WO2020246329A1 - PROCÉDÉ DE PRODUCTION D'UN COMPOSÉ DE β-CÉTOSULFONE - Google Patents

PROCÉDÉ DE PRODUCTION D'UN COMPOSÉ DE β-CÉTOSULFONE Download PDF

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WO2020246329A1
WO2020246329A1 PCT/JP2020/020859 JP2020020859W WO2020246329A1 WO 2020246329 A1 WO2020246329 A1 WO 2020246329A1 JP 2020020859 W JP2020020859 W JP 2020020859W WO 2020246329 A1 WO2020246329 A1 WO 2020246329A1
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halogen atoms
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裕美 林
俊之 木地
博美 貝瀬
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住友化学株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/16—Halogen atoms; Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms

Definitions

  • the present invention relates to a method for producing a ⁇ -ketosulfone compound.
  • ⁇ -ketosulfone compounds are an important group of compounds as intermediates and final products for the production of pharmaceuticals and pesticides.
  • Patent Document 1 describes that a ⁇ -ketosulfone compound is useful as a compound having anticancer activity against warm-blooded animals including humans.
  • a method for producing a ⁇ -ketosulfone compound an addition reaction of an alkylsulfone compound with a nitrile compound described in Patent Document 2 and Non-Patent Document 1 is known.
  • strong bases such as alkyllithium and sodium alkoxide are required, and industrial control of the reaction may be difficult, or the substrate may be damaged under basic conditions.
  • An object of the present invention is to provide an efficient method for producing a ⁇ -ketosulfone compound.
  • the present inventors As a result of investigating a method for producing a ⁇ -ketosulfone compound, the present inventors have obtained an ⁇ -sulfonyl ⁇ -ketoenamine compound by reacting a nitrile compound with a ⁇ -carbonyl sulfone compound in the presence of a metal salt and a base. Found to be generated. Then, it was found that the ⁇ -ketosulfone compound can be efficiently produced by reacting the compound with water in the presence of an acid. That is, the present invention is as follows.
  • X 1 represents CR 3 or a nitrogen atom
  • R 2 and R 3 are each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and an aryl group optionally substituted with one or more halogen atoms.
  • R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and an aryl group optionally substituted with one or more halogen atoms.
  • the benzene ring ⁇ the benzene ring may be substituted with one or more substituents selected from group A. ⁇ Is formed.
  • Group A Halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, an aryl group optionally substituted with one or more halogen atoms, even if substituted with one or more halogen atoms A group consisting of a good heteroaryl group or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms.
  • Compound represented by and formula (2) [In the formula, X represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms or an aryl group optionally substituted with one or more halogen atoms.
  • R 1 represents a C1-C6 alkyl group that may be substituted with one or more halogen atoms.
  • the compound represented by (4) is reacted in the presence of a metal salt and a base to formulate (4).
  • X, X 1 , R 1 , R 2 , R 4 and R 5 have the same meanings as described above.
  • Step of obtaining the compound represented by: A method for producing a compound represented by the formula (4), which comprises.
  • R 2 may be substituted with a hydrogen atom, a halogen atom, one or more halogen atoms, an aryl group, or one or more halogen atoms, or a C1-C6 alkoxy group.
  • ⁇ The production method according to any one of [1] to [3].
  • [5] The production method according to any one of [1] to [4], wherein X 1 is a nitrogen atom in the formula (1).
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom, a halogen atom, or three OCH 2 CF 2 CF groups.
  • [7] The production method according to any one of [1] to [6], wherein X is a methyl group in the formula (2).
  • [8] The production method according to any one of [1] to [7], wherein R 1 is an ethyl group in the formula (2).
  • the base is an inorganic base or an amine-based base.
  • Equation (4) in the presence of acid
  • X, X 1 , R 1 , R 2 , R 4 and R 5 have the same meanings as described above.
  • Equation (4) [During the ceremony, X represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms or an aryl group optionally substituted with one or more halogen atoms.
  • R 1 represents a C1-C6 alkyl group that may be substituted with one or more halogen atoms.
  • X 1 represents CR 3 or nitrogen atom
  • R 2 and R 3 are each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and an aryl group optionally substituted with one or more halogen atoms.
  • R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and an aryl group optionally substituted with one or more halogen atoms.
  • the benzene ring ⁇ the benzene ring may be substituted with one or more substituents selected from group A. ⁇ Is formed.
  • Group A Halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, an aryl group optionally substituted with one or more halogen atoms, even if substituted with one or more halogen atoms A group consisting of a good heteroaryl group or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms.
  • R 2 may be substituted with a hydrogen atom, a halogen atom, one or more halogen atoms, an aryl group, or one or more halogen atoms, or a C1-C6 alkoxy group.
  • a benzene ring may be substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of good aryl groups or C1-C6 alkoxy groups which may be substituted with one or more halogen atoms.
  • substituents selected from the group consisting of good aryl groups or C1-C6 alkoxy groups which may be substituted with one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom, a halogen atom, or three OCH 2 CF 2 CF groups.
  • [19] The compound according to any one of [13] to [18], wherein X is a methyl group in the formula (4).
  • [20] The compound according to any one of [13] to [19], wherein R 1 is an ethyl group in the formula (4).
  • a ⁇ -ketosulfone compound can be efficiently produced.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, a butyl group, and a tert-butyl group. Examples include a pentyl group and a hexyl group.
  • C1-C6 alkyl group optionally substituted with one or more halogen atoms examples include a difluoromethyl group, a trichloromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, and 2-.
  • aryl group include a phenyl group and a naphthyl group.
  • aryl group optionally substituted with one or more halogen atoms examples include a 2-bromophenyl group, a 3-iodophenyl group, a 4-chlorophenyl group, a 4-fluorophenyl group, and a 2,4-dichlorophenyl group.
  • heteroaryl group examples include pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, oxadiazolyl group, thiadiazolyl group and pyridyl group.
  • heteroaryl group examples include pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, oxadiazolyl group, thiadiazolyl group and pyridyl group.
  • examples thereof include a pyridazinyl group, a pyrimidinyl group, and a pyr
  • heteroaryl group optionally substituted with one or more halogen atoms examples include a 5-chloro-2-thienyl group, a 4-chloro-2-thienyl group, a 4-bromo-2-thienyl group, and 5 -Chloro-3-thienyl group, 5-chloro-2-pyrrrolyl group, 4-chloro-2-pyrrrolyl group, 4-bromo-2-pyrrrolyl group, 4-chloro-1-pyrrrolyl group, 5-chloro-2- Frill group, 4-chloro-2-furyl group, 5-fluoro-3-furyl group, 3-chloro-1-pyrazolyl group, 2-chloro-1-imidazolyl group, 4-bromo-1-imidazolyl group, 4- Fluoro-1,2,3-triazolyl group, 3-chloro-1,2,4-triazolyl group, 5-bromo-1,2,4-triazolyl group, 5-bromo-1,2,4-tri
  • alkoxy group examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a 1,1-dimethylpropoxy group, a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group, a butoxy group, and a tert-butoxy group. , Pentyloxy group, hexyloxy group and the like.
  • alkoxy group optionally substituted with one or more halogen atoms include a difluoromethoxy group, a trichloromethoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group and a 2-bromo-1 group.
  • Me represents a methyl group
  • Et represents an ethyl group
  • Bu represents a butyl group
  • Ac represents an acetyl group
  • THF represents tetrahydrofuran.
  • the compounds described herein may have, for example, the tautomers shown below.
  • the compound in the present invention may have one or more stereoisomers.
  • Stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • the present invention includes each stereoisomer and a mixture of stereoisomers in any ratio.
  • any stereoisomer or a mixture of stereoisomers contained in an arbitrary isomer ratio can be used as a compound represented by the formulas (2), (3) and (4), and is a geometric isomer. Since is not specified, the coupling is indicated by a wavy line.
  • Examples of the mode of the compound represented by the formula (1) include the following compounds.
  • X 1 is CR 3 or a nitrogen atom
  • R 3 is a C1-C6 alkyl group optionally substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, and one or more halogen atoms.
  • R 2 is a C1-C6 alkyl group optionally substituted with a hydrogen atom, a halogen atom or one or more halogen atoms, an aryl group optionally substituted with one or more halogen atoms, 1 or more.
