WO2021139370A1 - Amide compound and application thereof - Google Patents

Amide compound and application thereof Download PDF

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Publication number
WO2021139370A1
WO2021139370A1 PCT/CN2020/126091 CN2020126091W WO2021139370A1 WO 2021139370 A1 WO2021139370 A1 WO 2021139370A1 CN 2020126091 W CN2020126091 W CN 2020126091W WO 2021139370 A1 WO2021139370 A1 WO 2021139370A1
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spp
amide compound
compound
parasite control
animal parasite
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PCT/CN2020/126091
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French (fr)
Chinese (zh)
Inventor
张立新
张静
裴鸿艳
盛祝波
汪杰
康卓
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沈阳化工大学
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Publication of WO2021139370A1 publication Critical patent/WO2021139370A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 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
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/04—Insecticides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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
    • C07C237/40—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 the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the invention relates to a compound, in particular to a novel amide compound and its application.
  • the object of the present invention is to provide an amide compound with excellent insecticidal activity. It can be used to prepare drugs for controlling pests in agriculture and other fields, and for preparing drugs for controlling animal parasites in the field of veterinary medicine.
  • the present invention provides the following technical solutions:
  • R 1 is selected from halogen
  • R 2 is selected from halogen, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy;
  • R 3 is selected from CF 3 or CF 2 CF 3 ;
  • R 4 is selected from cyano C 1 -C 4 alkyl.
  • R 1 is selected from halogen
  • R 2 is selected from halogen, C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy;
  • R 3 is selected from CF 3 or CF 2 CF 3 ;
  • R 4 is selected from cyano C 1 -C 4 alkyl.
  • R 1 is selected from bromine or iodine
  • R 2 is selected from bromine, iodine, trifluoromethyl or difluoromethoxy
  • R 3 is selected from CF 3 or CF 2 CF 3 ;
  • R 4 is selected from CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 CH 2 CN, CH 2 CH 2 CH 2 CH 2 CN, CH(CH 3 )CN, CH(CH 2 CH 3 )CN, CH( CH 2 CH 2 CH 3 )CN, C(CH 3 )(CH 3 )CN or C(CH 3 )(CH 2 CH 3 )CN.
  • R 1 is selected from bromine or iodine
  • R 2 is selected from bromine, iodine or trifluoromethyl
  • R 3 is selected from CF 3 ;
  • R 4 is selected from CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 CH 2 CN, or CH 2 CH 2 CH 2 CH 2 CN.
  • the amide compound is selected from the compounds of Table 1, and the compounds of Table 1 have the structure of Formula I and R 1 , R 2 , R 3 and R 4 are as shown in Table 1:
  • the compound of the general formula III and the halogenated compound R 4 -LG are reacted in a suitable solvent at a temperature from -10°C to the boiling point of the solvent for 0.5-48 hours to obtain a compound of the general formula II.
  • the reaction is carried out in the presence of a base and a catalyst;
  • the compound of formula II and 6-cyanonicotinoyl chloride are reacted in a suitable solvent at a temperature from -10°C to the boiling point of the solvent for 0.5-48 hours to obtain a compound of formula I.
  • the reaction can be carried out in the presence of a base and a catalyst. .
  • Suitable solvents in the above steps can be the same or different.
  • Aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogenated hydrocarbons such as chloroform and dichloromethane; and methyl acetate.
  • the bases that can be the same or different are organic bases such as triethylamine, pyridine, DBU, 4-dimethylaminopyridine, alkali metal hydrides such as sodium hydride, potassium hydride, and alkali metals such as sodium hydroxide and potassium hydroxide.
  • the catalysts in each of the above steps may be the same or different: potassium iodide, sodium iodide, potassium fluoride, sodium fluoride, potassium bromide or sodium bromide.
  • the compound of general formula III can be prepared according to known methods, for example, with reference to WO20110201687, WO2011093415, WO2005021488, WO2005073165, WO2006137395, JP2007099761, WO2008000438, WO2008074427, WO2008107091, WO2010013567, WO2010018714, WO2010090282, WO2010127926, WO2010127928, JP20112012549, WO2014842012483, 077201 It is prepared by the methods reported in WO2013050261, WO2014069665, WO2014067838, WO2014161848, WO2014161850, WO2015097091 or WO2015097094; the halogenated substance R 4 -LG and alkali are usually commercially available, and they can also be made according to conventional methods.
  • the embodiments of the present invention also provide the use of the above-mentioned amide compounds in the preparation of insecticides.
  • the insecticide is used to control one or more of the following insects:
  • Beetles Coldosobruchus Chinensis, Sitophilus zeamais, Tribolium Castaneum, Epilachna vigintioctomaculata, Agfuriots cioglis ), Anomala rufocuprea, Potato leaf beetle (Leptinotarsa decemlineata), Diabrotica spp., Monochamus alternatus endai, Lissorhoptrus oryzophilus, Brown mealy beetle (Lyctus bruneus);
  • Lepidopteran pests for example, Lymantria dispar, Malacosoma neustria, Pieris rapae crucivola, Spodoptera litura, Mamestra brassicae), Chilo suppressalis, European corn borer (Ostrinia nubilalis), Cadra cautella, chyanokokakumonhamaki (Adoxophyes honmai), Cydia pomonella, Agrotis segetum, Galleria mellonella, Plutella xylostella, Heliothis virescens, Phyllocnistis citrella;
  • Hemipterous pests such as Nephotettix cincticeps, Nilaparvata lugens, Pseudococcuscomstocki, Unaspis yanonensis, Myzus persicas, Apple aphid (Aphis pomi), cotton aphid (Aphis gossypii), radish aphid (Lipaphis erysimi), pear crown bug (Stephanitis nashi), green stink (Nezara spp.), greenhouse whitefly (Trialeurodes vaporariorum), Pshylla spp. ;
  • Thysanoptera pests such as Thrips palmi, Franklinella occidentalis
  • Orthopteran pests such as Gryllotalpa Africa, Locusta migratoria
  • Blattarian pests such as German cockroach (Blattella germanica), American cockroach (Periplaneta americana), yellow breasted termites (Reticulitermes spermus), house termites (Coptotermes formosanus);
  • Dipterous pests such as Musca domestica, Aedesaegypti, Delia platura, Culex pipiens pallens, Anopheles sinensis, Three Culex tritaeniorhynchus, Liriomyza trifolii, etc.
  • Agricultural pest mites such as Tetranychus cinnabarinus, Tetrahychus urticae, Panonychus citri, Aculops pelekassi, Tarsonemus spp., etc. .
  • the insecticide is used to control one or more of Armyworm, Plutella xylostella, and Chilo suppressalis.
  • the embodiment of the present invention also provides an insecticide preparation, which contains the above-mentioned amide compound as an active component, and also contains one or more auxiliary materials.
  • the insecticide preparation is selected from the following dosage forms: solution, emulsion, wettable powder, granular wettable powder, suspension, powder, foam, ointment, tablet, granule Agents, aerosols, natural agents impregnated with active compounds, synthetic agents impregnated with active compounds, microcapsules, seed coatings, preparations equipped with a combustion device (the combustion device may be a chimney, a mist tube, a pot And coils, etc.) and ULV (cold mist, hot mist) and so on.
  • a combustion device may be a chimney, a mist tube, a pot And coils, etc.
  • ULV cold mist, hot mist
  • insecticide preparations or animal parasite control agents can be prepared by known methods, for example, by combining the active ingredients with fillers (such as liquid diluents or carriers, liquefied gas diluents or carriers, solid diluents or carriers) It is prepared by mixing, and optionally with surfactants (ie, emulsifiers and/or dispersants and/or foaming agents) and the like.
  • fillers such as liquid diluents or carriers, liquefied gas diluents or carriers, solid diluents or carriers
  • surfactants ie, emulsifiers and/or dispersants and/or foaming agents
  • the auxiliary material includes one or more of the following: filler (such as: liquid diluent or carrier, liquefied gas diluent or carrier, solid diluent or carrier), surfactant (such as: emulsifier and/or dispersant and/or foaming agent), adhesive, colorant;
  • filler such as: liquid diluent or carrier, liquefied gas diluent or carrier, solid diluent or carrier
  • surfactant such as: emulsifier and/or dispersant and/or foaming agent
  • adhesive such as: emulsifier and/or dispersant and/or foaming agent
  • the liquid diluent or carrier may include, for example, aromatic hydrocarbons (xylene, toluene, alkyl naphthalene, etc.), chlorinated aromatic hydrocarbons or chlorinated aliphatic hydrocarbons (such as chlorobenzene, vinyl chloride, methylene chloride, etc.), aliphatic hydrocarbons (Such as cyclohexane or paraffin wax (such as mineral oil fraction)), alcohol (such as butanol, ethylene glycol, and ether or ester thereof), ketone (such as acetone, methyl ethyl ketone, methyl isobutyl ketone) , Cyclohexanone, etc.), strong polar solvents (such as dimethylformamide, dimethyl sulfoxide), water, etc.
  • aromatic hydrocarbons xylene, toluene, alkyl naphthalene, etc.
  • chlorinated aromatic hydrocarbons or chlorinated aliphatic hydrocarbons such
  • Liquefied gas diluents or carriers may include those that exist in gaseous form at atmospheric pressure and temperature, for example, propane, nitrogen, carbon dioxide, and aerosol propellants such as halogenated hydrocarbons;
  • the solid diluent may include crushed natural minerals (such as kaolin, clay, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, etc.) and crushed synthetic minerals (such as finely divided silicic acid, alumina And silicate etc.) etc.;
  • crushed natural minerals such as kaolin, clay, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, etc.
  • crushed synthetic minerals such as finely divided silicic acid, alumina And silicate etc.
  • Emulsifiers and/or foaming agents may include nonionic and anionic emulsifiers [e.g., polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohol ethers (such as alkyl aryl polyethylene glycol ethers), alkyl sulfonates , Alkyl sulfate and aryl sulfonate] and albumin hydrolysate, etc.;
  • nonionic and anionic emulsifiers e.g., polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohol ethers (such as alkyl aryl polyethylene glycol ethers), alkyl sulfonates , Alkyl sulfate and aryl sulfonate] and albumin hydrolysate, etc.;
  • the dispersant may include lignin sulfite waste liquid and methyl cellulose;
  • the binder may include carboxymethyl cellulose, natural or synthetic polymers (for example, gum arabic, polyvinyl alcohol, polyvinyl acetate, etc.).
  • the colorant may include inorganic pigments (such as iron oxide, titanium oxide, and Prussian blue, etc.), organic dyes such as alizarin dyes, azo dyes, or metal phthalocyanine dyes; and trace elements such as iron salts, manganese salts, boron salts, copper Salt, cobalt salt, molybdenum salt or zinc salt.
  • inorganic pigments such as iron oxide, titanium oxide, and Prussian blue, etc.
  • organic dyes such as alizarin dyes, azo dyes, or metal phthalocyanine dyes
  • trace elements such as iron salts, manganese salts, boron salts, copper Salt, cobalt salt, molybdenum salt or zinc salt.
  • the amide compound of the present invention can exist as a mixture with a synergist, and the synergist itself does not have to be active. More precisely, it is a compound that enhances the activity of the active compound.
  • the amount of the above-mentioned amide compound contained in the pesticide formulation is 0.1 to 99% by weight, optionally 0.5 to 90% by weight.
  • the embodiment of the present invention also provides an insecticide composition, which includes the above-mentioned amide compound and other active compounds (such as insecticides, baits, disinfectants, acaricides, nematicides, fungicides, growth Regulators, herbicides, etc.).
  • the mixture can be provided in the form of a bulk drug, or can be provided in the form of a commercially available useful preparation or a use form prepared from its preparation.
  • the embodiment of the present invention also provides a method for controlling agricultural or forestry pests, which includes the following steps: applying an effective dose of materials to the pests to be controlled or their growth medium, and the materials are selected from one of the following group Or more: the above-mentioned amide compound, the above-mentioned insecticide preparation, and the above-mentioned insecticide composition.
  • the embodiments of the present invention also provide the use of the above-mentioned amide compounds in the preparation of animal parasite control agents.
  • the amide compound of the present invention can be effectively used to combat a variety of harmful animal parasites, especially endoparasites and ectoparasites.
  • animal parasites include one or more of the following:
  • Anoplurida such as Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp, and Solenopotes spp.; in particular, representative examples Yes, Linognathus setosus, Solenopotes capillatus;
  • Trichophagous order (Mallopha, Linognathus vituli), sheep jaw lice (Linognathus ovillus), Linognathus oviformis, foot jaw lice (Linognathus pedalis), goat jaw lice (Linognathus stenopsis), donkey blood lice (Haematopinus asini, macrocephalus) Bovine blood louse (Haematopinus eurysternus), pig blood louse (Haematopinus suis), head louse (Pediculus humanus capitis), body louse (Pediculus humanus corporis), grape phylloxera (Phylloera vastatrix), pubic louse (Phthirus pubis) gida) Amblycerina and Ischnocerin, for example, Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp.), Werneckiella spp., Lepi
  • Bovicola bovis bovine lice
  • wool louse Bovicola ovis
  • Angola goat feather louse Bovicola limbata
  • cattle louse Damalina bovis
  • dog hair louse Trichodectes canis
  • cat feather louse Felicola subrostratus
  • goat louse Bovicola caprae
  • Lepikentron ovis Werneckiella equi
  • Diptera and its Nematocerina and Brachycerina for example, Aedes spp., Anopheles ( Anopheles spp., Culex spp., Simulium spp, Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culex Culicoides spp., Chrysops spp., Odag mia spp.), Wilhelmia (Wilhelmia s
  • Siphonaptrida for example, Pulex spp., Ctenocephalides spp., Tunga spp., Xenopsylla spp., Ceratophyllus spp.);
  • representative examples include Ctenocephalides canis, Ctenocephalides felis, Pulex irritans, Tunga penetrans, and Ctenocephalides canis (Xenopsylla cheopis);
  • Acari or Acarina
  • Metastigmata and Mesostigmata for example, Argas spp., Ornithodorus spp., Remnant beak tick Otobius spp., Ixodes spp., Amblyomma spp., Rhipicephalus (Boophilus) spp., Dermacentor spp., Haemophysalis spp., Hyalomma (Hyalomma spp.), Dermanyssus spp., Rhipicephalus spp. (the original genus of heterotopic parasitic mites), Ornithonyssus spp.,
  • Pneumonyssus spp. Pneumonyssus spp., Pneumonyssus spp., Railietia spp., Pneumonyssus spp., Sternostoma spp., Varroa spp. .), Acarapis spp.; in particular, representative examples include Argas persicus, Argas reflexus, Ornithodorus moubata, and ear damage Otobius megnini, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) decoloratus), Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) decoloratus Rhipicephalus (Boophilus) annulatus), Rhipicephalus (Boophilus) calceratus, Hyalomma anatolicum, Hyalomma aegyp
  • Nematodes such as Meloidogyne incognita, Bursaphelenchus xylophilus, Aphelenchoides besseyi, Heterodera glycines, Pratylenchus spp., etc.;
  • Arthropods, worms and malaria parasites that invade animals. Controlling arthropods, worms and/or malaria parasites can reduce the mortality of domestic animals and improve the productivity (meat, milk, hair, skin, eggs and honey) and health of animals.
  • the animal parasite control agent is used to control one or more of cat fleas and American dog ticks.
  • the animals include one or more of the following: agricultural animals, such as cows, sheep, goats, horses, pigs, donkeys, camels, buffaloes, rabbits, chickens, turkeys, ducks, geese , Farmed fish, bees, etc.; also includes pets called companion animals, such as dogs, cats, caged birds, and ornamental fish; also includes animals used for experiments, such as hamsters, guinea pigs, rats, and mice.
  • agricultural animals such as cows, sheep, goats, horses, pigs, donkeys, camels, buffaloes, rabbits, chickens, turkeys, ducks, geese , Farmed fish, bees, etc.
  • companion animals such as dogs, cats, caged birds, and ornamental fish
  • animals used for experiments such as hamsters, guinea pigs, rats, and mice.
  • the embodiment of the present invention also provides an animal parasite control agent, which contains the above-mentioned amide compound as an active component, and also contains one or more auxiliary materials.
  • the animal parasite control agent is selected from the following dosage forms: tablets, capsules, drinks, drinkable drugs, granules, ointments and pills, suppositories, injections (muscle, subcutaneous, intravenous, Intraperitoneal, etc.), smears, aerosols, non-pressure sprays (such as pump sprays and atomized sprays).
