WO2020030094A1 - 一种含有间二酰胺类化合物的药物组合物及其应用 - Google Patents

一种含有间二酰胺类化合物的药物组合物及其应用 Download PDF

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WO2020030094A1
WO2020030094A1 PCT/CN2019/099950 CN2019099950W WO2020030094A1 WO 2020030094 A1 WO2020030094 A1 WO 2020030094A1 CN 2019099950 W CN2019099950 W CN 2019099950W WO 2020030094 A1 WO2020030094 A1 WO 2020030094A1
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Prior art keywords
compound
active ingredient
pharmaceutical composition
composition containing
hydrogen
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PCT/CN2019/099950
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English (en)
French (fr)
Inventor
周丽琪
相君成
吕亮
洪湖
刘吉永
邵佳礼
刘叙杆
倪珏萍
Original Assignee
上海泰禾国际贸易有限公司
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Priority claimed from CN201910704040.7A external-priority patent/CN110810414B/zh
Application filed by 上海泰禾国际贸易有限公司 filed Critical 上海泰禾国际贸易有限公司
Publication of WO2020030094A1 publication Critical patent/WO2020030094A1/zh

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    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/34—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles

Definitions

  • the present application belongs to the technical field of prevention and control of pests by pharmaceutical compositions, and relates to a pharmaceutical composition containing metadiamide compounds and its application, and in particular, to a compound containing metadiamide compounds, chlorantraniliprole and flubendiamide.
  • CN101208009A discloses that a composition containing a metadiamide compound has an insecticidal effect.
  • insecticides and fungicides of various structural types are widely used in various crops. With the continuous use of pesticides, pests and diseases will become resistant to some existing pesticide products, and the insecticidal activity of existing pesticide varieties may not always meet the needs of many agricultural practices. Insecticide compositions have an important role in improving the effectiveness of insecticides, expanding the spectrum of control, and delaying the development of resistance. Therefore, in the art, it is still desired to develop more efficient insecticide compositions or insecticidal bactericidal compositions to meet the needs of agriculture and the forestry industry.
  • the object of the present application is to provide a pharmaceutical composition containing a metadiamide compound and its application.
  • the pharmaceutical composition has a synergistic effect and can prevent and control various agricultural diseases caused by pests. , Forestry pests.
  • the present application provides a pharmaceutical composition containing an m-diamide compound.
  • the pharmaceutical composition includes an active ingredient A and an active ingredient B.
  • the active ingredient A is an amide compound having a structure represented by Formula I.
  • the active ingredient B includes any one or a combination of two other pesticides;
  • Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, substituted or unsubstituted 3-10 membered heterocyclic group, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl;
  • Q is selected from C 3 -C 8 cycloalkyl or C 3 -C 8 halocycloalkyl;
  • X is selected from hydrogen, fluorine or trifluoromethyl
  • Y 1 is selected from fluorine, chlorine, bromine, iodine, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 4 alkenyl , C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 2 -C 4 haloalkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 1- C 6 alkylcarbonyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl;
  • Y 2 is selected from bromine, iodine, cyano, nitro, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl, C 2 -C 4 alkynyl, C 2 -C 4 haloalkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 halocycloalkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl;
  • R 1 is selected from hydrogen, fluorine or methoxy
  • R 2 is selected from fluorine or trifluoromethyl
  • R 3 and R 4 are each independently selected from hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl , C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or C 3 -C 8 halocycloalkyl;
  • n represents an integer of 0 to 3 (for example, 0, 1, 2 or 3); W 1 and W 2 are independently an oxygen atom Or sulfur atom.
  • the pharmaceutical composition using the m-bisamide compound having the structure shown by the formula I as described in the present application as the active ingredient A and blended with the active ingredient B has a synergistic effect between the active ingredient A and the active ingredient B.
  • the present application provides a pharmaceutical composition containing a compound substituted at the 3-position of m-diamide with an N-cyclopropylmethyl derivative.
  • the pharmaceutical composition includes active ingredient A and active ingredient B.
  • the active ingredient A It is an m-bisamide compound having a structure represented by Formula II, and the active ingredient B includes any one or a combination of other fungicides, insecticides, or acaricides;
  • Z is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylsulfonyl, or C 1 -C 6 haloalkyl Sulfonyl
  • Y is selected from C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy;
  • R is selected from hydrogen or methyl.
  • an m-bisamide compound having a structure represented by Formula II is further preferred, and it is compounded with active ingredient B as an active ingredient of a pharmaceutical composition. Good results can be achieved at low doses, resulting in less drug residues and more environmental protection.
  • Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, trifluoromethoxy, trifluoromethyl, methanesulfonyl, or trifluoromethanesulfonyl.
  • Y is selected from trifluoromethyl or trifluoromethoxy
  • R is selected from hydrogen or methyl.
  • the m-bisamide compound is any one of the compounds shown in Table 1 below having the general formula II.
  • H is a hydrogen atom
  • F is a fluorine atom
  • Cl is a chlorine atom
  • Br is a bromine atom
  • I is an iodine atom
  • CN is a cyano group
  • CF 3 is a trifluoromethyl group
  • OCF 3 is a trifluoromethoxy group
  • MeS (O) 2 represents methanesulfonyl
  • CF 3 S (O) 2 represents trifluoromethanesulfonyl.
  • the m-diamide compound is any one or a combination of at least two selected from the following compounds 1-14:
  • C 1 -C 6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl and the like.
  • C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, n-propoxy, isopropyl Oxy, t-butoxy and the like.
  • C 1 -C 6 haloalkyl refers to an alkyl group having 1 to 6 carbon atoms substituted with a halogen, and includes, without limitation, chloromethyl, 1-chloroethyl, 2-bromo-n-propyl, and the like.
  • C 1 -C 6 haloalkoxy refers to an alkoxy group having 1 to 6 carbon atoms substituted with halogen; similarly the term “C 3 -C 8 cycloalkyl” refers to having 3 to 8 on the ring A cyclic alkyl group with a carbon atom, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc .; the term “C3-C8 halocycloalkane” used in this application "Group” refers to a cyclic alkyl group having 3 to 8 carbon atoms substituted with a halogen on the ring, and includes, without limitation, 1-chlorocyclopropyl, 1-fluorocyclopropyl, perfluorocyclopropyl , 1-chlorocyclobutyl, 1-chlorocyclopentyl and the like.
  • C 1 -C 6 , C 3 -C 8, etc. before the specific group indicate the number of carbon atoms contained in the group, for example, C 1 -C 6 indicates that the number of carbon atoms can be 1, 2 , 3, 4, 5, or 6 groups, C 3 -C 8 represent groups having 3 , 4, 5, 6, 7, or 8 carbon atoms, and so on.
  • the active ingredient B was selected. There are more than 680 known active ingredients of pesticides and more than 100 commonly used active ingredients. Most of them have developed different degrees of resistance. In actual production, the dosage must be increased. To use.
  • the active ingredient B is selected from any one or a combination of two pesticides or acaricides in the prior art.
  • the active ingredient B is selected from the group consisting of Chlorantraniliprole, flubendiamide, cyantraniliprole, tetrachlorantraniliprole, and Tetraniliprole. , Cyflufenamid, Cyclaniliprole, Fluxametamide, Fipronil, Ethiprole, Acetoprole, Indoxacarb , Metaflumizone, Chlorfenapyr, Tolfenpyrad, Lufenuron, Methoxyfenozide, Pyridalyl Species or a combination of both.
  • the pharmaceutical composition containing the metadiamide compound is a pharmaceutical composition containing the metadiamide compound (active ingredient A) and the active ingredient B described in Table 2 below, but not Limited to the combinations listed in the table.
  • the medicinal composition containing a metadiamide compound is a pharmaceutical composition containing the active ingredient A described in Table 1 and the active ingredient B described in the present application, and the active ingredient B is not limited to the present application Specific pesticide species listed.
  • the combined action of the pharmaceutical composition was tested using harmful organisms such as diamondback moth, armyworm, diploid pupae, Spodoptera exigua, brown planthopper, Spodoptera litura, and a composition having a synergistic effect was found.
  • the weight ratio of the active ingredient A and the active ingredient B described herein is 200: 1 to 1: 200, for example, 200: 1, 180: 1, 150: 1, 130: 1, 100: 1, 80: 1, and 60: 1, 40: 1, 20: 1, 10: 1, 1: 1, 1:10, 1:30, 1:50, 1:80, 1: 100, 1: 120, 1: 140, 1: 160, 1: 180 or 1: 200, etc.
  • the pharmaceutical composition containing the metadiamide compound has different preferred weight ratios according to the difference between the active ingredient A and the active ingredient B.
  • the active ingredient is When A and active ingredient B are selected from the components described in Table 3, their preferred weight ratios and particularly preferred weight ratios are shown in Table 3.
  • the isodiamide compound represented by Formula I shown in Table 3 as the active ingredient A is replaced with the isodiamide compound represented by Formula II, which also satisfies the preferred weight ratio in Table 3.
  • the m-diamide compound may also be replaced with a tautomer, an enantiomer, a diastereomer or a salt thereof.
  • a pharmaceutical composition containing the tautomer, enantiomer, diastereomer, or a salt of the m-diamide compound can also exert the same properties as the m-diamide-containing compound described in the present application.
  • the pharmaceutical composition has the same action effect, good insecticidal effect and fast-acting effect at a low dose.
  • the present application provides a pharmaceutical formulation comprising a pharmaceutical composition containing a metadiamide compound as described above and an agrochemically acceptable adjuvant and / or carrier as described above.
  • the weight percentage content of the mesodiamide compound-containing pharmaceutical composition is 0.01-99%, such as 0.01%, 0.1%, 1%, 3%, 5%, 8 %, 10%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99%, preferably 0.5 to 95%.
  • the agrochemically acceptable adjuvant includes any one or at least one of a dispersant, a wetting agent, an emulsifier, an antifreeze, a thickener, a defoamer, a preservative, a stabilizer, or a colorant. A combination of the two.
  • the dispersant includes lignin sulfonate, alkylphenol polyoxyethylene ether, naphthalenesulfonic acid formaldehyde condensate sodium salt, fatty amine polyoxyethylene ether, fatty acid polyoxyethylene ester, glycerin fatty acid ester polyoxylate Vinyl ether, polycarboxylate, formaldehyde condensate, calcium alkylbenzenesulfonate, alkylphenol polyoxyethylene ether.
  • the wetting agent is selected from the group consisting of sodium lauryl sulfate, alkyl naphthalene sulfonate, pulverized powder BX, polyoxyethylene ether, EO / PO block polyether, fatty alcohol polyoxyethylene ether, and fatty alcohol polyoxylate.
  • the emulsifier is selected from dodecylbenzenesulfonate, alkylnaphthalenesulfonate, alkylsulfonate, alkylphenol polyoxyethylene ether, benzylphenol polyoxyethylene, phenethylphenol polyoxyethylene Ether, fatty amine polyoxyethylene ether.
  • the antifreeze is selected from ethylene glycol, propylene glycol, and glycerol.
  • the thickener is selected from the group consisting of xanthan gum, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl starch, methyl cellulose, sodium starch phosphate, magnesium aluminum silicate, and polyvinyl alcohol.
  • the defoamer is selected from the group consisting of silicone oil, silicone compounds, tributyl phosphate, C10-20 saturated fatty acid compounds, and polyether defoamers.
  • the preservative is selected from the group consisting of formaldehyde, phenyl salicylate, butyl parahydroxybenzoate, and potassium sorbate
  • the stabilizer is selected from triphenyl phosphite, epichlorohydrin, epoxy soybean oil, and silicic acid.
  • Magnesium aluminum, the colorant is selected from the group consisting of azo pigments, titanium oxide, and iron oxide.
  • the carrier includes a filler and / or a solvent
  • the agrochemically acceptable carrier includes a solid carrier and / or a liquid carrier.
  • the solid support includes natural or synthetic clays and silicates, such as natural silica and diatomaceous earth; magnesium silicates such as talc; magnesium aluminum silicates such as kaolinite, kaolin, montmorillonite, and mica; White carbon black, calcium carbonate, light calcium carbonate; calcium sulfate; limestone; sodium sulfate; amine salts such as ammonium sulfate and hexamethylene diamine.
  • Liquid carriers include water and organic solvents.
  • Organic solvents include aromatic hydrocarbons such as xylene, benzene, xylene, toluene, etc .; chlorinated hydrocarbons such as chlorobenzene, vinyl chloride, trichloromethane, dichloromethane, etc .; aliphatic hydrocarbons such as petroleum distillates, Cyclohexane, light mineral oil; alcohols such as isopropanol, butanol, ethylene glycol, propylene glycol, glycerol, and cyclohexanol and their ethers and esters; ketones such as acetone, cyclohexanone, and dimethyl Formamide and N-methyl-pyrrolidone.
  • aromatic hydrocarbons such as xylene, benzene, xylene, toluene, etc .
  • chlorinated hydrocarbons such as chlorobenzene, vinyl chloride, trichloromethane, dichloromethane, etc .
  • the active ingredient may be mixed with a liquid carrier and / or a solid carrier, and auxiliary agents such as emulsifiers, dispersants, stabilizers, wetting agents, adhesives Mixtures, defoamers, antioxidants, etc.
