A peach aldehyde derivative containing 1,3,4-oxadiazole, its preparation method and use

Abstract

The application belongs to the field of fungicides, and discloses a 1,3,4-oxa / thia-diazole pyrogallol derivative, a preparation method and application, and the structure of the compound is as shown in the formula I: 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 effect of inhibiting plant pathogenic fungi and preventing and treating plant fungal diseases, and can be applied to plant protection as a fungicide.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of 1,3 4-oxadiazole or 1,3,4-oxadiazole modified diterpene natural product peach jianol derivatives, preparation method and its application in the prevention and treatment of plant fungal diseases, with the use of preparation of pesticide fungicide, belong to the technical field of organic synthesis chemistry and pesticide. BACKGROUND

[0002] The biological activity of natural products is an important research topic in the field of medicine. At present, researchers all over the world have extracted many natural products with anti-inflammatory, antioxidant, anticancer, immune stimulating and neuroprotective biological activities from plants. Natural products bring new opportunities for pesticide research and development due to their diversity of sources, structure and function. Taking natural products as lead compounds, further structure modification and analog synthesis can often produce a series of efficient and low-toxicity green pesticides. Peach jianol (Totarol) is a diterpene of pine resin, and terpenoids are the largest class of natural products, which have many different functions, including regulating plant growth. In terms of biological activity, peach jianol has shown high biological activity, human safety and product formula compatibility, and has applications in medicine, pesticides and cosmetics. Peach jianol has very strong antibacterial activity. Studies have shown that peach jianol has very effective antibacterial activity against gram-positive bacteria, especially against Staphylococcus aureus strains, and the antibacterial effect is more obvious. However, there are few reports on its agricultural fungicidal activity.

[0003] Heterocyclic compounds have become a hot spot for the development of new pesticides due to their special structural characteristics. Among them, oxadiazole heterocycles are important components of commercial pesticides, and have a wide range of biological activities, such as anticancer, fungicidal, anti-inflammatory, antiviral, etc. 1,3,4-oxadiazole compounds have a wide range of uses in the field of medicine and chemical industry. In 2021, Flufenoxadiazam developed by BASF is an oxadiazole fungicide. The unique HDACs fungicidal mechanism of oxadiazole compounds is different from the mainstream agents on the existing pesticide market, which not only shows good fungicidal activity, but also does not have the 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 high efficiency and high specificity. Currently, there are many agricultural fungicides containing 1,3,4-thiadiazole structure, such as leaf senescence, thiacopper, etc.

[0004] In summary, the diterpene natural product paeonol and the diazole compound have a broad spectrum of biological activity, and have guiding significance for discovering new pesticide lead compounds. In view of this, the present application modifies the structure of paeonol, 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 paeonol derivatives. The compounds prepared in the present application are all new compounds not reported in the literature. After testing, some of the compounds have good inhibitory activity on plant pathogenic fungi. SUMMARY

[0005] The purpose of the present application is to provide a 1,3 4-oxadiazole / thiadiazole containing paeonol derivative, its preparation method and use, by 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 paeonol derivatives are synthesized; such compounds have the characteristics of easy preparation and high yield; the paeonol derivative can be applied to plant disease control.

[0006] The present application provides a 1,3 4-oxadiazole / thiadiazole containing paeonol derivative, which has the structure general 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, Br.

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

[0013] The present application also provides a preparation method of a 1,3 4-oxadiazole / thiadiazole containing paeonol derivative, which is prepared according to the following reaction formula:

[0014]

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

[0016] In the reaction tube, add the peperin (0.3 mmol, 85.9 mg), different substituted 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole or 2-(chloromethyl)-5-phenyl-1,3,4-thiadiazole (0.45 mmol), potassium carbonate (0.45 mmol, 62.1 mg), acetonitrile (1.5 mL), and react at 80℃ for 5 hours. After the reaction is completed, the reaction system is transferred to a round-bottom flask, concentrated under reduced pressure, and the crude product is purified by column chromatography to obtain the final product, which is a compound shown in formula I.

