Process for producing optically active β-amino alcohols

Abstract

To provide a method for hydrogenating a substrate carbonyl compound with high efficiency and producing an optically active β-amino alcohol having asymmetric points at α, β sites of a hydroxy group, with high enantiomer purity and diastereomer purity.SOLUTION: In the presence of a Ru complex represented by general formula: RuXYAB [X and Y independently represent H or an anionic group; A is an optically active diphosphine represented by formula (2); B is a compound represented by formula (3)], a substrate carbonyl compound is reacted with hydrogen and / or a hydrogen-donating compound. R5R6P-C*HR1-CR3R4-C*HR2-PR7R8 (2) (R1-R8 each represent a hydrocarbon group or the like; * is asymmetric C; each D independently represent C or N; R9-R12 each represent a hydrocarbon group or the like; n is an integer of 0 or greater (4 minus the number of nitrogen D).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing optically active β-amino alcohols having asymmetric points at the α- and β-positions of a hydroxyl group.

Background Art

[0002] As a method for producing an optically active β-amino alcohol having asymmetry at each of a carbon atom substituted with an amino group and a carbon atom substituted with a hydroxyl group, a method of diastereoselectively and enantioselectively hydrogenating or reducing a racemic α-aminocarbonyl compound in the presence of an asymmetric catalyst is known. For example, a method using a ruthenium complex having an optically active diphosphine such as BINAP as a ligand is disclosed (Non-Patent Document 1, Patent Document 1). The method disclosed in Non-Patent Document 1 proceeds with high diastereoselectivity for a substrate containing a functional group that contributes to stereocontrol such as an ester site in the molecule and gives an optically active amino alcohol, but it is difficult to produce simple amino alcohols having no functional group. Further, the method disclosed in Patent Document 1 requires high temperature and high pressure conditions and is not a practical method. In addition, a method of diastereoselectively and enantioselectively hydrogenating or reducing a racemic α-aminocarbonyl compound using a ruthenium complex having both an optically active diphosphine such as BINAP and an optically active 1,2-ethylenediamine type ligand to obtain an optically active β-amino alcohol having asymmetry at both carbon atoms substituted with an amino group and a hydroxyl group is disclosed (Patent Documents 2, 3, 4). However, all of the methods disclosed therein are insufficient from the viewpoints of the stereoselectivity, catalytic efficiency, and substrate application range of the optically active β-amino alcohol. Furthermore, these methods mainly focus on the diastereomer purity due to the substituent effect of the amino group of the carbonyl substrate, and the effect of the diamine of the complex ligand is not touched upon. In particular, there is no description at all in these patents about the use of an α-picolylamine-like ligand. As an asymmetric reduction method of ketones using an asymmetric metal catalyst having an α-picolylamine ligand, a method for producing an optically active alcohol by an asymmetric reduction reaction of prochiral ketones using 2-propanol as a hydrogen source has been reported, but there is no description of its application to α-aminocarbonyl compounds (Patent Document 5). As described above, although there has been a long-felt need to develop a method for efficiently producing optically active β-aminoalcohols from racemic α-aminocarbonyl compounds, there has been no report of producing optically active β-aminoalcohols having asymmetry at both carbon atoms substituted with an amino group and a hydroxyl group in high yield, high enantiomeric purity, and high diastereomeric purity.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a method for highly efficiently hydrogenating a substrate carbonyl compound using a ruthenium complex having a specific optically active diphosphine compound and an amine compound that is easy to synthesize as ligands, and producing optically active β-amino alcohols having asymmetric points at the α and β positions of the hydroxyl group with high enantiomeric purity and diastereomeric purity. **Means for Solving the Problems**

[0006] In the intensive study of the hydrogenation reaction of the substrate carbonyl compound, the present inventors found that a ruthenium complex catalyst having an optically active SKEWPHOS (2,4-bis(diphenylphosphino)pentane) derivative compound, which is a diphosphine compound having asymmetry on an easily synthesizable carbon, and a PICA-type ligand has excellent performance as an asymmetric hydrogenation catalyst for carbonyl compounds. As a result, it was found that optically active β-amino alcohols having asymmetric points at the α and β positions of the hydroxyl group are produced with high enantiomeric purity and diastereomeric purity, and the present invention has been completed.

[0007] That is, the present invention relates to the following. [1] A method for producing optically active β-amino alcohols, comprising the following general formula (1) RuXYAB (1) [(In general formula (1), X and Y are the same as or different from each other and represent a hydrogen atom or an anionic group, and A represents the following general formula (2)

[0008] **[Chemical formula]** (In general formula (2), R 1 and R 2 are the same as or different from each other and represent a linear or cyclic hydrocarbon group having 1 to 20 carbon atoms which may have a substituent, R 3 and R 4 are the same as or different from each other and represent a hydrogen atom or a hydrocarbon group having 1 to 3 carbon atoms, R 5 、R 6 、R7 and R 8 are the same as or different from each other and each represents a hydrocarbon group which may have a substituent, and * represents an asymmetric carbon atom.) represents an optically active diphosphine represented by the formula:) B is represented by the following general formula (3)

[0009]

Chemical formula

[0010]

Chemical formula

[0011] [Chemical formula] (In the formula, J, K and L have the same meanings as described above, and * indicates the position of the asymmetric carbon) The method as described above for producing an optically active β-amino alcohol represented by the formula.

[0012] [2] In the reaction system, the following general formula (6) RuXYA (6) (In general formula (6), X, Y and A each independently have the same meanings as defined in general formula (1).) By allowing one or more complexes selected from the compounds represented by the formula and one or more amine compounds selected from the compounds represented by the general formula (3) to be present, the ruthenium complex represented by the general formula (1) is prepared in situ. The method according to [1] above. [3] Two Rs 12 are linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent, and the ring formed by the two Rs 12 and the ring formed by the ring containing D constitute a quinoline ring or an isoquinoline ring. The method according to [1] or [2] above. [4] In general formula (3), one or more of the four Ds are nitrogen atoms. The method according to any one of [1] to [3] above.

[0013] [5] A is 2,4-bis-(diphenylphosphino)pentane, 2,4-bis-(di-4-tolylphosphino)pentane, 2,4-bis-(di-3,5-xylylphosphino)pentane, 2,4-bis-(di-4-tert-butylphenylphosphino)pentane, 2,4-bis-(di-4-isopropylphenylphosphino)pentane, 2,4-bis-(di-3,5-diethylphenylphosphino)pentane, 2,4-bis-(di-3,5-diisopropylphenylphosphino)pentane, 2,4-bis-(di-3,5-di-tert-butylphenylphosphino)pentane, 2,4-bis-(diphenylphosphino)-3-methylpentane, 2,4-bis-(di-4-tolylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-xylylphosphino)-3-methylpentane, 2,4-bis-(di-4-tert-butylphenylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-diethylphenylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-diisopropylphenylphosphino)-3-methylpentane, 1,3-bis-(diphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-4-tolylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-xylylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-4-tert-butylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-diethylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-diisopropylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(diphenylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-4-tolylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-3,5-xylylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-4-tert-butylphenylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-3,5-diethylphenylphosphino)-1,3-diphenyl-2-methylpropane or 1,3-bis-(di-3,5-diisopropylphenylphosphino)-1,The method according to any one of [1] to [4], which is 3-diphenyl-2-methylpropane.

[0014] [6] The method according to any one of [1] to [5], wherein A is 2,4-bis-(diphenylphosphino)pentane, 2,4-bis-(di-4-tolylphosphino)pentane, 2,4-bis-(di-3,5-xylylphosphino)pentane, 2,4-bis-(di-4-tert-butylphenylphosphino)pentane, 2,4-bis-(di-4-isopropylphenylphosphino)pentane, 2,4-bis-(di-3,5-diethylphenylphosphino)pentane, 2,4-bis-(di-3,5-diisopropylphenylphosphino)pentane, 2,4-bis-(di-3,5-di-tert-butylphenylphosphino)pentane, or 2,4-bis-(diphenylphosphino)-3-methylpentane.

[0015] [7] B is 2-picolylamine, (6-(p-tolyl)-2-pyridyl)methanamine, 1-(2-pyridyl)ethylamine, 2-(aminomethyl)-6-methylpyridine, 2-(aminomethyl)-3-methylpyridine, 2-(aminomethyl)-4-methylpyridine, 2-(aminomethyl)-5-methylpyridine, 2-(aminomethyl)-6-ethylpyridine, 2-(aminomethyl)-3-ethylpyridine, 2-(aminomethyl)-4-ethylpyridine, 2-(aminomethyl)-5-ethylpyridine, 2-(aminomethyl)-6-n-propylpyridine, 2-(aminomethyl)-3-n-propylpyridine, 2-(aminomethyl)-4-n-propylpyridine, 2-(aminomethyl)-5-n-propylpyridine, 2-(aminomethyl)-6-isopropylpyridine, 2-(aminomethyl)-3-isopropylpyridine, 2-(aminomethyl)-4-isopropylpyridine, 2-(aminomethyl)-5-isopropylpyridine, 2-(aminomethyl)-6-tert-butylpyridine, 2-(aminomethyl)-3-tert-butylpyridine, 2-(aminomethyl)-4-tert-butylpyridine, 2-(aminomethyl)-5-tert-butylpyridine, 2-(N-benzyl-aminomethyl)pyridine, 2-(aminomethyl)pyrrolidine, 2-(aminomethyl)-1-ethylpyrrolidine, 2-(pyrrolidinylmethyl)pyrrolidine, 2-(1-amino-1,1-diphenylmethyl)pyrrolidine, 2-(aminomethyl)-6-phenylpyridine, 2-(aminomethyl)-3-phenylpyridine, 2-(aminomethyl)-4-phenylpyridine, 2-(aminomethyl)-5-phenylpyridine, 2-(aminomethyl)-3,4-dimethylpyridine, 2-(aminomethyl)-3,5-dimethylpyridine, 2-(aminomethyl)-3,6-dimethylpyridine, 2-(aminomethyl)-4,5-dimethylpyridine, 2-(aminomethyl)-4,6-dimethylpyridine, 2-(aminomethyl)-5,6-dimethylpyridine, 2-(aminomethyl)-3,4,5-trimethylpyridine, 2-(aminomethyl)-3,5,6-trimethylpyridine, 2-(aminomethyl)-4,5,6-trimethylpyridine, 2-(aminomethyl)-3,4,5,6-tetramethylpyridine, 2-(aminomethyl)-3,4-Diethylpyridine, 2-(aminomethyl)-3,5-diethylpyridine, 2-(aminomethyl)-3,6-diethylpyridine, 2-(aminomethyl)-4,5-diethylpyridine, 2-(aminomethyl)-4,6-diethylpyridine, 2-(aminomethyl)-5,6-diethylpyridine, 2-(aminomethyl)-3,4-di-n-propylpyridine, 2-(aminomethyl)-3,5-di-n-propylpyridine, 2-(aminomethyl)-3,6-di-n-propylpyridine, 2-(aminomethyl)-4,5-di-n-propylpyridine, 2-(aminomethyl)-4,6-di-n-propylpyridine, 2-(aminomethyl)-5,6-di-n-propylpyridine, 2-(aminomethyl)-3,4-diisopropylpyridine, 2-(aminomethyl)-3,5-diisopropylpyridine, 2-(aminomethyl)-3,6-diisopropylpyridine, 2-(aminomethyl)-4,5-diisopropylpyridine, 2-(aminomethyl)-4,6-diisopropylpyridine, 2-(aminomethyl)-5,6-diisopropylpyridine, 2-(aminomethyl)-3,4-di-n-butylpyridine, 2-(aminomethyl)-3,5-di-n-butylpyridine, 2-(aminomethyl)-3,6-di-n-butylpyridine, 2-(aminomethyl)-4,5-di-n-butylpyridine, 2-(aminomethyl)-4,6-di-n-butylpyridine, 2-(aminomethyl)-5,6-di-n-butylpyridine, 2-(aminomethyl)-3,4-diisobutylpyridine, 2-(aminomethyl)-3,5-diisobutylpyridine, 2-(aminomethyl)-3,6-diisobutylpyridine, 2-(aminomethyl)-4,5-diisobutylpyridine, 2-(aminomethyl)-4,6-diisobutylpyridine, 2-(aminomethyl)-5,6-diisobutylpyridine, 2-(aminomethyl)-3,4-di-tert-butylpyridine, 2-(aminomethyl)-3,5-di-tert-butylpyridine, 2-(aminomethyl)-3,6-di-tert-butylpyridine, 2-(aminomethyl)-4,5-di-tert-butylpyridine, 2-(aminomethyl)-4,6-di-tert-butylpyridine, 2-(aminomethyl)-5,6-di-tert-butylpyridine, 2-(aminomethyl)-3,4-diphenylpyridine, 2-(aminomethyl)-3,5-Diphenylpyridine, 2-(aminomethyl)-3,6-diphenylpyridine, 2-(aminomethyl)-4,5-diphenylpyridine, 2-(aminomethyl)-4,6-diphenylpyridine, 2-(aminomethyl)-5,6-diphenylpyridine, 2-(aminomethyl)-4-methoxy-3,5-dimethylpyridine, 2-(aminomethyl)quinoline, 1-(aminomethyl)isoquinoline, 3-(aminomethyl)isoquinoline, 2-(aminomethyl)pyrazine, 2-(aminomethyl)pyrimidine, 6-aminomethylphenanthridine, 2-(1-aminoethyl)-3,4-dimethylpyridine, 2-(1-aminoethyl)-3,5-dimethylpyridine, 2-(1-aminoethyl)-3,6-dimethylpyridine, 2-(1-aminoethyl)-4,5-dimethylpyridine, 2-(1-aminoethyl)-4,6-dimethylpyridine, 2-(1-aminoethyl)-5,6-dimethylpyridine, 2-(1-aminoethyl)-3,4,5-trimethylpyridine, 2-(1-aminoethyl)-3,5,6-trimethylpyridine, 2-(1-aminoethyl)-4,5,6-trimethylpyridine, 2-(1-aminoethyl)-3,4,5,6-tetramethylpyridine, 2-(1-aminoethyl)-3,4-diethylpyridine, 2-(1-aminoethyl)-3,5-diethylpyridine, 2-(1-aminoethyl)-3,6-diethylpyridine, 2-(1-aminoethyl)-4,5-diethylpyridine, 2-(1-aminoethyl)-4,6-diethylpyridine, 2-(1-aminoethyl)-5,6-diethylpyridine, 2-(1-aminoethyl)-3,4-di-n-propylpyridine, 2-(1-aminoethyl)-3,5-di-n-propylpyridine, 2-(1-aminoethyl)-3,6-di-n-propylpyridine, 2-(1-aminoethyl)-4,5-di-n-propylpyridine, 2-(1-aminoethyl)-4,6-di-n-propylpyridine, 2-(1-aminoethyl)-5,6-di-n-propylpyridine, 2-(1-aminoethyl)-3,4-diisopropylpyridine, 2-(1-aminoethyl)-3,5-diisopropylpyridine, 2-(1-aminoethyl)-3,6-diisopropylpyridine, 2-(1-aminoethyl)-4,5-diisopropylpyridine, 2-(1-aminoethyl)-4,6 - Diisopropylpyridine, 2-(1 - aminoethyl)-5,6 - diisopropylpyridine, 2-(1 - aminoethyl)-3,4 - din - butylpyridine, 2-(1 - aminoethyl)-3,5 - din - butylpyridine, 2-(1 - aminoethyl)-3,6 - din - butylpyridine, 2-(1 - aminoethyl)-4,5 - din - butylpyridine, 2-(1 - aminoethyl)-4,6 - din - butylpyridine, 2-(1 - aminoethyl)-5,6 - din - butylpyridine, 2-(1 - aminoethyl)-3,4 - diisobutylpyridine, 2-(1 - aminoethyl)-3,5 - diisobutylpyridine, 2-(1 - aminoethyl)-3,6 - diisobutylpyridine, 2-(1 - aminoethyl)-4,5 - diisobutylpyridine, 2-(1 - aminoethyl)-4,6 - diisobutylpyridine, 2-(1 - aminoethyl)-5,6 - diisobutylpyridine, 2-(1 - aminoethyl)-3,4 - ditert - butylpyridine, 2-(1 - aminoethyl)-3,5 - ditert - butylpyridine, 2-(1 - aminoethyl)-3,6 - ditert - butylpyridine, 2-(1 - aminoethyl)-4,5 - ditert - butylpyridine, 2-(1 - aminoethyl)-4,6 - ditert - butylpyridine, 2-(1 - aminoethyl)-5,6 - ditert - butylpyridine, 2-(1 - aminoethyl)-3,4 - diphenylpyridine, 2-(1 - aminoethyl)-3,5 - diphenylpyridine, 2-(1 - aminoethyl)-3,6 - diphenylpyridine, 2-(1 - aminoethyl)-4,5 - diphenylpyridine, 2-(1 - aminoethyl)-4,6 - diphenylpyridine, 2-(1 - aminoethyl)-5,6 - diphenylpyridine, 2-(1 - aminoethyl)quinoline, 1-(1 - aminoethyl)isoquinoline, 3-(1 - aminoethyl)isoquinoline, 2-(1 - aminoethyl)pyrazine, 2-(1 - aminoethyl)pyrimidine or 6-(1 - aminoethyl)phenanthridine, the method according to any one of [1] to [6] above.,