  • the amount of the above-mentioned active component contained in the animal parasite control agent is 1 to 80% by weight.
  • the embodiments of the present invention also provide an animal parasite control composition, which includes the above-mentioned amide compounds and other animal parasite control active compounds (such as acaricides, insecticides, parasiteicides, anti-plasmodium agents, etc.) )mixture.
  • the mixture can be provided in the form of a bulk drug, or can be provided in the form of a commercially available useful preparation or a use form prepared from its preparation.
  • the embodiment of the present invention also provides a method for controlling animal parasites, which includes the following steps: applying an effective dose of material to the animal parasites or their growth medium to be controlled, and the material is selected from one of the following group: One or more: the above-mentioned amide compounds; the above-mentioned animal parasite control agent; the above-mentioned animal parasite control composition.
  • suppositories for enteral administration; skin-based non-intestinal administration, such as injection (muscle, subcutaneous, intravenous, Intraperitoneal, etc.), implantation, nasal administration, including bathing or soaking, spraying, pouring, dripping, washing and dusting, and through the use of model products containing active compounds, such as collars, ear tags, labels, legs Use leg brace, net, marker, etc.
  • the active compound of the present invention has low toxicity and can be safely used in warm-blooded animals.
  • the amide compound of the present invention has an unexpectedly excellent insecticidal effect, it also exhibits a suitable control effect against toxic pests, and has no phytotoxicity to cultivated crop plants.
  • the compounds of the present invention can be used to control various pests, such as harmful sucking insects, chewing insects, and other plant parasitic pests, stored grain pests, sanitary pests, etc., and can be used to disinfect and kill them.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Halogenated alkyl groups straight or branched chain alkyl groups.
  • the hydrogen atoms on these alkyl groups can be partially or completely replaced by halogens, such as difluoromethyl (CHF 2 ), trifluoromethyl (CF 3 ), and the like.
  • Halogenated alkoxy group The hydrogen atoms on the alkoxy group can be partially or completely replaced by halogen, such as difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ), and the like.
  • halogen such as difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ), and the like.
  • Cyanoalkyl straight or branched chain alkyl groups, the hydrogen atoms on these alkyl groups may be partially or completely replaced by cyano groups, and C 1 -C 4 in the cyano C 1 -C 4 alkyl group represents an alkyl group Chain length, such as CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 CH 2 CN, CH 2 CH 2 CH 2 CH 2 CN, CH(CH 3 )CN, CH(CH 2 CH 3 )CN, CH( CH 2 CH 2 CH 3 )CN, C(CH 3 )(CH 3 )CN or C(CH 3 )(CH 2 CH 3 )CN.
  • Insecticides substances that have insecticidal effects on pests.
  • Animal parasite control agents refers to active compounds that can effectively reduce the incidence of various parasites in animals infected by parasites. Control means that the active compound can effectively kill parasites, inhibit their growth or reproduction.
  • the compound represented by the general formula I of the present invention can be prepared, which is further described in detail as follows:
  • intermediate III-4 prepared with reference to the method reported in WO2011093415 or WO2010018714
  • bromoacetonitrile was reacted with bromoacetonitrile to prepare intermediate II.7 (white solid).
  • the NMR and MS data of Intermediate II.7 are as follows:
  • compound 5 (white solid) was prepared by reacting intermediate II.2 with 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 5 are as follows:
  • compound 9 (yellow solid) was prepared by reacting intermediate II.3 with 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 9 are as follows:
  • compound 10 (yellow solid) was prepared by reacting intermediate II.4 and 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 10 are as follows:
  • compound 11 (yellow oil) was prepared by reacting intermediate II.5 with 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 11 are as follows:
  • compound 12 (yellow oil) was prepared by reacting intermediate II.6 with 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 12 are as follows:
  • compound 13 (yellow solid) was prepared by reacting Intermediate II.7 with 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 13 are as follows:
  • compound 14 (yellow solid) was prepared by reacting intermediate II.8 with 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 14 are as follows:
  • compound 15 (yellow solid) was prepared by reaction of Intermediate II.9 and 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 15 are as follows:
  • compound 16 (yellow solid) was prepared by reaction of Intermediate II.10 and 6-cyanonicotinoyl chloride.
  • the NMR and MS data of compound 16 are as follows:
  • Example 25 Determination of biological activity of Armyworm, Plutella xylostella, Chilo suppressalis
  • the insecticidal activity test of several insects was carried out with the compound of the present invention.
  • the measurement method is as follows:
  • test compound After the test compound is dissolved in a mixed solvent of acetone/methanol (1:1), it is diluted with water containing 0.1% (wt) Tween 80 to the desired concentration.
  • Measurement method cut corn leaves into 2cm leaf sections, the pressure of Airbrush spray treatment is 10psi (approximately 0.7kg/cm 2 ), the front and back sides of each leaf section are sprayed, and the spray volume of the compound to be tested is 0.5ml. After drying in the shade, 10 3rd instar larvae were inserted into each treatment, and repeated 3 times for each treatment. After the treatment, it was placed in an observation room at 25°C and a relative humidity of 60-70% for cultivation, and the number of surviving insects was investigated 3 days after the treatment, and the mortality rate was calculated.
  • Measurement method Use a punch to punch cabbage leaves into leaf discs with a diameter of 2 cm.
  • the pressure of Airbrush spray treatment is 10 psi (approximately 0.7 kg/cm 2 ), and the front and back sides of each leaf disc are sprayed.
  • the spray volume of the compound to be tested is 0.5ml. After drying in the shade, 10 3rd instar larvae were inserted into each treatment, and repeated 3 times for each treatment. After the treatment, it was placed in an observation room at 25°C and a relative humidity of 60-70%, and the number of surviving insects was investigated 3 days after the treatment, and the mortality rate was calculated.
  • the lethality of compounds 1, 5, 9, 10, 11, 12, 13, 14, 15, 16 to Plutella xylostella was more than 90%.
  • the lethality of compounds 9, 10, 11, 12, 13, 14, 15, 16 to Plutella xylostella was more than 90%.
  • Determination method 1) Preparation of rice seedlings: cultivate rice in a plastic cup with a diameter of 4.5 cm and a height of 4 cm in a constant temperature room (temperature 26-28°C, relative humidity 60-80%, light 16hL:8hD), and wait until the rice grows. At the 4 to 5 leaf stage, select robust and consistent rice seedlings for chemical treatment, and set 3 repetitions for each treatment. 2) Preparation for test insects: Chilo suppressalis, 3rd instar larvae continuously reared indoors. 3) The rice stalk is sprayed to catch insects. The spray method is adopted to uniformly spray the whole plant of the rice seedlings, with 15 ml of medicine per treatment.
  • the rice seedlings are sprayed, they are placed in a cool place to dry the liquid, and about 5 cm of the stalk at the base of the stem is cut to feed the test insects.
  • the compound 1 is compared with the control compounds 1-1 and 1-2, by comparing compound 9 with the control compounds 2-1 and 2-2, and by comparing compound 13 with the control compounds 3-1 and 3-2, it can be seen Out:
  • the cyano group on the benzene ring and the adjacent nitrogen atom are very important. The two cooperate with each other and are indispensable.
  • Example 26 Insecticidal test on cat fleas

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Abstract

Disclosed are an amide compound and an application thereof. The structure of the compound is as represented by general formula I. The definitions of substituents in the formula are described in the description. Also disclosed in the description is use of the compound as an insecticide and an animal parasite control agent.

Description

一种酰胺类化合物及其应用A kind of amide compound and its application 技术领域Technical field
本发明涉及一种化合物，具体涉及一种新型的酰胺类化合物及其应用。The invention relates to a compound, in particular to a novel amide compound and its application.
背景技术Background technique
由于现有药剂长期大量的不合理使用，害虫对杀虫剂的抗药性问题日益严重。另一方面，现有杀虫剂的杀虫效果尤其对水稻二化螟的活性仍不能令人满意，难以满足现实中杀虫剂不断提高的使用要求。在本领域仍需积极开发更高活性的新杀虫剂，以满足农业和其它领域的需求。Due to the long-term and unreasonable use of existing drugs, the problem of pest resistance to pesticides has become increasingly serious. On the other hand, the insecticidal effect of the existing insecticides, especially the activity of the rice borer, is still not satisfactory, and it is difficult to meet the increasing use requirements of insecticides in reality. There is still a need to actively develop new pesticides with higher activity in this field to meet the needs of agriculture and other fields.
现有技术中如本发明通式I所示的化合物及其杀虫活性未见报道。In the prior art, the compound represented by the general formula I of the present invention and its insecticidal activity have not been reported.
发明内容Summary of the invention
本发明的目的在于提供一种杀虫活性优异的酰胺类化合物。它可用于制备农业和其它领域中防治害虫的药物以及在兽药领域用于制备控制动物寄生虫的药物。The object of the present invention is to provide an amide compound with excellent insecticidal activity. It can be used to prepare drugs for controlling pests in agriculture and other fields, and for preparing drugs for controlling animal parasites in the field of veterinary medicine.
为实现本发明的发明目的，本发明提供了如下技术方案：In order to achieve the objective of the present invention, the present invention provides the following technical solutions:
一种酰胺类化合物，如通式I所示：An amide compound, as shown in general formula I:
Figure PCTCN2020126091-appb-000001
Figure PCTCN2020126091-appb-000001
通式IGeneral formula I
通式I中：In the general formula I:
R 1选自卤素； R 1 is selected from halogen;
R 2选自卤素、C 1-C 4卤代烷基或C 1-C 4卤代烷氧基； R 2 is selected from halogen, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy;
R 3选自CF 3或CF 2CF 3； R 3 is selected from CF 3 or CF 2 CF 3 ;
R 4选自氰基C 1-C 4烷基。 R 4 is selected from cyano C 1 -C 4 alkyl.
在一种可能的实现方式中，通式I中，In a possible implementation, in general formula I,
R 1选自卤素； R 1 is selected from halogen;
R 2选自卤素、C 1-C 2卤代烷基或C 1-C 2卤代烷氧基； R 2 is selected from halogen, C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy;
R 3选自CF 3或CF 2CF 3； R 3 is selected from CF 3 or CF 2 CF 3 ;
R 4选自氰基C 1-C 4烷基。 R 4 is selected from cyano C 1 -C 4 alkyl.
在一种可能的实现方式中，通式I中，In a possible implementation, in general formula I,
R 1选自溴或碘； R 1 is selected from bromine or iodine;
R 2选自溴、碘、三氟甲基或二氟甲氧基； R 2 is selected from bromine, iodine, trifluoromethyl or difluoromethoxy;
R 3选自CF 3或CF 2CF 3； R 3 is selected from CF 3 or CF 2 CF 3 ;
R 4选自CH 2CN、CH 2CH 2CN、CH 2CH 2CH 2CN、CH 2CH 2CH 2CH 2CN、CH(CH 3)CN、CH(CH 2CH 3)CN、CH(CH 2CH 2CH 3)CN、C(CH 3)(CH 3)CN或C(CH 3)(CH 2CH 3)CN。 R 4 is selected from CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 CH 2 CN, CH 2 CH 2 CH 2 CH 2 CN, CH(CH 3 )CN, CH(CH 2 CH 3 )CN, CH( CH 2 CH 2 CH 3 )CN, C(CH 3 )(CH 3 )CN or C(CH 3 )(CH 2 CH 3 )CN.
在一种可能的实现方式中，通式I中，In a possible implementation, in general formula I,
R 1选自溴或碘； R 1 is selected from bromine or iodine;
R 2选自溴、碘或三氟甲基； R 2 is selected from bromine, iodine or trifluoromethyl;
R 3选自CF 3； R 3 is selected from CF 3 ;
R 4选自CH 2CN、CH 2CH 2CN、CH 2CH 2CH 2CN或CH 2CH 2CH 2CH 2CN。 R 4 is selected from CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 CH 2 CN, or CH 2 CH 2 CH 2 CH 2 CN.
在一种可能的实现方式中，酰胺类化合物选自表1化合物，所述表1化合物具有如通式I的结构且R 1、R 2、R 3和R 4如表1中所示： In a possible implementation, the amide compound is selected from the compounds of Table 1, and the compounds of Table 1 have the structure of Formula I and R 1 , R 2 , R 3 and R 4 are as shown in Table 1:
表1Table 1
Figure PCTCN2020126091-appb-000002
Figure PCTCN2020126091-appb-000002
本发明的通式I化合物可按照以下方法制备(式中各基团除另有说明外定义同前，式中LG＝Cl,Br或I)：The compound of general formula I of the present invention can be prepared according to the following method (the groups in the formula are defined as before unless otherwise specified, where LG=Cl, Br or I):
Figure PCTCN2020126091-appb-000003
Figure PCTCN2020126091-appb-000003
通式III化合物与卤代物R 4-LG在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应0.5-48小时可制得通式II化合物，反应在碱和催化剂存在下进行；通式II化合物与6-氰基烟酰基氯化物在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应0.5-48小时可制得通式I化合物，反应可在碱和催化剂存在下进行。上述各步骤中适宜的溶剂可相同或不同的为苯、甲苯、二甲苯等芳烃类，丙酮、甲乙酮、甲基异丁基酮等酮类，氯仿、二氯甲烷等卤代烃类，乙酸甲酯、乙酸乙酯等酯类，四氢呋喃、二噁烷、二乙醚、1,2-二甲氧基乙烷等醚类，水、乙腈、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜等极性溶剂类或上述溶剂的混合溶剂。上述各步骤中碱可相同或不同的为三乙胺、吡啶、DBU、4-二甲氨基吡啶等有机碱，氢化钠、氢化钾等碱金属氢化物，氢氧化钠、氢氧化钾等碱金属氢氧化物，氢氧化钙等碱土类金属氢氧化物，碳酸钠、碳酸钾等碱金属碳酸盐，碳酸氢钠等碱金属碳酸氢盐，甲醇钠、乙醇钠、乙醇钾、叔丁醇钾、叔丁醇钠等金属醇盐。上述各步骤中催化剂可相同或不同的为碘化钾、碘化钠、氟化钾、氟化钠、溴化钾或溴化钠等。 The compound of the general formula III and the halogenated compound R 4 -LG are reacted in a suitable solvent at a temperature from -10°C to the boiling point of the solvent for 0.5-48 hours to obtain a compound of the general formula II. The reaction is carried out in the presence of a base and a catalyst; The compound of formula II and 6-cyanonicotinoyl chloride are reacted in a suitable solvent at a temperature from -10°C to the boiling point of the solvent for 0.5-48 hours to obtain a compound of formula I. The reaction can be carried out in the presence of a base and a catalyst. . Suitable solvents in the above steps can be the same or different. Aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogenated hydrocarbons such as chloroform and dichloromethane; and methyl acetate. Esters, ethyl acetate and other esters, tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane and other ethers, water, acetonitrile, N,N-dimethylformamide, N-methyl Polar solvents such as pyrrolidone and dimethyl sulfoxide, or mixed solvents of the above solvents. In the above steps, the bases that can be the same or different are organic bases such as triethylamine, pyridine, DBU, 4-dimethylaminopyridine, alkali metal hydrides such as sodium hydride, potassium hydride, and alkali metals such as sodium hydroxide and potassium hydroxide. Hydroxides, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide , Metal alkoxides such as sodium tert-butoxide. The catalysts in each of the above steps may be the same or different: potassium iodide, sodium iodide, potassium fluoride, sodium fluoride, potassium bromide or sodium bromide.
通式III化合物可以按公知方法制备，例如参照WO20110201687、WO2011093415、WO2005021488、WO2005073165、WO2006137395、JP2007099761、WO2008000438、WO2008074427、WO2008107091、WO2010013567、WO2010018714、WO2010090282、WO2010127926、WO2010127928、JP2011063549、WO2012020483、WO2012020484、WO2012077221、WO2012164698、WO2013050261、WO2014069665、WO2014067838、WO2014161848、WO2014161850、WO2015097091或WO2015097094等报道的方法制得；卤代物R 4-LG、碱通常有市售，也可按照常规方法自制。 The compound of general formula III can be prepared according to known methods, for example, with reference to WO20110201687, WO2011093415, WO2005021488, WO2005073165, WO2006137395, JP2007099761, WO2008000438, WO2008074427, WO2008107091, WO2010013567, WO2010018714, WO2010090282, WO2010127926, WO2010127928, JP20112012549, WO2014842012483, 077201 It is prepared by the methods reported in WO2013050261, WO2014069665, WO2014067838, WO2014161848, WO2014161850, WO2015097091 or WO2015097094; the halogenated substance R 4 -LG and alkali are usually commercially available, and they can also be made according to conventional methods.
