Method for synthesizing isoflaucram intermediate

Abstract

The invention relates to a method for preparing an isoflaucram intermediate, and provides a novel method for synthesizing 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid, which is high in yield and low in cost. The total yield reaches 65% or above.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing an isoflucypram intermediate, and in particular to a method for preparing 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid. Background Art

[0002] Iblon TM It is a new broad-spectrum fungicide with an active ingredient called isoflurane. It is a pyrazole amide fungicide developed by Bayer CropScience. In 2019, isoflurane was first registered in New Zealand and launched in 2020. In April 2020, Bayer registered a combination of isoflurane and prothioconazole, which was launched in 2021. Bayer's financial report shows that isoflurane has been approved by British regulators in 2023 and will be put into commercial use in 2024.

[0003] Isoflucypram can be used to control many grain diseases, has a long-lasting fungicidal effect, and can significantly improve grain yield and quality. According to Bayer's estimates, isoflucypram's annual peak sales are expected to reach US$250 million.

[0004] The structural formula of Isoflucypram is as follows:

[0005]

[0006] Ceciliano, Dahmen, Coqueron and others proposed a similar isoflucypram route, using cyclopropaneamine and 5-chloro-2-isopropylbenzaldehyde as intermediates, and the halide reacted with the amine group to obtain N-(2-isopropyl-5-methylbenzyl)cyclopropaneamine. The obtained secondary amine intermediate reacted with 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-yl chloride to obtain the product. The route is:

[0007]

[0008] The current process for synthesizing Isoflucypram requires the use of the intermediate 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid, as described in patents WO2013156559 and WO2014076007.

[0009] US20110207940 discloses a synthesis method:

[0010]

[0011] The first step is to react ethyl difluoroacetate with ethyl acetate through Claisen ester condensation reaction under the action of strong base sodium hydride to generate ethyl difluoroacetate, which is more dangerous. Then cyclize with methyl hydrazine to form pyrazole ring, then through the Vilsmayer-Hack reaction, generate 3-(difluoromethyl)-5-chloro-1-methyl-1H-pyrazole-4-carboxaldehyde, then through fluorination reaction, generate 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxaldehyde, through periodic acid oxidation, generate 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid. The whole process yield is no more than 25%. Oxidation aldehyde group uses periodic acid, and the price is higher, so this route is not suitable for industrial production.

[0012] In addition to the above methods, other preparation methods in the prior art have many problems such as low yield, use of uncommon raw materials, high pollution, and difficult wastewater treatment.

[0013] Therefore, it is of great significance to develop a method for synthesizing 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid with high yield and low cost. Summary of the invention

[0014] The invention provides a novel method for synthesizing 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid with high yield and low cost, and the total yield is more than 65%.

[0015] The present invention provides a method for synthesizing 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid, characterized in that:

[0016] The compound of formula 1 is used as a raw material, and is prepared via intermediate compounds of formula 2 and formula 3.

[0017] The structure of the compound of formula 1 is as follows:

[0018]

[0019] The structure of the compound of formula 2 is as follows:

[0020]

[0021] The compound of formula 3 is as follows:

[0022]

[0023] Wherein R1, R2, R3 and R4 are each the same or different and are independently selected from: H, substituted or unsubstituted straight or branched chain C1-C 10alkyl, substituted or unsubstituted straight chain or branched C1-C6 cyano, substituted or unsubstituted straight chain or branched C2-C6 alkenyl; substituted or unsubstituted straight chain or branched C2-C6 alkynyl; substituted or unsubstituted straight chain or branched C1-C6 keto; substituted or unsubstituted C3-C 10 Cycloalkyl; substituted or unsubstituted C1-C 10 Heterocyclic group; substituted or unsubstituted C1-C 10 The substituted groups are -OH, -NH2, halogen, nitro, substituted or unsubstituted straight or branched C1-C6 alkyl, substituted or unsubstituted straight or branched C1-C6 cyano, substituted or unsubstituted straight or branched C2-C6 alkenyl, substituted or unsubstituted straight or branched C2-C6 alkynyl, substituted or unsubstituted straight or branched C1-C6 alkoxy, substituted or unsubstituted straight or branched C1-C6 secondary, tertiary or quaternary amine, substituted or unsubstituted straight or branched C1-C6 ester, substituted or unsubstituted straight or branched C1-C6 amide, substituted or unsubstituted straight or branched C1-C6 keto, substituted or unsubstituted C3-C 10 Cycloalkyl; substituted or unsubstituted C1-C 10 Heterocyclic group; substituted or unsubstituted C1-C 10 substituted with aryl or heteroaryl.

