Deuterated pyrazolyl formamide compound as well as preparation method and application thereof

Abstract

The invention relates to a deuterated pyrazolyl formamide compound as well as a preparation method and application thereof. Specifically, the compound has a structure as shown in a formula I, and has a more excellent bactericidal effect and an effect of increasing the yield. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pesticide chemistry, and in particular to a deuterated pyrazolylcarboxamide compound and a preparation method and application thereof. Background Art

[0002] The use of pyrazole-4-carboxamide compounds and their derivatives in preventing and controlling plant diseases has been reported, such as patents CN1646494, CN101115723, and CN102239137.

[0003] Since the control of plant fungal diseases is very challenging, high application rates are often required to produce satisfactory control effects. Therefore, there is a need in the art to develop a better active compound against plant pathogenic harmful fungi. Summary of the invention

[0004] The purpose of the present 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;

[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 (such as 2, 3 or 4) groups selected from the following groups: halogen, C1-C3 haloalkyl.

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

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

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

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

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

[0018]

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

[0020]

[0021] The second aspect of the present invention provides a composition comprising i) a compound as described in the first aspect of the present invention, or its enantiomer or diastereomer 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 comprises an auxiliary agent.

[0024] In another preferred embodiment, the composition further comprises a substance selected from the group consisting of insecticides, attractants, disinfectants, bactericides, acaricides, nematicides, fungicides, growth regulators, safeners, fertilizers, semiochemicals, or a combination thereof.

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

[0026] In a fourth aspect, the present invention provides a method for controlling fungal diseases, comprising applying the compound described in the first aspect of the present invention, or its enantiomer or diastereoisomer or mixture thereof, or its pesticide acceptable salt or the composition described in the second aspect of the present invention to plants and their seeds that are suffering from or may suffer from fungal diseases, and the surrounding soil or environment.

[0027] In another preferred embodiment, the fungal disease is selected from: lawn brown spot, melon anthracnose, cucumber powdery mildew, tomato early blight, tomato leaf mold, apple leaf spot, apple rot, rapeseed sclerotinia, gray mold, rice sheath blight, rice curvature, wheat fusarium, wheat rust, and corn bacterial wilt.

[0028] In another preferred embodiment, the plant is selected from: cereals (wheat, barley, rye, oats, rice, corn, sorghum, etc.), corn, rapeseed, sunflower, legumes (soybeans, beans, peas, lentils), vegetables (spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes, eggplants, peppers, etc.), grapes, pome fruits, drupes, bananas, tobacco, nuts, coffee, tea, hops, lawns, stevia and other field crops, etc. In addition, 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 structure:

[0030]

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

[0032] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0033] The inventors have developed a deuterated pyrazole-4-carboxamide compound through extensive and in-depth research, through a large number of screenings and tests. Surprisingly, the deuterated pyrazole-4-carboxamide compound of the present invention has a significantly better bactericidal effect than non-deuterated similar compounds. On this basis, the present invention has been completed.

[0034] the term

[0035] Unless defined otherwise, 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 belongs.

[0036] As used herein, "halogen" or "halo" 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 or branched chain alkyl group comprising 1-4 carbon atoms (including alkyl groups of 1-3 or 1-2 carbon atoms), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or the like.

[0038] As used herein, "C1-C3 haloalkyl" or "halogenated C1-C3 alkyl" are used interchangeably and refer to a straight 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-fluoro-n-propyl, or the like.

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

[0040] As used herein, "deuterated" refers to one or more hydrogens in a compound or group being replaced by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted. The term "one or more deuterated" and "one or more deuterated" can be used interchangeably.

[0041] As used herein, "non-deuterated compound" or "undeuterated" refers to a compound containing a deuterium atom (D, 2 H) Compounds having a ratio no higher than the natural deuterium isotope content (about 0.015%).

[0042] As used herein, "enantiomers or diastereomers" refer to compounds made up of the same atoms, bonded by the same bonds, but having different three-dimensional structures.

[0043] In another preferred embodiment, the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), 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 may be selected to provide stable fragments and compounds.

[0048] Specific functional groups and chemical term definitions are detailed below. For purposes of this invention, chemical elements are referred to as Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

[0049] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their R and S enantiomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and their mixtures are encompassed by the present invention.

