Isoxazoline-substituted pyridine amide compounds, their preparation methods and applications

Abstract

This invention discloses isoxazoline-substituted pyridine amide compounds, their preparation methods, and applications. These isoxazoline-substituted pyridine amide compounds possess broad-spectrum and highly effective insecticidal activity, and are safe for non-target organisms, thus contributing to crop protection and environmental safety.

Description

Technical Field

[0001] This invention belongs to the field of agricultural insecticide technology. More specifically, it relates to isoxazoline-substituted pyridine amide compounds, their preparation methods, and applications. Background Technology

[0002] In agricultural production, pest infestations cause enormous economic losses to agriculture every year. Currently, my country mainly relies on chemical pesticides for pest control, with available agents including organophosphates, carbamates, pyrethroids, and benzoylurea. However, the irrational use of pesticides has led to pests developing resistance to these commonly used agents. Some insecticides (such as pyrethroids, carbamates, and benzoylurea) have even reached a high level of resistance, thus rendering them ineffective for control. There is an urgent need to develop new insecticides with better activity, lower dosage, and greater environmental friendliness.

[0003] Isoxazoline compounds have good insecticidal activity. Compounds B36, B37, B38, and B39, which have a 2-pyridine amide structure, are disclosed in patents WO2013026695A, WO2013026931A, WO2012104331A2, and CN103764644A.

[0004]

[0005] These compounds exhibit over 80% insecticidal activity against lepidopteran pests such as the diamondback moth and the beet armyworm at 200 ppm. However, at lower doses below 200 ppm, their insecticidal effect is poor. Therefore, developing isoxazoline insecticides with high insecticidal activity at low doses to meet the needs of agriculture, forestry, horticulture, and the health sector has become an urgent technical problem to be solved. Summary of the Invention

[0006] Based on the aforementioned existing technical problems, the primary objective of this invention is to provide isoxazoline-substituted pyridine amide compounds. These isoxazoline-substituted pyridine amide compounds possess broad-spectrum and highly effective insecticidal activity, and are safer against non-target organisms, thus contributing to crop protection and environmental safety.

[0007] A second objective of this invention is to provide a method for preparing isoxazoline-substituted pyridine amide compounds.

[0008] A third objective of this invention is to provide an agricultural composition.

[0009] A fourth object of the present invention is to provide the use of the isoxazoline-substituted pyridine amide compounds or the agricultural compositions in the preparation of medicaments for the control of pests or in the preparation of insecticides.

[0010] The above-mentioned objective of this invention is achieved through the following technical solution:

[0011] This invention seeks protection for isoxazoline-substituted pyridine amide compounds, the structures of which are shown in formula (I):

[0012]

[0013] In the formula, L is 1, 2, or 3;

[0014] n is 0 or 2;

[0015] R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, nitro, ester, C 1～6 Alkyl, C 1～6 Halogenated alkyl, C 1～6 Alkoxy or C 1～6 Halogenated alkoxy groups;

[0016] R 3 Selected from hydrogen, C 1～6 Alkyl, C 1～6 Halogenated alkyl, C 3～6 cycloalkyl, C 3～6 Halogenated cycloalkyl groups.

[0017] The inventors have discovered isoxazoline-substituted pyridine amide compounds having the structure shown in the present invention (I) that can exhibit broad-spectrum and highly efficient insecticidal activity at low doses and are safe for non-target organisms. Furthermore, due to their good efficacy at low doses, the amount of pesticide used in practical applications can be reduced, resulting in less pesticide residue and making them more environmentally friendly.

[0018] In some implementation schemes, R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, nitro, ester, C 1～4 Alkyl, C 1～4 Halogenated alkyl, C 1～4 Alkoxy or C 1～4 Haloalkoxy; R 3 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Halogenated alkyl, C 3～5 cycloalkyl, C 3～5 Halogenated cycloalkyl groups.

[0019] In some implementations, L is 1 or 2; n is 0 or 2; R 1 Selected from chlorine, bromine, iodine, cyano, C 1～4 Alkyl, C 1～4 Halogenated alkyl; R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1～4 Alkyl, C 1～4 Halogenated alkyl, C 1～4 Alkoxy or C 1～4 Haloalkoxy; R 3 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Halogenated alkyl, C 3～5 cycloalkyl, C 3～5 Halogenated cycloalkyl groups.

[0020] In some implementation schemes, R 1 Selected from chloro, cyano, methyl, ethyl, n-propyl, isopropyl, C 1～4 Fluoroalkyl; R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, C 1～4 Fluoroalkyl, methoxy, ethoxy, n-propoxy, isopropoxy, or C 1～4 Fluoroalkoxy; R 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, C 1～4 Fluoroalkyl, cyclopropyl, cyclobutyl, C 3～5 Fluorinated cycloalkyl groups.

[0021] In some implementation schemes, R 1 Selected from chlorine; R 2 Selected from hydrogen, fluorine, and chlorine; R 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl.

