N-cyclopropyl substituted picolinamide isoxazoline compound as well as preparation method and application thereof

Abstract

The invention discloses an N-cyclopropyl substituted picolinamide isoxazoline compound as well as a preparation method and application of the N-cyclopropyl substituted picolinamide isoxazoline compound. The N-cyclopropyl substituted picolinamide isoxazoline compound has broad-spectrum and efficient insecticidal activity, is safe to non-target organisms, and is more beneficial to crop protection and environmental safety.

Description

Technical Field

[0001] The present invention belongs to the technical field of agricultural pesticides, and more specifically, relates to N-cyclopropyl substituted pyridine amide isoxazoline compounds and preparation methods and applications thereof. Background Art

[0002] In agricultural production, pests infestation causes huge economic losses to agriculture every year. At present, my country mainly uses chemical pesticides to control pests, and the available pesticides include organophosphates, carbamates, pyrethroids and benzoylureas. However, the irrational use of pesticides has led to pests developing resistance to these commonly used pesticides. Some insecticides (such as pyrethroids, carbamates, and benzoylureas) have even reached a high level of resistance, and therefore cannot be effectively controlled. There is an urgent need to develop new insecticides with better activity, lower dosage, and more environmental friendliness.

[0003] Isoxazoline compounds have good insecticidal activity. Patent WO2008 / 108448 discloses compound A, and its structural formula is as follows.

[0004]

[0005] However, compound A cannot be registered as a normal pesticide due to its high toxicity to bees. Therefore, the development of isoxazoline insecticides with high insecticidal activity and low bee toxicity at low doses to meet the needs of agriculture, forestry, horticulture and health has become a technical problem that needs to be solved urgently. Summary of the invention

[0006] Based on the above existing technical problems, the primary purpose of the present invention is to provide N-cyclopropyl substituted pyridine amide isoxazoline compounds. The N-cyclopropyl substituted pyridine amide isoxazoline compounds have broad-spectrum and high-efficiency insecticidal activity, are safer to non-target organisms, and are more conducive to crop protection and environmental safety.

[0007] The second object of the present invention is to provide a method for preparing N-cyclopropyl substituted pyridine amide isoxazoline compounds.

[0008] The third object of the present invention is to provide an agricultural composition.

[0009] The fourth object of the present invention is to provide the use of the N-cyclopropyl substituted pyridine amide isoxazoline compound or the agricultural composition in the preparation of a drug for controlling pests or in the preparation of an insecticide.

[0010] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0011] The present invention seeks to protect N-cyclopropyl substituted pyridine amide isoxazoline compounds, the structure of which is shown in formula (I):

[0012]

[0013] Wherein, n is selected from 1-4;

[0014] R 1 , R 2 , R 3 are each independently selected from hydrogen, halogen, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Haloalkoxy;

[0015] R 4 Selected from hydrogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cycloalkyl or C 3～6 Halogenated cycloalkyl;

[0016] R 5 Selected from hydrogen, cyano, 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 Ester group, halogen substituents.

[0017] The inventors have discovered that N-cyclopropyl substituted pyridine amide isoxazoline compounds having a structure shown in formula (I) of the present invention can have broad-spectrum and high-efficiency insecticidal activity at low doses and are safe to non-target organisms. At the same time, due to the good effect at low doses, the amount of the agent used in actual applications is reduced, resulting in less drug residue during application, which is more environmentally friendly.

[0018] In some embodiments, R 1 Selected from chlorine, bromine, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Haloalkoxy; R 2 Selected from hydrogen, halogen, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Alkoxy or C 1～6Haloalkoxy; R 3 Selected from hydrogen, halogen, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, 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, cyano, 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 Ester group, halogen substituents.

