Preparation method of fluxapyroxad

Abstract

The invention discloses a preparation method of fluxapyroxad, aiming at the defects of high raw material cost and low yield in the existing process method, raw materials and intermediates required by reaction are prepared autonomously, and the yield of the intermediates is further improved by using a catalyst p-toluenesulfonic acid in the synthesis of 2-(ethoxymethylene)-4, 4-difluoro-3-oxobutyric acid ethyl ester. In the cyclization reaction of 2-(ethoxymethylene)-4, 4-difluoro-3-oxobutyric acid ethyl ester and methylhydrazine, the reaction system is optimized, so that the generation of an isomer is avoided, and the yield and the selectivity of the 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid are remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, specifically a novel preparation process for fluopyram, belonging to the fields of pesticides and synthetic chemistry. Background Technology

[0002] Fluopyram is a succinate dehydrogenase inhibitor fungicide developed by BASF. On one hand, fluopyram has the most optimized molecular structure among SDHI fungi, enabling it to rapidly and effectively inhibit the activity of succinate dehydrogenase in fungal mitochondria. On the other hand, it has a broad fungicidal spectrum, showing good control efficacy against various crop diseases caused by fungi such as *Syndromea*, *Botrytis*, powdery mildew, *Cercospora*, *Stenophyllaria*, *Rhizoctonia*, and *Sclerotium*, especially effective against Asian rust disease affecting soybeans. It exhibits excellent efficacy in crop application, including high efficiency, broad coverage, long-lasting effect, strong selectivity, and both preventative and curative effects. Its compound patent expires in 2026. From 2012 to 2019, its sales compound annual growth rate reached 26.4%, and it currently ranks 8th in the global fungicide market, aligning with national strategic needs and showing promising application prospects. However, there are currently few domestic patent documents on the synthesis of fluopyram.

[0003] Currently, the main methods for synthesizing fluopyram include: Method 1: Fluopyram is obtained by condensing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and 2-(3,4,5-trifluorophenyl)aniline as raw materials in the presence of a dehydrating agent; or by reacting 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxyl chloride and 2-(3,4,5-trifluorophenyl)aniline as raw materials in the presence or absence of an auxiliary base to obtain fluopyram (CN101115723A, CN101535274A, CN102015649A, etc.).

[0004] Method 2 involves first performing a dehydration condensation reaction of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid with haloaniline, and then coupling it with 3,4,5-trifluorophenylboronic acid via Suzuki to obtain fluopyram (CN113402464A).

[0005] The aforementioned methods use directly purchased raw materials, resulting in high process costs and making them unsuitable for industrial production. The acyl chloride involved in Method 1 is unstable in the reaction system and easily degrades, leading to low product yield. Furthermore, in existing studies on the total synthesis of fluopyram, the yields of various intermediates, such as ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate, still need improvement. Additionally, in the subsequent cyclization reaction with methylhydrazine to prepare 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid, the isomer 2-difluoromethyl-1-methyl-pyrazole-3-carboxylic acid (CN102015654A, CN101535274A) is still inevitably generated. Therefore, developing an economical, low-yield, and high-purity total synthetic process for the production of fluopyram is particularly important. Summary of the Invention

[0006] The purpose of this invention is to provide an improved method for the total synthesis of fluopyram, addressing the shortcomings of existing methods such as high raw material costs and low yields. This method involves the independent preparation of the required raw materials and intermediates for the reaction. By using p-toluenesulfonic acid as a catalyst in the synthesis of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate, the yield of the intermediate is further improved. In the cyclization reaction of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate with methylhydrazine, the formation of isomers is avoided by optimizing the reaction system, significantly improving the yield and selectivity of 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid.

