Method for producing fluorine-containing compounds

Abstract

The present invention provides a method for producing a fluorine-containing compound under relatively mild conditions by introducing a fluorine atom into a wide variety of oxygen-containing compounds having a ketone group, an aldehyde group, a hydroxy group, or the like using a SF5 - stabilized by forming a salt with a glyme coordinated alkali metal ion as a deoxygenating fluorinating agent. The present invention relates to a fluorine-containing compound production method in which a fluorine-containing compound is produced by the deoxyfluorination of an oxygen-containing compound having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group in one or more solvents selected from the group consisting of DMPU, G4, DMA, HMPA, and MeCN using a deoxyfluorinating agent represented by general formula (E1) [in the formula, M represents Cs+, K+, or Rb+, G4 represents a tetraethylene glycol dimethyl ether, and n is an integer of 1 to 4]. Formula E1: M(G4)n][SF5

Description

[Technical Field]

[0001] The present invention relates to a method for producing a fluorine-containing compound by introducing a fluorine atom into an oxygen-containing compound having a ketone group, an aldehyde group, a hydroxy group, or the like, using a deoxyfluorinating agent. This application claims priority based on Japanese Patent Application No. 2022-170509, filed on October 25, 2022, 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] Known examples of fluorinating agents include N-diethylaminosulfur trifluoride (DAST). For example, Non-Patent Document 1 reports that by protecting the NH group in the pyrrole ring of an acylpyrrole compound, DAST causes a deoxyfluorination reaction to synthesize a difluoroalkylpyrrolic compound. DAST also functions as a deoxyfluorinating agent for carboxylic acids and aldehydes. For example, Patent Document 1 reports that DAST produces retinoyl fluoride from retinoic acid and 15,15-difluoroaxerophthene from retinal. However, it is difficult to deoxyfluorinate compounds having a free NH group, such as acylpyrrole compounds, without protecting the NH group.

[0004] In addition, SF4 is also useful as a deoxyfluorination agent, but deoxyfluorination with SF4 requires the coexistence of HF. Therefore, Non-Patent Document 2 describes a more stable and easier-to-use complex of SF4, which is a glyme-coordinated alkali metal ion and SF5. - The use of the salt ([M(G4)n][SF5]) as a deoxyfluorinating agent has been reported. In this literature, it is reported that the deoxyfluorination product was obtained by reacting 3-phenyl-1-propanol with [Cs(G4)2][SF5] in THF, but the yield was low and further improvement is needed. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 4,473,503 [Non-patent literature]

[0006] [Non-Patent Document 1] Wang, et al., Tetrahedron Letters, 1995, vol.36(14), p.2389-2392. [Non-patent document 2] Matsumoto, et al., Inorganic Chemistry, 2018, vol.57, p.14882-14889. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides SF5 stabilized by forming a salt with a glyme-coordinated alkali metal ion under relatively mild conditions. - The present invention aims to provide a method for producing fluorine-containing compounds by using the above compound as a deoxyfluorinating agent to introduce fluorine atoms into a wide variety of oxygen-containing compounds having a ketone group, an aldehyde group, a hydroxy group, or the like. [Means for solving the problem]

[0008] The inventors have investigated the interaction between glyme-coordinated alkali metal ions and SF5 - The present inventors have found that deoxyfluorination using a salt of the formula (I) as a deoxyfluorination agent in a specific solvent can deoxyfluorinate a wide variety of oxygen-containing compounds under relatively mild conditions, thereby completing the present invention.

[0009] That is, the present invention is as follows. [1] The following general formula (E1)

[0010] [ka]

[0011] [In the formula, M represents a cesium ion, a potassium ion, or a rubidium ion; G4 represents tetraethylene glycol dimethyl ether; and n represents an integer of 1 to 4.] and a method for producing a fluorine-containing compound, comprising deoxyfluorinating an oxygen-containing compound having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group in one or more solvents selected from the group consisting of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, tetraethylene glycol dimethyl ether, dimethylacetamide, hexamethylphosphite triamide, and acetonitrile, using a deoxyfluorinating agent represented by the formula (I): [2] The oxygen-containing compound is represented by the following general formula (S1):

[0012] [ka]

