JP3778843B2 - Optically active amine derivatives and synthetic methods - Google Patents

Description

【００２１】
（式中、Ｒ１は天然型α−アミノ酸の無保護の側鎖または任意に保護化された側鎖を示し、Ｒ２は置換されていてもよいアルキル基、置換されてもよいアリール基又は置換されていてもよいアラルキル基を示す。）で表される光学活性５−オキサゾリジノン誘導体と、一般式（２）
【００２２】
【化３４】

【００２３】
（式中、Ｒ３は置換されていてもよいアリール基、置換されていてもよいヘテロ環を示し、ＭはＬｉ、ＭｇＸ、ＺｎＸ、ＴｉＸ₃、ＣｕＸの群から選択された１種を示し、さらにＸはハロゲン原子を示す。）で表される有機金属試薬と反応させ、一般式（３）
【００２４】
【化３５】

【００２５】
（式中、Ｒ１、Ｒ２およびＲ３は前記と同義である。）で表される光学活性５−ヒドロキシオキサゾリジン誘導体とし、続いて酸性条件下で処理することによって、一般式（４）
【００２６】
【化３６】

【００２７】
（式中、Ｒ１、Ｒ３は前記と同義である。Ｒ４は、水素原子あるいは保護基としての、置換されていてもよいアルキルオキシカルボニル基、置換されてもよいアリールオキシカルボニル基または置換されていてもよいアラルキルオキシカルボニル基を示す。）で表される光学活性アミノケトン誘導体に導いた後に、さらに還元剤での処理あるいは金属触媒を用いた接触水素化を施すことを特徴とする立体選択的な、一般式（５）
【００２８】
【化３７】

【００２９】
（式中、Ｒ１、Ｒ３およびＲ４は前記と同義）で表される光学活性アミノアルコール誘導体の製造方法（ただし、一般式（１）で表される光学活性５−オキサゾリジノン誘導体の４位の不斉炭素原子に結合しているＲ１および窒素原子で表される置換基の立体配置は、各反応を施しても変化しない。また、一般式（５）で表される光学活性アミノアルコール誘導体のアミノ基と水酸基の相対配置はエリスロ配置である。）。
【００３０】
（２） 一般式（１）
【００３１】
【化３８】

【００３２】
（式中、Ｒ１は天然型α−アミノ酸の無保護の側鎖または任意に保護化された側鎖を示し、Ｒ２は置換されていてもよいアルキル基、置換されてもよいアリール基又は置換されていてもよいアラルキル基を示す。）で表される光学活性５−オキサゾリジノン誘導体と、一般式（２）
【００３３】
【化３９】

【００３４】
（式中、Ｒ３は置換されていてもよいアリール基、置換されていてもよいヘテロ環を示し、ＭはＬｉ、ＭｇＸ、ＺｎＸ、ＴｉＸ₃、ＣｕＸの群から選択された１種を示し、さらにＸはハロゲン原子を示す。）で表される有機金属試薬と反応させ、一般式（３）
【００３５】
【化４０】

【００３６】
（式中、Ｒ１、Ｒ２およびＲ３は前記と同義である。）で表される光学活性５−ヒドロキシオキサゾリジン誘導体とし、続いて酸性条件下で処理することによって、一般式（４）
【００３７】
【化４１】

【００３８】
（式中、Ｒ１、Ｒ３は前記と同義である。Ｒ４は水素原子あるいは保護基としての、置換されていてもよいアルキルオキシカルボニル基、置換されてもよいアリールオキシカルボニル基または置換されていてもよいアラルキルオキシカルボニル基を示す。）で表される光学活性アミノケトン誘導体に導いた後に、さらに還元剤での処理あるいは金属触媒を用いた接触水素化を施すことで、一般式（５）
【００３９】
【化４２】

【００４０】
（式中、Ｒ１、Ｒ３およびＲ４は前記と同義）で表される光学活性アミノアルコール誘導体とし、Ｒ４が保護基である場合にアミノ基の脱保護化を行い、一般式（６）
【００４１】
【化４３】

【００４２】
（式中、Ｒ１およびＲ３は前記と同義である。）
で表わされる光学活性アミノアルコール誘導体を得ることを特徴とするアミノアルコール誘導体の製造方法（ただし、一般式（１）で表される光学活性５−オキサゾリジノン誘導体の４位の不斉炭素原子に結合しているＲ１および窒素原子で表される置換基の立体配置は、各反応を施しても変化しない。また、一般式（６）で表される光学活性アミノアルコール誘導体のアミノ基と水酸基の相対配置はエリスロ配置である。）。
【００４３】
（３） Ｒ１がメチル基、イソプロピル基、イソブチル基、ベンジル基、ヒドロキシメチル基、ベンジルオキシメチル基、フェニルチオメチル基、メチルチオメチル基、アルキルオキシカルボニルメチル基またはアルキルオキシカルボニルエチル基であり、Ｒ２がベンジル基、ｔｅｒｔ−ブチル基、メチル基、エチル基、イソプロピル基または９−フルオレニルメチル基である上記（１）または（２）に記載の光学活性アミノアルコール誘導体の製造方法。
【００４４】
（４） Ｒ３が、一般式（７）
【００４５】
【化４４】

【００４６】
（式中、Ｙはハロゲン原子を示す。）または一般式（８）
【００４７】
【化４５】

【００４８】
（式中、Ｒ５は水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアラルキル基、置換されてもよいフェニル基、置換されてもよいヘテロ環または置換されてもよいヘテロ環アルキル基を示す。）である上記（１）または（２）に記載の光学活性アミノアルコール誘導体の製造方法。
【００４９】
（５） Ｒ１がメチル基であり、かつＲ３が一般式（８）である上記（１）または（２）に記載の光学活性アミノアルコール誘導体の製造方法。
【００５０】
（６） 一般式（３）で表される光学活性５−ヒドロキシオキサゾリジン誘導体。
【００５１】
【化４６】

【００５２】
（式中、Ｒ１は天然型α−アミノ酸の無保護の側鎖または任意に保護化された側鎖を示し、Ｒ２は置換されていてもよいアルキル基、置換されてもよいアリール基又は置換されていてもよいアラルキル基を示し、Ｒ３は置換されていてもよいアリール基、置換されていてもよいヘテロ環を示す。）
（７） Ｒ１がメチル基、イソプロピル基、イソブチル基、ベンジル基、ヒドロキシメチル基、ベンジルオキシメチル基、フェニルチオメチル基、メチルチオメチル基、アルキルオキシカルボニルメチル基またはアルキルオキシカルボニルエチル基である上記（６）に記載の光学活性５−ヒドロキシオキサゾリジン誘導体。
【００５３】
（８） Ｒ２がベンジル基、ｔｅｒｔ−ブチル基、メチル基、エチル基、イソプロピル基または９−フルオレニルメチル基である上記（６）または（７）に記載の光学活性５−ヒドロキシオキサゾリジン誘導体。
【００５４】
（９） Ｒ３が、一般式（７）または（８）である上記（８）に記載の光学活性５−ヒドロキシオキサゾリジン誘導体。
【００５５】
【化４７】

【００５６】
（式中、Ｙはハロゲン原子を示す。）
【００５７】
【化４８】

【００５８】
（式中、Ｒ５は水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアラルキル基、置換されてもよいフェニル基、置換されてもよいヘテロ環または置換されてもよいヘテロ環アルキル基を示す。）
（１０） Ｒ１がメチル基である上記（９）に記載の光学活性５−ヒドロキシオキサゾリジン誘導体。
【００５９】
（１１） 一般式（１）
【００６０】
【化４９】

【００６１】
（式中、Ｒ１は天然型α−アミノ酸の無保護の側鎖または任意に保護化された側鎖を示し、Ｒ２は置換されていてもよいアルキル基、置換されてもよいアリール基又は置換されていてもよいアラルキル基を示す。）で表される光学活性５−オキサゾリジノン誘導体と、一般式（２）
【００６２】
【化５０】

【００６３】
（式中、Ｒ３は置換されていてもよいアリール基、置換されていてもよいヘテロ環を示し、ＭはＬｉ、ＭｇＸ、ＺｎＸ、ＴｉＸ₃、ＣｕＸの群から選択された１種を示し、さらにＸはハロゲン原子を示す。）で表される有機金属試薬と反応させ、一般式（３）
【００６４】
【化５１】

【００６５】
（式中、Ｒ１、Ｒ２およびＲ３は前記と同義である。）で表される光学活性５−ヒドロキシオキサゾリジン誘導体を得ることを特徴とする光学活性５−ヒドロキシオキサゾリジン誘導体の製造方法。
【００６６】
（１２） Ｒ１がメチル基、イソプロピル基、イソブチル基、ベンジル基、ヒドロキシメチル基、ベンジルオキシメチル基、フェニルチオメチル基、メチルチオメチル基、アルキルオキシカルボニルメチル基またはアルキルオキシカルボニルエチル基である上記（１１）に記載の光学活性５−ヒドロキシオキサゾリジン誘導体の製造方法。
【００６７】
（１３） Ｒ２がベンジル基、ｔｅｒｔ−ブチル基、メチル基、エチル基、イソプロピル基または９−フルオレニルメチル基である上記（１１）または（１２）に記載の光学活性５−ヒドロキシオキサゾリジン誘導体の製造方法。
【００６８】
（１４） Ｒ３が、一般式（７）または（８）である上記（１３）に記載の光学活性５−ヒドロキシオキサゾリジン誘導体の製造方法。
【００６９】
【化５２】

【００７０】
（式中、Ｙはハロゲン原子を示す。）
【００７１】
【化５３】

【００７２】
（式中、Ｒ５は水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアラルキル基、置換されてもよいフェニル基、置換されてもよいヘテロ環または置換されてもよいヘテロ環アルキル基を示す。）
（１５） Ｒ１がメチル基である上記（１４）に記載の光学活性５−ヒドロキシオキサゾリジン誘導体の製造方法。
【００７３】
（１６） 一般式（２）のＭが、ＭｇＸ（Ｘは前記と同義である。）である上記（１１）または（１２）記載の光学活性５−ヒドロキシオキサゾリジン誘導体の製造方法。
【００７４】
（１７） 一般式（４ａ）
【００７５】
【化５４】

【００７６】
（式中、Ｒ１ａはメチル基であり、かつＲ４ａが水素原子、ベンジルオキシカルボニル基、ｔｅｒｔ−ブトキシカルボニル基または９−フルオレニルメトキシカルボニル基であり、かつＲ３ａが４−ベンジルオキシフェニル基、４−メトキシフェニル基、２，４−ジフルオロフェニル基、２，４−ジクロロフェニル基または３−インドリル基である。）
で表わされることを特徴とするアミノケトン誘導体。
【００７７】
（１８） 一般式（３）
【００７８】
【化５５】

【００７９】
（式中、Ｒ１は天然型α−アミノ酸の無保護の側鎖または任意に保護化された側鎖を示し、Ｒ２は置換されていてもよいアルキル基、置換されてもよいアリール基又は置換されていてもよいアラルキル基を示し、Ｒ３は置換されていてもよいアリール基、置換されていてもよいヘテロ環を示す。）
で表わされる５−ヒドロキシオキサゾリジン誘導体を、酸性条件下で処理することにより、一般式（４）
【００８０】
【化５６】

【００８１】
（式中、Ｒ１、Ｒ３は前記と同義である。Ｒ４は、水素原子あるいは保護基としての、置換されていてもよいアルキルオキシカルボニル基、置換されてもよいアリールオキシカルボニル基または置換されていてもよいアラルキルオキシカルボニル基を示す。）
で表されるアミノケトン誘導体を得ることを特徴とするアミノケトン誘導体の製造方法。
【００８２】
（１９） 一般式（５ａ）
【００８３】
【化５７】

【００８４】
（式中、Ｒ１ａはメチル基であり、Ｒ３ｂが４−ベンジルオキシフェニル基であり、かつＲ４ｂがベンジルオキシカルボニル基であり、アミノ基と水酸基の相対配置はエリスロ配置である。）
で表わされることを特徴とする光学活性アルコール誘導体。
【００８５】
（２０） 一般式（４ｂ）
【００８６】
【化５８】

【００８７】
（式中、Ｒ１は天然型α−アミノ酸の無保護の側鎖または任意に保護化された側鎖を示し、Ｒ４は水素原子あるいは保護基としての、置換されていてもよいアルキルオキシカルボニル基、置換されてもよいアリールオキシカルボニル基または置換されていてもよいアラルキルオキシカルボニル基を示し、Ｒ３ｃが一般式（８）
【００８８】
【化５９】

【００８９】
で表わされる基であり、Ｒ５は水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアラルキル基、置換されてもよいフェニル基、置換されてもよいヘテロ環または置換されてもよいヘテロ環アルキル基を示す。）
で表わされる光学活性アミノケトン誘導体に対して、還元剤での処理あるいは金属触媒を用いた接触水素化を施すことにより、立体選択的な一般式（５ｂ）
【００９０】
【化６０】

【００９１】
（式中、Ｒ１、Ｒ３ｃおよびＲ４は前記と同義）で表される光学活性アミノアルコール誘導体を得ることを特徴とする光学活性アミノアルコール誘導体の製造方法（ただし、一般式（４ｂ）で表される光学活性アミノケトン誘導体の２位の不斉炭素原子に結合しているＲ１および窒素原子で表される置換基の立体配置は、各反応を施しても変化しない。一般式（５ｂ）で表される光学活性アミノアルコール誘導体のアミノ基と水酸基の相対配置はエリスロ配置である。）。
【００９２】
（２１） 一般式（４ｂ）
【００９３】
【化６１】

【００９４】
（式中、Ｒ１は天然型α−アミノ酸の無保護の側鎖または任意に保護化された側鎖を示し、Ｒ４は水素原子あるいは保護基としての、置換されていてもよいアルキルオキシカルボニル基、置換されてもよいアリールオキシカルボニル基または置換されていてもよいアラルキルオキシカルボニル基を示し、Ｒ３ｃが一般式（８）
【００９５】
【化６２】

【００９６】
で表わされる基であり、Ｒ５は水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアラルキル基、置換されてもよいフェニル基、置換されてもよいヘテロ環または置換されてもよいヘテロ環アルキル基を示す。）
で表わされる光学活性アミノケトン誘導体に対して、還元剤での処理あるいは金属触媒を用いた接触水素化を施すことにより立体選択的な一般式（５ｂ）
【００９７】
【化６３】

【００９８】
（式中、Ｒ１、Ｒ３ｃおよびＲ４は前記と同義）で表される光学活性アミノアルコール誘導体とし、Ｒ４が保護基である場合にアミノ基の脱保護化を行って一般式（６a）
【００９９】
【化６４】

