JP4208174B2 - Amino compounds and stereoselective production method thereof - Google Patents
Amino compounds and stereoselective production method thereof Download PDFInfo
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- HZPIXOYXQAYZGV-UHFFFAOYSA-N CN(C(CN=C(c1ccccc1)c1ccccc1)=O)OC Chemical compound CN(C(CN=C(c1ccccc1)c1ccccc1)=O)OC HZPIXOYXQAYZGV-UHFFFAOYSA-N 0.000 description 1
- KUQZOZDWESIDRV-GOSISDBHSA-N CN(C([C@@H](CC=C)N=C(c1ccccc1)c1ccccc1)=O)OC Chemical compound CN(C([C@@H](CC=C)N=C(c1ccccc1)c1ccccc1)=O)OC KUQZOZDWESIDRV-GOSISDBHSA-N 0.000 description 1
- FUQSRBDDSYZPPI-XMMPIXPASA-N CON(Cc1ccccc1)C([C@@H](CC=C)N=C(c1ccccc1)c1ccccc1)=O Chemical compound CON(Cc1ccccc1)C([C@@H](CC=C)N=C(c1ccccc1)c1ccccc1)=O FUQSRBDDSYZPPI-XMMPIXPASA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【0001】
【発明の属する技術分野】
シンおよびアンチ立体配置を有する光学活性β−アミノアルコール類は医薬農薬の合成中間体あるいは原体として有用である。本発明は、これらシンおよびアンチ立体配置を有する光学活性β−アミノアルコール類およびその前駆体の光学活性α−アミノケトン誘導体を、新規なα−アミノアミド誘導体を共通原料として、簡便・高收率かつ、高立体選択的に製造する技術に関する。
【0002】
【従来の技術】
シンおよびアンチ立体配置を有する光学活性β−アミノアルコール類の前駆体として、光学活性α−アミノケトン類は最も有用である。しかし、α−アミノケトン類はその構造上、酸性条件以外では不安定であるため、現実的な合成法としては、光学活性α−アミノ酸をα−フタルイミド酸などのα−(保護アミノ)酸の酸ハライドに誘導して、これをFriedel-Crafts反応によって光学活性α−アミノケトン類とする方法が挙げられる(J.Org.Chem.50,3481(1985), EP-304018)のみである。しかし、光学活性α−アミノ酸は高価であり特に非天然型は入手困難な場合も多い。さらにFriedel−Crafts反応工程に安定でありながら酸性条件で効率よく脱保護可能な保護基が必要であり、保護・脱保護操作自体も煩雑である。
従って、これまでは、一般性の高い有利な光学活性α−アミノケトン類の合成法は存在しなかった。この結果、シンおよびアンチ立体配置を有する光学活性β−アミノアルコール類の適当な合成法も知られていなかった。
【0003】
【発明が解決しようとする課題】
本発明は、新規なα−アミノアミド誘導体と、それから得られる新規な光学活性α−アミノケトン誘導体と、その光学活性α−アミノケトン誘導体を前駆体とするシンおよびアンチ立体配置を有する光学活性β−アミノアルコール類の簡便な製造方法を提供することを目的とする。
【0004】
【課題を解決するための手段】
本発明者等は、まず、光学活性α-アミノケトン類を有利に与える光学活性α−アミノアミドを見出すため鋭意研究した結果、ある特定の保護基を有する光学活性α−アミノアミド誘導体を用いると、もとの立体配置に影響を与えること無く、アミド部分をケトンに変換できることを見出した。第二に、該光学活性α-アミノケトン誘導体のアミノ基の保護基を脱保護せずそのまま還元すればシン立体配置を有する光学活性β−アミノアルコール類を得ることができ、脱保護した後還元すればアンチ立体配置を有する光学活性β−アミノアルコール類を得ることができることを見出し、本発明を完成するに至った。
【0005】
すなわち、本発明は、一般式(2)
【0006】
【化16】
【0007】
〔式中、Ra,Rbはそれぞれ独立して、水素原子、置換基を有していても良い炭素数1〜6のアルキル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基を示し、RaとRbは一緒になって環を形成してもよい。
Rc,Rdはそれぞれ独立して、水素原子、置換基を有していても良い炭素数1〜6のアルキル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基を示し、RcとRdは一緒になって環を形成してもよい。
R1は置換基を有していても良い炭素数1〜20のアルキル基、置換基を有していても良い炭素数2〜20のアルケニル基、置換基を有していても良い炭素数2〜20のアルキニル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基を示し、*は不斉炭素であることを示し、nは0または1、2の整数を示す。〕で表される光学活性α−アミノアミド誘導体に、一般式(3)
R2−X (3)
〔式中、R2は置換基を有していても良い炭素数1〜20のアルキル基、置換基を有していても良い炭素数2〜20のアルケニル基、置換基を有していても良い炭素数2〜20のアルキニル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基を示し、Xは臭化マグネシウム基、塩化マグネシウム基、リチウム原子を示す。〕で表される有機金属化合物を反応させることを特徴とする、一般式(1)
【0008】
【化17】
【0009】
〔式中、Ra、Rb、R1,R2、*は前記と同じ意味を示す。〕で表される光学活性α−アミノケトン誘導体の製造方法であり、また、一般式(1)
【0010】
【化18】
【0011】
〔式中、Ra、Rb、R1、R2、*は前記と同じ意味を示す。〕
で表されるα−アミノケトン誘導体を還元することを特徴とする、一般式(4’)
【0012】
【化19】
【0013】
〔式中、Ra、Rb、R1,R2、*は前記のものと同じ意味を示し、*'は*の炭素とシン立体配置の関係である不斉炭素であることを示す。〕で表されるシン立体配置の光学活性β−アミノアルコール誘導体の製造方法であり、また、一般式(2)
【0014】
【化20】
【0015】
〔式中、Ra、Rb、Rc、Rd、R1、nは前記のものと同じ意味を示す。〕で表される光学活性α−アミノアミド誘導体に、一般式(3)
R2−X (3)
〔式中、R2、Xは前記のものと同じ意味を示す。〕で表される有機金属化合物を反応させて、一般式(1)
【0016】
【化21】
【0017】
〔式中、Ra、Rb、R1、R2、*は前記のものと同じ意味を示す。〕で表される光学活性α−アミノケトン誘導体を得る工程(工程I)と、一般式(1)で表されるα−アミノケトン誘導体を還元して、一般式(4’)
【0018】
【化22】
【0019】
〔式中、Ra、Rb、R1、R2、*は前記のものと同じ意味を示し、*'は不斉炭素であることを示す。〕で表されるシン立体配置の光学活性β−アミノアルコール誘導体を得る工程(工程II)と、一般式(4’)で表わされる光学活性β−アミノアルコール誘導体のアミノ基の保護基を脱保護する工程(工程III)からなることを特徴とする一般式(4)
【0020】
【化23】
【0021】
〔式中、R1、R2、*、*'は前記のものと同じ意味を示す。〕で表されるシン立体配置の光学活性β−アミノアルコール類の製造方法であり、また、一般式(2)
【0022】
【化24】
【0023】
〔式中、Ra、Rb、Rc、Rd、R1、nは前記のものと同じ意味を示す。〕で表される光学活性α−アミノアミド誘導体に、一般式(3)
R2−X (3)
〔式中、R2、Xは請求項1と同じ意味を示す。〕で表される有機金属化合物を反応させて、一般式(1)
【0024】
【化25】
【0025】
〔式中、Ra、Rb、R1、R2、*は上記のものと同じ意味を示す。〕で表される光学活性α−アミノケトン誘導体を得る工程(工程I)と、一般式(1)で表されるα−アミノケトン誘導体のアミノ基を脱保護して一般式(5)
【0026】
【化26】
【0027】
〔式中、R1、R2、*は上記のものと同じ意味を示す。〕で表される光学活性α−アミノケトン類を得る工程(工程(IV)と、一般式(5)で表わされる化合物を還元する工程(工程V)からなる一般式(6)
【0028】
【化27】
【0029】
〔式中、R1、R2、*は上記のものと同じ意味を示し、*"は不斉炭素であることを示す。〕で表されるアンチ立体配置の光学活性β−アミノアルコール類の製造方法であり、また、一般式(2)
【0030】
【化28】
【0031】
〔式中、Ra、Rb、Rc、Rd、R1、nは上記のものと同じ意味を示す。〕で表される光学活性α−アミノアミド誘導体であり、また、一般式(1’)
【0032】
【化29】
【0033】
〔式中、Ra、Rb、R1、*は上記のものと同じ意味を示す。R2’は置換基を有していても良い炭素数1〜20のアルキル基、置換基を有していても良い炭素数2〜20のアルケニル基、置換基を有していても良い炭素数2〜20のアルキニル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基(ただし、クロロメチル基、ブロモメチル基、ジクロロメチル基、ジブロモメチル基、及び下記式
【0034】
【化30】
【0035】
で表わされる基を除く。)を示す。〕で表される光学活性α−アミノケトン誘導体である。
【0036】
なお、本発明において、ジアステレオ異性体の一方を意味するシン異性体(シン立体配置を有する化合物)とは、炭素鎖を主鎖としてジグザグに左右方向に置いた場合に、その上下方向にそれぞれ置換するアミノ基とヒドロキシル基が同じ面を向くような立体配置を有するものをいい、アンチ異性体(アンチ立体配置を有する化合物)とは、炭素鎖を主鎖としてジグザグに左右方向に置いた場合に、その上下方向にそれぞれ置換するアミノ基とヒドロキシル基が反対の面を向くような立体配置を有するものをいう。
【0037】
本発明によれば、医薬・農薬の合成中間体として有用な前記一般式(1)、(4)、(6)で表される光学活性アミノ化合物類を、高立体選択的かつ高収率に製造することができる。
【0038】
【発明の実施の形態】
以下、本発明を詳細に説明する。
一般式(1)、(1’)、(2)、(3)、(4)、(4’)、(5)、(6)において、
Ra,Rbはそれぞれ独立して、水素原子、置換基を有していても良い炭素数1〜6のアルキル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基を表わす。
