JP4562736B2 - Method for producing optically active alcohol - Google Patents

Description

  The present invention provides an industrially advantageous method for producing optically active alcohols. This application claims priority with respect to the Japan patent application 2004-333192 for which it applied on November 17, 2004, and uses the content here.

  Optically active alcohols are useful as agricultural pharmaceutical intermediates. As a method for producing optically active alcohols, various methods such as a resolution method, an enzyme / microorganism method, and an asymmetric synthesis method are known. From an industrial point of view, since there is little waste and the reducing agent is inexpensive hydrogen, many methods have been studied in the past for deriving ketones to the corresponding optically active alcohols by catalytic asymmetric hydrogenation. Yes. Among them, an asymmetric hydrogenation reaction of a carbonyl compound having a functional group with a homogeneous optically active ruthenium catalyst is one of effective techniques (for example, “Asymmetric Catalysis In Organic Synthesis” (USA) by R. Noyori, 1994, p. 56-82, JP-B-5-12353, JP-B-4-81596, JP-A-9-294932, JP-A-10-59992, JP-B-7-57758). However, the complex catalyst used in the reaction is extremely expensive, and it was necessary to reduce the amount of the catalyst in order to produce optically active alcohol at an industrially low cost.

  In order to reduce the amount of catalyst, it is known that catalytic activity is improved by adding a strong acid such as hydrogen chloride in the same reduction reaction as described above (for example, “Journal of Organic Chemistry (USA) 1992, 57, p. 6689, “Tetrahedron Asymmetry (UK)”, 1997, 8, p. 4041). However, in the case of an acid labile substrate such as a carbonyl compound having a functional group, it is expected that the yield is significantly reduced by addition of the acid. For this reason, in the industrial production of optically active alcohols, there has been a demand for a method that does not affect the substrate and has no problem in terms of operation and cost.

  An object of the present invention is to provide an industrially advantageous method for producing optically active alcohols that can be applied to an acid labile compound in an asymmetric hydrogenation reaction of a carbonyl compound.

［Ｒ^１は置換基を有していても良いアルキル基、置換基を有していても良いアリール基、置換基を有していても良いヘテロアリール基または置換基を有していても良いアラルキル基を示す。
Ｒ^２は、水素原子、置換基を有していても良いアルキル基、置換基を有していても良いアリール基、または置換基を有していても良いアラルキル基を示し、Ｒ^２同士が結合して環を形成しても良い。
Ｒ^３は、水酸基、置換基を有していても良いアルコキシ基、チオール基、またはアルキルチオ基を示す。］
で表される化合物を光学活性水素化錯体触媒の存在下、水素を作用させ、式（II）

［Ｒ^１、Ｒ^２、およびＲ^３は、式（Ｉ）と同じ意味を示し、＊は光学活性炭素原子を示す。］
で表される光学活性アルコール化合物を製造する方法において、
光学活性水素化錯体触媒が、組成式（Ｖ）

［式中、Ｌは光学活性の二座三級リン配位子を示し、Ｘはハロゲン原子を示し、Ｙは、式（Ａ）、（Ｂ）または（Ｃ）

（Ｒａ、ＲｂおよびＲｃはそれぞれ独立して、水素原子またはアルキル基を示し、ＲｂとＲｃとがいっしょになってアルキレン鎖を成してもよい。ｋは１〜４の整数を示す。）
で表される配位性化合物を示し、ｍ、ｎ及びｐはそれぞれ独立して１または２を示し、ｑは０〜２の実数を示す。］
で表されるルテニウム化合物であり、
塩化リチウム、臭化リチウム、塩化ナトリウム、塩化カリウムの中から選択される塩である無機塩を添加することを特徴とする製造方法である。
また、他の実施態様として、本発明は、式（III）

［Ｒ ^１ は置換基を有していても良いアルキル基、置換基を有していても良いアリール基、置換基を有していても良いヘテロアリール基または置換基を有していても良いアラルキル基を示し、Ｒ ^２ は水素原子、置換基を有していても良いアルキル基または置換基を有していても良いアラルキル基を示し、Ｒ ^２ 同士が結合して環を形成しても良い。］
で表される化合物を光学活性水素化錯体触媒の存在下、水素を作用させ、式（IV）