  • auxiliary agents such as emulsifiers, dispersants, stabilizers, wetting agents, adhesives Mixtures, defoamers, antioxidants, etc.
  • the dosage form of the pharmaceutical preparation is a solution, a soluble powder, a soluble granule, an emulsifiable concentrate, a wettable powder, an aqueous emulsion, a suspending agent, a dispersible oil suspending agent, a water-dispersible granule, and a microcapsule suspending agent.
  • Granules, microemulsions, suspension emulsions, microcapsule suspension-suspensions ultra-low-volume liquids, hot aerosols, film-spreading oils, suspended seed coatings, dry powders for seeds, suspensions for seeds, and seeds for Powder dissolving agent, seed treatment dispersible powder, seed treatment emulsion or seed treatment liquid.
  • the dosage form of the pharmaceutical preparation is a solution, a soluble granule, a suspension, an emulsifiable concentrate, a wettable powder, an aqueous emulsion, a water-dispersible granule, a dispersible oil suspension, a microcapsule suspension, and an ultra-low capacity.
  • Liquid, hot aerosol, suspension seed coating or seed treatment dispersible powder is a solution, a soluble granule, a suspension, an emulsifiable concentrate, a wettable powder, an aqueous emulsion, a water-dispersible granule, a dispersible oil suspension, a microcapsule suspension, and an ultra-low capacity.
  • the present application provides the application of the pharmaceutical composition or pharmaceutical preparation containing the metadiamide compound as described above in the prevention, control of plant diseases or insect pests in agriculture, forestry, and horticulture.
  • the medicinal composition or medicinal preparation containing the metadiamide compound described in the present application is suitable for controlling various agricultural, forestry, horticultural pests and sanitary pests that harm rice, corn, wheat, potato, fruit trees, vegetables, other crops and flowers, and Disease.
  • the composition of the present application has a wide range of applications, and the scope of plants or crops to be applied mainly includes the following categories: vegetables, cucumbers, loofahs, watermelons, melon, pumpkins, hanging melon, spinach, celery, cabbage, cabbage, gourd, pepper, eggplant , Tomato, shallot, ginger, garlic, leek, strawberry, lettuce, kidney bean, cowpea, broad bean, radish, carrot, potato, yam; cereal, wheat, barley, corn, rice, sorghum; fruit tree, apple, pear, banana , Citrus, grape, lychee, mango; flowers, peony, rose, flamingo; oil crops, peanuts, soybeans, rape, sunflower, sesame; sugar crops, sugar beets, sugar cane; other crops, such as potatoes, sweet potatoes, tobacco and Tea; horticulture, forestry, home health, public health areas, etc .; the above-listed plants or crops have no limiting effect on the scope of use of the pharmaceutical
  • the pests include lepidoptera, coleoptera, hemiptera, tarptera, diptera, orthoptera, homoptera, isoptera, hymenoptera, and spider mite
  • said Diseases include diseases caused by semi-known bacteria, ascomycetes, basidiomycetes, and the like.
  • the pests include but are not limited to: cotton bollworm, diamondback moth, Spodoptera exigua, Spodoptera litura, Pieris rapae, diploid pupae, pupae trichoderma, big pupae, Spodoptera frugipera, rice leaf roller, rice Thrips, western flower thrips, melon thrips, onion thrips, ginger thrips, mango thrips, peach aphid, cotton aphid, alfalfa aphid, apple yellow aphid, wheat aphid, jumping beetle, stink bug, gray planthopper, Brown planthopper, white-backed planthopper, termite, mosquito fly, spider mite, citrus red spider.
  • the diseases include, but are not limited to, wheat scab, rice sheath blight, rice blast and the like.
  • the method of using the pharmaceutical composition or pharmaceutical preparation is spraying, soil treatment, seed treatment, or the like.
  • the present application provides the use of a pharmaceutical composition containing an m-bisamide compound as described above in seed treatment of plants, crops, or flowers.
  • the present application provides a method for controlling plant diseases and insect pests, which method is: applying an effective dose of the above-mentioned pharmaceutical composition containing metadiamide compounds to a plant disease to be controlled or a growth medium thereof Or pharmaceutical preparations.
  • the effective dose is 10-1000g per hectare, such as 10g, 20g, 50g, 80g, 100g, 120g, 150g, 180g, 200g, 250g, 300g, 350g, 400g, 450g, 500g, 600g, 700g, 800g 900g or 1000g, preferably 15-900g per hectare.
  • composition of the present application may be applied to the disease or its growth medium in the form of a formulation.
  • the compound of the general formula I (especially the compound of the general formula II) is dissolved or dispersed in a carrier as an active ingredient or formulated into a formulation for easier dispersion when used as a fungicide.
  • these chemical preparations can be formulated as solution, emulsifiable concentrate, wettable powder, water emulsion, suspension, dispersible oil suspension, water-dispersible granule, seed treatment, microcapsule suspension, granule, microemulsion , Suspension emulsion, suspension-microcapsule suspension and so on.
  • the pharmaceutical composition of the present application has the following advantages in use:
  • composition of active ingredient A and active ingredient B in this application has a synergistic effect.
  • the amount of the composition used is greatly reduced compared with the single active ingredient alone, and the control effect is significantly improved; due to the significant resistance of active ingredient A to resistant pests
  • the activity also solves the diseases and insect pests of important crops such as pupae, diamondback moth and other important crops.
  • the drug resistance can be delayed after compounding, which is an effective resistance risk management tool and extends the life cycle of the drug.
  • the active ingredient A described in this application is compounded with the active ingredient B of different control objects, which expands the spectrum of control and saves labor costs of medication, and can be applied to vegetables, fruit trees, flowers, cereals, oil, sugar, etc. Crops, horticulture, forestry, health and various diseases and insect pests. In addition, it has extremely high activity against newly emerged Spodoptera frugiperda, which can be used for emergency prevention and control, which is conducive to maintaining environmental ecological security and social stability.
  • Methyl 2-fluoro-3- (N- (cyclopropylmethyl) benzamide) benzoate (13.00 g, 40.88 mmol) was dissolved in methanol (100 mL), and a 10% aqueous sodium hydroxide solution (6.54 g) was added. , 163.52 mmol, 65.4 mL), after stirring at room temperature for 2 h, the reaction was monitored by TLC for completion. The methanol was concentrated and removed under reduced pressure. The concentrated residue was dissolved in water (100 mL) and extracted with ethyl acetate (50 mL). The organic phase was discarded, and the pH of the aqueous phase was adjusted to 7 with a 2M aqueous hydrochloric acid solution.
  • 2-Bromo-6-trifluoromethyl-4-heptafluoroisopropylaniline (0.52 g, 1.28 mmol) was dissolved in tetrahydrofuran (4 mL), and lithium diisopropylaminoamide (0.77 mL) was added dropwise at -70 ° C. , 1.54 mmol), 5 minutes later, a tetrafluorofuran solution of 2-fluoro-3- [N- (cyclopropylmethyl) benzamido] benzoyl chloride synthesized in one step was added dropwise, stirred at -70 ° C for 30 minutes, and raised to Stirring was continued for 30 min at room temperature.
  • a saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Methyl 2-fluoro-3-aminobenzoate (2.00 g, 11.82 mmol) was dissolved in 1,2-dichloroethane (65 mL), and cyclopropylmethyl ketone (2.98 g, 35.47 mmol) was sequentially added at room temperature. ), Trifluoroacetic acid (8.08 g, 70.92 mmol) and sodium triacetoxyborohydride (7.51 g, 35.47 mmol). The reaction was heated to 45 ° C. for 1 h. When TLC monitored that the reaction was no longer in progress, the reaction was terminated. A saturated NaHCO 3 solution (50 mL) was added to the reaction solution, and extracted with dichloromethane (80 mL).
  • composition of 40% compound 8 lice mite urea cream is shown in Table 5:
  • Preparation method Calculate the amount of each material according to the formula, add 200 # solvent oil to the batching kettle, and then add compound 8 and lufenuron to dissolve completely, then add calcium dodecylbenzenesulfonate and castor oil polyoxyethylene Ether was added, and the mixture was stirred at 40 to 50 ° C. for 1.5 hours, and filtered to obtain 40% compound 8 ⁇ carnitur cream.
  • composition of 30% Compound 4 ⁇ Fipronil Suspension Seed Coating is shown in Table 6:
  • Preparation method In a batching kettle, according to the material ratio, deionized water, compound 4, fipronil, FS3000, TER4894, Casson, SAG1522, and propylene glycol are sanded after shearing to control the particle size of D90 and about 5 microns, and then Transfer to a blending kettle, add 2% xanthan gum solution, pigment F2R, and stir for 1 hour to obtain 30% Compound 4 ⁇ Fipronil seed coating.
  • Chlorantraniliprole Water-Dispersible Granules is shown in Table 7:
  • Preparation method Calculate the amount of each material according to the formula, and mix compound 6, chlorantraniliprole, sodium lauryl sulfate, sodium lignin sulfonate, sodium naphthalene formaldehyde polymer sulfonate, ammonium sulfate, corn starch, and kaolin Homogeneous, pulverized to an average particle size of 10 to 15 microns by a jet mill, kneaded with 17% of the powder, and then granulated by rotary extrusion, dried at 50 ° C for 3 hours, and sieved to obtain 25% of the compound 6. Chlorantraniliprole water dispersible granules.
  • Active ingredient A Bromocyanide 14
  • Active ingredient B Fatty alcohol polyoxyethylene ether 1.5 moisturizer Tristyryl phenol polyoxyethylene ether phosphate 2
  • Dispersant Propylene glycol 4 antifreeze 1% xanthan gum solution 10
  • Thickener Casson 0.1 preservative Polydimethylsiloxane 0.2 Silicone defoamer Deionized water make up 100 Carrier
  • Preparation method Calculate the amount of each material according to the formula, stir and dissolve the deionized water, propylene glycol, tristyryl phenol polyoxyethylene ether phosphate, sodium lignin sulfonate, carson, and defoamer, and add bromocyanide Amide and compound 8 were sheared uniformly, and then ground to an average particle diameter of 2 microns by a sand mill, and 10 parts of a 1% xanthan gum solution was added and stirred for 30 minutes to obtain 24% compound 8 ⁇ bromocyanide suspension.
  • Preparation method Calculate the amount of each material according to the formula, and mix compound 7, methoxyfenozide, sodium lauryl sulfate, sodium lignin sulfonate, sodium naphthalene formaldehyde polymer sulfonate, ammonium sulfate, corn starch, and kaolin Evenly, pulverize to an average particle size of 10 to 15 microns with a jet mill, knead with 17% of the powder, and then granulate by rotary extrusion, dry at 50 ° C for 3 hours, and sieving to obtain 30% of the compound. 7. Water-dispersible granules of methoxyfenozide.
  • Preparation method Calculate the amount of each material according to the formula. Dissolve compound 10, cyanfludizone, polyaryl polymethylene polyisocyanate, and xylene uniformly at 40-50 degrees as Phase A; take deionized water separately.
  • phase B D-800, propylene glycol, dissolve uniformly, as phase B; under high shear, slowly add phase A to phase B, cut to an average particle size of 2 to 3 microns, then add the material to a three-necked flask, add hexane Diamine, stirred and reacted at 50-60 ° C for 10 hours, and added tristyrenol phenol polyoxyethylene ether phosphate, carson, defoamer, 1% xanthan gum solution, and stirred for 1 hour to obtain 27% compound 10 ⁇ Cyflufenazone microcapsule suspension.
  • composition of the 25% compound 6, pyraclostrobin wettable powder is shown in Table 11:
  • Preparation method Calculate the amount of each material according to the formula. Put compound 6, pyraclostrobin, sodium dodecyl sulfate, sodium lignin sulfonate, and kaolin in the batching kettle. After mixing well, use a jet mill to pulverize to the average particle size. With a diameter of 10 micrometers, 25% of the compound 6. azoxystrobin wettable powder is obtained. .
  • composition of the 15% compound 7 ⁇ fluorooxazole amide dispersible liquid agent is shown in Table 12:
  • Active ingredient A Fluoxamide 10 Active ingredient B 100 solvent oil 15 Solvent Cyclohexanone 10 Solvent Castor oil polyoxyethylene ether (EL40) 5 Dispersant Fatty alcohol polyoxyethylene ether 10 moisturizer Polydimethylsiloxane emulsion (SAG1522) 0.2 Defoamer Deionized water Make up 100 Carrier
  • Preparation method In a batching kettle, according to the process ratio, add No. 100 solvent oil and cyclohexanone, add compound 7, fluorooxazole amide with stirring, and heat to 50 ° C. After the solvent is completely added, add EL40 and fatty alcohol polyoxyethylene. After the ether and SAG1522 were stirred for 10 minutes, deionized water was added after the temperature was reduced to obtain 15% compound 7 ⁇ fluorooxazole amide dispersible liquid agent.
