WO2012081585A1 - Production method for optically active alcohol compound - Google Patents

Abstract

The present invention provides a method for diastereo-selectively and enantioselectively producing an optically active alcohol compound indicated in formula (IIIa), etc., that includes hydrogenation of a carbonyl compound indicated in formula (I) in the presence of a ruthenium compound indicated in formula (II) and a base. (In formula (I) R indicates a C6-C10 aryl group with an unsubstituted or substituted group. Het indicates a 3- to 8-member heterocycle with an unsubstituted or substituted group.) (In formula (II), X and Y each independently indicate a hydrogen group, a tetrahydro borate, etc. Px indicates an optically active or racemate phosphine ligand. n indicates the number of Px and is 1 or 2. A indicates an optically active or racemate dyamine ligand. However, Px and A cannot both be a racemate.) (In formula (IIIa) R and Het have the same meaning as R and Het in formula (I).)

Description

Method for producing optically active alcohol compound

The present invention relates to a method for producing an optically active alcohol compound. In more detail, this invention relates to the manufacturing method of the optically active alcohol compound including hydrogenating the carbonyl compound represented by a formula (I) diastereoselectively and enantioselectively.

Optically active alcohol derivatives having a heterocycle are known as pharmaceuticals and intermediates thereof.
For example, esreboxetine (registered trademark) which is an antidepressant represented by formula (1), a compound effective for attention deficit hyperactivity disorder represented by formula (2), etc. (Patent Document 1), formula (3) A compound useful for pain disorder represented by (Patent Document 2), a compound having an aspartic protease inhibitory activity represented by Formula (4) (Patent Document 3), and the like are known.

(In formula (2), X represents a sulfur atom or an oxygen atom, R ¹ represents a C1-4 alkyl group, etc., and * represents an optically active carbon.)

(In Formula (3), R ² represents a halogen atom, R ³ represents a C1-6 alkyl group, etc., and * represents an optically active carbon.)

(In formula (4), R ⁴ represents an aminocarbonyloxy group, R ⁵ represents a C1-6 alkyl group, R ⁶ represents an aminocarbonyl group, etc., and * represents an optically active carbon. To express.)

As a synthesis method of such an optically active alcohol compound having a heterocycle, a synthesis method by asymmetric dihydroxylation (Patent Document 4, Non-Patent Document 1) or a method using an optically active raw material (Patent Documents 1, 5, 6, Patent Documents 2, 3, and 4) are known. However, these synthesis methods have a problem that a process is long and a raw material is limited to an optically active compound.

US Patent Application Publication No. 2006/0258654 International Publication No. 2010/011811 International Publication No. 2007/070201 International Publication No. 2007/005935 International Publication No. 2008/036247 US Patent Application Publication No. 2010/0010228

An object of the present invention is to provide a method for producing an optically active alcohol compound, comprising diastereoselectively and enantioselectively hydrogenating a carbonyl compound represented by the following formula (I).

As a result of intensive studies to solve the above problems, the present inventors reduced a carbonyl compound represented by the following formula (I) by an asymmetric hydrogenation reaction involving kinetic resolution using an optically active ruthenium catalyst. It was found that an optically active alcohol compound can be produced diastereoselectively and enantioselectively. The present invention has been completed as a result of further studies based on this finding.

That is, the present invention includes the following.
[1] comprising hydrogenating a carbonyl compound represented by formula (I) in the presence of a ruthenium compound represented by formula (II) and a base, formula (IIIa), formula (IIIb), A method for producing any of the optically active alcohol compounds represented by formula (IIIc) or formula (IIId).

(In the formula (I),
R represents an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted 5- to 8-membered heteroaryl group, or an unsubstituted or substituted vinyl group.
Het represents an unsubstituted or substituted 3- to 8-membered heterocycle.
* Indicates that the carbon atom is an asymmetric carbon. )

(In the formula (II), X and Y each independently represent a hydrogen atom, a hydroxyl group, a tetrahydroboric acid, a halogen atom, a C1-20 alkoxy group, or a C1-20 acyloxy group.
Px represents an optically active or racemic phosphine ligand.
n represents the number of Px and is 1 or 2.
A represents an optically active or racemic diamine ligand.
However, both Px and A are not racemic. )

(In formula (IIIa), formula (IIIb), formula (IIIc) and formula (IIId), R and Het have the same meaning as in formula (I).)

[2] The production method according to [1], wherein Het in the formula (I) is a 5- to 7-membered heterocycle.
[3] In Formula (II), A is a ligand represented by Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe), [1] or [2] The production method according to [2].

R ¹ CH (NH ₂ ) CH ₂ (NR ² R ³ ) (IIa)
R ¹ CH (NR ² R ³ ) CH ₂ (NH ₂ ) (IIb)
(H ₂ N) HR ⁴ CB—CHR ⁴ (NH ₂ ) (IIc)
R ¹ CH (NH ₂ ) CR ⁵ R ⁵ (NH ₂ ) (IId)
R ¹ CH (NH ₂ ) R ¹ CH (NH ₂ ) (IIe)

(In formula (IIa), formula (IIb), formula (IIc), formula (IId) and formula (IIe),
R ¹ is an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted Or a substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted 3- to 8-membered heterocyclic group.
R ² , R ³ and R ⁵ are each independently a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted A C3-8 cycloalkyl group having a group, or an unsubstituted or substituted C7-20 aralkyl group. R ² and R ³ may combine to form a ring. However, both R ² and R ³ are not hydrogen atoms.
R ⁴ represents a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, An unsubstituted or substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted 3- to 8-membered heterocyclic group.
B represents an unsubstituted or substituted ethylene group, or an unsubstituted or substituted heterocyclic divalent group. When B is an ethylene group having a plurality of substituents, the plurality of substituents may be bonded to form a ring. )

[4] The production method according to any one of [1] to [3], wherein Px in formula (II) is an optically active phosphine ligand.
[5] The production method according to any one of [1] to [4], wherein in formula (II), Px is a bidentate phosphine ligand having axial asymmetry.
[6] The production method according to any one of [1] to [5], wherein in formula (II), A is an optically active diamine ligand.

According to the method for producing an optically active alcohol compound of the present invention, diastereoselective and enantioselective is possible regardless of whether the carbon atom marked with * in the carbonyl compound represented by the formula (I) is optically active or racemic. Therefore, any one of the optically active alcohol compounds represented by formula (IIIa), formula (IIIb), formula (IIIc) or formula (IIId) can be obtained with high selectivity. The optically active alcohol compound represented by the formula (IIIa), the formula (IIIb), the formula (IIIc) or the formula (IIId) is a compound useful as a pharmaceutical and an intermediate thereof.

The method for producing an optically active alcohol compound of the present invention includes hydrogenating a carbonyl compound represented by the above formula (I) in the presence of a ruthenium compound represented by the above formula (II) and a base. It is a waste.

