A method for preparing fluralaner

Abstract

The application belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of fluralaner. The preparation method of fluralaner comprises the following steps: mixing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid, a catalyst, alcohol and an organic solvent to perform an esterification reaction, mixing the obtained esterification reaction liquid containing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ester and 2-amino-N-(2,2,2-trifluoroethyl)acetamide to perform an ester decomposition-amidation reaction, and obtaining fluralaner. The fluralaner is successfully prepared, the preparation method is simple to operate, and does not need to use acylation reagents, so that the problem of serious pollution in the traditional preparation method is solved; and the yield is high, and the yield in the examples is all above 98%.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing freranil. Background Technology

[0002] Fluranal is a broad-spectrum isoxazoline insecticide and acaricide used to treat animal parasites. It is currently registered and marketed as a veterinary drug under the trade name Bravectotm, and its structural formula is shown below:

[0003]

[0004] Fluranal has a similar target to other insecticides such as cyclopentadiene, phenylpyrazole, and macrolides. It mainly works by interfering with GABA-gated chloride ion channels and has good insecticidal effects on pests such as ticks, fleas, lice, hemiptera, and dipterans.

[0005] Currently reported methods for preparing freranil mainly involve the reaction of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid with 2-amino-N-(2,2,2-trifluoroethyl)acetamide. However, this method requires the prior preparation of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid into 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoyl chloride. This preparation process requires at least an equimolar amount of acylation reagents such as thionyl chloride or phosphorus trichloride. These acylation reagents generate large amounts of waste acid during the reaction, and neutralizing the waste acid produces large amounts of salt, resulting in significant pollution and serious waste problems. Summary of the Invention

[0006] In view of this, the object of the present invention is to provide a method for preparing freranal. The preparation method provided by the present invention is simple to operate and does not require the use of acylation reagents, thus solving the problem of serious pollution in traditional preparation methods.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0008] This invention provides a method for preparing fluorellanal, comprising the following steps:

[0009] An esterification reaction was carried out by mixing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid, a catalyst, an alcohol, and an organic solvent to obtain an esterification reaction solution containing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid ester.

[0010] The esterification reaction solution was mixed with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to carry out an ester decomposition-amidation reaction to obtain the fluranar.

[0011] Preferably, the catalyst comprises one or more of p-toluenesulfonic acid, sulfuric acid, phosphoric acid, sulfonic acid resin, phosphotungstic acid, silicotungstic acid, and silica-alumina molecular sieve.

[0012] Preferably, the weight ratio of the catalyst to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid is 0.001 to 0.2:1.

[0013] Preferably, the alcohol includes one or more of methanol, ethanol, isopropanol, and n-propanol.

[0014] Preferably, the molar ratio of the alcohol to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid is 1 to 10:1.

[0015] Preferably, the organic solvent includes one or more of toluene, xylene, ethylbenzene, and cyclohexane.

[0016] Preferably, the weight ratio of the organic solvent to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid is 2 to 8:1.

[0017] Preferably, the esterification reaction is carried out at a temperature of 70–130°C for 2–10 hours.

[0018] Preferably, the molar ratio of 2-amino-N-(2,2,2-trifluoroethyl)acetamide to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid is 1 to 3:1.

[0019] Preferably, the temperature of the ester decomposition-amidation reaction is 90–150°C, and the time is 3–12 hours.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] This invention provides a method for preparing freranal, comprising mixing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid, a catalyst, an alcohol, and an organic solvent to carry out an esterification reaction to obtain an esterification reaction solution containing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoate; and mixing the esterification reaction solution with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to carry out an esterification-amidation reaction to obtain the freranal. This invention uses 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoic acid as a raw material. An esterification reaction is first performed, and the resulting esterification reaction solution does not require post-treatment and can be directly reacted with 2-amino-N-(2,2,2-trifluoroethyl)acetamide for esterification-amidation reaction, successfully preparing freranal in a one-pot method. The preparation method provided by this invention is simple to operate and does not require the use of acylation reagents, solving the problem of severe pollution in traditional preparation methods. Moreover, the preparation method provided by this invention has a high yield; the yields in the examples are all above 98%. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 The 1H NMR spectrum of methyl 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoate prepared in Example 1;

[0024] Figure 2 The 1H NMR spectrum of the fluorellaranosate prepared in Example 1;

[0025] Figure 3 The liquid chromatogram of the fluranar prepared in Example 1 is shown. Detailed Implementation

[0026] This invention provides a method for preparing fluorellanal, comprising the following steps:

[0027] An esterification reaction was carried out by mixing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid, a catalyst, an alcohol, and an organic solvent to obtain an esterification reaction solution containing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid ester.

