Fluorine-containing substituted bisamide derivatives, processes for their preparation and uses thereof

Abstract

The application relates to the technical field of pesticide insecticides, in particular to a fluorine-substituted bisamide derivative, a preparation method and application thereof. The fluorine-substituted bisamide derivative is a compound shown in formula I, or a stereoisomer, a tautomer, an isotopic derivative and a pesticide-acceptable salt thereof. Biological activity tests show that the derivative has good insecticidal activity on oriental armyworm and Spodoptera exigua, and can be used for the prevention and control of agricultural pests, in particular lepidopteran pests. The fluorine-substituted bisamide derivative can improve insecticidal activity, has a wide insecticidal spectrum, and improves the resistance of existing compounds, avoids or delays the generation of resistance.

Description

Technical Field

[0001] This application relates to the field of agricultural insecticides, specifically to a class of fluorine-substituted diamide derivatives, their preparation methods, and uses. Background Technology

[0002] For decades, pesticides have played an indispensable role in ensuring human food supply and protecting human safety (by preventing and controlling the spread of diseases) and health (by killing pathogens and controlling their emergence), significantly reducing property damage. At the same time, pesticides are also essential production materials for ensuring stable agricultural production and increased income, and are vital strategic resources. However, in recent years, problems such as pest resistance and the serious environmental pollution caused by traditional pesticides have placed higher demands on pesticide development. Therefore, it is necessary to continuously develop highly efficient, low-toxicity, environmentally friendly, low-cost insecticides with novel modes of action to meet the needs of modern society.

[0003] In 2001, DuPont successfully developed o-formamidobenzamide compounds, which were proven to be ryanodine receptor insecticides. Studies have shown that o-formamidobenzamide compounds have a broader spectrum of insecticidal activity, exhibiting excellent insecticidal effects not only against lepidopteran pests but also against dipteran, hemiptera, and coleopteran pests. In recent years, DuPont, Bayer AgroScience, Syngenta, and many domestic research institutions have applied for numerous patents and reported a large number of compounds, such as: WO2003016300A1, WO2004067528A1, WO2005118552A2, WO2007031213A1, WO2008137970A1, and CN 103467380A.

[0004] There are various methods and strategies for creating new pesticides. Among them, fluorine, as a very special chemical element, has been widely used in the creation of new pesticides. On the one hand, because the van der Waals radii of fluorine atoms are similar to those of hydrogen atoms, replacing hydrogen atoms in compounds with fluorine atoms can reduce the hydrophilicity of the compounds and increase their lipid solubility. On the other hand, fluorine is the most electronegative element, which can change the electronic effects and physicochemical properties of compounds, resulting in significant changes in their biological activity. Relevant data from the past 10 years show that among more than 100 newly developed chemical pesticides, fluorine-containing pesticides account for nearly half. Fluorine-containing pesticides have the characteristics of high efficiency, low toxicity, and environmental friendliness, which are in line with the trend of contemporary pesticide development and have received increasing attention, becoming a key focus of the global pesticide industry.

[0005] There is still a need in this field to research and develop novel fluorinated o-formamidobenzamide compounds (i.e., diamide compounds) with excellent insecticidal activity and a broad insecticidal spectrum in order to improve the problem of pesticide resistance. Summary of the Invention

[0006] To address the technical problems existing in the prior art, the applicant of this application synthesized a class of fluorine-substituted diamide derivatives. Bioactivity tests showed that these derivatives exhibited good insecticidal activity against the fall armyworm, diamondback moth, and other insecticidal pests. These fluorine-substituted diamide derivatives can improve the resistance of existing compounds, enhance insecticidal activity, and possess a broad insecticidal spectrum.

[0007] In a first aspect, this application provides a fluorinated diamide derivative, wherein the fluorinated diamide derivative is a compound represented by Formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pesticide-acceptable salt thereof.

[0008]

[0009] R1, R3, and R5 are each independently selected from H and C1-C8 alkyl groups;

[0010] R2 is selected from C6-C10 haloaryl and 5-10 halogenated heteroaryl;

[0011] R4 and R7 are each independently selected from halogens;

[0012] R6 is selected from C1-C8 haloalkyl groups;

[0013] n is selected from 0, 1, 2, 3, 4 or 5.

[0014] In one set of embodiments, the halogen is selected from fluorine, chlorine, bromine, and iodine.

[0015] In one set of implementations, R1 and R3 are each independently selected from H.

[0016] In one set of embodiments, R4 is selected from fluorine and chlorine.

[0017] In one set of embodiments, R5 is selected from methyl.

[0018] In one set of embodiments, the compound represented by Formula I is as shown in Formula I-1.

[0019]

[0020] In one set of embodiments, R2 is selected from dihalophenyl, preferably difluorophenyl, and more preferably 2,4-difluorophenyl.

[0021] In one set of embodiments, R6 is selected from C1-C8 fluoroalkyl groups, preferably fluoroethyl groups, and more preferably -CH2CH2F or -CH2CHF2.

[0022] In one set of embodiments, R7 is independently selected from fluorine and chlorine. Preferably, -(R7)n Selected from 4-F, 2,4-difluoro, 2,3,4-trifluoro, 2,4,5-trifluoro, 2,4,6-trifluoro, 2-F-4-Cl, 2-Cl-4-F, 2-Cl-4,5-difluoro, and 2-Cl-4,6-difluoro.