  • Formulation agent 9 28% Compound 1 ⁇ Ethionil water emulsion
  • Preparation method In a batching kettle, first add solvent oil No. 150, then start stirring, add compound 1 and stir to dissolve. After the dissolution is complete, add acetonitrile and emulsifier TERMUL5030, continue stirring for 20 minutes, and mix evenly as the oil phase Put in deionized water, defoamer and antifreeze in the shear kettle, turn on the shearing device, and slowly add the oil phase materials after 5 minutes, and then shear for 10 minutes after adding, to obtain 28% compound 1 ⁇ Ethyl nitrile water emulsion.
  • Bioassay Example 1 When the active ingredient A is a compound of formula II, it has significant insecticidal activity against a variety of pests
  • Targets Plutella xylostella 3rd instar larvae, armyworm 3rd instar larvae, diploid pupae 3rd instar larvae, all reared indoors.
  • Plutella xylostella + leaf soaking feeding method With reference to NY / 1154.14-2008, the main operation description is as follows: immerse the clean bract leaf dish in the medicinal solution for 10s, dry it and place it in petri dishes, 4 dishes per dish, put filter paper in the petri dish to moisturize. Ten dishes of Plutella xylostella were received in each dish and repeated three times. It was placed in a light incubator at a temperature of 25 ° C under 14hL: 10hD and cultured. The number of dead and live insects of Plutella xylostella was investigated 3 days after the administration, and the mortality was calculated.
  • Feeding on slime + dipping leaf With reference to NY / 1154.14-2008, the main operation description is as follows: immerse the clean corn leaf section in the medicinal solution for 10s, dry it and place it in petri dishes, 4 pieces per dish, put filter paper in the petri dish to moisturize. Ten dishes of slimeworms were received in each dish, and 3 replicates were performed. It was placed in a light incubator at a temperature of 25 ° C under 14hL: 10hD and cultured. The number of dead and live insects of the armyworm was investigated 3 days after the administration, and the mortality was calculated.
  • Bioassay Example 2 Composition of active ingredient A being a compound of formula II and active ingredient B being chlorantraniliprole, flubendiamide, bromocyanidin, etc., tested against Plutella xylostella
  • Target Plutella xylostella, 3rd instar larva
  • Theoretical mortality 1-(1-mortality of active ingredient A at this dose) (1-mortality of active ingredient B at this dose)
  • Synergistic effect ⁇ 20 means significant synergy; 10 ⁇ synergistic effect ⁇ 20, synergistic effect; -10 ⁇ synergistic effect ⁇ 10, synergistic effect; synergistic effect ⁇ -10, antagonistic, negative value The greater the degree of antagonism.
  • Test agent or combination name Dose mg / L 3d mortality% Theoretical mortality% Synergy effect Joint mode of action Compound 1 0.01 36.67 / / / Compound 4 0.01 43.33 / / / Compound 8 0.02 53.33 / / /
  • Bioassay Example 3 A composition in which the effective ingredient A is a compound of formula II and the effective ingredient B is bromocrifamide, tetracloprid, cycloprofenil and the like, and has a synergistic effect on rice diploid
  • Target 3rd instar larvae of pupae, indoor breeding.
  • Test agent or combination name Dose mg / L 3d mortality% Theoretical mortality% Synergy effect Joint mode of action Compound 4 0.4 53.33 / / / Compound 5 1.0 63.33 Zh Zh Zh Compound 6 1.00 56.67 / / / Compound 7 0.5 50 / / / Compound 8 0.5 56.67 / / / Compound 9 1.0 66.67 / / / Compound 10 0.5 33.33 / / / Compound 11 1.25 76.67 / / / Compound 12 1.00 56.67 / / / Compound 13 0.5 33.33 / / Bromocyanide 4.0 53.33 / / / Tetrachloropyramid 2.5 70 / / / Cypromethoxam 1.0 66.67 / / / Compound 4 + Bromocyanid 0.4 + 4.0 100 78.22 21.78 Significant synergy Compound 5 +
  • Bioassay Example 4 The composition of active ingredient A is a compound of formula II and active ingredient B is fipronil, ethiprole, acetapronil, etc., and its activity is tested against brown planthopper
  • Target Brown planthopper, 3rd instar nymph.
  • the evaluation method is the same as the standard test example 2.
  • Test agent or combination name Dose mg / L 3d mortality% Theoretical mortality% Synergy effect Joint mode of action Compound 6 10 60.00 / / / Compound 8 5 71.55 / / / Compound 10 10 78.29 / / / Fipronil 2.5 53.22 / / / Ethiprole 80 61.86 / / / Acetofen 100 45.35 / / / Compound 6+ fipronil 10 + 2.5 100 81.33 18.67 Synergy Compound 8 + ethiprole 10 + 80 100 89.15 10.85 Synergy Compound 10+ Acetonitrile 10 + 100 100 88.14 11.86 Synergy
  • Bioassay Example 5 When the active ingredient A is a compound of formula II and the active ingredient B is indoxacarb, fenprofen, fenflubenzuron, acetamiprid, etc., the activity test on the armyworm
  • Soaking method The operation description is as follows: With reference to NY / 1154.6-2006, the main operation description is as follows: immerse 10 test insects in the medicinal solution for 10s, dry them and place them in petri dishes, put 4 clean corn leaf sections in each dish, and petri dishes Put filter paper inside to moisturize. 3 repetitions. It was placed in a light incubator at a temperature of 25 ° C under 14hL: 10hD and cultured. The number of dead insects of the armyworm was investigated 3 days after the administration, and the mortality was calculated.
  • the evaluation method was the same as that in Example 2.
  • Test agent or combination name Dose mg / L 3d mortality% Theoretical mortality% Synergy effect Joint mode of action Compound 2 0.04 53.33 / / / Compound 3 0.04 60 / / / Compound 5 0.04 75 / / / /
  • Bioassay Example 6 Tests on the activity of Spodoptera litura when the active ingredient A is a compound of formula I and the active ingredient B is methoxyfenozide, lufenuron, and acetamiprid.
  • Leaf soaking method 3rd instar larva.
  • the operation description is as follows: immerse the clean bract leaf dish in the medicinal solution for 10s, dry it, and place it in a 24-well plate. Each hole is connected with one Spodoptera litura test insect and each handles 24. It was placed in a light incubator at a temperature of 25 ° C under 14hL: 10hD and cultured. The number of dead insects was investigated 3 days after the treatment, and the mortality was calculated.
