WO2011069456A1 - 双联和氧桥杂环新烟碱化合物及其制备方法 - Google Patents

双联和氧桥杂环新烟碱化合物及其制备方法 Download PDF

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Publication number
WO2011069456A1
WO2011069456A1 PCT/CN2010/079591 CN2010079591W WO2011069456A1 WO 2011069456 A1 WO2011069456 A1 WO 2011069456A1 CN 2010079591 W CN2010079591 W CN 2010079591W WO 2011069456 A1 WO2011069456 A1 WO 2011069456A1
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compound
group
formula
carbonyl
hours
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PCT/CN2010/079591
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English (en)
French (fr)
Inventor
钱旭红
李忠
邵旭升
徐晓勇
须志平
宋恭华
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华东理工大学
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Priority to EP10835491.1A priority Critical patent/EP2511279B1/en
Application filed by 华东理工大学 filed Critical 华东理工大学
Priority to BR112012013846A priority patent/BR112012013846A2/pt
Priority to MX2012006663A priority patent/MX2012006663A/es
Priority to CA2783504A priority patent/CA2783504C/en
Priority to AU2010330474A priority patent/AU2010330474B2/en
Priority to US13/514,460 priority patent/US8809319B2/en
Priority to RU2012127868/04A priority patent/RU2531920C2/ru
Priority to KR1020127017848A priority patent/KR101504575B1/ko
Priority to JP2012542350A priority patent/JP5600750B2/ja
Priority to UAA201208318A priority patent/UA106256C2/ru
Publication of WO2011069456A1 publication Critical patent/WO2011069456A1/zh
Priority to IL220237A priority patent/IL220237A/en
Priority to ZA2012/05074A priority patent/ZA201205074B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/86—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • Double and oxygen bridge heterocyclic neonicotinoid compound and preparation method thereof Double and oxygen bridge heterocyclic neonicotinoid compound and preparation method thereof
  • the invention relates to a novel neonicotinoid insecticide, a preparation method and application thereof.
  • the present invention relates to a bi- and oxygen-bridged heterocyclic neonicotinoid compound constructed from an imidacloprid nitromethylene analog and a dialdehyde, and a process for the preparation thereof.
  • the neonicotinoid insecticide represented by imidacloprid has high insecticidal activity, wide insecticidal spectrum, low toxicity to mammals and aquatic animals, good systemic property and appropriate field stability and environmental friendliness. An important hot spot for the creation of new pesticides. Later, a series of nicotinic insecticides such as thiacloprid, clothianidin, thiamethoxam, acetamiprid, nitenpyram, and dinotefuran have been developed (see European patents 247477, 296453, 685477, 235725, 235725, 3 15826, 192060, 244777, 0386565, 580553, and 1031566, Japanese Patent Nos. 62292965, 8259568, 8291171, and 7242633).
  • the present invention provides a new and more effective insecticide, solves the problem of resistance of neonicotinoid insecticides, expands the insecticidal spectrum, and solves the problems in the prior art.
  • Another object of the invention is to provide protection for growing and harvested crops from insect attack and infestation.
  • the invention provides an oxygen bridged heterocyclic neonicotinoid compound selected from the group consisting of a compound having the structure of formula (A) or (; B), or an optical isomer or agrochemically acceptable compound of said compound Accepted salt -
  • an oxygen bridged heterocyclic neonicotinoid compound selected from the group consisting of a compound having the structure of formula (A) or (; B), or an optical isomer or agrochemically acceptable compound of said compound Accepted salt -
  • A oxygen bridged heterocyclic neonicotinoid compound
  • B an optical isomer or agrochemically acceptable compound of said compound Accepted salt -
  • ⁇ is a five- or six-membered heterocyclic group containing nitrogen, oxygen and/or sulfur, a halogenated five- or six-membered heterocyclic group containing nitrogen, oxygen and/or sulfur, or a substituted or unsubstituted phenyl group, Wherein the substituent is one or more selected from the group consisting of halogen, CM halogenated fluorenyl or chloroalkoxy;
  • R 3 are each independently H, d- 6 alkyl with, allyl, benzyl, d- 4 -d- 4 alkoxyalkyl group, alkoxy embankment - carbonyl, phenoxycarbonyl, C 2 - 6 alkynyl yl - carbonyl group, C 2 - 3 alkenyl - carbonyl group, C 3 - 6 cycloalkyl - carbonyl, benzoyl, or substituted with one or more substituents selected from a halogen atom, 4 alkyl, halo alkyl with D- 4, a benzoyl group substituted with a d- 4 methoxy group and a CM fluorenyl-carbonyl substituent, a furanylcarbonyl group or an N,N-dimethylcarbonyl group, or R 3 and a combination of -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - or -CH 2 -
  • R is a substituent on a hetero atom selected from H, d- 6 alkyl, allyl, benzyl, phenyl, d- 4 methoxy-d- 4 alkyl, d- 4 alkoxy-carbonyl, phenoxycarbonyl , C 2 -6 alkynyl-carbonyl, C 2 _ 3 alkenyl-carbonyl, C 3 -6 cycloalkyl-carbonyl, benzoyl, or one or more selected from halogen atoms, C ⁇ halogenated fluorenyl a benzoyl group substituted with a d- 8 saturated or unsaturated fluorenyl group or a substituent of a decyloxy group and a fluorenyl-carbonyl group, a furanylcarbonyl group or a hydrazine, a fluorenyl-dimethylcarbonyl group;
  • Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethanesulfonyl.
  • the oxygen bridge heterocyclic neonicotinoid compound is selected from the group consisting of
  • oxygen bridge heterocyclic neonicotinoid compound is selected from the group consisting of
  • the oxygen bridge heterocyclic neonicotinoid compound is an antagonist of an insect nicotinic acetylcholine receptor.
  • the oxygen bridged heterocyclic neonicotinoid compounds (la) and (lb) are 2 to 30 times more active against imidacloprid resistant brown planthopper and whitefly.
  • the present invention provides an agricultural composition comprising -
  • the invention relates to the use of the agricultural composition for killing or preventing agricultural pests, Pests and pests that are harmful to animal health; or insecticide compositions used to kill or prevent agricultural pests, sanitary pests, and animal health hazards.
  • the invention provides a pesticidal and/or pest control method comprising applying the above agricultural composition to a plant body that is or may be subject to pests, soil surrounding it, or the environment.
  • the present invention relates to the use of the above compounds, their optical isomers or agrochemically acceptable salts, or a combination thereof, in the preparation of a pesticide composition.
  • the present invention provides a process for the preparation of the above compound, its optical isomer or agrochemically acceptable salt, the method comprising the steps of:
  • the compound of formula (a) is reacted with a compound of formula (a) or (c) in the presence of a catalytic acid at room temperature to produce a compound of formula (A) (B),
  • R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and Y are as defined above.
  • the method comprises the steps of: - in acetonitrile, in the presence of a catalytic amount of an acid, at room temperature, at a temperature of from 2 to 24 hours to obtain a compound of formula (la):
  • the inventors of the present invention have studied the imidacloprid nitromethylene structure of the existing imidacloprid nitromethylene-based neonicotinoid insecticide through the dialdehyde and the imidacloprid nitromethylene compound through long-term and in-depth research.
  • a novel neonicotinoid compound was synthesized, which showed a marked increase in insecticidal activity and an expanded insecticidal spectrum.
  • the inventors have completed the present invention.
  • mercapto refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. , tert-butyl, or the like.
  • d- 4 methoxy refers to a straight or branched alkoxy group having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutylene.
  • halogen means fluoro, chloro, bromo, or iodo.
  • halogenated refers to a group substituted with one or more of the above halogen atoms, which may be the same or different, such as a trifluoromethyl group, a pentafluoroethyl group, or the like.
  • five- or six-membered heterocyclic group refers to a five- or six-membered ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur, such as pyridyl, thiazolyl, pyrimidinyl, tetrahydrofuranyl, or Azolyl and the like.
  • the compounds of the invention can be synthesized by the reaction steps described above.
  • the compound of formula (Id) (ld)
  • the synthesis of the compound of formula (2a) is as follows:
  • the compounds of formula (2a)-(2e) can be prepared by the following reaction:
  • active substance of the invention or “active compound of the invention” means a compound of the invention, an optical isomer or a pesticidally acceptable salt thereof, which has significantly enhanced insecticidal activity, and an expanded insecticidal activity. Spectrum.
  • a pesticidally acceptable salt means that the anion of the salt is known and acceptable in forming the pharmaceutically acceptable salt of the pesticide.
  • the salt is preferably water soluble.
