Amide derivative containing benzoxazole sulfone as well as preparation method and application of amide derivative

Abstract

The invention belongs to the technical field of prevention and control of plant bacterial diseases, and particularly relates to an amide derivative containing benzoxazole sulfone and a preparation method and application thereof.The amide compound containing benzoxazole sulfone has good antibacterial activity on plant pathogenic bacteria of rice bacterial leaf blight, rice bacterial streak and citrus canker, and can be used for preventing and controlling bacterial diseases of plants such as rice bacterial leaf blight, rice bacterial streak and citrus canker. The method has the advantages of simple preparation process, excellent reaction yield and low raw material cost; the structural formula of the derivative is shown as I,

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of plant bacterial disease prevention and control, and particularly relates to a benzoxazole sulfone-containing amide derivative and a preparation method and application thereof. BACKGROUND

[0002] Plant bacterial disease is a kind of plant disease with extremely great harm, which is caused by plant pathogenic bacteria. This kind of disease spreads rapidly and has seriously restricted the planting and production of agriculture, greatly affecting the yield and health of crops (Pham, D. Q.; Ba, D. T.; Dao, N. T.; Choi, G. J.; Vu, T. T.; Kim, J. C.; Giang, T. P. L.; Vu, H. D.; Dang, Q. L. Antimicrobial efficacy of extracts and constituents fractionated from Rheum tanguticum Maxim. ex Balf. rhizomes against phytopathogenic fungi and bacteria [J]. Ind. Crops Prod. 2017, 108: 442-450.).

[0003] Benzooxazole possesses broad-spectrum biological activity. For example, the herbicides oxazolidinone and pinoxaden, developed based on the benzooxazole skeleton, have demonstrated excellent herbicidal activity in the field of herbicides. Compared with traditional herbicides, they are characterized by low dosage, high activity, faster action, and longer residual effect (Barik, SR; Ganguly, P.; Patra, S.; Dutta, SK; Goon, A.; Bhattacharyya, A. Persistence behavior of metamifop and its metabolite in rice ecosystem[J]. Chemosphere. 2018, 193: 875-882.). Amide compounds have shown remarkable potential in the field of antibacterial activity against plant pathogenic bacteria (Chen M.H., Lu DW, Zhang X., Zhou ZY, Wang X.B., Shu H. Synthesis of novel coumarin substituted amide derivatives and their antibacterial activities[J]. Chemical Papers. 2017, 71, 1579-1586.). For example, in 2020, Xiang J., Liu D., Chen J.X., Hu D.Y., Song BA Design and synthesis of novel 1,3,4-oxadiazole sulfone compounds containing 3,4-dichloroisothiazolylamide moiety and evaluation of rice bacterial activity[J]. Pestic. Biochem. Physiol. 2020, 170, 104695.) successfully synthesized a series of novel 1,3,4-oxadiazole sulfone compounds containing 1,3-dichloroisothiazolylamide structures. Bioactivity test data showed that 3,4-dichloro-N-((5-(ethylsulfonyl)-1,3,4-oxadiazol-2-yl)methyl)isothiazol-5-carboxamide and 3,4-dichloro-N-((5-(propylsulfonyl)-1,3,4-oxadiazol-2-yl)methyl)isothiazol-5-carboxamide exhibited excellent performance against rice bacterial blight, with EC50 values ​​as low as 0.79 mg / L and 0.85 mg / L, respectively. They also showed outstanding performance against rice bacterial leaf streak, with EC50 values ​​of 2.21 mg / L and 1.12 mg / L, respectively.In-depth physiological and biochemical studies have revealed that the former mainly inhibits bacterial growth by suppressing extracellular polysaccharide synthesis, increasing cell membrane permeability, and interfering with the normal function of biological membranes. In 2021, Mou Honglan et al. (Mou H.L., Shi J., Chen JX, Hu DYSynthesis, antibacterial activity and mechanism of new butenolides derivatives containing an amide moiety[J]. Pestic. Biochem. Physiol. 2021, 178, 104913.) reported a series of novel butenolide derivatives containing amide structures and studied their antibacterial activity. The compound 2-((3-fluorobenzyl)(5-oxo-2,5-dihydrofuran-3-yl)amino)-N-(4-(trifluoromethyl)phenyl)acetamide showed outstanding performance in inhibiting rice bacterial blight pathogens, with an EC50 of 35.8 mg / L, which was significantly better than the control drug tebuconazole (73.5 mg / L). In vivo experiments on rice further confirmed that at 100 mg / L, it exhibited good in vivo activity against rice bacterial blight, with therapeutic and protective activities reaching 40.9% and 48.9%, respectively, which were superior to tebuconazole (31.2% and 31.4%). Mechanistic investigation revealed that this compound may enhance the plant's disease resistance by increasing the activity of rice defense enzymes. Its protective effect against rice bacterial blight is closely related to the regulation of oxidative phosphorylation and defense enzyme activity.

[0004] Currently, there are no reports, either domestically or internationally, on the synthesis of amide derivatives containing benzoxazole sulfone and their resistance to plant pathogenic bacteria. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention proposes an amide derivative containing benzoxazole sulfone, its preparation method, and its application.

[0006] Specifically, this is achieved through the following technical solutions:

[0007] The first objective of this invention is to provide an amide derivative containing benzoxazole sulfone, the structural formula of which is shown in Figure I:

[0008]

[0009] Among them, R 1 Or R 2 It is independently selected from any one of hydrogen, chlorine, bromine, fluorine and trifluoromethyl.

[0010] Furthermore, the benzamide structure with substituents is substituted at the 5th or 6th position of the benzoxazole ring.