Effect of the Invention

[0016] According to the present invention, a ruthenium complex catalyst having an optically active SKEWPHOS (2,4-bis(diphenylphosphino)pentane) derivative compound having asymmetry on carbon and a PICA type ligand, which is an easily synthesizable diphosphine compound, acts as a highly efficient hydrogenation catalyst. As a result, asymmetric hydrogenation does not proceed efficiently with the ruthenium complexes conventionally used, and the enantiomeric purity and diastereomeric purity are insufficient with expensive iridium complexes. The production of optically active β-amino alcohols having asymmetric points at the α and β positions of the hydroxyl group can be carried out with high enantiomeric purity and diastereomeric purity.

Mode for Carrying Out the Invention

[0017] Hereinafter, the present invention will be described in detail based on preferred embodiments. The present invention is a method for producing an optically active β-amino alcohol represented by the following general formula (5) by reacting a substrate carbonyl compound represented by the following general formula (4) with hydrogen or a compound that donates hydrogen in the presence of one or more ruthenium complexes selected from the compounds represented by the following general formula (1). First, the ruthenium complex used in this method will be described in detail, and then preferred embodiments of this method will be described in detail.

[0018] <Ruthenium Complex> The ruthenium complex used in the present invention has the general formula (1) RuXYAB (1) (wherein A is an optically active diphosphine compound A represented by the following general formula (2)

Chemical Formula

Chemical Formula

[0019] In the above general formula (1), the substituents X and Y are the same as or different from each other, and each represents a hydrogen atom or an anionic group. Examples of the anionic group include a halogen atom, a carboxyl group, a tetrahydroborate anion, and a substituted phenyl anion group. However, various other anionic groups may also be used. For example, an alkoxy group, a hydroxy group, etc. can also be used. X and Y are preferably a hydrogen atom, a halogen atom, a tetrahydroborate anion, a tolyl anion group, an acetoxy group, etc., more preferably a halogen atom or a tolyl anion group, and particularly preferably a chlorine atom or a bromine atom.

[0020] As described above, the optically active diphosphine compound A in the optically active ruthenium complex represented by the general formula (1) is represented by the following general formula (2).

Chemical formula

[0021] In the general formula (2), R 1 and R 2 are the same as or different from each other, and each represents a linear or cyclic hydrocarbon group having 1 to 20 carbon atoms which may have a substituent. R 3 and R 4 are the same as or different from each other, and each represents a hydrogen or a hydrocarbon group having 1 to 3 carbon atoms. R 5 , R 6 , R 7 and R 8 are the same as or different from each other, and each represents a hydrocarbon group which may have a substituent. * represents an asymmetric carbon atom. Here, R 1 and R 2 are not particularly limited. For example, they include a saturated or unsaturated linear aliphatic hydrocarbon group, a saturated or unsaturated monocyclic or polycyclic cyclic aliphatic hydrocarbon group, a monocyclic or polycyclic aromatic hydrocarbon group, and a group formed by combining these various hydrocarbon groups. These hydrocarbon groups may further have a substituent.

[0022] R 1 and R 2Examples include hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl such as phenyl and naphthyl, aralkyl such as phenylalkyl, and hydrocarbon groups having acceptable substituents such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group, cyano group, etc. further on these hydrocarbon groups. Among these, R 1 and R 2 are preferably a saturated chain aliphatic hydrocarbon group or a monocyclic aromatic hydrocarbon group, more preferably a methyl group, an ethyl group, a propyl group or a substituted or unsubstituted phenyl group, and particularly preferably a methyl group and a phenyl group.

[0023] R 3 and R 4 are a hydrogen atom or a hydrocarbon group having 1 to 3 carbon atoms, preferably an aliphatic saturated hydrocarbon group. Specifically, a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, etc. are preferable.

[0024] R 5 、R 6 、R 7 and R 8 are not particularly limited, but examples include saturated or unsaturated chain aliphatic hydrocarbon groups, saturated or unsaturated monocyclic or polycyclic cyclic aliphatic hydrocarbon groups, monocyclic or polycyclic aromatic hydrocarbon groups, and these hydrocarbon groups may further have substituents.

[0025] R 5 、R 6 、R 7 and R 8 Examples include hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl such as phenyl and naphthyl, aralkyl such as phenylalkyl, etc. and hydrocarbon groups having acceptable substituents such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, dialkylamino group, nitro group, cyano group, etc. further on these hydrocarbon groups.

[0026] Among these, R 5 、R 6 、R 7 and R 8 are preferably a substituted or unsubstituted monocyclic aromatic hydrocarbon group, more preferably a phenyl group and a substituted phenyl group, and particularly preferably a phenyl group and a substituted phenyl group having at least one substituent selected from a methyl group, an ethyl group, an isopropyl group, a propyl group and a tert-butyl group.

[0027] In addition, R 5 、R 6 、R 7 and R 8 The number of carbon atoms of is not particularly limited, but can be, for example, 1 to 20, preferably 5 to 10.

[0028] Examples of the optically active diphosphine represented by the general formula (2) include a pentane derivative having diphenylphosphino groups at the 2- and 4-positions, a pentane derivative having di-4-tolylphosphino groups at the 2- and 4-positions, a pentane derivative having di-4-t-butylphenylphosphino groups at the 2- and 4-positions, a pentane derivative having di-3,5-xylylphosphino groups at the 2- and 4-positions, a pentane derivative having di-3,5-diethylphenylphosphino groups at the 2- and 4-positions, a pentane derivative having di-3,5-diisopropylphenylphosphino groups at the 2- and 4-positions, a 1,3-diphenylpropane derivative having diphenylphosphino groups at the 1- and 3-positions, a 1,3-diphenylpropane derivative having di-4-tolylphosphino groups at the 1- and 3-positions, a 1,3-diphenylpropane derivative having di-4-t-butylphenylphosphino groups at the 1- and 3-positions, a 1,3-diphenylpropane derivative having di-3,5-xylylphosphino groups at the 1- and 3-positions, and a 1,3-diphenylpropane derivative having di-3,5-diethylphenylphosphino groups at the 1- and 3-positions.

[0029] More specifically, the optically active diphosphine compound A is SKEWPHOS: 2,4-bis-(diphenylphosphino)pentane, TolSKEWPHOS: 2,4-bis-(di-4-tolylphosphino)pentane, XylSKEWPHOS: 2,4-bis-(di-3,5-xylylphosphino)pentane, 4-t-BuSKEWPHOS: 2,4-bis-(di-4-tert-butylphenylphosphino)pentane, 4-i-PrSKEWPHOS: 2,4-bis-(di-4-isopropylphenylphosphino)pentane, 3,5-diEtSKEWPHOS: 2,4-bis-(di-3,5-diethylphenylphosphino)pentane, DIPSKEWPHOS: 2,4-bis-(di-3,5-diisopropylphenylphosphino)pentane, DTBSKEWPHOS: 2,4-bis-(di-3,5-ditert-butylphenylphosphino)pentane, 2,4-bis-(diphenylphosphino)-3-methylpentane, 2,4-bis-(di-4-tolylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-xylylphosphino)-3-methylpentane, 2,4-bis-(di-4-tert-butylphenylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-diethylphenylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-diisopropylphenylphosphino)-3-methylpentane, 1,3-bis-(diphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-4-tolylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-xylylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-4-tert-butylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-diethylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-diisopropylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(diphenylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-4-tolylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-3,5-xylylphosphino)-1,3-diphenyl-2-methylpropane, 1,It is 3-bis-(di-4-tert-butylphenylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-3,5-diethylphenylphosphino)-1,3-diphenyl-2-methylpropane or 1,3-bis-(di-3,5-diisopropylphenylphosphino)-1,3-diphenyl-2-methylpropane.,

[0030] The optically active diphosphine compound A is more preferably SKEWPHOS: 2,4-bis-(diphenylphosphino)pentane, TolSKEWPHOS: 2,4-bis-(di-4-tolylphosphino)pentane, XylSKEWPHOS: 2,4-bis-(di-3,5-xylylphosphino)pentane, 4-t-BuSKEWPHOS: 2,4-bis-(di-4-tert-butylphenylphosphino)pentane, 4-i-PrSKEWPHOS: 2,4-bis-(di-4-isopropylphenylphosphino)pentane, 3,5-diEtSKEWPHOS: 2,4-bis-(di-3,5-diethylphenylphosphino)pentane, DIPSKEWPHOS: 2,4-bis-(di-3,5-diisopropylphenylphosphino)pentane, DTBSKEWPHOS: 2,4-bis-(di-3,5-ditert-butylphenylphosphino)pentane or 2,4-bis-(diphenylphosphino)-3-methylpentane.,

[0031] Among these, SKEWPHOS, TolSKEWPHOS, 3,5-diEtSKEWPHOS, 4-t-BuSKEWPHOS, XylSKEWPHOS, DTBSKEWPHOS, and DIPSKEWPHOS are particularly preferred. However, of course, the optically active diphosphine compounds that can be used in the present invention are not limited to these at all.,

[0032] In addition, as the amine compound B in the optically active ruthenium complex represented by the general formula (1), the compound represented by the following formula (3) can be used.,

Chemical formula

[0033] In general formula (3), each D independently represents the same or different carbon atom or nitrogen atom, R 9 、R 10 and R 11 are the same as or different from each other, and each represents a hydrogen atom or a linear or cyclic hydrocarbon group having 1 to 20 carbon atoms which may have a substituent, and / or R 10 and R 11 may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent, each R 12 is the same as or different from each other, and each represents a linear or cyclic hydrocarbon group having 1 to 20 carbon atoms which may have a substituent, and / or two R 12 may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent, R 12 may be bonded to ruthenium as an anionic group X at least in part thereof, n is an integer of 0 to (4 - the number of D which is a nitrogen atom).

