Antifungal applications of pyrazoles

Abstract

The application belongs to the technical field of organic compounds and agricultural fungicides, and particularly relates to the antifungal application of a novel pyrazole compound. The application provides a novel pyrazole compound, which has a structure shown in formula (a). The pyrazole derivative has good antibacterial activity on various fungi and can be used for preparing an agricultural fungicide. Moreover, the pyrazole compound in the application has the advantages of simple synthesis and high yield, and overcomes the problems of complex synthesis and low yield of current pyrazole fungicides. The application has important significance for promoting the application of pyrazole fungicides in the disease control of crops, fruits and vegetables. The application not only provides a new control drug for crop fungi and fungal diseases caused by the fungi, but also enriches the resource library of pyrazole fungicides, and provides more choices for the application of pyrazole derivatives in the fields of medicine and agricultural research.

Description

Technical Field

[0001] This invention belongs to the field of organic compounds and agricultural fungicides, specifically relating to the antifungal application of novel pyrazole compounds. Background Technology

[0002] Plant pathogenic fungi are a serious global problem, posing a significant threat to agricultural production and causing severe yield losses and quality degradation. Fungal infections in crops can even produce mycotoxins, which can seriously harm human health. To date, chemical control remains the most effective measure for controlling these harmful pathogens, and several effective agrochemicals have been developed to stop the destructive activities of plant pathogenic fungi on food crops (P. Jeschke, Progress of modern agricultural chemistry and future prospects, Pest Management Science, 72(2016) 433-455; M. Ivanov, A.). D. Emerging Antifungal Targets and Strategies, International Journal of Molecular Sciences, 23(2022)2756. However, the long-term and large-scale application of single-target antifungal drugs leads to increasing resistance of plant pathogens to fungicides (MC.Fisher, N.J.Hawkins, D.Sanglard, S.J.Gurr, Worldwide emergence of resistance to antifungal drugs challenges human health and food security, Science, 360(2018)739-742. H.Sierotzki, G.Scalliet, A Review of Current Knowledge of Resistance Aspects for the Next-Generation Succinate Dehydrogenase Inhibitor Fungicides). 103(2013)880-887.). Therefore, there is an urgent need to develop bactericides with novel chemical structures, novel mechanisms of action, high efficiency, low toxicity, and environmental friendliness.

[0003] Pyrazole derivatives are an important class of nitrogen-containing five-membered heterocyclic compounds that have attracted much attention in recent years due to their unique performance in pharmaceutical and agrochemical research. They possess a wide range of biological activities, including antibacterial, antifungal, anti-inflammatory, anticancer, antituberculosis, antiviral, and antileishmaniasis activities (JVFaria,PFVegi,AGCMiguita,MSDos Santos,N.Boechat,AMRBernardino,Recently reported biological activities of pyrazole compounds,Bioorg Med Chem,25(2017)5891-5903.O.Ebenezer,M.Shapi,JATuszynski,A Review of the Recent Development in the Synthesis and Biological Evaluations of Pyrazole Derivatives,10(2022).). To date, many commercial fungicides containing pyrazole fragments have been approved for plant protection, and pyrazole fungicides have been widely used in the control of diseases in crops, fruits, and vegetables. However, current pyrazole fungicides suffer from problems such as complex synthesis and low yield, which are not conducive to practical production and application. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the present invention provides a novel pyrazole compound. This pyrazole derivative has good antibacterial activity against a variety of fungi and can be used to prepare agricultural fungicides. It is of great significance for promoting the application of pyrazole fungicides in the prevention and control of diseases in crops, fruits and vegetables.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A first aspect of the present invention provides a pyrazole compound having the structure shown in formula (a):

[0007]

[0008] In formula (a), R1 is selected from phenyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-trifluoromethylphenyl, 2,4,6-trimethylphenyl, pyridin-2-yl, 1-naphthyl, propylisopropyl, cyclopentyl, 4-ethoxycarbonyl, 4-methoxycarbonyl; R2 is selected from ester group, cycloalkyl; R3 is selected from 4-methoxycarbonyl, cycloalkyl.

[0009] Preferably, the pyrazole compound is selected from any one of the following structural formulas:

[0010]

[0011] The second aspect of this invention provides the application of the pyrazole compounds described in the first aspect in the preparation of agricultural fungicides.