[0011] Furthermore, an amide derivative containing benzoxazole sulfone includes, but is not limited to:

[0012] I1: 4-Fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide;

[0013] I2: 2-Chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-4-(trifluoromethyl)benzamide;

[0014] I3: 2,4-Dichloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide;

[0015] I4: 4-Fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide;

[0016] I5: 4-Chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)2-(trifluoromethyl)benzamide;

[0017] I6: 4-Chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide;

[0018] I7: 4-Bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide;

[0019] I8: N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide;

[0020] I9: 4-Fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide;

[0021] I10: 4-Trifluoromethyl-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-2-chlorobenzamide;

[0022] I11: 2,4-Dichloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide;

[0023] I12: 4-Bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)-2-(trifluoromethyl)benzamide;

[0024] I13: 4-Chloro-N-(2-(methanesulfonyl)benzo[d]oxazol-6-yl)-2-trifluoromethylbenzamide;

[0025] I14: 4-Chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide;

[0026] I15: 4-Bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide;

[0027] I16: N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide;

[0028] The synthetic route for an amide derivative of benzoxazole sulfone is as follows:

[0029]

[0030] A second objective of this invention is to provide a method for preparing an amide derivative containing benzoxazole, comprising the following steps:

[0031] Preparation of intermediate A1 in the first step:

[0032] Nitro-substituted o-aminophenol was stirred with potassium hydroxide in anhydrous ethanol, carbon disulfide was added under ice bath, and the reaction was refluxed. The reaction was detected by TCL and the starting material disappeared. The mixture was cooled to room temperature, water was added, and the pH of the system was adjusted to 3-4 with 5% dilute hydrochloric acid. The solid was filtered to obtain intermediate A1.

[0033] Preparation of intermediate A2 in the second step:

[0034] Intermediate A1 was stirred with potassium carbonate in acetonitrile, and iodomethane was slowly added. The reaction was carried out at room temperature. The starting material disappeared as detected by TCL. Acetonitrile was removed by desolventizing under reduced pressure. The mixture was then extracted twice with ethyl acetate and saturated sodium chloride solution. The organic layers were combined and dried with anhydrous sodium sulfate. Ethyl acetate was removed by desolventizing under reduced pressure to obtain intermediate A2.

[0035] Preparation of intermediate A3 in the third step:

[0036] Intermediate A2 was stirred with ammonium chloride and iron powder in a water and ethanol solution with a volume ratio of 1:1 and refluxed. The iron powder was filtered off, and the ethanol was removed by desolvation under reduced pressure. The mixture was then extracted twice with ethyl acetate and saturated sodium chloride solution. The organic layers were combined and dried with anhydrous sodium sulfate. The ethyl acetate was removed by desolvation under reduced pressure to obtain intermediate A3.

[0037] The fourth step involves the preparation of intermediate acyl chlorides a1-a8:

[0038] The substituted benzoic acid was added to dichloromethane and stirred. Excess SOCl2 was added, followed by 5 drops of DMF. The mixture was refluxed and the reaction was observed to have disappeared by TLC. The mixture was then directly distilled under reduced pressure to obtain compounds a1-a8.

[0039] Preparation of intermediates b1-b16 in step 5

[0040] Intermediate A3 was stirred with triethylamine in dichloromethane, and compounds a1-a8 were slowly added dropwise. The reaction was carried out under ice bath conditions, and dichloromethane was removed by desolventizing under reduced pressure. The mixture was then extracted twice with saturated sodium chloride solution, the organic layers were combined and dried with anhydrous sodium sulfate, and purified by column chromatography to obtain intermediates b1-b16.

[0041] Step 6: Preparation of compounds I1-I16

[0042] Intermediates b1-b16 were stirred in anhydrous ethanol, and ammonium molybdate dissolved in hydrogen peroxide was added. The reaction was carried out at room temperature, quenched with water, and the solid was filtered to obtain the target compound I1-I16.

[0043] The column chromatography column used in the column chromatography method has a PE / EA ratio of 3 / 1.

[0044] A third objective of this invention is to provide the use of an amide derivative containing benzoxazole sulfone in the preparation of drugs for the prevention and treatment of plant pathogenic bacterial diseases.

[0045] The plant pathogenic bacterial diseases mentioned refer to rice bacterial leaf blight, rice bacterial leaf streak, and citrus canker.

[0046] An amide derivative containing benzoxazole sulfone is used as an antibacterial agent for plant pathogenic bacteria.

[0047] The plant pathogenic bacteria antibacterial agent refers to a preparation that inhibits the growth or reproduction of pathogens causing rice bacterial leaf blight, rice bacterial leaf streak, or citrus canker.

[0048] The plant pathogenic bacteria antibacterial agent refers to a preparation that kills the pathogens causing rice bacterial leaf blight, rice bacterial leaf streak, or citrus canker.

[0049] The plant pathogenic bacteria antibacterial agent includes at least the aforementioned amide derivatives containing benzoxazole sulfone.

[0050] Beneficial effects:

[0051] The derivatives of this invention have the advantages of simple preparation process, excellent reaction yield and low raw material cost.

[0052] The derivatives of this invention have excellent inhibitory activity against plant pathogenic bacteria, especially against rice bacterial blight, rice bacterial leaf streak, and citrus canker. Detailed Implementation

[0053] The specific embodiments of the present invention will be described in further detail below, but the present invention is not limited to these embodiments. Any improvements or substitutions based on the basic spirit of these embodiments shall still fall within the scope of protection claimed by the claims of the present invention.

[0054] Example 1

[0055] The preparation method of 4-fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide (compound number I1) includes the following steps:

[0056] (1) Synthesis of 5-nitrobenzo[d]oxazol-2-thiol (A1):

[0057] 2-Amino-5-nitrophenol (8.0 g, 51.91 mmol) was added to a three-necked flask containing anhydrous ethanol (60 mL) and stirred thoroughly. Potassium hydroxide (5.82 g, 103.81 mmol) was added, and the mixture was stirred at room temperature for 20 min. Carbon disulfide (11.85 g, 155.72 mmol) was then slowly added dropwise. The mixture was refluxed at 80 °C for 5 h. A yellow solid gradually precipitated from the reaction system. The reaction was monitored by TLC until completion. The mixture was cooled to room temperature, quenched with water, and the pH was adjusted to 3-4 with 5% dilute hydrochloric acid. Compound A1 was directly filtered under reduced pressure; it was a grayish-white solid with a mass of 8.65 g, yielding 84.95%.

[0058] (2) Synthesis of 2-(methylthio)-5-nitrobenzo[d]oxazole (A2):

[0059] 5-Nitrobenzo[d]oxazol-2-thiol (0.98 g, 5.26 mmol) was added to a three-necked flask containing 50 mL of acetonitrile, followed by the addition of potassium carbonate (9.86 g, 71.36 mmol) and stirring thoroughly. Iodomethane (6.08 g, 42.82 mmol) was then added, and the mixture was stirred at room temperature for 3 h. Acetonitrile was removed by desolvation under reduced pressure. The mixture was then extracted with ethyl acetate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and desolvated under reduced pressure. The final product was 5.35 g, yielding 71.33%.

