JP2003277380A - Optically active 3-quinuclidinol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a desirable 3-quinuclidinol having high optical isomer content from a 3-quinuclidinone by utilizing an enantioselectively reducible complex catalyst. <P>SOLUTION: The method for producing the optically active 3-quinuclidinol by reducing 3-quinuclidinone comprises hydrogenating the 3-quinuclidinone in the presence of an optically active bidentate phosphine ligand and an optically active ruthenium (II) complex having an optically active 1,2-ethylenediamine type ligand represented by formula (1) [wherein R<SP>1</SP>and R<SP>2</SP>are each the same or different and represent each a hydrogen atom or an alkyl group; R<SP>3</SP>, R<SP>4</SP>, R<SP>5</SP>and R<SP>6</SP>are each the same or different and represents each an alkyl group, an aryl group or an aralkyl group which may have a substituent group: R<SP>4</SP>and R<SP>5</SP>together may form an alkylene group] and a base. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing optically active 3-quinuclidinol useful as a pharmaceutical intermediate safely and in high yield.

[0002]

2. Description of the Related Art Many naturally occurring organic compounds are optically active compounds. Among them, in compounds having physiological activity, only one optical isomer often has a desired activity. Further, it is known that one optical isomer that does not have a desired activity does not have useful physiological activity for living organisms, but may rather have toxicity to living organisms. Therefore, it is desired to develop a method for synthesizing a target compound or a compound having high optical purity as an intermediate thereof as a safe method for synthesizing a drug.

3-Quinuclidinol is a compound used as various pharmaceutical intermediates, but since it has an asymmetric carbon, optical isomers exist.

At present, an optically active 3-quinuclidinol is mainly produced by optical resolution of racemic 3-quinuclidinol obtained by reducing a ketone of 3-quinuclidinone. Since the racemate is optically resolved, the desired enantiomer yield can be obtained only from the ketone body at a maximum yield of 50%, and the undesired enantiomer becomes a waste.

Further, JP-A-9-194480 discloses an example of reduction of 3-quinuclidinone with a rhodium-phosphine complex. However, in the same publication, 3
-When quinuclidinone is not converted to a specific derivative, even if the technique disclosed in the above publication is used, the optical yield thereof is not more than 1%, and 3-quinuclidinone is converted to a specific derivative. Even in this case, a complicated manufacturing process was required. Therefore, a simple and high-yield method for producing optically active 3-quinuclidinol from 3-quinuclidinone has been desired.

[0006]

DISCLOSURE OF THE INVENTION The present invention is to solve the above problems, and an object of the present invention is to utilize a complex catalyst capable of reducing enantioselectively to obtain a desired optical isomer from 3-quinuclidinone. It is to provide a method for producing 3-quinuclidinol having a high content rate.

[0007]

That is, the present invention provides 3-
In the production of optically active 3-quinuclidinol by reducing quinuclidinone, the compound represented by the general formula (1) is used together with the optically active bidentate phosphine ligand.

[0008]

[Chemical 3]

(Wherein R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶
Are the same or different and each represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group or an aralkyl group, and R ⁴ and R ⁵ may be linked to each other to form an alkylene group. ), And an optically active ruthenium (II) complex having an optically active 1,2-ethylenediamine type ligand, and hydrogenation in the presence of a base. is there.

More preferably, the optically active ruthenium (II) complex in the above invention is represented by the general formula (2)

[0011]

[Chemical 4]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, and R ⁷ is an aryl group which may have a substituent, R ⁸ and R 6 ⁹ is the same or different and represents a hydrogen atom or an alkyl group, X is a hydrogen atom, a halogen atom,
An acyloxy group or an acetoacetonate group is shown. The present invention relates to a method for producing optically active 3-quinuclidinol, which is an optically active ruthenium (II) complex represented by the formula (1).