[0022] Furthermore, this invention claims protection for a method for preparing isoxazoline-substituted pyridine amide compounds, comprising the following steps:

[0023] (1) Compound (II-I) reacts with compound (II-VII) under the action of palladium catalyst to prepare compound (II-II);

[0024] (2) Compound (II-II) reacts with a brominating agent to obtain compound (II-III);

[0025] (3) Compounds of formula (II-III) were reacted in the presence of a phosphine complexing catalyst to obtain compounds of formula (II-IV);

[0026] (4) Compounds of formula (II-IV) react with compounds of formula (IV) to obtain compounds of formula (II-V);

[0027] (5) Compounds of formula (II-V) are reacted in the presence of a base, tetrabutylammonium bromide and hydroxylamine hydrochloride to obtain compounds of formula (II-VI);

[0028] (6) Compounds of formula (II-VI) are hydrolyzed in the presence of a base to obtain compound (II);

[0029] (7) Compound (II) undergoes a condensation reaction with compound (III) to obtain compound (I);

[0030] The reaction formula for the preparation method is shown below:

[0031]

[0032] Preferably, in step (1), the palladium catalyst can be an oxalic palladium catalyst or a divalent palladium catalyst. More specifically, the palladium catalyst is Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, or PdCl2.

[0033] Preferably, step (1) is performed under a protective gas atmosphere. More specifically, the protective gas is nitrogen.

[0034] Preferably, in step (2), the brominating agent can be N-bromosuccinimide (NBS).

[0035] Preferably, in step (3), the phosphine complexing catalyst can be triphenylphosphine.

[0036] Preferably, in step (5), the alkali can be lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0037] Preferably, in step (5), the amount of alkali used is 1 to 5 times the molar amount of the compound of formula (II-V), for example, 1, 1.3, 1.5, 1.8, 2, 2.5, 3, 3.5, 4, 4.5 or 5 times.

[0038] Preferably, in step (6), the hydrolysis is carried out in any one or a mixture of at least two of the following solvents: water, methanol, ethanol, tetrahydrofuran, or dioxane.

[0039] Preferably, in step (6), the alkali can be lithium hydroxide, sodium hydroxide, or potassium hydroxide. The amount of the alkaline substance is 1 to 5 times the molar amount of the compound of formula (II-VI), for example, 1, 1.3, 1.5, 1.8, 2, 2.5, 3, 3.5, 4, 4.5, or 5 times.

[0040] Preferably, in step (7), the condensation reaction is carried out in the presence of the base. The base can be an organic base and / or an inorganic base. Specifically, the organic base is 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-methylimidazolium, and 4-N,N-dimethylaminopyridine. Specifically, the inorganic base is any one or a combination of at least two of alkali metal hydroxides, carbonates, or phosphates. Specifically, the alkali metal hydroxide is any one or a combination of at least two of lithium hydroxide, sodium hydroxide, or potassium hydroxide. Specifically, the carbonate is any one or a combination of at least two of sodium bicarbonate, sodium carbonate, or potassium carbonate. Specifically, the phosphate is dipotassium hydrogen phosphate and / or trisodium hydrogen phosphate.

[0041] Preferably, in step (7), conventional condensation reagents in the art can be used, including but not limited to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, etc.

[0042] Preferably, in steps (1) to (7), the solvent for the reaction is selected from any one or more combinations of water, dichloromethane, chloroform, toluene, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, or hexamethylphosphoric triamine.

[0043] Preferably, in steps (1) to (7), the reaction temperature is greater than or equal to room temperature and less than or equal to the boiling point of the reaction solvent, such as 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or the reaction is carried out at the boiling point of the solvent, i.e., under reflux.

[0044] Preferably, in steps (1) to (7), the reaction time is 0.5 to 48 hours, for example, 0.5 hours, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

[0045] Furthermore, this invention claims protection for a method for preparing isoxazoline-substituted pyridine amide compounds, comprising the following steps:

[0046] (1) Compound of formula (II-I), N-formyl saccharin, 1,4-bis(diphenylphosphine)butane and palladium catalyst and base are mixed and reacted to prepare compound of formula (VI);

[0047] (2) The compound of formula (VI) and hydroxylamine hydrochloride are mixed and reacted to obtain the compound of formula (VII);

[0048] (3) Compound (VII) reacts with compound (VIII) in the presence of an inorganic salt to obtain compounds (II-VI);

[0049] (4) Compounds of formula (II-VI) are hydrolyzed in the presence of a base to obtain compound (II);

[0050] (7) Compound (II) undergoes a condensation reaction with compound (III) to obtain compound (I);

[0051] The reaction formula for the preparation method is shown below:

[0052]

[0053] Preferably, in step (1), the palladium catalyst can be an oxalic palladium catalyst or a divalent palladium catalyst. More specifically, the palladium catalyst is Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, or PdCl2.

[0054] Preferably, in step (1), the base can be an organic base and / or an inorganic base. Specifically, the organic base is any one or more combinations of trimethylamine, triethylamine, N,N-diisopropylethylamine, tri-n-butylamine, pyridine, piperidine, 3-methylpyridine, 2,6-dimethylpyridine, N-methylmorpholine, 3-methylimidazolium, 4-N,N-dimethylaminopyridine, and alkali metal alkoxides. Specifically, the alkali metal alkoxide is sodium methoxide and / or sodium ethoxide. Specifically, the inorganic base is any one or a combination of at least two of alkali metal hydroxides, carbonates, or phosphates. Specifically, the alkali metal hydroxide is any one or a combination of at least two of lithium hydroxide, sodium hydroxide, or potassium hydroxide. Specifically, the carbonate is any one or a combination of at least two of sodium bicarbonate, sodium carbonate, or potassium carbonate. Specifically, the phosphate is dipotassium hydrogen phosphate and / or trisodium hydrogen phosphate.

