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

Abstract

The invention discloses a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, which comprises the following steps: mixing a methylhydrazine aqueous solution, an organic base catalyst and a solvent, adding 2-(difluoroacetyl)-3-(dimethylamino) ethyl acrylate, reacting at the temperature of-20 DEG C to 20 DEG C, filtering, washing and drying to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester. And carrying out a reaction to obtain the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester. The preparation method disclosed by the invention has the advantages of high conversion rate, high product yield, low isomer content, simplicity in operation and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical product synthesis and relates to a method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. Background Art

[0002] Ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is an intermediate for the synthesis of succinate dehydrogenase inhibitor (SDHI) fungicides. The main SDHI fungicides include fluopicolide, bixafen, fluopicolide, pyraclostrobin, fluopicolide, etc. This type of fungicide has a novel mechanism of action, strong efficacy, low toxicity, long-lasting action, significant yield-increasing effect, high market sales share, and broad market prospects.

[0003] The synthetic route of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is:

[0004]

[0005] Patent document CN1871204A discloses a method for preparing 3-dihalomethylpyrazole-4-carboxylate, which is prepared by cyclization, washing, extraction and rectification of 2-dihaloacyl-3-dimethylamino ethyl acrylate and a hydrazine derivative (especially methyl hydrazine). The method generates a high content of isomer 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, and the amount of isomers cannot be well controlled after reaction at -20°C, the reaction conversion rate is low and the reaction conditions are harsh.

[0006] Patent document JP2013006778A discloses a method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, which is generated by cyclization of ethyl 2-(difluoroacetyl)-3-(dimethylamino)acrylate with methylhydrazine aqueous solution, and a water-soluble inorganic base, preferably sodium hydroxide and potassium hydroxide, is used as a catalyst to suppress the generation of isomer 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. However, the presence of metal hydroxide can cause the product and raw material 2-(difluoroacetyl)-3-(dimethylamino)acrylate to be hydrolyzed, and the lower the isomer control and the greater the amount of alkali, the greater the amount of hydrolysis, and the lower the yield. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate which has simple operation, high conversion rate, high product yield and low isomer content.

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] A preparation method of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate comprises the following steps: mixing a methylhydrazine aqueous solution, an organic base catalyst and a solvent, adding ethyl 2-(difluoroacetyl)-3-(dimethylamino)acrylate, and reacting at -20°C to 20°C to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0010] In the above-mentioned method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, preferably, the organic base catalyst is a sterically hindered organic base catalyst, and the sterically hindered organic base catalyst is one or more of DBU, DBN, TBD and MTBD;

[0011] The chemical structural formulas of DBU, DBN, TBD and MTBD are as follows:

[0012]

[0013] In the above-mentioned method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, preferably, the mass of the organic base catalyst is 0.5% to 2% of the mass of the ethyl 2-(difluoroacetyl)-3-(dimethylamino)acrylate.

[0014] In the above-mentioned method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, preferably, the molar ratio of the ethyl 2-(difluoroacetyl)-3-(dimethylamino)acrylate to the methylhydrazine is 1:1.0-1.5, and the mass fraction of the methylhydrazine aqueous solution is 40%.

[0015] In the above-mentioned method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, preferably, the mass ratio of the ethyl 2-(difluoroacetyl)-3-(dimethylamino)acrylate to the solvent is 1:2-5.

[0016] In the above-mentioned method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, preferably, the ethyl 2-(difluoroacetyl)-3-(dimethylamino)acrylate is added dropwise, the dropping time is 0.5h to 5h, and the temperature is kept for 30min to 60min after the dropping is completed.

[0017] In the above-mentioned method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, preferably, the solvent is one or more of benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform, 1,2-dichloroethane and 1,1,2-trichloroethane.

[0018] In the above-mentioned method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, preferably, after the reaction is completed, post-treatment is performed, and the post-treatment includes water washing and stratification, reaction solvent extraction, reduced pressure concentration and vacuum drying.

[0019] In the above-mentioned method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, preferably, the mass fraction of the product ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate: the mass fraction of the isomer ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is 94.5% to 98.0%: 4.5% to 1.5%, and the total yield of the product and the isomer is greater than 97%.

