Preparation and application of N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide

Abstract

The present invention relates to a new class of compounds, preparation methods and applications thereof, specifically N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)arylformamide compounds, preparation methods thereof, and applications thereof in preparing anti-plant pathogenic fungi drugs. The structural formula of the compound N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)arylformamide compound is as shown in Formula I: #imgabs0#; wherein R is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 5-pyrimidinyl, 2-pyridinyl, furan-2-methyl, and thiophene-2-methyl.

Description

Technical Field

[0001] The present invention relates to a new class of compounds, a preparation method and application thereof, in particular to N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide, a preparation method and application thereof. Background Art

[0002] Botryosphaeria dothidea is a widespread pathogen that poses a serious threat to a wide range of crops. It can infect a wide range of plants, causing disease. For example, it can cause trunk and branch diseases in apple and pear trees, resulting in bark rot and ulcers, affecting the growth and yield of the trees, and in severe cases, even the death of the trees. It can also cause diseases in some economic crops, such as grapes, affecting their quality and yield. It can also attack forest trees, causing damage to forest ecosystems. Furthermore, when Botryosphaeria infects plants, it impairs their physiological functions, reduces their resistance to stress, and makes them more susceptible to other pests and diseases.

[0003] Currently, the most common method for controlling Botrytis cinerea is spraying with fungicides. However, the long-term use of certain fungicides alone not only leads to the development of resistance in the pathogen, reducing control effectiveness, but also has certain impacts on the environment and non-target organisms. Therefore, the search for green, highly effective fungicides with novel mechanisms of action has become a key focus of pesticide research.

[0004] According to literature reports, 1,2,4-oxadiazole derivatives exhibit broad-spectrum biological activity. For example, Yang et al. designed and synthesized a series of novel 4-(1,2,4-oxadiazole-3-yl)-N-(4-phenoxyphenyl)benzamide derivatives and tested the antifungal activity of the target compounds. Preliminary in vitro antifungal tests showed that compound 3e had significant antifungal activity against tomato early blight (Alternariasolani), gray mold (Botrytis cinerea) and sclerotinia (Sclerotinia sclerotiorum), which was better than the positive control boscalid (Chem Biodivers., 2021, 18, 12). Liu et al. designed and synthesized a series of novel 1,2,4-oxadiazole derivatives containing amide fragments. Compound F15 showed excellent antifungal activity against sclerotinia (S. sclerotiorum) and in vitro, EC 50The value was 2.9 μg / mL, comparable to the commonly used fungicides thiopyram and fluopyram (Int J Mol Sci., 2022, 23, 1596). Tu et al. designed a series of novel benzamides substituted with 1,2,4-oxadiazoles linked to pyrazoles. Compound 14h showed good fungicidal activity against rice blast, with an inhibition rate of 77.8% (Molecules. 2022, 27, 4692).

[0005]

[0006] Therefore, it is of great significance to develop a new 1,2,4-oxadiazole derivative and explore its antifungal activity. Summary of the Invention

[0007] One of the purposes of the present invention is to provide a new 1,2,4-oxadiazole derivative N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)arylcarboxamide compound.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide compounds.

[0009] Another object of the present invention is to provide the use of the above-mentioned N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide compounds.

[0010] To achieve the above object, the present invention adopts the following technical solutions:

[0011] N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide compounds, the structural formula of which is shown in Formula I:

[0012]

[0013] Wherein, R is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 5-pyrimidinyl, 2-pyridinyl, furan-2-methyl, and thiophene-2-methyl.

[0014] The reaction formula of the above-mentioned N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide is as follows:

[0015]

[0016] Wherein, R is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 5-pyrimidinyl, 2-pyridinyl, furan-2-methyl, and thiophene-2-methyl. The amount of each reaction raw material used can refer to the reaction amount known to those skilled in the art.

[0017] Application of the above-mentioned N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylformamide compounds in the preparation of anti-plant pathogenic fungi drugs.

[0018] Preferably, the fungus is Botryosphaeria dothidea, Rhizoctonia zeae or Phakopsora pachyrhizi Syd.

[0019] The present invention also provides a fungicide, which contains a fungicide-effective amount of at least one of the above-mentioned N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamides and optionally contains auxiliary materials.

