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Preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid

A technology of difluoromethyl and methyl groups, applied in the field of preparation of 3--1-methyl-1H-pyrazole-4-carboxylic acid, can solve problems such as spending a lot of energy, and achieve the effect of easy operation

Inactive Publication Date: 2020-06-19
徐州圣元化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, isomers are inevitably produced during the cyclization process, and a lot of effort is required for subsequent purification

Method used

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  • Preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
  • Preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
  • Preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0029]

[0030] Under nitrogen protection, 154.3 g (1 mol) of 1-methyl-3-(trimethylsilyl) pyrazole was dissolved in 750 mL of dichloromethane. Cool down to -5-0°C, slowly add 159 g (1 mol) of bromine dropwise, and keep warm to continue the reaction overnight. TLC detects that the reaction is over, add 500mL of water to quench, add dropwise 30% sodium hydroxide aqueous solution to quench the reaction, and adjust the pH=9-10, then add 80mL of saturated aqueous sodium thiosulfate solution, let stand to separate layers, and concentrate the organic phase. Add 300 mL of n-heptane to obtain 208.3 g of 4-bromo-1-methyl-3-(trimethylsilyl)pyrazole, GC: 95.9%, yield 89.3%. 1 HNMR (400MHz, CDCl3) δ: 7.44(s, 1H), 3.95(s, 3H), 0.29(s, 9H).

Embodiment 2

[0032]

[0033] Under nitrogen protection, 154.3 g (1 mol) of 1-methyl-3-(trimethylsilyl) pyrazole was dissolved in 600 mL of dichloromethane. The temperature was lowered to -50°C, and 251.2 g (1 mol) of iodine was added in batches. After the addition was complete, the reaction was incubated for 5 hours. TLC detects that the reaction is over, adding 500mL of water to quench, standing for stratification, adding saturated aqueous sodium bisulfite to the organic phase for washing, concentrating the organic phase, adding 300mL of n-heptane to obtain 4-iodo-1-methyl-3- (Trimethylsilyl)pyrazole 238.4g, GC: 94.9%, yield 85.1%. 1 HNMR (400MHz, CDCl3): 7.47(s, 1H), 3.97(s, 3H), 0.30(s, 9H).

Embodiment 3

[0035]

[0036] Under nitrogen protection, 200 g (0.858 mol) of 4-bromo-1-methyl-3-(trimethylsilyl) pyrazole was dissolved in 600 mL 2-methyltetrahydrofuran. Cool down to -5°C, control the temperature range at -5-5°C and slowly add 726mL of 1.3M isopropylmagnesium chloride-lithium chloride in 2-methyltetrahydrofuran solution dropwise, and then raise the temperature to 5-10°C to react for 30 minutes , lower the temperature to -35°C, add 139.6 g of ethyl chloroformate dropwise, react at -35°C to -25°C for 1 hour after the dropwise addition, slowly raise the temperature to 10°C, add saturated ammonium chloride aqueous solution to quench, and separate layers. Extract the water layer with 400mL of 2-methyltetrahydrofuran, combine the organic phases, heat up to 35°C, add 1.25eq of 20% sodium hydroxide aqueous solution dropwise for hydrolysis, TLC detects that the hydrolysis is complete, let stand to separate the layers, keep the water phase, and cool down the water phase to 0°C, ...

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Abstract

The invention discloses a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, and belongs to the field of pesticide organic synthesis. The preparation method comprises thefollowing steps: step 1, enabling 1-methyl-3-(trimethylsilyl) pyrazole to react with halogen to obtain 4-halogen-1-methyl-3-(trimethylsilyl) pyrazole; step 2, after exchange is conducted through a Grignard reagent, enabling the 4-halogen-1-methyl-3-(trimethylsilyl) pyrazole to react with chloroformate to obtain 1-methyl-3-trimethylsilyl-1H-pyrazole-4-carboxylic acid; step 3, then carrying out a heating reaction with bromine, so as to obtain 3-bromo-1-methyl-1H-pyrazole-4-carboxylic acid; and step 4, finally, carrying out heating coupling on the 3-bromo-1-methyl-1H-pyrazole-4-carboxylic acid and difluoromethylboronic acid by adopting a palladium catalyst, and performing recrystallization to obtain the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The invention provides a new synthesis path for the synthesis of the compound, and has a potential industrial method prospect.

Description

technical field [0001] The invention relates to a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, belonging to the technical field of pesticide organic synthesis. Background technique [0002] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, English name 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, CAS: 176969-34 -9. It is the parent structure of difluoropyrazole carboxamides (pesticides), an important class of pharmaceutical and fine chemical intermediates, and can be used in the synthesis of various fine chemicals and drugs. [0003] In recent years, the application of difluoromethyl-substituted compounds in medicine and pesticides has attracted extensive attention, and difluoromethyl substituents can significantly improve the biological activity of organic compounds than trifluoromethyl substituents. This is because the difluoromethyl substituent not only exhibits the simulation effect, electronic effect, penetrat...

Claims

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Application Information

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IPC IPC(8): C07D231/14
CPCC07D231/14
Inventor 陈红於万里
Owner 徐州圣元化工有限公司
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