Method for producing difluoromethyl substituted aromatic heterocyclic compounds

Abstract

The object of the present invention is to provide a method for producing a difluoromethyl-substituted aromatic heterocyclic compound in a simple and inexpensive manner. The present invention relates to a method for producing a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by formula (II), characterized in that an N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is reacted with tetrafluoroethylene in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent and an ether solvent. [The symbols in the formula 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 Art

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

[0003] As a method for producing a fluorine-containing alkyl-substituted aromatic heterocyclic compound, the following method is known:

[0004] In N,N-dimethylformamide and water, quinoline N-oxide and hexafluoropropylene (CF 2 =CFCF 3 ) reaction to produce 2-(1,2,2,2-tetrafluoroethyl)quinoline (Non-Patent Document 1, Scheme 5);

[0005] In N,N-dimethylformamide, quinoline N-oxide was reacted with hexafluoropropylene (CF 2 =CFCF 3 ) reaction to produce 2-(1,2,2,2-tetrafluoroethyl)quinoline (Non-Patent Document 2, Scheme 1 and Table 1).

[0006] In any document, the preparation of difluoromethyl substituted aromatic heterocyclic compounds and tetrafluoroethylene (CF 2 =CF 2 )’s reactions were not recorded.

[0007] Prior art literature

[0008] Non-patent literature

[0009] Non-patent document 1: Chem. Eur. J. 2008, vol. 14, pp 2577-2589

[0010] Non-patent document 2: Mendeleev Commun. 2006, pp 161-163 Summary of the invention

[0011] Problem that the invention aims to solve

[0012] 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 a high yield.

[0013] Solutions for solving problems

[0014] The present inventors have conducted intensive studies to solve the above-mentioned problems and have found that by reacting an N-oxide aromatic heterocyclic compound having a partial structure represented by the following formula (I) with tetrafluoroethylene in a specific solvent, a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the following formula (II) can be produced in a single step, by a simple and inexpensive method, with few by-products and in good yield, thereby completing the present invention.

[0015] That is, the present invention is as follows. [1]

[0017] A method for producing a difluoromethyl-substituted aromatic heterocyclic compound (hereinafter also referred to as a difluoromethyl-substituted aromatic heterocyclic compound (II)), wherein the difluoromethyl-substituted aromatic heterocyclic compound has a partial structure represented by formula (II),

[0018] The production method is characterized in that an N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) (hereinafter also referred to as N-oxide aromatic heterocyclic compound (I)) is reacted with tetrafluoroethylene in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent and an ether solvent.

[0019] [2]

[0021] The production method according to the above [1], wherein the reaction is performed within a range of 100 to 300°C. [3]

[0023] The production method according to [1] or [2], wherein the reaction is performed within a range of 0.1 to 10.0 MPa. [4]

[0025] The production method according to any one of [1] to [3] above, wherein the reaction is performed in the presence of a buffer solution at pH 5.0 to 8.0. [5]

[0027] The production method according to any one of [1] to [4], wherein the N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is an N-oxide aromatic heterocyclic compound represented by formula (IA) or (IB) (hereinafter also referred to as N-oxide aromatic heterocyclic compound (IA) or (IB)):

[0028]

[0029] [Wherein,

[0030] X 1a Represents CR 1a or N;

[0031] X 1b Represents CR 1b or N;

[0032] X 1c Represents CR 1c or N;

[0033] X 1d Represents CR 1d or N;

[0034] R 1a , R 1b , R 1c and R 1d Each independently represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl, or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Optional together to form C 6-10 Aromatic hydrocarbons, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 Substitution of substituents in aralkyl groups;

[0035] X 2a Represents CR 2a , N, NR 2a , S or O;

[0036] X 2b Represents CR 2b or N;

[0037] X 2c Represents CR 2c , N, NR 2c , S or O;

[0038] R 2a , R 2b and R 2c Each independently represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl, or R 2a and R 2b , or R 2b and R 2c Optional together to form C 6-10 Aromatic hydrocarbons, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 Substituents in the aralkyl group are substituted.] [6]

[0040] The production method according to the above [5], wherein the N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is formula (IA), and R in the formula is 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together they form C 6-10 Aromatic hydrocarbons, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 The substituent in the aralkyl group is substituted. [7]

[0042] The production method according to the above [5], wherein the N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is formula (IA), and R in the formula is 1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl. [8]

[0044] The production method according to the above [5], wherein the N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is of formula (IB), and R in the formula is 2a and R 2b , or R 2b and R 2c Together they form C 6-10 Aromatic hydrocarbons, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 The substituent in the aralkyl group is substituted. [9]

[0046] The production method according to the above [5], wherein the N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is of formula (IB), and R in the formula is 2a , R 2b and R 2c are independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl.

