WO2024061178A1 - Compound containing five-membered heterocycle, preparation method therefor, and application thereof - Google Patents

Compound containing five-membered heterocycle, preparation method therefor, and application thereof Download PDF

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Publication number
WO2024061178A1
WO2024061178A1 PCT/CN2023/119499 CN2023119499W WO2024061178A1 WO 2024061178 A1 WO2024061178 A1 WO 2024061178A1 CN 2023119499 W CN2023119499 W CN 2023119499W WO 2024061178 A1 WO2024061178 A1 WO 2024061178A1
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compound
halogenated
alkyl
alkoxy
substituted
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PCT/CN2023/119499
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French (fr)
Chinese (zh)
Inventor
刘祥伟
柳英帅
韩勤安
刘保红
盛国柱
李佳兴
李德志
陈莹
刘瑞宾
杜瑶瑶
王世玲
宫辰
王莹
刘敏
孙韵晓
于海霞
冯睿杰
范世恩
陈瑜
李宁
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青岛康乔药业集团有限公司
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Publication of WO2024061178A1 publication Critical patent/WO2024061178A1/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • 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
    • A01P5/00—Nematocides
    • 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
    • A01P7/02—Acaricides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the technical field of pesticides, specifically to five-membered heterocyclic compounds and their preparation methods and applications, agricultural compositions and methods for preventing and controlling invertebrate pests.
  • Arylisoxazole derivatives containing heterocyclic compounds have unique insecticidal activity in modern crop and animal protection, such as fluoxazoleamide, the first isoxazoline insecticide developed and launched by Nissan Chemical.
  • Heterocyclic compounds are important intermediates or chemical entities in the process of pesticide synthesis and research and development. They have unique chemical structures and biological activities, and many of their derivatives have been developed as agrochemical products.
  • CN106045962A discloses that the compound (X.82) represented by the following structure is effective against Spodoptera litura, Spodoptera exigua, Diamondback moth, cucumber leaf beetle, thrips, two-spotted spider mite, peach at a concentration of 200ppm (200mg/L). It has a lethal activity of more than 80% against aphids, American stink bug, brown planthopper and other pests. However, its activity against agricultural pests at lower concentrations has not been reported.
  • Chlorantraniliprole is a bisamide insecticide developed by DuPont. It is the most successfully developed insecticide with the largest sales so far. It has a high control effect on lepidopteran pests such as diamondback moth. However, due to continuous use in the field for many years, the resistance of chlorantraniliprole to pests such as diamondback moth has become very serious, and its efficacy has decreased significantly. The market is in urgent need of insecticides with good control effect against lepidopteran pests such as diamondback moth.
  • insecticidal and acaricidal effects of the currently disclosed compounds are still unsatisfactory, and resistance to pests and mites is developing rapidly. Agricultural production still requires new and more efficient compounds to cope with the increasing development of resistance to pests and mites.
  • the purpose of the present invention is to overcome the technical problem in the prior art that existing compounds have low killing activity in the control of invertebrate pests (especially mites and diamondback moths), and to provide a more efficient five-element compound containing Heterocyclic compounds, methods for their preparation and uses, agricultural compositions and methods for controlling invertebrate pests.
  • the five-membered heterocycle-containing compound provided by the invention has efficient acaricidal and insecticidal activities, and especially shows a high control effect against spider mites, diamondback moths, etc.
  • the first aspect of the present invention provides a five-membered heterocyclic compound having a structure represented by formula (I) or an agriculturally acceptable salt thereof, or a stereoisomer thereof,
  • X 1 and X 3 are each independently F, Cl, Br, I or CF 3 ;
  • X2 is H, F, Cl, Br, I or CF3 ;
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 10 alkylcarbonyl, halo C 1 - C 10 alkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 cycloalkylmethylcarbonyl, C 1 -C 10 alkoxycarbonyl, halogenated C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkoxy C 1 -C 4 alkylcarbonyl, halo C 1 -C 10 alkoxy C 1 -C 4 alkyl carbonyl, C 1 -C 10 alkyl oxalyl, halo C 1 -C 10 alkyl oxalyl, C 1 -C 10 alkoxy oxalyl, halogenated C 1 -C 10 alkoxy oxalyl
  • n is selected from 0, 1 or 2.
  • a second aspect of the present invention provides a method for preparing a compound containing a five-membered heterocyclic ring.
  • the preparation method includes:
  • the compound II has the structure represented by formula (II)
  • the compound III has the structure represented by formula (III)
  • the compound IV has the structure represented by formula (IV)
  • the compound V has the formula The structure represented by (V)
  • the compound I has the structure represented by formula (I)
  • X 1 , X 2 and X 3 are each independently selected from F, Cl, Br, I or CF 3 ;
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 10 alkylcarbonyl, halo C 1 - C 10 alkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 cycloalkylmethylcarbonyl, C 1 -C 10 alkoxycarbonyl, halogenated C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkoxy C 1 -C 4 alkylcarbonyl, halo C 1 -C 10 alkoxy C 1 -C 4 alkyl carbonyl, C 1 -C 10 alkyl oxalyl, halo C 1 -C 10 alkyl oxalyl, C 1 -C 10 alkoxy oxalyl, halogenated C 1 -C 10 alkoxy oxalyl
  • L is selected from fluorine, chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl or p-toluenesulfonyl.
  • the third aspect of the present invention provides the use of the aforementioned compound or the compound prepared by the aforementioned preparation method in preventing and controlling invertebrate pests.
  • the fourth aspect of the present invention provides an agricultural composition, which composition contains at least one of the aforementioned compounds or compounds prepared by the aforementioned preparation method and at least one liquid carrier or solid carrier.
  • the fifth aspect of the present invention provides a method for preventing and controlling invertebrate pests, which method includes: directly or indirectly applying a pesticidally effective amount of at least one of the aforementioned compounds or compounds prepared by the aforementioned preparation method to the pests that need to be controlled. Invertebrate pests and/or the medium in which they grow.
  • the five-membered heterocycle-containing compounds and their agriculturally acceptable salts provided by the present invention are effective against a variety of harmful organisms, especially against spider mites, spider mites, Tetranychus kanzawa, and citrus alleles Spider mites represented by Tetranychus claw, lepidopterans represented by diamondback moth, thrips and flea beetles have shown high control effects and can be used to control a variety of pests and mites, with high efficiency. It has mite and insecticidal activity and has good application prospects.
  • the five-membered heterocyclic compound provided by the present invention has high activity against the following invertebrate pests (the following objects are only used to illustrate the present invention, but not to limit the present invention): Tetranychus cinnabarinus (such as Tetranychus cinnabarinus, Panonychus citri, Tetranychus urticae, Panonychus malus, Tetranychus kanzawa, Tetranychus villosa), Acaridae, Acaridae, Aphididae (such as Myzus persicae), Lepidoptera (such as Plutella xylostella, Spodoptera exigua, Chilo suppressalis, etc.), Thysanoptera (such as Western Flower Thrips, etc.) and Coleoptera (such as Yellow Striped Flea Beetle), etc. Therefore, the five-membered heterocyclic compound of the present invention can be used in agriculture or other fields to prepare insecticides and a
  • the first aspect of the present invention provides a five-membered heterocyclic compound having a structure represented by formula (I) or an agriculturally acceptable salt thereof, or a stereoisomer thereof,
  • X 1 and X 3 are each independently F, Cl, Br, I or CF 3 ;
  • X 2 is H, F, Cl, Br, I or CF 3 ;
  • R1 is selected from hydrogen, substituted or unsubstituted C1 - C6 alkyl, C1 - C4 alkoxy C1- C4 alkyl, C1 - C10 alkylcarbonyl, halogenated C1 -C10 alkylcarbonyl, C3 - C10 cycloalkylcarbonyl, C3-C10 cycloalkylmethylcarbonyl, C1- C10 alkoxycarbonyl, halogenated C1- C10 alkoxycarbonyl, C1- C10 alkoxy C1 -C4 alkylcarbonyl, halogenated C1 - C10 alkoxy C1- C4 alkylcarbonyl, C1 - C10 alkyloxalyl, halogenated C1 - C10 alkyloxalyl, C1 - C10 alkoxyoxalyl, halogenated C1 - C10 alkoxyoxalyl, C1-C10 alkylsul
  • X 1 and X 3 are not Cl at the same time. More preferably, when X 2 is H, X 3 is CF 3 .
  • each of X 1 , X 2 and X 3 is independently selected from F, Cl, Br or CF 3 .
  • R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxy Ethyl, ethoxymethyl, ethoxyethyl, trifluoromethyl, trichloromethyl, trifluoroethyl or trifluoromethoxymethyl, C 1 -C 6 alkylcarbonyl, halo C 1 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, C 3 -C 6 cycloalkylmethylcarbonyl, C 1 -C 6 alkoxycarbonyl, halogenated C 1 -C 6 alkoxy Carbonyl, C 1 -C 4 alkoxy C 1 - C 2 alkyl carbonyl, halo C 1 - C 4 alkoxy C 1 - C 2 alkyl carbonyl,
  • X 1 , X 2 , and X 3 are each independently selected from F, Cl, or CF 3 .
  • X 2 is selected from F or Cl
  • X 1 and X 3 are each independently selected from Cl or CF 3 .
  • R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxy Ethyl, ethoxymethyl, ethoxyethyl, acetyl, propionyl, n-butyryl, cyclopropylformyl, methoxyformyl, methoxyacetyl, methoxyacetyl, Methoxyoxalyl, ethoxyoxalyl.
  • the compound is selected from at least one of the compounds represented by the following structure, or an agriculturally acceptable salt thereof, or a stereoisomer thereof:
  • compounds I-13, I-14, I-15, I-16, I-17, I-18, I-19, and I-20 are stereoisomers of compound I-1; compounds I-27, I-29 and I-30 are stereoisomers of compound I-25, and compound I-28 is a stereoisomer of compound I-26.
  • the compound containing a five-membered heterocyclic ring may have optical isomers caused by having one or more asymmetric carbon atoms.
  • the present invention includes all optical isomers and racemic isomers. isomers or diastereomers.
  • the five-membered heterocycle-containing compound also includes its derivatives, but the compounds included in the derivatives of the present invention are by no means limited to these compounds.
  • agriculturally acceptable salts refer to salts formed from compounds containing five-membered heterocyclic rings and inorganic acids or organic acids.
  • inorganic acids include hydrochloric acid, sulfuric acid, hydrobromic acid, etc.
  • organic acids include formic acid, acetic acid, methanesulfonic acid, fumaric acid, maleic acid, and the like.
  • a second aspect of the present invention provides a method for preparing a compound containing a five-membered heterocyclic ring.
  • the preparation method includes:
  • the compound II has the structure represented by formula (II)
  • the compound III has the structure represented by formula (III)
  • the compound IV has the structure represented by formula (IV)
  • the compound V has the formula The structure represented by (V)
  • the compound I has the structure represented by formula (I)
  • X 1 , X 2 and X 3 are each independently selected from F, Cl, Br, I or CF 3 ;
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 10 alkylcarbonyl, halo C 1 - C 10 alkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 cycloalkylmethylcarbonyl, C 1 -C 10 alkoxycarbonyl, halogenated C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkoxy C 1 -C 4 alkylcarbonyl, halo C 1 -C 10 alkoxy C 1 -C 4 alkyl carbonyl, C 1 -C 10 alkyl oxalyl, halo C 1 -C 10 alkyl oxalyl, C 1 -C 10 alkoxy oxalyl, halogenated C 1 -C 10 alkoxy oxalyl
  • L is selected from fluorine, chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.
  • the condensing agent is selected from dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-nitrogen One or more of heterobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, thionyl chloride or oxalyl chloride.
  • the first solvent and the second solvent are each independently selected from toluene, xylene, dichloromethane, dichloroethane, acetonitrile, N,N-dimethylformamide (DMF) , one or more of tetrahydrofuran and acetone.
  • DMF N,N-dimethylformamide
  • the alkaline substance is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and hydrogen carbonate.
  • the alkaline substance is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and hydrogen carbonate.
  • sodium, potassium bicarbonate, sodium hydride and sodium amide sodium hydride and sodium amide.
  • the molar ratio of compound II to compound III is 1:0.8-1.5.
  • the molar ratio of compound IV to compound V is 1:0.7-1.5.
  • the molar ratio of the compound II to the condensing agent is 1:0.8-1.5.
  • the molar ratio of the compound IV to the basic substance is 1:0.7-1.5.
  • the temperature of the first reaction ranges from -10°C to the boiling point of the first solvent, and the reaction time ranges from 10 min to 48 h.
  • the temperature of the first reaction is -10°C to 210°C, preferably 0°C to 150°C, more preferably 10-100°C; the time is 0.5-24h, preferably 1-12h, More preferably, it is 2-6h.
  • the temperature of the second reaction is from -10°C to the boiling point of the second solvent, and the reaction time is from 10 min to 48 h.
  • the temperature of the second reaction is -10°C to 210°C, preferably 0°C to 150°C, more preferably 10-100°C; the time is 0.5-24h, preferably 1-12h, More preferably, it is 2-6h.
  • the compound represented by formula (I) has unexpectedly high acaricidal activity. Therefore, the compound of the present invention can also be used in agriculture or other fields to prepare acaricide drugs.
  • the compound represented by formula (I) has high activity against the following invertebrate pests (the following objects are only used to illustrate the present invention, but not to limit the present invention): Tetranychus (such as Tetranychus cinnabarinus, Panonychus citri, Tetranychus urticae, Panonychus apple, Tetranychus kanzawa, Tetranychus villosa), Acaridae, Acaridae, Aphididae (such as Myzus persicae), Lepidoptera (such as Plutella xylostella, Spodoptera exigua, Chilo suppressalis, etc.). Therefore, the compound of the present invention can also be used in agriculture or other fields to prepare acaricide drugs
  • the third aspect of the present invention provides the use of the aforementioned compound or the compound prepared by the aforementioned preparation method in preventing and controlling invertebrate pests.
  • the invertebrate pest is an acarid pest, an insect, and/or a nematode.
  • the compound can be used to protect important crops, livestock, etc. in agriculture and horticulture from being harmed by or less susceptible to mites.
  • the dosage of the compound varies depending on various factors, such as the compound used, the crop to be pre-protected, the type of pest, the degree of infection, the application method, and the application environment. , dosage form and other factors.
  • one or more other insecticides, acaricides, fungicides, herbicides, plant growth agents, etc. can be added to the acaricidal composition of the present invention.
  • Conditioners or fertilizers, etc. which can produce additional advantages and effects.
  • the fourth aspect of the present invention provides an agricultural composition, which composition contains at least one of the aforementioned compounds or compounds prepared by the aforementioned preparation method and at least one liquid carrier or solid carrier.
  • the present invention has no particular limitation on the liquid carrier or solid carrier, as long as it can meet the requirements of the present invention.
  • the concentration of the compound containing a five-membered heterocyclic ring is 0.5-35 mg/L. In some embodiments, the concentration of the compound containing a five-membered heterocyclic ring is 1-30 mg/L, and in other embodiments, the concentration of the compound containing a five-membered heterocyclic ring is 10-25 mg/L.
  • the liquid carrier can be water, various aromatic hydrocarbons, aliphatic hydrocarbons, ketones, ethers, etc., such as toluene, xylene, acetone, cyclohexanone, xylene, benzene, cyclohexane, isopropanol, ethylene glycol, sorbitol, methanol, ethanol, butanol, dimethylformamide, N-methylpyrrolidone, decalin, engine oil, One or more of petroleum ether, cyclohexanone, methyl oleate, methylated soybean oil, etc.; solid carriers can include natural or synthetic clays and silicates, and solid carriers suitable for powders can include naturally formed rock powders, chalk, quartz, clay, montmorillonite, white carbon black, diatomaceous earth, pumice, gypsum, talc, bentonite, kaolin, clay and synthetic ground minerals (such as micro-dispersed silicic acid or aluminum
  • the composition can be administered in the form of a preparation.
  • the compound described in claim 1 is dissolved or dispersed in a carrier as an active component, or is formulated into a preparation so that it is easier to disperse when used for insecticide and acaricide.
  • the composition can be made into wettable powder, water-dispersible granule, suspension, water emulsion, water or emulsifiable concentrate, etc.
  • at least one liquid or solid carrier is added, and when necessary, a suitable surfactant is also added.
  • surfactants may include dodecyl benzene sulfonate, fatty alcohol sulfate, Tween, agricultural milk, sorbitol polyoxyethylene ether, fatty alcohol polyoxyethylene ether, lignin sulfonate, alkyl naphthalene Sulfonate etc.
  • the fifth aspect of the present invention provides a method for preventing and controlling invertebrate pests, which method includes: directly or indirectly applying a pesticidally effective amount of at least one of the aforementioned compounds or compounds prepared by the aforementioned preparation method to the pests that need to be controlled. Invertebrate pests and/or the medium in which they grow.
  • the present invention is not particularly limited to direct or indirect methods, as long as the purpose of preventing and controlling invertebrate pests can be achieved.
  • the direct method may include directly combining a substance containing the component of the five-membered heterocycle-containing compound with an invertebrate pest.
  • invertebrate pests including invertebrate pests directly eating substances containing the components of the five-membered heterocyclic compound, direct contact between the body surface of invertebrate pests and substances containing the components of the five-membered heterocyclic compound) etc.
  • indirect methods may include treating places where invertebrate pests are infested (its habitat or breeding ground or plants and soil where invertebrate pests grow) with substances containing the components of the five-membered heterocycle-containing compound. Or substances containing components of the five-membered heterocycle-containing compound are processed into their food chain.
  • the method comprises: treating plants where invertebrate pests grow with an insecticidal effective amount of at least one of the five-membered heterocyclic compound.
  • the invertebrate pests are mite pests, insects and/or nematodes.
  • the plant is a plant of Gymnosperm and/or Angiosperm, preferably at least one of Rutaceae, Solanaceae, Brassicaceae and Rosaceae.
  • the present invention has no particular limitation on the insecticidal effective dose.
  • it can refer to a dose of 5 grams to 3 kilograms of the five-membered heterocycle-containing compound per hectare, which can provide sufficient control.
  • the insecticidally effective amount can be 8 to 1000 grams per hectare, more preferably, the insecticidally effective amount can be 10 to 300 grams per hectare.
  • the five-membered heterocycle-containing compound provided by the invention is effective against a variety of harmful organisms, especially against spider mites and diamondback moths represented by Tetranychus two-spotted, Tetranychus kanzawa, Tetranychus citrus, etc.
  • Lepidoptera exhibits excellent insecticidal and acaricidal activity.
  • Step 4 Synthesis of 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid:
  • the reaction solution was cooled to room temperature, and 20 mL of concentrated hydrochloric acid, 100 mL of water, and 100 mL of ethyl acetate were added. After extraction and liquid separation, 100 mL of ethyl acetate was added to the aqueous phase again. After extraction and liquid separation, the organic phases were combined. The organic phase was dried by adding 10 g of anhydrous sodium sulfate and then rotary evaporated to dryness to obtain 8.5 g of a light yellow solid compound.
  • Step six 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-( Synthesis of 1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-1):
  • the target compound was prepared according to the method described in Example 1, except that (R)-3-aminotetrahydrothiophene 1,1-dioxide hydrochloride (compound III-2) was used instead of 3-aminotetrahydrothiophene. 1,1-dioxide (compound III-1) was used to prepare the target compound I-14 as a white solid powder.
  • the target compound was prepared according to the method described in Example 1, except that (S)-3-aminotetrahydrothiophene 1,1-dioxide hydrochloride (compound III-3) was used instead of 3-aminotetrahydrothiophene. 1,1-dioxide (compound III-1) was used to prepare the target compound I-13 as a white solid powder.
  • the target compound was prepared according to the method described in Example 1, except that 3-aminotetrahydrothiophene (compound III-4) was used instead of 3-aminotetrahydrothiophene 1,1-dioxide (compound III-1),
  • the target compound I-21 was prepared as a white solid powder.
  • the target compound was prepared according to the method described in Example 1, except that (4-(5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroiso Oxazol-3-yl)-2-methylbenzoic acid (compound II-2) instead of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4, 5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (compound II-1) was used to prepare the target compound I-13 as a white solid powder.
  • reaction solution was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. After extraction and separation, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The mixture was purified by column chromatography to obtain 303 mg of a white solid.
  • the target compound was prepared according to the method described in Example 6, except that acetyl chloride (compound V-2) was used instead of oxalyl chloride monomethyl ester (compound V-1) to prepare the target compound I-9 as a white solid powder.
  • the target compound was prepared according to the method described in Example 6, except that propionyl chloride (compound V-3) was used instead of oxalyl chloride monomethyl ester (compound V-1) to prepare the target compound I-10 as a white solid powder.
  • the target compound was prepared according to the method described in Example 6, except that isobutyryl chloride (Compound V-4) was used instead of oxalyl chloride monomethyl ester (Compound V-1) to prepare the target compound I-21 as a white solid powder. .
  • the target compound was prepared according to the method described in Example 6, except that cyclopropylformyl chloride (Compound V-5) was used instead of oxalyl chloride monomethyl ester (Compound V-1) to prepare the target compound I-22, white Solid powder.
  • Step 1 Preparation of (S)-methyl 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4-4-trifluoro-3-hydroxybutyryl)-2-methylbenzoate
  • Step 2 (S,Z)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4-4-trifluoro-3-hydroxy-1-(hydroxyimino)butan Preparation of methyl)-2-methylbenzoate
  • Step 3 (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) -Preparation of 2-methylbenzoic acid methyl ester
  • Step 4 (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) -Preparation of 2-methylbenzoic acid
  • Step 5 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) Preparation of -N-(1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-17)
  • Step 2 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[(methoxy Synthesis of amino)methylene]-2-methylbenzamide (fluoroxazoleamide)
  • the compound to be tested was dissolved in acetone and diluted to the desired concentration with a 0.1 wt % Tween 80 aqueous solution, with the acetone content not exceeding 5 wt %.
  • Lethality rate % (number of inoculated insects - number of live insects after treatment) ⁇ number of inoculated insects ⁇ 100%.
  • compound I-1, compound I-3, compound I-9, compound I-10, compound I-13, compound I-14, compound I-15, compound I-16, compound I-17, Compound I-18, Compound I-21, Compound I-22, Compound I-23, and Compound I-25 each showed a lethality rate of more than 90% against Tetranychus cinnabarus at 3.125 ppm (3.125 mg/L).
  • the compound containing a five-membered heterocyclic ring of the present invention still has a high acaricidal effect on spider mites when used at a lower concentration, and the acaricidal effect is significantly better than that of the commercially available insecticide and acaricide fluorine.
  • Azoleamide Azoleamide.
  • Test target Spodoptera frugiperda, 3rd instar larvae, a sensitive strain reared indoors.
  • Test method First, select fresh corn leaves cultivated in the greenhouse and cut them into 5cm long leaf segments. The test is designed in order from low dose to high dose. Dip into the prepared medicinal solution for 10 seconds, dry naturally in the shade and place on filter paper. Into a petri dish with a diameter of 9cm, neatly healthy test worms were inserted, 10 for each treatment, and each treatment was repeated 3 times, and a blank control was set up.
  • Compound I-1, Compound I-10, Compound I-14, and Compound I-25 showed a lethality rate of more than 90% to Spodoptera Frugiperda at 1 ppm (1 mg/L).
  • the compound to be tested is dissolved in acetone and diluted to the desired concentration.
  • compound I-1, compound I-3, compound I-9, compound I-10, compound I-13, compound I-14, compound I-15, compound I-16, compound I-17, Compound I-18, Compound I-21, Compound I-22, Compound I-23, and Compound I-25 respectively showed a lethality rate of more than 90% to western flower thrips larvae at 3.125 ppm (3.125 mg/L).
  • compound I-1, compound I-25, compound I-10, compound (X.82) disclosed in CN106045962A and fluoxazoleamide were selected to conduct parallel experiments to kill western flower thrips larvae.
  • the test results are shown in Table 2 below.
  • Test target Diamondback moth (Plutella xylostella), 3rd instar larvae, a sensitive strain reared indoors.
  • Test method First, select fresh cabbage leaves cultivated in the greenhouse, use a hole punch to make the cabbage leaves into round leaves with a diameter of 3cm, and put them into the prepared medicinal solution in order from low dose to high dose according to the test design. 10 s, dry naturally in the shade, then place in a 9cm diameter petri dish with filter paper, and insert neat healthy test worms, 10 for each treatment, repeat 3 times for each treatment, and set up a blank control.
  • compound I-1, compound I-3, compound I-9, compound I-10, compound I-13, compound I-14, compound I-15, compound I-16, compound I-17, Compound I-18, Compound I-21, Compound I-22, Compound I-23, and Compound I-25 each showed a lethality rate of more than 90% to Diamondback moth at 1 ppm (1 mg/L).
  • leaf dipping method uses the leaf dipping method to take an appropriate amount of radish leaves and soak them for 10 seconds, then place them in a plastic petri dish lined with filter paper to dry naturally in the shade. Pick 10 2-year-old diamondback moths in each dish and place them in an observation room at 24°C and light (16/8h). . Observe after 72 hours. Touch the insect body lightly with a brush. If there is no reaction, it will be regarded as dead. Repeat three times and set up a blank control without adding any chemicals.
  • the lethality data of some of the same compounds tested against the resistant Diamondback moth in Application Example 6 were significantly higher than the lethality data tested against the sensitive Diamondback moth in Application Example 5. This is due to different experimental methods, different experimental conditions, and insect sources. It is caused by different reasons. For example, in Application Example 5, cabbage leaves are used to soak leaves, and in Application Example 6, radish leaves are used to soak leaves. The thickness of cabbage leaves is much larger than that of radish leaves. When insects eat the same weight of food, they ingest the cabbage leaves. The dose of the compound is significantly lower, so there will be certain differences in the lethality rate when tested by different methods.

