N-heterocyclic isoxazoline-containing benzamide derivative as well as preparation method and application thereof

Abstract

The invention provides an N-heterocyclic isoxazoline benzamide derivative as well as a preparation method and application thereof, and belongs to the technical field of pesticide chemistry. When the concentration of the N-heterocyclic isoxazoline-containing benzamide derivative is 100 [mu] g / mL, the N-heterocyclic isoxazoline-containing benzamide derivative shows good insecticidal activity on agricultural pests such as plutella xylostella, spodoptera frugiperda, ostrinia nubilalis, armyworm, cotton bollworm, aphid and the like, and on the basis of the N-heterocyclic isoxazoline-containing benzamide derivative, the N-heterocyclic isoxazoline-containing benzamide derivative can be applied to the field of agricultural pests such as agricultural pests such as insect pests, insect pests and the like. The N-heterocyclic isoxazoline benzamide derivative provided by the invention can be used as a pesticide active ingredient to be applied to prevention and control of agricultural pests.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticide chemistry, and in particular, to an N-heterocyclic isoxazoline benzamide derivative, a preparation method thereof, and an application thereof. Background Art

[0002] With the development of green pesticides, isoxazoline derivatives play an important role in controlling crop pests. Some pesticides containing isoxazole structures have been developed one after another. For example, the isoxazole structures are contained in isoxazoline pesticides such as flutriafol, isoxathion, afoxolaner, and cyazofamid. Isoxazoline pesticides are favored by agricultural researchers due to their novel action mechanisms, excellent activities, low toxicity, long residual periods, etc. They have high insecticidal activities against various pests such as Lepidoptera, Hemiptera, Thysanoptera, Coleoptera, Diptera, and Acarina.

[0003] Oxadiazole compounds are an important class of five-membered heterocyclic compounds, which contain two nitrogen atoms and one oxygen atom in their structures (such as 1,3,4-oxadiazole or 1,2,4-oxadiazole). In the agricultural field, such compounds are widely used in the development of insecticides, fungicides, herbicides, and plant growth regulators due to their unique biological activities. Triazole heterocyclic derivatives have attracted much attention for their good activities in sterilization. Moreover, triazole heterocyclic derivatives also show certain plant growth regulatory activities, bringing more possibilities to agricultural production, which makes triazole fungicides occupy a prominent position in the fungicide market.

[0004] In view of the significant activities of isoxazoline pesticides and oxadiazole and triazole compounds, splicing and modifying the isoxazole fragment and oxadiazole and triazole heterocyclic fragments to synthesize a series of novel pesticides with good insecticidal activities is expected to further promote the prevention and control of agricultural pests. Summary of the Invention

[0005] The purpose of the present invention is to provide an N-heterocyclic isoxazoline benzamide derivative, a preparation method thereof, and an application thereof, so as to solve the technical problem that the effect is not significant when isoxazoline pesticides or oxadiazole and triazole compounds alone are used to kill pests in the prior art.

[0006] To achieve the above purpose, the present invention provides the following technical solutions:

[0007] An N-heterocyclic isoxazoline benzamide derivative, and the structural formula of the N-heterocyclic isoxazoline benzamide derivative is:

[0008]

[0009] Wherein, R is selected from 1,3-dichloro, 1-Cl-3-CF3, 1,2,3-trichloro or 1,3-dichloro-2-fluoro; n is 0 or 1;

[0010] X is selected from H or CH3;

[0011] Q is selected from 1,2,4-oxadiazole or 1,2,4-triazole;

[0012] M is selected from methyl, ethyl, cyclopropyl, methylthio, phenyl, pyridyl, substituted phenyl, heteroaryl or substituted heteroaryl, etc.

[0013] The present invention also provides a preparation method of the N-heterocyclic isoxazoline benzamide derivatives described in the above technical solution, including the following steps:

[0014] 1) Mix compound A, hydroxylamine hydrochloride, sodium acetate and an organic solvent, stir and react to obtain intermediate 1;

[0015] Wherein, the structural formula of compound A is The structural formula of intermediate 1 is

[0016] 2) Chlorinate the intermediate 1 obtained in step 1), and then mix the chlorinated product of intermediate 1, compound B and an organic solvent to obtain intermediate 2;

[0017] Wherein, the structural formula of compound B is The structural formula of intermediate 2 is

[0018] 3) Hydrolyze the intermediate 2 obtained in step 2) with lithium hydroxide as the base in a methanol solution to obtain intermediate 3;

[0019] The structural formula of intermediate 3 is

[0020] 4) React the intermediate 3 obtained in step 3), compound C, a base and a condensing agent in a solvent to obtain intermediate 4;

[0021] Wherein, the structural formula of compound C is The structural formula of intermediate 4 is

[0022] 5) React the intermediate 4 obtained in step 4), compound D, a base and a condensing agent to obtain intermediate 5;

[0023] Wherein, the structural formula of compound D is NH2OH·HCl, and the structural formula of intermediate 5 is

[0024] 6) React the intermediate 5 obtained in step 5) with compound E in a base reaction to obtain intermediate 6;

[0025] Among them, the structural formula of the said compound E is The structural formula of intermediate 6 is

[0026] 7) React the intermediate 6 obtained in step 6) with sodium acetate in ethanol to carry out a ring closure reaction to obtain the target compound, and its structural formula is

[0027] Furthermore, in the said step 1), the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol and water; the molar ratio of the said compound A, hydroxylamine hydrochloride, sodium acetate and the organic solvent is 1∶(1~3)∶(1~5)∶(2~5).

[0028] Furthermore, the said chlorinating agent is N-chlorosuccinimide; the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol and water; the molar ratio of the said compound B, the chlorinating agent, and the organic solvent is 1∶(1~4)∶(1~3)∶(2~8).

[0029] Furthermore, the said base is lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium tert-butoxide, sodium acetate, potassium acetate or sodium bicarbonate; the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol and water; the molar ratio of the said intermediate 1-4 and the target compound, the base and the organic solvent is 1∶(1~4)∶(1~3)∶(2~8).

[0030] Furthermore, the said base is ammonia water, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate or sodium bicarbonate, etc.; the said condensing agent is N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'-diisopropylcarbodiimide, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, etc.; the said solvent is dimethylformamide, dichloromethane, acetonitrile, toluene, etc.; the molar ratio of the said intermediate 5, 6 and the base is 1∶(1~4)∶(1~3).

[0031] The present invention also provides the application of the N-heterocyclic isoxazoline benzamide derivatives described in the above technical solution as pesticidal active ingredients in the control of agricultural pests.

[0032] Furthermore, the agricultural pests include Plutella xylostella, Spodoptera frugiperda, Mythimna separata, Helicoverpa armigera, Ostrinia furnacalis, and aphids.

[0033] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0034] The N-heterocyclic isoxazoline benzamide derivatives provided by the present invention exhibit good insecticidal activity against agricultural pests such as Plutella xylostella, Spodoptera frugiperda, Mythimna separata, Helicoverpa armigera, Ostrinia furnacalis, and aphids; the N-heterocyclic isoxazoline benzamide derivatives provided by the present invention can be used as pesticidal active ingredients in the control of agricultural pests. Detailed Description of the Invention

[0035] The various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be construed as limiting the present invention, but rather as a more detailed description of certain aspects, characteristics, and embodiments of the present invention. It should be understood that the terms used in the present invention are only for describing particular embodiments and are not intended to limit the present invention.

[0036] In addition, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the range.

[0037] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0038] Without departing from the scope or spirit of the present invention, various improvements and changes can be made to the specific embodiments of the present invention specification, which are obvious to those skilled in the art. Other embodiments obtained from the specification of the present invention are obvious to those skilled in the art. The specification and examples of the present invention are only exemplary.