[0034] Here, as described above, each D in the formula independently represents the same or different nitrogen atom or carbon atom. All of the four Ds in the formula can be carbon atoms, and one or more of the four Ds can also be nitrogen atoms. The number of nitrogen atoms present in the ring formed including D can be, for example, 1 to 3, preferably 1 to 2. Therefore, in this case, among the four Ds in the formula, 0 to 2, preferably 0 or 1 D is a nitrogen atom, and the remaining Ds are carbon atoms. The ring formed including D is not particularly limited, and can be, for example, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a triazine ring or a tetrazine ring. Among them, the ring formed including D is preferably a pyridine ring, a pyrazine ring or a pyrimidine ring.

[0035] In the formula, R 9 ~R11 Although not particularly limited, examples thereof include a hydrogen atom, a saturated or unsaturated chain aliphatic hydrocarbon group, a saturated or unsaturated monocyclic or polycyclic cycloaliphatic hydrocarbon group, and a monocyclic or polycyclic aromatic hydrocarbon group, and these hydrocarbon groups may further have a substituent. R 9 ~R 11 Examples of R

[0036] to R 9 include a hydrogen atom, a hydrocarbon group such as an alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl (e.g., phenyl, naphthyl), aralkyl (e.g., phenylalkyl), and a hydrocarbon group having various acceptable substituents such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group, and cyano group on these hydrocarbon groups. The above R 10 and R 11 are preferably a hydrogen atom, an alkyl group, a phenyl group, and a phenylalkyl group, more preferably a hydrogen atom, a benzyl group, and particularly preferably a hydrogen atom. 10 and R 11 are preferably a hydrogen atom, an alkyl group, a phenyl group, a phenylalkyl group, etc., and particularly preferably all are hydrogen atoms, or one of R

[0037] and R 10 and R 11 is a methyl group. 10 and R 11 may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent. Examples of such a hydrocarbon ring include a cycloalkane ring, a cycloalkene ring, and a cycloalkyne ring having 3 to 10, preferably 4 to 8 ring members. More specifically, examples of the ring formed by R

[0038] Also, R 12 is not particularly limited, and examples thereof include saturated or unsaturated chain aliphatic hydrocarbon groups, saturated or unsaturated monocyclic or polycyclic cycloaliphatic hydrocarbon groups, and monocyclic or polycyclic aromatic hydrocarbon groups. These hydrocarbon groups may further have substituents. R 12 Examples of R include hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, such as phenyl and naphthyl, aralkyl, such as phenylalkyl, and hydrocarbon groups having various acceptable substituents such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group, and cyano group further on these hydrocarbon groups. The above R 12 is preferably an alkyl group or an aryl group, more preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a substituted or unsubstituted phenyl group, and particularly preferably a methyl group, a phenyl group, or an o-, m- or p-tolyl group.

[0039] Also, two Rs 12 may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent. The two Rs linked to each other 12 are preferably Rs substituted on adjacent Ds 12 (Rs in the ortho-position relationship 12 ) or Rs substituted on Ds sandwiching one D 12 (Rs in the meta-position relationship 12 ), and it is preferable that they are Rs substituted on adjacent Ds 12 . Such two Rs 12Examples of the ring formed by the groups include saturated or unsaturated hydrocarbon rings or heterocyclic rings having 3 to 10 ring members, preferably 4 to 8 ring members. More specifically, examples thereof include benzene ring, naphthalene ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, triazine ring, tetrazine ring, imidazoline ring, pyrrole ring, imidazole ring, pyrazole ring, and those substituted with substituents thereon. Among those described above, monocyclic hydrocarbon aromatic groups, particularly benzene ring, are preferred.

[0040] Two Rs 12 Examples of the ring formed by the ring formed by the groups and the ring containing D include quinoline ring, isoquinoline ring, purine ring, quinoxaline ring, quinazoline ring, cinnoline ring, phthalazine ring, phenanthridine ring. Among these, quinoline ring or isoquinoline ring is preferred.

[0041] Also, as described above, in the formula, n is an integer of 0 to (4 - the number of Ds which are nitrogen atoms). That is, when the number of Ds which are nitrogen atoms is 0, n is 0 to 4; when the number of Ds which are nitrogen atoms is 1, n is 0 to 3; when the number of Ds which are nitrogen atoms is 2, n is 0 to 2; when the number of Ds which are nitrogen atoms is 3, n is 0 to 1; when the number of Ds which are nitrogen atoms is 4, n is 0.

[0042] More specifically, the amine compound B is, for example, PICA: 2-picolylamine, (6-(p-tolyl)-2-pyridyl)methanamine, 1-(2-pyridyl)ethylamine, 2-(aminomethyl)-6-methylpyridine, 2-(aminomethyl)-3-methylpyridine, 2-(aminomethyl)-4-methylpyridine, 2-(aminomethyl)-5-methylpyridine, 2-(aminomethyl)-6-ethylpyridine, 2-(aminomethyl)-3-ethylpyridine, 2-(aminomethyl)-4-ethylpyridine, 2-(aminomethyl)-5-ethylpyridine, 2-(aminomethyl)-6-n-propylpyridine, 2-(aminomethyl)-3-n-propylpyridine, 2-(aminomethyl)-4-n-propylpyridine, 2-(aminomethyl)-5-n-propylpyridine, 2-(aminomethyl)-6-isopropylpyridine, 2-(aminomethyl)-3-isopropylpyridine, 2-(aminomethyl)-4-isopropylpyridine, 2-(aminomethyl)-5-isopropylpyridine, 2-(aminomethyl)-6-tert-butylpyridine, 2-(aminomethyl)-3-tert-butylpyridine, 2-(aminomethyl)-4-tert-butylpyridine, 2-(aminomethyl)-5-tert-butylpyridine, 2-(N-benzyl-aminomethyl)pyridine, 2-(aminomethyl)pyrrolidine, 2-(aminomethyl)-1-ethylpyrrolidine, 2-(pyrrolidinylmethyl)pyrrolidine, 2-(1-amino-1,1-diphenylmethyl)pyrrolidine, 2-(aminomethyl)-6-phenylpyridine, 2-(aminomethyl)-3-phenylpyridine, 2-(aminomethyl)-4-phenylpyridine, 2-(aminomethyl)-5-phenylpyridine, 3,4-DMPICA: 2-(aminomethyl)-3,4-dimethylpyridine, 3,5-DMPICA: 2-(aminomethyl)-3,5-dimethylpyridine, 2-(aminomethyl)-3,6-dimethylpyridine, 2-(aminomethyl)-4,5-dimethylpyridine, 2-(aminomethyl)-4,6-dimethylpyridine, 2-(aminomethyl)-5,6-dimethylpyridine, 2-(aminomethyl)-3,4,5-trimethylpyridine, 2-(aminomethyl)-3,5,6-trimethylpyridine, 2-(aminomethyl)-4,5,6-trimethylpyridine, 2-(aminomethyl)-3,4,5,6 - Tetramethylpyridine, 2-(aminomethyl)-3,4 - diethylpyridine, 2-(aminomethyl)-3,5 - diethylpyridine, 2-(aminomethyl)-3,6 - diethylpyridine, 2-(aminomethyl)-4,5 - diethylpyridine, 2-(aminomethyl)-4,6 - diethylpyridine, 2-(aminomethyl)-5,6 - diethylpyridine, 2-(aminomethyl)-3,4 - di-n-propylpyridine, 2-(aminomethyl)-3,5 - di-n-propylpyridine, 2-(aminomethyl)-3,6 - di-n-propylpyridine, 2-(aminomethyl)-4,5 - di-n-propylpyridine, 2-(aminomethyl)-4,6 - di-n-propylpyridine, 2-(aminomethyl)-5,6 - di-n-propylpyridine, 2-(aminomethyl)-3,4 - diisopropylpyridine, 2-(aminomethyl)-3,5 - diisopropylpyridine, 2-(aminomethyl)-3,6 - diisopropylpyridine, 2-(aminomethyl)-4,5 - diisopropylpyridine, 2-(aminomethyl)-4,6 - diisopropylpyridine, 2-(aminomethyl)-5,6 - diisopropylpyridine, 2-(aminomethyl)-3,4 - di-n-butylpyridine, 2-(aminomethyl)-3,5 - di-n-butylpyridine, 2-(aminomethyl)-3,6 - di-n-butylpyridine, 2-(aminomethyl)-4,5 - di-n-butylpyridine, 2-(aminomethyl)-4,6 - di-n-butylpyridine, 2-(aminomethyl)-5,6 - di-n-butylpyridine, 2-(aminomethyl)-3,4 - diisobutylpyridine, 2-(aminomethyl)-3,5 - diisobutylpyridine, 2-(aminomethyl)-3,6 - diisobutylpyridine, 2-(aminomethyl)-4,5 - diisobutylpyridine, 2-(aminomethyl)-4,6 - diisobutylpyridine, 2-(aminomethyl)-5,6 - diisobutylpyridine, 2-(aminomethyl)-3,4 - di-tert-butylpyridine, 2-(aminomethyl)-3,5 - di-tert-butylpyridine, 2-(aminomethyl)-3,6 - di-tert-butylpyridine, 2-(aminomethyl)-4,5 - di-tert-butylpyridine, 2-(aminomethyl)-4,6 - di-tert-butylpyridine, 2-(aminomethyl)-5,6 - di-tert-butylpyridine, 2-(aminomethyl)-3,4-Diphenylpyridine, 2-(aminomethyl)-3,5-diphenylpyridine, 2-(aminomethyl)-3,6-diphenylpyridine, 2-(aminomethyl)-4,5-diphenylpyridine, 2-(aminomethyl)-4,6-diphenylpyridine, 2-(aminomethyl)-5,6-diphenylpyridine, 2-(aminomethyl)-4-methoxy-3,5-dimethylpyridine, 2-AMQ: 2-(aminomethyl)quinoline, 1-AMIQ: 1-(aminomethyl)isoquinoline, 3-AMIQ: 3-(aminomethyl)isoquinoline, AMPZ: 2-(aminomethyl)pyrazine, 2-AMPR: 2-(aminomethyl)pyrimidine, 6-aminomethylphenanthridine, 2-(1-aminoethyl)-3,4-dimethylpyridine, 2-(1-aminoethyl)-3,5-dimethylpyridine, 2-(1-aminoethyl)-3,6-dimethylpyridine, 2-(1-aminoethyl)-4,5-dimethylpyridine, 2-(1-aminoethyl)-4,6-dimethylpyridine, 2-(1-aminoethyl)-5,6-dimethylpyridine, 2-(1-aminoethyl)-3,4,5-trimethylpyridine, 2-(1-aminoethyl)-3,5,6-trimethylpyridine, 2-(1-aminoethyl)-4,5,6-trimethylpyridine, 2-(1-aminoethyl)-3,4,5,6-tetramethylpyridine, 2-(1-aminoethyl)-3,4-diethylpyridine, 2-(1-aminoethyl)-3,5-diethylpyridine, 2-(1-aminoethyl)-3,6-diethylpyridine, 2-(1-aminoethyl)-4,5-diethylpyridine, 2-(1-aminoethyl)-4,6-diethylpyridine, 2-(1-aminoethyl)-5,6-diethylpyridine, 2-(1-aminoethyl)-3,4-di-n-propylpyridine, 2-(1-aminoethyl)-3,5-di-n-propylpyridine, 2-(1-aminoethyl)-3,6-di-n-propylpyridine, 2-(1-aminoethyl)-4,5-di-n-propylpyridine, 2-(1-aminoethyl)-4,6-di-n-propylpyridine, 2-(1-aminoethyl)-5,6-di-n-propylpyridine, 2-(1-aminoethyl)-3,4-diisopropylpyridine, 2-(1-aminoethyl)-3,5-diisopropylpyridine, 2-(1-aminoethyl)-3,6 - Diisopropylpyridine, 2-(1 - aminoethyl)-4,5 - diisopropylpyridine, 2-(1 - aminoethyl)-4,6 - diisopropylpyridine, 2-(1 - aminoethyl)-5,6 - diisopropylpyridine, 2-(1 - aminoethyl)-3,4 - din - butylpyridine, 2-(1 - aminoethyl)-3,5 - din - butylpyridine, 2-(1 - aminoethyl)-3,6 - din - butylpyridine, 2-(1 - aminoethyl)-4,5 - din - butylpyridine, 2-(1 - aminoethyl)-4,6 - din - butylpyridine, 2-(1 - aminoethyl)-5,6 - din - butylpyridine, 2-(1 - aminoethyl)-3,4 - diisobutylpyridine, 2-(1 - aminoethyl)-3,5 - diisobutylpyridine, 2-(1 - aminoethyl)-3,6 - diisobutylpyridine, 2-(1 - aminoethyl)-4,5 - diisobutylpyridine, 2-(1 - aminoethyl)-4,6 - diisobutylpyridine, 2-(1 - aminoethyl)-5,6 - diisobutylpyridine, 2-(1 - aminoethyl)-3,4 - di - tert - butylpyridine, 2-(1 - aminoethyl)-3,5 - di - tert - butylpyridine, 2-(1 - aminoethyl)-3,6 - di - tert - butylpyridine, 2-(1 - aminoethyl)-4,5 - di - tert - butylpyridine, 2-(1 - aminoethyl)-4,6 - di - tert - butylpyridine, 2-(1 - aminoethyl)-5,6 - di - tert - butylpyridine, 2-(1 - aminoethyl)-3,4 - diphenylpyridine, 2-(1 - aminoethyl)-3,5 - diphenylpyridine, 2-(1 - aminoethyl)-3,6 - diphenylpyridine, 2-(1 - aminoethyl)-4,5 - diphenylpyridine, 2-(1 - aminoethyl)-4,6 - diphenylpyridine, 2-(1 - aminoethyl)-5,6 - diphenylpyridine, 2-(1 - aminoethyl)quinoline, 1-(1 - aminoethyl)isoquinoline, 3-(1 - aminoethyl)isoquinoline, 2-(1 - aminoethyl)pyrazine, 2-(1 - aminoethyl)pyrimidine or 6-(1 - aminoethyl)phenanthridine is preferred. Among these, PICA, 2 - AMQ, 1 - AMIQ, 3 - AMIQ, 3,4 - DMPICA, 3,5 - DMPICA, AMPZ, 2 - AMPR are particularly preferred.,

