JPWO2002055477A1 - Method for producing ruthenium compound, diamine compound and β-amino alcohol - Google Patents

Abstract

The present invention provides a method for producing a ruthenium (Ru) compound, a diamine ligand, and an optically active alcohol useful as an asymmetric hydrogenation catalyst in a high stereoselective and high yield. (1): Ru (Px) n1 [DIAMINE] (X) (Y) wherein Px represents a phosphine ligand, and DIAMINE represents a general formula (2): R1R2C * (NHR5)-(A)- R3R4C * (NH2) [R1 to R4 each independently represent a hydrogen atom, an alkyl group which may have a substituent, or the like, and A may have a substituent and contains an ether bond. Represents an optionally substituted C1-C3 alkylene, an optionally substituted C3-C8 cycloalkylene or the like, and R5 represents an optionally substituted alkyl group or an optionally substituted substituent. Aralkyl group or position Represents an aryl group which may have a group, C * represents an asymmetric carbon. X and Y each independently represent an anion, and n1 represents an integer of 1 or 2. This is a method for producing β-amino alcohol from an α-aminocarbonyl compound using a ruthenium compound represented by｝ as an asymmetric hydrogenation catalyst.

Description

すなわち、酸触媒の存在あるいは非存在下に、光学活性なＮ−アシルジアミン（２ａ）とカルボニル化合物（２ｂ）とを作用させてイミノ体（２ｃ）を得たのち（工程Ｉ）、これを適当な還元剤を用いて還元することにより（工程ＩＩ）、容易に化合物（２）を得ることができる。また、用いる還元剤によっては、Ｎ−アシル−Ｎ’−置換ジアミン（２ｄ）を経由して、これを加水分解によって化合物（２）に誘導することもできる（工程ＩＩＩ）。
出発原料として用いられる光学活性なＮ−アシルジアミン（２ａ）としては、例えば、（１Ｒ，２Ｒ）−Ｎ−ベンジルオキシカルボニル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｓ，２Ｓ）−Ｎ−ベンジルオキシカルボニル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｒ，２Ｒ）−Ｎ−イソプロピルオキシカルボニル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｓ，２Ｓ）−Ｎ−イソプロピルオキシカルボニル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｒ，２Ｒ）−Ｎ−ベンゾイル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｓ，２Ｓ）−Ｎ−ベンゾイル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｒ，２Ｒ）−Ｎ−アセチル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｓ，２Ｓ）−Ｎ−アセチル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｒ，２Ｒ）−Ｎ−トリクロロアセチル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｓ，２Ｓ）−Ｎ−トリクロロアセチル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｒ，２Ｒ）−Ｎ−トリフルオロアセチル−１，２−ジフェニル−１，２−エタンジアミン、（１Ｓ，２Ｓ）−Ｎ−トリフルオロアセチル−１，２−ジフェニル−１，２−エタンジアミン、
（２Ｒ，４Ｒ）−Ｎ−ベンジルオキシカルボニル−２，４−ジアミノペンタン、（２Ｓ，４Ｓ）−Ｎ−ベンジルオキシカルボニル−２，４−ジアミノペンタン、（２Ｒ，５Ｒ）−Ｎ−ベンジルオキシカルボニル−２，５−ジアミノヘキサン、１−（Ｎ−ベンジルオキシカルボニル−１（Ｒ）−アミノエチル）−２−（１（Ｒ）−アミノエチル）ベンゼン、１−（Ｎ−ベンジルオキシカルボニル−１（Ｓ）−アミノエチル）−２−（１（Ｓ）−アミノエチル）ベンゼン、（１Ｒ，２Ｒ）Ｎ−ベンジルオキシカルボニル−シクロヘキサンジアミン、（１Ｓ，２Ｓ）−Ｎ−ベンジルオキシカルボニル−シクロヘキサンジアミン、（１Ｒ，２Ｒ）−Ｎ−イソプロピルオキシカルボニル−シクロヘキサンジアミン、（１Ｓ，２Ｓ）−Ｎ−イソプロピルオキシカルボニル−シクロヘキサンジアミン、（１Ｒ，２Ｒ）−Ｎ−ベンゾイル−シクロヘキサンジアミン、（１Ｓ，２Ｓ）−Ｎ−ベンゾイル−シクロヘキサンジアミン、（１Ｒ，２Ｒ）−Ｎ−アセチル−シクロヘキサンジアミン、（１Ｓ，２Ｓ）−Ｎ−アセチル−シクロヘキサンジアミン等が挙げられる。
また、カルボニル化合物（２ｂ）の具体例としては、ホルムアルデヒド、アセトアルデヒド、プロピオンアルデヒド、シクロヘキサンアルデヒド、ベンズアルデヒド、４−ベンジルオキシベンズアルデヒド、３−ベンジルオキシベンズアルデヒド等のアルデヒド類；アセトン、シクロヘキサノン等のケトン類；等が挙げられる。
上記工程Ｉの反応は、ベンゼン、トルエン、テトラヒドロフラン、ジエチルエーテル、塩化メチレン、クロロホルム等の不活性溶媒中で、光学活性なＮ−アシルジアミン（２ａ）とカルボニル化合物（２ｂ）を反応させる一般的な方法によって行われる。この場合、モレキュラーシーブ等の脱水剤を共存させることや共沸脱水下に反応を行うのが好ましい。
カルボニル化合物（２ｂ）の使用量は、光学活性なＮ−アシルジアミン（２ａ）１モルに対して、通常等モル〜１０倍モル、好ましくは等モル〜２倍モルの範囲である。反応は−５０℃〜溶媒の沸点までの温度範囲、好ましくは室温〜溶媒の沸点までの温度範囲で行われる。反応時間は通常８〜１８時間程度である。また、用いられる酸としては、硫酸、パラトルエンスルホン酸等が挙げられ、酸の使用量は、好ましくは０〜１モル％の範囲である。
工程ＩＩはイミノ体（２ｃ）の還元反応である。この反応は、ベンゼン、トルエン、テトラヒドロフラン、ジエチルエーテル、ジメトキシエタン、ジオキサン、メタノール、エタノール、酢酸等、又はこれらの混合溶媒中で、一般に使用される還元剤を用い、室温あるいは加熱下に行われる。
用いられる還元剤の具体例としては、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、三水素化シアノホウ素ナトリウム、トリエチル水素化ホウ素リチウム、ジボラン等を挙げることができる。また、パラジウムや白金の炭素担持体を触媒として水添条件下で反応を行うこともできる。反応は−７８℃〜溶媒の沸点までの温度範囲、好ましくは−３０℃〜室温間での温度範囲で行われる。反応は、通常３〜１８時間程度で完結する。
工程ＩＩＩの反応ルートは、特に、工程ＩＩの条件においてアシル基が脱離しない化合物を用いる場合に好ましく適用される。この反応は、Ｎ−アシル−Ｎ’−置換ジアミン（２ｄ）を、ベンゼン、トルエン、テトラヒドロフラン、ジエチルエーテル、ジメトキシエタン、ジオキサン、メタノール、エタノール、水、又はこれらの混合溶媒中で、室温あるいは加熱下に、一般的に使用される酸あるいはアルカリを作用させることにより行われる。
用いられる酸としては、例えば、塩酸、硫酸、酢酸等の鉱酸が挙げられる。また、アルカリとしては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、ヒドラジン、アンモニア等が用いられる。反応は、通常、−５０℃〜溶媒の沸点までの温度範囲、好ましくは室温〜溶媒の沸点間での温度範囲で行われる。反応は、８〜１８時間程度で完結する。
また別法として、一般式（２）で表わされるジアミン化合物は、下記に示す反応式に従って、一般式（２ｅ）〔式中、Ｒ^２１、Ｒ^２１’は、それぞれ独立して水素原子、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ルケニル基、置換基を有していても良いシクロアルキル基、置換基を有していても良いアラルキル基又は置換基を有していても良いアリール基を表わし、また、Ｒ^２１、Ｒ^２１’は一緒になって結合して環を形成してもよい。Ｒ^２３、Ｒ^２４は、それぞれ独立して水素原子、置換基を有してもよいアルキル基、置換基を有してもよいアリール基又は置換基を有してもよいアラルキル基を表し、Ａは前記と同じ意味を表す。〕で表わされる光学活性ジアミンに、ハライド化合物（２ｆ）〔式中、Ｘは塩素原子、臭素原子、ヨウ素原子を表わす。〕を反応させて得ることもできる。