  • R 4 and R 5 are independently substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may be substituted with one or more halogen atoms, and one or more halogen atoms.
  • Aryl groups may be represented, heteroaryl groups may be substituted with one or more halogen atoms, or C1-C6 alkoxy groups may be substituted with one or more halogen atoms, or they are attached.
  • a benzene ring together with a carbon atom ⁇ the benzene ring may be substituted with one or more substituents selected from Group A.
  • X 1 is CR 3 or a nitrogen atom, and R 2 and R 3 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, respectively.
  • -C6 alkyl group aryl group optionally substituted with one or more halogen atoms, heteroaryl group optionally substituted with one or more halogen atoms, or C1 optionally substituted with one or more halogen atoms -C6 alkoxy group in which R 4 and R 5 are independently substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may be substituted with one or more halogen atoms, and one or more halogen atoms.
  • X 1 is CR 3 or a nitrogen atom
  • R 2 , R 3 , R 4 , and R 5 are independently substituted with hydrogen atom, halogen atom, or one or more halogen atoms.
  • C1-C6 alkyl group which may be substituted, an aryl group which may be substituted with one or more halogen atoms, a heteroaryl group which may be substituted with one or more halogen atoms, or a halogen atom substituted with one or more atoms.
  • benzene ring may be substituted with a halogen atom, one or more halogen atoms C1 -C6 alkyl group, aryl group optionally substituted with one or more halogen atoms, heteroaryl group optionally substituted with one or more halogen atoms, or C1 optionally substituted with one or more halogen atoms -C6 alkoxy group, R 4 and R 5 together with the carbon atom to which they are bonded, benzene ring ⁇ The benzene ring may be substituted with a halogen atom, one or more halogen atoms C1 -C6 alkyl group, aryl group optionally substituted with one or more halogen atoms, heteroaryl group optionally substituted with one or more halogen atoms, or C1 optionally substituted with one or more halogen atoms -It may be substituted with one or more substituents selected from the group consisting of C6 alkoxy groups.
  • X 1 is CR 3 and R 2 , R 3 , R 4 , and R 5 are independently substituted with hydrogen atom, halogen atom, and one or more halogen atoms.
  • a compound that is a good C1-C6 alkoxy group In formula (1), X 1 is CR 3 , and R 2 and R 3 are C1-C6 alkyl groups which may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms. An aryl group optionally substituted with one or more halogen atoms, a heteroaryl group optionally substituted with one or more halogen atoms, or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms.
  • a benzene ring ⁇ the benzene ring is a C1-C6 alkyl group that may be substituted with a halogen atom, one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 , R 4 , and R 5 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, C1-.
  • X 1 is a nitrogen atom and R 2 is substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
  • An aryl group which may be an aryl group, a heteroaryl group which may be substituted with one or more halogen atoms, or a C1-C6 alkoxy group which may be substituted with one or more halogen atoms, and R 4 and R 5
  • the benzene ring ⁇ the benzene ring is substituted with a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 , and R 5 are independent hydrogen atoms, halogen atoms, C1-C6 alkyl groups, and one or more halogen atoms.
  • X 1 is CR 3 and R 2 and R 3 are independently substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or one or more halogen atoms.
  • a benzene ring ⁇ the benzene ring is substituted with a halogen atom, a C1-C6 alkyl group, an aryl group optionally substituted with one or more halogen atoms, and one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of heteroaryl groups which may be present, or C1-C6 alkoxy groups which may be substituted with one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 , R 4 , and R 5 are independently substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group, and one or more halogen atoms.
  • Aryl group which may be an aryl group, a heteroaryl group which may be substituted with one or more halogen atoms, or a C1-C6 alkoxy group which may be substituted with one or more halogen atoms;
  • X 1 is a nitrogen atom and R 2 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, an aryl group which may be substituted with one or more halogen atoms, and one or more halogen atoms.
  • the benzene ring ⁇ the benzene ring is a halogen atom, a C1-C6 alkyl group, an aryl group that may be substituted with one or more halogen atoms, a heteroaryl group that may be substituted with one or more halogen atoms, or It may be substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy groups which may be substituted with one or more halogen atoms.
  • the benzene ring ⁇ the benzene ring is an aryl group optionally substituted with one or more halogen atoms, or a heteroaryl group optionally substituted with one or more halogen atoms, or one or more It may be substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy groups which may be substituted with a halogen atom.
  • X 1 is a nitrogen atom
  • R 2 , R 4 , and R 5 are aryl groups that may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • R 2 is an aryl group that may be substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, or one or more halogen atoms.
  • the benzene ring may be substituted with a halogen atom, an aryl group optionally substituted with one or more halogen atoms, a heteroaryl group optionally substituted with one or more halogen atoms, or one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy groups.
  • X 1 is a nitrogen atom
  • R 2 , R 4 , and R 5 are independently substituted with a hydrogen atom, a halogen atom, and one or more halogen atoms.
  • a heteroaryl group, or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms;
  • X 1 is a nitrogen atom and R 2 is an aryl group, a heteroaryl group, or one or more halogen atoms which may be substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 , R 4 , and R 5 are independently substituted with a hydrogen atom, a halogen atom, and one or more halogen atoms.
  • R 2 is substituted with a hydrogen atom, a halogen atom, an aryl group optionally substituted with one or more halogen atoms, or one or more halogen atoms.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 , and R 5 are each independently substituted with a hydrogen atom, a halogen atom, an aryl group, or one or more halogen atoms.
  • X 1 is CR 3
  • R 2 and R 3 may each be independently substituted with a hydrogen atom, a halogen atom, an aryl group, or one or more halogen atoms.
  • benzene ring ⁇ the benzene ring is substituted with a halogen atom, an aryl group, or one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy groups.
  • X 1 is a nitrogen atom
  • R 2 , R 4 , and R 5 are each independently substituted with a hydrogen atom, a halogen atom, an aryl group, or one or more halogen atoms.
  • a compound that is a good C1-C6 alkoxy group In formula (1), X 1 is a nitrogen atom and R 2 is a C1-C6 alkoxy group optionally substituted with a hydrogen atom, a halogen atom, an aryl group, or one or more halogen atoms, and R 4 , And R 5 together with the carbon atom to which they are attached, from the benzene ring ⁇ the benzene ring is from a C1-C6 alkoxy group that may be substituted with a halogen atom, an aryl group, or one or more halogen atoms. It may be substituted with one or more substituents selected from the group. ⁇ The compound forming;
  • X 1 is CR 3
  • R 2 , R 3 , R 4 , and R 5 are each independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • X 1 is CR 3
  • R 2 and R 3 may each be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, C1-C6 alkoxy.
  • C1-C6 which is a group and R 4 and R 5 together with the carbon atom to which they are bonded are substituted with a benzene ring
  • the benzene ring may be substituted with a halogen atom or one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of alkoxy groups.
  • X 1 is a nitrogen atom
  • R 2 , R 4 , and R 5 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, respectively.
  • X 1 is a nitrogen atom and R 2 is a C1-C6 alkoxy group optionally substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms
  • R 4 and R. 5 is selected from the group consisting of a benzene ring ⁇ the benzene ring is a halogen atom, or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms, together with the carbon atom to which they are bonded 1 It may be substituted with the above substituents.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 , and R 5 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, and methoxy group.
  • Ethoxy group, propoxy group isopropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy Group, 2,2,3,3-tetrafluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 1,1,2,3,3,3-hexafluoropropoxy group, or 2, Compounds that are 2,3,4,5,4-hexafluorobutoxy groups;
  • X 1 is CR 3
  • R 2 and R 3 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methoxy group, ethoxy group and propoxy group.
  • X 1 is a nitrogen atom
  • R 2 , R 4 , and R 5 are independent hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, methoxy groups, and ethoxy groups.
  • X 1 is a nitrogen atom and R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, 1,1-.
