N-cyclobutyl substituted benzamide isoxazoline compound as well as preparation method and application thereof

Abstract

The invention discloses an N-cyclobutyl substituted benzamide isoxazoline compound as well as a preparation method and application thereof. The N-cyclobutyl substituted benzamide isoxazoline compound has broad-spectrum and efficient insecticidal activity at a low dosage, and has a remarkable effect on prevention and treatment of diseases and insect pests in agriculture and forestry and pests in the field of sanitation; moreover, the pesticide composition is safer to non-target organisms, can reduce the damage to plants, non-target organisms and human beings due to overhigh pesticide concentration, and is more beneficial to crop protection and environmental safety.

Description

Technical Field

[0001] The present invention relates to the field of agricultural insecticides, and particularly to N-cyclobutyl-substituted benzamide isoxazoline compounds, their preparation methods and applications. Background Art

[0002] During the agricultural production process, pests feeding on crops can cause huge economic losses and threaten global food security. Therefore, the use of insecticides is an essential link. For decades, insecticides have been indispensable production materials to ensure stable agricultural production and increased income, and are also very important strategic materials.

[0003] Heterocyclic new pesticides represented by nitrogen-containing heterocycles have become an important hot field for the creation of new pesticides due to their high insecticidal activity, broad insecticidal spectrum, low toxicity to mammals, and appropriate field stability. In recent years, among the newly developed pesticides, Flupyrimin, flupyradifurone, epoxyflubendiamide, sulfoxaflor, flonicamid, spirotetramat, cyflumetofen, pyridaben, and cyantraniliprole all belong to nitrogen-containing heterocyclic compounds. However, existing insecticides usually do not have specific selectivity, have high toxicity to the environment while killing pests, and at the same time, due to the excessive and frequent use of single pesticides, serious resistance problems and cross-resistance have occurred, restricting the use of pesticides and restricting the development of agriculture and forestry. Therefore, how to develop new, more efficient, and environmentally friendly pesticides to solve the resistance problem has become an urgent technical problem in this field.

[0004] Isoxazoline compounds have good insecticidal activity effects against various pests. Patent WO2015 / 128358 discloses compound A (CAS: 1807794-12-2), and patent WO2005 / 085216 discloses compound B (CAS: 864730-54-1). The structural formulas are as follows:

[0005]

[0006] These disclosed isoxazoline compounds have insecticidal activity, but at lower doses, the insecticidal effect is not good. In addition, due to the high toxicity of compound A and compound B to bees, they cannot be registered as normal pesticides. Therefore, developing isoxazoline insecticides with high insecticidal activity and low bee toxicity at low doses to meet the needs of agriculture, forestry, horticulture, and the sanitary field has become an urgent technical problem to be solved. Summary of the Invention

[0007] Aiming at the deficiencies of the prior art, the primary object of the present invention is to provide N-cyclobutyl-substituted benzamide isoxazoline compounds or agriculturally acceptable salts. The N-cyclobutyl-substituted benzamide isoxazoline compounds have broad-spectrum and highly efficient insecticidal activities at low doses, which is beneficial to the "reduction of pesticide use and increase of efficiency", and are safer for non-target organisms, and are more conducive to crop protection and environmental safety.

[0008] The second object of the present invention is to provide a method for preparing N-cyclobutyl-substituted benzamide isoxazoline compounds.

[0009] The third object of the present invention is to provide an agricultural composition.

[0010] The fourth object of the present invention is to provide the use of the N-cyclobutyl-substituted benzamide isoxazoline compounds or the agricultural composition in the preparation of drugs for controlling pests or in the preparation of insecticides.

[0011] The above objects of the present invention are achieved by the following technical solutions:

[0012] The present invention claims N-cyclobutyl-substituted benzamide isoxazoline compounds or agriculturally acceptable salts, and the N-cyclobutyl-substituted benzamide isoxazoline compounds have the structure shown in formula (I):

[0013]

[0014] In the formula, R 1 , R 2 , R 3 are each independently selected from hydrogen, halogen, cyano, nitro, C 1～6 alkyl, C 1～6 haloalkyl, C 1～6 ester group, C 1～6 alkoxy or C 1～6 haloalkoxy;

[0015] R 4 is selected from hydrogen, C 1～6 alkyl, C 1～6 haloalkyl, C 3～6 cycloalkyl or C 3～6 halocycloalkyl;

[0016] R 5 is selected from hydrogen, halogen, cyano, nitro, C 1～6 alkyl, C 3～8 cycloalkyl, C 1～6 ester group or aryl; the C 1～6 alkyl and aryl are unsubstituted or substituted by one or more substituents selected from C 1～6 alkoxy, C 1～6 ester group, halogen;

[0017] R 6 、R 7 are each independently selected from hydrogen, halogen, cyano, nitro, C 1～6 alkyl, C 3～8 cycloalkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 1～6 ester group or aryl; the C 1～6 alkyl and aryl are unsubstituted or substituted by one or more substituents selected from C 1～6 alkoxy, C 1～6 ester group, halogen.

[0018] The inventors have found that N-cyclobutyl-substituted benzamide isoxazoline compounds having the structure shown in formula (I) of the present invention can have broad-spectrum and highly efficient insecticidal activity at low doses, are safe for non-target organisms, and at the same time, due to the good effect at low doses, the dosage of the medicament is reduced in practical applications, resulting in less drug residue during application and being more environmentally friendly.

