WO2022025117A1

WO2022025117A1 - Fluorinating agent and method for producing fluorine-containing compounds

Info

Publication number: WO2022025117A1
Application number: PCT/JP2021/027910
Authority: WO
Inventors: 隆岡添; 雄一郎石橋; 京子野崎; 光介相川; 晶哉足立
Original assignee: Ａｇｃ株式会社; 国立大学法人東京大学
Priority date: 2020-07-29
Filing date: 2021-07-28
Publication date: 2022-02-03
Also published as: JPWO2022025117A1

Abstract

The present invention provides the compound represented in general formula (A1) [Ar¹ is a C_6-14 aryl group or a C_5-14 nitrogen-containing heteroaryl group, substituted with at least two electron-attracting groups; R¹ is a C_1-30 alkyl group, a C_6-14 aryl group, or a C_5-14 nitrogen-containing heteroaryl group; the electron-attracting group is a halogen atom, a trihalomethyl group, a cyano group, a nitro group, -CO₂R or -CO₂N(R)₂ (the Rs independently represent C_1-30 alkyl groups)].

Description

Method for producing fluorinating agent and fluorine-containing compound

The present invention relates to a fluorinating agent that introduces a fluorine atom into an organic compound, and a method for producing a fluorinated compound obtained by using the fluorinating agent.
The present application claims priority under Japanese Patent Application No. 2020-128671 filed in Japan on July 29, 2020 and Japanese Patent Application No. 2021-044704 filed in Japan on March 18, 2021. Incorporate the content here.

Fluorine atom has a high electronegativity and is as small as a hydrogen atom. Due to this feature, fluorine atoms can be stably bonded to many atoms, and organic compounds into which fluorine has been introduced tend to have improved heat resistance, chemical resistance, light resistance, water resistance, etc. than before introduction. It is in. In particular, the carbon-fluorine bond has a short bond length, is rigid, and has a low polarizability. Due to the characteristics of this carbon-fluorine bond, the organic compound into which the carbon-fluorine bond is introduced has a reduced reactivity and an improved stability as a compound. Since useful organic compounds can be synthesized by fluorinating organic compounds, various fluorinating agents have been developed.

Examples of the fluorinating agent include N-fluorobenzenesulfonimide (NFSI). It has been reported that NFSI can introduce a fluorine atom into a carbon atom adjacent to a carbonyl group (Non-Patent Documents 1 and 2). N-fluorosulfonimides in which the benzene ring of NFSI is used as a naphthyl ring or a substituent is introduced into the benzene ring are also used for fluorination of nucleophilic organic compounds such as enol ethers, aromatic compounds, and organic metal species. (Patent Document 1). These N-fluorosulfonimides can be produced, for example, by reacting an alkali metal salt of sulfonimide with fluorine in the presence of water or a water / organic solvent mixture (Patent Document 2).

In addition, among the carbon atoms constituting the C = C bond of the silyl enol ether compound, N-fluoro-o is a fluorinating agent that introduces a fluorine atom into a carbon atom different from the carbon atom to which the silyl ether group is bonded. -Benzenedisulfonimide (NFOBS) (Non-Patent Document 3) and iodotoludifluoride (ITDF) (Non-Patent Document 4) have been reported. However, in NFOBS, it is difficult to obtain a raw material, and it is necessary to use CFCl ₃ which is a specific chlorofluorocarbon as a solvent in the synthesis of the raw material. When CHCl ₃ is used as the solvent instead of CFCl ₃ , CFCl ₃ is used. Is generated.

U.S. Pat. No. 5,254,732 Special Table No. 8-502494 Gazette

The present invention relates to a silyl enol ether compound in a fluorination reaction in which a fluorine atom is introduced into a carbon atom different from the carbon atom to which the silyl ether group is bonded among the carbon atoms constituting the C = C bond. It is an object of the present invention to provide a fluorinating agent capable of selectively synthesizing a fluorinated substance over a mono-fluorinated substance, and a method for producing a fluorine-containing compound using the fluorinated agent.

The present inventors use a fluorinated sulfoneimide compound protected with an arylsulfonyl group substituted with at least two electron-attracting groups and a sulfonyl group different from the arylsulfonyl group as a fluorinating agent. If so, a difluorinated product in which two fluorine atoms were introduced into one carbon atom constituting the C = C bond of the silyl enol ether compound was introduced, and one fluorine atom was introduced into the carbon atom. The present invention has been completed by finding that it is more selectively produced than a monofluorinated compound.

That is, the present invention is as follows.
[1] The following general formula (A1)

[In the formula, Ar ¹ is a C _6-14 aryl group or a C _5-14 nitrogen-containing heteroaryl group substituted with at least two electron-attracting groups (where Ar ¹ is C _5-14 ). In the case of a ₁₄ nitrogen-containing heteroaryl group, the sulfur atom binds to the carbon atom of the C _5-14 nitrogen-containing heteroaryl group); R ¹ is a C _1-30 alkyl group which may have a substituent, A group having 1 to 5 ether-bonding oxygen atoms between carbon atoms of a C _1-30 alkyl group which may have a substituent, and a C _6-14 aryl group which may have a substituent. , Or a C _5-14 nitrogen-containing heteroaryl group which may have a substituent (except when R ¹ is the same group as Ar ¹ ); the electron-attracting group is a halogen. Represented by an atom, a trihalomethyl group, a cyano group, a nitro group, -CO ₂ R, -CO ₂ N (R) ₂ (R each independently represents a C _1-30 alkyl group)]. Compound.
[2] The compound of the above [1], wherein at least two electron-withdrawing groups in the Ar ¹ are bonded to an atom other than the atom adjacent to the carbon atom bonded to the sulfur atom.
[3] The compound of [1] or [2], wherein Ar ¹ is substituted with two electron-withdrawing groups, and the two electron-withdrawing groups are present at the meta position. ..
[4] A fluorinating agent containing any of the compounds [1] to [3] as an active ingredient.
[5] Using the fluorinating agent of the above [4], the following general formula (A2)

(In the formula, R ²¹ , R ²² and R ²³ are independently C _1-4 alkyl groups; R ²⁴ is a C _1-30 fatty which may have a hydrogen atom and a substituent. Group hydrocarbon group, a group having 1 to 5 ether-bonding oxygen atoms or thioether-binding sulfur atoms between carbon atoms of a C _1-30 aliphatic hydrocarbon group which may have a substituent, A C _1-30 alkoxy group which may have a substituent or an aromatic group which may have a substituent; R ²⁵ may have a hydrogen atom and a substituent C _{1 -30} aliphatic hydrocarbon groups, C _1-30 aliphatic hydrocarbon groups may have substituents 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms of the aliphatic hydrocarbon group. It is an aromatic group which may have a group or a substituent; R ²⁴ and R ²⁵ may be linked to each other to form a ring) in the substrate compound represented by two atoms. Introducing a hydrocarbon atom, the following general formula (A4)

(In the formula, R ²⁴ and R ²⁵ are the same as the general formula (A2))
A method for producing a fluorine-containing compound, which comprises producing the fluorine-containing compound represented by.

Similar to NFSI, the compound according to the present invention can introduce a fluorine atom into a wide range of substrates having unsaturated bonds. The compound can selectively synthesize a difluorinated compound over a monofluorinated compound, particularly in a fluorination reaction of a silyl enol ether compound. Therefore, the compound is very useful as a fluorinating agent for synthesizing a difluorinated compound.

In the present invention and the present specification, "C _p1-p2 " (p1 and p2 are positive integers satisfying p1 <p2) means that the number of carbon atoms is a group of p1 to p2.