  • R 4 and R 5 are combined with the carbon atom to which they are attached to form a benzene ring ⁇ the benzene ring is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, an ethoxy group, a propoxy group, Isopropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy group, 2,2,3,3-tetrafluoropropoxy group, With 2,2,3,3,3-pentafluoropropoxy group, 1,1,2,3,3,3-hexafluoropropoxy group, or 2,2,3,4,5,4-hexafluorobutoxy group Yes, R 4 and R 5 are combined with the carbon atom to which they are attached to form a benzene ring ⁇ the benzene ring is a flu
  • X 1 is CR 3
  • R 2 , R 3 , and R 4 are independently hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms, and R 5
  • hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methoxy group, ethoxy group, propoxy group isopropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy Group, butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy group, 2,2,3,3-tetrafluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 1 , 1,2,3,3,3-hexafluoropropoxy group, or 2,2,3,4,5,4-hexafluorobutoxy group;
  • X 1 is CR 3
  • R 2 and R 3 are independently hydrogen atoms, fluorine
  • X 1 is a nitrogen atom
  • R 2 and R 4 are independently hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms
  • R 5 is hydrogen.
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom
  • R 4 and R 5 are carbon atoms to which they are bonded.
  • the benzene ring may be substituted with one or more substituents selected from the group consisting of fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.
  • substituents selected from the group consisting of fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.
  • R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a 1,1-dimethylpropoxy group, a 1,2-dimethylpropoxy group.
  • X 1 is CR 3
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom
  • R 4 and R 5 are.
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom
  • R 5 is a hydrogen atom.
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom
  • R 4 and R 5 are combined with the carbon atom to which they are bonded to form a benzene ring.
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom
  • R 5 is a hydrogen atom.
  • X 1 is a nitrogen atom
  • R 2 and R 4 are hydrogen atoms
  • R 5 is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, an ethoxy group, 2, 2 , 3,3,3-pentafluoropropoxy group, 1,1,2,3,3,3-hexafluoropropoxy group, or 2,2,3,4,5,4-hexafluorobutoxy group
  • X 1 is a nitrogen atom
  • R 2 and R 4 are hydrogen atoms
  • R 5 is a fluorine atom
  • a compound in which X 1 is a nitrogen atom, R 2 and R 4 are hydrogen atoms, and R 5 is a fluorine atom; In formula (1), a compound in which X 1 is a nitrogen atom, R 2 and R 4 are hydrogen atoms, and R 5 is a chlorine atom; In formula (1), a compound in which X 1 is a nitrogen atom, R 2 and R 4 are hydrogen atoms, and R 5 is a bromine atom; In formula (1), a compound in which X 1 is a nitrogen atom, R 2 and R 4 are hydrogen atoms, and R 5 is an iodine atom; In formula (1), a compound in which X 1 is a nitrogen atom, R 2 and R 4 are hydrogen atoms, and R 5 is a methoxy group; In formula (1), a compound in which X 1 is a nitrogen atom, R 2 and R 4 are hydrogen atoms, and R 5 is an ethoxy group; In formula (1), X 1 is a
  • Examples of the mode of the compound represented by the formula (2) include the following compounds.
  • formula (2) a compound in which R 1 is a C1-C6 alkyl group optionally substituted with one or more halogen atoms;
  • formula (2) the compound in which R 1 is a C1-C6 alkyl group;
  • the compound in which R 1 is a methyl group, an ethyl group, or a propyl group;
  • formula (2) the compound in which R 1 is an ethyl group;
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms, or an aryl group optionally substituted with one or more halogen atoms;
  • the compound in which X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms;
  • the compound in which X is an aryl group optionally substituted with one or more halogen atoms;
  • formula (2) the compound in which X
  • the compound in which X is a methyl group, an ethyl group, a propyl group, or a trifluoromethyl group;
  • the compound in which X is a methyl group;
  • R 1 is a C1-C6 alkyl group, and X is substituted with a C1-C6 alkyl group that may be substituted with one or more halogen atoms, or one or more halogen atoms.
  • R 1 is a C1-C6 alkyl group and X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms;
  • R 1 is a C1-C6 alkyl group and X is an aryl group optionally substituted with one or more halogen atoms;
  • R 1 is a methyl group, an ethyl group, or a propyl group, and X is a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a hexafluoroethyl group, 2,2,2-.
  • R 1 is a methyl group, an ethyl group, or a propyl group
  • X is a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a phenyl group, or a 4-chlorophenyl group.
  • R 1 is a methyl group, an ethyl group, or a propyl group
  • X is a methyl group, an ethyl group, a propyl group, or a trifluoromethyl group
  • a compound in which R 1 is an ethyl group and X is a methyl group.
  • Examples of the mode of the compound represented by the formula (4) include the following compounds.
  • X 1 is CR 3 or a nitrogen atom
  • R 3 is a C1-C6 alkyl group optionally substituted with a hydrogen atom, a halogen atom, 1 or more halogen atoms, and 1 or more halogen atoms.
  • R 2 is a C1-C6 alkyl group optionally substituted with a hydrogen atom, a halogen atom or one or more halogen atoms, an aryl group optionally substituted with one or more halogen atoms, 1 or more.
  • R 4 and R 5 are independently substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may be substituted with one or more halogen atoms, and one or more halogen atoms. It represents an aryl group which may be an aryl group, a heteroaryl group which may be substituted with one or more halogen atoms, or a C1-C6 alkoxy group which may be substituted with one or more halogen atoms, or they are bonded.
  • a benzene ring ⁇ the benzene ring may be a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and an aryl optionally substituted with one or more halogen atoms.
  • the group is substituted with one or more substituents selected from the group consisting of a heteroaryl group optionally substituted with one or more halogen atoms or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms. You may.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms or an aryl group optionally substituted with one or more halogen atoms
  • R 1 is a C1-C6 alkyl group optionally substituted with one or more halogen atoms
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms or an aryl group optionally substituted with one or more halogen atoms, and R 1 is one or more halogens.
  • X 1 is CR 3 or a nitrogen atom, and R 2 and R 3 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms C1-C6.
  • the groups, R 4 and R 5, are each independently substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may be substituted with one or more halogen atoms, and one or more halogen atoms.
  • the benzene ring is a C1-C6 alkyl group optionally substituted with one or more halogen atoms, an aryl group optionally substituted with one or more halogen atoms, Even if it is substituted with one or more substituents selected from the group consisting of a heteroaryl group optionally substituted with one or more halogen atoms or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms. Good.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms or an aryl group optionally substituted with one or more halogen atoms, and R 1 is one or more halogen atoms.
  • X 1 is CR 3 or a nitrogen atom, and R 2 , R 3 , R 4 and R 5 are independently substituted with a hydrogen atom, a halogen atom and one or more halogen atoms.
  • a C1-C6 alkyl group which may be substituted by one or more halogen atoms, an aryl group which may be substituted by one or more halogen atoms, a heteroaryl group which may be substituted by one or more halogen atoms, or one or more halogen atoms.
  • X is a C1-C6 alkyl group which may be substituted with one or more halogen atoms or an aryl group which may be substituted with one or more halogen atoms
  • R 1 is A compound that is a C1-C6 alkyl group that may be substituted with one or more halogen atoms
  • X 1 is CR 3 or a nitrogen atom
  • R 2 and R 3 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms C1-C6.
  • Alkyl group aryl group optionally substituted with one or more halogen atoms, heteroaryl group optionally substituted with one or more halogen atoms or C1-C6 alkoxy optionally substituted with one or more halogen atoms C1-C6 alkyl which is a group and R 4 and R 5 together with the carbon atom to which they are bonded, are substituted with a benzene ring ⁇ the benzene ring may be substituted with a halogen atom, one or more halogen atoms.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • C1-C6 Alkyl group aryl group optionally substituted with one or more halogen atoms, heteroaryl group optionally substituted with one or more halogen atoms or C1 optionally substituted with one or more halogen atoms -C6 alkoxy group
  • X is a C1-C6 alkyl group which may be substituted with 1 or more halogen atoms or an aryl group which may be substituted with 1 or more halogen atoms
  • R 1 is 1 or more.
  • X 1 is CR 3
  • R 2 and R 3 are C1-C6 alkyl groups, which may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • a benzene ring ⁇ the benzene ring is a C1-C6 alkyl group, which may be substituted with one or more halogen atoms, 1 A group consisting of an aryl group optionally substituted with the above halogen atoms, a heteroaryl group optionally substituted with one or more halogen atoms, or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms. It may be substituted with one or more substituents selected from.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms or an aryl group optionally substituted with one or more halogen atoms, and R 1 is one or more halogen atoms.
