WO2022127564A1 - Isoxazoline-containing pyridine biphenyl compounds, preparation method therefor and use thereof - Google Patents

Isoxazoline-containing pyridine biphenyl compounds, preparation method therefor and use thereof Download PDF

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WO2022127564A1
WO2022127564A1 PCT/CN2021/133602 CN2021133602W WO2022127564A1 WO 2022127564 A1 WO2022127564 A1 WO 2022127564A1 CN 2021133602 W CN2021133602 W CN 2021133602W WO 2022127564 A1 WO2022127564 A1 WO 2022127564A1
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alkyl
hydrogen
formula
independently selected
different
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Chinese (zh)
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唐剑峰
迟会伟
赵宝修
吴建挺
袁雪
赵士胜
刘立龙
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山东省联合农药工业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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
    • 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
    • A01N43/80—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 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P13/00—Herbicides; Algicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of agricultural herbicides, in particular to a pyridine biphenyl compound of isoxazoline and a preparation method and application thereof.
  • Harmful weeds in farmland are the enemy in agricultural production. According to statistics, crops all over the world lose an average of 12% of their output due to weed damage every year. Therefore, weed control is an important link to achieve efficient agriculture. Although there are various types of herbicides on the market, due to the continuous expansion of the market, the increasing resistance of weeds in recent years, and the increasing emphasis on environmental protection, people still need to continuously develop new high-efficiency and safe new varieties of herbicides .
  • Patent document WO2014048827 discloses an isoxazoline-containing compound CK 1 (compound number 1.1.1) as shown below:
  • the present invention provides compounds represented by general formula (I), stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or esters thereof , a solvate or a solvate of a pharmaceutically acceptable salt,
  • R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
  • R 9 and R 10 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
  • R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, COOR 13 or CONR 14 R 15 ;
  • R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, unsubstituted or 1-4 Ra substituted C 6 -C 10 aryl C 1 -C 6 alkyl, 5-10 membered heteroaryl C 1 -C 6 alkyl, 3-10 Membered heterocyclyl C 1 -C 6 alkyl; each Ra is the same or different and independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
  • R 14 and R 15 are the same or different and are independently selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 6 alkyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogenated C 1 -C 4 alkoxy;
  • R 9 and R 10 are the same or different and are independently selected from hydrogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
  • R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, COOR 13 or CONR 14 R 15 ;
  • R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 6 -C 8 aryl C 1 -C 4 alkyl, unsubstituted or substituted by 1-4 Ra, C 1 -C 4 alkyl, 5-8 membered heteroaryl C 1 -C 4 alkyl, 3-6 Membered heterocyclyl C 1 -C 4 alkyl; each Ra is the same or different and independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogenated C 1 -C 4 alkoxy;
  • R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy C 1 -C 6 alkyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy group, trifluoromethoxy or trifluoroethoxy;
  • R 9 and R 10 are the same or different and are independently selected from hydrogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
  • R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, COOR 13 or CONR 14 R 15 ;
  • R 13 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, unsubstituted or benzyl, furylmethyl or tetrahydrofurylmethyl substituted with 1-4 Ra; each Ra is the same or different, independently selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
  • R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy group, trifluoromethoxy or trifluoroethoxy;
  • R 9 and R 10 are the same or different and are independently selected from hydrogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
  • R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, COOR 13 or CONR 14 R 15 ;
  • R 13 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, benzyl, unsubstituted or substituted with 1-4 Ras, furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl; each Ra is the same or different, independently of each other selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
  • R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
  • R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl or trifluoroethyl;
  • R 11 , R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, COOR 13 or CONR 14 R 15 ;
  • R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, unsubstituted or benzyl, furylmethyl or tetrahydrofurylmethyl substituted with 1-4 Ra; each Ra is the same or different and independently selected from the group consisting of fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
  • R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
  • R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl or trifluoroethyl;
  • R 11 , R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, COOR 13 or CONR 14 R 15 ;
  • R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, unsubstituted or benzyl, furylmethyl, tetrahydrofuranylmethyl or 1,3-dioxolaneethyl substituted with 1-4 Ras; each Ra is the same or different and independently selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
  • R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different, and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
  • R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl or butyl;
  • R 11 and R 12 are the same or different, and are independently selected from hydrogen, methyl, ethyl or COOR 13 ;
  • R 13 is selected from hydrogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, benzyl , furylmethyl or tetrahydrofurylmethyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different, and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
  • R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl or butyl;
  • R 11 and R 12 are the same or different, and are independently selected from hydrogen, methyl, ethyl or COOR 13 ;
  • R 13 is selected from hydrogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, benzyl , furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine or trifluoromethyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
  • R 9 and R 10 are the same or different, and are independently selected from hydrogen or methyl;
  • R 11 and R 12 are the same or different, and are independently selected from methyl, ethyl or COOR 13 ;
  • R 13 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, allyl, propargyl, methoxy ethyl, ethoxyethyl, benzyl, furylmethyl or tetrahydrofurylmethyl.
  • R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine or trifluoromethyl;
  • R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
  • R 9 and R 10 are the same or different, and are independently selected from hydrogen or methyl;
  • R 11 and R 12 are the same or different, and are independently selected from methyl, ethyl or COOR 13 ;
  • R 13 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, allyl, propargyl, methoxy ethyl, ethoxyethyl, benzyl, furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl.
  • the compound represented by formula (I) has the following structure:
  • the present invention also provides the preparation method of the compound shown in the above formula (I), comprising the following steps:
  • the compound represented by the formula (II) is subjected to a cycloaddition reaction with the compound of the formula (III) to obtain the compound of the formula (I);
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are as defined above.
  • L is selected from leaving groups such as Cl or Br.
  • the reaction may be carried out in the presence of a base, which may be an organic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropyl At least one of ethylamine (DIEA);
  • a base which may be an organic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropyl At least one of ethylamine (DIEA);
  • the reaction is carried out in a solvent selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dioxane or toluene at least one;
  • the reaction temperature may be -5-120°C, such as 0-50°C, such as 15-50°C.
  • the cycloaddition reaction can be carried out in a one-pot reaction to prepare the dipole precursor II or in the presence of the isolated dipole precursor II.
  • reaction can be referred to literature such as 1,3 dipolar Cycloaddition Chemistry, Padwa (ed.), Wiley, New York, 1984; Heterocycles. 1990, 30, 719; J. Agric. Food. Chem.
  • Optically active isoxazolines can be obtained by chiral HPLC of suitable precursors or final products, and can also be obtained by enantioselective reactions, such as by enzymatic ester or amide cleavage reactions or by obtained using chiral auxiliaries, as described by J. Org. Chem. 1988, 53, 2468.
  • formula (I) in which R 12 is COOH can be prepared by a hydrolysis reaction known to those skilled in the art compounds shown.
  • R 12 COOR 13 , and R 13 is not H
  • the hydrolysis reaction can be carried out in the presence of a base selected from at least one of sodium hydroxide, potassium hydroxide or lithium hydroxide; or an acid such as trichloromethane in dichloromethane Fluoroacetic acid treatment;
  • the temperature of the hydrolysis reaction may be 0-150°C, eg, 15-80°C.
  • the formula (I) in which R 12 is COOR 13 can be prepared through the first step of halogenation reaction and then through the second step of esterification reaction compound of;
  • the halogenating agent in the first step of halogenation reaction is selected from thionyl chloride, oxalyl chloride or thionyl chloride;
  • the temperature of the first-step halogenation reaction may be 0-100°C, such as 0-50°C, such as 0-30°C;
  • the second-step esterification reaction may be carried out in the presence of a base, which may be selected from organic bases or inorganic bases, such as pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) ), diisopropylethylamine (DIEA), one, two or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium hydride.
  • the preferred solvent can be one or both of N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, toluene, dichloromethane or 1,2-dichloroethane species or more;
  • the temperature of the second-step esterification reaction may be 0-120°C, for example, 0-50°C, such as 15-30°C.
  • the carboxylic acid esterification reaction may be carried out in the presence of a condensing agent selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC), N,N'-di Isopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBT), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea at least one of hexafluorophosphate (HATU) or benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (PyBOP);
  • a condensing agent selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC), N,N'-di Isopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBT), 2-(7-azabenzotriazole)-N,N,N',N'
  • the carboxylic acid esterification reaction may be carried out in the presence of a base, which may be an inorganic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or At least one of diisopropylethylamine (DIEA);
  • a base which may be an inorganic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or At least one of diisopropylethylamine (DIEA);
  • the carboxylic acid esterification reaction is carried out in a solvent selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, 2-methyl At least one of tetrahydrofuran, dioxane, acetonitrile, toluene, dichloromethane or 1,2-dichloroethane;
  • the temperature of the carboxylic acid esterification reaction may be -5-120°C, for example, 0-50°C, such as 15-30°C.
  • R 12 in the compound of formula (I) when R 12 in the compound of formula (I) is COOH, the compound of formula (I) wherein R 12 is CONR 14 R 15 can be prepared through the first step of halogenation reaction and then through the second step of condensation reaction. compound shown;
  • the halogenating agent in the first step of halogenation reaction is selected from thionyl chloride, oxalyl chloride or thionyl chloride;
  • the temperature of the first-step halogenation reaction may be 0-100°C, such as 0-50°C, such as 0-30°C;
  • the second-step condensation reaction may be carried out in the presence of a base, which may be selected from organic or inorganic bases, such as pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) , diisopropylethylamine (DIEA), one, two or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium hydride.
  • the preferred solvent can be one or both of N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, toluene, dichloromethane or 1,2-dichloroethane species or more;
  • the temperature of the condensation reaction in the second step may be 0-120°C, for example, 0-50°C, such as 15-30°C.
  • carboxylic acid and amine can be directly obtained by condensation reaction.
  • the condensation reaction may be carried out in the presence of a condensing agent selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropyl Carbodiimide (DIC), 1-Hydroxybenzotriazole (HOBT), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphoric acid at least one of benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (HATU) or hexafluorophosphate (PyBOP);
  • DCC N,N'-dicyclohexylcarbodiimide
  • DIC N,N'-diisopropyl Carbodiimide
  • HOBT 1-Hydroxybenzotriazole
  • the condensation reaction may be carried out in the presence of a base, which may be an inorganic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropyl At least one of diethylamine (DIEA);
  • a base which may be an inorganic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropyl At least one of diethylamine (DIEA);
  • the condensation reaction is carried out in a solvent selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethy At least one of oxane, acetonitrile, toluene, dichloromethane or 1,2-dichloroethane;
  • the temperature of the condensation reaction may be -5-120°C, such as 0-50°C, such as 15-30°C.
  • the compound represented by formula (III) can be purchased as a commercial product or prepared by a method known to those skilled in the art.
  • the preparation method of the compound represented by formula (II) comprises the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , L are as defined above;
  • L 1 is selected from a leaving group such as Cl, Br, I or F ;
  • L is selected from leaving groups such as Cl or Br.
  • step (1) can be carried out in the presence of a catalyst selected from tetrakis(triphenylphosphine)palladium, palladium acetate or bis(triphenylphosphine)palladium dichloride;
  • a catalyst selected from tetrakis(triphenylphosphine)palladium, palladium acetate or bis(triphenylphosphine)palladium dichloride;
  • step (1) can be carried out in the presence of a base selected from one or both of sodium carbonate, potassium carbonate, pyridine, triethylamine or 4-(dimethylamino)pyridine or more; the solvent is selected from one, two or more of toluene, tetrahydrofuran, N,N-dimethylformamide or water; the temperature of the reaction can be 20-150°C, for example 50 ⁇ 80°C.
  • a base selected from one or both of sodium carbonate, potassium carbonate, pyridine, triethylamine or 4-(dimethylamino)pyridine or more
  • the solvent is selected from one, two or more of toluene, tetrahydrofuran, N,N-dimethylformamide or water
  • the temperature of the reaction can be 20-150°C, for example 50 ⁇ 80°C.
  • step (2) can be carried out in the presence of a base selected from one, two or more of organic bases such as triethylamine, sodium acetate, or inorganic bases such as sodium bicarbonate
  • a base selected from one, two or more of organic bases such as triethylamine, sodium acetate, or inorganic bases such as sodium bicarbonate
  • the reaction solvent is selected from alcohol solvents such as methanol, ethanol, or water or a mixture thereof; the reaction temperature can be 0-100°C, preferably 15-30°C.
  • step (3) may be performed in the presence of a halogenating agent, which may be N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS);
  • a halogenating agent which may be N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS);
  • NCS N-chlorosuccinimide
  • step (3) can be carried out in the presence of a base selected from at least one of triethylamine, pyridine, sodium bicarbonate or sodium carbonate; the temperature of the reaction can be 0 ⁇ 100°C, for example, 15 to 30°C.
  • the boronic acid represented by formula (VII) and the halide represented by formula (VI) can be purchased as commercial products or prepared by methods known to those skilled in the art.
  • the reaction can be referred to in WO2014048827 or WO2006090234.
  • the compounds of formula (I) and their starting materials can be prepared herein according to the appropriate reaction conditions and the choice of starting materials in each case, for example, in a one-step reaction by replacing only one substituent with another substituent according to the invention, or it can be carried out in the same Various substituents are replaced in the reaction steps with other substituents according to the present invention.
  • reaction mixture can be worked up in the customary manner, eg by mixing with water, separating the phases and, if appropriate, purifying the crude product by chromatography, eg on alumina or silica gel.
  • the pharmaceutically acceptable salts of the compounds of formula (I) of the present invention can be prepared by known methods. Salts of compounds of formula (I) are obtained, for example, by treatment with a suitable base. Its preparation method is as follows: react the compound of formula (I) with alkali such as sodium hydroxide, potassium hydroxide, calcium hydroxide, zinc hydroxide, etc. in solvents such as water, ether or toluene, and can easily obtain formula (I) A pharmaceutically acceptable salt of the compound.
  • alkali such as sodium hydroxide, potassium hydroxide, calcium hydroxide, zinc hydroxide, etc.
  • solvents such as water, ether or toluene
  • the above preparation method can obtain a mixture of isomers of the compound of formula (I). If pure isomers are required, conventional methods such as crystallization or chromatography can be used for separation.
  • the present invention also provides a pesticide composition, such as a herbicidal composition, comprising as an active ingredient the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotopic label, One, two or more of nitrogen oxides, pharmaceutically acceptable salts or esters, solvates, or solvates of pharmaceutically acceptable salts.
  • a pesticide composition such as a herbicidal composition, comprising as an active ingredient the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotopic label, One, two or more of nitrogen oxides, pharmaceutically acceptable salts or esters, solvates, or solvates of pharmaceutically acceptable salts.
  • the weight percent content of the active ingredient in the composition is 0.1-99.9%, for example, 0.5-99%.
  • one, two or more of agricultural and/or forestry and/or hygienically acceptable carriers are also included in the composition.
  • the composition may be administered in the form of a formulation.
  • the compound of formula (I) can be dissolved or dispersed as an active ingredient in a carrier or formulated so as to be easier to disperse when used as a herbicide.
  • the formulations include but are not limited to the following forms: granules, wettable powders, oil suspensions, water suspensions, water emulsions, water preparations, emulsifiable concentrates or microcapsules and the like.
  • a liquid or solid carrier may also be added to the composition.
  • a surfactant may also be added to the composition.
  • the present invention also provides one, two or more of the compounds represented by formula (I), their stereoisomers, racemates, tautomers, nitrogen oxides or their pharmaceutically acceptable salts
  • pesticides such as herbicides. It has excellent herbicidal efficacy against a wide range of economically important monocotyledonous and dicotyledonous annual harmful plants.
  • the active ingredient also acts effectively on perennial weeds that sprout from rhizomes, rhizomes and other perennial organs and are difficult to control.
  • the present invention also provides compounds represented by formula (I), its stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or esters, solvates or Use of one, two or more of the solvates of the pharmaceutically acceptable salts in the preparation of pesticides, eg, herbicides.
  • the effective amount is 10 grams to 1000 grams per hectare, preferably the effective amount is 20 grams to 500 grams per hectare.
  • the present invention also provides a method for controlling unwanted plants, comprising adding an effective amount of the compound represented by formula (I), its stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides drug, a pharmaceutically acceptable salt or ester, a solvate or a solvate of a pharmaceutically acceptable salt, or applying the composition to an unwanted plant (e.g. a harmful plant such as a monocot or dicot grasses or unwanted crop plants), seeds or tubers or other reproductive parts of a desired plant (e.g. grains, seeds or vegetative propagules such as tubers or shoot parts with buds) or growing areas of a desired plant (eg cultivation area).
  • an unwanted plant e.g. a harmful plant such as a monocot or dicot grasses or unwanted crop plants
  • seeds or tubers or other reproductive parts of a desired plant e.g. grains, seeds or vegetative propagules such as tubers or shoot parts with buds
  • growing areas of a desired plant eg cultivation area
  • the compounds according to the invention can be applied, for example, before sowing (if appropriate also by incorporation into the soil), before or after emergence.
  • Some representative specific examples of monocotyledonous and dicotyledonous weed flora that can be controlled by the compounds of the present invention are as follows, but the enumeration is not intended to be limited to a particular species.
  • the method can control Aegilops, Agropyron, Agrostis, Alopecurus, Apera, Avena ), Brachiaria, Bromus, Cenchrus, Commelina, Cynodon, Cyperus, Cynodon Dactyloctenium, Digitaria, Echinochloa, Eleocharis, Eleusine, Eragrostis, Eriochloa, Festuca , Fimbristylis, Imperata, Ischaemum, Heteranthera, Leptochloa, Lolium, Monochoria ), Panicum, Paspalum, Phalaris, Phleum, Poa, Rottboellia, Sagittaria, Scirpus, Setaria, Sorghum and Sphenoclea.
  • the method can control species such as Abutilon, Amaranthus, Ambrosia, Anoda, Anthemis, Aphanes, Artemisia Genus Artemisia, Atriplex, Bellis, Bidens, Capsella, Carduus, Cassia, Centaurea ( Centaurea, Chenopodium, Cirsium, Convolvulus, Datura, Desmodium, Emex, Geranium (Erodium), Erysimum, Euphorbia, Galeopsis, Galinsoga, Galium, Geranium, Hibiscus, Ipomoea, Kochia, Lamium, Lepidium, Lindernia, Matricaria, Mint Mentha, Mercurialis, Mullugo, Myosotis, Papaver, Pharbitis, Plantago, Polygonum, Portulaca Portulaca, Ranunculus, Raphanus, Rorippa, Rotala, Rumex, Salsola, Senecio
  • the active compound combinations according to the invention are applied to the soil surface pre-emergence, the emergence of weed seedlings is completely prevented, or the weeds grow until they reach the cotyledon stage, but then their growth stops and finally dies out completely in three to four weeks .
  • the active compounds are applied to the green parts of the plants post-emergence, the growth stops after the treatment, the harmful plants remain in the growth phase at the point of application, or die completely after a certain time, so that the harmful plants can be eliminated very early and in a lasting manner. Crop plants compete with harmful weeds.
  • the compounds of the present invention have excellent herbicidal activity against monocotyledonous and dicotyledonous weeds, but have negligible, if any, damage to many desirable plants or economically important crops, depending on Structures of specific compounds of the invention and their application rates.
  • Desirable plants or economically important crops herein such as dicotyledonous crops of the following genera: Arachis, Beta, Brassica, Cucumis, Cucurbita ( Cucurbita, Helianthus, Daucus, Glycine, Gossypium, Ipomoea, Lactuca, Linum, Lycopersicon , Miscanthus, Nicotiana, Phaseolus, Pisum, Solanum, Vicia; or monocotyledonous crops of the following genera: Allium , Ananas, Asparagus, Avena, Hordeum, Oryza, Panicum, Saccharum, Secale , Sorghum, Triticale, Triticum and Zea.
  • the compounds of the present invention are very suitable for selectively controlling the growth of unwanted plants in crop plant species, such as agriculturally useful plants or ornamental plants.
  • the compounds of the present invention (depending on their specific chemical structure and the application rates used) also have excellent growth regulating properties on crop plants. They intervene in the plant's own metabolism in a regulatory role and can thus be used to influence plant composition in a targeted manner and facilitate harvesting, for example by inducing dehydration and stunted growth. In addition, they are generally also suitable for general control and inhibition of undesired vegetative growth without killing the plants. Inhibition of vegetative growth plays an important role in many monocotyledonous and dicotyledonous crops by, for example, reducing or completely preventing lodging.
  • transgenic plants are characterized by particularly advantageous properties, such as resistance to certain pesticides, especially certain herbicides, resistance to plant diseases or pathogens of plant diseases, such as certain insects or Microorganisms such as fungi, bacteria or viruses.
  • Other specific properties relate, for example, to the quantity, quality, storability, composition and specific composition of the harvested material.
  • transgenic plants are known that have increased starch content or altered starch quality, or that contain a different fatty acid composition in the harvest.
  • Other specific characteristics may be resistance to abiotic stress factors such as heat, cold, drought, salinity and UV radiation.
  • the compounds of formula (I) according to the invention or their salts are preferably used in transgenic crops of economically important useful plants and ornamental plants such as cereals such as wheat, barley, rye, oats, millet , rice, cassava and corn, or other crops beet, cotton, soybean, rape, potato, tomato, pea and other vegetables.
  • the compounds of the formula (I) according to the invention or their salts are preferably used as herbicides in crops of useful plants which are resistant to the phytotoxic effects of the herbicides or in a recombinant manner to the phytotoxic effects of the herbicides Resistant.
  • nucleic acid molecules that permit mutagenesis or sequence modification by DNA sequence recombination can be added to plasmids.
  • base exchange to remove subsequences or add natural or synthetic sequences can be performed by standard methods.
  • Linkers or linkers can be added to ligate DNA fragments to each other, see, e.g., Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; or Winnacker "Gene und Klone” [Genes and Clones], VCH Weinheim, 2nd ed., 1996.
  • the above-mentioned genes can be successfully produced with reduced Product active plant cells.
  • a DNA molecule containing all of the coding sequence of the gene product, including any flanking sequences that may be present, can be used first, and a DNA molecule containing only part of the coding sequence, for which parts need to be of sufficient length to cause intracellular reactions righteous effect. It is also possible to use DNA sequences that have a high degree of homology to the coding sequences of gene products that are not identical thereto.
  • the synthesized protein can be located in any compartment of the plant cell.
  • the coding region can for example be linked to a DNA sequence that ensures its location in a specific compartment.
  • Such sequences are known to those skilled in the art (see, eg, Braun et al., EMBO J. 11 (1992), 3219-3227; Wolter et al., Proc. Natl. Acad. Sci. USA 85 (1988) , 846-850; Sonnewald et al., Plant J. 1 (1991), 95-106).
  • Nucleic acid molecules can also be expressed in organelles of plant cells.
  • Transgenic plant cells can be regenerated by known techniques to yield whole plants.
  • transgenic plants can be plants of any desired plant species, ie monocotyledonous and dicotyledonous plants.
  • the compounds of formula (I) according to the invention or their salts can preferably be used in transgenic crops that are tolerant to the compounds used or made tolerant.
  • the compounds of formula (I) of the present invention or their salts can also be used in transgenic crops resistant to growth substances such as dicamba; or inhibition of plant essential enzymes such as acetolactate synthase (ALS), Herbicides against EPSP synthase, glutamine synthase (GS) or hydroxyphenylpyruvate dioxygenase (HPPD); selected from sulfonylurea, glyphosate, glufosinate or benzoylisoxazole and Herbicides with similar active compounds.
