Preparation method of 3-(difluoromethyl)-1-methyl-pyrazole-4-formate

Abstract

The invention discloses a preparation method of 3-(difluoromethyl)-1-methyl-pyrazole-4-formic ether, which comprises the following steps of: reacting 5-(difluoromethyl)-1-methyl-pyrazole-4-formic ether in the presence of a methyl translocation reagent, an acid catalyst and a polar solvent in a pressurized system to obtain 3-(difluoromethyl)-1-methyl-pyrazole-4-formic ether, thereby obtaining the 3-(difluoromethyl)-1-methyl-pyrazole-4-formic ether. And carrying out a transposition reaction to obtain the 3-(difluoromethyl)-1-methyl-pyrazole-4-formate. The transposition reaction is carried out under the pressurization condition, and the methyl transposition reagent, the acid catalyst and the polar solvent are matched, so that the reaction time can be shortened, the use amount of the methyl transposition reagent, the acid catalyst and the polar solvent can be reduced, the content of isomerization products in reaction products can be reduced, and the yield can be improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a preparation method of 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate. BACKGROUND

[0002] Benzovindiflupyr is a SDHI fungicide developed by Syngenta, which has good control effect on Asian soybean rust, wheat leaf blight, peanut black spot, wheat take-all and wheat basal rot, and has long lasting effect and no cross resistance with many fungicides. There are two important precursor modules in benzovindiflupyr, one of which is 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate.

[0003] The chemical structural formula of the intermediate is as follows:

[0004]

[0005] At present, there are mainly five kinds of preparation methods of 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate.

[0006] The first preparation method is to use difluoroacetyl acetic acid ethyl ester as the starting material, react with trimethyl orthoformate to generate 2-(methoxymethylene)-4,4-difluoro-3-oxobutanoic acid ethyl ester, and finally use methyl hydrazine to close ring to obtain difluoro pyrazole carboxylate. It is disclosed in WO2011 / 113788 and CN101959840 of Syngenta.

[0007] The first preparation method has the following disadvantages: (1) The reaction needs ultra-low temperature-25℃, and also needs anhydrous and anaerobic conditions, which is harsh for reaction, and is not conducive to scale-up and safe production. (2) The isomerization ratio is high, which is not easy to remove, and the yield is low.

[0008] The second preparation method is to use dichloroacetyl acetic acid ethyl ester as the starting material, react with trimethyl orthoformate to generate 2-(methoxymethylene)-4,4-dichloro-3-oxobutanoic acid ethyl ester, and then use methyl hydrazine to close ring to obtain difluoro pyrazole carboxylate, and finally use potassium fluoride to fluorinate to obtain 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate. It is disclosed in CN103582631 of Rhodia and CN106467492 of Lianhua Science and Technology.

[0009] The second preparation method has the following disadvantages: (1) The method has too long steps, and the total yield is low. (2) The unit reaction operation is too much, which is not convenient for scale-up production. (3) A large amount of waste is generated after the reaction is completed. (4) The isomerization ratio is high, which is not easy to remove, and the yield is low. (5) The fluorine substitution yield is low.

[0010] The third preparation method is to condense dichloroacetyl chloride with vinyl methyl ether and methyl hydrazine to obtain 3-(dichloromethyl)-1-methyl-pyrazole, and then to obtain 3-(dichloromethyl)-4-bromo-1-methyl-pyrazole by bromination. Then, potassium fluoride is substituted, and finally, carbonylation is performed to obtain 3-(difluoromethyl)-1-methyl-pyrazole 4-ethyl carboxylate. It is reported in the patents CN101687806 of Sinochem and CN101679282A of BASF.

[0011] The third preparation method has the following disadvantages: (1) the method has too many steps, and the total yield is low; (2) a large amount of waste is generated after the reaction; (3) the isomerization ratio is high, which is difficult to remove, and the yield is low; and (4) the fluorine substitution yield is low.

[0012] The fourth preparation method is to use 2-(methoxymethylene)-4,4-dichloro-3-oxobutyric acid ethyl ester as a starting material, and methyl hydrazine and benzaldehyde are condensed to obtain difluoro pyrazole carboxylic acid ethyl ester, which is reported in BASF CN102596912A.

[0013] The fourth preparation method has the following disadvantages: (1) the methyl hydrazine used in the patent must be 98% pure, and there is a major safety hazard in the reaction; (2) benzaldehyde as a protecting group has low atomic economy, and it is difficult to recover benzaldehyde after the reaction; (3) the reaction and post-treatment are complicated, and there are many inconveniences in scale-up production, and a large amount of waste is generated after the reaction.

