Method for preparing aromatic heterocycle-substituted difluoroacetic acid derivatives

Abstract

The purpose of the present invention is to provide a method with which an aromatic heterocyclic ring-substituted difluoroacetic acid derivative can be produced using a simple and inexpensive method.　The present invention relates to a method for producing an aromatic heterocyclic ring-substituted difluoroacetic acid derivative having a partial structure represented by formula (III), the method being characterized by reacting tetrafluoroethylene with an N-oxide aromatic heterocyclic ring compound having a partial structure represented by formula (I), in the presence of a compound represented by formula (II): R-YH, in a solvent selected from among an aromatic hydrocarbon solvent, an ester solvent and an ether solvent. [Symbols in the formulae are as described in the description.]

Description

[Technical field]

[0001] The present invention relates to a method for preparing aromatic heterocycle-substituted difluoroacetic acid derivatives. [Background technology]

[0002] The aromatic heterocycle-substituted difluoroacetic acid derivatives are useful for the preparation of pharmaceutical or agrochemical synthesis intermediates.

[0003] As a method for producing an aromatic heterocycle-substituted fluoroalkyl carboxylic acid derivative, for example, Non-Patent Document 1 describes a method for producing methyl 2-(2-heteroaryl)perfluoropropionate in two steps by reacting various aromatic heterocycle N-oxides with hexafluoropropene (CF2=CFCF3) and methanol in N,N-dimethylformamide (Scheme 5, Table 2), a method for producing 2-(2-heteroaryl)perfluoropropionamide in two steps by reacting various aromatic heterocycle N-oxides with hexafluoropropene (CF2=CFCF3) and an amine in N,N-dimethylformamide (Schemes 12 and 13), and a method for producing chlorotrifluoromethyl 2-(2-heteroaryl)perfluoropropionate in two steps by reacting quinoline N-oxide with chlorotrifluoromethyl 2-(2-heteroaryl)perfluoropropionate in N,N-dimethylformamide (Schemes 14 and 15). ethylene A method for producing methyl 2-chloro-2-fluoro-2-(2-quinolyl)acetate by reaction with (CF2=CFCl) and methanol at 100° C. (Scheme 17) is known.

[0004] None of the documents describe the preparation of aromatic heterocycle-substituted difluoroacetic acid derivatives or their reaction with tetrafluoroethylene (CF2=CF2). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Chem. Eur. J. 2008, vol.14, pp2577-2589 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a method for producing an aromatic heterocycle-substituted difluoroacetic acid derivative in a simple and inexpensive manner. [Means for solving the problem]

[0007] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have found that an aromatic heterocycle-substituted difluoroacetic acid derivative having a partial structure represented by the following formula (III) can be produced with little by-products in a single step in a simple and inexpensive manner by reacting an N-oxide aromatic heterocycle compound having a partial structure represented by the following formula (I) with tetrafluoroethylene in the presence of a compound represented by the following formula (II) in a specific solvent, and have thus completed the present invention.

[0008] That is, the present invention is as follows. [1] In a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent, [In the formula, R is C 1-8 Alkyl group, C 3-8 Cycloalkyl groups, C 7-16 Aralkyl group or C 6-10 represents an aryl group, 1-8 The alkyl group is a halogen atom, a cyano group, 1-6 Alkoxy groups and C 1-6 haloalkoxy groups, 3-8 Cycloalkyl groups, C 7-16 Aralkyl groups and C 6-10 The aryl group is a halogen atom, a cyano group, 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 haloalkoxy groups, Y is O, S or NRY indicates, R Y is a hydrogen atom or C 1-8 It may represent an alkyl group or may form a nitrogen-containing heterocycle together with the nitrogen atom to which they are attached, together with R. In the presence of a compound represented by formula (I):

[0009] [ka]

[0010] The present invention relates to a compound represented by the formula (III):

[0011] [ka]

[0012] [Each symbol in the formula has the same meaning as defined above.] The present invention relates to a method for producing an aromatic heterocycle-substituted difluoroacetic acid derivative having a partial structure represented by the following formula (hereinafter, also referred to as aromatic heterocycle-substituted difluoroacetic acid derivative (III)). [2] The method according to the above [1], wherein the reaction is carried out at a temperature within the range of 100 to 300°C. [3] The method according to the above [1] or [2], wherein the reaction is carried out in the range of 0.1 to 10.0 MPa. [4] The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA) or (IB):

[0013] [ka]