  • ALS acetolactate synthase
  • EPSP Epoxyphenylpyruvate dioxygenase
  • HPPD hydroxyphenylpyruvate dioxygenase
  • the present invention also provides - if appropriate, in crops of useful plants, preferably on non-arable land or in cultivated crops - such a method for controlling unwanted plants, wherein a compound of (I), its Stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or solvates thereof are applied to harmful plants, plant parts or plant seeds thereof, or to a cultivated area.
  • a compound of (I) its Stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or solvates thereof are applied to harmful plants, plant parts or plant seeds thereof, or to a cultivated area.
  • the present invention also provides the compound represented by formula (I), its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvates thereof for use For the control - if appropriate, in crops of beneficial plants, preferably on non-arable land or in cultivated crops - the use of harmful plants.
  • the compounds of formula (I) can advantageously be used to protect important crops in cultivated and non-cultivated land, as well as the environment frequented by humans, from harmful weeds.
  • the amount of the compound of formula (I) to be used to obtain the desired effect will vary depending on factors such as the compound used, the crop to be pre-protected, the type of noxious weeds, the degree of infection, the climatic conditions, the method of application and the dosage form employed.
  • composition or composition ingredients described herein should be selected in accordance with the physical properties of the active ingredient, the mode of application and environmental factors such as soil type, humidity and temperature.
  • Useful dosage forms include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspending agents), and the like, which may optionally be viscous to form a gel.
  • Useful dosage forms also include solids such as powders, powders, granules, tablets, pills, films, and the like, which may be water-dispersible ("wettable") or water-soluble.
  • the active ingredient can be microencapsulated and then made into a suspension or solid dosage form; in addition, the entire dosage form of the active ingredient can also be encapsulated. Encapsulation can control or delay the release of the active ingredient.
  • Sprayable formulations can be diluted in a suitable medium using spray volumes of about one hundred to several hundred liters per hectare. Compositions in high concentrations are mainly used as intermediates for further processing.
  • Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, and Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, Lists Surfactants and recommended apps. All dosage forms may contain small amounts of additives to reduce foaming, coalescence, corrosion, microbial growth, etc., or thickeners to increase viscosity.
  • Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, sulfonated dialkyl succinates, alkyl sulfates, Alkylbenzenesulfonates, organosilanes, N,N-dialkyltaurates, lignosulfonates, aldehyde condensates for naphthalenesulfonates, polycarboxylates and polyoxyethylene/polyoxypropylene intercalation segmented copolymer.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sulfuric acid Sodium
  • liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfone, N-alkylpyrrolidones, ethylene glycol, polypropylene glycol, paraffin, alkylbenzenes, alkylnaphthalenes , olive oil, castor oil, linseed oil, tung oil, sesame oil, corn oil, peanut oil, cottonseed oil, soybean oil, rapeseed oil and cocoa butter, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, iso phorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as
  • Solutions can be prepared by simply mixing the ingredients. Powders and fines can be prepared by mixing and milling, usually in a hammer or liquid energy mill. Suspensions are usually prepared by wet milling; see, for example, U.S. 3060,084, granules and pellets are prepared by spraying the active substance onto a It is prepared on a prepared granular carrier or by a granulation technique. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp147-48, Perry's Chemical Engineer's Handbook, 4TH Ed., McGraw-Hill, New York, 1963, Pages 8-57 and following, and WO 91/ 13546. Preparation of pills as described in U.S.
  • one, two or more other fungicides, insecticides, acaricides, herbicides may be added to the herbicidal composition of the present invention.
  • Growth regulators or fertilizers, etc. thereby producing additional advantages and effects.
  • the compounds of formula (I) described in the present invention have good activity against various harmful weeds in agriculture or other fields. Moreover, these compounds can achieve good control effects at very low doses, so they can be used in the preparation of herbicides.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • C1- C6 alkyl refers to straight and branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,
  • C2 - C6 alkenyl is to be understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example, Has 2 or 3 carbon atoms (ie, C2 - C3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -Pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-eny
  • C2 - C6alkynyl is to be understood as preferably denoting a linear or branched monovalent hydrocarbon group comprising one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, eg , having 2 or 3 carbon atoms ("C2 - C3alkynyl").
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-alkynyl, 2-methylpent-3-y
  • heterocyclyl means a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S and N.
  • the heterocyclyl group can be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclyl group can include fused or bridged rings as well as spirocyclic rings.
  • the heterocyclic group may include, but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 1,3-dioxolane; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithi Alkyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyr
  • the heterocyclyl group can be benzo-fused.
  • the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrole The [1,2-a]pyrazin-2(1H)-yl ring.
  • a heterocyclyl group may be partially unsaturated, i.e.
  • it may contain one or more double bonds such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, alternatively, it may be benzo-fused such as but not limited to dihydro isoquinolinyl.
  • C6 - C10 aryl is to be understood as preferably denoting a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular A ring of 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or a ring of 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl , or a ring having 10 carbon atoms (“ C10 aryl”), such as tetralinyl, dihydronaphthyl, or naphthyl, such as fluorenyl.
  • C6 - C10 aryl group When the C6 - C10 aryl group is substituted, it may be monosubstituted or polysubstituted.
  • the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.
  • heteroaryl is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms and it contains 1-5, preferably 1-3 heteroatoms each independently selected from N, O and S and, in addition in each case may be benzo-fused .
  • Heteroaryl also refers to groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the root or point of attachment is on the heteroaromatic ring. Non-limiting examples include furyl, indolyl, isoindolyl, indolyl, indazolyl, purinyl.
  • reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in this application.
  • the techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification.
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituent When a substituent is described by a conventional formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left, so long as it conforms to the valence rules.
  • CH2O which is equivalent to OCH2 , may be attached to the substitution position with an oxygen atom or a methylene carbon atom.
  • the term "pharmaceutically acceptable salts” refers to salts that retain the biological potency of the free acid and free base of the designated compound and are not biologically or otherwise adversely affected.
  • the compounds of the present application also include pharmaceutically acceptable salts, such as sodium salts, potassium salts, calcium salts, zinc salts, and the like which are generally used in the fields of agriculture and horticulture.
  • a pharmaceutically acceptable salt refers to a form in which an acid group in the parent compound is converted into a salt.
  • Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic base salts of acid groups such as carboxylic acid (hydro) groups.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound by reacting an acidic group in the parent compound with 1-4 equivalents of a base in a solvent system. Suitable salts are listed in Remingtong's Pharmaceutical Sciences, 17th ed ., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eg, the sodium salt.
  • stereoisomers refer to isomers that result from different arrangements of atoms in a molecule in space.
  • the compounds of formula (I) contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. All stereostructures of formula (I) are the same as mixtures, including racemic mixtures, as part of the present application.
  • Diastereomeric mixtures can be separated into the individual diastereomers on the basis of their different physicochemical properties by well-known means, for example, resolution of enantiomers can be achieved by interaction with appropriate optically active substances (e.g., chiral isomers).
  • the compounds of formula (I) may exist in different tautomeric forms, all of which are included within the scope of this application. For example, compounds in the form of keto-enols and imine-enamines.
  • Detection wavelength 254nm; flow rate: 0.8mL/min; column temperature: 30°C;
  • the first step reaction Preparation of 2-chloro-4-fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)benzaldehyde: under nitrogen protection, 3.03g (0.015mol) (4- Chloro-2-fluoro-5-formylphenyl)boronic acid, 6.21g (0.045mol) potassium carbonate, 0.52g (0.00045mol) tetrakis (triphenylphosphine) palladium, 60ml tetrahydrofuran, 30ml water were added to the there-necked flask and stirred . To the above mixture was added portionwise 3.27 g (0.018 mol) of 2-chloro-5-(trifluoromethyl)pyridine.
  • the second step reaction preparation of 2-chloro-4-fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)benzaldehyde oxime: at room temperature, 2.27g (0.0075mol) of 2-chloro -4-Fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)benzaldehyde, 0.68g (0.0097mol) hydroxylamine hydrochloride, 0.86g (0.01mol) sodium acetate dissolved in 5ml water and mixed with 20ml tetrahydrofuran in solution. The reaction solution was stirred for 4 hours.
  • the reaction mixture was concentrated, diluted with ethyl acetate and aqueous sodium hydroxide (2M), and the phases were separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration and drying to obtain 2.22 g of the product with a yield of 93%.
  • reaction solution was cooled to room temperature, 0.68g (0.006mol) of ethyl methacrylate, 0.76g (0.0075mol) of triethylamine in 2ml of N,N-dimethylformamide solution were added to the above mixture, and stirred at room temperature for 5 hours .
  • the reaction mixture was diluted with water and ethyl acetate and the phases were separated.
  • the aqueous phase was extracted with ethyl acetate (2*20ml) and the organic phases were combined.
  • the organic phase was washed twice with water and once with saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • the residue was subjected to column chromatography (eluent: ethyl acetate: petroleum ether (1:9) to obtain 1.76 g of the product with a yield of 82%.
  • the first step reaction preparation of 2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorobenzaldehyde: under nitrogen protection, 3.03g (0.015mol ) (4-chloro-2-fluoro-5-formylphenyl)boronic acid, 6.21g (0.045mol) potassium carbonate, 0.52g (0.00045mol) tetrakis(triphenylphosphine)palladium, 60ml tetrahydrofuran, 30ml water were added to the Stir in a three-necked bottle.
  • the second step reaction preparation of 2-chloro-5-(3-chloro-5-trifluoromethyl)pyridin-2-yl)-4-fluorobenzaldehyde oxime: at room temperature, 2.53g (0.0075mol) of 2-Chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorobenzaldehyde, 0.68g (0.0097mol) hydroxylamine hydrochloride, 0.86g (0.01mol) sodium acetate In 5ml water and 20ml tetrahydrofuran mixed solution. The reaction solution was stirred for 4 hours.
  • reaction mixture was concentrated, diluted with ethyl acetate and aqueous sodium hydroxide (2M), and the phases were separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration and drying to obtain 2.38 g of product with a yield of 90%.
  • reaction solution was cooled to room temperature, 2ml N,N-dimethylformamide solution of 0.60g (0.006mol) methyl methacrylate and 0.76g (0.0075mol) triethylamine was added to the above mixture, and stirred at room temperature for 5 hours .
  • the reaction mixture was diluted with water and ethyl acetate and the phases were separated.
  • the aqueous phase was extracted with ethyl acetate (2*20ml) and the organic phases were combined.
  • the organic phase was washed twice with water and once with saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • the residue was subjected to column chromatography (eluent: ethyl acetate: petroleum ether (1:9) to obtain 1.92 g of the product with a yield of 85%.
  • the reaction mixture was diluted with water and ethyl acetate and the phases were separated.
  • the aqueous phase was extracted with ethyl acetate (2*20ml) and the organic phases were combined.
  • the organic phase was washed twice with water and once with saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • the residue was subjected to column chromatography (eluent: ethyl acetate: petroleum ether (1:9) to obtain 1.83 g of the product with a yield of 79%.
  • the second step reaction 2-(1,3-dioxolan-2-yl)ethyl 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl) )-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate preparation: 1.05 g (0.0023 mol) of 3-(2-chloro- 5-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-acid chloride, 0.46g (0.0046 mol) triethylamine, 0.29 g (0.0025 mol) 2-(1,3-dioxolan-2-yl) ethane-1-ol were dissolved in 15 ml of dichloromethane successively.
  • the present invention has also synthesized the following compounds with reference to the methods in the above examples:
  • the present embodiment uses the compound obtained in the above embodiment to prepare the wettable powder, and specifically adopts the raw material composition of the following proportions to prepare:
  • Compound 3 50.0%, dodecylphenol polyethoxy glycol ether 4.0%, sodium lignosulfonate 6.0%, sodium aluminosilicate 8.0%, montmorillonite (calcined) 32.0%.
  • This embodiment uses the compound obtained in the above embodiment to prepare granules, and specifically adopts the raw material composition of the following proportions to prepare:
  • Compound 121 20.0% other components are sodium lauryl sulfate 2.0%, calcium lignosulfonate 6.0%, potassium chloride 10.0%, polydimethylsiloxane 1.0%, soluble starch is filled to 100%.
  • This embodiment uses the compound obtained in the above embodiment to prepare extruded pellets, and specifically adopts the raw material composition of the following proportions to prepare:
  • the present embodiment uses the compound obtained in the above embodiment to prepare emulsifiable concentrate, and specifically adopts the raw material composition of the following proportions to prepare:
  • the present embodiment uses the compound obtained in the above embodiment to prepare the aqueous suspension, and specifically adopts the raw material composition of the following proportions to prepare:
  • the herbicidal activity of the compounds of the present invention is shown in the following greenhouse tests:
  • the quantitative crop seeds were sown in paper cups with nutrient soil with a diameter of 7cm, covered with soil 1cm after sowing, and cultivated in a greenhouse after suppression and drenching. (2-3 leaf stage of rice), according to the experimental design dose, use a crawler-type crop sprayer (designed and produced by British Engineer Research Ltd.) to spray the stem and leaves (spray pressure 1.95kg/cm2, spray volume 50ml/m2, crawler speed 1.48km/h), the test was repeated three times. After the medicinal liquid was naturally air-dried, it was placed in a greenhouse for management according to conventional methods, the growth and development of the tested crops were observed for each treatment, and the safety of the tested chemicals on the tested crops was regularly inspected visually. Safety grading standard: 0 means no damage to the crop, 100 means the crop is completely killed or severely inhibited. The test results are shown in Table 6.

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Abstract

The present invention relates to the technical field of herbicides, and specifically to isoxazoline-containing pyridine biphenyl compounds, a preparation method therefor and the use thereof. The present invention specifically provides compounds as represented by the following formula (I) or salts thereof. The compounds as represented by the formula (I) exhibit good activity against various harmful weeds in agricultural or other fields. Furthermore, these compounds can achieve good control effects at very low doses, and therefore can be used for preparing herbicides and have better application prospects.

Description

一种含异噁唑啉的吡啶联苯类化合物及其制备方法与用途A kind of pyridine biphenyl compound containing isoxazoline and its preparation method and use
本申请要求享有于2020年12月17日向中国国家知识产权局提交的，专利申请号为202011497249.X，名称为“一种含异噁唑啉的吡啶联苯类化合物及其制备方法与用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。This application claims to enjoy the patent application No. 202011497249.X, which was submitted to the State Intellectual Property Office of China on December 17, 2020, and is entitled "A pyridine biphenyl compound containing isoxazoline and its preparation method and use" the priority of the earlier application. The entire contents of this prior application are incorporated herein by reference.
技术领域technical field
本发明属于农用除草剂技术领域，具体涉及一种异噁唑啉的吡啶联苯类化合物及其制备方法与用途。The invention belongs to the technical field of agricultural herbicides, in particular to a pyridine biphenyl compound of isoxazoline and a preparation method and application thereof.
背景技术Background technique
农田有害杂草是农业生产中的大敌，据统计全世界的农作物每年由于草害平均要损失12％的产量，因此杂草的防治是实现高效农业的重要环节。尽管市场上的除草剂品种多样，但由于市场的不断扩大、近些年杂草抗药性日益严重以及人们对环境保护的日益重视，人们仍需要不断开发出新的高效、安全的除草剂新品种。Harmful weeds in farmland are the enemy in agricultural production. According to statistics, crops all over the world lose an average of 12% of their output due to weed damage every year. Therefore, weed control is an important link to achieve efficient agriculture. Although there are various types of herbicides on the market, due to the continuous expansion of the market, the increasing resistance of weeds in recent years, and the increasing emphasis on environmental protection, people still need to continuously develop new high-efficiency and safe new varieties of herbicides .
专利文献WO2014048827公开了如下所示含异噁唑啉化合物CK 1(化合物编号1.1.1)： Patent document WO2014048827 discloses an isoxazoline-containing compound CK 1 (compound number 1.1.1) as shown below:
Figure PCTCN2021133602-appb-000001
Figure PCTCN2021133602-appb-000001
然而，这些已知化合物对有害植物的除草性能并不总是令人满意。为发现性能更加优异的除草剂，发明人进行了深入研究。However, the herbicidal properties of these known compounds against harmful plants are not always satisfactory. In order to find herbicides with better performance, the inventors have conducted intensive research.
发明内容SUMMARY OF THE INVENTION
为改善上述问题，本发明提供通式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物，In order to improve the above problems, the present invention provides compounds represented by general formula (I), stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or esters thereof , a solvate or a solvate of a pharmaceutically acceptable salt,
Figure PCTCN2021133602-appb-000002
Figure PCTCN2021133602-appb-000002
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、卤素、C 1-C 6烷基或卤代C 1-C 6烷基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、卤素、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
R 9、R 10相同或不同，彼此独立地选自氢、氰基、C 1-C 6烷基或卤代C 1-C 6烷基； R 9 and R 10 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 6烷基、卤代C 1-C 6烷基、COOR 13或CONR 14R 15； R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, COOR 13 or CONR 14 R 15 ;
R 13选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 3烷氧基C 1-C 6烷基、C 3-C 6烯基、C 3-C 6炔基、未取代或被1-4个Ra取代的C 6-C 10芳基C 1-C 6烷基、5-10元杂芳基C 1-C 6烷基、3-10元杂环基C 1-C 6烷基；每个Ra相同或不同，彼此独立地选自卤素、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, unsubstituted or 1-4 Ra substituted C 6 -C 10 aryl C 1 -C 6 alkyl, 5-10 membered heteroaryl C 1 -C 6 alkyl, 3-10 Membered heterocyclyl C 1 -C 6 alkyl; each Ra is the same or different and independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 6烷基或C 1-C 4烷氧基C 1-C 6烷基。 R 14 and R 15 are the same or different and are independently selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 6 alkyl.
本发明较为优选的化合物为，通式(I)中The more preferred compound of the present invention is, in the general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、卤素、C 1-C 4烷基或卤代C 1-C 4烷基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、卤素、C 1-C 4烷基、卤代C 1-C 4烷基、C 1-C 4烷氧基或卤代C 1-C 4烷氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogenated C 1 -C 4 alkoxy;
R 9、R 10相同或不同，彼此独立地选自氢、C 1-C 4烷基或卤代C 1-C 4烷基； R 9 and R 10 are the same or different and are independently selected from hydrogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 6烷基、卤代C 1-C 6烷基、COOR 13或CONR 14R 15； R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, COOR 13 or CONR 14 R 15 ;
R 13选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、C 3-C 6烯基、C 3-C 6炔基、未取代或被1-4个Ra取代的C 6-C 8芳基C 1-C 4烷基、5-8元杂芳基C 1-C 4烷基、3-6元杂环基C 1-C 4烷基；每个Ra相同或不同，彼此独立地选自卤素、氰基、硝基、C 1-C 4烷基、卤代C 1-C 4烷基、C 1-C 4烷氧基或卤代C 1-C 4烷氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 6 -C 8 aryl C 1 -C 4 alkyl, unsubstituted or substituted by 1-4 Ra, C 1 -C 4 alkyl, 5-8 membered heteroaryl C 1 -C 4 alkyl, 3-6 Membered heterocyclyl C 1 -C 4 alkyl; each Ra is the same or different and independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogenated C 1 -C 4 alkoxy;
R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 4烷基或C 1-C 4烷氧基C 1-C 6烷基。 R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy C 1 -C 6 alkyl.
本发明进一步优选的化合物为，通式(I)中The further preferred compound of the present invention is, in general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、溴、甲基、乙基、三氟甲基或三氟乙基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、溴、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy group, trifluoromethoxy or trifluoroethoxy;
R 9、R 10相同或不同，彼此独立地选自氢、C 1-C 4烷基或卤代C 1-C 4烷基； R 9 and R 10 are the same or different and are independently selected from hydrogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 4烷基、卤代C 1-C 4烷基、COOR 13或CONR 14R 15； R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, COOR 13 or CONR 14 R 15 ;
R 13选自氢、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 3烷氧基C 1-C 3烷基、C 3-C 6烯基、C 3-C 6炔基、未取代或被1-4个Ra取代的苄基、呋喃基甲基或四氢呋喃基甲基；每个Ra相同或不同，彼此独立地选自氟、氯、氰基、硝基、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, unsubstituted or benzyl, furylmethyl or tetrahydrofurylmethyl substituted with 1-4 Ra; each Ra is the same or different, independently selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 4烷基或C 1-C 3烷氧基C 1-C 3烷基。 R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
或者，本发明进一步优选的化合物为，通式(I)中Or, the further preferred compound of the present invention is, in general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、溴、甲基、乙基、三氟甲基或三氟乙基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、溴、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy group, trifluoromethoxy or trifluoroethoxy;
R 9、R 10相同或不同，彼此独立地选自氢、C 1-C 4烷基或卤代C 1-C 4烷基； R 9 and R 10 are the same or different and are independently selected from hydrogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 4烷基、卤代C 1-C 4烷基、COOR 13或CONR 14R 15； R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, COOR 13 or CONR 14 R 15 ;
R 13选自氢、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 3烷氧基C 1-C 3烷基、C 3-C 6烯基、C 3-C 6炔基、未取代或被1-4个Ra取代的苄基、呋喃基甲基、四氢呋喃基甲基或1,3-二氧环戊烷乙基； 每个Ra相同或不同，彼此独立地选自氟、氯、氰基、硝基、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, benzyl, unsubstituted or substituted with 1-4 Ras, furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl; each Ra is the same or different, independently of each other selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 4烷基或C 1-C 3烷氧基C 1-C 3烷基。 R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
本发明更为优选的化合物为，通式(I)中The more preferred compound of the present invention is, in the general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、甲基、乙基、三氟甲基或三氟乙基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
R 9、R 10相同或不同，彼此独立地选自氢、甲基、乙基、丙基、丁基、三氟甲基或三氟乙基； R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl or trifluoroethyl;
R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 4烷基、C 1-C 4卤代烷基、COOR 13或CONR 14R 15； R 11 , R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, COOR 13 or CONR 14 R 15 ;
R 13选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、烯丙基、炔丙基、C 1-C 3烷氧基C 1-C 3烷基、未取代或被1-4个Ra取代的苄基、呋喃基甲基或四氢呋喃基甲基；每个Ra相同或不同，彼此独立地选自氟、氯、氰基、硝基、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, unsubstituted or benzyl, furylmethyl or tetrahydrofurylmethyl substituted with 1-4 Ra; each Ra is the same or different and independently selected from the group consisting of fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 4烷基或C 1-C 3烷氧基C 1-C 3烷基。 R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
或者，本发明更为优选的化合物为，通式(I)中Or, the more preferred compound of the present invention is, in general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、甲基、乙基、三氟甲基或三氟乙基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
R 9、R 10相同或不同，彼此独立地选自氢、甲基、乙基、丙基、丁基、三氟甲基或三氟乙基； R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl or trifluoroethyl;
R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 4烷基、C 1-C 4卤代烷基、COOR 13或CONR 14R 15； R 11 , R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, COOR 13 or CONR 14 R 15 ;
R 13选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、烯丙基、炔丙基、C 1-C 3烷氧基C 1-C 3烷基、未取代或被1-4个Ra取代的苄基、呋喃基甲基、四氢呋喃基甲基或1,3-二氧环戊烷乙基；每个Ra相同或不同，彼此独立地选自氟、氯、氰基、硝基、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, unsubstituted or benzyl, furylmethyl, tetrahydrofuranylmethyl or 1,3-dioxolaneethyl substituted with 1-4 Ras; each Ra is the same or different and independently selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 4烷基或C 1-C 3烷氧基C 1-C 3烷基。 R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
本发明再进一步优选的化合物为，通式(I)中The further preferred compound of the present invention is, in the general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、甲基或三氟甲基； R 1 , R 2 , R 3 , R 4 are the same or different, and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基、三氟甲基、甲氧基或三氟甲氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
R 9、R 10相同或不同，彼此独立地选自氢、甲基、乙基、丙基或丁基； R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl or butyl;
R 11、R 12相同或不同，彼此独立地选自氢、甲基、乙基或COOR 13； R 11 and R 12 are the same or different, and are independently selected from hydrogen, methyl, ethyl or COOR 13 ;
R 13选自氢、C 1-C 4烷基、卤代C 1-C 4烷基、烯丙基、炔丙基、C 1-C 3烷氧基C 1-C 3烷基、苄基、呋喃基甲基或四氢呋喃基甲基。 R 13 is selected from hydrogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, benzyl , furylmethyl or tetrahydrofurylmethyl.