[0055] Preferably, in step (2), the base can be an organic base and / or an inorganic base. Specifically, the organic base is any one or a combination of trimethylamine, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, piperidine, 3-methylpyridine, 2,6-dimethylpyridine, N-methylmorpholine, 3-methylimidazolium, and 4-N,N-dimethylaminopyridine. Specifically, the inorganic base is any one or a combination of alkali metal hydroxides and carbonates.

[0056] Preferably, the amount of alkali used is 1 to 5 times the molar amount of the compound of formula (II-VI), for example, 1, 1.3, 1.5, 1.8, 2, 2.5, 3, 3.5, 4, 4.5 or 5 times.

[0057] Preferably, in step (3), the molar ratio of compound (VII) to compound (VIII) is 0.5 to 2:1, for example 0.5:1, 0.8:1, 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1 or 2:1.

[0058] Preferably, in step (3), the inorganic salt is any one or a combination of at least two of sodium chloride, potassium chloride, sodium bromide, potassium bromide, sodium iodide, and potassium iodide.

[0059] Preferably, in steps (1) to (5), the reaction temperature is greater than or equal to room temperature and less than or equal to the boiling point of the reaction solvent, such as 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc., or the reaction is carried out at the boiling point of the solvent, i.e., under reflux.

[0060] Preferably, in steps (1) to (5), the reaction time is 0.5 to 48 hours, for example, 0.5 hours, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

[0061] Furthermore, the present invention claims protection for an agricultural composition comprising:

[0062] (a) 0.001-99.99% by weight of the above-described isoxazoline-substituted pyridine amide compounds, their optical isomers, cis-trans isomers, or pesticide-acceptable salts thereof, or combinations thereof; and

[0063] (b) Acceptable carriers and / or excipients for pesticides.

[0064] Preferably, in this invention, the agricultural composition can be formulated into formulations such as wettable powder, suspension, water-in-oil emulsion, or emulsifiable concentrate.

[0065] Furthermore, the present invention claims protection for the use of isoxazoline-substituted pyridine amide compounds or the agricultural compositions thereof in the preparation of medicaments for the control of pests or in the preparation of insecticides.

[0066] Preferably, the drug or insecticide is applied directly to the pest or the place where it comes into contact with it. Preferably, the area or place for pest control includes, but is not limited to, agriculture, forestry, horticulture, sanitary areas, or plants.

[0067] Preferably, the pests include agricultural and forestry pests, sanitary pests, or pests that harm animal health. Preferably, the pests include, but are not limited to, one or more of the following: Lepidoptera, Coleoptera, Hemiptera, Thysanoptera, Diptera, Orthoptera, Homoptera, Isoptera, Hymenoptera, and Blattodea. Preferably, the pests that harm animal health include parasitic fleas, ticks, mites, or nematodes. Specifically, the pests include, but are not limited to: cotton bollworm, diamondback moth, beet armyworm, cotton bollworm, cabbage caterpillar, rice stem borer, rice leaf roller, rice thrips, western flower thrips, melon thrips, onion thrips, ginger thrips, mango thrips, peach aphid, cotton aphid, alfalfa aphid, apple aphid, wheat aphid, flea beetle, stink bug, gray planthopper, brown planthopper, white-backed planthopper, termite, mosquito fly, carmine spider mite, and citrus red spider mite.

[0068] Furthermore, the plants involved in the agricultural field mainly include the following categories: vegetables, such as cucumber, loofah, watermelon, cantaloupe, pumpkin, gourd, spinach, celery, cabbage, Chinese cabbage, gourd, chili pepper, eggplant, tomato, scallion, ginger, garlic, leek, lettuce, green beans, cowpeas, broad beans, radish, carrot, potato, or yam; cereals, such as wheat, barley, corn, rice, or sorghum; fruit trees, such as apple, pear, banana, citrus, grape, lychee, or mango; flowers, such as peony, rose, or flamingo flower; oil crops, such as peanut, soybean, rapeseed, sunflower, or sesame; sugar crops, such as sugar beet or sugarcane; and other crops, such as strawberry, potato, sweet potato, tobacco, or tea. The above-listed plants or scope do not limit the scope of use of the isoxazoline-substituted pyridine amide compounds of this invention.

[0069] Compared with the prior art, the present invention has the following beneficial effects:

[0070] This invention provides a novel class of isoxazoline-substituted pyridine amide compounds, which exhibit significant effects in controlling pests and diseases in agriculture, forestry, and public health. These compounds achieve excellent insecticidal effects at low doses and are characterized by rapid onset of action. They can reduce the harm to plants, non-target organisms, and humans caused by excessive drug concentrations. Furthermore, these isoxazoline-substituted pyridine amide compounds produce low drug residues upon application, making them more environmentally friendly. Their preparation method is simple, efficient, and easy to scale up, indicating broad application prospects. Detailed Implementation

[0071] The present invention will be further illustrated below with reference to specific embodiments, but these embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in this technical field. Unless otherwise specified, the reagents and materials used in the following embodiments are commercially available.