［Ｒ ^１ 、Ｒ ^２ は、式（Ｉ）と同じ意味を示し、＊は光学活性炭素原子を示す。］
で表される光学活性アルコール化合物を製造する方法において、
光学活性水素化錯体触媒が、組成式（Ｖ）

［式中、Ｌは光学活性の二座三級リン配位子を示し、Ｘはハロゲン原子を示し、Ｙは、式（Ａ）、（Ｂ）または（Ｃ）

（Ｒａ、ＲｂおよびＲｃはそれぞれ独立して、水素原子またはアルキル基を示し、ＲｂとＲｃとがいっしょになってアルキレン鎖を成してもよい。ｋは１〜４の整数を示す。）
で表される配位性化合物を示し、ｍ、ｎ及びｐはそれぞれ独立して１または２を示し、ｑは０〜２の実数を示す。］
で表されるルテニウム化合物であり、
塩化リチウム、臭化リチウム、塩化ナトリウム、塩化カリウムの中から選択される塩である無機塩を添加することを特徴とする製造方法である。 As a result of intensive studies on a method for producing optically active alcohols, the present inventors have found a method for reducing the amount of catalyst and have completed the present invention. That is, the present invention provides, as one embodiment, the formula (I)

[R ¹ may have an alkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a substituent. An aralkyl group is shown.
R ² is a hydrogen atom, an optionally substituted alkyl group, which may have a substituent, an aryl group or have a substituent indicates also aralkyl group, R ² to each other, They may combine to form a ring.
R ³ represents a hydroxyl group, an alkoxy group which may have a substituent, a thiol group, or an alkylthio group. ]
The compound represented by formula (II) is reacted with hydrogen in the presence of an optically active hydrogenation complex catalyst.

[R ¹ , R ² , and R ³ have the same meaning as in formula (I), and * represents an optically active carbon atom. ]
In the method for producing an optically active alcohol compound represented by:
The optically active hydrogenation complex catalyst has the composition formula (V)

[Wherein L represents an optically active bidentate tertiary phosphorus ligand, X represents a halogen atom, and Y represents a formula (A), (B) or (C)

(Ra, Rb and Rc each independently represents a hydrogen atom or an alkyl group, and Rb and Rc may be combined to form an alkylene chain. K represents an integer of 1 to 4.)
And m, n and p each independently represent 1 or 2, and q represents a real number of 0 to 2. ]
A ruthenium compound represented by:
An inorganic salt which is a salt selected from lithium chloride, lithium bromide, sodium chloride and potassium chloride is added.
In another embodiment, the present invention provides a compound of formula (III)

[R ¹ may have an alkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a substituent. An aralkyl group, R ² represents a hydrogen atom, an alkyl group which may have a substituent or an aralkyl group which may have a substituent, and R ² may be bonded to form a ring; good. ]
The compound represented by formula (IV) is reacted with hydrogen in the presence of an optically active hydrogenation complex catalyst.

[R ¹ and R ² have the same meaning as in formula (I), and * represents an optically active carbon atom. ]
In the method for producing an optically active alcohol compound represented by:
The optically active hydrogenation complex catalyst has the composition formula (V)

[Wherein L represents an optically active bidentate tertiary phosphorus ligand, X represents a halogen atom, and Y represents a formula (A), (B) or (C)

(Ra, Rb and Rc each independently represents a hydrogen atom or an alkyl group, and Rb and Rc may be combined to form an alkylene chain. K represents an integer of 1 to 4.)
And m, n and p each independently represent 1 or 2, and q represents a real number of 0 to 2. ]
A ruthenium compound represented by:
An inorganic salt which is a salt selected from lithium chloride, lithium bromide, sodium chloride and potassium chloride is added.

  The present invention provides an inexpensive and efficient method for producing optically active alcohols that can reduce the amount of catalyst without decomposition of raw materials and products. In addition, the present invention is an industrially advantageous method for producing optically active alcohols that can be applied to an acid labile compound.