[0023] Specifically, the compound represented by Formula I can be selected from one of the following:

[0024]

[0025]

[0026] In a second aspect, this application provides a method for preparing the fluorine-substituted diamide derivatives described in the first aspect, which is carried out according to the following synthetic route:

[0027]

[0028] The groups R1-R7 and n are defined as described in the first aspect, and R8 is a C1-C8 alkyl group, preferably a C1-C4 alkyl group, and more preferably an ethyl, n-propyl, or isopropyl group.

[0029] In one set of embodiments, the preparation method of the fluorine-substituted diamide derivative described in the first aspect includes the following specific preparation steps:

[0030] (1) The compound shown in Formula II is prepared by reacting the phenylhydrazine compound shown in Formula III with the maleic acid diester shown in Formula III in the presence of a base.

[0031] (2) The compound shown in formula IV was reacted in the presence of glacial acetic acid, persulfate and sulfuric acid to prepare the compound shown in formula V;

[0032] (3) The compound shown in formula V is reacted with iodide R6-I in the presence of an acid-binding agent to prepare the compound shown in formula VI;

[0033] (4) The compound shown in formula VI is prepared by ester hydrolysis in the presence of a base to prepare the compound shown in formula VII;

[0034] (5) Prepare the corresponding acyl chloride compound from the compound shown in Formula VII, and then condense it with the compound shown in Formula VIII in the presence of an acid-binding agent to obtain the compound shown in Formula I.

[0035] In step (1), the alkali is an organic alkali, preferably an alkali metal alkoxide, more preferably a sodium alkoxide such as sodium ethoxide or sodium methoxide. In step (2), the persulfate is an alkali metal persulfate, preferably potassium persulfate or sodium persulfate. In step (3), the acid-binding agent is an inorganic alkali, preferably an alkali metal carbonate, more preferably potassium carbonate, sodium carbonate, or lithium carbonate. In step (4), the alkali is an inorganic alkali, preferably an alkali metal hydroxide, more preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide. In step (5), the acid-binding agent is an organic or inorganic alkali, preferably diisopropylethylamine (DIPEA) or triethylamine.

[0036] In one set of embodiments, the preparation method of the fluorine-substituted diamide derivative described in the first aspect includes the following specific preparation steps:

[0037] (1) Sodium alkoxide is prepared by adding metallic sodium to alcohols such as ethanol or methanol, then phenylhydrazine compound shown in formula II is added, and after heating and refluxing, maleic acid diester shown in formula III is added dropwise. The reaction is continued under reflux, the solvent is removed by vacuum concentration, and the compound shown in formula IV is obtained by extraction with saturated sodium bicarbonate aqueous solution.

[0038] (2) Dissolve the compound shown in formula IV in acetonitrile, add concentrated sulfuric acid, potassium persulfate and glacial acetic acid, reflux the reaction, remove the solvent under reduced pressure, and purify by column chromatography to obtain the compound shown in formula V.

[0039] (3) Dissolve the compound shown in formula V in DMF, add potassium carbonate and iodide R6-I and heat to react, dilute with ethyl acetate, extract with saturated brine, collect the organic phase, remove the solvent under reduced pressure, and purify by column chromatography to prepare the compound shown in formula VI.

[0040] (4) Dissolve the compound shown in formula VI in alcohol such as methanol or ethanol, add lithium hydroxide aqueous solution, hydrolyze the ester at room temperature, remove the alcohol under reduced pressure, add a small amount of water, adjust the pH to about 1-2 with hydrochloric acid aqueous solution, precipitate a large amount of white solid, filter, and obtain the compound shown in formula VII.

[0041] (5) The compound shown in Formula VII was dissolved in dichloromethane, oxalyl chloride and DMF were added, the reaction was carried out at room temperature, and the solvent was removed under reduced pressure to obtain the corresponding acyl chloride compound. Under ice-salt bath, the tetrahydrofuran solution of the acyl chloride compound was added dropwise to the tetrahydrofuran solution of the compound shown in Formula VIII and DIPEA, the reaction was carried out at room temperature, the solvent was removed under reduced pressure, the mixture was diluted with dichloromethane and extracted with hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine respectively, the organic phase was collected, the organic phase was removed under reduced pressure, and the mixture was recrystallized with dichloromethane and n-hexane, filtered, and the compound shown in Formula I was obtained as a white solid.

[0042] In a third aspect, this application also provides an insecticidal composition having at least one of the fluorine-substituted diamide derivatives described in the first aspect of this application as an active ingredient; the insecticidal composition further comprises a pesticide-acceptable carrier.

[0043] The insecticidal composition of this application can be applied in the form of a formulation, wherein the fluorinated diamide derivative is dissolved or dispersed in a carrier as an active ingredient or formulated into a formulation for easier dispersion when used as an insecticide. The insecticidal composition can be formulated into various dosage forms such as liquids, emulsifiable concentrates, suspensions, aqueous suspensions, microemulsions, emulsions, water-in-oil emulsions, powders, wettable powders, soluble powders, granules, water-dispersible granules, or capsules.

[0044] The insecticidal composition of this application may contain one or more other insecticides, fungicides, herbicides, plant growth regulators, or fertilizers.

[0045] This application also discloses the use of the fluorinated substituted diamide derivatives described in the first aspect or the insecticidal composition described in the third aspect in controlling plant pests; preferably for use in agriculture, forestry, horticulture, and sanitation. Preferably, an insecticidally effective amount of the fluorinated substituted diamide derivatives or the insecticidal composition described above is used on plants, and / or pests, and / or habitats.

