Method for photoisomerization of optically active amino acid

Abstract

Provided is a method for the photoisomerization of an optically active amino acid, the method comprising irradiating an optically active amino acid represented by formula (1) with light in a solvent containing a basic compound. In the formula, R1 represents a protecting group, R2 represents an organic group, R3 and R4 each independently represent a hydrogen atom or an organic group, R5 represents a hydrogen atom or a protecting group, n represents an integer of 0-3, and * represents an asymmetric carbon atom.

Description

Photoisomerization method for optically active amino acids

[0001] The present invention relates to a method for photoisomerizing optically active amino acids.

[0002] Optically active amino acids are important compounds used as intermediates in the production of pharmaceuticals and pesticides, industrial chemicals, food additives, etc. Optically active amino acids can be obtained, for example, by optical resolution of racemic amino acids. However, optical resolution can only obtain the desired enantiomer in a maximum yield of 50%. For this reason, it is desirable to racemize (isomerize) the remaining enantiomers after recovering the desired enantiomer, and then optically resolve the resulting enantiomeric mixture again.

[0003] Conventionally, a method for racemizing (isomerizing) an optically active amino acid has been known, for example, by heating an optically active amino acid in an aqueous solution in the alkaline region in the presence of an alkali metal (see Patent Document 1).

[0004] Japanese Unexamined Patent Publication No. 63-54346

[0005] However, the method described in Patent Document 1 requires heating at a high temperature of 100° C. or higher for about one hour, and is therefore not practical from the standpoint of cost and the like.

[0006] Therefore, an object of the present invention is to provide a method for photoisomerizing optically active amino acids that allows the isomerization reaction to proceed efficiently even at temperatures near room temperature.

[0007] Specific means for solving the above problems include the following embodiments: <1> A method for photoisomerizing an optically active amino acid, comprising irradiating an optically active amino acid represented by the following formula (1) with light in a solvent containing a basic compound: (In the formula, R １ represents a protecting group, and R ２ represents an organic group, and R ３ and R ４ each independently represents a hydrogen atom or an organic group, R ５ represents a hydrogen atom or a protecting group, n represents an integer of 0 to 3, and * represents an asymmetric carbon atom. When n is 2 or 3, n R ３ and R４ may be the same or different from each other.)

[0008] <2> The method for photoisomerizing an optically active amino acid according to <1>, wherein the wavelength of the light is 200 to 500 nm.

[0009] <3> The method for photoisomerizing an optically active amino acid according to <1> or <2>, wherein the reaction temperature during the light irradiation is 0°C or higher and lower than 80°C.

[0010] <4> The method for photoisomerizing an optically active amino acid according to any one of <1> to <3>, wherein the basic compound is an inorganic base.

[0011] <5> The method for photoisomerizing an optically active amino acid according to any one of <1> to <4>, wherein the amount of the basic compound is 0.01 to 5.0 mol per 1 mol of the optically active amino acid represented by formula (1).

[0012] <6> The method for photoisomerizing an optically active amino acid according to any one of <1> to <5>, wherein the optically active amino acid represented by formula (1) is irradiated with light in the presence of a photosensitizer.

[0013] <7> The method for photoisomerizing an optically active amino acid according to <6>, wherein the photosensitizer has a thioxanthone skeleton.

[0014] <8> The method for photoisomerizing an optically active amino acid according to <6> or <7>, wherein the photosensitizer is immobilized on a carrier.

[0015] <9> The photoisomerization method according to any one of <1> to <8>, wherein n in formula (1) is 0.

[0016] <10> The photoisomerization method according to any one of <1> to <9>, wherein the amount of the most abundant stereoisomer is reduced by 5 mol % or more when the total amount of stereoisomers based on asymmetric carbon atoms contained in the optically active amino acid represented by formula (1) is taken as 100 mol %.

[0017] According to the present invention, it is possible to provide a method for photoisomerizing an optically active amino acid, which allows the isomerization reaction to proceed efficiently even at temperatures around room temperature.

[0018] Fig. 1 is a diagram showing the absorption spectrum of thioxanthone as a photosensitizer. Fig. 2 is a diagram showing the absorption spectrum of a photosensitizer in which a substituent has been introduced into thioxanthone. Fig. 3 is a diagram showing the absorption spectrum of a photosensitizer in which a substituent has been introduced into thioxanthone. Fig. 4 is a diagram showing the absorption spectrum of a photosensitizer in which a substituent has been introduced into thioxanthone.

[0019] Hereinafter, specific embodiments of the present invention will be described. In this specification, a numerical range indicated using "to" indicates a range that includes the numerical values ​​written before and after "to."

[0020] <Method for Photoisomerizing Optically Active Amino Acid> The method for photoisomerizing an optically active amino acid according to this embodiment includes irradiating a specific optically active amino acid with light in a solvent containing a basic compound (hereinafter also referred to as a "photoisomerization step").

[0021] [Optical Active Amino Acid] In the method for photoisomerizing an optically active amino acid according to this embodiment, an optically active amino acid represented by the following formula (1) (hereinafter also referred to as a "specific optically active amino acid") is used.

