JP2015024975A - Production method of optically active secondary alcohol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a chemical catalytic method allowing efficient production of a corresponding optically active secondary alcohol from an aromatic ketone having a substituent at each of two β-positions in an aromatic ring to the carbonyl site, so that both enantiomers can be separately made.SOLUTION: A production method of optically active secondary alcohol is characterized by reacting a ketone compound such as acetophenone derivatives with hydrogen in the presence of a ruthenium complex catalyst having an optically active diphosphine ligand.

Description

  The present invention relates to a method for producing an optically active secondary alcohol, and more particularly to a method for producing an optically active secondary alcohol useful as an optically active physiologically active compound or liquid crystal material synthesis intermediate used in medicines, agricultural chemicals and the like.

  Many naturally occurring organic compounds are optically active substances. Among them, a compound having physiological activity often has a desirable activity only in one optical isomer. It is also known that the other optical isomer that does not have the desired activity not only has no physiological activity useful for the living body, but may be toxic to the living body. Therefore, development of a method for synthesizing an optically active compound having high optical purity as a target compound or an intermediate thereof is desired as a method for synthesizing a safe pharmaceutical or agricultural chemical.

  Optically active alcohols are useful as chiral building blocks for the synthesis of various optically active compounds. In general, optically active alcohols are produced by optical resolution of racemates, or by asymmetric synthesis using a biological catalyst, an asymmetric organic molecular catalyst, or an asymmetric metal complex catalyst. In particular, the synthesis of optically active alcohols by these asymmetric syntheses is considered an indispensable technique for producing a large amount of optically active alcohols.

  Optically active secondary alcohols in which the carbonyl moiety of a ketone having a substituent on each of two carbons adjacent to an atom substituted with a carbonyl group of an aromatic compound or an aromatic compound containing a heteroatom is reduced are pharmaceuticals, agricultural chemicals It is an intermediate for the synthesis of optically active physiologically active compounds used in the field, and is an industrially useful optically active alcohol. For example, optically active 1- (2,6-dichloro-3-fluorophenyl) ethanol is a synthetic intermediate for c-Met inhibitors or tyrosine kinase inhibitors for non-differentiated lymphoid kinase (ALK) fusion gene positive non-small cell lung cancer. (Patent Documents 1 and 2, Non-Patent Document 1). 1- (2,6-dichlorophenyl) ethanol is known as a c-Met inhibitor synthesis intermediate (Patent Document 3). Furthermore, 1- (2,6-difluorophenyl) ethanol is used as a nicotinic acid receptor agonist (Patent Document 4).

As methods for synthesizing optically active secondary alcohols, optical resolution, enzyme (microorganism) reduction, chemical asymmetric synthesis, and the like are known.
As an optical resolution method using an enzyme, an example is known in which an optically active 1- (2,6-dichloro-3-fluorophenyl) ethanol is obtained by acetylating a racemic alcohol and then reacting with Pig River Esterase. (Patent Document 5, Non-Patent Document 2). Such a method has high optical purity of the resulting alcohol form, but is not only difficult to separate from the acetylated form, but also has a yield of about 50% at the maximum. Since it becomes unnecessary, it is difficult to say that it is an efficient synthesis method.

  Examples of optical resolution by a chemical method include optical resolution by asymmetric acylation of a racemic alcohol using an organic base having an asymmetric structure as a catalyst (Non-Patent Documents 3 to 5). Such a method has the advantage of obtaining an alcohol form having the opposite steric structure by changing the structure of the catalyst to the opposite enantiomer, but it is difficult to separate from the acylated form, and the yield is also high. Since it is 50% at the maximum and other than the required three-dimensional structure is unnecessary, it cannot be said that it is an efficient synthesis method.

  One method for preferentially synthesizing one enantiomer of a target alcohol using a prochiral ketone as a raw material is enzyme (microorganism) reduction. As an example of a method for synthesizing optically active secondary alcohols by enzyme (microorganism) reduction, a modified ketoreductase enzyme or a host cell capable of expressing the same is used, and 2 ′, 6′-dichloro-3′-fluoroacetophenone is used as a raw material. In addition, there is a synthesis example of (S) -1- (2,6-dichloro-3-fluorophenyl) ethanol having high optical purity (Patent Document 6). In addition, S.P. (S) -1- (2,3,4,5,6-pentafluorophenyl) from 2 ′, 3 ′, 4 ′, 5 ′, 6′-pentafluoroacetophenone by reduction using Elongatus PPC7942 A synthesis example of ethanol is known (Non-Patent Document 6). However, in these methods, only one enantiomer can be obtained, and when the other enantiomer is desired, these methods cannot be used. Furthermore, when using a non-natural type enzyme, utilization of the obtained enantiomer for a pharmaceutical may be regarded as a problem from the viewpoint of safety.

  As a method capable of selectively synthesizing each enantiomer, there is a chemical asymmetric synthesis method. This can be broadly classified into those using a stoichiometric amount of the asymmetric source and those using a catalytic amount.

  As an example of a method using a stoichiometric amount of an asymmetric source, B-chlorodiisopinocinfeylborane (DIP-Chloride (TM)) is used for the determination of acetophenones having two substituents at the 2 ′ and 6 ′ positions. Simultaneous reduction has been reported (Non-patent Document 7). However, this method is not an efficient method because the obtained compound has a low optical purity and uses an expensive asymmetric source in a stoichiometric amount.

  On the other hand, examples of catalytic asymmetric synthesis using a catalytic amount of an asymmetric source include asymmetric hydrosilylation with optically active diphosphine as a ligand or a cobalt catalyst (Non-patent Documents 8 and 9) and ferrocene. Hydrosilylation of substituted acetophenone with rhodium catalyst having PN ligand with bone nucleus (Non-patent Document 10), hydroboration of styrene derivative with rhodium catalyst having optically active diphosphine as ligand (Non-patent Document 11, 12) and the like. However, in these methods, the optical purity of the obtained compound is often low, and since the substrate catalyst ratio is low, it is necessary to use a large amount of catalyst, and further hydrolysis is required to obtain an alcohol form. Therefore, it is not efficient.

  As a catalytic asymmetric synthesis method capable of obtaining an optically active alcohol in one step, a synthesis example of (R) -1- (2,6-dichloro-3-fluorophenyl) ethanol by a CBS reduction method (Non-patent Document 13) ) And (S) -1- (2,4,6-trimethylphenyl) ethanol and (S) -1- (2,3,4,5,6-pentafluorophenyl) ethanol synthesis examples (non-patent literature) 14) has been reported. However, these methods require about 10 mol% of a catalyst, and there are problems that high optical purity cannot be obtained depending on the substrate.

  A more efficient example is an optical activity in which an aromatic ring is substituted with fluorine by hydrogen transfer asymmetric reduction of a ketone using 2-propanol as a hydrogen source with a ruthenium arene complex having an optically active amino alcohol as a ligand. Synthesis of phenethyl alcohol (Non-patent Document 15) and hydrogen transfer asymmetric reduction using 2-propanol as a hydrogen source using a ruthenium complex catalyst having an optically active (phosphinoferrocenyl) oxazoline as a ligand Has reported the synthesis of (R) -1- (2,4,6-trimethylphenyl) ethanol (Non-patent Document 16). However, these reactions are also not efficient methods because the substrate / catalyst ratio is as low as about 200 to 500 and the substrate concentration is low.

  Recently, asymmetric hydrogenation reaction of 2 ′, 6′-dimethoxyacetophenone and 2 ′, 4 ′, 6′-trimethylacetophenone with a ruthenium complex catalyst having a bis (oxazolinyl) phenyl (Phebox) ligand has also been carried out. It has been reported (Non-patent Document 17). However, this reaction also requires high pressure hydrogen of 30 atm, a substrate / catalyst ratio as low as 100, and 10 mol% of optically active 1- (9-anthracenyl) ethanol for improving optical purity. There are many problems, such as the need to add.

  By the way, as one method for efficiently obtaining an optically active alcohol, a ruthenium metal complex having an optically active diphosphine compound such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) and an ethylenediamine type A method of asymmetric hydrogenation of a carbonyl compound in the presence of an optically active diamine compound and a base such as an alkali metal or alkaline earth metal hydroxide (Patent Document 7), or an optically active diphosphine compound such as BINAP and an ethylenediamine type A method of asymmetric hydrogenation of a carbonyl compound in the presence of a base such as a ruthenium metal complex having an optically active diamine compound as a ligand and an alkali metal or alkaline earth metal hydroxide is disclosed (Patent Document 8). ). In addition, a method using an optically active phosphine such as 2,4-bis (diphenylphosphino) pentane (SKEWPHOS) and a ruthenium complex having an optically active 1,2-ethylenediamine type ligand is also known (Patent Document 9). ). However, in these methods, only substrates having only one substituent at any position of the unsubstituted acetophenones and aromatic rings are used.

  On the other hand, a ruthenium complex having optically active diphosphine and 2-picolylamine (PICA) as ligands is known to asymmetrically reduce ketones using 2-propanol as a hydrogen source (Patent Document 10). In the reduction of unsubstituted acetophenone, although the effect of accelerating the reaction rate by hydrogenation is described, there is no effect of increasing the reaction rate by hydrogen pressurization, and there is a problem that the optical purity of the generated phenylethanol is lowered. Further exemplified aromatic ketones as substrates are only unsubstituted acetophenone, benzophenone or acetophenones having only one substituent on the aromatic ring.

  As an example of using a ruthenium complex having an optically active diphosphine and 2-picolylamine (PICA) as a ligand for hydrogenation, an optically active diphosphine compound such as BINAP and a ruthenium catalyst having 2-picolylamine as a ligand are used. Hydrogenation of tert-alkyl ketones has been reported (Patent Document 11). However, the exemplified substrate structure is limited to tert-alkyl ketones.

  Examples of the use of a catalyst having a ligand of diphosphine having a SKEWPHOS skeleton and 2-picolylamine for hydrogenation include hydrogenation of 3-quinuclidinone (Patent Document 12) or hydrogenation of a heterocyclic ring having a benzoyl group (Patent Document 13) has been reported.

Special table 2008-510790 gazette Japanese translation of PCT publication No. 2008-510788 Special table 2011-500651 gazette Japanese translation of PCT publication 2010-509397 Japanese translation of PCT publication No. 2008-510791 Special table 2010-535657 JP-A-8-225466 JP 11-189600 A JP 2003-25284 A Special table 2007-536338 gazette International Publication No. 2006/046508 International Publication No. 2006/103756 JP 2011-51929 A

Org. Process Res. Dev. 15, 1018-1026 (2011) Tetrahedron Asymmetry, 21, 2408-2412 (2010) J. Org. Chem., 65, 3154-3159 (2000) Tetrahedron, 60, 4513-4525 (2004) J. Org. Chem., 77, 1722-1737 (2012) Chem. Commun., 1782-1783 (2002) Tetrahedron Lett., 45, 2603-2605 (2004) Org. Biomol. Chem., 9, 5652-5654 (2011) Adv. Synth. Catal., 353, 1457-1462 (2011)

Angew. Chem. Int. Ed., 41, 3892-3894 (2002) Chem. Commun., 464-465 (2004) J. Fluorine Chem., 128, 827-831 (2007) Tetrahedron Lett., 41, 10281-10283 (2000) Tetrahedron, 58, 1069-1074 (2002) J. Org. Chem., 69, 4885-4890 (2004) J. Org. Chem., 62, 6104-6105 (1997) Chem. Commun., 48, 1105-1107 (2012)

  As described above, the corresponding optically active secondary alcohol is converted into both enantiomers from the ketone having a substituent on each of two carbons adjacent to the atom substituted with the carbonyl group of the aromatic compound or the aromatic compound containing a hetero atom. There has been no known chemical catalytic method that can be produced efficiently. Accordingly, an object of the present invention is to provide a corresponding optically active secondary alcohol from a ketone having a substituent on each of two carbons adjacent to an atom substituted with a carbonyl group of an aromatic compound or an aromatic compound containing a hetero atom. Another object of the present invention is to provide a chemical catalytic method for preferentially and efficiently producing a target enantiomer.

