Preparation method and application of benzoylurea substituted isoxazoline derivative

Abstract

The invention provides a benzoylurea substituted isoxazoline derivative as well as a preparation method and application thereof. The compound has the following chemical structural general formula, wherein in the chemical structural general formula CY, R is substituted aryl or aliphatic chain. In particular to a series of benzene ring, pyridine ring, benzyl or aliphatic chain substituted derivatives, a novel insecticide with high efficiency, low toxicity and broad-spectrum insecticidal performance is synthesized, the novel insecticide can be alternately used with existing insecticides, generation of resistance is avoided or delayed, preparation conditions are conventional, follow-up treatment is simple and convenient, and industrialization is easy to achieve.

Description

Technical Field

[0001] This invention belongs to the field of agricultural insecticide technology, and relates to isoxazoline derivatives substituted with benzoylurea. The technical solution involves derivatives containing substituted aryl or aliphatic chains, specifically derivatives containing substituted benzene rings, pyridine rings and aliphatic chains. Background Technology

[0002] In recent decades, pesticides have played an irreplaceable role in ensuring human food supply and safety, including preventing the spread of diseases, controlling epidemics, and maintaining health. Pesticides not only significantly reduce various losses but are also a key factor in ensuring stable agricultural production and increased income, thus being considered a vital strategic resource. However, in recent years, challenges such as pest resistance to traditional pesticides and pesticide pollution have become increasingly prominent, requiring researchers to place higher demands on the development of new pesticides. Therefore, continuously developing highly efficient, low-toxicity, environmentally friendly, low-cost insecticides with novel mechanisms of action to meet the needs of modern society is one of the tasks of researchers. Isoxazoline insecticides are an important class of insecticides widely used in agricultural production to control various pests. Their chemical structures contain isoxazoline and thiazole rings, hence they are also called thiazole insecticides. These compounds cause pests to die by affecting their nervous system or metabolic pathways.

[0003] Isoxazoline insecticides offer several advantages. First, they possess broad-spectrum insecticidal activity, effectively controlling a variety of pests such as borers, aphids, and planthoppers. Second, their relatively long residual period provides sustained control, reducing the frequency of crop spraying and saving labor and costs. Furthermore, isoxazoline insecticides have relatively low environmental and non-target organism impacts during application, making them a relatively environmentally friendly type of pesticide. However, it is important to note that due to long-term, large-scale use, pests are gradually developing resistance to isoxazoline insecticides, posing a challenge to agricultural production. Therefore, researchers and agricultural experts need to continuously develop and promote new isoxazoline insecticides to address evolving pest resistance and environmental protection needs.

[0004] There are various methods and strategies for creating new pesticides, among which the splicing of active fragments is an indispensable method. Benzoylurea insecticides are an important class of pesticides, commonly used to control various pests, including but not limited to aphids, beetles, and locusts. These pesticides typically contain a benzoylurea group in their chemical structure, hence their name. Benzoylurea insecticides cause pest death by affecting the nervous system or metabolic pathways of pests. Benzoylurea insecticides are characterized by broad-spectrum insecticidal activity, rapid action, and relatively short residual periods. They are widely used in agricultural production for the control of pests in field crops, fruit trees, vegetables, and other crops. At the same time, due to their high efficiency and relatively low toxicity, benzoylurea insecticides are generally considered one of the safer pesticide choices. In order to design and synthesize new derivatives with high insecticidal activity, broad insecticidal spectrum and significant improvement of insecticide resistance, this patent designs and synthesizes a class of isoxazoline derivatives substituted with benzoylurea. Bioactivity assays show that these derivatives have good insecticidal activity against the oriental armyworm, diamondback moth, and fall armyworm, and some compounds exceed the performance of commercial drugs.

[0005] The purpose of this invention is to provide, based on the above-mentioned technical analysis, a class of benzoylurea-substituted isoxazoline derivatives that can improve the drug resistance of existing compounds, enhance insecticidal activity, and have a broad insecticidal spectrum. The preparation method and application of these derivatives are also described. Summary of the Invention

[0006] To address the shortcomings of the prior art, this invention proposes a class of isoxazoline derivatives substituted with benzoylurea, their preparation methods, and uses.

[0007] The technical solution of this invention is implemented as follows:

[0008] A method for preparing and using a class of isoxazoline derivatives substituted with benzoylurea, characterized by having the following general chemical structural formula CY:

[0009]

[0010] In the above general chemical structural formula CY: R is a substituted aryl group or aliphatic chain.

