Fluorinating agent and method for producing fluorine-containing compounds

Abstract

The present invention provides the compound represented in general formula (A1) [Ar1 is a C6-14 aryl group or a C5-14 nitrogen-containing heteroaryl group, substituted with at least two electron-attracting groups; R1 is a C1-30 alkyl group, a C6-14 aryl group, or a C5-14 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 C1-30 alkyl groups)].

Description

[Technical Field]

[0001] The present invention relates to a fluorinating agent that introduces fluorine atoms into organic compounds, and a method for producing fluorine-containing compounds obtained by using the fluorinating agent. This application claims priority based on 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, the contents of which are incorporated herein by reference. [Background technology]

[0002] Fluorine atoms have a high electronegativity and are as small as hydrogen atoms. This characteristic allows fluorine atoms to bond stably with many atoms, and organic compounds into which fluorine has been introduced tend to have improved heat resistance, chemical resistance, light resistance, water resistance, and other properties compared to before the introduction of fluorine. In particular, carbon-fluorine bonds have a short bond length, are rigid, and have low polarizability. Due to this characteristic of carbon-fluorine bonds, organic compounds into which carbon-fluorine bonds have been introduced have reduced reactivity and improved stability as compounds. Fluorination of organic compounds can be used to synthesize useful organic compounds, and a variety of fluorinating agents have been developed.

[0003] An example of a fluorinating agent is N-fluorobenzenesulfonimide (NFSI). It has been reported that NFSI can introduce a fluorine atom to the carbon atom adjacent to a carbonyl group (Non-Patent Documents 1 and 2). N-fluorosulfonimides in which the benzene ring of NFSI is replaced with a naphthyl ring or a substituent is introduced into the benzene ring are also used to fluorinate nucleophilic organic compounds such as enol ethers, aromatic compounds, and organometallic 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).

[0004] In addition, N-fluoro-o-benzenedisulfonimide (NFOBS) (Non-Patent Document 3) and iodotoluene difluoride (ITDF) (Non-Patent Document 4) have been reported as fluorinating agents that introduce fluorine atoms into carbon atoms other than the carbon atom bonded to the silyl ether group among the carbon atoms constituting the C=C bond of a silyl enol ether compound. However, NFOBS has problems in that the raw materials are difficult to obtain, and the raw materials must be synthesized using CFCl3, a specified fluorocarbon, as a solvent, and when CHCl3 is used as the solvent instead of CFCl3, CFCl3 is produced. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 5,254,732 [Patent Document 2] Special Publication No. 8-502494 [Non-patent literature]

[0006] [Non-Patent Document 1] Vaithiyanathan, et al., Chemistry A European Journal, 2017, vol.23, p.1268-1272. [Non-patent document 2] Stavber, et al., Advanced synthesis & catalysis, 2010, vol.352, p.2838-2846. [Non-patent document 3] Davis, et al., Journal of Organic Chemistry, 1995, vol.60, p.4730-4737. [Non-patent document 4] Sato, et al., Synthesis, 2005, vol.15, p.2602-2605. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to provide a fluorinating agent capable of selectively synthesizing a difluorinated product over a monofluorinated product in a fluorination reaction of a silyl enol ether compound by introducing a fluorine atom into a carbon atom other than the carbon atom bonded to the silyl ether group among carbon atoms constituting a C=C bond, and a method for producing a fluorine-containing compound using the fluorinating agent. [Means for solving the problem]

[0008] The present inventors have found that when a fluorinated sulfonimide compound protected with an arylsulfonyl group substituted with at least two electron-withdrawing groups and a sulfonyl group different from the arylsulfonyl group is used as a fluorinating agent, a difluorinated product in which two fluorine atoms are introduced to one of the carbon atoms constituting the C=C bond of a silyl enol ether compound is selectively produced over a monofluorinated product in which one fluorine atom is introduced to the carbon atom constituting the C=C bond of the silyl enol ether compound, and have completed the present invention.

[0009] That is, the present invention is as follows. [1] The following general formula (A1):

[0010] [ka]

[0011] [In the formula, Ar 1 is substituted with at least two electron-withdrawing groups, C 6-14 Aryl group or C 5-14 Nitrogen-containing heteroaryl groups (where Ar 1 C 5-14 In the case of a nitrogen-containing heteroaryl group, the sulfur atom is 5-14 bonded to a carbon atom of a nitrogen-containing heteroaryl group); R 1 C may have a substituent 1-30 alkyl group, optionally substituted C 1-30A group having 1 to 5 ether-bonded oxygen atoms between carbon atoms of an alkyl group, optionally having a substituent 6-14 an aryl group or an optionally substituted C 5-14 A nitrogen-containing heteroaryl group (where R 1 Ar 1 and the electron-withdrawing group is a halogen atom, a trihalomethyl group, a cyano group, a nitro group, -CO2R, or -CO2N(R)2 (wherein each R is independently C 1-30 A compound represented by the formula (I) wherein: [2] The Ar 1 The compound of [1] above, wherein at least two electron-withdrawing groups are bonded to atoms other than the atoms adjacent to the carbon atom bonded to the sulfur atom. [3] The Ar 1 is substituted with two electron-withdrawing groups, and the two electron-withdrawing groups are present at meta positions. [4] A fluorinating agent containing any one of the compounds [1] to [3] above as an active ingredient. [5] Using the fluorinating agent of the above [4], a compound represented by the following general formula (A2)

[0012] [ka]

[0013] (In the formula, R 21 , R 22 , and R 23 are each independently 1-4 is an alkyl group; R 24 is a hydrogen atom, optionally substituted C 1-30 Aliphatic hydrocarbon group, optionally substituted C 1-30 A group having 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms of an aliphatic hydrocarbon group, optionally having a substituent 1-30 an alkoxy group or an aromatic group which may have a substituent; R 25 is a hydrogen atom, optionally substituted C 1-30An aliphatic hydrocarbon group, C which may have a substituent 1-30 A group having 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms of an aliphatic hydrocarbon group, or an aromatic group which may have a substituent; R 24 and R 25 (which may be linked to each other to form a ring) are introduced into a substrate compound represented by the following general formula (A4)

[0014] [Chemical formula]

[0015] (In the formula, R 24 and R 25 are the same as those in the general formula (A2)) A method for producing a fluorine-containing compound, which produces a fluorine-containing compound represented by the following formula [Advantages of the Invention]

[0016] The compound according to the present invention can introduce fluorine atoms into a wide range of substrates having unsaturated bonds, similar to NFSI. In particular, in the fluorination reaction of silyl enol ether compounds, the difluorinated product can be selectively synthesized more than the monofluorinated product. Therefore, the compound is very useful as a fluorinating agent for synthesizing difluorinated compounds. [Modes for Carrying Out the Invention]

[0017] In the present invention and the present specification, "C p1-p2 "(p1 and p2 are positive integers satisfying p1 < p2) means a group having a carbon number of p1 to p2.