In the present invention and the present specification, the "ether-bonded oxygen atom" is an oxygen atom that connects carbon atoms, and does not include an oxygen atom in which oxygen atoms are connected in series. In the present invention and the present specification, the "thioether-bonded sulfur atom" is a sulfur atom that connects carbon atoms, and does not include a sulfur atom in which sulfur atoms are connected in series. The maximum number of ether-bonded oxygen atoms or thioether-bonded sulfur atoms that an alkyl group having Nc carbon atoms (Nc is an integer of 2 or more) can be is Nc-1.

In the present invention and the present specification, the "C _6-14 aryl group" is an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a C _6-12 aryl group is particularly preferable. Examples of the C _6-14 aryl group include a phenyl group, a naphthyl group, an anthryl group, a 9-fluorenyl group and the like, and a phenyl group is particularly preferable.

In the present invention and the present specification, the "C _6-14 aryl group having a substituent" is one or more hydrogen atoms bonded to the carbon atom of the C _6-14 aryl group, preferably one. ~ 3 are groups substituted with other functional groups. When having two or more substituents, the substituents may be the same kind or different from each other. The substituents include C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, methylenedioxy group (-O- _CH2 -O-), halogen atom (fluorine atom, chlorine atom). , Bromine atom, or iodine atom), trihalomethyl group, cyano group, nitro group and the like. Examples of "C _6-14 aryl group which may have a substituent" are phenyl group, naphthyl group, anthryl group, 2-methylphenyl group, 4-methylphenyl group and 3,5-dimethylphenyl group. , 2,6-dimethylphenyl group, 2,4-dimethylphenyl group, 2-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3,5-di (trifluoromethyl) phenyl group, 2,6- Di (trifluoromethyl) phenyl group, 2,4-di (trifluoromethyl) phenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2-Methylthiophenyl group, 4-methylthiophenyl group, 2,4-dimethylthiophenyl group, 3,5-dimethylthiophenyl group, 3-chlorophenyl group, 4-cyanophenyl group, 4-nitrophenyl group, 1,3 -Benzodioxol-5-yl group and the like can be mentioned.

In the present invention and the present specification, the "heteroaryl group" is a cyclic group having aromaticity, and the ring is a group composed of a carbon atom and an atom other than the carbon atom. The heteroaryl group may be a group containing a nitrogen atom (nitrogen-containing heteroaryl group), a group containing an oxygen atom (oxygen-containing heteroaryl group), or a group containing a sulfur atom (sulfur-containing heteroaryl group). It may be a heteroaryl group). Further, the number of atoms other than the carbon atom constituting the aromatic ring may be two or more.

Examples of the C _5-14 nitrogen-containing heteroaryl group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, an isoindryl group, a benzoimidazolyl group and a benzotriazolyl group. Examples thereof include a quinolyl group, an isoquinolyl group, a quinazolyl group and a carbazolyl group. Examples of the C _5-14 oxygen-containing heteroaryl group include a furanyl group, a pyranyl group, a benzopyranyl group, a xanthenyl group and the like. Examples of the C _5-14 sulfur-containing heteroaryl group include a thienyl group and the like. Examples of the C _5-14 heteroaryl group containing two or more kinds of heteroatoms include an oxazolyl group, an isooxazolyl group, a thiazolyl group, an isothiazolyl group and the like.

In the present invention and the present specification, the "heteroaryl group having a substituent" is one or more hydrogen atoms bonded to an atom constituting the aromatic ring of the heteroaryl group, preferably 1 to 3. The individual is a group substituted with another functional group. When having two or more substituents, the substituents may be the same kind or different from each other. The substituents include C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, methylenedioxy group (-O- _CH2 -O-), halogen atom (fluorine atom, chlorine atom). , Bromine atom, or iodine atom), trihalomethyl group, cyano group, nitro group and the like.

In the present invention and the present specification, the "aromatic group" is an aryl group (aromatic hydrocarbon group) which may have a substituent and a heteroaryl group (heterocyclic ring) which may have a substituent. Formula group) including both.

In the present invention and the present specification, the "C _1-30 alkyl group" is an alkyl group having 1 to 30 carbon atoms, and may be a straight chain or a branched chain. The "C _2-30 alkyl group" is an alkyl group having 2 to 30 carbon atoms, and may be a straight chain or a branched chain. Examples of C _1-30 alkyl groups are methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert- Pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group, heneicosyl group. , Docosyl group, tricosyl group, tetracosyl group, pentacosyl group, hexacosyl group, heptacosyl group, octacosyl group, nonacosyl group, triacontyl group and the like.

In the present invention and the present specification, the "C _1-10 alkyl group" is an alkyl group having 1 to 10 carbon atoms, and may be a straight chain or a branched chain. The "C _2-10 alkyl group" is an alkyl group having 2 to 10 carbon atoms, and may be a straight chain or a branched chain. Examples of C _1-10 alkyl groups are methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert- Examples thereof include a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group and the like.

In the present invention and the present specification, the "C _1-6 alkyl group" is an alkyl group having 1 to 6 carbon atoms, and may be a straight chain or a branched chain. Examples of C _1-6 alkyl groups are methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert- Examples thereof include a pentyl group and a hexyl group.

In the present invention and the present specification, the "C _1-4 alkyl group" is an alkyl group having 1 to 4 carbon atoms, and may be a straight chain or a branched chain. Examples of the C _1-4 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group.

In the present invention and the present specification, the "C _1-3 alkyl group" is an alkyl group having 1 to 3 carbon atoms, and may be a straight chain or a branched chain. Examples of the _C1-3 alkyl group include a methyl group, an ethyl group, a propyl group and an isopropyl group.

In the present invention and the present specification, the "C _p1-p2 alkyl group having a substituent" is one or more, preferably one or more hydrogen atoms bonded to the carbon atom of the C _p1-p2 alkyl group. ~ 3 are groups substituted with other functional groups. When having two or more substituents, the substituents may be the same kind or different from each other. Examples of the substituent include a halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), a _C6-14 aryl group which may have a substituent, a cyano group, a nitro group, and the like.

Examples of the "C _p1-p2 alkyl group having a substituent" include, for example, a C _6-14 aryl-C _1-6 alkyl group. A "C _6-14 aryl-C _1-6 alkyl group" is a group in which one hydrogen atom bonded to a carbon atom of a C _1-6 alkyl group is replaced with a C _6-14 aryl group. Examples of the C _{6-14 aryl group in the C 6-14} _aryl -C _1-6 alkyl group include a phenyl group, a naphthyl group, an anthryl group, a 9-fluorenyl group and the like, and a phenyl group or a 9-fluorenyl group is particularly preferable. .. As the C _1-6 alkyl group in the C _6-14 aryl-C _1-6 alkyl group, a C _1-4 alkyl group is preferable. Examples of the C _6-14 aryl-C _1-6 alkyl group include a benzyl group, a diphenylmethyl group, a triphenylmethyl group, a 2-phenylethyl group, a 9-anthrylmethyl group, a 9-fluorenylmethyl group and the like. Can be mentioned.

In the present invention and the present specification, the "C _1-30 aliphatic hydrocarbon group" may have a C _1-30 alkyl group which may have a substituent and a C _2-30 which may have a substituent. It contains all of alkenyl groups, C _2-30 alkynyl groups which may have substituents. The "C _1-30 aliphatic hydrocarbon group" may be a straight chain, a branched chain, or a cyclic group. Examples of the C _2-30 alkenyl group include a group having a single bond between at least one carbon atom among the groups mentioned in the C _2-30 alkyl group as a double bond. Examples of the C _2-30 alkynyl group include a group in which a single bond between at least one carbon atom among the groups mentioned in the C _2-30 alkyl group is a triple bond. More specifically, the C _2-30 alkenyl group includes a vinyl group, a propenyl group, a 2-propenyl group, a butenyl group, a 1-methylpropenyl group, a 2-methylpropenyl group, a pentenyl group, a hexenyl group and a heptenyl group. Examples thereof include an octenyl group, a nonenyl group, a decenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group and the like. Examples of the C _2-30 alkynyl group include an ethynyl group, a propynyl group, a butynyl group, a 1-methylpropynyl group, a pentynyl group, a 2-methylbutynyl group, a hexynyl group, a heptynyl group, an octynyl group and the like.

