Method for producing alkyl fluoride compound, and method for producing optically active alkyl fluoride compound

Abstract

To provide a method for efficiently producing an alkyl fluoride compound by directly converting an aliphatic alkylamine, widely present in nature, into a fluorine substituent.SOLUTION: An alkylamine compound having at least one amino group linked to an alkyl carbon is reacted with a deaminative fluorinating agent to produce an alkyl fluoride compound.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing an alkyl fluoride compound and a method for producing an optically active alkyl fluoride compound. [Background technology]

[0002] Organic compounds containing fluorine, such as alkyl fluoride compounds, often exhibit unique properties due to the electronic and steric effects of fluorine atoms. For this reason, alkyl fluoride compounds are used as particularly useful compounds in the fields of medicine, agricultural chemicals, functional materials, organic synthesis intermediates, etc. In order to express such unique properties, it is important to introduce fluorine groups at appropriate positions, and a method for efficiently substituting various functional groups with fluorine groups is desired.

[0003] Conventionally, alkyl fluoride compounds have generally been synthesized from alcohols or alkyl halide compounds, and the most common synthesis method is the use of a deoxygenating-fluorinating agent. For example, it is known that a deoxygenation-fluorination agent or a dehalogenation-fluorination agent can be used in a reaction for replacing a specific functional group bonded to an alkyl group with a fluorine group.

[0004] There are various methods for synthesizing such alkyl fluoride compounds, and a deoxygenative fluorination reaction of an aliphatic alcohol is commonly used (see, for example, Non-Patent Document 1). In the method disclosed in Non-Patent Document 1, a fluorinating agent reacts with an alcohol, and an oxygen substituent is nucleophilically converted to a fluorine substituent.

[0005] Examples of deoxygenation-fluorination agents used in such a method include diethylaminosulfur trifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride (DeoxoFluor), and 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead).

[0006] In addition to the above, a reaction for replacing a specific functional group bonded to an alkyl group with a fluorine group is also known, for example, in which an alkyl fluoride is synthesized by reacting a nucleophilic fluorine source such as tetrabutylammonium fluoride (TBAF) or potassium fluoride with an alkyl halide compound or a pseudo-alkyl halide compound such as an alkyl sulfonate (see, for example, Non-Patent Document 2).

[0007] On the other hand, no reaction is known for directly deamination fluorination of primary alkylamines. Although the amino group (NH group) on an alkyl group is a structure that is widely and commonly found, particularly in natural products, and there are a wide variety of substituents, only very limited examples of conversion reactions via deamination of primary alkylamines have been reported (see, for example, Non-Patent Documents 3 and 4), and no reaction for directly converting to an alkyl fluoride is known.

[0008] For example, the Balz-Schiemann reaction is known as a method for synthesizing a fluorine compound by converting an amino group into a fluorine substituent, and this is a method for obtaining an aromatic fluorine compound by thermal decomposition of an aromatic diazonium tetrafluoroborate. Although there are known examples of such a reaction for converting an amino group into a fluorine substituent in the case of aromatic alkylamines (for example, see Non-Patent Document 5), a method for synthesizing a fluorine compound by directly converting an aliphatic alkylamine into a fluorine substituent has not been known. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Ayane Sudo; Junichiro Yamaguchi Journal of the Society of Synthetic Organic Chemistry, vol.79, 910-967 (2021). [Non-Patent Document 2] Gabriele Pupo; Veronique Gouverneur. Journal of the American Chemical Society (2022), 144(12), 5200-5213. [Non-Patent Document 3] Kathleen J. Berger; Mark D. Levin. Organic & Biomolecular Chemistry (2020), 19, 11-36. [Non-Patent Document 4] Jiang-Hao Xue; Yin Li; Dong-Hang Tan; Fang-Hai Tu; Yuan Liu; Qingjiang Li; Honggen Wang. iScience (2023), 26(3), 106255. [Non-Patent Document 5] R. Manuel Perez-Garcia; Gaute Gronnevik; Patrick J. Riss. Organic Letters (2021), 23(3), 1011-1015. Summary of the Invention [Problem to be solved by the invention]

[0010] Although methods for synthesizing alkyl fluoride compounds in a stepwise manner as shown in the above-mentioned Non-Patent Documents 1 to 4 and a method for synthesizing alkyl fluoride compounds by directly deamination fluorination of aromatic alkylamines as shown in Non-Patent Document 5 are known, a method for synthesizing alkyl fluoride compounds by directly deamination fluorination of aliphatic alkylamines has not been known.

[0011] The present invention has been made in view of the above-mentioned circumstances, and an object of the present invention is to provide a method for efficiently producing an alkyl fluoride compound by directly converting an aliphatic alkylamine, which is widely present in nature, into a fluorine substituent. [Means for solving the problem]

[0012] The present inventors have newly discovered a synthetic reaction that can produce alkyl fluoride compounds by directly replacing the amino groups constituting primary alkylamine compounds with fluorine groups using a fluorinating agent. That is, by focusing on compounds that have two reactive sites (sulfonyl fluoride groups) in the same molecule, such as the compound represented by FSO2(CF2)3SO2F, and using them as deamination-fluorinating agents, it is possible to directly convert the amino groups into fluorine substituents and efficiently produce alkyl fluoride compounds.

[0013] In order to solve the above problems, the method for producing an alkyl fluoride compound according to aspect 1 of the present invention is characterized in that an alkylamine compound having at least one amino group bonded to an alkyl carbon atom, represented by the following general formula (1), is reacted with a deamination-fluorination agent to produce an alkyl fluoride compound represented by the following general formula (2). [ka] (In the above general formula (1), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocyclic ring having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. In addition, the amino group (-NH2) may form a salt with an acid such as hydrogen halide or sulfuric acid. [ka] (In the above general formula (2), R 1 , R 2 and R 3each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring.