【０１００】
（式中、Ｒ１およびＲ３ｃは前記と同義である。）
で表わされる光学活性アミノアルコール誘導体を得ることを特徴とする光学活アミノアルコール誘導体の製造方法（ただし、一般式（４ｂ）で表される光学活性アミノケトン誘導体の２位の不斉炭素原子に結合しているＲ１および窒素原子で表される置換基の立体配置は、各反応を施しても変化しない。一般式（６ａ）で表される光学活性アミノアルコール誘導体のアミノ基と水酸基の相対配置はエリスロ配置である。）。
【０１０１】
【発明の実施の形態】
以下、本発明についてさらに詳細に説明する。
【０１０２】
本発明の「天然型α−アミノ酸の無保護側鎖または任意に保護化された側鎖」とは、例えば「天然型α−アミノ酸の無保護側鎖」であるならば、アラニン、バリン、ロイシン、イソロイシン、セリン、スレオニン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、リジン、ヒドロキシリジン、アルギニン、システイン、シスチン、メチオニン、フェニルアラニン、チロシン、トリプトファン、ヒスチジン及びオルニチン等のα−炭素原子上の側鎖である。
【０１０３】
「任意に保護化された側鎖」であるならば、上記天然型α−アミノ酸のα−炭素原子上の側鎖の任意の官能基が、保護基によって保護化されたものを挙げることができる。この保護基は、当業者に周知の慣用の方法および保護基であって、本発明の方法において利用できるものであればよい。例えば、通常のアミノ酸の合成などにおいて使用されるアミノ基の保護基、チオールの保護基、水酸基の保護基、フェノールの保護基またはカルボキシル基の保護基でなどを用いることができる。
【０１０４】
「置換されてもよいアルキル基」とは、アルキル基の任意の位置が置換されてもよいアルキル基を意味する。アルキル基としては、メチル基、エチル基、イソプロピル基、tert-ブチル基、ペンチル基、ヘキシル基、オクチル基、デシル基またはアリル基等を挙げることができる。置換基としては、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【０１０５】
「置換されてもよいアリール基」とは、アリール基の任意の位置が置換されてもよいアリール基を意味する。アリール基としては、フェニル基、ナフチル基、アントラセニル基、フルオレニル基またはフェナントレニル基等を挙げることができる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【０１０６】
「置換されてもよいアラルキル基」とは、アラルキル基の任意の位置が置換されてもよいアラルキル基を意味する。アラルキル基としては、ベンジル基、ナフチルメチル基、フェニルエチル基または９−フルオレニルメチル基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【０１０７】
「置換されていてもよいヘテロ環」とは、ヘテロ環の任意の位置が置換されていてもよいヘテロ環を意味する。ヘテロ環としては、テトラヒドロピラニル基、テトラヒドロフラニル基、テトラヒドロチエニル基、ピペリジル基、モルホリニル基、ピペラジニル基、ピロリル基、フリル基、チエニル基、ピリジル基、フルフリル基、テニル基、ピリジルメチル基、ピリミジル基、ピラジル基、イミダゾイル基、イミダゾイルメチル基、インドリル基、インドリルメチル基、イソキノリル基、キノリル基またはチアゾリル基等が挙げられる。置換基としては、メチル基、tert-ブチル基またはベンジル基等のアルキル基、シクロプロパン、シクロペンタンまたはシクロヘキサン等のシクロアルキル基、フェニル基、水酸基、メトキシ基、ベンジルオキシ基またはメトキシエトキシ基等のアルコキシ基、フェノキシ基、ニトロ基、アミノ基、アミド基、カルボキシル基、アルコキシカルボニル基、フェノキシカルボニル基あるいはフッ素原子、塩素原子、臭素原子またはヨウ素原子等のハロゲン原子などを挙げることができる。
【０１０８】
置換されていてもよいヘテロ環アルキル基における「ヘテロ環アルキル基」とはアルキル基の任意の１または２以上の位置がヘテロ環で置換された基を意味し、この「ヘテロ環アルキル基」自体も置換されていてもよい。ヘテロ環及びアルキル基、並びにこれらの置換基の具体例としては、上記の「置換されてもよいアルキル基」及び「置換されていてもよいヘテロ環」の説明において例示したものと同様のものを挙げることができる。
【０１０９】
「置換されていてもよいアルキルオキシカルボニル基]とは、アルキルオキシカルボニル基の任意の１または２以上の位置が置換されていてもよいアルキルオキシカルボニル基を意味する。アルキルオキシカルボニル基としては、メトキシカルボニル基、エトキシカルボニル基、イソプロポキシカルボニル基、tert-ブトキシカルボニル基、ペンチルオキシカルボニル基、ヘキシルオキシカルボニル基、オクチルオキシカルボニル基、デシルオキシカルボニル基及びアリルオキシカルボニル基等を挙げることができる。置換基としては、水酸基、メトキシ基、ベンジルオキシ基及びメトキシエトキシ基等のアルコキシ基；フェノキシ基；ニトロ基；アミノ基；アミド基；カルボキシル基；アルコキシカルボニル基；フェノキシカルボニル基；及びフッ素原子、塩素原子、臭素原子及びヨウ素原子等のハロゲン原子；などを挙げることができる。
【０１１０】
「置換されていてもよいアリールオキシカルボニル基」とは、アリールオキシカルボニル基の任意の１または２以上の位置が置換されていてもよいアリールオキシカルボニル基を意味する。アリールオキシカルボニル基としては、フェノキシカルボニル基、ナフチルオキシカルボニル基、アントラセニルオキシカルボニル基、フルオレニルオキシカルボニル基及びフェナントレニルオキシカルボニル基等を挙げることができる。置換基としては、メチル基、tert-ブチル基及びベンジル基等のアルキル基及びアルアルキル基；シクロプロパン、シクロペンタンまたはシクロヘキサン等から得られるシクロアルキル基（例えばシクロプロピル基、シクロペンチル基及びシクロヘキシル基など）；フェニル基；水酸基；メトキシ基、ベンジルオキシ基及びメトキシエトキシ基等のアルコキシ基；フェノキシ基；ニトロ基；アミノ基；アミド基；カルボキシル基；アルコキシカルボニル基；フェノキシカルボニル基；及びフッ素原子、塩素原子、臭素原子及びヨウ素原子等のハロゲン原子；などを挙げることができる。
【０１１１】
「置換されていてもよいアラルキルオキシカルボニル基」とは、アラルキルオキシカルボニル基の任意の１または２以上の位置が置換されていてもよいアラルキルオキシカルボニル基を意味する。アラルキルオキシカルボニル基としては、ベンジルオキシカルボニル基、ナフチルメチルオキシカルボニル基、フェニルエチルオキシカルボニル基及び９−フルオレニルメチルオキシカルボニル基等が挙げられる。置換基としては、メチル基、tert-ブチル基及びベンジル基等のアルキル基及びアルアルキル基；シクロプロパン、シクロペンタンまたはシクロヘキサン等から得られるシクロアルキル基（例えばシクロプロピル基、シクロペンチル基及びシクロヘキシル基など）；フェニル基；水酸基；メトキシ基、ベンジルオキシ基及びメトキシエトキシ基等のアルコキシ基；フェノキシ基；ニトロ基；アミノ基；アミド基；カルボキシル基；アルコキシカルボニル基；フェノキシカルボニル基；及びフッ素原子、塩素原子、臭素原子及びヨウ素原子等のハロゲン原子；などを挙げることができる。
【０１１２】
上記の置換されていてもよい各基については、１または２以上の置換基を有することができ、複数の置換基を有する場合は各置換基がそれぞれ独立して上記の例示置換基から選択されたいずれかであることができる。
【０１１３】
「ハロゲン原子」としては、フッ素、塩素、臭素またはヨウ素等を挙げることができる。なお、一般式（７）における２つの「Ｙ」は同一でも異なるものでもよい。
【０１１４】
「還元剤」とは、一般式（４）で表されるアミノケトン誘導体のケトン部分をアルコール体に還元できる試薬を意味し、ボラン−テトラヒドロフラン錯体等のボラン試薬、水素化ホウ素ナトリウム、水素化ホウ素亜鉛、水素化トリメトキシホウ素ナトリウム等の水素化ホウ素試薬、水素化ジイソプロピルアルミニウム等のアルキルアルミニウム試薬、水素化アルミニウムリチウム、水素化トリアルコキシアルミニウムリチウム等の水素化アルミニウム試薬、トリクロロシラン、トリエチルシラン等のシラン試薬、液体アンモニア中のナトリウム金属またアルコール中のマグネシウム金属等が挙げられる。
【０１１５】
「金属触媒を用いた接触水素化」とは、金属触媒存在下における接触水素化反応による一般式（４）で表されるアミノケトン誘導体のケトン部分のアルコール体への還元を意味し、金属触媒としては、ラネーニッケル等のニッケル触媒、酸化白金等の白金触媒、パラジウム−炭素等のパラジウム触媒またはウィルキンソン触媒と呼ばれるクロロトリストリフェニルホスフィンロジウム等のロジウム触媒等を挙げることができる。
【０１１６】
「エリスロ配置」とは、連続する２個の不斉炭素原子の相対的な立体配置を示す表示法であり、例えば一般式（５）または（６）で表される化合物の場合、フィッシャーの投影式で表した時、置換基であるアミノ基および水酸基が同一側に存在する場合を、エリスロ配置と言う。
【０１１７】
以下に一般式（３）に含まれる代表的な光学活性５−ヒドロキシオキサゾリジン誘導体を表１〜表２１に例示する。また、一般式（４）に含まれる代表的な光学活性アミノケトン誘導体を表２２〜表２７に例示する。さらに、一般式（５）または（６）に含まれる代表的な光学活性アミノアルコール誘導体を表２８〜表３９に例示する。ただしこれら例示化合物は、本願発明を制限するものではない。なお、これらの表においてPhはフェニル基またはフェニレン基を、Meはメチル基を、Bocは保護基としてのtert−ブトキシカルボニル基をそれぞれ表わす。
【０１１８】
【表１】

【０１１９】
【表２】

【０１２０】
【表３】

【０１２１】
【表４】

【０１２２】
【表５】

【０１２３】
【表６】

【０１２４】
【表７】

【０１２５】
【表８】

【０１２６】
【表９】

【０１２７】
【表１０】

【０１２８】
【表１１】

【０１２９】
【表１２】

【０１３０】
【表１３】

【０１３１】
【表１４】

【０１３２】
【表１５】

【０１３３】
【表１６】

【０１３４】
【表１７】

【０１３５】
【表１８】

【０１３６】
【表１９】

【０１３７】
【表２０】

【０１３８】
【表２１】

【０１３９】
【表２２】

【０１４０】
【表２３】

【０１４１】
【表２４】

【０１４２】
【表２５】

【０１４３】
【表２６】

【０１４４】
【表２７】

【０１４５】
【表２８】

【０１４６】
【表２９】

【０１４７】
【表３０】

【０１４８】
【表３１】

【０１４９】
【表３２】

【０１５０】
【表３３】

【０１５１】
【表３４】

【０１５２】
【表３５】

【０１５３】
【表３６】

【０１５４】
【表３７】

【０１５５】
【表３８】

【０１５６】
【表３９】

【０１５７】
以下に、本発明の代表的な製造方法について説明する。
【０１５８】
本発明にかかる一般式（１）の化合物を出発物質とする一般式（５）または（６）の製造方法において、「光学活性５−オキサゾリジノン誘導体の４位の炭素原子に結合しているＲ１および窒素原子で表される置換基の立体配置は、各反応を施しても変化しない。また、一般式（５）で表される光学活性アミノアルコール誘導体のアミノ基と水酸基の相対配置はエリスロ配置である」で表される意味をさらに詳しく説明するならば、以下の反応式１および２で表わすことができる。
【０１５９】
【化６５】

【０１６０】
【化６６】

【０１６１】
すなわち、反応式１に示すように、一般式（９）で表されるＳ体の光学活性５−オキサゾリジノン誘導体からは、選択的に一般式（１２）または（１３）で表されるエリスロ配置で１Ｒ,２Ｓ体の光学活性アミノアルコール誘導体が得られる。また、反応式２に示すように、一般式（１４）で表されるＲ体の光学活性５−オキサゾリジノン誘導体からは、一般式（１７）または（１８）で表されるエリスロ配置で１Ｓ,２Ｒ体の光学活性アミノアルコール誘導体を製造することができる。
【０１６２】
各工程の製造方法についてさらに詳細に説明する。
【０１６３】
[一般式（１）で表される光学活性５−オキサゾリジノン誘導体の製造方法]
一般式（１）で表される光学活性５−オキサゾリジノン誘導体は、公知の方法、すなわち、入手容易でかつ安価な天然型α−アミノ酸から誘導されるＮ−ウレタン保護化された化合物とパラホルムアルデヒドを触媒量の酸の存在下反応させる方法（J.Am.Chem.Soc.1957.79.5736）に従って容易に製造することができる。
【０１６４】
[一般式（２）で表される有機金属試薬の製造方法]
一般式（２）で表される有機金属試薬は、公知の方法、例えば対応するハロゲン化合物に対する金属類の酸化的付加反応、あるいは有機金属試薬との金属交換反応等で容易に製造可能である。
【０１６５】
有機金属試薬の製造は、反応に対し不活性な溶媒であれば特に制限はないが、例えば、テトラヒドロフラン、ジエチルエーテル、ジオキサン、ジグライム等のエーテル類またはトルエン、キシレン等が使用可能である。これらのうちで基質の溶解性の点からテトラヒドロフラン単独またはテトラヒドロフランと他の溶媒との混合溶媒が好ましい。反応温度は、通常、−７８℃から溶媒の沸点で実施可能である。加えて、本発明にかかる製造方法においては、有機金属試薬として、特にグリニヤ試薬の使用が良好な結果を与える。
【０１６６】
グリニヤ試薬の製造方法としては、例えば、溶媒分散中のマグネシウムの中に１、２−ジブロモエタン、臭化エチルまたはヨウ素等の開始剤を触媒量添加した後、Ｒ３Ｘ（Ｘは前記と同義である。）で表されるハロゲン化合物を滴下することにより容易に実施することができる。
【０１６７】
[一般式（３）で表される光学活性５−ヒドロキシオキサゾリジン誘導体の製造方法]
一般式（１）で表される光学活性５−オキサゾリジノン誘導体と一般式（２）で表される有機金属試薬の反応において、反応溶媒は特に限定されないが有機金属試薬を調製した溶媒と同じ溶媒か、または反応に特に悪影響を与える事の無い混合溶媒が使用可能である。有機金属試薬の使用にあたり、その当量に特に制限は無いが、好ましくは基質の５−オキサゾリジノン誘導体に対し、等モルから５倍モル、さらに好ましくは１．0倍モルから２倍モルの範囲である。反応温度は特に制限はないが、好ましくは室温から−７８℃の範囲で実施可能である。本反応において光学活性５−オキサゾリジノン誘導体と有機金属試薬の添加順序は特に制限されず、光学活性５−オキサゾリジノン誘導体に有機金属試薬を添加しても、その逆に添加しても良い。反応は終了後、生成した光学活性５−ヒドロキシオキサゾリジン誘導体を得る場合は、反応液中の過剰の有機金属試薬を希塩酸、希硫酸、酢酸、塩化アンモニウム、クエン酸、硫酸水素カリウム等の水溶液で分解処理したのち、反応混合物から通常の分離精製手段、例えば抽出、濃縮、中和、濾過、再結晶、カラムクロマトグラフィー等の手段を用いることによって単離することができる。
【０１６８】
加えて、上述のとおりこの反応には、有機金属試薬として、特にグリニヤ試薬の使用が良好な結果を与える。有機金属試薬としてグリニヤ試薬を用いた場合、反応溶媒、使用当量、反応温度試薬の添加順序、反応の後処理、化合物の単離および精製については、前出の有機金属試薬を使用した場合の一般的な製造方法と同一である。
【０１６９】
また、上記の方法によって製造された光学活性５−オキサゾリジン誘導体は、通常、オキサゾリジンの５位の水酸基の立体に関してＲ体およびＳ体の両方が生成する為に、２種類のジアステレオマー体として得られる。場合によっては、高速液体クロマトグラフィーや核磁気共鳴スペクトル等を用いることでジアステレオマー混合比を決定することができる。また、ジアステレオマー混合比は、反応条件ならびに生成する化合物の特性によって変化するが、それぞれが単離可能な場合もあれば混合物として得られる場合もある。ただし、ジアステレオマー混合物は、次項で説明する酸処理等によって同一の一般式（４）で表される光学活性アミノケトン誘導体に変換できることから、製造中間体として考えた場合、製造コスト的な見地からあえて分離をする必要性は全くない。
【０１７０】
[一般式（４）で表される光学活性アミノケトン誘導体の製造方法]
光学活性５−ヒドロキシオキサゾリジン誘導体を一般式（４）で表される光学活性アミノケトン誘導体に酸性条件下にて変換する方法としては、通常、希釈溶媒中で実施可能である。使用される溶媒としては特に制限は無いが、メタノール、エタノールのアルコール類やアセトニトリル、テトラヒドロフラン、ベンゼン、トルエン、水等が挙げられる。またこれら溶媒は、単独もしくは混合溶媒として任意の混合比で用いることが可能である。使用される酸としては特に制限は無いが、塩酸、硫酸、過塩素酸などの無機酸類、ｐ−トルエンスルホン酸、メタンスルホン酸などの有機酸類、アンバーライトＩＲ−１２０、アンバーリストなどの酸性樹脂類やボロントリフルオロライドまたは塩化亜鉛等のルイス酸類が挙げられる。使用する酸の量は、光学活性５−ヒドロキシオキサゾリジン誘導体に対して等モルから３０倍モル、好ましくは１．５倍モルから１０倍モルである。また樹脂の場合は５重量％から２００重量％、好ましくは１０重量％〜１００重量％である。反応温度は−３０℃から溶媒の沸点で実施可能であり、特に０℃から１００℃が好ましい。反応混合物からアミノケトン誘導体の単離は、通常の分離精製手段、例えば抽出、濃縮、中和、濾過、再結晶、カラムクロマトグラフィー等の手段を用いることによって容易に単離することができる。
【０１７１】
[一般式（５）で表される光学活性アミノアルコール誘導体の製造方法]
一般式（４）で表されるアミノケトン誘導体を還元剤で還元し、一般式（５）で表される光学活性アルコール誘導体に変換する方法は、通常、希釈溶媒中で行われる。使用可能な溶媒としては特に制限は無いが、メタノール，エタノール、２−プロパノール、テトラヒドロフランまたは水等を挙げることができる。また、これらの希釈溶媒は、単独あるいは任意の混合比にて混合溶媒として使用することも可能である。
【０１７２】
還元剤としては、ボラン−テトラヒドロフラン錯体等のボラン試薬、水素化ホウ素ナトリウム、水素化ホウ素亜鉛、水素化トリメトキシホウ素ナトリウム等の水素化ホウ素試薬、水素化ジイソプロピルアルミニウム等のアルキルアルミニウム試薬、水素化アルミニウムリチウム、水素化トリアルコキシアルミニウムリチウム等の水素化アルミニウム試薬、トリクロロシラン、トリエチルシラン等のシラン試薬、液体アンモニア中のナトリウム金属またアルコール中のマグネシウム金属等が挙げられるが、特に、水素化ホウ素ナトリウム、水素化ホウ素亜鉛または水素化トリメトキシホウ素ナトリウム等の水素化ホウ素試薬が好適である。
【０１７３】
還元剤の使用量は、被還元物質に対し等モルから１０倍モルの範囲で使用可能である。反応温度は−７８℃〜溶媒の沸点の間で適宜選択され、好ましくは、−４０℃から８０℃の範囲である。
【０１７４】
一方、一般式（４）で表されるアミノケトン誘導体に対して、水素雰囲気下、適切な希釈溶媒中、適切な金属触媒の存在下に接触水素還元反応を行うことでもまた、一般式（５）で表される光学活性アミノアルコール誘導体が製造可能である。使用可能な水素圧に特に制限は無いが、常圧〜３ＭＰａ、好ましくは、０．３ＭＰａ〜１ＭＰａの範囲である。使用する溶媒は反応の進行を妨げないものであれば特に制限はないが、例えばメタノール、エタノール、ｎ−プロパノール、２−プロパノール、ｎ−ブタノールおよび水等を例示することができる。これらの使用溶媒は、単独あるいは任意の比率で混合して用いることも可能である。使用する溶媒の量は、化合物に対して１〜５０倍（重量／重量）であり、好ましくは３倍〜２０倍である。
【０１７５】
使用可能な金属触媒は、ラネーニッケル等のニッケル系触媒、白金−アルミナ、白金−炭素、酸化白金等の白金系触媒、パラジウム−アルミナ、パラジウム−炭素、水酸化パラジウム−炭素等パラジウム系触媒、酸化ルテニウム等のルテニウム系触媒またはウィルキンソン触媒と呼ばれるクロロトリストリフェニルホスフィンロジウム等のロジウム系触媒等を挙げることができ、さらに好適には、パラジウム系触媒を挙げることができる。反応に特に制限はないが、−２０〜２００℃の温度範囲で、さらに好ましくは０〜６０℃の範囲で実施可能である。
【０１７６】
さらに、必要に応じて一般式（５）に含有されるアミノ基が保護された化合物を脱保護化し、一般式（６）で表される遊離のアミン誘導体にする方法としては、酸または塩基による加水分解反応等が実施可能である。使用する酸または塩基に特に制限はないが、酸であるならば、塩酸、硫酸、臭化水素酸等の無機酸、トリフルオロメタンスルホン酸、トリフルオロ酢酸、p-トルエンスルホン酸、酢酸等の有機酸を、塩基であるならば、炭酸水素ナトリウム、炭酸カリウム、水酸化リチウム、水酸化ナトリウム等の無機塩基、トリエチルアミン、モルホリン、テトラブチルアンモニウムフルオライド、テトラエチルアンモニウムハイドロキシド等の有機塩基などを挙げることができる。
【０１７７】
このようにして得られた一般式（５）または（６）で表される光学活性アミノアルコール誘導体は、遊離アミンの結晶体として単離可能であるか、または必要に応じて適当な酸を付加して塩として単離可能である。また、これらの化合物は再結晶によって、ジアステレオマー純度および光学純度を向上させることも可能である。
【０１７８】
遊離アミンとして結晶で化合物を得る場合、結晶化に使用可能な溶媒は精製に適したものであれば特に制限は無いが、メタノール，エタノール、ｎ−プロパノール、２−プロパノール等のアルコール類、酢酸エチル、酢酸ブチル等のエステル類、クロロホルム、塩化メチレン等のハロゲン類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、水、アセトニトリル、２−ブタノン、トルエン等を単独もしくは混合して用いることができる。
【０１７９】
また塩にするため使用する酸として精製に適した結晶性の塩を与えるものであれば特に制限は無いが、例えば塩酸、臭化水素酸、硫酸、硝酸、硫酸、リン酸等の無機酸、酢酸、酒石酸、クエン酸、フマル酸、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等の有機酸が挙げられる。
【０１８０】
再結晶に使用する溶媒は、精製に適したものであれば特に制限は無いが、メタノール，エタノール、ｎ−プロパノール、２−プロパノール等のアルコール類、酢酸エチル、酢酸ブチル等のエステル類、クロロホルム、塩化メチレン等のハロゲン類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、水、アセトニトリル、２−ブタノン、トルエン等を単独もしくは混合して用いることができる。
【０１８１】
また、再結晶により精製した塩は、通常の方法によってアルカリ水溶液で処理し、遊離アミンとして単離することができる。
【０１８２】
【実施例】
以下に、本発明を参考例および実施例により更に詳細に説明するが、本発明はこれらによって限定されるものでない。
［参考例１］
（４Ｓ）−Ｎ−ベンジルオキシカルボニル−４−メチル−５−オキサゾリジノンの製造
【０１８３】
【化６７】

