WO2011043445A1 - 1-substituted-trans-3-(substituted amino)piperidin-4-ol - Google Patents

1-substituted-trans-3-(substituted amino)piperidin-4-ol Download PDF

Info

Publication number
WO2011043445A1
WO2011043445A1 PCT/JP2010/067698 JP2010067698W WO2011043445A1 WO 2011043445 A1 WO2011043445 A1 WO 2011043445A1 JP 2010067698 W JP2010067698 W JP 2010067698W WO 2011043445 A1 WO2011043445 A1 WO 2011043445A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
carbon atoms
substituted
represented
Prior art date
Application number
PCT/JP2010/067698
Other languages
French (fr)
Japanese (ja)
Inventor
修 徳田
哲哉 池本
Original Assignee
住友化学株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 住友化学株式会社 filed Critical 住友化学株式会社
Publication of WO2011043445A1 publication Critical patent/WO2011043445A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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

Definitions

  • the present invention relates to a process for producing 1-substituted-trans-3- (substituted amino) piperidin-4-ol and trans-3-aminopiperidin-4-ol.
  • 1-Substituted-trans-3- (substituted amino) piperidin-4-ol is useful as various chemicals such as pharmaceutical intermediates (see, for example, Journal of Medicinal Chemistry 1997, 40, 226-235), and the compound. More derived trans-3-aminopiperidin-4-ol compounds are useful as various chemicals such as pharmaceutical intermediates.
  • More derived trans-3-aminopiperidin-4-ol compounds are useful as various chemicals such as pharmaceutical intermediates.
  • the above-mentioned Journal of Medicinal Chemistry (Supporting Information) has a nitrogen atom on the piperidine ring protected with a benzyloxycarbonyl group.
  • 1-Substituted 3,4-epoxy piperidine is reacted with sodium azide to introduce an azide group regioselectively into the 3-position of the piperidine ring, the azide group is reduced to an amino group, and then the substituent is introduced.
  • the method of introduction is described.
  • the present invention relates to a compound of formula (I) (In the formula, R 1 is an aryl group, an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups, and an alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups.
  • the aryl group includes one or more substituents selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, a protected amino group, and a protected hydroxyl group. It means an aromatic hydrocarbon group which may have.
  • a 1 is an aryl group, an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups, and an alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups
  • a 2 represents an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups
  • a 1 and A 2 together represent a polymethylene group having 2 to 7 carbon atoms.
  • the aryl group includes one or more substituents selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, a protected amino group, and a protected hydroxyl group. It means an aromatic hydrocarbon group which may have.
  • R 1 examples of the aryl group represented by the formula include an aromatic hydrocarbon group having 6 to 10 carbon atoms such as an optionally substituted phenyl group and naphthyl group.
  • an aromatic hydrocarbon group having 6 to 10 carbon atoms such as an optionally substituted phenyl group and naphthyl group.
  • alkyl group having 1 to 12 carbon atoms examples include 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, undecyl, and dodecyl groups.
  • alkoxy group having 1 to 12 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.
  • halogen atom examples include a fluorine atom, a chlorine atom
  • protected amino group examples include a C 1-8 alkanoylamino group (typically an acetylamino group), and 1 or 2 of a hydrogen atom bonded to an aromatic ring.
  • phenylcarbonylamino group typically examples include benzoylamino group, p-toluoylamino group, 4-chlorobenzoylamino group, 4-nitrobenzoylamino group, 4-cyanobenzoylamino group, 4-tribenzoylamino group, Fluoromethylbenzoylamino group, 3,5-bis (trifluoromethyl) benzoylamino group), alkoxycarbonylamino group having 1 to 8 carbon atoms (representative examples include methoxycarbonylamino group, ethoxycarbonylamino group, t-butoxy group) Carbonylamino group), 1 or 2 of the hydrogen atoms bonded to the aromatic ring are substituted with an alkyl group
  • Examples of the protected hydroxyl group include an alkanoyloxy group having 1 to 8 carbon atoms.
  • 1 or 2 of hydrogen atoms bonded to an aromatic ring is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a nitro group, a cyano group or trifluoro
  • Benzoyloxy group optionally substituted with a methyl group representsative examples include benzoyloxy group and 4-nitrobenzoyloxy group
  • One or two hydrogen atoms bonded to the aromatic ring may be substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group.
  • Benzyloxy group (representative examples are benzyloxy group, 4-methoxybenzyloxy group, 4-nitrobenzyloxy group), alkoxymethoxy group having 1 to 8 carbon atoms of alkoxy group (representative example is methoxymethoxy group) ), 1- (alkoxy) ethoxy groups having 1 to 8 carbon atoms in the alkoxy group (typically, 1- (ethoxy) ethoxy group), 2-tetrahydropyranyloxy groups, and individual alkyl groups having carbon numbers Examples thereof include 1 to 8 trialkylsilyloxy groups (typically, t-butyldimethylsilyloxy group).
  • examples of the alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, Examples include a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, and a dodecyl group.
  • alkyl groups having 1 to 12 carbon atoms are 1 You may have the above aryl group.
  • Examples of the aryl group include R 1 The group illustrated as an aryl group represented by these is mentioned.
  • Examples of the alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups include 1-phenylethyl group, 2-phenylethyl group, 1-naphthylethyl group, 1-phenylpropyl group, 2- Examples thereof include a phenylpropyl group, a 3-phenylpropyl group, and a diphenylmethyl group.
  • alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups represented by the following
  • examples of the alkenyl group having 2 to 14 carbon atoms include a vinyl group, 1-propenyl group, allyl group, butenyl Group, butadienyl group, pentenyl group, hexenyl group, heptenyl group and octenyl group.
  • These alkenyl groups having 2 to 14 carbon atoms may have one or more aryl groups.
  • Examples of the aryl group include R 1 The group illustrated as an aryl group represented by these is mentioned.
  • Examples of the alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups include a cinnamyl group and a styryl group.
  • alkynyl groups having 2 to 12 carbon atoms may have one or more aryl groups.
  • R 1 The group illustrated as an aryl group represented by these is mentioned.
  • Examples of the alkynyl group having 2 to 12 carbon atoms which may be substituted with one or more aryl groups include a 3-phenyl-2-propynyl group.
  • R 1 Is preferably an alkyl group having 1 to 12 carbon atoms substituted with one or more aryl groups, and an alkyl group having 1 to 12 carbon atoms having an aryl group at the 1-position of an alkyl group such as a benzyl group or 1-phenylethyl group.
  • a group is more preferable in terms of easy elimination, and a benzyl group is more preferable.
  • compound (I) 1-substituted-3,4-epoxypiperidine (hereinafter abbreviated as compound (I)) represented by the formula (I), for example, 3-methyl-7-oxa-3-azabicyclo [4.1.0].
  • Compound (I) may be a racemate or an optically active substance.
  • Compound (I) is, for example, 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1-phenylethyl) -7-oxa-3-azabicyclo [4.1.0].
  • Substituent R such as heptane 1
  • 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane is particularly preferred.
  • Compound (I) is described, for example, in Chem. Pharm. Bull. 29, 3026 (1981).
  • a 1 An aryl group represented by 1 And A 2
  • a 1 And A 2 Examples of the polymethylene group having 2 to 7 carbon atoms represented together with an ethylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and a heptamethylene group.
  • Examples of the amine compound represented by formula (II) include methylamine, ethylamine, benzylamine, phenylethylamine, propylamine, isopropylamine, butylamine, vinylamine, and 1-propenylamine.
  • compound (II) When compound (II) has an asymmetric carbon atom, a racemate can be used, and an optically active substance can also be used.
  • Compound (II) may be a commercially available product, or may be prepared and used by any known method.
  • the reaction between compound (I) and compound (II) is carried out in a solvent.
  • the solvent As the solvent, the formula (III) (Wherein R 2 Is an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group, an alkoxyalkyl group having 2 to 14 carbon atoms which may have one or more alkoxy groups having 1 to 12 carbon atoms, or a hydrogen atom Represents.
  • R 3 And R 4 Each independently represents an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group, or a hydrogen atom.
  • alcohol solvents such as benzyl alcohol and cyclohexanol; pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane , Dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether and other aliphatic hydrocarbon solvents; benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochloro
  • the solvent is preferably an alcohol solvent, an aromatic solvent, or a nitrile solvent, and more preferably an alcohol solvent.
  • the alcohol solvent is preferably compound (III).
  • R 2 As the alkyl group having 1 to 11 carbon atoms in the alkyl group having 1 to 11 carbon atoms which may have a hydroxyl group, for example, 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 and undecyl group.
  • alkyl groups having 1 to 11 carbon atoms have one hydroxyl group. Also good. Examples of the alkyl group having 1 to 11 carbon atoms having a hydroxyl group include a 2-hydroxyethyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group.
  • R 2 The alkoxyalkyl group having 2 to 13 carbon atoms which may have an alkoxy group having 1 to 12 carbon atoms represented by the above formula is an alkyl group having 1 to 12 carbon atoms having one or more alkoxy groups having 1 to 12 carbon atoms It is an alkyl group.
  • alkoxyalkyl group having 2 to 13 carbon atoms examples include 2-methoxyethyl group, 2-ethoxyethyl group, 2- (propyloxy) ethyl group, 2-isopropyloxyethyl group, 2- (butyloxy) ethyl group, 2 -An isobutyloxyethyl group and a 2- (tert-butyloxy) ethyl group are exemplified, and these alkoxyalkyl groups having 2 to 13 carbon atoms may have one or more alkoxy groups having 1 to 12 carbon atoms.
  • alkoxy group having 1 to 12 carbon atoms examples include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.
  • R 2 Is preferably an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, a propyl group or an isopropyl group, or a carbon number of 2 such as a methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group or a 2-ethoxyethyl group.
  • 4 to 4 alkoxyalkyl groups more preferably a methyl group or a methoxymethyl group.
  • R 3 And R 4 As the alkyl group having 1 to 11 carbon atoms in the alkyl group having 1 to 11 carbon atoms which may have a hydroxyl group, for example, 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 and undecyl group.
  • Examples of the alkyl group having 1 to 11 carbon atoms having a hydroxyl group include a 2-hydroxyethyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group.
  • R 3 And R 4 Both are preferably hydrogen atoms.
  • the compound (III) include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isoheptyl 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 Methyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, di
  • the compound (III) is preferably an alcohol having 1 to 4 carbon atoms such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, tert-butyl alcohol, ethylene glycol monomethyl ether, ethylene glycol mono C3-C5 alkoxy alcohols such as ethyl ether, more preferably ethanol or ethylene glycol monomethyl ether.
  • the amount of compound (II) used is preferably 1 mol or more with respect to 1 mol of compound (I), and the upper limit is not limited.
  • the amount is preferably 1 to 5 moles, more preferably 1 to 2 moles in terms of economy with respect to 1 mole.
  • the amount of the solvent to be used is preferably 1-50 mL, more preferably 2-15 mL, per 1 g of compound (I).
  • a solvent can also be used independently and a mixture can also be used.
  • the reaction temperature is preferably a temperature from ⁇ 20 ° C. to the boiling point of the solvent used, and more preferably 35 to 120 ° C.
  • the reaction time is preferably 1 to 100 hours, although it depends on the reaction temperature, the amount of reaction reagent and solvent used, and the like. The degree of progress of the reaction can be confirmed by analytical 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.
  • compound (II) and solvent can be added to compound (I) in any order.
  • the target 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by the formula (IV-1) (hereinafter abbreviated as compound (IV-1)).
  • the main product As the main product.
  • Formula (IV-2) (Wherein R 1 , A 1 And A 2 Is as defined above.
  • compound (IV-2) 1-substituted-trans-4-substituted aminopiperidin-3-ol
  • compound (IV-2) 1-substituted-trans-4-substituted aminopiperidin-3-ol
  • post-treatment such as filtration, extraction, washing with water, etc.
  • an isolation treatment such as distillation or crystallization to give the compound (IV-1).
  • the extracted compound (IV-1) or a salt thereof can be purified by a purification treatment.
  • the purification treatment include recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; chromatography methods such as silica gel column chromatography, preferably recrystallization or chromatography methods, and more. Recrystallization is preferred.
  • recrystallization solvent examples include the above-described solvents that are present in the reaction between the compound (I) and the compound (II).
  • the recrystallization solvent may be used alone or as a mixture.
  • the recrystallization solvent is aliphatic such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether, etc.
  • a hydrocarbon solvent is preferred, and cyclohexane is more preferred.
  • Examples of the compound (IV-1) include trans-1-methyl-3- (methylamino) piperidin-4-ol, trans-1-ethyl-3- (methylamino) piperidin-4-ol, and trans-1- Benzyl-3- (methylamino) piperidin-4-ol, trans-1-benzyl-3- (ethylamino) piperidin-4-ol, trans-1-benzyl-3- (benzylamino) piperidin-4-ol, Trans-1-benzyl-3- (diethylamino) piperidin-4-ol, trans-1-benzyl-3- (dibenzylamino) piperidin-4-ol, trans-1-benzyl-3- (phenylamino) piperidine-ol 4-ol, trans-3- (benzylamino) -1- (1-phenylethyl) piperidin-4-ol Trans-3- (allylamino) -1-benzylpiperidin-4-ol, trans-3- (dial
  • the resulting compound (IV-1) is also an optically active substance.
  • the compound (IV-1) is a trans isomer, -NA with respect to the piperidine ring. 1 A 2 It means that the group and the hydroxyl group represented by are on opposite sides. -NA for the piperidine ring 1 A 2 A compound in which the group represented by and the hydroxyl group are on the same side is a cis isomer.
  • compound (I) is represented by formula (IA) (Wherein R 5 Represents an aralkyl group having 7 to 17 carbon atoms, an alkyl group having 1 to 11 carbon atoms, a phenyl group, or a hydrogen atom. ) (Hereinafter abbreviated as compound (IA)) to give compound (IV-1) as formula (IV-A) (Wherein R 5 , A 1 And A 2 Is as defined above. ) (Hereinafter abbreviated as compound (IV-A)).
  • R 5 As the alkyl group having 1 to 11 carbon atoms represented by, for example, 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, and undecyl group.
  • R 5 The aralkyl group having 7 to 17 carbon atoms represented by the formula is a group having one or more aromatic hydrocarbon groups such as a phenyl group and a naphthyl group on the alkyl group having 1 to 11 carbon atoms.
  • R 5 Is preferably a hydrogen atom.
  • Examples of the compound (IA) include 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1-phenylethyl) -7-oxa-3-azabicyclo [4.1. .0] heptane, 3- (1-phenylpropyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1-phenylbutyl) -7-oxa-3-azabicyclo [4.1.
  • Compound (IA) may be a racemate or an optically active substance.
  • Compound (IV-A) is, for example, trans-1-benzyl-3- (benzylamino) piperidin-4-ol, trans-3- (allylamino) -1-benzylpiperidin-4-ol, trans-1-benzyl- 3-[(1-Phenylethyl) amino] piperidin-4-ol, trans-1-benzyl-3-[(1-phenyl-2-methylpropyl) amino] piperidin-4-ol, trans-1-benzyl- 3-[(1-Phenylbutyl) amino] piperidin-4-ol, trans-1-benzyl-3- (dibenzylamino) piperidin-4-ol, trans-3- (benzylamino) -1- (1- Phenylethyl) piperidin-4-ol, trans-3- (allylamino) -1- (1-phenylethyl) piperidin-4-o , Trans-1- (1-phenylethyl) -3-[(1-
  • compound (IV-A) When at least one of compound (IA) and compound (II-A) is an optically active substance, the resulting compound (IV-A) is also an optically active substance.
  • compound (I) In the reaction of compound (I) with compound (II), compound (IA) is used as compound (I), and formula (II-A) is used as compound (II).
  • a 3 Represents a hydrogen atom or an alkyl group having 1 to 11 carbon atoms; 4 Represents a hydrogen atom, a benzyl group or an allyl group, and Z represents a phenyl group or a vinyl group.
  • compound (IV-1) is represented by formula (IV-B).
  • a 3 As the alkyl group having 1 to 11 carbon atoms represented by, for example, 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, and undecyl group.
  • Examples of the compound (II-A) include benzylamine, 1-phenylethylamine, 1-phenylpropylamine, 1-phenylbutylamine, 1-phenyl-2-methylpropylamine, 1-phenyl-2-methylbutylamine, dibenzylamine.
  • compound (II-A) When compound (II-A) has an asymmetric carbon atom, compound (II-A) may be a racemate or an optically active substance.
  • Examples of the compound (IV-B) include trans-1-benzyl-3- (benzylamino) piperidin-4-ol, trans-3- (allylamino) -1-benzylpiperidin-4-ol, and trans-1-benzyl.
  • compound (IV-B) When at least one of compound (IA) and compound (II-A) is an optically active substance, the resulting compound (IV-B) is also an optically active substance.
  • compound (IA) is used as compound (I)
  • formula (II-B) is used as compound (II).
  • a 5 Represents a hydrogen atom or an alkyl group having 1 to 11 carbon atoms
  • 6 Represents a hydrogen atom or a benzyl group.
  • compound (IV-C) where A 5 , A 6 And R 5 Is as defined above.
  • a 5 As the alkyl group having 1 to 11 carbon atoms represented by, for example, 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, and undecyl group.
  • Examples of the compound (II-B) include benzylamine, 1-phenylethylamine, 1-phenylpropylamine, 1-phenylbutylamine, 1-phenyl-2-methylpropylamine, 1-phenyl-2-methylbutylamine, dibenzylamine.
  • compound (II-B) When compound (II-B) has an asymmetric carbon atom, compound (II-B) may be a racemate or an optically active substance.
  • Examples of the compound (IV-C) include trans-1-benzyl-3- (benzylamino) piperidin-4-ol, trans-1-benzyl-3-[(1-phenylethyl) amino] piperidin-4-ol , Trans-1-benzyl-3-[(1-phenyl-2-methylpropyl) amino] piperidin-4-ol, trans-1-benzyl-3-[(1-phenylbutyl) amino] piperidin-4-ol Trans-1-benzyl-3- (dibenzylamino) piperidin-4-ol, trans-3- (benzylamino) -1- (1-phenylethyl) piperidin-4-ol, trans-1- (1- Phenylethyl) -3-[(1-phenylethyl) amino] pipe
  • compound (II) is represented by formula (II-C) (In the formula, Ar represents a phenyl group which may have a substituent, and the substituent includes an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, and a protected amino group.
  • butyl group isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group; as an alkoxy group having 1 to 12 carbon atoms, For example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group;
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom;
  • examples of the protected amino group include an acetylamino group, A benzoylamino group, a methoxycarbonylamino group, and an ethoxycarbonylamino group;
  • examples of the protected hydroxyl group include Acetoxy group, benzoyloxy group, benzyloxy group, a methoxymethoxy group, tert
  • Ar examples include 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4-dimethylphenyl group, 4-ethylphenyl group, 4-propylphenyl group, 2-methoxyphenyl group, 3 -Methoxyphenyl group, 4-methoxyphenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 4- (acetylamino) phenyl group, 4- (methoxycarbonylamino) phenyl group .
  • Examples of the compound (II-C) include aniline, o-toluidine, m-toluidine, p-toluidine, 2,4-xylidine, 4-ethylaniline, 4-propylaniline, o-anisidine, m-anisidine, p- Anisidine, 3-bromoaniline, 4- (acetylamino) aniline, methyl (4-aminophenyl) carbamate may be mentioned.
  • Examples of the compound (IV-D) include trans-1-benzyl-3- (phenylamino) piperidin-4-ol, trans-1-benzyl-3- (o-tolylamino) piperidin-4-ol, and trans-1.
  • the resulting compound (IV-D) is also an optically active substance.
  • the compound (IV-C) is reduced to give a compound of formula (V)
  • a process for obtaining trans-3-aminopiperidin-4-ol (hereinafter abbreviated as compound (V)) represented by formula (I) will be described.
  • a 5 And A 6 Both are preferably hydrogen atoms.
  • the mixture after completion of the above reaction may be used as it is, or may be used after post-treatment.
  • an isolated compound (IV-C) or a salt thereof may be used, or a purified compound (IV-C) or a salt thereof may be used.
  • This reduction step can be performed according to any known method capable of deprotecting a benzyl protected amino group.
  • a method of reacting compound (IV-C) with hydrogen in the presence of palladium carbon a method described in Green's Protective Groups in Organic Synthesis 4th edition (2007), Wiley Interscience can be mentioned.
  • a preferred method is a method of reacting compound (IV-C) with hydrogen in the presence of palladium carbon.
  • the palladium carbon may be a water-containing product or a dry product.
  • the content of palladium atoms is preferably 0.5 to 50% by weight, more preferably 5 to 20% by weight.
  • a commercially available palladium carbon can be used, and it can also be prepared and used by any known method.
  • the amount of palladium carbon to be used is preferably 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts per 1 part by weight of compound (IV-C) in terms of the amount of palladium atoms. The amount is within the range of parts by weight.
  • Palladium supported on carbon is preferably zero-valent. When a divalent or tetravalent palladium compound is supported, it is preferably used after being reduced to zero valence by a conventional method.
  • 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 preferably 0.1 to 5 MPa, more 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 compound (IV-C) with hydrogen is preferably carried out in a solvent inert to the reaction.
  • Examples of such a solvent include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, Aliphatic hydrocarbon solvents such as isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether; 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-dimethoxy ether Ether solvents such as diethylene
  • the amount of the solvent to be used is preferably 1 to 50 mL, more preferably 2 to 15 mL, per 1 g of compound (IV-C).
  • the reaction temperature is preferably 0 to 100 ° C, more preferably 20 to 70 ° C.
  • the reaction time depends on the reaction temperature, the amount of reaction reagent used, the hydrogen pressure, etc., but is preferably 1 to 24 hours.
  • the degree of progress of the reaction can be confirmed by analytical 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.
  • compound (IV-C) or a solution thereof and palladium carbon are mixed, hydrogen is added to the resulting mixture, or compound (( It can be carried out by the method of adding IV-C).
  • a method in which a solution of compound (IV-C) and palladium carbon are mixed and hydrogen is added to the obtained mixture is preferable.
  • Compound (V) is contained in the mixture after completion of the reaction.
  • the mixture is subjected to post-treatment such as filtration, extraction, washing with water, and then subjected to isolation treatment such as distillation and crystallization.
  • isolation treatment such as distillation and crystallization.
  • Compound (V) can be taken out. At this time, you may isolate a compound (V) as a salt with arbitrary acids, such as hydrochloric acid, benzoic acid, and tartaric acid.
  • the isolated compound (V) or a salt thereof is purified by recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; purification treatment such as chromatography methods such as silica gel column chromatography. Can do.
  • the compound (IV-C) when an optically active substance whose optical activity is derived from an asymmetric carbon on the piperidine ring is used, the resulting compound (V) is also an optically active substance.
  • Compound (V) is a 3-amino-compound in which the nitrogen atom contained in the piperidine ring is protected with a t-butoxycarbonyl group, a benzyloxycarbonyl group, or the like, for example, according to the method described in Example 1 of US2004 / 242888. It can also lead to a piperidin-4-ol compound. Next, the substituent on the amino group at the 3-position of the piperidine ring in compound (IV-B) is removed to remove the compound of formula (VI) (Wherein R 5 Is as defined above.
  • a 1-substituted-trans-3-aminopiperidin-4-ol (hereinafter abbreviated as compound (VI)) represented by formula (1), and carbamate protection of the amino group at the 3-position of the piperidine ring in compound (VI) Formula (VII) (Wherein R 5 Is as defined above and R 6 Represents an alkyl group having 1 to 12 carbon atoms. )
  • a 1-substituted-trans-3-protected aminopiperidin-4-ol (hereinafter abbreviated as compound (VII)) represented by formula (1), and substitution on a nitrogen atom contained in the piperidine ring in compound (VII) The group is removed to give the formula (VIII) (Wherein R 6 Is as defined above.
  • the step leading to trans-3- (protected amino) piperidin-4-ol (hereinafter abbreviated as compound (VIII)) represented by Compound (IV-B) subjected to the step leading to compound (VI) is A in formula (IV-B).
  • 4 Is a hydrogen atom or an allyl group, and Z is a vinyl group.
  • R 5 Is preferably a hydrogen atom, and A 3 And A 4 Both are preferably hydrogen atoms.
  • the mixture after completion of the reaction may be used as it is, or may be used after post-treatment.
  • an isolated compound (IV-B) or a salt thereof may be used, or a purified compound (IV-B) or a salt thereof may be used.
  • Removal of an allylic substituent on the 3-position amino group of the piperidine ring in compound (IV-B) is described in Green's Protective Groups in Organic Synthesis 4th edition (2007), Wiley Interscience, pages 807-808. It can be carried out according to the method.
  • Preferable methods include a method of reacting compound (IV-B) and palladium carbon in an alcohol solvent.
  • the palladium carbon to be reacted with the compound (IV-B) may be a hydrated product or a dried product.
  • the content of palladium atoms is preferably 0.5 to 50% by weight, more preferably 5 to 20% by weight.
  • a commercially available palladium carbon can be used, and it can also be prepared and used by any known method.
  • the amount of palladium carbon to be used is preferably 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts per 1 part by weight of compound (IV-B) in terms of the amount of palladium atoms.
  • the amount is within the range of parts by weight.
  • Palladium supported on carbon is preferably zero-valent. When a divalent or tetravalent palladium compound is supported, it is preferably used after being reduced to zero valence by a conventional method.
  • Examples of the alcohol solvent used for the reaction of the compound (IV-B) and palladium carbon include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 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 monoethyl ether, diethylene glycol monopropyl ether, di
  • alcohol solvents may be used alone or as a mixture.
  • ethanol is preferred.
  • the amount of the alcohol solvent to be used is preferably 1 to 50 mL, more preferably 2 to 15 mL, relative to 1 g of compound (IV-B).
  • the reaction between the compound (IV-B) and palladium carbon is preferably performed in an inert gas atmosphere such as nitrogen or argon. In addition, this reaction is preferably performed in the presence of aminoethanol.
  • the amount of aminoethanol to be used is preferably 0.5 to 1.5 mol with respect to 1 mol of compound (IV-B).
  • the reaction temperature is preferably 20 to 130 ° C, more preferably 60 to 90 ° C.
  • the reaction time depends on the reaction temperature, the amount of reaction reagent used, etc., but is preferably 1 to 24 hours.
  • the degree of progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
  • the mixing order of the reaction reagents is not particularly limited, and the method of adding compound (IV-B) and aminoethanol in an alcohol solvent, adding palladium carbon to the resulting mixture, mixing the alcohol solvent and palladium carbon, It is preferable to carry out by a method in which compound (IV-B) and aminoethanol are added to the obtained mixture. Compound (IV-B) and aminoethanol are mixed in an alcohol solvent, and the resulting mixture is mixed. A method of adding palladium carbon is more preferable.
  • Compound (VI) is contained in the mixture after completion of the reaction, and the mixture after completion of reaction containing this may be subjected to the step of leading to compound (VII).
  • after taking out compound (VI) by isolation processes, such as distillation and crystallization you may use for the process led to compound (VII), and also recrystallize; extraction purification; distillation; activated carbon, silica, alumina
  • the compound (VI) may be purified by a purification process such as a chromatography method such as silica gel column chromatography, and then subjected to a step leading to the compound (VII).
  • the compound (VI) may be taken out as a salt with any acid such as hydrochloric acid, benzoic acid, tartaric acid, etc. and then subjected to a step leading to the compound (VII).
  • Examples of the compound (VI) include trans-3-amino-1-benzylpiperidin-4-ol, trans-3-amino-1- (1-phenylethyl) piperidin-4-ol, and trans-3-amino-1.
  • Trans-3-amino-1-benzylpiperidin-4-ol is preferred.
  • an optically active substance whose optical activity is attributable to at least one of an asymmetric carbon atom on the piperidine ring and an asymmetric carbon atom of a substituent on the nitrogen atom constituting the piperidine ring
  • the resulting compound (VI) is also an optically active substance.
  • the amino group is protected with an alkoxycarbonyl group by being led to compound (VII). Protection of the amino group at the 3-position of the piperidine ring in compound (VI) is preferably carried out by reacting with an alkyl halocarbonate or dialkyl carbonate in the presence of a base.
  • the alkyl halocarbonate has the formula (IX-1) (Wherein R 6 Is as defined above, and X represents a halogen atom such as a chlorine atom or a bromine atom. )
  • the dialkyl carbonate is of the formula (IX-2) (Wherein R 6 Is as defined above.
  • R 6 As the alkyl group having 1 to 12 carbon atoms represented by, for example, 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 and dodecyl group.
  • An ethyl group, an isopropyl group, and a tert-butyl group are preferable, and a tert-butyl group is more preferable.
  • the base examples 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 amines 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; n -Alkyl metal compounds such as butyl lithium; alkali metal amide compounds such as lithium diisopropylamide and lithium hexamethyldisilazide are mentioned, and tertiary amines are preferred.
  • alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide
  • alkali metal carbonates such as potassium carbonate, sodium
  • alkyl halocarbonate examples include methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, and butyl chlorocarbonate.
  • dialkyl carbonate examples include ditert-butyl carbonate.
  • the amount of the base to be used is preferably 1 to 10 mol, more preferably 1 to 3 mol, per 1 mol of compound (VI).
  • the amount of alkyl halocarbonate or dialkyl carbonate to be used is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (V).
  • These reagents can be used commercially, or can be prepared and used by known methods.
  • the amino group is preferably protected in the presence of a solvent inert to the reaction. Examples of the solvent include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, and isodecane.
  • Aromatic solvents 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-dimethoxy Ether solvents such as ethane, diethylene glycol dimethyl ether, anisole, diphenyl ether; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone, ⁇ -butyrolactone, carbonic acid Dimethyl, diethyl carbonate, ethylene carbonate, propylene carbonate, 1,3-dimethyl-2-imidazo Examples include aprotic polar solvents
  • the amount of the solvent to be used is preferably 1 to 50 mL, more preferably 2 to 15 mL, relative to 1 g of compound (VI).
  • the reaction temperature is preferably in the range of ⁇ 30 ° C. to 70 ° C., more preferably 0 ° C. to 50 ° C.
  • the reaction time is preferably 1 to 20 hours, although it depends on the reaction temperature and the amount of reaction reagent used. The degree of progress of the reaction can be confirmed by analytical 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 it is preferable to mix them in the order of adding a base to the mixture of compound (VI) and a solvent inert to the reaction, followed by addition of alkyl halocarbonate or dialkyl carbonate.
  • Compound (VII) is contained in the mixture after completion of the reaction, and the mixture after completion of reaction containing this may be subjected to the step of leading to compound (VIII). You may use for the process led to compound (VIII), after attaching
  • compound (VII) after taking out compound (VII) by isolation processes, such as distillation and crystallization, you may use for the process led to compound (VIII), and also recrystallization; Extraction purification; Distillation; Activated carbon, silica, alumina
  • the compound (VII) may be purified by a purification process such as a chromatography method such as silica gel column chromatography and then subjected to a step leading to the compound (VIII).
  • compound (VII) may be taken out, for example, as a salt with any acid such as hydrochloric acid, benzoic acid, tartaric acid, etc., and then subjected to a step leading to compound (VIII).
  • Examples of the compound (VII) include methyl 1-benzyl-trans-4-hydroxypiperidin-3-ylcarbamate, methyl 1- (1-phenylethyl) -trans-4-hydroxypiperidin-3-ylcarbamate, methyl 1- (1-phenylpropyl) -trans-4-hydroxypiperidin-3-ylcarbamate, methyl 1- (1-phenyl-2-methylpropyl) -trans-4-hydroxypiperidin-3-ylcarbamate, ethyl 1-benzyl- Trans-4-hydroxypiperidin-3-ylcarbamate, ethyl 1- (1-phenylethyl) -trans-4-hydroxypiperidin-3-ylcarbamate, ethyl 1- (1-phenylpropyl) -trans-4-hydroxypiperidine -3-Ilka Baume Ethyl 1- (1-phenyl-2-methylpropyl) -trans-4-hydroxypiperidin-3-ylcarbamate, isopropyl 1-benzyl-
  • a method of reacting compound (VII) with hydrogen in the presence of palladium carbon for example, a method of reacting compound (VII) with hydrogen in the presence of palladium carbon, a method of reacting compound (VII) with hydrogen in the presence of palladium hydroxide, or a reaction of compound (VII) with sodium in liquid ammonia. And a method of reacting compound (VII) with hydrogen in the presence of palladium carbon is preferred.
  • the palladium carbon may be a water-containing product or a dry product.
  • the content of palladium atoms is preferably 0.5 to 50% by weight, more preferably 5 to 20% by weight.
  • a commercially available palladium carbon can be used, and it can also be prepared and used by any known method.
  • the amount of palladium carbon used is preferably 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts by weight, in terms of the amount of palladium atoms, relative to 1 part by weight of compound (VII). It is an amount within the included range.
  • Palladium supported on carbon is preferably zero-valent. When a divalent or tetravalent palladium compound is supported, it is preferably used after being reduced to zero valence by a conventional method.
  • 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 preferably 0.1 to 5 MPa, more preferably 0.1 to 1 MPa.
  • reaction of compound (VII) with hydrogen is preferably carried out in the presence of a solvent that does not inhibit the reaction.
  • Examples of such a solvent include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, Aliphatic hydrocarbon solvents such as decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether; 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-dimethoxy Ether solvents such as tan and di
  • the amount of the solvent to be used is preferably 1 to 50 mL, more preferably 2 to 15 mL, relative to 1 g of compound (VII).
  • the reaction temperature is preferably 0 to 100 ° C, more preferably 20 to 70 ° C.
  • the reaction time depends on the reaction temperature, the amount of reaction reagent used, the hydrogen pressure, etc., but is preferably 1 to 24 hours.
  • the degree of progress of the reaction can be confirmed by analytical 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.
  • compound (VII) or a solution thereof and palladium carbon are mixed, hydrogen is added to the resulting mixture, or compound (VII) is added to palladium carbon under a hydrogen atmosphere.
  • It can be implemented by the method of adding A method of mixing a solution of compound (VII) and palladium carbon and adding hydrogen to the resulting mixture is preferred.
  • the mixture after completion of the reaction contains compound (VIII), and the mixture after completion of the reaction containing this is subjected to post-treatment such as filtration, extraction, washing with water, etc., followed by isolation such as distillation and crystallization.
  • Compound (VIII) can be taken out after the treatment.
  • a compound (VIII) as salts with arbitrary acids, such as hydrochloric acid, benzoic acid, and tartaric acid.
  • the extracted compound (VIII) or a salt thereof is purified by, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; purification treatment such as chromatography methods such as silica gel column chromatography. You can also.
  • Examples of the compound (VIII) include methyl trans-4-hydroxypiperidin-3-ylcarbamate, ethyl trans-4-hydroxypiperidin-3-ylcarbamate, isopropyl trans-4-hydroxypiperidin-3-ylcarbamate, and tert-butyl. Examples include trans-4-hydroxypiperidin-3-ylcarbamate. Tert-butyl trans-3-hydroxypiperidin-4-ylcarbamate is preferred.
  • compound (VII) when the optical activity originates from an asymmetric carbon atom on the piperidine ring or an asymmetric carbon atom contained in an alkoxycarbonyl group, the resulting compound (VIII) is also an optically active substance.
  • Production Example 1 Production of 1-benzyl-1,2,3,6-tetrahydropyridine 10 g (126 mmol) of pyridine and 20 mL of acetonitrile were mixed, and then 16.2 g (126 mmol) of benzyl bromide was added at room temperature over 1 hour. It was dripped. After completion of the dropwise addition, the obtained mixture was adjusted to 70 to 72 ° C. and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to near room temperature, the solvent was distilled off from the reaction mixture, and then mixed with 150 mL of ethanol.
  • Production Example 2 Production of 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane 7.77 g of 1-benzyl-1,2,3,6-tetrahydropyridine obtained in Production Example 1 (44 .8 mmol) and 50 mL of water were mixed, and 5.11 g (44.8 mmol) of trifluoroacetic acid was added dropwise to the resulting mixture at room temperature over 10 minutes. To the resulting mixture, 7.18 g (53.8 mmol) of N-chlorosuccinimide was added in portions at room temperature over 1 hour. The obtained mixture was adjusted to 45 ° C., stirred at the same temperature for 2.5 hours, and then stirred overnight at room temperature.
  • Example 1 0.48 g (2.5 mmol) of 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane obtained in Production Example 2 and 5 mL of ethanol were mixed, and 0.32 mL (2 0.9 mmol) was added, and the resulting mixture was stirred at 75-80 ° C. for 34 hours.
  • Example 1 By recrystallizing the concentrated mixture obtained in Example 1 from 20 mL of cyclohexane, 0.55 g of (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol was obtained as crystals. Recrystallization yield 73%. When the 1 H-NMR spectrum of the obtained crystal was measured, no peak corresponding to (3RS, 4RS) -1-benzyl-4-benzylaminopiperidin-3-ol, ie, compound (IV-2) was observed. It was. Examples 2-6 In Example 1, it carried out according to Example 1 except having changed the conditions shown in Table 1.
  • the amount used indicates the amount of compound (II) used relative to 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane.
  • the 1 H-NMR spectrum of the obtained concentrated mixture was measured, no peak corresponding to compound (IV-2) was observed in any of Examples 2 to 6, and the target product was obtained position-selectively. It was.
  • the obtained compound (IV-1) and the yield are shown in Table 2.
  • the yield shown in Examples 2, 4, 5 and 6 represents the yield after purification by silica gel column chromatography.
  • Examples 7 and 8 In Example 1, ethanol was changed to 2-methoxyethanol, that is, ethylene glycol monomethyl ether, and the conditions shown in Table 3 were further changed.
  • Example 3 the amount of benzylamine used is the amount with respect to 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane.
  • Table 4 shows the obtained results.
  • the positional isomer ratio is (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol, that is, compound (IV-1) and its positional isomer (3RS, 4RS).
  • the positional isomer ratio with -1-benzyl-4-benzylaminopiperidin-3-ol, that is, compound (IV-2) is shown.
  • Examples 9-11 In Example 1, it carried out according to Example 1 except having changed ethanol into the solvent shown in Table 5, and having also changed the conditions shown in Table 5.
  • the amount of benzylamine used is the amount with respect to 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane.
  • the results obtained are shown in Table 6.
  • the regioisomer ratio is (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol, that is, compound (IV-1) and its regioisomer (3RS, 4RS) -1-benzyl-4-benzylaminopiperidin-3-ol, that is, the positional isomer ratio with compound (IV-2) is shown.
  • Example 12 Production of (3RS, 4RS) -3-amino-4-hydroxypiperidine (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol 100 mg obtained in the same manner as in Example 1 ( 0.334 mmol) and 10 mL of ethanol were mixed in an autoclave reactor, and the inside of the system was made a nitrogen atmosphere. Thereto was added 20 mg of 10% by weight palladium carbon (55% by weight water-containing product, PE type, manufactured by N.E. Chemcat Co., Ltd., Lot. The mixture was stirred at 65 ° C. for 8 hours at 5 MPa.
  • 1-Substituted-trans-3- (substituted amino) piperidin-4-ol is useful as various chemicals such as pharmaceutical intermediates and is derived from 1-substituted-trans-3- (substituted amino) piperidin-4-ol.
  • the trans-3-aminopiperidin-4-ol compound used is useful as various chemicals such as pharmaceutical intermediates.
  • the present invention is industrially applicable as a method for producing such a compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Disclosed is a 1-substituted-trans-3-(substituted amino)piperidin-4-ol which is useful for various chemical products such as a pharmaceutical intermediate. The 1-substituted-trans-3-(substituted amino)piperidin-4-ol is obtained by a method for producing a 1-substituted-trans-3-(substituted amino)piperidin-4-ol represented by formula (IV-1), said method comprising a step wherein a 1-substituted-3,4-epoxypiperidine represented by formula (I) (wherein R1 represents an aryl group, an alkyl group which may be substituted by an aryl group and has 1-12 carbon atoms, or the like) and an amine compound represented by formula (II) (wherein A1 and A2 each represents an aryl group, an alkyl group which may be substituted by an aryl group and has 1-12 carbon atoms, or the like) are caused to react with each other in a solvent.