[0011] Specifically, this includes compounds with the following chemical structural formula CY1-39:

[0012]

[0013] This invention employs the following synthetic route to prepare this type of derivative:

[0014]

[0015] The specific preparation method is as follows:

[0016] A. Preparation steps of intermediate 2: NH₂OH·HCl (1.9 g, 26.94 mmol) was placed in a 250 mL double-necked round-bottom flask, and MeOH (65 mL) and Et₃N (9.36 mL, 67.34 mmol) were added and stirred to dissolve at room temperature. Then, compound 1 (4.0 g, 22.45 mmol) was added and stirred for 3 h. After the reaction was completed by TLC, the solvent was evaporated to dryness under reduced pressure, and the mixture was extracted three times with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and dissolved under reduced pressure to obtain 3.8 g of white solid, with a yield of 88%.

[0017] B. Preparation of Intermediate 4: Compound 2 (4.0 g, 20.70 mmol) and DMF (60 mL) were placed in a 250 mL double-necked round-bottom flask, and the system was placed in an ice bath. NCS (4.15 g, 31.06 mmol) was weighed and dissolved in DMF (2 mL), and slowly added dropwise to the round-bottom flask. After the addition was complete, the temperature was raised to 40 °C, and the reaction was continued for 40 min. A DMF solution of compound 3 (4.37 mL, 24.84 mmol) and Et3N (3.14 g, 31.06 mmol) was added, and the mixture was stirred at room temperature for 18 h. After the reaction was complete as detected by TLC, 7.40 g of a white solid was obtained by filtration, with a yield of 83%.

[0018] C. Preparation of Intermediate 5: Compound 4 (0.5 g, 1.16 mmol) was placed in a 100 mL single-necked round-bottom flask, and EtOH (8 mL), water (4 mL), and NaOH (0.14 g, 3.47 mmol) were added sequentially. The reaction system was heated to 65 °C and stirred for 2 h. After the reaction was completed by TLC, the mixture was cooled to room temperature, and the pH of the system was adjusted to 2 with 1 mol / L HCl aqueous solution. The mixture was extracted with ethyl acetate (150 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 0.3 g of yellow solid, with a yield of 62%.

[0019] D. Preparation of Intermediate 6: Compound 5 (0.3 g, 0.72 mmol) was placed in a 100 mL single-necked round-bottom flask, and SOCl2 (0.16 mL, 2.15 mmol), CHCl3 (5 mL), and DMF (15 mL) were added sequentially. The reaction system was heated to 80 °C and stirred for 20 min. The reaction system turned into a brownish-red transparent liquid. The reaction was continued for 3 h, and TLC was used to confirm the completeness of the reaction. Under ice bath conditions, the system was slowly added dropwise to a mixed solution containing NH3·H2O (25 mL) and ice water (50 mL). The reaction was stirred for another 30 min, and then filtered to obtain 0.21 g of white solid, with a yield of 67%.

[0020] E. Preparation of the final product: Compound 6 (0.2 g, 0.48 mmol) was placed in a 100 mL single-necked round-bottom flask, and (COCl)₂ (0.12 mL, 1.44 mmol) and 1,2-dichloroethane (15 mL) were added. The mixture was heated to 80 °C for 6 h under nitrogen protection. After the reaction was completed by TLC, the solution was removed under reduced pressure, and anhydrous acetonitrile (5 mL) was added to dissolve the compound. Compound 7 (0.06 mL, 0.48 mmol) was placed in a 100 mL single-necked round-bottom flask, and anhydrous acetonitrile (15 mL) was added to dissolve the compound. The mixture was placed in an ice bath, and the reaction solution from step 1 was slowly added dropwise to the system containing compound 7. The reaction was carried out for 2 h, and the solvent was removed under reduced pressure. The mixture was extracted with ethyl acetate (150 mL × 3), and the combined organic phases were washed with water and dried over anhydrous Na₂SO₄. Ethyl acetate was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to give 0.12 g of white solid, with a yield of 71%.