[0012] Preferably, the pyrazole compound is selected from at least one of the following two compounds:

[0013]

[0014] Preferably, the agricultural fungicide is a fungicide, and the fungi include B. cinerea, M. oryzae, P. aphanidermatum, F. graminearum, C. micotianae, and V. mali.

[0015] A third aspect of the present invention provides an agricultural fungicide, wherein the agricultural fungicide uses the pyrazole compounds described in the first aspect as the main active ingredient.

[0016] Preferably, the agricultural fungicide further includes excipients acceptable in the pesticide field.

[0017] A fourth aspect of this invention provides a method for synthesizing the pyrazole compounds described in the first aspect, as shown in the following reaction formula, the method comprising the following steps:

[0018] (1) Compounds 3, 4 and 5 react to form compound 1a-1w;

[0019] (2) Compounds 3, 4d and 6 react to form compounds 2a and 2b;

[0020] (3) Compounds 3, 4d and 7 react to form compound 2c;

[0021] The reaction formula is as follows:

[0022]

[0023]

[0024] Compared with the prior art, the beneficial effects of the present invention are:

[0025] This invention discloses a novel pyrazole compound. This pyrazole derivative exhibits good antifungal activity against various fungi (B. cinerea, M. oryzae, P. aphanidermatum, F. graminearum, C. micotianae, V. mali, etc.), inhibiting the growth of multiple fungi and can be used to prepare agricultural fungicides (such as antifungal agents). Furthermore, the pyrazole compound of this invention has advantages such as simple synthesis and high yield, overcoming the problems of complex synthesis and low yield of current pyrazole fungicides. This is of great significance for promoting the application of pyrazole fungicides in the control of diseases in crops, fruits, and vegetables. This invention not only provides new control drugs for crop fungi and the fungal diseases they cause, but also enriches the pyrazole fungicide resource library, providing more options for the application of pyrazole derivatives in the fields of pharmaceutical and agrochemical research, and has significant potential application value. Detailed Implementation

[0026] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0027] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0028] Example 1: Preparation of novel pyrazole compounds

[0029] (1) As shown in the following reaction formula, compounds 3 (0.3 mmol), 4 (0.33 mmol), and 5 (0.6 mmol) were dissolved in a mixed solvent of acetonitrile and water. Potassium bromide (1.2 equiv.), potassium carbonate (2.5 equiv.), and potassium peroxymonosulfonate (3.0 equiv.) were added under ice bath conditions. After stirring for 10 minutes under ice bath conditions, the reaction was carried out at room temperature for 9 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with saturated sodium sulfite solution. The target product was obtained by extraction with ethyl acetate, and then the clean target compounds (23 compounds in total, named 1a-1w) were obtained by column chromatography.

[0030]

[0031] In the formula, the values ​​of R are as follows:

[0032]

[0033] (2) As shown in the following reaction formula, compounds 3 (0.3 mmol), 4d (0.33 mmol), and 6 (0.6 mmol) were dissolved in a mixed solvent of acetonitrile and water. Potassium bromide (1.2 equiv.), potassium carbonate (2.5 equiv.), and potassium peroxymonosulfonate (3.0 equiv.) were added under ice bath conditions. After stirring for 10 minutes under ice bath conditions, the reaction was carried out at room temperature for 9 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with saturated sodium sulfite solution. The target product was obtained by extraction with ethyl acetate, and then the clean target compounds (two compounds in total, named 2a and 2b) were obtained by column chromatography.

[0034]

[0035] (3) Compound 3 (0.3 mmol), compound 4d (0.33 mmol), and compound 7 (0.6 mmol) were dissolved in a mixed solvent of acetonitrile and water. Potassium bromide (1.2 equiv.), potassium carbonate (2.5 equiv.), and potassium peroxymonosulfonate (3.0 equiv.) were added under ice bath conditions. After stirring for 10 minutes under ice bath conditions, the reaction was carried out at room temperature for 9 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with saturated sodium sulfite solution. The target product was obtained by extraction with ethyl acetate, and then purified by column chromatography to obtain clean target compound 2c.