  • Suitable acid addition salts formed from the compounds of the formulae (A) and (B) include salts formed with inorganic acids, such as hydrochlorides, phosphates, sulfates, nitrates; and salts formed from organic acids, such as Acetate, benzoate.
  • the active material of the present invention can be used for controlling and eliminating a wide range of agricultural and forestry plant pests, storing cereal pests, public health pests, and pests that are harmful to animal health.
  • insecticide is a general term for substances having the action of controlling all the pests mentioned above. Examples of pests include, but are not limited to, Coleoptera: Sitophilus zeamais, ⁇ (2 0 //iTM castaneum), potato ticket melon
  • Pests that are harmful to animal health include BoopMus micmphis, long-horned blood clams
  • Hyalomama anatolicum cowhide! fe ⁇ ( Hypo derma spp. ), Fasciola hepatica, Moniezia blanchard, Oster nematode (Ostertagia spp.), Trypanosoma enansi, Babesia bigemina, etc.
  • the compound of the invention has special effects especially for sucking and sucking mouthparts pests, such as aphids, leafhoppers, planthoppers, thrips, whiteflies and the like.
  • Insecticide composition containing the active substance of the present invention is aphids, leafhoppers, planthoppers, thrips, whiteflies and the like.
  • the active substance of the present invention can be prepared into a pesticide composition in a conventional manner.
  • These active compounds can be formulated into conventional preparations such as solutions, emulsions, suspensions, powders, foams, pastes, granules; aerosols, natural and synthetic materials impregnated with active substances, Microcapsules in polymers, coatings for seeds, and preparations for use with combustion devices, such as smoking cartridges, smoked cans and smokers, as well as ULV cold mist and hot fog ( Warm mist) formulation.
  • compositions can be produced by known methods, for example, by mixing the active compound with an extender which is a liquid or liquefied gas or solid diluent or carrier, and optionally a surfactant which is emulsified.
  • an extender which is a liquid or liquefied gas or solid diluent or carrier
  • a surfactant which is emulsified.
  • Agents and/or dispersants and/or foam formers for example, when water is used as an extender, an organic solvent can also be used as an auxiliary.
  • a liquid solvent as a diluent or a carrier, such as: aromatic hydrocarbons such as xylene, toluene or decylnaphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons such as chlorobenzene, vinyl chloride or Dichloromethane; aliphatic hydrocarbons such as cyclohexane or paraffin, such as mineral oil fractions; alcohols such as ethanol or ethylene glycol and their ethers and lipids; ketones such as acetone, methyl ethyl ketone, methyl isobutyl Ketone or cyclohexanone; or less common polar solvents such as dimethylformamide and dimethyl sulfoxide, and water.
  • aromatic hydrocarbons such as xylene, toluene or decylnaphthalene
  • chlorinated aromatic or chlorinated aliphatic hydrocarbons such as chlorobenzene, vinyl chloride or Dichloromethane
  • the diluent or carrier for the liquefied gas refers to a liquid which will become a gas at normal temperature and normal pressure, such as an aerosol propellant such as a halogenated hydrocarbon, and butyl hydrazine, propylene carbonate, nitrogen gas and carbon dioxide.
  • an aerosol propellant such as a halogenated hydrocarbon, and butyl hydrazine, propylene carbonate, nitrogen gas and carbon dioxide.
  • Solid supports can be used as natural minerals on the ground, such as kaolin, clay, talc, quartz, activated clay, montmorillonite, or diatomaceous earth, and ground synthetic minerals such as highly dispersed silicic acid, alumina and silicates.
  • the solid carrier for the granules is a ground and graded natural stone, such as calcite, marble, pumice, sepiolite and dolomite, as well as inorganic and organic coarse powder synthetic particles, and organic materials such as sawdust, coconut shell, Corn cobs and granules of tobacco stems.
  • Nonionic and anionic emulsified columns can be used as emulsifiers and I or foam formers.
  • emulsifiers and I or foam formers polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, such as alkylaryl polyglycol ethers, mercaptosulfonates, alkyl sulfates, arylsulfonates, and white Protein hydrolysate.
  • Dispersing agents include, for example, lignin sulfite waste liquid and methyl cellulose.
  • Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions such as gum arabic, polyvinyl alcohol and polyvinyl acetate may be used in the formulation.
  • Colorants such as inorganic dyes such as iron oxide, oxidized diamonds and Prussian blue; organic dyes such as organic dyes such as azo dyes or metal phthalocyanine dyes; and trace nutrients such as iron, lanthanum, boron, copper may be used. , cobalt, aluminum and zinc salts, etc.
  • the active compounds of the present invention may be present in a commercial preparation or in a dosage form prepared from these preparations in combination with other active compounds, including but not limited to: insecticides, baits, bactericides, Acaricides, killing lines, fungicides, growth control agents, etc.
  • Insecticides include, for example, phosphates, carbamates, pyrethroids, chlorinated hydrocarbons, benzoylureas, nematodes, and microbial-derived substances such as avermectin.
  • the active compounds of the invention may also be formulated as a mixture with synergists in their commercial preparations in the dosage forms prepared from these preparations.
  • Synergists are compounds which increase the action of the active compound. Since the active compound itself is active, it is not necessary to add a synergist.
  • These formulations usually contain from 0.001 to 99.99% by weight, preferably from 0.01 to 99.9% by weight, more preferably from 0.05 to 90% by weight, of the active compound of the invention, of the insecticidal composition.
  • the concentration of the active compound in the dosage form prepared from the commercial preparation can be varied within a wide range.
  • the concentration of active compound in the dosage form used may range from 0.000000 l to 100% (g/v), preferably between 0.0001 and 1%.
  • Example 9 10-(4-Chlorobenzyl)-4-nitro-9-oxa-1 1,12-dihydroimidazo[2,3-albicyclo"3,3,11 ⁇ -3- Alkene (compound 2d)
  • a 25% aqueous solution of glutaraldehyde and a catalytic amount of HC1 were placed in a 50 ml round bottom flask. Stir at room temperature and TLC is followed by reaction. After the completion of the reaction, the solvent was removed, and the residue was purified by column chromatography to yield pale yellow powdery product.
  • Example 1 1 Insecticidal activity test of the compound of the present invention
  • Aphids belong to the homopteran pests and have a sucker, which is a common crop pest.
  • the soybean meal craccivora was used as the test object and tested by the dipping method.
  • Test method Accurately weigh each sample, add DMSO 2 mL and 18 mL water, add three drops of emulsifier 2201 into a liquid, blank with DMSO 2 mL and 18 mL water, add three drops of emulsifier 2201. Soak a certain number of insects to be tested with broad bean leaves in the liquid for 3-5 seconds, remove and dry, transfer the test insects and foodstuffs into a clean container, place in a dry thermostat recovery room, and check the test insects after 24 hours. Poisoning deaths. The results are shown in Table 1 below.
  • Rice brown planthopper is a homopteran pest with a sucker and is a common crop pest.
  • the rice brown planthopper (; N//aparvato / wgew was used as the test object, and the microdropping method reported by Nagata was used.
  • Procedure Select un-matted females with feathering for 2-3 days as test subjects, dilute the compounds to a series of concentrations with acetone, and test the insect paralysis with carbon dioxide, using a manual micro-dropper (Burkard Manufacturing Co. Ltd, Rickmansworth , UK) Drop the drug drop (0.08 L) before the test insect On the chest and back. Approximately 30 adults were treated at each concentration and each treatment was repeated 3 times. Take acetone as a control. The treated adults were housed on soilless cultivated rice seedlings in an incubator (20 x 20 x 10 cm) at a temperature of 25 ⁇ 1 V and 16 (L) / 8 (D) hours. The results were checked after 48 hours and LD 5 was calculated using standard probability analysis. value. The results are shown in Table 2 below.
  • the second instar larvae were tested with the larvae of Pseudaktia separate Walker, and the leaf leaching method was used.
  • the armyworm is an important heterophylla lepidopteran pest. It has a wide application range and is suitable for the determination of virulence, contact and residual effects such as stomach poisoning, contact and residual effects, and insect toxicology. For the screening test of new compounds, the test of the armyworm killing activity was carried out according to the method reported in the literature.
  • Operation process of dip-leaf method Accurately weigh each sample, add DMSO (2 mL) and 18 mL of water separately, then add three drops of emulsifier 2201 (provided by Shanghai Pesticide Factory) to prepare liquid medicine, blank DMSO (2 mL) And 28 mL of clear water, add three drops of emulsifier 2201. Tear fresh corn leaves into small pieces, soak them in the liquid for about 5 seconds, take them out and dry them, put them into a 100 mL jar, and put about 20 second-instar larvae, white gauze for the jar. The rubber band was tightened, and the corn immersed in the liquid was continuously fed, and the mortality of the larva was checked after 5 days.
