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

Abstract

The invention discloses a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-formic acid, which comprises the following steps: (1) reacting methylhydrazine with benzaldehyde substances in an organic solvent to obtain a reaction solution A, (2) firstly adding 2-(dimethylaminomethylene)-4, 4 '-diazole-4-carboxylic acid into the reaction solution A, and (3) adding 2-(dimethylaminomethylene)-4, 4'-diazole-4 '-carboxylic acid into the reaction solution A to obtain the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. And (3) adding a basic salt into the reaction liquid B for reaction, then separating a water phase, adding hydrochloric acid into the water phase for reaction to obtain a reaction liquid C, and filtering the reaction liquid C to obtain a solid product, namely 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-formic acid. According to the method, the hidden danger of isomer generation is eliminated, the separation and purification mode is simplified, the overall yield of the reaction is greatly increased, the reaction condition is mild, the organic solvent can be used mechanically, the preparation cost is reduced, three wastes are reduced, the practical value is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. Background Art

[0002] Benzovindiflupyr is an SDHI fungicide developed by Syngenta. It has broad-spectrum fungicidal activity and has good control effects on Asian soybean rust, wheat leaf blight, peanut black spot, wheat take-all, and wheat basal rot. It has a long-lasting effect and no cross-resistance with a variety of fungicides. 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is an important intermediate in the production of benzovindiflupyr and can be obtained by hydrolyzing the upstream intermediate ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0003] At present, the main preparation methods of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate include the following several:

[0004] The first preparation method uses ethyl difluoroacetoacetate as the starting material, reacts with trimethyl orthoformate to generate ethyl 2-(methoxymethylene)-4,4-difluoro-3-oxobutyrate, and finally closes the ring with methylhydrazine to obtain ethyl difluoropyrazolecarboxylate. For example, in patent CN101959840. This preparation method has a high isomerization ratio, which is not easy to remove, and the yield needs to be improved.

[0005] The second preparation method uses ethyl dichloroacetoacetate as the starting material, reacts with trimethyl orthoformate to generate ethyl 2-(methoxymethylene)-4,4-dichloro-3-oxobutyrate, closes the ring with methylhydrazine to obtain ethyl difluoropyrazolecarboxylate, and finally performs fluorination with potassium fluoride to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. For example, in patents CN103582631 and CN106467492. This preparation method has cumbersome steps, is inconvenient for large-scale production, has a high isomerization ratio, is not easy to remove, and the yield also needs to be improved.

[0006] The third preparation method uses dichloroacetyl chloride as the starting material, condenses and closes the ring with vinyl methyl ether and methylhydrazine to obtain 3-(dichloromethyl)-1-methyl-1H-pyrazole, brominates to obtain 3-(dichloromethyl)-4-bromo-1-methyl-1H-pyrazole, substitutes with potassium fluoride, and finally inserts carbonyl to obtain ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate. For example, in patents CN101687806 and CN101679282A. This preparation method has cumbersome steps, generates a large amount of three wastes after the reaction, is inconvenient for large-scale production, has a high isomerization ratio, is not easy to remove, and the yield also needs to be improved.

[0007] The fourth preparation method uses ethyl difluoroacetoacetate as the starting material, which reacts with trimethyl orthoformate to form ethyl 2-(methoxymethylene)-4,4-difluoro-3-oxobutyrate. Then, hydrazine hydrate is used for ring closure and dimethyl sulfate is used for condensation to obtain ethyl difluoropyrazolecarboxylate (containing 40% of isomeric products). Finally, the isomeric products are transposed, for example, in Patent CN102471278A and Patent CN103052625A. In this preparation method, the transposition reaction is not complete enough, and 5-10% of the isomers cannot be converted. An ionic intermediate appears during the transposition process and cannot be effectively converted.

[0008] Since the above preparation methods of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate all have more or less problems of isomers and cumbersome operations, it affects the purity and yield of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid obtained by the subsequent hydrolysis reaction. At the same time, it is difficult to scale up production and the cost is high. Summary of the Invention

[0009] The object of the present invention is to provide a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid that can completely avoid isomerization products, has high atom economy, high yield, and is convenient for scale-up production.

[0010] To achieve the above object, the technical solution adopted by the present invention is:

[0011] A preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, comprising the following steps:

[0012] (1) React methylhydrazine with a benzaldehyde substance in an organic solvent to obtain reaction solution A,

[0013] (2) Add ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate to reaction solution A first, and then add hydrochloric acid to react to obtain reaction solution B,

[0014] (3) Add a basic salt to reaction solution B to react, then separate out the aqueous phase, add hydrochloric acid to the aqueous phase to react to obtain reaction solution C, and the reaction solution C is filtered to obtain a solid product, which is the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid.