  In the present invention, the additive is not particularly limited as long as it is an inorganic salt, but an alkali metal salt or an alkaline earth metal salt is preferred. More preferably, lithium salt, sodium salt, potassium salt, among which lithium chloride, lithium bromide, sodium chloride, potassium chloride, etc. can be used. These salts can be added as commercial products during the reaction, or reacted with an inorganic base and an acid such as sodium hydroxide and hydrogen chloride, lithium hydroxide and hydrogen chloride, or potassium hydroxide and hydrogen chloride in the reaction solvent. May be used as an inorganic base.

R ¹ in the formulas (I) and (II) is an alkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or An aralkyl group which may have a substituent is shown.
Examples of the alkyl group which may have a substituent include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl and octyl. , Eicosanil, etc .;
As the aryl group of the aryl group which may have a substituent, phenyl, 1-naphthyl, 2-naphthyl and the like;
Examples of the aralkyl group of the aralkyl group which may have a substituent include benzyl, phenethyl, 3-phenylpropyl, diphenylmethyl and the like.
As the aryl group of the aryl group which may have a substituent, phenyl, 1-naphthyl, 2-naphthyl and the like;
As the heteroaryl group of the heteroaryl group which may have a substituent, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazoyl, 4-pyrazoyl, 5-pyrazoyl , 2-indolyl, 3-indoyl, quinolyl and the like.

The alkyl group, aryl group, aralkyl group, aryl group, heteroaryl group may have one or a plurality of the same or different substituents, such as fluorine, chlorine, bromine, Halogen atoms such as iodine;
Alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl;
Mention may be made of alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy and pentoxy.

R ² is a hydrogen atom, an optionally substituted alkyl group, which may have a substituent, an aryl group or have a substituent indicates also aralkyl group, R ² to each other, They may combine to form a ring.
Examples of the alkyl group which may have a substituent include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl and octyl. , Eicosanil, etc .;
As the aryl group of the aryl group which may have a substituent, phenyl, 1-naphthyl, 2-naphthyl and the like;
Examples of the aralkyl group of the aralkyl group which may have a substituent include benzyl, phenethyl, 3-phenylpropyl, diphenylmethyl and the like.

The alkyl group, aryl group and aralkyl group may have one or a plurality of the same or different substituents, and examples of the substituent include halogen atoms such as fluorine, chlorine, bromine and iodine;
Alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl;
Examples include alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy and pentoxy.

R ³ represents a hydroxyl group, an alkoxy group which may have a substituent, a thiol group, or an alkylthio group.
Examples of the alkoxy group which may have a substituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, t-butoxy and the like;
Examples of the alkylthio group which may have a substituent include methylthio, ethylthioethyl, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, t-butylthio and the like.

The alkoxy group and alkylthio group may have one or a plurality of the same or different substituents, and examples of the substituent include halogen atoms such as fluorine, chlorine, bromine and iodine;
Alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl;
Examples thereof include alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, pentoxy and the like.

［Ｒ^１は置換基を有していても良いアルキル基、置換基を有していても良いアリール基、置換基を有していても良いヘテロアリール基または置換基を有していても良いアラルキル基を示し、Ｒ^２は水素原子、置換基を有していても良いアルキル基または置換基を有していても良いアラルキル基を示し、Ｒ^２同士が結合して環を形成しても良い。］で表される化合物を原料にして式（IV）

［Ｒ^１、Ｒ^２は、式（III）と同じ意味を示し、＊は光学活性炭素原子を示す。］で表される化合物を得る反応が本発明の適用において好ましい。Among the compounds having the above substituents, the formula (III)

[R ¹ may have an alkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a substituent. An aralkyl group, R ² represents a hydrogen atom, an alkyl group which may have a substituent or an aralkyl group which may have a substituent, and R ² may be bonded to form a ring; good. A compound represented by formula (IV)

[R ¹ and R ² have the same meaning as in formula (III), and * represents an optically active carbon atom. In the application of the present invention, a reaction for obtaining a compound represented by the formula:

