Totarol derivative containing 1, 3, 4-oxadiazole / thiadiazole and preparation method and application thereof

Abstract

The invention belongs to the field of bactericides, and discloses a totarol derivative containing 1, 3, 4-oxadiazole / thiadiazole, a preparation method and application, the structure of the compound is as shown in the formula I: # imgabs0 #, in the formula I, X is an oxygen atom or a sulfur atom; r is a hydrogen atom, a halogen atom or a methoxy group; the halogen is one of F, Cl and Br. The compound has the effects of inhibiting plant pathogenic fungi and preventing and treating plant fungal diseases, and can be applied to plant protection as a bactericide.

Description

Technical Field

[0001] The present invention relates to a 1,34-oxadiazole or 1,3,4-thiadiazole modified diterpene natural product totarol derivative, a preparation method and application thereof in preventing and controlling plant fungal diseases. The derivative has the purpose of preparing pesticide bactericides and belongs to the technical field of organic synthetic chemistry and pesticide science. Background Art

[0002] The biological activity of natural products is an important research topic in the field of medicine. At present, researchers around the world have extracted many natural products with biological activities such as anti-inflammatory, antioxidant, anti-cancer, immunostimulatory and neuroprotective from plants. Natural products, due to their diverse sources, structural diversity and functional diversity, continuously bring new opportunities for pesticide creation research. Taking natural products as lead compounds, further structural modification and analog synthesis can often produce a series of high-efficiency and low-toxic green pesticides. Totarol is a rosin diterpene. Terpenoid compounds are the largest class of natural products. They have many different functions, including regulating plant growth. In terms of biological activity, totarol has shown high biological activity, human safety and product formulation compatibility, and has applications in the fields of medicine, pesticides and cosmetics. Totarol has very strong antibacterial activity. Studies have shown that totarol has very effective antibacterial activity against Gram-positive bacteria, especially against Staphylococcus aureus strains, and its antibacterial effect is more obvious. However, there are few reports on its agricultural bactericidal activity.

[0003] Heterocyclic compounds have become a hot spot for the development of new pesticides due to their special structural characteristics. Among them, oxadiazole heterocyclics are important components in commercial pesticides and have a wide range of biological activities, such as anti-cancer, bactericidal, anti-inflammatory, and antiviral. 1,3,4-oxadiazole compounds have a wide range of uses in the field of pharmaceuticals and chemicals. In 2021, Flufenoxadiazam, developed by BASF, is an oxadiazole fungicide. The unique HDACs bactericidal mechanism of oxadiazole compounds is different from the mainstream agents on the existing pesticide market. While showing good bactericidal activity, there is no problem of cross-resistance, making it an ideal choice for the development of new fungicides. In addition, 1,3,4-thiadiazole derivatives have a wide range of applications in pesticides due to their advantages such as high efficiency and high specificity. At present, agricultural fungicides containing 1,3,4-thiadiazole structures such as chlorothiazol and thiophanate-methyl have been commercialized.

[0004] In summary, the diterpene natural products totarol and diazole compounds have a broad spectrum of biological activities, which are of guiding significance for the discovery of new pesticide lead compounds. In view of this, the present invention modifies the structure of totarol, introduces 1,3 4-oxadiazole or 1,3,4-thiadiazole structural fragments, and synthesizes a series of 1,3 4-oxadiazole or 1,3,4-thiadiazole modified totarol derivatives. The compounds prepared by the present invention are all new compounds that have not been reported in the literature. After testing, some compounds have good inhibitory activity against plant pathogenic fungi. Summary of the invention

[0005] The purpose of the present invention is to provide a totarol derivative containing 1,3 4-oxadiazole / thiadiazole, a preparation method and use thereof, and to synthesize a series of 1,3 4-oxadiazole or 1,3,4-thiadiazole-modified diterpene totarol derivatives by introducing 1,3 4-oxadiazole or 1,3,4-thiadiazole fragments; the compounds have the characteristics of easy preparation and high yield; the totarol derivatives can be used in plant disease prevention and control.

[0006] The present invention provides a totarol derivative containing 1,3 4-oxathiadiazole, which has a general structural formula of formula I:

[0007]

[0008] In Formula I,

[0009] X is an oxygen atom or a sulfur atom;

[0010] R is a hydrogen atom, a halogen atom or a methoxy group;

[0011] The halogen is one of F, Cl and Br.

