Preparation method of 1-alkylpyrazole

Abstract

The invention relates to a preparation method of 1-alkylpyrazole, which can reduce the reaction temperature, simplify the operation steps and improve the reaction yield and the product purity by adding a specific catalyst and combining specific reaction parameters, and is favorable for realizing industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and specifically to a method for preparing 1-alkylpyrazoles. Background Art

[0002] Common alkylpyrazoles such as ethyl 3-methyl-1-methylpyrazole-4-carboxylate, ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate, ethyl 3-trifluoromethyl-1-methylpyrazole-4-carboxylate, etc. can be used for synthesizing various pesticides, pharmaceuticals, and high-performance materials, etc.

[0003] For the preparation of pyrazole compounds, there are various methods in the art. When using acyl ketone esters as raw materials to prepare pyrazole compounds, there are two synthetic routes. One is that acyl ketone esters directly react with alkyl hydrazines to generate the target product. Among them, the raw materials are expensive, the process conditions are harsh, and the reaction generates 10-20% of unnecessary isomers, and other methods are also required to purify the product, with low industrialization value. The other is that acyl ketone esters first react with hydrazine hydrate to obtain 1-H pyrazole intermediates, then alkylation is carried out to obtain the target product and 20-30% isomers, and the target product can be obtained in high yield through rearrangement.

[0004] For the second preparation method, the prior arts CN101044119A and CN103052625A use trimethyl phosphate and dimethyl sulfate as alkylating reagents. The reagents are highly toxic and expensive, and the reaction needs to be carried out at high temperature. The reaction conditions are harsh and a large amount of phosphorus-containing three wastes are generated, which is not conducive to industrial production.

[0005] To solve the problems existing in the prior art, the present invention avoids the expensive and regulated methyl hydrazine raw materials, and now provides a synthesis method of 1-alkylpyrazoles with mild reaction conditions, which can improve the reaction yield, reduce the production cost, and is conducive to realizing industrial production. Summary of the Invention

[0006] The present invention provides a method for preparing a compound represented by formula (I), specifically including the following content:

[0007] In a solvent, under the action of an alkylating reagent and a catalyst, the compound represented by formula (II) undergoes an alkylation reaction to obtain the compound represented by formula (I),

[0008]

[0009] Wherein,

[0010] R1 is selected from C1-C6 alkyl, C1-C6 haloalkyl;

[0011] R2 is selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxycarbonyl, C1-C6 alkylthiocarbonyl, C1-C6 alkylaminocarbonyl, arylaminocarbonyl;

[0012] R3 is selected from H, hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

[0013] The solvent is selected from water; halogenated alkanes such as dichloromethane, dichloroethane, dichloropropane and carbon tetrachloride; aromatic hydrocarbons such as toluene, xylenes and mesitylene; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; ketones such as acetone; ethers such as aliphatic C3-C 10 ethers such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, diethyl ether, dipropyl ether, methyl isobutyl ether, tert-butyl methyl ether and tert-butyl ethyl ether, alicyclic C4-C6 ethers such as THF, tetrahydropyran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran and 1,4-dioxane; amides such as N,N-dimethylamides of C1-C4 carboxylic acids such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMAC), N-C1-C4 alkyl lactams such as N-methylpyrrolidone (NMP); nitriles such as C1-C4 alkanenitriles such as acetonitrile and propionitrile; alcohols such as C1-C4 alkanols such as methanol, ethanol, n-propanol and isopropanol; nitrogen-containing hydrocarbons such as nitromethane, nitrobenzene, pyridine, acetonitrile and quinoline; sulfones such as sulfolane, diethyl sulfone, diphenyl sulfone, etc.; sulfoxides such as dimethyl sulfoxide (DMSO), diethyl sulfoxide, etc., and any combination thereof in any proportion, but not limited to these;

[0014] The alkylating agent is selected from monohalomethane;

[0015] The catalyst is selected from one or more of quaternary ammonium salt catalysts, quaternary phosphonium salt catalysts, polyether catalysts, crown ether catalysts, polyols, and iodine-containing salt catalysts;

[0016] In some embodiments of the present invention, R1 is selected from C1-C3 alkyl, C1-C3 haloalkyl;

[0017] R2 is selected from cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylthiocarbonyl, C1-C4 alkylaminocarbonyl, arylaminocarbonyl;

[0018] R3 is selected from H, hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl.

