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WO2010090341A1 - Method of manufacturing optically active trans-4-aminopiperidine-3-ol compound - Google Patents

Method of manufacturing optically active trans-4-aminopiperidine-3-ol compound Download PDF

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WO2010090341A1
WO2010090341A1 PCT/JP2010/052008 JP2010052008W WO2010090341A1 WO 2010090341 A1 WO2010090341 A1 WO 2010090341A1 JP 2010052008 W JP2010052008 W JP 2010052008W WO 2010090341 A1 WO2010090341 A1 WO 2010090341A1
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formula
carbon atoms
substituted
represented
optically active
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Japanese (ja)
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徳田修
池本哲哉
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing optically active substituted trans-4-aminopiperidin-3-ol by optical resolution of substituted trans-4-aminopiperidin-3-ol.
  • an optically active trans-4-aminopiperidin-3-ol compound used as a raw material for synthesis of pharmaceuticals a chiral ligand used for stereoselective chemical reaction, etc., for example, it is a starting material
  • An optically active 2-pyrrolidinemethanol derivative is obtained from optically active pyroglutaminol through several steps, and this is reacted with trifluoroacetic anhydride and a base at ⁇ 78 ° C. (Synth. Commun. 28, 4471 (1998)).
  • problems such as including a reaction that is not easy to implement industrially, and development of a more industrially advantageous production method has been demanded.
  • R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms.
  • R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms.
  • a substituted trans-4-aminopiperidin-3-ol (substituted trans-4-aminopiperidin-3-ol (1)) represented by formula (2) (Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
  • R 3 represents a protecting group
  • R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms
  • * represents that the carbon atom is an asymmetric carbon atom.
  • the optical resolution method of substituted trans-4-aminopiperidin-3-ol which comprises the step of reacting with an optically active N-protected amino acid represented by the formula (optically active N-protected amino acid (2))
  • Substituted trans-4-aminopiperidin-3-ol can be advantageously produced
  • the present invention is as follows.
  • a substituted trans-4-aminopiperidin-3-ol (1) is reacted with an optically active N-protected amino acid (2) in a solvent to obtain a compound of formula (3) (In the formula, R 1 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
  • the optically active substituted trans-4-aminopiperidin-3-ol (optically active substituted trans-4-aminopiperidin-3-ol (4)) shown by these.
  • a substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3).
  • R 3 is an optionally substituted (hydrocarbyl having 1 to 12 carbons) carbonyl group or an optionally substituted hydrocarbylsulfonyl group having 1 to 12 carbons [wherein the substituent is carbon A group consisting of an alkoxy group having 1 to 6 carbon atoms, (alkoxy having 1 to 6 carbon atoms) carbonyl group, alkanoyl group having 1 to 6 carbon atoms, alkanoyloxy group having 1 to 6 carbon atoms, halogen atom, nitro group and cyano group One or more substituents selected from the above. ] The method according to [1] or [2].
  • a substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3).
  • the diastereomeric salt (3) thus obtained is further treated with an acid or a base to give an optically active substituted trans-4-aminopiperidin-3-ol (4).
  • R 5 represents an alkyl group having 1 to 12 carbon atoms, and X represents a halogen atom.
  • a halocarbonate (halocarbonate (9)) or formula (10) (Wherein R 5 represents the same meaning as described above.)
  • a dialkyl dicarbonate (dialkyl dicarbonate (10)) represented by formula (11) (In the formula, R 1 , R 2 , R 5 and * represent the same meaning as described above.)
  • a substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3).
  • the diastereomeric salt (3) thus obtained is further treated with an acid or a base to give an optically active substituted trans-4-aminopiperidin-3-ol (4).
  • a substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3).
  • the obtained diastereomeric salt (3) is further treated with an acid or a base to give an optically active substituted trans-4-aminopiperidin-3-ol (4).
  • optically active compound (11) (14)
  • R 1 , R 5 and * represent the same meaning as described above.
  • the manufacturing method of the optically active compound shown by these.
  • a substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3).
  • the diastereomeric salt (3) thus obtained is further treated with an acid or a base to give an optically active substituted trans-4-aminopiperidin-3-ol (4).
  • the manufacturing method of the optically active compound (optically active compound (15)) shown by these. [14] Diastereomeric salt (3).
  • the process for producing optically active substituted trans-4-aminopiperidin-3-ol (4) comprises substituted trans-4-aminopiperidin-3-ol (1) and optically active N-protection in a solvent.
  • the reaction is carried out by reacting with the amino acid (2) to obtain a crystal of the diastereomeric salt (3).
  • R 1 Examples of the alkyl group having 1 to 5 carbon atoms represented by the formula include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, and a pentyl group.
  • an allyl group can be mentioned.
  • the aryl group having 6 to 10 carbon atoms that can be a substituent of the alkyl group having 1 to 5 carbon atoms or the alkenyl group having 3 to 6 carbon atoms include, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and the like.
  • R 2 Is a group in which the alkyl group having 1 to 5 carbon atoms is substituted with the aryl group having 6 to 10 carbon atoms.
  • R 1 And R 2 Examples of the alkyl group having 1 to 5 carbon atoms substituted by the aryl group having 6 to 10 carbon atoms represented by the formula: benzyl group, 1-phenylethyl group, 1-phenylpropyl group, 1-phenylbutyl group, 2 -Methyl-1-phenylpropyl group, 1-phenylpentyl group, 2-methyl-1-phenylbutyl group, 3-methyl-1-phenylbutyl group, diphenylmethyl group, 1,1-diphenylethyl group, triphenylmethyl Group, (1-naphthyl) methyl group, (2-naphthyl) methyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group and the like.
  • R 1 And R 2 are independently a 1-arylalkyl group, R 1 And R 2 Is more preferably a benzyl group.
  • trans-4-aminopiperidin-3-ol (1) for example, trans-1-benzyl-4- (methylamino) piperidin-3-ol, trans-1-benzyl-4- (allylamino) piperidine- 3-ol, trans-1-benzyl-4- (benzylamino) piperidin-3-ol, trans-1-benzyl-4- (1-phenylethylamino) piperidin-3-ol, trans-1-diphenylmethyl- 4- (methylamino) piperidin-3-ol, trans-1-diphenylmethyl-4- (allylamino) piperidin-3-ol, trans-1-diphenylmethyl-4- (benzylamino) piperidin-3-ol, trans -1-diphenylmethyl-4- (1-phenylethylamino) piperidine-3- Lumpur, and the like.
  • Trans-1-benzyl-4- (benzylamino) piperidin-3-ol is preferable in terms of resolution efficiency.
  • Substituted trans-4-aminopiperidin-3-ol (1) is obtained, for example, by a method via a reaction between a 3,4-epoxytetrahydropyran compound and an azide compound (J. Med. Chem. 41, 3563-3567 (1998). It can be produced by a known method such as In formula (2), R 3
  • the protecting group represented by the formula include an optionally substituted (hydrocarbon having 1 to 12 carbons) carbonyl group and an optionally substituted hydrocarbylsulfonyl having 1 to 12 carbons.
  • substituents include an alkoxy group having 1 to 6 carbon atoms, (alkoxy having 1 to 6 carbon atoms) carbonyl group, an alkanoyl group having 1 to 6 carbon atoms, an alkanoyloxy group having 1 to 6 carbon atoms, a halogen atom, Examples thereof include a nitro group and a cyano group.
  • hydrocarbylcarbonyl groups include acetyl, benzoyl, and biphenylcarbonyl groups.
  • hydrocarbylsulfonyl groups include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, pentafluoroethanesulfonyl, and toluenesulfonyl.
  • a benzenesulfonyl group which may be substituted is preferable in terms of resolution efficiency, and a paratoluenesulfonyl group is more preferable.
  • R 4 Examples of the alkyl group having 1 to 12 carbon atoms represented by: methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, Nonyl group, decyl group, undecyl group, dodecyl group can be mentioned.
  • Examples of the aryl group having 6 to 10 carbon atoms that can be a substituent of the alkyl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • the optically active N-protected amino acid (2) only needs to contain any one of its enantiomers.
  • the optical purity may be higher than the optical purity of the trans-4-aminopiperidin-3-ol compound (1) used as a raw material, but is preferably 90% ee or more, more preferably 95% ee or more. Preferably, it is more preferably 98% ee or more, and most preferably 100% ee.
  • optically active N-protected amino acid (2) examples include N- (paratoluenesulfonyl) -L-phenylalanine, N- (benzenesulfonyl) -L-phenylalanine, N- (methanesulfonyl) -L-phenylalanine, N- (Trifluoromethanesulfonyl) -L-phenylalanine, N- (paratoluenesulfonyl) -L-alanine, N- (benzenesulfonyl) -L-alanine, N- (methanesulfonyl) -L-alanine, N- (trifluoromethanesulfonyl) ) -L-alanine, N- (paratoluenesulfonyl) -L-leucine, N- (benzenesulfonyl) -L-leucine, N- (methane
  • N- (paratoluenesulfonyl) phenyl-L-alanine and N- (paratoluenesulfonyl) phenyl-D-alanine are preferable.
  • the optically active N-protected amino acid (2) a commercially available product can be used as it is, or a commercially available optically active amino acid can be used by N-protecting it by a known method.
  • the amount of the optically active N-protected amino acid (2) used is usually the desired optically active substituted trans-4-aminopiperidin-3-ol contained in the substituted trans-4-aminopiperidin-3-ol (1). It is equimolar or more with respect to (4).
  • the amount of the optically active N-protected amino acid (2) used when the racemate is used as the substituted trans-4-aminopiperidin-3-ol (1) is the same as that of the substituted trans-4-aminopiperidin-3-ol (1) 1 It is usually 0.5 mol or more with respect to mol. From the viewpoint of yield and economy, it is preferably 0.9 to 2 mol, more preferably 1.0 to 1.5 mol.
  • the solvent examples include fats such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, and petroleum ether.
  • fats such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, and petroleum ether.
  • Group hydrocarbon solvent benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, diethyl ether Ether solvents such as dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxye
  • Aprotic polar solvents ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate, etc .; acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, Include and water; Ropentanon, ketone solvents such as cyclohexanone. These solvents may be used alone or in combination of two or more. Among these, an alcohol solvent and a nitrile solvent are preferable, and a mixed solvent thereof is more preferable.
  • a mixed solvent of ethanol and acetonitrile is particularly preferable.
  • the amount of the solvent used may be appropriately selected according to the solubility of the diastereomeric salt (3), and is usually 1 to 100 L, preferably 1 to 100 L, preferably 1 kg of substituted trans-4-aminopiperidin-3-ol (1).
  • the ratio is 4 to 40L.
  • the reaction of the substituted trans-4-aminopiperidin-3-ol (1) and the optically active N-protected amino acid (2) is carried out by mixing them in a solvent, and even if the latter is added to the former, The former may be added to the latter.
  • the diastereomeric salt (3) crystal does not exist in the obtained mixture, the diastereomeric salt (3) may be crystallized by cooling the mixture.
  • the mixture may be cooled as it is, but the chemistry of the optically active substituted trans-4-aminopiperidin-3-ol (4) obtained.
  • the diastereomeric salt (3) In order to increase the purity and optical purity, it is preferable to crystallize the diastereomeric salt (3) by heating the mixture to dissolve the crystals of the diastereomeric salt (3) and then cooling. In the crystallization of the diastereomeric salt (3), a seed crystal of the diastereomeric salt (3) may be used.
  • the temperature at which the substituted trans-4-aminopiperidin-3-ol (1) and the optically active N-protected amino acid (2) are mixed is usually in the range of 0 ° C. or higher and the boiling point of the solvent or lower. When heating after mixing, it is heated to a range of 30 ° C. or higher and the boiling point of the solvent or lower.
  • the cooling temperature is usually in the range of 0 to 25 ° C., and in order to increase the chemical purity and optical purity of the resulting diastereomeric salt (3), it is preferable to cool gradually.
  • the diastereomeric salt (3) is a diastereomeric salt of the optically active substance in the substituted trans-4-aminopiperidin-3-ol (1) used and the optically active N-protected amino acid (2) used. is there.
  • N is added to the optically active N-protected amino acid (2).
  • the resulting diastereomeric salt (3) is (3R, 4R) -1-benzyl-4- (benzylamino) piperidin-3-ol and N- (para Diastereomeric salt with toluenesulfonyl) -D-phenylalanine, and diastereomeric salt obtained by using N- (paratoluenesulfonyl) -L-phenylalanine as the optically active N-protected amino acid (2)
  • (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol and N- (paratoluenesulfo Le) is a diastereomeric salts with -L- phenylalanine.
  • the mixture obtained by mixing substituted trans-4-aminopiperidin-3-ol (1) and optically active N-protected amino acid (2) in a solvent is subjected to solid-liquid separation treatment such as filtration or decantation.
  • solid-liquid separation treatment such as filtration or decantation.
  • the diastereomeric salt (3) can be isolated as a solid.
  • the diastereomeric salt (3) When the diastereomeric salt (3) is treated with an acid or a base, an optically active substituted trans-4-aminopiperidin-3-ol (4) or a salt thereof is obtained.
  • the isolated diastereomeric salt (3) may be used as it is, but the chemical purity and optical purity of the resulting optically active substituted trans-4-aminopiperidin-3-ol (4) are not affected.
  • the same solvent as described above can be used for washing. After washing, it is preferable to further dry. Drying is usually performed within a range of 20 to 80 ° C. under normal pressure or reduced pressure.
  • the acid used for the acid treatment of the diastereomeric salt (3) may be any acid having higher acidity than the optically active N-protected amino acid (2).
  • mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid, Organic acids such as paratoluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and the like can be mentioned.
  • Paratoluenesulfonic acid is preferable.
  • the acid treatment is usually performed in a solvent.
  • the solvent examples include fats such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, and petroleum ether.
  • fats such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, and petroleum ether.
  • Group hydrocarbon solvent benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, diethyl ether Ether solvents such as dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxye
  • the acid treatment is carried out by mixing the diastereomeric salt (3) and an acid.
  • a salt of the optically active substituted trans-4-aminopiperidin-3-ol (4) and the acid used is precipitated in the treated product, the mixture is used as it is, for example, filtration, decantation, etc.
  • solid-liquid separation treatment an optically active salt of substituted trans-4-aminopiperidin-3-ol (4) can be obtained.
  • the mixture can be concentrated, mixed with a solvent in which the salt is difficult to dissolve, or heated, for example.
  • the salt may be crystallized by cooling or cooling, and the resulting mixture may be subjected to a solid-liquid separation treatment such as filtration or decantation to remove the salt.
  • the obtained salt may be further purified by ordinary means such as recrystallization, and optically active substituted trans-4-aminopiperidin-3-ol (4 ) May be acquired.
  • the filtrate obtained by the above-described solid-liquid separation treatment usually contains the optically active N-protected amino acid (2) used, and the optically active N-protected amino acid (2) is recovered from the filtrate by a conventional method. And can be reused in the present invention.
  • Examples of the base used for the base treatment of the diastereomeric salt (3) include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methylate and sodium Examples thereof include alkali metal alcoholates such as ethylate, potassium methylate, and potassium ethylate. Alkali metal hydroxides are preferred, and sodium hydroxide is more preferred.
  • the base treatment is usually performed in the presence of an organic solvent and water.
  • organic solvent examples include ether solvents such as diethyl ether, tert-butyl methyl ether, methyl isobutyl ether, diisopropyl ether, methyl cyclopentyl ether, and 1,2-dimethoxymethane; aromatic solvents such as toluene, xylene, and chlorobenzene Aliphatic hydrocarbon solvents such as hexane and cyclohexane; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; ester solvents such as ethyl acetate and tert-butyl acetate; halogenated aliphatic hydrocarbon solvents such as dichloromethane; methanol, ethanol, 1 -Propanol, 2-propanol, butyl alcohol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol,
  • the base treatment is carried out by mixing the diastereomeric salt (3) and a base, and the latter may be added to the former or the former may be added to the latter.
  • a base for example, by adding a base to the organic solvent and a mixture of water and diastereomeric salt to make the aqueous layer basic (usually pH 8.5 or higher), the resulting mixture is subjected to a liquid separation treatment, An organic layer containing optically active substituted trans-4-aminopiperidin-3-ol (4) can be obtained.
  • it When it is made basic, when crystals are precipitated, it may be dissolved by heating or may be filtered off by filtration.
  • the optically active substituted trans-4-aminopiperidin-3-ol (4) can be isolated.
  • the obtained optically active substituted trans-4-aminopiperidin-3-ol (4) may be further purified by ordinary means such as rectification, recrystallization, column chromatography and the like.
  • Optically active substituted trans-4-aminopiperidin-3-ol (4) can also be taken out as an acid addition salt.
  • the optically active N-protected amino acid (2) used is contained in the aqueous layer and filtrate obtained by the liquid separation treatment, and the optically active N-protected amino acid (2) is obtained from the aqueous layer and the filtrate by a conventional method.
  • optically active substituted trans-4-aminopiperidin-3-ol (4) thus obtained has an improved optical purity compared to the substituted trans-4-aminopiperidin-3-ol (1) used as a raw material.
  • optically active substituted trans-4-aminopiperidin-3-ol (4) include (3S, 4S) -trans-1-benzyl-4- (methylamino) piperidin-3-ol, (3S, 4S).
  • R 1 Is an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms at the 1-position, from the obtained optically active substituted trans-4-aminopiperidin-3-ol (4)
  • R 1 And a group represented by 2 A method for producing optically active trans-4-aminopiperidin-3-ol, in which both groups represented by the above are removed, will be described.
  • equation (5) (Wherein R 11 And R 2 Represents the same meaning as above.
  • optically active substituted trans-4-aminopiperidin-3-ol (7) represented by 11 And R 2
  • group represented by formula (8) In the formula, * represents the same meaning as described above.
  • Optically active substituted trans-4-aminopiperidin-3-ol (7) is obtained in the same manner as the above-mentioned production method of optically active substituted trans-4-aminopiperidin-3-ol (4), and is optically active.
  • the reaction mixture containing the acid or base can be used as it is.
  • an optically active substituted trans-4-aminopiperidin-3-ol (7) or a salt thereof isolated from the reaction mixture by workup of the reaction may be used, or a further purified optically active substituted trans -4-Aminopiperidin-3-ol (7) or a salt thereof may be used.
  • R 1 And R 2 This removal may be carried out by a normal aralkyl removal method.
  • R 1 Removal and R 2 May be performed stepwise in an arbitrary order, or they may be removed simultaneously.
  • R 1 And R 2 When both are benzyl groups, it can be carried out by a reduction reaction for deprotecting a benzyl-protected amino group.
  • a method of reacting optically active substituted trans-4-aminopiperidin-3-ol (7) with hydrogen in the presence of palladium carbon, optically active substituted trans-4-aminopiperidine-3 in the presence of palladium hydroxide examples include a method of reacting ol (7) with hydrogen, a method of reacting optically active substituted trans-4-aminopiperidin-3-ol compound (7) with sodium in liquid ammonia, and the like.
  • a method in which an optically active substituted trans-4-aminopiperidin-3-ol (7) is reacted with hydrogen in the presence thereof is preferable.
  • the palladium carbon may be a water-containing product or a dry product.
  • the content of palladium atoms is usually 0.5 to 50% by weight, preferably 5 to 20% by weight.
  • Such palladium carbon may be a commercially available product, or may be prepared and used by any known method.
  • the amount of palladium carbon used is an amount in the range of usually 0.1 to 50 g, preferably 1 to 20 g of palladium with respect to 1 kg of optically active substituted trans-4-aminopiperidin-3-ol (7).
  • Palladium supported on carbon is usually zero-valent, and when a divalent or tetravalent palladium compound is supported, it is preferably used after being reduced to zero by a conventional method.
  • As hydrogen commercially available hydrogen gas can be used, or it can be generated and used by any known method.
  • the hydrogen pressure during the reaction is usually 0.1 to 5 MPa, preferably 0.1 to 1 MPa. It can also be used as a mixed gas with an inert gas such as nitrogen or argon, and the hydrogen partial pressure during the reaction in this case is the same as the hydrogen pressure described above.
  • the reaction of optically active substituted trans-4-aminopiperidin-3-ol (7) with hydrogen is usually carried out in a solvent.
  • the solvent is a solvent inert to the reaction, for example, pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert -Aliphatic hydrocarbon solvents such as butylcyclohexane and petroleum ether; tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether , Ether solvents such as cyclopentyl methyl ether
  • the amount of the solvent used is usually 1 to 50 L, preferably 2 to 15 L, per 1 kg of the optically active substituted trans-4-aminopiperidin-3-ol (7).
  • the reaction temperature is usually 0 to 100 ° C., preferably 20 to 70 ° C.
  • the reaction time is usually 1 to 24 hours, although it depends on the reaction temperature, the amount of reaction reagent used, the hydrogen pressure, and the like. The progress of the reaction can be confirmed by usual means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
  • the order of mixing the reaction reagents is not particularly limited.
  • optically active substituted trans-4-aminopiperidin-3-ol (7) and palladium carbon are mixed in a solvent and hydrogen is added to the resulting mixture.
  • a method of adding optically active substituted trans-4-aminopiperidin-3-ol (7) to palladium carbon under a hydrogen atmosphere is preferred.
  • a method of adding hydrogen to a mixture of optically active substituted trans-4-aminopiperidin-3-ol (7) and palladium carbon in a solvent is preferred.
  • the mixture after completion of the reaction contains optically active trans-4-aminopiperidin-3-ol, and this mixture is subjected to usual post-treatment such as filtration, extraction, washing with water, and then distillation and crystallization.
  • optically active trans-4-aminopiperidin-3-ol can be taken out.
  • optically active trans-4-aminopiperidin-3-ol may be taken out as a salt with an acid such as hydrochloric acid, benzoic acid or tartaric acid.
  • the extracted optically active trans-4-aminopiperidin-3-ol or a salt thereof is, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; chromatography method such as silica gel column chromatography Further purification may be carried out by the usual purification treatment.
  • the optically active trans-4-aminopiperidin-3-ol thus obtained usually maintains the optical activity of the optically active substituted trans-4-aminopiperidin-3-ol (7) subjected to the reaction. That is, (3S, 4S) -trans-1-benzyl-4- (benzylamino) piperidin-3-ol provides (3S, 4S) -trans-4-aminopiperidin-3-ol, (3R, 4R) -trans-4-aminopiperidin-3-ol is obtained from 4R) -trans-1-benzyl-4- (benzylamino) piperidin-3-ol.
  • trans-4-aminopiperidin-3-ol (4) or a salt thereof isolated from the reaction mixture by post-treatment may be used, or optically active substitution purified by the above-described purification treatment.
  • Trans-4-aminopiperidin-3-ol (4) or a salt thereof may be used.
  • the halogen atom represented by X in the formula (9) include a chlorine atom, a bromine atom, and an iodine atom.
  • R 5 Examples of the alkyl group having 1 to 12 carbon atoms represented by: methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, Nonyl group, decyl group, undecyl group, dodecyl group can be mentioned.
  • Examples of the aryl group having 6 to 10 carbon atoms, which is a substituent of the alkyl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • Examples of the halocarbonate (9) include methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, and butyl chlorocarbonate.
  • Examples of the dialkyl dicarbonate (10) include ditert-butyl dicarbonate.
  • As the carbamate agent dialkyl dicarbonate (10) is preferable, and ditert-butyl dicarbonate is more preferable.
  • These carbamate agents can be commercially available, or can be prepared and used by any known method.
  • the amount of the carbamate used is usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the optically active substituted trans-4-aminopiperidin-3-ol (4). This reaction is usually performed in the presence of a base.
  • Examples of the base include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali metal carbonates such as potassium carbonate, sodium carbonate and lithium carbonate; tertiary amine compounds such as triethylamine and diisopropylethylamine Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride; Examples thereof include alkyl metal compounds such as butyl lithium, lithium diisopropylamine, and lithium hexamethyldisilazane.
  • alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide
  • alkali metal carbonates such as potassium carbonate, sodium carbonate and lithium carbonate
  • tertiary amine compounds such as triethylamine
  • the amount of the base used is usually 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the optically active substituted trans-4-aminopiperidin-3-ol (4).
  • This reaction is usually performed in the presence of a solvent.
  • the solvent is a solvent inert to the reaction.
  • -Aliphatic hydrocarbon solvents such as butylcyclohexane and petroleum ether; benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, Aromatic solvents such as 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran , Diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether
  • the amount of the solvent to be used is generally 1 to 50 L, preferably 2 to 15 L, per 1 kg of the compound.
  • the reaction temperature is usually ⁇ 30 to 70 ° C., preferably 0 to 50 ° C.
  • the reaction time is usually 1 to 20 hours, although it depends on the reaction temperature and the amount of reaction reagent used. The progress of the reaction can be confirmed by usual means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
  • the order of mixing the reaction reagents is not particularly limited, and it is preferable to mix the optically active substituted trans-4-aminopiperidin-3-ol (4), the solvent and the base in the order of adding the carbamate agent. .
  • the mixture after completion of the reaction contains the optically active compound (11), and the mixture is subjected to usual post-treatment such as filtration, extraction and washing, followed by usual post-treatment such as distillation and crystallization. By performing the treatment, the optically active compound (11) can be isolated. At this time, the optically active compound (11) may be taken out as a salt with any acid such as hydrochloric acid, benzoic acid or tartaric acid.
  • the isolated optically active compound (11) or a salt thereof is, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; ordinary purification such as chromatography methods such as silica gel column chromatography It may be further purified by treatment.
  • optically active compound (11) examples include methyl benzyl [(3S, 4S) -1-benzyl-trans-3-hydroxypiperidin-4-yl] carbamate, methyl benzyl [(3R, 4R) -1-benzyl- Trans-3-hydroxypiperidin-4-yl] carbamate, ethyl benzyl [(3S, 4S) -1-benzyl-trans-3-hydroxypiperidin-4-yl] carbamate, benzyl [(3R, 4R) -1-benzyl -Trans-3-hydroxypiperidin-4-yl] carbamate, isopropyl benzyl [(3S, 4S) -1-benzyl-trans-3-hydroxypiperidin-4-yl] carbamate, [(3R, 4R) -1-benzyl -Trans-3-hydroxypiperidin-4-yl] carbamate, t tert-butyl benzyl [(3S, 4S) -1-
  • the optically active compound (11) thus obtained usually maintains the optical activity of the optically active substituted trans-4-aminopiperidin-3-ol (4) subjected to this reaction.
  • the manufacturing method of optically active compound (14) shown by is shown.
  • the optically active compound (11) used in this production method the mixture containing the above-mentioned reaction mixture after completion of the reaction can be used as it is.
  • the optically active compound (11) extracted from the reaction mixture by the isolation treatment or a salt thereof may be used, or the optically active compound (11) or salt thereof purified by the purification treatment is used.
  • the reaction is R 1 And COOR 5 R than the group represented by 2 If it is the conditions which can be removed preferentially, it will not specifically limit, It can implement by arbitrary well-known methods.
  • R 1 And R 2 When both are benzyl groups, the deprotection reaction conditions are, for example, a method of reacting optically active compound (11) with hydrogen in the presence of palladium carbon, or optically active compound (11) and hydrogen in the presence of palladium hydroxide.
  • the optically active compound (11) is preferably reacted with hydrogen in the presence of palladium carbon.
  • the method is a method for producing optically active trans-4-aminopiperidin-3-ol represented by the formula (8) from optically active substituted trans-4-aminopiperidin-3-ol (7). It can be carried out in the same way.
  • the mixture after completion of the reaction contains the optically active compound (14), and the mixture is subjected to usual post-treatment such as filtration, extraction and washing with water, and then subjected to usual isolation such as distillation and crystallization.
  • the optically active compound (14) can be obtained.
  • the optically active compound (14) may be isolated as a salt with an acid such as hydrochloric acid, benzoic acid or tartaric acid.
  • the extracted optically active compound (14) or a salt thereof is, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina or the like; chromatography method such as silica gel column chromatography; It may be further purified by treatment.
  • the optically active compound (14) include methyl benzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate, ethyl benzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate.
  • optically active compound (13) shown by The manufacturing method of optically active compound (13) shown by is demonstrated.
  • the optically active substituted trans-4-aminopiperidin-3-ol (4) subjected to this reaction the above-mentioned mixture after acid treatment or base treatment containing it can be used as it is.
  • an optically active substituted trans-4-aminopiperidin-3-ol (4) or a salt thereof taken out from the reaction mixture by the isolation treatment may be used, and further purified by the purification treatment.
  • optically active substituted trans-4-aminopiperidin-3-ol (4) or a salt thereof may be used.
  • the halogen atom represented by A in Formula (12) include a chlorine atom and a bromine atom.
  • Examples of the trihalomethyl group include a trichloromethyl group and a tribromomethyl group.
  • Examples of the carbonyl compound (12) include phosgene, triphosgene, and the formula In particular, carbonyldiimidazole that is easy to handle is preferable. These carbonylating agents may be commercially available or may be prepared and used by any known method.
  • the amount of the carbonyl compound (12) to be used is generally 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the optically active substituted trans-4-aminopiperidin-3-ol (4). This reaction is usually performed in the presence of a base.
  • Examples of the base include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali metal carbonates such as potassium carbonate, sodium carbonate and lithium carbonate; tertiary amine compounds such as triethylamine and diisopropylethylamine Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride; Examples thereof include alkyl metal compounds such as butyl lithium, lithium diisopropylamine, and lithium hexamethyldisilazane.
  • alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide
  • alkali metal carbonates such as potassium carbonate, sodium carbonate and lithium carbonate
  • tertiary amine compounds such as triethylamine
  • the amount of the base used is usually 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the optically active substituted trans-4-aminopiperidin-3-ol (4).
  • This reaction is usually performed in the presence of a solvent.
  • the solvent is a solvent inert to the reaction.
  • -Aliphatic hydrocarbon solvents such as butylcyclohexane and petroleum ether; benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, Aromatic solvents such as 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran , Diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether
  • the amount of the solvent to be used is generally 1 to 50 L, preferably 2 to 15 L, per 1 kg of the compound.
  • the reaction temperature is usually ⁇ 30 to 100 ° C., preferably 0 to 50 ° C.
  • the reaction time is usually 1 to 20 hours, although it depends on the reaction temperature and the amount of reaction reagent used. The progress of the reaction can be confirmed by usual means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
  • the order of mixing the reaction reagents is not particularly limited, but mixing in the order of adding the carbonylating agent to the optically active substituted trans-4-aminopiperidin-3-ol (4), solvent and base mixture. Is preferred.
  • the mixture after completion of the reaction contains the optically active compound (13).
  • the mixture is subjected to usual post-treatment such as filtration, extraction and washing with water, and then subjected to usual simple treatment such as distillation and crystallization. If the release treatment is performed, the optically active compound (13) can be obtained.
  • the optically active compound (13) may be isolated as a salt with any acid such as hydrochloric acid, benzoic acid, tartaric acid and the like.
  • the isolated optically active compound (13) or a salt thereof is, for example, recrystallized; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; ordinary purification treatment of chromatographic methods such as silica gel column chromatography And may be further purified.
  • optically active compound (13) examples include (3aS, 7aS) -1-benzyl-5-methylhexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS , 7aS) -1-allyl-5-methylhexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (1-phenylethyl)- 5-methylhexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (2-phenylethyl) -5-methylhexahydro [1, 3] Oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1,5-dibenzyl-hexahydro [1,3] oxazolo
  • the optically active compound (13) thus obtained usually maintains the optical activity of the optically active substituted trans-4-aminopiperidin-3-ol (4) subjected to this reaction.
  • a method for producing the optically active compound (15) represented by the formula will be described.
  • the optically active compound (13) to be subjected to this reaction the mixture containing the optically active compound (13) after completion of the reaction can be used as it is.
  • the optically active compound (13) or a salt thereof isolated from the reaction mixture by post-treatment may be used, or a further purified optically active compound (13) or a salt thereof may be used.
  • R 1 Than R 2 If it is the conditions which can be removed preferentially, it will not specifically limit, It can implement by arbitrary well-known methods.
  • R 1 And R 2 When both are benzyl groups, the deprotection reaction conditions are, for example, a method of reacting optically active compound (13) with hydrogen in the presence of palladium carbon, or optically active compound (13) and hydrogen in the presence of palladium hydroxide.
  • the optically active compound (13) is preferably reacted with hydrogen in the presence of palladium carbon.
  • the method is a method for producing optically active trans-4-aminopiperidin-3-ol represented by the formula (8) from optically active substituted trans-4-aminopiperidin-3-ol (7).
  • the mixture after completion of the reaction contains the optically active compound (15), and the mixture is subjected to usual post-treatment such as filtration, extraction and washing with water, and then subjected to usual isolation such as distillation and crystallization. If the treatment is applied, the optically active compound (15) can be taken out. At this time, the optically active compound (15) may be isolated as a salt with any acid such as hydrochloric acid, benzoic acid or tartaric acid.
  • the isolated optically active compound (15) or a salt thereof can be obtained by, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina or the like; chromatography method such as silica gel column chromatography; Further purification may be performed by a purification treatment.
  • optically active compound (15) examples include (3aS, 7aS) -1-benzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one (3aS, 7aS) -1- Allyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (1-phenylethyl) -hexahydro [1,3] oxazolo [5, 4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (2-phenylethyl) -hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one And compounds in which (3aS, 7aS) in each compound is replaced with (3aR, 7aR), respectively.
  • the optically active compound (15) thus obtained usually maintains the
  • Example 1 Optical resolution of (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol (3RS, 4RS) -1-benzyl-4- (benzylamino) piperidin-3-ol 1 0.1 g (3.7 mmol), ethanol 5 mL, and acetonitrile 10 mL were mixed. While maintaining the mixture at 20 to 35 ° C., 1.2 g (3.7 mmol) of N- (p-toluenesulfonyl) -L-phenylalanine was added thereto, and crystals were precipitated.
  • Table 1 shows the presence or absence of crystal precipitation and the optical purity of trans-1-benzyl-4- (benzylamino) piperidin-3-ol in the obtained crystal.
  • Example 4 Preparation of (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol (3S, 4S) -1-benzyl-4- (benzylamino) piperidine obtained in Example 1 A salt of 0.77 g (1.3 mmol) of -3-ol and N- (p-toluenesulfonyl) -L-phenylalanine, 10 mL of ethyl acetate and 1 mL of ethanol were mixed. While maintaining the internal temperature of the mixture at 20 to 35 ° C., 8 mL of 1 mol / L sodium hydroxide was added dropwise thereto.
  • Example 5 Preparation of (3S, 4S) -4-aminopiperidin-3-ol (3S, 4S) -1-benzyl-4-benzylaminopiperidin-3-ol 1 obtained in the same manner as in Example 4 0.01 g (3.4 mmol) and 10 mL of ethanol were mixed in an autoclave reactor, and the inside of the system was set to a nitrogen atmosphere. Thereto was added 0.10 g of 10 wt% palladium carbon (55 wt% water-containing product, PE type, manufactured by N.E. Chemcat Co., Ltd., Lot. 217-0776880), and the system was replaced with hydrogen. The mixture was stirred at 0.4 MPa at 50 ° C. for 6 hours.
  • Example 6 Preparation of tert-butyl benzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate (3S, 4S) -1-benzyl-4- () obtained in the same manner as in Example 4.
  • Example 7 Preparation of (3aS, 7aS) -1,5-dibenzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one Obtained in the same manner as in Example 4. (3S, 4S) -1-Benzyl-4- (benzylamino) piperidin-3-ol 1.83 g (6.17 mmol), toluene 15 mL and carbonyldiimidazole 1.10 g (6.79 mmol) were mixed at room temperature. .
  • Crystals were precipitated by cooling the resulting solution to room temperature, 6 mL of heptane was added thereto, cooled to 6 ° C. and filtered, and (3aS, 7aS) -1,5-dibenzyl-hexahydro [1, 3] 1.76 g of oxazolo [5,4-c] pyridin-2 (1H) -one was obtained. The yield was 88%.
  • Example 8 Preparation of (3aS, 7aS) -1-benzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one 0.50 g of the crystals obtained in Example 7 Ethanol 8mL was mixed in the autoclave reaction apparatus, and the inside of system was made into nitrogen atmosphere. Thereto was added 0.050 g of 10 wt% palladium carbon (55 wt% water-containing product, PE type, manufactured by N.E. Chemcat Co., Ltd., Lot. 217-0776880), and the system was replaced with hydrogen. The mixture was stirred at 0.4 MPa at 50 ° C. for 7 hours.
  • the catalyst was removed by filtration, and the obtained filtrate was concentrated to obtain 0.39 g of an oily substance.
  • the main component was (3aS, 7aS) -1-benzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one. there were.
  • optically active trans-4-aminopiperidin-3-ol obtained by the present invention and its analogs are described in Synth. Commun. 28, 4471 (1998), J. MoI. Med. Chem. 41, 3563-3567 (1998), WO2007 / 039462, etc., for example, it is useful as a raw material for synthesis of pharmaceuticals and the like, and as a raw material for the synthesis of chiral ligands used in stereoselective chemical reactions. It is useful as a method for producing such a compound.

