Method for producing difluoromethyl-substituted aromatic heterocyclic compounds

Abstract

The purpose of the present invention is to provide a method which is capable of producing a difluoromethyl-substituted aromatic heterocyclic compound by a simple and low-cost process.　The present invention relates to a method for producing a difluoromethyl-substituted aromatic heterocyclic compound that has a partial structure represented by formula (II), said method being characterized by reacting an N-oxide aromatic heterocyclic compound that has a partial structure represented by formula (I) with tetrafluoroethylene in a solvent that is selected from among an aromatic hydrocarbon solvent, an ester solvent and an ether solvent. (Symbols in the formulae are as described in the specification.)

Description

[Technical field]

[0001] The present invention relates to a method for producing a difluoromethyl-substituted aromatic heterocyclic compound. [Background technology]

[0002] Fluorine-containing alkyl group-substituted aromatic heterocyclic compounds, particularly difluoromethyl-substituted aromatic heterocyclic compounds, are useful as synthetic intermediates for pharmaceuticals or agricultural chemicals.

[0003] The method for producing a fluorine-containing alkyl group-substituted aromatic heterocyclic compound includes the following: A method for producing 2-(1,2,2,2-tetrafluoroethyl)quinoline by reacting quinoline N-oxide with hexafluoropropene (CF2=CFCF3) at room temperature in N,N-dimethylformamide and water in one or two steps (Non-Patent Document 1, Scheme 5); A method for producing 2-(1,2,2,2-tetrafluoroethyl)quinoline by reacting quinoline N-oxide with hexafluoropropene (CF2=CFCF3) at room temperature in N,N-dimethylformamide (Non-Patent Document 2, Scheme 1 and Table 1); It is known that.

[0004] None of the documents describe the preparation of difluoromethyl-substituted aromatic heterocyclic compounds 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 [Non-Patent Document 2] Mendeleev Commun. 2006, pp 161-163 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 a difluoromethyl-substituted aromatic heterocyclic compound in a simple and inexpensive manner with good yield. [Means for solving the problem]

[0007] As a result of intensive research aimed at solving the above problems, the present inventors have found that a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the following formula (II) can be produced in one step, in a simple and inexpensive manner, with little by-products and in good yield, by reacting an N-oxide aromatic heterocyclic compound having a partial structure represented by the following formula (I) with tetrafluoroethylene 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 aromatic hydrocarbon solvents, ester solvents and ether solvents, a compound of formula (I):

[0009] [ka]

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

[0011] [ka]

[0012] The present invention relates to a method for producing a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the following formula (hereinafter, also referred to as difluoromethyl-substituted aromatic heterocyclic compound (II)). [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 method according to any one of the above [1] to [3], wherein the reaction is carried out in the presence of a pH 5.0 to 8.0 buffer solution. [5] 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 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, 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 R1b , 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; 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 R2b 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 form an arene.] (hereinafter also referred to as N-oxide aromatic heterocyclic compound (IA) or (IB)).

[0015] [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 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. 6-10The method according to the above [5], in which an arene is formed.

[0016] [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 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 [5], wherein the R is an aralkyl group.

[0017] [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 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. 6-10The method according to the above [5], in which an arene is formed.

[0018] [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 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 [5], wherein the R is an aralkyl group. Effect of the Invention

[0019] According to the present invention, a difluoromethyl-substituted aromatic heterocyclic compound (II) can be produced in a single step with a small amount of by-products and in a good yield by a simple and inexpensive method of introducing tetrafluoroethylene into an N-oxide aromatic heterocyclic compound (I) in a specific solvent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The definitions of groups used in the present specification are described in detail below. Unless otherwise specified, groups have the following definitions.

[0021] 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.

[0022] In this specification, the term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

[0023] 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.

[0024] 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.

[0025] 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: 1-6Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, and hexyloxy. 1-4 Alkoxy groups are preferred.

[0026] In this specification, "C 1-6 Haloalkyl 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.

[0027] 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.

[0028] 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: 1-6Examples 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.

[0029] 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.

[0030] 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.

[0031] 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: 1-6Examples 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.

[0032] 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.

[0033] 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.

[0034] 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 C7-16 Examples of such groups include aralkyl groups.

[0035] The production method of the present invention will now be described. In the present invention, the difluoromethyl-substituted aromatic heterocyclic compound (II) is produced by reacting the N-oxide aromatic heterocyclic compound (I) with tetrafluoroethylene in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent, and an ether solvent. The reaction mechanism is as follows, for example, when a proton source is present and is water.

[0036] [ka]

[0037] Specific examples of the N-oxide aromatic heterocyclic compound (I) include the following N-oxide aromatic heterocyclic compounds (IA) and (IB).