[0013] [In the formula, R 1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R 11represents an optionally substituted aliphatic hydrocarbon group having 1 to 30 carbon atoms, an optionally substituted alkoxy group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. The fluorine-containing compound is a compound represented by the following general formula (P1):

[0014] [ka]

[0015] [In the formula, R 11 and R 1 is the same as the general formula (S1). The method for producing the fluorine-containing compound according to [1] above, wherein the compound is a compound represented by the formula: [3] The oxygen-containing compound is represented by the following general formula (S2):

[0016] [ka]

[0017] [In the formula, R 12 represents an optionally substituted aliphatic hydrocarbon group having 1 to 30 carbon atoms, an optionally substituted alkoxy group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. The fluorine-containing compound is a compound represented by the following general formula (P2):

[0018] [ka]

[0019] [In the formula, R 12 is the same as the general formula (S2). The method for producing the fluorine-containing compound according to [1] above, wherein the compound is a compound represented by the formula: [4] The oxygen-containing compound is represented by the following general formula (S3):

[0020] [Chemical formula]

[0021] [In the formula, R 13 is an aliphatic hydrocarbon group having 1 to 30 carbon atoms which may have a substituent] is a compound represented by the above formula, and the fluorine-containing compound is represented by the following general formula (P3)

[0022] [Chemical formula]

[0023] [In the formula, R 13 is the same as the general formula (S3)] is a compound represented by the above formula, and is a method for producing the fluorine-containing compound of [1] above. <000029​​​​​​​​​​​​​​​​​​​​​​​​​ 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. 1-30 The "aliphatic hydrocarbon group" may be a straight chain, a branched chain, or a cyclic group.

[0029] In the present invention and the present specification, "C having a substituent" p1-p2 Aliphatic hydrocarbon group" is C p1-p2 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 aliphatic hydrocarbon group has two or more substituents, the substituents may be the same or different.

[0030] 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 branched chain, or may be a group containing a cyclic structure. 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, triacontyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0031] In the present invention and the present specification, "C 1-10The "C alkyl group" is an alkyl group having 1 to 10 carbon atoms, and may be a straight chain or branched chain group, or may be a group containing a cyclic structure. 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, a decyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

[0032] 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 a straight chain or branched chain, or may be a group containing a cyclic structure. 1-6 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 cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0033] In the present invention and the present specification, "C having a substituent" p1-p2 "Alkyl group" is C p1-p2 One or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms of the 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.

[0034] C 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. Specifically, C 2-30Examples 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.

[0035] In the present invention and the present specification, "C having a substituent" p1-p2 "Alkenyl group" is C p1-p2 One or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms of the alkenyl group are substituted with other functional groups. When the alkenyl group has two or more substituents, the substituents may be the same or different.

[0036] 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 an alkyl group having a linear, branched, or cyclic structure and having 1 to 30 carbon atoms. 1-30 The alkyl group moiety in the alkoxy group may be any of the above C 1-30 The same as the alkyl group can be mentioned.

[0037] 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 an alkyl group having a linear, branched, or cyclic structure and having 1 to 10 carbon atoms. 1-10 The alkyl group moiety in the alkoxy group may be any of the above C 1-10 The same as the alkyl group can be mentioned.

[0038] In the present invention and the present specification, "C having a substituent" p1-p2 The "alkoxy group" is C p1-p2 One or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms of the alkoxy group are substituted with other functional groups. When the alkoxy group has two or more substituents, the substituents may be the same or different.

[0039] In the present invention and the present specification, "C 1-10 "Acyl group" means C 1-9 A group in which a carbonyl group is bonded to an alkyl group. 1-10 The alkyl group moiety in the acyl group is preferably a linear or branched alkyl group having 1 to 9 carbon atoms, more preferably a linear or branched alkyl group having 1 to 6 carbon atoms, even more preferably a linear or branched alkyl group having 1 to 3 carbon atoms, and particularly preferably an acetyl group.

[0040] In the present invention and the present specification, "C having a substituent" p1-p2 "Acyl group" is C p1-p2 One or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms of the acyl group are substituted with other functional groups. When the acyl group has two or more substituents, the substituents may be the same or different.

