Bisamide-containing isoxazoline derivative as well as preparation method and application thereof

Abstract

The invention relates to the field of chemical engineering and pesticides, in particular to an isoxazoline derivative containing bisamide as well as a preparation method and application of the isoxazoline derivative. The bisamide-containing isoxazoline derivative is a compound as shown in a formula (1). The novel bisamide-containing isoxazoline derivative is obtained by combining an isoxazoline structure and a bisamide structure and carrying out special structural design, and the bisamide-containing isoxazoline derivative has no cross resistance with the existing insecticide, has low toxic and side effects, and can be applied to the field of pesticides. Meanwhile, the insecticidal composition has broad-spectrum insecticidal activity and an excellent insecticidal effect, and the problem that the pesticide resistance of pests such as spodoptera frugiperda and plutella xylostella is enhanced at present is effectively solved. Formula (1) # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the fields of chemical engineering and pesticides, and particularly relates to an isoxazoline derivative containing a bisamide, a preparation method thereof, and an application thereof. Background Art

[0002] In recent years, the prevention and control of Spodoptera frugiperda and Plutella xylostella have been in a severe situation, bringing great challenges to agricultural production. Long-term chemical control has made the resistance of the two to a variety of pesticides more prominent. According to relevant research, the resistance multiples of Plutella xylostella to commonly used pesticides such as abamectin and emamectin benzoate have been continuously increasing, and the resistance multiples of field populations in some areas are as high as hundreds of times, resulting in a significant reduction in the control effect of pesticides. At the same time, Spodoptera frugiperda has also developed varying degrees of resistance to traditional insecticides such as organophosphates, pyrethroids, carbamates, and some new insecticides, seriously restricting the effect of chemical control.

[0003] As a new type of five-membered nitrogen-oxygen heterocyclic pesticide, isoxazoline compounds have become a research hotspot in the field of pesticide chemistry due to their non-competitive allosteric regulation mechanism (NCAM). Compared with traditional insecticides, isoxazoline compounds have no cross-resistance. Their target is a new type of γ-aminobutyric acid receptor, with novel action sites and broad-spectrum insecticidal characteristics, and low toxic side effects on non-target organisms and good environmental compatibility. Due to their characteristics of high activity, broad-spectrum, and high selectivity, they have become a research hotspot in recent years. However, before this, isoxazoline compounds were mostly used to control animal parasites.

[0004] Bisamide insecticides are a type of insecticidal product that has received the most attention in the market after neonicotinoid insecticides, and they are also a type of insecticidal product with the fastest growing usage in recent years. Bisamide insecticides have novel and diverse structures, unique action mechanisms, and broad-spectrum insecticidal activities. At the same time, they have high insecticidal efficiency, long residual periods, high safety, and medium systemic activity, so they are widely used.

[0005] In view of the current situation that the resistance of Spodoptera frugiperda and Plutella xylostella to traditional insecticides has increased significantly, how to develop a new type of pesticide with no cross-resistance to existing insecticides and low toxicity and high efficiency based on the above insecticides is an urgent problem to be solved in this field. Summary of the Invention

[0006] The purpose of the present invention is to overcome the problems existing in the above-mentioned prior art, and provide an isoxazoline derivative containing a bisamide, a preparation method thereof, and an application thereof. The isoxazoline derivative containing a bisamide has excellent insecticidal effects.

[0007] To achieve the above purpose, on the one hand, the present invention provides an isoxazoline derivative containing a bisamide, and the isoxazoline derivative containing a bisamide is a compound shown in formula (1):

[0008] Formula (1)

[0009] Wherein each R 1 is independently selected from one or more of H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, hydroxy, cyano, nitro, and halogen; R 2 is selected from one or more of H and C1-C6 perfluoroalkyl; each R 3 is independently selected from one or more of H and C1-C6 alkyl; R 4 is selected from one or more of H and C1-C6 alkyl; R 5 is selected from one or more of, wherein R 6 is selected from one or more of C1-C6 alkylene; R 7 and R 8 are each independently selected from H, substituted or unsubstituted C1-C 20 alkyl, substituted or unsubstituted C1-C 20 alkoxy, substituted or unsubstituted C3-C 20 cycloalkyl, substituted or unsubstituted C6-C 20 aryl, substituted or unsubstituted C3-C 20 heterocyclic group, and halogen, wherein the substituents of the substituted C1-C 20 alkyl, substituted C1-C 20 alkoxy, substituted C3-C 20 cycloalkyl, substituted C6-C 20 aryl, and substituted C3-C 20 heterocyclic group are each independently selected from C1-C 12 alkyl, C1-C 12 alkoxy, C3-C 12 cycloalkyl, C1-C 12 perfluoroalkyl, C6-C 14 aryl, C3-C 13 heterocyclic group, halogen, and cyano.

[0010] The second aspect of the present invention provides a method for preparing the above-mentioned bisamide-containing isoxazoline derivative, the method comprising: condensing the compound represented by formula (G) with R 7 -NH-R 8 to obtain the compound represented by formula (1);

[0011] Formula (G)

[0012] The third aspect of the present invention provides the application of the above-mentioned bisamide-containing isoxazoline derivatives in pest control.

[0013] By combining the isoxazoline structure with the bisamide structure and carrying out special structural design, the present invention obtains a novel bisamide-containing isoxazoline derivative. This bisamide-containing isoxazoline derivative has no cross-resistance with existing insecticides, has low toxicity and side effects, and at the same time has broad-spectrum insecticidal activity and excellent insecticidal effects, effectively solving the problem of enhanced pesticide resistance of pests such as Spodoptera frugiperda and Plutella xylostella. Detailed implementation manners

[0014] In the ranges disclosed herein, the endpoints and any values are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0015] In the present invention, "substituted or unsubstituted C1-C 12 alkyl" means that the alkyl has 1 to 12 carbon atoms, and the H on these carbon atoms can be substituted by substituents or not; when substituted by substituents, the substituted H can be one or more. When multiple H are substituted, they can be H on the same carbon atom or H on different carbon atoms. The same applies to other similar expressions.

[0016] In the present invention, the alkyl in expressions such as "C1-C 12 alkyl", "C1-C6 alkyl" can be a straight-chain alkyl or a branched-chain alkyl. The same applies to other similar expressions. For example, the alkyl part in "C1-C6 alkoxy" can be straight-chain or branched; the alkyl part in "C6-C 20 aryl" can be straight-chain or branched; and the same is true for other similar expressions such as "C1-C 12 cycloalkyl".

[0017] One aspect of the present invention provides a bisamide-containing isoxazoline derivative, and this bisamide-containing isoxazoline derivative is a compound represented by formula (1):

[0018] Formula (1)

[0019] Wherein, each R 1 independently selects one or more from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, hydroxy, cyano, nitro, and halogen; R 2One or more selected from H and perfluoroalkyls of C1-C6; each R 3 Each independently selected from one or more of H and alkyls of C1-C6; R 4 Selected from one or more of H and alkyls of C1-C6; R 5 Selected from One or more of them, wherein R 6 Selected from one or more of alkylene groups of C1-C6, R 7 And R 8 Each independently selected from H, substituted or unsubstituted alkyls of C1-C 20 Substituted or unsubstituted alkoxys of C1-C 20 Substituted or unsubstituted cycloalkyls of C3-C 20 Substituted or unsubstituted aryls of C6-C 20 Substituted or unsubstituted heterocyclic groups of C3-C 20 And halogens, wherein the substituents of the substituted alkyls of C1-C 20 Substituted alkoxys of C1-C 20 Substituted cycloalkyls of C3-C 20 Substituted aryls of C6-C 20 Substituted heterocyclic groups of C3-C 20 Each independently selected from alkyls of C1-C 12 Alkoxys of C1-C 12 Cycloalkyls of C3-C 12 Perfluoroalkyls of C1-C 12 Aryls of C6-C 14 Heterocyclic groups of C3-C 13 Halogens and cyano groups.

