Phenyl thiazole isoxazoline / isoxazole compound and application thereof as agricultural bactericide

Abstract

The invention discloses a phenylthiazole isoxazoline / isoxazole compound and application thereof as an agricultural bactericide, and relates to the technical field of organic synthesis of pesticides. The invention specifically provides a compound of phenyl thiazole isoxazoline or phenyl thiazole isoxazole type. According to the present invention, the two compounds having the general structural formula have good inhibition effects on crop infection fungi such as Botryodiplodia theobromae, Fusarium versicola, Magnaporthe oryzae, Diaporthe actinidia, Colletotrichum gloeosporioides, Physalospora piricola and the like under the condition of the low dose, can be used for preventing and treating diseases caused by the fungi, and further can be used for preventing and treating the crop infection, such that the crop infection prevention and treatment effects can be provided, and the crop infection prevention and treatment effects can be provided; and the selection diversity of the bactericide is increased.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticide organic synthesis, and particularly relates to a phenylthiazole isoxazoline / isoxazole compound and its application as an agricultural fungicide. Background Art

[0002] Pesticides play an important role in food security. Pesticides can effectively control pests, weeds and pathogens in farmland, ensuring the normal growth and development of crops. Fungal diseases are one of the main threats in food production, seriously affecting the yield and quality of crops. Appropriate use of fungicides can effectively control these harmful factors, reduce the damage to crops, and ensure food yield and quality.

[0003] Isoxazoline / isoxazole is an important member of nitrogen-containing heterocycles, with characteristics such as broad-spectrum, high-efficiency, and low-toxicity. It is commonly widely used as insecticides, fungicides, and herbicides in agriculture. Currently, a variety of isoxazoline / isoxazole pesticides have been on the market, such as Isoxaflutole, Karphos, Hymexazol, and Pyrisoxazole. Amino acids are one of the important biomolecules. Amino acids are an important biomolecule and can be used as the active part of pesticides. By optimizing the structure, the effect of pesticides can be improved, and the impact on non-target organisms can be reduced, achieving more reliable and environmentally friendly pesticides. Using amino acids as the active part of pesticides has become a research hotspot, and also provides new ideas and directions for the development of future pesticides.

[0004] The present invention provides a phenylthiazole isoxazoline / isoxazole compound, which combines the isoxazolinylphenylthiazole fragment with different types of amino acids to design and synthesize a series of novel phenylthiazole isoxazoline / isoxazole compounds. Compared with the structure of oxathiapiprolin in CN101888843A, the compounds provided by the present invention all connect the thiazole ring with the isoxazoline ring, but the present invention mainly combines phenylthiazole with phenylisoxazole. Oxathiapiprolin has a good inhibition rate against oomycetes, while a phenylthiazole isoxazoline / isoxazole compound provided by the present invention shows good inhibitory effects against Colletotrichum musae, Pseudocercospora sorghicola, Magnaporthe oryzae, Phomopsis sp., Colletotrichum gloeosporioides, and Physalospora piricola, and has the potential for the development and application of novel agricultural fungicides. Summary of the Invention

[0005] In view of the deficiencies of the above prior art, the present invention provides a phenylthiazole isoxazoline / isoxazole compound and its application as an agricultural fungicide. For fungi infecting crops such as Botryodipladia theobromae, Fusarium verticillioides, Magnaporthe oryzae, Diaporthe actinidiae, Colletotrichum musae, and Physalospora pyricola, the compounds provided by the present invention have very good inhibitory effects at very low doses. The specific implementation is as follows.

[0006] A phenylthiazole isoxazoline / isoxazole compound, including any one of the following structural general formulas:

[0007]

[0008] Formula I;

[0009]

[0010] Formula II;

[0011] Wherein, Ar 1 and Ar 2 are aryl or heteroaryl; R 1 is a hydrogen atom or a halogen, or is an alkyl or alkyl derivative of any one of C 1 -C 3 ; Y is the residue other than the carboxyl group in the structural general formula of an amino acid.

[0012] Further, Ar 1 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl or 3,5-dimethylphenyl, or is a group of the following structural general formula;

[0013] .

[0014] Further, Ar 2is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2-thienyl, 3-thienyl or naphthyl.

[0015] Further, R 1 is a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methyl group or a trifluoromethyl group.