【０１８４】
ベンジルオキシカルボニル−Ｌ−アラニン（１９．３ｇ）、パラホルムアルデヒド（６．５６ｇ）、ｐ−トルエンスルホン酸・１水和物（０．１７ｇ）をトルエン（１９０ｍｌ）に懸濁し、生成する水を除きながら加熱還流した。反応終了後、室温に戻し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し，得られたトルエン溶液を無水硫酸ナトリウムで乾燥した。溶媒を減圧下に濃縮し、生成した結晶を濾過することにより標題化合物（１９．０ｇ）を白色結晶として収率９３％で得た。
融点:91-93℃
¹HNMR(CDCl₃,400MHz)δppm：
1.54(d,3H,J=6.4Hz),4.29-4.31(m,1H),5.18(s,2H),5.28-5.29(m,1H),5.47(br,1H),7.33-7.41(m,5H)
IR(KBr)ν_max 1778,1685cm^-1。
【０１８５】
［参考例２］
４−ベンジルオキシブロモベンゼンの製造
【０１８６】
【化６８】

【０１８７】
ｐ−ブロモフェノール（２５．０ｇ）、無水炭酸カリウム（２０．０ｇ）をＮ，Ｎ−ジメチルホルムアミド（２５０ｍｌ）に懸濁し、室温で塩化ベンジル（２０．２ｇ）を滴下した。９５〜１００℃で１時間加熱後、室温に戻し水（４００ｍｌ）を加えた。酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥した．溶媒を減圧下に濃縮し，標題化合物（３４．３ｇ）を乳白色結晶として、収率９０％で得た。
融点:55-57℃
¹H-NMR(CDCl₃,400MHz)δppm：
5.04(s,2H),6.83-6.87(m,2H),7.31-7.43(m,2H)。
【０１８８】
［実施例１]
（４Ｓ）−Ｎ−ベンジルオキシカルボニル−５−（４−ベンジルオキシフェニル）−４−メチル−５−ヒドロキシオキサゾリジンの製造（例示化合物番号：１００１）
【０１８９】
【化６９】

【０１９０】
[グリニヤ試薬の製造]
窒素雰囲気下、無水テトラヒドロフラン（２０ｍｌ）に金属マグネシウム（１．１６ｇ）、臭化エチル（０．２６ｇ）を加え、室温で１時間攪拌した。溶媒を還流下、参考例２で製造した４−ベンジルオキシブロモベンゼン（１０．５ｇ）を無水テトラヒドロフラン（２０ｍｌ）に溶かした溶液を約１時間かけて滴下した。滴下終了後さらに還流条件で４０分攪拌し、グリニヤ試薬を得た。
[グリニヤ反応]
参考例１で製造した（４Ｓ）−Ｎ−ベンジルオキシカルボニル−４−メチル−５−オキサゾリジノン（７．８４ｇ）を無水テトラヒドロフラン（４０ｍｌ）に溶かし−２０℃に冷却した。窒素雰囲気下この溶液中へ調製したグリニヤ試薬を内温−２０℃に維持しながら滴下した。滴下終了後、さらにそのままの温度で１時間攪拌し、５％塩酸水溶液で処理した。溶液を室温に戻し、酢酸エチルで抽出し有機層を無水硫酸ナトリウムで乾燥した。溶液を減圧下に濃縮し、濃縮残渣をシリカカラムクロマトグラフィー（展開液：クロロホルム）で精製することにより標題化合物（９．８５ｇ）をジアステレオマー混合物の白色結晶として、収率７１％で得た。
融点：83-86℃
¹H-NMR(CDCl₃,400MHz)からジアステレオマー比は、約2：１であった。
（ジアステレオマーの主生成体）
¹H-NMR(CDCl₃,400MHz)δppm：
1.47(d,3H,J=7.3Hz),3.81-3.84(m,1H),4.79-5.07(m,2H),5.14(s,2H),5.14(d,1H,J=8.4Hz),5.20(d,1H,J=8.4Hz),5.87(q,1H,J=7.3Hz),7.02(d,2H,J=8.8Hz),7.23-7.44(m,10H),8.01(d,2H,J=8.8Hz)
（ジアステレオマーの副生成体）
¹H-NMR(CDCl₃,400MHz)δppm：
1.49(d,3H,J=7.3Hz),3.60-3.70(m,1H),4.79-5.15(m,4H),5.13(s,2H),5.57(q,1H,J=7.3Hz),6.91(d,2H,J=8.8Hz),7.23-7.44(m,10H),7.83(d,2H,J=8.8Hz)
IR(neat) ν_max 3436,3033,1671,1603,1508cm^-1。
【０１９１】
［実施例２］
（２Ｓ）−２−（ベンジルオキシカルボニル）アミノ−１−（４−ベンジルオキシフェニル）−１−プロパノンの製造（例示化合物番号：２２００１）
【０１９２】
【化７０】

【０１９３】
実施例１で製造した（４Ｓ）−Ｎ−ベンジルオキシカルボニル−５−（４−ベンジルオキシフェニル）−４−メチル−５−ヒドロキシオキサゾリジン（３．８ｇ）をトルエン（５０ｍｌ）に溶かしアンバーリスト（３００ｍｇ）を加えて室温で反応した。反応終了後、アンバーリストを濾過し、濾液を減圧濃縮した。濃縮残渣をシリカカラムクロマトグラフィー（展開液：クロロホルム）により精製することにより、標題化合物（３．１ｇ）を淡黄色結晶として収率８８％で得た。
融点：89-91℃
¹H-NMR(CDCl₃,400MH)δppm：
1.43(d,3H,J=6.83Hz),5.13(s,2H),5.15(s,2H),5.28-5.31(m,1H),5.88(br,1H),7.03(d,2H,J=9.0Hz),7.31-7.44(m,10H),7.96(d,2H,J=9.0Hz)
IR(KBr) ν_max 3374,1712,1690cm^-1
光学純度；９３％ｅｅ
ＨＰＬＣ分析条件
カラム：ダイセル キラルパックＡＤ−ＲＨ（４．６ｍｍφ × １５０ｍｍ）
移動相：メタノール
流速：０．５ｍｌ／ｍｉｎ
波長：２５４ｎｍ
温度：室温
ｔ_R：（２Ｓ体）；１９．８分
（２Ｒ体）；２４．３分。
【０１９４】
［実施例３］
（２Ｓ）−２−（ベンジルオキシカルボニル）アミノ−１−（４−ベンジルオキシフェニル）−１−プロパノンの製造（例示化合物番号：２２００１）
【０１９５】
【化７１】

【０１９６】
[グリニヤ試薬の製造]
窒素雰囲気下、無水テトラヒドロフラン（１５ｍｌ）に金属マグネシウム（１．１６ｇ）、臭化エチル（０．０５ｇ）を加え、室温で３０分間攪拌した。溶媒を還流下、参考例２で製造した４−ベンジルオキシブロモベンゼン（１０．９２ｇ）を無水テトラヒドロフラン（１０ｍｌ）に溶かした溶液を約１時間かけて滴下した。滴下終了後さらに還流条件で３０分攪拌し、グリニヤ試薬を得た。
[グリニヤ反応]
参考例１で製造した（４Ｓ）−Ｎ−ベンジルオキシカルボニル−４−メチル−５−オキサゾリジノン（６．９７ｇ）を無水テトラヒドロフラン（２６ｍｌ）に溶かし−２０℃に冷却した。窒素雰囲気下この溶液中へ、調製したグリニャール試薬を内温−２０℃に維持しながら滴下装入した。滴下終了後、さらにそのままの温度で１時間攪拌した。
[脱ホルミル化反応]
６．５％塩酸水溶液を加え、３５から４０℃で６時間撹拌した。水層を分液操作によって廃棄し、あらためて５％塩酸水溶液を加え４５から５０℃で４時間撹拌した。反応液をトルエンで抽出し有機層を水で洗浄した。溶液を減圧下に濃縮し、２−プロパノール（７０ｇ）を加え、室温で６時間攪拌した。反応液を０〜５℃に冷却し晶析した結晶を濾過することにより標題化合物（８．６１ｇ）を淡黄色結晶として、収率８０％で得た。
融点：89-91℃
¹H-NMR(CDCl₃,400MHz)δppm：
1.43(d,3H,J=6.8Hz),5.13(s,2H),5.15(s,2H),5.28-5.31(m,1H),5.88(br,1H),7.03(d,2H,J=9.0Hz),7.31-7.44(m,10H),7.96(d,2H,J=9.3Hz)
IR(KBr) ν_max 3374,1712,1690cm^-1
比旋光度：[α]^D ₂₄＝+26°(C＝1.00, CHCl3)
光学純度：９９％ｅｅ（分析条件は実施例２と同じ）。
【０１９７】
［実施例４］
エリスロ−（１Ｒ，２Ｓ）-ｐ-ヒドロキシノルエフェドリンの製造（例示化合物番号：２８００１）
【０１９８】
【化７２】

【０１９９】
実施例２または３で製造した（２Ｓ）−２−（ベンジルオキシカルボニル）アミノ−１−（４−ベンジルオキシフェニル）−１−プロパノン（４．８ｇ）、メタノール（１００ｍｌ）、水（５０ｍｌ）および５％Ｐｄ／Ｃ（５０％含水品）（１．０ｇ）の混合溶液を水素雰囲気下（０．５ＭＰａ）に２０℃以下で２８時間攪拌した。触媒を濾過し、濾液を減圧下に濃縮し、濃縮残渣を２-プロパノールでスラッチングすることにより標題化合物（１．４４ｇ）を白色結晶として、収率７０％で得た。
融点：163-165℃
¹H-NMR(DMSO-d₆,400MHz)δppm：
0.85(d,3H,J=6.3Hz),2.77-2.83(m,1H),4.17(d,1H,J=5.3Hz),4.96(brs,1H),6.70(d,2H,J=8.3Hz),7.09(d,2H,J=8.3Hz),8.31(s,1H)
IR(KBr) ν_max 3470,1593,1484,1242cm^-1
比旋光度：[α]^D ₂₄＝-18°(C＝0.2, MeOH)
エリスロ：スレオ＝９９．５：０．５
ＨＰＬＣ分析条件
カラム：ＹＭＣ ＴＭＳ Ａ-１０２(６ｍｍφ × １５０ｍｍ)
移動相：アセトニトリル：水＝３：９７（ＮａＨ₂ＰＯ₄、Ｎａ₂ＨＰＯ₄を各１０ｍＭ、ｐＨ６．９）
検出波長：２７５ｎｍ
流速：０．５ｍｌ／ｍｉｎ
カラム温度：４０℃
ｔ_R：エリスロ体；６．９分
スレオ体；７．１分
光学純度：９９％ｅｅ
ＨＰＬＣ分析条件
カラム：ダイセル クラウンパック ＣＲ（−）（４ｍｍφ × １５０ｍｍ）
移動相：ＨＣｌＯ₄ａｑ（ｐＨ３．５）
検出波長：２７５ｎｍ
流速：０．１ｍｌ／ｍｉｎ
カラム温度：２５℃。
【０２００】
［実施例５］
エリスロ−（１Ｒ，２Ｓ）-２-(ベンジルオキシカルボニル)アミノ-１-(４-ベンジルオキシフェニル)-１-プロパノールの製造（例示化合物番号：３６００２）
【０２０１】
【化７３】

【０２０２】
メタノール（２５ｍｌ)に、水素化ホウ素ナトリウム（０．３２ｇ）を加えて０〜５℃に冷却した。その溶液に実施例２または３で製造した（２Ｓ）−２−（ベンジルオキシカルボニル）アミノ−１−（４−ベンジルオキシフェニル）−１−プロパノン（２．００ｇ）を装入し室温で攪拌した。晶析した結晶を濾過し、メタノールで洗浄したあと乾燥することにより標題化合物を(１．３９ｇ)を白色結晶として、収率６９％で得た。
融点：８５〜９１℃
¹H-NMR(DMSO-d₆,400MHz)δppm：
0.99(d,3H,J=6.59Hz), 3.61-3.62(m,1H),4.46-4.49(m,1H),4.95(s,2H),
5.07(s,2H),5.23(m,1H),6.93(d,2H,J=7.08),7.19-7.40(m,10H),7.44(d,2H,J=7.08),8.30(s,1H)
IR(KBr) ν_max 3334,1690cm^-1。
【０２０３】
[実施例６]
エリスロ−（１Ｒ，２Ｓ）-ｐ−ヒドロキシノルエフェドリンの製造（例示化合物番号：２８００１）
【０２０４】
【化７４】

【０２０５】
実施例５で製造したエリスロ−（１Ｒ，２Ｓ）-２-(ベンジルオキシカルボニル)アミノ-１-(４-ベンジルオキシフェニル)-１-プロパノール（１．３９ｇ）をメタノールに溶かし、５％Ｐｄ／Ｃ（５０％含水品）（０．０３ｇ）水素雰囲気下（常圧）、室温で２時間攪拌した。触媒を濾過後、濾液を減圧下に濃縮し濃縮残渣を２−プロパノールにより結晶化することにより標題化合物（０．６５ｇ）を白色結晶として、収率７５％で得た。
融点：163-165℃
¹H-NMR(DMSO-d₆,400MHz)δppm：
0.85(d,3H,J=6.3Hz),2.77-2.83(m,1H),4.17(d,1H,J=5.3Hz),4.96(brs,1H),6.70(d,2H,J=8.3Hz),7.09(d,2H,J=8.3Hz),8.31(s,1H)
IR(KBr) ν_max 3470,1593,1484,1242cm^-1
比旋光度：[α]^D ₂₄＝-18°(C＝0.2, MeOH)
エリスロ：スレオ＝９７．５：２．５（分析条件は実施例４と同様）
光学純度：９９％ｅｅ（分析条件は実施例４と同様）。
【０２０６】
［参考例３］
（４Ｓ）−Ｎ−ｔｅｒｔ−ブトキシカルボニル−４−メチル−５−オキサゾリジノンの製造
【０２０７】
【化７５】

【０２０８】
ｔｅｒｔ−ブトキシカルボニル−Ｌ−アラニン（１８．９ｇ）、パラホルムアルデヒド（６．７０ｇ）、ｐ−トルエンスルホン酸・１水和物（０．１９ｇ）をトルエン（２５０ｍｌ）に懸濁し、生成する水を除きながら加熱還流した。反応終了後、室温に戻し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し，得られたトルエン溶液を無水硫酸ナトリウムで乾燥した。溶媒を減圧下に濃縮し、生成した結晶を濾過することにより標題化合物（１４．２ｇ）を白色結晶として、収率７１％で得た。
融点:66-68℃
¹HNMR(CDCl₃,400MHz)δppm：
1.49(s,9H),1.52(d,2H,J=7.1Hz),4.23(br,1H),5.23(br,1H),5.41(br,1H)
IR(KBr)ν_max 1798,1698cm^-1。
【０２０９】
［実施例７］
（４Ｓ）−５−（４−ベンジルオキシフェニル）−Ｎ−ｔｅｒｔ−ブトキシカルボニル−４−メチル−５−ヒドロキシオキサゾリジンの製造（例示化合物番号：１０１５）
【０２１０】
【化７６】

【０２１１】
参考例３で製造した（４Ｓ）−Ｎ−ｔｅｒｔ−ブトキシカルボニル−４−メチル−５−オキサゾリジノン（６．６４ｇ）を無水テトラヒドロフラン（４０ｍｌ）に溶かし−２０℃に冷却した。窒素雰囲気下この溶液中へ、実施例１と同様に調製したグリニャール試薬を内温を−２０℃に維持しながら滴下した。滴下終了後、さらにそのままの温度で１時間攪拌し、５％塩酸水溶液で処理した。溶液を室温に戻し、酢酸エチルで抽出し有機層を無水硫酸ナトリウムで乾燥した。溶液を減圧下に濃縮し、濃縮残渣をシリカカラムクロマトグラフィー（展開液：クロロホルム）で精製することにより標題化合物（１０．２ｇ）をジアステレオマー混合物の淡黄色シロップとして、収率８０％で得た。
¹H-NMR(CDCl₃,400MHz)δppm：
1.35-1.38(m,3H),1.44-1.49(m,9H),4.90-5.85(m,5H),6.99-7.03(m,2H),7.35-7.44(m,5H),7.80-8.00(m,2H)
IR(KBr) ν_max 3422,1683cm^-1。
【０２１２】
［参考例４］
（４Ｓ）−Ｎ−ベンジルオキシカルボニル−４−イソプロピル−５−オキサゾリジノンの製造
【０２１３】
【化７７】

【０２１４】
ベンジルオキシカルボニル−Ｌ−バリン（２５．１ｇ）、パラホルムアルデヒド（６．７０ｇ）、ｐ−トルエンスルホン酸・１水和物（０．１９ｇ）をトルエン（２５０ｍｌ）に懸濁し、生成する水を除きながら加熱還流した。反応終了後、室温に戻し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し，得られたトルエン溶液を無水硫酸ナトリウムで乾燥した。溶媒を減圧下に濃縮し、標題化合物（２３．７ｇ）を無色透明シロップとして収率９０％で得た。
¹H-NMR(CDCl₃,400MHz)δppm：
1.00(d,3H,J=6.6Hz),1.07(d,3H,J=6.6Hz),2.30-2.40(m,1H),4.22(bs,1H),5.15-5.22(m,3H),5.56(bs,1H),7.15-7.40(m,5H)
IR(KBr)ν_max 1798,1698cm^-1。
【０２１５】
［実施例８］
（４Ｓ）−５−（４−ベンジルオキシフェニル）−Ｎ−ベンジルオキシカルボニル−４−イソプロピル−５−ヒドロキシオキサゾリジンの製造（例示化合物番号：２００１）
【０２１６】
【化７８】

【０２１７】
参考例４で製造した（４Ｓ）−ベンジルオキシカルボニル−４−イソプロピル−５−オキサゾリジノン（５．２０ｇ）を無水テトラヒドロフラン（２２ｍｌ）に溶かし−２０℃に冷却した。窒素雰囲気下この溶液中へ、実施例１と同様に調製したグリニャール試薬を内温を−１０〜２０℃に維持しながら滴下した。滴下終了後、さらにそのままの温度で１時間攪拌し、１２．５％塩酸水溶液で処理した。溶液を室温に戻し、トルエンで抽出し有機層を無水硫酸マグネシウムで乾燥した。溶液を減圧下に濃縮し、濃縮残渣をシリカカラムクロマトグラフィー（展開液：ヘキサン／酢酸エチル＝２／１）で精製することにより標題化合物（４．７２ｇ）をジアステレオマー混合物の淡黄色シロップとして、収率５３％で得た。
【０２１８】
¹H-NMR(CDCl₃,400MHz)からジアステレオマー比は、約1.9：１であった。
（ジアステレオマーの主生成体）
¹H-NMR(CDCl₃,400MHz)δppm：
0.85(d,3H,J=6.6Hz),0.98.(d,2H,J=6.6),2.29-2.40(m,1H),3.29(m,1H),4.79(m,1H),5.10-5.50(m,6H),7.02(d,2H,J=8.7Hz),7.28-7.45(m,10H),8.11(d,2H,J=8.7Hz)
（ジアステレオマーの副生成体）
¹H-NMR(CDCl₃,400MHz)δppm：
0.83(d,3H,J=6.2Hz),1.00.(d,2H,J=6.2),2.29-2.40(m,1H),3.55(m,1H),4.79(m,1H),5.10-5.50(m,6H),6.81(d,2H,J=9.0Hz),7.28-7.45(m,10H),7.85(d,2H,J=9.0Hz)
IR(KBr) ν_max 3422,1683cm^-1。
【０２１９】
［実施例９］
（２Ｓ）−２−（ベンジルオキシカルボニル）アミノ−１−（４−ベンジルオキシフェニル）−３−メチル−１−ブタノンの製造（例示化合物番号：２３００１）
【０２２０】
【化７９】

