WO2020156297A1 - 一种丙二腈类化合物及其应用 - Google Patents

一种丙二腈类化合物及其应用 Download PDF

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WO2020156297A1
WO2020156297A1 PCT/CN2020/073095 CN2020073095W WO2020156297A1 WO 2020156297 A1 WO2020156297 A1 WO 2020156297A1 CN 2020073095 W CN2020073095 W CN 2020073095W WO 2020156297 A1 WO2020156297 A1 WO 2020156297A1
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acid
hydrogen
compound
alkyl
general formula
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French (fr)
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张立新
张静
张力群
康卓
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沈阳化工大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/30—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/34—Nitriles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms

Definitions

  • the invention belongs to the field of agricultural bactericides. Specifically, it relates to a malononitrile compound and its application.
  • Bacterial diseases have become the second most common disease in China’s agricultural production after fungal diseases. According to incomplete statistics, the area of bacterial diseases currently occurring in China is 120 million mu, and the market capacity of bacterial disease control exceeds 20 100 million yuan.
  • agents for the prevention and control of bacterial diseases mainly include relatively large amounts of copper preparations (including organic or inorganic copper preparations) and antibiotic products; among them, copper preparations have low control effects and a large amount of heavy metals are sprayed into the environment. Pollution of soil, water and food has caused environmental and food safety concerns; on the other hand, the massive use of antibiotics may cause human pathogens to become resistant to medical antibiotics.
  • the purpose of the present invention is to provide a malononitrile compound with a novel structure and its application as a bactericide in the fields of agriculture, forestry or health.
  • R 1 is selected from hydrogen, hydroxyl, mercapto, amino, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkyl sulfide Group, halogenated C 1 -C 6 alkylthio, C 1 -C 6 alkylamino or C 1 -C 6 dialkylamino;
  • R 2 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, cyano C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkane Carbonyl or C 1 -C 6 alkoxycarbonyl;
  • R 1 and R 2 are selected from hydrogen, X 1 , X 2 , X 3 , X 4 , and X 5 are not selected from hydrogen; or, when R 1 , R 2 , X 1 , X 2 , X 4 , When X 5 is selected from hydrogen, X 3 is not selected from methyl, N,N-dimethylamino, methoxy, methylthio or isopropyloxy; or, when R 1 , R 2 , X 2 , When X 3 , X 4 , and X 5 are selected from hydrogen, X 1 is not selected from hydrogen; or, when R 1 , R 2 , X 2 , X 4 , and X 5 are selected from hydrogen, X 1 and X 3 are not selected from Chlorine; or, when R 1 and R 2 are selected from hydrogen, X 2 is selected from methoxy, and X 3 is selected from n-propoxy, X 1 , X 4 , and X 5
  • R 1 is selected from hydrogen, hydroxyl, mercapto, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, C 1 -C 4 alkyl sulfide Group, halogenated C 1 -C 4 alkylthio, C 1 -C 4 alkylamino or C 1 -C 4 dialkylamino;
  • R 2 is selected from hydrogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, cyano C 1 -C 4 alkyl, C 1 -C 4 alkylcarbonyl, C 3 -C 6 cycloalkane Carbonyl or C 1 -C 4 alkoxycarbonyl;
  • a further preferred compound in the present invention is: in general formula I,
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, mercapto, amino, carboxy, methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, monochloromethyl, dichloromethyl, trichloromethyl, monobromomethyl, dibromomethyl, tribromomethyl , Monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, heptafluoroisopropyl, methoxy, ethoxy, n-propoxy, isopropoxy , Difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, trifluoromethylthio, 2,2,2-trifluoro
  • R 1 is selected from hydrogen, hydroxyl, mercapto, amino, cyano, methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Group, methylthio, ethylthio, n-propylthio, n-butylthio, methylamino, ethylamino, n-propylamino or n-butylamino;
  • R 2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyanomethyl, 2,2,2-trifluoroethyl , Acetyl, n-propionyl, cyclopropylformyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or n-butoxycarbonyl;
  • a further preferred compound in the present invention is: in general formula I,
  • R 1 is selected from hydrogen, amino, methyl, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
  • R 2 is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, cyanomethyl, acetyl, n-propionyl, cyclopropylformyl, methoxycarbonyl or ethoxycarbonyl;
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Alkyl straight or branched chain alkyl, such as methyl, ethyl, n-propyl, isopropyl or different butyl, pentyl or hexyl isomers.
  • Halogenated alkyl groups straight or branched chain alkyl groups.
  • the hydrogen atoms on these alkyl groups can be partially or completely replaced by halogens, such as monochloromethyl, dichloromethyl, trichloromethyl, monobromomethyl, and dichloromethyl.
  • Cyanoalkyl straight or branched chain alkyl groups, the hydrogen atoms on these alkyl groups can be partially or completely replaced by cyano groups, such as cyanomethyl (CNCH 2 -), cyanoethyl (CNCH 2 CH 2- ), CNCH 2 CH 2 CH 2 -, CNCH 2 CH 2 CH 2 CH 2 -etc.
  • Alkoxy straight or branched chain alkyl, connected to the structure via oxygen atom bond, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc. .
  • Halogenated alkoxy groups straight or branched chain alkoxy groups, the hydrogen atoms on these alkoxy groups can be partially or completely replaced by halogens, such as chloromethoxy, dichloromethoxy, trichloromethoxy, fluorine Methoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, 2,2,2-trifluoroethoxy, etc.
  • halogens such as chloromethoxy, dichloromethoxy, trichloromethoxy, fluorine Methoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, 2,2,2-trifluoroethoxy, etc.
  • Alkylthio straight or branched chain alkyl, connected to the structure via a sulfur atom bond, such as methylthio, ethylthio and the like.
  • Halogenated alkylthio linear or branched alkylthio, the hydrogen atoms on these alkylthio groups can be partially or completely replaced by halogen, such as difluoromethylthio, trifluoromethylthio, 2,2,2- Trifluoroethylthio and so on.
  • Alkylamino straight or branched chain alkyl, connected to the structure via a nitrogen atom bond, such as methylamino, ethylamino, n-propylamino, isopropylamino or isomeric butylamine.
  • Dialkylamino Two identical or different linear or branched alkyl groups are connected to the structure via a nitrogen atom bond, such as N,N-dimethylamino, N-methyl-N-ethylamino, etc.
  • Alkylcarbonyl The alkyl group is connected to the structure via the carbonyl group, such as acetyl (CH3CO-), n-propionyl (CH3CH2CO-) and so on.
  • Cycloalkylcarbonyl Cycloalkyl is attached to the structure via a carbonyl group, such as cyclopropylformyl.