[0012] Furthermore, R is selected from H, 2-Br, 2-F, 3-Br, 3-F, 4-Cl, 4-OMe.

[0013] The present invention also provides a method for preparing a totarol derivative containing 1,3-dioxadiazole, which is prepared according to the following reaction formula:

[0014]

[0015] The following is a source of the compound represented by formula I, and the specific reaction steps are as follows:

[0016] Totarol (0.3 mmol, 85.9 mg), 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole or 2-(chloromethyl)-5-phenyl-1,3,4-thiadiazole (0.45 mmol) with different substitutions, potassium carbonate (0.45 mmol, 62.1 mg), acetonitrile (1.5 mL) were added to the reaction tube and reacted at 80° C. for 5 hours. After the reaction was completed, the reaction system was transferred to a round-bottom flask, concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain the final product, which is the compound shown in Formula I.

[0017] The preparation method of the totarol derivatives containing 1,3 4-oxathiadiazole provided by the present invention has the characteristics of simple steps, easy operation and high yield.

[0018] The 1,3-4-oxathiadiazole-modified tocopherol derivatives involved in the present invention preferably have any one of the following structures:

[0019]

[0020] Beneficial effects of the present invention: The diterpene natural product totarol used in the present invention has good fungicidal activity. By deriving its structure and introducing 1,3 4-oxadiazole or 1,3,4-thiadiazole fragments, a series of 1,3 4-oxadiazole or 1,3,4-thiadiazole-modified diterpene totarol derivatives are synthesized. This type of compound has the characteristics of easy preparation and high yield. All compounds are new compounds, and this type of compound can be applied to crop diseases caused by fungi, and can provide effective services for plant protection in agricultural production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the H NMR spectrum of the product I1 in Example 1.

[0022] Figure 2 This is the NMR carbon spectrum of the product I1 in Example 1.

[0023] Figure 3 This is the H NMR spectrum of the product I8 in Example 8.

[0024] Figure 4 This is the NMR carbon spectrum of the product I8 in Example 8. DETAILED DESCRIPTION

[0025] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited thereto.

[0026] Example 1

[0027] Preparation of 2-(((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-5-phenyl-1,3,4-oxadiazole (I1):

[0028]

[0029] In a pressure tube, totarol and 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole were dissolved in acetonitrile, potassium carbonate was added to the above reaction system, and the reaction was carried out at 80°C for 5 hours. After the reaction was completed, the reaction system was transferred to a round-bottom flask, concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain product I1. White solid, melting point 132-134°C, yield 83%; 1 H NMR (600MHz, CDCl3) δ8.10–8.04(m,2H),7.59–7.49(m,3H),7.14(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),5. 31(s,2H),3.37–3.20(m,1H),2.97(dd,J=17.1,6.5Hz,1H),2.77(ddd,J=17.5,11.3,8.1Hz,1H),2.26(d,J=1 2.6Hz,1H),1.93(dd,J=13.2,8.0Hz,1H),1.79–1.71(m,1H),1.70–1.65(m,1H),1.63–1.58(m,1H),1.48(d,J =13.2Hz,1H),1.39–1.32(m,7H),1.27(dd,J=12.7,2.1Hz,1H),1.24–1.18(m,4H),0.95(s,3H),0.93(s,3H); 13 C NMR (150MHz, CDCl3) δ169.3,166.7,162.0,154.1,144.4,134.2,133.5,129.5,123.0,122.7,114.5, 110.1,64.9,55.4,49.4,41.5,39.5,37.7,33.24,33.18,28.8,25.1,21.6,20.63,20.59,19.4,19.3.

