Amide derivative containing thiophene structure as well as preparation method and application of amide derivative

Abstract

The invention discloses an amide derivative containing a thiophene structure. The amide derivative is characterized in that the structural formula of the amide derivative is as follows: # imgabs0 #, wherein R1, R2 and R3 are hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 halogenated alkyl or C1-C6 halogenated alkoxy; r4 is hydrogen, halogen, a cyano group, a nitro group, a C1-C6 alkyl group or a C1-C6 halogenated alkyl group; r5 is hydrogen, halogen, nitryl, hydroxyl, amino, sulfydryl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 cycloalkyl or C1-C6 aryl; and R6 is a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 cycloalkyl group or a C1-C6 aryl group.

Description

Technical Field

[0001] This invention belongs to the field of agricultural chemicals, specifically the fields of chemicals and pesticides. It relates to thiophene-containing amide compounds, a method for preparing such thiophene-containing diamide compounds, and the application of such thiophene-containing diamide compounds in the control of lepidopteran pests. Background Technology

[0002] In the development of green pesticides, amide compounds are widely present in the chemical structures of various pesticides. Some commercially available pesticides, such as the insecticides fluoxetine, isoxetine, flufenoxuron, chlorantraniliprole, and bromfenoxuron-methyl, all contain amide structures. Therefore, amide insecticides have excellent commercial prospects. To discover new pesticide compounds, the inventors introduced amide fragments with excellent biological activity into their skeletons, obtaining a novel class of compounds represented by Formula I, and found that they control pests caused by agricultural pests. Therefore, this invention discloses a thiophene amide compound containing isoxetine, its preparation method, its application, and its use as an agricultural insecticide. Therefore, the study of synthetic methods for amide derivatives is a direction of considerable interest, and a large number of literature reports have been published (European Journal of Medicinal Chemistry, 2019, 180: 486-508; Pest Manag Sci, 2012, 68: 801–810; J. Agric. Food Chem, 2013, 61, 8730-8736; J. Agric. Food Chem, 2013, 61, 5483-5493; Journal of the American Chemical Society, 2010, 132, 28; Rsc Advances 2016, 6, 78307-78310; Green Chemistry, 2015, 17, 1113-1119; Asian Journal of Organic Chemistry, 2015, 4, 438-441; Chemical Communications, 2014, 50, 9533-9535; European Journal of Organic Chemistry, 2014, 7174-7183; J. Agric. Foo d Chem, 2022, 70, 12651-12662...etc.).

[0003] Imidacloprid is a broad-spectrum insecticide belonging to the novel cypermethrin class. It is characterized by high efficiency, low toxicity, penetrability, rapid killing action, and long-lasting effect, thus finding widespread application in agriculture and horticulture. It exhibits good biological activity against agricultural pests such as Lepidoptera, Thysanoptera, Diptera, and Hemiptera. Certain isoxazoline derivatives with insecticidal properties are disclosed in patents WO2005 / 085216A1, WO2009002809A2, WO2012120399A1, and WO2014090918A1.

[0004] In addition, five-membered heterocyclic derivatives have always been an important research subject. Thiophene, as a member of the five-membered heterocyclic group containing one heteroatom, is one of the simplest heterocyclic systems. It is a bioisosteric isostere of benzene. Compared with the simplest aromatic hydrocarbons, its spatial volume is slightly smaller, and one of the two lone electrons of the sulfur atom is conjugated with two double bonds to form a delocalized π bond. This gives it an electron-rich property. This can enhance the biological activity of the compound. There have been many related reports before (Pest Management Science., 2012, 68(5): 801-810; Archiv der Pharmazie, 2022, 11(6): 1-10; European Journal of Medicinal Chemistry., 2017, 128: 70-78; European Journal of Medicinal Chemistry., 2019, 180: 486-508, etc.). Summary of the Invention

[0005] The purpose of this invention is to provide an amide derivative containing a thiophene structure and its application as an agricultural insecticide.