本发明实施例还提供了上述酰胺类化合物在制备杀虫剂中的用途。The embodiments of the present invention also provide the use of the above-mentioned amide compounds in the preparation of insecticides.
在一种可能的实现方式中，所述杀虫剂用于防治以下昆虫的一种或多种：In a possible implementation, the insecticide is used to control one or more of the following insects:
甲虫(鞘翅目昆虫(Coleopteran))，例如绿豆象(Callosobruchus Chinensis)、玉米象(Sitophilus zeamais)、赤拟谷盗(Tribolium Castaneum)、马铃薯瓢虫(Epilachna vigintioctomaculata)、细胸叩甲(Agriotes ogurae fuscicollis)、多色异丽金龟(Anomala rufocuprea)、马铃薯叶甲(Leptinotarsa decemlineata)、叶甲属(Diabrotica spp.)、松墨天牛(Monochamus alternatus endai)、稻根象(Lissorhoptrus oryzophilus)、褐粉蠹(Lyctus bruneus)；Beetles (Coleopteran), such as Callosobruchus Chinensis, Sitophilus zeamais, Tribolium Castaneum, Epilachna vigintioctomaculata, Agfuriots cioglis ), Anomala rufocuprea, Potato leaf beetle (Leptinotarsa decemlineata), Diabrotica spp., Monochamus alternatus endai, Lissorhoptrus oryzophilus, Brown mealy beetle (Lyctus bruneus);
鳞翅目(lepidopteran)害虫，例如，舞毒蛾(Lymantria dispar)、黄褐天幕毛虫(Malacosoma neustria)、 菜粉蝶日本亚种(Pieris rapae crucivora)、斜纹夜蛾(Spodoptera litura)、甘蓝夜蛾(Mamestra brassicae)、二化螟(Chilo suppressalis)、欧洲玉米螟(Ostrinia nubilalis)、干果斑螟(Cadra cautella)、chyanokokakumonhamaki(Adoxophyes honmai)、苹果小卷蛾(Cydia pomonella)、黄地老虎(Agrotis segetum)、大蜡螟(Galleria mellonella)、菜蛾(Plutella xylostella)、烟芽夜蛾(Heliothis virescens)、桔潜蛾(Phyllocnistis citrella)；Lepidopteran pests, for example, Lymantria dispar, Malacosoma neustria, Pieris rapae crucivola, Spodoptera litura, Mamestra brassicae), Chilo suppressalis, European corn borer (Ostrinia nubilalis), Cadra cautella, chyanokokakumonhamaki (Adoxophyes honmai), Cydia pomonella, Agrotis segetum, Galleria mellonella, Plutella xylostella, Heliothis virescens, Phyllocnistis citrella;
半翅目(Hemipterous)害虫，例如，黑尾叶蝉(Nephotettix cincticeps)、褐飞虱(Nilaparvata lugens)、康氏粉蚧(Pseudococcus comstocki)、矢尖盾蚧(Unaspis yanonensis)、桃蚜(Myzus persicas)、苹果蚜(Aphis pomi)、棉蚜(Aphis gossypii)、萝卜蚜(Lipaphis erysimi)、梨冠网蝽(Stephanitis nashi)、绿椿属(Nezara spp.)、温室粉虱(Trialeurodes vaporariorum)、Pshylla spp.；Hemipterous pests, such as Nephotettix cincticeps, Nilaparvata lugens, Pseudococcuscomstocki, Unaspis yanonensis, Myzus persicas, Apple aphid (Aphis pomi), cotton aphid (Aphis gossypii), radish aphid (Lipaphis erysimi), pear crown bug (Stephanitis nashi), green stink (Nezara spp.), greenhouse whitefly (Trialeurodes vaporariorum), Pshylla spp. ；
缨翅目(Thysanoptera)害虫，例如棕榈蓟马(Thrips palmi)、西方花蓟马(Franklinella occidentalis)；直翅目(orthopteran)害虫，例如非洲蝼蛄(Gryllotalpa Africana)、非洲飞蝗(Locusta migratoria)；蜚蠊目(blattarian)害虫，例如德国蠊(Blattella germanica)、美洲大蠊(Periplaneta americana)、黄胸散白蚁(Reticulitermes speratus)、家白蚁(Coptotermes formosanus)；Thysanoptera pests, such as Thrips palmi, Franklinella occidentalis; Orthopteran pests, such as Gryllotalpa Africa, Locusta migratoria; Blattarian pests, such as German cockroach (Blattella germanica), American cockroach (Periplaneta americana), yellow breasted termites (Reticulitermes spermus), house termites (Coptotermes formosanus);
双翅目(Dipterous)害虫，例如家蝇(Musca domestica)、埃及伊蚊(Aedesaegypti)、灰地种蝇(Delia platura)、淡色库蚊(Culex pipiens pallens)、中华按蚊(Anopheles sinensis)、三带喙库蚊(Culex tritaeniorhynchus)、三叶草斑潜蝇(Liriomyza trifolii)等。Dipterous pests, such as Musca domestica, Aedesaegypti, Delia platura, Culex pipiens pallens, Anopheles sinensis, Three Culex tritaeniorhynchus, Liriomyza trifolii, etc.
农业害螨，如朱砂叶螨(Tetranychus cinnabarinus)、棉叶螨(Tetrahychus urticae)、桔全爪螨(Panonychus citri)、桔刺皮瘿螨(Aculops pelekassi)、跗线螨属(Tarsonemus spp.)等。Agricultural pest mites, such as Tetranychus cinnabarinus, Tetrahychus urticae, Panonychus citri, Aculops pelekassi, Tarsonemus spp., etc. .
在一种可能的实现方式中，所述杀虫剂用于防治粘虫、小菜蛾、二化螟中的一种或几种。In a possible implementation manner, the insecticide is used to control one or more of Armyworm, Plutella xylostella, and Chilo suppressalis.
本发明实施例还提供了一种杀虫剂制剂，该杀虫剂制剂中含有上述酰胺类化合物作为活性组分，还含有一种或多种辅料。The embodiment of the present invention also provides an insecticide preparation, which contains the above-mentioned amide compound as an active component, and also contains one or more auxiliary materials.
在一种可能的实现方式中，杀虫剂制剂选自以下剂型：溶液剂、乳剂、可湿性粉剂、颗粒状可湿性粉剂、悬浮剂、粉剂(powder)、泡沫剂、膏剂、片剂、颗粒剂、气雾剂、经活性化合物浸渍的天然试剂、经活性化合物浸渍的合成试剂、微胶囊剂、种子包衣剂、装备有燃烧装置的制剂(所述燃烧装置可为烟筒和雾筒、罐和盘管等)以及ULV(冷雾剂、热雾剂)等。这些杀虫剂制剂或动物寄生虫防治剂可用已知的方法制备，例如可通过将活性组分与填充剂(如：液体稀释剂或载体、液化气稀释剂或载体、固体稀释剂或载体)混合，以及可选地与表面活性剂(即乳化剂和/或分散剂和/或发泡剂)等混合而制备。In a possible implementation, the insecticide preparation is selected from the following dosage forms: solution, emulsion, wettable powder, granular wettable powder, suspension, powder, foam, ointment, tablet, granule Agents, aerosols, natural agents impregnated with active compounds, synthetic agents impregnated with active compounds, microcapsules, seed coatings, preparations equipped with a combustion device (the combustion device may be a chimney, a mist tube, a pot And coils, etc.) and ULV (cold mist, hot mist) and so on. These insecticide preparations or animal parasite control agents can be prepared by known methods, for example, by combining the active ingredients with fillers (such as liquid diluents or carriers, liquefied gas diluents or carriers, solid diluents or carriers) It is prepared by mixing, and optionally with surfactants (ie, emulsifiers and/or dispersants and/or foaming agents) and the like.
在一种可能的实现方式中，所述辅料包括以下的一种或多种：填充剂(如：液体稀释剂 或载体、液化气稀释剂或载体、固体稀释剂或载体)、表面活性剂(如：乳化剂和/或分散剂和/或发泡剂)、粘合剂、着色剂；In a possible implementation manner, the auxiliary material includes one or more of the following: filler (such as: liquid diluent or carrier, liquefied gas diluent or carrier, solid diluent or carrier), surfactant ( Such as: emulsifier and/or dispersant and/or foaming agent), adhesive, colorant;
液体稀释剂或载体可包括，例如，芳香烃(二甲苯、甲苯、烷基萘等)、氯代芳烃或氯代脂族烃(例如氯苯、氯乙烯、二氯甲烷等)、脂族烃(例如环己烷或石蜡(例如矿物油馏分))、醇(例如丁醇、乙二醇，及其醚或酯等)、酮(例如丙酮、甲基乙基酮、甲基异丁基酮、环己酮等)、强极性溶剂(例如二甲基甲酰胺、二甲亚砜)、水等。当使用水作为填充剂时，例如，可使用有机溶剂作为助溶剂；The liquid diluent or carrier may include, for example, aromatic hydrocarbons (xylene, toluene, alkyl naphthalene, etc.), chlorinated aromatic hydrocarbons or chlorinated aliphatic hydrocarbons (such as chlorobenzene, vinyl chloride, methylene chloride, etc.), aliphatic hydrocarbons (Such as cyclohexane or paraffin wax (such as mineral oil fraction)), alcohol (such as butanol, ethylene glycol, and ether or ester thereof), ketone (such as acetone, methyl ethyl ketone, methyl isobutyl ketone) , Cyclohexanone, etc.), strong polar solvents (such as dimethylformamide, dimethyl sulfoxide), water, etc. When water is used as a filler, for example, an organic solvent can be used as a co-solvent;
液化气稀释剂或载体可包括在大气压力和温度下以气体形式存在的那些，例如，丙烷、氮气、二氧化碳，以及气溶胶喷射剂例如卤代烃；Liquefied gas diluents or carriers may include those that exist in gaseous form at atmospheric pressure and temperature, for example, propane, nitrogen, carbon dioxide, and aerosol propellants such as halogenated hydrocarbons;
固体稀释剂可包括粉碎的天然矿物(例如高岭土、粘土、滑石、白垩、石英、绿坡缕石、蒙脱石或硅藻土等)以及粉碎的合成矿物(例如细分散的硅酸、氧化铝和硅酸盐等)等；The solid diluent may include crushed natural minerals (such as kaolin, clay, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, etc.) and crushed synthetic minerals (such as finely divided silicic acid, alumina And silicate etc.) etc.;
乳化剂和/或发泡剂可包括非离子及阴离子乳化剂[例如，聚氧乙烯脂肪酸酯、聚氧乙烯脂肪酸醇醚(如烷基芳基聚乙二醇醚)、烷基磺酸盐、烷基硫酸盐和芳基磺酸盐]以及白蛋白水解产物等；Emulsifiers and/or foaming agents may include nonionic and anionic emulsifiers [e.g., polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohol ethers (such as alkyl aryl polyethylene glycol ethers), alkyl sulfonates , Alkyl sulfate and aryl sulfonate] and albumin hydrolysate, etc.;
分散剂可包括木质素亚硫酸盐废液和甲基纤维素；The dispersant may include lignin sulfite waste liquid and methyl cellulose;
粘合剂可包括羧甲基纤维素、天然或合成的聚合物(例如阿拉伯树胶、聚乙烯醇和聚乙酸乙烯酯等)。The binder may include carboxymethyl cellulose, natural or synthetic polymers (for example, gum arabic, polyvinyl alcohol, polyvinyl acetate, etc.).
着色剂可包括无机颜料(例如氧化铁、氧化钛和普鲁士蓝等)、有机染料例如茜素染料、偶氮染料或金属酞菁染料；及微量元素，例如铁盐、锰盐、硼盐、铜盐、钴盐、钼盐或锌盐。The colorant may include inorganic pigments (such as iron oxide, titanium oxide, and Prussian blue, etc.), organic dyes such as alizarin dyes, azo dyes, or metal phthalocyanine dyes; and trace elements such as iron salts, manganese salts, boron salts, copper Salt, cobalt salt, molybdenum salt or zinc salt.
此外，本发明的酰胺类化合物可作为与一种增效剂的混合物存在，增效剂自身不必具有活性。更确切地，它是增强活性化合物活性的化合物。In addition, the amide compound of the present invention can exist as a mixture with a synergist, and the synergist itself does not have to be active. More precisely, it is a compound that enhances the activity of the active compound.
在一种可能的实现方式中，杀虫剂制剂中含有的上述酰胺类化合物的量为0.1至99重量％，可选地为0.5至90重量％。In a possible implementation manner, the amount of the above-mentioned amide compound contained in the pesticide formulation is 0.1 to 99% by weight, optionally 0.5 to 90% by weight.
本发明实施例还提供了一种杀虫剂组合物，其包括上述酰胺类化合物和其他活性化合物(例如杀虫剂、毒饵剂、消毒剂、杀螨剂、杀线虫剂、杀真菌剂、生长调节剂、除草剂等)的混合物。该混合物可以以原料药的形式提供，也可以以市售有用制剂的形式或者由其制剂制得的使用形式提供。The embodiment of the present invention also provides an insecticide composition, which includes the above-mentioned amide compound and other active compounds (such as insecticides, baits, disinfectants, acaricides, nematicides, fungicides, growth Regulators, herbicides, etc.). The mixture can be provided in the form of a bulk drug, or can be provided in the form of a commercially available useful preparation or a use form prepared from its preparation.
本发明实施例还提供了一种控制农业或林业害虫的方法，其包括以下步骤：将有效剂量的材料施用于需要控制的害虫或其生长介质上，所述材料选自下组中的一种或多种：上述酰胺类化合物、上述杀虫剂制剂、上述杀虫剂组合物。The embodiment of the present invention also provides a method for controlling agricultural or forestry pests, which includes the following steps: applying an effective dose of materials to the pests to be controlled or their growth medium, and the materials are selected from one of the following group Or more: the above-mentioned amide compound, the above-mentioned insecticide preparation, and the above-mentioned insecticide composition.
本发明实施例还提供了上述酰胺类化合物在制备动物寄生虫防治剂中的用途。在兽医领域内，即，兽医科学中，本发明酰胺类化合物可以有效地用于对抗多种有害的动物类寄生虫，特别是体内寄生虫和体外寄生虫。The embodiments of the present invention also provide the use of the above-mentioned amide compounds in the preparation of animal parasite control agents. In the field of veterinary medicine, that is, in veterinary science, the amide compound of the present invention can be effectively used to combat a variety of harmful animal parasites, especially endoparasites and ectoparasites.