Description

１−置換−トランス−３−（置換アミノ）ピペリジン−４−オール1-Substituted-trans-3- (substituted amino) piperidin-4-ol
　本発明は、１−置換−トランス−３−（置換アミノ）ピペリジン−４−オール及びトランス−３−アミノピペリジン−４−オールの製造方法に関する。 The present invention relates to a process for producing 1-substituted-trans-3- (substituted amino) piperidin-4-ol and trans-3-aminopiperidin-4-ol.
　１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールは医薬中間体等の各種化学品として有用（例えば、Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　１９９７，４０，２２６−２３５参照。）であり、該化合物より導かれるトランス−３−アミノピペリジン−４−オール化合物は、医薬中間体等の各種化学品として有用である。（例えば、ＷＯ２００６／１０６３２６の実施例１９０参照。）
　１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールの製造方法として、上記のＪｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ（Ｓｕｐｐｏｒｔｉｎｇ　Ｉｎｆｏｒｍａｔｉｏｎ）には、ピペリジン環上の窒素原子がベンジルオキシカルボニル基で保護された１−置換−３，４−エポキシピペリジンとアジ化ナトリウムとを反応させてピペリジン環の３位に位置選択的にアジド基を導入し、当該アジド基を還元してアミノ基とした後に置換基を導入する方法が記載されている。 1-Substituted-trans-3- (substituted amino) piperidin-4-ol is useful as various chemicals such as pharmaceutical intermediates (see, for example, Journal of Medicinal Chemistry 1997, 40, 226-235), and the compound. More derived trans-3-aminopiperidin-4-ol compounds are useful as various chemicals such as pharmaceutical intermediates. (See, eg, Example 190 of WO 2006/106326)
As a method for producing 1-substituted-trans-3- (substituted amino) piperidin-4-ol, the above-mentioned Journal of Medicinal Chemistry (Supporting Information) has a nitrogen atom on the piperidine ring protected with a benzyloxycarbonyl group. 1-Substituted 3,4-epoxy piperidine is reacted with sodium azide to introduce an azide group regioselectively into the 3-position of the piperidine ring, the azide group is reduced to an amino group, and then the substituent is introduced. The method of introduction is described.
　しかしながら、この方法は、爆発性のアジ化ナトリウムが必須であるという点で、必ずしも満足できる方法ではなかった。かかる状況下、取扱いに注意を要するアジ化ナトリウムを用いることなく、１−置換−３，４−エポキシピペリジンから目的とする１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールを製造する方法が求められていた。
　本発明は、式（Ｉ）
Figure JPOXMLDOC01-appb-I000020
（式中、Ｒ１はアリール基、１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基、１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基又は１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基を表す。
　ここで、アリール基は、炭素数１~１２のアルキル基、炭素数１~１２のアルコキシ基、ハロゲン原子、保護されたアミノ基及び保護された水酸基からなる群から選ばれる１以上の置換基を有していてもよい芳香族炭化水素基を意味する。）
で示される１−置換−３，４−エポキシピペリジンと式（ＩＩ）
Figure JPOXMLDOC01-appb-I000021
（式中、Ａ１はアリール基、１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基、１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基又は１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基を表し、Ａ２は１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基、１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基、１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基又は水素原子を表すか、
　あるいは、
　Ａ１とＡ２とが一緒になって炭素数２~７のポリメチレン基を表す。
　ここで、アリール基は、炭素数１~１２のアルキル基、炭素数１~１２のアルコキシ基、ハロゲン原子、保護されたアミノ基及び保護された水酸基からなる群から選ばれる１以上の置換基を有していてもよい芳香族炭化水素基を意味する。）
で示されるアミン化合物とを溶媒中で反応させる工程を含む式（ＩＶ−１）
Figure JPOXMLDOC01-appb-I000022
（式中、Ｒ１、Ａ１及びＡ２は上記で定義された通りである。）
で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールの製造方法を提供する。
　また、本発明は、式（Ｉ−Ａ）
Figure JPOXMLDOC01-appb-I000023
（式中、Ｒ５は炭素数７~１７のアラルキル基、炭素数１~１１のアルキル基、フェニル基又は水素原子を表す。）
で示される１−置換−３，４−エポキシピペリジンと式（ＩＩ−Ｂ）
Figure JPOXMLDOC01-appb-I000024
（式中、Ａ５は水素原子又は炭素数１~１１のアルキル基を表し、Ａ６は水素原子又はベンジル基を表す。）
で示されるアミン化合物とを溶媒中で反応させて式（ＩＶ−Ｃ）
Figure JPOXMLDOC01-appb-I000025
（式中、Ａ５、Ａ６及びＲ５は上記で定義された通りである。）
で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールを得る工程と、式（ＩＶ−Ｃ）で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールを還元する工程とを含む式（Ｖ）
Figure JPOXMLDOC01-appb-I000026
で示されるトランス−３−アミノピペリジン−４−オールの製造方法を提供する。 However, this method is not always satisfactory in that explosive sodium azide is essential. Under such circumstances, the desired 1-substituted-trans-3- (substituted amino) piperidin-4-ol is produced from 1-substituted-3,4-epoxypiperidine without using sodium azide which requires careful handling. There was a need for a way to do it.
The present invention relates to a compound of formula (I)
Figure JPOXMLDOC01-appb-I000020
(In the formula, R 1 is an aryl group, an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups, and an alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups. Represents an alkynyl group having 2 to 12 carbon atoms which may be substituted with a group or one or more aryl groups.
Here, the aryl group includes one or more substituents selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, a protected amino group, and a protected hydroxyl group. It means an aromatic hydrocarbon group which may have. )
1-substituted-3,4-epoxypiperidine represented by the formula (II)
Figure JPOXMLDOC01-appb-I000021
Wherein A 1 is an aryl group, an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups, and an alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups Represents an alkynyl group having 2 to 12 carbon atoms which may be substituted with a group or one or more aryl groups, and A 2 represents an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups; Represents an alkenyl group having 2 to 14 carbon atoms which may be substituted with the above aryl group, an alkynyl group having 2 to 12 carbon atoms which may be substituted with one or more aryl groups, or a hydrogen atom,
Or
A 1 and A 2 together represent a polymethylene group having 2 to 7 carbon atoms.
Here, the aryl group includes one or more substituents selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, a protected amino group, and a protected hydroxyl group. It means an aromatic hydrocarbon group which may have. )
Comprising a step of reacting an amine compound represented by formula (IV-1) in a solvent:
Figure JPOXMLDOC01-appb-I000022
(Wherein R 1 , A 1 and A 2 are as defined above.)
A method for producing 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by the formula:
The present invention also provides a compound of formula (IA)
Figure JPOXMLDOC01-appb-I000023
(In the formula, R 5 represents an aralkyl group having 7 to 17 carbon atoms, an alkyl group having 1 to 11 carbon atoms, a phenyl group, or a hydrogen atom.)
1-substituted-3,4-epoxypiperidine represented by the formula (II-B)
Figure JPOXMLDOC01-appb-I000024
(In the formula, A 5 represents a hydrogen atom or an alkyl group having 1 to 11 carbon atoms, and A 6 represents a hydrogen atom or a benzyl group.)
And an amine compound represented by the formula (IV-C)
Figure JPOXMLDOC01-appb-I000025
(Wherein A 5 , A 6 and R 5 are as defined above.)
A step of obtaining 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by formula (IV) and 1-substituted-trans-3- (substituted amino) piperidine-4-ol represented by formula (IV-C): And a step of reducing oar (V)
Figure JPOXMLDOC01-appb-I000026
A method for producing trans-3-aminopiperidin-4-ol represented by the formula:
　式（Ｉ）において、Ｒ１で表されるアリール基としては、例えば、置換基を有していてもよいフェニル基、ナフチル基等の炭素数６~１０の芳香族炭化水素基が挙げられ、該置換基は、炭素数１~１２のアルキル基、炭素数１~１２のアルコキシ基、ハロゲン原子、保護されたアミノ基及び保護された水酸基からなる群から選ばれる１以上のものである。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、炭素数１~１２のアルコキシ基としては、例えばメトキシ基、エトキシ基、プロポキシ基、ブトキシ基が挙げられ、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、沃素原子が挙げられ、保護されたアミノ基としては、例えば炭素数１~８のアルカノイルアミノ基（代表例としては、アセチルアミノ基）、芳香環と結合する水素原子の１又は２が炭素数１~８のアルキル基、炭素数１~８のアルコキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基で置換されていてもよいフェニルカルボニルアミノ基（代表例としては、ベンゾイルアミノ基、ｐ−トルオイルアミノ基、４−クロロベンゾイルアミノ基、４−ニトロベンゾイルアミノ基、４−シアノベンゾイルアミノ基、４−トリフルオロメチルベンゾイルアミノ基、３、５−ビス（トリフルオロメチル）ベンゾイルアミノ基）、炭素数１~８のアルコキシカルボニルアミノ基（代表例としては、メトキシカルボニルアミノ基、エトキシカルボニルアミノ基、ｔ−ブトキシカルボニルアミノ基）、芳香環と結合する水素原子の１又は２が炭素数１~８のアルキル基、炭素数１~８のアルコキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基で置換されていてもよいフェノキシカルボニルアミノ基（代表例としてはフェノキシカルボニルアミノ基、４−ニトロフェノキシカルボニルアミノ基）、芳香環と結合する水素原子の１又は２が炭素数１~８のアルキル基、炭素数１~８のアルコキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基で置換されていてもよいベンジルオキシカルボニルアミノ基（代表例としては、ベンジルオキシカルボニルアミノ基）が挙げられ、保護された水酸基としては、例えば炭素数１~８のアルカノイルオキシ基（代表例としてはアセトキシ基）、芳香環と結合する水素原子の１又は２が炭素数１~８のアルキル基、炭素数１~８のアルコキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基で置換されていてもよいベンゾイルオキシ基（代表例としては、ベンゾイルオキシ基、４−ニトロベンゾイルオキシ基）、芳香環と結合する水素原子の１又は２が炭素数１~８のアルキル基、炭素数１~８のアルコキシ基、ハロゲン原子、ニトロ基、シアノ基又はトリフルオロメチル基で置換されていてもよいベンジルオキシ基（代表例としては、ベンジルオキシ基、４−メトキシベンジルオキシ基、４−ニトロベンジルオキシ基）、アルコキシ基の炭素数が１~８のアルコキシメトキシ基（代表例としては、メトキシメトキシ基）、アルコキシ基の炭素数が１~８の１−（アルコキシ）エトキシ基（代表例としては、１−（エトキシ）エトキシ基）、２−テトラヒドロピラニルオキシ基、個々のアルキル基の炭素数がそれぞれ１~８のトリアルキルシリルオキシ基（代表例としては、ｔ−ブチルジメチルシリルオキシ基）が挙げられる。
　Ｒ１で表される１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基において、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、これら炭素数１~１２のアルキル基は、１以上のアリール基を有していてもよい。該アリール基としては、例えばＲ１で表されるアリール基として例示した基が挙げられる。１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基としては、例えば１−フェニルエチル基、２−フェニルエチル基、１−ナフチルエチル基、１−フェニルプロピル基、２−フェニルプロピル基、３−フェニルプロピル基、ジフェニルメチル基が挙げられる。
　Ｒ１で表される１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基において、炭素数２~１４のアルケニル基としては、例えばビニル基、１−プロペニル基、アリル基、ブテニル基、ブタジエニル基、ペンテニル基、ヘキセニル基、ヘプテニル基、オクテニル基が挙げられ、これら炭素数２~１４のアルケニル基は、１以上のアリール基を有していてもよい。該アリール基としては、例えばＲ１で表されるアリール基として例示した基が挙げられる。１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基としては、例えばシンナミル基、スチリル基が挙げられる。
　Ｒ１で表される１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基において、炭素数２~１２のアルキニル基としては、例えばエチニル基、プロピニル基、ブチニル基、ペンチニル基、ヘキシニル基、ヘプチニル基、オクチニル基が挙げられ、これら炭素数２~１２のアルキニル基は、１以上のアリール基を有していてもよい。アリール基としては、例えばＲ１で表されるアリール基として例示した基が挙げられる。１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基としては、例えば３−フェニル−２−プロピニル基が挙げられる。
　Ｒ１としては、１以上のアリール基で置換された炭素数１~１２のアルキル基が好ましく、ベンジル基、１−フェニルエチル基等のアルキル基の１位にアリール基を有する炭素数１~１２のアルキル基が脱離の容易な点でより好ましく、ベンジル基がさらに好ましい。
　式（Ｉ）で示される１−置換−３，４−エポキシピペリジン（以下、化合物（Ｉ）と略記する。）としては、例えば３−メチル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−エチル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１−フェニルエチル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（２−フェニルエチル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−プロピル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−イソプロピル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−ブチル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１−フェニルプロピル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（２−フェニルプロピル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（３−フェニルプロピル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１−フェニル−１−メチルエチル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１，１−ジフェニルメチル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−ブチル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−イソブチル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンが挙げられる。化合物（Ｉ）はラセミ体であってもよいし、光学活性体であってもよい。化合物（Ｉ）は、例えば３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１−フェニルエチル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン等の置換基Ｒ１を容易に除去できるものが好ましく、特に３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンが好ましい。化合物（Ｉ）は、例えばＣｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，２９，３０２６（１９８１）に記載された公知の方法に従って製造することができる。
　式（ＩＩ）において、Ａ１で表されるアリール基ならびにＡ１及びＡ２で示される１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基、１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基、１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基としては、それぞれＲ１で例示した基と同様の基が挙げられる。
　Ａ１とＡ２とが一緒になって表す炭素数２~７のポリメチレン基としては、エチレン基、トリメチレン基、テトラメチレン基、ペンタメチレン基、ヘキサメチレン基、ヘプタメチレン基が挙げられる。
　式（ＩＩ）で示されるアミン化合物（以下、化合物（ＩＩ）と略記する。）としては、例えばメチルアミン、エチルアミン、ベンジルアミン、フェニルエチルアミン、プロピルアミン、イソプロピルアミン、ブチルアミン、ビニルアミン、１−プロペニルアミン、アリルアミン、１−ブテニルアミン、２−ブテニルアミン、３−ブテニルアミン、１，３−ブタジエニルアミン、シンナミルアミン、スチリルアミン、エチニルアミン、２−プロピニルアミン、３−フェニル−２−プロピニルアミン、ジメチルアミン、Ｎ−メチルエチルアミン、Ｎ−メチルベンジルアミン、Ｎ−メチル−１−フェニルエチルアミン、Ｎ−メチル−２−フェニルエチルアミン、Ｎ−メチルアリルアミン、Ｎ−メチル−シンナミルアミン、Ｎ−メチル−２−プロピニルアミン、Ｎ−メチル−３−フェニル−２−プロピニルアミン、ジエチルアミン、Ｎ−エチルベンジルアミン、Ｎ−エチル−１−フェニルエチルアミン、Ｎ−エチル−２−フェニルエチルアミン、Ｎ−エチルアリルアミン、Ｎ−エチル−シンナミルアミン、Ｎ−エチル−２−プロピニルアミン、Ｎ−エチル−３−フェニル−２−プロピニルアミン、ジベンジルアミン、Ｎ−ベンジル−１−フェニルエチルアミン、Ｎ−ベンジル−２−フェニルエチルアミン、Ｎ−ベンジルアリルアミン、Ｎ−ベンジル−シンナミルアミン、Ｎ−ベンジル−２−プロピニルアミン、Ｎ−ベンジル−３−フェニル−２−プロピニルアミン、アニリン、アニシジン、アジリジン、トリメチレンイミン、ピロリジン、ピペリジン、ヘキサメチレンイミン、ヘプタメチレンイミンが挙げられる。化合物（ＩＩ）が不斉炭素原子を有する場合は、ラセミ体を用いることもできるし、光学活性体を用いることもできる。化合物（ＩＩ）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。
　化合物（Ｉ）と化合物（ＩＩ）との反応は、溶媒中で行われる。溶媒としては、式（ＩＩＩ）
Figure JPOXMLDOC01-appb-I000027
（式中、Ｒ２は１の水酸基を有していてもよい炭素数１~１１のアルキル基、１以上の炭素数１~１２のアルコキシ基を有していてもよい炭素数２~１４のアルコキシアルキル基又は水素原子を表す。
　Ｒ３およびＲ４は、それぞれ独立して、１の水酸基を有していてもよい炭素数１~１１のアルキル基または水素原子を表す。）
（以下、化合物（ＩＩＩ）と略記する。）で示される化合物、ベンジルアルコール、シクロヘキサノール等のアルコール溶媒；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；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；アセトニトリル、プロピオニトリル等のニトリル溶媒；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）−ピリミジノン等の非プロトン性極性溶媒、水が挙げられる。溶媒は、好ましくはアルコール溶媒、芳香族溶媒、ニトリル溶媒であり、より好ましくはアルコール溶媒である。アルコール溶媒としては、化合物（ＩＩＩ）であることが好ましい。
　式（ＩＩＩ）において、Ｒ２で表される水酸基を有していてもよい炭素数１~１１のアルキル基における、炭素数１~１１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、ウンデシル基が挙げられ、これら炭素数１~１１のアルキル基は、１の水酸基を有していてもよい。水酸基を有する炭素数１~１１のアルキル基としては、例えば２−ヒドロキシエチル基、２−ヒドロキシプロピル基、３−ヒドロキシプロピル基が挙げられる。
　Ｒ２で表される炭素数１~１２のアルコキシ基を有していてもよい炭素数２~１３のアルコキシアルキル基とは、１以上の炭素数１~１２のアルコキシ基を有する炭素数１~１２のアルキル基である。炭素数２~１３のアルコキシアルキル基としては、例えば２−メトキシエチル基、２−エトキシエチル基、２−（プロピルオキシ）エチル基、２−イソプロピルオキシエチル基、２−（ブチルオキシ）エチル基、２−イソブチルオキシエチル基、２−（ｔｅｒｔ−ブチルオキシ）エチル基が挙げられ、これら炭素数２~１３のアルコキシアルキル基は、１以上の炭素数１~１２のアルコキシ基を有していてもよい。炭素数１~１２のアルコキシ基としては、例えばメトキシ基、エトキシ基、プロポキシ基、ブトキシ基が挙げられる。
　Ｒ２は、好ましくはメチル基、エチル基、プロピル基、イソプロピル基等の炭素数１~３のアルキル基又はメトキシメチル基、エトキシメチル基、２−メトキシエチル基、２−エトキシエチル基等の炭素数２~４のアルコキシアルキル基であり、より好ましくはメチル基又はメトキシメチル基である。
　式（ＩＩＩ）において、Ｒ３及びＲ４で表される水酸基を有していてもよい炭素数１~１１のアルキル基における、炭素数１~１１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、ウンデシル基が挙げられる。水酸基を有する炭素数１~１１のアルキル基としては、例えば２−ヒドロキシエチル基、２−ヒドロキシプロピル基、３−ヒドロキシプロピル基が挙げられる。Ｒ３及びＲ４はともに水素原子であることが好ましい。
　化合物（ＩＩＩ）としては、例えばメタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、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、イソヘプチルアルコール、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−ブチルエーテルが挙げられる。化合物（ＩＩＩ）としては、好ましくはメタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、イソブチルアルコール、ｔｅｒｔ−ブチルアルコール等の炭素数１~４のアルコールまたは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等の炭素数３~５のアルコキシアルコールであり、より好ましくはエタノール又はエチレングリコールモノメチルエーテルである。
　化合物（Ｉ）と化合物（ＩＩ）との反応において、化合物（ＩＩ）の使用量は、化合物（Ｉ）１モルに対して、１モル以上であることが好ましく、その上限は制限されないが、化合物（Ｉ）１モルに対して、経済性の点で好ましくは１~５モル、より好ましくは１~２モルである。溶媒の使用量は、化合物（Ｉ）１ｇに対して、好ましくは１~５０ｍＬ、より好ましくは２~１５ｍＬである。
　溶媒は、単独で用いることもできるし、混合物を用いることもできる。
　反応温度は、好ましくは−２０℃から用いる溶媒の沸点までの温度であり、より好ましくは３５~１２０℃である。反応時間は、反応温度、反応試剤や溶媒の使用量等にもよるが、好ましくは１~１００時間である。反応の進行度合いは、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分析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、化合物（Ｉ）に、化合物（ＩＩ）と溶媒とを、任意の順序で加えるという方法により実施できる。
　反応終了後の混合物中には、目的とする式（ＩＶ−１）で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オール（以下、化合物（ＩＶ−１）と略記する。）が主生成物として含まれている。式（ＩＶ−２）
Figure JPOXMLDOC01-appb-I000028
（式中、Ｒ１、Ａ１及びＡ２は上記で定義された通りである。）
で示される１−置換−トランス−４−置換アミノピペリジン−３−オール（以下、化合物（ＩＶ−２）と略記する。）が副生物として含まれていることもあるが、それらの生成比は、例えば、化合物（ＩＶ−１）：化合物（ＩＶ−２）＝７０：３０~１００：０の範囲内、化合物（ＩＶ−１）：化合物（ＩＶ−２）＝８０：２０~１００：０の範囲内、又は化合物（ＩＶ−１）：化合物（ＩＶ−２）＝９０：１０~１００：０の範囲内である。
　化合物（ＩＶ−１）を含む反応終了後の混合物に、例えば濾過、抽出、水洗等の後処理を施し、次いで、蒸留や結晶化等の単離処理を施せば、化合物（ＩＶ−１）を単独で、または化合物（ＩＶ−２）との混合物として、取り出すことができる。このとき、化合物（ＩＶ−１）を、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。
　取り出された化合物（ＩＶ−１）又はその塩を、精製処理により精製することもできる。精製処理としては、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が挙げられ、好ましくは再結晶又はクロマトグラフィー法であり、より好ましくは再結晶である。再結晶溶媒としては、例えば化合物（Ｉ）と化合物（ＩＩ）との反応に存在させる上述した溶媒が挙げられる。再結晶溶媒は単独であってもよいし、混合物であってもよい。再結晶溶媒は、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が好ましく、シクロヘキサンがより好ましい。精製処理後の位置異性体比は、例えば、化合物（ＩＶ−１）：化合物（ＩＶ−２）＝９０：１０~１００：０の範囲内、又は化合物（ＩＶ−１）：化合物（ＩＶ−２）＝９５：５~１００：０の範囲内である。
　化合物（ＩＶ−１）としては、例えばトランス−１−メチル−３−（メチルアミノ）ピペリジン−４−オール、トランス−１−エチル−３−（メチルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（メチルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（エチルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（ベンジルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（ジエチルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（ジベンジルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（フェニルアミノ）ピペリジン−４−オール、トランス−３−（ベンジルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（アリルアミノ）−１−ベンジルピペリジン−４−オール、トランス−３−（ジアリルアミノ）−１−ベンジルピペリジン−４−オール、トランス−３−（ベンジルアミノ）−１−プロピルピペリジン−４−オール、トランス−１−ベンジル−３−（フェニルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（ピロリジン−１−イル）ピペリジン−４−オール、トランス−１−ベンジル−３−（ピペリジン−１−イル）ピペリジン−４−オールが挙げられる。化合物（Ｉ）及び化合物（ＩＩ）のうち少なくともいずれかが光学活性体である場合は、得られる化合物（ＩＶ−１）も光学活性体である。また、化合物（ＩＶ−１）がトランス体であるとは、ピペリジン環に対して、−ＮＡ１Ａ２で示される基と水酸基とが互いに反対側にあることを意味する。ピペリジン環に対して、−ＮＡ１Ａ２で示される基と水酸基とが互いに同じ側にある化合物はシス体である。
　化合物（Ｉ）と化合物（ＩＩ）との反応において、化合物（Ｉ）として式（Ｉ−Ａ）
Figure JPOXMLDOC01-appb-I000029
（式中、Ｒ５は炭素数７~１７のアラルキル基、炭素数１~１１のアルキル基、フェニル基又は水素原子を表す。）
で示される化合物（以下、化合物（Ｉ−Ａ）と略記する。）を用いることにより、化合物（ＩＶ−１）として式（ＩＶ−Ａ）
Figure JPOXMLDOC01-appb-I000030
（式中、Ｒ５、Ａ１及びＡ２は上記で定義された通りである。）
で示される化合物（以下、化合物（ＩＶ−Ａ）と略記する。）が得られる。
　式（Ｉ−Ａ）において、Ｒ５で表される炭素数１~１１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、ウンデシル基が挙げられる。Ｒ５で表される炭素数７~１７のアラルキル基は、これら炭素数１~１１のアルキル基上に、１以上のフェニル基及びナフチル基等の芳香族炭化水素基を有する基であり、例えばベンジル基、１−フェニルエチル基、２−フェニルエチル基、１−ナフチルエチル基、１−フェニルプロピル基、２−フェニルプロピル基、３−フェニルプロピル基、１−フェニル−１−メチルエチル基、１−フェニルブチル基、２−フェニルブチル基、３−フェニルブチル基、４−フェニルブチル基、１−フェニル−１−メチルプロピル基が挙げられる。Ｒ５としては、水素原子が好ましい。
　化合物（Ｉ−Ａ）としては、例えば３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１−フェニルエチル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１−フェニルプロピル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１−フェニルブチル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１−フェニル−２−メチルプロピル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン、３−（１，３−ジフェニルプロピル）−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンが挙げられる。後述する脱保護の容易さの観点から、３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンが好ましい。化合物（Ｉ−Ａ）はラセミ体であってもよいし、光学活性体であってもよい。
　化合物（ＩＶ−Ａ）は、例えばトランス−１−ベンジル−３−（ベンジルアミノ）ピペリジン−４−オール、トランス−３−（アリルアミノ）−１−ベンジルピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニルエチル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニル−２−メチルプロピル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニルブチル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−（ジベンジルアミノ）ピペリジン−４−オール、トランス−３−（ベンジルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（アリルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−１−（１−フェニルエチル）−３−［（１−フェニルエチル）アミノ］ピペリジン−４−オール、トランス−１−（１−フェニルエチル）−３−［（１−フェニル−２−メチルプロピル）アミノ］ピペリジン−４−オール、トランス−３−［（１−フェニルブチル）アミノ］−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ジベンジルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ベンジルアミノ）−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−（アリルアミノ）−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニルエチル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニル−２−メチルプロピル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニルブチル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−（ジベンジルアミノ）−１−（１−フェニルプロピル）ピペリジン−４−オールが挙げられる。化合物（Ｉ−Ａ）及び化合物（ＩＩ−Ａ）のうち少なくともいずれかが光学活性体である場合は、得られる化合物（ＩＶ−Ａ）も光学活性体である。
　化合物（Ｉ）と化合物（ＩＩ）との反応において、化合物（Ｉ）として化合物（Ｉ−Ａ）を用い、化合物（ＩＩ）として式（ＩＩ−Ａ）
Figure JPOXMLDOC01-appb-I000031
（式中、Ａ３は水素原子又は炭素数１~１１のアルキル基を表し、Ａ４は水素原子、ベンジル基又はアリル基を表し、Ｚはフェニル基又はビニル基を表す。）
で示される化合物（以下、化合物（ＩＩ−Ａ）と略記する。）を用いれば、化合物（ＩＶ−１）として式（ＩＶ−Ｂ）
Figure JPOXMLDOC01-appb-I000032
（式中、Ｒ５、Ａ３、Ａ４及びＺは上記で定義された通りである。）
で示される化合物（以下、化合物（ＩＶ−Ｂ）と略記する。）が得られる。
　式（ＩＩ−Ａ）において、Ａ３で表される炭素数１~１１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、ウンデシル基が挙げられる。
　化合物（ＩＩ−Ａ）としては、例えばベンジルアミン、１−フェニルエチルアミン、１−フェニルプロピルアミン、１−フェニルブチルアミン、１−フェニル−２−メチルプロピルアミン、１−フェニル−２−メチルブチルアミン、ジベンジルアミン、ベンジル（１−フェニルエチル）アミン、ベンジル（１−フェニルプロピル）アミン、ベンジル（１−フェニルブチル）アミン、ベンジル（１−フェニル−２−メチルプロピル）アミン、ベンジル（１−フェニル−２−メチルブチル）アミン、アリルアミン、ジアリルアミンが挙げられる。化合物（ＩＩ−Ａ）が不斉炭素原子を有する場合は、化合物（ＩＩ−Ａ）はラセミ体であってもよいし、光学活性体であってもよい。