[Carbonyl Compound of Formula (I)]
In the formula (I), R represents an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted 5- to 8-membered heteroaryl group, or an unsubstituted or substituted vinyl group. Indicates.
Examples of the unsubstituted C6-10 aryl group in R include a phenyl group and a naphthyl group.

The “substituent” in the C6-10 aryl group having a substituent is not particularly limited, and examples thereof include a hydroxyl group; a thiol group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a cyano group; Group: formyl group; unsubstituted or substituted amino group such as amino group, methylamino group, benzylamino group, anilino group, dimethylamino group; methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group Group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group and other alkyl groups, preferably C1-6 alkyl groups; vinyl group, allyl group, 2-methoxyethenyl group and other alkenyl groups Alkynyl groups such as ethynyl group, 1-propynyl group, 2-phenylethynyl group, propargyl group; methoxy group, ethoxy group, propoxy group Alkoxy groups such as isopropoxy group, n-butoxy group, s-butoxy group and t-butoxy group, preferably C1-6 alkoxy group; alkenyloxy groups such as vinyloxy group and allyloxy group; ethynyloxy group, propargyloxy group and the like An alkynyloxy group such as phenoxy group and benzyloxy group; a heteroaryloxy group such as 2-pyridyloxy; a haloalkyl group such as chloromethyl group and trifluoromethyl group, preferably a C1-6 haloalkyl group; A haloalkoxy group such as a methoxy group and a dibromomethoxy group, preferably a C1-6 haloalkoxy group; an alkylthiocarbonyl group such as a methylthiocarbonyl group and an ethylthiocarbonyl group, preferably a C1-6 alkylthiocarbonyl group; An alkylsulfonylamino group such as a ruamino group and a t-butylsulfonylamino group (preferably a C1-6 alkylsulfonylamino group); an arylsulfonylamino group such as a phenylsulfonylamino group, preferably a C6-12 arylsulfonylamino group; piperazini A heteroarylsulfonylamino group such as a rusulfonylamino group, preferably a C3-12 heteroarylsulfonylamino group; an alkylcarbonylamino group such as a methylcarbonylamino group, an ethylcarbonylamino group, preferably a C1-6 alkylcarbonylamino group; Alkoxycarbonylamino groups such as methoxycarbonylamino group and ethoxycarbonylamino group, preferably C1-6 alkoxycarbonylamino group; fluoromethylsulfonylamino group, dichloromethyl A haloalkylsulfonylamino group such as a tilsulfonylamino group, preferably a C1-6 haloalkylsulfonylamino group; a bis (alkylsulfonyl) amino group such as a bis (methylsulfonyl) amino group, preferably a bis (C1-6 alkylsulfonyl) amino group A bis (haloalkylsulfonyl) amino group such as a bis (fluoromethylsulfonyl) amino group, preferably a bis (C1-6 haloalkylsulfonyl) amino group; a hydrazino group, an N′-phenylhydrazino group, an N′-methoxycarbonylhydra Unsubstituted or substituted hydrazino groups such as dino groups; alkoxycarbonyl groups such as methoxycarbonyl groups and ethoxycarbonyl groups, preferably C1-6 alkoxycarbonyl groups; aryls such as phenyl groups, 1-naphthyl groups and 2-naphthyl groups , Preferably a C6-12 aryl group; an aralkyl group such as a benzyl group or a phenethyl group, preferably a C7-20 aralkyl group; a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an isoxazolyl group, an isothiazolyl group, an imidazolyl group Unsaturated hetero 5-membered ring group such as pyrazolyl group; Unsaturated hetero 6-membered ring group such as pyridyl group, pyridazinyl group and pyrazinyl group; Saturated heterocyclic group such as tetrahydrofuranyl and piperidinyl group; Aminocarbonyl group, dimethylaminocarbonyl N-unsubstituted or N-substituted aminocarbonyl groups such as groups; alkylthio groups such as methylthio groups, ethylthio groups and t-butylthio groups; alkenylthio groups such as vinylthio groups and allylthio groups; alkynylthio groups such as ethynylthio groups and propargylthio groups ; Arylthio groups such as an phenylthio group and 4-chlorophenylthio group; heteroarylthio groups such as a 2-pyridylthio group; aralkylthio groups such as a benzylthio group and a phenethylthio group; a methylsulfonyl group, an ethylsulfonyl group, a t-butylsulfonyl group, and the like An alkylsulfonyl group such as an allylsulfonyl group; an alkynylsulfonyl group such as a propargylsulfonyl group; an arylsulfonyl group such as a phenylsulfonyl group; a heteroarylsulfonyl group such as a 2-pyridylsulfonyl group and a 3-pyridylsulfonyl group; An aralkylsulfonyl group such as a benzylsulfonyl group;

Examples of the unsubstituted 5- to 8-membered heteroaryl group in R include thienyl, furyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,3,4 -Thiadiazolyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, pyridyl group, pyrimidyl group, pyridazyl group, pyrazyl group, 1,2,4-triazyl group and the like. The “substituent” in the 5- to 8-membered heteroaryl group having a substituent is not particularly limited, and examples thereof include the same as those mentioned as the “substituent” in the aryl group having the substituent. be able to.

The “substituent” in the vinyl group having a substituent in R is not particularly limited, and examples thereof include the same as those mentioned as the “substituent” in the aryl group having the substituent.

In the formula (I), Het represents an unsubstituted or substituted 3- to 8-membered heterocycle.
Examples of the unsubstituted 3- to 8-membered heterocycle in Het include an epoxy group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholino group, a pyrrolidinyl group, a piperazinyl group, an oxazolinyl group, an imidazolinyl group, an oxazonidinyl group, and 1 , 2-pyranyl group, thiazinyl group, dioxanyl group, thiomorpholino group and the like. Of these, 5- to 7-membered heterocycles are preferred. The “substituent” in the 3- to 8-membered heterocycle having a substituent is not particularly limited, and examples thereof include the same as those mentioned as the “substituent” in the aryl group having the substituent. it can.
In the formula (I), * indicates that the carbon atom is an asymmetric carbon, and the carbon atom may be either optically active or racemic.

[Ruthenium compound of formula (II)]
In the above formula (II), X and Y each independently represent a hydrogen atom, a hydroxyl group, a tetrahydroboric acid, a halogen atom, a C1-20 alkoxy group, or a C1-20 acyloxy group.
As a halogen atom in X and Y, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc. can be mentioned, for example.
Examples of the C1-20 alkoxy group in X and Y include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an s-butoxy group, an i-butoxy group, and a t-butoxy group. Can do.

Examples of the C1-20 acyloxy group in X and Y include an acetoxy group, a propionyloxy group, a pivaloyloxy group, a benzoyloxy group, a 2-chlorobenzoyloxy group, and a 4-methylbenzoyloxy group.