[0014] A second aspect of the present invention is characterized in that in the method for producing an alkyl fluoride compound according to the first aspect, the deamination-fluorination agent is a compound represented by the following general formula (3): [ka] (In the above general formula (3), Rf 1 represents an alkyl group having 1 to 10 carbon atoms and which may have a linear, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or more hydrogen atoms on the carbon are substituted with fluorine; X 1 and X 2 each independently represents a carbonyl group or a sulfonyl group.

[0015] The method for producing an alkyl fluoride compound according to aspect 3 of the present invention is characterized by comprising a first reaction step of reacting an alkylamine compound according to aspect 1 with a deamination-fluorination agent according to aspect 2 to produce an intermediate compound represented by the following general formula (4), and a second reaction step of decomposing the intermediate compound to produce the alkyl fluoride compound according to aspect 1. [ka] (In the above general formula (4), R 1 , R 2 and R 3each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring; Rf 1 represents an alkyl group having 1 to 10 carbon atoms and which may have a linear, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or more hydrogen atoms on the carbon are substituted with fluorine; X 1 and X 2 each independently represents a carbonyl group or a sulfonyl group; M 1 represents hydrogen, metal, or organic quaternary ammonium.)

[0016] A fourth aspect of the present invention is characterized in that in the method for producing an alkyl fluoride compound according to the third aspect, the alkylamine compound is reacted with the deamination-fluorination agent in the presence of a basic substance, thereby allowing the first reaction step and the second reaction step to proceed simultaneously.

[0017] A fifth aspect of the present invention is characterized in that in the method for producing an alkyl fluoride compound according to the fourth aspect, a nucleophilic fluorine source material is further added together with the alkylamine compound, the deamination-fluorination agent, and the basic substance.

[0018] The method for producing an alkyl fluoride compound according to the sixth aspect of the present invention is characterized in that a compound represented by the following general formula (4) is reacted with a deamination-fluorination agent to produce an alkyl fluoride compound represented by the following general formula (2). [ka] (In the above general formula (4), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring; Rf 1 represents an alkyl group having 1 to 10 carbon atoms and which may have a linear, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or more hydrogen atoms on the carbon are substituted with fluorine; X 1 and X 2 each independently represents a carbonyl group or a sulfonyl group; M 1 represents hydrogen, metal, or organic quaternary ammonium.) [ka] (In the above general formula (2), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring.

[0019] The method for producing an optically active alkyl fluoride compound according to embodiment 7 of the present invention is characterized in that an optically active alkylamine compound having at least one amino group bonded to an alkyl carbon atom, represented by the following general formula (5), is reacted with a deamination-fluorination agent to produce an optically active alkyl fluoride compound represented by the following general formula (6). [ka] (In the above general formula (5), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocyclic ring having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. The amino group (-NH2) may form a salt with an acid such as hydrogen halide or sulfuric acid. * represents an asymmetric carbon.) [ka] (In the above general formula (6), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. * represents an asymmetric carbon.) Effect of the Invention

[0020] According to the present invention, it is possible to provide a method for efficiently producing an alkyl fluoride compound by directly converting an aliphatic alkylamine that is widely present in nature into a fluorine substituent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] A method for producing an alkyl fluoride compound and an optically active alkyl fluoride compound according to one embodiment of the present invention will be described below. Note that the following embodiment is specifically described to better understand the gist of the invention, and does not limit the present invention unless otherwise specified.

[0022] [Method for producing fluorinated alkyl compounds] The method for producing an alkyl fluoride compound of the present embodiment involves reacting an alkylamine compound having at least one amino group bonded to an alkyl carbon, represented by the following general formula (1), with a deamination-fluorination agent to produce an alkyl fluoride compound represented by the following general formula (2). [ka] (In the above general formula (1), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocyclic ring having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. In addition, the amino group (-NH2) may form a salt with an acid such as hydrogen halide or sulfuric acid. [ka] (In the above general formula (2), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring.

[0023] In addition, the method for producing an alkyl fluoride compound of the present embodiment may include a first reaction step in which an alkylamine compound of the above general formula (1) is reacted with a deamination-fluorination agent of the following general formula (3) to produce an intermediate compound of the following general formula (4), and a second reaction step in which the intermediate compound is decomposed to produce an alkyl fluoride compound of the above general formula (2). [ka] (In the above general formula (3), Rf 1 represents an alkyl group having 1 to 10 carbon atoms and which may have a linear, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or more hydrogen atoms on the carbon are substituted with fluorine; X 1 and X 2each independently represents a carbonyl group or a sulfonyl group. [ka] (In the above general formula (4), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring; Rf 1 represents an alkyl group having 1 to 10 carbon atoms and which may have a linear, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or more hydrogen atoms on the carbon are substituted with fluorine; X 1 and X 2 each independently represents a carbonyl group or a sulfonyl group; M 1 represents hydrogen, metal, or organic quaternary ammonium.)

[0024] In the above general formulas (1) and (2), specific examples of the alkyl group which may have a substituent or an unsaturated bond include alkyl groups substituted on any carbon atom of the alkyl group with any number and any combination of halogen atoms such as fluorine, chlorine, bromine, and iodine; alkoxy groups such as methoxy, ethoxy, and propoxy; haloalkoxy groups such as fluoromethoxy, chloromethoxy, and bromomethoxy; dialkylamino groups such as dimethylamino, diethylamino, and dipropylamino; alkylthio groups such as methylthio, ethylthio, and propylthio; ester groups such as cyano, nitro, formyl, methyl ester, ethyl ester, and propyl ester; unsaturated groups such as alkenyl and alkynyl; aromatic ring groups such as phenyl and naphthyl; aryloxy groups such as phenoxy and naphthoxy; protected hydroxyl groups, protected amino groups, protected thiol groups, protected carboxyl groups, and the like.