[0050] Active ingredients

[0051] The term "active substance of the present invention" or "active compound of the present invention" refers to a compound of formula (I), or an enantiomer or diastereomer thereof or a mixture thereof, or a pesticidally acceptable salt thereof,

[0052]

[0053] R1 and R2 are as defined herein.

[0054] The term also includes enantiomers or diastereomers of the compound of formula (I) or mixtures thereof, or pesticide-acceptable salts thereof. Salts of the compounds of the present invention include inorganic salts and organic salts. A preferred class of salts is 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, 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, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid.

[0055] Composition and use

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

[0057] If appropriate, the compounds of the invention may be present in a single crystalline form, multiple crystalline forms or mixtures thereof.

[0058] Typically, the composition of the present invention is a fungicide composition. The composition of the present invention may further include appropriate adjuvants, including but not limited to: solvents, liquid carriers, solid carriers or fillers, surfactants, dispersants, emulsifiers, wetting agents, adjuvants, solubilizers, penetration enhancers, protective colloids, adhesives, thickeners, humectants, compatibilizers, bactericides, antifreeze agents, defoamers, colorants, tackifiers and adhesives.

[0059] The compositions may be in the form of conventional preparations, such as solutions, emulsions, suspensions, wettable powders, dusts, powders, pastes, ointments, soluble powders, granules, molded products, suspoemulsion concentrates, natural and synthetic materials impregnated with the active compound, and microcapsules in polymers.

[0060] The composition can be used in the form of (but not limited to) aerosol, spray, foam, gel, vaporizer.

[0061] In addition to water, other polar or non-polar organic solvents can also be used as co-solvents. 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 methylene chloride, aliphatic hydrocarbons such as cyclohexane or paraffin (such as mineral oil fractions, mineral oil and vegetable oil), alcohols such as ethanol, propanol, benzyl alcohol, cyclohexanol, butanol or ethylene glycol and its ethers and esters, ketones such as acetone, cyclohexanone, methyl ethyl ketone, or methyl isobutyl ketone, esters such as lactic acid esters, carbonates, fatty acid esters, strong polar solvents such as amides (N, N-dimethylformamide, N-alkylpyrrolidone) and sulfones, 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 are, for example, natural mineral powders, such as kaolin, clay, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, and synthetic mineral powders, such as highly dispersed silica, alumina and silicates; suitable solid carriers for granules are: for example, crushed and classified natural rocks, such as calcite, marble, pumice, sepiolite and dolomite, and synthetic particles of inorganic and organic powders, and particles of organic matter such as cellulose, starch, such as paper, sawdust, coconut shells and other nut shell powder, bark powder, grain powder, corn cobs and tobacco stems, and mixtures thereof.

[0063] Suitable surfactants are various surface-active compounds known in the field of pesticide formulations, including anionic, cationic, nonionic and amphoteric surfactants, block polymers, polyelectrolytes. Such surfactants act as emulsifiers, dispersants, solubilizers, wetting agents, penetration enhancers, protective colloids or adjuvants. Mixtures thereof may also be used.

[0064] Suitable anionic surfactants are alkyl sulfonates, alkyl sulfates, aryl sulfonates, phosphates, carboxylates, ammonium salts and mixtures thereof, such as calcium dodecylbenzenesulfonate, sodium sulfate, sodium lauryl sulfate, sodium methylenenaphthalenesulfonate, sodium dodecylbenzenesulfonate, calcium dodecylbenzenesulfonate, sodium alkylnaphthalenesulfonate, fatty alcohol polyoxyethylene ether, and alkylphenol polyoxyethylene ether.

[0065] Suitable nonionic surfactants are alkoxylates, amine oxides, N-substituted fatty acid amides, esters, polymers, sugar-based surfactants, and mixtures thereof.

[0066] Suitable cationic surfactants include quaternary ammonium salts.

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

[0068] Suitable polymers include oligomers and polymers containing ethylene and acrylic acid monomers and alcohols and amines.

[0069] Suitable thickeners are polysaccharides (for example carboxymethylcellulose xanthan gum) and natural or synthetic polymers in the form of powders, granules or latexes (for example gum arabic, polyvinyl alcohol, polyvinyl acetate, and natural phospholipids such as cephalins and lecithins, and synthetic phospholipids), inorganic clays, silicates.

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

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

[0072] The compositions generally contain from 0.01 to 98% by weight of active compound, preferably from 0.5 to 90% by weight of active compound.

