Isoxazole-containing compound as well as preparation method and application thereof

Abstract

The invention discloses an isoxazole-containing compound as shown in the following general formula (T), wherein each substituent group of # imgabs0 # is shown in the specification. The invention also discloses a preparation method and application of the isoxazole-containing compound. The isoxazole-containing compound is especially suitable for sterilization.

Description

Technical Field

[0001] The present invention belongs to the field of agricultural fungicides, and particularly relates to a class of isoxazole-containing compounds, their preparation methods and applications. Background Art

[0002] In agriculture, long-term use of the same pesticide variety is likely to lead to the emergence of drug resistance in diseases. Therefore, it is necessary to continuously develop new varieties with different action mechanisms.

[0003] Isoxazoline compounds are widely used in the field of pesticides. Patent WO2005085216 discloses a general structural formula with insecticidal activity as shown in the following formula:

[0004]

[0005] Patent WO201106727 discloses a general structural formula with insecticidal activity as shown in the following formula:

[0006]

[0007] Patent WO2016095768 discloses a general structural formula with herbicidal activity as shown in the following formula:

[0008]

[0009] However, the above patents do not disclose isoxazoline compounds with a diphenyl ether structure, and there is no report on the bactericidal activity of similar compounds. Different linking structures make the compounds exhibit different biological activities. Summary of the Invention

[0010] In order to solve the above technical problems, the present invention provides a class of isoxazole-containing compounds, as shown in the following general formula (T):

[0011]

[0012] Wherein:

[0013] R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl;

[0014] R3 is selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

[0015] X is selected from O, S, NH;

[0016] R5 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, alkenyl-substituted C1-C6 alkyl;

[0017] R5 may also be selected from the following structures:

[0018]

[0019] R6, R7, and R8 are independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0020] As a further preferred embodiment, it is characterized in that in the general formula (T):

[0021] R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, methoxy, trifluoromethyl, and trifluoromethoxy;

[0022] R3 is selected from hydrogen, cyano, halogen, methyl, and trifluoromethyl;

[0023] X is selected from O, S, and NH;

[0024] R5 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and alkenyl-substituted C1-C6 alkyl;

[0025] R5 may also be selected from the following structures:

[0026]

[0027] R6, R7, and R8 are independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, methoxy, trifluoromethyl, and trifluoromethoxy.

[0028] More preferably, the isoxazole-containing compound is selected from the following structures:

[0029]

[0030] In the substituents of the present invention: alkyl refers to a straight-chain or branched-chain form, such as groups like methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.; haloalkyl refers to a group in which the alkyl is substituted by one or more halogen atoms; alkoxy refers to a group in which an alkyl is connected to an oxygen atom at the end, such as methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, etc.; haloalkoxy refers to a group in which the alkyl is substituted by one or more halogen atoms and is connected to an oxygen atom at the end; halogen refers to fluorine, chlorine, bromine, and iodine.

[0031] Some compounds in the general formula (T) of the present invention can be illustrated by Table 1 below, but these specific compounds do not limit the present invention.

[0032]

[0033] Table 1. Some typical compounds and their 1H NMR data

[0034]

[0035]

[0036] In Table 1: s represents singlet, b represents broad singlet, d represents doublet, dd represents double doublet, t represents triplet, q represents quartet, and m represents multiplet.

[0037] The present invention also provides a preparation method of the isoxazoline-containing compound represented by the general formula (T), and the preparation method includes:

[0038]

[0039] Wherein: the definition of the substituent is as described above, NCS is N-chlorosuccinimide, and the acyl chlorination reagent is selected from thionyl chloride and / or oxalyl chloride.

[0040] Specifically, the preparation method includes the following steps:

[0041] A1: In a first solvent, the intermediate (I-1), NCS, methyl 2-fluoroacrylate, and triethylamine react to form the intermediate (I-2);

[0042] A2: The intermediate (I-2) is hydrolyzed and acidified to form the intermediate (I-3);

[0043] A3: In a second solvent, the intermediate (I-3) reacts with the acyl chlorination reagent to form an intermediate acyl chloride, and in the presence of a base, the intermediate acyl chloride reacts with R5XH to form the isoxazoline-containing compound (T).