[0019] In some embodiments, R 1 Selected from chlorine, bromine, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Haloalkoxy; R 2 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Alkoxy or C 1～6 Haloalkoxy; R 3 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, 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, cyano, C 1～6 Alkyl, C 3～8 Cycloalkyl, C 1～6 ester group, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring; said C 1～6 Alkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring are unsubstituted or substituted with one or more selected from C 1～6 Alkoxy, C1～6 Ester group, halogen substituents.

[0020] In some embodiments, n is selected from 1 or 4; R 1 Selected from chlorine, C 1～6 Haloalkyl or C 1～6 Haloalkoxy; R 2 Selected from fluorine, chlorine, C 1～6 Alkoxy; R 3 is selected from chloro, trifluoromethyl; R 4 Selected from hydrogen, C 1～6 Haloalkyl, C 3～6 Halogenated cycloalkyl; R 5 Selected from hydrogen, cyano, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl.

[0021] In some embodiments, n is selected from 1; R 1 Selected from chlorine; R 2 is selected from fluorine and chlorine; R 3 is selected from chloro, trifluoromethyl; R 4 is selected from hydrogen; R 5 Selected from cyano.

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

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

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

[0025] (3) reacting the compound of formula (II-III) in the presence of a phosphine complex catalyst to obtain the compound of formula (II-IV);

[0026] (4) reacting the compound of formula (II-IV) with the compound of formula (IV) to obtain the compound of formula (II-V);

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

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

[0029] (7) condensing the compound of formula (II) with the compound of formula (III) to obtain the compound of formula (I);

[0030] The reaction formula of the preparation method is as follows:

[0031]

[0032] Preferably, in step (1), the palladium catalyst may be a zero-valent palladium catalyst or a divalent palladium catalyst. More specifically, the palladium catalyst is Pd(PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 、Pd(PPh 3 ) 4 、Pd(OAc) 2 or PdCl 2 .

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

[0034] Preferably, in the step (2), the bromination reagent may be N-bromosuccinimide (NBS).

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

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

[0037] Preferably, in step (5), the amount of the base used is 1 to 5 times the molar amount of the compound of formula (II-V), for example, 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.

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

[0039] Preferably, in step (6), the base may 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 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] Preferably, in the 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-lutidine, N-methylmorpholine, 3-methylimidazole, and 4-N,N-dimethylaminopyridine. Specifically, the inorganic base is any one or a combination of at least two of an alkali metal hydroxide, a carbonate, or a phosphate. 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 phosphate.

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

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

[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, for example, 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 h, for example, 0.5 h, 1 h, 3 h, 5 h, 8 h, 10 h, 12 h, 15 h, 18 h, 20 h, 23 h, 25 h, 28 h, 30 h, 33 h, 35 h, 38 h, 40 h, 44 h or 48 h.

[0045] Furthermore, the present invention claims an agricultural composition comprising:

[0046] (a) 0.001-99.99 wt % of the above-mentioned N-cyclopropyl substituted pyridine amide isoxazoline compound, its optical isomers, cis-trans isomers or its pesticide-acceptable salt, or a combination thereof; and

[0047] (b) pesticide-acceptable carriers and / or excipients.

[0048] Preferably, in the present invention, the agricultural composition can be prepared into a formulation such as a wettable powder, a suspension concentrate, an aqueous emulsion or an emulsifiable concentrate.

[0049] Furthermore, the present invention seeks to protect the use of N-cyclopropyl substituted pyridine amide isoxazoline compounds or the agricultural composition in the preparation of drugs for controlling pests or in the preparation of pesticides.

[0050] Preferably, the drug or pesticide is applied directly to the pest or the place where it comes into contact. Preferably, the field or place where the pest is controlled includes but is not limited to agriculture, forestry, gardening, sanitary areas or plants, etc.

[0051] Preferably, the pests include agricultural and forestry pests, sanitary pests or pests that endanger animal health.