[0020] According to the present invention, in order to further improve the insecticidal efficacy of the compound, the structure of the bisamide-containing isoxazoline derivatives can be further selected. Preferably, each R 1 Each independently selected from one or more of H, alkyls of C1-C3, alkoxys of C1-C3, perfluoroalkyls of C1-C3, hydroxyl groups, cyano groups, nitro groups and halogens; R 2 Selected from one or more of H and perfluoroalkyls of C1-C3; each R 3 Each independently selected from one or more of H and alkyls of C1-C3; R 4 Selected from one or more of H and alkyls of C1-C3; R 5 Selected from One or more of them, wherein R 6 Selected from one or more of alkylene groups of C1-C3, R 7 And R8 Each independently selected from H, substituted or unsubstituted C1-C 12 alkyl, substituted or unsubstituted C1-C 12 alkoxy, substituted or unsubstituted C3-C 12 cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C3-C 13 heterocyclic group, and one or more of halogens, wherein the substituted C1-C 12 alkyl, substituted C1-C 12 alkoxy, substituted C3-C 12 cycloalkyl, substituted C6-C 14 aryl, and the substituents of the substituted C3-C 13 heterocyclic group are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 perfluoroalkyl, C6-C 10 aryl, C3-C9 heterocyclic group, halogen, and cyano, one or more of them.

[0021] More preferably, each R 1 is each independently selected from one or more of H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, hexafluoroethyl, hydroxy, cyano, nitro, F, and Cl; R 2 is selected from one or more of H, trifluoromethyl, and hexafluoroethyl; each R 3 is each independently selected from one or more of H, methyl, ethyl, n-propyl, and isopropyl; R 4 is selected from one or more of H, methyl, ethyl, n-propyl, and isopropyl; R 5 is selected from one or more of them, wherein R 6 is selected from one or more of methylene, ethylene, n-propylene, and isopropylene; R 7 is selected from one or more of H, methyl, ethyl, n-propyl, and isopropyl; R 8 is selected from one or more of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C9 heterocyclic group, and halogen, wherein the substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C6 cycloalkyl, substituted C6-C 10 aryl, and the substituents of the substituted C3-C9 heterocyclic group are each independently selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl, C6-C10 One or more of aryl, C3-C9 heterocyclic group, halogen and cyano group.

[0022] More preferably, each R 1 Independently selected from one or more of H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, hexafluoroethyl, hydroxy, cyano, nitro, F and Cl; R 2 Selected from one or more of H, trifluoromethyl and hexafluoroethyl; each R 3 Independently selected from one or more of H, methyl, ethyl, n-propyl and isopropyl; R 4 Selected from one or more of H, methyl, ethyl, n-propyl and isopropyl; R 5 Selected from One or more of them, wherein, R 6 Selected from one or more of methylene, ethylene, n-propylene and isopropylene, R 7 Selected from one or more of H, methyl, ethyl, n-propyl and isopropyl, R 8 Selected from one or more of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C9 heterocyclic group and halogen, wherein the substituents of substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C6 cycloalkyl, substituted C6-C 10 Aryl and substituted C3-C9 heterocyclic group are independently selected from methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, hexafluoroethyl, phenyl, benzyl, One or more of F, Cl, Br and cyano group.

[0023] More preferably, at least two Rs 1 Selected from F and / or Cl, more preferably at least two Rs 1 Are Cl, even more preferably, the bisamide-containing isoxazoline derivatives are the compounds shown in formula (1-x):

[0024] Formula (1-x)

[0025] In a preferred embodiment of the present invention, R 5 Selected from the following groups:

[0026]

[0027] According to a preferred embodiment of the present invention, the bisamide-containing isoxazoline derivatives are selected from one or more of the compounds represented by the following formula:

[0028]

[0029]

[0030]

[0031] According to a particularly preferred embodiment of the present invention, the bisamide-containing isoxazoline derivatives are selected from one or more of the compounds represented by the following formula:

[0032]

[0033]

[0034] According to a preferred embodiment of the present invention, the bisamide-containing isoxazoline derivatives are selected from one or more of the optical isomers represented by the following formula:

[0035]

[0036] According to a particularly preferred embodiment of the present invention, the bisamide-containing isoxazoline derivatives are selected from one or more of the optical isomers represented by the following formula:

[0037]

[0038]

[0039] In a second aspect of the present invention, there is provided a method for preparing the above-mentioned bisamide-containing isoxazoline derivatives, the method comprising: condensing the compound represented by formula (G) with R 7 -NH-R 8 to obtain the compound represented by formula (1);

[0040] Formula (G)

[0041] According to the present invention, in order to improve the yield of the reaction, preferably, relative to 1 mmol of the compound represented by formula (G), the amount of R 7 -NH-R 8 is 0.6 - 2 mmol, preferably 1 - 1.5 mmol, and for example, it can be values such as 1 mmol, 1.1 mmol, 1.3 mmol, and 1.5 mmol and the ranges between any of these values.

[0042] According to the present invention, in order for the condensation reaction to proceed smoothly, preferably, the condensation reaction is carried out in the presence of a first basic reagent.

[0043] Preferably, the first basic reagent is selected from one or more of triethylamine, pyridine, sodium hydroxide, potassium hydroxide, 3-methylpyridine, and N,N-diisopropylethylamine, preferably one or more of triethylamine, pyridine, potassium hydroxide, and sodium hydroxide.

[0044] Preferably, relative to 1 mmol of the compound represented by formula (G), the amount of the first basic reagent used is 1 - 8 mmol, preferably 2 - 5 mmol, and for example, it can be values such as 2 mmol, 3 mmol, 4 mmol, and 5 mmol and the ranges between any of these values.

[0045] According to the present invention, in order to obtain a better reaction effect, preferably, the condensation reaction is carried out in the presence of a first condensing agent.

[0046] Preferably, the first condensing agent is selected from one or more of EDCl, HOBt, DCC, DMAP, DIC, and HATU, preferably EDCl and / or HOBt, and more preferably an EDCl / HOBt mixed condensing agent with a molar ratio of 1:0.8 - 1.2 (for example, it can be values such as 1:0.8, 1:1, 1:1.1, and 1:1.2 and the ranges between any of these values).

[0047] Preferably, relative to 1 mmol of the compound represented by formula (G), the amount of the first condensing agent used is 1 - 8 mmol, preferably 2 - 5 mmol, and for example, it can be values such as 2 mmol, 3 mmol, 4 mmol, and 5 mmol and the ranges between any of these values.

