Deuterated pyrazolylcarboxamide compounds, methods of making and uses thereof

Abstract

The present application relates to a kind of deuterated pyrazolyl carboxamide compounds and its preparation method and purposes. Specifically, the compound has the structure shown in formula I, which has more excellent bactericidal effect and the role of improving yield.

Description

Technical Field

[0001] This invention relates to the field of pesticide chemistry, specifically to a deuterated pyrazolyl formamide compound, its preparation method, and its uses. Background Technology

[0002] The use of pyrazole-4-carboxamide compounds and their derivatives in the control of plant diseases has been reported, for example, in patents CN1646494, CN101115723, and CN102239137.

[0003] Controlling plant fungal diseases is highly challenging, often requiring high application rates to achieve satisfactory results. Therefore, there is a need in this field to develop compounds with better activity against pathogenic plant fungi. Summary of the Invention

[0004] The purpose of this invention is to provide a deuterated pyrazole-4-carboxamide compound with stronger bactericidal activity.

[0005] In a first aspect, the present invention provides a compound of formula I, or an enantiomer thereof, or a mixture thereof, or a pesticide-acceptable salt thereof:

[0006]

[0007] R1 is selected from hydrogen, C1-C3 alkoxy group;

[0008] R2 is selected from -C1-C4 alkyl-phenyl, -halophenyl-phenyl, -phenyl-O-phenyl; and each phenyl group is optionally substituted by one or more (e.g., 2, 3 or 4) groups selected from the group consisting of halogens and C1-C3 haloalkyl groups.

[0009] In another preferred embodiment, R1 is H or methoxy.

[0010] In another preferred embodiment, R2 is selected from -C1-C4 alkyl-halogenated and / or C1-C3 haloalkyl-substituted phenyl, -halogenated phenyl-halogenated and / or C1-C3 haloalkyl-substituted phenyl, -halogenated or unsubstituted phenyl-O-halogenated and / or C1-C3 haloalkyl-substituted phenyl.

[0011] In another preferred embodiment, the C1-C4 alkyl group is -CH2CH2- or -CH2(CH2)CH2-.

[0012] In another preferred embodiment, the C1-C3 haloalkyl group is trifluoromethyl.

[0013] In another preferred embodiment, R2 is selected from -C1-C4 alkyl-halophenyl, -halophenyl-halophenyl, -halo or unsubstituted phenyl-O-halo and / or C1-C3 alkyl-halosubstituted phenyl.

[0014] In another preferred embodiment, R2 is selected from -C2-C3 alkyl-trihalophenyl, -monohalophenyl-dihalo or trihalophenyl, -halo or unsubstituted phenyl-O-monohalo and C1 alkyl-substituted phenyl.

[0015] In another preferred embodiment, the halogen is independently fluorine, chlorine, bromine, or iodine, with fluorine or chlorine being more preferred.

[0016] In another preferred embodiment, R2 is selected from -CH2(CH2)CH2-trichlorophenyl, -monofluorophenyl-dichloro or trifluorophenyl, -unsubstituted phenyl-O-monofluorophenyl, and trifluoromethyl-substituted phenyl.

[0017] In another preferred embodiment, the compound is selected from the group consisting of:

[0018]

[0019] In another preferred embodiment, the compound is:

[0020]

[0021] In a second aspect, the present invention provides a composition comprising i) a compound as described in the first aspect of the present invention, or an enantiomer or diastereomer thereof, or a mixture thereof, or a pesticide-acceptable salt thereof; and 2) a pesticide-acceptable carrier and / or excipient.

[0022] In another preferred embodiment, the composition is a bactericidal composition.

[0023] In another preferred embodiment, the composition further includes an adjuvant.

[0024] In another preferred embodiment, the composition further includes substances selected from the group consisting of insecticides, attractants, disinfectants, bactericides, acaricides, nematicides, fungicides, growth regulators, safety agents, fertilizers, chemical pheromones, or combinations thereof.

[0025] In a third aspect, the present invention provides the use of a compound as described in the first aspect of the present invention, or an enantiomer or diastereomer thereof, or a mixture thereof, or a pesticide-acceptable salt thereof, or a composition as described in the second aspect of the present invention, for the control of plant pathogenic fungi or in the preparation of a plant pathogenic fungicide.