In formula (II), Px represents an optically active or racemic phosphine ligand. The phosphine ligand is typically monodentate or bidentate.
Examples of the monodentate phosphine ligand include trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, tricyclohexylphosphine, tri (p-tolyl) phosphine, diphenylmethylphosphine, dimethylphenylphosphine, diisopropylmethylphosphine, 1- [ 2- (diphenylphosphino) ferrocenyl] ethyl methyl ether, 2- (diphenylphosphino) -2′-methoxy-1,1′-binaphthyl and the like.

Examples of the bidentate phosphine ligand include bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, unsubstituted or substituted 2,2′-bis- (diphenylphosphino)- 1,1′-binaphthyl (BINAP) and the like can be mentioned. Specific examples of BINAP having a substituent include 2,2′-bis- (di-p-triphosphino) -1,1′-binaphthyl (Tol-BINAP), 2,2′-bis [bis (3,5 -Dimethylphenyl) phosphino] -1,1'-binaphthyl (Xylyl-BINAP) and the like.
Among these, as Px, an optically active phosphine ligand is preferable, and a bidentate phosphine ligand having axial asymmetry is more preferable.
In the formula (II), n represents the number of Px and is 1 or 2.

In the formula (II), A represents an optically active or racemic diamine ligand. A is preferably an optically active diamine ligand.
In formula (II), both Px and A are not racemic.

The diamine ligand in A is not particularly limited as long as it can stably form a metal complex, but the above formula (IIa), the above formula (IIb), the above formula (IIc), the above A diamine ligand represented by the formula (IId) or the above formula (IIe) is preferred.

In formula (IIa), formula (IIb), formula (IId) and formula (IIe), R ¹ represents an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20. An alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted or substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted group Alternatively, it represents a 3- to 8-membered heterocyclic group having a substituent.

Examples of the unsubstituted C1-20 alkyl group in R ¹ include, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, Examples thereof include an n-pentyl group and an n-hexyl group.

The “substituent” in the C1-20 alkyl group having a substituent in R ¹ is not particularly limited, but examples thereof include a hydroxyl group; a thiol group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; Group; nitro group; formyl group; unsubstituted or substituted amino group such as amino group, methylamino group, benzylamino group, anilino group and dimethylamino group; alkenyl group such as vinyl group, allyl group and 2-methoxyethenyl group Alkynyl groups such as ethynyl group, 1-propynyl group, 2-phenylethynyl group, propargyl group; methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, t-butoxy group, etc. Alkoxy groups, preferably C1-6 alkoxy groups; alkeni such as vinyloxy group and allyloxy group Oxy group; alkynyloxy group such as ethynyloxy group and propargyloxy group; aryloxy group such as phenoxy group and benzyloxy group; heteroaryloxy group such as 2-pyridyloxy; haloalkoxy group such as fluoromethoxy group and dibromomethoxy group Group, preferably C1-6 haloalkoxy group; alkylthiocarbonyl group such as methylthiocarbonyl group, ethylthiocarbonyl group, etc., preferably C1-6 alkylthiocarbonyl group; alkylsulfonyl such as methylsulfonylamino group, t-butylsulfonylamino group An amino group, preferably a C1-6 alkylsulfonylamino group; an arylsulfonylamino group such as a phenylsulfonylamino group, preferably a C6-12 arylsulfonylamino group; a piperazinylsulfonylamino group; A heteroarylsulfonylamino group such as a methyl group, preferably a C3-12 heteroarylsulfonylamino group; an alkylcarbonylamino group such as a methylcarbonylamino group, an ethylcarbonylamino group, preferably a C1-6 alkylcarbonylamino group; Alkoxycarbonylamino groups such as amino groups and ethoxycarbonylamino groups, preferably C1-6 alkoxycarbonylamino groups; haloalkylsulfonylamino groups such as fluoromethylsulfonylamino groups and dichloromethylsulfonylamino groups, preferably C1-6 haloalkylsulfonylamino groups A bis (alkylsulfonyl) amino group such as a bis (methylsulfonyl) amino group, preferably a bis (C1-6 alkylsulfonyl) amino group; bis (fluoromethyl) Bis (haloalkylsulfonyl) amino group such as sulfonyl) amino group, preferably bis (C1-6 haloalkylsulfonyl) amino group; hydrazino group, N′-phenylhydrazino group, N′-methoxycarbonylhydrazino group, etc. Substituted or substituted hydrazino group; alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group, preferably C1-6 alkoxycarbonyl group; aryl group such as phenyl group, 1-naphthyl group and 2-naphthyl group, preferably C6-12 Aryl group; unsaturated 5-membered ring group such as furanyl group, thiophenyl group, pyrrolyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group; and the like, pyridyl group, pyridazinyl group, pyrazinyl group, etc. Saturated hetero 6-membered ring Groups; saturated heterocyclic groups such as tetrahydrofuranyl and piperidinyl groups; N unsubstituted or N-substituted aminocarbonyl groups such as aminocarbonyl groups and dimethylaminocarbonyl groups; alkylthio groups such as methylthio groups, ethylthio groups and t-butylthio groups; Groups, alkenylthio groups such as allylthio groups; alkynylthio groups such as ethynylthio groups and propargylthio groups; arylthio groups such as phenylthio groups and 4-chlorophenylthio groups; heteroarylthio groups such as 2-pyridylthio groups; benzylthio groups and phenethyl groups Aralkylthio group such as thio group; Alkylsulfonyl group such as methylsulfonyl group, ethylsulfonyl group and t-butylsulfonyl group; Alkenylsulfonyl group such as allylsulfonyl group; Alkylsulfonyl group such as propargylsulfonyl group Rusuruhoniru group; arylsulfonyl groups such as phenylsulfonyl group; aralkyl sulfonyl group such as benzylsulfonyl group; pyridylmethyl sulfonyl group, 3-heteroarylsulfonyl groups such as pyridyl sulfonyl group and the like.

Examples of the unsubstituted C2-20 alkenyl group for R ¹ include a vinyl group, an allyl group, and a 2-methoxyethenyl group. The “substituent” in the C2-20 alkenyl group having a substituent is not particularly limited, but examples thereof include the same as those mentioned as the “substituent” in the C1-20 alkyl group having the substituent. be able to.

Examples of the unsubstituted C3-8 cycloalkyl group in R ¹ include a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group. The “substituent” in the C3-8 cycloalkyl group having a substituent is not particularly limited. For example, the same “substituent” as the “substituent” in the C1-20 alkyl group having the substituent may be used. Can be mentioned.