　化合物（ＩＶ−Ｂ）としては、例えばトランス−１−ベンジル−３−（ベンジルアミノ）ピペリジン−４−オール、トランス−３−（アリルアミノ）−１−ベンジルピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニルエチル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニル−２−メチルプロピル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニルブチル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−（ジベンジルアミノ）ピペリジン−４−オール、トランス−３−（ベンジルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（アリルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−１−（１−フェニルエチル）−３−［（１−フェニルエチル）アミノ］ピペリジン−４−オール、トランス−１−（１−フェニルエチル）−３−［（１−フェニル−２−メチルプロピル）アミノ］ピペリジン−４−オール、トランス−３−［（１−フェニルブチル）アミノ］−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ジベンジルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ベンジルアミノ）−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−（アリルアミノ）−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニルエチル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニル−２−メチルプロピル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニルブチル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−（ジベンジルアミノ）−１−（１−フェニルプロピル）ピペリジン−４−オールが挙げられる。化合物（Ｉ−Ａ）及び化合物（ＩＩ−Ａ）のうち少なくともいずれかが光学活性体である場合は、得られる化合物（ＩＶ−Ｂ）も光学活性体である。
　化合物（Ｉ）と化合物（ＩＩ）との反応において、化合物（Ｉ）として化合物（Ｉ−Ａ）を用い、化合物（ＩＩ）として式（ＩＩ−Ｂ）
Figure JPOXMLDOC01-appb-I000033
（式中、Ａ５は水素原子又は炭素数１~１１のアルキル基を表し、Ａ６は水素原子又はベンジル基を表す。）
で示される化合物（以下、化合物（ＩＩ−Ｂ）と略記する。）を用いることにより、式（ＩＶ−Ｃ）
Figure JPOXMLDOC01-appb-I000034
（式中、Ａ５、Ａ６及びＲ５は上記で定義された通りである。）
で示される化合物（以下、化合物（ＩＶ−Ｃ）と略記する。）が得られる。
　式（ＩＩ−Ｂ）において、Ａ５で表される炭素数１~１１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、ウンデシル基が挙げられる。
　化合物（ＩＩ−Ｂ）としては、例えばベンジルアミン、１−フェニルエチルアミン、１−フェニルプロピルアミン、１−フェニルブチルアミン、１−フェニル−２−メチルプロピルアミン、１−フェニル−２−メチルブチルアミン、ジベンジルアミン、ベンジル（１−フェニルエチル）アミン、ベンジル（１−フェニルプロピル）アミン、ベンジル（１−フェニルブチル）アミン、ベンジル（１−フェニル−２−メチルプロピル）アミン、ベンジル（１−フェニル−２−メチルブチル）アミンが挙げられる。化合物（ＩＩ−Ｂ）が不斉炭素原子を有する場合は、化合物（ＩＩ−Ｂ）はラセミ体であってもよいし、光学活性体であってもよい。
　化合物（ＩＶ−Ｃ）としては、例えばトランス−１−ベンジル−３−（ベンジルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニルエチル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニル−２−メチルプロピル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（１−フェニルブチル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−（ジベンジルアミノ）ピペリジン−４−オール、トランス−３−（ベンジルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−１−（１−フェニルエチル）−３−［（１−フェニルエチル）アミノ］ピペリジン−４−オール、トランス−１−（１−フェニルエチル）−３−［（１−フェニル−２−メチルプロピル）アミノ］ピペリジン−４−オール、トランス−３−［（１−フェニルブチル）アミノ］−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ジベンジルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ベンジルアミノ）−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニルエチル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニル−２−メチルプロピル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−［（１−フェニルブチル）アミノ］−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−（ジベンジルアミノ）−１−（１−フェニルプロピル）ピペリジン−４−オールが挙げられる。化合物（Ｉ−Ａ）及び化合物（ＩＩ−Ｂ）のうち少なくともいずれかが光学活性体である場合は、得られる化合物（ＩＶ−Ｃ）も光学活性体である。
　化合物（Ｉ）と化合物（ＩＩ）との反応において、化合物（ＩＩ）として式（ＩＩ−Ｃ）
Figure JPOXMLDOC01-appb-I000035
（式中、Ａｒは置換基を有していてもよいフェニル基を表し、該置換基は、炭素数１~１２のアルキル基、炭素数１~１２のアルコキシ基、ハロゲン原子、保護されたアミノ基及び保護された水酸基からなる群から選ばれる１以上である。）
で示される化合物（以下、化合物（ＩＩ−Ｃ）と略記する。）を用いることにより、式（ＩＶ−Ｄ）
Figure JPOXMLDOC01-appb-I000036
（式中、Ｒ１及びＡｒは上記で定義された通りである。）
で示される化合物（以下、化合物（ＩＶ−Ｄ）と略記する。）が得られる。
　式（ＩＩ−Ｃ）において、Ａｒは置換基を有していてもよいフェニル基を表し、置換基である炭素数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；炭素数１~１２のアルコキシ基としては、例えばメトキシ基、エトキシ基、プロポキシ基、ブトキシ基が挙げられ；ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、沃素原子が挙げられ；保護されたアミノ基としては、例えばアセチルアミノ基、ベンゾイルアミノ基、メトキシカルボニルアミノ基、エトキシカルボニルアミノ基が挙げられ；保護された水酸基としては、例えばアセトキシ基、ベンゾイルオキシ基、ベンジルオキシ基、メトキシメトキシ基、ｔｅｒｔ−ブチルジメチルシリルオキシ基等が挙げられる。Ａｒとしては、例えば２−メチルフェニル基、３−メチルフェニル基、４−メチルフェニル基、２，４−ジメチルフェニル基、４−エチルフェニル基、４−プロピルフェニル基、２−メトキシフェニル基、３−メトキシフェニル基、４−メトキシフェニル基、２−ブロモフェニル基、３−ブロモフェニル基、４−ブロモフェニル基、４−（アセチルアミノ）フェニル基、４−（メトキシカルボニルアミノ）フェニル基が挙げられる。
　化合物（ＩＩ−Ｃ）としては、例えばアニリン、ｏ−トルイジン、ｍ−トルイジン、ｐ−トルイジン、２，４−キシリジン、４−エチルアニリン、４−プロピルアニリン、ｏ−アニシジン、ｍ−アニシジン、ｐ−アニシジン、３−ブロモアニリン、４−（アセチルアミノ）アニリン、メチル　（４−アミノフェニル）カルバメートが挙げられる。
　化合物（ＩＶ−Ｄ）としては、例えばトランス−１−ベンジル−３−（フェニルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（ｏ−トリルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（ｍ−トリルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−（ｐ−トリルアミノ）ピペリジン−４−オール、トランス−１−ベンジル−３−［（２−メトキシフェニル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（２，４−ジメチルフェニル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（４−エチルフェニル）アミノ］ピペリジン−４−オール、トランス−１−ベンジル−３−［（３−ブロモフェニル）アミノ］ピペリジン−４−オール、トランス−３−｛（４−アセチルアミノ）フェニル｝アミノ｝−１−ベンジルピペリジン−４−オール、メチル　３−［（１−ベンジル−４−ヒドロピペリジン−３−イル）アミノ］フェニルカルバメート、トランス−３−（フェニルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ｏ−トリルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ｍ−トリルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−（ｐ−トリルアミノ）−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−［（２−メトキシフェニル）アミノ］−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−［（２，４−ジメチルフェニル）アミノ］−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−［（４−エチルフェニル）アミノ］−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−［（３−ブロモフェニル）アミノ］−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−｛（４−アセチルアミノ）フェニル｝アミノ｝−１−（１−フェニルエチル）ピペリジン−４−オール、メチル　３−［４−ヒドロ−１−（１−フェニルエチル）ピペリジン−３−イル］アミノ］フェニルカルバメートが挙げられる。化合物（Ｉ）及び化合物（ＩＩ−Ｃ）のうち少なくともいずれかが光学活性体である場合は、得られる化合物（ＩＶ−Ｄ）も光学活性体である。
　次に、化合物（ＩＶ−Ｃ）を還元して、式（Ｖ）
Figure JPOXMLDOC01-appb-I000037
で示されるトランス−３−アミノピペリジン−４−オール（以下、化合物（Ｖ）と略記する。）を得る工程について説明する。化合物（ＩＶ−Ｃ）において、Ｒ５は水素原子であることが好ましく、Ａ５及びＡ６はともに水素原子であることが好ましい。
　化合物（ＩＶ−Ｃ）として、前述の反応終了後の混合物をそのまま用いてもよいし、後処理後に用いてもよい。また、単離された化合物（ＩＶ−Ｃ）又はその塩を用いてもよいし、精製された化合物（ＩＶ−Ｃ）又はその塩を用いてもよい。
　本還元工程は、ベンジル保護されたアミノ基を脱保護しうる任意の公知の方法に従って実施できる。例えば、パラジウムカーボン存在下で化合物（ＩＶ−Ｃ）と水素とを反応させる方法のほか、Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　４ｔｈ　ｅｄｉｔｉｏｎ（２００７），Ｗｉｌｅｙ　Ｉｎｔｅｒｓｃｉｅｎｃｅに記載される方法が挙げられる。好ましい方法は、パラジウムカーボン存在下で化合物（ＩＶ−Ｃ）と水素とを反応させる方法である。
　パラジウムカーボンは、含水品であってもよいし、乾燥品であってもよい。パラジウム原子の含有量は、好ましくは０．５~５０重量％、より好ましくは５~２０重量％である。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、化合物（ＩＶ−Ｃ）１重量部に対して、パラジウム原子の量に換算して好ましくは０．０００１~０．０５重量部、より好ましくは０．００１~０．０２重量部含まれる範囲内の量である。カーボンに担持されているパラジウムは、好ましくは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好ましくは０．１~５ＭＰａ、より好ましくは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。
　化合物（ＩＶ−Ｃ）と水素との反応は、反応に不活性な溶媒中で行われることが好ましく、かかる溶媒としては、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；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、１−ブタノール、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）−ピリミジノン等の非プロトン性極性溶媒；水；それらの混合物が挙げられる。中でも、アルコール溶媒が好ましく、エタノールがより好ましい。かかる溶媒の使用量は、化合物（ＩＶ−Ｃ）１ｇに対して、好ましくは１~５０ｍＬ、より好ましくは２~１５ｍＬである。
　反応温度は、好ましくは０~１００℃、より好ましくは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、好ましくは１~２４時間である。反応の進行度合いは、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分析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、化合物（ＩＶ−Ｃ）又はその溶液とパラジウムカーボンとを混合し、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化合物（ＩＶ−Ｃ）を加えていく方法等により実施できる。化合物（ＩＶ−Ｃ）の溶液とパラジウムカーボンとを混合し、得られた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化合物（Ｖ）が含まれており、かかる混合物に、例えば、濾過、抽出、水洗等の後処理を施し、次いで、蒸留や結晶化等の単離処理を施せば、化合物（Ｖ）を取り出すことができる。このとき、化合物（Ｖ）を、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。単離された化合物（Ｖ）又はその塩は、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精製処理により、精製することができる。化合物（ＩＶ−Ｃ）として、その光学活性がピペリジン環上の不斉炭素に起因する光学活性体を用いると、得られる化合物（Ｖ）も光学活性体である。
　化合物（Ｖ）は、例えばＵＳ２００４／２４２８８８の実施例１に記載される方法に準じて、ピペリジン環に含まれる窒素原子がｔ−ブトキシカルボニル基やベンジルオキシカルボニル基等で保護された３−アミノ−ピペリジン−４−オール化合物へ導くこともできる。
　次に、化合物（ＩＶ−Ｂ）におけるピペリジン環の３位のアミノ基上の置換基を除去して式（ＶＩ）
Figure JPOXMLDOC01-appb-I000038
（式中、Ｒ５は上記で定義した通りである。）
で示される１−置換−トランス−３−アミノピペリジン−４−オール（以下、化合物（ＶＩ）と略記する。）に導く工程と、化合物（ＶＩ）におけるピペリジン環の３位のアミノ基をカーバメート保護して式（ＶＩＩ）
Figure JPOXMLDOC01-appb-I000039
（式中、Ｒ５は上記で定義した通りであり、Ｒ６は炭素数１~１２のアルキル基を表す。）
で示される１−置換−トランス−３−保護アミノピペリジン−４−オール（以下、化合物（ＶＩＩ）と略記する。）に導く工程と、化合物（ＶＩＩ）におけるピペリジン環に含まれる窒素原子上の置換基を除去して式（ＶＩＩＩ）
Figure JPOXMLDOC01-appb-I000040
（式中、Ｒ６は上記で定義した通りである。）
で示されるトランス−３−（保護アミノ）ピペリジン−４−オール（以下、化合物（ＶＩＩＩ）と略記する。）に導く工程について説明する。化合物（ＶＩ）に導く工程に供する化合物（ＩＶ−Ｂ）は、式（ＩＶ−Ｂ）におけるＡ４が水素原子又はアリル基であり、Ｚがビニル基である。Ｒ５は水素原子であることが好ましく、Ａ３およびＡ４はともに水素原子であることが好ましい。
　化合物（ＩＶ−Ｂ）として、反応終了後の混合物をそのまま用いてもよいし、後処理後に用いてもよい。また、単離された化合物（ＩＶ−Ｂ）又はその塩を用いてもよいし、精製された化合物（ＩＶ−Ｂ）又はその塩を用いてもよい。
　化合物（ＩＶ−Ｂ）におけるピペリジン環の３位のアミノ基上のアリル型置換基の除去は、Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　４ｔｈ　ｅｄｉｔｉｏｎ（２００７），Ｗｉｌｅｙ　Ｉｎｔｅｒｓｃｉｅｎｃｅ，８０７~８０８頁に記載される方法に従って実施できる。好ましい方法としては、アルコール溶媒中で化合物（ＩＶ−Ｂ）とパラジウムカーボンとを反応させる方法が挙げられる。
　化合物（ＩＶ−Ｂ）と反応させるパラジウムカーボンは、含水品であってもよいし、乾燥品であってもよい。パラジウム原子の含有量は、好ましくは０．５~５０重量％、より好ましくは５~２０重量％である。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、化合物（ＩＶ−Ｂ）１重量部に対して、パラジウム原子の量に換算して好ましくは０．０００１~０．０５重量部、より好ましくは０．００１~０．０２重量部含まれる範囲内の量である。カーボンに担持されているパラジウムは、好ましくは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。
　化合物（ＩＶ−Ｂ）とパラジウムカーボンとの反応に用いられるアルコール溶媒としては、例えばメタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、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−ブチルエーテルが挙げられる。これらアルコール溶媒は、単独でもよいし、混合物でもよい。アルコール溶媒としては、エタノールが好ましい。アルコール溶媒の使用量は、化合物（ＩＶ−Ｂ）１ｇに対して、好ましくは１~５０ｍＬ、より好ましくは２~１５ｍＬである。
　化合物（ＩＶ−Ｂ）とパラジウムカーボンとの反応は、窒素やアルゴン等の不活性ガス雰囲気下で行われることが好ましい。また、本反応は、アミノエタノールの存在下で行うことが好ましい。アミノエタノールの使用量は、化合物（ＩＶ−Ｂ）１モルに対して、好ましくは０．５~１．５モルである。反応温度は、好ましくは２０~１３０℃、より好ましくは６０~９０℃である。反応時間は、反応温度、反応試剤の使用量等にもよるが、好ましくは１~２４時間である。反応の進行度合いは、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分析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、アルコール溶媒中で化合物（ＩＶ−Ｂ）とアミノエタノールを混合し、得られた混合物にパラジウムカーボンを加える方法や、アルコール溶媒とパラジウムカーボンとを混合し、得られた混合物に化合物（ＩＶ−Ｂ）とアミノエタノールとを加えていく方法により実施することが好ましく、アルコール溶媒中で化合物（ＩＶ−Ｂ）とアミノエタノールとを混合し、得られた混合物にパラジウムカーボンを加える方法がより好ましい。
　反応終了後の混合物中には化合物（ＶＩ）が含まれており、これを含む反応終了後の混合物を、化合物（ＶＩＩ）に導く工程に供してもよいし、反応終了後の混合物を、例えば濾過、抽出、水洗等の後処理に付した後に、化合物（ＶＩＩ）に導く工程に供してもよい。また、蒸留や結晶化等の単離処理により化合物（ＶＩ）を取り出してから、化合物（ＶＩＩ）に導く工程に供してもよいし、さらに、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精製処理により、化合物（ＶＩ）を精製してから、化合物（ＶＩＩ）に導く工程に供してもよい。さらに、化合物（ＶＩ）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から化合物（ＶＩＩ）に導く工程に供してもよい。
　化合物（ＶＩ）としては、例えばトランス−３−アミノ−１−ベンジルピペリジン−４−オール、トランス−３−アミノ−１−（１−フェニルエチル）ピペリジン−４−オール、トランス−３−アミノ−１−（１−フェニルプロピル）ピペリジン−４−オール、トランス−３−アミノ−１−（１−フェニル−２−メチルプロピル）ピペリジン−４−オール、トランス−３−アミノ−１−（１−フェニルブチル）ピペリジン−４−オールが挙げられる。トランス−３−アミノ−１−ベンジルピペリジン−４−オールが好ましい。化合物（ＩＶ−Ｂ）として、その光学活性がピペリジン環上の不斉炭素原子と、ピペリジン環を構成する窒素原子上の置換基の不斉炭素原子とのうち少なくともいずれかに起因する光学活性体を用いると、得られる化合物（ＶＩ）も光学活性体である。
　化合物（ＶＩ）は、化合物（ＶＩＩ）に導かれることにより、アミノ基がアルコキシカルボニル基で保護される。化合物（ＶＩ）におけるピペリジン環の３位のアミノ基の保護は、塩基の存在下でハロ炭酸アルキルまたは炭酸ジアルキルと反応させることにより行われることが好ましい。ここで、ハロ炭酸アルキルは式（ＩＸ−１）
Figure JPOXMLDOC01-appb-I000041
（式中、Ｒ６は上記で定義された通りであり、Ｘは塩素原子、臭素原子等のハロゲン原子を表す。）
で示され、炭酸ジアルキルは式（ＩＸ−２）
Figure JPOXMLDOC01-appb-I000042
（式中、Ｒ６は上記で定義された通りである。）
で示される。
　式（ＶＩＩ）において、Ｒ６で表される炭素数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。エチル基、イソプロピル基、ｔｅｒｔ−ブチル基が好ましく、ｔｅｒｔ−ブチル基がより好ましい。
　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第三級アミン；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；ｎ−ブチルリチウム等のアルキル金属化合物；リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド等のアルカリ金属アミド化合物が挙げられ、第三級アミンが好ましい。
　ハロ炭酸アルキルとしては、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。炭酸ジアルキルとしては、例えば炭酸ジｔｅｒｔ−ブチルが挙げられる。化合物（ＶＩ）をカーバメート化合物である化合物（ＶＩＩ）に導くのに、炭酸ジアルキルを反応させるのが好ましく、炭酸ジｔｅｒｔ−ブチルを反応させるのがより好ましい。
　塩基の使用量は、化合物（ＶＩ）１モルに対して、好ましくは１~１０モル、より好ましくは１~３モルである。ハロ炭酸アルキル又は炭酸ジアルキルの使用量は、化合物（Ｖ）１モルに対して、好ましくは１~５モル、より好ましくは１~２モルである。これらの試薬は市販のものを用いることもできるし、公知の方法により調製して用いることもできる。
　アミノ基の保護は、反応に不活性な溶媒の存在下で行われることが好ましく、かかる溶媒としては、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；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）−ピリミ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；水；それらの混合物が挙げられる。なかでもエーテル溶媒が好ましく、テトラヒドロフランがより好ましい。かかる溶媒の使用量は、化合物（ＶＩ）１ｇに対して、好ましくは１~５０ｍＬ、より好ましくは２~１５ｍＬである。
　反応温度は好ましくは−３０℃~７０℃、より好ましくは０℃~５０℃の範囲内である。反応時間は、反応温度や反応試剤の使用量等にもよるが、好ましくは１~２０時間である。反応の進行度合いは、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分析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、化合物（ＶＩ）と反応に不活性な溶媒との混合物中に塩基を加え、続いてハロ炭酸アルキルまたは炭酸ジアルキル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化合物（ＶＩＩ）が含まれており、これを含む反応終了後の混合物を、化合物（ＶＩＩＩ）に導く工程に供してもよいし、反応終了後の混合物を、例えば濾過、抽出、水洗等の後処理に付した後に、化合物（ＶＩＩＩ）に導く工程に供してもよい。また、蒸留や結晶化等の単離処理により化合物（ＶＩＩ）を取り出してから、化合物（ＶＩＩＩ）に導く工程に供してもよいし、さらに、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精製処理により、化合物（ＶＩＩ）を精製してから、化合物（ＶＩＩＩ）に導く工程に供してもよい。また、化合物（ＶＩＩ）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から、化合物（ＶＩＩＩ）に導く工程に供してもよい。
　化合物（ＶＩＩ）としては、例えばメチル　１−ベンジル−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、メチル　１−（１−フェニルエチル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、メチル１−（１−フェニルプロピル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、メチル　１−（１−フェニル−２−メチルプロピル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、エチル　１−ベンジル−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、エチル　１−（１−フェニルエチル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、エチル　１−（１−フェニルプロピル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、エチル　１−（１−フェニル−２−メチルプロピル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、イソプロピル　１−ベンジル−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、イソプロピル　１−（１−フェニルエチル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、イソプロピル　１−（１−フェニルプロピル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、イソプロピル　１−（１−フェニル−２−メチルプロピル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、ｔｅｒｔ−ブチル　１−ベンジル−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、ｔｅｒｔ−ブチル　１−（１−フェニルエチル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、ｔｅｒｔ−ブチル　１−（１−フェニルプロピル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメート、ｔｅｒｔ−ブチル　１−（１−フェニル−２−メチルプロピル）−トランス−４−ヒドロキシピペリジン−３−イルカーバメートが挙げられる。ｔｅｒｔ−ブチル　１−ベンジル−トランス−４−ヒドロキシピペリジン−３−イルカーバメートが好ましい。化合物（ＶＩ）、ハロ炭酸アルキルおよび炭酸ジアルキルのうち少なくともいずれかが光学活性体である場合は、得られる化合物（ＶＩＩ）も光学活性体である。
　化合物（ＶＩＩ）は、化合物（ＶＩＩＩ）に導かれることにより、ピペリジン環に含まれる窒素原子上の置換基が除去される。化合物（ＶＩＩ）におけるピペリジン環に含まれる窒素原子上の置換基の除去は、アルコキシカルボニル基で保護されたアミノ基に対して不活性な条件下で行われることが好ましい。例えば、パラジウムカーボン存在下で化合物（ＶＩＩ）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化合物（ＶＩＩ）と水素とを反応させる方法、液体アンモニア中で化合物（ＶＩＩ）とナトリウムとを反応させる方法等が挙げられ、パラジウムカーボン存在下で化合物（ＶＩＩ）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、含水品であってもよいし、乾燥品であってもよい。パラジウム原子の含有量は、好ましくは０．５~５０重量％、より好ましくは５~２０重量％である。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、化合物（ＶＩＩ）１重量部に対して、パラジウム原子の量に換算して好ましくは０．０００１~０．０５重量部、より好ましくは０．００１~０．０２重量部含まれる範囲内の量である。カーボンに担持されているパラジウムは、好ましくは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好ましくは０．１~５ＭＰａ、より好ましくは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。
　化合物（ＶＩＩ）と水素との反応は、反応を阻害しない溶媒の存在下で行われることが好ましく、かかる溶媒としては、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；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、１−ブタノール、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）−ピリミジノン等の非プロトン性極性溶媒；水；それらの混合物が挙げられる。中でもアルコール溶媒が好ましく、エタノールがより好ましい。かかる溶媒の使用量は、化合物（ＶＩＩ）１ｇに対して、好ましくは１~５０ｍＬ、より好ましくは２~１５ｍＬである。
　反応温度は、好ましくは０~１００℃、より好ましくは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、好ましくは１~２４時間である。反応の進行度合いは、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分析手段により確認できる。
　反応試剤の混合順序は特に限定されず、例えば、化合物（ＶＩＩ）又はその溶液とパラジウムカーボンとを混合し、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化合物（ＶＩＩ）を加えていく方法等により実施できる。化合物（ＶＩＩ）の溶液とパラジウムカーボンとを混合し、得られた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化合物（ＶＩＩＩ）が含まれており、これを含む反応終了後の混合物に、例えば濾過、抽出、水洗等の後処理を施し、次いで、蒸留や結晶化等の単離処理を施せば、化合物（ＶＩＩＩ）を取り出すことができる。このとき、化合物（ＶＩＩＩ）を、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。取り出された化合物（ＶＩＩＩ）またはその塩は、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精製処理により、精製することもできる。
　化合物（ＶＩＩＩ）としては、例えばメチル　トランス−４−ヒドロキシピペリジン−３−イルカーバメート、エチル　トランス−４−ヒドロキシピペリジン−３−イルカーバメート、イソプロピル　トランス−４−ヒドロキシピペリジン−３−イルカーバメート、ｔｅｒｔ−ブチル　トランス−４−ヒドロキシピペリジン−３−イルカーバメートが挙げられる。ｔｅｒｔ−ブチル　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好ましい。化合物（ＶＩＩ）として、その光学活性がピペリジン環上の不斉炭素原子又はアルコキシカルボニル基に含まれる不斉炭素原子に起因する場合は、得られる化合物（ＶＩＩＩ）も光学活性体である。 In formula (I), R 1 Examples of the aryl group represented by the formula include an aromatic hydrocarbon group having 6 to 10 carbon atoms such as an optionally substituted phenyl group and naphthyl group. One or more selected from the group consisting of an alkyl group of ˜12, an alkoxy group of 1 to 12 carbon atoms, a halogen atom, a protected amino group and a protected hydroxyl group. Examples of the alkyl group having 1 to 12 carbon atoms include 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, undecyl, and dodecyl groups. Examples of the alkoxy group having 1 to 12 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, Examples of the protected amino group include a C 1-8 alkanoylamino group (typically an acetylamino group), and 1 or 2 of a hydrogen atom bonded to an aromatic ring. Placed with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a nitro group, a cyano group or a trifluoromethyl group Optionally substituted phenylcarbonylamino group (typical examples include benzoylamino group, p-toluoylamino group, 4-chlorobenzoylamino group, 4-nitrobenzoylamino group, 4-cyanobenzoylamino group, 4-tribenzoylamino group, Fluoromethylbenzoylamino group, 3,5-bis (trifluoromethyl) benzoylamino group), alkoxycarbonylamino group having 1 to 8 carbon atoms (representative examples include methoxycarbonylamino group, ethoxycarbonylamino group, t-butoxy group) Carbonylamino group), 1 or 2 of the hydrogen atoms bonded to the aromatic ring are substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a nitro group, a cyano group or a trifluoromethyl group Phenoxycarbonylamino group which may be substituted (typical example is phenoxycarbo Nylamino group, 4-nitrophenoxycarbonylamino group), 1 or 2 of hydrogen atoms bonded to the aromatic ring are alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, halogen atoms, nitro groups, cyano groups Or a benzyloxycarbonylamino group (typically a benzyloxycarbonylamino group) which may be substituted with a trifluoromethyl group. Examples of the protected hydroxyl group include an alkanoyloxy group having 1 to 8 carbon atoms. (Typically an acetoxy group), 1 or 2 of hydrogen atoms bonded to an aromatic ring is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a nitro group, a cyano group or trifluoro Benzoyloxy group optionally substituted with a methyl group (representative examples include benzoyloxy group and 4-nitrobenzoyloxy group) One or two hydrogen atoms bonded to the aromatic ring may be substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a nitro group, a cyano group, or a trifluoromethyl group. Benzyloxy group (representative examples are benzyloxy group, 4-methoxybenzyloxy group, 4-nitrobenzyloxy group), alkoxymethoxy group having 1 to 8 carbon atoms of alkoxy group (representative example is methoxymethoxy group) ), 1- (alkoxy) ethoxy groups having 1 to 8 carbon atoms in the alkoxy group (typically, 1- (ethoxy) ethoxy group), 2-tetrahydropyranyloxy groups, and individual alkyl groups having carbon numbers Examples thereof include 1 to 8 trialkylsilyloxy groups (typically, t-butyldimethylsilyloxy group).
R 1 In the alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups represented by the following, examples of the alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, Examples include a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, and a dodecyl group. These alkyl groups having 1 to 12 carbon atoms are 1 You may have the above aryl group. Examples of the aryl group include R 1 The group illustrated as an aryl group represented by these is mentioned. Examples of the alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups include 1-phenylethyl group, 2-phenylethyl group, 1-naphthylethyl group, 1-phenylpropyl group, 2- Examples thereof include a phenylpropyl group, a 3-phenylpropyl group, and a diphenylmethyl group.
R 1 In the alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups represented by the following, examples of the alkenyl group having 2 to 14 carbon atoms include a vinyl group, 1-propenyl group, allyl group, butenyl Group, butadienyl group, pentenyl group, hexenyl group, heptenyl group and octenyl group. These alkenyl groups having 2 to 14 carbon atoms may have one or more aryl groups. Examples of the aryl group include R 1 The group illustrated as an aryl group represented by these is mentioned. Examples of the alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups include a cinnamyl group and a styryl group.
