Evodiamine derivatives targeting insect ryanodine receptors and preparation and use thereof

Abstract

The application discloses a class of evodiamine derivatives targeting insect ryanodine receptors and preparation and application thereof. The compound of the application has a structural formula as shown in I, wherein R, R 1 , R 2 are defined in claim 1. The compound of the general formula I of the application has medium to excellent insecticidal activity on pests of Lepidoptera such as oriental armyworm and diamondback moth, and research on the insecticidal mechanism finds that it is a class of insect ryanodine receptor activators. The application synthesizes a class of insecticides targeting insect ryanodine receptors, which can be used alternatively with existing insecticides to avoid or delay the generation of resistance, has conventional preparation conditions, simple subsequent treatment and is easy to realize industrialization, and is an insecticide with wide application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of agricultural insecticides, and relates to an Evodia plant source insecticide containing multiple N heteroatoms, in particular to preparation of an Evodia alkaloid derivative targeting the insect Ryanodine receptor and application thereof in preventing and treating agricultural pests. BACKGROUND

[0002] Insecticides not only ensure the high yield of food, but also are very important for human production and life, transportation, health care and epidemic prevention. However, the overuse of traditional insecticides has caused serious environmental problems, safety problems and resistance problems, prompting the development of green, efficient and ecological insecticides.

[0003] Natural products are a huge treasure trove of resources. With the development of high-tech and organic synthesis chemistry, and the emphasis on green pesticides and ecological environment, searching for pesticide active ingredients from the natural resource treasure trove and optimizing and modifying them as a lead structure have become an important way to create ecological pesticides. According to statistics, among the 102 pesticide active ingredients (excluding biological pesticides) registered globally for the first time between 2011 and 2017, natural products accounted for 4.9%, and natural product derivatives accounted for 19.6% (Liu Wei-jie, Li Qing-shan, Xu Feng-bo. 2011-2017 New Pesticide Active Ingredients and Application of Natural Product Pharmacophore Derivation Method in Pesticide Molecular Design. Natural Product Research and Development. 2019, 31, 363-371.). Natural products are produced by the biological world to meet their own survival and population proliferation, and are not necessarily designed to improve human living standards and agricultural production levels. They need further structural modification and optimization to meet the requirements of pesticides (Sparks, T.C.;Crouse, G.D.;Demeter, D.A.;etc. Discovery of highly insecticidal synthetic spinosynmimics-CAMD enabled de novo design simplifying a complex natural product. Pest Manag. Sci., 2019, 75, 309-313.). Therefore, it is very important to synthesize natural product derivatives, which helps to quickly and efficiently determine the pharmacophore and structure-activity relationship rules, and to deeply understand the action mode of natural products and biological targets, providing tools for chemical biology research (Li, G.;Lou, H.X. Strategies to diversify natural products for drug discovery. Med. Res. Rev., 2018, 38, 1255-1294.).

