JP5507931B2 - Method for producing optically active alcohol having aromatic heterocycle - Google Patents

Description

  The present invention relates to a method for producing an optically active alcohol using a ruthenium complex as a catalyst. More specifically, an optical system using a ruthenium complex which is a highly efficient catalyst effective for producing optically active alcohols useful as synthetic intermediates for optically active physiologically active compounds or liquid crystal materials used for pharmaceuticals and agricultural chemicals. The present invention relates to a method for producing an active alcohol.

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

The optically active alcohol is useful as an asymmetric source for synthesizing various optically active substances, and is expected, for example, as a synthetic intermediate of pharmaceuticals exhibiting antiallergic action and various intermediates such as agricultural chemicals. As synthesis methods, in general, 1) a method for optically resolving racemates, 2) a method for asymmetric synthesis and derivatization of chiral substrates, and 3) precursor carbonyl compounds using enzymes such as baker's yeast 4) A method of asymmetric hydrogenation and asymmetric reduction of a precursor carbonyl compound using a metal complex is known.
Of these, production by asymmetric synthesis is considered to be an indispensable technique for producing a large amount of optically active alcohol, and many methods have been proposed.

  For example, an optically active cyanohydrin trimethylsilyl ether is synthesized by an asymmetric cyanation reaction of an aldehyde using cyanotrimethylsilane under a vanadium catalyst, and then via two steps of a [2 + 2 + 2] cyclization reaction of a cyano group and acetylene under a cobalt catalyst. And a method for obtaining a phenylpyridinyl alcohol derivative (see Non-patent Document 1), a method for reducing a benzoylpyridine derivative using baker's yeast (see Non-Patent Document 2), p-catalyzed by an oxaborolidine catalyst in the presence of catecholborane. Method by asymmetric reduction of chlorobenzoyl-2-pyridine (see Non-patent Document 3), Method by hydrogen transfer-type asymmetric reduction of 2-benzoylpyridine with formic acid / triethylamine system using ruthenium complex as catalyst (Non-patent Document 4) See).

  However, in the [2 + 2 + 2] cyclization reaction using a transition metal catalyst, there are difficulties such as using acetylene gas. In addition, the synthetic method using an enzyme is complicated in operation, has a limitation on the type of reaction substrate, and the absolute configuration of the resulting alcohols is limited to a specific one.

  In addition, various transition metal catalysts capable of asymmetric reduction and asymmetric hydrogenation of carbonyl compounds are generally ketones having both an aromatic group and an aliphatic group, such as acetophenone derivatives. In some cases, relatively good results have been reported, but there are few methods for asymmetric hydrogenation of carbonyl compounds having aromatic hydrocarbon groups and heterocycles.

  Non-Patent Document 5 discloses a method for asymmetric hydrogenation of a 2-benzoylpyridine derivative using a ruthenium complex catalyst comprising potassium hydroxide, an optically active diphosphine, and an optically active diamine ligand as a method for producing a phenylpyridinylmethanol derivative. Is described. However, this method often has low enantioselectivity. For example, in a reaction using 2-benzoylpyridine as a substrate, the optical purity of the product is 70% ee at the maximum, and p-chlorobenzoyl-2-pyridine is used as a substrate. Even in this reaction, the optical purity of the product is only 60% ee at the maximum.

  In addition, Non-Patent Document 6 reports a method for asymmetric reduction of a 2-benzoylpyridine derivative by a hydrogen transfer reaction using a ruthenium complex having an optically active SKEWPHOS ligand and a picolylamine ligand as a catalyst. ing. However, this method also has low reaction efficiency and low enantioselectivity, and satisfactory results have not been obtained.

SYNTHESIS, 2008, 1, p. 69-74 Chem. Pharm. Bull., 1996, 44, 4, p. 853-855 Tetrahedron Letters., 1996, 37, 32, p. 5675-5678 Tetrahedron Letters., 2000, 41, p. 9277-9280 Tetrahedron, 2008, 64, p.8700-8708 Organometallics, 2005, 24, p.1660-1669

  An object of the present invention is to efficiently use an optically active alcohol having an aromatic hydrocarbon group and a heterocyclic ring, which has high optical purity, in the production of optically active alcohol compounds expected as various intermediates such as pharmaceutical intermediates and agricultural chemicals. To provide a method of synthesis.

  In order to solve the above-mentioned problems, the present inventors have intensively studied asymmetric hydrogenation and asymmetric reduction reactions of carbonyl compounds having an aromatic hydrocarbon group and a heterocyclic ring. It has been found that a catalyst containing a ruthenium complex having an active diphosphine compound and a specific diamine compound as a ligand has excellent performance as an asymmetric catalyst for a carbonyl compound derivative having an aromatic hydrocarbon group and a heterocyclic ring. As a result of research, the present invention has been completed.

（式中、
Ａｒ^１は環内に窒素原子、硫黄原子、または、酸素原子を少なくとも１つ含み、これらのヘテロ原子は塩を形成していてもよい５員環、６員環または７員環芳香族複素環基であり、
Ａｒ^２は０〜１０個の各々同じでも異なってもよい炭素数１〜２０のアルキル基、アルコキシ基、ヒドロキシアルキル基、ハロゲン基、アミノ基、エステル基、アミド基、ニトロ基、シアノ基を有してもよい、芳香族炭化水素基である）
で表されるケトンを、不斉触媒の存在下において、水素源と反応させて、 That is, the present invention
General formula (1)

(Where
Ar ¹ contains at least one nitrogen atom, sulfur atom, or oxygen atom in the ring, and these heteroatoms may form a salt, a 5-membered ring, a 6-membered ring or a 7-membered aromatic heterocycle Group,
Ar ² has 0 to 10 alkyl groups, alkoxy groups, hydroxyalkyl groups, halogen groups, amino groups, ester groups, amide groups, nitro groups, and cyano groups, which may be the same or different. May be an aromatic hydrocarbon group)
Is reacted with a hydrogen source in the presence of an asymmetric catalyst,

（式中、
Ａｒ^１およびＡｒ^２は前記と同じ意味を示し、
＊は不斉炭素の位置を示す）
で表される光学活性アルコールを製造する方法であって、 General formula (2)

(Where
Ar ¹ and Ar ² have the same meaning as described above,
* Indicates the position of the asymmetric carbon)
A process for producing an optically active alcohol represented by:

（式中、
Ｒ^１およびＲ^２は、互いに同一または異なっていてもよい、炭素数１〜２０のアルキル基または置換基を有してもよい環状炭化水素基であり、
Ｒ^３およびＲ^４は互いに同一または異なっていてもよい、水素、炭素数１〜３の炭化水素基であり、
Ｒ^５、Ｒ^６、Ｒ^７およびＲ^８は、互いに同一または異なっていてもよい、置換基を有してもよい炭化水素基である）で表される化合物であり、 The asymmetric catalyst is represented by the general formula (3)
RuXYAB (3)
(Where
X and Y represent hydrogen or anionic groups, which may be the same or different from each other,
A represents the general formula (4)

(Where
R ¹ and R ² are cyclic hydrocarbon groups which may have the same or different from each other and may have an alkyl group having 1 to 20 carbon atoms or a substituent,
R ³ and R ⁴ may be the same or different from each other, hydrogen, a hydrocarbon group having 1 to 3 carbon atoms,
R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrocarbon groups which may be the same or different from each other and may have a substituent,

（式中、
Ｒ^９は水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、
Ｒ^１０、Ｒ^１１は互いに同一または異なっていてもよい水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、Ｒ^１０とＲ^１１は、互いに連結して、アルキル基、アルケニル基、シクロアルキル基、アリール基、アルコキシ基、エステル基、アシルオキシ基、ハロゲン原子、ニトロ基、またはシアノ基の置換基を有してもよい、飽和または不飽和の炭化水素基を形成してもよく、
Ｒ^１２、Ｒ^１３、Ｒ^１４、およびＲ^１５は、互いに同一または異なっていてもよい水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、Ｒ^１２とＲ^１３、Ｒ^１３とＲ^１４、またはＲ^１４とＲ^１５は互いに連結して、飽和または不飽和の炭化水素基を形成してもよく、Ｎを含む飽和または不飽和の炭化水素基を形成してもよい）
で表される化合物 B is the general formula (5),

(Where
R ⁹ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, or a cyclic hydrocarbon group which may have a substituent,
R ¹⁰ and R ¹¹ represent a hydrogen atom which may be the same or different from each other, a C 1-20 alkyl group or a cyclic hydrocarbon group which may have a substituent, and R ¹⁰ and R ¹¹ Linked and may have a substituent of alkyl group, alkenyl group, cycloalkyl group, aryl group, alkoxy group, ester group, acyloxy group, halogen atom, nitro group, or cyano group, saturated or unsaturated May form a hydrocarbon group,
R ¹² , R ¹³ , R ¹⁴ , and R ¹⁵ represent a hydrogen atom that may be the same as or different from each other, an alkyl group having 1 to 20 carbon atoms, or a cyclic hydrocarbon group that may have a substituent, R ¹² and R ¹³ , R ¹³ and R ¹⁴ , or R ¹⁴ and R ¹⁵ may be connected to each other to form a saturated or unsaturated hydrocarbon group, and a saturated or unsaturated hydrocarbon group containing N May be formed)
Compound represented by

（式中、
Ｒ^１６、Ｒ^１７、およびＲ^１８は、少なくとも一つは水素原子であり、Ｒ^１６、Ｒ^１７は互いに同一または異なっていてもよい水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、またはＲ^１６およびＲ^１７は互いに連結してＮを含む環を形成してもよく、
Ｒ^１８は水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、
Ｒ^１９、Ｒ^２０は、互いに同一または異なっていてもよい水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、Ｒ^１９とＲ^２０は、互いに連結して、アルキル基、アルケニル基、シクロアルキル基、アリール基、アルコキシ基、エステル基、アシルオキシ基、ハロゲン原子、ニトロ基、またはシアノ基の置換基を有してもよい、飽和または不飽和の炭化水素基を形成してもよく、
Ｒ^２１は、互いに異なっていてもよく、水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、隣接するＲ^２１が互いに連結して、飽和または不飽和の炭化水素基を形成してもよく、ｍは１〜１０の整数を示し、ｎは１〜３の整数を示す）で表される化合物である）
で表されるルテニウム錯体を含む触媒であり、水素源が水素ガスまたは水素供与性化合物であり、ただし、前記ケトンにおいて、一般式（Ｉ）中、Ａｒ^１がピリジル基およびＡｒ^２が置換されていないフェニル基であり、かつ前記不斉触媒において、一般式（４）中のＲ^５、Ｒ^６、Ｒ^７およびＲ^８が置換されていないフェニル基であり、かつ前記水素源および溶媒が２−プロパノールである場合を除く、前記方法に関する。 Or general formula (6)

(Where
At least one of R ¹⁶ , R ¹⁷ and R ¹⁸ is a hydrogen atom, and R ¹⁶ and R ¹⁷ have a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or a substituent which may be the same or different from each other. An optionally substituted cyclic hydrocarbon group, or R ¹⁶ and R ¹⁷ may be linked together to form a ring containing N;
R ¹⁸ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent,
R ¹⁹ and R ²⁰ represent a hydrogen atom which may be the same or different from each other, an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent, and R ¹⁹ and R ²⁰ are Linked to each other and may have a substituent of an alkyl group, alkenyl group, cycloalkyl group, aryl group, alkoxy group, ester group, acyloxy group, halogen atom, nitro group, or cyano group, saturated or unsaturated May form a hydrocarbon group of
R ²¹ may be different from each other, and represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent, and adjacent R ²¹ are connected to each other and saturated. Or an unsaturated hydrocarbon group may be formed, m represents an integer of 1 to 10, and n represents an integer of 1 to 3).
In which the hydrogen source is hydrogen gas or a hydrogen-donating compound, provided that in the general formula (I), Ar ¹ is substituted with a pyridyl group and Ar ^2. In the asymmetric catalyst, R ⁵ , R ⁶ , R ⁷ and R ⁸ in the general formula (4) are unsubstituted phenyl groups, and the hydrogen source and the solvent are 2- This relates to the process, except for propanol.

The present invention also relates to a method for producing an optically active alcohol, wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ in the general formula (4) are aryl groups having one or two methyl groups.
Furthermore, the present invention, ^{R 5,} R 6 in the general formula (4), ^{R 7} and ^{R 8} is a xylyl group, relates to a process for producing an optically active alcohol.
In the present invention, Ar ¹ in the general formula (2) is a 2-thienyl group, 2-furyl group, 1-trityl-4-imidazolyl group, 2-pyrazyl group, 2-pyrimidinyl group or 2-pyridyl group. And Ar ² is an optionally substituted aryl group, and relates to a method for producing an optically active alcohol.
Furthermore, the present invention relates to a method for producing an optically active alcohol, wherein Ar ¹ is a 2-pyridyl group and Ar ² is a p-chlorophenyl group.
The present invention also relates to a method for producing an optically active alcohol, wherein the hydrogen source is hydrogen gas.