[0030] Example 2

[0031] Preparation of 2-(2-bromophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-oxadiazole (I2):

[0032]

[0033] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(2-bromophenyl)-5-(chloromethyl)-1,3,4-oxadiazole to obtain compound product I2. Yellow solid, melting point 120-122°C, yield 56%; 1 H NMR (600MHz, CDCl3) δ8.09–8.04(m,1H),7.58–7.52(m,1H),7.30(t,J=7.4Hz,1H),7.27–7.23(m,1H),7.13(d,J=8.8Hz,1H),6 .86(d,J=8.7Hz,1H),5.31(s,2H),3.38–3.20(m,1H),2.96(dd,J=17.0,6.6Hz,1H),2.77(ddd,J=17.0,11.4,7.9Hz,1H),2.26( dd,J=12.8,3.5Hz,1H),1.91(ddd,J=9.9,5.8,3.9Hz,1H),1.78–1.70(m,1H),1.69–1.63(m,1H),1.61–1.56(m,1H),1.49–1.45 (m,1H),1.38–1.31(m,7H),1.26(dd,J=12.8,2.1Hz,1H),1.21(dd,J=13.5,4.3Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 C NMR (150MHz, CDCl3) δ163.1, 162.5 (d, J = 4.4Hz), 160.1 (d, J = 259.3Hz), 154.2, 144.6, 134.3, 134.0, 133.7 (d, J = 8.6Hz), 129.8, 124.7 (d, J = 3.4Hz) ,123.0,117.1(d,J=20.7Hz),112.2(d,J=11.0Hz),110.2,59.8,49.4,41. 5,39.6,37.8,33.3,33.2,31.4,28.7,27.5,25.1,21.6,20.4,19.4,19.3.

[0034] Example 3

[0035] Preparation of 2-(2-fluorophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-oxadiazole (I3):

[0036]

[0037] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(2-fluorophenyl)-5-(chloromethyl)-1,3,4-oxadiazole to obtain compound product I3. White solid, melting point 116-118°C, yield 45%; 1 H NMR (600MHz, CDCl3) δ8.22(t,J=1.8Hz,1H),8.01–7.97(m,1H),7.68(ddd,J=8.1,2.0,1.1Hz,1H),7.40(t,J=7.9Hz,1H),7.1 4(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),5.31(s,2H),3.39–3.20(m,1H),2.97(dd,J=17.1,6.6Hz,1H),2.77(ddd,J=17.8,1 1.4,7.9Hz,1H),2.29–2.23(m,1H),1.95–1.90(m,1H),1.78–1.72(m,1H),1.71–1.65(m,1H),1.62–1.58(m,1H),1.48–1.45( m,1H),1.38–1.32(m,7H),1.27(dd,J=12.8,2.1Hz,1H),1.22(dd,J=13.2,4.3Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 C NMR (150MHz, CDCl3) δ164.3,163.1,154.1,144.7,134.8,134.3,133.9,130.6,129.9,125.5,125.4,12 3.1,123.0,110.2,59.7,49.3,41.5,39.5,37.7,33.2,33.1,28.7,27.4,25.1,21.5,20.5,19.4,19.2.

[0038] Example 4

[0039] Preparation of 2-(3-bromophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-oxadiazole (I4):

[0040]

[0041] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(3-bromophenyl)-5-(chloromethyl)-1,3,4-oxadiazole to obtain compound product I4. White solid, melting point 126-128°C, yield 74%; 1 H NMR (600MHz, CDCl3) δ7.86(d,J=7.8Hz,1H),7.80–7.70(m,1H),7.53–7.46(m,1H),7.27–7.23(m,1H),7.14(d,J=8.8Hz, 1H),6.86(d,J=8.8Hz,1H),5.31(s,2H),3.39–3.22(m,1H),2.96(dd,J=17.1,6.6Hz,1H),2.77(ddd,J=17.1,11.4,7.9H z,1H),2.30–2.20(m,1H),1.96–1.90(m,1H),1.78–1.70(m,1H),1.68–1.65(m,1H),1.63–1.57(m,1H),1.50–1.45(m,1H) ),1.39–1.32(m,7H),1.27(dd,J=12.7,2.1Hz,1H),1.22(dd,J=13.6,4.0Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 C NMR (150MHz, CDCl3) δ164.6 (d, J = 3.3Hz), 163.1, 162.8 (d, J = 247.5Hz), 154 .2,144.7,134.3,133.9,131.0(d,J=7.7Hz),125.5(d,J=8.7Hz),123.0,12 2.7(d,J=3.2Hz),119.0(d,J=20.8Hz),114.0(d,J=24.1Hz),110.2,59.8,4 9.4,41.5,39.6,37.8,33.3,33.2,28.7,27.5,25.1,21.6,20.5,19.4,19.2.