[0019] In some embodiments of the present invention, R1 is selected from methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl;

[0020] R2 is selected from cyano, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, methylaminocarbonyl, anilinocarbonyl, benzidinocarbonyl;

[0021] R3 is selected from H, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl.

[0022] In some embodiments of the present invention, the solvent is preferably selected from one or more of water, dichloromethane, dichloroethane, dichloropropane, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, NMP, DMF, DMSO, acetonitrile, ethanol, sulfolane;

[0023] In some embodiments of the present invention, the alkylating agent is selected from fluoromethane, chloromethane, bromomethane or iodomethane;

[0024] In some embodiments of the present invention, the catalyst is selected from one or more of benzyltriethylammonium chloride, tetramethylammonium chloride, tetrabutylammonium bromide, trioctylmethylammonium chloride, PEG400, PEG800, 18-crown-6, pentaerythritol, potassium iodide, sodium iodide.

[0025] In some embodiments of the present invention, the reaction temperature is selected from 10 - 200 °C, preferably 20 - 110 °C, and most preferably 30 - 80 °C.

[0026] In some embodiments of the present invention, in terms of the amount of substance, the usage ratio of the compound shown in formula (II) to the alkylating agent is 1:1 - 5.0, preferably 1:1 - 2.0.

[0027] In some embodiments of the present invention, in terms of the amount of substance, the usage ratio of the compound shown in formula (II) to the catalyst is 1:0.01 - 1.0, preferably 1:0.01 - 0.5.

[0028] In some embodiments of the present invention, the reaction pressure is selected from 0 - 10 MPa. Further, the reaction can be promoted by appropriate pressurization. The reaction pressure is preferably 0.1 - 5.0 MPa, and most preferably 0.1 - 0.5 MPa.

[0029] In some embodiments of the present invention, further, a post-treatment method is also included. After the reaction is completed, water is added and washed until the pH is neutral, and the solvent is removed by distillation to obtain the target product;

[0030] The present invention has the following beneficial technical effects:

[0031] The present invention provides a new preparation method for 1-alkylpyrazole compounds. By adding a specific catalyst and combining specific reaction parameters, the reaction temperature can be reduced, side reactions can be decreased, the operation steps can be simplified, the reaction yield and the product purity can be improved, the production cost can be reduced, which is beneficial to realizing large-scale industrial production. Detailed implementation manners

[0032] Example 1

[0033] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after discounting to 100% purity, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of 30% aqueous solution of tetrabutylammonium bromide (0.12 eq) were added into the reaction kettle. After closing the exhaust, the temperature was raised to 30 - 35 °C, and methyl chloride gas was introduced until the system pressure reached 0.1 MPa. The reaction was carried out under insulation for 3 - 4 h, and sampling was taken for qualified detection.

[0034] After the reaction was completed, 155 kg of water was added, stirred until dissolved and clarified, allowed to stand for layering. The organic layer was washed with water 2 - 3 times until the pH = 7, and DMSO was recovered by vacuum distillation to 170 °C. A total of 194.0 kg of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate product and its isomerization product after discounting to 100% purity were obtained, with a yield of 95.0%. After analysis and detection by HPLC, the total purity of the product and its isomerization product was 99.0%, among which the product: isomerization product = 78:22.

[0035] Example 2

[0036] Under nitrogen protection, 200.0 kg of 5-(difluoromethyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole (1.0 eq) after discounting to 100% purity, 670.0 kg of DMF, 179.5 kg of potassium carbonate (1.3 eq), and 127.4 kg of 30% aqueous solution of tetrabutylammonium bromide (0.12 eq) were added into the reaction kettle. After closing the exhaust, the temperature was raised to 30 - 35 °C, and methyl chloride gas was introduced until the system pressure reached 0.1 MPa. The reaction was carried out under insulation for 3 - 4 h, and sampling was taken for qualified detection.