［式中、ｍ、ｎ及びｐはそれぞれ独立して１または２を示し、ｑは０〜２の実数を示す。］
で表される不斉水素化錯体触媒において、Ｌで表される二座三級リン配位子は光学活性であれば、何ら限定されるものではない。具体的には、リン原子が光学活性な２座配位の３級ホスフィンとして、ビス（メチルｔＢｕホスフィノ）メタン（ＭｉｎｉＰＨＯＳ）、１，２−ビス（メチルｔＢｕホスフィノ）エタン（ＢｉｓＰ＊）等、リン原子上に同一の２個の置換基を有する光学活性な２座配位の３級ホスフィン、例えば、ＢＰＰＦＡ：１−〔１′，２−ビス（ジフェニルホスフィノ）フェロセニル〕エチルジアミン、ＢＩＣＨＥＰ：２，２′−ビス−（ジシクロヘキシルホスフィノ）−６，６′−ジメチル−１，１′−ビフェニル、ＣＨＩＲＡＰＨＯＳ：２，３−ビス−（ジフェニルホスフィノ）ブタン、ＣＹＣＰＨＯＳ：１−シクロヘキシル−１，２−ビス−（ジフェニルホスフィノ）エタン、ＤＥＧＰＨＯＳ：１−置換−３，４−ビス−（ジフェニルホスフィノ）ピロリジン、ＤＩＯＰ：２，３−Ｏ−イソプロピリデン−２，３−ジヒドロキシ−１，４−ビス−（ジフェニルホスフィノ）ブタン、ＤＩＰＡＭＰ：１，２−ビス〔（Ｏ−メトキシフェニル）フェニルホスフィノ〕エタン、ＤｕＰＨＯＳ：（置換−１，２−ビス（ホスホラノ）ベンゼン）、ＮＯＲＰＨＯＳ：５，６−ビス−（ジフェニルホスフィノ）−２−ノルボルネン、ＰＮＮＰ：Ｎ，Ｎ′−ビス−（ジフェニルホスフィノ）−Ｎ，Ｎ′−ビス〔１−フェニルエチル〕エチレンジアミン、ＰＲＯＰＨＯＳ：１，２−ビス−（ジフェニルホスフィノ）プロパン、ＳＫＥＷＰＨＯＳ：２，４−ビス−（ジフェニルホスフィノ）ペンタン、さらに、軸不斉２座配位の３級ホスフィンとして、例えば、ＭｅＯ−ＢＩＰＨＥＰ：（６，６′−ジメトキシビフェニル−２，２′−ジイル）−ビス−（ジフェニルホスフィン）、Ｃｌ−ＭｅＯ−ＢＩＰＨＥＰ：（５，５′−ジクロロ−６，６′−ジメトキシ−２，２′−ビス−（ジフェニルホスフィノ）−１，１′−ビフェニル、ＢＩＰＨＭＰ：（６，６′−ジメチルビフェニル−２，２′−ビス−（ジフェニルホスフィノ）−１，１′−ビフェニル、ＴＵＮＥＰＨＯＳ類（Ｃ１〜Ｃ６）、例えば、Ｃ３−ＴＵＮＥＰＨＯＳ：１，１３−ビス（ジフェニルホスフィノ）−７，８−ジヒドロ−６Ｈ−ジベンゾ｛ｆ、ｈ｝｛１，５｝ジオキソニン、ＳＹＮＰＨＯＳ：６，６’−ビス（ジフェニルホスフィノ）−２，２’−３，３’−テトラヒドロ−５，５’−ビ−１，４−ベンゾジオキシン、Ｐ−ＰＨＯＳ：２，２’−６，６’−テトラメトキシ−４，４’−ビス（ジフェニルホスフィノ）−３，３’−ビピリジン、ＢＩＮＡＰ：２，２′−ビス−（ジフェニルホスフィノ）−１，１′−ビナフチル、およびＢＩＮＡＰのナフチル環にアルキル基やアリール基等の置換基をもつＢＩＮＡＰ誘導体、フッ素置換基を有するＢＩＮＡＰ誘導体、リン原子上の同一の２個のベンゼン環にそれぞれアルキル、アルコキシ等の基置換基をそれぞれ１〜５個有するＢＩＮＡＰ等の誘導体、例えば、Ｔｏｌ−ＢＩＮＡＰ：２，２′−ビス−（ジ−ｐ−トリルホスフィノ）−１，１′−ビナフチル、Ｘｙｌｙｌ−ＢＩＮＡＰ：２，２′−ビス〔ビス（３，５−ジメチルフェニル）ホスフィノ〕−１，１′−ビナフチル、リン原子上の置換基がアルキル基であるもの、例えば、２，２′−ビス−（ジシクロヘキシルホスフィノ）−１，１′−ビナフチル、ＳＥＧＰＨＯＳ：［（５，６），（５′，６′）−ビス（メチレンジオキシ）ビフェニル−２，２′−ジイル］ビス（ジフェニルホスフィン）等が挙げられる。Composition formula (V) used in the present invention

