2-(Sulphonyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds and their preparation methods and applications

Abstract

The present invention discloses 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds and their preparation methods and applications. The above compounds have the following structure: #imgabs0# wherein R 1 , R 2 Each of the following groups is selected from: a saturated C1-C8 linear or branched hydrocarbon group, an unsaturated C1-C8 hydrocarbon group, a halogen-substituted C1-C8 hydrocarbon group, a C3-C8 cycloalkyl group; and a phenyl group substituted with one or more saturated or unsaturated hydrocarbon groups, alkoxy groups, halogen groups, fluorinated methyl groups, nitro groups, cyano groups, ester groups, ketone groups, or aldehyde groups; a substituted pyridyl group, a substituted furyl group, a substituted pyrimidyl group, a substituted pyrazolyl group, a substituted thiazolyl group, a substituted thienyl group, a substituted imidazolyl group, and a substituted triazolyl group; X is selected from S or O; and n is 1 or 2. The compound has good application in the preparation of pesticides for controlling fungal and bacterial diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pesticide compound preparation, and in particular relates to 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds and a preparation method and application thereof. Background Art

[0002] Thiasporine A is a yellow powder. Its molecular formula is C 10 H8N2O2S. MacMillan's group first isolated H8N2O2S from the metabolites of the marine bacterium SNC-032 in 2015. The following year, the Christmann group in the same laboratory revised its structure, which is shown in Formula 1.

[0003]

[0004] Aside from the applicant's research group, no other literature has reported on the agricultural bioactivity of Thiasporine A. The applicant discovered a phenylthiazole skeleton with agricultural fungicidal activity within the natural product Thiasporine A. Modifying this structure and designing and synthesizing compounds with agricultural activity remains an urgent challenge. Summary of the Invention

[0005] To address the shortcomings of the prior art, the present invention aims to provide 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds, their preparation methods, and applications. The prepared 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds can be used to control fungal and bacterial diseases in agricultural production.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] 2-(Sulphonyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds having the structure described in Formula I:

[0008]

[0009] Among them, R 1 , R 2Each of the following groups is selected from: a saturated C1-C8 straight-chain or branched hydrocarbon group, an unsaturated C1-C8 hydrocarbon group, a halogen-substituted C1-C8 hydrocarbon group, a C3-C8 cycloalkyl group; and a phenyl group substituted with one or more saturated or unsaturated hydrocarbon groups, alkoxy groups, halogen groups, fluorinated methyl groups, nitro groups, cyano groups, ester groups, ketone groups, or aldehyde groups, a substituted pyridyl group, a substituted furyl group, a substituted pyrimidinyl group, a substituted pyrazolyl group, a substituted thiazolyl group, a substituted thienyl group, a substituted imidazolyl group, and a substituted triazolyl group;

[0010] X is selected from S or O;

[0011] n is 1 or 2.

[0012] Preferably, the R 1 、R 2 , X and n are selected from the combinations in Table 1:

[0013] Table 1 Compound group combination

[0014]

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023] Preferably, R 1 One selected from H, alkane and halogen; R 2 is selected from alkanes or halogenated alkanes; X is selected from O; and n is 2.

[0024] The above-mentioned 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds are prepared using different substituted benzonitriles as raw materials through Ritter reaction, Hantzsch reaction, hydrazinolysis reaction and cyclization reaction. The steps are as follows:

[0025]

[0026] The use of the above-mentioned 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds in the preparation of pesticides for controlling fungal and bacterial diseases. The pesticides for controlling fungal and bacterial diseases can be prepared into wettable powders, dusts, granules, effervescent tablets or solutions, emulsifiable concentrates, emulsions, suspension concentrates, aerosols or mists.

[0027] Preferably, the fungus is at least one of Oomycetes, Basidiomycetes, Ascomycetes and Deuteromycetes.

[0028] Preferably, the bacterium is at least one of oryzae bacterial blight, citrus canker, ginger bacterial wilt and rice bacterial leaf streak.

[0029] Preferably, the application includes the following steps: mixing a carrier and the 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound to prepare a pesticide for preventing and controlling fungal and bacterial diseases; the 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound here is one or more compounds satisfying formula I.

[0030] After the carrier is formulated with the active ingredient (2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound), it is convenient to apply to the site to be treated, or to facilitate storage, transportation or handling.

[0031] Preferably, the carrier is one of a plant, a seed, a solid carrier and a liquid carrier.

[0032] Preferably, the solid carrier is at least one of natural or synthetic clay and silicates, calcium carbonate, calcium sulfate, synthetic silica, calcium silicate and aluminum silicate, carbon, sulfur, natural or synthetic resins, polyvinyl chloride and styrene polymers or copolymers, solid polychlorinated phenols, asphalt and wax.

[0033] Preferably, the natural or synthetic clay and silicate is at least one of diatomaceous earth, talc, attapulgite, kaolin, montmorillonite and mica.

[0034] Preferably, the natural or synthetic resin is a coumarone resin.

[0035] Preferably, the wax is beeswax or paraffin.

[0036] Preferably, the liquid carrier is one or more of water, alcohol, ketone, ether, aromatic hydrocarbon, petroleum fraction and biomass oil.

[0037] Preferably, the alcohol is ethanol or isopropanol.

[0038] Preferably, the ketone is acetone, methyl ethyl ketone, methyl isopropyl ketone or cyclohexanone.

[0039] Preferably, the aromatic hydrocarbon is benzene, toluene, xylene or solvent oil.

[0040] Preferably, the petroleum fraction is kerosene or mineral oil.