置換基を有していても良い炭素数1〜6のアルキル基のアルキル基としては、メチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、s−ブチル基、t−ブチル基、n−ペンチル基、n−ヘキシル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基等;
置換基を有していても良いアリール基のアリール基としては、フェニル基、1−ナフチル基、2−ナフチル基等;
置換基を有していても良いアラルキル基のアラルキル基としてはベンジル基、フェニルエチル基等を挙げることができる。
【0039】
これらの基の置換基としては、ヒドロキシル基、フッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子、メチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、s−ブチル基、t−ブチル基、n−ペンチル基、n−ヘキシル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基等の炭素数1〜6の直鎖または分岐または環状のアルキル基;メトキシ基、エトキシ基、n−プロポキシ基、n−ブトキシ基、t−ブトキシ基等の炭素数1〜6の直鎖または分岐等のアルコキシ基、ビニル基、アリル基、イソプロペニル基等の炭素数1〜6の直鎖または分岐のアルケニル基;エチニル基、2−プロピニル基等の炭素数1〜6の直鎖または分岐のアルキニル基;フェニル基、1−ナフチル基、2−ナフチル基等のアリール基;ベンジル基、フェニルエチル基、ナフチルメチル基等のアラルキル基を挙げることができる。
【0040】
また、RaとRbは一緒になって環を形成してもよく、例えば下記式で表わされる基を挙げることができる。
【0041】
【化31】
【0042】
Ra,Rbはいずれも置換基を有していてもよいアリール基であるか、又は、いずれか一方が置換基を有していても良いアリール基であり他方が水素原子であるのが好ましい。
置換基としては、炭素数1〜6のアルキル基、炭素数1〜6のアルコキシ基、ハロゲン原子が好ましい。
【0043】
Rc、Rdは、それぞれ独立して、水素原子、置換基を有していても良い炭素数1〜6のアルキル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基を表わす。
置換基を有していても良い炭素数1〜6のアルキル基のアルキル基としては、メチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、s−ブチル基、t−ブチル基、n−ペンチル基、n−ヘキシル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基等;
置換基を有していても良いアリール基のアリール基としては、フェニル基、1−ナフチル基、2−ナフチル基等;
置換基を有していても良いアラルキル基のアラルキル基としてはベンジル基、フェニルエチル基等のアラルキル基等を挙げることができる。また、RcとRdが酸素原子、窒素原子と一緒になって、例えばモルホリン環等の環を形成しても良い。
【0044】
これらの基の置換基としては、ヒドロキシル基;フッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子;メチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、s−ブチル基、t−ブチル基、n−ペンチル基、n−ヘキシル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基等の炭素数1〜6の直鎖または分岐または環状のアルキル基;メトキシ基、エトキシ基、n−プロポキシ基、n−ブトキシ基、t−ブトキシ基等の炭素数1〜6の直鎖または分岐等のアルコキシ基、ビニル基、アリル基、イソプロペニル基等の炭素数1〜6の直鎖または分岐のアルケニル基;エチニル基、2−プロピニル基等の炭素数1〜6の直鎖または分岐のアルキニル基;フェニル基、1−ナフチル基、2−ナフチル基等のアリール基;ベンジル基、フェニルエチル基等のアラルキル基を挙げることができる。
【0045】
R1は、置換基を有していても良い炭素数1〜20のアルキル基、置換基を有していても良い炭素数2〜20のアルケニル基、置換基を有していても良い炭素数2〜20のアルキニル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基を表わす。
具体的には、メチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、t−ブチル基、s−ブチル基、イソブチル基、n−ペンチル基、s−ペンチル基、イソペンチル基、ネオペンチル基、n−ヘキシル基、s−ヘキシル基、1,1−ジメチル−n−ヘキシル基、n−ヘプチル基、n−デシル基、n−ドデシル基、シクロプロピル基、シクロブチル基、シクロペンチル基等の炭素数1〜20の直鎖または分岐または環状のアルキル基;
ビニル基、アリル基、2−ブテニル基、1−メチル−2−プロペニル基、4−オクテニル基、シクロペンテン、シクロヘキセン等の炭素数2〜20の直鎖または分岐または環状のアルケニル基;
エチニル基、プロパルギル基、1−メチル−プロピニル基等の炭素数2〜20の直鎖または分岐または環状のアルキニル基;
フェニル基、1−ナフチル基、2−ナフチル基、9−アントラセニル基等のアリール基;
ベンジル基、フェニルエチル基、ナフチルメチル基等のアラルキル基を挙げることができる。
【0046】
これらの基の置換基としては、ヒドロキシル基;シアノ基;フッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子;メチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、s−ブチル基、t−ブチル基、n−ペンチル基、n−ヘキシル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基等の炭素数1〜6の直鎖または分岐または環状のアルキル基;メトキシ基、エトキシ基、n−プロポキシ基、n−ブトキシ基、t−ブトキシ基等の炭素数1〜6の直鎖または分岐等のアルコキシ基、メトキシカルボニル、エトキシカルボニル、n−プロポキシカルボニル等の炭素数1〜7のアルコキシカルボニル基;ビニル基、アリル基、イソプロペニル基等の炭素数1〜6の直鎖または分岐のアルケニル基;エチニル基、2−プロピニル基等の炭素数1〜6の直鎖または分岐のアルキニル基;フェニル基、1−ナフチル基、2−ナフチル基等のアリール基;ベンジル基、フェニルエチル基等のアラルキル基を挙げることができる。
【0047】
R2は、有機合成化学上でのいわゆるGrignard試薬とリチウム試薬を調製可能な基であれば特に制限はないが、好ましくは置換基を有していても良い炭素数1〜20のアルキル基、置換基を有していても良い炭素数2〜20のアルケニル基、置換基を有していても良い炭素数2〜20のアルキニル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基である。
具体的には、メチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、t−ブチル基、s−ブチル基、イソブチル基、n−ペンチル基、s−ペンチル基、イソペンチル基、ネオペンチル基、n−ヘキシル基、s−ヘキシル基、1,1−ジメチル−n−ヘキシル基、n−ヘプチル基、n−デシル基、n−ドデシル基、シクロプロピル基、シクロブチル基、シクロペンチル基等の炭素数1〜20の直鎖または分岐または環状のアルキル基;
ビニル基、アリル基、2−ブテニル基、1−メチル−2−プロペニル基、4−オクテニル基、シクロペンテン、シクロヘキセン等の炭素数2〜20の直鎖または分岐または環状のアルケニル基;
エチニル基、プロパルギル基、1−メチル−プロピニル基等の炭素数2〜20の直鎖または分岐または環状のアルキニル基;
フェニル基、1−ナフチル基、2−ナフチル基、9−アントラセニル基等のアリール基;
ベンジル基、フェニルエチル基、ナフチルメチル基等のアラルキル基を挙げることができる。
【0048】
これらの基の置換基としては、ヒドロキシル基;フッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子;メチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、s−ブチル基、t−ブチル基、n−ペンチル基、n−ヘキシル基、シクロプロピル基、シクロペンチル基、シクロヘキシル基等の炭素数1〜6の直鎖または分岐または環状のアルキル基;メトキシ基、エトキシ基、n−プロポキシ基、n−ブトキシ基、t−ブトキシ基等の炭素数1〜6の直鎖または分岐等のアルコキシ基、ビニル基、アリル基、イソプロペニル基等の炭素数1〜6の直鎖または分岐のアルケニル基;エチニル基、2−プロピニル基等の炭素数1〜6の直鎖または分岐のアルキニル基;フェニル基、1−ナフチル基、2−ナフチル基等のアリール基;ベンジル基、フェニルエチル基等のアラルキル基を挙げることができる。
【0049】
以下、本発明に係る反応について詳細に述べる。
【0050】
【化32】
【0051】
一般式(1)で表される化合物の合成方法(工程I):
一般式(2)で表される化合物の不活性溶媒溶液に一般式(3)で表わされる化合物のの不活性溶媒溶液を−100℃〜沸点まで好ましくは−78℃〜60℃で滴下し、さらにこの混合液を−78℃〜60℃で1〜48時間好ましくは4〜18時間攪拌する。不活性溶媒としてはベンゼン、トルエン等の芳香族炭化水素系、ヘキサン、アイソパーE等の炭化水素系、クロロホルム、クロロベンゼン等の塩素系、THF、ジエチルエーテル等のエーテル系溶媒を挙げることができる。その後、この反応混合液を0℃〜室温で好ましくは0℃〜5℃で水にあけることにより、一般式(1)で表される化合物を得ることができる。
【0052】
一般式(4’)で表される化合物の合成方法(工程II):
一般式(1)で表される化合物の不活性溶媒溶液に還元剤を添加し、この混合液を−100℃〜沸点まで好ましくは−78℃〜−30℃で0.5〜48時間好ましくは1〜18時間攪拌すれば一般式(4’)で表される化合物が得られる。不活性溶媒としてはベンゼン、トルエン等の芳香族炭化水素系、ヘキサン、アイソパーE等の炭化水素系、クロロホルム、クロロベンゼン等の塩素系、THF、ジエチルエーテル等のエーテル系溶媒を挙げることができる。還元剤としては、水素化リチウムアルミニウム、ジイソブチル水素化アルミニウム等の水素化アルミニウム系還元剤、水素化ホウ素ナトリウム、ソジウムシアノボロヒドリド、K−セレクトライド、L−セレクトライド等の水素化ホウ素系還元剤であり、L−セレクトライドが好ましい。また、パラジウム、白金など金属の炭素担持体を触媒として水素を還元剤とした接触還元も可能である。還元剤の使用量は一般式(1)で表される化合物の1〜5等量であり好ましくは2〜3等量である。
【0053】
一般式(4)で表される化合物の合成方法(工程III):