[0042] Example 5

[0043] Preparation of 2-(3-fluorophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-oxadiazole (I5):

[0044]

[0045] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(3-fluorophenyl)-5-(chloromethyl)-1,3,4-oxadiazole to obtain compound product I5. Yellow solid, melting point 124-126°C, yield 48%; 1 H NMR (600MHz, CDCl3) δ7.92(d,J=8.4Hz,2H),7.66(d,J=8.5Hz,2H),7.13(d,J=8.7Hz,1H),6.85(d,J=8.7Hz,1H),5. 30(s,2H),3.39–3.20(m,1H),2.96(dd,J=17.1,6.5Hz,1H),2.77(ddd,J=17.2,11.4,7.9Hz,1H),2.29–2.24(m,1H) ,1.92(ddd,J=9.7,5.8,4.0Hz,1H),1.78–1.70(m,1H),1.70–1.64(m,1H),1.64–1.58(m,1H),1.50–1.45(m,1H),1. 37–1.31(m,7H),1.27(dd,J=12.7,2.1Hz,1H),1.21(dd,J=13.5,4.0Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H) · ; 13 C NMR (150MHz, CDCl3) δ164.9,163.0,154.2,144.7,134.3,133.9,132.5,128.4,126.7,123.0,12 2.5,110.2,59.8,49.4,41.5,39.5,37.8,33.3,33.2,28.7,27.5,25.1,21.6,20.5,19.4,19.3.

[0046] Example 6

[0047] Preparation of 2-(4-chlorophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-oxadiazole (I6):

[0048]

[0049] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(4-chlorophenyl)-5-(chloromethyl)-1,3,4-oxadiazole to obtain compound product I6. Yellow solid, melting point 140-142°C, yield 49%; 1 H NMR (600MHz, CDCl3) δ8.09–7.90(m,2H),7.53–7.46(m,2H),7.13(d,J=8.8Hz,1H),6.85(d,J=8.7Hz,1H),5.30( s,2H),3.37–3.20(m,1H),2.96(dd,J=17.1,6.5Hz,1H),2.77(ddd,J=17.1,11.5,7.9Hz,1H),2.29–2.22(m,1H), 1.93(dd,J=13.2,8.0Hz,1H),1.78–1.70(m,1H),1.69–1.63(m,1H),1.61–1.57(m,1H),1.50–1.45(m,1H),1.38– 1.31(m,1H),1.27(dd,J=12.7,2.1Hz,1H),1.21(dd,J=13.6,4.1Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 C NMR (150MHz, CDCl3) δ164.9,163.0,154.2,144.7,138.3,134.3,133.9,129.5,128.2,123.0,12 2.1,110.2,59.8,49.4,41.5,39.6,37.8,33.3,33.2,28.7,27.5,25.2,21.6,20.5,19.4,19.3.

[0050] Example 7

[0051] Preparation of 2-(((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-yl)oxy)methyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (I7):

[0052]

[0053] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(chloromethyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole to obtain compound product I7. White solid, melting point 145-147°C, yield 93%; 1 H NMR (600MHz, CDCl3) δ8.00(d,J=8.9Hz,2H),7.13(d,J=8.8Hz,1H),7.01(d,J=8.9Hz,2H),6.86(d,J=8.8Hz,1H), 5.28(s,2H),3.88(s,3H),3.30(s,1H),2.96(dd,J=17.0,6.6Hz,1H),2.77(ddd,J=17.1,11.4,7.9Hz,1H),2.26( d,J=12.6Hz,1H),1.96–1.89(m,1H),1.79–1.70(m,1H),1.68–1.65(m,1H),1.62–1.57(m,1H),1.47(d,J=13.1Hz ,1H),1.38–1.32(m,7H),1.28–1.26(m,1H),1.22(dd,J=13.1,4.3Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 C NMR (150MHz, CDCl3) δ165.6,162.5,162.4,154.3,144.6,134.2,133.9,128.8,123.1,116.2,114. 6,110.3,59.9,55.5,49.5,41.6,39.6,37.8,33.3,33.2,28.8,27.5,25.2,21.6,20.5,19.5,19.3.