[0014] [In the formula, X 1ais CR 1a or N; X 1b is CR 1b or N; X 1c is CR 1c or N; X 1d is CR 1d or N; R 1a , R 1b , R 1c and R 1d are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, they form halogen atoms, cyano groups, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C may be substituted with a substituent selected from an aralkyl group. 6-10 may form an arene; X2a is CR 2a , N, N.R. 2a , indicating S or O; X 2b is CR 2b or N; X 2c is CR 2c , N, N.R. 2c , indicating S or O; R 2a , R 2b and R 2c are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 2a and R 2b , or R 2b and R 2c Together, they form halogen atoms, cyano groups, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C may be substituted with a substituent selected from an aralkyl group. 6-10 It may also form an arene. (hereinafter also referred to as N-oxide aromatic heterocyclic compound (IA) or (IB)). [5] The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA), and in the formula, R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, they form halogen atoms, cyano groups, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C may be substituted with a substituent selected from an aralkyl group. 6-10 The method according to the above [4], in which an arene is formed. [6] The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA), and in the formula, R 1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C6-10 Aryl group or C 7-16 The method according to the above [4], wherein the R is an aralkyl group. [7] The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IB), and R 2a and R 2b , or R 2b and R 2c Together, they form halogen atoms, cyano groups, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C may be substituted with a substituent selected from an aralkyl group. 6-10 The method according to the above [4], in which an arene is formed. [8] The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IB), and R 2a , R 2b and R 2c are independently a hydrogen atom, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 The method according to the above [4], wherein the R is an aralkyl group. Effect of the Invention

[0015] According to the present invention, an aromatic heterocycle-substituted difluoroacetic acid derivative (III) can be produced in one step with little by-products by a simple and inexpensive method in which tetrafluoroethylene is introduced into an N-oxide aromatic heterocycle compound (I) in the presence of compound (II) in a specific solvent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The definitions of groups used in the present specification are described in detail below. Unless otherwise specified, groups have the following definitions.

[0017] In the present specification, compounds represented by formulas are represented by the formula number attached to the "compound." For example, a compound represented by formula (1) is represented as "compound (1)." In this specification, a numerical range represented by "~" or "-" means a numerical range with the numbers before and after "~" or "-" as the lower or upper limit. In this specification, when the element symbol "C" is used with a numerical range indicated by the numbers before and after "-" in the name of any group, it indicates an arbitrary group having an integer number of carbon atoms, with the numbers before and after "-" being the lower or upper limit, respectively. For example, an alkyl group having 1 to 3 carbon atoms is represented as "C 1-3 An alkyl group is sometimes referred to as an "alkyl group," which means -CH3, -C2H5, -C3H7, etc. The same applies to other groups.

[0018] In this specification, the term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

[0019] In this specification, "C 1-8 The term "alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. 1-8Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, and octyl. 1-4 Alkyl groups are preferred.

[0020] In this specification, "C 1-6 The term "alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. 1-4 Alkyl groups are preferred.

[0021] In this specification, "C 1-4 The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 "Alkyl group" includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0022] In this specification, "C 1-6 An "alkoxy group" is a group represented by the formula R 11 O-(where R 11 is C 1-6 "C" means a group represented by the formula: 1-6 Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, and hexyloxy. 1-4 Alkoxy groups are preferred.

[0023] In this specification, "C 1-6Haloalkyl group means "C 1-6 "C alkyl group" means a group in which one or more hydrogen atoms are replaced with halogen atoms. 1-6 Examples of the "haloalkyl group" include fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, trifluoromethyl, difluoromethyl, perfluoroethyl, perfluoropropyl, chloromethyl, 2-chloroethyl, bromomethyl, 2-bromoethyl, iodomethyl, 2-iodoethyl and the like, with trifluoromethyl being preferred.

[0024] In this specification, "C 1-6 Haloalkoxy group means "C 1-6 "Alkoxy group" means a group in which one or more hydrogen atoms are replaced with halogen atoms. 1-6 Examples of the "haloalkoxy group" include bromomethoxy, 2-bromoethoxy, 3-bromopropoxy, 4-bromobutoxy, iodomethoxy, 2-iodoethoxy, 3-iodopropoxy, 4-iodobutoxy, fluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, tribromomethoxy, trichloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroethoxy, perfluoropropoxy, perfluoroisopropoxy, 1,1,2,2-tetrafluoroethoxy, and 2-chloro-1,1,2-trifluoroethoxy.