一般式(4’)で表される化合物の不活性溶媒溶液に酸を添加し、この混合液を−10℃〜沸点まで好ましくは0℃〜室温で0.5〜48時間好ましくは1〜18時間攪拌すれば一般式(4)で表される化合物が得られる。不活性溶媒としてはベンゼン、トルエン等の芳香族炭化水素系、ヘキサン、アイソパーE等の炭化水素系、クロロホルム、クロロベンゼン等の塩素系、THF、ジエチルエーテル等のエーテル系、メタノール、エタノールなどのアルコール系溶媒、および水を挙げることができ、これらの混合溶媒を用いることも可能である。酸としては、塩化水素、硫酸、などの無機酸およびその水溶液、酢酸、クエン酸などの有機酸およびその水溶液が用いられる。酸の使用量は一般式(4’)で表される化合物の等量以上であればよく、好ましくは2〜3等量であるが、大過剰用いることも可能である。
【0054】
一般式(5)で表される化合物の合成方法(工程IV):
一般式(1)で表される化合物の不活性溶媒溶液に酸を添加し、この混合液を−10℃〜沸点まで好ましくは0℃〜室温で0.5〜48時間好ましくは1〜18時間攪拌すれば一般式(5)で表される化合物が得られる。不活性溶媒としてはベンゼン、トルエン等の芳香族炭化水素系、ヘキサン、アイソパーE等の炭化水素系、クロロホルム、クロロベンゼン等の塩素系、THF、ジエチルエーテル等のエーテル系、メタノール、エタノールなどのアルコール系溶媒、および水を挙げることができ、これらの混合溶媒を用いることも可能である。酸としては、塩化水素、硫酸、などの無機酸およびその水溶液、酢酸、クエン酸などの有機酸およびその水溶液が用いられる。酸の使用量は一般式(1)で表される化合物の等量以上であればよく、好ましくは2〜3等量であるが、大過剰用いることも可能である。
【0055】
また、以下の方法でも一般式(5)で表わされる化合物を合成することがでいる。
一般式(2)で表される化合物の不活性溶媒溶液に一般式(3)で表わされる化合物のの不活性溶媒溶液を−100℃〜沸点まで好ましくは−78℃〜60℃で滴下し、さらにこの混合液を−78℃〜60℃で1〜48時間好ましくは4〜18時間攪拌する。不活性溶媒としてはベンゼン、トルエン等の芳香族炭化水素系、ヘキサン、アイソパーE等の炭化水素系、クロロホルム、クロロベンゼン等の塩素系、THF、ジエチルエーテル等のエーテル系溶媒を挙げることができる。その後、この反応混合液を0℃〜室温で好ましくは0℃〜5℃で酸の水溶液にあけることにより、一般式(5)で表される化合物を得ることができる。酸としては、塩化水素、硫酸、などの無機酸およびその、酢酸、クエン酸などの有機酸が用いられるが、反応操作性から塩化水素がこのましい。酸の使用量は一般式(3)で表される化合物の2等量以上であればよく、好ましくは3〜5等量であるが、大過剰用いることも可能である。
【0056】
一般式(6)で表わされる化合物の合成法(工程V):
一般式(5)で表される化合物が得られた反応溶液に還元剤を添加し、この混合液を−100℃〜沸点まで好ましくは−78℃〜−30℃で0.5〜48時間好ましくは1〜18時間攪拌すれば一般式(6)で表される化合物が得られる。還元剤としては、水素化リチウムアルミニウム、ジイソブチル水素化アルミニウム等の水素化アルミニウム系還元剤、水素化ホウ素ナトリウム、ソジウムシアノボロヒドリド、K−セレクトライド、L−セレクトライド等の水素化ホウ素系還元剤であり、水素化ホウ素ナトリウムが好ましい。還元剤の使用量は一般式(1)で表される化合物の1〜5等量であり好ましくは2〜3等量である。
【0057】
本発明に用いる原料である一般式(2)で表わされる化合物は、例えば、グリシン誘導体(a−1)を原料として以下のようにして合成することが出来る。
【0058】
【化33】
【0059】
(式中、Zは保護基、Yはハロゲン原子を表わし、Ra、Rb,Rc,Rd、R1,nは前記と同様である。)
(a−6)で表わされる化合物を、アルカリ条件下で、水―トルエン混合溶媒中、相関移動触媒を用いて不斉アルキル化することにより一般式(2)で表わされる化合物を得ることができる。
この時使用する触媒としては例えば、下記式(以下(S,S)−Aと表記する)で表わされる化合物を挙げることができる。
【0060】
【化34】
【0061】
以上の方法で合成できる一般式(2)および一般式(1’)で表わされる化合物の例を第1表、第2表に示す。
第1表、第2表中、Phはフェニル基を表わし、A−1からA−5、B−1からB−6はそれぞれ下記式を表わす。
【0062】
【化35】
【0063】
【表1】
【0064】
【表2】
【0065】
【実施例】
次に実施例を挙げ、本発明をさらに詳細に説明する。なお、本発明はこれらに限定されるものではない。
【0066】
参考例1 化合物〔b−2〕の合成
【0067】
【化36】
【0068】
化合物〔b−1〕(2.09g、10mmol)とN−メチルモルホリン(2.2ml、20mmol)をジクロロメタン50ml中で攪拌し、そこへClCO2C2H5(0.95ml、10mmol)を0℃で加えた。混合液を0℃で15分間攪拌した。粉末のN,O−ジメチルヒドロキシルアミン塩酸塩(0.98g、10mmol)を少しずつ加え、混合液を0℃で30分間攪拌し、さらに室温で3時間攪拌した。このようにして得られた混合液を水で処理し、ジエチルエーテルで3回抽出した。抽出液は食塩水で洗浄し、硫酸ナトリウムで脱水した後、濃縮した。粗生成物を、シリカゲルカラムクロマトグラフィー(溶離液:ヘキサン/酢酸エチル=1/1から1/2)で精製し、無色の粘性オイル状の化合物(2.16g、8.56mmol、収率86%)を得た。得られた化合物(2.16g、8.56mmol、86%yield)をメタノール(43ml)に溶解し、ベンジルオキシカルボニル基部分を10%Pd−C(0.09g)と水素ガスで水素化して脱保護した。12時間室温で攪拌後、得られた混合物をセライトで濾過した。
塩酸のメタノール溶液(1M)9.5mlを0℃で濾液に加え、室温に戻し、20分間攪拌後、エバポレーションで揮散性物質を除去し、残渣をジクロロメタン43mlに懸濁させた。そこにベンゾフェノンイミン(1.44ml、8.6mmol)を加え、室温で6時間攪拌した。生成した白い懸濁液をセライトで濾過し、濾液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶離液:ヘキサン/酢酸エチル=1/1から1/3)で精製し、表記化合物〔b−2〕を無色の粘着性オイルとして得た(1.92g、6.8mmol、収率68%)。
1H NMR (400 MHz, CDCl3)δ: 7.67-7.65 (2H, m, Ar-H), 7.49-7.37 (4H, m, Ar-H), 7.33 (2H, t, J = 7.2 Hz, Ar-H), 7.24-7.22 (2H, m, Ar-H), 4.35 (2H, s, NCH2CO), 3.64 (3H, s, OMe), 3.21 (3H, s, NMe).
【0069】
参考例2 化合物〔b−3〕の合成
【0070】
【化37】
【0071】
N,O−ジメチルヒドロキシルアミン塩酸塩の代わりにN−ベンジル−O−メチルヒドロキシルアミンを用い、また半量のN−メチルモルホリンを用いた以外は参考例1と同様の方法で、合成を行った。粗生成物をシリカゲルカラムクロマトグラフィーシリカゲルカラムクロマトグラフィー(溶離液:ヘキサン/酢酸エチル=1.5/1から1/1)で精製し、無色の粘着性オイルの表記化合物〔b−3〕を得た(収率79%)。
1H NMR (400 MHz, CDCl3) δ:
7.68-7.65 (2H, m, Ar-H), 7.47-7.16 (13H, m, Ar-H), 4.81 (2H, s, NCH2Ph), 4.40 (2H, s, NCH2CO), 3.56 (3H, s, OMe).
【0072】
参考例3 化合物〔b−4〕の合成
【0073】
【化38】
【0074】
参考例1で合成した化合物 (0.20 mmol) と 前記触媒(S,S)−A (4 mg, 0.004 mmol, 2 mol%) のトルエン溶液に、ヨウ化メチル(0.22mmol)と50%KOH水溶液(0.65ml)を、アルゴン雰囲気下、0℃で加え、同温度で6時間攪拌した。生成物を水で蒸留し、ジエチルエーテルで3回抽出した。抽出液を食塩水で洗浄し、硫酸ナトリウムで脱水し、濃縮した。粗生成物をシリカゲルカラムクロマトグラフィーシリカゲルカラムクロマトグラフィー(溶離液:ヘキサン/ジエチルエーテル=1.5/1から1/3)で精製し、無色の粘着性オイルの表記化合物〔b−4〕を得た(収率97%、96%ee)。光学純度は、HPLCで決定した(光学カラム:DAICEL Chiralcel-OD-H、移動相: ヘキサン/エタノール =50/1, 流速:0.5 mL/min、保持時間 :(D体)20.1分、(L体)22.3分)。
[a]D 23 = +25.8o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDCl3)δ:
7.70-7.65 (2H, m, Ar-H), 7.49-7.42 (3H, m, Ar-H), 7.38 (1H, tt, J = 7.2, 1.2 Hz, Ar-H), 7.33-7.29 (2H, m, Ar-H), 7.21-7.19 (2H, m, Ar-H), 5.73 (1H, ddt, J = 17.2, 10.0, 7.2 Hz, CH2=CH-CH2), 5.06-4.98 (2H, m, CH 2=CH-CH2), 4.41 (1H, t, J = 6.8 Hz, NCHCO), 3.27 (3H, s, OMe), 3.15 (3H, s, NMe), 2.81 (1H, ddd, J = 13.9, 7.2, 6.8 Hz, CH2=CH-CH 2), 2.64 (1H, ddd, J = 13.9, 7.2, 6.8 Hz, CH2=CH-CH 2).
【0075】
参考例4 化合物〔b−5〕の合成
【0076】
【化39】
【0077】
臭化アリルの代わりにヨウ化メチルを用いた以外は参考例3と同様にして合成し、無色の粘着性オイル状の表記化合物〔b−5〕を得た(収率64%、90%ee)。
1H NMR (400 MHz, CDCl3)δ:
7.65 (2H, d, J = 7.6 Hz, Ar-H), 7.50-7.43 (3H, m, Ar-H), 7.37 (1H, t, J = 7.6 Hz, Ar-H), 7.31 (1H, t, J = 7.6 Hz, Ar-H), 7.22-7.19 (2H, m, Ar-H), 4.43 (1H, q, J = 6.8 Hz, NCHCO), 3.34 (3H, s, NCH3), 3.17 (3H, s, NOCH3), 1.37 (3H, d, J = 6.8 Hz, CH3);
IR(KBr) :
3059, 2997, 2976, 2932, 1665, 1611, 1574, 1491, 1447, 1387, 1375, 1315, 1281, 1267, 1200, 1180, 1096, 1045, 986, 949, 928, 789, 772, 720, 700 cm-1.
