JP3855323B2

JP3855323B2 - Method for producing 3-amino-2-oxo-1-halogenopropane derivative

Info

Publication number: JP3855323B2
Application number: JP30605196A
Authority: JP
Inventors: 裕本多; 智片山; 邦輔井澤; 正和中沢; 孝之鈴木; 直子菅野
Original assignee: Ajinomoto Co Inc
Current assignee: Ajinomoto Co Inc
Priority date: 1995-11-17
Filing date: 1996-11-18
Publication date: 2006-12-06
Anticipated expiration: 2016-11-18
Also published as: JPH09194444A

Description

【０００１】
【発明の属する技術分野】
ＨＩＶプロテアーゼ阻害剤あるいはある種の酵素阻害剤の中間体として重要なα−アミノアルコール誘導体の等価体であって光学活性３−置換−３−アミノ−１，２−エポキシプロパン誘導体に容易に変換可能な３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体の製造方法に関する。
【０００２】
【従来の技術】
光学活性３−置換−３−アミノ−１，２−エポキシプロパン誘導体から容易に変換できるα−アミノアルコール誘導体はＲｏ３１−８９５９（Ｐａｒｋｅｓ，Ｋ．ら（Ｒｏｃｈｅ），Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９４，５９，３６５６．）、ＳＣ−５２１５１（Ｇｅｔｍａｎ，Ｄ．Ｐ．ら（Ｍｏｎｓａｎｔｏ），Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９３，３６，２８８．）、ＶＸ４７８（（Ｖｅｒｔｅｘ）ＷＯ９４０５６３９）、ＡＧ１３４３（（Ｌｉｌｌｙ）ＷＯ９５２１１６４）等の多くのＨＩＶプロテアーゼ阻害剤等の合成中間体として用いられている。
【０００３】
３−アミノ−１，２−エポキシプロパン誘導体の製造法はいくつか知られているが、例えば、Ｎ保護された３−アミノ−２−オキソ−１−ハロゲノプロパンの２位を立体選択的に還元しアルコールに導いた後に脱ハロゲン化水素的にエポキシ化する方法（Ｇｅｔｍａｎ，Ｄ．Ｐ．ら，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９３，３６，２８８．等）、Ｎ保護された３−アミノ−１−プロペンを酸化的に不斉エポキシ化する方法（Ｌｕｌｙ，Ｊ．Ｒ．ら，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９８７，５２，１４８７．等）、Ｎ保護された３−アミノ−１−プロパナールにメチレンを挿入する方法（Ｓｅａｒｌｅ，Ｇ．Ｄ．，ＷＯ９３／２３３８８．等）がある。
【０００４】
１番目の方法においては鍵中間体であるＮ保護された３−アミノ−２−オキソ−１−ハロゲノプロパンまたはこの等価体をいかに工業的に安価に製造できるかが重要であるが、これまで知られている方法では副原料にきわめて爆発性が高く毒性の強いジアゾメタンを用いなければならないことから、これらの方法の工業化においては限界がある（例えばＧｅｔｍａｎ，Ｄ．Ｐ．ら，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９３，３６，２８８．，Ｏｋａｄａ，Ｙら，Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，１９８８，３６，４７９４．，ＥＰ３４６８６７．Ｒａｄｄａｔｚ，Ｐら，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９１，３４，３２６７．）。その他、Ｎ保護されたアミノ酸のエステルにハロメチルアニオンを作用させる方法があるが、非常に不安定なハロメチルアニオンを用いることや、１−位に導入するハロゲンは化学に関する一般的な知見からは塩素またはフッ素と限定できると推測されるため、この方法の工業化には限界があった（Ｂａｒｌｕｅｎｇａら，Ｊ．Ｃｈｅｍ．Ｓｏｃ．，Ｃｈｅｍ．Ｃｏｍｍｕｎ．，１９９４．）。さらに、本件に関連した既存技術として、Ｎ保護されたアミノ酸のＣ端を活性化した後にフルオロマロン酸ハーフエステルを反応させ脱カルボキシル化する方法（ＥＰ４４２７５４）を挙げることができるが、これはハロゲンがフッ素という特殊な元素に限定されており、塩素、臭素といった本目的を達成するための系には適用できない。
２番目の方法においては鍵中間体であるＮ保護された３−アミノ−１−プロペンを製造するために高価なアルデヒド（３−アミノ−１−プロパナール）のＷｉｔｔｉｇ反応を利用しているため非常に高コストな製造方法になる。さらに３番目の方法においては上記と同じ中間体であるＮ保護されたアルデヒドの製造方法が高コストであるばかりでなく、メチレンを挿入反応において低温でカルベンを発生させる必要があり、工業的に適した製造法とはならない。
【０００５】
【発明が解決しようとする課題】
本発明の課題は、３−アミノ−１，２−エポキシプロパン誘導体に容易に変換可能な３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体の工業的な製造方法を提供することにある。
【０００６】
【課題を解決するための手段】
本発明者らは、前記の課題を解決すべく検討した結果、３−アミノ−１，２−エポキシプロパン誘導体またはその等価体が対応する３−アミノ−２−オキソ−１−ハロゲノプロパンから高収率で製造できることに着目し、その前駆体であるα−ハロゲノ−β−ケトエステル誘導体とそれらの製造方法を見出し、本発明を完成するに至った。
【０００７】
すなわち、本発明は下記一般式(I)で示される化合物に、
【０００８】
【化１０】

【０００９】
（式中のＲｓは水素、それぞれ置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基もしくは炭素数７〜２０のアラルキル基、又はこれらの炭素骨格中にヘテロ原子を含む置換基を、Ｐ₁、Ｐ₂は互いに独立して水素もしくはアミノ保護基、又はＰ₁及びＰ₂は一体となって二官能性のアミノ保護基を、Ｅ₁ はカルボキシ末端として、炭素数１〜１０のアルコキシのエステル残基、それぞれ環上に置換基を有していてもよいフェノキシ基もしくはベンジルオキシ基、Ｎ−オキシコハク酸イミドもしくは１−オキシベンゾトリアゾールの活性エステル残基、活性チオエステル残基、イミダゾリル基、酸ハロゲン化物、酸無水物、又は酸アジドを形成しうる残基を表す。）
【００１０】
酢酸のエステルのアルカリ金属エノラートを反応させて下記一般式(II)で示される化合物を得、
【００１１】
【化１１】

【００１２】
（式中のＲ_S、Ｐ₁、Ｐ₂、は上記した意味を有し、Ｒ₁は置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基、炭素数７〜２０のアラルキル基、炭素数４〜１０のトリアルキルシリル基、炭素数８〜１０のフェニルジアルキルシリル基または炭素数１３〜１５のジフェニルアルキルシリル基を表す。）
【００１３】
これに、ハロゲン化試剤を作用させ、２位をハロゲン化して下記一般式(III)で示される４−アミノ−３−オキソ−２−ハロゲノブタン酸エステル誘導体を製造するか、
【００１４】
【化１２】

【００１５】
（式中のＲｓ、Ｐ₁、Ｐ₂、Ｒ₁は上記した意味を有する。）
【００１６】
または一般式(I)に下記一般式(IV)で示される化合物のアルカリ金属エノラート又はジアニオンを反応させて
【００１７】
【化１３】

【００１８】
（式中のＲ₂は水素、置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基、炭素数７〜２０のアラルキル基、炭素数３〜１０のトリアルキルシリル基、炭素数８〜１０のフェニルジアルキルシリル基または炭素数１３〜１５のジフェニルアルキルシリル基を表す。Ｘは上記した意味を有する。）
【００１９】
下記一般式(III')で示される４−アミノ−３−オキソ−２−ハロゲノブタン酸エステルまたは塩の誘導体を製造し、
【００２０】
【化１４】

【００２１】
（式中のＲｓ、Ｐ₁、Ｐ₂は上記した意味を有し、
Ｒ₃はアルカリ金属、置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基、炭素数７〜２０のアラルキル基、炭素数３〜１０のトリアルキルシリル基、炭素数８〜１０のフェニルジアルキルシリル基または炭素数１３〜１５のジフェニルアルキルシリル基を表す。Ｘは上記した意味を有する。）
【００２２】
さらに得られた(III)または(III')の加水分解を行い、脱炭酸を行うことを特徴とする下記一般式(V)で示される３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体またはその塩の製造方法、
【００２３】
【化１５】

【００２４】
（式中のＲｓ、Ｐ₁、Ｐ₂、Ｘは上記した意味を有する。）
【００２５】
【発明の実施の形態】
本発明に用いる式 (I) で示される化合物は、天然または非天然のα−アミノ酸のアミノ基が保護基により保護され、カルボキシル基が求核試剤と反応しうる官能基に変換されたある種の保護アミノ酸である。
【００２６】
なお、式(I)で示される化合物はアミノ基の根元の炭素原子の立体により光学活性を有し、例えば光学活性アミノ酸を出発原料に選ぶことにより光学活性を有する目的の化合物の合成に容易に適用できる。
【００２７】
式(I)におけＲｓは水素または通常のアルキル、アリール、アラルキル等の置換基を表し、例えばメチル基であればアラニン骨格、ベンジル基であればフェニルアラニン骨格を持つ化合物となる。Ｐ₁、Ｐ₂は通常用いられるアミノ保護基を表し、Ｐ₁またはＰ₂のどちらかが水素原子でもよく、Ｐ₁とＰ₂は一体となった２官能性のアミノ保護基でもよい。例としては、ベンジルオキシカルボニル、第３ブトキシカルボニル、アセチル、ホルミル、ベンゾイル、ジベンジル、フタロイル等何でもよく、後述するエステル基（Ｒ₁）の加水分解、脱炭酸における官能基選択性を考慮して決定すればよい。また、Ｅ₁は求核試剤と反応しうるカルボキシ末端の官能基を示し、低級エステル、活性エステル、酸ハロゲン化物、酸無水物等の残基がこれに含まれる。例としてはメトキシ、エトキシ、ベンゾキシ及び置換ベンゾキシ、フェノキシ及び置換フェノキシ、Ｎ−オキシコハク酸イミド、１−オキシベンゾトリアゾール、イミダゾリル、塩素、臭素、メトキシカルボキシ、イソブトキシカルボキシ、第３ブチルカルボキシ等がある。
式(I)で示される化合物を具体的に例示するならば、Ｎ−ベンジルオキシカルボニル−Ｌ−フェニルアラニンメチルエステル、Ｎ−ベンジルオキシカルボニル−Ｌ−フェニルアラニン−Ｎ−オキシコハク酸イミドエステル、Ｎ，Ｎ−ジベンジル−Ｌ−フェニルアラニンｐ−ニトロフェニルエステル、Ｎ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システインメチルエステル、等があげられる。
【００２８】
式(I)で示される化合物は、天然または非天然のα−アミノ酸のアミノ基をペプチド合成で通常用いられる方法で保護した後、カルボキシル基を同じくペプチド合成で通常用いられる方法でエステル化、もしくはハロゲン化することにより得ることができる。
【００２９】
式(I)より式(II)への変換は、式(I)で示されるエステル、酸ハロゲン化物または酸無水物に酢酸エステルより誘導した酢酸エステルエノラートを反応させてβ−ケトエステルを生成させる反応である。酢酸エステルエノラートとしてはアルカリ金属塩をさし、リチウム塩が最も好ましい。これらのエノラートは、塩基、例えばリチウムアミド、リチウムジイソプロピルアミド、リチウム第３ブトキシド等の溶液中に酢酸エステルを加えることにより調製する。酢酸エステルのエステルは通常用いられるカルボン酸のエステルを表すが、例えばアルキルエステル、アラルキルエステル、シリルエステル等であり、具体的にはメチル、エチル、第３ブチル、ベンジル、トリエチルシリル等の加水分解可能なエステル基であれば何でもよい。
酢酸エノラートは基質(I)に対し１当量以上必要であるが、生成物のβ−ケトエステルのエノラート形成に１当量分の塩基が供せられることから通常２当量以上の酢酸エノラートを用いることにより反応が好収率で進行する。
この反応はマイナス１００度より室温程度の温度で速やかに進行する。至適温度は化合物により異なるが、典型的な例としてはマイナス７５度からマイナス３０度程度で５分から６０分で反応は完結する。反応溶媒は炭化水素、エーテル等が用いられ、テトラヒドロフラン、ヘキサン、トルエン及びこれらの混合溶媒が例として挙げられる。反応濃度は特に限定する必要はなく、反応物の溶解度に応じて決定すれば良い。
反応終了後、反応液を酸で処理することにより、生成物のアルキル金属塩をプロトン化して、一般式(II)で表されるβ−ケトエステルを与える。当化合物はシリカゲルクロマトグラフィーにより容易に精製可能であるが、未精製の状態で次反応の原料として供することもできる。
【００３０】
式(II)より式(III)への変換は、各種ハロゲン化剤により式(II)で示されるβ −ケトエステルの活性メチレンの水素を酸化的にハロゲン化させ、式(III)で示される４−アミノ−３−オキソ−２−ハロゲノブタン酸エステル誘導体を得る反応である。反応はβ−ケトエステルとハロゲン化剤を溶媒中で混合するだけで容易に好収率で進行する。
ハロゲン化剤としては、臭素化の場合は、例としては、Ｎ−ブロモコハク酸イミド、臭化銅（ＩＩ）、臭素等でよく、塩素化の場合は、例としては、Ｎ−クロロコハク酸イミド、塩化銅（ＩＩ）、スルフリルクロリド、塩素等でよい。ハロゲン化剤はβ−ケトエステル(II)に対し理論当量以上必要であるが、副反応の進行を阻止する目的から理論当量ちょうどに設定することで最も好収率が得られることが多い。ここでの理論当量とは、化学方程式上必要とされる量をいい、例えばＮ−ブロモコハク酸イミドの場合はβ−ケトエステルに対し１当量、臭化銅（ＩＩ）の場合は２当量を表す。
この反応の条件は反応物の構造や試剤に強く依存しそれぞれの化合物に応じ決定しなければならない。典型的な例としてＲｓがベンジル、Ｐ₁がベンジルオキシカルボニル、Ｐ₂が水素、Ｒ₁がｔ−ブチルで、反応試剤としてＮ−ブロモコハク酸イミドを用いた場合、マイナス２０度から室温程度で１０分から６０分で反応は完結する。反応溶媒は塩化メチレンやクロロホルム等のハロゲン溶媒の他、酢酸エチルやエーテル、トルエンを用いることもできる。反応濃度は特に限定する必要はなく、反応物の溶解度に応じて決定すれば良い。
必要に応じ再結晶等の手段で精製可能であるが、反応生成物は未精製で次反応の原料として用いることができる。また、ハロゲン化の過程でその選択性によりジアステレオマーを生成し、これらは薄層クロマトグラフィーまたはシリカゲルカラム等により分離可能であるが、本製造プロセスの目的からはその分離は要求されない。
【００３１】
一方、式(III)で示される化合物、そのトリメチルシリルエステル体、及びそのカルボン酸塩、すなわち式(III')で示される化合物は式(I)で示される化合物にハロゲノ酢酸エステルエノラートまたはハロゲノ酢酸のジアニオンを反応させることによっても変換可能である。すなわち、先に説明した様に式(III')で示される化合物を合成するに当たり、式(II)を経由する方法において用いた酢酸エステル類の代わりにクロロ酢酸エステル類またはブロモ酢酸エステル類(VI)を用いることにより１段階で目的とする化合を得ることができる。
また、この反応においてハロゲノ酢酸トリメチルシリルから調製されるエノラートまたはハロゲノ酢酸から調製されるジアニオンを反応させた場合には、生成する式(III')で示される化合物（Ｒ₃はトリメチルシリルまたはアルカリ金属）は酸で処理すると容易に脱炭酸まで進行し、１段階で式(V)で示される化合物を得ることができる。
ハロゲノ酢酸エステルエノラートは一般式(II)を経由する方法においてエノラートを調整する方法に準じて合成することができ、このエノラートを一般式(I) に反応させる条件は先に説明した物と同様である。
但し、ハロゲノ酢酸エステルのエノラートの安定性は酢酸エステルのそれに比べ劣るため、マイナス６０度以下の低温で反応を行うことが必要である。
【００３２】
式(III)または(III')で示される化合物を合成するに当たり式(I)で示される化合物から直接変換するか、式(II)を経由して変換するかは式(I)で示される化合物の置換基や保護基により収率が異なるので適宜選択して行えばよい。
【００３３】
なお、式(III)または式(III')で示される化合物は新規であり、本発明において重要な中間体となる化合物である。また、この化合物の構造は対応するエノール体を互変異性体として含むと解釈される。たとえば、互変異性体としては、下記一般式(VIII)で表される４−アミノ−３−オキソ−２−ハロゲノブタン酸エステル誘導体があげられる。
【００３４】
【化１６】

【００３５】
（式中のＲｓ、Ｐ₁、Ｐ₂、Ｒ₁、Ｒ₃、Ｘは上記した意味を有する。）
【００３６】
式(III)または式(III')で示される化合物より式(V)への変換は、式(III)または式(III')で示される４−アミノ−３−オキソ− ２−ハロゲノブタン酸エステル誘導体を加水分解し、同時に脱炭酸させることにより行われる。
加水分解の方法としては、通常有機化学的に用いられる方法は何でも良く、低級アルキルエステルのアルカリ加水分解、３級アルキルエステルの酸加水分解、ベンジルエステルの接触水素添加、シリルエステルの弱酸性〜中性での加水分解等が適用できる。但し、これらの加水分解条件により導入したハロゲンが影響を受けないことが必要であり、最適条件は化合物の構造により異なるが、３級アルキルエステルまたはシリルエステルの系で好結果を示す場合が多い。
目的物は反応液中から有機溶媒に抽出単離することができ、必要に応じシリカゲルクロマトグラフィー、再結晶等の手段により精製可能である。
この反応の条件の典型的な例としてＲ₁がｔ−ブチルの場合、ギ酸溶液中で室温で数時間から数十時間で反応は完結するが、反応温度を上げることにより数分から１時間程度に反応時間を短縮することができる。反応濃度は特に限定する必要はなく、反応物の溶解度に応じて決定すれば良い。
【００３７】
これらの方法により得られた式(V)で示される３−アミノ−２−オキソ−１− ハロゲノプロパン誘導体は文献に示されるように（例えばＧｅｔｍａｎ，Ｄ．Ｐ．ら，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９３，３６，２８８．，Ｏｋａｄａ，Ｙら，Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，１９８８，３６，４７９４．，ＥＰ３４６８６７．Ｒａｄｄａｔｚ，Ｐら，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９１，３４，３２６７．）ＨＩＶプロテアーゼ阻害剤の中間体として有用な公知の化合物であり、例えば以下のような２段階の既存反応を経ることにより、より進んだ形の中間体に誘導されることが知られている。（Ｇｅｔｍａｎ，Ｄ．Ｐ．ら，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９３，３６，２８８．等）
すなわち、式(V)で示される３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体はハロゲノメチルケトン骨格を持ちカルボニル基の還元反応により下記一般式(VI)で示されるハロヒドリンに導かれ、
【００３８】
【化１７】