[0019] In one embodiment of the present invention, wherein, R 1 is selected from hydrogen, halogen, cyano, nitro, C 1～4 alkyl, C 1～4 haloalkyl, C 1～4 ester group, C 1～4 alkoxy or C 1～4 haloalkoxy; R 2 is selected from hydrogen, halogen, cyano, nitro, C 1～4 ester group, C 1～4 alkyl, C 1～4 haloalkyl, C 1～4 alkoxy or C 1～4 haloalkoxy; R 3 is selected from hydrogen, halogen, cyano, nitro, C 1～4 alkyl, C 1～4 haloalkyl, C 1～4 ester group, C 1～4 alkoxy or C 1～ haloalkoxy; R 4 is selected from hydrogen, C 1～4 alkyl, C 1～4 haloalkyl, C 3～6 cycloalkyl or C 3～6 halocycloalkyl; R 5 is selected from hydrogen, halogen, cyano, nitro, C 1～4 alkyl, C 3～6 cycloalkyl, C 1～4 ester group or aryl; the C 1～4 alkyl and aryl are unsubstituted or substituted by one or more substituents selected from C 1～4 alkoxy, C 1～4Substituted by substituents of ester group and halogen; R 6 and R 7 are each independently selected from hydrogen, halogen, cyano, nitro, C 1～4 alkyl, C 3～6 cycloalkyl, C 2～4 alkenyl, C 2～4 alkynyl, C 1～4 ester group or aryl; the C 1～4 alkyl and aryl are unsubstituted or substituted by one or more substituents selected from C 1～4 alkoxy, C 1～4 ester group and halogen.

[0020] In another embodiment of the present invention, wherein R 1 is selected from hydrogen, chlorine, cyano, nitro, C 1～3 alkyl, C 1～3 haloalkyl, C 1～3 ester group, C 1～3 alkoxy or C 1～3 haloalkoxy; R 2 is selected from hydrogen, chlorine, fluorine, C 1～3 ester group, C 1～3 alkyl, C 1～3 haloalkyl, C 1～3 alkoxy or C 1～3 haloalkoxy; R 3 is selected from hydrogen, chlorine, cyano, nitro, C 1～3 alkyl, C 1～3 haloalkyl, C 1～3 ester group, C 1～3 alkoxy or C 1～3 haloalkoxy; R 4 is selected from hydrogen, C 1～3 alkyl, C 1～3 haloalkyl, C 3～6 cycloalkyl or C 3～6 halocycloalkyl; R 5 is selected from hydrogen, halogen, cyano, nitro, C 1～4 alkyl, C 3～6 cycloalkyl, C 1～4 ester group or aryl; the C 1～4 alkyl and aryl are unsubstituted or substituted by one or more substituents selected from C 1～4 alkoxy, C 1～4 ester group and halogen; R 6 and R 7 are each independently selected from hydrogen, halogen, cyano, nitro, nitro, C 1～4 alkyl, C 3～6 cycloalkyl, C 2～4 alkenyl, C 2～4 alkynyl; the C 1～4The alkyl group is unsubstituted or substituted with one or more substituents selected from C 1～4 alkoxy, C 1～4 ester group, and halogen.

[0021] In another embodiment of the present invention, R 1 is selected from chlorine, cyano, C 1～3 haloalkyl, C 1～3 haloalkoxy; R 2 is selected from hydrogen, chlorine, C 1～3 haloalkyl; R 3 is selected from hydrogen, chlorine, C 1～3 haloalkyl, C 1～3 haloalkoxy; R 4 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R 5 is selected from hydrogen, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R 6 and R 7 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, propyl, C 1～3 haloalkyl.

[0022] In another embodiment of the present invention, wherein R 1 is selected from chlorine, cyano, difluoromethyl, trifluoromethyl, trifluoromethoxy; R 2 is selected from hydrogen, chlorine; R 3 is selected from hydrogen, chlorine, difluoromethyl, trifluoromethyl, trifluoromethoxy; R 4 is selected from hydrogen, methyl; R 5 is selected from hydrogen, cyano; R 6 and R 7 are each independently selected from hydrogen, fluorine, trifluoromethyl.

[0023] In another embodiment of the present invention, the N-cyclobutyl-substituted benzamide isoxazoline compounds are selected from any one of the following structures:

[0024]

[0025] Furthermore, the present invention claims a method for preparing N-cyclobutyl-substituted benzamide isoxazoline compounds, comprising the following steps:

[0026] (1) The compound of formula (A) reacts under the action of hydroxylamine hydrochloride and a base, and then reacts under the action of NaNO2 and an acid to form a compound of formula (B);

[0027] (2) The compound of formula (C) and 2-bromo-3,3,3-trifluoropropene react under the action of a base and a palladium catalyst to form a compound of formula (D);

[0028] (3) The compound of formula (B) and the compound of formula (D) react under the action of a base to form the compound of formula (E);

[0029] (4) The compound of formula (E) reacts under the action of a base to form the compound of formula (F);

[0030] (5) The compound of formula (F) undergoes an acyl chloride reaction and then reacts with formula (F-1) to form the compound of formula (I); The reaction formula of the preparation method is as follows:

[0031]

[0032] In another embodiment of the present invention, in the step (1), the base can be a base conventionally used in the art; More specifically, the base includes but is not limited to any one or a combination of at least two of trimethylamine, triethylamine, N,N-diisopropylethylamine, tri-n-butylamine, pyridine, piperidine, 3-methylpyridine, 2,6-dimethylpyridine, N-methylmorpholine, 3-methylimidazole, 4-N,N-dimethylaminopyridine.

[0033] In another embodiment of the present invention, in the step (1), the amount of the base used is 1-5 times the molar amount of the compound of formula (A), such as 1 time, 1.3 times, 1.5 times, 1.8 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times or 5 times.