[0041] In the present invention and this specification, the term "aliphatic heterocyclic group" refers to a group containing an aliphatic heterocycle, i.e., a group in which 1 to 3 carbon atoms forming the cyclic structure of an aliphatic hydrocarbon group containing a cyclic structure are substituted with atoms other than carbon atoms. The aliphatic heterocyclic group may be a group containing a nitrogen atom (nitrogen-containing aliphatic heterocyclic group), a group containing an oxygen atom (oxygen-containing aliphatic heterocyclic group), or a group containing a sulfur atom (sulfur-containing aliphatic heterocyclic group). The aliphatic heterocyclic group may also contain two or more types of atoms other than carbon atoms. Examples of the aliphatic heterocyclic group include a pyrrolidyl group, a piperidyl group, a piperazyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothiophenyl group, a thianyl group, a morpholyl group, a thiomorpholyl group, a dioxanyl group, and a dithianyl group.

[0042] In the present invention and this specification, a "substituted aliphatic heterocyclic group" is a group in which one or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms forming the cyclic structure of the aliphatic heterocyclic group have been substituted with other functional groups. When the aliphatic heterocyclic group has two or more substituents, the substituents may be the same or different.

[0043] In the present invention and this specification, an "aryl group" is a cyclic group having aromaticity, the ring of which is composed only of carbon atoms. 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.

[0044] In the present invention and the present specification, a "substituted aryl group" 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. Examples of the substituents include C 1-6 Alkyl group, C s-6 Alkenyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), nitro group, aldehyde group, C 1-10 Acyl group, optionally substituted amino group, optionally substituted C 6-14 Aryl group and optionally substituted C 6-14 Heteroaryl groups and the like are examples of C groups which may have a substituent. 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 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 4-chlorophenyl group, a 4-bromophenyl group, a 4-nitrophenyl group, a 4-aminophenyl group, a 4-(methylamino)phenyl group, a 4-(dimethylamino)phenyl group, and a 4-(acetylamino)phenyl group.

[0045] 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.

[0046] C 5-14 Examples of nitrogen-containing heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, 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. 5-14 Examples of the heteroaryl group include an oxazolyl group, an isoxazolyl group, a thiazolyl group, and an isothiazolyl group.

[0047] In the present invention and the present specification, a "substituted heteroaryl group" refers to a heteroaryl group in which one or more, preferably 1 to 3, hydrogen atoms bonded to carbon atoms are substituted with other functional groups. When the heteroaryl group has two or more substituents, the substituents may be the same or different. Examples of the substituents include C 1-6 Alkyl group, C s-6 Alkenyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-10 Acyl group, halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), trihalomethyl group, nitro group, aldehyde group, optionally substituted amino group, optionally substituted C 6-14 Aryl group and optionally substituted C 6-14 Examples thereof include heteroaryl groups.

[0048] 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.

[0049] <Deoxygenating Fluorinating Agent> The deoxyfluorinating agent used in the present invention (hereinafter sometimes referred to as the "deoxyfluorinating agent of the present invention") is a compound represented by the following general formula (E1). - The SF5 ion functions as a nucleophilic reagent for the carbon atoms of the ketone group and the carbon atoms bonded to the hydroxyl group, thereby bonding fluorine atoms in place of the oxygen atoms bonded to these carbon atoms. -The ions form salts with the glyme-coordinated alkali metal ions, resulting in improved thermal stability and low-pressure resistance. Specifically, the deoxyfluorinating agent of the present invention is resistant to SF4 elimination even in low-pressure environments, and thermal decomposition at about 100°C is also suppressed. Therefore, the deoxyfluorinating reaction can proceed under relatively mild conditions, and structural restrictions on the substrate to be deoxyfluorinated are alleviated. The deoxyfluorinating agent of the present invention can use a wide variety of oxygen-containing compounds having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group as substrates.

[0050] [ka]

[0051] In general formula (E1), M represents a cesium ion, a potassium ion, or a rubidium ion. G4 represents tetraethylene glycol dimethyl ether (tetraglyme) (CAS No.: 143-24-8), and n represents an integer of 1 to 4. As the deoxyfluorinating agent used in the present invention, a compound in which M represents a cesium ion in general formula (E1) ([Cs(G4)n][SF5]) is preferred, and a compound in which M represents a cesium ion and n is 2 ([Cs(G4)2][SF5]) is particularly preferred.