[0073] As used herein, the term "preventing and controlling" includes but is not limited to sterilizing, slowing down bacterial growth or reproduction rate.

[0074] The compound of the present invention, or its enantiomer or diastereomer or mixture thereof, or its salt and the composition of the present invention can be used for controlling pests.

[0075] The active compound of the present invention can be used to treat propagation materials and plants, and can also be used to treat plant roots. The method can be used for sterilization. The target diseases to be controlled include lawn brown spot, melon anthracnose, cucumber powdery mildew, tomato early blight, tomato leaf mold, apple leaf spot disease, apple rot, rape sclerotinia, gray mold, rice sheath blight, rice curvature, wheat scab, wheat rust, and corn bacterial wilt.

[0076] The method of the present invention can protect plants from the above-mentioned pests and diseases, such as cereals (wheat, barley, rye, oats, rice, corn, sorghum, etc.), corn, rapeseed, sunflower, legumes (soybeans, beans, peas, lentils), vegetables (spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes, eggplants, peppers, etc.), grapes, pome fruits, drupes, bananas, tobacco, nuts, coffee, tea, hops, lawns, stevia and other field crops, etc. In addition, natural rubber plants, ornamental and forest plants, such as flowers and evergreen trees, are also included.

[0077] The composition may also include (but not limited to) a substance selected from the group consisting of bactericides, fungicides, growth regulators, safeners, fertilizers, chemical semiochemicals, or a combination thereof. The substances constituting the composition may be selected from, but not limited to, the following examples: prothioconazole, tebuconazole, fluoxastrobin, spiroxabiocin, fluepiconazole, pyraclostrobin, difenoconazole, benzazole, propiconazole, fludioxonil, azoxystrobin, fluoxathiapiprolin, metalaxyl-M, clofoconazole, fluopicolide, fluopicolide, and bixafen.

[0078] Plants in the present invention refer to naturally occurring plants and plants obtained through conventional plant breeding and optimization methods, or through biotechnology and genetic engineering methods, such as transgenic plants.

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

[0080] The composition of the invention is suitable for protecting seeds of plants used in agriculture, greenhouses, forests or horticulture, such as cotton seeds.

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

[0082] The compound shown in the general formula of the present invention can be prepared by the following method, but the conditions of the method, such as the amount of reactants, solvents, alkalis, compounds used, reaction temperature, reaction time required, etc. are not limited to the following explanation. The compounds of the present invention can also be prepared conveniently by combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs. If feasible, the reagent can be purchased through commercial channels.

[0083] Typical embodiments of the compounds of the present invention can be synthesized using the following general reaction schemes. It is apparent from the description given herein that the general scheme can be changed by replacing with other materials with similar structures to obtain corresponding different products. The synthetic method can provide a large amount of production as required. The raw materials can be obtained by commercial methods or synthesized using disclosed methods. The examples given herein, through simple inspection steps, the characteristics of the final product usually make the characteristics of the necessary raw materials obvious.

[0084] Synthesis reaction parameters can use, for example, the following general methods and procedures to prepare compounds of the present invention from readily available starting materials. It will be appreciated that other process conditions may also be used where typical or optimized process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, catalyst, pressure, etc.) are given, unless otherwise noted. Optimum reaction conditions may vary with specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0085] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials can be obtained from commercial suppliers, and others can be prepared by procedures described in standard reference texts or obvious modifications thereof.

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

[0087]

[0088] R1 and R2 are as defined in the present invention; R3 is C1-C6 alkoxy, hydroxy 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 being selected from amide lithium compounds, such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS) alkali metal salts of alcohol, such as sodium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide; alkyl metal lithium compounds, such as butyl lithium, phenyl lithium; organic amines, such as pyridine, triethylamine, triethylenediamine (DABCO), DMAP, N-methylmorpholine. The reaction solvent can be an ether, such as tetrahydrofuran, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran. Nitriles, such as acetonitrile or propionitrile. Amides, such as N,N-dimethylformamide, diethylformamide, N-methylpyrrolidone.

[0090] When R3 is halogen, the reaction can be carried out in a hydrocarbon solvent such as dichloromethane, chloroform, tetrachloromethane, chlorobenzene, toluene, etc. The base can be selected from a base selected from an amide lithium compound, such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS); or an organic amine, such as pyridine, triethylamine, triethylenediamine (DABCO), DMAP, N-methylmorpholine.