[0037] After the reaction was completed, 155 kg of water was added, stirred until dissolved and clarified, allowed to stand for layering. The organic layer was washed with water 2 - 3 times until the pH = 7, and DMF was recovered by vacuum distillation to 150 °C. A total of 202.2 kg of 5-(difluoromethyl)-4-methyl-3-(trifluoromethyl)-1-methylpyrazole product and its isomerization product after discounting to 100% purity were obtained, with a yield of 94.5%. After analysis and detection by HPLC, the purity of the product and its isomerization product was 99.5%, among which the product: isomerization product = 75:25.

[0038] Example 3

[0039] Under nitrogen protection, 180.0 kg of 3-(difluoromethyl)-5-fluoro-1H-pyrazole-4-carboxylic acid (1.0 eq) after discounting to 100% purity, 500.1 kg of sulfolane, 165.6 kg of potassium carbonate (1.2 eq), and 127.5 kg of 30% aqueous solution of tetrabutylammonium bromide (0.12 eq) were added into the reaction kettle. The exhaust was closed, and the temperature was raised to 30 - 35 °C. Chloromethane gas was introduced until the system pressure reached 0.1 MPa, and the reaction was carried out under insulation for 3 - 4 h. Sampling was taken for inspection and it was qualified.

[0040] After the reaction was completed, 155 kg of water was added, stirred until dissolved and clear, left to stand for liquid separation. The organic layer was washed with water 2 - 3 times until the pH = 7. Sulfolane was recovered by vacuum distillation up to 200 °C, and 3-(difluoromethyl)-5-fluoro-1-methylpyrazole-4-carboxylic acid and its isomerization products, totaling 183.9 kg after discounting to 100% purity, were obtained. The yield was 94.8%. By HPLC analysis and detection, the purity of the product and its isomerization products was 99.2%, and the ratio of the product to the isomerization product was 77:23.

[0041] Example 4

[0042] Under nitrogen protection, 152.0 kg of 3-(trifluoromethyl)-1H-pyrazol-5-ol (1.0 eq) after discounting to 100% purity, 500.0 kg of DMAC, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of 30% aqueous solution of tetrabutylammonium bromide (0.12 eq) were added into the reaction kettle. The exhaust was closed, and the temperature was raised to 70 - 80 °C. Chloromethane gas was introduced until the system pressure reached 0.4 MPa, and the reaction was carried out under insulation for 3 - 4 h. Sampling was taken for inspection and it was qualified.

[0043] After the reaction was completed, 155 kg of water was added, stirred until dissolved and clear, left to stand for liquid separation. The organic layer was washed with water 2 - 3 times until the pH = 7. DMAC was recovered by vacuum distillation up to 160 °C, and 3-(trifluoromethyl)-1-methylpyrazol-5-ol and its isomerization products, totaling 157.9 kg after discounting to 100% purity, were obtained. The yield was 95.1%. By HPLC analysis and detection, the purity of the product and its isomerization products was 99.1%, and the ratio of the product to the isomerization product was 76:24.

[0044] Example 5

[0045] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after discounting to 100% purity, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 38.2 kg of tetrabutylammonium bromide (0.12 eq) were added into the reaction kettle. The exhaust was closed, and the temperature was raised to 30 - 35 °C. Chloromethane gas was introduced until the system pressure reached 0.1 MPa, and the reaction was carried out under insulation for 3 - 4 h. Sampling was taken for inspection and it was qualified.

[0046] After the reaction was completed, 155 kg of water was added, and the mixture was stirred until clear. It was allowed to stand for liquid separation. The organic layer was washed with water 2 - 3 times until the pH reached 7. DMSO was recovered by vacuum distillation up to 170 °C. A total of 163.4 kg of the ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate product and its isomerization product were obtained in terms of 100% purity, with a yield of 80.0%. After analysis by HPLC, the purity of the product and its isomerization product was 82.0%, and the ratio of the product to the isomerization product was 75:25.