[0036]

[0037] The characterization data of compounds 1a-1w and 2a-c are as follows:

[0038] 1a.84mg, 77% yield; White solid.mp=134-136℃. 1 H NMR (400MHz, CDCl3) δ: 7.88-7.85 (m, 2H), 7.56 (d, J = 8.8Hz, 2H), 7.46-7.42 (m, 2H), 7.39-7.32 (m, 4H), 3.85 (s, 3H). 13C NMR(100 MHz,CDCl3)δ:159.6,152.0,149.2(q,J=1.9 Hz),138.7,134.3,131.9,129.0(2×C),128.8,127.7(2×C),125.9(2×C),121.2(2×C),120.5(q,J=256 Hz),110.0,52.4. 19 F NMR(376MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculated forC 18 H 14 O3N2F3 + [M+H] + 363.0951,found 363.0956。

[0039] 1b.89 mg,79%yield;White solid.m.p.=124-126℃. 1 H NMR(400 MHz,CDCl3)δ:7.75(d,J=8.0 Hz,2H),7.55(d,J=8.8 Hz,2H),7.32(d,J=8.8 Hz,2H),7.31(s,1H)7.24(d,J=8.0 Hz,2H),3.84(s,3H),2.39(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.6,152.1,149.1,138.7,138.6,134.2,129.6(2×C),129.1,127.7(2×C),125.8(2×C),121.2(2×C),120.5(q,J=256 Hz),109.9,52.3,21.5. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculated for C 19 H 16 O3N2F3 + [M+H] + 377.1108,found 377.1114。

[0040] 1c.90 mg,79%yield;White solid.m.p.=109-111℃. 1H NMR(400 MHz,CDCl3)δ:7.83(dd,J=8.8,5.2 Hz,2H),7.54(d,J=8.8 Hz,2H),7.33(d,J=8.8 Hz,2H),7.29(s,1H),7.12(t,J=8.8 Hz,2H),3.84(s,3H). 13 C NMR(100 MHz,CDCl3)δ:163.2(d,J=246Hz),159.5,151.1,149.2(q,J=1.9 Hz),138.6,134.5,128.2(d,J=3.2 Hz),127.7(2×C),127.6(d,J=7.4 Hz,2×C),121.2(2×C),120.5(q,J=256 Hz),115.9(d,J=21.7 Hz,2×C),109.8,52.4. 19 F NMR(376 MHz,CDCl3)δ:-113.0,-57.8(3×F).HRMS(ESI)m / zcalculated for C 18 H 13 O3N2F4 + [M+H] + 381.0857,found 381.0860。

[0041] 1d.96 mg,81%yield;White solid. 1 H NMR(400 MHz,CDCl3)δ:7.79(d,J=8.8Hz,2H),7.54(d,J=9.2 Hz,2H),7.40(d,J=8.8 Hz,2H),7.33(d,J=8.8 Hz,2H),7.31(s,1H),3.84(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.5,150.9,149.2,138.5,134.6,134.5,130.5,129.2(2×C),127.7(2×C),127.2(2×C),121.2(2×C),120.5(q,J=256 Hz),109.9,52.4。

[0042] 1e.110 mg,83%yield;White solid.m.p.=149-151℃. 1H NMR(400 MHz,CDCl3)δ:7.73(d,J=8.8 Hz,2H),7.56(d,J=8.8 Hz,2H),7.54(d,J=8.8 Hz,2H),7.33(d,J=8.8 Hz,2H), 7.32(s,1H),3.84(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.4,150.9,149.2(q,J=1.9 Hz),138.5,134.5,132.1(2×C),130.9,127.7(2×C),127.4(2×C),122.8,121.2(2×C),120.5(q,J=256 Hz),109.9,52.4. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculated for C 18 H 13 O3N2F3Br + [M+H] + 441,0056,found 441,0057。

[0043] 1f.90 mg,70\yield;White solid.mp=107-109°C. 1 H NMR(400 MHz,CDCl3)δ:7.98(d,J=8.0 Hz,2H),7.69(d,J=8.0 Hz,2H),7.56(d,J=8.8 Hz,2H),7.39(s,1H),7.35(8d.8,J Hz,2H), 3.86(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.4,150.6,149.3,138.5,135.4,134.7,130.6(q,J=32.3 Hz), 127.7(2×C),126.1(2×C),125.9(q,J=3.8Hz,2×C),124.2(q,J=270 Hz),121.2(2×C),120.5(q,J=256 Hz),110.5.3,1 19 FNMR(376 MHz,CDCl3)δ:-62.6(3×F),-57.8(3×F).HRMS(ESI)m / z calculated forC 19 H 13 O3N2F6 + [M+H] +431.0825,found 431.0834。