[0017] The preparation method of the peperin derivative containing 1,3,4-oxadiazole or 1,3,4-thiadiazole provided by the present application has the characteristics of simple steps, easy operation and high yield.

[0018] The peperin derivative containing 1,3,4-oxadiazole or 1,3,4-thiadiazole modification involved in the present application preferably has any one of the following structures:

[0019]

[0020] The present application has the following beneficial effects: The diterpene natural product peperin used in the present application has good bactericidal activity. By derivatizing the structure thereof, 1,3,4-oxadiazole or 1,3,4-thiadiazole fragments are introduced, and a series of 1,3,4-oxadiazole or 1,3,4-thiadiazole modified diterpene peperin derivatives are synthesized. The compounds have the characteristics of easy preparation and high yield. All the compounds are new compounds, and the compounds can be used in crop diseases caused by fungi, and can provide effective services for plant protection in agricultural production. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 It is the nuclear magnetic hydrogen spectrum of the product I1 in Example 1.

[0022] Figure 2 It is the nuclear magnetic carbon spectrum of the product I1 in Example 1.

[0023] Figure 3 It is the nuclear magnetic hydrogen spectrum of the product I8 in Example 8.

[0024] Figure 4 It is the nuclear magnetic carbon spectrum of the product I8 in Example 8. DETAILED DESCRIPTION

[0025] The present application will be further described below in combination with specific embodiments, but the present application 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 (II):

[0028]

[0029] In a pressure tube, methyl 2-(bromomethyl)-5-phenyl-1,3,4-oxadiazole was dissolved in acetonitrile and potassium carbonate was added to the above reaction system. The reaction was carried out at 80 °C for 5 hours. After completion of the reaction, the reaction system was transferred to a round bottom flask and concentrated under reduced pressure. The crude product was purified using column chromatography (eluent: petroleum ether: ethyl acetate) to obtain the product II. White solid, melting point 132-134 °C, yield 83 %; 1 H NMR (600 MHz, CDC13) δ 8.10 - 8.04 (m, 2H), 7.59 - 7.49 (m, 3H), 7.14 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.31 (s, 2H), 3.37 - 3.20 (m, 1H), 2.97 (dd, J = 17.1, 6.5 Hz, 1H), 2.77 (ddd, J = 17.5, 11.3, 8.1 Hz, 1H), 2.26 (d, J = 12.6 Hz, 1H), 1.93 (dd, J = 13.2, 8.0 Hz, 1H), 1.79 - 1.71 (m, 1H), 1.70 - 1.65 (m, 1H), 1.63 - 1.58 (m, 1H), 1.48 (d, J = 13.2 Hz, 1H), 1.39 - 1.32 (m, 7H), 1.27 (dd, J = 12.7, 2.1 Hz, 1H), 1.24 - 1.18 (m, 4H), 0.95 (s, 3H), 0.93 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 169.3, 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 (II):

[0032]

[0033] The preparation method is the same as Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced by 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 (600 MHz, CDC13) δ 8.09 - 8.04 (m, 1H), 7.58 - 7.52 (m, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.31 (s, 2H), 3.38 - 3.20 (m, 1H), 2.96 (dd, J = 17.0, 6.6 Hz, 1H), 2.77 (ddd, J = 17.0, 11.4, 7.9 Hz, 1H), 2.26 (dd, J = 12.8, 3.5 Hz, 1H), 1.91 (ddd, J = 9.9, 5.8, 3.9 Hz, 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, 2.1 Hz, 1H), 1.21 (dd, J = 13.5, 4.3 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 163.1, 162.5 (d, J = 4.4 Hz), 160.1 (d, J = 259.3 Hz), 154.2, 144.6, 134.3, 134.0, 133.7 (d, J = 8.6 Hz), 129.8, 124.7 (d, J = 3.4 Hz), 123.0, 117.1 (d, J = 20.7 Hz), 112.2 (d, J = 11.0 Hz), 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] 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) was prepared according to the procedure of Example 1, substituting 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole with 2-(2-fluorophenyl)-5-(chloromethyl)-1,3,4-oxadiazole. White solid, mp 116-118 °C, 45% yield;

[0036]