【0078】
参考例5 化合物〔b−6〕の合成
【0079】
【化40】
【0080】
参考例1で合成した化合物〔b−2〕の代わりに、参考例2で合成した化合物〔b−3〕を用いた以外は、参考例3と同様の方法で合成し、無色の粘着性オイルの表記化合物〔b−6〕を定量的に得た(97%ee)。
光学純度は、HPLCで決定した(光学カラム:DAICEL Chiralcel-OD-H、移動相: ヘキサン/エタノール =50/1, 流速:0.5 mL/min、保持時間 :(D体)21.6分、(L体)24.8分)。
[a]D 23 = +23.4o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDCl3)δ:
7.65-7.62 (2H, m, Ar-H), 7.46-7.36 (4H, m, Ar-H), 7.34-7.25 (7H, m, Ar-H), 7.19-7.16 (2H, m, Ar-H), 5.74 (1H, ddt, J = 17.2, 10.0, 6.8 Hz, CH2=CH-CH2), 5.05-4.97 (2H, m, CH 2=CH-CH2), 4.79 (1H, d, J = 15.4 Hz, CH2Ph), 4.74 (1H, d, J = 15.4 Hz, CH2Ph), 4.40 (1H, t, J = 6.8 Hz, NCHCO), 3.17 (4H, s, OMe), 2.82 (1H, ddd, J = 13.6, 6.8, 6.8 Hz, CH2=CH-CH 2), 2.48 (1H, ddd, J = 13.6, 6.8, 6.8 Hz, CH2=CH-CH 2).
【0081】
実施例1 化合物〔c−1〕の合成
【0082】
【化41】
【0083】
化合物 〔b−6〕(240 mg, 0.602 mmol, 97.2% ee)の THF溶液3mlにフェニルマグネシウムブロマイドのジエチルエーテル溶液 (0.87M 、1.1 ml、0.99 mmol)を、0℃、アルゴン雰囲気下で加え、同温度で20分間攪拌した。生成した薄茶色の溶液を冷水にあけて、混合物をジエチルエーテルで抽出した。抽出液を食塩水で洗浄し、硫酸ナトリウムで脱水した後、濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(溶離液:ヘキサン/ジエチルエーテル=6/1から4/1)で冷却しながら精製し、無色のオイルとして表記化合物〔c−1〕を得た (171 mg, 0.506 mmol, 収率84% , 96.5%ee)。
光学純度は、HPLCで決定した〔光学カラム:DAICEL Chiralcel-OD-H、移動相: ヘキサン/イソプロパノール=200/1, 流速:0.5 mL/min、保持時間 :20.3分 (S体)、26.3分(R体)〕。
[a]D 21 = +23.4o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDCl3)δ:
7.87-7.84 (2H, m, Ar-H), 7.67-7.64 (2H, m, Ar-H), 7.51 (1H, tt, J = 7.4, 1.2 Hz, Ar-H), 7.45-7.36 (6H, m, Ar-H), 7.32 (2H, tt, J = 7.4, 1.2 Hz, Ar-H), 7.12-7.08 (2H, m, Ar-H), 5.74 (1H, ddt, J = 17.2, 10.0, 7.3 Hz, CH2=CH-CH2), 5.05-4.99 (2H, m, CH 2=CH-CH2), 4.87 (1H, dd, J = 7.3, 5.8 Hz, NCHCO), 2.83-2.69 (2H, m, CH2=CH-CH 2).
【0084】
実施例2 化合物〔c−2〕の合成
【0085】
【化42】
【0086】
化合物〔c−1〕 (179 mg, 0.527 mmol) の THF溶液(2.6 mL) を L−セレクトライドのTHF溶液(1.0M、1.1ml、1.1mmol) に−78℃で加えた。同温度で、1時間攪拌後、生成物を冷却した飽和塩化アンモニウム水溶液にあけた。ジエチルエーテルで3回抽出した後、抽出液を食塩水で洗浄し、硫酸ナトリウムで脱水した後、濃縮した。 粗生成物をシリカゲルカラムクロマトグラフィー(溶離液:ヘキサン/ジクロロメタン=1/1)で冷却しながら精製し、無色のオイルとして表記化合物〔c−2〕を得た (152 mg, 0.446 mmol, 収率85% )。
1H NMR (400 MHz, CDCl3)δ:
7.75-7.72 (2H, m, Ar-H), 7.61-7.59 (2H, m, Ar-H), 7.39-7.22 (9H, m, Ar-H), 7.17-7.15 (2H, m, Ar-H), 5.83 (1H, ddt, J = 17.1, 10.2, 6.8 Hz, CH2=CH-CH2), 5.11 (1H, dd, J = 17.1, 1.6 Hz, cis-CH 2=CH-CH2), 5.06 (1H, dd, J = 10.2, 1.6 Hz, trans-CH 2=CH-CH2), 4.53 (1H, d, J = 8.4 Hz, CHPh), 3.18 (1H, ddd, J = 8.4, 8.0, 4.4 Hz, Ph2C=NCH), 2.61 (1H, s, OH), 2.41-2.33 (1H, m, CH2=CH-CH 2), 2.20 (1H, ddd, J = 14.8, 8.0, 6.8 Hz, CH2=CH-CH 2).
【0087】
実施例3 化合物〔c−3〕の合成
【0088】
【化43】
【0089】
化合物〔c−2〕 (70.1 mg, 0.205 mmol)のTHF溶液4ml に10%クエン酸4mlを加え室温で10時間攪拌し、表記化合物〔c−3〕を得た。
物性値を分析するために、〔c−3〕を以下の方法で〔c−3’〕に誘導し、〔c−3’〕の物性値を測定した。
ベンジルクロライド (36 ml, 0.31 mmol) と 炭酸水素ナトリウム過剰量を、上記生成物に0℃で徐々に加えた。室温で4時間攪拌した後、生成した混合物を水で蒸留し、ジエチルエーテルで3回抽出した。抽出液を食塩水で洗浄し、硫酸ナトリウムで脱水した後、濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(溶離液:ヘキサン/酢酸エチル=1.5/1から1/1)で精製し、無色結晶の誘導体〔c−3’〕を得た (49.1mg、0.175mmol、収率85%、97%ee、99%de)。
[a]D 20 = -56.4o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDCl3)δ:
7.69-7.67 (2H, m, Ar-H), 7.49 (1H, tt, J = 7.4, 1.2 Hz, Ar-H), 7.42-7.24 (7H, m, Ar-H), 6.42 (1H, d, J = 7.6 Hz, NH), 5.86 (1H, ddt, J = 17.2, 10.0, 7.4 Hz, CH2=CH-CH2), 5.19-5.12 (2H, CH 2=CH-CH2), 4.87 (1H, dd, J = 4.6, 4.6 Hz, CHPh), 4.33 (1H, dtd, J = 7.6, 7.4, 4.6 Hz, NCH), 3.55 (1H, br, OH), 2.49 (1H, dt, J = 14.0, 7.4 Hz, CH2=CH-CH 2), 2.35 (1H, dt, J = 14.0, 7.4 Hz, CH2=CH-CH 2).
【0090】
実施例4 化合物〔c−5〕の合成
【0091】
【化44】
【0092】
化合物〔b−6〕 (48.7 mg, 0.122 mmol, 97% ee) のTHF溶液 0.61 mlをフェニルマグネシウムブロマイドのジエチルエーテル溶液 (0.90 M 、0.22 ml、 0.20 mmol)に、0℃、アルゴン雰囲気下で加えた。生成した薄茶色の溶液を同じ温度で20分間攪拌した後、冷却した1N塩酸に直ちに加えて、室温に戻した。20分攪拌後、混合物を減圧下で濃縮し、残渣をメタノール1.2mlに溶解し、NaBH4 (11 mg, 0.29 mmol)を0℃で加え室温で2時間攪拌し、表記化合物〔c−5〕を得た。
物性値を分析するために、〔c−5〕を以下の方法で〔c−5’〕に誘導し、〔c−5’〕の物性値を測定した。
ベンジルクロライド (43 ml, 0.37 mmol) と 炭酸水素ナトリウム過剰量を、化合物〔c−5〕を含む混合生成物に0℃で加えた。室温で3時間攪拌した後、混合物を水で蒸留し、ジエチルエーテルで3回抽出した。抽出液を食塩水で洗浄し、硫酸ナトリウムで脱水した後、濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(溶離液:ヘキサン/酢酸エチル=1.5/1から1/1)で精製し、無色結晶の誘導体〔c−5’〕を得た (32.1 mg, 0.114 mmol, 90% yield, 97% ee, 97% de)。
光学純度は、HPLCで決定した(光学カラム:DAICEL Chiralcel-OD-H、移動相: ヘキサン/イソプロパノール=10/1, 流速:0.5 mL/min、保持時間 :24.6 min (1S,2R), 29.5 min (1S,2S), 38.6 min (1R,2S) and 42.2 min (1R,2R))。
[a]D 22 = -39.9o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDCl3)δ:
7.73-7.70 (2H, m, Ar-H), 7.51 (1H, tt, J = 7.4, 1.2 Hz, Ar-H), 7.43-7.33 (6H, m, Ar-H), 7.29 (1H, tt, J = 6.8, 1.8 Hz, Ar-H), 6.20 (1H, d, J = 7.8 Hz, NH), 5.77 (1H, dddd, J = 16.7, 10.5, 8.2, 6.0 Hz, CH2=CH-CH2), 5.10-5.02 (3H, m, CH 2=CH-CH2 and CHPh), 4.50 (1H, dddd, J = 9.7, 7.8, 4.8, 3.2 Hz, CHNHBz), 3.89 (1H, s, OH), 2.37-2.31 (1H, m, CH2=CH-CH 2), 2.21 (1H, ddd, J = 14.7, 9.7, 8.2 Hz, CH2=CH-CH 2).