[0018] In the present invention and this specification, an "ether-bonded oxygen atom" refers to an oxygen atom that connects carbon atoms, and does not include oxygen atoms in which oxygen atoms are connected in series. In the present invention and this specification, a "thioether-bonded sulfur atom" refers to a sulfur atom that connects carbon atoms, and does not include sulfur atoms in which sulfur atoms are connected in series. An alkyl group having Nc carbon atoms (Nc is an integer of 2 or more) may have a maximum of Nc-1 ether-bonded oxygen atoms or thioether-bonded sulfur atoms.

[0019] In the present invention and the present specification, "C 6-14 The "aryl group" is an aromatic hydrocarbon group having 6 to 14 carbon atoms, 6-12 An aryl group is particularly preferred. 6-14 Examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, and a 9-fluorenyl group, with a phenyl group being particularly preferred.

[0020] In the present invention and the present specification, "C having a substituent" 6-14 The "aryl group" is C 6-14 It is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms of the aryl group are substituted with other functional groups. When the aryl group has two or more substituents, the substituents may be the same or different from each other. The substituents include C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Examples of the alkylthio group, the methylenedioxy group (-O-CH2-O-), the halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), the trihalomethyl group, the cyano group, and the nitro group are mentioned. 6-14Examples of the "aryl group" include a phenyl group, a naphthyl group, an anthryl group, a 2-methylphenyl group, a 4-methylphenyl group, a 3,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a 2,4-dimethylphenyl group, a 2-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group, a 3,5-di(trifluoromethyl)phenyl group, a 2,6-di(trifluoromethyl)phenyl group, a 2,4-di(trifluoromethyl)phenyl group, a 2-methoxyphenyl group, a 4-methoxyphenyl group, a 2,4-dimethoxyphenyl group, a 3,5-dimethoxyphenyl group, a 2-methylthiophenyl group, a 4-methylthiophenyl group, a 2,4-dimethylthiophenyl group, a 3,5-dimethylthiophenyl group, a 3-chlorophenyl group, a 4-cyanophenyl group, a 4-nitrophenyl group, and a 1,3-benzodioxol-5-yl group.

[0021] In the present invention and this specification, a "heteroaryl group" refers to a cyclic group having aromaticity, and the ring is composed of carbon atoms and atoms other than carbon atoms. 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). In addition, the aromatic ring may contain two or more types of atoms other than carbon atoms.

[0022] C 5-14 Examples of nitrogen-containing heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, and carbazolyl groups. 5-14 Examples of oxygen-containing heteroaryl groups include furanyl, pyranyl, benzopyranyl, and xanthenyl groups. 5-14 Examples of sulfur-containing heteroaryl groups include thienyl groups. 5-14Examples of the heteroaryl group include an oxazolyl group, an isoxazolyl group, a thiazolyl group, and an isothiazolyl group.

[0023] In the present invention and the present specification, a "substituted heteroaryl group" refers to a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to atoms constituting the aromatic ring of the heteroaryl group are substituted with other functional groups. When the heteroaryl group has two or more substituents, the substituents may be the same or different from each other. Examples of the substituents include C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Examples include an alkylthio group, a methylenedioxy group (-O-CH2-O-), a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a trihalomethyl group, a cyano group, and a nitro group.

[0024] In the present invention and this specification, the term "aromatic group" includes both an aryl group (aromatic hydrocarbon group) which may have a substituent and a heteroaryl group (heterocyclic group) which may have a substituent.

[0025] In the present invention and the present specification, "C 1-30 The "alkyl group" is an alkyl group having 1 to 30 carbon atoms, and may be a straight chain or a branched chain. 2-30 The "alkyl group" is an alkyl group having 2 to 30 carbon atoms, and may be either a straight chain or a branched chain. 1-30 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, and triacontyl groups.

[0026] In the present invention and the present specification, "C 1-10 The "C alkyl group" is an alkyl group having 1 to 10 carbon atoms, and may be either a straight chain or a branched chain. 2-10 The "alkyl group" is an alkyl group having 2 to 10 carbon atoms, and may be either a straight chain or a branched chain. 1-10 Examples of alkyl groups include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group.

[0027] In the present invention and the present specification, "C 1-6 The "alkyl group" is an alkyl group having 1 to 6 carbon atoms, and may be either a straight chain or a branched chain. 1-6 Examples of the 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, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and a hexyl group.

[0028] In the present invention and the present specification, "C 1-4 The "alkyl group" is an alkyl group having 1 to 4 carbon atoms, and may be either a straight chain or a branched chain. 1-4 Examples of the 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.

[0029] In the present invention and the present specification, "C 1-3 The "alkyl group" is an alkyl group having 1 to 3 carbon atoms, and may be either a straight chain or a branched chain. 1-3 Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

[0030] In the present invention and the present specification, "C having a substituent" p1-p2"Alkyl group" is C p1-p2 It is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to a carbon atom of an alkyl group are substituted with other functional groups. When the alkyl group has two or more substituents, the substituents may be the same or different. The substituents include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms), optionally substituted C 6-14 Examples include an aryl group, a cyano group, and a nitro group.

[0031] "C having a substituent p1-p2 Examples of "alkyl groups" include C 6-14 Aryl-C 1-6 Alkyl groups are examples of C 6-14 Aryl-C 1-6 "Alkyl group" is C 1-6 One hydrogen atom attached to a carbon atom of an alkyl group is C 6-14 It is a group substituted with an aryl group. 6-14 Aryl-C 1-6 C in alkyl groups 6-14 Examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, and a 9-fluorenyl group, with a phenyl group or a 9-fluorenyl group being particularly preferred. 6-14 Aryl-C 1-6 C in alkyl groups 1-6 The alkyl group is C 1-4 Alkyl groups are preferred. 6-14 Aryl-C 1-6 Examples of the alkyl group include a benzyl group, a diphenylmethyl group, a triphenylmethyl group, a 2-phenylethyl group, a 9-anthrylmethyl group, and a 9-fluorenylmethyl group.

[0032] In the present invention and the present specification, "C 1-30 The "aliphatic hydrocarbon group" is a C 1-30 alkyl group, optionally substituted C 2-30 Alkenyl group, optionally substituted C 2-30 Alkynyl groups, including all of the above. 1-30The "aliphatic hydrocarbon group" may be a straight chain, a branched chain, or a cyclic group. 2-30 Examples of alkenyl groups include C 2-30 Among the alkyl groups mentioned above, groups in which at least one single bond between carbon atoms is converted into a double bond are exemplified. 2-30 Examples of alkynyl groups include C 2-30 Among the alkyl groups mentioned above, groups in which at least one single bond between carbon atoms is converted into a triple bond are exemplified. More specifically, C 2-30 Examples of the alkenyl group include 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, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group. 2-30 Examples of the 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, and an octynyl group.

