Use of naringin derivatives in the preparation of drugs for preventing and treating plant pathogenic fungi

Abstract

The application provides a naringin derivative, a preparation method of the naringin derivative, and application of the naringin derivative in preparation of medicines for preventing and treating wheat scab, tobacco black stem disease, phomopsis stem rot and pepper wilt, and has good bacteriostatic activity on wheat scab fungus, tobacco black stem fungus, phomopsis stem rot fungus and pepper wilt fungus, has a good prevention and treatment effect on plant pathogenic fungal diseases such as wheat scab, tobacco black stem disease, phomopsis stem rot and pepper wilt, and has a broad application prospect and development potential.

Description

Technical Field

[0001] This invention relates to the field of pesticide technology, and in particular to the application of a naringin derivative in the preparation of drugs for controlling plant pathogenic fungi. Background Technology

[0002] Plant pathogens are the leading cause of yield reductions in major food and cash crops, affecting wheat, peppers, tobacco, kiwifruit, and many others. Currently, the control of plant pathogens mainly relies on chemical pesticides, but these have many side effects. For example, prochloraz, a widely used chemical fungicide, has been found to have carcinogenic, mutagenic, and toxic metabolites, such as 2,4,6-trichlorophenoxyacetic acid, which are also environmental pollutants. Furthermore, long-term use of chemical pesticides such as carbendazim and methyl thiophanate can easily increase pesticide resistance in pathogens, leading to pesticide residues, environmental pollution, and disruption of the ecological balance.

[0003] With the introduction of the concept of "green plant protection," plant-derived pesticides are naturally decomposable and less prone to generating resistance. The development of environmentally friendly, safe, low-toxicity, and highly effective plant-derived pesticides is receiving increasing attention.

[0004] Grapefruit is a traditional fruit, widely used in people's lives, and is non-toxic. Grapefruit oil is also non-toxic, and as an additive, various brands (green) of detergents containing grapefruit oil are available on the market. Grapefruit oil contains a large amount of fatty acids and sesquiterpenes, among which naringin is the most abundant. It belongs to the bicyclic sesquiterpene ketone of the argyrocyanine family and has a 3-chiral center. At low concentrations, naringin exhibits a strong grapefruit aroma with sweet orange and woody notes, but it tastes bitter, and its odor threshold is low, only 1 μg / L. As an important component of grapefruit flavoring, naringin is often used in food, beverages, and daily chemical products. In beverages, its dosage is generally 2-6 mg / L. In daily chemical fragrance formulations, naringin is used in combination with other citrus essential oils (such as bitter orange oil and bergamot oil) to enhance the citrus flavor of the product.

[0005] The inventors considered synthesizing naringin derivatives using naringin as a precursor and conducting experiments on pathogenic fungi of four different genera of plants, namely wheat scab, tobacco black stem rot, pseudostem mold, and pepper wilt, in order to discover highly effective antibacterial agents. Summary of the Invention

[0006] The technical problem solved by this invention is to provide a cynomolgus ketone derivative and its preparation method, as well as its application in the preparation of drugs for the prevention and control of wheat scab, tobacco black stem disease, pseudostem mold, and pepper wilt. It has good control effects on plant pathogenic fungal diseases such as wheat scab, tobacco black stem disease, pseudostem mold, and pepper wilt.

[0007] In view of this, the present invention provides the application of a naringin derivative in the preparation of a drug for controlling wheat scab, wherein the naringin derivative has the structure shown in Formula 1:

[0008]

[0009] Where R is any one of N-1, N-2, N-3, N-4, N-5, N-6, N-7, and N-8.

[0010]

[0011] This invention also provides the application of a naringin derivative in the preparation of a drug for preventing and treating tobacco black stem disease, wherein the naringin derivative has the structure shown in Formula 1:

[0012]

[0013] Where R is any one of N-1, N-2, N-3, N-4, N-5, N-6, N-7, and N-8.

[0014]

[0015] This invention also provides the application of a naringin derivative in the preparation of a drug for controlling stem spot disease, wherein the naringin derivative has the structure shown in Formula 1:

[0016]

[0017] Where R is any one of N-1, N-2, N-3, N-4, N-5, N-6, N-7, and N-8.