[0038] [ka]

[0039] [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, 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 1-6Alkylsulfanyl 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; 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 1-6Alkylsulfanyl 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 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 1-6 C 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 R2a and R 2b , or R 2b and R 2c Together, C 6-10 An arene may be formed.

[0040] 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.

[0041] Specific examples of the N-oxide aromatic heterocyclic compound (IA) include the following N-oxide aromatic heterocyclic compounds (IA-a) to (IA-e).

[0042] [ka]

[0043] [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:

[0044] [ka]

[0045] [In the formula, R 1aa , R 1bb , R 1cc and R1dd 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 1ee are preferably each independently 1-6 is an alkoxy-carbonyl group; n is 0 or 1.

[0046] Specific examples of the N-oxide aromatic heterocyclic compound (IB) include the following N-oxide aromatic heterocyclic compounds (IB-a) to (IB-ff).

[0047] [ka]

[0048] [ka]

[0049] [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:

[0050] [ka]

[0051] [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 C 7-16 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 1-6Alkylsulfanyl 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.

[0052] The N-oxide aromatic heterocyclic compound (I) may be a commercially available product, or may be produced by a method known per se.

[0053] 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).

[0054] The reaction is carried out using a proton source. The proton source may be present from the start of the reaction, may be added during the reaction, or may be a compound generated during the reaction (e.g., hydrogen fluoride). From the viewpoint of reaction rate, however, it is preferable that the proton source is present from the start of the reaction. Examples of the proton source include inorganic acids, organic acids, and water, and more specifically, hydrogen fluoride, hydrogen chloride, ammonium salts, water, and buffer solutions. Among these, water and hydrogen fluoride are preferred. The water may be water molecules hydrated to the raw material N-oxide aromatic heterocyclic compound (I). The hydrogen fluoride may be hydrogen fluoride molecules generated during the reaction process. The amount of the proton source used can be appropriately selected, but in the case of the water or buffer solution, for example, it is preferably 0.05 to 0.5 times the volume of the solvent described below. In addition, when the proton source is, for example, the hydrated water molecule, it is preferably 1 to 10 moles per mole of the N-oxide aromatic heterocyclic compound (I). In addition, when the proton source is, for example, the hydrogen fluoride molecule generated in the reaction process, it is preferably 1 mole per mole of the N-oxide aromatic heterocyclic compound (I).

[0055] The reaction may be carried out in the presence of an additive.

[0056] 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 difluoromethyl-substituted aromatic heterocyclic compound (II) can be produced with a small amount of by-products and in a good yield. 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, xylene, 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).

[0057] The reaction may be carried out in a flow system while flowing tetrafluoroethylene into a mixture of the N-oxide aromatic heterocyclic compound (I), a proton source and a solvent, or may be carried out in a closed system after flowing tetrafluoroethylene into a mixture of the N-oxide aromatic heterocyclic compound (I), a proton source and a solvent. From the viewpoints of reaction efficiency, yield 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, and in terms of shortening the reaction time, the reaction may be carried out under a pressure within the range of 0.1 to 30.0 MPa, further within the range of 1.5 to 3.0 MPa, and particularly 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.

[0058] The reaction is preferably carried out in the presence of a buffer solution of pH 5.0 to 8.0, more preferably in the presence of a buffer solution of pH 5.0 to 7.0. This reduces the production of by-products and improves the yield. An example of the buffer solution is a phosphate buffer solution (pH 7.0 to 7.5). For example, in the case of a phosphate buffer solution (pH 7.0 to 7.5), the amount of the buffer solution used is preferably 0.05 to 0.5 times the volume of the above-mentioned solvent.

[0059] 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. 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, and the reaction may be carried out within the range of 200 to 300°C, particularly within the range of 200 to 250°C, since the reaction proceeds easily.

[0060] The reaction time varies depending on the type of N-oxide aromatic heterocyclic compound (I) and the reaction temperature, but is usually 12 to 120 hours, preferably 24 to 48 hours.

[0061] After completion of the reaction, the desired difluoromethyl-substituted aromatic heterocyclic compound (II) can be isolated and / or purified from the reaction mixture by a conventional separation method such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc.

[0062] 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.

[0063] The difluoromethyl-substituted aromatic heterocyclic compound (II) thus obtained is useful as a synthetic intermediate for pharmaceuticals or agricultural chemicals, and can lead to various pharmaceuticals or agricultural chemicals. EXAMPLES

[0064] 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).