[0015] In the embodiment of the present invention, the benzaldehyde substance is one or more of benzaldehyde, p-methoxybenzaldehyde, o-methoxybenzaldehyde, m-methoxybenzaldehyde, p-nitrobenzaldehyde, o-nitrobenzaldehyde, m-nitrobenzaldehyde, p-chlorobenzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, p-fluorobenzaldehyde, o-fluorobenzaldehyde, and m-fluorobenzaldehyde.

[0016] In an embodiment of the present invention, the organic solvent is one or more of toluene, tetrahydrofuran, methylcyclohexane, n-hexane, and cyclohexane.

[0017] According to some specific embodiments of the present invention, the organic solvent is toluene.

[0018] And / or, the basic salt is one or more of sodium hydroxide, potassium hydroxide, or calcium hydroxide.

[0019] In an embodiment of the present invention, the methylhydrazine is fed as a methylhydrazine solution with a mass concentration of 35% - 45%.

[0020] In an embodiment of the present invention, the hydrochloric acid in the step (2) and the step (3) is fed as concentrated hydrochloric acid with a mass concentration of 36% - 38%.

[0021] In an embodiment of the present invention, the basic salt in the step (3) is fed as a basic salt solution with a mass concentration of 40% - 60%.

[0022] In an embodiment of the present invention, the organic phase after separating the aqueous phase in the step (3) can be recycled and reused as the organic solvent in the step (1).

[0023] In an embodiment of the present invention, the molar ratio of the methylhydrazine, the benzaldehyde substance, and the ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is 1:(1 - 1.5):(1 - 1.5), and more preferably 1:(1 - 1.2):(1 - 1.2).

[0024] In an embodiment of the present invention, in the step (2), the molar ratio of the ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate to hydrochloric acid is 1:(0.1 - 0.7), and more preferably 1:(0.1 - 0.4).

[0025] In an embodiment of the present invention, the molar ratio of the basic salt to hydrochloric acid in the step (3) to the molar amount of the ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate in the step (2) is (1 - 2):(1.2 - 2.2):1, and more preferably (1.3 - 1.7):(1.5 - 1.9):1.

[0026] In an embodiment of the present invention, the reaction temperature in the step (1) is 35°C - 45°C, and more preferably 35°C - 40°C.

[0027] In an embodiment of the present invention, the reaction temperature in the step (2) is 0°C - 10°C, and more preferably 0°C - 5°C.

[0028] In an embodiment of the present invention, the reaction temperature in step (3) is 60°C - 70°C, and more preferably 60°C - 65°C.

[0029] In an embodiment of the present invention, the reaction time in step (1) is 3h - 7h, and more preferably 3 - 5h.

[0030] In an embodiment of the present invention, the reaction time for the reaction of adding ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate in step (2) is 2h to 4h, and the reaction time for the reaction of adding hydrochloric acid in step (2) is 1h to 3h.

[0031] In an embodiment of the present invention, the reaction time for the reaction of adding a basic salt in step (2) is 1h to 3h, and the reaction time for the reaction of adding hydrochloric acid in step (3) is 10 to 40 minutes.

[0032] In an embodiment of the present invention, in step (2), ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate and hydrochloric acid are respectively fed in a dropwise manner.

[0033] In an embodiment of the present invention, in step (3), the basic salt is fed in a manner of dropping a basic salt solution, and the hydrochloric acid is fed in a dropwise manner.

[0034] In some specific embodiments of the present invention, in step (2), the dropping time of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is controlled to be 1h - 2h, more preferably 1h - 1.5h, the dropping time of hydrochloric acid is 20min - 30min, and the dropping temperatures are respectively 0°C - 10°C.

[0035] In some specific embodiments of the present invention, in step (3), the dropping time of the basic salt solution is controlled to be 0.5h - 1h, the dropping time of hydrochloric acid is controlled to be 20 - 30min, and the dropping temperatures are respectively 60°C - 70°C.

[0036] In an embodiment of the present invention, the reactions in step (1) and step (2) are both carried out under the protection of an inert gas.