[0039] Regarding the use of "comprising", "including", "having", "containing", etc. herein, they are all open-ended terms, meaning including but not limited to.

[0040] A N-heterocyclic isoxazoline benzamide derivative, the structural formula of the N-heterocyclic isoxazoline benzamide derivative is:

[0041]

[0042] In the formula, R is selected from 1,3-dichloro, 1-Cl-3-CF3, 1,2,3-trichloro or 1,3-dichloro-2-fluoro; n is 0 or 1;

[0043] X is selected from H or CH3;

[0044] Q is selected from 1,2,4-oxadiazole or 1,2,4-triazole;

[0045] M is selected from methyl, ethyl, cyclopropyl, methylthio, phenyl, pyridyl, substituted phenyl, heteroaryl or substituted heteroaryl, etc.

[0046] Preferably, in the formula, R is 1,3-dichloro-2-fluoro, 1-Cl-3-CF3; n is 0 or 1, Q is selected from 1,2,4-triazole; M is selected from methyl, ethyl or pyridyl, etc.

[0047] More preferably, in the formula, R is selected from 1,3-dichloro, 1-Cl-3-CF3, 1,2,3-trichloro or 1,3-dichloro-2-fluoro; n is 0 or 1, Q is 1,2,4-oxadiazole or 1,2,4-triazole; M is methyl, ethyl, propyl, cyclohexyl, tert-butyl, methoxy, cyclopropyl, methylthioethyl, phenyl, pyridyl, etc.

[0048] The present invention also provides a preparation method of the N-heterocyclic isoxazoline benzamide derivative described in the above technical solution, including the following steps:

[0049] 1) Mix compound A, hydroxylamine hydrochloride, sodium acetate and an organic solvent, stir and react to obtain intermediate 1;

[0050] Among them, the structural formula of compound A is The structural formula of intermediate 1 is

[0051] 2) Chlorinate the intermediate 1 obtained in step 1), and then mix the chlorinated product of intermediate 1, compound B and an organic solvent to obtain intermediate 2;

[0052] Among them, the structural formula of the compound B is The structural formula of the intermediate 2 is

[0053] 3) Hydrolyze the intermediate 2 obtained in step 2) with lithium hydroxide as the base in a methanol solution to obtain intermediate 3;

[0054] The structural formula of the intermediate 3 is

[0055] 4) React the intermediate 3 obtained in step 3), compound C, a base, and a condensing agent in a solvent to obtain intermediate 4;

[0056] Among them, the structural formula of the compound C is The structural formula of the intermediate 4 is

[0057] 5) React the intermediate 4 obtained in step 4), compound D, a base, and a condensing agent to obtain intermediate 5;

[0058] Among them, the structural formula of the compound D is NH2OH·HCl, and the structural formula of the intermediate 5 is

[0059] 6) React the intermediate 5 obtained in step 5) with compound E in a base reaction to obtain intermediate 6;

[0060] Among them, the structural formula of the compound E is The structural formula of the intermediate 6 is

[0061] 7) React the intermediate 6 obtained in step 6) with sodium acetate in ethanol to carry out a ring closure reaction to obtain the target compound, and its structural formula is

[0062] In the present invention, in the step 1), the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol, and water; the molar ratio of the compound A, hydroxylamine hydrochloride, sodium acetate, and the organic solvent is 1∶(1-3)∶(1-5)∶(2-5).

[0063] In the present invention, the chlorinating agent is N-chlorosuccinimide; the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol, and water; the molar ratio of the compound B, the chlorinating agent, the compound C, and the organic solvent is 1∶(1-4)∶(1-3)∶(2-8).

[0064] In the present invention, the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium tert-butoxide, sodium acetate, potassium acetate or sodium bicarbonate; the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol and water; the molar ratio of the intermediate 1-4, the target compound and the organic solvent is 1∶(1~4)∶(1~3)∶(2~8).

[0065] In the present invention, the base is ammonia water, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate or sodium bicarbonate, etc.; the condensing agent is N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'-diisopropylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, etc.; the solvent is dimethylformamide, dichloromethane, acetonitrile, toluene, etc.; the molar ratio of the intermediate 5, 6 and the base is 1∶(1~4)∶(1~3).

[0066] The synthetic route of the preparation method of the N-heterocyclic isoxazoline benzamide derivatives described in the present invention is as follows:

[0067]

[0068] The typical structures of the N-heterocyclic isoxazoline benzamide derivatives described in the present invention include:

[0069]

[0070]

[0071] The H series technical solutions of the present invention:

[0072] The above preparation method of an N-heterocyclic isoxazoline benzamide derivative includes the following steps:

[0073] 1) Mix compound A, hydroxylamine hydrochloride, sodium acetate and an organic solvent, stir and react to obtain intermediate 1;

[0074] Among them, the structural formula of compound A is The structural formula of intermediate 1 is

[0075] 2) Chlorinate the intermediate 1 obtained in step 1), and then mix and react the chlorinated product of intermediate 1, compound B and an organic solvent to obtain intermediate 2;

[0076] Among them, the structural formula of compound B is The structural formula of Intermediate 2 is

[0077] 3) Hydrolyze Intermediate 2 obtained in Step 2 with lithium hydroxide as the base in a methanol solution to obtain Intermediate 3;

[0078] Among them, the structural formula of Intermediate 3 is

[0079] 4) React Compound A with hydrazine hydrate in ethanol to obtain Intermediate 4, where the structural formula of A is The structure of Intermediate 4 is

[0080] 5) React Intermediate 4 obtained in Step 4, Compound B, a base, and a solvent to obtain Intermediate 5, and the structural formula of Compound B is: The structural formula of Intermediate 5 is

[0081] 6) Reflux Intermediate 5 obtained in Step 5 in a solvent to obtain Intermediate 6, and the structural formula is:

[0082]

[0083] 7) React Intermediate 6 with hydrazine hydrate in a solvent to obtain Intermediate 7, and its structural formula is:

[0084]

[0085] 8) React Intermediate 7 with Intermediate 3 in a DMF solution of a base and a condensing agent to obtain the H series of products, and the structural formula is:

[0086]

[0087] In the present invention, in Step 1), the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol, and water.

[0088] In the present invention, in Step 1), the molar ratio of Compound A, hydroxylamine hydrochloride, sodium acetate, and the organic solvent is 1∶(1 - 3)∶(1 - 5)∶(2 - 5).

[0089] In the present invention, in Step 2), the chlorinating agent is N-chlorosuccinimide.

[0090] In the present invention, in Step 2), the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol, and water.

[0091] In the present invention, in step 2), the molar ratio of intermediate 1, the chlorinating agent, intermediate 2 and the organic solvent is 1∶(1 - 4)∶(1 - 3)∶(2 - 8).

[0092] In the present invention, in step 3), the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium tert-butoxide, ammonia water, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, sodium acetate, potassium acetate or sodium bicarbonate.

[0093] In the present invention, in step 3), the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol and water.

[0094] In the present invention, in step 3), the molar ratio of intermediate 2, intermediate 3, the base and the organic solvent is 1∶(1 - 4)∶(1 - 3)∶(2 - 8).

[0095] The synthetic route of the preparation method of the N-heterocyclic isoxazoline benzamide derivatives of the present invention is as follows:

[0096]

[0097] The present invention also provides the application of the N-heterocyclic isoxazoline benzamide derivatives described in the above technical solution as pesticidal active ingredients in the control of agricultural pests.

[0098] In the present invention, the agricultural pests include Plutella xylostella, Spodoptera frugiperda, Mythimna separata, Helicoverpa armigera, Ostrinia furnacalis and aphids.

