Method for producing optically active hydroxy esters or hydroxy amides

Abstract

To provide a method of hydrogenating a substrate carbonyl compound at high efficiency to produce an optically active hydroxyester or hydroxyamide having an asymmetric point at the α, β position of a hydroxy group with high enantiomeric purity and diastereomeric purity.SOLUTION: A method comprises reacting a substrate carbonyl compound with hydrogen and / or a hydrogen-donating compound in the presence of a ruthenium compound represented by general formula: RuXYAB, where X and Y are identical to or different from each other and each represent a hydrogen atom or anionic group; A represents a specific optically active diphosphine; and B also represents a specific compound.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a process for producing optically active hydroxyesters or hydroxyamides. [Background technology]

[0002] As an efficient method for producing optically active β-hydroxyesters or hydroxyamides having asymmetry at both carbon atoms substituted with a hydroxyl group and an ester group or an amide group, a method is known in which racemic β-ketoesters or β-ketoamides are diastereoselectively and enantioselectively hydrogenated or reduced in the presence of an asymmetric catalyst. For example, a method is known in which a ruthenium complex having an optically active diphosphine ligand such as BINAP is used as a catalyst (Non-Patent Documents 1, 2, 3). However, the methods disclosed in these documents require a large amount of catalyst and high-pressure hydrogen, making them difficult to carry out industrially. In addition, a method has been disclosed in which a reaction proceeds under low hydrogen pressure by using an iridium complex with an optically active diphosphine ligand as a catalyst in the presence of NaBARF as an additive (Non-Patent Document 4). However, this method has problems such as the need to use expensive iridium and being limited to hydroxyesters in which the substituent at the α-position is a nitrogen atom. In addition, a method has been disclosed in which racemic β-ketoesters are diastereoselectively and enantioselectively hydrogenated using an iridium complex having ligands coordinated with optically active phosphorus and nitrogen atoms to obtain optically active β-hydroxyesters having asymmetry at both carbon atoms substituted with an ester group and a hydroxyl group (Non-Patent Documents 5 and 6). However, all of the methods disclosed in these documents require expensive iridium and are insufficient in terms of substrate applicability, stereoselectivity, and catalytic efficiency. On the other hand, as a method for asymmetric reduction of ketones using an asymmetric metal catalyst having an α-picolylamine ligand, a method for producing optically active alcohols by asymmetric reduction of prochiral ketones with an asymmetric ruthenium complex using 2-propanol as a hydrogen source has been reported. However, this document does not disclose its application to β-ketoesters or β-ketoamides having a substituent at the α-position (Patent Document 1). As described above, there has been a demand for the development of a method for efficiently producing optically active β-hydroxyesters or β-hydroxyamides from racemic β-ketoesters or β-ketoamides. However, there have been no reports of the production of optically active β-hydroxyesters or β-hydroxyamides having asymmetry at both carbon atoms substituted with a hydroxyl group and an ester group or an amide group in high yield and with high enantiomeric purity or high diastereomeric purity. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Special Publication No. 2007-536338 [Non-patent literature]

[0004] [Non-Patent Document 1] J. Am. Chem. Soc., 111, 9134-9135 (1989) [Non-Patent Document 2] J. Am. Chem. Soc., 126, 1626-1627 (2004) [Non-Patent Document 3] Chem. Commun., 1296-1297 (2004) [Non-Patent Document 4] Org. Lett., 8, 4573-4576 (2006) [Non-Patent Document 5] Org. Lett., 18, 5592-5595 (2016) [Non-Patent Document 6] Org. Lett., 20, 1888-1892 (2018) Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a method for producing optically active hydroxyesters or hydroxyamides having asymmetric centers at the α- and β-positions of the hydroxyl groups with high enantiomeric and diastereomeric purity by hydrogenating a substrate carbonyl compound with high efficiency using a ruthenium complex having a specific optically active diphosphine compound and an easily synthesized amine compound as a ligand as a catalyst. [Means for solving the problem]

[0006] While intensively investigating the hydrogenation reaction of substrate carbonyl compounds, the present inventors discovered that an optically active SKEWPHOS (2,4-bis(diphenylphosphino)pentane) derivative compound, which is an easy-to-synthesize diphosphine compound having asymmetry at carbon, and a ruthenium complex catalyst having a PICA-type ligand, have excellent performance as an asymmetric hydrogenation catalyst for carbonyl compounds, and that this produces optically active hydroxyesters or hydroxyamides having asymmetric centers at the α- and β-positions of the hydroxyl group with high enantiomeric and diastereomeric purity, thereby completing the present invention.

[0007] That is, the present invention relates to the following. [1] A method for producing optically active hydroxy esters or hydroxy amides, comprising the steps of: RuXYAB (1) [In the general formula (1), X and Y are the same or different and each represents a hydrogen atom or an anionic group, and A represents a compound represented by the following general formula (2):

[0008] [ka] (In general formula (2), R 1 and R 2are the same or different 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 or different 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 or different and each represents a hydrocarbon group which may have a substituent, and * represents an asymmetric carbon atom. The optically active diphosphine represented by the formula: B is represented by the following general formula (3):

[0009] [ka] In the general formula (3), each D is independently the same or different and represents a carbon atom or a nitrogen atom, R 9 , R 10 and R 11 are the same or different and represent 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 heterocycle which may have a substituent, Each R 12 are the same or different and each represents a chain 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 heterocycle which may have a substituent, R 12 may be at least partially bonded to ruthenium as anionic groups X, and n is an integer of 0 to (4-(the number of D, which is a nitrogen atom)). In the presence of one or more ruthenium complexes selected from compounds represented by the following general formula (4):

[0010] [ka] (wherein J is an aromatic ring or an alkyl group, each of which may have a substituent; K is any of an alkyl group, an aryl group, an allyl group, an amino group, an amide group bonded at the N atom of an amide bond, and a sulfonamide group bonded at the N atom of an amide bond, each of which may have a substituent; and L is any of an ester group bonded at the C atom of an ester bond, and an amide group bonded at the C atom of an amide bond), with hydrogen and / or a hydrogen-donating compound to obtain a carbonyl compound represented by the following general formula (5):

[0011] [ka] (In the formula, J, K and L are as defined above, and * indicates the position of the asymmetric carbon.) The method for producing an optically active hydroxy ester or hydroxy amide 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 meaning as defined in general formula (1)), and one or more amine compounds selected from compounds represented by general formula (3). The method according to item [1] above, in which a ruthenium complex represented by general formula (1) is prepared in situ by causing one or more complexes selected from compounds represented by general formula (6), [3] Two R’s 12 are linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocycle which may have a substituent, and the two R 12 The method according to [1] or [2] above, wherein the ring formed by the ring formed by both of them and the ring containing D is a quinoline ring or an isoquinoline ring. [4] The method according to any one of the above [1] to [3], wherein in general formula (3), one or more of the four Ds is a nitrogen atom.

[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-ditert-butylphenyl phosphino)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-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-(diphenylphosphine 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 the above [1] to [4], wherein the compound is 3-diphenyl-2-methylpropane.

[0014] [6] The method according to any one of the above [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-ditert-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)- 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) 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-diisobu 2-(aminomethyl)-5,6-diisobutylpyridine, 2-(aminomethyl)-3,4-ditert-butylpyridine, 2-(aminomethyl)-3,5-ditert-butylpyridine, 2-(aminomethyl)-3,6-ditert-butylpyridine, 2-(aminomethyl)-4,5-ditert-butylpyridine, 2-(aminomethyl)-4,6-ditert-butylpyridine, 2-(aminomethyl)-5,6-ditert-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, 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- 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-( The method according to any one of the above [1] to [6], wherein the compound is selected from the group consisting of 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, and 6-(1-aminoethyl)phenanthridine. 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, which is an easily synthesized diphosphine compound having asymmetry on carbon, and a PICA-type ligand acts as a highly efficient hydrogenation catalyst. This makes it possible to produce optically active hydroxyesters or hydroxyamides having asymmetric centers at the α- and β-positions of the hydroxyl group with high enantiomeric and diastereomeric purity, whereas asymmetric hydrogenation does not proceed efficiently with conventionally used ruthenium complexes and expensive iridium complexes have insufficient enantiomeric and diastereomeric purity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention will be described in detail below based on preferred embodiments. The present invention relates to a method for producing optically active hydroxyesters or hydroxyamides represented by the general formula (5) described later, by reacting a substrate carbonyl compound represented by the general formula (4) described later with hydrogen or a hydrogen-donating compound in the presence of one or more ruthenium complexes selected from compounds represented by the general formula (1) described later. Hereinafter, the ruthenium complexes used in the present method will first be described in detail, and then preferred embodiments of the present method will be described in detail.

