Preparation and application of N-(substituted phenyl) carbamoyl-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) aryl formamide

Abstract

The invention relates to a novel compound as well as a preparation method and application thereof, in particular to an N-(substituted phenyl) carbamoyl-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) aryl formamide compound as well as a preparation method and application thereof in preparation of a medicine for resisting plant pathogenic fungi. The structural formula of the compound N-(substituted phenyl) carbamoyl-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) aryl formamide compound is as shown in a formula I: # imgabs0 #, and the structural formula of the compound N-(substituted phenyl) carbamoyl-4-(5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl) aryl formamide compound is as shown in a formula I, wherein R is selected from the group consisting of phenyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 5-pyrimidinyl, 2-pyridyl, furan-2-methyl and thiophene-2-methyl. The structural formula of the compound is shown in the description.

Description

Technical Field

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

[0002] Botryosphaeria dothidea is a kind of pathogen that is widely distributed and has serious harm to many crops. It can infect many plants and cause diseases. For example, it causes branch and trunk diseases of apple trees, pear trees, etc., causing bark rot and ulcers, affecting the growth and yield of trees, and in severe cases, it can cause tree death; it can also cause diseases in some economic crops such as grapes, affecting the quality and yield of grapes. It may also attack forests and cause damage to forest ecosystems. In addition, after Botryosphaeria infects plants, it will damage the physiological functions of plants, reduce the resistance of plants to stress, and make them more vulnerable to other diseases and pests.

[0003] At present, the common method of controlling Botrytis cinerea is to spray fungicides. However, the long-term use of certain fungicides alone will not only cause the bacteria to gradually develop drug resistance and reduce the control effect, but also have a certain impact on the environment and non-target organisms. Therefore, finding green and efficient fungicides with novel mechanisms of action has become the focus of current 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 S. sclerotiorum and in vitro, EC 50The value was 2.9 μg / mL, which is comparable to the commonly used fungicides thiopyram and fluopyram (Int J Mol Sci., 2022, 23, 1596). Tu et al. designed a series of new benzamides substituted with 1,2,4-oxadiazoles connected by pyrazole. 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: 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, thiophene-2-methyl.

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

[0015]

[0016] In the formula, R is selected from: 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, thiophene-2-methyl. The amount of each reaction raw material can refer to the reaction amount known to those skilled in the art.

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

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

[0019] The present invention also provides a fungicide, which contains a fungicidal 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 dosage form of the fungicide is selected from at least one of emulsifiable concentrate, suspension, 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 a new class of compounds, N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)arylformamide compounds, for use in the preparation of anti-plant pathogenic fungi drugs. The compounds are prepared from p-cyanobenzoic acid through addition, cyclization and other multi-step reactions, and have a simple preparation method, high yield and low cost. Tests show that the compounds of the present invention show good antifungal activity, especially against soybean rust pathogen (Phakopsorapachyrhizi Syd.). The compounds of the present invention will provide more options for the research and development of antifungal drugs and have broad application prospects. DETAILED DESCRIPTION

[0023] The present invention is further described below in conjunction with 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, and the reagents used in the examples are all analytically pure or chemically pure, and can be purchased commercially or prepared by methods well known to those of ordinary skill in the art. The following examples all achieve the purpose 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 bottle, and 25 mL of anhydrous ethanol: water (5:2) was added to dissolve the mixture. The mixture was refluxed at 85°C for 4 h and monitored by TLC (dichloromethane: methanol = 5:1) until the reaction was completed. After the reaction was completed, heating was stopped, and the reaction solution was cooled, and the ethanol was dried by spin drying. The pH of the solution was adjusted to 5-6 with concentrated hydrochloric acid. A large amount of yellow solid precipitated, and a light yellow solid B was obtained by suction filtration and drying. The yield was 100%.

[0029] Example 2

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

[0031]

[0032] 300 mg (1.62 mmol) of compound B was placed in a round-bottom flask, 20 mL of tetrahydrofuran was added, and the mixture was stirred until the compound was completely dissolved, and the mixture was cooled to 0-5°C in an ice bath, 550 μL (1.97 mmol) of trifluoroacetic anhydride was taken, and a small amount of tetrahydrofuran was added to dilute the mixture, and the above solution was slowly added dropwise to the reaction solution, the ice bath environment was removed, and the reaction was continued under stirring at room temperature for 5 h. TLC (dichloromethane: methanol = 5:1) was used to monitor the reaction until the end, the solvent was dried, distilled water was added for washing, and the mixture was filtered to obtain a white compound C with a yield of 50%.