In the present invention and the present specification, the "C _p1-p2 aliphatic hydrocarbon group having a substituent" is one of the hydrogen atoms bonded to the carbon atom of the C _p1-p2 aliphatic hydrocarbon group or A plurality of groups, preferably 1 to 3 groups, are substituted with other functional groups. When having two or more substituents, the substituents may be the same kind or different from each other. Examples of the substituent include a halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), a _C6-14 aryl group which may have a substituent, a cyano group, a nitro group, and the like.

In the present invention and the present specification, the "C _1-30 alkoxy group" means a group in which an oxygen atom is bonded to the bond end of a linear or branched alkyl group having 1 to 30 carbon atoms. In the present invention and the present specification, the "C _1-30 alkylthio group" means a group in which a sulfur atom is bonded to the bond end of a linear or branched alkyl group having 1 to 30 carbon atoms. Examples of the linear or branched alkyl group having 1 to 30 carbon atoms in the C _1-30 alkoxy group or the C _1-30 alkyl thio group include the same group as the C _1-30 alkyl group.

In the present invention and the present specification, the "C _1-10 alkoxy group" means a group in which an oxygen atom is bonded to the bond end of a linear or branched alkyl group having 1 to 10 carbon atoms. In the present invention and the present specification, the "C _1-10 alkylthio group" means a group in which a sulfur atom is bonded to the bond end of a linear or branched alkyl group having 1 to 10 carbon atoms. Examples of the linear or branched alkyl group having 1 to 10 carbon atoms in the C _1-10 alkoxy group or the C _1-10 alkyl thio group include the same group as the C _1-10 alkyl group.

In the present invention and the present specification, the "C _1-6 alkoxy group" means a group in which an oxygen atom is bonded to the bond end of a linear or branched alkyl group having 1 to 6 carbon atoms. In the present invention and the present specification, the "C _1-6 alkylthio group" means a group in which a sulfur atom is bonded to the bond end of a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the linear or branched alkyl group having 1 to 6 carbon atoms in the C _1-6 alkoxy group or the C _1-6 alkyl thio group include the same group as the C _1-6 alkyl group. Examples of the C _1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group and the like. Examples of the C _1-6 alkylthio group include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a tert-butylthio group, a pentylthio group, a hexylthio group and the like.

In the present invention and the present specification, the "C _p1-p2 alkoxy group having a substituent" is one or more, preferably one or more hydrogen atoms bonded to the carbon atom of the C _p1-p2 alkoxy group. ~ 3 are groups substituted with other functional groups. In the present invention and the present specification, the "C _p1-p2 alkylthio group having a substituent" is one or more, preferably one or more hydrogen atoms bonded to the carbon atom of the C _p1-p2 alkylthio group. ~ 3 are groups substituted with other functional groups. When having two or more substituents, the substituents may be the same kind or different from each other. Examples of the substituent include a halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), a _C6-14 aryl group which may have a substituent, a cyano group, a nitro group, and the like.

Further, hereinafter, "compound (n)" means a compound represented by the formula (n).

Subsequent chemical reactions can be carried out in a solvent inert to the reaction. Examples of the solvent include inert solvents such as methanol, 1,4-dioxane, diethyl ether, tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, N, N-dimethylformamide and N, N-dimethylacetamide.

[Fluorinating agent]
The compound according to the present invention is a compound represented by the following general formula (A1).

In the general formula (A1), Ar ¹ is a C _6-14 aryl group or a C _5-14 nitrogen-containing heteroaryl group substituted with at least two electron-withdrawing groups. However, when Ar ¹ is a C _5-14 nitrogen-containing heteroaryl group, the sulfur atom in the sulfonyl group bonded to Ar ¹ is bonded to the carbon atom of the C _5-14 nitrogen-containing heteroaryl group, and nitrogen is present. Not bonded to an atom. The compound (A1) is preferably a phenyl group, a pyridyl group, a pyrimidinyl group, a quinolyl group, or an isoquinolyl group in which Ar ¹ is substituted with at least two electron-withdrawing groups, and at least two electron-withdrawing groups are preferable. Phenyl groups substituted with sex groups are particularly preferred.

The electron-attracting groups of Ar ¹ are halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom), trihalomethyl group, cyano group, nitro group, -CO ₂ R, -CO ₂ N (R) ₂ . Is. Here, R independently represents a C _1-30 alkyl group. As the -CO ₂ R, a group in which R is a C _1-10 alkyl group is preferable, a group in which R is a C _1-6 alkyl group is more preferable, and a group in which R is a C _1-4 alkyl group is further preferable. , -CO ₂ CH ₃ or -CO ₂ C ₂ H ₅ is even more preferred. As the -CO ₂ N (R) ₂ , a group in which R is a C _1-10 alkyl group is preferable, a group in which R is a C _1-6 alkyl group is more preferable, and R is a C _1-4 alkyl group. Groups are even more preferred, and -CO 2N (CH ₃ ) ₂ is even _more preferred. As the halogen atom, a fluorine atom is particularly preferable. As the electron-attracting group of Ar ¹ , a halogen atom, a trihalomethyl group, a cyano group or a nitro group is preferable, a halogen atom or a trihalomethyl group is more preferable, and a fluorine atom or a trifluoromethyl group is further preferable.

Ar ¹ has at least two electron-withdrawing groups. The plurality of electron-withdrawing groups possessed by Ar ¹ may be the same type of group or different groups from each other. When Ar ¹ is a trihalomethyl group, a cyano group, a nitro group, -CO ₂ R, or -CO ₂ N (R) ₂ , the electron-withdrawing group is less likely to cause steric hindrance during the fluorination reaction. , Ar ¹ preferably has two electron-withdrawing groups, and more preferably two electron-withdrawing groups at the meta positions of each other. When Ar ¹ is a halogen atom, the number of electron-withdrawing groups possessed by Ar ¹ may be two or more. For example, all hydrogen atoms bonded to carbon atoms constituting the aromatic ring of Ar ¹ are all. It may be substituted with a halogen atom.

Since at least two electron-withdrawing groups possessed by Ar ¹ are less likely to cause steric hindrance during the fluorination reaction, Ar ¹ and Ar 1 are among the atoms constituting the aromatic ring of Ar ¹ . It is preferable that the sulfonyl group is bonded to an atom other than the atom adjacent to the carbon atom bonded to the sulfur atom.

Ar ¹ may have a substituent other than the electron-withdrawing group. Examples of the substituent include a C _1-6 alkyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group and the like.

In the general formula (A1), R ¹ may have a C _1-30 alkyl group which may have a substituent (may have 1 to 5 ether-bonding oxygen atoms between carbon atoms). , A C _6-14 aryl group which may have a substituent, or a C _5-14 nitrogen-containing heteroaryl group which may have a substituent. However, this does not apply when R ¹ is the same group as Ar ¹ . In the present invention and the present specification, "a C _1-30 alkyl group which may have a substituent (may have 1 to 5 ether-bonding oxygen atoms between carbon atoms)". "1 to 5 ether-bonded oxygens between the carbon atoms of the C _1-30 alkyl group, which may have a substituent, or the C _1-30 alkyl group, which may have a substituent. It means "a group having an atom".