[0018] <Ruthenium complex> The ruthenium complex used in the present invention is represented by the general formula (1): RuXYAB (1) (In the formula, A represents the following general formula (2): [ka] and B is an optically active diphosphine compound A represented by the following general formula (3): [ka] The amine compound B is represented by the formula: It is expressed as:

[0019] In the above general formula (1), the substituents X and Y are the same or different and each represents a hydrogen atom or an anionic group. The anionic group is preferably a halogen atom, a carboxyl group, a tetrahydroborate anion, or a substituted phenyl anion group, but may also be any other anionic group, such as an alkoxy group, a hydroxyl group, etc. X and Y are preferably a hydrogen atom, a halogen atom, a tetrahydroborate anion, a tolyl anionic group, an acetoxy group, etc., more preferably a halogen atom or a tolyl anionic 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 general formula (1) is represented by the following general formula (2). [ka]

[0021] In general formula (2), R 1 and R 2 are the same or different 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 or different and represent hydrogen or a hydrocarbon group having 1 to 3 carbon atoms; R 5 , R 6 , R 7 and R 8 are the same or different and each represents a hydrocarbon group which may have a substituent, and * represents an asymmetric carbon atom. Here, R 1 and R 2 Examples of the alkyl group include, but are not limited to, saturated or unsaturated chain aliphatic hydrocarbon groups, saturated or unsaturated monocyclic or polycyclic aliphatic hydrocarbon groups, monocyclic or polycyclic aromatic hydrocarbon groups, and groups that combine these various hydrocarbon groups, and these hydrocarbon groups may further have a substituent.

[0022] R 1 and R2 Examples of the hydrocarbon groups include hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, e.g., phenyl and naphthyl, aralkyl, e.g., phenylalkyl, and these hydrocarbon groups further include hydrocarbon groups having permissible substituents such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atoms, nitro groups, cyano groups, and the like. Of these, R 1 and R 2 is 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 or a phenyl group.

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

[0024] R 5 , R 6 , R 7 and R 8 Examples of the alkyl group include, but are not limited to, saturated or unsaturated chain aliphatic hydrocarbon groups, saturated or unsaturated monocyclic or polycyclic aliphatic hydrocarbon groups, and monocyclic or polycyclic aromatic hydrocarbon groups, and these hydrocarbon groups may further have a substituent.

[0025] R 5 , R 6 , R 7 and R 8Examples of the alkyl group include hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, e.g., phenyl and naphthyl, aralkyl, e.g., phenylalkyl, and these hydrocarbon groups further include hydrocarbon groups having permissible substituents such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atoms, dialkylamino groups, nitro groups, cyano groups, and the like.

[0026] Of these, R 5 , R 6 , R 7 and R 8 is preferably a substituted or unsubstituted monocyclic aromatic hydrocarbon group, more preferably a phenyl group or a substituted phenyl group, and particularly preferably a phenyl group or 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 is not particularly limited, but can be, for example, 1 to 20, and preferably 5 to 10.

[0028] Examples of the optically active diphosphine represented by the general formula (2) include pentane derivatives having diphenylphosphino groups at the 2- and 4-positions, pentane derivatives having di-4-tolylphosphino groups at the 2- and 4-positions, pentane derivatives having di-4-t-butylphenylphosphino groups at the 2- and 4-positions, pentane derivatives having di-3,5-xylylphosphino groups at the 2- and 4-positions, pentane derivatives having di-3,5-diethylphenylphosphino groups at the 2- and 4-positions, and pentane derivatives having di-3,5-diisopropylphenylphosphino groups at the 2- and 4-positions. pentane derivatives having diphenylphosphino groups at the 1st and 3rd positions, 1,3-diphenylpropane derivatives having di-4-tolylphosphino groups at the 1st and 3rd positions, 1,3-diphenylpropane derivatives having di-4-t-butylphenylphosphino groups at the 1st and 3rd positions, 1,3-diphenylpropane derivatives having di-3,5-xylylphosphino groups at the 1st and 3rd positions, and 1,3-diphenylpropane derivatives having di-3,5-diethylphenylphosphino groups at the 1st and 3rd 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-diEtS KEWPHOS: 2,4-bis-(di-3,5-diethylphenylphosphino)pentane, DIPSKEWPHOS: 2,4-bis-(di-3,5-diisopropylphenylphosphino)pentane, DTBSKEWPHOS: 2,4-bis-(di-3,5-ditertbutylphenylphosphino)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-butyl 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)-1,3-diphenyl-2-methylpropane.

[0030] The optically active diphosphine compound A is more preferably selected from the group consisting of 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-ditertbutylphenylphosphino)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, the optically active diphosphine compounds that can be used in the present invention are not limited to these.

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

[0033] In general formula (3), each D is independently the same or different and represents a carbon atom or a nitrogen atom; R 9 , R 10 and R 11 are the same or different and represent 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 heterocycle which may have a substituent, Each R 12 are the same or different and each represents a chain 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 heterocycle which may have a substituent, R 12 may be at least partially bonded to ruthenium as anionic groups X, 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 is independently the same or different and represents a nitrogen atom or a carbon atom. All four D in the formula can be carbon atoms, and one or more of the four D can be a nitrogen atom. The number of nitrogen atoms present in the ring containing D can be, for example, 1 to 3, preferably 1 to 2. Accordingly, in this case, of the four Ds in the formula, 0 to 2, preferably 0 or 1 D are nitrogen atoms, and the remaining Ds are carbon atoms. The ring containing D is not particularly limited, but may be, for example, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a triazine ring, or a tetrazine ring. Among these, the ring containing D is preferably a pyridine ring, a pyrazine ring, or a pyrimidine ring.

[0035] In the formula, R 9 ~R11 Examples of the alkyl group include, but are not limited to, a hydrogen atom, a saturated or unsaturated linear aliphatic hydrocarbon group, a saturated or unsaturated monocyclic or polycyclic aliphatic 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 the alkyl group include a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, such as a phenyl group, a naphthyl group, an aralkyl group, such as a phenylalkyl group, and hydrocarbon groups having various permissible substituents such as an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an alkoxy group, an ester group, an acyloxy group, a halogen atom, a nitro group, a cyano group, and the like.

[0036] Above R 9 is preferably a hydrogen atom, an alkyl group, a phenyl group or a phenylalkyl group, more preferably a hydrogen atom or a benzyl group, and particularly preferably a hydrogen atom. The above R 10 and R 11 are preferably a hydrogen atom, an alkyl group, a phenyl group, a phenylalkyl group, or the like, and particularly preferably all are hydrogen atoms or R 10 and R 11 One of the groups is a methyl group.

[0037] Also, R 10 and R 11 R may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocycle which may have a substituent. Examples of such a hydrocarbon ring include a cycloalkane ring, a cycloalkene ring, and a cycloalkyne ring each having 3 to 10 ring members, preferably 4 to 8 ring members. 10 and R 11 More specifically, examples of the ring formed by and include cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, piperidylidene, and those substituted with a substituent. Among the above, monocyclic hydrocarbon groups, particularly cyclopentylidene and cyclohexylidene, are preferred.

[0038] Also, R 12 Examples of the alkyl group include, but are not limited to, saturated or unsaturated chain aliphatic hydrocarbon groups, saturated or unsaturated monocyclic or polycyclic aliphatic hydrocarbon groups, and monocyclic or polycyclic aromatic hydrocarbon groups, and these hydrocarbon groups may further have a substituent. R 12 Examples of the hydrocarbon groups include hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, e.g., phenyl, naphthyl, aralkyl, e.g., phenylalkyl, and the like, as well as hydrocarbon groups having various permissible substituents such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atoms, nitro groups, and cyano groups. 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, or a substituted or unsubstituted phenyl group, particularly preferably a methyl group, a phenyl group, or an o-, m-, or p-tolyl group.

[0039] Also, two R 12 may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocycle which may have a substituent. 12 is replaced by adjacent D. 12 (R in the ortho position 12 ) or R to replace one D with a D between them 12 (R in meta position 12 ) is preferable, and R replacing adjacent D is preferable. 12 It is preferable that Two such R 12Examples of the ring formed by these rings include saturated or unsaturated hydrocarbon rings or heterocycles having 3 to 10 ring members, preferably 4 to 8 ring members, and more specifically, for example, 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 rings substituted with a substituent. Among the above, monocyclic hydrocarbon aromatic groups, particularly benzene rings, are preferred.

[0040] The Two R's 12 Examples of the ring formed by the ring formed by themselves and the ring containing D include a quinoline ring, an isoquinoline ring, a purine ring, a quinoxaline ring, a quinazoline ring, a cinnoline ring, a phthalazine ring, and a phenanthridine ring. Of these, a quinoline ring or an isoquinoline ring is preferred.