或者，本发明再进一步优选的化合物为，通式(I)中Or, the further preferred compound of the present invention is, in the general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、甲基或三氟甲基； R 1 , R 2 , R 3 , R 4 are the same or different, and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基、三氟甲基、甲氧基或 三氟甲氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
R 9、R 10相同或不同，彼此独立地选自氢、甲基、乙基、丙基或丁基； R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl or butyl;
R 11、R 12相同或不同，彼此独立地选自氢、甲基、乙基或COOR 13； R 11 and R 12 are the same or different, and are independently selected from hydrogen, methyl, ethyl or COOR 13 ;
R 13选自氢、C 1-C 4烷基、卤代C 1-C 4烷基、烯丙基、炔丙基、C 1-C 3烷氧基C 1-C 3烷基、苄基、呋喃基甲基、四氢呋喃基甲基或1,3-二氧环戊烷乙基。 R 13 is selected from hydrogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, benzyl , furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl.
本发明更进一步优选的化合物为，通式(I)中The further preferred compound of the present invention is, in the general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯或三氟甲基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine or trifluoromethyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基或三氟甲基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
R 9、R 10相同或不同，彼此独立地选自氢或甲基； R 9 and R 10 are the same or different, and are independently selected from hydrogen or methyl;
R 11、R 12相同或不同，彼此独立地选自甲基、乙基或COOR 13； R 11 and R 12 are the same or different, and are independently selected from methyl, ethyl or COOR 13 ;
R 13选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、三氟甲基、三氟乙基、烯丙基、炔丙基、甲氧基乙基、乙氧基乙基、苄基、呋喃基甲基或四氢呋喃基甲基。 R 13 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, allyl, propargyl, methoxy ethyl, ethoxyethyl, benzyl, furylmethyl or tetrahydrofurylmethyl.
或者，本发明更进一步优选的化合物为，通式(I)中Or, the more preferred compound of the present invention is, in general formula (I)
R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯或三氟甲基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine or trifluoromethyl;
R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基或三氟甲基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
R 9、R 10相同或不同，彼此独立地选自氢或甲基； R 9 and R 10 are the same or different, and are independently selected from hydrogen or methyl;
R 11、R 12相同或不同，彼此独立地选自甲基、乙基或COOR 13； R 11 and R 12 are the same or different, and are independently selected from methyl, ethyl or COOR 13 ;
R 13选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、三氟甲基、三氟乙基、烯丙基、炔丙基、甲氧基乙基、乙氧基乙基、苄基、呋喃基甲基、四氢呋喃基甲基或1,3-二氧环戊烷乙基。 R 13 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, allyl, propargyl, methoxy ethyl, ethoxyethyl, benzyl, furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl.
本发明的部分化合物可以用表1～3所述具体化合物说明，但本发明并不限于这些化合物。表1中化合物R 1＝H，R 2＝CF 3，R 3＝H，R 6＝H，R 8＝H，其他基团如表所示。 Some of the compounds of the present invention can be described with specific compounds described in Tables 1 to 3, but the present invention is not limited to these compounds. The compounds in Table 1 are R 1 =H, R 2 =CF 3 , R 3 =H, R 6 =H, R 8 =H, and other groups are shown in the table.
Figure PCTCN2021133602-appb-000003
Figure PCTCN2021133602-appb-000003
表1Table 1
Figure PCTCN2021133602-appb-000004
Figure PCTCN2021133602-appb-000004
Figure PCTCN2021133602-appb-000005
Figure PCTCN2021133602-appb-000005
Figure PCTCN2021133602-appb-000006
Figure PCTCN2021133602-appb-000006
Figure PCTCN2021133602-appb-000007
Figure PCTCN2021133602-appb-000007
Figure PCTCN2021133602-appb-000008
Figure PCTCN2021133602-appb-000008
Figure PCTCN2021133602-appb-000009
Figure PCTCN2021133602-appb-000009
Figure PCTCN2021133602-appb-000010
Figure PCTCN2021133602-appb-000010
Figure PCTCN2021133602-appb-000011
Figure PCTCN2021133602-appb-000011
Figure PCTCN2021133602-appb-000012
Figure PCTCN2021133602-appb-000012
Figure PCTCN2021133602-appb-000013
Figure PCTCN2021133602-appb-000013
Figure PCTCN2021133602-appb-000014
Figure PCTCN2021133602-appb-000014
Figure PCTCN2021133602-appb-000015
Figure PCTCN2021133602-appb-000015
Figure PCTCN2021133602-appb-000016
Figure PCTCN2021133602-appb-000016
Figure PCTCN2021133602-appb-000017
Figure PCTCN2021133602-appb-000017
Figure PCTCN2021133602-appb-000018
Figure PCTCN2021133602-appb-000018
Figure PCTCN2021133602-appb-000019
Figure PCTCN2021133602-appb-000019
Figure PCTCN2021133602-appb-000020
Figure PCTCN2021133602-appb-000020
表2中化合物R 1＝H，R 2＝CF 3，R 3＝H，R 5＝H，R 6＝H，其他基团如表所示。 In the compounds in Table 2, R 1 =H, R 2 =CF 3 , R 3 =H, R 5 =H, R 6 =H, and other groups are shown in the table.
Figure PCTCN2021133602-appb-000021
Figure PCTCN2021133602-appb-000021
表2Table 2
Figure PCTCN2021133602-appb-000022
Figure PCTCN2021133602-appb-000022
Figure PCTCN2021133602-appb-000023
Figure PCTCN2021133602-appb-000023
Figure PCTCN2021133602-appb-000024
Figure PCTCN2021133602-appb-000024
表3中化合物R 5＝F，R 6＝H，R 7＝Cl，R 8、R 10＝H其他基团如表所示。 In Table 3, the compounds R 5 =F, R 6 =H, R 7 =Cl, R 8 , R 10 =H and other groups are shown in the table.
Figure PCTCN2021133602-appb-000025
Figure PCTCN2021133602-appb-000025
表3table 3
Figure PCTCN2021133602-appb-000026
Figure PCTCN2021133602-appb-000026
Figure PCTCN2021133602-appb-000027
Figure PCTCN2021133602-appb-000027
Figure PCTCN2021133602-appb-000028
Figure PCTCN2021133602-appb-000028
Figure PCTCN2021133602-appb-000029
Figure PCTCN2021133602-appb-000029
Figure PCTCN2021133602-appb-000030
Figure PCTCN2021133602-appb-000030
Figure PCTCN2021133602-appb-000031
Figure PCTCN2021133602-appb-000031
优选地，式(I)所示的化合物具有以下结构：Preferably, the compound represented by formula (I) has the following structure:
Figure PCTCN2021133602-appb-000032
Figure PCTCN2021133602-appb-000032
本发明还提供如上式(I)所示化合物的制备方法，包括如下步骤：The present invention also provides the preparation method of the compound shown in the above formula (I), comprising the following steps:
式(II)所示化合物与式(III)化合物发生环加成反应得到式(I)化合物；The compound represented by the formula (II) is subjected to a cycloaddition reaction with the compound of the formula (III) to obtain the compound of the formula (I);
Figure PCTCN2021133602-appb-000033
Figure PCTCN2021133602-appb-000033
其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12具有如上所述的定义。L选自离去基团，例如Cl或Br。 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are as defined above. L is selected from leaving groups such as Cl or Br.
根据本发明的实施方案，所述反应可以在碱存在下进行，所述碱可以为有机碱，例如选自吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)或二异丙基乙胺(DIEA)中的至少一种；According to an embodiment of the present invention, the reaction may be carried out in the presence of a base, which may be an organic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropyl At least one of ethylamine (DIEA);
根据本发明的实施方案，所述反应在溶剂中进行，所述溶剂选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、二氧六环或甲苯中的至少一种；According to an embodiment of the present invention, the reaction is carried out in a solvent selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dioxane or toluene at least one;
根据本发明的实施方案，所述反应温度可以为-5～120℃，例如0-50℃，如15～50℃。According to an embodiment of the present invention, the reaction temperature may be -5-120°C, such as 0-50°C, such as 15-50°C.
根据本发明的实施方案，所述环加成反应可在制备偶极前体II的一锅反应中进行或在分离后的偶极前体II存在下进行。According to an embodiment of the present invention, the cycloaddition reaction can be carried out in a one-pot reaction to prepare the dipole precursor II or in the presence of the isolated dipole precursor II.
所述反应可参考文献例如1,3 dipolar Cycloaddition Chemistry,Padwa(编),Wiley,New York,1984；Heterocycles.1990,30,719；J.Agric.Food.Chem.2005,53,8639-8643或WO2006090234。The reaction can be referred to literature such as 1,3 dipolar Cycloaddition Chemistry, Padwa (ed.), Wiley, New York, 1984; Heterocycles. 1990, 30, 719; J. Agric. Food. Chem.
通常，此反应得到非对映体异构体的混合物，其可通过柱色谱法分离。光学活性的异噁唑啉可通过合适的前体或最终产物的手性HPLC得到，以及还可通过对映选择性反应得到，例如通过酶促酯或酰胺切断反应得到或通过在亲偶极体上使用手性助剂得到，如由J.Org.Chem.1988，53，2468所描述的。Typically, this reaction yields a mixture of diastereoisomers, which can be separated by column chromatography. Optically active isoxazolines can be obtained by chiral HPLC of suitable precursors or final products, and can also be obtained by enantioselective reactions, such as by enzymatic ester or amide cleavage reactions or by obtained using chiral auxiliaries, as described by J. Org. Chem. 1988, 53, 2468.
根据本发明的实施方案，当式(I)化合物中R 12为COOR 13，且R 13不为H时，可通过本领域技术人员已知的水解反应制备得到R 12为COOH的式(I)所示的化合物。 According to an embodiment of the present invention, when R 12 in the compound of formula (I) is COOR 13 and R 13 is not H, formula (I) in which R 12 is COOH can be prepared by a hydrolysis reaction known to those skilled in the art compounds shown.
Figure PCTCN2021133602-appb-000034
Figure PCTCN2021133602-appb-000034
R 12＝COOR 13，且R 13不为H R 12 =COOR 13 , and R 13 is not H
根据本发明的实施方案，所述水解反应可以在碱存在下进行，所述碱选自氢氧化钠、氢氧化钾或氢氧化锂中的至少一种；或者在二氯甲烷中用酸如三氟乙酸处理；According to an embodiment of the present invention, the hydrolysis reaction can be carried out in the presence of a base selected from at least one of sodium hydroxide, potassium hydroxide or lithium hydroxide; or an acid such as trichloromethane in dichloromethane Fluoroacetic acid treatment;
根据本发明的实施方案，所述水解反应的温度可以为0～150℃，例如15～80℃。According to an embodiment of the present invention, the temperature of the hydrolysis reaction may be 0-150°C, eg, 15-80°C.
根据本发明的实施方案，当式(I)化合物中R 12为COOH时，可通过第一步卤化反应、再经过第二步酯化反应制备得到R 12为COOR 13的式(I)所示的化合物； According to an embodiment of the present invention, when R 12 in the compound of formula (I) is COOH, the formula (I) in which R 12 is COOR 13 can be prepared through the first step of halogenation reaction and then through the second step of esterification reaction compound of;
Figure PCTCN2021133602-appb-000035
Figure PCTCN2021133602-appb-000035
根据本发明的实施方案，第一步卤化反应所述卤化剂选自亚硫酰氯、草酰氯或二氯亚砜；According to an embodiment of the present invention, the halogenating agent in the first step of halogenation reaction is selected from thionyl chloride, oxalyl chloride or thionyl chloride;
根据本发明的实施方案，第一步卤化反应的温度可以为0～100℃，例如0-50℃，如0～30℃；According to an embodiment of the present invention, the temperature of the first-step halogenation reaction may be 0-100°C, such as 0-50°C, such as 0-30°C;
根据本发明的实施方案，第二步酯化反应可以在碱的存在下进行，所述碱可选自有机碱或无机碱，如吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)、二异丙基乙胺(DIEA)、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾或氢化钠等中的一种、两种或者更多种。优选的溶剂可为N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二氧六环、甲苯、二氯甲烷或1,2-二氯乙烷中的一种、两种或者更多种；According to an embodiment of the present invention, the second-step esterification reaction may be carried out in the presence of a base, which may be selected from organic bases or inorganic bases, such as pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) ), diisopropylethylamine (DIEA), one, two or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium hydride. The preferred solvent can be one or both of N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, toluene, dichloromethane or 1,2-dichloroethane species or more;
根据本发明的实施方案，第二步酯化反应的温度可以为0～120℃，例如0-50℃，如15～30℃。According to an embodiment of the present invention, the temperature of the second-step esterification reaction may be 0-120°C, for example, 0-50°C, such as 15-30°C.
或通过羧酸酯化反应得到。Or obtained by carboxylic acid esterification.
Figure PCTCN2021133602-appb-000036
Figure PCTCN2021133602-appb-000036
根据本发明的实施方案，所述羧酸酯化反应可以在缩合剂存在下进行，所述缩合剂选自N,N′-二环己基碳二亚胺(DCC)、N,N′-二异丙基碳二亚胺(DIC)、1-羟基苯并***(HOBT)、2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)或六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBOP)中的至少一种；According to an embodiment of the present invention, the carboxylic acid esterification reaction may be carried out in the presence of a condensing agent selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC), N,N'-di Isopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBT), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea at least one of hexafluorophosphate (HATU) or benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (PyBOP);
根据本发明的实施方案，所述羧酸酯化反应可以在碱存在下进行，所述碱可以为无机碱， 例如选自吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)或二异丙基乙胺(DIEA)中的至少一种；According to an embodiment of the present invention, the carboxylic acid esterification reaction may be carried out in the presence of a base, which may be an inorganic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or At least one of diisopropylethylamine (DIEA);
根据本发明的实施方案，所述羧酸酯化反应在溶剂中进行，所述溶剂选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、2-甲基四氢呋喃、二氧六环、乙腈、甲苯、二氯甲烷或1,2-二氯乙烷中的至少一种；According to an embodiment of the present invention, the carboxylic acid esterification reaction is carried out in a solvent selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, 2-methyl At least one of tetrahydrofuran, dioxane, acetonitrile, toluene, dichloromethane or 1,2-dichloroethane;
根据本发明的实施方案，所述羧酸酯化反应的温度可以为-5～120℃，例如0-50℃，如15～30℃。According to an embodiment of the present invention, the temperature of the carboxylic acid esterification reaction may be -5-120°C, for example, 0-50°C, such as 15-30°C.
根据本发明的实施方案，当式(I)化合物中R 12为COOH时，可通过第一步卤化反应、再经过第二步缩合反应制备得到R 12为CONR 14R 15的式(I)所示的化合物； According to an embodiment of the present invention, when R 12 in the compound of formula (I) is COOH, the compound of formula (I) wherein R 12 is CONR 14 R 15 can be prepared through the first step of halogenation reaction and then through the second step of condensation reaction. compound shown;
Figure PCTCN2021133602-appb-000037
Figure PCTCN2021133602-appb-000037
根据本发明的实施方案，第一步卤化反应所述卤化剂选自亚硫酰氯、草酰氯或二氯亚砜；According to an embodiment of the present invention, the halogenating agent in the first step of halogenation reaction is selected from thionyl chloride, oxalyl chloride or thionyl chloride;
根据本发明的实施方案，第一步卤化反应的温度可以为0～100℃，例如0-50℃，如0～30℃；According to an embodiment of the present invention, the temperature of the first-step halogenation reaction may be 0-100°C, such as 0-50°C, such as 0-30°C;
根据本发明的实施方案，第二步缩合反应可以在碱的存在下进行，所述碱可选自有机碱或无机碱，如吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)、二异丙基乙胺(DIEA)、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾或氢化钠等中的一种、两种或者更多种。优选的溶剂可为N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二氧六环、甲苯、二氯甲烷或1,2-二氯乙烷中的一种、两种或者更多种；According to an embodiment of the present invention, the second-step condensation reaction may be carried out in the presence of a base, which may be selected from organic or inorganic bases, such as pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) , diisopropylethylamine (DIEA), one, two or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium hydride. The preferred solvent can be one or both of N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, toluene, dichloromethane or 1,2-dichloroethane species or more;
根据本发明的实施方案，第二步缩合反应的温度可以为0～120℃，例如0-50℃，如15～30℃。According to an embodiment of the present invention, the temperature of the condensation reaction in the second step may be 0-120°C, for example, 0-50°C, such as 15-30°C.
或羧酸与胺直接通过缩合反应得到。Or carboxylic acid and amine can be directly obtained by condensation reaction.
Figure PCTCN2021133602-appb-000038
Figure PCTCN2021133602-appb-000038
根据本发明的实施方案，所述缩合反应可以在缩合剂存在下进行，所述缩合剂选自N,N′-二环己基碳二亚胺(DCC)、N,N′-二异丙基碳二亚胺(DIC)、1-羟基苯并***(HOBT)、2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)或六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBOP)中的至少一种；According to an embodiment of the present invention, the condensation reaction may be carried out in the presence of a condensing agent selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropyl Carbodiimide (DIC), 1-Hydroxybenzotriazole (HOBT), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphoric acid at least one of benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (HATU) or hexafluorophosphate (PyBOP);
根据本发明的实施方案，所述缩合反应可以在碱存在下进行，所述碱可以为无机碱，例如选自吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)或二异丙基乙胺(DIEA)中的至少一种；According to an embodiment of the present invention, the condensation reaction may be carried out in the presence of a base, which may be an inorganic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropyl At least one of diethylamine (DIEA);
根据本发明的实施方案，所述缩合反应在溶剂中进行，所述溶剂选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、2-甲基四氢呋喃、二氧六环、乙腈、甲苯、二氯甲烷或1,2-二氯乙烷中的至少一种；According to an embodiment of the present invention, the condensation reaction is carried out in a solvent selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethy At least one of oxane, acetonitrile, toluene, dichloromethane or 1,2-dichloroethane;
根据本发明的实施方案，所述缩合反应的温度可以为-5～120℃，例如0-50℃，如15～30℃。According to an embodiment of the present invention, the temperature of the condensation reaction may be -5-120°C, such as 0-50°C, such as 15-30°C.
根据本发明的实施方案，式(III)所示的化合物可以作为商品购买或用本领域技术人员所知方法制备。According to an embodiment of the present invention, the compound represented by formula (III) can be purchased as a commercial product or prepared by a method known to those skilled in the art.
根据本发明的实施方案，式(II)所示的化合物的制备方法，包括如下步骤：According to an embodiment of the present invention, the preparation method of the compound represented by formula (II) comprises the following steps:
Figure PCTCN2021133602-appb-000039
Figure PCTCN2021133602-appb-000039
(1)式(VI)化合物与式(VII)化合物发生SUZUKI偶联反应得到式(V)化合物；(1) The compound of formula (VI) and the compound of formula (VII) undergo SUZUKI coupling reaction to obtain the compound of formula (V);
(2)式(V)化合物与羟胺或盐酸羟胺反应得到式(IV)化合物；(2) the compound of formula (V) reacts with hydroxylamine or hydroxylamine hydrochloride to obtain the compound of formula (IV);
(3)式(IV)化合物发生氯化反应得到式(II)化合物；(3) the compound of formula (IV) undergoes chlorination reaction to obtain the compound of formula (II);
其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、L具有如上所述的定义；L 1选自离去基团，例如Cl、Br、I或F；L选自离去基团，例如Cl或Br。 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , L are as defined above; L 1 is selected from a leaving group such as Cl, Br, I or F ; L is selected from leaving groups such as Cl or Br.
根据本发明的实施方案，步骤(1)可以在催化剂存在下进行，所述催化剂选自四(三苯基膦)钯、乙酸钯或双(三苯基膦)二氯化钯；According to an embodiment of the present invention, step (1) can be carried out in the presence of a catalyst selected from tetrakis(triphenylphosphine)palladium, palladium acetate or bis(triphenylphosphine)palladium dichloride;
根据本发明的实施方案，步骤(1)可以在碱存在下进行，所述碱选自碳酸钠、碳酸钾、吡啶、三乙胺或4-(二甲氨基)吡啶中的一种、两种或者更多种；所述在溶剂选自甲苯、四氢呋喃、N,N-二甲基甲酰胺或水中的一种、两种或者更多种；所述反应的温度可以为20～150℃，例如50～80℃。According to an embodiment of the present invention, step (1) can be carried out in the presence of a base selected from one or both of sodium carbonate, potassium carbonate, pyridine, triethylamine or 4-(dimethylamino)pyridine or more; the solvent is selected from one, two or more of toluene, tetrahydrofuran, N,N-dimethylformamide or water; the temperature of the reaction can be 20-150°C, for example 50～80℃.
根据本发明的实施方案，步骤(2)可以在碱存在下进行，所述碱选自有机碱，如三乙胺、乙酸钠，或无机碱如碳酸氢钠中的一种、两种或者更多种；所述反应溶剂选自甲醇、乙醇等醇类溶剂或水或它们的混合物；所述反应的温度可以为0～100℃，优选15～30℃。According to an embodiment of the present invention, step (2) can be carried out in the presence of a base selected from one, two or more of organic bases such as triethylamine, sodium acetate, or inorganic bases such as sodium bicarbonate The reaction solvent is selected from alcohol solvents such as methanol, ethanol, or water or a mixture thereof; the reaction temperature can be 0-100°C, preferably 15-30°C.
根据本发明的实施方案，步骤(3)可以在卤化剂的存在下进行，所述卤化剂可以为N-氯代琥珀酰亚胺(NCS)或N-溴代琥珀酰亚胺(NBS)；所述反应的温度可以为0～100℃，例如15～50℃；According to an embodiment of the present invention, step (3) may be performed in the presence of a halogenating agent, which may be N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS); The temperature of the reaction can be 0-100°C, for example, 15-50°C;
根据本发明的实施方案，步骤(3)可以在碱存在下进行，所述碱选自三乙胺、吡啶、碳酸氢钠或碳酸钠中的至少一种；所述反应的温度可以为0～100℃，例如15～30℃。According to an embodiment of the present invention, step (3) can be carried out in the presence of a base selected from at least one of triethylamine, pyridine, sodium bicarbonate or sodium carbonate; the temperature of the reaction can be 0～ 100°C, for example, 15 to 30°C.