Abstract

Disclosed are a compound containing a five-membered heterocycle, a preparation method therefor, an application thereof, an agricultural composition, and a method for preventing and controlling invertebrate pests. The present invention provides a compound containing a five-membered heterocycle having a structure represented by formula (I), or an agriculturally acceptable salt thereof, or a stereoisomer thereof. The compound containing a five-membered heterocycle and the agriculturally acceptable salt thereof provided by the present invention exhibit an excellent prevention and control effect against various pests, especially spider mites such as carmine spider mites, red spider mites, Kanzawa spider mites and citrus spider mites and lepidopteran insects such as the diamondback moths. The compound may be used for preventing and controlling various pests and pest mites, exhibits highly effective acaricidal and insecticidal activity, and has good application prospects.

Description

含五元杂环的化合物及其制备方法和应用Compounds containing five-membered heterocyclic rings and their preparation methods and applications
相关申请的交叉引用Cross-references to related applications
本申请要求2022年09月21日提交的中国专利申请202211151575.4和202211151392.2的权益，该申请的内容通过引用被合并于本文。This application claims the rights and interests of Chinese patent applications 202211151575.4 and 202211151392.2 submitted on September 21, 2022, the contents of which are incorporated herein by reference.
技术领域Technical field
本发明涉及农药技术领域，具体涉及含五元杂环化合物及其制备方法和应用、农业用组合物以及防治无脊椎动物害虫的方法。The present invention relates to the technical field of pesticides, specifically to five-membered heterocyclic compounds and their preparation methods and applications, agricultural compositions and methods for preventing and controlling invertebrate pests.
背景技术Background technique
害虫害螨危害数百种植物，尤其是蔬菜、花卉和果树，造成严重的经济损失。含杂环化合物的芳基异噁唑类衍生物在现代农作物和动物保护方面具有独特的杀虫活性，如日产化学开发上市的首个异噁唑啉类杀虫剂氟噁唑酰胺。
Pest mites damage hundreds of plants, especially vegetables, flowers and fruit trees, causing serious economic losses. Arylisoxazole derivatives containing heterocyclic compounds have unique insecticidal activity in modern crop and animal protection, such as fluoxazoleamide, the first isoxazoline insecticide developed and launched by Nissan Chemical.
杂环化合物是农药合成和研发过程中的重要中间体或化学实体，具有独特的化学结构和生物活性，其衍生物很多被开发为农化产品。Heterocyclic compounds are important intermediates or chemical entities in the process of pesticide synthesis and research and development. They have unique chemical structures and biological activities, and many of their derivatives have been developed as agrochemical products.
CN106045962A公开了如下结构所示的化合物(X.82)在200ppm(200mg/L)浓度下对斜纹夜蛾、烟夜蛾、小菜蛾、黄瓜条叶甲、烟蓟马、二斑叶螨、桃蚜、英雄美洲椿、稻褐飞虱等害虫具有80％以上的致死活性，然而其在更低浓度下对农业害虫的活性未见报道。
CN106045962A discloses that the compound (X.82) represented by the following structure is effective against Spodoptera litura, Spodoptera exigua, Diamondback moth, cucumber leaf beetle, thrips, two-spotted spider mite, peach at a concentration of 200ppm (200mg/L). It has a lethal activity of more than 80% against aphids, American stink bug, brown planthopper and other pests. However, its activity against agricultural pests at lower concentrations has not been reported.
氯虫苯甲酰胺为杜邦公司开发的双酰胺类杀虫剂，是目前为止开发最成功、销售额最大的杀虫剂，特别是对小菜蛾等鳞翅目害虫具有很高的防治效果。然而由于田间连续多年使用，氯虫苯甲酰胺对小菜蛾等害虫的抗性已经非常严重，药效显著下降，市场上急需对抗性小菜蛾等鳞翅目害虫防治效果好的杀虫剂。
Chlorantraniliprole is a bisamide insecticide developed by DuPont. It is the most successfully developed insecticide with the largest sales so far. It has a high control effect on lepidopteran pests such as diamondback moth. However, due to continuous use in the field for many years, the resistance of chlorantraniliprole to pests such as diamondback moth has become very serious, and its efficacy has decreased significantly. The market is in urgent need of insecticides with good control effect against lepidopteran pests such as diamondback moth.
目前公开的化合物杀虫杀螨效果仍然不能令人满意，并且害虫害螨的抗性发展速度很快，农业生产上仍然需要更加高效的新型化合物来应对日益增加的害虫害螨抗性发展。The insecticidal and acaricidal effects of the currently disclosed compounds are still unsatisfactory, and resistance to pests and mites is developing rapidly. Agricultural production still requires new and more efficient compounds to cope with the increasing development of resistance to pests and mites.
发明内容Contents of the invention
本发明的目的是为了克服现有技术存在的现有化合物在无脊椎动物害虫(特别是螨虫、小菜蛾)防治中具有较低的杀灭活性的技术问题，提供一种更加高效的含五元杂环化合物及其制备方法和应用、农业用组合物以及防治无脊椎动物害虫的方法。本发明提供的含五元杂环的化合物具有高效的杀螨和杀虫活性，特别是对朱砂叶螨、小菜蛾等表现出了很高的防治效果。The purpose of the present invention is to overcome the technical problem in the prior art that existing compounds have low killing activity in the control of invertebrate pests (especially mites and diamondback moths), and to provide a more efficient five-element compound containing Heterocyclic compounds, methods for their preparation and uses, agricultural compositions and methods for controlling invertebrate pests. The five-membered heterocycle-containing compound provided by the invention has efficient acaricidal and insecticidal activities, and especially shows a high control effect against spider mites, diamondback moths, etc.
为了实现上述目的，本发明第一方面提供一种具有式(I)所示结构的含五元杂环的化合物或其农业上可接受的盐，或其立体异构体，
In order to achieve the above object, the first aspect of the present invention provides a five-membered heterocyclic compound having a structure represented by formula (I) or an agriculturally acceptable salt thereof, or a stereoisomer thereof,
式(I)中，In formula (I),
X1和X3各自独立地为F、Cl、Br、I或CF3；X 1 and X 3 are each independently F, Cl, Br, I or CF 3 ;
X2为H、F、Cl、Br、I或CF3； X2 is H, F, Cl, Br, I or CF3 ;
R1选自氢、取代或未被取代的C1-C6烷基、C1-C4烷氧基C1-C4烷基、C1-C10烷基羰基、卤代C1-C10烷基羰基、C3-C10环烷基羰基、C3-C10环烷基甲基羰基、C1-C10烷氧基羰基、卤代C1-C10烷氧基羰基、C1-C10烷氧基C1-C4烷基羰基、卤代C1-C10烷氧基C1-C4烷基羰基、C1-C10烷基草酰基、卤代C1-C10烷基草酰基、C1-C10烷氧基草酰基、卤代C1-C10烷氧基草酰基、C1-C10烷基磺酰基、卤代C1-C10烷基磺酰基、C1-C10烷基亚磺酰基、卤代C1-C10烷基亚磺酰基、取代或未取代的苯甲酰基、取代或未取代的苯磺酰基、取代或未取代的杂芳基羰基、取代或未被取代的C1-C6烷基或C1-C4烷氧基C1-C4烷基；R 1 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 10 alkylcarbonyl, halo C 1 - C 10 alkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 cycloalkylmethylcarbonyl, C 1 -C 10 alkoxycarbonyl, halogenated C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkoxy C 1 -C 4 alkylcarbonyl, halo C 1 -C 10 alkoxy C 1 -C 4 alkyl carbonyl, C 1 -C 10 alkyl oxalyl, halo C 1 -C 10 alkyl oxalyl, C 1 -C 10 alkoxy oxalyl, halogenated C 1 -C 10 alkoxy oxalyl, C 1 -C 10 alkyl sulfonyl, halogenated C 1 -C 10 alkyl Sulfonyl group, C 1 -C 10 alkylsulfinyl group, halogenated C 1 -C 10 alkylsulfinyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted benzenesulfonyl group, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 4 alkyl;
n选自0、1或2。n is selected from 0, 1 or 2.
本发明第二方面提供一种含五元杂环的化合物的制备方法，该制备方法包括：A second aspect of the present invention provides a method for preparing a compound containing a five-membered heterocyclic ring. The preparation method includes:
(1)在第一溶剂中，在缩合剂存在下，将化合物II和化合物III进行第一反应，得到化合物IV；(1) In the first solvent, in the presence of a condensing agent, the compound II and the compound III are subjected to the first reaction to obtain the compound IV;
(2)在第二溶剂中，在碱性物质存在下，将所述化合物IV和化合物V进行第二反应，得到化合物I；(2) In the second solvent, in the presence of a basic substance, the compound IV and the compound V are subjected to a second reaction to obtain the compound I;
其中，所述化合物II具有式(II)所示的结构，所述化合物III具有式(III)所示的结构，所述化合物IV具有式(IV)所示的结构，所述化合物V具有式(V)所示的结构，所述化合物I具有式(I)所示的结构，
Wherein, the compound II has the structure represented by formula (II), the compound III has the structure represented by formula (III), the compound IV has the structure represented by formula (IV), and the compound V has the formula The structure represented by (V), the compound I has the structure represented by formula (I),
式(I)、式(II)、式(III)、式(IV)和式(V)中，In formula (I), formula (II), formula (III), formula (IV) and formula (V),
X1、X2和X3各自独立地选自F、Cl、Br、I或CF3；X 1 , X 2 and X 3 are each independently selected from F, Cl, Br, I or CF 3 ;
R1选自氢、取代或未被取代的C1-C6烷基、C1-C4烷氧基C1-C4烷基、C1-C10烷基羰基、卤代C1-C10烷基羰基、C3-C10环烷基羰基、C3-C10环烷基甲基羰基、C1-C10烷氧基羰基、卤代C1-C10烷氧基羰基、C1-C10烷氧基C1-C4烷基羰基、卤代C1-C10烷氧基C1-C4烷基羰基、C1-C10烷基草酰基、卤代C1-C10烷基草酰基、C1-C10烷氧基草酰基、卤代C1-C10烷氧基草酰基、C1-C10烷基磺酰基、卤代C1-C10烷基磺酰基、C1-C10烷基亚磺酰基、卤代C1-C10烷基亚磺酰基、取代或未取代的苯甲酰基、取代或未取代的苯磺酰基、取代或未取代的杂芳基羰基、取代或未被取代的C1-C6烷基或C1-C4烷氧基C1-C4烷基；R 1 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 10 alkylcarbonyl, halo C 1 - C 10 alkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 cycloalkylmethylcarbonyl, C 1 -C 10 alkoxycarbonyl, halogenated C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkoxy C 1 -C 4 alkylcarbonyl, halo C 1 -C 10 alkoxy C 1 -C 4 alkyl carbonyl, C 1 -C 10 alkyl oxalyl, halo C 1 -C 10 alkyl oxalyl, C 1 -C 10 alkoxy oxalyl, halogenated C 1 -C 10 alkoxy oxalyl, C 1 -C 10 alkyl sulfonyl, halogenated C 1 -C 10 alkyl Sulfonyl group, C 1 -C 10 alkylsulfinyl group, halogenated C 1 -C 10 alkylsulfinyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted benzenesulfonyl group, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 4 alkyl;
L选自氟、氯、溴、碘、甲磺酰基、三氟甲磺酰基、苯磺酰基或对甲苯磺酰基。L is selected from fluorine, chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl or p-toluenesulfonyl.
本发明第三方面提供一种前述的化合物或前述的制备方法制得的化合物在防治无脊椎动物害虫中的应用。 The third aspect of the present invention provides the use of the aforementioned compound or the compound prepared by the aforementioned preparation method in preventing and controlling invertebrate pests.
本发明第四方面提供一种农业用组合物，所述组合物包含至少一种前述的化合物或前述的制备方法制得的化合物以及至少一种液体载体或固体载体。The fourth aspect of the present invention provides an agricultural composition, which composition contains at least one of the aforementioned compounds or compounds prepared by the aforementioned preparation method and at least one liquid carrier or solid carrier.
本发明第五方面提供一种防治无脊椎动物害虫的方法，所述方法包括：将杀虫有效量的至少一种前述的化合物或前述的制备方法制得的化合物直接或间接施于需要控制的无脊椎动物害虫和/或其生长的介质上。The fifth aspect of the present invention provides a method for preventing and controlling invertebrate pests, which method includes: directly or indirectly applying a pesticidally effective amount of at least one of the aforementioned compounds or compounds prepared by the aforementioned preparation method to the pests that need to be controlled. Invertebrate pests and/or the medium in which they grow.
通过上述技术方案，本发明所取得的有益技术效果如下：Through the above technical solutions, the beneficial technical effects achieved by the present invention are as follows:
(1)本发明提供的含五元杂环的化合物及其农业上可接受的盐对多种有害生物、特别是对以朱砂叶螨、二斑叶螨、神泽氏叶螨、柑桔全爪叶螨等为代表的叶螨类、小菜蛾为代表的鳞翅目昆虫、蓟马和跳甲等表现出了很高的防治效果，可用于防治多种害虫和害螨，具有高效的杀螨和杀虫活性，具有良好的应用前景。(1) The five-membered heterocycle-containing compounds and their agriculturally acceptable salts provided by the present invention are effective against a variety of harmful organisms, especially against spider mites, spider mites, Tetranychus kanzawa, and citrus alleles Spider mites represented by Tetranychus claw, lepidopterans represented by diamondback moth, thrips and flea beetles have shown high control effects and can be used to control a variety of pests and mites, with high efficiency. It has mite and insecticidal activity and has good application prospects.
(2)本发明提供的含五元杂环的化合物对下述无脊椎动物害虫具有高活性(下述所列对象仅用来说明本发明，但非用来限定本发明)：叶螨科(如朱砂叶螨、柑橘全爪螨、二斑叶螨、苹果全爪螨、神泽叶螨、山楂叶螨)、瘿螨科、走螨科、细须螨科、蚜科(如桃蚜)、鳞翅目昆虫(如小菜蛾、甜菜夜蛾、二化螟等)、缨翅目昆虫(如西花蓟马等)和鞘翅目昆虫(如黄曲条跳甲)等。因此，本发明的含五元杂环的化合物可以应用在农业或者其他领域中用作制备杀虫杀螨剂药物。(2) The five-membered heterocyclic compound provided by the present invention has high activity against the following invertebrate pests (the following objects are only used to illustrate the present invention, but not to limit the present invention): Tetranychus cinnabarinus (such as Tetranychus cinnabarinus, Panonychus citri, Tetranychus urticae, Panonychus malus, Tetranychus kanzawa, Tetranychus villosa), Acaridae, Acaridae, Aphididae (such as Myzus persicae), Lepidoptera (such as Plutella xylostella, Spodoptera exigua, Chilo suppressalis, etc.), Thysanoptera (such as Western Flower Thrips, etc.) and Coleoptera (such as Yellow Striped Flea Beetle), etc. Therefore, the five-membered heterocyclic compound of the present invention can be used in agriculture or other fields to prepare insecticides and acaricides.
具体实施方式Detailed ways
本发明第一方面提供一种具有式(I)所示结构的含五元杂环的化合物或其农业上可接受的盐，或其立体异构体，
The first aspect of the present invention provides a five-membered heterocyclic compound having a structure represented by formula (I) or an agriculturally acceptable salt thereof, or a stereoisomer thereof,
式(I)中，In formula (I),
X1和X3各自独立地为F、Cl、Br、I或CF3；X 1 and X 3 are each independently F, Cl, Br, I or CF 3 ;
X2为H、F、Cl、Br、I或CF3；X 2 is H, F, Cl, Br, I or CF 3 ;
R1选自氢、取代或未被取代的C1-C6烷基、C1-C4烷氧基C1-C4烷基、C1-C10烷基羰基、卤代C1-C10烷基羰基、C3-C10环烷基羰基、C3-C10环烷基甲基羰基、C1-C10烷氧基羰基、卤代C1-C10烷氧基羰基、C1-C10烷氧基C1-C4烷基羰基、卤代C1-C10烷氧基C1-C4烷基羰基、C1-C10烷基草酰基、卤代C1-C10烷基草酰基、C1-C10烷氧基草酰基、卤代C1-C10烷氧基草酰基、C1-C10烷基磺酰基、卤代C1-C10烷基磺酰基、C1-C10烷基亚磺酰基、卤代C1-C10烷基亚磺酰基、取代或未取代的苯甲酰基、取代或未取代的苯磺酰基、取代或未取代的杂芳基羰基、取代或未被取代的C1-C6烷基或C1-C4烷氧基C1-C4烷基。 R1 is selected from hydrogen, substituted or unsubstituted C1 - C6 alkyl, C1 - C4 alkoxy C1- C4 alkyl, C1 - C10 alkylcarbonyl, halogenated C1 -C10 alkylcarbonyl, C3 - C10 cycloalkylcarbonyl, C3-C10 cycloalkylmethylcarbonyl, C1- C10 alkoxycarbonyl, halogenated C1- C10 alkoxycarbonyl, C1- C10 alkoxy C1 -C4 alkylcarbonyl, halogenated C1 - C10 alkoxy C1- C4 alkylcarbonyl, C1 - C10 alkyloxalyl, halogenated C1 - C10 alkyloxalyl, C1 - C10 alkoxyoxalyl, halogenated C1 - C10 alkoxyoxalyl, C1-C10 alkylsulfonyl, halogenated C1 - C10 alkylsulfonyl, C3 - C10 cycloalkylmethylcarbonyl, C1 - C10 alkoxycarbonyl, halogenated C1-C10 alkoxycarbonyl, C1 -C10 alkoxy C1 - C4 alkylcarbonyl, halogenated C1 - C10 alkoxy C1-C4 alkylcarbonyl, 1 -C 10 alkylsulfinyl, halogenated C 1 -C 10 alkylsulfinyl, substituted or unsubstituted benzoyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 4 alkyl.
依据本发明，在一些优选实施方式中，X2为H时，X1和X3不同时为Cl。更优选地，X2为H时，X3为CF3。According to the present invention, in some preferred embodiments, when X 2 is H, X 1 and X 3 are not Cl at the same time. More preferably, when X 2 is H, X 3 is CF 3 .
在一些实施方式中，X1、X2和X3各自独立地选自F、Cl、Br或CF3。In some embodiments, each of X 1 , X 2 and X 3 is independently selected from F, Cl, Br or CF 3 .
在一些实施方式中，R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、三氟甲基、三氯甲基、三氟乙基或三氟甲氧基甲基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C3-C6环烷基羰基、C3-C6环烷基甲基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、C1-C4烷氧基C1-C2烷基羰基、卤代C1-C4烷氧基C1-C2烷基羰基、C1-C6烷基草酰基、卤代C1-C6烷基草酰基、C1-C4烷氧基草酰基、卤代C1-C4烷氧基草酰基、C1-C4烷基磺酰基、卤代C1-C4烷基磺酰基、C1-C4烷基亚磺酰基、卤代C1-C4烷基亚磺酰基、卤素取代或未取代的苯甲酰基、卤素取代或未取代的苯磺酰基、含有1-2个选自O、S或N的杂原子取代的五元或六元芳杂环取代的羰基。In some embodiments, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxy Ethyl, ethoxymethyl, ethoxyethyl, trifluoromethyl, trichloromethyl, trifluoroethyl or trifluoromethoxymethyl, C 1 -C 6 alkylcarbonyl, halo C 1 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, C 3 -C 6 cycloalkylmethylcarbonyl, C 1 -C 6 alkoxycarbonyl, halogenated C 1 -C 6 alkoxy Carbonyl, C 1 -C 4 alkoxy C 1 - C 2 alkyl carbonyl, halo C 1 - C 4 alkoxy C 1 - C 2 alkyl carbonyl, C 1 - C 6 alkyl oxalyl, halo Substituted C 1 -C 6 alkyl oxalyl, C 1 -C 4 alkoxy oxalyl, halogenated C 1 -C 4 alkoxy oxalyl, C 1 -C 4 alkyl sulfonyl, halogenated C 1 - C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, halogenated C 1 -C 4 alkylsulfinyl, halogen substituted or unsubstituted benzoyl, halogen substituted or unsubstituted benzenesulfonyl , a five- or six-membered aromatic heterocyclic substituted carbonyl group containing 1-2 heteroatoms selected from O, S or N.
在一些实施方式中，X1、X2和X3各自独立地选自F、Cl或CF3。In some embodiments, X 1 , X 2 , and X 3 are each independently selected from F, Cl, or CF 3 .
在一些优选实施方式中，X2选自F或Cl，X1和X3选自各自独立地选自Cl或CF3。In some preferred embodiments, X 2 is selected from F or Cl, and X 1 and X 3 are each independently selected from Cl or CF 3 .
在一些实施方式中，R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、乙酰基、丙酰基、正丁酰基、环丙基甲酰基、甲氧基甲酰基、甲氧基乙酰基、甲氧基乙酰基、甲氧基草酰基、乙氧基草酰基。In some embodiments, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxy Ethyl, ethoxymethyl, ethoxyethyl, acetyl, propionyl, n-butyryl, cyclopropylformyl, methoxyformyl, methoxyacetyl, methoxyacetyl, Methoxyoxalyl, ethoxyoxalyl.
在一些实施方式中，所述化合物选自如下结构所示的化合物中的至少一种，或其农业上可接受的盐，或其立体异构体：


In some embodiments, the compound is selected from at least one of the compounds represented by the following structure, or an agriculturally acceptable salt thereof, or a stereoisomer thereof:


其中，化合物I-13、I-14、I-15、I-16、I-17、I-18、I-19、I-20为化合物I-1的立体异构体；化合物I-27、I-29、I-30为化合物I-25的立体异构体，化合物I-28为化合物I-26的立体异构体。Among them, compounds I-13, I-14, I-15, I-16, I-17, I-18, I-19, and I-20 are stereoisomers of compound I-1; compounds I-27, I-29 and I-30 are stereoisomers of compound I-25, and compound I-28 is a stereoisomer of compound I-26.
本发明中，所述含五元杂环的化合物存在由具有1个或2个以上的不对称碳原子而引起的光学异构体的情况，本发明包括所有的光学异构体、外消旋体或非对映体。In the present invention, the compound containing a five-membered heterocyclic ring may have optical isomers caused by having one or more asymmetric carbon atoms. The present invention includes all optical isomers and racemic isomers. isomers or diastereomers.
本发明中，所述含五元杂环的化合物还包含其衍生物，但是本发明衍生物所包括的化合物绝非仅限定于这些化合物。In the present invention, the five-membered heterocycle-containing compound also includes its derivatives, but the compounds included in the derivatives of the present invention are by no means limited to these compounds.
本发明中，所谓农业上可接受的盐，是指含五元杂环的化合物与无机酸或有机酸形成的盐。作为无机酸，例如盐酸、硫酸、氢溴酸等，作为有机酸，例如甲酸、乙酸、甲磺酸、富马酸、马来酸等。In the present invention, agriculturally acceptable salts refer to salts formed from compounds containing five-membered heterocyclic rings and inorganic acids or organic acids. Examples of inorganic acids include hydrochloric acid, sulfuric acid, hydrobromic acid, etc. Examples of organic acids include formic acid, acetic acid, methanesulfonic acid, fumaric acid, maleic acid, and the like.
本发明第二方面提供一种含五元杂环的化合物的制备方法，该制备方法包括：A second aspect of the present invention provides a method for preparing a compound containing a five-membered heterocyclic ring. The preparation method includes:
(1)在第一溶剂中，在缩合剂存在下，将化合物II和化合物III进行第一反应，得到化合物IV；(1) In the first solvent, in the presence of a condensing agent, the compound II and the compound III are subjected to the first reaction to obtain the compound IV;
(2)在第二溶剂中，在碱性物质存在下，将所述化合物IV和化合物V进行第二反应，得到化合物I；(2) In the second solvent, in the presence of a basic substance, the compound IV and the compound V are subjected to a second reaction to obtain the compound I;
其中，所述化合物II具有式(II)所示的结构，所述化合物III具有式(III)所示的结构，所述化合物IV具有式(IV)所示的结构，所述化合物V具有式(V)所示的结构，所述化合物I具有式(I)所示的结构，

Wherein, the compound II has the structure represented by formula (II), the compound III has the structure represented by formula (III), the compound IV has the structure represented by formula (IV), and the compound V has the formula The structure represented by (V), the compound I has the structure represented by formula (I),

