Amino acid having fluorine at α-position, and derivative of same

Abstract

A first purpose of the present invention is to provide an amino acid compound in which the α-position of the amino acid compound is fluorinated by performing a fluorination reaction with respect to the α-position at a high yield. A second purpose of the present invention is to provide an amino acid compound in which the α-position of the amino acid compound is fluorinated by performing a fluorination reaction with respect to the α-position in a highly enantioselective manner. The present invention pertains to: an amino acid having fluorine at the α-position; and a derivative of the same.

Description

Amino acids with fluorine at the α-position and their derivatives

[0001] The present invention relates to an amino acid having a fluorine atom at the α-position and a derivative thereof.

[0002] Patent Document 1 discloses a method for synthesizing an amino acid fluorinated at the α-position by performing a Michael addition reaction utilizing a nitro group.

[0003] Org. Biomol. Chem, 13, 2350-2359, 2015

[0004] A first object of the present invention is to provide an amino acid compound fluorinated at the α-position by carrying out a fluorination reaction at the α-position in high yield.

[0005] A second object of the present invention is to provide an amino acid compound in which the α-position of the amino acid compound is fluorinated by a fluorination reaction at the α-position with high enantioselectivity.

[0006] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that the α-position of an amino acid compound can be fluorinated in high yield and with high enantioselectivity by reacting an amino acid compound in which the amine is protected (Nphth group) with a phthaloyl group (Phth group) with a fluorinating agent such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) in an organic solvent in the presence of a catalyst.

[0007] Based on this finding, the present inventors have conducted further research and have completed the present invention.

[0008] That is, the present invention includes the following fluorinated amino acid compounds and methods for producing the same.

[0009] Item 1. The following general formula (1):

[0010] In formula (1), R represents an alkyl group, an alkoxy group, an aryl group, an ester group, an aralkyl group, an alkenyl group, or an alkynyl group; Nphth represents an N-phthaloyl group:

[0011] Fluorinated amino acid compounds represented by the formula:

[0012] Item 2. The following general formula (2):

[0013] In formula (2), R represents an alkyl group, an alkoxy group, an aryl group, an ester group, an aralkyl group, an alkenyl group, or an alkynyl group; and Nphth represents an N-phthaloyl group:

[0014] The present invention relates to a method for producing a fluorinated amino acid compound represented by the following general formula (3):

[0015] (in formula (3), R and Nphth are the same as in formula (1) above) with a fluorinating agent, and performing a fluorination reaction at the α-position of the compound represented by general formula (3).

[0016] Item 3. The production method according to Item 2, wherein the organic solvent is at least one organic solvent selected from the group consisting of nitrile solvents, nitro solvents, alcohol solvents, halogenated solvents, ether solvents, ester solvents, hydrocarbon solvents, and aromatic solvents.

[0017] Item 4. The production method according to Item 2 or 3, wherein the catalyst is an amine compound.

[0018] Item 5. The production method according to any one of Items 2 to 4, wherein the fluorinating agent is at least one fluorinating agent selected from the group consisting of N-fluorobenzenesulfonimide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, and 2,6-dichloro-1-fluoropyridinium triflate.

[0019] The compounds represented by the general formulas (1) and (2) can be used to synthesize amino acid compounds in which the α-position is fluorinated.

[0020] The compound represented by the general formula (2) can improve the stability of the amino acid compound under the transition state by using an aldehyde compound, and can smoothly proceed with the fluorination of the α-position of the amino acid compound.

[0021] First, the present invention makes it possible to carry out a fluorination reaction at the α-position in high yield to produce an amino acid compound in which the α-position of the amino acid compound is fluorinated.

[0022] Secondly, the present invention makes it possible to carry out a fluorination reaction at the α-position with high enantioselectivity, thereby producing an amino acid compound in which the α-position of the amino acid compound is fluorinated.

[0023] The present invention will be described in detail below.

[0024] In this specification, the terms "comprise" and "contain" are concepts that encompass all of "comprise," "consist essentially of," and "consist only of."

[0025] In this specification, when a numerical range is expressed as "A to B," it means A or more and B or less.