[0026] In a fourth aspect, the present invention provides a method for controlling fungal diseases, comprising applying the compound of the first aspect of the present invention, or its enantiomers or diastereomers or mixtures thereof, or its agrochemically acceptable salts, or the composition of the second aspect of the present invention, to plants suffering from or potentially suffering from fungal diseases, their seeds, the surrounding soil, or the environment.

[0027] In another preferred embodiment, the fungal diseases are selected from: turf brown spot, cucurbit anthracnose, cucumber powdery mildew, tomato early blight, tomato leaf mold, apple spot leaf drop, apple rot fungus, rapeseed sclerotium rot fungus, gray mold fungus, rice sheath blight fungus, rice curvularia fungus, wheat scab fungus, wheat rust fungus, and corn bacterial wilt fungus.

[0028] In another preferred embodiment, the plants are selected from: grains (wheat, barley, rye, oats, rice, corn, sorghum, etc.), corn, rapeseed, sunflower, legumes (soybeans, kidney beans, peas, lentils), vegetables (spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes, eggplants, peppers, etc.), grapes, pome fruits, stone fruits, bananas, tobacco, nuts, coffee, tea, hops, lawns, stevia, and other field crops. Additionally, natural rubber plants, ornamental and forest plants, such as flowers and evergreen trees, are also included.

[0029] In a third aspect, the present invention provides a deuterated pyrazole intermediate having the following structure:

[0030]

[0031] R3 is a C1-C6 alkoxy, hydroxyl, or halogen.

[0032] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0033] Through extensive and in-depth research, and through numerous screenings and tests, the inventors have developed a deuterated pyrazole-4-carboxamide compound. Surprisingly, this deuterated pyrazole-4-carboxamide compound exhibits significantly superior bactericidal effects compared to its non-deuterated counterparts. Based on this, the present invention was completed.

[0034] the term

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0036] As used herein, "halogen" or "halogenated" refers to F, Cl, Br, and I. More preferably, the halogen atom is selected from F, Cl, and Br.

[0037] As used herein, “C1-C4 alkyl” refers to a straight-chain or branched alkyl group comprising 1-4 carbon atoms (including alkyl groups with 1-3 or 1-2 carbon atoms), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or similar groups.

[0038] As used herein, “C1-C3 haloalkyl” or “halogenated C1-C3 alkyl” are used interchangeably and refer to a straight-chain or branched alkyl group comprising 1-3 carbon atoms substituted with one or more halogen atoms, such as difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 3-fluoropropyl, or similar groups.

[0039] As used herein, “C1-C6 alkoxy” refers to a straight-chain or branched alkyloxy group comprising 1-6 carbon atoms (including alkyl groups with 1-3 or 1-2 carbon atoms), such as methoxy, ethoxy, isopropoxy, or tert-butoxy.

[0040] As used herein, “deuterated” means that one or more hydrogen atoms in a compound or group are replaced by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms “one or more deuterated” and “one or more deuterated” are used interchangeably.

[0041] As used in this article, "non-deuterated compound" or "undeuterated" refers to a compound containing deuterium atoms (D, 2 Compounds whose H content is not higher than the natural deuterium isotope content (approximately 0.015%).

[0042] As used in this article, “enantiomers or diastereomers” refers to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures.

[0043] In another preferred embodiment, the deuterium isotope content at the deuterium substitution site is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%, and more preferably greater than 99.5%.

[0044] Preferably, in the compound of formula (I), N is 14 N and / or O are 16 O.

[0045] In another preferred embodiment, in the compound, 14 The isotopic content of N at the position of the nitrogen atom is ≥95%, more preferably ≥99%.

[0046] In another preferred embodiment, in the compound, 16 The isotopic content of O at the position of the oxygen atom is ≥95%, more preferably ≥99%.

[0047] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0048] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0049] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their R and S enantiomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0050] Active ingredients

[0051] The terms "active substance of the present invention" or "active compound of the present invention" refer to a compound of formula (I), or an enantiomer or diastereomer thereof, or a mixture thereof, or a pesticide-acceptable salt thereof.

[0052]

[0053] R1 and R2 are as defined in this invention.

[0054] The term also includes enantiomers or diastereomers of compounds of formula (I), mixtures thereof, or pesticide-acceptable salts thereof. Salts of the compounds of the present invention include inorganic and organic salts. A preferred class of salts are salts formed by the compounds of the present invention with acids. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0055] Composition and Use

[0056] The present invention provides a composition comprising the compound described in the first aspect of the invention, or an enantiomer or diastereomer thereof, or a mixture thereof, or an agrochemically acceptable salt thereof and an agrochemically acceptable carrier and / or excipient thereof.