[0052] 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. Preferably, the pests that endanger animal health include animal parasitic fleas, acarid pests or nematodes. Specifically, the pests include but are not limited to: cotton bollworm, diamondback moth, beet armyworm, Spodoptera litura, cabbage worm, striped stem borer, yellow stem borer, stem borer, fall armyworm, rice leaf roller, rice thrips, western flower thrips, melon thrips, onion thrips, ginger thrips, mango thrips, peach aphids, cotton aphids, alfalfa aphids, apple yellow aphids, wheat aphids, flea beetles, stink bugs, gray planthoppers, brown planthoppers, white-backed planthoppers, termites, mosquitoes and flies, cinnabar spider mites, citrus red spiders.

[0053] 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, cabbage, gourd, pepper, eggplant, tomato, onion, ginger, garlic, leek, 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 flamingo; 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 limiting effect on the scope of use of the isoxazoline substituted pyridine amide compounds of the present invention.

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] The present invention provides a class of N-cyclopropyl substituted pyridine amide isoxazoline compounds, which have significant effects on preventing and controlling pests in agriculture, forestry and health fields, and can achieve good insecticidal effects at low doses, and have the characteristics of rapid onset. It can reduce the damage of excessive drug concentration to plants, non-target organisms and humans. The N-cyclopropyl substituted pyridine amide isoxazoline compounds produce less drug residues when used, which is more conducive to environmental protection, and the preparation method thereof is simple and efficient, easy to mass produce, and has broad application prospects. DETAILED DESCRIPTION

[0056] The present invention is further described below in conjunction with specific examples, 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 art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0057] In the present invention, unless otherwise specified in the context, the words, phrases and symbols used below have the following meanings. The following abbreviations and terms have the following meanings throughout the text:

[0058] DIPEA is N,N-diisopropylethylamine; PE is petroleum ether; EA is ethyl acetate; TLC is thin layer chromatography; Oxone is potassium persulfate; HATU is a common polypeptide condensation reagent, systematically named 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DMF is N,N-dimethylformamide; KF is potassium fluoride; THF is tetrahydrofuran; NBS is N-bromosuccinimide; RT refers to room temperature; TBAB is tetrabutylammonium bromide.

[0059] Example 1

[0060] The synthetic route is as follows:

[0061]

[0062] The reaction formula of the preparation method is shown above. In this embodiment, N-(1-cyanocyclopropyl)-3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)picolinamide (Compound I-49 in Table 1 below) is taken as an example, and the specific synthesis process is as follows:

[0063] (1) Preparation of 5-(1-ethoxyvinyl)-3-methylpyridinecarbonitrile:

[0064] Under nitrogen protection, 4.9 g (25 mmol) of 5-bromo-3-methylpyridinecarbonitrile was dissolved in 50 ml of dry DMF, and 526 mg (0.75 mmol, 0.03 eq) of Pd(PPh3 ) 2 Cl 2 and 10 g (27.5 mmol, 1.1 eq) tributyl(1-ethoxyethylene)tin, the reaction solution was stirred at 90 ° C for 6 h, the reaction was completed after monitoring by TLC, cooled to room temperature, 50 ml of saturated KF solution was added, 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 in vacuo to obtain a dark brown oily nitrile 5-(1-ethoxyvinyl)-3-methylpyridine, which was directly used in the next step.

[0065] (2) Preparation of 5-(2-bromoacetyl)-3-methylpyridinecarbonitrile:

[0066] The 5-(1-ethoxyvinyl)-3-methylpyridinecarbonitrile obtained in step (1) was dissolved in 100 ml THF / H 2 O (v / v=5:1), 4.67g (26.25mmol, 1.05eq) NBS was added at 0℃, and the mixture was stirred at RT for 30min. The reaction was completed after monitoring by TLC, and the mixture was diluted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a red-brown oil. 200ml PE / EA (20:1) was added to dissolve the oil, 6g silica gel powder (300-400 mesh) was added, and the mixture was stirred for 20min, and then filtered. The filter cake was washed with 100ml PE / EA (20:1), and the filtrate was concentrated and dried in vacuo to obtain 5.74g yellow-brown solid 5-(2-bromoacetyl)-3-methylpyridinecarbonitrile with a yield of 96%.