[0026] [1] Method for producing a fluorinated amino acid compound The method for producing a fluorinated amino acid compound of the present invention (a method for producing an amino acid compound in which the α-position of an amino acid compound is fluorinated (hereinafter also referred to as the "production method of the present invention")) comprises a step of mixing an amino acid compound in which the amine is protected (Nphth group) with a phthaloyl group (Phth group) with a fluorinating agent in a liquid phase in the presence of a catalyst, and fluorinating the α-position of the amino acid compound.

[0027] The production method of the present invention makes it possible to stably produce an amino acid compound in which the α-position of the amino acid compound is fluorinated from a raw material amino acid compound in high yield (74% to 99% yield) and with high enantioselectivity (75% ee to 95% ee).

[0028] [1-1] Amino acid compound (substrate, raw material compound) The production method of the present invention includes a step of using an amino acid compound (an amino acid compound in which an amine is protected (Nphth group) with a phthaloyl group (Phth group)) as a substrate and fluorinating the α-position of the amino acid compound.

[0029] The substrate is an amino acid compound having a structure represented by the following general formula (3):

[0030]

[0031] In formula (3), R is an alkyl group, an alkoxy group, an aryl group, an ester group, an aralkyl group, an alkenyl group, or an alkynyl group.

[0032] Nphth is an N-phthaloyl group.

[0033]

[0034] The substrate is stabilized under the transition state by using an aldehyde compound, and fluorination of the α-position of the amino acid compound can be carried out satisfactorily.

[0035] In formula (3), R is an alkyl group, an alkoxy group, an aryl group, an ester group, an aralkyl group, an alkenyl group, an alkynyl group, or the like.

[0036] The alkyl group is preferably a linear, branched, or cyclic alkyl group. Specific examples include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 1-ethylpropyl; linear or branched alkyl groups having 1 to 18 carbon atoms, including n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 5-propylnonyl, n-tridecyl, n-tetradecyl, n-pentadecyl, hexadecyl, heptadecyl, and octadecyl; and cyclic alkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0037] The alkoxy group is preferably a linear, branched or cyclic alkoxy group, and specific examples thereof include linear or branched alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and 1-ethylpropyloxy; n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, n-heptyloxy, and n-octyloxy; linear or branched alkoxy groups having 1 to 18 carbon atoms, such as alkoxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, 5-propylnonyloxy, n-tridecyloxy, n-tetradecyloxy, n-pentadecyloxy, hexadecyloxy, heptadecyloxy, or octadecyloxy; and cyclic alkoxy groups having 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0038] The aryl group is preferably a phenyl, biphenyl, naphthyl, dihydroindenyl, 9H-fluorenyl group, or the like.

[0039] The ester group is preferably a group in which the alkyl group is bonded via an ester bond. The ester group is also referred to as an alkoxycarbonyl group, an alkoxycarbonylalkyl group, or a carboxyalkyl group. The ester group is preferably a methyl ester group (COOMe), an ethyl ester group (COOEt), or the like. The ester group is preferably a 3-carboxypropyl group ((CH2)3COOH), a 3-methyloxycarbonylpropyl group ((CH2)3COOMe), or the like.

[0040] The aralkyl group is preferably a benzyl, phenethyl, trityl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl group, or the like.

[0041] The alkenyl group is preferably an ethenyl group (vinyl group), a 2-propenyl group (allyl group), an isopropenyl group, a butenyl group, an isobutenyl group, a tert-butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octynyl group, an isooctynyl group, a nonenyl group, or the like.

[0042] The alkynyl group is preferably an ethynyl group, a propynyl group, an isopropynyl group, a butynyl group, an isobutynyl group, a tert-butynyl group, a pentynyl group, a hexynyl group, an octynyl group, or a nonynyl group.

[0043] In formula (3), Nphth is an N-phthaloyl group.

[0044]

[0045] The phthaloyl group (Phth group) is a protecting group for imide-based amines. Phthaloyl protection is achieved by dehydration condensation of phthalic anhydride with an amine.

[0046] [1-2] Organic Solvent The production method of the present invention includes a step of fluorinating the α-position of an amino acid compound in which the amine is protected (Nphth group) with a phthaloyl group (Phth group) in an organic solvent.