[0052] <Method of producing fluorine-containing compounds> The method for producing a fluorine-containing compound according to the present invention involves deoxyfluorinating an oxygen-containing compound having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group using the deoxyfluorinating agent of the present invention in one or more solvents selected from the group consisting of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), tetraethylene glycol dimethyl ether (tetraglyme) (G4), dimethylacetamide (DMA), hexamethylphosphorous triamide (HMPA), and acetonitrile (MeCN) to produce the fluorine-containing compound. The deoxyfluorinating agent of the present invention is stable at room temperature but is easily decomposed when the temperature is raised in the solvent. In particular, the deoxyfluorinating agent decomposes at around 60°C in tetrahydrofuran (THF) or dimethyl ether (DME), but is stable up to around 80°C in MeCN, and is hardly decomposed in DMPU, G4, DMA, or HMPA at room temperature to 120°C. In the present invention, a fluorine-containing compound can be efficiently produced by using one or more solvents selected from the group consisting of DMPU, G4, DMA, HMPA, and MeCN as the solvent for the deoxyfluorination reaction. The solvent used in the method for producing a fluorine-containing compound according to the present invention may be one type of solvent or a mixed solvent of two or more types of solvents.

[0053] In the method for producing a fluorine-containing compound according to the present invention, the deoxyfluorination reaction can be carried out by adding a substrate compound and the deoxyfluorinating agent of the present invention to a solvent consisting of one or more compounds selected from the group consisting of DMPU, G4, DMA, and HMPA, and maintaining the mixture at room temperature to 120°C for a predetermined period of time. During the reaction, the temperature of the reaction system may be changed stepwise within a range of room temperature to 120°C. The amounts of the substrate compound and the deoxyfluorinating agent of the present invention added to the reaction system are preferably 0.5 to 100 molar equivalents, more preferably 0.5 to 50 molar equivalents, and even more preferably 0.5 to 10 molar equivalents, of the deoxyfluorinating agent of the present invention per mole of the substrate compound.

[0054] The substrate compound used in the method for producing a fluorine-containing compound according to the present invention is not particularly limited as long as it is an oxygen-containing compound having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group. The oxygen-containing compound may have at least one of an aldehyde group, a ketone group, a carboxy group, and a hydroxy group, and may have two or more of an aldehyde group, a ketone group, a carboxy group, and a hydroxy group. When the oxygen-containing compound has a plurality of aldehyde groups, ketone groups, carboxy groups, and hydroxy groups, the functional groups may be the same, or two or more of the aldehyde groups, ketone groups, carboxy groups, and hydroxy groups may be combined.

[0055] In the method for producing a fluorine-containing compound according to the present invention, for example, when the oxygen-containing compound used as a substrate is a compound represented by the following general formula (S1), a compound represented by the following general formula (P1) can be produced as the fluorine-containing compound.

[0056] [ka]

[0057] In the general formulas (S1) and (P1), R 1 is a hydrogen atom or C 1-6 is an alkyl group. 1 C 1-6 When it is an alkyl group, it is an unsubstituted C 1-6 C which may be an alkyl group and has a substituent 1-6 The substituent may be an alkyl group. There are no particular limitations on the substituent, as long as it is a group that does not inhibit deoxyfluorination by the deoxyfluorinating agent of the present invention. Examples of the substituent include C 1-6 Alkoxy group, C 1-6 Examples of the amino group include an alkylthio group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a trihalomethyl group, a nitro group, and an amino group which may have a substituent. The amino group which may have a substituent is an amino group in which one or two hydrogen atoms of the amino group are replaced by C 1-6 Alkyl group, C1-10 It is a group substituted with an acyl group or the like, and specific examples thereof include a dimethylamino group, a diethylamino group, a methylamino group, an acetylamino group, an acetylmethylamino group, etc. In the method for producing a fluorine-containing compound according to the present invention, the substrate is a group represented by the general formula (E1), R 1 is a hydrogen atom or an unsubstituted C 1-6 It is preferably an alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group, and even more preferably a hydrogen atom or a methyl group.

[0058] In the general formulas (S1) and (P1), R 11 C may have a substituent 1-30 The group is an aliphatic hydrocarbon group, an alkoxy group which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent.

[0059] R 11 C may have a substituent 1-30 In the case of an aliphatic hydrocarbon group, the substituent is not particularly limited as long as it is a group that does not inhibit deoxyfluorination by the deoxyfluorinating agent of the present invention. 1-6 Alkoxy group, C 1-6 Examples of the optionally substituted amino group include alkylthio groups, halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms), trihalomethyl groups, nitro groups, optionally substituted amino groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups. 1 The same groups as those mentioned as the substituents of the above can be used.

