Substituted quinazolinone-isoxazoline compounds, their preparation methods and applications

Abstract

This invention discloses a substituted quinazolinone-isoxazoline compound, its preparation method, and its application. Using toluene as a solvent, sodium trifluoromethyl sulfinate is reacted with compound (I) to generate compound (II). Compound (II) reacts with compound (III) to generate compound (IV). Compound (IV) reacts with R1I to generate compound (V). Compound (V) is heated under reflux using a prepared sulfuric acid / acetic acid / aqueous solution as a solvent to generate an acidic hydrolysis product. Using DCM as a solvent and EDCl and DMAP as condensing agents, the acidic hydrolysis product is condensed to obtain the target product, a substituted quinazolinone-isoxazoline compound. Herbicidal activity tests show that at a concentration of 10 ppm, it exhibits excellent herbicidal activity in dicotyledonous rapeseed and monocotyledonous wheat VI13 and VI15.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to substituted quinazolinone-isoxazolinone compounds, their preparation methods, and applications. Background Technology

[0002] Heterocyclic compounds are widely distributed in nature and constitute the largest class of organic compounds. The presence of heteroatoms such as nitrogen, sulfur, and oxygen in their structures endows them with broad biological activity and ease of modification, making them a source of inspiration for new pesticides. In particular, novel nitrogen-containing heterocyclic compounds, due to their unique electron distribution and spatial configuration, have become a hot topic in modern research on highly efficient and low-toxicity pesticides.

[0003] Among numerous nitrogen-containing heterocycles, the isoxazoline skeleton has been proven to be a "star" structure in pesticide molecule design due to its unique mechanism of action and broad biological activity. Several insecticides, fungicides, and herbicides containing isoxazoline structures have been successfully commercialized, such as the novel isoxazoline insecticide Flometoquin and the isoxazoline fungicide Ipflufenoquin. Meanwhile, quinazolinones and their thione derivatives, as another important class of bioactive skeletons, have also shown excellent fungicidal, herbicidal, and antiviral activities in the pharmaceutical and pesticide fields. However, with the increasing resistance of pests, diseases, and weeds to pesticides, compounds with a single skeleton often face the problem of decreased activity. To overcome these challenges, the "active substructure splicing" strategy, which couples two pharmacophores with different mechanisms of action or biological activities—i.e., quinazolinone (or thione) fragments—to the isoxazoline skeleton through specific linking groups, holds promise for generating novel compounds with synergistic effects.

[0004] The substituted quinazolinone-isoxazoline compounds, as shown in Formula (VI), utilize a fluorine- or chlorine-substituted phenyl group as a bridge, connecting the 2-thio(oxy)-quinazolin-4-one structure on the left with the isoxazoline carboxylic acid derivative (ester or amide) on the right. This design aims to combine the advantages of two types of skeletons, introducing halogen atoms to enhance the lipophilicity and metabolic stability of the molecule, and modifying its conductivity through modification of the terminal ester or amide groups. Although such hybrid structures have great application potential, there are currently few reports on quinazolinone-isoxazoline compounds with this specific substitution pattern, and the synthesis of existing related compounds often suffers from problems such as long routes, low yields, cumbersome post-processing, and some compounds failing to meet expected biological activities. Therefore, this invention aims to provide an efficient synthetic method and designs and synthesizes a series of novel isoxazoline compounds containing quinazolinone (thion) fragments, with the goal of obtaining new herbicides with higher activity and broader spectrum, providing an effective solution for agricultural plant protection.

[0005] Summary of the Invention

[0006] In view of the above-mentioned problems existing in the prior art, the purpose of the present invention is to provide substituted isoxazoline compounds, their preparation methods and applications.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] The substituted quinazolinone-isoxazoline compound disclosed in this invention has the structural formula shown in formula (VI):

[0009]

[0010] In formula (VI), R1 is hydrogen or alkyl; R2 is alkyl, cycloalkyl, alkenyl, alkoxy, or alkyl substituted with alkoxy; R3 is cycloalkyl, that is, the H at the corresponding position is replaced by R1, R2, or R3.

[0011] Furthermore, the present invention further specifies that in the target compound shown in (VI), R1 is hydrogen or methyl; R2 is methyl, ethyl, isopropyl, n-butyl, tert-butyl, cyclohexyl, cyclopropyl, 2-propoxyethoxy, citronelloloxy, linaloxy, nerolithoxy, or trans-2-hexenoxy; and R3 is cyclopropyl.