[0047] The organic solvent is preferably at least one organic solvent selected from the group consisting of nitrile solvents (such as acetonitrile), nitro solvents (such as nitromethane), alcohol solvents (such as hexafluoroisopropanol (HFIP)), halogen-based solvents, ether-based solvents, ester-based solvents, hydrocarbon-based solvents, and aromatic solvents.

[0048] The nitrile solvents include acetonitrile and acrylonitrile.

[0049] The nitro solvents include nitromethane, nitroethane, and nitropropane.

[0050] The alcohol solvent is hexafluoroisopropanol (HFIP), trifluoromethanol, pentafluoroethanol, or the like.

[0051] The halogen-based solvent is preferably dichloromethane (CH2Cl2), trichloromethane (CHCl3), or the like.

[0052] The ether solvent is preferably tetrahydrofuran (THF), dioxane, diethyl ether (Et2O), isopropyl ether (IPE), or the like.

[0053] The ester solvent is preferably ethyl acetate (AcOEt) or the like.

[0054] The hydrocarbon solvent is preferably n-hexane or the like.

[0055] The aromatic solvent is preferably toluene or the like.

[0056] The organic solvent is more preferably acetonitrile, nitromethane, or hexafluoroisopropanol (HFIP).

[0057] The amount of the organic solvent used is adjusted so that the concentration (M (mol / L)) of the substrate amino acid compound having a structure represented by general formula (3) is preferably 0.005 M to 5 M, more preferably 0.05 M to 2 M.

[0058] [1-3] Catalyst The production method of the present invention includes a step of fluorinating the α-position of a substrate amino acid compound having a structure represented by general formula (3) in the presence of a catalyst.

[0059] The catalyst used in the production method of the present invention is preferably the following amine compound.

[0060]

[0061] The catalyst used in the production method of the present invention is preferably the following amine compound.

[0062]

[0063] The catalyst used in the production method of the present invention is preferably an amine compound represented by the following general formula (A):

[0064]

[0065] In formula (A), R is preferably an alkyl group, an aralkyl group, or the like.

[0066] The alkyl group is preferably a linear, branched, or cyclic alkyl group. Specific examples include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 1-ethylpropyl; linear or branched alkyl groups having 1 to 18 carbon atoms, including n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 5-propylnonyl, n-tridecyl, n-tetradecyl, n-pentadecyl, hexadecyl, heptadecyl, and octadecyl; and cyclic alkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0067] The aralkyl group is preferably a benzyl, phenethyl, trityl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl group, or the like.

[0068] In formula (A), R is preferably an alkyl group such as methyl or tert-butyl, or an aralkyl group such as benzyl.

[0069] The catalyst used in the production method of the present invention is preferably an amine compound represented by the following general formula (B):

[0070]

[0071] In formula (B), R and R' may be the same or different and are preferably each a hydrogen atom, an alkyl group, an aralkyl group, or the like.

[0072] The alkyl group is preferably a linear, branched, or cyclic alkyl group. Specific examples include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 1-ethylpropyl; linear or branched alkyl groups having 1 to 18 carbon atoms, including n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 5-propylnonyl, n-tridecyl, n-tetradecyl, n-pentadecyl, hexadecyl, heptadecyl, and octadecyl; and cyclic alkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0073] The aralkyl group is preferably a benzyl, phenethyl, trityl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl group, or the like.

[0074] In formula (B), R and R' may be the same or different and are preferably a hydrogen atom, an alkyl group such as ethyl or tert-butyl, or the like.

[0075] The catalyst used in the production method of the present invention is preferably an amine compound represented by the following general formula (C):

[0076]

[0077] In formula (C), R is preferably an alkyl group, an aralkyl group, or the like.

[0078] The alkyl group is preferably a linear, branched, or cyclic alkyl group. Specific examples include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 1-ethylpropyl; linear or branched alkyl groups having 1 to 18 carbon atoms, including n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 5-propylnonyl, n-tridecyl, n-tetradecyl, n-pentadecyl, hexadecyl, heptadecyl, and octadecyl; and cyclic alkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0079] The aralkyl group is preferably a benzyl, phenethyl, trityl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl group, or the like.