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The substrate used in the present invention has the chemical formula (3)

[0014]

[Chemical 5]

3-quinuclidinone represented by: As the substrate used in the present invention, 3-quinuclidinone may be an inorganic salt such as hydrochloride, and an organic salt such as acetate. The structure of the complex catalyst used in the present invention is
(1) Optically active diphosphine-type ligand moiety, (2) II
It can be divided into three parts: a valent ruthenium part and (3) an optically active 1,2-ethylenediamine derivative part.

The 1,2-ethylenediamine derivative moiety of the complex catalyst of the present invention has the general formula (1)

[0017]

[Chemical 6]

(In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶
Are the same or different and each represent a hydrogen atom, an alkyl group which may have a substituent, an aryl group or an aralkyl group, and R ⁴ and R ⁵ may be linked to each other to form an alkylene group. ).

R ¹ and R ² of the optically active 1,2-ethylenediamine type ligand are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

In the general formula (1), the optically active 1,2
-R at the ethylenediamine derivative site ³, R^Four, R^Fiveand
R⁶The portion represented by is an optionally substituted alkyl group.
R represents a kill group, an aryl group or an aralkyl group, and R³，
R^Four, R^FiveAnd R⁶The number of carbon atoms as the alkyl group in
1-10 alkyl groups are mentioned, and also as a "substituent"
Include methoxy, ethoxy, propoxy, butoxy,
Alkoxy having 1 to 6 carbon atoms such as tonoxy and hexoxy
Groups, halogen atoms such as chlorine, bromine, iodine, etc.
To be

Examples of the "aryl group optionally having a substituent" in R ³ , R ⁴ , R ⁵ and R ⁶ include phenyl and naphthyl, and the "substituent" is, for example, methoxy. , Ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc., C1-C6 alkoxy groups, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. C1-C6 alkyl groups, chlorine, bromine, iodine and other halogen atoms And so on.

The number of substituents is not particularly limited, but usually 1
~ 3 are suitable. Particularly preferable examples of the “aryl group which may have a substituent” include a phenyl group, a phenyl group substituted with an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. , Specifically 2-, 3- or 4-methylphenyl, 2,3
Examples thereof include-, 3,4- or 3,5-dimethylphenyl.

"Aralkyl group" of "aralkyl group optionally having substituent (s)" in R ³ , R ⁴ , R ⁵ and R ⁶
Is, for example, carbon number 6 such as phenyl or naphthyl.
Examples thereof include an alkyl group having an aryl group of 10 to 10 such as methyl, ethyl, propyl and the like, and specifically, benzyl, phenethyl, phenylpropyl, naphthylmethyl and the like.

Examples of the "substituent" include C1-C6 alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy, and methyl groups such as methyl, ethyl, propyl, butyl, pentyl, and hexyl. Examples of the alkyl group include halogen atoms such as chlorine, bromine and iodine.

Further, R ⁴ and R ⁵ may be linked to each other to form a ring structure with, for example, an alkylene having 4 to 5 carbon atoms, that is, butylene or pentylene. R ³ , R ⁴ , R
Particularly preferred as ⁵ and R ⁶ are hydrogen and C 1
To alkyl groups, phenyl groups, 4-methoxyphenyl groups, naphthyl groups and the like.

Preferred examples of the optically active 1,2-ethylenediamine type ligand are 1,2-diphenylethylenediamine, 2,3-dimethyl-2,3-butanediamine,
2,2-diphenyl-1-methylethylenediamine,
2,2-diphenyl-1-isopropylethylenediamine, 2,2-diphenyl-1-isobutylethylenediamine, 2,2-di (p-methoxyphenyl) -1-methylethylenediamine, 2,2-di (p-methoxyphenyl) -1-isopropylethylenediamine, 2,2-di (p-methoxyphenyl) -1-isobutylethylenediamine, 1-benzyl-2,2-di (p-methoxyphenyl) ethylenediamine, 2,2-dinaphthyl-1-methylethylenediamine 2,2-Dinaphthyl-1-isopropylethylenediamine, 2,2-Dinaphthyl-1-
Examples thereof include isobutylethylenediamine, 1,2-cyclohexanediamine and 1,2-cycloheptanediamine.