【０２２１】
実施例８で製造した（４Ｓ）−Ｎ−ベンジルオキシカルボニル−５−（４−ベンジルオキシフェニル）−４−イソプルピル−５−ヒドロキシオキサゾリジン（１．３８ｇ）をテトラヒドロフラン（４ｍｌ）に溶解し、水（５ｍｌ）および濃塩酸（２ｍｌ）を加え、室温で２４時間撹拌した。反応液をトルエンで希釈し、水層を廃棄した後、有機層を水にて３回洗浄した。有機層を無水硫酸マグネシウムで乾燥した後に、減圧濃縮した。濃縮残渣をシリカカラムクロマトグラフィー（展開液：ヘキサン／酢酸エチル＝２／１）により精製し、標題化合物（４６６ｍｇ）を淡黄色結晶として、収率３６％で得た。
融点：75〜77℃
¹H-NMR(CDCl₃,400MHz)δppm：
0.76(d,3H,J=6.8Hz),1.04(d,3H,J=6.8Hz),2.16(m,1H),5.11(s,1H),5.14(s,1H),5.24(dd,1H,J=8.8,4Hz),5.70(d,1H,J=8.8Hz),7.03(d,2H,J=8.8Hz),7.30-7.45(m,10H),7.96(d,2H,J=8.8Hz)
IR(KBr) ν_max 3422,1683cm^-1。
【０２２２】
［実施例１０］
（４Ｓ）−Ｎ−ベンジルオキシカルボニル−５−（４−メトキシフェニル）−４−メチル−５−ヒドロキシオキサゾリジンの製造（例示化合物番号：１０２０）
【０２２３】
【化８０】

【０２２４】
[グリニヤ試薬の製造]
窒素雰囲気下、無水テトラヒドロフラン（２０ｍｌ）に金属マグネシウム（７５６ｍｇ）、臭化エチル（０．１ｇ）を加え、室温で１時間攪拌した。溶媒を還流下、４−ブロモアニソール（３．７６ｇ）を無水テトラヒドロフラン（２０ｍｌ）に溶かした溶液を約１時間かけて滴下した。滴下終了後さらに還流条件で４０分攪拌し、グリニヤ試薬を得た。
[グリニヤ反応]
参考例１で製造した（４Ｓ）−Ｎ−ベンジルオキシカルボニル−４−メチル−５−オキサゾリジノン（７．７０ｇ）を無水テトラヒドロフラン（３０ｍｌ）に溶かし−２０℃に冷却した。窒素雰囲気下この溶液中へ調製したグリニヤ試薬を内温−２０℃に維持しながら滴下した。滴下終了後、さらにそのままの温度で１時間攪拌し、５％塩酸水溶液で処理した。溶液を室温に戻し、酢酸エチルで抽出し有機層を無水硫酸ナトリウムで乾燥した。溶液を減圧下に濃縮し、濃縮残渣をシリカカラムクロマトグラフィー（展開液：ヘキサン／酢酸エチル＝２／１→３／２）で精製することにより題記化合物（４．５６ｇ）をジアステレオマー混合物の無色透明シロップとして収率６６％で得た。
【０２２５】
¹H-NMR(CDCl₃,400MHz)による分析から、ジアステレオマー混合比は約２：１であった。
（ジアステレオマー：主生成物）
¹H-NMR(CDCl₃,400MHz)δppm：
1.47(d,3H,J=7Hz),3.70-3.75(m,1H),3.87(s,3H),4.80-5.20(m,2H),5.16(d,1H,J=12.4Hz),5.25(d,1H,J=12.4Hz),5.88(q,1H,J=7Hz),6.95(d,2H,J=9.0Hz),7.23-7.36(m,5H),8.02(d,2H,J=9.0Hz)
（ジアステレオマー：副生成物）
¹H-NMR(CDCl₃,400MHz)δppm：
1.48(d,3H,J=7Hz),3.70-3.75(m,1H),3.86(s,3H),4.80-5.20(m,2H),5.16(d,1H,J=12.4Hz),5.25(d,1H,J=12.4Hz),5.57(q,1H,J=7Hz),6.83(d,2H,J=8.8Hz),7.23-7.36(m,5H),8.83(d,2H,J=8.8Hz)
IR(neat) ν_max 3443,1697,1601cm^-1。
【０２２６】
［実施例１１］
（２Ｓ）−２−（ベンジルオキシカルボニル）アミノ−１−（４−メトキシフェニル）−１−プロパノンの製造（例示化合物番号：２２０２０）
【０２２７】
【化８１】

【０２２８】
実施例１０で得られた（４Ｓ）−Ｎ−ベンジルオキシカルボニル−５−（４−メトキシフェニル）−４−メチル−５−ヒドロキシオキサゾリジン（１．７２ｇ）をテトラヒドロフラン（４ｍｌ）に溶解し、水（５ｍｌ）および濃塩酸（２ｍｌ）を加え、室温で２４時間撹拌した。反応液をトルエンで希釈し、水層を廃棄した後、有機層を水にて３回洗浄した。有機層を無水硫酸マグネシウムで乾燥した後に、減圧濃縮した。濃縮残渣をシリカカラムクロマトグラフィー（展開液：ヘキサン／酢酸エチル＝３／１）により精製し、標題化合物（１．４０ｍｇ）を白色結晶として、収率８９％で得た。
融点：46〜48℃
¹H-NMR(CDCl₃,400MHz)δppm：
1.43(d,3H,J=6.8Hz),3.88(s,3H),5.13(s,2H),5.30(dq,1H,J=7.1,6.8Hz),5.91(d,1H,J=7.1Hz),6.96(d,2H,J=8.8Hz),7.29-7.37(m,5H),7.96(d,2H,J=8.8Hz)
IR(KBr) ν_max 3458,2958,1714,1676,1597,1527cm^-1。
【０２２９】
［実施例１２］
（４Ｓ）−Ｎ−ベンジルオキシカルボニル−５−（２，４−ジフルオロフェニル）−４−メチル−５−ヒドロキシオキサゾリジンの製造（例示化合物番号：１０３０）
【０２３０】
【化８２】

【０２３１】
[グリニヤ試薬の製造]
窒素雰囲気下、無水テトラヒドロフラン（２０ｍｌ）に金属マグネシウム（２．５６ｇ）、ヨウ素（３０mｇ）を加え、室温で２,４−ジフルオロブロモベンゼン（１９．３ｇ）を無水テトラヒドロフラン（６０ｍｌ）に溶かした溶液の１／５を一括装入した。装入５分後から反応液温度の上昇を伴なって、グリニヤ試薬の生成が確認された。反応温度を４５℃以下に保ったまま、残りの試薬４／５を約３０分かけて滴下した。滴下終了後さらに２５〜４０℃で３０分攪拌し、グリニヤ試薬を得た。
[グリニヤ反応]
参考例１で製造した（４Ｓ）−Ｎ−ベンジルオキシカルボニル−４−メチル−５−オキサゾリジノン（２１．２ｇ）を無水テトラヒドロフラン（６８ｍｌ）に溶かし−２０℃に冷却した。窒素雰囲気下この溶液中へ調製したグリニヤ試薬を内温−２０℃に維持しながら滴下した。滴下終了後、さらにそのままの温度で１時間攪拌し、５％塩酸水溶液で処理した。溶液を室温に戻し、トルエンで抽出し有機層を無水硫酸マグネシウムで乾燥した。溶液を減圧下に濃縮し、濃縮残渣をシリカカラムクロマトグラフィー（展開液：ヘキサン／酢酸エチル＝２／１）で精製することにより標題化合物（２１．４ｇ）をジアステレオマー混合物の淡黄色シロップとして、収率６８％で得た。
¹H-NMR(CDCl₃,400MHz)δppm：
1.52and1.51(2d,3H,J=6.8Hz),3.20-3.45(m,1H),4.30-4.50(m,1H),4.70-5.45(m,4H),6.55-6.90(m,2H),7.30-7.40(m,5H),7.50-7.90(m,1H)
IR(KBr) ν_max 3402,1803,1701,1614cm^-1。
【０２３２】
［実施例１３］
（２Ｓ）−２−（ベンジルオキシカルボニル）アミノ−１−（２,４−ジフルオロフェニル）−１−プロパノンの製造（例示化合物番号：２２０３０）
【０２３３】
【化８３】

【０２３４】
実施例１２で製造された（４Ｓ）−２−（ベンジルオキシカルボニル）アミノ−５−（２,４−ジフルオロフェニル）−４−メチル−５−ヒドロキシオキサゾリジン（１４．０ｇ）をテトラヒドロフラン（７０ｍｌ）に溶解し、水（５０ｍｌ）および濃塩酸（２０ｍｌ）を加え、室温で２４時間撹拌した。反応液をトルエンで希釈し、水層を廃棄した後、有機層を水にて３回洗浄した。有機層を無水硫酸マグネシウムで乾燥した後に、減圧濃縮した。濃縮残渣をシリカカラムクロマトグラフィー（展開液：ヘキサン／酢酸エチル＝３／１）により精製し、標題化合物（１１．７ｇ）を淡黄色シロップとして収率９２％で得た。
¹H-NMR(CDCl₃,400MHz)δppm：
1.40(d,3H,J=7.0Hz),5.10(s,2H),5.05-5.20(m,1H),5.75-5.80(m,1H),6.88-6.94(m,1H),6.98-7.02(m,1H),7.30-7.37(m,5H),7.95-8.01(m,1H)
IR(neat) ν_max 3358,1718,1681,1611,1532cm^-1
光学純度：９０％ee
ＨＰＬＣ分析条件
カラム：ダイセル キラルパックＡＤ−ＲＨ（４．６ｍｍφ × １５０ｍｍ）
移動相：メタノール
流速：０．５ｍｌ／ｍｉｎ
波長：２５４ｎｍ
温度：室温
ｔ_R：（２Ｒ体）；６．５分
（２Ｓ体）；７．５分。
【０２３５】
［参考例５］
（４Ｒ）−Ｎ−ベンジルオキシカルボニル−４−メチル−５−オキサゾリジノンの製造
【０２３６】
【化８４】

【０２３７】
ベンジルオキシカルボニル−Ｄ−アラニン（１９．３ｇ）、パラホルムアルデヒド（６．５６ｇ）、ｐ−トルエンスルホン酸・１水和物（０．１７ｇ）をトルエン（１９０ｍｌ）に懸濁し、生成する水を除きながら加熱還流した。反応終了後、室温に戻し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し，得られたトルエン溶液を無水硫酸ナトリウムで乾燥した。溶媒を減圧下に濃縮し、生成した結晶を濾過することにより標題化合物（１７．４ｇ）を白色結晶として、収率８５％で得た。
融点:89-91℃
¹HNMR(CDCl₃,400MHz)δppm：
1.54(d,3H,J=6.4Hz),4.29-4.31(m,1H),5.18(s,2H),5.28-5.29(m,1H),5.47(br,1H),7.33-7.41(m,5H)
IR(KBr)ν_max 1778,1685cm^-1。
【０２３８】
［実施例１４］
（４Ｒ）−Ｎ−ベンジルオキシカルボニル−５−（４−ベンジルオキシフェニル）−４−メチル−５−ヒドロキシオキサゾリジンの製造（例示化合物番号：１９００１）
【０２３９】
【化８５】

【０２４０】
参考例５で製造された（４Ｒ）−Ｎ−ベンジルオキシカルボニル−４−メチル−５−オキサゾリジノン（２．６１ｇ）を実施例１と同様に処理し、標題化合物（９．０ｇ）をジアステレオマー混合物の白色結晶として、収率６５％で得た。
融点：82-86℃
¹H-NMR(CDCl₃,400MHz)からジアステレオマー比は、約2：１であった。
（ジアステレオマーの主生成体）
¹H-NMR(CDCl₃,400MHz)δppm：
1.47(d,3H,J=7.3Hz),3.81-3.84(m,1H),4.79-5.07(m,2H),5.14(s,2H),5.14(d,1H,J=8.4Hz),5.20(d,1H,J=8.4Hz),5.87(q,1H,J=7.3Hz),7.02(d,2H,J=8.8Hz),7.23-7.44(m,10H),8.01(d,2H,J=8.8Hz)
（ジアステレオマーの副生成体）
¹H-NMR(CDCl₃,400MHz)δppm：
1.49(d,3H,J=7.3Hz),3.60-3.70(m,1H),4.79-5.15(m,4H),5.13(s,2H),5.57(q,1H,J=7.3Hz),6.91(d,2H,J=8.8Hz),7.23-7.44(m,10H),7.83(d,2H,J=8.8Hz)
IR(neat) ν_max 3436,3033,1671,1603,1508cm^-1。
【０２４１】
［実施例１５］
（２Ｒ）−２−（ベンジルオキシカルボニル）アミノ−１−（４−ベンジルオキシフェニル）−１−プロパノンの製造（例示化合物番号：２５００１）
【０２４２】
【化８６】

【０２４３】
実施例１４で製造された（４Ｒ）−Ｎ−ベンジルオキシカルボニル−５−（４−ベンジルオキシフェニル）−４−メチル−５−ヒドロキシオキサゾリジン（２．１ｇ）を実施例９と同様に処理し、標題の化合物（１．８５ｇ）を淡黄色結晶として、収率９５％で得た。
融点：88-90℃
¹H-NMR(CDCl₃,400MH)δppm：
1.43(d,3H,J=6.83Hz),5.13(s,2H),5.15(s,2H),5.28-5.31(m,1H),5.88(br,1H),7.03(d,2H,J=9.0Hz),7.31-7.44(m,10H),7.96(d,2H,J=9.0Hz)
IR(KBr) ν_max 3374,1712,1690cm^-1
比旋光度：[α]^D ₂₄＝-25°(C＝1.00, CHCl3)
光学純度：９８％ee（分析条件は実施例３と同じ）。
【０２４４】
［実施例１６］
（４Ｒ）−Ｎ−ベンジルオキシカルボニル−５−（２，４−ジフルオロフェニル）−４−メチル−５−ヒドロキシオキサゾリジンの製造（例示化合物番号：１９０３０）
【０２４５】
【化８７】

【０２４６】
[グリニヤ試薬の製造]
窒素雰囲気下、無水テトラヒドロフラン（１０ｍｌ）に金属マグネシウム（１．２８ｇ）、ヨウ素（２０mｇ）を加え、室温で２,４−ジフルオロブロモベンゼン（９．６５ｇ）を無水テトラヒドロフラン（３０ｍｌ）に溶かした溶液を用い、実施例１２と同様に処理し、グリニヤ試薬を得た。
[グリニヤ反応]
（４Ｒ）−Ｎ−ベンジルオキシカルボニル−４−メチル−５−オキサゾリジノン（１０．６ｇ）を無水テトラヒドロフラン（３４ｍｌ）に溶解し、実施例１２と同様に処理し、標題化合物（１０．７ｇ）をジアステレオマー混合物の淡黄色シロップとして、収率６８％で得た。
¹H-NMR(CDCl₃,400MHz)δppm：
1.52and1.51(2d,3H,J=6.8Hz),3.20-3.45(m,1H),4.30-4.50(m,1H),4.70-5.45(m,4H),6.55-6.90(m,2H),7.30-7.40(m,5H),7.50-7.90(m,1H)
IR(KBr) ν_max 3402,1803,1701,1614cm^-1。
【０２４７】
［実施例１７］
（２Ｒ）−２−（ベンジルオキシカルボニル）アミノ−１−（２,４−ジフルオロフェニル）−１−プロパノンの製造（例示化合物番号：２５０３０）
【０２４８】
【化８８】

