JP2011098950A - Process for producing 1-substituted-trans-3-(substituted amino)piperidin-4-ol and trans-3-aminopiperidin-4-ol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a process for producing 1-substituted-trans-3-(substituted amino)piperidin-4-ol without using sodium azide which requires careful handling. <P>SOLUTION: The production process for 1-substituted-trans-3-(substituted amino)piperidin-4-ol represented by formula (IV-1) includes a step of allowing 1-substituted-3,4-epoxy piperidine to react with an amine compound represented by formula (II) (wherein A<SP>1</SP>and A<SP>2</SP>each represent a 1-12C alkyl group which may have one or more aromatic hydrocarbon ring groups) in the presence of a solvent. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  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, Non-Patent Document 1), and 1-substituted-trans-3- ( The trans-3-aminopiperidin-4-ol compound derived from (substituted amino) piperidin-4-ol is useful as various chemicals such as pharmaceutical intermediates (see, for example, Patent Document 1 Example 190).

  As a method for producing 1-substituted-trans-3- (substituted amino) piperidin-4-ol, Non-Patent Document 1 (Supporting Information) describes a 1-substituted 1-nitrobenzene group protected with a benzyloxycarbonyl group on the piperidine ring. A substituted 3,4-epoxy piperidine and sodium azide are reacted to introduce an azide group regioselectively into the 3-position of the piperidine ring, and the substituent is introduced after the azide group is reduced to an amino group. A method is described.

Special table 2008-534664 gazette

Journal of Medicinal Chemistry 1997, 40, 226-235.

  However, the method described in Non-Patent Document 1 is not always a satisfactory method in that sodium azide requiring attention in handling 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.

  As a result of intensive studies on a production method capable of solving the above problems, the present inventors have reached the present invention.

That is, the present invention provides the inventions described in the following [1] to [14].
[1] Formula (I)

(In the formula, R ¹ has an aromatic carbocyclic group, an alkyl group having 1 to 12 carbon atoms which may have one or more aromatic carbocyclic groups, and one or more aromatic carbocyclic groups. Or an alkynyl group having 2 to 12 carbon atoms which may have an alkenyl group having 2 to 14 carbon atoms or one or more aromatic carbocyclic groups.
Here, each aromatic carbocyclic group is 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 halogeno group, a protected amino group, and a protected hydroxyl group. You may have the above substituent. )
1-substituted-3,4-epoxypiperidine represented by the formula (II)

(In the formula, A ¹ has an aromatic carbocyclic group, an alkyl group having 1 to 12 carbon atoms which may have one or more aromatic carbocyclic groups, and one or more aromatic carbocyclic groups. An alkynyl group having 2 to 14 carbon atoms or an alkynyl group having 2 to 12 carbon atoms which may have one or more aromatic carbocyclic groups,
A ² is an alkyl group having 1 to 12 carbon atoms which may have one or more aromatic carbocyclic groups, and an alkenyl group having 2 to 14 carbon atoms which may have one or more aromatic carbocyclic groups. Represents a C2-C12 alkynyl group or a hydrogen atom which may have one or more aromatic carbocyclic groups,
Or
A ¹ and A ² together represent a polymethylene group having 2 to 7 carbon atoms.
Here, each aromatic carbocyclic group is 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 halogeno group, a protected amino group, and a protected hydroxyl group. You may have the above substituent. )
Comprising the step of reacting with an amine compound represented by formula (IV-1) in the presence of a solvent:

(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] The production method according to [1], wherein the solvent is an alcohol solvent.
[3] The solvent is represented by the formula (III)

(In the formula, R ² may have 1 hydroxyl group and may have 1 to 11 carbon atoms, and 1 or more C 1 to 12 alkoxy groups may have 2 to 14 carbon atoms. Represents an alkoxyalkyl group or a hydrogen atom.
R ³ and R ⁴ each independently represent an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group or a hydrogen atom. )
[1] The production method described in [1].
[4] R ² in Formula (III) 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 in Formula (III) are both hydrogen atoms [3 ] The manufacturing method described in.
[5] A 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)

(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):

(Wherein R ⁵ , A ¹ and A ² are as defined above.)
The manufacturing method described in any one of [1]-[4] which is a compound shown by these.
[6] The 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)