[0047] Example 6

[0048] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) in terms of 100% purity, 636.1 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of a 30% aqueous solution of tetrabutylammonium bromide (0.12 eq) were added to the reaction kettle. The exhaust was closed, and the temperature was raised to 30 - 35 °C. Methyl bromide gas was introduced until the system pressure reached 0.1 MPa, and the reaction was carried out under heat preservation for 3 - 4 h. Sampling and testing were qualified.

[0049] After the reaction was completed, 155 kg of water was added, and the mixture was stirred until clear. It was allowed to stand for liquid separation. The organic layer was washed with water 2 - 3 times until the pH reached 7. DMSO was recovered by vacuum distillation up to 170 °C. A total of 194.8 kg of the ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate product and its isomerization product were obtained in terms of 100% purity, with a yield of 95.4%. After analysis by HPLC, the purity of the product and its isomerization product was 99.1%, and the ratio of the product to the isomerization product was 77:23.

[0050] Example 7

[0051] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) in terms of 100% purity, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of a 30% aqueous solution of tetrabutylammonium bromide (0.12 eq) were added to the reaction kettle. The exhaust was closed, and the temperature was raised to 70 - 80 °C. Fluoromethane gas was introduced, and the system pressure was controlled at 0.5 MPa. The reaction was carried out under heat preservation for 3 - 4 h. Sampling and testing were qualified.

[0052] After the reaction was completed, 155 kg of water was added, and the mixture was stirred until clear. It was allowed to stand for liquid separation. The organic layer was washed with water 2 - 3 times until the pH reached 7. DMSO was recovered by vacuum distillation up to 170 °C. A total of 193.8 kg of the ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate product and its isomerization product were obtained in terms of 100% purity, with a yield of 94.9%. After analysis by HPLC, the purity of the product and its isomerization product was 99.3%, and the ratio of the product to the isomerization product was 78:22.

[0053] Example 8

[0054] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after converting to 100% purity, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 90.1 kg of 30% aqueous TEBA solution (0.12 eq) were added into the reaction kettle. The exhaust was closed, and the temperature was raised to 30 - 35 °C. Chloromethane gas was introduced until the system pressure reached 0.1 MPa, and the reaction was carried out under insulation for 3 - 4 h. Sampling and testing showed it was qualified.

[0055] After the reaction was completed, 155 kg of water was added, stirred until dissolved and clarified, allowed to stand for layering. The organic layer was washed with water 2 - 3 times until pH = 7. DMSO was recovered by vacuum distillation up to 170 °C. A total of 187.9 kg of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate product and its isomerization product after converting to 100% purity were obtained, with a yield of 92.0%. Through HPLC analysis and detection, the purity of the product and its isomerization product was 98.7%, and the ratio of the product to the isomerization product was 76:24.

[0056] Example 9

[0057] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after converting to 100% purity, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 27.0 kg of TEBA (0.12 eq) were added into the reaction kettle. The exhaust was closed, and the temperature was raised to 30 - 35 °C. Chloromethane gas was introduced until the system pressure reached 0.1 MPa, and the reaction was carried out under insulation for 3 - 4 h. Sampling and testing showed it was qualified.

[0058] After the reaction was completed, 155 kg of water was added, stirred until dissolved and clarified, allowed to stand for layering. The organic layer was washed with water 2 - 3 times until pH = 7. DMSO was recovered by vacuum distillation up to 170 °C. A total of 159.3 kg of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate product and its isomerization product after converting to 100% purity were obtained, with a yield of 78.0%. Through HPLC analysis and detection, the purity of the product and its isomerization product was 79.1%, and the ratio of the product to the isomerization product was 75:25.

[0059] Example 10

[0060] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after converting to 100% purity, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 158.2 kg of 30% aqueous PEG400 solution (0.12 eq) were added into the reaction kettle. The exhaust was closed, and the temperature was raised to 30 - 35 °C. Chloromethane gas was introduced until the system pressure reached 0.1 MPa, and the reaction was carried out under insulation for 3 - 4 h. Sampling and testing showed it was qualified.