Examples of the unsubstituted C7-20 aralkyl group in R ¹ include a benzyl group and a phenethyl group. The “substituent” in the C7-20 aralkyl group having a substituent is not particularly limited, and examples thereof include the same as those mentioned as the substituent in the C1-20 alkyl group having the substituent. it can.
The unsubstituted or substituted C6-10 aryl group of R ^{1 and} the unsubstituted or substituted 3- to 8-membered heterocyclic group are not particularly limited, and examples thereof include unsubstituted or substituted R in R A C6-10 aryl group having a group, an unsubstituted or substituted 5- to 8-membered heteroaryl ring in R, and an unsubstituted or substituted 3- to 8-membered heterocyclic group in Het The same thing as what was mentioned as a specific example of can be mentioned.
Among these, R ¹ is preferably an unsubstituted or substituted C 6-10 aryl group.

In formula (IIa), formula (IIb) and formula (IId), R ² , R ³ and R ⁵ are each independently a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted group Or a C2-20 alkenyl group having a substituent, a C3-8 cycloalkyl group having an unsubstituted or substituted group, or a C7-20 aralkyl group having an unsubstituted or substituted group. Note that R ² and R ³ are not both hydrogen atoms.
In R ² , R ³ and R ⁵ , an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cyclo The alkyl group or the unsubstituted or substituted C7-20 aralkyl group is not particularly limited. For example, in R ¹ , an unsubstituted or substituted C1-20 alkyl group, unsubstituted or substituted The same as those mentioned as specific examples of the C2-20 alkenyl group having a substituent, the C3-8 cycloalkyl group having an unsubstituted or substituted group, or the C7-20 aralkyl group having an unsubstituted or substituted group Can be mentioned.
Among these, as R ² , R ³ and R ⁵ , an unsubstituted or substituted C1-20 alkyl group is preferable, and an unsubstituted or substituted C1-6 alkyl group is particularly preferable.
R ² and R ³ may combine to form a ring. Specific examples of the ring formed by combining R ² and R ³ include, for example, a pyrrolidine ring, a piperidine ring, and a morpholine ring.

In the formula (IIc), R ⁴ represents a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3 -8 cycloalkyl group, unsubstituted or substituted C7-20 aralkyl group, unsubstituted or substituted C6-10 aryl group, or unsubstituted or substituted 3- to 8-membered heterocyclic group Indicates.

In R ⁴ , an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted Alternatively, a C7-20 aralkyl group having a substituent, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted 3-8 membered heterocyclic group is not particularly limited. In the above R ¹ , an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, A substituted or substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or Examples thereof include the same ones as mentioned as specific examples of the substituted or substituted 3- to 8-membered heterocyclic group.
Among these, as R ⁴ , an unsubstituted or substituted C1-20 alkyl group is preferable, and an unsubstituted or substituted C1-6 alkyl group is particularly preferable.

In formula (IIc), B represents an unsubstituted or substituted ethylene group, or an unsubstituted or substituted heterocyclic divalent group.
The “substituent” in the ethylene group having a substituent in B is not particularly limited. For example, the same as those mentioned as the “substituent” in the C6-10 aryl group having a substituent in R above Can be mentioned.
When B is an ethylene group having a plurality of substituents, the plurality of substituents may be bonded to form a ring. Examples of the ring formed by combining a plurality of substituents include hydrocarbon rings such as cyclobutane ring, cyclopentane ring and cyclohexane ring; ether bonds such as tetrahydrofuran ring, 1,3-dioxolane ring and morpholine ring. A saturated ring having a nitrogen atom such as a pyrrolidine ring, a piperidine ring or a piperazine ring; an aromatic ring such as a benzene ring or a pyridine ring;

Specific examples of the “unsubstituted or substituted heterocycle” in the divalent group of the unsubstituted or substituted heterocycle in B are not particularly limited. For example, in the formula (I), In Het, there can be mentioned the same ones as mentioned as specific examples of unsubstituted or substituted 3- to 8-membered heterocycles.

[base]
Examples of the base used in the hydrogenation reaction of the present invention include triethylamine, diisopropylethylamine, pyridine, 1,4-diazabicyclo [2.2.2] octane (DABCO), and 1,8-diazabicyclo [5.4. 0] Organic bases such as undec-7-ene (DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium methoxide, magnesium ethoxide; organolithium compounds such as n-butyllithium Lithium amides such as lithium diisopropylamide and lithium bistrimethylsilylamide; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; sodium hydride and calcium hydride And metal hydrides thereof.

[Hydrogenation]
Hydrogenation in the method for producing an optically active alcohol compound of the present invention is not particularly limited by the method. For example, a carbonyl compound represented by formula (I) serving as a reaction substrate, a ruthenium compound represented by formula (II) serving as a catalyst, and a base are charged into a reactor, and then hydrogen gas at a predetermined pressure or a predetermined amount of Hydrogenation can be carried out by supplying a hydrogen donor.

The ruthenium compound represented by the formula (II) is prepared according to the method described in Japanese Patent Application Laid-Open No. 2005-068113, Japanese Patent Application Laid-Open No. 2003-104993, and the like. Or may be prepared and used in a hydrogenation reaction system.
The amount of the ruthenium compound represented by the formula (II) in the hydrogenation reaction system varies depending on the size of the reaction vessel and the activity of the ruthenium compound, but is preferably 1/50 to the carbonyl compound as the reaction substrate. It is 1 / 2,000,000 times mole, more preferably 1/500 to 1 / 500,000 times mole.
The amount of the base used is preferably 2 to 500,000 times mol, more preferably 2 to 5,000 times mol, with respect to the ruthenium compound represented by the formula (II).

The hydrogenation reaction can be carried out without solvent or in a solvent. The solvent used in the hydrogenation reaction is not particularly limited as long as it is inert to the hydrogenation reaction and can dissolve the carbonyl compound and the ruthenium compound. Specific examples of the solvent used include aromatic hydrocarbon solvents such as toluene and xylene; aliphatic hydrocarbon solvents such as pentane and hexane; halogen-containing hydrocarbon solvents such as methylene chloride; diethyl ether and tetrahydrofuran (THF) Ether solvents such as methanol, ethanol and benzyl alcohol; organic solvents containing heteroatoms such as acetonitrile, dimethylformamide (DMF), N-methylpyrrolidone and dimethyl sulfoxide (DMSO); it can. Among these, alcohol solvents are preferable as the solvent.
The amount of the solvent used depends on the solubility of the carbonyl compound represented by the formula (I) and is preferably 0.1 to 10,000 with respect to 100 parts by weight of the carbonyl compound represented by the formula (I). Part by weight, more preferably 20 to 1,000 parts by weight.

When supplying hydrogen gas, the pressure of the hydrogen gas is preferably 1 to 200 atm, more preferably 3 to 50 atm.
When supplying a hydrogen donor, as the hydrogen donor, for example, a hydrogen storage alloy or diimide can be used, and the supply amount of the hydrogen donor is based on the carbonyl compound represented by the formula (I): The equivalent is preferably 1 to 100 times equivalent.
The temperature in the hydrogenation reaction is preferably −50 ° C. to + 100 ° C., more preferably + 25 ° C. to + 40 ° C. The reaction time depends on the reaction conditions such as the concentration of the reaction substrate, temperature and pressure, the size of the reaction vessel, etc., but is preferably several minutes to several days. The reaction format may be a batch type or a continuous type.