式(I)、式(II)、式(III)、式(IV)和式(V)中，In formula (I), formula (II), formula (III), formula (IV) and formula (V),
X1、X2和X3各自独立地选自F、Cl、Br、I或CF3；X 1 , X 2 and X 3 are each independently selected from F, Cl, Br, I or CF 3 ;
R1选自氢、取代或未被取代的C1-C6烷基、C1-C4烷氧基C1-C4烷基、C1-C10烷基羰基、卤代C1-C10烷基羰基、C3-C10环烷基羰基、C3-C10环烷基甲基羰基、C1-C10烷氧基羰基、卤代C1-C10烷氧基羰基、C1-C10烷氧基C1-C4烷基羰基、卤代C1-C10烷氧基C1-C4烷基羰基、C1-C10烷基草酰基、卤代C1-C10烷基草酰基、C1-C10烷氧基草酰基、卤代C1-C10烷氧基草酰基、C1-C10烷基磺酰基、卤代C1-C10烷基磺酰基、C1-C10烷基亚磺酰基、卤代C1-C10烷基亚磺酰基、取代或未取代的苯甲酰基、取代或未取代的苯磺酰基、取代或未取代的杂芳基羰基、取代或未被取代的C1-C6烷基或C1-C4烷氧基C1-C4烷基；R 1 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 10 alkylcarbonyl, halo C 1 - C 10 alkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 cycloalkylmethylcarbonyl, C 1 -C 10 alkoxycarbonyl, halogenated C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkoxy C 1 -C 4 alkylcarbonyl, halo C 1 -C 10 alkoxy C 1 -C 4 alkyl carbonyl, C 1 -C 10 alkyl oxalyl, halo C 1 -C 10 alkyl oxalyl, C 1 -C 10 alkoxy oxalyl, halogenated C 1 -C 10 alkoxy oxalyl, C 1 -C 10 alkyl sulfonyl, halogenated C 1 -C 10 alkyl Sulfonyl group, C 1 -C 10 alkylsulfinyl group, halogenated C 1 -C 10 alkylsulfinyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted benzenesulfonyl group, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 4 alkyl;
L选自氟、氯、溴、碘、甲磺酰基、三氟甲磺酰基、苯磺酰基或对甲苯磺酰基。L is selected from fluorine, chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.
本发明中，X1、X2、X3和R1的选择与前述化合物相同，在此不再赘述。In the present invention, the selection of X 1 , X 2 , X 3 and R 1 is the same as that of the aforementioned compounds, and will not be described again.
在一些实施方式中，所述缩合剂选自二环己基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、氯化亚砜或草酰氯中的一种或多种。In some embodiments, the condensing agent is selected from dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-nitrogen One or more of heterobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, thionyl chloride or oxalyl chloride.
在一些实施方式中，所述第一溶剂和所述第二溶剂各自独立地选自甲苯、二甲苯、二氯甲烷、二氯乙烷、乙腈、N,N-二甲基甲酰胺(DMF)、四氢呋喃和丙酮中的一种或多种。In some embodiments, the first solvent and the second solvent are each independently selected from toluene, xylene, dichloromethane, dichloroethane, acetonitrile, N,N-dimethylformamide (DMF) , one or more of tetrahydrofuran and acetone.
在一些实施方式中，所述碱性物质选自三乙胺、二异丙基乙基胺、吡啶、N-甲基吗啉、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、氢化钠和氨基钠中的一种或多种。In some embodiments, the alkaline substance is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and hydrogen carbonate. One or more of sodium, potassium bicarbonate, sodium hydride and sodium amide.
在一些实施方式中，所述化合物II与化合物III的摩尔比为1:0.8-1.5。In some embodiments, the molar ratio of compound II to compound III is 1:0.8-1.5.
在一些实施方式中，所述化合物IV与化合物V的摩尔比为1:0.7-1.5。In some embodiments, the molar ratio of compound IV to compound V is 1:0.7-1.5.
在一些实施方式中，所述化合物II与所述缩合剂的摩尔比为1:0.8-1.5。In some embodiments, the molar ratio of the compound II to the condensing agent is 1:0.8-1.5.
在一些实施方式中，所述化合物IV与所述碱性物质的摩尔比为1:0.7-1.5。In some embodiments, the molar ratio of the compound IV to the basic substance is 1:0.7-1.5.
在一些实施方式中，所述第一反应的温度为-10℃至所述第一溶剂的沸点，所述反应的时间为10min-48h。In some embodiments, the temperature of the first reaction ranges from -10°C to the boiling point of the first solvent, and the reaction time ranges from 10 min to 48 h.
在一些优选实施方式中，所述第一反应的温度为-10℃至210℃，优选为0℃至150℃，更优选为10-100℃；时间为0.5-24h，优选为1-12h，更优选为2-6h。In some preferred embodiments, the temperature of the first reaction is -10°C to 210°C, preferably 0°C to 150°C, more preferably 10-100°C; the time is 0.5-24h, preferably 1-12h, More preferably, it is 2-6h.
在一些实施方式中，所述第二反应的温度为-10℃至所述第二溶剂的沸点，所述反应的时间为10min-48h。In some embodiments, the temperature of the second reaction is from -10°C to the boiling point of the second solvent, and the reaction time is from 10 min to 48 h.
在一些优选实施方式中，所述第二反应的温度为-10℃至210℃，优选为0℃至150℃，更优选为10-100℃；时间为0.5-24h，优选为1-12h，更优选为2-6h。In some preferred embodiments, the temperature of the second reaction is -10°C to 210°C, preferably 0°C to 150°C, more preferably 10-100°C; the time is 0.5-24h, preferably 1-12h, More preferably, it is 2-6h.
本发明的发明人发现，式(I)所示的化合物具有意想不到的高杀螨活性，因此，本发明的化合物还可以应用在农业或者其他领域中用作制备杀螨剂药物。尤其是，经研究发现，式(I)所示的化合物对下述无脊椎动物害虫具有高活性(下述所列对象仅用来说明本发明，但非用来限定本发明)：叶螨科(如朱砂叶螨、柑橘全爪螨、二斑叶螨、苹果全爪螨、神泽叶螨、山楂叶螨)、瘿螨科、走螨科、细须螨科、蚜科(如桃蚜)、鳞翅目昆虫(如小菜蛾、甜菜夜蛾、二化螟等)等。因此，本发明的化合物还可以应用在农业或者其他领域中用作制备杀螨剂药物。The inventors of the present invention have found that the compound represented by formula (I) has unexpectedly high acaricidal activity. Therefore, the compound of the present invention can also be used in agriculture or other fields to prepare acaricide drugs. In particular, it has been found that the compound represented by formula (I) has high activity against the following invertebrate pests (the following objects are only used to illustrate the present invention, but not to limit the present invention): Tetranychus (such as Tetranychus cinnabarinus, Panonychus citri, Tetranychus urticae, Panonychus apple, Tetranychus kanzawa, Tetranychus villosa), Acaridae, Acaridae, Aphididae (such as Myzus persicae), Lepidoptera (such as Plutella xylostella, Spodoptera exigua, Chilo suppressalis, etc.). Therefore, the compound of the present invention can also be used in agriculture or other fields to prepare acaricide drugs.
本发明第三方面提供一种前述的化合物或前述的制备方法制得的化合物在防治无脊椎动物害虫中的应用。The third aspect of the present invention provides the use of the aforementioned compound or the compound prepared by the aforementioned preparation method in preventing and controlling invertebrate pests.
在一些实施方式中，所述无脊椎动物害虫为螨科害虫、昆虫和/或线虫。In some embodiments, the invertebrate pest is an acarid pest, an insect, and/or a nematode.
本发明中，优选地，所述化合物可以用于保护农业和园艺业中重要的作物、家畜等不受或少受害螨的伤害。In the present invention, preferably, the compound can be used to protect important crops, livestock, etc. in agriculture and horticulture from being harmed by or less susceptible to mites.
本发明中，为获得理想效果，在一些应用中，所述化合物的用量因各种因素而改变，例如所用化合物、预保护的作物、有害生物的类型、感染程度、施药方法、施药环境、施用剂型等因素。In the present invention, in order to obtain the desired effect, in some applications, the dosage of the compound varies depending on various factors, such as the compound used, the crop to be pre-protected, the type of pest, the degree of infection, the application method, and the application environment. , dosage form and other factors.
本发明中，优选地，对于某些应用，例如在农业上可在本发明的杀螨组合物中加入一种或多种其他的杀虫剂、杀螨剂、杀菌剂、除草剂、植物生长调节剂或肥料等，由此可产生附加的优点和效果。In the present invention, preferably, for certain applications, such as in agriculture, one or more other insecticides, acaricides, fungicides, herbicides, plant growth agents, etc. can be added to the acaricidal composition of the present invention. Conditioners or fertilizers, etc., which can produce additional advantages and effects.
本发明第四方面提供一种农业用组合物，所述组合物包含至少一种前述的化合物或前述的制备方法制得的化合物以及至少一种液体载体或固体载体。The fourth aspect of the present invention provides an agricultural composition, which composition contains at least one of the aforementioned compounds or compounds prepared by the aforementioned preparation method and at least one liquid carrier or solid carrier.
本发明对所述液体载体或固体载体没有特别的限定，只要能够满足本发明的需求即可。所述组合物中，优选地，所述含五元杂环的化合物的浓度为0.5-35mg/L。在一些实施方式中，所述含五元杂环的化合物的浓度为1-30mg/L，在另一些实施方式中，所述含五元杂环的化合物的浓度为10-25mg/L。The present invention has no particular limitation on the liquid carrier or solid carrier, as long as it can meet the requirements of the present invention. In the composition, preferably, the concentration of the compound containing a five-membered heterocyclic ring is 0.5-35 mg/L. In some embodiments, the concentration of the compound containing a five-membered heterocyclic ring is 1-30 mg/L, and in other embodiments, the concentration of the compound containing a five-membered heterocyclic ring is 10-25 mg/L.
本发明中，液体载体可以为水、各种芳烃、脂肪烃、酮类、醚类等，如甲苯、二甲苯、丙酮、环已酮、二甲苯、苯、环己烷、异丙醇、乙二醇、山梨醇、甲醇、乙醇、丁醇、二甲基甲酰胺、N-甲基吡咯烷酮、萘烷、机油、 石油醚、环己酮、油酸甲酯、甲基化大豆油等中的一种或几种；固体载体可以包括天然的或合成的粘土和硅酸盐，适用于粉剂的固体载体可以包括天然形成的岩石粉末、白垩、石英、粘土、蒙脱土、白炭黑、硅藻土、浮石、石膏、滑石、膨润土、高岭土、陶土及合成的磨碎的矿物质(如微分散的硅酸或氧化铝)。适合的颗粒载体可以包括破碎的和分级的天然岩石例如方解石、大理石、浮石、海泡石和白云石及由有机物和无机物的粉末制成的合成颗粒。In the present invention, the liquid carrier can be water, various aromatic hydrocarbons, aliphatic hydrocarbons, ketones, ethers, etc., such as toluene, xylene, acetone, cyclohexanone, xylene, benzene, cyclohexane, isopropanol, ethylene glycol, sorbitol, methanol, ethanol, butanol, dimethylformamide, N-methylpyrrolidone, decalin, engine oil, One or more of petroleum ether, cyclohexanone, methyl oleate, methylated soybean oil, etc.; solid carriers can include natural or synthetic clays and silicates, and solid carriers suitable for powders can include naturally formed rock powders, chalk, quartz, clay, montmorillonite, white carbon black, diatomaceous earth, pumice, gypsum, talc, bentonite, kaolin, clay and synthetic ground minerals (such as micro-dispersed silicic acid or aluminum oxide). Suitable particle carriers can include broken and graded natural rocks such as calcite, marble, pumice, sepiolite and dolomite and synthetic particles made of organic and inorganic powders.
本发明中，优选地，所述组合物可以以制剂的形式施用。其中，权利要求1中所述的化合物作为活性组分溶解或分散于载体中，或配置成制剂以便进行杀虫、杀螨使用时更易于分散。例如：所述组合物可以被制成可湿性粉剂、水分散粒剂、悬浮剂、水乳剂、水剂或乳油等。在所述组合物中，至少加入一种液体或固体载体，并且当需要时还可以加入适当的表面活性剂。其中，表面活性剂可以包括十二烷基苯磺酸盐、脂肪醇硫酸盐、吐温、农乳、山梨醇聚氧乙烯醚、脂肪醇聚氧乙烯醚、木质素磺酸盐、烷基萘磺酸盐等。In the present invention, preferably, the composition can be administered in the form of a preparation. Wherein, the compound described in claim 1 is dissolved or dispersed in a carrier as an active component, or is formulated into a preparation so that it is easier to disperse when used for insecticide and acaricide. For example: the composition can be made into wettable powder, water-dispersible granule, suspension, water emulsion, water or emulsifiable concentrate, etc. In the composition, at least one liquid or solid carrier is added, and when necessary, a suitable surfactant is also added. Among them, surfactants may include dodecyl benzene sulfonate, fatty alcohol sulfate, Tween, agricultural milk, sorbitol polyoxyethylene ether, fatty alcohol polyoxyethylene ether, lignin sulfonate, alkyl naphthalene Sulfonate etc.
本发明第五方面提供一种防治无脊椎动物害虫的方法，所述方法包括：将杀虫有效量的至少一种前述的化合物或前述的制备方法制得的化合物直接或间接施于需要控制的无脊椎动物害虫和/或其生长的介质上。The fifth aspect of the present invention provides a method for preventing and controlling invertebrate pests, which method includes: directly or indirectly applying a pesticidally effective amount of at least one of the aforementioned compounds or compounds prepared by the aforementioned preparation method to the pests that need to be controlled. Invertebrate pests and/or the medium in which they grow.
本发明对于直接或间接的方式没有特别的限定，只要能够达到防治无脊椎动物害虫的目的即可，例如直接的方式可以包括直接将含有所述含五元杂环的化合物的成分的物质与无脊椎动物害虫接触(包括无脊椎动物害虫直接食用含有所述含五元杂环的化合物的成分的物质、无脊椎动物害虫身体表面与含有所述含五元杂环的化合物的成分的物质直接接触等)；间接的方式可以包括将含有所述含五元杂环的化合物的成分的物质处理无脊椎动物害虫出没的场所(其栖息地或其繁殖地或无脊椎动物害虫生长的植物、土壤)或者将含有所述含五元杂环的化合物的成分的物质处理其食物链。The present invention is not particularly limited to direct or indirect methods, as long as the purpose of preventing and controlling invertebrate pests can be achieved. For example, the direct method may include directly combining a substance containing the component of the five-membered heterocycle-containing compound with an invertebrate pest. Contact with vertebrate pests (including invertebrate pests directly eating substances containing the components of the five-membered heterocyclic compound, direct contact between the body surface of invertebrate pests and substances containing the components of the five-membered heterocyclic compound) etc.); indirect methods may include treating places where invertebrate pests are infested (its habitat or breeding ground or plants and soil where invertebrate pests grow) with substances containing the components of the five-membered heterocycle-containing compound. Or substances containing components of the five-membered heterocycle-containing compound are processed into their food chain.
根据本发明一种优选的实施方式，所述方法包括：用杀虫有效量的至少一种所述的含五元杂环的化合物处理无脊椎动物害虫生长的植物。According to a preferred embodiment of the present invention, the method comprises: treating plants where invertebrate pests grow with an insecticidal effective amount of at least one of the five-membered heterocyclic compound.
本发明中，所述无脊椎动物害虫为螨科害虫、昆虫和/或线虫。In the present invention, the invertebrate pests are mite pests, insects and/or nematodes.
本发明中，所述植物为裸子植物门和/或被子植物门的植物，优选为芸香科植物、茄科植物、十字花科植物和蔷薇科植物中的至少一种。In the present invention, the plant is a plant of Gymnosperm and/or Angiosperm, preferably at least one of Rutaceae, Solanaceae, Brassicaceae and Rosaceae.