[0037] According to some specific embodiments of the present invention, the preparation method is specifically as follows:

[0038] (1) Under the protection of an inert gas, at 35°C - 45°C, methylhydrazine reacts with a benzaldehyde substance in an organic solvent for 3h - 7h;

[0039] (2) Under the protection of inert gas, at 0°C - 10°C, ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is added dropwise to the reaction solution of step (1). The dropping time is controlled to be 1 h - 2 h. After the dropping is completed, the reaction is carried out at 0°C - 10°C for 1 h - 2 h while keeping warm. Then hydrochloric acid is added dropwise, the dropping time is controlled to be 20 min - 30 min. After the dropping is completed, the reaction is carried out at 0°C - 10°C for 1 h - 1.5 h while keeping warm;

[0040] (3) At 60°C - 70°C, an alkaline salt solution is added dropwise to the reaction solution of step (2). The dropping time is controlled to be 0.5 h - 1 h. After the dropping is completed, the reaction is carried out at 60°C - 70°C for 1 h - 1.5 h while keeping warm. Then the aqueous phase is separated out. Hydrochloric acid is added dropwise to the aqueous phase, the dropping time is controlled to be 20 min - 30 min. After the dropping is completed, after cooling, filtration by suction and drying, the 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid is obtained.

[0041] Due to the adoption of the above technical solution, the present invention has the following advantages compared with other processes:

[0042] By adjusting and optimizing the synthesis route of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, when synthesizing ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate, benzaldehyde substances are used to protect the terminal amino group, eliminating the hidden danger of generating isomers, simplifying the separation and purification method, greatly increasing the overall yield of the reaction, and having mild reaction conditions, simplified operation, recyclable organic solvents, reducing the consumption of materials and labor costs, reducing the three wastes, shortening the time, having high practical value, being suitable for industrial production and having broad application prospects. Specific embodiments

[0043] In order to avoid generating isomerization products during preparation, improve the yield and simplify the operation difficulty, and provide a green and easy-to-scale-up preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the inventor has put forward the technical solution of the present invention through long-term research and a large number of practices. The following will further explain the technical solution, its implementation process and principle, etc.

[0044] The present invention provides a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which comprises the following steps:

[0045] (1) Under the protection of inert gas, at 35°C - 45°C, methylhydrazine reacts with benzaldehyde substances in an organic solvent for 3 h - 7 h;

[0046] (2) Under the protection of inert gas, at 0 °C - 10 °C, ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate was added dropwise to the reaction solution of step (1). The dropping time was controlled to be 1 h - 2 h. After the dropping was completed, the reaction was carried out under insulation at 0 °C - 10 °C for 1 h - 2 h. Then hydrochloric acid was added dropwise, and the dropping time was controlled to be 20 min - 30 min. After the dropping was completed, the reaction was carried out under insulation at 0 °C - 10 °C for 1 h - 1.5 h;

[0047] (3) At 60 °C - 70 °C, the alkaline salt solution was added dropwise to the reaction solution of step (2). The dropping time was controlled to be 0.5 h - 1 h. After the dropping was completed, the reaction was carried out under insulation at 60 °C - 70 °C for 1 h - 1.5 h. Then the aqueous phase was separated, and the organic phase was recycled for subsequent use. Hydrochloric acid was added dropwise to the aqueous phase, and the dropping time was controlled to be 20 min - 30 min. After the dropping was completed, it was cooled, filtered by suction, and dried to obtain the 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid.

[0048] The present invention will be further described below in conjunction with embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific uses. The implementation conditions not specified are the conventional conditions in this industry. The technical features involved in various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0049] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0050] In the present invention, operations without special instructions are carried out at room temperature.

[0051] In the following examples and comparative examples, the preparation of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate refers to Example 12 in Patent CN100422141C. Other raw materials are directly purchased as commercial reagents. Among them, 40% methylhydrazine and 50% sodium hydroxide solution are both mass concentrations, and the mass concentration of concentrated hydrochloric acid is 36% - 38%.

[0052] The reaction equations of the following examples are as follows:

[0053]

[0054] Among them, R is a hydrogen group, a methoxy group, a nitro group or a halogen group.

[0055] Example 1

[0056] This example provides a preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which is as follows:

[0057] (1) Under N2 protection, 100 g (735.3 mmol, 1.05 eq) of p-methoxybenzaldehyde, 80.5 g (700.3 mmol, 1.0 eq) of 40% methylhydrazine and 160 g of toluene were added to the reaction flask. Stirring was started, and the temperature was raised to 40 °C and kept for reaction for 4.5 hours. The reaction of p-methoxybenzaldehyde was completed as detected by GC.