[0012] Furthermore, the present invention also specifies a method for preparing the substituted quinazolinone-isoxazolinone compound, which specifically includes the following steps:

[0013] 1) Sodium trifluoromethyl sulfinate was reacted with the compound shown in formula (I) in toluene as a solvent to produce the compound shown in formula (II);

[0014] 2) Using isopropanol as a solvent, react the compound of formula (II) obtained in step 1) with the compound of formula (III) to generate the compound of formula (IV);

[0015] 3) Using DMF as a solvent, the compound obtained in step 2) as shown in formula (Ⅳ) is reacted with a haloalkane R1I to generate the compound shown in formula (Ⅴ);

[0016] 4) Using the mixed solution obtained by adding sulfuric acid and acetic acid to water as a solvent, the compound obtained in step 3) as shown in formula (V) is heated under reflux to generate the acidic hydrolysis product of the compound as shown in formula (V). In the embodiments of the present invention, the mass ratio of sulfuric acid, acetic acid and water in the mixed solution is 1:1:1.

[0017] 5) Using DCM as solvent and EDCl and DMAP as condensing agents, the hydrolysis product of the compound shown in formula (V) obtained in step 4) is condensed to obtain the substituted quinazolinone-isoxazoline compound shown in formula (VI), and the reaction formula is as follows:

[0018]

[0019] In formula (VI), R1 is hydrogen or methyl; R2 is alkyl, cycloalkyl, alkenyl, alkoxy, or alkyl substituted with alkoxy; and R3 is cycloalkyl.

[0020] Furthermore, the present invention also specifies that the molar ratio of the compound represented by formula (I) in step 1) to sodium trifluoromethyl sulfinate is 1:2-3.

[0021] Furthermore, the present invention also specifies that the molar ratio of the compound represented by formula (Ⅱ) to the compound represented by formula (ⅡI) in step 2) is 1:1.2-2.

[0022] Furthermore, the present invention also specifies that the molar ratio of the compound shown in formula (Ⅳ) to the haloalkane R1I in step 3) is 1:1.5-3.

[0023] Furthermore, the present invention also specifies that the molar ratio of EDCI to DMAP and (V) in step 5) is 1:1.2-2.5:1.2-2.5.

[0024] Furthermore, the present invention also defines the use of the substituted quinazolinone-isoxazoline compounds as herbicides.

[0025] The preparation process of the compound of the present invention as shown in formula (III) is as follows:

[0026] 1) Using concentrated sulfuric acid as a solvent, concentrated nitric acid reacts with 2-chloro-4-fluorobenzaldehyde to produce 2-chloro-4-fluoro-5-nitrobenzaldehyde. The molar ratio of 2-chloro-4-fluorobenzaldehyde to concentrated nitric acid is 1:1.2-2.

[0027] 2) Using anhydrous ethanol as a solvent, 2-chloro-4-fluoro-5-nitrobenzaldehyde is reacted with a saturated aqueous solution of hydroxylamine hydrochloride to generate 2-chloro-4-fluoro-5-nitrobenzaldehyde oxime. The molar ratio of 2-chloro-4-fluoro-5-nitrobenzaldehyde to hydroxylamine hydrochloride is 1:1.5-3.

[0028] 3) Using DMF as solvent and TEA as acid-binding agent, 2-chloro-4-fluoro-5-nitrobenzaldehyde oxime is reacted with NCS and MMA to generate methyl 3-(2-chloro-4-fluoro-5-nitrophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate. The molar ratio of 2-chloro-4-fluoro-5-nitrobenzaldehyde oxime to NCS and MMA is 1:1.2-2.5:1.2-2.5.

[0029] 4) Using iron powder as a reducing agent, methyl 3-(2-chloro-4-fluoro-5-nitrophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate is reduced to methyl 3-(2-chloro-4-fluoro-5-aminophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate. The molar ratio of methyl 3-(2-chloro-4-fluoro-5-nitrophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate to iron powder is 1:4-6.