  • Test agent or combination name Dose mg / L 5d mortality% Theoretical mortality% Synergy effect Joint mode of action Compound 1 1.0 73.33 / / / Compound 4 0.4 60.00 / / / Compound 6 1.0 50.00 / / / Methoxyfenozide 4.0 40.00 / / / Lufenuron 0.8 50.00 / / / Acetamiprid 20 46.67 / / / Compound 1 + Methofenazide 1.0 + 4.0 100 84.00 16.00 Synergy Compound 4+ 0.4 + 0.8 100 80.00 20.00 Significant synergy Compound 6+ acetamiprid 1.0 + 20 100 73.33 26.67 Significant synergy
  • Bioassay Example 7 Test of the activity of a combination of compound 8 and tetrazole on dioxin
  • Insect source 3rd instar larvae of pupae, indoor breeding.
  • Example 1 Rice stalk immersion method, the operation description is described in Example 1.
  • the evaluation method is referred to NY / T1154.7-2006, and the co-toxicity coefficient is used for evaluation.
  • the co-toxicity coefficient (CTC value) of the mixture is calculated according to formula (1), formula (2), and formula (3):
  • LC 50 of M-mixture, unit is milligram per liter (mg / L).
  • the percentage content of PA-A agent in the mixture is percentage (%);
  • the percentage content of PB-B agent in the mixture is percentage (%).
  • CTC co-toxicity coefficient
  • ATI mixed measured virulence index
  • TTI mixed theoretical virulence index
  • the co-toxicity coefficient (CTC) ⁇ 120 of the compounding agent is synergistic; CTC ⁇ 80 is antagonistic; 80 ⁇ CTC ⁇ 120 is additive.
  • Bioassay Example 8 Activity test of a composition of compound 9 and fluoxazole amide on Plutella xylostella
  • Insect source Plutella xylostella 3rd instar larvae, reared indoors.
  • Bioassay Example 9 Activity test of a composition of compound 3 and cyanofazone on Spodoptera exigua
  • Insect source 3rd instar larvae of Spodoptera exigua, reared indoors.
  • Soaked leaf dish feeding method Soaked leaf dish feeding method. The operation description is as follows: immerse the clean bract leaf dish in the medicinal solution for 10s, dry it, and place it in a 24-well plate. Each well receives one test of beet armyworm, and each handles 24. It was placed in a light incubator at a temperature of 25 ° C under 14hL: 10hD and cultured. The number of dead insects was investigated 3 days after the treatment, and the mortality was calculated.
  • Bioassay Example 10 Activity test of a combination of compound 7 and ethiprole against brown planthopper
  • Target Brown planthopper, 3rd instar nymph.
  • Bioassay Example 11 Activity test of a compound 12 and acarid urea on Plutella xylostella
  • Insect source Plutella xylostella 3rd instar larvae, reared indoors.

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Abstract

一种含有间二酰胺类化合物的药物组合物及其应用，所述药物组合物包括有效成分A和有效成分B，所述有效成分A为具有式I所示结构的间二酰胺类化合物，所述有效成分B为其他杀虫剂或杀菌剂中任意一种或两种的组合。所述含有效成分A和有效成分B的组合物，具有协同增效、治理抗性害虫，扩大活性谱、控制传毒昆虫等独特作用，可有效防治水稻、玉米、小麦、蔬菜、果树、花卉、油料、糖料等作物及园艺、林业上的多种病虫害。

Description

一种含有间二酰胺类化合物的药物组合物及其应用 技术领域
本申请属于药物组合物防治有害生物的技术领域，涉及一种含有间二酰胺类化合物的药物组合物及其应用，尤其涉及一种含有间二酰胺类化合物与氯虫苯甲酰胺、氟苯双酰胺、溴氰虫酰胺、四氯虫酰胺、四唑虫酰胺、氯氟氰虫酰胺、环溴虫酰胺、氟噁唑酰胺、氟虫腈、乙虫腈、乙酰虫腈、茚虫威、虫螨腈、氰氟虫腙、唑虫酰胺、甲氧虫酰肼、虱螨脲、啶虫丙醚等杀虫剂的组合物及其应用。
背景技术
在农业及园艺等作物生产中，由病虫害等引起的侵害依然非常显著，害虫对现有杀虫剂产生抗性及现有农药的环境不友好等原因，一直需要开发活性更好、用量更低、环境更友好的新杀虫剂或者杀虫剂组合物。
例如CN101208009A公开了含有间二酰胺类化合物的组合物具有杀虫效果，现有技术中各种不同结构类型的杀虫剂、杀菌剂广泛用于各种不同的农作物。随着农药的不断使用，病虫害会对一些现有农药产品产生抗性，现有农药品种的杀虫活性不总是能满足许多农业实践的需要。杀虫剂组合物对提高杀虫剂的防效、扩大防治谱和延缓抗性产生具有重要的作用。因此，在本领域中，仍然期望开发出更加高效的杀虫剂组合物或杀虫杀菌组合物以满足农业以及林木业需求。
发明内容
针对现有技术存在的问题，本申请的目的在于提供一种含有间二酰胺类化合物的药物组合物及其应用，所述药物组合物具有协同增效作用，能够防治由害虫引起的多种农业、林业虫害。
为达此目的，本申请采用以下技术方案：
一方面，本申请提供一种含有间二酰胺类化合物的药物组合物，所述药物组合物包括有效成分A和有效成分B，所述有效成分A为具有式I所示结构的酰胺类化合物，所述有效成分B包括其他杀虫剂中任意一种或两种的组合；
Figure PCTCN2019099950-appb-000001
其中，Z选自氢、氟、氯、溴、碘、氰基、硝基、取代或未取代的3-10元杂环基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷基亚磺酰基、C 1-C 6卤代烷基亚磺酰基、C 1-C 6烷基磺酰基或C 1-C 6卤代烷基磺酰基；Q选自C 3-C 8环烷基或C 3-C 8卤代环烷基；
X选自氢、氟或三氟甲基；
Y 1选自氟、氯、溴、碘、氰基、硝基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 4烯基、C 2-C 4卤代烯基、C 2-C 4炔基、C 2-C 4卤代炔基、C 3-C 8环烷基、C 3-C 8卤代环烷基、C 1-C 6烷基羰基、C 1-C 6烷基亚磺酰基、C 1-C 6卤代烷基亚磺酰基、C 1-C 6烷基磺酰基或C 1-C 6卤代烷基磺酰基；
Y 2选自溴、碘、氰基、硝基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 4烯基、C 2-C 4卤代烯基、C 2-C 4炔基、C 2-C 4卤代炔基、C 3-C 8环烷基、C 3-C 8卤代环烷基、C 1-C 6烷基羰基、C 1-C 6烷基亚磺酰基、C 1-C 6卤代烷基亚磺酰基、C 1-C 6烷基磺酰基或C 1-C 6卤代烷基磺酰基；
R 1选自氢、氟或甲氧基；R 2选自氟或三氟甲基；R 3和R 4分别独立地选自氢、卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 8环烷基或C 3-C 8卤代环烷基；
m表示0～5的整数(例如0、1、2、3、4或5)；n表示0～3的整数(例如0、1、2或3)；W 1和W 2独立地为氧原子或硫原子。
以本申请所述的式I所示结构的间二酰胺类化合物作为有效成分A，并配合有效成分B的药物组合物，由于有效成分A和有效成分B之间的协同增效作用，一方面可以减少单一活性成分的使用量，另一方面防治效果显著提高。
优选地，本申请提供一种含有间二酰胺3位为N-环丙甲基衍生物取代的化合物的药物组合物，所述药物组合物包括有效成分A和有效成分B，所述有效成分A为具有式II所示结构的间二酰胺类化合物，所述有效成分B包括其他杀菌剂、杀虫剂或杀螨剂中任意一种或两种的组合；
Figure PCTCN2019099950-appb-000002
式II中，
Z选自氢、氟、氯、溴、碘、氰基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 1-C 6烷基磺酰基或C 1-C 6卤代烷基磺酰基；
Y选自C 1-C 6卤代烷基或C 1-C 6卤代烷氧基；
R选自氢或甲基。
本申请中，进一步优选了具有式II所示结构的间二酰胺类化合物，与有效成分B配合作为药物组合物的有效成分，二者协同增效，起效快，具有良好的速效性，在低剂量下能够达到较好的效果，使得药物残留少，更加利于环保。
本申请中，作为优选技术方案，在式I中，Z选自氢、氟、氯、溴、碘、氰基、三氟甲氧基、三氟甲基、甲磺酰基或三氟甲磺酰基；Y选自三氟甲基或三氟甲氧基；R选自氢或甲基。
作为本申请进一步优选的技术方案，所述间二酰胺类化合物为具有通式II的如下表1所示化合物中的任意一种。
表1有效成份A
Figure PCTCN2019099950-appb-000003
表1中H为氢原子、F代表氟原子、Cl代表氯原子、Br代表溴原子、I代表碘原子、CN代表氰基、CF 3为三氟甲基、OCF 3为三氟甲氧基、MeS(O) 2代表甲磺酰基、CF 3S(O) 2代表三氟甲磺酰基。
本申请中，作为特别优选的技术方案，所述间二酰胺类化合物为选自以下化合物1-14中的任意一种或至少两种的组合：
Figure PCTCN2019099950-appb-000004
本申请所用术语“C 1-C 6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、特丁基、正戊基、异戊基、正己基等。术语“C 1-C 6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、正丙氧基、异丙氧基、特丁氧基等。术语“C 1-C 6卤代烷基”是指具有卤素取代的1至6个碳原子的烷基，非限制性地包括氯甲基、1-氯乙基、2-溴正丙基等。术语“C 1-C 6卤代烷氧基”是指具有卤素取代的1至6个碳原子的烷氧基；同理术语“C 3-C 8环烷基”是指在环上具有3至8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、 环己基、环庚基、环辛基等；本申请所用术语“C3-C8卤代环烷基”是指在环上具有卤素取代的3至8个碳原子的环状烷基，非限制性地包括1-氯代环丙基、1-氟代环丙基、全氟代环丙基、1-氯代环丁基、1-氯代环戊基等。
在本申请中，所述特定基团之前的C 1-C 6、C 3-C 8等表示基团中所含碳原子个数，例如C 1-C 6表示碳原子数可以为1、2、3、4、5或6的基团，C 3-C 8表示碳原子数可以为3、4、5、6、7或8的基团等等，以此类推。
本申请中对有效成份B进行了选择，已知的农药有效成份有680多种，常用有效成份有100多种，大多数已经产生不同程度的抗药性，在实际生产中不得不加大用药量来使用。所述有效成分B选自现有技术中的杀虫剂或杀螨剂中的任意一种或两种的组合。