[0041] As described above, in the formula, n is an integer of 0 to (4-(the number of D nitrogen atoms)). That is, when the number of D nitrogen atoms is 0, n is 0 to 4; when the number of D nitrogen atoms is 1, n is 0 to 3; when the number of D nitrogen atoms is 2, n is 0 to 2; when the number of D nitrogen atoms is 3, n is 0 to 1; and when the number of D 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-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)- 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-diisobuty 2-(aminomethyl)-4,6-diisobutylpyridine, 2-(aminomethyl)-5,6-diisobutylpyridine, 2-(aminomethyl)-3,4-ditert-butylpyridine, 2-(aminomethyl)-3,5-ditert-butylpyridine, 2-(aminomethyl)-3,6-ditert-butylpyridine, 2-(aminomethyl)-4,5-ditert-butylpyridine, 2-(aminomethyl)-4,6-ditert-butylpyridine, 2-(aminomethyl)-5,6-ditert-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-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 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 are preferred. Among these, PICA, 2-AMQ, 1-AMIQ, 3-AMIQ, 3,4-DMPICA, 3,5-DMPICA, AMPZ, and 2-AMPR are particularly preferred.

[0043] The ruthenium complex represented by the general formula (1) explained above has, as an amine ligand, an amine compound B represented by the general formula (3) which has multiple substituents on a nitrogen-containing ring or in which the nitrogen-containing ring contains multiple 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 hydroxyesters or hydroxyamides having asymmetric centers at the α- and β-positions of the hydroxyl group can be obtained with enantiomeric and diastereomeric purities far higher than when a conventionally known ruthenium complex having an achiral ligand is used.

[0044] The ruthenium complex represented by the general formula (1) used in the present invention may be prepared in situ when the substrate carbonyl compound is reacted with hydrogen in the presence of a base. There is no limitation on the method, but as an example, a precursor compound represented by the following general formula (6) may be added to the reaction system. RuXYA (6) [In general formula (6), X, Y and A each independently have the meaning as defined in general formula (1)], and one or more amine compounds selected from the compounds represented by general formula (3) are present, whereby the ruthenium complex represented by 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 generate the catalyst precursor represented by the general formula (1). Therefore, the molar ratio of the complex represented by the general formula (6) and 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 without changing into the catalyst precursor represented by the general formula (1), which is disadvantageous from the viewpoint of the economic efficiency of the reaction. Therefore, the complex represented by the general formula (6) and the amine compound represented by the general formula (3) can be charged in a vessel in which the substrate carbonyl compound is reacted with hydrogen and / or a hydrogen donating compound at a molar ratio of preferably 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 any problem, except for the fact that the reactivity decreases.

[0046] In addition, the ruthenium complexes represented by general formula (1) and general formula (6) may contain one or more organic compounds that are reaction reagents used in the synthesis. Here, the organic compound indicates a coordinating organic solvent, and examples thereof include aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ether-based solvents such as ether and tetrahydrofuran, alcohol-based solvents such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, and benzyl alcohol, ketone-based 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 by reacting the 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 the optically active diphosphine compound with the raw material ruthenium complex. The complex represented by the general formula (1) may be prepared in advance as described above, or may be prepared in the hydrogenation reaction system. The preparation method of the ruthenium complex represented by the general formula (1) can be any method reported up to now, including the structure of the raw material used, and is not particularly limited, but one embodiment is shown below.

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

[0049] Examples of the ruthenium complex that can be used as a starting material include inorganic ruthenium compounds such as ruthenium chloride (III) hydrate, ruthenium bromide (III) hydrate, and ruthenium iodide (III) hydrate; ruthenium compounds coordinated with dienes such as [ruthenium dichloride (norbornadiene)] polynuclear compounds, [ruthenium dichloride (cycloocta-1,5-diene)] polynuclear compounds, and bis(methylallyl)ruthenium (cycloocta-1,5-diene); ruthenium complexes coordinated with aromatic compounds such as [ruthenium dichloride (benzene)] polynuclear compounds, [ruthenium dichloride (p-cymene)] polynuclear compounds, [ruthenium dichloride (trimethylbenzene)] polynuclear compounds, and [ruthenium dichloride (hexamethylbenzene)] polynuclear compounds; and complexes coordinated with phosphines such as dichlorotris(triphenylphosphine)ruthenium. In addition, the starting material is not particularly limited 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. For example, various ruthenium complexes shown in COMPREHENSIVE ORGANOMETALLIC CHEMISTRY II, Vol. 7, p. 294-296 (PERGAMON) can be used as the starting material.

[0050] When a trivalent ruthenium complex is used as a starting material, for example, a phosphine-ruthenium halide complex can be synthesized by reacting a ruthenium (III) halide with an excess of phosphine. The resulting phosphine-ruthenium halide complex can then be reacted with an amine to obtain the desired 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)]. That is, RuCl synthesized by the method described in Inorg, Synth., vol. 12, 237 (1970) and the like. 2 (PPh 3 ) 3 is reacted with ethylenediamine in benzene to give RuCl 2 (PPh 3 ) 2(en) has been obtained (although the yield is not stated). However, in this method, the reaction is heterogeneous and there is a tendency for unreacted raw materials to remain. On the other hand, if the reaction solvent is changed to methylene chloride, chloroform, etc., the reaction can be carried out in a homogeneous state, improving operability.

[0051] The reaction between ruthenium halide and phosphine ligand can be carried out in 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-based solvents such as ether and tetrahydrofuran, alcohol-based solvents such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, and benzyl alcohol, and organic solvents containing heteroatoms such as acetonitrile, DMF, N-methylpyrrolidone, and DMSO at reaction temperatures between -100°C and 200°C to obtain a phosphine-ruthenium halide complex represented by general formula (6).

[0052] The reaction of the obtained phosphine-ruthenium halide complex represented by general formula (6) with the amine ligand represented by general formula (3) can be 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-based solvent such as ether or tetrahydrofuran, an alcohol-based solvent such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol or benzyl alcohol, or an organic solvent containing a hetero atom such as acetonitrile, DMF, N-methylpyrrolidone or DMSO, at a reaction temperature between -100°C and 200°C, to obtain the amine-phosphine-ruthenium halide complex represented by general formula (1).

[0053] On the other hand, a method is also used in which a divalent ruthenium complex is used from the beginning, and this is reacted with a phosphine compound and an amine compound in sequence, in the reverse order, or simultaneously. As an example, a ruthenium compound coordinated with a diene such as [ruthenium dichloride (norbornadiene)] polynuclear compound, [ruthenium dichloride (cyclooc-1,5-tadiene)] polynuclear compound, or bis(methylallyl)ruthenium (cyclooctadiene) or other diene, or a ruthenium complex coordinated with an aromatic compound such as [ruthenium dichloride (benzene)] binuclear compound, [ruthenium dichloride (p-cymene)] binuclear compound, [ruthenium dichloride (trimethylbenzene)] binuclear compound, or [ruthenium dichloride (hexamethylbenzene)] binuclear compound, or a complex coordinated with a phosphine such as dichlorotris(triphenylphosphine)ruthenium, is reacted with an aromatic compound such as toluene or xylene. A phosphine-ruthenium-halide complex or a phosphine-ruthenium-methylallyl complex represented by the general formula (6) can be obtained by reacting with a phosphine compound in an aromatic hydrocarbon solvent, an aliphatic hydrocarbon solvent such as pentane or hexane, a halogen-containing hydrocarbon solvent such as methylene chloride, an ether-based solvent such as ether or tetrahydrofuran, an alcohol-based 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. 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 be carried out with an amine ligand 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-based solvent such as ether or tetrahydrofuran, an alcohol-based 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 complex. In addition, under similar 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] The complex in which the cyclic hydrocarbon group bound to the diamine compound represented by the general formula (3) is bound to ruthenium as an anionic group X can be synthesized by the method described in the literature [Organometallics, 29, 3563 (2010)], etc. That is, similar to the above-mentioned amine-phosphine-ruthenium halide complex synthesis method, an amine ligand is added to the phosphine-ruthenium halide complex represented by the general formula (6) to synthesize the amine-phosphine-ruthenium halide complex, and then the complex is reacted with a base such as triethylamine at a temperature between -100°C and 200°C 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-based solvent such as ether or tetrahydrofuran, an alcohol-based 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. Alternatively, it can be synthesized by reacting a phosphine-ruthenium halide complex represented by the general formula (6) with an amine ligand in the presence of a base such as triethylamine in the above-mentioned solvent at a temperature between -100°C and 200°C.