[0006] The technical solution of this invention is: an amide derivative containing a thiophene structure, the structural formula of which is as follows: Where: R 1 R 2 R 3 It can be hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0007] R 4 It can be hydrogen, halogen, cyano, nitro, C1-C6 alkyl, or C1-C6 haloalkyl;

[0008] R 5 It can be hydrogen, halogen, nitro, hydroxyl, amino, mercapto, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 cycloalkyl or C1-C6 aryl;

[0009] R6 It can be a halogen atom, cyano group, nitro group, C1-C6 alkyl group, C1-C6 cycloalkyl group, or C1-C6 aryl group.

[0010] Furthermore, R 1 R 2 R 3 It is hydrogen or halogen; R 4 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 5 It is a C1-C6 cycloalkyl or C1-C6 aryl; R 6 It can be nitro, C1-C6 alkyl, C1-C6 cycloalkyl, or C1-C6 aryl.

[0011] Furthermore, R 1 and R 3 It is chlorine; R 2 It is hydrogen or chlorine; R 4 It is trifluoromethyl; R 5 Methyl; R 6 The compounds are 2,2-difluoroethylamino, methylamino, ethylamino, propylamino, butylamino, glycine methyl ester hydrochloride, glycine ethyl ester hydrochloride, aminoacetonitrile hydrochloride, (R)-1-methylthio-2-propylamine, dimethylamine, cyclopropylamine, cyclopropylmethylamine, (aminomethyl)cyclopentane, and cyclobutylmethylamine.

[0012] The method for preparing an amide derivative containing a thiophene structure, as described above.

[0013]

[0014] The method for preparing an amide derivative containing a thiophene structure specifically includes the following steps: (1) adding the compound of formula II, an aqueous solution of hydroxylamine hydrochloride and an organic solvent into a round-bottom flask, adjusting the pH of the reaction solution to neutral with a saturated alkaline solution to obtain the compound of formula III, wherein the molar ratio of compound of formula II: hydroxylamine hydrochloride: organic solvent is 1:1 to 3:2 to 5, and reacting at -5℃ to 40℃ to obtain the compound of formula III;

[0015] (2) After chlorination of compound III and chlorination reagent, it is reacted with compound IV in an organic solvent to obtain compound V. The molar ratio of compound III: chlorination reagent: compound IV: organic solvent is 1:1~4:1~3:2~8. The reaction is carried out at -5℃~50℃ to obtain the above-mentioned compound V.

[0016] (3) The compound of formula V is hydrolyzed to obtain the compound of general formula VI. The hydrolysis solvent is one or more of water, methanol, ethanol, tetrahydrofuran or dioxane.

[0017] (4) The compound of formula VI reacts with a chlorination reagent or a condensation reagent. After reacting for 1 to 8 hours, formula VII and a base are added, and the reaction is carried out in an organic solvent to obtain formula I.

[0018] The molar ratio of each reactant used is 1:1-5:1-2:1-2.5:2-8, where the ratio is compound of formula VI: chlorination reagent or condensation reagent: compound of formula VII: base: organic solvent.

[0019] The chlorination reagent used is one or more of thionyl chloride, sulfonyl chloride, oxalyl chloride, carbamate, phosphorus trichloride, or phosphorus pentachloride; the condensation reagent used is dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), diisopropylcarbodiimide (DIC), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIEA), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOBt).

[0020] The base is triethylamine, N,N-diisopropylethylamine, pyridine, piperidine, 3-methylpyridine, N-methylmorpholine, 3-methylimidazolium, alkali metal alkoxide, sodium hydroxide, potassium hydroxide, or lithium hydroxide;

[0021] The organic solvents used are dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, or N,N-dimethylformamide.

[0022] The application of the thiophene-containing amide derivative in the preparation of pesticides for controlling agricultural pests.

[0023] The agricultural pests mentioned include diamondback moth, corn borer, and fall armyworm.