[0091] The main advantages of the present invention include:

[0092] 1. The present invention provides a novel deuterated pyrazolylcarboxamide compound;

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

[0094] 3. The deuterated pyrazolylcarboxamide compounds of the present invention provide deuterated standards of fluopyram, fluopyram, and bixafen, which can be detected by residual 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 described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The raw materials or instruments used in the examples of the present invention are commercially available unless otherwise specified.

[0097] Embodiment 1:

[0098] Compound (1): 5-(difluoromethyl)-N-methoxy-1-(deuterated methyl)-N-(1-(2,4,6-trichlorophenyl)propan-2-yl)-1H-pyrazole-4-carboxamide

[0099]

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

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

[0102]

[0103] To a 100 mL round-bottom flask, ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (570 mg, 1 equiv) and K2CO3 (624 mg, 1.5 equiv) were added, followed by 30 mL of THF and CD3I (642 mg, 1.5 equiv), stirred at 60 ° C for 12 h, filtered, extracted three times with ethyl acetate, the organic phases were combined and washed three times with saturated brine, the organic phase was dried over anhydrous magnesium sulfate, filtered, spin-dried, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:3) to give ethyl 3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxylate (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-carboxylate (133.5 mg, 1 equiv) substrate was dissolved in 3 ml of ethanol, 1.0 mmol of NaOH was added, 3 ml of water was added, and the mixture was stirred at 90 degrees Celsius for 1 hour. 1 ml of 1N hydrochloric acid was added to the system, all the solvents were dried by spin drying, acetonitrile was added to the system, and the mixture was filtered after heating, and the filtrate was dried by spin drying to obtain 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)propan-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, the residual acid chloride was dissolved in dichloromethane, and added dropwise to a dichloromethane solution containing O-methyl-N-(1-(2,4,6-trichlorophenyl)propan-2-yl)hydroxylamine (157 mg, 1 equiv) and triethylamine (237 mg, 4 equiv) at 0 degrees. The mixture was slowly returned 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 dried by spin chromatography on a silica gel column (petroleum ether: ethyl acetate = 2:1). Extraction column chromatography gave 5-(difluoromethyl)-N-methoxy-1-(deuterated methyl)-N-(1-(2,4,6-trichlorophenyl)propan-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] Embodiment 2:

[0114] Compound (2): Preparation of 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, the residual acid chloride was dissolved in dichloromethane, and 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 degrees. The mixture was slowly returned 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 dried by spin chromatography on a silica gel column (petroleum ether: ethyl acetate = 3:7). N-(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxamide (400 mg, 86%) was obtained by extraction column chromatography. 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] Embodiment 3:

[0118] Compound (2): Preparation of 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-carboxylate (114 mg, 1.0 equiv) was dissolved in 22 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, the aqueous phase was extracted with EA, dried, filtered, spin-dried, and purified (petroleum ether: ethyl acetate = 3:7) to obtain the compound N-(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxamide (260 mg, 86%).

[0121] Embodiment 4:

[0122] Compound (3): Preparation of 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, the residual acid chloride was dissolved in dichloromethane, and added dropwise 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) at 0 degrees, and then slowly stirred. The mixture was returned 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 dried by spin drying. The mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate petroleum ether: ethyl acetate = 3:7). 3-(difluoromethyl)-1-(deuterated methyl)-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (360 mg, 84%) was obtained by extraction column chromatography.

[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] Embodiment 5:

[0127] Compound (4): Preparation of 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, the residual acid chloride was dissolved in dichloromethane, and added dropwise to a dichloromethane solution containing 2-(2-chloro-4-(trifluoromethyl)phenoxy)aniline (321 mg, 1 equiv) and triethylamine (452 ​​mg, 4 equiv) at 0 degrees, and the temperature was slowly restored to room temperature. The reaction was allowed to proceed for 4 hours. After the reaction was completed, the product was washed three times with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and dried by spin drying. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:7), and N-(2-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-3-(difluoromethyl)-1-(deuterated methyl)-1H-pyrazole-4-carboxamide (380 mg, 88%) was obtained by extraction column chromatography.

[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 experiments

[0132] The deuterated purity of the active compounds of the present invention used in the following biological test experiments is greater than or equal to 95%, generally greater than or equal to 98%.

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

[0134] Test method: Rhizoctonia solani and Colletotrichumorbiculare were both preserved and cultured in vitro indoors, using the mycelium growth rate method; culture medium: PDA culture medium.