[0060] R 11 C may have a substituent 1-30 When the C is an aliphatic hydrocarbon group, the C may have the substituent. 1-30 The aliphatic hydrocarbon group is a C 1-10C which may have an alkyl group or a substituent 2-10 An alkenyl group is preferred, and C may have an optionally substituted aryl group or an optionally substituted heteroaryl group as a substituent. 1-10 C optionally having an alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group as a substituent 2-10 An alkenyl group is more preferred, and C may have an optionally substituted phenyl group as a substituent. 1-10 C optionally having an alkyl group or an optionally substituted phenyl group as a substituent 2-10 An alkenyl group is more preferred. Among them, a methyl group, an ethyl group, a propyl group, or a vinyl group, which may have a phenyl group as a substituent, which may have a substituent, is particularly preferred. Examples of the phenyl group which may have a substituent include a phenyl group having one or more groups as a substituent selected from the group consisting of a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an amino group, a dimethylamino group, a methylamino group, an acetylamino group, a methoxy group, a vinyl group, a propenyl group, a 1-methylvinyl group, and a hydroxy group, and an unsubstituted phenyl group.

[0061] R 11 When is an alkoxy group which may have a substituent, the alkoxy group is, for example, C 1-10 An alkoxy group is preferred, and the alkyl group moiety is a straight-chain or branched C 1-10 An alkoxy group is more preferred, and the alkyl group moiety is a linear C 1-6 Alkoxy groups are more preferred.

[0062] R 11 When is an alkoxy group which may have a substituent, the substituent is not particularly limited as long as it is a group which does not inhibit deoxyfluorination by the deoxyfluorinating agent of the present invention. 1-6 Alkoxy group, C 1-6Examples include an alkylthio group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an aryl group which may have a substituent, and a heteroaryl group which may have a substituent.

[0063] R 11 is an alkoxy group which may have a substituent, the alkoxy group which may have a substituent is, for example, C 1-10 An alkoxy group is preferred, and the alkyl group moiety is linear or branched and may have a substituent. 1-10 An alkoxy group is more preferred, and the alkyl group moiety is linear and may have a substituent. 1-6 An alkoxy group is more preferred. Among them, an alkoxy group in which the alkyl group portion is linear and C 1-6 C optionally having one or more substituents selected from the group consisting of an alkoxy group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, and a phenyl group optionally having a substituent. 1-6 An alkoxy group is preferred, and a C having an optionally substituted phenyl group as a substituent is preferred. 1-6 C having an alkoxy group or an unsubstituted phenyl group as a substituent 1-6 C having no alkoxy group or substituent 1-6 An alkoxy group is more preferred, and a C having an unsubstituted phenyl group as a substituent is more preferred. 1-6 Alkoxy groups are more preferred.

[0064] R 11When is an aliphatic heterocyclic group optionally having a substituent, the aliphatic heterocyclic group is preferably a nitrogen-containing aliphatic heterocyclic group, more preferably a pyrrolidyl group, a piperidyl group, a piperadyl group, or a morpholyl group, and even more preferably a pyrrolidyl group or a piperidyl group. In these nitrogen-containing aliphatic heterocyclic groups, the nitrogen atom forming the heterocycle may be protected with a protecting group. As the protecting group, those used as protecting groups for amines, such as a tert-butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Cbz) group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, an allyloxycarbonyl (Alloc) group, or a 2,2,2-triethoxycarbonyl (Troc) group, can be appropriately used.

[0065] R 11 When is an aliphatic heterocyclic group which may have a substituent, the substituent may be C 1-6 Alkyl group, C s-6 Alkenyl group, C 1-6 Alkoxy group, C 1-6 Examples of the optionally substituted amino group include alkylthio groups, halogen atoms (fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms), trihalomethyl groups, nitro groups, optionally substituted amino groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups. 1 The same groups as those mentioned as the substituents of the above can be used.