[0024] The beneficial effects of this invention are as follows: This invention utilizes the phenylisoxaazole fragment, which can effectively control pests such as Lepidoptera and Thysanoptera. The amide fragment has the characteristics of wide application in insecticides for Lepidoptera pests. By introducing the thiophene structural unit into the diamide skeleton, experiments have confirmed that some thiophene-containing isoxazoline compounds have good insecticidal activity against Lepidoptera pests such as diamondback moth, corn borer, and fall armyworm, and can be used as insecticides in agriculture. Detailed Implementation

[0025] Example 1: Preparation of 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-N-(2,2-difluoroethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide:

[0026] Step 1: An aqueous solution of methyl p-formyl-2-methylbenzoate (10.0 g, 56.12 mmol), hydroxylamine hydrochloride (4.68 g, 67.34 mmol), and 10 mL of anhydrous ethanol were added to a 100 mL round-bottom flask. The reaction solution was adjusted to neutral with saturated sodium carbonate solution, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum, and recrystallized from anhydrous ethanol to give 8.93 g of a yellow solid, which is intermediate 2, with a yield of 82.8%.

[0027]

[0028] Step 2: Methyl (Z)-4-((hydroxyimino)methyl)benzoate (5.0 g, 27.90 mmol) and NCS (5.59 g, 41.87 mmol) were added to a 100 mL round-bottom flask. After stirring at 40 °C for 40 min, styrene (3.49 g, 33.48 mmol) and triethylamine (4.24 g, 41.87 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by column chromatography to obtain 6.32 g of white solid, which is intermediate 4, with a yield of 80.5%.

[0029]

[0030] Step 3: Methyl 4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzoate (5.0 g, 17.77 mmol) and sodium hydroxide (2.13 g, 53.32 mmol) aqueous solution were added to a 100 mL round-bottom flask and stirred under reflux for 1 h. After the reaction was completed, the reaction solution was poured into 50 mL of ice water, and the pH of the solution was adjusted to 3-4 with concentrated hydrochloric acid. The solution was filtered through a Buchner funnel, and the filter cake was dried to obtain 4.32 g of white solid, which is intermediate 5, with a yield of 91.0%.

[0031]

[0032] Step 4: 4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzoic acid (0.3 g, 1.12 mmol) and thionyl chloride (2.67 g, 22.45 mmol) were added to a 50 mL round-bottom flask. The mixture was heated and stirred at 45 °C for 4 h. Excess thionyl chloride was removed by rotary evaporation. Triethylamine (0.22 g, 1.68 mmol), 15 mL of anhydrous acetonitrile, and 2-amino-4,5,6,7-tetrahydrobenzo[B]thiophene-3-carboxylic acid (0.20 g, 1.35 mmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was washed with water, extracted with DCM, concentrated under vacuum, and purified by column chromatography to obtain 0.35 g of brown solid, which is intermediate 6, with a yield of 78.1%.

[0033]

[0034] Step 5: 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), 2,2-difluoroethylamine (0.38 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to precipitate the solid. The solid was filtered and purified by column chromatography to obtain 0.160 g of a yellow solid, with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ12.53 (s, 1H), 8.18–6.82 (m, 4H), 6.01 (ddt, J = 56.0, 7.8, 4.9Hz ,2H),3.86(ddd,J=79.7,42.0,17.2Hz,2H),2.97–2.65(m,2H),1.89(d,J=4.8Hz,2H).

[0035]

[0036] Example 2: Preparation of 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0037] The methods for steps one through four are the same as in Example 1, except that in step five, methylamine is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0038]

[0039] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), methylamine hydrochloride (0.68 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.160 g of a yellow solid, with a yield of 60%.

[0040] Example 3: Preparation of 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-N-ethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0041] The methods for steps one through four are the same as in Example 1, except that in step five, ethylamine is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0042]

[0043] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), ethylamine (0.37 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.150 g of a yellow solid, with a yield of 57%.

[0044] Example 4: Preparation of 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-N-propyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0045] The methods for steps one through four are the same as in Example 1, except that in step five, propylamine is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0046]

[0047] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), propylamine (0.49 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.163 g of a yellow solid, with a yield of 61%.