[0018]

[0019]

[0020] This invention also provides the application of a naringin derivative in the preparation of a drug for controlling wilt disease in peppers, wherein the naringin derivative has the structure shown in Formula 1:

[0021]

[0022] Where R is any one of N-1, N-2, N-3, N-4, N-5, N-6, N-7, and N-8.

[0023]

[0024] Preferably, the dosage form of the drug is one of powder, suspension, granules, water dispersible and microemulsion.

[0025] The present invention also provides a method for preparing naringin hydroxylamine, comprising the following steps: dissolving nocaketone in ethanol, adding hydroxylamine hydrochloride and sodium bicarbonate, then refluxing at 85°C, tracking the reaction of the raw materials by TLC until complete, cooling the reaction solution to room temperature, washing with saturated NaCl aqueous solution, drying with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and separating and purifying to obtain naringin hydroxylamine N-1.

[0026] This invention also provides a method for preparing naringin hydroxylamine ester, comprising the following steps: dissolving the naringin hydroxylamine prepared by the above technical solution in dichloromethane, adding DMAP, triethylamine, and 4-methylbenzoyl chloride sequentially, stirring the reaction at room temperature under argon protection, tracking the starting material by TLC until the reaction is complete, washing with saturated tartaric acid aqueous solution, washing with saturated NaCl aqueous solution, drying with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and separating by silica gel column chromatography to obtain naringin hydroxylamine ester N-3.

[0027] This invention also provides a method for preparing naringin hydroxylamine ester, comprising the following steps: dissolving the naringin hydroxylamine prepared by the above technical solution in dichloromethane, adding DMAP, triethylamine, and 4-fluorobenzoyl chloride sequentially, stirring the reaction at room temperature under argon protection, tracking the starting material by TLC until the reaction is complete, washing with saturated tartaric acid aqueous solution, washing with saturated NaCl aqueous solution, drying with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and separating the naringin hydroxylamine ester N-4 by silica gel column chromatography.

[0028] This invention also provides a method for preparing naringin hydroxylamine ester, comprising the following steps: dissolving the naringin hydroxylamine prepared by the above technical solution in dichloromethane, sequentially adding DMAP, 2-chlorothiophene-5-carboxylic acid, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stirring the reaction at room temperature under argon protection, tracking the starting material by TLC until the reaction is complete, washing with saturated tartaric acid aqueous solution, washing with saturated NaCl aqueous solution, drying with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and separating the naringin hydroxylamine ester N-5 by silica gel column chromatography.

[0029] This invention also provides a method for preparing naringin hydroxylamine ester, comprising the following steps: dissolving the naringin hydroxylamine prepared by the above technical solution in dichloromethane, adding 4-dimethylaminopyridine and triethylamine, and finally adding 3,5-dimethylisoxazole carbonyl chloride, stirring the reaction at room temperature under argon protection, tracking the starting material by TLC until the reaction is complete, washing with saturated tartaric acid aqueous solution, washing with saturated NaCl aqueous solution, drying with anhydrous Na2SO4, filtering and concentrating under reduced pressure, and separating the naringin hydroxylamine ester N-6 by silica gel column chromatography.

[0030] This invention provides a cynomolgus ketone derivative and its preparation method, as well as its application in the preparation of drugs for the prevention and control of wheat scab, tobacco black stem rot, pseudostem mold, and pepper wilt. It has good antibacterial activity against wheat scab, tobacco black stem rot, pseudostem mold, and pepper wilt, and has good control effect on plant pathogenic fungal diseases such as wheat scab, tobacco black stem rot, pseudostem mold, and pepper wilt, showing broad application prospects and development potential. Attached Figure Description

[0031] Figure 1 The diagram shows the growth of *Pseudomonas stolonifera* hyphae on the *Pseudomonas stolonifera* mycelium prepared according to an embodiment of the present invention. Detailed Implementation

[0032] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.