[0034] In another embodiment of the present invention, in the step (1), the solvent used for dissolving the compound of formula (A) can be a solvent conventionally used in the art; More specifically, the solvent includes but is not limited to methanol, etc.

[0035] In another embodiment of the present invention, in the step (1), the compound of formula (A) reacts at room temperature.

[0036] In another embodiment of the present invention, in the step (1), the acid is a mixed acid; More specifically, the mixed acid can be a composition of concentrated sulfuric acid, acetic acid, etc.; More specifically, the mixed acid is concentrated sulfuric acid and glacial acetic acid with a volume ratio of 1-3:1-3.

[0037] In another embodiment of the present invention, in the step (1), the reaction temperature under the action of NaNO2 and the acid is -2 to 2 °C.

[0038] In another embodiment of the present invention, in step (2), the palladium catalyst is selected from at least one of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, palladium dichloride, palladium acetate, and 1,1-bis(diphenylphosphino)ferrocene dichloride; the temperature at which the compound of formula (C) and 2-bromo-3,3,3-trifluoropropene are mixed is 5-10 °C; the reaction temperature is 80-95 °C.

[0039] In another embodiment of the present invention, in step (3), the base can be a base conventionally used in the art; more specifically, the base includes, but is not limited to, any one or a combination of at least two of potassium carbonate, cesium carbonate, trimethylamine, triethylamine, N,N-diisopropylethylamine, tri-n-butylamine, pyridine, piperidine, 3-methylpyridine, 2,6-dimethylpyridine, N-methylmorpholine, 3-methylimidazole, and 4-N,N-dimethylaminopyridine. In another embodiment of the present invention, in step (3), the amount of the base used is 1 to 5 times the molar amount of the compound of formula (D), such as 1 time, 1.3 times, 1.5 times, 1.8 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, or 5 times.

[0040] In another embodiment of the present invention, in step (3), the solvent used for dissolving the compound of formula (B) can be a solvent conventionally used in the art; more specifically, the solvent includes, but is not limited to, N,N-dimethylformamide, etc.

[0041] In another embodiment of the present invention, in step (3), the reaction is carried out at room temperature.

[0042] In another embodiment of the present invention, in step (4), the base can be lithium hydroxide, sodium hydroxide, or potassium hydroxide. In another embodiment of the present invention, in step (4), the amount of the base used is 1-5 times the molar amount of the compound of formula (E), such as 1 time, 1.3 times, 1.5 times, 1.8 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, or 5 times.

[0043] In another embodiment of the present invention, in step (4), the reaction is carried out at 50-70 °C.

[0044] In another embodiment of the present invention, in step (5), the acyl chloride reaction is carried out under reflux conditions.

[0045] In another embodiment of the present invention, in the step (5), the base can be a base conventionally used in the art; more specifically, the base includes but is not limited to any one or a combination of at least two of trimethylamine, triethylamine, N,N - diisopropylethylamine, tri - n - butylamine, pyridine, piperidine, 3 - methylpyridine, 2,6 - dimethylpyridine, N - methylmorpholine, 3 - methylimidazole, 4 - N,N - dimethylaminopyridine. In another embodiment of the present invention, in the step (5), the amount of the base used is 1 - 5 times the molar amount of the compound of formula (F), such as 1 time, 1.3 times, 1.5 times, 1.8 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times or 5 times.

[0046] In another embodiment of the present invention, in the step (5), the temperature for the reaction with formula (F - 1) is - 2 to 2 °C.

[0047] Furthermore, the present invention claims protection for an agricultural composition, comprising:

[0048] (a) 0.001 - 99.99% by weight of the N - cyclobutyl - substituted benzamide isoxazoline compound or a pesticidally acceptable salt, its optical isomers, cis - trans isomers, or a combination thereof;

[0049] and (b) a pesticidally acceptable carrier and / or excipient.

[0050] Preferably, in the present invention, the agricultural composition can be formulated into dosage forms such as wettable powders, suspensions, emulsifiable concentrates, emulsions in water, or baits.

[0051] Furthermore, the present invention claims protection for the use of the N - cyclobutyl - substituted benzamide isoxazoline compound or the agricultural composition in the preparation of a medicament for controlling pests or in the preparation of an insecticide.

[0052] Preferably, the medicament or insecticide is directly applied to the pests or the places they contact. Preferably, the fields or places for pest control include but are not limited to agriculture, forestry, horticulture, sanitary areas, or plants, etc.

[0053] Preferably, the pests include agricultural and forestry pests, sanitary pests, or pests harmful to animal health.

[0054] Preferably, the pests include one or more of Lepidoptera pests, Coleoptera pests, Hemiptera pests, Thysanoptera pests, Diptera pests, Orthoptera pests, Homoptera pests, Isoptera pests, Hymenoptera pests, Blattodea pests.

[0055] Preferably, the pests harmful to animal health include fleas, tick mites or nematodes that are parasitic to animals. Specifically, the pests include, but are not limited to: Helicoverpa armigera, Plutella xylostella, Spodoptera exigua, Spodoptera litura, Pieris rapae, Chilo suppressalis, Tryporyza incertulas, Sesamia inferens, Spodoptera frugiperda, Cnaphalocrocis medinalis, Thrips oryzae, Frankliniella occidentalis, Thrips palmi, Thrips tabaci, Thrips mymarae, Myzus persicae, Aphis gossypii, Aphis medicaginis, Aphis citricola, Sitobion avenae, Altica spp., stink bugs, Laodelphax striatellus, Nilaparvata lugens, Sogatella furcifera, termites, mosquitoes and flies, Tetranychus cinnabarinus, Panonychus citri.