(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-A):

(In the formula, 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):

(Wherein R ⁵ , A ³ , A ⁴ and Z are as defined above.)
The manufacturing method described in any one of [1]-[4] which is a compound shown by these.
[7] A 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)

(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)

(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):

(Wherein A ⁵ , A ⁶ and R ⁵ are as defined above.)
The manufacturing method described in any one of [1]-[4] which is a compound shown by these.
[8] R ⁵ in formula (IA) and formula (IV-C) is a hydrogen atom, and A ⁵ and A ⁶ in formula (II-B) and formula (IV-C) are both hydrogen atoms. [7] The production method described in [7].
[9] The amine compound represented by the formula (II) is represented by the 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 halogeno group, 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):

(Wherein R ¹ and Ar are as defined above.)
The manufacturing method described in any one of [1]-[4] which is a compound shown by these.
[10] The production method according to [9], wherein R ¹ in (IV-D) is a benzyl group.
[11] Formula (IA)

(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)

(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.)
Is reacted with an amine compound represented by formula (IV-C) in the presence of a solvent.

(Wherein A ⁵ , A ⁶ and R ⁵ are each 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)

A process for producing trans-3-aminopiperidin-4-ol represented by the formula:
[12] The production method according to [11], wherein the solvent is an alcohol solvent.
[13] The solvent is represented by the formula (III)

(In the formula, R ² may have 1 hydroxyl group and may have 1 to 11 carbon atoms, and 1 or more C 1 to 12 alkoxy groups may have 2 to 14 carbon atoms. Represents an alkoxyalkyl group or a hydrogen atom.
R ³ and R ⁴ each independently represent an alkyl group having 1 to 11 carbon atoms which may have one hydroxyl group or a hydrogen atom. )
[11] The production method described in [11].
[14] R ² in formula (III) 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 in formula (III) are both hydrogen atoms [13 ] The manufacturing method described in.

  According to the present invention, a desired 1-substituted-trans-3- (substituted amino) piperidin-4-ol can be obtained from 1-substituted-3,4-epoxypiperidine without using sodium azide which requires careful handling. Can be manufactured.

  Hereinafter, the present invention will be described in detail.

In the formula (I), examples of the aromatic carbocyclic group represented by R ¹ include an aromatic hydrocarbon group having 6 to 10 carbon atoms such as a phenyl group and a naphthyl group, and the aromatic carbocyclic group is , May have 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 halogeno group, 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 group, undecyl group, dodecyl group are mentioned. Examples of the alkoxy group having 1 to 12 carbon atoms include methoxy group, ethoxy group, propoxy group, butoxy group, and examples of halogeno group are fluoro group, chloro group, A bromo group, an iodo group,

As the protected amino group, for example, an alkanoylamino group having 1 to 8 carbon atoms (typically, an acetylamino group), an alkyl group in which 1 or 2 of a hydrogen atom bonded to an aromatic ring is 1 to 8 carbon atoms, A phenylcarbonylamino group optionally substituted by an alkoxy group having 1 to 8 carbon atoms, a halogeno group, a nitro group, a cyano group or a trifluoromethyl group (typically, a benzoylamino group, a p-toluoylamino group, 4-chlorobenzoylamino group, 4-nitrobenzoylamino group, 4-cyanobenzoylamino group, 4-trifluoromethylbenzoylamino group, 3,5-bis (trifluoromethyl) benzoylamino group), carbon number 1-8 Alkoxycarbonylamino group (representative examples include methoxycarbonylamino group, ethoxycarbonylamino group t-butoxycarbonylamino 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, halogeno group, nitro group, cyano group or trifluoromethyl A phenyloxycarbonylamino group optionally substituted by a group (typically a phenyloxycarbonylamino group, 4-nitrophenyloxycarbonylamino group), 1 or 2 of a hydrogen atom bonded to an aromatic ring is 1 to 2 carbon atoms A benzyloxycarbonylamino group (typically a benzyloxycarbonylamino group which may be substituted with an alkyl group having 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogeno group, a nitro group, a cyano group or 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 a hydrogen atom bonded to an aromatic ring is an alkyl group having 1 to 8 carbon atoms, and 1 carbon atom. ˜8 alkoxy groups, halogeno groups, nitro groups, cyano groups or trifluoromethyl groups optionally substituted with benzoyloxy groups (typically benzoyloxy groups, 4-nitrobenzoyloxy groups), aromatic rings and A benzyloxy group in which 1 or 2 of the hydrogen atoms to be bonded may be substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogeno group, a nitro group, a cyano group or a trifluoromethyl group (Typical examples include benzyloxy group, 4-methoxybenzyloxy group, 4-nitrobenzyloxy group) and alkoxy groups having 1 to 8 carbon atoms. An alkoxymethoxy group (typically a methoxymethoxy group), a 1- (alkoxy) ethoxy group having 1 to 8 carbon atoms (typically a 1- (ethoxy) ethoxy group), 2-tetrahydropyrani And a trialkylsilyloxy group having 1 to 8 carbon atoms in each alkyl group (typically, t-butyldimethylsilyloxy group).