[0047] Effects of the Invention

[0048] 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 a high yield by a simple and inexpensive method of flowing tetrafluoroethylene into an N-oxide aromatic heterocyclic compound (I) in a specific solvent. DETAILED DESCRIPTION

[0049] The following is a detailed description of the definitions of the groups used in this specification. Groups not otherwise specified have the following definitions.

[0050] In the present specification, the compound represented by the chemical formula is indicated by attaching the number of the chemical formula to the "compound". For example, the compound represented by formula (1) is indicated as "compound (1)".

[0051] In the present specification, the numerical range indicated by “to” or “-” means a numerical range in which the numbers before and after “to” or “-” are the lower limit or the upper limit.

[0052] In this specification, when the element symbol "C" is indicated by adding a numerical range with numbers before and after "-" and appended to the name of an arbitrary group, it means an arbitrary group with an integer number of carbon atoms with the numbers before and after "-" as the lower limit or upper limit, respectively. For example, an alkyl group with 1 to 3 carbon atoms may be indicated as "C 1-3 Alkyl", which respectively represent -CH 3 , -C 2 H 5 , -C 3 H 7 Etc. The same is true for other groups.

[0053] In the present specification, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0054] In this manual, "C 1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 The "alkyl group" includes 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, etc., preferably C 1-4 alkyl.

[0055] In this manual, "C 1-4 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 The “alkyl group” includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0056] In this manual, "C 1-6 "Alkoxy" means a 11 O-(here, R 11 Represents C 1-6 Alkyl. ) group. As "C 1-6 "Alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like, preferably C 1-4 Alkoxy.

[0057] In this manual, "C 1-6 "Haloalkyl" means "C 1-6 A group in which one or more hydrogen atoms in an alkyl group are replaced by halogen atoms. 1-6 The “haloalkyl” includes, for example, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, trifluoromethyl, difluoromethyl, perfluoroethyl, perfluoropropyl, chloromethyl, 2-chloroethyl, bromomethyl, 2-bromoethyl, iodomethyl, 2-iodoethyl and the like, and preferably trifluoromethyl.

[0058] In this manual, "C 1-6 "Haloalkoxy" means "C 1-6 A group in which one or more hydrogen atoms in an alkoxy group are replaced by halogen atoms. 1-6The “haloalkoxy” includes, for example, 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.

[0059] In this manual, C 1-6 "Alkylthio" means a group of formula R 11 S-(here, R 11 Represents C 1-6 Alkyl. ) group. As "C 1-6 "Alkylthio" includes methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like, preferably C 1-4 Sulfur group.

[0060] In this manual, "Single-C 1-6 "Alkylamino" means a group of the formula R 11 NH-(here, R 11 Represents C 1-6 Alkyl.) As a "mono-C 1-6 "Alkylamino" includes methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino and the like, preferably mono-C 1-4 Alkylamino.

[0061] In this specification, "di-C 1-6 "Alkylamino" means a group of the formula R 11 2 N-(here, 2 R 11 Each independently represents C 1-6 Alkyl.) As a "di-C 1-6 "Alkylamino" includes dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, dihexylamino and the like, preferably di-C 1-4 Alkylamino.

[0062] In this manual, "C 1-6 "Alkoxy-carbonyl" means a group of formula R 11 OC(=O)-(here, R 11 Represents C 1-6 Alkyl. ) group. As "C1-6 "Alkoxy-carbonyl" includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like, preferably C 1-4 Alkoxy-carbonyl.

[0063] In this manual, "C 6-10 The term "aryl" means a hydrocarbon group having 6 to 10 carbon atoms and having aromaticity. 6-10 The "aryl group" includes phenyl, 1-naphthyl and 2-naphthyl, and phenyl is preferred.

[0064] In this manual, "C 7-16 "Arylalkyl" means "C 6-10 Aryl" substituted "C 1-6 Alkyl. As "C 7-16 The "aralkyl group" includes benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, (1-naphthyl)methyl, (2-naphthyl)methyl and the like, and preferably benzyl.

