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WO2010090341A1 - Procédé de fabrication de composé de trans-4-aminopipéridine-3-ol optiquement actif - Google Patents

Procédé de fabrication de composé de trans-4-aminopipéridine-3-ol optiquement actif Download PDF

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Publication number
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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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne un procédé de fabrication d'un composé de trans-4-aminopipéridine-3-ol optiquement actif par résolution optique de trans-4-aminopipéridine-3-ol substitué. Ce procédé comporte une opération consistant à faire réagir dans un solvant un trans-4-aminopipéridine-3-ol substitué représenté par la formule (1) avec un acide aminé N-protégé optiquement actif représenté par la formule (2). Dans la formule (1), R1 est un groupe alkyle en C1-C5 éventuellement substitué par un groupe aryle en C6-C10, ou un groupe alcényle en C3-C6 éventuellement substitué par un groupe aryle en C6-C10, et R2 est un groupe alkyle en C1-C5 éventuellement substitué par un groupe aryle en C6-C10. Dans la formule (2), R3 est un groupe protecteur, R4 est un groupe alkyle en C1-C12 éventuellement substitué, et * indique qu'un atome de carbone correspondant est un atome de carbone asymétrique.
PCT/JP2010/052008 2009-02-09 2010-02-04 Procédé de fabrication de composé de trans-4-aminopipéridine-3-ol optiquement actif Ceased WO2010090341A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004143139A (ja) * 2002-05-29 2004-05-20 Tanabe Seiyaku Co Ltd 新規ピペリジン誘導体
JP2005154381A (ja) * 2003-11-28 2005-06-16 Tanabe Seiyaku Co Ltd ピペリジン化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004143139A (ja) * 2002-05-29 2004-05-20 Tanabe Seiyaku Co Ltd 新規ピペリジン誘導体
JP2005154381A (ja) * 2003-11-28 2005-06-16 Tanabe Seiyaku Co Ltd ピペリジン化合物

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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