[0048] Example 5: Preparation of N,N-butyl-2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0049] The methods for steps one through four are the same as in Example 1, except that in step five, butylamine is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0050]

[0051] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), butylamine (0.61 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.163 g of a yellow solid, with a yield of 73%.

[0052] Example 6: Preparation of methyl glycine of (2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonyl)glycine

[0053] The methods for steps one through four are the same as in Example 1, except that in step five, methyl amine glycine hydrochloride is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0054]

[0055] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), glycine methyl ester hydrochloride (0.74 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.155 g of a yellow solid, with a yield of 55%.

[0056] Example 7: Preparation of ethyl glycine of (2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonyl)glycine

[0057] The methods for steps one through four are the same as in Example 1, except that in step five, the amine used is glycine ethyl ester hydrochloride amine. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0058]

[0059] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), glycine ethyl ester hydrochloride (0.86 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.155 g of a yellow solid, with a yield of 55%.

[0060] Example 8: Preparation of N-(cyanomethyl)-2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide. Steps one through four are the same as in Example 1, except that in step five, the amine used is aminoacetonitrile hydrochloride amine. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0061]

[0062] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), glycine acetonitrile hydrochloride (0.47 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.148 g of a yellow solid, with a yield of 56%.

[0063] Example 9: Preparation of 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-N-(1-(methylthio)propyl-2-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0064] The methods for steps one through four are the same as in Example 1, except that in step five, the amine used is (R)-1-methylthio-2-propylamine. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0065]

[0066] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), (R)-1-methylthio-2-propylamine (0.88 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.135 g of a yellow solid, with a yield of 47%.

[0067] Example 10: Preparation of 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-N,N-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide. Steps one through four were performed using the same methods as in Example 1, except that in step five, dimethylamine was used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0068]

[0069] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), dimethylamine (0.37 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.120 g of a yellow solid, with a yield of 46%.

[0070] Example 11: Preparation of N-cyclopropyl-2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0071] The methods for steps one through four are the same as in Example 1, except that in step five, the amine used is cyclopropylamine. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0072]

[0073] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), dimethylamine (0.37 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.120 g of a yellow solid, with a yield of 46%.

[0074] Example 12: Preparation of N-(cyclopropylmethyl)-2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0075] The methods for steps one through four are the same as in Example 1, except that in step five, the amine used is cyclopropylmethylamine. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0076]

[0077] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), cyclopropylmethylamine (0.59 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.120 g of a yellow solid, with a yield of 44%.

[0078] Example 13: Preparation of N-(cyclobutylmethyl)-2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide. Steps one through four are the same as in Example 1, except that in step five, cyclobutylmethylamine is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0079]

[0080] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), cyclopropylmethylamine (0.26 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.126 g of a yellow solid, with a yield of 45%.

[0081] Example 14: Preparation of N-cyclopentylmethyl-2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0082] The methods for steps one through four are the same as in Example 1, except that in step five, the amine used is (aminomethyl)cyclopentane. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0083]

[0084] 2-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), (aminomethyl)cyclopentane (0.26 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.135 g of a yellow solid, with a yield of 48%.

[0085] Example 15: Preparation of N-(2,2-difluoroethyl)-2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0086] The method in the first step is the same as in Example 1, but the second to fifth steps are different. The specific steps are as follows;

[0087] Step 2: Methyl (Z)-4-((hydroxyimino)methyl)benzoate (5.0 g, 27.90 mmol) and NCS (5.59 g, 41.87 mmol) were added to a 100 mL round-bottom flask. After stirring at 40 °C for 40 min, 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.49 g, 33.48 mmol) and triethylamine (4.24 g, 41.87 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by column chromatography to obtain 6.32 g of white solid, which is intermediate 4, with a yield of 80.5%.