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

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

[0058] [ka] It is expressed as:

[0059] In the above general formula (4), J represents an aromatic ring or an alkyl group, each of which may have a substituent. The aromatic ring includes an aromatic hydrocarbon ring or an aromatic heterocycle. The aromatic hydrocarbon ring is not particularly limited and may be a monocyclic or polycyclic ring, and the number of ring members is not particularly limited, but is preferably 5 to 20, and more preferably 5 to 15. Specific examples include 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, and among these, a benzene ring and a naphthalene ring are preferred. In addition, the aromatic heterocycle is not particularly limited, and for example, a monocyclic or polycyclic heterocycle having a nitrogen atom, an oxygen atom, or a sulfur atom as a hetero atom is preferable. 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 a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a triazine ring, a tetrazine ring, an imidazoline ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a quinoline ring, an isoquinoline ring, a purine ring, a quinoxaline ring, a quinazoline ring, a cinnoline ring, a phthalazine ring, a phenanthridine ring, a furan ring, an oxazole ring, an isoxazole ring, a thiophene ring, a thiazole ring, and an isothiazole ring. Among these, a pyridine ring, a pyrazine ring, a pyrimidine ring, a furan ring, and a thiophene ring are preferable.

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

[0061] 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 that the alkyl group may have include alkoxy, an ester group bonded at a C atom of an ester bond, a halogen atom, an amino group, an amide group bonded at a C atom of an amide bond, a nitro group, a cyano group, an N-acetamide group, and the aromatic hydrocarbon rings described above for J.

[0062] In the above general formula (4), K represents an alkyl group, an aryl group, an allyl group, an amino group, an amide group bonded at the N atom of an amide bond, or a sulfonamide group bonded at the N atom of an amide bond, each of which may 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 that the alkyl group may have include alkoxy, ester, halogen atoms, amino groups, amido groups, nitro groups, cyano groups, N-acetamide groups, and aromatic hydrocarbon rings described above for J. Examples of the aryl group include the aromatic hydrocarbon rings described above for J, and the preferred ranges are also the same. Examples of the substituent that the aryl group may have include the same substituents on the aromatic ring described above for J. Examples of the substituent that the allyl group and amino group may have include linear or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms.

[0063] The amide group bonded through 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 general formula (4). Examples of the group bonded to the other side (C atom) of the amide bond include an alkyl group, an alkoxy group, or an aromatic ring, each of which may have a substituent. In addition, the N atom of the amide bond may further have a substituent such as those listed as the substituent that the amino group may have. Examples of the alkyl group or alkoxy group bonded to the other end 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 atoms, amino groups, amide groups, nitro groups, cyano groups, N-acetamide groups, and aromatic hydrocarbon rings described above for J. Examples of the aromatic ring bonded to the other of the amide bonds include the aromatic rings described above for J. Examples of the substituent that the aromatic ring may have include the same substituents on the aromatic ring as those described above for J.

[0064] The sulfonamide group bonded through 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 general formula (4). Examples of the group bonded to the other side of the amide bond (S atom) include an alkyl group, an alkoxy group, or an aromatic ring, each of which may have a substituent. In addition, the N atom of the amide bond may further have a substituent such as those listed as the substituent that the amino group may have. Examples of the alkyl group or alkoxy group bonded to the other end 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 atoms, amino groups, amide groups, nitro groups, cyano groups, N-acetamide groups, and aromatic hydrocarbon rings described above for J. Examples of the aromatic ring bonded to the other of the amide bonds include the aromatic rings described above for J. Examples of the substituent that the aromatic ring may have include the same substituents on the aromatic ring as those described above for J.

[0065] In the above general formula (4), L is either an ester group bonded at the C atom of an ester bond, or an amide group bonded at the C atom of an amide bond. The ester group bonded through the C atom of the ester bond means an ester group in which the C atom of the ester bond is bonded to the α-position of the carbonyl group in general formula (4). Examples of the group bonded to the other side of the ester bond (O atom side) include an alkyl group or an aromatic ring, each of which may have a substituent. The alkyl group bonded to the other of the ester bonds may be, for example, a straight-chain or branched-chain alkyl group 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, a halogen atom, an amino group, an amido group, a nitro group, a cyano group, an N-acetamide group, and the aromatic hydrocarbon rings described above for J. Examples of the aromatic ring bonded to the other of the ester bonds include the aromatic rings described above for J. Examples of the substituent that the aromatic ring may have include the same substituents on the aromatic ring as those described above for J.

[0066] The amide group bonded through the C atom of the amide bond means an amide group in which the C atom of the amide bond is bonded to the α-position of the carbonyl group in general formula (4). Examples of the group bonded to the other side of the amide bond (the N atom side) include an alkyl group or an aromatic ring, each of which may have a substituent. The alkyl group bonded to the other end of the amide bond may be, for example, a straight-chain or branched-chain alkyl group 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, a halogen atom, an amino group, an amide group, a nitro group, a cyano group, an N-acetamide group, and the aromatic hydrocarbon rings described above for J. Examples of the aromatic ring bonded to the other of the amide bonds include the aromatic rings described above for J. Examples of the substituent that the aromatic ring may have include the same substituents on the aromatic ring as those 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 compound that can be used is not particularly limited as long as it satisfies the general formula (4). For example, 3-oxo-3-phenylpropanoic acid ester derivatives, 3-oxo-3-pyridylpropanoic acid ester derivatives, 3-oxo-3-furylpropanoic acid ester derivatives, 3-oxo-3-thienylpropanoic acid ester derivatives, 3-oxo-3-naphthylpropanoic acid ester derivatives, 3-oxo-3-phenyl ... Examples of the amide derivatives include 3-oxo-3-pyridylpropanoic acid ester derivatives, 3-oxo-3-furylpropanoic acid ester derivatives, 3-oxo-3-thienylpropanoic acid ester derivatives, 3-oxo-3-naphthylpropanoic acid ester derivatives, 3-oxo-3-phenylpropanoic acid amide derivatives, 3-oxo-3-pyridylpropanoic acid amide derivatives, 3-oxo-3-furylpropanoic acid amide derivatives, 3-oxo-3-thienylpropanoic acid amide derivatives, 3-oxo-3-naphthylpropanoic acid amide derivatives, 3-oxo-3-phenylpropanoic acid amide derivatives, 3-oxo-3-pyridylpropanoic acid amide derivatives, 3-oxo-3-furylpropanoic acid amide derivatives, 3-oxo-3-thienylpropanoic acid amide derivatives, 3-oxo-3-naphthylpropanoic acid amide derivatives, and the like.

[0068] Specific examples of particularly effective substrate carbonyl compounds include ethyl 2-methyl-3-oxo-3-phenylpropanoate, ethyl 3-(4-chlorophenyl)-2-methyl-3-oxopropanoate, ethyl 3-(2-bromophenyl)-2-methyl-3-oxopropanoate, ethyl 3-(4-methoxyphenyl)-2-methyl-3-oxopropanoate, ethyl 3-(furan-3-yl)-3-methyl-3-oxopropanoate, ethyl 3-(furan-2-yl)-3-methyl-3-oxopropanoate, ethyl 3-(thiophen-3 ... Ethyl oxopropanoate, ethyl 3-(thiophen-2-yl)-3-methyl-3-oxopropanoate, ethyl 3-(pyridin-3-yl)-3-methyl-3-oxopropanoate, ethyl 3-(pyridin-2-yl)-3-methyl-3-oxopropanoate, ethyl 3-(pyridin-4-yl)-3-methyl-3-oxopropanoate, ethyl 2-methyl-3-(naphthalen-1-yl)-3-oxopropanoate, ethyl 2-methyl-3-(naphthalen-2-yl)-3-oxopropanoate, ethyl 2-benzoylbutanoate, ethyl 2-benzoyl-3-methyl Ethyl 2-benzoyl-4-pentenoate, Ethyl 3-oxo-2,3-diphenylpropanoate, Ethyl 2-acetamidomethyl-3-oxo-3-phenylpropanoate, Ethyl 2-(dimethylamino)-3-oxo-3-phenylpropanoate, Methyl 2-methyl-3-oxo-3-phenylpropanoate, Propyl 2-methyl-3-oxo-3-phenylpropanoate, Isopropyl 2-methyl-3-oxo-3-phenylpropanoate, Butyl 2-methyl-3-oxo-3-phenylpropanoate, 2-Methyl-3-oxo-3-phenylpropanoate, Examples of the phenylpropanoic acid include isobutyl phenylpropanoate, tert-butyl 2-methyl-3-oxo-3-phenylpropanoate, phenyl 2-methyl-3-oxo-3-phenylpropanoate, N-benzyl-2-methyl-3-oxo-3-phenylpropanamide, N-methyl-2-methyl-3-oxo-3-phenylpropanamide, N-ethyl-2-methyl-3-oxo-3-phenylpropanamide, N-propyl-2-methyl-3-oxo-3-phenylpropanamide, and N,N-dimethyl-2-methyl-3-oxo-3-phenylpropanamide.The substrate carbonyl compounds exemplified here may further have the above-mentioned substituents.