【０２４９】
実施例１６で製造された（４Ｒ）−２−（ベンジルオキシカルボニル）アミノ−５−（２,４−ジフルオロフェニル）−４−メチル−５−ヒドロキシオキサゾリジン（６．９８ｇ）をテトラヒドロフラン（３５ｍｌ）に溶解し、水（２５ｍｌ）および濃塩酸（１０ｍｌ）を加え、実施例１３と同様に処理し、標題化合物（５．８７ｇ）を淡黄色シロップとして収率９２％で得た。
¹H-NMR(CDCl₃,400MHz)δppm：
1.40(d,3H,J=7.0Hz),5.10(s,2H),5.05-5.20(m,1H),5.75-5.80(m,1H),6.88-6.94(m,1H),6.98-7.02(m,1H),7.30-7.37(m,5H),7.95-8.01(m,1H)
IR(neat) ν_max 3358,1718,1681,1611,1532cm^-1
光学純度：９０％ee（分析条件は、実施例１２と同様）
【０２５０】
【発明の効果】
本発明により、医薬、農薬等の製造中間体として有用な一般式（５）または（６）で表される光学活性アミノアルコール誘導体を、工業的な観点から見て、光学純度良く、安価に、かつ大量製造時においても安定的に製造することが可能となった。加えて、上記の光学活性アミノアルコール誘導体、またはその他の光学活性アミン誘導体を製造する上で重要な中間体である一般式（３）で表される光学活性５−ヒドロキシオキサゾリジン誘導体およびその一般的な製造方法、ならびに一般式（４）で表される光学活性アミノケトン誘導体およびその一般的な製造方法を確立した。これらの製造技術は、上記の光学活性アミノアルコール誘導体の製造以外にも、広く光学活性アミン誘導体の製造方法に利用可能であり、工業的な観点から非常に優れた技術である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing an optically active amino alcohol derivative useful as a production intermediate for pharmaceuticals, agricultural chemicals and the like, for example, erythro- (1R, 2S) -p-hydroxynorephedrine. Furthermore, the present invention relates to an optically active 5-hydroxyoxazolidine derivative which is an important intermediate in the production of the above optically active amino alcohol derivative or to the production of many other optically active amine derivatives, and a method for producing the same. The optically active 5-hydroxyoxazolidine derivative according to the present invention is also very useful as an intermediate for producing an azole antibacterial agent, for example. In addition, the compound containing the asymmetric carbon substituted with R1 and the amino group represented by the general formula (1), (3) or (4) represents an R form or an S form, and represents a racemic mixture of R and S. Absent. In the case of a compound containing two consecutive asymmetric carbons substituted with an amino group and a hydroxyl group represented by the general formula (5) or (6), it represents an R—S or S—R isomer, and R—R Or SS form is not shown.
[0002]
[Prior art]
In recent years, the demand for optically active substances has been increasing in various fields including medical and agricultural chemicals. From an industrial standpoint, development of a simpler and less expensive method for producing an optically active substance is strongly demanded.
[0003]
First, the following three methods have been used as conventional techniques relating to the production of an optically active amino alcohol derivative according to the present invention. That is,
[1] A method of chemically synthesizing a racemate of a target compound and then optically resolving it through a diastereomeric salt to obtain a target optically active substance.
[2] A method for obtaining an optically active substance from an optically inactive substance by using a chemical or biological asymmetric synthesis technique.
[3] A method based on a so-called chiral pool method in which an optically active substance is obtained while starting from an optically active raw material and suppressing racemization.
[0004]
[1] “Method of optically resolving the corresponding racemate after chemically synthesizing via diastereomeric salt”, etc., as an example, in the category of optically active amino alcohol derivatives as target compounds in the present invention If the conventional manufacturing method of the erythro- (1R, 2S) -p-hydroxynorephedrine contained is given, after first chemically synthesizing the racemic body which has the target structure, optically active carboxylic acids, for example, D-tartaric acid etc. (J. Med. Chem., 1977, 20, 7, 978).
[0005]
However, as long as the production method by the optical resolution method is performed, the yield cannot theoretically exceed 50% unless the enantiomer is recovered and further subjected to a special operation such as racemization. In addition, the optically active carboxylic acid or the like necessary for resolution is generally expensive, and in many cases, it is necessary to repeat the recrystallization operation and the like several times. In other words, the optical resolution method requires an expensive resolution agent and requires a multi-stage operation, and thus is an expensive production method from an industrial standpoint.
[0006]
[2] “Method for obtaining optically active substance from optically inactive substance using chemical or biological asymmetric synthesis technique” has been particularly remarkable in technical development in recent years. For example, a chemical synthesis asymmetric synthesis technology (J. Am. Chem. Soc., 1980, 102, 7932) including the use of an asymmetric reduction catalyst or the like, or biotechnological asymmetric using an enzyme, etc. Examples thereof include a synthesis technique (Japanese Patent Laid-Open No. 62-29998). However, unfortunately, the specificity for each substrate is greatly involved in actual production, and it has not necessarily been able to be applied to all production. It was hard to say that it was an inexpensive method. In fact, in the case of the optically active aminoalcohol derivative as the target compound in the present invention, the industrially suitable production method based on the chemical or biotechnological asymmetric synthesis technique as described above has been put into practical use until now. Absent.
[0007]
In [3], “a method based on the so-called chiral pool method, in which an optically active substance is obtained while starting from an optically active raw material while suppressing racemization” has been difficult to suppress until now. Left many problems to be solved, such as requiring multiple processes. Until now, no industrially satisfactory production method has been reported for the optically active amino alcohol derivative as the target compound in the present invention.
[0008]
That is, in the conventional technique for the production of optically active amino alcohol derivatives, only industrially difficult or very costly methods are known, and a cheaper and simpler new production method is known. Is strongly desired.
[0009]
Moreover, only the following [4] to [6] are known as conventional techniques relating to the production of an optically active 5-hydroxyoxazolidine derivative which is an important production intermediate in the production method of the present invention. .
[4] A method of reacting (4S) -N- (ethoxycarbonyl) -4- (2-phenylethyl) -5-oxazolidinone with 4-chloro-3-methoxyphenylmagnesium bromide (WO95 / 09155).
[5] A method of reacting a 5-oxazolidinone derivative with halomethyllithium (WO00 / 53571).
[6] A method in which a 5-oxazolidinone derivative is reacted with (trifluoromethyl) trimethylsilane (J. Org. Chem. 1998, 63 (15), 5179).
[0010]
However, in the case of the above [4], the compound used as a raw material is a special non-natural amino acid-related compound having a phenylethyl group in the side chain, and a multi-stage reaction is required for its production, In general, it is difficult to obtain. Also, in terms of manufacturing cost, it is not an inexpensive raw material but has a big problem in terms of raw material supply. In addition, the compound described in the above [4] is an extremely limited production method having only one example of production having a 4-chloro-3-methoxyphenyl group at the 5-position of the main skeleton oxazolidinone, and uses thereof. However, it is only used as a raw material for a limited drug (Sch39166). Therefore, it is difficult to say that the production method exemplified in [4] is a widely general production method, and as a conventional technique, for a versatile optically active 5-hydroxyoxazolidine derivative, the production method is as follows. It is hard to say that it was well established.
[0011]
Furthermore, the compound according to the above [5] or [6] reacts a special functional group such as a haloalkyl group such as a chloromethyl group or a trifluoromethyl group at the 5-position of the main skeleton oxazolidine, As a synthetic intermediate for agricultural chemicals, no highly versatile aryl group or heterocycle was contained.
[0012]
That is, although the demand for optically active aminoalcohol derivatives having an aryl group or a heterocycle is increasing in various fields including the pharmaceutical and agrochemical fields, the conventional technology has been No general production method has been found for an optically active 5-hydroxyoxazolidine derivative having an aryl group or heterocycle at the 5-position, which is an important intermediate.
[0013]
In addition, as a conventional technique relating to a method for producing an optically active aminoketone derivative according to the present invention, a method is known in which a carboxyl group of an N-protected amino acid is converted to an acid chloride and is produced using a Friedel-Crafts reaction ( J. Am. Chem. Soc. 1981, 103, 6157). However, acylation by Friedel-Crafts reaction causes racemization, is greatly restricted by the structure of the acylated compound, and it may be difficult to isolate the resulting aminoketone, producing aminoketone derivatives. It is difficult to say that this is a general manufacturing method, and a method that can be industrially manufactured is required.
[0014]
[Problems to be solved by the invention]
An object of the present invention is to use an optically active amino alcohol derivative represented by the general formula (5) useful as an intermediate for producing pharmaceuticals, agricultural chemicals, etc. And providing a method for stereoselectively producing only the target optically active substance without racemization. It is another object of the present invention to provide a technique that can be manufactured from an industrial viewpoint with good optical purity, low cost, and stable production even in mass production. In addition, a novel optically active 5-hydroxy compound represented by the general formula (3), which is an important intermediate in the production of the above optically active amino alcohol derivatives or in the production of many optically active amine derivatives other than those described above An object is to provide an oxazolidine derivative and a novel aminoketone derivative represented by the general formula (4) and a novel production method thereof.
[0015]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventors easily and inexpensively obtained an optically active amino alcohol derivative represented by the general formula (5), which is extremely important as an intermediate for producing pharmaceuticals and agricultural chemicals. A method for producing from available raw materials was found. That is, “a natural α-L-amino acid that is industrially available in large quantities and is inexpensive” and “a racemization and optical resolution of a natural α-L-amino acid and a selective assimilation method (Japanese Patent Laid-Open No. 63-198997). A new method for producing in a short and stereoselective manner while suppressing racemization using a natural α-D-amino acid that is commercially available in large quantities and inexpensive as a starting material is disclosed. I found it.
[0016]
That is, the method according to the present invention relates to the production of an optically active aminoalcohol derivative, which is very highly useful from an industrial point of view, which has good optical purity, is inexpensive, and can be stably produced even in mass production. A manufacturing method was found.
[0017]
In addition, a novel optically active 5-hydroxyoxazolidine derivative represented by the general formula (3) having an aryl group or a heterocycle at the 5-position of oxazolidine, which is an important intermediate for producing the above optically active amino alcohol derivative The inventors have found a novel aminoketone derivative represented by the general formula (4) and a novel production method thereof, and have completed the present invention.
[0018]
That is, the present invention includes the following aspects.
[0019]
(1) General formula (1)
[0020]
Embedded image

[0021]
Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An optically active 5-oxazolidinone derivative represented by the general formula (2):
[0022]
Embedded image

[0023]
(In the formula, R3 represents an optionally substituted aryl group or an optionally substituted heterocycle, and M represents Li, MgX, ZnX, TiX._Three, One selected from the group of CuX, and X represents a halogen atom. And an organic metal reagent represented by the general formula (3)
[0024]
Embedded image

[0025]
(Wherein R1, R2 and R3 have the same meanings as described above), and then treated under acidic conditions to give a general formula (4)
[0026]
Embedded image

[0027]
(In the formula, R1 and R3 have the same meanings as above. R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group, an optionally substituted aryloxycarbonyl group or a substituted group. A stereoselective, characterized in that after being led to an optically active aminoketone derivative represented by the formula (1), a further treatment with a reducing agent or catalytic hydrogenation using a metal catalyst is performed. General formula (5)
[0028]
Embedded image

[0029]
(Wherein R1, R3 and R4 are as defined above), wherein the optically active aminoalcohol derivative represented by formula (1) is asymmetric at the 4-position of the optically active 5-oxazolidinone derivative represented by the general formula (1) The configuration of the substituent represented by R1 and the nitrogen atom bonded to the carbon atom does not change even when each reaction is performed, and the amino group of the optically active amino alcohol derivative represented by the general formula (5) And the relative arrangement of hydroxyl groups is erythro.)
[0030]
(2) General formula (1)
[0031]
Embedded image

[0032]
Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An optically active 5-oxazolidinone derivative represented by the general formula (2):
[0033]
Embedded image

[0034]
(In the formula, R3 represents an optionally substituted aryl group or an optionally substituted heterocycle, and M represents Li, MgX, ZnX, TiX._Three, One selected from the group of CuX, and X represents a halogen atom. And an organic metal reagent represented by the general formula (3)
[0035]
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[0036]
(Wherein R1, R2 and R3 have the same meanings as described above), and then treated under acidic conditions to give a general formula (4)
[0037]
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[0038]
(In the formula, R1 and R3 have the same meanings as described above. R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group, an optionally substituted aryloxycarbonyl group, or a substituted group. A good aralkyloxycarbonyl group.), Followed by treatment with a reducing agent or catalytic hydrogenation using a metal catalyst, followed by general formula (5)
[0039]
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[0040]
(Wherein R1, R3 and R4 are as defined above), and when R4 is a protecting group, the amino group is deprotected, and the general formula (6)
[0041]
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[0042]
(Wherein R1 and R3 have the same meanings as described above.)
A process for producing an amino alcohol derivative characterized in that it is bonded to the 4-position asymmetric carbon atom of the optically active 5-oxazolidinone derivative represented by the general formula (1). The configuration of the substituent represented by R1 and the nitrogen atom does not change even when each reaction is performed, and the relative configuration of the amino group and hydroxyl group of the optically active aminoalcohol derivative represented by the general formula (6) Is an erythro arrangement.)
[0043]
(3) R1 is a methyl group, isopropyl group, isobutyl group, benzyl group, hydroxymethyl group, benzyloxymethyl group, phenylthiomethyl group, methylthiomethyl group, alkyloxycarbonylmethyl group or alkyloxycarbonylethyl group, R2 Is a benzyl group, a tert-butyl group, a methyl group, an ethyl group, an isopropyl group, or a 9-fluorenylmethyl group. The method for producing an optically active amino alcohol derivative according to the above (1) or (2).
[0044]
(4) R3 is represented by the general formula (7)
[0045]
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[0046]
(Wherein Y represents a halogen atom) or general formula (8)
[0047]
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[0048]
(Wherein R5 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, an optionally substituted heterocycle or (It represents a heterocyclic alkyl group which may be substituted.) The method for producing an optically active amino alcohol derivative according to the above (1) or (2).
[0049]
(5) The method for producing an optically active amino alcohol derivative according to the above (1) or (2), wherein R1 is a methyl group and R3 is the general formula (8).
[0050]
(6) An optically active 5-hydroxyoxazolidine derivative represented by the general formula (3).
[0051]
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[0052]
Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An aralkyl group which may be substituted, and R3 represents an aryl group which may be substituted or a heterocyclic ring which may be substituted.
(7) The above wherein R1 is methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl The optically active 5-hydroxyoxazolidine derivative according to 6).
[0053]
(8) The optically active 5-hydroxyoxazolidine derivative according to the above (6) or (7), wherein R2 is benzyl group, tert-butyl group, methyl group, ethyl group, isopropyl group or 9-fluorenylmethyl group.
[0054]
(9) The optically active 5-hydroxyoxazolidine derivative according to the above (8), wherein R3 is the general formula (7) or (8).
[0055]
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[0056]
(In the formula, Y represents a halogen atom.)
[0057]
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[0058]
(Wherein R5 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, an optionally substituted heterocycle or It represents an optionally substituted heterocyclic alkyl group.)
(10) The optically active 5-hydroxyoxazolidine derivative according to the above (9), wherein R1 is a methyl group.
[0059]
(11) General formula (1)
[0060]
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[0061]
Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An optically active 5-oxazolidinone derivative represented by the general formula (2):
[0062]
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[0063]
(In the formula, R3 represents an optionally substituted aryl group or an optionally substituted heterocycle, and M represents Li, MgX, ZnX, TiX._Three, One selected from the group of CuX, and X represents a halogen atom. And an organic metal reagent represented by the general formula (3)
[0064]
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[0065]
(Wherein R1, R2 and R3 have the same meanings as described above). A method for producing an optically active 5-hydroxyoxazolidine derivative, characterized in that:
[0066]
(12) R1 is a methyl group, isopropyl group, isobutyl group, benzyl group, hydroxymethyl group, benzyloxymethyl group, phenylthiomethyl group, methylthiomethyl group, alkyloxycarbonylmethyl group or alkyloxycarbonylethyl group The manufacturing method of the optically active 5-hydroxy oxazolidine derivative as described in 11).
[0067]
(13) The optically active 5-hydroxyoxazolidine derivative according to the above (11) or (12), wherein R2 is benzyl group, tert-butyl group, methyl group, ethyl group, isopropyl group or 9-fluorenylmethyl group Production method.
[0068]
(14) The method for producing an optically active 5-hydroxyoxazolidine derivative according to the above (13), wherein R3 is the general formula (7) or (8).
[0069]
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[0070]
(In the formula, Y represents a halogen atom.)
[0071]
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[0072]
(Wherein R5 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, an optionally substituted heterocycle or It represents an optionally substituted heterocyclic alkyl group.)
(15) The method for producing an optically active 5-hydroxyoxazolidine derivative according to the above (14), wherein R1 is a methyl group.
[0073]
(16) The method for producing an optically active 5-hydroxyoxazolidine derivative according to the above (11) or (12), wherein M in the general formula (2) is MgX (X is as defined above).
[0074]
(17) General formula (4a)
[0075]
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[0076]
Wherein R 1a is a methyl group, R 4a is a hydrogen atom, a benzyloxycarbonyl group, a tert-butoxycarbonyl group or a 9-fluorenylmethoxycarbonyl group, and R3a is a 4-benzyloxyphenyl group, 4 -Methoxyphenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group or 3-indolyl group.)
An aminoketone derivative characterized by being represented by:
[0077]
(18) General formula (3)
[0078]
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[0079]
Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An aralkyl group which may be substituted, and R3 represents an aryl group which may be substituted or a heterocyclic ring which may be substituted.
By treating a 5-hydroxyoxazolidine derivative represented by general formula (4) under acidic conditions,
[0080]
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[0081]
(In the formula, R1 and R3 have the same meanings as above. R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group, an optionally substituted aryloxycarbonyl group or a substituted group. Represents a good aralkyloxycarbonyl group.)
A method for producing an aminoketone derivative, comprising obtaining an aminoketone derivative represented by the formula:
[0082]
(19) General formula (5a)
[0083]
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[0084]
(In the formula, R1a is a methyl group, R3b is a 4-benzyloxyphenyl group, and R4b is a benzyloxycarbonyl group, and the relative arrangement of the amino group and the hydroxyl group is an erythro arrangement.)
An optically active alcohol derivative represented by the formula:
[0085]
(20) General formula (4b)
[0086]
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[0087]
(Wherein R1 represents an unprotected side chain of a natural α-amino acid or an optionally protected side chain, R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group as a protecting group, An aryloxycarbonyl group which may be substituted or an aralkyloxycarbonyl group which may be substituted, wherein R3c is represented by the general formula (8)
[0088]
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[0089]
R5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, or an optionally substituted group. A heterocycle or a heterocyclic alkyl group which may be substituted is shown. )
A stereoselective general formula (5b) is obtained by subjecting the optically active aminoketone derivative represented by the formula (5b) to a treatment with a reducing agent or catalytic hydrogenation using a metal catalyst.
[0090]
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[0091]
(Wherein R1, R3c, and R4 are as defined above) to obtain an optically active aminoalcohol derivative represented by the general formula (4b) The configuration of the substituent represented by R1 and the nitrogen atom bonded to the asymmetric carbon atom at the 2-position of the optically active aminoketone derivative does not change even when each reaction is performed, represented by the general formula (5b). The relative arrangement of the amino group and the hydroxyl group of the optically active amino alcohol derivative is an erythro arrangement.)
[0092]
(21) General formula (4b)
[0093]
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[0094]
(Wherein R1 represents an unprotected side chain of a natural α-amino acid or an optionally protected side chain, R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group as a protecting group, An aryloxycarbonyl group which may be substituted or an aralkyloxycarbonyl group which may be substituted, wherein R3c is represented by the general formula (8)
[0095]
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[0096]
R5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, or an optionally substituted group. A heterocycle or a heterocyclic alkyl group which may be substituted is shown. )
The stereoselective general formula (5b) is obtained by subjecting the optically active aminoketone derivative represented by the formula (5b) to a treatment with a reducing agent or catalytic hydrogenation using a metal catalyst.
[0097]
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[0098]
(Wherein R1, R3c and R4 are as defined above), and when R4 is a protecting group, the amino group is deprotected to give a general formula (6a)
[0099]
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[0100]
(Wherein R1 and R3c have the same meanings as described above.)
A method for producing an optically active aminoalcohol derivative represented by general formula (4b), wherein the optically active aminoalcohol derivative represented by formula (4b) is bonded to the asymmetric carbon atom at the 2-position: The configuration of the substituent represented by R1 and the nitrogen atom does not change even when each reaction is carried out.The relative configuration of the amino group and the hydroxyl group of the optically active amino alcohol derivative represented by the general formula (6a) is erythro. Arrangement.)
[0101]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in more detail.
[0102]
The “unprotected side chain of natural α-amino acid or an optionally protected side chain” of the present invention is, for example, “alanine, valine, leucine” if it is “unprotected side chain of natural α-amino acid”. , Isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine, and ornithine. .
[0103]
Examples of the “optionally protected side chain” include those in which any functional group of the side chain on the α-carbon atom of the natural α-amino acid is protected by a protecting group. . The protecting group may be any conventional method and protecting group well known to those skilled in the art, as long as it can be used in the method of the present invention. For example, amino-protecting groups, thiol-protecting groups, hydroxyl-protecting groups, phenol-protecting groups, carboxyl-protecting groups and the like used in usual amino acid synthesis can be used.
[0104]
The “optionally substituted alkyl group” means an alkyl group that may be substituted at any position of the alkyl group. Examples of the alkyl group include a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a pentyl group, a hexyl group, an octyl group, a decyl group, and an allyl group. Substituents include alkoxy groups such as hydroxyl group, methoxy group, benzyloxy group or methoxyethoxy group, phenoxy group, nitro group, amino group, amide group, carboxyl group, alkoxycarbonyl group, phenoxycarbonyl group or fluorine atom, chlorine atom And halogen atoms such as bromine atom or iodine atom.
[0105]
The “aryl group that may be substituted” means an aryl group that may be substituted at any position of the aryl group. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a fluorenyl group, and a phenanthrenyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0106]
The “aralkyl group which may be substituted” means an aralkyl group in which any position of the aralkyl group may be substituted. Examples of the aralkyl group include a benzyl group, a naphthylmethyl group, a phenylethyl group, and a 9-fluorenylmethyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0107]
The “optionally substituted heterocycle” means a heterocycle in which any position of the heterocycle may be substituted. Heterocycles include tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, furyl, thienyl, pyridyl, furfuryl, tenenyl, pyridylmethyl, pyrimidyl Group, pyrazyl group, imidazolyl group, imidazolylmethyl group, indolyl group, indolylmethyl group, isoquinolyl group, quinolyl group or thiazolyl group. Examples of the substituent include an alkyl group such as a methyl group, tert-butyl group or benzyl group, a cycloalkyl group such as cyclopropane, cyclopentane or cyclohexane, a phenyl group, a hydroxyl group, a methoxy group, a benzyloxy group or a methoxyethoxy group. Examples thereof include an alkoxy group, a phenoxy group, a nitro group, an amino group, an amide group, a carboxyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0108]
The “heterocyclic alkyl group” in the optionally substituted heterocyclic alkyl group means a group in which any one or more positions of the alkyl group are substituted with a heterocyclic ring, and this “heterocyclic alkyl group” itself May also be substituted. Specific examples of the heterocycle and the alkyl group, and these substituents are the same as those exemplified in the description of the “optionally substituted alkyl group” and the “optionally substituted heterocycle”. Can be mentioned.
[0109]
The “optionally substituted alkyloxycarbonyl group” means an alkyloxycarbonyl group in which one or more positions of the alkyloxycarbonyl group may be substituted. As the alkyloxycarbonyl group, Examples include methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, octyloxycarbonyl group, decyloxycarbonyl group, and allyloxycarbonyl group. Substituents include alkoxy groups such as hydroxyl, methoxy, benzyloxy and methoxyethoxy groups; phenoxy groups; nitro groups; amino groups; amide groups; carboxyl groups; alkoxycarbonyl groups; And the like; Tsu atom, a chlorine atom, a halogen atom such as a bromine atom and an iodine atom.
[0110]
The “optionally substituted aryloxycarbonyl group” means an aryloxycarbonyl group in which one or more positions of the aryloxycarbonyl group may be substituted. Examples of the aryloxycarbonyl group include phenoxycarbonyl group, naphthyloxycarbonyl group, anthracenyloxycarbonyl group, fluorenyloxycarbonyl group, and phenanthrenyloxycarbonyl group. Examples of the substituent include alkyl groups and aralkyl groups such as methyl group, tert-butyl group and benzyl group; cycloalkyl groups obtained from cyclopropane, cyclopentane or cyclohexane (for example, cyclopropyl group, cyclopentyl group and cyclohexyl group) ); Phenyl group; hydroxyl group; alkoxy group such as methoxy group, benzyloxy group and methoxyethoxy group; phenoxy group; nitro group; amino group; amide group; carboxyl group; alkoxycarbonyl group; phenoxycarbonyl group; A halogen atom such as an atom, a bromine atom and an iodine atom;
[0111]
The “optionally substituted aralkyloxycarbonyl group” means an aralkyloxycarbonyl group in which one or more positions of the aralkyloxycarbonyl group may be substituted. Examples of the aralkyloxycarbonyl group include a benzyloxycarbonyl group, a naphthylmethyloxycarbonyl group, a phenylethyloxycarbonyl group, and a 9-fluorenylmethyloxycarbonyl group. Examples of the substituent include alkyl groups and aralkyl groups such as methyl group, tert-butyl group and benzyl group; cycloalkyl groups obtained from cyclopropane, cyclopentane or cyclohexane (for example, cyclopropyl group, cyclopentyl group and cyclohexyl group) ); Phenyl group; hydroxyl group; alkoxy group such as methoxy group, benzyloxy group and methoxyethoxy group; phenoxy group; nitro group; amino group; amide group; carboxyl group; alkoxycarbonyl group; phenoxycarbonyl group; A halogen atom such as an atom, a bromine atom and an iodine atom;
[0112]
Each of the above-mentioned optionally substituted groups may have one or more substituents, and when having a plurality of substituents, each substituent is independently selected from the above-described exemplary substituents. Can be either.
[0113]
Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine. Note that two “Y” s in the general formula (7) may be the same or different.
[0114]
“Reducing agent” means a reagent capable of reducing the ketone moiety of the aminoketone derivative represented by the general formula (4) to an alcohol form, such as borane reagent such as borane-tetrahydrofuran complex, sodium borohydride, zinc borohydride. Boron hydride reagents such as sodium trimethoxyborohydride, alkylaluminum reagents such as diisopropylaluminum hydride, aluminum hydride reagents such as lithium aluminum hydride and trialkoxyaluminum hydride, silanes such as trichlorosilane and triethylsilane Examples of the reagent include sodium metal in liquid ammonia and magnesium metal in alcohol.
[0115]
“Catalytic hydrogenation using a metal catalyst” means the reduction of the ketone moiety of the aminoketone derivative represented by the general formula (4) to the alcohol form by a catalytic hydrogenation reaction in the presence of a metal catalyst. May be a nickel catalyst such as Raney nickel, a platinum catalyst such as platinum oxide, a palladium catalyst such as palladium-carbon, or a rhodium catalyst such as chlorotristriphenylphosphine rhodium called Wilkinson catalyst.
[0116]
The “erythro configuration” is a display method showing the relative configuration of two consecutive asymmetric carbon atoms. For example, in the case of a compound represented by the general formula (5) or (6), the projection of Fischer When expressed by the formula, the case where an amino group and a hydroxyl group as substituents are present on the same side is called erythro configuration.
[0117]
The typical optically active 5-hydroxyoxazolidine derivatives included in the general formula (3) are exemplified in Tables 1 to 21 below. Moreover, the typical optically active amino ketone derivative contained in General formula (4) is illustrated in Table 22-Table 27. Further, typical optically active amino alcohol derivatives included in the general formula (5) or (6) are exemplified in Tables 28 to 39. However, these exemplary compounds do not limit the present invention. In these tables, Ph represents a phenyl group or phenylene group, Me represents a methyl group, and Boc represents a tert-butoxycarbonyl group as a protecting group.
[0118]
[Table 1]