In the alkyl group having 1 to 12 carbon atoms which may have an aromatic carbocyclic group represented by R ¹ , examples of the alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, a propyl group, and isopropyl. Group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, and these alkyl groups having 1 to 12 carbon atoms are It may have one or more aromatic carbocyclic groups. Examples of the aromatic carbocyclic group include the groups exemplified as the aromatic carbocyclic group represented by R ¹ , and the aromatic carbocyclic group may have a substituent similarly to R ^1. . Examples of the alkyl group having 1 to 12 carbon atoms having an aromatic carbocyclic group include 1-phenylethyl group, 2-phenylethyl group, 1-naphthylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3 -A phenylpropyl group and a diphenylmethyl group are mentioned.

In the alkenyl group having 2 to 14 carbon atoms which may have an aromatic carbocyclic group represented by R ¹ , examples of the alkenyl group having 2 to 14 carbon atoms include a vinyl group, a 1-propenyl group and an 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 aromatic carbocyclic groups. The aromatic carbocyclic group, for example the groups exemplified are exemplified as the aromatic carbocyclic group represented by R ^1, aromatic carbocyclic group, like an aromatic carbocyclic group represented by R ¹ It may have a substituent. As a C2-C14 alkenyl group which has an aromatic carbocyclic group, a cinnamyl group and a styryl group are mentioned, for example.

In the aromatic an alkynyl group having 2 to 12 carbon atoms which may have a carbocyclic group represented by R ^1, the alkynyl group having 2 to 12 carbon atoms, such as ethynyl group, propynyl group, butynyl group, pentynyl Group, hexynyl group, heptynyl group, and octynyl group. These alkynyl groups having 2 to 12 carbon atoms may have one or more aromatic carbocyclic groups. The aromatic carbocyclic radicals, for example the groups exemplified are exemplified as the aromatic carbocyclic group represented by R ^1, aromatic carbocyclic group is substituted as defined aromatic carbocyclic group represented by R ¹ It may have a group. As a C2-C12 alkynyl group which has an aromatic carbocyclic group, 3-phenyl-2- propynyl group is mentioned, for example.

R ¹ is preferably an alkyl group having 1 to 12 carbon atoms having an aromatic carbocyclic group, and having 1 to 12 carbon atoms having an aromatic group at the 1-position of an alkyl group such as a benzyl group or 1-phenylethyl group. An alkyl 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]. Those capable of easily removing the substituent R ¹ such as heptane 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), an aromatic carbocyclic group and A ¹ and 1 or more aromatic alkyl group having 1 to 12 carbon atoms which may have a carbocyclic group represented by A ² represented by A ^1, As an alkynyl group having 2 to 14 carbon atoms which may have one or more aromatic carbocyclic groups, and an alkynyl group having 2 to 12 carbon atoms which may have one or more aromatic carbocyclic groups, Examples thereof include the same groups as those exemplified for R ¹ .