[0033] In the present invention and the present specification, "C having a substituent" p1-p2 Aliphatic hydrocarbon group" is C p1-p2 It is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms of an aliphatic hydrocarbon group are substituted with other functional groups. When the group has two or more substituents, the substituents may be the same or different from each other. The substituents include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms), optionally substituted C 6-14 Examples include an aryl group, a cyano group, and a nitro group.

[0034] In the present invention and the present specification, "C 1-30 The term "alkoxy group" refers to a group in which an oxygen atom is bonded to the bond terminal of a linear or branched alkyl group having 1 to 30 carbon atoms. 1-30 The term "alkylthio group" refers to a group in which a sulfur atom is bonded to the bond terminal of a linear or branched alkyl group having 1 to 30 carbon atoms. 1-30Alkoxy group or C 1-30 The linear or branched alkyl group having 1 to 30 carbon atoms in the alkylthio group includes the above-mentioned C 1-30 The same as the alkyl group can be mentioned.

[0035] In the present invention and the present specification, "C 1-10 The term "alkoxy group" refers to a group in which an oxygen atom is bonded to the bond terminal of a linear or branched alkyl group having 1 to 10 carbon atoms. 1-10 The term "alkylthio group" refers to a group in which a sulfur atom is bonded to the bond terminal of a linear or branched alkyl group having 1 to 10 carbon atoms. 1-10 Alkoxy group or C 1-10 The linear or branched alkyl group having 1 to 10 carbon atoms in the alkylthio group includes the above-mentioned C 1-10 The same as the alkyl group can be mentioned.

[0036] In the present invention and the present specification, "C 1-6 The term "alkoxy group" refers to a group in which an oxygen atom is bonded to the bond terminal of a linear or branched alkyl group having 1 to 6 carbon atoms. 1-6 The term "alkylthio group" refers to a group in which a sulfur atom is bonded to the bond terminal of a linear or branched alkyl group having 1 to 6 carbon atoms. 1-6 Alkoxy group or C 1-6 The linear or branched alkyl group having 1 to 6 carbon atoms in the alkylthio group includes the above-mentioned C 1-6 The same as alkyl groups can be used. 1-6 Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group. 1-6 Examples of the alkylthio group include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a tert-butylthio group, a pentylthio group, and a hexylthio group.

[0037] In the present invention and the present specification, "C having a substituent" p1-p2 The "alkoxy group" is C p1-p2In the present invention and this specification, "substituted C" refers to a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to a carbon atom of an alkoxy group are substituted with other functional groups. p1-p2 The alkylthio group is C p1-p2 It is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to the carbon atom of the alkylthio group are substituted with other functional groups. When the alkylthio group has two or more substituents, the substituents may be the same or different. The substituents include halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms), optionally substituted C 6-14 Examples include an aryl group, a cyano group, and a nitro group.

[0038] In the following description, "compound (n)" means a compound represented by formula (n).

[0039] The subsequent chemical reactions can be carried out in an inert solvent such as methanol, 1,4-dioxane, diethyl ether, tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, N,N-dimethylformamide, or N,N-dimethylacetamide.

[0040] [Fluorinating agent] The compound according to the present invention is a compound represented by the following general formula (A1).

[0041] [ka]

[0042] In general formula (A1), Ar 1 is substituted with at least two electron-withdrawing groups, C 6-14 Aryl group or C 5-14 A nitrogen-containing heteroaryl group, provided that Ar 1 C 5-14 In the case of a nitrogen-containing heteroaryl group, Ar 1 The sulfur atom in the sulfonyl group that is bonded to the C 5-14The compound (A1) is bonded to a carbon atom of the nitrogen-containing heteroaryl group, but not to a nitrogen atom. 1 is substituted with at least two electron-withdrawing groups, a phenyl group, a pyridyl group, a pyrimidinyl group, a quinolyl group, or an isoquinolyl group is preferred, and a phenyl group substituted with at least two electron-withdrawing groups is particularly preferred.

[0043] Ar 1 The electron-withdrawing group has a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), a trihalomethyl group, a cyano group, a nitro group, -CO2R, or -CO2N(R)2. Here, each R is independently C 1-30 Represents an alkyl group. -CO2R is when R is C 1-10 Preferred are groups that are alkyl groups, and R is C 1-6 More preferred are groups that are alkyl groups, and R is C 1-4 More preferred are groups that are alkyl groups, with -CO2CH3 or -CO2C2H5 being even more preferred. As -CO2N(R)2, R is C 1-10 Preferred are groups that are alkyl groups, and R is C 1-6 More preferred are groups that are alkyl groups, and R is C 1-4 An alkyl group is more preferred, and -CO2N(CH3)2 is even more preferred. As a halogen atom, a fluorine atom is particularly preferred. Ar 1 The electron-withdrawing group contained in is preferably a halogen atom, a trihalomethyl group, a cyano group, or a nitro group, more preferably a halogen atom or a trihalomethyl group, and even more preferably a fluorine atom or a trifluoromethyl group.

[0044] Ar 1 has at least two electron-withdrawing groups. 1 The plurality of electron-withdrawing groups contained in Ar may be the same or different. 1 When is a trihalomethyl group, a cyano group, a nitro group, -CO2R, or -CO2N(R)2, the electron-withdrawing group is less likely to cause steric hindrance during the fluorination reaction, and therefore, Ar 1The number of electron-withdrawing groups contained in Ar is preferably two, and more preferably the two electron-withdrawing groups are located at the meta position relative to each other. 1 If is a halogen atom, Ar 1 The number of electron-withdrawing groups may be two or more, for example, Ar 1 All of the hydrogen atoms bonded to the carbon atoms constituting the aromatic ring may be substituted with halogen atoms.

[0045] Ar 1 The at least two electron-withdrawing groups in Ar are unlikely to cause steric hindrance during the fluorination reaction. 1 Among the atoms that make up the aromatic ring of 1 It is preferred that the carbon atom bonded to the sulfur atom in the sulfonyl group is an atom other than the atom adjacent to the carbon atom bonded to the sulfur atom in the sulfonyl group.

[0046] Ar 1 may have a substituent other than the electron-withdrawing group. Examples of the substituent include C 1-6 Alkyl group, C 1-6 Alkyl group, C 1-6 Examples thereof include an alkoxy group.

