WO2016127723A1 - 水杨酸类反-(β)-法尼烯类似物及其应用 - Google Patents

水杨酸类反-(β)-法尼烯类似物及其应用 Download PDF

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WO2016127723A1
WO2016127723A1 PCT/CN2016/000006 CN2016000006W WO2016127723A1 WO 2016127723 A1 WO2016127723 A1 WO 2016127723A1 CN 2016000006 W CN2016000006 W CN 2016000006W WO 2016127723 A1 WO2016127723 A1 WO 2016127723A1
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salicylic acid
alkyl
farnesene
nitro
halogen
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French (fr)
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杨新玲
秦耀果
宋敦伦
张景朋
凌云
谭晓庆
曲焱焱
李文浩
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中国农业大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C205/60—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms in ortho-position to the carboxyl group, e.g. nitro-salicylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups

Definitions

  • the invention belongs to the field of organic chemical synthesis, and particularly relates to salicylic acid trans-( ⁇ )-farnesene analogs and a preparation method thereof, and the application of the compounds in the control of aphids, plant disease resistance and sterilization.
  • the locust alarm pheromone is an oily droplet secreted by the abdominal tube when the mites are attacked by natural enemies. It can cause the surrounding mites to have an alarm function, stop feeding, and quickly escape from the hazard site, thereby stopping the damage to the host plant.
  • Bowers and Edwards et al. first identified the aphid alarm pheromone in 1972.
  • the main component of the locust alarm pheromone was (E)- ⁇ -farnesene ((E)- ⁇ -farnesene, or EBF for short.
  • Francis et al. found that EBF is a locust alarm pheromone.
  • the main component, even EBF as the only component, has 12 species of aphids.
  • EBF can regulate winged and wingless in the offspring of aphids.
  • the proportion of cockroaches; EBF has a similar function to juvenile hormone III to certain insects, affecting the metamorphosis of insects; EBF has a significant toxic effect on aphids at 100 ng/Aphid dose, and when EBF and commercial pharmaceutical imidacloprid When mixed with aphids, it can play a synergistic role.
  • EBF has a stimulating effect on natural enemies of aphids; EBF can also induce scorpion flies, scorpion bees to locate and prey on aphids, and regulate the spawning of ticks Behavior.
  • Francis et al. quantitatively studied the induction of EBF on the aphid natural enemies, and when the EBF dosage was greater than 2g, it induced the ladybugs significantly; the EBF synthesis gene was introduced. EBF can be released into the potato crop, and its effect of repelling aphids is not ideal, but it can effectively attract the natural enemies of grasshoppers.
  • EBF The structural formula of EBF is as shown in Formula A: it is not difficult to find from the structural formula of EBF that it contains a plurality of double bonds, especially a pair of conjugated double bonds at the end, so EBF is easily oxidized and volatile in the air, and the properties are not Stable, limiting the application of EBF in the field.
  • many researchers at home and abroad have carried out structural modification and modification of EBF molecules, and it is expected to find compounds with both activity and stability.
  • Salicylic acid levels in plants are closely related to the development of plant disease resistance.
  • Salicylic acid is an important endogenous signal molecule that can activate plant allergic reactions and systemic resistance.
  • Salicylic acid can induce plant-related disease resistance genes and proteins. It produces plants that are resistant to disease, such as the ability to induce disease resistance in plants such as tobacco and cucumber against bacteria, fungi, viruses, etc. (Malamy, J. et al. Science. 1990, 250 (4983): 1002-1004; Former Yong Bing et al., Botany Bulletin, 1994, 11(3): 1-9; A. Corina Vlot et al. Annual Review of Phytopathology. 2009, 47: 177-206; Milwaukee et al. 2012, 486: 198-199).
  • Salicylic acid analogs have also been studied intensively in the field of medicine and in the field of antiseptic and antibacterial (Alib et al. J. Pharmacol Exp Ther, 1983, 226(2): 589-594).
  • the invention adopts the method of active substructure splicing to introduce a salicylic acid reactive group having plant disease-inducing activity and antibacterial activity into (trans)- ⁇ -farnesene, and replacing (anti)- ⁇ -method
  • a class of hydrated salicylic acid (trans)- ⁇ -farnesene analogs was developed by increasing the stability of the conjugated double bond in the nicene structure and broadening its spectrum of action.
  • One of the objects of the present invention is to provide a class of salicylic acid trans- ⁇ -farnesene analogs.
  • Another object of the present invention is to provide a process for preparing a salicylic acid-trans-beta-farnesene analog.
  • a third object of the present invention is to provide a use of a class of salicylic acid anti-beta-farnesene analogs as novel aphid control agents.
  • a fourth object of the present invention is to provide a use of a salicylic acid-type anti-beta-farnesene analog as a plant antiviral agent and a bactericide.
  • a fifth object of the present invention is to provide a type of salicylic acid-trans-beta-farnesene analog as an application for an anti-insect pest.
  • R 1 is H, C1 to C10 alkyl, haloalkyl, phenyl (halogen, nitro, C1-10 alkyl and alkoxy substituted phenyl), benzyl (halogen, nitro, C1 ⁇ ) 10 alkyl and alkoxy substituted benzyl), halogen, nitro, C1-10 alkyl and alkoxy substituted phenyl, thiazole, pyridine;
  • R 2 is H, OH, C1 to C10 alkyl, C1 ⁇ C10 alkoxy, haloalkyl, halogen, nitro, trifluoromethyl;
  • R 3 is H, C1-C10 alkyl, halogen, nitro, C1-10 alkyl and alkoxy substituted phenyl;
  • X It is O, N;
  • Y is O, S.
  • R 1 is H, methyl, ethyl, phenyl, benzyl
  • R 2 is H, OH, methyl, methoxy, Cl, F, CF 3 , NO 2
  • R 3 is H, CH 3
  • X is O, N
  • Y is O.