[0004] Evodia rutaecarpa (Juss.) Benth. is a medicinal plant of Rutaceae family, which has the effects of dispelling cold and relieving pain, reducing adverse and stopping vomiting, and helping yang and stopping diarrhea. In recent years, domestic and foreign researches have found that Evodia rutaecarpa contains various chemical active ingredients, mainly including alkaloids, volatile oils, and bitter principles, etc., which have the activities of anti-tumor, anti-virus, and anti-bacteria (Matsui, T.; Kodama, T.; Mori, T.; etc. 2-Alkylquinolone alkaloid biosynthesis in the medicinal plant Evodia rutaecarpa involves collaboration of two novel type III polyketide synthases. J. Biol. Chem., 2017, 292, 9117-9135.; Park, E.; Lee, M. Y.; Seo, C. S.; etc. Ethanol extract of Evodia rutaecarpa attenuates cell growth through caspase-dependent apoptosis in benign prostatic hyperplasia-1 cells. Nutrients, 2018, 10, 523), which have attracted extensive attention and research. However, the research on Evodia rutaecarpa mainly focuses on medical research, and the research on the prevention and control of agricultural pests and diseases is less. The early record in “China Soil Pesticide Record” shows that the leaves of Evodia rutaecarpa are crushed and added with water to form a liquid, which is sprayed on crops, which can not only prevent and control aphids, borers, and cotton aphids, but also effectively prevent and control maggots and hole larvae. Miyazawa et al. found that the methanol extract of Evodia rutaecarpa fruit has toxic effects on the larvae and adults of Drosophila melanogaster, and further research proved that the half lethal concentration LC 50The values were 0.28 mg / L and 3.58 mg / L, respectively (Miyazawa, M.; Fujioka, J.; Ishikawa, Y. Insecticidal compounds from Evodia rutaecarpa against Drosophila melanogaster. J. Sci. Food Agric., 2002, 82, 1574-1578.). Professor Jiang Hongyun's research group of Institute of Plant Protection, Chinese Academy of Agricultural Sciences found that different extracts of Evodia rutaecarpa fruit extract had non-selective antifeedant activity on 3rd instar Spodoptera exigua, among which chloroform extract and n-butanol extract showed higher antifeedant activity. The non-selective antifeedant concentration AFC 50 The values were 1.82 mg / L and 1.85 mg / L, respectively (Feng, X. H.; Jiang, H. Y.; Zhang, Y. N. et al. Preliminary study on the antifeedant activity of Evodia rutaecarpa against Spodoptera exigua. Grain Safety and Plant Protection Technology Innovation, 2009, 780-783.). Professor Liu Zhilong's research group of China Agricultural University also isolated three alkaloids, evodiamine, rutaecarpine and evocarpine, and two limonoids, evodol and limonin, from the fruits of Evodia rutaecarpa, and found that they had insecticidal activity against Aedes albopictus larvae and Meloidogyne incognita. Among them, evodiamine and rutaecarpine had more prominent insecticidal activity, with LC 50 The values were 12.51 mg / L and 17.02 mg / L, respectively (Liu, Z. L.; Liu, Q. Z.; Du, S. S.; etc. Mosquito larvicidal activity of alkaloids and limonoids derived from Evodia rutaecarpa unripe fruits against Aedes albopictus (Diptera: Culicidae). Parasitol. Res., 2012, 111, 991-996.; Liu, Q. Z.; Li, H. Q.; Liu, Z. L. Nematocidal constituents from the ethanol extract of Evodia rutaecarpa hort unripe fruits. J. Chem-NY, 2013, 939215.). The above studies show that Evodia rutaecarpa is a potential insecticidal plant.

[0005] Based on the insecticidal effect of evodia, the evaluation of evodia alkaloids as lead compounds of insecticide is also carried out by the research group. By using modern chemical separation and purification means, evodiamine, rutaecarpine and dehydroevodiamine and other alkaloid monomer compounds are separated from the fruits of traditional Chinese medicine Rutaceae plant evodia, the monomer compounds are evaluated for insecticidal activity by using leaf dipping method, and the results show that evodiamine, rutaecarpine and dehydroevodiamine have good insecticidal activity, wherein the insecticidal activity of evodiamine is the most outstanding, and the preliminary mechanism study finds that evodiamine can produce certain influence on the action potential of the nervous system of lepidopteran pest oriental armyworm. Therefore, evodiamine can be used as a plant source insecticide lead for further structure optimization, and has potential research and development value. Based on this, the preparation method, insecticidal activity and mechanism of evodiamine derivatives are reported, which has not been disclosed in the prior art. SUMMARY

[0006] The purpose of the present application is to provide evodiamine derivatives, preparation methods, mechanisms and applications thereof. The compounds have insecticidal activity, are insect ryanodine receptor activators, and can be applied to the prevention and control of agricultural pests.

[0007] The evodiamine derivatives provided by the present application have a structural formula as shown in general formula I:

[0008]

[0009] Among them, R 1 and R 2 are CH3, OCH3, H, F, Cl, Br, CF3; R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, allyl, benzyl, formyl, acetyl, benzoyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, n-butylsulfonyl, phenylsulfonyl.

[0010] The evodiamine derivatives I are prepared by the following synthesis route:

[0011]

[0012] The synthesis method of the evodiamine derivatives I is divided into the following steps:

[0013] (1) 3, 4-dihydro-β-carboline A is added to a single-necked round-bottom flask, anhydrous dichloromethane is added to the flask, and then 1 equivalent of N-methyl indigo red anhydride B is added, and the mixture is stirred at room temperature for 12-24 hours. After the reaction is completed, a large amount of solid is generated. The solid is filtered, washed and dried to obtain compound C.