The optically active diphosphine type ligand moiety is an optically active bidentate phosphine ligand, and is 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (commonly known as B
INAP) s, 4-dicyclophosphino-2-diphenylphosphinomethylmethyl-N-methyl-1-pyrrolidinecarboxamide (commonly known as MCCPM), 1- (1-
Examples thereof include dimethylaminoethyl) -1 ′, 2-bisdiphenylphosphinoferrocene, and 1,1′-binaphthyl-2, as an optically active bidentate phosphine ligand.
2′-bisdiphenylphosphine (BINAPs) is easily available, and 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (BINAPs) is introduced.
1,1′-binaphthyl-represented by the general formula (2)
Most preferred is a complex of a 2,2'-bisdiphenylphosphine ruthenium halide (II) 1,2-ethylenediamine derivative.

Optically active 1,1'-binaphthyl-2,
Specific examples of the 2'-bisdiphenylphosphine moiety include 1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1,1'-binaphthyl-2,2 '.
Examples thereof include -bis (bis-4-methylphenyl) phosphine.

Optically active 1,1'-binaphthyl-2,
2'-bisdiarylphosphine moiety and optically active 1,
There are various complexes based on the combination of 2-ethylenediamine derivative moieties, and the general formula (2)

[0030]

[Chemical 7]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, and R ⁷ is an aryl group which may have a substituent, R ⁸ and R 6 ⁹ is the same or different and represents a hydrogen atom or an alkyl group, X is a hydrogen atom, a halogen atom,
An acyloxy group or an acetoacetonate group is shown. ).

In the general formula (2), examples of the aryl group which may have a substituent represented by R ⁷ include phenyl and naphthyl, and the “substituent” is, for example, methoxy. , Ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc.
Examples thereof include an alkoxy group having 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and hexyl, and a halogen atom such as chlorine, bromine and iodine. The number of substituents is not particularly limited, but is usually 1 to 3.
Individuals are appropriate. Particularly preferred R ⁷ is a phenyl group, an alkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms.
Examples thereof include a phenyl group substituted with 6 alkoxy groups, and specific examples include 2-, 3- or 4-methylphenyl, 2,3-, 3,4- or 3,5-dimethylphenyl. be able to.

The substituents represented by R ⁸ and R ⁹ of the 1,1′-binaphthyl-2,2′-bisdiarylphosphine moiety in the general formula (2) are, for example, alkyl groups,
Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and hexyl, and an alkyl group having 1 to 3 carbon atoms is particularly preferable.

In the general formula (2), the "halogen atom" represented by X at the ruthenium halide (II) site is, for example, fluorine, chlorine, bromine or iodine.
Examples of the "acyloxy group" include an acyloxy group derived from an aliphatic or aromatic carboxylic acid having about 1 to 12 carbon atoms, such as acetoxy, propionyloxy, benzoyloxy and the like.

A preferable example of the 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ruthenium halide (II) 1,2-ethylenediamine complex represented by the general formula (2) is dichloro [(S)- 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl]
[(S, S) -1,2-diphenylethanediamine] ruthenium (II) may be mentioned. 1,1-bis (p-methoxyphenyl) as 1,2-ethylenediamine derivative
Dichloro [(S) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] [(S) 1,1-bis (p- with 2-isopropylethane-1,2-diamine Methoxyphenyl) -2-isopropylethane-
1,2-diamine] ruthenium (II) can also be used, and these ruthenium complexes are commercially available, for example, from Kanto Chemical Co., Inc.

1,1'-binaphthyl-2,2'-bisdiphenylphosphine ruthenium halide (II) 1,2-
As an ethylenediamine complex, dichloro [(S) -2,
Complex obtained by combining 2'-bis (diphenylphosphino) -1,1'-binaphthyl] [(S, S) -1,2-diphenylethanediamine] ruthenium (II) and enantiomers of phosphine and diamine Are particularly preferred.