[0088]

[0089] Step 3: Methyl 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzoate (5.0 g, 17.77 mmol) and sodium hydroxide (2.13 g, 53.32 mmol) aqueous solution were added to a 100 mL round-bottom flask and stirred under reflux for 1 h. After the reaction was completed, the reaction solution was poured into 50 mL of ice water, and the pH of the solution was adjusted to 3-4 with concentrated hydrochloric acid. The solution was filtered through a Buchner funnel, and the filter cake was dried to give 4.32 g of white solid, which is intermediate 5, with a yield of 91.0%.

[0090]

[0091] Step 4: 2-Methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (0.3 g, 1.12 mmol) and thionyl chloride (2.67 g, 22.45 mmol) were added to a 50 mL round-bottom flask. The mixture was heated and stirred at 45 °C for 4 h. Excess thionyl chloride was removed by rotary evaporation. Triethylamine (0.22 g, 1.68 mmol), 15 mL of anhydrous acetonitrile, and 2-amino-4,5,6,7-tetrahydrobenzo[B]thiophene-3-carboxylic acid (0.20 g, 1.35 mmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was washed with water, extracted with DCM, concentrated under vacuum, and purified by column chromatography to obtain 0.35 g of brown solid, which is intermediate 6, with a yield of 78.1%.

[0092]

[0093] Step 5: 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), 2,2-difluoroethylamine (0.38 g, 2 mmol), and N,N-diisopropylethylamine (0.135 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.238 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to obtain 0.160 g of a yellow solid, with a yield of 60%.

[0094]

[0095] Example 16: Preparation of N-methyl-2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0096] The methods for steps one through four are the same as in Example 15, except that in step five, methylamine is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0097]

[0098] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), methylamine (0.25 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.180 g of a yellow solid, with a yield of 71%.

[0099] Example 17: Preparation of N-ethyl-2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide.

[0100] The methods for steps one through four are the same as in Example 15, except that in step five, ethylamine is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0101]

[0102] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), ethylamine (0.35 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.125 g of a yellow solid, with a yield of 48%.

[0103] Example 18: Preparation of 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-N-propyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0104] The methods for steps one through four are the same as in Example 15, except that in step five, propylamine is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0105]

[0106] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), propylamine (0.46 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.110 g of a yellow solid, with a yield of 41%.

[0107] Example 19: Preparation of N-isopropyl-2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0108] The methods for steps one through four are the same as in Example 15, except that in step four, isopropylamine is used. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0109]

[0110] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), isopropylamine (0.46 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.100 g of a yellow solid, with a yield of 38%.

[0111] Example 20: Preparation of methyl glycine of (2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonyl)glycine

[0112] The methods for steps one through four are the same as in Example 15, except that in step five, methyl amine glycine hydrochloride is used. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0113]

[0114] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), glycine methyl ester hydrochloride (0.70 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.105 g of a yellow solid, with a yield of 39%.

[0115] Example 21: Preparation of (2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonyl)glycine ethyl ester. Steps one through four are the same as in Example 15, except that in step five, glycine ethyl ester hydrochloride is used as the amine. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0116]

[0117] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), glycine ethyl ester hydrochloride (0.81 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.111 g of a yellow solid, with a yield of 39%.

[0118] Example 22: Preparation of N-(cyanomethyl)-2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0119] The methods for steps one through four are the same as in Example 15, except that in step five, the amine used is aminoacetonitrile hydrochloride. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0120]

[0121] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), aminoacetonitrile hydrochloride (0.44 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.100 g of a yellow solid, with a yield of 37%.

[0122] Example 23: Preparation of 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-N-(1-(methylthio)ethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0123] The methods for steps one through four are the same as in Example 15, except that in step five, the amine used is R)-1-methylthio-2-propylamine. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0124]

[0125] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), aminoacetonitrile hydrochloride (0.44 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.122 g of a yellow solid, with a yield of 46%.

[0126] Example 24: Preparation of N-(3-chloro-4-fluorophenyl)-2-((5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide

[0127] The methods for steps one through four are the same as in Example 1, except that in step four, the amine used is 3-chloro-4-fluoro-aniline. The reaction route, operation, and physicochemical data of the product for step five are as follows.