[0099] Example 1

[0100] Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)benzamide (C1)

[0101] 1) Add methyl 4-formyl-2-methylbenzoate (1.0 mmol) and ethanol:water = 2:1 as the solvent to a 50 ml single-necked round-bottom flask. Under stirring at room temperature, successively add hydroxylamine hydrochloride (1.3 mmol) and sodium acetate (1.5 mmol). After monitoring the completion of the reaction by TLC, pour the reaction solution into a beaker and stir. After the solid has completely precipitated, filter by suction and dry to obtain intermediate 1;

[0102]

[0103] After calculation, the yield of Intermediate 1 was 95%;

[0104] 2) In step 1), first, under an ice bath, Intermediate 1 (1.2 eq) and NCS (1.5 eq) were added to a three-necked flask, with DMF as the solvent. After reacting under the ice bath for half an hour, the system was placed at room temperature and stirred for reaction, and the reaction progress was monitored by TLC. After the reaction was completed, substituted -5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1 eq) was added to the above reaction system in batches under ice bath conditions, and then triethylamine (1.5 eq) was slowly added to the system using a constant pressure dropping funnel, and the reaction was carried out at room temperature for 18 h. After the reaction was completed, the reaction system was poured into saturated brine and extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and Intermediate 2 was obtained through column chromatography purification;

[0105]

[0106] After detection, the yield of Intermediate 2 was 94.6%;

[0107] 3) Intermediate 2 (1.0 eq) was dissolved in an anhydrous ethanol solution, and then an aqueous solution of lithium hydroxide (1.5 eq) was added, and the reaction was stirred under reflux for 2 h. After the reaction was completed, ethanol and part of the water were removed, and then a small amount of ice water was poured into the solution and stirred, and the insoluble matter was filtered off. Then the pH of the filtrate was adjusted to 3 - 4 with 10% hydrochloric acid, and the solid was filtered out and dried to obtain Intermediate 3;

[0108]

[0109] After detection, the yield of Intermediate 3 was 98%;

[0110] 4) Weigh Intermediate 3 (1 eq) into a round-bottomed flask, and then add 1-hydroxybenzotriazole (1.2 eq) and carbodiimide hydrochloride (1.2 eq), with dichloromethane as the solvent, and react at room temperature for 2 h to obtain System A.

[0111] Aminoacetonitrile hydrochloride (1.3 eq) was dissolved in dichloromethane, and then triethylamine (1.3 eq) was slowly added dropwise to the solution to obtain System B, and the reaction was carried out for half an hour. Subsequently, System A was slowly added dropwise to System B, and the reaction was stirred at room temperature. After monitoring the completion of the reaction, dichloromethane in the system was removed by rotary evaporation, and the mixture was extracted with ethyl acetate, and the organic layer was collected and purified by column chromatography to obtain Intermediate 4;

[0112]

[0113] After calculation, the yield of Intermediate 4 was 86%.

[0114] 5) Weigh hydroxylamine hydrochloride (1.5 eq) and finely ground potassium carbonate (2.0 eq) into a reaction flask. Using absolute ethanol as the solvent, stir at room temperature for 15 minutes. Then, dissolve intermediate 4 (1.0 eq) in absolute ethanol and slowly add it dropwise to the system. Stir the reaction under reflux. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic layer, and purify by column chromatography to obtain intermediate 5;

[0115]

[0116] Calculated, the yield of intermediate 5 is 66%.

[0117] 6) Weigh HATU (2 eq) into a round-bottom flask, using dichloromethane as the solvent. Then add DIPEA (2 eq), and then acetic acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and rotary evaporate to obtain intermediate 6.

[0118]

[0119] Calculated, the yield of intermediate 6 is 62%.

[0120] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system. Stir the reaction under reflux. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify by column chromatography to obtain the target compound C1.

[0121]

[0122] The yield is 67.0%, and the spectral data are as follows:

[0123] 1 H NMR(500MHz,CDCl3)δ7.50(t,J=3.2Hz,4H),7.48(d,J=8.3Hz,1H),7.42(d,J=3.8Hz,1H),6.39(t,J=5.5Hz,1H),4.74(d,J=5.6Hz,2H),4.08(d,J=17.2Hz,1H),3.69(d,J=17.2Hz,1H),2.60(s,3H),2.48(s,3H).

[0124] 1313C NMR (125 MHz, CDCl3) δ 178.00, 169.04, 167.78, 155.57, 138.97, 137.76, 137.67, 135.71, 129.89, 129.59, 129.31, 127.65, 125.40, 124.43, 44.05, 36.05, 27.93, 19.98, 16.34.

[0125] Example 2

[0126] Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((5-ethyl-1,2,4-oxadiazol-3-yl)methyl)-2-methylbenzamide (C2)

[0127] Steps 1) - 5) are the same as in Example 1;

[0128] 6) Weigh HATU (2.0 eq) into a round-bottom flask, using dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add propionic acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and dry it by evaporation to obtain intermediate 6.

[0129]

[0130] Calculated, the yield of intermediate 6 is 62%.

[0131] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux with stirring. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C2.

[0132]

[0133] The yield is 65.0%, and the spectral data are as follows:

[0134] 11H NMR (500 MHz, CDCl3) δ 7.49 (q, J = 2.4 Hz, 4H), 7.47 (d, J = 8.5 Hz, 1H), 7.41 (t, J = 1.7 Hz, 1H), 6.45 (t, J = 5.5 Hz, 1H), 4.73 (d, J = 5.4 Hz, 2H), 4.07 (d, J = 17.2 Hz, 1H), 3.69 (d, J = 17.2 Hz, 1H), 2.90 (q, J = 7.7 Hz, 2H), 2.47 (s, 3H), 1.38 (t, J = 15.4 Hz, 3H).

[0135] 13 13C NMR (125 MHz, CDCl3) δ 181.64, 169.02, 167.37, 155.59, 139.00, 137.89, 137.63, 135.70, 129.87, 129.55, 129.25, 127.65, 125.39, 124.40, 44.05, 36.08, 20.35, 19.93, 10.74.

[0136] Example 3

[0137] Steps 1) - 5) are the same as in Example 1;

[0138] 6) Weigh HATU (2.0 eq) into a round-bottom flask, use dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add butyric acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and dry it by rotary evaporation to obtain intermediate 6.

[0139]

[0140] Calculated, the yield of intermediate 6 is 61%.

[0141] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C3.

[0142]

[0143] The yield is 62.0%, and the spectral data are as follows:

[0144] 11H NMR (500 MHz, CDCl3) δ 7.52–7.49 (m, 4H), 7.49–7.41 (m, 2H), 6.46 (s, 1H), 4.74 (d, J = 5.6 Hz, 2H), 4.08 (d, J = 17.2 Hz, 1H), 3.70 (d, J = 17.4 Hz, 1H), 2.86 (t, J = 7.5 Hz, 2H), 2.48 (s, 3H), 1.84 (q, J = 7.5 Hz, 2H), 1.02 (d, J = 14.9 Hz, 3H).

[0145] 13 13C NMR (125 MHz, CDCl3) δ 180.81, 169.01, 167.34, 155.59, 139.00, 137.89, 137.62, 135.70, 129.87, 129.54, 129.25, 127.66, 125.39, 124.40, 44.05, 36.08, 28.48, 20.12, 19.92, 13.67.

[0146] Example 4

[0147] Steps 1) to 5) are the same as in Example 1;

[0148] 6) Weigh HATU (2.0 eq) into a round-bottom flask, using dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add cyclohexanecarboxylic acid (1.5 eq), and react at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and spin-dry to obtain intermediate 6.

[0149]

[0150] Calculated, the yield of intermediate 6 is 62%.

[0151] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C4.