[0119]
[Table 2]

[0120]
[Table 3]

[0121]
[Table 4]

[0122]
[Table 5]

[0123]
[Table 6]

[0124]
[Table 7]

[0125]
[Table 8]

[0126]
[Table 9]

[0127]
[Table 10]

[0128]
[Table 11]

[0129]
[Table 12]

[0130]
[Table 13]

[0131]
[Table 14]

[0132]
[Table 15]

[0133]
[Table 16]

[0134]
[Table 17]

[0135]
[Table 18]

[0136]
[Table 19]

[0137]
[Table 20]

[0138]
[Table 21]

[0139]
[Table 22]

[0140]
[Table 23]

[0141]
[Table 24]

[0142]
[Table 25]

[0143]
[Table 26]

[0144]
[Table 27]

[0145]
[Table 28]

[0146]
[Table 29]

[0147]
[Table 30]

[0148]
[Table 31]

[0149]
[Table 32]

[0150]
[Table 33]

[0151]
[Table 34]

[0152]
[Table 35]

[0153]
[Table 36]

[0154]
[Table 37]

[0155]
[Table 38]

[0156]
[Table 39]

[0157]
Below, the typical manufacturing method of this invention is demonstrated.
[0158]
In the production method of the general formula (5) or (6) starting from the compound of the general formula (1) according to the present invention, “R1 bonded to the carbon atom at the 4-position of the optically active 5-oxazolidinone derivative and The steric configuration of the substituent represented by the nitrogen atom does not change even when each reaction is performed, and the relative configuration of the amino group and the hydroxyl group of the optically active amino alcohol derivative represented by the general formula (5) is an erythro configuration. If the meaning represented by “is” is explained in more detail, it can be represented by the following reaction formulas 1 and 2.
[0159]
Embedded image

[0160]
Embedded image

[0161]
That is, as shown in Reaction Formula 1, from the S-form optically active 5-oxazolidinone derivative represented by the general formula (9), the erythro configuration represented by the general formula (12) or (13) is selectively used. An optically active amino alcohol derivative of 1R, 2S form is obtained. Further, as shown in Reaction Formula 2, from the optically active 5-oxazolidinone derivative of the R isomer represented by the general formula (14), 1S, 2R in the erythro configuration represented by the general formula (17) or (18) The optically active amino alcohol derivative of the body can be produced.
[0162]
The manufacturing method of each process will be described in further detail.
[0163]
[Method for producing optically active 5-oxazolidinone derivative represented by the general formula (1)]
The optically active 5-oxazolidinone derivative represented by the general formula (1) is obtained by a known method, that is, an N-urethane protected compound derived from a natural α-amino acid which is readily available and inexpensive and paraformaldehyde. It can be easily produced according to a method of reacting in the presence of a catalytic amount of acid (J. Am. Chem. Soc. 1957.79.5736).
[0164]
[Method for producing organometallic reagent represented by general formula (2)]
The organometallic reagent represented by the general formula (2) can be easily produced by a known method, for example, an oxidative addition reaction of metals to the corresponding halogen compound or a metal exchange reaction with an organometallic reagent.
[0165]
The production of the organometallic reagent is not particularly limited as long as it is a solvent inert to the reaction. For example, ethers such as tetrahydrofuran, diethyl ether, dioxane and diglyme, toluene, xylene and the like can be used. Of these, tetrahydrofuran alone or a mixed solvent of tetrahydrofuran and another solvent is preferable from the viewpoint of solubility of the substrate. The reaction temperature is usually from −78 ° C. to the boiling point of the solvent. In addition, in the production method according to the present invention, the use of a Grignard reagent as an organometallic reagent gives particularly good results.
[0166]
As a method for producing a Grignard reagent, for example, a catalytic amount of an initiator such as 1,2-dibromoethane, ethyl bromide or iodine is added to magnesium in a solvent dispersion, and then R3X (X is as defined above). It can be easily carried out by dropping a halogen compound represented by.
[0167]
[Method for Producing Optically Active 5-Hydroxyoxazolidine Derivative Represented by General Formula (3)]
In the reaction of the optically active 5-oxazolidinone derivative represented by the general formula (1) and the organometallic reagent represented by the general formula (2), the reaction solvent is not particularly limited, but is the same solvent as the solvent in which the organometallic reagent was prepared? Alternatively, a mixed solvent that does not particularly adversely influence the reaction can be used. In the use of the organometallic reagent, the equivalent amount is not particularly limited, but is preferably in the range of equimolar to 5-fold mole, more preferably 1.0-fold mole to 2-fold mole with respect to the substrate 5-oxazolidinone derivative. . The reaction temperature is not particularly limited, but it can be preferably carried out in the range of room temperature to -78 ° C. In this reaction, the addition order of the optically active 5-oxazolidinone derivative and the organometallic reagent is not particularly limited, and the organometallic reagent may be added to the optically active 5-oxazolidinone derivative or vice versa. When the resulting optically active 5-hydroxyoxazolidine derivative is obtained after the reaction is completed, the excess organometallic reagent in the reaction solution is decomposed with an aqueous solution of dilute hydrochloric acid, dilute sulfuric acid, acetic acid, ammonium chloride, citric acid, potassium hydrogen sulfate, etc. After the treatment, the reaction mixture can be isolated by using usual separation and purification means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and the like.
[0168]
In addition, as described above, the use of a Grignard reagent as an organometallic reagent gives particularly good results for this reaction. When a Grignard reagent is used as the organometallic reagent, the reaction solvent, equivalent amount used, reaction temperature reagent addition order, reaction post-treatment, compound isolation and purification are generally the same as when using the organometallic reagent described above. It is the same as a typical manufacturing method.
[0169]
In addition, the optically active 5-oxazolidine derivative produced by the above method is usually obtained as two types of diastereomers because both the R-form and the S-form are produced with respect to the stereo of the 5-position hydroxyl group of oxazolidine. It is done. In some cases, the diastereomeric mixing ratio can be determined by using high performance liquid chromatography, nuclear magnetic resonance spectrum, or the like. In addition, the diastereomeric mixing ratio varies depending on the reaction conditions and the properties of the compound to be produced, but each may be isolated or may be obtained as a mixture. However, since the diastereomeric mixture can be converted into the optically active aminoketone derivative represented by the same general formula (4) by acid treatment or the like described in the next section, from the viewpoint of production cost when considered as a production intermediate. There is absolutely no need to separate.
[0170]
[Method for producing optically active aminoketone derivative represented by the general formula (4)]
The method for converting the optically active 5-hydroxyoxazolidine derivative into the optically active aminoketone derivative represented by the general formula (4) under acidic conditions can be usually carried out in a diluting solvent. Although there is no restriction | limiting in particular as a solvent used, Methanol, alcohol of ethanol, acetonitrile, tetrahydrofuran, benzene, toluene, water etc. are mentioned. These solvents can be used alone or as a mixed solvent in any mixing ratio. The acid to be used is not particularly limited, but inorganic acids such as hydrochloric acid, sulfuric acid and perchloric acid, organic acids such as p-toluenesulfonic acid and methanesulfonic acid, acidic resins such as Amberlite IR-120 and Amberlyst And Lewis acids such as boron trifluoride or zinc chloride. The amount of the acid to be used is equimolar to 30 times mol, preferably 1.5 times mol to 10 times mol, with respect to the optically active 5-hydroxyoxazolidine derivative. In the case of resin, it is 5 to 200% by weight, preferably 10 to 100% by weight. The reaction can be carried out at a temperature from -30 ° C to the boiling point of the solvent, and particularly preferably from 0 ° C to 100 ° C. Isolation of the aminoketone derivative from the reaction mixture can be easily performed by using usual separation and purification means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and the like.
[0171]
[Method for producing optically active amino alcohol derivative represented by general formula (5)]
The method of reducing the aminoketone derivative represented by the general formula (4) with a reducing agent and converting it to the optically active alcohol derivative represented by the general formula (5) is usually performed in a diluting solvent. Although there is no restriction | limiting in particular as a solvent which can be used, Methanol, ethanol, 2-propanol, tetrahydrofuran, water, etc. can be mentioned. These diluting solvents can be used alone or as a mixed solvent at an arbitrary mixing ratio.
[0172]
Examples of the reducing agent include borane reagents such as borane-tetrahydrofuran complex, borohydride reagents such as sodium borohydride, zinc borohydride, sodium trimethoxyborohydride, alkylaluminum reagents such as diisopropylaluminum hydride, aluminum hydride, and the like. Examples include lithium, aluminum hydride reagents such as trialkoxyaluminum hydride lithium, silane reagents such as trichlorosilane and triethylsilane, sodium metal in liquid ammonia, magnesium metal in alcohol, etc., in particular, sodium borohydride, A borohydride reagent such as zinc borohydride or sodium trimethoxyborohydride is preferred.
[0173]
The reducing agent can be used in an amount ranging from equimolar to 10-fold molar relative to the substance to be reduced. The reaction temperature is appropriately selected between -78 ° C and the boiling point of the solvent, and preferably in the range of -40 ° C to 80 ° C.
[0174]
On the other hand, it is also possible to perform a catalytic hydrogen reduction reaction on the aminoketone derivative represented by the general formula (4) in a hydrogen atmosphere in a suitable diluting solvent in the presence of a suitable metal catalyst. The optically active amino alcohol derivative represented by these can be manufactured. Although there is no restriction | limiting in particular in the hydrogen pressure which can be used, It is the range of normal pressure-3MPa, Preferably, 0.3MPa-1MPa. The solvent to be used is not particularly limited as long as it does not hinder the progress of the reaction, and examples thereof include methanol, ethanol, n-propanol, 2-propanol, n-butanol and water. These solvents can be used alone or in admixture at any ratio. The amount of the solvent used is 1 to 50 times (weight / weight) with respect to the compound, preferably 3 to 20 times.
[0175]
Usable metal catalysts include nickel-based catalysts such as Raney nickel, platinum-based catalysts such as platinum-alumina, platinum-carbon, platinum oxide, palladium-based catalysts such as palladium-alumina, palladium-carbon, palladium hydroxide-carbon, ruthenium oxide And the like, and rhodium-based catalysts such as chlorotristriphenylphosphine rhodium called Wilkinson's catalyst, and more preferably palladium-based catalysts. Although there is no restriction | limiting in particular in reaction, It can implement in the temperature range of -20-200 degreeC, More preferably, it is 0-60 degreeC.
[0176]
Furthermore, as a method of deprotecting the compound in which the amino group contained in the general formula (5) is protected as necessary to obtain a free amine derivative represented by the general formula (6), an acid or a base may be used. A hydrolysis reaction or the like can be performed. There are no particular restrictions on the acid or base used, but if it is an acid, inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc., organic substances such as trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, acetic acid, etc. If the acid is a base, mention may be made of inorganic bases such as sodium bicarbonate, potassium carbonate, lithium hydroxide and sodium hydroxide, organic bases such as triethylamine, morpholine, tetrabutylammonium fluoride and tetraethylammonium hydroxide. Can do.
[0177]
The optically active amino alcohol derivative represented by the general formula (5) or (6) thus obtained can be isolated as a free amine crystal or added with an appropriate acid as necessary. And can be isolated as a salt. These compounds can also be improved in diastereomeric purity and optical purity by recrystallization.
[0178]
When the compound is obtained as crystals as a free amine, the solvent that can be used for crystallization is not particularly limited as long as it is suitable for purification, but alcohols such as methanol, ethanol, n-propanol, and 2-propanol, ethyl acetate Esters such as butyl acetate, halogens such as chloroform and methylene chloride, ethers such as 1,4-dioxane and tetrahydrofuran, water, acetonitrile, 2-butanone, toluene and the like can be used alone or in combination.
[0179]
Further, there is no particular limitation as long as it gives a crystalline salt suitable for purification as an acid used for forming a salt, but for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfuric acid, phosphoric acid, Examples thereof include organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, methanesulfonate, and p-toluenesulfonate.
[0180]
The solvent used for recrystallization is not particularly limited as long as it is suitable for purification, but alcohols such as methanol, ethanol, n-propanol and 2-propanol, esters such as ethyl acetate and butyl acetate, chloroform, Halogens such as methylene chloride, ethers such as 1,4-dioxane and tetrahydrofuran, water, acetonitrile, 2-butanone, toluene and the like can be used alone or in combination.
[0181]
Further, the salt purified by recrystallization can be isolated as a free amine by treating with an alkaline aqueous solution by an ordinary method.
[0182]
【Example】
Hereinafter, the present invention will be described in more detail with reference examples and examples, but the present invention is not limited thereto.
[Reference Example 1]
Preparation of (4S) -N-benzyloxycarbonyl-4-methyl-5-oxazolidinone
[0183]
Embedded image

[0184]
Benzyloxycarbonyl-L-alanine (19.3 g), paraformaldehyde (6.56 g), p-toluenesulfonic acid monohydrate (0.17 g) are suspended in toluene (190 ml), and the water produced is removed. The mixture was heated to reflux. After completion of the reaction, the reaction solution was returned to room temperature, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the resulting toluene solution was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting crystals were filtered to give the title compound (19.0 g) as white crystals in a yield of 93%.
Melting point: 91-93 ℃
¹HNMR (CDCl_Three, 400MHz) δppm:
1.54 (d, 3H, J = 6.4Hz), 4.29-4.31 (m, 1H), 5.18 (s, 2H), 5.28-5.29 (m, 1H), 5.47 (br, 1H), 7.33-7.41 (m, 5H)
IR (KBr) ν_max 1778,1685cm^-1.
[0185]
[Reference Example 2]
Production of 4-benzyloxybromobenzene
[0186]
Embedded image

[0187]
p-Bromophenol (25.0 g) and anhydrous potassium carbonate (20.0 g) were suspended in N, N-dimethylformamide (250 ml), and benzyl chloride (20.2 g) was added dropwise at room temperature. After heating at 95-100 ° C. for 1 hour, the temperature was returned to room temperature and water (400 ml) was added. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain the title compound (34.3 g) as milky white crystals in a yield of 90%.
Melting point: 55-57 ℃
¹H-NMR (CDCl_Three, 400MHz) δppm:
5.04 (s, 2H), 6.83-6.87 (m, 2H), 7.31-7.43 (m, 2H).
[0188]
[Example 1]
Production of (4S) -N-benzyloxycarbonyl-5- (4-benzyloxyphenyl) -4-methyl-5-hydroxyoxazolidine (Exemplary compound number: 1001)
[0189]
Embedded image