[0046] This application also discloses a method for controlling plant pests, comprising applying an effective amount of the fluorine-substituted diamide derivative or the insecticidal composition described in the first aspect to the plant and / or pests and / or habitat.

[0047] The fluorine-substituted diamide derivatives described in the first aspect of this application are suitable for controlling various agricultural, forestry, and horticultural pests, sanitary pests, and nematodes that harm plants.

[0048] The pests described in this application include Lepidoptera, Coleoptera, Hemiptera, Thysanoptera, Diptera, Orthoptera, Homoptera, Isoptera, Hymenoptera, Blattodea, mites, nematodes, etc. The preferred pests are Lepidoptera.

[0049] Preferably, the pests include, but are not limited to: armyworms, bollworms, diamondback moths, beet armyworms, cotton bollworms, cabbage caterpillars, rice stem borers, rice leaf rollers, corn borers, sugarcane borers, citrus leafminers, codling moths, cutworms, mole crickets, wireworms, flea beetles, beetles, stink bugs, tussock moths, flower thrips, rice thrips, watermelon thrips, melon thrips, palm thrips, yellow thrips, onion thrips, ginger thrips, mango thrips, peach aphids, cotton aphids, alfalfa aphids, apple aphids, wheat aphids, gray planthoppers, brown planthoppers, white-backed planthoppers, stink bugs, mosquitoes, flies, termites, red imported fire ants, cockroaches, carmine spider mites, citrus red spider mites, and nematodes.

[0050] More preferably, the pest is an armyworm, a fall armyworm, or a diamondback moth.

[0051] The fluorine-substituted diamide derivatives described in the first aspect of this application or the insecticidal compositions of the third aspect are applicable to a wide range of plants, including but not limited to the following: vegetables, such as cabbage, broccoli, cauliflower, bok choy, Chinese cabbage, radish, mustard greens, cucumber, loofah, watermelon, cantaloupe, pumpkin, zucchini, tomato, eggplant, chili pepper, green pepper, green bean, cowpea, adzuki bean, broad bean, pea, celery, spinach, lettuce, asparagus, onion, scallion, garlic, potato, yam, taro, lotus root; cereals, such as rice, barley, wheat, buckwheat, rye, oats, corn, sorghum, millet; and fruit trees. Fruits and vegetables include: apples, pears, peaches, citrus fruits, navel oranges, lemons, grapefruits, cherries, plums, apricots, grapes, and bananas; oil crops such as peanuts, soybeans, rapeseed, sunflowers, and sesame; sugar crops such as sugar beets and sugarcane; garden flowers such as camphor trees, sycamores, peonies, roses, chrysanthemums, and orchids; pasture grasses such as orchard grasses, sorghum, timothy grasses, alfalfa, purple alfalfa, clover, and lupins; turfgrasses such as Bermuda grass, Kentucky bluegrass, bromegrass, fescue, zoysia grass, and creeping bentgrass; other crops such as cotton, jujube trees, strawberries, blueberries, sweet potatoes, tobacco, walnuts, and tea trees; forestry, public health, and household hygiene areas.

[0052] The fluorine-substituted diamide derivatives described in the first aspect of this application can be used in conjunction with one or more other insecticides, fungicides, herbicides, plant growth regulators, or fertilizers.

[0053] The beneficial effects of this invention are as follows:

[0054] This application provides a class of fluorine-substituted diamide derivatives, which exhibit good insecticidal activity against pests such as the fall armyworm, the diamondback moth, and the oriental armyworm, and can be used for the control of agricultural pests, especially lepidopteran pests. These fluorine-substituted diamide derivatives can improve the resistance of existing compounds, enhance insecticidal activity, and possess a broad insecticidal spectrum. They can be used alternately with existing insecticides to avoid or delay the development of resistance. Detailed Implementation

[0055] The term "haloalkyl" refers to a monovalent saturated aliphatic hydrocarbon group, preferably containing 1-20, 1-18, 1-16, 1-12, or 1-10 carbon atoms, more preferably 1-8 carbon atoms (C1-8 alkyl) straight-chain or branched group (the number of carbon atoms is between 1 and 8, specifically 1, 2, 3, 4, 5, 6, 7, or 8), more preferably containing 1-6 carbon atoms (i.e., C1-6 alkyl, the number of carbon atoms is between 1 and 6, specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0056] The aryl group in the term "haloaryl" refers to an aromatic carbocyclic system containing 6-14 or 6-10 carbon atoms, whether monocyclic, bicyclic, or polycyclic. Examples of aryl groups include phenyl and naphthyl groups, such as 1-naphthyl, 2-naphthyl, 3-naphthyl, and 4-naphthyl.

[0057] The term "halogenated heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing a 5-20 member structure, preferably a 5-10 or 6-10 member structure, and more preferably a 5-6 member structure, wherein one, two, three, four, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, three, or four. The heteroaryl group can be an aromatic monocyclic ring containing one or two 5-6 member structures selected from N, S, or O, preferably an aromatic monocyclic ring containing one or two N or S member structures. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroloyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyrrolo[2,3b]pyridyl, imidazoleyl [1,2a]pyridyl, pyrazolo[1,5a]pyridyl, pyrazolo[1,5a]pyrimidinyl, imidazo[1,2b]pyridazinyl, [1,2,4]triazolo[4,3b]pyridazinyl, [1,2,4]triazolo[1,5a]pyrimidinyl, [1,2,4]triazolo[1,5a]pyridyl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl, quinoline-8-yl, etc.