[0067] (3) Preparation of (2-(6-cyano-5-methylpyridin-3-yl)-2-oxoethyl)triphenylphosphonium bromide:

[0068] 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-methylpyridinecarbonitrile obtained in step (2) was slowly added dropwise under vigorous stirring. After the addition was completed, the mixture was stirred at RT for 18 h. The reaction was monitored by TLC to complete. The solid was filtered and collected. 20 ml of toluene was added to slurry for 3 h, followed by filtration. The filter cake was washed with toluene, collected, and dried in vacuo to obtain 8.32 g of a light orange solid powder (2-(6-cyano-5-methylpyridin-3-yl)-2-oxoethyl)triphenylphosphonium bromide. The yield was 83%.

[0069] (4) Preparation of (Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enyl)pyridinecarbonitrile:

[0070] At 0°C, 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), and 3.05 g (11 mmol) of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-one in DMF (3 M) was added dropwise under vigorous stirring. After the addition, the mixture was stirred at 0°C for 15 min, and then stirred at 80°C for 3 h. The reaction was monitored by TLC, and the mixture was quenched with saturated ammonium chloride solution, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, 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 washed with 100 ml of 4% ethyl acetate. The residue was washed with PE / EA (40:1), and the filtrate was concentrated and dried in vacuo to obtain 4.95 g of a light yellow oil with a yield of 72%.

[0071] (5) Preparation of 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)pyridinecarbonitrile:

[0072] At 0°C, 4.55 g (11.8 mmol) of (Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enyl)picolinonitrile obtained in step (4) and 1.14 g (3.54 mmol, 0.3 eq) of TBAB were dissolved in 22 ml of toluene (0.5 M). Under vigorous stirring, 1.89 g (47.2 mmol, 4 eq) of sodium hydroxide and 1.64 g (23 .6mmol, 2eq) aqueous solution of hydroxylamine hydrochloride (11ml), after addition, stir at RT overnight, monitor the completion of the reaction by TLC, extract with EA, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuo, and purify on a silica gel column (PE / EA=40:1) to obtain 4.78g of light yellow foamy 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)picolinonitrile with a yield of 93%.

[0073] (6) Preparation of 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)picolinic acid:

[0074] 4.78 g (11 mmol) of 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)picolinonitrile obtained in step (5) was dissolved in 22 ml of THF (0.5 M), and 5.5 ml of methanol (v / v=4:1) was added. Under stirring, 1.76 g (44 mmol, 4 eq) of sodium hydroxide aqueous solution (11 ml, 4 M) was added. After the addition was completed, the mixture was refluxed and stirred for 2 h. The reaction was monitored by TLC. 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 in vacuo, and dried to obtain 4.99 g of light yellow foamy solid 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)picolinic acid with a yield of 100%.

[0075] (7) Preparation of N-cyclopropyl-5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-methyl-N-(thietan-3-yl)picolinamide (I-49):

[0076] 0.453 g (1 mmol) of 3-methyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)picolinic acid obtained in step (6) 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 HATU (1.2 equivalents) were added at room temperature. After stirring, 0.178 g (1.5 equivalents) of 1-amino-1-cyclopropylcyanamide hydrochloride was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC, and the mixture was filtered and diluted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and dried to obtain 0.5 g of a white solid with a yield of 98%. 1 HNMR (600MHz, CDCl 3 )δ8.66(d,J=2.0Hz,1H),8.57(s,1H),7.85(dd,J=2.1,0.9Hz,1H),7.64(s,2H),4.11(d,J =17.2Hz,1H),3.72(d,J=17.2Hz,1H),2.79(s,3H),1.68-1.63(m,2H),1.40-1.35(m,2H).