Examples of the C2-C7 polymethylene group represented by A ¹ and A ^{2 taken} together include 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 the 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-propynyl Ami 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 , Heptamethylene imi 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 the presence of a solvent. Examples of the solvent include compounds represented by formula (III) (hereinafter abbreviated as compound (III)), benzyl alcohol, cyclohexanol and other alcohol solvents; pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, Aliphatic hydrocarbon solvents such as nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether; benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, Xylene, mesitylene, monochlorobenzene, monofluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,3-trichloroben , Aromatic solvents such as 1,2,4-trichlorobenzene; tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert- Ether solvents such as butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, anisole, diphenyl ether; ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate, Ester solvents such as isoamyl acetate; nitrile solvents such as acetonitrile and propionitrile; dimethyl sulfoxide, sulfolane, N, -Dimethylformamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N-methylpyrrolidone, γ-butyrolactone, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, 1,3-dimethyl-2-imidazolide Non-protic polar solvents such as non- 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyridinone. 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 the formula (III), 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 represented by R ² includes, for example, a methyl group, an ethyl group, n- Propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, and those having 1 to 11 carbon atoms The alkyl group may have one hydroxyl group. As a C1-C11 alkyl group which has a hydroxyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group is mentioned, for example.

In the alkoxyalkyl group having 2 to 13 carbon atoms which may have an alkoxy group having 1 to 12 carbon atoms represented by R ² , the alkoxyalkyl group having 2 to 13 carbon atoms is, for example, a 2-methoxyethyl group 2-ethoxyethyl group, 2- (n-propyloxy) ethyl group, 2-isopropyloxyethyl group, 2- (n-butyloxy) ethyl group, 2-isobutyloxyethyl group, 2- (tert-butyloxy) ethyl Group, and these C2-C13 alkoxyalkyl groups may have one or more C1-C12 alkoxy 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.

R ² is preferably an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, an n-propyl group or an isopropyl group, or a methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group or the like. And an alkoxyalkyl group having 2 to 4 carbon atoms, more preferably a methyl group or a methoxymethyl group.

In the formula (III), 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 represented by R ³ and R ⁴ may be, for example, a methyl group or an ethyl group. , N-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group and undecyl group. The alkyl group of ˜11 may have one hydroxyl group. As a C1-C11 alkyl group which has a hydroxyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group is mentioned, for example. R ³ and R ⁴ are preferably both hydrogen atoms.

  Examples of the compound (III) include methanol, ethanol, 1-propanol, 2-propanol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, and 1-hexanol. 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isoheptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol mono n-propyl ether, ethylene glycol monoisopropyl ether, Ethylene glycol mono n-butyl ether, ethylene glycol monoisobutyl ether, ethylene glycol mono tert-butyl ether, diethylene glycol Glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n- propyl ether, diethylene glycol monoisopropyl ether, diethylene glycol mono n- butyl ether, diethylene glycol mono isobutyl ether, diethylene glycol monobutyl tert- butyl ether. Compound (III) is preferably an alcohol having 1 to 4 carbon atoms such as methanol, ethanol, 1-propanol, 2-propanol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, ethylene glycol monomethyl ether, ethylene glycol C3-C5 alkoxy alcohols such as monoethyl ether, more preferably ethanol or ethylene glycol monomethyl ether.

  In the reaction of compound (I) with compound (II) in the presence of a solvent, the amount of compound (II) used is preferably 1 mol or more with respect to 1 mol of compound (I). Is not limited. The amount of compound (II) to be used is more preferably 1 to 5 mol, still more preferably 1 to 2 mol in terms of economy with respect to 1 mol of compound (I). 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 (I).

  A solvent can also be used independently and a mixture can also be used. Mixtures with water 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 amounts of reaction reagents and solvents 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, and can be carried out, for example, by adding the compound (II) and the solvent to the compound (I) in any order.

  In the mixture after completion of the reaction, 1-substituted-trans-3- (substituted amino) piperidin-4-ol represented by the target formula (IV-1) (hereinafter abbreviated as compound (IV-1)). .) As the main product. Formula (IV-2)

(Wherein R ¹ , A ¹ and A ² are as defined above.)
1-substituted-trans-4-substituted aminopiperidin-3-ol (hereinafter abbreviated as compound (IV-2)) may be contained as a by-product, 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 within the range of 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 solvents described above 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. 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, Lance-3- (allylamino) -1-benzylpiperidin-4-ol, trans-3- (diallylamino) -1-benzylpiperidin-4-ol, trans-3- (benzylamino) -1-propylpiperidine-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. Further, the compound (IV-1) being in a trans form means that a group represented by -NA ¹ A ² and a hydroxyl group are on the opposite sides with respect to the piperidine ring. The compound in which the group represented by —NA ¹ A ² and the hydroxyl group are on the same side with respect to the piperidine ring is a cis isomer, but in the present invention, it is preferable that the cis isomer is not generated.