[0060] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-5-amine (A3):

[0061] 2-(methylthio)-5-nitrobenzo[d]oxazole (8.65 g, 41.15 mmol) was dissolved in 5 mL of ethanol and aqueous solution (1:1 v / v). After thorough stirring, iron powder (6.89 g, 123.45 mmol) and ammonium chloride (8.80 g, 164.60 mmol) were added. The mixture was stirred at room temperature for 30 min and then refluxed at 110 °C for 2 h. The reaction was monitored by TLC until completion. Acetonitrile was removed by desolventizing under reduced pressure. The mixture was then extracted with ethyl acetate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and desolventized under reduced pressure. The final mass was 4.90 g, yielding 66.07%.

[0062] (4) Synthesis of p-fluorobenzoyl chloride (a1):

[0063] p-Fluorobenzoic acid (0.35 g, 2.50 mmol) was added to a three-necked flask containing dichloromethane (20 mL) and stirred thoroughly. 8 mL of SOCl2 was added, followed by 5 drops of DMF. The mixture was refluxed at 80 °C for 8 h. The white solid in the reaction system slowly disappeared until the system became a colorless and transparent liquid. The reaction was monitored by TLC until it was complete. The mixture was then directly distilled under reduced pressure to obtain compound a1, which was a white solid with a mass of 0.30 g and a yield of 75.74%.

[0064] (5) Synthesis of 4-fluoro-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide (b1):

[0065] 2-(methylthio)benzo[d]oxazol-5-amine (0.2 g, 1.11 mmol) was added to a 50 mL three-necked flask containing 15 mL of dichloromethane. Triethylamine (0.37 mg, 3.33 mmol) was added and the mixture was stirred thoroughly. Then, p-fluorobenzoyl chloride (0.21 mg, 1.33 mmol) was added, and the mixture was stirred at room temperature for 6 h. After the reaction was completed, the mixture was extracted three times with saturated brine. The organic layers were combined and distilled under reduced pressure to obtain 4-fluoro-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide)benzamide, with a mass of 0.21 g and a yield of 62.59%.

[0066] (6) Synthesis of 4-fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide (I1):

[0067] 4-Fluoro-N-(2-(methanesulfonyl)benzo[d]oxazol-5-yl)benzamide (0.20 g, 661.54 μmol) was dissolved in 3 mL of ethanol, and a mixture of ammonium molybdate (163.53 mg, 132.31 μmol) and hydrogen peroxide (450.03 mg, 13.23 mmol) was added. The reaction was carried out at room temperature for 8 h. The reaction was quenched by adding 20 mL of water, filtered, and washed with a small amount of ethanol to give the target compound I1, yielding 168.00 mg of a white solid, with a yield of 76.2%.

[0068] Physicochemical properties of compound I1: white solid, melting point 112.1-113.5℃.

[0069] Example 2

[0070] A method for preparing 2-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-4-(trifluoromethyl)benzamide (compound number I2) includes the following steps:

[0071] (1) Synthesis of 5-nitrobenzo[d]oxazol-2-thiol (A1):

[0072] As in Example 1(1), the method and conditions are synthesized.

[0073] (2) Synthesis of 2-(methylthio)-5-nitrobenzo[d]oxazole (A2):

[0074] As in Example 1(2), the method and conditions are synthesized.

[0075] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-5-amine (A3):

[0076] As in Example 1(3), the method and conditions are synthesized.

[0077] (4) Synthesis of 2-chloro-4-trifluoromethylbenzoyl chloride (a2):

[0078] The synthesis was performed using the same method and conditions as in Example 1(4), except that 2-chloro-4-trifluoromethylbenzoyl chloride (350.00 mg, 1.56 mmol) was added to obtain 280.00 mg of 2-chloro-4-trifluoromethylbenzoyl chloride, which was a yellow oily substance with a yield of 73.93%.

[0079] (5) Synthesis of 2-chloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)-4-(trifluoromethyl)benzamide (b2):

[0080] The synthesis was performed using the same method and conditions as in Example 1(5), except that 2-chloro-4-trifluoromethylbenzoyl chloride (323.60 mg, 1.33 mmol) was added to obtain 330.00 mg of 2-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-4-(trifluoromethyl)benzamide, which was a white solid with a yield of 76.89%.

[0081] (6) Synthesis of 2-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-4-(trifluoromethyl)benzamide (I2):

[0082] The synthesis was performed using the same method and conditions as in Example 1(6), except that 2-chloro-N-(2-(methanesulfonyl)benzo[d]oxazol-5-yl)-4-(trifluoromethyl)benzamide (150.00 mg, 425.74 μmol) was added to obtain 75.30 mg of 2-chloro-N-(2-(methanesulfonyl)benzo[d]oxazol-5-yl)-4-(trifluoromethyl)benzamide as a white solid with a yield of 46.2%.

[0083] Physicochemical properties of compound I2: white solid, melting point 171.3-172.6℃.

[0084] Example 3

[0085] A method for preparing 2,4-dichloro-N-(2-(methanesulfonyl)benzo[d]oxazol-5-yl)benzamide (compound number I3) includes the following steps:

[0086] (1) Synthesis of 5-nitrobenzo[doxazol-2-thiol (A1):

[0087] As in Example 1(1), the method and conditions are synthesized.

[0088] (2) Synthesis of 2-(methylthio)-5-nitrobenzo[d]oxazole (A2):

[0089] As in Example 1(2), the method and conditions are synthesized.

[0090] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-5-amine (A3):

[0091] As in Example 1(3), the method and conditions are synthesized.

[0092] (4) Synthesis of 2,4-dichlorobenzoyl chloride (a3):

[0093] The synthesis was performed using the same method and conditions as in Example 1(4), except that 2,4-dichlorobenzoic acid (300.00 mg, 1.57 mmol) was added to obtain 310.00 mg of 2,4-dichlorobenzoyl chloride, which was a yellow oily substance with a yield of 94.23%.