[0020] Preferably, the formulation of the fungicide is selected from at least one of emulsifiable concentrate, suspension concentrate, wettable powder, dust, granule, aqueous solution, mother liquor or mother powder.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] The present invention provides the use of a novel class of N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide compounds in the preparation of antifungal agents against plant pathogens. These compounds are synthesized using p-cyanobenzoic acid as a starting material through multiple steps, including addition and cyclization reactions. The preparation method is simple, high in yield, and low in cost. Experiments have shown that the compounds exhibit particularly good antifungal activity against the soybean rust pathogen (Phakopsora pachyrhizi Syd.). These compounds will provide more options for the development of antifungal agents and have broad application prospects. DETAILED DESCRIPTION

[0023] The present invention will be further described below with reference to the following examples. The following examples are only for illustration and are not intended to limit the scope of protection of the present invention in any way.

[0024] The processes and methods not described in detail in the following examples are conventional methods known in the art. The reagents used in the examples are all analytically pure or chemically pure and are commercially available or prepared by methods well known to those skilled in the art. The following examples all achieve the objectives of the present invention.

[0025] Example 1

[0026] Synthesis of 4-(N'-hydroxycarbamide)benzoic acid (B):

[0027]

[0028] 500 mg (3.44 mmol) of p-cyanobenzoic acid, 700 mg (5.11 mmol) of anhydrous potassium carbonate, 435 mg (6.26 mmol) of hydroxylamine hydrochloride, and 22 mg (0.19 mmol) of 8-hydroxyquinoline were placed in a reaction flask and dissolved in 25 mL of anhydrous ethanol:water (5:2). The mixture was refluxed at 85°C for 4 hours and monitored by TLC (dichloromethane:methanol = 5:1) until completion. After the reaction was complete, heating was discontinued, the reaction solution was allowed to cool, and the ethanol was evaporated. The pH of the solution was adjusted to 5-6 with concentrated hydrochloric acid. A large amount of yellow solid precipitated, which was filtered and dried to obtain a pale yellow solid B. The yield was 100%.

[0029] Example 2

[0030] Synthesis of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (C):

[0031]

[0032] Place 300 mg (1.62 mmol) of compound B in a round-bottom flask, add 20 mL of tetrahydrofuran, and stir until the compound is completely dissolved. Cool to 0-5°C in an ice bath. Take 550 μL (1.97 mmol) of trifluoroacetic anhydride, dilute with a small amount of tetrahydrofuran, and slowly add the solution dropwise to the reaction mixture. Remove the ice bath and continue stirring at room temperature for 5 hours. Monitor the reaction by TLC (dichloromethane:methanol = 5:1) until completion. After the solvent is evaporated, the mixture is washed with distilled water and filtered to obtain white compound C in a 50% yield.

[0033] Example 3

[0034] Synthesis of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoyl chloride (D):

[0035]

[0036] To a round-bottom flask, add 80 mg (0.31 mmol) of compound C and 5 mL of thionyl chloride. Stir thoroughly, raise the temperature to 80°C, and reflux for 4 hours. After the reaction is complete, stop heating. Remove the thionyl chloride under reduced pressure to obtain compound D as a yellow oil in a 100% yield.

[0037] Example 4

[0038] Preparation of N-(phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0039]

[0040] In a three-necked flask, 0.2169mmol of 4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)benzoyl chloride (D) was added to acetonitrile (15mL) and dissolved. Potassium thiocyanate (0.6483mmol) and an appropriate amount of PEG300 in acetonitrile were then slowly added dropwise to the three-necked flask. After stirring at room temperature for 4h, 0.3360mmol of R-NH2 (R in this embodiment is phenyl) was added and stirred at room temperature for 4h with TLC monitoring. After completion of the reaction, the solvent was spin-dried, dichloromethane was added to dissolve the mixture, and the mixture was extracted with saturated brine. The organic phase was taken, the solvent was spin-dried, and the product was separated by column chromatography with a total yield of 86%.