[0061] After the reaction was completed, 155 kg of water was added, and the mixture was stirred until clear. It was allowed to stand for layer separation. The organic layer was washed with water 2 - 3 times until the pH reached 7. DMSO was recovered by vacuum distillation up to 170 °C, obtaining a total of 183.8 kg of the product of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate and its isomerization product in terms of 100% purity, with a yield of 90.0%. After analysis and detection by HPLC, the purity of the product and its isomerization product was 98.5%, and the ratio of the product to the isomerization product was 77:23.

[0062] Example 11

[0063] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) in terms of 100% purity, 636.0 kg of dichloroethane, 179.4 kg of potassium carbonate (1.3 eq), and 104.4 kg of a 30% aqueous solution of 18-crown-6 (0.12 eq) were added into the reaction kettle. The exhaust was closed, and the temperature was raised to 30 - 35 °C. Methyl chloride gas was introduced until the system pressure reached 0.1 MPa, and the reaction was carried out under heat preservation for 3 - 4 h. Sampling and testing showed it was qualified.

[0064] After the reaction was completed, 155 kg of water was added, and the mixture was stirred until clear. It was allowed to stand for layer separation. The organic layer was washed with water 2 - 3 times until the pH reached 7. DMSO was recovered by vacuum distillation up to 170 °C, obtaining a total of 185.8 kg of the product of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate and its isomerization product in terms of 100% purity, with a yield of 91.1%. After analysis and detection by HPLC, the purity of the product and its isomerization product was 98.4%, and the ratio of the product to the isomerization product was 76:24.

[0065] Example 12

[0066] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) in terms of 100% purity, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of a 30% aqueous solution of tetrabutylammonium bromide (0.12 eq) were added into the reaction kettle. The exhaust was closed, and the temperature was raised to 30 - 35 °C. Methyl chloride gas (2 equivalents) was slowly introduced under normal pressure, and after introduction, the reaction was carried out under heat preservation for 3 - 4 h. Sampling and testing showed it was qualified.

[0067] After the reaction was completed, 155 kg of water was added, and the mixture was stirred until clear. It was allowed to stand for layer separation. The organic layer was washed with water 2 - 3 times until the pH reached 7. DMSO was recovered by vacuum distillation up to 170 °C, obtaining a total of 173.6 kg of the product of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate and its isomerization product in terms of 100% purity, with a yield of 85.0%. After analysis and detection by HPLC, the purity of the product and its isomerization product was 91.3%, and the ratio of the product to the isomerization product was 76:24.

[0068] Example 13

[0069] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after discounting to 100%, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of 30% aqueous tetrabutylammonium bromide solution (0.12 eq) were added into the reaction kettle. The exhaust was closed, the temperature was raised to 30 - 35 °C, and chloromethane gas was introduced until the system pressure reached 0.05 MPa. After completion, the mixture was kept warm and reacted for 3 - 4 h, and the sample was tested and qualified.

[0070] After the reaction was completed, 155 kg of water was added, stirred until dissolved and clear, allowed to stand for liquid separation. The organic layer was washed with water 2 - 3 times until pH = 7, and DMSO was recovered by vacuum distillation to 170 °C. A total of 178.5 kg of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate product and its isomerization product after discounting to 100% were obtained, with a yield of 87.4%. After analysis and detection by HPLC, the purity of the product and its isomerization product was 96.3%, and the ratio of the product to the isomerization product was 77:23.

[0071] Example 14

[0072] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after discounting to 100%, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of 30% aqueous tetrabutylammonium bromide solution (0.12 eq) were added into the reaction kettle. The exhaust was closed, the temperature was raised to 30 - 35 °C, and chloromethane gas was introduced until the system pressure reached 0.5 MPa. After completion, the mixture was kept warm and reacted for 3 - 4 h, and the sample was tested and qualified.