[0016] Further, Y is any one of the following groups:

[0017] , , , , , , , , , , , , , , , , .

[0018] The present invention also provides a method for preparing the phenylthiazole isoxazoline / isoxazole compound according to any one of the above, comprising the following steps:

[0019] Mix a substance containing an unsaturated bond evenly with acetonitrile and sodium bicarbonate, add a chlorooxime compound for reaction, filter, concentrate, and recrystallize to obtain an isoxazoline intermediate;

[0020] Take the isoxazoline intermediate, dissolve it in ethanol, add 4-aminophenylthioamide, a first organic solvent and a phase transfer catalyst respectively, and carry out a reflux heat reaction; place the system in ice water to precipitate a solid, filter to obtain a primary reaction product;

[0021] Dissolve the primary reaction product in a first organic solvent, add an N-Boc protected amino acid corresponding to Y and a condensation reagent, and react at 10-30 °C; after the reaction is complete, pour it into ice water, add while stirring, let stand, filter, and wash to obtain a secondary reaction product;

[0022] The condensation reagent is one or more of EDC hydrochloride, 4-dimethylaminopyridine (DMAP), dicyclohexylcarbodiimide (DCC), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (uronium hexafluorophosphate, HATU), benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (molecular formula C 18 H 28 F 6 N 6 OP 2 , PyBOP), tetramethylchlorouronium hexafluorophosphate (molecular formula C 5 H 12 ClF 6 N 2 P, TCFH), 1-propylphosphonic anhydride (molecular formula C 9 H 21 O 6 P 3 , also known as T3P, PPAA, PPACA, etc.), 1-hydroxybenzotriazole (molecular formula C 6 H 5 N 3 O, HOBt);

[0023] Dissolve the secondary reaction product in a second organic solvent, add an acidic reagent to remove the corresponding N-Boc protecting group, and concentrate; add a saturated sodium bicarbonate solution to adjust the pH value of the system to 7-8, let it stand, filter, and wash to obtain the phenylthiazole isoxazoline / isoxazole compound.

[0024] Furthermore, in the above preparation method provided by the present invention, the molar ratio of the substance containing an unsaturated bond, the chlorooxime compound, and 4-aminophenylthioamide is (0.1-3):(0.1-3):1.

[0025] Optionally, the molar ratio of the substance containing an unsaturated bond, the chlorooxime compound, and 4-aminophenylthioamide is 1.2:1:1.

[0026] Furthermore, in the above preparation method provided by the present invention, the mass ratio of the primary reaction product, N-Boc amino acid, and the condensation reagent is (0.1-3):1:(0.1-3).

[0027] Optionally, the mass ratio of the primary reaction product, N-Boc amino acid, and the condensation reagent is 1:1:1.5.

[0028] Furthermore, in the above preparation method provided by the present invention, the ratio of the secondary reaction product to the acidic reagent is (0.1-1):1.

[0029] Optionally, the ratio of the secondary reaction product to the acidic reagent is 1:1.

[0030] In the above preparation method provided by the present invention, according to the different specific structures of phenylthiazole isoxazoline / isoxazole compounds, different substances and compounds containing unsaturated bonds are selected.

[0031] Optionally, the substance containing an unsaturated bond is: an organic compound containing a carbon-carbon double bond (alkene bond) or a carbon-carbon triple bond (alkyne bond), such as styrene or phenylacetylene.

[0032] Optionally, the chlorooxime compound is 3-chloro-N-hydroxy-2-oxopropanamide.

[0033] Similarly, the selection of the amino acid also corresponds to the structure of Y in the structural general formula of the phenylthiazole isoxazoline / isoxazole compound.

[0034] In the above preparation method provided by the present invention, the first organic solvent can be selected from one or more of pyridine, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, petroleum ether (60-90 °C), n-butanol, benzene, toluene, xylene, ether, and tetrahydrofuran.

[0035] In the above preparation method provided by the present invention, the second organic solvent can be selected from any one or more of dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, petroleum ether (60-90 °C), n-butanol, benzene, toluene, xylene, ether, and tetrahydrofuran.

[0036] In the above preparation method provided by the present invention, the phase transfer catalyst can be selected from one or more of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), 18-crown-6, 15-crown-5, cyclodextrin, polyethylene glycol, polyoxyethylene sorbitan succinate, triethylamine, and tetrabutylammonium hydroxide.