  • Alkoxycarbonyl alkyl-O-CO-, such as methoxycarbonyl (CH 3 OCO-), ethoxycarbonyl (CH 3 CH 2 OCO-), n-propoxycarbonyl (CH 3 CH 2 CH 2 OCO-), n-butoxycarbonyl (CH 3 CH 2 CH 2 CH 2 OCO-), etc.
  • the compound of general formula I of the present invention can be prepared according to the following method (each group in the formula is defined as above unless otherwise specified):
  • Method 1 When R 1 is hydrogen or C 1 -C 6 alkyl, the compound of general formula I can be prepared by the following method (where Alkoxyl represents C 1 -C 6 alkoxy, such as methoxy, ethoxy Wait):
  • the compound of general formula II-1 and the compound of general formula III-1 are reacted in a suitable solvent at a temperature from -10°C to the boiling point of the solvent for 0.5-48 hours to obtain a compound of general formula I-1; the reaction can be carried out in the presence of a base .
  • suitable solvents can be the same or different, and can be alcohols (e.g., methanol, ethanol, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl Isobutyl ketone, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), esters (such as methyl acetate, ethyl acetate, etc.), ethers (such as tetrahydrofuran, dioxane, diethyl ether) , 1,2-dimethoxyethane, etc.), polar solvents (such as water, acetonitrile, dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dimethylene Sulfone, etc.) or a mixed solvent of the above solvents.
  • alcohols
  • the bases can be the same or different, and can be organic bases such as trimethylamine, triethylamine, pyridine, DBU, 4-dimethylaminopyridine (eg, trimethylamine, triethylamine, pyridine, DBU, 4-dimethylaminopyridine, etc.) , Alkali metal hydrides (such as sodium hydride, potassium hydride, etc.), alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (such as calcium hydroxide, etc.), alkali Metal carbonates (such as sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonates (such as sodium bicarbonate, etc.), metal alkoxides (such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, tertiary Sodium butoxide, etc.).
  • Alkali metal hydrides such as sodium hydride, potassium hydr
  • Method 2 When R 1 is C 1 -C 6 alkylthio or halogenated C 1 -C 6 alkylthio, the compound of general formula I can be prepared according to the following method (where A represents C 1 -C 6 alkyl Or halogenated C 1 -C 6 alkyl):
  • the method of preparing the compound of general formula I-4 from the compound of general formula I-3 is the same as the method of preparing the compound of general formula I-2 from the compound of general formula I-1.
  • suitable solvents can be the same or different, and can be alcohols (e.g., methanol, ethanol, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl Isobutyl ketone, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), esters (such as methyl acetate, ethyl acetate, etc.), ethers (such as tetrahydrofuran, dioxane, diethyl ether) , 1,2-dimethoxyethane, etc.), polar solvents (such as water, acetonitrile, dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dimethylene Sulfone, etc.) or a mixed solvent of the above solvents.
  • alcohols
  • the bases can be the same or different, and can be organic bases such as trimethylamine, triethylamine, pyridine, DBU, 4-dimethylaminopyridine (eg, trimethylamine, triethylamine, pyridine, DBU, 4-dimethylaminopyridine, etc.) , Alkali metal hydrides (such as sodium hydride, potassium hydride, etc.), alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (such as calcium hydroxide, etc.), alkali Metal carbonates (such as sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonates (such as sodium bicarbonate, etc.), metal alkoxides (such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, tertiary Sodium butoxide, etc.).
  • Alkali metal hydrides such as sodium hydride, potassium hydr
  • the nucleophile is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrosulfide, sodium amide, ammonia, C 1 -C 6 alkyl ammonia (such as methylamine, ethylamine, etc.) or its hydrochloric acid Salt (such as methylamine hydrochloride, ethylamine hydrochloride, etc.).
  • Suitable bases are preferably trimethylamine, triethylamine, pyridine, and carbonic acid. Potassium, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc.
  • suitable solvents can be the same or different, and can be alcohols (e.g., methanol, ethanol, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl Isobutyl ketone, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), esters (such as methyl acetate, ethyl acetate, etc.), ethers (such as tetrahydrofuran, dioxane, diethyl ether) , 1,2-dimethoxyethane, etc.), polar solvents (such as water, acetonitrile, dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dimethylene Sulfone, etc.) or a mixed solvent of the above solvents.
  • alcohols
  • the nucleophile is sodium cyanide, potassium cyanide, alkali metal salts of C 1 -C 6 alkanols (such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, etc.), halogenated C 1 -C 6 Alkali metal salt of alkanol (such as sodium 2,2,2-trifluoroethoxide or potassium 2,2,2-trifluoroethoxide, etc.), C 1 -C 6 dialkyl ammonia (such as N,N-dimethyl Ammonia, N-methyl-N-ethylamine, etc.) or its hydrochloride (such as N,N-dimethylammonium hydrochloride, N-methyl-N-ethylammonium hydrochloride, etc.).
  • C 1 -C 6 alkanols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, etc.
  • Suitable bases are preferably trimethylamine, triethylamine, pyridine, Potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc.
  • suitable solvents can be the same or different, and can be alcohols (e.g., methanol, ethanol, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl Isobutyl ketone, etc.), halogenated hydrocarbons (such as chloroform, dichloromethane, etc.), esters (such as methyl acetate, ethyl acetate, etc.), ethers (such as tetrahydrofuran, dioxane, diethyl ether) , 1,2-dimethoxyethane, etc.), polar solvents (such as water, acetonitrile, dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dimethylene Sulfone, etc.) or a mixed solvent of the above solvents.
  • alcohols
  • the method for preparing compounds of general formula I-8 from compounds of general formula I-7 is the same as the method for preparing compounds of general formula I-2 from compounds of general formula I-1.
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • the compound of general formula II-1 can be prepared by reacting compound of general formula III-2 with compound of general formula I-9.
  • the method for preparing the compound of the general formula I-9 from the compound of the general formula II-1 is the same as the method for preparing the compound of the general formula I-1 from the compound of the general formula II-1.
  • R 1 is not hydrogen or C 1 -C 6 alkyl (where K represents hydroxyl, mercapto, amino, cyano, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy Group, C 1 -C 6 alkylamino or C 1 -C 6 dialkylamino):
  • the compound of general formula II-2 can be reacted with compound of general formula III-2 to prepare compound of general formula I-10.
  • the method for preparing the compound of the general formula I-10 from the compound of the general formula II-2 is the same as the method for preparing the compound of the general formula I-3 from the compound of the general formula II-2.
  • the compound of general formula I-10 can be prepared by reacting the compound of general formula I-10 with a nucleophile.
  • the method for preparing the compound of the general formula I-11 from the compound of the general formula I-10 is the same as the method for preparing the compound of the general formula I-6 from the compound of the general formula I-4 or preparing the compound of the general formula I-8 from the compound of the general formula I-4.