[0058] (2) Under N2 protection, the reaction solution in step (1) was cooled to 0 - 5 °C. At 0 - 5 °C, 154.7 g (700 mmol, 1.0 eq) of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate was slowly added dropwise to the reaction solution, and the dropping time was controlled to be 1.5 hours. After the dropping was completed, the reaction was continued at 0 - 5 °C for 1.5 hours. The reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate was completed as detected by GC. 6.8 g (68.3 mmol, 0.1 eq) of concentrated hydrochloric acid was slowly added dropwise to the reaction solution, and the dropping time was controlled to be 0.5 hours. After the dropping was completed, the reaction was continued at 0 - 5 °C for 1.5 hours. The product in the reaction solution contained a large amount of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate as detected by HPLC.

[0059] (2) The reaction solution in step (3) was heated to 60 °C - 70 °C. At 60 °C - 70 °C, 84 g (1050 mmol, 1.5 eq) of 50% sodium hydroxide solution was slowly added dropwise to the reaction solution, and the dropping time was controlled to be 30 minutes. After the dropping was completed, the reaction was kept at 60 °C - 70 °C for 1 hour. The reaction of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate was completed as detected by HPLC. The aqueous phase was separated from the reaction solution, and the organic phase was extracted with 50 g of water. The aqueous phases were combined, and the organic phase was used for subsequent batches. 111.9 g (1120 mmol, 1.6 eq) of concentrated hydrochloric acid was added dropwise to the aqueous phase solution, and the dropping time was controlled to be 20 minutes. After cooling, filtration and drying were carried out to obtain 119.7 g of solid product, which was identified as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid by NMR detection. The purity was 97.5% and the yield was 94.7% as detected by HPLC.

[0060] Example 2

[0061] This example provides another preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which is as follows:

[0062] (1) Under N2 protection, 100 g (735.3 mmol, 1.05 eq) of o-methoxybenzaldehyde, 80.5 g (700.3 mmol, 1.0 eq) of 40% methylhydrazine and 160 g of toluene were added to the reaction flask. Stirring was started, and the temperature was raised to 40 °C and kept for reaction for 5 hours. The reaction of o-methoxybenzaldehyde was completed as detected by GC.

[0063] (2) Under N2 protection, cool the reaction solution of step (1) to 0 - 5 °C. At 0 - 5 °C, slowly add 154.7 g (700 mmol, 1.0 eq) of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate dropwise to the reaction solution, control the dropping time to 2 hours. After the dropping is completed, continue to keep the reaction at 0 - 5 °C for 2 hours. When the reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is detected to be complete by GC, slowly add 6.8 g (68.3 mmol, 0.1 eq) of concentrated hydrochloric acid dropwise to the reaction solution, control the dropping time to 1 hour. After the dropping is completed, continue to react at 0 - 5 °C for 2 hours. HPLC detection shows that the reaction solution contains a large amount of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0064] (3) Heat the reaction solution of step (2) to 60 °C - 70 °C. At 60 °C - 70 °C, slowly add 84 g (1050 mmol, 1.5 eq) of 50% sodium hydroxide solution dropwise to the reaction solution, control the dropping time to 20 minutes. After the dropping is completed, keep the reaction at 60 °C - 70 °C for 1.5 hours. When the reaction of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is detected to be complete by HPLC, separate the aqueous phase from the reaction solution, extract the organic phase with 50 g of water, combine the aqueous phases, and the organic phase is used for subsequent runs. Drop 111.9 g (1120 mmol, 1.6 eq) of concentrated hydrochloric acid dropwise into the aqueous phase solution, control the dropping time to 20 minutes, cool and then filter and dry to obtain 118.7 g of solid product, which is identified as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid by NMR detection, and the HPLC detection purity is 97.1%, and the yield is 93.6%.

[0065] Example 3

[0066] This example provides another preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which is as follows:

[0067] (1) Under N2 protection, add 100 g (735.3 mmol, 1.05 eq) of m-methoxybenzaldehyde, 80.5 g (700.3 mmol, 1.0 eq) of 40% methylhydrazine and 160 g of toluene into the reaction flask, start stirring, heat up to 40 °C and keep the reaction for 4 hours. When the reaction of m-methoxybenzaldehyde is detected to be complete by GC.