[0048] According to the present invention, in order to provide a good reaction environment, preferably, the solvent for the condensation reaction is selected from one or more of dichloromethane, chloroform, toluene, xylene, ether, and tetrahydrofuran, preferably dichloromethane and / or chloroform.

[0049] Preferably, relative to 1 mmol of the compound represented by formula (G), the amount of the solvent for the condensation reaction used is 2 - 15 mL, preferably 5 - 8 mL, and for example, it can be values such as 5 mL, 6 mL, 7 mL, and 8 mL and the ranges between any of these values.

[0050] According to the present invention, in order to make the reaction proceed more smoothly and obtain a higher yield and purity, preferably, the conditions for the condensation reaction include: a temperature of 10 - 40 °C and a time of 4 - 24 h; more preferably, the conditions for the condensation reaction include: a temperature of 20 - 30 °C (for example, it can be values such as 20 °C, 22 °C, 25 °C, and 30 °C and the ranges between any of these values) and a time of 8 - 16 h (for example, it can be values such as 8 h, 10 h, 12 h, and 16 h and the ranges between any of these values).

[0051] According to the present invention, in order to avoid the generation of impurities, preferably, the condensation reaction is carried out in an inert gas atmosphere. Among them, the inert gas can be, for example, nitrogen and / or argon.

[0052] According to the present invention, after the condensation reaction is completed, the reaction solution can be post-treated. The post-treatment method can be selected within a relatively wide range. Preferably, the post-treatment method of the condensation reaction includes: extracting the reaction solution (for example, extracting with dichloromethane after adding water), washing (for example, washing with saturated brine), drying (for example, drying with desiccants such as anhydrous sodium sulfate and anhydrous magnesium sulfate), and after the organic phase is concentrated by rotary evaporation of the solvent, the product is separated by column chromatography (for example, using a dichloromethane / methanol mixed solvent with a volume ratio of 50:1 as the eluent).

[0053] According to the present invention, in the preparation method of the above-mentioned isoxazoline derivatives containing diamide, the preparation method of the compound represented by formula (G) can also be included. Among them, the preparation method of the compound represented by formula (G) can be selected within a relatively wide range. Preferably, the preparation method of the compound represented by formula (G) includes: subjecting the compound represented by formula (F) to a hydrolysis reaction to obtain the compound represented by formula (G);

[0054] Formula (F) Among them, R is selected from C1-C6 alkyl groups.

[0055] According to the present invention, in order to achieve a better hydrolysis effect, preferably, the hydrolysis reaction is carried out in the presence of a second basic reagent, and the second basic reagent in the hydrolysis reaction is selected from sodium hydroxide and / or potassium hydroxide.

[0056] Preferably, relative to 1 mmol of the compound represented by formula (F), the amount of the second basic reagent used is 1-8 mmol, preferably 3-6 mmol, and can be, for example, numerical values such as 3 mmol, 4 mmol, 5 mmol, and 6 mmol and the ranges between any of these numerical values.

[0057] According to the present invention, in order to make the hydrolysis reaction proceed better, the solvent and its amount used in the hydrolysis reaction can be adjusted. Preferably, the solvent for the hydrolysis reaction is selected from one or more of water, methanol, and ethanol, preferably a water / ethanol mixed solvent with a volume ratio of 1:2-5, and more preferably a water / ethanol mixed solvent with a volume ratio of 1:3-4 (for example, numerical values such as 1:3, 1:3.5, 1:3.8, and 1:4 and the ranges between any of these numerical values).

[0058] Preferably, relative to 1 mmol of the compound represented by formula (F), the amount of the solvent used in the hydrolysis reaction is 5 - 20 mL, preferably 8 - 15 mL, and can be, for example, values such as 8 mL, 10 mL, 12 mL, and 15 mL, and ranges between any of these values.

[0059] According to the present invention, in order to promote the reaction, preferably, the conditions of the hydrolysis reaction include: a temperature of 60 - 100 °C and a time of 4 - 24 h; more preferably, the conditions of the hydrolysis reaction include: a temperature of 70 - 90 °C (which can be, for example, values such as 70 °C, 80 °C, 85 °C, and 90 °C, and ranges between any of these values), and a time of 8 - 16 h (which can be, for example, values such as 8 h, 10 h, 12 h, and 16 h, and ranges between any of these values).

[0060] According to the present invention, in order to avoid the generation of impurities, preferably, the hydrolysis reaction is carried out in an inert gas atmosphere. Among them, the inert gas can be, for example, nitrogen and / or argon.

[0061] According to the present invention, after the hydrolysis reaction is completed, the reaction solution can be post-treated. The post-treatment method can be selected within a relatively wide range. Preferably, the post-treatment method of the hydrolysis reaction includes: extracting the reaction solution (for example, extracting with dichloromethane), adjusting the pH of the aqueous phase to acidic (for example, adjusting the pH of the aqueous phase to 3 - 5 with a 2 M hydrochloric acid aqueous solution), extracting the aqueous phase again (for example, extracting with dichloromethane), and obtaining the product after removing the solvent by rotary evaporation from the organic phase.

[0062] According to the present invention, in the preparation method of the above-mentioned isoxazoline derivatives containing bisamide, it may further include the preparation method of the compound represented by formula (F). Among them, the preparation method of the compound represented by formula (F) can be selected within a relatively wide range. Preferably, the preparation method of the compound represented by formula (F) includes: reacting the compound represented by formula (E) with to carry out an amidation reaction to obtain the compound represented by formula (F);

[0063] Formula (E)

[0064] According to the present invention, in order to improve the product yield and purity, preferably, relative to 1 mmol of the compound represented by formula (E), the amount used is 0.6 - 2 mmol, preferably 1 - 1.5 mmol, and can be, for example, values such as 1 mL, 1.1 mL, 1.3 mL, and 1.5 mL, and ranges between any of these values.

[0065] According to the present invention, in order to obtain a better reaction effect, preferably, the amidation reaction is carried out in the presence of a third basic reagent.

[0066] Preferably, the third basic reagent is selected from one or more of triethylamine, pyridine, sodium hydroxide, potassium hydroxide, 3-methylpyridine, and N,N-diisopropylethylamine, preferably one or more of triethylamine, pyridine, potassium hydroxide, and sodium hydroxide.

[0067] Preferably, relative to 1 mmol of the compound represented by formula (E), the amount of the third basic reagent used is 1 - 8 mmol, preferably 2 - 5 mmol, and can be, for example, numerical values such as 2 mmol, 3 mmol, 4 mmol, and 5 mmol and ranges between any of these numerical values.

[0068] According to the present invention, in order to further improve the reaction efficiency, preferably, the amidation reaction is carried out in the presence of a second condensing agent.

[0069] Preferably, the second condensing agent is selected from one or more of EDCl, HOBt, DCC, DMAP, DIC, and HATU, preferably EDCl and / or HOBt, and more preferably an EDCl / HOBt mixed condensing agent with a molar ratio of 1:0.8 - 1.2 (which can be, for example, numerical values such as 1:0.8, 1:1, 1:1.1, and 1:1.2 and ranges between any of these numerical values).

[0070] Preferably, relative to 1 mmol of the compound represented by formula (E), the amount of the second condensing agent used is 1 - 8 mmol, preferably 2 - 5 mmol, and can be, for example, numerical values such as 2 mmol, 3 mmol, 4 mmol, and 5 mmol and ranges between any of these numerical values.