优选地，所述有效成分B选自氯虫苯甲酰胺(Chlorantraniliprole)、氟苯双酰胺(flubendiamide)、溴氰虫酰胺(cyantraniliprole)、四氯虫酰胺(tetrachlorantraniliprole)、四唑虫酰胺(Tetraniliprole)、氯氟氰虫酰胺、环溴虫酰胺(Cyclaniliprole)、氟噁唑酰胺(Fluxametamide)、氟虫腈(Fipronil)、乙虫腈(Ethiprole)、乙酰虫腈(Acetoprole)、茚虫威(Indoxacarb)、氰氟虫腙(Metaflumizone)、虫螨腈(Chlorfenapyr)、唑虫酰胺(Tolfenpyrad)、虱螨脲(Lufenuron)、甲氧虫酰肼(Methoxyfenozide)、啶虫丙醚(Pyridalyl)中的任意一种或两种的组合。
作为本申请进一步优选的技术方案，所述含有间二酰胺类化合物的药物组合物为含有下表2中所述间二酰胺类化合物(有效成分A)和有效成分B的药物组合物，但不限于表中所列组合。
表2
Figure PCTCN2019099950-appb-000005
Figure PCTCN2019099950-appb-000006
Figure PCTCN2019099950-appb-000007
Figure PCTCN2019099950-appb-000008
作为本申请的优选技术方案，所述含有间二酰胺类化合物的药物组合物为含有表1中所述有效成分A和本申请所述有效成分B的药物组合物，有效成份B不限于本申请所具体列举的杀虫剂品种。
本申请采用小菜蛾、粘虫、二化螟、甜菜夜蛾、褐飞虱、斜纹夜蛾等有害生物测试了药物组合物的联合作用，发现了具有增效作用的组合物。
本申请所述有效成分A和有效成分B的重量比是200:1～1:200，例如200:1、180:1、150:1、130:1、100:1、80:1、60:1、40:1、20:1、10:1、1:1、1:10、1:30、1:50、1:80、1:100、1:120、1:140、1:160、1:180或1:200 等。
在本申请中，所述含有间二酰胺类化合物的药物组合物，根据其含有的有效成分A和有效成分B的不同，其优选重量配比不同，作为本申请的优选技术方案，当有效成分A和有效成分B选择表3中所述成分时，其优选的重量配比以及特别优选的重量配比如表3所示。
表3
Figure PCTCN2019099950-appb-000009
更优选地，将表3中有效成分A所示式I所述间二酰胺类化合物替换为式II所述间二酰胺类化合物，同样满足表3中的优选重量配比。
在本申请中，所述间二酰胺类化合物还可以替换为其互变异构体、对映体、非对映体或其盐。
在本申请中，包含所述间二酰胺类化合物的互变异构体、对映体、非对映体或其盐的药物组合物同样能够发挥与本申请所述含有间二酰胺类化合物的药物组合物同样的作用效果，在低剂量下杀虫效果好、速效性佳。
另一方面，本申请提供了一种药物制剂，所述药物制剂包括如上所述的含有间二酰胺类化合物的药物组合物以及农药学上可接受的助剂和/或载体。
优选地，在所述药物制剂中，所述含有间二酰胺类化合物的药物组合物的重量百分含量为0.01-99％，例如0.01％、0.1％、1％、3％、5％、8％、10％、15％、18％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％或99％，优选为0.5～95％。
优选地，所述农药学上可接受的助剂包括分散剂、润湿剂、乳化剂、防冻剂、增稠剂、消泡剂、防腐剂、稳定剂或染色剂中的任意一种或至少两种的组合。
优选地，所述分散剂包括木质素磺酸盐、烷基酚聚氧乙烯醚、萘磺酸甲醛缩合物钠盐、脂肪胺聚氧乙烯醚、脂肪酸聚氧乙烯酯、甘油脂肪酸酯聚氧乙烯醚、聚羧酸盐、甲醛缩合物、烷基苯磺酸钙盐、烷基酚聚氧乙烯醚。所述润湿剂选自十二烷基硫酸钠、烷基萘磺酸盐、拉开粉BX、聚氧乙烯醚、EO/PO嵌段聚醚、脂肪醇聚氧乙烯醚、脂肪醇聚氧乙烯醚硫酸盐、烷基磷酸钠、烷基萘磺酸盐、烷基酚聚氧乙烯基硫酸钠。所述乳化剂选自十二烷基苯磺酸盐、烷基萘磺酸盐、烷基磺酸盐、烷基酚聚氧乙烯醚、苄基酚聚氧乙烯、苯乙基酚聚氧乙烯醚、脂肪胺聚氧乙烯醚。所述防冻剂选自乙二醇、丙二醇和丙三醇。所述增稠剂选自黄原胶、羟甲基纤维素、羟乙基纤维素、羟丙基淀粉、甲基纤维素、淀粉磷酸酯钠、硅酸镁铝和聚乙烯醇。所述消泡剂选自硅油、硅酮类化合物、磷酸三丁酯、C10～20饱和脂肪酸类化合物和聚醚类消泡剂。所述防腐剂选自甲醛、水杨酸苯酯、对羟基苯甲酸丁酯和山梨酸钾，所述稳定剂选自亚磷酸三苯酯、环氧氯苯烷、环氧大豆油和硅酸镁铝，所述染色剂选自偶氮颜料、氧化钛和氧化铁。
优选地，所述载体包括填料和/或溶剂；
优选地，所述农药学上可接受的载体包括固体载体和/或液体载体。
优选地，所述固体载体包括天然的或合成的粘土和硅酸盐，例如天然硅石和硅藻土；硅酸镁例如滑石；硅酸铝镁例如高岭石、高岭土、蒙脱土和云母；白碳黑、碳酸钙、轻质碳酸钙；硫酸钙；石灰石；硫酸钠；胺盐如硫酸铵、六甲撑二胺。液体载体包括水和有机溶剂，有机溶剂包括芳烃例如三甲苯、苯、二甲苯、甲苯等；氯代烃例如氯代苯、氯乙烯、三氯甲烷、二氯甲烷等；脂肪烃例如石油馏分、环己烷、轻质矿物油；醇类例如异丙醇、丁醇、乙二醇、丙二醇、丙三醇和环己醇以及它们的醚和酯；酮类例如丙酮、环己酮以及二甲基甲酰胺和N-甲基-吡咯烷酮。
在杀虫剂组合物(即所述药物制剂)的配制过程中可以将活性组分与液体载体和/或固体载体混合，同 时加入助剂如乳化剂、分散剂、稳定剂、湿润剂、粘合剂、消泡剂、抗氧化剂等。
优选地，所述药物制剂的剂型为可溶液剂、可溶粉剂、可溶粒剂、乳油、可湿性粉剂、水乳剂、悬浮剂、可分散油悬浮剂、水分散粒剂、微囊悬浮剂、颗粒剂、微乳剂、悬浮乳剂、微囊悬浮-悬浮剂、超低容量液剂、热雾剂、展膜油剂、悬浮种衣剂、种子处理干粉剂、种子处理悬浮剂、种子处理可溶粉剂、种子处理可分散粉剂、种子处理乳剂或种子处理液剂。
优选地，所述药物制剂的剂型为可溶液剂、可溶粒剂、悬浮剂、乳油、可湿性粉剂、水乳剂、水分散粒剂、可分散油悬浮剂、微囊悬浮剂、超低容量液剂、热雾剂、悬浮种衣剂或种子处理可分散粉剂。
另一方面，本申请提供了如上所述的含有间二酰胺类化合物的药物组合物或药物制剂在农业、林业、园艺上防治植物病害或虫害中的应用。
本申请所述的含有间二酰胺类化合物的药物组合物或药物制剂适用于防治危害水稻、玉米、小麦、马铃薯、果树、蔬菜、其它作物及花卉等的各种农林、园艺虫害及卫生害虫和病害。
本申请组合物应用范围广泛，所应用的植物或作物范围主要包括以下几类：蔬菜类，黄瓜、丝瓜、西瓜、甜瓜、南瓜、吊瓜、菠菜、芹菜、甘蓝、白菜、葫芦、辣椒、茄子、番茄、葱、姜、蒜、韭菜、草莓、莴笋、菜豆、豇豆、蚕豆、萝卜、胡萝卜、马铃薯、山药；禾谷类，小麦、大麦、玉米、水稻、高粱；果树类，苹果、梨、香蕉、柑橘、葡萄、荔枝、芒果；花卉类，牡丹、月季、火鹤；油料作物，花生、大豆、油菜、向日葵、芝麻；糖料作物，甜菜、甘蔗；其他作物，如马铃薯、甘薯、烟草和茶；园艺、林业、家庭卫生、公共卫生区域等；以上列举植物或作物范围对药物组合物使用范围无限制作用。
在本申请中，所述害虫包括鳞翅目、鞘翅目、半翅目、缨翅目、双翅目、直翅目、同翅目、等翅目、膜翅目、叶螨害虫，所述病害包括由半知菌、子囊菌、担子菌等引起的病害。
优选地，所述害虫包括但不限于：棉铃虫、小菜蛾、甜菜夜蛾、斜纹夜蛾、菜青虫、二化螟、三化螟、大螟、草地夜蛾、稻纵卷叶螟、稻蓟马、西花蓟马、瓜蓟马、葱蓟马、大姜蓟马、芒果蓟马、桃蚜、棉蚜、苜蓿蚜、苹果黄蚜、麦蚜、跳甲、椿象、灰飞虱、褐飞虱、白背飞虱、白蚁、蚊蝇、朱砂叶螨、柑橘红蜘蛛。所述病害包括但不限于小麦赤霉病、水稻纹枯病、水稻稻瘟病等。
在本申请中，所述药物组合物或药物制剂的使用方式为喷雾、土壤处理、种子处理等。
另一方面，本申请提供了如上所述的含有间二酰胺类化合物的药物组合物在植物、作物或花卉的种子处理中的应用。
另一方面，本申请提供一种防治植物病虫害的方法，所述方法为：向需要控制的植物病害或其生长的介质上施用有效剂量的如上所述的含有间二酰胺类化合物的药物组合物或药物制剂。
优选地，所述有效剂量为每公顷10-1000g，例如10g、20g、50g、80g、100g、120g、150g、180g、200g、250g、300g、350g、400g、450g、500g、600g、700g、800g、900g或1000g，优选每公顷15-900g。
本申请的组合物可以制剂的形式施用在病害或其生长介质上。通式I化合物(特别是通式II化合物)作为活性组分溶解或分散于载体中或配制成制剂以便作为杀菌剂使用时更易于分散。例如：这些化学制剂可被配制成可溶液剂、乳油、可湿性粉剂、水乳剂、悬浮剂、可分散油悬浮剂、水分散粒剂、种子处理剂、微囊悬浮剂、颗粒剂、微乳剂、悬浮乳剂、悬浮-微囊悬浮剂等。
相对于现有技术，本申请具有以下有益效果：
本申请药物组合物与传统杀虫剂相比，在使用中具有以下优点：
(1)本申请中有效成分A和有效成分B的组合物具有协同增效作用，组合物使用量较单一活性成分单独使用时大大降低，防治效果显著提高；由于有效成份A对抗性害虫的显著活性，也解决了抗性二化螟、小菜蛾等重要农作物病虫害的防控用药。
(2)因为有效成份A和有效成份B的不同作用机制，复配后可以延缓药剂抗药性产生，是有效的抗性风险管理工具，延长了药剂生命周期。
(3)本申请所述有效成分A与不同防治对象的有效成分B进行复配组合，扩大了防治谱，节省用药人工成本，可应用于蔬菜、果树、花卉、禾谷、油料、糖料等作物及园艺、林业、卫生上的多种病虫害，此外，针对新出现的草地贪夜蛾具有极高的活性，可用于紧急防控，有利于维护环境生态安全和社会稳定。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
合成实施例
合成实施例1
N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)-苯甲酰胺基]-2-氟苯甲酰胺(化合物编号1)的制备：
(1)2-氟-[3-(环丙甲基)胺基]苯甲酸甲酯的合成
Figure PCTCN2019099950-appb-000010
向反应瓶中依次加2-氟-3-胺基苯甲酸甲酯(20g，118.23mmol)、溴甲基环丙烷(20.75g，153.70mmol)，碳酸钾(21.24g，153.70mmol)，N,N-二甲基甲酰胺(200mL)，在回流条件下搅拌16h，TLC监测至反应不再进行时，关闭加热，结束反应。待反应液冷至室温后，向反应液中加入水(200mL)，用乙酸乙酯(100mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝10：1)，得淡黄色液体产物2-氟-[3-(环丙甲基)胺基[苯甲酸甲酯(13g，收率49.39％)。
(2)2-氟-3-[N-(环丙甲基)苯甲酰胺基]苯甲酸甲酯的合成
Figure PCTCN2019099950-appb-000011
向反应瓶中依次加苯甲酸(6.67g，53.78mmol)、甲苯(50mL)和二氯亚砜(31.99g，268.9mmol)，在回流条件下反应2h，减压下浓缩甲苯，将浓缩后的残余物溶解在四氢呋喃(30mL)中待用。将2-氟-3-(N-环丙甲基胺基)苯甲酸甲酯(10.00g，44.82mmol)溶解在四氢呋喃(100mL)，加入吡啶(4.25g，53.78mmol)，滴加上步制得的苯甲酰氯四氢呋喃溶液，常温搅拌4h。TLC监测至反应不再进行时，结束反应。向反应液中加入用乙酸乙酯(50mL)溶解，有机层经依次用2M盐酸和饱和碳酸氢钠洗涤，经无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝8：1)，得无色液体产物2-氟-3-(N-(环丙甲基)苯甲酰胺)苯甲酸甲酯(13.00g，收率88.70％)。
(3)2-氟-3-[N-(环丙甲基)苯甲酰胺基]苯甲酸的合成
Figure PCTCN2019099950-appb-000012
将2-氟-3-(N-(环丙甲基)苯甲酰胺)苯甲酸甲酯(13.00g，40.88mmol)溶解在甲醇(100mL)中，加入10％的氢氧化钠水溶液(6.54g，163.52mmol，65.4mL)，常温搅拌2h后，TLC监测反应完全。减压下浓缩除去甲醇，将浓缩后的残渣溶解在水(100mL)中，用乙酸乙酯(50mL)萃取，舍弃有机相，用2M盐酸水溶液调节水相的PH为7，继续用乙酸乙酯(100mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，得到无色溶液产物，2-氟-3-[N-(环丙甲基)苯甲酰胺]苯甲酸(12.00g，收率93.82％)，放置过夜后成白色固体。
(4)N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)苯甲酰胺基]-2-氟苯甲酰胺的合成
Figure PCTCN2019099950-appb-000013
向反应瓶中依次加2-氟-3-(N-(环丙甲基)苯甲酰胺基)苯甲酸(0.40g，1.28mmol)、甲苯(6mL)，二氯亚砜(0.75g，6.40mmol)，在140℃下搅拌反应2h，减压下浓缩，将浓缩后的残渣溶解在四氢呋喃(3mL)中待用。
将2-溴-6-三氟甲基-4-七氟异丙基苯胺(0.52g，1.28mmol)溶解在四氢呋喃(4mL)，在-70℃下滴加二异丙基氨基锂(0.77mL，1.54mmol)，5min后滴加上一步合成的2-氟-3-[N-(环丙甲基)苯甲酰胺基]苯甲酰氯的四氢呋喃溶液，在-70℃下搅拌30min，升至室温继续搅拌30min。TLC监测至反应不再进行时，结束反应。向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝3：1)，得N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)-苯甲酰胺基]-2-氟苯甲酰胺(0.25g，收率27.84％)。
化合物1的 1H NMR(400MHz,CDCl 3-d),δ[ppm]：8.15(d,J＝2.1Hz,1H),8.03(br s,2H),7.92(d,J＝2.1Hz,1H),7.55(br s,1H),7.35-7.21(m,5H),3.84(d,J＝93.6Hz,2H),1.14(br s,1H),0.59-0.40(m,2H),0.20(d,J＝42.2Hz,2H)。
合成实施例2
N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-三氟甲氧基苯基]-3-[N-(环丙甲基)苯甲酰胺基]-2-氟苯甲酰胺(化合物编号3)的合成的合成