[0022] (In the formula, R １ represents a protecting group, and R ２ represents an organic group, and R ３ and R ４ each independently represents a hydrogen atom or an organic group, R ５ represents a hydrogen atom or a protecting group, n represents an integer of 0 to 3, and * represents an asymmetric carbon atom. When n is 2 or 3, n R ３ and R ４ may be the same or different from each other.)

[0023] In the above formula (1), R １The protecting group represented by the formula (I) is not particularly limited as long as it serves as a protecting group for an amino group, and for example, an electron-withdrawing protecting group is used. Examples of the electron-withdrawing protecting group include sulfonyl protecting groups such as methanesulfonyl group (mesyl group), p-toluenesulfonyl group (tosyl group), o-nitrobenzenesulfonyl group (nosyl group), and trifluoromethanesulfonyl group; acyl protecting groups such as trifluoroacetyl group and pentafluorobenzoyl group; and carbamate protecting groups such as tert-butoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group. From the viewpoint of the efficiency of the isomerization reaction, R １ As the protecting group, a sulfonyl protecting group is preferred, and a methanesulfonyl group and a p-toluenesulfonyl group are more preferred.

[0024] In the above formula (1), R ２ Examples of the organic group represented by the formula (I) include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, and a heteroaryl group; -OR, -C(=O)R, -C(=O)OR, -OC(=O)R, -NHR, and -NR ２ , -C(=NR)R, -C(=NR)NHR, -C(=NR)NR ２ , -SR, -C(=O)NHR, -C(=O)NR ２ , -C(=N-OR)R, -C(=NR)OR, -OC(=NR)R, -OC(=O)NHR, -OC(=O)NR ２ , -NHC(=O)R, -NRC(=O)R, -NHC(=O)OR, -NRC(=O)OR, -NHC(=O)NHR, -NRC(=O)NHR, -NHC(=O)NR ２ , -NRC(=O)NR ２ , -NHC(=NR)R, -NRC(=NR)R, -S(=O) ２ R, -S(=O) ２ OR, -OS (=O) ２ R, -NHS (=O) ２ R, -NRS (=O) ２ R, -NHC(=S)NHR, -NRC(=S)NHR, -NHC(=S)NR ２ , -NRC(=S)NR ２ , -S(=O) ２ NHR, -S (=O)２ NR ２ , -P(=O)R ２ , -P(=O)(OR) ２ , -P(=O)(NHR) ２ , -P(=O)(NR ２ ) ２ , or -SiR ３ (wherein R each independently represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group); and the like.

[0025] Examples of the alkyl group include linear or branched groups having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, and an n-hexyl group.

[0026] Examples of cycloalkyl groups include groups having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, bicyclo[2.2.1]heptyl group, bicyclo[3.2.1]octyl group, and tricyclo[2.2.1.0]heptyl group.

[0027] Examples of the alkenyl group include linear or branched groups having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, such as a vinyl group, an allyl group, a propenyl group, an isopropenyl group, a butenyl group, an isobutenyl group, a 1,3-butadienyl group, a pentenyl group, and a hexenyl group.

[0028] Examples of the alkynyl group include linear or branched groups having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups.

[0029] Examples of the aryl group include monocyclic and fused polycyclic groups having 2 to 4 rings, such as a phenyl group, naphthyl group, anthryl group, phenanthryl group, pyrenyl group, fluorenyl group, indenyl group, acenaphthylenyl group, indanyl group, and acenaphthenyl group.

[0030] Examples of non-aromatic heterocyclic groups include monocyclic nitrogen-containing groups such as an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a piperidyl group, a tetrahydropyridyl group, a homopiperidinyl group, an octahydroazocinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, a piperazinyl group, a homopiperazinyl group, and a 2-piperazinonyl group; monocyclic oxygen-containing groups such as a tetrahydrofuranyl group, a tetrahydropyranyl group, and a pyranyl group; monocyclic nitrogen-oxygen-containing groups such as a morpholinyl group; monocyclic nitrogen-sulfur-containing groups such as a thiomorpholinyl group; an indolinyl group, an isoindolinyl group, a tetrahydroquinolinyl group, a tetrahydroisoquinolinyl group, and a 2,3-dihydrobenzyl group. bicyclic oxygen-containing groups such as a benzofuranyl group, a chromanyl group, a chromenyl group, an isochromanyl group, a 1,3-benzodioxolyl group, a 1,3-benzodioxanyl group, and a 1,4-benzodioxanyl group; bicyclic sulfur-containing groups such as a 2,3-dihydrobenzothienyl group; bicyclic nitrogen-oxygen-containing groups such as a benzomorpholinyl group, a dihydropyranopyridyl group, a dihydrodioxinopyridyl group, and a dihydropyridoxazinyl group; heterocyclic spiro groups such as a 2-azaspiro[3.3]octyl group, a 2-oxaspiro[3.3]octyl group, a 6-aza-2-oxaspiro[3.3]octyl group, a 1-azaspiro[4.5]decyl group, and a 1-oxaspiro[4.5]decyl group; and the like.