[0058] The fluorine-substituted diamide derivatives described in this application are interpreted as including the compound of Formula I and its stereoisomers, tautomers, isotopic derivatives, or pesticide-acceptable salts thereof. The stereoisomers, tautomers, isotopic derivatives, or pesticide-acceptable salts of the compound are obtained through conventional techniques in the art and exert the same or similar effects in vitro and in vivo through substantially the same mechanism of action as the compound.

[0059] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers. Configurational isomers include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometric isomers may be present in this compound. Optical isomers refer to substances with identical molecular structures and similar physicochemical properties, but different optical rotations. The compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds with asymmetrically substituted carbon atoms (having equal numbers of R and S configurations) are racemic at those carbon atoms. Having an excess of atoms in one configuration (relative to another) results in a higher quantity of that configuration, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and even more preferably an excess greater than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0060] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0061] The term "isotope derivative" refers to compounds of the present invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine include, but are not limited to: 2 H, 3 H,13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, 80 Br and 125 I. Compounds containing these and / or other isotopes are within the scope of this invention. The isotopically labeled compounds of this invention can be prepared using general methods well known to those skilled in the art.

[0062] The term "pesticide-acceptable salt" refers to a salt obtained by reacting the fluorinated diamide derivative of this application with a chemically acceptable acid, wherein the chemically acceptable acid can be an inorganic acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid) or an organic acid (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, or benzoic acid); the pesticide-acceptable salt can also be a salt obtained by reacting the fluorinated diamide derivative of this application with a chemically acceptable base, wherein the chemically acceptable base can be an inorganic base (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) or an organic base (such as trimethylamine, triethylamine, etc.). Further, the pesticide-acceptable salt can be a potassium salt, sodium salt, ammonium salt, calcium salt, pyridine salt, choline salt, hydrochloride salt, phosphate salt, acetate salt, benzenesulfonate salt, or oxalate salt.

[0063] The term "pesticide-acceptable carrier" includes, but is not limited to, surfactants, including ionic and nonionic surfactants. The surfactants include emulsifiers, dispersants, or wetting agents. Specifically, the emulsifiers may be polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty amines, and commercially available emulsifiers; the dispersants include sodium lignosulfonate, dispersing agents, calcium lignosulfonate, or methylnaphthalenesulfonate formaldehyde condensate, etc.; the wetting agents include sodium lauryl sulfate, sodium dodecylbenzenesulfonate, or alkylnaphthalenesulfonate, etc. The pesticide-acceptable carrier includes solid carriers and / or liquid carriers. Preferably, the solid carrier includes natural or synthetic clays and silicates, such as natural silica and diatomaceous earth; magnesium silicate, such as talc; magnesium aluminum silicate, such as kaolinite, montmorillonite, and mica; white carbon black, calcium carbonate, light calcium carbonate; calcium sulfate; limestone; sodium sulfate; and amine salts such as ammonium sulfate and hexamethylenediamine. Preferably, the liquid carrier comprises water and an organic solvent; when water is used as a solvent or diluent, the organic solvent can be used as an adjuvant or antifreeze additive. Preferably, the organic solvent includes aromatic hydrocarbons (e.g., benzene, xylene, or toluene), chlorinated hydrocarbons (e.g., chlorobenzene, vinyl chloride, chloroform, or dichloromethane), aliphatic hydrocarbons (e.g., petroleum fractions, cyclohexane, or light mineral oil), alcohol solvents (e.g., isopropanol, butanol, ethylene glycol, glycerol, or cyclohexanol), ether solvents, ester solvents, ketone solvents (e.g., acetone, cyclohexanone, or N-methylpyrrolidone), or dimethylformamide. During the formulation of the insecticide composition, the active ingredient can be mixed with the liquid carrier and / or solid carrier, and surfactants (e.g., emulsifiers, dispersants, stabilizers, wetting agents) can be added, as well as other adjuvants (e.g., binders, defoamers, oxidants, etc.).

[0064] According to this application, the fluorine-substituted diamide derivatives can be used together with one or more other insecticides, fungicides, herbicides, plant growth regulators or fertilizers, etc., and the components can be applied simultaneously, sequentially or separately.

[0065] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0066] Example: N-(4-chloro-2-methyl-6-(2,4-difluorophenylcarbamoyl)phenyl)-3-monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxamide

[0067] Step 1: Preparation of ethyl 2-(2,4-difluorophenyl)-5-oxopyrazolidine-3-carboxylic acid

[0068] Sodium metal (1.1 g) was added to 60 mL of ethanol. After the sodium metal reacted completely, (2,4-difluorophenyl)hydrazine (3.0 g) was added. The mixture was heated to reflux, and diethyl maleate (4.5 g) was added dropwise. After reflux for another 3 hours, the reaction of the starting material was completed. After quenching, the solvent was removed by concentration under reduced pressure, and the mixture was extracted with a saturated sodium bicarbonate aqueous solution to obtain ethyl 2-(2,4-difluorophenyl)-5-oxopyrazolidine-3-carboxylic acid.

[0069] Step 2: Preparation of ethyl 1-(2,4-difluorophenyl)-3-hydroxy-1H-pyrazole-5-carboxylate

[0070] Ethyl 2-(2,4-difluorophenyl)-5-oxopyrazolidine-3-carboxylate (2.0 g) was added to 20 mL of acetonitrile, followed by the addition of 98% concentrated sulfuric acid (0.73 mL), potassium persulfate (2.0 g), and HAC (3 mL). After reflux for 3 hours, the solvent was removed under reduced pressure, and the product was purified by column chromatography to obtain ethyl 1-(2,4-difluorophenyl)-3-hydroxy-1H-pyrazolidine-5-carboxylate.