[0030] By adopting the above-described technology, compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] This invention first reacts sodium trifluoromethyl sulfinate with a specific compound. The resulting intermediate compound is then reacted with reagents such as iodomethane, EDCl, and DMAP to synthesize a series of target compounds. The preparation method is simple and convenient. The structure of the obtained products was confirmed by 1H NMR spectroscopy. The herbicidal activity of the 16 target products (VI series compounds) was tested. At a concentration of 100 ppm, compounds VI1, VI8, VI13, VI14, and VI15 showed excellent inhibitory effects on wheat plant height and roots, with inhibition rates reaching 100%. Except for compound VI1, the other compounds showed 100% inhibition rates against rapeseed. Compounds VI2, VI4, VI9, and VI11 showed good inhibitory effects on wheat plant height and roots (70–89%). Furthermore, for rapeseed seeds, compounds VI2, VI3, VI5, VI9, and VI11 showed good inhibitory effects on rapeseed stems and radicles (70–89%), while compound VI16 achieved a 100% inhibition rate. When the sample concentration was reduced to 10 ppm, the inhibitory effects of compounds VI1, VI8, VI13, VI14, and VI15 on wheat decreased, but their inhibitory effects on wheat roots remained good. Compounds VI8, VI9, and VI14 showed inhibition rates of 84.8%, 80.7%, and 85.7% on wheat plant height, respectively. Compounds VI1, VI11, and VI15 exhibited moderate inhibitory activity (50–69%) on wheat plant height. For rapeseed, only compound VI8 showed a good inhibitory effect, with inhibition rates of 80.4% on rapeseed stems and 72.1% on radicles. Compounds VI2, VI5, VI9, and VI11 showed moderate inhibitory activity (50–69%) on rapeseed. The remaining compounds did not show ideal inhibitory effects on rapeseed. Structure-activity relationship analysis showed that compounds with a methyl group attached to the nitrogen atom of the pyrimidine di(thio)one ring exhibited superior herbicidal inhibitory activity. In addition, when the ester-linked group on the fifth carbon atom of isoxazoline is ethylene glycol monopropyl ether or ethyl, the herbicidal and inhibitory activity of the compound is better. Detailed Implementation

[0032] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0033] definition:

[0034] "Alkyl" refers to a compound consisting only of carbon and hydrogen atoms, without any degree of unsaturation, and can be a C1-6 alkyl group. In some embodiments, the alkyl group is methyl, ethyl, isopropyl, n-butyl, or tert-butyl.

[0035] "Cycloalkyl" refers to a non-aromatic carbocyclic system, which may be a C3-7 alkyl group. In some embodiments, representative cycloalkyl groups include, but are not limited to, cyclopropyl and cyclohexyl.

[0036] "Alkenyl" refers to an unsaturated hydrocarbon group containing at least one carbon-carbon double bond, which may be a C2-7 alkyl group. In some embodiments, the alkenyl group is an alkenyl segment contained in the structure of citronellol, linalool, cis-3,7-dimethyl-2,6-octadienol, or trans-2-hexen-1-ol.

[0037] "Alkoxy" refers to an "alkyl" molecule that is attached to the parent molecule through an oxygen atom, where "alkyl" has the definition described above.

[0038] "Alkoxy-substituted alkyl" refers to a group formed by replacing one or more hydrogen atoms in the "alkyl" group as defined above with the aforementioned "alkoxy group". A representative example is the 2-propoxyethyl fragment in the 2-propoxyethanol structure.

[0039] The preparation process of the compound of formula (III) of this invention is as follows:

[0040] 1) Preparation of 2-chloro-4-fluoro-5-nitrobenzaldehyde

[0041] 2-Chloro-4-fluorobenzaldehyde (15.00 g, 94.60 mmol) was added to a 500 mL three-necked flask, and concentrated sulfuric acid (150 mL) was added as a solvent. The reactants were dissolved by stirring at 0 °C. Then, 65% nitric acid (7.15 g, 73.75 mmol) was slowly added dropwise using a dropping funnel while stirring the reaction mixture. The reaction was monitored by TLC (VL). EA :V PE =1:5) Monitor the reaction progress. After 8 hours, the reaction ends. Slowly pour the reaction solution into an ice-water mixture to precipitate the solid. Filter, wash with water, and dry to obtain 2-chloro-4-fluoro-5-nitrobenzaldehyde, a white solid with a yield of 90.3%. No purification is required. Keep it for later use.