  • the compound of general formula II-1 can be purchased or according to known methods (for example, US2503524, RSC Advances, 6(29), 24491-24500; 2016, Huaxue Shiji, 35(9), 849-850; 2013, WO2010019637, WO2014139326, WO2004009602 , WO2005117909, WO2010086118).
  • Compounds of general formula II-2 can be purchased or according to known methods (for example, Organic Process Research & Development, 15(3), 556-564; 2011, CN102001977, WO2018089786, Journal of Enzyme Inhibition and Medicinal Chemistry, 28(1), 163-171; The method described in 2013) was prepared.
  • the compound of general formula III-1, compound of general formula III-2 and other raw materials and reagents can be purchased or self-made according to conventional methods.
  • the compound represented by the general formula I of the present invention is used as a bactericide in the fields of agriculture, forestry or health. Furthermore, the compound is used to control plant bacterial diseases, and can be used to control a variety of plant bacterial diseases, such as fruit spot (such as melon fruit spot, etc.), leaf spot (such as tomato bacterial leaf spot) Diseases, etc.), bacterial wilt (such as tomato bacterial wilt, potato bacterial wilt, etc.), bacterial blight, canker disease (such as citrus canker, kiwi fruit canker, etc.), soft rot (such as soft rot of Chinese cabbage, etc.) ), bacterial angular leaf spot disease (such as cucumber bacterial angular leaf spot, etc.), bacterial leaf streak disease (such as rice bacterial leaf spot disease, etc.), leaf blight, bacterial leaf blight (such as rice bacterial leaf blight, etc.) ), wildfire and bacterial scab, etc.
  • plant bacterial diseases such as fruit spot
  • the compounds represented by the general formula I of the present invention can be prepared separately, which are further described in detail as follows:
  • the raw material 2-(bis(methylthio)methylene)malononitrile can be prepared according to known methods, for example, refer to the method reported in Organic Process Research & Development, 15(3), 556-564; 2011.
  • Example 11 Determination of the control effect on plant bacterial diseases
  • the compound of the present invention has been used for the prevention and control of various plant bacterial diseases.
  • the test procedure is as follows:
  • melon fruit spot disease For melon fruit spot disease, dissolve the test compound with a small amount of N,N dimethylformamide and dilute with water to the required concentration.
  • the pathogenic bacteria cultivated to the stable growth period are mixed with the quantitative compound solution uniformly, the melon seeds that have been germinated are soaked in the mixture of the bacterial solution and the compound for half an hour, and then the seeds are sown in the earthworm soil culture cup and placed in the greenhouse Medium moisturizing culture, usually cultured for two weeks, after the control is fully onset, the control effect investigation will be carried out.
  • the compound is sprayed on the surface of the plant test material, the surface drug solution is air-dried in a cool place, and the pathogenic bacteria liquid cultured to a stable growth stage is sprayed on the surface of the plant test material, and then the plant test material is placed in a greenhouse for moisturizing culture. It is usually cultivated for about ten days, and after the control has fully developed disease, the control effect investigation will be conducted.