本发明对杀虫有效量没有特别的限定，例如可以指每公顷施用5克到3公斤的所述含五元杂环的化合物的剂量，便能够提供充分的防治。优选地，杀虫有效量可以为每公顷施用8克到1000克，更优选地，杀虫有效量为每公顷施用10克到300克。The present invention has no particular limitation on the insecticidal effective dose. For example, it can refer to a dose of 5 grams to 3 kilograms of the five-membered heterocycle-containing compound per hectare, which can provide sufficient control. Preferably, the insecticidally effective amount can be 8 to 1000 grams per hectare, more preferably, the insecticidally effective amount can be 10 to 300 grams per hectare.
应当明确的是，在本发明的权利要求所限定的范围内，可进行各种变换和改动与现有技术相比，本发明至少具有以下优势：It should be clear that within the scope defined by the claims of the present invention, various transformations and modifications can be made. Compared with the prior art, the present invention at least has the following advantages:
本发明提供的含五元杂环的化合物对多种有害生物、特别是对以二斑叶螨、神泽氏叶螨、柑桔全爪叶螨等为代表的叶螨类及小菜蛾为代表的鳞翅目昆虫显示出卓越的杀虫杀螨活性。The five-membered heterocycle-containing compound provided by the invention is effective against a variety of harmful organisms, especially against spider mites and diamondback moths represented by Tetranychus two-spotted, Tetranychus kanzawa, Tetranychus citrus, etc. Lepidoptera exhibits excellent insecticidal and acaricidal activity.
为了进一步理解本发明，下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅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做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 further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of the embodiments. . Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.
以下将通过实施例对本发明进行详细描述。以下实施例中，在没有特殊说明的情况下，使用的各种原料均来自商购，且为分析纯。The present invention will be described in detail below through examples. In the following examples, unless otherwise specified, all raw materials used are commercially available and of analytical grade.
实施例1Example 1
4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-1)的合成：4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1,1 -Synthesis of tetrahydrothiophen-3-yl(dioxide)-2-methylbenzamide (compound I-1):
步骤一、4-乙酰基-2-甲基苯甲酸的合成：
Step 1. Synthesis of 4-acetyl-2-methylbenzoic acid:
将正丁醇(400mL)加入到四口烧瓶中，然后依次加入1,3-双(二苯基膦基)丙烷(1.15g)、4-溴-2甲基苯甲酸(100g，0.465mol)、碳酸钾(77.12g，0.51mmol)和正丁基乙烯基醚(138.73g，1.38mol)，氮气保护下加入乙酸钯(0.21g)，氮气保护下加热回流反应5小时；Add n-butanol (400mL) to the four-necked flask, then add 1,3-bis(diphenylphosphino)propane (1.15g) and 4-bromo-2methylbenzoic acid (100g, 0.465mol) in sequence. , potassium carbonate (77.12g, 0.51mmol) and n-butyl vinyl ether (138.73g, 1.38mol), add palladium acetate (0.21g) under nitrogen protection, and heat and reflux for 5 hours under nitrogen protection;
将反应溶液冷却至80℃后，在减压下蒸馏出正丁醇和正丁基乙烯基醚，加入500mL乙酸乙酯和1000mL水后，通过加入50ml浓盐酸后萃取分液，水相再次加入500mL乙酸乙酯萃取分液，合并有机相，加入无水硫酸钠干燥后旋蒸至干，得到类白色固体72.5g。After cooling the reaction solution to 80°C, distill n-butanol and n-butyl vinyl ether under reduced pressure. After adding 500 mL of ethyl acetate and 1000 mL of water, add 50 ml of concentrated hydrochloric acid and extract and separate the liquids. Add 500 mL of water phase again. Extract and separate the liquids with ethyl acetate, combine the organic phases, add anhydrous sodium sulfate to dry and then spin-evaporate to dryness to obtain 72.5g of off-white solid.
步骤二、1-(3,5-二氯-4-氟苯基)2,2,2-三氟乙酮的合成：
Step 2. Synthesis of 1-(3,5-dichloro-4-fluorophenyl)2,2,2-trifluoroethanone:
将3,5二氯-4氟溴苯(122g，0.5mol)加入到3L四口烧瓶中，氮气保护下加入四氢呋喃(600mL)溶解，加入氯化锂(10.5g，0.25mol)，冰浴(10℃以下)滴加1M异丙基溴化镁(600mL，0.6mol)，反应1h后，点板检测反应程度，反应完滴加三氟乙酸乙酯(85.2g，0.6mol)，继续搅拌反应2小时；反应完毕，反应液加入到2L水中，加入0.2L饱和氯化铵水溶液，1L乙酸乙酯萃取分液，水相再次加入1L乙酸乙酯萃取，合并有机相，加入无水硫酸钠干燥后旋蒸至干，减压蒸馏，得到82g无色油状物。Add 3,5-dichloro-4-fluorobenzene (122g, 0.5mol) into a 3L four-necked flask, add tetrahydrofuran (600mL) under nitrogen protection to dissolve, add lithium chloride (10.5g, 0.25mol), and ice bath ( (below 10°C), add 1M isopropylmagnesium bromide (600mL, 0.6mol) dropwise. After 1 hour of reaction, check the degree of reaction with a spot plate. After the reaction, add ethyl trifluoroacetate (85.2g, 0.6mol) dropwise, and continue to stir the reaction. 2 hours; after the reaction is completed, add the reaction solution to 2L of water, add 0.2L of saturated ammonium chloride aqueous solution, extract and separate the liquids with 1L of ethyl acetate, add 1L of ethyl acetate to the water phase again for extraction, combine the organic phases, and add anhydrous sodium sulfate to dry. Afterwards, the mixture was evaporated to dryness and distilled under reduced pressure to obtain 82g of colorless oil.
步骤三、4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟-3-羟基丁酰基)-2-甲基苯甲酸的合成：
Step 3. Synthesis of 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid:
将甲苯(30mL)加入到烧瓶中，然后依次加入4-乙酰基-2-甲基苯甲酸(6.14g，34.48mmol)，1-(3,5-二氯-4-氟苯基)2,2,2-三氟乙酮(9.0g，34.48mmol)，加入三乙胺(5.22g，51.72mmol)，反应瓶于60℃下搅拌13小时，将反应液冷却至室温；减压过滤反应溶液，并用少量甲苯洗涤固体，得到13.0g淡黄色固体。Add toluene (30 mL) into the flask, then add 4-acetyl-2-methylbenzoic acid (6.14g, 34.48mmol), 1-(3,5-dichloro-4-fluorophenyl)2, 2,2-Trifluoroethanone (9.0g, 34.48mmol), add triethylamine (5.22g, 51.72mmol), stir the reaction bottle at 60°C for 13 hours, cool the reaction solution to room temperature; filter the reaction solution under reduced pressure , and washed the solid with a small amount of toluene to obtain 13.0g of light yellow solid.
MS：[M-H]-:437.15,439.21。MS: [MH] - :437.15,439.21.
步骤四、4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟-2-丁烯酰基)-2-甲基苯甲酸的合成：
Step 4: Synthesis of 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid:
将4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟-3-羟基丁酰基)-2-甲基苯甲酸三乙胺盐(10.0g，18.49mmol)加入到圆底烧瓶中，加少量甲苯(30mL)和4-二甲基氨基吡啶(0.22g)，并将混合物加热至60℃。然后，加入乙酸酐(5.66g，55.46mmol)，并将混合物在60℃下搅拌9小时；4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt (10.0g , 18.49mmol) into the round-bottomed flask, add a small amount of toluene (30mL) and 4-dimethylaminopyridine (0.22g), and heat the mixture to 60°C. Then, acetic anhydride (5.66g, 55.46mmol) was added, and the mixture was stirred at 60°C for 9 hours;
将反应溶液冷却至室温，加入20mL浓盐酸，100mL水，100mL乙酸乙酯。萃取分液，水相再次加入100mL乙酸乙酯，萃取分液后合并有机相，有机相加入10g无水硫酸钠干燥后，旋蒸至干，得到8.5g淡黄色固体化合物。The reaction solution was cooled to room temperature, and 20 mL of concentrated hydrochloric acid, 100 mL of water, and 100 mL of ethyl acetate were added. After extraction and liquid separation, 100 mL of ethyl acetate was added to the aqueous phase again. After extraction and liquid separation, the organic phases were combined. The organic phase was dried by adding 10 g of anhydrous sodium sulfate and then rotary evaporated to dryness to obtain 8.5 g of a light yellow solid compound.
MS：[M-H]-:419.21,421.18。MS: [MH] - :419.21,421.18.
步骤五、4-(5-(3,5-二氯-4-氟苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基)-2-甲基苯甲酸的合成：
Step 5. 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzene Synthesis of formic acid:
将甲苯(25mL)和四丁基溴化铵(0.65g)加入到圆底烧瓶中，加入4-(3-(3,5-二氯-4-氟苯基)-4,4,4-三氟-2-丁烯酰基)-2-甲基苯甲酸(8.5g，20mol)，将反应瓶在0℃下搅拌；然后依次加入氢氧化钠(3.36g，84mmol)，纯净水(25ml)和盐酸羟胺(2.78g，40mmol)，反应瓶继续冰浴下搅拌反应5小时；Add toluene (25 mL) and tetrabutylammonium bromide (0.65 g) into the round-bottomed flask, and add 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4- Trifluoro-2-butenoyl)-2-methylbenzoic acid (8.5g, 20mol), stir the reaction bottle at 0°C; then add sodium hydroxide (3.36g, 84mmol) and purified water (25ml) in sequence and hydroxylamine hydrochloride (2.78g, 40mmol), and the reaction bottle continued to stir and react in an ice bath for 5 hours;
将反应溶液加入20mL浓盐酸，100mL水，100mL乙酸乙酯；萃取分液，水相再次加入100mL乙酸乙酯，萃取分液后合并有机相，有机相加入10g无水硫酸钠干燥后，旋蒸至干，得到7.2g类白色固体。Add 20mL concentrated hydrochloric acid, 100mL water, and 100mL ethyl acetate to the reaction solution; extract and separate the liquids, add 100mL of ethyl acetate to the water phase again, combine the organic phases after extraction and separation, add 10g of anhydrous sodium sulfate to the organic phase, dry, and then evaporate To dryness, 7.2g of off-white solid was obtained.
MS：[M-H]-:434.14,436.11。MS: [MH] - :434.14,436.11.
步骤六、4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-1)的合成：
Step six, 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-( Synthesis of 1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-1):
将4-(5-(3,5-二氯-4-氟苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基)-2-甲基苯甲酸(4.36g，10mmol)加入到40mL甲苯中，加入氯化亚砜(1.43g，12mmol)，加热回流2h后减压除氯化氢等气体，加入二氯乙烷(40mL)；冰浴条件下反应液中依次加入3-氨基四氢噻吩1,1-二氧化物(2.02g，15mmol)和三乙胺(2.02g，20mmol)，继续反应1h后反应液加入100mL水和50mL乙酸乙酯，萃取分液后水相再次加入50mL乙酸乙酯，再次萃取分液合并有机相后旋蒸至干，柱层析纯化，得到白色固体4.06g。4-(5-(3,5-Dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid ( 4.36g, 10mmol) was added to 40mL toluene, added thionyl chloride (1.43g, 12mmol), heated to reflux for 2 hours, then decompressed to remove hydrogen chloride and other gases, added dichloroethane (40mL); in the reaction solution under ice bath conditions Add 3-aminotetrahydrothiophene 1,1-dioxide (2.02g, 15mmol) and triethylamine (2.02g, 20mmol) in sequence, continue the reaction for 1 hour, add 100mL water and 50mL ethyl acetate to the reaction solution, extract and separate the liquids Add 50 mL of ethyl acetate to the aqueous phase again, extract and separate the liquids again, combine the organic phases, spin evaporate to dryness, and purify by column chromatography to obtain 4.06 g of a white solid.
1H NMR(400MHz,CDCl3)δ7.59(d,J＝6.0Hz,2H),7.52(d,J＝8.7Hz,2H),7.43(d,J＝7.9Hz,1H),6.48(d,J＝7.7Hz,1H),4.99(d,J＝6.5Hz,1H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H),3.45(dd,J＝13.8,7.2Hz,1H),3.33–3.16(m,2H),3.11(dd,J＝14.7,4.6Hz,1H),2.65(t,J＝7.8Hz,1H),2.48(s,3H),2.42(d,J＝6.3Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.59 (d, J = 6.0 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 7.9 Hz, 1H), 6.48 (d ,J＝7.7Hz,1H),4.99(d,J＝6.5Hz,1H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H),3.45(dd,J ＝13.8,7.2Hz,1H),3.33–3.16(m,2H),3.11(dd,J＝14.7,4.6Hz,1H),2.65(t,J＝7.8Hz,1H),2.48(s,3H) ,2.42(d,J＝6.3Hz,1H).
MS：[M+Na]+:575.43,577.48。MS: [M+Na] + :575.43,577.48.
实施例2Example 2
4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-((R)-1,1-二氧代四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-14)的合成：
4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R) Synthesis of -1,1-dioxotetrahydrothiophen-3-yl)-2-methylbenzamide (compound I-14):
按照实施例1中所述方法制备目标化合物，不同的是，使用(R)-3-氨基四氢噻吩1,1-二氧化物盐酸盐(化合物III-2)代替3-氨基四氢噻吩1,1-二氧化物(化合物III-1)，制备得到目标化合物I-14，白色固体粉末。The target compound was prepared according to the method described in Example 1, except that (R)-3-aminotetrahydrothiophene 1,1-dioxide hydrochloride (compound III-2) was used instead of 3-aminotetrahydrothiophene. 1,1-dioxide (compound III-1) was used to prepare the target compound I-14 as a white solid powder.
1H NMR(400MHz,Chloroform-d)δ7.52(d,J＝6.0Hz,2H),7.45(d,J＝9.3Hz,2H),7.35(d,J＝7.9Hz,1H),6.40(d,J＝7.7Hz,1H),4.92(d,J＝7.8Hz,1H),4.01(d,J＝17.2Hz,1H),3.62(d,J＝17.2Hz,1H),3.38(dd,J＝13.8,7.2Hz,1H),3.25–2.99(m,3H),2.58(td,J＝14.8,7.3Hz,1H),2.41(s,3H),2.34(dt,J＝14.0,7.3Hz,1H). 1 H NMR (400MHz, Chloroform-d) δ7.52 (d, J = 6.0 Hz, 2H), 7.45 (d, J = 9.3 Hz, 2H), 7.35 (d, J = 7.9 Hz, 1H), 6.40 ( d,J＝7.7Hz,1H),4.92(d,J＝7.8Hz,1H),4.01(d,J＝17.2Hz,1H),3.62(d,J＝17.2Hz,1H),3.38(dd, J＝13.8,7.2Hz,1H),3.25–2.99(m,3H),2.58(td,J＝14.8,7.3Hz,1H),2.41(s,3H),2.34(dt,J＝14.0,7.3Hz ,1H).
MS：[M+Na]+:575.42,577.38。MS: [M+Na] + :575.42,577.38.
实施例3Example 3
4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-((S)-1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-13)的合成：
4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((S) Synthesis of -1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-13):
按照实施例1中所述方法制备目标化合物，不同的是，使用(S)-3-氨基四氢噻吩1,1-二氧化物盐酸盐(化合物III-3)代替3-氨基四氢噻吩1,1-二氧化物(化合物III-1)，制备得到目标化合物I-13，白色固体粉末。The target compound was prepared according to the method described in Example 1, except that (S)-3-aminotetrahydrothiophene 1,1-dioxide hydrochloride (compound III-3) was used instead of 3-aminotetrahydrothiophene. 1,1-dioxide (compound III-1) was used to prepare the target compound I-13 as a white solid powder.
1H NMR(400MHz,Chloroform-d)δ7.59(d,J＝6.0Hz,2H),7.51(d,J＝9.4Hz,2H),7.42(d,J＝7.9Hz,1H),6.49(d,J＝7.6Hz,1H),4.98(d,J＝6.6Hz,1H),4.16–4.08(m,1H),3.69(d,J＝17.2Hz,1H),3.44(dd,J＝13.8,7.2Hz,1H),3.32–3.05(m,3H),2.65(ddt,J＝14.7,9.0,4.4Hz,1H),2.47(s,3H),2.40(dt,J＝13.9,7.0Hz,1H). 1 H NMR (400MHz, Chloroform-d) δ7.59(d,J＝6.0Hz,2H),7.51(d,J＝9.4Hz,2H),7.42(d,J＝7.9Hz,1H),6.49( d,J＝7.6Hz,1H),4.98(d,J＝6.6Hz,1H),4.16–4.08(m,1H),3.69(d,J＝17.2Hz,1H),3.44(dd,J＝13.8 ,7.2Hz,1H),3.32–3.05(m,3H),2.65(ddt,J＝14.7,9.0,4.4Hz,1H),2.47(s,3H),2.40(dt,J＝13.9,7.0Hz, 1H).