[0057] If appropriate, the compounds of the present invention may exist in a single crystal form, in polymorphs, or in mixtures thereof.

[0058] Typically, the compositions of the present invention are fungicidal compositions. The compositions of the present invention may further include suitable adjuvants, including but not limited to: solvents, liquid carriers, solid carriers or fillers, surfactants, dispersants, emulsifiers, wetting agents, auxiliaries, solvents, penetration enhancers, protective colloids, adhesives, thickeners, humectants, compatibilizers, bactericides, antifreeze agents, defoamers, colorants, tackifiers, and binders.

[0059] The composition may be a conventional formulation, such as a solution, emulsion, suspension, wettable powder, powder, paste, ointment, soluble powder, granule, molded product, suspension concentrate, natural and synthetic materials impregnated with active compounds, and microcapsules in polymers.

[0060] The composition can be used (but is not limited to) in the following forms: aerosol, spray, foam, gel, or evaporator.

[0061] Besides water, other polar or nonpolar organic solvents can also be used as cosolvents. Suitable liquid solvents are basically: aromatic hydrocarbons such as xylene, toluene, alkylbenzene, or alkylnaphthalene; chlorinated aromatic hydrocarbons or chlorinated aliphatic hydrocarbons such as chlorobenzene, vinyl chloride, or dichloromethane; aliphatic hydrocarbons such as cyclohexane or paraffins (such as mineral oil fractions, mineral oil, and vegetable oil); alcohols such as ethanol, propanol, benzyl alcohol, cyclohexanol, butanol, or ethylene glycol and their ethers and esters; ketones such as acetone, cyclohexanone, methyl ethyl ketone, or methyl isobutyl ketone; esters such as lactates, carbonates, and fatty acid esters; and strongly polar solvents such as amides (N,N-dimethylformamide, N-alkylpyrrolidone) and sulfones and sulfoxides such as dimethyl sulfoxide. The filler can also be a mixture of the above solvents, such as water and acetone.

[0062] Suitable solid carriers or fillers include natural mineral powders such as kaolin, clay, talc, chalk, quartz, attapulgite, montmorillonite, or diatomaceous earth, as well as synthetic mineral powders such as highly dispersed silica, alumina, and silicates; suitable solid carriers for granules include, for example, crushed and graded natural rocks such as calcite, marble, pumice, sepiolite, and dolomite, as well as synthetic granules of inorganic and organic powders, and organic granules such as cellulose, starches, granules of paper, sawdust, coconut shells and other nut shell powders, bark powder, grain powder, corn cobs and tobacco stems, and mixtures thereof.

[0063] Suitable surfactants are a variety of surface-active compounds known in the field of pesticide formulation, including anionic, cationic, nonionic, and amphoteric surfactants, block polymers, and polyelectrolytes. These surfactants function as emulsifiers, dispersants, solubilizers, wetting agents, penetration enhancers, protective colloids, or adjuvants. Mixtures of these surfactants can also be used.

[0064] Suitable anionic surfactants are alkyl sulfonates, alkyl sulfates, aryl sulfonates, phosphates, carboxylates, ammonium salts, and mixtures thereof. Examples include calcium dodecylbenzenesulfonate, sodium sulfate, sodium lauryl sulfate, sodium methylene naphthalene sulfonate, sodium dodecylbenzenesulfonate, calcium dodecylbenzenesulfonate, sodium alkyl naphthalene sulfonate, fatty alcohol polyoxyethylene ether, and alkylphenol polyoxyethylene ether.

[0065] Suitable nonionic surfactants include alkoxylates, amine oxides, N-substituted fatty acid amides, esters, polymers, glycosyl surfactants, and mixtures of the above.

[0066] Suitable cationic surfactants such as quaternary ammonium compounds.

[0067] Suitable amphiphilic surfactants include alkyl betaines and imidazolines.

[0068] Suitable polymers, such as oligomers and polymers containing ethylene, acrylic acid monomers, alcohols, and amines.

[0069] Suitable thickeners are polysaccharides (such as carboxymethyl cellulose xanthan gum) and natural or synthetic polymers in powder, granule or latex form (such as gum arabic, polyvinyl alcohol, polyvinyl acetate, and natural phospholipids such as cephalin and lecithin, as well as synthetic phospholipids), inorganic clays, and silicates.

