Process for the preparation of an inhibitor of nadh-ase and use thereof

Abstract

The application discloses a preparation method and application of an NADH enzyme inhibitor. The application provides a compound of formula I and a salt thereof, wherein R1, X and n are defined in the description. The compound of the application has good bactericidal effect and has good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pesticide chemistry, specifically relating to an NADH enzyme inhibitor compound, its preparation method, and its application. Background Technology

[0002] NADH fungicides are a class of pesticides that exert their bactericidal effect by inhibiting the activity of NADH dehydrogenase in the mitochondrial respiratory chain of pathogens. These fungicides disrupt the NAD⁺ / NADH homeostasis by blocking the electron transport chain, inhibiting the energy metabolism of pathogens, and ultimately leading to their death.

[0003] Currently, there are few reports on novel fungicides targeting NADH dehydrogenase in the market, and even fewer domestically developed novel fungicides targeting NADH dehydrogenase. Among the reported products are a novel broad-spectrum fungicide targeting NADH dehydrogenase developed by Northwest A&F University, and natural product-derived fungicides such as carabrone. These products exhibit good protective and curative activity against wheat take-all, powdery mildew, and gray mold.

[0004] Therefore, researching and developing NADH fungicides that are environmentally friendly, highly safe, and less likely to induce resistance is an important direction for green pesticides. Summary of the Invention

[0005] This invention provides a NADH enzyme inhibitor pesticide fungicide compound with excellent bactericidal effect.

[0006] Specifically, the present invention provides a compound of formula I and its salt.

[0007] I,

[0008] in,

[0009] R1 is one of H, C1-C6 alkyl, C1-C6 alkyl carbonyl or halo-C1-C6 alkyl; X is one of H, halogen, cyano, nitro, C1-C6 alkyl, halo-C1-C6 alkyl or C1-C6 alkoxy, and n is a natural number from 0 to 10.

[0010] The present invention also provides a pesticide composition containing the compounds and their salts described herein.

[0011] The present invention also provides a method for preparing the compound of formula I of the present invention, the synthetic route of which is as follows:

[0012] ,

[0013] Wherein, R1 is one of H, C1-C6 alkyl, C1-C6 alkyl carbonyl or halogenated C1-C6 alkyl; X is one of H, halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl or C1-C6 alkoxy; n is a natural number from 0 to 10; Y is a leaving group, preferably halogen.

[0014] Beneficial effects

[0015] The compounds of this invention have excellent bactericidal effects and good application prospects. Detailed Implementation

[0016] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components or steps, without excluding other substances or steps.

[0017] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.

[0018] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some embodiments, materials, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0019] If the compound of Formula I described in this invention can form geometric isomers, such as E / Z isomers, then both the pure isomers and mixtures thereof can be used in the compositions of this invention.

[0020] If the compound of Formula I described in this invention has one or more chiral centers and is therefore present as an enantiomer or diastereomer, then the pure enantiomer, the racemic version, or the diastereomer may be used in the compositions of this invention.

[0021] It should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “each…independently is”, and “independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0022] In this invention, all hydrocarbon chains, i.e., all alkyl groups, can be straight-chain or branched, C n -C m The subscript indicates the number of carbon atoms in the group in all cases. The term "alkyl" as used herein (and in the alkyl structural part containing other groups such as alkoxy groups) is used. Examples of C1-C6 alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, ... 2-Methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0023] Alkoxy groups, without specific definition, generally refer to "alkyl-O-", for example, C1-C. 10 Alkoxy groups, preferably C1-C6 alkoxy groups, more preferably methoxy, ethoxy, propoxy, etc., but not limited thereto.

[0024] The halogens in this invention refer to fluorine, chlorine, bromine, and iodine.