[0033] This invention focuses on optimizing the ketone group in naringin to prepare naringin hydrazone derivatives, hydroxylamine, and hydroxylamine ester derivatives. All raw materials used in the embodiments of this invention are commercially available. The general formula of the compounds is as shown in formula (1):

[0034]

[0035] in (Nardone),

[0036] (N-8).

[0037] Activity of the compound against Phoppsis sp.

[0038] General formula of the compound: in (Nardone),

[0039] First, select the best option. Its resistance to EC. 50 Less than 1 μg / mL, EC 50 The value is 2.02 μM.

[0040] Secondly, the preferred option is... Its resistance to EC. 50 Less than 3 μg / mL, EC 50 It is 6.55 μM.

[0041] Further optimization Its resistance to EC.50 Less than 10 μg / mL, EC 50 The values ​​were 20.56 and 25.89 μM.

[0042] Final selection,

[0043] To further understand the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments. The scope of protection of the present invention is not limited by the following embodiments.

[0044] All raw materials used in the embodiments of this invention are commercially available.

[0045] Example 1

[0046] Preparation of naringin hydroxylamine (N-1)

[0047]

[0048] Nocaketone (3 g, 1 equiv.) was dissolved in 25 mL of ethanol, and hydroxylamine hydrochloride (1.9 g, 2.0 equiv.) and sodium bicarbonate (1.7 g, 1.7 equiv.) were added. The mixture was then refluxed at 85 °C. The reaction mixture was monitored by TLC (anisaldehyde with sulfuric acid) until complete. The reaction solution was cooled to room temperature, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 3.0 g of a crude mixture of Z and E products. This crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain 2.1 g of the trans product (E)N-1. The yield was 65%.

[0049] 1 H NMR (600MHz, CDCl3) δ5.86–5.77(m,1H),4.74–4.66(m,2H),2.95(dd,J=17.4,4.2Hz,1H ),2.45–2.37(m,1H),2.34–2.23(m,2H),1.96(dd,J=17.4,13.7Hz,1H),1.89(dt,J=13.0 ,2.6Hz,1H),1.83(ddq,J=12.4,5.0,2.5Hz,1H),1.73(s,3H),1.67(dqd,J=13.7,6.8,4. 5Hz,1H),1.29–1.24(m,1H),1.04(t,J=12.8Hz,1H),0.99(s,3H),0.96(d,J=6.8Hz,3H); 13C NMR (150MHz, CDCl3) δ 157.3, 154.7, 150.1, 118.2, 109.0, 44.2, 40.8, 39.1, 38.7, 32.8, 32.0, 27.2, 21.0, 17.3, 15.1. Through analysis of... 1 H, 13 Analysis of the C NMR data confirmed that the (E)N-1 structure is nootkatone(E)-oxime.

[0050] Example 2

[0051] Preparation of naringin hydroxylamine (N-2)

[0052]

[0053] Nocaketone (100 mg, 1 equiv.) was dissolved in 10 mL of ultra-dry ethanol, and 2-iodobenzoyl hydrazine (144 mg, 1.2 equiv.) and a catalytic amount of acetic acid were added. The mixture was refluxed at 85 °C for 48 h under argon protection. The reaction was confirmed to be complete by TLC (5% sulfuric acid in ethanol). The reaction solution was cooled to room temperature, washed with saturated NaCl aqueous solution, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (chloroform:acetone = 40:1) to obtain a light yellow solid (E)N-2 (83 mg), with a yield of 39%.

[0054] 1 H NMR (600MHz, CDCl3) δ8.52(s,1H),7.89(d,J=8.0Hz,1H),7.51(dd,J=7.6,1.8Hz,1H),7.4 1(t,J=6.9Hz,1H),7.14(td,J=7.7,1.8Hz,1H),6.16(s,1H),4.72(d,J=10.9Hz,2H),2.48– 2.40(m,2H),2.28–2.25(m,1H),2.09–1.94(m,2H),1.92–1.86(m,2H),1.81–1.79(m,1H),1 .73(s,3H),1.29(dd,J=12.9,4.6Hz,1H),1.07(s,1H),1.01(s,3H),0.98(d,J=6.9Hz,3H); 13C NMR (150MHz, CDCl3) δ171.1,155.8,151.5,149.7,140.1,131.8,129.6,128.4,127.6, 121.7,109.1,93.2,44.1,40.8,39.3,38.6,32.8,31.9,29.4,21.0,17.3,15.3; ESI-MS m / z485.0[M+Na] + 947.2 [2M+Na] + Through the analysis of 1 H, 13 Analysis of C NMR and ESI-MS data confirmed that the (E)N-2 structure is nootkatone-2-iodobenzoyl hydrazone.