[0014] (2) The compound C obtained in step (1) is added into a single-neck flask, anhydrous N, N-dimethylformamide and 1.3 equivalent of sodium hydride (60%) are added into the flask, stirring at room temperature for 0.5-1 hour, then halogenated alkane / acyl chloride / sulfonyl chloride is added, stirring at room temperature for 12-24 hours, the reaction progress is monitored by TLC, after the reaction is completed, extraction and column chromatography are carried out to finally obtain evodiamine derivatives (formula I).

[0015] The compound of the present application has moderate to excellent insecticidal activity on agricultural pests such as oriental armyworm and diamondback moth.

[0016] The insecticidal mechanism of the compound of the present application is studied by using electrophysiology, patch clamp combined with fluorescence calcium measurement technology, it is found that they can act on insect ryanodine receptor, and are a kind of insect ryanodine receptor insecticides, which has important significance for solving the problem of resistance to ryanodine receptor insecticides.

[0017] The present application also includes the use of the compound of formula I as an active ingredient and an agriculturally acceptable adjuvant to form a pesticide composition for controlling agricultural pests such as oriental armyworm and diamondback moth.

[0018] Compared with the prior art, the present application synthesizes a kind of green and efficient insecticide with unique target, which can be used alternately with existing insecticides to avoid or delay the generation of resistance, has conventional preparation conditions, simple subsequent treatment and easy industrialization, and is a kind of insecticide with broad application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 The figure is the influence diagram of the intracellular calcium ion concentration [Ca 2+ ]i of the neuron cells of the oriental armyworm after the treatment of evodiamine derivatives I-1, I-9, I-18, I-33, evodiamine and chlorantraniliprole (in the absence of extracellular calcium) in the present application.

[0020] Figure 2 The figure is the influence diagram of the intracellular calcium ion concentration [Ca 2+ ]i of the neuron cells of the oriental armyworm 3rd instar larvae after the treatment of evodiamine derivative I-33 in the present application. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the embodiments of the present application, and the purpose is to better understand the content and embody the essential characteristics of the present application. Therefore, the described embodiments are only some of the embodiments of the present application, not all the embodiments. It is also particularly pointed out that the specific experimental methods and equipment involved in the embodiments are implemented according to the conventional methods or the suggested conditions of the manufacturer's instruction manual if no special instructions are given, and the reagents involved are commercially available if no special instructions are given.

[0022] Example 1

[0023] Preparation of 13-(cyclopropylsulfonyl)-10,14-dimethyl-8,13,13b,14- tetrahydroindolo[2',3':3,4]pyrrolo[2,1-b]quinazolin-5(7H)-one (I-20)

[0024] 1 mmol of 6-methyl-4,9-dihydro-3H-pyrrolo[3,4-b]indole (A-20) was added to a 50 mL single-necked round-bottom flask, 10 mL of anhydrous dichloromethane was added to the flask, and then 1 mmol of N-methyl isatin anhydride (B-20) was added. After stirring at room temperature for 16 hours, a large amount of white solid was obtained. After filtration, washing, and drying under reduced pressure, 10,14-dimethyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrrolo[2,1-b]quinazolin-5(7H)-one (C-20) was obtained.

[0025] The obtained compound C-20 was added to a 25 mL single-necked flask, 5 mL of anhydrous N,N-dimethylformamide and 1.3 eq of sodium hydride (60%) were added to the flask, and stirring was performed at room temperature for 0.5 hours. Then, 1.1 eq of cyclopropylsulfonyl chloride was added, and stirring was performed at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, extraction and column chromatography were performed, and finally 13-(cyclopropylsulfonyl)-10,14-dimethyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrrolo[2,1-b]quinazolin-5(7H)-one (I-20) was obtained in a yield of 78%.