【００３９】
（式中のＲｓ、Ｐ₁、Ｐ₂、Ｘは上記した意味を有する。）
さらにアルカリ条件下で容易にエポキシ化され下記一般式(VII)で示される化合物に誘導することができる。
【００４０】
【化１８】

【００４１】
（式中のＲｓ、Ｐ₁、Ｐ₂は上記した意味を有する。）
【００４２】
上記カルボニル基の還元反応においては、３位のＲｓで表される置換基の結合の立体に対して立体選択的な還元を行うことが可能であり、例えば水素化ホウ素ナトリウムで代表されるような通常の還元剤を用いることでもそれは達成できる。例えばＲｓはベンジル基であり、３位の立体はＳ体であり、アミノ保護基としてウレタン型保護基を選んだ化合物を水素化ホウ素ナトリウムで還元することにより水酸基の立体は２：１から２０：１程度の比率でＳ体を優位に与え、さらに再結晶による精製も可能である。また得られるアルコールからは（２Ｓ，３Ｓ）のエポキシ体に導かれるが、この化合物はＨＩＶプロテアーゼ阻害剤中間体として重要な化合物である。
【００４３】
下記に、本発明の原料化合物(I)から目的化合物である(V)並びに上記エポキシ化合部(VII)までの流れを示した。
【００４４】
【化１９】