[0065] In this manual, "C 6-10 "Aromatic hydrocarbon" means a hydrocarbon ring having 6 to 10 carbon atoms and having aromaticity. 6-10 The "aromatic hydrocarbon" includes a benzene ring and a naphthalene ring, and a benzene ring is preferred.

[0066] In this specification, the term "optionally substituted C 6-10 The substituents of "aromatic hydrocarbon" include halogen atoms, cyano groups, C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 Aralkyl.

[0067] Hereinafter, the production method of the present invention will be described.

[0068] In the present invention, the difluoromethyl-substituted aromatic heterocyclic compound (II) is prepared by reacting an N-oxide aromatic heterocyclic compound (I) with tetrafluoroethylene in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent and an ether solvent. For example, in the presence of a proton source, which is water, the reaction principle is as follows.

[0069]

[0070] Specific examples of the N-oxide aromatic heterocyclic compound (I) include the following N-oxide aromatic heterocyclic compounds (IA) and (IB).

[0071]

[0072] [Wherein,

[0073] X 1a Represents CR 1a or N;

[0074] X 1b Represents CR 1b or N;

[0075] X 1c Represents CR 1c or N;

[0076] X 1d Represents CR 1d or N;

[0077] R 1a , R 1b , R 1c and R 1d Each independently represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl, or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Optional together to form C 6-10 Aromatic hydrocarbons, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10Aryl and C 7-16 Substitution of substituents in aralkyl groups;

[0078] X 2a Represents CR 2a , N, NR 2a , S or O;

[0079] X 2b Represents CR 2b or N;

[0080] X 2c Represents CR 2c , N, NR 2c , S or O;

[0081] R 2a , R 2b and R 2c Each independently represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl, or R 2a and R 2b , or R 2b and R 2c Optional together to form C 6-10 Aromatic hydrocarbons, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, acyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 Substituents in the aralkyl group are substituted.]

[0082] R 1a , R 1b , R 1c and R 1d Preferably, each independently is a hydrogen atom, a cyano group or a C 1-6 Alkyl, or R1a and R 1b , R 1b and R 1c , or R 1c and R 1d Optional together to form optional C 1-6 Alkoxy-carbonyl substituted C 6-10 Aromatic hydrocarbons.

[0083] R 2a , R 2b and R 2c Preferably, each independently is a hydrogen atom, C 1-6 Alkyl or C 7-16 Aralkyl, or R 2a and R 2b , or R 2b and R 2c Optional together to form C 6-10 Aromatic hydrocarbons.

[0084] In formula (IB), bond R 2a -R 2b and key R 2b -R 2c One of them is a single bond and the other is a double bond. 2a When it is S or O, key R 2a -R 2b is a single bond, bond R 2b -R 2c In addition, X 2c When it is S or O, key R 2a -R 2b For double bonds, bond R 2b -R 2c For a single key.

[0085] Specific examples of the N-oxide aromatic heterocyclic compound (IA) include the following N-oxide aromatic heterocyclic compounds (IA-a) to (IA-e).

[0086]

[0087] [The symbols in the formula have the same meanings as above.]

[0088] Among them, (IA-a), (IA-b) and (IA-d) are preferred.

[0089] Preferred specific examples of the N-oxide aromatic heterocyclic compound (IA) include the following compounds.

[0090]

[0091] [Wherein,

[0092] R 1aa , R 1bb , R 1cc and R 1dd Each independently represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl;

[0093] n R 1ee Each independently represents a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl;

[0094] n represents an integer from 0 to 4.]

[0095] R 1aa , R 1bb , R 1cc and R 1dd Preferably, each independently is a hydrogen atom, a cyano group or a C 1-6 alkyl;

[0096] n R 1ee Preferably, each independently is C 1-6 Alkoxy-carbonyl;

[0097] n is 0 or 1.

[0098] Specific examples of the N-oxide aromatic heterocyclic compound (IB) include the following N-oxide aromatic heterocyclic compounds (IB-a) to (IB-ff).

[0099]

[0100]

[0101] [The symbols in the formula have the same meanings as above.]

[0102] Among them, (IB-e), (IB-u) and (IB-w) are preferred.

[0103] Preferred specific examples of the N-oxide aromatic heterocyclic compound (IB) include the following compounds.