ここで、具体的なＲ^２１、Ｒ^２１’、Ｒ^２３、Ｒ^２４としてはＲ^１〜Ｒ^４と同様の置換基が挙げられる。
光学活性なジアミン（２ｅ）の使用量は、ハライド化合物（２ｆ）１モルに対して、等モル〜１０倍モル、好ましくは２．５モル〜５倍モルである。反応は溶媒の融点〜溶媒の沸点までの温度範囲、好ましくは室温〜溶媒の沸点までの温度範囲で行われる。反応時間は通常８〜１８時間程度である。また、用いられる溶媒としては、通常ベンゼン、トルエン、クロロホルム、塩化メチレン、テトラヒドロフラン、ジエチルエーテル、ジメトキシエタン、ジオキサン、メタノール、エタノール等、又はこれらの混合溶媒を用い、好ましくはクロロホルム、塩化メチレンを用いる。
一般式（１）で表されるルテニウム化合物を製造するための出発物質としては、０価、１価、２価、３価、及びさらに高原子価のルテニウム錯体を用いることができる。これらの中でも、本発明においては２価のルテニウム錯体を用いるのが好ましい。
出発原料の２価のルテニウムハライド錯体としては、例えば、〔２塩化ルテニウム（ノルボルナジエン）〕多核体、〔２塩化ルテニウム（シクロオクタジエン）〕多核体、〔ビス（メチルアリル）ルテニウム（シクロオクタジエン）〕等のジエンが配位したハロゲン化ルテニウム化合物、〔２塩化ルテニウム（ベンゼン）〕二核体、〔２塩化ルテニウム（ｐ−シメン）〕二核体、〔２塩化ルテニウム（トリメチルベンゼン）〕二核体、〔２塩化ルテニウム（ヘキサメチルベンゼン）〕二核体等の芳香族化合物が配位したハロゲン化ルテニウム錯体等が挙げられる。また、この他、ホスフィン配位子、アミン配位子と置換可能な配位子を有するルテニウム錯体であれば、特に上記に限定されるものではない。
本発明の一般式（１）で表されるルテニウム化合物を製造する方法としては、原料となるルテニウム錯体にホスフィン配位子（Ｐｘ）及びジアミン配位子（ＤＩＡＭＩＮＥ）を反応させて得ることができるものであれば、出発原料、ホスフィン配位子（Ｐｘ）及びジアミン配位子（ＤＩＡＭＩＮＥ）の種類や反応順序等に特に制約はない。
これらの製造方法の中でも、Ａｎｇｅｗ．Ｃｈｅｍ．Ｉｎｔ．Ｅｄ．，３７，１７０３（１９９８）に記載の方法に準拠した２価ルテニウム錯体を用いる方法が簡便である。例えば、２価のルテニウムハライド錯体とホスフィン配位子（Ｐｘ）の溶媒溶液を加熱後、光学活性ジアミン（ＤＩＡＭＩＮＥ）を加えることで、一般式（１）中、ｎ１＝１、（Ｘ）（Ｙ）＝Ｈａｌ_２であるルテニウム化合物を製造することができる（Ｈａｌはハロゲン原子イオンを表す）。
すなわち、出発原料の２価のルテニウムハライド錯体とホスフィン配位子との反応は、これらの混合物を溶媒中、加熱することで行われ、ルテニウムにホスフィン配位子が配位結合したホスフィン−ルテニウムハライド錯体を得ることができる。
ホスフィン配位子の使用量は、ルテニウム−ハライド錯体１モルに対して、単座の場合は、通常２〜３倍モル、好ましくは２倍モルであり、２座の場合は、通常１〜２倍モル、好ましくは等モルである。
この反応に用いられる溶媒としては、例えば、トルエン、キシレン等の芳香族炭化水素系溶媒；ペンタン、ヘキサン等の脂肪族炭化水素系溶媒；塩化メチレン等のハロゲン化炭化水素系溶媒；ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）等のエーテル系溶媒；メタノール、エタノール、２−プロパノール、ブタノール、ベンジルアルコール等のアルコール系溶媒；アセトニトリル等のニトリル系溶媒；Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）等の非プロトン性極性有機溶媒等が挙げられる。
また、溶媒の使用量は、基質１ｇに対して、通常、１ｍｌ〜１００ｍｌ程度、好ましくは１ｍｌ〜１０ｍｌの範囲である。反応は０℃〜２００℃の間、好ましくは室温〜１００℃の範囲で行われる。
次いで、得られたホスフィン−ルテニウムハライド錯体に、一般式（２）で表わされるジアミン化合物を反応させることにより、一般式（１）で表されるルテニウム化合物（ｎ１＝１、（Ｘ）（Ｙ）＝Ｈａｌ_２）を得ることができる。この反応は、前記のホスフィン−ルテニウムハライド錯体の溶媒溶液にこれと等量のアミン配位子を溶解し、−１００℃〜２００℃、好ましくは−１０℃〜５０℃の温度範囲で反応させることにより、対応する一般式（１）で表されるルテニウム化合物（ｎ１＝１、（Ｘ）（Ｙ）＝Ｈａｌ_２）を得ることができる。
また、ホスフィン−ルテニウム錯体を一旦単離した後、前記と同様の条件下にジアミン化合物を作用させることによっても、目的とする一般式（１）で表されるルテニウム化合物を得ることができる。
さらに、得られたアミン−ホスフィン−ルテニウムハライド錯体に、溶媒中、塩基を反応させることによって、一般式（１：ｎ１１、（Ｘ）（Ｙ）＝Ｈ_２）で表されるアミン−ホスフィン−ルテニウムヒドリド錯体を得ることができる。
用いられる溶媒としては、トルエン、キシレン等の芳香族炭化水素系溶媒；ペンタン、ヘキサン等の脂肪族炭化水素系溶媒；塩化メチレン等のハロゲン化炭化水素系溶媒；ジエチルエーテル、ＴＨＦ等のエーテル系溶媒；メタノール、エタノール、２−プロパノール、ブタノール、ベンジルアルコール等のアルコール系溶媒；アセトニトリル等のニトリル系溶媒；ＤＭＦ、Ｎ−メチルピロリドン、ＤＭＳＯ等の非プロトン性極性有機溶媒；等が挙げられる。
ここで用いられる塩基としては、例えば、ＫＯＨ、ＫＯＣＨ_３、ＫＯＣＨ（ＣＨ_３）_２、ＫＣ_１０Ｈ_８、Ｋ_２ＣＯ_３、ＮａＯＨ、ＮａＯＣＨ_３、ＮａＯＣＨ（ＣＨ_３）_２、Ｎａ_２ＣＯ_３、ＬｉＯＨ、ＬｉＯＣＨ_３、ＬｉＯＣＨ（ＣＨ_３）_２、Ｃａ（ＯＨ）_２、ＣａＣＯ_３、Ｍｇ（ＯＥｔ）_２等のアルカリ、アルカリ土類金属の水酸化物、塩あるいは４級アンモニウム塩等が挙げられる。
溶媒の使用量としては、基質１ｇに対して、通常、１ｍｌ〜１００ｍｌ程度、好ましくは１ｍｌ〜１０ｍｌの範囲である。反応は、通常、−１００℃〜２００℃の間、好ましくは−１０℃〜５０℃の範囲で行われる。また、塩基の使用量は、触媒１モルに対して、２モル〜５０，０００倍モル、好ましくは２〜５、０００倍モルの範囲である。
また、アミン−ホスフィン−ルテニウムヒドリド錯体は、０価のルテニウム錯体に、ホスフィン配位子及びジアミン配位子の等量混合物を溶媒中、水素雰囲気下に作用させることによっても得ることができる。
用いられる０価のルテニウム錯体としては、例えば、Ｒｕ（ＣＯＤ）（ＣＯＴ）が挙げられる。ここで、ＣＯＤは１，３−シクロオクタジエンを、ＣＯＴは１，３，５−シクロオクタトリエンをそれぞれ表す。
この反応に用いられる溶媒としては、トルエン、キシレン等の芳香族炭化水素系溶媒；ペンタン、ヘキサン等の脂肪族炭化水素系溶媒；塩化メチレン等のハロゲン化炭化水素系溶媒；ジエチルエーテル、ＴＨＦ等のエーテル系溶媒；メタノール、エタノール、２−プロパノール、ブタノール、ベンジルアルコール等のアルコール系溶媒；アセトニトリル等のニトリル系溶媒；ＤＭＦ、Ｎ−メチルピロリドン、ＤＭＳＯ等の非プロトン性極性有機溶媒；等が挙げられる。
溶媒の使用量は、基質１ｇに対して、通常、１ｍｌ〜１００ｍｌ程度、好ましくは１ｍｌ〜１０ｍｌの範囲である。水素ガスの圧力としては、通常、１〜２００気圧、好ましくは３〜５０気圧の範囲である。反応は、通常、０℃〜２００℃の間、好ましくは室温〜１００℃の温度範囲で行われる。
以上のようにして合成される一般式（１）で表されるルテニウム化合物は、一般式（８）：Ｒａ−ＣＯ−ＣＨ（Ｒｂ）−Ｒｃで表されるα−アミノケトン類の不斉水素化触媒として有用である。
一般式（８）において、Ｒａ、Ｒｃは、それぞれ独立して水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいシクロアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアラルキル基又は置換基を有していてもよいアリール基を表す。
前記Ｒａ、Ｒｃの置換基を有していてもよい直鎖もしくは分岐のアルキル基のアルキル基としては、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ−ブチル、ｔ−ブチル、ペンチル、イソペンチル、ネオペンチル、ｔ−ペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル、ドデシル基等の炭素数１〜２０のアルキル基を例示することができる。
前記置換基を有していてもよい直鎖もしくは分岐のアルケニル基のアルケニル基としては、ビニル、１−プロペニル、２−プロペニル、１−イソプロペニル、１−ブテニル、１−イソプロペニル、２−ブテニル、３−ブテニル、１，３−ブタジエニル、１−ペンテニル、２−ペンテニル、３−ペンテニル基等の炭素数２〜２０のアルケニル基を例示することができる。前記置換基を有していてもよいシクロアルキル基のシクロアルキル基としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基等の炭素数３〜８のシクロアルキル基を挙げることができる。前記置換基を有していてもよいアラルキル基のアラルキル基としては、例えば、ベンジル、α−メチルベンジル、α，α−ジメチルベンジル、α−エチルベンジル基等の炭素数７〜２０のアラルキル基を挙げることができる。
また、前記置換基を有していてもよいアリール基のアリール基としては、フェニル、１−ナフチル、２−ナフチル基等の芳香族炭化水素基；フラニル、ピラニル、ジオキソラニル基等の含酸素複素環基；チエニル基等の含イオウ複素環基；ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、トリアゾリル、チアゾリル、イソチアゾリル、ピリジル、ピラダジル、ピラジニル、ベンゾイミダゾリル、ベンゾピラゾリル、ペンゾチアゾリル、キノリル、アントラニル、インドリル、フェナントロニリル基等の飽和若しくは不飽和の含窒素複素環基；等を例示することができる。
さらにこれらの基は、任意の位置に１ないしは２個以上の同一若しくは相異なる置換基を有していてもよい。かかる置換基としては、例えば、ヒドロキシ基；カルボキシル基；アミノ基；メチルアミノ、エチルアミノ、プロピルアミノ、アセチルアミノ、ベンゾイルアミノ、ベンジルアミノ基等のモノ置換アミノ基；ジメチルアミノ、ジエチルアミノ、メチルエチルアミノ、ジフェニルアミノ、ジベンジルアミノ、フェニルメチルアミノ、アセチルメチルアミノ基等のジ置換アミノ基；メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ−ブチル、ｔ−ブチル、ペンチル、ヘキシル基等のアルキル基；メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、ｔ−ブトキシ基等のアルコキシ基；メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、ｔ−ブトキシカルボニル基等のアルコキシカルボニル基；ベンゼン環の任意の位置に置換基を有していてもよいフェニル基；（ナフタレン環の任意の位置に置換基を有していてもよい）１−ナフチル、２−ナフチル基等のナフチル基；、フラン、ピラン、ジオキソラン、ジオキサン、ピロール、チオフェン、イミダゾール、ピラゾール、オキサゾール、イソオキサゾール、トリアゾール、チアゾール、イソチアゾール、ピリジン、ピリダジン、ピラジン、ベンゾイミダゾール、ベンゾピラゾール、ベンゾチアゾール、キノリン等の複素環基（これらの基は、任意の位置に置換基を有していてもよい）；フッ素、塩素、臭素等のハロゲン原子；等が挙げられる。
Ｒｂは、下記一般式（９）、（１０）、（１１）のいずれかの基を表す。
（９）　Ｒ^６ＣＯ（Ｒ^７）Ｎ−
（１０）Ｒ^６ＣＯ（Ｒ^８ＣＯ）Ｎ−
（１１）Ｒ^６Ｒ^７Ｎ−
ここで、Ｒ^６、Ｒ^７及びＲ^８は、同一又は相異なって、水素原子、ホルミル基、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいシクロアルキル基、置換基を有していてもよいシクロアルコキシ基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアラルキルオキシ基、置換基を有していてもよいアリール基又は置換基を有していてもよいアリールオキシ基をそれぞれ表す。また、Ｒ^６とＲ^７又はＲ^６とＲ^８とが結合して５〜８員の含窒素ヘテロ環を形成してもよい。
前記Ｒ^６、Ｒ^７及びＲ^８の具体例としては、水素原子；メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、ｓｅｃ−ブチル、ｔ−ブチル、ｎ−ペンチル、イソペンチル、ネオペンチル、ｔ−ペンチル、ｎ−ヘキシル、ｎ−ヘプチル基等の炭素数１〜１０のアルキル基；シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基等の炭素数３〜８のシクロアルキル基；フェニル基、２−メチルフェニル、２−エチルフェニル、２−イソプロピルフェニル、２−ｔ−ブチルフェニル、２−メトキシフェニル、２−クロロフェニル、２−ビニルフェニル、３−メチルフェニル、３−エチルフェニル、３−イソプロピルフェニル、３−メトキシフェニル、３−クロロフェニル、３−ビニルフェニル、４−メチルフェニル、４−エチルフェニル、４−イソプロピルフェニル、４−ｔ−ブチルフェニル、４−ビニルフェニル、クメニル、メシチル、キシリル、１−ナフチル、２−ナフチル、アントリル、フェナントリル、インデニル基等の置換基を有していてもよいアリール基；
ベンジル、４−クロロベンジル、α−メチルベンジル基等の置換基を有していてもよい炭素数７〜２０のアラルキル基；ビニル、アリル、クロチル基等の炭素数２〜１０のアルケニル基；メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｔ−ブトキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ｔ−ペンチルオキシ、ヘキシルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、ヘプチルオキシ基等の炭素数１〜１０のアルコキシ基；シクロプロピル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロクチル基等の炭素数３〜８のシクロアルコキシ基；フェノキシ基、２−メチルフェノキシ、２−エチルフェノキシ、２−イソプロピルフェノキシ、２−ｔ−ブチルフェノキシ、２−メトキシフェノキシ、２−クロロフェノキシ、２−ビニルフェノキシ、３−メチルフェノキシ、３−エチルフェノキシ、３−イソプロピルフェノキシ、３−メトキシフェノキシ、３−クロロフェノキシ、３−ビニルフェノキシ、４−メチルフェノキシ、４−エチルフェノキシ、４−イソプロピルフェノキシ、４−ｔ−ブチルフェノキシ、４−ビニルフェノキシ、１−ナフトキシ、２−ナフトキシ基等のアリールオキシ基；及び、ベンジルオキシ、４−クロロベンジルオキシ、４−メチルベンジルオキシ基等の置換基を有していてもよい炭素数７〜２０のアラルキルオキシ基；等が挙げられる。
また、Ｒ^６とＲ^７又はＲ^６とＲ^８とが結合して、含窒素ヘテロ環を形成する場合の複素環の例としては、スクシンイミド、マレイミド、フタルイミド、１，２−シクロヘキサンカルボキサミド、２，４，６−トリオキソピペリジン、α−ピリドン等のイミド類等を挙げることができる。
Ｒｂの具体例としては、アセチルアミノ、プロピオニルアミノ、プロピルカルボニルアミノ、ベンゾイルアミノ、４−メチルベンゾイルアミノ、２−クロロベンゾイルアミノ、３−メトキシベンゾイルアミノ、２−クロロ−４−メトキシベンゾイルアミノ基等のアシルアミノ基；ジベンゾイルアミノ基等のジアシルアミノ基；Ｎ−アセチルＮ−メチルアミノ、Ｎ−ベンゾイル−Ｎ−メチルアミノ、Ｎ−アセチル−Ｎ−エチルアミノ、Ｎ−ベンゾイル−Ｎ−エチルアミノ、Ｎ−アセチル−Ｎ−ベンジルアミノ、Ｎ−ベンゾイル−Ｎ−ベンジルアミノ、４−メチルベンゾイルメチルアミノ基等のＮ−アルキル−Ｎ−アシルアミノ基；Ｎ−アセチル−Ｎ−フェニルアミノ、Ｎ−アセチル−Ｎ−４−メチルファニルアミノ、Ｎ−アセチル−Ｎ−２−クロロフェニルアミノ、Ｎ−アセチル−Ｎ−２，４−ジクロロフェニルアミノ、Ｎ−ベンジル−Ｎ−フェニルアミノ、Ｎ−ベンジル−Ｎ−４−メチルフェニルアミノ、Ｎ−ベンジル−Ｎ−２−クロロフェニルアミノ、Ｎ−ベンジル−Ｎ−２，４−ジクロロフェニルアミノ基等のＮ−アリール−Ｎ−アシルアミノ基；
Ｎ−メトキシカルボニル−Ｎ−メチルアミノ、Ｎ−エトキシカルボニル−Ｎ−メチルアミノ、Ｎ−メトキシカルボニル−Ｎ−エチルアミノ、Ｎ−エトキシカルボニル−Ｎ−エチルアミノ、Ｎ−プロポキシカルボニル−Ｎ−プロピルアミノ、Ｎ−イソプロポキシカルボニル−Ｎ−メチルアミノ、Ｎ−ブトキシカルボニル−Ｎ−エチルアミノ、Ｎ−ｔ−ブトキシカルボニル−Ｎ−ブトキシアミノ基等のＮ−アルコキシカルボニル−Ｎ−アルキルアミノ基；Ｎ−メトキシカルボニル−Ｎ−メチルアミノ、Ｎ−エトキシカルボニル−Ｎ−メチルアミノ、Ｎ−メトキシカルボニル−Ｎ−エチルアミノ、Ｎ−エトキシカルボニル−Ｎ−エチルアミノ、Ｎ−プロポキシカルボニル−Ｎ−プロピルアミノ、Ｎ−イソプロポキシカルボニル−Ｎ−メチルアミノ、Ｎ−ブトキシカルボニル−Ｎ−エチルアミノ、Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ、Ｎ−ｔ−ブトキシカルボニル−Ｎ−ブトキシアミノ基等のＮ−アルコキシカルボニル−Ｎ−アルキルアミノ基；
Ｎ−メトキシカルボニル−Ｎ−フェニルアミノ、Ｎ−エトキシカルボニル−Ｎ−フェニルアミノ、Ｎ−プロポキシカルボニル−Ｎ−フェニルアミノ、Ｎ−イソプロポキシカルボニル−Ｎ−フェニルアミノ、Ｎ−ブトキシカルボニル−Ｎ−フェニルアミノ、Ｎ−ｔ−ブトキシカルボニル−Ｎ−フェニルアミノ基等のＮ−アルコキシカルボニル−Ｎ−アリールアミノ基；Ｎ−メチル−メチルスルホニルアミノ、Ｎ−エチル−メチルスルホニルアミノ、Ｎ−プロピル−メチルスルホニルアミノ、Ｎ−イソプロピル−メチルスルホニルアミノ、Ｎ−ベンジル−メチルスルホニルアミノ、Ｎ−ブチル−メチルスルホニルアミノ、Ｎ−メチル−エチルスルホニルアミノ、Ｎ−エチル−エチルスルホニルアミノ、Ｎ−メチル−プロピルスルホニルアミノ、Ｎ−エチル−プロピルスルホニルアミノ、Ｎ−メチル−イソプロピルスルホニルアミノ、Ｎ−エチル−イソプロピルスルホニルアミノ、Ｎ−メチル−ブチルスルホニルアミノ、Ｎ−エチル−ブチルスルホニルアミノ、Ｎ−メチル−ｔ−ブチルスルホニルアミノ、Ｎ−エチル−ｔ−ブチルスルホニルアミノ、Ｎ−メチル−フェニルスルホニルアミノ、Ｎ−エチル−フェニルスルホニルアミノ、Ｎ−ベンジル−フェニルスルホニルアミノ、Ｎ−メチル−４−メチルフェニルスルホニルアミノ、Ｎ−ベンジル−４−メチルフェニルスルホニルアミノ、Ｎ−エチル−２−クロロフェニルスルホニルアミノ、Ｎ−メチル−２，４−ジクロロフェニルスルホニルアミノ基等のＮ−アルキル−アルキルスルホニルアミノ基又はＮ−アルキル−置換フェニルスルホニルアミノ基；
Ｎ−フェニル−メチルスルホニルアミノ、Ｎ−フェニル−エチルスルホニルアミノ、Ｎ−フェニル−プロピルスルホニルアミノ、Ｎ−フェニル−イソプロピルスルホニルアミノ、Ｎ−フェニル−ブチルスルホニルアミノ、Ｎ−フェニル−ｔ−ブチルスルホニルアミノ、Ｎ−フェニル−フェニルスルホニルアミノ、Ｎ−フェニル−４−メチルフェニルスルホニルアミノ、Ｎ−フェニル−２−クロロフェニルスルホニルアミノ、Ｎ−フェニル−２，４−ジクロロフェニルスルホニルアミノ基等のＮ−アリール−アルキルスルホニルアミノ基又はＮ−アリール−置換フェニルスルホニルアミノ基；
スクシンイミドイル、マレイミドイル、フタルイミドイル、３−メチルフタルイミドイル、４−メチルフタルイミドイル、４−ｎ−ブチルフタルイミドイル、４−クロロフタルイミドイル、テトラメチルフタルイミドイル、１，２−シクロヘキサンカルボキサミドイル、２，４，６−トリオキソピペリジン−１−イル、α−ピリドン−１−イル基等のイミド基；等を挙げることができる。
この不斉水素化反応において用いる一般式（１）で表されるルテニウム錯体化合物の使用量は反応容器や経済性によって異なるが、反応基質であるカルボニル化合物１モルに対して、１／５０〜１／２，０００，０００倍モル、好ましくは１／５００〜１／５００，０００倍モルの範囲である。
一般式（１）で表されるルテニウム化合物のうち、Ｘ，Ｙが水素（ヒドリド）である化合物を用いる場合は、ケトン類及び所望により塩基を添加して、水素ガス雰囲気下又は水素供与性化合物の存在下に攪拌することにより、カルボニル化合物の水素化を行うことができる。
Ｘ，Ｙが、水素（ヒドリド）以外の基である化合物を用いる場合には、塩基の存在下、ケトン類と混合後、水素圧をかけるか、又は水素供与性化合物の存在下に攪拌することにより、ケトン類の水素化を行うことができる。添加する塩基の量は、ルテニウム錯体化合物１モルに対し、２〜５００，０００倍モル、好ましくは、２〜５，０００倍モルの範囲である。
ここで用いられる塩基としては、一般式（１３）：（Ｍｂ）_ｐ（Ｚ）_ｑ（式中、Ｍｂは、アルカリ金属又はアルカリ土類金属イオンを表し、Ｚは、水酸基、アルコキシ基、芳香族アニオン、メルカプト基、アルキルチオ基又は炭酸イオンを表し、ｐ、ｑは１、２又は３を表す。）で表される化合物であるのが好ましい。
かかる塩基の具体例としては、ＫＯＨ、ＫＯＣＨ_３、ＫＯＣＨ（ＣＨ_３）_２、ＫＣ_１０Ｈ_８、Ｋ_２ＣＯ_３、ＮａＯＨ、ＮａＯＣＨ_３、ＮａＯＣＨ（ＣＨ_３）_２、Ｎａ_２ＣＯ_３、ＬｉＯＨ、ＬｉＯＣＨ_３、ＬｉＯＣＨ（ＣＨ_３）_２、Ｃａ（ＯＨ）_２、ＣａＣＯ_３、Ｍｇ（ＯＥｔ）_２等のアルカリ、アルカリ土類金属の水酸化物、塩あるいは４級アンモニウム塩等が挙げられる。
また、本発明においては、ルテニウム化合物の原料となる▲１▼ルテニウム錯体（又はルテニウム塩）、リン化合物（Ｐｘ）及びジアミン化合物（ＤＩＡＭＩＮＥ）とを別々に反応系に添加、又は▲２▼ホスフィン−ルテニウム錯体（又はルテニウム塩）及びジアミン化合物（ＤＩＡＭＩＮＥ）とを別々に反応系に添加して、必要に応じて塩基を添加してルテニウム化合物を生成させた後、該ルテニウム化合物を単離することなく、そこへ基質を添加することにより、ｉｎ　ｓｉｔｕで不斉水素化反応を行わせることもできる。
不斉水素化反応に用いられる溶媒としては、基質及び触媒を可溶化するものであれば特に制限はなく、適宜選択して用いることができる。例えば、トルエン、キシレン等の芳香族炭化水素溶媒；ペンタン、ヘキサン等の脂肪族炭化水素溶媒；塩化メチレン等のハロゲン含有炭化水素溶媒；ジエチルエーテル、ＴＨＦ、１，２−ジメトキシエタン等のエーテル系溶媒；メタノール、エタノール、２−プロパノール、ブタノール、ベンジルアルコール等のアルコール系溶媒；アセトニトリル、ＤＭＦ、Ｎ−メチルピロリドン、ＤＭＳＯ等のヘテロ原子を含む極性有機溶媒；及びこれらの２種以上の混合物からなる混合溶媒を用いることができる。これらの中でも、反応生成物がアルコール化合物であることから、アルコール系溶媒が特に好適である。
溶媒の使用量は反応基質の溶解度及び経済性により定められる。例えば、２−プロパノールの場合、基質濃度は、無溶媒に近い状態〜１００重量％以上の高希釈条件で反応を行うことができ、通常は、２０〜５０重量％で用いることが望ましい。
水素化反応における水素の圧力は、通常１〜２００気圧の範囲、好ましくは３〜５０気圧の範囲である。反応は、通常−５０〜１００℃の温度範囲で行うことが好ましいが、２５〜４０℃の室温付近で実施することができる。反応時間は反応基質濃度、温度、圧力等の反応条件によって異なるが数分から数日で反応は完結する。
この発明におけるケトン化合物類の水素化反応は反応形式がバッチ式においても連続式においても実施することができる。
発明を実施する為の最良の形態：
以下、実施例により、更に本発明を詳細に説明する。尚、各実施例における物性の測定に用いた装置は次の通りである。
ＮＭＲスペクトル：Ｖａｒｉａｎ　ＧＥＭＩＮＩ−３００（バリアン社製）
旋光度：ＪＡＳＣＯ　ＤＩＰ−３６０（日本分光（株）製）
高速液体クロマトグラフィー：ＬＣ−１０Ａｄｖｐ、ＳＰＤ−１０Ａｖｐ
（島津製作所（株）製）
また、以下に示す化学式において、＊は不斉炭素原子であることを表す。
（参考例１）（１Ｓ，２Ｓ）−Ｎ−ベンジルオキシカルボニル−１，２−ジフェニル−１，２−エタンジアミンの合成