[0094] (5) Synthesis of 2,4-dichloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide (b3):

[0095] Synthesized using the same method and conditions as in Example 1(5), except that 2,4-dichlorobenzoyl chloride (323.60 mg, 1.33 mmol) was added to obtain 330.00 mg of 2,4-dichloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide as a white solid with a yield of 84.19%.

[0096] (6) Synthesis of 2,4-dichloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide:

[0097] Synthesized using the method and conditions of Example 1(6), except that 2,4-dichloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide (150.00 mg, 425.74 μol) was added to obtain 94.57 mg of 2,4-dichloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide as a white solid with a yield of 57.8%.

[0098] Physicochemical properties of compound I3: white solid, melting point 155.3-156.6℃.

[0099] Example 4

[0100] The preparation method of 4-bromo-N-(2-(methanesulfonyl)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide (compound number I4) includes the following steps:

[0101] (1) Synthesis of 5-nitrobenzo[d]oxazol-2-thiol (A1):

[0102] As in Example 1(1), the method and conditions are synthesized.

[0103] (2) Synthesis of 2-(methylthio)-5-nitrobenzo[d]oxazole (A2):

[0104] As in Example 1(2), the method and conditions are synthesized.

[0105] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-5-amine (A3):

[0106] As in Example 1(3), the method and conditions are synthesized.

[0107] (4) Synthesis of 2-trifluoromethyl-4-bromobenzoyl chloride (a4):

[0108] Synthesized using the same method and conditions as in Example 1(4), except that 2-trifluoromethyl-4-bromobenzoic acid (400.00 mg, 1.49 mmol) was added to obtain 390.00 mg of 2-trifluoromethyl-4-bromobenzoyl chloride, which was a yellow oily substance with a yield of 91.24%.

[0109] (5) Synthesis of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide (b4):

[0110] The synthesis was performed using the same method and conditions as in Example 1(5), except that 2-trifluoromethyl-4-bromobenzoyl chloride (390.00 mg, 1.36 mmol) was added to obtain 360.00 mg of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide, a white solid with a yield of 75.23%.

[0111] (6) Synthesis of 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide (I4):

[0112] The synthesis was performed using the same method and conditions as in Example 1(6), except that 4-bromo-N-(2-(methylthio)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide (150.00 mg, 347.84 μmol) was added to obtain 117.46 mg of 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide, which was a white solid with a yield of 72.9%.

[0113] Physicochemical properties of compound I4: white solid, melting point 125.4-125.7℃.

[0114] Example 5

[0115] A method for preparing 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-2-(trifluoromethyl)benzamide (compound number I5) includes the following steps:

[0116] (1) Synthesis of 5-nitrobenzo[d]oxazol-2-thiol (A1):

[0117] As in Example 1(1), the method and conditions are synthesized.

[0118] (2) Synthesis of 2-(methylthio)-5-nitrobenzo[d]oxazole (A2):

[0119] As in Example 1(2), the method and conditions are synthesized.

[0120] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-5-amine (A3):

[0121] As in Example 1(3), the method and conditions are synthesized.

[0122] (4) Synthesis of 2-trifluoromethyl-4-chlorobenzoyl chloride (a5):

[0123] The synthesis was performed using the same method and conditions as in Example 1(4), except that 2-trifluoromethyl-4-chlorobenzoic acid (350.00 mg, 1.56 mmol) was added to obtain 330.00 mg of 2-trifluoromethyl-4-bromobenzoyl chloride, which was a yellow oily substance with a yield of 87.13%.

[0124] (5) Synthesis of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)-2-(trifluoromethyl)benzamide (b5):

[0125] Synthesized using the same method and conditions as in Example 1(5), except that 2-trifluoromethyl-4-chlorobenzoyl chloride (330.00 mg, 1.33 mmol) was added to obtain 310.00 mg of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)-2-(trifluoromethyl)benzamide, a white solid with a yield of 72.23%.

[0126] (6) Synthesis of 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-2-(trifluoromethyl)benzamide (I5):

[0127] The synthesis was performed using the same method and conditions as in Example 1(6), except that 150.00 mg (347.84 μmol) of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)-2-(trifluoromethyl)benzamide was added to obtain 106.40 mg of 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide as a white solid with a yield of 31.7%.

[0128] Physicochemical properties of compound I5: white solid, melting point 181.6-182.3℃.

[0129] Example 6

[0130] A method for preparing 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide (compound number I6) includes the following steps:

[0131] (1) Synthesis of 5-nitrobenzo[d]oxazol-2-thiol (A1):

[0132] As in Example 1(1), the method and conditions are synthesized.

[0133] (2) Synthesis of 2-(methylthio)-5-nitrobenzo[d]oxazole (A2):

[0134] As in Example 1(2), the method and conditions are synthesized.

[0135] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-5-amine (A3):

[0136] As in Example 1(3), the method and conditions are synthesized.

[0137] (4) Synthesis of 4-chlorobenzoyl chloride (a6):

[0138] Synthesized using the same method and conditions as in Example 1(4), except that 4-chlorobenzoic acid (300.00 mg, 1.71 mmol) was added to obtain 300.00 mg of 4-chlorobenzoyl chloride, which was a yellow oily substance with a yield of 89.46%.

[0139] (5) Synthesis of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide (b6):

[0140] Synthesized using the same method and conditions as in Example 1(5), except that 4-chlorobenzoyl chloride (300.00 mg, 1.71 mmol) was added to obtain 270.00 mg of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide, a white solid with a yield of 76.32%.

[0141] (6) Synthesis of 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide (I6):

[0142] The synthesis was performed using the same method and conditions as in Example 1(6), except that 150.00 mg (347.84 μmol) of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide was added to obtain 106.06 mg of 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide as a white solid with a yield of 35.7%.

[0143] Physicochemical properties of compound I6: white solid, melting point 118.1-119.4℃.

[0144] Example 7

[0145] A method for preparing 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide (compound number I7) includes the following steps:

[0146] (1) Synthesis of 5-nitrobenzo[d]oxazol-2-thiol (A1):

[0147] As in Example 1(1), the method and conditions are synthesized.

[0148] (2) Synthesis of 2-(methylthio)-5-nitrobenzo[d]oxazole A2:

[0149] As in Example 1(2), the method and conditions are synthesized.

[0150] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-5-amine (A3):

[0151] As in Example 1(3), the method and conditions are synthesized.