The complex catalyst used in this reaction varies depending on the reaction conditions, scale, and economic efficiency, but it is a substrate of 3-
Equivalent ratio to quinuclidinone is about 1 / 1000-1
/ 1,000,000 equivalents, preferably 1/5000
~ 1/30000 equivalent.

The amount of catalyst added is 1/10 with respect to the substrate.
The reaction is completed even if added in an amount of more than 00 equivalents, but the effect of the addition is slowed, which is not economical, and the step of taking out the optically active 3-quinuclidinol from the reaction solution becomes difficult, which is not preferable. The amount of catalyst added is 1/1 with respect to the substrate
If the amount is less than 000000, the reaction from 3-quinuclidinone to 3-quinuclidinol is not completed, which is not preferable.

As the base used in the reaction, an alkali metal hydroxide or an alkali metal alkoxide is used, and specifically, KOH, K ₂ CO ₃ and KOC are used.
_{H 3, KOCH (CH 3)} 2, KOC (CH 3) 3, NaO
H, Na ₂ CO ₃ , NaOCH ₃ , NaOCH (C
H ₃ ) ₂ , NaOC (CH ₃ ) ₃ , LiOH, LiOC
H ₃ , LiOCH (CH ₃ ) ₂ , LiO (CH ₃ ) _{3 and the} like can be mentioned, and particularly preferably KOH and KOC (C
H ₃₎ is _3, NaOH, the amount of these bases are 0.01 to 10 equivalents of an equivalent ratio to the substrate, more preferably 0.02 to 0.5 equivalents.

The added base is an essential requirement of the present invention, and if the addition equivalent ratio to the substrate is less than 0.01 equivalent, the optically active 3-quinuclidinol cannot be obtained in a high yield, which is not preferable. When the amount of the added base is more than 10 equivalents with respect to the substrate, it becomes difficult to take out 3-quinuclidinol including neutralization of the reaction product, which is not preferable.

The present invention is usually carried out in the presence of a solvent. As the solvent used, alcohols such as methanol, ethanol, 2-propanol, butanol,
It is also possible to use a mixed solvent of tetrahydrofuran, dioxane, benzene, toluene, xylene, dichloromethane and the like. 2-Propanol is more preferable, and the reaction yield is better than the case of using another solvent for unknown reasons.

The amount of the solvent used is 1 to 500 times the volume of 3-quinuclidinone as the substrate, but is preferably 2 to 10 times the volume.

The reaction temperature is usually -30 to 100 ° C.
And preferably 0 ° C to 70 ° C.

The pressure of hydrogen is arbitrarily selected within the range of atmospheric pressure to 10 MPa, but in terms of economy and efficiency,
After the reaction at 0.3 MPa to 7.0 MPa is preferable, 3-quinuclidinol can be isolated and purified by a conventional method such as extraction, recrystallization and chromatography.

[0045]

EXAMPLES The contents of the present invention will be described in more detail with reference to examples. Example 1 In a 200 ml autoclave, 5.0 g of 3-quinuclidinone (3
9.9 mmol), t-BuOK 90 mg (0.8 mmol), degassed 2-propanol 95 ml and (S) -1,1'-binaphthyl-
2,2'-bis (diphenyl) phosphine ruthenium chloride (II) (1S, 2S) -1,2-diphenylethylenediamine complex 20.1mg (20μmol, S / C = 2,000) was added and then the vessel was replaced with nitrogen gas. did. Next, hydrogen gas was charged into the container at 8.0 MPa, and the reaction mixture was stirred at 30 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, water (30 ml) and toluene (30 ml) were added to the residue, and after extraction, the aqueous layer was concentrated to dryness.
4.99 g of quinuclidinol was obtained. When the obtained product was analyzed, the optical rotation was +0.4905 (C = 2, 1 mol / L HCl), and the enantiomer excess was 53.1% ee (S).