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Abstract

本发明公开了一种结构新颖的丙二腈类化合物，结构如通式I所示，式中各取代基的定义见说明书。通式I化合物具有优异的杀细菌活性，对多种植物细菌性病害具有良好的防治效果，本发明包括通式I化合物在农业和其它领域中用作杀细菌剂的用途。

Description

一种丙二腈类化合物及其应用 技术领域
本发明属农用杀细菌剂领域。具体地涉及一种丙二腈类化合物及其应用。
背景技术
细菌性病害已成为我国农业生产中仅次于真菌性病害的第二大常发性病害，据不完全统计，我国细菌性病害目前发生面积在1.2亿亩次，细菌性病害防治市场容量超过20亿元。目前农业生产中，防治细菌性病害药剂主要包括用量较大的铜制剂(包括有机或无机铜制剂)和抗生素类产品；其中，铜制剂的防效较低并且大量的重金属喷施到环境中，对土壤、水体和食品形成污染，引发环境及食品的安全担忧；而另一方面，抗生素的大量使用，可能引起人体病原菌对医用抗生素产生抗药性。其它能用于农业细菌治疗的仅有少量品种，实际生产中受到抗性及防效的双重限制，推广面积较小。因此，研发新型、高效、低毒、环境友好型细菌性病害防治药剂是非常必要而迫切的。
现有技术中，如本发明所示的丙二腈类化合物及其杀细菌活性未见报道。
发明内容
本发明的目的是提供一种结构新颖的丙二腈类化合物及其在农业、林业或卫生领域中作为杀细菌剂的应用。
为实现上述目的，本发明的技术方案如下：
一种丙二腈类化合物，如通式I所示：
Figure PCTCN2020073095-appb-000001
式中：
X 1、X 2、X 3、X 4、X 5各自独立地选自氢、卤素、氰基、硝基、羟基、巯基、氨基、羧基、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷硫基、卤代C 1-C 6烷硫基、C 1-C 6烷基氨基、C 1-C 6二烷基氨基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、-NHCH＝C(CN) 2或-CH 2NHCH＝C(CN) 2；
R 1选自氢、羟基、巯基、氨基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷硫基、卤代C 1-C 6烷硫基、C 1-C 6烷基氨基或C 1-C 6二烷基氨基；
R 2选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、氰基C 1-C 6烷基、C 1-C 6烷基羰基、C 3-C 6环烷基羰基或C 1-C 6烷氧基羰基；
但，当R 1、R 2选自氢时，X 1、X 2、X 3、X 4、X 5不选自氢；或者，当R 1、R 2、X 1、X 2、X 4、X 5选自氢时，X 3不选自甲基、N,N-二甲基氨基、甲氧基、甲硫基或异丙基氧基；或者，当R 1、R 2、X 2、X 3、X 4、X 5选自氢时，X 1不选自氢；或者，当R 1、R 2、X 2、X 4、X 5选自氢时，X 1、X 3不选自氯；或者，当R 1、R 2选自氢，X 2选自甲氧基，X 3选自正丙氧基时，X 1、X 4、X 5不选自氢；或者，当R 1、R 2选自氢，X 2选自甲氧基，X 3选自正丁氧基时，X 1、X 4、X 5不选自氢；或者，当R 1、R 2选自氢，X 2选自甲氧基，X 3选自异戊氧基时，X 1、X 4、X 5不选自氢；或者，当R 1、R 2选自氢，X 1选自氯，X 3、X 4选自甲氧基时，X 2、X 5不选自氢；或者，当R 1选自甲硫基，R 2选自氢时，X 1、X 2、X 3、X 4、X 5不选自氢；或者，当R 1选自甲硫基，R 2、X 1、X 2、X 4、X 5选自氢时，X 3不选自氨基、甲氧基、氟或氯；或者，当R 1选自甲硫基，R 2、X 1、X 3、X 4、X 5选自氢时，X 2不选自甲基或甲氧基；或者，当R 1选自甲硫基，R 2选自氢，X 1、X 3选自氯时，X 2、X 4、X 5不选自氢；或者，当R 1选自甲硫基，R 2选自氢，X 2、X 3选自甲氧基时， X 1、X 4、X 5不选自氢；或者，当R 1选自甲硫基，R 2选自氢，X 2、X 4选自三氟甲基时，X 1、X 3、X 5不选自氢；或者，当R 1选自甲硫基，R 2选自甲基时，X 1、X 2、X 3、X 4、X 5不选自氢；或者，当X 1、X 2、X 3、X 4、X 5、R 2选自氢时，R 1不选自甲基、氨基、氰基或巯基；或者，当R 1选自氨基，R 2选自氢，X 3选自甲氧基时，X 1、X 2、X 4、X 5不选自氢；或者，当R 1选自氨基，R 2选自氢，X 1选自氯时，X 2、X 3、X 4、X 5不选自氢；或者，当R 1选自氨基，R 2选自乙基时，X 1、X 2、X 3、X 4、X 5不选自氢；或者，当R 1选自甲基，R 2选自氢，X 3选自氯时，X 1、X 2、X 4、X 5不选自氢；或者，当X 1、X 2、X 3、X 4、X 5、R 1选自氢时，R 2不选自氰乙基；
或通式I化合物的盐。
本发明中较优选的化合物为：通式I中，
X 1、X 2、X 3、X 4、X 5各自独立地选自氢、卤素、氰基、硝基、羟基、巯基、氨基、羧基、C 1-C 4烷基、卤代C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、C 1-C 4烷硫基、卤代C 1-C 4烷硫基、C 1-C 4烷基氨基、C 1-C 4二烷基氨基、C 1-C 4烷基羰基、C 1-C 4烷氧基羰基、-NHCH＝C(CN) 2或-CH 2NHCH＝C(CN) 2；
R 1选自氢、羟基、巯基、氨基、氰基、C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、C 1-C 4烷硫基、卤代C 1-C 4烷硫基、C 1-C 4烷基氨基或C 1-C 4二烷基氨基；
R 2选自氢、C 1-C 4烷基、卤代C 1-C 4烷基、氰基C 1-C 4烷基、C 1-C 4烷基羰基、C 3-C 6环烷基羰基或C 1-C 4烷氧基羰基；
或通式I化合物与盐酸、氢溴酸、硫酸、磷酸、甲酸、乙酸、丙酸、丁酸、戊酸、三氟乙酸、草酸、丙二酸、甲磺酸、4-甲苯磺酸、苹果酸、富马酸、乳酸、马来酸、水杨酸、酒石酸或柠檬酸形成的盐。
本发明中进一步优选的化合物为：通式I中，
X 1、X 2、X 3、X 4、X 5各自独立地选自氢、氟、氯、溴、氰基、硝基、羟基、巯基、氨基、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、一氯甲基、二氯甲基、三氯甲基、一溴甲基、二溴甲基、三溴甲基、一氟甲基、二氟甲基、三氟甲基、2,2,2-三氟乙基、七氟异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、二氟甲氧基、三氟甲氧基、甲硫基、乙硫基、三氟甲硫基、2,2,2-三氟乙硫基、甲氨基、乙氨基、N,N-二甲基氨基、-NHCH＝C(CN) 2或-CH 2NHCH＝C(CN) 2；