[0021] This invention proposes a class of benzoylurea-substituted isoxazoline derivatives for the preparation of agricultural insecticides, particularly for the control of lepidopteran insects. These derivatives can be used alone or as active ingredients in pesticide compositions with agriculturally acceptable adjuvants. Compared to existing technologies, this invention introduces a benzoylurea group into isoxazoline derivatives, generating a novel class of highly effective, low-toxicity, and broad-spectrum insecticides that can be used alternately with existing insecticides, avoiding or delaying the development of resistance. Detailed Implementation

[0022] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0023] Example 1

[0024] Step 1: Preparation of (E)-4-((hydroxyimino)methyl)-2-methylbenzoate

[0025] 1.9 g (26.94 mmol) of NH₂OH·HCl was added to a 250 mL double-necked round-bottom flask, along with 65 mL of MeOH and 9.36 mL (67.34 mmol) of Et₃N. The mixture was stirred and dissolved at room temperature. Then, 4.0 g (22.45 mmol) of methyl 4-aldehyde-2-methylbenzoate was added and stirred for 3 h. After the reaction was completed by TLC, the solvent was evaporated to dryness under reduced pressure, and the mixture was extracted three times with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and the solvent was removed under reduced pressure to give 3.8 g of a white solid, with a yield of 88%.

[0026] Step 2: Preparation of methyl 4-(5-(3-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate

[0027] Methyl (E)-4-((hydroxyimino)methyl)-2-methylbenzoate (4.0 g, 20.70 mmol) and DMF (60 mL) were placed in a 250 mL double-necked round-bottom flask and the system was placed in an ice bath. NCS (4.15 g, 31.06 mmol) was weighed and dissolved in DMF (2 mL), and this solution was slowly added dropwise to the round-bottom flask. After the addition was complete, the temperature was raised to 40 °C and the reaction was allowed to proceed for 40 min. A DMF solution of 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (4.37 mL, 24.84 mmol) and Et3N (3.14 g, 31.06 mmol) was added, and the mixture was stirred for another 18 h at room temperature. After the reaction was complete as determined by TLC, 7.40 g of a white solid was obtained by filtration, with a yield of 83%.

[0028] Step 3: Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid

[0029] 0.5 g (1.16 mmol) of methyl 4-(5-(3-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate was placed in a 100 mL single-necked round-bottom flask. EtOH (8 mL), water (4 mL), and NaOH (0.14 g, 3.47 mmol) were added sequentially. The reaction mixture was heated to 65 °C and stirred for 2 h. After the reaction was complete as determined by TLC, the mixture was cooled to room temperature. The pH was adjusted to 2 with 1 mol / L HCl aqueous solution, and the mixture was extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, and the solvent was removed under reduced pressure to obtain 0.3 g of a yellow solid, with a yield of 62%.

[0030] Step 4: Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide

[0031] Compound 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (0.3 g, 0.72 mmol) was placed in a 100 mL single-necked round-bottom flask. SOCl2 (0.16 mL, 2.15 mmol), CHCl3 (5 mL), and DMF (15 mL) were added sequentially. The reaction system was heated to 80 °C and stirred for 20 min. The system turned into a brownish-red transparent liquid. The reaction was continued for 3 h, and TLC confirmed complete reaction. Under ice bath conditions, the system was slowly added dropwise to a mixed solution containing NH3·H2O (25 mL) and ice water (50 mL). The reaction was stirred for 30 min, and then filtered to obtain 0.21 g of a white solid, with a yield of 67%.

[0032] Step 5: Preparation of the target product

[0033] Compound 6 (0.2 g, 0.48 mmol) was placed in a 100 mL single-necked round-bottom flask, and (COCl)₂ (0.12 mL, 1.44 mmol) and 1,2-dichloroethane (15 mL) were added. The mixture was heated to 80 °C for 6 h under nitrogen protection. After the reaction was completed by TLC, the solution was removed under reduced pressure, and anhydrous acetonitrile (5 mL) was added to dissolve the compound. Compound 7 (0.06 mL, 0.48 mmol) was placed in a 100 mL single-necked round-bottom flask, and anhydrous acetonitrile (15 mL) was added to dissolve the compound. The mixture was placed in an ice bath, and the reaction solution from the first step was slowly added dropwise to the system containing compound 7. The reaction was allowed to proceed for 2 h. After removing the solvent under reduced pressure, the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with water, and dried over anhydrous Na₂SO₄. The ethyl acetate was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give 0.12 g of a white solid, with a yield of 71%.

[0034] The same preparation method as in Example 1 was used, but different raw materials (the amounts of which were the same as those in Example 1) were used to prepare 39 target products. The physical constants of some target products are shown in Table 1, and their proton nuclear magnetic resonance spectra (NMR spectra) are also shown. 1 The HNMR (H2NMR) values ​​are shown in Table 2.