[0028] The esterification reaction solution was mixed with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to carry out an ester decomposition-amidation reaction to obtain the fluranar.

[0029] Unless otherwise specified, all materials and equipment used in this invention are commercially available products in the field.

[0030] In this invention, 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid, a catalyst, an alcohol, and a solvent are mixed and subjected to an esterification reaction to obtain an esterification reaction solution containing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid ester.

[0031] In this invention, the catalyst preferably comprises one or more of p-toluenesulfonic acid, sulfuric acid, phosphoric acid, sulfonic acid resin, phosphotungstic acid, silicotungstic acid, and silica-alumina molecular sieve; the catalyst of this invention will not cause the raw material carboxylic acid to form a stable salt, thus hindering the esterification reaction.

[0032] In this invention, the weight ratio of the catalyst to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid is preferably 0.001 to 0.2:1, more preferably 0.01 to 0.1:1.

[0033] In this invention, the alcohol preferably includes one or more of methanol, ethanol, isopropanol, and n-propanol. The alcohol in this invention is preferably a low-boiling-point alcohol, which is easily distilled off directly after the esterification-amidation reaction, promoting a shift in equilibrium towards product formation.

[0034] In this invention, the molar ratio of the alcohol to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid is 1 to 10:1, more preferably 2 to 8:1.

[0035] In this invention, the organic solvent preferably includes one or more of toluene, xylene, ethylbenzene, and cyclohexane.

[0036] In this invention, the weight ratio of the organic solvent to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid is preferably 2 to 8:1, more preferably 3 to 6:1.

[0037] In this invention, the temperature of the esterification reaction is preferably 70–130°C, more preferably 80–110°C, and the time is preferably 2–10 hours, more preferably 3–5 hours. The reaction formula of the esterification reaction is shown in Formula I, where 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid (I) undergoes an esterification reaction with an alcohol to generate 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoate (II).

[0038]

[0039] In this invention, the 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, catalyst, alcohol and organic solvent are preferably mixed in a reaction vessel equipped with a thermometer, stirrer and water separator, and the esterification reaction is preferably stopped when no more water is generated in the system.

[0040] In this invention, the esterification reaction is preferably followed by cooling, and the temperature after cooling is preferably 50°C.

[0041] After obtaining an esterification reaction solution containing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoate, the present invention mixes the esterification reaction solution with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to carry out an esterification-amidation reaction to obtain the fluranar.

[0042] In this invention, the molar ratio of 2-amino-N-(2,2,2-trifluoroethyl)acetamide to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid is preferably 1 to 3:1, more preferably 2:1.

[0043] In this invention, the preferred temperature for the ester decomposition-amidation reaction is 90–150°C, more preferably 120–130°C; the preferred time is 3–12 hours, more preferably 5–7 hours. The reaction formula for the ester decomposition-amidation reaction is shown in Formula II, where 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoate (II) undergoes an ester decomposition-amidation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to generate freranal (III).

[0044]

[0045] In this invention, the ester decomposition-amidation reaction is preferably stopped when no more alcohol is generated in the system.

[0046] In this invention, the ester decomposition-amidation reaction preferably includes a post-treatment process, which preferably includes sequential cooling, washing, solvent removal, and drying to obtain the fluorellana. When the catalyst is solid, the cooling process preferably includes solid-liquid separation, which is preferably performed by filtration, and the liquid obtained by filtration contains fluorellana.

[0047] In this invention, when the molar ratio of 2-amino-N-(2,2,2-trifluoroethyl)acetamide to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid is 1:1, the washing is preferably a water wash; when the molar ratio of 2-amino-N-(2,2,2-trifluoroethyl)acetamide to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methyl-benzoic acid is greater than 1:1, the washing preferably includes sequential acid washing and water washing, wherein the reagent used for acid washing is preferably a hydrochloric acid solution, and the purpose of acid washing is to salt the excess organic amine and dissolve it in the aqueous phase.

[0048] In this invention, the method for removing the solvent is preferably atmospheric distillation.

[0049] In this invention, the drying temperature is preferably 30-70°C, and the drying time is preferably 2-6 hours.