  • the compound (la) was subjected to electrophysiological experiments and isotopic label substitution experiments, and the compound (la) inhibited the agonist reaction; the compound (la) expressed ⁇ ⁇ to the nicotinic acetylcholine receptor and oocyte of the United States.
  • the 1/1 2 receptor has no agonistic effect; the compound (la) inhibits the agonist acetylcholine response, and these experiments indicate that the compound is an antagonist of nicotinic acetylcholine receptors (nAChRs).
  • Example 13 Preparation of a Pesticide Composition Containing a Compound of the Invention
  • the following components were prepared in proportion: 25% by weight of the compound la-le and 2a-2e; 5% polyoxyethylene sorbitol hexaoleate; 70% higher aliphatic hydrocarbon oil.
  • the components were ground together in a sanding mill until the solid particles fell below about 5 microns.
  • the resulting viscous suspension can be used as it is, but it can also be used after emulsification in water.
  • the following components were prepared in proportion: 25% of the compounds la-le and 2a-2e; 3% hydrate attapulgit; 10% calcium lignosulfonate; 0.5% sodium dihydrogen phosphate; 61.5 %water.
  • the components are ground together in a ball mill until the solid particles fall below about 10 microns. This aqueous suspension can be used directly.

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Description

双联和氧桥杂环新烟碱化合物及其制备方法 技术领域
本发明涉及新型新烟碱类的杀虫剂、及其制备方法和应用。具体而言， 本发明涉 及吡虫啉硝基亚甲基类似物和二醛构建的双联和氧桥杂环新烟碱化合物及其制备方 法。 背景技术
以吡虫啉为代表的新烟碱类杀虫剂因杀虫活性高，杀虫谱广，对哺乳动物和水 生动物毒性低，且有良好的系统物性及适当的田间稳定性和环境友好性，成为新农 药创制的重要热点领域。 后来又相继开发出噻虫啉、 噻虫胺、 噻虫嗪、 啶虫脒、 烯 啶虫胺、 呋虫胺等一系列烟碱类杀虫剂 (参见欧洲专利 247477、 296453、 685477、 235725、 235725、 3 15826、 192060、 244777、 0386565、 580553和 1031566， 日本 专利 62292765、 8259568、 8291171和 7242633)。
但是由于吡虫啉过量频繁使用造成较为严重的抗性问题以及由于结构相似性 带来的新烟碱杀虫剂之间的交互抗性，在一定程度上限制了该类化合物的应用，制 约了此类化合物发展， 同时新烟碱类杀虫剂主要对同翅目和鞘翅目害虫高效，其相 对较窄的杀虫谱也限制了虫害防治方面的用药选择性。
因此， 如何对具有高活性的硝基亚甲基化合物进行结构改造， 以产生新的、 更有效的杀虫剂， 解决新烟碱类杀虫剂的抗性问题， 扩大杀虫谱， 使其应用于杀虫 剂组合物就成为本领域迫切需要解决的技术问题。 发明内容
本发明提供了新的、更有效的杀虫剂， 解决了新烟碱类杀虫剂的抗性问题， 扩大 了杀虫谱， 解决了现有技术中存在的问题。
本发明目的在于， 提供一类高效防治害虫的化合物及其制备方法。
本发明的另一个目的是为生长中的和收获的作物不受昆虫攻击和侵扰而提供 保护。
一方面， 本发明提供了氧桥杂环新烟碱化合物， 该化合物选自具有式 (A)或 (； B) 所示结构的化合物、 或者所述化合物的光学异构体或农药学上可接受的盐-
Figure imgf000004_0001
式中:
！^为含氮、 氧和 /或硫的五元或六元杂环基， 卤代的含氮、 氧和 /或硫的五元或 六元杂环基， 或者取代或未取代的苯基， 其中， 所述取代基为选自下组中的一个或 多个： 卤素， CM卤代垸基或 氯代烷氧基；
R3和 各自独立地为 H， d— 6垸基， 烯丙基， 苄基， d— 4烷氧基 -d— 4烷基， 垸氧基-羰基， 苯氧羰基， C2— 6炔基-羰基， C2— 3烯基-羰基， C3— 6环烷基-羰基， 苯甲酰基， 或者被一个或多个选自卤原子、 4烷基、 d— 4卤代垸基、 d— 4垸氧基 和 CM垸基-羰基的取代基所取代的苯甲酰基， 呋喃羰基或 N，N-二甲基羰基， 或者 R3和 共同构成 -CH2-CH2-， -CH2-CH2-CH2-或 -CH2-XR-CH2-， 式中 X为杂原子，
R为杂原子上的取代基， 选自 H， d_6烷基， 烯丙基， 苄基， 苯基， d_4垸氧基 -d_4 烷基， d_4烷氧基-羰基， 苯氧羰基， C2_6炔基-羰基， C2_3烯基-羰基， C3_6环烷基- 羰基， 苯甲酰基， 或者被一个或多个选自卤原子、 C^卤代垸基、 d_8饱和或不饱 和垸基或垸氧基和 垸基-羰基的取代基所取代的苯甲酰基， 呋喃羰基或 Ν,Ν- 二甲基羰基；
R5， R6， R7， 和 为11， 饱和或不饱和 d_4垸基， 卤素， 饱和或不饱 和垸氧基， 卤代 d_4饱和或不饱和垸氧基， d— 4垸基-羰基， d— 8垸基-酯基， d— 4 垸基 -磺酸酯基， 苯基或苄基；
Y为硝基， 氰基， 三氟甲基， 三氟乙酰基或三氟甲磺酰基。
在一个优选的实施方式中， 所述氧桥杂环新烟碱化合物选自下组：
Figure imgf000004_0002
Figure imgf000005_0001
(lc)， (Id),
Figure imgf000005_0002
(2a)， (2b)，
Figure imgf000005_0003
(2c)， (2d) .
Figure imgf000005_0004
(le)， 以及 (2e)。 在另一个优选的实施方式中， 所述氧桥杂环新烟碱化合物选自下组:
Figure imgf000005_0005
(la), 以及 （lb)。
在另一个优选的实施方式中，所述氧桥杂环新烟碱化合物是昆虫烟碱乙酰胆碱 受体的拮抗剂。
在另一个优选的实施方式中， 所述氧桥杂环新烟碱化合物 (la)和 (lb)对吡虫啉 抗性褐飞虱和烟粉虱的活性是吡虫啉的 2-30倍。
另一方面， 本发明提供了一种农用组合物， 它包含-
(a) 0.001-99.99重量％的上述氧桥杂环新烟碱化合物、 其光学异构体或农药学 上可接受的盐、 或者它们的组合； 以及
(b) 农药学上可接受的载体和 /或赋形剂。
另一方面， 本发明涉及所述农用组合物的用途， 用于杀灭或预防农业害虫、卫 生害虫和危害动物健康的害虫；或用作用于杀灭或预防农业害虫、卫生害虫和危害 动物健康的杀虫剂组合物。
另一方面， 本发明提供了一种杀虫和 /或防虫方法， 所述方法包括将上述农用 组合物施加于遭受或可能遭受虫害的植物体、 其周围的土壤或环境中。
另一方面， 本发明涉及上述化合物、其光学异构体或农药学上可接受的盐、或 它们的组合在制备杀虫剂组合物中的用途。
再一方面，本发明提供了上述化合物、其光学异构体或农药学上可接受的盐的 制备方法， 所述方法包括步骤：
在催化量酸的存在下， 于室温下， 使式 (a)化合物与式 )或 (c)化合物反应， 从 而制得具有式 (A) (B)的化合物，
Figure imgf000006_0001
式中， 、 R3、 、 R5、 R6， R7， R8， R9和 Y如上述定义。
在一个优选的实施方式中， 所述方法包括歩骤- 在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (la)的化合物：
Figure imgf000006_0002
在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (
Figure imgf000006_0003
于室温下， 进行如下反应 2-24小时， 获得式 (lc)的化合物:
Figure imgf000006_0004
在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (Id)的化合物：
Figure imgf000007_0001
在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (2a)的化合物：
Figure imgf000007_0002
在乙腈中， 于催化 的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (2b)的化合物-
Figure imgf000007_0003
(2b ) ； 在乙腈中， 于催化] ：的酸存在下， 于室温下， 进行如下反应 2-24小时， 获得式 (2c)的化合物：
Figure imgf000007_0004
( 2c ) ； 在乙腈中， 于催化量的酸存在下， 于室温下 进行如下反应 2-24小时， 获得式 (2d)的化合物-
Figure imgf000007_0005
获得式 (le)的化合物:
Figure imgf000007_0006
在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (2e)的化合物-
Figure imgf000008_0001
具体实施方式
本发明的发明人通过长期而深入的研究，基于现有的吡虫啉硝基亚甲基类新烟 碱杀虫剂的吡虫啉硝基亚甲基结构， 通过二醛与吡虫啉硝基亚甲基类化合物反应， 合成了一种新型的新烟碱化合物，该化合物的杀虫活性显著提高， 并具有扩大的杀 虫谱。 在此基础上， 发明人完成了本发明。 基团定义
如本文所用， 术语 " 垸基"指具有 1-6个碳原子的直链或支链烷基， 例如 甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 仲丁基、 叔丁基、 或类似基团。
术语 " d_4垸氧基"指具有 1-4个碳原子的直链或支链烷氧基， 例如甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基、 异丁氧基、 仲丁氧基、 叔丁氧基、 或类似基 团。
术语 "卤素"指氟、 氯、 溴、 或碘。 术语 "卤代的"指被相同或不同的一个或 多个上述卤原子取代的基团， 例如三氟甲基、 五氟乙基、 或类似基团。
术语"五元或六元杂环基"指含一个或多个选自氮、氧或硫的杂原子的五元或 六元环， 例如吡啶基、 噻唑基、 嘧啶基、 四氢呋喃基、 或噁唑基等。 本发明化合物的制备方法
本发明化合物可通过上文所描述的反应步骤合成。
在本发明的一个具体实施方式中， 式 (la)化合物的合成方法如下-
Figure imgf000008_0002
在本发明的一个具体实施方式中， 式 (lb)化合物的合成方法如下:
Figure imgf000009_0001
在本发明的一个具体实施方式中， 式 (lc)化合物的合成方法如下:
r.t.