[0068] (2) Under the protection of N2, cool the reaction solution in step (1) to 0 - 5 °C. At 0 - 5 °C, slowly add 154.7 g (700 mmol, 1.0 eq) of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate dropwise to the reaction solution, control the dropping time to 1.5 hours. After the dropping is completed, continue to keep the reaction at 0 - 5 °C for 1.5 hours. When the reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is detected to be complete by GC, slowly add 6.8 g (68.3 mmol, 0.1 eq) of concentrated hydrochloric acid dropwise to the reaction solution, control the dropping time to 0.5 hours. After the dropping is finished, continue to react at 0 - 5 °C for 1.5 hours. HPLC detection shows that the product in the reaction solution contains a large amount of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0069] (3) Heat the reaction solution in step (2) to 60 °C - 70 °C. At 60 °C - 70 °C, slowly add 84 g (1050 mmol, 1.5 eq) of 50% sodium hydroxide solution dropwise to the reaction solution, control the dropping time to 30 minutes. After the dropping is completed, keep the reaction at 60 °C - 70 °C for 1 hour. When the reaction of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is detected to be complete by HPLC, separate the aqueous phase from the reaction solution, extract the organic phase with 50 g of water, combine the aqueous phases, and the organic phase is used for subsequent batches. Drop 111.9 g (1120 mmol, 1.6 eq) of concentrated hydrochloric acid dropwise into the aqueous phase solution, control the dropping time to 20 minutes, cool and then filter and dry to obtain 114.8 g of solid product, which is identified as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid by NMR detection, and the purity is 96.7% and the yield is 90.1% by HPLC detection.

[0070] Example 4

[0071] This example provides another preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which is as follows:

[0072] (1) Under the protection of N2, add 100 g (735.3 mmol, 1.05 eq) of benzaldehyde, 80.5 g (700.3 mmol, 1.0 eq) of 40% methylhydrazine and 160 g of toluene into the reaction flask, start stirring, heat up to 40 °C and keep the reaction for 5 hours. When the reaction of benzaldehyde is detected to be complete by GC.

[0073] (2) Under the protection of N2, cool the reaction solution in step (1) to 0 - 5 °C. At 0 - 5 °C, slowly add 154.7 g (700 mmol, 1.0 eq) of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate dropwise to the reaction solution, control the dropping time to be 1.5 hours. After the dropping is completed, continue to keep the temperature at 0 - 5 °C for reaction for 2 hours. When the reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is detected to be complete by GC, slowly add 6.8 g (68.3 mmol, 0.1 eq) of concentrated hydrochloric acid dropwise to the reaction solution, control the dropping time to be 0.5 hours. After the dropping is completed, continue to react at 0 - 5 °C for 1.5 hours. The reaction solution is detected by HPLC to contain a large amount of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0074] (3) Heat the reaction solution in step (2) to 60 °C - 70 °C. At 60 °C - 70 °C, slowly add 84 g (1050 mmol, 1.5 eq) of 50% sodium hydroxide solution dropwise to the reaction solution, control the dropping time to be 30 minutes. After the dropping is completed, keep the temperature at 60 °C - 70 °C for reaction for 1 hour. When the reaction of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is detected to be complete by HPLC, separate the aqueous phase from the reaction solution, extract the organic phase with 50 g of water, combine the aqueous phases, and the organic phase is used for subsequent batches. Drop 111.9 g (1120 mmol, 1.6 eq) of concentrated hydrochloric acid dropwise into the aqueous phase solution, control the dropping time to be 20 minutes. After cooling, filter and dry to obtain 118.4 g of solid product, which is identified as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid by NMR detection, and the purity is 97.3% and the yield is 93.5% by HPLC detection.

[0075] Example 5

[0076] This example provides another preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which is as follows:

[0077] (1) Under the protection of N2, add 100 g (735.3 mmol, 1.05 eq) of p-nitrobenzaldehyde, 80.5 g (700.3 mmol, 1.0 eq) of 40% methylhydrazine and 160 g of toluene into the reaction flask, start stirring, heat up to 40 °C and keep the temperature for reaction for 4.5 hours. When the reaction of p-nitrobenzaldehyde is detected to be complete by GC.