[0025] In this specification, "C 1-6 An "alkylsulfanyl group" is a group represented by the formula R 11 S-(where R 11 is C 1-6 "C" means a group represented by the formula: 1-6 Examples of the "alkylsulfanyl group" include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, and hexylsulfanyl. 1-4 The sulfanyl group is preferred.

[0026] As used herein, "mono-C 1-6 An "alkylamino group" is a group represented by the formula R 11 NH-(where R 11 is C 1-6 "Mono-C" means a group represented by the formula: 1-6 Examples of the alkylamino group include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino. 1-4 Alkylamino groups are preferred.

[0027] As used herein, "di-C 1-6 An "alkylamino group" is a group represented by the formula R 11 2N-(where R 11 are each independently 1-6 "Di-C" means a group represented by the formula: 1-6 Examples of the alkylamino group include dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, disec-butylamino, ditert-butylamino, dipentylamino, and dihexylamino. 1-4 Alkylamino groups are preferred.

[0028] In this specification, "C 1-6 An "alkoxy-carbonyl group" is a group represented by the formula R 11 OC(=O)-(where R 11 is C 1-6 "C" means a group represented by the formula: 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. 1-4 Alkoxy-carbonyl groups are preferred.

[0029] In this specification, "C 3-8 The term "cycloalkyl group" means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. 3-8 The "cycloalkyl group" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0030] In this specification, "C 6-10 The term "aryl group" refers to a hydrocarbon group having 6 to 10 carbon atoms and having aromaticity. 6-10 The "aryl group" includes phenyl, 1-naphthyl, and 2-naphthyl, with phenyl being preferred.

[0031] In this specification, "C 7-16 Aralkyl groups are defined as groups consisting of C 6-10 "C" substituted with "aryl group" 1-6 "C" means "alkyl group". 7-16 Examples of the aralkyl group include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, (1-naphthyl)methyl, (2-naphthyl)methyl and the like, with benzyl being preferred.

[0032] In this specification, "C 6-10 "Arene" means a hydrocarbon ring having 6 to 10 carbon atoms and having aromaticity. 6-10 The "arenes" include benzene and naphthalene, with benzene being preferred. In the present specification, "optionally substituted C 6-10 The substituents of "arene" include halogen atoms, cyano groups, C 1-6 Alkyl group, hydroxyl group, C 1-6 Alkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16Examples of such groups include aralkyl groups.

[0033] In the present specification, the term "nitrogen-containing heterocycle" refers to a ring containing at least one nitrogen atom and optionally containing a heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of the "nitrogen-containing heterocycle" include aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine, and are preferably 3- to 8-membered nitrogen-containing heterocycles, and more preferably 5- or 6-membered nitrogen-containing heterocycles.

[0034] The production method of the present invention will now be described. In the present invention, the aromatic heterocycle-substituted difluoroacetic acid derivative (III) is produced by reacting the N-oxide aromatic heterocycle compound (I) with tetrafluoroethylene in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent in the presence of the compound (II). The reaction mechanism is as follows:

[0035] [ka]

[0036] Specific examples of the N-oxide aromatic heterocyclic compound (I) include the following N-oxide aromatic heterocyclic compounds (IA) and (IB).

[0037] [ka]

[0038] [In the formula, X 1a is CR 1a or N; X 1b is CR 1b or N; X 1c is CR 1c or N; X 1d is CR 1d or N; R1a , R 1b , R 1c and R 1d are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, they form halogen atoms, cyano groups, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C may be substituted with a substituent selected from an aralkyl group. 6-10 may form an arene; X 2a is CR 2a , N, N.R. 2a , indicating S or O; X 2b is CR 2b or N; X 2c is CR 2c , N, N.R. 2c , indicating S or O; R2a , R 2b and R 2c are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Indicates an aralkyl group or R 2a and R 2b , or R 2b and R 2c Together, they form halogen atoms, cyano groups, and C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl groups and C 7-16 C may be substituted with a substituent selected from an aralkyl group. 6-10 It may also form an arene. R 1a , R 1b , R 1c and R 1d are preferably each independently a hydrogen atom, a cyano group or C 1-6 is an alkyl group or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, C 1-6C optionally substituted with an alkoxy-carbonyl group 6-10 An arene may be formed. R 2a , R 2b and R 2c are preferably each independently a hydrogen atom, C 1-6 Alkyl group or C 7-16 aralkyl group or R 2a and R 2b , or R 2b and R 2c Together, C 6-10 An arene may be formed.

