthesis method is from m-dinitrobenzene as raw material, through reduction, diazotization, fluorination, acetylation, oxidation, etc. Reaction steps to complete, the method steps are numerous and complicated, the operation is difficult, and the production method has high requirements on equipment, which greatly increases the preparation cost
However, 2,4-dinitrotoluene is oxidized and explosive at high temperature, and it is also easy to decarboxylate at high temperature, and the product yield is low

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] A kind of synthetic method of pharmaceutical intermediate 2,4-difluorobenzoic acid, comprises the following steps:

[0021] (1) Mix and stir absolute ethanol and cetyltrimethylammonium chloride evenly, then add Pd, then transfer to a three-necked flask, add ethyl orthosilicate and triethylamine dropwise, and heat up after the dropwise addition to 60°C, reflux and stir at constant temperature for 15 hours, cool to room temperature after the reaction, filter the reaction system, dry the obtained solid and put it into a crucible, and place the crucible in a muffle furnace at 550°C for 1 hour, after the treatment, follow The furnace is cooled to room temperature and ground to obtain a catalyst; wherein, the mass ratio of absolute ethanol, cetyltrimethylammonium chloride, and Pd is 20:0.5:1; Pd, ethyl orthosilicate, and triethylamine The dosage ratio is 1g: 1mL: 7mL;

[0022] (2) Add ammonium chloride and absolute ethanol to the four-necked flask in turn, stir and mix evenl...

Embodiment 2

[0026] A kind of synthetic method of pharmaceutical intermediate 2,4-difluorobenzoic acid, comprises the following steps:

[0027] (1) Mix and stir absolute ethanol and cetyltrimethylammonium chloride evenly, then add Pd, then transfer to a three-necked flask, add ethyl orthosilicate and triethylamine dropwise, and heat up after the dropwise addition to 90°C, reflux and stir at constant temperature for 5 hours, cool to room temperature after the reaction, filter the reaction system, dry the obtained solid and add it to a crucible, and place the crucible in a muffle furnace at 550°C for 4 hours. The furnace is cooled to room temperature and ground to obtain a catalyst; wherein, the mass ratio of absolute ethanol, cetyltrimethylammonium chloride, and Pd is 20:0.5:3; Pd, ethyl orthosilicate, and triethylamine The dosage ratio is 1g: 5mL: 7mL;

[0028] (2) Add ammonium chloride and absolute ethanol to the four-necked flask in turn, stir and mix evenly, then add 2,4-dinitrotoluene...

Embodiment 3

[0032] A kind of synthetic method of pharmaceutical intermediate 2,4-difluorobenzoic acid, comprises the following steps:

[0033] (1) Mix and stir absolute ethanol and cetyltrimethylammonium chloride evenly, then add Pd, then transfer to a three-necked flask, add ethyl orthosilicate and triethylamine dropwise, and heat up after the dropwise addition to 65°C, reflux and stir at constant temperature for 13 hours, cool to room temperature after the reaction, filter the reaction system, dry the obtained solid and put it into a crucible, and place the crucible in a muffle furnace at 550°C for 2 hours, after the treatment, follow The furnace is cooled to room temperature and ground to obtain a catalyst; wherein, the mass ratio of absolute ethanol, cetyltrimethylammonium chloride, and Pd is 20:0.5:1.5; Pd, ethyl orthosilicate, and triethylamine The dosage ratio is 1g: 2mL: 7mL;

[0034](2) Add ammonium chloride and absolute ethanol to the four-necked flask in turn, stir and mix eve...

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PUM

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Abstract

The invention discloses a synthetic method of medical intermediate 2, 4-difluorobenzoic acid. The synthetic method specifically includes following steps: adopting a sol-gel method to prepare nano silicon oxide loaded Pd as a catalyst; adding cetyl trimethyl ammonium chloride to perform in-situ modification on the surface of the catalyst in the process of preparation; adding ammonium chloride and the prepared catalyst into the raw material, namely 2, 4-dinitrotoluene, for reaction, collecting filtrate, and adding tetrabutylammonium bromide, manganese dioxide and hydrogen peroxide for reaction to obtain white solid; allowing N, N-dimethyl formamide, sodium fluoride, white solid and tetrabutylammonium bromide for reaction to obtain 2, 4-difluorobenzoic acid. The synthetic method is simple tooperate and high in target product yield.

Description

Technical field: [0001] The invention relates to the field of preparation of pharmaceutical intermediates, in particular to a method for synthesizing the pharmaceutical intermediate 2,4-difluorobenzoic acid. Background technique: [0002] 2,4-Difluorobenzoic acid is an important intermediate of the antifungal drug fluconazole. Its current synthesis method is from m-dinitrobenzene as raw material, through reduction, diazotization, fluorination, acetylation, oxidation, etc. Reaction steps to complete, the method steps are numerous and complicated, the operation is difficult, and the production method has high requirements on equipment, which greatly increases the preparation cost. [0003] Patent 201410705773.X discloses a preparation method of 2,4-difluorobenzoic acid, which uses 2,4-dinitrotoluene as a raw material to prepare the pharmaceutical intermediate 2,4-difluorobenzoic acid through oxidation and fluorination. Potassium permanganate is used as an oxidizing agent, and...

Claims

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Application Information

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IPC IPC(8): C07C51/363C07C63/70B01J23/44
CPCC07C51/363B01J23/44C07C209/36C07C227/02C07C63/70C07C229/60C07C211/51
Inventor李晓明
OwnerSUZHOU GAIDE FINE MATERIALS CO LTD