  In the reaction of compound (I) with compound (II), if compound (I) is represented by formula (IA) (hereinafter abbreviated as compound (IA)), compound (IV) -1) is obtained as a compound represented by the formula (IV-A) (hereinafter abbreviated as compound (IV-A)).

In the formula (IA), examples of the alkyl group having 1 to 11 carbon atoms represented by R ⁵ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and pentyl. Group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, and undecyl group. The aralkyl group having 7 to 17 carbon atoms represented by R ⁵ is a group having an aryl group such as one or more phenyl group or naphthyl group on the alkyl group having 1 to 11 carbon atoms, such as a benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-naphthylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-phenyl-1-methylethyl group, 1-phenylbutyl Group, 2-phenylbutyl group, 3-phenylbutyl group, 4-phenylbutyl group, 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-ol Trans-1- (1-phenylethyl) -3-[(1-phenylethyl) amino] piperidin-4-ol, trans-1- (1-phenylethyl) -3-[(1-phenyl-2-methyl) Propyl) 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) piperidin-4-ol, Lance-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 compound (II-A) is represented by formula (II-A) as compound (II). (Abbreviated as A)), a compound represented by formula (IV-B) (hereinafter abbreviated as compound (IV-B)) is obtained as compound (IV-1).

In the formula (II-A), examples of the alkyl group having 1 to 11 carbon atoms represented by A ³ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and 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-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- (allylamino) -1- (1 -Phenylpropyl) piperidin-4-ol, trans-3-[(1-phenylethyl) amino] -1- (1-phenylpropyl) piperidin-4-o , 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 compound (II-B) is used as compound (II) (hereinafter referred to as compound (II-B)). (Abbreviated as B)), a compound represented by the formula (IV-C) (hereinafter abbreviated as compound (IV-C)) can be obtained.

In formula (II-B), the alkyl group having 1 to 11 carbon atoms represented by ^{A 5,} for example a methyl group, an ethyl group, a propyl group, an isopropyl group, n- 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 All, trans-3-[(1-phenylbutyl) amino] -1- (1-phenylpropyl) piperidin-4-ol, trans-3- ( And 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 between the compound (I) and the compound (II), the compound represented by the formula (II-C) (hereinafter abbreviated as the compound (II-C)) is used as the compound (II). -D) (hereinafter abbreviated as compound (IV-D)) is obtained.

  In the formula (II-C), Ar represents a phenyl group which may have a substituent. 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 isopropyl. Group, n-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group; alkoxy group having 1 to 12 carbon atoms Examples include methoxy, ethoxy, propoxy, and butoxy groups; halogeno groups include fluoro, chloro, bromo, and iodo groups; and protected amino groups include, for example, acetylamino Groups, benzoylamino groups, methoxycarbonylamino groups, ethoxycarbonylamino groups; examples of protected hydroxyl groups include If an 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, Su-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) Mino] -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 step of reducing compound (IV-C) to obtain trans-3-aminopiperidin-4-ol represented by formula (V) (hereinafter abbreviated as compound (V)) (hereinafter referred to as the present). Will be described as a reduction step). In compound (IV-C), R ⁵ is preferably a hydrogen atom, and both A ⁵ and A ⁶ 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 is exemplified. 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. Such palladium carbon may be a commercially available product, or may be prepared and used by any known method. The amount of palladium carbon used is a range in which the palladium atom is preferably 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts by weight with respect to 1 part by weight of the compound (IV-C). Is the amount within. 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 the presence of a solvent inert to the reaction. Examples of such a solvent include n-pentane, n-hexane, isohexane, n-heptane, Aliphatic hydrocarbon solvents such as isoheptane, n-octane, isooctane, n-nonane, isononane, n-decane, isodecane, n-undecane, n-dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether Tetrahydrofuran, methyltetrahydrofuran, diethyl ether, di n-propyl ether, diisopropyl ether, di n-butyl ether, di n-pentyl ether, di n-hexyl ether, di n-heptyl ether, di n-octyl ether, tert-butyl methyl ether Ether solvents such as ter, cyclopentyl methyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, 1-propanol, 2-propanol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene Glycol mono n-propyl ether, ethylene glycol monoisopropyl ether, ethylene glycol mono n-butyl ether, ethylene glycol Ether monoisobutyl ether, ethylene glycol mono tert-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono n-propyl ether, diethylene glycol monoisopropyl ether, diethylene glycol mono n-butyl ether, diethylene glycol monoisobutyl ether, diethylene glycol mono tert-butyl ether, etc. Alcohol solvents: ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate, and the like; dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N- Dimethylacetamide, N, N-dimethylpropionami N-methylpyrrolidone, γ-butyrolactone, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro- Aprotic polar solvents such as 2 (1H) -pyridinone; water; mixtures thereof. 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 is preferably 1 to 24 hours, although it depends on the reaction temperature, the amount of reaction reagent used, the hydrogen pressure, 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 (IV-C) or a solution thereof and palladium carbon are mixed and hydrogen is added to the resulting mixture, or compound (( It can be carried out by the method of adding IV-C). A method of mixing a solution of compound (IV-C) and palladium carbon and adding hydrogen to the resulting mixture is preferred.