[0056] Further, the plants involved in the agricultural field mainly include the following categories: vegetables, such as cucumber, loofah, watermelon, melon, pumpkin, hanging melon, spinach, celery, cabbage, gourd, pepper, eggplant, tomato, onion, ginger, garlic, leek, asparagus lettuce, kidney bean, cowpea, broad bean, radish, carrot, potato or yam; cereals, such as wheat, barley, corn, rice or sorghum; fruit trees, such as apple, pear, banana, citrus, grape, litchi or mango; flowers, such as peony, rose or anthurium; oil crops, such as peanut, soybean, rapeseed, sunflower or sesame; sugar crops, such as beet or sugarcane; other crops, such as strawberry, potato, sweet potato, tobacco or tea. The above-listed plants or ranges have no restrictive effect on the scope of use of the isoxazoline-substituted pyridine amide compounds of the present invention.

[0057] For the sake of simplicity, the "N-cyclobutyl-substituted benzamide isoxazoline compounds", "compounds of formula (I)" or "compounds of the present invention" described hereinafter may also cover any optical isomers, cis-trans isomers or their combinations of the compounds of formula (I).

[0058] The term "optical isomers" means that when a compound has one or more chiral centers, each chiral center can exist in the R configuration or the S configuration, and the various isomers thus formed are optical isomers. Optical isomers include all diastereomers, enantiomers, meso forms, racemates or mixtures thereof. For example, optical isomers can be separated by a chiral chromatographic column or by chiral synthesis.

[0059] "Cis-trans isomers", also known as "geometric isomers", mean that when there is a double bond in a compound, the compound can exist in cis isomers, trans isomers, E isomers and Z isomers. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or mixtures thereof.

[0060] Compared with the prior art, the present invention has the following beneficial effects:

[0061] The present invention provides a class of N-cyclobutyl-substituted benzamide isoxazoline compounds, which have remarkable effects on preventing and controlling pests in the fields of agriculture, forestry and the hygiene field, and can achieve good insecticidal effects at low doses, with the characteristics of rapid onset. It can reduce the harm caused by excessive drug concentration to plants, non-target organisms and humans. The N-cyclobutyl-substituted benzamide isoxazoline compounds have less drug residue during application, are more environmentally friendly, and their preparation methods are simple, efficient, easy to scale up production, and have broad application prospects. Detailed implementation manners

[0062] The following specific examples are used to further illustrate the present invention, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available.

[0063] In the present invention, unless otherwise specified in the context, the meanings of the words, phrases and symbols to be used below are stipulated as follows. The meanings of the following abbreviations and terms run through the whole text:

[0064] NaNO2 is sodium nitrite; Et3N is triethylamine; PE is petroleum ether; EA is ethyl acetate; SOCl2 is thionyl chloride; NaCl is sodium chloride; Na2SO4 is sodium sulfate; TLC is thin layer chromatography technology; RT refers to room temperature.

[0065] Example 1

[0066] The synthesis route is as follows:

[0067]

[0068] The reaction formula of the preparation method is as shown above. In this example, N-(3,3-difluorocyclobutyl)-2-methyl-4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzamide (Compound I-30 in Table 1 below) is taken as an example, and its specific synthesis process is as follows:

[0069] S1: Preparation of 4-[chloro(oximino)methyl]-2-methylbenzoate (B)

[0070] Methyl 4-cyano-2-methylbenzoate (0.1 mol) was dissolved in methanol (150 mL). Under stirring, hydroxylamine hydrochloride (0.15 mol) and Et3N (0.3 mol) were added successively. Subsequently, the mixture was stirred at room temperature for 10 h. After monitoring the completion of the reaction by TLC, methanol was evaporated, 100 mL of ethyl acetate was added for extraction, and the organic phase was washed successively with water and saturated NaCl solution, dried over anhydrous Na2SO4, and the solvent was evaporated to obtain a white solid intermediate (amino intermediate), which was used without purification. At 0 °C, NaNO2 was slowly added to the mixed acid of concentrated sulfuric acid (50 mL) and glacial acetic acid (50 mL). After stirring for 5 min, the acetic acid solution (50 mL) of the white solid intermediate (amino intermediate) prepared previously was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 5 h. After monitoring the completion of the reaction by TLC, the reaction solution was poured into ice water (800 mL), and extracted with EA (150 mL×3). The combined organic phases were washed successively with water and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid with a yield of 88%.

[0071] S2: Preparation of 1,3-bis(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene

[0072] 3,5-Bis(trifluoromethyl)phenylboronic acid (0.1 mol) and tetrakis(triphenylphosphine)palladium (0.005 mol) were dissolved in 150 mL of tetrahydrofuran (in a 500 mL pressure-resistant flask). The system was cooled to about 10 °C, and potassium carbonate (0.2 mol), water (50 mL), and 2-bromo-3,3,3-trifluoropropene (0.12 mol) were slowly added under stirring. Then, the mixture was heated to 90 °C and stirred for 5 h. After the reaction system was cooled to room temperature and the completion of the reaction was monitored by TLC, 150 mL of water was added, and the mixture was extracted with ether (3×150 mL). The combined organic phases were washed successively with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure (below 30 °C), and purified by silica gel column chromatography to obtain 1,3-bis(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene (the eluent was PE), a brown liquid with a yield of 85%.