MS：[M+Na]+:575.38,577.36。MS: [M+Na] + :575.38,577.36.
实施例4Example 4
4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-2-甲基-N-(四氢噻吩-3-基)苯甲酰胺(化合物I-21)的合成：
4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N Synthesis of -(tetrahydrothiophen-3-yl)benzamide (compound I-21):
按照实施例1中所述方法制备目标化合物，不同的是，使用3-氨基四氢噻吩(化合物III-4)代替3-氨基四氢噻吩1,1-二氧化物(化合物III-1)，制备得到目标化合物I-21，白色固体粉末。The target compound was prepared according to the method described in Example 1, except that 3-aminotetrahydrothiophene (compound III-4) was used instead of 3-aminotetrahydrothiophene 1,1-dioxide (compound III-1), The target compound I-21 was prepared as a white solid powder.
MS：[M+H]+:521.33；[M+Na]+:543.32。MS: [M+H] + :521.33; [M+Na] + :543.32.
实施例5Example 5
N-(1,1-二氧化四氢噻吩-3-基)-2-甲基-4-(5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)苯甲酰胺(化合物I-3)的合成：
N-(1,1-Tetrahydrothiophenyldioxide-3-yl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)- Synthesis of 4,5-dihydroisoxazol-3-yl)benzamide (compound I-3):
按照实施例1中所述方法制备目标化合物，不同的是，使用(4-(5-(3,4,5-三氯苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基)-2-甲基苯甲酸(化合物II-2)代替4-(5-(3,5-二氯-4-氟苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基)-2-甲基苯甲酸(化合物II-1)，制备得到目标化合物I-13，白色固体粉末。The target compound was prepared according to the method described in Example 1, except that (4-(5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroiso Oxazol-3-yl)-2-methylbenzoic acid (compound II-2) instead of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4, 5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (compound II-1) was used to prepare the target compound I-13 as a white solid powder.
1H NMR(400MHz,CDCl3)δ7.65(s,2H),7.57–7.48(m,2H),7.42(d,J＝8.0Hz,1H),6.44(d,J＝7.6Hz,1H),4.99(d,J＝5.9Hz,1H),4.09(d,J＝17.2Hz,1H),3.69(d,J＝17.3Hz,1H),3.45(dd,J＝13.8,7.2Hz,1H),3.35–3.15(m,2H),3.11(dd,J＝13.8,3.8Hz,1H),2.74–2.59(m,1H),2.47(s,3H),2.43(s,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 2H), 7.57–7.48 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 6.44 (d, J=7.6 Hz, 1H), 4.99 (d, J=5.9 Hz, 1H), 4.09 (d, J=17.2 Hz, 1H), 3.69 (d, J=17.3 Hz, 1H), 3.45 (dd, J=13.8, 7.2 Hz, 1H), 3.35–3.15 (m, 2H), 3.11 (dd, J=13.8, 3.8 Hz, 1H), 2.74–2.59 (m, 1H), 2.47 (s, 3H), 2.43 (s, 1H).
MS：[M+H]+:569.03,571.27,573.32。MS: [M+H] + :569.03,571.27,573.32.
实施例6Example 6
2-(4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧基四氢噻吩-3-基)-2-甲基苯甲酰胺基)-2-氧乙酸甲酯(化合物I-12)的合成：
Synthesis of methyl 2-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1,1-dioxytetrahydrothiophene-3-yl)-2-methylbenzamide)-2-oxoacetate (Compound I-12):
将4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧基四氢噻吩-3-基)-2-甲基苯甲酰胺(553mg，1mmol)加入到圆底烧瓶中，加入二氯乙烷(10mL)，然后依次加入三乙胺(303mg，3mmol)和草酰氯单甲酯(245mg，2mmol)，反应液加热至回流，3小时后反应液冷却至室温，加入50mL水和50mL乙酸乙酯，萃取分液后有机相加入饱和食盐水洗涤，无水硫酸钠干燥后有机相减压浓缩至干，柱层析纯化，得白色固体303mg。4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1,1-dioxytetrahydrothiophene-3-yl)-2-methylbenzamide (553 mg, 1 mmol) was added to a round-bottom flask, and dichloroethane (10 mL) was added, followed by triethylamine (303 mg, 3 mmol) and monomethyl oxalyl chloride (245 mg, 2 mmol). The reaction solution was heated to reflux. After 3 hours, the reaction solution was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. After extraction and separation, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The mixture was purified by column chromatography to obtain 303 mg of a white solid.
MS：[M+Na]+:661.39，663.37。MS: [M+Na] + :661.39, 663.37.
实施例7Example 7
N-乙酰基-4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-9)的合成：
N-acetyl-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N Synthesis of -(1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-9):
按照实施例6中所述方法制备目标化合物，不同的是，使用乙酰氯(化合物V-2)代替草酰氯单甲酯(化合物V-1)，制备得到目标化合物I-9，白色固体粉末。The target compound was prepared according to the method described in Example 6, except that acetyl chloride (compound V-2) was used instead of oxalyl chloride monomethyl ester (compound V-1) to prepare the target compound I-9 as a white solid powder.
1H NMR(400MHz,CDCl3)δ7.66–7.54(m,4H),7.31(d,J＝8.0Hz,1H),4.98–4.84(m,1H),4.10(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,3H),3.22–2.97(m,2H),2.63–2.49(m,2H),2.47(s,3H),2.12(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.66–7.54(m,4H),7.31(d,J＝8.0Hz,1H),4.98–4.84(m,1H),4.10(d,J＝17.2Hz, 1H),3.70(d,J＝17.2Hz,3H),3.22–2.97(m,2H),2.63–2.49(m,2H),2.47(s,3H),2.12(s,3H).
MS：[M+H]+:595.33；[M+Na]+:617.32。MS: [M+H] + :595.33; [M+Na] + :617.32.
实施例8Example 8
N-丙酰基-4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-10)的合成：
N-propionyl-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N Synthesis of -(1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-10):
按照实施例6中所述方法制备目标化合物，不同的是，使用丙酰氯(化合物V-3)代替草酰氯单甲酯(化合物V-1)，制备得到目标化合物I-10，白色固体粉末。The target compound was prepared according to the method described in Example 6, except that propionyl chloride (compound V-3) was used instead of oxalyl chloride monomethyl ester (compound V-1) to prepare the target compound I-10 as a white solid powder.
1H NMR(400MHz,CDCl3)δ7.59(dd,J＝13.3,7.4Hz,4H),7.29(d,J＝8.0Hz,1H),4.90(s,1H),4.10(d,J＝17.2Hz,1H),3.77–3.52(m,3H),3.22–3.03(m,2H),2.56–2.43(m,5H),2.36(dd,J＝14.6,7.3Hz,2H),1.05(t,J＝7.3Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.59 (dd, J＝13.3, 7.4Hz, 4H), 7.29 (d, J＝8.0Hz, 1H), 4.90 (s, 1H), 4.10 (d, J＝ 17.2Hz,1H),3.77–3.52(m,3H),3.22–3.03(m,2H),2.56–2.43(m,5H),2.36(dd,J＝14.6,7.3Hz,2H),1.05(t ,J＝7.3Hz,3H).
MS：[M+Na]+:631.32,633.29。MS: [M+Na] + :631.32, 633.29.
实施例9Example 9
N-异丙酰基-4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-21)的合成：
N-Isopropionyl-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- Synthesis of N-(1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-21):
按照实施例6中所述方法制备目标化合物，不同的是，使用异丁酰氯(化合物V-4)代替草酰氯单甲酯(化合物V-1)，制备得到目标化合物I-21，白色固体粉末。The target compound was prepared according to the method described in Example 6, except that isobutyryl chloride (Compound V-4) was used instead of oxalyl chloride monomethyl ester (Compound V-1) to prepare the target compound I-21 as a white solid powder. .
1H NMR(400MHz,CDCl3)δ7.59(dd,J＝15.1,9.1Hz,4H),7.28(s,1H),5.07–4.91(m,1H),4.10(d,J＝17.2Hz,1H),3.76–3.54(m,3H),3.17(dd,J＝12.6,8.6Hz,1H),3.14–3.02(m,1H),2.63(dd,J＝13.3,6.7Hz,1H),2.56–2.45(m,5H),1.00(dt,J＝14.8,7.4Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.59 (dd, J＝15.1, 9.1Hz, 4H), 7.28 (s, 1H), 5.07–4.91 (m, 1H), 4.10 (d, J＝17.2Hz, 1H),3.76–3.54(m,3H),3.17(dd,J＝12.6,8.6Hz,1H),3.14–3.02(m,1H),2.63(dd,J＝13.3,6.7Hz,1H),2.56 –2.45(m,5H),1.00(dt,J＝14.8,7.4Hz,6H).
MS：[M+H]+:623.26；[M+Na]+:645.28。MS: [M+H] + :623.26; [M+Na] + :645.28.
实施例10Example 10
N-环丙酰基-4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-22)的合成：
N-cyclopropionyl-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- Synthesis of N-(1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-22):
按照实施例6中所述方法制备目标化合物，不同的是，使用环丙基甲酰氯(化合物V-5)代替草酰氯单甲酯(化合物V-1)，制备得到目标化合物I-22，白色固体粉末。The target compound was prepared according to the method described in Example 6, except that cyclopropylformyl chloride (Compound V-5) was used instead of oxalyl chloride monomethyl ester (Compound V-1) to prepare the target compound I-22, white Solid powder.
1H NMR(400MHz,CDCl3)δ7.65–7.51(m,4H),7.34(d,J＝8.0Hz,1H),5.29(dt,J＝16.7,8.4Hz,1H),4.09(d,J＝17.2Hz,1H),3.69(d,J＝17.4Hz,2H),3.56(dt,J＝12.5,8.0Hz,1H),3.26(dd,J＝12.5,8.4Hz,1H),3.21–3.03(m,1H),2.57(s,2H),2.49(s,3H),1.55(s,3H),1.16–0.98(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.65–7.51(m,4H),7.34(d,J＝8.0Hz,1H),5.29(dt,J＝16.7,8.4Hz,1H),4.09(d, J＝17.2Hz,1H),3.69(d,J＝17.4Hz,2H),3.56(dt,J＝12.5,8.0Hz,1H),3.26(dd,J＝12.5,8.4Hz,1H),3.21– 3.03(m,1H),2.57(s,2H),2.49(s,3H),1.55(s,3H),1.16–0.98(m,2H).
MS：[M+Na]+:643.36。MS: [M+Na] + :643.36.
实施例11Example 11
4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧基四氢噻吩-3-基)-N,2-二甲基苯甲 酰胺(化合物I-7)的合成：
4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1,1 -Dioxytetrahydrothiophen-3-yl)-N,2-dimethylbenzyl Synthesis of amide (compound 1-7):
将4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧基四氢噻吩-3-基)-2-甲基苯甲酰胺(553mg，1mmol)加入到耐压瓶中，加入无水四氢呋喃(5mL)，冰浴降温至0℃，然后用注射器加入碘甲烷(213mg，15mmol)，反应瓶封口后升温至100℃，加热搅拌3小时后降至室温，加入50mL水和50mL乙酸乙酯，萃取分液后有机相加入饱和食盐水洗涤，无水硫酸钠干燥后有机相减压浓缩至干，柱层析纯化，得白色固体110mg。4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1, 1-Dioxytetrahydrothiophen-3-yl)-2-methylbenzamide (553 mg, 1 mmol) was added to a pressure-resistant bottle, anhydrous tetrahydrofuran (5 mL) was added, cooled to 0°C in an ice bath, and then Add methyl iodide (213 mg, 15 mmol) to the syringe, seal the reaction bottle and raise the temperature to 100°C. Heat and stir for 3 hours before returning to room temperature. Add 50 mL of water and 50 mL of ethyl acetate. After extraction and separation, the organic phase is washed with saturated saline. After drying over sodium sulfate, the organic phase was concentrated under reduced pressure to dryness and purified by column chromatography to obtain 110 mg of white solid.
1HNMR(400MHz,CDCl3)δ7.59(d,J＝6.0Hz,4H),7.22(d,J＝7.8Hz,1H),4.08(d,J＝17.1Hz,1H),3.70(dd,J＝16.8,11.0Hz,1H),3.56–3.34(m,2H),3.14(dd,J＝23.1,14.5Hz,3H),2.79(s,3H),2.57–2.34(m,2H),2.30(s,3H). 1 HNMR (400MHz, CDCl 3 ) δ7.59 (d, J = 6.0 Hz, 4H), 7.22 (d, J = 7.8 Hz, 1H), 4.08 (d, J = 17.1 Hz, 1H), 3.70 (dd, J＝16.8,11.0Hz,1H),3.56–3.34(m,2H),3.14(dd,J＝23.1,14.5Hz,3H),2.79(s,3H),2.57–2.34(m,2H),2.30 (s,3H).
MS：[M+H]+:567.28；[M+Na]+:589.18。MS: [M+H] + :567.28; [M+Na] + :589.18.
实施例12Example 12
4-(5-(3,5-双(三氟甲基)苯基)-5-(三氟甲酯)-4,5-二氢异恶唑-3-基)-N-(1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-25)的合成
4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1, Synthesis of 1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-25)
将4-(5-(3,5-双(三氟甲基)苯基)-5-(三氟甲酯)-4,5-二氢异恶唑-3-基)-2-甲基苯甲酸(485mg，1mmol)加入到二氯乙烷中，加入二异丙基乙基胺(258mg，2mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(494mg，1.3mmol)，搅拌30分钟后加入3-氨基四氢噻吩1,1-二氧化物(202.5mg，1.5mmol),继续搅拌反应30分钟后，反应液加入50mL水和50mL二氯甲烷，萃取分液后，有机相减压浓缩至干，柱层析纯化得到白色固体426mg。4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl Benzoic acid (485mg, 1mmol) was added to dichloroethane, diisopropylethylamine (258mg, 2mmol) and 2-(7-azabenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate (494 mg, 1.3 mmol), stir for 30 minutes, add 3-aminotetrahydrothiophene 1,1-dioxide (202.5 mg, 1.5 mmol), continue stirring for 30 minutes and react , 50 mL water and 50 mL methylene chloride were added to the reaction solution. After extraction and liquid separation, the organic phase was concentrated to dryness under reduced pressure and purified by column chromatography to obtain 426 mg of white solid.
1H NMR(400MHz,CDCl3)δ8.08(s,2H),7.97(s,1H),7.53(d,J＝8.4Hz,2H),7.42(d,J＝8.0Hz,1H),6.53(d,J＝7.6Hz,1H),4.97(dd,J＝10.9,5.5Hz,1H),4.20(d,J＝17.3Hz,1H),3.76(d,J＝17.3Hz,1H),3.44(dd,J＝13.8,7.2Hz,1H),3.32–3.14(m,2H),3.14–3.03(m,1H),2.73–2.54(m,1H),2.47(s,3H),2.46–2.30(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.08 (s, 2H), 7.97 (s, 1H), 7.53 (d, J = 8.4Hz, 2H), 7.42 (d, J = 8.0Hz, 1H), 6.53 (d,J＝7.6Hz,1H),4.97(dd,J＝10.9,5.5Hz,1H),4.20(d,J＝17.3Hz,1H),3.76(d,J＝17.3Hz,1H),3.44 (dd,J＝13.8,7.2Hz,1H),3.32–3.14(m,2H),3.14–3.03(m,1H),2.73–2.54(m,1H),2.47(s,3H),2.46–2.30 (m,1H).
MS：[M+Na]+:625.24。MS: [M+Na] + :625.24.
实施例13Example 13
步骤1：(S)-4-(3-(3,5-二氯-4-氟苯基)-4,4-4-三氟-3-羟基丁酰基)-2-甲基苯甲酸甲酯的制备
Step 1: Preparation of (S)-methyl 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4-4-trifluoro-3-hydroxybutyryl)-2-methylbenzoate
向1-(3,5-二氯-4-氟苯基)-2,2,2-三氟-乙酮(10.44g，40mmol)在甲苯(42mL)中的溶液中加入1-[3,5-双(三氟甲基)苯基]-3-[(1R,2R)-(-)-2-(二甲氨基)环己基]硫脲(1.5g，3.65mmol)和4-乙酰基-2-甲基-苯甲酸甲酯(7.0g，36.5mmol),并将混合物在20至25℃下搅拌过夜。反应完全后，减压浓缩脱除溶剂，残留物柱层析纯化得到4.5g白色固体，即为标题化合物。To a solution of 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoro-ethanone (10.44 g, 40 mmol) in toluene (42 mL) was added 1-[3, 5-bis(trifluoromethyl)phenyl]-3-[(1R,2R)-(-)-2-(dimethylamino)cyclohexyl]thiourea (1.5g, 3.65mmol) and 4-acetyl -2-Methyl-benzoic acid methyl ester (7.0 g, 36.5 mmol) and the mixture was stirred at 20 to 25°C overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography to obtain 4.5 g of white solid, which was the title compound.
1HNMR(400MHz,Chloroform-d)δ8.00(d,J＝8.6Hz,1H),7.81–7.74(m,2H),7.56(d,J＝6.1Hz,2H),5.66(s,1H),3.94(s,3H),3.84(d,J＝17.6Hz,1H),3.69(d,J＝17.6Hz,1H),2.66(s,3H). 1 HNMR(400MHz,Chloroform-d)δ8.00(d,J＝8.6Hz,1H),7.81–7.74(m,2H),7.56(d,J＝6.1Hz,2H),5.66(s,1H) ,3.94(s,3H),3.84(d,J＝17.6Hz,1H),3.69(d,J＝17.6Hz,1H),2.66(s,3H).