Figure imgf000009_0002
在本发 一个具体实施方式中， 式 (Id)化合物
Figure imgf000009_0003
(ld 在本发明的一个具体实施方式中， 式 (2a)化合物的合成方法如下:
Figure imgf000009_0004
在本发明的一个具体实施方式中， 式 (2b)化合物的合成方法如下:
Figure imgf000009_0005
在本发明的一个具体实施方式中， 式 (2c)化合物的合成方法如下:
Figure imgf000009_0006
(2c)。
一个具体实施方式中， 式 ( 法如下:
Figure imgf000009_0007
(2d)。
在本发明的一个具体实施方式中 式 (le)化合物的合成方法如下:
Figure imgf000009_0008
(le)。
在本发明的一个具体实施方式中 式 (2e)化合物的合成方法如下:
Figure imgf000009_0009
(2e)。
在本发明的一个实施方式中， 式 (la^le)的化合物可通过下列反应制备: 将 2,5-二乙氧基四氢呋喃 （2 g, 12.5 mmol) 和盐酸水溶液 （0.1 M, 10 mL) 的 混合液加热到 90 °C 反应一个小时，然后冷却到室温。然后以此加入乙腈（40 mL), 吡虫啉硝基亚甲基类似物 （10 mmol) ， 常温搅拌反应， TLC跟踪反应， 反应完毕 后， 饱和碳酸氢钠水溶液中和至中性，萃取，减压蒸除溶剂， 柱层析分离（洗脱剂： 二氯甲垸 /丙酮 = 3/1 (v/v) 得到淡黄色粉末， 即产品。
在另一个实施方式中， 式 (2a)-(2e)的化合物可通过下列反应制备：
将吡虫啉硝基亚甲基类似物 （5mmol) ， 30ml的无水乙腈， 3ml 25%戊二醛水 溶液， 催化量的 HC1置于 50ml的圆底烧瓶中。 常温下搅拌， TLC跟踪反应。 反应 结束后， 饱和碳酸氢钠水溶液中和至中性， 萃取， 减压蒸除溶剂， 柱层析分离（洗 脱剂： 二氯甲烷 /丙酮 = 3/1 (v/v) 得到淡黄色粉末， 即产品。 本发明活性物质的杀虫活性
术语 "本发明的活性物质"或 "本发明的活性化合物"是指本发明化合物、 其 光学异构体或农药学上可接受的盐，其具有显著提高的杀虫活性， 以及扩大的杀虫 谱。
术语"农药学上可接受的盐"意指该盐的阴离子在形成杀虫剂药学上可接受的 盐时为已了解的和可接受的。 该盐较好的为水溶性的。 合适的、 由式 (A)和 (B)化合 物形成的酸加成盐包括有无机酸形成的盐，例如盐酸盐、磷酸盐、硫酸盐、硝酸盐； 及包括有机酸形成的盐， 如醋酸盐， 苯甲酸盐。
本发明的活性物质能用作控制和消灭广泛的农林植物害虫、 贮藏谷类的害虫、 公共卫生害虫以及危害动物健康的害虫等。在本说明书中， "杀虫剂"是具有防治 上述提到的所有害虫的作用的物质的统称。害虫的例子包括但不限于：鞘翅目昆虫： 玉 象 (Sitophilus zeamais) , 赤拟谷盗 (2 0 //i™ castaneum), 马铃薯票瓜虫
{Henosepilachna vigintioctomacuiata)， ) M ^( enosepilachna spars a)， 细月匈 叩头虫 ( g ofey f cicollis)， 红脚绿金龟 ( wo /" cupripes), 四纹丽金龟 (/¾^〃/" quadriguttata)， ≤/ f R† {Monolepta hieroglyphica), H牛 {Monocham alternatus)， 禾窗 ^^ Echinocnemus squameus)， 泡桐叶甲 (Basiprionota bisignata)， 星天牛 (Anoplophora chinensis), 桑天牛 (Ap pona germari)， 胺腹小囊 (Sco/j/1/^ schevy),或细胸金针虫 ；鳞翅目昆虫：舞毒娥 ( ^^ /" ifc "r)， 天幕毛虫 (M /"co o " neustria testacea), 黄杨绢野螟 (Ζ)/ ρ? / perspectalis), 大 袋蛾 (C/a 'a variegata) , 黄朿 I撤 ( w'tfoccwzpa fla escens) , 马尾松毛虫 (Z)e〃< ro/z' z« punctatus) , ^^^{Orgyia gonostigma), 白杨透翅蛾 (/¾ra"i^e"e toba"z/or / ， 斜
Figure imgf000011_0001
litura), 二化蟆 (C n7o suppressalis), 玉米螟 ((¾Zrz«'a nubilalis), f^i (Ephestia cautella), ti¾ ¾ !t {A doxophyes or ana), 栗子小卷娥 (/i^pjrew'a splendana) , J iik ¾ J¾ (Agro tis fucosa) , la), 菜蛾 ( ¾te〃a xylostella), n diP yllocnistis citrella
Figure imgf000011_0002
separata); 同翅目 昆虫： 黑尾
Figure imgf000011_0003
c/"c ce;^)， 稻褐飞 Sl(N//a/?arrato /wge"s)， 康氏粉虫介 (Pse dococcus comstocki) , ^<,^kM(Unaspis yanonensis) , ^&^(Myzus persicae), 棉 (Aphis gossydii), 萝 (Lipaphis erysimi pseudobrassicae), ^(Stephanitis nashi), i{Bemisia tabaci); 直翅目昆虫： 德国小蠊 gemzcw/ca), 美国
Figure imgf000011_0004
talpa africana) , 或亚洲飞虫皇 ( ociw migratoria); 等翅目昆虫： 入侵红火蚁 (So/ewopw^ /"w'cto)， 或家白奴
(Coptotermes formosanus)； 双翅目昆虫： " -^iMusca domestica), 埃及伊紋 (ylecfes aegypti), ^ (Delia platura), 库蚊 ( We ¾?.)， 或中华按蚊 ½ο ½/<¾
危害动物健康的害虫包括微小牛蜱 (BoopMus micmphis)， 长角血蜱
(Haemaphysalis longicornis )， 小亚璃眼婢 (Hyalomma anatolicum ) , 牛皮 !fe黾 ( Hypo derma spp. )， 肝片吸虫 (Fasciola hepatica)， 贝氏莫尼茨缘虫 (Moniezia blanchard )， 奧斯特线虫 (Ostertagia spp. )， Trypanosoma enansi, Babesia bigemina等。
本发明涉及的化合物尤其对剌吸式、 矬吸式口器害虫， 如蚜虫、 叶蝉、 飞虱、 蓟马、 粉虱等农林害虫有特效。 含本发明活性物质的杀虫剂组合物
可将本发明的活性物质以常规的方法制备成杀虫剂组合物。这些活性化合物可 做成常规的制剂， 例如溶液剂， 乳剂， 混悬剂， 粉剂， 泡沬剂， 糊剂， 颗粒剂； 气 雾剂， 用活性物质浸渍的天然的和合成的材料， 在多聚物中的微胶囊， 用于种子的 包衣复方， 和与燃烧装置一起使用的制剂， 例如烟熏药筒， 烟熏罐和烟熏盘， 以及 ULV冷雾 (Cold mist)和热雾 (Warm mist)制剂。
这些制剂可用巳知的方法生产， 例如， 将活性化合物与扩充剂混合， 这些扩充 剂就是液体的或液化气的或固体的稀释剂或载体，并可任意选用表面活性剂即乳化 剂和 /或分散剂和 /或泡沫形成剂。例如在用水作扩充剂时，有机溶剂也可用作助 剂。