  The present inventors provide a method for efficiently producing an optically active secondary alcohol from a ketone having a substituent on each of two carbons adjacent to an atom substituted with a carbonyl group of an aromatic compound or an aromatic compound containing a hetero atom. As a result, the ketone having a substituent on each of two carbons adjacent to the atom substituted by the carbonyl group of the aromatic compound or the aromatic compound containing a hetero atom is not substituted with a conventionally used catalyst. We faced the problem that the optical purity of the optically active secondary alcohol which is difficult to reduce or the optically active secondary alcohol produced is lower than the aromatic ketone which does not have.

  As a result of diligent studies to solve this problem, the present inventors have found that a ketone having a substituent on each of two carbons adjacent to an atom substituted with a carbonyl group of an aromatic compound or an aromatic compound containing a hetero atom. In the intensive study of efficient synthesis methods of optically active secondary alcohols obtained by reduction, 2-picolyl having a specific optically active diphosphine and a substituent at any position on the 2-picolylamine or pyridine ring A ruthenium complex catalyst having a ruamine derivative or a nitrogen-containing aliphatic cyclic compound having an aminomethyl group as a ligand is found to have excellent performance as an asymmetric hydrogenation catalyst for the above-mentioned aromatic ketone, and the present invention is completed. I came to let you.

  That is, the present invention relates to the following.

[1] A method for producing an optically active secondary alcohol comprising the following general formula (1)
RuXYAB (1)
[In the general formula (1), X and Y are the same or different from each other, and represent a hydrogen atom or an anionic group, and A represents the following general formula (2)
(In general formula (2),
R ¹ and R ² are the same or different from each other, and represent a C1-C20 linear or cyclic hydrocarbon group which may have a substituent,
R ³ and R ⁴ are the same or different from each other, 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 from each other and represent a hydrocarbon group which may have a substituent,
* Represents an asymmetric carbon atom. ), And B represents the following general formula (3) or general formula (4)
(In general formula (3),
R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different from each other, and each represents a hydrogen atom or a C 1-20 linear or cyclic hydrocarbon group which may have a substituent,
R ¹⁰ and R ¹¹ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent,
R ¹² may be bonded at least partly to ruthenium as an anionic group X;
n represents an integer of 0 or 1,
In general formula (4),
R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different from each other at each occurrence, and are each a linear or cyclic group having 1 to 20 carbon atoms which may have a hydrogen atom or a substituent. Represents a hydrocarbon group, provided that at least one of R ¹³ , R ¹⁴ and R ¹⁵ is a hydrogen atom;
R ¹³ and R ¹⁴ may combine with each other to form a ring containing a nitrogen atom,
R ¹⁶ and R ¹⁷ and / or two adjacent R ¹⁸ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent,
Each R ¹⁸ may be independently bonded to ruthenium as at least a part thereof as an anionic group X;
m represents an integer of 1 to 3,
k represents an integer of 0 to 10. )
The amine compound represented by these is shown. ]
In the presence of one or two or more ruthenium complexes selected from the compounds represented by the following general formulas (5) to (7)
[D ^{1 to} D ³ in the general formulas (5) to (7) represent a carbon atom or a nitrogen atom, and any one of D ^{1 to} D ³ is a nitrogen atom,
R ¹⁹ and R ²⁰ are the same or different and each represents a linear or branched alkyl group having 1 to 9 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a halogen group, or a nitro group. Show
R ²¹ represents a branched or straight chain alkyl or alkoxy group having 1 to 9 carbon atoms which may be substituted with a hetero atom, an amino group, an amide group, a nitro group, an acyl group, an ester group, or a cyclic aliphatic hydrocarbon. Group,
R ^{22 to} R ²⁴ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a substituent. A cyclic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a halogen group or a nitro group, provided that when D ^{1 to} D ³ are nitrogen atoms, There is no group selected from the group consisting of the corresponding R ²² , R ²³ and R ²⁴ on the atom;
E represents an oxygen or sulfur atom]
A process wherein the ketone selected from the compounds represented by is reacted with hydrogen.

[2] In the reaction system, the following general formula (8)
RuXYA (8)
[In general formula (8), X, Y, and A have the meaning as defined in general formula (1) mutually independently. And one or more amines selected from the compounds represented by the general formula (3) or the general formula (4) The method according to [1], wherein the ruthenium complex represented by the general formula (1) is prepared in situ by the presence of the compound.

[3] A is 2,4-bis- (diphenylphosphino) pentane, 2,4-bis- (di-4-tolylphosphino) pentane, 2,4-bis- (di-3,5-xylylphosphine) Fino) 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- (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-t rt-butylphenylphosphino) -3-methylpentane, 2,4-bis- (di-3,5-diethylphenylphosphino) -3-methylpentane, 2,4-bis- (di-3,5- Diisopropylphenylphosphino) -3-methylpentane, 1,3-bis- (diphenylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-4-tolylphosphino) -1,3-diphenylpropane 1,3-bis- (di-3,5-xylylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-4-tert-butylphenylphosphino) -1,3- Diphenylpropane, 1,3-bis- (di-3,5-diethylphenylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-3,5-diisopropylphenylphosphine) Dino) -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, [1] or [2].

[4] 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-) The method according to any one of [1] to [3], which is 3,5-diethylphenylphosphino) pentane or 2,4-bis- (diphenylphosphino) -3-methylpentane.

[5] 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-phenyl The method according to any one of [1] to [4], which is nylpyridine, 2- (aminomethyl) -4-phenylpyridine, or 2- (aminomethyl) -5-phenylpyridine.

[6] 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) -4-isopropylpyrpyridine or 2- ( The method according to any one of [1] to [5], which is aminomethyl) -4-tert-butylpyridine.

[7] In general formulas (5) to (7),
R ¹⁹ and R ²⁰ are the same or different and each represent a linear or branched alkyl group or alkoxy group having 1 to 5 carbon atoms which may have a halogen group, a halogen group or a nitro group,
R ²¹ represents a branched or linear alkyl group having 1 to 6 carbon atoms which may be substituted with an aromatic ring or a hetero atom, an acyl group, an ester group or a cyclic hydrocarbon group, according to [1] to [6] The method according to any one.

[8] In general formulas (5) to (7),
The method according to any one of [1] to [7], wherein R ²¹ is an alkyl group having 1 to 3 carbon atoms.
[9] In general formulas (5) to (7),
The method according to [8], wherein R ²¹ is a methyl group.

[10] In general formulas (5) to (7),
R ¹⁹ and R ²⁰ are a linear or branched alkyl group having 1 to 3 carbon atoms which may have a halogen group, an alkoxy group or a halogen group,
R ²¹ is an alkyl group having 1 to 3 carbon atoms,
R ^{22 to} R ²⁴ may be hydrogen or a C 1-3 linear or branched alkyl group which may have a halogen group, an alkoxy group, a halogen group or a cyclic hydrocarbon group which may have a substituent or a substituent A heterocyclic ring optionally having a group,
[1] The method according to any one of [8].

[11] A method for producing an optically active secondary alcohol, the following general formula (8)
RuXYA (8)
[In the general formula (8), X and Y are the same or different from each other, each represents a hydrogen atom or an anionic group, and A represents the following general formula (2)
(In general formula (2),
R ¹ and R ² are the same or different from each other, and represent a C1-C20 linear or cyclic hydrocarbon group which may have a substituent,
R ³ and R ⁴ are the same or different from each other, 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 from each other and represent a hydrocarbon group which may have a substituent,
* Represents an asymmetric carbon atom. 1 or 2 or more types of complex selected from the compound represented by the following general formula (3) or general formula (4)
[In general formula (3),
R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different from each other, and each represents a hydrogen atom or a C 1-20 linear or cyclic hydrocarbon group which may have a substituent,
R ¹⁰ and R ¹¹ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent,
R ¹² may be bonded at least partly to ruthenium as an anionic group X;
n represents an integer of 0 or 1,
In general formula (4),
R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different from each other at each occurrence, and are each a linear or cyclic group having 1 to 20 carbon atoms which may have a hydrogen atom or a substituent. Represents a hydrocarbon group, provided that at least one of R ¹³ , R ¹⁴ and R ¹⁵ is a hydrogen atom;
R ¹³ and R ¹⁴ may combine with each other to form a ring containing a nitrogen atom,
R ¹⁶ and R ¹⁷ and / or two adjacent R ¹⁸ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent,
Each R ¹⁸ may be independently bonded to ruthenium as at least a part thereof as an anionic group X;
m represents an integer of 1 to 3,
k represents an integer of 0 to 10. In the presence of one or more amine compounds selected from the compounds represented by formula (5) to (7):
[D ^{1 to} D ³ in the general formulas (5) to (7) represent a carbon atom or a nitrogen atom, and any one of D ^{1 to} D ³ is a nitrogen atom,
R ¹⁹ and R ²⁰ are the same or different and each represents a linear or branched alkyl group having 1 to 9 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a halogen group, or a nitro group. Show
R ²¹ represents a branched or straight chain alkyl or alkoxy group having 1 to 9 carbon atoms which may be substituted with a hetero atom, an amino group, an amide group, a nitro group, an acyl group, an ester group, or a cyclic aliphatic hydrocarbon. Group,
R ^{22 to} R ²⁴ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a substituent. A cyclic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a halogen group or a nitro group, provided that when D ^{1 to} D ³ are nitrogen atoms, There is no group selected from the group consisting of the corresponding R ²² , R ²³ and R ²⁴ on the atom;
E represents an oxygen or sulfur atom]
A process wherein the ketone selected from the compounds represented by is reacted with hydrogen.

[12] In any one of [1] to [11], the reaction of the ketone selected from the compounds represented by the general formulas (5) to (7) with hydrogen is performed in the presence of a base. The method described.

  According to the present invention, a ketone having a substituent on each of two carbons adjacent to an atom substituted with a carbonyl group of an aromatic compound or an aromatic compound containing a hetero atom, particularly in the general formulas (5) to (7) Arbitrary enantiomers of the optically active secondary alcohols obtained by reducing the carbonyl group of the ketones represented can be obtained with high reaction yield and high enantioselectivity. It can be said that this method is an industrially and economical method compared with the conventional method.