[0043] The ruthenium complex represented by the general formula (1) described above has, as an amine ligand, an amine compound B represented by the general formula (3), which has a plurality of substituents on a nitrogen-containing ring or in which the nitrogen-containing ring is composed of a plurality of nitrogen atoms. When a substrate carbonyl compound is hydrogenated using a ruthenium complex having such an amine compound B and an optically active diphosphine compound A represented by the general formula (2), optically active β-aminoalcohols having asymmetric points at the α- and β-positions of the hydroxyl group can be obtained with much higher enantiomeric purity and diastereomeric purity as compared with the case of using a ruthenium complex having a conventionally known achiral ligand.

[0044] Incidentally, the ruthenium complex represented by the general formula (1) used in the present invention may be prepared in situ in the reaction system when the substrate carbonyl compound is reacted with hydrogen in the presence of a base. Although there is no limitation on the method, as an example, in the reaction system, a precursor represented by the following general formula (6) RuXYA (6) [In the general formula (6), X, Y and A each independently have the same meaning as defined in the general formula (1).] By allowing one or more complexes selected from the compounds represented by the formula and one or more amine compounds selected from the compounds represented by the general formula (3) to be present, the ruthenium complex represented by the general formula (1) can be prepared in situ.

[0045] The complex represented by the general formula (6) and the amine compound represented by the general formula (3) react with each other to form the catalyst precursor represented by the general formula (1). Therefore, the molar ratio of the complex represented by the general formula (6) to the amine compound represented by the general formula (3) is not particularly limited. However, when the amount of the amine compound represented by the general formula (3) is less than that of the complex represented by the general formula (6), the complex represented by the general formula (6) remains unchanged and does not convert into the catalyst precursor represented by the general formula (1), which is disadvantageous from the perspective of reaction economy. Thus, the complex represented by the general formula (6) and the amine compound represented by the general formula (3) are preferably charged into a container for reacting the substrate carbonyl compound with hydrogen and / or a hydrogen-donating compound at a molar ratio of 1:1 to 1:50, more preferably 1:1 to 1:20. Even when the amount of the amine compound represented by the general formula (3) is less than that of the complex represented by the general formula (6), it can be used without problems except that the reactivity decreases.

[0046] In addition, the ruthenium complexes represented by the general formulas (1) and (6) may contain one or more organic compounds that are reaction reagents used in their synthesis. Here, the organic compound refers to a coordinating organic solvent, for example, aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ether solvents such as ether and tetrahydrofuran, alcohol solvents such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, and benzyl alcohol, ketone solvents such as acetone, methyl ethyl ketone, and cyclohexyl ketone, and organic solvents containing heteroatoms such as acetonitrile, DMF, N-methylpyrrolidone, DMSO, and triethylamine.

[0047] The synthesis of the ruthenium complex represented by the general formula (1) can be carried out, for example, by reacting an optically active ruthenium complex represented by the general formula (6) with an amine compound or an optically active amine compound. The synthesis of the optically active ruthenium complex represented by the general formula (6) can be carried out by reacting an optically active diphosphine compound with a ruthenium complex as a raw material. The complex represented by the general formula (1) may be one prepared in advance as described above, or one prepared in the system of the hydrogenation reaction. As a method for preparing the ruthenium complex represented by the general formula (1), any method reported to date including the structure of the raw materials used can be used, and there is no particular limitation, but one of its embodiments is shown below.

[0048] As the ruthenium complex which is a starting material for complex synthesis, ruthenium complexes of zero valence, monovalent, divalent, trivalent and even higher valence can be used. When zero-valent and monovalent ruthenium complexes are used, oxidation of ruthenium is required until the final stage. When a divalent complex is used, it can be synthesized by reacting the ruthenium complex with an optically active diphosphine compound and an optically active diamine compound sequentially or in the reverse order, or simultaneously. When trivalent and tetravalent or higher ruthenium complexes are used as starting materials, reduction of ruthenium is required until the final stage.

[0049] As the ruthenium complex used as the starting material, inorganic ruthenium compounds such as ruthenium(III) chloride hydrate, ruthenium(III) bromide hydrate, ruthenium(III) iodide hydrate, [ruthenium(II) chloride(norbornadiene)] polynuclear complex, [ruthenium(II) chloride(cycloocta-1,5-diene)] polynuclear complex, ruthenium compounds coordinated with dienes such as bis(methylallyl)ruthenium(cycloocta-1,5-diene), [ruthenium(II) chloride(benzene)] polynuclear complex, [ruthenium(II) chloride(p-cymene)] polynuclear complex, [ruthenium(II) chloride(trimethylbenzene)] polynuclear complex, [ruthenium(II) chloride(hexamethylbenzene)] polynuclear complex, etc., ruthenium complexes coordinated with aromatic compounds, and complexes coordinated with phosphines such as dichlorotris(triphenylphosphine)ruthenium are used. In addition, as long as it is a ruthenium complex having a ligand that can be substituted with an optically active diphosphine compound or an optically active diamine compound, it is not particularly limited to the above. For example, various ruthenium complexes shown in COMPREHENSIVE ORGANOMETALLIC CHEMISTRY II, Volume 7, p294-296 (PERGAMON) can be used as the starting material.

[0050] When a trivalent ruthenium complex is used as the starting material, for example, a phosphine-ruthenium halide complex can be synthesized by reacting ruthenium(III) halide with an excess of phosphine. Then, the obtained phosphine-ruthenium halide complex can be reacted with an amine to obtain the target amine-phosphine-ruthenium halide complex represented by the general formula (1). For example, this synthesis is described in the literature [J.Mol.Cat., 15, 297 (1982)] and others. That is, RuCl2(PPh3)3 synthesized by the method described in Inorg, Synth., vol 12, 237(1970) etc. was reacted with ethylenediamine in benzene to obtain RuCl2(PPh3)2(en) (however, the yield is not described). However, in this method, the reaction is a heterogeneous system and unreacted raw materials tend to remain. On the other hand, when the reaction solvent is changed to a solvent such as methylene chloride or chloroform, the reaction can be carried out in a homogeneous state and the operability is improved.

[0051] The reaction between ruthenium halide and phosphine ligand is carried out in an aromatic hydrocarbon solvent such as toluene or xylene, an aliphatic hydrocarbon solvent such as pentane or hexane, a halogen-containing hydrocarbon solvent such as methylene chloride, an ether solvent such as ether or tetrahydrofuran, an alcohol solvent such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol or benzyl alcohol, or an organic solvent containing a heteroatom such as acetonitrile, DMF, N-methylpyrrolidone or DMSO at a reaction temperature between -100 °C and 200 °C to obtain a phosphine-ruthenium halide complex represented by the general formula (6).

[0052] The reaction between the obtained phosphine-ruthenium halide complex represented by the general formula (6) and the amine ligand represented by the general formula (3) is carried out in an aromatic hydrocarbon solvent such as toluene or xylene, an aliphatic hydrocarbon solvent such as pentane or hexane, a halogen-containing hydrocarbon solvent such as methylene chloride, an ether solvent such as ether or tetrahydrofuran, an alcohol solvent such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol or benzyl alcohol, or an organic solvent containing a heteroatom such as acetonitrile, DMF, N-methylpyrrolidone or DMSO at a reaction temperature between -100 °C and 200 °C to obtain an amine-phosphine-ruthenium halide complex represented by the general formula (1).

[0053] On the other hand, a method is also used in which a divalent ruthenium complex is initially used and reacted with a phosphine compound and an amine compound sequentially, in the reverse order, or simultaneously. As an example, ruthenium compounds coordinated with dienes such as [ruthenium dichloride (norbornadiene)] polynuclear complex, [ruthenium dichloride (cyclooct-1,5-diene)] polynuclear complex, bis(methylallyl)ruthenium(cyclooctadiene), or ruthenium complexes coordinated with aromatic compounds such as [ruthenium dichloride (benzene)] dinuclear complex, [ruthenium dichloride (p-cymene)] dinuclear complex, [ruthenium dichloride (trimethylbenzene)] dinuclear complex, [ruthenium dichloride (hexamethylbenzene)] dinuclear complex, and complexes coordinated with phosphine such as dichlorotris(triphenylphosphine)ruthenium are reacted with a phosphine compound in an aromatic hydrocarbon solvent such as toluene and xylene, an aliphatic hydrocarbon solvent such as pentane and hexane, a halogen-containing hydrocarbon solvent such as methylene chloride, an ether solvent such as ether and tetrahydrofuran, an alcohol solvent such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, benzyl alcohol, and an organic solvent containing a heteroatom such as acetonitrile, DMF, N-methylpyrrolidone, DMSO at a reaction temperature between -100°C and 200°C to obtain a phosphine-ruthenium-halide complex or a phosphine-ruthenium-methylallyl complex represented by the general formula (6). The phosphine-ruthenium-methylallyl complex can be reacted with hydrogen halide to obtain a phosphine-ruthenium-halide complex.

[0054] The reaction of the obtained phosphine-ruthenium halide complex represented by the general formula (6) with a diamine compound can react with an amine ligand in an aromatic hydrocarbon solvent such as toluene and xylene, an aliphatic hydrocarbon solvent such as pentane and hexane, a halogen-containing hydrocarbon solvent such as methylene chloride, an ether solvent such as ether and tetrahydrofuran, an alcohol solvent such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, and benzyl alcohol, and an organic solvent containing a heteroatom such as acetonitrile, DMF, N-methylpyrrolidone, and DMSO at a reaction temperature between -100°C and 200°C to obtain an amine-phosphine-ruthenium complex. Also, under the same conditions, a cationic ruthenium complex such as [chlororuthenium(BINAP)(benzene)] chloride can be reacted with an amine ligand to obtain an amine-phosphine-ruthenium halide complex represented by the general formula (1).

[0055] As a method for synthesizing a complex in which a cyclic hydrocarbon group bonded to the diamine compound represented by the general formula (3) is bonded to ruthenium as an anionic group X, it can be synthesized by the method described in literature [Organometallics, 29, 3563(2010)]. That is, similar to the above amine-phosphine-ruthenium halide complex synthesis method, after adding an amine ligand to the phosphine-ruthenium halide complex represented by the general formula (6) to synthesize an amine-phosphine-ruthenium halide complex, in an aromatic hydrocarbon solvent such as toluene and xylene, an aliphatic hydrocarbon solvent such as pentane and hexane, a halogen-containing hydrocarbon solvent such as methylene chloride, an ether solvent such as ether and tetrahydrofuran, an alcohol solvent such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, and benzyl alcohol, and an organic solvent containing a heteroatom such as acetonitrile, DMF, N-methylpyrrolidone, and DMSO, a base such as triethylamine is reacted at a temperature between -100°C and 200°C. Alternatively, it can be synthesized by reacting the phosphine-ruthenium halide complex represented by the general formula (6) with an amine ligand in the above solvent in the presence of a base such as triethylamine at a temperature between -100°C and 200°C.