[0152]

[0153] The yield is 62.0%, and the spectral data are as follows:

[0154] 11H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 1.2 Hz, 3H), 7.48–7.47 (m, 2H), 7.46–7.40 (m, 1H), 6.54 (t, J = 5.5 Hz, 1H), 4.72 (d, J = 5.7 Hz, 2H), 4.07 (d, J = 17.2 Hz, 1H), 3.69 (d, J = 17.3 Hz, 1H), 2.94–2.88 (m, 1H), 2.46 (s, 3H), 2.05 (dd, J = 13.1, 3.3 Hz, 2H), 1.84–1.79 (m, 2H), 1.73–1.55 (m, 4H), 1.38 (dt, J = 5.3, 2.9 Hz, 2H).

[0155] 13 13C NMR (125 MHz, CDCl3) δ 183.89, 169.05, 167.15, 155.61, 139.00, 137.96, 137.59, 135.70, 129.86, 129.51, 129.20, 127.67, 125.39, 124.39, 53.53, 44.05, 36.37, 36.11, 30.24, 25.51, 25.37, 19.91.

[0156] Example 5

[0157] Preparation of N-((5-(tert-butyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (C5).

[0158] Steps 1) - 5) are the same as in Example 1;

[0159] 6) Weigh HATU (2.0 eq) into a round-bottom flask, using dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add pivalic acid (1.5 eq), and react at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and evaporate to dryness to obtain intermediate 6.

[0160]

[0161] Calculated, the yield of intermediate 6 is 60%.

[0162] 7) After dissolving intermediate 6 (1.0 eq) in absolute ethanol, sodium acetate (1.5 eq) was added to the reaction system, and the reaction was stirred under reflux. After the reaction was completed, ethanol was removed, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried, and then purified by column chromatography to obtain the target compound C5.

[0163]

[0164] The yield was 61.0%, and the spectral data were as follows:

[0165] 1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 1.0 Hz, 3H), 7.46 (dd, J = 8.0, 1.3 Hz, 1H), 7.41 (dd, J = 4.6, 2.6 Hz, 2H), 7.15 (t, J = 6.2 Hz, 1H), 4.18 (d, J = 6.3 Hz, 2H), 4.07 (d, J = 17.2 Hz, 1H), 3.69 (d, J = 17.3 Hz, 1H), 2.42 (s, 3H), 1.23 (s, 9H).

[0166] 13 C NMR (125 MHz, CDCl3) δ 175.43, 171.36, 156.79, 155.55, 138.95, 137.49, 137.26, 135.71, 129.89, 129.51, 129.42, 127.71, 125.39, 124.42, 44.01, 40.63, 38.93, 27.45, 19.95.

[0167] Example 6

[0168] Preparation of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)benzamide (C6)

[0169] Steps 1) - 5) were the same as in Example 1, where 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene in the second step was replaced with 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)benzene;

[0170] 6) Weigh HATU (2.0 eq) into a round-bottom flask, using dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add acetic acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction was completed, dichloromethane was removed, and the mixture was extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected and dried by evaporation to obtain intermediate 6.

[0171]

[0172] After calculation, the yield of intermediate 6 was 67%.

[0173] 7) After dissolving intermediate 6 (1.0 eq) in absolute ethanol, sodium acetate (1.5 eq) was added to the reaction system, and the reaction was stirred under reflux. After the reaction was completed, ethanol was removed, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried, and then purified by column chromatography to obtain the target compound C6.

[0174]

[0175] The yield was 68.0%, and the spectral data were as follows:

[0176] 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 6.0 Hz, 1H), 7.49 (d, J = 1.4 Hz, 2H), 7.49–7.40 (m, 2H), 6.44 (t, J = 5.5 Hz, 1H), 4.72 (d, J = 5.6 Hz, 2H), 4.07 (d, J = 17.2 Hz, 1H), 3.68 (d, J = 17.2 Hz, 1H), 2.59 (s, 3H), 2.47 (s, 3H).

[0177] 13 C NMR (125 MHz, CDCl3) δ 177.45, 168.97, 167.53, 155.60, 153.85, 138.99, 137.89, 137.68, 135.70, 133.03, 133.00, 129.87, 129.57, 129.27, 129.16, 127.67, 127.55, 125.39, 124.40, 123.23, 123.09, 44.11, 36.00, 19.95, 12.47.

[0178] Example 7

[0179] Preparation of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((5-ethyl-1,2,4-oxadiazol-3-yl)methyl)-2-methylbenzamide (C7)

[0180] Steps 1) to 5) were the same as in Example 6;

[0181] 6) Weigh HATU (2.0 eq) into a round-bottom flask, use dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add propionic acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and spin-dry to obtain intermediate 6.

[0182]

[0183] After calculation, the yield of intermediate 6 is 66%.

[0184] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C7.

[0185]

[0186] The yield is 64.0%, and the spectral data are as follows:

[0187] 1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 5.9 Hz, 2H), 7.52–7.49 (m, 3H), 6.36 (t, J = 5.5 Hz, 1H), 4.75 (d, J = 5.6 Hz, 2H), 4.07 (d, J = 17.1 Hz, 1H), 3.68 (d, J = 17.2 Hz, 1H), 2.92 (q, J = 7.5 Hz, 2H), 2.49 (s, 3H), 1.40 (t, J = 7.5 Hz, 3H).

[0188] 13 C NMR (125 MHz, CDCl3) δ 181.67, 168.95, 167.34, 155.88, 155.56, 153.86, 137.95, 137.70, 133.01, 129.59, 129.19, 127.67, 127.55, 124.44, 123.25, 123.10, 44.14, 36.13, 20.36, 19.96, 10.75.

[0189] Example 8

[0190] Preparation of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((5-propyl-1,2,4-oxadiazol-3-yl)methyl)benzamide (C8)

[0191] Steps 1) - 5) are the same as in Example 6;

[0192] 6) Weigh HATU (2.0 eq) into a round - bottom flask, using dichloromethane as the solvent. Then add DIPEA (2.0 eq), and then add butyric acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and spin - dry to obtain intermediate 6.

[0193]

[0194] Calculated, the yield of intermediate 6 is 65%.

[0195] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C8.

[0196]

[0197] The yield is 62.0%, and the spectral data are as follows:

[0198] 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 6.0 Hz, 2H), 7.51–7.45 (m, 3H), 6.45 (t, J = 5.5 Hz, 1H), 4.73 (d, J = 5.6 Hz, 2H), 4.07 (d, J = 17.2 Hz, 1H), 3.68 (d, J = 17.2 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.47 (s, 3H), 1.84 (dt, J = 14.9, 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0199] 13 C NMR (125 MHz, CDCl3) δ 180.81, 169.01, 167.34, 155.59, 139.00, 137.89, 137.62, 135.70, 129.87, 129.54, 129.25, 127.66, 125.39, 124.40, 44.05, 36.08, 28.48, 20.12, 19.92, 13.67.

[0200] Example 9

[0201] Preparation of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((5-(methoxymethyl)-1,2,4-oxadiazol-3-yl)methyl)-2-methylbenzamide (C9)

[0202] Steps 1) to 5) are the same as in Example 6;

[0203] 6) Weigh HATU (2.0 eq) into a round-bottom flask, using dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add methoxyacetic acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and evaporate to dryness to obtain intermediate 6.

[0204]

[0205] Calculated, the yield of intermediate 6 is 61%.

[0206] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C9.

[0207]

[0208] The yield is 59.0%, and the spectral data are as follows:

[0209] 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 6.1 Hz, 2H), 7.54–7.45 (m, 3H), 6.43 (t, J = 5.7 Hz, 1H), 4.79 (d, J = 5.7 Hz, 2H), 4.68 (s, 2H), 4.07 (d, J = 17.3 Hz, 1H), 3.68 (d, J = 17.1 Hz, 1H), 3.51 (s, 3H), 2.48 (s, 3H).