[0054] Example 8

[0055] Preparation of 2-(((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-5-phenyl-1,3,4-thiadiazole (I8):

[0056]

[0057] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(chloromethyl)-5-phenyl-1,3,4-thiadiazole to obtain compound product I8. White solid, melting point 130-132°C, yield 74%; 1H NMR(600MHz, CDCl3) δ7.99(dd,J=7.5,2.0Hz,2H),7.57–7.44(m,3H),7.12(d,J=8.7Hz,1H),6.82(d,J=8.7Hz,1 H),5.48(s,2H),3.40–3.24(m,1H),2.97(dd,J=17.0,6.6Hz,1H),2.78(ddd,J=17.9,11.4,7.9Hz,1H),2.28–2.2 3(m,1H),1.98–1.88(m,1H),1.78–1.71(m,1H),1.69–1.63(m,1H),1.61–1.58(m,1H),1.49–1.44(m,1H),1.39– 1.32(m,7H),1.28(dd,J=12.9,2.4Hz,1H),1.22(dd,J=13.6,4.1Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 CNMR (150MHz, CDCl3) δ169.6,167.6,154.1,144.5,133.6,131.2,130.0,129.2,128.0,123. 1,110.1,64.9,49.4,41.5,39.6,37.8,33.3,33.2,28.8,25.2,21.6,20.7,20.6,19.4,19.3.

[0058] Example 9

[0059] Preparation of 2-(2-fluorophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-thiadiazole I9:

[0060]

[0061] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(chloromethyl)-5-(2-fluorophenyl)-1,3,4-thiadiazole to obtain compound product I9. Yellow solid, melting point 117-119°C, yield 87%; 1HNMR (600MHz, CDCl3) δ8.45–8.35(m,1H),7.53–7.46(m,1H),7.36–7.29(m,1H),7.24(ddd,J=10.8,8.4,1.1Hz,1H),7.13(d, J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),5.53(s,2H),3.41–3.28(m,1H),2.97(dd,J=17.0,6.5Hz,1H),2.78(ddd,J=17.8,11.3, 7.9Hz,1H),2.31–2.22(m,1H),1.98–1.89(m,1H),1.78–1.71(m,1H),1.70–1.65(m,1H),1.62–1.57(m,1H),1.47(d,J=12.4H z,1H),1.39–1.32(m,7H),1.28(dd,J=12.8,2.3Hz,1H),1.22(dd,J=13.5,4.1Hz,1H),1.19(s,3H),0.96(s,3H),0.92(s,3H); 13 C NMR (150MHz, CDCl3) δ168.8 (d, J = 5.3Hz), 161.7 (d, J = 7.6Hz), 159.6 (d, J = 252 .8Hz), 154.1, 144.5, 134.2, 133.7, 132.6 (d, J = 8.7Hz), 129.0, 124.9 (d, J = 3. 3Hz),123.0,118.2(d,J=12.0Hz),116.2(d,J=21.8Hz),110.1,64.9,49.4,41 .5,39.55,37.8,33.3,33.2,28.8,27.5,25.2,21.6,20.63,20.59,19.4,19.3.

[0062] Example 10

[0063] Preparation of 2-(4-chlorophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-thiadiazole I10:

[0064]

[0065] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(chloromethyl)-5-(4-chlorophenyl)-1,3,4-thiadiazole to obtain compound product I10. Yellow solid, melting point 141-143°C, yield 80%;1 HNMR (600MHz, CDCl3) δ8.29(d,J=8.5Hz,2H),7.83(d,J=8.5Hz,2H),7.48(d,J=8.8Hz,1H),7.17(d,J=8.8Hz,1H) ,5.84(s,2H),3.79–3.58(m,1H),3.33(dd,J=17.1,6.6Hz,1H),3.14(ddd,J=17.9,11.3,7.9Hz,1H),2.61(d,J=1 2.7Hz,1H),2.34–2.26(m,1H),2.14–2.07(m,1H),2.06–2.00(m,1H),1.98–1.93(m,1H),1.85–1.81(m,1H),1.75 –1.68(m,7H),1.63(dd,J=12.8,2.1Hz,1H),1.58(dd,J=13.8,4.4Hz,1H),1.55(s,3H),1.31(s,3H),1.28(s,3H); 13 C NMR (150MHz, CDCl3) δ168.4,167.9,154.0,144.6,137.3,133.6,129.5,129.1,128.5,123.1,1 10.1,64.9,49.4,41.5,39.6,37.8,33.3,33.2,28.9,27.5,25.2,21.6,20.7,20.6,19.4,19.3.