  The present invention relates to an optically active diphosphine compound having asymmetry on carbon and a catalyst containing a ruthenium complex having a specific diamine compound as a ligand, and a carbonyl compound having an aromatic hydrocarbon group and a heterocyclic ring. By reacting with a hydrogen source, an optically active alcohol having an aromatic heterocycle can be produced with high activity, high yield, and high selectivity.

The present invention is a method for producing an optically active alcohol by reacting a carbonyl compound having an aromatic hydrocarbon group and a heterocyclic ring with a hydrogen source in the presence of an asymmetric catalyst. 3).
RuXYAB (3)
In the general formula (3), the substituents X and Y represent hydrogen or anionic groups which may be the same as or different from each other. Examples of the anionic group include a halogen anion such as a fluorine anion, a chlorine anion, a bromine anion, and an iodine anion, an acetoxy anion, a benzoyloxy anion, a (2,6-dihydroxybenzoyl) oxy anion, and a (2,5-dihydroxybenzoyl). Oxyanion, (3-aminobenzoyl) oxyanion, (2,6-methoxybenzoyl) oxyanion, (2,4,6-triisopropylbenzoyl) oxyanion, 1-naphthalenecarboxylate anion, 2-naphthalenecarboxylate anion Trifluoroacetoxy anion, trifluoromethanesulfoxy anion, tetrahydroborate anion, tetrafluoroborate anion, hydride and the like. Of these, halogen anions such as fluorine anion, chlorine anion, bromine anion and iodine anion, tetrahydroborate anion, tetrafluoroborate anion and the like are preferable.

ここで、Ｒ^１、Ｒ^２は、同じであっても互いに異なってもよく、炭素数１〜２０のアルキル基または置換基を有してもよい環状炭化水素基を示し、Ｒ^３、Ｒ^４は同じであっても互いに異なってもよく、水素、炭素数１〜３の炭化水素基であり、Ｒ^５、Ｒ^６、Ｒ^７、およびＲ^８は、同じであっても互いに異なってもよく、置換基を有してもよい炭化水素基を示す。 The optically active diphosphine compound A in the asymmetric catalyst represented by the general formula (3) is represented by the general formula (4).

Here, R ¹ and R ² may be the same or different from each other, and each represents an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent, and R ³ and R ^{4. May be} the same or different from each other, and are hydrogen or a hydrocarbon group having 1 to 3 carbon atoms, and R ⁵ , R ⁶ , R ⁷ , and R ⁸ may be the same or different from each other. Represents a hydrocarbon group which may have a substituent.

Here, R ¹ and R ² are aliphatic, alicyclic saturated or unsaturated hydrocarbon groups, monocyclic or polycyclic aromatic or araliphatic hydrocarbon groups, or those carbons having a substituent. Various kinds of hydrogen groups may be used.

  For example, hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl, and phenylalkyl, and further to these hydrocarbon groups, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group And those having various permissible substituents such as a cyano group. Among these, preferred are a methyl group, an ethyl group, a propyl group, and a substituted phenyl group, and particularly preferred are a methyl group and a phenyl group.

When R ³ and R ⁴ are aliphatic saturated hydrocarbon groups which are hydrocarbon groups having 1 to 3 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, etc. Is preferred.

Here, R ⁵ , R ⁶ , R ⁷ and R ⁸ are aliphatic, alicyclic saturated or unsaturated hydrocarbon groups, monocyclic or polycyclic aromatic or araliphatic hydrocarbon groups, or Various types of these hydrocarbon groups having a substituent may be used.

  For example, hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl, and phenylalkyl, and further to these hydrocarbon groups, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group And those having various permissible substituents such as a cyano group. Among these, preferred are a phenyl group and a substituted phenyl group, and particularly preferred are a phenyl group and a phenyl group substituted with 1 to 5 methyl, ethyl, propyl, or t-butyl groups.

Examples of the optically active diphosphine compound represented by the general formula (4) include the following:
[1] As a pentane derivative having a diphenylphosphino group at the 2nd and 4th positions, it has 1 or 2 alkyl group substituents having 1 to 3 carbon atoms at the 3rd position, or an alkyl group substituent. No SKEWPHOS: 2,4-bis (diphenylphosphino) pentane, 2,4-bis (diphenylphosphino) -3-methylpentane, 2,4-bis (diphenylphosphino) -3 , 3-Dimethylpentane, 2,4-bis (diphenylphosphino) -3-ethylpentane, 2,4-bis (diphenylphosphino) -3,3-diethylpentane, 2,4-bis (diphenyl) Phosphino) -3-n-propylpentane, 2,4-bis (diphenylphosphino) -3,3-di-n-propylpentane, 2,4-bis (diphenylphosphino) -3-isop Pyrpentane, 2,4-bis (diphenylphosphino) -3,3-diisopropylpentane, 2,4-bis (diphenylphosphino) -3-ethyl-3-methylpentane, 2,4-bis (diphenylphosphino) ) -3-Methyl-3-n-propylpentane, 2,4-bis (diphenylphosphino) -3-methyl-3-isopropylpentane, 2,4-bis (diphenylphosphino) -3-ethyl-3- Examples include n-propylpentane, 2,4-bis (diphenylphosphino) -3-ethyl-3-isopropylpentane, 2,4-bis (diphenylphosphino) -3-n-propyl-3-isopropylpentane, and the like. The

  [2] The pentane derivative having a di-4-tolylphosphino group at the 2nd and 4th positions has 1 or 2 alkyl group substituents having 1 to 3 carbon atoms at the 3rd position, or an alkyl group substituent. In addition, TolSKEPPHOS: 2,4-bis (di-4-tolylphosphino) pentane, 2,4-bis (di-4-tolylphosphino) -3-methylpentane, 2,4-bis (di-4) -Tolylphosphino) -3,3-dimethylpentane, 2,4-bis (di-4-tolylphosphino) -3-ethylpentane, 2,4-bis (di-4-tolylphosphino) -3,3-diethylpentane, 2 , 4-Bis (di-4-tolylphosphino) -3-n-propylpentane, 2,4-bis (di-4-tolylphosphino) -3,3-di-n-propylpentane, 2,4-bi (Di-4-tolylphosphino) -3-isopropylpentane, 2,4-bis (di-4-tolylphosphino) -3,3-diisopropylpentane, 2,4-bis (di-4-tolylphosphino) -3-ethyl- 3-methylpentane, 2,4-bis (di-4-tolylphosphino) -3-methyl-3-n-propylpentane, 2,4-bis (di-4-tolylphosphino) -3-methyl-3-isopropylpentane 2,4-bis (di-4-tolylphosphino) -3-ethyl-3-n-propylpentane, 2,4-bis (di-4-tolylphosphino) -3-ethyl-3-isopropylpentane, 2,4 -Bis (di-4-tolylphosphino) -3-n-propyl-3-isopropylpentane and the like are exemplified.

  [3] As a pentane derivative having a di (4-t-butylphenyl) phosphino group at the 2-position and 4-position, the 3-position has one or two alkyl group substituents having 1 to 3 carbon atoms, Or 4-t-BuSKEWPHOS: 2,4-bis [di (4-t-butylphenyl) phosphino] pentane, and other 2,4-bis [di (4-t-butyl) having no alkyl group substituent Phenyl) phosphino] -3-methylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3,3-dimethylpentane, 2,4-bis [di (4-t-butylphenyl) Phosphino] -3-ethylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3,3-diethylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3-n- Lopylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3,3-di-n-propylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3 -Isopropylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3,3-diisopropylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3-ethyl -3-methylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3-methyl-3-n-propylpentane, 2,4-bis [di (4-t-butylphenyl) Phosphino] -3-methyl-3-isopropylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3-ethyl-3-n-propylpentane, 2,4-bis [di ( -T-butylphenyl) phosphino] -3-ethyl-3-isopropylpentane, 2,4-bis [di (4-t-butylphenyl) phosphino] -3-n-propyl-3-isopropylpentane, etc. The

  [4] The pentane derivative having a di-3,5-xylylphosphino group at the 2-position and 4-position has one or two alkyl group substituents having 1 to 3 carbon atoms at the 3-position, Or XylSKEWPHOS: 2,4-bis (di-3,5-xylylphosphino) pentane, and other 2,4-bis (di-3,5-xylylphosphino) having no alkyl group substituent -3-methylpentane, 2,4-bis (di-3,5-xylylphosphino) -3,3-dimethylpentane, 2,4-bis (di-3,5-xylylphosphino)- 3-ethylpentane, 2,4-bis (di-3,5-xylylphosphino) -3,3-diethylpentane, 2,4-bis (di-3,5-xylylphosphino)- 3-n-propylpentane, 2,4-bis (di-3,5-xylylphosphino 3,3-di-n-propylpentane, 2,4-bis (di-3,5-xylylphosphino) -3-isopropylpentane, 2,4-bis (di-3,5-xylylphosphine) Fino) -3,3-diisopropylpentane, 2,4-bis (di-3,5-xylylphosphino) -3-ethyl-3-methylpentane, 2,4-bis (di-3,5-chi) Silylphosphino) -3-methyl-3-n-propylpentane, 2,4-bis (di-3,5-xylylphosphino) -3-methyl-3-isopropylpentane, 2,4-bis (Di-3,5-xylylphosphino) -3-ethyl-3-n-propylpentane, 2,4-bis (di-3,5-xylylphosphino) -3-ethyl-3-isopropyl Pentan, 2,4-bis (di-3,5-xylylphosphino) -3 Such as n- propyl-3-isopropyl-pentane and the like.

  [5] The pentane derivative having a bis (3,5-diethylphenyl) phosphino group at the 2-position and 4-position has one or two alkyl group substituents having 1 to 3 carbon atoms at the 3-position, Or 3,5-diEtSKEPPHOS without an alkyl group substituent: 2,4-bis [bis (3,5-diethylphenyl) phosphino] pentane, other 2,4-bis [bis (3,5-diethyl) Phenyl) phosphino] -3-methylpentane, 2,4-bis [bis (3,5-diethylphenyl) phosphino] -3,3-dimethylpentane, 2,4-bis [bis (3,5-diethylphenyl) ) Phosphino] -3-ethylpentane, 2,4-bis [bis (3,5-diethylphenyl) phosphino] -3,3-diethylpentane, 2,4-bis [bis (3,5-diethyl) Enyl) phosphino] -3-n-propylpentane, 2,4-bis [bis (3,5-diethylphenyl) phosphino] -3,3-di-n-propylpentane, 2,4-bis [bis ( 3,5-diethylphenyl) phosphino] -3-isopropylpentane, 2,4-bis [bis (3,5-diethylphenyl) phosphino] -3,3-diisopropylpentane, 2,4-bis [bis (3 5-diethylphenyl) phosphino] -3-ethyl-3-methylpentane, 2,4-bis [bis (3,5-diethylphenyl) phosphino] -3-methyl-3-n-propylpentane, 2,4 -Bis [bis (3,5-diethylphenyl) phosphino] -3-methyl-3-isopropylpentane, 2,4-bis [bis (3,5-diethylphenyl) phosphino -3-ethyl-3-n-propylpentane, 2,4-bis [bis (3,5-diethylphenyl) phosphino] -3-ethyl-3-isopropylpentane, 2,4-bis [bis (3 , 5-diethylphenyl) phosphino] -3-n-propyl-3-isopropylpentane and the like.

  [6] As a 1,3-diphenylpropane derivative having a diphenylphosphino group at the 1-position and the 3-position, 1,3-diphenylpropane derivatives having 1 or 2 alkyl group substituents having 1 to 3 carbon atoms at the 2-position, -Bis (diphenylphosphino) -1,3-diphenyl-2-methylpropane, 1,3-bis (diphenylphosphino) -1,3-diphenyl-2,2-dimethylpropane, 1,3-bis (diphenyl) Phosphino) -1,3-diphenyl-2-ethylpropane, 1,3-bis (diphenylphosphino) -1,3-diphenyl-2,2-diethylpropane, 1,3-bis (diphenylphosphino)- 1,3-diphenyl-2-n-propylpropane, 1,3-bis (diphenylphosphino) -1,3-diphenyl-2,2-di-n-propylpropane, 1,3-bis Diphenylphosphino) -1,3-diphenyl-2-isopropylpropane, 1,3-bis (diphenylphosphino) -1,3-diphenyl-2,2-diisopropylpropane, 1,3-bis (diphenylphosphino) -1,3-diphenyl-2-ethyl-2-methylpropane, 1,3-bis (diphenylphosphino) -1,3-diphenyl-2-methyl-2-n-propylpropane, 1,3-bis ( Diphenylphosphino) -1,3-diphenyl-2-methyl-2-isopropylpropane, 1,3-bis (diphenylphosphino) -1,3-diphenyl-2-ethyl-2-n-propylpropane, 1, 3-bis (diphenylphosphino) -1,3-diphenyl-2-ethyl-2-isopropylpropane, 1,3-bis (diphenylphos Etc. I Bruno) -1,3-diphenyl -2-n-propyl-2-isopropyl-propane and the like.