[0073] S3: Preparation of methyl 4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-2-methylbenzoate

[0074] Dissolve 4-[chloro(hydroxyimino)methyl]-2-methylbenzoate (50 mmol) in DMF (80 mL). While stirring, add 1,3-bis(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene (60 mmol) and Et3N (100 mmol), and stir at room temperature for 5 h. Monitor the reaction process of the raw materials by TLC. After the reaction is complete, add 300 mL of water, extract with EA (3×100 mL), combine the organic phases, wash with saturated aqueous sodium chloride solution (200 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by column chromatography to obtain methyl 4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-2-methylbenzoate (PE / EA = 20:1), a yellow solid, with a yield of 75%.

[0075] S4: Preparation of 4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-2-methylbenzoic acid

[0076] Dissolve sodium hydroxide (NaOH, 60 mmol) in H2O (50 mL), and then add it to a solution of methyl 4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-2-methylbenzoate (20 mmol) in EtOH (100 mL). Stir at 65 °C overnight. After monitoring the completion of the reaction by TLC, cool the reaction system to room temperature, concentrate the organic solvent under reduced pressure. Adjust the crude product to pH = 2 with 1N HCl, extract with EA (3×50 mL), combine the organic phases, wash successively with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-2-methylbenzoic acid, a white solid, with a yield of 94%.

[0077] S5: Preparation of N-(3,3-difluorocyclobutyl)-2-methyl-4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}benzamide

[0078] 4-{5-[3,5-Bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-2-methylbenzoic acid (1 mmol) was dissolved in SOCl2 (5 mL), and the mixture was refluxed with stirring for 3 h. After the reaction was cooled to room temperature, the solvent was evaporated to dryness, and the crude acyl chloride product was reserved for use. 3,3-Difluorocyclobutylamine hydrochloride (1.2 mmol) and Et3N (4.0 mmol) were successively added to dichloromethane (5 mL). The system was cooled to 0 °C, and a dichloromethane solution (5 mL) of the crude acyl chloride product was slowly added dropwise with stirring. After the addition was completed, the mixture was slowly warmed to room temperature and stirred for 2 h. After the reaction was monitored by TLC to be complete, the solvent was evaporated to dryness, and silica gel column chromatography was used to obtain N-(3,3-difluorocyclobutyl)-2-methyl-4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}benzamide (PE / EA = 5:1), a white solid, with a yield of 93%. 1 1H NMR (600 MHz, Chloroform-d) δ 8.08 (s, 2H), 7.97 (s, 1H), 7.48 - 7.38 (m, 2H), 7.32 (d, J = 7.9 Hz, 1H), 6.47 (d, J = 6.8 Hz, 1H), 4.44 - 4.31 (m, 1H), 4.20 (d, J = 17.2 Hz, 1H), 3.76 (d, J = 17.2 Hz, 1H), 3.10 - 2.96 (m, 2H), 2.56 (tdd, J = 15.9, 10.2, 5.3 Hz, 2H), 2.38 (s, 3H).

[0079] The other compounds represented by General Formula I in Table 1 below of the present invention can all be prepared by referring to the method in Example 1.

[0080] Referring to the preparation method of Example 1 above, N-cyclobutyl-substituted benzamide isoxazoline compounds represented by Formula (I) of the present invention were synthesized. The substituents of the N-cyclobutyl-substituted benzamide isoxazoline compounds numbered I-1 to I-65 are shown in Table 1 below.

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092] Example 2 Insecticidal Activity Assay

[0093] (1) Indoor Bioactivity Assay against Plutella xylostella, Spodoptera exigua and Spodoptera litura

[0094] Plutella xylostella, Spodoptera exigua, and Spodoptera litura belong to Lepidoptera pests with chewing mouthparts and are common vegetable pests.

[0095] The leaf-dipping method was used to test the insecticidal activity of the target compounds against Plutella xylostella, Spodoptera exigua, and Spodoptera litura. The compounds were dissolved in dimethyl sulfoxide to prepare a stock solution of 10000 mg / L, and then diluted with dechlorinated water containing 0.05% Tween-80 to the required concentration of the liquid medicine. Fresh cabbage leaves were made into leaf discs of the same size with a leaf puncher, immersed in the liquid medicine for 5 s, taken out and air-dried naturally, and then placed in a petri dish containing 10 - 12 3rd instar Plutella xylostella larvae or 2nd instar Spodoptera exigua larvae or 2nd instar Spodoptera litura larvae (starved for 3 h in advance). Each treatment was repeated 3 times. Dechlorinated water containing 0.05% Tween-80 was used as the blank control, and cultured in an environment of 26 - 28 °C, 85% relative humidity, and 16 h of light (8 h of darkness). After 48 h, the treatment results were checked to calculate the mortality rate, and the median lethal concentration value (LC 50 ) of the compound was calculated. After 48 h, the treatment results were checked to calculate the mortality rate, and the median lethal concentration value (LC 50 ) of the compound was calculated using SPSS software. The formula for calculating the corrected mortality rate (%) is as follows:

[0096] Mortality rate (%) = Number of dead insects / Number of tested insects × 100

[0097] Corrected mortality rate (%) = (Mortality rate of treatment group - Mortality rate of control group) / (100 - Mortality rate of control group) × 100

[0098] (2) Indoor Bioactivity Assay against Spodoptera frugiperda

[0099] The fall armyworm (Spodoptera frugiperda) belongs to the pests of Lepidoptera, has chewing mouthparts, and is a common omnivorous pest. It mainly damages corn in the Chinese region.