[0210] 13 C NMR (125 MHz, CDCl3) δ 176.86, 168.98, 167.57, 155.88, 155.57, 153.86, 137.81, 137.71, 133.00, 129.59, 129.22, 127.66, 127.55, 124.86, 124.42, 123.24, 123.10, 65.20, 59.83, 44.12, 35.97, 19.94.

[0211] Example 10

[0212] Preparation of N-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (C10)

[0213] Steps 1) to 5) are the same as in Example 6;

[0214] 6) Weigh HATU (2.0 eq) into a round-bottom flask, use dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add cyclopropanecarboxylic acid (1.5 eq), and react at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and spin-dry to obtain intermediate 6.

[0215]

[0216] Calculated, the yield of intermediate 6 is 63%.

[0217] 7) After dissolving intermediate 6 (1.0 eq) in absolute ethanol, add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C10.

[0218]

[0219] The yield is 61.0%, and the spectral data are as follows:

[0220] 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 6.0 Hz, 2H), 7.52–7.45 (m, 3H), 6.38 (t, J = 5.4 Hz, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.07 (d, J = 17.2 Hz, 1H), 3.68 (d, J = 17.2 Hz, 1H), 2.47 (s, 3H), 2.18 (tt, J = 8.1, 5.5 Hz, 1H), 1.26–1.23 (m, 2H), 1.22 (dd, J = 2.9, 1.6 Hz, 2H).

[0221] 1313C NMR (125 MHz, CDCl3) δ 182.56, 168.94, 167.25, 155.87, 155.59, 153.85, 137.99, 137.64, 133.01, 129.55, 129.13, 127.67, 127.55, 124.42, 123.23, 123.09, 44.13, 36.06, 19.92, 10.52, 7.83.

[0222] Example 11

[0223] Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)benzamide (C11).

[0224] Steps 1) - 5) are the same as in Example 1, where 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene in the second step is replaced with 1-chloro-3-trifluoromethyl-5-trifluoromethylphenyl ethylene;

[0225] 6) Weigh HATU (2.0 eq) into a round-bottom flask, use dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add acetic acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and spin-dry to obtain intermediate 6.

[0226]

[0227] Calculated, the yield of intermediate 6 is 66%.

[0228] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C11.

[0229]

[0230] The yield is 65.0%, and the spectral data are as follows:

[0231] 11H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.50 (s, 1H), 7.49–7.46 (m, 1H), 6.44 (t, J = 5.5 Hz, 1H), 4.73 (d, J = 5.7 Hz, 2H), 4.13 (d, J = 17.2 Hz, 1H), 3.72 (d, J = 17.2 Hz, 1H), 2.59 (s, 3H), 2.48 (s, 3H).

[0232] 13 13C NMR (125 MHz, CDCl3) δ 177.48, 169.00, 167.52, 155.65, 138.83, 137.87, 137.71, 135.84, 133.07, 132.81, 130.50, 129.60, 129.14, 127.68, 126.98, 126.95, 124.43, 121.92, 44.12, 36.01, 19.97, 12.50.

[0233] Example 12

[0234] Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((5-ethyl-1,2,4-oxadiazol-3-yl)methyl)-2-methylbenzamide (C12)

[0235] Steps 1) - 5) are the same as in Example 11;

[0236] 6) Weigh HATU (2.0 eq) into a round-bottom flask, using dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add propionic acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and concentrate by rotary evaporation to obtain intermediate 6.

[0237]

[0238] Calculated, the yield of intermediate 6 is 65%.

[0239] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux with stirring. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C12.

[0240]

[0241] The yield was 65.0%, and the spectral data are as follows:

[0242] 1 H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.52 (s, 1H), 7.51–7.47 (m, 1H), 6.39 (t, J = 5.5 Hz, 1H), 4.75 (d, J = 5.6 Hz, 2H), 4.13 (d, J = 17.2 Hz, 1H), 3.72 (d, J = 17.2 Hz, 1H), 2.91 (q, J = 7.6 Hz, 2H), 2.49 (s, 3H), 1.39 (t, J = 7.5 Hz, 3H).

[0243] 13 C NMR (125 MHz, CDCl3) δ 181.68, 168.99, 167.34, 155.63, 138.84, 137.94, 137.70, 135.84, 133.08, 130.50, 129.60, 129.15, 127.68, 126.96, 124.45, 121.94, 44.13, 36.12, 20.37, 19.97, 10.76.

[0244] Example 13

[0245] Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((5-propyl-1,2,4-oxadiazol-3-yl)methyl)benzamide (C13)

[0246] Steps 1) to 5) are the same as in Example 11;

[0247] 6) Weigh HATU (2.0 eq) into a round-bottom flask, use dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add butyric acid (1.5 eq), and react at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and spin-dry to obtain intermediate 6.

[0248]

[0249] Calculated, the yield of intermediate 6 was 65%.

[0250] 7) After dissolving intermediate 6 (1.0 eq) in absolute ethanol, sodium acetate (1.5 eq) was added to the reaction system, and the reaction was stirred under reflux. After the reaction was completed, ethanol was removed, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried, and then purified by column chromatography to obtain the target compound C13.

[0251]

[0252] The yield was 65.0%, and the spectral data were as follows:

[0253] 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.51 (d, J = 5.8 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 6.45 (t, J = 5.4 Hz, 1H), 4.74 (d, J = 5.6 Hz, 2H), 4.13 (d, J = 17.2 Hz, 1H), 3.72 (d, J = 17.3 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.47 (s, 3H), 1.82 (dt, J = 14.9, 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0254] 13 C NMR (125 MHz, CDCl3) δ 180.83, 169.00, 167.32, 155.65, 138.83, 137.95, 137.67, 135.90, 132.80, 130.50, 129.58, 129.12, 127.68, 126.95, 124.44, 121.92, 44.12, 36.10, 28.48, 20.14, 19.95, 13.70.

[0255] Example 14

[0256] Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((5-(methylthio)methyl)-1,2,4-oxadiazol-3-yl)methylbenzamide (C14)

[0257] Steps 1) - 5) were the same as in Example 11;

[0258] 6) Weigh HATU (2.0 eq) into a round-bottom flask, use dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add methylthiocarboxylic acid (1.5 eq). React at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and spin-dry to obtain intermediate 6.

[0259]

[0260] After calculation, the yield of intermediate 6 is 62%.

[0261] 7) After dissolving intermediate 6 (1.0 eq) in absolute ethanol, add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C14.

[0262]

[0263] The yield is 60.0%, and the spectral data are as follows:

[0264] 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.52–7.49 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 6.47 (t, J = 5.6 Hz, 1H), 4.76 (d, J = 5.7 Hz, 2H), 4.13 (d, J = 17.2 Hz, 1H), 3.81 (s, 2H), 3.72 (d, J = 17.3 Hz, 1H), 2.47 (s, 3H), 2.22 (s, 3H).

[0265] 13 C NMR (125 MHz, CDCl3) δ 178.00, 169.03, 167.78, 155.64, 138.81, 137.84, 137.68, 135.84, 133.07, 130.50, 129.60, 129.17, 129.11, 127.67, 126.96, 124.45, 121.92, 44.11, 36.04, 27.92, 19.96, 16.33.

[0266] Example 15

[0267] Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl)-2-methylbenzamide (C15)

[0268] Steps 1) to 5) are the same as in Example 11;

[0269] 6) Weigh HATU (2.0 eq) into a round-bottom flask, use dichloromethane as the solvent, then add DIPEA (2.0 eq), and then add cyclopropanecarboxylic acid (1.5 eq), and react at room temperature for half an hour. After activation, dissolve intermediate 5 (1.0 eq) in dichloromethane and add it dropwise to the system. React for 2 hours. After the reaction is completed, remove dichloromethane, extract with ethyl acetate, wash with saturated sodium chloride solution, collect the organic layer, and spin-dry to obtain intermediate 6.