【００４５】
（式中のＲｓ、Ｒ₁、Ｅ₁、Ｘ、Ｐ₁、Ｐ₂は上記した意味を有する。）
【００４６】
【実施例】
以下、実施例により本発明をさらに詳しく説明するが、もとより本発明はこれらに限定されるものではない。特に断らない限り温度は摂氏で示される。プロトン核磁気共鳴（ＮＭＲ）スペクトルはバリアン３００ＭＨｚスペクトロメーター上に記録した；化学シフト（δ）はｐｐｍで示される。実施例中において使用された略語は、Ｂｏｃ：第３ブトキシカルボニル；Ｚ：ベンジルオキシカルボニル；ＴＨＦ：テトラヒドロフラン；ＬＤＡ：リチウムジイソプロピルアミド；ＮＣＳ：Ｎ−クロロコハク酸イミド；ＮＢＳ：Ｎ−ブロモコハク酸イミドを包含する。
【００４７】
製造例１Ｎ，Ｎ−ジベンジル−Ｌ−フェニルアラニンベンジルエステル (Ia) の製造
２５．０ｇ（１５１．３ｍｍｏｌ）の（Ｌ）−フェニルアラニンおよび６６．６７ｇ（４８２．４ｍｍｏｌ）の炭酸カリウムを水１００ｍｌに溶解した後、塩化ベンジル５７．５１ｇ（４５４．３ｍｍｏｌ）を加え、９５℃で１９時間加熱攪拌した。室温まで冷却した後、ｎ−ヘプタン６７ｍｌおよび水５０ｍｌを加え分層した。有機層を５０ｍｌのメタノール／水＝１／２の溶液で２回洗浄した後、無水硫酸ナトリウムで乾燥した。これを濾過、濃縮し、表題化合物(Ia)を６１．６４ｇ（９０％，１２１．８ｍｍｏｌ）を得た（収率８４．７％）。
1H-NMR(300MHz、CDCl3) δ:3.00(dd,1H),3.14(dd,1H),3.53(d,2H),3.71(t,1H),3.92(d,2H),5.12(d,1H),5.23(d,1H),6.99-7.40(m,20H).
マススペクトル(FAB) 436(MH+)
【００４８】
製造例２Ｎ，Ｎ−ジベンジル−Ｌ−フェニルアラニンパラニトロフェニルエステル (Ib) の製造
クロロホルム（５０ｍｌ）にＮ，Ｎ−ジベンジル−Ｌ−フェニルアラニン塩酸塩（７．６４ｇ，２０．０ｍｍｏｌ）を加え、その懸濁液に１０％アンモニア水（２０．０ｍｌ）を滴下して中和した。有機層を分離し、水（２０ｍｌ）で洗浄後硫酸マグネシウムで乾燥、ろ過した。濾液を濃縮して得られた残渣をクロロホルム（５０ｍｌ）に溶解し、氷冷下、パラニトロフェノール（２．８９ｇ，２０．４ｍｍｏｌ）及び、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミド（４．１３ｇ，２０．０ｍｍｏｌ）を順次加え、一晩反応させた。反応液に酢酸エチル（３０ｍｌ）を加え、析出したＮ，Ｎ’−ジシクロヘキシル尿素をろ過し、濾液を１０％炭酸カリウム水溶液で洗浄した。有機層を分離し、濃縮して得られた残渣を再度酢酸エチル（３０ｍｌ）に溶かし、析出した不溶物をろ過した。濾液を濃縮して得られた粗製物をシリカゲルカラムクロマトグラフィーにより精製して、表題化合物(Ib)（７．７７ｇ，１６．６５ｍｍｏｌ）を得た。
1HNMR(300MHz,CDCl3) δ :3.13(dd,J=7.4,13.7Hz,1H),3.26(dd,J=8.2,13.9Hz,1H),3.72(d,J=14.0Hz,2H),3.96(dd,J=7.4,8.2Hz,1H),4.06(d,J=14.0Hz,2H),7.14(d,J=9.2Hz,2H),7.06-7.37(m,15H),8.26(d,J=9.3Hz,2H)
マススペクトル(FAB) 467(MH+)
【００４９】
実施例１（４Ｓ）−４−（Ｎ，Ｎ−ジベンジルアミノ）−４−ベンジル−３−オキソブタン酸ｔ−ブチルエステル（ IIa ）の製造
アルゴン雰囲気下、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（２４ｍｌ，４８ｍｍｏｌ）を無水ＴＨＦ（６４ｍｌ）に溶解し−５３℃に冷却した。この溶液に対し、酢酸ｔｅｒｔ−ブチル（５．８ｇ，５０ｍｍｏｌ）のＴＨＦ（１２ｍｌ）溶液を約１５分間で温度−４５〜−５０℃に維持しつつ滴下した。滴下後、−５３℃で１時間攪拌した後、さらにこの溶液に対し、Ｎ，Ｎ−ジベンジル−Ｌ−フェニルアラニンベンジルエステル(Ia)（純度９０％，７．２ｇ，１５ｍｍｏｌ）のＴＨＦ（８ｍｌ）溶液を約１５分間で温度−４８〜−５２℃に維持しつつ滴下した。滴下後、反応液を−５℃まで加温し、３時間後、クエン酸（１６．５ｇ）の水（５０ｍｌ）溶液を反応液に加え、反応を停止した。酢酸エチルで２回（１００ｍｌ，５０ｍｌ）抽出し、有機層を１０％クエン酸（２０ｍｌ）、飽和食塩水（１０ｍｌ）、５％炭酸水素ナトリウム水溶液（２０ｍｌ×４）、飽和食塩水（１０ｍｌ）の順で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、ろ液を濃縮した。濃縮液をシリカゲルカラムクロマト（ｎ−ヘキサン：酢酸エチル＝４／１）で精製し、表題化合物(IIa）（６．０９ｇ，１３．７ｍｍｏｌ）を得た。
1HNMR(300MHz, CDCl3) δ: 1.25(s,9H),2.93(dd,J=3.9,13.5Hz,1H),3.20(dd,J=9.0,13.5,Hz,1H),3.40(d,J=15.6Hz,2H),3.55(m,2H),3.62(dd,J=3.9,9.0Hz,1H),3.82(d,J=13.5Hz,2H),7.107.38(m,15H)
マススペクトル(FAB) 444(MH+)
【００５０】
実施例２（４Ｓ）−４−（Ｎ−ベンジルオキシカルボニルアミノ）−４−ベンジル−３−オキソブタン酸ｔ−ブチルエステル (IIb) の製造
アルゴン雰囲気下、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（１４ｍｌ，２８ｍｍｏｌ）を無水ＴＨＦ（３０ｍｌ）に溶解し−４５℃に冷却した。この溶液に対し、酢酸ｔｅｒｔ−ブチル（３．７ｇ，３２ｍｍｏｌ）のＴＨＦ（４ｍｌ）溶液を約１５分間で温度−４０〜−４５℃に維持しつつ滴下した。滴下後、−５０℃で３０分間攪拌した後、さらにこの溶液に対し、Ｎ−ベンジルオキシカルボニル−Ｌ−フェニルアラニンメチルエステル(Ic)（２．５ｇ，８ｍｍｏｌ）のＴＨＦ（４ｍｌ）溶液を約１０分間で温度−４０〜−４５℃に維持しつつ滴下した。滴下後、反応液を−４０℃で３０分攪拌した後、０℃まで加温し２０分攪拌した。２０％クエン酸水溶液（４０ｍｌ）を反応液に加え反応を停止した。酢酸エチル（５０ｍｌ×２）で抽出し、有機層を水（５ｍｌ）、５％炭酸水素ナトリウム水溶液（２０ｍｌ）、水（１０ｍｌ）の順で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、ろ液を濃縮した。濃縮液をシリカゲルカラムクロマト（ｎ−ヘキサン：酢酸エチル＝４／１）で精製し、表題化合物(IIb)（３．０８ｇ，７．７７ｍｍｏｌ）を得た。
1HNMR(300MHz, CDCl3) δ: 1.44(s,9H),2.99(dd,J=7.1,14.1Hz,1H),3.17(dd,J=6.1,14.1Hz,1H),3.38(m,2H),4.68(bq,J=approx.7,1H),5.07(s,2H),5.38(bd,J=7.9Hz,1H),7.12-7.35(m,10H)
13CNMR(75MHz, CDCl3) δ: 28.0,37.1,48.2,60.7,67.0,82.4,127.1,128.1,128.2,128.5,128.7,129.2,135.8,137.9,165.8,182.0,201.7
マススペクトル(FAB) 398(MH+)
【００５１】
実施例３（４Ｓ）−４−（Ｎ−ベンジルオキシカルボニルアミノ）−４−ベンジル−３−オキソブタン酸エチルエステル (IIc) の製造
アルゴン雰囲気下、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（４ｍｌ，８ｍｍｏｌ）を無水ＴＨＦ（８ｍｌ）に溶解し−５０℃に冷却した。この溶液に対し、酢酸エチル（７４０ｍｇ，８ｍｍｏｌ）のＴＨＦ（２ｍｌ）溶液を約５分間で温度−５０〜−４５℃に維持しつつ滴下した。滴下後、−５０℃で３０分間攪拌した後、さらにこの溶液に対し、Ｎ−ベンジルオキシカルボニル−Ｌ−フェニルアラニンメチルエステル(Ic)（６２６ｍｇ，２ｍｍｏｌ）のＴＨＦ（２ｍｌ）溶液を約５分間で温度−５０〜−４５℃に維持しつつ滴下した。滴下後、反応液を−５０℃で３０分攪拌した後、室温まで加温し５分攪拌した。１０％クエン酸水溶液（１０ｍｌ）を反応液に加え反応を停止した。酢酸エチルで抽出し、有機層をシリカゲルカラムに通した後、濃縮し粗製の表題化合物(IIc)（８２６ｍｇ）を油状物として得た。
1HNMR(300MHz, CDCl3) δ: 1.22-1.30(m,3H),2.92-3.05(m,1H),3.05-3.22(m,1H),3.40-3.54(m,2H),4.10-4.19(m,2H),4.66(m,1H),5.07(bs,2H),5.55(bd,J=7.8Hz,1H),7.11-7.38(m,10H)
【００５２】
実施例４（４Ｓ）−４−（Ｎ−ｔ−ブトキシカルボニルアミノ）−４−ベンジル−３−オキソブタン酸ｔ−ブチルエステル (IId) の製造
アルゴン雰囲気下、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（２７ｍｌ，５４ｍｍｏｌ）を無水ＴＨＦ（５０ｍｌ）に溶解し−４５℃に冷却した。この溶液に対し、酢酸ｔｅｒｔ−ブチル（７．０ｇ，６０ｍｍｏｌ）のＴＨＦ（５ｍｌ）溶液を約２０分間で温度−４０〜−４５℃に維持しつつ滴下した。滴下後、−５０℃で３０分間攪拌した後、さらにこの溶液に対し、Ｎ−ブトキシカルボニル−Ｌ−フェニルアラニンメチルエステル(Id)（４．１８ｇ，１５ｍｍｏｌ）のＴＨＦ（５ｍｌ）溶液を約２０分間で温度−４０〜−４５℃に維持しつつ滴下した。滴下後、反応液を−５０℃で３０分攪拌した後、２５％クエン酸水溶液（４０ｍｌ）を反応液に加え反応を停止した。反応液中の有機溶媒を減圧留去した後、酢酸エチル（１００ｍｌ）で抽出し、有機層を水（２０ｍｌ）で洗浄した。有機層を濃縮し、シリカゲルカラム（ｎ−ヘキサン：酢酸エチル＝４／１）を通し、結晶（５．９２ｇ）を得た。ＮＭＲ分析の結果、１５％の未反応原料(Id)を含む表題化合物(IId)であった。
1HNMR(300MHz, CDCl3) δ: 1.39(s,9H),1.46(s,9H),2.96(dd,J=7.4,14.0Hz,1H),3.16(dd,J=5.7,14.0Hz,1H),3.34-3.45(m,2H),4.57(bq,J=approx.6.Hz,1H),5.09(bd,J=7.7Hz,1H),7.11-7.30(m,5H)
13CNMR(75MHz, CDCl3) δ: 27.8,28.2,36.9,48.0,60.4,80.0,82.0,126.9,128.4,129.2,136.2,155.1,166.0,202.2
【００５３】
実施例５（４Ｓ）−４−（Ｎ，Ｎ−ジベンジルアミノ）−４−ベンジル−３−オキソ−２−ブロモブタン酸ｔ−ブチルエステル (IIIa) の製造
（１）細かくすりつぶした臭化銅（ＩＩ）（０．４５ｇ，２．０ｍｍｏｌ）を酢酸エチル（２ｍｌ）に溶解した。２５℃で攪拌下、酢酸エチル（２ｍｌ）に実施例１で得た(IIa)（０．４４ｇ，１．０ｍｍｏｌ）とトリエチルアミン（０．１４ｍｌ，１．０ｍｍｏｌ）を溶解した液を一気に加えた。アルゴン雰囲気下、２５℃で３６時間反応させた後に、５％クエン酸水溶液（５ｍｌ）を加え、有機層を分離した。有機層を濃縮し表題化合物(IIIa)を異性体混合物（０．４５ｇ，０．８６ｍｍｏｌ）として褐色結晶を得た。
1HNMR(300MHz, CDCl3)（異性体混合物） δ: 0.90(s,9/2H),1.44(s,9/2H),2.99(dd,J=3.7,13.5Hz,1H),3.14-3.29(m,1H),3.50(dd,J=5.6,13.3,2H),3.83(dd,10.3,13.3,2H),3.82(dd,1/2H),4.03(dd,3.7,9.5,1/2H),5.42(s,1/2H),5.51(s,1/2H),7.14-7.34(m,15H)
マススペクトル(ESI) 522.3,524.3(MH+)
（２）実施例１で得た(IIa)（０．８９ｇ，２．０ｍｍｏｌ）をジエチルエーテル（１０ｍｌ）に溶解した。氷冷下で攪拌しつつＮＢＳ（０．３９ｇ，２．０ｍｍｏｌ）を加え、そのままさらに２時間攪拌した。室温でさらに１３時間反応させた後に、水（５ｍｌ）を加え、有機層を分離した。有機層を濃縮し褐色結晶（１．２３ｇ）を得た。ＮＭＲで分析したところ、原料の(IIa)が約３５％残存しており、主生成物は表題化合物(IIIa)の異性体混合物であった。
【００５４】
実施例６（４Ｓ）−４−（Ｎ−ベンジルオキシカルボニルアミノ）−４−ベンジル−３−オキソ−２−クロロブタン酸ｔ−ブチルエステル (IIIb) の製造
実施例２で得た(IIb)（０．８ｇ，２．０ｍｍｏｌ）をクロロホルム（５ｍｌ）に溶解した。氷冷下で攪拌しつつＮＣＳ（２６４ｍｇ，１．９８ｍｍｏｌ）を加え、氷冷下で３時間攪拌した。反応液に水（２ｍｌ）を加え、有機層を分離した。この有機層を濃縮し結晶（９１２ｍｇ）を得た。この結晶の一部（１００ｍｇ）をシリカゲル薄層クロマト（ｎ−ヘキサン：酢酸エチル＝４／１）で展開し分取して表題化合物(IIIb)を異性体混合物（４０ｍｇ）として得た。
1HNMR(300MHz, CDCl3)（異性体混合物）δ: 1.45-1.48(m,9H),2.95-3.05(m,1H),3.18-3.38(m,1H),4.85-5.10(m,4H),5.20-5.35(m,1H),7.14-7.35(m,10H)
【００５５】
実施例７（４Ｓ）−４−（Ｎ−ベンジルオキシカルボニルアミノ）−４−ベンジル−３−オキソ−２−ブロモブタン酸ｔ−ブチルエステル (IIIc) の製造
実施例２で得た(IIb)（０．８ｇ，２．０ｍｍｏｌ）をクロロホルム（５ｍｌ）に溶解した。氷冷下で攪拌しつつＮＢＳ（３３８ｍｇ，１．９ｍｍｏｌ）を加え、氷冷下で３０分間攪拌した。反応液に水（３ｍｌ）を加え、有機層を分離した。この有機層を濃縮し粗製の表題化合物(IIIc)の異性体混合物（９２１ｍｇ）として淡茶結晶を得た。
1HNMR(300MHz, CDCl3)（異性体混合物）δ: 1.43-1.50(m,9H),3.00(dd,J=7.4,14.1Hz,1H),3.21(dd,J=5.7,14.1Hz,1H),4.82-5.03(m,1H),4.89(bs,1H),5.07(bs,2H),5.20(bd,J=6.0Hz,1H),7.17-7.35(m,10H)
マススペクトル(FAB) 476,478(MH+)
【００５６】
実施例８（３Ｓ）−３−（Ｎ，Ｎ−ジベンジルアミノ）−３−ベンジル−２−オキソ−１−ブロモプロパン (Va) の製造
実施例５で得た(IIIa)（４１ｍｇ，０．０７８ｍｍｏｌ）を４Ｎ−塩化水素（酢酸エチル溶液，１ｍｌ）に溶解した。室温で１３時間攪拌し反応させた。反応液に酢酸エチル（３ｍｌ）を加え、飽和炭酸水素ナトリウム水溶液で中和した。この有機層を濃縮し粗製の(Va)（３０ｍｇ）を得た。
1HNMR(300MHz, CDCl3) δ: 3.00(dd,J=3.9,13.5Hz,1H),3.25(dd,J=9.0,13.5,Hz,1H),3.55(d,J=15.6Hz,2H),3.67(dd,J=3.9,9.0Hz,1H),3.84(d,J=15.6Hz,2H),4.42(s,1H),4.48(s,1H),7.10-7.38(m,15H)
【００５７】
実施例９（３Ｓ）−３−（Ｎ−ベンジルオキシカルボニルアミノ）−３−ベンジル−２−オキソ−１−クロロプロパン (Vb) の製造
実施例２で得られた(IIb)（３５ｇ，８８ｍｍｏｌ）を塩化メチレン（８８ｍｌ）に溶解した。氷冷下で攪拌しつつ塩化スルフリル（７．２３ｍｌ，９０ｍｍｏｌ）を加え、氷冷下で１時間攪拌した後、室温でさらに３０分間攪拌した。反応液を濃縮したところ粗製の(IIIb)（３７ｇ）を結晶として得た。この結晶３５ｇをギ酸（純度９０％、８０ｍｌ）に懸濁し、攪拌しつつ８０度に加熱し３０分間反応させた。反応液を冷却しギ酸を減圧留去し(Vb)の結晶を得た。さらにこの結晶をイソプロパノール（２００ｍｌ）より再結晶し、結晶を乾燥し表題化合物(Vb)（１９．５５ｇ）を得た。
1H-NMR(300MHz, CDCl3) δ: 3.05(dd,J=7.2,14.0Hz,1H),3.25(dd,J=7.1,14.0,Hz,1H),3.97(d,J=16.2Hz,1H),4.14(d,J=16.2Hz,1H),4.77(q,J=4.77Hz,2H),5.08(s,2H),5.29(d,J=7.2Hz,1H),7.12-7.35(m,10H)
13C-NMR(75MHz, CDCl3) δ: 37.8, 47.4, 58.7, 67.3, 127.5, 128.1, 128.3, 128.6, 129.0, 129.1, 135.2, 135.9, 155.7, 201.0
【００５８】
実施例１０（３Ｓ）−３−（Ｎ−ベンジルオキシカルボニルアミノ）−３−ベンジル−２−オキソ−１−ブロモプロパン (Vc) の製造
（１）実施例７で得た(IIIc)（５６ｍｇ，０．１２ｍｍｏｌ）を塩化メチレン（１ｍｌ）に溶解し、トリフルオロ酢酸（０．３ｍｌ）を加え６０℃で１７時間攪拌し反応させた。反応液を飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルを加え抽出した。有機層を濃縮した後、シリカゲル薄層クロマト（ｎ−ヘキサン：酢酸エチル＝４／１）で展開し分取して表題化合物(Vc)（２０ｍｇ）を得た。
1HNMR(300MHz, CDCl3) δ: 3.06(dd,J=7.2,13.9Hz,1H),3.09(dd,J=6.9,13.9Hz,1H),3.81(d,J=13.7Hz,1H),3.93(d,J=13.7Hz,1H),4.82(bq,J=7.3Hz,1H),4.89(bs,1H),5.08(bs,2H),5.34(bd,J=7.2Hz,1H),7.13-7.39(m,10H)
13CNMR(75MHz, CDCl3) δ: 33.1,37.7,58.8,67.2,127.3,128.0,128.3,128.5,128.9,129.1,135.5,136.0,155.8,200.4
マススペクトル(ESI) 376(MH+)
（２） (IIIc)（３６０ｍｇ，０．７５６ｍｍｏｌ）をギ酸（２ｍｌ）に溶解し、２５℃で１５時間攪拌し反応させた。議酸を減圧留去した後、濃縮液を５％炭酸水素ナトリウム水溶液で中和し、酢酸エチルを加え抽出した。有機層を濃縮し粗製のVc（２９６ｍｇ）を結晶として得た。さらに、この結晶をシリカゲル薄層クロマト（ｎ−ヘキサン：酢酸エチル＝４／１）で展開し分取して精製表題化合物(Vc)結晶（１４９ｍｇ）を得た。
【００５９】
実施例１１（３Ｓ）−３−（Ｎ−ベンジルオキシカルボニルアミノ）−３−ベンジル−２−ヒドロキシ−１−クロロプロパン (VIb) の製造
実施例９で得た(Vｂ)（１３６ｍｇ，０．４ｍｍｏｌ）をメタノール（１．５ｍｌ）に溶解した。この溶液に対し、０℃で水素化ホウ素ナトリウム（１７ｍｇ，０．４４ｍｍｏｌ）を加え、さらに０℃で２時間攪拌し反応させた。反応液に１Ｎ塩酸を加え反応を停止させた後、メタノールを減圧留去した。この液に酢酸エチルを加え抽出し、有機層を濃縮して表題化合物（２Ｓ，３Ｓ）−(VIb)と（２Ｒ，３Ｓ）−(VIｂ)の混合物（７４：２６，１３８ｍｇ）を淡黄色結晶として得た。
1HNMR(300MHz, CDCl3)（ジアステレオマー混合物）δ: 2.93(dd,J=8.4,14.0Hz,1H),3.00(dd,J=4.9,14.0Hz,1H),3.50-3.60(m,1H),3.65(dd,J=4.2,12.0Hz,1H),3.81-3.89(m,1H),3.92-4.03(m,1H),4.87(bd,J=approx.8Hz,1H),5.03(bs,2H),7.17-7.37(m,10H)
【００６０】
実施例１２（３Ｓ）−３−（Ｎ−ベンジルオキシカルボニルアミノ）−３−ベンジル−２−ヒドロキシ−１−ブロモプロパン (VIc) の製造
実施例１０で得た(Vc)（１４２ｍｇ，０．３７ｍｍｏｌ）をメタノール（３ｍｌ）、ＴＨＦ（１ｍｌ）の混合溶媒に溶解した。この溶液に対し、０℃で水素化ホウ素ナトリウム（１６ｍｇ，０．４１ｍｍｏｌ）を加え、さらに０〜５℃で２時間攪拌し反応させた。反応液に１Ｎ塩酸（２ｍｌ）を加え反応を停止させた後、メタノール、ＴＨＦを減圧留去した。得られたスラリーに酢酸エチルを加え抽出し、有機層を濃縮して表題化合物の（２Ｓ，３Ｓ）−(VIc)と（２Ｒ，３Ｓ） −(VIc)の混合物（８４：１６，１６４ｍｇ）を淡黄色結晶として得た。
1HNMR(300MHz, CDCl3)（ジアステレオマー混合物）δ: 2.90(dd,J=9.7,14.0Hz,1H),2.99(dd,J=4.7,14.0Hz,1H),3.38-3.47(m,1H),3.53(dd,J=3.6,10.6Hz,1H),3.81-3.90(m,1H),3.93-4.03(m,1H),4.86(bd,J=approx.8Hz,1H),5.03(s,2H),7.16-7.35(m,10H)
【００６１】
実施例１３（３Ｓ）−３−（Ｎ−ベンジルオキシカルボニルアミノ）−３−ベンジル−１，２−エポキシプロパン (VIIb) の製造