用液体溶剂作稀释剂或载体时基本上是合适的， 如： 芳香烃类， 例如二甲苯， 甲苯或垸基萘； 氯化的芳香或氯化的脂肪烃类， 例如氯苯， 氯乙烯或二氯甲垸； 脂 肪烃类， 例如环己烷或石蜡， 例如矿物油馏分； 醇类， 例如乙醇或乙二醇以及它们 的醚和脂类； 酮类， 例如丙酮， 甲乙酮， 甲基异丁基酮或环已酮； 或不常用的极性 溶剂， 例如二甲基甲酰胺和二甲基亚砜， 以及水。液化气的稀释剂或载体是指在常 温常压下将成为气体的液体， 例如气溶胶推进剂， 如卤化的烃类以及丁垸， 丙垸， 氮气和二氧化碳。
固体载体可用地面天然的矿物质， 例如高岭土， 粘土， 滑石， 石英， 活性白土， 蒙脱土，或硅藻土，和地面合成的矿物质，例如高度分散的硅酸，氧化铝和硅酸盐。 供颗粒用的固体载体是碾碎的和分级的天然告石， 例如方解石， 大理石， 浮石， 海 泡石和白云石，以及无机和有机粗粉合成的颗粒，和有机材料例如锯木屑，椰子壳， 玉米棒子和烟草梗的颗粒等。
非离子的和阴离子的乳化列可用作乳化剂和 I或泡沫形成剂。 例如聚氧乙烯- 脂肪酸酯类， 聚氧乙烯-脂肪醇醚类， 例如烷芳基聚乙二醇醚类， 垸基磺酸酯类， 烷基硫酸酯类， 芳基磺酸酯类以及白蛋白水解产物。分散剂包括， 例如木质素亚硫 酸盐废液和甲基纤维素。
在制剂中可以用粘合剂， 例如羧甲基纤维素和以粉末， 颗粒或乳液形式的天然 和合成的多聚物， 例如阿拉伯胶， 聚乙烯基醇和聚乙烯醋酸酯。可以用着色剂例如 无机染料， 如氧化铁， 氧化钻和普鲁士蓝； 有机染料， 如有机染料， 如偶氯染料或 金属钛菁染料； 和用痕量营养剂， 如铁， 猛， 硼， 铜， 钴， 铝和锌的盐等。
本发明的这些活性化合物可与其它活性化合物制成混合物存在于商品制剂中 或从这些制剂制备的使用剂型中， 所述其它的活性化合物包括但不限于： 杀虫剂， 合饵， 杀菌剂， 杀螨剂， 杀线， 杀真菌剂， 生长控制剂等。 杀虫剂包括， 例如磷酸 酯类， 氨基甲酸酯类， 除虫菊酯类， 氯化烃类， 苯甲酰脲类， 沙蚕毒素类以及由微 生物产生的物质， 如阿维菌素。
此外，本发明的这些活性化合物也可与增效剂制成一种混合物存在于它们的商 品制剂中成从这些制剂制备的使用剂型中。 增效剂是提高活性化合物作用的化合 物， 由于活性化合物本身有活性， 也可不必加增效剂。 这些制剂通常含有占所述杀虫剂组合物 0.001-99.99重量％， 优选 0.01-99.9重 量％， 更优选 0.05-90重量％的本发明的活性化合物。 从商品制剂制成使用剂型中 的活性化合物的浓度可在广阔的范围内变动。使用剂型中的活性化合物的浓度可从 0.000000 l- 100%(g/v) , 最好在 0.0001与 1%之间。 实施例
下面结合具体实施例， 进一步阐述本发明。应理解， 这些实施例仅用于说明本 发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常 按照常规条件， 或按照制造厂商所建议的条件。 除非另外说明， 否则百分比和份数 按重量计算。 其中， r. t.代表室温。 实施例 1 : 9-(Ϊ6-氯吡啶 -3-基）甲基) -4-硝基 -8-氧杂 -10, 1 1-二氢咪唑并「2,3-al双环 [3，2，1]辛 -3-烯 (
Figure imgf000013_0001
2,5-二乙氧基四氢呋喃 （2 g, 12.5 mmol ) 和盐酸水溶液 （0.1 M, 10 mL ) 的混 合液加热到 90 °C 反应一个小时， 然后冷却到室温。 然后以此加入乙腈（40 mL) , 2-氯 -5-0硝基亚甲基-咪唑垸 -1-基甲基) -吡啶 （2.54g lO mmol) ， 常温搅拌反应， TLC跟踪反应， 反应完毕后， 饱和碳酸氢钠水溶液中和至中性， 萃取， 减压蒸除 溶剂，柱层析分离（洗脱剂：二氯甲烷 /丙酮 = 3/l (V/V;> 得到淡黄色粉末。产率， 53%; mp = 149.0-150.0。C; 1H NMR (400 Mz, OMSO-d6): δ 8.35 (d, J= 2.4 Hz, 1H), 7.81 (dd, J! = 2.4 Hz, J2 = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 5.36-5.39 (s, 2H), 5.00 (d, J = 15.6 Hz, 1H), 4.68 (d, J = 15.6 Hz, 1H), 3.57-3.73 (m, 4H), 1.94-2.04 (m, 4H) ppm; 13C NMR (100 Mz, OM O-d6): δ 155.6, 149.7, 149.6, 139.7, 132.6, 124.5, 109.6, 87.0, 75.1, 51.2, 50.3, 46.6, 3 1.9, 31.7 ppm; HRMS (ES+) 计算值： C14H16N403 35C1 (M+H)+, 323.091 1 ; 实测值： 323.0912. 计算值： C14H16N403 37C1 (M+H)+, 325.081 1; 实测值： 325.0895. 计算值： C14H15N403 35ClNa (M+Na)+, 345.0730; 计算值： 345.0722. 计算值： C14H15N403 37ClNa(M+Na)+, 347.0701; 计算值： 347.0692。 实施例 2:9-(ϊ2-氯噻唑 -5-基）甲基) -4-硝基 -8-氧杂 -10,11-二氢咪唑并「2,3-al双环 [3,2,1]辛 -3-烯 (
Figure imgf000014_0001
方法同上， 减压蒸除溶剂，柱层析分离（洗脱剂：二氯甲垸 /丙酮 =3/1 (ν/ν) 得 到淡黄色粉末状固体。 产率， 56%; mp = 136.5-138.0 °C; !H NMR (400 Mz,
DMSO-c¾: δ 7.47 (s, 1H), 5.61 (d, J= 5.2 Hz, 1H), 5.28 (d, J= 15.4 Hz, 1H), 5.16 (d, J = 5.00 Hz, 1H), 4.70 (d, J= 15.4 Hz, 1H), 3.66-3.82 (m, 3H), 3.54-3.61 (m, 1H), 2.22-2.29 (m, 1H), 2.12-2.21 (m, 2H), 1.99-2.07 (m, 1H) ppm; 13C NMR (100 Mz, OMSO-d6): δ 154.6, 154.3, 140.6, 135.1, 110.4, 87.4, 75.4, 49.6, 47.9, 46.5, 31.8, 31.8 ppm; HRMS (ES+) 计算值： C12H14N403S35C1 (M+H)十， 329.0475; 计算值： 329.0475. 计算值： C12H14N403S37C1(M+H)+, 331.0446; 计算值： 331.0461。 实施例 3: 9-苄基 -4-硝基 -8-氧杂 -10,11-二氢咪唑并 [2,3-a]双环 [3,2,1]辛 -3-烯 (化 合物 lc)的合成
Figure imgf000014_0002
方法同上， 减压蒸除溶剂，柱层析分离（洗脱剂：二氯甲垸 /丙酮 =3/1 (ν/ν) 得 到淡黄色粉末状固体。 产率， 58%; mp = 149.0-149.8。C; !H NMR (400 Mz,
DMSO-c¾: δ 7.28-7.39 (m, 5H), 5.66 (d, J= 4.3 Hz, 1H), 5.14 (d, J= 4.5 Hz, 1H), 4.92-5.01 (m, 2H), 3.57-3.74 (m, 3H), 3.47-3.53 (m, 1H), 2.30-2.34 (m, 1H),