[0037] In the above preparation method provided by the present invention, the acidic reagent is trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid, or butyric acid. The role of the acidic reagent in the above preparation method is to remove the corresponding N-Boc protecting group.

[0038] The present invention also provides the application of the phenylthiazole isoxazoline / isoxazole compound described in any one of the above, for preparing an agricultural fungicide, or for preventing and controlling fungal diseases of crops.

[0039] Furthermore, the fungal diseases of crops are diseases caused by Botryodiplodia theobromae, Fusarium verticillioides, Magnaporthe oryzae, Diaporthe actinidiae, Colletotrichum musae or Physalospora pyricola.

[0040] The present invention also provides an agricultural fungicide for controlling fungal diseases of crops, comprising the phenylthiazole isoxazoline / isoxazole compound described in any one of the above.

[0041] Furthermore, the agricultural fungicide is at least one of a suspension concentrate, an oil-based suspension concentrate, a wettable powder, a water dispersible granule, an emulsifiable concentrate, a microemulsion, and an emulsion in water.

[0042] Compared with the prior art, the beneficial effects of the present invention are as follows: Compared with the prior art, the present invention provides a phenylthiazole isoxazoline / isoxazole compound. Such compounds have very good inhibitory effects on Botryodiplodia theobromae, Fusarium verticillioides, Magnaporthe oryzae, Diaporthe actinidiae, Colletotrichum musae and Physalospora pyricola, and good bactericidal effects can be obtained at very low doses. The phenylthiazole isoxazoline / isoxazole compound described in the present invention can control diseases caused by fungi, increasing the diversity of choices of fungicides. Detailed Embodiments

[0043] The technical solutions of the present invention will be described clearly and completely below. Apparently, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0044] The phenylthiazole isoxazoline / isoxazole compounds provided in some embodiments of the present invention include any one of the following general structural formulas:

[0045]

[0046] Formula I;

[0047]

[0048] Formula II;

[0049] Wherein, Ar 1 and Ar 2 are aryl or heteroaryl; R1 is a hydrogen atom or a halogen, or is a C 1 -C 3 alkyl or alkyl derivative of any one of (for example, an alkyl derivative containing a halogen); Y is a residue other than the carboxyl group in the general structural formula of an amino acid.

[0050] Optionally, Ar 1 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl or 3,5-dimethylphenyl, or is a group of the following general structural formula;

[0051] .

[0052] Optionally, Ar 2 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2-thienyl, 3-thienyl or naphthyl.

[0053] Optionally, R 1 is a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methyl group or a trifluoromethyl group.

[0054] Optionally, Y is any one of the following groups:

[0055] , , , , , , , , , , , , , , , , .

[0056] The preparation method of the phenylthiazole isoxazoline / isoxazole compound described in any one of the above in some embodiments of the present invention includes the following steps:

[0057] Mix a substance containing an unsaturated bond evenly with acetonitrile and sodium bicarbonate, add a compound for reaction, filter, concentrate, and recrystallize to obtain an isoxazoline intermediate; the compound is;

[0058] Take the isoxazoline intermediate, dissolve it in ethanol, add 4-aminophenylthioamide, a first organic solvent, and a phase transfer catalyst respectively, and carry out a reflux heat reaction; place the system in ice water to precipitate a solid, filter to obtain a primary reaction product;

[0059] Dissolve the primary reaction product in a first organic solvent, add an N-Boc protected amino acid corresponding to Y and a condensation reagent, and react at 10 - 30 °C; after the reaction is complete, pour it into ice water, add while stirring, let it stand, filter, and wash to obtain a secondary reaction product; the condensation reagent is one or more of EDC hydrochloride (EDC·HCl), DMAP, DCC, HATU, PyBOP, TCFH, T3P, HOBt;

[0060] Dissolve the secondary reaction product in a second organic solvent, add an acidic reagent to remove the corresponding N-Boc protecting group, and concentrate; add a saturated sodium bicarbonate solution to adjust the pH value of the system to 7 - 8, let it stand, filter, and wash to obtain the phenylthiazole isoxazoline / isoxazole compound.

[0061] Furthermore, in the above preparation method provided by the present invention, the molar ratio of the substance containing an unsaturated bond, the chlorooxime compound, and 4-aminophenylthioamide is (0.1 - 3):(0.1 - 3):1.