（１Ｓ，２Ｓ）−１，２−ジフェニル−１，２−エタンジアミン１３．８５ｇ（６５．２ｍｍｏｌ）のクロロホルム３００ｍｌ溶液に、クロロ炭酸ベンジル３．３ｍｌ（２１．７ｍｍｏｌ）を０℃でゆっくりと滴下し、滴下終了後、更に室温で１９時間攪拌した。反応液に水と濃塩酸１．８ｍｌを加え、クロロホルムで抽出を数回行った。クロロホルム層を無水硫酸マグネシウムで乾燥し、減圧濃縮して得られた残留物をシリカゲルクロマトグラフィー（溶媒クロロホルム／メタノール）にて精製して、標記化合物を７．１２ｇ得た。収率９５％
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δｐｐｍ）：７．５−７．３（ｍ，１５Ｈ），６．６（ｄ，１Ｈ），５．１−４．８（ｍ，３Ｈ），４．４（ｄ，１Ｈ）［α］_Ｄ ^２３．１＝−１０．７５°（ｃ＝１．００，ＣＨＣｌ_３）
また、水層を強アルカリにした後、クロロホルムで抽出し、クロロホルム層を濃縮することにより（１Ｓ，２Ｓ）−１，２−ジフェニル−１，２−エタンジアミン７．７８ｇを回収した。
（参考例２）（１Ｓ，２Ｓ）−Ｎ−イソプロピル−１，２−ジフェニル−１，２−ジアミノエタンの合成

（１Ｓ，２Ｓ）−Ｎ−ベンジルオキシカルボニル−１，２−ジフェニル−１，２−ジアミノエタン１．０ｇ（２．８９ｍｍｏｌ）をエタノール２０ｍｌとアセトン５ｍｌの混合溶媒に溶解させ、０℃に冷却した後、酢酸５ｍｌを加えた。この溶液に、水素化ホウ素ナトリウム０．６８ｇ（１８ｍｍｏｌ）を、０℃で撹拌しながら、数回に分けて加えた。反応液を室温でさらに１時間撹拌した後、水を加えて反応を停止させた。反応混合物をエバポレータで減圧濃縮して溶媒を留去した後、クロロホルム抽出を数回行なった。クロロホルム層を合わせて、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物を６規定塩酸に懸濁させ、不溶結晶をろ取した。この結晶を５％水酸化ナトリウム水溶液に懸濁させ、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥した後、減圧濃縮することにより、（１Ｓ，２Ｓ）−Ｎ−ベンジルオキシカルボニル−Ｎ’−イソプロピル−１，２−ジフェニル−１，２−ジアミノエタン１．０ｇを得た。収率８９％
上記で得た（１Ｓ，２Ｓ）−Ｎ−ベンジルオキシカルボニル−Ｎ’−イソプロピル−１，２−ジフェニル−１，２−ジアミノエタン１．０ｇ（２．５７ｍｍｏｌ）をメタノール５０ｍｌに溶解し、そこへ、５％パラジウムカーボン（Ｐｄ−Ｃ）３．５ｇを加えた。反応系内を十分に脱気し、完全に水素置換（常圧）を行なって、室温で２時間撹拌した。反応混合物から不溶物をろ別した後、ろ液を濃縮した。得られた残留物にジエチルエーテルを徐々に加えて結晶を析出させた。析出結晶をろ取し、乾燥することにより、標記化合物０．５２ｇを得た。収率７９％
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δｐｐｍ）：７．１（ｍ，１０Ｈ）、４．０（ｄ，１Ｈ）、３．８（ｄ，１Ｈ）、２．５（ｍ，１Ｈ）、１．７（ｂｓ，３Ｈ）、１．０（ｄ，６Ｈ）［α］_Ｄ ^２４＝−５３．１°（ｃ＝３．５３，ＥｔＯＨ）
（参考例３）（１Ｓ，２Ｓ）−Ｎ−（４−ベンジルオキシベンジリデン）−Ｎ’−ベンジルオキシカルボニル−１，２−ジフェニル−１，２−エタンジアミンの合成

（１Ｓ，２Ｓ）−Ｎ−ベンジルオキシカルボニル−１，２−ジフェニル−１，２−エタンジアミン１．５３ｇ（４．４２ｍｍｏｌ）のクロロホルム３０ｍｌ溶液に、４−ベンジルオキシベンズアルデヒド０．９３７ｇ（４．４２ｍｍｏｌ）とモレキュラーシーブ４Ａを添加し、室温で１９時間攪拌した。その後、反応液から不溶物をろ別し、ろ液を濃縮した。得られた残留物にエーテルを加えて、結晶を析出させた。析出結晶をろ取し、洗浄及び乾燥することにより、標記化合物２．０１ｇを得た。収率８４％
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δｐｐｍ）：７．８（ｓ，１Ｈ），７．６（ｄ，２Ｈ），７．５−７．１（ｍ，２０Ｈ），７．０（ｄ，２Ｈ），６．３（ｄ，１Ｈ），５．３（ｂｒ，１Ｈ），５．１（ｓ，２Ｈ），５．０（ｂｒｓ，２Ｈ），４．６（ｂｒ，１Ｈ）
［α］_Ｄ ^２３．１＝−１０．７５°（ｃ＝１．００，ＣＨＣｌ_３）
（実施例１）（１Ｓ，２Ｓ）−Ｎ−（４−ヒドロキシベンジル）−１，２−ジフェニル−１，２−エタンジアミンの合成

メタノールとテトラヒドロフランの１：１混合溶液３０ｍｌに、（１Ｓ，２Ｓ）−Ｎ−（４−ベンジルオキシベンジリデン）−Ｎ’−ベンジルオキシカルボニル−１，２−ジフェニル−１，２−エタンジアミン７．４５ｇ（１３．８ｍｍｏｌ）と５％パラジウムカーボン３．０ｇを加え、脱気した後、反応系を水素置換して、室温で１８時間撹拌した。その後、反応混合物中の不溶物をハイフローろ過により除去し、ろ液を濃縮することによって標記化合物を２．１３ｇ得た。収率４８％
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δｐｐｍ）：７．６−７．１（ｍ，１０Ｈ），７．０（ｄ，２Ｈ），６．７（ｄ，２Ｈ），４．０（ｄ，１Ｈ），３．７（ｄ，１Ｈ），３．６（ｄ，１Ｈ），３．４（ｄ，１Ｈ）
［α］_Ｄ ^２３．１＝−１０．７５°（ｃ＝１．００，ＣＨＣｌ_３）
（実施例２）（１Ｓ，２Ｓ）−Ｎ−（４−ベンジルオキシベンジル）−１，２−ジフェニル−１，２−エタンジアミンの合成