[0071] According to the present invention, in order to provide a good reaction environment, preferably, the solvent for the amidation reaction is selected from one or more of dichloromethane, chloroform, toluene, xylene, ether, and tetrahydrofuran, preferably dichloromethane and / or chloroform.

[0072] Preferably, relative to 1 mmol of the compound represented by formula (E), the amount of the solvent for the amidation reaction used is 2 - 15 mL, preferably 5 - 8 mL, and can be, for example, numerical values such as 5 mL, 6 mL, 7 mL, and 8 mL and ranges between any of these numerical values.

[0073] According to the present invention, in order to obtain a better product, the reaction conditions of the amidation reaction can be adjusted. Preferably, the conditions of the amidation reaction include: temperature is 10 - 40 °C, time is 4 - 24 h; more preferably, the conditions of the amidation reaction include: temperature is 20 - 30 °C (which can be, for example, numerical values such as 20 °C, 22 °C, 25 °C, and 30 °C and ranges between any of these numerical values), time is 8 - 16 h (which can be, for example, numerical values such as 8 h, 10 h, 12 h, and 16 h and ranges between any of these numerical values).

[0074] According to the present invention, in order to avoid the generation of impurities, preferably, the amidation reaction is carried out in an inert gas atmosphere. Among them, the inert gas can be, for example, nitrogen and / or argon.

[0075] According to the present invention, after the amidation reaction is completed, the reaction solution can be post-treated. The post-treatment method can be selected within a relatively wide range. Preferably, the post-treatment method of the amidation reaction includes: extracting the reaction solution (for example, extracting with dichloromethane after adding water), washing (for example, washing with saturated brine), drying (for example, drying with desiccants such as anhydrous sodium sulfate and anhydrous magnesium sulfate), removing the solvent from the organic phase by rotary evaporation, and then separating the product by column chromatography (for example, using a dichloromethane / methanol mixed solvent with a volume ratio of 50:1 as the eluent).

[0076] According to the present invention, in the preparation method of the above-mentioned isoxazoline derivatives containing bisamide, the preparation method of the compound represented by formula (E) can also be included. Among them, the preparation method of the compound represented by formula (E) can be selected within a relatively wide range. Preferably, the preparation method of the compound represented by formula (E) includes: carrying out a first hydrolysis reaction on the compound represented by formula (D) to obtain the compound represented by formula (E);

[0077] Formula (D)

[0078] According to the present invention, in order to achieve a better hydrolysis effect, preferably, the first hydrolysis reaction is carried out in the presence of a fourth basic reagent, and the fourth basic reagent is selected from sodium hydroxide and / or potassium hydroxide.

[0079] Preferably, relative to 1 mmol of the compound represented by formula (D), the amount of the fourth basic reagent used is 2 - 10 mmol, preferably 4 - 8 mmol, and can be, for example, values such as 4 mmol, 6 mmol, 7 mmol, and 8 mmol and the ranges between any of these values.

[0080] According to the present invention, in order for the first hydrolysis reaction to proceed better, the solvent and its amount used in the first hydrolysis reaction can be adjusted. Preferably, the solvent for the first hydrolysis reaction is selected from one or more of water, methanol, and ethanol, preferably a water / ethanol mixed solvent with a volume ratio of 1:2 - 5, and more preferably a water / ethanol mixed solvent with a volume ratio of 1:3 - 4 (for example, values such as 1:3, 1:3.5, 1:3.8, and 1:4 and the ranges between any of these values).

[0081] Preferably, relative to 1 mmol of the compound represented by formula (D), the amount of the solvent for the first hydrolysis reaction used is 5 - 20 mL, preferably 8 - 15 mL, and can be, for example, values such as 8 mL, 10 mL, 12 mL, and 15 mL and the ranges between any of these values.

[0082] According to the present invention, in order to improve the yield and product purity of the first hydrolysis reaction, the reaction conditions of the first hydrolysis reaction can be adjusted. Preferably, the conditions of the first hydrolysis reaction include: the temperature is 60 - 150 °C, and the time is 4 - 24 h; more preferably, the conditions of the first hydrolysis reaction include: the temperature is 80 - 130 °C (such as numerical values like 80 °C, 100 °C, 120 °C, 130 °C, and the ranges between any of these numerical values), and the time is 8 - 16 h (such as numerical values like 8 h, 10 h, 12 h, 16 h, and the ranges between any of these numerical values).

[0083] According to the present invention, in order to avoid the generation of impurities, preferably, the first hydrolysis reaction is carried out in an inert gas atmosphere. Among them, the inert gas can be, for example, nitrogen and / or argon.

[0084] According to the present invention, after the first hydrolysis reaction is completed, the reaction solution can be post - treated. The post - treatment method can be selected within a relatively wide range. Preferably, the post - treatment method of the first hydrolysis reaction includes: extracting the reaction solution (for example, extracting with dichloromethane), adjusting the pH of the aqueous phase to acidic (for example, adjusting the pH of the aqueous phase to 3 - 5 with 2M hydrochloric acid aqueous solution), extracting the aqueous phase again (for example, extracting with dichloromethane), washing (for example, washing with saturated brine), drying (for example, drying with anhydrous sodium sulfate), and the product is obtained after the solvent in the organic phase is removed by rotary evaporation.

[0085] According to the present invention, in the preparation method of the above isoxazoline derivatives containing bis - amide, the preparation method of the compound shown in formula (D) can also be included. Among them, the preparation method of the compound shown in formula (D) can be selected within a relatively wide range. Preferably, the preparation method of the compound shown in formula (D) includes: carrying out a substitution reaction between the compound shown in formula (C) and a cyanide to obtain the compound shown in formula (D);

[0086] Formula (C)

[0087] According to the present invention, in order to obtain a better reaction effect, the selection and dosage of the cyanide can be adjusted. Preferably, the cyanide is selected from one or more of zinc cyanide, copper cyanide, and potassium ferrocyanide.

[0088] Preferably, relative to 1 mmol of the compound shown in formula (C), the dosage of the cyanide is 0.5 - 3 mmol, preferably 1 - 2 mmol, such as numerical values like 1 mmol, 1.2 mmol, 1.5 mmol, 1.8 mmol, 2 mmol, and the ranges between any of these numerical values.

[0089] According to the present invention, in order to improve the reaction efficiency, preferably, the substitution reaction is carried out in the presence of a catalyst, and the catalyst is a palladium catalyst, and the palladium catalyst is selected from tetrakis(triphenylphosphine)palladium and / or dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium.

[0090] Preferably, relative to 1 mmol of the compound represented by formula (C), the amount of the catalyst used is 0.05 - 0.5 mmol, preferably 0.1 - 0.15 mmol, and for example, it can be values such as 0.1 mmol, 0.13 mmol, and 0.15 mmol and the ranges between any of these values.

[0091] According to the present invention, in order to make the reaction proceed more smoothly, the solvent for the substitution reaction and its amount can be adjusted. Preferably, the solvent for the substitution reaction is selected from one or more of toluene, N,N-dimethylformamide, N-methylpyrrolidone, xylene, and dimethyl sulfoxide, and preferably toluene and / or N,N-dimethylformamide.