  • X 1 is a nitrogen atom, and R 2 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms C1-C6.
  • Alkyl group aryl group optionally substituted with one or more halogen atoms, heteroaryl group optionally substituted with one or more halogen atoms or C1-C6 alkoxy optionally substituted with one or more halogen atoms
  • X 1 is a nitrogen atom and R 2 is a C1-C6 alkyl group optionally substituted with a hydrogen atom, a halogen atom, 1 or more halogen atoms, and 1 or more halogen atoms.
  • the aryl group may be a heteroaryl group which may be substituted with one or more halogen atoms or a C1-C6 alkoxy group which may be substituted with one or more halogen atoms, and R 4 and R 5 are them.
  • the benzene ring ⁇ the benzene ring is substituted with a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
  • a halogen atom a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms or an aryl group optionally substituted with one or more halogen atoms, and R 1 is one or more halogen atoms.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • C1-C6 alkyl group, aryl group optionally substituted with one or more halogen atoms, heteroaryl group optionally substituted with one or more halogen atoms or C1 optionally substituted with one or more halogen atoms -C1-C6 is a C1-C6 alkyl group or aryl group that represents a C6 alkoxy group and in which X may be substituted with one or more halogen atoms and R 1 may be substituted with one or more halogen atoms.
  • X 1 is CR 3
  • R 2 and R 3 are C1-C6 alkyl groups, which may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • a benzene ring ⁇ the benzene ring is a C1-C6 alkyl group, which may be substituted with one or more halogen atoms, 1 A group consisting of an aryl group optionally substituted with the above halogen atoms, a heteroaryl group optionally substituted with one or more halogen atoms, or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms. It may be substituted with one or more substituents selected from.
  • Alkyl group aryl group optionally substituted with one or more halogen atoms, heteroaryl group optionally substituted with one or more halogen atoms or C1-C6 alkoxy optionally substituted with one or more halogen atoms
  • X 1 is a nitrogen atom and R 2 is a C1-C6 alkyl group optionally substituted with a hydrogen atom, a halogen atom, 1 or more halogen atoms, and 1 or more halogen atoms.
  • the aryl group may be a heteroaryl group which may be substituted with one or more halogen atoms or a C1-C6 alkoxy group which may be substituted with one or more halogen atoms, and R 4 and R 5 are them.
  • the benzene ring ⁇ the benzene ring is substituted with a halogen atom, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
  • a halogen atom a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
  • X 1 is CR 3
  • R 2 and R 3 may be independently substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or one or more halogen atoms.
  • aryl group a heteroaryl group that may be substituted with one or more halogen atoms, or a C1-C6 alkoxy group that may be substituted with one or more halogen atoms, where R 4 and R 5 are attached.
  • the benzene ring ⁇ the benzene ring is substituted with a halogen atom, a C1-C6 alkyl group, an aryl group optionally substituted with one or more halogen atoms, and one or more halogen atoms.
  • ⁇ Is a C1-C6 alkyl group or aryl group in which X may be substituted with one or more halogen atoms, and a C1-C6 alkyl group in which R 1 may be substituted with one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 , R 4 and R 5 are independently substituted with a hydrogen atom, a halogen atom, a C1-C6 alkyl group and one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, an aryl group that may be substituted with one or more halogen atoms, and one or more halogen atoms.
  • Ring ⁇ The benzene ring is a halogen atom, a C1-C6 alkyl group, an aryl group optionally substituted with one or more halogen atoms, a heteroaryl group optionally substituted with one or more halogen atoms, or one or more heteroaryl groups. It may be substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy groups which may be substituted with a halogen atom.
  • Aryl group represents a heteroaryl group optionally substituted with one or more halogen atoms or a C1-C6 alkoxy group optionally substituted with one or more halogen atoms, where X is substituted with one or more halogen atoms.
  • X 1 is CR 3
  • R 2 and R 3 are independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, and one or more aryl groups.
  • a heteroaryl group that may be substituted with a halogen atom or a C1-C6 alkoxy group that may be substituted with one or more halogen atoms, with R 4 and R 5 combined with the carbon atom to which they are attached.
  • the benzene ring ⁇ the benzene ring is a halogen atom, an aryl group optionally substituted with one or more halogen atoms, a heteroaryl group optionally substituted with one or more halogen atoms, or one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy groups which may be substituted.
  • X 1 is a nitrogen atom and R 2 may be substituted with a hydrogen atom, a halogen atom, an aryl group that may be substituted with one or more halogen atoms, or one or more halogen atoms.
  • a C1-C6 alkoxy group that may be substituted with a heteroaryl group or one or more halogen atoms, with R 4 and R 5 combined with the carbon atom to which they are attached, the benzene ring ⁇ the benzene ring is , Halogen atom, an aryl group optionally substituted with one or more halogen atoms, a heteroaryl group optionally substituted with one or more halogen atoms, or C1-C6 optionally substituted with one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of alkoxy groups.
  • X 1 is CR 3
  • R 2 and R 3 are independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, or an aryl group or a heteroaryl group.
  • it is a C1-C6 alkoxy group that may be substituted with one or more halogen atoms, and R 4 and R 5 are combined with the carbon atom to which they are bonded to form a benzene ring ⁇ the benzene ring is a halogen atom.
  • X is a C1-C6 alkyl group or aryl group that may be substituted with one or more halogen atoms
  • X 1 is a nitrogen atom and R 2 is substituted with a hydrogen atom, a halogen atom, an aryl group optionally substituted with one or more halogen atoms, a heteroaryl group or one or more halogen atoms.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 and R 5 may be independently substituted with hydrogen atom, halogen atom, or one or more halogen atoms.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms, R.
  • a compound in which 1 is a C1-C6 alkyl group optionally substituted with one or more halogen atoms;
  • X 1 is CR 3
  • R 2 and R 3 are independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, or an aryl group or a heteroaryl group.
  • it is a C1-C6 alkoxy group that may be substituted with one or more halogen atoms
  • R 4 and R 5 are combined with the carbon atom to which they are bonded to form a benzene ring ⁇ the benzene ring is a halogen atom.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms and R 1 is a C1-C6 alkyl group optionally substituted with one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 , R 4 and R 5 are independently substituted with a hydrogen atom, a halogen atom and one or more halogen atoms, respectively.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms
  • R 1 is 1.
  • X 1 is a nitrogen atom and R 2 is substituted with a hydrogen atom, a halogen atom, an aryl group optionally substituted with one or more halogen atoms, a heteroaryl group or one or more halogen atoms.
  • It is a C1-C6 alkoxy group that may be present, in which R 4 and R 5 , together with the carbon atom to which they are bonded, are substituted with a benzene ring ⁇ the benzene ring is replaced with a halogen atom, one or more halogen atoms.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms and R 1 is a C1-C6 alkyl group optionally substituted with one or more halogen atoms.
  • R 1 is a C1-C6 alkyl group optionally substituted with one or more halogen atoms.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 and R 5 may be independently substituted with hydrogen atom, halogen atom, or one or more halogen atoms.
  • X is a C1-C6 alkyl group that may be substituted with one or more halogen atoms
  • R 1 is 1 or more.
  • X 1 is CR 3
  • R 2 and R 3 are independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, or an aryl group or one or more.
  • X is a C1-C6 alkyl group optionally substituted with one or more halogen atoms and R 1 is a C1-C6 alkyl group optionally substituted with one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • X is a C1-C6 alkyl group that may be substituted with 1 or more halogen atoms
  • R 1 is 1 or more halogen atoms.
  • X 1 is a nitrogen atom and R 2 may be substituted with a hydrogen atom, a halogen atom, an aryl group which may be substituted with one or more halogen atoms, or one or more halogen atoms. It is a C1-C6 alkoxy group, and R 4 and R 5 are combined with the carbon atom to which they are bonded, and the benzene ring ⁇ the benzene ring may be substituted with a halogen atom and one or more halogen atoms.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • X 1 is CR 3
  • R 2 and R 3 are independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms, or an aryl group or one or more.
  • X is a C1-C6 alkyl group and R 1 is a C1-C6 alkyl group;
  • X 1 is a nitrogen atom, and R 2 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom, or one or more halogen atoms.