[0044] In step A1, the first solvent can be an organic solvent commonly used in the art. Preferably, the first solvent is selected from at least one of N,N-dimethylformamide, toluene, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetonitrile, or dimethyl sulfoxide; more preferably, the first solvent is selected from at least one of N,N-dimethylformamide, acetonitrile, or tetrahydrofuran. The reaction temperature in step A1 is 0 to 100 °C, and the preferred reaction temperature is 20 to 100 °C.

[0045] In step A2, hydrolysis is carried out in a sodium hydroxide-water-water-soluble organic solvent system, and the water-soluble organic solvent is selected from ethanol or tetrahydrofuran; after the hydrolysis is completed, it is acidified with hydrochloric acid to form the intermediate (I-3).

[0046] In step A3, the second solvent may be an organic solvent commonly used in the art. Preferably, the second solvent is selected from at least one of N,N-dimethylformamide, toluene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrahydrofuran or dimethyl sulfoxide; more preferably, the second solvent is selected from at least one of dichloromethane, chloroform or carbon tetrachloride. The reaction temperature in step A3 is 0 to 100 °C, and the preferred reaction temperature is 0 °C to the solvent reflux temperature. The base is selected from at least one of organic bases and inorganic bases, and is preferably triethylamine or potassium carbonate.

[0047] The present invention also provides a use of an isoxazoline compound represented by the general formula (T), and the isoxazoline compound represented by the general formula (T) is suitable for sterilization, and is particularly suitable for the control of powdery mildew on crops.

[0048] The present invention also provides a pesticide formulation, and the pesticide formulation contains 0.001%-99.99% by weight of an isoxazole-containing compound represented by the general formula (T). The pesticide formulation can be formulated into emulsifiable concentrates, suspensions, aqueous suspensions, microemulsions, (aqueous) emulsions, powders, wettable powders, soluble powders, (water-dispersible) granules or capsules, etc.

[0049] The pesticide formulation provided by the present invention, in addition to containing 0.001%-99.99% by weight of an isoxazole-containing compound represented by the general formula (T), may further contain an agriculturally acceptable carrier.

[0050] The carrier can be solid or liquid. Suitable solid carriers include natural or synthetic clays and silicates, such as natural silica and diatomaceous earth; magnesium silicate such as talc; magnesium aluminum silicate such as kaolinite, kaolin, montmorillonite and mica; silica white, calcium carbonate, light calcium carbonate; calcium sulfate; limestone; sodium sulfate; amine salts such as ammonium sulfate, hexamethylenediamine. Liquid carriers include water and organic solvents. When water is used as a solvent or diluent, organic solvents can also be used as adjuvants or antifreeze additives. Suitable organic solvents include aromatic hydrocarbons such as benzene, xylene, toluene, etc.; chlorinated hydrocarbons, such as chlorobenzene, vinyl chloride, chloroform, dichloromethane, etc.; aliphatic hydrocarbons, such as petroleum fractions, cyclohexane, light mineral oil; alcohols, such as isopropanol, butanol, ethylene glycol, glycerol and cyclohexanol, etc.; and their ethers and esters; and ketones, such as acetone, cyclohexanone and dimethylformamide and N-methyl-pyrrolidone.

[0051] The carrier can also be a surfactant. Suitable surfactants can be emulsifiers, dispersants or wetting agents; they can be ionic or non-ionic. Non-ionic emulsifiers such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty amines, and commercially available emulsifiers: agricultural emulsion 2201B, agricultural emulsion 0203B, agricultural emulsion 100#, agricultural emulsion 500#, agricultural emulsion 600#, agricultural emulsion 600-2#, agricultural emulsion 1601, agricultural emulsion 2201, agricultural emulsion NP-10, agricultural emulsion NP-15, agricultural emulsion 507#, agricultural emulsion OX-635, agricultural emulsion OX-622, agricultural emulsion OX-653, agricultural emulsion OX-667, Ning emulsion 36#. Dispersants include sodium lignosulfonate, Nekal, calcium lignosulfonate, methylnaphthalenesulfonic acid formaldehyde condensate, etc. Wetting agents are: sodium lauryl sulfate, sodium dodecylbenzenesulfonate, alkylnaphthalenesulfonate, etc.