[0031] Examples of heteroaryl groups include monocyclic nitrogen-containing groups such as pyrrolyl, pyridyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, and tetrazolyl groups; monocyclic oxygen-containing groups such as furanyl groups; monocyclic sulfur-containing groups such as thienyl; monocyclic nitrogen- and oxygen-containing groups such as oxazolyl, isoxazolyl, and oxadiazolyl groups; monocyclic nitrogen- and sulfur-containing groups such as thiazolyl, isothiazolyl, and thiadiazolyl groups; indolyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrahydroquinolyl, quinolyl, tetrahydroisoquinolyl, and iso bicyclic nitrogen-containing groups such as a quinolyl group, a quinolidinyl group, a cinnolinyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, a naphthyridinyl group, a pyrrolopyridyl group, an imidazopyridyl group, a pyrazolopyridyl group, a pyridopyrazyl group, a purinyl group, and a pteridinyl group; bicyclic oxygen-containing groups such as a benzofuranyl group and an isobenzofuranyl group; bicyclic sulfur-containing groups such as a benzothienyl group; bicyclic nitrogen-oxygen groups such as a benzoxazolyl group, a benzoisoxazolyl group, and a benzoxadiazolyl group; and bicyclic nitrogen-sulfur groups such as a benzothiazolyl group, a benzoisothiazolyl group, a benzothiadiazolyl group, and a thiazolopyridyl group.

[0032] R ２ The organic group represented by the formula (I) may be a group to which one or more of the above-mentioned organic groups are bonded. Examples of the group to which one or more organic groups are bonded include an arylalkyl group and a heteroarylalkyl group.

[0033] Also, R ２ The organic group represented by the formula (R) may be appropriately substituted with one or more groups such as a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), a hydroxy group, a carboxy group, an amino group, a carbamoyl group, a guanidino group, a nitro group, a nitroxy group, a mercapto group, a cyanate group, a thiocyanate group, an isothiocyanate group, a sulfo group, a sulfamino group, a sulfino group, a sulfamoyl group, a phospho group, a phosphono group, or a boronyl group. ２When the organic group represented by the formula (I) has a hydroxy group, a carboxy group, or an amino group as a substituent, the substituent may be protected with a protecting group.

[0034] From the viewpoint of the efficiency of the isomerization reaction, R ２ As the group, a group containing no nitrogen atom is preferred.

[0035] In the above formula (1), R ３ or R ４ As the organic group represented by R ２ Examples of the organic group include the same groups as those represented by the following formula:

[0036] In the above formula (1), R ５ The protecting group represented by the formula (I) is not particularly limited as long as it serves as a protecting group for a carboxy group. Examples of the protecting group include alkyl groups such as a methyl group, an ethyl group, and a tert-butyl group; and arylalkyl groups such as a benzyl group.

[0037] In the above formula (1), n ​​is preferably 0 or 1, and more preferably 0. When n is 0, -COOR ５ is a group represented by R ２ is bonded to the carbon atom to which it is bonded.

[0038] The specific optically active amino acid is R ２ In addition to the asymmetric carbon atom to which R is bonded, R may further have one or more asymmetric carbon atoms. ２ ~R ４ At least one group in may have an asymmetric carbon atom, and R ３ and R ４ (When n is 2 or 3, R ３ and R ４ At least one of the carbon atoms to which is bonded may be an asymmetric carbon atom.

[0039] The absolute configuration of the specific optically active amino acid is not particularly limited. When the specific optically active amino acid has one asymmetric carbon atom, the absolute configuration of the specific optically active amino acid may be either the R-configuration or the S-configuration.

[0040] The specific optically active amino acid is not limited to an optically pure one, and may be a mixture of multiple stereoisomers based on an asymmetric carbon atom. When the specific optically active amino acid has one asymmetric carbon atom, the enantiomeric excess of the specific optically active amino acid may be 20% ee or more, 40% ee or more, 60% ee or more, 80% ee or more, or 90% ee or more.

[0041] [Photoisomerization Step] In the photoisomerization step, a specific optically active amino acid is irradiated with light in a solvent containing a basic compound. ２ After a proton is released from the asymmetric carbon atom to which the isomer is bonded, the isomer rebonds, resulting in the isomerization of the specific optically active amino acid.

[0042] The basic compound may be an inorganic base or an organic base, and is preferably an inorganic base. Examples of inorganic bases include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; metal hydrides such as lithium hydride, sodium hydride, and calcium hydride; and phosphates such as trisodium phosphate and tripotassium phosphate. Among these, metal hydroxides are preferred, and potassium hydroxide is more preferred.

[0043] The solvent is not particularly limited, but an organic solvent that is compatible with water and can dissolve the specific optically active amino acid and basic compound can be used. The organic solvent preferably has a solubility of 25 g or more in 100 g of water (25°C). Examples of the organic solvent include various organic solvents such as sulfoxide solvents such as dimethyl sulfoxide; nitrile solvents such as acetonitrile; ketone solvents such as acetone and 2-butanone; and ester solvents such as ethyl acetate. These organic solvents may be used alone or in combination of two or more. Among these organic solvents, dimethyl sulfoxide and acetonitrile are preferred, and dimethyl sulfoxide is more preferred.

[0044] When an inorganic base is used as the basic compound, water may be used in addition to the organic solvent to dissolve the inorganic base. When a mixed solvent of an organic solvent and water is used, the volume ratio of the organic solvent to water is preferably 2:1 to 100:1, more preferably 5:1 to 50:1, and even more preferably 5:1 to 20:1.