[0056] In addition, the synthesized amine-phosphine-ruthenium halide complex represented by the general formula (1) may be a mixture of complexes with different coordination modes, but it can be directly used in the hydrogenation reaction without purification to obtain a complex with a single structure.

[0057] <Substrate carbonyl compound> The substrate carbonyl compound used in the present invention has the general formula (4)

[0058]

Chemical formula

[0059] In the above general formula (4), J represents an aromatic ring which may have a substituent. Examples of the aromatic ring include an aromatic hydrocarbon ring or an aromatic heterocyclic ring. The aromatic hydrocarbon ring is not particularly limited and can be monocyclic or polycyclic, and the number of ring members is not particularly limited, but 5 to 20 is preferable, and 5 to 15 is more preferable. Specific examples include, for example, a benzene ring, a naphthalene ring, an azulene ring, an acenaphthylene ring, an anthracene ring, a fluorene ring, a phenanthrene ring, a biphenylene ring, a pyrene ring, and a tetracene ring. Among these, a benzene ring and a naphthalene ring are preferable. The aromatic heterocyclic ring is not particularly limited. For example, a monocyclic or polycyclic heterocyclic ring having a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom is preferable. There is no particular limitation on the number of ring members, but 5 to 20 is preferable, and 5 to 15 is more preferable. Specific examples include, for example, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, triazine ring, tetrazine ring, imidazoline ring, pyrrole ring, imidazole ring, pyrazole ring, quinoline ring, isoquinoline ring, purine ring, quinoxaline ring, quinazoline ring, cinnoline ring, phthalazine ring, phenanthridine ring, furan ring, oxazole ring, isoxazole ring, thiophene ring, thiazole ring, isothiazole ring. Among these, pyridine ring, pyrazine ring, pyrimidine ring, furan ring, thiophene ring are preferable.

[0060] Examples of the substituent on the aromatic ring include alkyl, alkenyl, cycloalkyl, aryl, cycloalkylalkyl, cycloalkylalkyloxy, arylalkyl, arylalkyloxy, alkoxy, an ester group bonded to the C atom of an ester bond, a halogen atom, an amino group, an N-alkylamino group, an N,N-dialkylamino group, an amide group bonded to the C atom of an amide bond, a nitro group, and a cyano group.

[0061] In the general formula (4) above, K represents an amino group which may have a substituent, an amide group bonded to the N atom of an amide bond, a sulfonamide group bonded to the N atom of an amide bond, or an imide group bonded to the N atom of an imide bond.

[0062] Examples of the substituent which the amino group may have include a linear or branched alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. Further, the two substituents of the amino group may be bonded to each other to form a saturated or unsaturated heterocyclic ring which may have a substituent. Examples of such a heterocyclic ring include a morpholine ring, a piperidine ring, a piperazine ring, a pyridine ring, a pyrrole ring, and a pyrrolidine ring, each of which may have a substituent. Examples of the substituent that the heterocyclic ring may have include a linear or branched alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms.

[0063] The amide group bonded to the N atom of the amide bond means an amide group in which the N atom of the amide bond is bonded to the α-position of the carbonyl group in the general formula (4). Examples of the group bonded to the other (C atom) of the amide bond include an alkyl group, an alkoxy group, or an aromatic ring, each of which may have a substituent. Further, the N atom of the amide bond may further have a substituent such as those exemplified as the substituent that the amino group may have. Examples of the alkyl group or alkoxy group bonded to the other of the amide bond include a linear or branched alkyl group or alkoxy group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. Examples of the substituent that the alkyl group or alkoxy group may have include alkoxy, ester, halogen atom, amino group, amide group, nitro group, cyano group, N-acetamide group, and the aromatic hydrocarbon ring described above for J. Examples of the aromatic ring bonded to the other of the amide bond include the aromatic rings described above for J. Examples of the substituent that the aromatic ring may have include the same as those of the substituent on the aromatic ring described above for J.

[0064] The sulfonamide group bonded to the N atom of the amide bond means a sulfonamide group in which the N atom of the amide bond is bonded to the α-position of the carbonyl group in the general formula (4). Examples of the group bonded to the other (S atom) of the amide bond include an alkyl group, an alkoxy group, or an aromatic ring, each of which may have a substituent. Further, the N atom of the amide bond may further have a substituent such as those exemplified as the substituent that the amino group may have. Examples of the alkyl group or alkoxy group that binds to the other side of the amide bond include linear or branched alkyl groups or alkoxy groups having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. Examples of the substituent that the alkyl group or alkoxy group may have include alkoxy, ester, halogen atom, amino group, amide group, nitro group, cyano group, N - acetamide group, and the aromatic hydrocarbon ring described above for J. Examples of the aromatic ring that binds to the other side of the amide bond include the aromatic rings described above for J. Examples of the substituent that the aromatic ring may have include the same ones as the substituents on the aromatic ring described above for J.

[0065] The imide group bonded to the N atom of the imide bond means an imide group in which the N atom of the imide group is bonded to the α - position of the carbonyl group in the general formula (4). Examples of the group that binds to the other side (two C atoms) of the imide group include, independently of each other, an alkyl group or an aromatic ring, each of which may have a substituent, or a saturated or unsaturated hydrocarbon ring or heterocyclic ring that may have a substituent and is formed by linking two groups that bind to the other side of the imide group. Examples of the alkyl group that binds to the other side of the imide bond include linear or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. Examples of the substituent that the alkyl group may have include alkoxy, ester, halogen atom, amino group, amide group, nitro group, cyano group, N - acetamide group, and the aromatic hydrocarbon ring described above for J. Examples of the aromatic ring that binds to the other side of the imide bond include the aromatic rings described above for J. Examples of the substituent that the aromatic ring may have include the same ones as the substituents on the aromatic ring described above for J. Examples of the saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent and which is formed by the two groups bonded to the other side of the imide group being linked to each other include the aromatic rings described above for J. Examples of the substituent which the aromatic ring may have include the same substituents as those on the aromatic ring described above for J. As a result of the two groups bonded to the other side of the imide group being linked to each other, it is preferable that K forms a phthalimide group.

[0066] In the above general formula (4), L represents an alkyl group or an aryl group which may each have a substituent. Examples of the alkyl group include linear or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. Examples of the substituent which the alkyl group may have include alkoxy, ester, halogen atom, amino group, amide group, nitro group, cyano group, N - acetamide group, and the aromatic hydrocarbon rings described above for J. Examples of the aryl group include the aromatic hydrocarbon rings described above for J, and the preferable ranges are the same. Examples of the substituent which the aryl group may have include the same substituents as those on the aromatic ring described above for J.

[0067] The substrate carbonyl compound represented by the general formula (4) can be used alone or in combination of two or more. The substrate carbonyl compounds that can be used are not particularly limited as long as they satisfy the general formula (4). For example, amino groups protected with common protecting groups such as phthalimide group (Nphth group), tert-butoxycarbonylamino group (NHBoc group), benzyloxycarbonylamino group (NHCbz group), 9-fluorenylmethyloxycarbonylamino group (NHFmoc group), 2,2,2-trichloroethoxycarbonylamino group (NHTroc group), allyloxycarbonylamino group (NHAlloc group), acetylamino group (NHAc group), benzoylamino group (NHBz group), pivaloylamino group (NHPiv group), benzylamino group (NHBn group), etc. at the α-position of the carbonyl group, or propiophenone derivatives, butyrophenone derivatives, 1-phenylpentan-1-one derivatives, 1,2-diphenylethane-1-one derivatives, 1-pyridylpropane-1-one derivatives, 1-furylpropane-1-one derivatives, 1-thienylpropane-1-one derivatives, 1-naphthylpropane-1-one derivatives, etc. having any of alkylamino group, dialkylamino group, morpholino group, piperidine ring, piperazine ring, pyridine ring, pyrrole ring or pyrrolidine ring can be mentioned.

[0068] Specific examples of the particularly effective substrate carbonyl compounds include 2-phthalimidoylpropiophenone, 4'-benzyloxy-2-phthalimidoylpropiophenone, 2-phthalimidoyl-1-(p-tolyl)-propan-1-one, 2-phthalimidoylbutyrophenone, 2-phthalimidoyl-1-(m-chlorophenyl)-propan-1-one, 2-phthalimidoyl-1,2-diphenylethan-1-one, 2-phthalimidoyl-1-(3-pyridyl)-propan-1-one, 2-phthalimidoyl-1-(2-pyridyl)-propan-1-one, 2-phthalimidoyl-1-(4-pyridyl)-propan-1-one, 2-phthalimidoyl-1-(3-furyl)-propan-1-one, 2-phthalimidoyl-1-(2-furyl)-propan-1-one, 2-phthalimidoyl-1-(3-thienyl)-propan-1-one, 2-phthalimidoyl-1-(2-thienyl)-propan-1-one, N-(1-oxo-1-phenylpropan-2-yl)benzamide, N-(1-oxo-1-phenylbutan-2-yl)benzamide, N-(2-oxo-1,2-diphenylethyl)benzamide, N-(1-oxo-1-(pyridin-3-yl)propan-2-yl)benzamide, N-(1-oxo-1-(pyridin-4-yl)propan-2-yl)benzamide, N-(1-oxo-1-(pyridin-2-yl)propan-2-yl)benzamide, N-(1-(furan-3-yl)-1-oxopropan-2-yl)benzamide, N-(1-(furan-2-yl)-1-oxopropan-2-yl)benzamide, N-(1-(thiophen-3-yl)-1-oxopropan-2-yl)benzamide, N-(1-(thiophen-2-yl)-1-oxopropan-2-yl)benzamide, tert-butyl (1-oxo-1-phenylpropan-2-yl)carbamate, tert-butyl (1-oxo-1-phenylbutan-2-yl)carbamate, tert-butyl (2-oxo-1,(2-Diphenylethyl)carbamate, tert-butyl (1-oxo-1-(pyridin-3-yl)propan-2-yl)carbamate, tert-butyl (1-oxo-1-(pyridin-4-yl)propan-2-yl)carbamate, tert-butyl (1-oxo-1-(pyridin-2-yl)propan-2-yl)carbamate, tert-butyl (1-(furan-3-yl)-1-oxopropan-2-yl)carbamate, tert-butyl (1-(furan-2-yl)-1-oxopropan-2-yl)carbamate, tert-butyl (1-(thiophen-3-yl)-1-oxopropan-2-yl)carbamate, tert-butyl (1-(thiophen-2-yl)-1-oxopropan-2-yl)carbamate, 2-morpholinopropiophenone, 2-morpholinobutyrophenone, 2-morpholino-1,2-diphenylethan-1-one, 2-morpholino-1-(3-pyridyl)-propan-1-one, 2-morpholino-1-(2-pyridyl)-propan-1-one, 2-morpholino-1-(4-pyridyl)-propan-1-one, 2-morpholino-1-(3-furyl)-propan-1-one, 2-morpholino-1-(2-furyl)-propan-1-one, 2-morpholino-1-(3-thienyl)-propan-1-one, 2-morpholino-1-(2-thienyl)-propan-1-one may be mentioned. The substrate carbonyl compounds exemplified here may further have the substituents described above.,

[0069] <Process for producing optically active β-aminoalcohols having an asymmetric point at the α and β positions of the hydroxyl group> Next, a process for producing optically active β-aminoalcohols having an asymmetric point at the α and β positions of the hydroxyl group according to this embodiment will be described. The process for producing optically active β-aminoalcohols having an asymmetric point at the α and β positions of the hydroxyl group according to this embodiment is carried out in the presence of one or more ruthenium complexes represented by the above general formula (1), and the substrate carbonyl compound represented by the above general formula (4) is reacted with hydrogen and / or a compound that donates hydrogen to obtain the following general formula (5)

[0070]

Chemical formula

[0071] It is a method for producing optically active β - amino alcohols represented by the following.

[0072] In the above general formula (5), the definitions of J, K, and L are the same as the definitions of J, K, and L in general formula (4), respectively, and their preferred ranges are also the same.

[0073] The optically active β - amino alcohols represented by the above general formula (5) are particularly useful as optically active bioactive compounds used in pharmaceuticals, agricultural chemicals, etc., or as intermediates for liquid crystal material synthesis.

[0074] The ruthenium complex functions as a catalyst in this method. As the ruthenium complex, any one represented by the above - mentioned general formula (1) may be used. However, among the optically active diphosphine compounds represented by general formula (2) in the ruthenium complex represented by general formula (1), by selecting either the (R,R) form or the (S,S) form of these, optically active β - amino alcohols having asymmetric points at the α and β positions of the hydroxyl group can be differentiated with the desired absolute configuration.