[Wherein, m, n and p each independently represent 1 or 2, and q represents a real number of 0 to 2. ]
In the asymmetric hydrogenation complex catalyst represented by the formula (2), the bidentate tertiary phosphorus ligand represented by L is not limited as long as it is optically active. Specifically, as a bidentate tertiary phosphine in which the phosphorus atom is optically active, bis (methyl tBu phosphino) methane (MiniPHOS), 1,2-bis (methyl tBu phosphino) ethane (BisP *), etc. Optically active bidentate tertiary phosphine having the same two substituents on the atom, for example, BPPFA: 1- [1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethyldiamine, BICHEP: 2 , 2'-bis- (dicyclohexylphosphino) -6,6'-dimethyl-1,1'-biphenyl, CHIRAPHOS: 2,3-bis- (diphenylphosphino) butane, CYCPHOS: 1-cyclohexyl-1,2 -Bis- (diphenylphosphino) ethane, DEGPHOS: 1-substituted-3,4-bis- (diphenylphosphino) Pyrrolidine, DIOP: 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis- (diphenylphosphino) butane, DIPAMP: 1,2-bis [(O-methoxyphenyl) phenylphosphino] Ethane, DuPHOS: (substituted-1,2-bis (phosphorano) benzene), NORPHOS: 5,6-bis- (diphenylphosphino) -2-norbornene, PNNP: N, N'-bis- (diphenylphosphino) -N, N'-bis [1-phenylethyl] ethylenediamine, PROPHOS: 1,2-bis- (diphenylphosphino) propane, SKEWPHOS: 2,4-bis- (diphenylphosphino) pentane, and axial asymmetry As a bidentate tertiary phosphine, for example, MeO-BIPHEP: (6,6'-dimeth Cibiphenyl-2,2'-diyl) -bis- (diphenylphosphine), Cl-MeO-BIPHEP: (5,5'-dichloro-6,6'-dimethoxy-2,2'-bis- (diphenylphosphino) ) -1,1′-biphenyl, BIPHMP: (6,6′-dimethylbiphenyl-2,2′-bis- (diphenylphosphino) -1,1′-biphenyl, TUNEPHOSs (C1-C6), for example, C3-TUNEPHOS: 1,13-bis (diphenylphosphino) -7,8-dihydro-6H-dibenzo {f, h} {1,5} dioxonine, SYNPHOS: 6,6′-bis (diphenylphosphino)- 2,2′-3,3′-tetrahydro-5,5′-bi-1,4-benzodioxin, P-PHOS: 2,2′-6,6′-tetramethoxy-4,4′- Su (diphenylphosphino) -3,3′-bipyridine, BINAP: 2,2′-bis- (diphenylphosphino) -1,1′-binaphthyl, and substitution of alkyl group or aryl group on the naphthyl ring of BINAP A BINAP derivative having a group, a BINAP derivative having a fluorine substituent, a derivative such as BINAP having 1 to 5 group substituents such as alkyl and alkoxy on the same two benzene rings on the phosphorus atom, for example, Tol -BINAP: 2,2'-bis- (di-p-tolylphosphino) -1,1'-binaphthyl, Xylyl-BINAP: 2,2'-bis [bis (3,5-dimethylphenyl) phosphino] -1, 1'-binaphthyl, where the substituent on the phosphorus atom is an alkyl group, for example 2,2'-bis- (dicyclohexylphosphine No) -1,1'-binaphthyl, SEGPHOS: [(5,6), (5 ', 6')-bis (methylenedioxy) biphenyl-2,2'-diyl] bis (diphenylphosphine) It is done.

  The halogen atom represented by X is chlorine, bromine or iodine, and is a counter anion of a divalent ruthenium complex available as a raw material.