[0045] The concentration of the specific optically active amino acid in the solvent is preferably 0.001 to 0.1 mol / L, more preferably 0.005 to 0.05 mol / L. The amount of the basic compound in the solvent is preferably 0.01 to 5.0 mol, more preferably 0.1 to 5.0 mol, and even more preferably 0.5 to 2.0 mol, relative to 1 mol of the specific optically active amino acid.

[0046] The wavelength of light irradiated onto the specific optically active amino acid is preferably adjusted appropriately depending on the type of specific optically active amino acid, the presence or absence of a photosensitizer (described later), and the like, and may be, for example, 200 to 500 nm, 250 to 450 nm, or 365 to 450 nm. The light irradiation time varies depending on the type of specific optically active amino acid, the wavelength of the irradiated light, the presence or absence of a photosensitizer, and the like, but generally 1 to 30 minutes is sufficient. The light irradiation dose is 500 to 100,000 mJ / cm. ２ It is preferable that the intensity is 1680 to 50400 mJ / cm ２ The reaction temperature is preferably 0°C or higher and lower than 80°C, more preferably 10 to 60°C, even more preferably 10 to 50°C, and particularly preferably 10 to 40°C.

[0047] When the total amount of stereoisomers based on asymmetric carbon atoms contained in the specific optically active amino acid to be subjected to the photoisomerization step is taken as 100 mol %, the amount of the stereoisomer with the largest amount is reduced by, for example, 5 mol % or more through the photoisomerization step.

[0048] As an example, when the specific optically active amino acid to be subjected to the photoisomerization step has one asymmetric carbon atom, the enantiomeric excess of the specific optically active amino acid is reduced by the photoisomerization step by, for example, 10% ee or more, preferably 20% ee or more, and more preferably 30% ee or more.

[0049] [Photosensitizer] In the photoisomerization step, the specific optically active amino acid may be irradiated with light in the presence of a photosensitizer. By irradiating with light in the presence of a photosensitizer, it is possible to further increase the efficiency of isomerization.

[0050] As the photosensitizer, conventionally known photosensitizers can be used. Among these, photosensitizers having a maximum absorption wavelength in the wavelength region of 365 to 450 nm are preferred. Specific examples of the photosensitizer include cyanoarene compounds such as 1,2,4,5-tetracyanobenzene, 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, 6,6'-dicyano-2,2'-bipyridyl, 1,2-dicyanonaphthalene, and 9,10-dicyanoanthracene; pyrylium compounds such as 2,4,6-triphenylpyrylium salts and 2,4,6-triphenylthiopyrylium salts; 10-methyl-9-(2,4,6-trimethylphenyl)acridinium salts; Examples include acridinium compounds such as 3,6-diamino-10-methylacridinium salts; quinone compounds such as 2,3-dichloro-5,6-dicyano-p-benzoquinone and anthraquinone; quinolinium compounds such as 1-methylquinolinium salts and 1-methyl-6-methoxyquinolinium salts; xanthene compounds such as fluorescein and rhodamine B; thiazine compounds such as 10-phenylphenothiazine and methylthioninium salts; and benzophenone compounds such as benzophenone and thioxanthone. Among these, photosensitizers having a thioxanthone skeleton are preferred.

[0051] Thioxanthone has an absorption maximum near 380 nm, and it is known that the introduction of a substituent can shift the absorption maximum wavelength toward longer or shorter wavelengths (see L.D. Elliott et al., J. Am. Chem. Soc., 2020, 142, 14947-14956). The absorption spectrum of thioxanthone is shown in Figure 1A, and the absorption spectra of photosensitizers incorporating various substituents into thioxanthone are shown in Figures 1B to 1D. By using a photosensitizer with a thioxanthone skeleton that has an absorption maximum in the wavelength range of 365 to 450 nm and by setting the wavelength of light irradiated to the specific optically active amino acid to be in the range of 365 to 450 nm, it is possible to further increase the efficiency of isomerization.

[0052] The photosensitizer may be immobilized on a carrier to form a solid-phase photosensitizer. Immobilizing the photosensitizer on a carrier makes it easier to separate the specific optically active amino acid and the photosensitizer after the photoisomerization step. Furthermore, immobilizing the photosensitizer on a carrier makes the photosensitizer less susceptible to decomposition by light irradiation, making it possible to repeatedly use the separated solid-phase photosensitizer. The method of immobilization on the carrier is not particularly limited, and may be a covalent bond or an ionic bond.

[0053] An example of the solid-phase photosensitizer is one represented by the following formula (2):

[0054] (In the formula, R ６ represents an alkyl group, a hydroxy group, or an alkoxycarbonyl group, m represents an integer of 0 to 5, p represents an integer of 1 to 10, q represents an integer of 2 to 10, and X represents a carrier. When m is an integer of 2 to 5, m R ６ may be the same or different.)

[0055] In the above formula (2), R ６ Examples of the alkyl group represented by the formula (I) include linear or branched groups having 1 to 3 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0056] In the above formula (2), R ６Examples of the alkoxycarbonyl group represented by the formula (I) include groups having a linear or branched alkyl moiety having 1 to 3 carbon atoms.