[0100] The leaf-dipping method was used to test the insecticidal activity of the compound against the fall armyworm. The test compound was dissolved in dimethyl sulfoxide to prepare a stock solution of 10,000 mg / L, and then diluted with dechlorinated water containing 0.05% Tween-80 to the required concentration of the medicament solution. Fresh and tender corn leaves were cut into rectangular leaves 5 cm long with scissors, immersed in the medicament solution for 5 s, taken out and air-dried naturally, and then placed in a petri dish containing 10 second-instar fall armyworm larvae (starved for 3 h in advance). Each treatment was repeated 3 times. Dechlorinated water containing 0.1% Tween-80 was used as the blank control, and it was cultured in an environment of 26 - 28 °C, 85% relative humidity, and 16 h of light (8 h of darkness). After 48 h, the treatment results were checked to calculate the mortality rate, and the median lethal concentration value (LC 50 ) of the compound was calculated.

[0101] (3) Indoor bioactivity determination against Chilo suppressalis

[0102] Chilo suppressalis (Walker) belongs to the pests of Lepidoptera, has chewing mouthparts, and is a common pest of Lepidoptera. It mainly damages rice.

[0103] The leaf-dipping method was used to test the indoor insecticidal activity of the target compound against Chilo suppressalis. The target compound was dissolved in dimethyl sulfoxide to prepare a stock solution of 10,000 mg / L, and then diluted with dechlorinated water containing 0.1% Tween-80 to the medicament solution of the concentration to be tested. The water bamboo strips were immersed in the medicament solution to be tested for 10 s, taken out and dried, and placed in a disposable petri dish lined with filter paper. Ten third-instar Chilo suppressalis larvae of the same size were selected and put into it (starved for 3 h in advance). Each treatment was repeated 3 times. Dechlorinated water containing 0.1% Tween-80 was used as the blank control, and it was cultured in an environment of 26 - 28 °C, 85% relative humidity, and 16 h of light (8 h of darkness). After 48 h, the treatment results were checked to calculate the mortality rate, and the median lethal concentration value (LC 50 ) of the compound was calculated.

[0104] (4) Indoor bioactivity determination against thrips

[0105] Thrips (Thripidae) belongs to the insects of Thysanoptera and mainly damages vegetables, causing serious reduction in vegetable yields.

[0106] The leaf-dipping method was used to test the insecticidal activity of the compounds against cowpea thrips. The test compounds were dissolved in dimethyl sulfoxide to prepare a stock solution of 10,000 mg / L, and then diluted with dechlorinated water containing 0.1% Tween-80 to the required concentration of the medicament solution. Cowpea was cut into small segments of 0.5 cm and placed in a 12-well microtiter plate and sprayed with the test solution. After drying, these cowpea segments were infested with a mixed-age thrips population (10 - 12 individuals). Each treatment was repeated 3 times, and a blank treatment, dechlorinated water containing 0.1% Tween-80 was set as the blank control, and cultured in an environment of 26 - 28 °C, 85% relative humidity, and 16 h of light (8 h of darkness). After 48 h, the treatment results were examined to calculate the corrected mortality rate, and the median lethal concentration value (LC 50 ) of the compound was calculated.

[0107] (5) Indoor bioactivity determination against mosquitoes

[0108] Culex pipiens pallens, Culex quinquefasciatus, Aedes albopictus, Anopheles sinensis, etc. are Diptera insects and are vectors of various diseases, seriously endangering human health.

[0109] The larval immersion method was used to test the insecticidal activity of the compounds against mosquito larvae. The test compounds were dissolved in acetone to prepare a stock solution of 10,000 mg / L, and then diluted with dechlorinated water containing 0.1% Tween-80 to the required concentration of the medicament solution. The pre-selected 3rd instar mosquito larvae were added to the prepared medicament solution. Each treatment was repeated 3 times, and a blank treatment, dechlorinated water containing 0.1% Tween-80 was set as the blank control, and placed in a greenhouse at 26 - 28 °C and 60% - 85% relative humidity. After 72 h, the treatment results were examined to calculate the corrected mortality rate, and the median lethal concentration value (LC 50 ) of the compound was calculated.

[0110] (6) Indoor bioactivity determination against Blattella germanica

[0111] Blattella germanica belongs to the order Blattodea insects, with extremely strong survival ability and extremely strong reproductive ability, and it is difficult to completely eliminate, bringing great troubles to people's lives.

[0112] The insecticidal activity of the compounds against Blattella germanica was tested by the drug film method. The test compounds were dissolved in acetone to prepare the required concentration of the liquid medicine. 2.5 mL of the liquid medicine with different concentrations was added to a 500 mL conical flask, and the conical flask was continuously rotated to make the liquid medicine evenly distributed on the inner wall of the flask. Then it was placed in a fume hood overnight to volatilize all the organic solvents. Then 10 test insects were placed in each flask and sealed with a gauze or a piece of cloth. Each concentration test was repeated 3 times, and the corresponding solvent treatment was used as the control group. After 24 h, the number of dead insects was recorded, and the median lethal concentration value (LC 50 ) was calculated.

[0113] (7) Indoor bioactivity determination against Solenopsis invicta

[0114] Solenopsis invicta Buren belongs to Hymenoptera insects and causes great harm to the ecological environment and agricultural production.

[0115] The insecticidal activity of the candidate compounds against Solenopsis invicta was determined by the water test tube method. The test compounds were dissolved in dimethyl sulfoxide to prepare a stock solution of 10000 mg / L, and then diluted with dechlorinated water containing 0.1% Tween-80 to the required concentration of the liquid medicine and placed in a 1.5 mL plastic centrifuge tube. The tube mouth was plugged with absorbent cotton. 20 Solenopsis invicta of the same size were selected in advance and placed in an aviation plastic cup and starved for 3 h. Then the centrifuge tube containing the liquid medicine was horizontally placed in a disposable aviation plastic cup. Each treatment was repeated three times, and dechlorinated water containing 0.1% Tween-80 and dimethyl sulfoxide was used as the blank control. The plastic cup was placed in an environment of 26 - 28 °C, 85% relative humidity, and 16 h of light (8 h of darkness) for cultivation. Finally, the mortality rates after 1 day, 3 days, and 5 days of treatment were recorded respectively, and the median lethal concentration value (LC 50 ) was calculated.