[0072] In this invention, unless otherwise specified in the context, the words, phrases, and symbols used below have the following meanings. The meanings of the following abbreviations and terms are consistent throughout the text:

[0073] DIPEA stands for N,N-diisopropylethylamine; PE stands for petroleum ether; EA stands for ethyl acetate; TLC stands for thin-layer chromatography; Oxone stands for potassium persulfate; HATU is a common peptide condensation reagent, systematically named 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DMF stands for N,N-dimethylformamide; KF stands for potassium fluoride; THF stands for tetrahydrofuran; NBS stands for N-bromosuccinimide; RT refers to room temperature; TBAB stands for tetrabutylammonium bromide.

[0074] Example 1

[0075] The synthesis route is as follows:

[0076]

[0077] The reaction formula for the preparation method is shown above. In this embodiment, N-cyclopropyl-5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methyl-N-(thiocyclobutane-3-yl)pyridine amide (compound I-17 in Table 1 below) is used as an example, and its specific synthesis process is as follows:

[0078] (1) Preparation of 5-(1-ethoxyvinyl)-3-methylpyridine nitrile:

[0079] Under nitrogen protection, 4.9 g (25 mmol) of 5-bromo-3-methylpyridinium nitrile was dissolved in 50 mL of dry DMF. 526 mg (0.75 mmol, 0.03 eq) of Pd(PPh3)2Cl2 and 10 g (27.5 mmol, 1.1 eq) of tributyl(1-ethoxyethylene)tin were added. The reaction mixture was stirred at 90 °C for 6 h. The reaction was monitored by TLC until completion. After cooling to room temperature, 50 mL of saturated KF solution was added, and the mixture was stirred for 24 h. The solid was filtered, the filter cake was washed with EA, the filtrate was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a dark brown oily nitrile, 5-(1-ethoxyethylene)-3-methylpyridine, which was used directly in the next step.

[0080] (2) Preparation of 5-(2-bromoacetyl)-3-methylpyridinium nitrile:

[0081] The 5-(1-ethoxyvinyl)-3-methylpyridinium nitrile obtained in step (1) was dissolved in 100 ml THF / H2O (v / v = 5:1), and 4.67 g (26.25 mmol, 1.05 eq) NBS was added at 0 °C. The mixture was stirred at RT for 30 min, and the reaction was monitored by TLC until it ended. The mixture was diluted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a reddish-brown oily substance. This substance was dissolved in 200 ml PE / EA (20:1), and 6 g of silica gel powder (300-400 mesh) was added. After stirring for 20 min, the mixture was filtered, and the filter cake was washed with 100 ml PE / EA (20:1). The filtrate was concentrated and dried under vacuum to obtain 5.74 g of yellowish-brown solid 5-(2-bromoacetyl)-3-methylpyridinium nitrile, with a yield of 96%.

[0082] (3) Preparation of (2-(6-cyano-5-methylpyridin-3-yl)-2-oxoethyl)triphenylphosphonium bromide:

[0083] 5.77 g (22 mmol, 1.1 eq) of triphenylphosphine was dissolved in 22 ml of toluene. 4.78 g (20 mmol) of a toluene solution (20 ml) of 5-(2-bromoacetyl)-3-methylpyridinium nitrile obtained in step (2) was slowly added dropwise under vigorous stirring. After the addition was complete, the mixture was stirred at RT for 18 h. The reaction was monitored by TLC until it ended. The mixture was filtered and the solid was collected. 20 ml of toluene was added and the mixture was stirred for 3 h. The mixture was then filtered again, and the filter cake was washed with toluene. The filter cake was collected and dried under vacuum to obtain 8.32 g of a pale orange solid powder (2-(6-cyano-5-methylpyridin-3-yl)-2-oxoethyl)triphenylphosphine bromide, with a yield of 83%.

[0084] (4) Preparation of (E)-5-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enyl)-3-methylpyridinenitrile:

[0085] At 0℃, 8.27 g (16.5 mmol, 1.5 eq) of 2-(6-cyano-5-methylpyridin-3-yl)-2-oxoethyl)triphenylphosphonium bromide obtained in step (3) was dissolved in 41 ml of dry THF (0.4 M). 2.67 g (11 mmol) of 1-(3,4-dichloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethane-1-one in DMF solution (3 M) was added dropwise with vigorous stirring. After addition, the mixture was stirred at 0℃ for 15 min, followed by stirring at 80℃ for 3 h. The reaction was monitored by TLC until completion. The reaction was quenched with saturated ammonium chloride solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, dissolved in 200 ml of PE / EA (40:1), and 4 g of silica gel powder (300-400 mesh) was added. After stirring for 20 min, the mixture was filtered, and the filter cake was treated with 100 ml of... Wash with PE / EA (40:1), concentrate the filtrate, and vacuum dry to obtain 4.55 g of a light yellow oily substance (E)-5-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enyl)-3-methylpyridinium.