  [7] As the 1,3-diphenylpropane derivative having a di-4-tolylphosphino group at the 1-position and 3-position, the 2-position has 1 or 2 alkyl group substituents having 1 to 3 carbon atoms, Or 1,3-bis (di-4-tolylphosphino) -1,3-diphenylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2- having no alkyl group substituent Methylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2,2-dimethylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2- Ethylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2,2-diethylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2- -Propylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2,2-di-n-propylpropane, 1,3-bis (di-4-tolylphosphino) -1,3 -Diphenyl-2-isopropylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2,2-diisopropylpropane, 1,3-bis (di-4-tolylphosphino) -1,3 -Diphenyl-2-ethyl-2-methylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2-methyl-2-n-propylpropane, 1,3-bis (di- 4-Tolylphosphino) -1,3-diphenyl-2-methyl-2-isopropylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2-ethyl 2-n-propylpropane, 1,3-bis (di-4-tolylphosphino) -1,3-diphenyl-2-ethyl-2-isopropylpropane, 1,3-bis (di-4-tolylphosphino) -1, Examples include 3-diphenyl-2-n-propyl-2-isopropylpropane.

  [8] As a 1,3-diphenylpropane derivative having a di (4-t-butylphenyl) phosphino group at the 1-position and 3-position, substitution of one or two alkyl groups having 1 to 3 carbon atoms at the 2-position 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3-diphenylpropane, 1,3-bis [di (4-t) having a group or no alkyl group substituent -Butylphenyl) phosphino] -1,3-diphenyl-2-methylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2,2-dimethylpropane, , 3-bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2-ethylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3- Diphenyl-2,2- Ethylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2-n-propylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino ] -1,3-diphenyl-2,2-di-n-propylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2-isopropylpropane, 1, 3-bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2,2-diisopropylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3 -Diphenyl 2-ethyl-2-methylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2-methyl-2-n-propylpropane, 1,3 Bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2-methyl-2-isopropylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3 -Diphenyl-2-ethyl-2-n-propylpropane, 1,3-bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2-ethyl-2-isopropylpropane, 1,3 -Bis [di (4-t-butylphenyl) phosphino] -1,3-diphenyl-2-n-propyl-2-isopropylpropane and the like are exemplified.

  [9] As a 1,3-diphenylpropane derivative having a di-3,5-xylylphosphino group at the 1-position and the 3-position, substitution of one or two alkyl groups having 1 to 3 carbon atoms at the 2-position 1,3-bis (di-3,5-xylylphosphino) -1,3-diphenylpropane, 1,3-bis (di-3,5) having a group or no alkyl group substituent -Xylylphosphino) -1,3-diphenyl-2-methylpropane, 1,3-bis (di-3,5-xylylphosphino) -1,3-diphenyl-2,2-dimethylpropane, , 3-bis (di-3,5-xylylphosphino) -1,3-diphenyl-2-ethylpropane, 1,3-bis (di-3,5-xylylphosphino) -1,3- Diphenyl-2,2-diethylpropane, 1,3-bis (di-3,5-xy Ruphosphino) -1,3-diphenyl-2-n-propylpropane, 1,3-bis (di-3,5-xylylphosphino) -1,3-diphenyl-2,2-di-n-propylpropane 1,3-bis (di-3,5-xylylphosphino) -1,3-diphenyl-2-isopropylpropane, 1,3-bis (di-3,5-xylylphosphino) -1, 3-diphenyl-2,2-diisopropylpropane, 1,3-bis (di-3,5-xylylphosphinolyl) -1,3-diphenyl-2-ethyl-2-methylpropane, 1,3-bis (Di-3,5-xylylphosphino) -1,3diphenyl-2-methyl-2-n-propylpropane, 1,3-bis (di-3,5-xylylphosphino) -1,3 -Diphenyl-2-methyl-2-isopropyl Bread, 1,3-bis (di-3,5-xylylphosphino) -1,3-diphenyl-2-ethyl-2-n-propylpropane, 1,3-bis (di-3,5-ki Silylphosphino) -1,3-diphenyl-2-ethyl-2-isopropylpropane, 1,3-bis (di-3,5-xylylphosphino) -1,3-diphenyl-2-n-propyl- Examples include 2-isopropylpropane.

  [10] As a 1,3-diphenylpropane derivative having a bis (3,5-diethylphenyl) phosphino group at the 1-position and the 3-position, substitution of one or two alkyl groups having 1 to 3 carbon atoms at the 2-position 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenylpropane, 1,3-bis [bis (3,5) having a group or no alkyl group substituent -Diethylphenyl) phosphino] -1,3-diphenyl-2-methylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenyl-2,2-dimethylpropane, , 3-bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenyl-2-ethylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1 3-diphenyl-2,2-diethylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenyl-2-n-propylpropane, 1,3-bis [bis ( 3,5-diethylphenyl) phosphino] -1,3-diphenyl-2,2-di-n-propylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenyl 2-isopropylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenyl-2,2-diisopropylpropane, 1,3-bis [bis (3,5-diethyl) Phenyl) phosphino] -1,3-diphenyl-2-ethyl-2-methylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1,3 diphe Ru-2-methyl-2-n-propylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenyl-2-methyl-2-isopropylpropane, 1,3- Bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenyl-2-ethyl-2-n-propylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1 , 3-diphenyl-2-ethyl-2-isopropylpropane, 1,3-bis [bis (3,5-diethylphenyl) phosphino] -1,3-diphenyl-2-n-propyl-2-isopropylpropane, and the like. Illustrated. In particular, SKEWPHOS, TolSKEWPHOS, 3,5-diEtSKEWPHOS, 4-t-BuSKEWPHOS, and XylSKEPPHOS are suitable. However, of course, the optically active diphosphine compound that can be used in the present invention is not limited to these.

一般式（５）中、Ｒ^９は水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、Ｒ^１０、Ｒ^１１は互いに同一または異なっていてもよい水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、Ｒ^１０とＲ^１１は、互いを連結して、アルキル基、アルケニル基、シクロアルキル基、アリール基、アルコキシ基、エステル基、アシルオキシ基、ハロゲン原子、ニトロ基、またはシアノ基などの置換基を有してもよい、飽和または不飽和の炭化水素基を形成してもよく、Ｒ^１２、Ｒ^１３、Ｒ^１４およびＲ^１５は、互いに同一または異なっていてもよい水素原子、炭素数１〜２０のアルキル基または置換基を有していてもよい環状炭化水素基を示し、Ｒ^１２とＲ^１３、Ｒ^１３とＲ^１４、またはＲ^１４とＲ^１５は互いを連結して飽和または不飽和の炭化水素基を形成してもよく、Ｎを含む飽和または不飽和の炭化水素基を形成してもよい。 In the optically active ruthenium complex represented by the general formula (3), in the general formula (5) or the general formula (6) which is an amine ligand or an optically active diamine compound represented by B,

In general formula (5), R ⁹ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent, and R ¹⁰ and R ¹¹ are the same or different from each other. A hydrogen atom, an alkyl group having 1 to 20 carbon atoms, or an optionally substituted cyclic hydrocarbon group, wherein R ¹⁰ and R ¹¹ are connected to each other to form an alkyl group, an alkenyl group, a cyclo A saturated or unsaturated hydrocarbon group which may have a substituent such as an alkyl group, an aryl group, an alkoxy group, an ester group, an acyloxy group, a halogen atom, a nitro group, or a cyano group, R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ represent a hydrogen atom which may be the same or different from each other, an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent, and R ¹² And R ¹³ , R ¹³ and R ¹⁴ , or R ¹⁴ and R ¹⁵ may be connected to each other to form a saturated or unsaturated hydrocarbon group, and form a saturated or unsaturated hydrocarbon group containing N May be.

Here, R ⁹ represents a hydrogen atom, an aliphatic or alicyclic saturated or unsaturated hydrocarbon group, a monocyclic or polycyclic aromatic or araliphatic hydrocarbon group, or a carbon atom having a substituent. Various kinds of hydrogen groups may be used.

  For example, hydrocarbon groups such as hydrogen atoms, alkyls, alkenyls, cycloalkyls, cycloalkenyls, phenyls, naphthyls, phenylalkyls, etc., and further to these hydrocarbon groups, alkyls, alkenyls, cycloalkyls, aryls, alkoxys, esters, acyloxys, halogen atoms , A nitro group, a cyano group, etc. which have various allowable substituents. Among these, preferred are a hydrogen atom, an alkyl group, a phenyl group, and a phenylalkyl group, and particularly preferred is a hydrogen atom.

R ¹⁰ and R ¹¹ are each a hydrogen atom, an aliphatic or alicyclic saturated or unsaturated hydrocarbon group, a monocyclic aromatic or araliphatic hydrocarbon group, or a hydrocarbon group having a substituent. It can be of various types.

  For example, hydrocarbon groups such as hydrogen atoms, alkyls, alkenyls, cycloalkyls, cycloalkenyls, phenyls, naphthyls, phenylalkyls, etc., and further to these hydrocarbon groups, alkyls, alkenyls, cycloalkyls, aryls, alkoxys, esters, acyloxys, halogen atoms , A nitro group, a cyano group, etc. which have various allowable substituents. Of these, preferred are a hydrogen atom, an alkyl group, a phenyl group, and a phenylalkyl group, and particularly preferred are all hydrogen atoms.

R ¹⁰ and R ¹¹ are connected to each other to form a substituent such as an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an alkoxy group, an ester group, an acyloxy group, a halogen atom, a nitro group, or a cyano group. In the case of forming a saturated or unsaturated hydrocarbon group which may be contained, an aliphatic, alicyclic saturated or unsaturated hydrocarbon group, a monocyclic aromatic or araliphatic hydrocarbon group There may be. For example, hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl and the like can be mentioned.

R ^{12 to} R ¹⁵ are each a hydrogen atom, an aliphatic or alicyclic saturated or unsaturated hydrocarbon group, a monocyclic aromatic or araliphatic hydrocarbon group, or a hydrocarbon group having a substituent. It can be of various types.

  For example, hydrocarbon groups such as hydrogen atoms, alkyls, alkenyls, cycloalkyls, cycloalkenyls, phenyls, naphthyls, phenylalkyls, etc., and further to these hydrocarbon groups, alkyls, alkenyls, cycloalkyls, aryls, alkoxys, esters, acyloxys, halogen atoms , A nitro group, a cyano group, etc. which have various allowable substituents. Among these, preferred are a hydrogen atom, alkyl, phenyl, and phenylalkyl, and particularly preferred is a hydrogen atom.

In addition, when R ¹² and R ¹³ , R ¹³ and R ¹⁴ or R ¹⁴ and R ¹⁵ are connected to each other to form a saturated or unsaturated hydrocarbon group, they may contain an N atom. Various kinds of cyclic saturated or unsaturated hydrocarbon groups, monocyclic aromatic or araliphatic hydrocarbon groups, heterocyclic groups, or substituted hydrocarbon groups and heterocyclic groups. Good.

