And Napos; -aryl-4-[5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl] benzoyl hydrazine compound as well as preparation and application thereof

Abstract

The invention relates to a novel compound as well as a preparation method and an application thereof, in particular to an N '-aryl-4-[5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl] benzoyl hydrazine compound as well as a preparation method and an application of the N'-aryl-4-[5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl] benzoyl hydrazine compound. The structural formula of the N '-aryl-4-[5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl] benzoyl hydrazine compound is as shown in a formula I: # imgabs0 #, and the structural formula of the N'-aryl-4-[5-(trifluoromethyl)-1, 2, 4-oxadiazole-3-yl] benzoyl hydrazine compound is as shown in a formula II, wherein R is selected from hydrogen, methyl, naphthyl, chlorine, bromine, trifluoromethyl, 2, 4-dichloro and 2-fluoro-4-chlorine. The compound disclosed by the invention particularly shows relatively good antifungal activity on botryosphaeria dothidea, pythium aphanidermatum and soybean rust, more choices can be provided for research and development of antifungal drugs, and the compound disclosed by the invention has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to a new class of compounds and a preparation method and application thereof, and in particular to N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]benzoyl hydrazide compounds and a preparation method and application thereof. Background Art

[0002] Botryosphaeria dothidea can infect a variety of plants, causing diseases in trees and fruit trees, such as trunk ulcers, branch blight, fruit rot, etc., causing losses in agriculture and forestry. Pythium aphanidermatum mainly causes pythium aphanidermatum, which causes watermelon plants to wilt, rhizomes to rot, and fruits to rot, seriously reducing watermelon yield and quality; the toxins it produces also pose a threat to human and animal health. Soybean rust (Phakopsora pachyrhizi Syd.) mainly causes soybean rust, causing plant leaves to turn yellow and fall early, seriously affecting photosynthesis and reducing grain yield. At present, the common control method for Botryosphaeria dothidea, Pythium aphanidermatum and soybean rust is to use fungicides for spraying. However, the long-term use of certain fungicides alone will not only cause the pathogens to gradually develop drug resistance and reduce the control effect, but also have certain impacts 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.

[0003] According to literature reports, hydrazides and their derivative structures exhibit broad-spectrum biological activities. For example, Jing Chang et al. reviewed the comprehensive research on hydrazides and their derivative structures in the field of agricultural sterilization, and summarized the antifungal mechanisms of hydrazide derivatives, mainly involving succinate dehydrogenase inhibitors, laccase inhibitors and targeting plasma membranes (J. Agri. Food. Chem., 2023, 71(22): 8297-8316). Ruiyuan Liu et al. designed and synthesized a series of diaryl hydrazide compounds and screened their antifungal activities. Among them, compound 1 can effectively inhibit the growth of Pyricularia oryzae, Fusarium solani, Alternaria solani, Alternaria brassicae and Alternaria alternata, and is superior to the positive controls carbendazim and thiabendazole (J. Agri. Food. Chem., 2023, 71(18): 6803-6817). Li Zhang et al. designed and synthesized a series of citral-thiazolylhydrazine derivatives, among which compound 2 showed significant antifungal activity against Colletotrichum gloeosporioides, Rhizoctonia solani, Phytophthoranicotianae var. nicotianae, Diplodia pinea, Colletotrichum acutatum and Fusarium oxysporum f. sp. niveum, all of which were superior to the positive control tricyclazole (J. Agri. Food. Chem., 2021, 69(48): 14512-14519).

[0004]

[0005] In addition, Chinese patent CN115108978A discloses the synthesis of a class of pyridine carboxyhydrazide compounds and their application as plant antifungal drugs, Chinese patent CN113968852A discloses a thiazole hydrazide derivative and its preparation method and application, and Chinese patent CN108033897A discloses a naphthylohydrazide compound and its preparation method, all of which indicate that hydrazide compounds have the characteristics of a broad antibacterial spectrum.

[0006] Therefore, it is of great significance to develop a new type of hydrazide derivatives and explore their antifungal activity. Summary of the invention

[0007] One of the purposes of the present invention is to provide a new hydrazide derivative N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compound.