[0086] (5) Preparation of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinium:

[0087] At 0℃, 4.55g (11.8mmol) of (E)-5-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enyl)-3-methylpyridinium nitrile and 1.14g (3.54mmol, 0.3eq) of TBAB obtained in step (4) were dissolved in 22ml of toluene (0.5M). Under vigorous stirring, 1.89g (47.2mmol, 4eq) of sodium hydroxide and 1.64g (23... 11 ml of an aqueous solution of 0.6 mmol (2 eq) hydroxylamine hydrochloride was added, and the mixture was stirred overnight at RT. The reaction was monitored by TLC until it ended. The mixture was extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (PE / EA = 40:1) to give 4.4 g of a pale yellow bubbly precipitate, 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinium, with a yield of 93%.

[0088] (6) Preparation of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinecarboxylic acid:

[0089] Dissolve 4.4 g (11 mmol) of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinium obtained in step (5) in 22 ml THF (0.5 M) was added to 5.5 mL of methanol (v / v = 4:1). While stirring, 1.76 g (44 mmol, 4 eq) of sodium hydroxide aqueous solution (11 mL, 4 M) was added. After the addition was complete, the mixture was refluxed and stirred for 2 h. The reaction was monitored by TLC until it ended. At 0 °C, the pH was adjusted to 1 with concentrated hydrochloric acid. The reaction solution was concentrated, diluted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and dried to obtain 4.6 g of a pale yellow bubbly solid (5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinecarboxylic acid), with a yield of 100%.

[0090] (7) Preparation of N-cyclopropyl-5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methyl-N-(thiocyclobutane-3-yl)pyridine amide (Ⅰ-100):

[0091] 0.418 g (1 mmol) of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinecarboxylic acid obtained in step (6) was dissolved in 5 ml of dry DMF (N,N-dimethylformamide). 0.38 ml of LDIPEA (2.2 equivalents) and 0.456 g of HATU (1.2 equivalents) were added at room temperature. After stirring until homogeneous, 0.194 g (1.5 equivalents) of N-(cyclopropyl)thiobutane-3-amine was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC until it ended. The mixture was filtered, diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and dried to obtain 0.52 g of a white solid, with a yield of 98%. 1 H NMR(500MHz,Chloroform-d)δ9.18(d,J=1.1Hz,1H),8.01(d,J=1.3Hz,1H),7.83(d,J=2.0Hz,1H),7.62(d,J=2.0Hz,1H),4.85(p,J=7.0Hz,1H), 3.88(dd,J=11.2,7.0Hz,2H),3.32–3.24(m,3H),3.07(d,J=17.8Hz,1H) ,2.32(s,3H),2.27–2.22(m,1H),0.50–0.41(m,2H),0.18–0.09(m,2H).

[0092] Other compounds of general formula I listed in Table 1 below can be prepared by referring to the method in Example 1.

[0093] Example 2

[0094] The synthesis route is as follows:

[0095]

[0096] Taking N-cyclopropyl-5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methyl-N-(thiocyclobutane-3-yl)pyridine amide (compound I-17 in Table 1 below) as an example, its specific synthesis process is as follows:

[0097] (1) Preparation of 5-formyl-3-methylpyridine nitrile:

[0098] 2.96 g (15 mmol) of 5-bromo-3-methylpyridin-2-carboxylonitrile, 4.75 g (22.5 mmol) of N-formylsaccharin, 0.102 g (0.45 mmol) of palladium acetate, 0.288 g (0.675 mmol) of 1,4-bis(diphenylphosphine)butane, 2.38 g (22.5 mmol) of sodium carbonate, and 3.11 mL (19.5 mmol) of triethylsilane were mixed in 30 mL of DMF. The mixture was purged with nitrogen three times and reacted at 90 °C for 16 h. After the reaction was completed, the mixture was diluted with water, extracted three times with ethyl acetate, washed with brine, and the combined organic phases were dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (PE / EA = 10:1) to give 1.277 g of white solid 5-formyl-3-methylpyridinium nitrile, with a yield of 58%. 1H NMR (500MHz, Chloroform-d) δ9.36 (d, J = 1.3Hz, 1H), 8.19 (d, J = 1.1Hz, 1H), 2.45 (s, 3H).

[0099] (2) Preparation of (E)-5-((hydroxyimino)methyl)-3-methylpyridinium nitrile:

[0100] 3.83 g (55 mmol, 1.1 eq) of hydroxylamine hydrochloride was dissolved in 50 mL of water. The mixture was added dropwise to a 100 mL ethanol solution of 5.25 g (50 mmol) of 5-formyl-3-methylpyridinium obtained in step (1). The mixture was stirred at RT for 1–2 h, and the reaction progress was monitored by TLC. The ethanol was evaporated, and the residue was diluted with water. The residue was extracted three times with dichloromethane and washed with brine. The combined organic phases were dried over anhydrous sodium sulfate. After evaporating the solvent, 8.06 g of (E)-5-((hydroxyimino)methyl)-3-methylpyridinium was obtained, with a yield of 100%. 1H NMR (500MHz, Chloroform-d) δ8.98(d,J=1.3Hz,1H),7.87(d,J=1.3Hz,1H),7.77(s,1H),2.49(s,1H),2.43(s,3H).