[0080] In formula (A), R is preferably an alkyl group such as methyl or isopropyl, or an aralkyl group such as benzyl.

[0081] In formula (C), n (the number of carbon atoms) is preferably an integer of 0, 1, or 2.

[0082] The catalyst used in the production method of the present invention is preferably an amine compound represented by the following general formula (D):

[0083]

[0084] In formula (D), X is preferably a carbon atom, an oxygen atom, or the like.

[0085] In the production method of the present invention, preferably, at least one amine compound selected from the group consisting of the above-mentioned amine compounds is used.

[0086] The amount of catalyst used in the fluorination reaction is preferably 1 mol % to 50 mol %, more preferably 10 mol % to 40 mol %, and even more preferably 10 mol % to 25 mol %, in terms of molar ratio relative to the substrate amino acid compound having a structure represented by general formula (3) (when the substrate is taken as 100 mol %).

[0087] In the production method of the present invention, by using the above catalyst in the fluorination reaction, it is possible to produce an amino acid compound in which the α-position of the amino acid compound is fluorinated in high yield and with high enantioselectivity.

[0088] [1-4] Fluorinating Agent The production method of the present invention includes a step of mixing a substrate amino acid compound having a structure represented by general formula (3) with a fluorinating agent to fluorinate the α-position of the substrate amino acid compound having a structure represented by general formula (3).

[0089] The fluorinating agent is preferably at least one selected from the group consisting of N-fluorobenzenesulfonimide (NFSI), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor(R)), 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, and 2,6-dichloro-1-fluoropyridinium triflate, more preferably N-fluorobenzenesulfonimide (NFSI) or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), and particularly preferably 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).

[0090] 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) has the following structure:

[0091]

[0092] The amount of catalyst used in the fluorination reaction is preferably 0.1 to 20 equivalents, more preferably 0.9 to 5 equivalents, and even more preferably 1 to 3 equivalents, in molar ratio relative to the amino acid compound having a structure represented by general formula (3) as the substrate (when the substrate is taken as 1 equivalent).

[0093] In the production method of the present invention, by using the above-mentioned fluorinating agent in the fluorination reaction, it is possible to produce an amino acid compound in which the α-position of the amino acid compound is fluorinated in high yield and with high enantioselectivity.

[0094] [1-5] Acidic Compound (TFA, etc.) The production method of the present invention includes a step of fluorinating the α-position of a substrate amino acid compound having a structure represented by general formula (3) in the presence of an acidic compound (TFA, etc.) as a catalyst.

[0095] The catalyst is preferably at least one acidic compound selected from the group consisting of trifluoroacetic acid (TFA), trifluoromethanesulfonic acid (TfOH), sulfuric acid (H2SO4), acetic acid (AcOH), and formic acid (HCOOH).

[0096] The amount of the acidic compound used in the fluorination reaction is, in terms of molar ratio, preferably 1 mol % to 100 mol %, more preferably 5 mol % to 50 mol %, and even more preferably 10 mol % to 30 mol %, as the amount used in the organic solvent (when the entire organic solvent is taken as 100 mol %).

[0097] In the production method of the present invention, by using the above-mentioned acidic compound in the fluorination reaction, an amino acid compound in which the α-position of the amino acid compound is fluorinated can be produced in high yield and with high enantioselectivity.

[0098] [1-6] Step of fluorinating the α-position of an amino acid compound (substrate) According to the production method of the present invention, a compound fluorinated at the α-position of an amino acid compound can be produced from an amino acid compound having a structure represented by general formula (3) as a substrate (starting compound) in high yield (74% to 99% yield) and with high enantioselectivity (75%ee to 95%ee).

[0099] The reaction temperature in the fluorination reaction step is preferably 0°C to 90°C, more preferably 0°C to 60°C, and more preferably 10°C to 35°C (room temperature, etc.).

[0100] The reaction time in the fluorination reaction step is preferably 0.5 to 70 hours, more preferably 10 to 60 hours, and further preferably 20 to 50 hours.