[0073] After the reaction was completed, 155 kg of water was added, stirred until dissolved and clear, allowed to stand for liquid separation. The organic layer was washed with water 2 - 3 times until pH = 7, and DMSO was recovered by vacuum distillation to 170 °C. A total of 193.8 kg of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate product and its isomerization product after discounting to 100% were obtained, with a yield of 94.9%. After analysis and detection by HPLC, the purity of the product and its isomerization product was 99.1%, and the ratio of the product to the isomerization product was 75:25.

[0074] Example 15

[0075] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after discounting to 100%, 636.0 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of 30% aqueous tetrabutylammonium bromide solution (0.12 eq) were added into the reaction kettle. The exhaust was closed, the temperature was raised to 20 - 25 °C, and chloromethane gas was introduced until the system pressure reached 0.1 MPa. After completion, the mixture was kept warm and reacted for 3 - 4 h, and the sample was tested and qualified.

[0076] After the reaction was completed, 155 kg of water was added, and the mixture was stirred until dissolved and clarified. Then it was allowed to stand for liquid separation. The organic layer was washed with water 2 - 3 times until the pH reached 7. DMSO was recovered by vacuum distillation to 170 °C, and a total of 186.0 kg of the product of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate and its isomerization product with a yield of 91.1% were obtained. After analysis and detection by HPLC, the purity of the product and its isomerization product was 96.5%, and the ratio of the product to the isomerization product was 76:24.

[0077] Example 16

[0078] Under nitrogen protection, 190.2 kg of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (1.0 eq) after converting to 100% strength, 636.1 kg of DMSO, 179.4 kg of potassium carbonate (1.3 eq), and 127.5 kg of a 30% aqueous solution of tetrabutylammonium bromide (0.12 eq) were added to the reaction kettle. The exhaust was closed, and the temperature was raised to 90 - 100 °C. Chloromethane gas was introduced until the system pressure reached 0.1 MPa. After the introduction, the mixture was kept warm and reacted for 3 - 4 h, and the sample was detected to be qualified.

[0079] After the reaction was completed, 155 kg of water was added, and the mixture was stirred until dissolved and clarified. Then it was allowed to stand for liquid separation. The organic layer was washed with water 2 - 3 times until the pH reached 7. DMSO was recovered by vacuum distillation to 170 °C, and a total of 184.8 kg of the product of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate and its isomerization product with a yield of 90.5% were obtained. After analysis and detection by HPLC, the purity of the product and its isomerization product was 98.8%, and the ratio of the product to the isomerization product was 75:25.

[0080] Comparative Example 1 Refer to the preparation method of Example 1 in CN101044119A

[0081] A mixture of 5.7 g of ethyl 3-difluoromethyl-1H-pyrazole-4-carboxylate (30 mmol) and 25 ml of trimethyl phosphate (214 mmol) was stirred at 180 °C for 18 hours. Then 250 ml of an ice-water mixture was added. The resulting reaction product was filtered, washed with water and dissolved in 50 ml of ethyl acetate. The organic phase was washed with 50 ml of saturated sodium chloride solution, dried with sodium sulfate and evaporated to concentrate. 3.85 g (63.2% of the theoretical value) of ethyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate in crystalline form and its isomerization product were obtained.

[0082] This preparation method requires the use of expensive trimethyl phosphate reagent, the reaction needs to be carried out at high temperature, the operation is complex. In addition, a large amount of phosphorus-containing wastewater is generated during the reaction, which is difficult to post-treat and is not conducive to industrial production.

[0083] Comparative Example 2 Refer to the preparation method of Example 7 in CN103052625A

[0084] To 1.9 g of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate, 2.5 g of N,N-dimethylformamide / dimethyl sulfate salt was added. The mixture was heated to 160 °C and stirred for 7 - 10 hours. Based on GC analysis, at the end of the reaction time, 1.43 g (70.6% of the theoretical value) of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate in crystalline form and its isomerization product were obtained.

[0085] This preparation method requires the use of highly toxic dimethyl sulfate reagent, the reaction needs to be carried out at high temperature, the operation is complex. In addition, a large amount of wastewater is generated in the reaction, which is difficult to post-treat and is not conducive to industrial production.