[0041] Pesticides are usually formulated and shipped as concentrates that are diluted by the user before application. The presence of small amounts of surfactants aids the dilution process.

[0042] Preferably, the application further comprises mixing a surfactant with a carrier and a 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound. The surfactant is at least one of Tween 20, Tween 80, potassium fatty acid soap (SFP), and fatty alcohol polyoxyethylene ether (AEO-7).

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] (1) The raw materials of the present invention are easy to obtain and can be prepared into various dosage forms to meet the needs of different conditions and different usage scenarios.

[0045] (2) The 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds prepared by the present invention have stronger agricultural fungicidal and bactericidal activities than Thiasporine A, and also have improved broad-spectrum bactericidal properties, and can be used as pesticides for preventing and controlling fungal and bacterial diseases. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0047] Example 1

[0048] 2-(Methylsulfonyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole and 2-(methylsulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole (R in Formula I) 1 H, R 2 is CH3, X is O) synthesis:

[0049] 1) Synthesis of thiobenzamide:

[0050]

[0051] To a 100 mL single-necked reaction flask, add 1.03 g (10 mmol) of benzonitrile and 20 mL of DMF. Stir to dissolve the solid completely. Add 2.03 g (10 mmol) of magnesium chloride hexahydrate at room temperature and stir to dissolve completely. Then add 1.12 g (20 mmol) of sodium hydrosulfide monohydrate. Allow to react for approximately 16 hours, monitoring with a microplate. The reaction is complete. Dilute with 70 mL of water and 10 mL of brine, and extract with 4 × 50 mL of ethyl acetate. The combined organic phases are cross-extracted with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate stripped of solvent to yield a high-purity product that can be used directly in the next step without purification.

[0052] 2) Synthesis of 2-phenylthiazole ethyl ester:

[0053]

[0054] To a 100 mL single-necked reaction flask, add 1.37 g (10 mmol) of thiobenzamide and 20 mL of anhydrous ethanol. Stir to completely dissolve the solid. Add 1.95 g (10 mmol) of ethyl 3-bromopyruvate and heat under reflux for approximately 2 h. Monitor the reaction until complete. Add saturated sodium bicarbonate solution dropwise until weakly alkaline. Remove the solvent from the reaction solution, add 50 mL of dichloromethane, and cross-extract with brine (3 × 50 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Pass the concentrate through a chromatography column and dry to obtain a yellow solid.

[0055] 3) Synthesis of 2-phenylthiazole-4-carbohydrazide:

[0056]

[0057] 3.49 g (10.90 mmol) of hydrazine hydrate was slowly added to a solution of 8.47 g (3.63 mmol) of 2-phenylthiazole ethyl ester in methanol (30 mL) and stirred at reflux for 4 h. After the reaction was complete (monitored by TLC), the crude product, 2-phenylthiazole-4-carbohydrazide, was precipitated and filtered. Purification was performed by washing with water several times.

[0058] 4) Synthesis of 5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole-2-thiol:

[0059]

[0060] In a 250mL flask, 2-phenylthiazole-4-carbohydrazide 6.78g (3.09mmol) and potassium hydroxide are dissolved in methyl alcohol 50mL, then slowly add carbon disulfide 0.60g (7.72mmol).After at room temperature stirring 30min, by reaction heating and reflux 8 hours.After reaction is completed (by TLC monitoring), with frozen water dilution mixture and pH regulator to 5-6.Solution is filtered and recrystallized with methanol to obtain the target compound of purification.

[0061] 5) 2-(2-phenylthiazol-4-yl)-5-(methylthio)-1,3,4-oxadiazole:

[0062]

[0063] In a 100 mL flask, dissolve 2.61 g (10 mmol) of 5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole-2-thiol, 1.87 g (11.1 mmol) of potassium carbonate, and 1.42 g (10 mmol) of iodomethane in DMF and heat under reflux. After the reaction, pour the mixture into ice water to precipitate a solid. Filter the solid, extract it with dichloromethane, and recrystallize it from ethanol to obtain the desired product.

[0064] 6) 2-(2-phenylthiazol-4-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole:

[0065]

[0066] To a 25 mL round-bottom flask, add 2.75 g (10 mmol) of 2-(2-phenylthiazol-4-yl)-5-(methylsulfanyl)-1,3,4-oxadiazole, 10 mL of ethanol, and 0.62 g (0.5 mmol) of ammonium molybdate dissolved in 0.9 g (50 mmol) of 30% hydrogen peroxide. Mix and react at room temperature for 1-6 hours. Pour the mixture into distilled water; filter or extract the crude product with CHCl. ​​Recrystallize from ethanol or pass through a chromatography column to obtain the pure target compound: 2-(2-phenylthiazol-4-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole.

[0067] The melting point, H NMR, C NMR, and high-resolution mass spectrometry data of the synthesized compound are: mp, 160.4-162.6℃. 1 H NMR (400MHz, CDCl3) δ: 8.30 (s, 1H), 8.09–7.99 (m, 2H), 7.50 (dd, J = 5.2, 1.6Hz, 3H), 3.55 (s, 3H). 13C NMR(101MHz, CDCl3)δ:170.78,162.07,161.96,139.02,132.16,131.32,129.21(2C),127.04(2C),124.91,43.12.HRMS(ESI):calcd forC 12 H9N3O3S2{[M+H] +},308.0158;found,308.0158.