（１Ｓ，２Ｓ）−Ｎ−（４−ヒドロキシベンジル）−１，２−ジフェニル−１，２−エタンジアミン０．３２ｇ（１．０１ｍｍｏｌ）の無水Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）溶液５ｍｌに、水素化ナトリウム２４．０ｍｇ（１．０１ｍｍｏｌ）を加えて、室温で２時間攪拌したのち、反応混合物にベンジルブロミド１７１ｍｇ（１．０１ｍｍｏｌ）を添加して、さらに室温で４時間撹拌した。反応液を水にあけ、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥したのち、溶媒を減圧留去して得られた黄色粘稠オイルをシリカゲルクロマトグラフィー（溶媒：クロロホルム／メタノール）にて精製し、標記化合物（以下、「ＤＩＡＭＩＮＥ（２〜１）」という。）を２１２ｍｇ得た。収率５３％
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，δｐｐｍ）：７．５−７．１（ｍ，１７Ｈ），６．９（ｄ，２Ｈ），５．０（ｓ，２Ｈ），４．０（ｄ，１Ｈ），３．７（ｄ，１Ｈ），３．６（ｄ，１Ｈ），３．４（ｄ，１Ｈ）
［α］_Ｄ ^２０＝１７．９°（ｃ＝０．２８，ＥｔＯＨ）
（実施例３）
（１Ｒ，２Ｒ）−（Ｎ−（４−ベンジルオキシベンジル））ジフェニルエチレンジアミンの合成
（１Ｒ，２Ｒ）−ジフェニルエチレンジアミン９．４３ｇ（４４．４ｍｍｏｌ）の無水クロロホルム溶液１００ｍｌに４−ベンジルオキシベンジルクロリド３．４５ｇ（１４．８ｍｍｏｌ）を０℃で加えて、さらに４２時間加熱還流した。反応終了後、ろ過により内容物から（１Ｒ，２Ｒ）−ジフェニルエチレンジアミン塩酸塩をろ別した。ろ液をロータリーエバポレーターにより溶媒留去後、粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝８：１）により精製する事で目的とする（１Ｒ，２Ｒ）−（４−ベンジルオキシベンジル）ジフェニルエチレンジアミンを３．７６ｇ（収率６４％）で得る事ができた。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：２．３（３Ｈ，ｂｓ），３．４（１Ｈ，ｄ），３．６（１Ｈ，ｄ），３．７（１Ｈ，ｄ），４．０（１Ｈ，ｄ），５．０（２Ｈ，ｓ），６．９（２Ｈ，ｓ），７．２（１７Ｈ，ｍ）
（実施例４）
（１Ｒ，２Ｒ）−（Ｎ−（３，５−ジメトキシベンジル））ジフェニルエチレンジアミンの合成
（１Ｒ，２Ｒ）−ジフェニルエチレンジアミン　１．２７ｇ（６．００ｍｍｏｌ）の無水クロロホルム溶液１０ｍｌに３，５−ジメトキシベンジルクロリド３７３ｍｇ（２．００ｍｍｏｌ）を加えて、室温で１７時間攪拌した後、ろ過により内容物から（１Ｒ，２Ｒ）−ジフェニルエチレンジアミン塩酸塩をろ別した。ろ液をロータリーエバポレーターにより溶媒留去後、粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）により精製する事で目的とする（１Ｒ，２Ｒ）−（３，５−ジメトキシベンジル）ジフェニルエチレンジアミン（以下、「ＤＩＡＭＩＮＥ（２−２）」という。）を１８０ｍｇ（収率２５％）で得る事ができた。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．８（３Ｈ，ｂｓ），３．４（１Ｈ，ｄ），３．６（１Ｈ，ｄ），３．７（６Ｈ，ｓ），３．７（１Ｈ，ｄ），４．０（１Ｈ，ｄ），６．４（２Ｈ，ｍ），７．２（１３Ｈ，ｍ）
同様にして合成したジアミン化合物を第１表に示す。

（実施例５）［（Ｒ）−ｔｏｌ−Ｂｉｎａｐ］Ｒｕ［ＤＩＡＭＩＮＥ（２−１）］Ｃｌ_２の合成

Ｏｒｇ．Ｓｙｎｔｈ．，７１，１（１９９３）に記載の方法に従い、｛［（Ｒ）−ｔｏｌ−Ｂｉｎａｐ］ＲｕＣｌ_２｝のＤＭＦ付加物を得た。
次いで、アルゴン置換した１００ｍｌシュレンク管に、実施例２で合成したＤＩＡＭＩＮＥ（２−１）１００ｍｇ（０．２５ｍｍｏｌ）、｛［（Ｒ）−ｔｏｌ−Ｂｉｎａｐ］ＲｕＣｌ_２｝のＤＭＦ付加物２５０ｍｇ（０．２６ｍｍｏｌ）及びクロロホルム２０ｍｌを仕込み、室温で３０分間攪拌した。その後、その温度で減圧濃縮して析出した粗結晶をヘキサンで２回洗浄して、標記の化合物を３５０ｍｇ得た（定量的）。
この化合物の^３１Ｐ−ＮＭＲ（Ｃ_６Ｄ_６）スペクトルを測定した結果、４８．８、４６．３、３７．０、３３．６ｐｐｍにピークが観測された。
（実施例６）［（Ｓ）−Ｂｉｎａｐ］Ｒｕ［ＤＩＡＭＩＮＥ（２−２）］Ｃｌ_２の合成
Ｏｒｇ．Ｓｙｎｔｈ．，７１，１（１９９３）に記載の方法に従い、｛［（Ｓ）−ＢＩＮＡＰ］ＲｕＣｌ_２｝のＤＭＦ付加物を得た。
ついで、アルゴン置換した１００ｍｌシュレンクに、実施例４で合成したＤＩＡＭＩＮＥ（２−２）１００ｍｇ（０．２７６ｍｍｏｌ）、｛［（Ｓ）−ＢＩＮＡＰ］ＲｕＣｌ_２｝のＤＭＦ付加物２５０ｍｇ（０．２６６ｍｍｏｌ）、およびクロロホルム２０ｍｌを仕込み、室温で３０分攪拌した。その後、その温度で減圧濃縮して析出した粗結晶をヘキサンで２回洗浄して、目的の触媒を３０７ｍｇ得た。（定量的）
この化合物の３１Ｐ−ＮＭＲ（ＣＤＣｌ_３）スペクトルを測定した結果、３６．１、３８．６、４７．７、５０．１ｐｐｍにピークが観測された。
（実施例７）光学活性−１−フェニル−２−（Ｎ−メチル−Ｎ−ベンゾイルアミノ）−１−プロパノールの合成（１）

アルゴン雰囲気下、簡易型オートクレーブ（容量１００ｍｌ）中で｛［（Ｓ）−ｔｏｌ−Ｂｉｎａｐ］ＲｕＣｌ_２｝（ｄｍｆ）ｎ（５ｍｇ，０．００５ｍｍｏｌ）、ＤＩＡＭＩＮＥ（２−１）２ｍｇ（０．００５ｍｍｏｌ）、０．５Ｍのカリウムｔ−ブトキシドの２−プロパノール溶液（０．３ｍｌ）、及び１−フェニル−２−（Ｎ−メチル−Ｎ−ベンゾイルアミノ）プロパン−１−オン１３４ｍｇ（０．５ｍｍｏｌ）の２−プロパノール３ｍｌ溶液を室温で添加した。反応系内を脱気した後、水素を１２気圧まで圧入し、室温にて２時間攪拌した。反応混合物をシリカゲルショートカラムクロマトグラフィー（溶離液：ジエチルエーテル）により精製することにより、標記化合物を得た（定量的）。
得られた１−フェニル−２−（Ｎ−メチル−Ｎ−ベンゾイルアミノ）−１−プロパノールの光学純度及びジアステレオ純度を、ＨＰＬＣ（カラム：Ｄａｉｃｅｌ　Ｃｈｉｒａｌｃｅｌ　ＯＪ；移動相；ヘキサン：エタノール＝１５：１）で測定したところ、光学純度は８９％ｅｅであり、ジアステレオ純度は９９％ｄｅ以上であった。生成物の絶対配座は（１Ｓ，２Ｓ）であった。
（実施例８）光学活性１−フェニル−２−（Ｎ−メチル−Ｎ−ベンゾイルアミノ）−１−プロパノールの合成（２）
アルゴン雰囲気下、簡易型オートクレーブ（容量１００ｍｌ）中で｛［（Ｓ）−ＢＩＮＡＰ］ＲｕＣｌ_２｝のＤＭＦ付加物９．４ｍｇ（０．０１ｍｍｏｌ）、ＤＩＡＭＩＮＥ（２−２）３．６ｍｇ（０．０１ｍｍｏｌ）、１−フェニル−２−（Ｎ−メチル−Ｎ−ベンゾイルアミノ）プロパン−１−オン２６７ｍｇ（１．００ｍｍｏｌ）の２−プロパノール２．５ｍｌ溶液を室温で添加した。反応系内を脱気後、０．５Ｍのカリウムｔ−ブトキシドの２−プロパノール溶液を添加、さらに水素を１０気圧まで圧入し、室温で１時間攪拌した。反応混合物をシリカゲルショートカラムクロマトグラフィー（溶離液＝ジエチルエーテル）により精製する事により、光学活性１−フェニル−２−（Ｎ−メチル−Ｎ−ベンゾイルアミノ）−１−プロパノールを定量的に得た。
得られた１−フェニル−２−（Ｎ−メチル−Ｎ−ベンゾイルアミノ）−１−プロパノールの光学純度およびジアステレオ選択性を、ＨＰＬＣ（カラム：Ｄａｉｃｅｌ　Ｃｈｉｒａｌｃｅｌ　ＯＪ；移動相；ヘキサン：２−プロパノール：エタノール＝８：１：１）で測定した所、光学純度は９５％ｅｅであり、ジアステレオ純度は９９％ｄｅ以上であった。生成物の絶対配座は（１Ｒ，２Ｒ）であった。
（実施例９〜１９）
ジアミンを変更した以外は、実施例８と同様の条件で実験を行い、得られた光学活性なシン体の１−フェニル−２−（Ｎ−メチル−Ｎ−ベンゾイルアミノ）−１−プロパノールの光学純度（％ｅｅ）の比較を行った。結果を第２表に示した。