[0070] Suitable antifreeze agents are one or more of ethylene glycol, glycerin, urea, and glycerol.

[0071] Stabilizers such as low-temperature stabilizers, preservatives, antioxidants, light stabilizers, or other reagents that improve chemical and / or physical stability may be added.

[0072] The composition typically contains 0.01-98% by weight of the active compound, preferably 0.5-90% by weight of the active compound.

[0073] As used in this article, “prevention” includes, but is not limited to, sterilization and slowing down the growth or reproduction of bacteria.

[0074] The compounds of the present invention, or their enantiomers or diastereomers, or mixtures thereof, or their salts, and the compositions thereof, can be used to control pests.

[0075] The active compounds of this invention can be used to treat propagation materials and plants, and also to treat plant roots. This method can be used for sterilization. Target diseases for prevention and control include turfgrass brown spot, cucurbit anthracnose, cucumber powdery mildew, tomato early blight, tomato leaf mold, apple scab, apple rot fungus, rapeseed sclerotium rot, gray mold, rice sheath blight, rice curvature spores, wheat scab, wheat rust, and corn bacterial wilt.

[0076] This invention can protect plants from the aforementioned pests and diseases, including grains (wheat, barley, rye, oats, rice, corn, sorghum, etc.), corn, rapeseed, sunflower, legumes (soybeans, kidney beans, peas, lentils), vegetables (spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes, eggplants, peppers, etc.), grapes, pome fruits, stone fruits, bananas, tobacco, nuts, coffee, tea, hops, lawns, stevia, and other field crops. It also includes natural rubber plants, ornamental and forest plants, such as flowers and evergreen trees.

[0077] The composition may also include (but is not limited to) substances selected from the group consisting of bactericides, fungicides, growth regulators, safeners, fertilizers, chemical pheromones, or combinations thereof. The substances constituting the composition may be selected from, but are not limited to, the following examples: prothioconazole, tebuconazole, fluopyram, spirocyclam, flutriafol, pyraclostrobin, difenoconazole, benzoyl propiconazole, fludioxonil, azoxystrobin, fluoxastrobin, metalaxyl, chlorfluazuron, fluopyram, fluopyram, fluopyram, bifenthion.

[0078] In this invention, "plant" refers to plants that exist naturally or are obtained through conventional plant breeding and selection methods, or through biotechnology and genetic engineering methods, such as transgenic plants.

[0079] The active compounds provided by this invention are suitable for seed protection.

[0080] The compositions of this invention are suitable for protecting plant seeds used in agriculture, greenhouses, forestry, or horticulture, such as cotton seeds.

[0081] Preparation method of the compound of the present invention

[0082] The compounds represented by the general formula of this invention can be prepared by the following method; however, the conditions of this method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to those explained below. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art. Reagents can be commercially available if feasible.

[0083] Typical embodiments of the compounds of this invention can be synthesized using the general reaction scheme described below. It will be apparent from the description given herein that the general scheme can be modified by substituting other materials having similar structures to obtain correspondingly different products. The synthetic methods can be tailored to provide large-scale production. The starting materials can be obtained commercially or synthesized using publicly available methods. In the examples given herein, the characteristics of the final products generally make the characteristics of the necessary starting materials readily apparent through simple testing steps.

[0084] The synthetic reaction parameters can be used, for example, the general methods and procedures described below, to prepare the compounds of the present invention from readily available starting materials. It will be appreciated that other method conditions may also be used, unless otherwise indicated, given typical or optimized method conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, catalyst, pressure, etc.). Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0085] The starting materials used in the following reactions are typically known compounds, or can be prepared by known steps or by obvious modifications thereof. For example, many starting materials are available from commercial suppliers, while others can be prepared by steps described in the text of the standard references or by obvious modifications.

[0086] Preferably, the present invention is prepared by the following method:

[0087]

[0088] R1 and R2 are as defined in this invention; R3 is a C1-C6 alkoxy, hydroxyl, or halogen.

[0089] When R3 is a C1-C6 alkoxy group, the reaction can be carried out in an aprotic solvent in the presence of a base. The base is selected from amine lithium compounds, such as diisopropylamine lithium (LDA), hexamethyldisilazine lithium (LiHMDS), alkali metal salts of alcohols such as sodium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide; alkyl lithium metal compounds such as butyllithium, phenyllithium; organic amines such as pyridine, triethylamine, triethylenediamine (DABCO), DMAP, and N-methylmorpholine. The reaction solvent can be ethers, such as tetrahydrofuran, ethylene glycol dimethyl ether, and 2-methyltetrahydrofuran; nitriles, such as acetonitrile or propionitrile; or amides, such as N,N-dimethylformamide, diethylformamide, and N-methylpyrrolidone.