[0190]
[Manufacture of Grignard reagent]
Under a nitrogen atmosphere, magnesium metal (1.16 g) and ethyl bromide (0.26 g) were added to anhydrous tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 1 hour. Under reflux of the solvent, a solution of 4-benzyloxybromobenzene (10.5 g) prepared in Reference Example 2 dissolved in anhydrous tetrahydrofuran (20 ml) was added dropwise over about 1 hour. After completion of the dropwise addition, the mixture was further stirred for 40 minutes under reflux conditions to obtain a Grignard reagent.
[Grinya reaction]
(4S) -N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (7.84 g) prepared in Reference Example 1 was dissolved in anhydrous tetrahydrofuran (40 ml) and cooled to -20 ° C. Under a nitrogen atmosphere, the prepared Grignard reagent was dropped into the solution while maintaining the internal temperature at -20 ° C. After completion of the dropwise addition, the mixture was further stirred at the same temperature for 1 hour and treated with a 5% hydrochloric acid aqueous solution. The solution was returned to room temperature, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the concentrated residue was purified by silica column chromatography (developing solution: chloroform) to give the title compound (9.85 g) as white crystals of a diastereomeric mixture in a yield of 71%. .
Melting point: 83-86 ℃
¹H-NMR (CDCl_ThreeFrom 400 MHz), the diastereomeric ratio was about 2: 1.
(Main product of diastereomers)
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.47 (d, 3H, J = 7.3Hz), 3.81-3.84 (m, 1H), 4.79-5.07 (m, 2H), 5.14 (s, 2H), 5.14 (d, 1H, J = 8.4Hz), 5.20 (d, 1H, J = 8.4Hz), 5.87 (q, 1H, J = 7.3Hz), 7.02 (d, 2H, J = 8.8Hz), 7.23-7.44 (m, 10H), 8.01 (d, 2H, (J = 8.8Hz)
(By-product of diastereomer)
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.49 (d, 3H, J = 7.3Hz), 3.60-3.70 (m, 1H), 4.79-5.15 (m, 4H), 5.13 (s, 2H), 5.57 (q, 1H, J = 7.3Hz), 6.91 (d, 2H, J = 8.8Hz), 7.23-7.44 (m, 10H), 7.83 (d, 2H, J = 8.8Hz)
IR (neat) ν_max 3436,3033,1671,1603,1508cm^-1.
[0191]
[Example 2]
Production of (2S) -2- (benzyloxycarbonyl) amino-1- (4-benzyloxyphenyl) -1-propanone (Exemplary Compound Number: 22001)
[0192]
Embedded image

[0193]
(4S) -N-benzyloxycarbonyl-5- (4-benzyloxyphenyl) -4-methyl-5-hydroxyoxazolidine (3.8 g) prepared in Example 1 was dissolved in toluene (50 ml) and Amberlyst (300 mg ) And reacted at room temperature. After completion of the reaction, the amberlist was filtered and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica column chromatography (developing solution: chloroform) to give the title compound (3.1 g) as pale yellow crystals in a yield of 88%.
Melting point: 89-91 ℃
¹H-NMR (CDCl_Three, 400MH) δppm:
1.43 (d, 3H, J = 6.83Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28-5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J = 9.0Hz), 7.31-7.44 (m, 10H), 7.96 (d, 2H, J = 9.0Hz)
IR (KBr) ν_max 3374,1712,1690cm^-1
Optical purity: 93% ee
HPLC analysis conditions
Column: Daicel Chiralpak AD-RH (4.6 mmφ x 150 mm)
Mobile phase: methanol
Flow rate: 0.5 ml / min
Wavelength: 254nm
Temperature: Room temperature
t_R: (2S form); 19.8 minutes
(2R form); 24.3 minutes.
[0194]
[Example 3]
Production of (2S) -2- (benzyloxycarbonyl) amino-1- (4-benzyloxyphenyl) -1-propanone (Exemplary Compound Number: 22001)
[0195]
Embedded image

[0196]
[Manufacture of Grignard reagent]
Under a nitrogen atmosphere, magnesium metal (1.16 g) and ethyl bromide (0.05 g) were added to anhydrous tetrahydrofuran (15 ml), and the mixture was stirred at room temperature for 30 minutes. Under reflux of the solvent, a solution of 4-benzyloxybromobenzene (10.92 g) prepared in Reference Example 2 dissolved in anhydrous tetrahydrofuran (10 ml) was added dropwise over about 1 hour. After completion of the dropwise addition, the mixture was further stirred for 30 minutes under reflux conditions to obtain a Grignard reagent.
[Grinya reaction]
(4S) -N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (6.97 g) prepared in Reference Example 1 was dissolved in anhydrous tetrahydrofuran (26 ml) and cooled to -20 ° C. The prepared Grignard reagent was dropped into this solution under a nitrogen atmosphere while maintaining the internal temperature at -20 ° C. After completion of dropping, the mixture was further stirred at the same temperature for 1 hour.
[Deformylation reaction]
A 6.5% aqueous hydrochloric acid solution was added, and the mixture was stirred at 35 to 40 ° C. for 6 hours. The aqueous layer was discarded by a liquid separation operation, 5% aqueous hydrochloric acid was added again, and the mixture was stirred at 45 to 50 ° C. for 4 hours. The reaction solution was extracted with toluene, and the organic layer was washed with water. The solution was concentrated under reduced pressure, 2-propanol (70 g) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled to 0-5 ° C. and the crystallized crystals were filtered to give the title compound (8.61 g) as pale yellow crystals in a yield of 80%.
Melting point: 89-91 ℃
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.43 (d, 3H, J = 6.8Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28-5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J = 9.0Hz), 7.31-7.44 (m, 10H), 7.96 (d, 2H, J = 9.3Hz)
IR (KBr) ν_max3374,1712,1690cm^-1
Specific rotation: [α]^D _{twenty four}= + 26 ° (C = 1.00, CHCl3)
Optical purity: 99% ee (analysis conditions are the same as in Example 2).
[0197]
[Example 4]
Production of erythro- (1R, 2S) -p-hydroxynorephedrine (exemplary compound number: 28001)
[0198]
Embedded image

[0199]
(2S) -2- (benzyloxycarbonyl) amino-1- (4-benzyloxyphenyl) -1-propanone (4.8 g), methanol (100 ml), water (50 ml) prepared in Example 2 or 3 and A mixed solution of 5% Pd / C (50% water-containing product) (1.0 g) was stirred in a hydrogen atmosphere (0.5 MPa) at 20 ° C. or lower for 28 hours. The catalyst was filtered, the filtrate was concentrated under reduced pressure, and the concentrated residue was slit with 2-propanol to give the title compound (1.44 g) as white crystals in a yield of 70%.
Melting point: 163-165 ° C
¹H-NMR (DMSO-d₆, 400MHz) δppm:
0.85 (d, 3H, J = 6.3Hz), 2.77-2.83 (m, 1H), 4.17 (d, 1H, J = 5.3Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J = 8.3Hz) ), 7.09 (d, 2H, J = 8.3Hz), 8.31 (s, 1H)
IR (KBr) ν_max3470,1593,1484,1242cm^-1
Specific rotation: [α]^D _{twenty four}= -18 ° (C = 0.2, MeOH)
Erythro: Threo = 99.5: 0.5
HPLC analysis conditions
Column: YMC TMS A-102 (6mmφ x 150mm)
Mobile phase: acetonitrile: water = 3:97 (NaH₂PO_Four, Na₂HPO_Four10 mM each, pH 6.9)
Detection wavelength: 275 nm
Flow rate: 0.5 ml / min
Column temperature: 40 ° C
t_R: Erythro body; 6.9 minutes
Threo body; 7.1 minutes
Optical purity: 99% ee
HPLC analysis conditions
Column: Daicel Crown Pack CR (-) (4mmφ x 150mm)
Mobile phase: HClO_Fouraq (pH 3.5)
Detection wavelength: 275 nm
Flow rate: 0.1 ml / min
Column temperature: 25 ° C.
[0200]
[Example 5]
Production of erythro- (1R, 2S) -2- (benzyloxycarbonyl) amino-1- (4-benzyloxyphenyl) -1-propanol (exemplary compound number: 36002)
[0201]
Embedded image

[0202]
Sodium borohydride (0.32 g) was added to methanol (25 ml) and cooled to 0-5 ° C. The solution was charged with (2S) -2- (benzyloxycarbonyl) amino-1- (4-benzyloxyphenyl) -1-propanone (2.00 g) prepared in Example 2 or 3, and stirred at room temperature. . The crystallized crystals were filtered, washed with methanol and dried to give the title compound (1.39 g) as white crystals in a yield of 69%.
Melting point: 85-91 ° C
¹H-NMR (DMSO-d₆, 400MHz) δppm:
0.99 (d, 3H, J = 6.59Hz), 3.61-3.62 (m, 1H), 4.46-4.49 (m, 1H), 4.95 (s, 2H),
5.07 (s, 2H), 5.23 (m, 1H), 6.93 (d, 2H, J = 7.08), 7.19-7.40 (m, 10H), 7.44 (d, 2H, J = 7.08), 8.30 (s, 1H )
IR (KBr) ν_max3334,1690cm^-1.
[0203]
[Example 6]
Production of erythro- (1R, 2S) -p-hydroxynorephedrine (exemplary compound number: 28001)
[0204]
Embedded image

[0205]
Erythro- (1R, 2S) -2- (benzyloxycarbonyl) amino-1- (4-benzyloxyphenyl) -1-propanol (1.39 g) prepared in Example 5 was dissolved in methanol and dissolved in 5% Pd / C (50% water-containing product) (0.03 g) The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (normal pressure). After filtering the catalyst, the filtrate was concentrated under reduced pressure, and the concentrated residue was crystallized from 2-propanol to give the title compound (0.65 g) as white crystals in a yield of 75%.
Melting point: 163-165 ° C
¹H-NMR (DMSO-d₆, 400MHz) δppm:
0.85 (d, 3H, J = 6.3Hz), 2.77-2.83 (m, 1H), 4.17 (d, 1H, J = 5.3Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J = 8.3Hz) ), 7.09 (d, 2H, J = 8.3Hz), 8.31 (s, 1H)
IR (KBr) ν_max3470,1593,1484,1242cm^-1
Specific rotation: [α]^D _{twenty four}= -18 ° (C = 0.2, MeOH)
Erythro: Threo = 97.5: 2.5 (analysis conditions are the same as in Example 4)
Optical purity: 99% ee (analysis conditions are the same as in Example 4).
[0206]
[Reference Example 3]
Preparation of (4S) -N-tert-butoxycarbonyl-4-methyl-5-oxazolidinone
[0207]
Embedded image

[0208]
tert-Butoxycarbonyl-L-alanine (18.9 g), paraformaldehyde (6.70 g), p-toluenesulfonic acid monohydrate (0.19 g) were suspended in toluene (250 ml), and the water produced was The mixture was heated to reflux while removing. After completion of the reaction, the reaction solution was returned to room temperature, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the resulting toluene solution was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the produced crystals were filtered to give the title compound (14.2 g) as white crystals in a yield of 71%.
Melting point: 66-68 ℃
¹HNMR (CDCl_Three, 400MHz) δppm:
1.49 (s, 9H), 1.52 (d, 2H, J = 7.1Hz), 4.23 (br, 1H), 5.23 (br, 1H), 5.41 (br, 1H)
IR (KBr) ν_max 1798,1698cm^-1.
[0209]
[Example 7]
Production of (4S) -5- (4-benzyloxyphenyl) -N-tert-butoxycarbonyl-4-methyl-5-hydroxyoxazolidine (Exemplary Compound Number: 1015)
[0210]
Embedded image

[0211]
(4S) -N-tert-butoxycarbonyl-4-methyl-5-oxazolidinone (6.64 g) prepared in Reference Example 3 was dissolved in anhydrous tetrahydrofuran (40 ml) and cooled to -20 ° C. A Grignard reagent prepared in the same manner as in Example 1 was added dropwise to this solution under a nitrogen atmosphere while maintaining the internal temperature at -20 ° C. After completion of the dropwise addition, the mixture was further stirred at the same temperature for 1 hour and treated with a 5% hydrochloric acid aqueous solution. The solution was returned to room temperature, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the concentrated residue was purified by silica column chromatography (developing solution: chloroform) to obtain the title compound (10.2 g) as a pale yellow syrup of a diastereomeric mixture in a yield of 80%. It was.
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.35-1.38 (m, 3H), 1.44-1.49 (m, 9H), 4.90-5.85 (m, 5H), 6.99-7.03 (m, 2H), 7.35-7.44 (m, 5H), 7.80-8.00 (m , 2H)
IR (KBr) ν_max 3422,1683cm^-1.
[0212]
[Reference Example 4]
Preparation of (4S) -N-benzyloxycarbonyl-4-isopropyl-5-oxazolidinone
[0213]
Embedded image

[0214]
Benzyloxycarbonyl-L-valine (25.1 g), paraformaldehyde (6.70 g), p-toluenesulfonic acid monohydrate (0.19 g) are suspended in toluene (250 ml), and the produced water is removed. The mixture was heated to reflux. After completion of the reaction, the reaction solution was returned to room temperature, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the resulting toluene solution was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain the title compound (23.7 g) as a colorless transparent syrup in a yield of 90%.
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.00 (d, 3H, J = 6.6Hz), 1.07 (d, 3H, J = 6.6Hz), 2.30-2.40 (m, 1H), 4.22 (bs, 1H), 5.15-5.22 (m, 3H), 5.56 (bs, 1H), 7.15-7.40 (m, 5H)
IR (KBr) ν_max 1798,1698cm^-1.
[0215]
[Example 8]
Production of (4S) -5- (4-benzyloxyphenyl) -N-benzyloxycarbonyl-4-isopropyl-5-hydroxyoxazolidine (Exemplary Compound Number: 2001)
[0216]
Embedded image

[0217]
(4S) -Benzyloxycarbonyl-4-isopropyl-5-oxazolidinone (5.20 g) prepared in Reference Example 4 was dissolved in anhydrous tetrahydrofuran (22 ml) and cooled to -20 ° C. A Grignard reagent prepared in the same manner as in Example 1 was added dropwise to this solution under a nitrogen atmosphere while maintaining the internal temperature at -10 to 20 ° C. After completion of the dropwise addition, the mixture was further stirred at the same temperature for 1 hour and treated with a 12.5% aqueous hydrochloric acid solution. The solution was returned to room temperature, extracted with toluene, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the concentrated residue was purified by silica column chromatography (developing solution: hexane / ethyl acetate = 2/1) to give the title compound (4.72 g) as a pale yellow syrup of a diastereomeric mixture. And obtained in 53% yield.
[0218]
¹H-NMR (CDCl_ThreeFrom 400 MHz), the diastereomeric ratio was about 1.9: 1.
(Main product of diastereomers)
¹H-NMR (CDCl_Three, 400MHz) δppm:
0.85 (d, 3H, J = 6.6Hz), 0.98. (D, 2H, J = 6.6), 2.29-2.40 (m, 1H), 3.29 (m, 1H), 4.79 (m, 1H), 5.10-5.50 (m, 6H), 7.02 (d, 2H, J = 8.7Hz), 7.28-7.45 (m, 10H), 8.11 (d, 2H, J = 8.7Hz)
(By-product of diastereomer)
¹H-NMR (CDCl_Three, 400MHz) δppm:
0.83 (d, 3H, J = 6.2Hz), 1.00. (D, 2H, J = 6.2), 2.29-2.40 (m, 1H), 3.55 (m, 1H), 4.79 (m, 1H), 5.10-5.50 (m, 6H), 6.81 (d, 2H, J = 9.0Hz), 7.28-7.45 (m, 10H), 7.85 (d, 2H, J = 9.0Hz)
IR (KBr) ν_max 3422,1683cm^-1.
[0219]
[Example 9]
Production of (2S) -2- (benzyloxycarbonyl) amino-1- (4-benzyloxyphenyl) -3-methyl-1-butanone (Exemplary Compound Number: 23001)
[0220]
Embedded image

[0221]
(4S) -N-benzyloxycarbonyl-5- (4-benzyloxyphenyl) -4-isopropylpropyl-5-hydroxyoxazolidine (1.38 g) prepared in Example 8 was dissolved in tetrahydrofuran (4 ml), and water ( 5 ml) and concentrated hydrochloric acid (2 ml) were added and stirred at room temperature for 24 hours. The reaction solution was diluted with toluene, the aqueous layer was discarded, and the organic layer was washed 3 times with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica column chromatography (developing solution: hexane / ethyl acetate = 2/1) to give the title compound (466 mg) as pale yellow crystals in a yield of 36%.
Melting point: 75-77 ° C
¹H-NMR (CDCl_Three, 400MHz) δppm:
0.76 (d, 3H, J = 6.8Hz), 1.04 (d, 3H, J = 6.8Hz), 2.16 (m, 1H), 5.11 (s, 1H), 5.14 (s, 1H), 5.24 (dd, 1H , J = 8.8,4Hz), 5.70 (d, 1H, J = 8.8Hz), 7.03 (d, 2H, J = 8.8Hz), 7.30-7.45 (m, 10H), 7.96 (d, 2H, J = 8.8 Hz)
IR (KBr) ν_max 3422,1683cm^-1.
[0222]
[Example 10]
Production of (4S) -N-benzyloxycarbonyl-5- (4-methoxyphenyl) -4-methyl-5-hydroxyoxazolidine (Exemplary Compound Number: 1020)
[0223]
Embedded image

[0224]
[Manufacture of Grignard reagent]
Under a nitrogen atmosphere, magnesium metal (756 mg) and ethyl bromide (0.1 g) were added to anhydrous tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 1 hour. Under reflux of the solvent, a solution of 4-bromoanisole (3.76 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise over about 1 hour. After completion of the dropwise addition, the mixture was further stirred for 40 minutes under reflux conditions to obtain a Grignard reagent.
[Grinya reaction]
(4S) -N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (7.70 g) produced in Reference Example 1 was dissolved in anhydrous tetrahydrofuran (30 ml) and cooled to -20 ° C. Under a nitrogen atmosphere, the prepared Grignard reagent was dropped into the solution while maintaining the internal temperature at -20 ° C. After completion of the dropwise addition, the mixture was further stirred at the same temperature for 1 hour and treated with a 5% hydrochloric acid aqueous solution. The solution was returned to room temperature, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the concentrated residue was purified by silica column chromatography (developing solution: hexane / ethyl acetate = 2/1 → 3/2) to give the title compound (4.56 g) as a diastereomer mixture. A colorless transparent syrup was obtained with a yield of 66%.
[0225]
¹H-NMR (CDCl_Three, 400 MHz), the diastereomeric mixing ratio was about 2: 1.
(Diastereomer: main product)
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.47 (d, 3H, J = 7Hz), 3.70-3.75 (m, 1H), 3.87 (s, 3H), 4.80-5.20 (m, 2H), 5.16 (d, 1H, J = 12.4Hz), 5.25 ( d, 1H, J = 12.4Hz), 5.88 (q, 1H, J = 7Hz), 6.95 (d, 2H, J = 9.0Hz), 7.23-7.36 (m, 5H), 8.02 (d, 2H, J = 9.0Hz)
(Diastereomer: By-product)
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.48 (d, 3H, J = 7Hz), 3.70-3.75 (m, 1H), 3.86 (s, 3H), 4.80-5.20 (m, 2H), 5.16 (d, 1H, J = 12.4Hz), 5.25 ( d, 1H, J = 12.4Hz), 5.57 (q, 1H, J = 7Hz), 6.83 (d, 2H, J = 8.8Hz), 7.23-7.36 (m, 5H), 8.83 (d, 2H, J = (8.8Hz)
IR (neat) ν_max 3443,1697,1601cm^-1.
[0226]
[Example 11]
Production of (2S) -2- (benzyloxycarbonyl) amino-1- (4-methoxyphenyl) -1-propanone (Exemplary Compound Number: 22020)
[0227]
Embedded image