[0014] The fifth preparation method is to use difluoroacetyl acetic acid ethyl ester as a starting material, react with trimethyl orthoformate to generate 2-(methoxymethylene)-4,4-difluoro-3-oxobutyric acid ethyl ester, and then to condense with hydrazine hydrate and dimethyl sulfate to obtain difluoro pyrazole carboxylic acid ethyl ester (containing 40% isomer product), and finally to perform transposition on the isomer product. It is reported in the patents CN102471278A and CN103052625A of Sinochem.

[0015] In CN102471278A, trimethyl phosphate is used as a transposition reagent, and the transposition reaction is performed at normal pressure and high temperature, and the reaction time is more than 7 hours. This method has the following disadvantages: (1) the transposition reaction is not complete, and 5-10% of the isomer cannot be converted, which needs to be removed by distillation; (2) an ionic intermediate is generated in the transposition process, which cannot be effectively converted, and needs to be removed by dissolving the crude product in toluene and washing with water; and (3) trimethyl phosphate is expensive.

[0016] CN103052625A utilizes dimethyl sulfate and N,N-dimethylacetamide as catalysts for the transposition reaction, carrying out the transposition reaction at ambient pressure and high temperature, with a reaction time exceeding 7 hours. Although this method avoids the use of expensive trimethyl phosphate, it still has the following drawbacks: (1) The transposition reaction is not complete, with more than 4% isomerization remaining. (2) The large amount of catalyst required leads to high production costs. Summary of the Invention

[0017] The technical problem to be solved by the present invention is to provide a method for obtaining 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate by transposition reaction under pressure.

[0018] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0019] This application provides a method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate, wherein 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate undergoes a transposition reaction in the presence of a methyl transposition reagent, an acidic catalyst, and a polar solvent under pressure to obtain the 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate.

[0020] According to some specific embodiments, the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is methyl 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate, and correspondingly, the 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is methyl 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate. The 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is ethyl 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate, and correspondingly, the 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is ethyl 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate.

[0021] According to some specific embodiments, the pressure of the pressurization system is 0.2 to 2 MPa, for example 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 0.9 MPa, 1 MPa, 1.1 MPa, 1.2 MPa, 1.3 MPa, 1.4 MPa, 1.5 MPa, 1.6 MPa, 1.7 MPa, 1.8 MPa, 1.9 MPa or 2 MPa.

[0022] According to some further embodiments, the pressure of the pressurized system is 0.5–2 MPa to ensure reaction yield. Even further, the pressure of the pressurized system is 0.5–1 MPa.

[0023] According to some further embodiments, the pressure of the pressurization system is 0.7 to 1 MPa, in order to reduce production costs while ensuring yield.

[0024] According to some specific embodiments, the translocation reaction time is 2 to 8 hours, for example, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, or 8 hours. The reaction time varies depending on the reaction pressure; when the reaction pressure is above 0.7 MPa, the translocation reaction time can be shortened to less than 3 hours.

[0025] According to some further embodiments, the transposition reaction takes 2 to 5 hours.

[0026] According to some specific embodiments, the molar ratio of the methyl transposition reagent to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.05 to 0.15:1, for example, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, or 0.15:1. Further, the molar ratio of the methyl transposition reagent to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.08 to 0.12:1.

[0027] According to some specific embodiments, the molar ratio of the acidic catalyst to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.01 to 0.02:1, for example, 0.01:1, 0.011:1, 0.012:1, 0.013:1, 0.014:1, 0.015:1, 0.016:1, 0.017:1, 0.018:1, 0.019:1, or 0.02:1. Further, the molar ratio of the acidic catalyst to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.012 to 0.018:1.

[0028] According to some specific embodiments, the molar ratio of the polar solvent to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.2 to 0.4:1, for example, 0.2:1, 0.21:1, 0.22:1, 0.23:1, 0.24:1, 0.25:1, 0.26:1, 0.27:1, 0.28:1, 0.29:1, 0.3:1, 0.31:1, 0.32:1, 0.33:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1, or 0.4:1. Further, the molar ratio of the polar solvent to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.3 to 0.36:1.

[0029] According to some specific embodiments, the methyl transposition reagent is one or more selected from dimethyl sulfate, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, trimethyl phosphate, triethyl phosphate, trimethyl phosphite, and triethyl phosphite.