[0104]

[0105] [Where R 2aa , R 2bb and R 2cc Each independently represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl;

[0106] n R 2ee Each independently represents a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl;

[0107] n represents an integer from 0 to 4.]

[0108] R 2aa , R 2bb and R 2cc Preferably, each independently is a hydrogen atom, C 1-6 Alkyl or C 7-16 Aralkyl;

[0109] n is 0.

[0110] The N-oxide aromatic heterocyclic compound (I) may be a commercially available product or may be produced by a method known per se.

[0111] Tetrafluoroethylene (CF 2 =CF 2 ) can be produced by a known method. Tetrafluoroethylene is a gas at atmospheric pressure and room temperature, so it is added to the reaction system by flowing. At this time, tetrafluoroethylene diluted with nitrogen can also be flowed in. The amount of tetrafluoroethylene used is usually 1 to 100 mol, preferably 1 to 10 mol, relative to 1 mol of the N-oxide aromatic heterocyclic compound (I).

[0112] This 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, it is preferably present from the start of the reaction.

[0113] As the proton source, inorganic acids, organic acids, water, etc. can be mentioned, and specifically, hydrogen fluoride, hydrogen chloride, ammonium salts, water, buffer solutions, etc. can be mentioned. Among them, water and hydrogen fluoride are preferred. In addition, water can also be hydrated water molecules in the raw material N-oxide aromatic heterocyclic compound (I). Hydrogen fluoride can be hydrogen fluoride molecules generated during the reaction.

[0114] The amount of the proton source used can be appropriately selected. For example, in the case of water or buffer solution, the amount 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 aforementioned hydrated water molecule, the amount is preferably 1 to 10 mol relative to 1 mol of the N-oxide aromatic heterocyclic compound (I). In addition, when the proton source is, for example, a hydrogen fluoride molecule generated during the reaction, the amount is preferably 1 mol relative to 1 mol of the N-oxide aromatic heterocyclic compound (I).

[0115] This reaction can also be carried out in the presence of an additive.

[0116] The reaction is carried out in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent and an ether solvent. By using such a solvent, tetrafluoroethylene can be well dissolved, and the difluoromethyl-substituted aromatic heterocyclic compound (II) can be produced with a small amount of by-products and a high yield.

[0117] Examples of the aromatic hydrocarbon solvent include toluene, xylene, and nitrobenzene.

[0118] Examples of the ester solvent include butyl acetate and octyl acetate.

[0119] Examples of the ether solvent include dibutyl ether and cyclopentyl methyl ether.

[0120] From the viewpoint of 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, and cyclopentyl methyl ether, among which toluene, xylene, and butyl acetate are preferred.

[0121] The amount of the solvent used is generally 100 to 1000 times by volume, preferably 100 to 200 times by volume, based on the N-oxide aromatic heterocyclic compound (I).

[0122] The reaction can be carried out in a circulating system while tetrafluoroethylene is flowing into a mixture of the N-oxide aromatic heterocyclic compound (I), a proton source and a solvent, or can be carried out in a closed system after tetrafluoroethylene is flowing into a mixture of the N-oxide aromatic heterocyclic compound (I), a proton source and a solvent. From the viewpoint of reaction efficiency, yield and reduction of by-products, the reaction is preferably carried out in a closed system, preferably in the range of 0.1 to 100.0 MPa, particularly preferably in the range of 0.1 to 10.0 MPa.

[0123] The N-oxide aromatic heterocyclic compound (I) is of the formula (IA), and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together they form the above C 6-10 In the case of aromatic hydrocarbons, the reaction is preferably carried out under a pressure in the range of 0.1 to 10.0 MPa, further in the range of 0.1 to 1.0 MPa, and particularly in the range of 0.1 to 0.5 MPa, from the viewpoint of facilitating the reaction and increasing the reaction rate.

[0124] On the other hand, the N-oxide aromatic heterocyclic compound (I) is of the formula (IA) and does not form the above C 6-10 In the case of aromatic hydrocarbons, the pressure may be in the above-mentioned range, and from the viewpoint of shortening the reaction time, it is also preferable to carry out the reaction under a pressure in the range of 0.1 to 30.0 MPa, further in the range of 1.5 to 3.0 MPa, and particularly in the range of 2.0 to 2.5 MPa.