[0068]

[0069] To a 10 mL test tube, 2.75 g (10 mmol) of 2-(phenylthiazol-4-yl)-5-(methylthio)-1,3,4-oxadiazole and DPDME (1 mL) were added and stirred at 80°C for 20 h. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous NaSO₄, filtered, and all volatiles were evaporated under reduced pressure. Purification by column chromatography afforded the pure title compound.

[0070] The melting point, H NMR, C NMR, and high-resolution mass spectrometry data of the synthesized compound are: mp, 166.2-167.8℃. 1 H NMR (400MHz, CDCl3) δ: 8.30 (s, 1H), 8.09–7.99 (m, 2H), 7.55 (dd, J = 4.8, 1.6Hz, 3H), 3.55 (s, 3H). 13 C NMR(101MHz, CDCl3)δ:170.78,162.12,161.96,139.02,132.18,131.32,129.23(2C),127.06(2C),124.91,43.12.HRMS(ESI):calcd forC 12 H9N3O2S2{[M+H] +},300.0158;found,300.0158.

[0071] Example 2

[0072] 2-(Methylsulfonyl)-5-(2-(o-chlorophenyl)thiazol-4-yl)-1,3,4-oxadiazole and 2-(methylsulfinyl)-5-(2-(o-chlorophenyl)thiazol-4-yl)-1,3,4-oxadiazole (R in Formula I) 1 Cl, R 2 For CH3) synthesis:

[0073] 1) Synthesis of 2-chlorothiobenzamide:

[0074]

[0075] To a 100 mL single-necked reaction flask, add 1.38 g (10 mmol) of 2-chlorobenzonitrile and 20 mL of DMF. Stir to completely dissolve the solid. Add 2.03 g (10 mmol) of magnesium chloride hexahydrate at room temperature and stir to completely dissolve. Then add 1.12 g (20 mmol) of sodium hydrosulfide monohydrate. Allow to react for approximately 16 hours, monitoring with a microplate. The reaction is complete. Dilute with 70 mL of water and 10 mL of brine, and extract with 4 × 50 mL of ethyl acetate. The combined organic phases are cross-extracted with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate stripped of solvent to yield a high-purity product that can be used directly in the next step without further purification.

[0076] 2) Synthesis of 2-(2-chloro)phenylthiazole ethyl ester:

[0077]

[0078] To a 100 mL single-necked reaction flask, add 1.72 g (10 mmol) of 2-chlorothiobenzamide and 30 mL of anhydrous ethanol. Stir to completely dissolve the solid. Add 1.95 g (10 mmol) of ethyl 3-bromopyruvate and heat under reflux for approximately 2 h. Monitor the reaction until complete. Add saturated sodium bicarbonate solution dropwise until weakly alkaline. Remove the solvent from the reaction solution, add 50 mL of dichloromethane, and cross-extract with brine (3 × 50 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Pass the concentrate through a chromatography column and dry to obtain a yellow solid.

[0079] 3) Synthesis of 2-(2-chlorophenyl)thiazole-4-carbohydrazide:

[0080]

[0081] 0.35 g (10.90 mmol) of hydrazine hydrate was slowly added to a solution of 0.97 g (3.63 mmol) of ethyl 2-(2-chlorophenyl)thiazole in 20 mL of methanol and stirred at reflux for 4 h. After the reaction was complete (monitored by TLC), the crude product, 2-(2-chlorophenyl)thiazole-4-carbohydrazide, was precipitated and filtered. Purification was performed by washing with water several times.

[0082] 4) Synthesis of 5-(2-(2-chlorophenyl)thiazol-4-yl)-1,3,4-oxadiazole-2-thiol:

[0083]

[0084] In a 250mL flask, 2-(2-chlorophenyl)thiazole-4-carbohydrazide 0.78g (3.09mmol) and potassium hydroxide 0.52g (9.27mmol) are dissolved in 50mL of methanol, and then 0.59g (7.72mmol) of carbon disulfide is slowly added. After stirring at room temperature for 30min, the reaction is heated and refluxed for 8 hours. After the reaction is completed (monitored by TLC), the mixture is diluted with ice water and the pH is adjusted to 5-6. The solution is filtered and recrystallized from methanol to obtain the target compound of purification.

[0085] 5) 2-(2-(2-chlorophenyl)thiazol-4-yl)-5-(methylthio)-1,3,4-oxadiazole:

[0086]

[0087] In a 100 mL flask, dissolve 0.30 g (10 mmol) of 5-(2-(2-chlorophenyl)thiazol-4-yl)-1,3,4-oxadiazole-2-thiol, 2.10 g (11.1 mmol) of potassium carbonate, and 1.42 g (10 mmol) of iodomethane in DMF and heat under reflux. After the reaction, pour the mixture into ice water to precipitate a solid. Filter the solid, extract it with CH2Cl2, and recrystallize it from ethanol to obtain the desired product.

[0088] 6) 2-(2-(2-chlorophenyl)thiazol-4-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole:

[0089]

[0090] To a 25 mL round-bottom flask, add 0.31 g (10 mmol) of 2-(2-(2-chlorophenyl)thiazol-4-yl)-5-(methylthio)-1,3,4-oxadiazole, 10 mL of ethanol, and 0.62 g (0.5 mmol) of ammonium molybdate dissolved in 0.9 g (50 mmol) of 30% hydrogen peroxide. Mix and react at room temperature for 1-6 hours. Pour the mixture into distilled water; filter or extract the crude product with dichloromethane. Recrystallize from ethanol or pass through a chromatography column to obtain the pure target compound.