[0042] 2) Preparation of 2-chloro-4-fluoro-5-nitrobenzaldehyde oxime

[0043] In a 500 mL three-necked flask, 17.00 g (83.52 mmol) of 2-chloro-4-fluoro-5-nitrobenzaldehyde and 150 mL of anhydrous ethanol were added. The reaction was stirred in an ice bath. When the temperature dropped to 0–5 °C, a saturated aqueous solution of hydroxylamine hydrochloride (8.70 g, 12.53 mmol) was slowly added dropwise. The reaction was allowed to return to room temperature. TLC (V1) was then performed. EA :V PE =1:3) Monitor the reaction progress. After 2 hours, the reaction ends. Pour the reaction solution into 500 mL of water. A large amount of solid precipitates. Filter, wash with water, and dry to obtain 2-chloro-4-fluoro-5-nitrobenzaldehyde oxime, a light yellow solid with a yield of 85.4%. No purification is required. Keep it for later use.

[0044] 3) Preparation of methyl 3-(2-chloro-4-fluoro-5-nitrophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate

[0045] 2-Chloro-4-fluoro-5-nitrobenzaldehyde oxime (8.89 g, 25.64 mmol), NCS (4.11 g, 30.78 mmol), and DMF (100 mL) were added to a 250 mL round-bottom flask. The mixture was stirred at room temperature, and the reaction progress was monitored by TLC (VEA:VPE = 1:5). After 1 h of reaction, MMA (3.08 g, 30.77 mmol) and TEA (3.08 g, 30.77 mmol) were dissolved in DMF (60 mL) and slowly added dropwise using a dropping funnel. The mixture was added to the reaction solution and stirred at room temperature. The reaction progress was monitored by TLC (VEA:VPE = 1:3). After 3 hours, the reaction was completed. The reaction solution was poured into 1600 mL of water, extracted with EA, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and EA was removed by rotary evaporation. The solution was purified by column chromatography (VEA:VPE = 1:4) to obtain methyl 3-(2-chloro-4-fluoro-5-nitrophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate, a white solid with a yield of 52.4%. No further purification was required.

[0046] 4) Preparation of methyl 3-(2-chloro-4-fluoro-5-aminophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate

[0047] In a 250 mL three-necked flask, methyl 3-(2-chloro-4-fluoro-5-nitrophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate (5.00 g, 15.78 mmol) was added, along with acetic acid (40 mL) as a solvent. The mixture was stirred at 50 °C, and reduced iron powder was added in three batches during the stirring process. TLC (V EA :V PE =1:1) Monitor the reaction progress, stop the reaction after 8 hours, and wait for the reaction to cool to room temperature before filtration. Wash with EA, extract the filtrate with EA, neutralize with saturated sodium bicarbonate solution, extract with EA three times, wash with saturated brine, dry with anhydrous Na2SO4, remove EA by rotary evaporation, and then perform column chromatography (V EA :V PE Separation was performed at a ratio of 1:3 to obtain methyl 3-(2-chloro-4-fluoro-5-aminophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate, a yellow solid, as shown in formula (III), with a yield of 70.1%.

[0048] Example 1: Preparation of the compound as shown in formula (II)

[0049] In a 500 mL three-necked flask, add the compound shown in formula (I) (10.00 g, 66.16 mmol), sodium trifluoromethyl sulfinate (20.65 g, 132.31 mmol), diethyl phosphite (18.27 g, 132.31 mmol), and cuprous iodide (0.63 g, 3.31 mmol), with toluene (150 mL) as solvent. Heat the reaction mixture to reflux. Monitor the reaction progress by TLC (VEA:VPE = 1:20). After 12 h, the reaction is complete. Allow the reaction solution to cool to room temperature, then pour it into a beaker and add EA (200 mL) and saturated sodium carbonate solution (200 mL). Stir for 10 min, collect the organic phase, extract the aqueous phase with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, remove EA by rotary evaporation, and separate the compound shown in formula (II) by column chromatography (VEA:VPE = 1:20). No purification is required; keep for later use. Pale yellow liquid, yield 76.3%.