在一种可能的实现方式中，动物寄生虫包括以下的一种或多种：In a possible implementation, animal parasites include one or more of the following:
虱目(Anoplurida)，例如血虱属(Haematopinus spp.)、毛虱属(Linognathus spp.)、虱属(Pediculus spp.)、Phtirus spp和管虱属(Solenopotes spp.)；特别地，代表性实例有，棘颚虱(Linognathus setosus)、牛管虱(Solenopotes capillatus)；From the order of the Anoplurida, such as Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp, and Solenopotes spp.; in particular, representative examples Yes, Linognathus setosus, Solenopotes capillatus;
食毛目(Mallopha、牛颚虱(Linognathus vituli)、绵羊颚虱(Linognathus ovillus)、Linognathus oviformis、足颚虱(Linognathus pedalis)、山羊颚虱(Linognathus stenopsis)、驴血虱(Haematopinus asini macrocephalus)、牛血虱(Haematopinus eurysternus)、猪血虱(Haematopinus suis)、头虱(Pediculus humanus capitis)、体虱(Pediculus humanus corporis)、葡萄根瘤蚜(Phylloera vastatrix)、阴虱(Phthirus pubis)gida)和钝角亚目(Amblycerina)和细角亚目(Ischnocerin)，例如，毛羽虱属(Trimenopon spp.)、禽虱属(Menopon spp.)、巨羽虱属(Trinoton spp.)、牛羽虱属(Bovicola spp.)、Werneckiella spp.、Lepikentron spp.、畜虱属(Damalina spp.)、嚼虱属(Trichodectes spp.)和猫羽虱属(Felicola spp.)；特别地，代表性实例有，牛毛虱(Bovicola bovis)、羊毛虱(Bovicola ovis)、安哥拉山羊羽虱(Bovicola limbata)、牛畜虱(Damalina bovis)、犬毛虱(Trichodectes canis)、猫羽虱(Felicola subrostratus)、山羊毛虱(Bovicola caprae)、Lepikentron ovis、咬虱(Werneckiella equi)；双翅目(Diptera)及其长角亚目(Nematocerina)和短角亚目(Brachycerina)，例如，伊蚊属(Aedes spp.)、按蚊属(Anopheles spp.)、库蚊属(Culex spp.)、蚋属(Simulium spp)、真蚋属(Eusimulium spp.)、白蛉属(Phlebotomus spp.)、罗蛉属(Lutzomyia spp.)、库蠓属(Culicoides spp.)、斑虻属(Chrysops spp.)、短蚋属(Odagmia spp.)、维蚋属(Wilhelmia spp.)、瘤虻属(Hybomitra spp.)、黄虻属(Atylotus spp.)、虻属(Tabanus spp.)、麻虻属(Haematopota spp.)、Philipomyia spp.、蜂虱蝇属(Braula spp.)、家蝇属(Musca spp.)、齿股蝇属(Hydrotaea spp.)、螫蝇属(Stomoxys spp.)、黑角蝇属(Haematobia spp.)、莫蝇属(Morellia spp.)、厕蝇属(Fannia spp.)、舌蝇属(Glossina spp.)、丽蝇属(Calliphora spp.)、绿蝇属(Lucilia spp.)、金蝇属(Chrysomyia spp.)、污蝇属(Wohlfahrtia spp.)、麻蝇属(Sarcophaga spp.)、狂蝇属(Oestrus spp.)、皮蝇属(Hypoderma spp.)、胃蝇属(Gasterophilus spp.)、虱蝇属(Hippobosca spp.)、羊虱蝇属(Lipoptena spp.)、蜱蝇属(Melophagus spp.)、鼻狂蝇属(Rhinoestrus spp.)、大蚊属(Tipula spp.)；特别地，代表性实例有，埃及伊蚊(Aedes aegypti)、白纹伊蚊(Aedes albopictus)、带喙伊蚊(Aedes taeniorhynchus)、冈比亚按蚊(Anopheles gambiae)、五斑按蚊(Anopheles maculipennis)、红头丽蝇(Calliphora erythrocephala)、高额麻虻 (Chrysozona pluvialis)、五带淡色库蚊(Culex quinquefasciatus)、尖音库蚊(Culex pipiens)、环喙库蚊(Culex tarsalis)、夏厕蝇(Fannia canicularis)、肉蝇(Sarcophaga carnaria)、厩螯蝇(Stomoxys calcitrans)、欧洲大蚊(Tipula paludosa)、铜绿蝇(Lucilia cuprina)、丝光绿蝇(Lucilia sericata)、爬蚋(Simulium reptans)、静食白蛉(Phlebotomus papatasi)、长须白蛉(Phlebotomus longipalpis)、华丽短蚋(Odagmia ornata)、马维蚋(Wilhelmia equina)、红头厌蚋(Boophthora erythrocephala)、多声虻(Tabanus bromius)、夜蛾虻(Tabanus spodopterus)、北美黑虻(Tabanus atratus)、猪虻(Tabanus sudeticus)、古氏瘤虻(Hybomitra ciurea)、盲斑虻(Chrysops caecutiens)、黄缘斑虻(Chrysops relictus)、高额麻虻(Haematopota pluvialis)、Haematopotaitalica、秋家蝇(Musca autumnalis)、家蝇(Musca domestica)、西方角蝇(Haematobia irritans irritans)、西方角蝇(Haematobia irritans exigua)、刺扰血蝇(Haematobia stimulans)、Hydrotaea irritans、白斑齿股蝇(Hydrotaea albipuncta)、Chrysomya chloropyga、蛆症金蝇(Chrysomya bezziana)、羊狂蝇(Oestrus ovis)、牛皮蝇(Hypoderma bovis)、纹皮蝇(Hypoderma lineatum)、Przhevalskiana silenus、人肤蝇(Dermatobia hominis)、羊蜱蝇(Melophagus ovinus)、Lipoptena capreoli、鹿羊虱蝇(Lipoptena cervi)、Hippobosca variegata、马虱蝇(Hippobosca equina)、肠胃蝇(Gasterophilus intestinalis)、赤尾胃蝇(Gasterophilus haemorroidalis)、裸节胃蝇(Gasterophilus interrnis)、鼻胃蝇(Gasterophilus nasalis)、黑角胃蝇(Gasterophilus nigricornis)、黑腹胃蝇(Gasterophilus pecorum)、蜂虱蝇(Braula coeca)；Trichophagous order (Mallopha, Linognathus vituli), sheep jaw lice (Linognathus ovillus), Linognathus oviformis, foot jaw lice (Linognathus pedalis), goat jaw lice (Linognathus stenopsis), donkey blood lice (Haematopinus asini, macrocephalus) Bovine blood louse (Haematopinus eurysternus), pig blood louse (Haematopinus suis), head louse (Pediculus humanus capitis), body louse (Pediculus humanus corporis), grape phylloxera (Phylloera vastatrix), pubic louse (Phthirus pubis) gida) Amblycerina and Ischnocerin, for example, Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp.), Werneckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp. and Felicola spp.; in particular, representative examples include bovine lice (Bovicola bovis), wool louse (Bovicola ovis), Angola goat feather louse (Bovicola limbata), cattle louse (Damalina bovis), dog hair louse (Trichodectes canis), cat feather louse (Felicola subrostratus), goat louse (Bovicola caprae) , Lepikentron ovis, Werneckiella equi; Diptera and its Nematocerina and Brachycerina, for example, Aedes spp., Anopheles ( Anopheles spp., Culex spp., Simulium spp, Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culex Culicoides spp., Chrysops spp., Odag mia spp.), Wilhelmia (Wilhelmia spp.), Hybomitra spp., Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp. , Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Lucilia spp. Chrysomyia spp.), Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp., Lice Hippobosca spp., Lipoptena spp., Melophagus spp., Rhinoestrus spp., Tipula spp.; in particular, representative Sexual examples include Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Anopheles gambiae, Anopheles maculipennis, Red-headed blow fly (Calliphora erythrocephala), Chrysozona pluvialis, Culex quinquefasciatus, Culex pipiens, Culex tarsalis, Fannia canicularis, Sarcophaga carnaria, Stomoxys calcitrans, Tipula paludosa, Lucilia cuprina, Lucilia sericata, Simulium reptans, Silent sand flies ( Phlebotomus papatasi), long beard White sandfly (Phlebotomus longipalpis), ornate short gnat (Odagmia ornata), mawei gnat (Wilhelmia equina), red-headed gnat (Boophthora erythrocephala), polyphonic flies (Tabanus bromius), night moths (Tabanus bromius), spodopterus (Tabanus atratus), Tabanus sudeticus, Hybomitra ciurea, Chrysops caecutiens, Chrysops relictus, Haematopota, Haematopvii Musca autumnalis, Musca domestica, Haematobia irritans irritans, Haematobia irritans exigua, Haematobia stimulans, Hydrotaea irritans, Hydrotaea irritans, Hydrotaea irritans albipuncta), Chrysomya chloropyga, Chrysomya bezziana, Oestrus ovis, Hypoderma bovis, Hypoderma lineatum, Przhevalskiana silenus, Dermatobia hominis Tick fly (Melophagus ovinus), Lipoptena capreoli, Deer louse fly (Lipoptena cervi), Hippobosca variegata, Hippobosca equiina, Gastrophilus intestinalis, Gasterophilus haemorroidalis, Gastrophilus haemorroidalis Gasterophilus interrnis, Gasterophilus nasalis, Gasterophilus nigricornis, Gasterophilus pecorum, Braula coeca;
蚤目(Siphonapterida)，例如，蚤属(Pulex spp.)、栉首蚤属(Ctenocephalides spp.)、潜蚤属(Tunga spp.)、客蚤属(Xenopsylla spp.)、角叶蚤属(Ceratophyllus spp.)；特别地，代表性实例有，犬栉首蚤(Ctenocephalides canis)、猫栉首蚤(Ctenocephalides felis)、人蚤(Pulex irritans)、穿皮潜蚤(Tunga penetrans)、印鼠客蚤(Xenopsylla cheopis)；Siphonapterida, for example, Pulex spp., Ctenocephalides spp., Tunga spp., Xenopsylla spp., Ceratophyllus spp.); In particular, representative examples include Ctenocephalides canis, Ctenocephalides felis, Pulex irritans, Tunga penetrans, and Ctenocephalides canis (Xenopsylla cheopis);
异翅目(Heteropterida)，例如，臭虫属(Cimex spp.)、锥猎椿属(Triatoma spp.)、红猎蝽属(Rhodnius spp.)、锥蝽属(Panstrongylus spp.)；From the order of the Heteropterida, for example, Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.;
蜚蠊目(Blattarida)，例如，东方蜚蠊(Blatta orientalis)、美洲大蠊、德国蠊、夏柏拉蟑螂属(Supella spp.)(例如，Suppella longipalpa)；From the order of the Blatta (Blattarida), for example, Blatta orientalis, Periplaneta americana, German cockroach, Supella spp. (for example, Suppella longipalpa);
蜱螨目(Acari)(或Acarina)，后气门目(Metastigmata)和中气门目(Mesostigmata)，例如，锐缘蜱属(Argas spp.)、钝缘蜱属(Ornithodorus spp.)、残喙蜱属(Otobius spp.)、硬蜱属(Ixodes spp.)、花蜱属(Amblyomma spp.)、牛蜱属(Rhipicephalus(Boophilus)spp.)、革蜱属(Dermacentor spp.)、Haemophysalis spp.、璃眼蜱属(Hyalomma spp.)、皮刺螨属(Dermanyssus spp.)、扇头蜱属(Rhipicephalus spp.)(异主寄生型螨的原属)、禽刺螨属(Ornithonyssus spp.)、Acari (or Acarina), Metastigmata and Mesostigmata, for example, Argas spp., Ornithodorus spp., Remnant beak tick Otobius spp., Ixodes spp., Amblyomma spp., Rhipicephalus (Boophilus) spp., Dermacentor spp., Haemophysalis spp., Hyalomma (Hyalomma spp.), Dermanyssus spp., Rhipicephalus spp. (the original genus of heterotopic parasitic mites), Ornithonyssus spp.,
肺刺螨属(Pneumonyssus spp.)、Pneumonyssus spp.、刺利螨属(Raillietia spp.)、肺刺螨属(Pneumonyssus spp.)、胸刺螨属(Sternostoma spp.)、蜂螨属(Varroa spp.)、蜂盾螨属(Acarapis spp.)；特别地，代表性实例有，波斯锐缘蜱(Argas persicus)、鸽锐缘蜱(Argas reflexus)、非洲钝缘蜱(Ornithodorus moubata)、耳残喙蜱(Otobius megnini)、微小扇头蜱(微小牛蜱)(Rhipicephalus(Boophilus)microplus)、消色扇头蜱(消色牛蜱)(Rhipicephalus(Boophilus)decoloratus)、具环扇头蜱(具环牛蜱)(Rhipicephalus(Boophilus)annulatus)、有矩扇头蜱(有矩牛蜱)(Rhipicephalus(Boophilus)calceratus)、Hyalomma anatolicum、埃及璃眼蜱(Hyalommaaegypticum)、Hyalomma marginatum、Hyalomma transiens、外翻扇头蜱(Rhipicephalusevertsi)、蓖子硬蜱(Ixodes ricinus)、六角硬蜱(Ixodes hexagonus)、原野硬蜱(Ixodes canisuga)、多毛硬蜱(Ixodes pilosus)、浅红硬蜱(Ixodes rubicundus)、肩突硬蜱(Ixodes scapularis)、全环硬蜱(Ixodes holocyclus)、嗜群血蜱(Haemaphysalis concinna)、刻点血蜱(Haemaphysalis punctata)、Haemaphysalis cinnabarina、Haemaphysalis otophila、犬血蜱(Haemaphysalis leachi)、长角血蜱(Haemaphysalis longicorni)、边缘革蜱(Dermacentor marginatus)、网纹革蜱(Dermacentor reticulatus)、Dermacentor pictus、白纹革蜱(Dermacentor albipictus)、安氏革蜱(Dermacentor andersoni)、变异革蜱(Dermacentor variabilis)、毛里求斯璃眼蜱(Hyalomma mauritanicum)、血红扇头蜱(Rhipicephalus sanguineus)、囊形扇头蜱(Rhipicephalus bursa)、非洲扇头蜱(Rhipicephalus appendiculatus)、好望角扇头蜱(Rhipicephalus capensis)、图兰扇头蜱(Rhipicephalus turanicus)、Rhipicephalus zambeziensis、美洲花蜱(Amblyomma americanum)、彩饰花蜱(Amblyomma variegatum、有斑花蜱(Amblyomma maculatum)、希伯来花蜱(Amblyomma hebraeum)、卡延花蜱(Amblyomma cajennense)、鸡皮刺螨(Dermanyssus gallinae)、囊禽刺螨(Ornithonyssus bursa)、林禽刺螨(Ornithonyssus sylviarum)、大蜂螨(Varroa jacobsconi)；轴螨目(Actinedida)(前气门亚目(Prostigmata))和粉螨目(Acaridida)(无气门亚目(Astigmata))，例如，蜂盾螨属(Acarapis spp.)、姬螯螨属(Cheyletiella spp.)、禽螯螨属(Ornithocheyletia spp.)、肉螨属(Myobia spp.)、疮螨属(Psorergates spp.)、蠕形螨属(Demodex spp.)、恙螨属(Trombicula spp.)、Listrophorus spp.、粉螨属(Acarus spp.)、食酪螨属(Tyrophagus spp.)、嗜木螨属(Caloglyphus spp.)、颈下螨属(Hypodectes spp.)、翅螨属(Pterolichus spp.)、痒螨属(Psoroptes spp.)、皮螨属(Chorioptes spp.)、耳疥螨属(Otodectes spp.)、疥螨属(Sarcoptes spp.)、耳螨属(Notoedres spp.)、疙螨属(Knemidocoptes spp.)、气囊螨属(Cytodites spp.)和鸡雏螨属(Laminosioptes spp.)；特别是，雅氏姬螯螨(C heyletiella yasguri)、布氏姬螯螨(C heyletiella blakei)、犬蠕形螨(Demodex  canis)、牛蠕形螨(Demodex bovis)、绵羊蠕形螨(Demodex ovis)、山羊蠕形螨(Demodex caprae)、马蠕形螨(Demodex equi)、Demodex caballi、猪蠕形螨(Demodex suis)、Neotrombicula autumnalis、Neotrombiculadesaleli、Neoschonegastia xerothermobia、秋收恙螨(Trombicula akamushi)、狗耳螨(Otodectes cynotis)、猫痂螨(Notoedres cati)、狗疥螨(Sarcoptis canis)、牛疥螨(Sarcoptes bovis)、绵羊疥螨(Sarcoptes ovis)、山羊疥螨(Sarcoptes rupicaprae(＝S.caprae))、马疥螨(Sarcoptes equi)、猪疥螨(Sarcoptes suis)、绵羊瘙螨(Psoroptes ovis)、兔瘙螨(Psoroptes cuniculi)、马瘙螨(Psoroptes equi)、牛痒螨(Chorioptes bovis)、Psoergates ovis、Pneumonyssoidic mange、犬鼻疥蟲(Pneumonyssoides caninum)、伍氏蜂跗线螨(Acarapis woodi)；Pneumonyssus spp., Pneumonyssus spp., Railietia spp., Pneumonyssus spp., Sternostoma spp., Varroa spp. .), Acarapis spp.; in particular, representative examples include Argas persicus, Argas reflexus, Ornithodorus moubata, and ear damage Otobius megnini, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) decoloratus), Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) decoloratus Rhipicephalus (Boophilus) annulatus), Rhipicephalus (Boophilus) calceratus, Hyalomma anatolicum, Hyalomma aegypticum, Hyalomamarginatum, Hyalomma transiens, Eversion Rhipicephaluse vertsi, Ixodes ricinus, Ixodes hexagonus, Ixodes canisuga, Ixodes pilosus, Ixodes rubicundus, Ixodes rubicundus Ixodes scapularis, Ixodes holocyclus, Haemaphysalis concinna, Haemaphysalis punctata, Haemaphysalis cinnabarina, Haemaphysalis otophila, Haemaphysalis leachi, Haemaphysalis concinna Haemaphysalis longicorni, Dermacentor marginatus, Dermacentor reticulatus, Dermacentor pictus, Dermacentor albipictus, Dermacentor albipictus, Dermacentor marginatus orandersoni), Dermacentor variabilis, Hyalomma mauritanicum, Rhipicephalus sanguineus, Rhipicephalus bursa, Rhipicephalus appendiculatus, Cape of Good Hope Rhipicephalus capensis, Rhipicephalus turanicus, Rhipicephalus zambeziensis, American flower tick (Amblyomma americanum), colored flower tick (Amblyomma variegatum, Amblyomma maculatum), Hebrew flower tick (Amblyomma maculatum) (Amblyomma heebraeum), Amblyomma cajennense, Dermanyssus gallinae, Ornithonyssus bursa, Ornithonyssus sylviarum, Varroa jacobsconi Order (Actinedida) (Prostigmata) and Acaridida (Astigmata), for example, Acarapis spp., Cheyletiella spp. ), Ornithocheyletia spp., Myobia spp., Psorergates spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp. , Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Notoedres spp. (Knemidocoptes spp.), Cytodites spp. and Lamin osioptes spp.); especially, C heyletiella yasguri, C heyletiella blakei, Demodex canis, Demodex canis, Demodex bovis, Sheep Demodex ovis, Demodex caprae, Demodex equi, Demodex caballi, Demodex suis, Neotrombicula autumnalis, Neotrombicula desaleli, Neoschonegastia xerulae mobia akamushi), dog ear mites (Otodectes cynotis), cat scab mites (Notoedres cati), dog scabies mites (Sarcoptis canis), cattle scabies mites (Sarcoptes bovis), sheep scabies mites (Sarcoptes ovis), goat scabies mites (Sarcoptes rupicaprae( ＝S.caprae)), horse scabies (Sarcoptes equi), pig scabies (Sarcoptes suis), sheep mites (Psoroptes ovis), rabbit mites (Psoroptes cuniculi), horse pruritus (Psoroptes equi), bovine itchy mites (Chorioptes bovis), Psoergates ovis, Pneumonyssoidic mange, Pneumonyssoides caninum, Acarapis woodi;
线虫，例如南方根结线虫(Meloidogyne incognita)、松材线虫(Bursaphelenchus xylophilus)、水稻干尖线虫(Aphelenchoides besseyi)、大豆异皮线虫(Heterodera glycines)、短体线虫属(Pratylenchus spp.)等；Nematodes, such as Meloidogyne incognita, Bursaphelenchus xylophilus, Aphelenchoides besseyi, Heterodera glycines, Pratylenchus spp., etc.;
侵袭动物的节肢动物、蠕虫和疟原虫。防治节肢动物、蠕虫和/或疟原虫，可减少家养动物的死亡率，并且可改善动物的生产率(肉、奶、毛、皮、蛋和蜜)和健康。Arthropods, worms and malaria parasites that invade animals. Controlling arthropods, worms and/or malaria parasites can reduce the mortality of domestic animals and improve the productivity (meat, milk, hair, skin, eggs and honey) and health of animals.