[0092] Preferably, relative to 1 mmol of the compound represented by formula (C), the amount of the solvent for the substitution reaction used is 2 - 8 mL, preferably 3 - 5 mL, and for example, it can be values such as 3 mL, 3.5 mL, 4 mL, and 5 mL and the ranges between any of these values.

[0093] According to the present invention, in order to obtain a higher yield and purity, the reaction conditions of the substitution reaction can be adjusted. Preferably, the conditions of the substitution reaction include: the temperature is 80 - 180 °C, and the time is 4 - 24 h; more preferably, the conditions of the substitution reaction include: the temperature is 100 - 150 °C (for example, it can be values such as 100 °C, 120 °C, 140 °C, and 150 °C and the ranges between any of these values), and the time is 8 - 16 h (for example, it can be values such as 8 h, 10 h, 12 h, and 16 h and the ranges between any of these values).

[0094] According to the present invention, in order to avoid the generation of impurities, preferably, the substitution reaction is carried out in an inert gas atmosphere. Among them, the inert gas can be, for example, nitrogen and / or argon.

[0095] According to the present invention, after the substitution reaction is completed, the reaction solution can be post-treated. The post-treatment method can be selected within a relatively wide range. Preferably, the post-treatment method of the substitution reaction includes: filtering the reaction solution by suction, extracting the filtrate (for example, extracting with ethyl acetate), washing the organic phase (for example, washing with saturated brine), drying (for example, drying with anhydrous sodium sulfate), and after the solvent in the organic phase is removed by rotary evaporation, separating the product by column chromatography (for example, using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 20:1 to 10:1 as the eluent).

[0096] According to the present invention, the preparation method of the above-mentioned isoxazoline derivatives containing bisamides may also include a preparation method of the compound represented by formula (C). The preparation method of the compound represented by formula (C) may be selected from a wide range. Preferably, the preparation method of the compound represented by formula (C) comprises: contacting the compound represented by formula (B) with hydroxylamine hydrochloride to obtain the compound represented by formula (C);

[0097] Formula (B)

[0098] According to the present invention, in order to obtain a better reaction effect, preferably, relative to 1mmol of the compound represented by formula (B), the amount of hydroxylamine hydrochloride used is 0.5-3mmol, preferably 1-2mmol, for example, it can be 1mmol, 1.2mmol, 1.5mmol and 1.8mmol and the range of any value therebetween.

[0099] According to the present invention, in order to better carry out the reaction, preferably, the contact reaction is carried out in the presence of a fifth alkaline reagent, and the fifth alkaline reagent is selected from one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate, preferably sodium hydroxide and / or potassium hydroxide.

[0100] Preferably, the fifth alkaline agent is provided in the form of an aqueous solution with a concentration of 20-40 wt % (eg, 20 wt %, 30 wt %, 35 wt % and 40 wt % and any range therebetween).

[0101] Preferably, relative to 1 mmol of the compound represented by formula (B), the amount of the aqueous solution of the fifth alkaline agent used is 0.1-0.5 mL, for example, it can be 0.1 mL, 0.13 mL, 0.3 mL and 0.5 mL and any range therebetween.

[0102] According to the present invention, in order to make the materials fully contact and obtain better reaction effect, preferably, the solvent of the contact reaction is selected from one or more of methanol, ethanol and dichloromethane.

[0103] Preferably, relative to 1 mmol of the compound represented by formula (B), the amount of the solvent used in the contact reaction is 2-8 mL, preferably 3-5 mL, for example, 3 mL, 3.5 mL, 4 mL and 5 mL and any range therebetween.

[0104] According to the present invention, in order to obtain a product with better state and higher purity, the reaction conditions of the contact reaction can be adjusted. Preferably, the conditions of the contact reaction include: the temperature is 10 - 40 °C, and the time is 2 - 10 h; more preferably, the conditions of the contact reaction include: the temperature is 20 - 30 °C (for example, it can be values such as 20 °C, 22 °C, 25 °C, and 30 °C and the ranges between any of these values), and the time is 4 - 8 h (for example, it can be values such as 4 h, 5 h, 6 h, and 7 h and the ranges between any of these values).

[0105] According to the present invention, in order to avoid the generation of impurities, preferably, the contact reaction is carried out in an inert gas atmosphere. Among them, the inert gas can be, for example, nitrogen and / or argon.

[0106] According to the present invention, after the contact reaction is completed, the reaction solution can be post-treated. The post-treatment method can be selected within a relatively wide range. Preferably, the post-treatment method of the contact reaction includes: filtering the reaction solution by suction and washing (for example, washing the filter cake with water) to obtain the product.

[0107] According to the present invention, in the preparation method of the above-mentioned isoxazoline derivatives containing bisamide, the preparation method of the compound shown in formula (B) can also be included. Among them, the preparation method of the compound shown in formula (B) can be selected within a relatively wide range. Preferably, the preparation method of the compound shown in formula (B) includes: carrying out a first contact reaction between the compound shown in formula (A) and a dehydrating agent to obtain the compound shown in formula (B);

[0108] Formula (A)

[0109] According to the present invention, in order to make the first contact reaction proceed better, the selection and dosage of the dehydrating agent can be adjusted. Preferably, the dehydrating agent is selected from SOCl2 and / or trifluoroacetic acid.

[0110] Preferably, relative to 1 mmol of the compound shown in formula (A), the dosage of the dehydrating agent is 0.5 - 3 mmol, preferably 0.7 - 2 mmol, for example, it can be values such as 0.75 mmol, 1 mmol, 1.5 mmol, and 2 mmol and the ranges between any of these values.

[0111] According to the present invention, in order to make the reaction proceed smoothly, preferably, the first contact reaction is carried out in the presence of a sixth basic reagent, and the sixth basic reagent is one or more of pyridine, 4 - methylpyridine, N,N - diisopropylethylamine, and piperidine, preferably pyridine and / or N,N - diisopropylethylamine.

[0112] Preferably, relative to 1 mmol of the compound represented by formula (A), the amount of the sixth basic reagent is 5 - 10 mmol, preferably 6 - 8 mmol, and for example, it can be values such as 6 mmol, 6.5 mmol, 7 mmol, and 8 mmol and the ranges between any of these values.

[0113] According to the present invention, in order to improve the reaction rate, preferably, the solvent for the first contact reaction is selected from one or more of toluene, methyl tert-butyl ether, dichloromethane, chloroform, and acetonitrile, and preferably it is toluene and / or methyl tert-butyl ether.

[0114] Preferably, relative to 1 mmol of the compound represented by formula (A), the amount of the solvent for the first contact reaction is 1 - 8 mL, preferably 2 - 5 mL, and for example, it can be values such as 2 mL, 3 mL, 4 mL, and 5 mL and the ranges between any of these values.

[0115] According to the present invention, in order to reduce the occurrence of side reactions and obtain a better reaction effect, the reaction conditions of the first contact reaction can be adjusted. Preferably, the conditions of the first contact reaction include: the temperature is 40 - 90 °C and the time is 3 - 12 h; more preferably, the conditions of the first contact reaction include: the temperature is 50 - 80 °C (for example, it can be values such as 50 °C, 65 °C, 70 °C, and 80 °C and the ranges between any of these values), and the time is 5 - 8 h (for example, it can be values such as 5 h, 6 h, 7 h, and 8 h and the ranges between any of these values).