根据本发明的实施方案，式(VII)所示的硼酸与式(VI)所示的卤化物可作为商品购买获得或用本领域技术人员所知方法制备。According to an embodiment of the present invention, the boronic acid represented by formula (VII) and the halide represented by formula (VI) can be purchased as commercial products or prepared by methods known to those skilled in the art.
所述反应可参考文献WO2014048827或WO2006090234。The reaction can be referred to in WO2014048827 or WO2006090234.
本文中式(I)化合物及其原料的制备可根据各情况下适合的反应条件和原料的选择，可以例如在一步反应中用根据本发明的另一取代基仅替换一个取代基，或可在相同反应步骤中用根据本发明的其他取代基替换多个取代基。The compounds of formula (I) and their starting materials can be prepared herein according to the appropriate reaction conditions and the choice of starting materials in each case, for example, in a one-step reaction by replacing only one substituent with another substituent according to the invention, or it can be carried out in the same Various substituents are replaced in the reaction steps with other substituents according to the present invention.
如果各化合物不可经由上述路线得到，则它们可通过衍生其他化合物或通过将所述合成路线常规变化而制备。If individual compounds are not obtainable via the above-mentioned routes, they can be prepared by derivatizing other compounds or by routine variations of the described synthetic routes.
反应完成后可以将反应混合物以常规方式后处理，如通过与水混合、分离相以及合适的话通过色谱法例如在氧化铝或硅胶上提纯粗产物。After completion of the reaction, the reaction mixture can be worked up in the customary manner, eg by mixing with water, separating the phases and, if appropriate, purifying the crude product by chromatography, eg on alumina or silica gel.
本发明式(I)化合物药学上可接受的盐，其可以通过已知的方法来制备。例如通过适宜的碱处理得到式(I)化合物的盐。其制备方法如下：将式(I)化合物与碱如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化锌等在水、***或甲苯等溶剂中反应，可以很方便地得到式(I)化合物药学上可接受的盐。The pharmaceutically acceptable salts of the compounds of formula (I) of the present invention can be prepared by known methods. Salts of compounds of formula (I) are obtained, for example, by treatment with a suitable base. Its preparation method is as follows: react the compound of formula (I) with alkali such as sodium hydroxide, potassium hydroxide, calcium hydroxide, zinc hydroxide, etc. in solvents such as water, ether or toluene, and can easily obtain formula (I) A pharmaceutically acceptable salt of the compound.
以上制备方法可以获得式(I)化合物的异构体混合物，如需得到纯异构体，可采用常规方法如结晶或色谱法进行分离。The above preparation method can obtain a mixture of isomers of the compound of formula (I). If pure isomers are required, conventional methods such as crystallization or chromatography can be used for separation.
除非另外指明，上述所有反应可便利地在大气压力下或具体反应的自身压力下进行。All of the above reactions are conveniently carried out at atmospheric pressure or at the own pressure of the particular reaction unless otherwise indicated.
本发明还提供一种农药组合物，例如除草组合物，其包含作为活性成分的式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物中的一种、两种或者更多种。The present invention also provides a pesticide composition, such as a herbicidal composition, comprising as an active ingredient the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotopic label, One, two or more of nitrogen oxides, pharmaceutically acceptable salts or esters, solvates, or solvates of pharmaceutically acceptable salts.
根据本发明的实施方案，所述组合物中活性成分的重量百分含量为0.1-99.9％，例如为0.5-99％。According to an embodiment of the present invention, the weight percent content of the active ingredient in the composition is 0.1-99.9%, for example, 0.5-99%.
根据本发明的实施方案，所述组合物中还包括农业和/或林业和/或卫生上可接受的载体中的一种、两种或者更多种。According to embodiments of the present invention, one, two or more of agricultural and/or forestry and/or hygienically acceptable carriers are also included in the composition.
根据本发明的实施方案，所述组合物可以以制剂的形式施用。According to an embodiment of the present invention, the composition may be administered in the form of a formulation.
例如，式(I)所示化合物作为活性成分溶解或分散于载体中或配制成制剂以便作为除草使用时更易于分散。For example, the compound of formula (I) can be dissolved or dispersed as an active ingredient in a carrier or formulated so as to be easier to disperse when used as a herbicide.
根据本发明的实施方案，所述制剂包括但不限于如下形式：颗粒剂、可湿性粉剂、油悬剂、水悬剂、水乳剂、水剂、乳油或微胶囊等。According to the embodiments of the present invention, the formulations include but are not limited to the following forms: granules, wettable powders, oil suspensions, water suspensions, water emulsions, water preparations, emulsifiable concentrates or microcapsules and the like.
根据发明的实施方案，所述组合物中还可以加入一种液体或固体载体，及任选地表面活性剂。According to embodiments of the invention, a liquid or solid carrier, and optionally a surfactant, may also be added to the composition.
本发明还提供式(I)所示的化合物、其立体异构体、消旋体、互变异构体、氮氧化物或其药学上可接受的盐中的一种、两种或者更多种作为农药，例如除草剂的用途。其对宽范围的经济上重要的单子叶和双子叶一年生有害植物具有优异的除草功效。所述活性成分还有效地作用于由根茎、根状茎和其他多年生器官发芽并且难以防治的多年生杂草。The present invention also provides one, two or more of the compounds represented by formula (I), their stereoisomers, racemates, tautomers, nitrogen oxides or their pharmaceutically acceptable salts Use of species as pesticides, such as herbicides. It has excellent herbicidal efficacy against a wide range of economically important monocotyledonous and dicotyledonous annual harmful plants. The active ingredient also acts effectively on perennial weeds that sprout from rhizomes, rhizomes and other perennial organs and are difficult to control.
本发明还提供式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物中的一种、两种或者更多种在制备农药，例如制备除草剂中的用途。The present invention also provides compounds represented by formula (I), its stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or esters, solvates or Use of one, two or more of the solvates of the pharmaceutically acceptable salts in the preparation of pesticides, eg, herbicides.
根据本发明的实施方案，所述有效量为每公顷10克到1000克，优选有效量为每公顷20克到500克。According to an embodiment of the present invention, the effective amount is 10 grams to 1000 grams per hectare, preferably the effective amount is 20 grams to 500 grams per hectare.
本发明还提供一种防治不想要的植物的方法，包括将有效量的式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物，或将所述组合物施于不想要的植物(例如有害植物，如单子叶或双子叶杂草或不想要的作物植物)、想要的植物的种子或块茎或其他可繁殖部位(例如谷粒、种子或无性繁殖体，如块茎或带芽的枝条部位)或想要的植物的生长区域(例如栽培区域)。本发明化合物例如可以在播种前施用(如果合适，也通过掺入土壤中)、发芽前或发芽后施用。可通过本发明的化合物防治的单子叶和双子叶杂草植物群的一些代表性 具体实例如下，但并非意欲将列举限于特定种类。The present invention also provides a method for controlling unwanted plants, comprising adding an effective amount of the compound represented by formula (I), its stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides drug, a pharmaceutically acceptable salt or ester, a solvate or a solvate of a pharmaceutically acceptable salt, or applying the composition to an unwanted plant (e.g. a harmful plant such as a monocot or dicot grasses or unwanted crop plants), seeds or tubers or other reproductive parts of a desired plant (e.g. grains, seeds or vegetative propagules such as tubers or shoot parts with buds) or growing areas of a desired plant (eg cultivation area). The compounds according to the invention can be applied, for example, before sowing (if appropriate also by incorporation into the soil), before or after emergence. Some representative specific examples of monocotyledonous and dicotyledonous weed flora that can be controlled by the compounds of the present invention are as follows, but the enumeration is not intended to be limited to a particular species.
例如在单子叶有害植物种中，所述方法可防治山羊草属(Aegilops)、冰草属(Agropyron)、剪股颖属(Agrostis)、看麦娘属(Alopecurus)、Apera、燕麦属(Avena)、臂形草属(Brachiaria)、雀麦属(Bromus)、蒺藜草属(Cenchrus)、鸭跖草属(Commelina)、狗牙根属(Cynodon)、莎草属(Cyperus)、龙爪茅属(Dactyloctenium)、马唐属(Digitaria)、稗属(Echinochloa)、荸荠属(Eleocharis)、蟋蟀草属(Eleusine)、画眉草属(Eragrostis)、野黍属(Eriochloa)、羊茅属(Festuca)、飘拂草属(Fimbristylis)、白茅属(Imperata)、鸭嘴草属(Ischaemum)、异蕊花属(Heteranthera)、千金子属(Leptochloa)、黑麦草属(Lolium)、雨久花属(Monochoria)、黍属(Panicum)、雀稗属(Paspalum)、虉草属(Phalaris)、梯牧草属(Phleum)、早熟禾属(Poa)、筒轴茅属(Rottboellia)、慈姑属(Sagittaria)、莞草属(Scirpus)、狗尾草属(Setaria)、高粱属(Sorghum)和尖瓣花属(Sphenoclea)。For example in monocotyledonous pest species, the method can control Aegilops, Agropyron, Agrostis, Alopecurus, Apera, Avena ), Brachiaria, Bromus, Cenchrus, Commelina, Cynodon, Cyperus, Cynodon Dactyloctenium, Digitaria, Echinochloa, Eleocharis, Eleusine, Eragrostis, Eriochloa, Festuca , Fimbristylis, Imperata, Ischaemum, Heteranthera, Leptochloa, Lolium, Monochoria ), Panicum, Paspalum, Phalaris, Phleum, Poa, Rottboellia, Sagittaria, Scirpus, Setaria, Sorghum and Sphenoclea.
对于双子叶杂草种，所述方法可防治以下种，例如苘麻属(Abutilon)、苋属(Amaranthus)、豚草属(Ambrosia)、Anoda属、春黄菊属(Anthemis)、Aphanes属、蒿属(Artemisia)、滨藜属(Atriplex)、雏菊属(Bellis)、鬼针属(Bidens)、荠属(Capsella)、飞廉属(Carduus)、决明属(Cassia)、矢车菊属(Centaurea)、藜属(Chenopodium)、蓟属(Cirsium)、旋花属(Convolvulus)、曼陀罗属(Datura)、山蚂蝗属(Desmodium)、刺酸模属(Emex)、牻牛儿苗属(Erodium)、糖芥属(Erysimum)、大戟属(Euphorbia)、鼬瓣花属(Galeopsis)、牛膝菊属(Galinsoga)、拉拉藤属(Galium)、老鹳草属(Geranium)、芙蓉属(Hibiscus)、番薯属(Ipomoea)、地肤属(Kochia)、野芝麻属(Lamium)、独行菜属(Lepidium)、母草属(Lindernia)、母菊属(Matricaria)、薄荷属(Mentha)、山靛属(Mercurialis)、Mullugo属、勿忘我属(Myosotis)、罂粟属(Papaver)、牵牛属(Pharbitis)、车前属(Plantago)、蓼属(Polygonum)、马齿苋属(Portulaca)、毛茛属(Ranunculus)、萝卜属(Raphanus)、蔊菜属(Rorippa)、节节菜属(Rotala)、酸模属(Rumex)、猪毛菜属(Salsola)、千里光属(Senecio)、田菁属(Sesbania)、黄花稔属(Sida)、白芥属(Sinapis)、茄属(Solanum)、苦苣菜属(Sonchus)、尖瓣花属(Sphenoclea)、繁缕属(Stellaria)、蒲公英属(Taraxacum)、菥蓂属(Thlaspi)、车轴草属(Trifolium)、荨麻属(Urtica)、婆婆纳属(Veronica)、堇菜属(Viola)、苍耳属(Xanthium)。For dicotyledonous weed species, the method can control species such as Abutilon, Amaranthus, Ambrosia, Anoda, Anthemis, Aphanes, Artemisia Genus Artemisia, Atriplex, Bellis, Bidens, Capsella, Carduus, Cassia, Centaurea ( Centaurea, Chenopodium, Cirsium, Convolvulus, Datura, Desmodium, Emex, Geranium (Erodium), Erysimum, Euphorbia, Galeopsis, Galinsoga, Galium, Geranium, Hibiscus, Ipomoea, Kochia, Lamium, Lepidium, Lindernia, Matricaria, Mint Mentha, Mercurialis, Mullugo, Myosotis, Papaver, Pharbitis, Plantago, Polygonum, Portulaca Portulaca, Ranunculus, Raphanus, Rorippa, Rotala, Rumex, Salsola, Senecio ), Sesbania, Sida, Sinapis, Solanum, Sonchus, Sphenoclea, Stellaria ), Taraxacum, Thlaspi, Trifolium, Urtica, Veronica, Viola, Xanthium.
如果将本发明的活性化合物结合物在芽前施用于土壤表面，则杂草幼苗的出苗被完全阻止，或者杂草生长直至达到子叶期，但随后其生长停止，并最终在三至四周彻底死亡。If the active compound combinations according to the invention are applied to the soil surface pre-emergence, the emergence of weed seedlings is completely prevented, or the weeds grow until they reach the cotyledon stage, but then their growth stops and finally dies out completely in three to four weeks .
如果将所述活性化合物苗后施用于植物的绿色部位，处理后生长停止，有害植物停留在施用时间点的生长阶段，或在一定时间后彻底死亡，从而能够非常早的以持久的方式消除对作物植物有害的杂草的竞争。If the active compounds are applied to the green parts of the plants post-emergence, the growth stops after the treatment, the harmful plants remain in the growth phase at the point of application, or die completely after a certain time, so that the harmful plants can be eliminated very early and in a lasting manner. Crop plants compete with harmful weeds.
本发明的化合物具有出色的抵抗单子叶和双子叶杂草的除草活性，但对很多想要的植物或者经济上重要的作物，如果有的话，也只具有可忽略程度的损害，这取决于本发明具体化合物的结构及其施用率。本文中的想要的植物或者经济上重要的作物，例如以下属的双子叶作物：花生属(Arachis)、甜菜属(Beta)、芸苔属(Brassica)、黄瓜属(Cucumis)、南瓜属(Cucurbita)、向日葵属(Helianthus)、胡萝卜属(Daucus)、大豆属(Glycine)、棉属(Gossypium)、番薯属(Ipomoea)、莴苣属(Lactuca)、亚麻属(Linum)、番茄属(Lycopersicon)、芒属(Miscanthus)、烟草属(Nicotiana)、菜豆属(Phaseolus)、豌豆属(Pisum)、茄属(Solanum)、 蚕豆属(Vicia)；或以下属的单子叶作物：葱属(Allium)、凤梨属(Ananas)、天门冬属(Asparagus)、燕麦属(Avena)、大麦属(Hordeum)、稻属(Oryza)、黍属(Panicum)、甘蔗属(Saccharum)、黑麦属(Secale)、高粱属(Sorghum)、小黑麦属(Triticale)、小麦属(Triticum)和玉蜀黍属(Zea)。由于这些原因，因此本发明化合物非常适合用于在作物植物种，例如农业上有用的植物或观赏植物中选择性地防治不想要的植物的生长。The compounds of the present invention have excellent herbicidal activity against monocotyledonous and dicotyledonous weeds, but have negligible, if any, damage to many desirable plants or economically important crops, depending on Structures of specific compounds of the invention and their application rates. Desirable plants or economically important crops herein, such as dicotyledonous crops of the following genera: Arachis, Beta, Brassica, Cucumis, Cucurbita ( Cucurbita, Helianthus, Daucus, Glycine, Gossypium, Ipomoea, Lactuca, Linum, Lycopersicon , Miscanthus, Nicotiana, Phaseolus, Pisum, Solanum, Vicia; or monocotyledonous crops of the following genera: Allium , Ananas, Asparagus, Avena, Hordeum, Oryza, Panicum, Saccharum, Secale , Sorghum, Triticale, Triticum and Zea. For these reasons, the compounds of the present invention are very suitable for selectively controlling the growth of unwanted plants in crop plant species, such as agriculturally useful plants or ornamental plants.
此外，本发明的化合物(取决于它们特定的化学结构和使用的施用率)对作物植物还具有出色的生长调节性能。它们以调控作用干预植物自身的新陈代谢，从而可用于定向影响植物成分和利于采收，例如通过引发脱水和矮化生长。此外，它们通常还适用于一般性的防治和抑制不希望的营养生长而不杀死植物。抑制营养生长由于例如可减少或完全防止倒伏而对许多单子叶和双子叶作物起到到重要作用。In addition, the compounds of the present invention (depending on their specific chemical structure and the application rates used) also have excellent growth regulating properties on crop plants. They intervene in the plant's own metabolism in a regulatory role and can thus be used to influence plant composition in a targeted manner and facilitate harvesting, for example by inducing dehydration and stunted growth. In addition, they are generally also suitable for general control and inhibition of undesired vegetative growth without killing the plants. Inhibition of vegetative growth plays an important role in many monocotyledonous and dicotyledonous crops by, for example, reducing or completely preventing lodging.
由于其除草和植物生长调节性质，所述化合物可用于防治已知植物作物或有待通过常规诱变或基因方式开发和改性的耐受作物植物中的有害植物。一般而言，转基因植物的特征为特别有利的性质，例如对某些农药、特别是某些除草剂的抗性，对于植物病害或植物病害的病原体的抗性，所述病原体例如某些昆虫或微生物如真菌、细菌或病毒。其他具体特性涉及例如采收物的数量、品质、可储存性、组成和具体成分。例如，已知具有增加的淀粉含量或改变的淀粉品质的转基因植物，或者在采收物中含有不同的脂肪酸组成的转基因植物。其他具体特性可为对非生物胁迫因素—例如热、冷、干旱、盐度和紫外线辐射—的抗性。Due to their herbicidal and plant growth regulating properties, the compounds can be used to control harmful plants in known plant crops or in tolerant crop plants to be developed and modified by conventional mutagenesis or genetic means. In general, transgenic plants are characterized by particularly advantageous properties, such as resistance to certain pesticides, especially certain herbicides, resistance to plant diseases or pathogens of plant diseases, such as certain insects or Microorganisms such as fungi, bacteria or viruses. Other specific properties relate, for example, to the quantity, quality, storability, composition and specific composition of the harvested material. For example, transgenic plants are known that have increased starch content or altered starch quality, or that contain a different fatty acid composition in the harvest. Other specific characteristics may be resistance to abiotic stress factors such as heat, cold, drought, salinity and UV radiation.
优选将本发明的式(I)化合物或其盐用于经济上重要的有用植物和观赏性植物转基因作物中，所述有用植物和观赏性植物例如谷类如小麦、大麦、黑麦、燕麦、黍、稻、木薯和玉米，或其他作物甜菜、棉花、大豆、油菜、马铃薯、番茄、豌豆以及其他蔬菜。The compounds of formula (I) according to the invention or their salts are preferably used in transgenic crops of economically important useful plants and ornamental plants such as cereals such as wheat, barley, rye, oats, millet , rice, cassava and corn, or other crops beet, cotton, soybean, rape, potato, tomato, pea and other vegetables.
优选将本发明的式(I)化合物或其盐用作有用植物作物中的除草剂，所述有用植物作物对除草剂的植物毒性效果具有抗性或以通过重组方式对除草剂的植物毒性效果具有抗性。The compounds of the formula (I) according to the invention or their salts are preferably used as herbicides in crops of useful plants which are resistant to the phytotoxic effects of the herbicides or in a recombinant manner to the phytotoxic effects of the herbicides Resistant.
制备与现有植物相比具有改性特征的新植物的常规方法有，例如常规育种方法和产生突变体。或者，可使用重组方法产生具有改性特征的新植物(参见，例如EP-A-0221044、EP-A-0131624)。例如多种情况已描述：Conventional methods of producing new plants with modified characteristics compared to existing plants are, for example, conventional breeding methods and the generation of mutants. Alternatively, recombinant methods can be used to generate new plants with modified characteristics (see, eg, EP-A-0221044, EP-A-0131624). For example several situations have been described:
-重组改性作物植物以改性植物中合成的淀粉(例如WO 92/11376、WO 92/14827、WO 91/19806)，- recombinant modification of crop plants to modify starches synthesized in plants (eg WO 92/11376, WO 92/14827, WO 91/19806),
-对其他除草剂例如磺酰脲有抗性的转基因作物植物(EP-A-0257993、US-A-5013659)，- transgenic crop plants resistant to other herbicides such as sulfonylureas (EP-A-0257993, US-A-5013659),
-能够产生使植物对某些有害物具有抗性的苏云金杆菌毒素(Bt毒素)的转基因作物植物(EP-A-0142924、EP-A-0193259)，- transgenic crop plants capable of producing Bacillus thuringiensis toxins (Bt toxins) that make plants resistant to certain pests (EP-A-0142924, EP-A-0193259),
-具有改性的脂肪酸组成的转基因作物植物(WO 91/13972)，- transgenic crop plants with modified fatty acid composition (WO 91/13972),
-含有新成分或次生化合物—例如提供提高的病害抗性的新植物抗毒素—的基因改性作物植物(EPA 309862、EPA0464461)，- genetically modified crop plants containing new constituents or secondary compounds, such as new phytoalexins providing improved disease resistance (EPA 309862, EPA 0464461),
-光呼吸作用降低—其提供更高的产率且具有更高的胁迫耐受性—的基因改性植物(EPA0305398)，- genetically modified plants with reduced photorespiration, which provide higher yields and have higher stress tolerance (EPA0305398),
-产生制药或诊断上重要的蛋白质的转基因作物植物(“分子制药”)，- genetically modified crop plants producing pharmaceutical or diagnostically important proteins ("molecular pharmaceuticals"),
-特征为产率更高或质量更好的转基因作物植物，- Transgenic crop plants characterized by higher yields or better quality,
-特征为具有例如以上提及的新特性组合的转基因作物植物(“基因叠加”)。- Transgenic crop plants ("gene stacks") characterized as having novel combinations of properties such as those mentioned above.
大量的可用于产生具有经修饰的特性的新转基因植物的分子生物技术原则上是已知的，参见例如I.Potrykus和G.Spangenberg(eds.)Gene Transfer to Plants,Springer Lab Manual(1995)，Springer Verlag Berlin，Heidelberg or Christou，“Trends in Plant Science”1(1996)423-431)。Numerous molecular biotechnologies that can be used to generate new transgenic plants with modified properties are known in principle, see e.g. I. Potrykus and G. Spangenberg (eds.) Gene Transfer to Plants, Springer Lab Manual (1995), Springer Verlag Berlin, Heidelberg or Christou, "Trends in Plant Science" 1 (1996) 423-431).
为进行此类重组操作，可将允许诱变或通过DNA序列重组序列改性的核酸分子加入质粒中。例如，可以借助标准方法进行碱基交换，以除去子序列或添加天然或合成序列。可加入连接物或接头以使DNA片段彼此连接，参见，例如Sambrook et al.，1989，Molecular Cloning，ALaboratory Manual，第2版，Cold Spring Harbor Laboratory Press，Cold Spring Harbor，NY；或Winnacker“Gene und Klone”[Genes and Clones]，VCH Weinheim，第2版，1996。To perform such recombination manipulations, nucleic acid molecules that permit mutagenesis or sequence modification by DNA sequence recombination can be added to plasmids. For example, base exchange to remove subsequences or add natural or synthetic sequences can be performed by standard methods. Linkers or linkers can be added to ligate DNA fragments to each other, see, e.g., Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; or Winnacker "Gene und Klone" [Genes and Clones], VCH Weinheim, 2nd ed., 1996.