[0128]

[0129] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), aminoacetonitrile hydrochloride (0.44 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.140 g of a yellow solid, with a yield of 52%.

[0130] Example 25: Preparation of N-cyclopropyl-2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0131] The methods for steps one through four are the same as in Example 15, except that in step five, the amine used is cyclopropylamine. The reaction route, operation, and physicochemical data of the product in step five are as follows.

[0132]

[0133] 2-(2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.25 g, 1 mmol), cyclopropylamine (0.45 g, 2 mmol), and N,N-diisopropylethylamine (0.127 g, 2.5 mmol) were added to a 50 ml round-bottom flask containing 15 ml of DMF. After stirring at room temperature for 30 min, HATU (0.225 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to precipitate the solid, which was then filtered and purified by column chromatography to give 0.112 g of a yellow solid, with a yield of 42%.

[0134] Compounds 1-25 can be prepared using the above examples. The physicochemical properties of compounds 1-25 are shown in Table 1; the NMR data of compounds 1-25 are shown in Table 2.

[0135] Table 1. Physicochemical properties of compounds 1-25

[0136] serial number <![CDATA[R 6 ]]> Properties Yield 1 <![CDATA[CH2CHF2]]> Yellow solid 60％ 2 <![CDATA[CH3]]> Yellow solid 60％ 3 <![CDATA[CH2CH3]]> Yellow solid 57％ 4 <![CDATA[CH2CH2CH3]]> Yellow solid 61％ 5 <![CDATA[CH2CH2CH2CH3]]> Yellow solid 73％ 6 <![CDATA[CH2COOCH3]]> Yellow solid 55％ 7 <![CDATA[CH2COOCH2CH3]]> Yellow solid 55％ 8 <![CDATA[CH2CN]]> Yellow solid 56％ 9 <![CDATA[CH2(CH3)CHSCH3]]> Yellow solid 47％ 10 <![CDATA[(CH3)2]]> Yellow solid 46％ 11 <![CDATA[CH(CH2)2]]> Yellow solid 46％ 12 <![CDATA[CH2CH( C H2)2]]> Yellow solid 44％ 13 <![CDATA[CH2CH(CH2)3]]> Yellow solid 45％ 14 <![CDATA[CH2CH(CH2)4]]> Yellow solid 48％ 15 <![CDATA[CH2CHF2]]> Yellow solid 60％ 16 <![CDATA[CH3]]> Yellow solid 71％ 17 <![CDATA[CH2CH3]]> Yellow solid 48％ 18 <![CDATA[CH2CH2CH3]]> Yellow solid 41％ 19 <![CDATA[CH(CH3)2]]> Yellow solid 38％ 20 <![CDATA[CH2COOCH3]]> Yellow solid 39％ 21 <![CDATA[CH2COOCH2CH3]]> Yellow solid 39％ 22 <![CDATA[CH2CN]]> Yellow solid 37％ 23 <![CDATA[CH2(CH3)CHSCH3]]> Yellow solid 46％ 24 <![CDATA[(CH3)2]]> Yellow solid 52％ 25 <![CDATA[CH(CH2)2]]> Yellow solid 42％

[0137] Table 2. 1H NMR spectra of compounds 1-25 ( 1 H NMR data

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144] Example 26: Activity test of the compound against diamondback moth

[0145] Freshly prepared cabbage discs were immersed in a solution containing the compound for 30 seconds, air-dried, and placed in petri dishes lined with filter paper. Fifteen third-instar diamondback moths were then carefully transferred to the petri dishes. The petri dishes were stored in an incubator at 26°C and 85% relative humidity, with a light / dark ratio of 16:8. The mortality rate was assessed after 3 days. Each activity test was repeated three times (15 larvae per test). The larvae's body was gently touched. If it could not crawl normally, it was considered dead.

[0146] Corrected lethality rate = XY / X × 100%

[0147] Where X represents the percentage of total live larvae, and Y represents the percentage of surviving larvae after treatment in the petri dish. Data on the antidiarrheal activity of some compounds in Formula I are shown in Table 3.