When the R ¹ is a C _1-30 alkyl group which may have a substituent, the alkyl group may have 1 to 5 ether-bonding oxygen atoms between carbon atoms. .. Further, the substituent may be an electron-withdrawing group or may be other than an electron-withdrawing group. As the compound (A1), the R ¹ is preferably a C _1-10 alkyl group which may have a substituent, and more preferably a C _1-6 alkyl group which may have a substituent. A C _1-6 alkyl group having no group or a C _6-14 aryl-C _1-6 alkyl group is more preferable, and a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and sec. -More preferably, it is a butyl group, a tert-butyl group, a benzyl group, a diphenylmethyl group, a triphenylmethyl group, a 2-phenylethyl group, a 9-anthrylmethyl group, or a 9-fluorenylmethyl group. Particularly preferably, it is a tert-butyl group, a benzyl group, or a 2-phenylethyl group.

When the R ¹ is a C _6-14 aryl group which may have a substituent, the substituent may be an electron-withdrawing group or may be other than an electron-withdrawing group. .. The number of substituents is not particularly limited as long as the function of the compound (A1) as a fluorinating agent is not impaired and the group is the same as Ar ¹ , for example, 1 to 3 substituents. May have. As the compound (A1), R ¹ is preferably, for example, a phenyl group which may have 1 to 3 substituents, a C _1-6 alkyl group, a C _1-6 alkyl group, and a C _1-6 . A phenyl group which may have 1 to 3 substituents selected from the group consisting of an alkoxy group, a halogen atom and a trihalomethyl group is more preferable, and a phenyl group, a 2-methylphenyl group and a 3-methylphenyl group are more preferable. Group, 4-methylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2,6-dimethylphenyl group, 2,4-dimethylphenyl group, 2-trifluoromethylphenyl group, 3- Trifluoromethyl group, 4-trifluoromethylphenyl group, 3,4-di (trifluoromethyl) phenyl group, 3,5-di (trifluoromethyl) phenyl group, 2,6-di (trifluoromethyl) phenyl Group, 2,4-di (trifluoromethyl) phenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 3-chlorophenyl group, 4- A chlorophenyl group, a 2,6-dichlorophenyl group, a 3,4-dichlorophenyl group, a 4-cyanophenyl group and a 4-nitrophenyl group are more preferable, and a phenyl group is particularly preferable.

In the case of the C _5-14 nitrogen-containing heteroaryl group in which R ¹ may have a substituent, the substituent may be an electron-withdrawing group and may be other than an electron-withdrawing group. May be. The number of substituents is not particularly limited as long as the function of the compound (A1) as a fluorinating agent is not impaired and the group is the same as Ar ¹ , for example, 1 to 3 substituents. May have. As the compound (A1), R ¹ is, for example, a pyridyl group, a pyrimidinyl group, a quinolyl group, or an isoquinolyl group, and a group having no substituent or having 1 to 3 substituents is preferable. , A pyridyl group having no substituent or having 1 to 3 substituents is more preferable.

Examples of the compound (A1) include compounds represented by the following general formula (A1-1) or general formula (A1-2). In the general formulas (A1-1) and (A1-2), R ¹ is the same as the general formula (A1). In the general formula (A1-1), W is an electron-withdrawing group. The electron-withdrawing group is the same as the electron-withdrawing group possessed by Ar ¹ . The two Ws in one molecule of compound (A1-1) may be groups of the same kind or different groups from each other.

Examples of the compound (A1-1) include compounds represented by the following general formulas (A1-1-1) to (A1-1-4). Examples of the compound (A1-2) include compounds represented by the following formulas (A1-2-1) and general formulas (A1-2-2) to (A1-2-4).

In the general formula (A1-1-1) to the general formula (A1-1-4) and the general formula (A1-2-1) to the general formula (A1-2-4), W is the general formula (A1-1). The same as above, two or three Ws in one molecule may be groups of the same kind or different groups from each other. As W in the general formula (A1-1-1) and the like, a halogen atom, a trihalomethyl group, a nitro group or a cyano group is preferable, and a fluorine atom, a trifluoromethyl group, a nitro group or a cyano group is more preferable.

In the general formula (A1-1-4) and the general formula (A1-2-4), R ¹¹ is a C _1-30 alkyl group which may have a substituent (1 to 5 between carbon atoms). It may have an ether-bonding oxygen atom), a C _1-6 alkyl group which may have a substituent is preferable, and a C _1-4 alkyl group which may have a substituent. More preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group is more preferable, and a methyl group, an ethyl group, a propyl group, or an isopropyl group is more preferable. More preferred.

The compound (A1) synthesizes a sulfonimide by, for example, a condensation reaction between a sulfonyl halide and a sulfonamide, replaces the hydrogen atom bonded to the nitrogen atom of the imide group with a lithium atom, and further replaces the lithium atom with a fluorine atom. It can be synthesized by replacing it with an atom. In the following formula, Ar ¹ and R ¹ are the same as Ar ¹ and R ¹ in the general formula (A1).

[Manufacturing method of fluorine-containing compound]
Compound (A1) can be used as an active ingredient of a fluorinating agent in various reactions. Compound (A1) can fluorinate carbon atoms in various organic compounds as in NFSI. Examples of the organic compound serving as a substrate include compounds having an unsaturated bond such as an alkene, an allyl compound, an alkyne, and an aromatic compound. The unsaturated bond may be a bond formed between carbon atoms or a bond between a carbon atom and an atom other than the carbon atom.

The compound (A1) is particularly suitable as a fluorinating agent for a silyl enol ether compound. For example, by using the compound (A1) as a fluorinating material, two fluorine atoms are introduced into the substrate compound (silyl enol ether compound) represented by the general formula (A2), and the general formula (A4) is used. The fluorine-containing compound to be produced can be produced.

In the general formula (A2), R ²¹ , R ²² and R ²³ are independently C _1-4 alkyl groups. As the compound (A2), a compound in which R ²¹ , R ²² and R ²³ are each independently a methyl group or an ethyl group is preferable, and R ²¹ , R ²² and R ²³ are all methyl groups or Compounds that are ethyl groups are more preferable, and compounds in which R ²¹ , R ²² , and R ²³ are all methyl groups are particularly preferable.

In the general formula (A2), R ²⁴ is a hydrogen atom, a C _1-30 aliphatic hydrocarbon group which may have a substituent (1 to 5 ether-bonded oxygen atoms or thioethers between carbon atoms). It may have a bonding sulfur atom), a C _1-30 alkoxy group which may have a substituent, or an aromatic group which may have a substituent. Further, in the general formula (A2), R ²⁵ is a C _1-30 aliphatic hydrocarbon group which may have a hydrogen atom and a substituent (1 to 5 ether-bonded oxygen atoms between carbon atoms). Alternatively, it may have a thioether-binding sulfur atom), or it may have a substituent. In the present invention and the present specification, "C _1-30 aliphatic hydrocarbon group which may have a substituent (1 to 5 ether-bonding oxygen atom or thioether-bonding sulfur atom between carbon atoms). "May have a C _{1-30 aliphatic hydrocarbon group which may have a substituent, or a C 1-30} _aliphatic hydrocarbon which may have a substituent" It means "a group having 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between the carbon atoms of the group".

When the R ²⁴ or R ²⁵ is a C _1-30 aliphatic hydrocarbon group which may have a substituent, the aliphatic hydrocarbon group has 1 to 5 ether bonds between carbon atoms. It may have an oxygen atom or may have 1 to 5 thioether-bonded sulfur atoms between carbon atoms. As the C _1-30 aliphatic hydrocarbon group, a C _1-30 alkyl group which may have a substituent is preferable, and a C _1-10 alkyl group which may have a substituent is more preferable. A C _1-6 alkyl group which may have a substituent is further preferable, and a C _1-6 alkyl group which does not have a substituent is particularly preferable.