[0024] The preparation method as described above is characterized in that: the compound of formula 3 is further prepared into a compound of formula 4, and the structure of the compound of formula 4 is:

[0025]

[0026] R5 is halogen, and specifically preferably Cl, Br, or I.

[0027] The preparation method as described above is characterized in that: 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid is prepared from the compound of formula 4.

[0028] The preparation method as described above is characterized in that the steps of preparing the compound of formula 2 from the compound of formula 1 are:

[0029] The compound of formula 2 is prepared by reacting the compound of formula 1 with difluoroacetyl halide.

[0030] The preparation method as described above is characterized in that the steps of preparing the compound of formula 3 from the compound of formula 2 are:

[0031] The compound of formula 2 is reacted with an alkyl hydrazine to obtain a compound of formula 3.

[0032] The preparation method as described above is characterized in that the steps of preparing the compound of formula 4 from the compound of formula 3 are:

[0033] The compound of formula 3 is reacted with a halogenating agent (the halogenating agent is preferably HCl, HBr, HI, phosphorus trichloride, phosphorus tribromide, thionyl chloride, alkyl acyl chloride, dichlorotriphenylphosphine, dibromotriphenylphosphine, preferably thionyl chloride) to prepare a compound of formula 4.

[0034] The preparation method as described above is characterized in that: the compound of formula 4 is reacted with a fluorinated reagent (preferably NaF, KF, CaF2, MgF2, etc., more preferably KF) to prepare a compound of formula 5;

[0035]

[0036] The preparation method as described above is characterized in that: the compound of formula 5 is subjected to a hydrolysis reaction to prepare 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid.

[0037] The preparation method as described above is characterized in that the structures of the compounds of Formula 1, Formula 2, Formula 3, Formula 4 and Formula 5 are respectively:

[0038]

[0039] The preparation method as described above is characterized in that the preparation steps are:

[0040] condensation

[0041]

[0042] loop

[0043]

[0044] Chlorination

[0045]

[0046] Fluorinated

[0047]

[0048] hydrolysis

[0049]

[0050] Wherein X is F, Cl, Br or I; M is a metal ion.

[0051] The present invention also provides a method for synthesizing 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid, which is characterized in that: the compound of formula 2 is used as a raw material, and the compound of formula 3 and the compound of formula 4 are used as intermediate compounds to prepare the compound.

[0052] The preparation steps are as described above.

[0053] Furthermore, each step of the preparation method of the present application is preferably selected from the following methods:

[0054] (1) The condensation reaction is a condensation reaction of the compound of formula 1 with difluoroacetyl halide in the presence of an organic base to generate diethyl 2-difluoroacylmalonate, wherein the organic base is preferably triethylamine, pyridine, quinoline, piperidine, etc., and X is: F, Cl, Br. The solvent used is selected from toluene, chlorobenzene, xylene, nitrile, amide and ether, and is preferably dichloromethane. The reaction temperature is -30-80°C, preferably 30°C.

[0055] (2) The cyclization reaction is to form 3-(difluoromethyl)-5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester by reacting the compound of formula 2 with alkyl hydrazine. The solvent used is selected from toluene, chlorobenzene, xylene, nitrile, amide and ether, preferably dichloromethane. The reaction temperature is -30-80°C, preferably 40°C. The alkyl hydrazine is preferably methyl hydrazine.

[0056] (3) Chlorination reaction is to use thionyl chloride as a chlorination reagent to react with the compound of formula 3 to generate 3-(difluoromethyl)-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, and the solvent used is selected from toluene, chlorobenzene, xylene, nitrile, amide and ether, preferably toluene. The reaction temperature is 20-120°C, preferably 80°C.

[0057] (4) Fluorination reaction is to use fluoride of alkali metal or alkaline earth metal as fluorination reagent to react with compound of formula 4 to generate 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, wherein the fluorination reagent is NaF, KF, CaF, etc., preferably KF. The solvent is selected from sulfolane, dimethylacetamide, dimethylformamide or N-methylpyrrolidone. Preferably dimethylformamide. The reaction temperature is 80-160°C, preferably 150°C.