[0025] This disclosure defines "salt" as salts that have undergone acid addition, which can be salts that have undergone addition with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or salts that have undergone addition with an organic acid, such as formic acid, carbonic acid, and alkyl acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, and propionic acid, as well as glycolic acid, thiocyanate, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, and saturated, monounsaturated, or diunsaturated C6-C... 20 Fatty acids, alkyl sulfate monoesters, alkyl sulfonic acids (sulfonic acids with straight-chain or branched alkyl groups having 1-20 carbon atoms), aryl sulfonic acids or aryl disulfonic acids (aromatic groups with one or two sulfonic acid groups, such as phenyl and naphthyl), alkyl phosphonic acids (phosphonic acids with straight-chain or branched alkyl groups having 1-20 carbon atoms), aryl phosphonic acids or aryl diphosphonic acids (aromatic groups with one or two phosphonic acid groups, such as phenyl and naphthyl), wherein the alkyl and aryl groups may have other substituents, such as p-toluenesulfonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc., but not limited thereto.

[0026] This invention first provides a compound of formula I and its salt.

[0027]

[0028] I,

[0029] in,

[0030] R1 is one of H, C1-C6 alkyl, C1-C6 alkyl carbonyl or halogenated C1-C6 alkyl; X is one of H, halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl or C1-C6 alkoxy; n is a natural number from 0 to 10, preferably 1, 2 or 3.

[0031] In a preferred embodiment, R1 is H, and X is H, halogen, cyano, or nitro.

[0032] In a preferred technical solution, n is 1 or 2.

[0033] The compounds particularly preferred in this invention are selected from the following compounds.

[0034] , , , , , , .

[0035] The present invention also provides a pesticide composition containing a compound of formula I of the present invention and its salt.

[0036] This invention also provides a method for preparing a compound of formula I, the synthetic route of which is as follows:

[0037] ,

[0038] Wherein, R1 is one of H, C1-C6 alkyl, C1-C6 alkyl carbonyl or halogenated C1-C6 alkyl; X is one of H, halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl or C1-C6 alkoxy, n is a natural number from 0 to 10, and Y is halogen.

[0039] The synthesis steps include reacting compound II and compound III in an organic solvent in the presence of an acid-binding agent to prepare compound I. The organic solvent is preferably one of DMF, DMSO and DMA, and the acid-binding agent is preferably potassium carbonate or sodium carbonate, particularly preferably anhydrous potassium carbonate or anhydrous sodium carbonate.

[0040] The compounds of this invention have certain control effects on plant diseases caused by various fungal pathogens. Examples of these pathogens include, but are not limited to: oomycetes, such as *Pythium*, *Pseudomonas*, *Phytophthora*, *Phytophthora*, and other genera; deuteromycetes, such as *Fusarium*, *Rhizoctonia*, *Anthracnose*, *Curvularia*, and other genera; ascomycetes, such as *Cyclocarya*, *Fusarium*, *Pythium*, *Phytophthora*, *Hypericum*, *Cercospora*, *Ustilago*, and other genera; and other pathogens such as bacteria that cause plant diseases. Examples of diseases caused by these pathogens include, but are not limited to: wheat stem base rot, wheat root rot, wheat sheath blight, wheat Fusarium head blight, wheat Pythium, wheat take-all disease, corn bacterial wilt, corn seedling blight, corn stem base rot, and soil-borne diseases such as Pythium.

[0041] The plant species that can be used with the compounds of this invention are not particularly limited; examples include, for instance, cereals (e.g., rice, barley, wheat, rye, oats, corn, sorghum, etc.), legumes (soybeans, mung beans, broad beans, peas, peanuts, etc.), fruit trees / fruits (apples, citrus fruits, pears, grapes, peaches, Japanese apricots, cherries, walnuts, apricots, bananas, strawberries, etc.), vegetables (cabbage, tomatoes, spinach, cabbage, lettuce, onions, scallions, green peppers, etc.), and root vegetables (carrots, potatoes, sweet potatoes, etc.). Radishes, lotus roots, and wild grasses, etc.), industrial crops (cotton, paper mulberry, daphne, rapeseed, sugar beets, hops, sugarcane, sugar beets, olives, rubber, coffee, tobacco, tea, etc.), berries (pumpkin, cucumber, watermelon, melon, etc.), forage grasses (orchard grass, sorghum, timothy grass, alfalfa, purple alfalfa, etc.), turfgrass (Korean zoysia grass, creeping bentgrass, etc.), spice crops (lavender, rosemary, thyme, parsley, pepper, ginger, etc.), and flowers (chrysanthemums, roses, orchids, etc.).