R 1选自氢、羟基、巯基、氨基、氰基、甲基、乙基、正丙基、正丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、甲硫基、乙硫基、正丙硫基、正丁硫基、甲氨基、乙氨基、正丙氨基或正丁氨基；
R 2选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、氰甲基、2,2,2-三氟乙基、乙酰基、正丙酰基、环丙基甲酰基、甲氧基羰基、乙氧基羰基、正丙氧基羰基或正丁氧基羰基；
或通式I化合物与盐酸、氢溴酸、硫酸、磷酸、甲酸、乙酸、丙酸、丁酸、戊酸、三氟乙酸、草酸、丙二酸、甲磺酸、4-甲苯磺酸、苹果酸、富马酸、乳酸、马来酸、水杨酸、酒石酸或柠檬酸形成的盐。
本发明中更进一步优选的化合物为：通式I中，
X 1、X 2、X 3、X 4、X 5各自独立地选自氢、氟、氯、溴、氰基、硝基、羟基、巯基、氨基、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟甲基、甲氧基、乙氧基、三氟甲氧基、甲硫基、甲氨基、N,N-二甲基氨基、-NHCH＝C(CN) 2或-CH 2NHCH＝C(CN) 2；
R 1选自氢、氨基、甲基、甲氧基、乙氧基、甲硫基、乙硫基、甲氨基或乙氨基；
R 2选自氢、甲基、乙基、2,2,2-三氟乙基、氰甲基、乙酰基、正丙酰基、环丙基甲酰基、甲氧基羰基或乙氧基羰基；
或通式I化合物与盐酸、氢溴酸、硫酸、磷酸、甲酸、乙酸、丙酸、丁酸、戊酸、三氟乙酸、草酸、丙二酸、甲磺酸、4-甲苯磺酸、苹果酸、富马酸、乳酸、马来酸、水杨酸、酒石酸或柠檬酸形成的盐。
上面给出的通式化合物的定义中，汇集所用术语一般代表如下取代基：
卤素：指氟、氯、溴或碘。
烷基：直链或支链烷基，例如甲基、乙基、正丙基、异丙基或不同的丁基、戊基或己基异构体等。
卤代烷基：直链或支链烷基，在这些烷基上的氢原子可部分或全部被卤素所取代，例如一氯甲基、二氯甲基、三氯甲基、一溴甲基、二溴甲基、三溴甲基、一氟甲基、二氟甲基、三氟甲基、2,2,2-三氟乙基、七氟异丙基等。
氰基烷基：直链或支链烷基，在这些烷基上的氢原子可部分或全部被氰基所取代，例如氰甲基(CNCH 2-)、氰乙基(CNCH 2CH 2-)、CNCH 2CH 2CH 2-、CNCH 2CH 2CH 2CH 2-等。
烷氧基：直链或支链烷基，经氧原子键连接到结构上，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基等。
卤代烷氧基：直链或支链烷氧基，在这些烷氧基上的氢原子可部分或全部被卤素所取代，例如氯甲氧基、二氯甲氧基、三氯甲氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、氯氟甲氧基、2,2,2-三氟乙氧基等。
烷硫基：直链或支链烷基，经硫原子键连接到结构上，例如甲硫基、乙硫基等。
卤代烷硫基：直链或支链烷硫基，在这些烷硫基上的氢原子可部分或全部被卤素所取代，例如二氟甲硫基、三氟甲硫基、2,2,2-三氟乙硫基等。
烷基氨基：直链或支链烷基，经氮原子键连接到结构上，例如甲氨基、乙氨基、正丙基氨基、异丙基氨基或同分异构的丁基胺。
二烷基氨基：两个相同或不同的直链或支链烷基，经氮原子键连接到结构上，例如N,N-二甲基氨基、N-甲基-N-乙基氨基等。
烷基羰基：烷基经羰基连接到结构上，例如乙酰基(CH3CO-)，正丙酰基(CH3CH2CO-)等。
环烷基羰基：环烷基经羰基连接到结构上，例如环丙基甲酰基。
烷氧基羰基：烷基-O-CO-，例如甲氧基羰基(CH 3OCO-)、乙氧基羰基(CH 3CH 2OCO-)、正丙氧基羰基(CH 3CH 2CH 2OCO-)、正丁氧基羰基(CH 3CH 2CH 2CH 2OCO-)等。
本发明部分通式I化合物如表1所示，但本发明绝非仅限于这些化合物。
Figure PCTCN2020073095-appb-000002
表1
编号 X 1 X 2 X 3 X 4 X 5 R 1 R 2
1 F H H H H H H
2 Br H H H H H H
3 H F H H H H H
4 H Cl H H H H H
5 H Br H H H H H
6 H H F H H H H
7 H H Cl H H H H
8 H H Br H H H H
9 CH 3 H H H H H H
10 H CH 3 H H H H H
11 H H C(CH 3) 3 H H H H
12 H CF 3 H H H H H
13 H H CF 3 H H H H
14 H H -CH 2NHCH＝C(CN) 2 H H H H
15 H Cl Cl H H H H
16 H CF 3 H CF 3 H H H
17 CH 3 H H H H CH 3 H
18 H H C(CH 3) 3 H H CH 3 H
19 H Cl Cl H H CH 3 H
20 CH 3 H H H H SCH 3 H
21 H H C(CH 3) 3 H H SCH 3 H
22 H Cl Cl H H SCH 3 H
23 CH 3 H H H H NH 2 H
24 H H C(CH 3) 3 H H NH 2 H
25 CH 3 H H H H NHCH 3 H
26 H H C(CH 3) 3 H H NHCH 3 H
27 H H H H H NHCH 3 H
28 CH 3 H H H H OCH 3 H
29 H H C(CH 3) 3 H H OCH 3 H
30 H H H H H OCH 3 H
31 H Cl Cl H H H CH 3
32 H Cl Cl H H H CH 2CN
33 H Cl Cl H H H 环丙基甲酰基
34 H Cl Cl H H H 乙氧基羰基
表1所列举的具体化合物的物化性质及其核磁数据、质谱数据如表2所示：
表2
Figure PCTCN2020073095-appb-000003
Figure PCTCN2020073095-appb-000004
Figure PCTCN2020073095-appb-000005
本发明的通式I化合物可按照以下方法制备(式中各基团除另有说明外定义同前)：
方法1：当R 1为氢或C 1-C 6烷基时，通式I化合物可按以下方法进行制备(式中Alkoxyl表示C 1-C 6烷氧基，如甲氧基、乙氧基等)：
Figure PCTCN2020073095-appb-000006
通式II-1化合物与通式III-1化合物在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应0.5-48小时可制得通式I-1化合物；反应可在碱存在进行。
通式I-1化合物与烷基化试剂(如碘甲烷、碘乙烷、碘丙烷、硫酸二甲酯、硫酸二乙酯、2,2,2-三氟碘乙烷、氯乙腈、溴乙腈等)或酰基化试剂(如乙酰氯、正丙酰氯、 乙酸酐、环丙基甲酰氯、氯甲酸甲酯、氯甲酸乙酯等)在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应0.5-48小时可制得通式I-2化合物；反应可在碱存在进行。