  • the preparation method of the salicylic acid trans-( ⁇ )-farnesene analog comprises the following steps:
  • R 1 is H, C1-C10 alkyl, haloalkyl, phenyl (halogen, nitro, C1-10 alkyl and alkoxy substituted phenyl), benzyl (halogen, nitro, C1- 10 alkyl and alkoxy substituted benzyl), halogen, nitro, C1-10 alkyl and alkoxy substituted thiazole, pyridine;
  • R 2 is H, OH, C1-C10 alkyl, C1-C10 alkane Oxy, haloalkyl, halogen, nitro, trifluoromethyl;
  • R 3 is H, C1-C10 alkyl, halogen, nitro, C1-10 alkyl and alkoxy substituted phenyl: Y is O, S.
  • the compounds provided by the present invention are prepared according to the following steps:
  • the synthesis of the compound of formula I comprises the steps of:
  • the salicylic acid is mixed with an organic solvent, and then gradually added a dehydrating agent and a condensing agent or an acid binding agent, and mixed with geraniol or geraniol or a substituted geranylamine, a catalyst and an organic solvent to carry out a condensation reaction, and the solvent is removed under reduced pressure. Separation by silica gel column chromatography gave the compound of formula I.
  • R 1 is benzyl (halogen, nitro, C1-10 alkyl and alkoxy substituted benzyl), halogen, nitro, C1-10 alkyl and alkoxy substituted thiazole, pyridine
  • the synthesis of the compound I comprises the steps of: mixing salicylic acid with an organic solvent, adding benzyl bromide or a halogenated aromatic hydrocarbon, obtaining a key intermediate to replace the salicylic acid under the action of a phase transfer catalyst, and then sequentially adding a dehydrating agent and a condensing agent or a binding acid.
  • the mixture is further mixed with geraniol or geraniol or substituted geranylamine, a catalyst and an organic solvent to carry out a condensation reaction, and the solvent is removed under reduced pressure, and the mixture is separated by silica gel column chromatography to give the compound of formula I.
  • the reaction temperature is in a wide range of from -50 ° C to 200 ° C, and preferably the reaction temperature is from 20 ° C to 50 ° C.
  • the organic solvent used includes methanol, ethanol, n-propanol, isopropanol, benzene, toluene, xylene, acetonitrile, propionitrile, butyronitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, N, N-dimethyl Formamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, petroleum ether, methyl acetate, acetic acid Ester, diethyl ether, diisopropyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dichloromethane, chloroform, At least one or a combination of at least one of carbon tet
  • the dehydrating agent is selected from the group consisting of dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • the condensing agent is N,N'-carbonyldiimidazole
  • the catalyst is 4-dimethylaminopyridine
  • the acid binding agent is an organic base or an inorganic base, preferably piperidine, sodium hydroxide, potassium carbonate, One or more optional combinations of pyridine, triethylamine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium methoxide and sodium hydride.
  • the phase transfer catalyst is a polyether: chain polyethylene glycol, chain polyethylene glycol dialkyl ether, cyclic crown ether: 18 crown 6, 15 crown, cyclodextrin, quaternary ammonium salt: Benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate (TBAB), trioctylmethylammonium chloride, dodecyl three One or more combinations of methyl ammonium chloride, tetradecyl trimethyl ammonium chloride, etc., tertiary amines: R4N X, pyridine, tributylamine, quaternary ammonium base, quaternary phosphonium salt, and the like .
  • TEBA Benzyltriethylammonium chloride
  • TBAB tetrabutylammoni
  • the reaction product is obtained by column chromatography.
  • a drug having a salicylic acid trans-( ⁇ )-farnesene analog as an active ingredient is also within the scope of the present invention.
  • the salicylic acid anti-( ⁇ )-farnesene analog of the invention has obvious chemical acaricidal action and repellent activity by experiments, that is, has direct chemical control effect on aphids, and also has activity for regulating aphid behavior.
  • the salicylic acid anti-( ⁇ )-farnesene analog of the invention has the inhibitory activity against tobacco mosaic virus and various pathogenic bacteria, wherein the pathogenic bacteria are scab, sheath blight, early blight, It is also a plant disease-resistant fungicide that can be used in agriculture as a plant disease-resistant fungicide.
  • the invention has the beneficial effects of the salicylic acid anti-( ⁇ )-farnesene analog synthesized by the invention, the preparation method is simple and convenient, the operation is simple, the product purification is easy, the cost is low, and the lead anti-( ⁇ - farnesene has a large molecular weight and improved stability; the compound of the invention has multiple biological activities, and has obvious killing and repellent activity against agricultural pests, but also has plant antiviral activity and bactericidal activity, and can be used as Green pesticides are used in agricultural pest control.
  • the target compounds numbered I-2 to I-4, I-12 to I-14, I-18 to I-25, and I-27 to I-38, respectively, were obtained by the same method.
  • Step 1 Preparation of 3-hydroxysalicylic acid acetonitrile (intermediate 1)
  • the target compounds numbered I-1, I-6 and I-26 were prepared by the same method.
  • Step 3 Preparation of 3-methyl-2-benzyloxy-salicylic acid-(E)-3,7-dimethyl-2,6-octadienyl ester (I-7)
  • the target compounds numbered I-8 to I-9, I-11, I-15 to I-17, and I-39 to I-42, respectively, were prepared by the same method.
  • Table 1 below lists the structure and basic physical and chemical data of the target compounds, which were all prepared in accordance with various methods similar to those shown in the foregoing examples.
  • Example 4 Insecticidal activity against aphids at high concentrations of the compounds of the invention
  • 50 mg of the compound sample was weighed in a 20 ml weighing bottle with a one-tenth of a thousandth of the target compound, and introduced into a 10 mL volumetric flask to prepare a measuring solution of 5000 mg/L. Then, 1 ml of acetone was added to the weighing bottle with a 1-5 ml pipetting gun, and 9 ml of an aqueous solution containing 0.1% Triton X-100 was added and thoroughly mixed to obtain a measuring solution of 500 mg/L.
  • the soybean leaves that have not been exposed to any chemicals and insects are cultivated indoors, and the suitable size leaves are punched with a punch of 15 mm in diameter, respectively, immersed in the diluted chemical solution for 15 seconds, taken out and dried, and placed in the raw test plate.
  • the back side is facing up, and 1% agar is added to the bottom to moisturize.