産業上の利用可能性：
以上説明したように、本発明によれば、不斉水素還元触媒として有用で、入手容易なルテニウム化合物及びその配位子として好適な光学活性ジアミン化合物が提供される。また、本発明のルテニウム化合物を不斉還元触媒として用いることにより、医薬やその合成中間体として有用な光学活性アルコール類を高選択的、高収率かつ工業的に有利に製造することができる。Technical field:
The present invention relates to a ruthenium compound, a diamine compound suitably used as a ligand of the ruthenium compound, and an asymmetric hydrogenation reaction of α-aminoketones using the ruthenium compound as an asymmetric hydrogenation catalyst.
Background technology:
Conventional methods for efficiently obtaining the corresponding amino alcohol by hydrogenation of α-aminoketones include, for example, Japanese Patent Application No. 2000-208664 and J. Am. Am. Chem, Soc. ,122, 6510 (2000).
However, in these methods, good results could not be obtained unless an asymmetric hydrogenation catalyst having an expensive bidentate phosphorus ligand having a plurality of substituents was used. For this reason, there has been a demand for the development of a practical asymmetric hydrogenation catalyst for highly selective asymmetric hydrogenation reduction of α-aminoketones to the corresponding optically active alcohols using a cheaper catalyst than before. .
DISCLOSURE OF THE INVENTION:
The present invention relates to a readily available ruthenium compound, a novel diamine compound useful as a ligand for the ruthenium compound, and asymmetric hydrogenation reduction of α-aminoketones using the ruthenium compound as an asymmetric hydrogenation catalyst. It is an object to provide a method for producing optically active alcohols.
In order to solve the above problems, the present invention firstly provides a compound represented by the following general formula (1):
Ru (Px)_n1[DIAMINE] (X) (Y)
Ｐwherein Px represents a phosphine ligand,
DIAMINE is represented by the general formula (2): R¹R²C^*(NHR⁵)-(A) -R³R⁴C^*(NH₂) [R¹~ R⁴Each independently represent a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, Represents an aralkyl group which may be substituted or an aryl group which may have a substituent.
A is a C1 to C3 alkylene that may have a substituent and may contain an ether bond, a C3 to C8 cycloalkylene that may have a substituent, A good arylene, a divalent heterocyclic ring or a single bond which may have a substituent, and when A is a single bond or alkylene,¹And R²Any of and R³And R⁴May combine to form a ring.
R⁵Represents an alkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent,
C^*Represents an asymmetric carbon. Represents an optically active diamine represented by
X and Y each independently represent an anion;
n1 represents an integer of 1 or 2. ｝
A ruthenium compound represented by the formula:
In the ruthenium compound of the present invention, the DIAMINE is represented by (1) a general formula (2 '): R¹R²C^*(NHR⁵)-(A) -R¹R²C^*(NH₂) [Where R¹, R², R⁵, A and C^*Represents the same meaning as described above. And (2) general formula (3): R¹R²C^*(NHR⁵) -R³R⁴C^*(NH₂) [Where R¹~ R⁵And C^*Represents the same meaning as described above. And the optically active diamine represented by the general formula (3 '): R¹R²C^*(NHR⁵) -R¹R²C^*(NH₂) [Where R¹, R², R⁵And C^*Represents the same meaning as described above. And (4) the general formula (7): R¹R²C^*(NHR⁵’) -R³R⁴C^*(NH₂) [Where R¹~ R⁴, And C^*Represents the same meaning as described above, and R⁵′ Represents an aryl group which may have a substituent or an aralkyl group which may have a substituent. And (5) the general formula (7 '): R¹R²C^*(NHR⁵’) -R¹R²C^*(NH₂) [Where R¹~ R⁴, R⁵’And C^*Represents the same meaning as described above. Is more preferable.
The phosphine ligand represented by Px includes: (1) a general formula (4):
R_DR_EP- (W) -PR_FR_G
(Where R_D, R_E, R_F, R_GEach independently has an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, Represents an optionally substituted aralkyl group or an optionally substituted aryl group. Also, R_DAnd R_EOr R_FAnd R_GMay together form an alicyclic group which may have a substituent. W represents a hydrocarbon group which may have a substituent. )), A bidentate phosphorus ligand represented by the general formula (5): R_DR_EP- (W) -PR_FR_G(Where R_D, R_E, R_F, R_GAnd W have the same meaning as described above. ) Is more preferably an optically active bidentate phosphorus ligand.
The present invention secondly provides a compound of the general formula (6): R useful as a ligand of the ruthenium compound of the present invention.¹R²C^*(NHR⁵))-(A) -R³R⁴C^*(NH₂)
(R¹~ R⁴, C^*And A have the same meanings as described above;⁵′ Represents an aryl group which may have a substituent or an aralkyl group which may have a substituent. ) Is provided.
The optically active diamine represented by the general formula (6) includes (1) a general formula (6 '): R¹R²C^*(NHR⁵))-(A) -R¹R²C^*(NH₂) [R¹, R², C^*, R⁵'And A have the same meaning as described above. ] (2) General formula (7): R¹R²C^*(NHR⁵’) -R³R⁴C^*(NH₂) (Where R¹~ R⁴, R⁵’And C^*Represents the same meaning as described above. ) Is preferable, and (3) the general formula (7 '): R¹R²C^*(NHR⁵’) -R¹R²C^*(NH₂) (Where R¹, R², R⁵’And C^*Represents the same meaning as described above. Is more preferred.
Thirdly, the present invention provides a compound represented by the general formula (8): Ra-CO-CH (Rb) -Rc
[Wherein, Ra and Rc each independently represent a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent which may have a substituent. It represents an alkenyl group, an aralkyl group which may have a substituent or an aryl group which may have a substituent.
Rb represents any one of the following formulas (9), (10), and (11).
General formula (9): R⁶CO (R⁷) N-
General formula (10): R⁶CO (R⁸CO) N-
General formula (11): R⁶R⁷N-
(Where R⁶, R⁷And R⁸Are each independently a hydrogen atom, a formyl group, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, a cycloalkyl group which may have a substituent, A cycloalkoxy group optionally having a group, an alkenyl group optionally having a substituent, an aralkyl group optionally having a substituent, an aralkyloxy group optionally having a substituent, Represents an aryl group which may have a group or an aryloxy group which may have a substituent. Also, R⁶And R⁷Or R⁶And R⁸And may combine with each other to form a 5- to 8-membered nitrogen-containing heterocyclic ring. A) hydrogenating the racemic α-aminoketones represented by the formula (1) in the presence of one or more of the ruthenium compounds of the present invention using hydrogen gas or a hydrogen-donating compound as a hydrogen source. Characteristic, general formula (12):
Ra-C^*H (OH) -C^*H (Rb) -Rc
(Wherein Ra, Rb, Rc and C^*Represents the same meaning as described above. The present invention provides a method for producing an optically active β-amino alcohol represented by the following formula:
The ruthenium compound of the present invention is a catalyst which is easy to prepare and has a stereoselective and highly efficient asymmetric hydrogenation reduction of α-aminoketones despite having no expensive phosphorus ligand. Therefore, by using the ruthenium compound of the present invention as an asymmetric hydrogenation catalyst, α-aminoketones can be asymmetrically hydrogenated and reduced, and represented by the general formula (12), which is useful as an intermediate for the synthesis of pharmaceuticals and agricultural chemicals. Optically active amino alcohols can be produced with high stereoselectivity and high yield.
Hereinafter, the present invention will be described in detail.
A first aspect of the present invention is a general formula (1):
Ru (Px)_n1[DIAMINE] A ruthenium compound represented by (X) (Y).
In the general formula (1), examples of the phosphine ligand represented by Px include a general formula PR_AR_BR_CA monodentate ligand of phosphorus represented by_DR_EP-W-PR_FR_GAnd an optically active bidentate phosphorus ligand.
General formula: PR_AR_BR_CIn, R_A, R_B, R_CRepresents the same or different and represents an alkyl group, a phenyl group or a cycloalkyl group which may have a substituent, or the like;_A, R_B, R_COf these, two may be taken together to form an alicyclic group which may have a substituent. In addition, the general formula: PR_AR_BR_CIs optically active, R_A, R_B, R_CAmong them, at least one group is optically active, or a phosphorus atom composed of three different substituents becomes optically active.
The general formula: PR_AR_BR_CExamples of the monodentate phosphine ligand represented by are, for example, trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, tricyclohexylphosphine, tri (p-tolyl) phosphine, diphenylmethylphosphine, dimethylphenylphosphine, isopropyl Such as methylphosphine, cyclohexyl (O-anisyl) -methylphosphine, 1- [2- (diphenylphosphino) ferrocenyl] ethyl methyl ether, and 2- (diphenylphosphino) -2′-methoxy-1,1′-binaphthyl; Tertiary phosphines can be mentioned as preferred. Further, R_A, R_B, R_CMay also be used phosphine ligands consisting of different substituents.
The general formula: R_DR_EP- (W) -PR_FR_GIn, R_D, R_E, R_F, R_GAre the same or different and each have an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, Represents an aralkyl group which may be optionally substituted or an aryl group which may have a substituent;_DAnd R_EOr R_FAnd R_GMay together form an alicyclic group which may have a substituent. (W) represents a hydrocarbon group, for example, a C1-C6 alkylene such as methylene, ethylene, propylene, butylene, phenylene, naphthylene, 1,1′-biphenyl-2,2′-diyl, 1,1 ′ And arylene groups which may have a substituent such as -binaphthyl-2,2'-diyl and 1,1'-binaphthyl-7,7'-diyl.
The general formula: R_DR_EP- (W) -PR_FR_GExamples of the racemic or optically active bidentate phosphine ligand represented by are bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, bisdiphenylphosphinobutane, bisdimethylphosphinoethane, Examples include bidentate tertiary phosphine compounds such as bisdimethylphosphinopropane.
Examples of the optically active bidentate phosphine ligand include, for example, BINAP [2,2′-bis- (diphenylphosphino) -1,1′-binaphthyl]; substitution of an alkyl group or an aryl group on the naphthyl ring of BINAP. Derivatives having a group; BINAP derivatives having a fluorine substituent; derivatives such as BINAP having 1 to 5 group substituents such as alkyl and alkoxy on the same two benzene rings on a 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};
Compounds having the same two substituents on a phosphorus atom, for example, BPPFA {1- [1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethyldiamine}; BICHEP [2,2′-bis- (dicyclohexyl) Phosphino) -6,6′-dimethyl-1,1′-biphenyl]; CHIRAPHOS [2,3-bis- (diphenylphosphino) butane]; CYCPHOS [1-cyclohexyl-1,2-bis- (diphenylphospho) DEGPHOS [1-substituted-3,4-bis- (diphenylphosphino) pyrrolidine]; DIOP [2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis- (diphenyl) Phosphino) 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]; SEGPHOS {[(5,6), (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl] bis (diphenylphosphine)} and a bidentate in which the phosphorus atom is optically active Ligands, for example, 1,2-bis (t-butylmethylphosphino) ethane and the like.
The phosphine ligand that can be used in the present invention is not limited to those listed above as long as it can form a metal complex stably.
The DIAMINE is represented by the general formula (2):
R¹R²C^*(NHR⁵)-(A) -R³R⁴C^*(NH₂) Is an optically active diamine.
In the general formula (2), R¹~ R⁴Are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, Represents an aralkyl group which may be possessed or an aryl group which may be possessed by a substituent.
The R¹~ R⁴Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, Examples thereof include an alkyl group having 1 to 10 carbon atoms such as an n-decyl group. Examples of the alkenyl group include alkenyl groups having 1 to 10 carbon atoms such as propenyl, isopropenyl, allyl, butenyl, pentenyl, hexenyl, heptynyl, octenyl and dodecenyl groups. Examples of the cycloalkyl group include a cyclopropyl, cyclopentyl, cyclohexyl group and the like. Examples of the aralkyl group include benzyl, 2-phenylethyl, 3-phenylpropyl, pyridylmethyl and the like. Examples of the aryl group include phenyl, pyridyl, 1-naphthyl, 2-naphthyl, and the like.
These groups may have one or more identical or different substituents at any position. Examples of such a substituent include an alkyl group such as methyl, ethyl and propyl. Alkoxy groups such as methoxy and ethoxy; halogen atoms such as fluorine and chlorine; nitro groups; cyano groups; Among these, from the viewpoint of availability and ease of synthesis, R¹~ R⁴Is preferably a hydrogen atom; an alkyl group having 1 to 3 carbon atoms such as a methyl group or an ethyl group; or a phenyl group which may have a substituent.
R⁵Represents an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. Examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, and n-hexyl group. . Examples of the aryl group include a phenyl, 1-naphthyl, 2-naphthyl group and the like. Examples of the aralkyl group include benzyl, phenyl, naphthylmethyl, and anthracenylmethyl. Among these, preferred substituents include R⁵’(Where R⁵'Represents an aryl group such as phenyl, 1-naphthyl and 2-naphthyl; and an aralkyl group such as benzyl, phenyl, naphthylmethyl, anthracenylmethyl and the like.
These groups may have one or more identical or different substituents at any position. Examples of such a substituent include an alkyl group such as methyl, ethyl and propyl; an alkoxy group such as methoxy and ethoxy; an aryl group such as phenyl; an aryloxy group such as phenoxy; an aralkyloxy group such as benzyloxy; A hydroxyl group; a nitro group; a cyano group; and the like.
A is a C1 to C3 alkylene which may have a substituent and may contain an ether bond, a C3 to C8 cycloalkylene which may have a substituent, and may have a substituent. It represents a good arylene, a divalent heterocyclic ring which may have a substituent, or a single bond.
C1-C3 alkylene as methylene, ethylene, propylene and the like; C3-C8 cycloalkylene as cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene; arylene as phenylene, naphthylene and the like; Examples of the heterocycle of the heterocycle include furan, pyran, dioxolan, thiophene, thiopyran, pyrrole, imidazole, pyrazole, oxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, benzimidazole, benzopyrazole, benzothiazole, and quinoline. , Indoline, phenanthroline, dioxolan-2-one, dioxane, oxazolidine, oxazolidinone, tetrahydrofuran, tetrahydrothiophene, saturation of sulfolane or the like or Include saturated heterocyclic ring is. Further, the alkylene group may contain an ether bond at an arbitrary position.
These groups may further have a substituent, such as a C1-C6 alkyl group such as methyl, ethyl and propyl; a C1-C6 alkoxy group such as methoxy, ethoxy and propoxy; phenyl, naphthyl and the like. An aryloxy group such as phenoxy; an aralkyloxy group such as a benzyloxy group.
When A is a single bond or alkylene,¹And R²Any of and R³And R⁴May combine to form a ring.
The DIAMINE represented by the general formula (2) is preferably a compound represented by the general formula (3):
R¹R²C^*(NHR⁵) -R³R⁴C^*(NH₂) (Where R¹~ R⁵And C^*Represents the same meaning as described above. ) Is an optically active diamine.
Preferred specific examples of the DIAMINE include optically active N-methyl-1,2-diphenyl-1,2-ethanediamine, optically active N-ethyl-1,2-diphenyl-1,2-ethanediamine, optically active N -Benzyl-1,2-diphenyl-1,2-ethanediamine, optically active N-diphenylmethyl-1,2-diphenyl-1,2-ethanediamine, optically active N- (4-methoxybenzyl) -1,2 -Diphenyl-1,2-ethanediamine, optically active N- (4-benzyloxybenzyl) -1,2-diphenyl-1,2-ethanediamine, optically active N-isopropyl-1,2-diphenyl-1,2 -Ethanediamine,
Optically active N-methyl-2,4-diaminopentane, optically active N-benzyl-2,4-diaminopentane, optically active N- (4-benzyloxybenzyl) -2,4-diaminopentane, optically active N-isopropyl -2,4-diaminopentane, optically active N-methyl-2,5-diaminohexane, optically active N-benzyl-2,5-diaminohexane, optically active N- (4-benzyloxybenzyl) -2,5- Diaminohexane, optically active N-isopropyl-2,5-diaminohexane, optically active N-methyl-2-aminopropyl-2′-aminopropyl ether, optically active N- (4-benzyloxybenzyl) -2-aminopropyl -2'-aminopropyl ether, optically active N-isopropyl-2-aminopropyl-2'-aminopropyl ate Le,
Optically active N-methyl-2-amino-2-phenylethyl-2′-amino-2′-phenylethyl ether, optically active N- (4-benzyloxybenzyl) -2-amino-2-phenylethyl-2 ′ -Amino-2'-phenylethyl ether, optically active N-isopropyl-2-amino-2-phenylethyl-2'-amino-2'-phenylethylether, optically active N-methyl-1,3-diamino-1 , 3-diphenylpropane, optically active N- (4-benzyloxybenzyl) -1,3-diamino-1,3-diphenylpropane, optically active N-isopropyl-1,3-diamino-1,3-diphenylpropane, Optically active N-methyl-1,4-diamino-1,4-diphenylbutane, optically active N- (4-benzyloxybenzyl) -1,4-dia Roh-1,4-diphenyl butane, optically active N- isopropyl-1,4-diamino-1,4-diphenyl butane,
Optically active 1- (N-methyl-1-aminoethyl) -2- (1-aminoethyl) benzene, optically active 1- {1- [N- (4-benzyloxybenzyl) amino] ethyl} -2- ( 1-aminoethyl) benzene, optically active 1- (N-isopropyl-1-aminoethyl) -2- (1-aminoethyl) benzene, optically active N-methyl-cyclohexanediamine, optically active N-benzyl-cyclohexanediamine, Examples include optically active N- (4-benzyloxybenzyl) -cyclohexanediamine and optically active N-isopropyl-cyclohexanediamine.
Of course, the diamine ligand that can be used in the present invention is not limited to these as long as it can stably form a metal complex.
X and Y each independently represent an anion. Examples of the anion include a hydride (hydrogen atom); a halogen atom such as fluorine, chlorine and bromine; a carboxyl group such as formyl and acetoxy group; a hydroxyl group; an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy and butoxy group. No. Among these, X and Y are preferably halogen atoms, and particularly preferably chlorine atoms.
The diamine compound represented by the general formula (2) can be synthesized, for example, according to the description in JP-A-10-045721. Further, for example, according to the reaction formula shown below, a compound represented by the general formula (2a)²¹Represents an alkyl group, an aryl group, or an aralkyl group which may have a substituent. Also, two R²¹May combine together to form a ring. R²²Represents a hydrogen atom, which may have a substituent (an alkyl group, an alkenyl group, an aryl group, an aralkyl group or an alkoxy group);²³, R²⁴Represents the same or different hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent or an aralkyl group which may have a substituent, wherein A is as defined above. Express the same meaning. * Represents an asymmetric carbon atom. Can be produced by using the N-acyl compound of the optically active diamine represented by the formula (1) as a starting material through two or three steps.