R 1 In the alkynyl group having 2 to 12 carbon atoms which may be substituted with one or more aryl groups represented by the following, examples of the alkynyl group having 2 to 12 carbon atoms include ethynyl group, propynyl group, butynyl group, pentynyl group, Examples include a hexynyl group, a heptynyl group, and an octynyl group. These alkynyl groups having 2 to 12 carbon atoms may have one or more aryl groups. As the aryl group, for example, R 1 The group illustrated as an aryl group represented by these is mentioned. Examples of the alkynyl group having 2 to 12 carbon atoms which may be substituted with one or more aryl groups include a 3-phenyl-2-propynyl group.
R 1 Is preferably an alkyl group having 1 to 12 carbon atoms substituted with one or more aryl groups, and an alkyl group having 1 to 12 carbon atoms having an aryl group at the 1-position of an alkyl group such as a benzyl group or 1-phenylethyl group. A group is more preferable in terms of easy elimination, and a benzyl group is more preferable.
As the 1-substituted-3,4-epoxypiperidine (hereinafter abbreviated as compound (I)) represented by the formula (I), for example, 3-methyl-7-oxa-3-azabicyclo [4.1.0]. ] Heptane, 3-ethyl-7-oxa-3-azabicyclo [4.1.0] heptane, 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1-phenylethyl ) -7-oxa-3-azabicyclo [4.1.0] heptane, 3- (2-phenylethyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3-propyl-7-oxa -3-Azabicyclo [4.1.0] heptane, 3-isopropyl-7-oxa-3-azabicyclo [4.1.0] heptane, 3-butyl-7-oxa-3-azabicyclo [4.1.0] ] Heptane, 3- (1 Phenylpropyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3- (2-phenylpropyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3- (3- Phenylpropyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1-phenyl-1-methylethyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3 -(1,1-diphenylmethyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3-butyl-7-oxa-3-azabicyclo [4.1.0] heptane, 3-isobutyl- 7-oxa-3-azabicyclo [4.1.0] heptane. Compound (I) may be a racemate or an optically active substance. Compound (I) is, for example, 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1-phenylethyl) -7-oxa-3-azabicyclo [4.1.0]. Substituent R such as heptane 1 Are preferred, and 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane is particularly preferred. Compound (I) is described, for example, in Chem. Pharm. Bull. 29, 3026 (1981).
In formula (II), A 1 An aryl group represented by 1 And A 2 An alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups represented by formula (1), an alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups, and one or more aryl groups Examples of the alkynyl group having 2 to 12 carbon atoms which may be substituted with 1 And the same groups as those exemplified in the above.
A 1 And A 2 Examples of the polymethylene group having 2 to 7 carbon atoms represented together with an ethylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and a heptamethylene group.
Examples of the amine compound represented by formula (II) (hereinafter abbreviated as compound (II)) include methylamine, ethylamine, benzylamine, phenylethylamine, propylamine, isopropylamine, butylamine, vinylamine, and 1-propenylamine. , Allylamine, 1-butenylamine, 2-butenylamine, 3-butenylamine, 1,3-butadienylamine, cinnamylamine, styrylamine, ethynylamine, 2-propynylamine, 3-phenyl-2-propynylamine, dimethylamine N-methylethylamine, N-methylbenzylamine, N-methyl-1-phenylethylamine, N-methyl-2-phenylethylamine, N-methylallylamine, N-methyl-cinnamylamine, N-methyl-2-propini Amine, N-methyl-3-phenyl-2-propynylamine, diethylamine, N-ethylbenzylamine, N-ethyl-1-phenylethylamine, N-ethyl-2-phenylethylamine, N-ethylallylamine, N-ethyl- Cinnamylamine, N-ethyl-2-propynylamine, N-ethyl-3-phenyl-2-propynylamine, dibenzylamine, N-benzyl-1-phenylethylamine, N-benzyl-2-phenylethylamine, N- Benzylallylamine, N-benzyl-cinnamylamine, N-benzyl-2-propynylamine, N-benzyl-3-phenyl-2-propynylamine, aniline, anisidine, aziridine, trimethyleneimine, pyrrolidine, piperidine, hexamethyleneimine , Heptamethyle Imine, and the like. When compound (II) has an asymmetric carbon atom, a racemate can be used, and an optically active substance can also be used. Compound (II) may be a commercially available product, or may be prepared and used by any known method.
The reaction between compound (I) and compound (II) is carried out in a solvent. As the solvent, the formula (III)
Figure JPOXMLDOC01-appb-I000027
(Wherein R 2 Is an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group, an alkoxyalkyl group having 2 to 14 carbon atoms which may have one or more alkoxy groups having 1 to 12 carbon atoms, or a hydrogen atom Represents.
R 3 And R 4 Each independently represents an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group, or a hydrogen atom. )
(Hereinafter abbreviated as compound (III)), alcohol solvents such as benzyl alcohol and cyclohexanol; pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane , Dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether and other aliphatic hydrocarbon solvents; benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene , Α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-tri Aromatic solvents such as chlorobenzene; 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, Ether solvents such as 2-dimethoxyethane, diethylene glycol dimethyl ether, anisole, diphenyl ether; ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate; acetonitrile, propio Nitrile solvents such as nitrile; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, 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 Examples include aprotic polar solvents such as -3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, and water. The solvent is preferably an alcohol solvent, an aromatic solvent, or a nitrile solvent, and more preferably an alcohol solvent. The alcohol solvent is preferably compound (III).
In formula (III), R 2 As the alkyl group having 1 to 11 carbon atoms in the alkyl group having 1 to 11 carbon atoms which may have a hydroxyl group, for example, 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 and undecyl group. These alkyl groups having 1 to 11 carbon atoms have one hydroxyl group. Also good. Examples of the alkyl group having 1 to 11 carbon atoms having a hydroxyl group include a 2-hydroxyethyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group.
R 2 The alkoxyalkyl group having 2 to 13 carbon atoms which may have an alkoxy group having 1 to 12 carbon atoms represented by the above formula is an alkyl group having 1 to 12 carbon atoms having one or more alkoxy groups having 1 to 12 carbon atoms It is an alkyl group. Examples of the alkoxyalkyl group having 2 to 13 carbon atoms include 2-methoxyethyl group, 2-ethoxyethyl group, 2- (propyloxy) ethyl group, 2-isopropyloxyethyl group, 2- (butyloxy) ethyl group, 2 -An isobutyloxyethyl group and a 2- (tert-butyloxy) ethyl group are exemplified, and these alkoxyalkyl groups having 2 to 13 carbon atoms may have one or more alkoxy groups having 1 to 12 carbon atoms. Examples of the alkoxy group having 1 to 12 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.
R 2 Is preferably an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, a propyl group or an isopropyl group, or a carbon number of 2 such as a methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group or a 2-ethoxyethyl group. 4 to 4 alkoxyalkyl groups, more preferably a methyl group or a methoxymethyl group.
In formula (III), R 3 And R 4 As the alkyl group having 1 to 11 carbon atoms in the alkyl group having 1 to 11 carbon atoms which may have a hydroxyl group, for example, 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 and undecyl group. Examples of the alkyl group having 1 to 11 carbon atoms having a hydroxyl group include a 2-hydroxyethyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group. R 3 And R 4 Both are preferably hydrogen atoms.
Examples of the compound (III) include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isoheptyl 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 Methyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol isobutyl ether, diethylene glycol monobutyl tert- butyl ether. The compound (III) is preferably an alcohol having 1 to 4 carbon atoms such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutyl alcohol, tert-butyl alcohol, ethylene glycol monomethyl ether, ethylene glycol mono C3-C5 alkoxy alcohols such as ethyl ether, more preferably ethanol or ethylene glycol monomethyl ether.
In the reaction between compound (I) and compound (II), the amount of compound (II) used is preferably 1 mol or more with respect to 1 mol of compound (I), and the upper limit is not limited. (I) The amount is preferably 1 to 5 moles, more preferably 1 to 2 moles in terms of economy with respect to 1 mole. The amount of the solvent to be used is preferably 1-50 mL, more preferably 2-15 mL, per 1 g of compound (I).
A solvent can also be used independently and a mixture can also be used.
The reaction temperature is preferably a temperature from −20 ° C. to the boiling point of the solvent used, and more preferably 35 to 120 ° C. The reaction time is preferably 1 to 100 hours, although it depends on the reaction temperature, the amount of reaction reagent and solvent used, and the like. The degree of progress of the reaction can be confirmed by analytical 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, compound (II) and solvent can be added to compound (I) in any order.
In the mixture after completion of the reaction, the target 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by the formula (IV-1) (hereinafter abbreviated as compound (IV-1)). .) As the main product. Formula (IV-2)
Figure JPOXMLDOC01-appb-I000028
(Wherein R 1 , A 1 And A 2 Is as defined above. )
1-substituted-trans-4-substituted aminopiperidin-3-ol (hereinafter abbreviated as compound (IV-2)) may be contained as a by-product, the ratio of their production is For example, compound (IV-1): compound (IV-2) = 70: 30 to 100: 0, compound (IV-1): compound (IV-2) = 80: 20 to 100: 0 Within the range, or compound (IV-1): compound (IV-2) = 90: 10 to 100: 0.
The mixture after completion of the reaction containing the compound (IV-1) is subjected to post-treatment such as filtration, extraction, washing with water, etc., and then subjected to an isolation treatment such as distillation or crystallization to give the compound (IV-1). It can be taken out alone or as a mixture with compound (IV-2). At this time, you may take out a compound (IV-1) as salts with arbitrary acids, such as hydrochloric acid, benzoic acid, and tartaric acid.
The extracted compound (IV-1) or a salt thereof can be purified by a purification treatment. Examples of the purification treatment include recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; chromatography methods such as silica gel column chromatography, preferably recrystallization or chromatography methods, and more. Recrystallization is preferred. Examples of the recrystallization solvent include the above-described solvents that are present in the reaction between the compound (I) and the compound (II). The recrystallization solvent may be used alone or as a mixture. The recrystallization solvent is aliphatic such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether, etc. A hydrocarbon solvent is preferred, and cyclohexane is more preferred. The positional isomer ratio after the purification treatment is, for example, within the range of compound (IV-1): compound (IV-2) = 90: 10 to 100: 0, or compound (IV-1): compound (IV-2). ) = 95: 5 to 100: 0.
Examples of the compound (IV-1) include trans-1-methyl-3- (methylamino) piperidin-4-ol, trans-1-ethyl-3- (methylamino) piperidin-4-ol, and trans-1- Benzyl-3- (methylamino) piperidin-4-ol, trans-1-benzyl-3- (ethylamino) piperidin-4-ol, trans-1-benzyl-3- (benzylamino) piperidin-4-ol, Trans-1-benzyl-3- (diethylamino) piperidin-4-ol, trans-1-benzyl-3- (dibenzylamino) piperidin-4-ol, trans-1-benzyl-3- (phenylamino) piperidine-ol 4-ol, trans-3- (benzylamino) -1- (1-phenylethyl) piperidin-4-ol Trans-3- (allylamino) -1-benzylpiperidin-4-ol, trans-3- (diallylamino) -1-benzylpiperidin-4-ol, trans-3- (benzylamino) -1-propylpiperidin-4 -Ol, trans-1-benzyl-3- (phenylamino) piperidin-4-ol, trans-1-benzyl-3- (pyrrolidin-1-yl) piperidin-4-ol, trans-1-benzyl-3- (Piperidin-1-yl) piperidin-4-ol. When at least one of compound (I) and compound (II) is an optically active substance, the resulting compound (IV-1) is also an optically active substance. In addition, when the compound (IV-1) is a trans isomer, -NA with respect to the piperidine ring. 1 A 2 It means that the group and the hydroxyl group represented by are on opposite sides. -NA for the piperidine ring 1 A 2 A compound in which the group represented by and the hydroxyl group are on the same side is a cis isomer.
In the reaction of compound (I) with compound (II), compound (I) is represented by formula (IA)
Figure JPOXMLDOC01-appb-I000029
(Wherein R 5 Represents an aralkyl group having 7 to 17 carbon atoms, an alkyl group having 1 to 11 carbon atoms, a phenyl group, or a hydrogen atom. )
(Hereinafter abbreviated as compound (IA)) to give compound (IV-1) as formula (IV-A)
Figure JPOXMLDOC01-appb-I000030
(Wherein R 5 , A 1 And A 2 Is as defined above. )
(Hereinafter abbreviated as compound (IV-A)).
In the formula (IA), R 5 As the alkyl group having 1 to 11 carbon atoms represented by, for example, 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, and undecyl group. R 5 The aralkyl group having 7 to 17 carbon atoms represented by the formula is a group having one or more aromatic hydrocarbon groups such as a phenyl group and a naphthyl group on the alkyl group having 1 to 11 carbon atoms. 1-phenylethyl group, 2-phenylethyl group, 1-naphthylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-phenyl-1-methylethyl group, 1-phenyl Examples thereof include a butyl group, a 2-phenylbutyl group, a 3-phenylbutyl group, a 4-phenylbutyl group, and a 1-phenyl-1-methylpropyl group. R 5 Is preferably a hydrogen atom.
Examples of the compound (IA) include 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1-phenylethyl) -7-oxa-3-azabicyclo [4.1. .0] heptane, 3- (1-phenylpropyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1-phenylbutyl) -7-oxa-3-azabicyclo [4.1. .0] heptane, 3- (1-phenyl-2-methylpropyl) -7-oxa-3-azabicyclo [4.1.0] heptane, 3- (1,3-diphenylpropyl) -7-oxa-3 -Azabicyclo [4.1.0] heptane. From the viewpoint of ease of deprotection described later, 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane is preferable. Compound (IA) may be a racemate or an optically active substance.
Compound (IV-A) is, for example, trans-1-benzyl-3- (benzylamino) piperidin-4-ol, trans-3- (allylamino) -1-benzylpiperidin-4-ol, trans-1-benzyl- 3-[(1-Phenylethyl) amino] piperidin-4-ol, trans-1-benzyl-3-[(1-phenyl-2-methylpropyl) amino] piperidin-4-ol, trans-1-benzyl- 3-[(1-Phenylbutyl) amino] piperidin-4-ol, trans-1-benzyl-3- (dibenzylamino) piperidin-4-ol, trans-3- (benzylamino) -1- (1- Phenylethyl) piperidin-4-ol, trans-3- (allylamino) -1- (1-phenylethyl) piperidin-4-o , Trans-1- (1-phenylethyl) -3-[(1-phenylethyl) amino] piperidin-4-ol, trans-1- (1-phenylethyl) -3-[(1-phenyl-2- Methylpropyl) amino] piperidin-4-ol, trans-3-[(1-phenylbutyl) amino] -1- (1-phenylethyl) piperidin-4-ol, trans-3- (dibenzylamino) -1 -(1-phenylethyl) piperidin-4-ol, trans-3- (benzylamino) -1- (1-phenylpropyl) piperidin-4-ol, trans-3- (allylamino) -1- (1-phenylpropiyl L) Piperidin-4-ol, trans-3-[(1-phenylethyl) amino] -1- (1-phenylpropyl) piperidin-4-ol Trans-3-[(1-phenyl-2-methylpropyl) amino] -1- (1-phenylpropyl) piperidin-4-ol, trans-3-[(1-phenylbutyl) amino] -1- (1 -Phenylpropyl) piperidin-4-ol, trans-3- (dibenzylamino) -1- (1-phenylpropyl) piperidin-4-ol. When at least one of compound (IA) and compound (II-A) is an optically active substance, the resulting compound (IV-A) is also an optically active substance.
In the reaction of compound (I) with compound (II), compound (IA) is used as compound (I), and formula (II-A) is used as compound (II).
Figure JPOXMLDOC01-appb-I000031
(Where A 3 Represents a hydrogen atom or an alkyl group having 1 to 11 carbon atoms; 4 Represents a hydrogen atom, a benzyl group or an allyl group, and Z represents a phenyl group or a vinyl group. )
(Hereinafter abbreviated as compound (II-A)), compound (IV-1) is represented by formula (IV-B).
Figure JPOXMLDOC01-appb-I000032
(Wherein R 5 , A 3 , A 4 And Z are as defined above. )
(Hereinafter abbreviated as compound (IV-B)).
In formula (II-A), A 3 As the alkyl group having 1 to 11 carbon atoms represented by, for example, 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, and undecyl group.
Examples of the compound (II-A) include benzylamine, 1-phenylethylamine, 1-phenylpropylamine, 1-phenylbutylamine, 1-phenyl-2-methylpropylamine, 1-phenyl-2-methylbutylamine, dibenzylamine. Benzyl (1-phenylethyl) amine, benzyl (1-phenylpropyl) amine, benzyl (1-phenylbutyl) amine, benzyl (1-phenyl-2-methylpropyl) amine, benzyl (1-phenyl-2-methylbutyl) ) Amine, allylamine, diallylamine. When compound (II-A) has an asymmetric carbon atom, compound (II-A) may be a racemate or an optically active substance.
Examples of the compound (IV-B) include trans-1-benzyl-3- (benzylamino) piperidin-4-ol, trans-3- (allylamino) -1-benzylpiperidin-4-ol, and trans-1-benzyl. -3-[(1-phenylethyl) amino] piperidin-4-ol, trans-1-benzyl-3-[(1-phenyl-2-methylpropyl) amino] piperidin-4-ol, trans-1-benzyl -3-[(1-Phenylbutyl) amino] piperidin-4-ol, trans-1-benzyl-3- (dibenzylamino) piperidin-4-ol, trans-3- (benzylamino) -1- (1 -Phenylethyl) piperidin-4-ol, trans-3- (allylamino) -1- (1-phenylethyl) piperidine-4 All, trans-1- (1-phenylethyl) -3-[(1-phenylethyl) amino] piperidin-4-ol, trans-1- (1-phenylethyl) -3-[(1-phenyl-2 -Methylpropyl) amino] piperidin-4-ol, trans-3-[(1-phenylbutyl) amino] -1- (1-phenylethyl) piperidin-4-ol, trans-3- (dibenzylamino)- 1- (1-phenylethyl) piperidin-4-ol, trans-3- (benzylamino) -1- (1-phenylpropyl) piperidin-4-ol, trans-3- (allylamino) -1- (1- Phenylpropyl) piperidin-4-ol, trans-3-[(1-phenylethyl) amino] -1- (1-phenylpropyl) piperidine-4-ol , Trans-3-[(1-phenyl-2-methylpropyl) amino] -1- (1-phenylpropyl) piperidin-4-ol, trans-3-[(1-phenylbutyl) amino] -1 -(1-Phenylpropyl) piperidin-4-ol, trans-3- (dibenzylamino) -1- (1-phenylpropyl) piperidin-4-ol. When at least one of compound (IA) and compound (II-A) is an optically active substance, the resulting compound (IV-B) is also an optically active substance.
In the reaction between compound (I) and compound (II), compound (IA) is used as compound (I), and formula (II-B) is used as compound (II).
Figure JPOXMLDOC01-appb-I000033
(Where A 5 Represents a hydrogen atom or an alkyl group having 1 to 11 carbon atoms; 6 Represents a hydrogen atom or a benzyl group. )
(Hereinafter abbreviated as compound (II-B)) to give a compound of formula (IV-C)
Figure JPOXMLDOC01-appb-I000034
(Where A 5 , A 6 And R 5 Is as defined above. )
(Hereinafter abbreviated as compound (IV-C)).
In formula (II-B), A 5 As the alkyl group having 1 to 11 carbon atoms represented by, for example, 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, and undecyl group.
Examples of the compound (II-B) include benzylamine, 1-phenylethylamine, 1-phenylpropylamine, 1-phenylbutylamine, 1-phenyl-2-methylpropylamine, 1-phenyl-2-methylbutylamine, dibenzylamine. Benzyl (1-phenylethyl) amine, benzyl (1-phenylpropyl) amine, benzyl (1-phenylbutyl) amine, benzyl (1-phenyl-2-methylpropyl) amine, benzyl (1-phenyl-2-methylbutyl) ) Amines. When compound (II-B) has an asymmetric carbon atom, compound (II-B) may be a racemate or an optically active substance.