[0062] Optionally, the molar ratio of the substance containing an unsaturated bond, the chlorooxime compound, and 4-aminophenylthioamide is 1.2:1:1.

[0063] Furthermore, in the above preparation method provided by the present invention, the mass ratio of the primary reaction product, the N-Boc amino acid, and the acidic reagent is (0.1 - 3):1:(0.1 - 3).

[0064] Optionally, the mass ratio of the primary reaction product, the N-Boc amino acid, and the condensation reagent is 1:1:1.5.

[0065] Furthermore, in the above preparation method provided by the present invention, the mass ratio of the secondary reaction product and trifluoroacetic acid is (0.1 - 1):1.

[0066] Optionally, the mass ratio of the secondary reaction product and trifluoroacetic acid is 1:1.

[0067] According to the different specific structures of phenylthiazole isoxazoline / isoxazole compounds, substances and compounds containing unsaturated bonds with corresponding different structures are selected.

[0068] Optionally, the substance containing an unsaturated bond is: an organic compound containing a carbon-carbon double bond (alkene bond) or a carbon-carbon triple bond (alkyne bond) such as styrene or phenylacetylene.

[0069] Optionally, the chlorooxime compound is 3-chloro-N-hydroxy-2-oxopropanamide.

[0070] Similarly, the selection of amino acids also corresponds to the structure of Y in the general structural formula of phenylthiazole isoxazoline / isoxazole compounds.

[0071] In the above preparation method provided by the present invention, the first organic solvent can be selected from one or more of pyridine, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, petroleum ether (60-90 °C), n-butanol, benzene, toluene, xylene, ether, and tetrahydrofuran.

[0072] In the above preparation method provided by the present invention, the second organic solvent can be selected from any one or more of dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, petroleum ether (60-90 °C), n-butanol, benzene, toluene, xylene, ether, and tetrahydrofuran.

[0073] In the above preparation method provided by the present invention, the phase transfer catalyst can be selected from one or more of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), 18-crown-6, 15-crown-5, cyclodextrin, polyethylene glycol 20000, polyoxyethylene sorbitan succinate, triethylamine, and tetrabutylammonium hydroxide.

[0074] In the above preparation method provided by the present invention, the acidic reagent is trifluoroacetic acid (EDC·HCl), hydrochloric acid, sulfuric acid, formic acid, acetic acid, or butyric acid.

[0075] In some embodiments of the present invention, the application of the above phenylthiazole isoxazoline / isoxazole compounds is also provided, specifically for preparing agricultural fungicides or directly for controlling fungal diseases of crops.

[0076] Furthermore, the fungal diseases of crops are diseases caused by Botryodiplodia theobromae, Fusarium verticillioides, Magnaporthe oryzae, Diaporthe actinidiae, Colletotrichum musae or Physalospora pyricola.

[0077] In some embodiments of the present invention, an agricultural fungicide for controlling fungal diseases of crops is also provided, and its main component includes the phenylthiazole isoxazoline / isoxazole compound described in any one of the above.

[0078] Optionally, the agricultural fungicide is at least one of a suspension concentrate, an oil-based suspension concentrate, a wettable powder, a water dispersible granule, an emulsifiable concentrate, a microemulsion, and an emulsion in water.

[0079] Example 1: Preparation of isoxazoline compound I-1

[0080] This example is used to prepare isoxazoline compound I-1, and its chemical structural formula is shown as follows.

[0081]

[0082] The specific preparation method is as follows:

[0083] (1) Weigh 0.126 g of styrene (a substance containing unsaturated bonds, C 8 H 8 , about 1.2 mmol) into a 25 mL flask, add 3 mL of acetonitrile and 0.636 g of sodium bicarbonate to form a mixed solution, and add 0.156 g of 3-chloro-N-hydroxy-2-oxopropanamide (a chlorooxime compound, about 1 mmol) in batches, and react for 5 h.