[0125] The reaction system is preferably degassed before tetrafluoroethylene is introduced. The reaction is preferably carried out under a nitrogen atmosphere.

[0126] The reaction is preferably carried out in the presence of a pH 5.0 to 8.0 buffer, more preferably in the presence of a pH 5.0 to 7.0 buffer. Thus, the generation of by-products is reduced and the yield is improved. As the buffer, a phosphate buffer solution (pH 7.0 to 7.5) can be cited. For example, in the case of a phosphate buffer solution (pH 7.0 to 7.5), the amount of the buffer used is preferably 0.05 to 0.5 times the volume of the above-mentioned solvent.

[0127] The reaction is preferably performed usually at 100°C or higher, preferably in the range of 100 to 300°C.

[0128] The N-oxide aromatic heterocyclic compound (I) is of the formula (IA), and R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together they form the above C 6-10 In the case of aromatic hydrocarbons, the reaction is preferably carried out at a temperature in the range of 100 to 200°C, particularly in the range of 100 to 150°C, from the viewpoint of the ease of the reaction.

[0129] On the other hand, the N-oxide aromatic heterocyclic compound (I) is of the formula (IA) and does not form the above C 6-10 In the case of aromatic hydrocarbons, the temperature may be within the above-mentioned range, and from the viewpoint of the ease of the reaction, the reaction is preferably carried out within the range of 200 to 300°C, particularly within the range of 200 to 250°C.

[0130] The reaction time depends on the type of the N-oxide aromatic heterocyclic compound (I) and the reaction temperature, but is usually 12 to 120 hours, preferably 24 to 48 hours.

[0131] After the reaction is completed, the target difluoromethyl-substituted aromatic heterocyclic compound (II) can be isolated and / or purified from the reaction mixture by conventional methods using separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography, etc.

[0132] As a container for reacting tetrafluoroethylene with N-oxide aromatic heterocyclic compound (I), there is no particular limitation within the scope of not causing adverse effects on the reaction, and for example, a metal container can be used. It should be noted that the present invention treats gaseous olefins under reaction conditions, so an airtight pressure-resistant container is preferred. In addition, the compound generated together with the reaction has concerns about reacting with the metal of the reaction container and becoming a reaction inhibitor, so a resin-lined or glass-lined container is preferably used with PFA or the like.

[0133] The difluoromethyl-substituted aromatic heterocyclic compound (II) thus obtained is useful as a synthetic intermediate for pharmaceuticals or pesticides, and can be derived into various pharmaceuticals or pesticides.

[0134] Example

[0135] Hereinafter, the present invention will be specifically described using Examples, but the present invention is not limited to these Examples.

[0136] [Analysis method]

[0137] Hereinafter, the present invention will be described using examples, but the present invention is not limited to these examples. Nuclear magnetic resonance spectra (NMR) were measured using JNM-AL300 manufactured by JEOL Ltd. 1 H-NMR was measured at 300 MHz using tetramethylsilane as a standard.

[0138] The mass spectrometry (LC-MS) was measured using a liquid chromatography-mass spectrometry system (LCMS6120B) manufactured by Agilent Technologies, Inc. The mass spectrometry (GC-MS) was determined by electron ionization (EI) using a gas chromatograph-mass spectrometer (GCMS-QP5000V2 or GCMS-QP2010Ultra) manufactured by Shimadzu Corporation.

[0139] Example 1

[0140]

[0141] In volume 25cm 3 Toluene (10 ml) and water (1 ml) were added to a SUS reactor lined with PFA and stirred at 25°C. Then, quinoline N-oxide (109 mg, 0.751 mmol, compound 1) was added and degassed under vacuum. Tetrafluoroethylene diluted with nitrogen to 50% was introduced until the reactor pressure reached 0.1 MPa, and heating and stirring were continued at 140°C for 48 hours. The crude liquid after the reaction was measured. 1 H-NMR and GC-MS showed that compound 2 was obtained in a yield of 33%.

[0142] The above compound (2) 1 H-NMR and GC-MS are shown below.

