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A kind of preparation method of 4-bromo-1-methyl-2-(trifluoromethyl)benzene

A technology of aminotrifluorotoluene and trifluoromethyl, which is applied in the field of preparation of 4-bromo-1-methyl-2-benzene, can solve the problems such as the inability to meet the high-purity requirements of pharmaceutical intermediates

Active Publication Date: 2020-09-22
KINGCHEM LIAONING CHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the 4-bromo-1-methyl-2-(trifluoromethyl)benzene prepared by this method contains 2% isomer impurities, which cannot meet the high purity requirements of pharmaceutical intermediates

Method used

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  • A kind of preparation method of 4-bromo-1-methyl-2-(trifluoromethyl)benzene
  • A kind of preparation method of 4-bromo-1-methyl-2-(trifluoromethyl)benzene
  • A kind of preparation method of 4-bromo-1-methyl-2-(trifluoromethyl)benzene

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preparation example Construction

[0029] The invention provides a kind of preparation method of 4-bromo-1-methyl-2-(trifluoromethyl)benzene, comprising the following steps:

[0030] (1) Under an inert atmosphere, after mixing 2-methyl-5-aminobenzotrifluoride, aqueous hydrogen bromide, water and acetic acid, carry out a salt-forming reaction to obtain the bromine of 2-methyl-5-aminobenzotrifluoride Hydrogen salt;

[0031] (2) carry out diazotization reaction after the hydrogen bromide salt of described 2-methyl-5-aminobenzotrifluoride and sodium nitrite aqueous solution are mixed, obtain the diazonium of 2-methyl-5-aminobenzotrifluoride Salt;

[0032] (3) After mixing the diazonium salt of the 2-methyl-5-aminobenzotrifluoride, cuprous bromide and hydrogen bromide aqueous solution, carry out the Sandmeyer reaction to obtain 4-bromo-1-methyl- 2-(Trifluoromethyl)benzene.

[0033] In the present invention, all raw materials used in the preparation process can be commercially available products well known to thos...

Embodiment 1

[0058] Under nitrogen protection, add 50.1g48% hydrogen bromide aqueous solution, 33.4g water and 16.7g glacial acetic acid (pure acetic acid) at room temperature, stir, and dropwise add 16.7g2-methyl-5-aminotrifluorotoluene ( The isomer accounts for 0.037%, and the gas phase area is normalized), after the dropwise addition is completed, the temperature is raised to 93° C. and stirred for 30 minutes to obtain a hydrogen bromide salt solution.

[0059] Cool down to 3°C, a large amount of solids precipitated into a suspension, and 23.0g of 30% sodium nitrite aqueous solution was added dropwise to the suspension at 3°C. After the addition was complete, react at 3°C ​​for 1.0h to obtain a diazonium salt solution.

[0060] The prepared diazonium salt solution was added dropwise to 6.8g of cuprous bromide and 94.8g of 48% hydrogen bromide aqueous solution prepared in advance at 66°C, a large amount of nitrogen gas was released, after the dropwise addition was completed, it was stirre...

Embodiment 2

[0065] Under nitrogen protection, add 2642.3g48% hydrogen bromide aqueous solution at room temperature, 1760.0g water and 880.0g acetic acid, stir, and dropwise add 880.0g2-methyl-5-amino-trifluorotoluene (isomer accounts for 0.037 %, normalized gas phase area), after the dropwise addition was completed, the temperature was raised to 95° C. and stirred for 30 min to obtain a hydrogen bromide salt solution.

[0066] Cool down to 0°C, and add 1213.3g of 30% sodium nitrite aqueous solution dropwise at 0°C, and react for 1.0h after the dropwise addition. The prepared diazonium salt was added dropwise to 360.4g of cuprous bromide and 4997.0g of 48% aqueous hydrogen bromide solution prepared in advance at 65°C, a large amount of nitrogen gas was released, and the dropwise addition was completed and stirred for 1 hour to obtain 4-bromo-1 -Methyl-2-(trifluoromethyl)benzene solution.

[0067] After the reaction, cool down to 20°C and stir for 1.0h, let stand, separate layers, add 1046...

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Abstract

The invention provides a preparation method of 4-bromo-1-methyl-2-(trifluoromethyl) benzene. A special preparation process is adopted, 2-methyl-5-aminotrifluorotoluene is used as a raw material, hydrobromic acid is used for carrying out salifying on the 2-methyl-5-aminotrifluorotoluene at first, then nitrite is used as a diazo reagent for diazotization, finally, bromination is carried out under catalyzing of cuprous bromide, and by special process setting, the high-purity 4-bromo-1-methyl-2-(trifluoromethyl) benzene can be obtained successfully. From results of an embodiment, the content of isomer of the 4-bromo-1-methyl-2-(trifluoromethyl) benzene obtained by the preparation method is lower than 0.1%.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4-bromo-1-methyl-2-(trifluoromethyl)benzene. Background technique [0002] 4-Bromo-1-methyl-2-(trifluoromethyl)benzene is an important pharmaceutical intermediate for the synthesis of GlyT1 inhibitors, the potent CRTh2 receptor antagonist Fevipiprant (NVP-QAW039) for the treatment of asthma and chemotaxis Factor receptor antagonists for the treatment of pain, etc. [0003] In the prior art, Japanese Patent JPH09263549A reports the synthesis of 4-bromo-1-methyl-2-(trifluoromethyl)benzene, and its synthetic route is: [0004] [0005] The method uses 1-methyl-2-(trifluoromethyl)benzene as a raw material, bromine bromination, and Na-X type zeolite as a catalyst. However, the 4-bromo-1-methyl-2-(trifluoromethyl)benzene prepared by this method contains 2% isomer impurities, which cannot meet the high purity requirements of pharmaceutical intermed...

Claims

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Application Information

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IPC IPC(8): C07C17/093C07C25/02
CPCC07C17/093C07C209/00C07C245/20C07C25/02C07C211/52
Inventor 王彦明王永灿秦龙宋桐集陈碧微
Owner KINGCHEM LIAONING CHEMICAL CO LTD
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