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

[0009] Another object of the present invention is to provide the use of the above-mentioned N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compounds.

[0010] In order to achieve the above object, the present invention adopts the following technical solutions:

[0011] N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compounds, the structural formula of which is shown in Formula I:

[0012]

[0013] Wherein, R is selected from: hydrogen, methyl, naphthyl, chlorine, bromine, trifluoromethyl, 2,4-dichloro or 2-fluoro-4-chloro.

[0014] Preferably, the above-mentioned N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide compound is selected from: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13 or A14; wherein,

[0015] A1 is N′-(phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0016] A2 is N′-(2-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0017] A3 is N′-(3-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0018] A4 is N′-(4-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0019] A5 is N′-(2,4-dichloro-phenyl)-4007A-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0020] A6 is N′-(1-naphthyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0021] A7 is N′-(2-fluoro-4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0022] A8 is N′-(2-naphthyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0023] A9 is N′-(2-methyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0024] A10 is N′-(3-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0025] A11 is N′-(2-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0026] A12 is N′-(4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0027] A13 is N′-(3-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0028] A14 is N'-(4-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide.

[0029] The preparation method of the above-mentioned N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compound has the following reaction formula:

[0030]

[0031] In the formula, R is selected from: hydrogen, methyl, naphthyl, chlorine, bromine, trifluoromethyl, 2,4-dichloro or 2-fluoro-4-chloro. The amount of each reaction raw material can refer to the reaction amount known to those skilled in the art.

[0032] Application of the above N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compounds in the preparation of antifungal drugs.

[0033] When the fungus is Botryosphaeria dothidea or Pythiumaphanidermatum, the N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide compound is selected from A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13 or A14, wherein

[0034] A1 is N′-(phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0035] A2 is N′-(2-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0036] A3 is N′-(3-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0037] A4 is N′-(4-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0038] A5 is N′-(2,4-dichloro-phenyl)-4007A-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0039] A6 is N′-(1-naphthyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0040] A7 is N′-(2-fluoro-4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0041] A8 is N′-(2-naphthyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0042] A9 is N′-(2-methyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0043] A10 is N′-(3-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0044] A11 is N′-(2-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0045] A12 is N′-(4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0046] A13 is N′-(3-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0047] A14 is N'-(4-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide.

[0048] When the fungus is soybean rust (Phakopsora pachyrhizi Syd.), the N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide compound is selected from A2, A3, A4, A7, A9, A13 or A14, wherein:

[0049] The definitions of A2, A3, A4, A7, A9, A13, and A14 are as follows:

[0050] A2 is N′-(2-trifluoromethylphenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0051] A3 is N′-(3-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0052] A4 is N′-(4-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0053] A7 is N′-(2-fluoro-4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0054] A9 is N′-(2-methyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0055] A13 is N′-(3-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide;

[0056] A14 is N'-(4-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide.

[0057] The present invention also provides a fungicide, which contains a fungicidal effective amount of at least one of the above-mentioned N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compounds, and optionally contains auxiliary materials.

[0058] 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.

[0059] Compared with the prior art, the present invention has the following advantages:

[0060] The present invention provides a new class of compounds, N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]benzoylhydrazide compounds, and preparation methods and applications thereof. The compounds are synthesized by multi-step reactions with p-cyanobenzoic acid as a raw material, and the preparation method is simple, the yield is high, and the cost is low. Experiments show that the compounds of the present invention show good antifungal activity, especially against Botryosphaeria dothidea, Pythium aphanidermatum, and Phakopsora pachyrhizi Syd., and the antifungal activity of some compounds is comparable to that of the positive control Fluxapyroxad. 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

[0061] 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.

[0062] 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.