[0143] 1 H-NMR (CDCl 3 )δ8.34(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)

[0144] GC-MS (EI): [M+] = 179

[0145] Example 2

[0146]

[0147] In volume 25cm 3 In a SUS reactor, butyl acetate (10 ml) and sodium dihydrogen phosphate (NaH 2 PO 4 ) and disodium hydrogen phosphate (Na 2 HPO 4 ) was added with 0.1 mol / l, pH 7.0 phosphate buffer (1 ml) and stirred, maintained at 25°C. Then, quinoline N-oxide (109 mg, 0.751 mmol, compound 1) was added and deaerated under vacuum. Tetrafluoroethylene diluted with nitrogen to 50% was introduced until the reactor pressure reached 0.1 MPa, and heating and stirring were continued at 140°C for 150 hours. 1 The crude liquid after the reaction was quantified by H-NMR, and the result showed that compound 2 was obtained in a yield of 43%.

[0148] Comparative Example 1

[0149]

[0150] In volume 25cm 3 DMF (10 ml) and water (1 ml) were added to a SUS reactor and stirred at 25°C. Then, quinoline N-oxide (109 mg, 0.751 mmol, compound 1) was added and degassed under vacuum. Tetrafluoroethylene diluted to 50% with nitrogen was introduced until the reactor pressure reached 0.1 MPa, and heating and stirring were continued at 140°C for 48 hours. 1 The crude liquid after the reaction was quantified by H-NMR, and the compound 3 was obtained at a yield of 56% instead of the compound 2. The structure of the compound 3 was determined by confirming that the spectrum of the compound 3 purchased from FUJIFILM Wako Pure Chemical Corporation was consistent.

[0151] Reference Example 1

[0152]

[0153] 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 not added and the solvent-free condition was used. 1 H-NMR and GC-MS showed that compound 2 was obtained in a yield of 13%.

[0154] Example 3

[0155]

[0156] 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 replaced with butyl acetate. 1 H-NMR and GC-MS showed that compound 5 was obtained in a yield of 62%. It should be noted that in this example, a hydrated raw material of compound 4 was used.

[0157] The above compound (5) 1 H-NMR and GC-MS are shown below.

[0158] 1 H-NMR (CDCl 3 )δ9.19(s,1H),8.14-8.23(m,2H),7.84-7.91(m,2H),6.84(t,1H)

[0159] GC-MS (EI): [M+] = 180

[0160] Example 4

[0161]

[0162] 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 replaced with butyl acetate. 1 H-NMR and GC-MS showed that compound 7 was obtained in a yield of 56%. It should be noted that in this example, a hydrated raw material of compound 6 was used.

[0163] The above compound (7) 1 H-NMR and GC-MS are shown below.

[0164] 1 H-NMR (CDCl 3 )δ9.62(s,1H),8.22(m,2H),8.08(m,2H),7.28(t,1H)

[0165] GC-MS (EI): [M+] = 180

[0166] Example 5

[0167]

[0168] In volume 300cm 3 In a SUS reactor lined with PFA, xylene (30 ml) and water (3 ml) were added and stirred, and maintained at 25°C. After that, pyridine N-oxide (336.4 mg, 3.54 mmol, compound 8) was added and refrigerated degassing was performed. Tetrafluoroethylene diluted with nitrogen to 50% was flowed in until the reactor pressure reached 0.3 MPa, and heating and stirring were continued at 250°C for 8 hours. The GC-MS of the crude liquid after the reaction was measured, and compound 9 was obtained with a yield of 49%. Structural identification was carried out by confirming that the spectrum of compound 9 purchased from FUJIFILM Wako Pure Chemical Corporation was consistent.

[0169] GC-MS (EI): [M+] = 129

[0170] Example 6

[0171]

[0172] In the same manner as described in Example 1, a crude solution containing compound 11 was obtained from compound 10. The crude solution after the reaction was measured. 1 According to H-NMR and LC-MS, compound 11 was obtained in a yield of 78%.

[0173] The above compound (11) 1 H-NMR and LC-MS are shown below.

[0174] 1 H-NMR (CDCl 3 )δ8.63(d,1H),8.34-8.43(m,2H),8.18(d,1H),7.79(d,1H),6.78(t,1H),4.02(s,3H)

[0175] LC-MS: [M+1] = 238

[0176] Example 7

[0177]

[0178] 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 showed that compound 13 was obtained in a yield of 60%.

[0179] The above compound (13) 1 H-NMR and GC-MS are shown below.