[0041] A1: 1 H NMR (600MHz, CDCl3) δ12.48(s,1H,-CSNH-),9.14(s,1H,-CONH-),8.32(d,J=

[0042] 8.1Hz,2H,Ph-H),8.07(d,J=8.1Hz,2H,Ph-H),7.72(d,J=7.9Hz,2H,Ph-H),7.44(t,J=7.7Hz,2H,Ph-H),7.31(t,J=7.4Hz,1H,Ph-H); 13 C NMR (151MHz, CDCl3) δ177.02,167.06,165.52,165.23,164.77,136.45,133.92 ,128.70,127.99,127.48,127.31,126.10,123.12,115.75,113.94; HR-MS-ESI m / z calcd for C 17 H 11 F3N4O2S[M+H] + 393.0628,found393.0634.

[0043] Example 5

[0044] Preparation of N-(2-chlorophenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0045]

[0046] The preparation method is the same as that of Example 4, except that R in R-NH2 is 2-chlorophenyl. The total yield is 84%.

[0047] A2: 1 H NMR (600MHz, CDCl3) δ12.65(s,1H,-CSNH-),9.22(s,1H,-CONH-),8.41(d,J=

[0048] 8.1Hz,1H,Ph-H),8.32(d,J=8.1Hz,2H,Ph-H),8.09(d,J=8.2Hz,2H,Ph-H),7.50 (d,J=8.0Hz,1H,Ph-H),7.36(t,J=7.7Hz,1H,Ph-H),7.24(d,J=7.7Hz,1H,Ph-H); 13 C NMR (151MHz, CDCl3) δ177.33,167.08,165.53,165.23,164.60,133.89,133.79,12 8.74,127.47,127.44,126.99,126.87,125.98,125.13,115.77,113.95; HR-MS-ESI m / z calcdfor C 17 H 10 ClF3N4O2S[M+H] + 427.0238,found 427.0247.

[0049] Example 6

[0050] Preparation of N-(3-chlorophenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0051]

[0052] The preparation method is the same as that of Example 4, except that R in R-NH2 is 3-chlorophenyl. The total yield is 72%.

[0053] A3: 1 H NMR (600MHz, CDCl3) δ12.54(s,1H,-CSNH-),9.16(s,1H,-CONH-),8.32(d,J=

[0054] 8.2Hz,2H,Ph-H),8.06(d,J=8.2Hz,2H,Ph-H),7.86(s,1H,Ph-H),7.60(d,J=8.0Hz,1H,Ph-H),7.36(t,J=8.0Hz,1H,Ph-H),7.28(d,J=8.1Hz,1H,Ph-H); 13 C NMR (151MHz, CDCl3) δ177.08,167.03,165.55,165.25,164.86,137.54,133.72,133.54 ,128.93,128.82,127.51,127.34,126.11,123.07,121.14,115.75,113.93; HR-MS-ESI m / zcalcd for C 17 H 10 ClF3N4O2S[M+H] + 427.0238,found 427.0246.

[0055] Example 7

[0056] Preparation of N-(4-chlorophenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0057]

[0058] The preparation method is the same as that of Example 4, except that R in R-NH2 is 4-chlorophenyl. The total yield is 94%.

[0059] A4: 1 H NMR (600MHz, CDCl3) δ12.50(s,1H,-CSNH-),9.16(s,1H,-CONH-),8.32(d,J=

[0060] 8.2Hz, 2H, Ph-H), 8.06 (d, J=8.2Hz, 2H, Ph-H), 7.69 (d, J=8.6Hz, 2H, Ph-H), 7.40 (d, J=8.6Hz, 2H, Ph-H); 13 C NMR (151MHz, CDCl3) δ177.12,167.04,165.55,165.25,164.87,134.98,133.75 ,131.39,128.80,128.11,127.51,127.33,124.34,115.75,113.94; HR-MS-ESI m / z calcd for C 17 H10 ClF3N4O2S[M+H] + 427.0238,found 427.0248.

[0061] Example 8

[0062] Preparation of N-(2-fluorophenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0063]

[0064] The preparation method is the same as that of Example 4, except that R in R-NH2 is 2-fluorophenyl. The total yield is 88%.

