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

A technology of difluoromethyl and pyrazole carboxylic acid, which is applied in the field of synthesis of fine chemical intermediates, can solve the problems of high industrialization cost, long route, and high price, and achieve the effects of low synthesis cost, high yield, and low raw material cost

Active Publication Date: 2016-01-06
JIANGSU HERUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 2. CN103570623 (Hunan Chemical Industry Research Institute), CN200880022057.4 (Syngenta) and US7358387 (Bayer) use N,N-dimethylaminoethyl acrylate as raw material, first react with difluoroacetyl chloride to generate 2-difluoroacetyl Base-3-(dimethylamino)ethyl acrylate, then cyclized with hydrazine hydrate, methylated with dimethyl sulfate, and finally hydrolyzed to obtain 1-methyl-3-difluoromethyl-4-pyrazolecarboxylic acid , the total reaction yield is 54.6%, the route is longer, and the industrialization cost is high
The disadvantage of this route is the use of highly toxic and expensive difluoroacetyl chloride

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Step 1: Synthesis of ethyl 2-dichloroacetyl-3-(dimethylamino)acrylate (IV)

[0063] Put 100.12g of ethyl dichloroacetoacetate and 400g of toluene into a 2L reaction bottle, cool down to 0-10°C, add 20.56g of 60% sodium hydride in batches, control the internal temperature to less than 50°C, and keep for 1 hour after the addition ; Cool to 0-10°C, add 69.5g of [(CH 3 ) 2 N + =CHCl]Cl -

[0064] Soluble in 300g toluene solution. The reaction was maintained at 15-25°C for 2 hours. Pour the reaction material into ice water for quenching, and let stand to separate the toluene layer. After removing about 100 g of the solvent from the toluene layer under reduced pressure, 800 g of a toluene solution of ethyl 2-dichloroacetyl-3-(dimethylamino)acrylate (IV) was obtained (the nominal content was 13.40%, and the yield was 85%) ), used directly in the next step.

[0065] [(CH 3 ) 2 N + =CHCl]Cl - Prepare according to the following method: put 26.50g DMF and 300g toluene ...

Embodiment 2

[0080] Step 1: Synthesis of ethyl 2-dichloroacetyl-3-(dimethylamino)acrylate (IV)

[0081] In a 2L reaction flask, put 100g of ethyl dichloroacetoacetate and 400g of dichloromethane, cool down to 0-10°C, add 135g of [(CH3)2N + =CHCl][PO 2 Cl 2 ] - Dissolved in 300g dichloromethane solution. At 15-25°C, keep the reaction for 2 hours; slowly add 80g triethylamine dropwise at 0-5°C for about 1 hour; react at room temperature for 2 hours, add water and stir, separate the dichloromethane layer; Dissolved to obtain 135 g of crude product of ethyl 2-dichloroacetyl-3-(dimethylamino)acrylate (IV), which was directly used in the next step.

[0082] [(CH 3 ) 2 N + =CHCl][PO 2 Cl 2 ] - Prepare according to the following method: put 60.50g DMF and 300g dichloromethane into a 1L reaction bottle; stir and cool down to 0-10°C, add 85.55g phosphorus trichloride dropwise for about half an hour, and control the temperature 0-5 ℃, continue to stir for half an hour and set aside.

[00...

Embodiment 3

[0090] Step 1: Synthesis of ethyl 2-dichloroacetyl-3-(dimethylamino)acrylate (IV)

[0091] In a 2L reaction flask, put 100g of ethyl dichloroacetoacetate and 400g of methylene chloride into it, cool down to 0-10°C, add 135g of [(CH 3 ) 2 N + =CHCl][PO 2 Cl 2 ]- Dissolve in 300g toluene solution; slowly add 80g triethylamine dropwise at 0-5°C for about 1 hour; react at room temperature for 2 hours, add water and stir, separate the dichloromethane layer; desolvate under reduced pressure to obtain 2-dichloro The crude product of ethyl acetyl-3-(dimethylamino)acrylate (IV) was 150 g, the nominal yield was 76%, and it was directly used in the next step.

[0092] Step 2: Synthesis of ethyl 1-methyl-3-dichloromethyl-4-pyrazolecarboxylate (V)

[0093] In a 2L reaction flask, put 106.50g of 2-dichloroacetyl-3-(dimethylamino)ethyl acrylate (IV) and 400g of toluene, cool down to -60°C under nitrogen protection, and drop 19.62g of formazan Hydrazine (dissolved in 100 g of toluene); ...

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Abstract

The invention discloses a synthesis method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, and relates to the synthesis method of the fine chemical intermediate. The method includes the following four steps: step 1, with dichloro ethyl acetoacetate as a raw material, and under the action of an alkali, carrying out a reaction with a Vilsmeier reagent to obtain an intermediate (IV); step 2, carrying out a cyclization reaction of the intermediate (IV) and methyl hydrazine to obtain 1-methyl-3-dichloromethyl-ethyl-4-pyrazole carboxylate (V); step 3, carrying out a halogen exchange reaction of the intermediate (V) with a fluorination reagent to obtain 3-(difluoromethyl)-1-methyl-1H-ethyl-4-pyrazole carboxylate (VI); and step 4, carrying out a hydrolysis reaction of the intermediate (VI) obtained in the step 3 with a sodium hydroxide solution, then carrying out neutralization treatment with an acid to obtain high-purity 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (I). The method has the advantages of easily bought raw materials, low price, simple preparation method, mild reaction conditions and low requirements on equipment, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a synthesis method of a fine chemical intermediate, in particular to a synthesis method of 1-methyl-3-difluoromethyl-4-pyrazolecarboxylic acid. Background technique [0002] 1-methyl-3-difluoromethyl-4-pyrazolecarboxylic acid (as shown in formula (I)), English name is 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid; Molecular weight is 176.12; CAS: 176969-34-9; the structural formula is shown in formula I: [0003] [0004] The compound is fungicides sedaxane, isopyrazam, benzovindiflupyr, bixafen and fluxapyroxad, etc. The key intermediate of the original drug. Fluorine-containing pyrazole carboxamide fungicides are a new type of fungicides developed in recent years. They have been marketed in droves with a strong momentum, and have become a new hot spot in the research and development of fungicides. For example, Sumitomo Chemical Co., Ltd. discloses a new fungicide under research in WO2013186325A1, its structu...

Claims

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Application Information

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IPC IPC(8): C07D231/14
CPCC07D231/14
Inventor 高德华李安排刘建树孙磊吴正华顾兴华顾爱红史荣先
Owner JIANGSU HERUN PHARMA CO LTD
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