[0047] In general formula (A1), R 1 C may have a substituent 1-30 Alkyl group (which may have 1 to 5 ether-bonded oxygen atoms between carbon atoms), optionally substituted C 6-14 an aryl group or an optionally substituted C 5-14 A nitrogen-containing heteroaryl group, provided that R 1 Ar 1 In the present invention and the specification of this application, "optionally substituted C 1-30 "Alkyl group (which may have 1 to 5 ether-bonded oxygen atoms between carbon atoms)" means "C 1-30 alkyl group or optionally substituted C 1-30 The term "a group having 1 to 5 ether-bonding oxygen atoms between carbon atoms of an alkyl group" means "a group having 1 to 5 ether-bonding oxygen atoms between carbon atoms of an alkyl group."

[0048] R 1 C may have a substituent 1-30 In the case of an alkyl group, the alkyl group may have 1 to 5 ether-bonding oxygen atoms between carbon atoms. The substituent may be an electron-withdrawing group or may be other than an electron-withdrawing group. Compound (A1) may be a group having the above R 1 C which may have a substituent 1-10 An alkyl group is preferred, and optionally substituted C 1-6 Alkyl groups are more preferred, and unsubstituted C 1-6 Alkyl group or C 6-14 Aryl-C 1-6 An alkyl group is more preferred, and a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-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 is even more preferred, and a tert-butyl group, a benzyl group, or a 2-phenylethyl group is particularly preferred.

[0049] R 1 C may have a substituent 6-14 In the case of an aryl group, the substituent may be an electron-withdrawing group or a group other than an electron-withdrawing group. The number of substituents is determined so as not to impair the function of the compound (A1) as a fluorinating agent and to be within the range of Ar 1 As long as the substituent is not the same as the group represented by R, the compound (A1) may have, for example, 1 to 3 substituents. 1 is preferably, for example, a phenyl group which may have 1 to 3 substituents, and C 1-6 Alkyl group, C 1-6 Alkyl group, C 1-6A phenyl group optionally having 1 to 3 substituents selected from the group consisting of an alkoxy group, a halogen atom, and a trihalomethyl group is more preferred, and a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 3,4-dimethylphenyl group, a 3,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a 2,4-dimethylphenyl group, a 2-trifluoromethylphenyl group, a 3-trifluoromethyl group, a 4-trifluoromethylphenyl group, a 3,4-di(trifluoromethyl)phenyl group, a 3,5-di(trifluoromethyl)phenyl group, a 2,6-di(trifluoromethyl)phenyl group, a 2,4-di(trifluoromethyl)phenyl group, a 2-methoxyphenyl group, a 4-methoxyphenyl group, a 2,4-dimethoxyphenyl group, a 3,5-dimethoxyphenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2,6-dichlorophenyl group, a 3,4-dichlorophenyl group, a 4-cyanophenyl group, or a 4-nitrophenyl group is even more preferred, and a phenyl group is particularly preferred.

[0050] R 1 C may have a substituent 5-14 In the case of a nitrogen-containing heteroaryl group, the substituent may be an electron-withdrawing group or a group other than an electron-withdrawing group. The number of substituents is determined so as not to impair the function of the compound (A1) as a fluorinating agent and to be within the range of Ar 1 As long as the substituent is not the same as the group represented by R, the compound (A1) may have, for example, 1 to 3 substituents. 1 is, for example, a pyridyl group, a pyrimidinyl group, a quinolyl group, or an isoquinolyl group, and is preferably a group having no substituents or 1 to 3 substituents, more preferably a pyridyl group having no substituents or 1 to 3 substituents.

[0051] The compound (A1) may be a compound represented by the following general formula (A1-1) or general formula (A1-2): 1 is the same as in general formula (A1). In general formula (A1-1), W is an electron-withdrawing group. The electron-withdrawing group is the same as in the above Ar 1The two Ws in one molecule of the compound (A1-1) may be the same type of group or different types of groups.

[0052] [ka]

[0053] 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 (A1-2-2) to (A1-2-4):

[0054] [ka]

[0055] In general formulas (A1-1-1) to (A1-1-4) and general formulas (A1-2-1) to (A1-2-4), W is the same as in general formula (A1-1), and two or three Ws in one molecule may be the same or different groups. W in general formula (A1-1-1) etc. is preferably a halogen atom, a trihalomethyl group, a nitro group, or a cyano group, more preferably a fluorine atom, a trifluoromethyl group, a nitro group, or a cyano group.

[0056] In general formula (A1-1-4) and general formula (A1-2-4), R 11 C may have a substituent 1-30 an alkyl group (which may have 1 to 5 ether-bonded oxygen atoms between carbon atoms) and optionally substituted; 1-6 An alkyl group is preferred, and optionally substituted C 1-4 An alkyl group is more preferred, 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 even more preferred, and a methyl group, an ethyl group, a propyl group, or an isopropyl group is even more preferred.

[0057] Compound (A1) can be synthesized, for example, by synthesizing a sulfonimide by the condensation reaction of a sulfonyl halide with a sulfonamide, substituting a hydrogen atom bonded to the nitrogen atom of the imide group with a lithium atom, and then substituting the lithium atom with a fluorine atom. 1 and R 1 is Ar in general formula (A1) 1 and R 1 is the same as

[0058] [ka]

[0059] [Method of producing fluorine-containing compounds] Compound (A1) can be used as an active ingredient of a fluorinating agent in various reactions. Similar to NFSI, compound (A1) can fluorinate carbon atoms in various organic compounds. Examples of organic compounds that can be used as substrates include compounds having unsaturated bonds, such as alkenes, allyl compounds, alkynes, and aromatic compounds. The unsaturated bond may be a bond formed between carbon atoms, or may be a bond between a carbon atom and an atom other than a carbon atom.

[0060] Compound (A1) is particularly suitable as a fluorinating agent for silyl enol ether compounds. For example, by using compound (A1) as a fluorinating agent, two fluorine atoms can be introduced into a substrate compound (silyl enol ether compound) represented by general formula (A2) to produce a fluorine-containing compound represented by general formula (A4).

[0061] [ka]

[0062] In general formula (A2), R 21 , R 22 , and R 23 are each independently 1-4 The compound (A2) is an alkyl group.21 , R 22 , and R 23 are each independently a methyl group or an ethyl group, and R 21 , R 22 , and R 23 and R are each a methyl group or an ethyl group, 21 , R 22 , and R 23 However, compounds in which both are methyl groups are particularly preferred.