[0090] When R3 is a halogen, the reaction can be carried out in hydrocarbon solvents such as dichloromethane, trichloromethane, tetrachloromethane, chlorobenzene, and toluene. The base can be selected from lithium amino compounds, such as lithium diisopropylamino (LDA) and lithium hexamethyldisilamino (LiHMDS); or organic amines, such as pyridine, triethylamine, triethylenediamine (DABCO), DMAP, and N-methylmorpholine.

[0091] The main advantages of this invention include:

[0092] 1. This invention provides a novel class of deuterated pyrazolyl formamide compounds;

[0093] 2. The deuterated pyrazolyl formamide compounds of the present invention have excellent bactericidal effects, and are better than non-deuterated compounds;

[0094] 3. The deuterated pyrazolyl formamide compounds of the present invention provide deuterated standards for fluopyram, fluopyram, and bifenthiophanate-methyl, which can be detected by residue mass spectrometry;

[0095] 4. The preparation method of the present invention has good deuteration selectivity and high yield.

[0096] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the raw materials or instruments used in the embodiments of the present invention are commercially available.

[0097] Example 1:

[0098] Compound (1): 3-(difluoromethyl)-N-methoxy-1-(deuterated methyl)-N-(1-(2,4,6-trichlorophenyl)propane-2-yl)-1H-pyrazole-4-carboxamide

[0099]

[0100] Step 1: Preparation of ethyl 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid ester:

[0101] ethyl 3-(difluoromethyl)-1-(methyl-d3)-1H-pyrazole-4-carboxylate

[0102]

[0103] Ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ester (570 mg, 1 equiv) and K2CO3 (624 mg, 1.5 equiv) were added to a 100 mL round-bottom flask, followed by the addition of 30 mL THF and CD3I (642 mg, 1.5 equiv). The mixture was stirred at 60 °C for 12 h, filtered, and extracted three times with ethyl acetate. The organic phases were combined and washed three times with saturated brine. The organic phases were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The mixture was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:3) to give the compound ethyl 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid ester (466 mg, 75%).

[0104] Spectrum 11 1 H NMR (400MHz, Chloroform-d) δ = 7.87 (s, 1H), 7.07 (t, J = 54.0Hz, 1H), 4.28 (q, J = 7.2Hz, 2H), 1.32 (t, J = 7.1Hz, 3H).

[0105] Step 2: Preparation of 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid:

[0106]

[0107] Ethyl 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid ester (133.5 mg, 1 equiv) was dissolved in 3 mL of ethanol, 1.0 mmol of NaOH was added, followed by 3 mL of water. The mixture was stirred at 90 °C for 1 hour. 1 mL of 1N hydrochloric acid was added to the system, and all solvent was evaporated to dryness. Acetonitrile was added to the system, and the mixture was heated and filtered. The filtrate was evaporated to dryness to give 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid (105 mg, 92%).

[0108] 1 H NMR (400MHz, CD3CN) δ9.31(br,1H),8.03(s,1H),7.13(t,1H).

[0109] Step 3: Preparation of deuterated 3-difluoromethyl-N-methoxy-1-methyl-N-(1-(2,4,6-trichlorophenyl)prop-2-yl)-1H-pyrazole-4-carboxamide:

[0110]

[0111] The 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid obtained in the previous step was refluxed in excess SOCl2 for 4 hours. The solvent was evaporated to dryness, and the remaining acyl chloride was dissolved in dichloromethane. This solution was then added dropwise at 0°C to a dichloromethane solution containing O-methyl-N-(1-(2,4,6-trichlorophenyl)propane-2-yl)hydroxylamine (157 mg, 1 equiv) and triethylamine (237 mg, 4 equiv). The mixture was slowly brought back to room temperature and reacted for 4 hours. After the reaction was complete, the mixture was washed three times with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Extraction column chromatography yielded 3-(difluoromethyl)-N-methoxy-1-(deuterated methyl)-N-(1-(2,4,6-trichlorophenyl)propane-2-yl)-1H-pyrazole-4-carboxamide (200 mg, 79%).