[0101] (3) Preparation of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinium (see non-patent literature: Tetrahedron Letters, 2014, 5, 2308-2311):

[0102] 8.06 g (50 mmol) of (E)-5-((hydroxyimino)methyl)-3-methylpyridinium nitrile obtained in step (2), 22 mL (125 mmol, 2.5 eq) of 1,2-dichloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene, and 3.7 g (50 mmol, 1 eq) of KCl were carefully added to a flask, followed by 100 mL of water, and finally 75 mmol, 1.5 eq of Oxone 26.0 was added with stirring. The mixture was stirred at room temperature for 3 h until the reaction was complete. The mixture was poured into a separatory funnel and the flask was washed with 30 mL of CH2Cl2. The mixture was extracted with CH2Cl2 (2 × 50 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 40:1) to give 15.01 g of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinium, yield 75%. 1 H NMR(500MHz,Chloroform-d)δ9.11(d,J=1.3Hz,1H),8.01(d,J=1.3Hz,1H),7.52(d,J=2.0H z, 2H), 7.24 (t, J = 2.0Hz, 1H), 3.25 (d, J = 17.9Hz, 1H), 3.06 (d, J = 17.9Hz, 1H), 2.41 (s, 3H).

[0103] (4) Preparation of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinecarboxylic acid:

[0104] 15.01 g (37.5 mol) of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinecarboxylic acid obtained in step (3) was dissolved in 100 ml of KOH (5M). After the addition was complete, the mixture was refluxed and stirred for 2 h. The reaction was monitored by TLC until it ended. The pH was adjusted to 1 with concentrated hydrochloric acid at 0 °C. The reaction solution was concentrated, diluted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and dried to obtain 13.33 g of brownish-yellow solid 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinecarboxylic acid, with a yield of 85%. 1 H NMR(500MHz,Chloroform-d)δ9.08(d,J=1.3Hz,1H),8.03(d,J=1.3Hz,1H),7.52(d,J=2.0H z,2H),7.24(t,J=2.0Hz,1H),3.26(d,J=17.8Hz,1H),3.07(d,J=17.8Hz,1H),2.42(s,3H).

[0105] (5) Preparation of N-cyclopropyl-5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methyl-N-(thiocyclobutane-3-yl)pyridine amide (I-100):

[0106] 0.418 g (1 mmol) of 5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methylpyridinecarboxylic acid obtained in step (4) was dissolved in 5 ml of dry DMF (N,N-dimethylformamide), and 0.38 mL of DIPEA (2.2 equivalents) and 0.456 g of [unclear text] were added at room temperature. HATU (1.2 equivalents) was stirred until homogeneous and then added dropwise to 0.194 g (1.5 equivalents) of N-(cyclopropyl)thiocyclobutane-3-amine. After the addition was complete, the mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC until it was complete. The mixture was filtered, diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and dried to give 0.511 g of white solid N-cyclopropyl-5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methyl-N-(thiocyclobutane-3-yl)pyridineamide (Ⅰ-17), with a yield of 92%. 1H NMR(600MHz,Chloroform-d)δ8.62(d,J=2.0Hz,1H),7.97–7.89(m,1H),7.52(d,J=1.8Hz,2H),7.45(t,J=1.9Hz,1H),5.31(s,1H),4.12(d ,J=17.2Hz,1H),4.05(t,J=9.2Hz,2H),3.73(d,J=17.3Hz,1H),3.33(s,2H),2.73(s,1H),2.38(s,3H),0.51(d,J=6.8Hz,2H),0.41(s,2H).

[0107] Other compounds of general formula I listed in Table 1 below can be prepared by referring to the method in Example 1.

[0108] Example 3

[0109] Referring to the preparation method of Example 1 or Example 2 above, isoxazoline-substituted pyridine amide compounds of the present invention represented by formula (I) were synthesized. The substituents of the isoxazoline-substituted pyridine amide compounds numbered I-1 to I-171 are as follows:

[0110] As shown in Table 1.

[0111]

[0112] Table 1

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131] Example 4 Insecticidal Activity Determination

[0132] (1) Indoor bioactivity assay of diamondback moth

[0133] The diamondback moth (Plutella xylostella (L.)) is a lepidopteran pest with chewing mouthparts and is a common vegetable pest. Third instar larvae of the diamondback moth were used as test subjects, and the leaf-dipping feeding method was employed.

[0134] Procedure: Accurately weigh each test compound and add the corresponding volume of dimethyl sulfoxide to prepare a 10 g / L stock solution. During the experiment, continuously dilute the stock solution to different concentrations using an aqueous solution containing 0.5 ppm Tween-80. Use a 1.0 cm diameter punch to create leaf discs from washed cabbage leaves. Immerse the leaf discs in the solution for 5 seconds, then remove them, allow them to air dry, and transfer them to clean containers. Introduce approximately 35 third-instar larvae of diamondback moths into the containers and rear them at a constant temperature of 28°C. Perform three replicates for each concentration, and take the average of the three results, rounded to the nearest integer. The control group consisted of an aqueous solution containing 0.5 ppm Tween-80 as a blank test solution. After 48 hours of treatment, count the number of dead diamondback moths. Calculate the mortality rate (%) using the formula: Mortality Rate (%) = (Number of live control moths - Number of live treated moths) / Number of live control moths × 100%.

[0135] (2) Indoor bioactivity assay of beet armyworm

[0136] The beet armyworm (Spodoptera exigua) is a lepidopteran pest with chewing mouthparts and is a common vegetable pest. Second instar larvae of the beet armyworm were used as test subjects, and the leaf-dipping feeding method was employed.