[0101] [1-7] Fluorinated Amino Acid Compound (Target Compound) The production method of the present invention can provide a fluorinated amino acid compound having a structure represented by the following general formula (2).

[0102] General formula (2):

[0103] In formula (2), R represents an alkyl group, an alkoxy group, an aryl group, an ester group, an aralkyl group, an alkenyl group, or an alkynyl group; and Nphth represents an N-phthaloyl group:

[0104] It is.)

[0105] The present invention encompasses a fluorinated amino acid compound having a structure represented by the following general formula (1): By oxidizing a fluorinated amino acid compound having a structure represented by the following general formula (2), a fluorinated amino acid compound having a structure represented by the following general formula (1) can be obtained.

[0106] General formula (1):

[0107] In formula (1), R represents an alkyl group, an alkoxy group, an aryl group, an ester group, an aralkyl group, an alkenyl group, or an alkynyl group; Nphth represents an N-phthaloyl group:

[0108] Fluorinated amino acid compounds represented by the formula:

[0109] [2] Application Examples As an application example of the production method of the present invention, diol compounds, aldol compounds, allyl compounds, etc. can be further produced with high enantioselectivity from the fluorinated amino acid compounds prepared by the production method of the present invention.

[0110] Although the embodiments of the present invention have been described above, the present invention is not limited to these examples and can be embodied in various forms without departing from the spirit and scope of the present invention.

[0111] Hereinafter, the embodiments of the present invention will be described more specifically based on examples.

[0112] The present invention is not limited to these.

[0113] [1] Fluorination Reaction As shown in Scheme 1 and Table 1, the α-position of an amino acid compound (substrate) was fluorinated.

[0114] Organic solvent: Substrate concentration 0.5M / various organic solvents MeCN: Acetonitrile MeNO2: Nitromethane HFIP / MeCN: Hexafluoroisopropanol / Acetonitrile HFIP: Hexafluoroisopropanol Catalyst: Various catalysts 20 mol% / substrate Fluorinating agent: 1.5 equivalents / substrate Fluorinating agent: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor(R)) Acidic compound (additive): Trifluoroacetic acid (TFA) 20 mol% / organic solvent Reaction conditions: Room temperature, 2 to 48 hours

[0115] Fluorinating agents (F + Using N-fluorobenzenesulfonimide (NFSI, F1 compound) as a reagent, in the presence of various catalysts and various organic solvents, a substrate amino acid compound (1a compound) having a structure represented by general formula (3) was subjected to a fluorination reaction to obtain the target compound, a fluorinated amino acid compound (2a compound) having a structure represented by general formula (2).

[0116] The substrate is an amino acid compound having a structure represented by the general formula (3) in which R is a benzyl group (Ph-CH2-, C6H5CH2-).

[0117]

[0118]

[0119] Example: Yield (%) (Catalysts C1 to C15) Fluorination of the α-position of an amino acid compound (compound 1a) was carried out using catalysts C1 to C13 in an organic solvent (MeCN, MeNO2, HFIP / MeCN, or HFIP). When the fluorination reaction of amino acid compound (compound 1a) was carried out using catalysts C1 to C13, a fluorinated amino acid compound (compound 2a) could be produced in high yield.

[0120]

[0121] Example: Enantioselectivity (%ee) (Solvents: MeNO2, HFIP / MeCN, HFIP) The α-position of an amino acid compound (compound 1a) was fluorinated using catalyst C13 in an organic solvent (MeNO2, HFIP / MeCN, or HFIP). When the fluorination reaction of amino acid compound 1a was carried out using catalyst C13 in MeNO2, HFIP / MeCN, or HFIP as the organic solvent, a fluorinated amino acid compound (compound 2a) could be produced with high enantioselectivity.

[0122]

[0123] [2] Scheme 2: Types of Substrates The range of substrates for the amino acid compounds shown in Scheme 2 was examined.