[0007] A method for preparing fluopyram according to the present invention includes the following steps: A) The 3,4,5-trifluorobromobenzene shown in Formula I undergoes a Grignard reaction, followed by the addition of trimethyl borate and a hydrolysis reaction to obtain the 3,4,5-trifluorophenylboronic acid shown in Formula II. B) 3,4,5-trifluorophenylboronic acid, represented by Formula II, is reacted with o-haloaniline via a Suzuki coupling reaction to yield 2-(3,4,5-trifluorophenyl)aniline, represented by Formula III; wherein the o-haloaniline is o-chloroaniline, o-bromoaniline, or o-iodoaniline. C) Ethyl 4,4-difluoroacetoacetate of Formula IV reacts with triethyl orthoformate to give ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate of Formula V; D) Ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate, as shown in Formula V, is reacted with methylhydrazine via cyclization, hydrolysis, and acidification to yield 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid, as shown in Formula VII. E) The 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid shown in Formula VII is acyl-chlorinated with a chlorinating agent, and then condensed with 2-(3,4,5-trifluorophenyl)aniline shown in Formula III to obtain fluopyram shown in Formula VIII.

[0008] The reaction formula is as follows: ; ; ; In the formula, X represents a halogen, selected from chlorine, bromine or iodine, preferably iodine.

[0009] Preferably, in this invention, step A) specifically comprises: The 3,4,5-trifluorobromobenzene shown in Formula I was prepared as a Grignard reagent, reacted with trimethyl borate, and then hydrolyzed to obtain 3,4,5-trifluorophenylboronic acid shown in Formula II.

[0010] Furthermore, when the 3,4,5-trifluorobromobenzene represented by Formula I undergoes the Grignardization reaction, the preferred temperature is -10℃ to 70℃.

[0011] Furthermore, the solvent used for the Grignard reagent in step A) is selected from any one or more of diethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0012] The mass ratio of 3,4,5-trifluorobromobenzene shown in Formula I to the organic solvent is 1.0:(1.5-10).

[0013] The molar ratio of 3,4,5-trifluorobromobenzene to trimethyl borate shown in Formula I is 1.0:(1.1 to 3.0).

[0014] Preferably, step B) of this invention specifically comprises: 3,4,5-trifluorophenylboronic acid as shown in Formula II and o-haloaniline were added to a small amount of solution as a base, a certain amount of alkali was added, the temperature was raised and a catalyst was added to carry out the reaction.

[0015] Furthermore, the halogenated aniline in step B) includes o-chloroaniline, o-bromoaniline, and o-iodoaniline.

[0016] Further, the solvent selected for the base solution in step B) is any one or more of toluene, methanol, ethanol, isopropanol, and DMF, or a mixture of the above solvents and water, preferably a toluene / water mixture.

[0017] Furthermore, the heating temperature in step B) is between 50°C and 120°C.

[0018] Further, the catalyst in step B) can be palladium acetate / triphenylphosphine, Pd[P(C6H5)3]4, or a combination of palladium catalyst and one or more of AsPh3, n-Bu3P, (MeO)3P, Ph2P(CH2)3PPh2(dppp), Ph2P(CH2)2PPh2(dppe). The base is any one of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

[0019] Further, in step B), the molar ratio of 3,4,5-trifluorophenylboronic acid as shown in Formula II to the catalyst is 1.0:(0.0005~0.01).

[0020] Preferably, in this invention, step C) specifically comprises: Ethyl 4,4-difluoroacetoacetate of Formula IV was reacted with triethyl orthoformate in a solvent in the presence of a catalyst and heated to obtain ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate of Formula V.

[0021] Further, in step C), the molar ratio of ethyl 4,4-difluoroacetoacetate (Formula IV) to triethyl orthoformate is 1.0:(1.2–7.0); the catalyst is p-toluenesulfonic acid.

[0022] Further, the solvent in step C) is selected from any one or more of toluene, xylene, acetic acid, and acetic anhydride, preferably acetic anhydride; the mass ratio of ethyl 4,4-difluoroacetoacetate shown in Formula IV to the solvent is 1.0:(1.5~10.0).

[0023] Furthermore, the heating temperature in step C) is between 30°C and 120°C.

[0024] Preferably, in this invention, step D) specifically comprises: Ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate (Formula V) was added to an organic solvent, with optional addition of tetramethylammonium iodide as a catalyst. The temperature was controlled and the pH was adjusted to alkaline by adding alkali. Methylhydrazine was slowly added, and after reacting for 2 hours, ethyl 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid (Formula VI) was obtained. Strong alkali was added, and the mixture was heated to reflux and stirred for 3 hours for hydrolysis. After acidification and filtration, 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid (Formula VII) was obtained.