  • a compound representing a C1-C6 alkoxy group that may be substituted with one or more halogen atoms where X is a C1-C6 alkyl group and R 1 is a C1-C6 alkyl group;
  • X 1 is a nitrogen atom and R 2 may be substituted with a hydrogen atom, a halogen atom, an aryl group which may be substituted with one or more halogen atoms, or one or more halogen atoms.
  • R 4 and R 5 are combined with the carbon atom to which they are bonded, and the benzene ring ⁇ the benzene ring may be substituted with a halogen atom and one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of an aryl group or a C1-C6 alkoxy group which may be substituted with one or more halogen atoms.
  • X is a C1-C6 alkyl group and R 1 is a C1-C6 alkyl group;
  • X 1 is CR 3
  • R 2 , R 3 , R 4 and R 5 are each independently substituted with a hydrogen atom, a halogen atom, an aryl group or one or more halogen atoms.
  • X 1 is CR 3
  • R 2 and R 3 may be independently substituted with a hydrogen atom, a halogen atom, an aryl group or one or more halogen atoms, C1-C6. It is an alkoxy group
  • R 4 and R 5 together with the carbon atom to which they are bonded, a benzene ring ⁇ the benzene ring may be substituted with a halogen atom, an aryl group or one or more halogen atoms. It may be substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy groups.
  • X is a C1-C6 alkyl group and R 1 is a C1-C6 alkyl group;
  • X 1 is a nitrogen atom, and R 2 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom, an aryl group or one or more halogen atoms.
  • a compound representing a C1-C6 alkoxy group where X is a C1-C6 alkyl group and R 1 is a C1-C6 alkyl group;
  • X 1 is a nitrogen atom and R 2 is a C1-C6 alkoxy group optionally substituted with a hydrogen atom, a halogen atom, an aryl group or one or more halogen atoms
  • R 4 and R 5 is a benzene ring together with the carbon atom to which they are attached ⁇ from the group consisting of a halogen atom, an aryl group or a C1-C6 alkoxy group which may be substituted with one or more halogen atoms.
  • X 1 is CR 3
  • R 2 , R 3 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom or one or more halogen atoms.
  • a compound representing a C1-C6 alkoxy group where X is a C1-C6 alkyl group and R 1 is a C1-C6 alkyl group;
  • X 1 is CR 3
  • R 2 and R 3 are C1-C6 alkoxy groups that may be independently substituted with hydrogen atoms, halogen atoms, or one or more halogen atoms.
  • R 4 and R 5 together with the carbon atom to which they are attached, from the benzene ring ⁇ the benzene ring is from a C1-C6 alkoxy group that may be substituted with a halogen atom or one or more halogen atoms.
  • X 1 is a nitrogen atom
  • R 2 , R 4 and R 5 may be independently substituted with a hydrogen atom, a halogen atom or one or more halogen atoms C1-C6.
  • a compound representing an alkoxy group where X is a C1-C6 alkyl group and R 1 is a C1-C6 alkyl group;
  • X 1 is a nitrogen atom
  • R 2 is a C1-C6 alkoxy group optionally substituted with a hydrogen atom, a halogen atom or one or more halogen atoms
  • R 4 and R 5 are: Together with the carbon atom to which they are attached, the benzene ring ⁇ the benzene ring is one or more substitutions selected from the group consisting of C1-C6 alkoxy groups optionally substituted with one or more halogen atoms. It may be substituted with a group.
  • X is a C1-C6 alkyl group and R 1 is a C1-C6 alkyl group;
  • X 1 is CR 3
  • R 2 , R 3 , R 4 and R 5 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom and methoxy group.
  • Ethoxy group, propoxy group isopropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy group , 2,2,3,3-tetrafluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 1,1,2,3,3,3-hexafluoropropoxy group or 2,2 3,4,4,4-hexafluorobutoxy group,
  • X is methyl group, ethyl group, propyl group, trifluoromethyl group, phenyl group or 4-chlorophenyl group
  • R 1 is methyl group, ethyl group, Compounds that are propyl or isopropyl groups;
  • X 1 is CR 3
  • R 2 and R 3 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, me
  • Ethoxy group, propoxy group isopropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy Group, 2,2,3,3-tetrafluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 1,1,2,3,3,3-hexafluoropropoxy group or 2,2 , 3, 4, 4, 4-Hexafluorobutoxy groups may be substituted with one or more substituents selected from the group.
  • X is a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a phenyl group or a 4-chlorophenyl group
  • R 1 is a methyl group, an ethyl group, a propyl group or an isopropyl group
  • X 1 is a nitrogen atom
  • R 2 , R 4 and R 5 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methoxy group and ethoxy group.
  • Propyl group isopropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy group, 2, 2,3,3-tetrafluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 1,1,2,3,3,3-hexafluoropropoxy group or 2,2,3,4 , 4,4-Hexafluorobutoxy group, X is methyl group, ethyl group, propyl group, trifluoromethyl group, phenyl group or 4-chlorophenyl group, R 1 is methyl group, ethyl group, propyl group or Compounds that are isopropyl groups; In formula (4), X 1 is a nitrogen atom and R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
  • Dimethylpropoxy group 1,2-dimethylpropoxy group, 1-ethylpropoxy group, butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy group, 2,2,3,3-tetrafluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 1,1,2,3,3,3-hexafluoropropoxy group or 2,2,3,4,5,4-hexafluorobutoxy group.
  • a benzene ring ⁇ the benzene ring is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy.
  • X is a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a phenyl group or a 4-chlorophenyl group
  • R 1 is a methyl group, an ethyl group, a propyl group or an isopropyl group
  • X 1 is CR 3 , R 2 , R 3 and R 4 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom or iodine atom, and R 5 is.
  • X is a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a phenyl group or a 4-chlorophenyl group
  • R 1 is a methyl group, an ethyl group, a propyl group or an isopropyl group
  • X 1 is a nitrogen atom
  • R 2 and R 4 are independently hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms or iodine atoms
  • R 5 is a hydrogen atom.
  • the benzene ring ⁇ the benzene ring may be substituted with one or more substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • X is a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a phenyl group or a 4-chlorophenyl group
  • R 1 is a methyl group, an ethyl group, a propyl group or an isopropyl group;
  • X 1 is CR 3 , R 2 , R 3 and R 4 are independently hydrogen atom, fluorine atom, chlorine atom, bromine atom or iodine atom, and R 5 is. Hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methoxy group, ethoxy group, propoxy group, isopropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, Butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy group, 2,2,3,3-tetrafluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 1,1 , 2,3,3,3-hexafluoropropoxy group or 2,2,3,4,5,4-hexafluorobutoxy group, X is methyl group, ethyl group or propyl group, R 1 is methyl Compounds that are groups
  • X 1 is a nitrogen atom
  • R 2 and R 4 are independently hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms or iodine atoms
  • R 5 is a hydrogen atom.
  • X is methyl group, ethyl group or propyl group
  • R 1 is methyl group, ethyl Compounds that are groups or propyl groups;
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iod
  • the benzene ring ⁇ the benzene ring may be substituted with one or more substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • R 5 is hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methoxy group, ethoxy group, propoxy group, isopropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 1- Ethyl propoxy group, butoxy group, tert-butoxy group, 2,2,2-trifluoroethoxy group, 2,2,3,3-tetrafluoropropoxy group, 2,2,3,3,3-pentafluoropropoxy group , 1,1,2,3,3,3-hexafluoropropoxy group or 2,2,3,4,5,4-hexafluorobutoxy group, X is a methyl group, an ethyl group or a propyl group.
  • X 1 is CR 3
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • R 4 and R 5 are them.
  • a compound that forms a benzene ring together with the carbon atom to which it is attached where X is a methyl, ethyl or propyl group and R 1 is a methyl, ethyl or propyl group;
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • R 5 is a hydrogen atom and a fluorine atom.
  • X is methyl group, ethyl group or propyl group
  • R 1 is methyl group, ethyl group or Compounds that are propyl groups;
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom
  • R 4 and R 5 together with the carbon atom to which they are bonded form a benzene ring
  • X 1 is a nitrogen atom
  • R 2 is a hydrogen atom
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • R 5 is a hydrogen atom and a fluorine atom.