[0091] The melting point, H NMR, C NMR and high-resolution mass spectrometry data of the synthesized compound are: mp, 163.0-164.6°C; 1 H NMR(400MHz, CDCl3)δ:8.48–8.39(m,2H),7.57–7.49(m,1H),7.46–7.41(m,2H),3.55(s,3H). 13C NMR(101MHz, CDCl3)δ:165.99,162.16,162.02,137.78,132.18,131.55,131.31,130.74,130.53,127.43,126.39,43.12.HRMS(ESI):calcd forC 12 H8ClN3O3S2{[M+H] +},341.9768;found,341.9771.

[0092]

[0093] To a 10 mL test tube, 0.31 g (10 mmol) of 2-(2-(2-chlorophenyl)thiazol-4-yl)-5-(methylthio)-1,3,4-oxadiazole and DPDME (1 mL) were added and stirred at 80°C for 20 h. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous NaSO4, filtered, and all volatiles were evaporated under reduced pressure. Purification by column chromatography afforded the pure title compound.

[0094] The melting point, H NMR, C NMR and high-resolution mass spectrometry data of the synthesized compound are: mp, 155.0-156.8°C; 1 H NMR(400MHz, CDCl3)δ:8.32–8.22(m,2H),7.57–7.49(m,1H),7.48–7.46(m,2H),3.55(s,3H). 13 C NMR(101MHz, CDCl3)δ:165.99,162.16,162.04,137.78,132.16,131.55,131.31,130.76 130.53,127.43,126.39,43.13.HRMS(ESI):calcd forC 12 H8ClN3O2S2{[M+H] +},333.9768;found,333.9771.

[0095] Example 3

[0096] 2-(Methylsulfonyl)-5-(2-(o-tolyl)thiazol-4-yl)-1,3,4-oxadiazole and 2-(methylsulfinyl)-5-(2-(o-tolyl)thiazol-4-yl)-1,3,4-oxadiazole (R in Formula I) 1 CH3, R 2 For CH3) synthesis:

[0097] 1) Synthesis of 2-methylthiobenzamide:

[0098]

[0099] To a 100 mL single-necked reaction flask, add 1.17 g (10 mmol) of 2-methylbenzonitrile and 30 mL of DMF. Stir to dissolve the solid completely. Add 2.03 g (10 mmol) of magnesium chloride hexahydrate at room temperature and stir to dissolve completely. Then add 1.12 g (20 mmol) of sodium hydrosulfide monohydrate. Allow to react for approximately 16 hours, monitoring with a microplate. The reaction is complete. Dilute with 70 mL of water and 10 mL of brine, and extract with 4 × 50 mL of ethyl acetate. The combined organic phases are cross-extracted with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate stripped of solvent to yield a high-purity product that can be used directly in the next step without purification.

[0100] 2) Synthesis of 2-(2-methyl)phenylthiazole ethyl ester:

[0101]

[0102] To a 100 mL single-necked reaction flask, add 1.51 g (10 mmol) of 2-methylthiobenzamide and 20 mL of anhydrous ethanol. Stir to completely dissolve the solid. Add 1.95 g (10 mmol) of ethyl 3-bromopyruvate and heat under reflux for approximately 2 h. Monitor the reaction until complete. Add saturated sodium bicarbonate solution dropwise until weakly alkaline. Remove the solvent from the reaction solution, add 50 mL of dichloromethane, and cross-extract with brine (3 × 50 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Pass the concentrate through a chromatography column and dry to obtain a yellow solid.

[0103] 3) Synthesis of 2-(2-methylphenyl)thiazole-4-carbohydrazide:

[0104]

[0105] 0.35 g (10.90 mmol) of hydrazine hydrate was slowly added to a solution of 0.90 g (3.63 mmol) of ethyl 2-(2-methylphenyl)thiazole in 30 mL of methanol and stirred at reflux for 4 h. After the reaction was complete (monitored by TLC), the crude product, 2-(2-methylphenyl)thiazole-4-carbohydrazide, was precipitated and filtered. Purification was performed by washing with water several times.

[0106] 4) Synthesis of 5-(2-(2-methylphenyl)thiazol-4-yl)-1,3,4-oxadiazole-2-thiol:

[0107]

[0108] In a 250mL flask, 2-(2-methylphenyl)thiazole-4-carbohydrazide 0.72g (3.09mmol) and potassium hydroxide 5.20g (9.27mmol) are dissolved in 50mL of methanol, and then carbon disulfide 0.60g (7.72mmol) is slowly added. After stirring at room temperature for 30min, the reaction is heated and refluxed for 8 hours. After the reaction is completed (monitored by TLC), the mixture is diluted with frozen water and dilute hydrochloric acid and the pH is adjusted to 5-6. The solution is filtered and recrystallized with methanol to obtain the target compound of purification.

[0109] 5) 2-(2-(2-methylphenyl)thiazol-4-yl)-5-(methylthio)-1,3,4-oxadiazole:

[0110]

[0111] In a 100 mL flask, dissolve 0.28 g (10 mmol) of 5-(2-(2-methylphenyl)thiazol-4-yl)-1,3,4-oxadiazole-2-thiol, 2.10 g (11.1 mmol) of potassium carbonate, and 1.42 g (10 mmol) of iodomethane in DMF and heat under reflux. After the reaction, pour the mixture into ice water to precipitate a solid. Filter the solid, extract it with dichloromethane, and recrystallize it from ethanol to obtain the desired product.