For example, hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl, phenylalkyl, pyridine and the like, and further to these hydrocarbon groups, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, Examples thereof include those having various permissible substituents such as a nitro group and a cyano group.
Among these, preferred are alkyl and alkenyl, and particularly preferred is alkenyl.
As described above, the diamine compound represented by the general formula (5) is
[1] PICA in which all substituents are hydrogen: 2-picolylamine,

[2] MePICA having a substituent at R ⁹ : 2- (N-methylaminomethyl) pyridine, EtPICA: 2- (N-ethylaminomethyl) pyridine, n-PrPICA: 2- (Nn-propylaminomethyl) ) Pyridine, i-PrPICA: 2- (N-isopropylaminomethyl) pyridine, n-BtPICA: 2- (Nn-butylaminomethyl) pyridine, t-BtPICA: 2- (Nt-butylaminomethyl) Pyridine, PhPICA: 2- (N-phenylaminomethyl) pyridine, BnPICA: 2- (N-benzylaminomethyl) pyridine,

[3] 2- (1-aminoethyl) pyridine, 2- (1-phenylaminomethyl) pyridine, 2- (1-methyl-1-aminoethyl) pyridine having a substituent at R ¹⁰ and R ¹¹ , 2- (1-phenyl-1-aminoethyl) pyridine, 2- (1,1-diphenylaminomethyl) pyridine,

  [4] 3-Me-PICA having a substituent on the pyridine ring: 2- (aminomethyl) -3-methylpyridine, 4-Me-PICA: 2- (aminomethyl) -4-methylpyridine, 5-Me -PICA: 2- (aminomethyl) -5-methylpyridine, 6-Me-PICA: 2- (aminomethyl) -6-methylpyridine, 3-Et-PICA: 2- (aminomethyl) -3-ethylpyridine 4-Et-PICA: 2- (aminomethyl) -4-ethylpyridine, 5-Et-PICA: 2- (aminomethyl) -5-ethylpyridine, 6-Et-PICA: 2- (aminomethyl)- 6-ethylpyridine, 3-n-Pr-PICA: 2- (aminomethyl) -3-n-propylpyridine, 4-n-Pr-PICA: 2- (aminomethyl) -4- n-propylpyridine, 5-n-Pr-PICA: 2- (aminomethyl) -5-n-propylpyridine, 6-n-Pr-PICA: 2- (aminomethyl) -6-n-propylpyridine, 3 -I-Pr-PICA: 2- (aminomethyl) -3-i-propylpyridine, 4-i-Pr-PICA: 2- (aminomethyl) -4-i-propylpyridine, 5-i-Pr-PICA : 2- (aminomethyl) -5-i-propylpyridine, 6-i-Pr-PICA: 2- (aminomethyl) -6-i-propylpyridine, 3-Ph-PICA: 2- (aminomethyl)- 3-Phenylpyridine, 4-Ph-PICA: 2- (aminomethyl) -4-phenylpyridine, 5-Ph-PICA: 2- (aminomethyl) -5-phenylpyridine, 6-Ph PICA: 2- (aminomethyl) -6-phenylpyridine, 3-Bn-PICA: 2- (aminomethyl) -3-benzylpyridine, 4-Bn-PICA: 2- (aminomethyl) -4-benzylpyridine, 5-Bn-PICA: 2- (aminomethyl) -5-benzylpyridine, 6-Bn-PICA: 2- (aminomethyl) -6-benzylpyridine,

[5] AMQ which is a 2-quinoline derivative in which R ⁹ is hydrogen: 2-aminomethylquinoline,
[6] MeAMQ: 2- (N-methylaminomethyl) quinoline which is a 2-quinoline derivative having a substituent at R ⁹ , EtAMQ: 2- (N-ethylaminomethyl) quinoline, n-PrAMQ: 2- (N -N-propylaminomethyl) quinoline, i-PrAMQ: 2- (N-isopropylaminomethyl) quinoline, n-BuAMQ: 2- (Nn-butylaminomethyl) quinoline, t-BuAMQ: 2- (N- t-butylaminomethyl) quinoline, PhAMQ: 2- (N-phenylaminomethyl) quinoline, BnAMQ: 2- (N-benzylaminomethyl) quinoline,

[7] 2- (1-aminoethyl) quinoline, 2- (1-phenylaminomethyl) quinoline, 2- (1-methyl-1-amino), which are 2-quinoline derivatives having a substituent at R ¹⁰ and R ¹¹ Ethyl) quinoline, 2- (1-phenyl-1-aminoethyl) quinoline, 2- (1,1-diphenylaminomethyl) quinoline,

  [8] 3-MeAMQ which is a 2-quinoline derivative having a cyclic substituent: 2- (aminomethyl) -3-methylquinoline, 4-MeAMQ: 2- (aminomethyl) -4-methylquinoline, 5-MeAMQ : 2- (aminomethyl) -5-methylquinoline, 6-MeAMQ: 2- (aminomethyl) -6-methylquinoline, 7-MeAMQ: 2- (aminomethyl) -7-methylquinoline, 8-MeAMQ: 2 -(Aminomethyl) -8-methylquinoline, 3-EtAMQ: 2- (aminomethyl) -3-ethylquinoline, 4-EtAMQ: 2- (aminomethyl) -4-ethylquinoline, 5-EtAMQ: 2- ( Aminomethyl) -5-ethylquinoline, 6-EtAMQ: 2- (aminomethyl) -6-ethylquinoline, 7-EtAMQ: 2- (aminomethyl) 7-ethylquinoline, 8-EtAMQ: 2- (aminomethyl) -8-ethylquinoline, 3-n-PrAMQ: 2- (aminomethyl) -3-n-propylquinoline, 4-n-PrAMQ: 2- ( Aminomethyl) -4-n-propylquinoline, 5-n-PrAMQ: 2- (aminomethyl) -5-n-propylquinoline, 6-n-PrAMQ: 2- (aminomethyl) -6-n-propylquinoline 7-n-PrAMQ: 2- (aminomethyl) -7-n-propylquinoline, 8-n-PrAMQ: 2- (aminomethyl) -8-n-propylquinoline, 3-i-PrAMQ: 2- ( Aminomethyl) -3-i-propylquinoline, 4-i-PrAMQ: 2- (aminomethyl) -4-i-propylquinoline, 5-i-PrAMQ: 2- (aminomethyl)- -I-propylquinoline, 6-i-PrAMQ: 2- (aminomethyl) -6-i-propylquinoline, 7-i-PrAMQ: 2- (aminomethyl) -7-i-propylquinoline, 8-n- PrAMQ: 2- (aminomethyl) -8-i-propylquinoline, 3-n-BuAMQ: 2- (aminomethyl) -3-n-butylquinoline, 4-n-BuAMQ: 2- (aminomethyl) -4 -N-butylquinoline, 5-n-BuAMQ: 2- (aminomethyl) -5-n-butylquinoline, 6-n-BuAMQ: 2- (aminomethyl) -6-n-butylquinoline, 7-n- BuAMQ: 2- (aminomethyl) -7-n-butylquinoline, 8-n-BuAMQ: 2- (aminomethyl) -8-n-butylquinoline, 3-t-BuAMQ: 2- (aminomethyl)- 3-t-butylquinoline, 4-t-BuAMQ: 2- (aminomethyl) -4-t-butylquinoline, 5-t-BuAMQ: 2- (aminomethyl) -5-t-butylquinoline, 6-t -BuAMQ: 2- (aminomethyl) -6-t-butylquinoline, 7-t-BuAMQ: 2- (aminomethyl) -7-t-butylquinoline, 8-t-BuAMQ: 2- (aminomethyl)- 8-t-butylquinoline, 3-PhAMQ: 2- (aminomethyl) -3-phenylquinoline, 4-PhAMQ: 2- (aminomethyl) -4-phenylquinoline, 5-PhAMQ: 2- (aminomethyl)- 5-phenylquinoline, 6-PhAMQ: 2- (aminomethyl) -6-phenylquinoline, 7-PhAMQ: 2- (aminomethyl) -7-phenylquinoline, 8-PhAM : 2- (aminomethyl) -8-phenylquinoline, 3-BnAMQ: 2- (aminomethyl) -3-benzylquinoline, 4-BnAMQ: 2- (aminomethyl) -4-benzylquinoline, 5-BnAMQ: 2 -(Aminomethyl) -5-benzylquinoline, 6-BnAMQ: 2- (aminomethyl) -6-benzylquinoline, 7-BnAMQ: 2- (aminomethyl) -7-benzylquinoline, 8-BnAMQ: 2- ( Aminomethyl) -8-benzylquinoline,

[9] AM-1-IQ which is a 1-isoquinoline derivative in which R ⁹ is hydrogen: 1-aminomethylisoquinoline,

[10] MeAM-1-IQ: 1- (N-methylaminomethyl) isoquinoline which is a 1-isoquinoline derivative having a substituent at R ⁹ , EtAM-1-IQ: 1- (N-ethylaminomethyl) quinoline, n-PrAM-1-IQ: 1- (Nn-propylaminomethyl) isoquinoline, i-PrAM-1-IQ: 1- (N-isopropylaminomethyl) isoquinoline, n-BuAM-1-IQ: 1- (Nn-butylaminomethyl) isoquinoline, t-BuAM-1-IQ: 1- (Nt-butylaminomethyl) isoquinoline, PhAM-1-IQ: 1- (N-phenylaminomethyl) isoquinoline, BnAM -1-IQ: 1- (N-benzylaminomethyl) isoquinoline,

[11] 1- (1-aminoethyl) isoquinoline, 1- (1-phenylaminomethyl) isoquinoline, 1- (1-methyl-1-amino) which is a 1-isoquinoline derivative having a substituent in R ¹⁰ and R ¹¹ Ethyl) isoquinoline, 1- (1-phenyl-1-aminoethyl) isoquinoline, 1- (1,1-diphenylaminomethyl) isoquinoline

  [12] 3-MeAM-1-IQ: 1- (aminomethyl) -3-methylisoquinoline, 4-MeAM-1-IQ: 1- (aminomethyl) which is a 1-isoquinoline derivative having a substituent on the ring -4-methylisoquinoline, 5-MeAM-1-IQ: 1- (aminomethyl) -5-methylisoquinoline, 6-MeAM-1-IQ: 1- (aminomethyl) -6-methylisoquinoline, 7-MeAM- 1-IQ: 1- (aminomethyl) -7-methylisoquinoline, 8-MeAM-1-IQ: 1- (aminomethyl) -8-methylisoquinoline, 3-EtAM-1-IQ: 1- (aminomethyl) -3-ethylisoquinoline, 4-EtA-1-IQ: 1- (aminomethyl) -4-ethylisoquinoline, 5-EtAM-1-IQ: 1- (aminomethyl) -5-e Ruisoquinoline, 6-EtAM-1-IQ: 1- (aminomethyl) -6-ethylisoquinoline, 7-EtAM-1-IQ: 1- (aminomethyl) -7-ethylisoquinoline, 8-EtAM-1-IQ : 1- (aminomethyl) -8-ethylisoquinoline, 3-n-PrAM-1-IQ: 1- (aminomethyl) -3-n-propylisoquinoline, 4-n-PrAM-1-IQ: 1- ( Aminomethyl) -4-n-propylisoquinoline, 5-n-PrAM-1-IQ: 1- (aminomethyl) -5-n-propylisoquinoline, 6-n-PrAM-1-IQ: 1- (aminomethyl ) -6-n-propylisoquinoline, 7-n-PrAM-1-IQ: 1- (aminomethyl) -7-n-propylisoquinoline, 8-n-PrAM-1-IQ: 1- (amino Methyl) -8-n-propylisoquinoline, 3-i-PrAM-1-IQ: 1- (aminomethyl) -3-i-propylisoquinoline, 4-i-PrAM-1-IQ: 1- (aminomethyl) -4-i-propylisoquinoline, 5-i-PrAM-1-IQ: 1- (aminomethyl) -5-i-propylisoquinoline, 6-i-PrAM-1-IQ: 1- (aminomethyl) -6 -I-propylisoquinoline, 7-i-PrAM-1-IQ: 1- (aminomethyl) -7-i-propylisoquinoline, 8-n-PrAM-1-IQ: 1- (aminomethyl) -8-i -Propylisoquinoline, 3-n-BuAM-1-IQ: 1- (aminomethyl) -3-n-butylisoquinoline, 4-n-BuAM-1-IQ: 1- (aminomethyl) -4-n-butyliso Quinoline, 5-n-BuAM-1-IQ: 1- (aminomethyl) -5-n-butylisoquinoline, 6-n-BuAM-1-IQ: 1- (aminomethyl) -6-n-butylisoquinoline, 7-n-BuAM-1-IQ: 1- (aminomethyl) -7-n-butylisoquinoline, 8-n-BuAM-1-IQ: 1- (aminomethyl) -8-n-butylisoquinoline, 3- t-BuAM-1-IQ: 1- (aminomethyl) -3-t-butylisoquinoline, 4-t-BuAM-1-IQ: 1- (aminomethyl) -4-t-butylisoquinoline, 5-t- BuAM-1-IQ: 1- (aminomethyl) -5-t-butylisoquinoline, 6-t-BuA-1-MQ: 1- (aminomethyl) -6-t-butylisoquinoline, 7-t-BuAM- 1-IQ: 1- ( Minomethyl) -7-t-butylisoquinoline, 8-t-BuAM-1-IQ: 1- (aminomethyl) -8-t-butylisoquinoline, 3-PhAM-1-IQ: 1- (aminomethyl) -3 -Phenylisoquinoline, 4-PhAM-1-IQ: 1- (aminomethyl) -4-phenylisoquinoline, 5-PhAM-1-IQ: 1- (aminomethyl) -5-phenylisoquinoline, 6-PhAM-1- IQ: 1- (aminomethyl) -6-phenylisoquinoline, 7-PhAM-1-IQ: 1- (aminomethyl) -7-phenylisoquinoline, 8-PhAM-1-IQ: 1- (aminomethyl) -8 -Phenylisoquinoline, 3-BnAM-1-IQ: 1- (aminomethyl) -3-benzylisoquinoline, 4-BnAM-1-IQ: 1- (aminomethyl) ) -4-benzylisoquinoline, 5-BnAM-1-IQ: 1- (aminomethyl) -5-benzylisoquinoline, 6-BnAM-1-IQ: 1- (aminomethyl) -6-benzylisoquinoline, 7-BnAM -1-IQ: 1- (aminomethyl) -7-benzylisoquinoline, 8-BnAM-1-IQ: 1- (aminomethyl) -8-benzylisoquinoline,