[0063] Example 1

[0064] Preparation of 4-(N′-hydroxycarbamoyl)benzoic acid (B):

[0065]

[0066] Add 10g (68mmol) of p-cyanobenzoic acid (A), 8.7g (126mmol) of hydroxylamine hydrochloride, and 0.49g (3mmol) of 8-hydroxyquinoline into a single-necked flask, add 100mL of anhydrous ethanol and 40mL of water as solvent, and stir at 85°C for about 5h to complete the reaction. Cool the reaction solution to room temperature, remove ethanol by rotary evaporation, filter, adjust the pH of the filtrate to 5-6, stir for 0.5h and filter again, combine the two filter residues, put them into an oven to dry, and obtain a light yellow solid B with a yield of 94%.

[0067] Example 2

[0068] Preparation of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (C):

[0069]

[0070] Add 11.43g (63mmol) of compound B to a single-mouth bottle, dissolve it in 100mL of tetrahydrofuran, and slowly drop 11.77g (84mmol) of trifluoroacetic anhydride dissolved in 100mL of tetrahydrofuran using a constant pressure dropping funnel under ice bath conditions. Continue stirring and reacting for 5h after the addition is complete. Then, remove the tetrahydrofuran by rotary evaporation, add an appropriate amount of distilled water and stir for 2h. Finally, filter to obtain white solid C with a yield of 70%.

[0071] Example 3

[0072] Preparation of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoyl chloride (D):

[0073]

[0074] Compound C 0.5 g (1.94 mmol) and SOCl2 0.23 g (1.94 mmol) were placed in a single-necked bottle and reacted at 80°C for 3 h. Unreacted SOCl2 was removed by rotary evaporation to obtain a yellow-green liquid D with a yield of 95%.

[0075] Example 4

[0076] Preparation of N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A1):

[0077]

[0078] 0.108 g (1 mmol) of phenylhydrazine was added to a single-necked flask, dissolved with DCM, cooled to 0-5°C in an ice bath, 0.276 g (1 mmol) of compound D dissolved in DCM was slowly added dropwise to the single-necked flask, the ice bath was removed, the reaction was stirred at room temperature for 2 h, and the reaction was monitored by TCL until the end. The reaction solution was washed with a saturated Na2CO3 solution, extracted with DCM, and the organic phase was separated by column chromatography to obtain product A1 as a light yellow solid with a yield of 72%.

[0079] A1: melting point 495.80~497.10℃, yield 72%, 1 H NMR(600MHz,CDCl3)δ6.39(s,1H,NH),

[0080] 6.95(t,J=7.2Hz,3H,C6H5 2-H 4-H 6-H),7.27(d,J=8.4Hz,2H,C6H5 3-H 5-H),7.99(d,J=

[0081] 8.3Hz, 2H, C6H4 2-H 6-H), 8.12 (s, 1H NH), 8.23 ​​(d, J = 8.3Hz, 2H, C6H4 3-H 5-H).

[0082] Example 5

[0083] Preparation of N′-(2-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A2):

[0084]

[0085] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A2 as a white solid in a yield of 74%.

[0086] A2: melting point 523.10~526.21℃, yield 74%, 1 H NMR (600MHz, CDCl3) δ6.78(s,1H,NH),6.99(t,J=7.6Hz,1H,2-CF3-C6H4 4-H),7.11(d,J=8.3Hz,1H,2-CF3-C6H4 6-H),7.41(t,J=7.7Hz,1H,2-CF3-C6H4 5-H), 7.55 (d, J = 7.8Hz, 1H, 2-CF3-C6H4 3-H), 8.00 (d, J = 8.2Hz, 2H, C6H42-H 6-H), 8.13 (d, J = 1.5Hz, 1H, NH), 8.22 (d, J = 8.2Hz, 2H, C6H4).

[0087] Example 6

[0088] Preparation of N'-(3-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A3):

[0089]

[0090] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A3 as a white solid in a yield of 76%.

[0091] A3: melting point 522.45~525.63℃, yield 76%, 1 H NMR (600MHz, CDCl3) δ6.50 (d, J=2.9Hz,

[0092] 1H,NH),7.10(d,J=8.1Hz,1H,3-CF3-C6H4 4-H),7.16(s,1H,3-CF3-C6H4 2-H),7.19(d,J=7.7Hz,1H,3-CF3-C6H4 6-H),7.36(t,J=7.9Hz,1H,3-CF3-C6H4 5-H),8.01(d,J=8.0Hz,2H,C6H42-H 6-H),8.10(d,J=2.7Hz,1H,NH),8.25(d,J=8.0Hz,2H,C6H4 3-H 5-H).Molecular formula: C 17 H 10 F6N4O2,HRMS-EST m / z calcd for[M+H] + 417.0781, found 417.0789.