Examples of the compound (IV-C) include trans-1-benzyl-3- (benzylamino) piperidin-4-ol, trans-1-benzyl-3-[(1-phenylethyl) amino] piperidin-4-ol , Trans-1-benzyl-3-[(1-phenyl-2-methylpropyl) amino] piperidin-4-ol, trans-1-benzyl-3-[(1-phenylbutyl) amino] piperidin-4-ol Trans-1-benzyl-3- (dibenzylamino) piperidin-4-ol, trans-3- (benzylamino) -1- (1-phenylethyl) piperidin-4-ol, trans-1- (1- Phenylethyl) -3-[(1-phenylethyl) amino] piperidin-4-ol, trans-1- (1-phenylethyl) -3- (1-phenyl-2-methylpropyl) amino] piperidin-4-ol, trans-3-[(1-phenylbutyl) amino] -1- (1-phenylethyl) piperidin-4-ol, trans-3- (Dibenzylamino) -1- (1-phenylethyl) piperidin-4-ol, trans-3- (benzylamino) -1- (1-phenylpropyl) piperidin-4-ol, trans-3-[(1 -Phenylethyl) amino] -1- (1-phenylpropyl) piperidin-4-ol, trans-3-[(1-phenyl-2-methylpropyl) amino] -1- (1-phenylpropyl) piperidine-4 -Ol, trans-3-[(1-phenylbutyl) amino] -1- (1-phenylpropyl) piperidin-4-ol, trans-3 (Dibenzylamino) -1- (1-phenylpropyl) piperidin-4-ol. When at least one of compound (IA) and compound (II-B) is an optically active substance, the resulting compound (IV-C) is also an optically active substance.
In the reaction of compound (I) and compound (II), compound (II) is represented by formula (II-C)
Figure JPOXMLDOC01-appb-I000035
(In the formula, Ar represents a phenyl group which may have a substituent, and the substituent includes an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, and a protected amino group. 1 or more selected from the group consisting of a group and a protected hydroxyl group.)
(Hereinafter abbreviated as compound (II-C)) to give a compound of formula (IV-D)
Figure JPOXMLDOC01-appb-I000036
(Wherein R 1 And Ar are as defined above. )
(Hereinafter abbreviated as compound (IV-D)).
In the formula (II-C), Ar represents a phenyl group which may have a substituent, and examples of the alkyl group having 1 to 12 carbon atoms as the substituent include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group; as an alkoxy group having 1 to 12 carbon atoms, For example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group; examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; examples of the protected amino group include an acetylamino group, A benzoylamino group, a methoxycarbonylamino group, and an ethoxycarbonylamino group; examples of the protected hydroxyl group include Acetoxy group, benzoyloxy group, benzyloxy group, a methoxymethoxy group, tert- butyldimethylsilyl group, and the like. Examples of Ar include 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4-dimethylphenyl group, 4-ethylphenyl group, 4-propylphenyl group, 2-methoxyphenyl group, 3 -Methoxyphenyl group, 4-methoxyphenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 4- (acetylamino) phenyl group, 4- (methoxycarbonylamino) phenyl group .
Examples of the compound (II-C) include aniline, o-toluidine, m-toluidine, p-toluidine, 2,4-xylidine, 4-ethylaniline, 4-propylaniline, o-anisidine, m-anisidine, p- Anisidine, 3-bromoaniline, 4- (acetylamino) aniline, methyl (4-aminophenyl) carbamate may be mentioned.
Examples of the compound (IV-D) include trans-1-benzyl-3- (phenylamino) piperidin-4-ol, trans-1-benzyl-3- (o-tolylamino) piperidin-4-ol, and trans-1. -Benzyl-3- (m-tolylamino) piperidin-4-ol, trans-1-benzyl-3- (p-tolylamino) piperidin-4-ol, trans-1-benzyl-3-[(2-methoxyphenyl) Amino] piperidin-4-ol, trans-1-benzyl-3-[(2,4-dimethylphenyl) amino] piperidin-4-ol, trans-1-benzyl-3-[(4-ethylphenyl) amino] Piperidin-4-ol, trans-1-benzyl-3-[(3-bromophenyl) amino] piperidin-4-ol, 3-{(4-acetylamino) phenyl} amino} -1-benzylpiperidin-4-ol, methyl 3-[(1-benzyl-4-hydropiperidin-3-yl) amino] phenylcarbamate, trans- 3- (phenylamino) -1- (1-phenylethyl) piperidin-4-ol, trans-3- (o-tolylamino) -1- (1-phenylethyl) piperidin-4-ol, trans-3- ( m-tolylamino) -1- (1-phenylethyl) piperidin-4-ol, trans-3- (p-tolylamino) -1- (1-phenylethyl) piperidin-4-ol, trans-3-[(2 -Methoxyphenyl) amino] -1- (1-phenylethyl) piperidin-4-ol, trans-3-[(2,4-dimethylphenyl) Amino] -1- (1-phenylethyl) piperidin-4-ol, trans-3-[(4-ethylphenyl) amino] -1- (1-phenylethyl) piperidin-4-ol, trans-3- [ (3-Bromophenyl) amino] -1- (1-phenylethyl) piperidin-4-ol, trans-3-{(4-acetylamino) phenyl} amino} -1- (1-phenylethyl) piperidine-4 -Ol, methyl 3- [4-hydro-1- (1-phenylethyl) piperidin-3-yl] amino] phenylcarbamate. When at least one of compound (I) and compound (II-C) is an optically active substance, the resulting compound (IV-D) is also an optically active substance.
Next, the compound (IV-C) is reduced to give a compound of formula (V)
Figure JPOXMLDOC01-appb-I000037
A process for obtaining trans-3-aminopiperidin-4-ol (hereinafter abbreviated as compound (V)) represented by formula (I) will be described. In the compound (IV-C), R 5 Is preferably a hydrogen atom, and A 5 And A 6 Both are preferably hydrogen atoms.
As the compound (IV-C), the mixture after completion of the above reaction may be used as it is, or may be used after post-treatment. In addition, an isolated compound (IV-C) or a salt thereof may be used, or a purified compound (IV-C) or a salt thereof may be used.
This reduction step can be performed according to any known method capable of deprotecting a benzyl protected amino group. For example, in addition to a method of reacting compound (IV-C) with hydrogen in the presence of palladium carbon, a method described in Green's Protective Groups in Organic Synthesis 4th edition (2007), Wiley Interscience can be mentioned. A preferred method is a method of reacting compound (IV-C) with hydrogen in the presence of palladium carbon.
The palladium carbon may be a water-containing product or a dry product. The content of palladium atoms is preferably 0.5 to 50% by weight, more preferably 5 to 20% by weight. A commercially available palladium carbon can be used, and it can also be prepared and used by any known method. The amount of palladium carbon to be used is preferably 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts per 1 part by weight of compound (IV-C) in terms of the amount of palladium atoms. The amount is within the range of parts by weight. Palladium supported on carbon is preferably zero-valent. When a divalent or tetravalent palladium compound is supported, it is preferably used after being reduced to zero valence 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 preferably 0.1 to 5 MPa, more 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 compound (IV-C) with hydrogen is preferably carried out in a solvent inert to the reaction. Examples of such a solvent include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, Aliphatic hydrocarbon solvents such as isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether; 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-dimethoxy ether Ether solvents such as diethylene glycol dimethyl ether; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 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 , Alcohol solvents such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, 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 , Ester solvents such as isobutyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone , Γ-butyrolactone, dimethyl carbonate, diethyl carbonate, ethylene Aprotic polar solvents such as boronate, propylene carbonate, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone; water; Of the mixture. Among these, an alcohol solvent is preferable, and ethanol is more preferable. The amount of the solvent to be used is preferably 1 to 50 mL, more preferably 2 to 15 mL, per 1 g of compound (IV-C).
The reaction temperature is preferably 0 to 100 ° C, more preferably 20 to 70 ° C. The reaction time depends on the reaction temperature, the amount of reaction reagent used, the hydrogen pressure, etc., but is preferably 1 to 24 hours. The degree of progress of the reaction can be confirmed by analytical 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, compound (IV-C) or a solution thereof and palladium carbon are mixed, hydrogen is added to the resulting mixture, or compound (( It can be carried out by the method of adding IV-C). A method in which a solution of compound (IV-C) and palladium carbon are mixed and hydrogen is added to the obtained mixture is preferable.
Compound (V) is contained in the mixture after completion of the reaction. For example, the mixture is subjected to post-treatment such as filtration, extraction, washing with water, and then subjected to isolation treatment such as distillation and crystallization. Compound (V) can be taken out. At this time, you may isolate a compound (V) as a salt with arbitrary acids, such as hydrochloric acid, benzoic acid, and tartaric acid. The isolated compound (V) or a salt thereof is purified by recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; purification treatment such as chromatography methods such as silica gel column chromatography. Can do. As the compound (IV-C), when an optically active substance whose optical activity is derived from an asymmetric carbon on the piperidine ring is used, the resulting compound (V) is also an optically active substance.
Compound (V) is a 3-amino-compound in which the nitrogen atom contained in the piperidine ring is protected with a t-butoxycarbonyl group, a benzyloxycarbonyl group, or the like, for example, according to the method described in Example 1 of US2004 / 242888. It can also lead to a piperidin-4-ol compound.
Next, the substituent on the amino group at the 3-position of the piperidine ring in compound (IV-B) is removed to remove the compound of formula (VI)
Figure JPOXMLDOC01-appb-I000038
(Wherein R 5 Is as defined above. )
A 1-substituted-trans-3-aminopiperidin-4-ol (hereinafter abbreviated as compound (VI)) represented by formula (1), and carbamate protection of the amino group at the 3-position of the piperidine ring in compound (VI) Formula (VII)
Figure JPOXMLDOC01-appb-I000039
(Wherein R 5 Is as defined above and R 6 Represents an alkyl group having 1 to 12 carbon atoms. )
A 1-substituted-trans-3-protected aminopiperidin-4-ol (hereinafter abbreviated as compound (VII)) represented by formula (1), and substitution on a nitrogen atom contained in the piperidine ring in compound (VII) The group is removed to give the formula (VIII)
Figure JPOXMLDOC01-appb-I000040
(Wherein R 6 Is as defined above. )
The step leading to trans-3- (protected amino) piperidin-4-ol (hereinafter abbreviated as compound (VIII)) represented by Compound (IV-B) subjected to the step leading to compound (VI) is A in formula (IV-B). 4 Is a hydrogen atom or an allyl group, and Z is a vinyl group. R 5 Is preferably a hydrogen atom, and A 3 And A 4 Both are preferably hydrogen atoms.
As the compound (IV-B), the mixture after completion of the reaction may be used as it is, or may be used after post-treatment. In addition, an isolated compound (IV-B) or a salt thereof may be used, or a purified compound (IV-B) or a salt thereof may be used.
Removal of an allylic substituent on the 3-position amino group of the piperidine ring in compound (IV-B) is described in Green's Protective Groups in Organic Synthesis 4th edition (2007), Wiley Interscience, pages 807-808. It can be carried out according to the method. Preferable methods include a method of reacting compound (IV-B) and palladium carbon in an alcohol solvent.
The palladium carbon to be reacted with the compound (IV-B) may be a hydrated product or a dried product. The content of palladium atoms is preferably 0.5 to 50% by weight, more preferably 5 to 20% by weight. A commercially available palladium carbon can be used, and it can also be prepared and used by any known method. The amount of palladium carbon to be used is preferably 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts per 1 part by weight of compound (IV-B) in terms of the amount of palladium atoms. The amount is within the range of parts by weight. Palladium supported on carbon is preferably zero-valent. When a divalent or tetravalent palladium compound is supported, it is preferably used after being reduced to zero valence by a conventional method.
Examples of the alcohol solvent used for the reaction of the compound (IV-B) and palladium carbon include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 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 monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol isobutyl ether, diethylene glycol monobutyl tert- butyl ether. These alcohol solvents may be used alone or as a mixture. As the alcohol solvent, ethanol is preferred. The amount of the alcohol solvent to be used is preferably 1 to 50 mL, more preferably 2 to 15 mL, relative to 1 g of compound (IV-B).
The reaction between the compound (IV-B) and palladium carbon is preferably performed in an inert gas atmosphere such as nitrogen or argon. In addition, this reaction is preferably performed in the presence of aminoethanol. The amount of aminoethanol to be used is preferably 0.5 to 1.5 mol with respect to 1 mol of compound (IV-B). The reaction temperature is preferably 20 to 130 ° C, more preferably 60 to 90 ° C. The reaction time depends on the reaction temperature, the amount of reaction reagent used, etc., but is preferably 1 to 24 hours. The degree of progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
The mixing order of the reaction reagents is not particularly limited, and the method of adding compound (IV-B) and aminoethanol in an alcohol solvent, adding palladium carbon to the resulting mixture, mixing the alcohol solvent and palladium carbon, It is preferable to carry out by a method in which compound (IV-B) and aminoethanol are added to the obtained mixture. Compound (IV-B) and aminoethanol are mixed in an alcohol solvent, and the resulting mixture is mixed. A method of adding palladium carbon is more preferable.
Compound (VI) is contained in the mixture after completion of the reaction, and the mixture after completion of reaction containing this may be subjected to the step of leading to compound (VII). You may use for the process led to compound (VII), after attaching | subjecting post-processing, such as filtration, extraction, and water washing. Moreover, after taking out compound (VI) by isolation processes, such as distillation and crystallization, you may use for the process led to compound (VII), and also recrystallize; extraction purification; distillation; activated carbon, silica, alumina The compound (VI) may be purified by a purification process such as a chromatography method such as silica gel column chromatography, and then subjected to a step leading to the compound (VII). Further, the compound (VI) may be taken out as a salt with any acid such as hydrochloric acid, benzoic acid, tartaric acid, etc. and then subjected to a step leading to the compound (VII).
Examples of the compound (VI) include trans-3-amino-1-benzylpiperidin-4-ol, trans-3-amino-1- (1-phenylethyl) piperidin-4-ol, and trans-3-amino-1. -(1-phenylpropyl) piperidin-4-ol, trans-3-amino-1- (1-phenyl-2-methylpropyl) piperidin-4-ol, trans-3-amino-1- (1-phenylbutyl) ) Piperidin-4-ol. Trans-3-amino-1-benzylpiperidin-4-ol is preferred. As compound (IV-B), an optically active substance whose optical activity is attributable to at least one of an asymmetric carbon atom on the piperidine ring and an asymmetric carbon atom of a substituent on the nitrogen atom constituting the piperidine ring When is used, the resulting compound (VI) is also an optically active substance.
In compound (VI), the amino group is protected with an alkoxycarbonyl group by being led to compound (VII). Protection of the amino group at the 3-position of the piperidine ring in compound (VI) is preferably carried out by reacting with an alkyl halocarbonate or dialkyl carbonate in the presence of a base. Here, the alkyl halocarbonate has the formula (IX-1)
Figure JPOXMLDOC01-appb-I000041
(Wherein R 6 Is as defined above, and X represents a halogen atom such as a chlorine atom or a bromine atom. )
Wherein the dialkyl carbonate is of the formula (IX-2)
Figure JPOXMLDOC01-appb-I000042
(Wherein R 6 Is as defined above. )
Indicated by
In formula (VII), R 6 As the alkyl group having 1 to 12 carbon atoms represented by, for example, 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 and dodecyl group. An ethyl group, an isopropyl group, and a tert-butyl group are preferable, and a tert-butyl group is more preferable.
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 amines 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; n -Alkyl metal compounds such as butyl lithium; alkali metal amide compounds such as lithium diisopropylamide and lithium hexamethyldisilazide are mentioned, and tertiary amines are preferred.
Examples of the alkyl halocarbonate include methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate, and butyl chlorocarbonate. Examples of the dialkyl carbonate include ditert-butyl carbonate. In order to convert the compound (VI) to the compound (VII) which is a carbamate compound, it is preferable to react with dialkyl carbonate, and it is more preferable to react with di-tert-butyl carbonate.
The amount of the base to be used is preferably 1 to 10 mol, more preferably 1 to 3 mol, per 1 mol of compound (VI). The amount of alkyl halocarbonate or dialkyl carbonate to be used is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (V). These reagents can be used commercially, or can be prepared and used by known methods.
The amino group is preferably protected in the presence of a solvent inert to the reaction. Examples of the solvent include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, and isodecane. , Undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether and other aliphatic hydrocarbon solvents; benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, mono Fluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, etc. Aromatic solvents: 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-dimethoxy Ether solvents such as ethane, diethylene glycol dimethyl ether, anisole, diphenyl ether; 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-imidazo Examples include aprotic polar solvents such as lizinone and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone; nitrile solvents such as acetonitrile and propionitrile; water; and mixtures thereof. . Of these, ether solvents are preferable, and tetrahydrofuran is more preferable. The amount of the solvent to be used is preferably 1 to 50 mL, more preferably 2 to 15 mL, relative to 1 g of compound (VI).
The reaction temperature is preferably in the range of −30 ° C. to 70 ° C., more preferably 0 ° C. to 50 ° C. The reaction time is preferably 1 to 20 hours, although it depends on the reaction temperature and the amount of reaction reagent used. The degree of progress of the reaction can be confirmed by analytical 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 it is preferable to mix them in the order of adding a base to the mixture of compound (VI) and a solvent inert to the reaction, followed by addition of alkyl halocarbonate or dialkyl carbonate.