[0152] (4) Synthesis of 4-bromobenzoyl chloride (a7):

[0153] Synthesized using the same method and conditions as in Example 1(4), except that 4-bromobenzoic acid (310.00 mg, 1.46 mmol) was added to obtain 320.00 mg of 4-bromobenzoyl chloride, which was a yellow oily substance with a yield of 94.55%.

[0154] (5) Synthesis of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide (b7):

[0155] Synthesized using the same method and conditions as in Example 1(5), except that 4-bromobenzoyl chloride (320.00 mg, 1.46 mmol) was added to obtain 310.00 mg of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide, a white solid with a yield of 76.91%.

[0156] (6) Synthesis of 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide (I7):

[0157] The synthesis was performed using the same method and conditions as in Example 1(6), except that 200.00 mg of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide (627.40 μmol) was added to obtain 65.12 mg of 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide as a white solid with a yield of 29.6%.

[0158] Physicochemical properties of compound I7: white solid, melting point 151.7-152.8℃.

[0159] Example 8

[0160] The preparation method of N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide (compound number I8) includes the following steps:

[0161] (1) Synthesis of 5-nitrobenzo[d]oxazol-2-thiol (A1):

[0162] As in Example 1(1), the method and conditions are synthesized.

[0163] (2) Synthesis of 2-(methylthio)-5-nitrobenzo[d]oxazole (A2):

[0164] As in Example 1(2), the method and conditions are synthesized.

[0165] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-5-amine (A3):

[0166] As in Example 1(3), the method and conditions are synthesized.

[0167] (4) Synthesis of benzoyl chloride (a8):

[0168] The synthesis was performed using the same method and conditions as in Example 1(4), except that benzoic acid (360.00 mg, 1.46 mmol) was added to obtain 380.00 mg of benzoyl chloride, which was a yellow oily substance with a yield of 91.71%.

[0169] (5) Synthesis of N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide (b8):

[0170] The synthesis was performed using the same method and conditions as in Example 1(5), except that benzoyl chloride (380.00 mg, 2.70 mmol) was added to obtain N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide 350.00 mg, which was a white solid with a yield of 82.71%.

[0171] (6) Synthesis of N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide (I8):

[0172] The synthesis was performed using the same method and conditions as in Example 1(6), except that N-(2-(methylthio)benzo[d]oxazol-5-yl)benzamide (200.00 mg, 1.23 mmol) was added to obtain 192.08 mg of N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide as a white solid with a yield of 45.1%.

[0173] Physicochemical properties of compound I8: white solid, melting point 192.7-193.8℃.

[0174] Example 9

[0175] The preparation method of 4-fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide (compound number I9) includes the following steps:

[0176] (1) Synthesis of 6-nitrobenzo[d]oxazol-2-thiol (A1):

[0177] Synthesized as described in Example 1(1) using the same method and conditions. The difference was the addition of 2-amino-6-nitrophenol (8.0 g, 51.91 mmol) to yield 6.42 g of 2-(methylthio)-6-nitrobenzo[d]oxazole, with a yield of 93.7%.

[0178] (2) Synthesis of 2-(methylthio)-6-nitrobenzo[d]oxazole (A2):

[0179] Synthesized as described in Example 1(2) using the same method and conditions. The difference was the addition of 6-nitrobenzo[d]oxazole-2-thiol (5.98 g, 5.26 mmol) to yield 6.72 g of 2-(methylthio)-6-nitrobenzo[d]oxazole, in 73.42% yield.

[0180] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-6-amine (A3):

[0181] Synthesized as described in Example 1(3) using the same method and conditions. The difference was the addition of 2-(methylthio)-6-nitrobenzo[d]oxazole (8.65 g, 41.15 mmol), yielding 5.13 g of 2-(methylthio)benzo[d]oxazole-6-amine in 71.02% yield.

[0182] (4) Synthesis of p-fluorobenzoyl chloride (a1):

[0183] As in Example 1(4), the method and conditions are synthesized.

[0184] (5) Synthesis of 4-fluoro-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide (b9):

[0185] Synthesized using the same method and conditions as in Example 1(5), except that p-fluorobenzoyl chloride (290.00 mg, 1.83 mmol) was added to obtain 319.00 mg of 4-fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide, a white solid with a yield of 70.43%.

[0186] (6) Synthesis of 4-fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide (I9):

[0187] The synthesis was performed using the same method and conditions as in Example 1(6), except that 200.00 mg (661.54 μmol) of 4-fluoro-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide was added to obtain 150.61 mg of 4-fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide as a white solid with a yield of 68.1%.

[0188] Physicochemical properties of compound I9: white solid, melting point 183.2-184.6℃.

[0189] Example 10

[0190] A method for preparing 4-trifluoromethyl-N-(2-(methanesulfonyl)benzo[d]oxazol-5-yl)-2-chlorobenzamide (compound number I10) includes the following steps:

[0191] (1) Synthesis of 6-nitrobenzo[d]oxazol-2-thiol (A1):

[0192] As in Example 9(1), the method and conditions are synthesized.

[0193] (2) Synthesis of 2-(methylthio)-6-nitrobenzo[d]oxazole (A2):

[0194] As in Example 9(2), the method and conditions are synthesized.

[0195] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-6-amine (A3):

[0196] As in Example 9(3), the method and conditions are synthesized.

[0197] (4) Synthesis of 2-chloro-4-trifluoromethylbenzoyl chloride (a2):

[0198] As in Example 1(4), the method and conditions are synthesized.

[0199] (5) Synthesis of 4-trifluoromethyl-N-(2-(methylthio)benzo[d]oxazol-6-yl)-2-chlorobenzamide (b10):

[0200] Synthesized using the same method and conditions as in Example 9(5), except that 2-chloro-4-trifluoromethylbenzoyl chloride (298.00 mg, 1.23 mmol) was added to obtain 450.00 mg of 4-trifluoromethyl-N-(2-(methylthio)benzo[d]oxazol-6-yl)-2-chlorobenzamide as a white solid with a yield of 77.66%.