[0044] 1g.79 mg,70%yield;White solid.m.p.=123-125℃. 1 H NMR(400 MHz,CDCl3)δ:7.71(s,1H),7.64(d,J=7.6 Hz,1H),7.56(d,J=8.8 Hz,2H),7.34-7.30(m,4H),7.19(d,J=7.6 Hz,1H),3.84(s,3H),2.41(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.6,152.2,149.2,138.7,138.6,134.3,131.8,129.6,128.8,127.8(2×C),126.5,123.1,121.2(2×C),120.5(q,J=256 Hz),110.1,52.4,21.6. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / zcalculated for C 19 H 16 O3N2F3 + [M+H] + 377.1108,found 377.1101。

[0045] 1h.82 mg,72%yield;White solid.m.p.=118-120℃. 1 H NMR(400 MHz,CDCl3)δ:7.63(dt,J=7.6,1.2 Hz,1H),7.59-7.53(m,1H),7.55(d,J=8.8 Hz,2H),7.40(dt,J=6.0,8.0 Hz,1H),7.34(d,J=8.8 Hz,2H),7.33(s,1H),7.06(tdd,J=8.8,2.4,0.8 Hz,1H),3.85(s,3H). 13C NMR(100MHz,CDCl3)δ:163.3(d,J=244 Hz),159.4,150.9(d,J=2.7Hz),149.2(q,J=1.9 Hz),138.5,134.5,134.1(d,J=8.4 Hz),130.5(d,J=8.2 Hz),127.7(2×C),121.5(d,J=2.8 Hz),121.2(2×C),120.5(q,J=256 Hz),115.6(d,J=21Hz),112.8(d,J=23 Hz),110.1,52.4. 19 F NMR(376 MHz,CDCl3)δ:-112.7,-57.8(3×F).HRMS(ESI)m / z calculated for C 18 H 13 O3N2F4 + [M+H] + 381.0857,found 381.0859。

[0046] 1i.101 mg,85%yield;White solid.m.p.=153-155℃. 1 H NMR(400 MHz,CDCl3)δ:7.87(s,1H),7.74-7.72(m,1H),7.55(d,J=8.8 Hz,2H),7.38-7.33(m,5H),3.85(s,3H). 13 C NMR(100MHz,CDCl3)δ:159.4,150.7,149.2(q,J=1.5 Hz),138.5,135.0,134.5,133.7,130.2,128.7,127.7(2×C),126.0,124.0,121.2(2×C),120.5(q,J=256 Hz),110.1,52.4. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculated forC 18 H 13 O3N2F3Cl + [M+H] + 397.0561,found397.0562。

[0047] 1j.103 mg,78%yield;White solid.m.p.=165-167℃. 1H NMR(400 MHz,CDCl3)δ:8.03(t,J=1.6 Hz,1H),7.77(dt,J=7.6,1.2 Hz,1H),7.56(d,J=8.8 Hz,2H),7.49(ddd,J=8.0,2.0,1.2Hz,1H),7.34(d,J=8.8 Hz,2H),7.33(s,1H),7.30(t,J=8.0 Hz,1H),3.85(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.4,150.5,149.3(q,J=1.9 Hz),138.5,134.5,133.9,131.6,130.5,128.9,127.7(2×C),124.4,123.1,121.2(2×C),120.5(q,J=256 Hz),110.1,52.4. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculatedfor C 18 H 13 O3N2F3Br + [M+H] + 441.0056,found441.0061。