Hereinafter, the present invention will be described in detail based on preferred embodiments.
The present invention is a compound represented by the following general formulas (5) to (7) in the presence of one or more ruthenium complexes selected from compounds represented by the following general formula (1). An optically active secondary alcohol is obtained by reacting a ketone selected from hydrogen with hydrogen.
Hereinafter, first, the ruthenium complex and ketone used in the present method will be described in detail, and then a preferred embodiment of the present method will be described in detail.

<Ruthenium complex>
The ruthenium complex used in the present invention has the following general formula (1):
RuXYAB (1)
(In the formula, A represents the following general formula (2)
Is an optically active diphosphine compound A represented by the following general formula (3) or general formula (4):
It is an amine compound B represented by these. )
It is represented by

In the general formula (1), the substituents X and Y are the same or different from each other, and represent a hydrogen atom or an anionic group.
As the anionic group, a halogen atom, a carboxyl group, a tetrahydroborate anion, and a substituted phenyl anion group are preferable, but various other anionic groups may be used, for example, an alkoxy group, a hydroxy group, and the like can be used. . X and Y are preferably a hydrogen atom, a halogen atom, a tetrahydroborate anion, a tolyl anionic group, an acetoxy group or the like, more preferably a halogen atom or a tolyl anionic group, and particularly preferably a chlorine atom or a bromine atom. It is.

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

In the general formula (2), R ¹ and R ² are the same or different from each other, and represent a C1-C20 chain or cyclic hydrocarbon group which may have a substituent, and R ³ and R ⁴ are the same as each other Or, it represents 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 from each other, and represent a hydrocarbon group which may have a substituent, * Indicates an asymmetric carbon atom.
Here, R ¹ and R ² are not particularly limited, and examples thereof include saturated or unsaturated chain aliphatic hydrocarbon groups, saturated or unsaturated monocyclic or polycyclic cyclic aliphatic hydrocarbon groups, and monocyclic rings. Or the group etc. which combined the polycyclic aromatic hydrocarbon group and these various hydrocarbon groups, etc. are mentioned, These hydrocarbon groups may have a substituent further.

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

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

Examples of R ⁵ , R ⁶ , R ⁷ and R ⁸ include, but are not limited to, for example, a saturated or unsaturated chain aliphatic hydrocarbon group, a saturated or unsaturated monocyclic or polycyclic cyclic aliphatic hydrocarbon Groups, monocyclic or polycyclic aromatic hydrocarbon groups, and the like, and these hydrocarbon groups may further have a substituent.

Examples of R ⁵ , R ⁶ , R ⁷ and R ⁸ include hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl such as phenyl and naphthyl, aralkyl such as phenylalkyl, and these hydrocarbon groups. Further, hydrocarbon groups having an acceptable substituent such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, dialkylamino group, nitro group, cyano group and the like can be mentioned.

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

^{Incidentally,} R ^5, R 6, the number of carbon atoms of ^{R 7} and ^{R 8} is not particularly limited, for example, 1 to 20, preferably, may be 5 to 10.

  Examples of the optically active diphosphine represented by the general formula (2) include pentane derivatives having diphenylphosphino groups at the 2-position and 4-position, pentane derivatives having di-4-tolylphosphino groups at the 2-position and 4-position, Pentane derivatives having di-4-t-butylphenylphosphino groups at positions 4 and 4, pentane derivatives having di-3,5-xylylphosphino groups at positions 2 and 4 A pentane derivative having a 3,5-diethylphenylphosphino group, a 1,3-diphenylpropane derivative having a diphenylphosphino group at the 1-position and the 3-position, and a 1 having a di-4-tolylphosphino group at the 1-position and the 3-position , 3-Diphenylpropane derivative, 1,3-diphenylpropane having di-4-tert-butylphenylphosphino groups at the 1- and 3-positions 1,3-diphenylpropane derivative having a di-3,5-xylylphosphino group at the 1-position and 3-position, 1,1-diphenylpropane derivative having a di-3,5-diethylphenylphosphino group at the 1-position and the 3-position Examples include 3-diphenylpropane derivatives.

  More specifically, the optically active diphosphine compound A is preferably SKEWPHOS: 2,4-bis- (diphenylphosphino) pentane, TolSKEWPHOS: 2,4-bis- (di-4-tolylphosphino) pentane, XylSKEWPHOS: 2,4-bis- (di-3,5-xylylphosphino) pentane, 4-t-BuSKEWPHOS: 2,4-bis- (di-4-tert-butylphenylphosphino) pentane, 3,5- diEtSKEWPHOS: 2,4-bis- (di-3,5-diethylphenylphosphino) pentane, 2,4-bis- (di-3,5-diisopropylphenylphosphino) pentane, 2,4-bis- (diphenyl) Phosphino) -3-methylpentane, 2,4-bis- (di-4-tolylphosphino) -3-me Rupentane, 2,4-bis- (di-3,5-xylylphosphino) -3-methylpentane, 2,4-bis- (di-4-tert-butylphenylphosphino) -3-methylpentane, 2,4-bis- (di-3,5-diethylphenylphosphino) -3-methylpentane, 2,4-bis- (di-3,5-diisopropylphenylphosphino) -3-methylpentane, 1, 3-bis- (diphenylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-4-tolylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-3,5 -Xylylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-4-tert-butylphenylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-3) , 5-Di Tylphenylphosphino) -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.

  The optically active diphosphine compound A is more preferably SKEWPHOS: 2,4-bis- (diphenylphosphino) pentane, TolSKEPPHOS: 2,4-bis- (di-4-tolylphosphino) pentane, XylSKEWPHOS: 2,4-bis -(Di-3,5-xylylphosphino) pentane, 4-i-PrSKEWPHOS: 2,4-bis- (di-4-isopropylphenylphosphino) pentane, 4-t-BuSKEWPHOS: 2,4-bis -(Di-4-tert-butylphenylphosphino) pentane, 3,5-diEtSKEWPHOS: 2,4-bis- (di-3,5-diethylphenylphosphino) pentane, or 2,4-bis- (diphenyl) Phosphino) -3-methylpentane.

  Of these, SKEWPHOS, TolSKEWPHOS, 3,5-EtSKEWPHOS, t-BuSKEWPHOS, and XylSKEWPHOS are particularly preferable. However, of course, the optically active diphosphine compound A that can be used in the present invention is not limited to these.

Moreover, 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.

In the formula, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different from each other, and each represents a hydrogen atom or a C 1-20 linear or cyclic hydrocarbon group which may have a substituent,
R ¹⁰ and R ¹¹ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent,
R ¹² may be bonded at least partly to ruthenium as an anionic group X;
n represents an integer of 0 or 1.

Here, R ^{9 to} R ¹² are not particularly limited, and examples thereof include a hydrogen atom, a saturated or unsaturated chain aliphatic hydrocarbon group, a saturated or unsaturated monocyclic or polycyclic cyclic aliphatic hydrocarbon. Groups, monocyclic or polycyclic aromatic hydrocarbon groups, and the like, and these hydrocarbon groups may further have a substituent.
Examples of R ^{9 to} R ¹² include a hydrogen atom, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, for example, a hydrocarbon group such as phenyl, naphthyl, aralkyl, for example, phenylalkyl, and further to these hydrocarbon groups, alkyl, Examples include hydrocarbon groups having various permissible substituents such as alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group, and cyano group.

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.

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 a hydrogen atom, or any one of R ¹⁰ and R ¹¹ is a methyl group. .
R ¹² is preferably a hydrogen atom, an alkyl group or an aryl group, more preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a substituted or unsubstituted phenyl group, particularly preferably A hydrogen atom, a methyl group, a phenyl group or an o-, m- or p-tolyl group;

R ¹⁰ and R ¹¹ may be connected to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent. Examples of such cyclic hydrocarbon groups include cycloalkyl groups, cycloalkenyl groups, and cycloalkynyl groups having 3 to 10 ring members, preferably 4 to 8 ring members. More specifically, examples of the ring formed by R ¹⁰ and R ¹¹ include cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, piperidylidene, and those in which a substituent is substituted. . Among the above-mentioned, monocyclic hydrocarbon rings, particularly cyclopentylidene and cyclohexylidene are preferable.

Moreover, as the amine compound B in the optically active ruthenium complex represented by the general formula (1), a compound represented by the following formula (4) can also be used.

R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different from each other at each occurrence, and are each a linear or cyclic group having 1 to 20 carbon atoms which may have a hydrogen atom or a substituent. Represents a hydrocarbon group, provided that at least one of R ¹³ , R ¹⁴ and R ¹⁵ is a hydrogen atom;
R ¹³ and R ¹⁴ may combine with each other to form a ring containing a nitrogen atom,
R ¹⁶ and R ¹⁷ and / or two adjacent R ¹⁸ may be linked to each other to form a saturated or unsaturated cyclic hydrocarbon group which may have a substituent,
Each R ¹⁸ may be independently bonded to ruthenium as at least a part thereof as an anionic group X;
k represents an integer of 1 to 3,
m shows the integer of 0-10.

R ^{13 to} R ¹⁸ are not particularly limited, and examples thereof include saturated or unsaturated chain aliphatic hydrocarbon groups, saturated or unsaturated monocyclic or polycyclic cycloaliphatic hydrocarbon groups, monocyclic or polycyclic Ring aromatic hydrocarbon groups and the like, and these hydrocarbon groups may further have a substituent.
Examples of R ^{13 to} R ¹⁸ include hydrocarbon groups such as alkyl, such as methyl, ethyl, n-propyl, isopropyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, such as phenyl and naphthyl, aralkyl, such as phenylalkyl, and These hydrocarbon groups further include hydrocarbon groups having an acceptable substituent such as alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group, and cyano group.

R ¹³ and R ¹⁴ are preferably a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, more preferably a methyl, ethyl, n-propyl, isopropyl or hydrogen atom, and more preferably And particularly preferably both of R ¹³ and R ¹⁴ are hydrogen atoms.

Further, as described above, R ¹³ and R ¹⁴ may be connected to each other to form a ring containing a nitrogen atom. Examples of such a ring include a 4- to 8-membered saturated or unsaturated nitrogen-containing ring, and more specifically, an azetidine ring, a pyrrolidine ring, a piperidine ring, a homopiperidine ring, and a hexamethyleneimine ring. Pyrrole ring, azatropyridene ring, imidazole ring, imidazoline ring, pyrazole ring, pyrazine ring, morpholine ring and the like.

R ¹⁵ is preferably a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or an n-propyl group, and particularly preferably It is a hydrogen atom.

R ¹⁶ and R ¹⁷ are preferably a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group or a phenyl group, and particularly preferably a hydrogen atom. is there.
Further, as described above, R ¹⁶ and R ¹⁷ may be connected to each other to form a saturated or unsaturated hydrocarbon ring that may have a substituent. Examples of such a cyclic hydrocarbon group include a cycloalkane ring, a cycloalkene ring, and a cycloalkyne ring having 3 to 10, preferably 4 to 8 ring members, and more specifically, for example, cyclopropylidene, cyclocyclo Examples include butylidene, cyclopentylidene, cyclohexylidene, and those substituted with a substituent. Among the above-mentioned, monocyclic hydrocarbon rings, particularly cyclopentylidene and cyclohexylidene are preferable.