[0058] The hydrolysis reaction is to first hydrolyze with sodium hydroxide solution and then acidify with hydrochloric acid to hydrolyze the compound of formula 5 into the target product 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid. The concentration of the sodium hydroxide solution is 1-32%, preferably 5%, and the end point of the hydrochloric acid acidification is pH 2-3. The temperature of the hydrolysis is 30-80°C, preferably 60°C, and the temperature of the acidification is 30-80°C, preferably 60°C.

[0059] Furthermore, the preparation method is specifically as follows:

[0060] (1) The condensation reaction is a condensation reaction of diethyl malonate and difluoroacetyl halide in the presence of an organic base to generate diethyl 2-difluoroacyl malonate, wherein the organic base is triethylamine, pyridine, quinoline, piperidine, etc., and X is: F, Cl, Br. The solvent used is selected from toluene, chlorobenzene, xylene, nitrile, amide and ether, preferably dichloromethane. The reaction temperature is -30-80°C, preferably 30°C.

[0061] (2) The cyclization reaction is to form 3-(difluoromethyl)-5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester by cyclization with methylhydrazine, and the solvent used is selected from toluene, chlorobenzene, xylene, nitrile, amide and ether, preferably dichloromethane. The reaction temperature is -30-80°C, preferably 40°C.

[0062] (3) The chlorination reaction is to use thionyl chloride as a chlorination reagent to react with 3-(difluoromethyl)-5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester to generate 3-(difluoromethyl)-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, and the solvent used is selected from toluene, chlorobenzene, xylene, nitrile, amide and ether, preferably toluene. The reaction temperature is 20-120°C, preferably 80°C.

[0063] (4) Fluorination reaction is to use fluoride of alkali metal or alkaline earth metal as fluorination reagent, and react with 3-(difluoromethyl)-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester to produce 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, wherein the fluorination reagent is NaF, KF, CaF, etc., preferably KF. The solvent is selected from sulfolane, dimethylacetamide, dimethylformamide or N-methylpyrrolidone. Preferably dimethylformamide. The reaction temperature is 80-160°C, preferably 150°C.

[0064] The hydrolysis reaction is to first hydrolyze with sodium hydroxide solution and then acidify with hydrochloric acid to hydrolyze 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester into the target product 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid. The concentration of the sodium hydroxide solution is 1-32%, preferably 5%, and the end point of the hydrochloric acid acidification is pH 2-3. The temperature of the hydrolysis is 30-80°C, preferably 60°C, and the temperature of the acidification is 30-80°C, preferably 60°C.

[0065] All the compounds mentioned above include various salts of the compounds, such as pharmaceutically acceptable salts.

[0066] The preparation method of the present invention adopts commonly used compounds, has low cost, is easy to treat wastewater, does not cause environmental pollution, and has high yield. After the preparation process of the present invention is optimized, the yield reaches more than 65%.

[0067] Terminology Conventions:

[0068] "Alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups and has a specified number of carbon atoms, generally 1 to about 12 carbon atoms. As used herein, the term C1-C6 alkyl refers to an alkyl group having 1 to about 6 carbon atoms. When a C0-C6 alkyl group is used in conjunction with another group, n When an alkyl group is used, for example, (phenyl) C0-C4 alkyl, the specified group, in this case, the phenyl group is directly bonded by a single covalent bond (C0) or connected by an alkyl chain having a specified number of carbon atoms (in this case, 1 to about 4 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.

[0069] "Alkenyl" or "alkene group" refers to straight and branched hydrocarbon chains that include one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain. The alkenyl groups described herein typically have 2 to about 12 carbon atoms. Preferred alkenyl groups are lower alkenyl groups, those having 2 to about 8 carbon atoms, such as: C2-C8, C2-C6, and C2-C4 alkenyl. Examples of alkenyl groups include ethenyl, propenyl, and butenyl.

[0070] "Alkoxy" refers to an alkyl group as defined above with the specified number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.

[0071] "Aryl" or "heteroaryl" means a stable 5- or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. When the total number of S and O atoms in the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heteroaryl is not more than 2. It is particularly preferred that the total number of S and O atoms in the heteroaryl is not more than 1. The nitrogen atom in the heterocycle can be optionally quaternized. When indicated, these heteroaryl groups can also be substituted with carbon or non-carbon atoms or groups. This substitution can include fusion with a 5 to 7-membered saturated ring group optionally containing 1 or 2 heteroatoms independently selected from N, O and S, thereby forming, for example, [1,3] dioxazolo[4,5-c] pyridinyl. Examples of heteroaryl groups include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolyl, pyrrolyl, pyrazolyl, benzo[b]thiophenyl, isoquinolyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8-tetrahydroisoquinoline.