[0201] (6) Synthesis of 4-trifluoromethyl-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-2-chlorobenzamide:

[0202] The synthesis was performed using the same method and conditions as in Example 9(6), except that 200.00 mg (661.54 μmol) of 4-trifluoromethyl-N-(2-(methylthio)benzo[d]oxazol-5-yl)-2-chlorobenzamide was added to obtain 87.05 mg of 4-trifluoromethyl-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-2-chlorobenzamide as a white solid with a yield of 40.2%.

[0203] Physicochemical properties of compound I10: white solid, melting point 146.7-147.1℃.

[0204] Example 11

[0205] A method for preparing 2,4-dichloro-N-(2-(methanesulfonyl)benzo[d]oxazol-6-yl)benzamide (compound number I11) includes the following steps:

[0206] (1) Synthesis of 6-nitrobenzo[d]oxazol-2-thiol (A1):

[0207] As in Example 9(1), the method and conditions are synthesized.

[0208] (2) Synthesis of 2-(methylthio)-6-nitrobenzo[d]oxazole (A2):

[0209] As in Example 9(2), the method and conditions are synthesized.

[0210] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-6-amine (A3):

[0211] As in Example 9(3), the method and conditions are synthesized.

[0212] (4) Synthesis of 2,4-dichlorobenzoyl chloride (a3):

[0213] As in Example 1(4), the method and conditions are synthesized.

[0214] (5) Synthesis of 2,4-dichloro-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide (b11):

[0215] Synthesized using the same method and conditions as in Example 9(5), except that 2,4-dichlorobenzoyl chloride (281.00 mg, 1.34 mmol) was added to obtain 318.00 mg of 2,4-dichloro-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide as a white solid with a yield of 81.13%.

[0216] (6) Synthesis of 2,4-dichloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide (I11):

[0217] The synthesis was performed using the same method and conditions as in Example 9(6), except that 2,4-dichloro-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide (200.00 mg, 661.54 μmol) was added to obtain 122 mg of 2,4-dichloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide as a white solid with a yield of 56.1%.

[0218] Physicochemical properties of compound I11: white solid, melting point 176.1-178.2℃.

[0219] Example 12

[0220] A method for preparing 4-bromo-N-(2-(methanesulfonyl)benzo[d]oxazol-6-yl)-2-(trifluoromethyl)benzamide (compound number I12) includes the following steps:

[0221] (1) Synthesis of 6-nitrobenzo[d]oxazol-2-thiol (A1):

[0222] As in Example 9(1), the method and conditions are synthesized.

[0223] (2) Synthesis of 2-(methylthio)-6-nitrobenzo[d]oxazole (A2):

[0224] As in Example 9(2), the method and conditions are synthesized.

[0225] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-6-amine (A3):

[0226] As in Example 9(3), the method and conditions are synthesized.

[0227] (4) Synthesis of 4-bromo-2-trifluoromethylbenzoyl chloride (a4):

[0228] As in Example 9(4), the method and conditions are synthesized.

[0229] (5) Synthesis of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-6-yl)-2-(trifluoromethyl)benzamide (b12):

[0230] Synthesized using the same method and conditions as in Example 9(5), except that 4-bromo-2-trifluoromethyl (370.00 mg, 1.29 mmol) was added to obtain 350.00 mg of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-6-yl)-2-(trifluoromethyl)benzamide as a white solid with a yield of 73.14%.

[0231] (6) Synthesis of 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)-2-(trifluoromethyl)benzamide (I12):

[0232] The synthesis was performed using the same method and conditions as in Example 9(6), except that 200.00 mg (463.79 μmol) of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-6-yl)-2-(trifluoromethyl)benzamide was added to obtain 75.54 mg of 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)-2-(trifluoromethyl)benzamide as a white solid with a yield of 35.3%.

[0233] Physicochemical properties of compound I12: white solid, melting point 156.3-157.2℃.

[0234] Example 13

[0235] A method for preparing 4-chloro-N-(2-(methanesulfonyl)benzo[d]oxazol-6-yl)-2-trifluoromethylbenzamide (compound number I13) includes the following steps:

[0236] (1) Synthesis of 6-nitrobenzo[d]oxazol-2-thiol (A1):

[0237] As in Example 9(1), the method and conditions are synthesized.

[0238] (2) Synthesis of 2-(methylthio)-6-nitrobenzo[d]oxazole (A2):

[0239] As in Example 9(2), the method and conditions are synthesized.

[0240] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-6-amine (A3):

[0241] As in Example 9(3), the method and conditions are synthesized.

[0242] (4) Synthesis of 4-chloro-2-trifluoromethylbenzoyl chloride (a5):

[0243] As in Example 1(4), the method and conditions are synthesized.

[0244] (5) Synthesis of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-6-yl)-2-trifluoromethylbenzamide (I13):

[0245] Synthesized using the same method and conditions as in Example 9(5), except that 4-chloro-2-trifluoromethylbenzoyl chloride (362.00 mg, 1.49 mmol) was added to obtain 310.00 mg of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-6-yl)-2-trifluoromethylbenzamide as a white solid with a yield of 72.23%.

[0246] (6) Synthesis of 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)-2-trifluoromethylbenzamide (I13):

[0247] The synthesis was performed using the same method and conditions as in Example 9(6), except that 200.00 mg (463.79 μmol) of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-6-yl)-2-trifluoromethylbenzamide was added to obtain 141.00 mg of 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)-2-trifluoromethylbenzamide as a white solid with a yield of 65.4%.

[0248] Physicochemical properties of compound I13: white solid, melting point 121.3-122.2℃.

[0249] Example 14

[0250] A method for preparing 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide (compound number I14) includes the following steps:

[0251] (1) Synthesis of 6-nitrobenzo[d]oxazol-2-thiol (A1):

[0252] As in Example 9(1), the method and conditions are synthesized.

[0253] (2) Synthesis of 2-(methylthio)-6-nitrobenzo[d]oxazole (A2):

[0254] As in Example 9(2), the method and conditions are synthesized.

[0255] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-6-amine (A3):

[0256] As in Example 9(3), the method and conditions are synthesized.

[0257] (4) Synthesis of 4-chlorobenzoyl chloride (a6):

[0258] As in Example 1(4), the method and conditions are synthesized.

[0259] (5) Synthesis of 4-chloro-N-(2-(methylthiobenzo[d]oxazol-6-yl)benzamide (b14):

[0260] Synthesized using the same method and conditions as in Example 9(5), except that 4-chlorobenzoyl chloride (390.00 mg, 2.23 mmol) was added to obtain 297.00 mg of 4-chloro-N-(2-(methylthiobenzo[d]oxazol-6-yl)benzamide, a white solid with a yield of 69.20%.