[0020] Compared with the prior art, the advantages of the present invention are:

[0021] (1) The present invention adopts an organic base to catalyze the cyclization reaction. During the cyclization process, the organic base first reacts with 2-(difluoroacetyl)-3-(dimethylamino)ethyl acrylate to form a large steric hindrance group, which inhibits the leaving group from preferentially participating in the reaction, thereby inhibiting the formation of isomers. This method has obvious advantages over metal hydroxide in controlling isomers. The isomer control is low, and the decomposition of products and raw materials during the reaction process can be avoided.

[0022] (2) The organic base selected by the present invention has a unique structure and has a highly efficient catalytic effect, which can effectively increase the reaction rate and the total conversion rate of the product plus isomers. DETAILED DESCRIPTION

[0023] The present invention is further described below in conjunction with specific preferred embodiments, but the protection scope of the present invention is not limited thereby. The materials and instruments used in the following embodiments are all commercially available, wherein the catalysts DBU, DBN, TBD, and MTBD are all purchased from Aladdin Biochemical Technology Co., Ltd. The chemical structural formulas of DBU, DBN, TBD, and MTBD are as follows:

[0024]

[0025] Example 1

[0026] A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate of the present invention comprises the following steps:

[0027] 25.3g 40wt% methylhydrazine aqueous solution (0.22mol methylhydrazine) and 180.4g toluene are added to a four-mouth reactor with stirring, a thermometer and a constant pressure dropping funnel, 0.45g of DBU catalyst is added under stirring, stirring is continued, and the temperature in the reactor is controlled to be 0 ℃, 45.1g 2-(difluoroacetyl)-3-(dimethylamino) ethyl acrylate (98%, 0.2mol) is dripped in the reactor, and the addition is completed in 1 hour, and the temperature is kept for half an hour. 20g water is added to the obtained reaction solution for washing and stratification, and reaction solvent is adopted to extract, and the product is 39.78g of white solid 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester obtained through concentrating under reduced pressure and vacuum drying. After testing, the ratio of the mass fraction of the product to the isomer is 97.5%: 2.1%, and the total recovery is 97.1%.

[0028] Example 2

[0029] A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate of the present invention comprises the following steps:

[0030] 34.5g 40wt% methylhydrazine aqueous solution (0.3mol methylhydrazine) and 225.5g dimethylbenzene are added to a four-mouth reaction kettle with stirring, a thermometer and a constant pressure dropping funnel, 0.9g of DBU catalyst is added under stirring, stirring is continued, the temperature in the kettle is controlled to be -5°C, and 45.1g 2-(difluoroacetyl)-3-(dimethylamino)ethyl acrylate (98%, 0.2mol) is added dropwise in the reaction kettle, the addition is completed in 0.5 hour, and the temperature is kept for half an hour. The obtained reaction solution is washed with 20g water, layered, extracted with a reaction solvent, concentrated under reduced pressure, and dried in vacuo to obtain 40.41g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid. The ratio of the mass fraction of the product to the isomer is 98%: 1.5%, and the total yield is 98.5%.

[0031] Example 3

[0032] A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate of the present invention comprises the following steps:

[0033] 23.0g of 40wt% methylhydrazine aqueous solution (0.2mol methylhydrazine) and 90.2g of 1,2-dichloroethane were added to a four-mouth reaction kettle with stirring, thermometer, and constant pressure dropping funnel. 0.45g of catalyst DBN was added under stirring, stirring was continued, and the temperature in the kettle was controlled to be 5°C. 45.1g of 2-(difluoroacetyl)-3-(dimethylamino) ethyl acrylate (98%, 0.2mol) was added dropwise to the reaction kettle. The addition was completed in 1 hour and the temperature was kept for half an hour. The obtained reaction solution was washed with 20g of water, layered, extracted with the reaction solvent, concentrated under reduced pressure, and dried in vacuum to obtain 40.24g of white solid 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester. The mass fraction ratio of the product to the isomer was 94.5%:4%, and the total yield was 97.1%.