  • Each well is connected to 20 soybeans, each of which is repeated 3 times. The results were checked after 48 hours.
  • the criterion for death is: light touch on the worm, and individuals who cannot crawl normally are considered dead.
  • Table 2 indicate that the compounds of the present invention have killing activity against aphids at high concentrations, among which compounds 1-10, 1-14, I-15, I-16, I-17, I-18, I-19 and I-25 has a mortality inhibition rate of more than 80% against aphids at a dose of 500 mg/L, and has a value for further development as a mites control agent.
  • Example 5 Repellent activity against aphids at low concentrations of the compounds of the invention
  • More than 20 heads of peach aphid were released from the release port, and each arm was passed through a humid air of activated carbon and distilled water at 0.2 L/min through an air pump.
  • the humid air introduced by the test arm first passed through 5 ⁇ g of the sample source, and the other arm was used as a control arm, and the introduced humid air was passed through the solvent.
  • the number of aphids on each arm when the sample was introduced for 15 min was recorded.
  • the olfactometer and the skin tube were washed with absolute ethanol, the filter paper was replaced, and the two arms were used, and each sample was repeated four times.
  • the treatment group or the control group was counted 2 cm beyond the center of the olfactometer, and the aphids that had not crossed were recorded as the unreacted group.
  • Repellent rate (control group number - treatment group number) / (control group number + treatment group number) * 100
  • the compounds of the present invention have repellent activity against Myzus persicae at low concentrations, among which compounds I-2, I6, I-8, I-9, I-10, I-14, I-17, I-18 And I-25 inhibited the repellent rate of Myzus persicae at a dose of 5 ⁇ g above 60%, and Compounds I-2, I-6, I-8, I-9, I-10, I-14, I
  • the stability of -17, I-18 and I-25 is higher than that of the lead compound EBF, which is green and environmentally friendly. It has the value of further development as a locust behavior control agent and has a good application prospect.
  • test agent was dissolved in phosphate buffer solution (0.01mol/L) and then formulated into a drug solution containing 10mg/L TMV, with water as the control, the concentration of the drug was 100mg/L. .
  • concentration of the drug was 100mg/L.
  • the leaves were inoculated into 5-8 leaf-necked tobacco leaves, and each treatment was repeated 3 times. After culturing for 3 to 4 days in a greenhouse at 24 ° C and 60% relative humidity, the number of leaf spots was counted and the control effect was calculated.
  • Therapeutic effect against tobacco mosaic virus activity Tobacco seedlings of 5-8 leaf stage were selected, the inoculation concentration was 10 mg/L TMV, and after 5 hours, 5 mL of stem and leaf spray was applied per treatment (concentration was 100 mg/L), and 3 replicates were set. After culturing for 3 to 4 days in a greenhouse at 24 ° C and a relative humidity of 60%, the number of leaf spots was counted and the control effect was calculated.
  • Control effect (number of leaves in the control group - number of leaves in the treated group) / (number of dead leaves in the control group) * 100
  • the compounds of the present invention also have certain anti-pathogenic activities against tobacco mosaic virus, among which compounds I-7, I-9, I-11, I-13, I-14, I-18, I-19 I-21, I-23, I-25, I-37, I-38, I-39 and I-40 have anti-tobacco mosaic virus activity at a concentration of 100 mg/L, and their protection and treatment
  • the activity and in vitro passivation activity are all above 30%, and it has the value of being developed as a plant antiviral agent, which is economical, efficient and environmentally friendly, and has a good application prospect.
  • Example 7 bactericidal activity of the compound of the present invention
  • the bactericidal activity of the target compound was determined by the mycel growth rate method.
  • the tested strains were wheat scab, rice sheath blight, cucumber gray mold, tomato early blight, tobacco brown spot and cucumber anthracnose.
  • the target compound 50 mg was weighed separately, and then the sample was dissolved in dimethyl sulfoxide, and the solution was adjusted to a concentration of 5000 mg/L for use.
  • a drug solution having a concentration of 5000 mg/L was mixed with 98 mL of melted potato dextrose agar (PDA) medium to prepare 100 mL of a toxic medium having a concentration of 50 mg/L.
  • the toxic medium was divided into 4 portions on average and poured into 4 Petri dishes having a diameter of 9 cm to prepare a toxic PDA plate. After the toxic medium in the dish was condensed, the cultured pathogen mushroom having a diameter of 0.5 cm was separately introduced. Incubate in a 25 ° C incubator.
  • the same concentration of polyoxytetracycline B was used as the control agent, dimethyl sulfoxide was used as the solvent control, and sterile water was used as the blank control, and each sample was repeated 4 times.
  • the above operations were all aseptic operations. After the colonies in the blank control were sufficiently grown, the diameters of the colonies of each treatment were measured by the cross method, and the average value was taken.
  • Inhibition rate (control colony diameter - treated colony diameter) / control colony diameter * 100
  • the compound of the invention has certain bactericidal activity, especially the compound having the amide structure (X is N, Y is O) in formula I has obvious bactericidal activity, especially for wheat scab and cucumber gray mold. There is significant inhibitory activity.
  • some compounds of the formula I having an ester group structure (X is O, Y is O) such as I-17 have an effect on the activity of Rhizoctonia solani and I-20 on the activity of Fusarium graminearum (inhibition rate respectively) It is 80% and 86%) and has a value for further development as a fungicide.