[0048] 1k.85 mg,66%yield;White solid.m.p.=174-176℃. 1 H NMR(400 MHz,CDCl3)δ:8.13(s,1H),8.04(d,J=7.6 Hz,1H),7.62(d,J=7.6 Hz,1H),7.58-7.53(m,3H),7.39(s,1H),7.35(d,J=8.4 Hz,2H),3.86(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.4,150.6,149.3,138.4,134.7,132.8,131.4(q,J=32.2 Hz),129.5,129.0,127.8(2×C),125.3(q,J=3.8Hz),124.2(q,J=271 Hz),122.7(q,J=3.7 Hz),121.2(2×C),120.5(q,J=256 Hz),110.1,52.5. 19F NMR(376 MHz,CDCl3)δ:-62.7(3×F),-57.8(3×F).HRMS(ESI)m / zcalculated for C 19 H 13 O3N2F6 + [M+H] + 431.0825,found 431.0827。

[0049] 1l.86 mg,76%yield;White solid.m.p.=87-89℃. 1 H NMR(400 MHz,CDCl3)δ:7.63-7.61(m,1H),7.57(d,J=8.8 Hz,2H),7.33(d,J=8.8 Hz,2H),7.31-7.24(m,3H),7.21(s,1H),3.85(s,3H),2.53(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.7,152.4,149.0(q,J=2.0 Hz),138.6,136.3,133.4,131.6,131.1,129.4,128.6,127.6(2×C),126.2,121.1(2×C),120.5(q,J=256 Hz),113.1,52.3,21.4. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculated for C 19 H 16 O3N2F3 + [M+H] + 377.1108,found 377.1109。

[0050] 1m.101 mg,88%yield;White solid.m.p.=149-151℃. 1 H NMR(400 MHz,CDCl3)δ:8.06(td,J=7.6,1.6 Hz,1H),7.56(d,J=8.8 Hz,2H),7.49(d,J=3.6 Hz,1H),7.37-7.31(m,3H),7.23-7.15(m,2H),3.85(s,3H). 13C NMR(100 MHz,CDCl3)δ:160.4(d,J=248Hz),159.6,149.2(q,J=1.9 Hz),146.7,138.6,134.1(d,J=2.0 Hz),130.1(d,J=8.3Hz),128.5(d,J=3.3Hz),127.8(2×C),124.5(d,J=3.5 Hz),121.2(2×C),120.5(q,J=256 Hz),119.8(d,J=11.6 Hz),116.3(d,J=21.9 Hz),113.5(d,J=10.8 Hz),52.4. 19 FNMR(376 MHz,CDCl3)δ:-115.8,-57.8(3×F).HRMS(ESI)m / z calculated for C 18 H 13 O3N2F4 + [M+H] + 381.0857,found 381.0859。

[0051] 1n.91 mg,76%yield;White solid.m.p.=79-81℃. 1 H NMR(400 MHz,CDCl3)δ:7.89-7.85(m,1H),7.58(s,1H),7.57(d,J=8.8 Hz,2H),7.50-7.47(m,1H),7.36-7.29(m,4H),3.85(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.6,149.7,149.2(q,J=1.9 Hz),138.5,133.5,132.5,130.8,130.7,130.6,129.8,127.8(2×C),127.2,121.2(2×C),120.5(q,J=256 Hz),113.9,52.4. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculatedfor C 18 H 13 O3N2F3Cl + [M+H] + 397.0561,found 397.0565。

[0052] 1o.115 mg,87%yield;White solid.m.p.=136-138℃. 1 H NMR(400 MHz,CDCl3)δ:7.77(dd,J=7.6,1.6 Hz,1H),7.69(dd,J=7.6,1.2 Hz,1H),7.59-7.55(m,3H),7.38(td,J=7.6,1.2 Hz,1H),7.33(d,J=8.8 Hz,2H),7.24(td,J=7.6,1.6 Hz,1H),3.85(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.6,151.1,149.2(q,J=1.9 Hz),138.5,133.8,133.3,133.0,131.2,130.0,127.8(2×C),127.7,122.1,121.1(2×C),120.5(q,J=256 Hz),113.9,52.4. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculated forC 18 H 13 O3N2F3Br + [M+H] + 441.0056,found441.0061。