（１）実施例１１で得た（２Ｓ，３Ｓ）−(VIb)と（２Ｒ，３Ｓ）−(VIc)の混合物（約３：１，１００ｍｇ，０．３ｍｍｏｌ）をＴＨＦ（２ｍｌ）に溶解した。この溶液に対し、−１０℃でカリウムｔｅｒｔ−ブトキシド（４０ｍｇ，０．２７ｍｍｏｌ）を加え、さらに−１０℃で１５分間攪拌し反応させた。反応液に水（３ｍｌ）と塩化メチレン（１０ｍｌ）を加え抽出し有機層を分離し濃縮した。得られた結晶をシリカゲル薄層クロマト（ｎ−ヘキサン：酢酸エチル＝２／１）で展開し分取して表題化合物の（２Ｓ，３Ｓ）−(VIIb)と（２Ｒ，３Ｓ）−(VIIb)の混合物（約３：１）（２０ｍｇ）を白色結晶として得た。
1HNMR(300MHz, CDCl3)（ジアステレオマー混合物）δ: 2.52-2.58(m,2/4H,(2R,3S)),2.71-2.80(m,6/4H,(2S,3S))2.83-2.95(m,1H),2.99(dd,J=5.0,14.2Hz,1H),3.69-3.72(m,1H,3/4H,(2S,3S)),4.12-4.25(m,1H,1/4H,(2R,3S)),4.67-4.80(m,1H),5.03(s,6/4H,(2S,3S)),5.05(s,2/4H,(2R,3S)),7.18-7.35(m,10H)
（２）実施例１２で得た（２Ｓ，３Ｓ）−(VIc)と（２Ｒ，３Ｓ）−(VIc)の混合物（約５：１，１６４ｍｇ）をメタノール（４．５ｍｌ）に溶解した。この溶液に対し、室温で炭酸カリウム（５８ｍｇ，０．４１ｍｍｏｌ）を加え、さらに室温で１時間攪拌し反応させた。反応液に１Ｎ塩酸（３ｍｌ）と酢酸エチル（１０ｍｌ）を加え抽出し有機層を分離し濃縮した。得られた結晶をシリカゲル薄層クロマト（ｎ−ヘキサン：酢酸エチル＝２／１）で展開し分取して表題化合物の（２Ｓ，３Ｓ）−(VIIb)と（２Ｒ，３Ｓ）−(VIIb)の混合物（約５：１）（７９ｍｇ）を白色結晶として得た。
【００６２】
実施例１４（４Ｓ）−４−（Ｎ，Ｎ−ジベンジルアミノ）−４−ベンジル−３−オキソ−２−クロロブタン酸ｔ−ブチルエステル (IIId) の製造
アルゴン雰囲気下、無水ＴＨＦ（３．２ｍｌ）とＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（０．３９ｍｌ，０．７８ｍｍｏｌ）を混合し、−７０℃に冷却した。この溶液に、クロロ酢酸ｔｅｒｔ−ブチル(IVa)（０．１３ｍｌ，０．８５ｍｍｏｌ）を滴下し３０分間攪拌した後、(Ib)（１５４ｍｇ，０．３４ｍｍｏｌ）を無水ＴＨＦ（１．０ｍｌ）に溶かした溶液を滴下し、徐々に昇温しながら３時間攪拌した。この反応液を室温まで昇温した後、１０％クエン酸水溶液（３．０ｍｌ）を加え、次いで酢酸エチル（１０ｍｌ）を加えて抽出した。有機層を水（１０ｍｌ）で洗浄し、硫酸マグネシウムで乾燥、ろ過した。濾液を濃縮して得られた粗製物をシリカゲル分取薄層クロマトグラフィーにて精製し、表題化合物の（２Ｓ，４Ｓ）−(IIId)および（２Ｒ，４Ｓ）−(IIId）の混合物（２００．２ｍｇ）を得た。ジアステレオ比は１Ｈ−ＮＭＲ積分比より約２：１であった。
1HNMR(300MHz,CDCl3)（ジアステレオマー混合物）δ:0.86(s,6H),1.44(s,3H),2.943.04(m,1H),3.17(dd,J=9.8,13.4Hz,1/3H),3.26(dd,J=9.8,13.3Hz,2/3H),3.50(d,J=13.2Hz,4/3H),3.51(d,J=13.2Hz,2/3H),3.81(d,J=13.2Hz,4/3H),3.85(d,J=13.1Hz,2/3H),3.87(dd,J=3.0,9.7Hz,2/3H),4.00(dd,J=3.0,9.7Hz,1/3H),5.37(s,1/3H),5.48(s,2/3H),7.08-7.39(m,15H)
マススペクトル(FAB) 478(MH+)
【００６３】
実施例１５（４Ｓ）−４−（Ｎ−ベンジルオキシカルボニル）アミノ−４−ベンジル−３−オキソブタン酸ｔ−ブチルエステル (IIb) の製造
アルゴン雰囲気下、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（２３１ｍｌ,４６２ｍｍｏｌ）を無水ＴＨＦ（４００ｍｌ）に溶解し−５０℃に冷却した。この溶液に対し、酢酸ｔｅｒｔ−ブチル（５８．１ｇ，５００ｍｍｏｌ）のＴＨＦ（４０ｍｌ）溶液を約４０分間で温度−４５〜−５０℃に維持しつつ滴下した。滴下後、−４５℃で３０分間攪拌した後、さらにこの溶液に対し、Ｎ−ベンジルオキシカルボニル−Ｌ−フェニルアラニンメチルエステル(Ic)（３９．４ｇ，１２５ｍｍｏｌ）のＴＨＦ（４０ｍｌ）溶液を約３０分間で温度−４５〜−５０℃に維持しつつ滴下した。滴下後、反応液を−４５℃で６０分攪拌した後、反応液を２Ｎ塩酸（５００ｍｌ）と氷（１５０ｇ）の混合物にあけて反応を停止した。混合液を室温に戻し、有機層を分離した。水層をさらにトルエン（３５０ｍｌ）で抽出し２つの有機層をあわせ、５％炭酸水素ナトリウム水溶液（５０ｍｌ）、２５％食塩水（５０ｍｌ）の順で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、ろ液を濃縮して粗製の表題化合物(IIb)（５８．１ｇ，純度８６．４％，１２６ｍｍｏｌ）を得た。
【００６４】
実施例１６（４Ｓ）−４−（Ｎ−ベンジルオキシカルボニル）アミノ−４−ベンジル−３−オキソ−２−クロロブタン酸ｔ−ブチルエステル (IIIb) の製造
（４Ｓ）−４−（Ｎ−ベンジルオキシカルボニルアミノ）−４−ベンジル−３−オキソブタン酸ｔ−ブチルエステル(IIb)（４０．５ｇ，純度８６．４％，８８ｍｍｏｌ）を塩化メチレン（８８ｍｌ）に溶解した。氷冷下で攪拌しつつ塩化スルフリル（７．２３ｍｌ，９０ｍｍｏｌ）を加え、氷冷下で１時間攪拌した後、室温でさらに３０分間攪拌した。反応液を３０℃以下で濃縮したところ粗製の表記化合物（４８．６ｇ）を結晶として得た。
この結晶（２ｇ）をトルエン（１０ｍｌ）から再結晶し精製結晶を得た。
1H-NMR(300MHz,CDCl3)
(異性体混合物)δ:1.45-1.48(m,9H), 2.95-3.05(m,1H), 3.18-3.38(m,1H), 4.85-5.10(m,4H), 5.20-5.35(m,1H)7.14-7.35(m,10H)
(主異性体)δ:1.44(s,9H), 2.99(dd,J=7.5,14.1Hz,1H), 3.20(dd,J=6.1,14.1Hz,1H), 4.85(s,1H), 4.97(bq,J=8.4Hz,1H), 5.60(s,2H), 5.25(bd,J=8.4Hz,1H)7.14-7.35(m,10H)
13C-NMR(75MHz,CDCl3)
(主異性体)δ:27.5, 37.7, 59.5, 60.0, 67.2, 85.0, 127.3, 128.1, 128.3, 128.5, 128.9, 129.2, 135.3, 136.0, 155.6, 163.1, 197.4
マススペクトル(FAB) 432(MH+), 454(MNa+)
【００６５】
実施例１７（３Ｓ）−３−（Ｎ−ベンジルオキシカルボニル）アミノ−３−ベンジル−２−オキソ−１−クロロプロパン (Vb) の製造
実施例１６で得られた（４Ｓ）−４−（Ｎ−ベンジルオキシカルボニルアミノ）−４−ベンジル−３−オキソ−２−クロロブタン酸ｔ−ブチルエステル(IIIb)の粗結晶（４６．６ｇ）をギ酸(純度９０％，８０ｍｌ）に懸濁し、攪拌しつつ８０℃に加熱し２０分間反応させた。反応液を冷却しギ酸を減圧留去し表題化合物の粗結晶を得た。
さらにこの結晶をイソプロパノール（２００ｍｌ）に６０℃で溶解し５℃に冷却再結晶し、結晶をイソプロパノール（５０ｍｌ）で洗浄後、乾燥し表題化合物の結晶（２０．１ｇ，６０ｍｍｏｌ）を得た。
【００６６】
実施例１８（２Ｓ，３Ｓ）−３−（Ｎ−ベンジルオキシカルボニル）アミノ−３−ベンジル−２−ヒドロキシ−Ｉ−クロロプロパン (VIb) の製造
（３Ｓ）−３−（Ｎ−ベンジルオキシカルボニルアミノ）−３−ベンジル−２−オキソ−１−クロロプロパン(Vb)（１７．０ｇ，５１．２ｍｍｏｌ）を塩化メチレン（１８０ｍｌ）に溶解し、さらにメタノール（１８０ｍｌ）を加えた。この溶液に対し、０℃で水素化ホウ素ナトリウム（２．０３ｇ，５３．８ｍｍｏｌ）を約１０分かけて加え、さらに０℃で３０分間攪拌し反応させた。反応液に酢酸（１２．９ｍｌ，２２６ｍｍｏｌ）を加え反応を停止させた後、メタノールを減圧留去した。この液に水（５０ｍｌ）を加え、塩化メチレンで２回（１５０ｍｌ＋５０ｍｌ）抽出した。有機層を濃縮して表題化合物とそのジアステレオマーである（２Ｒ，３Ｓ）体の混合物（８４：１６）を白色結晶として得た。
この結晶（１ｇ）を酢酸エチル/ｎ−ヘキサン（５／１，１５ｍｌ）から再結晶し表題化合物の結晶（９７％ｄｅ，０．６ｇ）を得た。
1H-NMR(300MHz,CDCl3)
((2S, 3S)体)δ:2.87(dd,J=9.0,14.1Hz, 1H), 3.00(dd,J=4.6,14.1Hz,1H), 3.55(dd,J=7.3,11.3Hz,1H), 3.60(bs,1H), 3.62(dd,J=4.3,11.3Hz,1H), 3.86(bq,J=approx5Hz,1H), 3.96-4.06(m,1H), 5.01(s,2H), 5.31(bd,J=approx.8.5Hz,1H), 7.18-7.33(m,10H)
13C-NMR(75MHz,CDCl3)
((2S, 3S)体)δ:35.3, 47.1, 54.6, 66.5, 73.2, 126.4, 127.8, 127.9, 128.3, 128.3, 129.3, 136.3, 137.5, 156.0
マススペクトル(ESI) 334.2(MH+), 356.2(MNa+), 689.3(2MNa+)
【００６７】
実施例１９（２Ｓ，３Ｓ）−３−（Ｎ−ベンジルオキシカルボニル）アミノ−３−ベンジル−１，２−エポキシプロパン (VIIb) の製造
実施例１８で得られた（２Ｓ，３Ｓ）−３−（Ｎ−ベンジルオキシカルボニルアミノ）−３−ベンジル−２−ヒドロキシ−Ｉ−クロロプロパン(VIb)とそのジアステレオマー（（２Ｒ，３Ｓ）体）の混合物（８４：１６）の粗結晶をメタノール（６００ｍｌ）に溶解した。この溶液に対し、室温で炭酸カリウム（１４．１ｇ，１０２ｍｍｏｌ）を加え、さらに室温で３時間攪拌し反応させた。反応液をろ過し塩を取り除きさらにメタノール（２０ｍｌ）で洗浄し、ろ液を３５℃以下で約１００ｍｌまで濃縮した。濃縮液に０．５Ｎ塩酸（１００ｍｌ）を加え酸性にした後、塩化メチレンで２回（１５０ｍｌ＋１５０ｍｌ）抽出した。有機層を４０℃以下で濃縮し、表題化合物とそのジアステレオマー（（２Ｒ，３Ｓ）体）の混合物（８４：１６）を白色結晶（１４．０ｇ，４７．１ｍｍｏｌ）として得た。
この結晶(1g)を酢酸エチル／ｎ−ヘキサン（１／１，６ｍｌ）から再結晶し表題化合物の結晶（９７％ｄｅ，０．５８ｇ）を得た。
1H-NMR(300MHz,CDCl3)
((2S,3S)体)δ:2.71-2.80(m,2H), 2.85(dd,J=8.1, 14.1Hz,1H), 2.91(dd,J=2.7,6.4Hz,1H), 2.98(dd,J=5.1,14.1Hz,1H), 3.68-3.82(m,1H), 4.77(bd,J=5.9Hz,1H),5.03(s,2H), 7.17-7.33(m,10H)
13C-NMR(75MHz,CDCl3)
((2S,3S)体)δ:37.5, 46.7, 53.0, 53.2, 66.8, 126.8, 128.0, 128.1, 128.5, 128.6, 129.3, 136.2, 136.4, 155.7
マススペクトル(ESI) 298.2(MH+), 320.2(MNa+), 336.3(MK+), 617.5(2MNa+)
【００６８】
実施例２０（２Ｒ，３Ｓ）−３−（Ｎ−ベンジルオキシカルボニル）アミノ−２−ヒドロキシ−１−（Ｎ−イソブチルアミノ）−４−フェニルブタン (IXa) の製造
３−（Ｎ−ベンジルオキシカルボニルアミノ）−３−ベンジル−１，２−エポキシプロパン(VIIb)（（２Ｓ，３Ｓ）／（２Ｒ，３Ｓ）＝８４／１６，４．４７ｇ，１５．０ｍｍｏｌ）をエタノール（２９ｍｌ）に懸濁させ、イソブチルアミン（２２．４ｍｌ，２２５ｍｍｏｌ）に加えた。この溶液を７０℃に加熱し６０分間反応させた。反応液を濃縮して表題化合物とそのジアステレオマー（（２Ｓ，３Ｓ）体）の混合物（８４／１６）を白色結晶として得た。
また、（２Ｓ，３Ｓ）体の結晶を用いて同様に反応させ、表題化合物を得た。
1H-NMR(300MHz,CDCl3)
((2R,3S)体)δ:0.90(d,J=6.6Hz,6H), 1.60-1.80(m,1H), 2.38(d,J=6.8Hz,2H), 2.65(dd,J=6.8,12.4Hz,1H), 2.70(dd,J=4.0,12.4Hz,1H), 2.70(bs,1H), 2.86(ddJ=8.1,14.1Hz,1H), 2.99(dd,J=4.8,14.1Hz,1H), 3.49(bq,J=approx4.5Hz,1H), 3.80-3.95(m,1H), 5.02(s,2H), 5.11(bd,J=9.0Hz,1H), 7.19-7.32(m,10H)
13C-NMR(75MHz,CDCl3)
((2R,3S)体)δ: 20.5, 28.3, 36.6, 51.4, 55.0, 57.9, 66.5, 70.4, 126.4, 127.8, 128.0, 128.4, 128.4, 129.5, 136.6, 137.7, 156.3
マススペクトル(ESI) 371.2(MH+)
【００６９】
実施例２１４−ニトロ−Ｎ−（（２’Ｒ（ｓｙｎ），３’Ｓ）−３’−（Ｎ−ベンジルオキシカルボニル）アミノ−２’−ヒドロキシ−４’−フェニルブチル）−Ｎ−イソブチル−ベンゼンスルホンアミド (IXb) の製造
（２Ｒ，３Ｓ）−３−（Ｎ−ベンジルオキシカルボニルアミノ）−２−ヒドロキシ−１−（Ｎ−イソブチルアミノ）−４−フェニルブタン(IXa)（（２Ｒ，３Ｓ）／（２Ｓ，３Ｓ）＝８４／１６，６．０８ｇ，１５．０ｍｍｏｌ）を塩化メチレン（４０ｍｌ）に溶解した。炭酸ソーダ（２．５５ｇ，２４．１ｍｍｏｌ）を水（２０ｍｌ）溶液を上記の溶液に加え２層系の液を調製した。この溶液に対し、氷冷下、4-ニトロベンゼンスルホニルクロライド（４．０ｇ，１８．０ｍｍｏｌ）の塩化メチレン（５ｍｌ）溶液を約１０分間で加え、反応液を室温に戻しさらに３時間反応させた。有機層を分離、濃縮し表題化合物とそのジアステレオマー（２’Ｓ，３’Ｓ）の混合物（８４：１６）を白色結晶として得た。この結晶をエタノール（１００ｍｌ）より再結晶した。再結晶は７０℃で溶解し、約５５℃で起晶後、その温度で１時間熟成し、最終的には２０℃まで冷却した。分離結晶をエタノール（３０ｍｌ）で洗浄し乾燥し表題化合物（６．０７ｇ，１０．９ｍｍｏｌ，９６．４％ｄｅ）を白色結晶として得た。
1H-NMR(300MHz,CDCl3)
((2'R(syn),3'S)体)δ:0.84(d,J=6.1Hz,3H), 0.86(d,J=6.3Hz,3H), 1.75-1.95(m,1H), 2.88(dd,J=7.5,14.1Hz,2H), 2.96(d,J=6.8Hz,2H), 3.00(dd,J=4.7,14.1Hz,1H),2.90(bs,1H), 3.12-3.26(m,2H), 3.80-3.91(m,2H), 4.99(bd,J=8.7Hz,1H),5.01(s,2H), 7.21-7.32(m,10H), 7.92(d,J=8.7Hz,2H), 8.29(d,J=8.7Hz,2H)
13C-NMR(75MHz,CDCl3)
((2'R(syn),3S)体)δ:19.8, 19.9, 35.5, 52.4, 57.7, 66.9, 72.1, 124.3, 126.7, 127.8, 128.2, 128.5, 128.5, 128.6, 129.3, 136.1, 137.2, 144.6, 150.0, 156.5
【００７０】
実施例２２４−ニトロ−Ｎ−（（２’Ｒ（ｓｙｎ），３’Ｓ）−３’−（Ｎ−ｔ−ブチルオキシカルボニル）アミノ−２’−ヒドロキシ−４’−フェニルブチル）−Ｎ−イソブチル−ベンゼンスルホンアミド (IXc) の製造
４−ニトロ−Ｎ−（（２’Ｒ（ｓｙｎ），３’Ｓ）−３’−（Ｎ−ベンジルオキシカルボニルアミノ）−２’−ヒドロキシ−４’−フェニルブチル）−Ｎ−イソブチル−ベンゼンスルホンアミド(IXb)（１３．０ｇ，２３．４ｍｍｏｌ，９６％ｄｅ）を塩化メチレン（７７ｍｌ）に溶解しメタノール（２ｍｌ，４６．８ｍｍｏｌ）を加えた。氷冷下、この溶液３０％臭化水素酸/酢酸溶液（１９．３ｍｌ，ＨＢｒ９３．６ｍｍｏｌ）を加えた後、室温に戻し３時間攪拌した。反応液に１０％炭酸ナトリウム水溶液（３００ｍｌ）を加えアルカリ性にし、さらに塩化メチレン（１００ｍｌ）を加えた。有機層を分離し、ここにジ炭酸ジ−ｔｅｒｔ−ブチル（５．６２ｇ，２５．７ｍｍｏｌ）の塩化メチレン（５０ｍｌ）を加え室温で２時間反応させた。反応液を約１００ｍｌになるまで濃縮しここにメタノール（１００ｍｌ）と炭酸カリウム（３．２３ｇ，２３．４ｍｍｏｌ）を加え、室温で攪拌した。途中ＨＰＬＣで反応を追い３時間後、２位のAc化体が消失したところで、酢酸（１．３４ｍｌ，２３．４ｍｍｏｌ）を加え反応を停止させた。反応液を濃縮し、水（５０ｍｌ）を加え、塩化メチレン（２００ｍｌ）で抽出した。有機層を濃縮して表題化合物の粗結晶を得た。この結晶をエタノール（５５０ｍｌ）から再結晶した。再結晶は５５℃で溶解し、約４０℃で起晶後、最終的には５℃まで冷却した。分離結晶をエタノール（１００ｍｌ）で洗浄し乾燥し表題化合物（８．７１ｇ，１６．７ｍｍｏｌ，１００％ｄｅ）を白色結晶として得た。
1H-NMR(300MHz,CDCl3)
((2R'(syn),3'S)体)δ:0.87(d,J=6.6Hz,3H), 0.88(d,J=6.6Hz,3H), 1.36(s,9H), 1.81-1.96(m,1H), 2.83-2.2.96(m,2H), 2.99(d,J=7.5Hz,2H), 3.20(d,J=5.3Hz,2H), 3.70-3.85(m,2H), 3.82(bs,1H), 4.64(bd,J=7.6Hz,1H), 7.21-7.33(m,10H),7.96(d,J=8.8Hz,2H), 8.33(d,J=8.8Hz,2H)
13C-NMR(75MHz,CDCl3)
((2R'(syn),3S)体)δ:19.8, 20.0, 26.9, 28.2, 35.6, 52.5, 55.2, 57.5, 72.2, 80.1, 124.3, 126.6, 128.5, 128.6, 129.4, 137.5, 144.8, 150.0, 156.3
マススペクトル(ESI) 522.3(MH+), 544.5(MNa+), 560.4(MK+)
【００７１】
実施例２３Ｎ−（Ｓ）−テトラヒドロフラン−３−イルオキシカルボニル−Ｌ−フェニルアラニンメチルエステル (Ie) の製造
（Ｓ）−３−ヒドロキシテトラヒドロフラン（０．８８１ｇ，１０ｍｍｏｌ）を塩化メチレン（１０ｍｌ）に溶解し、トリホスゲン（１．３４ｇ，４．５ｍｍｏｌ）を加え溶解した。この液を−４０℃に冷却し、ピリジン（１．０４ｍｌ，１３．５ｍｍｏｌ）の塩化メチレン（５ｍｌ）溶液を約１５分かけて滴下した。滴下後、室温で３．５時間反応させクロロギ酸エステルを調製した。
上記に得られた反応液を氷冷し、Ｌ−フェニルアラニンメチルエステル塩酸塩（１．９４ｇ，９ｍｍｏｌ）を塩化メチレン（５ｍｌ）に溶解した液を添加した。さらに氷冷下で、炭酸ソーダ（２．１２ｇ，２０ｍｍｏｌ）を溶かした水溶液（２０ｍｌ）を約１５分かけて滴下した。滴下後、室温で２．５時間反応させた。反応後の反応液の水層のｐＨを測定したところアルカリ性であった。この水層を分離し、有機層を１Ｎ塩酸（１０ｍｌ）で２回洗浄し、さらに水（１０ｍｌ）で洗浄した。溶媒を留去し、表題化合物（２．１０ｇ，７．２ｍｍｏｌ）を黄色オイルとして得た。
1H-NMR(300MHz,CDCl3)
δ:1.96-2.15(m,2H), 3.05(dd,J=5.6,13.9Hz,1H), 3.13(dd,J=6.4,13.9Hz,1H), 3.72(s,3H), 3.75-3.91(m,4H), 4.62(bq,J=approx.6Hz,1H), 5.19-5.23(m,1H), 5.26(bq,J=8.7Hz,1H), 7.10-7.29(m,5H)
13C-NMR(75MHz,CDCl3)
δ:32.7, 38.2, 52.3, 54.7, 66.9, 73.2, 75.5, 127.1, 128.6, 129.2, 135.7, 155.3, 172.0
マススペクトル(FAB) 294(MH+)
【００７２】
実施例２４（４Ｓ）−４−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニル）アミノ−５−フェニル−３−オキソ−ペンタン酸ｔｅｒｔ−ブチル (IIe) の製造
アルゴン雰囲気下、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（９ｍｌ，１８ｍｍｏｌ）を無水ＴＨＦ（２０ｍｌ）に溶解し−５０℃に冷却した。この溶液に対し、酢酸tert-ブチル（２．３ｇ，２０ｍｍｏｌ）のＴＨＦ（３ｍｌ）溶液を約１０分間で温度−４５〜−５０℃に維持しつつ滴下した。滴下後、−４５℃で３０分間攪拌した後、さらにこの溶液に対し、Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニル−Ｌ−フェニルアラニンメチルエステル(Ie)（１．７５ｇ，５．３ｍｍｏｌ）のＴＨＦ（３ｍｌ）溶液を約１０分間で温度−４０〜−４５℃に維持しつつ滴下した。滴下後、反応液を−４５℃で６０分攪拌した後、酢酸（２．３ｍｌ，４０ｍｍｏｌ）を反応液に加え反応を停止した。反応液に水（２０ｍｌ）とトルエン（５０ｍｌ）を加え抽出し、５％炭酸水素ナトリウム水溶液（１０ｍｌ）、水（１０ｍｌ）の順で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、ろ液を濃縮して粗製の表題化合物（１．９５ｇ，５．２ｍｍｏｌ）を得た。