[0078] (2) Under the protection of N2, cool the reaction solution in step (1) to 0 - 5 °C. At 0 - 5 °C, slowly add 154.7 g (700 mmol, 1.0 eq) of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate dropwise to the reaction solution, control the dropping time to be 1.5 hours. After the dropping is completed, continue to keep the temperature at 0 - 5 °C for 2 hours for reaction. When the reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is detected to be complete by GC, slowly add 6.8 g (68.3 mmol, 0.1 eq) of concentrated hydrochloric acid dropwise to the reaction solution, control the dropping time to be 0.5 hours. After the dropping is completed, continue to react at 0 - 5 °C for 1.5 hours. The reaction solution is detected by HPLC and contains a large amount of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0079] (3) Heat the reaction solution in step (2) to 60 °C - 70 °C. At 60 °C - 70 °C, slowly add 84 g (1050 mmol, 1.5 eq) of 50% sodium hydroxide solution dropwise to the reaction solution, control the dropping time to be 30 minutes. After the dropping is completed, keep the temperature at 60 °C - 70 °C for 1 hour for reaction. When the reaction of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is detected to be complete by HPLC, separate the aqueous phase from the reaction solution. The organic phase is extracted with 50 g of water, and the aqueous phases are combined. The organic phase is used for subsequent batches. Add 111.9 g (1120 mmol, 1.6 eq) of concentrated hydrochloric acid dropwise to the aqueous phase solution, control the dropping time to be 20 minutes. After cooling, filter and dry to obtain 116.4 g of solid product, which is identified as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid by NMR detection. The purity detected by HPLC is 97.5%, and the yield is 92.1%.

[0080] Example 6

[0081] This example provides another preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which is as follows:

[0082] (1) Under the protection of N2, add 100 g (735.3 mmol, 1.05 eq) of o-nitrobenzaldehyde, 80.5 g (700.3 mmol, 1.0 eq) of 40% methylhydrazine and 160 g of toluene into the reaction flask, start stirring, heat up to 40 °C and keep the temperature for 4.5 hours for reaction. When the reaction of o-nitrobenzaldehyde is detected to be complete by GC.

[0083] (2) Under the protection of N2, cool the reaction solution in step (1) to 0 - 5 °C. At 0 - 5 °C, slowly add 154.7 g (700 mmol, 1.0 eq) of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate dropwise to the reaction solution, control the dropping time to be 1.5 hours. After the dropping is completed, continue to keep the reaction at 0 - 5 °C for 2 hours. When the reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is detected to be complete by GC, slowly add 6.8 g (68.3 mmol, 0.1 eq) of concentrated hydrochloric acid dropwise to the reaction solution, control the dropping time to be 0.5 hours. After the dropping is completed, continue to react at 0 - 5 °C for 1.5 hours. The reaction solution is detected by HPLC to contain a large amount of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0084] (3) Heat the reaction solution in step (2) to 60 °C - 70 °C. At 60 °C - 70 °C, slowly add 84 g (1050 mmol, 1.5 eq) of 50% sodium hydroxide solution dropwise to the reaction solution, control the dropping time to be 30 minutes. After the dropping is completed, keep the reaction at 60 °C - 70 °C for 1 hour. When the reaction of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is detected to be complete by HPLC, separate the aqueous phase from the reaction solution, extract the organic phase with 50 g of water, combine the aqueous phases, and the organic phase is recycled for subsequent use. Drop 111.9 g (1120 mmol, 1.6 eq) of concentrated hydrochloric acid dropwise into the aqueous phase solution, control the dropping time to be 20 minutes. After cooling, filter and dry to obtain 117 g of solid product, which is identified as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid by NMR detection. The purity detected by HPLC is 96.6%, and the yield is 91.7%.

[0085] Example 7

[0086] This example provides another preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which is as follows:

[0087] (1) Under the protection of N2, add 100 g (735.3 mmol, 1.05 eq) of m-nitrobenzaldehyde, 80.5 g (700.3 mmol, 1.0 eq) of 40% methylhydrazine and 160 g of toluene into the reaction flask, start stirring, heat up to 40 °C and keep the reaction for 4.5 hours. When the reaction of m-nitrobenzaldehyde is detected to be complete by GC.