R ¹⁸ is preferably a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, an n-propyl group, or a phenyl group. Particularly preferred is a hydrogen atom.
Examples of the cyclic hydrocarbon group that can be formed by the adjacent R ¹⁸ include a cycloalkyl group, a cycloalkenyl group having 3 to 10, preferably 4 to 8 ring members that may have a substituent, A cycloalkynyl group and an aryl group are mentioned, More specifically, the phenyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group etc. which may have a substituent are mentioned. Among those mentioned above, an aryl group having 4 to 8 ring members which may have a substituent, particularly a phenyl group is preferable. When adjacent R ¹⁸ forms a phenyl group, for example, an indoline ring, an isoindoline ring, or the like can be formed together with the ring substituted by R ¹⁸ .
In the formula, m is preferably 1 or 2.
Moreover, in the formula, k is preferably 0 to 5, and more preferably 0 to 3.

  More specifically, the amine compound B is preferably 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-propi Pyridine, 2- (aminomethyl) -6-isopropylpyridine, 2- (aminomethyl) -3-isopropylpyridine, 2- (aminomethyl) -4-isopropylpyridine, 2- (aminomethyl) -5-isopropyl Pyridine, 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-phenylpyridy Is 2- (aminomethyl) -3-phenylpyridine, 2- (aminomethyl) -4-phenyl pyridine or 2- (aminomethyl) -5-phenylpyridine.

  More preferably, the amine compound B is PICA: 2-picolylamine, TolPICA: (6- (p-tolyl) -2-pyridyl) methanamine, AEP: 1- (2-pyridyl) ethylamine, 6-MePICA: 2- (Aminomethyl) -6-methylpyridine, 3-MePICA: 2- (aminomethyl) -3-methylpyridine, 4-MePICA: 2- (aminomethyl) -4-methylpyridine, 5-MePICA: 2- (amino Methyl) -5-methylpyridine, 4-iPr-PICA: 2- (aminomethyl) -4-isopropylpyridine or 2- (aminomethyl) -4-tert-butylpyridine, particularly preferably PICA, TolPICA, AEP, 3-MePICA, 4-MePICA, 5-MePICA, 6-MePICA Is a 4-iPr-PICA.

  In addition, the preferable optically active diphosphine compound A and amine compound B in General formula (1) can be used in combination as appropriate.

In addition, the ruthenium complex represented by the general formula (1) may be prepared in advance before the reaction in the present method, but during the reaction, that is, the general formulas (5) to (5) to be described later. When the compound represented by (7) is reacted with hydrogen, it may be prepared in the reaction system (in situ). As an example of the method, for example, the following general formula (8) which is a precursor
Ru X Y A (8)

(In General Formula (8), X, Y, and A each have the same meaning as in General Formula (1) above), the following General Formula (3) and / Or the following general formula (4)
(In General Formula (3) and General Formula (4), each symbol is as described above), and by allowing one or more amine compounds selected from the compounds represented by The ruthenium complex represented by the general formula (1) can be prepared in situ.

  The complex represented by the general formula (8) and the amine compound represented by the general formula (3) and / or the general formula (4) include the complex represented by the general formula (8) and the general formula (3 ) And / or an amine compound represented by the general formula (4) reacts to produce a catalyst precursor represented by the general formula (1), and thus a complex represented by the general formula (8) The molar ratio of the amine compound represented by the formula (3) and / or the general formula (4) is not particularly limited, but compared with the complex represented by the general formula (8), the general formula (3) and / or the general formula When the amine compound represented by the formula (4) is small, the complex represented by the general formula (8) remains without being changed to the catalyst precursor represented by the general formula (1). It is disadvantageous from the viewpoint of sex. Therefore, the complex represented by the general formula (8) and the amine compound represented by the general formula (3) and / or the general formula (4) (the compound represented by the general formula (3) and the general formula (4) The total amount of the compounds represented is preferably charged at a molar ratio of 1: 1 to 1:50, more preferably at a molar ratio of 1: 1 to 1:20, in a vessel in which the substrate carbonyl compound is reacted with hydrogen. be able to. Even when the amount of amine compound represented by general formula (3) and / or general formula (4) is small compared to the complex represented by general formula (8), there is no problem except that the reactivity is lowered. Can be used.

  In addition, the ruthenium complex represented by the general formula (1) may contain one or more organic compounds that are reaction reagents used for the synthesis thereof. Here, the organic compound represents a coordinating organic solvent, for example, 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, diethyl Ether solvents such as ether, dimethyl ether and tetrahydrofuran; alcohol solvents such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol; ketone solvents such as acetone, methyl ethyl ketone and cyclohexyl ketone; acetonitrile, DMF and N-methylpyrrolidone And organic solvents containing heteroatoms such as DMSO and triethylamine.

  As an example, the synthesis of the ruthenium complex represented by the general formula (1) can be performed by reacting the optically active ruthenium complex represented by the general formula (8) with an amine compound or an optically active amine compound. . The optically active ruthenium complex represented by the general formula (8) can be synthesized by reacting an optically active diphosphine compound with a ruthenium complex that is a raw material. As the complex represented by the general formula (8), one prepared in advance as described above may be used, or one prepared in a hydrogenation reaction system may be used. As a method for preparing the ruthenium complex represented by the general formula (8), any method reported so far including the structure of the raw material to be used can be used, and there is no particular limitation. One is shown below.

  As a ruthenium complex which is a starting material for complex synthesis, 0-valent, 1-valent, 2-valent, 3-valent and higher-valent ruthenium complexes can be used. When zero-valent and monovalent ruthenium complexes are used, ruthenium must be oxidized until the final stage. When a divalent complex is used, it can be synthesized by reacting a ruthenium complex, an optically active diphosphine compound, and an optically active diamine compound sequentially, in the reverse order, or simultaneously. When a trivalent or tetravalent or higher valent ruthenium complex is used as a starting material, it is necessary to reduce the ruthenium by the final stage.

  Examples of the ruthenium complex used as a starting material include ruthenium chloride (III) hydrate, ruthenium bromide (III) hydrate, ruthenium iodide (III) hydrate and other inorganic ruthenium compounds, [ruthenium dichloride (norbornadiene) ] Polynuclear compounds, [Ruthenium dichloride (cycloocta-1,5-diene)] polynuclear compounds, ruthenium compounds coordinated with dienes such as bis (methylallyl) ruthenium (cycloocta-1,5diene), [ruthenium dichloride (benzene) )] Aromatic compounds such as polynuclear, [ruthenium dichloride (p-cymene)] polynuclear, [ruthenium dichloride (trimethylbenzene)] polynuclear, [ruthenium dichloride (hexamethylbenzene)] polynuclear, etc. Coordinated ruthenium complexes and phosphines such as dichlorotris (triphenylphosphine) ruthenium Complex, or the like is used. In addition, the ruthenium complex having a ligand that can be substituted with an optically active diphosphine compound or an optically active diamine compound is not particularly limited to the above. For example, various ruthenium complexes shown in COMPREHENSIVEORGANOMETALLICIC CHEMISTRY II Vol. 7, p294-296 (PERGAMON) can be used as starting materials.

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. Next, the amine-phosphine-ruthenium halide complex represented by the general formula (1) can be obtained by reacting the obtained phosphine-ruthenium halide complex with an amine. For example, this synthesis is described in the literature [J. Mol. Cat. 15, 297 (1982)].
That is, Inorg, Synth. , Vol 12, 237 (1970), etc., RuCl ₂ (PPh ₃ ) ₃ was reacted with ethylenediamine in benzene to obtain RuCl ₂ (PPh ₃ ) ₂ (en) ( However, there is no description of the yield). However, in this method, the reaction is heterogeneous, and there is a tendency that unreacted raw materials remain. On the other hand, when the reaction solvent is changed to a solvent such as methylene chloride or chloroform, the reaction can be performed in a uniform state, and the operability is improved.

  Reactions of ruthenium halides with phosphine ligands 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 and tetrahydrofuran. The reaction temperature is −100 ° C. to 200 ° C. in an ether solvent, an alcohol solvent such as methanol, ethanol, 2-propanol, butanol, and benzyl alcohol, and an organic solvent containing a hetero atom such as acetonitrile, DMF, N-methylpyrrolidone, and DMSO. The phosphine-ruthenium halide complex represented by the general formula (8) can be obtained.

  The reaction of the obtained phosphine-ruthenium halide complex represented by the general formula (8) with the amine ligand represented by the general formula (3) or (4) is an aromatic hydrocarbon such as toluene or xylene. Solvents, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ether solvents such as ether and tetrahydrofuran, alcohol solvents such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol, An amine-phosphine-ruthenium halide complex represented by the general formula (1) is carried out in an organic solvent containing a heteroatom such as acetonitrile, DMF, N-methylpyrrolidone, DMSO at a reaction temperature between −100 ° C. and 200 ° C. Can be obtained.

  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 sequentially, in the reverse order, or simultaneously. As an example, a ruthenium compound coordinated by a diene such as [ruthenium dichloride (norbornadiene)] polynuclear body, [ruthenium dichloride (cyclooct-1,5-tadiene)] polynuclear body, bis (methylallyl) ruthenium (cyclooctadiene), etc. Or [ruthenium dichloride (benzene)] dinuclear, [ruthenium dichloride (p-cymene)] dinuclear, [ruthenium dichloride (trimethylbenzene)] dinuclear, [ruthenium dichloride (hexamethylbenzene) )] Ruthenium complexes coordinated by aromatic compounds such as dinuclear compounds, and complexes coordinated by phosphines such as dichlorotris (triphenylphosphine) ruthenium, aromatic hydrocarbon solvents such as toluene and xylene, pentane, Aliphatic hydrocarbon solvents such as hexane, halogen-containing hydrocarbon solvents such as methylene chloride, Le, ether solvents such as tetrahydrofuran, methanol, ethanol, 2-propanol. It reacts with a phosphine compound at a reaction temperature between −100 ° C. and 200 ° C. in an organic solvent containing a heteroatom such as butanol, benzyl alcohol or the like, or acetonitrile, DMF, N-methylpyrrolidone, DMSO, etc. The phosphine-ruthenium-methylallyl complex represented by 8) can be obtained.

  The reaction of the phosphine-ruthenium halide complex represented by the general formula (8) with an amine compound is carried out by using an aromatic hydrocarbon solvent such as toluene or xylene, an aliphatic hydrocarbon solvent such as pentane or hexane, methylene chloride or the like. Organic solvents containing heteroatoms such as halogen-containing hydrocarbon solvents, ether solvents such as ether and tetrahydrofuran, alcohol solvents such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol, acetonitrile, DMF, N-methylpyrrolidone and DMSO It can react with an amine ligand in a solvent at a reaction temperature between −100 ° C. and 200 ° C. to obtain an amine-phosphine-ruthenium complex. Further, an amine-phosphine-ruthenium halide complex represented by the general formula (1) is prepared by reacting a cationic ruthenium complex such as [chlororuthenium (BINAP) (benzene)] chloride with an amine ligand under the same conditions. Can be obtained.