1H-NMR(300MHz,CDCl3)
δ:1.46(s,9H), 1.96-2.17(m,2H), 2.97(dd,J=7.3,14.2Hz,1H), 3.17(dd,J=6.2,14.2Hz,1H), 3.39(bs,2H), 3.70-3.90(m,4H), 4.66(bq,J=approx.6.5Hz,1H), 5.15-5.23(m,1H), 5.34(bd,J=7.8Hz,1H), 7.15-7.31(m,5H)
13C-NMR(75MHz,CDCl3)
δ:27.9, 32.7, 37.1, 48.2, 60.6, 66.9, 73.2, 75.6, 82.3, 127.1, 128.7, 129.2, 135.7, 155.4, 165.8, 201.6
【００７３】
実施例２５（４Ｓ）−４−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニル）アミノ−２−クロロ−５−フェニル−３−オキソ−ペンタン酸ｔｅｒｔ−ブチル (IIIe) の製造
（４Ｓ）−４−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニル）アミノ−５−フェニル−３−オキソ−ペンタン酸ｔｅｒｔ−ブチル(IIe)（１．８ｇ，４．７ｍｍｏｌ）を塩化メチレン（５ｍｌ）に溶解した。氷冷下で攪拌しつつ塩化スルフリル（０．３９ｍｍｏｌ，４．７ｍｍｏｌ）を加え、室温で６０分間攪拌した。反応液を３０℃以下で濃縮したところ粗製の表題化合物を得た。
1H-NMR(300MHz,CDCl3)
δ:1.40(s,9H), 1.95-2.17(m,2H), 2.92-3.02(m,1H), 3.17-3.25(m,1H), 3.67-3.90(m,4H), 4.90(d,J=13.5Hz,1H), 4.98(bq,J=approx.6.0Hz,1H), 5.15-5.19(m,1H), 5.27(bd,J=8.3Hz,1H), 7.18-7.30(m,5H)
13C-NMR(75MHz,CDCl3)
δ:27.7, 32.7, 37.6, 59.1, 60.9, 66.9, 73.0, 75.9, 84.8, 127.3, 128.8, 129.3, 135.3, 155.3, 163.3, 197.4
【００７４】
実施例２６（３Ｓ）−１−クロロ−２−オキソ−３−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニル）アミノ−４−フェニルブタン (Vd) の製造
実施例２５で得られた固体(IIIe)にギ酸（５ｍｌ）を加え、８０℃で１５分攪拌した。ギ酸を留去し得られた残渣にイソプロパノール（１０ｍｌ）を加えたところ結晶化した。６０℃で溶解し室温で２時間、５℃で３０分晶析し、結晶を分離した。イソプロパノール（２ｍｌ）で結晶を洗浄、乾燥して表題化合物（０．８５４ｇ，２．７ｍｍｏｌ）を白色結晶として得た。
1H-NMR(300MHz,CDCl3)
δ:1.93-2.03(m,1H), 2.08-2.20(m,1H), 3.00(dd,J=7.1,13.8Hz,1H), 3.10(dd,J=6.8,13.8Hz,1H), 3.75-3.92(m,4H), 3.98(d,J=16.2Hz,1H), 4.16(d,J=16.2Hz,1H), 4.75(bq,J=approx.7.5Hz,1H), 5.17-5.22(m,1H), 5.36(bd,J=7.14Hz,1H), 5.15-5.21(m,1H), 7.20-7.34(m,5H)
13C-NMR(75MHz,CDCl3)
δ:32.7, 37.7, 47.3, 58.5, 66.9, 73.1, 75.9, 127.5, 129.0, 129.0, 135.2, 155.4, 201.0
【００７５】
実施例２７（２Ｓ，３Ｓ）−１−クロロ−２−ヒドロキシ−３−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニルアミノ）−４−フェニルブタン (VId) の製造
（３Ｓ）−１−クロロ−２−オキソ−３−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニルアミノ）−４−フェニルブタン(Vd)（０．７０６ｇ，２．２６ｍｍｏｌ）を塩化メチレン（８ｍｌ）に溶解し、さらにメタノール（８０ｍｌ）を加えた。この溶液に対し、−３℃で水素化ホウ素ナトリウム（６０ｍｇ，１．６ｍｍｏｌ）を約５分かけて加え、さらに−３℃で６０分間攪拌し反応させた。反応液に酢酸（０．３８５ｍｌ，６．７２ｍｍｏｌ）を加え反応を停止させた後、メタノールを減圧留去した。この液に水（５ｍｌ）を加え、塩化メチレンで２回（２０ｍｌ＋１０ｍｌ）抽出した。有機層を濃縮して表題化合物とそのジアステレオマー（（２Ｒ，３Ｓ）体）の混合物（８３：１７）を白色結晶として得た。
1H-NMR(300MHz,CDCl3)
δ:(2S,3S): 1.90-2.00(m,1H), 2.05-2.18(m,1H), 2.80(dd,J=9.3,14.0Hz,1H), 3.01(dd,J=4.3,14.0Hz,1H), 3.54(bs,1H), 3.52-3.66(m,2H), 3.67-3.90(m,5H), 3.94-4.03(m,1H), 5.08-5.16(m,1H), 5.64(bd,J=9.4Hz,1H), 7.20-7.30(m,5H)
13C-NMR(75MHz,CDCl3)
δ:(2S,3S): 32.4, 35.1, 46.8, 54.2, 66.5, 72.9, 73.0, 74.7, 126.0, 128.0, 129.1, 137.6, 155.5
マススペクトル(ESI) 314.3(MH+)
【００７６】
実施例２８（２Ｓ，３Ｓ）−３−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニルアミノ）−４−フェニルブタン−１，２−エポキシド (VIIc) の製造
実施例２７で得られた結晶(VId)をメタノール（２０ｍｌ）に懸濁し、室温で炭酸カリウム（６２４ｍｇ，４．５２ｍｍｏｌ）を加え、室温で２時間攪拌し反応させた。反応液をろ過し塩を取り除いた後、ろ液を３５℃以下で濃縮した。濃縮液に０．５Ｎ塩酸（１０ｍｌ）を加え酸性にした後、塩化メチレンで２回（１０ｍｌ＋１０ｍｌ）で抽出した。有機層を４０℃以下で濃縮し、表題化合物とそのジアステレオマー（（２Ｒ，３Ｓ）体）の混合物（８３：１７）を白色結晶（０．５８ｇ，２．１ｍｍｏｌ）として得た。
1H-NMR(300MHz, CDCl3)
δ:(1S,1'S): 2.72-2.78(m, 2H), 2.78-2.83(m, 1H), 2.86-3.02(m, 2H), 3.70-3.90(m, 5H), 4.65-4.68(b, 1H), 5.15-5.21(m, 1H), 7.20-7.34(m, 5H)
13C-NMR(75MHz, CDCl3)
δ:(1S,1'S): 32.7, 37.5, 46.7, 53.0, 53.0, 66.9, 73.2, 75.4, 126.9, 128.7, 129.4, 136.3, 155.5
マススペクトル(ESI) 278.2(MH+)
【００７７】
実施例２９（２Ｒ，３Ｓ）−３−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニルアミノ）−２−ヒドロキシ−１−Ｎ−イソブチルアミノ−４−フェニルブタン (IXd) の製造
（２Ｓ，３Ｓ）−３−（Ｎ−（Ｓ）−テトラヒドロフラン−３’−イルオキシカルボニルアミノ）−４−フェニルブタン−１，２−エポキシド(VIIc)（（２Ｓ，３Ｓ）：（２Ｒ，３Ｓ）＝８３：１７，０．５８ｇ，２．１ｍｍｏｌ）をエタノール（４ｍｌ）に懸濁させ、イソブチルアミン（３．４ｍｌ，３３．９ｍｍｏｌ）に加えた。この溶液を７０℃に加熱し６０分間反応させた。反応液を濃縮し表題化合物とそのジアステレオマー（（２Ｓ，３Ｓ）体）の混合物（８３：１７）を白色結晶として得た。
1H-NMR(300MHz, CDCl3)
δ:(2R,3S): 0.91(d, J=6.6Hz, 6H), 1.72(hep, J=6.6Hz, 1H), 1.80-1.95(m, 1H), 2.02-2.14(m, 1H), 2.37-2.44(m, 2H), 2.64-2.99(m, 5H), 3.55-3.86(m, 5H), 5.11(b, 1H), 5.43(bd, J=8.7Hz, 1H), 7.19-7.28(m, 5H)
13C-NMR(75MHz, CDCl3)
δ:(2R,3S): 20.4, 28.2, 32.7, 36.6, 51.4, 55.2, 57.7, 66.8, 70.3, 73.2, 75.0, 126.3, 128.3, 129.3, 137.7, 155.9
マススペクトル(ESI) 351.3(MH+)
【００７８】
実施例３０４−ニトロ−Ｎ−（（２’Ｒ（ｓｙｎ），３’Ｓ）−２’−ヒドロキシ−４’−フェニル−３’−（Ｎ−（Ｓ）−テトラヒドロフラン−３”−イルオキシカルボニル）アミノ−ブチル）−Ｎ−イソブチル−ベンゼンスルホンアミド (IXe) の製造
実施例２９で得られた結晶(IXd)を塩化メチレン（２ｍｌ）に溶解した。炭酸ソーダ（０．２３３ｇ，２．２ｍｍｏｌ）を水（２ｍｌ）溶液を上記の溶液に加え２層系の液を調製した。この溶液に対し、氷冷下、４−ニトロベンゼンスルホニルクロライド（０．４８８ｇ，２．２ｍｍｏｌ）の塩化メチレン（１ｍｌ）溶液を約２分間で加え、反応液を室温に戻しさらに３時間反応させた。反応途中、結晶が析出し攪拌が困難になったので塩化メチレン（６ｍｌ）と水（２ｍｌ）を足した。有機層を分離、濃縮し表題化合物とそのジアステレオマー（（２Ｓ（ａｎｔｉ），３Ｓ）体）の混合物（８３：１７，０．９７４ｇ）を白色結晶として得た。この結晶をエタノール（６０ｍｌ）より再結晶した。再結晶は７０℃で溶解し、約５５℃で起晶後、５℃まで冷却し晶析した。分離結晶をエタノール（５ｍｌ）で洗浄、乾燥し表題化合物（０．６４２ｇ，９６．４％ｄｅ）を白色結晶として得た。
この結晶をさらにエタノール（５０ｍｌ）より再結晶、乾燥し、表題化合物（０．５８３ｇ，１００ｄｅ）を得た。
1H-NMR(300MHz, CDCl3)
(2R'(syn),3S体)δ: 0.87(d, J=7.0Hz, 3H), 0.89(d, J=7.0Hz, 3H), 1.89(hep, J=6.8Hz, 1H), 1.90-1.94(m, 1H), 2.08-2.15(m, 1H), 2.86-3.04(m, 4H), 3.11-3.24(m, 2H), 3.58(bs, 6H), 3.65-3.87(m, 6H), 4.85(bd, J=5.2Hz, 1H), 5.10-5.18(m, 1H), 7.20-7.37(m, 5H), 7.95(d, J=8.9Hz, 2H), 8.34(d, J=8.9Hz, 2H)
13C-NMR(75MHz, CDCl3)
(2R'(syn),3S体)δ: 19.8, 19.9, 27.0, 32.7, 35.4, 52.7, 55.3, 57.8, 66.8, 72.1, 73.1, 75.6, 124.3,126.7, 128.5, 128.6, 129.3, 137.2, 144.7, 150.0, 156.2
マススペクトル(FAB) 536(MH+)
【００７９】
実施例３１（４Ｒ）−４−（Ｎ−ベンジルオキシカルボニル）アミノ−３−オキソ−５−フェニルチオペンタン酸ｔ−ブチル (IIf) の製造
アルゴン雰囲気下、テトラヒドロフラン８００ｍｌにリチウムジイソプロピルアミドの２．０Ｍヘプタン、テトラヒドロフラン、エチルベンゼン溶液４２０ｍｌ（８４０ｍｍｏｌ）を加え−６６℃に冷却した。この溶液中に酢酸ｔ−ブチル９９．５４ｇ（８５６．９ｍｍｏｌ）のテトラヒドロフラン５３ｍｌ溶液を−６６℃から−７１℃に保ちながら４５分かけて滴下した後、−６９℃〜−７４℃で１時間攪拌した。この溶液にＮ−ベンジルオキシカルボニル−（Ｓ−フェニル）−Ｌ−システインメチルエステル(If)８０．００ｇ（２３１．６ｍｍｏｌ）のテトラヒドロフラン１３５ｍｌ溶液を−６９℃〜−７４℃に保ちながら４５分かけて滴下した。−６９℃〜−７３℃で２時間３０分攪拌した後、この反応液を３６％塩酸１５０ｍｌの水７５０ｍｌ溶液中に注いだ。酢酸エチル８０ｍｌを加えて分層した後、水層より酢酸エチル５５０ｍｌで抽出した。有機層を合わせて１Ｎ塩酸３００ｍｌで洗浄後、飽和炭酸水素ナトリウム水溶液に続けて飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、ろ過、濃縮し、上記表題化合物１０８．０４ｇ（純度７９．９％、８６．３３ｇ）を得た（収率８６．８％）。
１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）
δ：３．２８（ｄｄ，１Ｈ），３．３６−３．５２（ｍ，３Ｈ），４．６０（ｄｄ，１Ｈ），５．０７（ｄ，１Ｈ），５．１０（ｄ，１Ｈ），５．５８（ｂｄ．ｄ，１Ｈ），７．１９−７．４０（ｍ，１０Ｈ）．
マススペクトル（ＥＳＩ）４５２（Ｍ＋Ｎａ⁺）
【００８０】
実施例３２（３Ｒ）−３−（Ｎ−ベンジルオキシカルボニル）アミノ−１−クロロ−２−オキソ−４−フェニルチオブタン (Ve) の製造
実施例３１により得られた（４Ｒ）−４−（Ｎ−ベンジルオキシカルボニル）アミノ−３−オキソ−５−フェニルチオペンタン酸ｔ−ブチル(IIf)１０８．０４ｇ（純度７９．９％，８６．３３ｇ，２０１．０ｍｍｏｌ）をジクロロメタン３２０ｍｌに溶解し、−３２℃に冷却した。この溶液に塩化スルフリル３４．３８ｇ（２５４．７ｍｍｏｌ）のジクロロメタン２２ｍｌ溶液を−３２℃〜−３１℃に保ちながら１時間２０分かけて滴下した。−３２℃〜−３１℃で１時間２０分攪拌した後、水３００ｍｌを加えて分層した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、さらに飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。ろ過、濃縮し、得られた残渣にギ酸１９２ｍｌを加え５０℃〜５２℃で４時間攪拌した。得られた反応液を濃縮し、イソプロピルアルコール２００ｍｌを加えさらに濃縮した。イソプロピルアルコール４００ｍｌを加え５２℃に加熱して、固体を溶解させた後、５℃まで冷却して、生じた結晶を濾取し、これをイソプロピルアルコール１５０ｍｌで洗浄した。結晶を真空乾燥し、上記表題化合物５１．５ｇ（純度９８．０％，５０．４７ｇ）を得た（収率５９．９％）。１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）
δ：３．３２（ｄｄ，１Ｈ），３．４２（ｄｄ，１Ｈ），４．１３（ｄ，１Ｈ），４．７２（ｄ，１Ｈ），４．７３（ｄｄ，１Ｈ），５．００（ｓ，２Ｈ），５．５７（ｂｒ．ｄ，１Ｈ），７．２２−７．４０（ｍ，１０Ｈ）．
マススペクトル（ＥＳＩ）３６４（ＭＨ⁺）
【００８１】
実施例３３（２Ｓ，３Ｒ）−３−（Ｎ−ベンジルオキシカルボニル）アミノ−１−クロロ−２−ヒドロキシ−４−フェニルチオブタン (VIe) の製造
（３Ｒ）−３−（Ｎ−ベンジルオキシカルボニル）アミノ−１−クロロ−２−オキソ−４−フェニルチオブタン(Ve)５１．５ｇ（純度９８．０％，５０．４７ｇ，１３８．７ｍｍｏｌ）をジクロロメタン３００ｍｌおよびメタノール１８７ｍｌに溶解し、−１０℃に冷却した。これに水素化ほう素ナトリウム３．６４ｇ（９６．２ｍｍｏｌ）を−１１℃〜−９℃に保ちながら１時間かけて添加した。−１２℃〜−９℃で４０分攪拌した後、２Ｎ塩酸４８ｍｌを加え、反応液を濃縮した。濃縮残渣にジクロロメタン５００ｍｌおよび水３００ｍｌを加え分層した後、有機層を飽和食塩水３００ｍｌで洗浄した。無水硫酸ナトリウムで乾燥した後、これをろ過濃縮した。得られた化合物はＨＰＬＣ分析の結果、（２Ｓ，３Ｒ）：（２Ｒ：３Ｒ）＝８３：１７のジアステレオ混合物であった。この混合物に酢酸エチル２００ｍｌおよびヘキサン３００ｍｌを加え、６０℃に加熱して溶解し、５℃まで徐冷した。得られた結晶をろ取し、酢酸エチル／ヘキサン＝１／２の溶液１７０ｍｌで洗浄した。この結晶を真空乾燥し、上記表題化合物３８．７７ｇ（（２Ｓ，３Ｒ）：（２Ｒ，３Ｒ）＝９９．３：０．７）を得た（収率７６．４％）。
１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）
δ：３．２９（ｄ，２Ｈ），３．６０（ｄｄ，１Ｈ），３．６８（ｄｄ，１Ｈ），３．８８−３．９６（ｍ，２Ｈ），５．０７（ｓ，２Ｈ），５．１５（ｂｒ．，２Ｈ），７．１８−７．３９（ｍ，１０Ｈ）．
【００８２】
実施例３４（３Ｓ）−３−（Ｎ−ベンジルオキシカルボニル）アミノ−３−ベンジル−２−オキソ−１−クロロプロパン (Vb) の製造
アルゴン雰囲気下、Ｎ−ベンジルオキシカルボニル−Ｌ−フェニルアラニンｐ−ニトロフェニルエステルエステル(Ig)（１．００ｇ，２．３８ｍｍｏｌ）およびクロロ酢酸トリメチルシリル(IVb)（１．４５ｍｌ，９．３８ｍｍｏｌ）を無水ＴＨＦ（１０ｍｌ）に溶解し、−７０℃に冷却した。この溶液に対し、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（４．５２ｍｌ,９．０４ｍｍｏｌ）を無水ＴＨＦ（４ｍｌ）に溶解したものを約１時間１５分間で温度−７２〜−６５℃に維持しつつ滴下した。滴下後、−７２℃で３時間攪拌した後、１０％クエン酸水溶液（３５ｍｌ）を加えて反応を停止した。混合液を室温に戻し、酢酸エチル（２０ｍｌ）を加えた後、有機層を分離し、水（１０ｍｌ）で２回洗浄した。有機層を無水硫酸マグネシウムで乾燥し、ろ液を濃縮して粗製の表題化合物(Vb)を得た。ＨＰＬＣ分析の結果、この粗製物は表題化合物(Vb)３１６．６ｍｇ（０．９５４ｍｍｏｌ，収率４０．１％）および出発物質であるＮ−ベンジルルオキシカルボニル−Ｌ−フェニルアラニンｐ−ニトロフェニルエステルエステル(Ig)３９８．８ｍｇ（０．９４９ｍｍｏｌ，３９．９％）含有していた。
【００８３】
実施例３５（３Ｓ）−３−（Ｎ−ｔｅｒｔ−ブチルオキシカルボニル）アミノ−３−ベンジル−２−オキソ−１−クロロプロパン (Vf) の製造
アルゴン雰囲気下、Ｎ−ｔｅｒｔ−ブチルオキシカルボニル−Ｌ−フェニルアラニンｐ−ニトロフェニルエステルエステル(Ih)（１．００２ｇ，２．５９４ｍｍｏｌ）およびクロロ酢酸トリメチルシリル(IVb)（２．０４ｍｌ，１２．９６ｍｍｏｌ）を無水ＴＨＦ（１０ｍｌ）に溶解し、−７０℃に冷却した。この溶液に対し、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（６．４７ｍｌ,１２．９５ｍｍｏｌ）を無水ＴＨＦ（９ｍｌ）に溶解したものを約１時間１０分間で温度−７０〜−６８℃に維持しつつ滴下した。滴下後、−７０℃で３時間攪拌した後、１０％クエン酸水溶液（５４ｍｌ）を加えて反応を停止した。混合液を室温に戻し、酢酸エチル（２０ｍｌ）を加え、有機層を分離し、水（１０ｍｌ）で２回洗浄した。有機層を無水硫酸マグネシウムで乾燥し、ろ液を濃縮して粗製の表題化合物(Vf)を得た。ＨＰＬＣ分析の結果、この粗製物は表題化合物(Vf)４１３．５ｍｇ（１．３８９ｍｍｏｌ，収率５３．５％）および出発物質であるＮ−ｔｅｒｔ−ブチルオキシカルボニル−Ｌ−フェニルアラニンｐ−ニトロフェニルエステルエステル(Ih)１６４ｍｇ（０．４２５ｍｍｏｌ，１６．４％）含有していた。
【００８４】
実施例３６（３Ｓ）−３−（Ｎ−ｔｅｒｔ−ブチルオキシカルボニル）アミノ−３−ベンジル−２−オキソ−１−クロロプロパン (Vf) の製造
アルゴン雰囲気下、ＬＤＡのヘプタン、ＴＨＦ、エチルベンゼン溶液（２．０Ｍ）（４．９ｍｌ,９．８ｍｍｏｌ）を無水ＴＨＦ（１０ｍｌ）に溶解し−７５℃に冷却した。この溶液に対し、クロロ酢酸(IVc)（４６３ｍｇ，４．９ｍｍｏｌ）のＴＨＦ（３．５ｍｌ）溶液を約２０分間で温度−７５〜−７０℃に維持しつつ滴下した。滴下後、−７５〜−７０℃で３０分間攪拌した後、さらにこの溶液に対し、Ｎ−ｔｅｒｔ−ブチルオキシカルボニル−Ｌ−フェニルアラニンｐ−ニトロフェニルエステルエステル(Ih)（５００ｍｇ，１．２９ｍｍｏｌ）のＴＨＦ（４ｍｌ）溶液を約１５分間で温度−７５〜−７０℃に維持しつつ滴下した。滴下後、反応液を−７５〜−７０℃で３時間攪拌した後、１０％クエン酸水溶液（２０ｍｌ）を加えて反応を停止した。混合液を室温に戻し、酢酸エチル（２０ｍｌ）を加え、有機層を分離し、飽和炭酸水素ナトリウム水溶液（２０ｍｌ、１０ｍｌ）、飽和食塩水（２０ｍｌ）の順で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、ろ液を濃縮して粗製の表題化合物(Vf)を得た。ＨＰＬＣ分析の結果、この粗製物は表題化合物(Vf)を１８６ｍｇ（０．６２５ｍｍｏｌ）含有していた（収率４８．４％）。
【００８５】
上記製造例および実施例で用いたか、合成した化合物を下記に示す。
【００８６】
【化２０】