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Abstract

本发明公开了一类水杨酸类反-(β)-法尼烯类似物及其制备方法与应用，属于有机化合物合成领域。该化合物是通过原料水杨酸及其类似物、香叶醇、香叶胺或取代香叶胺与有机溶剂混合，缩合反应得到不同取代的水杨酸类反-(β)-法尼烯类似物，通过硅胶柱层析分离纯化，得到式Ｉ所示的化合物。该类化合物制备方法反应温和、操作简便、收率较高、成本较低，且比反-(β)-法尼烯更稳定。式I所示的化合物具有多重生物活性，在高剂量时对蚜虫有较好的杀死活性，低剂量时对蚜虫具有报警驱避活性，同时还具有抗烟草花叶痫毒活性及杀菌活性，在农业生产中可以用于治虫防病，具有较好的应用开发价值。

Description

水杨酸类反-(β)-法尼烯类似物及其应用 技术领域
本发明属于有机化学合成领域，具体涉及水杨酸类反-(β)-法尼烯类似物及其制备方法，以及该类化合物在蚜虫防治、植物抗病及杀菌中的应用。
背景技术
蚜虫报警信息素是蚜虫受到天敌攻击时，腹管分泌出的油状液滴，它能使周围的蚜虫产生报警作用，停止取食，迅速逃离危害现场，从而停止对寄主植物的为害。Bowers及Edwards等1972年首次分离鉴定出蚜虫报警信息素的主要成分为(反)-β-法尼烯((E)-β-farnesene，简称EBF。Francis等研究发现，EBF是蚜虫报警信息素的主要成分，甚至以EBF为唯一成分的有12种蚜虫。研究结果表明，蚜虫报警信息素除了众所周知的报警活性外还有其他多重生物活性，例如EBF可以调控蚜虫后代中有翅蚜与无翅蚜的比例；EBF对某些昆虫具有类似于保幼激素III的功能，影响昆虫的变态发育；EBF在100ng/蚜虫剂量时，对蚜虫有明显的毒杀作用，而且当EBF与商品化药剂吡虫啉混用防治蚜虫时，可以起到增效作用。进一步研究发现，EBF对蚜虫天敌具有利它素作用；EBF还可以诱导食蚜蝇、蚜茧蜂定位并捕食蚜虫，并且调节食蚜蝇的产卵行为。Francis等定量的研究了EBF对蚜虫天敌瓢虫的诱导反应，当EBF用量大于2g时对瓢虫有明显的诱导作用；将EBF合成基因引入到马铃薯作物中可以释放EBF，其驱避蚜虫的效果不是很理想，但其可以有效的吸引蚜虫天敌草蛉。
EBF的结构式如式A所示：从EBF的结构式中不难发现，含有多个双键，尤其是末端存在一对共轭双键，因此EBF在空气中极易被氧化而且易挥发，性质不稳定，限制了EBF在田间的应用。针对这种情况，国内外众多科研工作者对EBF分子进行结构改造修饰，期望发现活性及稳定性兼备的化合物。
Figure PCTCN2016000006-appb-000001
关于EBF的结构改造与修饰，国内外专家分别从降低不饱和度、引入杂原子、提高分子量、左端双键打开等方面入手，得到了一些兼具一定的生物活性和稳定性较好的EBF类似物(Nishino et al.Applied Entomology and Zoology.1976，11(4)，340-343；Bowers et al.Journal of Insect Physiology.1977，23(6)，697-701；Dawson et al.Journal of Chemical  Ecology.1982，8(11)，1377-1388；Gibson et al.Annals of Applied Biology.1984，104(2)，203-209；Briggs et al.Pestic.Sci.1986，17(4)，441-448；李正名等，化学学报，1987，45(11)：1124-1128；张钟宁等，昆虫学报，1988，31(4)：435-438)。近年来，在(反)-β-法尼烯结构中引入含氮杂环，如咪唑烷、噁二嗪环、吡唑环及其他含氮杂环等，合成得到的部分化合物对蚜虫具有较好的抑制活性，为潜在的新型蚜虫控制剂的开发和应用提供了良好的理论和应用依据。(杨新玲等，高等学校化学学报，2004，25(9)：1657-1661；有机化学，2008，28(4)：617-621；中国发明专利：CN200310113701.8，CN200410098491.4，CN200710121334，CN201010564801.2，CN201110084058.5)。
植物体内水杨酸水平与植物抗病性的产生密切相关，水杨酸是重要的能够激活植物过敏反应和系统获得抗性的內源信号分子，水杨酸可以诱导植物相关抗病基因和蛋白的产生，使植物获得系统抗病性，如能诱导烟草和黄瓜等植物对细菌、真菌、病毒等多种病害的抗病性(Malamy，J.et al.Science.1990，250(4983)：1002-1004；原永兵等，植物学通报，1994，11(3)：1-9；A.Corina Vlot et al.Annual Review of Phytopathology.2009，47：177-206；Milwaukee et al.Nature.2012，486：198-199)。水杨酸类似物在医药领域及防腐抗菌方向亦有较为深入的研究(Alib et al.J.Pharmacol Exp Ther，1983，226(2)：589-594)。
本发明采用活性亚结构拼接的方法，将具有植物抗病诱导活性、及抗菌活性的水杨酸类活性基团引入到(反)-β-法尼烯中，替代(反)-β-法尼烯结构中的共轭双键以提高其稳定性和拓宽其作用谱，发明了一类含水杨酸类(反)-β-法尼烯类似物。
发明内容
本发明的目的之一是提供一类水杨酸类反-β-法尼烯类似物。
本发明的目的之二是提供一类水杨酸类反-β-法尼烯类似物的制备方法。