When the R ²⁴ or R ²⁵ is an aromatic group which may have a substituent, the aromatic group may be an aryl group or a heteroaryl group. The aromatic group is preferably a C _6-14 aryl group which may have a substituent or a nitrogen-containing heteroaryl group which may have a substituent, and may have a substituent. A C _6-14 aryl group is more preferred.

When the R ²⁴ is a C _1-30 alkoxy group which may have a substituent, the alkoxy group may have 1 to 5 ether-bonding oxygen atoms between carbon atoms. .. As the compound (A2), the R ²⁴ is preferably a C _1-10 alkoxy group which may have a substituent, and more preferably a C _1-6 alkoxy group which may have a substituent. A C _1-6 alkoxy group having no group is further preferable, and a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group and a hexyloxy group are even more preferable.

The R ²⁴ and R ²⁵ may be connected to each other to form a ring. The ring composed of R ²⁴ and R ²⁵ is preferably a 5-membered ring, a 6-membered ring, or a 7-membered ring, and may be a ring in which an aromatic ring or a saturated ring is condensed. Further, it may be a hydrocarbon ring or a heterocycle. Examples of the ring include an indane ring, an inden ring, a tetrahydronaphthalene ring, a dihydronaphthalene ring, a chromane ring, a thiochroman ring, a chromane ring, an isochromen ring, a tetrahydrofuran ring, an indoline ring, an indole ring, a cycloheptene ring, and a benzocycloheptene ring. And so on.

The ring composed of R ²⁴ and R ²⁵ may have a substituent. When having two or more substituents, the substituents may be the same kind or different from each other. The substituent may have a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), a trihalomethyl group, and a substituent. C _6-14 aryl group, cyano group, nitro group and the like can be mentioned.

The fluorination reaction of compound (A2) by compound (A1) can be carried out by mixing compound (A1) and compound (A2) in a solvent inert to the reaction at a temperature of 100 ° C. or lower. can. The compound (A1) is preferably 0.5 to 100 mol, more preferably 0.5 to 50 mol, still more preferably 0.5 to 10 mol, based on 1 mol of the compound (A2).

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to these Examples.

The NMR apparatus used for the analysis of Examples and Comparative Examples is JEM-ECS400 (400 MHz) or ECZ500R (500 MHz) manufactured by JEOL Ltd. In ¹ H NMR, tetramethylsilane was used as the reference value of 0 PPM, and in ¹⁹ F NMR, C ₆ F ₆ was used as the reference value of -162 PPM. For HPLC (High Performance Liquid Chromatography), LC-20 manufactured by Shimadzu Corporation was used. As the high-resolution mass spectrum apparatus, a JMS-T100LP spectrum meter manufactured by JEOL Ltd. was used in the ESI-TOF (electron spray ionization time-of-flight) mode. The unit of yield (%) described in the examples is mol%.

[Example 1]
A compound in which Ar ¹ in the general formula (A1) was a phenyl group substituted with two trifluoromethyl groups and R ¹ was a phenyl group was synthesized.

Benzene sulfonamide (2-1) (0.24 g, 1.5 mmol) and sodium hydride (> 55%, dispersed in liquid paraffin) (0.14 g, 2 equal volumes) in tetrahydrofuran (20 mL) under a nitrogen atmosphere. The dissolved solution was added at 0 ° C. and stirred at room temperature for 1 hour. After the solution was brought to 0 ° C. again, a solution prepared by dissolving 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (1-1) (0.56 g, 1.2 equal volume) in tetrahydrofuran (2 mL) was added. In addition, the mixture was stirred at room temperature for 2 hours. Then, it was quenched with water and ethyl acetate was added. After washing 3 times with 1 M sodium hydroxide water, the organic phase was dried over magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and silica gel column chromatography was performed in a hexane / ethyl acetate mixed solvent system. The obtained solid was dissolved in methylene chloride, washed 3 times with 3M hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained solid was dissolved in toluene again and the solvent was distilled off under reduced pressure to obtain the desired compound (3-H) (0.54 g, 1.2 mmol) as a white solid.

^{1 1} H NMR (d-chloroform): δ = 8.43 (s, 2H), 8.14 (s, 1H), 8.01-7.99 (d, 2H), 7.72-7.68 ( t, 1H), 7.60-7.56 (t, 2H) ¹⁹ F NMR (d-chloroform): δ = -62.85 (s, 6F).

^{1 1} H NMR (400MHz, Deuterated-D6) δ 8.45 (s, 1H), 8.23 (s, 2H), 7.94 (d, J = 8.4Hz, 2H), 7.74 (t, J = 7.6Hz, 1H), 7.62 (t, J = 7.8Hz, 2H) ¹⁹ F NMR (376MHz, Deuterated-D6) δ-63.36 (s, 6F) HRMS (ESI-TOF): calcd for C ₁₄ H ₉ F ₆ NAO ₄ S ₂ [M-Na] ⁺ : 455.97749, found: 455.97666.

A solution of compound (3-H) (0.54 g) and sodium fluoride (0.16 g, 3 equal volumes) in acetonitrile (30 g) was ice-cooled to 0 ° C. using an ice bath. A fluorine / nitrogen mixed gas of 2% by volume was adjusted to 100 mL / min with a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. Then, the precipitate was filtered, the solvent was distilled off under reduced pressure, and then the target product (4) (0.42 g, 0.9 mmol) was subjected to silica gel column chromatography using a hexane / ethyl acetate mixed solvent system. Got

^{1 1} H NMR (d-chloroform): δ = 8.46 (s, 2H), 8.25 (s, 1H), 8.04-8.02 (d, 2H), 7.84-7.80 ( t, 1H), 7.67-7.63 (t, 2H) ¹⁹ F NMR (d-chloroform): δ = -35.71 (s, 1F), -62.86 (s, 6F).

^{1 1} H NMR (500 MHz, CDCl ₃ ) δ 8.46 (s, 2H), 8.25 (s, 1H), 8.03 (d, J = 7.5Hz, 2H), 7.82 (t, J) = 7.5Hz, 1H), 7.65 (t, J = 7.8Hz, 2H) ¹⁹ F NMR (470MHz, CDCl ₃ ) δ-35.74 (s, 1F), -62.84 (s, 6F) ) HRMS (ESI-TOF): calcd for C ₁₄ H ₈ F ₇ NNaO ₄ S ₂ [M-Na] ⁺ : 473.96807, found: 473.96616

[Example 2]
A compound in which Ar ¹ in the general formula (A1) was a phenyl group substituted with two trifluoromethyl groups and R ¹ was a methyl group was synthesized.

Under a nitrogen atmosphere, methanesulfonamide (2-2) (0.29 g, 3.0 mmol) and sodium hydride (> 55%, dispersed in liquid paraffin) (0.29 g, 3 equal volumes) in tetrahydrofuran (45 mL). The dissolved solution was added at 0 ° C. and stirred at room temperature for 1 hour. After the solution was brought to 0 ° C. again, a solution prepared by dissolving 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (1-1) (1.03 g, 1.1 equivalent) in tetrahydrofuran (5 mL) was prepared. In addition, the mixture was stirred at room temperature for 2 hours. Then, it was quenched with water and ethyl acetate was added. The organic phase was dried over magnesium sulfate after washing 3 times with 1 M sodium hydroxide water. Subsequently, the solvent was distilled off under reduced pressure, and silica gel column chromatography was performed in a hexane / ethyl acetate mixed solvent system. The obtained solid was dissolved in methylene chloride, washed 3 times with 3M hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained solid was dissolved in toluene again and the solvent was distilled off under reduced pressure to obtain the desired compound (5-H) (0.92 g, 2.5 mmol) as a white solid.

^{1 1} H NMR (d-chloroform): δ = 8.35 (s, 2H), 8.09 (s, 1H), 2.85 (s, 3H) ¹⁹ F NMR (d-chloroform): δ = -63 .19 (s, 6F).