Example 2 In a 200 ml autoclave, 5.0 g of 3-quinuclidinone (3 g
9.9 mmol), t-BuOK 90 mg (0.8 mmol), degassed 2-propanol 95 ml and (S) -1,1'-binaphthyl-
2,2'-bis (diphenyl) phosphine ruthenium chloride (II) (S) -1,1-bis (p-methoxyphenyl) -2-isopropylethane-1,2-diamine complex 10.1 mg (20 μmol, S / C = 4,385) was added and the inside of the container was replaced with nitrogen gas. Next, add hydrogen gas to the container at 8.0 MPa.
Charged and the reaction mixture was stirred at 30 ° C. for 63 hours. The reaction mixture was concentrated under reduced pressure, and 30 ml of water and 30 ml of toluene were added to the residue.
In addition, after extraction, the aqueous layer was concentrated to dryness to obtain 5.06 g of 3-quinuclidinol. The obtained product was analyzed, and the optical rotation was +0.3925 (C = 2, 1mol / L HCl), and the enantiomer excess was 42.5.
It was% ee (S).

Example 3 The same operation as in Example 1 was carried out except that the amount of the complex catalyst used was 2.0 mg (2 μmol, S / C = 20,000), the mixture was stirred for 20 hours, post-treated, and then 3-quinuclidinol. I got 5.0g. The product obtained was analyzed and the optical rotation was +0.4772 (C = 2,
1 mol / L HCl), enantiomer excess: 51.7% ee (S).

Example 4 The same operation as in Example 1 was carried out except that the reaction temperature was 80 ° C., the mixture was stirred for 14 hours, and after post-treatment, 5.05 g of 3-quinuclidinol was obtained. The product thus obtained was analyzed and found to have an optical rotation of +0.4225 (C = 2, 1mol / L HCl) and an enantiomeric excess of 45.8.
It was% ee (S).

Example 5 The ruthenium complex catalyst used in the reaction was (R) -1,1 '.
-Binaphtyl-2,2'-bis (diphenyl) phosphine ruthenium chloride (II) (1R, 2R) -1,2-
The same operation as in Example 1 was performed except that a diphenylethylenediamine complex was used, stirring was performed for 6.7 hours, and after the post-treatment, 3
-4.98 g of quinuclidinol was obtained. When the obtained product was analyzed, the optical rotation was -0.5015 (C = 2, 1mol / L HCl), and the enantiomer excess was 54.3% ee (R).

Example 6 The same conditions as in Example 1 were carried out except that the solvent used in the reaction was changed to MeOH. When the obtained product was analyzed, the optical rotation was +0.1470 (C = 2, 1 mol / L HCl), and the enantiomer excess was 53.1% ee (S).

Comparative Example 1 The same operation as in Example 1 was carried out except that t-BuOK was not added to the reaction system, and the reaction was carried out for 13 hours. When analyzed by gas chromatography, the reaction hardly progressed.

Comparative Example 2 In a 200 ml autoclave, 5.0 g of 3-quinuclidinone (3
9.9 mmol) and 45 ml of degassed methanol were added. Here, [RuCl ₂ COD] and (S) -BINAP were prepared with DMF solvent in the presence of triethylamine, and RuCl ₂ [(S) -BINAP] TEA, 34
mg (20 μmol, S / C = 2,000) was added to replace nitrogen in the system. Next, 9.0 MPa of hydrogen gas was filled in the container, and the reaction mixture was reacted at 70 ° C. for 7 hours. The reaction solution was concentrated under reduced pressure, 30 ml of water and 30 ml of toluene were added to the residue, and after extraction, the aqueous layer was concentrated to dryness to obtain 5.0 g of 3-quinuclidinol. The optical rotation was +0.0295 (C = 2, 1mol / L HCl), and the enantiomer excess was 3.2% ee (S).