[0039] In formula (IB), the bond R 2a -R 2b and bond R 2b -R 2c One of X is a single bond and the other is a double bond. 2a When is S or O, bond R 2a -R 2b is a single bond, and the bond R 2b -R 2c is a double bond. Also, X 2c When is S or O, bond R 2a -R 2b is a double bond, and bond R 2b -R 2c is a single bond.

[0040] Specific examples of the N-oxide aromatic heterocyclic compound (IA) include the following N-oxide aromatic heterocyclic compounds (IA-a) to (IA-e).

[0041] [ka]

[0042] [Each symbol in the formula has the same meaning as defined above.] Of these, (IA-a), (IA-b) and (IA-d) are preferred. Preferable specific examples of the N-oxide aromatic heterocyclic compound (IA) include the following compounds:

[0043] [ka]

[0044] [In the formula, R 1aa , R 1bb , R 1cc and R 1dd are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Represents an aralkyl group; n R 1ee are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Represents an aralkyl group; n represents an integer of 0 to 4. R 1aa , R 1bb , R 1cc and R 1dd are preferably each independently a hydrogen atom, a cyano group or C 1-6 is an alkyl group; n R 1eeare preferably each independently 1-6 is an alkoxy-carbonyl group; n is 0 or 1.

[0045] Specific examples of the N-oxide aromatic heterocyclic compound (IB) include the following N-oxide aromatic heterocyclic compounds (IB-a) to (IB-ff).

[0046] [ka]

[0047] [ka]

[0048] [Each symbol in the formula has the same meaning as defined above.] Of these, (IB-e), (IB-u) and (IB-w) are preferred. Preferable specific examples of the N-oxide aromatic heterocyclic compound (IB) include the following compounds:

[0049] [ka]

[0050] [In the formula, R 2aa , R 2bb and R 2cc are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C7-16 Represents an aralkyl group; n R 2ee are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, sulfanyl group, C 1-6 Alkylsulfanyl group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, formyl group, carboxy group, C 1-6 Alkoxy-carbonyl group, C 6-10 Aryl group or C 7-16 Represents an aralkyl group; n represents an integer of 0 to 4. R 2aa , R 2bb and R 2cc are preferably each independently a hydrogen atom, C 1-6 Alkyl group or C 7-16 is an aralkyl group; n is 0.

[0051] The N-oxide aromatic heterocyclic compound (I) may be a commercially available product, or may be produced by a method known per se.

[0052] Tetrafluoroethylene (CF2=CF2) can be produced by a known method. Tetrafluoroethylene is a gas at room temperature under atmospheric pressure, so it is added to the reaction system by inflow. At this time, tetrafluoroethylene diluted with nitrogen gas may be inflowed. The amount of tetrafluoroethylene used is usually 1 to 100 moles, preferably 1 to 10 moles, per mole of the N-oxide aromatic heterocyclic compound (I).

[0053] The reaction is carried out in the presence of compound (II). R in compound (II) is preferably a halogen atom, a cyano group, C 1-6 Alkoxy groups and C 1-6 C may be substituted with a group selected from haloalkoxy groups.1-8 Alkyl group; halogen atom, cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 C, each of which may be substituted with a group selected from haloalkoxy groups. 7-16 Aralkyl group or C 6-10 Aryl groups are preferred, more preferably C 1-6 It is an alkyl group. Y in compound (II) is preferably O or NR Y and more preferably O. R in compound (II) Y is preferably a hydrogen atom or C 1-6 They are either alkyl groups or, together with R, form, together with the nitrogen atom to which they are attached, a 5- or 6-membered nitrogen-containing heterocycle (eg, morpholine). Preferable specific examples of compound (II) include butanol, morpholine, etc. The amount of compound (II) used can be appropriately selected, but is preferably 0.05 to 0.5 times the volume of the solvent described below.

[0054] The reaction may be carried out in the presence of an additive.

[0055] The reaction is carried out in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent. By using the solvent, tetrafluoroethylene can be dissolved well, and the aromatic heterocycle-substituted difluoroacetic acid derivative (III) can be produced with few by-products. Examples of aromatic hydrocarbon solvents include toluene, xylene, and nitrobenzene. Ester solvents include butyl acetate, octyl acetate, and the like. Examples of the ether solvent include dibutyl ether and cyclopentyl methyl ether. From the viewpoint of the reaction temperature, the solvent used in the reaction is preferably a solvent having a boiling point of 80° C. or higher, more preferably a solvent having a boiling point of 100° C. or higher, and particularly preferably a solvent having a boiling point of 110° C. or higher. Examples of such a solvent include toluene, xylene, nitrobenzene, butyl acetate, octyl acetate, dibutyl ether, cyclopentyl methyl ether, and the like, and among these, toluene and butyl acetate are preferred. The amount of the solvent used is usually 100 to 1000 times, and preferably 100 to 200 times, by volume, the amount of the N-oxide aromatic heterocyclic compound (I).