¹ H NMR (500 MHz, Deuterated-D6) δ 8.42 (s, 2H), 8.12 (s, 1H), 2.87 (s, 3H) ¹⁹ F NMR (470 MHz, Deuterated-D6) δ-63 .18 (s, 6F) HRMS (ESI-TOF): calcd for C ₉ H ₇ F ₆ NNaO ₄ S ₂ [M-Na] ⁺ : 393.96184, found: 393.96221.

A solution of compound (5-H) (0.47 g, 1.3 mmol) and sodium fluoride (0.16 g, 3 equal volumes) in acetonitrile (30 g) was ice-cooled to 0 ° C. using an ice bath. A fluorine / nitrogen mixed gas of 2% by volume was adjusted to 100 mL / min with a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. Then, the precipitate was filtered, the solvent was distilled off under reduced pressure, and then the target product (6) (0.20 g, 0.5 mmol) was subjected to silica gel column chromatography using a hexane / ethyl acetate mixed solvent system. Got

^{1 1} H NMR (d-chloroform): δ = 8.49 (s, 2H), 8.28 (s, 1H), 3.43 (d, 3H) ¹⁹ F NMR (d-chloroform): δ = -37 .99 (s, 1F), -62.94 (s, 6F).

^{1 1} H NMR (500 MHz, CDCl ₃ ) δ 8.49 (s, 2H), 8.28 (s, 1H), 3.43 (s, 3H) ¹⁹ F NMR (470 MHz, CDCl ₃ ) δ-37.93 (s, 1F), -62.90 (s, 6F) HRMS (ESI-TOF): calcd for C ₉ H ₆ F ₇ NNaO ₄ S ₂ [M-Na] ⁺ : 411.95422, found: 411.95222

[Example 3]
A compound in which Ar ¹ in the general formula (A1) was a phenyl group substituted with two trifluoromethyl groups and R ¹ was a phenyl group substituted with a nitro group was synthesized.

Tetrahydrofuran (35 mL) of 4-nitrobenzene sulfonamide (2-3) (0.61 g, 3.0 mmol) and sodium hydride (> 55%, dispersed in liquid paraffin) (0.29 g, 3 equal volumes) under a nitrogen atmosphere. ) Was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After the solution was brought to 0 ° C. again, a solution prepared by dissolving 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (1-1) (1.00 g, 1.1 equivalent) in tetrahydrofuran (5 mL) was prepared. In addition, the mixture was stirred at room temperature for 2 hours. Then, it was quenched with water and ethyl acetate was added. The organic phase was dried over magnesium sulfate after washing 3 times with 1 M sodium hydroxide water. Subsequently, the solvent was distilled off under reduced pressure, and silica gel column chromatography was performed in a hexane / ethyl acetate mixed solvent system. The obtained solid was dissolved in methylene chloride, washed 3 times with 3M hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained solid was dissolved in toluene again and the solvent was distilled off under reduced pressure to obtain the desired compound (7-H) (1.22 g, 2.6 mmol) as a white solid.

^{1 1} H NMR (d-chloroform): δ = 8.04 (s, 2H), 7.94-7.95 (m, 2H), 7.81-7.78 (m, 2H), 7.73 ( s, 1H) ¹⁹ F NMR (d-chloroform): δ = -63.05 (s, 6F).

A solution of compound (7-H) (0.60 g, 1.3 mmol) and sodium fluoride (0.16 g, 3 equal volumes) in acetonitrile (30 g) was iced to 0 ° C. using an ice bath. It was chilled. A fluorine / nitrogen mixed gas of 2% by volume was adjusted to 100 mL / min with a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. After completion of the reaction, the crude liquid was quantified by ¹⁹ F NMR, and it was confirmed that compound (8) was produced in a yield of 15%.

¹⁹ F NMR (neat): δ = -37.03 (s, 1F), -63.55 (s, 6F).

[Example 4]
A compound in which Ar ¹ in the general formula (A1) is a phenyl group substituted with 5 fluorine atoms and R ¹ is a phenyl group was synthesized.

A solution of benzenesulfonamide (2-1) (0.47 g, 3.0 mmol) and sodium hydride (> 55%, dispersed in liquid paraffin) (0.29 g) in tetrahydrofuran (45 mL) under a nitrogen atmosphere. Was added at 0 ° C. and stirred at room temperature for 1 hour. After the solution was brought to 0 ° C. again, a solution prepared by dissolving a benzenesulfonyl chloride derivative (1-2) (0.88 g, 1.1 equal amount) in tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 2 hours. Then, it was quenched with water and ethyl acetate was added. The organic phase was dried over sodium sulfate after washing 3 times with 1 M sodium hydroxide water. Subsequently, the solvent was distilled off under reduced pressure to obtain the desired compound (9-Na) (1.13 g, 2.8 mmol) as a white solid.

^{1 1} H NMR (Acetone-D6): δ = 7.70-7.68 (d, 2H), 7.41-7.37 (t, 1H), 7.34-7.30 (t, 2H) ¹⁹ F NMR (Acetone-D6): δ = 137.75 (d, 2F), 154.95 (t, 1F), -164.58 (t, 2F).

A solution prepared by dissolving compound (9-Na) (0.52 g, 1.3 mmol) in acetonitrile (30 g) was ice-cooled to 0 ° C. using an ice bath. A fluorine / nitrogen mixed gas of 2% by volume was adjusted to 100 mL / min with a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. Then, the precipitate was filtered, the solvent was distilled off under reduced pressure, and then the target product (10) (0.18 g, 0.4 mmol) was subjected to silica gel column chromatography using a hexane / ethyl acetate mixed solvent system. Got

^{1 1} H NMR (d-chloroform): δ = 8.08-8.06 (d, 2H), 7.86-7.83 (t, 1H), 7.70-7.66 (t, 2H) ¹⁹ F NMR (d-chloroform): δ = -35.87 (s, 1F), -130.01 (m, 2F), 137.98 (m, 1F), -156.71 (m, 2F).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J = 8.8 Hz, 2H), 7.82 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 8. 0Hz, 2H) ¹⁹ F NMR (376MHz, CDCl ₃ ) δ-35.94 (s, 1F), -129.92 (d, J = 17.3Hz, 2F), -137.88 (m, 1F), -156.60 (m, 2F) HRMS (ESI-TOF): calcd for C ₁₂ H ₅ F ₆ NNaO ₄ S ₂ [M-Na] ⁺ : 427.94619, found: 427.94658

[Example 5]
A compound in which Ar ¹ in the general formula (A1) was a phenyl group substituted with two trifluoromethyl groups and R ¹ was a phenyl group was synthesized.

Under a nitrogen atmosphere, benzenesulfonamide (2-1) (0.47 g, 3.0 mmol) and sodium hydride (> 55%, dispersed in liquid paraffin) (0.29 g, 3 equal volumes) in tetrahydrofuran (40 mL). The dissolved solution was added at 0 ° C. and stirred at room temperature for 1 hour. After the solution was brought to 0 ° C. again, a solution prepared by dissolving 2,4-bis (trifluoromethyl) benzenesulfonyl chloride (1-3) (1.11 g, 1.1 equivalent) in tetrahydrofuran (4 mL) was added. In addition, the mixture was stirred at room temperature for 2 hours. Then, it was quenched with water and ethyl acetate was added. The organic phase was dried over magnesium sulfate after washing 3 times with 1 M sodium hydroxide water. Subsequently, the solvent was distilled off under reduced pressure, and silica gel column chromatography was performed in a hexane / ethyl acetate mixed solvent system. The obtained solid was dissolved in methylene chloride, washed 3 times with 3M hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained solid was dissolved in toluene again and the solvent was distilled off under reduced pressure to obtain the desired compound (11-H) (1.13 g, 2.6 mmol) as a white solid.