[0035] Table 1 Physical constants of each target product (general formula)

[0036]

[0037]

[0038]

[0039] Table 2 Target Products 1 H NMR

[0040]

[0041] Insecticidal activity assay of the benzoylurea-substituted isoxazoline derivative CY1-39 of the present invention:

[0042] The derivatives provided by this invention were used for testing to verify their biological activity against pests.

[0043] Any derivative provided by this invention can be dissolved in a solvent, water, and a surfactant to form a homogeneous aqueous phase. When used, it can be diluted with water to any desired concentration. The test objects and test methods are as follows:

[0044] (1) Evaluation of the bioactivity of the Eastern Armyworm: The test insect was the Eastern Armyworm (Mythimna separata Walker), a normal population reared indoors with corn leaves. The armyworms were tested using the leaf-immersion method, in which seedling corn leaves were immersed in a prepared solution, dried, and then placed in 7 cm diameter petri dishes. Third instar larvae were then introduced, and each concentration was repeated three times. The control group was reared by immersing corn leaves in acetone solution. The experimental results were observed after 24 hours, 48 ​​hours, and 72 hours.

[0045] (2) Evaluation of biological activity against fall armyworm: The test insect was fall armyworm (Spodopterafrugiperda), a normal population reared indoors with corn leaves. The leaf-immersion method was used, in which seedling corn leaves were immersed in a prepared solution, dried, and then placed in 7 cm diameter petri dishes. Third instar larvae were inoculated, and each concentration was repeated 3 times. The control group was reared by immersing corn leaves in acetone solution. The experimental results were observed after 24 hours, 48 ​​hours, and 72 hours.

[0046] (3) Evaluation of the biological activity of diamondback moth: The test insects were third-instar larvae of diamondback moth (Plutellaxylostella), which were normal populations raised indoors. The leaf immersion method was used. The cabbage leaves were immersed in the prepared solution with tweezers for 2-3 seconds and the excess solution was removed. One leaf was used each time, and three leaves were used for each sample. After the solution dried, the leaves were placed in a 10cm long straight test tube, and second-instar diamondback moth larvae were introduced. The tube opening was covered with gauze. The test treatment was placed in the standard treatment room, and the test results were observed after 24 hours, 48 ​​hours and 72 hours.

[0047] Insecticide Test 1: Live Insect Inhibitory Activity Test

[0048] The common Lepidoptera insects tested in this invention are as follows: Eastern Armyworm (Mythimnaseparata), Fall Armyworm (Spodoptera frugiperda), and Diamondback Moth (Plutella xylostella). These Lepidoptera insects are highly representative and can represent most of the insects that cause pests in the field during agricultural production.

[0049] Table 3. Insecticidal activity of a class of benzoylurea-substituted isoxazoline derivatives CY1-39 of the present invention against *Armoria spp.*

[0050]

[0051] Table 4. Insecticidal activity of a class of benzoylurea-substituted isoxazoline derivatives CY1-39 of the present invention against fall armyworm.

[0052]

[0053]

[0054] Table 5. Insecticidal activity of a class of benzoylurea-substituted isoxazoline derivatives CY1-39 of the present invention against diamondback moth.

[0055]

[0056] Table 6. LC-150 of a class of benzoylurea-substituted isoxazoline derivatives of the present invention against diamondback moth CY1-39. 50

[0057]

[0058]

[0059] Based on the above bioactivity results, most compounds showed significantly improved activity compared to the control drugs acetamiprid and lufenuron. Furthermore, when the R group of the target compound CY was benzyl, the activity of the compound was greatly enhanced against both the fall armyworm and the common armyworm. Specifically, compound CY-5 still exhibited 60% insecticidal activity against the fall armyworm at a concentration of 0.25 mg / L, exceeding that of the control drug fleranal. It was also found that when R was 2,6-dimethylpyridine, CY-29 also showed good insecticidal activity. This indicates that in this series of compounds, the introduction of a methyl substitution on the aromatic ring, or the presence of a benzyl group, resulted in excellent insecticidal activity, exceeding that of the control drug fleranal. Notably, compounds CY-32 to CY-36 maintained insecticidal activity against both the fall armyworm and the common armyworm at 0.25 mg / L, and compound CY-38 showed insecticidal activity comparable to isoxazolamide, indicating high development potential.