[0034] Example 4

[0035] A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate of the present invention comprises the following steps:

[0036] 27.6g 40wt% methylhydrazine aqueous solution (0.24mol methylhydrazine) and 180.4g toluene are added to a four-mouth reaction kettle with stirring, a thermometer and a constant pressure dropping funnel, 0.23g of DBU catalyst is added under stirring, stirring is continued, the temperature in the kettle is controlled to be 20°C, and 45.1g 2-(difluoroacetyl)-3-(dimethylamino) ethyl acrylate (98%, 0.2mol) is added dropwise in the reaction kettle, and the addition is completed in 1 hour, and the temperature is kept for half an hour. The obtained reaction solution is washed with 20g water, layered, extracted with a reaction solvent, concentrated under reduced pressure, and dried in vacuo to obtain 40.0g of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid. The ratio of the mass fraction of the product to the isomer is 95.0%: 4.5%, and the total recovery is 97.5%.

[0037] Example 5

[0038] A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate of the present invention comprises the following steps:

[0039] 25.3g 40wt% methylhydrazine aqueous solution (0.22mol methylhydrazine) and 135.3g chloroform were added to a four-mouth reaction kettle with stirring, thermometer and constant pressure dropping funnel, 0.451g MTBD catalyst was added under stirring, stirring was continued, the temperature in the kettle was controlled to be 10°C, and 45.1g 2-(difluoroacetyl)-3-(dimethylamino) ethyl acrylate (98%, 0.2mol) was added dropwise to the reaction kettle, and the addition was completed in 1 hour, and the temperature was kept for half an hour. The obtained reaction solution was washed with 20g water, layered, extracted with the reaction solvent, concentrated under reduced pressure, and dried in vacuo to obtain 40.2g of white solid 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester. The mass fraction ratio of the product to the isomer was 97.5%: 1.6%, and the total yield was 97.6%. When TBD was used instead of MTBD, the reaction mechanism was the same, and the effect of this embodiment could be achieved.

[0040] The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as above in the preferred embodiment, it is not used to limit the present invention. Any technician familiar with the art can make many possible changes and modifications to the technical solution of the present invention by using the methods and technical contents disclosed above without departing from the spirit and technical solution of the present invention, or modify it into an equivalent embodiment of equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention, still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, characterized in that: The following steps are involved: A methylhydrazine aqueous solution, an organic base catalyst and a solvent are mixed, 2-(difluoroacetyl)-3-(dimethylamino) ethyl acrylate is added, and the reaction is carried out at -20°C to 20°C to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

2. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 1, characterized in that: The organic base catalyst is a sterically hindered organic base catalyst, and the sterically hindered organic base catalyst is one or more of DBU, DBN, TBD and MTBD; The chemical structural formulas of DBU, DBN, TBD and MTBD are as follows:

3. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 2, characterized in that: The mass of the organic base catalyst is 0.5% to 2% of the mass of the 2-(difluoroacetyl)-3-(dimethylamino)ethyl acrylate.

4. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 1, characterized in that: The molar ratio of the 2-(difluoroacetyl)-3-(dimethylamino)ethyl acrylate to the methylhydrazine is 1:1.0-1.5, and the mass fraction of the methylhydrazine aqueous solution is 40%.

5. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to claim 1, characterized in that: The mass ratio of the 2-(difluoroacetyl)-3-(dimethylamino)ethyl acrylate to the solvent is 1:2-5.

6. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to any one of claims 1 to 5, characterized in that: The 2-(difluoroacetyl)-3-(dimethylamino) ethyl acrylate is added dropwise for 0.5 h to 5 h, and the temperature is kept for 30 min to 60 min after the addition is completed.

7. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to any one of claims 1 to 5, characterized in that: The solvent is one or more of benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform, 1,2-dichloroethane and 1,1,2-trichloroethane.

8. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to any one of claims 1 to 5, characterized in that: After the reaction is completed, post-treatment is performed, which includes water washing and layer separation, reaction solvent extraction, reduced pressure concentration and vacuum drying.

9. The method for preparing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate according to any one of claims 1 to 5, characterized in that: The mass fraction of the product 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester: the mass fraction of the isomer 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester is 94.5% to 98.0%: 4.5% to 1.5%, and the total yield of the product and the isomer is greater than 97%.

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