[0050] Example 2: Preparation of the compound as shown in formula (Ⅳ)

[0051] In a 100 mL three-necked flask, compound (3.00 g, 10.46 mmol) as shown in formula (III) and compound (2.43 g, 12.56 mmol) as shown in formula (II) prepared in Example 1 were added. Isopropanol (30 mL) was used as the solvent. The mixture was stirred at room temperature, and the reaction progress was monitored by TLC (VEA:VPE = 1:2). After 48 h, the reaction was stopped, filtered, and washed with petroleum ether and water to obtain compound (IV) as shown in formula (IV). No purification was required. It was a white solid with a yield of 72.4%.

[0052] Example 3: Preparation of the compound as shown in formula (V)

[0053] The prepared compound (2.00 g, 6.89 mmol) as shown in formula (Ⅳ) was added to a 100 mL round-bottom flask. Anhydrous potassium carbonate (1.90 g, 13.78 mmol) and DMF (20 mL) were used as solvents. After stirring at room temperature for 15 min, iodomethane (0.98 g, 8.27 mmol) was added dropwise. The reaction was stirred at room temperature. The reaction progress was monitored by TLC (VEA:VPE = 1:3). After 6 h, the reaction was completed. The reaction solution was poured into ice water to precipitate a white solid. The solid was filtered, washed with water, and dried to obtain the target compound V2 as shown in formula (Ⅴ) (when R1 is H, the target compound shown in formula (Ⅴ) is the same as the compound shown in formula (Ⅳ)). The solid was gray with a yield of 42.8%. The physicochemical data and proton NMR data of the two compounds shown in formula (Ⅴ) are shown in Table 1 and Table 2, respectively.

[0054] Table 1 shows the physicochemical data of the compounds represented by formula (V).

[0055] <![CDATA[R1 group]]> Appearance Yield % methyl Yellow solid 42.8 hydrogen White solid 47.7

[0056] Table 2 shows the proton NMR data of the compounds represented by formula (V).

[0057]

[0058] Example 4: Preparation of the compound as shown in formula (VI)

[0059] Taking the synthesis steps of the target product VI2 as an example, the compound (1.00 g, 2.17 mmol) prepared in Example 3 as shown in formula (V) was added to a 100 mL round-bottom flask, and an appropriate amount of prepared sulfuric acid / acetic acid / water (1:1:1) solution was added as a solvent. The reaction was heated to 110 °C, and the reaction progress was monitored by TLC (VEA:VPE=1:2). After 8 h, the reaction was stopped, and the reaction was allowed to cool to room temperature. The reaction solution was poured into ice water to precipitate solids, which were then filtered, washed with water, and dried to obtain the chemical hydrolysis product shown in formula (V). The hydrolysis product (0.20 g, 0.43 mmol) was weighed into a 50 mL round-bottom flask, and EDCI (0.10 g, 0.52 mmol), DMAP (0.005 g, 0.04 mmol), and anhydrous ethanol (0.04 g, 0.87 mmol) were added sequentially. The starting material was dissolved in DCM (4 mL) as the solvent. The mixture was stirred overnight at room temperature. After the reaction was complete, DCM and excess anhydrous ethanol were removed by rotary evaporation. A suitable amount of water was added, and the mixture was extracted with EA, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and EA was removed by rotary evaporation. The target compound VI2 was obtained by column chromatography (VEA:VPE = 1:4) as a yellow liquid. Other target compounds VI1, VI3–VI16 were synthesized using the same method. The physicochemical data of the obtained compounds are shown in Table 3.

[0060] The physicochemical data of the compounds shown in Table 3(VI)

[0061] target compound <![CDATA[R1 group]]> <![CDATA[Group R2]]> <![CDATA[R3 group]]> Appearance Melting point / °C Yield % VI1 methyl methyl / Yellow solid 170-172 42.8 VI2 methyl Ethyl / Yellow liquid / 38.9 VI3 methyl Isopropyl / Yellow liquid / 40.7 VI4 methyl n-Butyl / Yellow liquid / 41.4 VI5 methyl 2-Propoxyethoxy / Yellow oily liquid / 48.7 VI6 methyl Cyclohexyl / Yellow oily liquid 48-50 50.4 VI7 methyl Citronelloloxy / Yellow oily liquid / 56.3 VI8 methyl linaloyl group / Yellow oily liquid 116-118 49.8 VI9 methyl Orange Oxygen / Yellow oily liquid 105-107 42.7 VI10 methyl trans-2-hexenoxy / Yellow oily liquid / 47.1 VI11 methyl / Cyclopropyl Yellow oily liquid / 52.3 VI12 methyl tert-butyl / Yellow oily liquid 101-103 54.9 VI13 hydrogen 2-Propoxyethoxy / Yellow solid 103-105 60.3 VI14 hydrogen methyl / White solid 185-187 47.7 VI15 hydrogen Ethyl / Yellow solid 108-110 50.2 VI16 hydrogen Isopropyl / Yellow solid 137-139 62.1

[0062] Table 4(VI) shows the proton NMR data of the compounds.