[13] AM-3-IQ: 3-aminomethylisoquinoline, which is a 3-isoquinoline derivative in which R ⁹ is hydrogen;

[14] MeAM-3-IQ: 3- (N-methylaminomethyl) isoquinoline which is a 3-isoquinoline derivative having a substituent at R ⁹ , EtAM-3-IQ: 3- (N-ethylaminomethyl) quinoline, n-PrAM-3-IQ: 3- (Nn-propylaminomethyl) isoquinoline, i-PrAM-3-IQ: 3- (N-isopropylaminomethyl) isoquinoline, n-BuAM-3-IQ: 3- (Nn-butylaminomethyl) isoquinoline, t-BuAM-3-IQ: 3- (Nt-butylaminomethyl) isoquinoline, PhAM-3-IQ: 3- (N-phenylaminomethyl) isoquinoline, BnAM -3-IQ: 3- (N-benzylaminomethyl) isoquinoline,

[15] 3- (1-aminoethyl) isoquinoline, 3- (1-phenylaminomethyl) isoquinoline, 3- (1-methyl-1-amino) which are 3-isoquinoline derivatives having a substituent at R ¹⁰ and R ¹¹ Ethyl) isoquinoline, 3- (1-phenyl-1-aminoethyl) isoquinoline, 3- (1,1-diphenylaminomethyl) isoquinoline,

  [16] 1-MeAM-3-IQ: 3- (aminomethyl) -1-methylisoquinoline, 4-MeAM-3-IQ: 3- (aminomethyl) which is a 3-isoquinoline derivative having a substituent on the ring -4-methylisoquinoline, 5-MeAM-3-IQ: 3- (aminomethyl) -5-methylisoquinoline, 6-MeAM-3-IQ: 3- (aminomethyl) -6-methylisoquinoline, 7-MeAM- 3-IQ: 3- (aminomethyl) -7-methylisoquinoline, 8-MeAM-3-IQ: 3- (aminomethyl) -8-methylisoquinoline, 1-EtAM-3-IQ: 3- (aminomethyl) -1-ethylisoquinoline, 4-EtA-3-IQ: 3- (aminomethyl) -4-ethylisoquinoline, 5-EtAM-3-IQ: 3- (aminomethyl) -5-e Ruisoquinoline, 6-EtAM-3-IQ: 3- (aminomethyl) -6-ethylisoquinoline, 7-EtAM-3-IQ: 3- (aminomethyl) -7-ethylisoquinoline, 8-EtAM-3-IQ : 3- (aminomethyl) -8-ethylisoquinoline, 1-n-PrAM-3-IQ: 3- (aminomethyl) -1-n-propylisoquinoline, 4-n-PrAM-3-IQ: 3- ( Aminomethyl) -4-n-propylisoquinoline, 5-n-PrAM-3-IQ: 3- (aminomethyl) -5-n-propylisoquinoline, 6-n-PrAM-3-IQ: 3- (aminomethyl) ) -6-n-propylisoquinoline, 7-n-PrA-3-MQ: 3- (aminomethyl) -7-n-propylisoquinoline, 8-n-PrAM-3-IQ: 3- (amino Til) -8-n-propylisoquinoline, 1-i-PrAM-3-IQ: 3- (aminomethyl) -1-i-propylisoquinoline, 4-i-PrAM-3-IQ: 3- (aminomethyl) -4-i-propylisoquinoline, 5-i-PrAM-3-IQ: 3- (aminomethyl) -5-i-propylisoquinoline, 6-i-PrAM-3-IQ: 3- (aminomethyl) -6 -I-propylisoquinoline, 7-i-PrAM-3-IQ: 3- (aminomethyl) -7-i-propylisoquinoline, 8-n-PrAM-3-IQ: 3- (aminomethyl) -8-i -Propylisoquinoline, 1-n-BuAM-3-IQ: 3- (aminomethyl) -1-n-butylisoquinoline, 4-n-BuAM-3-IQ: 3- (aminomethyl) -4-n-butylisoxy Norin, 5-n-BuAM-3-IQ: 3- (aminomethyl) -5-n-butylisoquinoline, 6-n-BuAM-3-IQ: 3- (aminomethyl) -6-n-butylisoquinoline, 7-n-BuAM-3-IQ: 3- (aminomethyl) -7-n-butylisoquinoline, 8-n-BuAM-3-IQ: 3- (aminomethyl) -8-n-butylisoquinoline, 1- t-BuAM-3-IQ: 3- (aminomethyl) -1-t-butylisoquinoline, 4-t-BuAM-3-IQ: 3- (aminomethyl) -4-t-butylisoquinoline, 5-t- BuAM-3-IQ: 3- (aminomethyl) -5-t-butylisoquinoline, 6-t-BuAM-3-IQ: 3- (aminomethyl) -6-t-butylisoquinoline, 7-t-BuAM- 3-IQ: 3- ( Minomethyl) -7-t-butylisoquinoline, 8-t-BuAM-3-IQ: 3- (aminomethyl) -8-t-butylisoquinoline, 1-PhAM-3-IQ: 3- (aminomethyl) -1 -Phenylisoquinoline, 4-PhAM-3-IQ: 3- (aminomethyl) -4-phenylisoquinoline, 5-PhAM-3-IQ: 3- (aminomethyl) -5-phenylisoquinoline, 6-PhAM-3- IQ: 3- (aminomethyl) -6-phenylisoquinoline, 7-PhAM-3-IQ: 3- (aminomethyl) -7-phenylisoquinoline, 8-PhAM-3-IQ: 3- (aminomethyl) -8 -Phenylisoquinoline, 1-BnAM-3-IQ: 3- (aminomethyl) -1-benzylisoquinoline, 4-BnAM-3-IQ: 3- (aminomethyl) ) -4-benzylisoquinoline, 5-BnAM-3-IQ: 3- (aminomethyl) -5-benzylisoquinoline, 6-BnAM-3-IQ: 3- (aminomethyl) -6-benzylisoquinoline, 7-BnAM -3-IQ: 3- (aminomethyl) -7-benzylisoquinoline, 8-BnAM-3-IQ: 3- (aminomethyl) -8-benzylisoquinoline and the like. Particularly, 2- (aminomethyl) -6-methylpyridine and 2-picolylamine are preferable.

In General Formula (6), at least one of R ¹⁶ , R ¹⁷ , and R ¹⁸ is a hydrogen atom, and R ¹⁶ and R ¹⁷ may be the same or different from each other, and each may be the same or different. An alkyl group or an optionally substituted cyclic hydrocarbon group, R ¹⁶ and R ¹⁷ may be linked to each other to form a ring containing N; R ¹⁸ is a hydrogen atom, 20 represents a cyclic hydrocarbon group which may have an alkyl group or a substituent, and R ¹⁹ and R ²⁰ are the same or different from each other, a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or a substituent And R ¹⁹ and R ²⁰ are connected to each other to form an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an alkoxy group, an ester group, an acyloxy group, a halogen atom. A saturated or unsaturated hydrocarbon group which may have a substituent such as an atom, a nitro group, or a cyano group may be formed, and R ²¹ may be different from each other, and may be a hydrogen atom, a carbon number 1 to 20 alkyl groups or a cyclic hydrocarbon group which may have a substituent, adjacent R ²¹ may be connected to each other to form a saturated or unsaturated hydrocarbon group, m is The integer of 1-10 is shown, n shows the integer of 1-3.

R ¹⁶ and R ¹⁷ are a hydrogen atom, an aliphatic or alicyclic saturated or unsaturated hydrocarbon group, a monocyclic or polycyclic aromatic or araliphatic hydrocarbon group, or a carbon atom having a substituent. Various kinds of hydrogen groups may be used.

  For example, hydrocarbon groups such as hydrogen atoms, alkyls, alkenyls, cycloalkyls, cycloalkenyls, phenyls, naphthyls, phenylalkyls, etc., and further to these hydrocarbon groups, alkyls, alkenyls, cycloalkyls, aryls, alkoxys, esters, acyloxys, halogen atoms , A nitro group, a cyano group, etc. which have various allowable substituents. Among these, preferred are a hydrogen atom, an alkyl group, a phenyl group, a phenylalkyl group, a cyclic alkylene group, or an alkenylene group, and particularly preferred are all hydrogen atoms.

When R ¹⁶ and R ¹⁷ are connected to each other to form a ring containing N, they are aliphatic, alicyclic saturated or unsaturated hydrocarbon groups, monocyclic aromatic or araliphatic hydrocarbons. Various types of these hydrocarbon groups having a group or a substituent may be used.

For example, hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl, and phenylalkyl, and further to these hydrocarbon groups, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group And those having various permissible substituents such as a cyano group.
Of these, preferred are alkyl and alkenyl, and particularly preferred is alkyl.

R ¹⁸ represents a hydrogen atom, an aliphatic or alicyclic saturated or unsaturated hydrocarbon group, a monocyclic or polycyclic aromatic or araliphatic hydrocarbon group, or a hydrocarbon group having a substituent. It can be of various types.

  For example, hydrocarbon groups such as hydrogen atoms, alkyls, alkenyls, cycloalkyls, cycloalkenyls, phenyls, naphthyls, phenylalkyls, etc., and further to these hydrocarbon groups, alkyls, alkenyls, cycloalkyls, aryls, alkoxys, esters, acyloxys, halogen atoms , A nitro group, a cyano group, etc. which have various allowable substituents. Among these, preferred are a hydrogen atom, an alkyl group, a phenyl group, and a phenylalkyl group, and particularly preferred is a hydrogen atom.

R ¹⁹ and R ²⁰ are a hydrogen atom, an aliphatic or alicyclic saturated or unsaturated hydrocarbon group, a monocyclic or polycyclic aromatic or araliphatic hydrocarbon group, or a carbon atom having a substituent. Various kinds of hydrogen groups may be used.

  For example, hydrocarbon groups such as hydrogen atoms, alkyls, alkenyls, cycloalkyls, cycloalkenyls, phenyls, naphthyls, phenylalkyls, etc., and further to these hydrocarbon groups, alkyls, alkenyls, cycloalkyls, aryls, alkoxys, esters, acyloxys, halogen atoms , A nitro group, a cyano group, etc. which have various allowable substituents.

R ¹⁹ and R ²⁰ are linked to each other and have a substituent such as an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an alkoxy group, an ester group, an acyloxy group, a halogen atom, a nitro group, or a cyano group. It forms a saturated or unsaturated hydrocarbon group that may be present. Among these substituents, preferred are a hydrogen atom, an alkyl group, a phenyl group, and a phenylalkyl group, and particularly preferred is a hydrogen atom.

R ²¹ represents a hydrogen atom, aliphatic, alicyclic saturated or unsaturated hydrocarbon group, monocyclic or polycyclic on the ring of 2-aminomethylpyrrolidine, 2-aminomethylpiperidine, and 2-aminomethylhomopiperidine. One to ten aromatic or araliphatic hydrocarbon groups in the ring or various hydrocarbon groups having a substituent may be substituted.

  For example, hydrocarbon groups such as hydrogen atoms, alkyls, alkenyls, cycloalkyls, cycloalkenyls, phenyls, naphthyls, phenylalkyls, etc., and further to these hydrocarbon groups, alkyls, alkenyls, cycloalkyls, aryls, alkoxys, esters, acyloxys, halogen atoms , A nitro group, a cyano group, etc. which have various allowable substituents.

Further, when adjacent R ²¹ are connected to each other to form a saturated or unsaturated hydrocarbon group, an aliphatic, alicyclic saturated or unsaturated hydrocarbon group, monocyclic or polycyclic aromatic group Alternatively, it may be an araliphatic hydrocarbon group or various types of these hydrocarbon groups having a substituent.

  For example, hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl, and phenylalkyl, and further to these hydrocarbon groups, alkyl, alkenyl, cycloalkyl, aryl, alkoxy, ester, acyloxy, halogen atom, nitro group And those having various permissible substituents such as a cyano group.