本发明的目的之三是提供一类水杨酸类反-β-法尼烯类似物作为新型蚜虫控制剂的应用。
本发明的目的之四是提供一类水杨酸类反-β-法尼烯类似物作为植物抗病毒剂及杀菌剂的应用。
本发明的目的之五是提供一类水杨酸类反-β-法尼烯类似物作为兼具防虫治病药物的应用。
一类水杨酸类反-β-法尼烯类似物，其特征在于，所述化合物的结构通式(式I)为：
Figure PCTCN2016000006-appb-000002
其中R1为H、C1～C10烷基、卤代烷基、苯基(含卤素、硝基、C1～10烷基及烷氧基取代的苯基)、苄基(含卤素、硝基、C1～10烷基及烷氧基取代的苄基)，卤素、硝基、C1～10烷基及烷氧基取代的苯基、噻唑、吡啶；R2为H、OH、C1～C10烷基、C1～C10烷氧基、卤代烷基、卤素、硝基、三氟甲基；R3为H、C1～C10烷基、卤素、硝基、C1～10烷基及烷氧基取代的苯基；X为O、N；Y为O、S。
优选的，R1为H、甲基、乙基、苯基、苄基；R2为H、OH、甲基、甲氧基、Cl、F、CF3、NO2；R3为H、CH3；X为O、N；Y为O。
水杨酸类反-(β)-法尼烯类似物的制备方法包括以下步骤：
在脱水剂和缩合剂或缚酸剂存在下，在有机溶剂中由香叶醇、香叶胺或取代香叶胺与结构式II所示的化合物在催化剂的作用下，进行缩合反应，得到式I所示的化合物：
Figure PCTCN2016000006-appb-000003
其中R1为H、C1-C10烷基、卤代烷基、苯基(含卤素、硝基、C1-10烷基及烷氧基取代的苯基)、苄基(含卤素、硝基、C1-10烷基及烷氧基取代的苄基)，卤素、硝基、C1-10烷基及烷氧基取代的噻唑、吡啶；R2为H、OH、C1-C10烷基、C1-C10烷氧基、卤代烷基、卤素、硝基、三氟甲基；R3为H、C1-C10烷基、卤素、硝基、C1-10烷基及烷氧基取代的苯基：Y为O、S。
本发明所提供的化合物按照以下步骤进行制备：
当R1是H、C1-C10烷基、卤代烷基、苯基(含卤素、硝基、C1-10烷基及烷氧基取代的苯基)时，式I化合物合成包括以下步骤：将水杨酸与有机溶剂混合，然后依次逐渐加入脱水剂和缩合剂或缚酸剂，与香叶醇或香叶胺或取代香叶胺、催化剂及有机溶剂混合，进行缩合反应，减压脱去溶剂，硅胶柱层析分离，得到式I所示的化合物。
当R1是苄基(含卤素、硝基、C1-10烷基及烷氧基取代的苄基)、卤素、硝基、C1-10烷基及烷氧基取代的噻唑、吡啶时，式I化合物合成包括以下步骤：将水杨酸与有机溶剂混合， 加入苄溴或卤代芳烃，在相转移催化剂作用下得到关键中间体取代水杨酸，然后依次加入脱水剂和缩合剂或缚酸剂，再与香叶醇或香叶胺或取代香叶胺、催化剂及有机溶剂混合，进行缩合反应，减压脱去溶剂，硅胶柱层析分离，得到式I所示的化合物。
反应方程式如下：
Figure PCTCN2016000006-appb-000004
水杨酸类反-(β)-法尼烯类似物的制备过程中，所述反应温度范围较宽，为-50℃～200℃，优选反应温度为20℃～50℃。
所用的有机溶剂包括甲醇、乙醇、正丙醇、异丙醇、苯、甲苯、二甲苯、乙腈、丙腈、丁腈、丙酮、丁酮、甲基异丁酮、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基-甲酰苯胺、N-甲基吡咯烷酮、六甲基磷酰三胺、二甲亚砜、石油醚、乙酸甲酯、乙酸乙酯、乙醚、二异丙醚、乙二醇单甲醚、乙二醇单乙醚、二乙二醇单甲醚、二乙二醇单乙醚、乙二醇二甲醚、二氯甲烷、氯仿、四氯化碳、己烷、环己烷、四氢呋喃中的至少一种或一种以上任意组合。
所述的脱水剂选自二环己基碳二亚胺、N，N-二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺一种或一种以上任意组合；缩合剂为N，N′-羰基二咪唑；催化剂为4-二甲氨基吡啶，缚酸剂为有机碱或无机碱，优选为哌啶、氢氧化钠、碳酸钾、吡啶、三乙胺、4-二甲氨基吡啶、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、甲醇钠和氢化钠一种或一种以上任意组合。
所述的相转移催化剂为聚醚类：链状聚乙二醇、链状聚乙二醇二烷基醚，环状冠醚类：18冠6、15冠，环糊精，季铵盐：苄基三乙基氯化铵(TEBA)、四丁基溴化铵、四丁基氯化铵、四丁基硫酸氢铵(TBAB)、三辛基甲基氯化铵、十二烷基三甲基氯化铵、十四烷基三甲基氯化铵等，叔胺类：R4N X、吡啶、三丁胺等，季铵碱，季膦盐等中的一种或一种以上任意组合。
所述方法中，通过柱层析纯化得到反应产物。
水杨酸类反-(β)-法尼烯类似物为活性成分的药物也为本发明保护范围。
本发明水杨酸类反-(β)-法尼烯类似物，经试验证实有明显的化学杀蚜作用及驱避活性，即对蚜虫有直接的化学防治效果，还具有调控蚜虫行为的活性，可作为蚜虫控制剂，用 于防治农作物、果树、中草药及花卉害虫，优选用于防治蚜虫；
本发明水杨酸类反-(β)-法尼烯类似物，经试验证实对烟草花叶病毒及多种病原菌具有抑制活性，其中病原菌为赤霉病菌、纹枯病菌、早疫病菌、赤星病菌或炭疽病菌，故也可以作为植物抗病杀菌剂在农业上应用。
本发明的有益效果：本发明合成的水杨酸类反-(β)-法尼烯类似物，制备方法简便易行，操作简单，产物纯化容易，成本较低，且较先导反-(β)-法尼烯分子量大，稳定性提高；所发明的化合物具有多重生物活性，不仅对农业害虫蚜虫具有明显的杀死作用及驱避活性，而且还具有植物抗病毒活性及杀菌活性，可以作为绿色农药用于农业防虫治病中。
具体实施方式
本发明以下面几个下实施例作进一步说明，但本发明并不仅限于这些实施例，下述实施例中的方法，如无特别说明，均为常规方法。