[0065] Example 1

[0066] [ka]

[0067] Volume is 25cm 3 Toluene (10 ml) and water (1 ml) were added to a PFA-lined SUS reactor, which was then stirred and maintained at 25°C. Quinoline N-oxide (109 mg, 0.751 mmol, compound 1) was then added and vacuum decompression degassing was performed. Tetrafluoroethylene diluted to 50% with nitrogen gas was then introduced until the reactor pressure reached 0.1 MPa, after which the reactor was heated and stirred at 140°C for 48 hours. 1 H-NMR and GC-MS were measured to obtain compound 2 in 33% yield. The above compound (2)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

[0068] Example 2

[0069] [ka]

[0070] Volume is 25cm 3 Butyl acetate (10 ml) and a 0.1 mol / l, pH 7.0 phosphate buffer solution (1 ml) prepared from sodium dihydrogen phosphate (NaH2PO4) and disodium hydrogen phosphate (Na2HPO4) 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 degassing 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 150 hours. The crude liquid after the reaction was 1 Compound 2 was obtained in 43% yield as determined by 1 H-NMR quantification.

[0071] Comparative Example 1

[0072] [ka]

[0073] Volume is 25cm 3DMF (10 ml) and water (1 ml) were added to the SUS reactor, and the mixture was stirred and maintained at 25°C. Quinoline N-oxide (109 mg, 0.751 mmol, compound 1) was then added, and the mixture was degassed under reduced pressure in a vacuum. Tetrafluoroethylene diluted to 50% with nitrogen gas was then introduced until the reactor pressure reached 0.1 MPa, and the mixture was heated and stirred at 140°C for 48 hours. The crude liquid after the reaction was 1 Quantitative analysis by H-NMR revealed that compound 3 was obtained in a 56% yield without giving compound 2. The structure of compound 3 was determined by confirming its spectral agreement with compound 3 purchased from FUJIFILM Wako Chemical Co., Ltd.

[0074] Reference example 1

[0075] [ka]

[0076] A crude liquid containing compounds 2 and 3 was obtained from compound 1 in the same manner as in Example 1, except that toluene and water were omitted and the reaction was carried out under solvent-free conditions. 1 H-NMR and GC-MS were measured to obtain compound 2 in 13% yield.

[0077] Example 3

[0078] [ka]

[0079] A crude liquid containing compound 5 was obtained from compound 4 in the same manner as in Example 1, except that toluene and water were changed to butyl acetate. 1 H-NMR and GC-MS were measured, and compound 5 was obtained in a yield of 62%. In this example, a hydrate of compound 4 was used as a raw material. The above compound (5) 1 H-NMR and GC-MS are shown below. 1H-NMR(CDCl3)δ 9.19 (s, 1H), 8.14 - 8.23(m, 2H), 7.84 - 7.91 (m, 2H), 6.84 (t,1H) GC-MS(EI):[M+]=180

[0080] Example 4

[0081] [ka]

[0082] A crude liquid containing compound 7 was obtained from compound 6 in the same manner as in Example 1, except that toluene and water were changed to butyl acetate. 1 H-NMR and GC-MS were measured, and compound 7 was obtained in a yield of 56%. In this example, a hydrate of compound 6 was used as a raw material. The above compound (7) 1 H-NMR and GC-MS are shown below. 1 H-NMR(CDCl3)δ 9.62 (s, 1H), 8.22(m, 2H), 8.08 (m, 2H), 7.28 (t,1H) GC-MS(EI):[M+]=180

[0083] Example 5

[0084] [ka]

[0085] Volume is 300cm 3Xylene (30 ml) and water (3 ml) were added to a PFA-lined SUS reactor, stirred, and maintained at 25°C. Pyridine N-oxide (336.4 mg, 3.54 mmol, compound 8) was then added and freeze-degassed. Tetrafluoroethylene diluted to 50% with nitrogen gas was introduced until the reactor pressure reached 0.3 MPa, and the reactor was heated and stirred at 250°C for 8 hours. The crude liquid after the reaction was measured by GC-MS, and compound 9 was obtained in a yield of 49%. The structure was identified by confirming the spectrum match with compound 9 purchased from FUJIFILM Wako Chemical Co., Ltd. GC-MS(EI):[M+]=129

[0086] Example 6

[0087] [ka]

[0088] A crude liquid containing compound 11 was obtained from compound 10 in the same manner as in Example 1. 1 Compound 11 was obtained in 78% yield as determined by 1 H-NMR and LC-MS. The above compound (11) 1 H-NMR and LC-MS are shown below. 1 H-NMR(CDCl3)δ 8.63 (d, 1H), 8.34-8.43(m, 2H), 8.18 (d, 1H), 7.79 (d,1H), 6.78 (t,1H), 4.02(s,3H) LC-MS: [M+1]=238

[0089] Example 7

[0090] [ka]

[0091] A crude liquid containing compound 13 was obtained from compound 12 in the same manner as in Example 1, except that toluene was replaced with xylene. 1 H-NMR and GC-MS were measured to give compound 13 in 60% yield. The above compound (13) 1 H-NMR and GC-MS are shown below. 1 H-NMR(DMSO)δ 7.38-7.70 (m, 3H), 8.20(m, 1H), 8.26 (m, 1H) GC-MS(EI):[M+]=186