【0093】
実施例5 化合物〔c−6〕の合成
【0094】
【化45】
【0095】
化合物〔b−5〕(59mg、0.20mmol、99.9%ee)のTHF(1ml)溶液に、パラクロロフェニルマグネシウムブロマイドの0.89Mエーテル溶液(0.36ml、0.32mmol)を0℃アルゴン雰囲気下で加え、同温度で20分間撹拌した。淡黄色化した反応溶液を氷冷した1N塩酸(3ml)にすばやくあけ、この混合溶液を20分間で撹拌しながら室温にした。溶媒を減圧留去し、残滓をTHF(2ml)に懸濁し、表記化合物〔c−6〕を得た。
物性値を分析するために、〔c−6〕を以下の方法で〔c−6’〕に誘導し、〔c−6’〕の物性値を測定した。
化合物〔c−5〕を含む混合生成物に、Boc2O(138μl、0.60mmol)と粉体のまま重曹(過剰量)を0℃で添加して3時間撹拌した。反応溶液を濃縮し残滓をカラムクロマトグラフィーで精製して(ヘキサン/酢酸エチル=4:1〜3:1)、無色結晶の〔c−6’〕を得た(55.3mg、0.188mmol、収率94%)。
[a]D 22 = -23.2o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDCl3)δ:
7.92 (2H, d, J =8.4 Hz, p-Cl-Ph), 7.47 (2H, d, J =8.4 Hz, p-Cl-Ph), 5.48 (1H, br d, J = 6.8 Hz, NH), 5.24 (1H, dq, J = 6.8, 7.2 Hz, NCHCO), 1.45 (9H, s, t-Bu), 1.39 (3H, d, J = 7.2 Hz, CH3).
【0096】
【発明の効果】
本発明によれば、医薬品やその合成中間体として有用な光学活性アミノアルコール類やアミノケトン類を高選択的、高収率かつ工業的に有利に製造することができる。[0001]
BACKGROUND OF THE INVENTION
Optically active β-aminoalcohols having syn and anti configurations are useful as synthetic intermediates or drug substances for pharmaceutical pesticides. In the present invention, optically active β-aminoalcohols having these syn and anti configurations and optically active α-aminoketone derivatives of precursors thereof are used as a common raw material for a novel α-aminoamide derivative as a common raw material. The present invention relates to a technology for highly stereoselective manufacturing.
[0002]
[Prior art]
Optically active α-aminoketones are most useful as precursors of optically active β-amino alcohols having syn and anti configurations. However, since α-amino ketones are unstable due to their structure except under acidic conditions, an optically active α-amino acid is an acid of α- (protected amino) acid such as α-phthalimidic acid as a practical synthesis method. There is a method of inducing a halide into an optically active α-aminoketone by a Friedel-Crafts reaction (J. Org. Chem.50, 3481 (1985), EP-304018). However, optically active α-amino acids are expensive, and unnatural forms are often difficult to obtain. Furthermore, a protecting group that is stable in the Friedel-Crafts reaction step and can be efficiently deprotected under acidic conditions is required, and the protection / deprotection operation itself is complicated.
Therefore, until now, there has been no method for synthesizing advantageous optically active α-aminoketones having high generality. As a result, an appropriate method for synthesizing optically active β-amino alcohols having syn and anti configurations has not been known.
[0003]
[Problems to be solved by the invention]
The present invention relates to a novel α-aminoamide derivative, a novel optically active α-aminoketone derivative obtained therefrom, and an optically active β-aminoalcohol having a syn and anti configuration with the optically active α-aminoketone derivative as a precursor. It aims at providing the simple manufacturing method of a kind.
[0004]
[Means for Solving the Problems]
First, as a result of intensive studies to find an optically active α-aminoamide that advantageously gives optically active α-aminoketones, the present inventors have found that when an optically active α-aminoamide derivative having a specific protecting group is used, The present inventors have found that the amide moiety can be converted to a ketone without affecting the configuration of. Secondly, optically active β-aminoalcohols having a syn configuration can be obtained by reducing the protective group of the amino group of the optically active α-aminoketone derivative without deprotection. Thus, it was found that optically active β-amino alcohols having an anti-configuration can be obtained, and the present invention has been completed.
[0005]
That is, the present invention relates to the general formula (2)
[0006]
Embedded image
[0007]
[In the formula, each of Ra and Rb independently has a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted aryl group or a substituent. An aralkyl group which may be substituted, and Ra and Rb may be combined to form a ring.
Rc and Rd are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, or a substituent. A good aralkyl group is shown, and Rc and Rd may form a ring together.
R1 is an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 20 carbon atoms, and an optionally substituted carbon number 2 -20 alkynyl group, optionally substituted aryl group, optionally substituted aralkyl group, * represents an asymmetric carbon, n is 0 or 1, 2 Indicates an integer. An optically active α-aminoamide derivative represented by the general formula (3)
R2-X (3)
[In the formula, R2 may have a substituent, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms that may have a substituent, or a substituent. A good alkynyl group having 2 to 20 carbon atoms, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and X represents a magnesium bromide group, a magnesium chloride group and a lithium atom Show. A reaction with an organometallic compound represented by the general formula (1)
[0008]
Embedded image
[0009]
[Wherein, Ra, Rb, R1, R2, and * have the same meaning as described above. ] Production method of optically active α-aminoketone derivatives represented byIn lawYes, and general formula (1)
[0010]
Embedded image
[0011]
[In the formula, Ra, Rb, R1, R2, and * have the same meaning as described above. ]
A α-aminoketone derivative represented by the general formula (4 ′):
[0012]
Embedded image
[0013]
[In the formula, Ra, Rb, R1, R2, *Said* 'Indicates an asymmetric carbon having a relationship between the carbon of * and the syn configuration. A method for producing an optically active β-aminoalcohol derivative having a steric configuration represented byIn lawYes, and general formula (2)
[0014]
Embedded image
[0015]
[In the formula, Ra, Rb, Rc, Rd, R1, n areThe aboveIndicates the same meaning. An optically active α-aminoamide derivative represented by the general formula (3)
R2-X (3)
[Wherein R2 and X areThe aboveIndicates the same meaning. The organic metal compound represented by the general formula (1)
[0016]
Embedded image
[0017]
[In the formula, Ra, Rb, R1, R2, *The aboveIndicates the same meaning. And a step of obtaining an optically active α-aminoketone derivative represented by the general formula (4 ′).
[0018]
Embedded image
[0019]
[In the formula, Ra, Rb, R1, R2, *The aboveAnd * 'indicates an asymmetric carbon. A step of obtaining an optically active β-aminoalcohol derivative having a syn configuration represented by formula (Step II), and deprotecting the amino protecting group of the optically active β-aminoalcohol derivative represented by the general formula (4 ′) A general formula (4) characterized in that it comprises a step (Step III)
[0020]
Embedded image
[0021]
[In the formula, R1, R2, *, * 'The aboveIndicates the same meaning. A method for producing optically active β-amino alcohols having a steric configuration represented byIn lawYes, and general formula (2)
[0022]
Embedded image
[0023]
[In the formula, Ra, Rb, Rc, Rd, R1, n areThe aboveIndicates the same meaning. An optically active α-aminoamide derivative represented by the general formula (3)
R2-X (3)
[Wherein R 2 and X have the same meaning as in claim 1. The organic metal compound represented by the general formula (1)
[0024]
Embedded image
[0025]
[In the formula, Ra, Rb, R1, R2, *AboveIndicates the same meaning. A step of obtaining an optically active α-aminoketone derivative represented by the general formula (5) and deprotecting the amino group of the α-aminoketone derivative represented by the general formula (1)
[0026]
Embedded image
[0027]
[Wherein R1, R2 and * areAboveIndicates the same meaning. A process for obtaining an optically active α-aminoketone represented by general formula (6) comprising a process (process (IV) and a process for reducing the compound represented by general formula (5) (process V)).
[0028]
Embedded image
[0029]
[Wherein R1, R2 and * areAboveAnd "" indicates an asymmetric carbon.] Method for producing optically active β-amino alcohols having an anti-configuration represented byIn lawYes, and general formula (2)
[0030]
Embedded image
[0031]
[In the formula, Ra, Rb, Rc, Rd, R1, n areAboveIndicates the same meaning. An optically active α-aminoamide derivative represented byIn the bodyAnd the general formula (1 ')
[0032]
Embedded image
[0033]
[In the formula, Ra, Rb, R1, *the aboveIndicates the same meaning as R2 ′ is an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 20 carbon atoms, and an optionally substituted carbon number. 2-20 alkynyl groups, aryl groups optionally having substituents, aralkyl groups optionally having substituents (however, chloromethyl group, bromomethyl group, dichloromethyl group, dibromomethyl group, and formula
[0034]
Embedded image
[0035]
The group represented by is excluded. ). An optically active α-aminoketone derivative represented byIn the bodyis there.
[0036]
In the present invention, a syn isomer (compound having a syn steric configuration), which means one of diastereoisomers, is defined in the vertical direction when the carbon chain is placed in a zigzag horizontal direction as the main chain. It has a configuration in which the substituted amino group and hydroxyl group face the same surface. Anti isomers (compounds with an anti configuration) are those in which the carbon chain is placed in a zigzag left and right direction as the main chain. In addition, it has a configuration in which the amino group and the hydroxyl group to be substituted in the vertical direction are directed to opposite surfaces.
[0037]
According to the present invention, the optically active amino compounds represented by the general formulas (1), (4) and (6) useful as synthetic intermediates for pharmaceuticals and agricultural chemicals can be obtained with high stereoselectivity and high yield. Can be manufactured.
[0038]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
In the general formulas (1), (1 '), (2), (3), (4), (4'), (5), (6),
Each of Ra and Rb may independently have a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted aryl group, or a substituent. Represents a good aralkyl group.
Examples of the alkyl group having 1 to 6 carbon atoms which may have a substituent include a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, t -Butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group and the like;
As the aryl group of the aryl group which may have a substituent, a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like;
Examples of the aralkyl group of the aralkyl group which may have a substituent include a benzyl group and a phenylethyl group.
[0039]
Substituents for these groups include hydroxyl groups, fluorine atoms, chlorine atoms, bromine atoms, halogen atoms such as iodine atoms, methyl groups, ethyl groups, n-propyl groups, i-propyl groups, n-butyl groups, s A linear, branched or cyclic alkyl group having 1 to 6 carbon atoms such as -butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group; methoxy group, ethoxy Group, n-propoxy group, n-butoxy group, t-butoxy group and the like having 1 to 6 carbon atoms such as linear or branched alkoxy group, vinyl group, allyl group, isopropenyl group and the like. Linear or branched alkenyl group; linear or branched alkynyl group having 1 to 6 carbon atoms such as ethynyl group and 2-propynyl group; phenyl group, 1-naphthyl group, 2-naphthyl group and the like Aryl group; a benzyl group, phenylethyl group, and an aralkyl group such as naphthylmethyl group.