[0030] According to some further embodiments, the methyl transposition reagent is one or more of dimethyl sulfate, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, trimethyl phosphate, and trimethyl phosphite.

[0031] According to some further embodiments, the methyl transposition reagent is one or more of dimethyl sulfate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, and trimethyl phosphate.

[0032] Furthermore, the methyl transposition reagent is dimethyl sulfate and / or methyl trifluoromethanesulfonate.

[0033] According to some specific embodiments, the acidic catalyst is one or more of phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, concentrated sulfuric acid, p-toluenesulfonic acid, and succinic acid.

[0034] According to some further embodiments, the acidic catalyst is one or more of phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.

[0035] According to some further embodiments, the acidic catalyst is one or more of phosphoric acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

[0036] Furthermore, the acidic catalyst is methanesulfonic acid and / or trifluoromethanesulfonic acid.

[0037] According to some specific embodiments, the polar solvent is one or more selected from sulfolane, DMSO, DMF, NMP, N,N-dimethylethylamine, diethylene glycol ethyl ether, and triethylene glycol ethyl ether.

[0038] According to some further embodiments, the polar solvent is one or more of sulfolane, DMSO, DMF, NMP, and N,N-dimethylethylamine.

[0039] According to some further embodiments, the polar solvent is sulfolane and / or DMSO.

[0040] Furthermore, the polar solvent is sulfolane.

[0041] According to some specific embodiments, the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate, the methyl transposition reagent, the acidic catalyst, and the polar solvent are added to a high-pressure reactor, purged with nitrogen, heated to 150-190°C, and pressurized with nitrogen. After the reaction is completed, the reaction solution is subjected to vacuum distillation to recover the untransposed 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate, which is then added to the next transposition reaction.

[0042] According to some specific embodiments, the temperature of the transposition reaction is 150–190°C, and more specifically 165–175°C.

[0043] According to some specific embodiments, the distillate after vacuum distillation is directly used for hydrolysis to prepare difluoropyrazole acid.

[0044] By adopting the above technical solution, the present invention has the following advantages compared with other processes:

[0045] This invention utilizes a pressure-driven transposition reaction and a combination of a methyl transposition reagent, an acidic catalyst, and a polar solvent. This approach shortens the reaction time while reducing the amounts of these components, thereby decreasing the content of isomerization products in the reaction product and increasing the yield. Attached Figure Description

[0046] Figure 1 The image shows the NMR spectrum of the product synthesized in Example 1. Detailed Implementation

[0047] Because existing transposition reactions still have the shortcomings described in the background section, the applicant has conducted extensive research and finally obtained the technical solution of this application.

[0048] (1) This application avoids using expensive methylhydrazine as a raw material by carrying out the transposition reaction under pressure conditions in synergy of methyl transposition reagent, acid catalyst and polar solvent.

[0049] (2) This application adopts a pressurized reaction method, which can effectively shorten the reaction time. Compared with the traditional transposition reaction, the time can be reduced from 7 hours to 3 hours, thereby doubling the production capacity under the same reaction time.

[0050] (3) This application employs a pressurized reaction method, which effectively avoids the drawbacks of atmospheric pressure reactions requiring large amounts of methyl transposition reagents and acidic catalysts. It effectively reduces the amount of methyl transposition reagents, acidic catalysts, and polar solvents used. With lower amounts of methyl transposition reagents, acidic catalysts, and polar solvents, isomerization to the target product can be effectively achieved. Compared to traditional transposition reactions, under the same production capacity, the amount of methyl transposition reagent used can be reduced by 80%, significantly reducing reaction costs and pollution.

[0051] (4) The preparation method of this application can effectively reduce the impurities in the reaction system, thereby greatly increasing the overall yield of the reaction, shortening the time, having high practical value, being suitable for industrial production, and having broad application prospects.

[0052] The reaction route of this application is as follows:

[0053]

[0054] R = Me, Et

[0055] All features disclosed in this invention, or steps in all methods or processes disclosed, may be combined in any way, except for mutually exclusive features or steps.

[0056] The technical solutions of the present invention will be further described below with reference to specific embodiments. However, the present invention should not be limited to these embodiments. Unless specifically stated otherwise, all features can be replaced by other equivalent or similar alternative features. Unless specifically stated otherwise, each feature is only one example of a series of equivalent or similar features. The terminology used in the present invention, unless otherwise stated, generally has the meaning commonly understood by those skilled in the art. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use. Implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0057] In this invention, operations without specific instructions are performed at room temperature. The raw materials used in this application are commercially available or obtained through conventional methods in the prior art. In this invention, unless otherwise specified, all contents refer to mass content, and "%" represents a percentage by mass.