[0063] In general formula (A2), R 24 is a hydrogen atom, optionally substituted C 1-30 Aliphatic hydrocarbon group (which may have 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms), optionally substituted C 1-30 In general formula (A2), R is an alkoxy group or an aromatic group which may have a substituent. 25 is a hydrogen atom, optionally substituted C 1-30 It is an aliphatic hydrocarbon group (which may have 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms), or an aromatic group which may have a substituent. 1-30 "Aliphatic hydrocarbon group (which may have 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms)" means "a C group which may have a substituent 1-30 an aliphatic hydrocarbon group or a C group which may have a substituent 1-30 The term "a group having 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms of an aliphatic hydrocarbon group" means "a group having 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms of an aliphatic hydrocarbon group."

[0064] R 24 or R 25 C may have a substituent 1-30 In the case of an aliphatic hydrocarbon group, the aliphatic hydrocarbon group may have 1 to 5 oxygen atoms in an ether bond between carbon atoms, or may have 1 to 5 sulfur atoms in a thioether bond between carbon atoms.1-30 The aliphatic hydrocarbon group is a C 1-30 An alkyl group is preferred, and optionally substituted C 1-10 An alkyl group is more preferred, and C 1-6 An alkyl group is more preferred, and an unsubstituted C 1-6 Alkyl groups are particularly preferred.

[0065] R 24 or R 25 When C is an aromatic group which may have a substituent, the aromatic group may be an aryl group or a heteroaryl group. 6-14 An aryl group or an optionally substituted nitrogen-containing heteroaryl group is preferred, and an optionally substituted C 6-14 An aryl group is more preferred.

[0066] R 24 C may have a substituent 1-30 In the case of an alkoxy group, the alkoxy group may have 1 to 5 ether-bonding oxygen atoms between carbon atoms. 24 C which may have a substituent 1-10 An alkoxy group is preferred, and optionally substituted C 1-6 An alkoxy group is more preferred, and an unsubstituted C 1-6 Alkoxy groups are more preferred, and methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups are even more preferred.

[0067] R 24 and R 25 may be linked to each other to form a ring. 24 and R 25The ring constituted by is preferably a 5-membered ring, a 6-membered ring, or a 7-membered ring, and may be a ring to which an aromatic ring or a saturated ring is condensed. It may also be a hydrocarbon ring or a heterocyclic ring. Examples of such rings include an indane ring, an indene ring, a tetrahydronaphthalene ring, a dihydronaphthalene ring, a chroman ring, a thiochroman ring, a chromene ring, an isochromene ring, a tetrahydrofuran ring, an indoline ring, an indole ring, a cycloheptene ring, and a benzocycloheptene ring.

[0068] R 24 and R 25 The ring constituted by may have a substituent. When two or more substituents are present, the substituents may be the same or different. Examples of the substituents include C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), trihalomethyl group, optionally substituted C 6-14 Examples include an aryl group, a cyano group, and a nitro group.

[0069] The fluorination reaction of compound (A2) with compound (A1) can be carried out by mixing compound (A1) and compound (A2) in a solvent inert to the reaction at a temperature of not more than 100° C. The amount of compound (A1) relative to 1 mole of compound (A2) is preferably 0.5 to 100 moles, more preferably 0.5 to 50 moles, and even more preferably 0.5 to 10 moles. [Example]

[0070] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0071] The NMR apparatus used for the analyses in the Examples and Comparative Examples was a JNM-ECS400 (400 MHz) or ECZ500R (500 MHz) manufactured by JEOL Ltd. 1 In H NMR, tetramethylsilane was used as the reference value of 0 ppm. 19In F NMR, the reference value for C6F6 was -162 ppm. The HPLC (high performance liquid chromatograph) used was an LC-20 manufactured by Shimadzu Corporation. The high-resolution mass spectrometer used was a JEOL JMS-T100LP spectrometer operating in ESI-TOF (electron spray ionization time-of-flight) mode. The yields (%) described in the examples are in mol%.

[0072] [Example 1] Ar in general formula (A1) 1 is a phenyl group substituted with two trifluoromethyl groups, and R 1 We synthesized a compound in which is a phenyl group.

[0073] [ka]

[0074] Under a nitrogen atmosphere, a solution of benzenesulfonamide (2-1) (0.24 g, 1.5 mmol) and sodium hydride (>55%, dispersed in liquid paraffin) (0.14 g, 2 equivalents) dissolved in tetrahydrofuran (20 mL) was added at 0 °C and stirred at room temperature for 1 hour. After the solution was returned to 0 °C, a solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (1-1) (0.56 g, 1.2 equivalents) dissolved in tetrahydrofuran (2 mL) was added and stirred at room temperature for 2 hours. The mixture was then quenched with water, and ethyl acetate was added. After washing three times with 1 M aqueous sodium hydroxide, the organic phase was dried over magnesium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and silica gel column chromatography was performed using a hexane / ethyl acetate mixed solvent system. The resulting solid was dissolved in methylene chloride, washed three times with 3 M hydrochloric acid, and the solvent was evaporated under reduced pressure. The obtained solid was dissolved again in toluene, and the solvent was distilled off under reduced pressure to obtain the target compound (3-H) (0.54 g, 1.2 mmol) as a white solid.

[0075] 1H 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).

[0076] 1 H NMR(400MHz,Acetone-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,Acetone-D6) δ -63.36 (s, 6F)HRMS (ESI-TOF) :calcd for C 14 H9F6NNaO4S2[M-Na] + :455.97749,found:455.97666.

[0077] [ka]

[0078] A solution of compound (3-H) (0.54 g) and sodium fluoride (0.16 g, 3 equivalents) in acetonitrile (30 g) was cooled to 0°C using an ice bath. A 2% by volume fluorine / nitrogen mixed gas was introduced into the reaction vessel at 100 mL / min using a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. The precipitate was then filtered, and the solvent was distilled off under reduced pressure. The target product (4) (0.42 g, 0.9 mmol) was obtained by silica gel column chromatography using a hexane / ethyl acetate mixed solvent system.

[0079] 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) 19F NMR (d-chloroform): δ = −35.71 (s, 1F), −62.86 (s, 6F).

[0080] 1 H NMR(500MHz,CDCl3) 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,CDCl3) δ -35.74(s, 1F), -62.84(s, 6F)HRMS (ESI-TOF) :calcd for C 14 H8F7NNaO4S2[M-Na] + :473.96807,found:473.96616

[0081] [Example 2] Ar in general formula (A1) 1 is a phenyl group substituted with two trifluoromethyl groups, and R 1 We synthesized a compound in which is a methyl group.