[0270]

[0271] Calculated, the yield of intermediate 6 is 63%.

[0272] 7) Dissolve intermediate 6 (1.0 eq) in absolute ethanol, then add sodium acetate (1.5 eq) to the reaction system, and reflux and stir the reaction. After the reaction is completed, remove ethanol, extract with ethyl acetate, collect the organic phase and dry it, and then purify it by column chromatography to obtain the target compound C15.

[0273]

[0274] The yield is 61.0%, and the spectral data are as follows:

[0275] 1 1H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.50 (d, J = 6.5 Hz, 2H), 7.48–7.45 (m, 1H), 6.40 (t, J = 5.5 Hz, 1H), 4.68 (d, J = 5.5 Hz, 2H), 4.13 (d, J = 17.2 Hz, 1H), 3.72 (d, J = 17.3 Hz, 1H), 2.47 (s, 3H), 2.18 (tt, J = 7.9, 5.2 Hz, 1H), 1.25–1.21 (m, 4H).

[0276] 1313C NMR (125 MHz, CDCl3) δ 182.58, 168.97, 167.25, 155.65, 138.83, 137.97, 137.65, 135.83, 133.07, 132.80, 130.50, 129.57, 129.10, 127.67, 126.98, 124.43, 121.92, 44.12, 36.06, 19.94, 10.57, 7.85.

[0277] Example 16

[0278] Preparation of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((S)-1-(3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)ethyl)benzamide (H1)

[0279] Steps 1) - 3) are the same as in Example 1;

[0280] 4) Add 2-cyanopyridine to a single-necked flask. Dropwise add 15.24 mL of hydrazine hydrate through a dropping funnel under an ice bath. After addition, remove the ice bath and return to room temperature. After the reaction is complete, remove half of the solvent from the system, add an excess of ice-cold petroleum ether to it, and a large amount of crystalline yellow solid precipitates. Dry at room temperature to obtain 2-pyridylaminohydrazone, a yellow solid, with a yield of 56%.

[0281]

[0282] 5) Add phthaloyl-L-alanine to a single-necked flask, add a drop of DMF, and heat under reflux in thionyl chloride. After half an hour, evaporate the solvent to dryness to obtain the corresponding acyl chloride. Add intermediate 4 and sodium carbonate to a mixed solution of DMF and THF (2:1), stir at 0 °C for 15 minutes, and slowly add the acyl chloride to the mixture through a dropping funnel. After the reaction is over, add saturated brine to precipitate a solid, filter by suction, and dry to obtain yellow solid intermediate 5, with a yield of 43%.

[0283]

[0284] 6) Add intermediate 2 and a small amount of solvent ethylene glycol to a single-necked flask, stir, and heat to 190 °C. After the reaction is complete, cool to room temperature, add water to precipitate a solid, filter out the off-white solid by suction, and dry to obtain intermediate 6.

[0285]

[0286] 7) Different substituted amines were added to the reaction flask, 15 mL of dry dichloroethane was added as a solvent, and after stirring and cooling in an ice-salt bath, chloroacetyl chloride was slowly added dropwise. After removing the ice bath pot 20 min later and warming up to room temperature, the reaction was completed after 2 - 3 hours. After rotary evaporation of the solvent dichloromethane, it was washed 2 - 3 times with petroleum ether (PE) or n-hexane to obtain the solid intermediate 7.

[0287]

[0288] 8) Intermediate 3 and 7 were added to a round-bottom flask, DMF was used as a solvent, and N,N-diisopropylethylamine and HATU were added for reaction. After the reaction was completely finished, the DMF in the round-bottom flask was dropped into the stirred ice-saturated brine with a dropper to precipitate a white solid. The white solid was dissolved in dichloromethane and rotary evaporated until the solvent in the flask was completely evaporated. After cooling to room temperature, the solid in the flask was washed with a small amount of dichloromethane and filtered by suction to obtain the target compound H1.

[0289]

[0290] The yield was 60%. The spectral data are as follows:

[0291] 1 H NMR (500 MHz, DMSO-d6) δ 8.64 (dd, J = 3.5, 1.3 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1), 7.79 (d, J = 8.4 Hz, 1), 7.78 (td, J = 7.6, 1.3 Hz, 1H), 7.64 (s, 2H), 7.45 (dd, J = 8.3, 2.2 Hz, 1H), 7.45–7.41 (m, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.32 (dd, J = 7.8, 1.4 Hz, 1H), 4.65 (dq, J = 8.6, 6.1 Hz, 1H), 3.80 (d, J = 15.2 Hz, 1H), 3.30 (d, J = 15.2 Hz, 1H), 2.45 (s, 2H), 1.46 (d, J = 6.2 Hz, 3H).

[0292] 13C NMR (125MHz, DMSO-d6) δ167.79, 162.75, 156.51 (d, J = 251.8Hz), 155.19, 154.89 (q, J = 29.9Hz ),149.20,144.73,137.54,136.92,134.19,133.78,128.87(qd,J=6.0,3.0Hz),128.02,127.5 1,127.13(q,J=2.1Hz),127.07(q,J=1.9Hz),124.77(q,J=268.0Hz),124.37,123.86,123.75 (d,J=19.8Hz),122.11,90.98(q,J=26.9Hz),51.56(q,J=10.0Hz),45.60,20.23(d,J=1.4Hz).

[0293] Example 17

[0294] Preparation of N-((S)-1-(3-(5-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)ethyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (H2)

[0295] Steps 1) to 3) are the same as in Example 31; wherein, in step 4, 5-bromo-2-cyanopyridine is used as the raw material, and the remaining steps are the same as in Example 31 to obtain the H2 compound.

[0296]

[0297] Yield 23%. Spectral data are as follows:

[0298] 1 H NMR (500MHz, DMSO-d6) δ8.66(d,J=1.8Hz,1H,),8.26(d,J=8.6Hz,1H),7.79(d,J=8.4Hz,1H),7.58(dd,J=8.4,1.8Hz,1),7.56(s,2),7.48–7.3 7(m,1H),7.35(d,J=2.3Hz,1),4.65(dq,J=8.6,6.1Hz,1H),3.80(d,J=15.2Hz,1H),3.30(d,J=15.2Hz,1H),2.45(s,3H),1.46(d,J=6.2Hz,3H).

[0299] 1313C NMR(125 MHz, DMSO-d6) δ 167.79, 162.75, 154.89 (q, J = 30.0 Hz), 154.67, 150.82, 142.98, 138.17, 137.55, 134.22, 133.99, 133.78 (d, J = 1.9 Hz), 132.33 (q, J = 6.1 Hz), 128.02, 127.75 (q, J = 2.0 Hz), 127.53, 124.77 (q, J = 268.0 Hz), 124.38, 123.61, 118.74, 90.13 (q, J = 27.1 Hz), 51.55 (q, J = 10.0 Hz), 45.60, 20.24, 20.23.

[0300] Example 18

[0301] Preparation of N-((S)-1-(3-(5-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)ethyl)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (H3)

[0302] Steps 1) - 3) are the same as in Example 31; step four uses 5-bromo-2-cyanopyridine as the raw material, and the remaining steps are the same as in Example 31.