[0086] Summary of Examples in Table 1

[0087]

[0088] Application Example: Refer to Example 4 of CN102471278A

[0089] Take 4.1 g of the product and its isomerization product from Comparative Example 1 (product: isomerization product = 8:92), add 8.2 g of trimethyl phosphate and 0.82 g of polyphosphoric acid. The mixture was heated to 170 °C and stirred for 9 hours. Samples were taken for analysis, and the product content was 94.2%.

[0090] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for preparing 1-alkylpyrazole, characterized in that, In a solvent, under the action of an alkylating agent and a catalyst, the compound shown by formula (II) undergoes an alkylation reaction to obtain the compound shown by formula (I). Wherein, R1 is selected from C1-C6 alkyl, C1-C6 haloalkyl; R2 is selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxycarbonyl, C1-C6 alkylthiocarbonyl, C1-C6 alkylaminocarbonyl, arylaminocarbonyl; R3 is selected from H, hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl; The solvent is selected from one or more of water, haloalkanes, aromatic hydrocarbons, haloaromatic hydrocarbons, ketones, ethers, amides, nitriles, alcohols, sulfones, sulfoxides; The alkylating agent is selected from monohalomethane; The catalyst is selected from one or more of quaternary ammonium salt catalysts, quaternary phosphonium salt catalysts, polyether catalysts, crown ether catalysts, polyhydric alcohols, iodine-containing salt catalysts.

2. The preparation method according to claim 1, characterized in that, R1 is selected from C1-C3 alkyl, C1-C3 haloalkyl; R2 is selected from cyano, C1-C4 alkoxycarbonyl, C1-C4 alkylthiocarbonyl, C1-C4 alkylaminocarbonyl, arylaminocarbonyl; R3 is selected from H, hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl.

3. The preparation method according to claim 1, characterized in that, R1 is selected from methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl; R2 is selected from cyano, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, methylaminocarbonyl, anilinocarbonyl, benzidinocarbonyl; R3 is selected from H, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl.

4. The preparation method according to any one of claims 1 to 3, characterized in that, The organic solvent is selected from one or more of water, dichloromethane, dichloroethane, dichloropropane, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, NMP, DMF, DMSO, acetonitrile, ethanol, sulfolane; The alkylating agent is selected from fluoromethane, chloromethane, bromomethane or iodomethane; The catalyst is selected from one or more of benzyltriethylammonium chloride, tetramethylammonium chloride, tetrabutylammonium bromide, trioctylmethylammonium chloride, PEG400, PEG800, 18-crown-6, pentaerythritol, potassium iodide, sodium iodide.

5. The preparation method according to claim 4, characterized in that, The organic solvent is selected from one or more of water, dichloromethane, dichloroethane, dichloropropane, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, NMP, DMF, DMSO, acetonitrile, ethanol, sulfolane; The alkylating agent is selected from chloromethane, bromomethane; The catalyst is selected from one or more of benzyltriethylammonium chloride, tetramethylammonium chloride, tetrabutylammonium bromide, trioctylmethylammonium chloride, PEG400, PEG800, 18-crown-6, pentaerythritol, potassium iodide, sodium iodide.

6. The preparation method according to claim 1, characterized in that, The reaction temperature is selected from 10-200 °C.

7. The preparation method according to claim 1, characterized in that, Based on the amount of substance, the dosage ratio of the compound represented by the formula (II) to the alkylating agent is 1 to 5.0, preferably 1:1 to 2.

0.

8. The preparation method according to claim 1, characterized in that, Based on the amount of substance, the dosage ratio of the compound represented by the formula (II) to the catalyst is 1:0.01 to 1.0, preferably 1:0.01 to 0.

5.

9. The preparation method according to claim 1, wherein, The reaction pressure is selected from 0 - 10 MPa.

10. The preparation method according to claim 6, characterized in that, The reaction temperature is selected from 20 - 110 °C.

11. The preparation method according to claim 9, wherein, The reaction pressure is selected from 0.1 - 5 MPa.

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