[0058] Example 1

[0059] 50.00 g (245 mmol, 1.0 eq) of ethyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was added to an autoclave, followed by 3.1 g (24.5 mmol, 0.1 eq) of dimethyl sulfate, 0.55 g (3.675 mmol, 0.015 eq) of trifluoromethanesulfonic acid, and 10 g of sulfolane. After purging with nitrogen three times, the mixture was heated to 170 °C and pressurized to 1.0 MPa for 3 hours. LC analysis showed that the content of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 92.1%, and the content of ethyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 1-2%. The reaction solution was subjected to vacuum distillation to recover the untransposed isomers, which were then added to the next transposition reaction. The combined yield of the recovered isomers was 94.6%. The distillate after vacuum distillation can be directly used in the next hydrolysis reaction to prepare difluoropyrazolic acid, and the purity of the prepared difluoropyrazolic acid meets the requirements.

[0060] Under these conditions, the overall cost (including raw material costs, labor costs, and energy costs) is reduced by 4% to 5% per ton of product produced compared to the transposition method described in CN103052625A.

[0061] The synthesized product was structurally determined to be ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate. The 1H NMR and mass spectrometry data are as follows:

[0062] The nuclear magnetic resonance spectrometer selected is a Bruker model. 1 HNMR(300MHz, DMSO)8.403(s,1H),7.354-6.997(t,1H),4.256-4.185(q,2H,),3.908(s,3H),1.281-1.234(t,3H,).

[0063] MS-EI (m / z, %): 205 (M + +H + ); 227(M) + +Na + ).

[0064] Table 1 below shows experimental examples conducted basically according to the reaction conditions of Example 1, with the only difference being the different polar solvents used in each experimental example. The yields of ethyl 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate synthesized under different polar solvents are shown in Table 1.

[0065] Table 1

[0066] Experiment No. Pressure Time Methyl shift reagent Acid catalyst Polar solvent Combined yield Experiment 1-1 1.0 MPa 3 hours Dimethyl sulfate Triflic acid Sulfolane 94.6％ Experiment 1-2 1.0 MPa 3 hours Dimethyl sulfate Triflic acid NMP 81.7％ Experiment 1-3 1.0 MPa 3 hours Dimethyl sulfate Triflic acid N,N-dimethylethylamine 80.2％ Experiment 1-4 1.0 MPa 3 hours Dimethyl sulfate Triflic acid DMF 79.7％ Experiment 1-5 1.0 MPa 3 hours Dimethyl sulfate Triflic acid DMSO 84.1％ Experiment 1-6 1.0 MPa 3 hours Dimethyl sulfate Triflic acid Diethylene glycol ether 56.7％ Experiment 1-7 1.0 MPa 3 hours Dimethyl sulfate Triflic acid Triethylene glycol ether 60.1％

[0067] Example 2

[0068] 50.00 g (245 mmol, 1.0 eq) of ethyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was added to an autoclave, followed by 4.0 g (24.5 mmol, 0.1 eq) of methyl trifluoromethanesulfonate, 0.55 g (3.675 mmol, 0.015 eq) of trifluoromethanesulfonic acid, and 10 g of sulfolane. After purging with nitrogen three times, the mixture was heated to 170 °C and pressurized to 1.0 MPa for 3 hours. LC analysis showed that the content of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 88.1%, and the content of ethyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 4-5%. The reaction solution was subjected to vacuum distillation to recover the untransposed isomers, which were then added to the next transposition reaction. The combined yield of the recovered isomers was 90.7%.

[0069] Table 2 below shows experimental examples conducted basically according to the reaction conditions of Example 2, with the only difference being the different methyl transposition reagents used in each example. The yields of ethyl 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate synthesized under different methyl transposition reagent conditions are shown in Table 2.