Comparative Example 3 In a 200 ml autoclave, 5.0 g of 3-quinuclidinone (3 g
9.9 mmol) and 45 ml of degassed methanol were added. Into another 5 ml of degassed methanol in another container, the diphosphine ligand BPPFOH having a ferrocene skeleton and [RuCl ₂ COD] were added, and the complex catalyst solution prepared by stirring at room temperature for 15 minutes was added to the reaction system. Was replaced with nitrogen. Next, 0.5 MPa of hydrogen gas was filled in the container and reacted at 80 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, water and toluene (30 ml) were added to the residue, and after extraction, the aqueous layer was concentrated to dryness,
3.90 g of 3-quinuclidinol was obtained. Optical rotation +0.0434
(C = 2, 1 mol / L HCl), enantiomeric excess: 4.7% ee (S).

Comparative Examples 4 to 6 These comparative examples were carried out in the same manner as in Example 2 using a commercially available diphosphine ligand.

The results of Examples 1 to 6 and Comparative Examples 1 to 6 are shown in Table 1 below.

[0056]

[Table 1]

Notation of ligand abbreviation DPEN: 1,2-diphenylethylenediamine DAIPEN: 1,1-bis (p-methoxyphenyl) -2-isopropylethane-1,2-diamine (R)-(S) -BPPFA : (R) -N, N-Dimethyl-1-[(S) -1 ', 2
-Bis (diphenylphosphino) ferrocenyl] ethylamine MCCPM: (2S, 4S) -1-N-methylcarboxamide- [4-
Dicyclohexylphosphino-2- (diphenylphosphino) methyl] pyrrolidine (R)-(S) -BPPFA: (R) -1-[(S) -1 ', 2-bis (diphenylphosphino) ferrocenyl] ethanol

Comparing Example 1 with Comparative Example 1, it can be seen that in Comparative Example 1 in which the base component is not added, the reaction yield is extremely reduced and the reaction does not proceed.

Comparing Example 6 with Comparative Example 2, the reaction proceeds, but the enantiomeric excess of Comparative Example 2 having no optically active 1,2-ethylenediamine type ligand is a very low value. I understand.

Further comparing the examples of Comparative Examples 2 to 6 with each other,
Although it is a diphosphine-type ligand that exhibits excellent performance with other substrates, it does not have a 1,2-ethylenediamine-type ligand, so it is necessary to increase the enantiomeric excess in the reduction of 3-quinuclidine. I understand that I can not do it.

Further comparing Example 1 and Example 6,
The enantiomeric excess is almost the same, but it depends on the choice of solvent.
-It can be seen that the conversion yield of quinuclidinone varies. An optimal embodiment of the present invention is to perform hydrogenation in the presence of an optically active ruthenium (II) complex having an optically active 1,2-ethylenediamine type ligand together with an optically active bidentate phosphine ligand and a base. , Using 2-propanol as a solvent.

[0062]

INDUSTRIAL APPLICABILITY According to the present invention, 3-quinuclidinol having a high content of a desired optical isomer can be produced from 3-quinuclidinone by utilizing a complex catalyst capable of enantioselectively reducing.

Claims (2)

[Claims] 1. When optically reducing 3-quinuclidinone to produce optically active 3-quinuclidinol, optically active 2
Together with the bidentate phosphine ligand, the compound represented by the general formula (1) (Wherein R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each have a hydrogen atom or a substituent. A good alkyl group, an aryl group or an aralkyl group, and R ⁴ and R ⁵ may combine with each other to form an alkylene group.), Which has an optically active 1,2-ethylenediamine type ligand. Optically active 3-characterized by hydrogenation in the presence of active ruthenium (II) complex and base 3-
A method for producing quinuclidinol. 2. The optically active ruthenium (II) complex has the general formula (2): (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, R ⁷ is an aryl group which may have a substituent, and R ⁸ and R ⁹ are the same. Or a hydrogen atom or an alkyl group different from each other, and X represents a hydrogen atom, a halogen atom, an acyloxy group or an acetoacetonate group.), Which is an optically active ruthenium (II) complex. A method for producing the optically active 3-quinuclidinol described.