[0025] Further, in step D), the organic solvent is selected from acetone, and the mass ratio of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate (Formula V) to the organic solvent is 1.0:(1.5-10), with the reaction temperature controlled between 0℃ and 100℃. The molar ratio of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate (Formula V) to tetramethylammonium iodide is 1:0.05-0.2. During the reaction of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate (Formula V), the pH is adjusted to 8-11, and the added base is triethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc. The alkali added during the hydrolysis of ethyl 3-difluoromethyl-1-methyl-pyrazole-4-carboxylate as shown in Formula VI includes sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, etc. The molar ratio of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate as shown in Formula V to the alkali used for hydrolysis is 1.0:(2.0~5.0).

[0026] Preferably, in this invention, step E) specifically comprises: The compound shown in Formula VII was acyl-chlorinated with a chlorinating agent, and then added dropwise to the substrate of the compound shown in Formula III, which was mixed with an organic solvent and a base. The reaction was carried out at a controlled temperature for 2 hours to obtain fluopyram as shown in Formula VIII.

[0027] Furthermore, the chlorinating agent mentioned in step E includes thionyl chloride, oxalyl chloride, phosphorus oxychloride, etc., and the molar ratio of compound VII to the chlorinating agent is 1.0:(1.1 to 3.0).

[0028] Further, in step E), the molar ratio of compound VII to compound III is 1.0:(0.9 to 1.5).

[0029] Furthermore, the organic solvent used to mix with the substrate in step E) is any one of toluene, dichloromethane, dichloroethane, DMF, or CCl4.

[0030] Furthermore, the base added to the substrate in step E) is any one of triethylamine, diethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate, and the molar ratio of compound VII to base is 1.0:(1.1 to 3.0).

[0031] Compared with existing synthesis methods, the synthetic route of the present invention has the following advantages: 1. This invention provides a synthetic route with low raw material costs; 2. This invention provides a more specific and complete synthetic route, improving product content and yield. By using p-toluenesulfonic acid as a catalyst in the synthesis of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate, the intermediate yield is further improved. In the cyclization reaction of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate with methylhydrazine, the formation of isomers is avoided by optimizing the reaction system, significantly improving the yield and selectivity of 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid, making it suitable for large-scale production.

[0032] 3. The synthetic route provided by this invention is more convenient and safer in terms of solvents and post-processing, which greatly improves the safety of the reaction. Detailed Implementation

[0033] The technical solutions in the embodiments of the present invention will be clearly and completely described below. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0034] Example 1: Synthesis of Compound II

[0035] Weigh 50.0 g (0.238 mol) of 3,4,5-trifluorobromobenzene, add 300.0 g of tetrahydrofuran and dissolve completely. Under nitrogen protection, slowly add the solution dropwise to a 1000 ml four-necked flask lined with 11.4 g of Mg powder. After adding 60 ml, stop adding and allow the reaction to start. Maintain the temperature at 15℃~20℃ and continue to slowly add the remaining mixture of 3,4,5-trifluorobromobenzene and tetrahydrofuran over 2 hours. Then, continue stirring at 20℃ for 0.5 hours until the reaction is complete. Filter the solution and, under nitrogen protection, add 29.8 g (0.28 mol) of trimethyl borate dissolved in 90.0 g of tetrahydrofuran dropwise to the filtrate over 0.5 hours. Then, continue stirring at 45℃ for 2 hours until the reaction is complete. Add (31%) dilute hydrochloric acid to adjust the pH to 2-5, and stir at 25-30℃ for 3 hours. Add 120.0g of dichloromethane, stir at 25℃ for 0.5 hours, separate the organic phase, evaporate to dryness, and obtain 36.9g of white powdery target product with a purity of 96.5% and a yield of 85.0%.