[0065] A5: 1 H NMR (400MHz, CDCl3) δ12.51(s,1H,-CSNH-),9.20(s,1H,-CONH-),8.31(t,J=

[0066] 7.6Hz,1H,Ph-H),8.23(d,J=8.1Hz,2H,Ph-H),8.00(d,J=8.3Hz,2H,Ph-H),7.23-7.09(m,3H,Ph-H); 13 C NMR (101MHz, CDCl3) δ178.29,168.09,166.61,166.16,165.85,156.30,153.83,134.79,129.74,128.47,128.45,12 7.96,127.88,125.89,125.79,125.35,124.11,124.08,119.96,117.24,115.79,115.60,114.51,111.79; HR-MS-ESI m / z calcdfor C 17 H 10 F4N4O2S[M+H] + 411.0534,found 411.0543.

[0067] Example 9

[0068] Preparation of N-(3-fluorophenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0069]

[0070] The preparation method is the same as that of Example 4, except that R in R-NH2 is 3-fluorophenyl. The total yield is 73%.

[0071] A6: 1 H NMR (400MHz, CDCl3) δ12.60(s,1H,-CSNH-),9.22(s,1H,-CONH-),8.30(d,J=

[0072] 8.1Hz,2H,Ph-H),8.05(d,J=8.2Hz,2H,Ph-H),7.73(d,J=10.4Hz,1H,Ph-H),7.41-7.33(m,2H,Ph-H),6.99(t,J=7.6Hz,1H,Ph-H); 13 C NMR (101MHz, CDCl3) δ176.86,167.03,165.60,165.16,164.95,162.79,160.34,137.91,137.80,133.73,129.13,129.04 ,128.77,127.46,127.37,118.93,118.38,118.35,116.21,113.49,112.92,112.71,110.76,110.34,110.08; HR-MS-ESI m / z calcd for C 17 H 10 F4N4O2S[M+H] + 411.0534,found411.0541.

[0073] Example 10

[0074] Preparation of N-(4-fluorophenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0075]

[0076] The preparation method is the same as that of Example 4, except that R in R-NH2 is 4-fluorophenyl. The total yield is 95%.

[0077] A7: 1 H NMR (400MHz, CDCl3) δ12.41(s,1H,-CSNH-),9.23(s,1H,-CONH-),8.30(d,J=

[0078] 6.9Hz,2H,Ph-H),8.05(d,J=8.0Hz,2H,Ph-H),7.65(dd,J=5.2,3.4Hz,2H,Ph-H),7.12(dd,J=11.5,4.7Hz,2H,Ph-H); 13C NMR (101MHz, CDCl3) δ178.62,168.07,166.64,166.20,165.95,162.33,159.88,134.84,133.48 ,133.45,129.77,128.49,128.38,126.31,126.22,117.23,116.00,115.77,114.51; HR-MS-ESI m / z calcd for C 17 H 10 F4N4O2S[M+H] + 411.0534,found 411.0541.

[0079] Example 11

[0080] Preparation of N-(2-methylphenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0081]

[0082] The preparation method is the same as that of Example 4, except that R in R-NH2 is 2-methylphenyl, and the yield is 99%.

[0083] A8: 1 H NMR (600MHz, CDCl3) δ12.08(s,1H,-CSNH-),9.19(s,1H,-CONH-),8.24(d,J=

[0084] 8.1Hz,2H,Ph-H),8.01(d,J=8.2Hz,2H,Ph-H),7.68(d,J=7.6Hz,1H,Ph-H),7.23-7.18(m,3H,Ph-H),2.31(s,3H,-CH3); 13 C NMR (151MHz, CDCl3) δ178.03,167.07,165.51,165.22,164.86,135.21,133.91,132.28,12 9.85,128.67,127.45,127.38,126.83,125.53,125.10,115.75,113.94,17.00; HR-MS-ESI m / z calcd for C 18 H 13 F3N4O2S[M+H] + 407.0785,found 407.0792.

[0085] Example 12

[0086] Preparation of N-(3-methoxyphenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0087]

[0088] The preparation method is the same as that of Example 4, except that R in R-NH2 is 3-methoxyphenyl, and the yield is 95%.