[0088] (2) Under N2 protection, cool the reaction solution from step (1) to 0 - 5 °C. At 0 - 5 °C, slowly add 154.7 g (700 mmol, 1.0 eq) of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate dropwise to the reaction solution, control the dropping time to be 1.5 hours. After the dropping is completed, continue to keep the reaction at 0 - 5 °C for 2 hours. When GC detection shows that the reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is complete, slowly add 6.8 g (68.3 mmol, 0.1 eq) of concentrated hydrochloric acid dropwise to the reaction solution, control the dropping time to be 0.5 hours. After the dropping is completed, continue to react at 0 - 5 °C for 1.5 hours. HPLC detection shows that the product in the reaction solution contains a large amount of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0089] (3) Heat the reaction solution from step (2) to 60 °C - 70 °C. At 60 °C - 70 °C, slowly add 84 g (1050 mmol, 1.5 eq) of 50% sodium hydroxide solution dropwise to the reaction solution, control the dropping time to be 30 minutes. After the dropping is completed, keep the reaction at 60 °C - 70 °C for 1 hour. When HPLC detection shows that the reaction of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is complete, separate the aqueous phase from the reaction solution, extract the organic phase with 50 g of water, combine the aqueous phases, and the organic phase is recycled for subsequent use. Drop 111.9 g (1120 mmol, 1.6 eq) of concentrated hydrochloric acid dropwise into the aqueous phase solution, control the dropping time to be 20 minutes, cool and then filter and dry to obtain 119 g of solid product, which is identified as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid by NMR detection, and the HPLC detection purity is 95.7%, and the yield is 92.3%.

[0090] Example 8

[0091] This example provides another preparation method of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, which is as follows:

[0092] (1) Under N2 protection, add 100 g (735.3 mmol, 1.05 eq) of p-chlorobenzaldehyde, 80.5 g (700.3 mmol, 1.0 eq) of 40% methylhydrazine and 160 g of toluene to the reaction flask, start stirring, heat up to 40 °C and keep the reaction for 4.5 hours. When GC detection shows that the reaction of p-chlorobenzaldehyde is complete.

[0093] (2) Under N2 protection, cool the reaction solution from step (1) to 0 - 5 °C. At 0 - 5 °C, slowly add 154.7 g (700 mmol, 1.0 eq) of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate dropwise to the reaction solution, control the dropping time to 1.5 hours. After the dropping is completed, continue to keep the reaction at 0 - 5 °C for 2 hours. When GC detection shows that the reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is complete, slowly add 6.8 g (68.3 mmol, 0.1 eq) of concentrated hydrochloric acid dropwise to the reaction solution, control the dropping time to 0.5 hours. After the dropping is completed, continue to react at 0 - 5 °C for 1.5 hours. HPLC detection shows that the reaction solution contains a large amount of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate.

[0094] (3) Heat the reaction solution from step (2) to 60 °C - 70 °C. At 60 °C - 70 °C, slowly add 84 g (1050 mmol, 1.5 eq) of 50% sodium hydroxide solution dropwise to the reaction solution, control the dropping time to 30 minutes. After the dropping is completed, keep the reaction at 60 °C - 70 °C for 1 hour. When HPLC detection shows that the reaction of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate is complete, separate the aqueous phase from the reaction solution, extract the organic phase with 50 g of water, combine the aqueous phases, and recycle the organic phase for subsequent use. Drop 111.9 g (1120 mmol, 1.6 eq) of concentrated hydrochloric acid into the aqueous phase solution, control the dropping time to 20 minutes. After cooling, filter by suction and dry to obtain 119.1 g of solid product, which is identified as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid by NMR detection. HPLC detection shows that the purity is 96.7% and the yield is 93.5%.

[0095] Comparative Example 1

[0096] Under N2 protection, add 27.6 g of methylhydrazine (240 mmol, 1.2 eq, 40% purity) to 50 g of toluene. Under the condition of 0 ± 2 °C, drop a 70 g toluene solution of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate (200 mmol, 1.0 eq) into the reaction system, slowly drop for 3 hours, control the temperature at 0 ± 2 °C. After the dropping is completed, keep the reaction at 0 ± 2 °C for 1.0 hour. When GC detection shows that the reaction of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is complete, add ethyl acetate and water for extraction, concentrate the organic phase, and 33 g of solid is precipitated. After NMR identification, isomers exist, and the yield of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is 75.2%.

[0097] The above has made a detailed description of the present invention, aiming to enable those skilled in this field of technology to understand the content of the present invention and implement it. However, it should not be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for preparing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, characterized in that, It includes the following steps: (1) React methylhydrazine with benzaldehyde substances in an organic solvent to obtain reaction solution A, (2) Add ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate to reaction solution A first, react, and then add hydrochloric acid to obtain reaction solution B, (3) Add a basic salt to reaction solution B to react, then separate the aqueous phase, add hydrochloric acid to the aqueous phase to react to obtain reaction solution C, and the solid product is obtained by filtering reaction solution C, which is the 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid.