例如，通过表达至少一种合适的反义RNA，正义RNA实现共抑制效果，或通过表达至少一种具体分开基因产物的转录本的适当构成的核酶，可成功产生具有降低以上提及的基因产物活性的植物细胞。For example, by expressing at least one suitable antisense RNA, a sense RNA that achieves a co-suppressive effect, or by expressing at least one ribozyme of an appropriate composition that specifically separates the transcripts of the gene products, the above-mentioned genes can be successfully produced with reduced Product active plant cells.
为此，可以首先使用包含基因产物的所有编码序列，包括任意可能存在的旁侧序列的DNA分子，其次使用仅包含部分编码序列的DNA分子，对于这些部分需要足够的长度以引起细胞内的反义作用。还可以使用与基因产物的编码序列具有高度同源性的DNA序列，所述基因产物与其并不完全相同。For this purpose, a DNA molecule containing all of the coding sequence of the gene product, including any flanking sequences that may be present, can be used first, and a DNA molecule containing only part of the coding sequence, for which parts need to be of sufficient length to cause intracellular reactions righteous effect. It is also possible to use DNA sequences that have a high degree of homology to the coding sequences of gene products that are not identical thereto.
当植物中表达核酸分子时，合成的蛋白质可位于植物细胞的任意区室中。但为使其位于具体区室中，可以例如使编码区域与确保在特定隔室中位置的DNA序列连接。此类序列是本领域技术人员已知的(参见，例如Braun et al.，EMBO J.11(1992)，3219-3227；Wolter et al.，Proc.Natl.Acad.Sci.USA 85(1988)，846-850；Sonnewald et al.，Plant J.1(1991)，95-106)。核酸分子还可在植物细胞的细胞器中表达。When a nucleic acid molecule is expressed in a plant, the synthesized protein can be located in any compartment of the plant cell. However, in order to locate it in a specific compartment, the coding region can for example be linked to a DNA sequence that ensures its location in a specific compartment. Such sequences are known to those skilled in the art (see, eg, Braun et al., EMBO J. 11 (1992), 3219-3227; Wolter et al., Proc. Natl. Acad. Sci. USA 85 (1988) , 846-850; Sonnewald et al., Plant J. 1 (1991), 95-106). Nucleic acid molecules can also be expressed in organelles of plant cells.
转基因植物细胞可通过已知技术再生以得到完整植物。原则上，转基因植物可以是任意需要的植物种的植物，即单子叶和双子叶植物。因此，可通过过表达、抑制(suppression or inhibition)同源(＝天然)基因或基因序列，或表达异源(＝外源)基因或基因序列得到转基因植物。Transgenic plant cells can be regenerated by known techniques to yield whole plants. In principle, transgenic plants can be plants of any desired plant species, ie monocotyledonous and dicotyledonous plants. Thus, transgenic plants can be obtained by overexpressing, suppressing or inhibiting homologous (=natural) genes or gene sequences, or expressing heterologous (=foreign) genes or gene sequences.
本发明的式(I)化合物或其盐可优选用于对所使用的化合物有耐受性或被制成具有耐受性的转基因作物。The compounds of formula (I) according to the invention or their salts can preferably be used in transgenic crops that are tolerant to the compounds used or made tolerant.
优选地，本发明的式(I)化合物或其盐还可用于对以下物质具有抗性的转基因作物：生长物质，例如麦草畏；或分别抑制植物必需酶，例如乙酰乳酸合成酶(ALS)、EPSP合成酶、谷氨酰胺合成酶(GS)或羟苯基丙酮酸双加氧酶(HPPD)的除草剂；选自磺酰脲、草甘膦、草胺膦或苯甲酰基异噁唑和类似活性化合物的除草剂。Preferably, the compounds of formula (I) of the present invention or their salts can also be used in transgenic crops resistant to growth substances such as dicamba; or inhibition of plant essential enzymes such as acetolactate synthase (ALS), Herbicides against EPSP synthase, glutamine synthase (GS) or hydroxyphenylpyruvate dioxygenase (HPPD); selected from sulfonylurea, glyphosate, glufosinate or benzoylisoxazole and Herbicides with similar active compounds.
因此，本发明还提供了—如果合适，在有用植物作物中，优选在非耕地上或在栽培作物中—这样一种防治不想要的植物的方法，其中将(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或其溶剂合物施用于有害植物、植物部位或其植物种子、或栽培区域。Accordingly, the present invention also provides - if appropriate, in crops of useful plants, preferably on non-arable land or in cultivated crops - such a method for controlling unwanted plants, wherein a compound of (I), its Stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or solvates thereof are applied to harmful plants, plant parts or plant seeds thereof, or to a cultivated area.
本发明还提供了式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或其溶剂合物用于防治——如果合适，在有益植物作物中，优选在非耕地上或在栽培作物中——有害植物的用途。The present invention also provides the compound represented by formula (I), its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvates thereof for use For the control - if appropriate, in crops of beneficial plants, preferably on non-arable land or in cultivated crops - the use of harmful plants.
由于其积极的特性，式(I)化合物可有利地用于保护耕地和非耕地中重要的作物，以及人类常去的环境免于有害杂草的侵害。Due to their positive properties, the compounds of formula (I) can advantageously be used to protect important crops in cultivated and non-cultivated land, as well as the environment frequented by humans, from harmful weeds.
为获得理想效果，式(I)化合物的用量因各种因素而改变，例如所用化合物、预保护的作 物、有害杂草的类型、感染程度、气候条件、施药方法和采用的剂型。The amount of the compound of formula (I) to be used to obtain the desired effect will vary depending on factors such as the compound used, the crop to be pre-protected, the type of noxious weeds, the degree of infection, the climatic conditions, the method of application and the dosage form employed.
本文中所述剂型或组合物成分的选择应与有效成分的物理性质，应用方式和环境因素例如土壤类型，湿度与温度相一致。The formulation or composition ingredients described herein should be selected in accordance with the physical properties of the active ingredient, the mode of application and environmental factors such as soil type, humidity and temperature.
有用的剂型包括液剂如溶液(包括乳油)，悬浮剂，乳液(包括微乳剂和/或悬浮剂)等等，它们可任选被粘稠成胶状物。有用的剂型也包括固体的如粉剂，粉末，颗粒剂，片剂，丸剂，薄膜等，它们可以是水分散性的(“可湿的”)或水溶性的。有效成分可被微囊化再制成悬浮剂或固体剂型；另外有效成分的整个剂型也可以成胶囊化。成胶囊可以控制或延缓释放有效成分。可喷雾剂型可在适当的介质中冲稀，使用的喷雾体积为每公顷大约一百至几百升。高浓度的组合物主要用作进一步加工的中间体。Useful dosage forms include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspending agents), and the like, which may optionally be viscous to form a gel. Useful dosage forms also include solids such as powders, powders, granules, tablets, pills, films, and the like, which may be water-dispersible ("wettable") or water-soluble. The active ingredient can be microencapsulated and then made into a suspension or solid dosage form; in addition, the entire dosage form of the active ingredient can also be encapsulated. Encapsulation can control or delay the release of the active ingredient. Sprayable formulations can be diluted in a suitable medium using spray volumes of about one hundred to several hundred liters per hectare. Compositions in high concentrations are mainly used as intermediates for further processing.
典型的固体稀释剂在Watkins等人，Handbook of Insecticide Dust Diluents and Carriers，2nd Ed.，Dorland Books，Caldwell，New Jersey中作了介绍。典型的液体稀释剂在Marsden，SolventsGuide，2nd Ed.，Interscience，New York，1950中作了介绍。McCutcheon′s Detergents and Emulsifiers Annual，Allured Publ.Corp.，Ridgewood，New Jersey，以及Sisely and Wood，Encyclopedia of Surface Active Agents，Chemical Publ.Co.，Inc.，New York，1964，列出了表面活性剂和推荐应用。所有剂型都可含有少量的添加剂，以减少泡沫，结并，腐蚀，微生物的生长等，或加增稠剂以增加粘度。Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, and Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, Lists Surfactants and recommended apps. All dosage forms may contain small amounts of additives to reduce foaming, coalescence, corrosion, microbial growth, etc., or thickeners to increase viscosity.
表面活性剂包括，例如，聚乙氧基化醇，聚乙氧基化烷基酚，聚乙氧基化脱水山梨醇脂肪酸酯，磺化丁二酸二烷基酯，硫酸烷基酯，烷基苯磺酸盐，有机硅烷，N,N-二烷基牛磺酸酯，木质素磺酸盐，萘磺酸盐用醛缩合物，聚羧酸酯和聚氧乙烯/聚氧丙烯嵌段共聚物。Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, sulfonated dialkyl succinates, alkyl sulfates, Alkylbenzenesulfonates, organosilanes, N,N-dialkyltaurates, lignosulfonates, aldehyde condensates for naphthalenesulfonates, polycarboxylates and polyoxyethylene/polyoxypropylene intercalation segmented copolymer.
固体稀释剂包括，例如，粘土，如膨润土，蒙脱石，硅镁土和高岭土，淀粉，糖，二氧化硅，滑石，硅藻土，尿素，碳酸钙，碳酸钠和碳酸氢钠，和硫酸钠，液体稀释剂包括，例如，水，N,N-二甲基甲酰胺，二甲砜，N-烷基吡咯啉酮，乙二醇，聚丙二醇，石腊，烷基苯，烷基萘，橄榄油，蓖麻油，亚麻籽油，桐油，芝麻油，玉米油，花生油，棉籽油，大豆油，菜籽油和可可油，脂肪酸酯，酮类如环己酮，2-庚酮，异佛尔酮和4-羟基-4-甲基-2-戊酮，和醇类如甲醇，环己醇，十二烷醇和四氢呋喃醇。Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sulfuric acid Sodium, liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfone, N-alkylpyrrolidones, ethylene glycol, polypropylene glycol, paraffin, alkylbenzenes, alkylnaphthalenes , olive oil, castor oil, linseed oil, tung oil, sesame oil, corn oil, peanut oil, cottonseed oil, soybean oil, rapeseed oil and cocoa butter, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, iso phorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, dodecanol and tetrahydrofuranol.
溶液，包括乳油，可以通过简单地混合各组分来制备。粉剂和细粉可通过混合和通常在锤磨或液能磨中通过研磨来制备悬浮剂一般通过湿磨来制备；见，例如，U.S.3060,084，颗粒剂和丸剂通过将有效物质喷到刚制成的颗粒载体上或通过造粒技术来制备。See Browning，“Agglomeration”，Chemical Engineering，December 4，1967，pp147-48，Perry′s Chemical Engineer′s Handbook，4TH Ed.，McGraw-Hill，NewYork，1963，Pages 8-57and following，and WO 91/13546。丸剂的制备如U.S.4172714中介绍，水分散性和水溶性粒剂如U.S.4144050，U.S.3920442和DE 3246493中所述的方法来制备片剂如在US 5180587，U.S.5232701和U.S.5208030中所述的方法来制备。薄膜可通过在GB2095558和U.S.3299566中所述的方法来制备。Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Powders and fines can be prepared by mixing and milling, usually in a hammer or liquid energy mill. Suspensions are usually prepared by wet milling; see, for example, U.S. 3060,084, granules and pellets are prepared by spraying the active substance onto a It is prepared on a prepared granular carrier or by a granulation technique. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp147-48, Perry's Chemical Engineer's Handbook, 4TH Ed., McGraw-Hill, New York, 1963, Pages 8-57 and following, and WO 91/ 13546. Preparation of pills as described in U.S. 4172714, water dispersible and water soluble granules as described in U.S. 4144050, U.S. 3920442 and DE 3246493 to prepare tablets as described in US 5180587, U.S.5232701 and U.S.5208030 to prepare. Films can be prepared by the methods described in GB2095558 and U.S.3299566.
有关加工的更多信息可见U.S.3,235,361，Col.6，line 16 throughCol.7,line 19 and Examples 10-41；U.S.3,309,192，Col.5，line 43 through Col.7，line 62 and Examples 8，12，15，39，41，52，53，58，132，138-140，162-164，166，167and169-182；U.S.2,891,855，Col.3，line 66 through Col.5，line 17and Examples 1-4；Klingman，Weed Control as a Science，John Wiley and Sons，Inc.，New York 1961，pp 81-96；and Hance et al.，Weed Control Handbook，8th Ed.，Blackwell Scientific Publications，Oxford，1989。More information on processing can be found in U.S. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10-41; U.S. 3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Klingman , Weed Control as a Science, John Wiley and Sons, Inc., New York 1961, pp 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.
本文中，对于所述组合物的某些应用，例如在农业上可在本发明的除草组合物中加入一种、两种或多种其它的杀菌剂、杀虫杀螨剂、除草剂、植物生长调节剂或肥料等，由此可产生附加的优点和效果。Herein, for some applications of the composition, for example, in agriculture, one, two or more other fungicides, insecticides, acaricides, herbicides, plants may be added to the herbicidal composition of the present invention. Growth regulators or fertilizers, etc., thereby producing additional advantages and effects.
有益效果beneficial effect
本发明所述式(I)化合物对农业或其他领域中的多种有害杂草都表现出很好的活性。并且，这些化合物在很低的剂量下就可以获得很好的防治效果，因此可用于制备除草剂。The compounds of formula (I) described in the present invention have good activity against various harmful weeds in agriculture or other fields. Moreover, these compounds can achieve good control effects at very low doses, so they can be used in the preparation of herbicides.
术语定义与说明Definition and Explanation of Terms
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, publications cited throughout this document are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms in this document, the definitions in this chapter shall prevail.
应当理解，本文在描述1、2个或更多个中，“更多个”应当是指大于2，例如大于等于3的整数，例如3、4、5、6、7、8、9或10。It should be understood that in describing 1, 2 or more herein, "more" shall refer to an integer greater than 2, such as greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10 .
术语“卤素”表示氟、氯、溴和碘。The term "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“C 1-C 6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。 The term "C1- C6 alkyl" refers to straight and branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.
术语“C 2-C 6烯基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子，例如，具有2或3个碳原子(即，C 2-C 3烯基)。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。 The term "C2 - C6 alkenyl" is to be understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example, Has 2 or 3 carbon atoms (ie, C2 - C3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -Pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl , 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, ( Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methyl But-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2- Alkenyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E) )-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methyl But-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.
术语“C 2-C 6炔基”应理解为优选表示直链或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5或6个碳原子，，例如，具有2或3个碳原子(“C 2-C 3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。 The term "C2 - C6alkynyl " is to be understood as preferably denoting a linear or branched monovalent hydrocarbon group comprising one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, eg , having 2 or 3 carbon atoms ("C2 - C3alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-alkynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-Methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut- 2-alkynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbutanyl -3-alkynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
术语“3-10元杂环基”意指饱和的或不饱和的非芳族的环或环系，并且含有至少一个选自O、S和N的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环以及螺环的环。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、1,3-二氧杂环戊烷基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环 的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。杂环基可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于二氢呋喃基、二氢吡喃基、2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S and N. The heterocyclyl group can be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. The heterocyclyl group can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclic group may include, but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 1,3-dioxolane; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithi Alkyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group can be benzo-fused. The heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrole The [1,2-a]pyrazin-2(1H)-yl ring. A heterocyclyl group may be partially unsaturated, i.e. it may contain one or more double bonds such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, alternatively, it may be benzo-fused such as but not limited to dihydro isoquinolinyl.
术语“C 6-C 10芳基”应理解为优选表示具有6、7、8、9或10个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基，例如芴基。当所述C 6-C 10芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。 The term "C6 - C10 aryl" is to be understood as preferably denoting a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular A ring of 6 carbon atoms ("C 6 aryl"), such as phenyl; or biphenyl, or a ring of 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl , or a ring having 10 carbon atoms (" C10 aryl"), such as tetralinyl, dihydronaphthyl, or naphthyl, such as fluorenyl. When the C6 - C10 aryl group is substituted, it may be monosubstituted or polysubstituted. Also, the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.
术语“5-10元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。“杂芳基”还指其中杂芳族环与一个或多个芳基、脂环族或杂环基环稠合的基团，其中所述连接的根基或点在杂芳族环上。非限制性实例包括呋喃基、吲嗪基、异吲哚基、吲哚基、吲唑基、嘌呤基。The term "5-10 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms and it contains 1-5, preferably 1-3 heteroatoms each independently selected from N, O and S and, in addition in each case may be benzo-fused . "Heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the root or point of attachment is on the heteroaromatic ring. Non-limiting examples include furyl, indolyl, isoindolyl, indolyl, indazolyl, purinyl.
应当理解，可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4 TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基，只要其符合价键规则即可。举例而言，CH 2O等同于OCH 2，可以以氧原子或亚甲基的碳原子与取代位置连接。 It should be understood that definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the skill in the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in this application. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds. When a substituent is described by a conventional formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left, so long as it conforms to the valence rules. For example, CH2O , which is equivalent to OCH2 , may be attached to the substitution position with an oxygen atom or a methylene carbon atom.
本文所用术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。本申请化合物还包括药学上可以接受的盐，例如钠盐、钾盐、钙盐、锌盐等一般在农园艺领域能够使用的盐等。药学上可接受的盐是指把母体化合物中的酸基基团转换成盐的形式。药学上可接受的盐包括，但不仅限于，酸基基团例如羧酸(氢)基的无机或有机碱盐类。本申请药学上可接受的盐可以由母体化合物合成，即母体化合物中的酸性基团与1-4当量的碱在一个溶剂***中反应。合适的盐列举在Remingtong’s Pharmaceutical Scicences,17 thed.,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中，例如钠盐。 As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological potency of the free acid and free base of the designated compound and are not biologically or otherwise adversely affected. The compounds of the present application also include pharmaceutically acceptable salts, such as sodium salts, potassium salts, calcium salts, zinc salts, and the like which are generally used in the fields of agriculture and horticulture. A pharmaceutically acceptable salt refers to a form in which an acid group in the parent compound is converted into a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic base salts of acid groups such as carboxylic acid (hydro) groups. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound by reacting an acidic group in the parent compound with 1-4 equivalents of a base in a solvent system. Suitable salts are listed in Remingtong's Pharmaceutical Sciences, 17th ed ., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eg, the sodium salt.
本文使用的“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。式(I)化合物含有不对称或手性中心，因此，存在不同的立体异构形式。式(I)的所有立体结构和混合物一样，包括外消旋混合物，作为目前申请的一部分。非对映体混合物能够分离成单独的非对映体，基于它们不同的物理化学性质，采用众所周知的手段，例如，对映异构体的拆分可通过与适当的光学活性物质(例如手性醇或Mosher`s莫氏酰氯)反应转换为非对映异构体，将其分离并转化(如水解)为相对应的单一的异构体。式(I)中的一些化合物可能是阻转异构体(如取代芳基)也是本申请中的一部分。对映异构体也可利用手性色谱柱分离。式(I)中的化合物可能存在着不同的互变异构形式，这些形式都包含在本申请范围内。例如，酮-烯醇和亚胺-烯胺形式的化合物。As used herein, "stereoisomers" refer to isomers that result from different arrangements of atoms in a molecule in space. The compounds of formula (I) contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. All stereostructures of formula (I) are the same as mixtures, including racemic mixtures, as part of the present application. Diastereomeric mixtures can be separated into the individual diastereomers on the basis of their different physicochemical properties by well-known means, for example, resolution of enantiomers can be achieved by interaction with appropriate optically active substances (e.g., chiral isomers). alcohol or Mosher's Mohs acid chloride) reaction to convert the diastereomers, which are separated and converted (eg, hydrolyzed) to the corresponding single isomers. It is also part of this application that some of the compounds of formula (I) may be atropisomers (eg substituted aryl). Enantiomers can also be separated using chiral chromatography columns. The compounds of formula (I) may exist in different tautomeric forms, all of which are included within the scope of this application. For example, compounds in the form of keto-enols and imine-enamines.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the intended protection scope of the present invention.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.
下述实施例中LC-MS检测分析使用如下色谱条件：The following chromatographic conditions were used for LC-MS detection and analysis in the following examples:
色谱柱：Agilent ZORBAX SB-C18 150mm×4.6mm，5μm(i.d)；Chromatographic column: Agilent ZORBAX SB-C18 150mm×4.6mm, 5μm(i.d);
检测波长：254nm；流速：0.8mL/min；柱温：30℃；Detection wavelength: 254nm; flow rate: 0.8mL/min; column temperature: 30℃;
梯度洗脱条件：Gradient elution conditions:
时间(min)time (min) 乙腈(％)Acetonitrile (%) 0.1甲酸水溶液(体积％)0.1 formic acid aqueous solution (vol%)
0.000.00 5050 5050
5.005.00 5050 5050
15.0015.00 9090 1010
25.0025.00 9090 1010
合成实施例Synthesis Example
实施例1：乙基3-(2-氯-4-氟-5-(5-(三氟甲基)吡啶-2-基)苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯(化合物3)的制备Example 1: Ethyl 3-(2-chloro-4-fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-5-methyl-4,5-dihydroiso Preparation of oxazole-5-carboxylate (compound 3)
Figure PCTCN2021133602-appb-000040
Figure PCTCN2021133602-appb-000040
第一步反应：2-氯-4-氟-5-(5-(三氟甲基)吡啶-2-基)苯甲醛的制备：氮气保护下，室温将3.03g(0.015mol)(4-氯-2-氟-5-甲酰苯基)硼酸、6.21g(0.045mol)碳酸钾、0.52g(0.00045mol)四(三苯基膦)钯、60ml四氢呋喃、30ml水加入到三口瓶中搅拌。向上述混合物中分批加入3.27g(0.018mol)2-氯-5-(三氟甲基)吡啶。加毕，60℃下搅拌反应8小时。反应液冷至室温。减压脱溶。残余物用乙酸乙酯(2*20ml)萃取，合并有机相。水洗一次。饱和食盐水洗一次。无水硫酸钠干燥。过滤，滤液减压浓缩，柱层析(洗脱剂：乙酸乙酯：石油醚(1:12)得产品3.09g，收率68％。The first step reaction: Preparation of 2-chloro-4-fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)benzaldehyde: under nitrogen protection, 3.03g (0.015mol) (4- Chloro-2-fluoro-5-formylphenyl)boronic acid, 6.21g (0.045mol) potassium carbonate, 0.52g (0.00045mol) tetrakis (triphenylphosphine) palladium, 60ml tetrahydrofuran, 30ml water were added to the there-necked flask and stirred . To the above mixture was added portionwise 3.27 g (0.018 mol) of 2-chloro-5-(trifluoromethyl)pyridine. After the addition was completed, the reaction was stirred at 60°C for 8 hours. The reaction solution was cooled to room temperature. Desolvate under reduced pressure. The residue was extracted with ethyl acetate (2*20ml) and the organic phases were combined. Wash once. Wash once with saturated salt water. Dry over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, column chromatography (eluent: ethyl acetate: petroleum ether (1:12)) to obtain 3.09 g of product, yield 68%.
LC-MS[M+H] +＝304.02、[M+Na] +＝326、[M+K] +＝341.97。 LC-MS [M+H] + =304.02, [M+Na] + =326, [M+K] + =341.97.