[0066] R 11is an aliphatic heterocyclic group which may have a substituent, the aliphatic heterocyclic group which may have a substituent and whose nitrogen atom may be protected by a protecting group is preferred, a pyrrolidyl group or piperidyl group which may have a substituent and whose nitrogen atom may be protected by a protecting group is more preferred, a pyrrolidyl group or piperidyl group which may have a substituent and whose nitrogen atom may be protected by a Boc group or a Cbz group is even more preferred, and a pyrrolidyl group which may have a substituent and whose nitrogen atom may be protected by a Boc group or a Cbz group is even more preferred.

[0067] R 11 is an aryl group which may have a substituent, the aryl group is preferably a phenyl group which may have a substituent or a naphthyl group which may have a substituent, and more preferably a phenyl group which may have a substituent.

[0068] R 11 When is an aryl group which may have a substituent, the substituent may be C 1-6 Alkyl group, C 2-6 Alkenyl group, C 1-6 Alkoxy group, C 2-6 Examples of the amino group that may have a substituent include an acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an amino group that may have a substituent, a hydroxy group, an aryl group, and a heteroaryl group. 1 The same groups as those mentioned as the substituents of the above can be used.

[0069] R 11 is an aryl group which may have a substituent, the aryl group which may have a substituent is preferably a phenyl group which may have a substituent, 1-6 Alkyl group, C 2-6 Alkenyl group, C 1-6 Alkoxy group, C 2-6More preferred is a phenyl group optionally having one or more substituents selected from the group consisting of an acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an amino group, a dimethylamino group, a methylamino group, an acetylamino group, a phenyl group, a halogenated phenyl group (a phenyl group substituted with a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom)), a pyrrolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, an indolyl group, an isoindolyl group, a quinolyl group, an isoquinolyl group, a furanyl group, and a thienyl group.

[0070] R 11 is a heteroaryl group optionally having a substituent, the heteroaryl group is preferably a pyrrolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, an indolyl group, an isoindolyl group, a quinolyl group, an isoquinolyl group, a furanyl group, or a thienyl group, and more preferably a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a pyridyl group, an indolyl group, a quinolyl group, a furanyl group, or a thienyl group.

[0071] R 11 When is an optionally substituted heteroaryl group, the substituents include C 1-6 Alkyl group, C 2-6 Alkenyl group, C 1-6 Alkoxy group, C 2-6 Examples of the alkyl group include an acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a nitro group, an amino group which may have a substituent, a hydroxy group, an aryl group, and a heteroaryl group. 1-6 Alkyl group, C 2-6 Alkenyl group, C 1-6 Alkoxy group, C 2-6 Preferably, the amino group has one or more substituents selected from the group consisting of an acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group which may have a substituent, a hydroxy group, a phenyl group, and a halogenated phenyl group. 1The same groups as those mentioned as the substituents of the above can be used.

[0072] R 11 When is a heteroaryl group which may have a substituent, the heteroaryl group which may have a substituent is preferably a pyrrolyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolyl group, a furanyl group, or a thienyl group, and these heteroaryl groups may have a substituent. 1-6 Alkyl group, C 2-6 Alkenyl group, C 1-6 Alkoxy group, C 2-6 A pyrrolyl group, a pyrazolyl group, an imidazolyl group, a pyridyl group, an indolyl group, a quinolyl group, a furanyl group, or a thienyl group, which may have one or more substituents selected from the group consisting of an acyl group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a dimethylamino group, a methylamino group, an acetylamino group, a phenyl group, and a halogenated phenyl group, is more preferred, and a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a pyridyl group, an indolyl group, a quinolyl group, a furanyl group, or a thienyl group, which may have one or more substituents selected from the group consisting of a halogen atom, a phenyl group, and a halogenated phenyl group, is even more preferred.

[0073] In the method for producing a fluorine-containing compound according to the present invention, for example, when the oxygen-containing compound used as a substrate is a compound represented by the following general formula (S2), a compound represented by the following general formula (P2) can be produced as the fluorine-containing compound.

[0074] [ka]

[0075] In general formulas (S2) and (P2), R 12 C may have a substituent 1-30The alkyl group is an aliphatic hydrocarbon group, an alkoxy group which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. 1-30 The aliphatic hydrocarbon group, the alkoxy group which may have a substituent, the aliphatic heterocyclic group which may have a substituent, the aryl group which may have a substituent, and the heteroaryl group which may have a substituent are each selected from the groups represented by the above-mentioned R 11 The same groups as those listed in the above R 11 The groups that are preferred in the above are preferably used.