[0112] 1 H NMR(600MHz,Chloroform-d)δ7.82(s,1H),7.28(s,2H),7.08-7.27(m,1H),4. 94–4.88(m,1H),3.71(s,3H),3.36(dd,1H),3.28–3.21(m,1H),1.40(dd,3H).

[0113] Example 2:

[0114] Preparation of compound (2): N-(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxamide:

[0115]

[0116] 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid (200 mg, 1 equiv) was refluxed in excess SOCl2 for 4 hours, the solvent was evaporated to dryness, and the remaining acyl chloride was dissolved in dichloromethane. A dichloromethane solution containing 3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-amine (286 mg, 1 equiv) and triethylamine (452 ​​mg, 4 equiv) was added dropwise at 0°C. The mixture was slowly brought to room temperature and reacted for 4 hours. After the reaction was complete, the mixture was washed three times with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:7). Extraction column chromatography yielded N-(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxamide (400 mg, 86%). 1 H NMR (400MHz, Chloroform-d) δ = 8.05 (dd, J = 9.0, 5.3Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 4.5Hz, 1H), 7.50 (d, 1H), 7.46 (d, J = 2.1 Hz,1H),7.19(dd,J=8.2,2.1Hz,1H),7.11(ddd,J=9.0,7.9,3.0Hz,1H),6.97(dd,J=8.7,3.0Hz,1H),6.69(t,J=54.2Hz,1H).

[0117] Example 3:

[0118] Preparation of compound (2): 3-(difluoromethyl)-1-(deuterated methyl)-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide:

[0119]

[0120] Ethyl 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid ester (114 mg, 1.0 equiv) was dissolved in 2 mL of DMF, 3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-amine (247 mg, 1.33 equiv) was added, and LiHMDS (3.33 equiv) was added dropwise. The mixture was stirred at 40 °C for 12 h, quenched with ammonium chloride, separated, and the aqueous phase was extracted with EA. The mixture was dried, filtered, and evaporated to dryness. The solution was purified (petroleum ether: ethyl acetate = 3:7) to give N-(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxamide (260 mg, 86%).

[0121] Example 4:

[0122] Preparation of compound (3): 3-(difluoromethyl)-1-(deuterated methyl)-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide:

[0123]

[0124] 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid (200 mg, 1 equiv) was refluxed in excess SOCl2 for 4 hours, the solvent was evaporated to dryness, and the remaining acyl chloride was dissolved in dichloromethane. This solution was then slowly added dropwise at 0°C to a dichloromethane solution containing 3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-amine (286 mg, 1 equiv) and triethylamine (452 ​​mg, 4 equiv). The mixture was brought back to room temperature and reacted for 4 hours. After the reaction was completed, the mixture was washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The mixture was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:7). Extraction column chromatography yielded 3-(difluoromethyl)-1-(deuterated methyl)-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (360 mg, 84%).

[0125] 1 H NMR (400MHz, Chloroform-d) δ = 8.13 (d, J = 8.2Hz, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.41 (dd d,J=8.6,5.7,3.4Hz,1H),7.26–7.17(m,2H),7.04–6.93(m,2H),6.68(t,J=54.2Hz,1H).

[0126] Example 5:

[0127] Preparation of compound (4): N-(2-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxamide:

[0128]

[0129] 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylic acid (200 mg, 1 equiv) was refluxed in excess SOCl2 for 4 hours. The solvent was evaporated to dryness, and the remaining acyl chloride was dissolved in dichloromethane. A dichloromethane solution containing 2-(2-chloro-4-(trifluoromethyl)phenoxy)aniline (321 mg, 1 equiv) and triethylamine (452 ​​mg, 4 equiv) was added dropwise at 0°C. The mixture was slowly restored to room temperature and reacted for 4 hours. After the reaction was completed, the mixture was washed three times with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:7). Extraction column chromatography yielded N-(2-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxamide (380 mg, 88%).

[0130] 1 H NMR(400MHz,Chloroform-d)δ8.57(s,1H),8.52(s,1H),7.97(s,1H),7.70(s,1H),7.4 2(d,J=2.4Hz,1H),7.10(s,1H),6.96(d,J=8.6Hz,1H),6.91–6.84(m,1H),6.77(s,1H).

[0131] Biological Experiment

[0132] The active compounds of this invention used in the following biological testing experiments all have a deuterated purity of ≥95%, typically ≥98%.