That is, in the presence or absence of an acid catalyst, an optically active N-acyldiamine (2a) is reacted with a carbonyl compound (2b) to obtain an imino form (2c) (Step I). Compound (2) can be easily obtained by reduction using a suitable reducing agent (Step II). In addition, depending on the reducing agent used, the compound (2) can be induced by hydrolysis via the N-acyl-N'-substituted diamine (2d) (step III).
As the optically active N-acyldiamine (2a) used as a starting material, for example, (1R, 2R) -N-benzyloxycarbonyl-1,2-diphenyl-1,2-ethanediamine, (1S, 2S) -N-benzyloxycarbonyl-1,2-diphenyl-1,2-ethanediamine, (1R, 2R) -N-isopropyloxycarbonyl-1,2-diphenyl-1,2-ethanediamine, (1S, 2S) -N-isopropyloxycarbonyl-1,2-diphenyl-1,2-ethanediamine, (1R, 2R) -N-benzoyl-1,2-diphenyl-1,2-ethanediamine, (1S, 2S) -N -Benzoyl-1,2-diphenyl-1,2-ethanediamine, (1R, 2R) -N-acetyl-1,2-diphenyl-1,2-ethanedia , (1S, 2S) -N-acetyl-1,2-diphenyl-1,2-ethanediamine, (1R, 2R) -N-trichloroacetyl-1,2-diphenyl-1,2-ethanediamine, ( (1S, 2S) -N-trichloroacetyl-1,2-diphenyl-1,2-ethanediamine, (1R, 2R) -N-trifluoroacetyl-1,2-diphenyl-1,2-ethanediamine, (1S , 2S) -N-trifluoroacetyl-1,2-diphenyl-1,2-ethanediamine;
(2R, 4R) -N-benzyloxycarbonyl-2,4-diaminopentane, (2S, 4S) -N-benzyloxycarbonyl-2,4-diaminopentane, (2R, 5R) -N-benzyloxycarbonyl- 2,5-diaminohexane, 1- (N-benzyloxycarbonyl-1 (R) -aminoethyl) -2- (1 (R) -aminoethyl) benzene, 1- (N-benzyloxycarbonyl-1 (S ) -Aminoethyl) -2- (1 (S) -aminoethyl) benzene, (1R, 2R) N-benzyloxycarbonyl-cyclohexanediamine, (1S, 2S) -N-benzyloxycarbonyl-cyclohexanediamine, (1R , 2R) -N-isopropyloxycarbonyl-cyclohexanediamine, (1S, 2S) -N-isopropyl Cicarbonyl-cyclohexanediamine, (1R, 2R) -N-benzoyl-cyclohexanediamine, (1S, 2S) -N-benzoyl-cyclohexanediamine, (1R, 2R) -N-acetyl-cyclohexanediamine, (1S, 2S) —N-acetyl-cyclohexanediamine and the like.
Specific examples of the carbonyl compound (2b) include aldehydes such as formaldehyde, acetaldehyde, propionaldehyde, cyclohexanealdehyde, benzaldehyde, 4-benzyloxybenzaldehyde, and 3-benzyloxybenzaldehyde; ketones such as acetone and cyclohexanone; Is mentioned.
The reaction of the above step I is a general reaction in which an optically active N-acyldiamine (2a) is reacted with a carbonyl compound (2b) in an inert solvent such as benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, and chloroform. Done by the method. In this case, it is preferable to coexist a dehydrating agent such as molecular sieve or to carry out the reaction under azeotropic dehydration.
The amount of the carbonyl compound (2b) to be used is generally equimolar to 10-fold molar, preferably equimolar to 2-fold molar, relative to 1 mol of the optically active N-acyldiamine (2a). The reaction is carried out in a temperature range from -50 ° C to the boiling point of the solvent, preferably in a temperature range from room temperature to the boiling point of the solvent. The reaction time is usually about 8 to 18 hours. Examples of the acid used include sulfuric acid and p-toluenesulfonic acid, and the amount of the acid used is preferably in the range of 0 to 1 mol%.
Step II is a reduction reaction of the imino form (2c). This reaction is carried out in benzene, toluene, tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane, methanol, ethanol, acetic acid, or the like, or a mixed solvent thereof using a commonly used reducing agent at room temperature or under heating.
Specific examples of the reducing agent to be used include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, lithium triethylborohydride, diborane and the like. The reaction can also be carried out under hydrogenation conditions using a carbon support such as palladium or platinum as a catalyst. The reaction is carried out in a temperature range from -78 ° C to the boiling point of the solvent, preferably in a temperature range from -30 ° C to room temperature. The reaction is usually completed in about 3 to 18 hours.
The reaction route of Step III is preferably applied particularly when a compound from which an acyl group is not eliminated under the conditions of Step II is used. In this reaction, the N-acyl-N'-substituted diamine (2d) is reacted with benzene, toluene, tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane, methanol, ethanol, water, or a mixed solvent thereof at room temperature or under heating. The reaction is carried out by reacting a commonly used acid or alkali.
Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, and acetic acid. Further, as the alkali, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, hydrazine, ammonia and the like are used. The reaction is usually carried out in a temperature range from -50 ° C to the boiling point of the solvent, preferably in a temperature range from room temperature to the boiling point of the solvent. The reaction is completed in about 8 to 18 hours.
Alternatively, the diamine compound represented by the general formula (2) can be prepared by reacting the diamine compound represented by the general formula (2e) [wherein R²¹, R²¹'Independently represent a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, Represents an aralkyl group which may be possessed or an aryl group which may be possessed by a substituent;²¹, R²¹'May combine together to form a ring. R²³, R²⁴Each independently represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, or an aralkyl group which may have a substituent, and A has the same meaning as described above. Represents ] To the optically active diamine represented by the formula (1), wherein X represents a chlorine atom, a bromine atom or an iodine atom. ] In the reaction.