[0066] Embodiment 11

[0067] Preparation of 2-(4-bromophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-thiadiazole I11:

[0068]

[0069] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(chloromethyl)-5-(4-bromophenyl)-1,3,4-thiadiazole to obtain compound product I11. White solid, melting point 147-149°C, yield 69%; 1HNMR (600MHz, CDCl3) δ7.88–7.82(m,2H),7.65–7.59(m,2H),7.12(d,J=8.8Hz,1H),6.81(d,J=8.8Hz,1H),5.48 (s,2H),3.43–3.26(m,1H),2.97(dd,J=17.0,6.6Hz,1H),2.78(ddd,J=17.9,11.3,7.9Hz,1H),2.28–2.22(m,1H ),1.98–1.90(m,1H),1.78–1.71(m,1H),1.67(ddd,J=13.1,6.6,5.2Hz,1H),1.62–1.57(m,1H),1.49–1.45(m,1 H),1.38–1.32(m,7H),1.27(dd,J=12.9,2.1Hz,1H),1.23–1.20(m,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 CNMR (150MHz, CDCl3) δ168.4,167.9,154.0,144.6,134.3,133.6,132.4,129.3,128.9,125.7,123. 1,110.1,64.9,49.4,41.5,39.6,37.8,33.3,33.2,28.8,27.4,25.2,21.6,20.7,20.6,19.4,19.3.

[0070] Example 12

[0071] Preparation of 2-(4-fluorophenyl)-5-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydroanthracen-2-yl)oxy)methyl)-1,3,4-thiadiazole I12:

[0072]

[0073] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(chloromethyl)-5-(4-fluorophenyl)-1,3,4-thiadiazole to obtain compound product I12. Yellow solid, melting point 136-138°C, yield 85%; 1HNMR (600MHz, CDCl3) δ8.02–7.96(m,2H),7.20–7.16(m,2H),7.12(d,J=8.8Hz,1H),6.81(d,J=8.8Hz,1H),5. 47(s,2H),3.44–3.24(m,1H),2.97(dd,J=17.0,6.6Hz,1H),2.78(ddd,J=17.8,11.3,7.9Hz,1H),2.25(dd,J=1 2.9,3.7Hz,1H),1.96–1.90(m,1H),1.78–1.71(m,1H),1.70–1.64(m,1H),1.62–1.58(m,1H),1.50–1.45(m,1H ),1.38–1.34(m,7H),1.28–1.26(m,1H),1.21(dd,J=13.6,4.0Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 C NMR (150MHz, CDCl3) δ168.4, 167.7, 164.5 (d, J = 252.7Hz), 154.1, 144.6, 134.3, 133.6, 130.0 (d, J = 8.7Hz), 126.3 (d, J = 3.3Hz) ,123.1,116.4(d,J=21.9Hz),110.1,64.9,49.4,41.5,39.6,37.8,33.3,33.2,28.8,27.5,25.2,21.6,20.7,20.6,19.4,19.3.

[0074] Example 13

[0075] Preparation of 2-((((4bS)-1-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-yl)oxy)methyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole I13:

[0076]

[0077] The preparation method is the same as that of Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced with 2-(chloromethyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole to obtain compound product I13. Yellow solid, melting point 153-154°C, yield 75%; 1H NMR (600MHz, CDCl3) δ7.96–7.89(m,2H),7.12(d,J=8.8Hz,1H),7.01–6.96(m,2H),6.82(d,J=8.8Hz,1H),5.46(s,2 H),3.88(s,3H),3.43–3.19(m,1H),2.97(dd,J=17.0,6.6Hz,1H),2.78(ddd,J=17.8,11.3,8.0Hz,1H),2.28–2.23(m ,1H),1.93(dd,J=13.2,8.0Hz,1H),1.78–1.70(m,1H),1.69–1.64(m,1H),1.62–1.57(m,1H),1.49–1.46(m,1H),1. 39–1.32(m,7H),1.27(dd,J=12.7,2.2Hz,1H),1.22(dd,J=13.5,4.1Hz,1H),1.19(s,3H),0.95(s,3H),0.92(s,3H); 13 C NMR (150MHz, CDCl3) δ169.3,166.7,162.0,154.1,144.4,134.2,133.5,129.5,123.0,122.7,114.5,11 0.1,64.9,55.4,49.4,41.5,39.5,37.7,33.2,33.2,28.8,27.4,25.1,21.6,20.63,20.59,19.4,19.3.