[0072] "Pharmaceutically acceptable salts" or "salts of compounds" are derivatives of the disclosed compounds wherein the parent compound forms salts by addition salt preparation with non-toxic acids or bases. DETAILED DESCRIPTION

[0073] Embodiment 1:

[0074] (1) Condensation

[0075] A 500mL four-necked flask is equipped with a thermometer, a reflux condenser, a mechanical stirrer and a constant pressure dropping funnel. 150mL of dichloromethane is added in sequence, stirring is started, 40.2g (0.250mol) of diethyl malonate, 28.0g (0.275mol) of triethylamine is added, the temperature is controlled at 25-30°C, 30.7g (0.263mol) of difluoroacetyl chloride is added dropwise, and the reaction temperature is maintained at 30°C after the dropwise addition, and the reaction is stirred for 3-5h. In another three-necked flask, 80.0g of deionized water and 14.2g of hydrochloric acid are added, the temperature is controlled at <15°C, the above reaction solution is added dropwise, and the mixture is stirred for 30min after the dropwise addition, and the organic phase is washed once with 100g of deionized water to obtain an organic solution of diethyl 2-difluoroacyl malonate for standby use.

[0076] (2) Ring closure

[0077] A 500mL four-necked flask is equipped with a thermometer, a reflux condenser, a mechanical stirrer and a constant pressure dropping funnel. The above organic phase is added, stirring is started, the temperature is controlled at 35-40°C, and 28.9g (0.251mol) of 40% methyl hydrazine is added dropwise. After the dropwise addition, the reaction temperature is maintained at 40°C, and the reaction is stirred for 8-10h. In another three-necked flask, 30.0g of deionized water and 10.9g of hydrochloric acid are added, stirred evenly, and added dropwise to the above reaction solution, the temperature is controlled at <15°C, and after the dropwise addition, stirring is performed for 30min to stand and separate, and the organic phase is washed once with 100g of deionized water. The solvent is removed by negative pressure distillation, 150mL of methanol is added, heated to dissolve, the temperature is slowly lowered to -10 to -5°C, filtered and dried to obtain 49.5g of white solid crystals of 3-(difluoromethyl)-5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, the GC purity is greater than 99%, and the total yield of condensation and cyclization is 89.0%.

[0078] (3) Chlorination

[0079] A 500mL four-necked flask was equipped with a thermometer, a reflux condenser, a mechanical stirrer and a constant pressure dropping funnel. 350mL of toluene and 49.5g (0.223mol) of 3-(difluoromethyl)-5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid were added. The mixture was stirred to dissolve. The temperature was controlled at 70-80°C. 28.1g (0.234mol) of dichlorothionyl was added dropwise. After the dropwise addition, the temperature was controlled at 80°C for reaction for 5-7h. After the reaction was completed, the solvent was evaporated under negative pressure to obtain 51.1g (0.206mol) of 3-(difluoromethyl)-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as a light yellow solid with a yield of 92.5%.

[0080] (4) Fluorinated

[0081] A 500mL four-necked flask was equipped with a thermometer, a reflux condenser, and a mechanical stirrer. 300mL of DMF and 51.1g (0.206mol) of 3-(difluoromethyl)-5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid were added, stirred to dissolve, 19.3g (0.329mol) of potassium fluoride were added, the temperature was raised to 150°C, and the reaction was carried out for 6-10h. After completion, the temperature was lowered to 70°C, and the solvent DMF was removed under negative pressure. The temperature was then lowered to 60°C, and 250mL of 1,2-dichloroethane was added with stirring. The material became a light yellow uniformly dissolved state, and then the temperature was lowered to 30°C, and 100mL of deionized water was added to wash twice. The solvent was evaporated under negative pressure, 150 mL of methanol was added, the temperature was raised to 60°C to dissolve, and then the temperature was slowly lowered to -10 to -5°C, filtered and dried to obtain 37.3 g (0.165 mol) of ethyl 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylate as white solid crystals. The GC purity was 98.5%, and the yield was 80.4%.

[0082] (5) Hydrolysis

[0083] A 500mL four-necked flask was equipped with a thermometer, a reflux condenser and a mechanical stirrer. 140g of deionized water was added, and 7.4g (0.182mol) of solid sodium hydroxide was added under stirring. The mixture was dissolved by stirring. 37.3g of white solid 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester was added. The mixture was heated to 60°C and stirred for 1h to dissolve. The mixture was cooled by 20-30°C. 21.2g of hydrochloric acid was slowly added dropwise until the pH value was about 2-3. The mixture was heated to 60°C and stirred for 1h before slowly cooling to 5-10°C. The mixture was filtered and dried to obtain 32.0g (0.164mol) of white solid 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid. The GC purity was 99% and the yield was 99%.