在一种可能的实现方式中，所述动物寄生虫防治剂用于防治猫蚤、美洲犬蜱中的一种或几种。In a possible implementation manner, the animal parasite control agent is used to control one or more of cat fleas and American dog ticks.
在一种可能的实现方式中，动物包括以下的一种或多种：农业动物，例如牛、绵羊、山羊、马、猪、驴、骆驼、水牛、兔、家鸡、火鸡、鸭、鹅、养殖鱼、蜜蜂等；也包括被称为伴侣动物的宠物，例如，狗、猫、笼鸟、观赏鱼；还包括用于实验的动物，例如仓鼠、豚鼠、大鼠和小鼠等。In a possible implementation, the animals include one or more of the following: agricultural animals, such as cows, sheep, goats, horses, pigs, donkeys, camels, buffaloes, rabbits, chickens, turkeys, ducks, geese , Farmed fish, bees, etc.; also includes pets called companion animals, such as dogs, cats, caged birds, and ornamental fish; also includes animals used for experiments, such as hamsters, guinea pigs, rats, and mice.
本发明实施例还提供了一种动物寄生虫防治剂，该动物寄生虫防治剂中含有上述酰胺类化合物作为活性组分，还含有一种或多种辅料。The embodiment of the present invention also provides an animal parasite control agent, which contains the above-mentioned amide compound as an active component, and also contains one or more auxiliary materials.
在一种可能的实现方式中，动物寄生虫防治剂选自以下剂型：片剂、胶囊剂、饮剂、可饮用药、颗粒剂、膏剂和丸剂、栓剂、注射剂(肌肉、皮下、静脉内、腹膜内等)、涂抹剂、气雾剂、无压喷雾剂(例如泵喷雾剂和雾化喷雾剂)。In a possible implementation, the animal parasite control agent is selected from the following dosage forms: tablets, capsules, drinks, drinkable drugs, granules, ointments and pills, suppositories, injections (muscle, subcutaneous, intravenous, Intraperitoneal, etc.), smears, aerosols, non-pressure sprays (such as pump sprays and atomized sprays).
在一种可能的实现方式中，动物寄生虫防治剂中含有的上述活性组分的量为1至80重量％的量。In a possible implementation, the amount of the above-mentioned active component contained in the animal parasite control agent is 1 to 80% by weight.
本发明实施例还提供了一种动物寄生虫防治组合物，其包括上述酰胺类化合物和其他动物寄生虫防治活性化合物(例如杀螨剂、杀昆虫剂、杀寄生虫剂、抗疟原虫剂等)的混合物。该混合物可以以原料药的形式提供，也可以以市售有用制剂的形式或者由其制剂制得的使用形式提供。The embodiments of the present invention also provide an animal parasite control composition, which includes the above-mentioned amide compounds and other animal parasite control active compounds (such as acaricides, insecticides, parasiteicides, anti-plasmodium agents, etc.) )mixture. The mixture can be provided in the form of a bulk drug, or can be provided in the form of a commercially available useful preparation or a use form prepared from its preparation.
本发明实施例还提供了一种控制动物寄生虫的方法，其包括以下步骤：将有效剂量的材料施于需要控制的动物寄生虫或其生长介质上，所述材料选自下组中的一种或多种：上述酰胺类化合物；上述动物寄生虫防治剂；上述动物寄生虫防治组合物。例如：采用片剂、胶囊剂、饮剂、可饮用药、颗粒剂、膏剂、丸剂、栓剂进行肠内给药；基于皮肤施用的非肠内给药，例如注射(肌肉、皮下、静脉内、腹膜内等)、植入、鼻部给药，包括洗浴或浸泡、喷雾、泼浇、点滴、清洗和撒粉，和通过使用含有活性化合物的模型制品，例如项圈、耳标、标签、腿部缚带(leg brace)、网、标识器等施用。本发明的活性化合物具有低毒性，可以安全地用于温血动物。The embodiment of the present invention also provides a method for controlling animal parasites, which includes the following steps: applying an effective dose of material to the animal parasites or their growth medium to be controlled, and the material is selected from one of the following group: One or more: the above-mentioned amide compounds; the above-mentioned animal parasite control agent; the above-mentioned animal parasite control composition. For example: using tablets, capsules, drinks, drinkable drugs, granules, ointments, pills, suppositories for enteral administration; skin-based non-intestinal administration, such as injection (muscle, subcutaneous, intravenous, Intraperitoneal, etc.), implantation, nasal administration, including bathing or soaking, spraying, pouring, dripping, washing and dusting, and through the use of model products containing active compounds, such as collars, ear tags, labels, legs Use leg brace, net, marker, etc. The active compound of the present invention has low toxicity and can be safely used in warm-blooded animals.
有益效果Beneficial effect
本发明的酰胺类化合物具有意想不到的优异的杀虫效果，其也对有毒的害虫展现出合适的防治效果，且对栽培的作物植物没有植物毒性。此外，本发明的化合物可用于防治多种害虫，例如有害的刺吸式昆虫、咀嚼式昆虫以及其他植物寄生害虫、储存谷物害虫、卫生害虫等，并且可用于消毒和杀灭它们。The amide compound of the present invention has an unexpectedly excellent insecticidal effect, it also exhibits a suitable control effect against toxic pests, and has no phytotoxicity to cultivated crop plants. In addition, the compounds of the present invention can be used to control various pests, such as harmful sucking insects, chewing insects, and other plant parasitic pests, stored grain pests, sanitary pests, etc., and can be used to disinfect and kill them.
具体实施方式Detailed ways
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。。In order to make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, but not all of them.的实施例。 Example. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention. .
另外，为了更好的说明本发明，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本发明同样可以实施。在一些实施例中，对于本领域技术人员熟知的原料、元件、方法、手段等未作详细描述，以便于凸显本发明的主旨。In addition, in order to better illustrate the present invention, numerous specific details are given in the following specific embodiments. Those skilled in the art should understand that the present invention can also be implemented without certain specific details. In some embodiments, raw materials, elements, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.
除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分除另有注明外，所用原料均有市售。Unless otherwise expressly stated otherwise, throughout the specification and claims, the term "comprising" or its transformations such as "including" or "including" will be understood to include the stated elements or components, and not It is not excluded that other components or other components are commercially available unless otherwise noted.
本发明中，所用术语具有如下含义：In the present invention, the terms used have the following meanings:
卤素：指氟、氯、溴或碘。Halogen: refers to fluorine, chlorine, bromine or iodine.
卤代烷基：直链或支链烷基，在这些烷基上的氢原子可以部分或全部被卤素所取代，例如二氟甲基(CHF 2)、三氟甲基(CF 3)等。 Halogenated alkyl groups: straight or branched chain alkyl groups. The hydrogen atoms on these alkyl groups can be partially or completely replaced by halogens, such as difluoromethyl (CHF 2 ), trifluoromethyl (CF 3 ), and the like.
卤代烷氧基：烷氧基上的氢原子可部分或全部被卤素所取代，例如二氟甲氧基(OCHF 2)、三氟甲氧基(OCF 3)等。 Halogenated alkoxy group: The hydrogen atoms on the alkoxy group can be partially or completely replaced by halogen, such as difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ), and the like.
氰基烷基：直链或支链烷基，在这些烷基上的氢原子可部分或全部被氰基所取代，氰基C 1-C 4烷基中C 1-C 4表示烷基的链长，例如CH 2CN、CH 2CH 2CN、CH 2CH 2CH 2CN、CH 2CH 2CH 2CH 2CN、CH(CH 3)CN、CH(CH 2CH 3)CN、CH(CH 2CH 2CH 3)CN、C(CH 3)(CH 3)CN或C(CH 3)(CH 2CH 3)CN。 Cyanoalkyl: straight or branched chain alkyl groups, the hydrogen atoms on these alkyl groups may be partially or completely replaced by cyano groups, and C 1 -C 4 in the cyano C 1 -C 4 alkyl group represents an alkyl group Chain length, such as CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 CH 2 CN, CH 2 CH 2 CH 2 CH 2 CN, CH(CH 3 )CN, CH(CH 2 CH 3 )CN, CH( CH 2 CH 2 CH 3 )CN, C(CH 3 )(CH 3 )CN or C(CH 3 )(CH 2 CH 3 )CN.
杀虫剂：对害虫具有杀虫效果的物质。Insecticides: substances that have insecticidal effects on pests.
动物寄生虫防治剂：是指能有效地将被寄生虫感染的动物中的各种寄生虫的发病率减少的活性化合物。防治意味着活性化合物能有效地杀灭寄生虫、抑制其生长或繁殖。Animal parasite control agents: refers to active compounds that can effectively reduce the incidence of various parasites in animals infected by parasites. Control means that the active compound can effectively kill parasites, inhibit their growth or reproduction.
合成实施例Synthesis Example
按照上述记载的合成路线，采用不同的原料化合物，即可制备获得本发明通式I所示化合物，进一步具体描述如下：According to the synthetic route described above, using different raw material compounds, the compound represented by the general formula I of the present invention can be prepared, which is further described in detail as follows:
实施例1：中间体II.1的制备Example 1: Preparation of Intermediate II.1
Figure PCTCN2020126091-appb-000004
Figure PCTCN2020126091-appb-000004
向30毫升DMF中加入1.00克(1.80毫摩尔)N-(2,6-二溴-4-七氟异丙基苯基)-2-氟-3-氨基苯甲酰胺(中间体III-1，参照WO2011093415或WO2010018714报道的方法制得)、0.37克(2.68毫摩尔)碳酸钾、0.27克(1.80毫摩尔)碘化钠及0.26克(2.19毫摩尔)溴乙腈，升温至100度反应。TLC监测反应完毕后，加入水和乙酸乙酯萃取，有机相减压脱溶，残余物柱层析纯化，得白色固体0.50克，即中间体II.1。中间体II.1的核磁及质谱数据如下：To 30 ml DMF was added 1.00 g (1.80 mmol) N-(2,6-dibromo-4-heptafluoroisopropylphenyl)-2-fluoro-3-aminobenzamide (Intermediate III-1 , Prepared by referring to the method reported in WO2011093415 or WO2010018714), 0.37 g (2.68 mmol) of potassium carbonate, 0.27 g (1.80 mmol) of sodium iodide and 0.26 g (2.19 mmol) of bromoacetonitrile, heated to 100 degrees for reaction. After the reaction was monitored by TLC, water and ethyl acetate were added for extraction, the organic phase was desolvated under reduced pressure, and the residue was purified by column chromatography to obtain 0.50 g of a white solid, that is, Intermediate II.1. The NMR and MS data of Intermediate II.1 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.11(d,1H),7.88(s,2H),7.64–7.58(m,1H),7.29(t,1H),7.05(td,1H),4.52-4.44(br,1H),4.24(d,2H).LC-MS(m/z,ESI):594.01(M+H) +. 1 H NMR(600MHz,Chloroform-d)δ8.11(d,1H),7.88(s,2H),7.64-7.58(m,1H),7.29(t,1H),7.05(td,1H),4.52 -4.44(br,1H),4.24(d,2H).LC-MS(m/z,ESI):594.01(M+H) + .
实施例2：中间体II.2的制备Example 2: Preparation of Intermediate II.2.
Figure PCTCN2020126091-appb-000005
Figure PCTCN2020126091-appb-000005
加入10克N-(2-溴-6-碘-4-七氟异丙基苯基)-2-氟-3-硝基苯甲酰胺(参照CN109206335A报道的方法制得)、15克无水氯化亚锡、200毫升1,4-二氧六环及8毫升浓盐酸，升温至60度搅拌反应。TLC监测反应结束后，减压蒸馏除去有机溶剂。加入500毫升乙酸乙酯，并加入适量饱和氢氧化钠水溶液调节pH＝10，充分搅拌后使用硅藻土滤除析出的不溶物，滤液用乙酸乙酯和水萃取后，有机层用无水硫酸镁干燥、过滤并减压浓缩，得到灰褐色固体，粗产物柱 层析纯化，得到7.91克N-(2-溴-6-碘-4-七氟异丙基苯基)-2-氟-3-氨基苯甲酰胺(中间体III-2)。Add 10 grams of N-(2-bromo-6-iodo-4-heptafluoroisopropylphenyl)-2-fluoro-3-nitrobenzamide (prepared with reference to the method reported in CN109206335A), 15 grams of anhydrous Stannous chloride, 200 ml of 1,4-dioxane and 8 ml of concentrated hydrochloric acid, heated to 60 degrees and stirred for reaction. After the reaction was monitored by TLC, the organic solvent was distilled off under reduced pressure. Add 500 ml of ethyl acetate, and add an appropriate amount of saturated sodium hydroxide aqueous solution to adjust the pH=10. After thorough stirring, use Celite to filter out the precipitated insoluble matter. After the filtrate is extracted with ethyl acetate and water, the organic layer is washed with anhydrous sulfuric acid It was dried over magnesium, filtered and concentrated under reduced pressure to obtain a beige solid. The crude product was purified by column chromatography to obtain 7.91 g of N-(2-bromo-6-iodo-4-heptafluoroisopropylphenyl)-2-fluoro- 3-Aminobenzamide (Intermediate III-2).