[0076] In the method for producing a fluorine-containing compound according to the present invention, for example, when the oxygen-containing compound used as a substrate is a compound represented by the following general formula (S3), a compound represented by the following general formula (P3) can be produced as the fluorine-containing compound.

[0077] [ka]

[0078] In general formulas (S3) and (P3), R 13 C may have a substituent 1-30 It is an aliphatic hydrocarbon group. Specifically, it is a C 1-30 The aliphatic hydrocarbon group includes the above-mentioned R 11 The same groups as those listed in the above R 11 The groups that are preferred in the above are preferably used.

[0079] The hydroxy group in compound (S3) may be protected with a protecting group. The protecting group can be appropriately selected from known protecting groups used as protecting groups for alcohols. Specific examples of the protecting group include a trialkylsilyl group, a tetrahydropyranyl group (THP group), a methoxymethyl ether group (MOM group), a trityl group (Tr group), and a tert-butyl group. Examples of the trialkylsilyl group include a trimethylsilyl group (TMS group), a triethylsilyl group (TES group), a triisopropylsilyl group (TIPS group), and a tritert-butylsilyl group (TBS group). [Example]

[0080] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0081] The NMR apparatus used in the analyses in the examples and the like was a JNM-ECS400 (400 MHz) or ECZ500R (500 MHz) manufactured by JEOL Ltd. 19 In F NMR, the reference value for C6F6 was -162 PPM. The yields (%) described in the examples are in mol%.

[0082] [Manufacturing Example 1] In the following experiments, [Cs(G4)2][SF5] used as a deoxyfluorinating agent was synthesized according to the method of Matsumoto et al. (Non-Patent Document 2).

[0083] [ka]

[0084] [Example 1] The effect of solvent on the deoxyfluorination reaction of silyl-protected alcohols with [Cs(G4)2][SF5] (hereinafter sometimes referred to as "Cs(G4)2SF5") was investigated.

[0085] The following compound (1) was used as the silyl-protected alcohol. The solvents used were G4, THF, DME, diethylene glycol dimethyl ether (CAS No.: 111-96-6) (G2), acetonitrile (MeCN), dimethylformamide (DMF), N-methylpyrrolidone (NMP), DMPU, DMA, HMPA, and dimethyl sulfoxide (DMSO).

[0086] [ka]

[0087] In a glove box filled with argon gas, compound (1) (0.1 mmol) as the starting material (substrate) and 1,4-difluorobenzene (0.5 mmol, 5 μL) as the internal standard were dissolved in a solvent (0.5 mL) in a glass vial to prepare a substrate solution. Solid Cs(G4)2SF5 (0.15 mmol, 1.5 equivalents relative to the substrate) was placed in another glass vial, and the substrate solution was added using a syringe. The mixture was thoroughly mixed to prepare a homogeneous reaction mixture. The resulting reaction mixture was transferred to an NMR tube containing an FEP inlet and sealed with a PTFE plug. The NMR tube was then heated to 60°C to carry out the reaction. The progress of the reaction was monitored by: 19 The reaction was followed by F NMR.

[0088] [Table 1]

[0089] Table 1 shows the reaction time, substrate conversion rate (fluorination rate) (%), and yield (%) calculated from NMR measurement data for each reaction. As shown in Table 1, in the reaction systems using DMPU, G4, DMA, and HMPA as solvents, fluorine-containing compounds were obtained in high yields of over 70% after 72 hours of reaction. Furthermore, when MeCN was used as the solvent, although the conversion rate was low after 22 hours of reaction, decomposition of Cs(G4)2SF5 did not progress and by-products were minimal. In particular, DMPU was the optimal reaction solvent for the deoxyfluorination reaction using Cs(G4)2SF5 because it produced few by-products and very high yields. On the other hand, fluorine-containing compounds were not obtained in THF or DME, in which Cs(G4)2SF5 is easily decomposed.

[0090] [Example 2] Fluorine-containing compounds were synthesized by deoxyfluorination reactions using Cs(G4)2SF5 as a deoxyfluorinating agent and DMPU as a reaction solvent for various substrate compounds.