【００８７】
【発明の効果】
本発明により、各種ＨＩＶプロテアーゼ阻害剤あるいはある種の酵素阻害剤を始めとする医薬品の中間体として重要なユニットである３−アミノ−１，２−エポキシプロパン類に容易に変換可能な３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体を工業的に短工程で高収率、しかも安全なプロセスで製造することが可能となった。[0001]
BACKGROUND OF THE INVENTION
An equivalent of an α-aminoalcohol derivative that is important as an intermediate for HIV protease inhibitors or certain enzyme inhibitors and can be easily converted to an optically active 3-substituted-3-amino-1,2-epoxypropane derivative The present invention relates to a method for producing a 3-amino-2-oxo-1-halogenopropane derivative.
[0002]
[Prior art]
An α-amino alcohol derivative that can be easily converted from an optically active 3-substituted-3-amino-1,2-epoxypropane derivative is Ro31-8959 (Parkes, K. et al. (Roche), J. Org. Chem., 1994, 59, 3656.), SC-52151 (Getman, DP et al. (Monsanto), J. Med. Chem., 1993, 36, 288.), VX478 ((Vertex) WO9405639), AG1343 ((Lilly) WO9521164 ) And other synthetic intermediates such as HIV protease inhibitors.
[0003]
Several methods for producing 3-amino-1,2-epoxypropane derivatives are known. For example, the 2-position of N-protected 3-amino-2-oxo-1-halogenopropane is stereoselectively reduced. And dehydrohalogenated epoxidation after being led to alcohol (Getman, DP et al., J. Med. Chem., 1993, 36, 288., etc.), N-protected 3-amino-1 -Oxidative asymmetric epoxidation of propene (Lury, JR, et al., J. Org. Chem., 1987, 52, 1487., etc.), N-protected 3-amino-1-propanal There is a method of inserting methylene (Seale, GD, WO93 / 23388. Etc.).
[0004]
In the first method, it is important how N-protected 3-amino-2-oxo-1-halogenopropane, which is a key intermediate, or an equivalent thereof can be produced industrially at low cost. In the conventional method, diazomethane which is extremely explosive and highly toxic must be used as an auxiliary raw material, so there is a limit in the industrialization of these methods (for example, Getman, DP et al., J. Med. Chem). , 1993, 36, 288., Okada, Y et al., Chem. Pharm. Bull., 1988, 36, 4794., EP 346867. Raddazz, P et al., J. Med. Chem., 1991, 34, 3267.). In addition, there is a method in which a halomethyl anion is allowed to act on an N-protected amino acid ester. However, the use of a very unstable halomethyl anion and the introduction of a halogen at the 1-position are based on general knowledge about chemistry. There was a limit to the industrialization of this method because it could be limited to chlorine or fluorine (Barluenga et al., J. Chem. Soc., Chem. Commun., 1994). Furthermore, as an existing technique related to the present case, there can be mentioned a method (EP442754) in which a fluoromalonic acid half ester is reacted and decarboxylated after activating the C-terminus of an N-protected amino acid. It is limited to a special element called fluorine, and cannot be applied to a system for achieving this purpose such as chlorine and bromine.
The second method uses a Wittig reaction of an expensive aldehyde (3-amino-1-propanal) to produce N-protected 3-amino-1-propene, which is a key intermediate. It becomes a high-cost manufacturing method. Furthermore, in the third method, not only is the production method of the N-protected aldehyde, which is the same intermediate as described above, expensive, but also it is necessary to generate carbene at a low temperature in the methylene insertion reaction, which is industrially suitable. It is not a manufacturing method.
[0005]
[Problems to be solved by the invention]
An object of the present invention is to provide an industrial production method of a 3-amino-2-oxo-1-halogenopropane derivative that can be easily converted into a 3-amino-1,2-epoxypropane derivative.
[0006]
[Means for Solving the Problems]
As a result of investigations to solve the above-mentioned problems, the present inventors have obtained a high yield from 3-amino-2-oxo-1-halogenopropane corresponding to the 3-amino-1,2-epoxypropane derivative or its equivalent. Is a precursor of theΑThe inventors have found halogeno-β-ketoester derivatives and production methods thereof, and have completed the present invention.
[0007]
That is, the present invention relates to a compound represented by the following general formula (I):
[0008]
[Chemical Formula 10]