[0133] In this invention, the definition of deuteration purity is as follows: by chemical methods, one or more specific hydrogen atoms at a specific position in a chemical structure are replaced with deuterium, a stable isotope of hydrogen, and the total content of deuterium at these positions is the percentage of the total content of hydrogen at these positions before the replacement.

[0134] Test methods: Rhizoctonia solani (lawn spot disease) and Colletotrichumorbiculare (cucurbit anthracnose) were both preserved and cultured in vitro indoors, and the mycelial growth rate method was used; culture medium: PDA medium.

[0135] Chemical treatment: The treatment agents were dissolved in acetone and prepared into stock solutions. According to the experimental design, the stock solutions were diluted stepwise with sterile water for in vitro experiments and diluted with 0.5% Tween 80 for in vivo experiments.

[0136] The test reagents were added to sterilized culture media cooled to about 45°C according to a certain concentration gradient and mixed well. Each bottle of culture media contained 60 ml of liquid, and the mixture was poured into 4 petri dishes to make drug-containing plates.

[0137] Place a bacterial culture dish in the center of a drug-containing plate, with the mycelium facing down. Incubate at 25°C until the blank control colonies cover more than 2 / 3 of the plate. Measure the colony diameter for each treatment. Measure each colony twice using the cross-sectional method, and use the average value to represent the colony size. Calculate the inhibitory effect of the drug on bacterial growth.

[0138] Wheat rust [Botrytis cinerea Pers.] was treated using a live spraying method with potted plants. Wheat rust samples were collected from the field.

[0139] Chemical treatment

[0140] The treatment agents were dissolved in acetone and prepared into stock solutions. According to the experimental design, the solutions were diluted stepwise with sterile water for in vitro experiments and diluted with 0.5% Tween 80 for in vivo experiments.

[0141] Rust disease treatment in pots: Spray the pesticide solution evenly onto the leaves until they are completely moistened, and allow the solution to air dry naturally. Inoculate with a spore suspension 24 hours after treatment. After inoculation, incubate the wheat seedlings in the dark with humidity for at least 12 hours, maintaining a temperature of 18℃~20℃ during this period. Then, cultivate them in a greenhouse at 18℃~22℃ with at least 12 hours of light per day.

[0142] When the incidence rate in the blank control group exceeds 80%, a graded survey of the incidence rate in each treatment group will be conducted. The grading method is as follows:

[0143] Level 0: No spore-bearing mass;

[0144] Level 1: The spore mass accounts for less than 5% of the total leaf area;

[0145] Level 3: The spore mass accounts for 5-10% of the total leaf area;

[0146] Level 5: The spore mass accounts for 10-25% of the total leaf area;

[0147] Level 7: The spore mass accounts for 25-50% of the total leaf area;

[0148] Level 9: The spore mass accounts for more than 50% of the total leaf area.

[0149] Cucumber powdery mildew [Erysiphe cucurbitacearum], indoor live preservation and culture. Cucumber variety: Changchun Honey Thorn, planted in pots, substrate is peat moss:vermiculite (3:1), grow until the second true leaf unfolds for use.

[0150] Chemical treatment: The treatment agent was dissolved in acetone and prepared into a stock solution with 0.1% Tween-80 emulsified water. The stock solution was then diluted stepwise according to the experimental design.

[0151] Fresh spores were collected from cucumber leaves by washing with 0.05% Tween-80 emulsified water, and the spore suspension was filtered through two layers of gauze; the concentration was adjusted to 1×10⁻⁶. 5 spores / ml.

[0152] According to the experimental design, the prepared fresh spore suspension was evenly inoculated onto the underside of the leaves. Inoculation was carried out using an ACO series electromagnetic air compressor powered by a 20ml glass sprayer, with 2ml of spore suspension used per pot. After inoculation, the cucumber seedlings were air-dried and then transferred to an artificial climate chamber, maintaining a temperature of 24℃, RH 60%, and alternating between 16 hours of 30000LUX light and 8 hours of darkness.

[0153] When the disease rate in the blank control reaches over 80%, a graded survey of disease incidence is conducted for each treatment, examining 1-2 true leaves. The grading criteria are as follows:

[0154] Level 0: No disease

[0155] Grade 1: The area of ​​lesions accounts for less than 5% of the total leaf area;

[0156] Grade 3: The lesion area accounts for 5% to 15% of the total leaf area;

[0157] Level 5: The lesion area accounts for 15% to 25% of the total leaf area;

[0158] Level 7: The lesion area accounts for 25% to 50% of the total leaf area;

[0159] Level 9: The lesion area accounts for 50% to 75% of the total leaf area;

[0160] Level 11: The lesion area accounts for more than 75% of the total leaf area.

