A synthetic method of fluralaner

Abstract

The present invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing flecainide. 4-Bromo-2-methyl-benzoic acid undergoes a substitution reaction with n-butyl vinyl ether to generate 4-acetyl-2-methylbenzoic acid, which successively undergoes a condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide, an addition reaction with 3,5-dichlorobenzaldehyde, an isocyclization reaction with tert-butyl nitrite, a substitution reaction with (trifluoromethyl)trimethylsilane, and preferably a heating reaction to generate flecainide. By controlling the types and dosages of catalysts in each step of the reaction, each step of the reaction has a high yield, and finally flecainide is obtained with a high yield.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing flurella. Background Art

[0002] Flurellan (FLLN) is a A broad-spectrum insecticide of the oxazoline class, with the characteristics of broad insecticidal spectrum, unique action site, and no cross-resistance. Its trade name is BRAVECTO, its CAS registration number is 864731-61-3, and its chemical name is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isothiazolyl]-1,4-dihydro-1,4-dihydro-2,4-dihydro-3-(3,5-dichlorophenyl) ... [oxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide, the chemical structure of which is shown below:

[0003]

[0004] Flurellana is mainly used for the treatment of animal parasites. It has similar targets to insecticides such as phenylpyrazoles, cyclopentadienes and macrolides. It is a γ-aminobutyric acid (GABA) gated chloride channel disruptor. Its mechanism of action is mainly to interfere with γ-aminobutyric acid gated chloride channels to achieve insecticidal effects. It has equivalent or higher insecticidal activity and is expected to be used for the prevention and control of agricultural pests. As a raw material drug, it has a large demand in the market, but the price is relatively expensive and the process needs to be simplified. Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing flurana, which is simple, efficient and low in cost, in view of the above problems.

[0006] The synthetic method of Flurellana in the technical solution of the present invention comprises the following steps:

[0007] (1) 4-bromo-2-methyl-benzoic acid (compound S1) undergoes a substitution reaction with n-butyl vinyl ether to generate 4-acetyl-2-methylbenzoic acid (compound S2), and the reaction formula is as follows:

[0008]

[0009] (2) 4-acetyl-2-methylbenzoic acid (compound S2) undergoes a condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to generate 4-acetyl-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide (compound S3), and the reaction formula is as follows:

[0010]

[0011] (3) 4-Acetyl-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide (Compound S3) undergoes an addition reaction with 3,5-dichlorobenzaldehyde to form 4-(3-(3,5-dichlorophenyl)-3-oxopropyl-1-en-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (Compound S4), and the reaction formula is as follows:

[0012]

[0013] (4) 4-(3-(3,5-Dichlorophenyl)-3-oxopropyl-1-en-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (Compound S4) undergoes an isocyclization reaction with tert-butyl nitrite to form 4-(5-(3,5-dichlorophenyl)-4-nitroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (Compound S5), and the reaction formula is as follows:

[0014]

[0015] (5) 4-(5-(3,5-Dichlorophenyl)-4-nitroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (Compound S5) undergoes a substitution reaction with (trifluoromethyl)trimethylsilane to form 4-(5-(3,5-dichlorophenyl)-4-nitro-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (Compound S6), and the reaction formula is as follows:

[0016]

[0017] (6) 4-(5-(3,5-Dichlorophenyl)-4-nitro-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (Compound S6) undergoes a heating reaction to form fluralaner, and the reaction formula is as follows:

[0018]

[0019] Furthermore, in step (1), the molar ratio of 4-bromo-2-methyl-benzoic acid to n-butyl vinyl ether is 1:3 to 8.

[0020] Further, the substitution reaction in step (1) is carried out in the presence of a catalyst, and the molar amount of the catalyst is 1.5 to 2.0 times the molar amount of 4-bromo-2-methyl-benzoic acid.

[0021] Further, the catalyst in step (1) comprises components in the following mole percentages: 0.5 to 1.0% palladium acetate, 2.0 to 3.0% 1,3-bis(diphenylphosphino)propane (DPPP), and 96.0 to 98.0% potassium carbonate.