[0116] According to the present invention, in order to avoid the generation of impurities, preferably, the first contact reaction is carried out in an inert gas atmosphere. Among them, the inert gas can be, for example, nitrogen and / or argon.

[0117] According to the present invention, after the first contact reaction is completed, the reaction solution can be post-treated, and the post-treatment method can be selected within a relatively wide range. Preferably, the post-treatment method of the first contact reaction includes: extracting the reaction solution (for example, extracting with ethyl acetate after adding water), washing (for example, washing with water and saturated brine respectively), drying (for example, drying with anhydrous sodium sulfate), and the organic phase is concentrated to remove the solvent to obtain the product.

[0118] According to the present invention, in the preparation method of the above-mentioned isoxazoline derivatives containing bisamides, it may further include the preparation method of the compound represented by formula (A). Among them, the preparation method of the compound represented by formula (A) can be selected within a relatively wide range. Preferably, the preparation method of the compound represented by formula (A) includes: React with to carry out a second contact reaction to obtain the compound represented by formula (A).

[0119] According to the present invention, in order to obtain a good yield, preferably, relative to 1 mmol the dosage is 0.5 - 3 mmol, preferably 1 - 2 mmol, and for example, it can be values such as 1 mmol, 1.5 mmol, 1.8 mmol, and 2 mmol and the ranges between any of these values.

[0120] According to the present invention, in order for the reaction to proceed better, preferably, the second contact reaction is carried out in the presence of a seventh basic reagent, and the seventh basic reagent is selected from one or more of triethylamine, DBN, DBU, diethylamine, potassium tert - butoxide, and sodium hydroxide, and preferably one or more of triethylamine, DBN, DBU, and diethylamine.

[0121] Preferably, relative to 1 mmol the dosage of the seventh basic reagent is 0.4 - 2 mmol, preferably 0.6 - 1.5 mmol, and for example, it can be values such as 1 mmol, 1.5 mmol, 1.8 mmol, and 2 mmol and the ranges between any of these values.

[0122] According to the present invention, in order to obtain a higher reaction efficiency, the solvent and its dosage for the second contact reaction can be adjusted. Preferably, the solvent for the second contact reaction is selected from one or more of toluene, methyl tert - butyl ether, dichloromethane, chloroform, and acetonitrile, and preferably toluene and / or methyl tert - butyl ether.

[0123] Preferably, relative to 1 mmol the dosage of the solvent for the second contact reaction is 2 - 10 mL, preferably 4 - 8 mL, and for example, it can be values such as 4 mL, 5 mL, 6 mL, and 8 mL and the ranges between any of these values.

[0124] According to the present invention, in order to achieve a better reaction effect, preferably, the conditions for the second contact reaction include: the temperature is 40 - 90 °C, and the time is 3 - 12 h; more preferably, the conditions for the second contact reaction include: the temperature is 50 - 80 °C (for example, it can be values such as 50 °C, 65 °C, 70 °C, and 80 °C and the ranges between any of these values), and the time is 5 - 8 h (for example, it can be values such as 5 h, 6 h, 7 h, and 8 h and the ranges between any of these values).

[0125] According to the present invention, in order to avoid the generation of impurities, preferably, the second contact reaction is carried out in an inert gas atmosphere. Among them, the inert gas can be, for example, nitrogen and / or argon.

[0126] According to the present invention, after the second contact reaction is completed, the reaction solution can be post-treated, and the post-treatment method can be selected within a relatively wide range. Preferably, the post-treatment method for the second contact reaction includes: removing the solvent from the reaction solution by rotary evaporation and then separating the product by column chromatography (for example, using a petroleum ether / ethyl acetate mixed solvent with a volume ratio of 25:1 as the eluent).

[0127] The third aspect of the present invention provides the application of the above-mentioned bisamide-containing isoxazoline derivatives in pest control. Among them, the bisamide-containing isoxazoline derivatives have better selectivity and excellent insecticidal effects against Spodoptera frugiperda and Plutella xylostella.

[0128] By combining the isoxazoline structure with the bisamide structure and conducting special structural design, the present invention obtains a novel bisamide-containing isoxazoline derivative. This bisamide-containing isoxazoline derivative has no cross-resistance with existing insecticides, low toxicity and side effects, and at the same time has broad-spectrum insecticidal activity and excellent insecticidal effects, effectively solving the problem of enhanced pesticide resistance of pests such as Spodoptera frugiperda and Plutella xylostella at present. The insecticidal activity of the bisamide-containing isoxazoline derivative of the present invention against Spodoptera frugiperda and Plutella xylostella can be as high as 100%.

[0129] The present invention will be described in detail below through examples.

[0130] In the following examples, the apparatuses used are all conventional experimental apparatuses in the art, the operations adopted are all conventional operations in the art, and the raw materials, reagents, etc. used can all be obtained through commercial purchase. Among them, tetrakis(triphenylphosphine)palladium catalyst and NH2-R 8 each of the compounds shown is purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.

[0131] Examples 1 - 42

[0132] This example is used to illustrate the preparation process of the bisamide-containing isoxazoline derivatives shown in formulas (1-1) to (1-32), and the preparation process of the optical isomers of the bisamide-containing isoxazoline derivatives shown in formulas (1-1), (1-7), (1-8), (1-9) and (1-10).

[0133]

[0134] (1) Under a nitrogen atmosphere, 10 mmol was added to 50 mL of toluene, 13 mmol of DBN was slowly added, and the reaction was carried out at room temperature for 30 min. Then 15 mmol React at 65 °C for 7 h. After the reaction is completed, cool to room temperature, rotary evaporate the reaction solution and separate by column chromatography (the eluent is a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of 25:1) to obtain the compound shown by formula (A-a).

[0135] (2) Under a nitrogen atmosphere, add 39 mmol of the compound shown by formula (A-a) to 123 mL of toluene, slowly add 58.5 mmol of SOCl2 and 273 mmol of pyridine under an ice bath, and react at 70 °C for 7 h. After the reaction is completed, cool to room temperature, extract the reaction solution with ethyl acetate, wash the organic phase with water and saturated brine respectively, dry over anhydrous sodium sulfate, rotary evaporate to obtain the compound shown by formula (B-a).

[0136] (3) Under a nitrogen atmosphere, add 36.8 mmol of the compound shown by formula (B-a) to 168 mL of ethanol, add 36.8 mmol of hydroxylamine hydrochloride, slowly add 5 mL of 30 wt% aqueous sodium hydroxide solution, and react at 25 °C for 5 h. After the reaction is completed, filter the reaction solution and wash the filter cake with water to obtain the compound shown by formula (C-a).

[0137] (4) Under an argon atmosphere, add 20 mmol of the compound shown by formula (C-a) to 100 mL of N,N-dimethylformamide, add 2 mmol of tetrakis(triphenylphosphine)palladium catalyst and 30 mmol of zinc cyanide, and react at 150 °C for 16 h. After the reaction is completed, cool to room temperature, filter the reaction solution, extract the filtrate with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, rotary evaporate and separate by column chromatography (the eluent is a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of 20:1 to 10:1) to obtain the compound shown by formula (D-a).