[0089] A9: 1 H NMR (400MHz, CDCl3) δ12.43(s,1H,-CSNH-),9.12(s,1H,-CONH-),8.22(d,J=

[0090] 8.4Hz,2H,Ph-H),7.97(d,J=8.4Hz,2H,Ph-H),7.40(s,1H,Ph-H),7.24(t,J=8.1Hz,1H,P h-H),7.13(d,J=7.9Hz,1H,Ph-H),6.76(dd,J=8.2,1.7Hz,1H,Ph-H),3.76(s,3H,-OCH3); 13 C NMR (101MHz, CDCl3) δ177.69,168.09,166.60,166.16,165.87,159.97,138.54,134.92,129.6 8,128.46,128.38,119.96,117.24,116.11,114.52,112.90,111.79,109.49,55.46; HR-MS-ESI m / z calcd for C 18 H 13 F3N4O3S[M+H] + 423.0734,found 423.0743.

[0091] Example 13

[0092] Preparation of N-(4-methoxyphenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0093]

[0094] The preparation method is the same as that of Example 4, except that R in R-NH2 is 4-methoxyphenyl. The total yield is 91%.

[0095] A10: 1H NMR (600MHz, CDCl3) δ12.30(s,1H,-CSNH-),9.12(s,1H,-CONH-),8.31(d,J=

[0096] 8.3Hz,2H,Ph-H),8.06(d,J=8.3Hz,2H,Ph-H),7.58(d,J=8.7Hz,2H,Ph-H),6.96(d,J=8.8Hz,2H,Ph-H),3.84(s,3H,-OCH3); 13 C NMR (151MHz, CDCl3) δ178.29,168.10,166.55,166.25,165.76,158.42,135.00,13 0.40,129.68,128.50,128.31,125.84,116.78,114.96,114.19,55.51; HR-MS-ESI m / z calcd for C 18 H 13 F3N4O3S[M+H] + 423.0734,found423.0743.

[0097] Example 14

[0098] Preparation of N-(2,4-fluorophenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0099]

[0100] The preparation method is the same as that of Example 4, except that R in R-NH2 is 2,4-difluorophenyl. The total yield is 79%.

[0101] A11: 1 H NMR (400MHz, CDCl3) δ12.36(s,1H,-CSNH-),9.19(s,1H,-CONH-),8.25(d,J=

[0102] 8.2Hz,2H,Ph-H),8.21-8.13(m,1H,Ph-H),8.01(d,J=8.3Hz,2H,Ph-H),6.90(dt,J=15.5,5.3Hz,2H,Ph-H); 13C NMR (101MHz, CDCl3) δ178.95,168.07,166.65,166.20,165.92,162.28,1 62.17,159.79,159.68,156.87,156.75,154.37,154.25,134.69,129.83 ,128.51,128.44,127.03,126.94,122.18,122.11,117.23,114.51,111. 30,111.26,111.08,111.04,104.66,104.43,104.40,104.17; HR-MS-ESI m / z calcd for C 17 H9F5N4O2S[M+H] + 429.0440,found 429.0449.

[0103] Example 15

[0104] Preparation of N-(5-pyrimidinyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0105]

[0106] The preparation method is the same as that of Example 4, except that R in R-NH2 is 5-pyrimidinyl. The total yield is 83%.

[0107] A12: 1 H NMR(400MHz, CDCl3)δ12.52(s,1H,-CSNH-),9.27(s,1H,-CONH-),9.09(s,2H,Pyrimidine -H),9.07(s,1H,Pyrimidine-H),8.28(d,J=8.1Hz,2H,Ph-H),8.02(d,J=8.2Hz,2H,Ph-H); 13 C NMR (101MHz, CDCl3) δ179.45,168.00,166.71,166.17,157.46,157.36,155.31,153.26,151.32,134.34,13 3.35,130.14,129.48,129.42,129.31,129.25,127.83,127.77,127.69,127.63,117.22,114.50; HR-MS-ESI m / z calcd for C 15 H9F3N6O2S[M+H] +395.0533,found 395.0541.

[0108] Example 16

[0109] Preparation of N-(2-pyridyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0110]

[0111] The preparation method is the same as that of Example 4, except that R in R-NH2 is 2-pyridyl. The total yield is 67%.