[0077] The other compounds represented by the general formula I in Table 1 below of the present invention can be prepared by referring to the method in Example 1.

[0078] Example 2

[0079] Referring to the preparation method of Example 1, the N-cyclopropyl substituted pyridine amide isoxazoline compounds of the present invention represented by the following formula (I) were synthesized. The substituents of the isoxazoline substituted pyridine amide compounds numbered I-1 to I-81 are shown in Table 1 below.

[0080]

[0081] Table 1

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100] Example 3 Insecticidal activity assay

[0101] (1) Indoor bioactivity test against Plutella xylostella

[0102] The diamondback moth Plutella xylostella (L.) belongs to the order Lepidoptera, has chewing mouthparts, and is a common vegetable pest. The third instar larvae of the diamondback moth were used as the test object and the leaf dipping feeding method was used for the test.

[0103] Operation process: Accurately weigh each compound to be tested, add the corresponding volume of dimethyl sulfoxide to prepare a 10g / L mother solution, and dilute it continuously to different concentrations with an aqueous solution containing 0.5 ppm Tween-80 during the experiment. Use a 1.0 cm diameter puncher to make leaf discs from the washed cabbage leaves, immerse the leaf discs in the solution, take them out after 5 seconds, dry them naturally, and move them into a clean container. Inoculate about 35 3rd instar larvae of the diamondback moth into the container and raise them at a constant temperature of 28 degrees Celsius. Set up 3 repetitions for each concentration, and take the average of the 3 results as the experimental results, and round the results. The control group is 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. And calculate the mortality rate (%) according to the formula: mortality rate (%) = (number of live insects in the control - number of live insects in the treatment) / number of live insects in the control × 100%.

[0104] (2) Indoor bioactivity test against Spodoptera exigua

[0105] Spodoptera exigua is a Lepidoptera pest with chewing mouthparts. It is a common vegetable pest. The second-instar larvae of Spodoptera exigua were used as the test objects and the leaf dipping feeding method was used for the test.

[0106] Operation process: Accurately weigh each compound to be tested, add the corresponding volume of dimethyl sulfoxide to prepare a 10g / L mother solution, and dilute it to different concentrations with an aqueous solution containing 0.5 ppm Tween-80 during the experiment. Use a 1.0 cm diameter puncher to make leaf discs from the washed cabbage leaves, immerse the leaf discs in the solution, take them out after 5 seconds, dry them naturally, and move them into a clean container. Inoculate about 35 second-instar larvae of beet armyworm into the container and raise them at a constant temperature of 28 degrees Celsius. Set up 3 repetitions for each concentration, and take the average of the 3 results as the experimental results, and round the results. The control group is 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 (%) according to the formula: mortality rate (%) = (number of live insects in the control - number of live insects in the treatment) / number of live insects in the control × 100%.

[0107] (3) Indoor bioactivity assay against rice planthopper (Nilaparvata lugens)

[0108] According to the method of (1) or (2) above, different concentrations of the test compound are prepared as the test solution, and the 24-well microtiter plate (MTP) with artificial diet is treated with the test solution of different concentrations through a pipette. The control group is an aqueous solution containing 0.5 ppm Tween-80 as a blank test solution. After drying, the MTP is infested with L2 larvae (6-10 per well). Each concentration is repeated 3 times, and the experimental results are taken as the average of the 3 results, and the results are rounded. After 2 days of incubation, the samples are checked for larval mortality.

[0109] (4) Indoor bioactivity assay against cowpea thrips

[0110] According to the method of (1) or (2) above, different concentrations of the test compound are prepared as the test solution, and the cowpea is cut into small sections of 0.5 cm and placed in a 12-well microtiter plate and sprayed with the test solution of different concentrations. The control group is an aqueous solution containing 0.5 ppm Tween-80 as a blank test solution. After drying, these cowpea sections are infested with a thrips group of mixed ages. Each concentration is repeated 3 times, and the experimental results are taken as the average of the 3 results, and the results are rounded. After 2 days of cultivation, the samples are checked for mortality.