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

[0136] Add the test drugs to the sterilized culture medium cooled to about 45°C according to a certain concentration gradient and mix well. Pour 60 ml of each bottle of culture medium into 4 plates evenly to prepare drug-containing plates.

[0137] Place a bacterial plate in the center of the drug-containing plate, with the hyphae facing downward. Cultivate at 25°C until the blank control colonies cover more than 2 / 3 of the culture dish, and measure the colony diameter of each treatment. Measure each colony twice using the cross method, and use the average number to represent the size of the colony. Calculate the inhibition of the drug on the bacterial growth rate.

[0138] Wheat rust [Botrytis cinerea Pers.] was tested by potted plant spraying. Wheat rust was 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, they were diluted stepwise with sterile water for in vitro experiments and with 0.5% Tween 80 for in vivo experiments.

[0141] Rust potting method: spray the liquid medicine evenly on the leaves until they are completely wet, and wait for the liquid medicine to dry naturally; 24 hours after the treatment, spray the spore suspension for inoculation. After the wheat seedlings are inoculated, they are cultured in the dark and moisturizing for more than 12 hours, and the temperature during the moisturizing stage is controlled at 18℃~20℃. Then they are cultured in a greenhouse at 18℃~22℃, with more than 12 hours of light per day.

[0142] When the incidence of the blank control group exceeds 80%, the incidence of each treatment will be investigated in a graded manner. The grading method is:

[0143] Level 0: No spore pile;

[0144] Level 1: Spore piles occupy less than 5% of the entire leaf area;

[0145] Level 3: spore piles occupy 5-10% of the entire leaf area;

[0146] Level 5: The spore pile occupies 10-25% of the entire leaf area;

[0147] Level 7: Spore piles occupy 25-50% of the entire leaf area;

[0148] Level 9: The spore pile occupies more than 50% of the entire leaf area.

[0149] Cucumber powdery mildew [Erysiphe cucurbitacearum], indoor live preservation and culture. Cucumber variety: Changchun honeythorn, planted in pots, the substrate is peat soil: vermiculite (3:1), grow until the second true leaf unfolds and then set aside.

[0150] Drug treatment: The treatment agent was dissolved in acetone and prepared into a mother solution with 0.1% Tween-80 emulsified water, and diluted step by step according to the experimental design.

[0151] Wash fresh spores on cucumber leaves with 0.05% Tween-80 emulsified water, filter the spore suspension with two layers of gauze; adjust the concentration to 1×10 5 spores / ml.

[0152] According to the experimental design, the prepared fresh spore suspension was evenly inoculated on the back of the leaves. The inoculation was carried out using an ACO series electromagnetic air compressor to drive a 20ml glass sprayer, and 2ml of spore suspension was used for each pot. The inoculated cucumber seedlings were dried in the shade and moved into an artificial climate box, maintaining a temperature of 24℃, RH 60%, 30000LUX light for 16h, and dark for 8h alternately.

[0153] When the diseased leaf rate of the blank control reaches more than 80%, investigate the disease situation of each treatment in a graded manner, and investigate 1 to 2 true leaves. The classification standards are:

[0154] Level 0: No disease

[0155] Level 1: The lesion area accounts for less than 5% of the entire leaf area;

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

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

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

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

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

[0161] In vitro inhibitory activity test on apple rot (Valsa mali), rapeseed sclerotinia (Sclerotinia scleotiorum), gray mold (Botrytis cinerea), rice sheath blight (Rhizoctonia solani), wheat fusarium (Fusarium graminearum), corn bacterial wilt (Pythium graminicola), rice Curvularia salsa leaf spot (Curvularialunata), pepper blight (Phytophthora capsici Leonian), and peanut white rot (Sclerotium rolfsiiSacc).

[0162] With 1% DMSO aqueous solution as blank control, the accurately weighed test compound was dissolved with DMSO and added to potato dextrose agar (PDA) medium at about 50°C to make the concentration of the compound in the medium reach 20mg / L. After the medium solidified, the above-mentioned plant pathogenic fungi (the diameter of the fungus cake was 5mm) were inoculated with a sterile inoculation needle. Each test group had 3 parallels. After being placed in a constant temperature incubator at 25°C for 2-5 days, the colony diameter (mm) was measured by the cross method, and the antifungal effect was averaged. The relative inhibition rate (I%) was calculated as follows: I (%) = [(CT) / (C-5)] × 100

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

[0164] Methods for evaluating the biological activity of fungicides:

[0165] In vitro evaluation method

[0166]

[0167] In vivo evaluation method

[0168] Calculation method of disease index

[0169]

[0170] Calculation method of drug efficacy

[0171]

[0172] Example 6: Control effects of the compounds of the present invention on multiple target diseases

[0173] The experimental results are shown in Table 1.