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Abstract

An optically active trans-4-aminopiperidine-3-ol compound can be manufactured using a method of optical resolution of substituted trans-4-aminopiperidine-3-ol, which includes a step in which a substituted trans-4-aminopiperidine-3-ol represented by formula (1): (1) (In the formula, R1 represents an alkyl group with 1‑5 carbons that may be substituted with an aryl group with 6‑10 carbon atoms, or an alkenyl group with 3‑6 carbon atoms that may be substituted with an aryl group with 6‑10 carbons, and R2 represents an alkyl group with 1‑5 carbon atoms that may be substituted with an aryl group with 6‑10 carbon atoms.) and an optically active N-protected amino acid represented by formula (2): (2) (In the formula, R3 represents a protecting group, R4 represents an alkyl group with 1‑12 carbon atoms that may be substituted, and * indicates that the corresponding carbon atom is an asymmetric carbon atom.) are reacted in a solvent.

Description

光学活性なトランス−４−アミノピペリジン−３−オール化合物の製造方法Process for producing optically active trans-4-aminopiperidin-3-ol compound

　本発明は、置換トランス−４−アミノピペリジン−３−オールを光学分割することにより、光学活性な置換トランス−４−アミノピペリジン−３−オールを製造する方法に関する。 The present invention relates to a method for producing optically active substituted trans-4-aminopiperidin-3-ol by optical resolution of substituted trans-4-aminopiperidin-3-ol.

　医薬品等の合成原料、立体選択的な化学反応に用いるキラルなリガンドの合成原料などに使用される光学活性なトランス−４−アミノピペリジン−３−オール化合物の製造方法として、例えば、出発原料である光学活性なピログルタミノールから数工程を経て光学活性な２−ピロリジンメタノール誘導体を得、これを無水トリフルオロ酢酸及び塩基と−７８℃で反応させる方法が知られている（Ｓｙｎｔｈ．Ｃｏｍｍｕｎ．２８，４４７１（１９９８）参照。）。しかしながら、かかる方法では、工業的に実施することが容易でない反応を含む等の問題があり、より工業的に有利な製造方法の開発が求められていた。 As a method for producing an optically active trans-4-aminopiperidin-3-ol compound used as a raw material for synthesis of pharmaceuticals, a chiral ligand used for stereoselective chemical reaction, etc., for example, it is a starting material An optically active 2-pyrrolidinemethanol derivative is obtained from optically active pyroglutaminol through several steps, and this is reacted with trifluoroacetic anhydride and a base at −78 ° C. (Synth. Commun. 28, 4471 (1998)). However, in such a method, there are problems such as including a reaction that is not easy to implement industrially, and development of a more industrially advantageous production method has been demanded.