MS：[M+Na]+:475.12，477.36。MS: [M+Na] + :475.12, 477.36.
步骤2：(S,Z)-4-(3-(3,5-二氯-4-氟苯基)-4,4-4-三氟-3-羟基-1-(羟基亚氨基)丁基)-2-甲基苯甲酸甲酯的制备
Step 2: (S,Z)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4-4-trifluoro-3-hydroxy-1-(hydroxyimino)butan Preparation of methyl)-2-methylbenzoate
在20至25℃下向(S)-4-(3-(3,5-二氯-4-氟苯基)-4,4-4-三氟-3-羟基丁酰基)-2-甲基苯甲酸甲酯(1g，2.2mmol)和2,6-二甲基吡啶(7ml)的混合物中加入固体羟胺盐酸盐(0.31g，4.4mmol)。在搅拌过夜后，向体系中加入10ml冰水淬灭后经二氯甲烷萃取分液，合并的有机层用盐酸水溶液(6N)和水洗涤，经无水硫酸钠干燥，过滤并在真空中浓缩。得0.6g浅棕色油状物，即为标题化合物。To (S)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4-4-trifluoro-3-hydroxybutyryl)-2-methyl at 20 to 25°C To a mixture of methyl benzoate (1 g, 2.2 mmol) and 2,6-lutidine (7 ml) was added solid hydroxylamine hydrochloride (0.31 g, 4.4 mmol). After stirring overnight, 10 ml of ice water was added to the system to quench, and the liquids were separated by extraction with dichloromethane. The combined organic layers were washed with aqueous hydrochloric acid solution (6N) and water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. . 0.6g of light brown oil was obtained, which is the title compound.
1H NMR(400MHz,Chloroform-d)δ7.89(d,J＝8.1Hz,1H),7.41(d,J＝6.1Hz,2H),7.06(dd,J＝8.2,1.8Hz,1H),6.99(d,J＝1.8Hz,1H),5.23(s,1H),3.91(s,3H),3.32(d,J＝1.1Hz,2H),2.56(s,3H). 1 H NMR (400MHz, Chloroform-d) δ7.89 (d, J = 8.1Hz, 1H), 7.41 (d, J = 6.1Hz, 2H), 7.06 (dd, J = 8.2, 1.8Hz, 1H), 6.99(d,J＝1.8Hz,1H),5.23(s,1H),3.91(s,3H),3.32(d,J＝1.1Hz,2H),2.56(s,3H).
MS：[M+Na]+:490.49，492.46。MS: [M+Na] + :490.49, 492.46.
步骤3：(S)-4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异恶唑-3-基)-2-甲基苯甲酸甲酯的制备
Step 3: (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) -Preparation of 2-methylbenzoic acid methyl ester
向(S,Z)-4-(3-(3,5-二氯-4-氟苯基)-4,4-4-三氟-3-羟基-1-(羟基亚氨基)丁基)-2-甲基苯甲酸甲酯(1g，2.14mmol)在无水四氢呋喃(10ml)的溶液中加入三苯基膦(0.84g，3.21mmol)，在20℃以下分批加入偶氮二甲酸二乙酯(0.56g，3.21mmol)，并将混合物在室温下搅拌过夜。反应完全后，向体系中加入20ml水并经二氯甲烷萃取分液，经无水硫酸钠干燥，过滤并在真空中浓缩，浓缩物通过在硅胶上的快速色谱法提纯得到0.5g无色油状物，即为标题化合物。To (S,Z)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4-4-trifluoro-3-hydroxy-1-(hydroxyimino)butyl) -Methyl 2-methylbenzoate (1g, 2.14mmol) was added to a solution of anhydrous tetrahydrofuran (10ml). Triphenylphosphine (0.84g, 3.21mmol) was added in batches below 20°C. ethyl ester (0.56 g, 3.21 mmol) and the mixture was stirred at room temperature overnight. After the reaction is complete, 20 ml of water is added to the system and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The concentrate is purified by flash chromatography on silica gel to obtain 0.5 g of colorless oil. The substance is the title compound.
1H NMR(400MHz,CDCl3)δ8.08–7.92(m,1H),7.59(d,J＝6.0Hz,2H),7.53(d,J＝4.5Hz,2H),4.10(d,J＝17.2Hz,1H),3.91(s,3H),3.70(d,J＝17.2Hz,1H),2.63(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.08–7.92(m,1H),7.59(d,J＝6.0Hz,2H),7.53(d,J＝4.5Hz,2H),4.10(d,J＝ 17.2Hz,1H),3.91(s,3H),3.70(d,J=17.2Hz,1H),2.63(s,3H).
MS：[M+H]+:450.50，452.54。MS: [M+H] + :450.50, 452.54.
步骤4：(S)-4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异恶唑-3-基)-2-甲基苯甲酸的制备
Step 4: (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) -Preparation of 2-methylbenzoic acid
向(S)-4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异恶唑-3-基)-2-甲基苯甲酸甲酯(0.5g，1.11mmol)在四氢呋喃(3ml)的溶液中加入10％氢氧化锂水溶液(0.5g)，反应升温至70℃搅拌5h后反应完全，体系降至室温并用6M盐酸水溶液调节PH至2～3后，经二氯甲烷萃取后干燥脱溶得浅棕色油状物0.3克。To a solution of (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid methyl ester (0.5 g, 1.11 mmol) in tetrahydrofuran (3 ml) was added 10% lithium hydroxide aqueous solution (0.5 g). The reaction was heated to 70°C and stirred for 5 h until the reaction was complete. The system was cooled to room temperature and the pH was adjusted to 2-3 with 6M hydrochloric acid aqueous solution. After extraction with dichloromethane, it was dried and desolvated to obtain 0.3 g of a light brown oil.
MS：[M+H]-:434.57，436.56。MS: [M+H] - :434.57, 436.56.
步骤5：4-((S)-5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异恶唑-3-基)-N-(1,1-二氧化四氢噻吩-3-基)-2-甲基苯甲酰胺(化合物I-17)的制备
Step 5: 4-((S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) Preparation of -N-(1,1-tetrahydrothiophen-3-yldioxide)-2-methylbenzamide (compound I-17)
向(S)-4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异恶唑-3-基)-2-甲基苯甲酸(0.3g，0.688mmol)在二氯甲烷(5ml)的溶液中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.39g，1.03mmol)和N,N-二异丙基乙胺(0.18g，1.38mmol)，在室温下搅拌0.5后，向体系中加入3-氨基环丁砜盐酸盐(0.18g，1.03mmol)，在室温下搅拌过夜。反应完全后，向体系中加入10ml水并经二氯甲烷萃取分液，经无水硫酸钠干燥，过滤并在真空中浓缩并通过在硅胶上的快速色谱法提纯得到0.28g白色固体，即为标题化合物。To (S)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2 -To a solution of methylbenzoic acid (0.3g, 0.688mmol) in dichloromethane (5ml), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (0.39g, 1.03mmol) and N,N-diisopropylethylamine (0.18g, 1.38mmol) were stirred at room temperature for 0.5, and then 3-aminocyclosulfolane hydrochloride ( 0.18g, 1.03mmol), stir at room temperature overnight. After the reaction is complete, add 10 ml of water to the system and extract and separate the liquids with dichloromethane, dry with anhydrous sodium sulfate, filter and concentrate in vacuum and purify by flash chromatography on silica gel to obtain 0.28 g of white solid, which is Title compound.
1H NMR(400MHz,CDCl3)δ7.59(d,J＝6.0Hz,2H),7.51(d,J＝9.4Hz,2H),7.41(d,J＝7.9Hz,1H),6.52(d,J ＝7.7Hz,1H),4.97(dd,J＝10.9,5.7Hz,1H),4.17(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H),3.44(dd,J＝13.8,7.2Hz,1H),3.35–3.14(m,2H),3.10(dd,J＝13.8,4.1Hz,1H),2.65(ddd,J＝21.8,8.7,6.6Hz,1H),2.48(d,J＝11.6Hz,3H),2.40(dd,J＝13.9,6.9Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.59 (d, J = 6.0 Hz, 2H), 7.51 (d, J = 9.4 Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 6.52 (d ,J ＝7.7Hz,1H),4.97(dd,J＝10.9,5.7Hz,1H),4.17(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H),3.44(dd,J ＝13.8,7.2Hz,1H),3.35–3.14(m,2H),3.10(dd,J＝13.8,4.1Hz,1H),2.65(ddd,J＝21.8,8.7,6.6Hz,1H),2.48( d, J＝11.6Hz, 3H), 2.40 (dd, J＝13.9, 6.9Hz, 1H).
MS：[M+H]+:553.46，555.47。MS: [M+H] + :553.46, 555.47.
对比例1Comparative example 1
4-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(1,1-二氧化噻吩-3-基)-2-甲基苯甲酰胺(CN106045962A中化合物X.82)的合成：
4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(1,1 -Synthesis of thiophen-3-yl(dioxide)-2-methylbenzamide (compound X.82 in CN106045962A):
参照实施例1中所述方法，使用3-氨基噻丁环-1,1-二氧化物(cas号：88511-13-1)代替3-氨基四氢噻吩1,1-二氧化物(化合物III-1)，制备得到目标化合物X.82，白色固体粉末。Referring to the method described in Example 1, 3-aminothiazine-1,1-dioxide (cas number: 88511-13-1) was used instead of 3-aminotetrahydrothiophene 1,1-dioxide (compound III-1) to prepare the target compound X.82 as a white solid powder.
1H NMR(400MHz,CDCl3)δ7.59(d,J＝6.0Hz,2H),7.54(d,J＝7.3Hz,2H),7.46(s,1H),6.50(d,J＝6.8Hz,1H),4.89(dd,J＝9.4,6.0Hz,1H),4.62(s,2H),4.13–3.99(m,3H),3.71(s,1H),2.48(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.59 (d, J = 6.0Hz, 2H), 7.54 (d, J = 7.3Hz, 2H), 7.46 (s, 1H), 6.50 (d, J = 6.8Hz ,1H),4.89(dd,J=9.4,6.0Hz,1H),4.62(s,2H),4.13–3.99(m,3H),3.71(s,1H),2.48(s,3H).
MS：[M+H]+:539.15,541.12；[M+Na]+:561.19,563.14。MS: [M+H] + :539.15,541.12; [M+Na] + :561.19,563.14.
对比例2Comparative example 2
4-[5-(3,5-二氯苯基)-4,5-二氢-5-(三氟甲基)-3-异恶唑基]-N-[(甲氧基氨基)亚甲基]-2-甲基苯甲酰胺(氟噁唑酰胺)的合成4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[(methoxyamino)ylidene Synthesis of methyl]-2-methylbenzamide (fluoroxazoleamide)
步骤一、4-(5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异恶唑-3-基)-2-甲基苯甲酰胺的合成
Step 1, 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide Synthesis
将4-(5-(3,5-二氯-苯基)-5-三氟甲基-4,5-二氢异噁唑-3-基)-2-甲基苯甲酸(4.18g，10mmol)加入到40mL甲苯中，加入氯化亚砜(1.43g，12mmol)，加热回流2h后减压除氯化氢等气体，加入四氢呋喃(40mL)；冰浴条件下反应液中加入氨水(10ml)，继续反应1h后反应液加入100mL水和50mL乙酸乙酯，萃取分液后水相再次加入50mL乙酸乙酯，再次萃取分液合并有机相后旋蒸至干，柱层析纯化，得到白色固体3.6g。4-(5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (4.18g, 10mmol) into 40mL toluene, add thionyl chloride (1.43g, 12mmol), heat to reflux for 2 hours, remove hydrogen chloride and other gases under reduced pressure, add tetrahydrofuran (40mL); add ammonia water (10ml) to the reaction solution under ice bath conditions, After continuing the reaction for 1 hour, 100 mL of water and 50 mL of ethyl acetate were added to the reaction solution. After extraction and separation, 50 mL of ethyl acetate was added to the aqueous phase. The organic phase was again extracted, separated and combined, then spin-evaporated to dryness. Purified by column chromatography, a white solid 3.6 was obtained. g.
MS：[M+H]+:417.07,418.99。MS: [M+H] + :417.07,418.99.
步骤二、4-[5-(3,5-二氯苯基)-4,5-二氢-5-(三氟甲基)-3-异恶唑基]-N-[(甲氧基氨基)亚甲基]-2-甲基苯甲酰胺(氟噁唑酰胺)的合成
Step 2, 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[(methoxy Synthesis of amino)methylene]-2-methylbenzamide (fluoroxazoleamide)
将4-(5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异恶唑-3-基)-2-甲基苯甲酰胺(1.5g，3.6mmol)加入到N,N-二甲基甲酰胺二甲缩醛(10mL)中，于110℃中加热回流3小时后加入二氧六环(5mL)。4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (1.5 g, 3.6 mmol) was added to N,N-dimethylformamide dimethyl acetal (10 mL), heated to reflux at 110°C for 3 hours, and then dioxane (5 mL) was added.
另取一圆底烧瓶，加入甲氧胺盐酸盐(0.60g，7.2mmol)，加入氢氧化钠(0.56g，14.4mmol)水溶液(8mL)，加入冰乙酸16mL，搅拌5分钟后缓慢滴加入上述二氧六环溶液。室温继续搅拌30分钟后，加入50mL乙酸乙酯和50mL水，萃取后有机相加入无水硫酸钠干燥，减压浓缩至干，浓缩物柱层析纯化得到0.64g白色固体。Take another round-bottomed flask, add methoxyamine hydrochloride (0.60g, 7.2mmol), add sodium hydroxide (0.56g, 14.4mmol) aqueous solution (8mL), add 16mL of glacial acetic acid, stir for 5 minutes and then add slowly dropwise The above dioxane solution. After continuing to stir at room temperature for 30 minutes, 50 mL of ethyl acetate and 50 mL of water were added. After extraction, the organic phase was dried by adding anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography to obtain 0.64 g of a white solid.
1H NMR(400MHz,CDCl3)δ8.53(d,J＝9.7Hz,1H),7.75(d,J＝9.3Hz,1H),7.61–7.47(m,5H),7.43(t,J＝1.8Hz,1H),4.10(d,J＝17.3Hz,1H),3.90(d,J＝6.3Hz,3H),3.76–3.63(m,1H),2.52(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.53 (d, J＝9.7Hz, 1H), 7.75 (d, J＝9.3Hz, 1H), 7.61–7.47 (m, 5H), 7.43 (t, J＝ 1.8Hz,1H),4.10(d,J＝17.3Hz,1H),3.90(d,J＝6.3Hz,3H),3.76–3.63(m,1H),2.52(s,3H).
MS：[M+H]+:474.13,476.07。MS: [M+H] + :474.13,476.07.
应用例1Application example 1
朱砂叶螨活性试验：Verniciflua cinnabarinus activity test:
将待测化合物用丙酮溶解，并用0.1重量％的吐温80水溶液稀释至所需浓度，丙酮含量不超过5重量％。The compound to be tested was dissolved in acetone and diluted to the desired concentration with a 0.1 wt % Tween 80 aqueous solution, with the acetone content not exceeding 5 wt %.
将生长至两片真叶的菜豆苗去掉一片真叶，接种朱砂叶螨后调查基数，用手持喷雾器进行整株喷雾处理，每处理重复3次(制剂施用量约为0.5g)，处理后于恒温观察室观察，72小时后调查活螨数量，计算致死率。每次接种朱砂叶螨的数量为35-100只。 Remove one true leaf from the bean seedlings that have grown to two true leaves. After inoculation with cinnabar spider mites, check the base number. Use a hand-held sprayer to spray the whole plant. Repeat each treatment 3 times (the dosage of the preparation is about 0.5g). After treatment, Observe in a constant-temperature observation room, investigate the number of live mites after 72 hours, and calculate the fatality rate. The number of spider mites to be inoculated each time is 35-100.
致死率％＝(接种虫数－药后活虫数)÷接种虫数×100％。Lethality rate % = (number of inoculated insects - number of live insects after treatment) ÷ number of inoculated insects × 100%.
在该试验中，化合物I-1、化合物I-3、化合物I-9、化合物I-10、化合物I-13、化合物I-14、化合物I-15、化合物I-16、化合物I-17、化合物I-18、化合物I-21、化合物I-22、化合物I-23、化合物I-25在3.125ppm(3.125mg/L)下分别对朱砂叶螨显示出超过90％的致死率。In this test, compound I-1, compound I-3, compound I-9, compound I-10, compound I-13, compound I-14, compound I-15, compound I-16, compound I-17, Compound I-18, Compound I-21, Compound I-22, Compound I-23, and Compound I-25 each showed a lethality rate of more than 90% against Tetranychus cinnabarus at 3.125 ppm (3.125 mg/L).
在该试验中，化合物I-1、化合物I-3、化合物I-9、化合物I-10、化合物I-14、化合物I-17、化合物I-25在1.56ppm(1.56mg/L)下分别对朱砂叶螨显示出超过90％的致死率。In this test, compound I-1, compound I-3, compound I-9, compound I-10, compound I-14, compound I-17, and compound I-25 were detected at 1.56 ppm (1.56 mg/L) respectively. Shows over 90% lethality against cinnabar spider mites.
按照上述方法，选取化合物I-1、化合物I-10、化合物I-14、化合物I-25、化合物I-17与氟噁唑酰胺分别进行杀螨(朱砂叶螨)的平行试验。试验结果见下表1。According to the above method, Compound I-1, Compound I-10, Compound I-14, Compound I-25, Compound I-17 and Fluoxazolamide were selected to conduct parallel tests on killing acarids (Tetranychus cinnabar). The test results are shown in Table 1 below.
表1