[0091] In a glove box filled with argon gas, the substrate compound (0.05 mmol) and 1,4-difluorobenzene (0.5 mmol, 5 μL) as an internal standard were dissolved in DMPU (0.4 mL) in a glass vial to prepare a substrate solution. Solid Cs(G4)2SF5 (0.1-0.2 mmol, 2-4 equivalents relative to the substrate) was charged into another glass vial, and the substrate solution was added using a syringe. Mixing thoroughly prepared a homogeneous reaction mixture. The resulting reaction mixture was transferred to an NMR tube containing an FEP inlet and sealed with a PTFE plug. The NMR tube was then heated to a predetermined temperature to carry out the reaction. The progress of the reaction was monitored by 19 The reaction was followed by F NMR.

[0092] The reaction product was isolated as follows. In an argon-filled glove box, the starting material (0.2 mmol) was placed in a PTFE round-bottom test tube containing a stirrer. A solution of Cs(G4)2SF5 (0.4–0.8 mmol, 2–4 equivalents relative to the substrate) in DMPU (1.5 mL) was prepared in a glass vial and placed in the round-bottom test tube. The PTFE round-bottom test tube was sealed with a screw cap and reacted at a predetermined temperature for a predetermined time. The crude reaction mixture was then cooled to room temperature, and water (10 mL) was added. The product was extracted using dichloromethane. The resulting organic layer was washed with water and saturated brine and dehydrated over magnesium sulfate. The solvent was then removed by evaporation to obtain a crude product. The crude product was purified by silica gel column chromatography.

[0093] [Table 2]

[0094] [Table 3]

[0095] [Table 4]

[0096] [Table 5]

[0097] [Table 6]

[0098] [Table 7]

[0099] [Table 8]

[0100] [Table 9] [Industrial Applicability]

[0101] In the method for producing a fluorine-containing compound according to the present invention, SF5 stabilized by forming a salt with a glyme-coordinated alkali metal ion is used. - As a result of using the above as a deoxyfluorinating agent, deoxyfluorination can be carried out under relatively mild conditions on a wide variety of oxygen-containing compounds having a ketone group, an aldehyde group, a hydroxyl group, etc. Therefore, the present invention is useful for synthesizing a wide variety of fluorine-containing compounds.

Claims

1. The following general formula (E1) 【Chemistry 1】 [In the formula, M represents a cesium ion, a potassium ion, or a rubidium ion; G4 represents tetraethylene glycol dimethyl ether; and n represents an integer of 1 to 4.] The present invention relates to a method for producing a fluorine-containing compound, comprising deoxyfluorinating an oxygen-containing compound having an aldehyde group, a ketone group, a carboxy group, or a hydroxy group in one or more solvents selected from the group consisting of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, tetraethylene glycol dimethyl ether, dimethylacetamide, hexamethylphosphite triamide, and acetonitrile, using a deoxyfluorinating agent represented by the formula (I):

2. The oxygen-containing compound is represented by the following general formula (S1): 【Chemistry 2】 [In the formula, R １ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R １１ represents an optionally substituted aliphatic hydrocarbon group having 1 to 30 carbon atoms, an optionally substituted alkoxy group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. The fluorine-containing compound is a compound represented by the following general formula (P1): 【Transformation 3】 [In the formula, R １ and R １１ is the same as the general formula (S1). The method for producing a fluorine-containing compound according to claim 1, wherein the compound is a compound represented by the formula:

3. The oxygen-containing compound is represented by the following general formula (S2): 【Chemistry 4】 [In the formula, R １２ represents an optionally substituted aliphatic hydrocarbon group having 1 to 30 carbon atoms, an optionally substituted alkoxy group, an optionally substituted aliphatic heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. The fluorine-containing compound is a compound represented by the following general formula (P2): 【Transformation 5】 [In the formula, R １２ is the same as the general formula (S2). The method for producing a fluorine-containing compound according to claim 1, wherein the compound is a compound represented by the formula:

4. The oxygen-containing compound is represented by the following general formula (S3): 【Transformation 6】 [In the formula, R １３ represents an aliphatic hydrocarbon group having 1 to 30 carbon atoms which may have a substituent. The fluorine-containing compound is a compound represented by the following general formula (P3): 【Transformation 7】 [In the formula, R １３ is the same as the general formula (S3). The method for producing a fluorine-containing compound according to claim 1, wherein the compound is a compound represented by the formula:

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