^{1 1} H NMR (d-acetone): δ = 8.60 (s, 1H), 8.33-8.31 (d, 1H), 8.27-8.23 (d, 1H), 7.92- 7.90 (d, 2H), 7.74-7.70 (t, 1H), 7.63-7.59 (t, 2H), 5.14 (brs, 1H) ¹⁹ F NMR (d-acetone) ): δ = -58.36 (s, 3F), -63.89 (s, 3F).

^{1 1} H NMR (500 MHz, Deuterated-D6) δ 8.61 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.5Hz, 2H), 7.71 (t, J = 8.0Hz, 1H), 7.61 (t, J = 8.0Hz, 2H) ¹⁹ F NMR (470MHz, Acetone-D6) δ-58.35 (s, 3F), -63.87 (s, 3F) HRMS (ESI-TOF): calcd for C ₁₄ H ₉ F ₆ NNaO ₄ S ₂ [M-Na] ⁺ : 455.97749, found: 455.97721.

A solution of compound (11-H) (0.56 g, 1.3 mmol) and sodium fluoride (0.16 g, 3 equal volumes) in acetonitrile (30 g) was iced to 0 ° C. using an ice bath. It was chilled. A fluorine / nitrogen mixed gas of 2% by volume was adjusted to 100 mL / min with a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. Then, the precipitate was filtered, the solvent was distilled off under reduced pressure, and then the target product (12) (0.52 g, 1.2 mmol) was subjected to silica gel column chromatography using a hexane / ethyl acetate mixed solvent system. Got

^{1 1} H NMR (d-chloroform): δ = 8.50 (s, 1H), 8.17-8.12 (m, 4H), 7.87-7.83 (t, 1H), 7.70- 7.66 (t, 2H) ¹⁹ F NMR (d-chloroform): δ = -35.27 (s, 1F), -57.62 (s, 3F), -63.29 (s, 3F).

^{1 1} H NMR (500 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 8.10-8.15 (m, 4H), 7.84 (t, J = 7.5 Hz, 1H), 7.67 (t, J = 7.5Hz, 2H) ¹⁹ F NMR (470MHz, CDCl ₃ ) δ-35.22 (s, 1F), -57.60 (s, 3F), -63.24 (s, 3F) HRMS (ESI-TOF): calcd for C ₁₄ H ₈ F ₇ NNaO ₄ S2 [M-Na] ⁺ : 473.96807, found: 473.96706

[Example 6]
The compound (4) synthesized in Example 1 was used as a fluorinating agent, and the silyl enol ether compound (13) was fluorinated.

The silyl enol ether compound (13) (28 mg, 0.15 mmol) was added dropwise to a solution of compound (4) (149 mg, 0.33 mmol) dissolved in 0.1 M 1,2-dichloroethane under a nitrogen atmosphere. .. Then, after stirring at 50 ° C. for 24 hours, the crude liquid was quantified by ¹⁹ F NMR, and it was confirmed that the compound (14a) was produced in a yield of 91%. At this time, the formation of compound (14b) was not confirmed. From the results, it was found that by using compound (4) as a fluorinating agent, a difluorinated compound can be synthesized more selectively than a monofluorinated compound.

¹⁹ F NMR (CDCl ₃ ) of compound (14a): δ = -94.24 (m, 2F).

[Comparative Example 1]
The silyl enol ether compound (13) was fluorinated using NFSI as a fluorinating agent.

Under the same conditions as in Example 6, a fluorination reaction was carried out using NFSI (105 mg, 0.33 mmol) instead of compound (4) as a fluorinating agent. As a result, it was confirmed that the compound (14a) was produced in 53% and the compound (14b) was produced in 31%. From the results, it was clarified that both the monofluorinated compound and the difluorinated compound were synthesized when NFSI was used.

¹⁹ F NMR (CDCl ₃ ) of compound (14a): δ = -94.24 (m, 2F). ¹⁹ F NMR (CDCl ₃ ) of compound (14b): δ = -191.64 (m, 1F).

[Reference Example 1]
A fluorinated sulfone imide compound protected with a phenylsulfonyl group substituted with one trifluoromethyl group and a quinolylsulfonyl group was synthesized.

4-Trifluoromethylbenzenesulfonamide (2-4) (0.68 g, 3.0 mmol) and sodium hydride (> 55%, dispersed in liquid paraffin) (0.29 g, 3 equal volumes) under a nitrogen atmosphere. The solution dissolved in tetrahydrofuran (35 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After the solution was brought to 0 ° C. again, a solution prepared by dissolving a benzenesulfonyl chloride derivative (1-4) (0.73 g, 1.1 equal amount) in tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 2 hours. Then, it was quenched with water and ethyl acetate was added. The organic phase was dried over sodium sulfate after washing 3 times with 1 M sodium hydroxide water. Subsequently, the solvent was distilled off under reduced pressure to obtain the desired compound (15-Na) (1.27 g, 2.9 mmol) as a white solid.

^{1 1} H NMR (Acetone-D6): δ = 9.16-9.14 (dd, 1H), 8.38-8.37 (brd, 1H), 8.27-8.25 (dd, 1H), 7.99-7.96 (dd, 1H), 7.60-7.57 (d, 2H), 7.59-7.55 (m, 1H), 7.54-7.51 (dd, 1H) ), 7.20-7.18 (d, 2H) ¹⁹ F NMR (Acetone-D6): δ = -63.26 (s, 3F).

A solution prepared by dissolving compound (15-Na) (0.55 g, 1.3 mmol) in acetonitrile (30 g) and water (1.5 g) was ice-cooled to 0 ° C. using an ice bath. A fluorine / nitrogen mixed gas of 2% by volume was adjusted to 100 mL / min with a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. After completion of the reaction, the crude liquid was quantified by ¹⁹ F NMR, and it was confirmed that compound (16) was produced in a yield of 43%.

¹⁹ F NMR (neat): δ = -36.68 (s, 1F), -63.08 (s, 3F).

[Example 7]
A fluorinated sulfone imide compound protected with a phenylsulfonyl group substituted with one trifluoromethyl group and a phenylsulfonyl group substituted with two trifluoromethyl groups was synthesized.

4-Trifluoromethylbenzenesulfonamide (2-4) instead of benzenesulfonamide (2-1) for 1.5 mmol of 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (1-1) Compound (17-H) (0.69 g, yield 92%) was obtained in the same procedure as in Example 1 except that 1.2 equal amounts were used.

^{1 1} H NMR (500 MHz, Deuterated-D6): δ = 8.18 (s, 2H), 8.01 (s, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.61 ( d, J = 6.8Hz, 2H) ¹⁹ F NMR (470MHz, Acetone-D6): δ = -63.34 (s, 6F), -63.40 (s, 3F). HRMS (ESI-TOF): calcd for C ₁₅ H ₈ F ₉ NNaO ₄ S ₂ [M-Na] ⁺ : 523.96487, found: 523.96519.

Subsequently, using compound (17-H) (2.95 mmol), fluorination with a 2% fluorine / nitrogen mixed gas was carried out in the same manner as in Example 1, and the target product (18) (0.11 g) was carried out. , Yield 11%) was obtained.

^{1 1} H NMR (500 MHz, CDCl ₃ ): δ = 8.47 (s, 2H), 8.28 (s, 1H), 8.19 (d, J = 8.0 Hz, 2H), 7.93 (d) , J = 8.0Hz, 2H) ¹⁹ F NMR (470MHz, CDCl ₃ ): δ = -34.91 (s, 1F), -62.87 (s, 6F), -63.43 (s, 3F) .. HRMS (ESI-TOF): calcd for C ₁₅ H ₇ F ₁₀ NNaO ₄ S ₂ [M-Na] ⁺ : 541.95545, found: 541.95501

[Examples 8 to 10]
The compounds (6), (10), and (18) synthesized in Examples 2, 4, and 7 were used as fluorinating agents, and the compound (13) was fluorinated in the same manner as in Example 6.