[0112] A13: 1 H NMR (400MHz, CDCl3) δ13.01(s,1H,-CSNH-),9.22(s,1H,-CONH-),8.79(d,J=

[0113] 8.3Hz,1H,Pyridine-H),8.45(d,J=4.1Hz,1H,Pyridine-H),8.29(d,J=8.2Hz,2H,Ph-H),8.0 7(d,J=8.1Hz,2H,Ph-H),7.79(t,J=7.8Hz,1H,Pyridine-H),7.22-7.15(m,1H,Pyridine-H); 13 C NMR (101MHz, CDCl3) δ176.69,168.10,166.58,166.13,165.37,151.09,148.50,137.88 ,134.95,129.66,128.45,121.65,119.96,117.24,116.14,114.51,111.79; HR-MS-ESI m / z calcd for C 16 H 10 F3N5O2S[M+H] + 394.0581,found 394.0590.

[0114] Example 17

[0115] Preparation of N-(furan-2-methyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0116]

[0117] The preparation method is the same as that of Example 4, except that R in R-NH2 is furan-2-methyl, and the total yield is 67%.

[0118] A14: 1 H NMR (400MHz, CDCl3) δ10.90(s,1H,-CSNH-),9.22(s,1H,-CONH-),8.27(d,J=

[0119] 8.1Hz,2H,Ph-H),8.00(d,J=8.1Hz,2H,Ph-H),7.42(s,1H,Furan-H),6.41-6.35(m,2H,Furan-H),4.91(d,J=5.1Hz,2H,-CH2-); 13 C NMR (101MHz, DMSO) δ174.94,163.35,162.26,161.82,161.38,161.02,160.93,144.22,138.07,13 0.24,124.78,123.65,123.60,115.20,112.47,109.75,107.03,105.83,104.07,37.97; HR-MS-ESI m / z calcd forC 16 H 11 F3N4O3S[M+H] + 397.0577,found 397.0586.

[0120] Example 18

[0121] Preparation of N-(thiophene-2-methyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide:

[0122]

[0123] The preparation method is the same as that of Example 4, except that R in R-NH2 is thiophene-2-methyl. The total yield is 51%.

[0124] A15: 1 H NMR (400MHz, CDCl3) δ10.92(s,1H,-CSNH-),9.19(s,1H,-CONH-),8.26(d,J=

[0125] 8.3Hz, 2H, Ph-H), 7.98 (d, J = 8.4Hz, 2H, Ph-H), 7.28 (t, J = 4.4Hz, 1H, Thiophene-H), 7.12 (d, J = 2. 5Hz, 1H, Thiophene-H), 7.00 (dd, J=4.7, 3.8Hz, 1H, Thiophene-H), 5.09 (d, J=5.3Hz, 2H, -CH2-); 13 C NMR (101MHz, DMSO) δ174.73,163.34,162.27,161.82,161.38,161.02,160.93,133.27,130.23,124.79 ,123.65,123.62,123.60,122.46,122.24,121.19,115.20,112.47,109.75,107.03,39.65; HR-MS-ESI m / z calcd for C 16 H 11 F3N4O2S2[M+H] + 413.0349,found 413.0358.

[0126] Example 19

[0127] In vitro antifungal activity assay of N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamides

[0128] 1) In vitro antifungal activity assay

[0129] The mycelial growth rate method is one of the conventional methods for determining the antifungal activity of fungicides, also known as the toxic medium method. It involves mixing the test agent with the culture medium and measuring the toxicity of the compound by the growth rate of the colonies on the culture medium.

[0130] 2) In vitro antifungal activity assay

[0131] Sample: Compounds A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, and A15 of the present invention prepared in Examples 4-18:

[0132] Fungi: Botryosphaeria dothidea, Rhizoctoniazeae.

[0133] Reagents: antibiotics (Adamas); agar (Tianjin Kemeiou Chemical Reagent Co., Ltd.); glucose (Tianjin Kemeiou Chemical Reagent Co., Ltd.); dimethyl sulfoxide (Tianjin Kemeiou Chemical Reagent Co., Ltd.).

[0134] Instruments: LDZX-75KBS vertical pressure steam autoclave (Shanghai Shen'an Medical Instrument Factory), biochemical incubator (Shanghai Hengyi Scientific Instrument Co., Ltd.); biological safety cabinet (Sujie Medical Instrument Co., Ltd.); electronic balance (Ohaus Instrument Co., Ltd.).

[0135] Experimental Procedure: For fungal testing, each sample was diluted to a concentration of 100 μg / mL, and the experiment was repeated two or more times. Conclusions were drawn from the positive control, Fluxapyroxad.