　本発明によれば、溶媒中で、式（１）

Figure JPOXMLDOC01-appb-I000047
（式中、Ｒ１は炭素数６~１０のアリール基で置換されていてもよい炭素数１~５のアルキル基又は炭素数６~１０のアリール基で置換されていてもよい炭素数３~６のアルケニル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表す。）
で示される置換トランス−４−アミノピペリジン−３−オール（置換トランス−４−アミノピペリジン−３−オール（１））と、式（２）
Figure JPOXMLDOC01-appb-I000048
（式中、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性Ｎ−保護アミノ酸（光学活性Ｎ−保護アミノ酸（２））とを反応させる工程を含む置換トランス−４−アミノピペリジン−３−オールの光学分割方法を用いることにより、光学活性な置換トランス−４−アミノピペリジン−３−オールが工業的に有利に製造できる。
　即ち、本発明は以下の通りである。
［１］溶媒中で、置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを反応させ、式（３）
Figure JPOXMLDOC01-appb-I000049
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩（ジアステレオマー塩（３））を優先的に晶出させる工程を含む式（４）
Figure JPOXMLDOC01-appb-I000050
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オール（光学活性な置換トランス−４−アミノピペリジン−３−オール（４））の製造方法。
［２］溶媒中で、置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを反応させ、ジアステレオマー塩（３）を優先的に晶出させ、得られたジアステレオマー塩（３）を、さらに、酸又は塩基で処理する光学活性な置換トランス−４−アミノピペリジン−３−オール（４）の製造方法。
［３］Ｒ３が、置換されていてもよい（炭素数１~１２のヒドロカルビル）カルボニル基又は置換されていてもよい炭素数１~１２のヒドロカルビルスルホニル基、［ここで、置換基は、炭素数１~６のアルコキシ基、　　　（炭素数１~６のアルコキシ）カルボニル基、炭素数１~６のアルカノイル基、炭素数１~６のアルカノイルオキシ基、ハロゲン原子、ニトロ基及びシアノ基よりなる群より選ばれる一以上の置換基である。］である［１］又は［２］に記載の方法。
［４］Ｒ１及びＲ２がベンジル基である［１］~［３］に記載の方法。
［５］Ｒ１及びＲ２がベンジル基であり、Ｒ３がパラトルエンスルホニル基であり、Ｒ４がベンジル基である［４］に記載の方法。
［６］溶媒が、アルコール溶媒及び／又はニトリル溶媒である［１］~［５］に記載の方法。
［７］溶媒中で、置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを反応させ、ジアステレオマー塩（３）を優先的に晶出させる工程を含む該ジアステレオマー塩の製造方法。
［８］溶媒中で、式（５）
Figure JPOXMLDOC01-appb-I000051
（式中、Ｒ１１は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表し、Ｒ２は上記と同じ意味を表す。）
で示される置換トランス−４−アミノピペリジン−３−オール（置換トランス−４−アミノピペリジン−３−オール（５））と光学活性Ｎ−保護アミノ酸（２）とを反応させ、式（６）
Figure JPOXMLDOC01-appb-I000052
（式中、Ｒ１１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩（ジアステレオマー塩（６））を優先的に晶出させ、得られた該ジアステレオマー塩（６）を酸又は塩基で処理して式（７）
Figure JPOXMLDOC01-appb-I000053
（式中、Ｒ１１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オール（光学活性な置換トランス−４−アミノピペリジン−３−オール（７））に導き、次いでＲ１１及びＲ２で表される基を除去する式（８）
Figure JPOXMLDOC01-appb-I000054
（式中、＊は上記と同じ意味を表す。）
で示される光学活性トランス−４−アミノピペリジン−３−オールの製造方法。
［９］Ｒ１１及びＲ２がベンジル基である［８］に記載の方法。
［１０］溶媒中で、置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを反応させ、ジアステレオマー塩（３）を優先的に晶出させ、得られたジアステレオマー塩（３）を、さらに、酸又は塩基で処理して光学活性な置換トランス−４−アミノピペリジン−３−オール（４）を得、次いで、該化合物と、式（９）
Figure JPOXMLDOC01-appb-I000055
（式中、Ｒ５は炭素数１~１２のアルキル基を表し、Ｘはハロゲン原子を表す。）
で示されるハロ炭酸エステル（ハロ炭酸エステル（９））又は式（１０）
Figure JPOXMLDOC01-appb-I000056
（式中、Ｒ５は上記と同じ意味を表す。）
で示されるジアルキルジカーボネート（ジアルキルジカーボネート（１０））とを反応させる式（１１）
Figure JPOXMLDOC01-appb-I000057
（式中、Ｒ１、Ｒ２、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物（光学活性化合物（１１））の製造方法。
［１１］溶媒中で、置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを反応させ、ジアステレオマー塩（３）を優先的に晶出させ、得られたジアステレオマー塩（３）を、さらに、酸又は塩基で処理して光学活性な置換トランス−４−アミノピペリジン−３−オール（４）を得、該化合物とハロ炭酸エステル（９）又はジアルキルジカーボネート（１０）とを反応させて光学活性化合物（１１）を得、次いで、光学活性化合物（１１）と式（１２）
Figure JPOXMLDOC01-appb-I000058
（式中、Ａはハロゲン原子、トリハロメトキシ基又は１−イミダゾリル基を表す。）
で示されるカルボニル化合物（カルボニル化合物（１２））とを反応させる式（１３）
Figure JPOXMLDOC01-appb-I000059
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物（光学活性化合物（１３））の製造方法。
［１２］溶媒中で、置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを反応させ、ジアステレオマー塩（３）を優先的に晶出させ、得られたジアステレオマー塩（３）を、さらに、酸又は塩基で処理して光学活性な置換トランス−４−アミノピペリジン−３−オール（４）を得、該化合物と、ハロ炭酸エステル（９）又はジアルキルジカーボネート（１０）とを反応させ、光学活性化合物（１１）を得、次いで、光学活性化合物（１１）からＲ２で示される基を除去する式（１４）
Figure JPOXMLDOC01-appb-I000060
（式中、Ｒ１、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物（光学活性化合物（１４））の製造方法。
［１３］溶媒中で、置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを反応させ、ジアステレオマー塩（３）を優先的に晶出させ、得られたジアステレオマー塩（３）を、さらに、酸又は塩基で処理して光学活性な置換トランス−４−アミノピペリジン−３−オール（４）を得、該化合物とハロ炭酸エステル（９）又はジアルキルジカーボネート（１０）とを反応させて光学活性化合物（１１）を得、光学活性化合物（１１）とカルボニル化合物（１２）とを反応させ、光学活性化合物（１３）を得、次いで、光学活性化合物（１３）からＲ２で示される基を除去する式（１５）
Figure JPOXMLDOC01-appb-I000061
（式中、Ｒ１及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物（光学活性化合物（１５））の製造方法。
［１４］ジアステレオマー塩（３）。
［１５］Ｒ１、Ｒ２及びＲ４が全てベンジル基であり、Ｒ３がパラトルエンスルホニル基である［１４］のジアステレオマー塩。
［１６］（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールとＮ−（パラトルエンスルホニル）−Ｌ−フェニルアラニンとのジアステレオマー塩である［１５］のジアステレオマー塩。 According to the invention, in a solvent, the formula (1)
Figure JPOXMLDOC01-appb-I000047
(Wherein R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms. R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms.)
A substituted trans-4-aminopiperidin-3-ol (substituted trans-4-aminopiperidin-3-ol (1)) represented by formula (2)
Figure JPOXMLDOC01-appb-I000048
(Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
By using the optical resolution method of substituted trans-4-aminopiperidin-3-ol, which comprises the step of reacting with an optically active N-protected amino acid represented by the formula (optically active N-protected amino acid (2)) Substituted trans-4-aminopiperidin-3-ol can be advantageously produced industrially.
That is, the present invention is as follows.
[1] A substituted trans-4-aminopiperidin-3-ol (1) is reacted with an optically active N-protected amino acid (2) in a solvent to obtain a compound of formula (3)
Figure JPOXMLDOC01-appb-I000049
(In the formula, R 1 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
Comprising a step of preferentially crystallizing the diastereomeric salt (diastereomeric salt (3)) represented by formula (4)
Figure JPOXMLDOC01-appb-I000050
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
The optically active substituted trans-4-aminopiperidin-3-ol (optically active substituted trans-4-aminopiperidin-3-ol (4)) shown by these.
[2] A substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3). The method for producing optically active substituted trans-4-aminopiperidin-3-ol (4), wherein the obtained diastereomeric salt (3) is further treated with an acid or a base.
[3] R 3 is an optionally substituted (hydrocarbyl having 1 to 12 carbons) carbonyl group or an optionally substituted hydrocarbylsulfonyl group having 1 to 12 carbons [wherein the substituent is carbon A group consisting of an alkoxy group having 1 to 6 carbon atoms, (alkoxy having 1 to 6 carbon atoms) carbonyl group, alkanoyl group having 1 to 6 carbon atoms, alkanoyloxy group having 1 to 6 carbon atoms, halogen atom, nitro group and cyano group One or more substituents selected from the above. ] The method according to [1] or [2].
[4] The method according to [1] to [3], wherein R 1 and R 2 are benzyl groups.
[5] The method according to [4], wherein R 1 and R 2 are benzyl groups, R 3 is a paratoluenesulfonyl group, and R 4 is a benzyl group.
[6] The method according to [1] to [5], wherein the solvent is an alcohol solvent and / or a nitrile solvent.
[7] The substituted trans-4-aminopiperidin-3-ol (1) and the optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3). The manufacturing method of this diastereomeric salt including a process.
[8] Formula (5) in a solvent
Figure JPOXMLDOC01-appb-I000051
(Wherein R 11 represents an alkyl group having 1 to 5 carbon atoms substituted by an aryl group having 6 to 10 carbon atoms, and R 2 represents the same meaning as described above.)
A substituted trans-4-aminopiperidin-3-ol represented by the formula (substituted trans-4-aminopiperidin-3-ol (5)) and an optically active N-protected amino acid (2),
Figure JPOXMLDOC01-appb-I000052
(Wherein R 11 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
The diastereomeric salt (diastereomeric salt (6)) represented by formula (7) is preferentially crystallized out, and the resulting diastereomeric salt (6) is treated with an acid or base to give the formula (7)
Figure JPOXMLDOC01-appb-I000053
(Wherein R 11 , R 2 and * represent the same meaning as described above.)
In optically active substituted trans-4-aminopiperidine shown -3- led ol (optically active substituted trans-4-amino-3-ol (7)), then the groups represented by R 11 and R 2 (8) to remove
Figure JPOXMLDOC01-appb-I000054
(In the formula, * represents the same meaning as described above.)
A process for producing optically active trans-4-aminopiperidin-3-ol represented by the formula:
[9] The method according to [8], wherein R 11 and R 2 are benzyl groups.
[10] A substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3). The diastereomeric salt (3) thus obtained is further treated with an acid or a base to give an optically active substituted trans-4-aminopiperidin-3-ol (4). 9)
Figure JPOXMLDOC01-appb-I000055
(In the formula, R 5 represents an alkyl group having 1 to 12 carbon atoms, and X represents a halogen atom.)
A halocarbonate (halocarbonate (9)) or formula (10)
Figure JPOXMLDOC01-appb-I000056
(Wherein R 5 represents the same meaning as described above.)
A dialkyl dicarbonate (dialkyl dicarbonate (10)) represented by formula (11)
Figure JPOXMLDOC01-appb-I000057
(In the formula, R 1 , R 2 , R 5 and * represent the same meaning as described above.)
The manufacturing method of the optically active compound (optically active compound (11)) shown by these.
[11] A substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3). The diastereomeric salt (3) thus obtained is further treated with an acid or a base to give an optically active substituted trans-4-aminopiperidin-3-ol (4). The compound and the halocarbonate (9 ) Or dialkyl dicarbonate (10) to obtain an optically active compound (11), and then the optically active compound (11) and the formula (12)
Figure JPOXMLDOC01-appb-I000058
(In the formula, A represents a halogen atom, a trihalomethoxy group or a 1-imidazolyl group.)
A carbonyl compound (carbonyl compound (12)) represented by formula (13)
Figure JPOXMLDOC01-appb-I000059
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
The manufacturing method of the optically active compound (optically active compound (13)) shown by these.
[12] A substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3). The obtained diastereomeric salt (3) is further treated with an acid or a base to give an optically active substituted trans-4-aminopiperidin-3-ol (4). The compound and the halocarbonate ( 9) or a dialkyl dicarbonate (10) is reacted to obtain an optically active compound (11), and then the group represented by R 2 is removed from the optically active compound (11) (14)
Figure JPOXMLDOC01-appb-I000060
(Wherein R 1 , R 5 and * represent the same meaning as described above.)
The manufacturing method of the optically active compound (optically active compound (14)) shown by these.
[13] A substituted trans-4-aminopiperidin-3-ol (1) and an optically active N-protected amino acid (2) are reacted in a solvent to preferentially crystallize the diastereomeric salt (3). The diastereomeric salt (3) thus obtained is further treated with an acid or a base to give an optically active substituted trans-4-aminopiperidin-3-ol (4). The compound and the halocarbonate (9 ) Or a dialkyl dicarbonate (10) to obtain an optically active compound (11), an optically active compound (11) and a carbonyl compound (12) to react to obtain an optically active compound (13), Formula (15) for removing the group represented by R 2 from the optically active compound (13)
Figure JPOXMLDOC01-appb-I000061
(In the formula, R 1 and * represent the same meaning as described above.)
The manufacturing method of the optically active compound (optically active compound (15)) shown by these.
[14] Diastereomeric salt (3).
[15] The diastereomeric salt of [14], wherein R 1 , R 2 and R 4 are all benzyl groups and R 3 is a paratoluenesulfonyl group.
[16] Diastereomer of [15], which is a diastereomeric salt of (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol and N- (paratoluenesulfonyl) -L-phenylalanine Mer salt.

　以下、本発明を詳細に説明する。
　本発明に係る光学活性な置換トランス−４−アミノピペリジン−３−オール（４）の製造方法は、溶媒中で、置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを反応させ、ジアステレオマー塩（３）の結晶を取得することにより実施される。
　式（１）において、Ｒ１で示される炭素数１~５のアルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｔｅｒｔ−ブチル基、ペンチル基等が挙げられ、炭素数３~６のアルケニル基としては、例えばアリル基が挙げられる。かかる炭素数１~５のアルキル基又は炭素数３~６のアルケニル基の置換基であり得る炭素数６~１０のアリール基としては、例えば、フェニル基、１−ナフチル基、２−ナフチル基等が挙げられる。Ｒ２で示される基は、上記炭素数１~５のアルキル基が上記炭素数６~１０のアリール基で置換された基を表す。Ｒ１及びＲ２で示される炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基としては、例えば、ベンジル基、１−フェニルエチル基、１−フェニルプロピル基、１−フェニルブチル基、２−メチル−１−フェニルプロピル基、１−フェニルペンチル基、２−メチル−１−フェニルブチル基、３−メチル−１−フェニルブチル基、ジフェニルメチル基、１，１−ジフェニルエチル基、トリフェニルメチル基、（１−ナフチル）メチル基、（２−ナフチル）メチル基、１−（１−ナフチル）エチル基、１−（２−ナフチル）エチル基等が挙げられる。ジアステレオマーの分割効率及び後述するその後の反応の容易さの点で、Ｒ１及びＲ２が独立に、１−アリールアルキル基であることが好ましく、Ｒ１及びＲ２がベンジル基であることがより好ましい。
　置換トランス−４−アミノピペリジン−３−オール（１）には、式（１ａ）及び式（１ｂ）