As described above, the diamine compound represented by the general formula (6) is
[1] AMPY in which all substituents are hydrogen: 2-aminomethylpyrrolidine, AMPI: 2-aminomethylpiperidine, AMHPI: 2-aminomethylhomopiperidine,

[2] 2- (N-methylaminomethyl) pyrrolidine, 2- (N-ethylaminomethyl) pyrrolidine, 2- (Nn-propylaminomethyl) pyrrolidine having R ¹⁶ as hydrogen and a substituent at R ¹⁷ , 2- (N-isopropylaminomethyl) pyrrolidine, 2- (N-methylaminomethyl) piperidine, 2- (N-ethylaminomethyl) piperidine, 2- (Nn-propylaminomethyl) piperidine, 2- (N -Isopropylaminomethyl) piperidine,
2- (N-methylaminomethyl) homopiperidine, 2- (N-ethylaminomethyl) homopiperidine, 2- (Nn-propylaminomethyl) homopiperidine, 2- (N-isopropylaminomethyl) homopiperidine,

[3] 1- (2-Pyrrolidinylmethyl) pyrrolidine, 1- (2-piperidinylmethyl) pyrrolidine, 1- (2-homo) in which R ¹⁶ and R ¹⁷ are linked to each other to form a hydrocarbon group. Piperidinylmethyl) pyrrolidine,

[4] 2- (1-aminoethyl) pyrrolidine, 2- (1-phenylaminomethyl) pyrrolidine, 2- (1-methyl-1) wherein R ¹⁶ and R ¹⁷ are hydrogen and R ¹⁹ and R ²⁰ have a substituent -Aminoethyl) pyrrolidine, 2- (1-phenyl-1-aminoethyl) pyrrolidine, 2- (1,1-diphenylaminomethyl) pyrrolidine, 2- (1-aminoethyl) piperidine, 2- (1-phenylamino) Methyl) piperidine, 2- (1-methyl-1-aminoethyl) piperidine, 2- (1-phenyl-1-aminoethyl) piperidine, 2- (1,1-diphenylaminomethyl) piperidine, 2- (1- Aminoethyl) homopiperidine, 2- (1-phenylaminomethyl) homopiperidine, 2- (1-methyl-1-aminoethyl) homopiperidine, 2- (1 Phenyl-1-aminoethyl) Homopipejin, 2- (1,1-diphenyl aminomethyl) homopiperidine,

[5] 2- (aminomethyl) -1-methylpyrrolidine, 2- (aminomethyl) -1-ethylpyrrolidine, 2- (aminomethyl) -1-n-propylpyrrolidine having a substituent at R ¹⁸ , 2- (Aminomethyl) -1-isopropylpyrrolidine, 2- (aminomethyl) -1-methylpiperidine, 2- (aminomethyl) -1-ethylpiperidine, 2- (aminomethyl) -1-n-propylpiperidine, 2- (Aminomethyl) -1-isopropylpiperidine, 2- (aminomethyl) -1-methylhomopiperidine, 2- (aminomethyl) -1-ethylhomopiperidine, 2- (aminomethyl) -1-n-propylhomopiperidine 2- (aminomethyl) -1-isopropylhomopiperidine,

[6] 2- (aminomethyl) -3-methylpyrrolidine, 2- (aminomethyl) -4-methylpyrrolidine, 2- (aminomethyl) -5-methylpyrrolidine, 2- (amino) having a substituent at R ²¹ Methyl) -3-ethylpyrrolidine, 2- (aminomethyl) -4-ethylpyrrolidine, 2- (aminomethyl) -5-ethylpyrrolidine,
2- (aminomethyl) -3-n-propylpyrrolidine, 2- (aminomethyl) -4-n-propylpyrrolidine, 2- (aminomethyl) -5-n-propylpyrrolidine, 2- (aminomethyl) -3 -Phenylpyrrolidine, 2- (aminomethyl) -4-phenylpyrrolidine, 2- (aminomethyl) -5-phenylpyrrolidine, 2- (aminomethyl) -3-methylpiperidine, 2- (aminomethyl) -4-methyl Piperidine, 2- (aminomethyl) -5-methylpiperidine, 2- (aminomethyl) -6-methylpiperidine, 2- (aminomethyl) -3-ethylpiperidine, 2- (aminomethyl) -4-ethylpiperidine, 2- (aminomethyl) -5-ethylpiperidine, 2- (aminomethyl) -6-ethylpiperidine, 2- (aminomethyl) -3- -Propylpiperidine, 2- (aminomethyl) -4-n-propylpiperidine, 2- (aminomethyl) -5-n-propylpiperidine, 2- (aminomethyl) -6-n-propylpiperidine, 2- (amino Methyl) -3-phenylpiperidine, 2- (aminomethyl) -4-phenylpiperidine, 2- (aminomethyl) -5-phenylpiperidine, 2- (aminomethyl) -6-phenylpiperidine, 2- (aminomethyl) -3-methyl homopiperidine, 2- (aminomethyl) -4-methyl homopiperidine, 2- (aminomethyl) -5-methyl homopiperidine, 2- (aminomethyl) -6-methyl homopiperidine, 2- (amino Methyl) -7-methylhomopiperidine, 2- (aminomethyl) -3-ethylhomopiperidine, 2- (aminomethyl) 4-ethyl homopiperidine, 2- (aminomethyl) -5-ethyl homopiperidine, 2- (aminomethyl) -6-ethyl homopiperidine, 2- (aminomethyl) -7-ethyl homopiperidine, 2- (aminomethyl) ) -3-n-propyl homopiperidine, 2- (aminomethyl) -4-n-propyl homopiperidine, 2- (aminomethyl) -5-n-propyl homopiperidine, 2- (aminomethyl) -6-n -Propyl homopiperidine, 2- (aminomethyl) -7-n-propyl homopiperidine, 2- (aminomethyl) -3-phenyl homopiperidine, 2- (aminomethyl) -4-phenyl homopiperidine, 2- (amino Methyl) -5-phenylhomopiperidine, 2- (aminomethyl) -6-phenylhomopiperidine, 2- (aminomethyl) -7- Phenylhomopiperidine,

^[7] adjacent substituents are 2-aminomethyl indoline linked to ^{R 21,} 1-aminomethyl-isoindoline, 3-aminomethyl-isoindoline, also substituents ^{R 16,} R ^17, R ^{18, R 19} and R ²⁰ is a hydrogen atom, an aliphatic or alicyclic saturated or unsaturated hydrocarbon group, a monocyclic or polycyclic aromatic or araliphatic hydrocarbon group, or various types of these hydrocarbon groups having a substituent. It may be a substituted 2-aminomethylindoline derivative, 1-aminomethylisoindoline derivative, or 3-aminomethylisoindoline derivative. For example, hydrocarbon groups such as hydrogen atoms, alkyls, alkenyls, cycloalkyls, cycloalkenyls, phenyls, naphthyls, phenylalkyls, etc. , 2-aminomethylindoline derivatives, 1-aminomethylisoindoline derivatives and 3-aminomethylisoindoline derivatives having various permissible substituents such as nitro group and cyano group. In particular, 2-aminomethylpyrrolidine is preferred.

  Further, optically active diamine compounds that can be used include the exemplified 2-picolylamine derivatives, 2-aminomethylquinoline derivatives, 1-aminomethylisoquinoline derivatives, 3-aminomethylisoquinoline derivatives, 2-aminomethylpyrrolidine derivatives, 2-amino It is not limited to methyl piperidine derivatives, 2-aminomethyl homopiperidine derivatives, 2-aminomethylindoline derivatives, 1-aminomethylisoindoline derivatives, and 3-aminomethylisoindoline derivatives.

を持つが、置換基Ｘ、Ｙ、および光学活性ジホスフィン化合物は、一般式（３）と同様のもののうちから適宜に選択されたものであってよい。 Further, the general formula (7) representing the ruthenium complex of the present invention.
RuXYA (7)
Is an optically active diphosphine compound A represented by the following general formula (4)

However, the substituents X and Y and the optically active diphosphine compound may be appropriately selected from the same as those in the general formula (3).

  In addition, the asymmetric catalyst may contain one or more organic compounds as reaction reagents. 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, an ether. , Ether solvents such as tetrahydrofuran, alcohol solvents such as methanol, ethanol, 2-propanol, butanol, benzyl alcohol, ketone solvents such as acetone, methyl ethyl ketone, cyclohexyl ketone, acetonitrile, DMF, N-methylpyrrolidone, DMSO, Examples include organic solvents containing heteroatoms such as triethylamine.

  The synthesis of the asymmetric catalyst represented by the general formula (3) can be performed by reacting the optically active ruthenium complex represented by the general formula RuXYA with a diamine compound or an optically active diamine compound. The synthesis of the optically active ruthenium complex represented by the general formula RuXYA can be performed by reacting the optically active diphosphine compound represented by the general formula (4) with the ruthenium complex serving as a starting material.

  As the ruthenium complex which is a starting material for the asymmetric catalyst synthesis, zero-valent, monovalent, divalent, trivalent 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 amine compound sequentially or 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. Phosphine compounds such as ruthenium complex and dichlorotris (triphenylphosphine) ruthenium Coordinated complex, or the like is used. In addition, the optically active diphosphine compound, the diamine compound, or the ruthenium complex having a ligand that can be substituted with the optically active diamine compound is not particularly limited to the above. For example, various ruthenium complexes shown in COMPREHENSIVE ORGANOMETALLIC 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 ruthenium (III) halide with an excess phosphine compound. Next, by reacting the obtained phosphine-ruthenium halide complex with an amine compound, a target amine-phosphine-ruthenium halide complex can be obtained.
That is, RuCl ₂ (PPh ₃ ) ₃ is reacted with ethylenediamine in benzene to obtain RuCl ₂ (PPh ₃ ) ₂ (en). 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.

  The reaction of the ruthenium complex of the starting material with the phosphine compound includes aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ethers and tetrahydrofuran, etc. An phosphine-ruthenium halide complex is obtained in an ether solvent, an alcohol solvent such as methanol, ethanol, 2-propanol, butanol or benzyl alcohol, or an organic solvent containing a heteroatom such as acetonitrile, DMF, N-methylpyrrolidone or DMSO. Can do. Although there is no restriction | limiting in particular in reaction temperature, It can carry out suitably between -10 degreeC-100 degreeC.

  The reaction of the complex represented by the general formula RuXYA 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, or a halogen-containing hydrocarbon solvent such as methylene chloride. , Ether solvents such as ether and tetrahydrofuran, alcohol solvents such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol, and organic solvents containing heteroatoms such as acetonitrile, DMF, N-methylpyrrolidone and DMSO. . Although there is no restriction | limiting in particular in reaction temperature, Preferably it can carry out between -10 degreeC-100 degreeC, and can obtain an amine-phosphine-ruthenium halide complex.

  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 with a diene such as [ruthenium dichloride (norbornadiene)] polynuclear body, [ruthenium dichloride (cycloocta-1,5-diene)] 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 phosphine compounds 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 Reacts with phosphine compounds in ether solvents such as ether and tetrahydrofuran, alcohol solvents such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol, and organic solvents containing heteroatoms such as acetonitrile, DMF, N-methylpyrrolidone and DMSO. Thus, a phosphine-ruthenium halide complex can be obtained. Although there is no restriction | limiting in particular in reaction temperature, It can carry out suitably between -10 degreeC-100 degreeC.

  The reaction of the complex represented by the general formula RuXYA 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, a halogen-containing hydrocarbon solvent such as methylene chloride, Reacts with amine compounds in organic solvents containing heteroatoms such as 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 Thus, an amine-phosphine-ruthenium complex can be obtained. In addition, an amine-phosphine-ruthenium halide complex can be obtained by reacting a cationic ruthenium complex such as [chlororuthenium (BINAP) (benzene)] chloride with an amine compound under the same conditions.

  Moreover, a ruthenium hydride complex can be obtained by hydrogenating the obtained amine-phosphine-ruthenium halide complex with a borohydride metal salt. For example, an amine-phosphine-ruthenium halide complex is converted into 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, or an ether type such as ether or tetrahydrofuran. Solvent, alcohol solvents such as methanol, ethanol, 2-propanol, butanol, benzyl alcohol, etc., organic solvents containing heteroatoms such as acetonitrile, DMA, DMF, N-methylpyrrolidone, DMSO, sodium borohydride and potassium borohydride A ruthenium hydride complex can be obtained by reacting with a borohydride metal salt such as.

  Alternatively, first, a phosphine-ruthenium halide complex can be converted into a phosphine-ruthenium hydride complex, and then reacted with an amine compound to obtain a ruthenium hydride complex. The temperature in these reactions is not particularly limited, but it can be preferably carried out between -10 ° C and 100 ° C.