[0070] Table 2

[0071] Experiment No. Pressure Time Methyl shift reagent Acid catalyst Polar solvent Combined yield Experiment 2-1 1.0 MPa 3 hours Trimethyl phosphate Triflic acid Sulfolane 87.1％ Experiment 2-2 1.0 MPa 3 hours Dimethyl carbonate Triflic acid Sulfolane 79.3％ Experiment 2-3 1.0 MPa 3 hours Methyl triflate Triflic acid Sulfolane 90.7％ Experiment 2-4 1.0 MPa 3 hours Methyl p-toluenesulfonate Triflic acid Sulfolane 81.5％ Experiment 2-5 1.0 MPa 3 hours Triethyl phosphate Triflic acid Sulfolane 29.7％ Experiment 2-6 1.0 MPa 3 hours Trimethyl phosphite Triflic acid Sulfolane 76.4％ Experiment 2-7 1.0 MPa 3 hours Triethyl phosphite Triflic acid Sulfolane 31.7％

[0072] By comparing Experiment 1-1 and the experimental examples in Table 2, it can be seen that dimethyl sulfate, trimethyl phosphate, and methyl trifluoromethanesulfonate can be used as methyl transposition reagents to obtain better yields. However, considering the cost of raw materials (for example, the cost of trimethyl phosphate is about 12 times that of dimethyl sulfate) and the isomer content in the reaction solution, dimethyl sulfate is preferred as the methyl transposition reagent.

[0073] Example 3

[0074] 50.00 g (245 mmol, 1.0 eq) of ethyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was added to an autoclave, followed by 3.1 g (24.5 mmol, 0.1 eq) of dimethyl sulfate, 0.35 g (3.675 mmol, 0.015 eq) of methanesulfonic acid, and 10 g of sulfolane. After purging with nitrogen three times, the mixture was heated to 170 °C and pressurized to 1.0 MPa for 3 hours. LC analysis showed that the content of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 87.9%, and the content of ethyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 4-5%. The reaction solution was subjected to vacuum distillation to recover the untransposed isomers, which were then added to the next transposition reaction. The combined yield of the recovered isomers was 89.1%.

[0075] Table 3 below shows experimental examples conducted basically according to the reaction conditions of Example 3, with the only difference being the different acid catalysts used in each experimental example. The yields of ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole 4-carboxylate synthesized under different acid catalysts are shown in Table 3.

[0076] Table 3

[0077] Experiment No. Pressure Time Methyl shift reagent Acid catalyst Polar solvent Yield Experiment 3-1 1.0 MPa 3 hours Dimethyl sulfate Phosphoric acid Sulfolane 80.2％ Experiment 3-2 1.0 MPa 3 hours Dimethyl sulfate Polyphosphoric acid Sulfolane 77.5％ Experiment 3-3 1.0 MPa 3 hours Dimethyl sulfate Methanesulfonic acid Sulfolane 89.1％ Experiment 3-4 1.0 MPa 3 hours Dimethyl sulfate Concentrated sulfuric acid Sulfolane 56.7％ Experiment 3-5 1.0 MPa 3 hours Dimethyl sulfate p-Toluenesulfonic acid Sulfolane 74.3％ Experiment 3-6 1.0 MPa 3 hours Dimethyl sulfate Succinic acid Sulfolane 67.9％

[0078] Example 4

[0079] 50.00 g (245 mmol, 1.0 eq) of ethyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was added to an autoclave, followed by 3.1 g (24.5 mmol, 0.1 eq) of dimethyl sulfate, 0.55 g (3.675 mmol, 0.015 eq) of trifluoromethanesulfonic acid, and 10 g of sulfolane. After purging with nitrogen three times, the mixture was heated to 170 °C and pressurized to 0.7 MPa for 3 hours. LC analysis showed that the content of ethyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 90.7%, and the content of ethyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 2-3%. The reaction solution was subjected to vacuum distillation to recover the untransposed isomers, which were then added to the next transposition reaction. The combined yield of the recovered isomers was 92.1%.

[0080] Table 4 below shows experimental examples conducted basically according to the reaction conditions of Example 4, with the only difference being the pressure and time used in each experimental example. The yields of ethyl 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate synthesized under different pressures and times are shown in Table 4.

[0081] Table 4

[0082]

[0083]

[0084] Example 5

[0085] 46.55 g (245 mmol, 1.0 eq) of methyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was added to an autoclave, followed by 3.1 g (24.5 mmol, 0.1 eq) of dimethyl sulfate, 0.55 g (3.675 mmol, 0.015 eq) of trifluoromethanesulfonic acid, and 10 g of sulfolane. After purging with nitrogen three times, the mixture was heated to 170 °C and pressurized to 1.0 MPa for 3 hours. LC analysis showed that the content of methyl 3-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 91.7%, and the content of methyl 5-(difluoromethyl)-1-methylpyrazole-4-carboxylate was 1-2%. The reaction solution was then subjected to vacuum distillation to recover the untransposed isomers, which were then added to the next transposition reaction. The combined yield of the recovered isomers was 93.9%.