[0069] <Method for producing optically active hydroxyesters or hydroxyamides having asymmetric centers at the α- and β-positions of the hydroxyl group> Next, the method for producing optically active hydroxyesters or hydroxyamides having asymmetric centers at the α, β positions of the hydroxyl group according to this embodiment will be described. In this embodiment, a method for producing an optically active hydroxy ester or hydroxy amide having an asymmetric center at the α- and β-positions of a hydroxyl group includes reacting a substrate carbonyl compound represented by the above general formula (4) with hydrogen and / or a hydrogen-donating compound in the presence of one or more ruthenium complexes represented by the above general formula (1) to produce a carbonyl compound represented by the following general formula (5):

[0070] [ka]

[0071] The present invention relates to a method for producing optically active hydroxy esters or hydroxy amides represented by the following formula:

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

[0073] The optically active hydroxy esters or hydroxy amides represented by the above general formula (5) are useful as optically active physiologically active compounds used in medicines, agricultural chemicals, etc., or as synthetic intermediates for liquid crystal materials.

[0074] The ruthenium complex functions as a catalyst in this method. The ruthenium complex may be one represented by the above general formula (1), but by selecting either the (R,R) or (S,S) form of the optically active diphosphine compound represented by general formula (2) in the ruthenium complex represented by general formula (1), optically active hydroxyesters or hydroxyamides having the desired absolute configuration with respect to the α-position of the hydroxyl group and asymmetric centers at the α- and β-positions of the hydroxyl group can be prepared.

[0075] In addition, when the amine compound represented by general formula (3) in the ruthenium complex represented by general formula (1) is optically active, 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 optically active amine compound to be added is important in order to obtain high optical purity. For example, the appropriate combination of the absolute structure of the diphosphine compound and the absolute structure of the amine compound varies depending on the structure of the substrate. When a complex having an inappropriate combination is used, the catalytic activity may decrease or the enantiomeric purity or diastereomeric purity of the product may decrease compared to when a complex having an appropriate combination is used.

[0076] The amount of the ruthenium complex represented by general formula (1) used will vary 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 considerations, but can be used in a molar ratio of 1 / 100 to 1 / 10,000,000, preferably 1 / 500 to 1 / 1,000,000 relative to the substrate carbonyl compound.

[0077] As the hydrogen source used in this method, hydrogen (hydrogen gas) and / or a compound that donates hydrogen (hydrogen donor) can be used as described above. Here, in this specification, the hydrogen donor refers to a compound that has the effect of supplying intramolecular hydrogen to a ruthenium catalyst. Examples of such compounds include, but are not limited to, lower alcohols such as 2-propanol, propanol, butanol, ethanol, and methanol; formic acid; and formate salts such as potassium formate and sodium formate. Among the above, it is preferable to use a lower alcohol as the hydrogen donor, and it is more preferable to use 2-propanol.

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

[0079] As the hydrogen source, it is preferable to use hydrogen gas from the viewpoint of obtaining sufficient reactivity. When hydrogen gas is used, the pressure of the hydrogen gas is not particularly limited, but is, for example, 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. Incidentally, hydrogen gas and a hydrogen donor may be used in combination.

[0080] In the reaction, it is preferable to have a base present in the reaction system. The base that can be used is not particularly limited, but examples thereof include KOH, KOCH 3 , KOCH(CH 3 ) 2 , KOC(CH 3 ) 3 , K.O.C. 10 H 8 , KOC(CH 3 ) 2 (CH 2 CH 3 ), NaOC(CH 3 ) 3、 NaOC(CH 3 ) 2 (CH 2 CH 3 ), LiOH, LiOCH 3 , LiOCH(CH3 ) 2 , LiOC(CH 3 ) 3 Examples of the base include salts of alkali metals, alkaline earth metals, and quaternary ammonium salts, and these can be used alone or in combination of two or more. Of these, the base is preferably KOH, KOCH(CH 3 ) 2 , KOC(CH 3 ) 3 or NaOC(CH 3 ) 3 and particularly preferably KOCH(CH 3 ) 2 , KOC(CH 3 ) 3 or NaOC(CH 3 ) 3 It is.

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

[0082] As described above, in order to produce optically active hydroxyesters or hydroxyamides having asymmetric centers at the α- and β-positions of the hydroxyl group with high enantiomeric and diastereomeric purity by a smooth asymmetric hydrogenation reaction, it is preferable to use a ruthenium complex represented by the general formula (1) used as a catalyst in combination with 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 is achieved by a smooth asymmetric hydrogenation reaction of the substrate carbonyl compound without adding a base. In such a case, for example, the ruthenium complex and the substrate carbonyl compound may be mixed without adding a base, and then the reaction may be carried out by stirring under hydrogen pressure.

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

[0085] The amount of the solvent is determined based on the solubility of the reaction substrate and economic efficiency. For example, the substrate concentration may range from a low concentration of 0.1 mol / L or less to a nearly solvent-free state depending on the substrate, but it is preferable to use a substrate concentration in the range of 0.3 to 5 mol / L.

[0086] The upper limit of the reaction temperature must be set within a range in which decomposition of the ruthenium complex used as a catalyst does not occur, and the lower limit must be set in consideration of activity. The reaction is preferably carried out at, for example, 0 to 60°C, preferably 25 to 40°C, and such a temperature range is also excellent from the viewpoint of economy.

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

[0088] Even if the reaction operation is continued after the reduction reaction of the carbonyl group of the substrate is completed, no particular problem is observed. Therefore, in carrying out the present invention, it is not necessary to constantly monitor the progress of the reaction, and it is not necessary to immediately terminate the reaction after the reaction is completed. In other words, the reaction time can be set longer than the substantial reaction completion time, which is an advantageous method for industrial implementation. By hydrogenating a substrate carbonyl compound according to the above-mentioned method, it is possible to obtain the corresponding optically active hydroxyesters or hydroxyamides having asymmetric centers at the α, β-positions of the hydroxyl group.

[0089] However, even in the process of the present invention, the hydrogenation reaction product may contain the starting ketone, the added base, or a salt formed by the reaction of the complex with the base, etc. These can be purified by commonly known purification procedures such as distillation, water washing, recrystallization, chromatography, etc.

[0090] The reaction format of the above reaction is not particularly limited, and the reaction can be carried out in any of a batch system, a continuous system, and a flow reactor.

[0091] According to the present invention, an optically active SKEWPHOS (2,4-bis(diphenylphosphino)pentane) derivative compound, which is a diphosphine compound having asymmetricity at 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 heterocycle having multiple nitrogen atoms, act as a hydrogenation catalyst with high efficiency. This complex is inexpensive because it can use an achiral amine, which is easy to synthesize, as the ligand, instead of the optically active amine that has been used conventionally. This feature can be said to be a method that is industrially and economically superior to conventional methods. Furthermore, the optically active hydroxyesters or hydroxyamides having asymmetric centers at the α and β positions of the hydroxyl group obtained by this method have higher enantiomeric and diastereomeric purity than those obtained by conventional methods.

[0092] According to another embodiment of the present invention, there is provided a method for producing an optically active hydroxyester or hydroxyamide having an asymmetric center at the α- or β-position of a hydroxyl group, comprising reacting a compound represented by the following general formula (6): RuXYA (6) [In general formula (6), X and Y are the same or different and each independently have the meaning as defined in general formula (1)], and in the presence of one or more amine compounds selected from compounds represented by general formula (3), a substrate carbonyl compound represented by general formula (4) is reacted with hydrogen and / or a hydrogen-donating compound.

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

[0094] As other conditions in this embodiment, the above-mentioned conditions can be used. The same effect can be obtained by the method of this embodiment.

[0095] The hydrogenation reaction of the substrate carbonyl compound in the present invention can be carried out either batchwise or continuously. EXAMPLES

[0096] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples. In the following examples, all reactions were carried out under an inert gas atmosphere such as argon gas or nitrogen gas. Furthermore, the solvents used in the reactions were dried and degassed, unless otherwise specified. The hydrogenation reaction of the carbonyl compound was carried out in an autoclave by pressurizing with hydrogen.

[0097] Unless otherwise specified, the substrate carbonyl compounds described in the Examples and Comparative Examples were directly purchased reagents and used. The solvents used in the reactions were directly obtained from dehydrated solvents manufactured by Kanto Chemical Co., Ltd. For other chemicals, the reagents manufactured by Kanto Chemical Co., Ltd. were directly used unless otherwise specified. In the following examples and comparative examples, S / C represents the substrate / catalyst molar ratio. Also, [Substance name] 0 denotes the initial concentration of the substance.

[0098] The following instruments were used for the measurements below. NMR: JNM-ECX400P type (400MHz) (manufactured by JEOL Ltd.) Internal standard: 1H-NMR...Tetramethylsilane

[0099] Optical purity measurement by HPLC Measurement equipment: LC-20 (high-performance liquid chromatograph, manufactured by Shimadzu Corporation), Agilent 1260 INFINITY (high-performance liquid chromatograph, manufactured by Agilent), Agilent 1260 INFINITY II (high-performance liquid chromatograph, manufactured by Agilent) Column: The column described in each example was used.

