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Preparation method of pyrazole derivative

A technology of pyrazole derivatives and derivatives, applied in hydrazone preparation, organic chemistry, etc., can solve the problems of low yield, harsh reaction conditions, inconvenient operation, etc., and achieve ordinary reaction conditions, high reaction yield and high product quality high effect

Active Publication Date: 2018-02-06
SUQIAN KEYLAB BIOCHEMICAL CO LTD
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Problems solved by technology

Although there are certain advantages in cost control, the reaction conditions are relatively harsh, in which dichloroacetyl chloride and vinyl ether compounds need to react at -40~-20°C; The temperature is 150°C, and the pressure in the kettle must be constantly changed during the process, which is inconvenient to operate, and the isomers are not easy to separate; 2) WO2009000442 reported that ethyl difluoroacetate was used as a raw material to react with hydrazine hydrate to form hydrazide, which was methylated and then 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (DFMMP) is obtained by ring closure with ethyl propiolate, the yield of this method is not high, and ethyl propiolate Esters are more expensive and not suitable for industrial production

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  • Preparation method of pyrazole derivative
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preparation example Construction

[0068] One, the preparation method of the intermediate compound shown in formula IV of the present invention, concrete steps are as follows:

[0069] First, the p-substituted phenyl derivative shown in formula I reacts with the hydrazine compound shown in formula II to generate the hydrazone compound shown in formula III,

[0070] ,

[0071] in,

[0072] R 1 for OR A or NR B R C , where R A C1~C8 alkyl, R B C1~C8 alkyl, R C is C1~C8 alkyl; R 6 is a hydrogen atom or a C1-C8 alkyl group, R 7 It is a C1-C8 alkyl group.

[0073] R 6 When it is a hydrogen atom, the para-substituted phenyl derivative shown in formula I is a para-substituted benzaldehyde derivative; R 6 When it is an alkyl group, the para-substituted phenyl derivative shown in formula I is a para-substituted phenyl alkyl ketone derivative.

[0074] Then by one of the following three methods (preferably the third method), the intermediate compound shown in formula IV is synthesized.

[0075] ,

[0...

Embodiment 1

[0097] The synthesized pyrazole derivative was 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA).

[0098] The preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of the present embodiment comprises the following steps:

[0099] Step 1. Synthesis of fluorine-containing intermediate compound (VI).

[0100] In the three-necked round bottom flask, add the intermediate compound (Ⅳ, R 1 for -N(CH 3 ) 2 , R 6 is a hydrogen atom, R 2 for-OC 2 h 5 ) 275g, (1.0 mol) and dichloromethane 1375ml, under the protection of nitrogen, the temperature was lowered to 5°C, and 108g, (1.1 mol) of difluoroacetyl fluoride gas was introduced. During the ventilation process, the temperature of the system was kept below 30°C, and three After passing through 110 grams of 1.08 (mol) ethylamine, it was incubated and stirred for 2 hours to obtain a methylene chloride solution of the fluorine-containing intermediate compound (VI). The gas phase purity was gr...

Embodiment 2

[0109] The synthesized pyrazole derivative was 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (DFPA).

[0110] The preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of the present embodiment comprises the following steps:

[0111] Step 1. Synthesis of fluorine-containing intermediate compound (VI).

[0112] In the three-necked round bottom flask, add the intermediate compound (Ⅳ, R 1 for -N(CH 3 ) 2 , R 6 is a hydrogen atom, R 2 for -CH 3 ) 245g, (1.0 mol) and dichloromethane 1375ml, under the protection of nitrogen, the temperature was lowered to 5°C, and 108g, (1.1 mol) of difluoroacetyl fluoride gas was introduced. During the ventilation process, the temperature of the system was kept below 20°C, and three Ethylamine 110 grams, heat preservation and stirring for 2 hours after passing through to obtain a dichloromethane solution of the fluorine-containing intermediate compound (VI), the gas phase purity is greater than 95%, and ...

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Abstract

The invention relates to a preparation method of a pyrazole derivative. An intermediate compound shown in formula IV and a fluoro-acetic halide derivative shown in formula V react to produce a fluorine-containing intermediate compound shown in formula VI, the fluorine-containing intermediate compound shown in formula VI is hydrolyzed under the action of acid and subjected to pyrazole ring closingto produce 3-fluoroalkyl-1-methyl pyrazole derivative shown in formula VII, and the 3-fluoroalkyl-1-methyl pyrazole derivative shown in formula VII reacts and then is acidized under the alkaline condition to produce 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid shown in formula VIII. The invention also relates to a structure of the intermediate compound of the pyrazole derivative obtained with the preparation method. The preparation method of the pyrazole derivative is suitable for industrial production.

Description

technical field [0001] The invention relates to an industrial synthesis method of pyrazole derivatives, belonging to the technical field of chemical synthesis. Background technique [0002] Substituted pyrazole derivatives, especially fluorine-containing pyrazole derivatives are intermediates of many medicines or pesticides. Among these fluorine-containing pyrazole derivatives, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid is an important pesticide intermediate, and plays a very important role as an intermediate in many new pesticide varieties , such as the cereal fungicide Bixafen (Bixafen) launched by Bayer CropScience, the new fungicide Fluxapyroxad (Fluxapyroxad) launched by BASF, the pyrazapyrazam (Isopyrazam) launched by Syngenta, Fluxapyrox Sedaxane, etc. [0003] [0004] Since 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is a key intermediate for the synthesis of the above-mentioned novel fungicides of amides, the research on its synthesis pr...

Claims

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Application Information

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IPC IPC(8): C07D231/14C07C249/16C07C251/86
CPCC07C249/16C07C251/86C07D231/14
Inventor 王明春李庆毅罗治斌
Owner SUQIAN KEYLAB BIOCHEMICAL CO LTD
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