上述反应中，适宜的溶剂可相同或不同，可为醇类(如，甲醇、乙醇等)、芳烃类(如，苯、甲苯、二甲苯等)、酮类(如，丙酮、甲乙酮、甲基异丁基酮等)、卤代烃类(如，氯仿、二氯甲烷等)、酯类(如，乙酸甲酯、乙酸乙酯等)、醚类(如，四氢呋喃、二噁烷、二乙醚、1,2-二甲氧基乙烷等)、极性溶剂类(如，水、乙腈、二氧六环、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜等)或上述溶剂的混合溶剂。碱可相同或不同，可为三甲胺、三乙胺、吡啶、DBU、4-二甲氨基吡啶等有机碱(如，三甲胺、三乙胺、吡啶、DBU、4-二甲氨基吡啶等)、碱金属氢化物(如，氢化钠、氢化钾等)、碱金属氢氧化物(如，氢氧化钠、氢氧化钾等)、碱土类金属氢氧化物(如，氢氧化钙等)、碱金属碳酸盐(如，碳酸钠、碳酸钾等)、碱金属碳酸氢盐(如，碳酸氢钠等)、金属醇盐(如，甲醇钠、乙醇钠、乙醇钾、叔丁醇钾、叔丁醇钠等)。
方法2：当R 1为C 1-C 6烷硫基或卤代C 1-C 6烷硫基时，通式I化合物可按以下方法进行制备(式中A表示C 1-C 6烷基或卤代C 1-C 6烷基)：
Figure PCTCN2020073095-appb-000007
通式II-2化合物与通式III-1化合物在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应0.5-48小时可制得通式I-3化合物；在该反应中，通式II-2化合物:通式III-1化合物≥1:1(摩尔比)；反应可在碱存在进行。
由通式I-3化合物制备通式I-4化合物的方法与由通式I-1化合物制备通式I-2化合物的方法相同。
上述反应中，适宜的溶剂可相同或不同，可为醇类(如，甲醇、乙醇等)、芳烃类(如，苯、甲苯、二甲苯等)、酮类(如，丙酮、甲乙酮、甲基异丁基酮等)、卤代烃类(如，氯仿、二氯甲烷等)、酯类(如，乙酸甲酯、乙酸乙酯等)、醚类(如，四氢呋喃、二噁烷、二乙醚、1,2-二甲氧基乙烷等)、极性溶剂类(如，水、乙腈、二氧六环、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜等)或上述溶剂的混合溶剂。碱可相同或不同，可为三甲胺、三乙胺、吡啶、DBU、4-二甲氨基吡啶等有机碱(如，三甲胺、三乙胺、吡啶、DBU、4-二甲氨基吡啶等)、碱金属氢化物(如，氢化钠、氢化钾等)、碱金属氢氧化物(如，氢氧化钠、氢氧化钾等)、碱土类金属氢氧化物(如，氢氧化钙等)、碱金属碳酸盐(如，碳酸钠、碳酸钾等)、碱金属碳酸氢盐(如，碳酸氢钠等)、金属醇盐(如，甲醇钠、乙醇钠、乙醇钾、叔丁醇钾、叔丁醇钠等)。
方法3：当R 1为羟基、巯基、氨基或C 1-C 6烷基氨基时，通式I化合物可按以下方法进行制备：
Figure PCTCN2020073095-appb-000008
通式I-3化合物与亲核试剂在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应 0.5-48小时可制得通式I-5化合物；通式I-4化合物与亲核试剂在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应0.5-48小时可制得通式I-6化合物。
上述反应中，亲核试剂为氢氧化钠、氢氧化钾、氢氧化锂、硫氢化钠、氨基钠、氨水、C 1-C 6烷基氨(如甲胺、乙胺等)或其盐酸盐(如甲胺盐酸盐、乙胺盐酸盐等)。
上述反应中，当亲核试剂为C 1-C 6烷基氨盐酸盐时，反应需要适宜的碱参与，以中和盐酸盐，适宜的碱优选三甲胺、三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠等。
上述反应中，适宜的溶剂可相同或不同，可为醇类(如，甲醇、乙醇等)、芳烃类(如，苯、甲苯、二甲苯等)、酮类(如，丙酮、甲乙酮、甲基异丁基酮等)、卤代烃类(如，氯仿、二氯甲烷等)、酯类(如，乙酸甲酯、乙酸乙酯等)、醚类(如，四氢呋喃、二噁烷、二乙醚、1,2-二甲氧基乙烷等)、极性溶剂类(如，水、乙腈、二氧六环、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜等)或上述溶剂的混合溶剂。
方法4：当R 1为氰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基或C 1-C 6二烷基氨基时，通式I化合物可按以下方法进行制备：
Figure PCTCN2020073095-appb-000009
通式I-3化合物与亲核试剂在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应0.5-48小时可制得通式I-7化合物；通式I-4化合物与亲核试剂在适宜的溶剂中，在温度从-10℃到溶剂沸点下反应0.5-48小时可制得通式I-8化合物。
上述反应中，亲核试剂为氰化钠、氰化钾、C 1-C 6烷醇的碱金属盐(如甲醇钠、甲醇钾、乙醇钠、乙醇钾等)、卤代C 1-C 6烷醇的碱金属盐(如2,2,2-三氟乙醇钠或2,2,2-三氟乙醇钾等)、C 1-C 6二烷基氨(如N,N-二甲基氨、N-甲基-N-乙基氨等)或其盐酸盐(如N,N-二甲基氨盐酸盐、N-甲基-N-乙基氨盐酸盐等)。
上述反应中，当亲核试剂为C 1-C 6二烷基氨盐酸盐时，反应需要适宜的碱参与，以中和盐酸盐，适宜的碱优选三甲胺、三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠等。
上述反应中，适宜的溶剂可相同或不同，可为醇类(如，甲醇、乙醇等)、芳烃类(如，苯、甲苯、二甲苯等)、酮类(如，丙酮、甲乙酮、甲基异丁基酮等)、卤代烃类(如，氯仿、二氯甲烷等)、酯类(如，乙酸甲酯、乙酸乙酯等)、醚类(如，四氢呋喃、二噁烷、二乙醚、1,2-二甲氧基乙烷等)、极性溶剂类(如，水、乙腈、二氧六环、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜等)或上述溶剂的混合溶剂。
由通式I-7化合物制备通式I-8化合物的方法与由通式I-1化合物制备通式I-2化合物的方法相同。
方法5：当R 2为C 1-C 6烷基、卤代C 1-C 6烷基或氰基C 1-C 6烷基时，通式I化合物可按以下方法进行制备：
(1)当R 1为氢或C 1-C 6烷基时：
Figure PCTCN2020073095-appb-000010
通式II-1化合物与通式III-2化合物反应可制得通式I-9化合物。
由通式II-1化合物制备通式I-9化合物的方法与由通式II-1化合物制备通式I-1化合物的方法相同。
(2)当R 1不为氢或C 1-C 6烷基时(式中K表示羟基、巯基、氨基、氰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷基氨基或C 1-C 6二烷基氨基)：
Figure PCTCN2020073095-appb-000011
通式II-2化合物与通式III-2化合物反应可制得通式I-10化合物。
由通式II-2化合物制备通式I-10化合物的方法与由通式II-2化合物制备通式I-3化合物的方法相同。
通式I-10化合物与亲核试剂反应可制得通式I-11化合物。
由通式I-10化合物制备通式I-11化合物与由通式I-4化合物制备通式I-6化合物或由通式I-4化合物制备通式I-8化合物的方法相同。
通式II-1化合物可以通过购买或按公知方法(例如US2503524、RSC Advances,6(29),24491-24500；2016、Huaxue Shiji,35(9),849-850；2013、WO2010019637、WO2014139326、WO2004009602、WO2005117909、WO2010086118中所描述的方法)制备。