  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 method such as silica gel column chromatography. Can do. As the compound (IV-C), when an optically active substance whose optical activity is attributable to 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 WO2003 / 55858. 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 the compound (IV-B) is removed to remove the 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)

(In the formula, 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 In the compound (IV-B) used for the step leading to the compound (VI), A ⁴ in the formula (IV-B) is a hydrogen atom or an allyl group, and Z is a vinyl group. R ⁵ is preferably a hydrogen atom, and both A ³ and A ⁴ 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 amino group at the 3-position 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. A preferable method includes a method of reacting compound (IV-B) with 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. Such palladium carbon may be a commercially available product, or may be prepared and used by any known method. The amount of palladium carbon used is preferably in the range of 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts by weight of palladium atoms per 1 part by weight of compound (IV-B). Is the amount within. 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 in 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- 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, and diethylene glycol 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 carried out 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 per 1 mol of compound (IV-B). The reaction temperature is preferably 20 to 130 ° C, more preferably 60 to 90 ° C. The reaction time is preferably 1 to 24 hours, although it depends on the reaction temperature, the amount of reaction reagent 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 mixing order of the reaction reagents is not particularly specified, and the method of adding compound (IV-B) and aminoethanol in an alcohol solvent and adding palladium carbon to the resulting mixture, or 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 the compound (VI) may be subjected to a step leading to compound (VII). You may use for the process led to compound (VII), after giving 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), Furthermore, recrystallization; 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 the compound (VI), the amino group is protected with an alkoxycarbonyl group by being led to the compound (VII). The 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)

(Wherein R ⁶ is as defined above, and X represents a halogeno group such as a chloro group or a bromo group.)
Dialkyl carbonate is represented by the formula (IX-2)

(Wherein R ⁶ is as defined above.)
Indicated by

In the formula (VII), examples of the alkyl group having 1 to 12 carbon atoms represented by R ⁶ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, Examples include 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 lead 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) -pyridinone; 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 add the base in the mixture of the compound (VI) and the solvent inert to the reaction, and then add the 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). In addition, compound (VII) 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 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-Ilker swallow 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-methyl) Propyl) -trans-4-hydroxypiperidin-3-ylcarbamate, tert-butyl 1-benzyl-trans-4-hydroxypiperidin-3-ylcarbamate, tert-butyl 1- (1-phenylethyl) -trans-4- Hydro Cypiperidin-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 a 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 by 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. 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 in the range of 0.0001 to 0.05 parts by weight, more preferably 0.001 to 0.02 parts by weight of palladium atoms per 1 part by weight of compound (VII). Amount. 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 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) -pyridinone; water; Of the mixture. 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 is preferably 1 to 24 hours, although it depends on the reaction temperature, the amount of reaction reagent used, the hydrogen pressure, 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 (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 the 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. If the treatment is carried out, the compound (VIII) can be taken out. At this time, compound (VIII) may be taken out as a salt with any acid such as hydrochloric acid, benzoic acid, tartaric acid and the like. 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 method 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.