Figure JPOXMLDOC01-appb-I000062
で示される化合物が存在し、本発明においては、これらの任意の割合の混合物、通常ラセミ体（（１ａ）：（１ｂ）＝１：１）を原料として用いる。
　置換トランス−４−アミノピペリジン−３−オール（１）としては、例えば、トランス−１−ベンジル−４−（メチルアミノ）ピペリジン−３−オール、トランス−１−ベンジル−４−（アリルアミノ）ピペリジン−３−オール、トランス−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オール、トランス−１−ベンジル−４−（１−フェニルエチルアミノ）ピペリジン−３−オール、トランス−１−ジフェニルメチル−４−（メチルアミノ）ピペリジン−３−オール、トランス−１−ジフェニルメチル−４−（アリルアミノ）ピペリジン−３−オール、トランス−１−ジフェニルメチル−４−（ベンジルアミノ）ピペリジン−３−オール、トランス−１−ジフェニルメチル−４−（１−フェニルエチルアミノ）ピペリジン−３−オール等が挙げられる。分割効率の点で、トランス−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールが好ましい。
　置換トランス−４−アミノピペリジン−３−オール（１）は、例えば、３，４−エポキシテトラヒドロピラン化合物とアジド化合物との反応を経由する方法（Ｊ．Ｍｅｄ．Ｃｈｅｍ．４１，３５６３−３５６７（１９９８）参照。）等の公知の方法により製造することができる。
　式（２）において、Ｒ３で示される保護基としては、例えば、置換されていてもよい（炭素数１~１２のヒドロカルビル）カルボニル基及び置換されていてもよい炭素数１~１２のヒドロカルビルスルホニル基が挙げられる。これらの置換基としては、炭素数１~６のアルコキシ基、　　（炭素数１~６のアルコキシ）カルボニル基、炭素数１~６のアルカノイル基、炭素数１~６のアルカノイルオキシ基、ハロゲン原子、ニトロ基、シアノ基が挙げられる。ヒドロカルビルカルボニル基の例としては、アセチル基、ベンゾイル基、ビフェニルカルボニル基が挙げられ、ヒドロカルビルスルホニル基の例としては、メタンスルホニル基、エタンスルホニル基、トリフルオロメタンスルホニル基、ペンタフルオロエタンスルホニル基、トルエンスルホニル基、ベンゼンスルホニル基、ペンタフルオロベンゼンスルホニル基が挙げられる。分割効率の点で置換されていてもよいベンゼンスルホニル基が好ましく、パラトルエンスルホニル基がより好ましい。
　式（２）において、Ｒ４で示される炭素数１~１２のアルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基が挙げられる。かかるアルキル基の置換基であり得る炭素数６~１０のアリール基としては、例えば、フェニル基、１−ナフチル基、２−ナフチル基が挙げられる。分割効率の点で、１−アリールアルキル基であることが好ましく、ベンジル基がより好ましい。
　光学活性Ｎ−保護アミノ酸（２）は、その鏡像異性体のうち、いずれか一方が多く含まれていればよい。その光学純度は、原料に用いるトランス−４−アミノピペリジン−３−オール化合物（１）の光学純度より高ければよいが、９０％ｅｅ以上であることが好ましく、９５％ｅｅ以上であることがより好ましく、９８％ｅｅ以上であることがさらに好ましく、１００％ｅｅであることが最も好ましい。
　光学活性Ｎ−保護アミノ酸（２）としては、例えば、Ｎ−（パラトルエンスルホニル）−Ｌ−フェニルアラニン、Ｎ−（ベンゼンスルホニル）−Ｌ−フェニルアラニン、Ｎ−（メタンスルホニル）−Ｌ−フェニルアラニン、Ｎ−（トリフルオロメタンスルホニル）−Ｌ−フェニルアラニン、Ｎ−（パラトルエンスルホニル）−Ｌ−アラニン、Ｎ−（ベンゼンスルホニル）−Ｌ−アラニン、Ｎ−（メタンスルホニル）−Ｌ−アラニン、Ｎ−（トリフルオロメタンスルホニル）−Ｌ−アラニン、Ｎ−（パラトルエンスルホニル）−Ｌ−ロイシン、Ｎ−（ベンゼンスルホニル）−Ｌ−ロイシン、Ｎ−（メタンスルホニル）−Ｌ−ロイシン、Ｎ−（トリフルオロメタンスルホニル）−Ｌ−ロイシン、及び上記Ｌ体に相当するＤ体の化合物が挙げられる。なかでも、Ｎ−（パラトルエンスルホニル）フェニル−Ｌ−アラニン及びＮ−（パラトルエンスルホニル）フェニル−Ｄ−アラニンが好ましい。
　光学活性Ｎ−保護アミノ酸（２）は、市販のものをそのまま用いることもできるし、市販の光学活性アミノ酸を公知の方法によりＮ保護することにより製造して用いることもできる。
　光学活性Ｎ−保護アミノ酸（２）の使用量は、通常、置換トランス−４−アミノピペリジン−３−オール（１）中に含まれる目的の光学活性な置換トランス−４−アミノピペリジン−３−オール（４）に対して等モル以上である。置換トランス−４−アミノピペリジン−３−オール（１）にラセミ体を用いるときの光学活性Ｎ−保護アミノ酸（２）の使用量は、置換トランス−４−アミノピペリジン−３−オール（１）１モルに対して、通常０．５モル以上である。収率及び経済性の観点から、０．９~２モルであることが好ましく、１．０~１．５モルであることがより好ましい。
　溶媒としては、例えば、ペンタン、ヘキサン、イソヘキサン、ヘプタン、イソヘプタン、オクタン、イソオクタン、ノナン、イソノナン、デカン、イソデカン、ウンデカン、ドデカン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、ｔｅｒｔ−ブチルシクロヘキサン、石油エーテル等の脂肪族炭化水素溶媒；ベンゼン、トルエン、エチルベンゼン、イソプロピルベンゼン、ｔｅｒｔ−ブチルベンゼン、キシレン、メシチレン、モノクロロベンゼン、モノフルオロベンゼン、α，α，α−トリフルオロメチルベンゼン、１，２−ジクロロベンゼン、１，３−ジクロロベンゼン、１，２，３−トリクロロベンゼン、１，２，４−トリクロロベンゼン等の芳香族溶媒；テトラヒドロフラン、メチルテトラヒドロフラン、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル、ジブチルエーテル、ジペンチルエーテル、ジヘキシルエーテル、ジヘプチルエーテル、ジオクチルエーテル、ｔｅｒｔ−ブチルメチルエーテル、シクロペンチルメチルエーテル、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル、アニソール、ジフェニルエーテル等のエーテル溶媒；メタノール、エタノール、１−プロパノール、２−プロパノール、ブチルアルコール、イソブチルアルコール、ｔｅｒｔ−ブチルアルコール、１−ペンタノール、２−ペンタノール、イソペンチルアルコール、１−ヘキサノール、２−ヘキサノール、イソヘキシルアルコール、１−ヘプタノール、２−ヘプタノール、３−ヘプタノール、イソペプチルアルコール、エチレングリコールモノメチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールモノプロピルエーテル、エチレングリコールモノイソプロピルエーテル、エチレングリコールモノブチルエーテル、エチレングリコールモノイソブチルエーテル、エチレングリコールモノｔｅｒｔ−ブチルエーテル、ジエチレングリコールモノメチルエーテル、ジエチレングリコールモノエチルエーテル、ジエチレングリコールモノプロピルエーテル、ジエチレングリコールモノイソプロピルエーテル、ジエチレングリコールモノブチルエーテル、ジエチレングリコールモノイソブチルエーテル、ジエチレングリコールモノｔｅｒｔ−ブチルエーテル等のアルコール溶媒；アセトニトリル、プロピオニトリル、ベンゾニトリル等のニトリル溶媒；ジクロロメタン、クロロホルム、１，２−ジクロロエタン等の塩素化脂肪族炭化水素溶媒；ジメチルスルホキシド、スルホラン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ，Ｎ−ジメチルプロピオンアミド、Ｎ−メチルピロリドン、γ−ブチロラクトン、炭酸ジメチル、炭酸ジエチル、エチレンカーボネート、プロピレンカーボネート、１，３−ジメチル−２−イミダゾリジノン、１，３−ジメチル−３，４，５，６−テトラヒドロ−２（１Ｈ）−ピリジノン等の非プロトン性極性溶媒；酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸イソブチル、酢酸ｔｅｒｔ−ブチル、酢酸アミル、酢酸イソアミル等のエステル溶媒；アセトン、メチルエチルケトン、メチルイソプロピルケトン、メチルイソブチルケトン、シクロペンタノン、シクロヘキサノン等のケトン溶媒；及び水が挙げられる。これら溶媒は単独で用いてもよいし、２種以上を混合して用いてもよい。なかでも、アルコール溶媒及びニトリル溶媒が好ましく、これらの混合溶媒がより好ましい。ここで、アルコール溶媒とニトリル溶媒との混合割合は、容積比で、アルコール溶媒：ニトリル溶媒＝１：１０~５：１の範囲内が好ましい。光学純度や収率の観点から、エタノールとアセトニトリルの混合溶媒が特に好ましい。
　溶媒の使用量は、ジアステレオマー塩（３）の溶解度に応じて適宜選択すればよく、置換トランス−４−アミノピペリジン−３−オール（１）１ｋｇに対して、通常１~１００Ｌ、好ましくは４~４０Ｌの割合である。
　置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）との反応は、溶媒中で、それらを混合することにより実施され、前者に後者を加えても、後者に前者を加えてもよい。得られた混合物中にジアステレオマー塩（３）の結晶が存在していない場合は、混合物を冷却することにより、ジアステレオマー塩（３）を晶出させればよい。また、混合物中にジアステレオマー塩（３）の結晶が存在する場合、そのまま混合物を冷却してもよいが、得られる光学活性な置換トランス−４−アミノピペリジン−３−オール（４）の化学純度や光学純度を高くするため、混合物を加熱してジアステレオマー塩（３）の結晶を溶解させた後に冷却することにより、ジアステレオマー塩（３）を晶出させることが好ましい。かかるジアステレオマー塩（３）の晶出において、ジアステレオマー塩（３）の種晶を用いてもよい。
　置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを混合する温度は、通常０℃以上、溶媒の沸点以下の範囲内である。混合後に加熱する場合は、３０℃以上、溶媒の沸点以下の範囲に加熱する。冷却温度は、通常０~２５℃の範囲内であり、得られるジアステレオマー塩（３）の化学純度や光学純度を高くするため、徐々に冷却することが好ましい。
　ジアステレオマー塩（３）は、用いた置換トランス−４−アミノピペリジン−３−オール（１）中の光学活性体と、用いた光学活性Ｎ−保護アミノ酸（２）とのジアステレオマー塩である。例えば、置換トランス−４−アミノピペリジン−３−オール（１）にトランス−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールを用いた場合、光学活性Ｎ−保護アミノ酸（２）にＮ−（パラトルエンスルホニル）−Ｄ−フェニルアラニンを用いれば、得られるジアステレオマー塩（３）は（３Ｒ，４Ｒ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールとＮ−（パラトルエンスルホニル）−Ｄ−フェニルアラニンとのジアステレオマー塩であり、光学活性Ｎ−保護アミノ酸（２）としてＮ−（パラトルエンスルホニル）−Ｌ−フェニルアラニンを用いれば、得られるジアステレオマー塩（３）は（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールとＮ−（パラトルエンスルホニル）−Ｌ−フェニルアラニンとのジアステレオマー塩である。
　置換トランス−４−アミノピペリジン−３−オール（１）と光学活性Ｎ−保護アミノ酸（２）とを溶媒中で混合して得られる混合物に、例えば濾過やデカンテーション等の固液分離処理を施すことにより、ジアステレオマー塩（３）を固体として単離することができる。また、上記の固液分離処理により得られる液体中には、単離されたジアステレオマー塩（３）を構成するものとは逆の鏡像異性体に富む置換トランス−４−アミノピペリジン−３−オールが含まれており、該液体から常法により、かかる置換トランス−４−アミノピペリジン−３−オールを取得することもできる。
　ジアステレオマー塩（３）を酸又は塩基で処理すれば、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）又はその塩が得られる。かかる処理には、単離されたジアステレオマー塩（３）をそのまま用いてもよいが、得られる光学活性な置換トランス−４−アミノピペリジン−３−オール（４）の化学純度や光学純度の観点から、ジアステレオマー塩（３）を洗浄した後に、酸又は塩基で処理することが好ましい。洗浄には、通常、上記と同じ溶媒を用いることができる。洗浄後は、さらに乾燥処理することが好ましい。乾燥は、常圧又は減圧条件下で、通常２０~８０℃の範囲内で行われる。
　ジアステレオマー塩（３）の酸処理に用いる酸は、光学活性Ｎ−保護アミノ酸（２）よりも酸性度の高いものであればよく、例えば、塩酸、リン酸、硫酸等の鉱酸や、パラトルエンスルホン酸、ベンゼンスルホン酸、カンファースルホン酸等の有機酸が挙げられる。好ましくはパラトルエンスルホン酸である。
　酸処理は、通常、溶媒中で行われる。溶媒としては、例えば、ペンタン、ヘキサン、イソヘキサン、ヘプタン、イソヘプタン、オクタン、イソオクタン、ノナン、イソノナン、デカン、イソデカン、ウンデカン、ドデカン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、ｔｅｒｔ−ブチルシクロヘキサン、石油エーテル等の脂肪族炭化水素溶媒；ベンゼン、トルエン、エチルベンゼン、イソプロピルベンゼン、ｔｅｒｔ−ブチルベンゼン、キシレン、メシチレン、モノクロロベンゼン、モノフルオロベンゼン、α，α，α−トリフルオロメチルベンゼン、１，２−ジクロロベンゼン、１，３−ジクロロベンゼン、１，２，３−トリクロロベンゼン、１，２，４−トリクロロベンゼン等の芳香族溶媒；テトラヒドロフラン、メチルテトラヒドロフラン、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル、ジブチルエーテル、ジペンチルエーテル、ジヘキシルエーテル、ジヘプチルエーテル、ジオクチルエーテル、ｔｅｒｔ−ブチルメチルエーテル、シクロペンチルメチルエーテル、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル、アニソール、ジフェニルエーテル等のエーテル溶媒；メタノール、エタノール、１−プロパノール、２−プロパノール、ブチルアルコール、イソブチルアルコール、ｔｅｒｔ−ブチルアルコール、１−ペンタノール、２−ペンタノール、イソペンチルアルコール、１−ヘキサノール、２−ヘキサノール、イソヘキシルアルコール、１−ヘプタノール、２−ヘプタノール、３−ヘプタノール、イソペプチルアルコール、エチレングリコールモノメチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールモノプロピルエーテル、エチレングリコールモノイソプロピルエーテル、エチレングリコールモノブチルエーテル、エチレングリコールモノイソブチルエーテル、エチレングリコールモノｔｅｒｔ−ブチルエーテル、ジエチレングリコールモノメチルエーテル、ジエチレングリコールモノエチルエーテル、ジエチレングリコールモノプロピルエーテル、ジエチレングリコールモノイソプロピルエーテル、ジエチレングリコールモノブチルエーテル、ジエチレングリコールモノイソブチルエーテル、ジエチレングリコールモノｔｅｒｔ−ブチルエーテル等のアルコール溶媒；アセトニトリル、プロピオニトリル、ベンゾニトリル等のニトリル溶媒；酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸イソブチル、酢酸ｔｅｒｔ−ブチル、酢酸アミル、酢酸イソアミル等のエステル溶媒；アセトン、メチルエチルケトン、メチルイソプロピルケトン、メチルイソブチルケトン、シクロペンタノン、シクロヘキサノン等のケトン溶媒；ジクロロメタン、クロロホルム、１，２−ジクロロエタン等の塩素化脂肪族炭化水素溶媒；及び水が挙げられる。これらの溶媒は、単独で用いてもよいし、２種以上を混合して用いてもよい。なかでも、芳香族溶媒及びアルコール溶媒が好ましく、トルエン、キシレン、メタノール、エタノール及び２−プロパノールがより好ましい。
　酸処理は、ジアステレオマー塩（３）と酸とを混合することにより実施される。得られた処理物中に、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）と用いた酸との塩が析出している場合は、混合物をそのまま、例えば濾過やデカンテーション等の固液分離処理に付すことにより、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）の塩を取得できる。また、該塩の析出が不十分であったり、該塩が析出しなかったりする場合は、該混合物を、例えば、濃縮したり、該塩を溶解し難い溶媒と混合したり、あるいは、加熱したり、冷却したりすることにより、該塩を結晶化させ、得られた混合物を、例えば濾過やデカンテーション等の固液分離処理に付すことにより、該塩を取り出せばよい。得られた塩は、例えば再結晶等の通常の手段により、さらに精製されてもよいし、さらに後述する塩基処理と同様にして、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）を取得してもよい。また、上述した固液分離処理により得られる濾液には、通常、用いた光学活性Ｎ−保護アミノ酸（２）が含まれており、濾液から常法により光学活性Ｎ−保護アミノ酸（２）を回収して本発明に再利用することができる。
　ジアステレオマー塩（３）の塩基処理に用いる塩基としては、例えば、水酸化カリウム、水酸化ナトリウム等のアルカリ金属水酸化物；炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩；ナトリウムメチラート、ナトリウムエチラート、カリウムメチラート、カリウムエチラート等のアルカリ金属アルコラートが挙げられる。アルカリ金属水酸化物が好ましく、水酸化ナトリウムがより好ましい。
　塩基処理は、通常、有機溶媒及び水の存在下に行われる。かかる有機溶媒としては、例えば、ジエチルエーテル、ｔｅｒｔ−ブチルメチルエーテル、メチルイソブチルエーテル、ジイソプロピルエーテル、メチルシクロペンチルエーテル、１，２−ジメトキシメタン、等のエーテル溶媒；トルエン、キシレン、クロロベンゼン等の芳香族溶媒；ヘキサン、シクロヘキサン等の脂肪族炭化水素溶媒；メチルエチルケトン、メチルイソブチルケトン等のケトン溶媒；酢酸エチル、酢酸ｔｅｒｔ−ブチル等のエステル溶媒；ジクロロメタン等のハロゲン化脂肪族炭化水素溶媒；メタノール、エタノール、１−プロパノール、２−プロパノール、ブチルアルコール、イソブチルアルコール、ｔｅｒｔ−ブチルアルコール、１−ペンタノール、２−ペンタノール、イソペンチルアルコール、１−ヘキサノール、２−ヘキサノール、イソヘキシルアルコール、１−ヘプタノール、２−ヘプタノール、３−ヘプタノール、イソペプチルアルコール、エチレングリコールモノメチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールモノプロピルエーテル、エチレングリコールモノイソプロピルエーテル、エチレングリコールモノブチルエーテル、エチレングリコールモノイソブチルエーテル、エチレングリコールモノｔｅｒｔ−ブチルエーテル、ジエチレングリコールモノメチルエーテル、ジエチレングリコールモノエチルエーテル、ジエチレングリコールモノプロピルエーテル、ジエチレングリコールモノイソプロピルエーテル、ジエチレングリコールモノブチルエーテル、ジエチレングリコールモノイソブチルエーテル、ジエチレングリコールモノｔｅｒｔ−ブチルエーテル等のアルコール溶媒；アセトニトリル、プロピオニトリル、ベンゾニトリル等のニトリル溶媒が挙げられる。なかでも、芳香族溶媒及びエステル溶媒が好ましく、トルエン及び酢酸エチルがより好ましい。
　塩基処理は、ジアステレオマー塩（３）と塩基とを混合することにより実施され、前者に後者を加えても、後者に前者を加えてもよい。例えば、上記有機溶媒及び水とジアステレオマー塩との混合物に塩基を加えて、水層を塩基性（通常、ｐＨ８．５以上）とした後、得られた混合物を分液処理することにより、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）を含む有機層を得ることができる。塩基性とした際、結晶が析出する場合は加熱により溶解させてもよいし、濾過により濾別してもよい。該有機層を、必要により水洗処理した後、濃縮処理すれば、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）を単離することができる。得られた光学活性な置換トランス−４−アミノピペリジン−３−オール（４）は、例えば精留、再結晶、カラムクロマトグラフィー等の通常の手段により、さらに精製してもよい。光学活性な置換トランス−４−アミノピペリジン−３−オール（４）は、酸付加塩として取り出すこともできる。また、上記分液処理により得られる水層及び濾液には、用いた光学活性Ｎ−保護アミノ酸（２）が含まれており、該水層及び濾液から常法により光学活性Ｎ−保護アミノ酸（２）を回収して、本発明に再利用することができる。
　かくして得られる光学活性な置換トランス−４−アミノピペリジン−３−オール（４）は、原料に用いた置換トランス−４−アミノピペリジン−３−オール（１）よりも光学純度が向上している。光学活性な置換トランス−４−アミノピペリジン−３−オール（４）としては、例えば、（３Ｓ，４Ｓ）−トランス−１−ベンジル−４−（メチルアミノ）ピペリジン−３−オール、（３Ｓ，４Ｓ）−トランス−１−ベンジル−４−（アリルアミノ）ピペリジン−３−オール、（３Ｓ，４Ｓ）−トランス−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オール、（３Ｓ，４Ｓ）−トランス−１−ベンジル−４−（１−フェニルエチルアミノ）ピペリジン−３−オール、（３Ｓ，４Ｓ）−トランス−１−ジフェニルメチル−４−（メチルアミノ）ピペリジン−３−オール、（３Ｓ，４Ｓ）−トランス−１−ジフェニルメチル−４−（アリルアミノ）ピペリジン−３−オール、（３Ｓ，４Ｓ）−トランス−１−ジフェニルメチル−４−（ベンジルアミノ）ピペリジン−３−オール、（３Ｓ，４Ｓ）−トランス−１−ジフェニルメチル−４−（１−フェニルエチルアミノ）ピペリジン−３−オール、及び上記の各化合物において（３Ｓ，４Ｓ）がそれぞれ（３Ｒ，４Ｒ）に置き換わった化合物が挙げられる。
　次に、Ｒ１が、１位が炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基であって、得られた光学活性な置換トランス−４−アミノピペリジン−３−オール（４）からＲ１で示される基とＲ２で示される基をともに除去する光学活性トランス−４−アミノピペリジン−３−オールの製造方法について説明する。
　この場合、式（５）
Figure JPOXMLDOC01-appb-I000063
（式中、Ｒ１１及びＲ２は上記と同じ意味を表す。）
で示される置換トランス−４−アミノピペリジン−３−オール（５）と、光学活性Ｎ−保護アミノ酸（２）とを溶媒中で反応させ、式（６）
Figure JPOXMLDOC01-appb-I000064
（式中、Ｒ１１、Ｒ２、Ｒ３、Ｒ４及び＊は、それぞれ上記と同じ意味を表す。）
で示されるジアステレオマー塩（６）を優先的に晶出させ、得られた該ジアステレオマー塩（６）を酸又は塩基で処理して式（７）
Figure JPOXMLDOC01-appb-I000065
（式中、Ｒ１１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オール（７）に導き、次いでＲ１１及びＲ２で表される基を除去することにより式（８）
Figure JPOXMLDOC01-appb-I000066
（式中、＊は上記と同じ意味を表す。）
で示される光学活性トランス−４−アミノピペリジン−３−オールが製造される。
　光学活性な置換トランス−４−アミノピペリジン−３−オール（７）は上述した光学活性な置換トランス−４−アミノピペリジン−３−オール（４）の製造方法と同様にして得られ、光学活性な置換トランス−４−アミノピペリジン−３−オール（７）は、これを含む酸処理又は塩基処理後の反応混合物をそのまま用いることができる。また、反応の後処理により反応混合物から単離された光学活性な置換トランス−４−アミノピペリジン−３−オール（７）又はその塩を用いてもよいし、さらに精製された光学活性な置換トランス−４−アミノピペリジン−３−オール（７）又はその塩を用いてもよい。
　Ｒ１とＲ２の除去は、通常のアラルキルの除去方法により実施すればよい。Ｒ１の除去とＲ２の除去とを任意の順序で段階的に行ってもよいし、それらを同時に除去してもよい。例えば、Ｒ１とＲ２とがともにベンジル基である場合、ベンジル保護されたアミノ基を脱保護する還元反応により実施できる。例えば、パラジウムカーボン存在下で光学活性な置換トランス−４−アミノピペリジン−３−オール（７）と水素とを反応させる方法、水酸化パラジウム存在下で光学活性な置換トランス−４−アミノピペリジン−３−オール（７）と水素とを反応させる方法、液体アンモニア中で光学活性な置換トランス−４−アミノピペリジン−３−オール化合物（７）とナトリウムとを反応させる方法等が挙げられるが、パラジウムカーボン存在下で光学活性な置換トランス−４−アミノピペリジン−３−オール（７）と水素とを反応させる方法が好ましい。
　パラジウムカーボンは、含水品であっても乾燥品であってもよい。パラジウム原子の含有量は、通常０．５~５０重量％、好ましくは５~２０重量％である。かかるパラジウムカーボンは市販のものを用いることもできるし、任意の公知の方法により調製して用いることもできる。パラジウムカーボンの使用量は、光学活性な置換トランス−４−アミノピペリジン−３−オール（７）１ｋｇに対して、パラジウムが通常０．１~５０ｇ、好ましくは１~２０ｇ含まれる範囲の量である。カーボンに担持されているパラジウムは、通常０価であり、２価や４価のパラジウム化合物が担持されている場合は、常法により０価に還元して用いることが好ましい。
　水素は、市販の水素ガスを用いることもできるし、任意の公知の方法により発生させて用いることもできる。反応時の水素圧力は通常０．１~５ＭＰａ、好ましくは０．１~１ＭＰａである。また、窒素やアルゴン等の不活性ガスとの混合ガスとして用いることもでき、その場合の反応時の水素分圧は上記の水素圧力と同様である。
　光学活性な置換トランス−４−アミノピペリジン−３−オール（７）と水素との反応は、通常、溶媒中で行われる。該溶媒は、反応に不活性な溶媒であり、例えば、ペンタン、ヘキサン、イソヘキサン、ヘプタン、イソヘプタン、オクタン、イソオクタン、ノナン、イソノナン、デカン、イソデカン、ウンデカン、ドデカン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、ｔｅｒｔ−ブチルシクロヘキサン、石油エーテル等の脂肪族炭化水素溶媒；テトラヒドロフラン、メチルテトラヒドロフラン、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル、ジブチルエーテル、ジペンチルエーテル、ジヘキシルエーテル、ジヘプチルエーテル、ジオクチルエーテル、ｔｅｒｔ−ブチルメチルエーテル、シクロペンチルメチルエーテル、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル等のエーテル溶媒；メタノール、エタノール、１−プロパノール、２−プロパノール、ブチルアルコール、イソブチルアルコール、ｔｅｒｔ−ブチルアルコール、１−ペンタノール、２−ペンタノール、イソペンチルアルコール、１−ヘキサノール、２−ヘキサノール、イソヘキシルアルコール、１−ヘプタノール、２−ヘプタノール、３−ヘプタノール、イソペプチルアルコール、エチレングリコールモノメチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールモノプロピルエーテル、エチレングリコールモノイソプロピルエーテル、エチレングリコールモノブチルエーテル、エチレングリコールモノイソブチルエーテル、エチレングリコールモノｔｅｒｔ−ブチルエーテル、ジエチレングリコールモノメチルエーテル、ジエチレングリコールモノエチルエーテル、ジエチレングリコールモノプロピルエーテル、ジエチレングリコールモノイソプロピルエーテル、ジエチレングリコールモノブチルエーテル、ジエチレングリコールモノイソブチルエーテル、ジエチレングリコールモノｔｅｒｔ−ブチルエーテル等のアルコール溶媒；酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸イソブチル、酢酸ｔｅｒｔ−ブチル、酢酸アミル、酢酸イソアミル等のエステル溶媒；ジメチルスルホキシド、スルホラン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ，Ｎ−ジメチルプロピオンアミド、Ｎ−メチルピロリドン、γ−ブチロラクトン、炭酸ジメチル、炭酸ジエチル、エチレンカーボネート、プロピレンカーボネート、１，３−ジメチル−２−イミダゾリジノン、１，３−ジメチル−３，４，５，６−テトラヒドロ−２（１Ｈ）−ピリジノン等の非プロトン性極性溶媒及び水が挙げられる。これらの溶媒は、単独で用いてもよいし、２種以上を混合して用いてもよい。アルコール溶媒が好ましく、なかでもエタノールがより好ましい。溶媒の使用量は、光学活性な置換トランス−４−アミノピペリジン−３−オール（７）１ｋｇに対して、通常１~５０Ｌ、好ましくは２~１５Ｌの割合である。
　反応温度は、通常０~１００℃、好ましくは２０~７０℃である。反応時間は、反応温度、反応試剤の使用量、水素圧力等にもよるが、通常１~２４時間である。反応の進行は、薄層クロマトグラフィー，ガスクロマトグラフィー、高速液体クロマトグラフィー等の通常の手段により確認できる。
　反応試剤の混合順序は特に規定されず、例えば、溶媒中で、光学活性な置換トランス−４−アミノピペリジン−３−オール（７）とパラジウムカーボンを混合し、得られた混合物に水素を加える方法や、水素雰囲気下でパラジウムカーボンに光学活性な置換トランス−４−アミノピペリジン−３−オール（７）を加えていく方法等により実施される。溶媒中で、光学活性な置換トランス−４−アミノピペリジン−３−オール（７）とパラジウムカーボンとの混合物に水素を加える方法が好ましい。
　反応終了後の混合物には光学活性トランス−４−アミノピペリジン−３−オールが含まれており、かかる混合物に、例えば濾過、抽出、水洗等の通常の後処理を施し、次いで、蒸留や結晶化等の通常の単離処理を施せば、光学活性トランス−４−アミノピペリジン−３−オールを取り出すことができる。このとき、光学活性トランス−４−アミノピペリジン−３−オールを、例えば塩酸、安息香酸、酒石酸等の酸との塩として取り出してもよい。取り出された光学活性トランス−４−アミノピペリジン−３−オール又はその塩は、例えば、再結晶；抽出精製；蒸留；活性炭、シリカ、アルミナ等への吸着処理；シリカゲルカラムクロマトグラフィー等のクロマトグラフィー法の通常の精製処理により、さらに精製されてもよい。
　かくして得られる光学活性トランス−４−アミノピペリジン−３−オールは、通常、反応に供した光学活性な置換トランス−４−アミノピペリジン−３−オール（７）の光学活性を維持している。即ち、（３Ｓ，４Ｓ）−トランス−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールからは（３Ｓ，４Ｓ）−トランス−４−アミノピペリジン−３−オールが得られ、（３Ｒ，４Ｒ）−トランス−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールからは（３Ｒ，４Ｒ）−トランス−４−アミノピペリジン−３−オールが得られる。
　次に、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）とハロ炭酸エステル（９）又はジアルキルカーボネート（１０）とを反応させる式（１１）
Figure JPOXMLDOC01-appb-I000067
（式中、Ｒ１、Ｒ２、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性化合物（１１）の製造方法について説明する。以下、ハロ炭酸エステル（９）とジアルキルカーボネート（１０）とを総称して「カーバメート化剤」と称することもある。
　本反応に供される光学活性な置換トランス−４−アミノピペリジン−３−オール（４）は、これを含む前記の酸処理又は塩基処理後の混合物をそのまま用いることができる。後処理により反応混合物から単離された光学活性な置換トランス−４−アミノピペリジン−３−オール（４）又はその塩を用いてもよいし、さらに前記の精製処理により精製された光学活性な置換トランス−４−アミノピペリジン−３−オール（４）又はその塩を用いてもよい。
　式（９）においてＸで示されるハロゲン原子としては、例えば塩素原子、臭素原子、ヨウ素原子が挙げられる。
　式（９）及び（１０）において、Ｒ５で示される炭素数１~１２のアルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基が挙げられる。かかるアルキル基の置換基である炭素数６~１０のアリール基としては、例えば、フェニル基、１−ナフチル基、２−ナフチル基が挙げられる。
　ハロ炭酸エステル（９）としては、例えばクロロ炭酸メチル、クロロ炭酸エチル、クロロ炭酸イソプロピル、クロロ炭酸ブチルが挙げられる。ジアルキルジカーボネート（１０）としては、例えばジｔｅｒｔ−ブチルジカーボネートが挙げられる。カーバメート化剤としては、ジアルキルジカーボネート（１０）の方が好ましく、なかでもジｔｅｒｔ−ブチルジカーボネートがより好ましい。これらカーバメート化剤は、市販のものを用いることもできるし、任意の公知の方法により調製して用いることもできる。
　カーバメート化剤の使用量は、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）１モルに対して、通常１~５モル、好ましくは１~２モルの割合である。
　本反応は、通常、塩基の存在下で行われる。塩基としては、例えば、水酸化カリウム、水酸化ナトリウム、水酸化リチウム等のアルカリ金属水酸化物；炭酸カリウム、炭酸ナトリウム、炭酸リチウム等のアルカリ金属炭酸塩；トリエチルアミン、ジイソプロピルエチルアミン等の三級アミン化合物；ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ−ブトキシド、カリウムｔｅｒｔ−ブトキシド等のアルカリ金属アルコキシド；水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物；水素化カルシウム等のアルカリ土類金属水素化物；ブチルリチウム、リチウムジイソプロピルアミン、リチウムヘキサメチルジシラザン等のアルキル金属化合物が挙げられる。なかでも、三級アミン化合物が好ましい。
　塩基の使用量は、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）１モルに対して、通常１~１０モル、好ましくは１~３モルの割合である。
　本反応は、通常、溶媒の存在下で行われる。該溶媒は、反応に不活性な溶媒であり、例えば、ペンタン、ヘキサン、イソヘキサン、ヘプタン、イソヘプタン、オクタン、イソオクタン、ノナン、イソノナン、デカン、イソデカン、ウンデカン、ドデカン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、ｔｅｒｔ−ブチルシクロヘキサン、石油エーテル等の脂肪族炭化水素溶媒；ベンゼン、トルエン、エチルベンゼン、イソプロピルベンゼン、ｔｅｒｔ−ブチルベンゼン、キシレン、メシチレン、モノクロロベンゼン、モノフルオロベンゼン、α，α，α−トリフルオロメチルベンゼン、１，２−ジクロロベンゼン、１，３−ジクロロベンゼン、１，２，３−トリクロロベンゼン、１，２，４−トリクロロベンゼン等の芳香族溶媒；テトラヒドロフラン、メチルテトラヒドロフラン、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル、ジブチルエーテル、ジペンチルエーテル、ジヘキシルエーテル、ジヘプチルエーテル、ジオクチルエーテル、ｔｅｒｔ−ブチルメチルエーテル、シクロペンチルメチルエーテル、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル、アニソール、ジフェニルエーテル等のエーテル溶媒；ジメチルスルホキシド、スルホラン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ，Ｎ−ジメチルプロピオンアミド、Ｎ−メチルピロリドン、γ−ブチロラクトン、炭酸ジメチル、炭酸ジエチル、エチレンカーボネート、プロピレンカーボネート、１，３−ジメチル−２−イミダゾリジノン、１，３−ジメチル−３，４，５，６−テトラヒドロ−２（１Ｈ）−ピリジノン等の非プロトン性極性溶媒；アセトニトリル、プロピオニトリル等のニトリル溶媒及び水が挙げられる。これらの溶媒は、単独で用いてもよいし、２種以上を混合して用いてもよい。エーテル溶媒が好ましく、なかでもテトラヒドロフランがより好ましい。溶媒の使用量は、化合物１ｋｇに対して、通常１~５０Ｌ、好ましくは２~１５Ｌの割合である。
　反応温度は通常−３０~７０℃、好ましくは０~５０℃である。反応時間は、反応温度や反応試剤の使用量等にもよるが、通常１~２０時間である。反応の進行は、薄層クロマトグラフィー、ガスクロマトグラフィー、高速液体クロマトグラフィー等の通常の手段により確認できる。
　反応試剤の混合順序は特に規定されず、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）と溶媒と塩基の混合物中に、カーバメート化剤を加えるという順序で混合することが好ましい。
　反応終了後の混合物中には光学活性化合物（１１）が含まれており、かかる混合物に、例えば濾過、抽出、水洗等の通常の後処理を施し、次いで、蒸留や結晶化等の通常の後処理を施せば、光学活性化合物（１１）を単離することができる。このとき、光学活性化合物（１１）を、例えば塩酸、安息香酸、酒石酸等の任意の酸との塩として取り出してもよい。単離された光学活性化合物（１１）又はその塩は、例えば、再結晶；抽出精製；蒸留；活性炭、シリカ、アルミナ等への吸着処理；シリカゲルカラムクロマトグラフィー等のクロマトグラフィー法等の通常の精製処理により、されに精製されてもよい。
　光学活性化合物（１１）としては、例えば、メチル　ベンジル［（３Ｓ，４Ｓ）−１−ベンジル−トランス−３−ヒドロキシピペリジン−４−イル］カーバメート、メチル　ベンジル［（３Ｒ，４Ｒ）−１−ベンジル−トランス−３−ヒドロキシピペリジン−４−イル］カーバメート、エチル　ベンジル［（３Ｓ，４Ｓ）−１−ベンジル−トランス−３−ヒドロキシピペリジン−４−イル］カーバメート、ベンジル［（３Ｒ，４Ｒ）−１−ベンジル−トランス−３−ヒドロキシピペリジン−４−イル］カーバメート、イソプロピル　ベンジル［（３Ｓ，４Ｓ）−１−ベンジル−トランス−３−ヒドロキシピペリジン−４−イル］カーバメート、［（３Ｒ，４Ｒ）−１−ベンジル−トランス−３−ヒドロキシピペリジン−４−イル］カーバメート、ｔｅｒｔ−ブチル　ベンジル［（３Ｓ，４Ｓ）−１−ベンジル−トランス−３−ヒドロキシピペリジン−４−イル］カーバメート、ｔｅｒｔ−ブチル　ベンジル［（３Ｒ，４Ｒ）−１−ベンジル−トランス−３−ヒドロキシピペリジン−４−イル］カーバメートが挙げられる。かくして得られる光学活性化合物（１１）は、通常、本反応に供した光学活性な置換トランス−４−アミノピペリジン−３−オール（４）の光学活性を維持している。
　次に、得られた光学活性化合物（１１）からＲ２で示される基を除去する式（１４）
Figure JPOXMLDOC01-appb-I000068
（式中、Ｒ１、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性化合物（１４）の製造方法について説明する。
　本製造方法に使用される光学活性化合物（１１）は、これを含む前記の反応終了後の混合物をそのまま用いることができる。勿論、前記の単離処理により反応混合物からを取り出された光学活性化合物（１１）又はその塩を用いてもよいし、さらに前記の精製処理により精製された光学活性化合物（１１）又はその塩を用いてもよい。
　該反応は、Ｒ１やＣＯＯＲ５で示される基よりも、Ｒ２を優先して除去できる条件であれば、特に限定されず、任意の公知の方法にて実施できる。Ｒ１とＲ２がともにベンジル基であるとき、脱保護反応の条件は、例えば、パラジウムカーボン存在下で光学活性化合物（１１）と水素とを反応させる方法や水酸化パラジウム存在下で光学活性化合物（１１）と水素とを反応させる方法等が挙げられるが、好ましくは、パラジウムカーボン存在下で光学活性化合物（１１）と水素とを反応させる方法である。その方法は、具体的には、光学活性な置換トランス−４−アミノピペリジン−３−オール（７）より式（８）で示される光学活性トランス−４−アミノピペリジン−３−オールを製造する方法と同様に実施できる。
　反応終了後の混合物には光学活性化合物（１４）が含まれており、かかる混合物に、例えばろ過、抽出、水洗等の通常の後処理を施し、次いで、蒸留や結晶化等の通常の単離処理を施せば、光学活性化合物（１４）を得ることができる。このとき、光学活性化合物（１４）を、例えば塩酸、安息香酸、酒石酸等の酸との塩として単離してもよい。取り出された光学活性化合物（１４）又はその塩は、例えば、再結晶；抽出精製；蒸留；活性炭、シリカ、アルミナ等への吸着処理；シリカゲルカラムクロマトグラフィー等のクロマトグラフィー法；等の通常の精製処理により、さらに精製されてもよい。
　光学活性化合物（１４）としては、例えば、メチル　ベンジル［（３Ｓ，４Ｓ）−３−ヒドロキシピペリジン−４−イル］カーバメート、エチル　ベンジル［（３Ｓ，４Ｓ）−３−ヒドロキシピペリジン−４−イル］カーバメート、イソプロピルベンジル［（３Ｓ，４Ｓ）−３−ヒドロキシピペリジン−４−イル］カーバメート、ｔｅｒｔ−ブチル　ベンジル［（３Ｓ，４Ｓ）−３−ヒドロキシピペリジン−４−イル］カーバメート及び上記各化合物の（３Ｓ，４Ｓ）がそれぞれ（３Ｒ，４Ｒ）に置き換わった化合物が挙げられる。かくして得られる光学活性化合物（１４）は、通常、本反応に供した光学活性化合物（１１）の光学活性を維持している。
　次に、上述の光学分割により得られた光学活性な置換トランス−４−アミノピペリジン−３−オール（４）とカルボニル化合物（１２）とを反応させる式（１３）
Figure JPOXMLDOC01-appb-I000069
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性化合物（１３）の製造方法について説明する。
　本反応に供される光学活性な置換トランス−４−アミノピペリジン−３−オール（４）は、これを含む前記の酸処理又は塩基処理後の混合物をそのまま用いることができる。もちろん、前記の単離処理により反応混合物からを取り出された光学活性な置換トランス−４−アミノピペリジン−３−オール（４）又はその塩を用いてもよいし、さらに前記の精製処理により精製された光学活性な置換トランス−４−アミノピペリジン−３−オール（４）又はその塩を用いてもよい。
　式（１２）においてＡで示されるハロゲン原子としては、例えば塩素原子、臭素原子等が挙げられる。トリハロメチル基としては、例えばトリクロロメチル基、トリブロモメチル基等が挙げられる。
　カルボニル化合物（１２）としては、例えばホスゲン、トリホスゲン、式
Figure JPOXMLDOC01-appb-I000070
で示されるカルボニルジイミダゾール等が挙げられ、なかでも、取り扱いの容易なカルボニルジイミダゾールが好ましい。これらカルボニル化剤は、市販のものを用いることもできるし、任意の公知の方法により調製して用いることもできる。
　カルボニル化合物（１２）の使用量は、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）１モルに対して、通常１~５モル、好ましくは１~２モルの割合である。
　本反応は、通常、塩基の存在下で行われる。塩基としては、例えば、水酸化カリウム、水酸化ナトリウム、水酸化リチウム等のアルカリ金属水酸化物；炭酸カリウム、炭酸ナトリウム、炭酸リチウム等のアルカリ金属炭酸塩；トリエチルアミン、ジイソプロピルエチルアミン等の三級アミン化合物；ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ−ブトキシド、カリウムｔｅｒｔ−ブトキシド等のアルカリ金属アルコキシド；水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物；水素化カルシウム等のアルカリ土類金属水素化物；ブチルリチウム、リチウムジイソプロピルアミン、リチウムヘキサメチルジシラザン等のアルキル金属化合物が挙げられる。なかでも、三級アミン化合物が好ましい。
　塩基の使用量は、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）１モルに対して、通常１~１０モル、好ましくは１~３モルの割合である。
　本反応は、通常、溶媒の存在下で行われる。該溶媒は、反応に不活性な溶媒であり、例えば、ペンタン、ヘキサン、イソヘキサン、ヘプタン、イソヘプタン、オクタン、イソオクタン、ノナン、イソノナン、デカン、イソデカン、ウンデカン、ドデカン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、ｔｅｒｔ−ブチルシクロヘキサン、石油エーテル等の脂肪族炭化水素溶媒；ベンゼン、トルエン、エチルベンゼン、イソプロピルベンゼン、ｔｅｒｔ−ブチルベンゼン、キシレン、メシチレン、モノクロロベンゼン、モノフルオロベンゼン、α，α，α−トリフルオロメチルベンゼン、１，２−ジクロロベンゼン、１，３−ジクロロベンゼン、１，２，３−トリクロロベンゼン、１，２，４−トリクロロベンゼン等の芳香族溶媒；テトラヒドロフラン、メチルテトラヒドロフラン、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル、ジブチルエーテル、ジペンチルエーテル、ジヘキシルエーテル、ジヘプチルエーテル、ジオクチルエーテル、ｔｅｒｔ−ブチルメチルエーテル、シクロペンチルメチルエーテル、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル、アニソール、ジフェニルエーテル等のエーテル溶媒；ジメチルスルホキシド、スルホラン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ，Ｎ−ジメチルプロピオンアミド、Ｎ−メチルピロリドン、γ−ブチロラクトン、炭酸ジメチル、炭酸ジエチル、エチレンカーボネート、プロピレンカーボネート、１，３−ジメチル−２−イミダゾリジノン、１，３−ジメチル−３，４，５，６−テトラヒドロ−２（１Ｈ）−ピリジノン等の非プロトン性極性溶媒；アセトニトリル、プロピオニトリル等のニトリル溶媒及び水が挙げられる。これら溶媒は、単独で用いてもよいし、２種以上を混合して用いてもよい。芳香族溶媒が好ましく、なかでもトルエンがより好ましい。溶媒の使用量としては、化合物１ｋｇに対して、通常１~５０Ｌ、好ましくは２~１５Ｌの割合である。
　反応温度は、通常−３０~１００℃、好ましくは０~５０℃である。反応時間は、反応温度や反応試剤の使用量等にもよるが、通常１~２０時間である。反応の進行は、薄層クロマトグラフィー、ガスクロマトグラフィー、高速液体クロマトグラフィー等の通常の手段により確認できる。
　反応試剤の混合順序は特に規定されないが、光学活性な置換トランス−４−アミノピペリジン−３−オール（４）と溶媒と塩基の混合物中に、続いてカルボニル化剤を加えるという順序で混合することが好ましい。
　反応終了後の混合物中には光学活性化合物（１３）が含まれており、かかる混合物に、例えば濾過、抽出、水洗等の通常の後処理を施し、次いで、蒸留や結晶化等の通常の単離処理を施せば、光学活性化合物（１３）を得ることができる。このとき、光学活性化合物（１３）を、例えば塩酸、安息香酸、酒石酸等の任意の酸との塩として単離してもよい。単離された光学活性化合物（１３）又はその塩は、例えば、再結晶；抽出精製；蒸留；活性炭、シリカ、アルミナ等への吸着処理；シリカゲルカラムクロマトグラフィー等のクロマトグラフィー法の通常の精製処理により、されに精製されてもよい。
　光学活性化合物（１３）としては、例えば、（３ａＳ，７ａＳ）−１−ベンジル−５−メチルヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−アリル−５−メチルヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−（１−フェニルエチル）−５−メチルヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−（２−フェニルエチル）−５−メチルヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１，５−ジベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−アリル−５−ベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−（１−フェニルエチル）−５−ベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−（２−フェニルエチル）−５−ベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−ベンジル−５−ジフェニルメチル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−アリル−５−ジフェニルメチル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−（１−フェニルエチル）−５−ジフェニルメチル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−（２−フェニルエチル）−５−ジフェニルメチル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、及び上記各化合物における（３ａＳ，７ａＳ）がそれぞれ（３ａＲ，７ａＲ）に置き換わった化合物等が挙げられる。かくして得られる光学活性化合物（１３）は、通常、本反応に供した光学活性な置換トランス−４−アミノピペリジン−３−オール（４）の光学活性を維持している。
　次に、得られた光学活性化合物（１３）からＲ２で示される基を除去する式（１５）
Figure JPOXMLDOC01-appb-I000071
（式中、Ｒ１及び＊は上記と同じ意味を表す。）
で示される光学活性化合物（１５）の製造方法について説明する。
　本反応に供される光学活性化合物（１３）は、これを含む前記の反応終了後の混合物をそのまま用いることができる。後処理により反応混合物からを単離された光学活性化合物（１３）又はその塩を用いてもよいし、さらに精製された光学活性化合物（１３）又はその塩を用いてもよい。
　本反応は、Ｒ１よりもＲ２を優先して除去できる条件であれば、特に限定されず、任意の公知の方法にて実施できる。Ｒ１とＲ２がともにベンジル基であるとき、脱保護反応の条件は、例えば、パラジウムカーボン存在下で光学活性化合物（１３）と水素とを反応させる方法や水酸化パラジウム存在下で光学活性化合物（１３）と水素とを反応させる方法が挙げられるが、好ましくは、パラジウムカーボン存在下で光学活性化合物（１３）と水素とを反応させる方法である。その方法は、具体的には、光学活性な置換トランス−４−アミノピペリジン−３−オール（７）より式（８）で示される光学活性トランス−４−アミノピペリジン−３−オールを製造する方法と同様に実施できる。
　反応終了後の混合物には光学活性化合物（１５）が含まれており、かかる混合物に、例えば濾過、抽出、水洗等の通常の後処理を施し、次いで、蒸留や結晶化等の通常の単離処理を施せば、光学活性化合物（１５）を取り出すことができる。このとき、光学活性化合物（１５）を、例えば塩酸、安息香酸、酒石酸等の任意の酸との塩として単離してもよい。単離された光学活性化合物（１５）又はその塩は、例えば、再結晶；抽出精製；蒸留；活性炭、シリカ、アルミナ等への吸着処理；シリカゲルカラムクロマトグラフィー等のクロマトグラフィー法；等の通常の精製処理により、さらに精製されてもよい。
　光学活性化合物（１５）としては、例えば（３ａＳ，７ａＳ）−１−ベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン（３ａＳ，７ａＳ）−１−アリル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−（１−フェニルエチル）−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、（３ａＳ，７ａＳ）−１−（２−フェニルエチル）−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン、及び上記各化合物における（３ａＳ，７ａＳ）がそれぞれ（３ａＲ，７ａＲ）に置き換わった化合物等が挙げられる。かくして得られる光学活性化合物（１５）は、通常、本反応に供した光学活性化合物（１３）の光学活性を維持している。 Hereinafter, the present invention will be described in detail.
The process for producing optically active substituted trans-4-aminopiperidin-3-ol (4) according to the present invention comprises substituted trans-4-aminopiperidin-3-ol (1) and optically active N-protection in a solvent. The reaction is carried out by reacting with the amino acid (2) to obtain a crystal of the diastereomeric salt (3).
In formula (1), R 1 Examples of the alkyl group having 1 to 5 carbon atoms represented by the formula include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, and a pentyl group. For example, an allyl group can be mentioned. Examples of the aryl group having 6 to 10 carbon atoms that can be a substituent of the alkyl group having 1 to 5 carbon atoms or the alkenyl group having 3 to 6 carbon atoms include, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and the like. Is mentioned. R 2 Is a group in which the alkyl group having 1 to 5 carbon atoms is substituted with the aryl group having 6 to 10 carbon atoms. R 1 And R 2 Examples of the alkyl group having 1 to 5 carbon atoms substituted by the aryl group having 6 to 10 carbon atoms represented by the formula: benzyl group, 1-phenylethyl group, 1-phenylpropyl group, 1-phenylbutyl group, 2 -Methyl-1-phenylpropyl group, 1-phenylpentyl group, 2-methyl-1-phenylbutyl group, 3-methyl-1-phenylbutyl group, diphenylmethyl group, 1,1-diphenylethyl group, triphenylmethyl Group, (1-naphthyl) methyl group, (2-naphthyl) methyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group and the like. In terms of the resolution efficiency of diastereomers and the ease of subsequent reactions described below, R 1 And R 2 Are independently a 1-arylalkyl group, R 1 And R 2 Is more preferably a benzyl group.
Substituted trans-4-aminopiperidin-3-ol (1) includes formula (1a) and formula (1b)
Figure JPOXMLDOC01-appb-I000062
In the present invention, a mixture of these at an arbitrary ratio, usually a racemate ((1a) :( 1b) = 1: 1) is used as a raw material.
As substituted trans-4-aminopiperidin-3-ol (1), for example, trans-1-benzyl-4- (methylamino) piperidin-3-ol, trans-1-benzyl-4- (allylamino) piperidine- 3-ol, trans-1-benzyl-4- (benzylamino) piperidin-3-ol, trans-1-benzyl-4- (1-phenylethylamino) piperidin-3-ol, trans-1-diphenylmethyl- 4- (methylamino) piperidin-3-ol, trans-1-diphenylmethyl-4- (allylamino) piperidin-3-ol, trans-1-diphenylmethyl-4- (benzylamino) piperidin-3-ol, trans -1-diphenylmethyl-4- (1-phenylethylamino) piperidine-3- Lumpur, and the like. Trans-1-benzyl-4- (benzylamino) piperidin-3-ol is preferable in terms of resolution efficiency.
Substituted trans-4-aminopiperidin-3-ol (1) is obtained, for example, by a method via a reaction between a 3,4-epoxytetrahydropyran compound and an azide compound (J. Med. Chem. 41, 3563-3567 (1998). It can be produced by a known method such as
In formula (2), R 3 Examples of the protecting group represented by the formula include an optionally substituted (hydrocarbon having 1 to 12 carbons) carbonyl group and an optionally substituted hydrocarbylsulfonyl having 1 to 12 carbons. These substituents include an alkoxy group having 1 to 6 carbon atoms, (alkoxy having 1 to 6 carbon atoms) carbonyl group, an alkanoyl group having 1 to 6 carbon atoms, an alkanoyloxy group having 1 to 6 carbon atoms, a halogen atom, Examples thereof include a nitro group and a cyano group. Examples of hydrocarbylcarbonyl groups include acetyl, benzoyl, and biphenylcarbonyl groups. Examples of hydrocarbylsulfonyl groups include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, pentafluoroethanesulfonyl, and toluenesulfonyl. Group, benzenesulfonyl group, pentafluorobenzenesulfonyl group. A benzenesulfonyl group which may be substituted is preferable in terms of resolution efficiency, and a paratoluenesulfonyl group is more preferable.
In formula (2), R 4 Examples of the alkyl group having 1 to 12 carbon atoms represented by: methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, Nonyl group, decyl group, undecyl group, dodecyl group can be mentioned. Examples of the aryl group having 6 to 10 carbon atoms that can be a substituent of the alkyl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. From the viewpoint of resolution efficiency, a 1-arylalkyl group is preferable, and a benzyl group is more preferable.
The optically active N-protected amino acid (2) only needs to contain any one of its enantiomers. The optical purity may be higher than the optical purity of the trans-4-aminopiperidin-3-ol compound (1) used as a raw material, but is preferably 90% ee or more, more preferably 95% ee or more. Preferably, it is more preferably 98% ee or more, and most preferably 100% ee.
Examples of the optically active N-protected amino acid (2) include N- (paratoluenesulfonyl) -L-phenylalanine, N- (benzenesulfonyl) -L-phenylalanine, N- (methanesulfonyl) -L-phenylalanine, N- (Trifluoromethanesulfonyl) -L-phenylalanine, N- (paratoluenesulfonyl) -L-alanine, N- (benzenesulfonyl) -L-alanine, N- (methanesulfonyl) -L-alanine, N- (trifluoromethanesulfonyl) ) -L-alanine, N- (paratoluenesulfonyl) -L-leucine, N- (benzenesulfonyl) -L-leucine, N- (methanesulfonyl) -L-leucine, N- (trifluoromethanesulfonyl) -L- And leucine and D-form compounds corresponding to the L-form. Of these, N- (paratoluenesulfonyl) phenyl-L-alanine and N- (paratoluenesulfonyl) phenyl-D-alanine are preferable.
As the optically active N-protected amino acid (2), a commercially available product can be used as it is, or a commercially available optically active amino acid can be used by N-protecting it by a known method.
The amount of the optically active N-protected amino acid (2) used is usually the desired optically active substituted trans-4-aminopiperidin-3-ol contained in the substituted trans-4-aminopiperidin-3-ol (1). It is equimolar or more with respect to (4). The amount of the optically active N-protected amino acid (2) used when the racemate is used as the substituted trans-4-aminopiperidin-3-ol (1) is the same as that of the substituted trans-4-aminopiperidin-3-ol (1) 1 It is usually 0.5 mol or more with respect to mol. From the viewpoint of yield and economy, it is preferably 0.9 to 2 mol, more preferably 1.0 to 1.5 mol.
Examples of the solvent include fats such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, and petroleum ether. Group hydrocarbon solvent: benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, diethyl ether Ether solvents such as dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, anisole, diphenyl ether Methanol, ethanol, 1-propanol, 2-propanol, butyl alcohol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol mono Chill ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono tert-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl Alcohol solvents such as ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono tert-butyl ether; nitrile solvents such as acetonitrile, propionitrile, benzonitrile; dichloromethane, Chlorinated aliphatic hydrocarbon solvents such as chloroform and 1,2-dichloroethane; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone, γ -Butyrolactone, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyridinone, etc. Aprotic polar solvents: ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate, etc .; acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, Include and water; Ropentanon, ketone solvents such as cyclohexanone. These solvents may be used alone or in combination of two or more. Among these, an alcohol solvent and a nitrile solvent are preferable, and a mixed solvent thereof is more preferable. Here, the mixing ratio of the alcohol solvent and the nitrile solvent is preferably in the range of alcohol solvent: nitrile solvent = 1: 10 to 5: 1 as a volume ratio. From the viewpoint of optical purity and yield, a mixed solvent of ethanol and acetonitrile is particularly preferable.
The amount of the solvent used may be appropriately selected according to the solubility of the diastereomeric salt (3), and is usually 1 to 100 L, preferably 1 to 100 L, preferably 1 kg of substituted trans-4-aminopiperidin-3-ol (1). The ratio is 4 to 40L.
The reaction of the substituted trans-4-aminopiperidin-3-ol (1) and the optically active N-protected amino acid (2) is carried out by mixing them in a solvent, and even if the latter is added to the former, The former may be added to the latter. When the diastereomeric salt (3) crystal does not exist in the obtained mixture, the diastereomeric salt (3) may be crystallized by cooling the mixture. In addition, when diastereomeric salt (3) crystals are present in the mixture, the mixture may be cooled as it is, but the chemistry of the optically active substituted trans-4-aminopiperidin-3-ol (4) obtained. In order to increase the purity and optical purity, it is preferable to crystallize the diastereomeric salt (3) by heating the mixture to dissolve the crystals of the diastereomeric salt (3) and then cooling. In the crystallization of the diastereomeric salt (3), a seed crystal of the diastereomeric salt (3) may be used.
The temperature at which the substituted trans-4-aminopiperidin-3-ol (1) and the optically active N-protected amino acid (2) are mixed is usually in the range of 0 ° C. or higher and the boiling point of the solvent or lower. When heating after mixing, it is heated to a range of 30 ° C. or higher and the boiling point of the solvent or lower. The cooling temperature is usually in the range of 0 to 25 ° C., and in order to increase the chemical purity and optical purity of the resulting diastereomeric salt (3), it is preferable to cool gradually.
The diastereomeric salt (3) is a diastereomeric salt of the optically active substance in the substituted trans-4-aminopiperidin-3-ol (1) used and the optically active N-protected amino acid (2) used. is there. For example, when trans-1-benzyl-4- (benzylamino) piperidin-3-ol is used for substituted trans-4-aminopiperidin-3-ol (1), N is added to the optically active N-protected amino acid (2). When-(paratoluenesulfonyl) -D-phenylalanine is used, the resulting diastereomeric salt (3) is (3R, 4R) -1-benzyl-4- (benzylamino) piperidin-3-ol and N- (para Diastereomeric salt with toluenesulfonyl) -D-phenylalanine, and diastereomeric salt obtained by using N- (paratoluenesulfonyl) -L-phenylalanine as the optically active N-protected amino acid (2) (3) (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol and N- (paratoluenesulfo Le) is a diastereomeric salts with -L- phenylalanine.