[0138] (5) Under a nitrogen atmosphere, add 12.4 mmol of the compound shown by formula (D-a) to 124 mL of a water / ethanol (volume ratio of 1:3) mixed solvent, slowly add 74.4 mmol of sodium hydroxide, and react at 128 °C for 12 h. After the reaction is completed, cool to room temperature, extract the reaction solution with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, rotary evaporate to obtain the compound shown by formula (E-a).

[0139] (6) Under a nitrogen atmosphere, add 11.5 mmol of the compound shown by formula (E-a) to 60 mL of dichloromethane, slowly add 23 mmol of triethylamine, 17.25 mmol of EDCl, 17.25 mmol of HOBt and 12.65 mmol React at 25 °C for 12 h. After the reaction is completed, the reaction solution is extracted with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The compound shown in formula (F-a) is obtained by column chromatography (the eluent is a dichloromethane / methanol mixed solvent with a volume ratio of 50:1).

[0140] (7) Under a nitrogen atmosphere, 11.3 mmol of the compound shown in formula (F-a) is added to 113 mL of a water / ethanol (volume ratio 1:3) mixed solvent, and 45.2 mmol of sodium hydroxide is slowly added. React at 80 °C for 12 h. After the reaction is completed, cool to room temperature. The reaction solution is extracted with dichloromethane. The aqueous phase is adjusted to pH 4 with 2 M hydrochloric acid aqueous solution and then extracted with dichloromethane again. The combined organic phases are concentrated by rotary evaporation to obtain the compound shown in formula (G-a).

[0141] (8) Under a nitrogen atmosphere, 1.5 mmol of the compound shown in formula (G-a) is added to 7.5 mL of dichloromethane, and 3 mmol of triethylamine, 2.25 mmol of EDCl, 2.25 mmol of HOBt, and 1.65 mmol of NH2-R 8 are added slowly. React at 25 °C for 12 h. After the reaction is completed, water is added to the reaction solution and extracted with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The compound shown in formula (1-a) is obtained by column chromatography (the eluent is a dichloromethane / methanol mixed solvent with a volume ratio of 50:1).

[0142] In Examples 1-42, NH2-R 8 and the structures of the prepared bisamide-containing isoxazoline derivatives and the yields of step (8) are shown in Table 1.

[0143] Table 1

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] Test Example

[0151] The bisamide-containing isoxazoline derivatives prepared in Examples 1-42, as well as lotilaner, S-lotilaner, and R-lotilaner, were subjected to bioactivity tests against Spodoptera frugiperda and Plutella xylostella.

[0152] Accurately weigh the test agent using an electronic analytical balance. Completely dissolve the original drug in acetone and add an aqueous solution of 0.1 wt% [Tween - 80] to prepare a stock solution with a certain concentration. Then, dilute it into a series of medicated solutions with the set concentrations using an aqueous solution of 0.1 wt% [Tween - 80].

[0153] Spraying method: Remove the surface wax layer of the cabbage leaves cultivated in the greenhouse, and use a hole punch to make circular leaf discs with a diameter of 3 cm. Use a manual sprayer to evenly spray the prepared medicated solution on both the front and back of the leaves, and then place them in a petri dish with a diameter of 6 cm containing filter paper. After natural air drying, introduce 10 neat and healthy test insects. Take three leaf discs for each medicated solution for spraying treatment, and set up a water treatment as a blank control group. Place the petri dishes in an observation room at a temperature of 25 ± 1°C and a relative humidity of 40 - 60%. After 72 hours, check the number of dead and alive insects and calculate the mortality rate. The calculation formula is: Mortality rate (%) = (Number of dead insects after applying the drug / Total number of insects after applying the drug) × 100; Corrected mortality rate (%) = [(Mortality rate after applying the drug - Mortality rate of the blank) / (1 - Mortality rate of the blank)] × 100.

[0154] The insecticidal activities of the target compounds against Plutella xylostella are shown in Table 2, and those against Spodoptera frugiperda are shown in Table 3.

[0155] Table 2

[0156]

[0157]

[0158] Table 3

[0159]

[0160] As can be seen from Table 2, at three concentrations of 200 mg / L, 100 mg / L, and 50 mg / L, most of the compounds prepared in Examples 1 - 42 have excellent insecticidal activities against Plutella xylostella, and the higher the concentration, the better the effect. The insecticidal activities of some compounds can be as high as 100%. As can be seen from Table 3, at three concentrations of 200 mg / L, 100 mg / L, and 50 mg / L, compared with Plutella xylostella, the insecticidal activities of the compounds prepared in Examples 1 - 42 against Spodoptera frugiperda are average, but the insecticidal activities of some compounds can still reach 100%. In addition, as can be seen from Table 2 and Table 3, the insecticidal activities of S - configuration compounds are better than those of R - configuration compounds.

[0161] To intuitively illustrate the performance and characterization process of the bisamide-containing isoxazoline derivatives prepared by the method of the present invention, the present invention exemplarily provides the identification results of the bisamide-containing isoxazoline derivatives prepared in Examples 1-42, including nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, nuclear magnetic resonance fluorine spectrum, high-resolution data, ee value of the single configuration compound, as well as appearance and melting point, as specifically shown in Table 4.

[0162] Table 4

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within the protection scope of the present invention.

Claims

1. An isoxazoline derivative containing a bisamide, characterized in that: The isoxazoline derivative containing bisamide is a compound represented by formula (1): Formula (1) Among them, each R 1 Each is independently selected from one or more of H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkyl, hydroxyl, cyano, nitro and halogen; R 2 One or more selected from H and C1-C6 perfluoroalkyl; each R 3 Each independently selected from one or more of H and C1-C6 alkyl; R 4 One or more selected from H and C1-C6 alkyl; R 5 Selected from One or more of the following, where R 6 One or more selected from C1-C6 alkylene groups, R 7 and R 8 are each independently selected from H, substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C1-C 20 Alkoxy, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C6-C 20 aryl, substituted or unsubstituted C3-C 20 One or more of a heterocyclic group and a halogen, wherein the substituted C1-C 20 Alkyl, substituted C1-C 20 Alkoxy, substituted C3-C 20 Cycloalkyl, substituted C6-C 20 Aryl and substituted C3-C 20 The substituents of the heterocyclic group are each independently selected from C1-C 12 Alkyl, C1-C 12 Alkoxy, C3-C 12 Cycloalkyl, C1-C 12 Perfluoroalkyl, C6-C 14 Aryl, C3-C 13 The compound may be selected from the group consisting of a heterocyclic group, a halogen group and a cyano group.