[0116] In the insecticidal activity experiments of the above (1) - (7), control compound A (from patent WO2015 / 128358) and control compound B (from patent WO2005 / 085216) were used as positive controls. The structures of compounds A and B are shown as follows.

[0117]

[0118] According to the method of Example 2, the compounds of the present invention, control compound A and B were selected for parallel determination of the insecticidal activities against Plutella xylostella, Spodoptera exigua, Spodoptera litura, Spodoptera frugiperda, Chilo suppressalis, Thrips palmi, mosquitoes, Blattella germanica, and Solenopsis invicta to compare the insecticidal effects. The test results are shown in Tables 2, 3, 4, and 5.

[0119] Table 2 Comparison of the insecticidal activities of the compounds of the present invention, control compound A and B against Plutella xylostella

[0120]

[0121]

[0122] Table 3 Comparison of insecticidal activities of the compounds I-15, I-17, I-33, I-34, I-50, I-56, I-58 of the present invention with control compounds A and B against Spodoptera exigua, Spodoptera litura, Spodoptera frugiperda, Chilo suppressalis and Thrips palmi

[0123]

[0124]

[0125] Table 4 Comparison of insecticidal activities of the compounds I-15, I-17, I-33, I-34, I-50, I-56, I-58 of the present invention with control compounds A and B against Culex pipiens pallens, Culex quinquefasciatus, Aedes albopictus, Anopheles sinensis and Blattella germanica

[0126] Table 5 Comparison of insecticidal activities of the compounds I-15, I-17, I-33, I-34, I-50, I-56, I-58 of the present invention with control compounds A and B against Solenopsis invicta

[0127]

[0128] As can be seen from Table 2, Table 3, Table 4 and Table 5, compared with the control compounds A and B, the N-cyclobutyl-substituted benzamide isoxazoline compounds provided by the present invention have more excellent insecticidal activities against Plutella xylostella. In particular, for the compounds I-15, I-17, I-33, I-34, I-50, I-56, I-58, their insecticidal activities against Plutella xylostella, Spodoptera exigua, Spodoptera litura, Spodoptera frugiperda, Chilo suppressalis, Thrips palmi, mosquitoes, Blattella germanica and Solenopsis invicta are significantly better than those of compounds A and B, indicating that the compounds I-15, I-17, I-33, I-34, I-50, I-56, I-58 of the present application have better insecticidal effects at lower doses, have broad-spectrum and high-efficiency insecticidal activities, and the compounds of the present invention can reduce the usage amount of pesticides, achieving "reducing the dosage and increasing the efficiency".

[0129] Example 3 Comparative determination of safety

[0130] The experimental method refers to "GB / T 31270.10-2014". The mother liquor of the test compound at different concentrations was dispersed in the sucrose solution and used to feed adult worker bees. After the liquid medicine was consumed, the sucrose solution without the test compound was continued to be fed, and the mortality after 48 h was observed and recorded. The results are shown in Table 6.

[0131] Table 6 Comparison of the Toxicities of Compounds I-15, I-17, I-33, I-34, I-50, I-56, I-58 of the Present Invention and Control Compounds A and B to the Non-Target Organism Bees

[0132] Compound <![CDATA[48h LD 50 (μg / head)]]> I-15 3.11 I-17 2.88 I-33 2.03 I-34 3.28 I-50 2.23 I-56 2.10 I-58 3.53 Control Compound A 0.99 Control Compound B 1.85

[0133] As can be seen from Table 6, compared with control compounds A and B, compounds I-15, I-17, I-33, I-34, I-50, I-56, I-58 of the present invention have lower biological toxicity to the non-target organism bees.

[0134] In summary, the N-cyclobutyl-substituted benzamide isoxazoline compounds provided by the present invention have broad-spectrum and highly efficient insecticidal activities, can effectively control resistant pests, and have obvious advantages over control compounds A and B in terms of insecticidal activity and safety to non-target organisms.

[0135] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, rather than limitations on the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation manners here. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the claims of the present invention.

Claims

1. N-cyclobutyl substituted benzamide isoxazoline compounds or pesticide acceptable salts thereof, characterized in that: The N-cyclobutyl substituted benzamide isoxazoline compound has a structure shown in formula (I): In the formula, R 1 , R 2 , R 3 are each independently selected from hydrogen, halogen, cyano, nitro, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Ester group, C 1～6 Alkoxy or C 1～6 Haloalkoxy; R 4 Selected from hydrogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cycloalkyl or C 3～6 Halogenated cycloalkyl; R 5 Selected from hydrogen, halogen, cyano, nitro, C 1～6 Alkyl, C 3～8 Cycloalkyl, C 1～6 Ester group or aromatic group; said C 1～6 Alkyl, aryl are unsubstituted or substituted with one or more selected from C 1～6 Alkoxy, C 1～6 Substitution of ester groups and halogen substituents; R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, nitro, C 1～6 Alkyl, C 3～8 Cycloalkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Ester group or aromatic group; said C 1～6 Alkyl, aryl are unsubstituted or substituted with one or more selected from C 1～6 Alkoxy, C 1～6 Ester group, halogen substituents.