[0075] Also, when the amine compound represented by general formula (3) in the ruthenium complex represented by general formula (1) is an optically active form, the combination of the absolute structure of the diphosphine compound in the optically active ruthenium complex represented by general formula (6) and the absolute structure of the added optically active amine compound is important for obtaining high optical purity. For example, depending on the structure of the substrate, the appropriate combination of the absolute structure of the diphosphine compound and the absolute structure of the amine compound is different. When a complex with an inappropriate combination is used, compared with the case of using a complex with an appropriate combination, the catalytic activity may decrease, or the enantiomeric purity or diastereomeric purity of the product may decrease.

[0076] The amount of the ruthenium complex represented by the general formula (1) varies depending on reaction conditions such as the reaction vessel used, the purity of hydrogen, the type and purity of the solvent used, or the purity of the substrate, or economic efficiency, but it can be used in a molar ratio of 1 / 100 to 1 / 10,000,000, preferably in a range of 1 / 500 to 1 / 1,000,000, relative to the substrate carbonyl compound.

[0077] As the hydrogen source used in this method, as described above, hydrogen (hydrogen gas) and / or a hydrogen-donating compound (hydrogen donor) can be used. Here, in this specification, the hydrogen donor refers to a compound having an action of supplying hydrogen in the molecule to the ruthenium catalyst. Such compounds are not particularly limited, but examples include lower alcohols such as 2-propanol, propanol, butanol, ethanol, methanol, formic acid, or formates such as potassium formate and sodium formate. Among those described above, it is preferable to use a lower alcohol as the hydrogen donor, and it is more preferable to use 2-propanol.

[0078] The dosage of the hydrogen donor is not particularly limited, but it can be used in a range of 1 to 20 equivalents, preferably in a range of 1 to 10 equivalents, relative to the substrate carbonyl compound.

[0079] Also, from the viewpoint of obtaining sufficient reactivity, it is preferable to use hydrogen gas as the hydrogen source. When using hydrogen gas, the pressure of the hydrogen gas is not particularly limited, but for example, it is in the range of 1 to 200 atmospheres, preferably in the range of 1 to 100 atmospheres, and particularly preferably in the range of 1 to 20 atmospheres. Note that hydrogen gas and the hydrogen donor may be used in combination.

[0080] Also, in the reaction, it is preferable to have a base present in the reaction system. Also, the base that can be used is not particularly limited, but examples include KOH, KOCH3, KOCH(CH3)2, KOC(CH3)3, KOC 10Examples of the salts of alkali metals, alkaline earth metals or quaternary ammonium salts include H8, KOC(CH3)2(CH2CH3), NaOC(CH3)3, NaOC(CH3)2(CH2CH3), LiOH, LiOCH3, LiOCH(CH3)2, LiOC(CH3)3, etc., and one or more of these can be used in combination. Among these, the base is preferably KOH, KOCH(CH3)2, KOC(CH3)3 or NaOC(CH3)3, and particularly preferably KOCH(CH3)2, KOC(CH3)3 or NaOC(CH3)3.

[0081] The amount of the base to be added is not particularly limited. For example, it is an amount such that the base concentration is 0.001 to 0.2 mol / L in the reaction system, preferably an amount such that it is 0.005 to 0.1 mol / L, and more preferably an amount such that it is 0.01 to 0.05 mol / L.

[0082] As described above, in order to produce optically active β-amino alcohols having an asymmetric point at the α and β positions of the hydroxyl group with high enantiomeric purity and high diastereomeric purity by a smooth asymmetric hydrogenation reaction, it is preferable to use a combination of the ruthenium complex represented by the general formula (1) used as a catalyst and a base.

[0083] However, when X and Y of the ruthenium complex represented by the general formula (1) are hydrogen atoms, or when X is a hydrogen atom and Y is a tetrahydroborate anion, a high asymmetric yield by a smooth asymmetric hydrogenation reaction of the substrate carbonyl compound can be achieved without adding a base. In such a case, for example, the reaction may be carried out by mixing the ruthenium complex and the substrate carbonyl compound without adding a base and then applying a hydrogen pressure and stirring.

[0084] A solvent may also be present in the reaction system. The solvent that can be used is not particularly limited, and those that can solubilize the substrate and the catalyst system are preferred. For example, lower alcohols such as methanol, ethanol, n-propanol, 2-propanol, butanol, tert-butyl alcohol, tert-amyl alcohol, benzyl alcohol, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ether solvents such as ether, methyl-tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, organic solvents containing heteroatoms such as acetonitrile, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), etc. can be mentioned, and one or a combination of two or more of these can be used.

[0085] The amount of the solvent is determined by the solubility of the reaction substrate and economic efficiency. For example, the substrate concentration can be as low as 0.1 mol / L or less in the reaction system depending on the substrate, and the reaction can be carried out in a state close to solvent-free, but it is preferably used in the range of 0.3 to 5 mol / L.

[0086] The upper limit of the reaction temperature should be set within the range where the decomposition of the ruthenium complex used as the catalyst does not occur, and the lower limit should be set considering the activity. For example, the reaction is preferably carried out at 0 to 60 °C, preferably 25 to 40 °C, and such a temperature range can be said to be excellent from the viewpoint of economic efficiency.

[0087] The reaction time varies depending on reaction conditions such as the reaction solvent, reaction substrate concentration, temperature, pressure, substrate / catalyst ratio, etc. Considering both the ease of reaction operation and economic efficiency, it can be arbitrarily set so that the reaction is completed in several minutes to several tens of hours, for example, 10 minutes to 96 hours, preferably 2 hours to 48 hours.

[0088] Even if the reaction operation is continued as it is after the reduction reaction of the carbonyl group of the substrate is completed, no particular problem is observed. Therefore, when implementing the present invention, it is not necessary to constantly monitor the progress of the reaction, nor is it necessary to immediately terminate the reaction after completion. That is, the reaction time can be set longer than the substantial reaction completion time, which is an advantageous method for industrial implementation. By hydrogenating the substrate carbonyl compound by the method described above, the corresponding optically active β-amino alcohols having asymmetric points at the α and β positions of the hydroxyl group can be obtained.

[0089] However, even by the method of the present invention, the hydrogenation reaction product may contain raw ketones, added bases, or salts formed by the reaction of the complex with the base. These can be purified by generally known purification operations such as distillation, washing with water, recrystallization, chromatography, etc.

[0090] Also, the reaction form of the above reaction is not particularly limited and can be carried out in any of a batch type, a continuous type, or a flow reactor.

[0091] According to the present invention as described above, an optically active SKEWPHOS (2,4-bis(diphenylphosphino)pentane) derivative compound, which is a diphosphine compound having asymmetry on a carbon that is easy to synthesize, and a ruthenium complex catalyst having a PICA-type ligand or a PICA-type ligand in which a pyridine ring is substituted with a heterocyclic ring having a plurality of nitrogen atoms act as a highly efficient hydrogenation catalyst. This complex can use an achiral amine that is easy to synthesize instead of the optically active amine conventionally used, so it is inexpensive. Such a feature can be said to be an industrially and economically excellent method compared to the conventional method. And the optically active β-amino alcohols having asymmetric points at the α and β positions of the hydroxyl group obtained by this method have higher enantiomeric purity and diastereomeric purity than those obtained by the conventional method.

[0092] In addition, the method for producing optically active secondary alcohols according to another embodiment of the present invention is represented by the following general formula (6). RuXYA (6) [In the general formula (6), X and Y are the same as or different from each other and each independently has the same meaning as defined in the general formula (1).] In the presence of one or more complexes selected from the compounds represented by the above general formula (6) and one or more amine compounds selected from the compounds represented by the above general formula (3), the substrate carbonyl compound represented by the above general formula (4) is reacted with hydrogen and / or a hydrogen-donating compound. This is the method.

[0093] The complex represented by the general formula (6) and the amine compound represented by the general formula (3) are preferably charged into a container for reacting the substrate carbonyl compound with hydrogen and / or a hydrogen-donating compound in a molar ratio of 1:1 to 1:50, more preferably in a molar ratio of 1:1 to 1:20.

[0094] In addition, as other conditions in this embodiment, the above-described conditions can be used. By the method of such an embodiment, similar effects can also be obtained.

[0095] The hydrogenation reaction of the substrate carbonyl compound in the present invention can be carried out in either a batch mode or a continuous mode in terms of the reaction format.

Examples

[0096] Hereinafter, examples will be shown and the present invention will be described in more detail. Of course, the present invention is not limited by the following examples. In the following examples, the solvents used in the reactions were reagent purchased products. In addition, NMR was measured using JNM-LA400 (400 MHz, manufactured by JEOL Ltd.). 1 For 1H-NMR, tetramethylsilane (TMS) was used as an internal standard substance, and its signal was set to δ = 0 (δ is the chemical shift). The hydrogenation reaction of α-aminocarbonyl compounds was carried out under pressurized hydrogen in an autoclave.

[0097] For the following measurements, the following equipment was used. NMR: LA400 type apparatus (400 MHz) (manufactured by JEOL Ltd.) 1 Internal standard substance for 1H-NMR: Tetramethylsilane Optical purity: High performance liquid chromatography CHIRALPAK AD-H (0.46 cm × 25 cm) (manufactured by Daicel Corporation) CHIRALCEL OJ-H (0.46 cm × 25 cm) (manufactured by Daicel Corporation) CHIRALPAK IC (0.46 cm × 25 cm) (manufactured by Daicel Corporation) CHIRALCEL OD-H (0.46 cm × 25 cm) (manufactured by Daicel Corporation)

[0098] In addition, in the examples, "ee" mentioned with respect to optical purity indicates the enantiomeric excess, and "de" mentioned with respect to the diastereomer ratio indicates the diastereomeric excess.

[0099] [Example 1] Production of (1R,2R)-2-phthalimido-1-(4'-benzyloxy-phenyl)-1-propanol [Chemical formula] RuBr2[(S,S)-xylskewphos](pica) (5.5 mg, 0.006 mmol), 4'-benzyloxy-2-phthalimidyloylpropiophenone (1.16 g, 3 mmol), and KOC(CH3)3 (50.5 mg, 0.45 mmol) were charged into a 100 mL glass autoclave. After purging with argon, methylene chloride (7.5 mL) and 2-propanol (7.5 mL) were added, and the mixture was purged with deaerated argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to atmospheric pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; methylene chloride:ethyl acetate = 20:1) to obtain 807.9 mg (yield 69%) of the product (1R,2R)-2-phthalimidyloyl-1-(4'-benzyloxy-phenyl)-1-propanol.

[0100] The diastereomer ratio was 1 determined from the chemical shift in the 1H-NMR spectrum (syn form: δ 1.39 ppm, anti form: δ 1.49 ppm), and the ratio of the syn form to the anti form was 98:2. HPLC analysis was performed, and the optical purity of the syn form was determined to be 99.4% ee using CHIRALPAK AD-H×2 (eluent; n-hexane:2-propanol = 80:20).

[0101] [Examples 2 to 4] The reaction was carried out according to the conditions of Example 1 except that the type of ruthenium complex (catalyst), the substrate-to-catalyst ratio, the amount of solvent, the amount of base, and the stirring time were changed. The results are shown in Table 1.

[0102]

Table 1

[0103]

Chemical formula

[0104] [Example 5] Production of (1R,2R)-2-phthalimido-1-phenyl-1-propanol RuBr2[(S,S)-dipskewphos](3-amiq) (2.39 mg, 0.002 mmol), 2-phthalimidoylpropiophenone (279.2 mg, 1 mmol), and KOC(CH3)3 (16.83 mg, 0.15 mmol) were charged into a 100 mL glass autoclave. After purging with argon, methylene chloride (2.5 ml) and 2-propanol (2.5 ml) were added, and the mixture was purged with deaerated argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to normal pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; methylene chloride:ethyl acetate = 20:1) to obtain 170.9 mg (yield 61%) of the product (1R,2R)-2-phthalimido-1-phenyl-1-propanol.

[0105] The diastereomer ratio was 1 determined from the chemical shift in the 1H-NMR spectrum (syn isomer: δ 1.41 ppm, anti isomer: δ 1.47 ppm), and the ratio of the syn isomer to the anti isomer was 97:3. HPLC analysis was performed, and the optical purity of the syn isomer was determined to be 99.7% ee using CHIRALCEL OJ-H (eluent; n-hexane:2-propanol = 80:20).

[0106] [Example 6] Production of (1R,2R)-2-phthalimido-1-(p-tolyl)-1-propanol RuBr2[(S,S)-xylskewphos](pica) (1.84 mg, 0.002 mmol), 2-phthalimidoyl-1-(p-tolyl)-propan-1-one (293.0 mg, 1 mmol), and KOC(CH3)3 (16.83 mg, 0.15 mmol) were charged into a 100 mL glass autoclave. After purging with argon, methylene chloride (2.5 ml) and 2-propanol (2.5 ml) were added, and the mixture was purged with degassed argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to normal pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; methylene chloride:ethyl acetate = 20:1) to obtain 217.1 mg (yield 74%) of the product (1R,2R)-2-phthalimidoyl-1-(p-tolyl)-1-propanol.