[0063]

[0064]

[0065]

[0066]

[0067] Example 5 Herbicidal Activity Test

[0068] (1) Experimental subjects: seeds of dicotyledonous plant rapeseed (Brassica napus) and monocotyledonous plant wheat (Triticumaestivum).

[0069] (2) Experimental treatment: Seed pretreatment should be completed before conducting the herbicidal activity test to improve the seed germination rate and thus ensure the accuracy of the test. First, the seeds to be tested were disinfected by soaking them in a sodium hypochlorite solution of about 3% for 10 minutes. Then, they were rinsed repeatedly with deionized water from the Millipore ultrapure water system to remove the residual sodium hypochlorite solution. The seeds were then soaked in deionized water for 6 hours to allow them to absorb water and swell. After that, the seeds were removed and dried, and then placed in a constant temperature incubator at 25°C to germinate. The seeds were removed when they were just beginning to sprout.

[0070] (3) Solution preparation: Weigh 3 mg of the compound sample into a 5 mL EP tube, add 3 mL of acetone to the tube using a pipette, and shake well to completely dissolve the compound, preparing a 1 mg / L stock solution for later use. Take 1 mL of the stock solution into a 10 mL EP tube and dilute with 9 mL of deionized water to obtain a 100 ppm test solution. Take 0.1 mL of the stock solution into a 10 mL EP tube and dilute with 9.9 mL of deionized water to obtain a 10 ppm test solution.

[0071] (4) Test methods:

[0072] Wheat herbicidal activity test: Acetone was used as the solvent in the experiment. All biological tests were performed in duplicate in petri dishes. Contamination from the external environment should be avoided during the experiment. Filter paper with a diameter of 7.5 cm was laid flat in the petri dish, and 10 mL of a specific concentration of the compound sample solution was added. Ten or more wheat seeds were selected and cultured in a natural environment. After one week, the height of the wheat seedlings was measured and the growth of the wheat roots was visually observed. The herbicidal activity of the target compound was detected by inhibiting the growth of wheat plant height and seedling roots. The activity indicators were: stem growth inhibition rate (%) and radicle growth inhibition rate (%).

[0073] Rapeseed herbicidal activity test: Acetone was used as the solvent in the experiment. All biological tests were performed in duplicate in petri dishes. Contamination from the external environment should be avoided during the experiment. Filter paper with a diameter of 7.5 cm was laid flat in the petri dish, and 10 mL of a specific concentration of compound sample solution was added. Ten or more rapeseed seeds were selected and cultured in a natural environment. After one week, the length of rapeseed stems and radicles was measured. The herbicidal activity of the target compound was detected by inhibiting the growth of wheat seedling stems and roots. The activity indicators were: stem growth inhibition rate (%) and radicle growth inhibition rate (%).

[0074] Inhibition rate calculation:

[0075]

[0076] The herbicidal activity (inhibition rate %) of target compound VI at 100 ppm and 10 ppm is shown in Table 5:

[0077] Table 5. Herbicidal activity of target compound VI at 100 ppm and 10 ppm (inhibition rate %)

[0078]

[0079]