[0053] 1p.93 mg,72%yield;White solid.m.p.=70-72℃. 1 H NMR(400 MHz,CDCl3)δ:7.79(d,J=7.6 Hz,1H),7.73(d,J=7.6 Hz,1H),7.63-7.50(m,4H),7.33(d,J=8.8 Hz,2H),7.25(d,J=0.8Hz,1H),3.85(s,3H). 13 C NMR(100 MHz,CDCl3)δ:159.6,150.2,149.2(q,J=1.9 Hz),138.4,133.6,132.0,131.9,131.5,128.8,128.6(q,J=30.5 Hz),127.7(2×C),126.5(q,J=5.6 Hz),124.2(q,J=272 Hz),121.1(2×C),120.5(q,J=256 Hz),113.6(q,J=3.6 Hz),52.4. 19F NMR(376MHz,CDCl3)δ:-57.9(3×F),-57.8(3×F).HRMS(ESI)m / z calculated for C 19 H 13 O3N2F6 + [M+H] + 431.0825,found 431.0828。

[0054] 1q.86 mg,71%yield;Yellow oil. 1 H NMR(400 MHz,CDCl3)δ:7.55(d,J=8.8 Hz,2H),7.31(d,J=8.8 Hz,2H),6.95(s,1H),6.94(s,2H),3.85(s,3H),2.32(s,3H),2.17(s,6H). 13 C NMR(100 MHz,CDCl3)δ:159.8,151.6,149.0,138.6,138.2,137.5(2×C),133.3,129.2,128.4(2×C),127.5(2×C),121.1(2×C),120.5(q,J=256 Hz),114.2,52.3,21.3,20.8(2×C). 19 F NMR(376 MHz,CDCl3)δ:-57.9(3×F).HRMS(ESI)m / z calculated forC 21 H 20 O3N2F3 + [M+H] + 405.1421,found 405.1428。

[0055] 1r.73 mg,67%yield;White solid.m.p.=149-151℃. 1 H NMR(400 MHz,CDCl3)δ:8.66(dd,J=4.8,0.8 Hz,1H),8.02(d,J=8.0 Hz,1H),7.75(td,J=7.6,1.6 Hz,1H),7.68(s,1H),7.56(d,J=8.8 Hz,2H),7.33(d,J=8.8 Hz,2H),7.27(ddd,J=7.6,4.8,1.2 Hz,1H),3.84(s,3H). 13C NMR(100 MHz,CDCl3)δ:159.6,152.3,150.9,149.8,149.2(q,J=1.9Hz),138.6,136.9,134.6,127.8(2×C),123.4,121.2(2×C),120.5(q,J=256 Hz),120.4,111.5,52.4. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculated forC 17 H 13 O3N3F3 + [M+H] + 364.0904,found364.0911。

[0056] 1s.101 mg,81%yield;White solid.m.p.=72-74℃. 1 H NMR(400 MHz,CDCl3)δ:8.50(d,J=7.6 Hz,1H),7.93-7.90(m,2H),7.76(d,J=7.2 Hz,1H),7.64(d,J=8.8 Hz,2H),7.58-7.51(m,3H),7.38(s,1H),7.36(d,J=8.8 Hz,2H),3.88(s,3H). 13 C NMR(100MHz,CDCl3)δ:159.7,152.0,149.2,138.7,134.1,133.7,131.2,129.8,129.3,128.6,127.7(2×C),127.6,126.9,126.1,125.7,125.5,121.1(2×C),120.5(q,J=256 Hz),113.9,52.4. 19 F NMR(376 MHz,CDCl3)δ:-57.8(3×F).HRMS(ESI)m / z calculated forC 22 H 16 O3N2F3 + [M+H] + 413.1108,found413.1106。

[0057] 1t.78 mg,79%yield;Yellow oil. 1H NMR(400 MHz,CDCl3)δ:7.47(d,J=8.8 Hz,2H),7.29(d,J=8.8 Hz,2H),6.84(s,1H),3.80(s,3H),2.67(t,J=7.6 Hz,2H),1.77-1.67(m,2H),0.99(t,J=7.6 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ:159.8,154.1,148.9(q,J=1.9Hz),138.7,133.4,127.6(2×C),121.1(2×C),120.5(q,J=256 Hz),111.9,52.2,30.1,22.8,14.0. 19 F NMR(376 MHz,CDCl3)δ:-57.9(3×F).HRMS(ESI)m / z calculated forC 15 H 16 O3N2F3 + [M+H] + 329.1108,found 329.1110。