[0161] In vitro inhibitory activity tests on apple rot (Valsa mali), rapeseed sclerotinia scleotiorum, gray mold (Botrytis cinerea), rice sheath blight (Rhizoctonia solani), wheat scab (Fusarium graminearum), maize bacterial wilt (Pythium graminicola), rice leaf spot (Curvularialunata), pepper blight (Phytophthora capsici Leonian), and peanut white rot (Sclerotium rolfsii Sacc).

[0162] Using a 1% DMSO aqueous solution as a blank control, accurately weighed test compounds were dissolved in DMSO and added to potato dextrose agar (PDA) medium at approximately 50°C to achieve a compound concentration of 20 mg / L. After the medium solidified, the tested plant pathogenic fungi were inoculated using a sterile inoculation needle (cup diameter 5 mm). Each test group had three replicates. The fungi were incubated at 25°C for 2-5 days, and the colony diameter (mm) was measured using the cross-sectional method. The average antifungal effect was taken. The relative inhibition rate (I%) was calculated using the following formula: I(%) = [(CT) / (C-5)] × 100

[0163] Where I is the inhibition rate, C is the colony diameter (mm) of the control group, and T is the colony diameter (mm) of the treatment group.

[0164] Methods for evaluating the bioactivity of fungicides:

[0165] In vitro evaluation methods

[0166]

[0167] Blank control lesion diameter - drug-treated lesion diameter

[0168]

[0169] Live evaluation methods

[0170] Disease index calculation method

[0171]

[0172] Methods for calculating drug efficacy

[0173]

[0174] Example 6: The control effect of the compound of the present invention on multiple target diseases

[0175] The experimental results are shown in Table 1.

[0176] Table 1

[0177]

[0178]

[0179] Experimental results show that the compounds of this invention exhibit excellent biological activity against the target diseases.

[0180] Biological control experiment

[0181] The bioactivity differences between deuterated and undeuterated compounds were compared by pharmacological efficacy analysis.

[0182] The following is a comparison of the bioactivity of compounds from some preparation examples and their undeuterated compounds, and a method for evaluating the bioactivity of bactericides:

[0183]

[0184] Example 7: Relative toxicity of compound (1) and control compound

[0185] Test method: Mycelial growth rate method

[0186] Solvent: DMSO

[0187]

[0188]

[0189] The above experimental results show that the compounds of the present invention have superior bactericidal effects compared with non-deuterated compounds.

[0190] Example 8: Relative toxicity of compound (3) and control compound

[0191] Test method: Mycelial growth rate method;

[0192] Solvent: Acetone

[0193]

[0194] The above experimental results show that the compounds of the present invention have superior bactericidal effects compared with non-deuterated compounds. However, compared with compound 3, the bactericidal activity of compound 1 after deuteration is significantly higher.

[0195] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound, or a pesticide-acceptable salt thereof, characterized in that, The compound has the following structure: 。 2. A composition, characterized in that, It comprises i) the compound as claimed in claim 1, or a pesticide-acceptable salt thereof; and 2) a pesticide-acceptable carrier and / or excipient.

3. The use of a compound as claimed in claim 1, or a pesticide-acceptable salt thereof, or a composition as claimed in claim 2, for the control of plant pathogenic fungi or in the preparation of a fungicide for plant pathogenic fungi.

4. A method for controlling fungal diseases without diagnosing the cause or treating the disease, characterized in that, This includes applying the compound of claim 1, or a pesticide-acceptable salt thereof, or the composition of claim 2, to plants that are suffering from or may be suffering from fungal diseases, their seeds, the soil around them, or the environment.

5. The method as described in claim 4, characterized in that, The fungal diseases mentioned are selected from: turf brown spot, cucurbit anthracnose, cucumber powdery mildew, tomato early blight, tomato leaf mold, apple spot leaf drop, apple rot fungus, rapeseed sclerotium rot fungus, gray mold fungus, rice sheath blight fungus, rice curvularia fungus, wheat scab fungus, wheat rust fungus, and corn bacterial wilt fungus.

6. A deuterated pyrazole intermediate having the following structure: ； in, R3 is a C1-C6 alkoxy, hydroxyl, or halogen.

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