[0055] Example 3

[0056] Preparation of naringin hydroxylamine ester (N-3)

[0057]

[0058] (E)N-1 (100 mg, 1 equiv.) was dissolved in 10 mL of dichloromethane, and DMAP (52 mg, 1.0 equiv.), triethylamine (0.3 mL, 4.0 equiv.), and 4-methylbenzoyl chloride (132 mg, 2.0 equiv.) were added sequentially. The mixture was stirred at room temperature under argon protection. The reaction was monitored by TLC (anisaldehyde with sulfuric acid) until the reaction was complete. The mixture was washed with saturated tartaric acid aqueous solution and saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a pale yellow solid (E)N-3 (97 mg), with a yield of 64%.

[0059] 1H NMR (600MHz, CDCl3) δ7.97 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.5zz Hz,3H),6.12(s,1H),4.72(d,J=9.6Hz,2H),3.03(dd,J=17.5,4.3Hz,1H), 2.50–2.44(m,1H),2.42(s,4H),2.32–2.19(m,2H),1.92(dt,J=13.0,2.8H z,1H),1.90–1.83(m,1H),1.79–1.75(m,1H),1.73(s,3H),1.31(qd,J=12. 8,4.5Hz,1H),1.08(t,J=12.8Hz,1H),1.03(s,3H),1.01(d,J=6.8Hz,3H); 13 C NMR (150MHz, CDCl3) δ164.3,163.6,160.2,149.6,144.0,129.8,129.3,126.7,117 .5,109.2,44.1,40.7,39.0,38.8,33.1,31.9,29.1,21.8,21.0,17.2,15.1; ESI-MS m / z 374.1[M+Na] + 725.5 [2M+Na] + Through the analysis of 1 H, 13 Analysis of C10 NMR and ESI-MS data confirmed that the structure of (E)N-3 is nootkatone-(4-methylbenzoyl)oxime.

[0060] Example 4

[0061] Preparation of naringin hydroxylamine ester (N-4)

[0062]

[0063] (E)N-1 (150 mg, 1 equiv.) was dissolved in 10 mL of dichloromethane, and DMAP (78 mg, 1.0 equiv.), triethylamine (0.2 mL, 3.0 equiv.), and 4-fluorobenzoyl chloride (202 mg, 2.0 equiv.) were added sequentially. The mixture was stirred at room temperature under argon protection. The reaction was monitored by TLC (anisaldehyde with sulfuric acid) until the reaction was complete. The mixture was washed with saturated tartaric acid aqueous solution and saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain a white solid (E)N-4 (114 mg), with a yield of 50%.

[0064] 1 H NMR (600MHz, CDCl3) δ8.09 (dd, J=8.7, 5.5Hz, 2H), 7.14 (t, J=8.6Hz, 2H), 6.11 (s, 1H) ,4.72(d,J=10.5Hz,2H),3.00(dd,J=17.5,4.2Hz,1H),2.51–2.37(m,2H),2.32–2.19( m,2H),1.92(d,J=12.9Hz,1H),1.90–1.84(m,1H),1.80–1.73(m,1H),1.73(s,3H),1.3 1(qd,J=12.8,4.5Hz,1H),1.08(t,J=12.9Hz,1H),1.03(s,3H),1.01(d,J=6.8Hz,3H); 13 C NMR (150MHz, CDCl3) δ166.8,163.8,163.2,160.6,149.6,132.3,132.2,125.7,115. 9,115.8,109.2,44.0,40.7,39.0,38.8,33.1,31.9,29.1,21.0,17.2,15.1; ESI-MS m / z 378.1[M+Na] + 733.3[2M+Na] + Through the analysis of 1 H, 13 Analysis of C10 NMR and ESI-MS data confirmed that the (E)N-4 structure is nootkatone-(4-fluorobenzoyl)oxime.