[0093] Example 7

[0094] Preparation of N'-(4-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A4):

[0095]

[0096] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A4 as a white solid in a yield of 75%.

[0097] A4: melting point 523.63~527.81℃, yield 75%, 1H NMR (600MHz, CDCl3) δ6.50 (s, 1H, NH), 6.99 (d, J=8.3Hz, 2H, 4-CF3-C6H4 2-H 6-H), 7.51 (d, J=8.2Hz, 2H, 4-CF3-C6H4 3-H 5-H), 8.02 (d, J=8.1Hz, 2H, C6H4 2-H 6-H), 8.05 (s, 1H, NH), 8.27 (d, J=7.9Hz, 2H, C6H4 3-H 5-H). Molecular formula: C 17 H 10 F6N4O2,HRMS-EST m / z calcd for[M+H] + 417.0781, found 417.0778.

[0098] Example 8

[0099] Preparation of N'-(2,4-dichloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A5):

[0100]

[0101] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A5 as a light yellow solid in a yield of 68%.

[0102] A5: melting point 580.32~584.27℃, yield 68%, 1 H NMR (600MHz, CDCl3) δ6.63(s,1H,NH),6.93(d,J=8.7Hz,1H,2,4-2Cl-C6H3 6-H),7.15(dd,J=8.7,1.9Hz,1H,2,4-2Cl-C6H3 5-H),7.34(d,J=2.2Hz,1H,2,4-2Cl-C6H3 3-H),8.01(d,J=8.3Hz,3H,NH C6H4 2-H 6-H),8.26(d,J=8.2Hz,2H,C6H4 3-H 5-H). Molecular formula: C 16 H9Cl2F3N4O2,HRMS-EST m / z calcd for[M+H] + 417.0127, found 417.0136.

[0103] Example 9

[0104] Preparation of N'-(1-naphthyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A6):

[0105]

[0106] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A6 as a yellow solid in a yield of 54%.

[0107] A6: melting point 585.61~589.18℃, yield 54%. 1 H NMR (600MHz, CDCl3) δ7.05 (d, J = 7.1Hz, 2H, NH 1-C 10 H7 2-H),7.36(t,J=7.8Hz,1H,1-C 10 H7 3-H),7.48(d,J=8.2Hz,1H,1-C 10 H7 8-H),7.53–7.50(m,2H,1-C 10 H7 6-H 7-H),7.86–7.83(m,1H,1-C 10 H7 4-H),8.00–7.97(m,1H,1-C 10 H7 5-H), 8.02 (d, J = 8.1Hz, 2H, C6H4 2-H 6-H), 8.12 (d, J = 4.4Hz, 1H, NH), 8.21 (d, J = 8.1Hz, 2H, C6H4 3-H 5-H).

[0108] Example 10

[0109] Preparation of N′-(2-fluoro-4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A7):

[0110]

[0111] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A7 as a light yellow solid in a yield of 61%.

[0112] A7: melting point 548.29~552.61℃, yield 61%. 1 H NMR (600MHz, CDCl3) δ6.44(s,1H,NH),6.94(t,J=8.7Hz,1H,2F,4Cl-C6H3 3-H),7.02(d,J=8.5Hz,1H,2F,4Cl-C6H3 6-H),7.09(d,J=11.0Hz,1H,2F,4Cl-C6H3 5-H),7.99(d,J=8.0Hz,2H,C6H4 2-H 6-H),8.02(d,J=1.9Hz,1H,NH),8.25(d,J=8.0Hz,2H,C6H4 3-H 5-H).Molecular formula: C16 H9ClF4N4O2,HRMS-EST m / zcalcd for[M+H] + 401.0423, found 401.0429.