[0058] 1u.54mg,55%yield;Yellow oil. 1 H NMR(400MHz,CDCl3)δ:7.47(d,J=8.8Hz,2H),7.29(d,J=8.8Hz,2H),6.87(s,1H),3.80(s,3H),3.11-3.00(m,1H),1.31(d,J=6.8Hz,6H). 13 C NMR(100MHz,CDCl3)δ:159.9,159.8,148.9,138.8,133.3,127.6(2×C),121.1(2×C),120.5(q,J=256Hz),110.1,52.2,27.9,22.8(2×C). 19 F NMR(376MHz,CDCl3)δ:-57.9(3×F).HRMS(ESI)m / z calculated for C 15 H 16 O3N2F3 + [M+H] + 329.1108,found329.1113。

[0059] 1v.92mg,83%yield;Yellow solid.m.p.=89-91℃. 1H NMR(400MHz,CDCl3)δ:7.47(d,J=8.8Hz,2H),7.28(d,J=8.8Hz,2H),6.85(s,1H),3.80(s,3H),2.74-2.67(m,1H),2.03-2.00(m,2H),1.84-1.80(m,2H),1.75-1.71(m,1H),1.50-1.33(m,4H),1.31-1.21(m,1H). 13 C NMR(100MHz,CDCl3)δ:159.8,159.0,148.8,138.8,133.2,127.6(2×C),121.1(2×C),120.5(q,J=256Hz),110.3,52.2,37.4,33.2(2×C),26.3(2×C),26.1. 19 F NMR(376MHz,CDCl3)δ:-57.9(3×F).HRMS(ESI)m / z calculated for C 18 H 20 O3N2F3 + [M+H] + 369.1421,found 369.1425。

[0060] 1w.60mg,56%yield;Light yellow solid.m.p.=73-75℃. 1 H NMR(400MHz,CDCl3)δ:7.52(s,1H),7.50(d,J=8.8Hz,2H),7.32(d,J=8.8Hz,2H),4.44(q,J=7.2Hz,2H),3.83(s,3H),1.41(t,J=7.2Hz,3H). 13 C NMR(100MHz,CDCl3)δ:161.5,158.9,149.7,144.3,138.0,134.6,128.0(2×C),121.1(2×C),120.5(q,J=256Hz),115.1,61.7,52.6,14.5. 19 F NMR(376MHz,CDCl3)δ:-57.9(3×F).HRMS(ESI)m / z calculated for C 15 H 14 O5N2F3 + [M+H] + 359.0849,found 359.0855。

[0061] 2a.61mg,52%yield;Yellow solid. 1 1H NMR (400MHz,CDCl3)δ: 8.22(d,J=9.2Hz,2H), 7.80(d,J=8.8Hz,2H), 7.44(d,J=8.8Hz,2H), 7.32(d,J=8.4Hz,2H), 3.24-3.22(m,2H), 3.16-3.13(m,2H). 13 C NMR(100MHz,CDCl3)δ:189.2,147.7,146.7,145.4,144.8,137.7,134.6,130.4,12 9.3(2×C),127.3(2×C),121.9(2×C),121.4(2×C),120.6(q,J=256Hz),43.9,19.8。

[0062] 2b.65mg,53%yield;White solid. 1 1H NMR (400MHz,CDCl3)δ: 7.71(d,J=8.8Hz,2H), 7.60(d,J=9.2Hz,2H), 7.43(d,J=8.8Hz,2H), 7.31(d,J=8.8Hz,2H), 3.03(t,J=6.0Hz,2H), 2.65(dd,J=7.2,6.0Hz,2H), 2.26-2.20(m,2H). 13 C NMR(100MHz,CDCl3)δ:188.4,148.8,148.3,138.4,136.0,134.4,130.8,129.3,129. 1(2×C),128.5(2×C),126.9(2×C),121.1(2×C),120.5(q,J=256Hz),39.6,24.7,22.8。

[0063] 2c.93mg,68%yield;Yellow solid. 1 1H NMR (400MHz,CDCl3)δ: 7.69(d,J=8.8Hz,2H), 7.58(d,J=9.2Hz,2H), 7.41(d,J=8.8Hz,2H), 7.37(d,J=8.8Hz,2H), 3.88(s,3H), 3.84(s,3H). 13C NMR(100MHz, CDCl3)δ:163.3,160.4,151.2,149.5,137.3,137.0,135.3,130.2(2×C), 129.7, 128.7 (2×C), 126.4 (2×C), 121.7 (2×C), 120.5 (q, J=257Hz), 114.7, 53.5, 52.5.