[0228]
(4S) -N-benzyloxycarbonyl-5- (4-methoxyphenyl) -4-methyl-5-hydroxyoxazolidine (1.72 g) obtained in Example 10 was dissolved in tetrahydrofuran (4 ml), and water ( 5 ml) and concentrated hydrochloric acid (2 ml) were added and stirred at room temperature for 24 hours. The reaction solution was diluted with toluene, the aqueous layer was discarded, and the organic layer was washed 3 times with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica column chromatography (developing solution: hexane / ethyl acetate = 3/1) to obtain the title compound (1.40 mg) as white crystals in a yield of 89%.
Melting point: 46-48 ° C
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.43 (d, 3H, J = 6.8Hz), 3.88 (s, 3H), 5.13 (s, 2H), 5.30 (dq, 1H, J = 7.1,6.8Hz), 5.91 (d, 1H, J = 7.1Hz ), 6.96 (d, 2H, J = 8.8Hz), 7.29-7.37 (m, 5H), 7.96 (d, 2H, J = 8.8Hz)
IR (KBr) ν_max 3458,2958,1714,1676,1597,1527cm^-1.
[0229]
[Example 12]
Production of (4S) -N-benzyloxycarbonyl-5- (2,4-difluorophenyl) -4-methyl-5-hydroxyoxazolidine (Exemplary Compound Number: 1030)
[0230]
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[0231]
[Manufacture of Grignard reagent]
In a nitrogen atmosphere, magnesium sulfate (2.56 g) and iodine (30 mg) were added to anhydrous tetrahydrofuran (20 ml), and a solution of 2,4-difluorobromobenzene (19.3 g) in anhydrous tetrahydrofuran (60 ml) at room temperature was added. 1/5 was charged all at once. The formation of a Grignard reagent was confirmed with an increase in the reaction solution temperature 5 minutes after the charging. While maintaining the reaction temperature at 45 ° C. or lower, the remaining reagent 4/5 was added dropwise over about 30 minutes. After completion of dropping, the mixture was further stirred at 25 to 40 ° C. for 30 minutes to obtain a Grignard reagent.
[Grinya reaction]
(4S) -N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (21.2 g) produced in Reference Example 1 was dissolved in anhydrous tetrahydrofuran (68 ml) and cooled to -20 ° C. Under a nitrogen atmosphere, the prepared Grignard reagent was dropped into the solution while maintaining the internal temperature at -20 ° C. After completion of the dropwise addition, the mixture was further stirred at the same temperature for 1 hour and treated with a 5% hydrochloric acid aqueous solution. The solution was returned to room temperature, extracted with toluene, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the concentrated residue was purified by silica column chromatography (developing solution: hexane / ethyl acetate = 2/1) to give the title compound (21.4 g) as a pale yellow syrup of a diastereomeric mixture. In 68% yield.
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.52and1.51 (2d, 3H, J = 6.8Hz), 3.20-3.45 (m, 1H), 4.30-4.50 (m, 1H), 4.70-5.45 (m, 4H), 6.55-6.90 (m, 2H) , 7.30-7.40 (m, 5H), 7.50-7.90 (m, 1H)
IR (KBr) ν_max 3402,1803,1701,1614cm^-1.
[0232]
[Example 13]
Production of (2S) -2- (benzyloxycarbonyl) amino-1- (2,4-difluorophenyl) -1-propanone (Exemplary Compound Number: 22030)
[0233]
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[0234]
(4S) -2- (benzyloxycarbonyl) amino-5- (2,4-difluorophenyl) -4-methyl-5-hydroxyoxazolidine (14.0 g) prepared in Example 12 was added to tetrahydrofuran (70 ml). Dissolved, water (50 ml) and concentrated hydrochloric acid (20 ml) were added and stirred at room temperature for 24 hours. The reaction solution was diluted with toluene, the aqueous layer was discarded, and the organic layer was washed 3 times with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica column chromatography (developing solution: hexane / ethyl acetate = 3/1) to obtain the title compound (11.7 g) as a pale yellow syrup in a yield of 92%.
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.40 (d, 3H, J = 7.0Hz), 5.10 (s, 2H), 5.05-5.20 (m, 1H), 5.75-5.80 (m, 1H), 6.88-6.94 (m, 1H), 6.98-7.02 ( m, 1H), 7.30-7.37 (m, 5H), 7.95-8.01 (m, 1H)
IR (neat) ν_max 3358,1718,1681,1611,1532cm^-1
Optical purity: 90% ee
HPLC analysis conditions
Column: Daicel Chiralpak AD-RH (4.6 mmφ x 150 mm)
Mobile phase: methanol
Flow rate: 0.5 ml / min
Wavelength: 254nm
Temperature: Room temperature
t_R: (2R form); 6.5 minutes
(2S body); 7.5 minutes.
[0235]
[Reference Example 5]
Preparation of (4R) -N-benzyloxycarbonyl-4-methyl-5-oxazolidinone
[0236]
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[0237]
Benzyloxycarbonyl-D-alanine (19.3 g), paraformaldehyde (6.56 g), p-toluenesulfonic acid monohydrate (0.17 g) are suspended in toluene (190 ml), and the produced water is removed. The mixture was heated to reflux. After completion of the reaction, the reaction solution was returned to room temperature, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the resulting toluene solution was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the produced crystals were filtered to give the title compound (17.4 g) as white crystals in a yield of 85%.
Melting point: 89-91 ℃
¹HNMR (CDCl_Three, 400MHz) δppm:
1.54 (d, 3H, J = 6.4Hz), 4.29-4.31 (m, 1H), 5.18 (s, 2H), 5.28-5.29 (m, 1H), 5.47 (br, 1H), 7.33-7.41 (m, 5H)
IR (KBr) ν_max 1778,1685cm^-1.
[0238]
[Example 14]
Production of (4R) -N-benzyloxycarbonyl-5- (4-benzyloxyphenyl) -4-methyl-5-hydroxyoxazolidine (Exemplary Compound Number: 19001)
[0239]
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[0240]
(4R) -N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (2.61 g) prepared in Reference Example 5 was treated in the same manner as in Example 1 to give the title compound (9.0 g) as a diastereomer. Obtained as white crystals of the mixture in 65% yield.
Melting point: 82-86 ℃
¹H-NMR (CDCl_ThreeFrom 400 MHz), the diastereomeric ratio was about 2: 1.
(Main product of diastereomers)
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.47 (d, 3H, J = 7.3Hz), 3.81-3.84 (m, 1H), 4.79-5.07 (m, 2H), 5.14 (s, 2H), 5.14 (d, 1H, J = 8.4Hz), 5.20 (d, 1H, J = 8.4Hz), 5.87 (q, 1H, J = 7.3Hz), 7.02 (d, 2H, J = 8.8Hz), 7.23-7.44 (m, 10H), 8.01 (d, 2H, (J = 8.8Hz)
(By-product of diastereomer)
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.49 (d, 3H, J = 7.3Hz), 3.60-3.70 (m, 1H), 4.79-5.15 (m, 4H), 5.13 (s, 2H), 5.57 (q, 1H, J = 7.3Hz), 6.91 (d, 2H, J = 8.8Hz), 7.23-7.44 (m, 10H), 7.83 (d, 2H, J = 8.8Hz)
IR (neat) ν_max 3436,3033,1671,1603,1508cm^-1.
[0241]
[Example 15]
Production of (2R) -2- (benzyloxycarbonyl) amino-1- (4-benzyloxyphenyl) -1-propanone (Exemplary Compound Number: 25001)
[0242]
[Chemical Formula 86]

[0243]
(4R) -N-benzyloxycarbonyl-5- (4-benzyloxyphenyl) -4-methyl-5-hydroxyoxazolidine (2.1 g) prepared in Example 14 was treated in the same manner as in Example 9, The title compound (1.85 g) was obtained as pale yellow crystals in a yield of 95%.
Melting point: 88-90 ℃
¹H-NMR (CDCl_Three, 400MH) δppm:
1.43 (d, 3H, J = 6.83Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28-5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J = 9.0Hz), 7.31-7.44 (m, 10H), 7.96 (d, 2H, J = 9.0Hz)
IR (KBr) ν_max 3374,1712,1690cm^-1
Specific rotation: [α]^D _{twenty four}= -25 ° (C = 1.00, CHCl3)
Optical purity: 98% ee (analysis conditions are the same as in Example 3).
[0244]
[Example 16]
Production of (4R) -N-benzyloxycarbonyl-5- (2,4-difluorophenyl) -4-methyl-5-hydroxyoxazolidine (Exemplary compound number: 19030)
[0245]
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[0246]
 [Manufacture of Grignard reagent]
Under a nitrogen atmosphere, magnesium sulfate (1.28 g) and iodine (20 mg) were added to anhydrous tetrahydrofuran (10 ml), and a solution of 2,4-difluorobromobenzene (9.65 g) in anhydrous tetrahydrofuran (30 ml) at room temperature was added. And processed in the same manner as in Example 12 to obtain a Grignard reagent.
[Grinya reaction]
(4R) -N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (10.6 g) was dissolved in anhydrous tetrahydrofuran (34 ml) and treated in the same manner as in Example 12 to give the title compound (10.7 g). Obtained as a pale yellow syrup of the stereomeric mixture in 68% yield.
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.52and1.51 (2d, 3H, J = 6.8Hz), 3.20-3.45 (m, 1H), 4.30-4.50 (m, 1H), 4.70-5.45 (m, 4H), 6.55-6.90 (m, 2H) , 7.30-7.40 (m, 5H), 7.50-7.90 (m, 1H)
IR (KBr) ν_max 3402,1803,1701,1614cm^-1.
[0247]
[Example 17]
Production of (2R) -2- (benzyloxycarbonyl) amino-1- (2,4-difluorophenyl) -1-propanone (Exemplary Compound Number: 25030)
[0248]
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[0249]
(4R) -2- (benzyloxycarbonyl) amino-5- (2,4-difluorophenyl) -4-methyl-5-hydroxyoxazolidine (6.98 g) prepared in Example 16 was added to tetrahydrofuran (35 ml). After dissolution, water (25 ml) and concentrated hydrochloric acid (10 ml) were added, and the mixture was treated in the same manner as in Example 13 to obtain the title compound (5.87 g) as a pale yellow syrup in a yield of 92%.
¹H-NMR (CDCl_Three, 400MHz) δppm:
1.40 (d, 3H, J = 7.0Hz), 5.10 (s, 2H), 5.05-5.20 (m, 1H), 5.75-5.80 (m, 1H), 6.88-6.94 (m, 1H), 6.98-7.02 ( m, 1H), 7.30-7.37 (m, 5H), 7.95-8.01 (m, 1H)
IR (neat) ν_max 3358,1718,1681,1611,1532cm^-1
Optical purity: 90% ee (analysis conditions are the same as in Example 12)
[0250]
【The invention's effect】
According to the present invention, the optically active amino alcohol derivative represented by the general formula (5) or (6) useful as a production intermediate for pharmaceuticals, agricultural chemicals and the like is optically pure and inexpensive at an industrial point of view. In addition, it has become possible to manufacture stably even during mass production. In addition, an optically active 5-hydroxyoxazolidine derivative represented by the general formula (3), which is an important intermediate for producing the above optically active amino alcohol derivative or other optically active amine derivatives, and its general A production method, an optically active aminoketone derivative represented by the general formula (4) and a general production method thereof were established. These production techniques can be widely used in the production methods of optically active amine derivatives in addition to the production of the above optically active amino alcohol derivatives, and are very excellent techniques from an industrial viewpoint.

Claims (12)

General formula (1)

Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An optically active 5-oxazolidinone derivative represented by the general formula (2):

(In the formula, R3 represents an optionally substituted aryl group and an optionally substituted heterocycle, M represents one selected from the group of Li, MgX, ZnX, TiX ₃ , and CuX; X represents a halogen atom) and is reacted with an organometallic reagent represented by the general formula (3)

(Wherein R1, R2 and R3 have the same meanings as described above), and then treated under acidic conditions to give a general formula (4)

(Wherein R1 and R3 have the same meanings as above. R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group, an optionally substituted aryloxycarbonyl group or a substituted group as a protective group. also represents an aralkyloxycarbonyl group. represented after that led to optically active aminoketone derivative in), it stereoselective characterized subjected to catalytic hydrogenation using a metallic catalyst to further the general formula (5 )

(Wherein R1, R3 and R4 are as defined above), wherein the optically active aminoalcohol derivative represented by formula (1) is asymmetric at the 4-position of the optically active 5-oxazolidinone derivative represented by the general formula (1) The configuration of the substituent represented by R1 and the nitrogen atom bonded to the carbon atom does not change even when each reaction is performed, and the amino group of the optically active amino alcohol derivative represented by the general formula (5) And the relative arrangement of hydroxyl groups is erythro.) General formula (1)

Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An optically active 5-oxazolidinone derivative represented by the general formula (2):

(In the formula, R3 represents an optionally substituted aryl group and an optionally substituted heterocycle, M represents one selected from the group of Li, MgX, ZnX, TiX ₃ , and CuX; X represents a halogen atom) and is reacted with an organometallic reagent represented by the general formula (3)

(Wherein R1, R2 and R3 have the same meanings as described above), and then treated under acidic conditions to give a general formula (4)

(In the formula, R1 and R3 have the same meanings as described above. R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group, an optionally substituted aryloxycarbonyl group, or a substituted group. after that led to optically active aminoketone derivative represented by showing a good aralkyloxycarbonyl group.), by performing catalytic hydrogenation with metallic catalysts Furthermore, the general formula (5)

(Wherein R1, R3 and R4 are as defined above), and when R4 is a protecting group, the amino group is deprotected, and the general formula (6)

(Wherein R1 and R3 have the same meanings as described above). A method for producing an aminoalcohol derivative represented by the general formula (1): The configuration of R1 bonded to the 4-position asymmetric carbon atom of the 5-oxazolidinone derivative and the substituent represented by the nitrogen atom does not change even when each reaction is performed, and is represented by the general formula (6). The relative arrangement of the amino group and hydroxyl group of the optically active amino alcohol derivative is erythro configuration.  R1 is a methyl group, isopropyl group, isobutyl group, benzyl group, hydroxymethyl group, benzyloxymethyl group, phenylthiomethyl group, methylthiomethyl group, alkyloxycarbonylmethyl group or alkyloxycarbonylethyl group, and R2 is a benzyl group Or a tert-butyl group, a methyl group, an ethyl group, an isopropyl group, or a 9-fluorenylmethyl group. R3 is represented by the general formula (7)

(Wherein Y represents a halogen atom) or general formula (8)

(Wherein R5 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, an optionally substituted heterocycle or The method for producing an optically active amino alcohol derivative according to claim 1 or 2, wherein a heterocyclic alkyl group which may be substituted is represented.  The method for producing an optically active amino alcohol derivative according to claim 1 or 2, wherein R1 is a methyl group, and R3 is the general formula (8). An optically active 5-hydroxyoxazolidine derivative represented by the general formula (3).

Wherein R1 is an unprotected side chain or an optionally protected side chain of a natural α-amino acid, R2 is an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An aralkyl group which may be substituted, R3 is the general formula (7) or (8).

(In the formula, Y represents a halogen atom.)

(Wherein R5 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, an optionally substituted heterocycle or A heterocyclic alkyl group which may be substituted; The optically active 5-hydroxyoxazolidine derivative according to claim 6 , wherein R1 is a methyl group. General formula (1)

Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group or a substituted An optically active 5-oxazolidinone derivative represented by the general formula (2):

(In the formula, R3 represents an optionally substituted aryl group and an optionally substituted heterocycle, M represents one selected from the group of Li, MgX, ZnX, TiX ₃ , and CuX; X represents a halogen atom) and is reacted with an organometallic reagent represented by the general formula (3)

(Wherein R1 and R2 have the same meanings as described above, and R3 is the general formula (7) or (8).

(In the formula, Y represents a halogen atom.)

(Wherein R5 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, an optionally substituted heterocycle or And a heterocyclic alkyl group which may be substituted.) A method for producing an optically active 5-hydroxyoxazolidine derivative, which comprises obtaining an optically active 5-hydroxyoxazolidine derivative represented by the following formula : The method for producing an optically active 5-hydroxyoxazolidine derivative according to claim 8 , wherein R1 is a methyl group. General formula (3)

(Wherein R1 represents an unprotected side chain or an optionally protected side chain of a natural α-amino acid, and R2 represents an optionally substituted alkyl group, an optionally substituted aryl group, or a substituted side chain. An aralkyl group which may be substituted, R3 is the general formula (7) or (8) .

(In the formula, Y represents a halogen atom.)

(Wherein R5 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, an optionally substituted heterocycle or And represents a heterocyclic alkyl group which may be substituted.) By treating the 5-hydroxyoxazolidine derivative represented by) under acidic conditions, the compound represented by the general formula (4)

(Wherein R1 and R3 have the same meanings as above. R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group, an optionally substituted aryloxycarbonyl group or a substituted group as a protective group. A method for producing an aminoketone derivative, which comprises obtaining an aminoketone derivative represented by the formula: General formula (4b)

(Wherein R1 represents an unprotected side chain of a natural α-amino acid or an optionally protected side chain, R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group as a protecting group, An aryloxycarbonyl group which may be substituted or an aralkyloxycarbonyl group which may be substituted, wherein R3c is represented by the general formula (8)

R5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, or an optionally substituted group. A heterocycle or a heterocyclic alkyl group which may be substituted is shown. The stereoactive general formula (5b) is obtained by performing catalytic hydrogenation using a metal catalyst on the optically active aminoketone derivative represented by

(Wherein R1, R3c, and R4 are as defined above) to obtain an optically active aminoalcohol derivative represented by the general formula (4b) The configuration of the substituent represented by R1 and the nitrogen atom bonded to the asymmetric carbon atom at the 2-position of the optically active aminoketone derivative does not change even when each reaction is performed, represented by the general formula (5b). The relative arrangement of the amino group and the hydroxyl group of the optically active amino alcohol derivative is an erythro arrangement.) General formula (4b)

(Wherein R1 represents an unprotected side chain of a natural α-amino acid or an optionally protected side chain, R4 represents a hydrogen atom or an optionally substituted alkyloxycarbonyl group as a protecting group, An aryloxycarbonyl group which may be substituted or an aralkyloxycarbonyl group which may be substituted, wherein R3c is represented by the general formula (8)

R5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted phenyl group, or an optionally substituted group. A heterocycle or a heterocyclic alkyl group which may be substituted is shown. The optically active aminoketone derivative represented by), stereoselective formula by performing catalytic hydrogenation with metallic catalysts (5b)

(Wherein R1, R3c and R4 are as defined above), and when R4 is a protecting group, the amino group is deprotected to give a general formula (6b)

(Wherein R1 and R3c have the same meanings as described above). A method for producing an optically active aminoalcohol derivative represented by the general formula (4b) The configuration of the substituent represented by R1 and the nitrogen atom bonded to the asymmetric carbon atom at the 2-position of the optically active aminoketone derivative does not change even when each reaction is performed, represented by the general formula (6a). The relative arrangement of the amino group and the hydroxyl group of the optically active amino alcohol derivative is an erythro arrangement.)