2. The isoxazoline derivative containing bisamide according to claim 1, wherein Each R 1 Each is independently selected from one or more of H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 perfluoroalkyl, hydroxyl, cyano, nitro and halogen; R 2 One or more selected from H and C1-C3 perfluoroalkyl; each R 3 Each independently selected from one or more of H and C1-C3 alkyl; R 4 One or more selected from H and C1-C3 alkyl; R 5 Selected from One or more of the following, where R 6 One or more selected from C1-C3 alkylene groups, R 7 and R 8 are each independently selected from H, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C1-C 12 Alkoxy, substituted or unsubstituted C3-C 12 Cycloalkyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C3-C 13 One or more of a heterocyclic group and a halogen, wherein the substituted C1-C 12 Alkyl, substituted C1-C 12 Alkoxy, substituted C3-C 12 Cycloalkyl, substituted C6-C 14 Aryl and substituted C3-C 13 The substituents of the heterocyclic group are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 perfluoroalkyl, C6-C 10 One or more of an aryl group, a C3-C9 heterocyclic group, a halogen group and a cyano group; Preferably, each R 1 Each is independently selected from one or more of H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, hexafluoroethyl, hydroxyl, cyano, nitro, F and Cl; R 2 One or more selected from H, trifluoromethyl and hexafluoroethyl; each R 3 Each is independently selected from one or more of H, methyl, ethyl, n-propyl and isopropyl; R 4 is selected from one or more of H, methyl, ethyl, n-propyl and isopropyl; R 5 Selected from One or more of the following, where R 6 is selected from one or more of methylene, ethylene, n-propylene and isopropylene, R 7 is selected from one or more of H, methyl, ethyl, n-propyl and isopropyl, R 8 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C6 cycloalkyl, substituted C6-C 10 The substituents of the aryl group and the substituted C3-C9 heterocyclic group are each independently selected from C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl, C6-C 10 One or more of an aryl group, a C3-C9 heterocyclic group, a halogen group and a cyano group; More preferably, each R 1 Each is independently selected from one or more of H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, hexafluoroethyl, hydroxyl, cyano, nitro, F and Cl; R 2 One or more selected from H, trifluoromethyl and hexafluoroethyl; each R 3 Each is independently selected from one or more of H, methyl, ethyl, n-propyl and isopropyl; R 4 is selected from one or more of H, methyl, ethyl, n-propyl and isopropyl; R 5 Selected from One or more of the following, where R 6 is selected from one or more of methylene, ethylene, n-propylene and isopropylene, R 7 is selected from one or more of H, methyl, ethyl, n-propyl and isopropyl, R 8 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C6 cycloalkyl, substituted C6-C 10 The substituents of the aryl and substituted C3-C9 heterocyclic groups are each independently selected from methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, hexafluoroethyl, phenyl, benzyl, One or more of F, Cl, Br and cyano; More preferably, R 5 Selected from the following groups:

3. The isoxazoline derivative containing bisamide according to claim 1 or 2, wherein: The isoxazoline derivative containing bisamide is selected from one or more compounds represented by the following formula: Preferably, the isoxazoline derivative containing bisamide is selected from one or more optical isomers represented by the following formula:

4. The method for preparing the isoxazoline derivative containing bisamide according to any one of claims 1 to 3, characterized in that: The method comprises: reacting a compound represented by formula (G) with R 7 -NH-R 8 Carrying out a condensation reaction to obtain a compound represented by formula (1); Formula (G) 5. The method according to claim 4, wherein: Relative to 1 mmol of the compound represented by formula (G), R 7 -NH-R 8 The dosage is 0.6-2mmol, preferably 1-1.5mmol; Preferably, the condensation reaction is carried out in the presence of a first alkaline agent; more preferably, the first alkaline agent is selected from one or more of triethylamine, pyridine, sodium hydroxide, potassium hydroxide, 3-methylpyridine and N,N-diisopropylethylamine, preferably one or more of triethylamine, pyridine, potassium hydroxide and sodium hydroxide; more preferably, relative to 1 mmol of the compound represented by formula (G), the amount of the first alkaline agent is 1-8 mmol, preferably 2-5 mmol; Preferably, the condensation reaction is carried out in the presence of a first condensing agent; more preferably, the first condensing agent is selected from one or more of EDCl, HOBt, DCC, DMAP, DIC and HATU, preferably EDCl and / or HOBt; more preferably, relative to 1 mmol of the compound represented by formula (G), the amount of the first condensing agent is 1-8 mmol, preferably 2-5 mmol; Preferably, the solvent for the condensation reaction is selected from one or more of dichloromethane, chloroform, toluene, xylene, ether and tetrahydrofuran, preferably dichloromethane and / or chloroform; Preferably, relative to 1 mmol of the compound represented by formula (G), the amount of the solvent used in the condensation reaction is 2-15 mL, preferably 5-8 mL; Preferably, the conditions for the condensation reaction include: a temperature of 10-40°C and a time of 4-24 hours; more preferably, the conditions for the condensation reaction include: a temperature of 20-30°C and a time of 8-16 hours.

6. The method according to claim 4 or 5, wherein: The preparation method of the compound represented by formula (G) comprises: subjecting the compound represented by formula (F) to a hydrolysis reaction to obtain the compound represented by formula (G); Formula (F) Wherein, R is selected from C1-C6 alkyl.

7. The method according to claim 6, wherein: The hydrolysis reaction is carried out in the presence of a second alkaline agent, wherein the second alkaline agent is selected from sodium hydroxide and / or potassium hydroxide; Preferably, relative to 1 mmol of the compound represented by formula (F), the amount of the second alkaline agent is 1-8 mmol, preferably 3-6 mmol; Preferably, the solvent for the hydrolysis reaction is selected from one or more of water, methanol and ethanol, preferably a water / ethanol mixed solvent with a volume ratio of 1:2-5, more preferably a water / ethanol mixed solvent with a volume ratio of 1:3-4; Preferably, relative to 1 mmol of the compound represented by formula (F), the amount of the solvent used in the hydrolysis reaction is 5-20 mL, preferably 8-15 mL; Preferably, the conditions for the hydrolysis reaction include: a temperature of 60-100° C. and a time of 4-24 h; more preferably, the conditions for the hydrolysis reaction include: a temperature of 70-90° C. and a time of 8-16 h.

8. The method according to claim 6 or 7, wherein: The preparation method of the compound represented by formula (F) comprises: reacting the compound represented by formula (E) with Performing an amidation reaction to obtain a compound represented by formula (F); Formula (E) 9. The method according to claim 8, wherein: Relative to 1 mmol of the compound represented by formula (E), The dosage is 0.6-2mmol, preferably 1-1.5mmol; Preferably, the amidation reaction is carried out in the presence of a third alkaline agent; more preferably, the third alkaline agent is selected from one or more of triethylamine, pyridine, sodium hydroxide, potassium hydroxide, 3-methylpyridine and N,N-diisopropylethylamine, preferably one or more of triethylamine, pyridine, potassium hydroxide and sodium hydroxide; more preferably, the amount of the third alkaline agent is 1-8 mmol, preferably 2-5 mmol, relative to 1 mmol of the compound represented by formula (E); Preferably, the amidation reaction is carried out in the presence of a second condensing agent; more preferably, the second condensing agent is selected from one or more of EDCl, HOBt, DCC, DMAP, DIC and HATU, preferably EDCl and / or HOBt; more preferably, the amount of the second condensing agent is 1-8 mmol, preferably 2-5 mmol, relative to 1 mmol of the compound represented by formula (E); Preferably, the solvent for the amidation reaction is selected from one or more of dichloromethane, chloroform, toluene, xylene, ether and tetrahydrofuran, preferably dichloromethane and / or chloroform; Preferably, relative to 1 mmol of the compound represented by formula (E), the amount of the solvent used in the amidation reaction is 2-15 mL, preferably 5-8 mL; Preferably, the conditions for the amidation reaction include: temperature of 10-40°C, and time of 4-24h; more preferably, the conditions for the amidation reaction include: temperature of 20-30°C, and time of 8-16h.

10. Use of the isoxazoline derivative containing bisamide according to any one of claims 1 to 3 in pest control.

Images