[0082] [ka]

[0083] Under a nitrogen atmosphere, a solution of methanesulfonamide (2-2) (0.29 g, 3.0 mmol) and sodium hydride (>55%, dispersed in liquid paraffin) (0.29 g, 3 equiv.) dissolved in tetrahydrofuran (45 mL) was added at 0 °C and stirred at room temperature for 1 hour. After the solution was returned to 0 °C, a solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (1-1) (1.03 g, 1.1 equiv.) dissolved in tetrahydrofuran (5 mL) was added and stirred at room temperature for 2 hours. The mixture was then quenched with water and ethyl acetate was added. The mixture was washed three times with 1 M aqueous sodium hydroxide, and the organic phase was dried over magnesium sulfate. The solvent was then evaporated under reduced pressure, and silica gel column chromatography was performed using a hexane / ethyl acetate mixed solvent system. The resulting solid was dissolved in methylene chloride, washed three times with 3 M hydrochloric acid, and the solvent was evaporated under reduced pressure. The obtained solid was dissolved again in toluene, and the solvent was distilled off under reduced pressure to obtain the target compound (5-H) (0.92 g, 2.5 mmol) as a white solid.

[0084] 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).

[0085] 1 H NMR(500MHz,Acetone-D6) δ 8.42(s, 2H), 8.12(s, 1H), 2.87(s, 3H) 19 F NMR(470MHz,Acetone-D6) δ -63.18(s, 6F)HRMS (ESI-TOF) :calcd for C9H7F6NNaO4S2[M-Na] + :393.96184,found:393.96221.

[0086] [ka]

[0087] A solution of compound (5-H) (0.47 g, 1.3 mmol) and sodium fluoride (0.16 g, 3 equivalents) in acetonitrile (30 g) was cooled to 0 °C using an ice bath. A 2% by volume fluorine / nitrogen mixed gas was introduced into the reaction vessel at 100 mL / min using a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. The precipitate was then filtered, and the solvent was distilled off under reduced pressure. The target product (6) (0.20 g, 0.5 mmol) was obtained by silica gel column chromatography using a hexane / ethyl acetate mixed solvent system.

[0088] 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).

[0089] 1 H NMR(500MHz,CDCl3) δ 8.49(s, 2H), 8.28(s, 1H), 3.43(s, 3H) 19 F NMR(470MHz,CDCl3) δ -37.93(s, 1F), -62.90(s, 6F)HRMS (ESI-TOF) : calcd for C9H6F7NNaO4S2[M-Na] + : 411.95242, found:411.95222

[0090] [Example 3] Ar in general formula (A1) 1 is a phenyl group substituted with two trifluoromethyl groups, and R 1 We synthesized a compound in which the phenyl group was substituted with a nitro group.

[0091] [ka]

[0092] Under a nitrogen atmosphere, a solution of 4-nitrobenzenesulfonamide (2-3) (0.61 g, 3.0 mmol) and sodium hydride (>55%, dispersed in liquid paraffin) (0.29 g, 3 equiv.) dissolved in tetrahydrofuran (35 mL) was added at 0 °C and stirred at room temperature for 1 hour. After the solution was returned to 0 °C, a solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (1-1) (1.00 g, 1.1 equiv.) dissolved in tetrahydrofuran (5 mL) was added and stirred at room temperature for 2 hours. The mixture was then quenched with water and ethyl acetate was added. The mixture was washed three times with 1 M aqueous sodium hydroxide, and the organic phase was dried over magnesium sulfate. The solvent was then evaporated under reduced pressure, and the mixture was subjected to silica gel column chromatography using a hexane / ethyl acetate mixed solvent system. The resulting solid was dissolved in methylene chloride, washed three times with 3 M hydrochloric acid, and the solvent was evaporated under reduced pressure. The obtained solid was dissolved again in toluene, and the solvent was distilled off under reduced pressure to obtain the target compound (7-H) (1.22 g, 2.6 mmol) as a white solid.

[0093] 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).

[0094] [ka]

[0095] A solution of compound (7-H) (0.60 g, 1.3 mmol) and sodium fluoride (0.16 g, 3 equivalents) dissolved in acetonitrile (30 g) was cooled to 0°C using an ice bath. A 2% by volume fluorine / nitrogen mixed gas was adjusted to 100 mL / min using a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. After the reaction was completed, the crude liquid 19 Quantitative analysis by F NMR confirmed that compound (8) was produced in a yield of 15%.

[0096] 19 F NMR(neat):δ=-37.03(s,1F),-63.55(s,6F).

[0097] [Example 4] Ar in general formula (A1) 1 is a phenyl group substituted with five fluorine atoms, and R 1 We synthesized a compound in which is a phenyl group.

[0098] [ka]

[0099] Under a nitrogen atmosphere, a solution of benzenesulfonamide (2-1) (0.47 g, 3.0 mmol) and sodium hydride (>55%, dispersed in liquid paraffin) (0.29 g) dissolved in tetrahydrofuran (45 mL) was added at 0 °C and stirred at room temperature for 1 hour. After the solution was returned to 0 °C, a solution of benzenesulfonyl chloride derivative (1-2) (0.88 g, 1.1 equiv.) dissolved in tetrahydrofuran (5 mL) was added and stirred at room temperature for 2 hours. The mixture was then quenched with water and ethyl acetate was added. The mixture was washed three times with 1 M aqueous sodium hydroxide, and the organic phase was dried over sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure to give the target compound (9-Na) (1.13 g, 2.8 mmol) as a white solid.

[0100] 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).

[0101] [ka]

[0102] A solution of compound (9-Na) (0.52 g, 1.3 mmol) dissolved in acetonitrile (30 g) was cooled to 0 °C using an ice bath. A 2% by volume fluorine / nitrogen mixed gas was introduced into the reaction vessel at 100 mL / min using a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. The precipitate was then filtered, and the solvent was distilled off under reduced pressure. The target product (10) (0.18 g, 0.4 mmol) was obtained by silica gel column chromatography using a hexane / ethyl acetate mixed solvent system.

[0103] 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).

[0104] 1 H NMR(400MHz,CDCl3) δ 8.08(d, J=8.8Hz, 2H), 7.82(t, J=7.6Hz, 1H), 7.68(t, J=8.0Hz, 2H) 19 F NMR(376MHz,CDCl3) 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 H5F6NNaO4S2[M-Na] + :427.94619,found:427.94658

[0105] [Example 5] Ar in general formula (A1) 1 is a phenyl group substituted with two trifluoromethyl groups, and R 1 We synthesized a compound in which is a phenyl group.