2. The N-cyclobutyl substituted benzamide isoxazoline compound or its pesticide acceptable salt according to claim 1, characterized in that: R 1 Selected from hydrogen, halogen, cyano, nitro, C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Ester group, C 1～4 Alkoxy or C 1～4 Haloalkoxy; R 2 Selected from hydrogen, halogen, cyano, nitro, C 1～4 Ester group, C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy or C 1～4 Haloalkoxy; R 3 Selected from hydrogen, halogen, cyano, nitro, C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Ester group, C 1～4 Alkoxy or C 1～ Haloalkoxy; R 4 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Haloalkyl, C 3～6 Cycloalkyl or C 3～6 Halogenated cycloalkyl; R 5 Selected from hydrogen, halogen, cyano, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 1～4 Ester group or aromatic group; said C 1～4 Alkyl, aryl are unsubstituted or substituted with one or more selected from C 1～4 Alkoxy, C 1～4 Substitution of ester groups and halogen substituents; R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, C 1～4 Ester group or aromatic group; said C 1～4 Alkyl, aryl are unsubstituted or substituted with one or more selected from C 1～4 Alkoxy, C 1～4 Ester group, halogen substituents.

3. The N-cyclobutyl substituted benzamide isoxazoline compound or its pesticide acceptable salt according to claim 1, characterized in that: R 1 Selected from hydrogen, chlorine, cyano, nitro, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Ester group, C 1～3 Alkoxy or C 1～3 Haloalkoxy; R 2 Selected from hydrogen, chlorine, fluorine, C 1～3 Ester group, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy or C 1～3 Haloalkoxy; R 3 Selected from hydrogen, chlorine, cyano, nitro, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Ester group, C 1～3 Alkoxy or C 1～3 Haloalkoxy; R 4 Selected from hydrogen, C 1～3 Alkyl, C 1～3 Haloalkyl, C 3～6 Cycloalkyl or C 3～6 Halogenated cycloalkyl; R 5 Selected from hydrogen, halogen, cyano, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 1～4 Ester group or aromatic group; said C 1～4 Alkyl, aryl are unsubstituted or substituted with one or more selected from C 1～4 Alkoxy, C 1～4 Substitution of ester groups and halogen substituents; R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, nitro, nitro, C 1～4 Alkyl, C 3～6 Cycloalkyl, C 2～4 Alkenyl, C 2～4 Alkynyl; the C 1～4 The alkyl group is unsubstituted or substituted with one or more selected from C 1～4 Alkoxy, C 1～4 Ester group, halogen substituents.

4. The N-cyclobutyl substituted benzamide isoxazoline compound or its pesticide acceptable salt according to claim 1, characterized in that: R 1 Selected from chlorine, cyano, C 1～3 Haloalkyl, C 1～3 Haloalkoxy; R 2 Selected from hydrogen, chlorine, C 1～3 Haloalkyl; R 3 Selected from hydrogen, chlorine, C 1～3 Haloalkyl, C 1～3 Haloalkoxy; R 4 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R 5 is selected from hydrogen, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R 6 , R 7 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, propyl, C 1～3 Halogenated alkyl.

5. The N-cyclobutyl substituted benzamide isoxazoline compound or its pesticide acceptable salt according to claim 1, characterized in that: R 1 Selected from chloro, cyano, difluoromethyl, trifluoromethyl, trifluoromethoxy; R 2 Selected from hydrogen and chlorine; R 3 Selected from hydrogen, chlorine, difluoromethyl, trifluoromethyl, trifluoromethoxy; R 4 is selected from hydrogen, methyl; R 5 is selected from hydrogen, cyano; R 6 , R 7 Each is independently selected from hydrogen, fluorine and trifluoromethyl.

6. The N-cyclobutyl substituted benzamide isoxazoline compound or its pesticide acceptable salt according to claim 1, characterized in that: The N-cyclobutyl substituted benzamide isoxazoline compound is selected from any one of the following structures:

7. The method for preparing the N-cyclobutyl substituted benzamide isoxazoline compound according to any one of claims 1 to 6, characterized in that: The steps include: (1) The compound of formula (A) is reacted with hydroxylamine hydrochloride and a base, and then reacted with NaNO2 and an acid to produce a compound of formula (B); (2) reacting the compound of formula (C) with 2-bromo-3,3,3-trifluoropropene in the presence of a base and a palladium catalyst to produce a compound of formula (D); (3) the compound of formula (B) and the compound of formula (D) react in the presence of a base to produce a compound of formula (E); (4) the compound of formula (E) reacts under the action of a base to generate a compound of formula (F); (5) reacting the compound of formula (F) with an acyl chloride, and then reacting with the compound of formula (F-1) to produce a compound of formula (I); The reaction formula of the preparation method is as follows:

8. An agricultural composition, characterized in that Include: (a) 0.001-99.99 wt % of the N-cyclobutyl substituted benzamide isoxazoline compound or the pesticide acceptable salt thereof according to any one of claims 1 to 6, its optical isomers, cis-trans isomers or a combination thereof; and (b) a pesticidally acceptable carrier and / or excipient.

9. Use of the N-cyclobutyl substituted benzamide isoxazoline compound or the pesticide acceptable salt according to any one of claims 1 to 6 or the agricultural composition according to claim 8 in the preparation of a medicament for controlling pests or in the preparation of an insecticide.

10. The use according to claim 9, characterized in that: The pests include one or more of Lepidoptera pests, Coleoptera pests, Hemiptera pests, Thysanoptera pests, Diptera pests, Orthoptera pests, Homoptera pests, Isoptera pests, Hymenoptera pests, and Blattodea pests.

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