  • X is a methyl group, an ethyl group or a propyl group
  • R 1 is a methyl group, Compounds that are ethyl or propyl groups
  • X 1 is a nitrogen atom
  • R 2 and R 4 are hydrogen atoms
  • R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, an ethoxy group, and a propoxy.
  • X is a methyl group, an ethyl group or a propyl group
  • R 1 is a methyl group, an ethyl group or a propyl group
  • X 1 is a nitrogen atom
  • R 2 and R 4 are hydrogen atoms
  • R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methoxy group, an ethoxy group, and a propoxy.
  • R 1 is an ethyl group
  • X 1 is a nitrogen atom
  • R 2 and R 4 are hydrogen atoms
  • R 5 is a 1,1,2,3,3,3-hexafluoropropoxy group
  • X is a methyl.
  • a compound that is a group and R 1 is an ethyl group
  • X 1 is a nitrogen atom
  • R 2 and R 4 are hydrogen atoms
  • R 5 is a 2,2,3,4,5,4-hexafluorobutoxy group
  • X is a methyl.
  • a compound that is a group and R 1 is an ethyl group.
  • X is preferably a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a phenyl group, or a 4-chlorophenyl group, and more preferably a methyl group, an ethyl group, a propyl group, or a trifluoromethyl group.
  • R 1 is preferably a methyl group, an ethyl group, a propyl group, or an isopropyl group, and more preferably a methyl group, an ethyl group, or a propyl group.
  • R 2 is a C1-C6 alkyl group which may be substituted with a hydrogen atom, a halogen atom or one or more halogen atoms, an aryl group which may be substituted with one or more halogen atoms, or one or more.
  • Heteroaryl groups that may be substituted with halogen atoms or C1-C6 alkoxy groups that may be substituted with one or more halogen atoms are preferred, and are substituted with hydrogen atoms, halogen atoms, or one or more halogen atoms.
  • R 3 is a C1-C6 alkyl group which may be substituted with a hydrogen atom, a halogen atom or one or more halogen atoms, an aryl group which may be substituted with one or more halogen atoms, or one or more.
  • Heteroaryl groups that may be substituted with halogen atoms or C1-C6 alkoxy groups that may be substituted with one or more halogen atoms are preferred, and are substituted with hydrogen atoms, halogen atoms, or one or more halogen atoms. More preferably, a C1-C6 alkyl group which may be substituted, or a C1-C6 alkoxy group which may be substituted with one or more halogen atoms.
  • R 4 and R 5 are a C1-C6 alkyl group optionally substituted with a hydrogen atom, a halogen atom and one or more halogen atoms, and an aryl group optionally substituted with one or more halogen atoms.
  • a heteroaryl group that may be substituted with one or more halogen atoms, a C1-C6 alkoxy group that may be substituted with one or more halogen atoms, or a carbon atom to which R 4 and R 5 are bonded.
  • a benzene ring and a C1-C6 alkyl group which may be substituted with a hydrogen atom, a halogen atom or one or more halogen atoms, and a C1-C6 which may be substituted with one or more halogen atoms. It is more preferable to form a benzene ring together with an alkoxy group or a carbon atom to which R 4 and R 5 are bonded.
  • X 1 is preferably a nitrogen atom.
  • the symbols have the same meaning as above.
  • Compound (1) is a commercially available compound or can be produced according to a known method.
  • Compound (2) is a commercially available compound or can be produced according to a known method.
  • the amount of the compound (2) to be used is usually 0.5 to 10 mol, preferably 0.8 to 5 mol, per 1 mol of the compound (1).
  • the metal salt include a zinc metal salt and a silver metal salt.
  • Preferred zinc salts include zinc fluoride, zinc chloride, zinc bromide, zinc iodide, zinc sulfate, zinc trifluoromethanesulfonate, zinc nitrate, zinc perchlorate, zinc thiocyanate, zinc phosphate, diphosphate.
  • Examples thereof include zinc, zinc borate, zinc carbonate, zinc acetate, zinc propionate, zinc 2-ethylhexanate, zinc laurate, zinc stearate, zinc naphthenate, zinc acetylacetonate, zinc oxide and zinc sulfide. More preferably, zinc fluoride, zinc chloride, zinc bromide, zinc iodide, zinc sulfate, zinc trifluoromethanesulfonate, zinc nitrate, zinc perchlorate, zinc thiocyanate, zinc carbonate, zinc acetate, zinc propionate and Examples thereof include zinc 2-ethylhexanoate.
  • Preferred silver salts include silver fluoride, silver chloride, silver bromide, silver sulfate, silver trifluoromethanesulfonate, silver p-toluenesulfonate, silver methanesulfonate, silver carbonate, silver acetate, silver trifluoroacetate, Silver citrate, silver lactate, silver benzoate, silver nitrate, silver nitrite, silver diethylthiocarbamate, silver thiocyanate, silver phosphate, silver hexafluoroantimonate (V), silver tetrafluoroborate, silver oxide and silver sulfide Etc., more preferably silver fluoride, silver chloride, silver bromide, silver sulfate, silver trifluoromethanesulfonate, silver p-toluenesulfonate, silver methanesulfonate, silver carbonate, silver acetate, trifluoroacetic acid.
  • Examples thereof include silver, silver citrate, silver lactate, silver benzoate, silver nitrate, silver nitrite, silver thiocyanate, silver phosphate and silver tetrafluoroborate.
  • the amount of the metal salt used is usually 0.01 to 10 mol, preferably 0.01 to 5 mol, more preferably 0.05 to 3 mol, per 1 mol of compound (1). is there.
  • Bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium hydride, potassium hydride, etc .; trimethylamine, triethylamine, tributylamine, dimethyl Octylamine, trioctylamine, N, N-dimethylbenzylamine, N, N-diisopropylethylamine, tetramethylethylenediamine, tetramethylhexamethylenediamine, 4-methylmorpholin, 4-ethylmorpholin, N-methylpyrrolidin, N-ethyl Amine-based bases such as pyrrolidine, 1-methylpiperidin, 1-azabicyclo [2.2.2] octane, 1,4-diazabicyclo [2.2.2] octane, hexamethylenetetramine; 1,8-diazabicyclo [5] .4.0] Undeca-7-ene
  • Amidin-based bases that may be substituted with one or more active substituents; aniline-based bases such as N, N-dimethylaniline, N, N-diethylaniline; pyridine, 2-methylpyridine, 3-methylpyridine, 4 -Methylpyridine, 2-ethylpyridine, 2-propylpyridine, 2,4-lutidine, 3,4-lutidine, 2,6-lutidine, 3,5-lutidine, 2-methyl-5-ethylpyridine, 2,4 , 6-trimethylpyridine, 2,3,5-trimethylpyridine, 4- (dimethylamino) pyridine, 4-pyrrolidinopyridine, 2,2'-bipyridyl, etc.
  • aniline-based bases such as N, N-dimethylaniline, N, N-diethylaniline
  • aniline-based bases such as N, N-dimethylaniline, N, N-diethylaniline
  • pyridine 2-methylpyridine, 3-methylpyridine, 4
  • Pyridine-based bases which may be used; quinoline-based bases such as quinoline, 2-methylquinoline, and isoquinoline are mentioned, and inorganic substances such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydride, and sodium hydride are preferable.
  • Bases Amine-based bases such as trimethylamine, triethylamine, N, N-diisopropylethylamine, 4-methylmorpholin; pyridine-based bases such as pyridine, 2,6-lutidine, 4- (dimethylamino) pyridine; quinoline, 2-methylquinoline , Isoquinolin and other quinoline bases and the like.
  • the amount of the base used is usually 0.1 to 10 mol, preferably 0.1 to 5 mol, per 1 mol of compound (1).
  • the reaction is usually carried out in a solvent.
  • the solvent include ether solvents such as diethyl ether, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether and ethylene glycol dimethyl ether; alkyl nitrile solvents such as acetonitrile and propionitrile; N, N-dimethylformamide and N-methyl-2.
  • -Amid solvent such as pyrrolidone; aromatic solvents such as toluene, xylene, monochlorobenzene and mixed solvents thereof are mentioned, and ethers such as diethyl ether, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether and ethylene glycol dimethyl ether are preferable. Solvents can be mentioned.