Figure PCTCN2019099950-appb-000014
向反应瓶中依次加2-氟-3-(N-(环丙甲基)苯甲酰胺)苯甲酸(0.50g，1.60mmol)、甲苯(6mL)，二氯亚砜(1.07g，9.00mmol)，在回流条件下搅拌反应2h，减压下浓缩甲苯，将浓缩后的残渣溶解在四氢呋喃(3mL)中待用。
将2-溴-4-七氟异丙基-6-三氟甲氧基苯胺(0.68g，1.60mmol)溶解在四氢呋喃(4mL)，在-70℃下滴加2M的二异丙基氨基锂四氢呋喃溶液(0.96mL，1.93mmol)，5min后滴加上一步待用的四氢呋喃溶液，在-70℃下搅拌30min，升至室温继续搅拌30min。薄层层析色谱(TLC)监测至反应不再进行时，结束反应。向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝5：1)，得目标产物(0.24g，收率20.50％)，白色固体。
化合物3的 1H NMR(400MHz,CDCl 3-d)数据如下(δ[ppm])：8.01-7.81(m,2H),7.58–7.51(m,3H),7.35-7.21(m,6H),3.85(d,J＝64.0Hz,2H),1.20-1.13(m,1H),0.50(d,J＝7.8Hz,2H),0.20(d,J＝32.0Hz,2H).
合成实施例3
N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)-4-氰基苯甲酰胺基]-2-氟苯甲酰胺(化合物编号4)的制备：
(1)2-氟-3-[N-(环丙甲基)-4-氰基苯甲酰胺基]苯甲酸甲酯的合成
Figure PCTCN2019099950-appb-000015
向反应瓶中依次加4-氰基苯甲酸(0.80g，5.38mmol)、甲苯(6mL)，二氯亚砜(3.2g，26.9mmol)，在回流条件下搅拌反应2h，减压下浓缩甲苯，将浓缩后的残渣溶解在四氢呋喃(3mL)中待用。将2-氟-[3-(环丙甲基)胺基]苯甲酸甲酯(1.0g，4.48mmol)溶解在四氢呋喃(6mL)，加入三乙胺(0.74g，5.38mmol)，滴加4-氰基苯甲酰氯的四氢呋喃溶液，常温搅拌4h。TLC监测至反应不再进行时，结束反应。向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝3:1)，得无色液体产物2-氟-3-[N-(环丙甲基)-4-氰基苯甲酰胺]苯甲酸甲酯(1.40g，收率88.83％)。
(2)2-氟-3-[N-(环丙甲基)-4-氰基苯甲酰胺基]苯甲酸的合成
Figure PCTCN2019099950-appb-000016
将2-氟-3-[N-(环丙甲基)-4-氰基苯甲酰胺基]苯甲酸甲酯(1.40g,3.96mmol)溶解在甲醇(20mL)中，加入10％的氢氧化钠水溶液(0.63g,15.86mmol,6.3mL)，常温搅拌2h，TLC监测反应完全。减压下浓缩除去甲醇，将浓缩后的残渣溶解在水(20mL)中，用乙酸乙酯(10mL)萃取，舍弃有机相，用2M盐酸水溶液调节水相的PH为7，继续用乙酸乙酯(10mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，得到2-氟-3-[N-(环丙甲基)-4-氰基苯甲酰胺基]苯甲酸(1.30g，收率96.79％)，白色固体。
(3)N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)-4-氰基苯甲酰胺基]-2-氟苯甲酰胺的合成：
Figure PCTCN2019099950-appb-000017
向反应瓶中依次加2-氟-3-[N-(环丙甲基)-4-氰基苯甲酰胺]苯甲酸(0.75g，2.22mmol)、甲苯(6mL)和二氯亚砜(1.31g，11.10mmol)，在回流下搅拌反应2h，减压下浓缩，将浓缩后的残余物溶解在四氢呋喃(3mL)中待用。
将2-溴-6-三氟甲基-4-七氟异丙基苯胺(0.90g，2.22mmol)溶解在四氢呋喃(4mL)，在-70℃下滴加二异丙基氨基锂(1.30mL，2.66mmol)，5min后滴加上一步制得的2-氟-3-[N-(环丙甲基)-4-氰基苯甲酰胺]苯甲酰氯四氢呋喃溶液，在-70℃下搅拌30min，升至室温继续搅拌30min。TLC监测至反应不再进行时，结束反应。向反应液中加入饱和氯化铵水溶液(20mL)，用乙酸乙酯(20mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝3：1)，得N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)-4-氰基苯甲酰胺基]-2-氟苯甲酰胺(0.24g，收率14.91％)。
化合物4的 1H NMR(400MHz,CDCl 3-d),δ[ppm]：8.14(d,J＝2.0Hz,1H),8.12-7.94(m,2H),7.91(t,J＝1.4Hz,1H),7.58-7.39(m,4H),7.32(t,J＝7.9Hz,1H),3.81(dd,J＝76.0,18.8Hz,2H),1.11(br s,1H),0.5(br s,2H),0.20(d,J＝36.7Hz,2H)。
合成实施例4
N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)-4-(三氟甲基)苯甲酰胺基]-2-氟苯甲酰胺(化合物编号7)的制备：
Figure PCTCN2019099950-appb-000018
(1)向反应瓶中依次加2-氟-3-[N-(环丙甲基)-4-三氟甲基苯甲酰胺]苯甲酸(0.45g，1.12mmol)、甲苯(6mL)，二氯亚砜(0.67g，5.60mmol)，在回流条件下搅拌反应2h，减压下浓缩甲苯，将浓缩后的残渣溶解在四氢呋喃(3mL)中待用。
(2)将2-溴-6-三氟甲基-4-七氟异丙基苯胺(0.46g，1.12mmol)溶解在四氢呋喃(4mL)，在-70℃下滴加二异丙基氨基锂(0.70mL，1.42mmol)，5min后滴加上一步待用的四氢呋喃溶液，在-70℃下搅拌30min，升至室温继续搅拌30min。TLC监测至反应不再进行时，结束反应。向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝3：1)，得目标产物(0.11g，收率13.75％)。
化合物7的 1H NMR(400MHz,CDCl 3-d)δ[ppm]：8.21-7.79(m,4H),7.66-7.28(m,5H),3.85(d,J＝104.7Hz,2H),1.12(br s,1H),0.51(br s,2H),0.20(d,J＝42.7Hz,1H)。
合成实施例5
N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)-4-氟苯甲酰胺基]-2-氟苯甲酰胺(化合物编号8)的制备，制备方法如下：
Figure PCTCN2019099950-appb-000019
向反应瓶中依次加2-氟-3-[N-(环丙甲基)-4-氟-苯甲酰胺]苯甲酸(2.20g，6.67mmol)、甲苯(20mL)，二氯亚砜(3.97g，33.35mmol)，在回流条件下搅拌反应2h，减压下浓缩得到2-氟-3-[N-(环丙甲基)-4-氟苯甲酰胺]苯甲酰氯。将2-溴-6-三氟甲基-4-七氟异丙基苯胺(3.26g，7.99mmol)、N,N二异丙基乙胺(1.72g，13.30mmol)、4-N,N-二甲氨基吡啶(0.33g，2.69mmol)分别加入到2-氟-3-[N-(环丙甲基)-4-氟苯甲酰胺]苯甲酰氯中，在120℃下搅拌，反应2h后，停止加热。向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为PE：EA＝3：1)，得目标产物(1.80g，收率37.5％)。
化合物8的 1H NMR(400MHz,DMSO-d 6)δ[ppm]：10.56(s,1H),8.41(s,1H),7.95(s,1H),7.70-7.56(m,2H),7.38-7.32(m,3H),7.09(br s,2H),3.69(br s,2H),1.03-1.01(m,1H),0.41-0.39(m,2H),0.08-0.06(m,2H)。
合成实施例6
N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(环丙甲基)-4-氯苯甲酰胺基]-2-氟苯甲酰胺(化合物编号10)的制备，制备方法如下：
Figure PCTCN2019099950-appb-000020
(1)向反应瓶中依次加2-氟-3-[N-(环丙甲基)-4-氯苯甲酰胺]苯甲酸(0.60g，1.76mmol)、甲苯(6mL)，二氯亚砜(1.04g，8.80mmol)，在回流条件下搅拌反应2h，减压下浓缩甲苯，将浓缩后的残渣溶解在四氢呋喃(3mL)中待用。
(2)将2-溴-6-三氟甲基-4-七氟异丙基苯胺(0.72g，1.76mmol)溶解在四氢呋喃(4mL)，在-70℃下滴加二异丙基氨基锂(1.05mL，2.11mmol)，5min后滴加上一步待用的四氢呋喃溶液，在-70℃下搅拌30min，升至室温继续搅拌30min。TLC监测至反应不再进行时，结束反应。向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝3：1)，得目标产物(0.15g，收率11.63％)。
化合物10的 1H NMR(400MHz,CDCl 3-d)δ[ppm]：8.18-7.84(m,4H),7.53(t,J＝7.7Hz,1H),7.37-7.07(m,4H),3.81(d,J＝85.0Hz,2H),1.11(br s,1H),0.49(br s,2H),0.17(d,J＝32.1Hz,2H)。
合成实施例7
N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(1-环丙基-乙基)-苯甲酰胺基]-2-氟苯甲酰胺(化合物编号2)的制备，制备方法如下：
Figure PCTCN2019099950-appb-000021
(1)3-[N-(1-环丙基乙基)氨基]-2-氟苯甲酸甲酯的合成
将2-氟-3-氨基苯甲酸甲酯(2.00g，11.82mmol)溶解在1,2-二氯乙烷(65mL)中，室温下依次加入环丙基甲基酮(2.98g，35.47mmol)、三氟乙酸(8.08g，70.92mmol)和三乙酰氧基硼氢化钠(7.51g，35.47mmol)，反应加热至45℃反应1h。TLC监测至反应不再进行时，结束反应。向反应液中加入饱和NaHCO 3溶液(50mL)，用二氯甲烷(80mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝10：1)，得目标产物(1.50g，收率53.5％)，无色油状物。
(2)3-[N-(1-环丙基)乙基)苯甲酰胺基]-2-氟苯甲酸甲酯的合成
向反应瓶中依次加苯甲酸(1.54g，12.64mmol)、甲苯(15mL)和二氯亚砜(6.27g，52.68mmol)，在回流条件下搅拌反应2h，减压下浓缩甲苯，将浓缩后的残渣溶解在四氢呋喃(5mL)中待用。
将3-[N-(1-环丙基)乙基)氨基]-2-氟苯甲酸甲酯(2.50g，10.54mmol)溶解在四氢呋喃(15mL)，依次加入三乙胺(1.60g，15.80mmol)和上一步制备的酰氯的四氢呋喃溶液，在80℃下搅拌反应6h。TLC监测至反应不再进行时，结束反应。向反应液中加入水(50mL)，用乙酸乙酯(60mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝10：1)，得目标产物(1.03g，收率28.6％)，黄色固体。
(3)3-[N-(1-环丙基)乙基)苯甲酰胺基]-2-氟苯甲酸
将3-[(1-环丙基-乙基)苯甲酰胺基]-2-氟苯甲酸甲酯(1.00g，2.93mmol)溶解在甲醇(10mL)中，加入10％的氢氧化钠水溶液(0.46g，11.72mmol，4.6mL)，常温搅拌2h，TLC监测反应完全。减压下浓缩除去甲醇，将浓缩后的残渣溶解在水(20mL)中，用乙酸乙酯(10mL)萃取，舍弃有机相，用2M盐酸水溶液调节水相的pH值为3，继续用乙酸乙酯(10mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，得目标产物(0.60g，收率62.6％)。
(4)N-[2-溴-4-(1,1,1,2,3,3,3-七氟丙-2-基)-6-(三氟甲基)苯基]-3-[N-(1-环丙基-乙基)苯甲酰胺基]-2-氟苯甲酰胺的合成
向反应瓶中依次加3-(N-(1-环丙)-乙基)苯甲酰胺基)-2-氟苯甲酸(0.60g，1.83mmol)、甲苯(6mL)和二氯亚砜(1.09g，9.16mmol)，在140℃下搅拌反应2h，减压下浓缩甲苯，将浓缩后的残渣溶解在四氢呋喃(2mL)中待用。
将2-溴-6-三氟甲基-4-七氟异丙基苯胺(0.75g，1.83mmol)溶解在四氢呋喃(6mL)，在-70℃下滴加二异丙基氨基锂(1.10mL，2.20mmol)，5min后滴加上一步待用的四氢呋喃溶液，在-70℃下搅拌30 min，升至室温继续搅拌30min。TLC监测至反应不再进行时，结束反应。向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取，有机层经饱和食盐水洗涤、无水硫酸钠干燥后，减压下浓缩，残余物经柱色谱提纯(淋洗液为石油醚：乙酸乙酯＝5：1)，得目标产物(0.23g，收率17.5％)，黄色固体。
化合物2的 1H NMR(400MHz,CDCl 3-d),δ[ppm]：8.19(s,1H),8.05-7.95(m,1H),7.89(s,1H),7.77-7.73(m,1H),7.56-7.52(m,1H),7.28-7.11(m,6H),4.26-4.23(m,1H),1.63(br s,2H),1.51(br s,1H),0.89–0.40(m,5H)。
除上面描述的化合物外，表1中部分化合物参照合成实施例1-7中相似的方法制备或可制备，下文表4中给出了参照合成实施例1-7合成的部分化合物的核磁数据。
表4
Figure PCTCN2019099950-appb-000022
本申请的其他通式I化合物可参照上述方法合成。
制剂实施例