Compound (VII) is contained in the mixture after completion of the reaction, and the mixture after completion of reaction containing this may be subjected to the step of leading to compound (VIII). You may use for the process led to compound (VIII), after attaching | subjecting post-processing, such as filtration, extraction, and water washing. Moreover, after taking out compound (VII) by isolation processes, such as distillation and crystallization, you may use for the process led to compound (VIII), and also recrystallization; Extraction purification; Distillation; Activated carbon, silica, alumina The compound (VII) may be purified by a purification process such as a chromatography method such as silica gel column chromatography and then subjected to a step leading to the compound (VIII). Further, compound (VII) may be taken out, for example, as a salt with any acid such as hydrochloric acid, benzoic acid, tartaric acid, etc., and then subjected to a step leading to compound (VIII).
Examples of the compound (VII) include methyl 1-benzyl-trans-4-hydroxypiperidin-3-ylcarbamate, methyl 1- (1-phenylethyl) -trans-4-hydroxypiperidin-3-ylcarbamate, methyl 1- (1-phenylpropyl) -trans-4-hydroxypiperidin-3-ylcarbamate, methyl 1- (1-phenyl-2-methylpropyl) -trans-4-hydroxypiperidin-3-ylcarbamate, ethyl 1-benzyl- Trans-4-hydroxypiperidin-3-ylcarbamate, ethyl 1- (1-phenylethyl) -trans-4-hydroxypiperidin-3-ylcarbamate, ethyl 1- (1-phenylpropyl) -trans-4-hydroxypiperidine -3-Ilka Baume Ethyl 1- (1-phenyl-2-methylpropyl) -trans-4-hydroxypiperidin-3-ylcarbamate, isopropyl 1-benzyl-trans-4-hydroxypiperidin-3-ylcarbamate, isopropyl 1- (1- Phenylethyl) -trans-4-hydroxypiperidin-3-ylcarbamate, isopropyl 1- (1-phenylpropyl) -trans-4-hydroxypiperidin-3-ylcarbamate, isopropyl 1- (1-phenyl-2-methylpropyl) ) -Trans-4-hydroxypiperidin-3-ylcarbamate, tert-butyl 1-benzyl-trans-4-hydroxypiperidin-3-ylcarbamate, tert-butyl 1- (1-phenylethyl) -trans-4-hydroxy Pi Lysine-3-ylcarbamate, tert-butyl 1- (1-phenylpropyl) -trans-4-hydroxypiperidin-3-ylcarbamate, tert-butyl 1- (1-phenyl-2-methylpropyl) -trans-4 -Hydroxypiperidin-3-ylcarbamate. Tert-butyl 1-benzyl-trans-4-hydroxypiperidin-3-ylcarbamate is preferred. When at least one of compound (VI), alkyl halocarbonate and dialkyl carbonate is an optically active substance, the resulting compound (VII) is also an optically active substance.
Compound (VII) is led to compound (VIII) to remove the substituent on the nitrogen atom contained in the piperidine ring. Removal of the substituent on the nitrogen atom contained in the piperidine ring in compound (VII) is preferably carried out under conditions inert to the amino group protected with the alkoxycarbonyl group. For example, a method of reacting compound (VII) with hydrogen in the presence of palladium carbon, a method of reacting compound (VII) with hydrogen in the presence of palladium hydroxide, or a reaction of compound (VII) with sodium in liquid ammonia. And a method of reacting compound (VII) with hydrogen in the presence of palladium carbon is preferred.
The palladium carbon may be a water-containing product or a dry product. The content of palladium atoms is preferably 0.5 to 50% by weight, more preferably 5 to 20% by weight. A commercially available palladium carbon can be used, and it can also be prepared and used by any known method. The amount of palladium carbon used is preferably 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts by weight, in terms of the amount of palladium atoms, relative to 1 part by weight of compound (VII). It is an amount within the included range. Palladium supported on carbon is preferably zero-valent. When a divalent or tetravalent palladium compound is supported, it is preferably used after being reduced to zero valence 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 preferably 0.1 to 5 MPa, more 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 compound (VII) with hydrogen is preferably carried out in the presence of a solvent that does not inhibit the reaction. Examples of such a solvent include pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, Aliphatic hydrocarbon solvents such as decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether; 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-dimethoxy Ether solvents such as tan and diethylene glycol dimethyl ether; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 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 Alcohol solvents such as ter, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, 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, acetic acid Ester solvents such as butyl, isobutyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methyl Pyrrolidone, γ-butyrolactone, dimethyl carbonate, diethyl carbonate, ethyl Aprotic polar solvents such as ethylene carbonate, propylene carbonate, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone; water; A mixture thereof may be mentioned. Of these, alcohol solvents are preferable, and ethanol is more preferable. The amount of the solvent to be used is preferably 1 to 50 mL, more preferably 2 to 15 mL, relative to 1 g of compound (VII).
The reaction temperature is preferably 0 to 100 ° C, more preferably 20 to 70 ° C. The reaction time depends on the reaction temperature, the amount of reaction reagent used, the hydrogen pressure, etc., but is preferably 1 to 24 hours. The degree of progress of the reaction can be confirmed by analytical 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, compound (VII) or a solution thereof and palladium carbon are mixed, hydrogen is added to the resulting mixture, or compound (VII) is added to palladium carbon under a hydrogen atmosphere. It can be implemented by the method of adding A method of mixing a solution of compound (VII) and palladium carbon and adding hydrogen to the resulting mixture is preferred.
The mixture after completion of the reaction contains compound (VIII), and the mixture after completion of the reaction containing this is subjected to post-treatment such as filtration, extraction, washing with water, etc., followed by isolation such as distillation and crystallization. Compound (VIII) can be taken out after the treatment. At this time, you may take out a compound (VIII) as salts with arbitrary acids, such as hydrochloric acid, benzoic acid, and tartaric acid. The extracted compound (VIII) or a salt thereof is purified by, for example, recrystallization; extraction purification; distillation; adsorption treatment on activated carbon, silica, alumina, etc .; purification treatment such as chromatography methods such as silica gel column chromatography. You can also.
Examples of the compound (VIII) include methyl trans-4-hydroxypiperidin-3-ylcarbamate, ethyl trans-4-hydroxypiperidin-3-ylcarbamate, isopropyl trans-4-hydroxypiperidin-3-ylcarbamate, and tert-butyl. Examples include trans-4-hydroxypiperidin-3-ylcarbamate. Tert-butyl trans-3-hydroxypiperidin-4-ylcarbamate is preferred. As compound (VII), when the optical activity originates from an asymmetric carbon atom on the piperidine ring or an asymmetric carbon atom contained in an alkoxycarbonyl group, the resulting compound (VIII) is also an optically active substance.
　以下、実施例により本発明をさらに詳細に説明する。
製造例１：１−ベンジル−１，２，３，６−テトラヒドロピリジンの製造
　ピリジン１０ｇ（１２６ｍｍｏｌ）とアセトニトリル２０ｍＬとを混合し、そこにベンジルブロマイド１６．２ｇ（１２６ｍｍｏｌ）を室温で１時間かけて滴下した。滴下終了後、得られた混合物を７０~７２℃に調整し、同温度で３時間攪拌した。反応終了後、反応混合物を室温付近まで冷却し、反応混合物から溶媒を留去した後、エタノール１５０ｍＬと混合した。得られた混合物に水素化ホウ素ナトリウム９．５３ｇ（２５２ｍｍｏｌ）を４回に分けて、１時間かけて加えた。得られた混合物を室温で１２時間攪拌した。反応終了後、反応混合物を１５℃に調整し、そこに水１００ｍＬを滴下して混合した後、３５重量％塩酸１３．７ｇを加えて１時間攪拌した。その後、混合物の水層がｐＨ９を示すまで２５重量％水酸化ナトリウム水溶液を加え、トルエン２００ｍＬを用いて抽出した。得られた有機層を飽和食塩水５０ｍＬで洗浄した。得られた有機層を硫酸ナトリウムで脱水処理した後、溶媒を減圧留去して得た濃縮残渣を１０２~１０７℃／０．６ｋＰａの条件で蒸留し、１−ベンジル−１，２，３，６−テトラヒドロピリジン８．６ｇを得た。収率４０％。
製造例２：３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンの製造
　製造例１で得た１−ベンジル−１，２，３，６−テトラヒドロピリジン７．７７ｇ（４４．８ｍｍｏｌ）と水５０ｍＬとを混合し、得られた混合物にトリフルオロ酢酸５．１１ｇ（４４．８ｍｍｏｌ）を室温で１０分かけて滴下した。得られた混合物にＮ−クロロコハク酸イミド７．１８ｇ（５３．８ｍｍｏｌ）を室温で１時間かけて分割添加した。得られた混合物を４５℃に調整し、同温度で２．５時間攪拌した後、室温で終夜攪拌を行った。終夜室温攪拌後も反応が完結していなかったため、再び混合物を４５℃に調整し、同温度で７時間攪拌した。反応終了後、混合物を１２℃に調整し、そこにトルエン２５ｍＬを加え、さらに４８重量％水酸化ナトリウム水溶液２７．３ｇを３０分かけて滴下した。得られた混合物を４０℃に調整し、同温度で５．５時間攪拌した。その後、攪拌を停止して分液を行い、得られた水層をトルエン２５ｍＬによって再抽出した。有機層を合一した後、飽和食塩水２５ｍＬで洗浄した。得られた有機層を硫酸ナトリウムで脱水処理した後、溶媒を減圧留去して３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン７．６８ｇを得た。収率９０％。
実施例１
　製造例２で得た３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタン０．４８ｇ（２．５ｍｍｏｌ）とエタノール５ｍＬとを混合し、そこにベンジルアミン０．３２ｍＬ（２．９ｍｍｏｌ）を加えた後、得られた混合物を７５~８０℃で３４時間攪拌した。反応終了後、得られた混合物に水１０ｍＬを加えた後、酢酸エチル１０ｍＬを用いて抽出し、さらに得られた水層を酢酸エチル１０ｍＬで再抽出した。得られた有機層を合一し、飽和食塩水で洗浄した後、硫酸ナトリウムで脱水処理を行い、溶媒を減圧留去し濃縮混合物０．９１ｇを得た。収率＞９９％。得られた濃縮混合物の１Ｈ−ＮＭＲを測定して（３ＲＳ，４ＲＳ）−１−ベンジル−３−ベンジルアミノピペリジン−４−オール、即ち化合物（ＩＶ−１）と、その位置異性体である（３ＲＳ，４ＲＳ）−１−ベンジル−４−ベンジルアミノピペリジン−３−オール、即ち化合物（ＩＶ−２）との位置異性体比を決定したところ、位置異性体比は化合物（ＩＶ−１）：化合物（ＩＶ−２）＝１０．２：１であり、目的物が位置選択的に得られていた。
参考例１
　実施例１で得られた濃縮混合物をシクロヘキサン２０ｍＬから再結晶することにより、（３ＲＳ，４ＲＳ）−１−ベンジル−３−ベンジルアミノピペリジン−４−オール０．５５ｇを結晶として得た。再結晶収率７３％。得られた結晶の１Ｈ−ＮＭＲスペクトルを測定したところ、（３ＲＳ，４ＲＳ）−１−ベンジル−４−ベンジルアミノピペリジン−３−オール、即ち化合物（ＩＶ−２）に対応するピークは認められなかった。
実施例２~６
　実施例１において、表１に示す条件を変更した以外は実施例１に準じて行った。表１中、使用量は、３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンに対する化合物（ＩＩ）の使用量を示す。得られた濃縮混合物の１Ｈ−ＮＭＲスペクトルを測定したところ、実施例２~６のいずれにおいても化合物（ＩＶ−２）に対応するピークは認められず、目的物が位置選択的に得られていた。得られた化合物（ＩＶ−１）およびその収率を表２に示す。なお、実施例２、４、５および６に示す収率は、シリカゲルカラムクロマトグラフィーにより精製した後の収率を表す。
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
 　実施例７、８
　実施例１において、エタノールを２−メトキシエタノール、即ちエチレングリコールモノメチルエーテルに変更し、さらに表３に示す条件を変更した以外は実施例１に準じて行った。表３中、ベンジルアミンの使用量は、３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンに対する量を示す。
　得られた結果を表４に示す。表４中、位置異性体比は、（３ＲＳ，４ＲＳ）−１−ベンジル−３−ベンジルアミノピペリジン−４−オール、即ち化合物（ＩＶ−１）と、その位置異性体である（３ＲＳ，４ＲＳ）−１−ベンジル−４−ベンジルアミノピペリジン−３−オール、即ち化合物（ＩＶ−２）との位置異性体比を示す。
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
 実施例９~１１
　実施例１において、エタノールを表５に示す溶媒に変更し、さらに表５に示す条件を変更した以外は実施例１に準じて行った。表５中、ベンジルアミンの使用量は、３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンに対する量を示す。
　得られた結果を表６に示す。また、表６中、位置異性体比は、（３ＲＳ，４ＲＳ）−１−ベンジル−３−ベンジルアミノピペリジン−４−オール、即ち化合物（ＩＶ−１）と、その位置異性体である（３ＲＳ，４ＲＳ）−１−ベンジル−４−ベンジルアミノピペリジン−３−オール、即ち化合物（ＩＶ−２）との位置異性体比を示す。
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-I000048
Figure JPOXMLDOC01-appb-T000049
 参考例２
　実施例１において、３−ベンジル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンを非特許文献１に記載された方法に準じて製造した３−エトキシカルボンニル−７−オキサ−３−アザビシクロ［４．１．０］ヘプタンに変更し、７０℃で２５時間反応させた以外は実施例１に準じて行った。収率８４％。
　得られた濃縮混合物の１Ｈ−ＮＭＲを測定して（３ＲＳ，４ＲＳ）−１−エトキシカルボニル−３−ベンジルアミノピペリジン−４−オールと（３ＲＳ，４ＲＳ）−１−エトキシカルボニル−４−ベンジルアミノピペリジン−３−オールとの位置異性体比を決定したところ、位置異性体比は＜２：１であった。
実施例１２：（３ＲＳ，４ＲＳ）−３−アミノ−４−ヒドロキシピペリジンの製造
　実施例１と同様にして得た（３ＲＳ，４ＲＳ）−１−ベンジル−３−ベンジルアミノピペリジン−４−オール１００ｍｇ（０．３３４ｍｍｏｌ）とエタノール１０ｍＬと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）２０ｍｇを加えた後、系内を水素で置換し、水素圧０．５ＭＰａにて６５℃で８時間攪拌した。反応終了後、触媒を濾別し、得られた濾液を濃縮することにより、（３ＲＳ，４ＲＳ）−４−アミノ−３−ヒドロキシピペリジン３８ｍｇを定量的に得た。
　得られた化合物の１Ｈ−ＮＭＲスペクトルを測定したところ、化合物（ＩＶ−２）から導かれる（３ＲＳ，４ＲＳ）−４−アミノピペリジン−３−オールに対応するピークは認められなかった。 Hereinafter, the present invention will be described in more detail with reference to examples.
Production Example 1: Production of 1-benzyl-1,2,3,6-tetrahydropyridine 10 g (126 mmol) of pyridine and 20 mL of acetonitrile were mixed, and then 16.2 g (126 mmol) of benzyl bromide was added at room temperature over 1 hour. It was dripped. After completion of the dropwise addition, the obtained mixture was adjusted to 70 to 72 ° C. and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to near room temperature, the solvent was distilled off from the reaction mixture, and then mixed with 150 mL of ethanol. To the resulting mixture, 9.53 g (252 mmol) of sodium borohydride was added in 4 portions over 1 hour. The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was adjusted to 15 ° C., 100 mL of water was added dropwise thereto and mixed, and then 13.7 g of 35 wt% hydrochloric acid was added and stirred for 1 hour. Thereafter, a 25 wt% aqueous sodium hydroxide solution was added until the aqueous layer of the mixture showed pH 9, and extraction was performed using 200 mL of toluene. The obtained organic layer was washed with 50 mL of saturated brine. The obtained organic layer was dehydrated with sodium sulfate, the solvent was distilled off under reduced pressure, and the concentrated residue obtained was distilled under the conditions of 102 to 107 ° C./0.6 kPa, and 1-benzyl-1,2,3. 8.6 g of 6-tetrahydropyridine was obtained. Yield 40%.
Production Example 2: Production of 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane 7.77 g of 1-benzyl-1,2,3,6-tetrahydropyridine obtained in Production Example 1 (44 .8 mmol) and 50 mL of water were mixed, and 5.11 g (44.8 mmol) of trifluoroacetic acid was added dropwise to the resulting mixture at room temperature over 10 minutes. To the resulting mixture, 7.18 g (53.8 mmol) of N-chlorosuccinimide was added in portions at room temperature over 1 hour. The obtained mixture was adjusted to 45 ° C., stirred at the same temperature for 2.5 hours, and then stirred overnight at room temperature. Since the reaction was not complete after stirring overnight at room temperature, the mixture was again adjusted to 45 ° C. and stirred at the same temperature for 7 hours. After completion of the reaction, the mixture was adjusted to 12 ° C., 25 mL of toluene was added thereto, and 27.3 g of a 48 wt% aqueous sodium hydroxide solution was added dropwise over 30 minutes. The obtained mixture was adjusted to 40 ° C. and stirred at the same temperature for 5.5 hours. Then, stirring was stopped and liquid separation was performed, and the obtained aqueous layer was re-extracted with 25 mL of toluene. The organic layers were combined and washed with 25 mL of saturated brine. The obtained organic layer was dehydrated with sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 7.68 g of 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane. Yield 90%.
Example 1
0.48 g (2.5 mmol) of 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane obtained in Production Example 2 and 5 mL of ethanol were mixed, and 0.32 mL (2 0.9 mmol) was added, and the resulting mixture was stirred at 75-80 ° C. for 34 hours. After completion of the reaction, 10 mL of water was added to the obtained mixture, followed by extraction with 10 mL of ethyl acetate, and the obtained aqueous layer was re-extracted with 10 mL of ethyl acetate. The obtained organic layers were combined and washed with saturated brine, and then dehydrated with sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.91 g of a concentrated mixture. Yield> 99%. By measuring 1 H-NMR of the obtained concentrated mixture, (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol, that is, compound (IV-1) and its regioisomer ( 3RS, 4RS) -1-benzyl-4-benzylaminopiperidin-3-ol, i.e., the positional isomer ratio with compound (IV-2) was determined, and the positional isomer ratio was compound (IV-1): compound (IV-2) = 10.2: 1, and the target product was obtained position-selectively.
Reference example 1
By recrystallizing the concentrated mixture obtained in Example 1 from 20 mL of cyclohexane, 0.55 g of (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol was obtained as crystals. Recrystallization yield 73%. When the 1 H-NMR spectrum of the obtained crystal was measured, no peak corresponding to (3RS, 4RS) -1-benzyl-4-benzylaminopiperidin-3-ol, ie, compound (IV-2) was observed. It was.
Examples 2-6
In Example 1, it carried out according to Example 1 except having changed the conditions shown in Table 1. In Table 1, the amount used indicates the amount of compound (II) used relative to 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane. When the 1 H-NMR spectrum of the obtained concentrated mixture was measured, no peak corresponding to compound (IV-2) was observed in any of Examples 2 to 6, and the target product was obtained position-selectively. It was. The obtained compound (IV-1) and the yield are shown in Table 2. In addition, the yield shown in Examples 2, 4, 5 and 6 represents the yield after purification by silica gel column chromatography.
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
 Examples 7 and 8
In Example 1, ethanol was changed to 2-methoxyethanol, that is, ethylene glycol monomethyl ether, and the conditions shown in Table 3 were further changed. In Table 3, the amount of benzylamine used is the amount with respect to 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane.
Table 4 shows the obtained results. In Table 4, the positional isomer ratio is (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol, that is, compound (IV-1) and its positional isomer (3RS, 4RS). The positional isomer ratio with -1-benzyl-4-benzylaminopiperidin-3-ol, that is, compound (IV-2) is shown.
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
 Examples 9-11
In Example 1, it carried out according to Example 1 except having changed ethanol into the solvent shown in Table 5, and having also changed the conditions shown in Table 5. In Table 5, the amount of benzylamine used is the amount with respect to 3-benzyl-7-oxa-3-azabicyclo [4.1.0] heptane.
The results obtained are shown in Table 6. In Table 6, the regioisomer ratio is (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol, that is, compound (IV-1) and its regioisomer (3RS, 4RS) -1-benzyl-4-benzylaminopiperidin-3-ol, that is, the positional isomer ratio with compound (IV-2) is shown.
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-I000048
Figure JPOXMLDOC01-appb-T000049
 Reference example 2
In Example 1, 3-Benzyl-7-oxa-3-azabicyclo [4.1.0] heptane was produced according to the method described in Non-Patent Document 1 and 3-ethoxycarboninyl-7-oxa-3 -It carried out according to Example 1 except having changed into azabicyclo [4.1.0] heptane and making it react at 70 degreeC for 25 hours. Yield 84%.
1 H-NMR of the resulting concentrated mixture was measured to determine (3RS, 4RS) -1-ethoxycarbonyl-3-benzylaminopiperidin-4-ol and (3RS, 4RS) -1-ethoxycarbonyl-4-benzylamino. When the positional isomer ratio with piperidin-3-ol was determined, the positional isomer ratio was <2: 1.
Example 12: Production of (3RS, 4RS) -3-amino-4-hydroxypiperidine (3RS, 4RS) -1-benzyl-3-benzylaminopiperidin-4-ol 100 mg obtained in the same manner as in Example 1 ( 0.334 mmol) and 10 mL of ethanol were mixed in an autoclave reactor, and the inside of the system was made a nitrogen atmosphere. Thereto was added 20 mg of 10% by weight palladium carbon (55% by weight water-containing product, PE type, manufactured by N.E. Chemcat Co., Ltd., Lot. The mixture was stirred at 65 ° C. for 8 hours at 5 MPa. After completion of the reaction, the catalyst was removed by filtration, and the obtained filtrate was concentrated to quantitatively obtain 38 mg of (3RS, 4RS) -4-amino-3-hydroxypiperidine.
When the 1 H-NMR spectrum of the obtained compound was measured, no peak corresponding to (3RS, 4RS) -4-aminopiperidin-3-ol derived from compound (IV-2) was observed.
　１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールは医薬中間体等の各種化学品として有用であり、１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールから導かれるトランス−３−アミノピペリジン−４−オール化合物は、医薬中間体等の各種化学品として有用である。本発明は、かかる化合物の製造方法として産業上利用可能である。 1-Substituted-trans-3- (substituted amino) piperidin-4-ol is useful as various chemicals such as pharmaceutical intermediates and is derived from 1-substituted-trans-3- (substituted amino) piperidin-4-ol. The trans-3-aminopiperidin-4-ol compound used is useful as various chemicals such as pharmaceutical intermediates. The present invention is industrially applicable as a method for producing such a compound.