[0025] In the above general formulas (1) and (2), specific examples of the aryl group which may have a substituent or an unsaturated bond include aryl groups substituted on any carbon atom of the aryl group with any number and any combination of halogen atoms such as fluorine, chlorine, bromine, and iodine; alkoxy groups such as methoxy, ethoxy, and propoxy; haloalkoxy groups such as fluoromethoxy, chloromethoxy, and bromomethoxy; dialkylamino groups such as dimethylamino, diethylamino, and dipropylamino; alkylthio groups such as methylthio, ethylthio, and propylthio; ester groups such as cyano, nitro, formyl, methyl ester, ethyl ester, and propyl ester; unsaturated groups such as alkenyl and alkynyl; aromatic ring groups such as phenyl and naphthyl; aryloxy groups such as phenoxy and naphthoxy; protected hydroxyl groups, protected amino groups, protected thiol groups, protected carboxyl groups, and the like.

[0026] In the above general formulas (1) and (2), specific examples of the carbonyl group having an alkyl group which may have a substituent or an unsaturated bond include a carbonyl group having an alkyl group substituted on any carbon atom of the alkyl group with any number and any combination of halogen atoms such as fluorine, chlorine, bromine, and iodine; alkoxy groups such as methoxy, ethoxy, and propoxy; haloalkoxy groups such as fluoromethoxy, chloromethoxy, and bromomethoxy; dialkylamino groups such as dimethylamino, diethylamino, and dipropylamino; alkylthio groups such as methylthio, ethylthio, and propylthio; ester groups such as cyano, nitro, formyl, methyl ester, ethyl ester, and propyl ester; unsaturated groups such as alkenyl and alkynyl; aromatic ring groups such as phenyl and naphthyl; aryloxy groups such as phenoxy and naphthoxy; protected hydroxyl groups, protected amino groups, protected thiol groups, protected carboxyl groups, and the like.

[0027] In the above general formulae (1) and (2), specific examples of the carbonyl group having an aryl group which may have a substituent or an unsaturated bond include a carbonyl group having an aryl group substituted on any carbon atom of the aryl group with any number and any combination of halogen atoms such as fluorine, chlorine, bromine, and iodine; alkoxy groups such as methoxy, ethoxy, and propoxy; haloalkoxy groups such as fluoromethoxy, chloromethoxy, and bromomethoxy; dialkylamino groups such as dimethylamino, diethylamino, and dipropylamino; alkylthio groups such as methylthio, ethylthio, and propylthio; ester groups such as methyl ester, ethyl ester, and propyl ester; unsaturated groups such as alkenyl and alkynyl; aromatic ring groups such as phenyl and naphthyl; aryloxy groups such as phenoxy and naphthoxy; protected hydroxyl groups, protected amino groups, protected thiol groups, protected carboxyl groups, and the like.

[0028] In the above general formulas (3) and (4), specific examples of the fluoroalkyl group, which is an alkyl group having 1 to 10 carbon atoms and which may have a straight chain, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between the carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or all of the hydrogen atoms on the carbon are substituted with fluorine, include a difluoromethylene group, a tetrafluoroethylene group, a trifluoromethylfluoromethyl group, a hexafluoropropylene group, an octafluorobutylene group, and a -CF(CF3)OCF2CF2OCF(CF3)- group.

[0029] The substituent Rf of the deamination-fluorination agent represented by the above general formula (3) 1 ,X 1 ,X 2 For this, FSO2(CF2)3SO2F is the most desirable, but the reaction also proceeds with FSO2(CF2)2SO2F of different chain lengths and FSO2(CF2)3COF, a compound in which the sulfonyl group is replaced with a carbonyl group. However, the reaction does not proceed with the use of FSO2Rf, which is not a bifunctional type that has fluorine functional groups at both ends.

[0030] In addition, by reacting the above-mentioned alkylamine compound with a deamination-fluorination agent in the presence of a basic substance, the first and second reaction steps can proceed simultaneously, thereby making it possible to more efficiently produce an alkyl fluoride compound.

[0031] As described above, specific examples of the basic substance used to simultaneously carry out the first and second reaction steps include trimethylamine, triethylamine, diisopropylamine, tripropylamine, pyridine, 4-dimethylaminopyridine (DMAP), diazacrowndecene (DBU), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), diazabicyclononene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-enepyridine (MTBD), tert-butylimino-tris(dimethylamino)phosphorane, tert-butylimino-tri(pyrrolidino)phosphorane (BTPP), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), etc. Among these, diazacrowndecene (DBU) is particularly preferred.

[0032] The amount of the basic substance used relative to the alkylamine compound represented by the above general formula (1) is in the range of 0.5 to 10 in terms of molar ratio relative to one site of the reactive amino group (NH2-), preferably in the range of 1.5 to 3.0. If the amount of the basic substance used is less than 0.5 in terms of molar ratio, the amount of the fluorinated alkyl compound produced will be lower than the reaction equivalent. In addition, if the amount of the basic substance used is more than 10 in terms of molar ratio, there is a concern that the produced fluorinated alkyl compound will decompose.

[0033] As described above, in order to simultaneously carry out the first and second reaction steps, a nucleophilic fluorine source material can be further added in addition to the alkylamine compound, the deamination-fluorination agent, and the basic substance.

[0034] Specific examples of the above-mentioned nucleophilic fluorine source material include sodium fluoride, potassium fluoride, cesium fluoride, silver fluoride, triethylamine trihydrogen fluoride, pyridine hydrogen fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride (TBAF), tetrabutylammonium difluorotriphenylsilicate (TBAT), etc. Among these, tetrabutylammonium difluorotriphenylsilicate (TBAT) is particularly preferred.

[0035] The amount of the nucleophilic fluorine source material used for the alkylamine compound represented by the above general formula (1) is in the range of 0 to 10 in terms of molar ratio relative to one site of the reactive amino group (NH2-), and preferably in the range of 0.3 to 1.0 in terms of molar ratio. The first and second reaction steps proceed without the addition of a nucleophilic fluorine source material, but the amount (yield) of the fluorinated alkyl compound produced is lower than when the nucleophilic fluorine source material is added. In addition, when the amount of the nucleophilic fluorine source material used exceeds 10 in terms of molar ratio, no further increase in the amount of the fluorinated alkyl compound produced is observed, and only the cost of adding the nucleophilic fluorine source material increases.