After completion of the reaction, the optically active alcohol compounds represented by the formulas (IIIa) to (IIId), which are target products, are obtained by isolation and purification by methods such as distillation, recrystallization and silica gel column chromatography. be able to. The structure of the target product can be determined by known analytical means such as ¹ H-NMR, optical rotation measurement, liquid chromatography, gas chromatography and the like.
By the production method of the present invention, any of the optically active alcohol compounds represented by the formulas (IIIa) to (IIId) can be obtained with high selectivity.

Next, an Example is shown and this invention is demonstrated more concretely. However, the present invention is not limited to these examples.
The abbreviations shown in the examples represent the following meanings.
S / C: substrate / catalyst ratio RuCl ₂ {(S) -binap} {(R) -dmapen}:

RuCl ₂ {(S) -p-tolbinap} {(R) -dmapen}:

RuCl ₂ {(S) -binap} {(R) -iphan}:

RuCl ₂ {(S) -binap} {(R, R) -dpen}:

RuCl ₂ {(S) -binap} {(S, S) -dpen}:

RuCl ₂ {(S) -p-tolbinap} {(S, S) -dpen}:

RuCl ₂ {(S) -xylbinap} {(S, S) -dpen}:

The physical properties in each example were measured using the following apparatus.
(1) NMR: JNM-A300 (300 MHz, manufactured by JEOL Ltd.) and JNM-A400 (400 MHz, manufactured by JEOL Ltd.)
(2) Optical rotation: Optical rotation meter, JASCO DIP-360 (manufactured by JASCO)
(3) High performance liquid chromatography: LC-10Advp, SPD-10Avp (manufactured by Shimadzu Corporation)
(4) Gas chromatography: GC-17A (manufactured by Shimadzu Corporation)

Example 1
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine

In an autoclave under an argon atmosphere, 0.295 g (1 mmol, racemate) of N-benzoyl-morpholin-2-yl-phenyl-methanone, 0.5 ml of isopropanol, 0.5 ml of potassium t-butoxide as a 0.1 M isopropanol solution ( 0.05 mmol), and RuCl ₂ {(S) -binap} {(R) -dmapen} 9.6 mg (10 μmol, S / C = 100) were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. The obtained crude product was purified by HPLC (GL Science Inertsil ODS-3 (25 cm) acetonitrile / water / sodium dodecyl sulfate / 10% phosphoric acid = 400 ml / 600 ml / 9 g / 1 ml, 1 ml / min, 40 ° C., diastereomeric As a result of retention time 6.4 min, 7.3 min), the production ratio of diastereomers was> 99: 1. The crude product was concentrated and then purified by silica gel column chromatography to obtain 0.283 g (0.96 mmol) of optically active N-benzoyl-morpholin-2-yl-phenyl-methanol in a 96% yield. Enantiomeric excess was determined by HPLC (YMC-Pack SIL (25 cm) and Daicel Chiralcel OJ-H (15 cm) connected in series, hexane / isopropanol / ethanol = 85/15/5, 1 ml / min, 20 ° C., enantiomeric Body retention times of 36.4 minutes and 50.7 minutes) and 99% ee (enantiomer of retention time 36.4 minutes). This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 2
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl ₂ {(S) -binap} {(R) -dmapen} is converted to RuCl ₂ {(S)- The reaction was carried out in the same manner as in Example 1 except that p-tolbinap} {(R) -dmapen} (S / C = 100) was used, and the resulting crude product was purified. This resulted in an optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (enantiomer with a retention time of 36.4 minutes) in a diastereomer formation ratio of 99: 1, an isolation yield of 97%, and 97% ee. ) This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 3
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl ₂ {(S) -binap} {(R) -dmapen} is converted to RuCl ₂ {(S)- The resulting crude product was purified by reacting in the same manner as in Example 1 except that binap} {(R) -iphan} (S / C = 100) was used. As a result, optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (enantiomer with a retention time of 36.4 minutes) was obtained with a production ratio of diastereomer of 94: 6, an isolation yield of 96%, and 92% ee. ) This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 4
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl ₂ {(S) -binap} {(R) -dmapen} is converted to RuCl ₂ {(S)- The resulting crude product was purified by reacting in the same manner as in Example 1 except that binap} {(R, R) -dpen} (S / C = 100) was used. As a result, the optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (enantiomer with a retention time of 36.4 minutes) was obtained with a diastereomer production ratio of 96: 4, an isolation yield of 94%, and 87% ee. ) This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 5
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine 4.45 g (15 mmol, racemate) of N-benzoyl-morpholin-2-yl-phenyl-methanone The amount of isopropanol was 10.2 ml, the amount of potassium t-butoxide was 4.8 ml (0.48 mmol) as a 0.1 M isopropanol solution, and RuCl ₂ {(S) -binap} {(R) -dmapen } Was changed to 14.4 mg (15 μmol, S / C = 1,000) and reacted in the same manner as in Example 1, and the resulting crude product was purified. As a result, the production ratio of diastereomer> 99: 1, the isolation yield 99%, the optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (retention time 36.4 min enantiomer) with 99% ee Body). This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 6
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine 1.18 g (4 mmol, racemic) of N-benzoyl-morpholin-2-yl-phenyl-methanone The amount of isopropanol to 2.7 ml, the amount of potassium t-butoxide to 1.3 ml (0.13 mmol) as a 0.1 M isopropanol solution, and RuCl ₂ {(S) -p-tolbinap} {(R) -Dmapen} was reacted in the same manner as in Example 2 except that the amount was changed to 4.1 mg (4 μmol, S / C = 1,000), and the resulting crude product was purified. This resulted in an optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (enantiomer with a retention time of 36.4 minutes) in a diastereomer formation ratio of 99: 1, an isolation yield of 94%, and 98% ee. ) This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 7
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine 4.45 g (15 mmol, racemate) of N-benzoyl-morpholin-2-yl-phenyl-methanone The amount of isopropanol to 20.9 ml, the amount of potassium t-butoxide to 9.1 ml (0.91 mmol) as a 0.1 M isopropanol solution, and RuCl ₂ {(S) -binap} {(R) -dmapen } Was changed to 2.9 mg (3 μmol, S / C = 5,000) in the same manner as in Example 1, and the resulting crude product was purified. As a result, the production ratio of diastereomer> 99: 1, the isolation yield 99%, the optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (retention time 36.4 min enantiomer) with 99% ee Body). The specific rotation of this enantiomer was [α] _D = + 27.9 (c = 2.53, CHCl ₃ ). This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 8
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine 4.45 g (15 mmol, racemate) of N-benzoyl-morpholin-2-yl-phenyl-methanone The amount of isopropanol to 10.4 ml, the amount of potassium t-butoxide to 4.6 ml (0.46 mmol) as a 0.1 M isopropanol solution, and RuCl ₂ {(S) -binap} {(R) -dmapen } Was changed to 3.0 mg (3 μmol, S / C = 5,000), and the reaction was carried out in the same manner as in Example 1 except that the hydrogen pressure was changed to 50 atm. The resulting crude product was purified. did. This resulted in an optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (enantiomer with a retention time of 36.4 minutes) in a diastereomer formation ratio of 99: 1, an isolated yield of 98%, and 98% ee. ) This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 9
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl ₂ {(S) -binap} {(R) -dmapen} is converted to RuCl ₂ {(S)- The resulting crude product was purified by reacting in the same manner as in Example 1 except that binap} {(S, S) -dpen} (S / C = 100) was used. As a result, the optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (enantiomer with a retention time of 36.4 minutes) was obtained with a diastereomer formation ratio of 95: 5, an isolation yield of 96%, and 62% ee. ) This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 10
Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl ₂ {(S) -binap} {(R) -dmapen} is converted to RuCl ₂ {(S)- The reaction was performed in the same manner as in Example 1 except that p-tolbinap} {(S, S) -dpen} (S / C = 100) was used, and the resulting crude product was purified. As a result, the optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (retention time of 36.4 minutes) was obtained at a diastereomer production ratio of 93: 7, an isolated yield of 93%, and a yield of 64% ee. Enantiomers). This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.