Claims (14)

  1. 式（Ｉ）
    Figure JPOXMLDOC01-appb-I000001
    （式中、Ｒ１はアリール基、１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基、１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基又は１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基を表す。
    　ここで、アリール基は、炭素数１~１２のアルキル基、炭素数１~１２のアルコキシ基、ハロゲン原子、保護されたアミノ基及び保護された水酸基からなる群から選ばれる１以上の置換基を有していてもよい芳香族炭化水素基を意味する。）
    で示される１−置換−３，４−エポキシピペリジンと式（ＩＩ）
    Figure JPOXMLDOC01-appb-I000002
    （式中、Ａ１はアリール基、１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基、１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基又は１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基を表し、Ａ２は１以上のアリール基で置換されていてもよい炭素数１~１２のアルキル基、１以上のアリール基で置換されていてもよい炭素数２~１４のアルケニル基、１以上のアリール基で置換されていてもよい炭素数２~１２のアルキニル基又は水素原子を表すか、
    　あるいは、
    　Ａ１とＡ２とが一緒になって炭素数２~７のポリメチレン基を表す。
    　ここで、アリール基は、炭素数１~１２のアルキル基、炭素数１~１２のアルコキシ基、ハロゲン原子、保護されたアミノ基及び保護された水酸基からなる群から選ばれる１以上の置換基を有していてもよい芳香族炭化水素基を意味する。）
    で示されるアミン化合物とを溶媒中で反応させる工程を含む式（ＩＶ−１）
    Figure JPOXMLDOC01-appb-I000003
    （式中、Ｒ１、Ａ１及びＡ２は上記で定義された通りである。）
    で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールの製造方法。     Formula (I)
    Figure JPOXMLDOC01-appb-I000001
    (In the formula, R 1 is an aryl group, an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups, and an alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups. Represents an alkynyl group having 2 to 12 carbon atoms which may be substituted with a group or one or more aryl groups.
    Here, the aryl group includes one or more substituents selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, a protected amino group, and a protected hydroxyl group. It means an aromatic hydrocarbon group which may have. )
    1-substituted-3,4-epoxypiperidine represented by the formula (II)
    Figure JPOXMLDOC01-appb-I000002
    Wherein A 1 is an aryl group, an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups, and an alkenyl group having 2 to 14 carbon atoms which may be substituted with one or more aryl groups Represents an alkynyl group having 2 to 12 carbon atoms which may be substituted with a group or one or more aryl groups, and A 2 represents an alkyl group having 1 to 12 carbon atoms which may be substituted with one or more aryl groups; Represents an alkenyl group having 2 to 14 carbon atoms which may be substituted with the above aryl group, an alkynyl group having 2 to 12 carbon atoms which may be substituted with one or more aryl groups, or a hydrogen atom,
    Or
    A 1 and A 2 together represent a polymethylene group having 2 to 7 carbon atoms.
    Here, the aryl group includes one or more substituents selected from the group consisting of an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, a protected amino group, and a protected hydroxyl group. It means an aromatic hydrocarbon group which may have. )
    Comprising a step of reacting an amine compound represented by formula (IV-1) in a solvent:
    Figure JPOXMLDOC01-appb-I000003
    (Wherein R 1 , A 1 and A 2 are as defined above.)
    The manufacturing method of 1-substituted-trans-3- (substituted amino) piperidin-4-ol shown by these.
  2. 溶媒が式（ＩＩＩ）
    Figure JPOXMLDOC01-appb-I000004
    （式中、Ｒ２は１の水酸基を有していてもよい炭素数１~１１のアルキル基、１以上の炭素数１~１２のアルコキシ基を有していてもよい炭素数２~１４のアルコキシアルキル基又は水素原子を表す。
    　Ｒ３及びＲ４は、それぞれ独立して、１の水酸基を有していてもよい炭素数１~１１のアルキル基又は水素原子を表す。）
    で示される化合物である請求項１に記載される製造方法。     The solvent is of formula (III)
    Figure JPOXMLDOC01-appb-I000004
    (Wherein R 2 has an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group, and an alkoxy group having 1 to 12 or more carbon atoms having 1 to 12 carbon atoms. Represents an alkoxyalkyl group or a hydrogen atom.
    R 3 and R 4 each independently represents an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group or a hydrogen atom. )
    The production method according to claim 1, wherein the compound is represented by the formula:
  3. Ｒ２が炭素数１~３のアルキル基又は炭素数２~４のアルコキシアルキル基であり、Ｒ３及びＲ４がともに水素原子である請求項２に記載される製造方法。 The production method according to claim 2, wherein R 2 is an alkyl group having 1 to 3 carbon atoms or an alkoxyalkyl group having 2 to 4 carbon atoms, and R 3 and R 4 are both hydrogen atoms.
  4. 溶媒がエタノール又はエチレングリコールモノメチルエーテルである請求項１に記載される製造方法。 The production method according to claim 1, wherein the solvent is ethanol or ethylene glycol monomethyl ether.
  5. 式（Ｉ）で示される１−置換−３，４−エポキシピペリジンが式（Ｉ−Ａ）
    Figure JPOXMLDOC01-appb-I000005
    （式中、Ｒ５は炭素数７~１７のアラルキル基、炭素数１~１１のアルキル基、フェニル基又は水素原子を表す。）
    で示される化合物であり、式（ＩＶ−１）で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールが式（ＩＶ−Ａ）
    Figure JPOXMLDOC01-appb-I000006
    （式中、Ｒ５、Ａ１及びＡ２は上記で定義された通りである。）
    で示される化合物である請求項１~４のいずれかに記載される製造方法。     A 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)
    Figure JPOXMLDOC01-appb-I000005
    (In the formula, R 5 represents an aralkyl group having 7 to 17 carbon atoms, an alkyl group having 1 to 11 carbon atoms, a phenyl group, or a hydrogen atom.)
    Wherein 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by the formula (IV-1) is represented by the formula (IV-A):
    Figure JPOXMLDOC01-appb-I000006
    (Wherein R 5 , A 1 and A 2 are as defined above.)
    The production method according to any one of claims 1 to 4, which is a compound represented by the formula:
  6. 式（Ｉ）で示される１−置換−３，４−エポキシピペリジンが式（Ｉ−Ａ）
    Figure JPOXMLDOC01-appb-I000007
    （式中、Ｒ５は炭素数７~１７のアラルキル基、炭素数１~１１のアルキル基、フェニル基又は水素原子を表す。）
    で示される化合物であり、式（ＩＩ）で示されるアミン化合物が式（ＩＩ−Ａ）
    Figure JPOXMLDOC01-appb-I000008
    （式中、Ａ３は水素原子又は炭素数１~１１のアルキル基を表し、Ａ４は水素原子、ベンジル基又はアリル基を表し、Ｚはフェニル基又はビニル基を表す。）
    で示される化合物であり、式（ＩＶ−１）で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールが式（ＩＶ−Ｂ）
    Figure JPOXMLDOC01-appb-I000009
    （式中、Ｒ５、Ａ３、Ａ４及びＺは上記で定義された通りである。）
    で示される化合物である請求項１~４のいずれかに記載される製造方法。     A 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)
    Figure JPOXMLDOC01-appb-I000007
    (In the formula, R 5 represents an aralkyl group having 7 to 17 carbon atoms, an alkyl group having 1 to 11 carbon atoms, a phenyl group, or a hydrogen atom.)
    The amine compound represented by formula (II) is represented by formula (II-A)
    Figure JPOXMLDOC01-appb-I000008
    (Wherein A 3 represents a hydrogen atom or an alkyl group having 1 to 11 carbon atoms, A 4 represents a hydrogen atom, a benzyl group or an allyl group, and Z represents a phenyl group or a vinyl group.)
    Wherein 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by the formula (IV-1) is represented by the formula (IV-B):
    Figure JPOXMLDOC01-appb-I000009
    (Wherein R 5 , A 3 , A 4 and Z are as defined above.)
    The production method according to any one of claims 1 to 4, which is a compound represented by the formula:
  7. 式（Ｉ）で示される１−置換−３，４−エポキシピペリジンが式（Ｉ−Ａ）
    Figure JPOXMLDOC01-appb-I000010
    （式中、Ｒ５は炭素数７~１７のアラルキル基、炭素数１~１１のアルキル基、フェニル基又は水素原子を表す。）
    で示される化合物であり、式（ＩＩ）で示されるアミン化合物が式（ＩＩ−Ｂ）
    Figure JPOXMLDOC01-appb-I000011
    （式中、Ａ５は水素原子又は炭素数１~１１のアルキル基を表し、Ａ６は水素原子又はベンジル基を表す。）
    で示される化合物であり、式（ＩＶ−１）で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールが式（ＩＶ−Ｃ）
    Figure JPOXMLDOC01-appb-I000012
    （式中、Ａ５、Ａ６及びＲ５は上記で定義された通りである。）
    で示される化合物である請求項１~４のいずれかに記載される製造方法。     A 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)
    Figure JPOXMLDOC01-appb-I000010
    (In the formula, R 5 represents an aralkyl group having 7 to 17 carbon atoms, an alkyl group having 1 to 11 carbon atoms, a phenyl group, or a hydrogen atom.)
    Wherein the amine compound represented by the formula (II) is represented by the formula (II-B)
    Figure JPOXMLDOC01-appb-I000011
    (In the formula, A 5 represents a hydrogen atom or an alkyl group having 1 to 11 carbon atoms, and A 6 represents a hydrogen atom or a benzyl group.)
    Wherein 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by the formula (IV-1) is represented by the formula (IV-C):
    Figure JPOXMLDOC01-appb-I000012
    (Wherein A 5 , A 6 and R 5 are as defined above.)
    The production method according to any one of claims 1 to 4, which is a compound represented by the formula:
  8. Ｒ５が水素原子であり、Ａ５及びＡ６がともに水素原子である請求項７に記載される製造方法。 The production method according to claim 7, wherein R 5 is a hydrogen atom, and both A 5 and A 6 are hydrogen atoms.
  9. 式（ＩＩ）で示されるアミン化合物が式（ＩＩ−Ｃ）
    Figure JPOXMLDOC01-appb-I000013
    （式中、Ａｒは置換基を有していてもよいフェニル基を表し、該置換基は、炭素数１~１２のアルキル基、炭素数１~１２のアルコキシ基、ハロゲン原子、保護されたアミノ基及び保護された水酸基からなる群から選ばれる１以上である。）
    で示される化合物であり、式（ＩＶ−１）で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オール化合物が式（ＩＶ−Ｄ）
    Figure JPOXMLDOC01-appb-I000014
    （式中、Ｒ１及びＡｒは上記で定義された通りである。）
    で示される化合物である請求項１~４のいずれかに記載される製造方法。     The amine compound represented by the formula (II) is represented by the formula (II-C)
    Figure JPOXMLDOC01-appb-I000013
    (In the formula, Ar represents a phenyl group which may have a substituent, and the substituent includes an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a halogen atom, and a protected amino group. 1 or more selected from the group consisting of a group and a protected hydroxyl group.)
    A 1-substituted-trans-3- (substituted amino) piperidin-4-ol compound represented by the formula (IV-1) is represented by the formula (IV-D):
    Figure JPOXMLDOC01-appb-I000014
    (Wherein R 1 and Ar are as defined above.)
    The production method according to any one of claims 1 to 4, which is a compound represented by the formula:
  10. Ｒ１がベンジル基である請求項９に記載される製造方法。 The production method according to claim 9, wherein R 1 is a benzyl group.
  11. 式（Ｉ−Ａ）
    Figure JPOXMLDOC01-appb-I000015
    （式中、Ｒ５は炭素数７~１７のアラルキル基、炭素数１~１１のアルキル基、フェニル基又は水素原子を表す。）
    で示される１−置換−３，４−エポキシピペリジンと式（ＩＩ−Ｂ）
    Figure JPOXMLDOC01-appb-I000016
    （式中、Ａ５は水素原子又は炭素数１~１１のアルキル基を表し、Ａ６は水素原子又はベンジル基を表す。）
    で示されるアミン化合物とを溶媒中で反応させて式（ＩＶ−Ｃ）
    Figure JPOXMLDOC01-appb-I000017
    （式中、Ａ５、Ａ６及びＲ５は上記で定義された通りである。）
    で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールを得る工程と、式（ＩＶ−Ｃ）で示される１−置換−トランス−３−（置換アミノ）ピペリジン−４−オールを還元する工程とを含む式（Ｖ）
    Figure JPOXMLDOC01-appb-I000018
    で示されるトランス−３−アミノピペリジン−４−オールの製造方法。     Formula (IA)
    Figure JPOXMLDOC01-appb-I000015
    (In the formula, R 5 represents an aralkyl group having 7 to 17 carbon atoms, an alkyl group having 1 to 11 carbon atoms, a phenyl group, or a hydrogen atom.)
    1-substituted-3,4-epoxypiperidine represented by the formula (II-B)
    Figure JPOXMLDOC01-appb-I000016
    (In the formula, A 5 represents a hydrogen atom or an alkyl group having 1 to 11 carbon atoms, and A 6 represents a hydrogen atom or a benzyl group.)
    And an amine compound represented by the formula (IV-C)
    Figure JPOXMLDOC01-appb-I000017
    (Wherein A 5 , A 6 and R 5 are as defined above.)
    A step of obtaining 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by formula (IV) and 1-substituted-trans-3- (substituted amino) piperidine-4-ol represented by formula (IV-C): And a step of reducing oar (V)
    Figure JPOXMLDOC01-appb-I000018
    A process for producing trans-3-aminopiperidin-4-ol represented by
  12. 溶媒が式（ＩＩＩ）
    Figure JPOXMLDOC01-appb-I000019
    （式中、Ｒ２は１の水酸基を有していてもよい炭素数１~１１のアルキル基、１以上の炭素数１~１２のアルコキシ基を有していてもよい炭素数２~１４のアルコキシアルキル基又は水素原子を表す。
    　Ｒ３及びＲ４は、それぞれ独立して、１の水酸基を有していてもよい炭素数１~１１のアルキル基又は水素原子を表す。）
    で示される化合物である請求項１１に記載される製造方法。     The solvent is of formula (III)
    Figure JPOXMLDOC01-appb-I000019
    (Wherein R 2 has an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group, and an alkoxy group having 1 to 12 or more carbon atoms having 1 to 12 carbon atoms. Represents an alkoxyalkyl group or a hydrogen atom.
    R 3 and R 4 each independently represents an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group or a hydrogen atom. )
    The production method according to claim 11, which is a compound represented by the formula:
  13. Ｒ２が炭素数１~３のアルキル基又は炭素数２~４のアルコキシアルキル基であり、Ｒ３及びＲ４がともに水素原子である請求項１２に記載される製造方法。 13. The production method according to claim 12, wherein R 2 is an alkyl group having 1 to 3 carbon atoms or an alkoxyalkyl group having 2 to 4 carbon atoms, and R 3 and R 4 are both hydrogen atoms.
  14. 溶媒がエタノール又はエチレングリコールモノメチルエーテルである請求項１１に記載される製造方法。 The production method according to claim 11, wherein the solvent is ethanol or ethylene glycol monomethyl ether.
PCT/JP2010/067698 2009-10-07 2010-10-01 1-substituted-trans-3-(substituted amino)piperidin-4-ol WO2011043445A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2009233155 2009-10-07
JP2009-233155 2009-10-07
JP2010-002680 2010-01-08
JP2010002680A JP2011098950A (en) 2009-10-07 2010-01-08 Process for producing 1-substituted-trans-3-(substituted amino)piperidin-4-ol and trans-3-aminopiperidin-4-ol