[0026]

[0027] Example 2

[0028] Preparation of 13-(cyclopropylsulfonyl)-1-fluoro-14-methyl-8,13,13b,14- tetrahydroindolo[2',3':3,4]pyrrolo[2,1-b]quinazolin-5(7H)-one (I-28)

[0029] To a 50 mL single necked round bottom flask was added 1 mmol of 3,4-dihydro-β- carboline (A-28) and 10 mL of anhydrous dichloromethane. To the flask was added 1 mmol of 8-fluoro-l-methyl-2H-benzo[d][l,3]oxazin-2,4(lH)-dione (B-28). After stirring at room temperature for 12 hours, a large amount of white solid was formed. After filtration, washing and drying under reduced pressure, l-fluoro-l 4-methyl-8, 13, 13b, 14-tetrahydroindolo[2',3':3,4]pyrrolo[2,l- b]quinazolin-5(7H)-one (C-28) was obtained.

[0030] To a 25 mL single necked round bottom flask was added the obtained compound C-28, 5 mL of anhydrous N,N-dimethylformamide and 1.3 eq of sodium hydride (60%). After stirring at room temperature for 0.5 hours, 1.1 eq of cyclopropylsulfonyl chloride was added. After stirring at room temperature, the progress of the reaction was monitored by TLC. After the reaction was completed, extraction and column chromatography were performed to obtain 13-(cyclopropylsulfonyl)-l-fluoro-l 4-methyl-8, 13, 13b, 14-tetrahydroindolo[2',3':3,4]pyrrolo[2,l-b]quinazolin-5(7H)-one (I-28) in a yield of 68%.

[0031]

[0032] The remaining 32 target products were prepared by using the same preparation method as in Example 1-2, but using different starting materials (the amount of substance of the corresponding reaction starting materials of Example 1-2 was the same). The physicochemical data of the target products are shown in Table 1 and Table 2.

[0033] Table 1 Physical properties of evodiamine derivatives (general formula I) of the present application

[0034]

[0035]

[0036] Table 2 Proton nuclear magnetic resonance spectrum of evodiamine derivatives (general formula I) of the present application 1 H NMR)

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043] Example 3: Results of insecticidal activity determination of evodiamine derivative I of the present application:

[0044] Test target: Mythimna separata Walker, Plutella Xylostella.

[0045] Test method:

[0046] Test target: Mythimna separata Walker. Test method: leaf dipping method. Corn leaves were dipped in the test solution prepared in acetone, and 3rd instar larvae were introduced after the solution was dried. The main action was stomach toxicity and contact killing, and the feeding behavior of the larvae was observed. The blank control was a solution containing 1 mL of test solvent in water. The survival state of the larvae was checked 72 hours after treatment. The larvae were gently touched with a brush, and if there was no reaction, they were determined to be dead. The number of deaths and survivals was recorded, and the mortality and corrected mortality were calculated.

[0047] Test target: Plutella Xylostella. Test method: leaf dipping method, placed in a 100 ml beaker prepared at the desired concentration. The treatment was placed in a standard treatment room, and the blank control was a solution containing 1 mL of test solvent in water. The survival state of the larvae was checked 72 hours after treatment. The larvae were gently touched with a brush, and if there was no reaction, they were determined to be dead. The number of deaths and survivals was recorded, and the mortality and corrected mortality were calculated.

[0048] The results of the insecticidal determination of the above two agricultural pests are shown in Tables 3 and 4. Here, the activity data of evodiamine derivative I of the present application and the control drug were obtained under the same experimental conditions.

[0049] Table 3 Insecticidal activity (%) of evodiamine derivative (general formula I) of the present application on Mythimna separata Walker

[0050]

[0051]

[0052] Table 4 Insecticidal activity (%) of evodiamine derivative (general formula I) of the present application on Plutella Xylostella

[0053]

[0054]

[0055] As shown in Table 3, most evodiamine derivatives I exhibited superior insecticidal activity against the Oriental Armyworm compared to evodiamine, matrine, and rotenone. In particular, compounds I-20-I-34 exhibited significantly higher mortality against the Oriental Armyworm at a concentration of 5 mg / L than evodiamine, matrine, and rotenone. Furthermore, compound I-33 maintained a high mortality rate of 93% against the Oriental Armyworm at a concentration of 2.5 mg / L, suggesting that it could serve as a potential insecticide lead for further structural optimization.