[0057] In the above formula (2), p is preferably an integer of 1 to 8, and more preferably an integer of 1 to 6. q is preferably an integer of 2 to 8, and more preferably an integer of 2 to 6.

[0058] In the above formula (2), examples of the carrier represented by X include silica gel particles, polystyrene particles, etc. The particle diameter of the carrier is preferably 60 to 100 μm.

[0059] Other examples of solid-phase photosensitizers include those represented by the following formula (3):

[0060] (wherein r represents an integer of 1 to 10. R ６ , m, and X are defined as in formula (2) above.

[0061] In the above formula (3), r is preferably an integer of 1 to 8, and more preferably an integer of 1 to 6.

[0062] The present invention will be described in more detail below with reference to examples, but is not limited to these examples. Note that Me, Et, iPr, Ph, Ms, Bn, and Ts shown in the reaction schemes represent methyl, ethyl, isopropyl, phenyl, methanesulfonyl (mesyl), benzyl, and p-toluenesulfonyl (tosyl), respectively.

[0063] <Preparation Example 1: Preparation of solid-phase photosensitizer>

[0064] A dichloromethane solution (5 mL, 0.1 M) containing compound 10 (100 mg, 0.441 mmol), ethyl hydrogen pimelate (91.3 mg, 0.485 mmol, 1.1 equivalents), a condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (109.8 mg, 0.573 mmol, 1.3 equivalents), and a base 4-dimethylaminopyridine (DMAP) (107.8 mg, 0.882 mmol, 2.0 equivalents) was stirred at room temperature (23°C) for 15 hours. Water was added to quench the reaction, and the mixture was extracted with dichloromethane (100 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (CH ２ Cl ２ The mixture was purified using a solvent mixture containing 1,2-dichloromethane and methanol (methanol = 14 / 1 (volume ratio)) to obtain Compound 11 as a yellow solid (yield: 171.8 mg, yield: 98%, mp: 124-126°C).

[0065]

[0066] Sodium hydroxide (177 mg, 4.43 mmol, 10 equivalents) was added to a methanol solution (4 mL, 0.1 M) containing compound 11 (176.1 mg, 0.443 mmol), and the mixture was stirred at room temperature (23°C) for 15 hours. 2N hydrochloric acid was added to stop the reaction, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (CH ２ Cl ２ The mixture was purified using a solvent mixture containing 1,2-dimethyl-3-methyl-2,4-dichloro-1,4-dichloro ...

[0067]

[0068] An N,N-dimethylformamide solution (1 mL) containing compound 12 (25.1 mg, 0.065 mmol, 1.0 equivalent), 3-aminopropyl silica gel (50 mg, 0.03-0.065 mmol, 1.0 equivalent), the condensing agent 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (67.7 mg, 0.13 mmol, 2.0 equivalents), and the base N,N-diisopropylethylamine (55.3 μL, 0.325 mmol, 5.0 equivalents) was stirred at room temperature (23°C) for 15 hours. The solution was then filtered. The resulting solid was added to a 9:1 pyridine:acetic anhydride solution (5 mL), and the mixture was stirred at room temperature (23°C) for 16 hours, after which the solution was filtered. The resulting solid was dried to obtain a solid-phase photosensitizer (immobilized catalyst) 13.

[0069] <Test Example 1: Study of amino group protecting groups (1)>

[0070] Compound (S)-1a (5.15 mg, 0.02 mmol) was added to a septum-capped snap vial, followed by the addition of acetonitrile (2 mL) and water (0.2 mL). Thioxanthone (0.85 mg, 0.004 mmol, 0.2 equivalents) and tripotassium phosphate (4.25 mg, 0.02 mmol, 1.0 equivalents) were then added, followed by argon bubbling for 5 minutes. The mixture was then irradiated with 405 nm light at room temperature (23°C) for 5 minutes while stirring. A photoreactor (PhotoRedOx Box, HepatoChem) equipped with a blue LED (EvoluChem LED 405PF, HepatoChem) was used for the light irradiation. The LED irradiation intensity was 28 mW / cm. ２ The resultant mixture was extracted with ethyl acetate to remove water and tripotassium phosphate, then concentrated, and the isomer ratio was confirmed by high performance liquid chromatography (HPLC). The same procedure as above was carried out except that compound (S)-1b was used instead of compound (S)-1a. The HPLC conditions were as follows: - HPLC conditions - Column: CHIRALPACK IG (manufactured by Daicel Corporation) Mobile phase: acetonitrile Flow rate: 0.5 mL / min Detection: 254 nm

[0071]

[0072] As shown in Table 1, in both cases where a methanesulfonyl group (mesyl group) or a trifluoroacetyl group was used as the amino-protecting group, the isomerization reaction proceeded by irradiation with light at a wavelength of 405 nm at room temperature. In particular, when a methanesulfonyl group was used as the amino-protecting group, the enantiomeric excess decreased to 40% ee after 5 minutes of light irradiation.