[0107] The diastereomer ratio was 1 determined from the chemical shift in the 1H-NMR spectrum (syn form: δ 1.38 ppm, anti form: δ 1.47 ppm), and the ratio of the syn form to the anti form was 98:2. HPLC analysis was performed, and the optical purity of the syn form was determined to be 99.4% ee using CHIRALPAK AD-H × 2 (eluent; n-hexane:2-propanol = 80:20).

[0108] [Example 7] Production of (1R,2R)-2-phthalimidoyl-1-(m-chlorophenyl)-1-propanol RuBr2[(S,S)-xylskewphos](pica) (1.84 mg, 0.002 mmol), 2-phthalimidoyl-1-(m-chlorophenyl)-propan-1-one (314.2 mg, 1 mmol), and KOC(CH3)3 (16.83 mg, 0.15 mmol) were charged into a 100 mL glass autoclave. After purging with argon, methylene chloride (2.5 ml) and 2-propanol (2.5 ml) were added, and the mixture was purged with degassed argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to normal pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; methylene chloride:ethyl acetate = 20:1) to obtain 230.8 mg (yield 73%) of the product (1R,2R)-2-phthalimidoyl-1-(m-chlorophenyl)-1-propanol.

[0109] The diastereomer ratio 1 could be determined from the chemical shift in the 1H-NMR spectrum (syn form: δ 1.44 ppm, anti form: δ 1.42 ppm), and the ratio of the syn form to the anti form was 98:2. HPLC analysis was performed, and the optical purity of the syn form was determined to be 99.6% ee using CHIRALCEL OJ-H (eluent; n-hexane:2-propanol = 80:20).

[0110] [Example 8] Preparation of (1R,2R)-2-phthalimidoyl-1-(3-pyridyl)-1-propanol RuBr2[(S,S)-dipskewphos](3-amiq) (2.39 mg, 0.002 mmol), 2-phthalimidoyl-1-(3-pyridyl)-propan-1-one (284.5 mg, 1 mmol), and KOC(CH3)3 (16.83 mg, 0.15 mmol) were charged into a 100 mL glass autoclave. After purging with argon, methylene chloride (2.5 ml) and 2-propanol (2.5 ml) were added, and the mixture was purged with degassed argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to atmospheric pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; methylene chloride:ethyl acetate = 1:1) to obtain 235.7 mg (yield 82%) of the product (1R,2R)-2-phthalimidoyl-1-(3-pyridyl)-1-propanol.

[0111] The formation of the anti-form could not be confirmed, and it was >99% de. HPLC analysis was performed, and the optical purity of the syn-form was determined using CHIRALCEL OD-H×2 (eluent; n-hexane:2-propanol = 80:20), and it was >99% ee.

[0112] [Example 9] Preparation of N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)benzamide RuBr2[(S,S)-dipskewphos](ampz) (2.29 mg, 0.002 mmol), N-(1-oxo-1-phenylpropan-2-yl)benzamide (253.9 mg, 1 mmol), and KOC(CH3)3 (16.83 mg, 0.15 mmol) were charged into a 100 mL glass autoclave. After purging with argon, 2-propanol (5.0 mL) was added, and the mixture was purged with deaerated argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to atmospheric pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 243.7 mg (yield 95%) of the product N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)benzamide.

[0113] The diastereomer ratio was 1 determined from the chemical shift in the 1H-NMR spectrum (syn form: δ 4.76 ppm, anti form: δ 4.99 ppm), and the ratio of the syn form to the anti form was 87:13. HPLC analysis was performed, and using CHIRALCEL OD-H×2 (eluent; n-hexane:2-propanol = 90:10), the optical purity of the syn form was determined to be 96.9% ee.

[0114] [Example 10] Production of N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)benzamide RuBr2[(S,S)-dtbskewphos](ampz) (20.08 mg, 0.016 mmol), N-(1-oxo-1-phenylpropan-2-yl)benzamide (1013.1 mg, 4 mmol), and KOC(CH3)3 (67.33 mg, 0.60 mmol) were charged into a 100 mL glass autoclave. After purging with argon, 2-propanol (20.0 mL) was added, and the mixture was purged with degassed argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to atmospheric pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 1015.1 mg (yield 99%) of the product N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)benzamide.

[0115] The diastereomer ratio was 1 determined from the chemical shifts in the 1H-NMR spectrum (syn isomer: δ 4.76 ppm, anti isomer: δ 4.99 ppm), and the ratio of the syn isomer to the anti isomer was 98:2. HPLC analysis was performed, and the optical purity of the syn isomer was determined to be 97.6% ee using CHIRALCEL OD-H×2 (eluent; n-hexane:2-propanol = 90:10).

[0116] [Example 11] Preparation of tert-butyl ((1R,2R)-1-(4-(benzyloxy)phenyl)-1-hydroxypropan-2-yl)carbamate RuBr2[(S,S)-dipskewphos](3-amiq) (2.39 mg, 0.002 mmol), tert-butyl (1-(4-(benzyloxy)phenyl)-1-oxopropan-2-yl)carbamate (354.5 mg, 1 mmol), and KOC(CH3)3 (16.83 mg, 0.15 mmol) were charged into a 100 mL glass autoclave. After purging with argon, 2-propanol (5.0 ml) was added and the mixture was purged with degassed argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to atmospheric pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 2:1) to obtain 284.2 mg (yield 80%) of the product tert-butyl ((1R,2R)-1-(4-(benzyloxy)phenyl)-1-hydroxypropan-2-yl)carbamate.

[0117] The diastereomer ratio was 1 determined from the chemical shifts in the 1H-NMR spectrum (syn isomer: δ 4.50 ppm, anti isomer: δ 4.79 ppm), and the ratio of the syn isomer to the anti isomer was 85:15. HPLC analysis was performed, and using CHIRALCEL OJ-H×2 (eluent; n-hexane:2-propanol = 90:10), the optical purity of the syn isomer was determined to be 96.7% ee.

[0118] [Example 12] Preparation of (1R,2R)-2-morpholino-1-phenyl-1-propanol RuBr2[(S,S)-dipskewphos](3-amiq) (2.39 mg, 0.002 mmol), 2-morpholino-1-phenyl-propan-1-one (218.8 mg, 1 mmol), and KOC(CH3)3 (16.83 mg, 0.15 mmol) were charged into a 100 mL glass autoclave. After purging with argon, 2-propanol (5.0 mL) was added, and the mixture was purged with degassed argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to atmospheric pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 213.9 mg (yield 97%) of the product (1R,2R)-2-morpholino-1-phenyl-1-propanol.

[0119] The diastereomer ratio was 1 determined from the chemical shift in the 1H-NMR spectrum (syn form: δ 0.79 ppm, anti form: δ 0.83 ppm), and the ratio of the syn form to the anti form was 96:4. HPLC analysis was performed, and using CHIRALCEL OJ-H (eluent; n-hexane:2-propanol = 80:20), the optical purity of the syn form was determined to be 98.8% ee.

[0120] [Example 13] Preparation of (1R,2R)-2-phthalimido-1-phenyl-1-butanol RuBr2[(S,S)-dipskewphos](3-amiq) (2.39 mg, 0.002 mmol), 2-phthalimidoylbutyrophenone (293.1 mg, 1 mmol), and KOC(CH3)3 (16.83 mg, 0.15 mmol) were charged into a 100 mL glass autoclave. After purging with argon, methylene chloride (2.5 mL) and 2-propanol (2.5 mL) were added, and the mixture was purged with degassed argon. Hydrogen was charged to 0.8 MPa at 30 °C to initiate the reaction. The reaction solution was stirred for 2 hours. The reaction pressure was returned to normal pressure, saturated brine was added to the reaction solution, and then the reaction solution was extracted with methylene chloride. This methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and then purified by silica gel column chromatography (eluent; hexane:ethyl acetate = 1:1) to obtain 242.9 mg (yield 82%) of the product (1R,2R)-2-phthalimidoyl-1-phenyl-1-butanol.

[0121] The diastereomer ratio 1 could be determined from the chemical shift in the 1H-NMR spectrum (syn form: δ 0.89 ppm, anti form: δ 0.81 ppm). The formation of the anti form could not be confirmed, and it was >99% de. HPLC analysis was performed, and the optical purity of the syn form was determined to be 99.5% ee using CHIRALPAK IC (eluent; n-hexane:2-propanol = 80:20).

[0122] [Comparative Example 1] RuCl2[(R)-binap][(R)-daipen] (2.2 mg, 0.002 mmol), 4'-benzyloxy-2-phthalimidoylpropiophenone (0.39 g, 1 mmol), KOC(CH3)3 (56.1 mg, 0.5 mmol), methylene chloride (2.5 mL), 2-propanol (2.5 mL), and the stirring time was set to 19 hours. The reaction was carried out according to the conditions of Example 1, but the target product could not be obtained. Thus, it was confirmed that when a ruthenium complex having (R)-daipen as the diamine and (R)-binap as the diphosphine was used as the catalyst, the hydrogenation reaction did not proceed.

[0123] [Comparative Example 2] RuCl2[(R)-binap][(R,R)-dpen] (6.0 mg, 0.006 mmol), 4'-benzyloxy-2-phthalimidoylpropiophenone (1.16 g, 3 mmol), KOC(CH3)3 (50.5 mg, 0.45 mmol), methylene chloride (7.5 ml), 2-propanol (7.5 ml), and the reaction was carried out according to the conditions of Example 1 except that the stirring time was 16 hours. The yield was 459.8 mg (yield 40%), and the ratio of the syn form to the anti form was 90:10. When the optical purity of the syn form was determined, it was 69.6% ee. Thus, it was confirmed that when a ruthenium complex having (R,R)-DPEN as a diamine and (R)-BINAP as a diphosphine was used as a catalyst, the reactivity, diastereomer purity, and enantiomer purity decreased.

[0124] [Comparative Example 3] RuBr2[(S,S)-xylskewphos][(S,S)-dpen] (6.2 mg, 0.006 mmol), 4'-benzyloxy-2-phthalimidoylpropiophenone (1.16 g, 3 mmol), KOC(CH3)3 (50.5 mg, 0.45 mmol), methylene chloride (7.5 ml), 2-propanol (7.5 ml), and the reaction was carried out according to the conditions of Example 1 except that the stirring time was 16 hours. The yield was 710.9 mg (yield 61%), and the ratio of the syn form to the anti form was 92:8. When the optical purity of the syn form was determined, it was 75.1% ee. Thus, it was also confirmed that when a ruthenium complex having (S,S)-DPEN as a diamine and (S,S)-XylSKEWPHOS as a diphosphine was used as a catalyst, the reactivity, diastereomer purity, and enantiomer purity decreased.

[0125] [Comparative Example 4] RuCl2[(S)-tolbinap](pica) (2.2 mg, 0.002 mmol), 4'-benzyloxy-2-phthalimidoylpropiophenone (0.39 g, 1 mmol), KOC(CH3)3 (28.1 mg, 0.25 mmol), methylene chloride (2.5 ml), 2-propanol (2.5 ml), the reaction was carried out according to the conditions of Example 1 except that the stirring time was 19 hours. The yield was 34.5 mg (yield 9%), and the ratio of syn form to anti form was 86:14. When the optical purity of the syn form was determined, it was 84.6% ee. Thus, even when a ruthenium complex having PICA as a diamine and (S)-TolBINAP as a diphosphine is used as a catalyst, it was confirmed that the reactivity, diastereomer purity, and enantiomer purity decrease.

[0126] The results of Comparative Examples 1 to 4 are summarized in Table 2 below.

[0127]

Table 2

[0128]

Chemical formula

[0129]

Chemical formula

Claims

1. A method for producing optically active β - amino alcohols, comprising reacting a substrate carbonyl compound represented by the following general formula (4) with hydrogen in the presence of one or more ruthenium complexes selected from compounds represented by the following general formula (1): RuXYAB (1) [(In general formula (1), X and Y are the same as or different from each other and represent a hydrogen atom or an anionic group, A represents an optically active diphosphine represented by the following general formula (2): 【Chemical 1】 (In general formula (2), R １ and R ２ are the same as or different from each other and each represents a linear or cyclic hydrocarbon group having 1 to 20 carbon atoms which may have a substituent, R ３ and R ４ are the same as or different from each other and represent a hydrogen atom or a hydrocarbon group having 1 to 3 carbon atoms, R ５ 、 R ６ 、 R ７ and R ８ are the same as or different from each other and represent a hydrocarbon group which may have a substituent, and * represents an asymmetric carbon atom.) represents an optically active diphosphine.) B represents an amine compound represented by the following general formula (3): 【Chemical 2】 (In general formula (3), each D independently represents the same or different carbon atom or nitrogen atom, R ９ , R １０ and R １１ are the same as or different from each other and each represents a linear or cyclic hydrocarbon group having 1 to 20 carbon atoms which may have a hydrogen atom or a substituent, and / or R １０ and R １１ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent, Each R １２ is the same as or different from each other, and represents a linear or cyclic hydrocarbon group having 1 to 20 carbon atoms which may have a substituent, and / or two Rs １２ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent, and R １２ may be bonded to ruthenium as an anionic group X at least in part, n is an integer from 0 to (4 - the number of D's that are nitrogen atoms).)] (In the formula, J is an aromatic ring which may have a substituent, K is an amino group which may have a substituent, an amide group bonded to the N atom of an amide bond, a sulfonamide group bonded to the N atom of an amide bond, or an imide group bonded to the N atom of an imide bond, and L is an alkyl group or an aryl group which may each have a substituent.) to produce an optically active β - amino alcohol represented by the following general formula (5): [Chemical Formula 3] (In the formula, J, K and L have the same meanings as described above, and * indicates the position of the asymmetric carbon) 【Chemical Formula 4】 The above - mentioned method for producing an optically active β - amino alcohol.