The mixture obtained by mixing substituted trans-4-aminopiperidin-3-ol (1) and optically active N-protected amino acid (2) in a solvent is subjected to solid-liquid separation treatment such as filtration or decantation. Thus, the diastereomeric salt (3) can be isolated as a solid. Further, in the liquid obtained by the above solid-liquid separation treatment, substituted trans-4-aminopiperidine-3-rich in the opposite enantiomer to that constituting the isolated diastereomeric salt (3). Ole is contained, and such a substituted trans-4-aminopiperidin-3-ol can be obtained from the liquid by a conventional method.
When the diastereomeric salt (3) is treated with an acid or a base, an optically active substituted trans-4-aminopiperidin-3-ol (4) or a salt thereof is obtained. For such treatment, the isolated diastereomeric salt (3) may be used as it is, but the chemical purity and optical purity of the resulting optically active substituted trans-4-aminopiperidin-3-ol (4) are not affected. From the viewpoint, it is preferable to treat the diastereomeric salt (3) with an acid or a base after washing. Usually, the same solvent as described above can be used for washing. After washing, it is preferable to further dry. Drying is usually performed within a range of 20 to 80 ° C. under normal pressure or reduced pressure.
The acid used for the acid treatment of the diastereomeric salt (3) may be any acid having higher acidity than the optically active N-protected amino acid (2). For example, mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid, Organic acids such as paratoluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and the like can be mentioned. Paratoluenesulfonic acid is preferable.
The acid treatment is usually performed in a solvent. Examples of the solvent include fats such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, and petroleum ether. Group hydrocarbon solvent: benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1, Aromatic solvents such as 3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, diethyl ether Ether solvents such as dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, anisole, diphenyl ether Methanol, ethanol, 1-propanol, 2-propanol, butyl alcohol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol mono Chill ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono tert-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl Alcohol solvents such as ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono tert-butyl ether; nitrile solvents such as acetonitrile, propionitrile, benzonitrile; ethyl acetate, acetic acid Ester solvents such as propyl, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate; ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclopentanone, cyclohexanone; dichloromethane, Chlorinated aliphatic hydrocarbon solvents such as chloroform, 1,2-dichloroethane; and water. These solvents may be used alone or in combination of two or more. Of these, aromatic solvents and alcohol solvents are preferable, and toluene, xylene, methanol, ethanol and 2-propanol are more preferable.
The acid treatment is carried out by mixing the diastereomeric salt (3) and an acid. When a salt of the optically active substituted trans-4-aminopiperidin-3-ol (4) and the acid used is precipitated in the treated product, the mixture is used as it is, for example, filtration, decantation, etc. By subjecting to solid-liquid separation treatment, an optically active salt of substituted trans-4-aminopiperidin-3-ol (4) can be obtained. If the salt is not sufficiently precipitated or does not precipitate, the mixture can be concentrated, mixed with a solvent in which the salt is difficult to dissolve, or heated, for example. The salt may be crystallized by cooling or cooling, and the resulting mixture may be subjected to a solid-liquid separation treatment such as filtration or decantation to remove the salt. The obtained salt may be further purified by ordinary means such as recrystallization, and optically active substituted trans-4-aminopiperidin-3-ol (4 ) May be acquired. The filtrate obtained by the above-described solid-liquid separation treatment usually contains the optically active N-protected amino acid (2) used, and the optically active N-protected amino acid (2) is recovered from the filtrate by a conventional method. And can be reused in the present invention.
Examples of the base used for the base treatment of the diastereomeric salt (3) include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methylate and sodium Examples thereof include alkali metal alcoholates such as ethylate, potassium methylate, and potassium ethylate. Alkali metal hydroxides are preferred, and sodium hydroxide is more preferred.
The base treatment is usually performed in the presence of an organic solvent and water. Examples of the organic solvent include ether solvents such as diethyl ether, tert-butyl methyl ether, methyl isobutyl ether, diisopropyl ether, methyl cyclopentyl ether, and 1,2-dimethoxymethane; aromatic solvents such as toluene, xylene, and chlorobenzene Aliphatic hydrocarbon solvents such as hexane and cyclohexane; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; ester solvents such as ethyl acetate and tert-butyl acetate; halogenated aliphatic hydrocarbon solvents such as dichloromethane; methanol, ethanol, 1 -Propanol, 2-propanol, butyl alcohol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, -Hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol mono Butyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono tert-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethyl Alcohol solvents such as glycol monobutyl tert- butyl ether; acetonitrile, propionitrile, nitriles solvents such as benzonitrile. Of these, aromatic solvents and ester solvents are preferable, and toluene and ethyl acetate are more preferable.
The base treatment is carried out by mixing the diastereomeric salt (3) and a base, and the latter may be added to the former or the former may be added to the latter. For example, by adding a base to the organic solvent and a mixture of water and diastereomeric salt to make the aqueous layer basic (usually pH 8.5 or higher), the resulting mixture is subjected to a liquid separation treatment, An organic layer containing optically active substituted trans-4-aminopiperidin-3-ol (4) can be obtained. When it is made basic, when crystals are precipitated, it may be dissolved by heating or may be filtered off by filtration. If the organic layer is washed with water if necessary and then concentrated, the optically active substituted trans-4-aminopiperidin-3-ol (4) can be isolated. The obtained optically active substituted trans-4-aminopiperidin-3-ol (4) may be further purified by ordinary means such as rectification, recrystallization, column chromatography and the like. Optically active substituted trans-4-aminopiperidin-3-ol (4) can also be taken out as an acid addition salt. Moreover, the optically active N-protected amino acid (2) used is contained in the aqueous layer and filtrate obtained by the liquid separation treatment, and the optically active N-protected amino acid (2) is obtained from the aqueous layer and the filtrate by a conventional method. ) Can be recovered and reused in the present invention.
The optically active substituted trans-4-aminopiperidin-3-ol (4) thus obtained has an improved optical purity compared to the substituted trans-4-aminopiperidin-3-ol (1) used as a raw material. Examples of the optically active substituted trans-4-aminopiperidin-3-ol (4) include (3S, 4S) -trans-1-benzyl-4- (methylamino) piperidin-3-ol, (3S, 4S). ) -Trans-1-benzyl-4- (allylamino) piperidin-3-ol, (3S, 4S) -trans-1-benzyl-4- (benzylamino) piperidin-3-ol, (3S, 4S) -trans -1-benzyl-4- (1-phenylethylamino) piperidin-3-ol, (3S, 4S) -trans-1-diphenylmethyl-4- (methylamino) piperidin-3-ol, (3S, 4S) -Trans-1-diphenylmethyl-4- (allylamino) piperidin-3-ol, (3S, 4S) -trans-1-diphenylmethyl-4- (Benzylamino) piperidin-3-ol, (3S, 4S) -trans-1-diphenylmethyl-4- (1-phenylethylamino) piperidin-3-ol, and (3S, 4S) in each of the above compounds Examples include compounds in which (3R, 4R) is replaced.
Next, R 1 Is an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms at the 1-position, from the obtained optically active substituted trans-4-aminopiperidin-3-ol (4) R 1 And a group represented by 2 A method for producing optically active trans-4-aminopiperidin-3-ol, in which both groups represented by the above are removed, will be described.
In this case, equation (5)
Figure JPOXMLDOC01-appb-I000063
(Wherein R 11 And R 2 Represents the same meaning as above. )
The substituted trans-4-aminopiperidin-3-ol (5) represented by the formula (6) is reacted with an optically active N-protected amino acid (2) in a solvent to give a compound of formula (6)
Figure JPOXMLDOC01-appb-I000064
(Wherein R 11 , R 2 , R 3 , R 4 And * represent the same meaning as described above. )
The diastereomeric salt (6) represented by formula (7) is preferentially crystallized, and the resulting diastereomeric salt (6) is treated with an acid or a base to give the formula (7)
Figure JPOXMLDOC01-appb-I000065
(Wherein R 11 , R 2 And * represent the same meaning as described above. )
To an optically active substituted trans-4-aminopiperidin-3-ol (7) represented by 11 And R 2 By removing the group represented by formula (8)
Figure JPOXMLDOC01-appb-I000066
(In the formula, * represents the same meaning as described above.)
To produce optically active trans-4-aminopiperidin-3-ol.
Optically active substituted trans-4-aminopiperidin-3-ol (7) is obtained in the same manner as the above-mentioned production method of optically active substituted trans-4-aminopiperidin-3-ol (4), and is optically active. As the substituted trans-4-aminopiperidin-3-ol (7), the reaction mixture containing the acid or base can be used as it is. Further, an optically active substituted trans-4-aminopiperidin-3-ol (7) or a salt thereof isolated from the reaction mixture by workup of the reaction may be used, or a further purified optically active substituted trans -4-Aminopiperidin-3-ol (7) or a salt thereof may be used.
R 1 And R 2 This removal may be carried out by a normal aralkyl removal method. R 1 Removal and R 2 May be performed stepwise in an arbitrary order, or they may be removed simultaneously. For example, R 1 And R 2 When both are benzyl groups, it can be carried out by a reduction reaction for deprotecting a benzyl-protected amino group. For example, a method of reacting optically active substituted trans-4-aminopiperidin-3-ol (7) with hydrogen in the presence of palladium carbon, optically active substituted trans-4-aminopiperidine-3 in the presence of palladium hydroxide Examples include a method of reacting ol (7) with hydrogen, a method of reacting optically active substituted trans-4-aminopiperidin-3-ol compound (7) with sodium in liquid ammonia, and the like. A method in which an optically active substituted trans-4-aminopiperidin-3-ol (7) is reacted with hydrogen in the presence thereof is preferable.
The palladium carbon may be a water-containing product or a dry product. The content of palladium atoms is usually 0.5 to 50% by weight, preferably 5 to 20% by weight. Such palladium carbon may be a commercially available product, or may be prepared and used by any known method. The amount of palladium carbon used is an amount in the range of usually 0.1 to 50 g, preferably 1 to 20 g of palladium with respect to 1 kg of optically active substituted trans-4-aminopiperidin-3-ol (7). . Palladium supported on carbon is usually zero-valent, and when a divalent or tetravalent palladium compound is supported, it is preferably used after being reduced to zero by a conventional method.
As hydrogen, commercially available hydrogen gas can be used, or it can be generated and used by any known method. The hydrogen pressure during the reaction is usually 0.1 to 5 MPa, preferably 0.1 to 1 MPa. It can also be used as a mixed gas with an inert gas such as nitrogen or argon, and the hydrogen partial pressure during the reaction in this case is the same as the hydrogen pressure described above.
The reaction of optically active substituted trans-4-aminopiperidin-3-ol (7) with hydrogen is usually carried out in a solvent. The solvent is a solvent inert to the reaction, for example, pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert -Aliphatic hydrocarbon solvents such as butylcyclohexane and petroleum ether; tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether , Ether solvents such as cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether; , Ethanol, 1-propanol, 2-propanol, butyl alcohol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, isohexyl alcohol, 1- Heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene Glycol mono tert-butyl ether, diethylene glycol monomethyl ether, diethylene glycol Alcohol solvents such as ethyl acetate, diethylene glycol monopropyl ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono tert-butyl ether; ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert acetate Ester solvents such as butyl, amyl acetate, isoamyl acetate; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone, γ-butyrolactone, carbonic acid Dimethyl, diethyl carbonate, ethylene carbonate, propylene carbonate, 1,3-dimethyl-2-imi Zorijinon, 1,3-dimethyl-3,4,5,6-tetrahydro -2 (IH) - aprotic polar solvent and water can be mentioned, such as pyridinone. These solvents may be used alone or in combination of two or more. Alcohol solvents are preferred, with ethanol being more preferred. The amount of the solvent used is usually 1 to 50 L, preferably 2 to 15 L, per 1 kg of the optically active substituted trans-4-aminopiperidin-3-ol (7).
The reaction temperature is usually 0 to 100 ° C., preferably 20 to 70 ° C. The reaction time is usually 1 to 24 hours, although it depends on the reaction temperature, the amount of reaction reagent used, the hydrogen pressure, and the like. The progress of the reaction can be confirmed by usual means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
The order of mixing the reaction reagents is not particularly limited. For example, a method in which optically active substituted trans-4-aminopiperidin-3-ol (7) and palladium carbon are mixed in a solvent and hydrogen is added to the resulting mixture. Or a method of adding optically active substituted trans-4-aminopiperidin-3-ol (7) to palladium carbon under a hydrogen atmosphere. A method of adding hydrogen to a mixture of optically active substituted trans-4-aminopiperidin-3-ol (7) and palladium carbon in a solvent is preferred.
The mixture after completion of the reaction contains optically active trans-4-aminopiperidin-3-ol, and this mixture is subjected to usual post-treatment such as filtration, extraction, washing with water, and then distillation and crystallization. Etc., the optically active trans-4-aminopiperidin-3-ol can be taken out. At this time, optically active trans-4-aminopiperidin-3-ol may be taken out as a salt with an acid such as hydrochloric acid, benzoic acid or tartaric acid. The extracted optically active trans-4-aminopiperidin-3-ol or a salt thereof is, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; chromatography method such as silica gel column chromatography Further purification may be carried out by the usual purification treatment.
The optically active trans-4-aminopiperidin-3-ol thus obtained usually maintains the optical activity of the optically active substituted trans-4-aminopiperidin-3-ol (7) subjected to the reaction. That is, (3S, 4S) -trans-1-benzyl-4- (benzylamino) piperidin-3-ol provides (3S, 4S) -trans-4-aminopiperidin-3-ol, (3R, 4R) -trans-4-aminopiperidin-3-ol is obtained from 4R) -trans-1-benzyl-4- (benzylamino) piperidin-3-ol.
Next, the formula (11) in which an optically active substituted trans-4-aminopiperidin-3-ol (4) is reacted with a halocarbonate (9) or a dialkyl carbonate (10)
Figure JPOXMLDOC01-appb-I000067
(Wherein R 1 , R 2 , R 5 And * represent the same meaning as described above. )
The manufacturing method of optically active compound (11) shown by is demonstrated. Hereinafter, the halocarbonate (9) and the dialkyl carbonate (10) may be collectively referred to as “carbamate agent”.
As the optically active substituted trans-4-aminopiperidin-3-ol (4) subjected to this reaction, the above-mentioned mixture after acid treatment or base treatment containing it can be used as it is. An optically active substituted trans-4-aminopiperidin-3-ol (4) or a salt thereof isolated from the reaction mixture by post-treatment may be used, or optically active substitution purified by the above-described purification treatment. Trans-4-aminopiperidin-3-ol (4) or a salt thereof may be used.
Examples of the halogen atom represented by X in the formula (9) include a chlorine atom, a bromine atom, and an iodine atom.
In formulas (9) and (10), R 5 Examples of the alkyl group having 1 to 12 carbon atoms represented by: methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, Nonyl group, decyl group, undecyl group, dodecyl group can be mentioned. Examples of the aryl group having 6 to 10 carbon atoms, which is a substituent of the alkyl group, include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
Examples of the halocarbonate (9) include methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, and butyl chlorocarbonate. Examples of the dialkyl dicarbonate (10) include ditert-butyl dicarbonate. As the carbamate agent, dialkyl dicarbonate (10) is preferable, and ditert-butyl dicarbonate is more preferable. These carbamate agents can be commercially available, or can be prepared and used by any known method.
The amount of the carbamate used is usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the optically active substituted trans-4-aminopiperidin-3-ol (4).
This reaction is usually performed in the presence of a base. Examples of the base include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali metal carbonates such as potassium carbonate, sodium carbonate and lithium carbonate; tertiary amine compounds such as triethylamine and diisopropylethylamine Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride; Examples thereof include alkyl metal compounds such as butyl lithium, lithium diisopropylamine, and lithium hexamethyldisilazane. Of these, tertiary amine compounds are preferred.
The amount of the base used is usually 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the optically active substituted trans-4-aminopiperidin-3-ol (4).
This reaction is usually performed in the presence of a solvent. The solvent is a solvent inert to the reaction. -Aliphatic hydrocarbon solvents such as butylcyclohexane and petroleum ether; benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, α, α, α-trifluoromethylbenzene, Aromatic solvents such as 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran , Diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, anisole, Ether solvents such as diphenyl ether; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone, γ-butyrolactone, dimethyl carbonate, diethyl carbonate, ethylene carbonate , Propylene carbonate, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydride Aprotic polar solvents such as b-2 (1H) -pyridinone; nitrile solvents such as acetonitrile and propionitrile; and water. These solvents may be used alone or in combination of two or more. Ether solvents are preferred, and tetrahydrofuran is more preferred. The amount of the solvent to be used is generally 1 to 50 L, preferably 2 to 15 L, per 1 kg of the compound.
The reaction temperature is usually −30 to 70 ° C., preferably 0 to 50 ° C. The reaction time is usually 1 to 20 hours, although it depends on the reaction temperature and the amount of reaction reagent used. The progress of the reaction can be confirmed by usual means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
The order of mixing the reaction reagents is not particularly limited, and it is preferable to mix the optically active substituted trans-4-aminopiperidin-3-ol (4), the solvent and the base in the order of adding the carbamate agent. .
The mixture after completion of the reaction contains the optically active compound (11), and the mixture is subjected to usual post-treatment such as filtration, extraction and washing, followed by usual post-treatment such as distillation and crystallization. By performing the treatment, the optically active compound (11) can be isolated. At this time, the optically active compound (11) may be taken out as a salt with any acid such as hydrochloric acid, benzoic acid or tartaric acid. The isolated optically active compound (11) or a salt thereof is, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; ordinary purification such as chromatography methods such as silica gel column chromatography It may be further purified by treatment.
Examples of the optically active compound (11) include methyl benzyl [(3S, 4S) -1-benzyl-trans-3-hydroxypiperidin-4-yl] carbamate, methyl benzyl [(3R, 4R) -1-benzyl- Trans-3-hydroxypiperidin-4-yl] carbamate, ethyl benzyl [(3S, 4S) -1-benzyl-trans-3-hydroxypiperidin-4-yl] carbamate, benzyl [(3R, 4R) -1-benzyl -Trans-3-hydroxypiperidin-4-yl] carbamate, isopropyl benzyl [(3S, 4S) -1-benzyl-trans-3-hydroxypiperidin-4-yl] carbamate, [(3R, 4R) -1-benzyl -Trans-3-hydroxypiperidin-4-yl] carbamate, t tert-butyl benzyl [(3S, 4S) -1-benzyl-trans-3-hydroxypiperidin-4-yl] carbamate, tert-butyl benzyl [(3R, 4R) -1-benzyl-trans-3-hydroxypiperidine- 4-yl] carbamate. The optically active compound (11) thus obtained usually maintains the optical activity of the optically active substituted trans-4-aminopiperidin-3-ol (4) subjected to this reaction.
Next, from the obtained optically active compound (11), R 2 Formula (14) for removing the group represented by
Figure JPOXMLDOC01-appb-I000068
(Wherein R 1 , R 5 And * represent the same meaning as described above. )
The manufacturing method of optically active compound (14) shown by is shown.
As the optically active compound (11) used in this production method, the mixture containing the above-mentioned reaction mixture after completion of the reaction can be used as it is. Of course, the optically active compound (11) extracted from the reaction mixture by the isolation treatment or a salt thereof may be used, or the optically active compound (11) or salt thereof purified by the purification treatment is used. It may be used.
The reaction is R 1 And COOR 5 R than the group represented by 2 If it is the conditions which can be removed preferentially, it will not specifically limit, It can implement by arbitrary well-known methods. R 1 And R 2 When both are benzyl groups, the deprotection reaction conditions are, for example, a method of reacting optically active compound (11) with hydrogen in the presence of palladium carbon, or optically active compound (11) and hydrogen in the presence of palladium hydroxide. The optically active compound (11) is preferably reacted with hydrogen in the presence of palladium carbon. Specifically, the method is a method for producing optically active trans-4-aminopiperidin-3-ol represented by the formula (8) from optically active substituted trans-4-aminopiperidin-3-ol (7). It can be carried out in the same way.
The mixture after completion of the reaction contains the optically active compound (14), and the mixture is subjected to usual post-treatment such as filtration, extraction and washing with water, and then subjected to usual isolation such as distillation and crystallization. By performing the treatment, the optically active compound (14) can be obtained. At this time, the optically active compound (14) may be isolated as a salt with an acid such as hydrochloric acid, benzoic acid or tartaric acid. The extracted optically active compound (14) or a salt thereof is, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina or the like; chromatography method such as silica gel column chromatography; It may be further purified by treatment.
Examples of the optically active compound (14) include methyl benzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate, ethyl benzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate. , Isopropylbenzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate, tert-butylbenzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate and (3S, 4S) is replaced by (3R, 4R), respectively. The optically active compound (14) thus obtained usually maintains the optical activity of the optically active compound (11) subjected to this reaction.
Next, the formula (13) in which the optically active substituted trans-4-aminopiperidin-3-ol (4) obtained by the above optical resolution is reacted with the carbonyl compound (12)
Figure JPOXMLDOC01-appb-I000069
(Wherein R 1 , R 2 And * represent the same meaning as described above. )
The manufacturing method of optically active compound (13) shown by is demonstrated.
As the optically active substituted trans-4-aminopiperidin-3-ol (4) subjected to this reaction, the above-mentioned mixture after acid treatment or base treatment containing it can be used as it is. Of course, an optically active substituted trans-4-aminopiperidin-3-ol (4) or a salt thereof taken out from the reaction mixture by the isolation treatment may be used, and further purified by the purification treatment. Alternatively, optically active substituted trans-4-aminopiperidin-3-ol (4) or a salt thereof may be used.
Examples of the halogen atom represented by A in Formula (12) include a chlorine atom and a bromine atom. Examples of the trihalomethyl group include a trichloromethyl group and a tribromomethyl group.
Examples of the carbonyl compound (12) include phosgene, triphosgene, and the formula
Figure JPOXMLDOC01-appb-I000070
In particular, carbonyldiimidazole that is easy to handle is preferable. These carbonylating agents may be commercially available or may be prepared and used by any known method.
The amount of the carbonyl compound (12) to be used is generally 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the optically active substituted trans-4-aminopiperidin-3-ol (4).
This reaction is usually performed in the presence of a base. Examples of the base include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali metal carbonates such as potassium carbonate, sodium carbonate and lithium carbonate; tertiary amine compounds such as triethylamine and diisopropylethylamine Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride; Examples thereof include alkyl metal compounds such as butyl lithium, lithium diisopropylamine, and lithium hexamethyldisilazane. Of these, tertiary amine compounds are preferred.
The amount of the base used is usually 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the optically active substituted trans-4-aminopiperidin-3-ol (4).
This reaction is usually performed in the presence of a solvent. The solvent is a solvent inert to the reaction. -Aliphatic hydrocarbon solvents such as butylcyclohexane and petroleum ether; benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene, α, α, α-trifluoromethylbenzene, Aromatic solvents such as 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran , Diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, anisole, Ether solvents such as diphenyl ether; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone, γ-butyrolactone, dimethyl carbonate, diethyl carbonate, ethylene carbonate , Propylene carbonate, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydride Aprotic polar solvents such as b-2 (1H) -pyridinone; nitrile solvents such as acetonitrile and propionitrile; and water. These solvents may be used alone or in combination of two or more. Aromatic solvents are preferred, with toluene being more preferred. The amount of the solvent to be used is generally 1 to 50 L, preferably 2 to 15 L, per 1 kg of the compound.
The reaction temperature is usually −30 to 100 ° C., preferably 0 to 50 ° C. The reaction time is usually 1 to 20 hours, although it depends on the reaction temperature and the amount of reaction reagent used. The progress of the reaction can be confirmed by usual means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
The order of mixing the reaction reagents is not particularly limited, but mixing in the order of adding the carbonylating agent to the optically active substituted trans-4-aminopiperidin-3-ol (4), solvent and base mixture. Is preferred.
The mixture after completion of the reaction contains the optically active compound (13). The mixture is subjected to usual post-treatment such as filtration, extraction and washing with water, and then subjected to usual simple treatment such as distillation and crystallization. If the release treatment is performed, the optically active compound (13) can be obtained. At this time, the optically active compound (13) may be isolated as a salt with any acid such as hydrochloric acid, benzoic acid, tartaric acid and the like. The isolated optically active compound (13) or a salt thereof is, for example, recrystallized; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; ordinary purification treatment of chromatographic methods such as silica gel column chromatography And may be further purified.
Examples of the optically active compound (13) include (3aS, 7aS) -1-benzyl-5-methylhexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS , 7aS) -1-allyl-5-methylhexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (1-phenylethyl)- 5-methylhexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (2-phenylethyl) -5-methylhexahydro [1, 3] Oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1,5-dibenzyl-hexahydro [1,3] oxazolo [5,4-c] pyridine-2 (1H ) -On, (3aS, 7a ) -1-allyl-5-benzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (1-phenylethyl) -5 Benzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (2-phenylethyl) -5-benzyl-hexahydro [1,3] Oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1-benzyl-5-diphenylmethyl-hexahydro [1,3] oxazolo [5,4-c] pyridine-2 ( 1H) -one, (3aS, 7aS) -1-allyl-5-diphenylmethyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1 -(1- Enylethyl) -5-diphenylmethyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (2-phenylethyl) -5-diphenylmethyl -Hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, and compounds in which (3aS, 7aS) in each of the above compounds are replaced with (3aR, 7aR), respectively. The optically active compound (13) thus obtained usually maintains the optical activity of the optically active substituted trans-4-aminopiperidin-3-ol (4) subjected to this reaction.
Next, from the obtained optically active compound (13), R 2 Formula (15) for removing the group represented by
Figure JPOXMLDOC01-appb-I000071
(Wherein R 1 And * represent the same meaning as described above. )
A method for producing the optically active compound (15) represented by the formula will be described.
As the optically active compound (13) to be subjected to this reaction, the mixture containing the optically active compound (13) after completion of the reaction can be used as it is. The optically active compound (13) or a salt thereof isolated from the reaction mixture by post-treatment may be used, or a further purified optically active compound (13) or a salt thereof may be used.
This reaction is called R 1 Than R 2 If it is the conditions which can be removed preferentially, it will not specifically limit, It can implement by arbitrary well-known methods. R 1 And R 2 When both are benzyl groups, the deprotection reaction conditions are, for example, a method of reacting optically active compound (13) with hydrogen in the presence of palladium carbon, or optically active compound (13) and hydrogen in the presence of palladium hydroxide. The optically active compound (13) is preferably reacted with hydrogen in the presence of palladium carbon. Specifically, the method is a method for producing optically active trans-4-aminopiperidin-3-ol represented by the formula (8) from optically active substituted trans-4-aminopiperidin-3-ol (7). It can be carried out in the same way.
The mixture after completion of the reaction contains the optically active compound (15), and the mixture is subjected to usual post-treatment such as filtration, extraction and washing with water, and then subjected to usual isolation such as distillation and crystallization. If the treatment is applied, the optically active compound (15) can be taken out. At this time, the optically active compound (15) may be isolated as a salt with any acid such as hydrochloric acid, benzoic acid or tartaric acid. The isolated optically active compound (15) or a salt thereof can be obtained by, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina or the like; chromatography method such as silica gel column chromatography; Further purification may be performed by a purification treatment.
Examples of the optically active compound (15) include (3aS, 7aS) -1-benzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one (3aS, 7aS) -1- Allyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (1-phenylethyl) -hexahydro [1,3] oxazolo [5, 4-c] pyridin-2 (1H) -one, (3aS, 7aS) -1- (2-phenylethyl) -hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one And compounds in which (3aS, 7aS) in each compound is replaced with (3aR, 7aR), respectively. The optically active compound (15) thus obtained usually maintains the optical activity of the optically active compound (13) subjected to this reaction.