[0052] The present invention also provides a method for sterilization, the method comprising: applying the pesticide formulation of the present invention to a pest to be controlled or the medium on which it grows, wherein the effective application amount of the active ingredient, i.e., the isoxazoline compound represented by formula (T), is 10 grams to 1000 grams per hectare.

[0053] The isoxazole-containing compound represented by the general formula (T) provided by the present invention has the following advantages compared with the prior art:

[0054] (1) The compound has a novel structure;

[0055] (2) The compound has high bactericidal activity against powdery mildew and has high bactericidal activity at low concentrations. Detailed implementation manners

[0056] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to these specific implementation manners. Those skilled in the art should recognize that the present invention covers all alternative solutions, improvement solutions and equivalent solutions that may be included within the scope of the claims.

[0057] I. Compound synthesis

[0058] Example 1. Synthesis of the target compound T-001

[0059] Refer to the following reaction route:

[0060]

[0061] Synthesis of intermediate E:

[0062] 9.45 g (30 mmol) of intermediate D was added to a round-bottom flask and dissolved in 100 ml of N,N-dimethylformamide. 5.2 g (39 mmol) of NCS was added portionwise under an ice bath, and the mixture was stirred at room temperature for 1 hour. 3.0 g (30 mmol) of methyl 2-fluoropropenoate was added thereto, and the mixture was stirred for half an hour. 6.0 g (60 mmol) of triethylamine was added portionwise and added completely within half an hour, and the mixture was stirred for 1.5 hours. The reaction was monitored by TLC until completion, and then it was poured into 500 ml of ice water. It was extracted with ethyl acetate (100 ml × 3), washed with saturated brine 2 - 3 times, dried over anhydrous magnesium sulfate, filtered, concentrated, and separated by column chromatography to obtain 10.2 g of intermediate E.

[0063] The above steps may proceed through the transition state intermediate E-1. The isoxazoline intermediate E-1 is unstable and easily eliminates HF to synthesize the intermediate isoxazole E. Using methyl 2-chloropropenoate as the raw material, the same product E was obtained. The 1H NMR confirmed that the unique CH2 peak belonging to the isoxazoline disappeared, and the CH peak of the isoxazole ring increased.

[0064]

[0065] Synthesis of intermediate F:

[0066] Intermediate E (26.6 mmol) was added to a round-bottom flask and dissolved in 30 ml of tetrahydrofuran. 1.58 g (39.6 mmol) of sodium hydroxide in 10 ml of aqueous solution was added at room temperature, and the mixture was stirred for 4 - 5 hours. The reaction was monitored by TLC until completion, acidified to acidic with hydrochloric acid, filtered to obtain a white solid, and dried to obtain intermediate F. Synthesis of the target compound T-001:

[0067] Intermediate F (7.5 mmol) was dissolved in 10 ml of dichloromethane, and 10 mmol of oxalyl chloride was added dropwise. The mixture was stirred at room temperature for 1 - 2 hours, the solid material dissolved, and the solution became clear. The solvent was removed by a diaphragm pump to obtain the intermediate acyl chloride. The intermediate acyl chloride was dissolved in 5 ml of dichloromethane, and isopropanol (7.5 mmol) and triethylamine (10 mmol) were added thereto in sequence. The reaction was monitored by TLC until completion, and separated by chromatography to obtain a white solid with a yield of 61.4%. 1 HNMR(CDCl3,400MHz)δ:7.87 - 7.09(m,8H,Ph-H,isoxazole-H),5.35 - 5.28(m,1H,-CH),1.42(d,J=6.4Hz,6H,-CH3).

[0068] The other compounds described in Table 1 can be synthesized by referring to the same method.

[0069] II. Preparation of formulations

[0070] The following examples illustrate the processing and formulation of preparations using the isoxazole-containing compounds represented by the general formula (T) provided by the present invention as the active ingredient component. In the following examples, all "%" refers to weight percentage.