Where the specific R²¹, R²¹’, R²³, R²⁴As R¹~ R⁴And the same substituents as mentioned above.
The amount of the optically active diamine (2e) to be used is 1 mol to 10 mol, preferably 2.5 mol to 5 mol, per 1 mol of the halide compound (2f). The reaction is carried out in a temperature range from the melting point of the solvent to the boiling point of the solvent, preferably in a temperature range from room temperature to the boiling point of the solvent. The reaction time is usually about 8 to 18 hours. As the solvent to be used, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane, methanol, ethanol, or the like, or a mixed solvent thereof is preferably used, and chloroform and methylene chloride are preferably used.
As a starting material for producing the ruthenium compound represented by the general formula (1), a 0-valent, monovalent, divalent, trivalent, and even higher-valent ruthenium complex can be used. Among these, in the present invention, it is preferable to use a divalent ruthenium complex.
Examples of the divalent ruthenium halide complex as a starting material include [ruthenium dichloride (norbornadiene)] polynuclear, [ruthenium dichloride (cyclooctadiene)] polynuclear, and [bis (methylallyl) ruthenium (cyclooctadiene)]. Ruthenium halide compound, dirugen, etc., [ruthenium dichloride (benzene)] binuclear, [ruthenium dichloride (p-cymene)] binuclear, [ruthenium dichloride (trimethylbenzene)] binuclear , [Ruthenium dichloride (hexamethylbenzene)] and a ruthenium halide complex to which an aromatic compound such as a binuclear compound is coordinated. The ruthenium complex having a ligand that can be substituted with a phosphine ligand or an amine ligand is not particularly limited to the above.
The method for producing the ruthenium compound represented by the general formula (1) of the present invention can be obtained by reacting a ruthenium complex as a raw material with a phosphine ligand (Px) and a diamine ligand (DIAMINE). There are no particular restrictions on the types of starting materials, phosphine ligand (Px) and diamine ligand (DIAMINE), reaction order, and the like.
Among these production methods, Angew. Chem. Int. Ed. ,37,The method using a divalent ruthenium complex based on the method described in 1703 (1998) is simple. For example, by heating a solvent solution of a divalent ruthenium halide complex and a phosphine ligand (Px), and adding an optically active diamine (DIAMINE), n1 = 1, (X) (Y ) = Hal₂(Hal represents a halogen atom ion).
That is, the reaction between the divalent ruthenium halide complex as the starting material and the phosphine ligand is carried out by heating these mixtures in a solvent, and the phosphine-ruthenium halide in which the phosphine ligand is coordinated to ruthenium. A complex can be obtained.
The amount of the phosphine ligand used is usually 2 to 3 moles, preferably 2 moles in the case of monodentate, and usually 1 to 2 moles in the case of bidentate, relative to 1 mole of the ruthenium-halide complex. Molar, preferably equimolar.
Solvents used in this reaction include, for example, aromatic hydrocarbon solvents such as toluene and xylene; aliphatic hydrocarbon solvents such as pentane and hexane; halogenated hydrocarbon solvents such as methylene chloride; diethyl ether, tetrahydrofuran Ether solvents such as (THF); alcohol solvents such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol; nitrile solvents such as acetonitrile; N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl Aprotic polar organic solvents such as sulfoxide (DMSO);
The amount of the solvent to be used is generally about 1 ml to 100 ml, preferably 1 ml to 10 ml, per 1 g of the substrate. The reaction is carried out between 0 ° C and 200 ° C, preferably between room temperature and 100 ° C.
Next, the obtained phosphine-ruthenium halide complex is reacted with a diamine compound represented by the general formula (2), whereby a ruthenium compound represented by the general formula (1) (n1 = 1, (X) (Y) = Hal₂) Can be obtained. This reaction is carried out by dissolving an equivalent amount of an amine ligand in a solvent solution of the phosphine-ruthenium halide complex and reacting in a temperature range of -100 ° C to 200 ° C, preferably -10 ° C to 50 ° C. To form the corresponding ruthenium compound represented by the general formula (1) (n1 = 1, (X) (Y) = Hal₂) Can be obtained.
Alternatively, the desired ruthenium compound represented by the general formula (1) can also be obtained by isolating the phosphine-ruthenium complex once and then reacting the diamine compound under the same conditions as described above.
Further, by reacting the obtained amine-phosphine-ruthenium halide complex with a base in a solvent, the compound represented by the general formula (1: n11, (X) (Y) = H₂)), An amine-phosphine-ruthenium hydride complex represented by the following formula:
Examples of the solvent used include aromatic hydrocarbon solvents such as toluene and xylene; aliphatic hydrocarbon solvents such as pentane and hexane; halogenated hydrocarbon solvents such as methylene chloride; ether solvents such as diethyl ether and THF. Alcohol solvents such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol; nitrile solvents such as acetonitrile; aprotic polar organic solvents such as DMF, N-methylpyrrolidone and DMSO;
As the base used here, for example, KOH, KOCH₃, KOCH (CH₃)₂, KC₁₀H₈, K₂CO₃, NaOH, NaOCH₃, NaOCH (CH₃)₂, Na₂CO₃, LiOH, LiOCH₃, LiOCH (CH₃)₂, Ca (OH)₂, CaCO₃, Mg (OEt)₂And alkali or alkaline earth metal hydroxides and salts or quaternary ammonium salts.
The amount of the solvent to be used is generally about 1 ml to 100 ml, preferably 1 ml to 10 ml, per 1 g of the substrate. The reaction is usually performed at a temperature between -100 ° C and 200 ° C, preferably at a temperature between -10 ° C and 50 ° C. The amount of the base used is in the range of 2 mol to 50,000 times, preferably 2 to 5,000 times, per 1 mol of the catalyst.
The amine-phosphine-ruthenium hydride complex can also be obtained by reacting a zero-valent ruthenium complex with an equivalent mixture of a phosphine ligand and a diamine ligand in a solvent under a hydrogen atmosphere.
Examples of the zero-valent ruthenium complex used include Ru (COD) (COT). Here, COD represents 1,3-cyclooctadiene, and COT represents 1,3,5-cyclooctatriene.
Solvents used in this reaction include aromatic hydrocarbon solvents such as toluene and xylene; aliphatic hydrocarbon solvents such as pentane and hexane; halogenated hydrocarbon solvents such as methylene chloride; diethyl ether, THF and the like. Ether solvents; alcohol solvents such as methanol, ethanol, 2-propanol, butanol, and benzyl alcohol; nitrile solvents such as acetonitrile; aprotic polar organic solvents such as DMF, N-methylpyrrolidone, and DMSO; .
The amount of the solvent to be used is generally about 1 ml to 100 ml, preferably 1 ml to 10 ml, per 1 g of the substrate. The pressure of the hydrogen gas is usually in the range of 1 to 200 atm, preferably 3 to 50 atm. The reaction is usually performed at a temperature between 0 ° C and 200 ° C, preferably at room temperature to 100 ° C.
The ruthenium compound represented by the general formula (1) synthesized as described above is obtained by asymmetric hydrogenation of α-aminoketones represented by the general formula (8): Ra—CO—CH (Rb) —Rc Useful as a catalyst.
In the general formula (8), Ra and Rc each independently represent a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, and a substituent. Represents an alkenyl group which may be optionally substituted, an aralkyl group which may have a substituent or an aryl group which may have a substituent.
Examples of the alkyl group of the linear or branched alkyl group which may have a substituent of Ra and Rc include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, isopentyl and neopentyl. , T-pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl and the like.
Examples of the alkenyl group of the linear or branched alkenyl group which may have a substituent include vinyl, 1-propenyl, 2-propenyl, 1-isopropenyl, 1-butenyl, 1-isopropenyl, and 2-butenyl. Alkenyl groups having 2 to 20 carbon atoms such as, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl and 3-pentenyl groups. Examples of the cycloalkyl group of the cycloalkyl group which may have a substituent include a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of the aralkyl group of the aralkyl group which may have a substituent include aralkyl groups having 7 to 20 carbon atoms such as benzyl, α-methylbenzyl, α, α-dimethylbenzyl, and α-ethylbenzyl. Can be mentioned.
Examples of the aryl group of the aryl group which may have a substituent include aromatic hydrocarbon groups such as phenyl, 1-naphthyl and 2-naphthyl groups; and oxygen-containing heterocycles such as furanyl, pyranyl and dioxolanyl groups. Groups; sulfur-containing heterocyclic groups such as thienyl groups; pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyridyl, pyradadyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, quinolyl, anthranyl, indolyl, phenanthroni And a saturated or unsaturated nitrogen-containing heterocyclic group such as a lyl group; and the like.
Further, these groups may have one or two or more identical or different substituents at any position. Examples of such a substituent include a hydroxy group; a carboxyl group; an amino group; a monosubstituted amino group such as methylamino, ethylamino, propylamino, acetylamino, benzoylamino, and benzylamino group; dimethylamino, diethylamino, and methylethylamino. Disubstituted amino groups such as diphenylamino, dibenzylamino, dibenzylamino, phenylmethylamino and acetylmethylamino groups; alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl and hexyl groups; Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbo An alkoxycarbonyl group such as a phenyl group; a phenyl group optionally having a substituent at any position of a benzene ring; (optionally having a substituent at any position of a naphthalene ring) 1-naphthyl; -A naphthyl group such as a naphthyl group; furan, pyran, dioxolan, dioxane, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, benzimidazole, benzopyrazole, benzo. Heterocyclic groups such as thiazole and quinoline (these groups may have a substituent at any position); halogen atoms such as fluorine, chlorine and bromine;
Rb represents a group represented by any of the following formulas (9), (10), and (11).
(9) @R⁶CO (R⁷) N-
(10) R⁶CO (R⁸CO) N-
(11) R⁶R⁷N-
Where R⁶, R⁷And R⁸Are the same or different and are a hydrogen atom, a formyl group, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, a cycloalkyl group which may have a substituent An optionally substituted cycloalkoxy group, an optionally substituted alkenyl group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group , An aryl group which may have a substituent or an aryloxy group which may have a substituent. Also, R⁶And R⁷Or R⁶And R⁸And may combine with each other to form a 5- to 8-membered nitrogen-containing heterocyclic ring.
The R⁶, R⁷And R⁸Examples of a hydrogen atom include: a hydrogen atom; methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, n-hexyl, n-heptyl An alkyl group having 1 to 10 carbon atoms such as a group; a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group; phenyl group, 2-methylphenyl, 2-ethylphenyl, 2-isopropylphenyl , 2-t-butylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 2-vinylphenyl, 3-methylphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-vinylphenyl , 4-methylphenyl, 4-ethylphenyl, 4-iso Ropirufeniru, 4-t-butylphenyl, 4-vinylphenyl, cumenyl, mesityl, xylyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, an aryl group which may have a substituent such as an indenyl group;
An aralkyl group having 7 to 20 carbon atoms which may have a substituent such as benzyl, 4-chlorobenzyl and α-methylbenzyl group; an alkenyl group having 2 to 10 carbon atoms such as vinyl, allyl and crotyl; Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, cyclopentyloxy, cyclohexyloxy, heptyloxy, etc. 10 alkoxy groups; cycloalkoxy groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups; phenoxy, 2-methylphenoxy, 2-ethylphenoxy, 2-isopropylphenoxy, 2-t -Butylphenoxy 2-methoxyphenoxy, 2-chlorophenoxy, 2-vinylphenoxy, 3-methylphenoxy, 3-ethylphenoxy, 3-isopropylphenoxy, 3-methoxyphenoxy, 3-chlorophenoxy, 3-vinylphenoxy, 4-methylphenoxy, Aryloxy groups such as 4-ethylphenoxy, 4-isopropylphenoxy, 4-t-butylphenoxy, 4-vinylphenoxy, 1-naphthoxy and 2-naphthoxy groups; and benzyloxy, 4-chlorobenzyloxy and 4-methyl An aralkyloxy group having 7 to 20 carbon atoms which may have a substituent such as a benzyloxy group;
Also, R⁶And R⁷Or R⁶And R⁸Are bonded to form a nitrogen-containing heterocyclic ring, examples of the heterocyclic ring include succinimide, maleimide, phthalimide, 1,2-cyclohexanecarboxamide, 2,4,6-trioxopiperidine, α-pyridone, and the like. Examples include imides.
Specific examples of Rb include acetylamino, propionylamino, propylcarbonylamino, benzoylamino, 4-methylbenzoylamino, 2-chlorobenzoylamino, 3-methoxybenzoylamino, and 2-chloro-4-methoxybenzoylamino. Acylamino group; diacylamino group such as dibenzoylamino group; N-acetyl N-methylamino, N-benzoyl-N-methylamino, N-acetyl-N-ethylamino, N-benzoyl-N-ethylamino, N- N-alkyl-N-acylamino groups such as acetyl-N-benzylamino, N-benzoyl-N-benzylamino, 4-methylbenzoylmethylamino group; N-acetyl-N-phenylamino, N-acetyl-N-4 -Methylphanylamino, N-acetyl-N-2-c Rophenylamino, N-acetyl-N-2,4-dichlorophenylamino, N-benzyl-N-phenylamino, N-benzyl-N-4-methylphenylamino, N-benzyl-N-2-chlorophenylamino, N An N-aryl-N-acylamino group such as -benzyl-N-2,4-dichlorophenylamino group;
N-methoxycarbonyl-N-methylamino, N-ethoxycarbonyl-N-methylamino, N-methoxycarbonyl-N-ethylamino, N-ethoxycarbonyl-N-ethylamino, N-propoxycarbonyl-N-propylamino, N-alkoxycarbonyl-N-alkylamino groups such as N-isopropoxycarbonyl-N-methylamino, N-butoxycarbonyl-N-ethylamino, Nt-butoxycarbonyl-N-butoxyamino group; N-methoxycarbonyl -N-methylamino, N-ethoxycarbonyl-N-methylamino, N-methoxycarbonyl-N-ethylamino, N-ethoxycarbonyl-N-ethylamino, N-propoxycarbonyl-N-propylamino, N-isopropoxy Carbonyl-N-methylamino, - butoxycarbonylamino -N- ethylamino, N-t-butoxycarbonyl -N- methylamino, N- alkoxycarbonyl -N- alkylamino groups such as N-t-butoxycarbonyl -N- Butokishiamino group;
N-methoxycarbonyl-N-phenylamino, N-ethoxycarbonyl-N-phenylamino, N-propoxycarbonyl-N-phenylamino, N-isopropoxycarbonyl-N-phenylamino, N-butoxycarbonyl-N-phenylamino N-alkoxycarbonyl-N-arylamino groups such as Nt-butoxycarbonyl-N-phenylamino group; N-methyl-methylsulfonylamino, N-ethyl-methylsulfonylamino, N-propyl-methylsulfonylamino; N-isopropyl-methylsulfonylamino, N-benzyl-methylsulfonylamino, N-butyl-methylsulfonylamino, N-methyl-ethylsulfonylamino, N-ethyl-ethylsulfonylamino, N-methyl-propylsulfonylamino, N Ethyl-propylsulfonylamino, N-methyl-isopropylsulfonylamino, N-ethyl-isopropylsulfonylamino, N-methyl-butylsulfonylamino, N-ethyl-butylsulfonylamino, N-methyl-t-butylsulfonylamino, N- Ethyl-t-butylsulfonylamino, N-methyl-phenylsulfonylamino, N-ethyl-phenylsulfonylamino, N-benzyl-phenylsulfonylamino, N-methyl-4-methylphenylsulfonylamino, N-benzyl-4-methyl N-alkyl-alkylsulfonylamino groups such as phenylsulfonylamino, N-ethyl-2-chlorophenylsulfonylamino, N-methyl-2,4-dichlorophenylsulfonylamino group or N-alkyl-substituted phenylsulfone Niruamino group;
N-phenyl-methylsulfonylamino, N-phenyl-ethylsulfonylamino, N-phenyl-propylsulfonylamino, N-phenyl-isopropylsulfonylamino, N-phenyl-butylsulfonylamino, N-phenyl-t-butylsulfonylamino, N-aryl-alkylsulfonylamino such as N-phenyl-phenylsulfonylamino, N-phenyl-4-methylphenylsulfonylamino, N-phenyl-2-chlorophenylsulfonylamino, N-phenyl-2,4-dichlorophenylsulfonylamino group A group or an N-aryl-substituted phenylsulfonylamino group;
Succinimidoyl, maleimidoyl, phthalimidoyl, 3-methylphthalimidoyl, 4-methylphthalimidoyl, 4-n-butylphthalimidoyl, 4-chlorophthalimidoyl, tetramethylphthalimidoyl, 1,2-cyclohexanecarboxamidoyl, 2, Imide groups such as 4,6-trioxopiperidin-1-yl and α-pyridone-1-yl; and the like.
The amount of the ruthenium complex compound represented by the general formula (1) used in the asymmetric hydrogenation reaction varies depending on the reaction vessel and economical efficiency, but is 1/50 to 1 mol per mol of the carbonyl compound as the reaction substrate. / 2,000,000 times mole, preferably 1/500 to 1 / 500,000 times mole.
When a compound in which X and Y are hydrogen (hydride) among the ruthenium compounds represented by the general formula (1) is used, a ketone and a base are added, and the compound is added under a hydrogen gas atmosphere or a hydrogen-donating compound. The carbonyl compound can be hydrogenated by stirring in the presence of
When a compound in which X and Y are groups other than hydrogen (hydride) is used, the mixture is mixed with ketones in the presence of a base and then subjected to a hydrogen pressure or stirring in the presence of a hydrogen-donating compound. By this, the ketones can be hydrogenated. The amount of the base to be added is in the range of 2 to 500,000 times mol, preferably 2 to 5,000 times mol, per 1 mol of the ruthenium complex compound.
The base used herein is represented by the general formula (13): (Mb)_p(Z)_q(Wherein, Mb represents an alkali metal or alkaline earth metal ion, Z represents a hydroxyl group, an alkoxy group, an aromatic anion, a mercapto group, an alkylthio group or a carbonate ion, and p, q represent 1, 2 or 3 Is preferable.
Specific examples of such bases include KOH, KOCH₃, KOCH (CH₃)₂, KC₁₀H₈, K₂CO₃, NaOH, NaOCH₃, NaOCH (CH₃)₂, Na₂CO₃, LiOH, LiOCH₃, LiOCH (CH₃)₂, Ca (OH)₂, CaCO₃, Mg (OEt)₂And alkali or alkaline earth metal hydroxides and salts or quaternary ammonium salts.
In the present invention, (1) a ruthenium complex (or ruthenium salt), a phosphorus compound (Px) and a diamine compound (DIAMINE), which are raw materials for a ruthenium compound, are separately added to a reaction system; A ruthenium complex (or ruthenium salt) and a diamine compound (DIAMINE) are separately added to the reaction system, and if necessary, a base is added to generate a ruthenium compound. Then, the ruthenium compound is isolated without isolation. By adding a substrate thereto, an asymmetric hydrogenation reaction can be performed in situ.
The solvent used in the asymmetric hydrogenation reaction is not particularly limited as long as it can solubilize the substrate and the catalyst, and can be appropriately selected and used. For example, 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 diethyl ether, THF, and 1,2-dimethoxyethane An alcoholic solvent such as methanol, ethanol, 2-propanol, butanol, benzyl alcohol and the like; a polar organic solvent containing a hetero atom such as acetonitrile, DMF, N-methylpyrrolidone and DMSO; and a mixture comprising two or more of these Solvents can be used. Among these, alcohol-based solvents are particularly preferred because the reaction product is an alcohol compound.
The amount of the solvent used is determined by the solubility of the reaction substrate and economy. For example, in the case of 2-propanol, the reaction can be carried out under a high dilution condition of a substrate concentration close to no solvent to 100% by weight or more, and it is usually desirable to use 20 to 50% by weight.
The pressure of hydrogen in the hydrogenation reaction is generally in the range of 1 to 200 atm, preferably in the range of 3 to 50 atm. The reaction is usually preferably carried out in a temperature range of -50 to 100C, but can be carried out at around room temperature of 25 to 40C. Although the reaction time varies depending on the reaction conditions such as the concentration of the reaction substrate, the temperature, and the pressure, the reaction is completed in several minutes to several days.
The hydrogenation reaction of ketone compounds in the present invention can be carried out in a batch mode or a continuous mode.
BEST MODE FOR CARRYING OUT THE INVENTION:
Hereinafter, the present invention will be described in more detail with reference to Examples. In addition, the apparatus used for the measurement of the physical property in each Example is as follows.
NMR spectrum: Varian @ GEMINI-300 (manufactured by Varian)
Optical rotation: JASCO @ DIP-360 (manufactured by JASCO Corporation)
High performance liquid chromatography: LC-10Advp, SPD-10Avp
(Made by Shimadzu Corporation)
In the chemical formulas shown below, * represents an asymmetric carbon atom.
Reference Example 1 Synthesis of (1S, 2S) -N-benzyloxycarbonyl-1,2-diphenyl-1,2-ethanediamine

To a solution of 13.85 g (65.2 mmol) of (1S, 2S) -1,2-diphenyl-1,2-ethanediamine in 300 ml of chloroform, 3.3 ml (21.7 mmol) of benzyl chlorocarbonate is slowly dropped at 0 ° C. After the addition was completed, the mixture was further stirred at room temperature for 19 hours. Water and 1.8 ml of concentrated hydrochloric acid were added to the reaction solution, and extraction was performed several times with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (solvent: chloroform / methanol) to obtain 7.12 g of the title compound. 95% yield
¹H-NMR (CDCl₃, Δ ppm): 7.5-7.3 (m, 15H), 6.6 (d, 1H), 5.1-4.8 (m, 3H), 4.4 (d, 1H) [α]._D ^23.1= -10.75 ° (c = 1.00, CHCl₃)
The aqueous layer was made strongly alkaline, extracted with chloroform, and the chloroform layer was concentrated to recover 7.78 g of (1S, 2S) -1,2-diphenyl-1,2-ethanediamine.
Reference Example 2 Synthesis of (1S, 2S) -N-isopropyl-1,2-diphenyl-1,2-diaminoethane

1.0 g (2.89 mmol) of (1S, 2S) -N-benzyloxycarbonyl-1,2-diphenyl-1,2-diaminoethane was dissolved in a mixed solvent of 20 ml of ethanol and 5 ml of acetone, and cooled to 0 ° C. Thereafter, 5 ml of acetic acid was added. To this solution, 0.68 g (18 mmol) of sodium borohydride was added in several portions while stirring at 0 ° C. After the reaction solution was further stirred at room temperature for 1 hour, water was added to stop the reaction. After the reaction mixture was concentrated under reduced pressure by an evaporator to distill off the solvent, chloroform extraction was performed several times. The chloroform layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was suspended in 6N hydrochloric acid, and insoluble crystals were collected by filtration. The crystals were suspended in a 5% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.0 g of (1S, 2S) -N-benzyloxycarbonyl-N'-isopropyl-1,2-diphenyl-1,2-diaminoethane. Obtained. 89% yield
1.0 g (2.57 mmol) of (1S, 2S) -N-benzyloxycarbonyl-N'-isopropyl-1,2-diphenyl-1,2-diaminoethane obtained above was dissolved in 50 ml of methanol, and then dissolved therein. 3.5 g of 5% palladium carbon (Pd-C) was added. The inside of the reaction system was sufficiently degassed, completely replaced with hydrogen (normal pressure), and stirred at room temperature for 2 hours. After filtering off insolubles from the reaction mixture, the filtrate was concentrated. Diethyl ether was gradually added to the obtained residue to precipitate crystals. The precipitated crystals were collected by filtration and dried to give the title compound (0.52 g). 79% yield
¹H-NMR (CDCl₃, Δ ppm): 7.1 (m, 10H), 4.0 (d, 1H), 3.8 (d, 1H), 2.5 (m, 1H), 1.7 (bs, 3H), 1 .0 (d, 6H) [α]_D ²⁴= -53.1 ° (c = 3.53, EtOH)
Reference Example 3 Synthesis of (1S, 2S) -N- (4-benzyloxybenzylidene) -N'-benzyloxycarbonyl-1,2-diphenyl-1,2-ethanediamine