[0064] The structural formulas of compounds 1a-1w and 2a-c are as follows:

[0065]

[0066] Example 2: Antibacterial experiment of novel pyrazole compounds

[0067] The compound from Example 1 was dissolved in DMSO (0.5 mL) and then mixed with potato dextrose agar (PDA) 99.5 mL to prepare a test medium for antifungal testing. The final concentration of the compound in the medium was adjusted to 100 μg / mL. Six fungi (Table 1) were incubated in PDA at 25°C for 5 days to obtain new hyphae for the antifungal test. Mycelial discs with a diameter of approximately 0.45 cm were then cut from the medium using a sterile inoculation needle and inoculated into the center of the test PDA plate. The inoculated plates were incubated at 25°C for 5 days. Dimethyl sulfoxide in sterile distilled water was used as a control, and pyraclostrobin was used as a positive control; each treatment was performed in triplicate. Radial growth of colonies was measured on day 6, and the data were statistically analyzed. Compared with the blank control, the relative control efficacy of the compound was calculated using the formula: I(%) = [(CK - PT / CK)] × 100%, where I is the relative control efficacy, CK is the average disease index during the blank control period, and PT is the average disease index after compound treatment during the experimental period. The in vitro inhibitory effect of the experimental compound on fungi was calculated using the formula CV = (AB) / A, where A is the growth diameter of fungi on untreated PDAs, B is the growth diameter of fungi on compound-treated PDAs, and CV is the inhibition rate. All test strains were preserved in the Key Laboratory of Biological Pesticides and Chemical Biology, Ministry of Education, Fujian Agriculture and Forestry University (Fuzhou).

[0068] As shown in Table 1, all 26 compounds exhibited certain antifungal activity against 6 fungi (B. cinerea, M. oryzae, P. aphanidermatum, F. graminearum, C. micotianae, and V. mali). Among them, compounds 1v and 1t showed superior antifungal activity.

[0069] Based on the above results of in vitro antifungal activity, compounds with higher activity (1v, 1t) were selected, and their median effective concentrations (EC50) were determined according to the above method. 50 The stock solution of the compound was mixed with autoclaved PDA medium to prepare a series of media containing 100, 50, 25, 12.5, 6.25, and 3.125 μg / mL of the test compound. A medium containing 0.5% DMSO was used as a blank control. Each experiment was performed three times. Basic EC was used. 50 The SPSS 22.0 program calculates the EC50 value and its 95% confidence interval (95% CI).

[0070] As shown in Table 2, compound 1v exhibits low EC50 against F. graminearum and C. micotianae. 50 It exhibits superior antifungal activity. Compound 1t has a low EC50 against F. graminearum. 50 It exhibits superior antifungal activity.

[0071] Table 1. Antibacterial effects of novel pyrazole compounds

[0072]

[0073] Table 2. Antibacterial EC of compounds 1t and v1 50

[0074]

[0075] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and these variations still fall within the protection scope of the present invention.

Claims

1. The application of a pyrazole compound in the preparation of agricultural fungicides, characterized in that, The pyrazole compound is selected from any one of the following structural formulas: 。 2. The application according to claim 1, characterized in that, The pyrazole compound is selected from at least one of the following two compounds: 。 3. The application according to claim 1 or 2, characterized in that, The agricultural fungicide is a fungicide, and the fungi include B. cinerea, M. oryzae, P. aphandidamatum, F. graminearum, C. micotianae, and V. mali.

4. The application according to claim 1, characterized in that, The following reaction formula illustrates the method for synthesizing the pyrazole compounds. The process includes the following: (1) Compounds 3, 4 and 5 react to form compound 1a-1w; (2) Compounds 3, 4d, and 6 react to form compounds 2a and 2b; (3) Compounds 3, 4d, and 7 react to form compound 2c; The reaction formula is as follows: ； ； 。 5. An agricultural fungicide, characterized in that, The agricultural fungicide uses the pyrazole compound described in claim 1 as the main active ingredient.

6. An agricultural fungicide according to claim 5, characterized in that, The agricultural fungicide also includes excipients acceptable in the pesticide field.

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