2.13-2.22 (m, 2H), 2.00-2.07 (m, 1H) ppm; 13C NMR (100 Mz, DMSO-c¾: δ 155.5, 135.9, 128.9, 128.2, 128.1, 87.7, 75.6, 54.4, 48.9, 47.2, 31.8, 31.6 ppm; HRMS (ES+) 计算值： C15H17N303 (M+H)+, 287.1270; 计算值： 287.1272。 实施例 4: 9-(4-氯-苄基) -4-硝基 -8-氧杂 -10,11-二氢咪唑并 [2,3-a]双环 [3,2,1]辛 -3-烯 (化合物
Figure imgf000015_0001
方法同上， 减压蒸除溶剂，柱层析分离（洗脱剂：二氯甲垸 /丙酮 =3/l (v/v) 得 到淡黄色粉末状固体。 产率， 38%; mp = 140.0-140.9 °C; 1H NMR (400 Mz,
OMSO-d6): δ 7.27-7.34 (m, 4H), 5.63 (d, J= 5.4 Hz, IH), 5.14 (d, J= 5.2 Hz, IH), 5.04 (d, J= 15.1 Hz, IH), 4.78 (d, J= 15.1 Hz, IH), 3.62-3.73 (m, 3H), 3.45-3.51 (m, IH), 2.26-2.31 (m, IH), 2.11-2.21 (m, 2H), 1.98-2.07 (m, IH) ppm; 13C NMR (100 Mz, DMSO- ): δ 155.3, 134.4, 133.9, 129.6, 129.0, 110.2, 87.6, 75.5, 53.9, 49.2, 47.0, 31.8, 31.7 ppm; HRMS (ES+) 计算值： C15H17N303 35C1 (M+H)+, 322.0958; 计算值： 322.0972. 计算值： C15H17N303 37C1 (M+H)+, 324.0929; 计算值： 324.0938。 实施例 5: 9- ((四氢呋喃 -3-基）甲基) -4-硝基 -8-氧杂 -10,11-二氢咪唑并 [2,3-a]双环 [3,2,1] 辛 -3-烯 (化合物 le)的合成
Figure imgf000015_0002
方法同上， 减压蒸除溶剂，柱层析分离（洗脱剂：二氯甲垸 /丙酮 =3/l (V/V) 得 到淡黄色粉末状固体。收率：57%。mp = 126.3-127.9°C; 1H NMR (400 Mz, DMSO-c¾: (55.11 (s, IH), 5.00-5.03 (m, IH), 4.18 (d, J= 3.2 Hz, 2H), 4.05-4.25 (m, 2H),
3.85-3.96 (m, 4H), 2.25 (m, IH), 1.66-1.81 (m, 4H), 2.35-2.40 (m, IH), 2.17-2.21 (m, 2H), 1.93-2.01 (m, IH) ppm; ppm; 13C NMR (100 Mz, OMSO-d6): δ 81.9, 81.6, 77.9, 68.2, 53.1, 49.9, 48.0, 44.1, 36.4, 33.9, 29.5, 23.2, 19.8, ppm; HRMS (EI+) 计算值： C13H19N304(M+), 281.1376; 实测值： 281.1365。 实施例 6: 10-((6-氯吡啶 -3-基）甲基) -4-硝基 -9-氧杂 -11,12-二氢咪唑并 [2,3-a]双 环 [3,3,1]壬 -3-烯 (化合物 2a)的合成
Figure imgf000016_0001
将 1.27g(0.005mol)的 2-氯 -5-(2-硝基亚甲基-咪唑垸 -1-基甲基) -吡啶， 30ml的无 水乙腈， 3ml 25%戊二醛水溶液， 催化量的 HC1置于 50ml的圆底烧瓶中。 常温下 搅拌， TLC跟踪反应。 反应结束后， 饱和碳酸氢钠水溶液中和至中性， 萃取， 减 压蒸除溶剂， 柱层析分离 （洗脱剂： 二氯甲垸 /丙酮 = 3/l (V/v) 得到淡黄色粉末。 产率， 76%; mp = 174.7-175.4 C; !H NMR (400 Mz, DMSO- 6): δ 8.38 (dd, Ji = 0.6 Hz, J2 = 2.4 Hz, IH), 7.84 (dd, Ji = 2.4 Hz, J2 = 8.4 Hz, IH), 7.52 (dd, Ji = 0.6 Hz, J2 = 8.4 Hz, IH), 5.12 (s, IH), 5.04-5.05 (m, IH), 4.97 (d, J = 15.6 Hz, IH), 4.71 (d, J = 15.6 Hz, IH), 3.62-3.74 (m, 4H), 1.66-1.81 (m, 4H), 1.51-1.55 (m, IH), 1.32-1.44 (m IH) ppm; 13C NMR (100 Mz, DMSO-c¾: δ 156.6, 149.7, 149.6, 139.7, 132.9, 124.5, 105.8, 81.7, 68.9, 51.7, 50.0, 46.3, 28.8, 27.2, 14.8 ppm; HRMS (EI+) 计算值： C15H17N403 35C1 (M+), 336.0989; 计算值： 336.0988. 计算值： C15H17N403 37C1 (M 338.0960; 计算值： 338.0968 实施例 Ί·· 10-((2-氯噻唑 -5-基）甲基) -4-硝基 -9-氧杂 -11 12- 环 [3,3 1]壬 -3-
Figure imgf000016_0002
方法同上， 减压蒸除溶剂，柱层析分离（洗脱剂：二氯甲垸 /丙酮 = 3/l (V/V) 得 到白色粉末状固体。 产率， 62%; mp = 159.1-160.5 °C; 1H NMR (400 Mz, DMSO- 6): δ 7.48 (s, IH), 5.30 (d, J= 3.2 Hz, IH), 5.24 (d, J = 15.4 Hz, IH), 4.98 (s, IH), 4.78 (d J = 15.4 Hz, IH), 3.76-3.87 (m, IH), 3.60-3.71 (m, 3H), 2.12 (d, J = 14.0 Hz, IH), 1.82-1.96 (m, 2H), 1.64-1.77 (m, 2H), 1.48-1.60 (m, IH) ppm; 13C NMR (100 Mz, DMSO-c¾: δ 155.7, 154.1, 140.5, 135.6, 107.0, 82.7, 69.4, 49.4, 48.3, 46.2, 29.4, 26.5, 14.9 ppm; HRMS (EI+) 计算值： C13H15N403S35C1 (M ), 342.0553; 计算值： 342.0548. 计算值： C13H15N403S37C1 (M+), 344.0524; 计算值： 344.0564 实施例 8 : 10-苄基 -4-硝基 -9-氧杂 - 11, 12-二氢咪唑并 [2,3-a]双环 [3,3, 1]壬 -3-烯 (化 合物 2c)的合成
Figure imgf000017_0001
方法同上， 减压蒸除溶剂，柱层析分离（洗脱剂：二氯甲垸 /丙酮 = 3/l (v/v) 得 到淡黄色粉末状固体。 产率， 77%; mp = 180.5-181.2。C; 1H NMR (400 Mz,