向30毫升DMF中加入1.00克(1.66毫摩尔)N-(2-溴-6-碘-4-七氟异丙基苯基)-2-氟-3-氨基苯甲酰胺(中间体III-2)、0.34克(2.46毫摩尔)碳酸钾、0.25克(1.67毫摩尔)碘化钠及0.24克(2.00毫摩尔)溴乙腈，升温至100度反应。TLC监测反应完毕后，加入水和乙酸乙酯萃取，有机相减压脱溶，残余物柱层析纯化，得白色固体0.43克，即中间体II.2。中间体II.2的核磁及质谱数据如下：To 30 ml DMF was added 1.00 g (1.66 mmol) N-(2-bromo-6-iodo-4-heptafluoroisopropylphenyl)-2-fluoro-3-aminobenzamide (Intermediate III- 2) 0.34 g (2.46 mmol) of potassium carbonate, 0.25 g (1.67 mmol) of sodium iodide and 0.24 g (2.00 mmol) of bromoacetonitrile, heat to 100 degrees for reaction. After the reaction was monitored by TLC, water and ethyl acetate were added for extraction, the organic phase was desolvated under reduced pressure, and the residue was purified by column chromatography to obtain 0.43 g of a white solid, that is, Intermediate II.2. The NMR and MS data of Intermediate II.2 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.12(d,1H),8.08(d,1H),7.90(d,1H),7.61(t,1H),7.29(t,1H),7.05(td,1H),4.54-4.47(br,1H),4.24(d,2H).LC-MS(m/z,ESI):642.05(M+H) +. 1 H NMR (600MHz, Chloroform-d) δ 8.12 (d, 1H), 8.08 (d, 1H), 7.90 (d, 1H), 7.61 (t, 1H), 7.29 (t, 1H), 7.05 (td ,1H),4.54-4.47(br,1H),4.24(d,2H).LC-MS(m/z,ESI): 642.05(M+H) + .
实施例3：中间体II.3的制备Example 3: Preparation of Intermediate II.3
Figure PCTCN2020126091-appb-000006
Figure PCTCN2020126091-appb-000006
向60毫升DMF中加入2.00克(3.67毫摩尔)N-(2-溴-6-三氟甲基-4-七氟异丙基苯基)-2-氟-3-氨基苯甲酰胺(中间体III-3，参照WO2011093415或WO2010018714报道的方法制得)、0.76克(5.50毫摩尔)碳酸钾、0.56克(3.74毫摩尔)碘化钠及0.53克(4.42毫摩尔)溴乙腈，升温至100度反应。TLC监测反应完毕后，加入水和乙酸乙酯萃取，有机相减压脱溶，残余物柱层析纯化，得白色固体0.78克，即中间体II.3。中间体II.3的核磁及质谱数据如下：Add 2.00 g (3.67 mmol) N-(2-bromo-6-trifluoromethyl-4-heptafluoroisopropylphenyl)-2-fluoro-3-aminobenzamide (middle Body III-3, prepared by referring to the method reported in WO2011093415 or WO2010018714), 0.76 g (5.50 mmol) of potassium carbonate, 0.56 g (3.74 mmol) of sodium iodide and 0.53 g (4.42 mmol) of bromoacetonitrile, heating to 100 Degree reaction. After the reaction was monitored by TLC, water and ethyl acetate were added for extraction, the organic phase was de-solventized under reduced pressure, and the residue was purified by column chromatography to obtain 0.78 g of a white solid, that is, Intermediate II.3. The NMR and MS data of Intermediate II.3 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.18(d,1H),8.16–8.13(m,1H),7.94–7.90(m,1H),7.63–7.55(m,1H),7.29(t,1H),7.05(td,1H),4.52–4.45(m,1H),4.24(d,2H).LC-MS(m/z,ESI):584.04(M+H) +. 1 H NMR (600MHz, Chloroform-d) δ 8.18 (d, 1H), 8.16-8.13 (m, 1H), 7.94-7.90 (m, 1H), 7.63-7.55 (m, 1H), 7.29 (t, 1H),7.05(td,1H),4.52-4.45(m,1H),4.24(d,2H).LC-MS(m/z,ESI):584.04(M+H) + .
实施例4：中间体II.4的制备Example 4: Preparation of Intermediate II.4
Figure PCTCN2020126091-appb-000007
Figure PCTCN2020126091-appb-000007
向60毫升DMF中加入2.00克(3.67毫摩尔)N-(2-溴-6-三氟甲基-4-七氟异丙基苯基)-2-氟-3-氨基苯甲酰胺(中间体III-3)、0.76克(5.50毫摩尔)碳酸钾、0.55克(3.67毫摩尔)碘化钠及0.59克(4.40毫摩尔)溴丙腈，升温至100度反应。TLC监测反应完毕后，加入水和乙酸乙酯萃取，有机相减压脱溶，残余物柱层析纯化，得白色固体0.22克，即中间体II.4。中间体II.4的核磁及质谱数据如下：Add 2.00 g (3.67 mmol) N-(2-bromo-6-trifluoromethyl-4-heptafluoroisopropylphenyl)-2-fluoro-3-aminobenzamide (middle Body III-3), 0.76 g (5.50 mmol) of potassium carbonate, 0.55 g (3.67 mmol) of sodium iodide and 0.59 g (4.40 mmol) of bromopropionitrile, the temperature was raised to 100 degrees for reaction. After the reaction was monitored by TLC, water and ethyl acetate were added for extraction, the organic phase was de-solventized under reduced pressure, and the residue was purified by column chromatography to obtain 0.22 g of white solid, that is, Intermediate II.4. The NMR and MS data of Intermediate II.4 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.22(d,1H),8.16–8.13(m,1H),7.93–7.90(m,1H),7.50–7.45(m,1H),7.20(t,1H),6.91(td,1H),4.46–4.38(m,1H),3.63(q,2H),2.72(t,2H).LC-MS(m/z,ESI):598.05(M+H) +. 1 H NMR(600MHz, Chloroform-d)δ8.22(d,1H), 8.16-8.13(m,1H), 7.93-7.90(m,1H), 7.50-7.45(m,1H), 7.20(t, 1H),6.91(td,1H),4.46--4.38(m,1H),3.63(q,2H),2.72(t,2H).LC-MS(m/z,ESI):598.05(M+H) + .
实施例5：中间体II.5的制备Example 5: Preparation of Intermediate II.5
Figure PCTCN2020126091-appb-000008
Figure PCTCN2020126091-appb-000008
向40毫升DMF中加入1.30克(2.39毫摩尔)N-(2-溴-6-三氟甲基-4-七氟异丙基苯基)-2-氟-3-氨基苯甲酰胺(中间体III-3)、0.49克(3.55毫摩尔)碳酸钾、0.36克(2.40毫摩尔)碘化钠及0.46克(3.13毫摩尔)溴丁腈，升温至100度反应。TLC监测反应完毕后，加入水和乙酸乙酯萃取，有机相减压脱溶，残余物柱层析纯化，得白色固体0.19克，即中间体II.5。中间体II.5的核磁及质谱数据如下：Add 1.30 g (2.39 mmol) N-(2-bromo-6-trifluoromethyl-4-heptafluoroisopropylphenyl)-2-fluoro-3-aminobenzamide (middle Body III-3), 0.49 g (3.55 mmol) of potassium carbonate, 0.36 g (2.40 mmol) of sodium iodide and 0.46 g (3.13 mmol) of bromobutyronitrile, heated to 100 degrees for reaction. After the reaction was monitored by TLC, water and ethyl acetate were added for extraction, the organic phase was desolvated under reduced pressure, and the residue was purified by column chromatography to obtain 0.19 g of a white solid, that is, intermediate II.5. The NMR and MS data of Intermediate II.5 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.22(d,1H),8.15–8.13(m,1H),7.92–7.90(m,1H),7.46–7.40(m,1H),7.18(t,1H),6.94(td,1H),4.17–4.09(m,1H),3.43(q,2H),2.54(t,2H),2.08–2.02(m,2H).LC-MS(m/z,ESI):612.06(M+H) +. 1 H NMR(600MHz, Chloroform-d)δ8.22(d,1H), 8.15-8.13(m,1H), 7.92-7.90(m,1H), 7.46-7.40(m,1H), 7.18(t, 1H), 6.94 (td, 1H), 4.17-4.09 (m, 1H), 3.43 (q, 2H), 2.54 (t, 2H), 2.08-2.02 (m, 2H).LC-MS(m/z, ESI):612.06(M+H) + .
实施例6：中间体II.6的制备Example 6: Preparation of Intermediate II.6
Figure PCTCN2020126091-appb-000009
Figure PCTCN2020126091-appb-000009
向50毫升DMF中加入1.65克(3.03毫摩尔)N-(2-溴-6-三氟甲基-4-七氟异丙基苯基)-2-氟-3-氨基苯甲酰胺(中间体III-3)、0.62克(4.50毫摩尔)碳酸钾、0.46克(3.07毫摩尔)碘化钠及0.61克(3.79毫摩尔)溴戊腈，升温至100度反应。TLC监测反应完毕后，加入水和乙酸乙酯萃取，有机相减压脱溶，残余物柱层析纯化，得白色固体0.21克，即中间体II.6。中间体II.6的核磁及质谱数据如下：Add 1.65 g (3.03 mmol) N-(2-bromo-6-trifluoromethyl-4-heptafluoroisopropylphenyl)-2-fluoro-3-aminobenzamide (middle Body III-3), 0.62 g (4.50 mmol) of potassium carbonate, 0.46 g (3.07 mmol) of sodium iodide and 0.61 g (3.79 mmol) of bromvaleronitrile, the temperature was raised to 100 degrees for reaction. After the reaction was monitored by TLC, water and ethyl acetate were added for extraction, the organic phase was desolventized under reduced pressure, and the residue was purified by column chromatography to obtain 0.21 g of white solid, which is intermediate II.6. The NMR and MS data of Intermediate II.6 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.23(d,1H),8.14(d,1H),7.91(d,1H),7.42–7.37(m,1H),7.17(t,1H),6.91(td,1H),4.13–3.98(m,1H),3.28(t,2H),2.45(t,2H),1.93–1.80(m,4H).LC-MS(m/z,ESI):626.05(M+H) +. 1 H NMR (600MHz, Chloroform-d) δ 8.23 (d, 1H), 8.14 (d, 1H), 7.91 (d, 1H), 7.42-7.37 (m, 1H), 7.17 (t, 1H), 6.91 (td,1H),4.13-3.98(m,1H),3.28(t,2H),2.45(t,2H),1.93-1.80(m,4H).LC-MS(m/z,ESI):626.05 (M+H) + .
实施例7：中间体II.7的制备Example 7: Preparation of Intermediate II.7
Figure PCTCN2020126091-appb-000010
Figure PCTCN2020126091-appb-000010
按照实施例3所描述的方法，由中间体III-4(参照WO2011093415或WO2010018714报道的方法制得)和溴乙腈反应制备得到中间体II.7(白色固体)。中间体II.7的核磁及质谱数据如下：According to the method described in Example 3, intermediate III-4 (prepared with reference to the method reported in WO2011093415 or WO2010018714) was reacted with bromoacetonitrile to prepare intermediate II.7 (white solid). The NMR and MS data of Intermediate II.7 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.37–8.34(m,1H),8.22(d,1H),7.96–7.93(m,1H),7.64–7.57(m,1H),7.29(t,1H),7.05(td,1H),4.52–4.45(m,1H),4.25(d,2H).LC-MS(m/z,ESI):631.99(M+H) +. 1 H NMR(600MHz, Chloroform-d) δ8.37–8.34(m,1H), 8.22(d,1H), 7.96–7.93(m,1H), 7.64–7.57(m,1H), 7.29(t, 1H),7.05(td,1H),4.52-4.45(m,1H),4.25(d,2H).LC-MS(m/z,ESI):631.99(M+H) + .
实施例8：中间体II.8的制备Example 8: Preparation of Intermediate II.8
Figure PCTCN2020126091-appb-000011
Figure PCTCN2020126091-appb-000011
按照实施例4所描述的方法，由中间体III-4和溴丙腈反应制备得到中间体II.8(白色固体)。中间体II.8的核磁及质谱数据如下：According to the method described in Example 4, Intermediate II.8 (white solid) was prepared by reacting Intermediate III-4 with bromopropionitrile. The NMR and MS data of Intermediate II.8 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.36(d,1H),8.26(d,1H),7.94(d,1H),7.51–7.46(m,1H),7.21(t,1H),6.92(td,1H),4.47–4.39(m,1H),3.64(q,2H),2.72(t,2H).LC-MS(m/z,ESI):646.02(M+H) +. 1 H NMR (600MHz, Chloroform-d) δ 8.36 (d, 1H), 8.26 (d, 1H), 7.94 (d, 1H), 7.51-7.46 (m, 1H), 7.21 (t, 1H), 6.92 (td,1H),4.47--4.39(m,1H),3.64(q,2H),2.72(t,2H).LC-MS(m/z,ESI): 646.02(M+H) + .
实施例9：中间体II.9的制备Example 9: Preparation of Intermediate II.9
Figure PCTCN2020126091-appb-000012
Figure PCTCN2020126091-appb-000012
按照实施例5所描述的方法，由中间体III-4和溴丁腈反应制备得到中间体II.9(白色固体)。中间体II.9的核磁及质谱数据如下：According to the method described in Example 5, Intermediate II.9 (white solid) was prepared by reacting Intermediate III-4 with bromobutyronitrile. The NMR and MS data of Intermediate II.9 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.36–8.34(m,1H),8.27(d,1H),7.95–7.92(m,1H),7.45–7.40(m,1H),7.18(td,1H),6.94(td,1H),4.18–4.11(br s,1H),3.43(q,2H),2.54(t,2H),2.08–2.02(m,2H).LC-MS(m/z,ESI):682.24(M+Na+H) +. 1 H NMR (600MHz, Chloroform-d) δ 8.36--8.34 (m, 1H), 8.27 (d, 1H), 7.95-7.92 (m, 1H), 7.45-7.40 (m, 1H), 7.18 (td, 1H), 6.94(td,1H), 4.18–4.11(br s,1H), 3.43(q,2H), 2.54(t,2H), 2.08–2.02(m,2H).LC-MS(m/z ,ESI):682.24(M+Na+H) + .
实施例10：中间体II.10的制备Example 10: Preparation of Intermediate II.10
Figure PCTCN2020126091-appb-000013
Figure PCTCN2020126091-appb-000013
按照实施例6所描述的方法，由中间体III-4和溴戊腈反应制备得到中间体II.10(白色固体)。中间体II.10的核磁及质谱数据如下：According to the method described in Example 6, Intermediate II.10 (white solid) was prepared by reacting Intermediate III-4 with bromovaleronitrile. The NMR and MS data of Intermediate II.10 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.35(d,1H),8.28(d,1H),7.93(d,1H),7.43–7.38(m,1H),7.17(t,1H),6.91(td,1H),4.22–3.90(br s,1H),3.28(t,2H),2.45(t,2H),1.92–1.81(m,4H).LC-MS(m/z,ESI):696.26(M+Na+H) +. 1 H NMR (600MHz, Chloroform-d) δ 8.35 (d, 1H), 8.28 (d, 1H), 7.93 (d, 1H), 7.43-7.38 (m, 1H), 7.17 (t, 1H), 6.91 (td,1H),4.22-3.90(br s,1H),3.28(t,2H),2.45(t,2H),1.92-1.81(m,4H).LC-MS(m/z,ESI): 696.26(M+Na+H) + .
实施例15：化合物1的制备Example 15: Preparation of Compound 1
Figure PCTCN2020126091-appb-000014
Figure PCTCN2020126091-appb-000014
向20毫升甲苯中加入0.30克(0.51毫摩尔)中间体II.1及0.12克(0.72毫摩尔)6-氰基烟酰基氯化物，加热回流。TLC监测反应完毕后，减压脱溶，残余物柱层析纯化，得白色固体0.23克，即化合物1。化合物1的核磁及质谱数据如下：0.30 g (0.51 mmol) of Intermediate II.1 and 0.12 g (0.72 mmol) of 6-cyanonicotinoyl chloride were added to 20 ml of toluene and heated to reflux. After the reaction was monitored by TLC, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain 0.23 g of a white solid, namely compound 1. The NMR and MS data of compound 1 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.71–8.66(m,1H),8.19(t,1H),7.93–7.86(m,4H),7.64(d,1H),7.58–7.54(m,1H),7.42(t,1H),5.00(d,1H),4.65(d,1H).LC-MS(m/z,ESI):724.15(M+H) +. 1 H NMR(600MHz, Chloroform-d) δ8.71–8.66(m,1H), 8.19(t,1H), 7.93–7.86(m,4H), 7.64(d,1H), 7.58–7.54(m, 1H),7.42(t,1H),5.00(d,1H),4.65(d,1H).LC-MS(m/z,ESI): 724.15(M+H) + .