[0071] Step 3: Preparation of ethyl 3-monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxylate

[0072] Ethyl 1-(2,4-difluorophenyl)-3-hydroxy-1H-pyrazole-5-carboxylate (0.86 g) was dissolved in 10 mL of N,N-dimethylformamide, followed by the addition of potassium carbonate (2.2 g) and monofluoroiodoethane (1.5 g). The mixture was heated for 1 hour, diluted with ethyl acetate, and then extracted with saturated brine. The organic phase was collected, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain ethyl 3-monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxylate.

[0073] Step 4: Preparation of 3-monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxylic acid

[0074] Ethyl 3-monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxylic acid (1.0 g) was dissolved in 20 mL of methanol, and then 10 mL of aqueous solution containing lithium hydroxide (0.5 g) was added. After reacting at room temperature for 12 hours, the alcohol was removed under reduced pressure, and a small amount of water was added. The pH was adjusted to about 1-2 with hydrochloric acid aqueous solution, and a large amount of white solid precipitated. After filtration, 3-monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxylic acid was obtained.

[0075] Step 5: Preparation of N-(4-chloro-2-methyl-6-(2,4-difluorophenylcarbamoyl)phenyl)-3-monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxamide

[0076] 3-Monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxylic acid (100 mg) was dissolved in 3 mL of dichloromethane. Oxaloyl chloride (68 μL) and one drop of anhydrous N,N-dimethylformamide were added with stirring. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Then, 4 mL of dry tetrahydrofuran was added again. Under ice-salt bath conditions, the solution was added dropwise to a tetrahydrofuran solution (5 mL) containing N-2,4-difluorophenyl-2-amino-5-chloro-3-methylbenzamide (120 mg) and N,N-diisopropylethylamine (70 μL). The reaction was carried out at room temperature, the solvent was removed under reduced pressure, the mixture was diluted with dichloromethane, and then extracted with aqueous hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, respectively. The organic phase was collected, removed under reduced pressure, and recrystallized from dichloromethane and n-hexane. After filtration, N-(4-chloro-2-methyl-6-(2,4-difluorophenylcarbamoyl)phenyl)-3-monofluoroethoxy-1-(2,4-difluorophenyl)-1H-pyrazole-5-carboxamide was obtained.

[0077] The same preparation method as in the examples was used, but different raw materials (the amount of substance was the same as the reaction raw materials corresponding to the examples) were used to prepare the target product. The physical constants of the target product are shown in Table 1.

[0078] Table 1 Physical constants of each target product

[0079]

[0080]

[0081] target product 1 H NMR, 13 C NMR.

[0082] Compound 1: 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H,-CONH-Ph),10.01(s,1H,-NHCOPh),7.94–7.69(m,2H,Ph-H),7.63–7.20(m,5H,Ph-H),6.98 -6.78(m,2H,Ph-H,Pyrazole-H),4.86–4.66(m,2H,-OCH2CH2F),4.47–4.30(m,2H,-OCH2CH2F),2.23(s,3H,Ph-CH3).HRMS,calcd for C 26 H 19 ClF4N4O3([M+H) + ),547.1155; found,547.1154).

[0083] Compound 2:1 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H, -CONH-Ph), 10.00 (s, 1H, -NHCOPh), 7.84–7.60 (m, 2H, Ph-H), 7.56–7.20 (m, 5H, Ph-H), 6.92 - 6.73 (m, 2H, Ph-H, Pyrazole-H), 5.64 (m, 1H, -OCH2CHF2), 4.31 (m, 2H, -OCH2CHF2), 2.23 (s, 3H, Ph-CH3). HRMS, calcd for C 26 H 18 ClF5N4O3 ([M + H] + ), 564.0988; found, 564.0990).

[0084] Compound 3: 1 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H, -CONH-Ph), 10.10 (s, 1H, -NHCOPh), 7.89–7.69 (m, 2H, Ph-H), 7.60–7.24 (m, 4H, Ph-H), 6.93 - 6.72 (m, 2H, Ph-H, Pyrazole-H), 4.84–4.67 (m, 2H, -OCH2CH2F), 4.50–4.31 (m, 2H, -OCH2CH2F), 2.23 (s, 3H, Ph-CH3). HRMS, calcd for C 26 H 18 Cl2F4N4O3 ([M + H] + ), 581.0759; found, 581.0760).

[0085] Compound 4: 1 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H, -CONH-Ph), 10.01 (s, 1H, -NHCOPh), 7.94–7.62 (m, 2H, Ph-H), 7.50–7.21 (m, 4H, Ph-H), 6.88 - 6.78 (m, 2H, Ph-H, Pyrazole-H), 5.74 (m, 1H, -OCH2CHF2), 4.40 (m, 2H, -OCH2CHF2), 2.23 (s, 3H, Ph-CH3). HRMS, calcd for C 26 H 17 Cl2F5N4O3 ([M + H] + ), 598.0598; found, 598.0599).

[0086] Compound 5: 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H,-CONH-Ph),10.10(s,1H,-NHCOPh),7.74–7.62(m,2H,Ph-H),7.43–7.21(m,4H,Ph-H),6.92 -6.79(m,2H,Ph-H,Pyrazole-H),4.86–4.66(m,2H,-OCH2CH2F),4.47–4.30(m,2H,-OCH2CH2F),2.23(s,3H,Ph-CH3).HRMS,calcd for C 26 H 18 Cl2F4N4O3([M+H) + ),581.0765; found,581.0766).