で表される配位子化合物であり、Ｒａ、Ｒｂ、Ｒｃはそれぞれ独立して、水素原子、アルキル基を示し、ＲｂとＲｃがいっしょになってＣ２〜Ｃ７のアルキレン鎖を成してもよく、ｋは１〜４の整数を示す。より具体的には、式（Ａ）で表される化合物としてはＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ，Ｎ−ジエチルホルムアミド等が挙げられ、式（Ｂ）で表される化合物としてはＮ−メチル−２−ピロリジノン、Ｎ−イソプロピル−２−ピロリジノン、Ｎ−メチル−２−ピペリドン等が挙げられ、式（Ｃ）で表される化合物としてはＮ，Ｎ’−ジメチル−２−イミダゾリジノン、１，３−ジメチル−３，４，５，６−テトラヒドロ−２（１Ｈ）−ピリミジノン等が好適な化合物として挙げられる。Y is the formula (A), (B) or (C)

Wherein Ra, Rb, and Rc each independently represent a hydrogen atom or an alkyl group, and Rb and Rc may together form a C2-C7 alkylene chain. , K represents an integer of 1 to 4. More specifically, examples of the compound represented by the formula (A) include N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N, N-diethylformamide, and the like. Examples of the compound represented include N-methyl-2-pyrrolidinone, N-isopropyl-2-pyrrolidinone, N-methyl-2-piperidone, and the like. As the compound represented by the formula (C), N, N′— Examples of suitable compounds include dimethyl-2-imidazolidinone and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone.

The above catalyst is disclosed in Tetrahedron Lett. , 1991, 32, 4163. That is, divalent ruthenium complexes such as [RuCl ₂ (C ₆ H ₆ )] ₂ and [RuCl ₂ (1,5-C ₈ H ₁₂ )] _n (ruthenium (II) chloride 1,5-cyclooctadiene complex). It can be obtained by heating the optically active bidentate tertiary phosphorus ligand represented by L and L together with a coordinating compound such as DMF represented by Y at 50 to 200 ° C., preferably 100 to 160 ° C. it can. The molar ratio of the divalent ruthenium complex and the optically active bidentate tertiary phosphorus ligand represented by L is 1: 0.5 to 1: 5, preferably 1: 1 to 1: 1.5. is there. Since the compound that can be a ligand such as DMF is used as a reaction solvent, the amount used for the divalent ruthenium complex is not particularly limited, but is 2 to 10,000 times (w / w), preferably 5 Double to 300-fold amount. Moreover, after synthesizing the ruthenium compound represented by the general composition formula (V), V can be used as it is in the reaction solution, but Y is distilled from the reaction solution and used as a powder. It is preferable to do.

This reaction can be performed in the presence or absence of a solvent. Solvents that can be used are not particularly limited as long as they are inert to the reaction. For example, hydrocarbon solvents such as pentane, hexane, heptane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, four Halogen solvents such as carbon chloride, alcohols such as methanol and ethanol, nitrile solvents such as acetonitrile and propiononitrile, ether solvents such as diethyl ether, dioxane and tetrahydrofuran, aprotic polar solvents such as DMF and dimethyl sulfoxide, Water and a mixed solvent system in which two or more of these solvents are mixed may be mentioned. Of these, alcohols are particularly suitable.
The amount of the inert solvent can be used without any particular limitation, but from a practical viewpoint, the volume ratio of (compound represented by formula (I)) / (inert solvent) is 0 to 100, preferably 0 to 10. is there.

  The production of the optically active alcohol (II) according to the present invention involves the preparation of the compound represented by the formula (I), the optically active hydrogenation complex catalyst represented by the composition formula (V) and the inorganic salt in the presence or absence of a solvent. And hydrogen pressure is applied. By adding an inorganic salt, which is a feature of the present invention, a molar ratio of (compound represented by formula (I)) / (optically active hydrogenation catalyst represented by composition formula (V)) (hereinafter referred to as S / C). ) Can be kept large while achieving good optical and chemical yields.