[0036] In the first and second reaction steps, the addition ratio of the deamination-fluorination agent, the basic substance, and the nucleophilic fluorine source material to the alkylamine compound is particularly preferably about 2.0:2.0:0.5 (eq), but the addition ratio is not limited thereto.

[0037] As a solvent for dissolving the alkylamine compound used in the first reaction step or the second reaction step, an aprotic solvent can be used. Specific examples of the aprotic solvent include acetonitrile, propionitrile, dimethylformamide, dimethylacetamide, methylformamide, N-methylpyrrolidone, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,3-dioxane, 1,4-dioxane, diglyme, triglyme, dimethyl sulfoxide, sulfolane, pentane, hexane, heptane, octane, cyclohexane, benzene, toluene, xylene, and ethylbenzene. Among these, toluene is particularly preferred as a solvent. Also, a mixture of multiple solvents can be used.

[0038] The reaction temperature in the first reaction step and the second reaction step is preferably in the range of 0° C. or higher and the boiling point of the solvent used to dissolve the alkylamine compound or lower. If the reaction temperature is lower than 0° C., the reaction proceeds slowly. In addition, the first reaction step and the second reaction step are preferably carried out under conditions of refluxing the solvent.

[0039] The reaction time of the first reaction step and the second reaction step is preferably in the range of 1 hour or more and 3 hours or less. However, even if the reaction time is about 30 minutes, 50% or more of the entire reaction has progressed, so the reaction temperature may be less than 1 hour depending on the temperature conditions.

[0040] According to the method for producing a fluorinated alkyl compound of the present embodiment as described above, in order to directly replace the amino group constituting a primary alkylamine compound with a fluorine group, which could not be converted by a conventional fluorinating agent, a compound having two reaction sites in the same molecule is used as a deamination-fluorination agent, thereby making it possible to efficiently produce a fluorinated alkyl compound. This makes it possible to synthesize a fluorine compound that was previously difficult to synthesize, and to simplify the synthesis process. In addition, by using primary alkylamines, which are abundantly present as natural products, as a synthetic raw material, it becomes possible to efficiently produce a fluorinated alkyl compound at low cost.

[0041] [Method for producing optically active alkyl fluoride compounds] The method for producing an optically active alkyl fluoride compound of the present embodiment involves reacting an alkylamine compound having at least one amino group bonded to an alkyl carbon, as represented by the following general formula (5), with a deamination-fluorination agent to produce an alkyl fluoride compound as represented by the following general formula (6). [ka] (In the above general formula (1), R 1 , R 2 and R 3each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocyclic ring having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. The amino group (-NH2) may form a salt with an acid such as hydrogen halide or sulfuric acid. * represents an asymmetric carbon.) [ka] (In the above general formula (2), R 1 , R 2 and R 3 each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, or a carbonyl group having an alkyl group or aryl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, R 1 , R 2 and R 3 may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. * represents an asymmetric carbon.)

[0042] An optically active alkyl fluoride compound is an (optically active) alkyl fluoride compound that can rotate the plane of polarized light, and has optical rotation. The molecular structure of a substance that exhibits optical rotation does not have an inversion axis (center of symmetry, mirror plane, reversion axis), which is a second type of symmetric element, and there exists a structure that is an antipode. For optical isomers to exist, the compound must be chiral, and compounds that have asymmetric carbon atoms in the molecule are often chiral compounds.

[0043] In the method for producing an optically active alkyl fluoride compound of this embodiment, specific examples of the alkyl group which may have a substituent or an unsaturated bond, the aryl group which may have a substituent or an unsaturated bond, the carbonyl group having an alkyl group which may have a substituent or an unsaturated bond, and the carbonyl group having an aryl group which may have a substituent or an unsaturated bond of the above general formulas (5) and (6) can be the same as the respective specific examples relating to the above general formulas (1) and (2) in the method for producing an alkyl fluoride compound described above.

[0044] In addition, specific examples of the deamination-fluorination agent, basic substance, nucleophilic fluorine source material, and solvent in the method for producing an optically active alkyl fluoride compound of this embodiment can be the same as those in the respective specific examples related to the method for producing an alkyl fluoride compound described above.

[0045] Furthermore, the reaction conditions (molar ratio of reaction constituent materials, reaction temperature range, reaction time range) in the method for producing an optically active alkyl fluoride compound of this embodiment can be the same as those in each specific example of the method for producing an alkyl fluoride compound described above.

[0046] Although the embodiments of the present invention have been described above, these embodiments are presented as examples and are not intended to limit the scope of the invention. These embodiments can be implemented in various other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their modifications are included in the scope of the invention and its equivalents described in the claims, as well as in the scope and spirit of the invention. EXAMPLES

[0047] Specific synthesis examples of the present invention are listed below, but these synthesis examples are merely examples and do not limit the present invention. [Example 1] A fluorinated alkyl compound represented by the following formula (8) was synthesized using a primary alkylamine compound represented by the following formula (7). [ka] [ka]

[0048] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 1), and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (8) in a 53% yield. and, 19 F-NMR analysis confirmed that the compound was an alkyl fluoride compound represented by the above formula (8). 19 F-NMR (d2C12) analysis: δ -174.04 to -174.36 (m, 1F).

[0049] [Example 2] A fluorinated alkyl compound represented by the following formula (10) was synthesized using a primary alkylamine compound represented by the following formula (9). [ka] [ka]

[0050] Under a nitrogen atmosphere, 3-phenylpropylamine (67.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 1), and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (10) in a 35% yield. and, 19 F-NMR analysis confirmed that the compound was an alkyl fluoride compound represented by the above formula (10). 19 F-NMR (d2C12) analysis: δ-219.94~-220.32 (m, 1F).

[0051] [Example 3] A fluorinated alkyl compound represented by the following formula (12) was synthesized using a primary alkylamine compound represented by the following formula (11). [ka] [ka]

[0052] Under a nitrogen atmosphere, phenethylamine (60.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, and then quenched with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 1), and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (12) in a 31% yield. and, 19 F-NMR analysis confirmed that the compound was an alkyl fluoride compound represented by the above formula (12). 19 F-NMR (d2C12) analysis: δ-215.02-215.39 (m, 1F).