[0084] After calculation, the yield of the preparation method of the present invention reaches 65.5%. After large-scale production verification, the yield can reach more than 65%.

[0085] The above description is a general description of the present invention. According to the situation or actual needs, changes in form and substitution of equivalents can be made. Although specific terms are used herein, these terms are intended to describe rather than limit the purpose. Those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for synthesizing 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid, characterized in that: The compound of formula 1 is used as a raw material, and is prepared via intermediate compounds of formula 2 and formula 3, wherein the structure of the compound of formula 1 is as follows: The structure of the compound of formula 2 is as follows: The compound of formula 3 is as follows: Wherein R1, R2, R3 and R4 are each the same or different and are independently selected from: H, substituted or unsubstituted straight or branched chain C1-C 10 alkyl, substituted or unsubstituted straight chain or branched C1-C6 cyano, substituted or unsubstituted straight chain or branched C2-C6 alkenyl; substituted or unsubstituted straight chain or branched C2-C6 alkynyl; substituted or unsubstituted straight chain or branched C1-C6 keto; substituted or unsubstituted C3-C 10 Cycloalkyl; substituted or unsubstituted C1-C 10 Heterocyclic group; substituted or unsubstituted C1-C 10 The substituted groups are -OH, -NH2, halogen, nitro, substituted or unsubstituted straight or branched C1-C6 alkyl, substituted or unsubstituted straight or branched C1-C6 cyano, substituted or unsubstituted straight or branched C2-C6 alkenyl, substituted or unsubstituted straight or branched C2-C6 alkynyl, substituted or unsubstituted straight or branched C1-C6 alkoxy, substituted or unsubstituted straight or branched C1-C6 secondary, tertiary or quaternary amino, substituted or unsubstituted straight or branched C1-C6 ester, substituted or unsubstituted straight or branched C1-C6 amide, substituted or unsubstituted straight or branched C1-C6 keto, substituted or unsubstituted C3-C 10 Cycloalkyl; substituted or unsubstituted C1-C 10 Heterocyclic group; substituted or unsubstituted C1-C 10 substituted with aryl or heteroaryl.

2. The preparation method according to claim 1, characterized in that: Further, the compound of formula 3 is prepared into a compound of formula 4, and the structure of the compound of formula 4 is: R5 is halogen, and specifically preferably Cl, Br, or I.

3. The preparation method according to claim 2, characterized in that: Prepared from the compound of formula 4 3-(difluoromethyl)-5- Fluoro-1-methyl-1H-pyrazole-4-carboxylic acid.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The steps of preparing the compound of formula 2 from the compound of formula 1 are: The compound of formula 2 is prepared by reacting the compound of formula 1 with difluoroacetyl halide.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The steps of preparing the compound of formula 3 from the compound of formula 2 are: The compound of formula 2 is reacted with an alkyl hydrazine to obtain a compound of formula 3.

6. The preparation method according to any one of claims 1 to 3, characterized in that: The steps of preparing the compound of formula 4 from the compound of formula 3 are: The compound of formula 3 is reacted with a halogenating agent (the halogenating agent is selected from HCl, HBr, HI, phosphorus trichloride, phosphorus tribromide, thionyl chloride, alkyl acyl chloride, dichlorotriphenylphosphine, dibromotriphenylphosphine, preferably thionyl chloride) to prepare a compound of formula 4.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The compound of formula 4 is reacted with a fluorinated reagent (preferably NaF, KF, CaF2, etc., more preferably KF) to prepare a compound of formula 5; 8. The preparation method according to any one of claims 1 to 3, characterized in that: The compound of formula 5 is subjected to hydrolysis reaction to prepare 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid.

9. The preparation method according to any one of claims 1 to 3, characterized in that: The structures of the compounds of Formula 1, Formula 2, Formula 3, Formula 4 and Formula 5 are respectively:

10. The preparation method according to any one of claims 1 to 9, characterized in that: The preparation steps are: (1) Condensation (2) Ring closure (3) Chlorination (4) Fluorinated (5) Hydrolysis Wherein X is F, Cl, Br or I; M is a metal ion.

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