[0113] Embodiment 11

[0114] Preparation of N'-(2-naphthyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A8):

[0115]

[0116] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A8 as a yellow solid in a yield of 48%.

[0117] A8: melting point 584.75~588.30℃, yield 48%. 1 H NMR(600MHz, CDCl3)δ6.48(s,1H,NH),7.11–7.08(m,1H,2-C 10 H7 3-H),7.17(s,1H,2-C 10 H7 1-H),7.24(t,J=7.4Hz,1H,2-C 10 H7 4-H),7.34(t,J=7.4Hz,1H,2-C 10 H7 5-H),7.60(d,J=8.2Hz,1H,2-C 10 H7 8-H),7.68(t,J=9.0Hz,2H,2-C 10 H7 6-H 7-H), 7.98 (d, J=8.2Hz, 2H, C6H4 2-H 6-H), 8.09 (s, 1H, NH), 8.20 (d, J=8.2Hz, 2H, C6H4 3-H 5-H).

[0118] Example 12

[0119] Preparation of N'-(2-methyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A9):

[0120]

[0121] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A9 as a white solid in a yield of 65%.

[0122] A9: melting point 517.55~520.74℃, yield 65%. 1H NMR (600MHz, CDCl3) δ2.32(s,3H,CH3),6.29(d,J=2.6Hz,1H,NH),6.89(t,J=7.4Hz,1H,2-CH3-C6H4 4-H),6.94(d,J=7.9Hz,1H,2-CH3-C6H4 6-H), 7.16–7.12 (m, 2H, 2-CH3-C6H4 3-H 5-H), 8.00 (d, J=8.2Hz, 2H, C6H4 2-H6-H), 8.08 (s, 1H, NH), 8.23 ​​(d, J=8.2Hz, 2H, C6H4 3-H 5-H).

[0123] Embodiment 13

[0124] Preparation of N′-(3-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A10):

[0125]

[0126] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A10 as a white solid in a yield of 67%.

[0127] A10: melting point 537.16~540.63℃, yield 67%. 1 H NMR (600MHz, CDCl3) δ6.38 (d, J=2.9Hz, 1H, NH), 6.82 (d, J=7.9Hz, 1H, 3-Cl-C6H4 4-H), 6.96–6.89 (m, 2H, 3-Cl-C6H4 2-H 6-H), 7.18 (t, J=8.0Hz, 1H, 3-Cl-C6H4 5-H), 8.00 (d, J=8.1Hz, 2H, C6H4 2-H 6-H), 8.03 (s, 1H, NH), 8.25 (d, J=8.1Hz, 2H, C6H4 3-H 5-H).

[0128] Embodiment 14

[0129] Preparation of N'-(2-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A11):

[0130]

[0131] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A11 as a white solid with a yield of 70%.

[0132] A11: melting point 534.18~537.39℃, yield 70%. 1H NMR (600MHz, CDCl3) δ6.68 (d, J=2.4Hz, 1H, NH), 6.87 (t, J=7.6Hz, 1H, 2-Cl-C6H4 4-H), 6.99 (d, J=8.0Hz, 1H, 2-Cl-C6H4 6-H),7.17(t,J=7.7Hz,1H,2-Cl-C6H4 5-H),7.32(d,J=7.9Hz,1H,2-Cl-C6H4 3-H),8.00(d,J=8.1Hz,2H,C6H4 2-H 6-H), 8.13 (s, 1H, NH), 8.23 ​​(d, J = 8.1Hz, 2H, C6H4 3-H 5-H).

[0133] Embodiment 15

[0134] Preparation of N'-(4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A12):

[0135]

[0136] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A12 as a white solid in a yield of 63%.

[0137] A12: melting point 535.64~539.59℃, yield 63%. 1 H NMR (600MHz, CDCl3) δ7.24(s,2H,4-Cl-C6H4 2-H 6-H),7.60(d,J=6.7Hz,2H,4-Cl-C6H4 3-H 5-H),7.95(s,1H,NH),8.00(d,J=7.8Hz,2H,C6H4 2-H 6-H), 8.08 (d, J=7.7Hz, 2H, C6H4 3-H 5-H), 9.41 (s, 1H, NH).