[0053] [Example 4] A fluorinated alkyl compound represented by the following formula (14) was synthesized using a primary alkylamine compound represented by the following formula (13). [ka] [ka]

[0054] Under a nitrogen atmosphere, 2-(4-chlorophenyl)ethylamine (77.8 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 1), and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (14) in a 44% yield. and, 19 F-NMR analysis confirmed that the compound was an alkyl fluoride compound represented by the above formula (14). 19 F-NMR (d2C12) analysis: δ -215.87 to -216.24 (m, 1F).

[0055] [Example 5] A fluorinated alkyl compound represented by the following formula (16) was synthesized using a primary alkylamine compound represented by the following formula (15). [ka] [ka]

[0056] Under a nitrogen atmosphere, 2-(4-bromophenyl)ethylamine (100.0 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the layers were separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and the obtained organic layer was washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane to hexane / ethyl acetate = 20 / 1), and the solvent was distilled off under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (16) in a 32% yield. and, 19 F-NMR analysis confirmed that the compound was an alkyl fluoride compound represented by the above formula (16). 19 F-NMR (d2C12) analysis: δ -215.88 to -216.25 (m, 1F).

[0057] [Example 6] A fluorinated alkyl compound represented by the following formula (18) was synthesized using a primary alkylamine compound represented by the following formula (17). [ka] [ka]

[0058] Under a nitrogen atmosphere, 2-aminoindan (66.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, and then quenched with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the layers were separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and the obtained organic layer was washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane to hexane / ethyl acetate = 100 / 1), and the solvent was distilled off under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (18) in a 28% yield. and, 19 F-NMR analysis confirmed that the compound was a fluorinated alkyl compound represented by the above formula (18). 19 F-NMR (d2C12) analysis: δ -173.62 to -174.09 (m, 1F).

[0059] [Example 7] A fluorinated alkyl compound represented by the following formula (20) was synthesized using a primary alkylamine compound represented by the following formula (19). [ka] [ka]

[0060] Under a nitrogen atmosphere, 4-phenylbenzylamine (91.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, and then quenched with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 20 / 1), and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (20) in a 14% yield. and, 19 F-NMR analysis confirmed that the compound was a fluorinated alkyl compound represented by the above formula (20). 19 F-NMR (d2C12) analysis: δ-206.29 (t, 1F).

[0061] [Example 8] A fluorinated alkyl compound represented by the following formula (22) was synthesized using a primary alkylamine compound represented by the following formula (21). [ka] [ka]

[0062] Under a nitrogen atmosphere, benzhydrylamine (91.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the layers were separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and the obtained organic layer was washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane to hexane / ethyl acetate = 20 / 1), and the solvent was distilled off under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (22) in a 55% yield. and, 19 F-NMR analysis confirmed that the compound was a fluorinated alkyl compound represented by the above formula (22). 19 F-NMR (d2C12) analysis: δ-166.76 (d, 1F).

[0063] [Example 9] A fluorinated alkyl compound represented by the following formula (24) was synthesized using a primary alkylamine compound represented by the following formula (23). [ka] [ka]

[0064] Under a nitrogen atmosphere, 2-adamantanamine hydrochloride (93.8 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (228.4 mg, 1.5 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane), and the solvent was distilled off under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (24) in a 12% yield. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by the above formula (24). 19 F-NMR (d2C12) analysis: δ -173.81 to -173.97 (m, 1F).

[0065] [Example 10] A fluorinated alkyl compound represented by the following formula (26) was synthesized using a primary alkylamine compound represented by the following formula (25). [ka] [ka]

[0066] Under a nitrogen atmosphere, 1-adamantanamine (75.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, and then quenched with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane), and the solvent was distilled off under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (26) in a 20% yield. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by the above formula (26). 19 F-NMR (d2C12) analysis: δ -128.50 to -128.52 (m, 1F).

[0067] [Example 11] A fluorinated alkyl compound represented by the following formula (28) was synthesized using a primary alkylamine compound represented by the following formula (27). [ka] [ka]

[0068] Under a nitrogen atmosphere, cyclobutylamine (35.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 40° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, and then quenched with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the crude product obtained as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (28) was 12%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by the above formula (28). 19 F-NMR (d2C12) analysis: δ -159.39 to -159.71 (m, 1F).

[0069] [Example 12] A fluorinated alkyl compound represented by the following formula (30) was synthesized using a primary alkylamine compound represented by the following formula (29). [ka] [ka]

[0070] Under a nitrogen atmosphere, cyclopentylamine (42.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 40° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the crude product obtained as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (30) was 41%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by the above formula (30). 19 F-NMR (d2C12) analysis: δ -169.42 to -169.88 (m, 1F).

[0071] [Example 13] A fluorinated alkyl compound represented by the following formula (32) was synthesized using a primary alkylamine compound represented by the following formula (31). [ka] [ka]

[0072] Under a nitrogen atmosphere, cyclohexylamine (49.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 40° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the crude product obtained as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (32) was 2%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (32) above. 19 F-NMR (d2C12) analysis: δ -171.97 to -172.30 (m, 1F).

[0073] [Example 14] A fluorinated alkyl compound represented by the following formula (34) was synthesized using a primary alkylamine compound represented by the following formula (33). [ka] [ka]

[0074] Under a nitrogen atmosphere, cycloheptylamine (56.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to benzene (10 mL) and heated to 80° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the crude product obtained as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (34) was 51%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (34) above. 19 F-NMR (d2C12) analysis: δ -163.25 to -163.57 (m, 1F).

[0075] [Example 15] A fluorinated alkyl compound represented by the following formula (36) was synthesized using a primary alkylamine compound represented by the following formula (35). [ka] [ka]

[0076] Under a nitrogen atmosphere, cyclooctylamine (63.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to benzene (10 mL) and heated to 80° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the crude product obtained as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (36) was 21%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (36) above. 19 F-NMR (d2C12) analysis: δ -158.27 to -158.91 (m, 1F).