[0036] Synthesis of Compound III:

[0037] Under nitrogen protection, 60 g of toluene, 60 g of water, and 20.6 g (96.5%, 0.113 mol) of compound II and 22.5 g (0.10 mol) of o-iodoaniline were weighed into a four-necked flask and stirred. The temperature was maintained at 25℃–30℃. After purging with nitrogen, 116.4 mg (0.51 mmol) of palladium acetate, 269.6 mg (1.03 mmol) of triphenylphosphine, and 26.2 g (0.12 mol) of potassium phosphate were weighed into the flask and added sequentially. The temperature was raised to 90℃ and stirred for 3 h until the reaction was complete. The temperature was lowered to 30℃, and the phases were separated. The aqueous phase was extracted with 30 g of toluene, and the toluene phases were combined. Vacuum distillation yielded 21.9 g of the target product as a white powder, with a purity of 96.4% and a yield of 91.9%.

[0038] Synthesis of Compound V - 1

[0039] 110.0 g of acetic anhydride was weighed and added to a reaction flask, heated to 110 °C, and 22.4 g (0.135 mol) of compound IV and 26.0 g (0.176 mol) of triethyl orthoformate were added dropwise over 1 h. The mixture was then stirred at 60 °C for 8 h to 10 h until the reaction was complete. The product was then distilled under reduced pressure to obtain 27.5 g of the target product, which was a yellow oily liquid, with a yield of 91.8%.

[0040] Synthesis of Compound IV - 2 110.0 g of acetic anhydride and 2.57 g of p-toluenesulfonic acid monohydrate (0.0135 mol) were weighed and added to a reaction flask. The mixture was heated to 110 °C, and a mixture of 22.4 g (0.135 mol) of compound IV and 26.0 g (0.176 mol) of triethyl orthoformate was added dropwise over 1 hour. The mixture was then stirred at 60 °C for 8 to 10 hours until the reaction was complete. The product was then distilled under reduced pressure to obtain 29.2 g of the target product, a yellow oily liquid, with a yield of 97.4%.

[0041] Synthesis of Compound VII - 1:

[0042] At 0℃, 90g of methanol and 22.2g (0.10mol) of the above compound V were weighed and added to a four-necked flask and stirred. 16.8g (40% aqueous solution, 0.15mol) of methylhydrazine was slowly added dropwise over 30 min. The temperature was then raised to 30℃ and stirring continued for 6 h until the reaction was complete. After vacuum distillation, 60.0g of dichloroethane was added, and the mixture separated into layers. 90.0g (15%) of sodium hydroxide aqueous solution was added to the dichloroethane phase, and the reaction was carried out at 50℃ for 5 h. The temperature was lowered to 30℃ to separate the aqueous phase. Hydrochloric acid was slowly added dropwise to the aqueous phase until the pH became acidic. The mixture was filtered, dried, and 14.8g of a white powdery solid was obtained, with a yield of 84.1%. According to GC analysis, the ratio of 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid to its isomer 2-difluoromethyl-1-methyl-pyrazole-3-carboxylic acid in the product was 85:15.

[0043] Synthesis of Compound VII - Part 2: At 0℃, 90g of acetone and 22.2g (0.10mol) of the above compound V were weighed and added to a four-necked flask and stirred. 16.8g (40% aqueous solution, 0.15mol) of methylhydrazine was slowly added dropwise over 30 min. The temperature was then raised to 30℃ and stirring continued for 6 h until the reaction was complete. After vacuum distillation, 60.0g of dichloroethane was added, and the mixture separated into layers. 90.0g (15%) of sodium hydroxide aqueous solution was added to the dichloroethane phase, and the reaction was carried out at 50℃ for 5 h. The temperature was lowered to 30℃, and the aqueous phase was separated. Hydrochloric acid was slowly added dropwise to the aqueous phase until the pH became acidic. The mixture was filtered, dried, and 16.1g of a white powdery solid was obtained, with a yield of 91.5%. According to GC analysis, the ratio of 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid to its isomer 2-difluoromethyl-1-methyl-pyrazole-3-carboxylic acid in the product was approximately 150:1.