[0050] To further illustrate the present invention, the preparation method of freranil provided by the present invention will be described in detail below with reference to the accompanying drawings and embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0051] Example 1

[0052] In a reaction vessel equipped with a thermometer, stirrer, and water separator, 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 2.0 g of p-toluenesulfonic acid, 2.0 g of phosphotungstic acid, 50 g of methanol, and 1200 g of toluene were added. The reaction temperature was controlled at 90–100 °C, and the water produced in the reaction was fractionally distilled off while the reaction was underway. After 5 hours of reaction, the temperature was lowered to 50 °C, and 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added. The reaction temperature was controlled at 120–125 °C, and the methanol produced in the reaction was fractionally distilled off while the reaction was underway. After 3 hours of reaction, the reaction was stopped. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation, and the product was dried to obtain 551.1 g of white solid fluorellana, with a purity of 99.75% and a yield of 99.1%.

[0053] Figure 1 The 1H NMR spectrum of methyl 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoate prepared in Example 1. 1 H NMR (500MHz, CDCl3): δ7.95(d,J=8.7Hz,1H),7.55-7.49(m,4H),7.42(t,J=1.8H z, 1H), 4.10 (d, J = 17.2Hz, 1H), 3.91 (s, 3H), 3.71 (d, J = 17.2Hz, 1H), 2.62 (s, 3H).

[0054] Figure 2 The image shows the 1H NMR spectrum of the fluorellaranosate prepared in Example 1. 1 HNMR (500MHz, CDCl3): δ7.52(d,J=11.7Hz,4H),7.48-7.38(m,2H),7.07(t,J=5.9Hz,1H),6.79(t,J=5.2Hz, 1H), 4.21 (d, J = 5.2Hz, 2H), 4.08 (d, J = 17.2Hz, 1H), 3.98-3.89 (m, 2H), 3.70 (d, J = 17.2Hz, 1H), 2.46 (s, 3H).

[0055] The fluranar prepared in Example 1 was subjected to liquid chromatography analysis under the following conditions: instrument: Agilent Infinity 1260II; mobile phase (volume ratio): A (0.03% trifluoroacetic acid aqueous solution) / B (acetonitrile) initial ratio 85 / 15, gradient elution program as shown in Table 1; flow rate: 0.9 mL / min; run time: 35 min; injection volume: 10 μL; column temperature: 35 °C; wavelength: 256 nm; column: Agilent XDB-C184.6 × 250 mm.

[0056] Table 1 Gradient elution procedures for liquid chromatography detection.

[0057] T(min) 0 10 17 27 27.1 35 A 85％ 35％ 20％ 60％ 85％ 85％ B 15％ 65％ 80％ 40％ 15％ 15％

[0058] Determination method: Accurately weigh 25 mg of the finished product into a 50 mL volumetric flask, and dilute to volume with diluent (acetonitrile:water volume ratio of 60:40).

[0059] Figure 3 The image shows the liquid chromatogram of the fluranar prepared in Example 1. As can be seen from the image, the purity of fluranar is 99.75%.

[0060] Example 2

[0061] In a reaction vessel equipped with a thermometer, stirrer, and water separator, 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 1.0 g of sulfuric acid, 4.0 g of silicotungstic acid, 80 g of ethanol, and 936 g of toluene were added. The reaction temperature was controlled at 90–100 °C, and the water produced in the reaction was fractionally distilled off while the reaction was underway. After 5 hours of reaction, the temperature was lowered to 50 °C, and 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added. The reaction temperature was controlled at 120–125 °C, and the ethanol produced in the reaction was fractionally distilled off while the reaction was underway. After 3 hours of reaction, the reaction was stopped. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation, and the product was dried to obtain 550.1 g of white solid fluorellana, with a purity of 99.65% and a yield of 98.9%.

[0062] Example 3

[0063] In a reaction vessel equipped with a thermometer, stirrer, and water separator, 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 3.6 g of phosphoric acid, 80 g of silica-alumina molecular sieve, 80 g of ethanol, and 3344 g of toluene were added. The reaction temperature was controlled at 90–100 °C, and the water produced in the reaction was fractionally distilled off while the reaction was underway. After 5 hours of reaction, the temperature was lowered to 50 °C, and 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added. The reaction temperature was controlled at 120–125 °C, and the ethanol produced in the reaction was fractionally distilled off while the reaction was underway. After 3 hours of reaction, the reaction was stopped. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation, and the product was dried to obtain 550.6 g of white solid fluorellana, with a purity of 99.56% and a yield of 99.0%.