[0112] 6) 2-(2-(2-methylphenyl)thiazol-4-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole:

[0113]

[0114] To a 25 mL round-bottom flask, add 0.30 g (10 mmol) of 2-(2-(2-methylphenyl)thiazol-4-yl)-5-(methylthio)-1,3,4-oxadiazole, 10 mL of ethanol, and 0.62 g (0.5 mmol) of ammonium molybdate dissolved in 0.9 g (50 mmol) of 30% hydrogen peroxide. Mix and react at room temperature for 1-6 hours. Pour the mixture into distilled water; filter or extract the crude product with dichloromethane. Recrystallize from ethanol or pass through a chromatography column to obtain the pure target compound.

[0115] The melting point, H NMR, C NMR and high-resolution mass spectrometry data of the synthesized compound are: mp, 129.8-131.0°C; 1 H NMR(400MHz, DMSO-d6)δ:8.94(d,J=3.2Hz,1H),7.84(d,J=7.6Hz,1H),7.55–7.32(m,3H),3.73(s,3H),2.60(s,3H). 13C NMR(101MHz, DMSO)δ:169.64,162.29,161.92,138.41,136.68,132.21,131.69,130.96,130.30,127.95,127.09,43.54,21.57.HRMS(ESI):calcd for C 13 H 11 N3O3S2{[M+H] +},322.0315;found,322.0315.

[0116]

[0117] To a 10 mL test tube, 0.30 g (10 mmol) of 2-(2-(2-methylphenyl)thiazol-4-yl)-5-(methylthio)-1,3,4-oxadiazole and DPDME (1 mL) were added and stirred at 80°C for 20 h. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous NaSO₄, filtered, and all volatiles were evaporated under reduced pressure. Purification by column chromatography afforded the pure title compound.

[0118] The melting point, NMR and high-resolution mass spectrometry data of the synthesized compounds were: mp, 120.4-126.8°C; 1 H NMR (400MHz, DMSO-d6)δ:8.95(d,J=3.2Hz,1H),7.88(d,J=7.6Hz,1H),7.55–7.32(m,3H),3.73(s,3H),2.60(s,3H). 13 C NMR(101MHz,DMSO)δ:169.68,162.29,161.92,138.38,136.68,132.25,131.69,130.96,130.31,127.95,127.09,43.54,21.55.HRMS(ESI):calcdfor C 13 H 11 N3O2S2{[M+H] +},314.0315;found,314.0315.

[0119] Example 4

[0120] 2-((2-methylbenzyl)sulfonyl)-5-(2-(o-tolyl)thiazol-4-yl)-1,3,4-oxadiazole and 2-((2-methylbenzyl)sulfinyl)-5-(2-(o-tolyl)thiazol-4-yl)-1,3,4-oxadiazole (R in Formula I) 1CH3, R 2 (2-CH3-Bn, X is O) synthesis:

[0121] 1) Synthesis of 2-methylthiobenzamide:

[0122]

[0123] To a 100 mL single-necked reaction flask, add 1.17 g (10 mmol) of 2-methylbenzonitrile and 30 mL of DMF. Stir to dissolve the solid completely. Add 2.03 g (10 mmol) of magnesium chloride hexahydrate at room temperature and stir to dissolve completely. Then add 1.12 g (20 mmol) of sodium hydrosulfide monohydrate. Allow to react for approximately 16 hours, monitoring with a microplate. The reaction is complete. Dilute with 70 mL of water and 10 mL of brine, and extract with 4 × 50 mL of ethyl acetate. The combined organic phases are cross-extracted with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate stripped of solvent to yield a high-purity product that can be used directly in the next step without purification.

[0124] 2) Synthesis of 2-(2-methyl)phenylthiazole ethyl ester:

[0125]

[0126] To a 100 mL single-necked reaction flask, add 1.51 g (10 mmol) of 2-methylthiobenzamide and 20 mL of anhydrous ethanol. Stir to completely dissolve the solid. Add 1.95 g (10 mmol) of ethyl 3-bromopyruvate and heat under reflux for approximately 2 h. Monitor the reaction until complete. Add saturated sodium bicarbonate solution dropwise until weakly alkaline. Remove the solvent from the reaction solution, add 50 mL of dichloromethane, and cross-extract with brine (3 × 50 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Pass the concentrate through a chromatography column and dry to obtain a yellow solid.

[0127] 3) Synthesis of 2-(2-methylphenyl)thiazole-4-carbohydrazide:

[0128]

[0129] 0.35 g (10.90 mmol) of hydrazine hydrate was slowly added to a solution of 0.90 g (3.63 mmol) of ethyl 2-(2-methylphenyl)thiazole in 30 mL of methanol and stirred at reflux for 4 h. After the reaction was complete (monitored by TLC), the crude product, 2-(2-methylphenyl)thiazole-4-carbohydrazide, was precipitated and filtered. Purification was performed by washing with water several times.

[0130] 4) Synthesis of 5-(2-(2-methylphenyl)thiazol-4-yl)-1,3,4-oxadiazole-2-thiol:

[0131]

[0132] In a 250mL flask, 2-(2-methylphenyl)thiazole-4-carbohydrazide 0.72g (3.09mmol) and potassium hydroxide 5.20g (9.27mmol) are dissolved in methanol 50mL, and then carbon disulfide 0.60g (7.72mmol) is slowly added. After stirring at room temperature for 30 minutes, the reaction is heated and refluxed for 8 hours. After the reaction is completed (monitored by TLC), the mixture is diluted with frozen water and dilute hydrochloric acid and the pH is adjusted to 5-6. The solution is filtered and recrystallized from methanol to obtain the target compound of purification.