[0303]

[0304] Yield 73%. The spectral data are as follows:

[0305] 1 1H NMR(500 MHz, DMSO-d6) δ 8.66 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1), `7.79 (d, J = 8.4 Hz, 1), 7.60 (s, 2), 7.58 (dd, J = 8.4, 1.8 Hz, 1), 7.44 (dd, J = 8.4, 2.2 Hz, 1), 7.40 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 4.65 (dq, J = 8.6, 6.1 Hz, 1H), 3.80 (d, J = 15.2 Hz, 1H), 3.30 (d, J = 15.2 Hz, 1H), 2.45 (s, 3H), 1.46 (d, J = 6.2 Hz, 3H).

[0306] 1313C NMR (125 MHz, DMSO-d6) δ 167.79, 162.75, 156.51 (d, J = 251.8 Hz), 154.89 (q, J = 30.0 Hz), 154.67, 150.82, 142.98, 138.17, 137.55, 134.22, 133.78, 128.81 (qd, J = 6.2, 3.1 Hz), 128.02, 127.53, 127.00 (q, J = 2.0 Hz), 126.94 (q, J = 1.9 Hz), 124.77 (q, J = 268.0 Hz), 124.38, 123.69 (d, J = 19.5 Hz), 123.61, 118.74, 90.98 (q, J = 26.9 Hz), 51.56 (q, J = 10.0 Hz), 45.60, 20.24, 20.23.

[0307] Example 19

[0308] Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((S)-1-(3-(5-methylpyridin-2-yl)-1H-1,2,4-triazol-5-yl)ethyl)benzamide (H4)

[0309] Steps 1) - 3) are the same as in Example 31; in step four, 5-methyl-2-cyanopyridine is used as the raw material, and the remaining steps are the same as in Example 31.

[0310]

[0311] Yield 42%. The spectral data are as follows:

[0312] 1 1H NMR (500 MHz, DMSO-d6) δ 8.26 (d, J = 8.6 Hz, 1H), 7.83 (t, J = 2.1 Hz, 1), 7.76 (d, J = 1.8 Hz, 1), 7.72 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 2.1 Hz, 1), 7.46 (t, J = 2.1 Hz, 1H), 7.41 (dd, J = 8.4, 2.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1), 7.37–7.33 (m, 1), 7.04–6.97 (m, 1), 4.65 (dq, J = 8.6, 6.1 Hz, 1H), 3.80 (d, J = 15.2 Hz, 1H), 3.30 (d, J = 15.2 Hz, 1H), 2.45 (s, 3H), 2.30 (s, 3H), 1.46 (d, J = 6.2 Hz, 3H).

[0313] 13 C NMR(125MHz, DMSO-d6) δ 167.79, 162.75, 154.88(q, J = 29.9Hz), 154.57, 150.29, 142.36, 137.54, 135.94, 134.51(q, J = 2.0Hz), 134.18, 134.07, 133.78, 132.78(tdq, J = 6.0, 4.1, 2.0Hz), 132.51(q, J = 31.9Hz), 128.02, 127.62(q, J = 2.0Hz), 127.51, 125.86(q, J = 3.9Hz), 124.58(q, J = 268.1Hz), 124.38, 123.37(qq, J = 4.1, 2.1Hz), 122.82(q, J = 268.1Hz), 121.55, 91.01(q, J = 26.9Hz), 51.66(q, J = 10.0Hz), 45.60, 20.24, 20.20, 18.34.

[0314] Example 20

[0315] Preparation of N-((S)-1-(3-(6-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)ethyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (H5)

[0316] Steps 1) - 3) are the same as in Example 31; in step four, 6-bromo-2-cyanopyridine is used as the raw material, and the remaining steps are the same as in Example 31.

[0317]

[0318] The yield is 12%. The spectral data are as follows:

[0319] 1 H NMR(500MHz, DMSO-d6) δ 8.28(d, J = 8.6Hz, 1H), 7.79(d, J = 8.4Hz, 1), 7.61(t, J = 7.8Hz, 1H), 7.56(s, 2H), 7.56(dd, J = 7.8, 1.4Hz, 1H), 7.44(dd, J = 8.4, 2.2Hz, 1H), 7.40(dd, J = 7.6, 1.3Hz, 1H), 7.35(d, J = 2.3Hz, 1H), 4.65(dq, J = 8.6, 6.1Hz, 1H), 3.80(d, J = 15.2Hz, 1H), 3.30(d, J = 15.2Hz, 1H), 2.45(s, 3H), 1.46(d, J = 6.2Hz, 3H).

[0320] 13 C NMR (125 MHz, DMSO-d6) δ 167.79, 163.09, 154.89 (q, J = 30.0 Hz), 154.14, 142.05, 141.19, 139.95, 137.55, 134.22, 133.99, 133.78, 133.77, 132.33 (q, J = 6.1 Hz), 128.02, 127.75 (q, J = 2.0 Hz), 127.53, 126.99, 124.77 (q, J = 268.0 Hz), 124.38, 120.35, 90.13 (q, J = 27.1 Hz), 51.55 (q, J = 10.0 Hz), 45.60, 20.24, 20.23.

[0321] Effect verification

[0322] I. Insecticidal activity detection against Plutella xylostella and Tuta absoluta

[0323] Using the leaf dipping method, the target compound synthesized was tested for its toxicity against Plutella xylostella. First, fresh cabbage or tomato leaves were washed and air-dried, and then cut into small leaves with basically the same size and shape. Appropriate filter paper was placed at the bottom of the petri dish for later use. Then, the liquid medicine concentrations were prepared as 100 μg / mL and 50 μg / mL for standby. The cut cabbage leaves were immersed in the liquid medicine to be tested for 10 s, and then taken out and placed in the petri dish. There were three parallels for each medicine concentration. After the vegetable leaves were naturally air-dried, 15 second-instar Plutella xylostella were picked into each petri dish and transferred to an artificial intelligence climate incubator (temperature 26 °C, humidity 85%, light / dark 14:10) for cultivation. After 48 hours, they were taken out, the number of dead Plutella xylostella was counted, the data was recorded, and the mortality rate was calculated. The calculation formula for insecticidal activity is as follows:

[0324] Mortality rate = (number of dead insects with medicine - number of dead insects without medicine) / total number of Plutella xylostella put in × 100%

[0325] At a concentration of 100 μg / mL, the insecticidal activities of the N-heterocyclic isoxazoline benzamide compounds prepared in Examples 1 - 35 of this patent against the two pests were 100%. The results showed that the compounds provided by the present invention had good insecticidal activities against Plutella xylostella and Tuta absoluta, comparable to the control agent fluxametamide. It indicated that these compounds had the development prospect of controlling the agricultural pests Plutella xylostella and Tuta absoluta.

[0326] II. Insecticidal activity detection against Mythimna separata

[0327] The leaf dipping method was adopted to test the toxicity of the designed compounds against Mythimna separata. The test method was the same as that in Example 26, except that the cabbage leaves were replaced with corn leaves. After 72 hours, take them out, count the number of dead Mythimna separata, record the data, and calculate the mortality rate. The calculation formula for insecticidal activity is as follows:

[0328] Mortality rate = (number of dead insects with drug - number of dead insects without drug) / total number of Mythimna separata put in × 100%

[0329] The test results showed that at a mass concentration of 100 μg / mL, all the target compounds provided by the present invention had good insecticidal activity against Mythimna separata, comparable to the control agent fluxametamide. It indicated that these compounds had the development prospect for controlling the agricultural pest Mythimna separata.

[0330] III. Detection of insecticidal activity against Ostrinia furnacalis

[0331] The target compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution of 5000 mg / L, and continuously diluted to different concentrations with 0.05% (w / v) Triton X - 100. Equal amounts of DMSO and 0.05% (w / v) Triton X - 100 were added to the blank. The feed was added to a 24 - well plate. After the feed cooled and formed, 100 μL of the target compound solution was added to the surface of the supplementary feed. After drying at room temperature, the third - instar larvae were transferred to each well. The concentration of each group was repeated 3 times (24 larvae for each repetition). Finally, the 24 - well culture plate was stored in an incubator at 26°C and 85% relative humidity, with a light / dark cycle of 16:8. Record the larval mortality rate at 48 hours. Gently touch the body of the larva with a needle. If it cannot crawl normally, it is considered dead.