[0174] Table 1

[0175]

[0176]

[0177] The experimental results show that the compounds of the present invention exhibit very excellent biological activity against target diseases.

[0178] Biological control experiments

[0179] The difference in biological activity between deuterated compounds and non-deuterated compounds was compared by pharmacodynamics.

[0180] The following is a comparison of the biological activities of some of the compounds in the preparation examples and their non-deuterated compounds, and a method for evaluating the biological activity of fungicides:

[0181]

[0182] Example 7: Relative toxicity of compound (1) and control compound

[0183] Test method: Mycelial growth rate method

[0184] Solvent: DMSO

[0185]

[0186]

[0187] The above experimental results show that the compounds of the present invention have better bactericidal effects than non-deuterated compounds.

[0188] Example 8: Relative toxicity of compound (3) and control compound

[0189] Test method: mycelial growth rate method;

[0190] Solvent: Acetone

[0191]

[0192] The above experimental results show that the compounds of the present invention have a better bactericidal effect than the non-deuterated compounds. However, compared with compound 3, the bactericidal activity of compound 1 after deuteration is significantly improved.

[0193] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula I, or an enantiomer thereof, or a mixture thereof, or a pesticide-acceptable salt thereof: R1 is selected from hydrogen, C1-C3 alkoxy; R2 is selected from -C1-C4 alkyl-phenyl, -halophenyl-phenyl, -phenyl-O-phenyl; and each phenyl group is optionally substituted by one or more (such as 2, 3 or 4) groups selected from the following groups: halogen, C1-C3 haloalkyl.

2. The compound according to claim 1, or its enantiomer or diastereomer or mixture thereof, or its pesticide acceptable salt, characterized in that: R2 is selected from -C1-C4alkyl-halo and / or C1-C3haloalkyl substituted phenyl, -halophenyl-halo and / or C1-C3haloalkyl substituted phenyl, -halo or unsubstituted phenyl-O-halo and / or C1-C3haloalkyl substituted phenyl.

3. The compound according to claim 1, or its enantiomer or diastereomer or mixture thereof, or its pesticide acceptable salt, characterized in that: R2 is selected from -CH2(CH2)CH2-trichlorophenyl, -monofluorophenyl-dichloro- or trifluorophenyl, -unsubstituted phenyl-O-monofluoro and trifluoromethyl-substituted phenyl.

4. The compound according to claim 1, or its enantiomer or diastereomer or mixture thereof, or its pesticide acceptable salt, characterized in that: The compound is selected from the group consisting of:

5. The compound according to claim 1, or its enantiomer or diastereomer or mixture thereof, or its pesticide acceptable salt, characterized in that: The compound is:

6. A composition, characterized in that It comprises i) the compound according to claim 1, or its enantiomer or diastereomer or mixture thereof, or its pesticide acceptable salt; and 2) a pesticide acceptable carrier and / or excipient.

7. Use of the compound according to claim 1, or its enantiomer or diastereomer or mixture thereof, or its pesticide acceptable salt or the composition according to claim 5 for controlling plant pathogenic fungi or in the preparation of plant pathogenic fungicide.

8. A method for preventing and controlling fungal diseases, characterized in that: The method comprises applying the compound according to any one of claims 1 to 5, or its enantiomer or diastereomer or mixture thereof, or its pesticide acceptable salt or the composition according to claim 5 to plants and their seeds that are or may be affected by fungal diseases, and the soil or environment around them.

9. The method according to claim 7, characterized in that The fungal diseases are selected from: lawn brown spot, melon anthracnose, cucumber powdery mildew, tomato early blight, tomato leaf mold, apple leaf spot, apple rot, rapeseed sclerotinia, gray mold, rice sheath blight, rice curvature, wheat fusarium, wheat rust, and corn bacterial wilt.

10. A deuterated pyrazole intermediate having the structure: in, R3 is C1-C6 alkoxy, hydroxy or halogen.

Images