[0077] [Example 16] A fluorinated alkyl compound represented by the following formula (38) was synthesized using a primary alkylamine compound represented by the following formula (37). [ka] [ka]

[0078] Under a nitrogen atmosphere, cyclohexanemethylamine (56.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to benzene (10 mL) and heated to 80° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the obtained reaction solution, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the obtained crude product as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (38) was 23%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (38) above. 19 F-NMR (d2C12) analysis: δ -221.92 to -222.22 (m, 1F).

[0079] [Example 17] A fluorinated alkyl compound represented by the following formula (40) was synthesized using a primary alkylamine compound represented by the following formula (39). [ka] [ka]

[0080] Under a nitrogen atmosphere, 4,4-dimethoxybutylamine (66.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the obtained crude product as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (40) was 32%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by the above formula (40). 19 F-NMR (d2C12) analysis: δ -218.18 to -218.57 (m, 1F).

[0081] [Example 18] A fluorinated alkyl compound represented by the following formula (42) was synthesized using a primary alkylamine compound represented by the following formula (41). [ka] [ka]

[0082] Under a nitrogen atmosphere, DL-phenylalanine methyl ester hydrochloride (107.8 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 10 / 1), and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (42) in a 3% yield. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (42) above. 19 F-NMR (d2C12) analysis: δ -189.97~-190.24 (m, 1F).

[0083] [Example 19] A fluorinated alkyl compound represented by the following formula (44) was synthesized using a primary alkylamine compound represented by the following formula (43). [ka] [ka]

[0084] Under a nitrogen atmosphere, 1-Boc-4-piperidinamine (100.1 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane), and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (44) in a 33% yield. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (44) above. 19 F-NMR (d2C12) analysis: δ -181.99 to -182.33 (m, 1F).

[0085] [Example 20] A fluorinated alkyl compound represented by the following formula (46) was synthesized using a primary alkylamine compound represented by the following formula (45). [ka] [ka]

[0086] Under a nitrogen atmosphere, N-(tert-butoxycarbonyl)-1,4-diaminobutane (94.1 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane), and the solvent was removed under reduced pressure to obtain the alkyl fluoride compound represented by the above formula (46) in a 16% yield. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (46) above. 19 F-NMR (d2C12) analysis: δ -218.16 to -218.55 (m, 1F).

[0087] [Example 21] A fluorinated alkyl compound represented by the following formula (48) was synthesized using a primary alkylamine compound represented by the following formula (47). [ka] [ka]

[0088] Under a nitrogen atmosphere, 1,12-diaminododecane (100.2 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (632.3 mg, 2.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (270.0 mg, 0.50 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (304.5 mg, 2.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the layers were separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane to hexane / ethyl acetate = 20 / 1), and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (48) in a 21% yield. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (48) above. 19 F-NMR (d2C12) analysis: δ -217.88 to -218.27 (m, 2F).

[0089] [Example 22] A fluorinated alkyl compound represented by the following formula (50) was synthesized using a primary alkylamine compound represented by the following formula (49). [ka] [ka]

[0090] Under a nitrogen atmosphere, 1,4-butanediol bis(3-aminopropyl)ether (102.2 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (632.3 mg, 2.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (270.0 mg, 0.50 mmol) were added to toluene (10 mL) and heated to 110° C. Diazabicycloundecene (DBU) (304.5 mg, 2.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, followed by quenching with 2M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the obtained reaction solution, and the layers were separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and the obtained organic layer was washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 50 / 1 to hexane / ethyl acetate = 1 / 1), and the solvent was distilled off under reduced pressure to obtain the compound represented by the above formula (50) in a 36% yield. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (50) above. 19 F-NMR (d2C12) analysis: δ -221.68 to -222.07 (m, 2F).

[0091] [Example 23] A fluorinated alkyl compound represented by the following formula (52) was synthesized using a primary alkylamine compound represented by the following formula (51). [ka] [ka]

[0092] Under a nitrogen atmosphere, cis-4-methylcyclohexylamine (56.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to benzene (10 mL) and heated to 80° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, and then quenched with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the crude product obtained as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (52) was 7%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (52) above. 19 F-NMR (d2C12) analysis: δ -169.48~-169.80 (m, 1F).

[0093] [Example 24] A fluorinated alkyl compound represented by the following formula (54) was synthesized using a primary alkylamine compound represented by the following formula (53). [ka] [ka]

[0094] Under a nitrogen atmosphere, trans-4-methylcyclohexylamine (56.6 mg, 0.50 mmol), 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to benzene (10 mL) and heated to 80° C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, and then quenched with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Benzotrifluoride was added to the crude product obtained as an internal standard to determine the NMR yield. The yield of the compound represented by the above formula (54) was 20%. and, 19 F-NMR analysis confirmed that the compound was the alkyl fluoride compound represented by formula (54) above. 19 F-NMR (d2C12) analysis: δ -183.14 to -183.74 (m, 1F).

[0095] [Example 25] A fluorinated alkyl compound represented by the following formula (56) was synthesized using a primary alkylamine compound represented by the following formula (55). [ka] [ka]

[0096] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol) and 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (316.2 mg, 1.0 mmol) were added to toluene (5.0 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which chloroform (10 mL) and benzotrifluoride as an internal standard were added to determine the NMR yield. The yield of the alkyl fluoride compound represented by the above formula (56) was 35%.

[0097] [Example 26] The alkyl fluoride compound represented by the above formula (56) was synthesized using the primary alkylamine compound represented by the above formula (55).

[0098] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol), 1,1,2,2-tetrafluoroethane-1,2-disulfonyl fluoride (266.1 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (5.0 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to this, and after stirring for 1 hour, chloroform (10 mL) and benzotrifluoride as an internal standard were added to determine the NMR yield. The yield of the fluorinated alkyl compound represented by the above formula (56) was 31%.

[0099] [Example 27] The alkyl fluoride compound represented by the above formula (56) was synthesized using the primary alkylamine compound represented by the above formula (55).