2. In the reaction system, one or more complexes selected from compounds represented by the following general formula (6): RuXYA (6) (In general formula (6), X, Y and A independently have the same meanings as defined in general formula (1).) and one or more amine compounds selected from compounds represented by the above - mentioned general formula (3) are present, whereby the ruthenium complex represented by general formula (1) is prepared in situ. The method according to claim 1.

3.

4. Two Rs １２ are connected to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent, and the ring formed by the two Rs １２ and the ring formed by the ring containing D form a quinoline ring or an isoquinoline ring. The method according to claim 1 or 2 In general formula (3), one or more of the four D's are nitrogen atoms. The method according to any one of claims 1 to 3.

5.

6. A is 2,4-bis-(diphenylphosphino)pentane, 2,4-bis-(di-4-tolylphosphino)pentane, 2,4-bis-(di-3,5-xylylphosphino)pentane, 2,4-bis-(di-4-tert-butylphenylphosphino)pentane, 2,4-bis-(di-4-isopropylphenylphosphino)pentane, 2,4-bis-(di-3,5-diethylphenylphosphino)pentane, 2,4-bis-(di-3,5-diisopropylphenylphosphino)pentane, 2,4-bis-(di-3,5-ditert-butylphenylphosphino)pentane, 2,4-bis-(diphenylphosphino)-3-methylpentane, 2,4-bis-(di-4-tolylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-xylylphosphino)-3-methylpentane, 2,4-bis-(di-4-tert-butylphenylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-diethylphenylphosphino)-3-methylpentane, 2,4-bis-(di-3,5-diisopropylphenylphosphino)-3-methylpentane, 1,3-bis-(diphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-4-tolylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-xylylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-4-tert-butylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-diethylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(di-3,5-diisopropylphenylphosphino)-1,3-diphenylpropane, 1,3-bis-(diphenylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-4-tolylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-3,5-xylylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-4-tert-butylphenylphosphino)-1,3-diphenyl-2-methylpropane, 1,3-bis-(di-3,5-diethylphenylphosphino)-1,3-diphenyl-2-methylpropane or 1,3-bis-(di-3,5-diisopropylphenylphosphino)-1,The method according to any one of claims 1 to 4, which is 3-diphenyl-2-methylpropane. ​ The method according to any one of claims 1 to 5, wherein A is 2,4-bis-(diphenylphosphino)pentane, 2,4-bis-(di-4-tolylphosphino)pentane, 2,4-bis-(di-3,5-xylylphosphino)pentane, 2,4-bis-(di-4-tert-butylphenylphosphino)pentane, 2,4-bis-(di-4-isopropylphenylphosphino)pentane, 2,4-bis-(di-3,5-diethylphenylphosphino)pentane, 2,4-bis-(di-3,5-diisopropylphenylphosphino)pentane, 2,4-bis-(di-3,5-di-tert-butylphenylphosphino)pentane, or 2,4-bis-(diphenylphosphino)-3-methylpentane.

7. B is 2-picolylamine, (6-(p-tolyl)-2-pyridyl)methanamine, 1-(2-pyridyl)ethylamine, 2-(aminomethyl)-6-methylpyridine, 2-(aminomethyl)-3-methylpyridine, 2-(aminomethyl)-4-methylpyridine, 2-(aminomethyl)-5-methylpyridine, 2-(aminomethyl)-6-ethylpyridine, 2-(aminomethyl)-3-ethylpyridine, 2-(aminomethyl)-4-ethylpyridine, 2-(aminomethyl)-5-ethylpyridine, 2-(aminomethyl)-6-n-propylpyridine, 2-(aminomethyl)-3-n-propylpyridine, 2-(aminomethyl)-4-n-propylpyridine, 2-(aminomethyl)-5-n-propylpyridine, 2-(aminomethyl)-6-isopropylpyridine, 2-(aminomethyl)-3-isopropylpyridine, 2-(aminomethyl)-4-isopropylpyridine, 2-(aminomethyl)-5-isopropylpyridine, 2-(aminomethyl)-6-tert-butylpyridine, 2-(aminomethyl)-3-tert-butylpyridine, 2-(aminomethyl)-4-tert-butylpyridine, 2-(aminomethyl)-5-tert-butylpyridine, 2-(N-benzyl-aminomethyl)pyridine, 2-(aminomethyl)pyrrolidine, 2-(aminomethyl)-1-ethylpyrrolidine, 2-(pyrrolidinylmethyl)pyrrolidine, 2-(1-amino-1,1-diphenylmethyl)pyrrolidine, 2-(aminomethyl)-6-phenylpyridine, 2-(aminomethyl)-3-phenylpyridine, 2-(aminomethyl)-4-phenylpyridine, 2-(aminomethyl)-5-phenylpyridine, 2-(aminomethyl)-3,4-dimethylpyridine, 2-(aminomethyl)-3,5-dimethylpyridine, 2-(aminomethyl)-3,6-dimethylpyridine, 2-(aminomethyl)-4,5-dimethylpyridine, 2-(aminomethyl)-4,6-dimethylpyridine, 2-(aminomethyl)-5,6-dimethylpyridine, 2-(aminomethyl)-3,4,5-trimethylpyridine, 2-(aminomethyl)-3,5,6-trimethylpyridine, 2-(aminomethyl)-4,5,6-trimethylpyridine, 2-(aminomethyl)-3,4,5,6-tetramethylpyridine, 2-(aminomethyl)-3,4-Diethylpyridine, 2-(aminomethyl)-3,5-diethylpyridine, 2-(aminomethyl)-3,6-diethylpyridine, 2-(aminomethyl)-4,5-diethylpyridine, 2-(aminomethyl)-4,6-diethylpyridine, 2-(aminomethyl)-5,6-diethylpyridine, 2-(aminomethyl)-3,4-di-n-propylpyridine, 2-(aminomethyl)-3,5-di-n-propylpyridine, 2-(aminomethyl)-3,6-di-n-propylpyridine, 2-(aminomethyl)-4,5-di-n-propylpyridine, 2-(aminomethyl)-4,6-di-n-propylpyridine, 2-(aminomethyl)-5,6-di-n-propylpyridine, 2-(aminomethyl)-3,4-diisopropylpyridine, 2-(aminomethyl)-3,5-diisopropylpyridine, 2-(aminomethyl)-3,6-diisopropylpyridine, 2-(aminomethyl)-4,5-diisopropylpyridine, 2-(aminomethyl)-4,6-diisopropylpyridine, 2-(aminomethyl)-5,6-diisopropylpyridine, 2-(aminomethyl)-3,4-di-n-butylpyridine, 2-(aminomethyl)-3,5-di-n-butylpyridine, 2-(aminomethyl)-3,6-di-n-butylpyridine, 2-(aminomethyl)-4,5-di-n-butylpyridine, 2-(aminomethyl)-4,6-di-n-butylpyridine, 2-(aminomethyl)-5,6-di-n-butylpyridine, 2-(aminomethyl)-3,4-diisobutylpyridine, 2-(aminomethyl)-3,5-diisobutylpyridine, 2-(aminomethyl)-3,6-diisobutylpyridine, 2-(aminomethyl)-4,5-diisobutylpyridine, 2-(aminomethyl)-4,6-diisobutylpyridine, 2-(aminomethyl)-5,6-diisobutylpyridine, 2-(aminomethyl)-3,4-di-tert-butylpyridine, 2-(aminomethyl)-3,5-di-tert-butylpyridine, 2-(aminomethyl)-3,6-di-tert-butylpyridine, 2-(aminomethyl)-4,5-di-tert-butylpyridine, 2-(aminomethyl)-4,6-di-tert-butylpyridine, 2-(aminomethyl)-5,6-di-tert-butylpyridine, 2-(aminomethyl)-3,4-diphenylpyridine, 2-(aminomethyl)-3,5-Diphenylpyridine, 2-(aminomethyl)-3,6-diphenylpyridine, 2-(aminomethyl)-4,5-diphenylpyridine, 2-(aminomethyl)-4,6-diphenylpyridine, 2-(aminomethyl)-5,6-diphenylpyridine, 2-(aminomethyl)-4-methoxy-3,5-dimethylpyridine, 2-(aminomethyl)quinoline, 1-(aminomethyl)isoquinoline, 3-(aminomethyl)isoquinoline, 2-(aminomethyl)pyrazine, 2-(aminomethyl)pyrimidine, 6-aminomethylphenanthridine, 2-(1-aminoethyl)-3,4-dimethylpyridine, 2-(1-aminoethyl)-3,5-dimethylpyridine, 2-(1-aminoethyl)-3,6-dimethylpyridine, 2-(1-aminoethyl)-4,5-dimethylpyridine, 2-(1-aminoethyl)-4,6-dimethylpyridine, 2-(1-aminoethyl)-5,6-dimethylpyridine, 2-(1-aminoethyl)-3,4,5-trimethylpyridine, 2-(1-aminoethyl)-3,5,6-trimethylpyridine, 2-(1-aminoethyl)-4,5,6-trimethylpyridine, 2-(1-aminoethyl)-3,4,5,6-tetramethylpyridine, 2-(1-aminoethyl)-3,4-diethylpyridine, 2-(1-aminoethyl)-3,5-diethylpyridine, 2-(1-aminoethyl)-3,6-diethylpyridine, 2-(1-aminoethyl)-4,5-diethylpyridine, 2-(1-aminoethyl)-4,6-diethylpyridine, 2-(1-aminoethyl)-5,6-diethylpyridine, 2-(1-aminoethyl)-3,4-di-n-propylpyridine, 2-(1-aminoethyl)-3,5-di-n-propylpyridine, 2-(1-aminoethyl)-3,6-di-n-propylpyridine, 2-(1-aminoethyl)-4,5-di-n-propylpyridine, 2-(1-aminoethyl)-4,6-di-n-propylpyridine, 2-(1-aminoethyl)-5,6-di-n-propylpyridine, 2-(1-aminoethyl)-3,4-diisopropylpyridine, 2-(1-aminoethyl)-3,5-diisopropylpyridine, 2-(1-aminoethyl)-3,6-diisopropylpyridine, 2-(1-aminoethyl)-4,5-diisopropylpyridine, 2-(1-aminoethyl)-4,6 - Diisopropylpyridine, 2-(1-aminoethyl)-5,6-diisopropylpyridine, 2-(1-aminoethyl)-3,4-di-n-butylpyridine, 2-(1-aminoethyl)-3,5-di-n-butylpyridine, 2-(1-aminoethyl)-3,6-di-n-butylpyridine, 2-(1-aminoethyl)-4,5-di-n-butylpyridine, 2-(1-aminoethyl)-4,6-di-n-butylpyridine, 2-(1-aminoethyl)-5,6-di-n-butylpyridine, 2-(1-aminoethyl)-3,4-diisobutylpyridine, 2-(1-aminoethyl)-3,5-diisobutylpyridine, 2-(1-aminoethyl)-3,6-diisobutylpyridine, 2-(1-aminoethyl)-4,5-diisobutylpyridine, 2-(1-aminoethyl)-4,6-diisobutylpyridine, 2-(1-aminoethyl)-5,6-diisobutylpyridine, 2-(1-aminoethyl)-3,4-di-tert-butylpyridine, 2-(1-aminoethyl)-3,5-di-tert-butylpyridine, 2-(1-aminoethyl)-3,6-di-tert-butylpyridine, 2-(1-aminoethyl)-4,5-di-tert-butylpyridine, 2-(1-aminoethyl)-4,6-di-tert-butylpyridine, 2-(1-aminoethyl)-5,6-di-tert-butylpyridine, 2-(1-aminoethyl)-3,4-diphenylpyridine, 2-(1-aminoethyl)-3,5-diphenylpyridine, 2-(1-aminoethyl)-3,6-diphenylpyridine, 2-(1-aminoethyl)-4,5-diphenylpyridine, 2-(1-aminoethyl)-4,6-diphenylpyridine, 2-(1-aminoethyl)-5,6-diphenylpyridine, 2-(1-aminoethyl)quinoline, 1-(1-aminoethyl)isoquinoline, 3-(1-aminoethyl)isoquinoline, 2-(1-aminoethyl)pyrazine, 2-(1-aminoethyl)pyrimidine or 6-(1-aminoethyl)phenanthridine, the method according to any one of claims 1 to 6.,

Images