　以下、実施例により本発明をより詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
実施例１：（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールの光学分割
　（３ＲＳ，４ＲＳ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オール１．１ｇ（３．７ｍｍｏｌ）とエタノール５ｍＬとアセトニトリル１０ｍＬとを混合した。混合物を２０~３５℃に保ちながら、そこに、Ｎ−（ｐ−トルエンスルホニル）−Ｌ−フェニルアラニン１．２ｇ（３．７ｍｍｏｌ）を加えたところ、結晶が析出した。混合物を６０℃に加温し結晶を溶解した。次いで混合物を２０℃まで徐々に冷却し、結晶を析出させた。得られた結晶を濾過し、アセトニトリル３ｍＬで洗浄後、減圧乾燥することにより、白色結晶として（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールとＮ−（ｐ−トルエンスルホニル）−Ｌ−フェニルアラニンとの塩０．８５ｇを得た。収率は３７％であった。
１Ｈ−ＮＭＲ（ｐｐｍ　ｉｎ　ＣＤ３ＯＤ）δ：１．５９−１．７０（１Ｈ，ｍ），１．８９−１．９４（１Ｈ，ａｐｐｔ　ｔ，Ｊ＝１０Ｈｚ），２．０２−２．１４（２Ｈ，ｍ），２．３７（３Ｈ，ｓ），２．７４−２．７８（１Ｈ，ｍ），２．８０−３．１２（４Ｈ，ｍ），３．５５（１Ｈ，ｄ，Ｊ＝１３Ｈ），３．６２（１Ｈ，ｄ，Ｊ＝１３Ｈ），３．６６−３．７３（１Ｈ，ｍ），３．７８−３．８１（１Ｈ，ｍ），４．１７（１Ｈ，ｄ，Ｊ＝１３Ｈ），４．２２（１Ｈ，ｄ，Ｊ＝１３Ｈ），７．１２−７．２３（５Ｈ，ｍ），７．２５−７．３２（７Ｈ，ｍ），７．３８−７．４７（５Ｈ，ｍ），７．５９（２Ｈ，ｄ，Ｊ＝８Ｈｚ）
　高速液体クロマトグラフィー（ＨＰＬＣ）により分析したところ、該結晶中の（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールの光学純度は、９２％ｅｅであった。
＜ＨＰＬＣ分析条件＞
カラム　　：ダイセル化学工業製Ｃｈｉｒａｌｐａｋ（登録商標）
　　　　　　ＩＣ　２５０ｍｍ×４．６ｍｍ
カラム温度：４０℃
移動層　　：２−プロパノール（ジエチルアミン０．１容積％含有）／
　　　　　　ｎ−ヘキサン（ジエチルアミン０．１容積％含有）＝２０／８０
流速　　　：０．５ｍＬ／分
観測　　　：ＵＶ２１７ｎｍ
保持時間　：１４．３分（３Ｓ，４Ｓ体）、２０．４分（３Ｒ，４Ｒ体）
実施例２~３、比較例１~１３
　（３ＲＳ，４ＲＳ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オール８４μｍｏｌと表１に示す分割剤８４μｍｏｌと溶媒との混合物を３０~５０℃で５分間攪拌した後、２０~２５℃で静置した。結晶が析出しなかったものはさらに０~５℃まで冷却し静置した。結晶の析出の有無及び得られた結晶中のトランス−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールの光学純度を表１に示す。

Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-I000073
実施例４：（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールの製造
　実施例１で得た（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールとＮ−（ｐ−トルエンスルホニル）−Ｌ−フェニルアラニンとの塩０．７７ｇ（１．３ｍｍｏｌ）と酢酸エチル１０ｍＬとエタノール１ｍＬとを混合した。混合物の内温を２０~３５℃に保ちながら、そこに、１ｍｏｌ／Ｌ水酸化ナトリウム８ｍＬを滴下した。得られた混合物を分液し、有機層をさらに１ｍｏｌ／Ｌ水酸化ナトリウム３ｍＬで３回洗浄した。該有機層を飽和食塩水３ｍｌで洗浄し、無水硫酸ナトリウムで脱水処理した後、溶媒を減圧留去することにより、（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オール０．３６ｇを得た。収率は９７％であった。
実施例５：（３Ｓ，４Ｓ）−４−アミノピペリジン−３−オールの製造
　実施例４と同様の方法で得た（３Ｓ，４Ｓ）−１−ベンジル−４−ベンジルアミノピペリジン−３−オール１．０１ｇ（３．４ｍｍｏｌ）とエタノール１０ｍＬをオートクレーブ反応装置内で混合し、系内を窒素雰囲気とした。そこに、１０重量％パラジウムカーボン（５５重量％含水品、ＰＥ型、エヌ・イー　ケムキャット株式会社製、Ｌｏｔ．２１７−０７６８８０）０．１０ｇを加えた後、系内を水素で置換し、水素圧０．４ＭＰａにて５０℃で６時間攪拌した。反応終了後、触媒を濾去し、得られた濾液を濃縮することにより、潮解性の結晶０．４２ｇを得た。該結晶の１Ｈ−ＮＭＲを測定したところ、その主成分は（３Ｓ，４Ｓ）−４−アミノピペリジン−３−オールであった。
実施例６：ｔｅｒｔ−ブチル　ベンジル［（３Ｓ，４Ｓ）−３−ヒドロキシピペリジン−４−イル］カーバメートの製造
　実施例４と同様の方法で得た（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オール０．２７ｇ（０．９１ｍｍｏｌ）とトルエン１ｍＬを混合し、そこにトリエチルアミン０．２５ｍＬ（１．８３ｍｍｏｌ）とジｔｅｒｔ−ブチルジカーボネート０．２４ｇ（１．１０ｍｍｏｌ）及びテトラヒドロフラン１ｍＬを加え、得られた混合物を室温で２時間攪拌した。反応終了後、反応混合物に水５ｍＬを加えた後、トルエン１０ｍＬで抽出処理し、さらに水層をトルエン５ｍＬで抽出処理した。トルエン層を合わせ、無水硫酸ナトリウムで乾燥した後、濃縮した。得られた濃縮残渣０．４４ｇとエタノール１０ｍＬをオートクレーブ反応装置内で混合し、系内を窒素雰囲気とした。そこに、２０重量％水酸化パラジウムカーボン（５０重量％含水品）０．０４４ｇを加えた後、系内を水素で置換し、水素圧０．５ＭＰａにて５０℃で１２時間攪拌した。反応終了後、触媒を濾去し、得られた濾液を濃縮して、ｔｅｒｔ−ブチル　ベンジル［（３Ｓ，４Ｓ）−３−ヒドロキシピペリジン−４−イル］カーバメート０．２６ｇを得た。収率は９２％であった。
実施例７：（３ａＳ，７ａＳ）−１，５−ジベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オンの製造
　実施例４と同様の方法で得た（３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オール１．８３ｇ（６．１７ｍｍｏｌ）とトルエン１５ｍＬとカルボニルジイミダゾール１．１０ｇ（６．７９ｍｍｏｌ）とを室温で混合した。得られた混合物を８０℃の油浴で加熱しながら、そこにトリエチルアミン１．７ｍＬ（１２．３ｍｍｏｌ）を加え、そのまま３時間攪拌した。反応終了後、反応混合物を氷冷した後、飽和食塩水５ｍＬを加え、室温に戻して分液し、有機層を得た。さらに得られた有機層を飽和食塩水５ｍＬで洗浄し、無水硫酸ナトリウムで乾燥した後、濃縮した。得られた結晶にトルエン３ｍＬを加え、６０℃の油浴で加熱して結晶を溶解させた。得られた溶液を室温まで冷却することにより結晶を析出させ、そこにヘプタン６ｍＬを加え、６℃まで冷却して濾過し、結晶として（３ａＳ，７ａＳ）−１，５−ジベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オン１．７６ｇを得た。収率は８８％であった。
実施例８：（３ａＳ，７ａＳ）−１−ベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オンの製造
　実施例７で得た結晶の０．５０ｇとエタノール８ｍＬをオートクレーブ反応装置内で混合し、系内を窒素雰囲気とした。そこに、１０重量％パラジウムカーボン（５５重量％含水品、ＰＥ型、エヌ・イー　ケムキャット株式会社製、Ｌｏｔ．２１７−０７６８８０）０．０５０ｇを加えた後、系内を水素で置換し、水素圧０．４ＭＰａにて５０℃で７時間攪拌した。反応終了後、触媒を濾去し、得られた濾液を濃縮して、油状物０．３９ｇを得た。該油状物の１Ｈ−ＮＭＲを測定したところ、その主成分は（３ａＳ，７ａＳ）−１−ベンジル−ヘキサヒドロ［１，３］オキサゾロ［５，４−ｃ］ピリジン−２（１Ｈ）−オンであった。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.
Example 1: Optical resolution of (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol (3RS, 4RS) -1-benzyl-4- (benzylamino) piperidin-3-ol 1 0.1 g (3.7 mmol), ethanol 5 mL, and acetonitrile 10 mL were mixed. While maintaining the mixture at 20 to 35 ° C., 1.2 g (3.7 mmol) of N- (p-toluenesulfonyl) -L-phenylalanine was added thereto, and crystals were precipitated. The mixture was warmed to 60 ° C. to dissolve the crystals. The mixture was then gradually cooled to 20 ° C. to precipitate crystals. The obtained crystals were filtered, washed with 3 mL of acetonitrile, and then dried under reduced pressure to give (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol and N- (p- 0.85 g of a salt with toluenesulfonyl) -L-phenylalanine was obtained. The yield was 37%.
1 H-NMR (ppm in CD 3 OD) δ: 1.59-1.70 (1H, m), 1.89-1.94 (1H, apptt, J = 10 Hz), 2.02-2. 14 (2H, m), 2.37 (3H, s), 2.74-2.78 (1H, m), 2.80-3.12 (4H, m), 3.55 (1H, d, J = 13H), 3.62 (1H, d, J = 13H), 3.66-3.73 (1H, m), 3.78-3.81 (1H, m), 4.17 (1H, d, J = 13H), 4.22 (1H, d, J = 13H), 7.12-7.23 (5H, m), 7.25-7.32 (7H, m), 7.38- 7.47 (5H, m), 7.59 (2H, d, J = 8Hz)
When analyzed by high performance liquid chromatography (HPLC), the optical purity of (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol in the crystals was 92% ee.
<HPLC analysis conditions>
Column: Chiralpak (registered trademark) manufactured by Daicel Chemical Industries
IC 250mm x 4.6mm
Column temperature: 40 ° C
Moving layer: 2-propanol (containing 0.1% by volume of diethylamine) /
n-hexane (containing 0.1% by volume of diethylamine) = 20/80
Flow rate: 0.5 mL / min Observation: UV 217 nm
Retention time: 14.3 minutes (3S, 4S body), 20.4 minutes (3R, 4R body)
Examples 2-3 and Comparative Examples 1-13
After stirring a mixture of 84 μmol of (3RS, 4RS) -1-benzyl-4- (benzylamino) piperidin-3-ol, 84 μmol of the resolving agent shown in Table 1 and the solvent at 30 to 50 ° C. for 5 minutes, Allowed to stand at ° C. Those in which crystals did not precipitate were further cooled to 0 to 5 ° C. and allowed to stand. Table 1 shows the presence or absence of crystal precipitation and the optical purity of trans-1-benzyl-4- (benzylamino) piperidin-3-ol in the obtained crystal.
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-I000073
Example 4: Preparation of (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol (3S, 4S) -1-benzyl-4- (benzylamino) piperidine obtained in Example 1 A salt of 0.77 g (1.3 mmol) of -3-ol and N- (p-toluenesulfonyl) -L-phenylalanine, 10 mL of ethyl acetate and 1 mL of ethanol were mixed. While maintaining the internal temperature of the mixture at 20 to 35 ° C., 8 mL of 1 mol / L sodium hydroxide was added dropwise thereto. The obtained mixture was separated, and the organic layer was further washed with 3 mL of 1 mol / L sodium hydroxide three times. The organic layer was washed with 3 ml of saturated brine, dehydrated with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (3S, 4S) -1-benzyl-4- (benzylamino) piperidine-3- All 0.36g was obtained. The yield was 97%.
Example 5: Preparation of (3S, 4S) -4-aminopiperidin-3-ol (3S, 4S) -1-benzyl-4-benzylaminopiperidin-3-ol 1 obtained in the same manner as in Example 4 0.01 g (3.4 mmol) and 10 mL of ethanol were mixed in an autoclave reactor, and the inside of the system was set to a nitrogen atmosphere. Thereto was added 0.10 g of 10 wt% palladium carbon (55 wt% water-containing product, PE type, manufactured by N.E. Chemcat Co., Ltd., Lot. 217-0776880), and the system was replaced with hydrogen. The mixture was stirred at 0.4 MPa at 50 ° C. for 6 hours. After completion of the reaction, the catalyst was removed by filtration, and the obtained filtrate was concentrated to obtain 0.42 g of deliquescent crystals. When the 1 H-NMR of the crystal was measured, the main component was (3S, 4S) -4-aminopiperidin-3-ol.
Example 6: Preparation of tert-butyl benzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate (3S, 4S) -1-benzyl-4- () obtained in the same manner as in Example 4. Benzylamino) piperidin-3-ol 0.27 g (0.91 mmol) and toluene 1 mL were mixed, and triethylamine 0.25 mL (1.83 mmol), ditert-butyl dicarbonate 0.24 g (1.10 mmol) and Tetrahydrofuran (1 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, 5 mL of water was added to the reaction mixture, followed by extraction with 10 mL of toluene, and the aqueous layer was extracted with 5 mL of toluene. The toluene layers were combined, dried over anhydrous sodium sulfate, and concentrated. 0.44 g of the obtained concentrated residue and 10 mL of ethanol were mixed in an autoclave reactor, and the system was made a nitrogen atmosphere. Thereto was added 0.044 g of 20 wt% palladium hydroxide carbon (50 wt% water-containing product), and the system was replaced with hydrogen, followed by stirring at 50 ° C. for 12 hours at a hydrogen pressure of 0.5 MPa. After completion of the reaction, the catalyst was removed by filtration, and the resulting filtrate was concentrated to obtain 0.26 g of tert-butyl benzyl [(3S, 4S) -3-hydroxypiperidin-4-yl] carbamate. The yield was 92%.
Example 7: Preparation of (3aS, 7aS) -1,5-dibenzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one Obtained in the same manner as in Example 4. (3S, 4S) -1-Benzyl-4- (benzylamino) piperidin-3-ol 1.83 g (6.17 mmol), toluene 15 mL and carbonyldiimidazole 1.10 g (6.79 mmol) were mixed at room temperature. . While heating the obtained mixture in an oil bath at 80 ° C., 1.7 mL (12.3 mmol) of triethylamine was added thereto, and the mixture was stirred as it was for 3 hours. After completion of the reaction, the reaction mixture was ice-cooled, 5 mL of saturated brine was added, and the mixture was returned to room temperature and separated to obtain an organic layer. Further, the obtained organic layer was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. To the obtained crystals, 3 mL of toluene was added and heated in an oil bath at 60 ° C. to dissolve the crystals. Crystals were precipitated by cooling the resulting solution to room temperature, 6 mL of heptane was added thereto, cooled to 6 ° C. and filtered, and (3aS, 7aS) -1,5-dibenzyl-hexahydro [1, 3] 1.76 g of oxazolo [5,4-c] pyridin-2 (1H) -one was obtained. The yield was 88%.
Example 8: Preparation of (3aS, 7aS) -1-benzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one 0.50 g of the crystals obtained in Example 7 Ethanol 8mL was mixed in the autoclave reaction apparatus, and the inside of system was made into nitrogen atmosphere. Thereto was added 0.050 g of 10 wt% palladium carbon (55 wt% water-containing product, PE type, manufactured by N.E. Chemcat Co., Ltd., Lot. 217-0776880), and the system was replaced with hydrogen. The mixture was stirred at 0.4 MPa at 50 ° C. for 7 hours. After completion of the reaction, the catalyst was removed by filtration, and the obtained filtrate was concentrated to obtain 0.39 g of an oily substance. As a result of measuring 1 H-NMR of the oily substance, the main component was (3aS, 7aS) -1-benzyl-hexahydro [1,3] oxazolo [5,4-c] pyridin-2 (1H) -one. there were.