[0056] The reaction may be carried out in a flow system while feeding tetrafluoroethylene into a mixture of N-oxide aromatic heterocyclic compound (I), compound (II) and a solvent, or may be carried out in a closed system after feeding tetrafluoroethylene into a mixture of N-oxide aromatic heterocyclic compound (I), compound (II) and a solvent. From the viewpoints of reaction efficiency and reduction of by-products, the reaction is preferably carried out in a closed system, preferably within a pressure range of 0.1 to 100.0 MPa, particularly preferably within a pressure range of 0.1 to 10.0 MPa. The N-oxide aromatic heterocyclic compound (I) has the formula (IA) and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, these form the above C 6-10 When arenes are formed, the reaction is preferably carried out under a pressure within the range of 0.1 to 10.0 MPa, more preferably 0.1 to 1.0 MPa, and particularly preferably 0.1 to 0.5 MPa, in order to facilitate the reaction and increase the reaction rate. On the other hand, when the N-oxide aromatic heterocyclic compound (I) is represented by the formula (IA) and the above C 6-10 When arenes are not formed, the pressure may be within the above range, but in terms of facilitating the reaction and increasing the reaction rate, it is preferable to carry out the reaction under a pressure within the range of 0.1 to 30.0 MPa, preferably within the range of 1.5 to 3.0 MPa, and particularly preferably within the range of 2.0 to 2.5 MPa. It is preferable to degas the reaction system before the introduction of tetrafluoroethylene, and the reaction is preferably carried out under a nitrogen atmosphere.

[0057] The reaction is usually carried out at 100°C or higher, preferably within the range of 100 to 300°C. The N-oxide aromatic heterocyclic compound (I) has the formula (IA) and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together, these form the above C 6-10 When an arene is formed, the reaction is preferably carried out within a range of 100 to 200° C., particularly within a range of 100 to 150° C., since the reaction proceeds easily and the reaction rate increases. On the other hand, when the N-oxide aromatic heterocyclic compound (I) is represented by the formula (IA) and the above C 6-10 When arene is not formed, the above temperature range may be used, but it is preferable to carry out the reaction within the range of 200 to 300°C, particularly 200 to 250°C, since the reaction proceeds easily and the reaction rate increases. The reaction time varies depending on the types of N-oxide aromatic heterocyclic compound (I) and compound (II) and the reaction temperature, but is usually 12 to 120 hours, preferably 24 to 48 hours.

[0058] After completion of the reaction, the desired aromatic heterocycle-substituted difluoroacetic acid derivative (III) can be isolated and / or purified from the reaction mixture in accordance with a conventional method by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc.

[0059] The vessel in which tetrafluoroethylene and N-oxide aromatic heterocyclic compound (I) are reacted is not particularly limited as long as it does not adversely affect the reaction, and for example, a metal vessel or the like can be used. Since the present invention deals with olefins in a gaseous state under reaction conditions, an airtight pressure vessel is preferable. In addition, since compounds generated as the reaction proceeds may react with the metal of the reaction vessel and become a reaction inhibitor, a vessel lined with resin such as PFA or glass is preferable.

[0060] The aromatic heterocycle-substituted difluoroacetic acid derivative (III) thus obtained is useful as a synthetic intermediate for pharmaceuticals or agricultural chemicals by a known method, for example, in the case of the aromatic heterocycle-substituted difluoroacetic acid derivative (III) in which Y is O, after hydrolysis, a decarboxylation step is carried out to obtain a compound of the formula (IV):

[0061] [ka]

[0062] This can lead to a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the following formula: EXAMPLES

[0063] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. [Analysis method] The present invention will be described below with reference to examples, but the present invention is not limited to these examples. Nuclear magnetic resonance spectroscopy (NMR) was measured using a JNM-AL300 manufactured by JEOL Ltd. 1 H-NMR was measured at 300 MHz using tetramethylsilane as the standard. Mass spectrometry (LC-MS) was measured using a liquid chromatograph mass spectrometry system (LCMS6120B) manufactured by Agilent Technologies, Inc. Mass spectrometry (GC-MS) was measured using a gas chromatograph mass spectrometer (GCMS-QP5000V2 or GCMS-QP2010Ultra) manufactured by Shimadzu Corporation, using electron ionization (EI).