  As a method for synthesizing a complex in which a cyclic hydrocarbon group bonded to the diamine compound represented by the general formula (1) is bonded to ruthenium as an anionic group X, it is described in the literature [Organometrics, 29, 3563 (2010)] and the like. It can be synthesized by the method. That is, after synthesizing an amine-phosphine-ruthenium halide complex by adding a diamine to the phosphine-ruthenium halide complex represented by the general formula (8) in the same manner as the above-described amine-phosphine-ruthenium halide complex synthesis method, Aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ether solvents such as ether and tetrahydrofuran, methanol, ethanol, 2-propanol, A base such as triethylamine is reacted at a temperature between −100 ° C. and 200 ° C. in an alcohol solvent such as butanol or benzyl alcohol, or an organic solvent containing a heteroatom such as acetonitrile, DMF, N-methylpyrrolidone or DMSO. Alternatively, the phosphine-ruthenium halide complex represented by the general formula (8) and the diamine compound can be synthesized by reacting a base such as triethylamine in the above solvent at a temperature between −100 ° C. and 200 ° C.

  The synthesized amine-phosphine-ruthenium halide complex represented by the general formula (1) may be a mixture of several complexes having different coordination modes. It can be used directly in the hydrogenation reaction without acquisition.

<Ketone>
In the method of the present invention, the ketone is used as a reaction substrate.
Ketones that can be used in this method are the following general formulas (5) to (7).
[D ^{1 to} D ³ in the general formulas (5) to (7) represent a carbon atom or a nitrogen atom, and any one of D ^{1 to} D ³ is a nitrogen atom,
R ¹⁹ and R ²⁰ are the same or different and each represents a linear or branched alkyl group having 1 to 9 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a halogen group, or a nitro group. Show
R ²¹ represents an optionally substituted branched or straight chain alkyl or alkoxy group having 1 to 9 carbon atoms, an amino group, an amide group, a nitro group, an acyl group, an ester group, or a cyclic aliphatic hydrocarbon group,
R ^{22 to} R ²⁴ are the same or different and each represents a linear or branched alkyl group or alkoxy group having 1 to 8 carbon atoms which may have hydrogen or a halogen group, an ester group, an amide group, an amino group, or a substituent. A cyclic hydrocarbon group which may have, a heterocyclic group which may have a substituent, a halogen group or a nitro group, provided that when D ^{1 to} D ³ are nitrogen atoms, the nitrogen atom There is no group selected from the group consisting of the corresponding R ²² , R ²³ and R ^{24 above} ,
E represents an oxygen or sulfur atom. ]
It is a 1 type, or 2 or more types of combination selected from the compound represented by these.

  A ketone having a substituent on each of two carbons adjacent to an atom substituted with a carbonyl group of such an aromatic compound or an aromatic compound containing a heteroatom can be obtained by using the conventional carbonyl catalyst. Although the site is relatively difficult to reduce or has low enantioselectivity, when the ruthenium complex represented by the general formula (1) is used, the carbonyl site can be efficiently and efficiently reduced. it can.

In general formulas (5) to (7), as R ¹⁹ and R ²⁰ , specifically, halogen groups such as fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group, methoxycarbonyl, ethoxycarbonyl Amide groups such as isopropoxycarbonyl ester groups (preferably alkyl ester groups having 1 to 5 carbon atoms), N-methylamide groups, N, N-dimethylamide groups, N-ethylamide groups, N, N-diethylamide groups, etc. (Preferably mono- or dialkylamide group having 1 to 5 carbon atoms), dimethylamino group, amino group such as diethylamino group (preferably mono- or dialkylamino group having 1 to 5 carbon atoms), methyl group, ethyl group, n- C1-C5 straight chain such as propyl group, isopropyl group, n-butyl group, tert-butyl group, isobutyl group, n-pentyl group Or a linear or branched alkoxy group having 1 to 5 carbon atoms such as a branched alkyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a tert-butoxy group, and an n-pentoxy group, The phenoxy group and one or more hydrogen atoms of these alkyl groups, alkoxy groups, and phenoxy groups are substituted by the above ester group, amide group, amino group, nitro group or halogen atom, for example, fluorine atom, chlorine atom, bromine atom Or the thing substituted by the iodine atom is mentioned.

R ¹⁹ and R ²⁰ are preferably a linear or branched alkyl group having 1 to 3 carbon atoms which may have a halogen group, an alkoxy group or a halogen group, more preferably a fluorine atom or a chlorine atom. , A methyl group or a methoxy group.
R ¹⁹ and R ²⁰ may be the same or different, but are preferably a combination of substituents having high solubility from the viewpoint of reaction efficiency.

In general formulas (5) to (7), R ²¹ is specifically a nitro group or an ester group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, etc. (preferably an alkyl ester having 1 to 5 carbon atoms). Group), N-methylamide group, N, N-dimethylamide group, N-ethylamide group, N, N-diethylamide group and other amide groups (preferably mono- or dialkylamide groups having 1 to 5 carbon atoms), dimethylamino group , Amino groups such as diethylamino group (preferably mono- or dialkylamino groups having 1 to 5 carbon atoms), cycloaliphatic hydrocarbon groups such as cyclopropyl group, cyclopentyl group, cyclohexyl group, methyl group, ethyl group, n-propyl Group, isopropyl group, n-butyl group, tert-butyl group, isobutyl group, n-pentyl group, n-hept C1-C9 linear or branched alkyl group such as til group, n-octyl group, n-nonyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy Group, n-pentoxy group, n-heptoxy group, n-octoxy group, n-noninoxy group, etc., linear or branched alkoxy groups having 1 to 9 carbon atoms, and their cyclic aliphatic hydrocarbon groups, alkyl groups, alkoxy groups A group in which one or more hydrogen atoms are replaced by a halogen atom, for example a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, an aryl group, for example by a phenyl group, or an ester group as described above, Examples thereof include those substituted with an amino group, an amide group, an amino group or a nitro group.

R ²¹ is preferably an aryl group or a branched or straight chain alkyl group having 1 to 9 carbon atoms which may be substituted with a hetero atom, and more preferably an aryl group or a hetero atom. A good branched or straight chain alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms.
Moreover, although carbon number of an alkyl group and an alkoxy group should just be in the range mentioned above, Preferably, it is 1-6, More preferably, it is 1-3.

In general formulas (5) to (7), as R ^{22 to} R ²⁴ , specifically, halogen groups such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, phenyl group, o- , M-, p-tolyl group, 2,6-, 2,3-, 2,4-, 3,4-xylyl group and the like, an aryl group, pyridyl group, 3-methyl- 2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 2-methyl-3-pyridyl group, 4-methyl-3-pyridyl group, 5-methyl-2-pyridyl group, etc. A nitro group or an ester group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, etc. (preferably an alkyl ester group having 1 to 5 carbon atoms), an N-methylamide group, N, N-dimethylamide group, N-d Amide groups (preferably mono- or dialkylamido groups having 1 to 5 carbon atoms) such as a ruamide group and N, N-diethylamide group, amino groups such as dimethylamino groups and diethylamino groups (preferably mono- or mono-carbon having 1 to 5 carbon atoms) Dialkylamino group), cycloaliphatic hydrocarbon group such as cyclopropyl group, cyclopentyl group, cyclohexyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, isobutyl group, C1-C8 linear or branched alkyl group such as n-pentyl group, n-heptyl group, n-octyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert -C 1-8 linear or branched such as butoxy, n-pentoxy, n-heptoxy, n-octoxy Lucoxy group, phenoxy group and those alkyl groups, alkoxy groups, phenoxy groups in which one or more hydrogen atoms are replaced by halogen atoms, for example, fluorine atoms, chlorine atoms, bromine atoms or iodine atoms, aryl groups, For example, those substituted with a phenyl group or those substituted with the above-mentioned ester group, amino group, amide group, amino group or nitro group can be mentioned.

R ^{22 to} R ²⁴ are preferably a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms which may have a halogen group or an alkoxy group, and a cyclic carbon which may have a substituent. A hydrogen group, a heterocyclic ring optionally having a substituent, a halogen group or a nitro group, more preferably a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms which may have a halogen group Or an alkoxy group, a halogen group, a cyclic hydrocarbon group which may have a substituent, or a heterocyclic ring which may have a substituent, more preferably a hydrogen atom or a carbon which may have a halogen group A linear or branched alkyl group, an alkoxy group or a halogen group of 1 to 3;

  As specific examples of the ketones represented by preferable general formulas (5) to (7), 2 ′, 6′-dichloro-3′-fluoroacetophenone, 2 ′, 6′-dichloroacetophenone, 2 ′, 6′- Difluoroacetophenone, 2 ′, 4 ′, 6′-trifluoroacetophenone, 2 ′, 3 ′, 4 ′, 5 ′, 6′-trifluoroacetophenone, 2 ′, 6′-dimethylacetophenone, 2 ′, 4 ′, Examples include 6'-trimethylacetophenone, 2 ', 6'-dimethoxyacetophenone, 2', 4 ', 6'-trimethoxyacetophenone, 2', 6'-bis (trifluoromethyl) acetophenone, and the like.

<Method for producing optically active secondary alcohol>
Next, the manufacturing method of the optically active secondary alcohol of this embodiment is demonstrated.
The production method of the optically active secondary alcohol of this embodiment is represented by the above general formulas (5) to (7) in the presence of one or more ruthenium complexes represented by the above general formula (1). A ketone selected from the compounds to be reacted with hydrogen.

  The ruthenium complex functions as a catalyst in the present method. As the ruthenium complex, any compound represented by the above general formula (1) may be used, but the optically active diphosphine compound represented by the general formula (2) in the ruthenium complex represented by the general formula (1) may be used. Of these, optically active secondary alcohols having a desired absolute configuration can be produced by selecting either of these (R, R) isomers or (S, S) isomers.

  Further, when the amine compound represented by the general formula (3) or the general formula (4) in the ruthenium complex represented by the general formula (1) is an optically active substance, the optical compound represented by the general formula (8) The combination of the absolute structure of the diphosphine compound in the active ruthenium complex and the absolute structure of the optically active amine compound to be added is important for obtaining high optical purity. For example, the appropriate combination of the absolute structure of the diphosphine compound and the absolute structure of the amine compound differs depending on the structure of the substrate. When a complex having an inappropriate combination is used, the catalytic activity may be lowered or the optical purity of the product may be lowered as compared with the case where a complex having an appropriate combination is used.

  The amount of the ruthenium complex represented by the general formula (1) depends on the reaction vessel used, the purity of hydrogen, the type and purity of the solvent used, or the reaction conditions such as the purity of the substrate, or the economy, but the reaction substrate The molar ratio of the ketones represented by the general formulas (5) to (7) is 1/100 to 1 / 10,000,000, preferably 1/500 to 1 / 1,000,000. It can be used in the range.

Moreover, hydrogen for reacting with the ketone selected from the compounds represented by the general formulas (5) to (7) is supplied into the reaction system as hydrogen gas.
The pressure (partial pressure) of hydrogen gas is not particularly limited, but is, for example, in the range of 1 to 200 atm, preferably in the range of 1 to 100 atm, more preferably in the range of 1 to 20 atm, and more preferably 2 to 15 atm. A range of atmospheric pressure is desirable.