  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 dropping, 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, and the concentrated residue obtained by distilling off the solvent under reduced pressure 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, that is, the positional isomer ratio with the compound (IV-2) was determined. The positional isomer ratio was determined to be 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 regioselectively. 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.

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, the 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. 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, the 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.

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-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 can be used as a method for producing such a compound.

Claims (14)

Formula (I)
(In the formula, R ¹ has an aromatic carbocyclic group, an alkyl group having 1 to 12 carbon atoms which may have one or more aromatic carbocyclic groups, and one or more aromatic carbocyclic groups. Or an alkynyl group having 2 to 12 carbon atoms which may have an alkenyl group having 2 to 14 carbon atoms or one or more aromatic carbocyclic groups.
Here, each aromatic carbocyclic group is 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 halogeno group, a protected amino group, and a protected hydroxyl group. You may have the above substituent. )
1-substituted-3,4-epoxypiperidine represented by the formula (II)
(In the formula, A ¹ has an aromatic carbocyclic group, an alkyl group having 1 to 12 carbon atoms which may have one or more aromatic carbocyclic groups, and one or more aromatic carbocyclic groups. An alkynyl group having 2 to 14 carbon atoms or an alkynyl group having 2 to 12 carbon atoms which may have one or more aromatic carbocyclic groups,
A ² is an alkyl group having 1 to 12 carbon atoms which may have one or more aromatic carbocyclic groups, and an alkenyl group having 2 to 14 carbon atoms which may have one or more aromatic carbocyclic groups. Represents a C2-C12 alkynyl group or a hydrogen atom which may have one or more aromatic carbocyclic groups,
Or
A ¹ and A ² together represent a polymethylene group having 2 to 7 carbon atoms.
Here, each aromatic carbocyclic group is 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 halogeno group, a protected amino group, and a protected hydroxyl group. You may have the above substituent. )
Comprising the step of reacting with an amine compound represented by formula (IV-1) in the presence of a solvent:
(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. The production method according to claim 1, wherein the solvent is an alcohol solvent. The solvent is of formula (III)
(In the formula, R ² may have 1 hydroxyl group and may have 1 to 11 carbon atoms, and 1 or more C 1 to 12 alkoxy groups may have 2 to 14 carbon atoms. Represents an alkoxyalkyl group or a hydrogen atom.
R ³ and R ⁴ each independently represent 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, which is a compound represented by the formula: The R ² in the formula (III) is an alkyl group having 1 to 3 carbon atoms or an alkoxyalkyl group having 2 to 4 carbon atoms, and both R ³ and R ⁴ in the formula (III) are hydrogen atoms. Manufacturing method. A 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)
(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):
(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: A 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)
(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-A):
(In the formula, 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):
(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: A 1-substituted-3,4-epoxypiperidine represented by the formula (I) is represented by the formula (IA)
(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)
(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):
(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: R ⁵ in formula (IA) and formula (IV-C) is a hydrogen atom, and A ⁵ and A ⁶ in formula (II-B) and formula (IV-C) are both hydrogen atoms. The production method described in 1. The amine compound represented by the formula (II) is represented by the 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 halogeno group, 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):
(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: The production method according to claim 9, wherein R ¹ in (IV-D) is a benzyl group. Formula (IA)
(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)
(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.)
Is reacted with an amine compound represented by formula (IV-C) in the presence of a solvent.
(Wherein A ⁵ , A ⁶ and R ⁵ are each 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)
A process for producing trans-3-aminopiperidin-4-ol represented by the formula: The production method according to claim 11, wherein the solvent is an alcohol solvent. The solvent is of formula (III)
(In the formula, R ² may have 1 hydroxyl group and may have 1 to 11 carbon atoms, and 1 or more C 1 to 12 alkoxy groups may have 2 to 14 carbon atoms. Represents an alkoxyalkyl group or a hydrogen atom.
R ³ and R ⁴ each independently represent 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: The R ² in the formula (III) is an alkyl group having 1 to 3 carbon atoms or an alkoxyalkyl group having 2 to 4 carbon atoms, and both R ³ and R ⁴ in the formula (III) are hydrogen atoms. Manufacturing method.