下列实施例用于说明本申请的组成比例及制备方法：
制剂实施例1：40％化合物8·虱螨脲乳油(所述浓度40％指的是化合物8和虱螨脲在乳油剂中的浓度之和)
40％化合物8·虱螨脲乳油的组成如表5所示：
表5
名称 折百(W/W，％) 备注
化合物8 12 有效成分A
虱螨脲 28 有效成分B
十二烷基苯磺酸钙 8 乳化剂
蓖麻油聚氧乙烯醚 8 乳化剂
200号溶剂油 补足100 溶剂
制备方法：按照配方计算出各物料量，配料釜中，加入200号溶剂油，然后将化合物8、虱螨脲加入溶解完全后，再投入十二烷基苯磺酸钙、蓖麻油聚氧乙烯醚加入，在40～50℃搅拌1.5小时，过滤，即得到40％化合物8·虱螨脲乳油。
制剂实施例2：30％化合物4·氟虫腈悬浮种衣剂
30％化合物4·氟虫腈悬浮种衣剂的组成如表6所示：
表6
Figure PCTCN2019099950-appb-000023
制备方法：在配料釜中，根据物料配比，投入去离子水、化合物4、氟虫腈、FS3000、TER4894、卡松、SAG1522、丙二醇剪切后砂磨，控制粒径D90 5微米左右，然后转移到调配釜中，加入2％黄原胶溶液、颜料F2R混合搅拌1小时，即得到30％化合物4·氟虫腈悬浮种衣剂。
制剂实施例3：25％化合物6·氯虫苯甲酰胺水分散粒剂
25％化合物6·氯虫苯甲酰胺水分散粒剂的组成如表7所示：
表7
名称 折百(W/W，％) 备注
化合物6 10 有效成分A
氯虫苯甲酰胺 15 有效成分B
十二烷基硫酸钠 1.5 润湿剂
木质素磺酸钠 6 分散剂
萘甲醛聚合物磺酸钠 2 分散剂
硫酸铵 5 崩解剂
玉米淀粉 20 填料
高岭土 补足100 填料
制备方法：按照配方计算出各物料量，将化合物6、氯虫苯甲酰胺、十二烷基硫酸钠、木质素磺酸钠、萘甲醛聚合物磺酸钠、硫酸铵、玉米淀粉、高岭土混合均匀，通过气流粉碎机粉碎至平均粒径10～15微米，加入粉体量的17％的水捏合，然后通过旋转挤压造粒，50℃烘干3小时，筛分，即得到25％化合物6·氯虫苯甲酰胺水分散粒剂。
制剂实施例4：24％化合物8·溴氰虫酰胺悬浮剂
24％化合物8·溴氰虫酰胺悬浮剂的组成如表8所示：
表8
名称 折百(W/W，％) 备注
化合物8 10 有效成分A
溴氰虫酰胺 14 有效成分B
脂肪醇聚氧乙烯醚 1.5 润湿剂
三苯乙烯基苯酚聚氧乙烯醚磷酸酯 2 分散剂
木质素磺酸钠 3 分散剂
丙二醇 4 防冻剂
1％黄原胶溶液 10 增稠剂
卡松 0.1 防腐剂
聚二甲基硅氧烷 0.2 有机硅消泡剂
去离子水 补足100 载体
制备方法：按照配方计算出各物料量，将去离子水、丙二醇、三苯乙烯基苯酚聚氧乙烯醚磷酸酯、木质素磺酸钠、卡松、消泡剂搅拌溶解均匀，加入溴氰虫酰胺和化合物8剪切均匀，然后通过砂磨机研磨至平均粒径2微米，加入10份1％黄原胶溶液搅拌30分钟，即得到24％化合物8·溴氰虫酰胺悬浮剂。
。
制剂实施例5：30％化合物7·甲氧虫酰肼水分散粒剂
30％化合物7·甲氧虫酰肼水分散粒剂的组成如表9所示：
表9
名称 折百(W/W，％) 备注
化合物7 6 有效成分A
甲氧虫酰肼 24 有效成分B
十二烷基硫酸钠 1.5 润湿剂
木质素磺酸钠 6 分散剂
萘甲醛聚合物磺酸钠 2 分散剂
硫酸铵 5 崩解剂
玉米淀粉 20 填料
高岭土 补足100 填料
制备方法：按照配方计算出各物料量，将化合物7、甲氧虫酰肼、十二烷基硫酸钠、木质素磺酸钠、萘甲醛聚合物磺酸钠、硫酸铵、玉米淀粉、高岭土混合均匀，通过气流粉碎机粉碎至平均粒径10～15微 米，加入粉体量的17％的水捏合，然后通过旋转挤压造粒，50℃烘干3小时，筛分，即得到30％化合物7·甲氧虫酰肼水分散粒剂。
制剂实施例6：27％化合物10·氰氟虫腙微囊悬浮剂
27％化合物10·氰氟虫腙微囊悬浮剂的组成如表10所示：
表10
名称 折百(W/W，％) 备注
化合物10 5 有效成分A
氰氟虫腙 22 有效成分B
多芳基多亚甲基多异氰酸酯 2 囊材
三苯乙烯基苯酚聚氧乙烯醚磷酸酯 2 分散剂
EO/PO聚合物(D-800) 3 乳化剂
丙二醇 4 防冻剂
三甲苯 20 溶剂
己二胺 0.5 囊材
1％黄原胶溶液 10 增稠剂
卡松 0.1 防腐剂
聚二甲基硅氧烷 0.2 消泡剂
去离子水 补足100 载体
制备方法：按照配方计算出各物料量，将化合物10、氰氟虫腙、多芳基多亚甲基多异氰酸酯、三甲苯，于40～50度溶解均匀，作为A相；另取去离子水、D-800、丙二醇、溶解均匀，作为B相；在高剪切下，将A相缓慢加入B相，剪切至平均粒径2～3微米，然后将物料加入到三口烧瓶里，加入己二胺，于50～60℃搅拌反应10小时，加入三苯乙烯基苯酚聚氧乙烯醚磷酸酯、卡松、消泡剂、1％黄原胶溶液搅拌1小时，即得到27％化合物10·氰氟虫腙微囊悬浮剂。
制剂实施例7：25％化合物6·唑虫酰胺可湿性粉剂
25％化合物6·唑虫酰胺可湿性粉剂的组成如表11所示：
表11
名称 折百(W/W，％) 备注
化合物6 5 有效成分A
唑虫酰胺 20 有效成分B
十二烷基硫酸钠 1.5 润湿剂
木质素磺酸钠 6 分散剂
高岭土 补足100 载体
制备方法：按照配方计算出各物料量，在配料釜中投入化合物6、唑虫酰胺、十二烷基硫酸钠、木质素磺酸钠、高岭土，混合均匀后，用气流粉碎机粉碎至平均粒径10微米，即得到25％化合物6·唑虫酰胺可湿性粉剂。。
制剂实施例8：15％化合物7·氟噁唑酰胺可分散液剂
15％化合物7·氟噁唑酰胺可分散液剂的组成如表12所示：
表12
名称 折百(W/W，％) 备注
化合物5 5 有效成分A
氟噁唑酰胺 10 有效成分B
100号溶剂油 15 溶剂
环己酮 10 溶剂
蓖麻油聚氧乙烯醚(EL40) 5 分散剂
脂肪醇聚氧乙烯醚 10 润湿剂
聚二甲基硅氧烷乳液(SAG1522) 0.2 消泡剂
去离子水 补足100 载体
制备方法：在配料釜中，根据工艺配比，加入100号溶剂油、环己酮，搅拌下加入化合物7、氟噁唑酰胺，加热至50℃溶剂完全后，加入EL40、脂肪醇聚氧乙烯醚、SAG1522继续搅拌10分钟后，降温后加入去离子水，即得到15％化合物7·氟噁唑酰胺可分散液剂。
制剂实施剂9：28％化合物1·乙虫腈水乳剂
28％化合物1·乙虫腈水乳剂的组成如表13所示：
表13
Figure PCTCN2019099950-appb-000024
制备方法：在配料釜中，先加入150号溶剂油，然后开启搅拌，加入化合物1搅拌溶解，当溶解完全后，再投入乙虫腈以及乳化剂TERMUL5030，继续搅拌20分钟，混合均匀为油相，待用；在剪切釜中投入去离子水、消泡剂及防冻剂，开启剪切装置，5分钟后慢慢加入油相物料，加完再剪切10分钟，即得到28％化合物1·乙虫腈水乳剂。
生测实施例
下列实施例用于说明本申请技术方案的部分实施，本申请不限于以下实施例。
生测实施例1：有效成份A为式II化合物时，对多种害虫具有显著杀虫活性
靶标：小菜蛾3龄幼虫，粘虫3龄幼虫，二化螟3龄幼虫，均为室内饲养。
方法：小菜蛾+浸叶饲喂法，粘虫+浸叶片饲喂法，二化螟+稻茎浸渍法。
小菜蛾+浸叶饲喂法。参照NY/1154.14-2008，主要操作描述如下：将清洁的苞菜叶碟浸入药液中10s，晾干后置于培养皿中，每皿4碟，培养皿内放滤纸保湿。每皿接小菜蛾试虫10头，3次重复。置于光照培养箱内，温度25℃，光照14hL:10hD，培养。药后3天调查小菜蛾死活虫数，计算死亡率。
粘虫+浸叶片饲喂法。参照NY/1154.14-2008，主要操作描述如下：将清洁的玉米叶段浸入药液中10s，晾干后置于培养皿中，每皿4片，培养皿内放滤纸保湿。每皿接粘虫试虫10头，3次重复。置于光照培养箱内，温度25℃，光照14hL:10hD，培养。药后3天调查粘虫死活虫数，计算死亡率。
二化螟+稻茎浸渍法。参照NY/T1154.11-2008，主要操作如下：将清洁的稻茎浸入药液中10s后取出， 放置于阴凉处晾干，放入指形管中，接入3龄二化螟幼虫10头，每处理重复3次，用棉黑布封管口，橡皮筋扎紧，置于光照培养箱，温度28℃，黑暗培养。药后3天调查二化螟死活虫数，计算各药剂处理的死亡率。
结果如表14所示，由结果可以看出，化合物1-14对小菜蛾、粘虫、二化螟均具有极显著杀虫活性。
表14化合物1-14对小菜蛾、粘虫、二化螟的杀虫活性
Figure PCTCN2019099950-appb-000025
生测实施例2：有效成份A为式II化合物与有效成份B为氯虫苯甲酰胺、氟苯虫酰胺、溴氰虫酰胺、等的组合物，对小菜蛾的活性测试
靶标：蔬菜小菜蛾，3龄幼虫
方法：浸叶碟饲喂法，操作描述同生测实施例1。
评价方法与标准如下：
增效效果＝实际死亡率％─理论死亡率％
理论死亡率＝1─(1─有效成份A在该剂量下的死亡率)(1─有效成份B在该剂量下的死亡率)
增效效果≥20，表示显著增效；10≤增效效果＜20，表示增效；-10≤增效效果＜10之间，表示相加；增效效果＜-10，表示拮抗，负值越大，拮抗程度越大。
结果如表15所示，由结果可以看出，有效成份A为化合物1、化合物4、化合物8时，对小菜蛾具有优良活性；有效成份B为氯虫苯甲酰胺、氟苯虫酰胺、溴氰虫酰胺、四唑虫酰胺时，对小菜蛾具有优良活性；当A与B组合时，联合作用表现为增效或显著增效。
表15供试药剂对小菜蛾的杀虫活性
供试药剂或组合名称 剂量mg/L 3d死亡率％ 理论死亡率％ 增效效果 联合作用方式
化合物1 0.01 36.67 / / /
化合物4 0.01 43.33 / / /
化合物8 0.02 53.33 / / /
氯虫苯甲酰胺 0.5 60.00 / / /
氟苯虫酰胺 0.4 70.00 / / /
溴氰虫酰胺 0.25 66.67 / / /
化合物1+氯虫苯甲酰胺 0.01+0.5 100 74.67 25.33 显著增效
化合物4+氟苯虫酰胺 0.01+0.4 100 60.33 39.67 显著增效
化合物8+溴氰虫酰胺 0.02+0.25 100 84.44 15.56 增效
生测实施例3：有效成份A为式II化合物与有效成份B为溴氰虫酰胺、四氯虫酰胺、环溴虫酰胺等的组合物，对水稻二化螟具有增效作用
靶标：二化螟3龄幼虫，室内饲养。
方法：稻茎浸渍法。主要操作描述同生测实施1。评价方法与标准同生测实施例2。
结果如表16所示，由结果可以看出，有效成份A为化合物4、化合物5、化合物6、化合物7、化合物8、化合物9、化合物10、化合物11、化合物12、化合物13时，对二化螟具有优良活性；有效成份B为溴氰虫酰胺、四氯虫酰胺、环溴虫酰胺时，对二化螟具有优良活性；当A与B组合时，联合作用表现为增效或显著增效。
表16供试药剂对二化螟的杀虫活性
供试药剂或组合名称 剂量mg/L 3d死亡率％ 理论死亡率％ 增效效果 联合作用方式
化合物4 0.4 53.33 / / /
化合物5 1.0 63.33      
化合物6 1.00 56.67 / / /
化合物7 0.5 50 / / /
化合物8 0.5 56.67 / / /
化合物9 1.0 66.67 / / /
化合物10 0.5 33.33 / / /
化合物11 1.25 76.67 / / /
化合物12 1.00 56.67 / / /
化合物13 0.5 33.33 / / /
溴氰虫酰胺 4.0 53.33 / / /
四氯虫酰胺 2.5 70 / / /
环溴虫酰胺 1.0 66.67 / / /
化合物4+溴氰虫酰胺 0.4+4.0 100 78.22 21.78 显著增效
化合物5+溴氰虫酰胺 1.0+4.0 100 82.89 17.11 增效
化合物6+溴氰虫酰胺 1.0+4.0 100 79.78 20.22 显著增效
化合物7+四氯虫酰胺 0.5+2.5 100 85.00 15.00 增效
化合物8+环溴虫酰胺 0.5+1.0 100 85.56 14.44 增效
化合物9+环溴虫酰胺 1.0+4.0 100 88.89 11.11 增效
化合物10+溴氰虫酰胺 0.5+4.0 100 75.53 24.47 显著增效
化合物11+溴氰虫酰胺 1.25+4.0 100 89.11 10.89 增效
化合物12+环溴虫酰胺 1.0+1.0 100 85.56 14.44 增效
化合物13+溴氰虫酰胺 0.5+4.0 100 68.89 31.11 显著增效
生测实施例4：有效成份A为式II化合物与有效成份B为氟虫腈、乙虫腈、乙酰虫腈等的组合物，对褐飞虱的活性测试
靶标：褐飞虱，3龄若虫。
方法：稻苗浸渍法。参照NY/T1154.11-2008。
方法操作描述如下：药剂配置：按试验设计的比例和剂量，称取一定量的原药，用N,N-二甲基甲酰胺(DMF)溶解，之后加0.05％吐温80水配制成一定浓度的母液。每个配比设5～7个剂量，按照试验设计，依次用母液稀释至试验剂量。药剂处理：将水稻苗浸入药液中10s，然后装入一次性杯中，每杯接虫15头，用保鲜膜封口，每处理45头试虫。浸药时同种药剂从低浓度到高浓度依次进行，设空白对照和溶剂对照。处理完毕后置于光照培养箱内，温度为28±1℃，光暗比15h:9h。结果调查：药后3d调查死虫数。统计死亡率。
评价方法与标准同生测实施例2。
结果如表17所示，由结果可以看出，有效成份A为化合物6、化合物8、化合物10时，对褐飞虱具有良好活性；有效成份B为氟虫腈、乙虫腈、乙酰虫腈时，对褐飞虱具有良好活性；当A与B组合时，联合作用表现为增效。
表17供试药剂对褐飞虱的杀虫活性
供试药剂或组合名称 剂量mg/L 3d死亡率％ 理论死亡率％ 增效效果 联合作用方式
化合物6 10 60.00 / / /
化合物8 5 71.55 / / /
化合物10 10 78.29 / / /
氟虫腈 2.5 53.22 / / /
乙虫腈 80 61.86 / / /
乙酰虫腈 100 45.35 / / /
化合物6+氟虫腈 10+2.5 100 81.33 18.67 增效
化合物8+乙虫腈 10+80 100 89.15 10.85 增效
化合物10+乙酰虫腈 10+100 100 88.14 11.86 增效
生测实施例5：有效成份A为式II化合物与有效成份B为茚虫威、虫螨腈、氰氟虫腙、唑虫酰胺等时，对粘虫的活性测试
方法：浸虫法。操作描述如下：参照NY/1154.6-2006，主要操作描述如下：将10头试虫浸入药液中10s，晾干后置于培养皿中，每皿放入4片清洁的玉米叶段，培养皿内放滤纸保湿。3次重复。置于光照培养箱内，温度25℃，光照14hL:10hD，培养。药后3天调查粘虫死虫数，计算死亡率。
评价方法同生测实施例2。