[0044] Synthesis of Compound VII - 3: At 0℃, 90g of acetone and 22.2g (0.1mol) of the above compound V were weighed and added to a four-necked flask. Then, 2g (0.01mol) of tetramethylammonium iodide was added and stirred. 16.8g (40% aqueous solution, 0.15mol) of methylhydrazine was slowly added dropwise over 30 min. The temperature was then raised to 30℃ and stirring continued for 6 h until the reaction was complete. After vacuum distillation, 60.0g of dichloroethane was added, and the mixture separated into layers. 90.0g (15%) of sodium hydroxide aqueous solution was added to the dichloroethane phase, and the reaction was carried out at 50℃ for 5 h. The temperature was lowered to 30℃, and the aqueous phase was separated. Hydrochloric acid was slowly added dropwise to the aqueous phase until the pH became acidic. The mixture was filtered, dried, and 16.9g of a white powdery solid was obtained, with a yield of 96.0%. According to GC analysis, the ratio of 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid to its isomer 2-difluoromethyl-1-methyl-pyrazole-3-carboxylic acid in the product was approximately 175:1.

[0045] Synthesis of fluopyram

[0046] 90 g of dichloromethane and 18.1 g (97.8%) of compound VII were weighed into a 500 mL four-necked flask. 19.2 g of thionyl chloride was added, and the mixture was reacted at 25 °C for 4 h until complete. The reaction was then distilled under reduced pressure to give a yellow oily substance, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxyl chloride. 24.1 g (96.4%, 0.10 mol) of compound III and 12.1 g of triethylamine were added to 60 mL of dichloroethane and stirred. 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxyl chloride was slowly added dropwise at 10 °C. After the addition was complete, the temperature was raised to 50 °C and stirred for 4 h until complete. The reaction mixture was washed twice with 30 mL of water, and the organic phase was separated. The organic phase was distilled under reduced pressure and slurried with 60.0 g of toluene. The mixture was filtered to give 37.3 g of a white powdery solid compound, fluopyram, with a purity of 98.9% and a yield of 96.3%.

Claims

1. A method for preparing fluopyram, characterized in that, Includes the following steps: A) The 3,4,5-trifluorobromobenzene shown in Formula I undergoes a Grignard reaction, followed by the addition of trimethyl borate and a hydrolysis reaction to obtain the 3,4,5-trifluorophenylboronic acid shown in Formula II. B) 3,4,5-trifluorophenylboronic acid, represented by Formula II, is reacted with o-haloaniline via a Suzuki coupling reaction to yield 2-(3,4,5-trifluorophenyl)aniline, represented by Formula III; wherein the o-haloaniline is o-chloroaniline, o-bromoaniline, or o-iodoaniline. C) Ethyl 4,4-difluoroacetoacetate of Formula IV reacts with triethyl orthoformate to give ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate of Formula V; D) Ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate, as shown in Formula V, is reacted with methylhydrazine via cyclization, hydrolysis, and acidification to yield 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid, as shown in Formula VII. E) The 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid shown in Formula VII is acyl-chlorinated with a chlorinating agent, and then condensed with 2-(3,4,5-trifluorophenyl)aniline shown in Formula III to obtain fluopyram as shown in Formula VIII. The reaction formula is as follows: ； ； ； In the formula, X represents a halogen, selected from chlorine, bromine, or iodine.

2. The method according to claim 1, characterized in that, X is selected from iodine.

3. The method according to claim 1, characterized in that, Step A) specifically involves: The 3,4,5-trifluorobromobenzene shown in Formula I was prepared as a Grignard reagent, reacted with trimethyl borate, and then hydrolyzed to obtain 3,4,5-trifluorophenylboronic acid shown in Formula II. Optionally, the 3,4,5-trifluorobromobenzene represented by Formula I undergoes a Grignardization reaction at a temperature of -10°C to 70°C. Optionally, the solvent used for the Grignard reagent in step A) is selected from any one or more of diethyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran; Optionally, the mass ratio of 3,4,5-trifluorobromobenzene represented by Formula I to the organic solvent is 1.0:(1.5 to 10). Optionally, the molar ratio of 3,4,5-trifluorobromobenzene shown in Formula I to trimethyl borate is 1.0:(1.1 to 3.0).