[0033] Example 3

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

[0035]

[0036] Add 80 mg (0.31 mmol) of compound C and 5 mL of thionyl chloride to a round-bottom flask, stir evenly, heat to 80°C and reflux, and react for 4 hours. After the reaction is completed, stop heating. Distill off the thionyl chloride under reduced pressure to obtain a yellow oily compound D with a yield of 100%.

[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) to dissolve. Potassium thiocyanate (0.6483mmol) and an appropriate amount of PEG300 in acetonitrile were then slowly added dropwise to the three-necked flask, stirred at room temperature for 4h, and then 0.3360mmol of R-NH2 (R in this embodiment is phenyl) was added, stirred at room temperature for 4h, and monitored by TLC. After the reaction was completed, the solvent was dried, dichloromethane was added to dissolve, extracted with saturated brine, the organic phase was taken, the solvent was 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, found 393.0634.

[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, and 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, and 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, and 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, wherein R in R-NH2 is 2-fluorophenyl, and 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, and 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, found 411.0541.

[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, and 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] Embodiment 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] Embodiment 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, and 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] Embodiment 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, and 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] Embodiment 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, wherein R in R-NH2 is 5-pyrimidinyl, and 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, wherein R in R-NH2 is 2-pyridyl, and 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] Embodiment 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] Embodiment 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, and 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] Embodiment 19

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

[0128] 1) In vitro antifungal activity experiment

[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. The test agent is mixed with the culture medium and the growth rate of the colonies on the culture medium is used to measure the toxicity of the compound.

[0130] 2) In vitro antifungal activity experiment

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

[0132] Fungi: Botryosphaeria dothidea, Rhizoctoniazeae.

[0133] Reagents: antibiotics (Adamas); agar (Tianjin Komiou Chemical Reagent Co., Ltd.); glucose (Tianjin Komiou Chemical Reagent Co., Ltd.); dimethyl sulfoxide (Tianjin Komiou 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 operation: Test of samples for fungi. During one experiment, each sample was diluted to a concentration of 100 μg / mL, and the experiment was repeated 2 times or more, and the conclusion was drawn by comparing with the positive control Fluxapyroxad group.

[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] Embodiment 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 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, A15 of the present invention prepared in Examples 4-18:

[0146] Fungi: 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 agent 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 survey based on the incidence of the blank control. The test and investigation methods refer to the SOP-SC-1120 soybean rust pot method in the fungicide volume of the "Standard Operating Specifications for Pesticide Biological Activity Tests" compiled by Kang Zhuo and Gu Baogen, and the prevention and control effect is calculated using 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] / : Not measured

[0156] As shown in Table 1, the compounds of the present invention have antifungal activity against Botryosphaeria dothidea and Rhizoctonia zeae. In terms of the antifungal activity trend, the antifungal activity of para-substituted benzene rings is better than that of ortho- and meta-substituted benzene rings, and the para-F substituent on the benzene ring has a significant improvement in antifungal activity. The heterocyclic substitution activity is better than that of benzene ring substitution for Rhizoctonia zeae. The compounds of the present invention can be made into mixed preparations with pharmaceutical adjuvants or used as antifungal drugs in agriculture. In addition, all the compounds of the present invention have a control effect on the soybean rust pathogen (Phakopsorapachyrhizi Syd.) at the test concentration, and the control effect is equivalent to that of the positive control drug prothioconazole, and has 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 structural 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, thiophene-2-methyl.

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

3. Use of the N-(substituted phenyl)carbamoyl-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)arylcarboxamide compounds according to claim 1 in the preparation of anti-plant pathogenic fungi drugs.

4. The use according to claim 3, characterized in that: The plant pathogenic fungus is Botryosphaeria dothidea.

5. The use according to claim 3, characterized in that: The plant pathogenic fungus is Rhizoctonia zeae.

6. The use according to claim 3, characterized in that: The plant pathogenic fungus is soybean rust (Phakopsorapachyrhizi Syd.).

7. A bactericide, 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)arylcarboxamide compounds described in claim 1, and optionally contains auxiliary materials.

8. The fungicide according to claim 7, characterized in that The dosage form of the fungicide is selected from at least one of emulsifiable concentrate, suspension, wettable powder, dust, granule, aqueous solution, mother solution or mother powder.

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