[0111] (5) Indoor bioactivity assay against Chilo suppressalis

[0112] Chilo suppressalis (Walker) belongs to the order Lepidoptera, has chewing mouthparts, and is a common vegetable pest. The second-instar larvae of Chilo suppressalis were used as the test object, and the leaf dipping feeding method was used for the test.

[0113] Operation process: Accurately weigh each compound to be tested, add the corresponding volume of dimethyl sulfoxide to prepare a 10g / L mother solution, and dilute it to different concentrations with an aqueous solution containing 0.5 ppm Tween-80 during the experiment. Use a 1.0 cm diameter puncher to make leaf discs from the washed wild rice stem, immerse the leaf discs in the solution, take them out after 5 seconds, dry them naturally, and move them into a clean container. Inoculate about 35 second-instar larvae of beet armyworm into the container and raise them at a constant temperature of 28 degrees Celsius. Set up 3 repetitions for each concentration, and take the average of the 3 results as the experimental results, and round the results. The control group is 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 (%) according to the formula: mortality rate (%) = (number of live insects in the control - number of live insects in the treatment) / number of live insects in the control × 100%.

[0114] The insecticidal activity experiments of (1) to (5) above used control compound A (from patent WO2008 / 108448) as a positive control. The structure of compound A is shown below.

[0115]

[0116] According to the method of Example 4, the compounds of the present invention and the control compound A were selected for parallel determination of insecticidal activity against Plutella xylostella, Spodoptera exigua, Rice Planthopper and Cowpea Thrips to compare the insecticidal effects. The test results are shown in Tables 2 and 3.

[0117] Table 2 Comparison of the insecticidal activity of the compounds of the present invention and the control compound A against Plutella xylostella

[0118]

[0119]

[0120] Table 3 Comparison of insecticidal activity of compounds I-43, I-49, I-54 of the present invention and control compound A

[0121]

[0122] As can be seen from Table 2 and Table 3, the N-cyclopropyl substituted pyridine amide isoxazoline compounds provided by the present invention have better insecticidal activity against diamondback moth than the control compound A. In particular, the insecticidal activities of compounds I-43, I-49, and I-54 against diamondback moth, beet armyworm, rice planthopper, cowpea thrips, and striped stem borer are significantly better than those of compound A, indicating that compounds I-43, I-49, and I-54 of the present application have better insecticidal effects at lower dosages and have broad-spectrum and high-efficiency insecticidal activities.

[0123] Example 4 Comparative Determination of Safety

[0124] The experimental method was based on GB / T 31270.10-2014. The mother solution of the test compound of different concentrations was dispersed in a sucrose solution and used to feed adult worker bees. When the drug solution was consumed, the bees were fed with a sucrose solution without the test compound. The mortality rate after 48 hours was observed and recorded. The results are shown in Table 4.

[0125] Table 4 Comparison of the insecticidal activity of compounds I-43, I-49, I-54 of the present invention and control compound A against Apis mellifera

[0126] Compound No. <![CDATA[48-h LD 50 (μg / head)]]> I-43 2.166 I-49 3.272 I-54 3.691 Control Compound A 0.939

[0127] As can be seen from Table 4, compared with the control compound A, the compounds I-43, I-49 and I-54 of the present invention have lower biological toxicity to non-target organisms, bees.

[0128] In summary, the N-cyclopropyl substituted pyridine amide isoxazoline compounds provided by the present invention have broad-spectrum and high-efficiency insecticidal activity, can effectively control resistant pests, and have obvious advantages over the control compound A in terms of insecticidal activity and safety to non-target organisms.