[0084] 3-Chloro-N-hydroxy-2-oxopropanamide is an intermediate in the synthetic route "Scheme 2" of the literature "Discovery of oxathiapiprolin, a new oomycete fungicide that targets an oxysterol binding protein" (Robert J. Pasteris, Mary Ann Hanagan, John J. Bisaha, Bruce L. Finkelstein, Lisa E. Hoffman, Vann Gregory, John L. Andreassi, James A. Sweigard, Boris A. Klyashchitsky, Yewande T. Henry, Richard A. Berger, http: / / dx.doi.org / 10.1016 / j.bmc.2015.07.064), and its chemical structural formula is:

[0085] After the reaction, suction filtration was carried out. The filtrate was concentrated under reduced pressure and then recrystallized with 1-chlorobutane to obtain the isoxazoline intermediate with a yield of 96.8%.

[0086] (2) Weigh 0.976 g of the isoxazoline intermediate into a 50 mL eggplant-shaped flask, add 15 mL of ethanol to dissolve it, and then add 0.152 g of 4-aminophenylthioamide (4-aminothiobenzamide, C 7 H 8 N 2 S, about 1 mmol), 0.691 g of pyridine (the first organic solvent), and 0.281 g of TBAB (phase transfer catalyst), and heat the reaction under reflux at 60 °C for 3 h.

[0087] After the reaction was complete, the bottle was placed in ice water to precipitate a solid. Suction filtration was carried out to obtain 4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)aniline (primary reaction product), which was in the form of a light yellow powder with a yield of 86.6%.

[0088] (3) Weigh 0.642 g of 4-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)aniline into a bottle, add 10 mL of pyridine (the first organic solvent) to dissolve it, and then add 0.368 g of Boc-glycine and 0.581 g of EDC·HCl (C 8 H 18 N 3 Cl) and carry out the reaction at 25 °C.

[0089] After the reaction was completed, it was poured into ice water, stirred while adding, filtered by suction after standing for a period of time, washed with water, and a yellow solid Boc-intermediate (secondary reaction product) was obtained with a yield of 87%.

[0090] (4)Dissolve 0.478 g of Boc-intermediate in dichloromethane (the second organic solvent), and slowly add 0.113 g of trifluoroacetic acid.

[0091] After detecting the completion of the reaction by TLC (thin layer chromatography), concentrate, add saturated sodium bicarbonate solution, and adjust the pH value of the reaction system to 7 - 8; after standing for a period of time, filter by suction and wash to obtain a yellow solid.

[0092] Select ethyl acetate: methanol (v / v = 10:1) column chromatography to obtain isoxazoline compound 1, which is in the form of a white powder with a yield of 82.8%.

[0093] The mass spectrometry detection results of the phenylthiazole isoxazoline / isoxazole compounds in this example are as follows: 1 H NMR (400MHz, CDCl 3 ) δ 9.58 (s, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.75 – 7.65 (m, 3H),7.46 – 7.31 (m, 5H), 5.77 (dd, J = 10.9, 8.2 Hz, 1H), 3.94 (dd, J = 17.1,11.1 Hz, 1H), 3.53 (dd, J = 8.2, 4.8 Hz, 1H), 3.50 (t, 2H). 13 C NMR (101 MHz,CDCl 3 ) δ 171.02, 168.25, 152.98, 146.65, 140.93, 139.84, 128.96, 128.89,128.37, 127.70, 126.07, 119.58, 117.88, 82.81, 45.30, 44.19。

[0094] Example 2: Preparation of isoxazoline compound Ⅰ-1

[0095] The preparation method of this example is basically the same as that of Example 1, except that: the amount of styrene used in step (1) is 0.106 g, about 1 mmol; the amount of 4-aminophenylthiocarboxamide used in step (2) is 0.698 g, about 4.59 mmol.

[0096] Example 3: Preparation of isoxazoline compound Ⅰ-2

[0097] This example is used to prepare isoxazoline compound I-2, and its chemical structural formula is shown as follows.

[0098]

[0099] The specific preparation method is as follows:

[0100] (1) Weigh 0.143 g of 4-methylstyrene (a substance containing unsaturated bonds, C 9 H 10 , about 1.2 mmol) into a 50 mL flask, add 10 mL of acetonitrile and 2.524 g of sodium bicarbonate to form a mixed solution, and add 0.156 g of 3-chloro-N-hydroxy-2-oxopropanamide (a chlorooxime compound, about 1 mmol) in batches, and react for 5 h.

[0101] After the reaction is completed, filter by suction. After concentrating the filtrate under reduced pressure, recrystallize with 1-chlorobutane to obtain the isoxazoline intermediate, and the yield is 78.5%.