[0064] Example 4

[0065] In a reaction vessel equipped with a thermometer, stirrer, and water separator, 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 1.6 g of p-toluenesulfonic acid, 15 g of sulfonic acid resin, 32 g of methanol, and 1300 g of toluene were added. The reaction temperature was controlled at 70–80 °C, and the water produced in the reaction was fractionally distilled off while the reaction was underway. After 10 hours of reaction, the temperature was lowered to 50 °C, and 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added. The reaction temperature was controlled at 120–125 °C, and the methanol produced in the reaction was fractionally distilled off while the reaction was underway. After 3 hours of reaction, the reaction was stopped. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation, and the product was dried to obtain 551.3 g of white solid freranal with a purity of 99.58% and a yield of 99.2%.

[0066] Example 5

[0067] In a reaction vessel equipped with a thermometer, stirrer, and water separator, add 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 1.6 g of p-toluenesulfonic acid, 1.0 g of sulfuric acid, 15 g of sulfonic acid resin, 320 g of methanol, and 3000 g of toluene. Control the reaction temperature at 70–80 °C, and fractionally distill off the water produced during the reaction. After 6 hours of reaction, cool to 50 °C and add... 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added, and the reaction temperature was controlled at 120-125 °C. Methanol produced during the reaction was fractionally distilled off while the reaction was underway. The reaction was stopped after 3 hours. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation and dried to obtain 550.5 g of white solid fluorellana, with a purity of 99.63% and a yield of 99.0%.

[0068] Example 6

[0069] In a reaction vessel equipped with a thermometer, stirrer, and water separator, add 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 1.6 g of p-toluenesulfonic acid, 1.0 g of phosphoric acid, 30 g of sulfonic acid resin, 60 g of methanol, and 2000 g of cyclohexane. Control the reaction temperature at 70–80 °C, and fractionally distill off the water produced during the reaction. After 6 hours of reaction, cool to 50 °C. 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added, and the reaction temperature was controlled at 90-95 °C. Methanol produced during the reaction was fractionally distilled off while the reaction was underway. The reaction was stopped after 3 hours. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation and dried to obtain 548.1 g of white solid fluorellana, with a purity of 99.66% and a yield of 98.6%.

[0070] Example 7

[0071] In a reaction vessel equipped with a thermometer, stirrer, and water separator, add 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 1.6 g of p-toluenesulfonic acid, 1.0 g of sulfuric acid, 20 g of phosphotungstic acid, 60 g of methanol, and 1200 g of ethylbenzene. Control the reaction temperature at 70–80 °C, and fractionally distill off the water produced during the reaction. After 6 hours of reaction, cool to 50 °C and add... 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was used. The reaction temperature was controlled at 140–150 °C. Methanol produced during the reaction was fractionally distilled off while the reaction was underway. The reaction was stopped after 3 hours. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation and dried to obtain 549.7 g of white solid fluorellana, with a purity of 99.55% and a yield of 98.9%.

[0072] Example 8

[0073] In a reaction vessel equipped with a thermometer, stirrer, and water separator, add 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoic acid, 1.6 g of p-toluenesulfonic acid, 1.0 g of sulfuric acid, 20 g of phosphotungstic acid, 100 g of isopropanol, and 1200 g of xylene. Control the reaction temperature at 120–130 °C, and fractionally distill off the water produced during the reaction. After 3 hours of reaction, cool to 50 °C. 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added, and the reaction temperature was controlled at 140–150 °C. Isopropanol produced during the reaction was fractionally distilled off while the reaction was underway. The reaction was stopped after 3 hours. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation and dried to obtain 548.6 g of white solid freranal product with a purity of 99.69% and a yield of 98.7%.

[0074] Example 9

[0075] In a reaction vessel equipped with a thermometer, stirrer, and water separator, 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 0.42 g of p-toluenesulfonic acid, 100 g of methanol, and 1200 g of toluene were added. The reaction temperature was controlled at 80–90 °C, and the water produced in the reaction was fractionally distilled off while the reaction was underway. After 10 hours of reaction, the temperature was lowered to 50 °C, and 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added. The reaction temperature was controlled at 120–130 °C, and the methanol produced in the reaction was fractionally distilled off while the reaction was underway. After 12 hours of reaction, the reaction was stopped. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation, and the product was dried to obtain 547.7 g of white solid freranal with a purity of 99.66% and a yield of 98.5%.