OMSO-d6): δ 7.29-7.37 (m, 5H), 5.33 (d, J= 3.1 Hz, 1H), 5.02 (d, J = 15.0 Hz, 1H), 4.95 (s, 1H), 4.85 (d, J = 15.0 Hz, 1H), 3.68-3.75 (m, 1H), 3.48-3.64 (m, 3H), 2.14 (d, J = 13. 1 Hz, 1H), 1.81-1.93 (m, 2H), 1.51-1.70 (m, 3H) ppm; 13C NMR (100 Mz, DMSO- 6): δ 156.6, 136.4, 128.8, 128.3, 128.0, 106.7, 83.0, 69.7, 54.8, 48.6, 46.7, 29.5, 26.5, 15.0 ppm; HRMS (EI+) 计算值： C16H19N303 (M+), 301. 1426; 计算值： 301.1429。 实施例 9 : 10-(4-氯苄基 )-4-硝基 -9-氧杂 -1 1, 12-二氢咪唑并「2,3-al双环「3,3, 11壬 -3- 烯 (化合物 2d)
Figure imgf000017_0002
方法同上， 减压蒸除溶剂， 柱层析分离（洗脱剂： 二氯甲烷 /丙酮 = 3/l (V/v) 得 到淡黄色粉末状固体。 产率， 70%; mp = 156.9-158.3。C; !H NMR (400 Mz,
DMSO-c¾: δ 7.29-7.34 (m, 4H), 5.33 (d, J= 4.0 Hz, 1H), 5.05 (d, J = 15.1 Hz, 1H), 4.96 (s, 1H), 4.75 (d, J = 15.1 Hz, 1H), 3.66-3.73 (m, 1H), 3.55-3.60 (m, 3H), 2.14 (d, J = 13.6 Hz, 1H), 1.82-1.95 (m, 2H), 1.51-1.71 (m, 3H) ppm; 13C NMR (100 Mz, DMSO-c¾: δ 156.5, 134.9, 133.8, 129.7, 129.0, 106.8, 83.0, 69.6, 54.4, 48.9, 46.6, 29.6, 26.5, 15.0 ppm; HRMS (EI+) 计算值： C16H18N303 35C1 (M十), 335.1037; 计算 值： 335.1044. 计算值： C16H18N303 37C1 (M+), 337.1007; 计算值： 337.1036。 实施例 10 : 10- ((四氢呋喃 -3-基）甲基) -4-硝基 -9-氧杂 - 11，12-二氢咪唑并 [2，3-a] 双环 [3,3, 1]壬 -3-烯 (化合物 2e)的合成
Figure imgf000018_0001
将 1.065g(0.005mol)的 1- ((四氢呋喃 -3-基）甲基) -2- (-硝基亚甲基) - 1-咪唑啉， 3ml
25%戊二醛水溶液， 催化量的 HC1置于 50ml的圆底烧瓶中。 常温下搅拌， TLC跟 踪反应。 待反应结束后， 除去溶剂， 柱层析分离得到淡黄色粉末状纯品， 产率为 36%。
mp = 1 15.3- 1 16.9 °C ; 1H NM (400 Mz， DMSO-d6): δ 5. 1 1 (s， 1H), 5.00-5.03 (m, 1H)， 4. 18 (d, J = 3.2 Hz, 2H), 4.05-4.25 (m, 2H), 3.85-3.96 (m, 4H), 2.25 (m, 1H)， 1.66- 1.81 (m, 4H), 1.63 - 1.64 (m, 2H), 1.57- 1.59 (m, 2H), 1.51- 1.55 (m, 1H),
1.32- 1.44 (m, 1H) ppm; 13C NMR (100 Mz, DMSO-d6): δ 81.7， 80.6, 78.5， 68.9, 50.0, 49.7, 46.9, 44.6, 36.8, 33.9, 28.8, 27.2, 17.8， 14.8ppm; HRMS (EI+) 计算值：
C14H21N304 (M+), 295. 1532; 实测值： 295. 1598。 实施例 1 1 : 本发明化合物的杀虫活性测试
( 1) 对蚜虫的杀虫活性
蚜虫属于同翅目害虫，具有剌吸口器，是一种常见的农作物害虫。以豆蚜 craccivora)为测试对象， 采用浸渍法测试。
测试方法： 准确称量各样品， 分别加入 DMSO 2 mL及 18 mL清水， 再加入三 滴乳化剂 2201配成药液，空白用 DMSO 2 mL及 18 mL清水，加入三滴乳化剂 2201 配成。 将附有一定数量的待测昆虫蚕豆叶在药液中浸泡 3-5秒， 取出晾干， 将试虫 和食料移入干净的器皿内， 放置于干恒温恢复室内， 24小时后检査试虫中毒死亡 情况。 结果见下表 1。
(2) 对稻褐飞虱的杀虫活性
稻褐飞虱属于同翅目害虫， 具有刺吸口器， 是一种常见的农作物害虫。 以稻 褐飞虱 (； N//aparvato /wgew 为测试对象， 采用 Nagata报道的微量点滴测定法。
操作过程： 选取羽化 2-3天的未交配有翅雌虫作为测试对象，将化合物用丙酮 稀释成系列浓度， 用二氧化碳将测试昆虫麻痹后， 用手动微量点滴器 (Burkard Manufacturing Co. Ltd, Rickmansworth, UK) 将药滴 (0.08 L)点滴于测试昆虫的前 胸背板上。 每个浓度处理大约 30头成虫， 每个处理重复 3次。 以丙酮作对照。 处 理后的成虫饲养于培养箱 （20 x 20 x 10 cm) 内的无土栽培稻苗上， 温度控制在 25±1 V， 光照 16 ( L ) /8 ( D ) 小时。 48小时后检査结果， 用标准的概率值分析 法计算 LD5。值。 结果见下表 2。
(3) 对粘虫的杀虫活性
以粘虫 Pseudaktia separate Walker) 二龄的幼虫为测试对象， 采取浸叶法测 试。
粘虫是一种很重要的杂谷类鳞翅目害虫， 其应用面较广， 适应于作为杀虫剂的胃 毒， 触杀， 综合和残效等毒力测定以及昆虫毒理学方面的研究， 也适应于新化合物的 筛选试验， 按照文献报道的方法进行粘虫杀灭活性的测试。
浸叶法的操作过程： 准确称量各样品， 分别加入 DMSO (2 mL)及 18 mL清水， 再加入三滴乳化剂 2201(上海农药厂提供）配成药液，空白用 DMSO (2 mL)及 28 mL 清水， 加入三滴乳化剂 2201配成。 将新鲜的玉米叶片撕成小块， 在药液中浸泡 5 秒钟左右， 取出晾干， 放入 lOO mL的广口瓶中， 再放入二龄幼虫约 20头， 广口 瓶用白纱布及橡皮筋扎紧， 连续喂浸过药液的玉米， 5天后检查幼虫的死亡率。 要 求温度 22 - 27 °C， 湿度 70-80 %。 若空白死亡率在 5 %以下， 各处理死亡率不必校 正； 若对照死亡率在 5 - 20 %， 用 Abbott公式校正各处理死亡率。 Abbott公式为： 校正死亡率 =[ (死亡处理率-对照死亡率） I ( 100-对照死亡率） ] χ 100。
结果见表 1。
目标化合物对蚜虫和粘虫的活性
粘虫 Pseudaletia
Sl Aphis craccivora
separate Walker
化合物
死亡率 (％， LC50(mm 死亡率 (％， LC5o(mmol
500 mg L 1 ) ol L 1) 500 mg L 1) L-1)
4 78. 1 n. t. 100 106.97
5 97.7 n. t. 100 n. t.
6 100 5. 19 100 15.26
8a 100 1.52 100 12.5
8b 100 n. t. 100 n. t.
8c 13.6 n. t. 0 n. t.
8d 95.7 n. t. 0 n. t.
9a 87.3 n. t. 0 n. t.
9b 98.2 n. t. 0 n. t.
9c 55.6 n. t. 0 n. t.
9d 38.9 n. t. 0 n. t.