Table 1

由上可见，本发明的含五元杂环的化合物在较低的浓度下使用，仍然对朱砂叶螨具有较高的杀螨效果，并且杀螨效果明显优于上市杀虫杀螨剂氟噁唑酰胺。It can be seen from the above that the compound containing a five-membered heterocyclic ring of the present invention still has a high acaricidal effect on spider mites when used at a lower concentration, and the acaricidal effect is significantly better than that of the commercially available insecticide and acaricide fluorine. Azoleamide.
应用例2Application example 2
草地贪夜蛾室内毒力测定试验Indoor toxicity test of Spodoptera frugiperda
供试靶标：草地贪夜蛾(Spodopterafrugiperda)，3龄幼虫，室内饲养的敏感品系。Test target: Spodoptera frugiperda, 3rd instar larvae, a sensitive strain reared indoors.
试验方法：首先选择温室栽培的新鲜玉米叶片，剪成5cm长的叶段，试验设计从低剂量到高剂量的顺序，放入配制好的药液中浸渍10s，自然阴干后置于放有滤纸的直径为9cm的培养皿中，接入整齐的健康试虫，每处理10头，每处理3次重复，另设空白对照。Test method: First, select fresh corn leaves cultivated in the greenhouse and cut them into 5cm long leaf segments. The test is designed in order from low dose to high dose. Dip into the prepared medicinal solution for 10 seconds, dry naturally in the shade and place on filter paper. Into a petri dish with a diameter of 9cm, neatly healthy test worms were inserted, 10 for each treatment, and each treatment was repeated 3 times, and a blank control was set up.
化合物I-1、化合物I-10、化合物I-14、化合物I-25在1ppm(1mg/L)下对草地贪夜蛾显示出超过90％的致死率。Compound I-1, Compound I-10, Compound I-14, and Compound I-25 showed a lethality rate of more than 90% to Spodoptera Frugiperda at 1 ppm (1 mg/L).
应用例3Application example 3
黄曲条跳甲活性试验：Flea beetle activity test:
按试验设计浓度进行配置药液，选择新鲜白菜叶片，浸叶15s后，取出晾干后置于玻璃管中，每管接跳甲成虫20-25头，每处理3次重复，72小时后调查黄曲条跳甲死亡情况，并计算校正死亡率。Prepare the medicinal solution according to the experimental design concentration. Select fresh cabbage leaves. After soaking the leaves for 15 seconds, take them out to dry and place them in a glass tube. 20-25 flea beetle adults are collected in each tube. Each treatment is repeated 3 times and investigated after 72 hours. Mortality of yellow-curved flea beetles and calculated corrected mortality.
在该试验中，化合物I-1、化合物I-14、化合物I-17、化合物I-25在50ppm(50mg/L)下分别对黄曲条跳甲显示出超过90％的致死率。In this test, Compound I-1, Compound I-14, Compound I-17, and Compound I-25 respectively showed a lethality rate of more than 90% for flea beetles at 50 ppm (50 mg/L).
应用例4Application example 4
西花蓟马幼虫活性试验：Western flower thrips larvae activity test:
将待测化合物用丙酮溶解，并稀释至所需浓度。The compound to be tested is dissolved in acetone and diluted to the desired concentration.
将所配置丙酮药液0.5mL加入到玻璃管中(内径1cm、长度10cm)，将玻璃管于平整桌面上反复滚动至丙酮溶液挥发完全。将甘蓝叶片浸于相应浓度药液中15s后晾干，然后置于玻璃管中，玻璃管中接西花蓟马幼虫10-20头，每个处理重复三次，处理后于恒温观察室观察，72小时后调查活虫数量，计算死亡率。Add 0.5 mL of the prepared acetone solution into a glass tube (inner diameter 1 cm, length 10 cm), and roll the glass tube repeatedly on a flat table until the acetone solution evaporates completely. Soak the cabbage leaves in the corresponding concentration of medicinal solution for 15 seconds and then dry them, then place them in a glass tube. 10-20 Western flower thrips larvae are connected to the glass tube. Each treatment is repeated three times. After treatment, it is observed in a constant-temperature observation room. After 72 hours, the number of live insects was investigated and the mortality rate was calculated.
在该试验中，化合物I-1、化合物I-3、化合物I-9、化合物I-10、化合物I-13、化合物I-14、化合物I-15、化合物I-16、化合物I-17、化合物I-18、化合物I-21、化合物I-22、化合物I-23、化合物I-25在3.125ppm(3.125mg/L)下分别对西花蓟马幼虫显示出超过90％的致死率。In this test, compound I-1, compound I-3, compound I-9, compound I-10, compound I-13, compound I-14, compound I-15, compound I-16, compound I-17, Compound I-18, Compound I-21, Compound I-22, Compound I-23, and Compound I-25 respectively showed a lethality rate of more than 90% to western flower thrips larvae at 3.125 ppm (3.125 mg/L).
按照上述方法，选取化合物I-1、化合物I-25、化合物I-10与CN106045962A中公开的化合物(X.82)及氟噁唑酰胺分别进行杀西花蓟马幼虫的平行试验。试验结果见下表2。According to the above method, compound I-1, compound I-25, compound I-10, compound (X.82) disclosed in CN106045962A and fluoxazoleamide were selected to conduct parallel experiments to kill western flower thrips larvae. The test results are shown in Table 2 below.
表2

Table 2

应用例5Application example 5
敏感小菜蛾活性试验：Activity test on sensitive diamondback moth:
供试靶标：小菜蛾(Plutella xylostella)，3龄幼虫，室内饲养的敏感品系。Test target: Diamondback moth (Plutella xylostella), 3rd instar larvae, a sensitive strain reared indoors.
试验方法：首先选择温室栽培的新鲜甘蓝叶片，将甘蓝叶片用打孔器达成直径为3cm的圆形叶蝶，按试验设计从低剂量到高剂量的顺序，放入配制好的药液中浸渍10s，自然阴干后置于放有滤纸的直径为9cm的培养皿中，接入整齐的健康试虫，每处理10头，每处理3次重复，另设空白对照。Test method: First, select fresh cabbage leaves cultivated in the greenhouse, use a hole punch to make the cabbage leaves into round leaves with a diameter of 3cm, and put them into the prepared medicinal solution in order from low dose to high dose according to the test design. 10 s, dry naturally in the shade, then place in a 9cm diameter petri dish with filter paper, and insert neat healthy test worms, 10 for each treatment, repeat 3 times for each treatment, and set up a blank control.
在该试验中，化合物I-1、化合物I-3、化合物I-9、化合物I-10、化合物I-13、化合物I-14、化合物I-15、化合物I-16、化合物I-17、化合物I-18、化合物I-21、化合物I-22、化合物I-23、化合物I-25在1ppm(1mg/L)下分别对小菜蛾显示出超过90％的致死率。In this test, compound I-1, compound I-3, compound I-9, compound I-10, compound I-13, compound I-14, compound I-15, compound I-16, compound I-17, Compound I-18, Compound I-21, Compound I-22, Compound I-23, and Compound I-25 each showed a lethality rate of more than 90% to Diamondback moth at 1 ppm (1 mg/L).
按照上述方法，选取化合物I-1、化合物I-25、与专利CN106045962A中公开的化合物(X.82)及氟噁唑酰胺分别进行杀小菜蛾的平行试验。试验结果见下表3。According to the above method, compound I-1, compound I-25, compound (X.82) disclosed in the patent CN106045962A and fluoxazoleamide were selected to conduct parallel tests to kill diamondback moth. The test results are shown in Table 3 below.
表3

table 3

从表3的数据可见，在低浓度(小于等于1ppm)下，本发明的化合物I-1、I-25用药三天后的死亡率显著高于CN106045962A中公开的化合物(X.82)和氟噁唑酰胺。因此，本发明的化合物I-1、I-25在较低的浓度下使用，仍然对小菜蛾具有较高的杀虫效果。It can be seen from the data in Table 3 that at low concentrations (less than or equal to 1 ppm), the mortality rate of compounds I-1 and I-25 of the present invention after three days of administration is significantly higher than that of the compound (X.82) disclosed in CN106045962A and fluorine. Azoleamide. Therefore, the compounds I-1 and I-25 of the present invention still have a high insecticidal effect on diamondback moth when used at lower concentrations.
应用例6Application example 6
抗性小菜蛾活性试验：Activity test against diamondback moth:
采用浸叶法，取适量萝卜叶浸药10s后，置于垫有滤纸的塑料培养皿中自然阴干，每皿接2龄小菜蛾10头，置于24℃、光照(16/8h)观察室内。72h后观察，以毛笔轻触虫体，无反应视为死虫，重复3次，另设不加药剂的空白对照。Using the leaf dipping method, take an appropriate amount of radish leaves and soak them for 10 seconds, then place them in a plastic petri dish lined with filter paper to dry naturally in the shade. Pick 10 2-year-old diamondback moths in each dish and place them in an observation room at 24°C and light (16/8h). . Observe after 72 hours. Touch the insect body lightly with a brush. If there is no reaction, it will be regarded as dead. Repeat three times and set up a blank control without adding any chemicals.
选取化合物I-1、化合物I-9、化合物I-25与氟噁唑酰胺及氯虫苯甲酰胺对照分别进行杀抗性小菜蛾的平行试验。试验结果见下表4。Compound I-1, compound I-9, and compound I-25 were selected to be compared with fluoxazolamide and chlorantraniliprole to conduct parallel tests on killing the resistant diamondback moth. The test results are shown in Table 4 below.
表4