[0136] 3) Evaluation of in vitro antifungal activity

[0137] Calculation of fungal inhibition rate:

[0138]

[0139] The measurement results are shown in Table 1.

[0140] Example 20

[0141] In vivo antifungal activity assay of N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamides

[0142] 1) Principle of in vivo antifungal activity

[0143] The in vivo potted plant assay method is a method of inoculating potted seedlings with pathogens, treating them with pesticides, and determining the efficacy of the pesticides.

[0144] 2) In vivo antifungal activity test

[0145] Sample: Compounds A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, and A15 of the present invention prepared in Examples 4-18:

[0146] Fungus: soybean rust pathogen (Phakopsorapachyrhizi Syd.).

[0147] Experimental operation: Select two soybean potted seedlings in the true leaf stage and with the same growth. Use a throat sprayer to evenly spray the pesticide on the leaves of the plant, repeat 3 times for each treatment, and place it indoors to dry naturally after spraying. 24 hours after spraying, inoculate 2*105 / mL of soybean rust / corn rust / wheat rust spores on the leaves of the plant. Place the inoculated potted soybean seedlings in a moisturizing room for cultivation, maintain a relative humidity of 100%, and a temperature of 25-28℃. After 24 hours, place them in an observation room with a light-dark ratio of 12Lh:12Dh and a temperature of 25℃ for cultivation. After about 10 days, conduct a graded investigation based on the disease situation of the blank control. The test and investigation methods refer to the SOP-SC-1120 soybean rust potting method in the fungicide volume of the "Standard Operating Procedures for Pesticide Biological Activity Tests" compiled by Kang Zhuo and Gu Baogen, and calculate the prevention and control effect with the disease index.

[0148] 3) Evaluation of in vivo antifungal activity

[0149] Calculation of control effect:

[0150]

[0151] The measurement results are shown in Table 1.

[0152] Table 1 Inhibitory activity of the compounds of the present invention against fungi at a concentration of 100 μg / mL (%)

[0153]

[0154]

[0155] / : Untested

[0156] As shown in Table 1, the compounds of the present invention have antifungal activity against Botryosphaeria dothidea and Rhizoctonia zeae. In terms of antifungal activity trends, para-substituted benzene rings have better antifungal activity than ortho- and meta-substituted benzene rings, and the para-F substituent on the benzene ring has a significantly improved antifungal activity. Heterocyclic substitutions have better activity than benzene ring substitutions against Rhizoctonia zeae. The compounds of the present invention can be prepared into mixed preparations with pharmaceutical adjuvants or used as antifungal drugs in agriculture. In addition, all compounds of the present invention have a control effect on soybean rust pathogen (Phakopsorapachyrhizi Syd.) at the tested concentrations, and the control effect is comparable to that of the positive control drug prothioconazole, and have the potential for further development.

Claims

1. N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide compounds represented by chemical formula I: ； in, R is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 5-pyrimidinyl, 2-pyridinyl, furan-2-methyl, and thiophene-2-methyl.

2. The method for preparing the N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylformamide compound according to claim 1, characterized in that: The reaction formula is as follows: ； Wherein, R is defined as in claim 1.

3. Use of the N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide compound according to claim 1 in the preparation of an anti-plant pathogenic fungus drug, wherein the plant pathogenic fungus is Botrytis cinerea ( Botryosphaeria dothidea ) or soybean rust ( Phakopsorapachyrhizi Syd. ).

4. Use of N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide compounds represented by formula I in the preparation of anti-plant pathogenic fungi drugs, characterized in that: In formula I, R is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 5-pyrimidinyl, 2-pyridinyl, furan-2-methyl, and thiophene-2-methyl; the plant pathogenic fungus is Rhizoctonia graminearum ( Rhizoctonia zeae ) 。 5. A fungicide, characterized in that: The bactericide contains a bactericidal effective amount of at least one of the N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylformamide compounds according to claim 1, and optionally contains auxiliary materials.

6. The bactericide according to claim 5, characterized in that The formulation of the fungicide is selected from at least one of emulsifiable concentrate, suspension concentrate, wettable powder, dust, granule, aqueous solution, mother liquor or mother powder.

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