[0086] Comparative Example 1

[0087] Under N2 protection, 9.4 g (200 mmol, 98% purity) of methylhydrazine was added to 150 g of toluene. 21.4 g (200 mmol) of benzaldehyde was added to the reaction solution at 22-26°C. The mixture was heated to 40°C and reacted for 8 hours. The aqueous phase was removed by separation, and the polar solvent toluene was removed under reduced pressure at 40°C. The residue (91.1 g) was cooled to 3°C, and a solution of 60 g of toluene containing 45.7 g (200 mmol) of ethyl 2-(methoxymethylene)-4,4-dichloro-3-oxobutyrate was added dropwise. After the addition was complete, the mixture was heated to 25°C and reacted for 15 hours, forming a yellow emulsion. Finally, 1.7 g of p-toluenesulfonic acid was added, and the mixture was stirred at 70°C for 1 hour. The product was then desolventized to obtain 35.5 g of the target substance, with a purity of 95.1% and a yield of 82.7%.

[0088] Comparative Example 2

[0089] Under N2 protection, 27.6 g (240 mmol, 1.2 eq) of a 40% aqueous solution of methylhydrazine was added to 50 g of a toluene solution. At 0 °C, 45.7 g (200 mmol) of a 70 g toluene solution of ethyl 2-(methoxymethylene)-4,4-dichloro-3-oxobutyrate was slowly added dropwise to the reaction system for 1 h. After the intermediate was detected by GC, ethyl acetate and water were added for extraction. The organic phase was concentrated, and 35 g of solid precipitated with a purity of 92% was obtained. The overall yield was 79%.

[0090] The present invention has been described in detail above, with the aim of enabling those skilled in the art to understand and implement the invention. However, this description should not be construed as limiting the scope of protection of the invention. All equivalent changes or modifications made in accordance with the spirit and essence of the invention should be included within the scope of protection of the invention.

Claims

1. A method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate, characterized in that: The 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate ester was obtained by undergoing a transposition reaction in the presence of a methyl transposition reagent, an acidic catalyst, and a polar solvent under pressure.

2. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to claim 1, characterized in that: The 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is methyl 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate or ethyl 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate.

3. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to claim 1, characterized in that: The pressure of the pressurized system is 0.2–2 MPa, and the time of the displacement reaction is 2–8 hours.

4. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to claim 3, characterized in that: The pressure of the pressurized system is 0.5–2 MPa, and the time of the displacement reaction is 2–5 hours.

5. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to claim 1, characterized in that: The molar ratio of the methyl transposition reagent to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.05–0.15:1, the molar ratio of the acidic catalyst to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.01–0.02:1, and the molar ratio of the polar solvent to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.2–0.4:

1.

6. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to claim 5, characterized in that: The molar ratio of the methyl transposition reagent to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.08–0.12:1, the molar ratio of the acidic catalyst to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.012–0.018:1, and the molar ratio of the polar solvent to the 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate is 0.3–0.36:

1.

7. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to claim 1, characterized in that: The methyl transposition reagent is one or more selected from dimethyl sulfate, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, trimethyl phosphate, triethyl phosphate, trimethyl phosphite, and triethyl phosphite. The acidic catalyst is one or more of phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, concentrated sulfuric acid, p-toluenesulfonic acid, and succinic acid; The polar solvent is one or more of sulfolane, DMSO, DMF, NMP, N,N-dimethylethylamine, diethylene glycol ethyl ether, and triethylene glycol ethyl ether.

8. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to claim 7, characterized in that: The methyl transposition reagent is one or more selected from dimethyl sulfate, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, trimethyl phosphate, and trimethyl phosphite. The acidic catalyst is one or more of phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid; The polar solvent is one or more of sulfolane, DMSO, DMF, NMP, and N,N-dimethylethylamine.

9. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to any one of claims 1 to 8, characterized in that: The 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate, the methyl transposition reagent, the acidic catalyst, and the polar solvent were added to a high-pressure reactor, purged with nitrogen, heated to 150–190°C, and pressurized with nitrogen. After the reaction was completed, the reaction solution was subjected to vacuum distillation to recover the untransposed 5-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate, which was then added to the next transposition reaction.

10. The method for preparing 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylate according to claim 9, characterized in that: The distillate after vacuum distillation is directly used for hydrolysis to prepare difluoropyrazole acid.

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