[0078] Embodiment 14

[0079] Determination of antibacterial activity of 1,3,4-oxadiazole or 1,3,4-thiadiazole modified tocopherol derivatives I1-I13:

[0080] The mycelium growth rate method was used to determine the antibacterial activity of the synthesized totarol derivatives against strawberry gray mold (Botrytiscinerea), wheat fusarium (Fusarium graminearum), rice sheath blight (Rhizoctonia Solani) and rice blast (Pyricularia grisea). The compound was prepared to contain a drug concentration of 50 μg / mL, and the diterpene natural product totarol and the commercial agent carbendazim were used as positive control agents. The results were measured using the cross-cross method (measuring the diameter of each colony twice, accurate to mm), and each group was operated in parallel 3 times, and the average value was used to represent the colony size. The inhibition rate formula is as follows: Inhibition rate (%) = (blank control colony diameter-treated colony diameter) / (blank control colony diameter-0.5)*100%

[0081] Table 1: Inhibition rate of compounds I1-I13 at 50 μg / mL against five plant pathogens (%) a

[0082]

[0083] a Repeat three times and take the average value.

[0084] As shown in Table 1, at a concentration of 50 μg / mL, the synthesized 1,3,4-oxadiazole or 1,3,4-thiadiazole modified torrefaction phenol derivatives I have different degrees of inhibitory effects on four common plant pathogenic fungi. Among them, for strawberry gray mold, the inhibition rate of compounds I4 and I5 exceeded 50%. Compound I5 has the best effect on wheat fusarium, with an inhibition rate of 71.6%; compound I8 has an inhibition rate of 50.6% on rice sheath blight. For wheat fusarium, the inhibition rate exceeds 50% of compounds I3, I5, I11 and I12, among which compound I3 has the best inhibition effect (81.6%), which is better than the diterpene natural product torrefaction phenol. In addition, the antibacterial effects of most of the synthesized compounds are better than 2-chloromethyl-5-phenyl-1,3,4-oxadiazole or 2-chloromethyl-5-phenyl-1,3,4-thiadiazole. The above results prove that 1,3,4-oxadiazole or 1,3,4-thiadiazole modified tocopherol derivatives have the potential to be developed and applied as new agricultural fungicides.

[0085] The above description is only a preferred implementation case of the present invention and does not limit the present invention in any form. Any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention shall fall within the scope of the technical solution of the present invention.

Claims

1. A tocopherol derivative containing a diterpene natural product modified with 1,3,4-oxathiadiazole, characterized in that: Its structural formula is shown in Formula I: In Formula I, X is an oxygen atom or a sulfur atom; R is a hydrogen atom, a halogen atom or a methoxy group; The halogen is one of F, Cl and Br.

2. The tocopherol derivative containing 1,3,4-oxathiadiazole according to claim 1, characterized in that: R is H, 2-Br, 2-F, 3-Br, 3-F, 4-Cl or 4-Ome.

3. The method for preparing a totarol derivative containing 1,3,4-oxathiadiazole as claimed in claim 1 or 2, characterized in that Prepare according to the reaction formula: In the reaction formula: X is an oxygen atom or a sulfur atom; R is a hydrogen atom, a halogen atom or a methoxy group; the halogen is one of F, Cl and Br.

4. The method for preparing a totarol derivative containing 1,3,4-oxathiadiazole as claimed in claim 3, characterized in that: The compound represented by formula I is any one of formulas I1-I13; 5. The use of a totarol derivative containing 1,3,4-oxathiadiazole as claimed in claim 1 or 2, characterized in that: It can be used to prevent and control plant fungal diseases.

6. The use of a totarol derivative containing 1,3,4-oxathiadiazole as claimed in claim 1 or 2, characterized in that: The plant fungal diseases include tomato wilt pathogen, rice sheath blight pathogen, wheat fusarium wilt pathogen, strawberry anthracnose pathogen, strawberry gray mold pathogen and cucumber wilt pathogen.

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