[0042] The compounds of this invention are generally used as fungicide active ingredients in compositions, i.e., formulations, and typically also include pesticide-acceptable surfactants and carriers. The carrier can be a solid carrier or a liquid carrier.

[0043] Suitable solid carriers include natural or synthetic clays and silicates, such as natural silica and diatomaceous earth; magnesium silicates, such as talc; magnesium aluminum silicates, such as kaolinite, kaolin, montmorillonite and mica; silica, calcium carbonate, light calcium carbonate; calcium sulfate; limestone; sodium sulfate; ammonium salts, such as ammonium sulfate, hexamethylenediamine and urea, etc.

[0044] Liquid carriers include water and organic solvents. When water is used as a solvent or diluent, organic solvents can also be used as auxiliaries or antifreeze additives. Useful liquefied gaseous fillers or carriers are those liquids that are gaseous at standard temperatures and pressures, such as aerosol propellants like halogenated hydrocarbons, as well as butane, propane, nitrogen, and carbon dioxide, etc.

[0045] Suitable organic solvents include aromatic hydrocarbons, such as benzene, xylene, and toluene; chlorinated hydrocarbons, such as chlorobenzene, vinyl chloride, chloroform, and dichloromethane; aliphatic hydrocarbons, such as petroleum fractions, cyclohexane, and light mineral oils; alcohols, such as isopropanol, butanol, ethylene glycol, glycerol, and cyclohexanol; their ethers and esters; ketones, such as acetone, cyclohexanone, dimethylformamide, and N-methylpyrrolidone; vegetable oils, such as soybean oil, rapeseed oil, and cottonseed oil, etc.

[0046] Suitable surfactants (adjuvants, emulsifiers, dispersants, protective colloids, wetting agents, and binders) include all common ionic and nonionic substances, such as ethoxylated nonylphenol, polyalkylene glycol ethers of straight-chain or branched alcohols, reaction products of alkylphenols with ethylene oxide and / or propylene oxide, reaction products of fatty acid amines with ethylene oxide and / or propylene oxide, as well as fatty acid esters, alkyl sulfonates, alkyl sulfates, alkyl ether sulfates, alkyl ether phosphates, aryl sulfates, ethoxylated arylalkylphenols (such as tristyryl-phenol-ethoxylated compounds), and ethoxylated and propoxylated arylalkylphenols such as sulfated and phosphorylated arylalkylphenol-ethoxylated and -ethoxylated and -propoxylated compounds. Other examples are natural and synthetic water-soluble polymers, such as lignin sulfonates, gelatin, gum arabic, phospholipids, starch, hydrophobically modified starch, and cellulose derivatives, particularly cellulose esters and cellulose ethers, as well as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polyacrylic acid, polymethacrylic acid, and copolymers of (meth)acrylic acid and (meth)acrylates, copolymers of methacrylic acid and methacrylates neutralized with alkali metal hydroxides, and optionally substituted naphthalene sulfonates condensates with formaldehyde. The presence of a surfactant is necessary if one of the active ingredients and / or one of the inert carriers is insoluble in water and the application is carried out in water.

[0047] The pesticide fungicide described in this invention can be prepared by common methods. For example, the active substance is mixed with a liquid solvent and / or a solid carrier, and surfactants such as emulsifiers, dispersants, stabilizers, and wetting agents are added. Other adjuvants may also be added, such as binders, defoamers, foaming agents, antioxidants, crystallization inhibitors, viscosity modifiers, suspending agents, spray droplet modifiers, pigments, neutralizers and buffers, corrosion inhibitors, dyes, fragrances, spreading agents, penetration enhancers, micronutrients, dispersants, thickeners, freezing point depressants, antimicrobial agents, etc.

[0048] The pesticide bactericides described in this invention can be applied in their formulation form or in the form prepared therefrom. Such forms of application include, but are not limited to, capsule suspensions, fine granules, foaming agents, pastes, suspension concentrates, emulsion concentrates, soluble concentrates, suspensions, wettable powders, soluble powders, powders and granules, water-soluble and water-dispersible granules or tablets, etc.