[0087] Compound 6: 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H,-CONH-Ph),10.11(s,1H,-NHCOPh),7.74–7.60(m,2H,Ph-H),7.43–7.20(m,4H,Ph-H),6. 98-6.78(m,2H,Ph-H,Pyrazole-H),5.66(m,1H,-OCH2CHF2),4.40–4.30(m,2H,-OCH2CHF2),2.23(s,3H,Ph-CH3).HRMS,calcd for C 26 H 17 Cl2F5N4O3([M+H) + ),598.0598; found,598.0599).

[0088] Compound 7: 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H,-CONH-Ph),10.11(s,1H,-NHCOPh),7.84–7.61(m,2H,Ph-H),7.52–7.20(m,4H,Ph-H) ,6.84-6.78(m,2H,Ph-H,Pyrazole-H),4.86–4.66(m,2H,-OCH2CH2F),4.47–4.30(m,2H,-OCH2CH2F),2.23(s,3H,Ph-CH3).

[0089] Compound 8: 11H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H, -CONH-Ph), 10.11 (s, 1H, -NHCOPh), 7.93–7.66 (m, 2H, Ph-H), 7.60–7.20 (m, 4H, Ph-H), 6.88 - 6.78 (m, 2H, Ph-H, Pyrazole-H), 5.66 (m, 1H, -OCH2CHF2), 4.30 (m, 2H, -OCH2CHF2), 2.23 (s, 3H, Ph-CH3).

[0090] Compound 9: 1 1H NMR (400 MHz, DMSO-d6) δ 10.13 (d, J = 20.1 Hz, 2H, -NHCO- and -CONH-Ph), 7.89–7.73 (m, 2H, Ph-H), 7.63–7.45 (m, 3H, Ph-H), 7.32 (td, J = 11.6, 10.5, 2.8 Hz, 1H, Ph-H), 7.10 (dt, J = 8.7, 4.7 Hz, 1H, Ph-H), 6.79 (s, 1H, Pyrazole-H), 4.86–4.66 (m, 2H, -OCH2CH2F), 4.47–4.30 (m, 2H, -OCH2CH2F), 2.23 (s, 3H, Ph-CH3). 13 13C NMR (151 MHz, DMSO-d6) δ 166.76, 161.83, 156.85, 150.65–148.76 (m), 147.48 (d, J = 13.1 Hz), 139.25, 139.17, 136.30, 135.32 (dd, J = 8.5, 3.7 Hz), 132.20, 131.64, 131.25, 127.57 (dd, J = 8.8, 3.4 Hz), 125.78, 119.17, 118.83 (d, J = 21.4 Hz), 114.06 (t, J = 239.0 Hz), 94.62, 67.47 (t, J = 26.6 Hz), 26.50, 18.17. HRMS, calcd for C 26 H 17 Cl2F5N4O3 ([M + H] + ), 599.0671; found, 599.0666).

[0091] Compound 10: 11H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H, -NHCO-), 10.09 (s, 1H, -CONH-Ph), 7.89–7.73 (m, 2H, Ph-H), 7.61–7.46 (m, 3H, Ph-H), 7.36–7.26 (m, 1H, Ph-H), 7.16–7.02 (m, 1H, Ph-H), 6.82 (s, 1H, Pyrazole-H), 6.40 (tt, J=54.6, 3.0 Hz, 1H, -OCH2CHF2), 4.45 (td, J=14.9, 3.0 Hz, 2H, -OCH2CHF2), 2.23 (s, 3H, Ph-CH3). 13 13C NMR (151 MHz, DMSO-d6) δ 165.22, 161.77, 160.61–158.92 (m), 156.87, 155.71 (dd, J=250.0, 12.6 Hz), 149.79 (dd, J=222.6, 13.0 Hz), 148.14 (dd, J=219.5, 13.4 Hz), 139.16, 138.96, 135.91, 135.36 (t, J=5.7 Hz), 132.18, 132.14, 131.27, 127.85, 127.78, 126.25, 122.58–122.33 (m), 119.13 (d, J=20.0 Hz), 118.80, 114.04 (t, J=239.1 Hz), 111.59, 105.03–104.34 (m), 94.54, 67.44 (t, J=26.4 Hz), 18.12. HRMS, calcd for C 26 H 16 Cl2F6N4O3 ([M+H] + ), 617.0576; found, 617.0572).

[0092] Compound 11: 1 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H, -CONH-Ph), 10.01 (s, 1H, -NHCOPh), 7.92–7.64 (m, 2H, Ph-H), 7.53–7.20 (m, 3H, Ph-H), 6.88 - 6.78 (m, 2H, Ph-H, Pyrazole-H), 4.83–4.60 (m, 2H, -OCH2CH2F), 4.41–4.30 (m, 2H, -OCH2CH2F), 2.23 (s, 3H, Ph-CH3).

[0093] Compound 12: 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H,-CONH-Ph),10.01(s,1H,-NHCOPh),7.90–7.67(m,2H,Ph-H),7.60–7.22(m,3H, Ph-H),6.91-6.78(m,2H,Ph-H,Pyrazole-H),5.63(m,1H,-OCH2CHF2),4.38(m,2H,-OCH2CHF2),2.23(s,3H,Ph-CH3).