[0056] The structure-activity relationship shows that the introduction of alkyl, sulfonyl, acyl chloride and other groups on the nitrogen atom (N17) of the B ring has a positive and important effect on its insecticidal activity, especially the introduction of cyclopropylsulfonyl greatly improves its insecticidal activity. 1 When H is used, its insecticidal activity is the best. 2 The structure-activity relationship between the substituent type and the position on the E ring: R 2 The substitution type has an important influence on insecticidal activity. 2 When they are at the same position of the E ring, the order of insecticidal activity is: F>CF3, Cl≥Br>CH3>OCH3, which means that R on the E ring 2 The F substituent can improve the insecticidal activity against the oriental armyworm. 2 The position of the substituent on the E ring also has an important influence on its insecticidal activity. 2 When the substituent is at the 1-position of the E ring, the target compound shows a better effect on the oriental armyworm than R 2 The target compound has better insecticidal activity when the substituents are at positions 2, 3, and 4 of the E ring, indicating that R 2 Substituents at position 1 of the E ring have a positive and significant effect on insecticidal activity.

[0057] Based on the insecticidal activity of evodiamine derivative I against oriental armyworm, target compounds with higher activity were selected for insecticidal activity testing against diamondback moth. As shown in Table 4, the selected target compounds all showed good insecticidal activity, and all showed higher insecticidal activity than the control drugs evodiamine, matrine and rotenone. Preliminary structure-activity relationship showed that the introduction of cyclopropylsulfonyl group on the nitrogen atom (N17) of ring B was crucial for insecticidal activity; the insecticidal activity was related to R 2 The structure-activity relationship of substituent type and position on the E ring is similar to that of the oriental armyworm.

[0058] Example 4: Research method for the mechanism of action of the evodiamine derivative I of the present invention:

[0059] Based on the insecticidal activity evaluation, we selected I-1, I-9, I-18, and I-33 to explore the mechanism of action.

[0060] Research Methodology:

[0061] The P. xylii were reared on semi-synthetic diet based on agar

[15] at a temperature of 27 ± 1 °C, relative humidity of 75 ± 5% and LD 16:8 h photoperiod. The P. xylii were reared for two generations before the experiment. The third instar larvae of P. xylii were first anesthetized with 70% EtOH, thoracic-abdominal ganglion was removed and placed in physiological saline, then transferred to a solution containing 0.3% trypsin for half an hour, the cells were mechanically dispersed in a surface dish containing cell culture medium after the cells were dispersed using a fire-polished Pasteur pipette for 2 h at 28 °C, and the cells were allowed to adhere to the culture dish. All procedures were carried out under sterile conditions. The method proposed by Takahashi et al. was used for calibration of fluorescence signals

[20] , the adhered neurons were washed twice in standard physiological saline [(Mm): NaCl 150, KCl 4, MgCl2 2, CaCl2 2, HEPES 10], the buffer was pH adjusted to 7.0, then incubated in standard physiological saline containing dye fluo-3AM (10 μM) for 30 min in the dark, and the cells were washed twice with physiological saline after dye loading. The calcium ratio imaging study used an inverted fluorescence microscope coupled with an imaging system with a Fluor 40x oil immersion objective (Olympus IX71). The cell fluorescence excitation emission wavelength was 488 nm, and the images were captured using a CCD (Image Pro-6.0). Each experiment was repeated at least 3 times, data analysis was performed using GraphPad Prism 7.0, and the results were expressed as mean ± SD (n = number of cells). The compounds were added 100 s after the start of recording, the fluorescence signal was captured every 1 s for 200 s, and the fluorescence value was expressed as F / F0, F0 was the resting (or baseline) fluorescence, and F was the change in fluorescence relative to the baseline after drug application. The control group was a blank experiment.

[0062] As shown in Figure 1 Fig. 2, after the neurons of P. xylii were treated with I-1, I-9, I-18, I-33, evodiamine and chlorantraniliprole at a concentration of 10 mg / L in the absence of extracellular calcium, it can be seen from the figure that the peak value of cytoplasmic calcium concentration increased, which indicates that it can cause the release of calcium ions in the central neurons, and the increase in the peak value of calcium concentration is positively correlated with the insecticidal activity. The results of the study show that I can activate the calcium ion channel in the endoplasmic reticulum of central neuron cells, and release the calcium ions stored in the endoplasmic reticulum calcium store into the cytoplasm of central neuron cells.