结果如表18所示，由结果可以看出，有效成份A为化合物2、化合物3、化合物5、化合物10、化合物12、化合物14时，对粘虫具有优良活性；有效成份B为茚虫威、虫螨腈、氰氟虫腙、唑虫酰胺时，对粘虫具有良好活性；当A与B组合时，联合作用表现为增效或显著增效。
表18供试药剂室内对粘虫的杀虫活性
供试药剂或组合名称 剂量mg/L 3d死亡率％ 理论死亡率％ 增效效果 联合作用方式
化合物2 0.04 53.33 / / /
化合物3 0.04 60 / / /
化合物5 0.04 75 / / /
化合物10 0.04 80 / / /
化合物12 0.04 65 / / /
化合物14 0.04 60 / / /
茚虫威 0.8 50 / / /
虫螨腈 2.0 56.67 / / /
氰氟虫腙 4.0 43.33 /    
唑虫酰胺 2.5 50 / / /
化合物2+茚虫威 0.04+0.8 100 76.66 23.34 显著增效
化合物3+茚虫威 0.04+0.8 100 80.00 20.00 显著增效
化合物3+虫螨腈 0.04+2.0 100 82.67 17.33 增效
化合物5+茚虫威 0.04+0.8 100 87.50 12.5 增效
化合物10+氰氟虫腙 0.04+4.0 100 88.67 11.33 增效
化合物10+唑虫酰胺 0.04+2.5 100 90.00 10.00 增效
化合物12+氰氟虫腙 0.04+4.0 100 80.17 19.83 增效
化合物14+氰氟虫腙 0.04+4.0 100 77.32 22.68 显著增效
生测实施例6：有效成份A为式I化合物与有效成份B为甲氧虫酰肼、虱螨脲、啶虫丙醚时，对斜纹夜蛾的活性测试。
方法：浸叶法，3龄幼虫。操作描述如下：将清洁的苞菜叶碟浸入药液中10s，晾干后置于24孔板中，每孔接斜纹夜蛾试虫1头，每处理24头。置于光照培养箱内，温度25℃，光照14hL:10hD，培养。药后3天调查死虫数，计算死亡率。
结果如表19所示，由结果可以看出，有效成份A为化合物1、化合物4、化合物6时，对斜纹夜蛾具有优良活性；有效成份B为甲氧虫酰肼、虱螨脲、啶虫丙醚时，对斜纹夜蛾具有良好活性；当A与B组合时，联合作用表现为增效或显著增效。
表19供试药剂室内对斜纹夜蛾的杀虫活性表
供试药剂或组合名称 剂量mg/L 5d死亡率％ 理论死亡率％ 增效效果 联合作用方式
化合物1 1.0 73.33 / / /
化合物4 0.4 60.00 / / /
化合物6 1.0 50.00 / / /
甲氧虫酰肼 4.0 40.00 / / /
虱螨脲 0.8 50.00 / / /
啶虫丙醚 20 46.67 / / /
化合物1+甲氧虫酰肼 1.0+4.0 100 84.00 16.00 增效
化合物4+虱螨脲 0.4+0.8 100 80.00 20.00 显著增效
化合物6+啶虫丙醚 1.0+20 100 73.33 26.67 显著增效
生测实施例7：化合物8和四唑虫酰胺的组合物对二化螟具的活性测试
虫源：二化螟3龄幼虫，室内饲养。
方法：稻茎浸渍法，操作描述同生测实施例1，评价方法参照NY/T1154.7-2006，以共毒系数进行评价。
混剂的共毒系数(CTC值)按式(1)、式(2)、式(3)计算：
Figure PCTCN2019099950-appb-000026
式中：ATI—混剂实测毒力指数；
S—标准杀虫剂的LC 50，单位为毫克每升(mg/L)；
M—混剂的LC 50，单位为毫克每升(mg/L)。
TTI＝A×PA+B×PB···································································(2)
式中：TTI—混剂理论毒力指数；
A—A药剂毒力指数；
PA—A药剂在混剂中的百分含量，单位为百分率(％)；
B—B药剂毒力指数；
PB—B药剂在混剂中的百分含量，单位为百分率(％)。
Figure PCTCN2019099950-appb-000027
式中：CTC—共毒系数；ATI—混剂实测毒力指数；TTI—混剂理论毒力指数。
复配剂的共毒系数(CTC)≥120表现为增效作用；CTC≤80表现为拮抗作用；80＜CTC＜120表现为相加作用。
结果如表20所示，由结果可以看出，化合物8和四唑虫酰胺对二化螟均有较好活性；化合物8和四唑虫酰胺复配，配比160:1～1:160时共毒系数为101.97～163.88，表现为相加或增效；当配比80:1～1:80时共毒系数均大于120，表现为增效。
表20化合物8和四唑虫酰胺的组合物对二化螟的共毒系数
Figure PCTCN2019099950-appb-000028
生测实施例8：化合物9和氟噁唑酰胺的组合物对小菜蛾的活性测试
虫源：小菜蛾3龄幼虫，室内饲养。
浸叶饲喂法。操作描述同生测实施例1，统计评价同生测实施例7。
结果如表21所示，由结果可以看出，化合物9和氟噁唑酰胺对小菜蛾均有较好活性；化合物9和氟噁唑酰胺复配，配比120:1～1:120各个配比的共毒系数为111.07～173.06，均表现为相加或增效；在配比80:1～1:80均表现为增效。
表21化合物9和氟噁唑酰胺的组合物对小菜蛾的共毒系数
Figure PCTCN2019099950-appb-000029
生测实施例9：化合物3和氰氟虫腙的组合物对甜菜夜蛾的活性测试
虫源：甜菜夜蛾3龄幼虫，室内饲养。
方法：浸叶碟饲喂法。操作描述如下：将清洁的苞菜叶碟浸入药液中10s，晾干后置于24孔板中，每孔接甜菜夜蛾试虫1头，每处理24头。置于光照培养箱内，温度25℃，光照14hL:10hD，培养。药后3天调查死虫数，计算死亡率。
评价同生测实施例7。
结果如表22所示，由结果可以看出，化合物3和氰氟虫腙对甜菜夜蛾均有较好活性；化合物3和氰氟虫腙复配，100:1～1:100各个配比的共毒系数为94.11～189.71，均表现为相加或增效；在配比50:1～1:50之间均表现为增效。
表22化合物3和氰氟虫腙的组合物对甜菜夜蛾的共毒系数
Figure PCTCN2019099950-appb-000030
Figure PCTCN2019099950-appb-000031
生测实施例10：化合物7和乙虫腈的组合物对褐飞虱的活性测试
靶标：褐飞虱，3龄若虫。
方法：稻苗浸渍法。操作描述同生测实施例4，统计评价同生测实施例7。
结果如表23所示，由结果可以看出，化合物7和乙虫腈对褐飞虱具有较好活性；化合物7和乙虫腈复配，100:1～1:100各个配比的共毒系数为121.27～162.37，均表现为增效作用。
表23化合物7和乙虫腈的组合物对褐飞虱的共毒系数(药后3d)
Figure PCTCN2019099950-appb-000032
生测实施例11：化合物12和虱螨脲的组合物对小菜蛾的活性测试
虫源：小菜蛾3龄幼虫，室内饲养。
方法：浸叶饲喂法。操作描述同生测实施例1，统计评价同生测实施例7。
结果如表24所示，由结果可以看出，化合物12和虱螨脲对小菜蛾均有较好活性；化合物12和虱螨脲复配，配比150:1～1:150各个配比的共毒系数为89.09～224.74，均表现为相加或增效作用；在配比50:1～1:50均表现为增效作用。
表24化合物12和虱螨脲的组合物对小菜蛾的共毒系数
Figure PCTCN2019099950-appb-000033
Figure PCTCN2019099950-appb-000034
申请人声明，本申请通过上述实施例来说明本申请的含有间二酰胺类化合物的药物组合物及其应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (15)

  1. 一种含有间二酰胺类化合物的药物组合物，其中所述药物组合物包括有效成分A和有效成分B，所述有效成分A为具有式I所示结构的酰胺类化合物，所述有效成分B包括其他杀虫剂中任意一种或两种的组合；
    Figure PCTCN2019099950-appb-100001
    式I中，Z选自氢、氟、氯、溴、碘、氰基、硝基、取代或未取代的3-10元杂环基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷基亚磺酰基、C 1-C 6卤代烷基亚磺酰基、C 1-C 6烷基磺酰基或C 1-C 6卤代烷基磺酰基；Q选自C 3-C 8环烷基或C 3-C 8卤代环烷基；X选自氢、氟或三氟甲基；Y 1选自氟、氯、溴、碘、氰基、硝基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 4烯基、C 2-C 4卤代烯基、C 2-C 4炔基、C 2-C 4卤代炔基、C 3-C 8环烷基、C 3-C 8卤代环烷基、C 1-C 6烷基羰基、C 1-C 6烷基亚磺酰基、C 1-C 6卤代烷基亚磺酰基、C 1-C 6烷基磺酰基或C 1-C 6卤代烷基磺酰基；Y 2选自溴、碘、氰基、硝基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 4烯基、C 2-C 4卤代烯基、C 2-C 4炔基、C 2-C 4卤代炔基、C 3-C 8环烷基、C 3-C 8卤代环烷基、C 1-C 6烷基羰基、C 1-C 6烷基亚磺酰基、C 1-C 6卤代烷基亚磺酰基、C 1-C 6烷基磺酰基或C 1-C 6卤代烷基磺酰基；R 1选自氢、氟或甲氧基；R 2选自氟或三氟甲基；R 3和R 4分别独立地选自氢、卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 8环烷基或C 3-C 8卤代环烷基；m表示0～5的整数；n表示0～3的整数；W 1和W 2独立地为氧原子或硫原子。
  2. 根据权利要求1所述的含有间二酰胺类化合物的药物组合物，其中所述有效成分A为具有式II所示结构的间二酰胺类化合物：
    Figure PCTCN2019099950-appb-100002
    式II中，
    Z选自氢、氟、氯、溴、碘、氰基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 1-C 6烷基磺酰基或C 1-C 6卤代烷基磺酰基；
    Y选自C 1-C 6卤代烷基或C 1-C 6卤代烷氧基；
    R选自氢或甲基。
  3. 根据权利要求2所述的含有间二酰胺类化合物的药物组合物，其中在式II中，
    Z选自氢、氟、氯、溴、碘、氰基、三氟甲氧基、三氟甲基、甲磺酰基或三氟甲磺酰基；
    Y选自三氟甲基或三氟甲氧基；
    R选自氢或甲基。
  4. 根据权利要求1-3中任一项所述的含有间二酰胺类化合物的药物组合物，其中所述间二酰胺类化合物为选自以下化合物1-14中的任意一种或至少两种的组合：
    Figure PCTCN2019099950-appb-100003
  5. 根据权利要求1-4中任一项所述的含有间二酰胺类化合物的药物组合物，其中所述有效成分B选自氯虫苯甲酰胺、氟苯双酰胺、溴氰虫酰胺、四氯虫酰胺、四唑虫酰胺、氯氟氰虫酰胺、环溴虫酰胺、氟噁唑酰胺、氟虫腈、乙虫腈、乙酰虫腈、茚虫威、氰氟虫腙、虫螨腈、唑虫酰胺、虱螨脲、甲氧虫酰肼、啶虫丙醚中任意一种或两种的组合。
  6. 根据权利要求1-5中任一项所述的含有间二酰胺类化合物的药物组合物，其中所述有效成分A和有效成分B的重量比是200:1-1:200。
  7. 根据权利要求6所述的含有间二酰胺类化合物的药物组合物，其中当所述含间二酰胺类化合物的药物组合物中有效成分B为氯虫苯甲酰胺、氟苯双酰胺、溴氰虫酰胺、四氯虫酰胺、四唑虫酰胺、氯氟氰 虫酰胺或环溴虫酰胺时，有效成分A和有效成分B的重量比为80:1～1:80；
    当所述含有间二酰胺类化合物的药物组合物中有效成分B为氟噁唑酰胺时，有效成分A和有效成分B的重量比为80:1～1:80；
    当所述含有间二酰胺类化合物的药物组合物中有效成分B为氟虫腈、乙虫腈、乙酰虫腈时，有效成分A和有效成分B的重量比60:1～1:60；
    当所述含有间二酰胺类化合物的药物组合物中有效成分B为茚虫威、氰氟虫腙、虫螨腈或唑虫酰胺时，有效成分A和有效成分B的重量比50:1-1:50；或者
    当所述含有间二酰胺类化合物的药物组合物中有效成分B为虱螨脲、甲氧虫酰肼或啶虫丙醚时，有效成分A和有效成分B的重量比为50:1-1:50。
  8. 一种药物制剂，其包括权利要求1-7中任一项所述的含有间二酰胺类化合物的药物组合物以及农药学上可接受的助剂和/或载体。
  9. 根据权利要求8所述的药物制剂，其中所述农药学上可接受的助剂包括分散剂、润湿剂、乳化剂、防冻剂、增稠剂、消泡剂、防腐剂、稳定剂或染色剂中的任意一种或至少两种的组合；并且
    所述载体包括填料和/或溶剂。
  10. 根据权利要求8所述的药物制剂，其中所述药物制剂的剂型为可溶液剂、可溶粉剂、可溶粒剂、乳油、可湿性粉剂、水乳剂、悬浮剂、可分散油悬浮剂、水分散粒剂、微囊悬浮剂、颗粒剂、微乳剂、悬浮乳剂、微囊悬浮-悬浮剂、超低容量液剂、热雾剂、展膜油剂、悬浮种衣剂、种子处理干粉剂、种子处理悬浮剂、种子处理可溶粉剂、种子处理可分散粉剂、种子处理乳剂或种子处理液剂；
    优选地，所述药物制剂的剂型为可溶液剂、可溶粒剂、悬浮剂、乳油、可湿性粉剂、水乳剂、水分散粒剂、可分散油悬浮剂、微囊悬浮剂、超低容量液剂、热雾剂、悬浮种衣剂或种子处理可分散粉。
  11. 根据权利要求8所述的药物制剂，其中在所述药物制剂中，所述含间二酰胺类化合物的药物组合物的重量百分含量为0.01-99％，优选为0.5～95％。
  12. 根据权利要求1-7中任一项所述的药物组合物或权利要求8-11中任一项所述的药物制剂在农业、林业、园艺上防治植物病害或虫害中的应用。
  13. 根据权利要求12所述的应用，其中在应用时采用喷雾、浇灌或种子处理的用药方式。
  14. 一种防治植物病虫害的方法，其为：向需要控制的植物病虫害或其生长的介质上施用有效剂量的如权利要求1-7中任一项所述的含有间二酰胺类化合物的药物组合物或权利要求8-11中任一项所述的药物制剂。
  15. 根据权利要求14所述的方法，其中所述有效剂量为每公顷10-1000g，优选每公顷15-900g。
PCT/CN2019/099950 2018-08-10 2019-08-09 一种含有间二酰胺类化合物的药物组合物及其应用 WO2020030094A1 (zh)

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