第二步反应：2-氯-4-氟-5-(5-(三氟甲基)吡啶-2-基)苯甲醛肟的制备：室温下，依次将2.27g(0.0075mol)2-氯-4-氟-5-(5-(三氟甲基)吡啶-2-基)苯甲醛、0.68g(0.0097mol)盐酸羟胺、0.86g(0.01mol)乙酸钠溶于5ml水与20ml四氢呋喃混合溶液中。反应液搅拌4小时。浓缩反 应混合物，用乙酸乙酯和氢氧化钠水溶液(2M)稀释，分相。有机层饱和食盐水洗，无水硫酸钠干燥。抽滤，干燥得产品2.22g，收率93％。The second step reaction: preparation of 2-chloro-4-fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)benzaldehyde oxime: at room temperature, 2.27g (0.0075mol) of 2-chloro -4-Fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)benzaldehyde, 0.68g (0.0097mol) hydroxylamine hydrochloride, 0.86g (0.01mol) sodium acetate dissolved in 5ml water and mixed with 20ml tetrahydrofuran in solution. The reaction solution was stirred for 4 hours. The reaction mixture was concentrated, diluted with ethyl acetate and aqueous sodium hydroxide (2M), and the phases were separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration and drying to obtain 2.22 g of the product with a yield of 93%.
LC-MS[M+H] +＝319.03、[M+Na] +＝341.01、[M+K] +＝356.98。 LC-MS [M+H] + =319.03, [M+Na] + =341.01, [M+K] + =356.98.
第三、四步反应：乙基3-(2-氯-4-氟-5-(5-(三氟甲基)吡啶-2-基)苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯的制备：室温下，将1.60g(0.005mol)2-氯-4-氟-5-(5-(三氟甲基)吡啶-2-基)苯甲醛肟、1.01g(0.0075mol)N-氯代丁二酰亚胺、8ml N,N-二甲基甲酰胺加入到三口瓶中，在40℃下搅拌反应2小时。反应液冷至室温，向上述混合物中加入0.68g(0.006mol)甲基丙烯酸乙酯、0.76g(0.0075mol)三乙胺的2ml N,N-二甲基甲酰胺溶液，室温下搅拌5小时。用水和乙酸乙酯稀释反应混合物，分相。水相用乙酸乙酯(2*20ml)萃取，合并有机相。有机相水洗两次，饱和食盐水洗一次。无水硫酸钠干燥，过滤，滤液减压浓缩。残余物柱层析(洗脱剂：乙酸乙酯：石油醚(1:9)，得产品1.76g，收率82％。The third and fourth steps: ethyl 3-(2-chloro-4-fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-5-methyl-4,5- Preparation of dihydroisoxazole-5-carboxylate: 1.60 g (0.005 mol) of 2-chloro-4-fluoro-5-(5-(trifluoromethyl)pyridin-2-yl)benzene were added at room temperature Formaldehyde oxime, 1.01g (0.0075mol) N-chlorosuccinimide and 8ml N,N-dimethylformamide were added to the there-necked flask, and the reaction was stirred at 40°C for 2 hours. The reaction solution was cooled to room temperature, 0.68g (0.006mol) of ethyl methacrylate, 0.76g (0.0075mol) of triethylamine in 2ml of N,N-dimethylformamide solution were added to the above mixture, and stirred at room temperature for 5 hours . The reaction mixture was diluted with water and ethyl acetate and the phases were separated. The aqueous phase was extracted with ethyl acetate (2*20ml) and the organic phases were combined. The organic phase was washed twice with water and once with saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was subjected to column chromatography (eluent: ethyl acetate: petroleum ether (1:9) to obtain 1.76 g of the product with a yield of 82%.
LC-MS[M+H] +＝431.08、[M+Na] +＝453.06、[M+K] +＝469.03。 LC-MS [M+H] + =431.08, [M+Na] + =453.06, [M+K] + =469.03.
1H-NMR(400MHz,溶剂CDCl 3)δ(ppm):8.96(1H,s),8.34(1H,d),8.01(1H,dd),7.87(1H,d),7.56(1H,d),4.27(2H,q),4.01(1H,d),3.41(1H,d),1.73(3H,s),1.33(3H,t)。 1 H-NMR (400MHz, solvent CDCl 3 )δ(ppm): 8.96(1H,s), 8.34(1H,d), 8.01(1H,dd), 7.87(1H,d), 7.56(1H,d) , 4.27(2H,q), 4.01(1H,d), 3.41(1H,d), 1.73(3H,s), 1.33(3H,t).
实施例2：甲基3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯(化合物122)的制备Example 2: Methyl 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5-methyl-4,5 - Preparation of dihydroisoxazole-5-carboxylate (compound 122)
Figure PCTCN2021133602-appb-000041
Figure PCTCN2021133602-appb-000041
第一步反应：2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯甲醛的制备：氮气保护下，室温将3.03g(0.015mol)(4-氯-2-氟-5-甲酰苯基)硼酸、6.21g(0.045mol)碳酸钾、0.52g(0.00045mol)四(三苯基膦)钯、60ml四氢呋喃、30ml水加入到三口瓶中搅拌。向上述混合物中分批加入3.89g(0.018mol)2,3-二氯-5-(三氟甲基)吡啶。加毕，60℃下搅拌反应8小时。反应液冷至室温。减压脱溶。残余物用乙酸乙酯(2*20ml)萃取，合并有机相。水洗一次。饱和食盐水洗一次。无水硫酸钠干燥。过滤，滤液减压浓缩，柱层析(洗脱剂：乙酸乙酯：石油醚(1:12)得产品3.05g，收率60％。The first step reaction: preparation of 2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorobenzaldehyde: under nitrogen protection, 3.03g (0.015mol ) (4-chloro-2-fluoro-5-formylphenyl)boronic acid, 6.21g (0.045mol) potassium carbonate, 0.52g (0.00045mol) tetrakis(triphenylphosphine)palladium, 60ml tetrahydrofuran, 30ml water were added to the Stir in a three-necked bottle. To the above mixture was added portionwise 3.89 g (0.018 mol) of 2,3-dichloro-5-(trifluoromethyl)pyridine. After the addition was completed, the reaction was stirred at 60°C for 8 hours. The reaction solution was cooled to room temperature. Desolvate under reduced pressure. The residue was extracted with ethyl acetate (2*20ml) and the organic phases were combined. Wash once. Wash once with saturated salt water. Dry over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, column chromatography (eluent: ethyl acetate: petroleum ether (1:12)) to obtain 3.05 g of product, yield 60%.
LC-MS[M+H] +＝337.98、[M+Na] +＝359.96、[M+K] +＝375.93。 LC-MS [M+H] + =337.98, [M+Na] + =359.96, [M+K] + =375.93.
第二步反应：2-氯-5-(3-氯-5-三氟甲基)吡啶-2-基)-4-氟苯甲醛肟的制备：室温下，依次将2.53g(0.0075mol)2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯甲醛、0.68g(0.0097mol)盐酸羟胺、0.86g(0.01mol)乙酸钠溶于5ml水与20ml四氢呋喃混合溶液中。反应液搅拌4小时。浓缩反应混合物，用乙酸乙酯和氢氧化钠水溶液(2M)稀释，分相。有机层饱和食盐水洗，无水硫酸钠干燥。抽滤，干燥得产品2.38g，收率90％。The second step reaction: preparation of 2-chloro-5-(3-chloro-5-trifluoromethyl)pyridin-2-yl)-4-fluorobenzaldehyde oxime: at room temperature, 2.53g (0.0075mol) of 2-Chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorobenzaldehyde, 0.68g (0.0097mol) hydroxylamine hydrochloride, 0.86g (0.01mol) sodium acetate In 5ml water and 20ml tetrahydrofuran mixed solution. The reaction solution was stirred for 4 hours. The reaction mixture was concentrated, diluted with ethyl acetate and aqueous sodium hydroxide (2M), and the phases were separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration and drying to obtain 2.38 g of product with a yield of 90%.
LC-MS[M+H] +＝352.99、[M+Na] +＝374.97、[M+K] +＝390.94。 LC-MS [M+H] + =352.99, [M+Na] + =374.97, [M+K] + =390.94.
第三、四步反应：甲基3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯的制备：室温下，将1.77g(0.005mol)2-氯-5-(3-氯-5-三氟甲基)吡啶-2-基)-4-氟苯甲醛肟、1.01g(0.0075mol)N-氯代丁二酰亚胺、10ml N,N-二甲基甲酰胺加入到三口瓶中，在40℃下搅拌反应2小时。反应液冷至室温，向上述混合物中加入0.60g(0.006mol)甲基丙烯酸甲酯、0.76g(0.0075mol)三乙胺的2ml N,N-二甲基甲酰胺溶液，室温下搅拌5小时。用水和乙酸乙酯稀释反应混合物，分相。水相用乙酸乙酯(2*20ml)萃取，合并有机相。有机相水洗两次，饱和食盐水洗一次。无水硫酸钠干燥，过滤，滤液减压浓缩。残余物柱层析(洗脱剂：乙酸乙酯：石油醚(1:9)，得产品1.92g，收率85％。The third and fourth steps: methyl 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5-methyl- Preparation of 4,5-dihydroisoxazole-5-carboxylate: At room temperature, 1.77 g (0.005 mol) of 2-chloro-5-(3-chloro-5-trifluoromethyl)pyridine-2- base)-4-fluorobenzaldehyde oxime, 1.01g (0.0075mol) N-chlorosuccinimide, 10ml N,N-dimethylformamide were added to the there-necked flask, and the reaction was stirred at 40 ° C for 2 hours . The reaction solution was cooled to room temperature, 2ml N,N-dimethylformamide solution of 0.60g (0.006mol) methyl methacrylate and 0.76g (0.0075mol) triethylamine was added to the above mixture, and stirred at room temperature for 5 hours . The reaction mixture was diluted with water and ethyl acetate and the phases were separated. The aqueous phase was extracted with ethyl acetate (2*20ml) and the organic phases were combined. The organic phase was washed twice with water and once with saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was subjected to column chromatography (eluent: ethyl acetate: petroleum ether (1:9) to obtain 1.92 g of the product with a yield of 85%.
LC-MS[M+H] +＝451.03、[M+Na] +＝473.01、[M+K] +＝488.98。 LC-MS [M+H] + =451.03, [M+Na] + =473.01, [M+K] + =488.98.
1H-NMR(400MHz,溶剂CDCl 3)δ(ppm):8.85(1H,s),8.06(1H,s),7.83(1H,d),7.32(1H,d),4.27(3H,s),4.02(1H,d),3.40(1H,d),1.73(3H,s)。 1 H-NMR (400MHz, solvent CDCl 3 )δ(ppm): 8.85(1H,s), 8.06(1H,s), 7.83(1H,d), 7.32(1H,d), 4.27(3H,s) , 4.02(1H,d), 3.40(1H,d), 1.73(3H,s).
实施例3：乙基3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯(化合物123)的制备Example 3: Ethyl 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5-methyl-4,5 - Preparation of dihydroisoxazole-5-carboxylate (compound 123)
Figure PCTCN2021133602-appb-000042
Figure PCTCN2021133602-appb-000042
室温下，将1.77g(0.005mol)2-氯-5-(3-氯-5-三氟甲基)吡啶-2-基)-4-氟苯甲醛肟、1.01g(0.0075mol)N-氯代丁二酰亚胺、10ml N,N-二甲基甲酰胺加入到三口瓶中，在40℃下搅拌反应2小时。反应液冷至室温，向上述混合物中加入0.68g(0.006mol)甲基丙烯酸乙酯、0.76g(0.0075mol)三乙胺的2ml N,N-二甲基甲酰胺溶液，室温下搅拌5小时。用水和乙酸乙酯稀释反应混合物，分相。水相用乙酸乙酯(2*20ml)萃取，合并有机相。有机相水洗两次，饱和食盐水洗一次。无水硫酸钠干燥，过滤，滤液减压浓缩。残余物柱层析(洗脱剂：乙酸乙酯：石油醚(1:9)，得产品1.83g，收率79％。At room temperature, 1.77g (0.005mol) 2-chloro-5-(3-chloro-5-trifluoromethyl)pyridin-2-yl)-4-fluorobenzaldehyde oxime, 1.01g (0.0075mol) N- Chlorosuccinimide and 10ml of N,N-dimethylformamide were added to the three-necked flask, and the reaction was stirred at 40°C for 2 hours. The reaction solution was cooled to room temperature, 0.68g (0.006mol) of ethyl methacrylate, 0.76g (0.0075mol) of triethylamine in 2ml of N,N-dimethylformamide solution were added to the above mixture, and stirred at room temperature for 5 hours . The reaction mixture was diluted with water and ethyl acetate and the phases were separated. The aqueous phase was extracted with ethyl acetate (2*20ml) and the organic phases were combined. The organic phase was washed twice with water and once with saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was subjected to column chromatography (eluent: ethyl acetate: petroleum ether (1:9) to obtain 1.83 g of the product with a yield of 79%.
LC-MS[M+H] +＝465.04、[M+Na] +＝487.02、[M+K] +＝502.99。 LC-MS [M+H] + =465.04, [M+Na] + =487.02, [M+K] + =502.99.
1H-NMR(400MHz,溶剂CDCl 3)δ(ppm):8.86(1H,s),8.07(1H,s),7.84(1H,d),7.33(1H,d),4.27(2H,q),4.01(1H,d),3.41(1H,d),1.73(3H,s),1.33(3H,t)。 1 H-NMR (400MHz, solvent CDCl 3 )δ(ppm): 8.86(1H,s), 8.07(1H,s), 7.84(1H,d), 7.33(1H,d), 4.27(2H,q) , 4.01(1H,d), 3.41(1H,d), 1.73(3H,s), 1.33(3H,t).
实施例4：2,4-二氯苄基3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯(化合物136)的制备Example 4: 2,4-Dichlorobenzyl 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5- Preparation of methyl-4,5-dihydroisoxazole-5-carboxylate (compound 136)
Figure PCTCN2021133602-appb-000043
Figure PCTCN2021133602-appb-000043
第一步反应：3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸(化合物121)的制备：室温下将1.16g(0.0025mol)3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯加入到10ml 2N氢氧化钠水溶液中，10ml四氢呋喃稀释。反应混合物搅拌2小时，用1M稀盐酸调节pH＝2。抽滤，滤饼用水洗涤，干燥后得产品1.03g，收率95％。The first reaction: 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5-methyl-4,5- Preparation of dihydroisoxazole-5-carboxylic acid (compound 121): 1.16 g (0.0025 mol) of 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridine- 2-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate was added to 10 ml of 2N aqueous sodium hydroxide solution and diluted with 10 ml of tetrahydrofuran. The reaction mixture was stirred for 2 hours and adjusted to pH=2 with 1M dilute hydrochloric acid. After suction filtration, the filter cake was washed with water and dried to obtain 1.03 g of the product with a yield of 95%.
LC-MS[M+H] +＝437.01、[M+Na] +＝458.99、[M+K] +＝474.96。 LC-MS [M+H] + =437.01, [M+Na] + =458.99, [M+K] + =474.96.
第二步反应：2,4-二氯苄基3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯的制备：0℃下，将0.98g(0.0022mol)3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸、0.56g(0.0044mol)二(异丙基)乙胺、1.15g(0.0022mol)六氟磷酸苯并***-1-基-氧基三吡咯烷基磷依次溶于15ml二氯甲烷中。反应混合物搅拌2小时。室温下向上述溶液中加入0.45g(0.0025mol)2,4-二氯苯甲醇。室温下继续搅拌12小时。向反应体系中加入10ml水，分相。水相用二氯甲烷萃取两次。合并有机相，饱和食盐水洗，无水硫酸镁干燥。有机相减压脱溶，柱层析(洗脱剂：乙酸乙酯：石油醚(1:2)得产品1.30g，收率87％。The second step reaction: 2,4-dichlorobenzyl 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5 - Preparation of methyl-4,5-dihydroisoxazole-5-carboxylate: 0.98 g (0.0022 mol) of 3-(2-chloro-5-(3-chloro-5-( Trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid, 0.56g (0.0044mol) di(isopropyl) ) ethylamine, 1.15 g (0.0022 mol) of benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate were dissolved in 15 ml of dichloromethane in turn. The reaction mixture was stirred for 2 hours. To the above solution was added 0.45 g (0.0025 mol) of 2,4-dichlorobenzyl alcohol at room temperature. Stirring was continued for 12 hours at room temperature. 10 ml of water was added to the reaction system, and the phases were separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic phase was desolvated under reduced pressure and subjected to column chromatography (eluent: ethyl acetate: petroleum ether (1:2) to obtain 1.30 g of the product with a yield of 87%.
LC-MS[M+H] +＝594.98、[M+Na] +＝616.96、[M+K] +＝632.93。 LC-MS [M+H] + =594.98, [M+Na] + =616.96, [M+K] + =632.93.
1H-NMR(400MHz,溶剂CDCl 3)δ(ppm):8.87(1H,s),8.06(1H,s),7.85(1H,d),7.76(1H,d),7.36(1H,d),7.33(1H,d),7.26(1H,d),5.58(2H,s),4.01(1H,d),3.41(1H,d),1.73(3H,s)。 1 H-NMR (400MHz, solvent CDCl 3 )δ(ppm): 8.87(1H,s), 8.06(1H,s), 7.85(1H,d), 7.76(1H,d), 7.36(1H,d) , 7.33(1H,d), 7.26(1H,d), 5.58(2H,s), 4.01(1H,d), 3.41(1H,d), 1.73(3H,s).
实施例5：2-(1,3-二氧戊烷-2-基)乙基3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯(化合物141-1)的制备Example 5: 2-(1,3-dioxolan-2-yl)ethyl 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl) Preparation of -4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate (compound 141-1)
Figure PCTCN2021133602-appb-000044
Figure PCTCN2021133602-appb-000044
第一步反应：3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-酰氯的制备：室温下将1.09g(0.0025mol)3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸、0.60g(0.005mol)二氯亚砜先后加入到20ml二氯乙烷中，加热回流4小时，减压脱除溶剂及剩余二氯亚砜。得产品1.09g，收率96％。The first reaction: 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5-methyl-4,5- Preparation of dihydroisoxazole-5-acid chloride: 1.09 g (0.0025 mol) of 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)- 4-Fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid, 0.60g (0.005mol) thionyl chloride were successively added to 20ml of dichloroethane, heated to reflux for 4 hours, the solvent and remaining thionyl chloride were removed under reduced pressure. 1.09 g of product was obtained, and the yield was 96%.
第二步反应：2-(1,3-二氧戊烷-2-基)乙基3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-羧酸酯的制备：0℃下，将1.05g(0.0023mol)3-(2-氯-5-(3-氯-5-(三氟甲基)吡啶-2-基)-4-氟苯基)-5-甲基-4,5-二氢异噁唑-5-酰氯、0.46g(0.0046mol)三乙胺、0.29g(0.0025mol)2-(1,3-二氧戊烷-2-基)乙烷-1-醇依次溶于15ml二氯甲烷中。室温下搅拌8小时。向反应体系中加入10ml水，分相。水相用二氯甲烷萃取两次。合并有机相，饱和食盐水洗，无水硫酸镁干燥。有机相减压脱溶，柱层析(洗脱剂：乙酸乙酯：石油醚(1:3)得产品0.93g，收率75％。The second step reaction: 2-(1,3-dioxolan-2-yl)ethyl 3-(2-chloro-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl) )-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate preparation: 1.05 g (0.0023 mol) of 3-(2-chloro- 5-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-acid chloride, 0.46g (0.0046 mol) triethylamine, 0.29 g (0.0025 mol) 2-(1,3-dioxolan-2-yl) ethane-1-ol were dissolved in 15 ml of dichloromethane successively. Stir at room temperature for 8 hours. 10 ml of water was added to the reaction system, and the phases were separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic phase was desolvated under reduced pressure, and column chromatography (eluent: ethyl acetate: petroleum ether (1:3)) gave 0.93 g of the product with a yield of 75%.
LC-MS[M+H] +＝537.06、[M+Na] +＝559.04、[M+K] +＝575.01。 LC-MS [M+H] + =537.06, [M+Na] + =559.04, [M+K] + =575.01.
1H-NMR(400MHz,溶剂CDCl 3)δ(ppm):8.85(1H,s),8.05(1H,s),7.83(1H,d),7.32(1H,d), 5.52(1H,t),4.20(2H,t),4.12(2H,q),3.98(2H,q),3.92(1H,d),3.40(1H,d),1.93(2H,q),1.72(3H,s)。 1 H-NMR (400MHz, solvent CDCl 3 )δ(ppm): 8.85(1H,s), 8.05(1H,s), 7.83(1H,d), 7.32(1H,d), 5.52(1H,t) , 4.20(2H,t), 4.12(2H,q), 3.98(2H,q), 3.92(1H,d), 3.40(1H,d), 1.93(2H,q), 1.72(3H,s).
本发明还参考上述实施例中的方法合成了如下化合物：The present invention has also synthesized the following compounds with reference to the methods in the above examples:
表4Table 4
Figure PCTCN2021133602-appb-000045
Figure PCTCN2021133602-appb-000045
Figure PCTCN2021133602-appb-000046
Figure PCTCN2021133602-appb-000046
Figure PCTCN2021133602-appb-000047
Figure PCTCN2021133602-appb-000047
Figure PCTCN2021133602-appb-000048
Figure PCTCN2021133602-appb-000048
Figure PCTCN2021133602-appb-000049
Figure PCTCN2021133602-appb-000049
Figure PCTCN2021133602-appb-000050
Figure PCTCN2021133602-appb-000050
Figure PCTCN2021133602-appb-000051
Figure PCTCN2021133602-appb-000051
Figure PCTCN2021133602-appb-000052
Figure PCTCN2021133602-appb-000052
Figure PCTCN2021133602-appb-000053
Figure PCTCN2021133602-appb-000053
Figure PCTCN2021133602-appb-000054
Figure PCTCN2021133602-appb-000054
Figure PCTCN2021133602-appb-000055
Figure PCTCN2021133602-appb-000055
Figure PCTCN2021133602-appb-000056
Figure PCTCN2021133602-appb-000056
Figure PCTCN2021133602-appb-000057
Figure PCTCN2021133602-appb-000057
制剂实施例Formulation Example
在以下实施例中，所有百分数均以重量计，所有剂型都使用常规方法制备。In the following examples, all percentages are by weight, and all dosage forms were prepared using conventional methods.
实施例5：Example 5:
本实施例使用如上实施例中得到的化合物制备可湿性粉剂，具体采用如下配比的原料组成进行制备：The present embodiment uses the compound obtained in the above embodiment to prepare the wettable powder, and specifically adopts the raw material composition of the following proportions to prepare:
化合物3 50.0％、十二烷基酚聚乙氧基乙二醇醚4.0％、木质素磺酸钠6.0％、硅铝酸钠8.0％、蒙脱石(煅烧的)32.0％。Compound 3 50.0%, dodecylphenol polyethoxy glycol ether 4.0%, sodium lignosulfonate 6.0%, sodium aluminosilicate 8.0%, montmorillonite (calcined) 32.0%.