[0073] <Test Example 2: Examination of Solvent>

[0074] Compound (S)-1a (5.15 mg, 0.02 mmol) was added to a septum-capped snap vial, followed by the addition of various organic solvents (2 mL) and water (0.2 mL). Thioxanthone (0.85 mg, 0.004 mmol, 0.2 equivalents) and tripotassium phosphate (4.25 mg, 0.02 mmol, 1.0 equivalents) were then added, followed by argon bubbling for 5 minutes. The mixture was then irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 5 minutes while stirring. The same photoreactor as in Test Example 1 was used for the light irradiation. The mixture was then extracted with ethyl acetate to remove water and tripotassium phosphate, concentrated, and the isomer ratio was confirmed in the same manner as in Test Example 1.

[0075]

[0076] As shown in Table 2, when any organic solvent was used, the isomerization reaction proceeded by irradiation with light at a wavelength of 405 nm at room temperature. In particular, when dimethyl sulfoxide (DMSO) was used as the organic solvent, complete racemization was achieved by irradiation with light for 5 minutes.

[0077] <Test Example 3: Study of protecting groups for carboxy groups>

[0078] Compound (R)-2 (6.67 mg, 0.02 mmol) was added to a snap vial with a septum cap, followed by the addition of dimethyl sulfoxide (2 mL) and water (0.2 mL). Thioxanthone (0.85 mg, 0.004 mmol, 0.2 equivalents) and tripotassium phosphate (4.25 mg, 0.02 mmol, 1.0 equivalents) were then added, followed by argon bubbling for 5 minutes. The mixture was then irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 1 minute while stirring. The same photoreactor as in Test Example 1 was used for the light irradiation. The mixture was then extracted with ethyl acetate to remove water and tripotassium phosphate, and then concentrated, and the isomer ratio was confirmed by HPLC. The HPLC conditions were as follows. - HPLC conditions - Column: CHIRALPACK IG (manufactured by Daicel Corporation) Mobile phase: 30% ethanol Flow rate: 0.5 mL / min Detection: 254 nm

[0079] The isomer ratio was confirmed by HPLC, and the ratio of R to S isomers was (R):(S) = 75:25. That is, when the carboxyl protecting group was a benzyl group, the enantiomeric excess decreased to 50% ee by irradiation with light of 405 nm wavelength at room temperature for 1 minute.

[0080] <Test Example 4: Study of photoisomerization using solid-phase photosensitizer>

[0081] Compound (R)-2 (6.67 mg, 0.02 mmol) was placed in a septum-capped snap vial, followed by the addition of dimethyl sulfoxide (2 mL) and water (0.2 mL). Furthermore, solid-phase photosensitizer 13 (10 mg) prepared in Preparation Example 1 and tripotassium phosphate (4.25 mg, 0.02 mmol, 1.0 equivalent) were added, followed by argon bubbling for 5 minutes. Next, the mixture was irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 5 minutes while stirring. The same photoreactor as in Test Example 1 was used for the light irradiation. After that, the mixture was extracted with ethyl acetate to remove water and tripotassium phosphate, after which the solid-phase photosensitizer 13 was removed by filtration, and the isomer ratio was confirmed in the same manner as in Test Example 3.

[0082] The isomer ratio was confirmed by HPLC, and the ratio of R to S isomers was (R):(S) = 70:30. That is, when the solid-phase photosensitizer was used, the enantiomeric excess decreased to 40% ee by irradiation with light at a wavelength of 405 nm at room temperature for 5 minutes.

[0083] <Test Example 5: Examination of amino group protecting groups (2)>

[0084] Compound (S)-1c (6.67 mg, 0.02 mmol) was added to a snap vial with a septum cap, followed by the addition of dimethyl sulfoxide (2 mL) and water (0.2 mL). Thioxanthone (0.85 mg, 0.004 mmol, 0.2 equivalents) and tripotassium phosphate (4.25 mg, 0.02 mmol, 1.0 equivalents) were then added, followed by argon bubbling for 5 minutes. The mixture was then irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 5 minutes while stirring. The same photoreactor as in Test Example 1 was used for the light irradiation. The mixture was then extracted with ethyl acetate to remove water and tripotassium phosphate, and then concentrated, and the isomer ratio was confirmed by HPLC. The HPLC conditions were as follows. - HPLC conditions - Column: CHIRALPACK IG (manufactured by Daicel Corporation) Mobile phase: 50% ethanol Flow rate: 0.5 mL / min Detection: 254 nm

[0085] The isomer ratio was confirmed by HPLC, and the ratio of S to R isomers was (S):(R) = 75:25. That is, when a p-toluenesulfonyl group (tosyl group) was used as the protecting group for the amino group, the enantiomeric excess decreased to 50% ee by irradiation with light at a wavelength of 405 nm at room temperature for 5 minutes.

[0086] Test Example 6: Investigation of basic compounds

[0087] Compound (S)-1c was irradiated with light having a wavelength of 405 nm at room temperature for 5 minutes in the same manner as in Test Example 5, except that the type and amount of the basic compound were variously changed, and then the isomer ratio was confirmed by HPLC.

[0088]

[0089] As shown in Table 3, in both cases where potassium hydroxide and sodium hydroxide were used as the basic compound, the isomerization reaction proceeded by irradiation with light having a wavelength of 405 nm at room temperature, and in particular, the isomerization reaction proceeded more efficiently as the amount of the basic compound increased.