[0094] Compound 13: 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H,-CONH-Ph),10.31(s,1H,-NHCOPh),7.94–7.62(m,2H,Ph-H),7.53–7.20(m,3H,Ph-H) ,6.93-6.78(m,2H,Ph-H,Pyrazole-H),4.82–4.61(m,2H,-OCH2CH2F),4.46–4.31(m,2H,-OCH2CH2F),2.23(s,3H,Ph-CH3).

[0095] Compound 14: 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H,-CONH-Ph),10.01(s,1H,-NHCOPh),7.90–7.64(m,2H,Ph-H),7.60–7.22(m,3H, Ph-H),6.91-6.74(m,2H,Ph-H,Pyrazole-H),5.62(m,1H,-OCH2CHF2),4.37(m,2H,-OCH2CHF2),2.23(s,3H,Ph-CH3).

[0096] Compound 15: 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H,-CONH-Ph),10.03(s,1H,-NHCOPh),7.87–7.64(m,2H,Ph-H),7.53–7.20(m,3H,Ph-H) ,6.88-6.78(m,2H,Ph-H,Pyrazole-H),4.80–4.65(m,2H,-OCH2CH2F),4.43–4.31(m,2H,-OCH2CH2F),2.23(s,3H,Ph-CH3).

[0097] Compound 16: 1H NMR(400MHz,DMSO-d6)δ10.32(s,1H,-CONH-Ph),10.02(s,1H,-NHCOPh),7.94–7.70(m,2H,Ph-H),7.61–7.22(m,3H, Ph-H),6.94-6.75(m,2H,Ph-H,Pyrazole-H),5.66(m,1H,-OCH2CHF2),4.33(m,2H,-OCH2CHF2),2.23(s,3H,Ph-CH3).

[0098] Compound 17: 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H,-CONH-Ph),10.01(s,1H,-NHCOPh),7.91–7.65(m,2H,Ph-H),7.52–7.26(m,3H,Ph-H) ,6.88-6.70(m,2H,Ph-H,Pyrazole-H),4.87–4.64(m,2H,-OCH2CH2F),4.45–4.31(m,2H,-OCH2CH2F),2.23(s,3H,Ph-CH3).

[0099] Compound 18: 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H,-CONH-Ph),10.00(s,1H,-NHCOPh),7.94–7.66(m,2H,Ph-H),7.57–7.24(m,3H,Ph- H),6.84-6.72(m,2H,Ph-H,Pyrazole-H),5.60–5.32(m,1H,-OCH2CHF2),4.33(m,2H,-OCH2CHF2),2.23(s,3H,Ph-CH3).

[0100] Example 2:

[0101] Insecticidal activity assay of the fluorine-substituted diamide derivatives of the present invention:

[0102] The insecticidal bioactivity was verified by testing the diamide derivative provided by this invention:

[0103] Any derivative provided by this invention can be dissolved in a solvent, water, and a surfactant to form a homogeneous aqueous phase. When used, it can be diluted with water to any desired concentration. The test objects and test methods are as follows:

[0104] (1) Evaluation of the bioactivity of the Eastern Armyworm: The test insect was the Eastern Armyworm (Mythimna separata Walker), a normal population raised indoors on corn leaves. The armyworms were tested using the leaf-immersion method. Seedling corn leaves were immersed in a prepared solution, dried, and then placed in 7 cm diameter petri dishes. Fourth instar larvae were introduced, and each concentration was repeated three times. The negative control was fed with corn leaves immersed in acetone solution, and the positive control was fed with corn leaves immersed in chlorantraniliprole solution. The results were observed after 24 hours, 48 ​​hours, and 72 hours.

[0105] (2) Evaluation of the biological activity of the fall armyworm: The test insect was the fall armyworm (Spodopterafrugiperda), a normal population reared indoors with corn leaves. The fall armyworm was tested using the leaf-immersion method. Seedling corn leaves were immersed in a prepared solution, dried, and then placed in 7 cm diameter petri dishes. Fourth instar larvae were introduced, and each concentration was repeated three times. The negative control was reared by immersing corn leaves in acetone solution, and the positive control was reared by immersing corn leaves in chlorantraniliprole solution. The experimental results were observed after 24 hours, 48 ​​hours, and 72 hours.

[0106] (3) Evaluation of the biological activity of diamondback moth: The test insect was diamondback moth (Plutella xylostella), a normal population raised indoors on corn leaves. The diamondback moth was tested using the leaf-immersion method. Seedling corn leaves were immersed in a prepared solution, dried, and then placed in 7 cm diameter petri dishes. Fourth instar larvae were introduced, and each concentration was repeated three times. The negative control was fed corn leaves soaked in acetone solution, and the positive control was fed corn leaves soaked in chlorantraniliprole solution. The results were observed after 24 hours, 48 ​​hours, and 72 hours.

[0107] Oriental armyworm, fall armyworm, diamondback moth, these lepidopteran insects are very representative and can represent most of the insects that cause pests in the field during agricultural production.

[0108] Table 3 Different concentrations (mg·L) -1 Insecticidal activity (%) of fluorine-substituted diamide derivatives against armyworm.

[0109]

[0110] Table 4 Different concentrations (mg·L) -1 Insecticidal activity (%) of fluorine-substituted diamide derivatives against fall armyworm.

[0111]

[0112] Table 5 Different concentrations (mg·L) -1 Insecticidal activity (%) of fluorine-substituted diamide derivatives against diamondback moth.