[0065] Example 5

[0066] Preparation of naringin hydroxylamine ester (N-5)

[0067]

[0068] (E)N-1 (80 mg, 1 equiv.) was dissolved in 10 mL of dichloromethane, and DMAP (21 mg, 0.5 equiv.), 2-chlorothiophene-5-carboxylic acid (66 mg, 1.2 equiv.), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (234 mg, 3.0 equiv.) were added sequentially. The mixture was stirred at room temperature under argon protection, and the reaction was monitored by TLC (anisaldehyde-sulfuric acid) until the reaction was complete. The mixture was washed with saturated tartaric acid aqueous solution and saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a pale yellow solid (E)N-5 (110 mg), with a yield of 86%.

[0069] 1 H NMR (600MHz, CDCl3) δ7.70(d,J=4.0Hz,1H),6.97(d,J=4.0Hz,1H),6.08(s,1H),4.72(d,J=11.7Hz,2H ),2.95(dd,J=17.6,4.2Hz,1H),2.50–2.43(m,1H),2.40(ddd,J=15.1,4.1,2.7Hz,1H),2.29(tt,J=12. 3,2.5Hz,1H),2.19(dd,J=17.6,13.8Hz,1H),1.92(dt,J=13.0,2.6Hz,1H),1.90–1.84(m,1H),1.79–1. 74(m,1H),1.73(s,3H),1.35–1.26(m,1H),1.08(t,J=12.9Hz,1H),1.02(s,3H),1.00(d,J=6.8Hz,3H); 13 C NMR (150MHz, CDCl3) δ163.8,161.0,159.0,149.6,137.9,133.8,130.1,127.5,1 17.0,109.2,44.0,40.6,38.9,38.8,33.2,31.9,29.0,21.0,17.2,15.1; ESI-MS m / z 400.2[M+Na] + 777.5[2M+Na] + Through the analysis of 1 H, 13 Analysis of C NMR and ESI-MS data confirmed that the structure of (E)N-5 is nootkatone-(5-chlorothiophene-2-carbonyl)oxime.

[0070] Example 6

[0071] Preparation of naringin hydroxylamine ester (N-6)

[0072]

[0073] (E)N-1 (80 mg, 1 equiv.) was dissolved in 10 mL of dichloromethane, and 4-dimethylaminopyridine (DMAP) (21 mg, 0.5 equiv.), triethylamine (113 mg, 3.3 equiv.), and finally 3,5-dimethylisoxazole carbamate (108 mg, 2.0 equiv.) were added. The reaction was stirred at room temperature under argon protection, and the reaction was monitored by TLC (anisaldehyde-sulfuric acid) until the reaction was complete. The mixture was washed with saturated tartaric acid aqueous solution, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oil (E)N-6 (56 mg), with a yield of 46%.

[0074] 1 H NMR(600MHz, CDCl3) δ6.09(s,1H),4.72(dd,J=13.2,1.3Hz,2H),2.88(dd,J=17.4,4.4Hz,1 H),2.70(d,J=1.1Hz,3H),2.49(d,J=1.2Hz,3H),2.49–2.37(m,2H),2.29(t,J=12.3Hz,1H) ,2.18(dd,J=17.4,13.8Hz,1H),1.94–1.84(m,2H),1.76(dt,J=8.7,5.1Hz,1H),1.73(s,3H )1.31(dd,J=12.7,4.5Hz,1H),1.08(t,J=12.8Hz,1H),1.03(s,3H),0.99(d,J=6.9Hz,3H); 13 C NMR (150MHz, CDCl3) δ175.7,163.4,160.9,160.2,159.7,149.5,117.1,109.2,108 .0,44.0,40.6,38.9,38.8,33.1,31.8,29.8,21.0,17.2,15.2,13.7,12.3; ESI-MS m / z379.1[M+Na] + 735.3[2M+Na] + Through the analysis of 1 H, 13Analysis of C1 NMR and ESI-MS data confirmed that the (E)N-6 structure is nootkatone-(3,5-dimethylisoxazole-4-carbonyl)oxime.