[0090] <Reference Example 1: Deprotection of protecting groups>

[0091] Compound (S)-1c (91.0 mg, 0.27 mmol) and phenol (81.7 mg, 0.81 mmol, 3.0 equivalents) were placed in a 30 mL recovery flask. The mixture was then cooled to 0°C, and 47% aqueous HBr solution (1 mL) was added. The mixture was heated to reflux at 110°C for 3 hours in the presence of argon. After cooling to room temperature, the mixture was extracted with water. The aqueous layer was washed twice with ethyl acetate and then concentrated to obtain compound 3 (60.2 mg, 0.23 mmol, yield 86%) as a brown powder.

[0092] <Test Example 7: Examination of Amino Acid Side Chains (1)>

[0093] Compound (S)-3a (5.15 mg, 0.02 mmol) was placed in a septum-capped snap vial, followed by the addition of dimethyl sulfoxide (2 mL) and water (0.2 mL). Furthermore, 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN) (3.16 mg, 0.004 mmol, 0.2 equivalents) and potassium hydroxide (1.12 mg, 0.02 mmol, 1.0 equivalents) were added. The mixture was then irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 10 minutes while stirring. The same photoreactor as in Test Example 1 was used for the light irradiation. The mixture was then extracted with ethyl acetate to remove water and potassium hydroxide, concentrated, and the isomer ratio was confirmed by HPLC. The HPLC conditions were as follows: - HPLC conditions - Column: CHIRALPACK IG (manufactured by Daicel Corporation) Mobile phase: 50% ethanol Flow rate: 1.0 mL / min Detection: 254 nm

[0094] The isomer ratio was confirmed by HPLC, and as a result, the ratio of S- to R-isomers was S:R = 50:50. That is, compound (S)-3a was completely racemized by irradiation with light at a wavelength of 405 nm at room temperature for 10 minutes.

[0095] <Test Example 8: Examination of Amino Acid Side Chains (2)>

[0096] Compound (S)-3b (5.99 mg, 0.02 mmol) was added to a snap vial with a septum cap, followed by the addition of dimethyl sulfoxide (2 mL) and water (0.2 mL). Furthermore, 4-CzIPN (3.16 mg, 0.004 mmol, 0.2 equivalents) and potassium hydroxide (1.12 mg, 0.02 mmol, 1.0 equivalents) were added. Next, the mixture was irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 10 minutes while stirring. The same photoreactor as in Test Example 1 was used for the light irradiation. After that, the mixture was extracted with ethyl acetate to remove water and potassium hydroxide, and then concentrated, and the isomer ratio was confirmed by HPLC. The HPLC conditions were as follows. - HPLC conditions - Column: CHIRALPACK IG (manufactured by Daicel Corporation) Mobile phase: 50% ethanol Flow rate: 0.5 mL / min Detection: 254 nm

[0097] The isomer ratio was confirmed by HPLC, and the ratio of S- to R-isomers was found to be S:R=53:47. That is, the enantiomeric excess of compound (S)-3b was reduced to 6% ee by irradiation with light having a wavelength of 405 nm at room temperature for 10 minutes.

[0098] <Test Example 9: Examination of Amino Acid Side Chains (3)>

[0099] Compound (S)-3c (5.99 mg, 0.02 mmol) was added to a snap vial with a septum cap, followed by the addition of dimethyl sulfoxide (2 mL) and water (0.2 mL). Furthermore, 4-CzIPN (3.16 mg, 0.004 mmol, 0.2 equivalents) and potassium hydroxide (1.12 mg, 0.02 mmol, 1.0 equivalents) were added. Next, the mixture was irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 10 minutes while stirring. The same photoreactor as in Test Example 1 was used for the light irradiation. After that, the mixture was extracted with ethyl acetate to remove water and potassium hydroxide, and then concentrated, and the isomer ratio was confirmed by HPLC. The HPLC conditions were as follows. - HPLC conditions - Column: CHIRALPACK IG (manufactured by Daicel Corporation) Mobile phase: 50% ethanol Flow rate: 0.5 mL / min Detection: 254 nm

[0100] The isomer ratio was confirmed by HPLC, and the ratio of S- to R-isomers was found to be S:R=56:44. That is, the enantiomeric excess of compound (S)-3c was reduced to 12% ee by irradiation with light having a wavelength of 405 nm at room temperature for 10 minutes.

[0101] Test Example 10: Examination of photoisomerization when photosensitizer is used repeatedly

[0102] Compound (S)-1c (6.67 mg, 0.02 mmol) was added to a septum-capped snap vial, followed by the addition of dimethyl sulfoxide (2 mL) and water (0.2 mL). Thioxanthone (0.85 mg, 0.004 mmol, 0.2 equivalents) and potassium hydroxide (1.12 mg, 0.02 mmol, 1.0 equivalents) were then added, followed by argon bubbling for 5 minutes. The mixture was then irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 20 minutes while stirring. The same photoreactor as in Test Example 1 was used for the light irradiation. 100 μL of the reaction solution was dispensed, extracted with ethyl acetate to remove water and potassium hydroxide, then concentrated, and the isomer ratio was confirmed by HPLC. The resulting ratio of the S- and R-isomers was S:R = 55:45 (10% ee). The HPLC conditions were as follows: - HPLC conditions - Column: CHIRALPACK IG (manufactured by Daicel Corporation) Mobile phase: 50% ethanol Flow rate: 0.5 mL / min Detection: 254 nm

[0103] Next, compound (S)-1c (6.67 mg, 0.02 mmol) was added to the reaction solution and stirred thoroughly. 100 μL of the reaction solution was dispensed and extracted with ethyl acetate to remove water and potassium hydroxide, then concentrated, and the isomer ratio was confirmed by HPLC in the same manner as above. As a result, the ratio of the S- and R-configurations was S:R=88:12 (76% ee).