[0124] Organic solvent: substrate concentration 0.5M / solvent HFIP / MeCN = 7 / 3 (v / v, volume ratio) Catalyst: C13 catalyst 20 mol% / substrate Fluorinating agent: 1.5 equivalents / substrate Fluorinating agent: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor(R)) Acidic compound (additive): trifluoroacetic acid (TFA) 30 mol% / organic solvent Reaction conditions: room temperature, 7 to 23 hours The yield indicates the isolated yield.

[0125] The reaction time of the fluorination reaction was measured by monitoring the consumption of β-diketone compound 1 by TLC.

[0126] The enantioselectivity (ee(%)) was determined using HPLC equipped with a chiral stationary phase.

[0127]

[0128] Even when the amino acid compounds represented by substrates 2a to 2s were used as substrates, the enantioselectivity of the fluorinated amino acid compounds in which the α-position was fluorinated was high, and the fluorinated amino acid compounds could be produced in excellent yields.

[0129] [3] Scheme 3: Reference Examples Reference examples (synthetic applications) of fluorinated amino acid compounds produced using the fluorination reaction of the present invention are shown below.

[0130] [3-1] Synthesis of α-fluorinated RG-108 RG-108:

[0131]

[0132] RG-108 is a DNA methyltransferase (N-Phthalyl-L-tryptophan) inhibitor that inhibits the enzyme with an IC50 of 115 nM.

[0133] RG-108 has been shown by molecular modeling to bind directly to the active site of the enzyme.

[0134] RG-108 promotes the reprogramming of human and mouse somatic cells into iPS cells.

[0135] RG-108 has anti-cancer effects as an epigenomic drug.

[0136]

[0137] [3-2] Application to dipeptides

[0138]

[0139] Procedure: (i) NaClO2 (10 equiv), NaH2PO4 (8 equiv), 2-methyl-2-butene (30 equiv), t-BuOH / H2O (v / v = 2 / 1, 0.05 M), rt (ii) DIEP (3.0 equiv), HBTU (1.5 equiv), phenyl alanine methyl ester (1.1 equiv), THF (0.5 M), rt The dipeptide was obtained as two diastereoisomers (17% + 37%).

[0140] According to the method for producing a fluorinated amino acid compound (a compound in which the α-position of an amino acid compound is fluorinated) of the present invention, the fluorination reaction of the amino acid compound can be carried out in high yield and with high enantioselectivity.

[0141] The fluorinated amino acid compounds obtained by the production method of the present invention can be derived into special fluorinated amino acids, and are expected to have a wide range of industrial applications. For example, the fluorinated amino acid compounds obtained by the production method of the present invention can be used as precursors for synthesizing pharmaceuticals and peptides containing amino acids with fluorine at the α-position.

Claims

1. The following general formula (1): 【Chemistry 1】 (In formula (1), R is an alkyl group, alkoxy group, aryl group, ester group, aralkyl group, alkenyl group, or alkynyl group, Nphth is an N-phthaloyl group: 【Chemistry 2】 (That is the case.) A fluorinated amino acid compound represented by [formula].

2. The following general formula (2): 【Transformation 3】 (In formula (2), R is an alkyl group, alkoxy group, aryl group, ester group, aralkyl group, alkenyl group, or alkynyl group, Nphth is an N-phthaloyl group: 【Chemistry 4】 (That is the case.) A method for producing a fluorinated amino acid compound represented by the following: In an organic solvent, in the presence of a catalyst, The following general formula (3): 【Transformation 5】 (In equation (3), R and Nphth are the same as in equation (1) above.) A method for producing a compound represented by the general formula (3), comprising the step of mixing a compound represented by the general formula with a fluorinating agent and fluorinating the α-position of the compound represented by the general formula (3).

3. The manufacturing method according to claim 2, wherein the organic solvent is at least one organic solvent selected from the group consisting of nitrile solvents, nitro solvents, alcohol solvents, halogen solvents, ether solvents, ester solvents, hydrocarbon solvents, and aromatic solvents.

4. The production method according to claim 2 or 3, wherein the catalyst is an amine compound.

5. The method for producing a product according to claim 2 or 3, wherein the fluorinating agent is at least one fluorinating agent selected from the group consisting of N-fluorobenzenesulfonimide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate), 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, and 2,6-dichloro-1-fluoropyridinium triflate.

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