[0064] Example 1

[0065] [ka]

[0066] Volume is 25cm 3 Into the SUS reactor, 10 ml of butyl acetate and 1 ml of 1-butanol were added and stirred, and the temperature was maintained at 25°C. Quinoline N-Oxide (109 mg, 0.751 mmol, compound 1) was then added, and vacuum decompression was performed. Tetrafluoroethylene diluted to 50% with nitrogen gas was introduced until the reactor pressure reached 0.1 MPa, and the reactor was heated and stirred at 140°C for one week. The crude liquid after the reaction was 1 Compound 2 was obtained in 89% yield as determined by 1 H-NMR and LC-MS. The reaction solution was concentrated as it was, and compound 2 (20 mg, 0.0677 mmol) was dissolved in 0.2 ml of methanol, and 0.2 ml of 1N potassium carbonate aqueous solution was added and stirred, and the stirring was continued at 25°C for 18 hours. Then, 1 ml of 5% hydrochloric acid aqueous solution was added, and the organic layer was separated and extracted with ethyl acetate and washed with saturated saline. The crude product obtained by concentrating the organic layer was dissolved in 1 ml of N,N-dimethylformaldehyde, and 23 mg of sodium fluoride was added, and the mixture was heated and stirred at 170°C for 1 hour. The crude liquid after the reaction was 1 Compound 3 was obtained in 92% yield as determined by 1 H-NMR and GC-MS. The above compound (2) 1 H-NMR and LC-MS are shown below. 1H-NMR(CDCl3)δ 8.35 (d, 1H), 8.15 (d, 1H), 7.89 (d, 1H), 7.72-7.81(m, 2H), 7.63 (t, 1H), 4.36 (t, 2H), 1.67 (tt, 2H), 1.35 (tt, 2H), 0.88 (t, 3H) LC-MS: [M+1]=280 The above compound (3) 1 H-NMR and GC-MS are shown below. 1 H-NMR(CDCl3)δ 8.34 (d, 1H), 8.15 (d, 1H), 7.90 (d, 1H), 7.80 (dd, 1H), 7.74 (d, 1H), 7.65 (dd, 1H), 6.79 (t, 1H) GC-MS(EI):[M+]=179

[0067] Reference example 1

[0068] [ka] A crude liquid containing compounds 2 and 3 was obtained from compound 1 in the same manner as in Example 1, except that butyl acetate was not used. 1 H-NMR and GC-MS were measured to obtain compound 2 in 13% yield.

[0069] Example 2

[0070] [ka]

[0071] Volume is 25cm 37 ml of toluene and 0.3 ml of morpholine were added to the SUS reactor, stirred, and maintained at 25°C. Quinoline N-Oxide (109 mg, 0.751 mmol, compound 1) was then added, and vacuum decompression was performed. Tetrafluoroethylene diluted to 50% with nitrogen gas was introduced until the reactor pressure reached 0.1 MPa, and the reactor was heated and stirred at 140°C for 12 hours. The crude liquid after the reaction was 1 Compound 4 was obtained in 37% yield as determined by 1 H-NMR and LC-MS. The above compound (4) 1 H-NMR and LC-MS are shown below. 1 H-NMR(CDCl3)δ 8.33 (d, 1H), 8.11 (d, 1H), 7.88 (d,1H), 7.82-7.74 (m, 2H), 7.63 (t, 1H), 3.76 (s, 4H), 3.64 (t, 2H), 3.57 (t, 2H). LC-MS: [M+1]=293

[0072] Example 3

[0073] [ka]

[0074] A crude liquid containing compound 6 was obtained from compound 5 in the same manner as in Example 1. After completion of the reaction, the crude liquid was subjected to NMR and LC-MS measurement, and compound 6 was obtained in a yield of 61%. The above compound (6) 1 H-NMR and LC-MS are shown below. 1 H-NMR(CDCl3)δ 9.23 (s, 1H), 8.10-8.22 (m, 2H), 7.80-7.92 (m, 2H), 4.36 (t, 2H), 1.70 (tt, 2H), 1.38 (tt, 2H), 0.92 (t, 3H) LC-MS: [M+1]=281

[0075] Example 4

[0076] [ka]