实施例1：3-甲氧基水杨酸-(E)-3，7-二甲基-2，6-辛二烯酯(1-10)的制备
在100ml三口瓶中，加入2.18g 3-甲氧基水杨酸、3.20g DCC和1.74g DMAP和20mL THF，滴加2.00g香叶醇，20℃反应3小时。用水萃取三次，取有机相，减压脱去溶剂，硅胶柱层析分离(洗脱液为石油醚∶乙酸乙酯V∶V＝500∶1)，得黄色液体3-甲氧基水杨酸-(E)-3，7-二甲基-2，6-辛二烯酯(I-10)，收率53.8％。1H NMR：11.10(s，1H，ArOH)，7.26-7.47(m，1H，ArH)，7.02-7.09(m，1H，ArH)，6.81(t，1H，J＝8.07Hz，ArH)，5.43-5.48(m，1H，＝CH)，5.08-5.10(m，1H，＝CH)，4.87(d，2H，J＝7.14Hz，CH2)，3.90(s，3H，ArOCH3)，2.10-2.14(m，4H，CH2CH2)，1.80(s，3H，CH3)，1.75(s，3H，CH3)，1.60(s，3H，CH3)。
同法制得编号分别为I-2～I-4、I-12～I-14、I-18～I-25及I-27～I-38的目标化合物。
实施例2：3-羟基水杨酸-(E)-3，7-二甲基-2，6-辛二烯酯(I-5)的制备
步骤1：3-羟基水杨酸乙腈酯(中间体1)的制备
在100ml三口瓶中，加入0.50g 3-羟基水杨酸、0.29g氯乙腈、0.49g三乙胺和20mL丙酮，回流反应6小时。分别用CH2Cl2和水萃取三次，取有机相，减压脱去溶剂，硅胶柱层析分离，得黄色油状液体3-羟基水杨酸乙腈酯，收率75％。
步骤2：3-羟基水杨酸-(E)-3，7-二甲基-2，6-辛二烯酯(I-5)的制备
在100ml三口瓶中，加入2.00g 3-羟基水杨酸乙腈酯、2.19g碳酸钾、1.80g香叶醇和40mL N，N-二甲基甲酰胺，90℃反应6小时。水萃取，减压脱去溶剂，硅胶柱层析分离(洗脱液为石油醚∶乙酸乙酯V∶V＝500∶1)，得黄色液体3-羟基水杨酸-(E)-3，7-二甲基-2，6-辛二烯酯(I-5)，收率24.1％。1H NMR：7.37-7.40(m，1H，ArH)，7.08-7.71(m，1H，ArH)， 6.78(t，1H，J＝8.01Hz，ArH)，5.88-5.90(m，1H，＝CH)，5.43-5.48(m，1H，＝CH)，5.08(d，2H，J＝6.21Hz，CH2)，2.06-2.22(m，4H，CH2CH2)，1.77(s，3H，CH3)，1.67(s，3H，CH3)，1.60(s，3H，CH3)。
同法制得编号分别为I-1、I-6及I-26的目标化合物。
实施例3：3-甲基-2-苄氧基-水杨酸-(E)-3，7-二甲基-2，6-辛二烯酯(I-7)的制备
步骤1：3-甲基-2-苄氧基水杨酸苄酯(中间体2)的制备
在100ml三口瓶中，加入2.00g 3-甲基水杨酸、6.75g溴化苄、1.59g三NaOH、0.68gTBAB和15mL CH2Cl2、15mL水，室温反应4小时。水洗三次，取有机相，减压脱去溶剂，硅胶柱层析分离，得浅黄色液体3-甲基-2-苄氧基水杨酸苄酯，收率97％。
步骤2：3-甲基-2-苄氧基水杨酸(中间体3)的制备
在100ml三口瓶中，加入3.18g 3-甲基-2-苄氧基水杨酸苄酯、1.10g NaOH、和35mL乙醇，回流反应4小时。减压脱去溶剂，稀盐酸酸化，得白色固体３-甲基-2-苄氧基水杨酸，收率98％。
步骤3：3-甲基-2-苄氧基-水杨酸-(E)-3，7-二甲基-2，6-辛二烯酯(I-7)的制备
在100ml三口瓶中，加入1.60g 3-甲基-2-苄氧基水杨酸、1.53g DCC和0.83g DMAP和20mL THF，滴加0.95g香叶醇，20℃反应3小时。用水萃取三次，取有机相，减压脱去溶剂，硅胶柱层析分离(洗脱液为石油醚∶乙酸乙酯V∶V＝50∶1)，得淡黄色液体3-甲氧基水杨酸-(E)-3，7-二甲基-2，6-辛二烯酯(I-7)，收率41.7％。1H NMR：7.66-7.69(m，1H，ArH)，7.47-7.50(m，2H，ArH)，7.33-7.41(m，4H，ArH)，7.07(t，1H，J＝15.31Hz，ArH)，5.39-5.44(m，1H，＝CH)，5.07-5.09(m，1H，＝CH)，4.96(s，2H，CH2)，4.81(d，2H，J＝7.12Hz，CH2)，2.31(s，3H，ArCH3)，2.02-2.09(m，4H，CH2CH2)，1.70(s，3H，CH3)，1.64(s，3H，CH3)，1.59(s，3H，CH3)
同法制得编号分别为I-8～I-9、I-11、I-15～I-17及I-39～I-42的目标化合物。
下面表1列出了目标化合物的结构及基本理化数据，它们均是按照类似于前述实施例中所示的各种方法制备的。
Figure PCTCN2016000006-appb-000005
表1目标化合物(式I)的物化数据
Figure PCTCN2016000006-appb-000006
Figure PCTCN2016000006-appb-000007
实施例4：本发明化合物高浓度下对蚜虫的杀虫活性
将目标化合物用万分之一天平于20ml称量瓶称取50mg化合物样品，导入10mL容量瓶配成5000mg/L的测定液。再用1-5ml移液枪取1ml丙酮加入称量瓶，加入9ml含有0.1％曲拉通X-100的水溶液，充分混匀，得500mg/L的测定液。将室内培育未接触过任何药剂和昆虫的大豆叶片，用直径15mm的打孔器打出适合大小的叶片，分别浸入稀释好的药液中15秒，取出晾干，放入生测板中，叶背面朝上，底部加入1％的琼脂保湿，每孔接入大豆蚜20头，每个重复3次。48小时后检查结果。死亡判断标准为：轻触虫体，不能正常爬行个体视为死亡。