The molar ratio of (inorganic salt) / (optically active hydrogenation complex catalyst represented by composition formula (V)) is 50 to 1,000, preferably 3 to 400. The inorganic salt may be used as it is, or may be used by dissolving in the above solvent. In this case, S / C is 5,000 to 100,000, preferably 10,000 to 30,000.
If the amount of inorganic salt and S / C are in the above ranges, the reaction pressure, reaction temperature, and reaction time can be appropriately within the range according to practical restrictions. As long as there is no restriction | limiting on an apparatus, arbitrary pressure beyond a normal pressure is possible for a pressure. The temperature can be carried out as long as it is above the melting point of the reaction solution and below the decomposition point of the substrate. With respect to the reaction time, the reaction is completed in a short time under high pressure / high temperature conditions, and in a long time under low pressure / low temperature conditions. From a practical viewpoint, the reaction pressure is preferably 3 to 10 MPa and the reaction temperature is 5 to 100 ° C. In this case, the reaction time can be completed within 1 to 48 hours. Since good optical yield and chemical yield can be achieved, the optically active alcohol of the product after the reaction can be purified by a known method such as distillation.

  Next, the present invention will be described in more detail with reference examples and examples. The present invention is not limited to these.

Example 1:
Synthesis of optically active 1,3-butanediol The stirrer and the optically active hydrogenation complex catalyst (4.8 mg: 0.0051 mmol; S / C = 19,600) synthesized in Reference Example 1 were placed in a 100 ml autoclave and argon was added. Replaced. 3-Oxo-1-butanol (8.8 g: 99.9 mmol) and methanol (7.0 ml) were placed in a Schlenk tube and purged with argon, and then transferred to an autoclave with a syringe. Furthermore, 0.01N lithium chloride methanol solution (2.4 ml: 0.024 mmol) was added to the autoclave with a syringe, and the reaction was performed at a hydrogen pressure of 6 MPa and 60 ° C. for 7 hours. Thereafter, it was cooled and returned to normal pressure, and the reaction solution was analyzed by gas chromatography. (CP-Chirasil DEX-CB: 0.25 mm * 25 m, Inj: 200 ° C., column: 100 ° C., DET: 200 ° C.). The title compound was obtained with an optical purity of 96.7% ee, a conversion of 100%, and a yield of 91.5%.

Example 2:
Synthesis of optically active 2-methyl-2,4-pentanediol A stirrer and the optically active hydrogenation complex catalyst (4.8 mg: 0.0051 mmol; S / C = 19,600) synthesized in Reference Example 1 were used in a 100 ml autoclave. And replaced with argon. 2-Methyl-4-oxo-2-pentanol (11.6 g: 100 mmol) and methanol (11.6 ml) were placed in a Schlenk tube and purged with argon, and then transferred to an autoclave with a syringe. Furthermore, lithium chloride (60 mg: 1.4 mmol) was added to the autoclave, and the reaction was performed at a hydrogen pressure of 9 MPa and 60 ° C. for 12 hours. Thereafter, it was cooled and returned to normal pressure, and the reaction solution was analyzed by gas chromatography. (CP-Chirasil DEX-CB: 0.25 mm * 25 m, Inj: 200 ° C., column: 100 ° C., DET: 200 ° C.). The title compound was obtained with an optical purity of 96.7% ee, a conversion rate of 100%, and a GC yield of 99.1%.

Reference example 1:
An optically active hydrogenation complex catalyst represented by the composition formula [(R)-(binap) RuCl ₂ (dmf) q] ([L] = (R) -BINAP in Formula V, m = 1, n = 1, X = Cl, p = 2, Y = DMF, q = 1 to 2) (R) -BINAP (65 mg: 0.1 mmol) and [RuCl ₂ (COD)] (28 mg: 0.1 mmol) were added to a Schlenk tube. The atmosphere was replaced with argon. Degassed DMF (5 ml) was added and heated with stirring in an oil bath at 160 ° C. for 20 minutes. Thereafter, the mixture was cooled to room temperature, and DMF was distilled off under reduced pressure to obtain 93 mg of the title compound (yield: quantitative).