[0100] [Example 1] Synthesis of compound (2R,3S)-2a [ka]

[0101] In a 100mL Hyperglass inner tube, RuBr 2 [(S,S)-dipskewphos](3-amiq) (2.39 mg, 2 μmol, 0.002 equivalents) t BuONa (3.84 mg, 40 μmol, 0.04 equivalents) was weighed out, and the inside of the autoclave was replaced with an argon gas atmosphere. tBuOH (1.8 mL) and compound 1a (0.19 mL, 1 mmol, 1 equivalent) were added, and the mixture was stirred while repeatedly degassing under reduced pressure and filling with argon gas 5 times until it started to bubble lightly. The mixture was then pressurized with hydrogen gas up to 0.5 MPa and then leaked down to 0.1 MPa, and this process was repeated 10 times to replace the system with a hydrogen atmosphere. Hydrogen gas was pressurized up to 1.0 MPa, and the mixture was cooled to 100° C. for 25 minutes using a thermostatic water bath. o The mixture was stirred under condition C for 24 hours. After 24 hours, hydrogen gas was released and the reaction mixture was concentrated. The mixture was purified by column chromatography (eluent: hexane / ethyl acetate = 5:1) to obtain compound 2a as a colorless liquid (201.6 mg, 97% yield, diastereomeric ratio > 99: 1, > 99% ee).

[0102] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.03(d,J=7.4Hz,3H),δ1.26(t,J=7.4Hz,3H),δ2.80(dq,J=7.4,8.2Hz,1H),δ3.00(d ,J=4.6Hz,1H),δ4.19(q,J=7.4Hz,2H),δ4.75(dd,J=4.6,8.2Hz,1H),δ7.28-7.38(m,5H) The enantiomeric excess (ee) of (2R,3S)-2a was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALCEL OD-H (4.6 × 250 mm) (manufactured by Daicel), mobile phase: hexane / 2-PrOH = 97 / 3, flow rate: 0.8 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =12.2min,13.9min,15.8min,21.2min

[0103] [Example 2] Synthesis of compound (2R,3S)-2b [ka]

[0104] Compound 1b was synthesized using ethyl (4-methoxybenzoyl)acetate as the raw material, based on the method described in Angew. Chem. Int. Ed., 57, 1039-1043 (2018). In a 100mL glass tube, add RuBr 2 [(S,S)-dipskewphos](3-amiq) (2.39 mg, 2 μmol, 0.002 equivalents) t BuONa (3.84 mg, 40 μmol, 0.04 equivalents) was weighed out, and the inside of the stainless steel autoclave was replaced with an argon gas atmosphere. Under an argon gas atmosphere, compound 1b (236.27 mg, 1 mmol, 1 equivalents) was weighed out into a 20 mL Schlenk flask, t The mixture was diluted with BuOH (1.8 mL) and pumped into the autoclave using a cannula. After that, the mixture was degassed under reduced pressure and filled with argon gas five times while stirring until it started to bubble lightly. The mixture was then pressurized with hydrogen gas up to 0.5 MPa and then leaked down to 0.1 MPa, and this process was repeated ten times to replace the inside of the system with a hydrogen atmosphere. Hydrogen gas was pressurized up to 2.0 MPa and the mixture was cooled to 30° C. for 25 minutes using a thermostatic water bath. o The mixture was stirred under condition C for 24 hours. After 24 hours, the hydrogen gas was released and the reaction mixture was concentrated. The mixture was purified by column chromatography (eluent: hexane / ethyl acetate = 5 / 1) to give compound 2b as colorless crystals (225.7 mg, 95% yield, diastereomeric ratio > 99:1, > 99% ee).

[0105] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.00(d,J=6.9Hz,3H),δ1.27(t,J=7.3Hz,3H),δ2.78(dq,J=6.9,8.7Hz,1H),δ2.88(d,J=4.1,1H),δ3. 81(s,3H),δ4.20(q,J=7.3Hz,2H),δ4.71(dd,J=4.1,8.7Hz,1H),δ6.85-6.92(m,2H),δ7.25-7.29(m,2H) The enantiomeric excess (ee) of (2R,3S)-2b was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALCEL OD-H (4.6 × 250 mm) (manufactured by Daicel) × 2, mobile phase: hexane / 2-PrOH = 99:1, flow rate: 0.5 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =59.5min,66.2min,76.6min,79.2min

[0106] [Example 3] Synthesis of compound (2R,3S)-2c [ka]

[0107] Compound 1c was synthesized using ethyl 3-oxo-(4-chlorophenyl)propionate as the raw material according to the method described in Angew. Chem. Int. Ed., 57, 1039-1043 (2018). In a 100mL Hyperglass inner tube, RuBr 2 [(S,S)-dipskewphos](3-amiq) (2.39 mg, 2 μmol, 0.002 equivalents) t BuONa (3.84 mg, 40 μmol, 0.04 equivalents) was weighed out, and the inside of the autoclave was replaced with an argon gas atmosphere. Under an argon gas atmosphere, compound 1c (240.68 mg, 1 mmol, 1 equivalents) was weighed out into a 20 mL Schlenk flask, t The mixture was diluted with BuOH (1.8 mL) and pumped into the autoclave using a cannula. After that, the mixture was degassed under reduced pressure and filled with argon gas five times while stirring until it started to bubble lightly. The mixture was then pressurized with hydrogen gas up to 0.5 MPa and leaked down to 0.1 MPa, and this process was repeated ten times to replace the inside of the system with a hydrogen atmosphere. Hydrogen gas was pressurized up to 1.0 MPa and the mixture was cooled to 100°C for 25 min using a thermostatic water bath. o The mixture was stirred under condition C for 24 hours. After 24 hours, the hydrogen gas was released and the reaction solution was concentrated. The mixture was purified by column chromatography (eluent: hexane / ethyl acetate = 5 / 1) to give compound 2c as colorless crystals (231.6 mg, 95% yield, diastereomeric ratio 99:1, >99% ee). 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.04(d,J=7.3Hz,3H),δ1.26(t,J=7.3Hz,3H),δ2.75(dq,J=7.3,8.0Hz,1H),δ3.14( d,J=4.6,1H),δ4.18(q,J=7.3Hz,2H),δ4.74(dd,J=4.6,8.0Hz,1H),δ7.26-7.36(m,4H) The enantiomeric excess (ee) of (2R,3S)-2c was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALPAK AD-H (4.6 × 250 mm) (manufactured by Daicel) × 2, Mobile phase: Hexane / 2-PrOH = 97:3, Flow rate: 0.8 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =37.9min,40.3min,67.1min,70.7min

[0108] [Example 4] Synthesis of compound (2R,3S)-2d [ka]

[0109] Compound 1d was synthesized with reference to the method described in Angew. Chem. Int. Ed., 57, 1039-1043 (2018). In a 100mL Hyperglass inner tube, RuBr 2 [(S,S)-dipskewphos](3-amiq) (1.20 mg, 1 μmol, 0.002 equivalents) t BuONa (1.92 mg, 20 μmol, 0.04 equivalents) was weighed out, and the inside of the autoclave was replaced with an argon gas atmosphere. Under an argon gas atmosphere, compound 1d (140.25 mg, 0.5 mmol, 1 equivalents) was weighed out into a 20 mL Schlenk flask, tThe mixture was diluted with BuOH (0.86 mL) and pumped into the autoclave using a cannula. After that, the mixture was degassed under reduced pressure and filled with argon gas five times while stirring until it started to bubble lightly. The mixture was then pressurized with hydrogen gas up to 0.5 MPa and leaked down to 0.1 MPa, and this process was repeated ten times to replace the inside of the system with a hydrogen atmosphere. Hydrogen gas was pressurized up to 1.0 MPa and the mixture was cooled to 100°C for 25 min using a thermostatic water bath. o The mixture was stirred under condition C for 24 hours. After 24 hours, the hydrogen gas was released and the reaction solution was concentrated. The mixture was purified by column chromatography (eluent: hexane / ethyl acetate = 5 / 1) to obtain compound 2d as a colorless liquid (132.5 mg, 92% yield, diastereomeric ratio 98:2, >99% ee). 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.20(t,J=7.2Hz,3H),δ1.22(d,J=7.2Hz,3H),δ2.94(dq,J=6.8,7.2Hz,1H),δ3.54(d,J=6.8,1H),δ4.13(m,2H ), δ5.19(dd,J=6.8,6.8Hz,1H),δ7.12-7.17(m,1H),δ7.33-7.36(m,1H),δ7.45-7.48(m,1H),δ7.52-7.55(m,1H) The enantiomeric excess (ee) of (2R,3S)-2d was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALPAK AD-H (4.6 × 250 mm) (manufactured by Daicel) × 2, Mobile phase: Hexane / 2-PrOH = 99:1, Flow rate: 0.5 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =47.4min,69.1min,88.4min,91.1min