[0102] (2) Weigh 1.189 g of the isoxazoline intermediate into a 50 mL eggplant-shaped flask, dissolve it with 15 mL of ethanol, add 0.152 g of 4-aminophenylthioamide (about 1 mmol), 0.804 g of pyridine (the first organic solvent), and 0.200 g of TBAB (phase transfer catalyst) respectively, and reflux and heat the reaction at 60 °C for 3 h.

[0103] After the reaction is complete, place the bottle in ice water to precipitate a solid. Filter by suction to obtain 4-(4-(5-(p-tolyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)aniline (primary reaction product), which is light yellow, and the yield is 80.0%.

[0104] (3) Weigh 0.338 g of 4-(4-(5-(p-tolyl)-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)aniline into a bottle, dissolve it with 10 mL of pyridine (the first organic solvent), add 0.187 g of Boc-glycine and 0.294 g of EDC·HCl (C 8 H 18 N 3 Cl) respectively, and carry out the reaction at 25 °C.

[0105] After the reaction is complete, pour it into ice water, stir while adding, let it stand for a period of time, then filter by suction and wash with water to obtain the Boc-intermediate (secondary reaction product), and the yield is 94.5%.

[0106] (4) Dissolve 0.502 g of the Boc-intermediate with dichloromethane (the second organic solvent), and slowly add 0.113 g of trifluoroacetic acid.

[0107] After the reaction was completed as detected by TLC (thin layer chromatography), it was concentrated, saturated sodium bicarbonate solution was added, and the pH value of the reaction system was adjusted to 7 - 8. After standing for a period of time, it was filtered by suction and washed to obtain a yellow solid.

[0108] Column chromatography with ethyl acetate:methanol (v / v = 10:1) was selected to obtain isoxazoline compound 2, which was yellow in color with a yield of 67.7%.

[0109] The mass spectrometry detection results of the phenylthiazole isoxazoline / isoxazole compounds in this example were as follows: 1 H NMR (400MHz, CDCl 3 ) δ 9.58 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.75 – 7.63 (m, 3H),7.30 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 5.72 (dd, J = 10.8, 8.6Hz, 1H), 3.89 (dd, J = 17.2, 10.9 Hz, 1H), 3.54 – 3.43 (m, 3H), 2.34 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 171.09, 168.25, 153.00, 146.69, 139.81, 138.18,137.78, 129.53, 128.93, 127.67, 126.09, 119.58, 117.88, 82.84, 45.28, 44.00,21.28。

[0110] Example 4: Preparation of isoxazoline compound I - 2

[0111] The preparation method in this example was basically the same as that in Example 3, except that: the amount of 4 - methylstyrene used in step (1) was 0.598 g, about 5 mmol; the amount of 3 - chloro - N - hydroxy - 2 - oxopropanamide used was 0.782 g, about 5 mmol; the amount of 4 - aminophenylthioamide used in step (2) was 0.802 g, about 5 mmol.

[0112] Example 5: Preparation of isoxazoline compound I - 3:

[0113] This example was used to prepare isoxazoline compound I - 3, and its chemical structural formula is shown as follows.

[0114]

[0115] The preparation method is specifically as follows:

[0116] (1) Weigh 0.143 g of α-methylstyrene (a substance containing unsaturated bonds, about 1.2 mmol) into a 50 mL flask, add 10 mL of acetonitrile and 2.524 g of sodium bicarbonate to form a mixed solution, and add 0.156 g of 3-chloro-N-hydroxy-2-oxopropanamide (a chlorooxime compound, about 1 mmol) in batches, and react for 5 h.

[0117] After the reaction is completed, filter by suction. After concentrating the filtrate under reduced pressure, recrystallize with 1-chlorobutane to obtain the isoxazoline intermediate with a yield of 47.3%.

[0118] (2) Weigh 0.562 g of the isoxazoline intermediate into a 50 mL eggplant-shaped flask, add 15 mL of ethanol to dissolve it, and add 0.152 g of 4-aminophenylthioamide (about 1 mmol), 0.383 g of pyridine (the first organic solvent), and 0.153 g of TBAB (phase transfer catalyst) respectively, and reflux and heat at 60 °C for 3 h.

[0119] After the reaction is complete, place the flask in ice water to precipitate a solid. Filter by suction to obtain 4-(4-(5-methyl-5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)aniline, which is light yellow with a yield of 78.2%.