[0049] The formulations described in this invention may also contain other components, such as other fungicides, insecticides, herbicides, plant growth regulators, attractants, acaricides, nematicides, fertilizers, and safeners, which can be formulated together with liquid fertilizers or solid or granular fertilizer carriers such as ammonium nitrate and urea, or mixed with fine sand or soil.

[0050] I. Preparation Examples

[0051] In this specification, if there are any differences between chemical names and chemical structures, the structure is preferred. Generally, the compounds of this invention can be prepared by the methods described herein, unless further specified. The raw materials, reagents, etc., used to prepare the compounds of this invention are commercially available or can be prepared by methods conventional in the art.

[0052] Example 1 Preparation of compound I-01

[0053]

[0054] I-01

[0055] At 25°C, 1,2,4-triazol-3-amide (0.01 mol, 1.12 g, 1.0 eq.), 2-(chloromethyl)-2,3-dihydro-1H-indene (0.01 mol, 1.66 g, 1.0 eq.), 10 ml of N,N-dimethylformamide, and anhydrous potassium carbonate (0.2 mol, 2.76 g, 2.0 eq.) were added to a three-necked flask (50 ml) equipped with a thermometer and magnetic stirrer. The mixture was stirred and heated to 80°C, and the reaction was maintained at this temperature for 4–6 hours. The reaction was monitored by TLC. After the reaction was complete, 25 ml of water was added, and the mixture was extracted three times with ethyl acetate (50 ml). The combined organic layers were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 1.30 g of a white solid powder, with a yield of 53.7%.

[0056] 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.25 – 7.07 (m, 4H), 4.81 –4.61 (m, 2H), 2.95 (ddt, J = 32.7, 16.2, 7.7 Hz, 3H), 2.71 (dt, J = 15.4, 7.8Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 159.39, 150.18, 146.96, 142.37, 126.77,124.95, 53.99, 40.03, 36.33.

[0057] The following compounds of the present invention were synthesized according to Example 1.

[0058] Table 1 Compounds of the present invention

[0059]

[0060]

[0061] II. Biometrics

[0062] 1) Test Objective

[0063] Testing the bactericidal activity of the compounds of this invention

[0064] II) Test Targets

[0065] Fusarium graminearum (FG), Fusarium pseudograminearum (FP), Mango anthracnose fungus (CG), Wheat root rot fungus (BS), Phytophthora capsici (PC), Wheat rhizome blight fungus (RC), Apricot brown rot fungus (MF), Pear black spot fungus (AKT)

[0066] (III) Testing Methods

[0067] Using the mycelial growth method (NY / T 1156.2-2006), compounds I-01~I-09 (compounds of the present invention in Example 1 and Table 1) were prepared at concentrations of 100, 50, 25, 12.5, 6.25, 3.125, and 1.5625 ppm, respectively. Based on the experimental data, the in vitro inhibitory concentrations (EC5) of each compound against fungi such as *Fusarium graminearum* (FG), *Fusarium graminearum* (FP), *Anthracnose fungus of mango* (CG), *Helicobacter spp.* (BS), *Phytophthora capsici* (PC), *Rhizoctonia solani* (RC), *Brachys edulis* (MF), and *Aureobasidium aureum* (AKT) were calculated. 50 )as follows:

[0068] Table 2. Test activity of preferred compounds of the present invention

[0069]

[0070] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound of formula I and its salt, I , in, R1 is one of H, C1-C6 alkyl, C1-C6 alkyl carbonyl or halogenated C1-C6 alkyl; X is one of H, halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl or C1-C6 alkoxy; n is a natural number from 0 to 10, preferably 1, 2 or 3.

2. The compound and its salt according to claim 1, characterized in that, R1 is H, and X is H, halogen, cyano, or nitro.

3. The compound and its salt according to claim 1, characterized in that, n is 1 or 2.

4. The compound and its salt according to any one of claims 1-3, characterized in that, Selected from the following compounds, ， ， ， ， ， ， 。 5. A method for preparing the compound of any one of claims 1-4 and its salt, wherein the synthetic route is as follows: ， in, R1, X and n are defined as described in claims 1-4, and Y is a leaving group.

6. A bactericidal composition, characterized in that, Contains the compound as described in any one of claims 1-4 and its salt.

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