  • the amount of the solvent used is usually 1 to 10 times the weight, preferably 1 to 5 times the weight of the compound (1).
  • the reaction temperature is usually in the range of ⁇ 20 to 100 ° C., preferably in the range of 20 to 80 ° C.
  • the reaction time is usually in the range of 0.5 to 48 hours, preferably 3 to 48 hours.
  • the reaction mixture After completion of the reaction, the reaction mixture is concentrated; the reaction mixture is mixed with neutral or weakly basic water and then extracted with an organic solvent to dry or concentrate the obtained organic layer; the reaction mixture and alkali.
  • metal hydroxide, alkali metal carbonate or alkali metal hydrogen carbonate for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.
  • metal hydroxide, alkali metal carbonate or alkali metal hydrogen carbonate for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.
  • the insoluble material is filtered off, the filtrate is extracted with an organic solvent, and the obtained organic layer is dried or concentrated; the compound (4) is obtained by performing a post-treatment operation such as. Can be isolated. Further, the isolated compound (4) can be further purified by a method such as recrystallization, chromatography, or salting out. Further, the reaction mixture containing the compound (4) can be subjected to the next step (B) without isolating the compound (4) to produce the compound (3).
  • step (B) of obtaining the compound (3) from the compound (4) will be described.
  • the step proceeds by reacting compound (4) with water in the presence of an acid.
  • the theoretical amount of water used is usually 2 mol per 1 mol of compound (4), but an excess amount can be used.
  • the acid include carboxylic acids such as acetic acid, formic acid, citric acid, oxalic acid, 3-phenylacrylic acid, benzoic acid, 4-chlorobenzoic acid, terephthalic acid, isophthalic acid, 1-naphthalenecarboxylic acid; phosphoric acid; Nitrate; sulfonic acid such as sulfuric acid, methanesulfonic acid, 4-toluenesulfonic acid monohydrate; hydrogen halide such as hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen fluoride; and the like, preferably acetic acid.
  • carboxylic acids such as acetic acid, formic acid, citric acid, oxalic acid, 3-phenylacrylic acid, benzoic acid, 4-chlorobenz
  • Carboxylic acids such as formic acid and citric acid; phosphoric acid; nitric acid; sulfuric acid; hydrogen chloride and the like.
  • the reaction temperature is usually in the range of ⁇ 20 to 100 ° C., preferably in the range of 0 to 70 ° C.
  • the reaction time is usually in the range of 0.5 to 48 hours.
  • the step can also be carried out in a solvent, such as an ether solvent such as diethyl ether, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, ethylene glycol dimethyl ether; an alkylnitrile solvent such as acetonitrile and propionitrile.
  • Amid solvents such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; aromatic solvents such as toluene, xylene and monochlorobenzene and mixed solvents thereof are mentioned, preferably diethyl ether, tetrahydrofuran and methyl t.
  • ether solvents such as butyl ether, cyclopentyl methyl ether and ethylene glycol dimethyl ether.
  • an aqueous solution of carbonate or alkali metal hydrogen carbonate for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.
  • extraction is performed with an organic solvent, and the obtained organic layer is dried.
  • an aqueous solution of alkali metal hydroxide, alkali metal carbonate or alkali metal hydrogen carbonate eg, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.
  • the insoluble matter is filtered off, the filtrate is extracted with an organic solvent, and the obtained organic layer is dried or concentrated;
  • the compound (3) can be isolated by performing a post-treatment operation such as. Further, the isolated compound (3) can be further purified by a method such as recrystallization, chromatography, or salting out.
  • a compound having an excellent control effect on harmful arthropods can be produced by the production method described in International Publication No. 2017/065228.
  • Example 1 7.8 g of zinc chloride, 2.3 g of triethylamine, 3.9 g of the compound represented by the formula (2-1) and 10 g of THF were mixed at 25 ° C. for 30 minutes. 2.0 g of the compound represented by the formula (1-1) was added to the mixture, mixed, heated to 50 ° C., and stirred for 20 hours. The obtained reaction solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-1) was produced with an area percentage value of 86%. After cooling the reaction solution to 0 ° C., 30 g of water was added and the insoluble matter was filtered off.
  • Example 2 120 mg of zinc chloride, 150 mg of triethylamine, 130 mg of the compound represented by the formula (2-1) and 500 mg of toluene were mixed at 25 ° C. for 1 hour. 100 mg of the compound represented by the formula (1-1) was added to the mixture, mixed, heated to 50 ° C. for 5 hours at 25 ° C., and stirred for 5 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-1) was produced with an area percentage value of 31%.
  • Example 3 120 mg of zinc chloride, 150 mg of triethylamine, 130 mg of the compound represented by the formula (2-1) and 500 mg of methyl t-butyl ether were mixed at 25 ° C. for 1 hour. 100 mg of the compound represented by the formula (1-1) was added to the mixture, mixed, heated to 50 ° C. for 5 hours at 25 ° C., and stirred for 5 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-1) was produced with an area percentage value of 27%.
  • Example 4 6.0 mg of silver acetate, 40 mg of triethylamine, 70 mg of the compound represented by the formula (2-1) and 300 ⁇ L of THF were mixed at 25 ° C. for 20 minutes. 50 mg of the compound represented by the formula (1-2) was added to the mixture, mixed, heated to 50 ° C., and stirred for 6 hours. The obtained reaction solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-2) was produced with an area percentage value of 40%.
  • Example 5 0.10 g of zinc chloride, 50 mg of sodium hydride (purity 60%), 0.10 g of the compound represented by the formula (2-1) and 0.20 g of THF were mixed at 25 ° C. for 1 hour. To the mixture, 0.10 g of the compound represented by the formula (1-2) was added and mixed, the temperature was raised to 65 ° C., and the mixture was stirred for 8 hours. The obtained reaction solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-2) was produced with an area percentage value of 48%.
  • Example 6 11 mg of silver trifluoromethanesulfonate, 70 ⁇ L of diisopropylethylamine, 70 mg of the compound represented by the formula (2-1) and 300 ⁇ L of THF were mixed at 25 ° C. for 20 minutes. 50 mg of the compound represented by the formula (1-2) was added to the mixture, mixed, heated to 50 ° C., and stirred for 6 hours. The obtained reaction solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-2) was produced with an area percentage value of 73%.
  • Example 7 After dissolving 11 mg of silver trifluoromethanesulfonate, 55 ⁇ L of triethylamine, and 74 mg of the compound represented by the formula (2-1) in 570 ⁇ L of THF, the mixture was stirred at 20 ° C. for 20 minutes. To the obtained mixed solution, 0.10 g of the compound represented by the formula (1-3) was added and mixed, the temperature was raised to 50 ° C., and the mixture was stirred for 6 hours. The obtained reaction solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-3) was produced with an area percentage value of 58%.
  • Example 8 2.9 g of zinc chloride, 1.4 mL of triethylamine, 1.7 g of the compound represented by the formula (2-1) and 5 mL of THF were mixed at 25 ° C. for 1 hour. 1.0 g of the compound represented by the formula (1-5) was added to the mixture, mixed, heated to 45 ° C., and stirred for 20 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-5) was produced with an area percentage value of 20%. The reaction mixture was cooled to 25 ° C., water was added, and the mixture was extracted with 50 mL of ethyl acetate.
  • Example 9 150 mg of the compound represented by the formula (4-5) obtained by purification in Example 8 and 14 mL of 4N hydrochloric acid were mixed at 20 ° C. and stirred for 15 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (3-5) was produced with an area percentage value of 20%.
  • Example 10 15 g of zinc chloride, 16 mL of triethylamine, 9.0 g of the compound represented by the formula (2-1) and 70 mL of THF were mixed at 20 ° C. for 1 hour. 7.0 g of the compound represented by the formula (1-4) was added to the mixture and mixed, the temperature was raised to 50 ° C., and the mixture was stirred for 19 hours. The obtained reaction solution was cooled to 20 ° C., 23 mL of 20% hydrochloric acid was added, and the mixture was stirred at 20 ° C. for 16 hours.