[0332] Corrected mortality rate (%) = (T - C) × 100 / (100% - C%)

[0333] Where T represents the mortality rate of the test compound group, and C represents the mortality rate of the blank control group. All these parameters are expressed as percentages.

[0334] At a concentration of 100 μg / mL, the N - heterocyclic isoxazoline benzamide compounds prepared in Examples 1 - 35 of this patent had good insecticidal activity against Ostrinia furnacalis, with a mortality rate of 100%, comparable to the control agent fluxametamide, indicating that the compounds of this patent had the prospect for controlling the agricultural pest Ostrinia furnacalis.

[0335] IV. Detection of insecticidal activity against aphids

[0336] Select 1 broad bean seedling with a height of 3 - 5 cm, wash the roots with clean water and appropriately trim them with scissors, then transplant it into a plastic petri dish, and add an appropriate amount of clean quartz sand into it. Use a dropper to suck 4 mL of water and pour it on the quartz sand to keep it moist. Then select 30 - 50 wingless broad bean aphids from the broad bean seedlings, transfer them to the broad bean seedlings with a soft brush, and cover them with a nylon filter net. After all the aphids climb onto the broad bean seedlings, spray the medicine 20 times with a small sprayer, and finally place them in a light incubator for cultivation (24 - 26 °C, relative humidity: 70 - 80%, 14:10 h light / dark cycle). 0.1% Tween - 80 aqueous solution is used as a negative control, and isoxazolincarb is used as a positive control. There are 3 parallels for each test. After 48 hours, count the mortality rate. Gently touch the body of the larva with a needle. If it cannot crawl normally, it is considered dead.

[0337] Corrected mortality rate (%) = (T - C) × 100 / (100% - C%)

[0338] Where T represents the mortality rate of the test compound group, and C represents the mortality rate of the blank control group. All these parameters are expressed as percentages.

[0339] It can be seen from the results that at a concentration of 200 μg / mL, the N - heterocyclic isoxazoline benzamide compounds prepared in Examples 1 - 35 of this patent have a 100% mortality rate against aphids, which is comparable to that of the control drug flutriafolamide, indicating that the compounds provided by this patent have certain prospects in controlling aphids.

[0340] V. Detection of insecticidal activity against Spodoptera frugiperda

[0341] Add the test compound solution with a concentration of 100 μg / mL into a 24 - well plate, and add 24 third - instar Spodoptera frugiperda larvae into each well. Incubate them in an incubator at 26 °C and 85% relative humidity, with a light / dark ratio of 16 / 8, for 2 days. After the incubation, evaluate the mortality rate of Spodoptera frugiperda (gently touch the larva, and if the larva cannot crawl normally, it is considered dead), and conduct parallel detections 3 times;

[0342]

[0343] Where, X - the number of live insects before cultivation, Y - the number of live insects after cultivation;

[0344] The results of the activity test show that at a concentration of 200 μg / mL, the N - heterocyclic isoxazoline benzamide compounds prepared in Examples 1 - 35 of this patent have a 100% mortality rate against Spodoptera frugiperda, which is comparable to that of the control drug flutriafolamide, indicating that the compounds provided by this patent can be used as active ingredients of pesticides in the control of agricultural pests.

[0345] In summary, the compounds of the present invention have good insecticidal activities against agricultural pests such as Plutella xylostella, Spodoptera frugiperda, Ostrinia furnacalis, and aphids, and can be used as candidate insecticides for controlling these pests and applied to the control of agricultural pests.

[0346] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the above embodiments, those of ordinary skill in the art should understand that: modifications or equivalent replacements can still be made to the specific embodiments of the present invention, and any modification or equivalent replacement without departing from the spirit and scope of the present invention should be covered by the protection scope of the claims of the present invention.

Claims

1. A N-heterocyclic isoxazoline benzamide derivative, characterized in that, The structural formula of the N-heterocyclic isoxazoline benzamide derivatives is as follows: In the formula, R is selected from 1,3-dichloro, 1-Cl-3-CF3, 1,2,3-trichloro or 1,3-dichloro-2-fluoro; n is 0 or 1; X is selected from H or CH3; Q is selected from 1,2,4-oxadiazole or 1,2,4-triazole; M is selected from methyl, ethyl, cyclopropyl, methylthio, phenyl, pyridyl, substituted phenyl, heteroaryl or substituted heteroaryl, etc.

2. A preparation method of an N-heterocyclic isoxazoline benzamide derivative as described in claim 1, characterized in that, It includes the following steps: 1) Mix compound A, hydroxylamine hydrochloride, sodium acetate and an organic solvent, stir and react to obtain intermediate 1; Among them, the structural formula of compound A is The structural formula of intermediate 1 is 2) Chlorinate the intermediate 1 obtained in step 1), and then mix the chlorinated product of intermediate 1, compound B and an organic solvent to obtain intermediate 2; Among them, the structural formula of the compound B is The structural formula of the intermediate 2 is 3) Hydrolyze the intermediate 2 obtained in step 2) with lithium hydroxide as the base in a methanol solution to obtain intermediate 3; The structural formula of the intermediate 3 is 4) React the intermediate 3 obtained in step 3), compound C, a base and a condensing agent in a solvent to obtain intermediate 4; Among them, the structural formula of the compound C is The structural formula of Intermediate 4 is 5) React the intermediate 4 obtained in step 4), compound D, a base and a condensing agent to obtain intermediate 5; Among them, the structural formula of the compound D is NH2OH·HCl, and the structural formula of the intermediate 5 is 6) React the intermediate 5 obtained in step 5) with compound E in the presence of a base to obtain intermediate 6; Among them, the structural formula of the compound E is The structural formula of intermediate 6 is 7) React the intermediate 6 obtained in step 6) with sodium acetate in ethanol to form a closed loop to obtain the target compound, and its structural formula is 3. The preparation method according to claim 2, characterized in that, In the said step 1), the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol or water; the molar ratio of compound A, hydroxylamine hydrochloride, sodium acetate and the organic solvent is 1∶(1~3)∶(1~5)∶(2~5).

4. The preparation method according to claim 2, characterized in that, In step 2), the chlorinating agent is N-chlorosuccinimide; the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol and water; the molar ratio of compound B, the chlorinating agent, compound C and the organic solvent is 1∶(1~4)∶(1~3)∶(2~8).

5. The preparation method according to claim 2, wherein In step 3), the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium tert-butoxide, sodium acetate, potassium acetate or sodium bicarbonate; the organic solvent is one or more of methanol, ethanol, triethylamine, dichloromethane, chloroform, ethyl acetate, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, n-propanol and water; the molar ratio of intermediate 1-4 and the target compound, the base and the organic solvent is 1∶(1~4)∶(1~3)∶(2~8).

6. The preparation method according to claim 2, characterized in that In Steps 4 and 5), the alkali ammonia water, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, etc.; the condensing agent N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'-diisopropylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, etc.; the solvent dimethylformamide, dichloromethane, acetonitrile, toluene, etc.; the molar ratio of Intermediate 5, Intermediate 6 and the base is 1∶(1-4)∶(1-3).

7. Use of an N-heterocyclic isoxazoline benzamide derivative as claimed in claim 1 as a pesticidal active ingredient in the control of agricultural pests.

8. The application according to claim 7, wherein The agricultural pests include Plutella xylostella, Spodoptera frugiperda, Mythimna separata, Helicoverpa armigera, Ostrinia furnacalis and aphids.

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