4. The method according to claim 1, characterized in that, Step B) specifically involves: 3,4,5-trifluorophenylboronic acid as shown in Formula II and o-haloaniline were added to a small amount of solvent as a base, a certain amount of alkali was added, the temperature was raised and a catalyst was added to carry out the reaction. Optionally, the haloaniline in step B) is selected from one of o-chloroaniline, o-bromoaniline, and o-iodoaniline; Optionally, the solvent used for the base coat in step B) is any one or more of toluene, methanol, ethanol, isopropanol, and DMF, or a mixture of the above solvents and water. Optionally, the heating temperature in step B) is between 50°C and 120°C; Optionally, the catalyst in step B) is selected from palladium acetate / triphenylphosphine, Pd[P(C6H5)3]4, or a combination of palladium catalyst and one or more of AsPh3, n-Bu3P, (MeO)3P, Ph2P(CH2)3PPh2(dppp), Ph2P(CH2)2PPh2(dppe); the base is any one of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate. Optionally, the molar ratio of 3,4,5-trifluorophenylboronic acid as shown in Formula II in step B) to the catalyst is 1.0:(0.0005 to 0.01).

5. The method according to claim 4, characterized in that, Step B) The halogenated aniline o-iodoaniline; the catalyst is selected from palladium acetate / triphenylphosphine; the base solvent is a toluene / water mixture.

6. The method according to claim 1, characterized in that, Step C) specifically involves: Ethyl 4,4-difluoroacetoacetate of Formula IV was reacted with triethyl orthoformate in a solvent in the presence of a catalyst and heated to obtain ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate of Formula V. Optionally, in step C), the molar ratio of ethyl 4,4-difluoroacetoacetate (Formula IV) to triethyl orthoformate is 1.0:(1.2–7.0); the catalyst is p-toluenesulfonic acid. Optionally, the solvent in step C) is selected from any one or more of toluene, xylene, acetic acid, and acetic anhydride, and the mass ratio of ethyl 4,4-difluoroacetoacetate of Formula IV to the solvent is 1.0:(1.5 to 10.0). Optionally, the heating temperature in step C) is between 30°C and 120°C.

7. The method according to claim 6, characterized in that, Step C) The solvent is selected from acetic anhydride.

8. The method according to claim 1, characterized in that, Step D) specifically refers to: Ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate (Formula V) was added to an organic solvent, with optional addition of tetramethylammonium iodide as a catalyst. The temperature was controlled and the pH was adjusted to alkaline by adding alkali. Methylhydrazine was slowly added, and after reacting for 2 hours, ethyl 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid (Formula VI) was obtained. Strong alkali was added, and the mixture was heated to reflux and stirred for 3 hours for hydrolysis. After acidification and filtration, 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid (Formula VII) was obtained. Optionally, the organic solvent in step D) is selected from acetone; Optionally, the mass ratio of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate shown in Formula V to the organic solvent is 1.0:(1.5 to 10), and the reaction temperature is controlled between 0°C and 100°C. Optionally, the molar ratio of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate shown in Formula V to tetramethylammonium iodide is 1:0.05-0.2; during the reaction of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate shown in Formula V, the pH is adjusted to 8-11, and the added base is any one or more of triethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate; during the hydrolysis of ethyl 3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid shown in Formula VI, the added base is any one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide, and the molar ratio of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate shown in Formula V to the base used for hydrolysis is 1.0:(2.0-5.0).

9. The method according to claim 1, characterized in that, Step E) specifically refers to: The compound shown in Formula VII was acyl-chlorinated with a chlorinating agent, and then added dropwise to the substrate of the compound shown in Formula III, which was mixed with an organic solvent and a base. The reaction was carried out at a controlled temperature for 2 hours to obtain fluopyram as shown in Formula VIII. Optionally, the chlorinating agent in step E is selected from one or more of thionyl chloride, oxalyl chloride, and phosphorus oxychloride, and the molar ratio of compound VII to the chlorinating agent is 1.0:(1.1 to 3.0). Optionally, in step E), the molar ratio of compound VII to the compound shown in formula III is 1.0:(0.9 to 1.5). Optionally, the organic solvent used to mix with the substrate in step E) is any one of toluene, dichloromethane, dichloroethane, DMF, or CCl4; Optionally, the base added to the substrate in step E) is any one of triethylamine, diethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate, and the molar ratio of compound VII to base is 1.0:(1.1 to 3.0).

Images