[0009]
(In the formula, Rs is hydrogen, an alkyl group having 1 to 10 carbon atoms which may have a substituent, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, or a carbon skeleton thereof. Substituents containing heteroatoms in the P₁, P₂Are independently of each other hydrogen or amino protecting groups, or P₁And P₂Together form a bifunctional amino protecting group, E₁ IsRuboxyTerminalAs an alkoxy ester residue having 1 to 10 carbon atoms, an active ester residue of a phenoxy group or benzyloxy group, N-oxysuccinimide or 1-oxybenzotriazole, each optionally having a substituent on the ring Represents an active thioester residue, an imidazolyl group, an acid halide, an acid anhydride, or a residue that can form an acid azide. )
[0010]
A compound represented by the following general formula (II) is obtained by reacting an alkali metal enolate of an ester of acetic acid,
[0011]
Embedded image

[0012]
(R in the formula_S, P₁, P₂, Has the meaning described above and R₁Is an optionally substituted alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms, aralkyl group having 7 to 20 carbon atoms, trialkylsilyl group having 4 to 10 carbon atoms, carbon number It represents an 8-10 phenyldialkylsilyl group or a C13-15 diphenylalkylsilyl group. )
[0013]
A halogenated reagent is allowed to act on this to produce a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative represented by the following general formula (III) by halogenating the 2-position,
[0014]
Embedded image

[0015]
(Rs in the formula, P₁, P₂, R₁Has the above-mentioned meaning. )
[0016]
Alternatively, the alkali metal enolate or dianion of the compound represented by the following general formula (IV) is reacted with the general formula (I).
[0017]
Embedded image

[0018]
(R in the formula₂Is hydrogen, an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a trialkylsilyl group having 3 to 10 carbon atoms, A phenyl dialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms is represented. X has the above-mentioned meaning. )
[0019]
A 4-amino-3-oxo-2-halogenobutanoic acid ester or salt derivative represented by the following general formula (III ′):
[0020]
Embedded image

[0021]
(Rs in the formula, P₁, P₂Has the meaning described above,
R_ThreeIs an alkali metal, an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or a trialkylsilyl group having 3 to 10 carbon atoms. Represents a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms. X has the above-mentioned meaning. )
[0022]
The 3-amino-2-oxo-1-halogenopropane derivative represented by the following general formula (V) is characterized in that the obtained (III) or (III ′) is hydrolyzed and decarboxylated. Or a method for producing the salt thereof,
[0023]
Embedded image

[0024]
(Rs in the formula, P₁, P₂, X has the meaning described above. )
[0025]
DETAILED DESCRIPTION OF THE INVENTION
Formula used in the present invention (I) The compound represented by is a kind of protected amino acid in which the amino group of a natural or non-natural α-amino acid is protected by a protecting group and the carboxyl group is converted to a functional group capable of reacting with a nucleophilic reagent.
[0026]
NaThe compound represented by the formula (I) has optical activity due to the stereo of the carbon atom at the base of the amino group.For example, by selecting an optically active amino acid as a starting material, it is easy to synthesize a target compound having optical activity. Applicable.
[0027]
In the formula (I), Rs represents hydrogen or an ordinary alkyl, aryl, aralkyl, or other substituent. For example, a methyl group is an alanine skeleton, and a benzyl group is a compound having a phenylalanine skeleton. P₁, P₂Represents a commonly used amino protecting group, P₁Or P₂Either of them may be a hydrogen atom, and P₁And P₂May be an integral bifunctional amino protecting group. Examples include benzyloxycarbonyl, tertiary butoxycarbonyl, acetyl, formyl, benzoyl, dibenzyl, phthaloyl and the like, and an ester group (R₁It may be determined in consideration of the functional group selectivity in hydrolysis and decarboxylation. E₁Represents a carboxyl-terminated functional group capable of reacting with a nucleophilic reagent, and includes residues such as lower esters, active esters, acid halides, and acid anhydrides. Examples include methoxy, ethoxy, benzoxy and substituted benzoxy, phenoxy and substituted phenoxy, N-oxysuccinimide, 1-oxybenzotriazole, imidazolyl, chlorine, bromine, methoxycarboxy, isobutoxycarboxy, tertiary butylcarboxy and the like.
Specific examples of the compound represented by the formula (I) include N-benzyloxycarbonyl-L-phenylalanine methyl ester, N-benzyloxycarbonyl-L-phenylalanine-N-oxysuccinimide ester, N, N -Dibenzyl-L-phenylalanine p-nitrophenyl ester, N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester, and the like.
[0028]
In the compound represented by the formula (I), the amino group of a natural or non-natural α-amino acid is protected by a method usually used in peptide synthesis, and then the carboxyl group is esterified by a method commonly used in peptide synthesis. Alternatively, it can be obtained by halogenation.
[0029]
Conversion from formula (I) to formula (II) is a reaction in which an ester, acid halide or acid anhydride represented by formula (I) is reacted with an acetate enolate derived from acetate to produce a β-keto ester. It is. As the acetate ester enolate, an alkali metal salt is used, and a lithium salt is most preferable. These enolates are prepared by adding acetate to a solution of a base such as lithium amide, lithium diisopropylamide, lithium tert-butoxide and the like. The ester of acetate represents a commonly used ester of carboxylic acid, for example, alkyl ester, aralkyl ester, silyl ester, etc., specifically, hydrolyzable methyl, ethyl, tertiary butyl, benzyl, triethylsilyl, etc. Any ester group can be used.
Acetic acid enolate is required to be 1 equivalent or more relative to substrate (I). However, since 1 equivalent of base is used for enolate formation of the product β-keto ester, usually 2 equivalents or more of acetate enolate is used. The reaction proceeds in good yield.
This reaction proceeds promptly at temperatures from minus 100 degrees to room temperature. The optimum temperature varies depending on the compound, but as a typical example, the reaction is completed at about minus 75 to minus 30 degrees for 5 to 60 minutes. As the reaction solvent, hydrocarbon, ether or the like is used, and tetrahydrofuran, hexane, toluene and a mixed solvent thereof are exemplified. The reaction concentration is not particularly limited, and may be determined according to the solubility of the reactant.
After completion of the reaction, the reaction solution is treated with an acid to protonate the alkyl metal salt of the product to give a β-ketoester represented by the general formula (II). The compound can be easily purified by silica gel chromatography, but can also be used as a raw material for the next reaction in an unpurified state.
[0030]
The conversion from formula (II) to formula (III) is represented by formula (III) by oxidatively halogenating the active methylene hydrogen of the β-ketoester represented by formula (II) with various halogenating agents. This is a reaction for obtaining a 4-amino-3-oxo-2-halogenotanate derivative. The reaction proceeds easily in a good yield simply by mixing the β-ketoester and the halogenating agent in a solvent.
As the halogenating agent, in the case of bromination, examples include N-bromosuccinimide, copper (II) bromide, bromine and the like. In the case of chlorination, examples include N-chlorosuccinimide, Copper (II) chloride, sulfuryl chloride, chlorine or the like may be used. The halogenating agent is required to have a theoretical equivalent or more with respect to the β-ketoester (II), but the best yield is often obtained by setting it to just the theoretical equivalent for the purpose of preventing the side reaction from proceeding. The theoretical equivalent here means an amount required in the chemical equation, for example, 1 equivalent to β-ketoester in the case of N-bromosuccinimide, and 2 equivalent in the case of copper (II) bromide.
The conditions for this reaction are strongly dependent on the structure of the reactants and the reagents and must be determined for each compound. As a typical example, Rs is benzyl, P₁Is benzyloxycarbonyl, P₂Is hydrogen, R₁When t-butyl is used and N-bromosuccinimide is used as a reaction reagent, the reaction is completed at minus 20 degrees to room temperature for 10 to 60 minutes. As the reaction solvent, in addition to halogen solvents such as methylene chloride and chloroform, ethyl acetate, ether, and toluene can also be used. The reaction concentration is not particularly limited, and may be determined according to the solubility of the reactant.
Although it can be purified by means such as recrystallization as required, the reaction product can be used as a raw material for the next reaction without purification. In addition, diastereomers are generated by the selectivity in the course of halogenation, and these can be separated by thin layer chromatography or silica gel column, but the separation is not required for the purpose of this production process.
[0031]
On the other hand, a compound represented by the formula (III), a trimethylsilyl ester thereof, and a carboxylate salt thereof, that is, a compound represented by the formula (III ′) is a compound represented by the formula (I), which is a halogenoacetate enolate or halogenoacetate. It can also be converted by reacting a dianion. That is, as described above, in synthesizing the compound represented by the formula (III ′), chloroacetic acid esters or bromoacetic acid esters (VI ) Can be used to obtain the desired compound in one step.
In addition, in this reaction, when an enolate prepared from trimethylsilyl halogenoacetate or a dianion prepared from halogenoacetic acid is reacted, the compound represented by the formula (III ′) (R_ThreeIs trimethylsilyl or an alkali metal), when treated with an acid, it easily proceeds to decarboxylation, and a compound represented by the formula (V) can be obtained in one step.
The halogenoacetate enolate can be synthesized according to the method of adjusting the enolate in the method via the general formula (II), and the conditions for reacting this enolate with the general formula (I) are the same as those described above. is there.
However, since the stability of the enolate of the halogenoacetate is inferior to that of the acetate, it is necessary to perform the reaction at a low temperature of minus 60 degrees or less.
[0032]
Whether to convert directly from the compound represented by formula (I) or via formula (II) in the synthesis of the compound represented by formula (III) or (III ′) is represented by formula (I) Since the yield varies depending on the substituent or protecting group of the compound, it may be selected appropriately.
[0033]
The compound represented by the formula (III) or the formula (III ′) is novel and is an important intermediate in the present invention. Also, the structure of this compound is interpreted to include the corresponding enol form as a tautomer. For example, the tautomer includes a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative represented by the following general formula (VIII).
[0034]
Embedded image

[0035]
(Rs in the formula, P₁, P₂, R₁, R_Three, X has the meaning described above. )
[0036]
The conversion from the compound represented by the formula (III) or the formula (III ′) to the formula (V) is performed by converting a 4-amino-3-oxo-2-halogenobutanoic acid ester represented by the formula (III) or the formula (III ′). This is done by hydrolyzing the derivative and simultaneously decarboxylating.
As the method of hydrolysis, any method usually used in organic chemistry may be used. Alkaline hydrolysis of lower alkyl ester, acid hydrolysis of tertiary alkyl ester, catalytic hydrogenation of benzyl ester, weak acidity of silyl ester to medium Hydrolysis by nature can be applied. However, it is necessary for the halogen introduced by these hydrolysis conditions to be unaffected, and the optimum conditions vary depending on the structure of the compound, but in many cases, a tertiary alkyl ester or silyl ester system shows good results.
The target product can be extracted and isolated from the reaction solution into an organic solvent, and can be purified by means such as silica gel chromatography and recrystallization as necessary.
A typical example of the reaction conditions is R₁When t is butyl, the reaction is completed in a formic acid solution at room temperature for several hours to several tens of hours, but the reaction time can be shortened from several minutes to about one hour by raising the reaction temperature. The reaction concentration is not particularly limited, and may be determined according to the solubility of the reactant.
[0037]
The 3-amino-2-oxo-1-halogenopropane derivative represented by the formula (V) obtained by these methods is shown in the literature (for example, Getman, DP et al., J. Med. Chem. 1993, 36, 288., Okada, Y et al., Chem. Pharm. Bull., 1988, 36, 4794., EP 346867. Raddazz, P et al., J. Med. Chem., 1991, 34, 3267.) HIV protease. It is a known compound useful as an intermediate of an inhibitor, and is known to be derived into a more advanced intermediate through, for example, the following two-step existing reaction. (Getman, DP, et al., J. Med. Chem., 1993, 36, 288, etc.)
That is, the 3-amino-2-oxo-1-halogenopropane derivative represented by the formula (V) has a halogenomethyl ketone skeleton and is led to a halohydrin represented by the following general formula (VI) by a reduction reaction of the carbonyl group.
[0038]
Embedded image

[0039]
(Rs in the formula, P₁, P₂, X has the meaning described above. )
Furthermore, it can be easily epoxidized under alkaline conditions and derived into a compound represented by the following general formula (VII).
[0040]
Embedded image

[0041]
(Rs in the formula, P₁, P₂Has the above-mentioned meaning. )
[0042]
In the reduction reaction of the carbonyl group, it is possible to perform a stereoselective reduction with respect to the stereo bond of the substituent represented by Rs at the 3-position, for example, as represented by sodium borohydride. This can also be achieved by using a normal reducing agent. For example, Rs is a benzyl group, the 3-position stereo is S-form, and the hydroxyl group is 2: 1 to 20: 3 by reducing a compound in which a urethane type protective group is selected as an amino protecting group with sodium borohydride. The S form is preferentially given at a ratio of about 1, and further purification by recrystallization is possible. The resulting alcohol leads to the (2S, 3S) epoxy compound, which is an important compound as an intermediate for HIV protease inhibitors.
[0043]
The flow from the raw material compound (I) of the present invention to the target compound (V) and the epoxy compound part (VII) is shown below.
[0044]
Embedded image