[0110] [Example 5] Synthesis of compound (2R,3S)-2e [ka]

[0111] Compound 1e was synthesized using ethyl β-oxo-3-furanpropionate as the raw material, with reference to the method described in Angew. Chem. Int. Ed., 57, 1039-1043 (2018). The same procedure as in Example 2 was carried out to obtain 2e (131.0 mg, 67% yield, diastereomeric ratio 98:2, >99% ee). 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.13(d,J=7.3Hz,3H),δ1.27(t,J=7.3Hz,3H),δ2.78(dq,J=7.3,7.3Hz,1H),δ2.99(d,J=5.5,1 H),δ4.19(q,J=7.3Hz,2H),δ4.75(dd,J=5.5,7.3Hz,1H),δ6.39-6.42(m,1H),δ7.38-7.42(m,2H) The enantiomeric excess (ee) of (2R,3S)-2e was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALPAK AD-H (4.6 × 250 mm) (manufactured by Daicel) × 2, Mobile phase: Hexane / 2-PrOH = 97 / 3, Flow rate: 0.8 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =21.1min,24.4min,31.3min,34.3min

[0112] [Example 6] Synthesis of compound (2R,3S)-2f [ka]

[0113] Compound 1f was synthesized with reference to the method described in J. Med. Chem., 32, 757-765 (1989). The same procedure as in Example 3 was carried out to obtain 2f (248.8 mg, 96% yield, diastereomeric ratio >99:1, >99% ee). 1 H-NMR spectrum (400 MHz, CDCl 3)δ1.07(d,J=7.2Hz,3H),δ1.25(t,J=7.2Hz,3H),δ3.16(dq,J=7.6,7.6Hz,1H),δ3.29(d,J=4.4,1H),δ4.20(q,J=7.2Hz,2H ), δ5.53(dd,J=4.4,7.6Hz,1H),δ7.47-7.58(m,4H),δ7.81(d,J=8.4Hz,1H),δ7.88(d,J=8.0Hz,1H),δ8.23(d,J=8.4Hz,1H) The enantiomeric excess (ee) of (2R,3S)-2f was determined by HPLC measurement under the following conditions. Column: CHIRALCEL OD-H (4.6 × 250 mm) (manufactured by Daicel Corporation), mobile phase: hexane / 2-PrOH = 97 / 3, flow rate: 0.8 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =19.6min,29.5min,33.2min,62.7min

[0114] [Example 7] Synthesis of compound (2R,3S)-2g [ka]

[0115] Compound 1g was synthesized using iodoethane as a raw material by referring to the method described in Angew. Chem. Int. Ed., 57, 1039-1043 (2018). By carrying out the procedure under the same conditions as in Example 3, 2g was obtained (207.0 mg, 93% yield, diastereomeric ratio 96:4, 97.6% ee). 1 H-NMR spectrum (400 MHz, CDCl 3 )δ0.88(t,J=7.4Hz,3H),δ1.23(t,J=7.3Hz,3H),δ1.35-1.45(m,1H),δ1.50-1.64(m,1H),δ2.68(ddd ,7.8Hz,1H),δ2.86(d,J=5.5Hz,1H),δ4.17(m,2H),δ4.81(dd,J=5.5,7.8Hz,1H),δ7.27-7.38(m,5H) The enantiomeric excess (ee) of (2R,3S)-2g was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALCEL OD-H (4.6 × 250 mm) (manufactured by Daicel) × 2, Mobile phase: Hexane / 2-PrOH = 97 / 3, Flow: 0.8 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =21.5min,24.9min,31.4min,32.9min

[0116] [Example 8] Synthesis of compound (2R,3S)-2h [ka]

[0117] Compound 1h was synthesized using 2-iodopropane as a starting material, following the method described in Angew. Chem. Int. Ed., 57, 1039-1043 (2018). The same procedure as in Example 3 was used to obtain 2h (180.6 mg, 76% yield, diastereomeric ratio 93:7, >99% ee). 1 H-NMR spectrum (400 MHz, CDCl 3 )δ0.95(d,J=6.9Hz,3H),δ1.07(d,overlapped,3H),δ1.08(t,overlapped,3H),δ2.03(m,1H),δ2.53(dd,J=5 .5,8.2Hz,1H),δ3.42(d,J=7.8Hz,1H),δ4.00-4.07(m,2H),δ4.98(dd,J=5.5,7.8Hz,1H),δ7.24-7.38(m,5H) The enantiomeric excess (ee) of (2R,3S)-2h was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALPAK AD-H (4.6 x 250 mm) (manufactured by Daicel) x 2, mobile phase: hexane / 2-PrOH = 98 / 2, flow rate: 0.8 ml min -1 , Detector: UV 210nm, Column temperature: 30o C, t R =36.0min,38.8min,42.9min,50.0min

[0118] [Example 9] Synthesis of compound (2R,3S)-2i [ka]

[0119] Compound 1i was synthesized using 3-iodopropylene as a starting material, based on the method described in Angew. Chem. Int. Ed., 57, 1039-1043 (2018). The same procedure as in Example 2 was carried out to obtain 2i (217.6 mg, 93% yield, diastereomeric ratio 94:6, >99% ee). 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.20(t,J=7.3Hz,3H),δ2.14-2.23(m,1H),δ2.26-2.35(m,1H),δ2.84(m,1H),δ2.96(d,J=6.0Hz,1H), δ4.15(m,2H),δ4.83(dd,J=6.0,7.6Hz,1H),δ5.00-5.07(m,2H),δ5.64-5.76(m,1H),δ7.28-7.39(m,5H) The enantiomeric excess (ee) of (2R,3S)-2i was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALPAK AD-H (4.6 x 250 mm) (manufactured by Daicel) x 2, mobile phase: hexane / 2-PrOH = 98 / 2, flow rate: 0.8 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =37.8min,42.2min,66.0min,68.5min

[0120] [Example 10] Synthesis of compound (2R,3S)-2j [ka]

[0121] Compound 1j was synthesized with reference to the method described in Eur. J. Org. Chem., 2333-2336 (2015). In a 100 mL hyperglass inner tube, compound 1j (134.2 mg, 0.5 mmol, 1 equiv.), RuBr 2 [(S,S)-xylskewphos](3,5-dmpica) (4.75 mg, 5 μmol, 0.01 equivalent), t BuONa (1.92 mg, 20 μmol, 0.04 equivalents) was weighed out, and the inside of the autoclave was replaced with an argon gas atmosphere. t After adding BuOH (10 mL), the mixture was degassed under reduced pressure and filled with argon gas five times while stirring until it started to bubble lightly. The mixture was then pressurized with hydrogen gas to 0.5 MPa and leaked to 0.1 MPa, and this process was repeated ten times to replace the inside of the system with a hydrogen atmosphere. Hydrogen gas was pressurized to 1.0 MPa and the mixture was cooled to 100°C for 25 min using a thermostatic water bath. o The mixture was stirred under condition C for 24 hours. After 24 hours, hydrogen gas was released and the reaction solution was concentrated. The mixture was purified by column chromatography (eluent: hexane / ethyl acetate = 5 / 1) to obtain compound 2j as a colorless liquid (77.3 mg, 57% yield, diastereomeric ratio 94:6, 97.9% ee).

[0122] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.22(t,J=7.2Hz,3H),δ3.15(d,J=4.0Hz,1H),δ3.87(d,J=9.2Hz,1H),δ4.10-4.28(m,2H),δ5.17(dd,J=9.2,4.0Hz,1H),δ7.06-7.30(m,10H) The enantiomeric excess (ee) of (2R,3S)-2j was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALCEL OJ-H (4.6 × 250 mm) (manufactured by Daicel Corporation), mobile phase: hexane / 2-PrOH = 90 / 10, flow rate: 0.8 ml min -1, Detector: UV 210nm, Column temperature: 30 o C, t R =9.1min,14.1min,15.6min,25.5min

[0123] [Example 11] Synthesis of compound (2R,3S)-2k [ka]

[0124] In a 100 mL glass tube, compound 1k (131.7 mg, 0.5 mmol, 1 equiv.), RuBr 2 [(S,S)-dipskewphos](3-amiq) (5.98 mg, 5 μmol, 0.01 equivalent), t BuONa (1.92 mg, 20 μmol, 0.04 equivalents) was weighed out, and the inside of the autoclave was replaced with an argon gas atmosphere. t After adding BuOH (0.87 mL), the mixture was degassed under reduced pressure and filled with argon gas five times while stirring until it started to bubble lightly. The mixture was then pressurized with hydrogen gas up to 0.5 MPa and leaked down to 0.1 MPa, and this process was repeated ten times to replace the inside of the system with a hydrogen atmosphere. Hydrogen gas was pressurized up to 2.0 MPa and the mixture was cooled for 40 minutes using a thermostatic water bath. o The mixture was stirred under condition C for 24 hours. After 24 hours, hydrogen gas was released and the reaction solution was concentrated. The mixture was purified by column chromatography (eluent: hexane / ethyl acetate = 1 / 1) to obtain compound 2k as a colorless liquid (123.3 mg, 93% yield, diastereomeric ratio 90:10, >99% ee).