[0133] 5) 2-((2-methylbenzyl)thio)-5-(2-(o-tolyl)thiazol-4-yl)-1,3,4-oxadiazole:

[0134]

[0135] In a 100 mL flask, dissolve 0.28 g (10 mmol) of 5-(2-(2-methylphenyl)thiazol-4-yl)-1,3,4-oxadiazole-2-thiol, 2.10 g (11.1 mmol) of potassium carbonate, and 1.26 g (10 mmol) of 2-methylbenzyl chloride in DMF and heat under reflux. After the reaction, pour the mixture into ice water to precipitate a solid. Filter the solid, extract it with CH2Cl2, and recrystallize it from ethanol to obtain the desired product.

[0136] 6) 2-((2-methylbenzyl)sulfonyl)-5-(2-(o-tolyl)thiazol-4-yl)-1,3,4-oxadiazole:

[0137]

[0138] To a 25 mL round-bottom flask, add 0.38 g (10 mmol) of 2-((2-methylbenzyl)thio)-5-(2-(o-tolyl)thiazol-4-yl)-1,3,4-oxadiazole, 10 mL of ethanol, and 0.62 g (0.5 mmol) of ammonium molybdate dissolved in 0.9 g (50 mmol) of 30% hydrogen peroxide. Mix and react at room temperature for 1-6 hours. Pour the mixture into distilled water; filter or extract the crude product with CHCl. ​​Recrystallize from ethanol or pass through a chromatography column to obtain the pure target compound.

[0139] The melting point, H NMR, C NMR, and high-resolution mass spectrometry data of the synthesized compound were: mp 131.0-132.6°C; 1H NMR (400 MHz, CDCl3) δ: 8.30 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.43–7.26 (m, 6H), 7.21–7.14 (m, 1H), 4.91 (s, 2H), 2.65 (s, 3H), 2.48 (s, 3H). 13 C NMR(101MHz, CDCl3)δ:170.38,162.33,161.61,139.16,138.44,137.02,132.20,131.77,131.46,131 .37,130.52,130.16,130.07,126.62,126.36,125.42,123.05,59.54,21.60,19.87.HRMS(ESI):calcd for C20H17N3O3S 2{[M+H]+},412.0785; found,412.0785.

[0140]

[0141] To a 10 mL test tube, 0.38 g (10 mmol) of 2-((2-methylbenzyl)thio)-5-(2-(o-tolyl)thiazol-4-yl)-1,3,4-oxadiazole and DPDME (1 mL) were added and stirred at 80°C for 20 h. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous NaSO4, filtered, and all volatiles were evaporated under reduced pressure. The pure target compound was obtained by chromatography.

[0142] The melting point, nuclear magnetic resonance, and high-resolution mass spectrometry data of the synthesized compound were: mp 124.6-126.1°C; 1H NMR (400 MHz, CDCl3) δ: 8.35 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.43–7.26 (m, 6H), 7.21–7.14 (m, 1H), 4.90 (s, 2H), 2.64 (s, 3H), 2.48 (s, 3H). 13C NMR(101MHz, CDCl3)δ:170.40,162.33,161.62,139.16,138.45,137.02,132.20,131.78,131.46,131 .37,130.52,130.16,130.07,126.62,126.37,125.42,123.05,59.54,21.60,19.87.HRMS(ESI):calcd for C 20 H 17 N3O2S2{[M+H] +},404.0784;found,404.0784.

[0143] Example 5

[0144] 2-(Methylsulfonyl)-5-(2-phenylthiazol-4-yl)-1,3,4-thiadiazole and 2-(Methylsulfonyl)-5-(2-phenylthiazol-4-yl)-1,3,4-thiadiazole (R in Formula I) 1 H, R 2 is CH3, X is S) synthesis:

[0145] 1) Synthesis of thiobenzamide:

[0146]

[0147] To a 100 mL single-necked reaction flask, add 1.03 g (10 mmol) of benzonitrile and 20 mL of DMF. Stir to dissolve the solid completely. Add 2.03 g (10 mmol) of magnesium chloride hexahydrate at room temperature and stir to dissolve completely. Then add 1.12 g (20 mmol) of sodium hydrosulfide monohydrate. Allow to react for approximately 16 hours, monitoring with a microplate. The reaction is complete. Dilute with 70 mL of water and 10 mL of brine, and extract with 4 × 50 mL of ethyl acetate. The combined organic phases are cross-extracted with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate stripped of solvent to yield a high-purity product that can be used directly in the next step without purification.

[0148] 2) Synthesis of 2-phenylthiazole ethyl ester:

[0149]

[0150] To a 100 mL single-necked reaction flask, add 1.37 g (10 mmol) of thiobenzamide and 20 mL of anhydrous ethanol. Stir to completely dissolve the solid. Add 1.95 g (10 mmol) of ethyl 3-bromopyruvate and heat under reflux for approximately 2 h. Monitor the reaction until complete. Add saturated sodium bicarbonate solution dropwise until weakly alkaline. Remove the solvent from the reaction solution, add 50 mL of dichloromethane, and cross-extract with brine (3 × 50 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Pass the concentrate through a chromatography column and dry to obtain a yellow solid.

[0151] 3) Synthesis of 2-phenylthiazole-4-carbohydrazide:

[0152]

[0153] 3.49 g (10.90 mmol) of hydrazine hydrate was slowly added to a solution of 8.47 g (3.63 mmol) of 2-phenylthiazole ethyl ester in methanol (30 mL) and stirred at reflux for 4 h. After the reaction was complete (monitored by TLC), the crude product, 2-phenylthiazole-4-carbohydrazide, was precipitated and filtered. Purification was performed by washing with water several times.