[0022] Preferably, in step (1), 4-bromo-2-methyl-benzoic acid, n-butyl vinyl ether, DPPP, palladium acetate, and potassium carbonate are added to a reaction flask, using n-butanol as a solvent, purged with nitrogen 3 to 4 times, heated to 80 to 100 °C for reaction for 8 to 12 h, cooled to room temperature, adjusted to pH 1 to 2 with hydrochloric acid, the organic phase is extracted with ethyl acetate, washed successively with water and saturated sodium chloride solution, filtered through diatomaceous earth, and dried with anhydrous sodium sulfate to obtain the S2 compound.

[0023] Further, in step (2), the molar ratio of 4-acetyl-2-methyl-benzoic acid to 2-amino-N-(2,2,2-trifluoroethyl)acetamide is 1.0:1.2 to 1.8.

[0024] Further, the condensation reaction in step (2) is carried out in the presence of a catalyst, and the catalyst is a compound of triethylamine and diphenylphosphoryl azide in a molar ratio of 1.5 to 2.0:1.0; and / or the molar amount of the catalyst in step (2) is 2.0 to 5.0 times the molar amount of 4-acetyl-2-methyl-benzoic acid.

[0025] Preferably, in step (2), the S2 compound and N,N-dimethylformamide are added to a reaction flask, triethylamine and diphenylphosphoryl azide (DPPA) are added under ice bath conditions and stirred for reaction for 1 to 2 h, 2-amino-N-(2,2,2-trifluoroethyl)acetamide is added, stirred for 10 to 12 h, water and dichloromethane are added successively to extract the aqueous phase, after combining the dichloromethane phases, dried with anhydrous sodium sulfate, and dichloromethane is removed by distillation under reduced pressure at 15 to 20 °C to obtain the S3 compound.

[0026] Further, in step (3), the molar ratio of 4-acetyl-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide to 3,5-dichlorobenzaldehyde is 1.0:0.8 to 1.5.

[0027] Preferably, in step (3), the S3 compound, 3,5-dichlorobenzaldehyde, NaOH, and ethanol are added to a reaction flask and stirred for 1 to 2 h, extracted with ethyl acetate, the organic phase is washed successively with water and saturated sodium chloride solution, filtered through diatomaceous earth, and dried with anhydrous sodium sulfate to obtain the S4 compound.

[0028] Furthermore, in step (4), the molar ratio of 4-(3-(3,5-dichlorophenyl)-3-oxopropyl-1-en-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide to tert-butyl nitrite is 1:8 to 12.

[0029] Preferably, in step (4), the S4 compound, 1,4-dioxane and water are added to a reaction flask. Under nitrogen protection, tert-butyl nitrite is added dropwise to the reaction solution at 50-80 °C and stirred for 1-2 h. After cooling to room temperature, water and dichloromethane are successively added to the reaction solution to extract the aqueous phase. After combining the dichloromethane phases, the organic phase is dried with anhydrous sodium sulfate. After evaporating dichloromethane under reduced pressure, the S5 compound is obtained through column chromatography.

[0030] Furthermore, in step (5), the molar ratio of 4-(5-(3,5-dichlorophenyl)-4-nitroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide to (trifluoromethyl)trimethylsilane is 1.0:2.0 to 2.5; and / or the substitution reaction in step (5) is carried out in the presence of a catalyst, and the catalyst is a compound of cetyltrimethylammonium bromide and sodium acetate in a molar ratio of 1.0-3.0:8.0; and / or the molar amount of the catalyst in step (5) is 1.5-2.0 times the molar amount of 4-(5-(3,5-dichlorophenyl)-4-nitroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide.

[0031] Preferably, in step (5), under nitrogen protection, the S5 compound, cetyltrimethylammonium bromide (CTAB), sodium acetate, (trifluoromethyl)trimethylsilane and N,N-dimethylformamide are added to a reaction flask and stirred for 6-8 h. Hydrochloric acid is added and stirring is continued for 30-50 min. Water and dichloromethane are successively added to the reaction solution to extract the aqueous phase. After combining the dichloromethane phases, the organic phase is dried with anhydrous sodium sulfate. After evaporating dichloromethane under reduced pressure, the S6 compound is obtained through column chromatography.

[0032] Furthermore, the heating reaction in step (6) is carried out in the presence of a catalyst, and the catalyst is a compound of tributyltin hydride and azobisisobutyronitrile in a molar ratio of 2.5-3.5:1.0; and / or the molar amount of the catalyst in step (6) is 1.8-2.5 times the molar amount of 4-(5-(3,5-dichlorophenyl)-4-nitro-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide.