计算校正死亡率，公式如下所示：
校正死亡率(％)＝(样品死亡率-空白对照死亡率)/(1-空白对照死亡率)*100
杀蚜活性测试结果见表2
表2式I部分目标化合物对豆蚜的杀虫活性(浓度500mg/L)
Figure PCTCN2016000006-appb-000008
表2结果表明，本发明的化合物在高浓度下对蚜虫具有杀死活性，其中化合物1-10、1-14、I-15、I-16、I-17、I-18、I-19和I-25在500mg/L的剂量下对蚜虫的抑制死亡率均在80％以上，具有作为蚜虫防治剂进一步开发的价值。
实施例5：本发明化合物低浓度下对蚜虫的驱避活性
由释放口释放20头以上桃蚜无翅成蚜，每臂经抽气泵以0.2L/min通入经活性炭及蒸馏水的潮湿空气。测试臂导入的潮湿空气先经过5μg样品味源物，另一臂作为对照臂，导入的潮湿空气先经过溶剂。记录导入样品15min时蚜虫在各臂的数目。每重复一次均用无水乙醇清洗嗅觉仪及皮管、更换滤纸片、且对调两臂使用，每个样品实验重复四次。以越过嗅觉仪中心2cm为准计入处理组或对照组，未越过的蚜虫记为未反应组。
计算校正死亡率，公式如下所示：
驱避率＝(对照组虫数-处理组虫数)/(对照组虫数+处理组虫数)*100
桃蚜驱避活性测试结果见表3
表3式I部分目标化合物对桃蚜的驱避活性(5μg)
Figure PCTCN2016000006-appb-000009
结果表明，本发明的化合物在低浓度下对桃蚜具有驱避活性，其中化合物I-2、I6、I-8、I-9、I-10、I-14、I-17、I-18和I-25在5μg的剂量下对桃蚜的抑驱避率均在60％以上，且化合物I-2、I-6、I-8、I-9、I-10、I-14、I-17、I-18和I-25的稳定性高于先导化合物EBF，绿色环保，具有作为蚜虫行为控制剂进一步开发的价值，具有良好应用前景。
实施例6：本发明化合物抗烟草花叶病毒活性
体外钝化作用抗烟草花叶病毒活性：将供试药剂用磷酸缓冲液溶(0.01mol/L)解后配成含10mg/L TMV的药液，以清水为对照，药剂浓度为100mg/L。30min后接种于5～8叶龄烟草叶片，每处理重复3次，于24℃，相对湿度60％的温室中培养3～4d后，统计叶片枯斑数量并计算防效。
保护作用抗烟草花叶病毒活性：选用5～8叶期的烟草苗进行实验，每处理5mL茎叶喷施药剂(浓度为100mg/L)，设置3个重复。施药24h后接种TMV(浓度为10mg/L)，于24℃，相对湿度60％的温室中培养3～4d后，统计叶片枯斑数量并计算防效。
治疗作用抗烟草花叶病毒活性：选用5～8叶期的烟草苗进行，接种浓度为10mg/L TMV，24h后每处理5mL茎叶喷施药剂(浓度为100mg/L)，设置3个重复，于24℃，相对湿度60％的温室中培养3～4d后，统计叶片枯斑数量并计算防效。
防效＝(对照组叶片枯斑数量-处理组叶片枯斑数量)/(对照组叶片枯斑数量)*100
抗烟草花叶病毒活性测试结果见表4
表4式I目标化合物抗烟草花叶病毒活性
Figure PCTCN2016000006-appb-000010
Figure PCTCN2016000006-appb-000011
结果表明，本发明的化合物还对烟草花叶病毒均具有一定的抗病活性，其中化合物I-7、I-9、I-11、I-13、I-14、I-18、I-19、I-21、I-23、I-25、I-37、I-38、I-39和I-40在100mg/L的浓度下，具有抗烟草花叶病毒的活性，其保护作用、治疗作用及体外钝化作用活性均在30％以上，具有作为植物抗病毒剂进行开发的价值，经济高效环保，具有良好的应用前景。
实施例7：本发明化合物杀菌活性
对目标化合物采用菌丝生长速率法进行杀菌活性测定。
供试菌种为小麦赤霉病菌、水稻纹枯病菌、黄瓜灰霉病菌、蕃茄早疫病菌、烟草赤星病菌和黄瓜炭疽病菌等。
分别称取50mg目标化合物，然后将样品溶于二甲亚砜，分别定容成浓度为5000mg/L的药液备用。
取2mL浓度为5000mg/L的药液与98mL融化的马铃薯葡萄糖琼脂(PDA)培养基混匀，制备成浓度为50mg/L含毒培养基100mL。将含毒培养基平均分成4份，分别倒入4个直径为9cm的培养皿中，制成含毒PDA平板。待皿中含毒培养基冷凝后，分别接入培养好的直径为0.5cm的病原菌菌饼。置于25℃培养箱中培养。以相同浓度的多氧霉素B为对照药剂，二甲亚砜为溶剂对照，同时设无菌水为空白对照，每个样品4次重复，以上操作均为无菌操作。待空白对照中的菌落充分生长后，以十字交叉法测量各处理的菌落直径，取其平均值。
以校正后的空白对照和处理的菌落平均直径计算
抑制率＝(对照菌落直径-处理菌落直径)/对照菌落直径*100
杀菌活性测试结果见表5
表5式I目标化合物杀菌活性
Figure PCTCN2016000006-appb-000012
Figure PCTCN2016000006-appb-000013
Figure PCTCN2016000006-appb-000014
结果表明，本发明的化合物具有一定的杀菌活性，尤其是式I中含酰胺结构(X为N，Y为O)的化合物整体杀菌活性较为明显，特别是对小麦赤霉病菌、黄瓜灰霉病菌有明显的抑制活性。此外，式I中含酯基结构(X为O，Y为O)的部分化合物如I-17对水稻纹枯病菌的活性及I-20对小麦赤霉病菌的活性表现突出(抑制率分别为80％和86％)，具有作为杀菌剂进一步开发的价值。

Claims (15)

  1. 水杨酸类反-(β)-法尼烯类似物，其特征在于，所述类似物的结构式为式I所示：