In the reaction, it is preferable that a base is present in the reaction system.
The base that can be used is not particularly limited. For example, KOH, KOCH ₃ , KOCH (CH ₃ ) ₂ , KOC (CH ₃ ) _3, KC ₁₀ H ₈ , LiOH, LiOCH ₃ , LiOCH (CH ₃ ) ₂ , alkali metals such as LiOC (CH ₃ ) ₃ , alkaline earth metal salts, quaternary ammonium salts, and the like, and one or more of these can be used in combination. Of these, the base is preferably KOH or KOCH (CH ₃ ) ₂ , particularly preferably KOCH (CH ₃ ) ₂ .

  The amount of the base to be added is not particularly limited. For example, the amount of the base concentration in the reaction system is 0.001 to 0.2 mol / L, preferably 0.005 to 0.1 mol / L. The amount is more preferably 0.01 to 0.05 mol / L.

  As described above, the two components of the ruthenium complex and the base shown in the general formula (1) used as the catalyst are indispensable for the smooth asymmetric hydrogenation reaction to achieve a high asymmetric yield. If one component is insufficient, an optically active alcohol with sufficient reaction activity and high optical purity cannot be obtained.

  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, the ruthenium complex is added without adding a base. After mixing with the ketones represented by the general formulas (5) to (7), the reaction may be carried out by applying a hydrogen pressure and stirring. Even in such a case, the hydrogenation of the ketone represented by the general formulas (5) to (7) can be performed.

In addition, a solvent may be present in the reaction system.
The solvent that can be used is not particularly limited, and a solvent that solubilizes the substrate and the catalyst system is preferable. For example, lower alcohols such as methanol, ethanol, n-propanol, 2-propanol, butanol and benzyl alcohol, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ether, methyl-tert- Examples include ether solvents such as butyl ether, cyclopentyl methyl ether, and tetrahydrofuran; organic solvents containing heteroatoms such as acetonitrile, N, N-dimethylformamide (DMF), N-methylpyrrolidone, and dimethyl sulfoxide (DMSO). Among them, one kind or a combination of two or more kinds can be used.
The amount of solvent is determined by the solubility and economics of the reaction substrate. For example, depending on the substrate, the reaction can be carried out in a state close to solvent-free from a low concentration of 0.1 mol / L or less in the reaction system, but preferably in the range of 0.3 to 5 mol / L. It is desirable to use it.

  The reaction temperature should be set in such a range that the upper limit thereof does not cause decomposition of the ruthenium complex used as a catalyst, and the lower limit is set in consideration of the activity, for example, 0 to 60 ° C., preferably 25 to 40 ° C. It is preferable to carry out the reaction, and such a temperature range can be said to be excellent from the viewpoint of economy.

  The reaction time varies depending on the reaction conditions such as reaction solvent, reaction substrate concentration, temperature, pressure, substrate / catalyst ratio, etc., but taking into account both ease of reaction operation and economy, several minutes to several tens hours, for example, 10 minutes It can be arbitrarily set so that the reaction is completed in ˜96 hours, preferably in 2 hours to 48 hours. Even if the reaction operation is continued after completion of the reduction reaction of the carbonyl group, there is no racemization of the asymmetric carbon of the product optically active secondary alcohol, and the optical purity is lowered. Is hardly recognized. Therefore, when carrying out this method, it is not necessary to constantly monitor the progress of the reaction, and it is not necessary to terminate the reaction immediately after completion of the reaction. That is, the reaction time can be set longer than the substantial reaction completion time, which is an advantageous method for industrial implementation.

Optical activity wherein the carbonyl groups of the ketones represented by the general formulas (5) to (7) are reduced by hydrogenating the ketones represented by the general formulas (5) to (7) by the method described above. Secondary alcohols can be preferentially and efficiently obtained as target enantiomers.
However, even by the method of the present invention, the hydrogenation reaction product may contain a raw material ketone, a salt formed by reacting an added base or complex and a base, and the like. These can be purified by generally known purification operations such as distillation, washing with water, recrystallization, chromatography and the like.

  Moreover, the reaction form of the said reaction is not specifically limited, It can implement in any of a batch type, a continuous type, or a microflow reaction apparatus.

In addition, the method for producing an optically active secondary alcohol according to another embodiment of the present invention includes the following general formula (8).
RuXYA (8)
[In General Formula (8), X and Y are the same or different from each other, and have the same meaning as defined in General Formula (1) independently of each other. And one or more amine compounds selected from the compounds represented by the above general formulas (3) and / or (4) In the presence of a ketone, a ketone selected from the compounds represented by the general formulas (5) to (7) is reacted with a compound that reacts with hydrogen.

The complex represented by the general formula (8) and the amine compound represented by the general formula (3) and / or (4) are preferably in a molar ratio of 1: 1 to 1:50, more preferably 1 In a molar ratio of 1: 1 to 1:20, the compounds represented by the general formulas (5) to (7) can be charged into a container for reacting with hydrogen.
Moreover, the conditions mentioned above can be used as other conditions in this embodiment.
The same effect can be obtained by the method of this aspect.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by a following example. In the following examples, all reactions were performed in an inert gas atmosphere such as argon gas or nitrogen gas. The solvent used for the reaction was dried and degassed unless otherwise specified. The hydrogenation reaction of the carbonyl compound was performed by pressurizing hydrogen (hydrogen gas) in an autoclave.

For the ketone substrates described in Examples or Comparative Examples, reagents manufactured by Aldrich were used directly unless otherwise specified. Reagents manufactured by Kanto Chemical Co., Ltd. were used directly for other chemicals including the solvent used in the reaction.
In the examples and comparative examples described below, S / C represents a substrate / catalyst molar ratio.

The following equipment was used for the following measurements.
NMR: JNM-ECX400P type (400 MHz) (manufactured by JEOL Ltd.)
Internal standard: ¹ H-NMR: tetramethylsilane External standard: ³¹ P-NMR: 85% phosphoric acid

Optical purity measurement by GC Measuring device: Agilent GC7890A (manufactured by Agilent)
Column: CP Chirazil-DEX CB (0.25 mm ID × 25 m, DF = 0.25 μm) (manufactured by Agilent)

Optical purity measurement by HPLC Measuring device: LC-20A (UV detector, manufactured by Shimadzu Corporation)
Column: CHIRALPAK AD-RH (4.6 mmφ × 150 mm) (manufactured by Daicel)
CHIRALCEL OD-H (4.6 mmφ × 250 mm) 7 (Daicel)

<1. Synthesis of ruthenium complex>
[Synthesis Example 1]
_{RuBr 2 [(S, S)} -xylskewphos] (pica) Synthesis of the complex

(1) Synthesis of RuBr ₂ [(S, S) -xylskewphos] (methylallyl) _{2 In} a 50 mL Schlenk tube purged with argon, (S, S) -xylSKEPPHOS (110 mg, 0.2 mol), Ru (cycloocta-1,5- Diene) (methylallyl) ₂ (64 mg, 0.2 mmol) was charged. Thereafter, 5 mL of hexane was added and stirred at 70 ° C. for 6 hours. Insoluble matter was filtered through a glass filter, and the filtrate was concentrated to obtain the desired product. This was used in the next reaction without any further purification.

(2) Synthesis of RuBr ₂ [(S, S) -xylskewphos] RuBr ₂ [(S, S) -xylskewphos] (methylallyl) ₂ complex (153 mg, 0.2 mmol) was dissolved in 15 mL of acetone, and 47% HBr methanol The solution (0.046 mL, 0.4 mmol) was added, degassed and stirred at room temperature for 30 minutes. After the solvent was distilled off, it was used for the next reaction without purification.

(3) Synthesis of RuBr ₂ [(S, S) -xylskewphos] (pica) 50 mL Schlenk tube with RuBr ₂ [(S, S) -xylskewphos] complex (163 mg, 0.2 mmol) with 2-picolylamine (21. 6 mg, 0.2 mmol) was charged and replaced with argon gas. Subsequently, dimethylformamide (5 mL) was added, degassed, and stirred overnight at room temperature. The reaction solution was filtered through a glass filter packed with silica gel, and then the solvent was distilled off to obtain 177 mg (96% yield) of RuBr ₂ [(S, S) -xylskewphos] (pica).
³¹ P-NMR spectrum (161.7 MHz, C ₆ D ₆ ): δ 62.4 (d, J = 42 Hz), 43.5 (d, J = 43 Hz)

[Synthesis Example 2]
Synthesis of RuBr ₂ [(R, R) -xylskewphos] [(S) -aep] In place of (S, S) -xylSKEWPHOS used in Synthesis Example 1, (R, R) -xylSKEWPHOS was replaced with 2 as a diphosphine ligand. Synthesis was performed in the same manner as in Example 1 except that (S) -1- (2-pyridyl) ethylamine was changed to an amine ligand instead of picolylamine, and RuBr ₂ [(R, R) -xylskewphos] [ (S) -aep] was obtained in 134 mg (70% yield).

[Synthesis Example 3]
Synthesis of RuBr ₂ [(R, R) -xylskewphos] (tolpicaa) (the “a” at the end in (tolpicaa) indicates that the tolyl group is bonded to Ru as an anionic ligand).

(1) Synthesis of Ligand According to the following scheme, (6- (p-tolyl) -2-pyridyl) methanamine (tolPICA) was synthesized.

  First, in an argon gas atmosphere, a solution of 2- (p-tolyl) pyridine 5 mL (31 mmol) in THF 80 mL was ice-cooled, and mCPBA 9.5 g (36 mmol) was added little by little. After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with methylene chloride to obtain 1.97 g (34% yield) of 2- (p-tolyl) pyridine-N-oxide.

Then, under an argon gas atmosphere, 8.79 g (47.5 mmol) of 2- (p-tolyl) pyridine-N-oxide was dissolved in 120 mL of methylene chloride, 4.4 mL (48 mmol) of dimethylcarbamoyl chloride was added, and then trimethylsilyl 6.24 mL (50 mmol) of cyanide was charged and stirred overnight at room temperature. After quenching the reaction solution with 10% -K ₂ CO ₃ aqueous solution, the methylene chloride layer was separated, dried with sodium sulfate and concentrated to give 7.87 g (85% yield) of 6-cyano-2- (p-tolyl) pyridine. Obtained.

