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

A technology of difluoromethyl and dimethylamino groups, which is applied in the field of preparation of 3--1-methyl-1H-pyrazole-4-carboxylic acid, and can solve problems such as cumbersome operation

Active Publication Date: 2020-07-03
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

[0004] Currently existing synthetic methods such as the patent [US2011040096A1] adopt cyclization to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, but the proportion of its isomers is relatively large The chemical purity is 89:10, and the chemical purity is even less than 90%. Too many times of recrystallization are required, and the operation is relatively cumbersome to obtain a product with a chemical purity greater than 99.5%, and the yield is less than 75%.

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

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Experimental program
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Effect test

Embodiment 1

[0033]

[0034] Under nitrogen protection, put 393g (2.5mol, 1eq) of N,N-dimethylaminoisopropyl acrylate, 303.6g (3.0mol, 1.2eq) of triethylamine and 3000mL of 1,4-dioxane into the reaction bottle . Control the reaction temperature at -10-5°C, slowly add 235.3g (2.4mol, 0.96eq) of 2,2-difluoroacetyl fluoride dropwise, react at -5-5°C for 1 hour after the addition, and detect the raw materials by GC <0.5%, quenched by adding 500g of water, standing for stratification, cooling the organic phase to -5-5°C, adding 1000g of 10% NaOH aqueous solution dropwise, reacting at -5-5°C for 1 hour after the dropwise addition, and obtaining The mixed solution of sodium 2-difluoroacetyl-3-(dimethylamino)acrylate was stored under nitrogen at 5-5°C until use.

[0035]

[0036] Under the protection of nitrogen, add 187.4g (1.25mol, 0.5eq) of sodium iodide to the above mixed solution of sodium 2-difluoroacetyl-3-(dimethylamino)acrylate, cool the reaction solution to -30°C, add dropwise 40...

Embodiment 2

[0038]

[0039] Under nitrogen protection, put 428.1g (2.5mol, 1eq) of N,N-dimethylaminoacrylate tert-butyl ester, 355.4g (2.75mol, 1.1eq) of N,N-diisopropylethylamine and di Chloromethane 3500mL. Control the reaction temperature at -10-5°C, slowly add 280.5g (2.45mol, 0.98eq) of 2,2-difluoroacetyl chloride dropwise, and react at -5-5°C for 1 hour after the addition, the raw material is detected by GC < 0.5%, quenched by adding 500g of water, standing to separate layers. Cool the organic phase to -5-5°C, add 700g of 20% KOH aqueous solution dropwise, react at -5-5°C for 1 hour after the dropwise addition, and obtain 2-difluoroacetyl-3-(dimethylamino) after filtration Potassium acrylate mixed solution, and stored under nitrogen at 5-5 ° C until use.

[0040]

[0041]Under the protection of nitrogen, 249g (1.5mol, 0.6eq) of potassium iodide was added to the above mixed solution of potassium 2-difluoroacetyl-3-(dimethylamino)acrylate, the temperature of the reaction solut...

Embodiment 3

[0043]

[0044] Under nitrogen protection, 393g (2.5mol, 1eq) of N,N-methyl diethylaminoacrylate, 303.6g (3mol, 1.2eq) of triethylamine and 3500mL of tetrahydrofuran were put into the reaction flask. Control the reaction temperature at -10-5°C, slowly add 235.3g (2.4mol, 0.96eq) of 2,2-difluoroacetyl fluoride dropwise, react at -5-5°C for 1 hour after the addition, and detect the raw materials by GC <0.5%, quenched by adding 500g of water, and allowed to stand for stratification. Cool the organic phase to -5-5°C, add 1000g of 10% NaOH aqueous solution dropwise, react at -5-5°C for 1 hour after the dropwise addition, and obtain 2-difluoroacetyl-3-(diethylamino) after filtration The sodium acrylate mixed solution was stored under nitrogen at 5-5°C until use.

[0045]

[0046] Under the protection of nitrogen, add 187.4g (1.25mol, 0.5eq) of sodium iodide to the above mixed solution of sodium 2-difluoroacetyl-3-(diethylamino)acrylate, cool the reaction solution to -30°C, ad...

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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: by taking 2, 2-difluoroacetyl halide as a raw material, performing addition with alpha, beta-unsaturated ester, performing alkaline hydrolysis to obtain alpha-difluoroacetyl intermediate carboxylic acid, condensing and cyclizing the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid with a methylhydrazine aqueous solution in the presence of a catalyst to obtain a 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid crude product, and recrystallizing to obtain a pure product of the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The method has the advantages of simple operation, easily available raw materials, high reaction yield, reduction of isomers through a plurality of ways in the reaction process, and convenience in product purification.

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, CAS: 176969-34-9. The English name is 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. With the development of the pesticide industry and the continuous emergence of its compounds, heterocyclic compounds occupy a very important position, among which pyrazole derivatives, as an important category of heterocyclic compounds, play an important role in the field of new drug research and development. The characteristics of high efficiency, low toxicity and structural diversity of the derivatives have aroused people's widespread attention, and many new, high-efficiency, and environmentally friendly pesticide products of pyrazole derivatives have emerged as the times require. [0003] 3-(Difluoromethy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
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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