[0138] Example 16

[0139] Preparation of N'-(3-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A13):

[0140]

[0141] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A13 as a white solid in a yield of 71%.

[0142] A13: melting point 564.14~567.79℃, yield 71%. 1H NMR (600MHz, CDCl3) δ6.36(d,J=3.0Hz,1H,NH),6.87(d,J=7.8Hz,1H,3-Br-C6H4 6-H),7.07(d,J=7.9Hz,1H,3-Br-C6H4 4-H),7.09(s,1H,3-Br-C6H4 2-H),7.12(t,J=8.0Hz,1H,3-Br-C6H4 5-H),7.98(s,1H,NH),8.01(d,J=8.1Hz,2H,C6H4 2-H 6-H),8.26(d,J=8.1Hz,2H,C6H4 3-H 5-H). Molecular formula: C 16 H 10 BrF3N4O2,HRMS-EST m / z calcd for[M+H] + 427.0012, found 427.0020.

[0143] Embodiment 17

[0144] Preparation of N'-(4-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide (A14):

[0145]

[0146] The preparation method was the same as that of Example 4. The reaction was continued for 2 h to obtain A14 as a white solid in a yield of 74%.

[0147] A14: melting point 566.69~570.37℃, yield 74%. 1 H NMR (600MHz, CDCl3) δ6.34 (s, 1H, NH), 6.84 (d, J = 8.7Hz, 2H, 4-Br-C6H4, 2-H 6-H), 7.36 (d, J = 8.7Hz, 2H, 4-Br-C6H4, 3-H 5-H), 8.01 (t, J = 9.0Hz, 3H, NH C6H4 2-H 6-H), 8.25 (d, J=8.2Hz, 2H, C6H4 3-H 5-H). Molecular formula: C 16 H 10 BrF3N4O2,HRMS-EST m / z calcd for[M+Na] + 448.9831, found 448.9842.

[0148] Embodiment 18

[0149] In vitro antifungal activity of N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide compounds

[0150] 1) Principle of in vitro antifungal activity

[0151] The hyphal growth rate method is a method used to evaluate the inhibitory effect of antifungal drugs on fungal growth. The effect of drugs on fungal growth is determined by measuring the diameter or area of ​​hyphal growth of fungi on the culture medium.

[0152] 2) In vitro antifungal activity experiment

[0153] Samples: Compounds A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13 and A14 of the present invention prepared in Examples 4-17;

[0154] Test bacteria: Botryosphaeria dothidea and Pythium aphanidermatum.

[0155] Experimental operation:

[0156] (1) First, culture the above-mentioned plant fungi on a PDA plate at 25°C for about 3-6 days for use;

[0157] (2) Heat and melt the PDA medium, cool it to 45-50°C, add 10 μL of 20 mg / mL concentration of the test compound to prepare a medium containing 100 μg / mL of the drug solution, and pour it into a culture dish to cool. Fluopyraclostrobin is used as a positive control;

[0158] (3) Using aseptic operation procedures, use a cork puncher to punch a round bacterial cake (0.50 cm in diameter) at the edge of the hyphae of each strain after 6 days of culture (the growth conditions should be as consistent as possible), then use an inoculation needle to pick it to the center of the drug-containing plate, and then place the culture dish upside down in the incubator for culture;

[0159] (4) Observe and measure the growth of mycelium at different times after treatment, measure the diameter using the cross method, process the data, and calculate the inhibition rate;

[0160] (5) Inhibition rate (%) = (control colony diameter - treated colony diameter) / (control colony diameter - bacterial cake diameter) * 100%;

[0161] (6) Each treatment was repeated 3 times.

[0162] The measurement results are shown in Table 1.

[0163] Embodiment 19

[0164] Determination of the antifungal activity of N′-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide compounds in vivo

[0165] 1) Principle of in vivo antifungal activity

[0166] The in vivo pot assay is a method of inoculating the target pathogen in a potted plant, applying the drug to be tested, and evaluating the efficacy of the drug.