吡虫啉 100 8.93 100 38.7 表 2 化合物 D4和 D8对敏感和抗性褐飞虱的活性
口 玄 毒力曲线 抗性倍 口口 化合物 LD50 (ng/害虫） 相对毒力
y = a + bx
y =
8a 0.0742±0.0106 1.77 1.00
7.3 127+2.0474X
敏感品 y =
9a 4. 1440±0.6136 0.32 1.00
3.9543+1.6936
y =
吡虫啉 0. 13 16±0.0154 1.00 1.00
7. 1823+2.4778
y =
8a 0.4925±0.081 1 50.00 6.64
5.4068+1.3225
抗性品 y =
9a 18.9795±2.3501 1. 17 4.58
3. 1320+1.4613
y =
吡虫啉 22. 1614±3.7522 1.00 168.40
2.5873+1.7930X 测试了目标化合物对蚜虫，粘虫和褐飞虱的活性，其结果如表 1和 2。由表 1-2 可见， 氧桥杂环化合物 la具有很高的活性， 对蚜虫的 LC5Q为 1.52 mg L— 对粘虫 的 LC5。为 12.5 mg L—1 , 其活性显著超过吡虫啉。更为重要的是， 化合物 la对敏感 的褐飞虱活性和吡虫啉差不多， 而对吡虫啉抗性褐飞虱的活性是吡虫啉的 50倍。 化合物 la性则较弱。 有趣的是， 由戊二醛构建的氧桥杂环化合物 2a-2c的活性则 弱很多， 部分化合物只对蚜虫有活性。分析化合物化合物 la与 2a的晶体结构， 可 以看出化合物 la与 2a的氧桥构型不同，氧桥的指向相反，将二者分子叠合可以很 明显的看出这种差异。这种氧桥的构型的差异可能导致化合物 la与 2a活性显著的 不同。 实施例 12: 化合物 （la) 作用机制的研究
对化合物（la)分别进行了电生理实验和同位素标记物取代实验，化合物（la) 可以抑制激动剂的反应； 化合物（la)对美国蜚蠊烟碱乙酰胆碱受体和卵母细胞表 达的 Νΐ α 1/ 1 2受体没有激动作用；化合物（la)可以抑制激动剂乙酰胆碱的反应， 这些实验表明化合物是烟碱乙酰胆碱受体 （nAChRs ) 的拮抗剂。 实施例 13 : 含有本发明化合物的杀虫剂组合物的制备
(a) 油状悬浮液
按比例准备以下组分： 25% (重量百分比， 下同）化合物 la-le和 2a-2e中任一种 化合物； 5 %聚氧乙烯山梨醇六油酸酯； 70 %高级脂肪族烃油。 将各组分在沙磨中一 起研磨， 直到固体颗粒降至约 5微米以下为止。 所得的粘稠悬浮液可直接使用， 但也 可在水中乳化后使用。
(b)水悬浮液
按比例准备以下组分： 25%化合物 la-le和 2a-2e中任一种化合物； 3%水合硅镁 土 (hydrate attapulgit); 10%木质素磺酸钙； 0.5%磷酸二氢钠； 61.5%水。将各组分在球 磨机中一起研磨， 直到固体颗粒降至约 10微米以下为止。 该水悬浮液可直接使用。
(c)饵剂
按比例准备以下组分： 0.1-10%化合物 la-le和 2a-2e中任一种化合物； 80%小麦 面粉； 19.9-10%糖蜜。 将这些组分完全混合， 按需要形成饵形状。 可食用饵可以分散 到卫生害虫所侵染的场所，例如家居或工业场所，诸如厨房、医院或商店或户外区域， 以通过口服摄入来防治害虫。 本发明提及的所有文献都在本申请中引用作为参考， 就如同每一篇文献被单 独引用作为参考那样。此外应理解， 在阅读了本发明的上述讲授内容之后， 本领域 技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利 要求书所限定的范围。

Claims

权 利 要 求
1. 氧桥杂环新烟碱化合物， 该化合物选自具有式 (A)或 (B)所示结构的化合物、 或者所述化合物的光
Figure imgf000023_0001
式中：
！^为含氮、 氧和 /或硫的五元或六元杂环基， 卤代的含氮、 氧和 /或硫的五元或 六元杂环基， 或者取代或未取代的苯基， 其中， 所述取代基为选自下组中的一个或 多个： 卤素， 4卤代垸基或 d— 4氯代垸氧基；
R3和 各自独立地为 H， d— 6烷基， 烯丙基， 苄基， d_4垸氧基 -d_4烷基，
C^垸氧基-羰基， 苯氧羰基， C2_6炔基-羰基， C2_3烯基-羰基， C3_6环垸基-羰基， 苯甲酰基， 或者被一个或多个选自卤原子、 4烷基、 d— 4卤代烷基、 d— 4垸氧基 和 CM烷基-羰基的取代基所取代的苯甲酰基， 呋喃羰基或 N，N-二甲基羰基， 或者 R3和 共同构成 -CH2-CH2-， -CH2-CH2-CH2-或 -CH2-XR-CH2-， 式中 X为杂原子， R为杂原子上的取代基， 选自 H， d_6垸基， 烯丙基， 苄基， 苯基， d_4垸氧基 -d_4 垸基， d_4烷氧基-羰基， 苯氧羰基， C2_6炔基-羰基， C2_3烯基-羰基， C3_6环烷基- 羰基， 苯甲酰基， 或者被一个或多个选自卤原子、 卤代垸基、 d_8饱和或不饱 和垸基或垸氧基和 CM垸基-羰基的取代基所取代的苯甲酰基， 呋喃羰基或 Ν,Ν- 二甲基羰基；
R5， R6， R7， 和 为11， 饱和或不饱和 d.4烷基， 卤素， C 8饱和或不饱 和垸氧基， 卤代 d_4饱和或不饱和垸氧基， d— 4垸基-羰基， d— 8垸基-酯基， d— 4 烷基 -磺酸酯基， 苯基或苄基；
Y为硝基， 氰基， 三氟甲基， 三氟乙酰基或三氟甲磺酰基。
2. 如权利要求 1所述的氧桥杂环新烟碱化合物， 或者所述化合物的光学异构 体或农药学上可接受的盐， 其特征在于， 所述氧桥杂环新烟碱化合物选自下组-
Figure imgf000024_0001
(lc)， (Id),
Figure imgf000024_0002
(le)， (2a)，
(2b)， (2c)，
Figure imgf000024_0004
(2d) , 以及 （2e)。
3. 如权利要求 1所述的氧桥杂环新烟碱化合物， 或者所述化合物的光学异构 体或农药学上可接受的盐， 其特征在于， 所述氧桥杂环新烟碱化合物选自下组：
Figure imgf000024_0005
(la)， 以及 (lb；)。
4. 如权利要求 1-3 中任一项所述的氧桥杂环新烟碱化合物， 或者所述化合物 的光学异构体或农药学上可接受的盐，其特征在于，所述氧桥杂环新烟碱化合物是 昆虫烟碱乙酰胆碱受体的拮抗剂。
5. 如权利要求 3所述的氧桥杂环新烟碱化合物， 或者所述化合物的光学异构 体或农药学上可接受的盐， 其特征在于， 所述氧桥杂环新烟碱化合物 (la)和 (lb)对 吡虫啉抗性褐飞虱和烟粉虱的活性是吡虫啉的 2-30倍。
6. 一种农用组合物， 它包含：
(a) 0.001-99.99重量％的权利要求 1-5中任一项所述的氧桥杂环新烟碱化合物、 其光学异构体或农药学上可接受的盐、 或者它们的组合； 以及
(b) 农药学上可接受的载体和 /或赋形剂。
7. 权利要求 6所述的农用组合物的用途， 其特征在于， 用于杀灭或预防农业 害虫、卫生害虫和危害动物健康的害虫； 或用作用于杀灭或预防农业害虫、卫生害 虫和危害动物健康的杀虫剂组合物。
8. 权利要求 1-5中任一项所述的氧桥杂环新烟碱化合物、 其光学异构体或农 药学上可接受的盐的制备方法， 所述方法包括歩骤：
在催化量酸的存在下， 于室温下， 使式 (a)化合物与式 )或 (c)化合物反应， 从 而制得具有式 (A)或 (B)的化合物，
Figure imgf000025_0001
式中， 、 R3、 、 R5、 R6, R7， R8， R9和 Y如权利要求 1中所定义。
9. 如权利要求 8所述的方法， 其特征在于， 所述方法包括步骤- 于室温下， 进行如下反应 2-24小时， 获得式 (la)的化合物:
10% HCI aq. O
o'、。 一 o 90 °C
Figure imgf000025_0002
在乙腈中， 于催化量的酸存在下 于室温下， 进行如下反应 2-24小时， 从而 获得式 (lb)的化合物-
Figure imgf000025_0003
在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (lc)的化合物:
Figure imgf000026_0001
获得式 (Id
Figure imgf000026_0002
进行如下反应 2-24小时， 获得式 (le)的化合物:
Figure imgf000026_0003
在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (2a
Figure imgf000026_0004
( 2a) ； 在乙腈中， 于催化：！ ：的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (2b)的化合物-
Figure imgf000026_0005
在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从而 获得式 (2c)的化合物：
Figure imgf000026_0006
( 2c ) ；
进行如下反应 2-24小时， 获得式 (2d)的化合物:
Figure imgf000027_0001
在乙腈中， 于催化量的酸存在下， 于室温下， 进行如下反应 2-24小时， 从 获得式 (3b)的
Figure imgf000027_0002
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UA106256C2 (ru) 2014-08-11
US8809319B2 (en) 2014-08-19
CA2783504A1 (en) 2011-06-16
CR20120361A (es) 2012-12-18
JP5600750B2 (ja) 2014-10-01
RU2531920C2 (ru) 2014-10-27
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KR20120094111A (ko) 2012-08-23
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CA2783504C (en) 2013-07-09
RU2012127868A (ru) 2014-01-20
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BR112012013846A2 (pt) 2015-09-15

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