Example 11
Preparation of N-benzoyl- (2R) -2-[(S) -hydroxy-phenyl-methyl] -morpholine RuCl ₂ {(S) -binap} {(R) -dmapen} is converted to RuCl ₂ {(S)- The reaction was performed in the same manner as in Example 1 except that xylbinap} {(S, S) -dpen} (S / C = 100) was used, and the resulting crude product was purified. As a result, an optically active N-benzoyl-morpholin-2-yl-phenyl-methanol (enantiomer opposite to that in Example 1) was produced with a diastereomer production ratio of 95: 5, an isolation yield of 94%, and 33% ee. Got. This enantiomer was analyzed and found to be N-benzoyl- (2R) -2-[(S) -hydroxy-phenyl-methyl] -morpholine.

Example 12
Preparation of Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy-phenyl-methyl] -piperidine

Under an argon atmosphere, the autoclave was charged with Nt-butoxycarbonyl-piperidin-3-yl-phenyl-methanone 8.68 g (30 mmol, racemate), isopropanol 29.1 ml, potassium t-butoxide as a 1.0 M isopropanol solution. .91 ml (0.91 mmol) and RuCl ₂ {(S) -binap} {(R) -dmapen} 2.9 mg (3 μmol, S / C = 10,000) were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. The obtained crude product was purified by HPLC (GL Science Inertsil ODS-3 (25 cm) acetonitrile / water / sodium dodecyl sulfate / 10% phosphoric acid = 600 ml / 400 ml / 9 g / 1 ml, 1 ml / min, 40 ° C., diastereomeric Analysis with retention times (8.9 minutes, 10.2 minutes) showed a diastereomer formation ratio> 99: 1. The crude product was concentrated and purified by silica gel column chromatography to obtain 8.77 g (30.0 mmol) of optically active Nt-butoxycarbonyl-piperidin-3-yl-phenyl-methanol in 100% yield. . Enantiomeric excess was determined by HPLC (Daicel Chiralpack AD-H (25 cm), hexane / isopropanol / ethanol = 97/2/1, 1 ml / min, 20 ° C., enantiomer retention time 24.7 min and 32.5 Min), it was> 99% ee (enantiomer with a retention time of 32.5 minutes). The specific rotation of this enantiomer was [α] _D = −30.0 (c = 1.04, MeOH). The enantiomer was analyzed and found to be Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy-phenyl-methyl] -piperidine.

Example 13
Preparation of Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy-phenyl-methyl] -piperidine The amount of Nt-butoxycarbonyl-piperidin-3-yl-phenyl-methanone was 11.57 g ( 40 mmol, racemate), the amount of isopropanol to 38.8 ml, the amount of potassium t-butoxide to 1.2 ml (1.2 mmol) as a 1.0 M isopropanol solution, RuCl ₂ {(S) -binap} { The amount of (R) -dmapen} was changed to 1.9 mg (2 μmol, S / C = 20,000), and the reaction was performed in the same manner as in Example 12 except that the hydrogen pressure was changed to 50 atm. The crude product was purified. As a result, Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy-phenyl-methyl]-in a diastereomer formation ratio> 99: 1, isolation yield 97%,> 99% ee Piperidine was obtained.

Example 14
Preparation of Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy- (2-chloro-phenyl) -methyl] -piperidine

In an autoclave under an argon atmosphere, 4.86 g (15 mmol, racemate) of Nt-butoxycarbonyl-piperidin-3-yl-3-chloro-phenylmethanone, 14.5 ml of isopropanol, and 1.0 M of potassium t-butoxide. 0.46 ml (0.46 mmol) as an isopropanol solution and 2.9 mg (3 μmol, S / C = 5,000) of RuCl ₂ {(S) -binap} {(R) -dmapen} were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. The crude product thus obtained was analyzed by HPLC (same conditions as in Example 12, retention time of diastereomer 12.2 minutes, 14.8 minutes). The production ratio of diastereomer was> 99: 1. . The crude product was concentrated and purified by silica gel column chromatography, and 4.81 g (14.9 mmol) of optically active Nt-butoxycarbonyl-piperidin-3-yl-3-chloro-phenylmethanol was obtained in a yield of 99%. Obtained. The enantiomeric excess was determined by HPLC (Daicel Chiralpack AD-H (25 cm), hexane / isopropanol / ethanol = 98/1/1, 1 ml / min, 20 ° C., enantiomer retention time 30.7 min and 38.2. Min), it was> 99% ee (enantiomer of retention time 38.2 min). The specific rotation of this enantiomer was [α] _D = -25.0 (c = 1.01, MeOH). As a result of analysis, this enantiomer was found to be Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy- (2-chloro-phenyl) -methyl] -piperidine.