　本発明により得られる光学活性なトランス−４−アミノピペリジン−３−オール及びその類縁体は、Ｓｙｎｔｈ．Ｃｏｍｍｕｎ．２８，４４７１（１９９８）、Ｊ．Ｍｅｄ．Ｃｈｅｍ．４１，３５６３−３５６７（１９９８）、ＷＯ２００７／０３９４６２等に記載されるように、例えば、医薬品等の合成原料、立体選択的な化学反応に用いるキラルなリガンドの合成原料として有用であり、本発明は、かかる化合物の製造方法として有用である。 The optically active trans-4-aminopiperidin-3-ol obtained by the present invention and its analogs are described in Synth. Commun. 28, 4471 (1998), J. MoI. Med. Chem. 41, 3563-3567 (1998), WO2007 / 039462, etc., for example, it is useful as a raw material for synthesis of pharmaceuticals and the like, and as a raw material for the synthesis of chiral ligands used in stereoselective chemical reactions. It is useful as a method for producing such a compound.

Claims (16)

　溶媒中で、式（１）
Figure JPOXMLDOC01-appb-I000001
（式中、Ｒ１は炭素数６~１０のアリール基で置換されていてもよい炭素数１~５のアルキル基又は炭素数６~１０のアリール基で置換されていてもよい炭素数３~６のアルケニル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表す。）
で示される置換トランス−４−アミノピペリジン−３−オールと、式（２）
Figure JPOXMLDOC01-appb-I000002
（式中、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性Ｎ−保護アミノ酸とを反応させ、式（３）
Figure JPOXMLDOC01-appb-I000003
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩を優先的に晶出させる工程を含む式（４）
Figure JPOXMLDOC01-appb-I000004
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オールの製造方法。 Formula (1) in a solvent
Figure JPOXMLDOC01-appb-I000001
(Wherein R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms. R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms.)
A substituted trans-4-aminopiperidin-3-ol represented by formula (2)
Figure JPOXMLDOC01-appb-I000002
(Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
Is reacted with an optically active N-protected amino acid represented by formula (3):
Figure JPOXMLDOC01-appb-I000003
(In the formula, R 1 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
Comprising a step of preferentially crystallizing the diastereomeric salt represented by formula (4)
Figure JPOXMLDOC01-appb-I000004
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
The manufacturing method of optically active substituted trans-4-aminopiperidin-3-ol shown by these. 　溶媒中で、式（１）で示される置換トランス−４−アミノピペリジン−３−オールと、式（２）で示される光学活性Ｎ−保護アミノ酸とを反応させ、式（３）で示されるジアステレオマー塩を優先的に晶出させ、得られたジアステレオマー塩を、さらに、酸又は塩基で処理する、請求項１に記載の式（４）で示される光学活性な置換トランス−４−アミノピペリジン−３−オールの製造方法。 In a solvent, the substituted trans-4-aminopiperidin-3-ol represented by the formula (1) is reacted with the optically active N-protected amino acid represented by the formula (2) to obtain a dia represented by the formula (3). The optically active substituted trans-4- represented by the formula (4) according to claim 1, wherein the stereomeric salt is preferentially crystallized, and the obtained diastereomeric salt is further treated with an acid or a base. A method for producing aminopiperidin-3-ol. 　Ｒ３が、置換されていてもよい（炭素数１~１２のヒドロカルビル）カルボニル基又は置換されていてもよい炭素数１~１２のヒドロカルビルスルホニル基、［ここで、置換基は、炭素数１~６のアルコキシ基、　（炭素数１~６のアルコキシ）カルボニル基、炭素数１~６のアルカノイル基、炭素数１~６のアルカノイルオキシ基、ハロゲン原子、ニトロ基及びシアノ基よりなる群より選ばれる一以上の置換基である。］である請求項１に記載の方法。 R 3 is an optionally substituted (hydrocarbyl having 1 to 12 carbons) carbonyl group or an optionally substituted hydrocarbylsulfonyl group having 1 to 12 carbons [wherein the substituent is 1 to Selected from the group consisting of 6 alkoxy groups, (C 1-6 alkoxy) carbonyl groups, C 1-6 alkanoyl groups, C 1-6 alkanoyloxy groups, halogen atoms, nitro groups, and cyano groups. One or more substituents. The method according to claim 1, wherein 　Ｒ１及びＲ２がベンジル基である請求項１に記載の方法。 The method according to claim 1, wherein R 1 and R 2 are benzyl groups. 　Ｒ１及びＲ２がベンジル基であり、Ｒ３がパラトルエンスルホニル基であり、Ｒ４がベンジル基である請求項４に記載の方法。 The method according to claim 4, wherein R 1 and R 2 are benzyl groups, R 3 is a paratoluenesulfonyl group, and R 4 is a benzyl group. 　溶媒が、アルコール溶媒、ニトリル溶媒又はその混合物である請求項１に記載の方法。 The method according to claim 1, wherein the solvent is an alcohol solvent, a nitrile solvent or a mixture thereof. 　溶媒中で、式（１）
Figure JPOXMLDOC01-appb-I000005
（式中、Ｒ１は炭素数６~１０のアリール基で置換されていてもよい炭素数１~５のアルキル基又は炭素数６~１０のアリール基で置換されていてもよい炭素数３~６のアルケニル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表す。）
で示される置換トランス−４−アミノピペリジン−３−オールと、式（２）
Figure JPOXMLDOC01-appb-I000006
（式中、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性Ｎ−保護アミノ酸とを反応させ、式（３）
Figure JPOXMLDOC01-appb-I000007
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩を優先的に晶出させる工程を含む該ジアステレオマー塩の製造方法。 Formula (1) in a solvent
Figure JPOXMLDOC01-appb-I000005
(Wherein R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms. R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms.)
A substituted trans-4-aminopiperidin-3-ol represented by formula (2)
Figure JPOXMLDOC01-appb-I000006
(Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
Is reacted with an optically active N-protected amino acid represented by formula (3):
Figure JPOXMLDOC01-appb-I000007
(In the formula, R 1 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
The manufacturing method of this diastereomeric salt including the process of preferentially crystallizing the diastereomeric salt shown by these. 　溶媒中で、式（５）
Figure JPOXMLDOC01-appb-I000008
（式中、Ｒ１１は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表す。）
で示される置換トランス−４−アミノピペリジン−３−オールと、式（２）
Figure JPOXMLDOC01-appb-I000009
（式中、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性Ｎ−保護アミノ酸とを反応させ、式（６）
Figure JPOXMLDOC01-appb-I000010
（式中、Ｒ１１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩を優先的に晶出させ、得られた該ジアステレオマー塩を酸又は塩基で処理して式（７）
Figure JPOXMLDOC01-appb-I000011
で示される光学活性な置換トランス−４−アミノピペリジン−３−オールに導き、次いでＲ１１及びＲ２で表される基を除去する光学活性トランス−４−アミノピペリジン−３−オールの製造方法。 Formula (5) in a solvent
Figure JPOXMLDOC01-appb-I000008
(Wherein R 11 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms, and R 2 represents 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms) Represents an alkyl group of
A substituted trans-4-aminopiperidin-3-ol represented by formula (2)
Figure JPOXMLDOC01-appb-I000009
(Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
And an optically active N-protected amino acid represented by formula (6):
Figure JPOXMLDOC01-appb-I000010
(Wherein R 11 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
The diastereomeric salt represented by formula (7) is preferentially crystallized, and the resulting diastereomeric salt is treated with an acid or a base to give
Figure JPOXMLDOC01-appb-I000011
A method for producing optically active trans-4-aminopiperidin-3-ol, which is converted to an optically active substituted trans-4-aminopiperidin-3-ol represented by the following formula, and then the groups represented by R 11 and R 2 are removed. 　Ｒ１１及びＲ２がベンジル基である請求項８に記載の方法。 The method according to claim 8, wherein R 11 and R 2 are benzyl groups. 　溶媒中で、式（１）
Figure JPOXMLDOC01-appb-I000012
（式中、Ｒ１は炭素数６~１０のアリール基で置換されていてもよい炭素数１~５のアルキル基又は炭素数６~１０のアリール基で置換されていてもよい炭素数３~６のアルケニル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表す。）
で示される置換トランス−４−アミノピペリジン−３−オールと、式（２）
Figure JPOXMLDOC01-appb-I000013
（式中、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性Ｎ−保護アミノ酸とを反応させ、式（３）
Figure JPOXMLDOC01-appb-I000014
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩を優先的に晶出させ、得られたジアステレオマー塩を、さらに、酸又は塩基で処理して式（４）
Figure JPOXMLDOC01-appb-I000015
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オールを得、次いで、該化合物と、式（９）
Figure JPOXMLDOC01-appb-I000016
（式中、Ｒ５は炭素数１~１２のアルキル基を表し、Ｘはハロゲン原子を表す。）
で示されるハロ炭酸エステル又は式（１０）
Figure JPOXMLDOC01-appb-I000017
（式中、Ｒ５は上記と同じ意味を表す。）
で示されるジアルキルジカーボネートとを反応させる式（１１）
Figure JPOXMLDOC01-appb-I000018
（式中、Ｒ１、Ｒ２、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物の製造方法。 Formula (1) in a solvent
Figure JPOXMLDOC01-appb-I000012
(Wherein R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms. R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms.)
A substituted trans-4-aminopiperidin-3-ol represented by formula (2)
Figure JPOXMLDOC01-appb-I000013
(Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
Is reacted with an optically active N-protected amino acid represented by formula (3):
Figure JPOXMLDOC01-appb-I000014
(In the formula, R 1 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
The diastereomeric salt represented by formula (4) is preferentially crystallized, and the resulting diastereomeric salt is further treated with an acid or a base to give a compound of formula (4)
Figure JPOXMLDOC01-appb-I000015
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
An optically active substituted trans-4-aminopiperidin-3-ol represented by formula (9)
Figure JPOXMLDOC01-appb-I000016
(In the formula, R 5 represents an alkyl group having 1 to 12 carbon atoms, and X represents a halogen atom.)
Or a halocarbonate represented by the formula (10)
Figure JPOXMLDOC01-appb-I000017
(Wherein R 5 represents the same meaning as described above.)
A reaction with a dialkyl dicarbonate represented by formula (11)
Figure JPOXMLDOC01-appb-I000018
(In the formula, R 1 , R 2 , R 5 and * represent the same meaning as described above.)
The manufacturing method of the optically active compound shown by these. 溶媒中で、式（１）
Figure JPOXMLDOC01-appb-I000019
（式中、Ｒ１は炭素数６~１０のアリール基で置換されていてもよい炭素数１~５のアルキル基又は炭素数６~１０のアリール基で置換されていてもよい炭素数３~６のアルケニル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表す。）
で示される置換トランス−４−アミノピペリジン−３−オールと、式（２）
Figure JPOXMLDOC01-appb-I000020
（式中、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性Ｎ−保護アミノ酸とを反応させ、式（３）
Figure JPOXMLDOC01-appb-I000021
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩を優先的に晶出させ、得られたジアステレオマー塩を、さらに、酸又は塩基で処理して式（４）
Figure JPOXMLDOC01-appb-I000022
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オールを得、該化合物と、式（９）
Figure JPOXMLDOC01-appb-I000023
（式中、Ｒ５は炭素数１~１２のアルキル基を表し、Ｘはハロゲン原子を表す。）
で示されるハロ炭酸エステル又は式（１０）
Figure JPOXMLDOC01-appb-I000024
（式中、Ｒ５は上記と同じ意味を表す。）
で示されるジアルキルジカーボネートとを反応させて式（１１）
Figure JPOXMLDOC01-appb-I000025
（式中、Ｒ１、Ｒ２、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物を得、次いで、該化合物と、式（１２）
Figure JPOXMLDOC01-appb-I000026
（式中、Ａはハロゲン原子、トリハロメトキシ基又は１−イミダゾリル基を表す。）
で示されるカルボニル化合物とを反応させる式（１３）
Figure JPOXMLDOC01-appb-I000027
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物の製造方法。 Formula (1) in a solvent
Figure JPOXMLDOC01-appb-I000019
(Wherein R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms. R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms.)
A substituted trans-4-aminopiperidin-3-ol represented by formula (2)
Figure JPOXMLDOC01-appb-I000020
(Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
Is reacted with an optically active N-protected amino acid represented by formula (3):
Figure JPOXMLDOC01-appb-I000021
(In the formula, R 1 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
The diastereomeric salt represented by formula (4) is preferentially crystallized, and the resulting diastereomeric salt is further treated with an acid or a base to give a compound of formula (4)
Figure JPOXMLDOC01-appb-I000022
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
An optically active substituted trans-4-aminopiperidin-3-ol represented by formula (9)
Figure JPOXMLDOC01-appb-I000023
(In the formula, R 5 represents an alkyl group having 1 to 12 carbon atoms, and X represents a halogen atom.)
Or a halocarbonate represented by the formula (10)
Figure JPOXMLDOC01-appb-I000024
(Wherein R 5 represents the same meaning as described above.)
Is reacted with a dialkyl dicarbonate represented by the formula (11)
Figure JPOXMLDOC01-appb-I000025
(In the formula, R 1 , R 2 , R 5 and * represent the same meaning as described above.)
An optically active compound represented by the formula (12)
Figure JPOXMLDOC01-appb-I000026
(In the formula, A represents a halogen atom, a trihalomethoxy group or a 1-imidazolyl group.)
A reaction with a carbonyl compound represented by formula (13)
Figure JPOXMLDOC01-appb-I000027
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
The manufacturing method of the optically active compound shown by these. 　溶媒中で、式（１）
Figure JPOXMLDOC01-appb-I000028
（式中、Ｒ１は炭素数６~１０のアリール基で置換されていてもよい炭素数１~５のアルキル基又は炭素数６~１０のアリール基で置換されていてもよい炭素数３~６のアルケニル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表す。）
で示される置換トランス−４−アミノピペリジン−３−オールと、式（２）
Figure JPOXMLDOC01-appb-I000029
（式中、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性Ｎ−保護アミノ酸とを反応させ、式（３）
Figure JPOXMLDOC01-appb-I000030
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩を優先的に晶出させ、得られたジアステレオマー塩を、さらに、酸又は塩基で処理して式（４）
Figure JPOXMLDOC01-appb-I000031
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オールを得、該化合物と、式（９）
Figure JPOXMLDOC01-appb-I000032
（式中、Ｒ５は炭素数１~１２のアルキル基を表し、Ｘはハロゲン原子を表す。）
で示されるハロ炭酸エステル又は式（１０）
Figure JPOXMLDOC01-appb-I000033
（式中、Ｒ５は上記と同じ意味を表す。）
で示されるジアルキルジカーボネートとを反応させ、式（１１）
Figure JPOXMLDOC01-appb-I000034
（式中、Ｒ１、Ｒ２、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物を得、次いで、該化合物からＲ２で示される基を除去する式（１４）
Figure JPOXMLDOC01-appb-I000035
（式中、Ｒ１、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物の製造方法。 Formula (1) in a solvent
Figure JPOXMLDOC01-appb-I000028
(Wherein R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms. R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms.)
A substituted trans-4-aminopiperidin-3-ol represented by formula (2)
Figure JPOXMLDOC01-appb-I000029
(Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
Is reacted with an optically active N-protected amino acid represented by formula (3):
Figure JPOXMLDOC01-appb-I000030
(In the formula, R 1 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
The diastereomeric salt represented by formula (4) is preferentially crystallized, and the resulting diastereomeric salt is further treated with an acid or a base to give a compound of formula (4)
Figure JPOXMLDOC01-appb-I000031
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
An optically active substituted trans-4-aminopiperidin-3-ol represented by formula (9)
Figure JPOXMLDOC01-appb-I000032
(In the formula, R 5 represents an alkyl group having 1 to 12 carbon atoms, and X represents a halogen atom.)
Or a halocarbonate represented by the formula (10)
Figure JPOXMLDOC01-appb-I000033
(Wherein R 5 represents the same meaning as described above.)
Is reacted with a dialkyl dicarbonate represented by the formula (11):
Figure JPOXMLDOC01-appb-I000034
(In the formula, R 1 , R 2 , R 5 and * represent the same meaning as described above.)
And then removing the group represented by R 2 from the compound (14)
Figure JPOXMLDOC01-appb-I000035
(Wherein R 1 , R 5 and * represent the same meaning as described above.)
The manufacturing method of the optically active compound shown by these. 溶媒中で、式（１）
Figure JPOXMLDOC01-appb-I000036
（式中、Ｒ１は炭素数６~１０のアリール基で置換されていてもよい炭素数１~５のアルキル基又は炭素数６~１０のアリール基で置換されていてもよい炭素数３~６のアルケニル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表す。）
で示される置換トランス−４−アミノピペリジン−３−オールと、式（２）
Figure JPOXMLDOC01-appb-I000037
（式中、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性Ｎ−保護アミノ酸とを反応させ、式（３）
Figure JPOXMLDOC01-appb-I000038
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及び＊は上記と同じ意味を表す。）
で示されるジアステレオマー塩を優先的に晶出させ、得られたジアステレオマー塩を、さらに、酸又は塩基で処理して式（４）
Figure JPOXMLDOC01-appb-I000039
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オールを得、該化合物と、式（９）
Figure JPOXMLDOC01-appb-I000040
（式中、Ｒ５は炭素数１~１２のアルキル基を表し、Ｘはハロゲン原子を表す。）
で示されるハロ炭酸エステル又は式（１０）
Figure JPOXMLDOC01-appb-I000041
（式中、Ｒ５は上記と同じ意味を表す。）
で示されるジアルキルジカーボネートとを反応させて式（１１）
Figure JPOXMLDOC01-appb-I000042
（式中、Ｒ１、Ｒ２、Ｒ５及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物を得、次いで、この光学活性な化合物と、式（１２）
Figure JPOXMLDOC01-appb-I000043
（式中、Ａはハロゲン原子、トリハロメトキシ基又は１−イミダゾリル基を表す。）
で示されるカルボニル化合物とを反応させ、式（１３）
Figure JPOXMLDOC01-appb-I000044
（式中、Ｒ１、Ｒ２及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物を得、次いで、Ｒ２で示される基を除去する式（１５）
Figure JPOXMLDOC01-appb-I000045
（式中、Ｒ１及び＊は上記と同じ意味を表す。）
で示される光学活性な化合物の製造方法。 Formula (1) in a solvent
Figure JPOXMLDOC01-appb-I000036
(Wherein R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms. R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms.)
A substituted trans-4-aminopiperidin-3-ol represented by formula (2)
Figure JPOXMLDOC01-appb-I000037
(Wherein R 3 represents a protecting group, R 4 represents an optionally substituted alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
Is reacted with an optically active N-protected amino acid represented by formula (3):
Figure JPOXMLDOC01-appb-I000038
(In the formula, R 1 , R 2 , R 3 , R 4 and * represent the same meaning as described above.)
The diastereomeric salt represented by formula (4) is preferentially crystallized, and the resulting diastereomeric salt is further treated with an acid or a base to give a compound of formula (4)
Figure JPOXMLDOC01-appb-I000039
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
An optically active substituted trans-4-aminopiperidin-3-ol represented by formula (9)
Figure JPOXMLDOC01-appb-I000040
(In the formula, R 5 represents an alkyl group having 1 to 12 carbon atoms, and X represents a halogen atom.)
Or a halocarbonate represented by the formula (10)
Figure JPOXMLDOC01-appb-I000041
(Wherein R 5 represents the same meaning as described above.)
Is reacted with a dialkyl dicarbonate represented by the formula (11)
Figure JPOXMLDOC01-appb-I000042
(In the formula, R 1 , R 2 , R 5 and * represent the same meaning as described above.)
An optically active compound represented by the formula (12)
Figure JPOXMLDOC01-appb-I000043
(In the formula, A represents a halogen atom, a trihalomethoxy group or a 1-imidazolyl group.)
Is reacted with a carbonyl compound represented by the formula (13):
Figure JPOXMLDOC01-appb-I000044
(Wherein R 1 , R 2 and * represent the same meaning as described above.)
Is obtained, and then the group represented by R 2 is removed (15)
Figure JPOXMLDOC01-appb-I000045
(In the formula, R 1 and * represent the same meaning as described above.)
The manufacturing method of the optically active compound shown by these. 式（３）
Figure JPOXMLDOC01-appb-I000046
（式中、Ｒ１は炭素数６~１０のアリール基で置換されていてもよい炭素数１~５のアルキル基又は炭素数６~１０のアリール基で置換されていてもよい炭素数３~６のアルケニル基を表し、Ｒ２は炭素数６~１０のアリール基で置換された炭素数１~５のアルキル基を表し、Ｒ３は保護基を表し、Ｒ４は置換されていてもよい炭素数１~１２のアルキル基を表し、＊は当該炭素原子が不斉炭素原子であることを表す。）
で示される光学活性な置換トランス−４−アミノピペリジン−３−オールと光学活性Ｎ−保護アミノ酸とのジアステレオマー塩。 Formula (3)
Figure JPOXMLDOC01-appb-I000046
(Wherein R 1 is an alkyl group having 1 to 5 carbon atoms which may be substituted with an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms. 6 represents an alkenyl group having 6 carbon atoms, R 2 represents an alkyl group having 1 to 5 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms, R 3 represents a protecting group, and R 4 may be substituted. Represents an alkyl group having 1 to 12 carbon atoms, and * represents that the carbon atom is an asymmetric carbon atom.)
A diastereomeric salt of an optically active substituted trans-4-aminopiperidin-3-ol represented by the formula: and an optically active N-protected amino acid. Ｒ１、Ｒ２及びＲ４が全てベンジル基であり、Ｒ３がパラトルエンスルホニル基である請求項１４に記載のジアステレオマー塩。 The diastereomeric salt according to claim 14, wherein R 1 , R 2 and R 4 are all benzyl groups and R 3 is a paratoluenesulfonyl group. （３Ｓ，４Ｓ）−１−ベンジル−４−（ベンジルアミノ）ピペリジン−３−オールとＮ−（パラトルエンスルホニル）−Ｌ−フェニルアラニンとのジアステレオマー塩である請求項１５に記載のジアステレオマー塩。 The diastereomer according to claim 15, which is a diastereomeric salt of (3S, 4S) -1-benzyl-4- (benzylamino) piperidin-3-ol and N- (paratoluenesulfonyl) -L-phenylalanine. salt.
PCT/JP2010/052008 2009-02-09 2010-02-04 Method of manufacturing optically active trans-4-aminopiperidine-3-ol compound Ceased WO2010090341A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004143139A (en) * 2002-05-29 2004-05-20 Tanabe Seiyaku Co Ltd New piperidine derivatives
JP2005154381A (en) * 2003-11-28 2005-06-16 Tanabe Seiyaku Co Ltd Piperidine compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004143139A (en) * 2002-05-29 2004-05-20 Tanabe Seiyaku Co Ltd New piperidine derivatives
JP2005154381A (en) * 2003-11-28 2005-06-16 Tanabe Seiyaku Co Ltd Piperidine compounds

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DUBAY, S.K. ET AL.: "Stereospecific vicinal oxyamination of N-substituted 1,2,3,6-tetrahydropyridines and 1,2-dihydropyridines by N-chloro-N-metallocarbamates", CAN. J. CHEM., vol. 61, 1983, pages 565 - 572 *
NICOLE, L. ET AL.: "A Short and Efficient Synthesis of (3S,4S)-1-Benzyl-4-N-Benzylamino-3-Hydroxypiperidine", SYNTHETIC COMMUNICATIONS, vol. 28, no. 23, 1998, pages 4471 - 4477 *
VAN DAELE, G. H.P ET AL.: "Synthesis of cisapride, a gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine", DRUG DEVELOPMENT RESEARCH, vol. 8, 1986, pages 225 - 232 *

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