[0033] Preferably, in step (6), the S6 compound, tributyltin hydride, azobisisobutyronitrile and toluene are added to a reaction flask, heated to 80-100 °C and reacted for 2-5 h. After removing the solvent by vacuum distillation, fluralaner is obtained by column chromatography.

[0034] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0035] (1) By controlling the type and dosage of the catalyst in each step of the reaction, the present invention enables each step of the reaction to have a high yield, and finally obtains fluralaner with a high yield;

[0036] (2) The present invention first introduces a simple trifluoroethyl group onto 4-acetyl-2-methylbenzoic acid, which can reduce the steric hindrance effect and improve the yield of the subsequent steps. Specific Embodiments

[0037] The technical solution of the present invention will be further described and illustrated below through specific examples. It should be understood that the specific examples described herein are only used to help understand the present invention and are not used for the specific limitation of the present invention. If there is no special description, the raw materials used in the embodiments of the present invention are all commonly used raw materials in the art, and the methods used in the embodiments are all conventional methods in the art.

[0038] Example 1

[0039] The synthesis method of fluralaner in this example includes the following steps:

[0040] (1) 15 mmol of 4-bromo-2-methyl-benzoic acid, 75 mmol of n-butyl vinyl ether, 0.6 mmol of DPPP, 0.15 mmol of palladium acetate, and 24 mmol of potassium carbonate are added to a reaction flask, 25 mL of n-butanol is added, and the flask is purged with nitrogen three times. The mixture is heated to 90 °C and reacted for 10 h, cooled to room temperature, the pH is adjusted to 2 with hydrochloric acid, the organic phase is extracted with ethyl acetate, and then washed successively with water and saturated sodium chloride solution. After filtration through diatomaceous earth, it is dried with anhydrous sodium sulfate to obtain the S2 compound with a yield of 97%;

[0041] (2) 10 mmol of the S2 compound and 15 mL of N,N-dimethylformamide are added to a reaction flask. Under ice bath conditions, 20 mmol of triethylamine and 12 mmol of DPPA are added and stirred for 1 h. Then 14 mmol of 2-amino-N-(2,2,2-trifluoroethyl)acetamide is added, and the mixture is stirred at room temperature for 10 h. 20 mL of water and 30 mL of dichloromethane (the dichloromethane is added in three portions, 15 mL each time) are added successively to extract the aqueous phase. After combining the dichloromethane phases, the dichloromethane phase is dried with anhydrous sodium sulfate, and dichloromethane is removed by distillation under reduced pressure at 18 °C to obtain the S3 compound with a yield of 98%;

[0042] (3) 9.8 mmol of compound S3, 9.8 mmol of 3,5-dichlorobenzaldehyde, 14.7 mmol of NaOH and 10 mL of ethanol were added to a reaction flask and stirred for 1 h. After extraction with ethyl acetate, the organic phase was washed successively with water and saturated sodium chloride solution, filtered through diatomaceous earth and dried over anhydrous sodium sulfate to obtain compound S4 with a yield of 92%;

[0043] (4) 9 mmol of compound S4, 4 mL of 1,4-dioxane and 12 mL of water were added to a reaction flask. Under nitrogen protection, 90 mmol of tert-butyl nitrite was added dropwise to the reaction solution at 60 °C and stirred for 1 h. After cooling to room temperature, 30 mL of water and 45 mL of dichloromethane (dichloromethane was added in three portions, 15 mL each time) were added to the reaction solution to extract the aqueous phase. After combining the dichloromethane phases, the organic phase was dried over anhydrous sodium sulfate. After distilling off dichloromethane under reduced pressure, compound S5 was obtained by column chromatography with a yield of 89%;

[0044] (5) Under nitrogen protection, 5 mmol of compound S5, 1.5 mmol of cetyltrimethylammonium bromide (CTAB), 7.5 mmol of sodium acetate, 10 mmol of (trifluoromethyl)trimethylsilane and 15 mL of N,N-dimethylformamide were added to a reaction flask and stirred for 8 h. Hydrochloric acid was added and stirring was continued for 30 min. 30 mL of water and 30 mL of dichloromethane (dichloromethane was added in three portions, 10 mL each time) were added to the reaction solution to extract the aqueous phase. After combining the dichloromethane phases, the organic phase was dried over anhydrous sodium sulfate. After distilling off dichloromethane under reduced pressure, compound S6 was obtained by column chromatography with a yield of 87%;

[0045] (6) 4 mmol of compound S6, 6 mmol of tributyltin hydride, 2 mmol of azobisisobutyronitrile and 20 mL of toluene were added to a reaction flask and heated to 90 °C for reaction for 2 h. After distilling off the solvent under reduced pressure, fluralaner was obtained by column chromatography with a yield of 73%.