[0120] (3) Weigh 0.632 g of 4-(4-(5-methyl-5-phenyl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)aniline into a bottle, add 10 mL of pyridine (the first organic solvent) to dissolve it, and add 0.336 g of Boc-glycine and 0.364 g of EDC·HCl (C 8 H 18 N 3 Cl) and react at 25 °C.

[0121] After the reaction is complete, pour it into ice water, stir while adding, let it stand for a period of time, then filter by suction and wash with water to obtain the Boc-intermediate (secondary reaction product) with a yield of 89.6%.

[0122] (4) Dissolve 0.757 g of the Boc-intermediate in dichloromethane (the second organic solvent), and slowly add 0.113 g of trifluoroacetic acid.

[0123] After detecting the completion of the reaction by TLC (thin layer chromatography), concentrate, add saturated sodium bicarbonate solution, and adjust the pH value of the reaction system to 7-8; let it stand for a period of time, then filter by suction and wash to obtain a yellow solid.

[0124] Select ethyl acetate: methanol (v / v = 10:1) column chromatography to obtain isoxazoline compound 2, which is a yellow powder with a yield of 84.4%.

[0125] The mass spectrometry detection results of the phenylthiazole isoxazoline / isoxazole compounds in this example are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 9.60 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.77 – 7.66 (m, 3H),7.53 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 7.2 Hz, 1H),3.78 – 3.60 (m, 2H), 3.53 (s, 2H), 1.85 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ171.03, 168.13, 153.07, 147.03, 145.54, 139.79, 129.00, 128.63, 127.68,127.51, 124.88, 119.58, 117.52, 88.47, 49.75, 45.28, 28.39。

[0126] Example 7: Preparation of Other Isoxazoline Compounds

[0127] In this example, other isoxazoline compounds with different chemical structures were also prepared. The general chemical structure formula of the first isoxazoline compound is as follows.

[0128]

[0129] The specific structural formula is shown in Table 1 below.

[0130] Table 1

[0131]

[0132]

[0133]

[0134]

[0135] The general chemical structure formula of the second isoxazoline compound is as follows:

[0136]

[0137] The specific chemical structural formula is shown in Table 2 below.

[0138] Table 2

[0139]

[0140]

[0141]

[0142] Application Example: Antibacterial Activity Test of Isoxazoline Compounds Prepared in the Above Embodiments

[0143] The antibacterial experiment method adopted in this application example is as follows: The compound is dissolved in DMSO or acetone to prepare a stock solution of 2000 μM. Under aseptic conditions, the stock solution is diluted with a culture medium to a medicated culture medium of 100 μM, and a blank control is set, and the operation is repeated three times.

[0144] The present invention also selects three commercially available agricultural antibacterial agents, chlorothalonil, fenpicoxamid, and carbendazim, as controls.

[0145] The mycelial growth rate method is adopted: The cultured plant pathogenic bacteria are cut into agar discs with a diameter of 5 mm from the edge of the colony under aseptic conditions using a puncher, and the agar discs are inoculated onto the center of the medicated culture medium plate with a sterilized inoculation needle, with the mycelial surface facing downwards, covering the petri dish lid, and placed in an incubator at 28 °C for cultivation.

[0146] According to the growth of the colony in the blank control petri dish, the mycelial growth of the pathogenic bacteria is investigated. After the colony in the blank control grows to 2 / 3, the cross method is used to measure the colony diameter, and the following formula is used to calculate the inhibition rate of mycelial growth of each agent against various pathogenic bacteria, and the average value is taken.

[0147]

[0148] The test results of some compounds are shown in Table 3.

[0149] Table 3

[0150]

[0151]

[0152]

[0153] It can be seen from the results of the table that at a concentration of 100 mg / L, the phenylthiazole isoxazoline / isoxazole compounds provided by the present invention have good inhibitory effects on Botryodiplodia theobromae, Pseudocercospora sorghi, Magnaporthe oryzae, Phomopsis sp., Colletotrichum musae, and Physalospora piricola.

[0154] The above specific embodiments have described the implementation of the present invention in detail. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the claims and the technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple variations all fall within the protection scope of the present invention.