[0180] 1 H-NMR(DMSO)δ7.38-7.70(m,3H),8.20(m,1H),8.26(m,1H)

[0181] GC-MS (EI): [M+] = 186

[0182] Example 8

[0183]

[0184] In the same manner as described in Example 1, a crude solution containing compounds 15 and 16 was obtained from compound 14. 1 H-NMR and LC-MS showed that compound 15 was obtained in a yield of 38%.

[0185] The above compound (15) 1 H-NMR and LC-MS are shown below.

[0186] 1 H-NMR (CDCl 3 )δ7.27-7.39(m,5H),6.70(t,J=52.9Hz,1H),5.27(s,2H),2.19(s,3H),1.98(s,3H)

[0187] LC-MS: [M+1] = 237

[0188] Example 9

[0189]

[0190] In the same manner as described in Example 1, a crude solution containing compound 18 was obtained from compound 17. 1 H-NMR and GC-MS showed that compound 18 was obtained in a yield of 26%.

[0191] The above compound (18) 1 H-NMR and GC-MS are shown below.

[0192] 1 H-NMR (CDCl 3 )δ8.55(d,1H),7.62(s,1H),7.39(d,1H),6.64(t,1H),1.34(s,9H)

[0193] GC-MS (EI): [M+] = 185

[0194] Example 10

[0195]

[0196] In the same manner as described in Example 1, a crude solution containing compound 20 was obtained from compound 19. The crude solution after the reaction was measured. 1 H-NMR and GC-MS showed that compound 20 was obtained in a yield of 20%.

[0197] The above compound (20) 1 H-NMR and GC-MS are shown below.

[0198] 1 H-NMR (CDCl 3 )δ8.87(d,1H),7.88(s,1H),7.73-7.59(m,1H),6.68(t,1H)

[0199] GC-MS (EI): [M+] = 154

[0200] Industrial Applicability

[0201] According to the present invention, a difluoromethyl-substituted aromatic heterocyclic compound (II) can be produced in one step with a small amount of by-products and a high yield by a simple and inexpensive method of flowing tetrafluoroethylene into an N-oxide aromatic heterocyclic compound (I) in a specific solvent.

[0202] This application is based on Japanese Patent Application No. 2020-019210 filed on February 6, 2020 in Japan, the entire contents of which are incorporated herein by reference.

Claims

1. A method for producing a difluoromethyl-substituted aromatic heterocyclic compound, wherein: The difluoromethyl-substituted aromatic heterocyclic compound has a partial structure represented by formula (II), The production method is characterized in that an N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is reacted with tetrafluoroethylene in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent and an ether solvent in the presence of a proton source, wherein the proton source is hydrogen fluoride, hydrogen chloride, an ammonium salt, water or a pH 5.0 to 8.0 buffer. The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is an N-oxide aromatic heterocyclic compound represented by formula (IA) or (IB), 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 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl, or R 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Optional together to form C 6-10 Aromatics, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 Substitution of substituents in aralkyl groups; 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 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl, or R 2a and R 2b , or R 2b and R 2c Optional together to form C 6-10 Aromatics, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 The substituent in the aralkyl group is substituted.

2. The manufacturing method according to claim 1, wherein: The reaction is carried out in the range of 100 to 300°C.

3. The manufacturing 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 manufacturing method according to claim 1 or 2, wherein: The reaction is carried out in the presence of a buffer solution at pH 5.0 to 8.

0.

5. The manufacturing method according to claim 4, wherein: The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA), and R in the formula is 1a and R 1b , R 1b and R 1c , or R 1c and R 1d Together they form C 6-10 Aromatics, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 The substituent in the aralkyl group is substituted.

6. The manufacturing method according to claim 4, wherein: The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IA), and R in the formula is 1a , R 1b , R 1c and R 1d are independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl.

7. The manufacturing method according to claim 4, wherein: The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IB), and R in the formula 2a and R 2b , or R 2b and R 2c Together they form C 6-10 Aromatics, the C 6-10 Aromatic hydrocarbons are optionally selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl and C 7-16 The substituent in the aralkyl group is substituted.

8. The manufacturing method according to claim 4, wherein: The N-oxide aromatic heterocyclic compound having a partial structure represented by formula (I) is represented by formula (IB), and R in the formula 2a , R 2b and R 2c are independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, mercapto, C 1-6 Alkylthio, amino, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, formyl, carboxyl, C 1-6 Alkoxy-carbonyl, C 6-10 Aryl or C 7-16 Aralkyl.

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