[0040]
Ra and Rb may be combined to form a ring, and examples thereof include a group represented by the following formula.
[0041]
Embedded image
[0042]
Each of Ra and Rb is preferably an aryl group which may have a substituent, or either one is an aryl group which may have a substituent and the other is a hydrogen atom.
As a substituent, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a halogen atom are preferable.
[0043]
Rc and Rd each independently have a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted aryl group, and a substituent. Represents a good aralkyl group.
Examples of the alkyl group having 1 to 6 carbon atoms which may have a substituent include a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, t -Butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group and the like;
As the aryl group of the aryl group which may have a substituent, a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like;
Examples of the aralkyl group of the aralkyl group which may have a substituent include aralkyl groups such as a benzyl group and a phenylethyl group. Rc and Rd may be combined with an oxygen atom or a nitrogen atom to form a ring such as a morpholine ring.
[0044]
Substituents for these groups include hydroxyl groups; halogen atoms such as fluorine atoms, chlorine atoms, bromine atoms and iodine atoms; methyl groups, ethyl groups, n-propyl groups, i-propyl groups, n-butyl groups, s A linear, branched or cyclic alkyl group having 1 to 6 carbon atoms such as -butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group; methoxy group, ethoxy Group, n-propoxy group, n-butoxy group, t-butoxy group and the like having 1 to 6 carbon atoms such as linear or branched alkoxy group, vinyl group, allyl group, isopropenyl group and the like. Linear or branched alkenyl group; linear or branched alkynyl group having 1 to 6 carbon atoms such as ethynyl group and 2-propynyl group; phenyl group, 1-naphthyl group, 2-naphthyl group and the like Aryl group; a benzyl group, an aralkyl group such as a phenyl ethyl group.
[0045]
R1 is an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted alkenyl group having 2 to 20 carbon atoms, and an optionally substituted carbon number. 2-20 alkynyl groups, an aryl group which may have a substituent, and an aralkyl group which may have a substituent are represented.
Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, s-butyl group, isobutyl group, n-pentyl group, s-pentyl group, isopentyl group, Such as neopentyl, n-hexyl, s-hexyl, 1,1-dimethyl-n-hexyl, n-heptyl, n-decyl, n-dodecyl, cyclopropyl, cyclobutyl, cyclopentyl, etc. A linear or branched or cyclic alkyl group having 1 to 20 carbon atoms;
A linear, branched or cyclic alkenyl group having 2 to 20 carbon atoms such as vinyl group, allyl group, 2-butenyl group, 1-methyl-2-propenyl group, 4-octenyl group, cyclopentene, cyclohexene;
A linear or branched or cyclic alkynyl group having 2 to 20 carbon atoms, such as an ethynyl group, a propargyl group, or a 1-methyl-propynyl group;
Aryl groups such as a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and a 9-anthracenyl group;
Examples thereof include aralkyl groups such as benzyl group, phenylethyl group and naphthylmethyl group.
[0046]
Substituents for these groups include: hydroxyl group; cyano group; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom; methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl A linear, branched or cyclic alkyl group having 1 to 6 carbon atoms such as a group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group; Groups, ethoxy groups, n-propoxy groups, n-butoxy groups, t-butoxy groups, etc., straight or branched alkoxy groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, etc. 1 to 7 alkoxycarbonyl groups; linear or branched alkenyl groups having 1 to 6 carbon atoms such as vinyl, allyl, and isopropenyl groups; A linear or branched alkynyl group having 1 to 6 carbon atoms such as a group, 2-propynyl group; an aryl group such as phenyl group, 1-naphthyl group, 2-naphthyl group; an aralkyl group such as benzyl group, phenylethyl group, etc. Can be mentioned.
[0047]
R2 is not particularly limited as long as it is a group capable of preparing a so-called Grignard reagent and a lithium reagent in organic synthetic chemistry, but preferably an alkyl group having 1 to 20 carbon atoms which may have a substituent, An alkenyl group having 2 to 20 carbon atoms which may have a group, an alkynyl group having 2 to 20 carbon atoms which may have a substituent, an aryl group which may have a substituent, and a substituent. An aralkyl group which may be present.
Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, s-butyl group, isobutyl group, n-pentyl group, s-pentyl group, isopentyl group, Such as neopentyl, n-hexyl, s-hexyl, 1,1-dimethyl-n-hexyl, n-heptyl, n-decyl, n-dodecyl, cyclopropyl, cyclobutyl, cyclopentyl, etc. A linear or branched or cyclic alkyl group having 1 to 20 carbon atoms;
A linear, branched or cyclic alkenyl group having 2 to 20 carbon atoms such as vinyl group, allyl group, 2-butenyl group, 1-methyl-2-propenyl group, 4-octenyl group, cyclopentene, cyclohexene;
A linear or branched or cyclic alkynyl group having 2 to 20 carbon atoms, such as an ethynyl group, a propargyl group, or a 1-methyl-propynyl group;
Aryl groups such as a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and a 9-anthracenyl group;
Examples thereof include aralkyl groups such as benzyl group, phenylethyl group and naphthylmethyl group.
[0048]
Substituents for these groups include hydroxyl groups; halogen atoms such as fluorine atoms, chlorine atoms, bromine atoms and iodine atoms; methyl groups, ethyl groups, n-propyl groups, i-propyl groups, n-butyl groups, s A linear, branched or cyclic alkyl group having 1 to 6 carbon atoms such as -butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group; methoxy group, ethoxy Group, n-propoxy group, n-butoxy group, t-butoxy group and the like having 1 to 6 carbon atoms such as linear or branched alkoxy group, vinyl group, allyl group, isopropenyl group and the like. Linear or branched alkenyl group; linear or branched alkynyl group having 1 to 6 carbon atoms such as ethynyl group and 2-propynyl group; phenyl group, 1-naphthyl group, 2-naphthyl group and the like Aryl group; a benzyl group, an aralkyl group such as a phenyl ethyl group.
[0049]
Hereinafter, the reaction according to the present invention will be described in detail.
[0050]
Embedded image
[0051]
Method for synthesizing compound represented by general formula (1) (step I):
To the inert solvent solution of the compound represented by the general formula (2), the inert solvent solution of the compound represented by the general formula (3) is dropped from −100 ° C. to the boiling point, preferably at −78 ° C. to 60 ° C., The mixture is further stirred at -78 ° C to 60 ° C for 1 to 48 hours, preferably 4 to 18 hours. Examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene, hydrocarbons such as hexane and Isopar E, chlorines such as chloroform and chlorobenzene, and ethers such as THF and diethyl ether. Then, the compound represented by General formula (1) can be obtained by pouring this reaction liquid mixture into water at 0 degreeC-room temperature, Preferably it is 0 degreeC-5 degreeC.
[0052]
Method for synthesizing compound represented by general formula (4 ') (step II):
A reducing agent is added to the inert solvent solution of the compound represented by the general formula (1), and this mixed solution is preferably from −100 ° C. to the boiling point at −78 ° C. to −30 ° C. for 0.5 to 48 hours, preferably If it stirs for 1 to 18 hours, the compound denoted by general formula (4 ') will be obtained. Examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene, hydrocarbons such as hexane and Isopar E, chlorines such as chloroform and chlorobenzene, and ethers such as THF and diethyl ether. Reducing agents include aluminum hydride reducing agents such as lithium aluminum hydride and diisobutylaluminum hydride, borohydride reducing agents such as sodium borohydride, sodium cyanoborohydride, K-selectride, and L-selectride. It is an agent, and L-selectride is preferable. Further, catalytic reduction using hydrogen as a reducing agent using a carbon support of a metal such as palladium or platinum as a catalyst is also possible. The amount of the reducing agent used is 1 to 5 equivalents, preferably 2 to 3 equivalents, of the compound represented by the general formula (1).
[0053]
Method for synthesizing compound represented by general formula (4) (step III):
An acid is added to the inert solvent solution of the compound represented by the general formula (4 ′), and this mixed solution is −10 ° C. to boiling point, preferably 0 ° C. to room temperature for 0.5 to 48 hours, preferably 1 to 18 hours. If it stirs for a time, the compound represented by General formula (4) will be obtained. Inert solvents include aromatic hydrocarbons such as benzene and toluene, hydrocarbons such as hexane and isopar E, chlorines such as chloroform and chlorobenzene, ethers such as THF and diethyl ether, and alcohols such as methanol and ethanol. A solvent and water can be mentioned, It is also possible to use these mixed solvents. As the acid, inorganic acids such as hydrogen chloride and sulfuric acid and aqueous solutions thereof, organic acids such as acetic acid and citric acid and aqueous solutions thereof are used. The amount of the acid used may be equal to or more than the equivalent amount of the compound represented by the general formula (4 '), and preferably 2 to 3 equivalents, but a large excess can be used.
[0054]
Method for synthesizing compound represented by general formula (5) (step IV):
An acid is added to an inert solvent solution of the compound represented by the general formula (1), and this mixed solution is −10 ° C. to boiling point, preferably 0 ° C. to room temperature for 0.5 to 48 hours, preferably 1 to 18 hours. If it stirs, the compound represented by General formula (5) will be obtained. Inert solvents include aromatic hydrocarbons such as benzene and toluene, hydrocarbons such as hexane and isopar E, chlorines such as chloroform and chlorobenzene, ethers such as THF and diethyl ether, and alcohols such as methanol and ethanol. A solvent and water can be mentioned, It is also possible to use these mixed solvents. As the acid, inorganic acids such as hydrogen chloride and sulfuric acid and aqueous solutions thereof, organic acids such as acetic acid and citric acid and aqueous solutions thereof are used. The amount of the acid used may be equal to or more than the equivalent amount of the compound represented by the general formula (1), and preferably 2 to 3 equivalents, but a large excess can be used.
[0055]
Also, the compound represented by the general formula (5) can be synthesized by the following method.
To the inert solvent solution of the compound represented by the general formula (2), the inert solvent solution of the compound represented by the general formula (3) is dropped from −100 ° C. to the boiling point, preferably at −78 ° C. to 60 ° C., The mixture is further stirred at -78 ° C to 60 ° C for 1 to 48 hours, preferably 4 to 18 hours. Examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene, hydrocarbons such as hexane and Isopar E, chlorines such as chloroform and chlorobenzene, and ethers such as THF and diethyl ether. Then, the compound represented by the general formula (5) can be obtained by opening the reaction mixture in an aqueous acid solution at 0 ° C. to room temperature, preferably 0 ° C. to 5 ° C. As the acid, inorganic acids such as hydrogen chloride and sulfuric acid and organic acids such as acetic acid and citric acid are used, and hydrogen chloride is preferable from the viewpoint of reaction operability. The amount of the acid used may be 2 equivalents or more of the compound represented by the general formula (3), preferably 3 to 5 equivalents, but may be used in large excess.