[0075] Example 7

[0076] Preparation of naringin hydroxylamine ester (N-7)

[0077]

[0078] (E)N-1 (80 mg, 1 equiv.) was dissolved in 10 mL of dichloromethane, and 4-dimethylaminopyridine (DMAP) (21 mg, 0.5 equiv.), 2-furanacrylic acid (56 mg, 1.2 equiv.), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (234 mg, 3.0 equiv.) were added sequentially. The reaction was stirred at room temperature under argon protection. The reaction was monitored by TLC (anisaldehyde with sulfuric acid) until the reaction was complete. The sample was washed with saturated tartaric acid aqueous solution and saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain solid (E)N-7 (41 mg), with a yield of 34%.

[0079] 1 H NMR (600MHz, CDCl3) δ7.55(d,J=15.7Hz,1H),7.49(s,1H),6.64(d,J=3.4Hz,1H),6.48(dd,J=3.3,1.8Hz,1H),6.43( d,J=15.7Hz,1H),6.07(s,1H),4.72(d,J=10.2Hz,2H),2.96(dd,J=17.6,4.2Hz,1H),2.48–2.41(m,1H),2.38(dt,J=1 5.0,3.9Hz,1H),2.28(t,J=12.4Hz,1H),2.13(dd,J=17.6,13.8Hz,1H),1.93–1.88(m,1H),1.86(ddt,J=9.7,4.6,2.3 Hz,1H),1.76–1.70(m,4H),1.31(td,J=12.9,4.3Hz,1H),1.07(t,J=12.9Hz,1H),1.01(s,3H),0.98(d,J=6.8Hz,3H); 13C NMR (150MHz, CDCl3) δ165.1,163.2,160.2,151.1,149.7,145.0,132.1,117.5,115.4,1 13.7,112.5,109.2,44.1,40.7,39.0,38.8,33.1,31.9,29.0,21.0,17.2,15.0; ESI-MS m / z 376.1[M+Na] + 729.3 [2M+Na] + Through the analysis of 1 H, 13 Analysis of C1NMR and ESI-MS data confirmed that the (E)N-7 structure is nootkatone-((E)-3-(furan-2-yl)acryloyl)oxime.

[0080] Example 8

[0081] Preparation of naringin hydroxylamine ester (N-8)

[0082]

[0083] (E)N-3 (80 mg, 1 equiv.) was dissolved in 10 mL of dichloromethane, and 4-dimethylaminopyridine (DMAP) (38 mg, 0.5 equiv.), ozagrel (93 mg, 1.2 equiv.), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (234 mg, 3.0 equiv.) were added sequentially. The reaction was stirred at room temperature under argon protection. The reaction was monitored by TLC (anisaldehyde-sulfuric acid) until the reaction was complete. The sample was washed with saturated tartaric acid aqueous solution and saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a colorless transparent liquid (E)N-8 (94 mg), with a yield of 65%.

[0084] 1H NMR(600MHz, CDCl3)δ7.79(d,J=15.9Hz,1H),7.55(t,3H),7.16(d,J=8.0Hz,2H),7.10(s,1H),6 .90(s,1H),6.54(d,J=16.0Hz,1H),6.08(s,1H),5.15(s,2H),4.72(d,J=10.6Hz,2H),2.97(dd,J =17.6,4.2Hz,1H),2.50–2.35(m,2H),2.32–2.24(m,1H),2.18–2.12(m,1H),1.94–1.83(m,2H),1 .77–1.70(m,4H),1.32–1.27(m,1H),1.07(t,J=12.9Hz,1H),1.02(s,3H),0.99(d,J=6.8Hz,3H); 13 C NMR (150MHz, CDCl3) δ164.8,163.4,160.4,149.6,144.8,138.7,137.6,134.6,130.2,128.9,127.8,11 9.4,117.4,116.8,109.2,50.5,44.0,40.7,39.0,38.8,33.1,31.9,29.0,21.0,17.2,15.1,0.1; ESI-MS m / z 466.1[M+Na] + 909.5 [2M+Na] + Through the analysis of 1 H, 13 Analysis of C1NMR and ESI-MS data confirmed that the structure of (E)N-8 is nootkatone-((E)-3-(4-((1H-imidazol-1-yl)methyl)phenyl)acryloyl)oxime(nootkatone-(E)-3(4((1H-imidazol-1-yl)methylene)phenyl)acryloyl oxime).