[0080] The herbicidal activity results of 16 substituted quinazolinone-isoxazoline compounds showed that some compounds in the VI series had good inhibitory effects on rapeseed and wheat. At a sample concentration of 100 ppm, compounds VI1, VI8, VI13, VI14, and VI15 exhibited excellent inhibitory effects on wheat plant height and roots, with inhibition rates reaching 100%. Except for compound VI1, the other compounds showed 100% inhibition rates on rapeseed. Compounds VI2, VI4, VI9, and VI11 showed good inhibitory effects (70–89%) on wheat plant height and roots. Furthermore, for rapeseed seeds, compounds VI2, VI3, VI5, VI9, VI11, and VI16 showed good inhibitory effects (70–89%) on rapeseed stems and radicles. When the sample concentration decreased to 10 ppm, the inhibitory effects of VI1, VI8, VI13, VI14, and VI15 on wheat decreased, but their inhibitory effects on wheat roots remained good. Compounds VI8, VI9, and VI14 showed inhibition rates of 84.8%, 80.7%, and 85.7% on wheat plant height, respectively. Compounds VI1, VI11, and VI15 exhibited moderate inhibitory activity (50–69%) on wheat plant height. For rapeseed, only compound VI8 showed good inhibitory effects, with inhibition rates of 80.4% on rapeseed stems and 72.1% on radicles. Compounds VI2, VI5, VI9, and VI11 showed moderate inhibitory activity (50–69%) on rapeseed. The remaining compounds showed less than ideal inhibitory effects on rapeseed. Structure-activity relationship analysis showed that compounds exhibiting superior herbicidal inhibitory activity were those with a methyl group attached to the nitrogen atom of the pyrimidine di(thio)one ring. Furthermore, compounds with ethylene glycol monopropyl ether or ethyl groups attached to the ester atom at the fifth carbon position of the isoxazoline showed even better herbicidal inhibitory activity. Compounds VI13 and VI15 exhibited good herbicidal activity, and their structural formulas are shown below:

[0081]

Claims

1. A substituted quinazolinone-isoxazoline compound, characterized in that... Its structural formula is shown in equation (VI): In formula (VI), R1 is hydrogen or alkyl; R2 is alkyl, cycloalkyl, alkenyl, alkoxy, or alkyl substituted with alkoxy; and R3 is cycloalkyl.

2. The substituted quinazolinone-isoxazoline compound according to claim 1, characterized in that... R1 is hydrogen or methyl; R2 is methyl, ethyl, isopropyl, n-butyl, tert-butyl, cyclohexyl, cyclopropyl, 2-propoxyethoxy, citronelloloxy, linaloxy, neroxy, or trans-2-hexenoxy; R3 is cyclopropyl.

3. A method for preparing a substituted quinazolinone-isoxazoline compound as described in claim 1, characterized in that... Includes the following steps: 1) Sodium trifluoromethyl sulfinate was reacted with the compound shown in formula (I) in toluene as a solvent to produce the compound shown in formula (II); 2) Using isopropanol as a solvent, react the compound of formula (II) obtained in step 1) with the compound of formula (III) to generate the compound of formula (IV); 3) Using DMF as a solvent, the compound of formula (IV) obtained in step 2) is reacted with iodoalkane R1I to generate the compound of formula (V); 4) Using the mixed solution obtained by adding sulfuric acid and acetic acid to water as a solvent, the compound obtained in step 3) as shown in formula (V) is heated under reflux to generate the acidic hydrolysis product of the compound as shown in formula (V); 5) Using DCM as solvent and EDCl and DMAP as condensing agents, the hydrolysis product of the compound shown in formula (V) obtained in step 4) is condensed to obtain the substituted quinazolinone-isoxazolinone compound shown in (VI). In formula (VI), R1 is hydrogen or methyl; R2 is alkyl, cycloalkyl, alkenyl, alkoxy, or alkyl substituted with alkoxy; and R3 is cycloalkyl.

4. The method for preparing substituted quinazolinone-isoxazoline compounds according to claim 3, characterized in that... In step 1), the molar ratio of the compound shown in formula (I) to sodium trifluoromethyl sulfinate is 1:2-3.

5. The method for preparing substituted quinazolinone-isoxazoline compounds according to claim 3, characterized in that... In step 2), the molar ratio of the compound represented by formula (Ⅱ) to the compound represented by formula (ⅡI) is 1:1.2-2.

6. The method for preparing substituted quinazolinone-isoxazoline compounds according to claim 3, characterized in that... In step 3), the molar ratio of the compound shown in formula (Ⅳ) to R1I is 1:1.5-3.

7. The method for preparing substituted quinazolinone-isoxazoline compounds according to claim 3, characterized in that... In step 5), the molar ratio of EDCI to DMAP and (V) of the compound is 1:1.2-2.5:1.2-2.

5.

8. The use of a substituted quinazolinone-isoxazoline compound according to claim 1 as a herbicide.

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