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

A technology of potassium difluoromethyltrifluoroborate and difluoromethyl, which is applied in organic chemistry, products, reagents, etc., can solve the problems of 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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  • 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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024]

[0025] Into a three-necked reaction flask, put 97.1g (1mol, 1.0eq) of N-methyl-3-aminopyrazole, 800mL of water and 500mL of ethanol, and add 129.5g (0.51mol, 0.51eq) of iodine in batches at a controlled temperature of 15-25°C ), 72.9g (0.6mol, 0.6eq) of 28% hydrogen peroxide was added dropwise at 15-25°C. Raise the temperature to 30-35°C, react for 6 hours, sample GC material 1 HNMR (400MHz, CDCl 3 ):7.40(s,1H),5.81(s,2H),3.80(s,3H).

[0026]

[0027] Put 4-iodo-1-methyl-1H-pyrazol-3-amine (100g, 0.45mol) and 6mol / L hydrochloric acid aqueous solution into the reaction bottle, adjust the pH<1, cool down to -5°C, slowly add 40 % sodium nitrite aqueous solution 78.1g, reacted at -5-5°C for 1 hour after the dropwise addition, and transferred to the dropping funnel under nitrogen protection.

[0028] Under the protection of nitrogen, add 73.3g (470.8mmol, 1.05eq) of potassium difluoromethyltrifluoroborate, 4.5g (31.4mmol, 0.07eq) of cuprous oxide and 500mL tetrahyd...

Embodiment 2

[0032]

[0033] Put 97.1g (1mol, 1eq) of 1,3-dimethylpyrazole and 700mL ethanol into the reaction flask, and slowly add bromine 158.4g (0.99mol, 0.99eq) dropwise under stirring at 0-5°C. ℃ drop reaction for 1 hour, sample GC material 1 HNMR (400MHz, CDCl 3 ):7.41(s,1H),5.90(s,2H),3.82(s,3H).

[0034]

[0035]Under the protection of nitrogen, put 100g (568.1mmol) of 4-bromo-1-methyl-1H-pyrazol-3-amine and 6mol / L hydrochloric acid aqueous solution into the reaction flask, adjust the pH1 HNMR (400MHz, CDCl 3 ):7.93(s,1H),6.05(s,1H),3.95(s,3H).

[0036]

[0037] Under nitrogen protection, 95g (0.368mol, 1eq) of 4-iodo-3-difluoromethyl-1-methylpyrazole and 500mL of 2-methyltetrahydrofuran were put into the reaction flask, stirred evenly, and cooled to -5°C. Slowly add 311 mL of i-PrMgCl-LiCl (1.3M, 1.1 eq) in 2-methyltetrahydrofuran solution dropwise, and keep stirring for 2 hours after dropping to obtain a Grignard exchange solution. Sample was quenched and GC detected...

Embodiment 3

[0039]

[0040] Put 97.1g (1mol, 1eq) of 1,3-dimethylpyrazole and 700mL ethanol into the reaction flask, and slowly add bromine 158.4g (0.99mol, 0.99eq) dropwise under stirring at 0-5°C. ℃ drop reaction for 1 hour, sample GC material 1 HNMR (400MHz, CDCl 3 ):7.41(s,1H),5.90(s,2H),3.82(s,3H).

[0041]

[0042] Under the protection of nitrogen, put 100g (568.1mmol) of 4-bromo-1-methyl-1H-pyrazol-3-amine and 6mol / L hydrochloric acid aqueous solution into the reaction flask, adjust the pH1 HNMR (400MHz, CDCl 3 ):7.93(s,1H),6.05(s,1H),3.95(s,3H).

[0043]

[0044] Under the protection of nitrogen, 95g (0.368mol, 1eq) of 4-iodo-3-difluoromethyl-1-methylpyrazole and 500mL tetrahydrofuran were put into the reaction flask, stirred evenly, and cooled to -5°C. Slowly add 337 mL of tetrahydrofuran solution of s-BuMgCl-LiCl (1.2M, 1.1 eq) dropwise, and keep stirring for 2 hours after dropping to obtain a Grignard exchange solution. Sample was quenched and GC detected 1 HNMR (40...

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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 technical field of organic synthesis. The preparation method comprises thefollowing steps: reacting N-methyl-3-aminopyrazole as a raw material with bromine/iodine to replace pyrazole at site 4, then carrying out diazotizing and coupling with potassium difluoromethyl trifluoroborate to obtain 4-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole, then performing Grignard exchange by adopting isopropyl magnesium chloride and the like, and performing reaction with carbon dioxide to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The method is simple and convenient to operate, the total yield of the three steps is as high as 64%, the product purity can reach 99.5% or above, the situation in which isomers exist in a traditional process is avoided, and the method has potential process amplification prospects.

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 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. 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is an important class of pharmaceutical and fine chemical intermediates, which can be used in the synthesis of various fungicides and pesticides, Especially as a key intermediate for the synthesis of new amide fungicides such as fluflufen, bixafen and pyraclofen. [0003] At present, this compound shows more and more application value, and there are many reports on the synthesis of this compound, and its synthesis method usually uses hydrazine or methylhydrazine for cyclization, hydrolysis or oxidation, etc. However, isomers are inevitably generated during...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/14
CPCC07D231/14Y02P20/141
Inventor 陈红於万里
Owner 徐州圣元化工有限公司
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