实施例16：化合物5的制备Example 16: Preparation of Compound 5
Figure PCTCN2020126091-appb-000015
Figure PCTCN2020126091-appb-000015
按照实施例15所描述的方法，由中间体II.2和6-氰基烟酰基氯化物反应制备得到化合物5(白色固体)。化合物5的核磁及质谱数据如下：According to the method described in Example 15, compound 5 (white solid) was prepared by reacting intermediate II.2 with 6-cyanonicotinoyl chloride. The NMR and MS data of compound 5 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.71–8.66(m,1H),8.20(t,1H),8.08(d,1H),7.93–7.85(m,3H),7.63(d,1H),7.58(t,1H),7.43(t,1H),4.99(d,1H),4.66(d,1H).LC-MS(m/z,ESI):772.20(M+H) +. 1 H NMR (600MHz, Chloroform-d) δ 8.71--8.66 (m, 1H), 8.20 (t, 1H), 8.08 (d, 1H), 7.93 - 7.85 (m, 3H), 7.63 (d, 1H) ,7.58(t,1H),7.43(t,1H),4.99(d,1H),4.66(d,1H).LC-MS(m/z,ESI):772.20(M+H) + .
实施例17：化合物9的制备Example 17: Preparation of Compound 9
Figure PCTCN2020126091-appb-000016
Figure PCTCN2020126091-appb-000016
按照实施例15所描述的方法，由中间体II.3和6-氰基烟酰基氯化物反应制备得到化合物9(黄色固体)。化合物9的核磁及质谱数据如下：According to the method described in Example 15, compound 9 (yellow solid) was prepared by reacting intermediate II.3 with 6-cyanonicotinoyl chloride. The NMR and MS data of compound 9 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.72–8.57(m,1H),8.23–8.09(m,2H),8.01(d,1H),7.96–7.83(m,2H),7.64(d,1H),7.61–7.55(m,1H),7.43(t,1H),4.98(d,1H),4.66(d,1H).LC-MS(m/z,ESI):736.29(M+Na+H) +. 1 H NMR(600MHz, Chloroform-d) δ8.72–8.57(m,1H), 8.23–8.09(m,2H), 8.01(d,1H), 7.96–7.83(m,2H), 7.64(d, 1H), 7.61--7.55(m,1H),7.43(t,1H),4.98(d,1H),4.66(d,1H).LC-MS(m/z,ESI):736.29(M+Na+ H) + .
实施例18：化合物10的制备Example 18: Preparation of Compound 10
Figure PCTCN2020126091-appb-000017
Figure PCTCN2020126091-appb-000017
按照实施例15所描述的方法，由中间体II.4和6-氰基烟酰基氯化物反应制备得到化合物10(黄色固体)。化合物10的核磁及质谱数据如下：According to the method described in Example 15, compound 10 (yellow solid) was prepared by reacting intermediate II.4 and 6-cyanonicotinoyl chloride. The NMR and MS data of compound 10 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.64(s,1H),8.13(d,1H),8.05(t,1H),7.96(d,1H),7.91–7.89(m,1H),7.85(dd,1H),7.68(td,1H),7.61(d,1H),7.42(t,1H),4.19(t,2H),3.06–2.96(m,1H),2.95–2.84(m,1H).LC-MS(m/z,ESI):750.32(M+Na+H) +. 1 H NMR(600MHz, Chloroform-d)δ8.64(s,1H), 8.13(d,1H), 8.05(t,1H), 7.96(d,1H), 7.91-7.89(m,1H), 7.85 (dd,1H),7.68(td,1H),7.61(d,1H),7.42(t,1H),4.19(t,2H),3.06-2.96(m,1H),2.95-2.84(m,1H ).LC-MS(m/z,ESI):750.32(M+Na+H) + .
实施例19：化合物11的制备Example 19: Preparation of Compound 11
Figure PCTCN2020126091-appb-000018
Figure PCTCN2020126091-appb-000018
按照实施例15所描述的方法，由中间体II.5和6-氰基烟酰基氯化物反应制备得到化合物11(黄色油状物)。化合物11的核磁及质谱数据如下：According to the method described in Example 15, compound 11 (yellow oil) was prepared by reacting intermediate II.5 with 6-cyanonicotinoyl chloride. The NMR and MS data of compound 11 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.60(s,1H),8.14(d,1H),8.10–8.04(m,1H),7.97(d,1H),7.91(d,1H),7.83(dd,1H),7.62–7.53(m,2H),7.38(t,1H),4.16–4.04(m,2H),2.56(t,2H),2.18–2.02(m,2H).LC-MS(m/z,ESI):764.34(M+Na+H) +. 1 H NMR(600MHz, Chloroform-d)δ8.60(s,1H), 8.14(d,1H), 8.10-8.04(m,1H), 7.97(d,1H), 7.91(d,1H), 7.83 (dd,1H),7.62-7.53(m,2H),7.38(t,1H),4.16-4.04(m,2H),2.56(t,2H),2.18-2.02(m,2H).LC-MS (m/z,ESI):764.34(M+Na+H) + .
实施例20：化合物12的制备Example 20: Preparation of Compound 12
Figure PCTCN2020126091-appb-000019
Figure PCTCN2020126091-appb-000019
按照实施例15所描述的方法，由中间体II.6和6-氰基烟酰基氯化物反应制备得到化合物12(黄色油状物)。化合物12的核磁及质谱数据如下：According to the method described in Example 15, compound 12 (yellow oil) was prepared by reacting intermediate II.6 with 6-cyanonicotinoyl chloride. The NMR and MS data of compound 12 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.60(s,1H),8.20–8.11(m,2H),8.02(t,1H),7.90(d,1H),7.83–7.76(m,1H),7.58(d,1H),7.55–7.49(m,1H),7.39(t,1H),4.25(br s,1H),3.90–3.79(m,1H),2.57–2.36(m,2H),1.93–1.77(m,4H).LC-MS(m/z,ESI):778.37(M+Na+H) +. 1 H NMR(600MHz, Chloroform-d)δ8.60(s,1H), 8.20-8.11(m,2H), 8.02(t,1H), 7.90(d,1H), 7.83-7.76(m,1H) ,7.58(d,1H),7.55–7.49(m,1H),7.39(t,1H), 4.25(br s,1H), 3.90–3.79(m,1H), 2.57–2.36(m,2H), 1.93–1.77(m,4H).LC-MS(m/z,ESI):778.37(M+Na+H) + .
实施例21：化合物13的制备Example 21: Preparation of Compound 13
Figure PCTCN2020126091-appb-000020
Figure PCTCN2020126091-appb-000020
按照实施例15所描述的方法，由中间体II.7和6-氰基烟酰基氯化物反应制备得到化合物13(黄色固体)。化合物13的核磁及质谱数据如下：According to the method described in Example 15, compound 13 (yellow solid) was prepared by reacting Intermediate II.7 with 6-cyanonicotinoyl chloride. The NMR and MS data of compound 13 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.65(d,1H),8.35(d,1H),8.18–8.12(m,1H),8.07(d,1H),7.94(d,1H),7.89(dd,1H),7.64(d,1H),7.62–7.56(m,1H),7.43(t,1H),4.97(br s,1H),4.67(br s,1H).LC-MS(m/z,ESI):784.32(M+Na+H) +. 1 H NMR(600MHz, Chloroform-d) δ8.65(d,1H), 8.35(d,1H), 8.18-8.12(m,1H), 8.07(d,1H), 7.94(d,1H), 7.89 (dd,1H),7.64(d,1H),7.62--7.56(m,1H),7.43(t,1H),4.97(br s,1H),4.67(br s,1H).LC-MS(m /z,ESI):784.32(M+Na+H) + .
实施例22：化合物14的制备Example 22: Preparation of Compound 14
Figure PCTCN2020126091-appb-000021
Figure PCTCN2020126091-appb-000021
按照实施例15所描述的方法，由中间体II.8和6-氰基烟酰基氯化物反应制备得到化合物14(黄色固体)。化合物14的核磁及质谱数据如下：According to the method described in Example 15, compound 14 (yellow solid) was prepared by reacting intermediate II.8 with 6-cyanonicotinoyl chloride. The NMR and MS data of compound 14 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.65(s,1H),8.33(d,1H),8.09–7.97(m,2H),7.93(d,1H),7.84(dd,1H),7.69(td,1H),7.60(d,1H),7.43(t,1H),4.19(s,2H),3.08–2.97(m,1H),2.95–2.84(m,1H).LC-MS(m/z,ESI):798.34(M+Na+H) +. 1 H NMR(600MHz, Chloroform-d)δ8.65(s,1H), 8.33(d,1H), 8.09-7.97(m,2H), 7.93(d,1H), 7.84(dd,1H), 7.69 (td,1H),7.60(d,1H),7.43(t,1H),4.19(s,2H),3.08-2.97(m,1H),2.95-2.84(m,1H).LC-MS(m /z,ESI):798.34(M+Na+H) + .
实施例23：化合物15的制备Example 23: Preparation of Compound 15
Figure PCTCN2020126091-appb-000022
Figure PCTCN2020126091-appb-000022
按照实施例15所描述的方法，由中间体II.9和6-氰基烟酰基氯化物反应制备得到化合物15(黄色固体)。化合物15的核磁及质谱数据如下：According to the method described in Example 15, compound 15 (yellow solid) was prepared by reaction of Intermediate II.9 and 6-cyanonicotinoyl chloride. The NMR and MS data of compound 15 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.61(s,1H),8.34(d,1H),8.11–7.97(m,2H),7.93(d,1H),7.86–7.79(m,1H),7.62–7.54(m,2H),7.39(t,1H),4.17–4.04(m,2H),2.56(t,2H),2.18–2.02(m,2H).LC-MS(m/z,ESI):812.36(M+Na+H) +. 1 H NMR(600MHz, Chloroform-d) δ8.61(s,1H), 8.34(d,1H), 8.11-7.97(m,2H), 7.93(d,1H), 7.86-7.79(m,1H) ,7.62–7.54(m,2H),7.39(t,1H),4.17–4.04(m,2H),2.56(t,2H),2.18–2.02(m,2H).LC-MS(m/z, ESI): 812.36(M+Na+H) + .
实施例24：化合物16的制备Example 24: Preparation of Compound 16
Figure PCTCN2020126091-appb-000023
Figure PCTCN2020126091-appb-000023
按照实施例15所描述的方法，由中间体II.10和6-氰基烟酰基氯化物反应制备得到化合物16(黄色固体)。化合物16的核磁及质谱数据如下：According to the method described in Example 15, compound 16 (yellow solid) was prepared by reaction of Intermediate II.10 and 6-cyanonicotinoyl chloride. The NMR and MS data of compound 16 are as follows:
1H NMR(600MHz,Chloroform-d)δ8.60(s,1H),8.33(d,1H),8.19(s,1H),8.02(t,1H),7.92(d,1H),7.82–7.74(m,1H),7.61–7.50(m,2H),7.39(t,1H),4.26(br s,1H),3.83(br d,1H),2.55–2.36(m,2H),1.90–1.77(m,4H).LC-MS(m/z,ESI):826.41(M+Na+H) +. 1 H NMR(600MHz, Chloroform-d) δ8.60(s,1H), 8.33(d,1H), 8.19(s,1H), 8.02(t,1H), 7.92(d,1H), 7.82-7.74 (m,1H), 7.61--7.50(m,2H), 7.39(t,1H), 4.26(br s,1H), 3.83(br d,1H), 2.55--2.36(m,2H), 1.90-1.77 (m,4H).LC-MS(m/z,ESI): 826.41(M+Na+H) + .
参照以上实施例可以制备本发明通式I中其它化合物。With reference to the above examples, other compounds of the general formula I of the present invention can be prepared.
生物活性测定Biological activity determination
实施例25：粘虫、小菜蛾、二化螟的生物活性测定Example 25: Determination of biological activity of Armyworm, Plutella xylostella, Chilo suppressalis
用本发明化合物对几种昆虫进行了杀虫活性测定实验。测定方法如下：The insecticidal activity test of several insects was carried out with the compound of the present invention. The measurement method is as follows:
待测化合物用丙酮/甲醇(1:1)的混合溶剂溶解后，用含有0.1％(wt)吐温80的水稀释至所需的浓度。After the test compound is dissolved in a mixed solvent of acetone/methanol (1:1), it is diluted with water containing 0.1% (wt) Tween 80 to the desired concentration.
以粘虫、小菜蛾、二化螟为靶标，采用Airbrush喷雾法进行活性测定。With armyworm, diamondback moth and Chilo suppressalis as targets, airbrush spray method was used for activity determination.
(1)杀粘虫的活性测定(1) Determination of the activity of killing armyworm
测定方法：将玉米叶片剪成长2cm的叶段，Airbrush喷雾处理的压力为10psi(约合0.7kg/cm 2)，每叶段正反面喷雾，待测化合物的喷液量为0.5ml。阴干后每处理接入10头3龄幼虫，每处理3次重复。处理后放入25℃、相对湿度60～70％观察室内培养，药后3天调查存活虫数， 计算死亡率。 Measurement method: cut corn leaves into 2cm leaf sections, the pressure of Airbrush spray treatment is 10psi (approximately 0.7kg/cm 2 ), the front and back sides of each leaf section are sprayed, and the spray volume of the compound to be tested is 0.5ml. After drying in the shade, 10 3rd instar larvae were inserted into each treatment, and repeated 3 times for each treatment. After the treatment, it was placed in an observation room at 25°C and a relative humidity of 60-70% for cultivation, and the number of surviving insects was investigated 3 days after the treatment, and the mortality rate was calculated.
对粘虫的部分测试结果如下：Some of the test results on the armyworm are as follows:
在0.05mg/L剂量下，药后3天，化合物1、5、9、10、11、12、13、14、15、16对粘虫的致死率均在90％以上。At a dose of 0.05 mg/L, the lethality rates of compounds 1, 5, 9, 10, 11, 12, 13, 14, 15, 16 to Mythimna separata were all above 90% 3 days after the administration.
(2)杀小菜蛾的活性测定(2) Determination of the activity to kill Plutella xylostella
测定方法：将甘蓝叶片用打孔器打成直径2cm的叶碟，Airbrush喷雾处理的压力为10psi(约合0.7kg/cm 2)，每叶碟正反面喷雾，待测化合物的喷液量为0.5ml。阴干后每处理接入10头3龄幼虫，每处理3次重复。处理后放入25℃、相对湿度60～70％观察室内培养，药后3天调查存活虫数，计算死亡率。 Measurement method: Use a punch to punch cabbage leaves into leaf discs with a diameter of 2 cm. The pressure of Airbrush spray treatment is 10 psi (approximately 0.7 kg/cm 2 ), and the front and back sides of each leaf disc are sprayed. The spray volume of the compound to be tested is 0.5ml. After drying in the shade, 10 3rd instar larvae were inserted into each treatment, and repeated 3 times for each treatment. After the treatment, it was placed in an observation room at 25°C and a relative humidity of 60-70%, and the number of surviving insects was investigated 3 days after the treatment, and the mortality rate was calculated.
对小菜蛾的部分测试结果如下：Some test results of Plutella xylostella are as follows:
在1mg/L剂量下，化合物1、5、9、10、11、12、13、14、15、16对小菜蛾的致死率在90％以上。At a dose of 1 mg/L, the lethality of compounds 1, 5, 9, 10, 11, 12, 13, 14, 15, 16 to Plutella xylostella was more than 90%.
在0.05mg/L剂量下，化合物9、10、11、12、13、14、15、16对小菜蛾的致死率在90％以上。At a dose of 0.05 mg/L, the lethality of compounds 9, 10, 11, 12, 13, 14, 15, 16 to Plutella xylostella was more than 90%.
(3)杀二化螟的活性测定(3) Determination of the activity of Chilo suppressalis
测定方法：1)稻苗准备：在恒温室(温度26～28℃、相对湿度60～80％左右，光照16hL:8hD)内用直径为4.5cm、高4cm塑料小杯培养水稻，待水稻长至4～5叶期时，选择健壮的、长势一致的水稻幼苗进行药剂处理，每处理设3次重复。2)试虫准备：室内连续饲养的二化螟，3龄幼虫。3)稻茎喷雾接虫。采用喷雾法，对稻苗进行全株均匀喷雾处理，每处理用药15ml。先处理空白对照，然后按试验浓度由低到高的顺序重复上述操作。稻苗喷雾处理后，放置阴凉处将药液晾干，剪取茎基部上5厘米左右茎秆饲喂试虫。准备直径90mm的玻璃培养皿，皿底垫滤纸，加水保湿，每皿放入约5根稻茎，接幼虫10头，用无纺布密闭培养皿，置于恒温房间培养。药后3天调查残留活虫数。Determination method: 1) Preparation of rice seedlings: cultivate rice in a plastic cup with a diameter of 4.5 cm and a height of 4 cm in a constant temperature room (temperature 26-28°C, relative humidity 60-80%, light 16hL:8hD), and wait until the rice grows. At the 4 to 5 leaf stage, select robust and consistent rice seedlings for chemical treatment, and set 3 repetitions for each treatment. 2) Preparation for test insects: Chilo suppressalis, 3rd instar larvae continuously reared indoors. 3) The rice stalk is sprayed to catch insects. The spray method is adopted to uniformly spray the whole plant of the rice seedlings, with 15 ml of medicine per treatment. Treat the blank control first, and then repeat the above operations in the order of the test concentration from low to high. After the rice seedlings are sprayed, they are placed in a cool place to dry the liquid, and about 5 cm of the stalk at the base of the stem is cut to feed the test insects. Prepare a glass petri dish with a diameter of 90mm, pad filter paper at the bottom of the dish, add water to moisturize, put about 5 rice stalks in each dish, and pick up 10 larvae. Seal the petri dish with non-woven fabric and place it in a constant temperature room for cultivation. The number of remaining live insects was investigated 3 days after the administration.