[0137] Procedure: Accurately weigh each test compound and add the corresponding volume of dimethyl sulfoxide to prepare a 10 g / L stock solution. During the experiment, dilute the stock solution to different concentrations using an aqueous solution containing 0.5 ppm Tween-80. Use a 1.0 cm diameter punch to create leaf discs from washed cabbage leaves. Immerse the leaf discs in the solution for 5 seconds, then remove them, allow them to air dry, and transfer them to clean containers. Introduce approximately 35 second-instar larvae of the beet armyworm into the containers and rear them at a constant temperature of 28°C. Perform three replicates for each concentration, and take the average of the three results, rounded to the nearest whole number. The control group consisted of an aqueous solution containing 0.5 ppm Tween-80 as a blank test solution. After 24 hours of treatment, count the number of dead diamondback moths and calculate the mortality rate (%) using the formula: Mortality Rate (%) = (Number of live control moths - Number of live treated moths) / Number of live control moths × 100%.

[0138] (3) Indoor bioactivity assay against rice planthopper (Nilaparvata lugens)

[0139] Different concentrations of the test compound were prepared as test solutions according to method (1) or (2) above. 24-well microtiter plates (MTP) with artificial feed were treated with the test solutions of different concentrations using pipettes. A control group was prepared as a blank test solution containing 0.5 ppm Tween-80. After drying, L2 stage larvae were used to infect the MTP (6-10 larvae / well). Each concentration was replicated three times, and the result was the average of the three replicates, rounded to the nearest integer. After two days of cultivation, the samples were examined for larval mortality.

[0140] (4) Indoor bioactivity assay of cowpea thrips

[0141] Different concentrations of the test compound were prepared as test solutions according to method (1) or (2) above. Cowpeas were cut into 0.5 cm segments and placed in 12-well microtiter plates, then sprayed with different concentrations of the test solution. A control group was prepared using an aqueous solution containing 0.5 ppm Tween-80 as a blank test solution. After drying, these cowpea segments were infected with thrips colonies of mixed ages. Each concentration was replicated three times, and the result was the average of the three replicates, rounded to the nearest integer. After two days of cultivation, the samples were examined for mortality.

[0142] (5) Indoor bioactivity assay of rice stem borer

[0143] The rice stem borer (Chilo suppressalis (Walker)) is a lepidopteran pest with chewing mouthparts and is a common vegetable pest. Second-instar larvae of the rice stem borer were used as test subjects, and the leaf-dipping feeding method was employed.

[0144] Procedure: Accurately weigh each test compound and add the corresponding volume of dimethyl sulfoxide to prepare a 10 g / L stock solution. During the experiment, dilute the stock solution to different concentrations using an aqueous solution containing 0.5 ppm Tween-80. Use a 1.0 cm diameter punch to create leaf-shaped dishes from washed water chestnuts. Immerse the leaf-shaped dishes in the solution for 5 seconds, then remove them, allow them to air dry, and transfer them to clean containers. Introduce approximately 35 second-instar larvae of the beet armyworm into the containers and rear them at a constant temperature of 28°C. Each concentration was tested in triplicate, and the average of the three results was taken, rounded to the nearest integer. The control group consisted of an aqueous solution containing 0.5 ppm Tween-80 as a blank test solution. After 24 hours of treatment, count the number of dead diamondback moths and calculate the mortality rate (%) using the formula: Mortality rate (%) = (Number of live control moths - Number of live treated moths) / Number of live control moths × 100%.

[0145] The insecticidal activity experiments in (1) to (5) above used Syngenta's patented compound B38 and the isoxazoline commercial pesticide fluoxazolamide as positive controls. The structure of compound B38 is shown below.

[0146]

[0147] Following the method in Example 4, the insecticidal activity of the compound of this invention, compound B38 published in Syngenta's patent, and fluoxazolamide was measured in parallel to compare their insecticidal effects against diamondback moth, beet armyworm, rice planthopper, and cowpea thrips. The experimental results are shown in Tables 2 and 3.

[0148] Table 2 Comparison of the insecticidal activity of the compounds of this invention and B38 against diamondback moth.

[0149]

[0150]

[0151]

[0152] Table 3 Comparison of the insecticidal activities of compounds I-5 to I-7, I-13 to I-17 of the present invention with B38

[0153]

[0154]

[0155] As can be seen from Tables 2 and 3, the isoxazoline-substituted pyridine amide compounds provided by this invention exhibit superior insecticidal activity against diamondback moth compared to compound B38. In particular, compounds I-5 to I-7 and I-13 to I-17 show significantly better insecticidal activity against diamondback moth, beet armyworm, rice planthopper, cowpea thrips, and rice stem borer than compound B38, indicating that compounds I-5 to I-7 and I-13 to I-17 of this application have better insecticidal effects at lower doses, demonstrating broad-spectrum and highly efficient insecticidal activity.

[0156] Example 5: Comparative determination of safety

[0157] The experimental method followed GB / T 31270.10-2014. Different concentrations of the test compound stock solution were dispersed in sucrose solution and fed to adult worker bees. After the drug solution was consumed, the bees were fed a sucrose solution without the test compound. The mortality rate was observed and recorded after 48 hours. The results are shown in Table 4.