[0063] The ryanodine receptor and the IP3 receptor are two channels of the endoplasmic reticulum calcium ion release in the central neuron cell of insects. In order to further explore which channel the I-33 acts on, before the neuron cell of the oriental armyworm is treated by 2.5 mg / L I-33, the neuron cell of the oriental armyworm is pre-incubated by 0.6 μmol / L 2-APB and 0.25 μmol / L ryanodine respectively for 5 min, and the experimental results are shown in the following table. Figure 2 As shown in the table, when the neuron cell of the oriental armyworm is directly treated by 2.5 mg / L I-33 without pre-incubation of the neuron cell by 2-APB and ryanodine, the peak value of the cytoplasmic calcium ion concentration is slightly higher than that of the cell pre-incubated by 2-APB, but lower than that of the cell pre-incubated by ryanodine, which indicates that the I-33 is an activator of the endoplasmic reticulum calcium ion release in the central neuron cell of insects, and can act on the ryanodine receptor of insects to release the calcium ions stored in the endoplasmic reticulum calcium store to the cytoplasm of the central neuron cell.

[0064] The above only describes the preferred embodiments of the present application, and is not used to limit the present application, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application. The components or connection modes not specifically described in the present application adopt the prior art. The front side, rear side, left side and right side described in the present application are only used to conveniently describe the structure, and are not used to limit the protection scope of the present application.

Claims

1. A class of evodiamine derivatives, having a structural formula as shown in general formula I: The specific structure of the general formula I is: I-10: R 1 =H, R 2 =H, R=CH3CH2C=O; I-12: R 1 =H, R 2 =H, R= ; I-14: R 1 =H, R 2 =H, R=CH3CH2SO2; I-16: R 1 =H, R 2 =H, R=(CH3)2CHSO2; I-18: R 1 =H, R 2 =H, R =CH3(CH2)2CH2SO2; I-20: R 1 =CH3, R 2 =H, R= ; I-21: R 1 =OCH3, R 2 =H, R ; I-22: R 1 =F, R 2 =H, R ; I-23: R 1 = Cl, R 2 = H, R ; I-24: R 1 = Br, R 2 = H, R ; I-25: R 1 =CF3, R 2 =H, R ; I-26: R 1 =H, R 2 =2-CH3, R ; I-27: R 1 = H, R 2 = 2-OCH3, R ; I-28: R 1 = H, R 2 = 2-F, R ; I-29: R 1 = H, R 2 = 2-Cl, R ; I-30: R 1 = H, R 2 = 2-Br, R ; I-31 : R 1 = H, R 2 = 2-CF3, R ; I-32: R 1 = H, R 2 = 1-F, R ; I-33: R 1 = H, R 2 = 3-F, R ; I-34: R 1 = H, R 2 = 4-F, R .

2. The method for preparing a class of evodiamine derivatives according to claim 1, characterized in that The synthesis steps are as follows: The substituents are defined as in claim 1 and the specific synthesis is as follows: Step one: preparation of compound C Compound C was prepared by dissolving 3,4-dihydro-β-carboline with 1 equivalent of N-methylisatin anhydride in anhydrous dichloromethane, stirring at room temperature until the reaction was complete, and then filtering the solid obtained in the reaction flask under reduced pressure and drying. 1 2 The definitions of R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R​ Step two: preparation of evodiamine derivative I Compound C is dissolved in dry N,N-dimethylformamide, 1.3 equivalents of sodium hydride is added slowly, the reaction is carried out at room temperature for 0.5-1 hour, halogenated alkane / acyl chloride / sulfonyl chloride is added, the reaction is stirred at room temperature for 12-24 hours, the reaction progress is monitored by TLC, after the reaction is completed, compound I is prepared finally by extraction and column chromatography, the substituent R in the structural general formula of compound I 1 , R 2 is defined as described previously.

3. Use of a derivative of evodiamine according to claim 1 for the preparation of an agricultural insecticide, characterized in that, The evodiamine derivative is a class of insect fish nitrine receptor targeting insecticides.

4. Use according to claim 3, characterized in that, The use of the evodiamine derivative as an active ingredient and an agriculturally acceptable adjuvant to form a pesticide composition for the prevention and treatment of oriental armyworm and diamondback moth agricultural pests.

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