[0113]

[0114] Based on the above bioactivity results, the fluorinated diamide derivatives described in this application exhibit highly effective insecticidal activity against lepidopteran insects. Specifically, against the armyworm, they still exhibit insecticidal activity at a concentration of 0.1 mg / L, consistent with the positive control chlorantraniliprole. Against the fall armyworm, most compounds showed good insecticidal activity at a concentration of 0.25 mg / L, similar to the positive control chlorantraniliprole; compound 11 still showed insecticidal activity against the fall armyworm at a concentration of 0.1 mg / L. Against the diamondback moth, the insecticidal activity of the compounds described in this application was superior to chlorantraniliprole, especially compounds 9, 11, and 15 at 5 × 10⁻⁶. -3 mg / L, 5×10 -4 It still exhibits insecticidal activity at mg / L. In summary, fluorinated diamide derivatives possess extremely high insecticidal activity and can be used alternately with existing insecticides to avoid or delay the development of resistance.

[0115] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0116] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

[0117] Furthermore, various different embodiments of the present invention can be combined in any way, as long as they do not violate the spirit of the present invention, they should also be regarded as the content disclosed by the present invention.

Claims

1. A fluorine-substituted diamide derivative, characterized in that, The fluorine-substituted diamide derivatives are compounds represented by Formula I, or their stereoisomers, tautomers, isotopic derivatives, and pesticide-acceptable salts. R1, R3, and R5 are each independently selected from H and C1-C8 alkyl groups; R2 is selected from C6-C10 haloaryl and 5-10 halogenated heteroaryl; R4 and R7 are each independently selected from halogens; R6 is selected from C1-C8 haloalkyl groups; n is selected from 0, 1, 2, 3, 4 or 5.

2. The diamide derivative according to claim 1, characterized in that, The halogen is selected from fluorine, chlorine, and bromine.

3. The diamide derivative according to claim 2, characterized in that, R4 is selected from fluorine and chlorine.

4. The diamide derivative according to claim 1, characterized in that, R5 is selected from methyl.

5. The diamide derivative according to claim 1, characterized in that, The compound represented by Formula I is shown in Formula I-1.

6. The diamide derivative according to any one of claims 1-5, characterized in that, R2 is selected from dihalophenyl, preferably 2,4-difluorophenyl.

7. The diamide derivative according to any one of claims 1-6, characterized in that, R6 is selected from fluoroethyl groups, preferably -CH2CH2F or -CH2CHF2.

8. The diamide derivative according to any one of claims 1-7, characterized in that, R7 is independently selected from fluorine and chlorine.

9. The diamide derivative according to claim 1, characterized in that, The compound represented by Formula I is selected from one of the following:

10. A method for preparing the diamide derivative according to any one of claims 1-9, characterized in that, The following synthetic route was followed: The groups R1-R7 and n are defined as described in any one of claims 1-9, and R8 is a C1-C8 alkyl group, preferably a C1-C4 alkyl group.

11. The method for preparing the diamide derivative according to claim 10, characterized in that, The specific preparation steps are as follows: (1) The compound shown in Formula II is prepared by reacting the phenylhydrazine compound shown in Formula III with the maleic acid diester shown in Formula III in the presence of a base. (2) The compound shown in formula IV was reacted in the presence of glacial acetic acid, persulfate and sulfuric acid to prepare the compound shown in formula V; (3) The compound shown in formula V is reacted with iodide R6-I in the presence of an acid-binding agent to prepare the compound shown in formula VI; (4) The compound shown in formula VI is prepared by ester hydrolysis in the presence of a base to prepare the compound shown in formula VII; (5) Prepare the corresponding acyl chloride compound from the compound shown in Formula VII, and then condense it with the compound shown in Formula VIII in the presence of an acid-binding agent to obtain the compound shown in Formula I.

12. The method for preparing the diamide derivative according to claim 11, characterized in that, In step (1), the base is an alkali metal alkoxide; in step (2), the persulfate is an alkali metal persulfate; in step (3), the acid-binding agent is an alkali metal carbonate; in step (4), the base is an alkali metal hydroxide; in step (5), the acid-binding agent is diisopropylethylamine (DIPEA) or triethylamine.

13. An insecticidal composition, characterized in that, The active ingredient is at least one of the diamide derivatives according to any one of claims 1-9; preferably, the insecticidal composition further comprises a pesticide-acceptable carrier.

14. The insecticidal composition according to claim 13, characterized in that, The insecticidal composition contains one or more other insecticides, fungicides, herbicides, plant growth regulators, and fertilizers.

15. Use of the diamide derivative of any one of claims 1-9 or the insecticidal composition of any one of claims 13-14 for controlling plant pests; preferably, the insecticidal effective amount of the diamide derivative or the insecticidal composition as described above is used on plants, and / or pests, and / or habitats.

16. A method for controlling plant pests, comprising applying an insecticidal effective amount of a diamide derivative of any one of claims 1-9 or an insecticidal composition of any one of claims 13-14 to plants, and / or pests, and / or habitats.

17. The use according to claim 15 or the method according to claim 16, characterized in that, The pests mentioned are Lepidoptera, Coleoptera, Hemiptera, Thysanoptera, Diptera, Orthoptera, Homoptera, Isoptera, Hymenoptera, Blattodea, mites, and nematodes.

18. The use according to claim 15 or the method according to claim 16, characterized in that, The diamide derivatives or the insecticidal composition may be used in conjunction with one or more other insecticides, fungicides, herbicides, plant growth regulators or fertilizers.

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