[0106] [ka]

[0107] Under a nitrogen atmosphere, a solution of benzenesulfonamide (2-1) (0.47 g, 3.0 mmol) and sodium hydride (>55%, dispersed in liquid paraffin) (0.29 g, 3 equiv.) dissolved in tetrahydrofuran (40 mL) was added at 0 °C and stirred at room temperature for 1 hour. After the solution was returned to 0 °C, a solution of 2,4-bis(trifluoromethyl)benzenesulfonyl chloride (1-3) (1.11 g, 1.1 equiv.) dissolved in tetrahydrofuran (4 mL) was added and stirred at room temperature for 2 hours. The mixture was then quenched with water, and ethyl acetate was added. The mixture was washed three times with 1 M aqueous sodium hydroxide, and the organic phase was dried over magnesium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and silica gel column chromatography was performed using a hexane / ethyl acetate mixed solvent system. The resulting solid was dissolved in methylene chloride, washed three times with 3 M hydrochloric acid, and the solvent was evaporated under reduced pressure. The obtained solid was dissolved again in toluene, and the solvent was distilled off under reduced pressure to obtain the target compound (11-H) (1.13 g, 2.6 mmol) as a white solid.

[0108] 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).

[0109] 1 H NMR(500MHz,Acetone-D6) δ 8.61(s, 1H), 8.32(d, J=8.0Hz, 1H), 8.26(d, J=8.0Hz, 1H), 7.92(d, J=7.5Hz, 2H), 7.71(t, J=8.0Hz, 1H), 7.61(t, J=8.0Hz, 2H) 19F NMR(470MHz,Acetone-D6) δ -58.35 (s, 3F), -63.87 (s, 3F)HRMS (ESI-TOF) :calcd for C 14 H9F6NNaO4S2[M-Na] + :455.97749,found:455.97721.

[0110] [ka]

[0111] A solution of compound (11-H) (0.56 g, 1.3 mmol) and sodium fluoride (0.16 g, 3 equivalents) dissolved in acetonitrile (30 g) was cooled to 0 °C using an ice bath. A 2% by volume fluorine / nitrogen mixed gas was introduced into the reaction vessel at 100 mL / min using a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. The precipitate was then filtered, and the solvent was distilled off under reduced pressure. The target product (12) (0.52 g, 1.2 mmol) was obtained by silica gel column chromatography using a hexane / ethyl acetate mixed solvent system.

[0112] 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).

[0113] 1 H NMR(500MHz,CDCl3) δ 8.48(s, 1H), 8.10-8.15(m, 4H), 7.84(t, J=7.5Hz, 1H), 7.67(t, J=7.5Hz, 2H) 19 F NMR(470MHz,CDCl3) δ -35.22(s, 1F), -57.60(s, 3F), -63.24(s, 3F)HRMS (ESI-TOF) :calcd for C 14H8F7NNaO4S2 [M-Na] + :473.96807,found:473.96706

[0114] [Example 6] The compound (4) synthesized in Example 1 was used as a fluorinating agent to fluorinate the silyl enol ether compound (13).

[0115] [ka]

[0116] Under a nitrogen atmosphere, the silyl enol ether compound (13) (28 mg, 0.15 mmol) was added dropwise to a solution of the compound (4) (149 mg, 0.33 mmol) dissolved in 0.1 M 1,2-dichloroethane. After stirring at 50°C for 24 hours, the crude solution was 19 Quantitative analysis by F NMR confirmed that compound (14a) was produced in a yield of 91%. The production of compound (14b) was not confirmed. These results demonstrate that using compound (4) as a fluorinating agent allows for the synthesis of difluorinated compounds more selectively than monofluorinated compounds.

[0117] Compound (14a) 19 F NMR (CDCl3): δ = -94.24 (m, 2F).

[0118] [Comparative Example 1] Silyl enol ether compound (13) was fluorinated using NFSI as a fluorinating agent.

[0119] [ka]

[0120] A fluorination reaction was carried out under the same conditions as in Example 6, except that NFSI (105 mg, 0.33 mmol) was used as the fluorinating agent instead of compound (4). As a result, it was confirmed that compound (14a) was produced in an amount of 53% and compound (14b) in an amount of 31%. These results demonstrate that when NFSI is used, both monofluorinated and difluorinated compounds are synthesized.

[0121] Compound (14a) 19 F NMR (CDCl3): δ = -94.24 (m, 2F). Compound (14b) 19 F NMR(CDCl3):δ=-191.64(m,1F).

[0122] [Reference example 1] A fluorinated sulfonimide compound protected by a phenylsulfonyl group substituted with one trifluoromethyl group and a quinolylsulfonyl group was synthesized.

[0123] [ka]

[0124] Under a nitrogen atmosphere, a solution of 4-trifluoromethylbenzenesulfonamide (2-4) (0.68 g, 3.0 mmol) and sodium hydride (>55%, dispersed in liquid paraffin) (0.29 g, 3 equiv.) dissolved in tetrahydrofuran (35 mL) was added at 0 °C and stirred at room temperature for 1 h. After the solution was returned to 0 °C, a solution of benzenesulfonyl chloride derivative (1-4) (0.73 g, 1.1 equiv.) dissolved in tetrahydrofuran (5 mL) was added and stirred at room temperature for 2 h. The mixture was then quenched with water and ethyl acetate was added. The mixture was washed three times with 1 M aqueous sodium hydroxide, and the organic phase was dried over sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure to give the target compound (15-Na) (1.27 g, 2.9 mmol) as a white solid.

[0125] 1H 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).

[0126] [ka]

[0127] A solution of compound (15-Na) (0.55 g, 1.3 mmol) dissolved in acetonitrile (30 g) and water (1.5 g) was cooled to 0°C using an ice bath. A 2% by volume fluorine / nitrogen mixed gas was adjusted to 100 mL / min using a mass flow controller, and 1 equivalent of fluorine gas was introduced into the reaction vessel over 15 minutes. After the reaction was completed, the crude solution was 19 Quantitative analysis by F NMR confirmed that compound (16) was produced in a yield of 43%.

[0128] 19 F NMR(neat):δ=-36.68(s,1F),-63.08(s,3F).

[0129] [Example 7] Fluorinated sulfonimide compounds protected with a phenylsulfonyl group substituted with one trifluoromethyl group and a phenylsulfonyl group substituted with two trifluoromethyl groups were synthesized.

[0130] [ka]

[0131] Compound (17-H) (0.69 g, yield 92%) was obtained in the same manner as in Example 1, except that 4-trifluoromethylbenzenesulfonamide (2-4) was used in place of benzenesulfonamide (2-1) in an amount of 1.2 equivalents per 1.5 mmol of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (1-1).

[0132] 1 H NMR(500MHz,Acetone-D6):δ=8.18(s,2H),8.01(s,1H),7.87(d,J=6.4Hz,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 H8F9NNaO4S2[M-Na] + :523.96487,found:523.96519.

[0133] [ka]

[0134] Subsequently, compound (17-H) (2.95 mmol) was fluorinated with a 2% fluorine / nitrogen mixed gas in the same manner as in Example 1 to obtain the target product (18) (0.11 g, yield 11%).