In an autoclave, 4.1 g (21 mmol) of 6-cyano-2- (p-tolyl) pyridine, 0.3 g of Pd / C (50% water-containing product), 290 mL of methanol and 4.8 mL of concentrated hydrochloric acid were charged, and hydrogen was added at 5 atm. While stirring, the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated to dryness. This was recrystallized from ethanol / hexane to obtain 5.3 g (93% yield) of (6- (p-tolyl) -2-pyridyl) methanamine hydrochloride. This (6- (p-tolyl) -2-pyridyl) methanamine hydrochloride was treated with an aqueous sodium hydrogen carbonate solution to quantitatively obtain (6- (p-tolyl) -2-pyridyl) methanamine (tolPICA).
¹ H-NMR spectrum (399.78 MHz, CDCl ₃ ): δ 7.93 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 4. 02 (s, 2H), 2.41 (s, 3H), 1.92 (br, 2H)

(2) Synthesis of RuBr ₂ [(R, R) -xylskewphos] (tolpicaa) To 50 mL Schlenk tube RuBr ₂ [(R, R) -xylskewphos] complex (0.337 g, 0.4 mmol) tolPICA (0.09 g) , 0.45 mmol), and replaced with argon gas. Subsequently, dimethylformamide (10 mL) was added, deaerated, and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, toluene (15 mL) and triethylamine (58 μL) were added to the concentrate, and the mixture was stirred at 80 ° C. for 15 hr. The reaction solution was filtered through a glass filter, and hexane was added to the filtrate. The precipitated solid was collected by filtration to obtain 0.27 g (70% yield) of RuBr ₂ [(R, R) -xylskewphos] (tolpicaa).
³¹ P-NMR spectrum (161.7 MHz, C ₆ D ₆ ): δ 64.7 (d, J = 44 Hz), 44.8 (d, J = 48 Hz)

[Synthesis Examples 4 to 7]
Synthesis of various PICA type amine ligands Synthesis methods are described below using 2-aminomethyl-4-isopropylpyridine (4-i-PrPICA) as an example.

  First, 10.0 mL (76,7 mmol) of 4-isopropylpyridine was charged into a 300 ml four-necked flask under an argon gas atmosphere, and this was diluted with 160 mL of methylene chloride. This solution was ice-cooled, and 23.0 g (86.5 mmol) of 65% m-chloroperbenzoic acid (mCPBA) was added little by little. After stirring for 1 hour under ice cooling, the mixture was stirred for 21 hours at room temperature. After adding an aqueous sodium thiosulfate solution to the reaction solution, the reaction solution was extracted with methylene chloride. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated to obtain 3.22 g (31% yield) of 4-isopropylpyridine-N-oxide.

The resulting 4-isopropylpyridine-N-oxide (3.22 g, 23.4 mmol) was dissolved in 60 mL of methylene chloride under an argon gas atmosphere, dimethylcarbamoyl chloride (2.2 mL, 24.0 mmol) was added, and then trimethylsilyl Cyanide (3.0 mL, 24.0 mmol) was charged and stirred overnight at room temperature. After the reaction solution was quenched with 10% -K ₂ CO ₃ aqueous solution, the methylene chloride layer was separated, dried with sodium sulfate, and then concentrated to obtain 3.74 g (109% yield) of 6-cyano-4-isopropylpyridine.

  In an autoclave, 6.74 g (25.6 mmol) of 6-cyano-4-isopropylpyridine, 0.3 g of Pd / C (50% water-containing product), 220 mL of methanol and 5.3 mL of concentrated hydrochloric acid were charged, and hydrogen was pressurized to 5 atm. The mixture was stirred overnight at room temperature. The reaction solution was filtered through Celite, and the filtrate was concentrated to dryness. This was recrystallized from methanol / hexane to obtain 3.61 g (63% yield) of 2-aminomethyl-4-isopropylpyridine (4-i-PrPICA) hydrochloride. This (2-aminomethyl-3,4-dimethylpyridine hydrochloride was treated with an aqueous potassium carbonate solution to give 2-aminomethyl-4-isopropylpyridine (4-i-PrPICA) quantitatively.

  In the same way, 2-aminomethyl-4-tert-butylpyridine (4-tBuPICA) was synthesized. Since 2-aminomethyl-3-methylpyridine (3-MePICA) and 2-aminomethyl-4-methylpyridine (4-MePICA) are N-oxides, which are corresponding intermediates, are sold by Aldrich. This was used as a raw material. The synthesized yield is summarized in Table 1 below.

[Synthesis Examples 8 to 11]
Synthesis of ruthenium XylSKEPPHOS complex having various PICA ligands Synthesized by the same method as (3) of Synthesis Example 1 except that the amine ligands synthesized in Synthesis Examples 4-7 were used instead of 2-picolylamine. . The yield was almost quantitative. The synthesis results are summarized in Table 2 below.

2. Production of optically active secondary alcohol [Example 1]
Hydrogenation reaction of 2 ′, 6′-dichloro-3′-fluoroacetophenone In an autoclave, RuBr ₂ [(S, S) -xylskewphos] (pica) 3.12 mg (3.38 × 10 ⁻³ mmol, S / C = 1000) and 7.64 mg (6.81 × 10 ⁻² mmol) of potassium tert-butoxide were charged, and the atmosphere was replaced with argon gas. Under a stream of argon gas, 0.5 mL (3.39 mmol) of 2 ′, 6′-dichloro-3′-fluoroacetophenone and 2.9 mL of 2-propanol were weighed with a syringe, pressurized to 10 atm with hydrogen, When the mixture was stirred at 40 ° C. for 21 hours, a decrease in hydrogen pressure was confirmed, and (S) -1- (2,6-dichloro-3-fluorophenyl) ethanol was obtained in a 100% yield. In addition, HPLC (DAICEL CHRALPAK AD-RH, acetonitrile / water = 25/75, 0.5 mL / min, 25 ° C., 220 nm, the retention time of each enantiomer is (S) isomer: 56.1 min, (R) isomer: 64.5 min), the optical purity was measured and found to be 94.0% ee.

[Example 2]
In a 100 mL autoclave, RuBr ₂ [(R, R) -xylskewphos] (tolpicaa) 3.16 mg (3.40 × 10 ⁻³ mmol, S / C = 1000) and potassium tert-butoxide 13.48 mg (0.120 mmol) Was replaced with argon gas. Under an argon gas stream, 0.5 mL (3.39 mmol) of 2 ′, 6′-dichloro-3′-fluoroacetophenone and 1.1 mL of 2-propanol were weighed and added to a pressure of 10 atm with hydrogen, When the mixture was stirred at 40 ° C. for 21 hours, a decrease in hydrogen pressure was confirmed, and (R) -1- (2,6-dichloro-3-fluorophenyl) ethanol was obtained in a 100% yield. The optical purity measured under the conditions described in Example 1 was 95.3% ee.

[Examples 3 to 10, Comparative Examples 1 to 5]
The reaction was carried out under the same conditions as in Example 1 except that the type of catalyst was changed. The method of the present invention using the ruthenium complex represented by the general formula (1) is more effective than the case of using the catalyst having the optically active diphosphine ligand and the optically active diamine ligand known so far. It was confirmed that it acts on.

For example, RuCl ₂ [(S) -binap] [(S, S) -dpen], RuCl ₂ [(S) -xylbinap] [(S) -daipen] or RuCl ₂ [Proposed in Patent Documents 7 to 9] When a catalyst such as (S, S) -xylskewphos] [(S, S) -dpen] was used (Comparative Examples 1, 4, and 5), the yield was low and the optical purity was low.

Further, for example, when RuCl ₂ [(S) -tolbinap] (pica) proposed in Patent Document 11 is used as a catalyst (Comparative Example 3), although the yield is high, the produced 1- (2,6- (Dichloro-3-fluorophenyl) ethanol had very low optical purity.

[Example 11]
Under the same conditions as in Example 1, changes in optical purity over time in the hydrogenation reaction were confirmed. As a result, it was found that there was no change in the optical purity at the beginning of the reaction and after the completion of the reaction, and it was not necessary to stop the reaction immediately after the completion of the reaction. In addition, the produced | generated alcohol body was a (S) body as a main component.

[Examples 12 to 15]
For the purpose of improving the reaction efficiency, the reaction was carried out under the same conditions as in Example 1 except that S / C, substrate concentration, and potassium tert-butoxide (KOtBu) concentration were changed. This confirmed that the substrate was hydrogenated almost quantitatively under the condition of S / C = 20000.
In addition, all the produced | generated alcohol bodies were (S) body as a main component.

[Comparative Example 6]
Confirmation of hydrogen transfer type reduction reaction The reaction was carried out without pressurizing hydrogen under the conditions of Example 15. As a result, the ketone was not reduced at all and the raw material was recovered. From this result, it was found that reduction using 2-propanol as a hydrogen source did not occur, that is, no hydrogen transfer reduction reaction occurred.

[Example 16]
Scale-up synthesis In an autoclave made of 3L-SUS316, RuBr ₂ [(S, S) -xylskewphos] (pica) 0.120 g (1.30 × 10 ⁻¹ mmol, S / C = 10000) and potassium tert-butoxide 19 g (19.5 mmol) was charged and replaced with argon gas. Under an argon gas stream, 192 mL (1.30 mol) of 2 ′, 6′-dichloro-3′-fluoroacetophenone (manufactured by Jiangxi Jixiang Pharmaceutical) and 460 mL of 2-propanol were added with a cannula, and the pressure was increased to 10 atm with hydrogen. The mixture was stirred at 40 ° C. and 500 rpm. A decrease in hydrogen pressure was confirmed, and when the hydrogen pressure decreased to 7 atm, the pressure was increased again to 10 atm. After 8 hours, a decrease in hydrogen pressure was confirmed, and stirring was continued for an additional 13 hours. As a result of analyzing the reaction solution, (S) -1- (2,6-dichloro-3-fluorophenyl) ethanol was obtained in 100% yield. The reaction solution was concentrated with an evaporator and then distilled under reduced pressure to collect a fraction at 135 ° C./2000 Pa. The isolated yield was 98.6%, and it was found that it could be obtained quantitatively. Moreover, as a result of measuring optical purity by the conditions as described in Example 1, it was 94.5% ee.

[Examples 17 to 22]
Hydrogenation reaction of a ketone having an ortho disubstituted phenyl group other than 2 ′, 6′-dichloro-3′-fluoroacetophenone was performed. The reaction conditions were the same as Example 15 except that S / C = 2000. However, in Examples 19 and 22, the substrate concentration was set to 1.0 mol / L in consideration of the solubility of the substrate in 2-propanol.

The analysis conditions (optical purity analysis conditions) described in the table are as follows.
(Analysis condition A)
Measurement by gas chromatographic analysis (Agilent CP Chirazil-DEX CB (0.25 mmφ × 25 m, DF = 0.25 μm), 140 ° C. constant condition, pressure 47 KPa, split ratio 1/10, retention time of each enantiomer is (R) body: 40.2 min (S) body: 48.0 min)

(Analysis condition B)
Measurement by gas chromatographic analysis (Agilent CP Chirazil-DEX CB (0.25 mmφ × 25 m, DF = 0.25 μm), constant condition at 140 ° C., pressure 57 KPa, split ratio 1/10, retention time of each enantiomer is (R) body: 28.8 min (S) body: 33.6 min)

(Analysis condition C)
Measurement by HPLC analysis (DAICEL CHRALCEL OD-H, hexane / 2-propanol = 95/5, 0.5 mL / min, 25 ° C., 220 nm, one enantiomeric retention time is 32.1 min (minor), the other Is 67.7 min (major)) The absolute configuration is undecided

(Analysis condition D)
Measurement by gas chromatographic analysis (Agilent CP Chirazil-DEX CB (0.25 mmφ × 25 m, DF = 0.25 μm), 110 ° C. constant condition, pressure 47 KPa, split ratio 1/10, retention time of each enantiomer is (R) body: 21.5 min (S) body: 22.0 min)

(Analysis condition E)
Measurement by gas chromatographic analysis (Agilent CP Chirazil-DEX CB (0.25 mmφ × 25 m, DF = 0.25 μm), 110 ° C. constant condition, pressure 47 KPa, split ratio 1/10, retention time of each enantiomer is One is 20.7 min (minor) and the other is 26.0 min (major)) The absolute arrangement is undecided.