Claims

1. A phenylthiazole isoxazoline / isoxazole compound, characterized in that: Include any of the following structural formulas: ； Formula I; ； Formula II; Among them, Ar 1 and Ar 2 is aryl or heteroaryl; R 1 is a hydrogen atom or a halogen, or is an alkyl group or an alkyl derivative of any one of C1-C3; Y is a residue other than the carboxyl group in the general structural formula of the amino acid.

2. The phenylthiazole isoxazoline / isoxazole compound according to claim 1, characterized in that: Ar 1 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl or 3,5-dimethylphenyl, or a group of the following general structural formula; ； Ar 2 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2-thienyl, 3-thienyl or naphthyl; R 1 is a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methyl group or a trifluoromethyl group; Y is any one of the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. A method for preparing the phenylthiazole isoxazoline / isoxazole compound according to claim 1 or 2, characterized in that: The following steps are involved: The substance containing an unsaturated bond is mixed evenly with acetonitrile and sodium bicarbonate, a chlorooxime compound is added to react, filtered, concentrated, and recrystallized to obtain an isoxazoline intermediate; The isoxazoline intermediate is dissolved in ethanol, and 4-aminobenzenethioamide, a first organic solvent and a phase transfer catalyst are added respectively, and refluxed for thermal reaction; the system is placed in ice water to precipitate a solid, and filtered to obtain a primary reaction product; The primary reaction product is added to a first organic solvent for dissolution, and an N-Boc-protected amino acid corresponding to Y and a condensation reagent are added to react at 10-30° C.; after the reaction is complete, the mixture is poured into ice water, stirred while adding, allowed to stand, filtered, and washed to obtain a secondary reaction product; the condensation reagent is one or more of EDC hydrochloride, DMAP, DCC, HATU, PyBOP, TCFH, T3P, and HOBt; The secondary reaction product is dissolved in a second organic solvent, an acidic reagent is added to remove the corresponding N-Boc protecting group, and the mixture is concentrated; a saturated sodium bicarbonate solution is added to adjust the pH value of the system to 7-8, the mixture is allowed to stand, filtered, and washed to obtain the phenylthiazole isoxazoline / isoxazole compound.

4. The method for preparing the phenylthiazole isoxazoline / isoxazole compound according to claim 3, characterized in that: The molar ratio of the substance containing an unsaturated bond, the chlorooxime compound, and 4-aminobenzenethioamide is (0.1-3):(0.1-3):1; Preferably, the molar ratio of the substance containing an unsaturated bond, the chlorooxime compound, and 4-aminobenzenethioamide is 1.2:1:

1.

5. The method for preparing the phenylthiazole isoxazoline / isoxazole compound according to claim 3, characterized in that: The mass ratio of the primary reaction product, N-Boc amino acid and condensation reagent is (0.1-3):1:(0.1-3); Preferably, the mass ratio of the primary reaction product, the N-Boc amino acid and the condensation reagent is 1:1:1.

5.

6. The method for preparing the phenylthiazole isoxazoline / isoxazole compound according to claim 3, characterized in that: The mass ratio of the secondary reaction product to the acidic reagent is (0.1-1):1; Preferably, the mass ratio of the secondary reaction product to the acidic reagent is 1:

1.

7. Use of the phenylthiazole isoxazoline / isoxazole compound according to claim 1 or 2, characterized in that: Used to prepare agricultural fungicides or to prevent and control fungal diseases of crops.

8. The use of phenylthiazole isoxazoline / isoxazole compounds according to claim 7, characterized in that: The crop fungal disease is caused by mango stem rot fungus (Botryodipladia theobromae), wheat stem base rot fungus (Fusarium verticillioides), rice blast fungus (Magnaporthe oryzae), phomopsis fungus (Diaporthe actinidiae), banana anthracnose fungus (Colletotrichum musae) or apple ring rot fungus (Physalospora pyricola).

9. An agricultural fungicide for preventing and controlling fungal diseases of crops, characterized in that: It includes the phenylthiazole isoxazoline / isoxazole compound as described in claim 1 or 2.

10. The agricultural fungicide for preventing and controlling fungal diseases of crops according to claim 9, characterized in that: The agricultural fungicide is at least one of a suspension concentrate, an oil suspension concentrate, a wettable powder, a water-dispersible granule, an emulsifiable concentrate, a microemulsion, and an aqueous emulsion.

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