[0071] Example 2: Wettable Powder

[0072] Mix 15% of compound (T) (Table 1), 5% of lignosulfonate (M q ), 1% of lauryl alcohol polyoxyethylene ether (JFC), 40% of diatomaceous earth, and 44% of light calcium carbonate uniformly, and then pulverize to obtain the wettable powder.

[0073] Example 3: Emulsifiable Concentrate

[0074] Heat and stir 10% of compound (T) (Table 1), 5% of agricultural emulsifier 500 (calcium salt), 5% of agricultural emulsifier 602, 5% of N-methyl-2-pyrrolidone, and 75% of xylene uniformly to obtain the emulsifiable concentrate.

[0075] Example 4: Granules

[0076] Mix 5% of compound (T) (Table 1), 1% of polyvinyl alcohol (PVA), 4% of naphthalene sulfonate formaldehyde condensate (NMO), and 90% of clay uniformly, and then pulverize. Then add 20 parts of

[0077] water to this 100 parts of the mixture, knead, and use an extrusion granulator to make granules with a mesh size of 14 - 32, and then dry to obtain the granules.

[0078] Example 5: Water Dispersible Granules

[0079] Mix 20% of compound (T) (Table 1), 4% of naphthalene sulfonate formaldehyde condensate, 1% of naphthalene sulfonate, 2% of white carbon black, and 73% of kaolin, pulverize, then add water and knead, and then add it to a granulator equipped with a certain specification sieve to granulate. Then, after drying and screening (according to the sieve range), the granular product is obtained.

[0080] Example 6: Aqueous Suspension Concentrate

[0081] Pre-mix 20% of compound (T) (Table 1), 1% of fatty alcohol polyoxyethylene ether, 3% of rosin block polyoxyethylene polyoxypropylene ether sulfonate, 1% of magnesium aluminum silicate, 0.4% of silicone defoamer, 5% of propylene glycol, and deionized water (69.5%) uniformly, then add it to a sand mill for sanding, and after filtration, obtain the suspension mother liquor. Add the prepared xanthan gum (0.1%) aqueous solution and shear and mix uniformly.

[0082] III. Biological Activity Test

[0083] Examples of bioactivity assays using the compounds of the present invention are given below. It should be noted that the present invention is not limited solely to the scope of the following examples.

[0084] Example 7: Bactericidal Activity Assay

[0085] In vivo bactericidal activity test:

[0086] The targets for the bactericidal tests were cucumber powdery mildew, rice sheath blight, cucumber gray mold, and corn rust.

[0087] The leaf inoculation method was used for the test. Two pots of potted cucumber seedlings at the true leaf stage with consistent growth were selected. The samples were dissolved in an appropriate amount of DMF solvent to prepare medicated solutions with concentrations of 200, 100, 50, and 25 mg / L. The medicated solutions were sprayed on the leaf surface. After the medicated spray dried, inoculation cakes were placed on the leaves. After moisturizing in the dark at 24 - 26 °C for 24 hours, natural light was restored for moisturizing culture for about 3 days. After the control fully developed the disease, the diameter of the disease spots at each inoculation point was measured with a caliper, and the control efficacy was calculated.

[0088] After the test treatment, the disease incidence of the leaves and plants and the mycelial growth were observed and recorded. According to the disease index and mycelial diameter, referring to the fungicide volume of "SOP for the Evaluation of the Bioactivity of Newly Developed Pesticides", the relative control efficacy was calculated based on the disease index.

[0089] Formula for calculating bactericidal efficacy

[0090] Disease index = 100×∑(number of diseased leaves at each level × representative value at each level) / (total number of leaves surveyed × representative value at the highest level);

[0091] Control efficacy (%) = 100×(control disease index - treatment disease index) / control disease index.

[0092] The evaluation results of bactericidal activity are as follows.

[0093] At a concentration of 100 mg / L, all compounds had no control efficacy against rice sheath blight, cucumber gray mold, and corn rust.