(Analysis condition F)
Measurement by HPLC analysis (DAICEL CHRALCEL OD-H, hexane / 2-propanol = 95/5, 0.5 mL / min, 25 ° C., 220 nm, one enantiomer has a retention time of 10.9 min (major), the other Is 12.5 min (minor)) The absolute configuration is not yet determined.

[Comparative Examples 7 to 26]
RuBr ₂ [(S, S) -xylskewphos] (pica) -catalyzed 2-propanol as a hydrogen source in a ketone hydrogenation reaction having an ortho disubstituted phenyl group other than 2 ′, 6′-dichloro-3′-fluoroacetophenone The reactivity and enantioselectivity of ruthenium catalysts with optically active diphosphine ligands and optically active diamine ligands were compared. The reaction conditions were the same as in Examples 17 to 22 without adding hydrogen with respect to the investigation of the hydrogen transfer reduction ability of the RuBr ₂ [(S, S) -xylskewphos] (pica) catalyst. Other catalyst evaluations were performed in the same manner as in Example 1 except that the catalyst type and S / C were changed as described in Table 7.

As a result, the hydrogen transfer reduction of the RuBr ₂ [(S, S) -xylskewphos] (pica) catalyst is very slight, and the catalyst is more excellent in reactivity and enantioselectivity than other catalysts. Became clear.

Claims (12)

A process for producing an optically active secondary alcohol comprising the following general formula (1)
RuXYAB (1)
[In the general formula (1), X and Y are the same or different from each other, and represent a hydrogen atom or an anionic group, and A represents the following general formula (2)
(In general formula (2),
R ¹ and R ² are the same or different from each other, and represent a C1-C20 linear or cyclic hydrocarbon group which may have a substituent,
R ³ and R ⁴ are the same or different from each other, 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 from each other and represent a hydrocarbon group which may have a substituent,
* Represents an asymmetric carbon atom. ), And B represents the following general formula (3) or general formula (4)
(In general formula (3),
R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different from each other, and each represents a hydrogen atom or a C 1-20 linear or cyclic hydrocarbon group which may have a substituent,
R ¹⁰ and R ¹¹ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent,
R ¹² may be bonded at least partly to ruthenium as an anionic group X;
n represents an integer of 0 or 1,
In general formula (4),
R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different from each other at each occurrence, and are each a linear or cyclic group having 1 to 20 carbon atoms which may have a hydrogen atom or a substituent. Represents a hydrocarbon group, provided that at least one of R ¹³ , R ¹⁴ and R ¹⁵ is a hydrogen atom;
R ¹³ and R ¹⁴ may combine with each other to form a ring containing a nitrogen atom,
R ¹⁶ and R ¹⁷ and / or two adjacent R ¹⁸ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent,
Each R ¹⁸ may be independently bonded to ruthenium as at least a part thereof as an anionic group X;
m represents an integer of 1 to 3,
k represents an integer of 0 to 10. )
The amine compound represented by these is shown. ]
In the presence of one or two or more ruthenium complexes selected from the compounds represented by the following general formulas (5) to (7)
[D ^{1 to} D ³ in the general formulas (5) to (7) represent a carbon atom or a nitrogen atom, and any one of D ^{1 to} D ³ is a nitrogen atom,
R ¹⁹ and R ²⁰ are the same or different and each represents a linear or branched alkyl group having 1 to 9 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a halogen group, or a nitro group. Show
R ²¹ represents a branched or straight chain alkyl or alkoxy group having 1 to 9 carbon atoms which may be substituted with a hetero atom, an amino group, an amide group, a nitro group, an acyl group, an ester group, or a cyclic aliphatic hydrocarbon. Group,
R ^{22 to} R ²⁴ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a substituent. A cyclic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a halogen group or a nitro group, provided that when D ^{1 to} D ³ are nitrogen atoms, There is no group selected from the group consisting of the corresponding R ²² , R ²³ and R ²⁴ on the atom;
E represents an oxygen or sulfur atom]
A process wherein the ketone selected from the compounds represented by is reacted with hydrogen. In the reaction system, the following general formula (8)
RuXYA (8)
[In general formula (8), X, Y, and A have the meaning as defined in general formula (1) mutually independently. And one or more selected from the compounds represented by the general formula (3) and / or the general formula (4). The ruthenium complex represented by the general formula (1) is prepared in situ by the presence of the amine compound.   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- (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- Tylphenylphosphino) -3-methylpentane, 2,4-bis- (di-3,5-diethylphenylphosphino) -3-methylpentane, 2,4-bis- (di-3,5-diisopropylphenyl) Phosphino) -3-methylpentane, 1,3-bis- (diphenylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-4-tolylphosphino) -1,3-diphenylpropane, , 3-bis- (di-3,5-xylylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-4-tert-butylphenylphosphino) -1,3-diphenylpropane 1,3-bis- (di-3,5-diethylphenylphosphino) -1,3-diphenylpropane, 1,3-bis- (di-3,5-diisopropylphenylphosphino) 1,3-diphenylpropane, 1,3-bis- (diphenylphosphino) -1,3-diphenyl-2-methylpropane, 1,3-bis- (di-4-tolylphosphino) -1,3-diphenyl- 2-methylpropane, 1,3-bis- (di-3,5-xylylphosphino) -1,3-diphenyl-2-methylpropane, 1,3-bis- (di-4-tert-butylphenyl) Phosphino) -1,3-diphenyl-2-methylpropane, 1,3-bis- (di-3,5-diethylphenylphosphino) -1,3-diphenyl-2-methylpropane or 1,3-bis The method according to claim 1 or 2, which is-(di-3,5-diisopropylphenylphosphino) -1,3-diphenyl-2-methylpropane.   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-isopropylphenylphosphino) pentane, 2,4-bis- (di-4-tert-butylphenylphosphino) pentane, 2,4-bis- (di-3,5 The process according to any one of claims 1 to 3, which is -diethylphenylphosphino) pentane or 2,4-bis- (diphenylphosphino) -3-methylpentane.   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-i Propylpyridine, 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-phenylpi Jin, 2- (aminomethyl) -4-phenyl pyridine or 2-Process according to claim 1 which is (aminomethyl) -5-phenylpyridine.   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) -4-isopropylpyrpyridine or 2- (aminomethyl) 6. Process according to any one of claims 1 to 5, characterized in that it is -4-tert-butylpyridine. In general formulas (5) to (7),
R ¹⁹ and R ²⁰ are the same or different and each represent a linear or branched alkyl group or alkoxy group having 1 to 5 carbon atoms which may have a halogen group, a halogen group or a nitro group,
R ²¹ represents a branched or straight-chain alkyl group having 1 to 6 carbon atoms, an acyl group, an ester group, or a cyclic hydrocarbon group, which may be substituted with an aromatic ring or a heteroatom. The method according to one item. In general formulas (5) to (7),
The method according to any one of claims 1 to 7, wherein R ²¹ is an alkyl group having 1 to 3 carbon atoms. In general formulas (5) to (7),
The method according to claim 8, wherein R ²¹ is a methyl group. In general formulas (5) to (7),
R ¹⁹ and R ²⁰ are a linear or branched alkyl group having 1 to 3 carbon atoms which may have a halogen group, an alkoxy group or a halogen group,
R ²¹ is an alkyl group having 1 to 3 carbon atoms,
R ^{22 to} R ²⁴ may be hydrogen or a C 1-3 linear or branched alkyl group which may have a halogen group, an alkoxy group, a halogen group or a cyclic hydrocarbon group which may have a substituent or a substituent A heterocyclic ring optionally having a group,
The method according to claim 1. A process for producing an optically active secondary alcohol comprising the following general formula (8)
RuXYA (8)
[In the general formula (8), X and Y are the same or different from each other, each represents a hydrogen atom or an anionic group, and A represents the following general formula (2)
(In general formula (2),
R ¹ and R ² are the same or different from each other, and represent a C1-C20 linear or cyclic hydrocarbon group which may have a substituent,
R ³ and R ⁴ are the same or different from each other, 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 from each other and represent a hydrocarbon group which may have a substituent,
* Represents an asymmetric carbon atom. 1 or 2 or more types of complexes selected from compounds represented by the following general formula (3) and / or general formula (4):
[In general formula (3),
R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different from each other, and each represents a hydrogen atom or a C 1-20 linear or cyclic hydrocarbon group which may have a substituent,
R ¹⁰ and R ¹¹ may form a hydrocarbon ring or heterocyclic ring linked to the saturation may have a substituent group or an unsaturated one another,
R ¹² may be bonded at least partly to ruthenium as an anionic group X;
n represents an integer of 0 or 1,
In general formula (4),
R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different from each other at each occurrence, and are each a linear or cyclic group having 1 to 20 carbon atoms which may have a hydrogen atom or a substituent. Represents a hydrocarbon group, provided that at least one of R ¹³ , R ¹⁴ and R ¹⁵ is a hydrogen atom;
R ¹³ and R ¹⁴ may combine with each other to form a ring containing a nitrogen atom,
R ¹⁶ and R ¹⁷ and / or two adjacent R ¹⁸ may be linked to each other to form a saturated or unsaturated hydrocarbon ring or heterocyclic ring which may have a substituent,
Each R ¹⁸ may be independently bonded to ruthenium as at least a part thereof as an anionic group X;
m represents an integer of 1 to 3,
k represents an integer of 0 to 10. In the presence of one or more amine compounds selected from the compounds represented by formula (5) to (7):
[D ^{1 to} D ³ in the general formulas (5) to (7) represent a carbon atom or a nitrogen atom, and any one of D ^{1 to} D ³ is a nitrogen atom,
R ¹⁹ and R ²⁰ are the same or different and each represents a linear or branched alkyl group having 1 to 9 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a halogen group, or a nitro group. Show
R ²¹ represents a branched or straight chain alkyl or alkoxy group having 1 to 9 carbon atoms which may be substituted with a hetero atom, an amino group, an amide group, a nitro group, an acyl group, an ester group, or a cyclic aliphatic hydrocarbon. Group,
R ^{22 to} R ²⁴ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms which may have a halogen group, an ester group, an amide group, an amino group or an alkoxy group, a substituent. A cyclic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a halogen group or a nitro group, provided that when D ^{1 to} D ³ are nitrogen atoms, There is no group selected from the group consisting of the corresponding R ²² , R ²³ and R ²⁴ on the atom;
E represents an oxygen or sulfur atom]
Reacting a ketone selected from the compounds represented by hydrogen with hydrogen   The method according to any one of claims 1 to 11, wherein the reaction between the ketone selected from the compounds represented by the general formulas (5) to (7) and hydrogen is performed in the presence of a base.