[0148] Table 3 shows the anti-diarrheal activity data of some compounds in Formula I.

[0149]

[0150]

[0151] As shown in Table 3, some of the Formula I compounds provided by this invention exhibit certain insecticidal activity against the tested diamondback moth. In particular, some compounds show significant control efficacy against the diamondback moth and corn borer. For example, compounds 8, 15, 16, 17, 18, 22, 23, and 25 have a 100% lethality rate against the diamondback moth at concentrations above 50 μg / ml, comparable to the control agent Fluralaner; thus, they show promise as insecticides for controlling the agricultural pest, the diamondback moth.

[0152] Example 27: Activity test of the compound against the corn borer

[0153] A 5000 mg / L stock solution of the target compound was prepared by dissolving it in dimethyl sulfoxide (DMSO) and serially diluted to different concentrations with 0.05% (w / v) Triton X-100. Equal volumes of DMSO and 0.05% (w / v) Triton X-100 were added to a blank. Artificial feed was added to 24-well plates, and after the feed cooled and solidified, 100 μL of the target compound solution was added to the surface of the feed. After drying at room temperature, third-instar larvae were transferred to each well. Each concentration was replicated three times (24 larvae per replicate). Finally, the 24-well plates were stored in an incubator at 26°C and 85% relative humidity with a light / dark ratio of 16:8. Larval mortality was recorded at 48 hours. Larvae were considered dead if they could not crawl normally when gently touched with a needle.

[0154] Corrected lethality (%) = (TC) × 100 / (100% - C%)

[0155] Where T represents the mortality rate in the test compound group and C represents the mortality rate in the blank control group. All these parameters are expressed as a percentage.

[0156] Table 4 shows the activity data of some compounds in Formula I for corn borer.

[0157]

[0158] As can be seen from Table 4, some of the Formula I compounds provided by this invention have certain insecticidal activity against the tested corn borer. For example, compounds 15, 20, and 22 showed a 100% lethality against the corn borer at a concentration of 250 μg / ml, comparable to the control Fluralaner; they show promise as insecticides for controlling the agricultural pest corn borer.

[0159] Example 28 Activity test of fall armyworm

[0160] A 5000 mg / L stock solution of the target compound was prepared by dissolving it in dimethyl sulfoxide (DMSO) and serially diluted to different concentrations with 0.05% (w / v) Triton X-100. Equal volumes of DMSO and 0.05% (w / v) Triton X-100 were added to a blank. Artificial feed was added to 24-well plates, and after the feed cooled and solidified, 100 μL of the target compound solution was added to the surface of the feed. After drying at room temperature, third-instar larvae were transferred to each well. Each concentration was replicated three times (24 larvae per replicate). Finally, the 24-well plates were stored in an incubator at 26°C and 85% relative humidity with a light / dark ratio of 16:8. Larval mortality was recorded at 48 hours. Larvae were considered dead if they could not crawl normally when gently touched with a needle.

[0161] Corrected lethality (%) = (TC) × 100 / (100 - C)%

[0162] Where T represents the mortality rate in the test compound group and C represents the mortality rate in the blank control group. All these parameters are expressed as a percentage.

[0163] Table 5 shows the activity data of some compounds in Formula I for *Pteris vittata* in *Pteris vittata*.

[0164]

[0165]

[0166] As can be seen from Table 5, some of the Formula I compounds provided by this invention have certain insecticidal activity against the tested fall armyworm. For example, compound 10 has a 100% lethality against fall armyworm at a concentration of 200 μg / ml, which is comparable to the control Fluralaner; it shows promise as an insecticide for controlling the agricultural pest fall armyworm.

[0167] In summary, the compound of Formula I described in this invention has good insecticidal activity against diamondback moth, corn borer and fall armyworm, and can be used as a candidate agent for the control of these pests, which is conducive to the green control of these pests.