对二化螟的部分测试结果如下：Some test results of Chilo suppressalis are as follows:
在1mg/L剂量下，化合物1、5、9、10、11、12、13、14、15、16对二化螟的致死率在90％以上。At a dose of 1 mg/L, the lethality of compounds 1, 5, 9, 10, 11, 12, 13, 14, 15, 16 to Chilo suppressalis is above 90%.
在0.125mg/L剂量下，化合物9、10、11、12、13、14、15、16对二化螟的致死率在90％以上。At a dose of 0.125 mg/L, the lethality of compounds 9, 10, 11, 12, 13, 14, 15, 16 to Chilo suppressalis is above 90%.
选取本发明化合物1、9、13与对照化合物进行二化螟杀虫活性平行比较试验(药后3天)，测定方法同前所述；结果如表2所示：The compound 1, 9, 13 of the present invention and the control compound were selected for the parallel comparison test of Chilo suppressalis insecticidal activity (3 days after the drug), and the determination method was the same as that described above; the results are shown in Table 2:
表2本发明化合物1、9、13与对照化合物对二化螟杀虫活性平行比较试验Table 2 Parallel comparative test of the compound 1, 9, 13 of the present invention and the control compound against the insecticidal activity of Chilo suppressalis
Figure PCTCN2020126091-appb-000024
Figure PCTCN2020126091-appb-000024
Figure PCTCN2020126091-appb-000025
Figure PCTCN2020126091-appb-000025
注：表2中“-”表示未测。表中1-1、1-2、2-1、2-2、3-1、3-2均为本申请提供的对照化合物；化合物1-1、1-2参照本发明实施例15的方法可以获得；化合物2-1、2-2参照本发明实施例17的方法可以获得；化合物3-1、3-2参照本发明实施例21的方法可以获得；原料均为按照本发明实施例方法可以制备得到的或可以购买得到的或按照常规方法可以制得的。Note: "-" in Table 2 means untested. 1-1, 1-2, 2-1, 2-2, 3-1, and 3-2 in the table are all reference compounds provided by this application; compounds 1-1 and 1-2 refer to the method of Example 15 of the present invention Available; Compounds 2-1 and 2-2 can be obtained by referring to the method of Example 17 of the present invention; Compounds 3-1 and 3-2 can be obtained by referring to the method of Example 21 of the present invention; the raw materials are all according to the method of Example of the present invention Can be prepared or can be purchased or can be prepared according to conventional methods.
本发明实施例中通过对式I化合物中的R 1、R 2、R 3、R 4基团及其搭配进行选择，获得了杀虫效果更好的化合物，如表2所示，通过将化合物1和对照化合物1-1、1-2进行比较，通过将化合物9和对照化合物2-1、2-2进行比较，通过将化合物13和对照化合物3-1、3-2进行比较，可以看出：苯环上的氰基和与之相邻的氮原子非常重要，二者相互配合，缺一不可，当保留氰基，并将与之相邻的氮原子选择碳原子后，化合物对二化螟的活性会显著降低，甚至丧失；当保留氮原子，并将与之相邻的氰基选择氢后，化合物则完全丧失了对二化螟的活性。 In the embodiment of the present invention, by selecting the R 1 , R 2 , R 3 , R 4 groups and their combinations in the compound of formula I, a compound with better insecticidal effect is obtained. As shown in Table 2, the compound 1 is compared with the control compounds 1-1 and 1-2, by comparing compound 9 with the control compounds 2-1 and 2-2, and by comparing compound 13 with the control compounds 3-1 and 3-2, it can be seen Out: The cyano group on the benzene ring and the adjacent nitrogen atom are very important. The two cooperate with each other and are indispensable. When the cyano group is retained and the adjacent nitrogen atom is selected as the carbon atom, the compound The activity of Chilo suppressalis will be significantly reduced or even lost; when the nitrogen atom is retained and the adjacent cyano group is selected for hydrogen, the compound will completely lose its activity against Chilo suppressalis.
实施例26：对猫蚤的杀虫试验Example 26: Insecticidal test on cat fleas
将4mg待测化合物溶解于40ml丙酮，获得浓度100ppm的丙酮溶液，在内径5.3cm的培养皿的底面和侧面上涂布400μl药液，然后待丙酮挥发，在培养皿的内壁上制作本发明化合物的薄膜。所使用的培养皿的内壁为40cm 2，处理药量为1μg/cm 2；向其中放入10只猫蚤成虫(雌雄混合)，盖好后在25℃的恒温室内保存。检查72h后的死虫数，计算死虫率。试验按3次重复进行。测试结果：化合物1、5、9、10、11、12、13、14、15、16显示出90％以上的死虫率。 Dissolve 4 mg of the test compound in 40 ml of acetone to obtain an acetone solution with a concentration of 100 ppm. Spread 400 μl of the drug solution on the bottom and sides of a petri dish with an inner diameter of 5.3 cm, and then wait for the acetone to volatilize to prepare the compound of the invention on the inner wall of the petri dish的膜。 The film. The inner wall of the petri dish used was 40 cm 2 , and the treatment dose was 1 μg/cm 2 ; 10 adult cat fleas (mixed male and female) were put into it, covered and stored in a constant temperature room at 25°C. Check the number of dead insects after 72h and calculate the dead insect rate. The test was repeated 3 times. Test results: Compounds 1, 5, 9, 10, 11, 12, 13, 14, 15, 16 showed a mortality rate of more than 90%.
实施例27：对美洲犬蜱的杀虫试验Example 27: Insecticidal Test on American Dog Ticks
将4mg待测化合物溶解于40ml丙酮，获得浓度100ppm的丙酮溶液，在2个内径5.3cm的培养皿的底面和侧面上，涂布400μl药液，然后待丙酮挥发，在培养皿的内壁上制作本发明化合物的薄膜。所使用的培养皿的内壁为40cm 2，处理药量为1μg/cm 2。向其中放入10只美洲犬蜱的第1若虫(雌雄混合)，合并2个培养皿，使用胶带密封结合部以防止逃亡，在25℃的恒温室中保存。检查24h后的死虫数，计算死虫率。试验按3次重复进行。测试结果：化合物1、5、9、10、11、12、13、14、15、16显示出90％以上的死虫率。 Dissolve 4 mg of the test compound in 40 ml of acetone to obtain an acetone solution with a concentration of 100 ppm. Spread 400 μl of the drug solution on the bottom and sides of two petri dishes with an inner diameter of 5.3 cm, and then wait for the acetone to volatilize and prepare on the inner wall of the petri dishes Films of the compounds of the invention. The inner wall of the petri dish used is 40 cm 2 , and the treatment dose is 1 μg/cm 2 . 10 first nymphs of American dog ticks (mixed male and female) were put into it, the two petri dishes were combined, the joint was sealed with tape to prevent escape, and it was stored in a constant temperature room at 25°C. Check the number of dead insects after 24h and calculate the dead insect rate. The test was repeated 3 times. Test results: Compounds 1, 5, 9, 10, 11, 12, 13, 14, 15, 16 showed a mortality rate of more than 90%.

Claims (15)

  1. 一种酰胺类化合物，其特征在于：所述酰胺类化合物的结构如通式I所示：An amide compound, characterized in that: the structure of the amide compound is as shown in general formula I:
    Figure PCTCN2020126091-appb-100001
    Figure PCTCN2020126091-appb-100001
    通式I中：In the general formula I:
    R 1选自卤素； R 1 is selected from halogen;
    R 2选自卤素、C 1-C 4卤代烷基或C 1-C 4卤代烷氧基； R 2 is selected from halogen, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy;
    R 3选自CF 3或CF 2CF 3； R 3 is selected from CF 3 or CF 2 CF 3 ;
    R 4选自氰基C 1-C 4烷基。 R 4 is selected from cyano C 1 -C 4 alkyl.
  2. 根据权利要求1所述的化合物，其特征在于：通式I中The compound according to claim 1, characterized in that: in the general formula I
    R 1选自卤素； R 1 is selected from halogen;
    R 2选自卤素、C 1-C 2卤代烷基或C 1-C 2卤代烷氧基； R 2 is selected from halogen, C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy;
    R 3选自CF 3或CF 2CF 3； R 3 is selected from CF 3 or CF 2 CF 3 ;
    R 4选自氰基C 1-C 4烷基。 R 4 is selected from cyano C 1 -C 4 alkyl.
  3. 根据权利要求2所述的化合物，其特征在于：通式I中The compound according to claim 2, characterized in that: in the general formula I
    R 1选自溴或碘； R 1 is selected from bromine or iodine;
    R 2选自溴、碘、三氟甲基或二氟甲氧基； R 2 is selected from bromine, iodine, trifluoromethyl or difluoromethoxy;
    R 3选自CF 3或CF 2CF 3； R 3 is selected from CF 3 or CF 2 CF 3 ;
    R 4选自CH 2CN、CH 2CH 2CN、CH 2CH 2CH 2CN、CH 2CH 2CH 2CH 2CN、CH(CH 3)CN、CH(CH 2CH 3)CN、CH(CH 2CH 2CH 3)CN、C(CH 3)(CH 3)CN或C(CH 3)(CH 2CH 3)CN。 R 4 is selected from CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 CH 2 CN, CH 2 CH 2 CH 2 CH 2 CN, CH(CH 3 )CN, CH(CH 2 CH 3 )CN, CH( CH 2 CH 2 CH 3 )CN, C(CH 3 )(CH 3 )CN or C(CH 3 )(CH 2 CH 3 )CN.
  4. 根据权利要求3所述的化合物，其特征在于：通式I中The compound according to claim 3, characterized in that: in the general formula I
    R 1选自溴或碘； R 1 is selected from bromine or iodine;
    R 2选自溴、碘或三氟甲基； R 2 is selected from bromine, iodine or trifluoromethyl;
    R 3选自CF 3； R 3 is selected from CF 3 ;
    R 4选自CH 2CN、CH 2CH 2CN、CH 2CH 2CH 2CN或CH 2CH 2CH 2CH 2CN。 R 4 is selected from CH 2 CN, CH 2 CH 2 CN, CH 2 CH 2 CH 2 CN, or CH 2 CH 2 CH 2 CH 2 CN.
  5. 根据权利要求1所述的酰胺类化合物，其特征在于，酰胺类化合物选自：The amide compound of claim 1, wherein the amide compound is selected from:
    表1化合物，表1化合物具有如通式I的结构且R 1、R 2、R 3和R 4如表1中所示； Compounds of Table 1. The compounds of Table 1 have the structure of Formula I and R 1 , R 2 , R 3 and R 4 are as shown in Table 1;
    Figure PCTCN2020126091-appb-100002
    Figure PCTCN2020126091-appb-100002
    Figure PCTCN2020126091-appb-100003
    Figure PCTCN2020126091-appb-100003
  6. 一种根据权利要求1-5之一所述的酰胺类化合物在制备杀虫剂中的用途。A use of the amide compound according to any one of claims 1 to 5 in the preparation of insecticides.
  7. 根据权利要求6所述的用途，其特征在于：所述杀虫剂用于防治粘虫、小菜蛾、二化螟中的一种或几种。The use according to claim 6, wherein the insecticide is used to control one or more of Armyworm, Plutella xylostella and Chilo suppressalis.
  8. 一种杀虫剂制剂，其特征在于：所述杀虫剂制剂中含有权利要求1-5之一所述的酰胺类化合物作为活性组分，还含有一种或多种辅料；可选地，杀虫剂制剂中权利要求1-5之一所述的酰胺类化合物的量为0.1至99重量％，进一步可选地为0.5至90重量％。An insecticide preparation, characterized in that: the insecticide preparation contains the amide compound according to any one of claims 1 to 5 as an active component, and also contains one or more auxiliary materials; optionally, The amount of the amide compound described in any one of claims 1 to 5 in the pesticide formulation is 0.1 to 99% by weight, further optionally 0.5 to 90% by weight.
  9. 一种杀虫剂组合物，其特征在于：包括权利要求1-5之一所述的酰胺类化合物和其他活性化合物的混合物，所述其他活性化合物选自杀虫剂、毒饵剂、消毒剂、杀螨剂、杀线虫剂、杀真菌剂、生长调节剂、除草剂中的一种或多种。An insecticide composition, characterized in that it comprises a mixture of the amide compound described in any one of claims 1-5 and other active compounds, and the other active compounds are selected from suicide insecticides, poison baits, disinfectants, One or more of acaricides, nematicides, fungicides, growth regulators, and herbicides.
  10. 一种控制农业或林业害虫的方法，其特征在于：将有效剂量的材料施用于需要控制的害虫或其生长介质上，所述材料选自下组中的一种或多种：A method for controlling agricultural or forestry pests, which is characterized in that: an effective dose of material is applied to the pest to be controlled or its growth medium, and the material is selected from one or more of the following groups:
    权利要求1-5之一所述的酰胺类化合物；The amide compound of any one of claims 1-5;
    权利要求8所述的杀虫剂制剂；The pesticide formulation of claim 8;
    权利要求9所述的杀虫剂组合物。The insecticide composition of claim 9.
  11. 一种根据权利要求1-5之一所述的酰胺类化合物在制备动物寄生虫防治剂中的用途。A use of the amide compound according to any one of claims 1 to 5 in the preparation of an animal parasite control agent.
  12. 根据权利要求11所述的用途，其特征在于：所述动物寄生虫防治剂用于防治猫蚤、美洲犬蜱中的一种或几种。The use according to claim 11, wherein the animal parasite control agent is used to control one or more of cat fleas and American dog ticks.
  13. 一种动物寄生虫防治剂，其特征在于：所述动物寄生虫防治剂中含有权利要求1-5之一所 述的酰胺类化合物作为活性组分，还含有一种或多种辅料；可选地，动物寄生虫防治剂中权利要求1-5之一所述的酰胺类化合物的量为1至80重量％。An animal parasite control agent, characterized in that: the animal parasite control agent contains the amide compound according to any one of claims 1 to 5 as an active component, and also contains one or more auxiliary materials; optional Specifically, the amount of the amide compound described in any one of claims 1 to 5 in the animal parasite control agent is 1 to 80% by weight.
  14. 一种动物寄生虫防治组合物，其特征在于：包括权利要求1-5之一所述的酰胺类化合物和其他动物寄生虫防治活性化合物的混合物，所述其他动物寄生虫防治活性化合物选自杀螨剂、杀昆虫剂、杀寄生虫剂、抗疟原虫剂中的一种或多种。An animal parasite control composition, characterized in that it comprises a mixture of the amide compound described in any one of claims 1 to 5 and other animal parasite control active compounds, and the other animal parasite control active compounds are suicide mites One or more of insecticides, insecticides, parasiticides, and anti-plasmodium agents.
  15. 一种控制动物寄生虫的方法，其特征在于：包括以下步骤：将有效剂量的材料施于需要控制的动物寄生虫或其生长介质上，所述材料选自下组中的一种或多种：A method for controlling animal parasites, which is characterized in that it comprises the following steps: applying an effective dose of material to the animal parasites or their growth medium to be controlled, and the material is selected from one or more of the following group :
    权利要求1-5之一所述的酰胺类；The amides of any one of claims 1-5;
    权利要求13所述的动物寄生虫防治剂；The animal parasite control agent of claim 13;
    权利要求14所述的动物寄生虫防治组合物。The animal parasite control composition of claim 14.
PCT/CN2020/126091 2020-01-07 2020-11-03 Amide compound and application thereof WO2021139370A1 (en)

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