[0046] Example 2

[0047] The difference between this example and Example 1 is only that in step (1), 20 mmol of 4-bromo-2-methyl-benzoic acid, 75 mmol of n-butyl vinyl ether and 0.65 mmol of DPPP, 0.25 mmol of palladium acetate, 24 mmol of potassium carbonate were added to a reaction flask, 25 mL of n-butanol was added, the system was purged with nitrogen three times, heated to 90 °C for reaction for 10 h, cooled to room temperature, the pH was adjusted to 2 with hydrochloric acid, the organic phase was extracted with ethyl acetate, and washed successively with water and saturated sodium chloride solution, filtered through diatomaceous earth and dried over anhydrous sodium sulfate to obtain compound S2 with a yield of 98%.

[0048] Example 3

[0049] The difference between this example and Example 1 is only that in step (2), 10 mmol of compound S2 and 15 mL of N,N-dimethylformamide are added to a reaction flask, 20 mmol of triethylamine and 10 mmol of DPPA are added under ice bath conditions, and the mixture is stirred for 1 h. Then 16 mmol of 2-amino-N-(2,2,2-trifluoroethyl)acetamide is added, and the mixture is stirred at room temperature for 10 h. Subsequently, 20 mL of water and 30 mL of dichloromethane (the dichloromethane is added in three portions, 10 mL each time) are added to extract the aqueous phase. After combining the dichloromethane phases, the dichloromethane phase is dried over anhydrous sodium sulfate, and dichloromethane is removed under reduced pressure at 18 °C to obtain compound S3 with a yield of 97%.

[0050] Example 4

[0051] The difference between this example and Example 1 is only that in step (3), 9.8 mmol of compound S3, 12 mmol of 3,5-dichlorobenzaldehyde, 14.7 mmol of NaOH, and 10 mL of ethanol are added to a reaction flask and stirred for 1 h. After extraction with ethyl acetate, the organic phase is washed successively with water and saturated sodium chloride solution, filtered through diatomaceous earth, and dried over anhydrous sodium sulfate to obtain compound S4 with a yield of 93%.

[0052] Example 5

[0053] The difference between this example and Example 1 is only that in step (4), 9 mmol of compound S4, 4 mL of 1,4-dioxane, and 12 mL of water are added to a reaction flask. Under nitrogen protection, 95 mmol of tert-butyl nitrite is added dropwise to the reaction solution at 70 °C and stirred for 1 h. After cooling to room temperature, 30 mL of water and 45 mL of dichloromethane (the dichloromethane is added in three portions, 15 mL each time) are added to extract the aqueous phase. After combining the dichloromethane phases, the organic phase is dried over anhydrous sodium sulfate, and dichloromethane is removed under reduced pressure. Then, compound S5 is obtained through column chromatography with a yield of 89%.

[0054] Example 6

[0055] The difference between this example and Example 1 is only that in step (5), under nitrogen protection, 5 mmol of compound S5, 1.5 mmol of cetyltrimethylammonium bromide (CTAB), 6.5 mmol of sodium acetate, 12 mmol of (trifluoromethyl)trimethylsilane, and 15 mL of N,N-dimethylformamide are added to a reaction flask and stirred for 8 h. Hydrochloric acid is added and stirring is continued for 30 min. Then 30 mL of water and 30 mL of dichloromethane (the dichloromethane is added in three portions, 15 mL each time) are added to extract the aqueous phase. After combining the dichloromethane phases, the organic phase is dried over anhydrous sodium sulfate, and dichloromethane is removed under reduced pressure. Then, compound S6 is obtained through column chromatography with a yield of 85%.

[0056] Example 7

[0057] The difference between this example and Example 1 is only that in step (6), 3.8 mmol of S6 compound, 5.6 mmol of tributyltin hydride, 2 mmol of azobisisobutyronitrile and 20 mL of toluene are added to the reaction flask, heated to 90 °C and reacted for 2 h. After the solvent is removed by distillation under reduced pressure, fluralaner is obtained by column chromatography with a yield of 76%.