[0261] (6) Synthesis of 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide (I14):

[0262] The synthesis was performed using the same method and conditions as in Example 1(6), except that 200.00 mg of 4-chloro-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide (627.40 μmol) was added to obtain 159.33 mg of 4-chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-2-trifluoromethylbenzamide as a white solid with a yield of 72.4%.

[0263] Physicochemical properties of compound I14: white solid, melting point 137.3-138.6℃.

[0264] Example 15

[0265] A method for preparing 4-bromo-N-(2-(methanesulfonyl)benzo[d]oxazol-6-yl)benzamide (compound number I15) includes the following steps:

[0266] (1) Synthesis of 6-nitrobenzo[d]oxazol-2-thiol (A1):

[0267] As in Example 9(1), the method and conditions are synthesized.

[0268] (2) Synthesis of 2-(methylthio)-6-nitrobenzo[d]oxazole (A2):

[0269] As in Example 9(2), the method and conditions are synthesized.

[0270] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-6-amine (A3):

[0271] As in Example 9(3), the method and conditions are synthesized.

[0272] (4) Synthesis of 4-bromobenzoyl chloride (a7):

[0273] As in Example 1(4), the method and conditions are synthesized.

[0274] (5) Synthesis of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide (b15):

[0275] Synthesized using the same method and conditions as in Example 9(5), except that 4-bromobenzoyl chloride (420.00 mg, 1.91 mmol) was added to obtain 380.00 mg of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide as a white solid with a yield of 70.83%.

[0276] (6) Synthesis of 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide (I15):

[0277] The synthesis was performed using the same method and conditions as in Example 1(6), except that 250.00 mg (688.27 μmol) of 4-bromo-N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide was added to obtain 158.30 mg of 4-bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide as a white solid with a yield of 58.2%.

[0278] Physicochemical properties of compound I15: white solid, melting point 116.8-117.1℃.

[0279] Example 16

[0280] The preparation method of N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide (compound number I16) includes the following steps:

[0281] (1) Synthesis of 6-nitrobenzo[d]oxazol-2-thiol (A1):

[0282] As in Example 9(1), the method and conditions are synthesized.

[0283] (2) Synthesis of 2-(methylthio)-6-nitrobenzo[d]oxazole (A2):

[0284] As in Example 9(2), the method and conditions are synthesized.

[0285] (3) Synthesis of 2-(methylthio)benzo[d]oxazol-6-amine (A3):

[0286] As in Example 9(3), the method and conditions are synthesized.

[0287] (4) Synthesis of benzoyl chloride (a8):

[0288] As in Example 1(4), the method and conditions are synthesized.

[0289] (5) Synthesis of N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide (b16):

[0290] Synthesized using the same method and conditions as in Example 9(5), except that benzoyl chloride (340.00 mg, 2.42 mmol) was added to obtain 157.00 mg of N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide as a white solid with a yield of 39.81%.

[0291] (6) Synthesis of N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide (I16):

[0292] The synthesis was performed using the same method and conditions as in Example 1(6), except that N-(2-(methylthio)benzo[d]oxazol-6-yl)benzamide (250.00 mg, 688.27 μmol) was added to obtain 135.40 mg of N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide as a white solid with a yield of 48.7%.

[0293] Physicochemical properties of compound I16: white solid, melting point 112.8-113.1℃.

[0294] 1H NMR spectrum of a novel synthesized benzoxazole sulfone-containing amide derivative ( 1 HNMR and carbon nuclear magnetic resonance (NMR) 13 The C NMR data are shown in Table 1 and Table 2, respectively.

[0295] Table 1. Target compounds obtained in Examples I1-I6 1 HNMR data

[0296]

[0297]

[0298]

[0299]

[0300] Table 2 shows the target compounds obtained in Examples I1-I16. 13 C NMR data

[0301]

[0302]

[0303] Test Example: Antimicrobial Activity Tests against Plant Pathogenic Fungi (Examples I1-I16)

[0304] (1) Activation of plant pathogenic bacteria

[0305] Rice bacterial blight pathogen, rice bacterial leaf streak pathogen, and citrus canker pathogen need to be activated 3-4 days in advance before use.

[0306] (2) Antibacterial activity test against plant pathogens

[0307] Preparation of NB medium: NB medium, also known as nutrient broth medium, is widely used in bacterial culture and antibacterial activity assays.

[0308] Preparation method of NB medium: First, activate the pathogens with nutrient agar (NA) medium. The formula for NA medium is: 0.1% yeast extract, 0.3% beef peptone, 0.5% peptone, 1% glucose, and 2% agar. Adjust the pH to 7.0-7.2 with 5% sodium hydroxide solution to ensure optimal bacterial growth conditions. After the medium is prepared, autoclave at 121°C for 20 minutes. The difference with NB medium is that no agar powder is added.

[0309] Experimental method: Accurately weigh 3 mg of the target compound, dissolve it in 150 μL of dimethyl sulfoxide (DMSO), and prepare 0.1 mL solutions of compounds with a concentration of 50 mg / L. -1 / 100mg L -1The test solution was placed in centrifuge tubes (15 mL). Then, 3.9 mL of 0.1% Tween-20 solution was added to each solution and mixed thoroughly. The mixture was then dispensed sequentially into sterilized test tubes (15 mL), and 4 mL of NB medium was added. 40 μL of logarithmic growth phase Xoo bacterial suspension was inoculated. The test tubes containing the above system were placed in a constant temperature shaker (28℃, 180 r / min) for 24-36 h. After culturing, the OD of the bacterial suspension in each test tube was measured at a wavelength of 595 nm. 595 Values ​​were determined. DMSO was used as a blank control, and thiabendazole and tebuconazole were used as positive controls. Each experiment was conducted in triplicate.

[0310] To accurately calculate the inhibitory efficacy of the target compound against plant pathogens, the measured OD values ​​were used... 595 The value is corrected, and the OD is corrected. 595 The formulas for calculating the value and the inhibition rate of antibacterial activity are shown in Figure 1.