通式II-2化合物可以通过购买或按公知方法(例如Organic Process Research&Development,15(3),556-564；2011、CN102001977、WO2018089786、Journal ofEnzyme Inhibition and Medicinal Chemistry,28(1),163-171；2013中所描述的方法)制备。
通式III-1化合物、通式III-2化合物及其它原料和试剂可以通过购买或者按照常规方法自制。
本发明通式I所示的化合物在农业、林业或卫生领域中作为杀细菌剂的用途。进一步的说，化合物在用于控制植物细菌性病害的用途，可用于防治多种植物细菌性病害，例如果斑病(如甜瓜果斑病等)、叶斑病(如番茄细菌性叶斑病等)、青枯病(如番茄青枯病、马铃薯青枯病等)、细菌性疫病、溃疡病(如柑橘溃疡病、猕猴桃溃疡病等)、软腐病(如大白菜软腐病等)、细菌性角斑病(如黄瓜细菌性角斑病等)、细菌性条斑病(如水稻细菌性条斑病等)、叶枯病、白叶枯病(如水稻白叶枯病等)、野火病和细菌性疮痂病等。
具体实施方式
以下具体实施例用来进一步说明本发明，但本发明绝非限于这些例子。(除另有注明外，所用原料均有市售)
合成实施例
按照上述记载的合成路线，采用不同的原料化合物，即可分别制备获得本发明通式I所示化合物，进一步具体描述如下：
实施例1：化合物15的制备
Figure PCTCN2020073095-appb-000012
50毫升反应瓶中加入3,4-二氯苄胺(0.30克，1.71毫摩尔)、乙氧基亚甲基丙二腈(0.22克，1.80毫摩尔)和20毫升乙醇，室温搅拌反应，TLC监测反应完毕后，减压蒸除大部分乙醇，冷却、过滤、得到白色固体0.42克。
实施例2：化合物19的制备
Figure PCTCN2020073095-appb-000013
100毫升反应瓶中加入3,4-二氯苄胺(1.00克，5.71毫摩尔)、2-(1-乙氧基亚乙基)丙二腈(0.78克，5.73毫摩尔)和50毫升乙醇，80℃回流反应，TLC监测反应完毕后，减压蒸除大部分乙醇，冷却、过滤、得到白色固体1.36克。
实施例3：化合物20的制备
Figure PCTCN2020073095-appb-000014
50毫升反应瓶中加入2-甲基苄胺(0.50克，4.13毫摩尔)、2-(双(甲硫基)亚甲基)丙二腈(0.71克，4.18毫摩尔)和25毫升甲醇，65℃回流反应，TLC监测反应完毕后，减压蒸除大部分甲醇，冷却、过滤、得到白色固体0.90克。
原料2-(双(甲硫基)亚甲基)丙二腈可按公知方法进行制备，例如参照Organic Process Research&Development,15(3),556-564；2011所报道的方法。
实施例4：化合物23的制备
Figure PCTCN2020073095-appb-000015
称取化合物20(0.50克，2.06毫摩尔)、氨水(0.72克，20.55毫摩尔)和100毫升乙醇，置于250毫升反应瓶中，80℃回流反应，TLC监测反应完毕后，减压脱溶、柱层析后得到白色固体0.40克。
实施例5：化合物25的制备
Figure PCTCN2020073095-appb-000016
称取化合物20(0.50克，2.06毫摩尔)、甲胺盐酸盐(0.69克，10.22毫摩尔)、 三乙胺5毫升和40毫升乙醇，置于100毫升反应瓶中，80℃回流反应，TLC监测反应完毕后，减压脱溶、柱层析后得到白色固体0.47克。
实施例6：化合物28的制备
Figure PCTCN2020073095-appb-000017
称取化合物20(0.50克，2.06毫摩尔)、甲醇钠(0.56克，10.37毫摩尔)、三乙胺5毫升和25毫升乙醇，置于50毫升反应瓶中，80℃回流反应，TLC监测反应完毕后，减压脱溶、柱层析后得到白色固体0.47克。
实施例7：化合物31的制备
Figure PCTCN2020073095-appb-000018
50毫升反应瓶中加入N-甲基苄胺(1.00克，8.26毫摩尔)、乙氧基亚甲基丙二腈(1.01克，8.28毫摩尔)和30毫升乙醇，80℃回流反应，TLC监测反应完毕后，减压蒸除大部分乙醇，冷却、过滤、得到白色固体1.75克。
实施例8：化合物32的制备
Figure PCTCN2020073095-appb-000019
称取化合物15(0.29克，1.16毫摩尔)、溴乙腈(0.14克，1.18毫摩尔)、氢化钠(0.04克，1.00毫摩尔)和25毫升四氢呋喃，置于50毫升单口瓶中，常温搅拌反应，TLC监测反应完毕后，减压脱溶、柱层析后得到白色固体0.13克。
实施例9：化合物33的制备
Figure PCTCN2020073095-appb-000020
称取化合物15(0.38克，1.51毫摩尔)、环丙基甲酰氯(0.16克，1.54毫摩尔)和30毫升甲苯，置于50毫升单口瓶中，110℃回流反应，TLC监测反应完毕后，减压脱溶、柱层析后得到黄色固体0.17克。
实施例10：化合物34的制备
Figure PCTCN2020073095-appb-000021
称取化合物15(0.45克，1.79毫摩尔)、氯甲酸乙酯(0.20克，1.89毫摩尔)、氢化钠(0.068克，1.70毫摩尔)和25毫升四氢呋喃，置于50毫升单口瓶中，常温搅拌反应，TLC监测反应完毕后，减压脱溶、柱层析后得到黄色固体0.18克。
生物活性测定
实施例11：对植物细菌病害防治效果的测定
用本发明的化合物对多种植物细菌性病害进行了防效测定，针对不同的细菌性病害，试验程序如下：
甜瓜果斑病，将待测化合物用少量N,N二甲基甲酰胺溶解，用水稀释至所需要的浓度。将培养至稳定生长期的病原细菌与定量化合物溶液混合均匀，将经过催芽的甜瓜种子放入菌液与化合物的混合液中浸泡半小时，再将种子播种于蚯蚓土培养杯中，放入温室中保湿培养，一般培养两周时间，待对照充分发病后进行防效调查。
大白菜软腐病，切取2厘米见方的白菜叶片，放入垫有双层滤纸的玻璃培养皿中。将用N，N二甲基甲酰胺溶解，并用水稀释至所需浓度的化合物喷雾于白菜叶片表面，于通风橱内晾干白菜叶片表面药液后，使用接种针在白菜叶片表面针刺造成伤口，将培养至稳定生长期的大白菜软腐病菌取5微升加入伤口内，进行接种。最后将试材放入培养箱中避光培养48小时，待对照充分发病后进行防效调查。
黄瓜细菌性角斑病、番茄细菌性叶斑病、水稻细菌性条斑病、水稻白叶枯病，将待测化合物用少量N，N二甲基甲酰胺溶解，用水稀释至所需要的浓度。将化合物其喷雾于植物试材表面，于阴凉处风干表面药液后，将培养至稳定生长期的病原细菌菌液喷雾接种于植物试材表面，然后将植物试材放入温室中保湿培养。通常培养十天左右，待对照充分发病后，进行防效调查。
测试结果如下：
600mg/L时，化合物1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34对甜瓜果斑病的防效为100％。
400mg/L时，化合物1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34对黄瓜细菌性角斑病、水稻细菌性条斑病、水稻白叶枯病的防效为100％。
400mg/L时，化合物1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34对大白菜软腐病和番茄细菌性叶斑病的防效为100％。

Claims (6)

  1. 一种丙二腈类化合物，其特征在于，化合物如通式I所示：
    Figure PCTCN2020073095-appb-100001
    式中：