[0125] 1 H-NMR spectrum (400 MHz, CDCl 3)δ1.17(t,J=7.2Hz,3H),δ1.93(s,3H),δ3.07(dt,J=6.0,7.2Hz,1H),δ3.22(d,J=6.0Hz,1H),δ3.40-3.5 5(m,2H),δ4.09-4.15(q,J=7.2Hz,2H),δ4.94(dd,J=6.0,6.0Hz,1H),δ5.78(br,1H),δ7.27-7.36(m,5H) The enantiomeric excess (ee) of (2R,3S)-2k was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALCEL OJ-H (4.6 x 250 mm) (manufactured by Daicel) + CHIRALPAK AD-H (4.6 x 250 mm) (manufactured by Daicel), mobile phase: hexane / 2-PrOH = 90 / 10, flow rate: 1.0 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =23.0min,28.9min,31.9min,37.5min

[0126] [Example 12] Synthesis of compound (2R,3S)-2l [ka]

[0127] Compound 1l was obtained by synthesizing the hydrochloride salt with reference to the method described in Chem. A Eur. J., 16, 11954-11962 (2010) and neutralizing it. In a 100mL glass tube, add RuBr 2 [(S,S)-dipskewphos](3-amiq) (5.98 mg, 5 μmol, 0.01 equivalents) t BuONa (1.92 mg, 20 μmol, 0.04 equivalents) was weighed out, and the inside of the stainless steel autoclave was replaced with an argon gas atmosphere. Compound 1l (117.64 mg, 0.5 mmol, 1 equivalents) was weighed out into a 20 mL Schlenk flask under an argon gas atmosphere. tThe mixture was diluted with BuOH (0.88 mL) and pumped into the autoclave using a cannula. After that, the mixture was degassed under reduced pressure and filled with argon gas five times while stirring until it started to bubble lightly. The mixture was then pressurized with hydrogen gas up to 0.5 MPa and leaked down to 0.1 MPa, and this process was repeated ten times to replace the inside of the system with a hydrogen atmosphere. Hydrogen gas was pressurized up to 2.0 MPa and the mixture was cooled for 40 minutes using a thermostatic water bath. o The mixture was stirred under condition C for 72 hours. After 72 hours, hydrogen gas was released and the reaction mixture was concentrated. The mixture was purified by column chromatography (eluent: hexane / ethyl acetate = 5 / 1) to obtain compound 2l as a colorless liquid (89.0 mg, 75% yield, diastereomeric ratio 93:7, >99% ee).

[0128] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.16(d,J=7.2Hz,3H),δ2.36(s,6H),δ3.28(d,J=7.2Hz,1H),δ4.02-4.17 (m,2H),δ5.00-5.07(m,2H),δ5.02(d,J=7.2,4.1Hz,1H),δ7.26-7.38(m,5H) The enantiomeric excess (ee) of (2R,3S)-2l was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALCEL OD-H (4.6 × 250 mm) (manufactured by Daicel), mobile phase: hexane / 2-PrOH = 97 / 3, flow rate: 0.8 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =8.0min,9.0min,19.3min,21.4min

[0129] [Example 13] Synthesis of compound (2R,3S)-2n [ka]

[0130] In a 100 mL hyperglass inner tube, compound 1n (133.7 mg, 0.5 mmol, 1 equivalent) RuBr2 [(S,S)-dipskewphos](3-amiq) (1.20 mg, 1 μmol, 0.002 equivalents) t BuONa (1.92 mg, 40 μmol, 0.04 equivalents) was weighed out, and the inside of the autoclave was replaced with an argon gas atmosphere. t After adding BuOH (0.87 mL), the system was repeatedly depressurized and refilled with argon gas five times while stirring until it started to bubble lightly. The system was then pressurized with hydrogen gas to 0.5 MPa and then leaked to 0.1 MPa, and this process was repeated ten times to replace the system with a hydrogen atmosphere. Hydrogen gas was pressurized to 1.0 MPa and the system was heated for 25 minutes using a thermostatic water bath. o The mixture was stirred under condition C for 24 hours. After 24 hours, the hydrogen gas was released and the reaction mixture was concentrated. The mixture was purified by column chromatography (eluent: hexane / ethyl acetate = 2 / 1) to obtain compound 2n as a colorless solid (133.9 mg, 99% yield, diastereomeric ratio > 99:1, > 99% ee).

[0131] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ1.21(d,J=7.6Hz,3H),δ2.55(dq,J=6.0,7.6Hz,1H),δ3.84(d,J=6.0Hz,1H),δ4.30-4.50( m,2H),δ4.78(dd,J=6.0,6.0Hz,1H),δ5.85(brs,1H),δ7.08-7.11(m,2H),δ7.25-7.35(m,8H) The enantiomeric excess (ee) of (2R,3S)-2n was determined by HPLC optical purity measurement under the following conditions. Column: CHIRALCEL OD-H (4.6 × 250 mm) (manufactured by Daicel) × 2, Mobile phase: Hexane / 2-PrOH = 90 / 10, Flow: 1.0 ml min -1 , Detector: UV 210nm, Column temperature: 30 o C, t R =18.2min,24.2min,30.0min,32.7min

Claims

1. A method for producing optically active hydroxy esters or hydroxy amides, comprising the steps of: RuXYAB (1) [In the general formula (1), X and Y are the same or different and each represents a hydrogen atom or an anionic group, and A represents a compound represented by the following general formula (2): 【Chemistry 1】 (In general formula (2), R １ and R ２ are the same or different 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 or different and each represents 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 or different and each represents a hydrocarbon group which may have a substituent, and * represents an asymmetric carbon atom. The optically active diphosphine represented by the formula: B is represented by the following general formula (3): 【Chemistry 2】 In the general formula (3), each D is independently the same or different and represents a carbon atom or a nitrogen atom, R ９ , R １０ and R １１ are the same or different and represent 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 heterocycle which may have a substituent, Each R １２ are the same or different 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 heterocycle which may have a substituent, R １２ may be at least partially bonded to ruthenium as anionic group X, and n is an integer of 0 to (4-(the number of D which is a nitrogen atom)). In the presence of one or more ruthenium complexes selected from compounds represented by the following general formula (4): 【Chemistry 3】 (wherein J is an aromatic ring or an alkyl group, each of which may have a substituent; K is any of an alkyl group, an aryl group, an allyl group, an amino group, an amide group bonded at the N atom of an amide bond, and a sulfonamide group bonded at the N atom of an amide bond, each of which may have a substituent; and L is any of an ester group bonded at the C atom of an ester bond, and an amide group bonded at the C atom of an amide bond), with hydrogen to obtain a carbonyl compound represented by the following general formula (5): 【Chemistry 4】 (In the formula, J, K and L are as defined above, and * indicates the position of the asymmetric carbon.) The method for producing an optically active hydroxy ester or hydroxy amide represented by the formula:

2. In the reaction system, a compound represented by the following general formula (6) RuXYA (6) (In the general formula (6), X, Y and A each independently have the meaning as defined in the general formula (1)) and one or more amine compounds selected from the compounds represented by the general formula (3). The method according to claim 1, wherein the ruthenium complex represented by the general formula (1) is prepared in situ by causing one or more complexes selected from the compounds represented by the general formula (6) to be present.

3. Two R's １２ are linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocycle which may have a substituent, and the two R １２ The method according to claim 1 or 2, wherein the ring formed by the rings formed by the rings containing D is a quinoline ring or an isoquinoline ring.

4. The method according to any one of claims 1 to 3, wherein in general formula (3), one or more of the four Ds is a nitrogen atom.

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-ditert-butylphenylphosphino)pentane, phosphino)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-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-(diphenylphosphine 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, wherein the aryl group is 3-diphenyl-2-methylpropane.

6. 6. The method of 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-ditertbutylphenylphosphino)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)- 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) 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-diisobuty ethylpyridine, 2-(aminomethyl)-5,6-diisobutylpyridine, 2-(aminomethyl)-3,4-ditert-butylpyridine, 2-(aminomethyl)-3,5-ditert-butylpyridine, 2-(aminomethyl)-3,6-ditert-butylpyridine, 2-(aminomethyl)-4,5-ditert-butylpyridine, 2-(aminomethyl)-4,6-ditert-butylpyridine, 2-(aminomethyl)-5,6-ditert-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)- 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-ditert-butylpyridine, 2-(1-aminoethyl)-3,5-diter t-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 The method according to any one of claims 1 to 6, wherein the compound is 1-(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.

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