  • Example 11 570 mg of zinc chloride, 0.19 g of triethylamine, 0.34 g of the compound represented by the formula (2-1) and 1 g of THF were mixed at 25 ° C. for 30 minutes. 200 mg of the compound represented by the formula (1-1) was added to the mixture, mixed, heated to 50 ° C., and stirred for 18 hours. The obtained reaction solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-1) was produced with an area percentage value of 83%. After cooling the reaction solution to 0 ° C., 0.40 g of 35% hydrochloric acid was added, the temperature was raised to 25 ° C., and the mixture was stirred for 16 hours.
  • the obtained mixed solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (3-1) was produced with an area percentage value of 57%.
  • Analytical conditions for high performance liquid chromatography Column used: Shim-pack XR-ODS (dimensions 3 mm x 75 mm, particle size 2.2 ⁇ m, Shimadzu Corporation), mobile phase: solution A: 0.1% phosphoric acid, solution B: acetonitrile, flow velocity: 0.9 mL / min, detector: UV, 254 nm
  • Example 12 220 mg of zinc chloride, 70 mg of triethylamine, 130 mg of the compound represented by the formula (2-1) and 500 mg of THF were mixed at 25 ° C. for 1 hour. To the mixture, 100 mg of the compound represented by the formula (1-2) was added and mixed, the temperature was raised to 50 ° C. for 19 hours at 25 ° C., and the mixture was stirred for 10 hours. The obtained reaction solution was cooled to 20 ° C., 220 mg of 35% hydrochloric acid and 200 mg of water were added, and the mixture was stirred at 20 ° C. for 12 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (3-2) was produced with an area percentage value of 79%.
  • Example 13 After dissolving 320 mg of zinc trifluoromethanesulfonate, 55 ⁇ L of triethylamine, and 73 mg of the compound represented by the formula (2-1) in 720 ⁇ L of THF, the mixture was stirred at 20 ° C. for 20 minutes. To the obtained mixed solution, 100 mg of the compound represented by the formula (1-3) was added and mixed, the temperature was raised to 50 ° C., and the mixture was stirred for 6 hours. The obtained reaction solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-3) was produced with an area percentage value of 78%.
  • Example 14 500 mg of zinc trifluoromethanesulfonate, 0.1 mL of triethylamine, 100 mg of the compound represented by the formula (2-1) and 3.0 mL of THF were mixed at 25 ° C. for 1 hour. 0.1 g of the compound represented by the formula (1-6) was added to the mixture, mixed, the temperature was raised to 50 ° C., and the mixture was stirred for 20 hours. After cooling the obtained reaction solution to 20 ° C., 1 mL of 4N hydrochloric acid was added dropwise, and the mixture was stirred at 20 ° C. for 14 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (3-6) was produced with an area percentage value of 77%.
  • Example 15 500 mg of zinc trifluoromethanesulfonate, 50 mg of pyridine, 100 mg of the compound represented by the formula (2-1) and 3.0 mL of THF were mixed at 25 ° C. for 1 hour. 100 mg of the compound represented by the formula (1-6) was added to the mixture, mixed, heated to 45 ° C., and stirred for 30 hours. After cooling the obtained reaction solution to 20 ° C., 1 mL of 4N hydrochloric acid was added dropwise, and the mixture was stirred at 20 ° C. for 24 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (3-6) was produced with an area percentage value of 35%.
  • Example 16 500 mg of zinc trifluoromethanesulfonate, 0.1 mL of DBU, 100 mg of the compound represented by the formula (2-1) and 3.0 mL of THF were mixed at 25 ° C. for 1 hour. 100 mg of the compound represented by the formula (1-6) was added to the mixture, mixed, heated to 45 ° C., and stirred for 30 hours. After cooling the obtained reaction solution to 20 ° C., 1 mL of 4N hydrochloric acid was added dropwise, and the mixture was stirred at 20 ° C. for 24 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (3-6) was produced with an area percentage value of 51%.
  • Example 17 500 mg of zinc trifluoromethanesulfonate, 70 mg of sodium carbonate, 100 mg of the compound represented by the formula (2-1) and 3.0 mL of THF were mixed at 25 ° C. for 1 hour. 100 mg of the compound represented by the formula (1-6) was added to the mixture, mixed, heated to 45 ° C., and stirred for 30 hours. After cooling the obtained reaction solution to 20 ° C., 1 mL of 4N hydrochloric acid was added dropwise, and the mixture was stirred at 20 ° C. for 24 hours. The obtained mixture was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (3-6) was produced with an area percentage value of 49%.
  • Comparative Example 1 11 mg of silver trifluoromethanesulfonate, 74 mg of the compound represented by the formula (2-1), and 300 ⁇ L of THF were mixed at 20 ° C. for 30 minutes. 50 mg of the compound represented by the formula (1-2) was added to the mixture, mixed, heated to 50 ° C., and stirred for 6 hours. The obtained mixture was cooled to 20 ° C. and analyzed by high performance liquid chromatography, and the area percentage value of the compound represented by the formula (4-2) was 0%. After adding 55 ⁇ L of triethylamine to the mixture, the mixture was stirred at 50 ° C. for 5 hours.
  • reaction solution was analyzed by high performance liquid chromatography, and it was confirmed that the compound represented by the formula (4-2) was produced with an area percentage value of 67%.
  • Analytical conditions for high performance liquid chromatography Column used: Shim-pack XR-ODS (dimensions 3 mm x 75 mm, particle size 2.2 ⁇ m, Shimadzu Corporation), mobile phase: solution A: 0.1% phosphoric acid, solution B: acetonitrile, flow velocity: 0.9 mL / min, detector: UV, 254 nm
  • Comparative Example 2 1.6 g of the compound represented by the formula (5) (hereinafter, also referred to as compound (5)) was dissolved in 2 g of THF, cooled to 5 ° C., and 5.4 mL of a 2.6 M butyllithium hexane solution was added dropwise. After completion of the dropping, the temperature of the mixed solution was raised to 20 ° C. and the mixture was stirred for 1 hour to obtain a compound (5) butyllithium reaction solution. After dissolving 1 g of the compound represented by the formula (1-1) in 2 g of THF, the mixture was cooled to ⁇ 5 ° C.
  • Comparative Example 3 In Comparative Example 2, an attempt was made to synthesize the compound represented by the formula (6) from the compound represented by the formula (1-1) by the same method except that t-butoxypotassium was used instead of the 2.6M butyllithium hexane solution. It was. When the obtained reaction solution was analyzed by high performance liquid chromatography, the area percentage value of the compound represented by the formula (1-1) was 4%, and the area percentage value of the compound represented by the formula (6) was 0%. It was.
  • Example 1 Comparative Example 4, Comparative Example 5, Comparative Example 6 and Example 1
  • Q represents a hydrogen atom, a methoxy group or a nitro group.
  • the compound represented by the formula (1-7) is used in the same manner as in Example 1 except that the compound represented by the formula (1-7) is used instead of the compound represented by the formula (1-1).
  • Area percentage value of the compound represented by the formula (4-7) hereinafter, also referred to as the compound (4-7)
  • the compound represented by the formula (2-1) when the compound represented by the formula (2-1), the metal salt and the base are reacted. was 0%.
  • a ⁇ -ketosulfone compound can be efficiently produced.

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Abstract

L'invention concerne un procédé de production d'un composé représenté par la formule (4), ledit procédé comprenant une étape consistant à faire réagir un composé représenté par la formule (1) [dans la formule (1), X1 représente CR3 ou un atome d'azote, R2 et R3 représentent chacun indépendamment un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1-C6 qui peut être substitué par un ou plusieurs atomes d'halogène, ou similaire, et R4 et R5 représentent chacun indépendamment un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1-C6 qui peut être substitué par un ou plusieurs atomes d'halogène, ou similaire.] et un composé représenté par la formule (2) [dans la formule (2), X représente un groupe alkyle en C1-C6 qui peut être substitué par un ou plusieurs atomes d'halogène, ou similaire, et R1 représente un groupe alkyle en C1-C6 qui peut être substitué par un ou plusieurs atomes d'halogène.] en présence d'un sel métallique ou d'une base pour obtenir le composé représenté par la formule (4) [dans la formule (4), X, X1, R1, R2, R4, et R5 représentent les mêmes groupes que ceux décrits ci-dessus.].
PCT/JP2020/020859 2019-06-05 2020-05-27 PROCÉDÉ DE PRODUCTION D'UN COMPOSÉ DE β-CÉTOSULFONE WO2020246329A1 (fr)

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