Table 4

从表4的数据可见，在很低浓度(0.2ppm)下，采用萝卜叶浸液法测试，本发明的化合物I-1、I-25用药三天后对抗性小菜蛾的的死亡率均达到了100％，具有极高的杀抗性小菜蛾活性，活性显著高于上市杀虫剂氯虫苯甲酰胺及氟噁唑酰胺。因此，本发明的化合物I-1、I-25在很低的浓度下使用，仍然对抗性小菜蛾具有很高的杀虫效果。From the data in Table 4, it can be seen that at a very low concentration (0.2 ppm), using the radish leaf infusion method to test, the mortality of the resistant diamondback moth after three days of administration of the compounds I-1 and I-25 of the present invention has reached 100%, with extremely high activity against resistant diamondback moth, and its activity is significantly higher than that of chlorantraniliprole and fluoxazamide on the market. Therefore, the compounds I-1 and I-25 of the present invention still have a high insecticidal effect against the resistant diamondback moth when used at very low concentrations.
部分相同化合物在应用例6中对抗性小菜蛾活性测试的致死率数据明显高于在应用例5中对敏感小菜蛾活性测试的致死率数据，这是由于实验方法不同、实验条件不同、虫源不同等原因导致，如应用例5中采用甘蓝叶片浸叶，应用例6中采用萝卜叶片浸叶，甘蓝叶片厚度远大于萝卜叶片，昆虫在取食相同重量的食材时，取食甘蓝叶片摄入的化合物剂量明显更低，故不同方法测试时致死率会有一定差异。The lethality data of some of the same compounds tested against the resistant Diamondback moth in Application Example 6 were significantly higher than the lethality data tested against the sensitive Diamondback moth in Application Example 5. This is due to different experimental methods, different experimental conditions, and insect sources. It is caused by different reasons. For example, in Application Example 5, cabbage leaves are used to soak leaves, and in Application Example 6, radish leaves are used to soak leaves. The thickness of cabbage leaves is much larger than that of radish leaves. When insects eat the same weight of food, they ingest the cabbage leaves. The dose of the compound is significantly lower, so there will be certain differences in the lethality rate when tested by different methods.
以上详细描述了本发明的优选实施方式，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，包括各个技术特征以任何其它的合适方式进行组合，这些简单变型和组合同样应当视为本发明所公开的内容，均属于本发明的保护范围。 The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical concept of the present invention, many simple modifications can be made to the technical solution of the present invention, including the combination of various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the disclosed content of the present invention. All belong to the protection scope of the present invention.

Claims (10)

  1. 一种具有式(I)所示结构的含五元杂环的化合物或其农业上可接受的盐，或其立体异构体，
    A five-membered heterocyclic compound having a structure represented by formula (I) or an agriculturally acceptable salt thereof, or a stereoisomer thereof,
    式(I)中，In formula (I),
    X1和X3各自独立地为F、Cl、Br、I或CF3；X 1 and X 3 are each independently F, Cl, Br, I or CF 3 ;
    X2为H、F、Cl、Br、I或CF3； X2 is H, F, Cl, Br, I or CF3 ;
    R1选自氢、取代或未被取代的C1-C6烷基、C1-C4烷氧基C1-C4烷基、C1-C10烷基羰基、卤代C1-C10烷基羰基、C3-C10环烷基羰基、C3-C10环烷基甲基羰基、C1-C10烷氧基羰基、卤代C1-C10烷氧基羰基、C1-C10烷氧基C1-C4烷基羰基、卤代C1-C10烷氧基C1-C4烷基羰基、C1-C10烷基草酰基、卤代C1-C10烷基草酰基、C1-C10烷氧基草酰基、卤代C1-C10烷氧基草酰基、C1-C10烷基磺酰基、卤代C1-C10烷基磺酰基、C1-C10烷基亚磺酰基、卤代C1-C10烷基亚磺酰基、取代或未取代的苯甲酰基、取代或未取代的苯磺酰基、取代或未取代的杂芳基羰基、取代或未被取代的C1-C6烷基或C1-C4烷氧基C1-C4烷基； R1 is selected from hydrogen, substituted or unsubstituted C1 - C6 alkyl, C1 - C4 alkoxy C1-C4 alkyl , C1 - C10 alkylcarbonyl, halogenated C1 -C10 alkylcarbonyl, C3 - C10 cycloalkylcarbonyl, C3 - C10 cycloalkylmethylcarbonyl, C1- C10 alkoxycarbonyl, halogenated C1- C10 alkoxycarbonyl, C1- C10 alkoxy C1 -C4 alkylcarbonyl, halogenated C1 - C10 alkoxy C1- C4 alkylcarbonyl, C1 - C10 alkyloxalyl, halogenated C1-C10 alkyloxalyl, C1 - C10 alkoxyoxalyl, halogenated C1 - C10 alkoxyoxalyl, C1-C10 alkylsulfonyl, halogenated C1 - C10 alkylsulfonyl, C3 - C10 cycloalkylmethylcarbonyl, C1 - C10 alkoxycarbonyl, halogenated C1-C10 alkoxycarbonyl, C1 -C10 alkoxy C1 - C4 alkylcarbonyl, halogenated C1 - C10 alkoxy C1-C4 alkylcarbonyl, 1 -C 10 alkylsulfinyl, halogenated C 1 -C 10 alkylsulfinyl, substituted or unsubstituted benzoyl, substituted or unsubstituted benzenesulfonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 4 alkyl;
    n选自0、1或2。n is selected from 0, 1 or 2.
  2. 根据权利要求1所述的化合物，其中，X1、X2和X3各自独立地选自F、Cl、Br或CF3；The compound according to claim 1, wherein X 1 , X 2 and X 3 are each independently selected from F, Cl, Br or CF 3 ;
    R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、三氟甲基、三氯甲基、三氟乙基或三氟甲氧基甲基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C3-C6环烷基羰基、C3-C6环烷基甲基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、C1-C4烷氧基C1-C2烷基羰基、卤代C1-C4烷氧基C1-C2烷基羰基、C1-C6烷基草酰基、卤代C1-C6烷基草酰基、C1-C4烷氧基草酰基、卤代C1-C4烷氧基草酰基、C1-C4烷基磺酰基、卤代C1-C4烷基磺酰基、C1-C4烷基亚磺酰基、卤代C1-C4烷基亚磺酰基、卤素取代或未取代的苯甲酰基、卤素取代或未取代的苯磺酰基、含有1-2个选自O、S或N的杂原子取代的五元或六元芳杂环取代的羰基。R 1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxyethyl, ethoxy Methyl, ethoxyethyl, trifluoromethyl, trichloromethyl, trifluoroethyl or trifluoromethoxymethyl, C 1 -C 6 alkylcarbonyl, halogenated C 1 -C 6 alkyl Carbonyl group, C 3 -C 6 cycloalkyl carbonyl group, C 3 - C 6 cycloalkyl methyl carbonyl group, C 1 - C 6 alkoxy carbonyl group, halogenated C 1 - C 6 alkoxy carbonyl group, C 1 - C 4 alkoxy C 1 -C 2 alkylcarbonyl, halo C 1 -C 4 alkoxy C 1 -C 2 alkyl carbonyl, C 1 -C 6 alkyl oxalyl, halo C 1 -C 6 Alkyl oxalyl, C 1 -C 4 alkoxyoxalyl, halogenated C 1 -C 4 alkoxyoxalyl, C 1 -C 4 alkylsulfonyl, halogenated C 1 -C 4 alkylsulfonyl , C 1 -C 4 alkylsulfinyl group, halogenated C 1 -C 4 alkylsulfinyl group, halogen substituted or unsubstituted benzoyl group, halogen substituted or unsubstituted benzenesulfonyl group, containing 1-2 A five- or six-membered aromatic heterocyclic substituted carbonyl group substituted with a heteroatom selected from O, S or N.
  3. 根据权利要求1或2所述的化合物，其中，X1、X2和X3各自独立地选自F、Cl或CF3；The compound according to claim 1 or 2, wherein X 1 , X 2 and X 3 are each independently selected from F, Cl or CF 3 ;
    R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、乙酰基、丙酰基、正丁酰基、环丙基甲酰基、甲氧基甲酰基、甲氧基乙酰基、甲氧基乙酰基、甲氧基草酰基、乙氧基草酰基。 R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, acetyl, propionyl, n-butyryl, cyclopropylformyl, methoxyformyl, methoxyacetyl, methoxyacetyl, methoxyoxalyl, ethoxyoxalyl.
  4. 根据权利要求1-3中任意一项所述的化合物，其中，所述化合物选自如下结构所示的化合物中的至少一种，或其农业上可接受的盐，或其立体异构体：


    The compound according to any one of claims 1 to 3, wherein the compound is selected from at least one compound represented by the following structure, or an agriculturally acceptable salt thereof, or a stereoisomer thereof:


    其中，化合物I-13、I-14、I-15、I-16、I-17、I-18、I-19、I-20为化合物I-1的立体异构体；化合物I-27、I-29、I-30为化合物I-25的立体异构体，化合物I-28为化合物I-26的立体异构体。Among them, compounds I-13, I-14, I-15, I-16, I-17, I-18, I-19, and I-20 are stereoisomers of compound I-1; compounds I-27, I-29 and I-30 are stereoisomers of compound I-25, and compound I-28 is a stereoisomer of compound I-26.
  5. 一种含五元杂环的化合物的制备方法，其特征在于，该制备方法包括：A method for preparing a compound containing a five-membered heterocyclic ring, characterized in that the preparation method includes:
    (1)在第一溶剂中，在缩合剂存在下，将化合物II和化合物III进行第一反应，得到化合物IV；(1) In the first solvent, in the presence of a condensing agent, the compound II and the compound III are subjected to the first reaction to obtain the compound IV;
    (2)在第二溶剂中，在碱性物质存在下，将所述化合物IV和化合物V进行第二反应，得到化合物I； (2) In the second solvent, in the presence of a basic substance, the compound IV and the compound V are subjected to a second reaction to obtain the compound I;
    其中，所述化合物II具有式(II)所示的结构，所述化合物III具有式(III)所示的结构，所述化合物IV具有式(IV)所示的结构，所述化合物V具有式(V)所示的结构，所述化合物I具有式(I)所示的结构，
    Wherein, the compound II has the structure represented by formula (II), the compound III has the structure represented by formula (III), the compound IV has the structure represented by formula (IV), and the compound V has the formula The structure represented by (V), the compound I has the structure represented by formula (I),
    式(I)、式(II)、式(III)、式(IV)和式(V)中，In formula (I), formula (II), formula (III), formula (IV) and formula (V),
    X1和X3各自独立地为F、Cl、Br、I或CF3；X 1 and X 3 are each independently F, Cl, Br, I or CF 3 ;
    X2为H、F、Cl、Br、I或CF3；X 2 is H, F, Cl, Br, I or CF 3 ;
    R1选自氢、取代或未被取代的C1-C6烷基、C1-C4烷氧基C1-C4烷基、C1-C10烷基羰基、卤代C1-C10烷基羰基、C3-C10环烷基羰基、C3-C10环烷基甲基羰基、C1-C10烷氧基羰基、卤代C1-C10烷氧基羰基、C1-C10烷氧基C1-C4烷基羰基、卤代C1-C10烷氧基C1-C4烷基羰基、C1-C10烷基草酰基、卤代C1-C10烷基草酰基、C1-C10烷氧基草酰基、卤代C1-C10烷氧基草酰基、C1-C10烷基磺酰基、卤代C1-C10烷基磺酰基、C1-C10烷基亚磺酰基、卤代C1-C10烷基亚磺酰基、取代或未取代的苯甲酰基、取代或未取代的苯磺酰基、取代或未取代的杂芳基羰基、取代或未被取代的C1-C6烷基或C1-C4烷氧基C1-C4烷基；R 1 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 10 alkylcarbonyl, halo C 1 - C 10 alkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 cycloalkylmethylcarbonyl, C 1 -C 10 alkoxycarbonyl, halogenated C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkoxy C 1 -C 4 alkylcarbonyl, halo C 1 -C 10 alkoxy C 1 -C 4 alkyl carbonyl, C 1 -C 10 alkyl oxalyl, halo C 1 -C 10 alkyl oxalyl, C 1 -C 10 alkoxy oxalyl, halogenated C 1 -C 10 alkoxy oxalyl, C 1 -C 10 alkyl sulfonyl, halogenated C 1 -C 10 alkyl Sulfonyl group, C 1 -C 10 alkylsulfinyl group, halogenated C 1 -C 10 alkylsulfinyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted benzenesulfonyl group, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 4 alkyl;
    L选自氟、氯、溴、碘、甲磺酰基、三氟甲磺酰基、苯磺酰基或对甲苯磺酰基。L is selected from fluorine, chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl or p-toluenesulfonyl.
  6. 根据权利要求5所述的制备方法，其中，所述缩合剂选自二环己基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、氯化亚砜或草酰氯中的一种或多种；The preparation method according to claim 5, wherein the condensation agent is selected from dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, One or more of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, sulfoxide chloride or oxalyl chloride;
    和/或，所述第一溶剂和所述第二溶剂各自独立地选自甲苯、二甲苯、二氯甲烷、二氯乙烷、乙腈、N,N-二甲基甲酰胺、四氢呋喃和丙酮中的一种或多种；And/or, the first solvent and the second solvent are each independently selected from toluene, xylene, dichloromethane, dichloroethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran and acetone. one or more;
    和/或，所述碱性物质选自三乙胺、二异丙基乙基胺、吡啶、N-甲基吗啉、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、氢化钠和氨基钠中的一种或多种。And/or, the alkaline substance is selected from triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, One or more of potassium bicarbonate, sodium hydride and sodium amide.
  7. 一种权利要求1-4中任意一项所述的化合物或权利要求5-6中任意一项所述的制备方法制得的化合物在防治无脊椎动物害虫中的应用。Application of a compound according to any one of claims 1 to 4 or a compound prepared by a preparation method according to any one of claims 5 to 6 in preventing and controlling invertebrate pests.
  8. 一种农业用组合物，其特征在于，所述组合物包含至少一种权利要求1-4中任意一项所述的化合物或权利要求5-6中任意一项所述的制备方法制得的化合物以及至少一种液体载体或固体载体。An agricultural composition, characterized in that the composition contains at least one compound according to any one of claims 1-4 or prepared by the preparation method according to any one of claims 5-6. compound and at least one liquid or solid carrier.
  9. 一种防治无脊椎动物害虫的方法，其特征在于，所述方法包括：将杀虫有效量的至少一种权利要求1-4中任意一项所述的化合物或权利要求5-6中任意一项所述的制备方法制得的化合物直接或间接施于需要控制的无脊椎动物害虫和/或其生长的介质上。A method for controlling invertebrate pests, characterized in that the method includes: adding a pesticidally effective amount of at least one compound according to any one of claims 1-4 or any one of claims 5-6 The compound prepared by the preparation method described in the item is applied directly or indirectly to the invertebrate pests that need to be controlled and/or the medium in which they grow.
  10. 根据权利要求9所述的方法，其中，所述方法包括：用杀虫有效量的至少一种所述的化合物处理无脊椎动物害虫生长的植物；The method of claim 9, wherein said method comprises: treating a plant on which an invertebrate pest is growing with a pesticidally effective amount of at least one of said compounds;
    和/或，所述杀虫有效量为每公顷5g-3000g；And/or, the insecticidal effective dose is 5g-3000g per hectare;
    和/或，所述无脊椎动物害虫为螨科害虫、昆虫和/或线虫。 And/or, the invertebrate pests are mite pests, insects and/or nematodes.
PCT/CN2023/119499 2022-09-21 2023-09-18 Compound containing five-membered heterocycle, preparation method therefor, and application thereof WO2024061178A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1930136A (en) * 2004-03-05 2007-03-14 日产化学工业株式会社 Isoxazoline-substituted benzamide compound and noxious organism control agent
JP2009108046A (en) * 2007-10-10 2009-05-21 Nissan Chem Ind Ltd Insecticidal, miticidal, nematicidal, molluscicidal, sterilizing, or bactericidal composition and method for controlling pest
CN102939288A (en) * 2010-06-11 2013-02-20 先正达参股股份有限公司 Process for the preparation of dihydropyrrole derivatives
JP2014040412A (en) * 2012-07-27 2014-03-06 Sumitomo Chemical Co Ltd Pest control composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1930136A (en) * 2004-03-05 2007-03-14 日产化学工业株式会社 Isoxazoline-substituted benzamide compound and noxious organism control agent
JP2009108046A (en) * 2007-10-10 2009-05-21 Nissan Chem Ind Ltd Insecticidal, miticidal, nematicidal, molluscicidal, sterilizing, or bactericidal composition and method for controlling pest
CN102939288A (en) * 2010-06-11 2013-02-20 先正达参股股份有限公司 Process for the preparation of dihydropyrrole derivatives
JP2014040412A (en) * 2012-07-27 2014-03-06 Sumitomo Chemical Co Ltd Pest control composition

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