[0104] While stirring, the reaction solution was again irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 10 minutes. 100 μL of the reaction solution was dispensed and extracted with ethyl acetate to remove water and potassium hydroxide, then concentrated. The isomerization ratio was confirmed by HPLC in the same manner as above. The resulting ratio of S- to R-isomers was S:R = 84:16 (68% ee). At this time, decomposition of thioxanthone was observed in the reaction solution, and the ratio of thioxanthone to its decomposition products in the solution was 60:40.

[0105] Test Example 11: Investigation of photoisomerization when solid-phase photosensitizer is repeatedly used

[0106] Compound (S)-1c (6.67 mg, 0.02 mmol) was placed in a septum-capped snap vial, followed by the addition of dimethyl sulfoxide (2 mL) and water (0.2 mL). Furthermore, solid-phase photosensitizer (10 mg) and potassium hydroxide (1.12 mg, 0.02 mmol, 1.0 equivalent) were added, and argon bubbling was performed for 5 minutes. Next, while stirring, the mixture was irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 20 minutes. The same photoreactor as in Test Example 1 was used for the light irradiation. 100 μL of the reaction solution was dispensed, extracted with ethyl acetate to remove water and potassium hydroxide, and then concentrated. Furthermore, filtration was performed to remove the solid-phase photosensitizer, and the isomer ratio was confirmed by HPLC. The resulting ratio of the S- and R-isomers was S:R = 61:39 (22% ee). The HPLC conditions were as follows: - HPLC conditions - Column: CHIRALPACK IG (manufactured by Daicel Corporation) Mobile phase: 50% ethanol Flow rate: 0.5 mL / min Detection: 254 nm

[0107] Next, compound (S)-1c (6.67 mg, 0.02 mmol) was added to the reaction solution and stirred thoroughly. 100 μL of the reaction solution was dispensed, extracted with ethyl acetate to remove water and potassium hydroxide, and then concentrated. Furthermore, after filtration to remove the solid-phase photosensitizer, the isomer ratio was confirmed by HPLC in the same manner as above. As a result, the ratio of the S- and R-isomers was S:R = 92:8 (84% ee).

[0108] While stirring, the reaction solution was again irradiated with light at a wavelength of 405 nm at room temperature (23°C) for 10 minutes. 100 μL of the reaction solution was dispensed, extracted with ethyl acetate to remove water and potassium hydroxide, and then concentrated. After filtration to remove the solid-phase photosensitizer, the isomerization ratio was confirmed by HPLC in the same manner as above. The resulting ratio of S- and R-isomers was S:R = 85:15 (70% ee). No leakage of decomposition products from the solid-phase photosensitizer was observed.

Claims

1. A method for photoisomerizing an optically active amino acid, comprising irradiating an optically active amino acid represented by the following formula (1) with light in a solvent containing a basic compound: (In the formula, R １ represents a protecting group, R ２ represents an organic group; R ３ and R ４ each independently represents a hydrogen atom or an organic group; R ５ represents a hydrogen atom or a protecting group, n represents an integer of 0 to 3, and * represents an asymmetric carbon atom. When n is 2 or 3, n R ３ and R ４ may be the same or different from each other.) 2. The method for photoisomerizing an optically active amino acid according to claim 1, wherein the wavelength of the light is 200 to 500 nm.

3. The method for photoisomerizing an optically active amino acid according to claim 1 or 2, wherein the reaction temperature during the irradiation with light is 0°C or higher and lower than 80°C.

4. The method for photoisomerizing an optically active amino acid according to claim 1 or 2, wherein the basic compound is an inorganic base.

5. The method for photoisomerizing an optically active amino acid according to claim 1 or 2, wherein the amount of the basic compound is 0.01 to 5.0 mol per 1 mol of the optically active amino acid represented by formula (1).

6. A method for photoisomerizing an optically active amino acid according to claim 1 or 2, which comprises irradiating the optically active amino acid represented by formula (1) with light in the presence of a photosensitizer.

7. The method for photoisomerizing an optically active amino acid according to claim 6, wherein the photosensitizer has a thioxanthone skeleton.

8. The method for photoisomerizing an optically active amino acid according to claim 6, wherein the photosensitizer is immobilized on a carrier.

9. The photoisomerization method according to claim 1 or 2, wherein n in formula (1) is 0.

10. The photoisomerization method according to claim 1 or 2, wherein the amount of the most abundant stereoisomer is reduced by 5 mol % or more when the total amount of stereoisomers based on asymmetric carbon atoms contained in the optically active amino acid represented by formula (1) is taken as 100 mol %.

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