[0056]
Method for synthesizing compound represented by general formula (6) (step V):
A reducing agent is added to the reaction solution in which the compound represented by the general formula (5) is obtained, and this mixed solution is preferably from −100 ° C. to the boiling point, preferably at −78 ° C. to −30 ° C. for 0.5 to 48 hours. If it stirs for 1 to 18 hours, the compound represented by General formula (6) will be obtained. Reducing agents include aluminum hydride reducing agents such as lithium aluminum hydride and diisobutylaluminum hydride, borohydride reducing agents such as sodium borohydride, sodium cyanoborohydride, K-selectride, and L-selectride. It is an agent, and sodium borohydride is preferable. The amount of the reducing agent used is 1 to 5 equivalents, preferably 2 to 3 equivalents, of the compound represented by the general formula (1).
[0057]
The compound represented by the general formula (2), which is a raw material used in the present invention, can be synthesized as follows using, for example, a glycine derivative (a-1) as a raw material.
[0058]
Embedded image
[0059]
(In the formula, Z represents a protecting group, Y represents a halogen atom, and Ra, Rb, Rc, Rd, R1, and n are as defined above.)
The compound represented by the general formula (2) can be obtained by asymmetric alkylating the compound represented by (a-6) using a phase transfer catalyst in a water-toluene mixed solvent under alkaline conditions. .
Examples of the catalyst used at this time include compounds represented by the following formula (hereinafter referred to as (S, S) -A).
[0060]
Embedded image
[0061]
Examples of the compounds represented by the general formula (2) and the general formula (1 ') that can be synthesized by the above method are shown in Tables 1 and 2.
In Tables 1 and 2, Ph represents a phenyl group, and A-1 to A-5 and B-1 to B-6 represent the following formulas, respectively.
[0062]
Embedded image
[0063]
[Table 1]
[0064]
[Table 2]
[0065]
【Example】
EXAMPLES Next, an Example is given and this invention is demonstrated further in detail. The present invention is not limited to these.
[0066]
Reference Example 1 Synthesis of Compound [b-2]
[0067]
Embedded image
[0068]
Compound [b-1] (2.09 g, 10 mmol) and N-methylmorpholine (2.2 ml, 20 mmol) were stirred in 50 ml of dichloromethane, and ClCO was added thereto.2C2HFive(0.95 ml, 10 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 15 minutes. Powdered N, O-dimethylhydroxylamine hydrochloride (0.98 g, 10 mmol) was added in portions, and the mixture was stirred at 0 ° C. for 30 minutes and further at room temperature for 3 hours. The mixture thus obtained was treated with water and extracted three times with diethyl ether. The extract was washed with brine, dehydrated with sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1 to 1/2) to give a colorless viscous oily compound (2.16 g, 8.56 mmol, 86% yield). ) The obtained compound (2.16 g, 8.56 mmol, 86% yield) was dissolved in methanol (43 ml), and the benzyloxycarbonyl group part was dehydrogenated with 10% Pd-C (0.09 g) and hydrogen gas to remove it. Protected. After stirring for 12 hours at room temperature, the resulting mixture was filtered through celite.
9.5 ml of a methanol solution (1M) of hydrochloric acid was added to the filtrate at 0 ° C., the temperature was returned to room temperature, and after stirring for 20 minutes, volatile substances were removed by evaporation, and the residue was suspended in 43 ml of dichloromethane. Benzophenone imine (1.44 ml, 8.6 mmol) was added thereto and stirred at room temperature for 6 hours. The resulting white suspension was filtered through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1 to 1/3) to obtain the title compound [b-2] as a colorless sticky oil (1.92 g, 6. 8 mmol, yield 68%).
1H NMR (400 MHz, CDClThree) δ: 7.67-7.65 (2H, m, Ar-H), 7.49-7.37 (4H, m, Ar-H), 7.33 (2H, t, J = 7.2 Hz, Ar-H), 7.24-7.22 (2H , m, Ar-H), 4.35 (2H, s, NCH2CO), 3.64 (3H, s, OMe), 3.21 (3H, s, NMe).
[0069]
Reference Example 2 Synthesis of Compound [b-3]
[0070]
Embedded image
[0071]
Synthesis was performed in the same manner as in Reference Example 1 except that N-benzyl-O-methylhydroxylamine was used in place of N, O-dimethylhydroxylamine hydrochloride, and half of N-methylmorpholine was used. The crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1.5 / 1 to 1/1) to give the title compound [b-3] as a colorless sticky oil. (Yield 79%).
1H NMR (400 MHz, CDClThree) δ:
7.68-7.65 (2H, m, Ar-H), 7.47-7.16 (13H, m, Ar-H), 4.81 (2H, s, NCH2Ph), 4.40 (2H, s, NCH2CO), 3.56 (3H, s, OMe).
[0072]
Reference Example 3 Synthesis of Compound [b-4]
[0073]
Embedded image
[0074]
To a toluene solution of the compound synthesized in Reference Example 1 (0.20 mmol) and the catalyst (S, S) -A (4 mg, 0.004 mmol, 2 mol%), methyl iodide (0.22 mmol) and 50% aqueous KOH solution (0.65 ml) was added at 0 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 6 hours. The product was distilled with water and extracted three times with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane / diethyl ether = 1.5 / 1 to 1/3) to give the title compound [b-4] as a colorless sticky oil. (Yield 97%, 96% ee). The optical purity was determined by HPLC (optical column: DAICEL Chiralcel-OD-H, mobile phase: hexane / ethanol = 50/1, flow rate: 0.5 mL / min, retention time: (D form) 20.1 minutes (L form) 22.3 minutes).
[a]D twenty three = + 25.8o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDClThree) δ:
7.70-7.65 (2H, m, Ar-H), 7.49-7.42 (3H, m, Ar-H), 7.38 (1H, tt, J = 7.2, 1.2 Hz, Ar-H), 7.33-7.29 (2H, m, Ar-H), 7.21-7.19 (2H, m, Ar-H), 5.73 (1H, ddt, J = 17.2, 10.0, 7.2 Hz, CH2= CH-CH2), 5.06-4.98 (2H, m, CH 2= CH-CH2), 4.41 (1H, t, J = 6.8 Hz, NCHCO), 3.27 (3H, s, OMe), 3.15 (3H, s, NMe), 2.81 (1H, ddd, J = 13.9, 7.2, 6.8 Hz, CH2= CH-CH 2), 2.64 (1H, ddd, J = 13.9, 7.2, 6.8 Hz, CH2= CH-CH 2).
[0075]
Reference Example 4 Synthesis of Compound [b-5]
[0076]
Embedded image
[0077]
The compound was synthesized in the same manner as in Reference Example 3 except that methyl iodide was used instead of allyl bromide to obtain the colorless sticky oily title compound [b-5] (yield: 64%, 90% ee). ).
1H NMR (400 MHz, CDClThree) δ:
7.65 (2H, d, J = 7.6 Hz, Ar-H), 7.50-7.43 (3H, m, Ar-H), 7.37 (1H, t, J = 7.6 Hz, Ar-H), 7.31 (1H, t , J = 7.6 Hz, Ar-H), 7.22-7.19 (2H, m, Ar-H), 4.43 (1H, q, J = 6.8 Hz, NCHCO), 3.34 (3H, s, NCHThree), 3.17 (3H, s, NOCHThree), 1.37 (3H, d, J = 6.8 Hz, CHThree);
IR (KBr):
3059, 2997, 2976, 2932, 1665, 1611, 1574, 1491, 1447, 1387, 1375, 1315, 1281, 1267, 1200, 1180, 1096, 1045, 986, 949, 928, 789, 772, 720, 700 cm-1.
[0078]
Reference Example 5 Synthesis of Compound [b-6]
[0079]
Embedded image
[0080]
A colorless sticky oil was synthesized in the same manner as in Reference Example 3 except that the compound [b-3] synthesized in Reference Example 2 was used instead of the compound [b-2] synthesized in Reference Example 1. The title compound [b-6] was quantitatively obtained (97% ee).
The optical purity was determined by HPLC (optical column: DAICEL Chiralcel-OD-H, mobile phase: hexane / ethanol = 50/1, flow rate: 0.5 mL / min, retention time: (D form) 21.6 minutes (L form) 24.8 minutes).
[a]D twenty three = + 23.4o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDClThree) δ:
7.65-7.62 (2H, m, Ar-H), 7.46-7.36 (4H, m, Ar-H), 7.34-7.25 (7H, m, Ar-H), 7.19-7.16 (2H, m, Ar-H ), 5.74 (1H, ddt, J = 17.2, 10.0, 6.8 Hz, CH2= CH-CH2), 5.05-4.97 (2H, m, CH 2= CH-CH2), 4.79 (1H, d, J = 15.4 Hz, CH2Ph), 4.74 (1H, d, J = 15.4 Hz, CH2Ph), 4.40 (1H, t, J = 6.8 Hz, NCHCO), 3.17 (4H, s, OMe), 2.82 (1H, ddd, J = 13.6, 6.8, 6.8 Hz, CH2= CH-CH 2), 2.48 (1H, ddd, J = 13.6, 6.8, 6.8 Hz, CH2= CH-CH 2).
[0081]
Example 1 Synthesis of Compound [c-1]
[0082]
Embedded image
[0083]
A solution of the compound [b-6] (240 mg, 0.602 mmol, 97.2% ee) in 3 ml of THF was added phenylmagnesium bromide in diethyl ether (0.87 M, 1.1 ml, 0.99 mmol) at 0 ° C., argon It added under atmosphere and stirred for 20 minutes at the same temperature. The resulting light brown solution was poured into cold water and the mixture was extracted with diethyl ether. The extract was washed with brine, dehydrated with sodium sulfate, and concentrated. The crude product was purified while cooling with silica gel column chromatography (eluent: hexane / diethyl ether = 6/1 to 4/1) to obtain the title compound [c-1] as a colorless oil (171 mg, 0.506 mmol, 84% yield, 96.5% ee).