[0085] Example 9

[0086] Evaluation of the antifungal activity of naringin and its derivatives

[0087] The *Fusarium gibberella* zeae, *Phytophthora parasitica* var. *nicotianae*, *Phomopsis* sp., and *Fusarium oxysporum* used in the following examples were provided by the Key Laboratory of Natural Product Chemistry, Chinese Academy of Sciences, Guizhou Province. Activation of the strains was performed by inoculating three loops of the strain onto potato dextrose agar (PDA) medium and incubating at 28±1℃ for 72 hours.

[0088] The antibacterial activity of the compounds was evaluated using the virulence plate method. Using a punch (Ф4 mm in diameter), 5 mm diameter mycelial cakes were collected from activated Fusarium graminearum PDA plates. The active ingredient was then added to the center of both the virulence-containing and control plates, with each treatment repeated five times. The plates were incubated at 28 ± 1 °C, and the antibacterial effect was observed. The diameter of the mycelial cakes was measured using the cross-hatching method, and the specific inhibition rate was calculated.

[0089] Inhibition rate (I,%)=(CT) / (C-5mm)×100%

[0090] I. Inhibition rate of active substances; C. Diameter of bacterial growth on blank control plate; T. Diameter of bacterial growth on virulence plate.

[0091] EC was calculated based on different inhibition rates at gradient concentrations. 50 Values ​​and results are shown in Tables 1 and 2. Positive controls included pyrimethanil (CAS: 53112-28-0, molecular weight: 199) and thiophanate-methyl (CAS: 23564-05-8, molecular weight: 342). The effects of gradient concentrations of compound N-6 on the mycelial growth of *Phomopsis* sp. are shown below. Figure 1 As shown in the figures. The activity results are shown in Tables 1 and 2.

[0092]

[0093] Table 1. Antimicrobial activity of nocadol and its derivatives against four plant pathogenic fungi at 50 μg / mL*

[0094]

[0095]

[0096] *Mean±SD, n=3; "-" indicates no activity; *P. parasitica*, *F. oxysporum*, *WG zeae*, *P. sp.*

[0097] Table 2 EC50 of nocacon derivatives on Phhomopsis sp. 50 value

[0098]

[0099] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

[0100] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. The application of a naringin derivative in the preparation of a drug for controlling stem spot disease, characterized in that, The nobiletin derivative has a structure shown in formula 1: Wherein, R is any one of N-2, N-3, N-4, N-5, N-6, N-7, N-8, 2. Use according to claim 1, characterized in that, The dosage form of the medicine is one of powder, suspension, granule, water dispersible agent and microemulsion.

3. A process for the preparation of a naringenin hydroxyl amide ester, characterized by, The method comprises the following steps: Nobiletin is dissolved in ethanol, hydroxylamine hydrochloride is added, sodium bicarbonate is added, then the reaction is refluxed at 85 DEG C, the raw material is tracked by TLC until the reaction is complete, the reaction liquid is cooled to room temperature, washed with saturated NaCl aqueous solution, dried with anhydrous Na2SO4, filtered, concentrated under reduced pressure, separated and purified to obtain nobiletin hydroxylamine N-1; Nobiletin hydroxylamine N-1 prepared is dissolved in dichloromethane, 4-dimethylamino pyridine, triethylamine are added, finally 3, 5-dimethyl isoxazole carbonyl chloride is added, the reaction is stirred at room temperature under argon protection, the raw material is tracked by TLC until the reaction is complete, washed with saturated tartaric acid aqueous solution, washed with saturated NaCl aqueous solution, dried with anhydrous Na2SO4, filtered, concentrated under reduced pressure, separated by silica gel column chromatography to obtain nobiletin hydroxylamine ester N-6.

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