[0092] Example 8

[0093] [ka]

[0094] In the same manner as in Example 1, a crude liquid containing compounds 15 and 16 was obtained from compound 14. 1 Compound 15 was obtained in 38% yield as determined by 1 H-NMR and LC-MS. The above compound (15) 1 H-NMR and LC-MS are shown below. 1 H-NMR(CDCl3)δ 7.27-7.39 (m, 5H), 6.70 (t, J = 52.9 Hz, 1H), 5.27 (s, 2H), 2.19 (s, 3H), 1.98 (s, 3H) LC-MS: [M+1]=237

[0095] Example 9

[0096] [ka]

[0097] 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) 1 H-NMR and GC-MS are shown below. 1 H-NMR(CDCl3)δ 8.55 (d, 1H), 7.62(s, 1H), 7.39 (d, 1H), 6.64 (t,1H), 1.34 (s,9H) GC-MS(EI):[M+]=185

[0098] Example 10

[0099] [ka]

[0100] A crude liquid containing compound 20 was obtained from compound 19 in the same manner as in Example 1. 1 H-NMR and GC-MS were measured to give compound 20 in 20% yield. The above compound (20) 1 H-NMR and GC-MS are shown below. 1 H-NMR(CDCl3)δ 8.87 (d, 1H), 7.88(s, 1H), 7.73-7.59 (m, 1H), 6.68 (t,1H) GC-MS(EI):[M+]=154 [Industrial Applicability]

[0101] According to the present invention, a difluoromethyl-substituted aromatic heterocyclic compound (II) can be produced in a single step with a small amount of by-products and in a good yield by a simple and inexpensive method of introducing tetrafluoroethylene into an N-oxide aromatic heterocyclic compound (I) in a specific solvent.

[0102] This application is based on Japanese Patent Application No. 2020-019210 filed on February 6, 2020, the contents of which are incorporated in their entirety herein.

Claims

1. In a solvent selected from aromatic hydrocarbon solvents, ester solvents and ether solvents, a compound of 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 (II): 【Chemistry 2】 A method for producing a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the following formula: 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 represents CR 1a or N; X 1b represents CR 1b or N; X 1c represents CR 1c or N; X 1d represents CR 1d or N; R 1a , R 1b , R 1c and R 1d each independently represent a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a hydroxy group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a sulfanyl group, a C 1-6 alkylsulfanyl group, an amino group, a mono-C 1-6 alkylamino group, a di-C 1-6 alkylamino group, a formyl group, a carboxy group, a C 1-6 alkoxy-carbonyl group, a C 6-10 aryl group or a C 7-16 aralkyl group, or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d together represent a halogen atom, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a hydroxy group, a C 1-6 alkoxy group, a C may form a C 6-10 arene optionally substituted by a substituent selected from a 1-6 haloalkoxy group, a sulfanyl group, a C 1-6 alkylsulfanyl group, an amino group, a mono-C 1-6 alkylamino group, a di-C 1-6 alkylamino group, a formyl group, a carboxy group, a C 1-6 alkoxy-carbonyl group, a C 6-10 aryl group and a C 7-16 aralkyl group; X 2a represents CR 2a , N, NR 2a , S or O; X 2b represents CR 2b or N; X 2c represents CR 2c , N, NR 2c , S or O; R 2a , R 2b and R 2c each independently represent a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a hydroxy group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a sulfanyl group, a C 1-6 alkylsulfanyl group, an amino group, a mono-C 1-6 alkylamino group, a di-C 1-6 alkylamino group, a formyl group, a carboxy group, a C 1-6 alkoxy-carbonyl group, a C 6-10 aryl group or a C 7-16 aralkyl group, or R 2a and R 2b , or R 2b and R 2c together represent a halogen atom, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a hydroxy group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a sulfanyl group, a C 1-6 and may form a C 6-10 arene optionally substituted by a substituent selected from an alkylsulfanyl group, an amino group, a mono-C 1-6 alkylamino group, a di-C 1-6 alkylamino group, a formyl group, a carboxy group, a C 1-6 alkoxy-carbonyl group, a C 6-10 aryl group and a C 7-16 aralkyl group.] The production method of the N-oxide aromatic heterocyclic compound represented by the formula:

2. The process according to claim 1, wherein the reaction is carried out at a temperature in the range of 100 to 300°C.

3. The method according to claim 1 or 2, wherein the reaction is carried out in the range of 0.1 to 10.0 MPa.

4. The method according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of a pH 5.0 to 8.0 buffer solution.

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 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 of claim 1, wherein 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 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 1 , wherein the group 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 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 of claim 1, wherein 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 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 1 , wherein the group is an aralkyl group.

Images