Claims

1. An amide derivative containing a thiophene structure, characterized in that: Its structural formula is as follows: Where: R 1 , R 2 , R 3 is hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 haloalkoxy; R 4 is hydrogen, halogen, cyano, nitro, C1-C6 alkyl or C1-C6 haloalkyl; R 5 is hydrogen, halogen, nitro, hydroxyl, amino, mercapto, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 cycloalkyl or C1-C6 aryl; R 6 It is a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 cycloalkyl group or a C1-C6 aryl group.

2. The amide derivative containing a thiophene structure according to claim 1, characterized in that: R 1 , R 2 , R 3 is hydrogen or halogen; R 4 is C1~C6 alkyl or C1~C6 haloalkyl; R 5 is a C1-C6 cycloalkyl group or a C1-C6 aryl group; R 6 It is nitro, C1~C6 alkyl, C1~C6 cycloalkyl or C1~C6 aryl.

3. The amide derivative containing a thiophene structure according to claim 1, characterized in that: R 1 and R 3 is chlorine; R 2 is hydrogen or chlorine; R 4 is trifluoromethyl; R 5 is methyl; R 6 It is 2,2-difluoroethylamino, methylamino, ethylamino, propylamino, butylamino, glycine methyl ester hydrochloride, glycine ethyl ester hydrochloride, aminoacetonitrile hydrochloride, (R)-1-methylthio-2-propylamine, dimethylamine, cyclopropylamine, cyclopropylmethylamine, (aminomethyl)cyclopentane, and cyclobutylmethylamine.

4. A method for preparing an amide derivative containing a thiophene structure according to any one of claims 1 to 3, characterized in that:

5. The method for preparing an amide derivative containing a thiophene structure according to claim 4, characterized in that: Specifically, it comprises the following steps: (1) adding a compound of formula II, an aqueous solution of hydroxylamine hydrochloride and an organic solvent into a round-bottom flask, adjusting the pH of the reaction solution to neutral with a saturated alkaline solution to obtain a compound of formula III, wherein the molar ratio of the compound of formula II: hydroxylamine hydrochloride: organic solvent is 1:1-3:2-5, and reacting at -5°C to 40°C to obtain the compound of formula III; (2) After the compound of formula III is chlorinated with a chlorinating agent, it is reacted with a compound of formula IV in an organic solvent to obtain a compound of formula V, wherein the molar ratio of the compound of formula III: the chlorinating agent: the compound of formula IV: the organic solvent is 1:1-4:1-3:2-8, and the reaction is carried out at -5°C to 50°C to obtain the compound of formula V; (3) hydrolyzing the compound of formula V to obtain a compound of formula VI, wherein the hydrolysis solvent is a mixture of one or more of water, methanol, ethanol, tetrahydrofuran or dioxane; (4) The compound of formula VI is reacted with a chlorination agent or a condensation agent for 1 to 8 hours, and then the compound of formula VII and a base are added to react in an organic solvent to obtain the compound of formula I.

6. The method for preparing an amide derivative containing a thiophene structure according to claim 5, characterized in that: The molar ratio of the reactants used is 1:1-5:1-2:1-2.5:2-8.

7. The method for preparing an amide derivative containing a thiophene structure according to claim 5, characterized in that: The chlorination reagent used is one or more of thionyl chloride, thionyl chloride, oxalyl chloride, phosgene, phosphorus trichloride or phosphorus pentachloride; the condensation reagent used is dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), diisopropylcarbodiimide (DIC), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIEA), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOBt).

8. The method for preparing an amide derivative containing a thiophene structure according to claim 5, characterized in that: The base is triethylamine, N,N-diisopropylethylamine, pyridine, piperidine, 3-methylpyridine, N-methylmorpholine, 3-methylimidazole, alkali metal alcoholate, sodium hydroxide, potassium hydroxide or lithium hydroxide; the organic solvent used is dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile or N,N-dimethylformamide.

9. Use of an amide derivative containing a thiophene structure as claimed in any one of claims 1 to 3 in the preparation of pesticides for controlling agricultural pests.

10. The use according to claim 9, characterized in that: The agricultural pests include diamondback moth, corn borer and fall armyworm.

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