Example 15
Preparation of Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy- (2-thienyl) -methyl] -piperidine

In an autoclave under an argon atmosphere, 1.18 g (4 mmol, racemate) of Nt-butoxycarbonyl-piperidin-3-yl-2-thienyl-methanone, 5.4 ml of isopropanol, 0.1M isopropanol solution of potassium t-butoxide 2.6 ml (0.26 mmol), and RuCl ₂ {(S) -binap} {(R) -dmapen} 7.8 mg (8.1 μmol, S / C = 500) were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. The resulting crude product was purified by HPLC (GL Science Inertsil ODS-3 (25 cm) acetonitrile / water / sodium dodecyl sulfate / 10% phosphoric acid = 600 ml / 400 ml / 8 g / 1 ml, 1 ml / min, 40 ° C., diastereomeric Retention time 8.2 minutes, 9.2 minutes) The production ratio of diastereomers was> 99: 1. The crude product was concentrated and purified by silica gel column chromatography. 1.12 g (3.8 mmol) of optically active Nt-butoxycarbonyl-piperidin-3-yl-2-thienyl-methanol was obtained in a yield of 95%. Obtained. Enantiomeric excess was determined by HPLC (Daicel Chiralpack AD-H (25 cm), hexane / isopropanol / ethanol = 92/3/5, 1 ml / min, 20 ° C., retention time of enantiomers 10.5 min and 13.1. Min) was 99% ee (enantiomer with a retention time of 13.1 min). The specific rotation of this enantiomer was [α] _D = + 7.7 (c = 1.05, MeOH). As a result of analysis, this enantiomer was found to be Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy- (2-thienyl) -methyl] -piperidine.

Example 16
Preparation of Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy- (2-thienyl) -methyl] -piperidine RuCl ₂ {(S) -binap} {(R) -dmapen} is replaced by RuCl _{2 The} reaction was performed in the same manner as in Example 15 except that {(S) -p-tolbinap} {(R) -dmapen} (S / C = 500) was used, and the resulting crude product was purified. As a result, an optically active Nt-butoxycarbonyl-piperidin-3-yl-2-thienyl-methanol was obtained with a diastereomer production ratio> 99: 1, an isolation yield of 99%, and 95% ee. As a result of analysis, this enantiomer was found to be Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy- (2-thienyl) -methyl] -piperidine.

Example 17
Preparation of (1R, 8aR) -1-phenyl-hydroxy-oxazolo- [3,4-a] pyridin-3-one

In an autoclave under an argon atmosphere, 1.18 g of Nt-butoxycarbonyl-piperidin-2-yl-phenyl-methanone (4.0 mmol, racemate), 2.7 ml of isopropanol, 0.1 M isopropanol solution of potassium t-butoxide 1.3 ml (0.13 mmol) and RuCl ₂ {(S) -binap} {(R) -dmapen} 3.8 mg (4 μmol, S / C = 1,000) were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. The obtained crude product was analyzed by HPLC (same conditions as in Example 1, retention time of diastereomer 13.0 minutes, 15.3 minutes). The production ratio of diastereomer was> 99: 1. It was. The crude product was concentrated and purified by silica gel column chromatography. As a result, 0.888 g (4.0 mmol) of optically active 1-phenyl-hexahydro-oxazolo- [3,4-a] pyridin-3-one was 100%. Obtained in yield. Enantiomeric excess was determined by HPLC (Daicel Chiralcel OD-H (25 cm), hexane / ethanol = 95/5, 1.0 ml / min, 20 ° C., enantiomer retention times 16.6 min and 31.2 min) Was 96.7% ee (isomer with a retention time of 31.2 minutes). The specific rotation of this enantiomer was [α] _D = + 9.6 (c = 1.20, MeOH). As a result of analysis, this enantiomer was found to be (1R, 8aR) -1-phenyl-hydroxy-oxazolo- [3,4-a] pyridin-3-one.

Example 18
Preparation of (1R, 8aR) -1-phenyl-hydroxy-oxazolo- [3,4-a] pyridin-3-one RuCl ₂ {(S) -binap} {(R) -dmapen} is converted to RuCl ₂ {( S) -p-tolbinap} {(R) -dmapen} (S / C = 500) was used for the reaction in the same manner as in Example 17, and the resulting crude product was purified. As a result, an optically active 1-phenyl-hexahydro-oxazolo- [3,4-a] pyridin-3-one was obtained with a production ratio of diastereomer> 99: 1, an isolation yield of 98%, and 87% ee. . As a result of analysis, this enantiomer was found to be (1R, 8aR) -1-phenyl-hydroxy-oxazolo- [3,4-a] pyridin-3-one.

Example 19
Preparation of N-benzoyl (2R) -2-[(R) -hydroxy-phenyl-methyl] -piperidine

In an autoclave under an argon atmosphere, 0.880 g (3 mmol, racemate) of N-benzoyl-piperidin-2-yl-phenyl-methanone, 2.2 ml of isopropanol, and 2.1 ml of potassium t-butoxide as a 0.1 M isopropanol solution. (0.21 mmol) and RuCl ₂ {(S) -binap} {(R) -dmapen} 14.4 mg (15 μmol, S / C = 200) were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. The obtained crude product was purified by HPLC (GL Science Inertsil ODS-3 (25 cm) acetonitrile / water / sodium dodecyl sulfate / 10% phosphoric acid = 400 ml / 600 ml / 8 g / 1 ml, 1 ml / min, 40 ° C., diastereomeric Retention time 5.0 min, 6.3 min) The production ratio of diastereomers was> 99: 1. The crude product was concentrated and purified by silica gel column chromatography to obtain 0.834 g (2.85 mmol) of optically active N-benzoyl-piperidin-2-yl-phenyl-methanol in a yield of 95%. Enantiomeric excess was determined by HPLC (Daicel Chiralpack AD-H (25 cm), hexane / ethanol / isopropanol = 85/10/5 1.0 ml / min, 20 ° C., enantiomeric retention time 18.0 min and 21. 4 min), it was 96% ee (enantiomer with a retention time of 18.0 min). The specific rotation of this enantiomer was [α] _D = −118.5 (c = 1.10, MeOH). This enantiomer was analyzed and found to be N-benzoyl (2R) -2-[(R) -hydroxy-phenyl-methyl] -piperidine.

Example 20
Preparation of N-benzoyl (2R) -2-[(R) -hydroxy-phenyl-methyl] -pyrrolidine

In an autoclave under an argon atmosphere, 1.11 g (4 mmol, racemate) of N-benzoyl-pyrrolidin-2-yl-phenyl-methanone, 3.9 ml of isopropanol, 1.3 ml of dichloromethane, 0.1M isopropanol of potassium tert-butoxide As a solution, 2.8 ml (0.28 mmol) and RuCl ₂ {(S) -binap} {(R) -dmapen} 19.1 mg (20 μmol, S / C = 200) were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. The obtained crude product was analyzed by HPCL (YMC-Pack SIL (25 cm), hexane / ethanol = 98/2, retention time of diastereomer 15.9 minutes and 22.5 minutes). The production ratio was 98: 2. The crude product was concentrated and purified by silica gel column chromatography to obtain 1.10 g (39 mmol) of optically active N-benzoyl-piperidin-2-yl-phenyl-methanol in a yield of 98%. Enantiomeric excess was determined by HPLC (Daicel Chiralpack AD-H (25 cm), hexane / ethanol / isopropanol = 85/10/5, 1.0 ml / min, 20 ° C., enantiomeric retention times 35.0 min and 42 .8 minutes) and 94% ee (enantiomer with a retention time of 35.0 minutes). This enantiomer was analyzed and found to be N-benzoyl (2R) -2-[(R) -hydroxy-phenyl-methyl] -pyrrolidine.