    X 1、X 2、X 3、X 4、X 5各自独立地选自氢、卤素、氰基、硝基、羟基、巯基、氨基、羧基、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷硫基、卤代C 1-C 6烷硫基、C 1-C 6烷基氨基、C 1-C 6二烷基氨基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、-NHCH＝C(CN) 2或-CH 2NHCH＝C(CN) 2；
    R 1选自氢、羟基、巯基、氨基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷硫基、卤代C 1-C 6烷硫基、C 1-C 6烷基氨基或C 1-C 6二烷基氨基；
    R 2选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、氰基C 1-C 6烷基、C 1-C 6烷基羰基、C 3-C 6环烷基羰基或C 1-C 6烷氧基羰基；
    但，当R 1、R 2选自氢时，X 1、X 2、X 3、X 4、X 5不选自氢；或者，当R 1、R 2、X 1、X 2、X 4、X 5选自氢时，X 3不选自甲基、N,N-二甲基氨基、甲氧基、甲硫基或异丙基氧基；或者，当R 1、R 2、X 2、X 3、X 4、X 5选自氢时，X 1不选自氢；或者，当R 1、R 2、X 2、X 4、X 5选自氢时，X 1、X 3不选自氯；或者，当R 1、R 2选自氢，X 2选自甲氧基，X 3选自正丙氧基时，X 1、X 4、X 5不选自氢；或者，当R 1、R 2选自氢，X 2选自甲氧基，X 3选自正丁氧基时，X 1、X 4、X 5不选自氢；或者，当R 1、R 2选自氢，X 2选自甲氧基，X 3选自异戊氧基时，X 1、X 4、X 5不选自氢；或者，当R 1、R 2选自氢，X 1选自氯，X 3、X 4选自甲氧基时，X 2、X 5不选自氢；或者，当R 1选自甲硫基，R 2选自氢时，X 1、X 2、X 3、X 4、X 5不选自氢；或者，当R 1选自甲硫基，R 2、X 1、X 2、X 4、X 5选自氢时，X 3不选自氨基、甲氧基、氟或氯；或者，当R 1选自甲硫基，R 2、X 1、X 3、X 4、X 5选自氢时，X 2不选自甲基或甲氧基；或者，当R 1选自甲硫基，R 2选自氢，X 1、X 3选自氯时，X 2、X 4、X 5不选自氢；或者，当R 1选自甲硫基，R 2选自氢，X 2、X 3选自甲氧基时，X 1、X 4、X 5不选自氢；或者，当R 1选自甲硫基，R 2选自氢，X 2、X 4选自三氟甲基时，X 1、X 3、X 5不选自氢；或者，当R 1选自甲硫基，R 2选自甲基时，X 1、X 2、X 3、X 4、X 5不选自氢；或者，当X 1、X 2、X 3、X 4、X 5、R 2选自氢时，R 1不选自甲基、氨基、氰基或巯基；或者，当R 1选自氨基，R 2选自氢，X 3选自甲氧基时，X 1、X 2、X 4、X 5不选自氢；或者，当R 1选自氨基，R 2选自氢，X 1选自氯时，X 2、X 3、X 4、X 5不选自氢；或者，当R 1选自氨基，R 2选自乙基时，X 1、X 2、X 3、X 4、X 5不选自氢；或者，当R 1选自甲基，R 2选自氢，X 3选自氯时，X 1、X 2、X 4、X 5不选自氢；或者，当X 1、X 2、X 3、X 4、X 5、R 1选自氢时，R 2不选自氰乙基；
    或通式I化合物的盐。
  2. 根据权利要求1所述的化合物，其特征在于，通式I中，
    X 1、X 2、X 3、X 4、X 5各自独立地选自氢、卤素、氰基、硝基、羟基、巯基、氨基、羧基、C 1-C 4烷基、卤代C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、C 1-C 4烷硫基、卤代C 1-C 4烷硫基、C 1-C 4烷基氨基、C 1-C 4二烷基氨基、C 1-C 4烷基羰基、C 1-C 4烷氧基羰基、-NHCH＝C(CN) 2或-CH 2NHCH＝C(CN) 2；
    R 1选自氢、羟基、巯基、氨基、氰基、C 1-C 4烷基、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、C 1-C 4烷硫基、卤代C 1-C 4烷硫基、C 1-C 4烷基氨基或C 1-C 4二烷基氨基；
    R 2选自氢、C 1-C 4烷基、卤代C 1-C 4烷基、氰基C 1-C 4烷基、C 1-C 4烷基羰基、C 3-C 6环烷基羰基或C 1-C 4烷氧基羰基；
    或通式I化合物与盐酸、氢溴酸、硫酸、磷酸、甲酸、乙酸、丙酸、丁酸、戊酸、三氟乙酸、草酸、丙二酸、甲磺酸、4-甲苯磺酸、苹果酸、富马酸、乳酸、马来酸、水杨酸、酒石酸或柠檬酸形成的盐。
  3. 根据权利要求2所述的化合物，其特征在于，通式I中，
    X 1、X 2、X 3、X 4、X 5各自独立地选自氢、氟、氯、溴、氰基、硝基、羟基、巯基、氨基、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、一氯甲基、二氯甲基、三氯甲基、一溴甲基、二溴甲基、三溴甲基、一氟甲基、二氟甲基、三氟甲基、2,2,2-三氟乙基、七氟异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、二氟甲氧基、三氟甲氧基、甲硫基、乙硫基、三氟甲硫基、2,2,2-三氟乙硫基、甲氨基、乙氨基、N,N-二甲基氨基、-NHCH＝C(CN) 2或-CH 2NHCH＝C(CN) 2；
    R 1选自氢、羟基、巯基、氨基、氰基、甲基、乙基、正丙基、正丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、甲硫基、乙硫基、正丙硫基、正丁硫基、甲氨基、乙氨基、正丙氨基或正丁氨基；
    R 2选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、氰甲基、2,2,2-三氟乙基、乙酰基、正丙酰基、环丙基甲酰基、甲氧基羰基、乙氧基羰基、正丙氧基羰基或正丁氧基羰基；
    或通式I化合物与盐酸、氢溴酸、硫酸、磷酸、甲酸、乙酸、丙酸、丁酸、戊酸、三氟乙酸、草酸、丙二酸、甲磺酸、4-甲苯磺酸、苹果酸、富马酸、乳酸、马来酸、水杨酸、酒石酸或柠檬酸形成的盐。
  4. 根据权利要求3所述的化合物，其特征在于，通式I中，
    X 1、X 2、X 3、X 4、X 5各自独立地选自氢、氟、氯、溴、氰基、硝基、羟基、巯基、氨基、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、三氟 甲基、甲氧基、乙氧基、三氟甲氧基、甲硫基、甲氨基、N,N-二甲基氨基、-NHCH＝C(CN) 2或-CH 2NHCH＝C(CN) 2；
    R 1选自氢、氨基、甲基、甲氧基、乙氧基、甲硫基、乙硫基、甲氨基或乙氨基；
    R 2选自氢、甲基、乙基、2,2,2-三氟乙基、氰甲基、乙酰基、正丙酰基、环丙基甲酰基、甲氧基羰基或乙氧基羰基；
    或通式I化合物与盐酸、氢溴酸、硫酸、磷酸、甲酸、乙酸、丙酸、丁酸、戊酸、三氟乙酸、草酸、丙二酸、甲磺酸、4-甲苯磺酸、苹果酸、富马酸、乳酸、马来酸、水杨酸、酒石酸或柠檬酸形成的盐。
  5. 一种按照权利要求1所述的通式I化合物在农业、林业或卫生领域中作为杀细菌剂的用途。
  6. 按照权利要求5所述的通式I化合物在作为用于控制植物细菌性病害中的用途。
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