实施例6：Example 6:
本实施例使用如上实施例中得到的化合物制备颗粒剂，具体采用如下配比的原料组成进行制备：This embodiment uses the compound obtained in the above embodiment to prepare granules, and specifically adopts the raw material composition of the following proportions to prepare:
化合物121 20.0％、其他组分为十二烷基硫酸钠2.0％、木质素磺酸钙6.0％、氯化钾10.0％、聚二甲基硅氧烷1.0％、可溶性淀粉补齐至100％。Compound 121 20.0%, other components are sodium lauryl sulfate 2.0%, calcium lignosulfonate 6.0%, potassium chloride 10.0%, polydimethylsiloxane 1.0%, soluble starch is filled to 100%.
实施例7：Example 7:
本实施例使用如上实施例中得到的化合物制备挤压丸，具体采用如下配比的原料组成进行制备：This embodiment uses the compound obtained in the above embodiment to prepare extruded pellets, and specifically adopts the raw material composition of the following proportions to prepare:
化合物122 30.0％、无水硫酸钙9.0％、粗木质素磺酸钙4.0％、烷基萘磺酸钠1.0％、钙/镁膨润土56.0％。Compound 122 30.0%, anhydrous calcium sulfate 9.0%, crude calcium lignosulfonate 4.0%, sodium alkylnaphthalene sulfonate 1.0%, calcium/magnesium bentonite 56.0%.
实施例8：Example 8:
本实施例使用如上实施例中得到的化合物制备乳油，具体采用如下配比的原料组成进行制备：The present embodiment uses the compound obtained in the above embodiment to prepare emulsifiable concentrate, and specifically adopts the raw material composition of the following proportions to prepare:
化合物123 25.0％、溶剂150 60％、PEG400 5％、Rhodacal 70/B 3％、Rhodameen RAM/7 7％。Compound 123 25.0%, Solvent 150 60%, PEG400 5%, Rhodacal 70/B 3%, Rhodameen RAM/7 7%.
实施例9：Example 9:
本实施例使用如上实施例中得到的化合物制备水悬浮剂，具体采用如下配比的原料组成进行制备：The present embodiment uses the compound obtained in the above embodiment to prepare the aqueous suspension, and specifically adopts the raw material composition of the following proportions to prepare:
化合物126 30.0％、POE聚苯乙烯苯基醚硫酸盐5.0％、黄原胶0.5％、聚乙二醇5％、三乙醇胺1％、山梨糖醇0.5％和水加至100.0％。Compound 126 30.0%, POE polystyrene phenyl ether sulfate 5.0%, xanthan gum 0.5%, polyethylene glycol 5%, triethanolamine 1%, sorbitol 0.5% and water were added to 100.0%.
生物活性测定Biological activity assay
实施例10：Example 10:
1、除草活性测定1. Determination of herbicidal activity
本发明化合物的除草活性示于下述温室试验中：The herbicidal activity of the compounds of the present invention is shown in the following greenhouse tests:
将定量的禾本科杂草(稗草、马唐、多花黑麦草)和阔叶杂草(百日草、苘麻)种子分别播于直径为7cm的装有营养土的纸杯中，播后覆土1cm，镇压、淋水后在温室培养，苗前处理于播种后24小时进行；苗后处理需出苗后间苗、定植(禾本科杂草10-20株/杯，阔叶杂草(2-4株/杯)，待禾本科杂草1.5-2叶期，阔叶杂草长至2片真叶期，按试验设计剂量用履带式作物喷雾机(英国Engineer Research Ltd.设计生产)进行喷雾处理(喷雾压力1.95kg/cm 2，喷液量50ml/m 2，履带速度1.48km/h)。试验设3次重复。待药液自然风干后，置于温室内按常规方法管理，定期观察试材的生长发育情况，并根据实际情况，于处理后定期目测调查供试药剂对杂草的防除效果。 Quantitative amounts of grass weeds (barnyard grass, crabgrass, ryegrass) and broad-leaved weeds (zinnia, abalone) were sown in paper cups with a diameter of 7 cm and filled with nutrient soil. Covering soil 1cm, cultivated in greenhouse after suppression and drenching, pre-emergence treatment was carried out 24 hours after sowing; post-emergence treatment required post-emergence thinning, field planting (10-20 strains/cup of grass weeds, broad-leaved weeds (2- 4 plants/cup), when the grass weeds are at the 1.5-2 leaf stage, and the broad-leaved weeds grow to the 2 true leaf stage, spray them with a crawler crop sprayer (designed and produced by British Engineer Research Ltd.) according to the experimental design dose. Treatment (spray pressure 1.95kg/cm 2 , spray volume 50ml/m 2 , crawler speed 1.48km/h). The test was repeated 3 times. After the liquid was naturally air-dried, it was placed in a greenhouse and managed by conventional methods. Regular observation The growth and development of the test materials, and according to the actual situation, the control effect of the test chemicals on weeds was regularly inspected visually after treatment.
防除效果分级标准：0为无效，100％为将杂草完全杀死或严重抑制。Grading standard of control effect: 0 means no effect, 100% means that weeds are completely killed or severely inhibited.
部分苗后测试结果如下(所有质量浓度均以有效成分计)：Some post-emergence test results are as follows (all mass concentrations are based on active ingredients):
(1)示例性的实施例化合物对阔叶杂草的防效(1) Control effect of exemplary compound on broadleaf weeds
600g a.i./ha时，化合物1、2、3、4、5、6、15、18、22、36、42、43、121、122、123、124、125、126、130、131、133、135、136、138、140、141-1、144、145、152、162、163、166、175、185、202、203、213、242、243、258、281、282、283、286、290、295、296、305、316、323、326、335、362、363、364、402、403、415、441、442、443、446、481、482、483、486、493、496、523、526、536、562、563、577、599、600、621、634、639、640、658、659、676、698、699、702、709、716、738、739、777、778、779、818、819、822、841、843、852、868、869、872、881、895、896、899、906对苍耳、苘麻、百日草、马齿苋、婆婆纳的防效均高于80％。At 600g a.i./ha, compounds 1, 2, 3, 4, 5, 6, 15, 18, 22, 36, 42, 43, 121, 122, 123, 124, 125, 126, 130, 131, 133, 135 , 136, 138, 140, 141-1, 144, 145, 152, 162, 163, 166, 175, 185, 202, 203, 213, 242, 243, 258, 281, 282, 283, 286, 290, 295 , 296, 305, 316, 323, 326, 335, 362, 363, 364, 402, 403, 415, 441, 442, 443, 446, 481, 482, 483, 486, 493, 496, 523, 526, 536 , 562, 563, 577, 599, 600, 621, 634, 639, 640, 658, 659, 676, 698, 699, 702, 709, 716, 738, 739, 777, 778, 779, 818, 819, 822 , 841, 843, 852, 868, 869, 872, 881, 895, 896, 899, 906 were all higher than 80% in control effect on Xanthium, Abutilon, Zinnia, Purslane, and Granny.
150g a.i./ha时，化合物1、2、3、4、5、6、15、18、22、36、42、43、121、122、123、124、125、126、130、131、133、135、136、138、140、141-1、144、145、152、162、163、166、175、185、202、203、213、242、243、258、281、282、283、286、290、295、296、305、316、323、326、335、362、363、364、402、403、481、482、483、486、493、496、523、526、536、562、563、577、599、600、621、634、639、640、658、659、676、698、699、702、709、716、738、739、777、778、779、818、819、822、841、843、852、868、869、872、881、895、896、899、906对苍耳、苘麻、百日草、马齿苋、婆婆纳的防效高于80％。At 150g a.i./ha, compounds 1, 2, 3, 4, 5, 6, 15, 18, 22, 36, 42, 43, 121, 122, 123, 124, 125, 126, 130, 131, 133, 135 , 136, 138, 140, 141-1, 144, 145, 152, 162, 163, 166, 175, 185, 202, 203, 213, 242, 243, 258, 281, 282, 283, 286, 290, 295 , 296, 305, 316, 323, 326, 335, 362, 363, 364, 402, 403, 481, 482, 483, 486, 493, 496, 523, 526, 536, 562, 563, 577, 599, 600 , 621, 634, 639, 640, 658, 659, 676, 698, 699, 702, 709, 716, 738, 739, 777, 778, 779, 818, 819, 822, 841, 843, 852, 868, 869 , 872, 881, 895, 896, 899, 906 are more than 80% effective against cocklebur, abalone, zinnia, purslane and mother-in-law.
37.5g a.i./ha时，化合物2、3、4、5、6、15、18、22、36、42、43、121、122、123、124、125、126、130、131、133、135、136、138、140、141-1、162、163、166、175、185、202、203、213、242、243、258、281、282、283、286、290、295、296、316、323、326、335、362、363、364、481、482、483、486、493、496、523、526、536、658、659、676、 698、699、702、709、716、738、739、777、778、779、818、819、822、841、843、852、868、869、872、881、895、896、899、906对苍耳、苘麻、百日草、马齿苋、婆婆纳的防效高于80％。At 37.5g a.i./ha, compounds 2, 3, 4, 5, 6, 15, 18, 22, 36, 42, 43, 121, 122, 123, 124, 125, 126, 130, 131, 133, 135, 136, 138, 140, 141-1, 162, 163, 166, 175, 185, 202, 203, 213, 242, 243, 258, 281, 282, 283, 286, 290, 295, 296, 316, 323, 326, 335, 362, 363, 364, 481, 482, 483, 486, 493, 496, 523, 526, 536, 658, 659, 676, 698, 699, 702, 709, 716, 738, 739, 777, 778, 779, 818, 819, 822, 841, 843, 852, 868, 869, 872, 881, 895, 896, 899, 906 Protection against cocklebur, amaranth, zinnia, purslane and mother-in-law The efficiency is higher than 80%.
(2)示例性的实施例化合物对禾本科杂草的防效(2) Control effect of exemplary compound against grass weeds
600g a.i./ha时，化合物1、2、3、4、5、6、15、18、22、36、42、43、121、122、123、124、125、126、130、131、133、135、136、138、140、141-1、144、145、152、162、163、166、175、185、202、203、213、242、243、258、281、282、283、286、290、295、296、305、316、323、326、335、362、363、364、402、403、415、441、442、443、446、481、482、483、486、493、496、523、526、536、562、563、577、599、600、621、634、639、640、658、659、676、698、699、702、709、716、738、739、777、778、779、818、819、822、841、843、852、868、869、872、881、895、896、899、906对狗尾草、牛筋草、马唐的防效均高于80％。At 600g a.i./ha, compounds 1, 2, 3, 4, 5, 6, 15, 18, 22, 36, 42, 43, 121, 122, 123, 124, 125, 126, 130, 131, 133, 135 , 136, 138, 140, 141-1, 144, 145, 152, 162, 163, 166, 175, 185, 202, 203, 213, 242, 243, 258, 281, 282, 283, 286, 290, 295 , 296, 305, 316, 323, 326, 335, 362, 363, 364, 402, 403, 415, 441, 442, 443, 446, 481, 482, 483, 486, 493, 496, 523, 526, 536 , 562, 563, 577, 599, 600, 621, 634, 639, 640, 658, 659, 676, 698, 699, 702, 709, 716, 738, 739, 777, 778, 779, 818, 819, 822 , 841, 843, 852, 868, 869, 872, 881, 895, 896, 899, 906 were all higher than 80% in the control effects of foxtail, oxtenoid and crabgrass.
150g a.i./ha时，化合物1、2、3、4、5、6、15、18、22、36、42、43、121、122、123、124、125、126、130、131、133、135、136、138、140、141-1、144、145、152、162、163、166、175、185、202、203、213、242、243、258、281、282、283、286、290、295、296、305、316、323、326、335、362、363、364、402、403、481、482、483、486、493、496、523、526、536、562、563、599、600、639、640、658、659、676、698、699、702、709、716、738、739、777、778、779、818、819、822、841、843、852、868、869、872、881、895、896、899、906对狗尾草、牛筋草、马唐的防效均高于80％。At 150g a.i./ha, compounds 1, 2, 3, 4, 5, 6, 15, 18, 22, 36, 42, 43, 121, 122, 123, 124, 125, 126, 130, 131, 133, 135 , 136, 138, 140, 141-1, 144, 145, 152, 162, 163, 166, 175, 185, 202, 203, 213, 242, 243, 258, 281, 282, 283, 286, 290, 295 , 296, 305, 316, 323, 326, 335, 362, 363, 364, 402, 403, 481, 482, 483, 486, 493, 496, 523, 526, 536, 562, 563, 599, 600, 639 , 640, 658, 659, 676, 698, 699, 702, 709, 716, 738, 739, 777, 778, 779, 818, 819, 822, 841, 843, 852, 868, 869, 872, 881, 895 , 896, 899, 906 were all higher than 80% of the control effects on foxtail, oxtenoid and crabgrass.
37.5g a.i./ha时，化合物2、3、4、5、6、36、121、122、123、124、125、126、130、131、133、135、136、138、140、141-1、162、163、166、175、202、203、213、281、282、283、286、290、295、296、481、482、483、486、493、496、523、526、536、658、659、676、698、699、702、709、716、738、739、777、778、779、819、822、841、843、852、868、869、872、881、895、896、899、906对狗尾草、牛筋草、马唐的防效均高于80％。At 37.5g a.i./ha, compounds 2, 3, 4, 5, 6, 36, 121, 122, 123, 124, 125, 126, 130, 131, 133, 135, 136, 138, 140, 141-1, 162, 163, 166, 175, 202, 203, 213, 281, 282, 283, 286, 290, 295, 296, 481, 482, 483, 486, 493, 496, 523, 526, 536, 658, 659, 676, 698, 699, 702, 709, 716, 738, 739, 777, 778, 779, 819, 822, 841, 843, 852, 868, 869, 872, 881, 895, 896, 899, 906 The control effects of beef tendon and crabgrass were higher than 80%.
除上述列举的化合物外，本发明其他示例性的实施例化合物对如上测试的杂草均表现出较高的防效。In addition to the compounds listed above, other exemplary compounds of the present invention all showed higher control effects on the weeds tested as above.
2、示例性的实施例化合物与对照药剂的测试结果2. Test Results of Exemplary Example Compounds and Control Agents
本实施例进行了示例性的实施例化合物与对照药剂的活性对比试验(化合物CK 1为专利文献WO2014048827中的编号1.1.1，根据文献报道方法制备)。测试结果见下表5。 In this example, the activity comparison test of the exemplary compound of the example and the control agent was carried out (compound CK 1 is No. 1.1.1 in the patent document WO2014048827, prepared according to the method reported in the literature). The test results are shown in Table 5 below.
Figure PCTCN2021133602-appb-000058
Figure PCTCN2021133602-appb-000058
表5table 5
Figure PCTCN2021133602-appb-000059
Figure PCTCN2021133602-appb-000059
Figure PCTCN2021133602-appb-000060
Figure PCTCN2021133602-appb-000060
除上表中列举的化合物外，本发明其他示例性的实施例化合物对杂草的防效优于对照药剂。因此，本发明式(I)化合物对农业领域中的多种有害杂草都表现出很好的活性。In addition to the compounds listed in the above table, other exemplary compounds of the present invention have better control effects on weeds than the control agents. Therefore, the compounds of the formula (I) of the present invention show good activity against various harmful weeds in the agricultural field.
3、室内对作物的安全性试验3. Indoor safety test of crops
将定量的作物种子分别播于直径为7cm的装有营养土的纸杯中，播后覆土1cm，镇压、淋水后在温室培养，出苗后间苗、定植，待供试作物生长到所需叶期(水稻2～3叶期)，按试验设计剂量用履带式作物喷雾机(英国Engineer Research Ltd.设计生产)进行茎叶喷雾处理(喷雾压力1.95kg/cm2，喷液量50ml/m2，履带速度1.48km/h)，试验设3次重复。待药液自然风干后，放于温室内按常规方法管理，观察各个处理供试作物的生长发育情况，定期目测调查供试药剂对供试作物的安全性。安全性分级标准：0表示对作物无任何损伤，100为将作物完全杀死或严重抑制。测试结果见表6。The quantitative crop seeds were sown in paper cups with nutrient soil with a diameter of 7cm, covered with soil 1cm after sowing, and cultivated in a greenhouse after suppression and drenching. (2-3 leaf stage of rice), according to the experimental design dose, use a crawler-type crop sprayer (designed and produced by British Engineer Research Ltd.) to spray the stem and leaves (spray pressure 1.95kg/cm2, spray volume 50ml/m2, crawler speed 1.48km/h), the test was repeated three times. After the medicinal liquid was naturally air-dried, it was placed in a greenhouse for management according to conventional methods, the growth and development of the tested crops were observed for each treatment, and the safety of the tested chemicals on the tested crops was regularly inspected visually. Safety grading standard: 0 means no damage to the crop, 100 means the crop is completely killed or severely inhibited. The test results are shown in Table 6.
表6安全性试验结果表Table 6 Safety test results table
Figure PCTCN2021133602-appb-000061
Figure PCTCN2021133602-appb-000061
Figure PCTCN2021133602-appb-000062
Figure PCTCN2021133602-appb-000062
通过室内安全性测定发现化合物2、3、6、15、122、123、124、125、126、130、131、133、135、140、163、282、286等在苗前、苗后75-300g a.i./hm 2剂量下对玉米和水稻均有较好的安全性。 It was found that compounds 2, 3, 6, 15, 122, 123, 124, 125, 126, 130, 131, 133, 135, 140, 163, 282, 286, etc. were 75-300 g pre-emergence and post-emergence through indoor safety testing. The ai/hm 2 dose had good safety on corn and rice.
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (15)

  1. 式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物，Compounds represented by formula (I), stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or esters, solvates or pharmaceutically acceptable compounds thereof solvates of the salts,
    Figure PCTCN2021133602-appb-100001
    Figure PCTCN2021133602-appb-100001
    其中，in,
    R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、卤素、C 1-C 6烷基或卤代C 1-C 6烷基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
    R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、卤素、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
    R 9、R 10相同或不同，彼此独立地选自氢、氰基、C 1-C 6烷基或卤代C 1-C 6烷基； R 9 and R 10 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
    R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 6烷基、卤代C 1-C 6烷基、COOR 13或CONR 14R 15； R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, COOR 13 or CONR 14 R 15 ;
    R 13选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 3烷氧基C 1-C 6烷基、C 3-C 6烯基、C 3-C 6炔基、未取代或被1-4个Ra取代的C 6-C 10芳基C 1-C 6烷基、5-10元杂芳基C 1-C 6烷基、3-10元杂环基C 1-C 6烷基；每个Ra相同或不同，彼此独立地选自卤素、氰基、硝基、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, unsubstituted or 1-4 Ra substituted C 6 -C 10 aryl C 1 -C 6 alkyl, 5-10 membered heteroaryl C 1 -C 6 alkyl, 3-10 Membered heterocyclyl C 1 -C 6 alkyl; each Ra is the same or different and independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
    R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 6烷基或C 1-C 4烷氧基C 1-C 6烷基。 R 14 and R 15 are the same or different and are independently selected from hydrogen, C 1 -C 6 alkyl or C 1 -C 4 alkoxy C 1 -C 6 alkyl.
  2. 根据权利要求1所述的化合物，其中，式(I)中，The compound according to claim 1, wherein, in formula (I),
    R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、卤素、C 1-C 4烷基或卤代C 1-C 4烷基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
    R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、卤素、C 1-C 4烷基、卤代C 1-C 4烷基、C 1-C 4烷氧基或卤代C 1-C 4烷氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogenated C 1 -C 4 alkoxy;
    R 9、R 10相同或不同，彼此独立地选自氢、C 1-C 4烷基或卤代C 1-C 4烷基； R 9 and R 10 are the same or different and are independently selected from hydrogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
    R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 6烷基、卤代C 1-C 6烷基、COOR 13或CONR 14R 15； R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, COOR 13 or CONR 14 R 15 ;
    R 13选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 3烷氧基C 1-C 3烷基、C 3-C 6烯基、C 3-C 6炔基、未取代或被1-4个Ra取代的C 6-C 8芳基C 1-C 4烷基、5-8元杂芳基C 1-C 4烷基、3-6元杂环基C 1-C 4烷基；每个Ra相同或不同，彼此独立地选自卤素、氰基、硝基、C 1-C 4烷基、卤代C 1-C 4烷基、C 1-C 4烷氧基或卤代C 1-C 4烷氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 6 -C 8 aryl C 1 -C 4 alkyl, unsubstituted or substituted by 1-4 Ra, C 1 -C 4 alkyl, 5-8 membered heteroaryl C 1 -C 4 alkyl, 3-6 Membered heterocyclyl C 1 -C 4 alkyl; each Ra is the same or different and independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogenated C 1 -C 4 alkoxy;
    R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 4烷基或C 1-C 4烷氧基C 1-C 6烷基。 R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy C 1 -C 6 alkyl.
  3. 根据权利要求1或2所述的化合物，其中，式(I)中，The compound according to claim 1 or 2, wherein, in formula (I),
    R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、溴、甲基、乙基、三氟甲基或三氟乙基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
    R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、溴、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy group, trifluoromethoxy or trifluoroethoxy;
    R 9、R 10相同或不同，彼此独立地选自氢、C 1-C 4烷基或卤代C 1-C 4烷基； R 9 and R 10 are the same or different and are independently selected from hydrogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl;
    R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 4烷基、卤代C 1-C 4烷基、COOR 13或CONR 14R 15； R 11 and R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, COOR 13 or CONR 14 R 15 ;
    R 13选自氢、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 3烷氧基C 1-C 3烷基、C 3-C 6烯基、C 3-C 6炔基、未取代或被1-4个Ra取代的苄基、呋喃基甲基、四氢呋喃基甲基或1,3-二氧环戊烷乙基；每个Ra相同或不同，彼此独立地选自氟、氯、氰基、硝基、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, benzyl, unsubstituted or substituted with 1-4 Ras, furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl; each Ra is the same or different, independently of each other selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
    R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 4烷基或C 1-C 3烷氧基C 1-C 3烷基。 R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
  4. 根据权利要求1-3任一项所述的化合物，其中，式(I)中，The compound according to any one of claims 1-3, wherein, in formula (I),
    R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、甲基、乙基、三氟甲基或三氟乙基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl or trifluoroethyl;
    R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
    R 9、R 10相同或不同，彼此独立地选自氢、甲基、乙基、丙基、丁基、三氟甲基或三氟乙基； R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl, butyl, trifluoromethyl or trifluoroethyl;
    R 11、R 12相同或不同，彼此独立地选自氢、氰基、C 1-C 4烷基、C 1-C 4卤代烷基、COOR 13或CONR 14R 15； R 11 , R 12 are the same or different, and are independently selected from hydrogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, COOR 13 or CONR 14 R 15 ;
    R 13选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、烯丙基、炔丙基、C 1-C 3烷氧基C 1-C 3烷基、未取代或被1-4个Ra取代的苄基、呋喃基甲基、四氢呋喃基甲基或1,3-二氧环戊烷乙基；每个Ra相同或不同，彼此独立地选自氟、氯、氰基、硝基、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基或三氟乙氧基； R 13 is selected from hydrogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, unsubstituted or benzyl, furylmethyl, tetrahydrofuranylmethyl or 1,3-dioxolaneethyl substituted with 1-4 Ras; each Ra is the same or different and independently selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy;
    R 14、R 15相同或不同，彼此独立地选自氢、C 1-C 4烷基或C 1-C 3烷氧基C 1-C 3烷基。 R 14 and R 15 are the same or different, and are independently selected from hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkoxy C 1 -C 3 alkyl.