[0311] Correcting OD 595 Value = OD of bacterial solution 595 Value - OD of sterile culture medium 595 value

[0312]

[0313] Table 3. Activity against plant pathogenic bacteria

[0314]

[0315] Benzooxazole compounds exhibited good antifungal activity against *Bacillus oryzae*, the causal agent of rice bacterial leaf blight, and *Bacillus streak*, the causal agent of rice bacterial leaf streak. Most of the target compounds showed inhibition rates exceeding 50% against *Bacillus oryzae* at 50 mg / L. For example, compounds I2, I5, I6, I9, I10, I11, I13, I14, and I15 showed inhibition rates exceeding 90% against *Bacillus oryzae*, specifically 98.0% and 100%, respectively. Some compounds showed inhibition rates exceeding 50% against *Bacillus streak*; for instance, at 50 mg / L, compounds I2, I4, and I5 showed inhibition rates of 94.2%, 57.5%, and 92.4%, respectively.

[0316] Table 4. Effects of amide derivatives containing benzoxazole sulfone on the EC50 of Xoo 50 Value determination

[0317]

[0318]

[0319] As shown in Table 4, some of the target compounds exhibited good antibacterial activity against Xoo. Among them, compound I5 showed good antibacterial activity against the EC5 of Xoo. 50 The concentration was 2.2 mg / L, and its antibacterial activity was significantly better than that of the control drug.

Claims

1. An amide derivative containing benzoxazole sulfone, characterized in that, The structural formula of the derivative is shown in Figure I: Among them, R 1 Or R 2 It is independently selected from any one of hydrogen, chlorine, bromine, fluorine and trifluoromethyl.

2. The amide derivative containing benzoxazole sulfone as described in claim 1, characterized in that, The substitution refers to the substitution of the benzamide structure with a substituent at the 5th or 6th position of the benzoxazole ring.

3. An amide derivative containing benzoxazole sulfone as described in claim 1 or 2, characterized in that, The amide derivatives containing benzoxazole sulfone include, but are not limited to: I1: 4-Fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide; I2: 2-Chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-4-(trifluoromethyl)benzamide; I3: 2,4-Dichloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide; I4: 4-Fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)(-2-(trifluoromethyl)benzamide; I5: 4-Chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)2-(trifluoromethyl)benzamide; I6: 4-Chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide; I7: 4-Bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide; I8: N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)benzamide; I9: 4-Fluoro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide; I10: 4-Trifluoromethyl-N-(2-(methylsulfonyl)benzo[d]oxazol-5-yl)-2-chlorobenzamide; I11: 2,4-Dichloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide; I12: 4-Bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)-2-(trifluoromethyl)benzamide; I13: 4-Chloro-N-(2-(methanesulfonyl)benzo[d]oxazol-6-yl)-2-trifluoromethylbenzamide; I14: 4-Chloro-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide; I15: 4-Bromo-N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide; I16: N-(2-(methylsulfonyl)benzo[d]oxazol-6-yl)benzamide.

4. A method for preparing a benzoxazole-containing amide derivative as described in any one of claims 1-4, characterized in that, Includes the following steps: Preparation of intermediate A1 in the first step: Nitro-substituted o-aminophenol was stirred with potassium hydroxide in anhydrous ethanol, carbon disulfide was added under ice bath, and the reaction was refluxed. The reaction was detected by TCL and the starting material disappeared. The mixture was cooled to room temperature, water was added, and the pH of the system was adjusted to 3-4 with 5% dilute hydrochloric acid. The solid was filtered to obtain intermediate A1. Preparation of intermediate A2 in the second step: Intermediate A1 was stirred with potassium carbonate in acetonitrile, and iodomethane was slowly added. The reaction was carried out at room temperature. The starting material disappeared as detected by TCL. Acetonitrile was removed by desolventizing under reduced pressure. The mixture was then extracted twice with ethyl acetate and saturated sodium chloride solution. The organic layers were combined and dried with anhydrous sodium sulfate. Ethyl acetate was removed by desolventizing under reduced pressure to obtain intermediate A2. Preparation of intermediate A3 in the third step: Intermediate A2 was stirred with ammonium chloride and iron powder in a water and ethanol solution with a volume ratio of 1:1 and refluxed. The iron powder was filtered off, and the ethanol was removed by desolvation under reduced pressure. The mixture was then extracted twice with ethyl acetate and saturated sodium chloride solution. The organic layers were combined and dried with anhydrous sodium sulfate. The ethyl acetate was removed by desolvation under reduced pressure to obtain intermediate A3. The fourth step involves the preparation of intermediate acyl chlorides a1-a8: The substituted benzoic acid was added to dichloromethane and stirred. Excess SOCl2 was added, followed by 5 drops of DMF. The mixture was refluxed and the reaction was observed to have disappeared by TLC. The mixture was then directly distilled under reduced pressure to obtain compounds a1-a8. Preparation of intermediates b1-b16 in step 5 Intermediate A3 was stirred with triethylamine in dichloromethane, and then acyl chlorides (a1-a8) were added. The reaction was carried out at room temperature, and dichloromethane was removed by desolvation under reduced pressure. The mixture was then extracted twice with saturated sodium chloride solution, the organic layers were combined and dried with anhydrous sodium sulfate, and purified by column chromatography to obtain intermediates b1-b16. Step 6: Preparation of compounds I1-I16 Intermediates b1-b16 were stirred in anhydrous ethanol, and ammonium molybdate dissolved in hydrogen peroxide was added. The reaction was carried out at room temperature, quenched with water, and the solid was filtered to obtain the target compound I1-I16. The column chromatography column used in the column chromatography method has a PE / EA ratio of 3 / 1.

5. The use of a benzoxazole-containing amide derivative as described in any one of claims 1-4, or a benzoxazole-containing amide derivative prepared by the preparation method as described in claim 5, in the preparation of drugs for preventing and controlling plant pathogenic bacterial diseases.

6. The application as described in claim 6, characterized in that, The plant pathogenic bacterial diseases mentioned refer to rice bacterial leaf blight, rice bacterial leaf streak, and citrus canker.

7. An amide derivative containing benzoxazole as described in any one of claims 1-4, or an amide derivative containing benzoxazole sulfone prepared by the preparation method described in claim 5, used as an antibacterial agent for plant pathogenic bacteria.

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