[0100] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol) and 2,2,3,3,4,4-hexafluoro-4-(fluorosulfonyl)butanoyl fluoride (280.1 mg, 1.0 mmol) were added to toluene (5.0 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which chloroform (10 mL) and benzotrifluoride as an internal standard were added to determine the NMR yield. The yield of the alkyl fluoride compound represented by the above formula (56) was 3%.

[0101] [Example 28] The primary alkylamine represented by the above formula (55) was reacted with 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride as a deamination-fluorination agent to obtain a reaction product represented by the following formula (57), which was then isolated. The alkyl fluoride compound represented by the above formula (56) was then synthesized. [ka]

[0102] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (149.2 mg, 1.0 mmol) and 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl fluoride (379.4 mg, 1.2 mmol) were added to diisopropyl ether (20 mL). Triethylamine (151.8 mg, 1.5 mmol) was slowly added to the mixture, which was stirred for 27 hours and then quenched with 2M aqueous hydrochloric acid (20 mL) to obtain the reaction product. Chloroform (20 mL) was added to the obtained reaction solution, and the layers were separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and the obtained organic layer was washed twice with saturated aqueous sodium carbonate (20 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane to hexane / ethyl acetate = 20 / 1), and the solvent was removed under reduced pressure to obtain the reaction product represented by the above formula (57) in a 36% yield. and, 19 F-NMR analysis confirmed that the reaction product represented by formula (57) was obtained. 19 F-NMR (d2F) analysis: δ -46.76 to -46.69 (m, 1F), -107.22 to -107.35 (m, 2F), -112.40 to -112.63 (m, 2F), -118.38 to -118.49 (m, 2F).

[0103] Next, under a nitrogen atmosphere, the reactant (160.3 mg, 0.36 mmol) represented by the above formula (51) and TBAT (97.2 mg, 0.18 mmol) were added to toluene (7.2 mL). DBU (54.8 mg, 0.18 mmol) was slowly added thereto, and the mixture was stirred for 1 hour, and then quenched with 2 M aqueous hydrochloric acid (10 mL) to obtain a reaction solution. Chloroform (10 mL) was added to the reaction solution obtained, and the organic layer was separated. The organic layer was washed once with 2M aqueous hydrochloric acid (10 mL), and then washed twice with saturated aqueous sodium carbonate (10 mL). The washed organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by silica gel column chromatography, and the solvent was removed under reduced pressure to obtain the fluorinated alkyl compound represented by the above formula (56) in a 68% yield.

[0104] [Comparative Example 1] When the reaction was carried out using the primary alkylamine compound represented by the above formula (55) without adding a deamination-fluorination agent, the fluorinated alkyl compound represented by the above formula (56) was not produced.

[0105] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol) and tetrabutylammonium difluorotriphenylsilicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (5.0 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which benzotrifluoride was added as an internal standard to determine the NMR yield. As a result, the production of the alkyl fluoride compound represented by the above formula (56) could not be confirmed.

[0106] [Comparative Example 2] When a reaction was carried out using the primary alkylamine compound represented by the above formula (55) and adding (diethylamino)sulfur trifluoride (DAST) instead of the deamination-fluorination agent, the production of the alkyl fluoride compound represented by the above formula (56) was not confirmed.

[0107] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol) and (diethylamino)sulfur trifluoride (DAST) (161.2 mg, 1.0 mmol) were added to toluene (5 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which benzotrifluoride was added as an internal standard to determine the NMR yield. As a result, the production of the alkyl fluoride compound represented by the above formula (56) could not be confirmed.

[0108] [Comparative Example 3] When a reaction was carried out using the primary alkylamine compound represented by the above formula (55) and adding nonafluoro-1-butanesulfonyl fluoride instead of the deamination-fluorination agent, the production of the alkyl fluoride compound represented by the above formula (56) was not confirmed.

[0109] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol) and nonafluoro-1-butanesulfonyl fluoride (302.1 mg, 1.0 mmol) were added to toluene (5 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which benzotrifluoride was added as an internal standard to determine the NMR yield. As a result, the production of the alkyl fluoride compound represented by the above formula (56) could not be confirmed.

[0110] [Comparative Example 4] When a reaction was carried out using the primary alkylamine compound represented by the above formula (55) and adding propane-1,3-disulfonyl fluoride instead of the deamination-fluorination agent, the production of the alkyl fluoride compound represented by the above formula (56) was not confirmed.

[0111] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol), propane-1,3-disulfonyl fluoride (208.0 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which benzotrifluoride was added as an internal standard to determine the NMR yield. As a result, the production of the alkyl fluoride compound represented by the above formula (56) could not be confirmed.

[0112] [Comparative Example 5] When a reaction was carried out using the primary alkylamine compound represented by the above formula (55) and adding 1,2-benzenedisulfonyl fluoride instead of the deamination-fluorination agent, the production of the alkyl fluoride compound represented by the above formula (56) was not confirmed.

[0113] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol), 1,2-benzenedisulfonyl fluoride (242.2 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenyl silicate (TBAT) (135.0 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which benzotrifluoride was added as an internal standard to determine the NMR yield. As a result, the production of the alkyl fluoride compound represented by the above formula (56) could not be confirmed.

[0114] [Comparative Example 6] When a reaction was carried out using the primary alkylamine compound represented by the above formula (55) and adding propane-1,3-disulfonyl chloride instead of the deamination-fluorination agent, the production of the alkyl fluoride compound represented by the above formula (56) was not confirmed.

[0115] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol), propane-1,3-disulfonyl chloride (240.9 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (269.9 mg, 0.50 mmol) were added to toluene (10 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which benzotrifluoride was added as an internal standard to determine the NMR yield. As a result, the production of the alkyl fluoride compound represented by the above formula (56) could not be confirmed.

[0116] [Comparative Example 7] When a reaction was carried out using the primary alkylamine compound represented by the above formula (55) and adding 1,2-benzenedisulfonyl chloride instead of the deamination-fluorination agent, the production of the alkyl fluoride compound represented by the above formula (56) was not confirmed.