  For example, when an asymmetric catalyst that can be synthesized as described above is used, the amount used varies depending on the substrate structure, catalyst structure, solvent, reaction vessel, and economy, but it is used 1/100 to 1 / 10,000,000 for the reaction substrate. And preferably in the range of 1/500 to 1/1000000.

The asymmetric catalyst used in the present invention may contain a base.
When X or Y of the asymmetric catalyst represented by the general formula (3) is a hydride or tetrahydroborate anion, a base is not always necessary, and after mixing with a substrate, hydrogen pressure is applied and stirred. Thereby, the substrate represented by the general formula (1) can be reacted with the hydrogen source. When X or Y of the asymmetric catalyst represented by the general formula (3) is a halogen anion, it is preferable to add a base, and after adding this, mix with the substrate, apply hydrogen pressure and stir. To do. Thereby, the substrate represented by the general formula (1) reacts with the hydrogen source, and the optically active alcohol compound represented by the general formula (2) can be obtained.

The types of bases used are KOH, K ₂ CO ₃ , KOCH ₃ , KOCH (CH ₃ ) ₂ , KOC (CH ₃ ) ₃ , KC ₁₀ H ₈ , NaOH, Na ₂ CO ₃ , NaOCH ₃ , NaOCH (CH ₃ ) ₂ , NaOC (CH ₃ ) ₃ , NaC ₁₀ H ₈ , LiOH, LiOCH ₃ , LiOCH (CH ₃ ) ₂ , LiOC (CH ₃ ) _{3 and} other alkali metals, alkaline earth metal salts or quaternary ammonium salts, etc. Is not limited to this. Although there is no restriction | limiting in the quantity of the base to add, Preferably it is the quantity used as a base concentration 0.001-0.1M, More preferably, it is the quantity used as 0.01-0.02M.

  The asymmetric catalyst used in the method of the present invention has a diphosphine in its structure, but the aryl group bonded to the phosphorus atom is a substituent aryl from the viewpoint of the catalytic reaction efficiency and the enantioselectivity of the product. A group is preferred.

Furthermore, the method of the present invention is not particularly limited as a hydrogen source. For example, a hydrogen donating compound or hydrogen gas can be used. The hydrogen-donating compound refers to lower alcohol or formic acid having about 1 to 4 carbon atoms such as methanol, ethanol, n-propanol, 2-propanol, butanol and the like, and particularly ethanol and a mixed system of ethanol and other lower alcohols. It is preferable to use it.
However, sufficient optical purity may not be obtained under the conditions using the above-mentioned hydrogen-donating compound as a hydrogen source. This is because the catalyst of the present invention has the ability to activate alcohol, and is an optical product. It is presumed that the reaction using an active alcohol as a hydrogen source proceeds and the racemization of the product alcohol proceeds. On the other hand, under pressurized hydrogen conditions, hydrogen is considered to be a substantial hydrogen source. Therefore, it is preferable to use hydrogen gas as a hydrogen source from the viewpoint of efficiency in catalytic reaction and enantioselectivity.

  Any suitable solvent can be used as long as it can solubilize the substrate and the catalyst. Examples 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 solvents such as ether and tetrahydrofuran, methanol, ethanol, and n-propanol. Alcohol solvents such as 2-propanol, butanol and benzyl alcohol, and organic solvents containing heteroatoms such as acetonitrile, DMF, N-methylpyrrolidone and DMSO can be used. Since the reaction product is an alcohol compound, an alcohol solvent is more preferable. When the reaction substrate is difficult to solubilize in a solvent, a plurality of types can be selected from the solvents and used as a mixed solvent.

  The amount of the solvent used for the production of the optically active alcohol is determined by the solubility and economics of the reaction substrate. For example, when 2-propanol is used, the substrate concentration may be as low as 0.1 mol / L or less to about 2.0 mol / L depending on the substrate, but preferably 0.5 to 1.5 mol. It is desirable to use at / L. Note that when hydrogen gas is used as a hydrogen source, a reversible reaction does not occur, so that the substrate concentration can generally be made higher than when a hydrogen-donating compound that causes a reversible reaction is used. In this case, it is presumed that the solvent is hardly used as a hydrogen source.

The hydrogen pressure in the production of the optically active alcohol of the present invention can be set to 1 to 100 atm, preferably 2 to 20 atm in consideration of economy.
The reaction temperature in the production of the optically active alcohol derivative is preferably 30 to 100 ° C, particularly preferably 35 to 40 ° C. The reaction time varies depending on the reaction conditions such as reaction substrate concentration, temperature and pressure, but is preferably 10 to 24 hours, and particularly preferably 16 to 19 hours.

  The hydrogenation reaction of the carbonyl compound in the present invention can be carried out in a batch type or a continuous type. Hereinafter, the present invention will be described in more detail with reference to examples. Of course, the present invention is not limited to the following examples.

1. Test Example 1 (Examples 1 to 8, Comparative Example 1)
The solvent used for the reaction was dried and degassed.
The following apparatus was used for measurement of each spectrum in each example. In addition, the reaction conversion rate and optical purity of the product in each example were confirmed by light velocity liquid chromatography (HPLC) under the following conditions. The molar ratio (S / C) of benzoyl ketone (substrate) and ruthenium complex (C), the molar ratio of base to ruthenium complex (base / C), substrate concentration (M) and solvent are shown in Table 1. As expected.
¹ H-NMR: LA400 type apparatus (400 MHz) (manufactured by JEOL Ltd.)
Internal standard: Tetramethylsilane Solvent: Deuterated chloroform (CDCl ₃ )
Reaction conversion rate:
High performance liquid chromatography: SHIMADZU LC-10ADvp
Column: Mightysil RP-18 GP 150 – 4.6 (5 μm) (manufactured by Kanto Chemical Co., Inc.)
Mobile phase: acetonitrile / distilled water (concentration gradient volume ratio 30/70 (0 min.) → 30/70 (5 min.) → 50/50 (25 min.) → 50/50 (40 min.))
Wavelength: 216nm
Temperature: Constant temperature flow around 40 ° C .: 1.0 mL / min.
Optical purity:
High performance liquid chromatography: SHIMADZU LC-10ADvp
Column: CHIRALPAK AD-H (0.46 f × 25 cm) (manufactured by DAICEL)
Mobile phase: hexane / 2-propanol (volume ratio 95/5)
Wavelength: 216nm
Temperature: Constant temperature flow around 35 ° C .: 1.0 mL / min.

[Example 1]
Asymmetric hydrogenation of 2-benzoylpyridine (S / C = 2000 reaction) using an asymmetric catalyst consisting of RuBr ₂ [(S, S) -skewphos] (pica) and KOC (CH ₃ ) ₃
RuBr ₂ [(S, S) -skewphos] (pica) (1.1 mg, 0.0012 mmol) and 2-benzoylpyridine (0.44 g, 2.4 mmol) were charged into a 100 ml glass autoclave, and after substitution with argon, Ethanol (1.75 ml) was added, 0.1 M KOC (CH ₃ ) ₃ / ethanol solution (480 mL, 0.048 mmol) prepared separately was added, and the atmosphere was purged with argon. The reaction was started at 30 ° C. and hydrogen up to 9 atm. After stirring the reaction solution for 16 hours, the reaction pressure was returned to normal pressure, and the amount of phenyl-2-pyridinylmethanol as a product was determined by 1H-NMR of the reaction solution and the optical purity was determined by high performance liquid chromatography. Optically active phenyl-2-pyridinylmethanol was produced at a reaction conversion rate of 21.5% and 88.9% ee.

[Example 2]
Asymmetric hydrogenation reaction of 2-benzoylpyridine (reaction of S / C = 2000) using an asymmetric catalyst consisting of RuBr ₂ [(S, S) -xyls skewphos] (pica) and KOC (CH ₃ ) ₃
RuBr ₂ [(S, S) -xylskewphos] (PICA) (0.9 mg, 0.001 mmol) and 2-benzoylpyridine (0.37 g, 2 mmol) were charged into a 100 ml glass autoclave, and after substitution with argon, 2- Propanol (1.6 ml) was added, 0.1 M KOC (CH ₃ ) ₃ / ethanol solution (420 mL, 0.043 mmol) prepared separately was added, and hydrogen was added to 9 atm at 30 ° C. to initiate the reaction. After stirring the reaction solution for 16 hours, the reaction pressure was returned to normal pressure, and the reaction conversion rate and optical purity of the product phenyl-2-pyridinylmethanol were determined by gas chromatography of the reaction solution. Optically active phenyl-2-pyridinylmethanol was produced at 98.0% and 95.8% ee.

Example 3
Asymmetric hydrogenation reaction of p-chlorobenzoyl-2-pyridine (S / C = 2000) using an asymmetric catalyst consisting of RuBr ₂ [(S, S) -skewphos] (pica) and KOC (CH ₃ ) ₃ reaction)
RuBr ₂ [(S, S) -skewphos] (pica) (1.1 mg, 0.0012 mmol), p-chlorobenzoyl-2-pyridine (0.44 g, 2.4 mmol) was charged into a 100 ml glass autoclave, After purging with argon, 2-propanol (4.8 ml) was added, and 1.0 M KOC (CH ₃ ) ₃ / 2-propanol solution (96 mL, 0.096 mmol) prepared separately was added, followed by deaeration with argon. The reaction was started by charging hydrogen at 40 ° C. and 10 atm. After stirring the reaction solution for 19 hours, the reaction pressure was returned to normal pressure, a part of the reaction solution was concentrated under reduced pressure, and the product p-chlorophenyl-2-pyridinylmethanol was quantified by 1H-NMR of the reaction solution. When the optical purity by high performance liquid chromatography was determined, optically active p-chlorophenyl-2-pyridinylmethanol was produced at a reaction conversion rate of 51.4% and 88.7% ee.

Example 4
_{RuBr 2 [(S, S)} -xylskewphos] (pica) and using an asymmetric hydrogenation catalyst consisting of sodium hydroxide, using 2-propanol as a hydrogen donor, the p- chlorobenzoyl-2-pyridin asymmetric Reduction reaction (S / C = 2000 reaction)
RuBr ₂ [(S, S) -skewphos] (pica) (1.1 mg, 0.0012 mmol) and p-chlorobenzoyl-2-pyridine (0.52 g, 2.4 mmol) were charged into a 50 ml Schlenk tube, and argon After the substitution, 2-propanol (22.5 ml) was added, a separately prepared 0.1M sodium hydroxide / 2-propanol solution (480 mL, 0.048 mmol) was added, and the reaction was started at reflux. After stirring for 1 hour, a part of the reaction solution was concentrated under reduced pressure, and the quantitative determination of the product p-chlorophenyl-2-pyridinylmethanol and optical purity by high performance liquid chromatography were determined by 1H-NMR of the reaction solution. An optically active p-chlorophenyl-2-pyridinylmethanol was produced at a reaction conversion rate of 77.5% and an optical activity of 85.3% ee.

Example 5
Asymmetric hydrogenation reaction of p-chlorobenzoyl-2-pyridine (S / C = 2000) using an asymmetric catalyst consisting of RuBr ₂ [(S, S) -xyls skewphos] (pica) and KOC (CH ₃ ) ₃ reaction)
RuBr ₂ [(S, S) -xylskewphos] (pica) (0.9 mg, 0.001 mmol) and p-chlorobenzoyl-2-pyridine (0.44 g, 2 mmol) were charged into a 100 ml glass autoclave and purged with argon. Then, 2-propanol (4 ml) was added, a separately prepared 1.0 M KOC (CH ₃ ) ₃ / methanol solution (80 mL, 0.080 mmol) was added, and the reaction was started by charging hydrogen at 10 ° C. to 40 ° C. did. After stirring the reaction solution for 19 hours, the reaction pressure was returned to normal pressure, and the reaction conversion rate and optical purity of the product p-chlorophenyl-2-pyridinylmethanol were determined by high-speed liquid phase chromatography of the reaction solution. The optically active p-chlorophenyl-2-pyridinylmethanol was produced at a reaction conversion rate of 85.1% and 92.8% ee.

Example 6
Asymmetric hydrogenation of p-chlorobenzoyl-2-pyridine (S / C = 1000) using an asymmetric catalyst consisting of RuBr ₂ [(S, S) -xylskewphos] (pica) and KOC (CH ₃ ) ₃ reaction)
Hydrogenation of p-chlorobenzoyl-2-pyridine was carried out for 19 hours in the same manner as in Example 5 except that the substrate / catalyst ratio was 1000. Optically active p-chlorophenyl-2-pyridinylmethanol was produced at a reaction conversion rate of 99.5% and 92.6% ee.