0.937 g (4.42 mmol) of 4-benzyloxybenzaldehyde was added to a solution of 1.53 g (4.42 mmol) of (1S, 2S) -N-benzyloxycarbonyl-1,2-diphenyl-1,2-ethanediamine in 30 ml of chloroform. ) And Molecular Sieve 4A were added and stirred at room temperature for 19 hours. Thereafter, insolubles were filtered off from the reaction solution, and the filtrate was concentrated. Ether was added to the obtained residue to precipitate crystals. The precipitated crystals were collected by filtration, washed and dried to give 2.01 g of the title compound. 84% yield
¹H-NMR (CDCl₃, Δ ppm): 7.8 (s, 1H), 7.6 (d, 2H), 7.5-7.1 (m, 20H), 7.0 (d, 2H), 6.3 (d, 1H), 5.3 (br, 1H), 5.1 (s, 2H), 5.0 (brs, 2H), 4.6 (br, 1H).
[Α]_D ^23.1= -10.75 ° (c = 1.00, CHCl₃)
Example 1 Synthesis of (1S, 2S) -N- (4-hydroxybenzyl) -1,2-diphenyl-1,2-ethanediamine

7.45 g of (1S, 2S) -N- (4-benzyloxybenzylidene) -N′-benzyloxycarbonyl-1,2-diphenyl-1,2-ethanediamine was added to 30 ml of a 1: 1 mixed solution of methanol and tetrahydrofuran. (13.8 mmol) and 3.0 g of 5% palladium carbon were added, and after degassing, the reaction system was replaced with hydrogen and stirred at room temperature for 18 hours. Thereafter, insolubles in the reaction mixture were removed by high-flow filtration, and the filtrate was concentrated to obtain 2.13 g of the title compound. 48% yield
¹H-NMR (CDCl₃, Δ ppm): 7.6-7.1 (m, 10H), 7.0 (d, 2H), 6.7 (d, 2H), 4.0 (d, 1H), 3.7 (d, 1H), 3.6 (d, 1H), 3.4 (d, 1H)
[Α]_D ^23.1= -10.75 ° (c = 1.00, CHCl₃)
Example 2 Synthesis of (1S, 2S) -N- (4-benzyloxybenzyl) -1,2-diphenyl-1,2-ethanediamine

In 5 ml of anhydrous N, N-dimethylformamide (DMF) solution of 0.32 g (1.01 mmol) of (1S, 2S) -N- (4-hydroxybenzyl) -1,2-diphenyl-1,2-ethanediamine, After adding 24.0 mg (1.01 mmol) of sodium hydride and stirring at room temperature for 2 hours, 171 mg (1.01 mmol) of benzyl bromide was added to the reaction mixture, and the mixture was further stirred at room temperature for 4 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting yellow viscous oil was subjected to silica gel chromatography (solvent: chloroform / methanol). Then, 212 mg of the title compound (hereinafter, referred to as "DIAMINE (2-1)") was obtained. 53% yield
¹H-NMR (CDCl₃, Δ ppm): 7.5-7.1 (m, 17H), 6.9 (d, 2H), 5.0 (s, 2H), 4.0 (d, 1H), 3.7 (d, 1H), 3.6 (d, 1H), 3.4 (d, 1H)
[Α]_D ²⁰= 17.9 ° (c = 0.28, EtOH)
(Example 3)
Synthesis of (1R, 2R)-(N- (4-benzyloxybenzyl)) diphenylethylenediamine
3.45 g (14.8 mmol) of 4-benzyloxybenzyl chloride was added to 100 ml of anhydrous chloroform solution of 9.43 g (44.4 mmol) of (1R, 2R) -diphenylethylenediamine at 0 ° C., and the mixture was further heated under reflux for 42 hours. After completion of the reaction, (1R, 2R) -diphenylethylenediamine hydrochloride was separated from the contents by filtration. The solvent is distilled off from the filtrate by a rotary evaporator, and the crude product is purified by silica gel column chromatography (chloroform: methanol = 8: 1) to obtain the desired (1R, 2R)-(4-benzyloxybenzyl) diphenyl. 3.76 g (yield: 64%) of ethylenediamine could be obtained.
¹H-NMR (CDCl₃) Δ: 2.3 (3H, bs), 3.4 (1H, d), 3.6 (1H, d), 3.7 (1H, d), 4.0 (1H, d), 5. 0 (2H, s), 6.9 (2H, s), 7.2 (17H, m)
(Example 4)
Synthesis of (1R, 2R)-(N- (3,5-dimethoxybenzyl)) diphenylethylenediamine
373 mg (2.00 mmol) of 3,5-dimethoxybenzyl chloride was added to 10 ml of anhydrous chloroform solution of 1.27 g (6.00 mmol) of (1R, 2R) -diphenylethylenediamine, and the mixture was stirred at room temperature for 17 hours. (1R, 2R) -Diphenylethylenediamine hydrochloride was filtered off from the product. The solvent is distilled off from the filtrate using a rotary evaporator, and the crude product is purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the desired (1R, 2R)-(3,5-dimethoxybenzyl). 180 mg (25% yield) of diphenylethylenediamine (hereinafter referred to as "DIAMINE (2-2)") was obtained.
1H-NMR (CDCl3) δ: 1.8 (3H, bs), 3.4 (1H, d), 3.6 (1H, d), 3.7 (6H, s), 3.7 (1H, d), 4.0 (1H, d), 6.4 (2H, m), 7.2 (13H, m)
Table 1 shows the diamine compounds synthesized in the same manner.

(Example 5) [(R) -tol-Binap] Ru [DIAMINE (2-1)] Cl₂Synthesis of

Org. Synth. ,71, 1 (1993), {[(R) -tol-Binap] RuCl₂The DMF adduct of｝ was obtained.
Next, 100 mg (0.25 mmol) of DIAMINE (2-1) synthesized in Example 2 and {[(R) -tol-Binap] RuCl were placed in a 100 ml Schlenk tube purged with argon.₂250 mg (0.26 mmol) of the DMF adduct and ２０20 ml of chloroform were charged and stirred at room temperature for 30 minutes. Thereafter, the crude crystals precipitated at that temperature under reduced pressure were washed twice with hexane to obtain 350 mg of the title compound (quantitative).
This compound³¹P-NMR (C₆D₆) As a result of spectrum measurement, peaks were observed at 48.8, 46.3, 37.0, and 33.6 ppm.
(Example 6) [(S) -Binap] Ru [DIAMINE (2-2)] Cl₂Synthesis of
Org. Synth. ,71, [1] (1993), [[(S) -BINAP] RuCl₂The DMF adduct of｝ was obtained.
Then, 100 mg (0.276 mmol) of DIAMINE (2-2) synthesized in Example 4 and {[(S) -BINAP] RuCl were added to 100 ml of Schlenk substituted with argon.₂250 mg (0.266 mmol) of the DMF adduct of｝ and 20 ml of chloroform were charged and stirred at room temperature for 30 minutes. Thereafter, the crude crystals precipitated at that temperature under reduced pressure were washed twice with hexane to obtain 307 mg of the desired catalyst. (quantitative)
31P-NMR of this compound (CDCl₃) As a result of measuring the spectrum, peaks were observed at 36.1, 38.6, 47.7, and 50.1 ppm.
(Example 7) Synthesis of optically active-1-phenyl-2- (N-methyl-N-benzoylamino) -1-propanol (1)

In a simple autoclave (capacity 100 ml) under an argon atmosphere, {[(S) -tol-Binap] RuCl₂(Dmf) n (5 mg, 0.005 mmol), DIAMINE (2-1) 2 mg (0.005 mmol), 0.5 M potassium t-butoxide solution in 2-propanol (0.3 ml), and 1-phenyl- A solution of 134 mg (0.5 mmol) of 2- (N-methyl-N-benzoylamino) propan-1-one in 3 ml of 2-propanol was added at room temperature. After the inside of the reaction system was degassed, hydrogen was injected to 12 atm and stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel short column chromatography (eluent: diethyl ether) to obtain the title compound (quantitative).
The optical purity and diastereopurity of the obtained 1-phenyl-2- (N-methyl-N-benzoylamino) -1-propanol were determined by HPLC (column: Daicel Chiralcel OJ; mobile phase; hexane: ethanol = 15: 1). ), The optical purity was 89% ee and the diastereopurity was 99% de or more. The absolute conformation of the product was (1S, 2S).
Example 8 Synthesis of Optically Active 1-Phenyl-2- (N-methyl-N-benzoylamino) -1-propanol (2)
In a simple autoclave (capacity: 100 ml) under an argon atmosphere, [[(S) -BINAP] RuCl₂ＤＭ DMF adduct 9.4 mg (0.01 mmol), DIAMINE (2-2) 3.6 mg (0.01 mmol), 1-phenyl-2- (N-methyl-N-benzoylamino) propan-1-one A solution of 267 mg (1.00 mmol) in 2.5 ml of 2-propanol was added at room temperature. After the inside of the reaction system was degassed, a 0.5 M solution of potassium t-butoxide in 2-propanol was added, hydrogen was further injected to 10 atm, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel short column chromatography (eluent = diethyl ether) to quantitatively obtain optically active 1-phenyl-2- (N-methyl-N-benzoylamino) -1-propanol.
The optical purity and diastereoselectivity of the obtained 1-phenyl-2- (N-methyl-N-benzoylamino) -1-propanol were determined by HPLC (column: Daicel Chiralcel OJ; mobile phase; hexane: 2-propanol: When measured with ethanol = 8: 1: 1), the optical purity was 95% ee, and the diastereomeric purity was 99% de or more. The absolute conformation of the product was (1R, 2R).
(Examples 9 to 19)
An experiment was performed under the same conditions as in Example 8 except that the diamine was changed, and the optical activity of the obtained optically active syn-form 1-phenyl-2- (N-methyl-N-benzoylamino) -1-propanol was obtained. The purity (% ee) was compared. The results are shown in Table 2.

Industrial applicability:
As described above, according to the present invention, a ruthenium compound useful as an asymmetric hydrogen reduction catalyst and easily available and an optically active diamine compound suitable as a ligand thereof are provided. In addition, by using the ruthenium compound of the present invention as an asymmetric reduction catalyst, optically active alcohols useful as pharmaceuticals and synthetic intermediates thereof can be produced with high selectivity, high yield, and industrial advantage.

Claims (7)

General formula (1): Ru (Px) _n1 [DIAMINE] (X) (Y) wherein Px represents a phosphine ligand;
DIAMINE is represented by the general formula (2): R ¹ R ² C ^* (NHR ⁵ )-(A) -R ³ R ⁴ C ^* (NH ₂ ) wherein R ^{1 to} R ⁴ are each independently a hydrogen atom, An alkyl group which may have a group, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent Represents an aryl group which may have
A is a C1 to C3 alkylene that may have a substituent and may contain an ether bond, a C3 to C8 cycloalkylene that may have a substituent, Represents a good arylene, a divalent heterocyclic ring which may have a substituent, or a single bond, and when A is a single bond or alkylene, ^one of R ¹ and R ² and one of R ³ and R ⁴ They may combine to form a ring.
R ⁵ represents an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent;
C ^* represents an asymmetric carbon. Represents an optically active diamine represented by
X and Y each independently represent an anion;
n1 represents an integer of 1 or 2. ｝
A ruthenium compound represented by The DIAMINE is represented by the general formula (3):
R ¹ R ² C ^* (NHR ⁵ ) —R ³ R ⁴ C ^* (NH ₂ )
(In the formula, R ^{1 to} R ⁵ and C ^* represent the same meaning as described above.)
The ruthenium compound according to claim 1, which is an optically active diamine represented by the formula: Wherein Px is formula _(4): in R D R E P- (W) -PR F R G ( _{wherein, R D, R E, R} F, R G are each independently have a substituent Having an alkyl group which may be substituted, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or a substituent And R _D and R _E or R _F and R _G may be taken together to form an alicyclic group which may have a substituent. Represents a hydrocarbon group which may have a substituent.)
The ruthenium compound according to any one of claims 1 to 3, which is a phosphine ligand represented by the following formula: The Px is represented by the general formula (5):
_{R D R E P- (W)} -PR F R G
(In the formula, R _D , R _E , R _F , R _G and W represent the same meaning as described above.)
The ruthenium compound according to any one of claims 1 to 3, which is an optically active phosphine ligand represented by the formula: Formula ^{(6): R 1 R 2} C * (NHR 5 ') - (A) -R 3 R 4 C * (NH 2)
(R ^{1 to} R ⁴ , C ^* and A have the same meaning as described above. R ⁵ ′ represents an aryl group which may have a substituent or an aralkyl group which may have a substituent.)
An optically active diamine represented by Formula ^{(7): R 1 R 2} C * (NHR 5 ') -R 3 R 4 C * (NH 2)
(In the formula, R ^{1 to} R ⁴ , R ⁵ ′ and C ^* represent the same meaning as described above.)
An optically active diamine represented by General formula (8): Ra-CO-CH (Rb) -Rc
[Wherein, Ra and Rc each independently represent a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, It represents a good alkenyl group, an aralkyl group which may have a substituent or an aryl group which may have a substituent.
Rb represents any one of the following formulas (9), (10), and (11).
General formula (9): R ⁶ CO (R ⁷ ) N-
General formula (10): R ⁶ CO (R ⁸ CO) N—
General formula (11): R ⁶ R ⁷ N-
(Wherein, R ⁶ , R ⁷ and R ⁸ each independently represent a hydrogen atom, a formyl group, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, A cycloalkyl group which may have a group, a cycloalkoxy group which may have a substituent, an alkenyl group which may have a substituent, an aralkyl group which may have a substituent, aralkyloxy group optionally having a group, an aryloxy group which may have an optionally substituted aryl group or a substituent. Further, R ⁶ and R ⁷ or R ⁶ R ⁸ may combine to form a 5- to 8-membered nitrogen-containing heterocyclic ring.)]
Asymmetric hydrogenation of a racemic α-aminoketone represented by the formula (1) in the presence of one or more of the ruthenium compounds according to any one of claims 1 to 4 using hydrogen gas as a hydrogen source. Characterized by the fact that
General formula (12): Ra-C ^* H (OH) -C ^* H (Rb) -Rc
(Wherein Ra, Rb and C ^* have the same meanings as described above, and Rc has the same meaning as described above).