[0060] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention. Components or connection methods not specifically described in the present invention employ existing technology. The front, rear, left, and right sides described in the present invention are for ease of description of their structure and are not intended to limit the scope of protection of the present invention.

Claims

1. A method for preparing and using a class of isoxazoline derivatives substituted with benzoylurea, characterized in that: It has the following general chemical structural formula CY: In the above general chemical structural formula CY: R is a substituted aryl group or aliphatic chain.

2. The isoxazoline derivative containing benzoylurea substituted with the general chemical formula CY according to claim 1, characterized in that: It is a compound with the following chemical structural formula CY1-39:

3. A method for preparing the isoxazoline derivative containing benzoylurea substituted with the general chemical formula CY as described in any one of claims 1-2, the specific steps of which are shown in the following chemical reaction equation: A. Preparation steps of intermediate 2: NH2OH·HCl (1.9 g, 26.94 mmol) was placed in a 250 mL double-necked round-bottom flask, and MeOH (65 mL) and Et3N (9.36 mL, 67.34 mmol) were added and stirred to dissolve at room temperature. Then, compound 1 (4.0 g, 22.45 mmol) was added and stirred for 3 h. After the reaction was detected by TLC, the solvent was evaporated to dryness under reduced pressure, and the mixture was extracted three times with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and dissolved under reduced pressure to obtain 3.8 g of white solid, with a yield of 88%. B. Preparation of Intermediate 4: Compound 2 (4.0 g, 20.70 mmol) and DMF (60 mL) were placed in a 250 mL double-necked round-bottom flask. The system was placed in an ice bath. NCS (4.15 g, 31.06 mmol) was weighed and dissolved in DMF (2 mL). The solution was slowly added dropwise to the round-bottom flask. After the addition was complete, the temperature was raised to 40 °C and the reaction was allowed to proceed for 40 min. A DMF solution of Compound 3 (4.37 mL, 24.84 mmol) and Et3N (3.14 g, 31.06 mmol) was added. The mixture was stirred for 18 h at room temperature. After the reaction was completed by TLC, 7.40 g of white solid was obtained by filtration, with a yield of 83%. C. Preparation of Intermediate 5: Compound 4 (0.5 g, 1.16 mmol) was placed in a 100 mL single-necked round-bottom flask, and EtOH (8 mL), water (4 mL), and NaOH (0.14 g, 3.47 mmol) were added sequentially. The reaction system was heated to 65 °C and stirred for 2 h. After the reaction was completed by TLC, the mixture was cooled to room temperature, and the pH of the system was adjusted to 2 with 1 mol / L HCl aqueous solution. The mixture was extracted with ethyl acetate (150 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 0.3 g of yellow solid, with a yield of 62%. D. Preparation of Intermediate 6: Compound 5 (0.3 g, 0.72 mmol) was placed in a 100 mL single-necked round-bottom flask, and SOCl2 (0.16 mL, 2.15 mmol), CHCl3 (5 mL), and DMF (15 mL) were added sequentially. The reaction system was heated to 80 °C and stirred for 20 min. The reaction system turned into a brownish-red transparent liquid. The reaction was continued for 3 h, and TLC was used to confirm the completeness of the reaction. Under ice bath conditions, the system was slowly added dropwise to a mixed solution containing NH3·H2O (25 mL) and ice water (50 mL). After the addition was complete, the reaction was stirred for 30 min, and then filtered to obtain 0.21 g of white solid, with a yield of 67%. E. Preparation of the final product: Compound 6 (0.2 g, 0.48 mmol) was placed in a 100 mL single-necked round-bottom flask, and (COCl)2 (0.12 mL, 1.44 mmol) and 1,2-dichloroethane (15 mL) were added. The mixture was heated to 80 °C for 6 h under nitrogen protection. After the reaction was completed by TLC, the solution was removed under reduced pressure, and anhydrous acetonitrile (5 mL) was added to dissolve the compound. Compound 7 (0.06 mL, 0.48 mmol) was placed in a 100 mL single-necked round-bottom flask, and anhydrous acetonitrile (15 mL) was added to dissolve the compound. The mixture was placed in an ice bath, and the reaction solution from the first step was slowly added dropwise to the system containing compound 7. The reaction was carried out for 2 h. After removing the solvent under reduced pressure, the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined and washed with water. The organic phase was dried over anhydrous Na2SO4, and ethyl acetate was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 0.12 g of white solid, with a yield of 71%.

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