[0037] Preparation method is the same as Example 1, substituting 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole with 2-(2-fluorophenyl)-5-(chloromethyl)-1,3,4-oxadiazole, to obtain compound product I3. White solid, mp 116-118 °C, 45% yield; 1 H NMR (600 MHz, CDC13) δ 8.22 (t, J = 1.8 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.68 (ddd, J = 8.1, 2.0, 1.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.31 (s, 2H), 3.39 - 3.20 (m, 1H), 2.97 (dd, J = 17.1, 6.6 Hz, 1H), 2.77 (ddd, J = 17.8, 11.4, 7.9 Hz, 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, 2.1 Hz, 1H), 1.22 (dd, J = 13.2, 4.3 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 164.3, 163.1, 154.1, 144.7, 134.8, 134.3, 133.9, 130.6, 129.9, 125.5, 125.4, 123.1, 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] 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 Example 1, except that 2-(chloromethyl)-5- phenyl-1,3,4-oxadiazole is replaced by 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 (600 MHz, CDC13) δ 7.86 (d, J = 7.8 Hz, 1H), 7.80 - 7.70 (m, 1H), 7.53 - 7.46 (m, 1H), 7.27 - 7.23 (m, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.31 (s, 2H), 3.39 - 3.22 (m, 1H), 2.96 (dd, J = 17.1, 6.6 Hz, 1H), 2.77 (ddd, J = 17.1, 11.4, 7.9 Hz, 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, 2.1 Hz, 1H), 1.22 (dd, J = 13.6, 4.0 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 164.6 (d, J = 3.3 Hz), 163.1, 162.8 (d, J = 247.5 Hz), 154.2, 144.7, 134.3, 133.9, 131.0 (d, J = 7.7 Hz), 125.5 (d, J = 8.7 Hz), 123.0, 122.7 (d, J = 3.2 Hz), 119.0 (d, J = 20.8 Hz), 114.0 (d, J = 24.1 Hz), 110.2, 59.8, 49.4, 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] Preparation method same as Example 1, 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced by 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 (600 MHz, CDC13) δ 7.92 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.30 (s, 2H), 3.39 - 3.20 (m, 1H), 2.96 (dd, J = 17.1, 6.5 Hz, 1H), 2.77 (ddd, J = 17.2, 11.4, 7.9 Hz, 1H), 2.29 - 2.24 (m, 1H), 1.92 (ddd, J = 9.7, 5.8, 4.0 Hz, 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, 2.1 Hz, 1H), 1.21 (dd, J = 13.5, 4.0 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H) · ; 13 C NMR (150 MHz, CDC13) δ 164.9, 163.0, 154.2, 144.7, 134.3, 133.9, 132.5, 128.4, 126.7, 123.0, 122.5, 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 Example 1, except that 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced by 2-(4-chlorophenyl)-5-(chloromethyl)-1,3,4-oxadiazole to obtain compound product I6. Yellow solid, melting point 140-142℃, yield 49%; 1 H NMR (600 MHz, CDC13) δ 8.09 - 7.90 (m, 2H), 7.53 - 7.46 (m, 2H), 7.13 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.30 (s, 2H), 3.37 - 3.20 (m, 1H), 2.96 (dd, J = 17.1, 6.5 Hz, 1H), 2.77 (ddd, J = 17.1, 11.5, 7.9 Hz, 1H), 2.29 - 2.22 (m, 1H), 1.93 (dd, J = 13.2, 8.0 Hz, 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, 2.1 Hz, 1H), 1.21 (dd, J = 13.6, 4.1 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 164.9, 163.0, 154.2, 144.7, 138.3, 134.3, 133.9, 129.5, 128.2, 123.0, 122.1, 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- octahydrophenanthren-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, and 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced by 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 (600 MHz, CDC13) δ 8.00 (d, J = 8.9 Hz, 2H), 7.13 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 5.28 (s, 2H), 3.88 (s, 3H), 3.30 (s, 1H), 2.96 (dd, J = 17.0, 6.6 Hz, 1H), 2.77 (ddd, J = 17.1, 11.4, 7.9 Hz, 1H), 2.26 (d, J = 12.6 Hz, 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 = 13.1 Hz, 1H), 1.38 - 1.32 (m, 7H), 1.28 - 1.26 (m, 1H), 1.22 (dd, J = 13.1, 4.3 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 165.6, 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, and 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced by 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to obtain compound product I7. White solid, melting point 145-147°C, yield 93%; 1H NMR (600 MHz, CDC13) δ 7.99 (dd, J = 7.5, 2.0 Hz, 2H), 7.57 - 7.44 (m, 3H), 7.12 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 5.48 (s, 2H), 3.40 - 3.24 (m, 1H), 2.97 (dd, J = 17.0, 6.6 Hz, 1H), 2.78 (ddd, J = 17.9, 11.4, 7.9 Hz, 1H), 2.28 - 2.23 (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, 2.4 Hz, 1H), 1.22 (dd, J = 13.6, 4.1 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 CNMR (150 MHz, CDC13) δ 169.6, 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-octahydroxanthene-2-yl)oxy)methyl)-1,3,4-thiadiazoIe I9:

[0060]

[0061] Preparation method same as Example 1, 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced by 2-(chloromethyl)-5-(2-fluorophenyl)-1,3,4-thiadiazoze to obtain compound product I9. Yellow solid, melting point 117-119 °C, yield 87%; 1HNMR (600 MHz, CDC13) δ 8.45 - 8.35 (m, 1H), 7.53 - 7.46 (m, 1H), 7.36 - 7.29 (m, 1H), 7.24 (ddd, J = 10.8, 8.4, 1.1 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.53 (s, 2H), 3.41 - 3.28 (m, 1H), 2.97 (dd, J = 17.0, 6.5 Hz, 1H), 2.78 (ddd, J = 17.8, 11.3, 7.9 Hz, 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 = 12.4 Hz, 1H), 1.39 - 1.32 (m, 7H), 1.28 (dd, J = 12.8, 2.3 Hz, 1H), 1.22 (dd, J = 13.5, 4.1 Hz, 1H), 1.19 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 168.8 (d, J = 5.3 Hz), 161.7 (d, J = 7.6 Hz), 159.6 (d, J = 252.8 Hz), 154.1, 144.5, 134.2, 133.7, 132.6 (d, J = 8.7 Hz), 129.0, 124.9 (d, J = 3.3 Hz), 123.0, 118.2 (d, J = 12.0 Hz), 116.2 (d, J = 21.8 Hz), 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-octahydrochrysene-2-yl)oxy)methyl)-1,3,4-thiadiazole I10:

[0064]

[0065] Preparation method same as Example 1, replace 2-(chloromethyl)-5-phenyl-1,3,4- oxadiazole with 2-(chloromethyl)-5-(4-chlorophenyl)-1,3,4-thiadiazole, to get compound product I10. Yellow solid, melting point 141-143 °C, yield 80%;1 HNMR (600 MHz, CDC13) δ 8.29 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 5.84 (s, 2H), 3.79 - 3.58 (m, 1H), 3.33 (dd, J = 17.1, 6.6 Hz, 1H), 3.14 (ddd, J = 17.9, 11.3, 7.9 Hz, 1H), 2.61 (d, J = 12.7 Hz, 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, 2.1 Hz, 1H), 1.58 (dd, J = 13.8, 4.4 Hz, 1H), 1.55 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 168.4, 167.9, 154.0, 144.6, 137.3, 133.6, 129.5, 129.1, 128.5, 123.1, 110.1, 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] Example 11

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

[0068]