Publications (1)

Publication Number Publication Date
WO2011043445A1 true WO2011043445A1 (en) 2011-04-14

Family

ID=43856895

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/067698 WO2011043445A1 (en) 2009-10-07 2010-10-01 1-substituted-trans-3-(substituted amino)piperidin-4-ol

Country Status (2)

Country Link
JP (1) JP2011098950A (en)
WO (1) WO2011043445A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5287175A (en) * 1976-01-09 1977-07-20 Delmar Chem 44arylpiperidine derivative and its preparation
WO2010035902A1 (en) * 2008-09-29 2010-04-01 住友化学株式会社 Process for producing 1-substituted trans-4-(substituted amino)piperidin-3-ol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5287175A (en) * 1976-01-09 1977-07-20 Delmar Chem 44arylpiperidine derivative and its preparation
WO2010035902A1 (en) * 2008-09-29 2010-04-01 住友化学株式会社 Process for producing 1-substituted trans-4-(substituted amino)piperidin-3-ol

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DANG, Z. ET AL.: "Synthesis and antibacterial activity of novel fluoroquinolones containing substituted piperidines", BIOORG. & MED. CHEM. LETT., vol. 17, no. 16, 2007, pages 4523 - 4526, XP022181860, DOI: doi:10.1016/j.bmcl.2007.05.093 *
GANINA, O.G. ET AL.: "Synthesis of 4-aminopolymethoxycoumarins from 4-hydroxycoumarin triflates", RUSSIAN CHEMICAL BULETIN, vol. 55, no. 9, 2006, pages 1642 - 1647, XP008146255, DOI: doi:10.1007/s11172-006-0467-9 *
LAI, Y.-S. ET AL.: "Synthesis and Protein Kinase C Inhibitory Activities of Balanol Analogs with Replacement of the Perhydroazepine Moiety", J. MED. CHEM., vol. 40, no. 2, 1997, pages 226 - 235, XP002726221, DOI: doi:10.1021/jm960497g *
TOKUDA, 0. ET AL.: "Remarkable switch of regioselectivity in epoxide ring opening of 3-benzyl-7-oxa-3-azabicyclo[4.1.0]heptane with amines: practical synthesis of trans-4-amino-3-hydroxypiperidines and trans-3-amino-4-hydroxypiperidines", TETRAHEDRON LETT., vol. 51, April 2010 (2010-04-01), pages 2832 - 2834, XP027016177 *

Also Published As

Publication number Publication date
JP2011098950A (en) 2011-05-19

Similar Documents

Publication Publication Date Title
EP2938616A1 (en) The present invention relates to process for the preparation of tofacitinib and intermediates thereof.
CN1878751A (en) Urea derivative and process for producing the same
JP2013035842A5 (en)
JP2020528916A (en) Intermediates useful for the synthesis of selective inhibitors of protein kinases and the process for preparing them
WO2010010359A2 (en) A process for the preparation of cinacalcet and its salts
JP5548129B2 (en) Asymmetric organic catalyst
WO2011043445A1 (en) 1-substituted-trans-3-(substituted amino)piperidin-4-ol
WO2010035902A1 (en) Process for producing 1-substituted trans-4-(substituted amino)piperidin-3-ol
CN107778182B (en) Method for synthesizing N-alkyl arylamine
JP5073497B2 (en) Process for producing tetra-substituted-5-azaspiro [2.4] heptane derivative and optically active intermediate thereof
EP2674419A1 (en) Quaternary ammonium salt
CN1922131A (en) Synthesis of sterically hindered secondary aminoether alcohols
JP4084855B2 (en) Preparation of cyclic compounds
US20120010405A1 (en) Optically active 3-amino-2,5-dioxopyrrolidine-3-carboxylate, process for production of the compound, and use of the compound
JP2014526458A (en) Arylated β-dicarbonyl compound and process for producing the same
WO2004039785A1 (en) Process for the preparation of pyrrolidinyl ethylamine compounds via a copper-mediated aryl amination
CN111004264B (en) Preparation method of N-substituted tetrahydropyridine-3/4-boric acid/ester
AU2007285155B2 (en) A novel process for preparing 3-amino-5-fluoro-4-dialkoxypentanoic acid ester
EP3287448A1 (en) Method for producing dicarboxylic acid compound
US6150417A (en) Phenoxyethylamine derivatives, method of preparation application as medicine and pharmaceutical compositions containing same
JP4507390B2 (en) 1-alkyl-1-substituted-3-organosulfonyloxyazetidinium salts and process for producing the same
KR20220101702A (en) Manufacturing process of chroman compounds
JP2005104895A (en) Method for preparing optically active amino alcohol compound
WO2010029904A1 (en) Method for producing n-substituted-trans-4-azidopiperidine-3-ol
WO2010090341A1 (en) Method of manufacturing optically active trans-4-aminopiperidine-3-ol compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10822115

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10822115

Country of ref document: EP

Kind code of ref document: A1