[0154] 4) Synthesis of 5-(2-phenylthiazol-4-yl)-1,3,4-thiadiazole-2-thiol:

[0155]

[0156] In a 250mL flask, 2-phenylthiazole-4-carbohydrazide 6.78g (3.09mmol) and potassium hydroxide 5.20g (9.27mmol) are dissolved in methyl alcohol 50mL, then slowly add carbon disulfide 0.60g (7.72mmol).After at room temperature stirring 30min, the reaction is heated and refluxed for 8 hours.After reaction is completed (monitored by TLC), decompression is spin-dried for.Solid is reacted 6-12h in sulfuric acid.With frozen water diluted mixture and washed, filter.And use methanol recrystallization to obtain the target compound of purification.

[0157] 5) 2-(2-phenylthiazol-4-yl)-5-(methylthio)-1,3,4-thiadiazole:

[0158]

[0159] In a 100 mL flask, dissolve 2.61 g (10 mmol) of 5-(2-phenylthiazol-4-yl)-1,3,4-thiadiazole-2-thiol, 1.87 g (11.1 mmol) of potassium carbonate, and 1.42 g (10 mmol) of iodomethane in DMF and heat under reflux. After the reaction, pour the mixture into ice water to precipitate a solid. Filter the solid, extract it with dichloromethane, and recrystallize it from ethanol to obtain the desired product.

[0160] 6) 2-(2-phenylthiazol-4-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole:

[0161]

[0162] To a 25 mL round-bottom flask, add 0.29 g (10 mmol) of 2-(phenylthiazol-4-yl)-5-(methylthio)-1,3,4-thiadiazole, 10 mL of ethanol, and 0.62 g (0.5 mmol) of ammonium molybdate dissolved in 0.9 g (50 mmol) of 30% hydrogen peroxide. Mix and react at room temperature for 1-6 hours. Pour the mixture into distilled water; filter or extract the crude product with dichloromethane. Recrystallize from ethanol or pass through a chromatography column to obtain the pure target compound.

[0163] The melting point, H NMR, C NMR and high-resolution mass spectrometry data of the synthesized compound are: mp 170.4-171.5°C; 1 H NMR (400MHz, CDCl3) δ: 8.32 (s, 1H), 8.09–7.99 (m, 2H), 7.54 (dd, J = 5.2, 1.6Hz, 3H), 3.55 (s, 3H). 13 C NMR(101MHz, CDCl3)δ:171.78,162.07,161.98,139.02,132.14,131.32,129.20(2C),127.04(2C),124.91,43.12.HRMS(ESI):calcd forC 12 H9N3O2S3{[M+H] +},316.0160;found,316.0159.

[0164]

[0165] To a 10 mL test tube, 0.29 g (10 mmol) of 2-(phenylthiazol-4-yl)-5-(methylthio)-1,3,4-thiadiazole and DPDME (1 mL) were added and stirred at 80°C for 20 h. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over anhydrous NaSO₄, filtered, and all volatiles were evaporated under reduced pressure. Purification by column chromatography afforded the pure title compound.

[0166] The melting point, NMR and high-resolution mass spectrometry data of the synthesized compound were: mp 162.9-163.6°C; 1 H NMR (400MHz, CDCl3) δ: 8.32 (s, 1H), 8.09–7.99 (m, 2H), 7.54 (dd, J = 5.2, 1.6Hz, 3H), 3.55 (s, 3H). 13 C NMR(101MHz, CDCl3)δ:171.78,162.07,161.98,139.02,132.14,131.32,129.20(2C),127.04(2C),124.91,43.12.HRMS(ESI):calcd for C 12 H9N3OS3{[M+H] +},308.0154;found,308.0154.

[0167] Other compounds were synthesized according to the above method.

[0168] Fungicidal activity assay

[0169] The compounds synthesized by the present invention were tested for their fungicidal activity against various fungal diseases.

[0170] The experimental method is as follows: Dissolve the compound in acetone, dichloromethane, or DMSO to prepare a 500 μg / mL stock solution. Under sterile conditions, dilute the prepared 500 μg / mL stock solution with culture medium to plate a 50 μg / mL plate containing the drug. Experiments are designed as blank controls without drug treatment, and replicated three times.

[0171] The mycelial growth rate method was used to determine the growth rate of various pathogens, aseptically using a 7 mm diameter sterile punch to cut a bacterial cake from the edge of the colony. This cake was then inoculated into the center of a drug-containing plate using an inoculator and incubated in a 26 ± 2°C incubator.

[0172] The growth of pathogenic fungi hyphae was investigated according to the growth of the colonies in the blank control culture dish. After the colonies in the blank control were fully grown, the colony diameters of each treatment were measured by the cross method. The colony growth diameters were calculated using the following formula and the average value was taken.

[0173] Colony growth diameter = colony diameter - cake diameter

[0174] The determination results were calculated using the following method: the growth diameter of the blank control colony and the growth diameter of the drug-treated colony were used to calculate the mycelial growth inhibition rate of each drug treatment on various pathogens (see the formula below).

[0175] Mycelial growth inhibition rate (%) = [(control colony growth diameter - drug-treated colony growth diameter) / blank control colony growth diameter] × 100

[0176] The test results of some compounds are shown in Table 2 (wherein the compound numbers correspond to the numbers in Table 1):

[0177] Table 2: Antifungal activity test results of some compounds

[0178]

[0179]

[0180] a Three replicates per treatment

[0181] b Fg: wheat fusarium sclerotinia pathogen; Ss: rapeseed sclerotinia pathogen; Mo: rice blast pathogen; Rs: rice sheath blight pathogen

[0182] The compound synthesized by the present invention was used to carry out antibacterial activity tests on bacteria such as rice bacterial blight and ginger solanacearum.