Example 7
Asymmetric hydrogenation reaction of p-chlorobenzoyl-2-pyridine (S / C = 1000) using an asymmetric catalyst consisting of RuBr ₂ [(S, S) -tolskewphos] (pica) and KOC (CH ₃ ) ₃ reaction)
RuBr ₂ used in Example 6 [(S, S) -xylskewphos ] Instead RuBr ₂ of (pica) [(S, S ) -tolskewphos] in the same manner as in Example 6 except for using (pica) as a catalyst p Hydrogenation of -chlorobenzoyl-2-pyridine was carried out for 19 hours. Optically active p-chlorophenyl-2-pyridinylmethanol was produced at a reaction conversion rate of 61.1% and 91.6% ee.

Example 8
Asymmetric hydrogenation reaction of p-chlorobenzoyl-2-pyridine (S) using an asymmetric hydrogenation catalyst consisting of RuBr ₂ [(S, S) -xylskewphos] (3-amiq) and KOC (CH ₃ ) ₃ / C = 1000 reaction)
Similar to Example 6 except that RuBr ₂ [(S, S) -xylskewphos] (3-amiq) was used instead of RuBr ₂ [(S, S) -xylskewphos] (pica) used in Example 6. The p-chlorobenzoyl-2-pyridine was hydrogenated for 19 hours. P-Chlorophenyl-2-pyridinylmethanol was produced at a reaction conversion rate of 99.9% and an optical activity of 95.5% ee.

[Comparative Example 1]
Asymmetric reduction reaction of 2-benzoylpyridine (S / C) using an asymmetric catalyst consisting of RuBr ₂ [(S, S) -skewphos] (pica) and sodium hydroxide and 2-propanol as a hydrogen donor. = 2000 reactions)
RuBr ₂ [(S, S) -skewphos] (pica) (1.09 mg, 0.0012 mmol) and 2-benzoylpyridine (0.52 g, 2.4 mmol) were charged into a 50 ml Schlenk tube, purged with argon, and 2 -Propanol (22.5 ml) was added, and 0.1 M sodium hydroxide / 2-propanol solution (480 mL, 0.048 mmol) prepared separately under reflux was added to initiate the reaction. After stirring for 1 hour, a part of the reaction solution was concentrated under reduced pressure, and the amount of phenyl-2-pyridinylmethanol as a product was determined by 1H-NMR of the reaction solution and the optical purity was determined by high performance liquid chromatography. Optically active phenyl-2-pyridinylmethanol was produced at conversions of 59.0% and 83.9% ee.

  As described above, optically active alcohols having extremely high optical purity in Examples 1 to 8 could be obtained in a necessary yield. In any case, it was possible to obtain an optically active alcohol having higher optical purity when hydrogen gas was used as the hydrogen source. In Comparative Example 1 using the same substrate as in Example 1 and Example 2, it was confirmed that the optical purity was low.

2. Test Example 2 (Examples 9 to 16, Comparative Examples 2 to 11)
The reaction conversion rate of the product in each Example was confirmed by ¹ H NMR, and the optical purity was confirmed by high performance liquid chromatography (HPLC) under the following conditions.
Reaction conversion rate;
1H NMR: LA400 type apparatus (400 MHz) (manufactured by JEOL Ltd.)
Internal standard: Tetramethylsilane Solvent: Deuterated chloroform (CDCl ₃ )
Optical purity;
Phenyl-2-thienylmethanol high performance liquid chromatography: SHIMADZU LC-10ADvp
Column: CHIRALCEL OD-H (0.46 f × 25 cm) (manufactured by DAICEL)
Mobile phase: hexane / 2-propanol (volume ratio 98/2)
Wavelength: 254nm
Temperature: Constant temperature flow around 25 ° C: 1.0 mL / min
Phenyl-2-furylmethanol high performance liquid chromatography: SHIMADZU LC-10ADvp
Column: CHIRALPAK AD-H (0.46 f × 25 cm) (manufactured by DAICEL)
Mobile phase: hexane / 2-propanol (volume ratio 97/3)
Wavelength: 216nm
Temperature: Constant temperature flow around 25 ° C: 1.0 mL / min
Phenyl-4-trityl-1-imidazolylmethanol high performance liquid chromatography: SHIMADZU LC-10ADvp
Column: CHIRALPAK AD-H (0.46 f × 25 cm) (manufactured by DAICEL)
Mobile phase: Hexane / 2-propanol (volume ratio 90/10)
Wavelength: 216nm
Temperature: Constant temperature flow around 25 ° C: 1.0 mL / min
Phenyl-2-pyrazylmethanol high performance liquid chromatography: SHIMADZU LC-10ADvp
Column: CHIRALPAK AD-H (0.46 f × 25 cm) (manufactured by DAICEL)
Mobile phase: hexane / 2-propanol (volume ratio 95/5)
Wavelength: 254nm
Temperature: Constant temperature flow around 25 ° C: 1.0 mL / min
Phenyl-2-pyrimidinylmethanol high performance liquid chromatography: SHIMADZU LC-10ADvp
Column: CHIRALCEL OD-H (0.46 f × 25 cm) (manufactured by DAICEL)
Mobile phase: hexane / 2-propanol (volume ratio 95/5)
Wavelength: 254nm
Temperature: Constant temperature flow around 25 ° C: 1.0 mL / min

[Examples 9 to 16, Comparative Examples 2 to 11]
Hydrogenation reaction of heterocycles having a benzoyl ketone group Hydrogenation reactions of benzoyl ketones having various heteroaromatic rings shown in Examples 9 to 16 and Comparative Examples 2 to 11 in Table 2 and Table 3 were carried out, and the corresponding optics The active alcohol was obtained with high yield and high enantioselectivity (see the following formula (8)).

Below, the typical method of hydrogenation reaction is shown. That is, first, a 100 mL glass autoclave (containing a magnetic stirrer bar) previously dried at 60 ° C. in an oven was added to a ketone substrate (2.17 mmol) and an accurately weighed ruthenium complex (S, S) -3 (1 .155 mg, 1.08 μmol) and solid KOC (CH ₃ ) ₃ were placed in a high vacuum for at least 5 minutes before introducing argon. The solvent was placed in an autoclave under an argon atmosphere. A hydrogen cylinder and an autoclave were connected, and the operation of filling the autoclave with 0.5 MPa of hydrogen and releasing it to atmospheric pressure was repeated 10 times, and then the target hydrogen pressure was set. While this reaction was vigorously stirred at 30 ° C., the hydrogen consumption was monitored to carry out a hydrogenation reaction. After completion of the reaction, the solvent was concentrated and identified by 1H NMR to determine the conversion rate. The concentrate was purified through a short column of silica gel and analyzed by chiral HPLC to determine enantiomeric excess. In addition, the hydrogenation reaction of each Example is performed according to the representative method described above, and the molar ratio (S / C) of the benzoyl ketone (substrate) and the ruthenium complex (C), the mole of the base and the ruthenium complex. The ratio (base / C), substrate concentration (M) and solvent were as shown in Tables 2 and 3.

The ruthenium complexes used in Examples 9 to 16 and Comparative Examples 2 to 13 are complexes represented by the following formulas ((S, S) -3, (S, S) -4, (S) -5 and ( S) (S) -6) was used.

As is apparent from Tables 2 and 3, when ruthenium complex (S, S) -3 is used together with a strong base, a hydrogenation reaction of an asymmetric substrate of a heterocyclic group having a benzoyl ketone group proceeds, and the corresponding optics An active alcohol is obtained.
In addition, 2-benzoylthiophene used in Examples 9 and 10 and Comparative Examples 2 and 3 was purchased from Aldrich Chemical Company. The 2-benzoylfuran used in Examples 11 and 12 and Comparative Examples 4 and 5 was synthesized according to a method already reported (Tetrahedron 2007, 63, p.12917-12926). Benzoyl-4-trityl-2-imidazole used in Examples 13 and 14 and Comparative Examples 6 and 7 was synthesized according to a method already reported (Japanese Patent Laid-Open No. 2003-128656). The benzoyl-2-pyrazine used in Example 15 and Comparative Examples 8 and 9 was synthesized according to a method already reported (J. Heterocyclic Chem., 31, 1041-1046). Benzoyl-2-pyrimidine used in Example 16 and Comparative Examples 10 and 11 was synthesized according to a method already reported (HETEROCYCLES, 31, 895-909).

  The method according to the present invention can produce optically active alcohols useful as synthetic intermediates for optically active physiologically active compounds or liquid crystal materials used in medicines and agricultural chemicals with high optical purity and high efficiency. It is.

Claims (6)

General formula (1)

(Where
Ar ¹ contains at least one nitrogen atom, sulfur atom, or oxygen atom in the ring, and these heteroatoms may form a salt, a 5-membered ring, a 6-membered ring or a 7-membered aromatic heterocycle Group,
Ar ² has 0 to 10 alkyl groups, alkoxy groups, hydroxyalkyl groups, halogen groups, amino groups, ester groups, amide groups, nitro groups, and cyano groups, which may be the same or different. May be an aromatic hydrocarbon group)
Is reacted with a hydrogen source in the presence of an asymmetric catalyst to give a general formula (2)

(Where
Ar ¹ and Ar ² have the same meaning as described above,
* Indicates the position of the asymmetric carbon)
A process for producing an optically active alcohol represented by:
The asymmetric catalyst is represented by the general formula (3)
RuXYAB (3)
(Where
X and Y represent hydrogen or anionic groups, which may be the same or different from each other,
A represents the general formula (4)

(Where
R ¹ and R ² are cyclic hydrocarbon groups which may have the same or different from each other and may have an alkyl group having 1 to 20 carbon atoms or a substituent,
R ³ and R ⁴ may be the same or different from each other, hydrogen, a hydrocarbon group having 1 to 3 carbon atoms,
R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different and are each a phenyl group substituted with 1 to 5 methyl, ethyl, propyl or t-butyl groups. A compound,
B is the general formula (5),

(Where
R ⁹ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, or a cyclic hydrocarbon group which may have a substituent,
R ¹⁰ and R ¹¹ represent a hydrogen atom which may be the same or different from each other, a C 1-20 alkyl group or a cyclic hydrocarbon group which may have a substituent, and R ¹⁰ and R ¹¹ Linked and may have a substituent of alkyl group, alkenyl group, cycloalkyl group, aryl group, alkoxy group, ester group, acyloxy group, halogen atom, nitro group, or cyano group, saturated or unsaturated May form a hydrocarbon group,
R ¹² , R ¹³ , R ¹⁴ , and R ¹⁵ represent a hydrogen atom that may be the same as or different from each other, an alkyl group having 1 to 20 carbon atoms, or a cyclic hydrocarbon group that may have a substituent, R ¹² and R ¹³ , R ¹³ and R ¹⁴ , or R ¹⁴ and R ¹⁵ may be connected to each other to form a saturated or unsaturated hydrocarbon group, and a saturated or unsaturated hydrocarbon group containing N May be formed)
Or a compound represented by the general formula (6)

(Where
At least one of R ¹⁶ , R ¹⁷ and R ¹⁸ is a hydrogen atom, and R ¹⁶ and R ¹⁷ have a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or a substituent which may be the same or different from each other. An optionally substituted cyclic hydrocarbon group, or R ¹⁶ and R ¹⁷ may be linked together to form a ring containing N;
R ¹⁸ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent,
R ¹⁹ and R ²⁰ represent a hydrogen atom which may be the same or different from each other, an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent, and R ¹⁹ and R ²⁰ are Linked to each other and may have a substituent of an alkyl group, alkenyl group, cycloalkyl group, aryl group, alkoxy group, ester group, acyloxy group, halogen atom, nitro group, or cyano group, saturated or unsaturated May form a hydrocarbon group of
R ²¹ may be different from each other, and represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or a cyclic hydrocarbon group which may have a substituent, and adjacent R ²¹ are connected to each other and saturated. Or an unsaturated hydrocarbon group may be formed, m represents an integer of 1 to 10, and n represents an integer of 1 to 3).
In a catalyst containing a ruthenium complex represented, hydrogen source Ru der hydrogen gas or a hydrogen-donating compound, prior Symbol methods. The method according to claim 1, wherein R ⁵ , R ⁶ , R ⁷ and R ^{8 in the} general formula (4) are phenyl groups having one or two methyl groups. The method according to claim 2, wherein R ⁵ , R ⁶ , R ⁷ and R ^{8 in the} general formula (4) are xylyl groups. Ar ¹ in the general formula (2) is a 2-thienyl group, 2-furyl group, 1-trityl-4-imidazoyl group, 2-pyrazyl group, 2-pyrimidinyl group or 2-pyridyl group, and Ar ² is The method according to claim 1, wherein the aryl group is an optionally substituted aryl group. The method according to claim 4, wherein Ar ¹ is a 2-pyridyl group and Ar ² is a p-chlorophenyl group.   The method according to claim 1, wherein the hydrogen source is hydrogen gas.