The optical purity was determined by HPLC [optical column: DAICEL Chiralcel-OD-H, mobile phase: hexane / isopropanol = 200/1, flow rate: 0.5 mL / min, retention time: 20.3 minutes (S form) 26.3 minutes (R form)].
[a]D twenty one = + 23.4o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDClThree) δ:
7.87-7.84 (2H, m, Ar-H), 7.67-7.64 (2H, m, Ar-H), 7.51 (1H, tt, J = 7.4, 1.2 Hz, Ar-H), 7.45-7.36 (6H, m, Ar-H), 7.32 (2H, tt, J = 7.4, 1.2 Hz, Ar-H), 7.12-7.08 (2H, m, Ar-H), 5.74 (1H, ddt, J = 17.2, 10.0, 7.3 Hz, CH2= CH-CH2), 5.05-4.99 (2H, m, CH 2= CH-CH2), 4.87 (1H, dd, J = 7.3, 5.8 Hz, NCHCO), 2.83-2.69 (2H, m, CH2= CH-CH 2).
[0084]
Example 2 Synthesis of Compound [c-2]
[0085]
Embedded image
[0086]
A THF solution (2.6 mL) of compound [c-1] (179 mg, 0.527 mmol) was added to a THF solution of L-selectride (1.0 M, 1.1 ml, 1.1 mmol) at −78 ° C. After stirring for 1 hour at the same temperature, the product was poured into a cooled saturated aqueous ammonium chloride solution. After extracting three times with diethyl ether, the extract was washed with brine, dehydrated with sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane / dichloromethane = 1/1) while cooling to obtain the title compound [c-2] as a colorless oil (152 mg, 0.446 mmol, Yield 85%).
1H NMR (400 MHz, CDClThree) δ:
7.75-7.72 (2H, m, Ar-H), 7.61-7.59 (2H, m, Ar-H), 7.39-7.22 (9H, m, Ar-H), 7.17-7.15 (2H, m, Ar-H ), 5.83 (1H, ddt, J = 17.1, 10.2, 6.8 Hz, CH2= CH-CH2), 5.11 (1H, dd, J = 17.1, 1.6 Hz, cis-CH 2= CH-CH2), 5.06 (1H, dd, J = 10.2, 1.6 Hz, trans-CH 2= CH-CH2), 4.53 (1H, d, J = 8.4 Hz, CHPh), 3.18 (1H, ddd, J = 8.4, 8.0, 4.4 Hz, Ph2C = NCH), 2.61 (1H, s, OH), 2.41-2.33 (1H, m, CH2= CH-CH 2), 2.20 (1H, ddd, J = 14.8, 8.0, 6.8 Hz, CH2= CH-CH 2).
[0087]
Example 3 Synthesis of Compound [c-3]
[0088]
Embedded image
[0089]
4 ml of 10% citric acid was added to 4 ml of a THF solution of the compound [c-2] (70.1 mg, 0.205 mmol), and the mixture was stirred at room temperature for 10 hours to obtain the title compound [c-3].
In order to analyze the physical property value, [c-3] was induced to [c-3 '] by the following method, and the physical property value of [c-3'] was measured.
Benzyl chloride (36 ml, 0.31 mmol) and excess sodium bicarbonate were slowly added to the above product at 0 ° C. After stirring for 4 hours at room temperature, the resulting mixture was distilled with water and extracted three times with diethyl ether. The extract was washed with brine, dehydrated with sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1.5 / 1 to 1/1) to obtain a colorless crystal derivative [c-3 ′] (49.1 mg, 0 175 mmol, 85% yield, 97% ee, 99% de).
[a]D 20 = -56.4o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDClThree) δ:
7.69-7.67 (2H, m, Ar-H), 7.49 (1H, tt, J = 7.4, 1.2 Hz, Ar-H), 7.42-7.24 (7H, m, Ar-H), 6.42 (1H, d, J = 7.6 Hz, NH), 5.86 (1H, ddt, J = 17.2, 10.0, 7.4 Hz, CH2= CH-CH2), 5.19-5.12 (2H, CH 2= CH-CH2), 4.87 (1H, dd, J = 4.6, 4.6 Hz, CHPh), 4.33 (1H, dtd, J = 7.6, 7.4, 4.6 Hz, NCH), 3.55 (1H, br, OH), 2.49 (1H, dt , J = 14.0, 7.4 Hz, CH2= CH-CH 2), 2.35 (1H, dt, J = 14.0, 7.4 Hz, CH2= CH-CH 2).
[0090]
Example 4 Synthesis of Compound [c-5]
[0091]
Embedded image
[0092]
0.61 ml of THF solution of compound [b-6] (48.7 mg, 0.122 mmol, 97% ee) was added to diethyl magnesium bromide in diethyl ether (0.90 M, 0.22 ml, 0.20 mmol) at 0 ° C. under argon atmosphere. It was. The resulting light brown solution was stirred at the same temperature for 20 minutes, and then immediately added to cooled 1N hydrochloric acid to return to room temperature. After stirring for 20 minutes, the mixture is concentrated under reduced pressure, the residue is dissolved in 1.2 ml of methanol and NaBH is added.Four (11 mg, 0.29 mmol) was added at 0 ° C. and the mixture was stirred at room temperature for 2 hours to obtain the title compound [c-5].
In order to analyze the physical property value, [c-5] was induced to [c-5 '] by the following method, and the physical property value of [c-5'] was measured.
Benzyl chloride (43 ml, 0.37 mmol) and an excess amount of sodium bicarbonate were added to the mixed product containing the compound [c-5] at 0 ° C. After stirring for 3 hours at room temperature, the mixture was distilled with water and extracted three times with diethyl ether. The extract was washed with brine, dehydrated with sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1.5 / 1 to 1/1) to obtain a colorless crystal derivative [c-5 ′] (32.1 mg, 0.114 mmol). , 90% yield, 97% ee, 97% de).
The optical purity was determined by HPLC (optical column: DAICEL Chiralcel-OD-H, mobile phase: hexane / isopropanol = 10/1, flow rate: 0.5 mL / min, retention time: 24.6 min (1S, 2R), 29.5 min (1S, 2S), 38.6 min (1R, 2S) and 42.2 min (1R, 2R)).
[a]D twenty two = -39.9o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDClThree) δ:
7.73-7.70 (2H, m, Ar-H), 7.51 (1H, tt, J = 7.4, 1.2 Hz, Ar-H), 7.43-7.33 (6H, m, Ar-H), 7.29 (1H, tt, J = 6.8, 1.8 Hz, Ar-H), 6.20 (1H, d, J = 7.8 Hz, NH), 5.77 (1H, dddd, J = 16.7, 10.5, 8.2, 6.0 Hz, CH2= CH-CH2), 5.10-5.02 (3H, m, CH 2= CH-CH2 and CHPh), 4.50 (1H, dddd, J = 9.7, 7.8, 4.8, 3.2 Hz, CHNHBz), 3.89 (1H, s, OH), 2.37-2.31 (1H, m, CH2= CH-CH 2), 2.21 (1H, ddd, J = 14.7, 9.7, 8.2 Hz, CH2= CH-CH 2).
[0093]
Example 5 Synthesis of Compound [c-6]
[0094]
Embedded image
[0095]
To a THF (1 ml) solution of the compound [b-5] (59 mg, 0.20 mmol, 99.9% ee), a 0.89 M ether solution of parachlorophenyl magnesium bromide (0.36 ml, 0.32 mmol) was added in an argon atmosphere at 0 ° C. Stir at temperature for 20 minutes. The pale yellow reaction solution was quickly poured into ice-cooled 1N hydrochloric acid (3 ml), and this mixed solution was allowed to reach room temperature with stirring for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was suspended in THF (2 ml) to obtain the title compound [c-6].
In order to analyze the physical property values, [c-6] was derived into [c-6 '] by the following method, and the physical property values of [c-6'] were measured.
To the mixed product containing compound [c-5], Boc2Sodium bicarbonate (excess amount) was added in the form of O (138 μl, 0.60 mmol) and powder at 0 ° C. and stirred for 3 hours. The reaction solution was concentrated and the residue was purified by column chromatography (hexane / ethyl acetate = 4: 1 to 3: 1) to give colorless crystals of [c-6 ′] (55.3 mg, 0.188 mmol, yield) 94%).
[a]D twenty two = -23.2o (c 1.0, 99.5% EtOH);
1H NMR (400 MHz, CDClThree) δ:
7.92 (2H, d, J = 8.4 Hz, p-Cl-Ph), 7.47 (2H, d, J = 8.4 Hz, p-Cl-Ph), 5.48 (1H, br d, J = 6.8 Hz, NH) , 5.24 (1H, dq, J = 6.8, 7.2 Hz, NCHCO), 1.45 (9H, s, t-Bu), 1.39 (3H, d, J = 7.2 Hz, CHThree).
[0096]
【The invention's effect】
According to the present invention, optically active amino alcohols and amino ketones useful as pharmaceuticals and synthetic intermediates thereof can be produced with high selectivity, high yield and industrially advantageous.
Claims (6)
R2−X (3)
〔式中、R2は置換基を有していても良い炭素数1〜20のアルキル基、置換基を有していても良い炭素数2〜20のアルケニル基、置換基を有していても良い炭素数2〜20のアルキニル基、置換基を有していても良いアリール基、置換基を有していても良いアラルキル基を示し、Xは臭化マグネシウム基、塩化マグネシウム基、リチウム原子を示す。〕で表される有機金属化合物を反応させることを特徴とする、一般式(1)
R2-X (3)
[In the formula, R2 may have a substituent, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms that may have a substituent, or a substituent. A good alkynyl group having 2 to 20 carbon atoms, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and X represents a magnesium bromide group, a magnesium chloride group and a lithium atom Show. A reaction with an organometallic compound represented by the general formula (1)
R2−X (3)
〔式中、R2、Xは請求項1と同じ意味を示す。〕で表される有機金属化合物を反応させて、一般式(1)
R2-X (3)
[Wherein R 2 and X have the same meaning as in claim 1. The organic metal compound represented by the general formula (1)
R2−X (3)
〔式中、R2、Xは請求項1と同じ意味を示す。〕で表される有機金属化合物を反応させて、一般式(1)
R2-X (3)
[Wherein R 2 and X have the same meaning as in claim 1. The organic metal compound represented by the general formula (1)
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