The reaction was carried out using compound (13) (0.10 mmol), a fluorinating agent (0.22 mmol), and 1,2-dichloroethane (1.0 mL) at a reaction temperature of 50 ° C. Reaction time when each fluorinating agent was used, yield of compound (14a) and compound (14b), ratio of production amount of compound (14a) to production amount of compound (14b) (mol) (14a / 14b). Is shown in Table 1. For comparison, the results of Example 6 and Comparative Example 1 are also shown in Table 1.

From the results in Table 1, when the fluorinating agent of the present application was used, the compound (14a), which is a difluoroform, was obtained in a higher yield than the fluorinating agent of Comparative Example 1. In particular, by using the fluorinating agents of the compounds (4) and (18), only the compound (14a) was selectively obtained. Further, it was found that the fluorinating agent according to the present invention, particularly the fluorinating agent of compound (18), can complete fluorination in a shorter reaction time than that of Comparative Example 1.

[Examples 11 to 23]
The compound (4) synthesized in Example 1 was used as a fluorinating agent, and the silyl enol ether compounds (19) to (31) were fluorinated by the same method as in Example 6, and the α-position of the carbonyl was fluorinated. Compounds (32) to (44) were obtained. Here, among the compounds (32) to (44), the compound in which the α-position is difluorinated is indicated by a, and the monofluorinated compound is indicated by b.

The fluorinating agent (4) was used in an equal amount of 2.2 with respect to the silyl enol ether compound to carry out a fluorination reaction. The reaction solvent, temperature, and time were appropriately changed depending on the silyl enol ether compound used. The obtained compounds (32) to (44) were known compounds and were identified with reference to known spectral data.

Cyril enol ether compound used as a raw material in each example, α-difluorinated compound as a product (hereinafter referred to as difluoro compound, α-monofluoro compound is referred to as monofluoro compound), reaction solvent, temperature. , Time, yield of difluoro compound (a), ratio of difluoro compound / monofluoro compound in the product (mol) (a / b) are shown in Table 2. In Table 2, 1,2-dichloroethane is shown as (CH ₂ Cl ₂ ) ₂ , and dichloromethane is shown as CH ₂ Cl ₂ . As shown in the results in Table 2, by using the fluorinating agent according to the present invention, difluoroforms could be obtained with high selectivity for various silyl enol ether compounds.

[Example 24]
Aiming at application to bioactive compounds, fluorination of oxycarbazepine (45), which is known as a component of antiepileptic drugs, was performed.

Compound (45) (0.5 g, 1.98 mmol) was dissolved in dehydrated dichloromethane (20 mL), and triethylamine (3.96 mmol) was added dropwise at room temperature. Further, at 0 ° C., triethylsilyl methanesulfonate (TESOTf) (3.96 mmol) was added, the reaction mixture was cooled to −5 ° C., and the mixture was stirred for 24 hours. Then, the reaction solution was heated to room temperature and subjected to silica gel flash column chromatography using a hexane / ethyl acetate mixed solvent system. By distilling off the solvent, a yellow oily silyl enol ether compound (46) was obtained.

Subsequently, for the silyl enol ether compound (46) (0.1 mmol), the compound (4) synthesized in Example 1 was used as a fluorinating agent, and fluorination was carried out in the same procedure as in Examples 6, 12 to 26. gone. The fluorination reaction was carried out using the fluorinating agent (4) (4.0 equal amounts), the solvent was 1,2-dichloroethane, the reaction temperature was 80 ° C., and the reaction time was 24 hours. The α-position of the carbonyl group was fluorine. The fluorinated compound (47) was obtained. The difluoro / monofluoro ratio (mol) was 92/8. Purification by silica gel column chromatography gave compound (47a) (9.9 mg, yield 35%).

^{1 1} H NMR (500 MHz, CDCl ₃ ): δ = 8.24 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.0Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 7.62 (d, J = 7.5Hz, 1H), 7.58 (t, J = 7.5Hz, 1H) ), 7.51 (t, J = 7.5Hz, 1H), 7.41 (t, J = 7.5Hz, 1H), 4.78 (brs, 2H) ¹⁹ F NMR (470MHz, CDCl ₃ ) :. δ = -103.01 (d, J = 249.1Hz, 1F), 119.70 (d, J = 264.1Hz, 1F). HRMS (ESI-TOF): calcd for C ₁₅ H ₁₀ F ₂ N ₂ NaO ₂ [M-Na] ⁺ : 311.06080, found: 311.05490.

In the present invention, difluorine in which two fluorine atoms are introduced into a carbon atom different from the carbon atom to which the silyl ether group is bonded among the carbon atoms constituting the C = C bond with respect to the silyl enol ether compound. Provided are a fluorinating agent capable of selectively synthesizing a chemical compound, and a method for producing a difluorinated compound using the fluorinating agent. The fluorinating agent according to the present invention is particularly useful for synthesizing a difluorinated compound because it can selectively synthesize a difluorinated compound rather than a monofluorinated compound having two fluorine atoms introduced therein. ..

Claims

The following general formula (A1)

[In the formula, Ar 1 is a C 6-14 aryl group or a C 5-14 nitrogen-containing heteroaryl group substituted with at least two electron-attracting groups (where Ar 1 is C 5-14 ). In the case of a 14 nitrogen-containing heteroaryl group, the sulfur atom binds to the carbon atom of the C 5-14 nitrogen-containing heteroaryl group); R 1 is a C 1-30 alkyl group which may have a substituent, A group having 1 to 5 ether-bonding oxygen atoms between carbon atoms of a C 1-30 alkyl group which may have a substituent, and a C 6-14 aryl group which may have a substituent. , Or a C 5-14 nitrogen-containing heteroaryl group which may have a substituent (except when R 1 is the same group as Ar 1 ); the electron-attracting group is a halogen. Atomic, trihalomethyl group, cyano group, nitro group, -CO 2 R, -CO 2 N (R) 2 (R each independently represents a C 1-30 alkyl group)]. Compound.
The compound according to claim 1, wherein at least two electron-withdrawing groups in Ar 1 are bonded to an atom other than the atom adjacent to the carbon atom bonded to the sulfur atom.
The compound according to claim 1 or 2, wherein Ar 1 is substituted with two electron-withdrawing groups, and the two electron-withdrawing groups are present at the meta position.
A fluorinating agent containing the compound according to any one of claims 1 to 3 as an active ingredient.
Using the fluorinating agent according to claim 4, the following general formula (A2)

(In the formula, R 21 , R 22 and R 23 are independently C 1-4 alkyl groups; R 24 is a C 1-30 fatty which may have a hydrogen atom and a substituent. Group hydrocarbon group, a group having 1 to 5 ether-bonding oxygen atoms or thioether-binding sulfur atoms between carbon atoms of a C 1-30 aliphatic hydrocarbon group which may have a substituent, A C 1-30 alkoxy group which may have a substituent or an aromatic group which may have a substituent; R 25 may have a hydrogen atom and a substituent C 1 -30 aliphatic hydrocarbon groups, C 1-30 aliphatic hydrocarbon groups may have substituents 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms of the aliphatic hydrocarbon group. It is an aromatic group which may have a group or a substituent; R 24 and R 25 may be linked to each other to form a ring) in the substrate compound represented by two atoms. Introducing a hydrocarbon atom, the following general formula (A4)

(In the formula, R 24 and R 25 are the same as the general formula (A2))
A method for producing a fluorine-containing compound, which comprises producing the fluorine-containing compound represented by.