[0158] Table 4. Comparison of the insecticidal activity of compounds I-5~I-7, I-13~I-17 of the present invention and B38 against Italian honeybees.

[0159] Compound numbering <![CDATA[48-hLD 50 (μg / head)]]> I-5 5.264 I-6 2.238 I-7 2.166 I-13 4.625 I-14 7.136 I-15 3.272 I-16 9.868 I-17 3.691 B38 0.939

[0160] As can be seen from Table 4, compounds I-5 to I-7 and I-13 to I-17 of the present invention have lower biotoxicity to non-target organisms, honeybees, compared to compound B38.

[0161] In summary, the isoxazoline-substituted pyridine amide compounds provided by this invention have broad-spectrum and highly efficient insecticidal activity, effectively controlling resistant pests, and have significant advantages over compound B38 in terms of both insecticidal activity and safety against non-target organisms.

[0162] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. An isoxazoline-substituted pyridine amide compound, characterized in that, The structure of the isoxazoline-substituted pyridine amide compound is shown in formula (I): In the formula, L represents 1 or 2; n is 0 or 2; R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, nitro, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Halogenated alkoxy groups; R 3 Selected from hydrogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 cycloalkyl, C 3～6 Halogenated cycloalkyl groups.

2. The isoxazoline-substituted pyridine amide compound according to claim 1, characterized in that, R 1 R 2 Each is independently selected from hydrogen, halogen, cyano, nitro, C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy or C 1～4 Halogenated alkoxy groups; R 3 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Haloalkyl, C 3～5 cycloalkyl, C 3～5 Halogenated cycloalkyl groups.

3. The isoxazoline-substituted pyridine amide compound according to claim 1, characterized in that, L is 1 or 2; n is 0 or 2; R 1 Selected from chlorine, bromine, iodine, cyano, C 1～4 Alkyl, C 1～4 Halogenated alkyl groups; R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Alkoxy or C 1～4 Halogenated alkoxy groups; R 3 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Haloalkyl, C 3～5 cycloalkyl, C 3～5 Halogenated cycloalkyl groups.

4. The isoxazoline-substituted pyridine amide compound according to claim 3, characterized in that, R 1 Selected from chloro, cyano, methyl, ethyl, n-propyl, isopropyl, C 1～4 Fluorinated alkyl groups; R 2 Selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, C 1～4 Fluoroalkyl, methoxy, ethoxy, n-propoxy, isopropoxy, or C 1～4 Fluoroalkoxy; R 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, C 1～4 Fluoroalkyl, cyclopropyl, cyclobutyl, C 3～5 Fluorinated cycloalkyl groups.

5. The isoxazoline-substituted pyridine amide compound according to claim 4, characterized in that, R 1 Selected from chlorine; R 2 Selected from hydrogen, fluorine, and chlorine; R 3 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl.

6. A method for preparing the isoxazoline-substituted pyridine amide compound according to any one of claims 1-5, characterized in that, Includes the following steps: (1) Compound (II-I) reacts with compound (II-VII) under the action of palladium catalyst to prepare compound (II-II); (2) Compound (II-II) reacts with a brominating agent to obtain compound (II-III); (3) Compounds of formula (II-III) were reacted in the presence of a phosphine complexing catalyst to obtain compounds of formula (II-IV); (4) Compounds of formula (II-IV) react with compounds of formula (IV) to obtain compounds of formula (II-V); (5) Compounds of formula (II-V) are reacted in the presence of a base, tetrabutylammonium bromide and hydroxylamine hydrochloride to obtain compounds of formula (II-VI); (6) Compounds of formula (II-VI) are hydrolyzed in the presence of a base to obtain compound (II); (7) Compound (II) undergoes a condensation reaction with compound (III) to obtain compound (I); The reaction formula for the preparation method is shown below:

7. A method for preparing the isoxazoline-substituted pyridine amide compound according to any one of claims 1-5, characterized in that, Includes the following steps: (1) Compound of formula (II-I), N-formyl saccharin, 1,4-bis(diphenylphosphine)butane and palladium catalyst and base are mixed and reacted to prepare compound of formula (VI); (2) The compound of formula (VI) and hydroxylamine hydrochloride are mixed and reacted to obtain the compound of formula (VII); (3) Compound (VII) reacts with compound (VIII) in the presence of an inorganic salt to obtain compounds (II-VI); (4) Compounds of formula (II-VI) are hydrolyzed in the presence of a base to obtain compound (II); (7) Compound (II) undergoes a condensation reaction with compound (III) to obtain compound (I); The reaction formula for the preparation method is shown below:

8. An agricultural composition, characterized in that, Include: (a) 0.001-99.99% by weight of the isoxazoline-substituted pyridine amide compound of any one of claims 1-5 or a pesticide-acceptable salt thereof, or a combination thereof; and (b) Acceptable carriers and / or excipients for pesticides.

9. The use of the isoxazoline-substituted pyridine amide compound according to any one of claims 1-5 or the agricultural composition according to claim 8 in the preparation of a pesticide for controlling pests, characterized in that, The pests mentioned are Lepidoptera, Thysanoptera, or Homoptera.

10. The application according to claim 9, characterized in that, The drug is applied directly to the pest or to the site of contact with it.

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