Example 21
Preparation of (2S) -2-[(R) -hydroxy-phenyl-methyl] -tetrahydrofuran

Under an argon atmosphere, an autoclave was charged with 0.529 g (3 mmol, racemate) of phenyl- (tetrahydrofuran-2-yl) -methanone, 1.98 ml of isopropanol, and 1.02 ml (0) of a 0.1M isopropanol solution of potassium tert-butoxide. .102 mmol), and RuCl ₂ {(S) -binap} {(R) -dmapen} 5.8 mg (6 μmol, S / C = 500) were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. The obtained crude product was subjected to gas chromatography (β-DEX 120 (30 m × 0.25 μm), 120 ° C., 20 minutes, 5 ° C./minute, 150 ° C., 60 minutes, carrier gas: helium (100 kPa), detector. : FID, retention times of 4 isomers 54.1 min, 55.1 min, 56.6 min, 58.3 min) The production ratio of diastereomers was 95: 5. The crude product was concentrated and purified by silica gel column chromatography. As a result, 0.491 mg (2.76 mmol) of optically active phenyl- (tetrahydrofuran-2-yl) -methanol was obtained in a yield of 92%. When the enantiomeric excess was analyzed by gas chromatography under the same conditions as described above, it was 99% ee (enantiomer with a retention time of 58.3 minutes). This enantiomer was analyzed and found to be (2S) -2-[(R) -hydroxy-phenyl-methyl] -tetrahydrofuran.

Example 22
Preparation of Nt-butoxycarbonyl- (3S) -3-[(S) -hydroxy-phenyl-methyl-]-pyrrolidine

In an autoclave under an argon atmosphere, 1.10 g (4 mmol, racemate) of N-benzoyl-pyrrolidin-3-yl-phenyl-methanone, 2.7 ml of isopropanol, 1.3 ml of potassium tert-butoxide as a 0.1 M isopropanol solution. (0.13 mmol), and RuCl ₂ {(S) -binap} {(R) -dmapen} 3.8 mg (4 μmol, S / C = 1,000) were added. After the deaeration operation, hydrogen was injected to 10 atm, and the reaction was allowed to proceed with stirring at 25 ° C. for 20 hours. When the obtained crude product was analyzed by HPLC (same conditions as in Example 15, diastereomer retention time 8.4 minutes, 9.1 minutes), the diastereomer production ratio was 75:25. . The crude product was concentrated and purified by silica gel column chromatography. As a result, 0.833 g (3.0 mmol) of optically active N-benzoyl-piperidin-2-yl-phenyl-methanol was obtained in a yield of 75%. Enantiomeric excess was determined by HPLC (Daicel Chiralpack AD-H (25 cm), hexane / isopropanol = 90/10, 1.0 ml / min, 20 ° C., enantiomer retention times 15.8 min and 20.3 min) Was 98% ee (enantiomer with a retention time of 15.8 minutes). This enantiomer was analyzed and found to be Nt-butoxycarbonyl- (3S) -3-[(S) -hydroxy-phenyl-methyl-]-pyrrolidine.

Although the present invention has been described in detail, it will be apparent to those skilled in the art that various modifications and variations can be made without departing from the spirit and scope of the invention.
This application is based on Japanese Patent Application 2010-279412 filed on December 15, 2010 and Japanese Patent Application 2011-092511 filed on April 18, 2011, the contents of which are incorporated herein by reference. Moreover, all the content of the literature described in the specification is also taken in as a reference.

Claims (6)

1. Hydrogenating the carbonyl compound represented by formula (I) in the presence of a ruthenium compound represented by formula (II) and a base, formula (IIIa), formula (IIIb), formula (IIIc) Alternatively, a method for producing any of the optically active alcohol compounds represented by the formula (IIId).
   

   

   (In the formula (I),
   R represents an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted 5- to 8-membered heteroaryl group, or an unsubstituted or substituted vinyl group.
   Het represents an unsubstituted or substituted 3- to 8-membered heterocycle.
   * Indicates that the carbon atom is an asymmetric carbon. )
   

   

   (In the formula (II), X and Y each independently represent a hydrogen atom, a hydroxyl group, a tetrahydroboric acid, a halogen atom, a C1-20 alkoxy group, or a C1-20 acyloxy group.
   Px represents an optically active or racemic phosphine ligand.
   n represents the number of Px and is 1 or 2.
   A represents an optically active or racemic diamine ligand.
   However, both Px and A are not racemic. )
   

   

   

   

   

   (In formula (IIIa), formula (IIIb), formula (IIIc) and formula (IIId), R and Het have the same meaning as in formula (I).)
2. The production method according to claim 1, wherein Het in the formula (I) is a 5- to 7-membered heterocycle.
3. In Formula (II), A is a ligand represented by Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe). The manufacturing method as described.
   
   R ¹ CH (NH ₂ ) CH ₂ (NR ² R ³ ) (IIa)
   R ¹ CH (NR ² R ³ ) CH ₂ (NH ₂ ) (IIb)
   (H ₂ N) HR ⁴ CB—CHR ⁴ (NH ₂ ) (IIc)
   R ¹ CH (NH ₂ ) CR ⁵ R ⁵ (NH ₂ ) (IId)
   R ¹ CH (NH ₂ ) R ¹ CH (NH ₂ ) (IIe)
   
   (In formula (IIa), formula (IIb), formula (IIc), formula (IId) and formula (IIe),
   R ¹ is an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted Or a substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted 3- to 8-membered heterocyclic group.
   R ² , R ³ and R ⁵ are each independently a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted A C3-8 cycloalkyl group having a group, or an unsubstituted or substituted C7-20 aralkyl group. R ² and R ³ may combine to form a ring. However, both R ² and R ³ are not hydrogen atoms.
   R ⁴ represents a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, An unsubstituted or substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted 3- to 8-membered heterocyclic group.
   B represents an unsubstituted or substituted ethylene group, or an unsubstituted or substituted heterocyclic divalent group. When B is an ethylene group having a plurality of substituents, the plurality of substituents may be bonded to form a ring. )
4. The production method according to any one of claims 1 to 3, wherein Px in the formula (II) is an optically active phosphine ligand.
5. The production method according to any one of claims 1 to 4, wherein, in the formula (II), Px is a bidentate phosphine ligand having axial asymmetry.
6. The production method according to any one of claims 1 to 5, wherein in the formula (II), A is an optically active diamine ligand.