[0076] Example 10

[0077] In a reaction vessel equipped with a thermometer, stirrer, and water separator, add 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoic acid, 1.6 g of p-toluenesulfonic acid, 1.0 g of sulfuric acid, 20 g of phosphotungstic acid, 120 g of n-propanol, and 1400 g of ethylbenzene. Control the reaction temperature at 120–130 °C, and fractionally distill off the water produced during the reaction. After 3 hours of reaction, cool to 50 °C. 163.5 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added, and the reaction temperature was controlled at 135–145 °C. The n-propanol produced in the reaction was fractionally distilled off during the reaction. The reaction was stopped after 3 hours. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of hydrochloric acid (pH=1) and 300 g of water. The solvent was recovered by atmospheric distillation and dried to obtain 552.0 g of white solid freranal product with a purity of 99.58% and a yield of 99.3%.

[0078] Example 11

[0079] In a reaction vessel equipped with a thermometer, stirrer, and water separator, 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-3-yl]-2-methylbenzoic acid, 1.6 g of p-toluenesulfonic acid, 1.0 g of sulfuric acid, 15 g of sulfonic acid resin, 200 g of methanol, and 2000 g of toluene were added. The reaction temperature was controlled at 70–80 °C, and the water produced in the reaction was fractionally distilled off while the reaction was underway. After 6 hours of reaction, the temperature was lowered to 50 °C, and 156 g of 2-amino-N-(2,2,2-trifluoroethyl)acetamide was added. The reaction temperature was controlled at 120–125 °C, and the methanol produced in the reaction was fractionally distilled off while the reaction was underway. After 3 hours of reaction, the reaction was stopped. After the reaction was completed, the mixture was filtered, and the organic layer was washed successively with 500 g of water and 300 g of water. The solvent was recovered by atmospheric distillation and dried to obtain 546.2 g of white solid freranal product with a purity of 99.59% and a yield of 98.2%.

[0080] Example 12

[0081] In a reaction vessel equipped with a thermometer, stirrer, and water separator, add 418 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoic acid, 1.6 g of p-toluenesulfonic acid, 1.0 g of sulfuric acid, 15 g of sulfonic acid resin, 200 g of methanol, and 2500 g of toluene. Control the reaction temperature at 70–80 °C, and fractionate off the water produced during the reaction. After 6 hours of reaction, cool to 50 °C and add 468 g of 2… The reaction was carried out at 120–125 °C with amino-N-(2,2,2-trifluoroethyl)acetamide. Methanol produced during the reaction was fractionally distilled off. The reaction was stopped after 3 hours. After the reaction was complete, the mixture was filtered, and 500 g of water was added to the organic layer. The pH of the reaction solution was adjusted to 7 with hydrochloric acid. The mixture was then separated, and the organic layer was washed with 300 g of water. The solvent was recovered by atmospheric distillation and dried to obtain 546.6 g of white solid fluoranal, with a purity of 99.52% and a yield of 98.3%.

[0082] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, not all embodiments. People can obtain other embodiments based on the present invention without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of fluralaner characterized in that, The method comprises the following steps: carrying out an esterification reaction by mixing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid, a catalyst, an alcohol and an organic solvent to obtain an esterification reaction liquid containing 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ester; carrying out an ester decomposition-amidation reaction by mixing the esterification reaction liquid and 2-amino-N-(2,2,2-trifluoroethyl)acetamide to obtain the fluralaner; the catalyst comprises one or more of p-toluenesulfonic acid, sulfuric acid, phosphoric acid, a sulfonic acid resin, phosphotungstic acid, silicotungstic acid and a silicon-aluminum molecular sieve; the weight ratio of the catalyst to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid is 0.001-0.2:1; the alcohol comprises one or more of methanol, ethanol, isopropanol and n-propanol; the molar ratio of the alcohol to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid is 1-10:

1.

2. The production method according to claim 1, characterized by, the organic solvent comprises one or more of toluene, xylene, ethylbenzene and cyclohexane.

3. The production method according to claim 1 or 2, characterized by, the weight ratio of the organic solvent to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid is 2-8:

1.

4. The method of claim 1, wherein, the temperature of the esterification reaction is 70-130°C, and the time is 2-10 hours.

5. The preparation method according to claim 1, characterized in that, the molar ratio of 2-amino-N-(2,2,2-trifluoroethyl)acetamide to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid is 1-3:

1.

6. The production method according to claim 1 or 5, characterized by, the temperature of the ester decomposition-amidation reaction is 90-150°C, and the time is 3-12 hours.

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