[0077] A crude liquid containing compound 8 was obtained from compound 7 in the same manner as in Example 1. After completion of the reaction, the crude liquid was subjected to NMR and LC-MS measurement, and compound 8 was obtained in a yield of 41%. The above compound (8) 1 H-NMR and LC-MS are shown below. 1 H-NMR(CDCl3)δ9.58 (1H, s), 8.46 (1H, m), 7.77-8.09 (3H, m), 4.48 (2H,t), 1.73 (2H, tt), 1.44 (2H, tt), 0.95 (3H, t). LC-MS: [M+1]=281

[0078] Example 5

[0079] [ka]

[0080] Volume is 300cm 3 Butyl acetate (30 ml) and butanol (3 ml) were added to a PFA-lined SUS reactor, and the mixture was stirred and maintained at 25°C. Pyridine N-oxide (336.4 mg, 3.54 mmol, compound 9) was then added and freeze-degassed. Tetrafluoroethylene diluted to 50% with nitrogen gas was then introduced until the reactor pressure reached 0.3 MPa, after which the mixture was heated and stirred at 250°C for 8 hours. The crude liquid after the reaction was 1 Compound 10 was obtained in 28% yield as determined by 1 H-NMR and LC-MS. The above compound (10) 1 H-NMR and LC-MS are shown below. 1H-NMR(ACETN) δ8.69 (d, 1H), 8.08 (ddd, 1H), 7.84 (ddd, 1H), 7.60-7.63 (m, 1H), 4.33 (t, 2H), 1.65 (tt, 2H), 1.35 (tt, 2H), 0.89 (t, 3H) LC-MS: [M+1]=230

[0081] Example 6

[0082] [ka]

[0083] A crude liquid containing compound 12 was obtained from compound 11 in the same manner as in Example 1. After completion of the reaction, the crude liquid was subjected to NMR and LC-MS measurement, and compound 12 was obtained in a yield of 42%. The above compound (12) 1 H-NMR and LC-MS are shown below. 1 H-NMR(CDCl3)δ8.15 (1H, d), 7.97 (1H, d), 7.54 (2H, dt), 4.44 (2H,t), 1.59 (2H, tt), 1.34 (2H, tt), 0.94 (3H, t). LC-MS: [M+1]=286

[0084] Example 7

[0085] [ka]

[0086] A crude liquid containing compound 14 was obtained from compound 13 in the same manner as in Example 1. After completion of the reaction, the crude liquid was subjected to NMR and LC-MS measurement, and compound 14 was obtained in a yield of 55%. The above compound (14) 1 H-NMR and LC-MS are shown below. 1H-NMR(CDCl3)δ 7.31-7.36 (m, 2H), 7.09 (dd, 2H), 4.81 (s, 2H), 4.35 (t, 2H), 2.10 (s, 3H), 1.97 (s, 3H), 1.72 (tt, 2H), 1.41 (tt, 2H), 0.93 (t, 3H) LC-MS: [M+1]=337

[0087] Example 8

[0088] [ka]

[0089] A crude liquid containing compound 16 was obtained from compound 15 in the same manner as in Example 1. 1 H-NMR and GC-MS were measured to give compound 16 in 25% yield. The above compound (16) 1 H-NMR and GC-MS are shown below. 1 H-NMR(CDCl3)δ 8.50(d, 1H), 7.72(d, 1H),7.09(s, 1H), 3.90(t, 2H), 1.59(tq, 2H), 1.35(s, 9H), 1.34(m, 2H), 0.94(t, 3H) GC-MS(EI):[M+]=285

[0090] Example 9

[0091] [ka]

[0092] A crude liquid containing compound 18 was obtained from compound 17 in the same manner as in Example 1. 1 H-NMR and GC-MS were measured to give compound 18 in 26% yield. The above compound (18) 1H-NMR and GC-MS are shown below. 1 H-NMR(CDCl3)δ 8.95(d, 1H),8.02(s, 1H), 7.60(d, 1H), 3.90(t, 2H), 1.59(d, 2H), 1.34(tq, 2H), 0.94(t, 3H), GC-MS(EI):[M+]=254 [Industrial Applicability]

[0093] According to the present invention, an aromatic heterocycle-substituted difluoroacetic acid derivative (III) can be produced in one step with little by-products by a simple and inexpensive method in which tetrafluoroethylene is introduced into an N-oxide aromatic heterocycle compound (I) in the presence of compound (II) in a specific solvent.

[0094] This application is based on Japanese Patent Application No. 2020-019211 filed on February 6, 2020, the contents of which are incorporated in their entirety herein.