[0167] 2) In vivo antifungal activity test

[0168] Samples: Compounds A2, A3, A4, A7, A9, A13 and A14 of the present invention prepared in Examples 4-17;

[0169] Test bacteria: soybean rust (Phakopsora pachyrhizi Syd.).

[0170] Experimental operation: Select the soybean seedlings with the first pair of true leaves fully expanded and growing uniformly, write the label number with an oil-based marker pen and insert it into the pot, and arrange it in order for the test. After spraying, dry the test materials in a fume hood or greenhouse for 24 hours before inoculation. Cut the soybean leaves full of rust spores, add them to water containing surfactant, wash the spores with a brush, and filter them through double-layer gauze to make a spore suspension (2×10 6 ~5×10 6 / mL), and evenly spray inoculate on the soybean seedlings with an inoculation sprayer (pressure 0.1MPa). The inoculated potted soybean seedlings are placed in a moisturizing box or an artificial climate chamber for cultivation, maintaining a relative humidity of 100% and a temperature of 15-20°C. After 24 hours, they are placed in an incubator with a light intensity greater than 2000lx or a greenhouse for high humidity cultivation. After about 7 days, a graded investigation is conducted based on the incidence 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 Procedure for Pesticide Biological Activity Test compiled by Kang Zhuo and Gu Baogen, and the control effect is calculated using the disease index.

[0171] Inhibition rate (%) = (disease index of blank control - disease index of drug treatment) / disease index of blank control × 100%.

[0172] 3) Evaluation of antifungal activity

[0173] The measurement results are shown in Table 1.

[0174] Table 1 Inhibition rate of compounds A1 to A14 of the present invention on fungi (100 μg / mL, %)

[0175]

[0176] -: inactive; / : not tested

[0177] The results in Table 1 show that at a concentration of 100 μg / mL, most of the compounds of the present invention exhibited good antifungal activity against Botrytis cinerea, Pythium aphanidermatum and soybean rust, and the antifungal activity of compound A1 against Pythium aphanidermatum was even better than that of the positive control flupyracoxad. This proves that the series of compounds have potential uses in the preparation of plant antifungal drugs and can be used as active ingredients or synergistic ingredients of plant antifungal drugs.

Claims

1. N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compounds, the structural formula of which is shown in Formula I: in, R is selected from the group consisting of: hydrogen, methyl, naphthyl, chloro, bromo, trifluoromethyl, 2,4-dichloro, 2-fluoro-4-chloro.

2. The N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compound according to claim 1, characterized in that: Selected from: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13 or A14; wherein, A1 is N'-(phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A2 is N'-(2-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A3 is N'-(3-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A4 is N'-(4-trifluoromethyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A5 is N'-(2,4-dichloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A6 is N'-(1-naphthyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A7 is N'-(2-fluoro-4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A8 is N'-(2-naphthyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A9 is N'-(2-methyl-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A10 is N'-(3-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A11 is N'-(2-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A12 is N'-(4-chloro-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A13 is N'-(3-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide; A14 is N'-(4-bromo-phenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzohydrazide.

3. The method for preparing the N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compound according to claim 1, characterized in that: The reaction formula is as follows: In the formula, R is as defined in claim 1.

4. Use of the N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compound according to claim 1 in the preparation of antifungal drugs.

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

6. The use according to claim 4, characterized in that: The fungus is Pythium aphanidermatum.

7. The use according to any one of claims 5 or 6, characterized in that: The N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide compound is selected from A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13 or A14, wherein the definitions of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13 and A14 are as described in claim 2.

8. The use according to claim 4, characterized in that: The fungus is soybean rust (Phakopsorapachyrhizi Syd.).

9. The use according to claim 8, characterized in that: The N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoylhydrazide compound is selected from A2, A3, A4, A7, A9, A13 or A14, wherein the definitions of A2, A3, A4, A7, A9, A13 and A14 are as described in claim 2.

10. A bactericide, characterized in that: The bactericide contains a bactericidal effective amount of at least one of the N'-aryl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoyl hydrazide compounds according to claim 1 or 2, and optionally contains auxiliary materials.

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