[0135] 1 H NMR(500MHz,CDCl3):δ=8.47(s,2H),8.28(s,1H),8.19(d,J=8.0Hz,2H),7.93(d,J=8.0Hz,2H) 19 F NMR(470MHz,CDCl3):δ=-34.91(s,1F),-62.87(s,6F),-63.43(s,3F).HRMS (ESI-TOF) :calcd for C 15 H7F 10 NNaO4S2[M-Na] + :541.95545,found:541.95501

[0136] [Examples 8 to 10] Compound (13) was fluorinated in the same manner as in Example 6, except that compounds (6), (10), and (18) synthesized in Examples 2, 4, and 7 were used as fluorinating agents.

[0137] [ka]

[0138] 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. The reaction time when each fluorinating agent was used, the yield of compound (14a) and compound (14b), and the ratio (molar) (14a / 14b) of the amount of compound (14a) produced to the amount of compound (14b) produced are shown in Table 1. For comparison, the results of Example 6 and Comparative Example 1 are also shown in Table 1.

[0139] [Table 1]

[0140] The results in Table 1 show that when the fluorinating agent of the present invention was used, the difluoro compound (14a) was obtained in a higher yield than when the fluorinating agent of Comparative Example 1 was used. In particular, by using the fluorinating agents of compounds (4) and (18), only compound (14a) was selectively obtained. Furthermore, it was found that the fluorinating agent of the present invention, particularly the fluorinating agent of compound (18), was able to complete fluorination in a shorter reaction time than that of Comparative Example 1.

[0141] [Examples 11 to 23] Using compound (4) synthesized in Example 1 as a fluorinating agent, silyl enol ether compounds (19) to (31) were fluorinated in the same manner as in Example 6 to obtain compounds (32) to (44) in which the α-position of the carbonyl was fluorinated. Here, among compounds (32) to (44), compounds in which the α-position was difluorinated are indicated by a, and compounds in which the α-position was monofluorinated are indicated by b.

[0142] [ka]

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] The fluorination reaction was carried out using 2.2 equivalents of fluorinating agent (4) relative to the silyl enol ether compound. The reaction solvent, temperature, and time were appropriately changed depending on the silyl enol ether compound used. The resulting compounds (32) to (44) are known compounds and were identified by reference to their known spectral data.

[0147] Table 2 shows the silyl enol ether compounds used as raw materials in each example, the α-difluorinated compounds (hereinafter referred to as difluoro compounds, and α-monofluoro compounds as monofluoro compounds) that were the products, the reaction solvent, temperature, time, yield of difluoro compound (a), and the molar ratio of difluoro compound to monofluoro compound (a / b) in the products. In Table 2, 1,2-dichloroethane is represented as (CH2Cl2)2, and dichloromethane is represented as CH2Cl2. As shown by the results in Table 2, by using the fluorinating agent of the present invention, the difluoro compound could be obtained with high selectivity for various silyl enol ether compounds.

[0148] [Table 2]

[0149] [Example 24] In order to apply it to bioactive compounds, we fluorinated oxcarbazepine (45), a known component of antiepileptic drugs.

[0150] [ka]

[0151] 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. Furthermore, triethylsilyl methanesulfonate (TESOTf) (3.96 mmol) was added at 0°C, and the reaction mixture was cooled to -5°C and stirred for 24 hours. The reaction mixture was then warmed to room temperature and subjected to silica gel flash column chromatography using a hexane / ethyl acetate mixed solvent system. The solvent was evaporated to afford the silyl enol ether compound (46) as a yellow oil.

[0152] Subsequently, silyl enol ether compound (46) (0.1 mmol) was fluorinated using compound (4) synthesized in Example 1 as the fluorinating agent, following the same procedures as in Examples 6, 12 to 26. The fluorination reaction was carried out using fluorinating agent (4) (4.0 equivalents) in 1,2-dichloroethane as the solvent at 80°C for 24 hours to obtain compound (47), in which the α-position of the carbonyl group was fluorinated. The molar ratio of difluoro to monofluoro compounds was 92 / 8. Purification by silica gel column chromatography afforded compound (47a) (9.9 mg, 35% yield).

[0153] 1H NMR (500MHz, CDCl3): δ=8.24(d,J=8.0Hz,1H),7.79(d,J=8.5Hz,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,CDCl3):δ=-103.01(d,J=249.1Hz,1F),-119.70(d,J=264.1Hz,1F).HRMS (ESI-TOF) :calcd for C 15 H 10 F2N2NaO2[M-Na] + :311.06080,found:311.05490. [Industrial Applicability]

[0154] The present invention provides a fluorinating agent capable of selectively synthesizing a difluorinated compound in which, among carbon atoms constituting a C=C bond of a silyl enol ether compound, two fluorine atoms have been introduced to a carbon atom other than the carbon atom to which the silyl ether group is bonded, 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 difluorinated compounds because it can selectively synthesize difluorinated compounds over monofluorinated compounds in which two fluorine atoms have been introduced.

Claims

1. The following general formula (A1-1) or (A1-2) 【Chemical 1】 [In the formula, R １ is an unsubstituted C1-6 alkyl group or a phenyl group optionally having 1 to 3 substituents; W is an electron-withdrawing group; the electron-withdrawing group is a halogen atom, a trihalomethyl group, a cyano group, or a nitro group; and the two Ws in one molecule may be the same or different groups.

2. The compound of claim 1 , wherein W is a trifluoromethyl group.

3. The compound according to claim 1 or 2, wherein R 1 is a methyl group, a 4-nitrophenyl group, a 4-trifluoromethylphenyl group, a 4-cyanophenyl group, or a phenyl group.

4. A fluorinating agent comprising the compound according to any one of claims 1 to 3 as an active ingredient.

5. Fluorination of a compound represented by the following general formula (A2) using the fluorinating agent according to claim 4: 【Chemistry 2】 (In the formula, R ２１ , R ２２ , and R ２３ are each independently C １－４ is an alkyl group; R ２４ is a hydrogen atom, optionally substituted C １－３０ Aliphatic hydrocarbon group, optionally substituted C １－３０ A group having 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms of an aliphatic hydrocarbon group, optionally having a substituent １－３０ an alkoxy group or an aromatic group which may have a substituent; R ２５ is a hydrogen atom, optionally substituted C １－３０ Aliphatic hydrocarbon group, optionally substituted C １－３０ a group having 1 to 5 ether-bonded oxygen atoms or thioether-bonded sulfur atoms between carbon atoms of an aliphatic hydrocarbon group, or an aromatic group which may have a substituent; R ２４ and R ２５ may be linked to each other to form a ring), to form a compound represented by the following general formula (A4): 【Chemistry 3】 (In the formula, R ２４ and R ２５ is the same as in general formula (A2). A method for producing a fluorine-containing compound represented by the formula:

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