Claims

1. In a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent, [In the formula, R is C １－８ Alkyl group, C ３－８ Cycloalkyl group, C ７－１６ Aralkyl group or C ６－１０ represents an aryl group, １－８ The alkyl group is a halogen atom, a cyano group, １－６ Alkoxy group and C １－６ haloalkoxy groups, ３－８ Cycloalkyl group, C ７－１６ Aralkyl groups and C ６－１０ The aryl group is a halogen atom, a cyano group, １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group and C １－６ haloalkoxy groups, Y is O, S or NR Ｙ indicates, R Ｙ is a hydrogen atom or C １－８ It may represent an alkyl group, or may form a nitrogen-containing heterocycle together with R and the nitrogen atom to which they are attached. In the presence of a compound represented by formula (I): 【Chemistry 1】 The present invention relates to a method for producing an aromatic heterocyclic compound having a partial structure represented by the formula (III): 【Chemistry 2】 [Each symbol in the formula has the same meaning as defined above.] A method for producing an aromatic heterocycle-substituted difluoroacetic acid derivative having a partial structure represented by the following formula: The reaction is carried out within a temperature range of 100 to 300°C, and the boiling point of the solvent is 100°C or higher.

2. The manufacturing method described in claim 1, wherein the solvent is selected from toluene, xylene, nitrobenzene, butyl acetate, octyl acetate, dibutyl ether and cyclopentyl methyl ether.

3. The method of claim 1, wherein the solvent is selected from toluene and butyl acetate.

4. The method according to any one of claims 1 to 3, wherein the reaction is carried out in the range of 0.1 to 10.0 MPa.

5. The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA) or (IB): 【Chemistry 3】 [In the formula, X １ａ is CR １ａ or N; X １ｂ is CR １ｂ or N; X １ｃ is CR １ｃ or N; X １ｄ is CR １ｄ or N; R １ａ , R １ｂ , R １ｃ and R １ｄ are each independently a hydrogen atom, a halogen atom, a cyano group, １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkylsulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl group or C ７－１６ represents an aralkyl group, or R １ａ and R １ｂ , R １ｂ and R １ｃ , or R １ｃ and R １ｄ Together, they form a halogen atom, a cyano group, and C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkylsulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl groups and C ７－１６ C optionally substituted with a substituent selected from an aralkyl group ６－１０ may form an arene; X ２ａ is CR ２ａ , N.R. ２ａ , S or O; X ２ｂ is CR ２ｂ or N; X ２ｃ is CR ２ｃ , N.R. ２ｃ , S or O; R ２ａ , R ２ｂ and R ２ｃ are each independently a hydrogen atom, a halogen atom, a cyano group, １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkylsulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl group or C ７－１６ represents an aralkyl group, or R ２ａ and R ２ｂ , or R ２ｂ and R ２ｃ Together, they form a halogen atom, a cyano group, and C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkylsulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl groups and C ７－１６ C optionally substituted with a substituent selected from an aralkyl group ６－１０ An arene may be formed. The method according to any one of claims 1 to 4, wherein the compound is an N-oxide aromatic heterocyclic compound represented by the formula:

6. The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA), and in the formula, R １ａ and R １ｂ , R １ｂ and R １ｃ , or R １ｃ and R １ｄ Together, they form a halogen atom, a cyano group, and C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkylsulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl groups and C ７－１６ C optionally substituted with a substituent selected from an aralkyl group ６－１０ The method according to claim 5, wherein an arene is formed.

7. The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA), and in the formula, R １ａ , R １ｂ , R １ｃ and R １ｄ are each independently a hydrogen atom, a halogen atom, a cyano group, １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkylsulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl group or C ７－１６ The method according to claim 5 , wherein the group is an aralkyl group.

8. The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IB), and R ２ａ and R ２ｂ , or R ２ｂ and R ２ｃ Together, they form a halogen atom, a cyano group, and C １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkylsulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl groups and C ７－１６ C optionally substituted with a substituent selected from an aralkyl group ６－１０ The method according to claim 5, wherein an arene is formed.

9. The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IB), and R ２ａ , R ２ｂ and R ２ｃ are each independently a hydrogen atom, a halogen atom, a cyano group, １－６ Alkyl group, C １－６ Haloalkyl group, hydroxy group, C １－６ Alkoxy group, C １－６ Haloalkoxy group, sulfanyl group, C １－６ Alkylsulfanyl group, amino group, mono-C １－６ Alkylamino group, di-C １－６ Alkylamino group, formyl group, carboxy group, C １－６ Alkoxy-carbonyl group, C ６－１０ Aryl group or C ７－１６ The method according to claim 5 , wherein the group is an aralkyl group.

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