Reference example 2:
Production of optically active 1,3-butanediol (hydrochloric acid in methanol)
The stirrer and the optically active hydrogenation complex catalyst synthesized in Reference Example 1 (4.8 mg: 0.0051 mmol; S / C = 19,600) were placed in a 100 ml autoclave and purged with argon. 3-Oxo-1-butanol (8.8 g: 99.9 mmol) and methanol (7.3 ml) were placed in a Schlenk tube and purged with argon, and then transferred to an autoclave with a syringe. Furthermore, 0.012N hydrochloric acid methanol solution (2.0 ml: 0.024 mmol) was added to the autoclave with a syringe, and the reaction was performed at a hydrogen pressure of 6 MPa and 60 ° C. for 24 hours. Thereafter, it was cooled and returned to normal pressure, and the reaction solution was analyzed by gas chromatography. (CP-Chirasil DEX-CB: 0.25 mm * 25 m, Inj: 200 ° C., column: 100 ° C., DET: 200 ° C.). The title compound was obtained in an optical purity of 95.9% ee, a pass-through rate of 100%, and a yield of 77.5%.

Reference Example 3:
Production of optically active 1,3-butanediol (no inorganic salt added)
3-oxo-1-butanol (9.2 g: 0.105 mol) and an optically active hydrogenation complex catalyst (5.2 mg: 0.0055 mmol; S / C = 19000) synthesized in the same manner as in Reference Example 1. The mixture was placed in a Schlenk tube and purged with argon, and then transferred to a 100 ml autoclave which was purged with argon and purged with a syringe. The reaction was carried out at a hydrogen pressure of 10 MPa and 70 ° C. for 19 hours. Thereafter, the reaction mixture was cooled and returned to atmospheric pressure, and the reaction solution was analyzed. The obtained title compound had an optical purity of 96.0% ee and a conversion rate of 43%.

  According to the present invention, the amount of catalyst can be reduced without decomposing raw materials and products, and optically active alcohols can be produced at low cost and efficiently.

Claims (3)

Formula (I)

[R ¹ may have an alkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a substituent. An aralkyl group is shown.
R ² is a hydrogen atom, an optionally substituted alkyl group, which may have a substituent, an aryl group or have a substituent indicates also aralkyl group, R ² to each other, They may combine to form a ring.
R ³ represents a hydroxyl group, an alkoxy group which may have a substituent, a thiol group, or an alkylthio group. ]
The compound represented by formula (II) is reacted with hydrogen in the presence of an optically active hydrogenation complex catalyst.

[R ¹ , R ² , and R ³ have the same meaning as in formula (I), and * represents an optically active carbon atom. ]
In the method for producing an optically active alcohol compound represented by:
The optically active hydrogenation complex catalyst has the composition formula (V)

[Wherein L represents an optically active bidentate tertiary phosphorus ligand, X represents a halogen atom, and Y represents a formula (A), (B) or (C)

(Ra, Rb and Rc each independently represents a hydrogen atom or an alkyl group, and Rb and Rc may be combined to form an alkylene chain. K represents an integer of 1 to 4.)
And m, n and p each independently represent 1 or 2, and q represents a real number of 0 to 2. ]
A ruthenium compound represented by:
A production method comprising adding an inorganic salt which is a salt selected from lithium chloride, lithium bromide, sodium chloride and potassium chloride . Formula (III)

[R ¹ may have an alkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a substituent. An aralkyl group, R ² represents a hydrogen atom, an alkyl group which may have a substituent or an aralkyl group which may have a substituent, and R ² may be bonded to form a ring; good. ]
The compound represented by formula (IV) is reacted with hydrogen in the presence of an optically active hydrogenation complex catalyst.

[R ¹ and R ² have the same meaning as in formula (I), and * represents an optically active carbon atom. ]
In the method for producing an optically active alcohol compound represented by:
The optically active hydrogenation complex catalyst has the composition formula (V)

[Wherein L represents an optically active bidentate tertiary phosphorus ligand, X represents a halogen atom, and Y represents a formula (A), (B) or (C)

(Ra, Rb and Rc each independently represents a hydrogen atom or an alkyl group, and Rb and Rc may be combined to form an alkylene chain. K represents an integer of 1 to 4.)
And m, n and p each independently represent 1 or 2, and q represents a real number of 0 to 2. ]
A ruthenium compound represented by:
A production method comprising adding an inorganic salt which is a salt selected from lithium chloride, lithium bromide, sodium chloride and potassium chloride . The inorganic salts to optically active hydrogenation complex catalyst, in a molar ratio, process for producing an optically active alcohol according to any one of claims 1-2, characterized by adding 3 to 400.