[0183] The experimental method is as follows: the compound is dissolved in acetone or DMSO to prepare a 1000 μg / mL solution. According to the agricultural industry standard of the People's Republic of China (NY / T 1156.2-2006), the turbidity method is used for determination. 9 mL of nutrient broth (NB) medium, 1 mL of the test compound solution (final concentration: 100 μg / mL and 50 μg / mL) and 40 μL of rice bacterial blight or ginger solanacearum solution are added to a 15 mL test tube. The test tube is then incubated in a thermostatic shake flask at 180 rpm and 28±1°C for 12 to 72 hours. The optical density (OD) of the NB medium in each test tube is measured on a microplate reader (Model 680, BIO-RAD, Hercules, CA). 595) until the bacteria in the untreated NB medium are in logarithmic growth. The experiment was designed as a blank control without drug treatment, and each was repeated 3 times. The inhibition rate (%) was calculated by the following formula, where C represents the corrected absorbance value (OD) of the untreated NB medium. 595 ), T represents the NB corrected absorbance value (OD 595 ):

[0184] Inhibition rate (%) = (CT) / C×100

[0185] The test results of some compounds are shown in Table 3 (wherein the compound numbers correspond to the numbers in Table 1):

[0186] Table 3: Test results of the inhibitory activity of some compounds on rice bacterial blight

[0187]

[0188]

[0189] a Each treatment was repeated three times.

[0190] Example 6

[0191] A pesticide for controlling fungal and bacterial diseases, prepared as a 60% wettable powder, has the following formula (all components in the formula are expressed in percentage by weight), and the compound numbers are the same as in Table 1:

[0192]

[0193] The components are mixed together and crushed in a crusher until the particles reach the required size.

[0194] Example 7

[0195] A pesticide for controlling fungal and bacterial diseases is prepared as a 40% emulsifiable concentrate with the following formula (all components in the formula are expressed in percentage by weight). The compound numbers are the same as those in Table 1:

[0196]

[0197] Compound 70, PEO-10 ​​and ethoxylated triglyceride were dissolved in biodiesel to obtain a transparent solution.

[0198] Example 8

[0199] A pesticide for controlling fungal and bacterial diseases is prepared as a 30% aqueous suspension concentrate. The formula is as follows (all components in the formula are expressed in percentage by weight). The compound numbers are the same as in Table 1:

[0200]

[0201] Compound 121, 70% of the required amount of water and sodium dodecylbenzenesulfonate were ground in a ball mill, and the other components were dissolved in the remaining water, and the mixture was added with stirring and mixed uniformly to obtain an aqueous suspension.

[0202] The pesticides for preventing and controlling fungal and bacterial diseases prepared in Examples 6 to 8 have good prevention and control effects on fungal and bacterial diseases of plants after subsequent application.

[0203] The specific embodiments of the present invention described above do not limit the scope of protection of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the scope of protection of the claims of the present invention.

Claims

1. 2-(Sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compounds, characterized in that: Having the structure described in Formula I: Formula I Among them, R 1 One of the following groups: saturated C1-C8 linear or branched hydrocarbon group, C3-C8 cycloalkyl group, H and halogen; R 2 Derived from one of the following groups: saturated C1-C8 straight chain or branched hydrocarbon group, C3-C8 cycloalkyl group; X is selected from S or O; n is 2.

2. The 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound according to claim 1, characterized in that: X is selected from O; n is 2.

3. The method for preparing the 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound according to any one of claims 1 to 2, characterized in that: The compound is prepared by using different substituted benzonitriles as raw materials through the reaction described in the following reaction formula, and the steps are as follows, wherein: Hal is halogen: 。 4. Use of the 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound according to any one of claims 1 to 2 in the preparation of pesticides for controlling fungal and bacterial diseases.

5. The use according to claim 4, characterized in that The fungus is at least one of Oomycetes, Basidiomycetes, Ascomycetes and Deuteromycetes; The bacteria is at least one of rice bacterial leaf blight bacteria, citrus canker bacteria, ginger bacterial wilt bacteria and rice bacterial leaf streak disease.

6. The use according to claim 5, characterized in that The method comprises the following steps: mixing a carrier and the 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound to prepare a pesticide for preventing and controlling fungal and bacterial diseases.

7. The use according to claim 6, characterized in that The carrier is one of a plant, a seed, a solid carrier and a liquid carrier.

8. The use according to claim 7, characterized in that The solid carrier is at least one of natural or synthetic clay, silicate, calcium carbonate, calcium sulfate, synthetic silicon oxide, carbon, sulfur, natural or synthetic resin, solid polychlorinated phenol, asphalt and wax.

9. The use according to claim 7, characterized in that The liquid carrier is one or more of water, alcohol, ketone, ether, aromatic hydrocarbon, petroleum fraction and biomass oil.

10. The use according to claim 6, characterized in that The method also includes mixing a surfactant, a carrier and a 2-(sulfinyl)-5-(2-phenylthiazol-4-yl)-1,3,4-oxadiazole compound to prepare a pesticide for preventing and controlling fungal and bacterial diseases; the surfactant is at least one of Tween 20, Tween 80, fatty acid potassium soap and fatty alcohol polyoxyethylene ether.

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