[0058] Finally, it should be noted that the specific examples described herein are only illustrative of the spirit of the present invention and not a limitation on the embodiments of the present invention. Those skilled in the art to which the present invention pertains can make various modifications or supplements to the described embodiments or use similar methods to substitute. It is not necessary and impossible to list all embodiments here. And these obvious changes or variations derived from the essence of the present invention still fall within the protection scope of the present invention. Interpreting them as any additional limitation is contrary to the spirit of the present invention.

Claims

1. A synthetic method of fluralaner, characterized in that, It includes the following steps: (1) 4-bromo-2-methyl-benzoic acid undergoes a substitution reaction with n-butyl vinyl ether to form 4-acetyl-2-methyl-benzoic acid; (2) 4-acetyl-2-methyl-benzoic acid undergoes a condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to form 4-acetyl-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide; (3) 4-acetyl-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide undergoes an addition reaction with 3,5-dichlorobenzaldehyde to form 4-(3-(3,5-dichlorophenyl)-3-oxopropyl-1-en-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide; (4) 4-(3-(3,5-dichlorophenyl)-3-oxopropyl-1-en-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide undergoes an isocyclization reaction with tert-butyl nitrite to form 4-(5-(3,5-dichlorophenyl)-4-nitroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide; (5) 4-(5-(3,5-dichlorophenyl)-4-nitroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide undergoes a substitution reaction with (trifluoromethyl)trimethylsilane under the catalysis of cetyltrimethylammonium bromide and sodium acetate compounded in a molar ratio of 1.0~3.0:8.0 to form 4-(5-(3,5-dichlorophenyl)-4-nitro-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide; (6) 4-(5-(3,5-dichlorophenyl)-4-nitro-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide undergoes a heating reaction to form fluralaner.

2. The synthesis method according to claim 1, characterized in that, In step (1), the molar ratio of 4-bromo-2-methyl-benzoic acid to n-butyl vinyl ether is 1:3~8.

3. The synthesis method according to claim 1, characterized in that, The substitution reaction in step (1) is carried out in the presence of a catalyst, and the molar amount of the catalyst is 1.5~2.0 times the molar amount of 4-bromo-2-methyl-benzoic acid.

4. The synthesis method according to claim 3, characterized in that, The catalyst in step (1) includes the following components in mole percentages: 0.5~1.0% palladium acetate, 2.0~3.0% 1,3-bis(diphenylphosphino)propane, and 96.0~98.0% potassium carbonate.

5. The synthesis method according to claim 1, characterized in that, In step (2), the molar ratio of 4-acetyl-2-methyl-benzoic acid to 2-amino-N-(2,2,2-trifluoroethyl)acetamide is 1.0:1.2~1.

8.

6. The synthesis method according to claim 1, wherein The condensation reaction in step (2) is carried out in the presence of a catalyst, and the catalyst is a compound of triethylamine and diphenyl phosphorazidate with a molar ratio of 1.5 to 2.0:1.0; and / or the molar amount of the catalyst in step (2) is 2.0 to 5.0 times the molar amount of 4-acetyl-2-methylbenzoic acid.

7. The synthesis method according to claim 1, characterized in that, In step (3), the molar ratio of 4-acetyl-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide to 3,5-dichlorobenzaldehyde is 1.0:0.8 to 1.

5.

8. The synthesis method according to claim 1, wherein, In step (4), the molar ratio of 4-(3-(3,5-dichlorophenyl)-3-oxopropyl-1-en-1-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide to tert-butyl nitrite is 1:8 to 12.

9. The synthesis method according to claim 1, wherein In step (5), the molar ratio of 4-(5-(3,5-dichlorophenyl)-4-nitroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide to (trifluoromethyl)trimethylsilane is 1.0:2.0 to 2.5; and / or the molar amount of the catalyst in step (5) is 1.5 to 2.0 times the molar amount of 4-(5-(3,5-dichlorophenyl)-4-nitroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide.

10. The synthesis method according to claim 1, characterized in that, The heating reaction in step (6) is carried out in the presence of a catalyst, and the catalyst is a compound of tributyltin hydride and 2,2'-azobis(2-methylpropionitrile) with a molar ratio of 2.5 to 3.5:1.0; and / or the molar amount of the catalyst in step (6) is 1.8 to 2.5 times the molar amount of 4-(5-(3,5-dichlorophenyl)-4-nitro-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide.

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