[0129] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. N-cyclopropyl substituted pyridine amide isoxazoline compounds, characterized in that: The structure of the N-cyclopropyl substituted pyridine amide isoxazoline compound is shown in formula (I): Wherein, n is selected from 1-4; R 1 , R 2 , R 3 are each independently selected from hydrogen, halogen, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, 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, cyano, 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 Ester group, halogen substituents.

2. The N-cyclopropyl substituted pyridine amide isoxazoline compound according to claim 1, characterized in that: R 1 Selected from chlorine, bromine, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Haloalkoxy; R 2 Selected from hydrogen, halogen, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Alkoxy or C 1～6 Haloalkoxy; R 3 Selected from hydrogen, halogen, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, 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, cyano, 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 Ester group, halogen substituents.

3. The N-cyclopropyl substituted pyridine amide isoxazoline compound according to claim 1, characterized in that: R 1 Selected from chlorine, bromine, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 Haloalkoxy; R 2 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Alkoxy or C 1～6 Haloalkoxy; R 3 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, C 1～6 Ester group, C 1～6 Alkyl, C 1～6 Haloalkyl, 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, cyano, C 1～6 Alkyl, C 3～8 Cycloalkyl, C 1～6 ester group, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring; said C 1～6 Alkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring are unsubstituted or substituted with one or more selected from C 1～6 Alkoxy, C 1～6 Ester group, halogen substituents.

4. The N-cyclopropyl substituted pyridine amide isoxazoline compound according to claim 1, characterized in that: n is selected from 1 or 4; R 1 Selected from chlorine, C 1～6 Haloalkyl or C 1～6 Haloalkoxy; R 2 Selected from fluorine, chlorine, C 1～6 Alkoxy; R 3 Selected from chlorine, trifluoromethyl; R 4 Selected from hydrogen, C 1～6 Haloalkyl, C 3～6 Halogenated cycloalkyl; R 5 Selected from hydrogen, cyano, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl.

5. The N-cyclopropyl substituted pyridine amide isoxazoline compound according to claim 1, characterized in that: n is selected from 1; R 1 Selected from chlorine; R 2 Selected from fluorine and chlorine; R 3 Selected from chlorine, trifluoromethyl; R 4 Selected from hydrogen; R 5 Selected from cyano.

6. The method for preparing the N-cyclopropyl substituted pyridine amide isoxazoline compound according to any one of claims 1 to 5, characterized in that: The following steps are involved: (1) reacting the compound of formula (II-I) with the compound of formula (II-VII) under the action of a palladium catalyst to prepare a compound of formula (II-II); (2) the compound of formula (II-II) reacts with a brominating agent to obtain a compound of formula (II-III); (3) reacting the compound of formula (II-III) in the presence of a phosphine complex catalyst to obtain the compound of formula (II-IV); (4) reacting the compound of formula (II-IV) with the compound of formula (IV) to obtain the compound of formula (II-V); (5) reacting the compound of formula (II-V) in the presence of a base, tetrabutylammonium bromide and hydroxylamine hydrochloride to obtain the compound of formula (II-VI); (6) hydrolyzing the compound of formula (II-VI) in the presence of a base to obtain a compound of formula (II); (7) condensing the compound of formula (II) with the compound of formula (III) to obtain the compound of formula (I); The reaction formula of the preparation method is as follows:

7. An agricultural composition, characterized in that Include: (a) 0.001-99.99 wt % of the N-cyclopropyl substituted pyridine amide isoxazoline compound according to any one of claims 1 to 5, its optical isomers, cis-trans isomers or its pesticide-acceptable salts, or a combination thereof; and (b) pesticide-acceptable carriers and / or excipients.

8. Use of the N-cyclopropyl substituted pyridine amide isoxazoline compound according to any one of claims 1 to 5 or the agricultural composition according to claim 8 in the preparation of a medicament for controlling pests or in the preparation of an insecticide.

9. The use according to claim 8, characterized in that: The drug or pesticide is applied directly to the pest or the locus where it comes into contact.

10. The use according to claim 8, 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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