[0094] At a concentration of 100 mg / L, the control efficacy of compounds T001, T002, T003, T004, T005, T006, T007, T008, T009, T011, and T012 against cucumber powdery mildew was greater than 90%.

[0095] At a concentration of 20 mg / L, the control efficacy of compounds T001, T002, T003, T004, T005, T006, T007, T008, T009, and T012 against cucumber powdery mildew was greater than 90%.

Claims

1. A class of isoxazole-containing compounds represented by the following general formula ((T)): Wherein: R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl; R3 is selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl; X is selected from O, S, NH; R5 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, alkenyl-substituted C1-C6 alkyl; R5 may also be selected from the following structures: R6, R7, and R8 are independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy.

2. The isoxazole-containing compound represented by the general formula (T) according to claim 1, characterized in that, In the general formula (T): R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, methoxy, trifluoromethyl, trifluoromethoxy; R3 is selected from hydrogen, cyano, halogen, methyl, trifluoromethyl; X is selected from O, S, NH; R5 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, alkenyl-substituted C1-C6 alkyl, and R5 may also be selected from the following structures: R6, R7, and R8 are independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, methoxy, trifluoromethyl, trifluoromethoxy.

3. According to claim 2, the isoxazole-containing compound represented by the general formula (T), characterized in that the isoxazole-containing compound is selected from the following structures:

4. A method for preparing an isoxazole-containing compound represented by the general formula (T) according to any one of claims 1-3, characterized in that: The preparation method includes: Wherein: The definitions of the substituents are as in claim 1, NCS is N-chlorosuccinimide, and the acyl chlorination reagent is selected from thionyl chloride and / or oxalyl chloride.

5. The preparation method of the isoxazole-containing compound represented by the general formula (T) according to claim 4, characterized in that: The preparation method includes the following steps: A1: In a first solvent, intermediate (I-1), NCS, 2-fluoro-substituted methyl acrylate, and triethylamine react to form intermediate (I-2); A2: Intermediate (I-2) undergoes hydrolysis and acidification reactions to form intermediate (I-3); A3: In a second solvent, intermediate (I-3) reacts with the acyl chlorination reagent to form an intermediate acyl chloride, and in the presence of a base, the intermediate acyl chloride reacts with R5XH to form the isoxazole-containing compound (T).

6. According to claim 5, the preparation method of the isoxazole-containing compound represented by the general formula (T), characterized in that: In step A1, the reaction temperature is 0-100 °C, and the first solvent is selected from at least one of N,N-dimethylformamide, toluene, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetonitrile, and dimethyl sulfoxide; In step A2, the hydrolysis and acidification reactions are carried out in a sodium hydroxide-water-water-soluble organic solvent system, and the water-soluble organic solvent is selected from at least one of ethanol, methanol, 1,4-dioxane, or tetrahydrofuran; In step A3, the second solvent is selected from at least one of N,N-dimethylformamide, toluene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrahydrofuran, or dimethyl sulfoxide; the base is selected from at least one of organic bases and inorganic bases.

7. The preparation method of the isoxazole-containing compound represented by the general formula (T) according to claim 6, characterized in that: In step (1), the reaction temperature is 20-100 °C, and the first solvent is selected from at least one of N,N-dimethylformamide, acetonitrile or tetrahydrofuran; In step (2), the water-soluble organic solvent is selected from ethanol or tetrahydrofuran; In step (3), the second solvent is selected from at least one of dichloromethane, chloroform or carbon tetrachloride.

8. Use of the isoxazole-containing compound represented by the general formula (T) according to any one of claims 1-3, characterized in that: The isoxazole-containing compound is used for sterilization.

9. Use of the isoxazole compound according to claim 8, characterized in that: The isoxazole-containing compound is used for powdery mildew.

10. A pesticide formulation, characterized in that: The pesticide formulation contains 0.001%-99.99% by weight of the isoxazole-containing compound represented by the general formula (T) according to any one of claims 1-3, and the balance is an agriculturally acceptable carrier.

11. The pesticide formulation according to claim 10, characterized in that, The pesticide formulation is applied to the pathogens or growth medium to be controlled, and the effective application rate is 10-1000 grams per hectare.

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