2. The preparation method according to claim 1, characterized in that, The benzaldehyde substances are one or more of benzaldehyde, p-methoxybenzaldehyde, o-methoxybenzaldehyde, m-methoxybenzaldehyde, p-nitrobenzaldehyde, o-nitrobenzaldehyde, m-nitrobenzaldehyde, p-chlorobenzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, p-fluorobenzaldehyde, o-fluorobenzaldehyde, and m-fluorobenzaldehyde; and / or, the organic solvent is one or more of toluene, tetrahydrofuran, methylcyclohexane, n-hexane, and cyclohexane; and / or, the basic salt is one or more of sodium hydroxide, potassium hydroxide, and calcium hydroxide.

3. The preparation method according to claim 1, characterized in that The methylhydrazine is fed in as a methylhydrazine solution with a mass concentration of 35% - 45%; and / or, the hydrochloric acid in steps (2) and (3) is fed in as concentrated hydrochloric acid with a mass concentration of 36% - 38%; and / or, the basic salt in step (3) is fed in as a basic salt solution with a mass concentration of 40% - 60%.

4. The preparation method according to claim 1, wherein, The molar ratio of the fed methylhydrazine, the benzaldehyde substances, and ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is 1:(1 - 1.5):(1 - 1.5); and / or, in step (2), the molar ratio of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate to hydrochloric acid is 1:(0.1 - 0.7); and / or, the molar ratio of the basic salt to hydrochloric acid in step (3) and the molar amount of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate fed in step (2) is (1 - 2):(1.2 - 2.2):

1.

5. The preparation method according to claim 1, characterized in that, The reaction temperature in step (1) is 35°C - 45°C; and / or, the reaction temperature in step (2) is 0°C - 10°C; and / or, the reaction temperature in step (3) is 60°C - 70°C.

6. The preparation method according to claim 5, characterized in that, The reaction time in step (1) is 3h - 7h; and / or, in step (2), the reaction time for reacting with ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is 2h - 4h, and the reaction time for reacting with hydrochloric acid is 1h - 3h; and / or, in step (2), the reaction time for reacting with the basic salt is 1h - 3h, and the reaction time for reacting with hydrochloric acid in step (3) is 10 - 40 min.

7. The preparation method according to claim 1, characterized in that, In step (2), ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate and hydrochloric acid are respectively fed in by dropping, And / or, in step (3), the basic salt is fed in the form of dropping a basic salt solution, and the hydrochloric acid is fed in a dropping manner in step (3).

8. The preparation method according to claim 7, characterized in that, In step (2), the dropping time of ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is controlled to be 1 h - 2 h, the dropping time of hydrochloric acid is 20 min - 30 min, and the dropping temperatures are 0°C - 10°C respectively; And / or, in step (3), the dropping time of the basic salt solution is controlled to be 0.5 h - 1 h, the dropping time of hydrochloric acid is controlled to be 20 - 30 min, and the dropping temperatures are 60°C - 70°C respectively.

9. The preparation method according to claim 1, characterized in that, The reactions in step (1) and step (2) are both carried out under the protection of an inert gas.

10. The preparation method according to claim 1, characterized in that, The preparation method is specifically as follows: (1) Under the protection of an inert gas, at 35°C - 45°C, methylhydrazine reacts with a benzaldehyde substance in an organic solvent for 3 h - 7 h; (2) Under the protection of an inert gas, at 0°C - 10°C, ethyl 2-(dimethylaminomethylene)-4,4-difluoro-3-oxobutyrate is dropped into the reaction solution of step (1), the dropping time is controlled to be 1 h - 2 h, after the dropping is completed, the reaction is carried out under insulation at 0°C - 10°C for 1 h - 2 h, then hydrochloric acid is dropped, the dropping time is controlled to be 20 min - 30 min, and after the dropping is completed, the reaction is carried out under insulation at 0°C - 10°C for 1 h - 1.5 h; (3) At 60°C - 70°C, the basic salt solution is dropped into the reaction solution of step (2), the dropping time is controlled to be 0.5 h - 1 h, after the dropping is completed, the reaction is carried out under insulation at 60°C - 70°C for 1 h - 1.5 h, then the aqueous phase is separated out, hydrochloric acid is dropped into the aqueous phase, the dropping time is controlled to be 20 min - 30 min, and after the dropping is completed, the product is obtained through cooling, suction filtration, and drying, which is 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid.

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