  5. 根据权利要求1-4任一项所述的化合物，其中，式(I)中，The compound according to any one of claims 1-4, wherein, in formula (I),
    R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯、甲基或三氟甲基； R 1 , R 2 , R 3 , R 4 are the same or different, and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
    R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基、三氟甲基、甲氧基或三氟甲氧基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
    R 9、R 10相同或不同，彼此独立地选自氢、甲基、乙基、丙基或丁基； R 9 and R 10 are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl or butyl;
    R 11、R 12相同或不同，彼此独立地选自氢、甲基、乙基或COOR 13； R 11 and R 12 are the same or different, and are independently selected from hydrogen, methyl, ethyl or COOR 13 ;
    R 13选自氢、C 1-C 4烷基、卤代C 1-C 4烷基、烯丙基、炔丙基、C 1-C 3烷氧基C 1-C 3烷基、苄基、呋喃基甲基、四氢呋喃基甲基或1,3-二氧环戊烷乙基。 R 13 is selected from hydrogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, allyl, propargyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, benzyl , furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl.
  6. 根据权利要求1-5任一项所述的化合物，其中，式(I)中，The compound according to any one of claims 1-5, wherein, in formula (I),
    R 1、R 2、R 3、R 4相同或不同，彼此独立地选自氢、氟、氯或三氟甲基； R 1 , R 2 , R 3 , R 4 are the same or different and are independently selected from hydrogen, fluorine, chlorine or trifluoromethyl;
    R 5、R 6、R 7、R 8相同或不同，彼此独立地选自氢、氟、氯、甲基或三氟甲基； R 5 , R 6 , R 7 , R 8 are the same or different and are independently selected from hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
    R 9、R 10相同或不同，彼此独立地选自氢或甲基； R 9 and R 10 are the same or different, and are independently selected from hydrogen or methyl;
    R 11、R 12相同或不同，彼此独立地选自甲基、乙基或COOR 13； R 11 and R 12 are the same or different, and are independently selected from methyl, ethyl or COOR 13 ;
    R 13选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、三氟甲基、三氟乙基、烯丙基、炔丙基、甲氧基乙基、乙氧基乙基、苄基、呋喃基甲基、四氢呋喃基甲基或1,3-二氧环戊烷乙基。 R 13 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, allyl, propargyl, methoxy ethyl, ethoxyethyl, benzyl, furylmethyl, tetrahydrofurylmethyl or 1,3-dioxolaneethyl.
  7. 根据权利要求1-6任一项所述的化合物，其中，式(I)中，The compound according to any one of claims 1-6, wherein, in formula (I),
    当R 1＝H，R 2＝CF 3，R 3＝H，R 6＝H，R 8＝H时，其他基团如下表所示： When R 1 =H, R 2 =CF 3 , R 3 =H, R 6 =H, R 8 =H, other groups are shown in the following table:
    Figure PCTCN2021133602-appb-100002
    Figure PCTCN2021133602-appb-100002
    Figure PCTCN2021133602-appb-100003
    Figure PCTCN2021133602-appb-100003
    Figure PCTCN2021133602-appb-100004
    Figure PCTCN2021133602-appb-100004
    Figure PCTCN2021133602-appb-100005
    Figure PCTCN2021133602-appb-100005
    Figure PCTCN2021133602-appb-100006
    Figure PCTCN2021133602-appb-100006
    Figure PCTCN2021133602-appb-100007
    Figure PCTCN2021133602-appb-100007
    Figure PCTCN2021133602-appb-100008
    Figure PCTCN2021133602-appb-100008
    Figure PCTCN2021133602-appb-100009
    Figure PCTCN2021133602-appb-100009
    Figure PCTCN2021133602-appb-100010
    Figure PCTCN2021133602-appb-100010
    Figure PCTCN2021133602-appb-100011
    Figure PCTCN2021133602-appb-100011
    Figure PCTCN2021133602-appb-100012
    Figure PCTCN2021133602-appb-100012
    Figure PCTCN2021133602-appb-100013
    Figure PCTCN2021133602-appb-100013
    Figure PCTCN2021133602-appb-100014
    Figure PCTCN2021133602-appb-100014
    Figure PCTCN2021133602-appb-100015
    Figure PCTCN2021133602-appb-100015
    Figure PCTCN2021133602-appb-100016
    Figure PCTCN2021133602-appb-100016
    Figure PCTCN2021133602-appb-100017
    Figure PCTCN2021133602-appb-100017
    Figure PCTCN2021133602-appb-100018
    Figure PCTCN2021133602-appb-100018
    当R 1＝H，R 2＝CF 3，R 3＝H，R 5＝H，R 6＝H，其他基团如下表所示： When R 1 =H, R 2 =CF 3 , R 3 =H, R 5 =H, R 6 =H, other groups are shown in the following table:
    Figure PCTCN2021133602-appb-100019
    Figure PCTCN2021133602-appb-100019
    Figure PCTCN2021133602-appb-100020
    Figure PCTCN2021133602-appb-100020
    Figure PCTCN2021133602-appb-100021
    Figure PCTCN2021133602-appb-100021
    当R 5＝F，R 6＝H，R 7＝Cl，R 8、R 10＝H时，其他基团如下表所示： When R 5 =F, R 6 =H, R 7 =Cl, R 8, R 10 =H, other groups are shown in the following table:
    Figure PCTCN2021133602-appb-100022
    Figure PCTCN2021133602-appb-100022
    Figure PCTCN2021133602-appb-100023
    Figure PCTCN2021133602-appb-100023
    Figure PCTCN2021133602-appb-100024
    Figure PCTCN2021133602-appb-100024
    Figure PCTCN2021133602-appb-100025
    Figure PCTCN2021133602-appb-100025
    Figure PCTCN2021133602-appb-100026
    Figure PCTCN2021133602-appb-100026
    优选地，式(I)所示的化合物具有以下结构：Preferably, the compound represented by formula (I) has the following structure:
    Figure PCTCN2021133602-appb-100027
    Figure PCTCN2021133602-appb-100027
  8. 权利要求1-7任一项所述化合物的制备方法，其中，包括如下步骤：The preparation method of the compound described in any one of claim 1-7, wherein, comprises the steps:
    式(II)所示化合物与式(III)化合物发生环加成反应得到式(I)化合物；The compound represented by the formula (II) is subjected to a cycloaddition reaction with the compound of the formula (III) to obtain the compound of the formula (I);
    Figure PCTCN2021133602-appb-100028
    Figure PCTCN2021133602-appb-100028
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12具有权利要求1-7任一项所述的定义；L选自离去基团，例如Cl或Br； Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 have the definitions described in any one of claims 1-7 ; L is selected from leaving groups such as Cl or Br;
    优选地，所述反应可以在碱存在下进行，所述碱可以为有机碱，例如选自吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)或二异丙基乙胺(DIEA)中的至少一种；Preferably, the reaction may be carried out in the presence of a base, which may be an organic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropylethylamine (DIEA) at least one of );
    优选地，所述反应在溶剂中进行，所述溶剂选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、二氧六环或甲苯中的至少一种；Preferably, the reaction is carried out in a solvent selected from at least one of N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dioxane or toluene;
    优选地，所述反应温度可以为-5～120℃，例如0-50℃，如15～50℃；Preferably, the reaction temperature can be -5-120°C, for example, 0-50°C, such as 15-50°C;
    优选地，所述环加成反应可在制备偶极前体II的一锅反应中进行或在分离后的偶极前体II存在下进行。Preferably, the cycloaddition reaction can be carried out in a one-pot reaction to prepare the dipole precursor II or in the presence of the isolated dipole precursor II.
  9. 根据权利要求8所述的制备方法，其中，当式(I)化合物中R 12为COOR 13，且R 13不为H时，可通过水解反应制备得到R 12为COOH的式(I)所示的化合物； The preparation method according to claim 8, wherein, when R 12 in the compound of formula (I) is COOR 13 and R 13 is not H, the formula (I) in which R 12 is COOH can be prepared by a hydrolysis reaction compound of;
    Figure PCTCN2021133602-appb-100029
    Figure PCTCN2021133602-appb-100029
    R 12＝COOR 13，且R 13不为H R 12 =COOR 13 , and R 13 is not H
    优选地，所述水解反应可以在碱存在下进行，所述碱选自氢氧化钠、氢氧化钾或氢氧化锂中的至少一种；或者在二氯甲烷中用酸如三氟乙酸处理；Preferably, the hydrolysis reaction can be carried out in the presence of a base selected from at least one of sodium hydroxide, potassium hydroxide or lithium hydroxide; or treatment with an acid such as trifluoroacetic acid in dichloromethane;
    优选地，所述水解反应的温度可以为0～150℃，例如15～80℃；Preferably, the temperature of the hydrolysis reaction can be 0-150°C, for example, 15-80°C;
    当式(I)化合物中R 12为COOH时，可通过第一步卤化反应、再经过第二步酯化反应制备得到R 12为COOR 13的式(I)所示的化合物； When R 12 in the compound of formula (I) is COOH, the compound represented by formula (I) in which R 12 is COOR 13 can be prepared through the first step of halogenation reaction and then through the second step of esterification reaction;
    Figure PCTCN2021133602-appb-100030
    Figure PCTCN2021133602-appb-100030
    优选地，第一步卤化反应所述卤化剂选自亚硫酰氯、草酰氯或二氯亚砜；Preferably, the halogenating agent in the first step of halogenation reaction is selected from thionyl chloride, oxalyl chloride or thionyl chloride;
    优选地，第一步卤化反应的温度可以为0～100℃，例如0-50℃，如0～30℃；Preferably, the temperature of the first-step halogenation reaction can be 0-100°C, such as 0-50°C, such as 0-30°C;
    优选地，第二步酯化反应可以在碱的存在下进行，所述碱可选自有机碱或无机碱，如吡 啶、三乙胺、4-(二甲氨基)吡啶(DMAP)、二异丙基乙胺(DIEA)、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾或氢化钠等中的一种、两种或者更多种；优选的溶剂可为N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二氧六环、甲苯、二氯甲烷或1,2-二氯乙烷中的一种、两种或者更多种；Preferably, the second-step esterification reaction can be carried out in the presence of a base, which can be selected from organic bases or inorganic bases, such as pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP), diiso One, two or more of propylethylamine (DIEA), sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium hydride, etc.; the preferred solvent may be N,N - one, two or more of dimethylacetamide, N,N-dimethylformamide, dioxane, toluene, dichloromethane or 1,2-dichloroethane;
    优选地，第二步酯化反应的温度可以为0～120℃，例如0-50℃，如15～30℃；Preferably, the temperature of the esterification reaction in the second step may be 0-120°C, such as 0-50°C, such as 15-30°C;
    或者，通过羧酸酯化反应得到；Or, obtained by carboxylic acid esterification;
    Figure PCTCN2021133602-appb-100031
    Figure PCTCN2021133602-appb-100031
    优选地，所述羧酸酯化反应可以在缩合剂存在下进行，所述缩合剂选自N,N′-二环己基碳二亚胺(DCC)、N,N′-二异丙基碳二亚胺(DIC)、1-羟基苯并***(HOBT)、2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)或六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBOP)中的至少一种；Preferably, the carboxylic acid esterification reaction can be carried out in the presence of a condensing agent selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbon Diimine (DIC), 1-Hydroxybenzotriazole (HOBT), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) or at least one of benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (PyBOP);
    优选地，所述羧酸酯化反应可以在碱存在下进行，所述碱可以为无机碱，例如选自吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)或二异丙基乙胺(DIEA)中的至少一种；Preferably, the carboxylic acid esterification reaction can be carried out in the presence of a base, which can be an inorganic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropyl At least one of ethylamine (DIEA);
    优选地，所述羧酸酯化反应在溶剂中进行，所述溶剂选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、2-甲基四氢呋喃、二氧六环、乙腈、甲苯、二氯甲烷或1,2-二氯乙烷中的至少一种；Preferably, the carboxylic acid esterification reaction is carried out in a solvent selected from N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxygen At least one of hexacyclic, acetonitrile, toluene, dichloromethane or 1,2-dichloroethane;
    优选地，所述羧酸酯化反应的温度可以为-5～120℃，例如0-50℃，如15～30℃。Preferably, the temperature of the carboxylic acid esterification reaction may be -5-120°C, for example, 0-50°C, such as 15-30°C.
  10. 根据权利要求8所述的制备方法，其中，当式(I)化合物中R 12为COOH时，可通过第一步卤化反应、再经过第二步缩合反应制备得到R 12为CONR 14R 15的式(I)所示的化合物； The preparation method according to claim 8, wherein, when R 12 in the compound of formula (I) is COOH, a compound whose R 12 is CONR 14 R 15 can be prepared through the first step of halogenation reaction and then through the second step of condensation reaction. A compound represented by formula (I);
    Figure PCTCN2021133602-appb-100032
    Figure PCTCN2021133602-appb-100032
    优选地，第一步卤化反应所述卤化剂选自亚硫酰氯、草酰氯或二氯亚砜；Preferably, the halogenating agent in the first step of halogenation reaction is selected from thionyl chloride, oxalyl chloride or thionyl chloride;
    优选地，第一步卤化反应的温度可以为0～100℃，例如0-50℃，如0～30℃；Preferably, the temperature of the first-step halogenation reaction can be 0-100°C, such as 0-50°C, such as 0-30°C;
    优选地，第二步缩合反应可以在碱的存在下进行，所述碱可选自有机碱或无机碱，如吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)、二异丙基乙胺(DIEA)、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、叔丁醇钾或氢化钠等中的一种、两种或者更多种；优选的溶剂可为N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二氧六环、甲苯、二氯甲烷或1,2-二氯乙烷中的一种、两种或者更多种；Preferably, the second-step condensation reaction can be carried out in the presence of a base, which can be selected from organic bases or inorganic bases, such as pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP), diisopropyl One, two or more of ethyl ethylamine (DIEA), sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide or sodium hydride, etc.; the preferred solvent may be N,N- One, two or more of dimethylacetamide, N,N-dimethylformamide, dioxane, toluene, dichloromethane or 1,2-dichloroethane;
    优选地，第二步缩合反应的温度可以为0～120℃，例如0-50℃，如15～30℃；Preferably, the temperature of the condensation reaction in the second step can be 0-120°C, such as 0-50°C, such as 15-30°C;
    或者，羧酸与胺直接通过缩合反应得到；Alternatively, the carboxylic acid and the amine are directly obtained through the condensation reaction;
    Figure PCTCN2021133602-appb-100033
    Figure PCTCN2021133602-appb-100033
    优选地，所述缩合反应可以在缩合剂存在下进行，所述缩合剂选自N,N′-二环己基碳二亚胺(DCC)、N,N′-二异丙基碳二亚胺(DIC)、1-羟基苯并***(HOBT)、2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU)或六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBOP)中的至少一种；Preferably, the condensation reaction can be carried out in the presence of a condensing agent selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBT), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) or at least one of benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (PyBOP);
    优选地，所述缩合反应可以在碱存在下进行，所述碱可以为无机碱，例如选自吡啶、三乙胺、4-(二甲氨基)吡啶(DMAP)或二异丙基乙胺(DIEA)中的至少一种；Preferably, the condensation reaction can be carried out in the presence of a base, which can be an inorganic base such as selected from pyridine, triethylamine, 4-(dimethylamino)pyridine (DMAP) or diisopropylethylamine ( at least one of DIEA);
    优选地，所述缩合反应在溶剂中进行，所述溶剂选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、2-甲基四氢呋喃、二氧六环、乙腈、甲苯、二氯甲烷或1,2-二氯乙烷中的至少一种；Preferably, the condensation reaction is carried out in a solvent selected from N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, At least one of acetonitrile, toluene, dichloromethane or 1,2-dichloroethane;
    优选地，所述缩合反应的温度可以为-5～120℃，例如0-50℃，如15～30℃；Preferably, the temperature of the condensation reaction can be -5-120°C, for example, 0-50°C, such as 15-30°C;
    其中,R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15具有权利要求1-7任一项所述的定义；L选自离去基团，例如Cl或Br。 wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 have claim 1 The definition of any one of -7; L is selected from a leaving group such as Cl or Br.
  11. 根据权利要求8所述的制备方法，其中，式(II)所示的化合物的制备方法，包括如下步骤：The preparation method according to claim 8, wherein, the preparation method of the compound shown in formula (II) comprises the steps:
    Figure PCTCN2021133602-appb-100034
    Figure PCTCN2021133602-appb-100034
    (1)式(VI)化合物与式(VII)化合物发生SUZUKI偶联反应得到式(V)化合物；(1) The compound of formula (VI) and the compound of formula (VII) undergo SUZUKI coupling reaction to obtain the compound of formula (V);
    (2)式(V)化合物与羟胺或盐酸羟胺反应得到式(IV)化合物；(2) the compound of formula (V) reacts with hydroxylamine or hydroxylamine hydrochloride to obtain the compound of formula (IV);
    (3)式(IV)化合物发生氯化反应得到式(II)化合物；(3) the compound of formula (IV) undergoes chlorination reaction to obtain the compound of formula (II);
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8具有权利要求1-7任一项所述的定义；L 1选自离去基团，例如Cl、Br、I或F；L选自离去基团，例如Cl或Br； Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 have the definitions described in any one of claims 1-7; L 1 is selected from leaving groups, such as Cl , Br, I or F; L is selected from leaving groups such as Cl or Br;
    优选地，步骤(1)可以在催化剂存在下进行，所述催化剂选自四(三苯基膦)钯、乙酸钯或双(三苯基膦)二氯化钯；Preferably, step (1) can be carried out in the presence of a catalyst selected from tetrakis(triphenylphosphine) palladium, palladium acetate or bis(triphenylphosphine) palladium dichloride;
    优选地，步骤(1)可以在碱存在下进行，所述碱选自碳酸钠、碳酸钾、吡啶、三乙胺或 4-(二甲氨基)吡啶中的一种、两种或者更多种；所述在溶剂选自甲苯、四氢呋喃、N,N-二甲基甲酰胺或水中的一种、两种或者更多种；所述反应的温度可以为20～150℃，例如50～80℃；Preferably, step (1) can be carried out in the presence of a base selected from one, two or more of sodium carbonate, potassium carbonate, pyridine, triethylamine or 4-(dimethylamino)pyridine ; The solvent is selected from one, two or more of toluene, tetrahydrofuran, N,N-dimethylformamide or water; the temperature of the reaction can be 20 to 150° C., for example, 50 to 80° C. ;
    优选地，步骤(2)可以在碱存在下进行，所述碱选自有机碱，如三乙胺、乙酸钠，或无机碱如碳酸氢钠中的一种、两种或者更多种；所述反应溶剂选自甲醇、乙醇等醇类溶剂或水或它们的混合物；所述反应的温度可以为0～100℃，优选15～30℃；Preferably, step (2) can be carried out in the presence of a base selected from organic bases such as triethylamine, sodium acetate, or one, two or more of inorganic bases such as sodium bicarbonate; The reaction solvent is selected from alcohol solvents such as methanol, ethanol, or water or a mixture thereof; the reaction temperature can be 0-100°C, preferably 15-30°C;
    优选地，步骤(3)可以在卤化剂的存在下进行，所述卤化剂可以为N-氯代琥珀酰亚胺(NCS)或N-溴代琥珀酰亚胺(NBS)；所述反应的温度可以为0～100℃，例如15～50℃；Preferably, step (3) can be carried out in the presence of a halogenating agent, and the halogenating agent can be N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS); The temperature may be from 0 to 100°C, for example, from 15 to 50°C;
    优选地，步骤(3)可以在碱存在下进行，所述碱选自三乙胺、吡啶、碳酸氢钠或碳酸钠中的至少一种；所述反应的温度可以为0～100℃，例如15～30℃。Preferably, step (3) can be carried out in the presence of a base selected from at least one of triethylamine, pyridine, sodium bicarbonate or sodium carbonate; the reaction temperature can be 0-100°C, for example 15～30℃.
  12. 一种农药组合物，例如除草组合物，其中，所述农药组合物包含作为活性成分的权利要求1-7任一项所述式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物中的一种、两种或者更多种；A pesticide composition, such as a herbicidal composition, wherein the pesticide composition comprises as an active ingredient the compound represented by the formula (I) according to any one of claims 1-7, its stereoisomer, racemic one, two or more of isomers, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or esters, solvates, or solvates of pharmaceutically acceptable salts ;
    优选地，所述组合物中活性成分的重量百分含量为0.1-99.9％，例如为0.5-99％；Preferably, the weight percentage of the active ingredient in the composition is 0.1-99.9%, for example, 0.5-99%;
    优选地，所述组合物中还包括农业和/或林业和/或卫生上可接受的载体中的一种、两种或者更多种；Preferably, the composition further comprises one, two or more of agricultural and/or forestry and/or hygienically acceptable carriers;
    优选地，所述组合物可以以制剂的形式施用；Preferably, the composition may be administered in the form of a formulation;
    例如，式(I)所示化合物作为活性成分溶解或分散于载体中或配制成制剂以便作为除草使用时更易于分散；For example, the compound represented by formula (I) is dissolved or dispersed in a carrier as an active ingredient or formulated into a formulation for easier dispersion when used as a herbicide;
    优选地，所述制剂包括但不限于如下形式：颗粒剂、可湿性粉剂、油悬剂、水悬剂、水乳剂、水剂、乳油或微胶囊等；Preferably, the preparation includes but is not limited to the following forms: granules, wettable powders, oil suspensions, water suspensions, water emulsions, water preparations, emulsifiable concentrates or microcapsules, etc.;
    优选地，所述组合物中还可以加入一种液体或固体载体，及任选地表面活性剂。Preferably, a liquid or solid carrier, and optionally a surfactant, may also be added to the composition.
  13. 权利要求1-7任一项所述式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物中的一种、两种或者更多种作为农药，例如生长调节剂或除草剂的用途。The compound represented by formula (I) according to any one of claims 1-7, its stereoisomer, racemate, tautomer, isotopic label, nitrogen oxide, pharmaceutically acceptable salt or Use of one, two, or more of esters, solvates, or solvates of pharmaceutically acceptable salts as pesticides, such as growth regulators or herbicides.
  14. 权利要求1-7任一项所述式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物中的一种、两种或者更多种在制备农药，例如制备生长调节剂或除草剂中的用途。The compound represented by formula (I) according to any one of claims 1-7, its stereoisomer, racemate, tautomer, isotopic label, nitrogen oxide, pharmaceutically acceptable salt or Use of one, two, or more of an ester, solvate, or solvate of a pharmaceutically acceptable salt in the preparation of a pesticide, such as a growth regulator or herbicide.
  15. 一种防治不想要的植物的方法，其包括将有效量的权利要求1-7任一项所述的式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或酯、溶剂合物或者药学上可接受的盐的溶剂合物中的一种、两种或者更多种，或将有效量的权利要求12所述的农药组合物施于不想要的植物、想要的植物的种子或块茎、或想要的植物的生长区域。A method for controlling unwanted plants, comprising mixing an effective amount of the compound of formula (I) described in any one of claims 1-7, its stereoisomer, racemate, tautomer one, two or more of a pharmaceutically acceptable salt or ester, solvate or solvate of a pharmaceutically acceptable salt, or an effective amount of The pesticidal composition of claim 12 is applied to unwanted plants, seeds or tubers of a desired plant, or a growing area of a desired plant.
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