    Figure PCTCN2016000006-appb-100001
    其中R1为H、C1-C10烷基、卤代烷基、苯基(含卤素、硝基、C1-10烷基及烷氧基取代的苯基)、苄基(含卤素、硝基、C1-10烷基及烷氧基取代的苄基)，卤素、硝基、C1-10烷基及烷氧基取代的噻唑、吡啶；
    R2为H、OH、C1-C10烷基、C1-C10烷氧基、卤代烷基、卤素、硝基、三氟甲基；
    R3为H、C1-C10烷基、卤素、硝基、C1-10烷基及烷氧基取代的苯基；
    X为O、N；
    Y为O、S。
  2. 根据权利要求1所述的水杨酸类反-(β)-法尼烯类似物，其特征在于，R1为H、甲基、乙基、苯基、苄基；R2为H、OH、甲基、甲氧基、Cl、F、CF3、NO2；R3为H、CH3；X为O、N；Y为O。
  3. 根据权利要求1所述的水杨酸类反-(β)-法尼烯类似物的制备方法，其特征在于，制备方法包括以下步骤：
    在脱水剂和缩合剂或缚酸剂存在下，在有机溶剂中由香叶醇、香叶胺或取代香叶胺与结构式II所示的化合物在催化剂的作用下，进行缩合反应，得到式I所示的化合物：
    Figure PCTCN2016000006-appb-100002
    其中R1为H、C1-C10烷基、卤代烷基、苯基(含卤素、硝基、C1-10烷基及烷氧基取代的苯基)、苄基(含卤素、硝基、C1-10烷基及烷氧基取代的苄基)，卤素、硝基、C1-10烷基及烷氧基取代的噻唑、吡啶；R2为H、OH、C1-C10烷基、C1-C10烷氧基、卤代烷基、卤素、硝基、三氟甲基；R3为H、C1-C10烷基、卤素、硝基、C1-10烷基及烷氧基取代的苯基；Y为O、S。
  4. 根据权利要求3所述的水杨酸类反-(β)-法尼烯类似物的制备方法，其特征在于，当R1是H、C1-C10烷基、卤代烷基、苯基(含卤素、硝基、C1-10烷基及烷氧基取代的苯基) 时，式I化合物合成包括以下步骤：将水杨酸与有机溶剂混合，然后依次逐渐加入脱水剂和缩合剂或缚酸剂，与香叶醇或香叶胺或取代香叶胺、催化剂及有机溶剂混合，进行缩合反应，减压脱去溶剂，硅胶柱层析分离，得到式I所示的化合物。
  5. 根据权利要求3所述的水杨酸类反-(β)-法尼烯类似物的制备方法，其特征在于，当R1是苄基(含卤素、硝基、C1-10烷基及烷氧基取代的苄基)、卤素、硝基、C1-10烷基及烷氧基取代的噻唑、吡啶时，式I化合物合成包括以下步骤：将水杨酸与有机溶剂混合，加入苄溴或卤代芳烃，在相转移催化剂作用下得到关键中间体取代水杨酸，然后依次加入脱水剂和缩合剂或缚酸剂，再与香叶醇或香叶胺或取代香叶胺、催化剂及有机溶剂混合，进行缩合反应，减压脱去溶剂，硅胶柱层析分离，得到式I所示的化合物。
  6. 根据权利要求3-5任一所述的水杨酸类反-(β)-法尼烯类似物的制备方法，其特征在于，所述反应温度为-50℃～200℃。
  7. 根据权利要求3-5任一所述的水杨酸类反-(β)-法尼烯类似物的制备方法，其特征在于，所述反应温度为20℃～50℃。
  8. 根据权利要求3-5中任一所述的水杨酸类反-(β)-法尼烯类似物的制备方法，其特征在于：所用的有机溶剂包括甲醇、乙醇、正丙醇、异丙醇、苯、甲苯、二甲苯、乙腈、丙腈、丁腈、丙酮、丁酮、甲基异丁酮、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基-甲酰苯胺、N-甲基吡咯烷酮、六甲基磷酰三胺、二甲亚砜、石油醚、乙酸甲酯、乙酸乙酯、乙醚、二异丙醚、乙二醇单甲醚、乙二醇单乙醚、二乙二醇单甲醚、二乙二醇单乙醚、乙二醇二甲醚、二氯甲烷、氯仿、四氯化碳、己烷、环己烷、四氢呋喃中的至少一种或一种以上任意组合。
  9. 根据权利要求3-5任一所述的水杨酸类反-(β)-法尼烯类似物的制备方法，其特征在于：所述的脱水剂为二环己基碳二亚胺、N，N-二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺一种或一种以上任意组合；缩合剂为N，N′-羰基二咪唑；催化剂为4-二甲氨基吡啶；缚酸剂为有机碱或无机碱，优选为哌啶、氢氧化钠、碳酸钾、吡啶、三乙胺、4-二甲氨基吡啶、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、甲醇钠、氢化钠一种或一种以上任意组合。
  10. 根据权利要求5所述的水杨酸类反-(β)-法尼烯类似物的制备方法，其特征在于：所述的相转移催化剂为聚醚类：链状聚乙二醇、链状聚乙二醇二烷基醚，环状冠醚类：18冠6、15冠，环糊精；季铵盐；苄基三乙基氯化铵(TEBA)、四丁基溴化铵、四丁基氯化铵、四丁基硫酸氢铵(TBAB)、三辛基甲基氯化铵、十二烷基三甲基氯化铵、十四烷基三甲基氯化铵；叔胺类：R4N X、吡啶、三丁胺等，季铵碱，季膦盐中的一种或一种以上任意组合。
  11. 根据权利要求1所述的水杨酸类反-(β)-法尼烯类似物为活性成分的药物。
  12. 根据权利要求1所述的水杨酸类反-(β)-法尼烯类似物在农作物、果树、中草药及花卉害虫防治中的应用，其中所述害虫为蚜虫。
  13. 根据权利要求1所述的水杨酸类反-(β)-法尼烯类似物在农作物病害和烟草花叶病毒(TMV)防治中的用途。
  14. 根据权利要求13所述的用途，其特征在于，所述农作物病害为赤霉病菌、纹枯病菌、早疫病菌、赤星病菌或炭疽病菌。
  15. 根据权利要求1所述的水杨酸类反-(β)-法尼烯类似物同时在害虫和农作物病害防治方面的应用。
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