[0117] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol), 1,2-benzenedisulfonyl chloride (275.1 mg, 1.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (269.9 mg, 0.50 mmol) were added to toluene (10 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to the mixture and stirred for 1 hour, after which benzotrifluoride was added as an internal standard to determine the NMR yield. As a result, the production of the alkyl fluoride compound represented by the above formula (56) could not be confirmed.

[0118] [Comparative Example 8] When a reaction was carried out using the primary alkylamine compound represented by the above formula (55) and adding trifluoromethanesulfonic anhydride instead of the deamination-fluorination agent, the production of the alkyl fluoride compound represented by the above formula (56) was not confirmed.

[0119] Under a nitrogen atmosphere, 3-amino-1-phenylbutane (74.6 mg, 0.50 mmol), trifluoromethanesulfonic anhydride (564.3 mg, 2.0 mmol), and tetrabutylammonium difluorotriphenylsilicate (TBAT) (134.9 mg, 0.25 mmol) were added to toluene (10 mL) and heated to 110°C. Diazabicycloundecene (DBU) (152.2 mg, 1.0 mmol) was slowly added to this, and after stirring for 1 hour, benzotrifluoride was added as an internal standard to determine the NMR yield. As a result, the production of the fluorinated alkyl compound represented by the above formula (56) could not be confirmed. [Industrial Applicability]

[0120] According to the method for producing an alkyl fluoride compound and an optically active alkyl fluoride compound of the present invention, by using a compound having two reactive sites in the same molecule as a deamination-fluorination agent, primary alkylamines abundant in nature can be used as a synthetic raw material to fluorinate the amino group, thereby providing an alkyl fluoride compound useful as a medicine, an agricultural chemical, a functional material, or an organic synthesis intermediate, and thus has industrial applicability.

Claims

1. A method for producing an alkyl fluoride compound, comprising reacting an alkylamine compound having at least one amino group bonded to an alkyl carbon atom, represented by the following general formula (1), with a deamination-fluorination agent to produce an alkyl fluoride compound represented by the following general formula (2): 【Chemistry 1】 (In the above general formula (1), R １ , R ２ and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, or an aryl group, R １ , R ２ and R ３ may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. ２ ) may form a salt with an acid such as hydrogen halide or sulfuric acid. 【Chemistry 2】 (In the above general formula (2), R １ , R ２ and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, or an aryl group, R １ , R ２ and R ３ may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring.

2. The method for producing an alkyl fluoride compound according to claim 1, wherein the deamination-fluorination agent is a compound represented by the following general formula (3): 【Chemistry 3】 (In the above general formula (3), Rf １ represents an alkyl group having 1 to 10 carbon atoms and which may have a linear, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between the carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or more hydrogen atoms on the carbon are substituted with fluorine; X １ and X ２ each independently represents a carbonyl group or a sulfonyl group.

3. a first reaction step of reacting the alkylamine compound used in the method for producing an alkyl fluoride compound according to claim 1 with the deamination-fluorination agent used in the method for producing an alkyl fluoride compound according to claim 2 to produce an intermediate compound represented by the following general formula (4); and a second reaction step of decomposing the intermediate compound to produce the alkyl fluoride compound of the method for producing an alkyl fluoride compound according to claim 1. 【Chemistry 4】 (In the above general formula (4), R １ , R ２ and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, or an aryl group, R １ , R ２ and R ３ may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring; １ represents an alkyl group having 1 to 10 carbon atoms and which may have a linear, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between the carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or more hydrogen atoms on the carbon are substituted with fluorine; X １ and X ２ each independently represents a carbonyl group or a sulfonyl group; M １ represents hydrogen, metal, or organic quaternary ammonium.)

4. The method for producing an alkyl fluoride compound according to claim 3, characterized in that the alkylamine compound and the deamination-fluorination agent are reacted in the presence of a basic substance, thereby allowing the first reaction step and the second reaction step to proceed simultaneously.

5. The method for producing an alkyl fluoride compound according to claim 4, further comprising adding a nucleophilic fluorine source material together with the alkylamine compound, the deamination-fluorination agent, and the basic substance.

6. A method for producing a fluorinated alkyl compound, comprising reacting a compound represented by the following general formula (4) with a deamination-fluorination agent to produce a fluorinated alkyl compound represented by the following general formula (2): 【Chemistry 5】 (In the above general formula (4), R １ , R ２ and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, or an aryl group, R １ , R ２ and R ３ may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring; １ represents an alkyl group having 1 to 10 carbon atoms and which may have a linear, branched or cyclic structure and which may have 1 to 5 ether-type oxygen atoms or unsaturated bonds between the carbon atoms, or an aryl group having 6 to 14 carbon atoms and which may have a substituent, in which one or more hydrogen atoms on the carbon are substituted with fluorine; X １ and X ２ each independently represents a carbonyl group or a sulfonyl group; M １ represents hydrogen, metal, or organic quaternary ammonium.) 【Chemistry 6】 (In the above general formula (2), R １ , R ２ and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, or an aryl group, R １ , R ２ and R ３ may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring.

7. A method for producing an optically active alkyl fluoride compound, comprising reacting an optically active alkylamine compound having at least one amino group bonded to an alkyl carbon atom, represented by the following general formula (5), with a deamination-fluorination agent to produce an optically active alkyl fluoride compound represented by the following general formula (6): 【Chemistry 7】 (In the above general formula (5), R １ , R ２ and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, or an aryl group, R １ , R ２ and R ３ may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. ２ ) may form a salt with an acid such as hydrogen halide or sulfuric acid. ＊ represents an asymmetric carbon.) 【Chemistry 8】 (In the above general formula (6), R １ , R ２ and R ３ each independently represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, an aryl group, a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 20 carbon atoms which may have a linear, branched or cyclic structure and which may have a substituent or an unsaturated bond, or an aryl group, R １ , R ２ and R ３ may be bonded to each other to form a 3- to 8-membered carbon ring or a 3- to 8-membered heterocycle having one or more heteroatoms such as oxygen, nitrogen, or sulfur in the ring. ＊ represents an asymmetric carbon.)

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