[0069] Preparation method same as Example 1, 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced by 2-(chloromethyl)-5-(4-bromophenyl)-1,3,4-thiadiazole to obtain compound product II 1. White solid, melting point 147-149 °C, yield 69%; 1HNMR (600 MHz, CDC13) δ 7.88 - 7.82 (m, 2H), 7.65 - 7.59 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.48 (s, 2H), 3.43 - 3.26 (m, 1H), 2.97 (dd, J = 17.0, 6.6 Hz, 1H), 2.78 (ddd, J = 17.9, 11.3, 7.9 Hz, 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, 5.2 Hz, 1H), 1.62 - 1.57 (m, 1H), 1.49 - 1.45 (m, 1H), 1.38 - 1.32 (m, 7H), 1.27 (dd, J = 12.9, 2.1 Hz, 1H), 1.23 - 1.20 (m, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 CNMR (150 MHz, CDC13) δ 168.4, 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] Preparation method same as Example 1, 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole is replaced by 2-(chloromethyl)-5-(4-fluorophenyl)-1,3,4-thiadiazole to obtain compound product I12. Yellow solid, melting point 136-138 °C, yield 85%; 1HNMR (600 MHz, CDC13) δ 8.02 - 7.96 (m, 2H), 7.20 - 7.16 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.47 (s, 2H), 3.44 - 3.24 (m, 1H), 2.97 (dd, J = 17.0, 6.6 Hz, 1H), 2.78 (ddd, J = 17.8, 11.3, 7.9 Hz, 1H), 2.25 (dd, J = 12.9, 3.7 Hz, 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, 4.0 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 168.4, 167.7, 164.5 (d, J = 252.7 Hz), 154.1, 144.6, 134.3, 133.6, 130.0 (d, J = 8.7 Hz), 126.3 (d, J = 3.3 Hz), 123.1, 116.4 (d, J = 21.9 Hz), 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- octahydrophenanthren-2-yl)oxy)methyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole I13:

[0076]

[0077] Preparation method same as Example 1, replace 2-(chloromethyl)-5-phenyl-1,3,4- oxadiazole with 2-(chloromethyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole to get compound product I13. Yellow solid, melting point 153-154 °C, yield 75%; 1H NMR (600 MHz, CDC13) δ 7.96 - 7.89 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.01 - 6.96 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 5.46 (s, 2H), 3.88 (s, 3H), 3.43 - 3.19 (m, 1H), 2.97 (dd, J = 17.0, 6.6 Hz, 1H), 2.78 (ddd, J = 17.8, 11.3, 8.0 Hz, 1H), 2.28 - 2.23 (m, 1H), 1.93 (dd, J = 13.2, 8.0 Hz, 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, 2.2 Hz, 1H), 1.22 (dd, J = 13.5, 4.1 Hz, 1H), 1.19 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 169.3, 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, 33.2, 33.2, 28.8, 27.4, 25.1, 21.6, 20.63, 20.59, 19.4, 19.3.

[0078] Example 14

[0079] 1,3,4-Oxadiazole or 1,3,4-Thiadiazole Modified Phloxin Derivatives I1-I13 Antifungal Activity Assay:

[0080] The synthesized phloxin derivatives were tested for their antifungal activity against Botrytis cinerea, Fusarium graminearum, Rhizoctonia Solani and Pyricularia grisea by mycelial growth rate method. The compounds were prepared at a concentration of 50 μg / mL. The diterpenoid natural product phloxin and the commercial fungicide carbendazim were used as positive control agents. The results were measured by the cross method (measuring the diameter of each colony twice, accurate to mm), and each group was operated in triplicate. The average value represented the size of the colony, and the inhibition rate formula was as follows: inhibition rate (%) = (diameter of blank control colony - diameter of treated colony) / (diameter of blank control colony - 0.5) * 100%

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

[0082]

[0083] a Three replicates, and the average was taken.

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

[0085] The above is only a preferred embodiment of the present application, and does not limit the present application in any form. Any simple modification, equivalent change and modification of the above embodiments without departing from the technical solution content of the present application, according to the technical essence of the present application, all belong to the scope of the technical solution of the present application.

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 according to claim 1, wherein: 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 tocopherol derivative containing 1,3,4-oxathiadiazole according to claim 3, wherein: The compound represented by formula I is any one of formulas I1-I13; 。 5. The use of a tocopherol derivative containing 1,3,4-oxathiadiazole according to claim 1 or 2, characterized in that: Used to prevent and control tomato wilt, rice sheath blight, wheat fusarium, strawberry anthracnose, strawberry gray mold and cucumber wilt.

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