[0045]
(Rs in the formula, R₁, E₁, X, P₁, P₂Has the above-mentioned meaning. )
[0046]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these from the first. Temperatures are given in degrees Celsius unless otherwise noted. Proton nuclear magnetic resonance (NMR) spectra were recorded on a Varian 300 MHz spectrometer; chemical shifts (δ) are given in ppm. Abbreviations used in the examples include Boc: tertiary butoxycarbonyl; Z: benzyloxycarbonyl; THF: tetrahydrofuran; LDA: lithium diisopropylamide; NCS: N-chlorosuccinimide; NBS: N-bromosuccinimide. To do.
[0047]
Production Example 1N, N-dibenzyl-L-phenylalanine benzyl ester (Ia) Manufacturing of
25.0 g (151.3 mmol) of (L) -phenylalanine and 66.67 g (482.4 mmol) of potassium carbonate were dissolved in 100 ml of water, and then 57.51 g (454.3 mmol) of benzyl chloride was added at 95 ° C. The mixture was heated and stirred for 19 hours. After cooling to room temperature, 67 ml of n-heptane and 50 ml of water were added to separate the layers. The organic layer was washed twice with 50 ml of methanol / water = 1/2 solution and then dried over anhydrous sodium sulfate. This was filtered and concentrated to obtain 61.64 g (90%, 121.8 mmol) of the title compound (Ia) (yield 84.7%).
1H-NMR (300 MHz, CDCl3) δ: 3.00 (dd, 1H), 3.14 (dd, 1H), 3.53 (d, 2H), 3.71 (t, 1H), 3.92 (d, 2H), 5.12 (d, 1H ), 5.23 (d, 1H), 6.99-7.40 (m, 20H).
Mass spectrum (FAB) 436 (MH +)
[0048]
Production Example 2N, N-dibenzyl-L-phenylalanine paranitrophenyl ester (Ib) Manufacturing of
N, N-Dibenzyl-L-phenylalanine hydrochloride (7.64 g, 20.0 mmol) was added to chloroform (50 ml), and 10% aqueous ammonia (20.0 ml) was added dropwise to the suspension for neutralization. The organic layer was separated, washed with water (20 ml), dried over magnesium sulfate and filtered. The residue obtained by concentrating the filtrate was dissolved in chloroform (50 ml). Under ice cooling, paranitrophenol (2.89 g, 20.4 mmol) and N, N′-dicyclohexylcarbodiimide (4.13 g, 20. 0 mmol) was sequentially added and allowed to react overnight. Ethyl acetate (30 ml) was added to the reaction solution, the precipitated N, N′-dicyclohexylurea was filtered, and the filtrate was washed with a 10% aqueous potassium carbonate solution. The residue obtained by separating and concentrating the organic layer was dissolved again in ethyl acetate (30 ml), and the precipitated insoluble matter was filtered. The crude product obtained by concentrating the filtrate was purified by silica gel column chromatography to obtain the title compound (Ib) (7.77 g, 16.65 mmol).
1HNMR (300MHz, CDCl3) δ: 3.13 (dd, J = 7.4, 13.7Hz, 1H), 3.26 (dd, J = 8.2, 13.9Hz, 1H), 3.72 (d, J = 14.0Hz, 2H), 3.96 ( dd, J = 7.4,8.2Hz, 1H), 4.06 (d, J = 14.0Hz, 2H), 7.14 (d, J = 9.2Hz, 2H), 7.06-7.37 (m, 15H), 8.26 (d, J = 9.3Hz, 2H)
Mass spectrum (FAB) 467 (MH +)
[0049]
Example 1(4S) -4- (N, N-dibenzylamino) -4-benzyl-3-oxobutanoic acid t-butyl ester ( IIa )Manufacturing of
Under an argon atmosphere, a solution of LDA in heptane, THF, and ethylbenzene (2.0 M) (24 ml, 48 mmol) was dissolved in anhydrous THF (64 ml) and cooled to −53 ° C. To this solution, a solution of tert-butyl acetate (5.8 g, 50 mmol) in THF (12 ml) was added dropwise over about 15 minutes while maintaining the temperature at −45 to −50 ° C. After dropwise addition, the mixture was stirred at −53 ° C. for 1 hour, and further, a THF (8 ml) solution of N, N-dibenzyl-L-phenylalanine benzyl ester (Ia) (purity 90%, 7.2 g, 15 mmol) was added to this solution. Was added dropwise over about 15 minutes while maintaining the temperature at -48 to -52 ° C. After the dropwise addition, the reaction solution was heated to −5 ° C., and after 3 hours, a solution of citric acid (16.5 g) in water (50 ml) was added to the reaction solution to stop the reaction. Extracted twice with ethyl acetate (100 ml, 50 ml), and the organic layer was made of 10% citric acid (20 ml), saturated brine (10 ml), 5% aqueous sodium hydrogen carbonate solution (20 ml × 4), and saturated brine (10 ml). Washed in order. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated. The concentrated solution was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4/1) to obtain the title compound (IIa) (6.09 g, 13.7 mmol).
1HNMR (300MHz, CDCl3) δ: 1.25 (s, 9H), 2.93 (dd, J = 3.9, 13.5Hz, 1H), 3.20 (dd, J = 9.0, 13.5, Hz, 1H), 3.40 (d, J = 15.6Hz, 2H), 3.55 (m, 2H), 3.62 (dd, J = 3.9,9.0Hz, 1H), 3.82 (d, J = 13.5Hz, 2H), 7.107.38 (m, 15H)
Mass spectrum (FAB) 444 (MH +)
[0050]
Example 2(4S) -4- (N-Benzyloxycarbonylamino) -4-benzyl-3-oxobutanoic acid t-butyl ester (IIb) Manufacturing of
Under an argon atmosphere, LDA in heptane, THF, and an ethylbenzene solution (2.0 M) (14 ml, 28 mmol) were dissolved in anhydrous THF (30 ml) and cooled to −45 ° C. To this solution, a solution of tert-butyl acetate (3.7 g, 32 mmol) in THF (4 ml) was added dropwise over about 15 minutes while maintaining the temperature at −40 to −45 ° C. After dropping, the mixture was stirred at −50 ° C. for 30 minutes, and then a solution of N-benzyloxycarbonyl-L-phenylalanine methyl ester (Ic) (2.5 g, 8 mmol) in THF (4 ml) was further added to this solution for about 10 minutes. The solution was added dropwise while maintaining the temperature at -40 to -45 ° C. After dropping, the reaction solution was stirred at −40 ° C. for 30 minutes, then warmed to 0 ° C. and stirred for 20 minutes. A 20% aqueous citric acid solution (40 ml) was added to the reaction solution to stop the reaction. Extraction was performed with ethyl acetate (50 ml × 2), and the organic layer was washed with water (5 ml), 5% aqueous sodium hydrogen carbonate solution (20 ml) and water (10 ml) in this order. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated. The concentrated solution was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4/1) to obtain the title compound (IIb) (3.08 g, 7.77 mmol).
1HNMR (300MHz, CDCl3) δ: 1.44 (s, 9H), 2.99 (dd, J = 7.1, 14.1Hz, 1H), 3.17 (dd, J = 6.1, 14.1Hz, 1H), 3.38 (m, 2H), 4.68 (bq, J = approx.7,1H), 5.07 (s, 2H), 5.38 (bd, J = 7.9Hz, 1H), 7.12-7.35 (m, 10H)
13C NMR (75MHz, CDCl3) δ: 28.0,37.1,48.2,60.7,67.0,82.4,127.1,128.1,128.2,128.5,128.7,129.2,135.8,137.9,165.8,182.0,201.7
Mass spectrum (FAB) 398 (MH +)
[0051]
Example 3(4S) -4- (N-Benzyloxycarbonylamino) -4-benzyl-3-oxobutanoic acid ethyl ester (IIc) Manufacturing of
Under an argon atmosphere, a solution of LDA in heptane, THF, and ethylbenzene (2.0 M) (4 ml, 8 mmol) was dissolved in anhydrous THF (8 ml) and cooled to −50 ° C. To this solution, a solution of ethyl acetate (740 mg, 8 mmol) in THF (2 ml) was added dropwise over about 5 minutes while maintaining the temperature at −50 to −45 ° C. After dropping, the mixture was stirred at −50 ° C. for 30 minutes, and then a solution of N-benzyloxycarbonyl-L-phenylalanine methyl ester (Ic) (626 mg, 2 mmol) in THF (2 ml) was further added to the solution in about 5 minutes. The solution was added dropwise while maintaining at -50 to -45 ° C. After dropping, the reaction solution was stirred at −50 ° C. for 30 minutes, then warmed to room temperature and stirred for 5 minutes. A 10% aqueous citric acid solution (10 ml) was added to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the organic layer was passed through a silica gel column and then concentrated to obtain the crude title compound (IIc) (826 mg) as an oil.
1HNMR (300MHz, CDCl3) δ: 1.22-1.30 (m, 3H), 2.92-3.05 (m, 1H), 3.05-3.22 (m, 1H), 3.40-3.54 (m, 2H), 4.10-4.19 (m, 2H), 4.66 (m, 1H), 5.07 (bs, 2H), 5.55 (bd, J = 7.8Hz, 1H), 7.11-7.38 (m, 10H)
[0052]
Example 4(4S) -4- (Nt-butoxycarbonylamino) -4-benzyl-3-oxobutanoic acid t-butyl ester (IId) Manufacturing of
Under an argon atmosphere, a solution of LDA in heptane, THF, and ethylbenzene (2.0 M) (27 ml, 54 mmol) was dissolved in anhydrous THF (50 ml) and cooled to −45 ° C. To this solution, a solution of tert-butyl acetate (7.0 g, 60 mmol) in THF (5 ml) was added dropwise over about 20 minutes while maintaining the temperature at −40 to −45 ° C. After dropping, the mixture was stirred at −50 ° C. for 30 minutes, and then a solution of N-butoxycarbonyl-L-phenylalanine methyl ester (Id) (4.18 g, 15 mmol) in THF (5 ml) was added to the solution in about 20 minutes. The solution was added dropwise while maintaining the temperature at -40 to -45 ° C. After dropping, the reaction solution was stirred at −50 ° C. for 30 minutes, and then 25% aqueous citric acid solution (40 ml) was added to the reaction solution to stop the reaction. The organic solvent in the reaction solution was distilled off under reduced pressure, followed by extraction with ethyl acetate (100 ml), and the organic layer was washed with water (20 ml). The organic layer was concentrated and passed through a silica gel column (n-hexane: ethyl acetate = 4/1) to obtain crystals (5.92 g). As a result of NMR analysis, it was the title compound (IId) containing 15% of unreacted raw material (Id).
1HNMR (300MHz, CDCl3) δ: 1.39 (s, 9H), 1.46 (s, 9H), 2.96 (dd, J = 7.4, 14.0Hz, 1H), 3.16 (dd, J = 5.7, 14.0Hz, 1H), 3.34-3.45 (m, 2H), 4.57 (bq, J = approx.6.Hz, 1H), 5.09 (bd, J = 7.7Hz, 1H), 7.11-7.30 (m, 5H)
13C NMR (75MHz, CDCl3) δ: 27.8, 28.2, 36.9, 48.0, 60.4, 80.0, 82.0, 126.9, 128.4, 129.2, 136.2, 155.1, 166.0, 202.2
[0053]
Example 5(4S) -4- (N, N-dibenzylamino) -4-benzyl-3-oxo-2-bromobutanoic acid t-butyl ester (IIIa) Manufacturing of
(1) Finely ground copper (II) bromide (0.45 g, 2.0 mmol) was dissolved in ethyl acetate (2 ml). While stirring at 25 ° C., a solution in which (IIa) (0.44 g, 1.0 mmol) obtained in Example 1 and triethylamine (0.14 ml, 1.0 mmol) were dissolved in ethyl acetate (2 ml) was added all at once. After reacting at 25 ° C. for 36 hours under an argon atmosphere, 5% aqueous citric acid solution (5 ml) was added, and the organic layer was separated. The organic layer was concentrated to give brown crystals as the isomer mixture (0.45 g, 0.86 mmol) of the title compound (IIIa).
1HNMR (300MHz, CDCl3) (isomer mixture) δ: 0.90 (s, 9 / 2H), 1.44 (s, 9 / 2H), 2.99 (dd, J = 3.7,13.5Hz, 1H), 3.14-3.29 (m , 1H), 3.50 (dd, J = 5.6,13.3,2H), 3.83 (dd, 10.3,13.3,2H), 3.82 (dd, 1 / 2H), 4.03 (dd, 3.7,9.5,1 / 2H), 5.42 (s, 1 / 2H), 5.51 (s, 1 / 2H), 7.14-7.34 (m, 15H)
Mass spectrum (ESI) 522.3, 524.3 (MH +)
(2) (IIa) (0.89 g, 2.0 mmol) obtained in Example 1 was dissolved in diethyl ether (10 ml). NBS (0.39 g, 2.0 mmol) was added while stirring under ice cooling, and the mixture was further stirred for 2 hours. After further reaction at room temperature for 13 hours, water (5 ml) was added and the organic layer was separated. The organic layer was concentrated to obtain brown crystals (1.23 g). As a result of NMR analysis, about 35% of the starting material (IIa) remained, and the main product was an isomer mixture of the title compound (IIIa).
[0054]
Example 6(4S) -4- (N-Benzyloxycarbonylamino) -4-benzyl-3-oxo-2-chlorobutanoic acid t-butyl ester (IIIb) Manufacturing of
(IIb) (0.8 g, 2.0 mmol) obtained in Example 2 was dissolved in chloroform (5 ml). NCS (264 mg, 1.98 mmol) was added while stirring under ice cooling, and the mixture was stirred under ice cooling for 3 hours. Water (2 ml) was added to the reaction solution, and the organic layer was separated. The organic layer was concentrated to obtain crystals (912 mg). A part of this crystal (100 mg) was developed by silica gel thin layer chromatography (n-hexane: ethyl acetate = 4/1) and fractionated to obtain the title compound (IIIb) as an isomer mixture (40 mg).
1HNMR (300MHz, CDCl3) (mixture of isomers) δ: 1.45-1.48 (m, 9H), 2.95-3.05 (m, 1H), 3.18-3.38 (m, 1H), 4.85-5.10 (m, 4H), 5.20 -5.35 (m, 1H), 7.14-7.35 (m, 10H)
[0055]
Example 7(4S) -4- (N-Benzyloxycarbonylamino) -4-benzyl-3-oxo-2-bromobutanoic acid t-butyl ester (IIIc) Manufacturing of
(IIb) (0.8 g, 2.0 mmol) obtained in Example 2 was dissolved in chloroform (5 ml). NBS (338 mg, 1.9 mmol) was added while stirring under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Water (3 ml) was added to the reaction solution, and the organic layer was separated. The organic layer was concentrated to obtain pale brown crystals as a crude isomer mixture (921 mg) of the title compound (IIIc).
1HNMR (300MHz, CDCl3) (isomer mixture) δ: 1.43-1.50 (m, 9H), 3.00 (dd, J = 7.4, 14.1Hz, 1H), 3.21 (dd, J = 5.7, 14.1Hz, 1H), 4.82-5.03 (m, 1H), 4.89 (bs, 1H), 5.07 (bs, 2H), 5.20 (bd, J = 6.0Hz, 1H), 7.17-7.35 (m, 10H)
Mass spectrum (FAB) 476,478 (MH +)
[0056]
Example 8(3S) -3- (N, N-dibenzylamino) -3-benzyl-2-oxo-1-bromopropane (Va) Manufacturing of
(IIIa) (41 mg, 0.078 mmol) obtained in Example 5 was dissolved in 4N-hydrogen chloride (ethyl acetate solution, 1 ml). The reaction was stirred for 13 hours at room temperature. Ethyl acetate (3 ml) was added to the reaction solution, and neutralized with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was concentrated to obtain crude (Va) (30 mg).
1HNMR (300MHz, CDCl3) δ: 3.00 (dd, J = 3.9, 13.5Hz, 1H), 3.25 (dd, J = 9.0, 13.5, Hz, 1H), 3.55 (d, J = 15.6Hz, 2H), 3.67 (dd, J = 3.9,9.0Hz, 1H), 3.84 (d, J = 15.6Hz, 2H), 4.42 (s, 1H), 4.48 (s, 1H), 7.10-7.38 (m, 15H)
[0057]
Example 9(3S) -3- (N-benzyloxycarbonylamino) -3-benzyl-2-oxo-1-chloropropane (Vb) Manufacturing of
(IIb) (35 g, 88 mmol) obtained in Example 2 was dissolved in methylene chloride (88 ml). Sulfuryl chloride (7.23 ml, 90 mmol) was added while stirring under ice-cooling, followed by stirring for 1 hour under ice-cooling, and further stirring at room temperature for 30 minutes. The reaction solution was concentrated to obtain crude (IIIb) (37 g) as crystals. 35 g of these crystals were suspended in formic acid (purity 90%, 80 ml), heated at 80 ° C. with stirring and reacted for 30 minutes. The reaction solution was cooled and formic acid was distilled off under reduced pressure to obtain (Vb) crystals. Further, the crystals were recrystallized from isopropanol (200 ml), and the crystals were dried to obtain the title compound (Vb) (19.55 g).
1H-NMR (300MHz, CDCl3) δ: 3.05 (dd, J = 7.2, 14.0Hz, 1H), 3.25 (dd, J = 7.1, 14.0, Hz, 1H), 3.97 (d, J = 16.2Hz, 1H) , 4.14 (d, J = 16.2Hz, 1H), 4.77 (q, J = 4.77Hz, 2H), 5.08 (s, 2H), 5.29 (d, J = 7.2Hz, 1H), 7.12-7.35 (m, 10H)
13C-NMR (75MHz, CDCl3) δ: 37.8, 47.4, 58.7, 67.3, 127.5, 128.1, 128.3, 128.6, 129.0, 129.1, 135.2, 135.9, 155.7, 201.0
[0058]
Example 10(3S) -3- (N-benzyloxycarbonylamino) -3-benzyl-2-oxo-1-bromopropane (Vc) Manufacturing of
(1) (IIIc) (56 mg, 0.12 mmol) obtained in Example 7 was dissolved in methylene chloride (1 ml), trifluoroacetic acid (0.3 ml) was added, and the mixture was stirred at 60 ° C. for 17 hours to be reacted. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was concentrated, developed with silica gel thin layer chromatography (n-hexane: ethyl acetate = 4/1) and fractionated to obtain the title compound (Vc) (20 mg).
1HNMR (300MHz, CDCl3) δ: 3.06 (dd, J = 7.2, 13.9Hz, 1H), 3.09 (dd, J = 6.9, 13.9Hz, 1H), 3.81 (d, J = 13.7Hz, 1H), 3.93 ( d, J = 13.7Hz, 1H), 4.82 (bq, J = 7.3Hz, 1H), 4.89 (bs, 1H), 5.08 (bs, 2H), 5.34 (bd, J = 7.2Hz, 1H), 7.13- 7.39 (m, 10H)
13C NMR (75MHz, CDCl3) δ: 33.1, 37.7, 58.8, 67.2, 127.3, 128.0, 128.3, 128.5, 128.9, 129.1, 135.5, 136.0, 155.8, 200.4
Mass spectrum (ESI) 376 (MH +)
(2) (IIIc) (360 mg, 0.756 mmol) was dissolved in formic acid (2 ml) and stirred at 25 ° C. for 15 hours for reaction. After depressurizingly distilling the deuterated acid, the concentrate was neutralized with 5% aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was concentrated to obtain crude Vc (296 mg) as crystals. Further, this crystal was developed and separated by silica gel thin layer chromatography (n-hexane: ethyl acetate = 4/1) to obtain a purified title compound (Vc) crystal (149 mg).
[0059]
Example 11(3S) -3- (N-benzyloxycarbonylamino) -3-benzyl-2-hydroxy-1-chloropropane (VIb) Manufacturing of
(Vb) (136 mg, 0.4 mmol) obtained in Example 9 was dissolved in methanol (1.5 ml). To this solution, sodium borohydride (17 mg, 0.44 mmol) was added at 0 ° C., and the mixture was further stirred at 0 ° C. for 2 hours to be reacted. After 1N hydrochloric acid was added to the reaction solution to stop the reaction, methanol was distilled off under reduced pressure. Ethyl acetate was added to this solution for extraction, and the organic layer was concentrated to give a mixture of the title compounds (2S, 3S)-(VIb) and (2R, 3S)-(VIb) (74: 26,138 mg) as pale yellow crystals. Got as.
1HNMR (300 MHz, CDCl3) (diastereomeric mixture) δ: 2.93 (dd, J = 8.4, 14.0 Hz, 1H), 3.00 (dd, J = 4.9, 14.0 Hz, 1H), 3.50-3.60 (m, 1H) , 3.65 (dd, J = 4.2,12.0Hz, 1H), 3.81-3.89 (m, 1H), 3.92-4.03 (m, 1H), 4.87 (bd, J = approx.8Hz, 1H), 5.03 (bs, 2H), 7.17-7.37 (m, 10H)
[0060]
Example 12(3S) -3- (N-benzyloxycarbonylamino) -3-benzyl-2-hydroxy-1-bromopropane (VIc) Manufacturing of
(Vc) (142 mg, 0.37 mmol) obtained in Example 10 was dissolved in a mixed solvent of methanol (3 ml) and THF (1 ml). To this solution, sodium borohydride (16 mg, 0.41 mmol) was added at 0 ° C., and the mixture was further stirred at 0-5 ° C. for 2 hours to be reacted. 1N Hydrochloric acid (2 ml) was added to the reaction solution to stop the reaction, and methanol and THF were distilled off under reduced pressure. Ethyl acetate was added to the resulting slurry for extraction, and the organic layer was concentrated to give a mixture of the title compound (2S, 3S)-(VIc) and (2R, 3S)-(VIc) (84: 16,164 mg). Obtained as pale yellow crystals.
1HNMR (300 MHz, CDCl3) (diastereomeric mixture) δ: 2.90 (dd, J = 9.7, 14.0 Hz, 1H), 2.99 (dd, J = 4.7, 14.0 Hz, 1H), 3.38-3.47 (m, 1H) , 3.53 (dd, J = 3.6,10.6Hz, 1H), 3.81-3.90 (m, 1H), 3.93-4.03 (m, 1H), 4.86 (bd, J = approx.8Hz, 1H), 5.03 (s, 2H), 7.16-7.35 (m, 10H)
[0061]
Example 13(3S) -3- (N-benzyloxycarbonylamino) -3-benzyl-1,2-epoxypropane (VIIb) Manufacturing of
(1) A mixture (about 3: 1, 100 mg, 0.3 mmol) of (2S, 3S)-(VIb) and (2R, 3S)-(VIc) obtained in Example 11 was dissolved in THF (2 ml). It was. To this solution, potassium tert-butoxide (40 mg, 0.27 mmol) was added at −10 ° C., and the mixture was further reacted by stirring at −10 ° C. for 15 minutes. Water (3 ml) and methylene chloride (10 ml) were added to the reaction solution for extraction, and the organic layer was separated and concentrated. The obtained crystals were developed by silica gel thin layer chromatography (n-hexane: ethyl acetate = 2/1) and fractionated to obtain (2S, 3S)-(VIIb) and (2R, 3S)-(VIIb) of the title compounds. Of (3: 1) (20 mg) as white crystals.
1HNMR (300 MHz, CDCl3) (diastereomeric mixture) δ: 2.52-2.58 (m, 2 / 4H, (2R, 3S)), 2.71-2.80 (m, 6 / 4H, (2S, 3S)) 2.83-2.95 (m, 1H), 2.99 (dd, J = 5.0, 14.2Hz, 1H), 3.69-3.72 (m, 1H, 3 / 4H, (2S, 3S)), 4.12-4.25 (m, 1H, 1 / 4H , (2R, 3S)), 4.67-4.80 (m, 1H), 5.03 (s, 6 / 4H, (2S, 3S)), 5.05 (s, 2 / 4H, (2R, 3S)), 7.18-7.35 (m, 10H)
(2) The mixture (about 5: 1, 164 mg) of (2S, 3S)-(VIc) and (2R, 3S)-(VIc) obtained in Example 12 was dissolved in methanol (4.5 ml). To this solution, potassium carbonate (58 mg, 0.41 mmol) was added at room temperature, and the mixture was further stirred at room temperature for 1 hour to be reacted. The reaction mixture was extracted with 1N hydrochloric acid (3 ml) and ethyl acetate (10 ml), and the organic layer was separated and concentrated. The obtained crystals were developed by silica gel thin layer chromatography (n-hexane: ethyl acetate = 2/1) and fractionated to obtain (2S, 3S)-(VIIb) and (2R, 3S)-(VIIb) of the title compounds. Of white (about 5: 1) (79 mg) was obtained as white crystals.
[0062]
Example 14(4S) -4- (N, N-dibenzylamino) -4-benzyl-3-oxo-2-chlorobutanoic acid t-butyl ester (IIId) Manufacturing of
Under an argon atmosphere, anhydrous THF (3.2 ml), LDA heptane, THF, and an ethylbenzene solution (2.0 M) (0.39 ml, 0.78 mmol) were mixed and cooled to -70 ° C. To this solution, tert-butyl chloroacetate (IVa) (0.13 ml, 0.85 mmol) was added dropwise and stirred for 30 minutes, and then (Ib) (154 mg, 0.34 mmol) was dissolved in anhydrous THF (1.0 ml). The solution was added dropwise and stirred for 3 hours while gradually raising the temperature. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution (3.0 ml) was added, and then ethyl acetate (10 ml) was added for extraction. The organic layer was washed with water (10 ml), dried over magnesium sulfate and filtered. The crude product obtained by concentrating the filtrate was purified by silica gel preparative thin layer chromatography, and the mixture of the title compounds (2S, 4S)-(IIId) and (2R, 4S)-(IIId) (200. 2 mg) was obtained. The diastereo ratio was about 2: 1 from the 1H-NMR integration ratio.
1HNMR (300 MHz, CDCl3) (diastereomeric mixture) δ: 0.86 (s, 6H), 1.44 (s, 3H), 2.943.04 (m, 1H), 3.17 (dd, J = 9.8, 13.4 Hz, 1 / 3H), 3.26 (dd, J = 9.8, 13.3Hz, 2 / 3H), 3.50 (d, J = 13.2Hz, 4 / 3H), 3.51 (d, J = 13.2Hz, 2 / 3H), 3.81 (d , J = 13.2Hz, 4 / 3H), 3.85 (d, J = 13.1Hz, 2 / 3H), 3.87 (dd, J = 3.0,9.7Hz, 2 / 3H), 4.00 (dd, J = 3.0,9.7 Hz, 1 / 3H), 5.37 (s, 1 / 3H), 5.48 (s, 2 / 3H), 7.08-7.39 (m, 15H)
Mass spectrum (FAB) 478 (MH +)
[0063]
Example 15(4S) -4- (N-Benzyloxycarbonyl) amino-4-benzyl-3-oxobutanoic acid t-butyl ester (IIb) Manufacturing of
Under an argon atmosphere, a solution of LDA in heptane, THF, and ethylbenzene (2.0 M) (231 ml, 462 mmol) was dissolved in anhydrous THF (400 ml) and cooled to −50 ° C. To this solution, a solution of tert-butyl acetate (58.1 g, 500 mmol) in THF (40 ml) was added dropwise over about 40 minutes while maintaining the temperature at −45 to −50 ° C. After dropping, the mixture was stirred at −45 ° C. for 30 minutes, and then a solution of N-benzyloxycarbonyl-L-phenylalanine methyl ester (Ic) (39.4 g, 125 mmol) in THF (40 ml) was further added to this solution for about 30 minutes. The solution was added dropwise while maintaining the temperature at -45 to -50 ° C. After the dropwise addition, the reaction solution was stirred at −45 ° C. for 60 minutes, and then the reaction solution was poured into a mixture of 2N hydrochloric acid (500 ml) and ice (150 g) to stop the reaction. The mixture was returned to room temperature and the organic layer was separated. The aqueous layer was further extracted with toluene (350 ml), and the two organic layers were combined and washed with 5% aqueous sodium hydrogen carbonate solution (50 ml) and 25% brine (50 ml) in this order. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated to obtain the crude title compound (IIb) (58.1 g, purity 86.4%, 126 mmol).
[0064]
Example 16(4S) -4- (N-Benzyloxycarbonyl) amino-4-benzyl-3-oxo-2-chlorobutanoic acid t-butyl ester (IIIb) Manufacturing of
(4S) -4- (N-benzyloxycarbonylamino) -4-benzyl-3-oxobutanoic acid t-butyl ester (IIb) (40.5 g, purity 86.4%, 88 mmol) was added to methylene chloride (88 ml). Dissolved. Sulfuryl chloride (7.23 ml, 90 mmol) was added while stirring under ice-cooling, followed by stirring for 1 hour under ice-cooling, and further stirring at room temperature for 30 minutes. When the reaction solution was concentrated at 30 ° C. or lower, the crude title compound (48.6 g) was obtained as crystals.
The crystals (2 g) were recrystallized from toluene (10 ml) to obtain purified crystals.
1H-NMR (300MHz, CDCl3)
(Isomer mixture) δ: 1.45-1.48 (m, 9H), 2.95-3.05 (m, 1H), 3.18-3.38 (m, 1H), 4.85-5.10 (m, 4H), 5.20-5.35 (m, 1H 7.14-7.35 (m, 10H)
(Main isomer) δ: 1.44 (s, 9H), 2.99 (dd, J = 7.5, 14.1Hz, 1H), 3.20 (dd, J = 6.1, 14.1Hz, 1H), 4.85 (s, 1H), 4.97 (bq, J = 8.4Hz, 1H), 5.60 (s, 2H), 5.25 (bd, J = 8.4Hz, 1H) 7.14-7.35 (m, 10H)
13C-NMR (75MHz, CDCl3)
(Main isomer) δ: 27.5, 37.7, 59.5, 60.0, 67.2, 85.0, 127.3, 128.1, 128.3, 128.5, 128.9, 129.2, 135.3, 136.0, 155.6, 163.1, 197.4
Mass spectrum (FAB) 432 (MH +), 454 (MNa +)
[0065]
Example 17(3S) -3- (N-benzyloxycarbonyl) amino-3-benzyl-2-oxo-1-chloropropane (Vb) Manufacturing of
Crude crystals (46.6 g) of (4S) -4- (N-benzyloxycarbonylamino) -4-benzyl-3-oxo-2-chlorobutanoic acid t-butyl ester (IIIb) obtained in Example 16 were obtained. It was suspended in formic acid (purity 90%, 80 ml), heated to 80 ° C. with stirring and allowed to react for 20 minutes. The reaction solution was cooled and formic acid was distilled off under reduced pressure to obtain crude crystals of the title compound.
Further, the crystals were dissolved in isopropanol (200 ml) at 60 ° C., cooled to 5 ° C. and recrystallized. The crystals were washed with isopropanol (50 ml) and dried to obtain crystals of the title compound (20.1 g, 60 mmol).
[0066]
Example 18(2S, 3S) -3- (N-benzyloxycarbonyl) amino-3-benzyl-2-hydroxy-I-chloropropane (VIb) Manufacturing of
(3S) -3- (N-benzyloxycarbonylamino) -3-benzyl-2-oxo-1-chloropropane (Vb) (17.0 g, 51.2 mmol) was dissolved in methylene chloride (180 ml) and methanol was added. (180 ml) was added. To this solution, sodium borohydride (2.03 g, 53.8 mmol) was added at 0 ° C. over about 10 minutes, and the mixture was further reacted at 0 ° C. for 30 minutes. Acetic acid (12.9 ml, 226 mmol) was added to the reaction solution to stop the reaction, and then methanol was distilled off under reduced pressure. Water (50 ml) was added to this solution and extracted twice with methylene chloride (150 ml + 50 ml). The organic layer was concentrated to give a mixture (84:16) of the title compound and its diastereomer (2R, 3S) as white crystals.
The crystals (1 g) were recrystallized from ethyl acetate / n-hexane (5/1, 15 ml) to obtain crystals of the title compound (97% de, 0.6 g).
1H-NMR (300MHz, CDCl3)
((2S, 3S) body) δ: 2.87 (dd, J = 9.0, 14.1Hz, 1H), 3.00 (dd, J = 4.6, 14.1Hz, 1H), 3.55 (dd, J = 7.3, 11.3Hz, 1H ), 3.60 (bs, 1H), 3.62 (dd, J = 4.3,11.3Hz, 1H), 3.86 (bq, J = approx5Hz, 1H), 3.96-4.06 (m, 1H), 5.01 (s, 2H), 5.31 (bd, J = approx.8.5Hz, 1H), 7.18-7.33 (m, 10H)
13C-NMR (75MHz, CDCl3)
((2S, 3S)) δ: 35.3, 47.1, 54.6, 66.5, 73.2, 126.4, 127.8, 127.9, 128.3, 128.3, 129.3, 136.3, 137.5, 156.0
Mass spectrum (ESI) 334.2 (MH +), 356.2 (MNa +), 689.3 (2MNa +)
[0067]
Example 19(2S, 3S) -3- (N-benzyloxycarbonyl) amino-3-benzyl-1,2-epoxypropane (VIIb) Manufacturing of
(2S, 3S) -3- (N-benzyloxycarbonylamino) -3-benzyl-2-hydroxy-I-chloropropane (VIb) and its diastereomer ((2R, 3S) form obtained in Example 18 ) Crude crystals of the mixture (84:16) were dissolved in methanol (600 ml). To this solution, potassium carbonate (14.1 g, 102 mmol) was added at room temperature, and the mixture was further reacted by stirring at room temperature for 3 hours. The reaction solution was filtered to remove salts and further washed with methanol (20 ml), and the filtrate was concentrated to about 100 ml at 35 ° C. or lower. The concentrate was acidified with 0.5N hydrochloric acid (100 ml), and then extracted twice with methylene chloride (150 ml + 150 ml). The organic layer was concentrated at 40 ° C. or lower to obtain a mixture (84:16) of the title compound and its diastereomer ((2R, 3S) form) as white crystals (14.0 g, 47.1 mmol).
The crystals (1 g) were recrystallized from ethyl acetate / n-hexane (1/1, 6 ml) to obtain crystals of the title compound (97% de, 0.58 g).
1H-NMR (300MHz, CDCl3)
((2S, 3S) body) δ: 2.71-2.80 (m, 2H), 2.85 (dd, J = 8.1, 14.1Hz, 1H), 2.91 (dd, J = 2.7,6.4Hz, 1H), 2.98 (dd , J = 5.1,14.1Hz, 1H), 3.68-3.82 (m, 1H), 4.77 (bd, J = 5.9Hz, 1H), 5.03 (s, 2H), 7.17-7.33 (m, 10H)
13C-NMR (75MHz, CDCl3)
((2S, 3S)) δ: 37.5, 46.7, 53.0, 53.2, 66.8, 126.8, 128.0, 128.1, 128.5, 128.6, 129.3, 136.2, 136.4, 155.7
Mass spectrum (ESI) 298.2 (MH +), 320.2 (MNa +), 336.3 (MK +), 617.5 (2MNa +)
[0068]
Example 20(2R, 3S) -3- (N-benzyloxycarbonyl) amino-2-hydroxy-1- (N-isobutylamino) -4-phenylbutane (IXa) Manufacturing of
3- (N-benzyloxycarbonylamino) -3-benzyl-1,2-epoxypropane (VIIb) ((2S, 3S) / (2R, 3S) = 84/16, 4.47 g, 15.0 mmol) Suspended in ethanol (29 ml) and added to isobutylamine (22.4 ml, 225 mmol). This solution was heated to 70 ° C. and reacted for 60 minutes. The reaction mixture was concentrated to give a mixture (84/16) of the title compound and its diastereomer ((2S, 3S) form) as white crystals.
In addition, the title compound was obtained by reacting in the same manner using the (2S, 3S) form crystals.
1H-NMR (300MHz, CDCl3)
((2R, 3S) body) δ: 0.90 (d, J = 6.6Hz, 6H), 1.60-1.80 (m, 1H), 2.38 (d, J = 6.8Hz, 2H), 2.65 (dd, J = 6.8 , 12.4Hz, 1H), 2.70 (dd, J = 4.0,12.4Hz, 1H), 2.70 (bs, 1H), 2.86 (ddJ = 8.1,14.1Hz, 1H), 2.99 (dd, J = 4.8,14.1Hz , 1H), 3.49 (bq, J = approx4.5Hz, 1H), 3.80-3.95 (m, 1H), 5.02 (s, 2H), 5.11 (bd, J = 9.0Hz, 1H), 7.19-7.32 (m , 10H)
13C-NMR (75MHz, CDCl3)
((2R, 3S)) δ: 20.5, 28.3, 36.6, 51.4, 55.0, 57.9, 66.5, 70.4, 126.4, 127.8, 128.0, 128.4, 128.4, 129.5, 136.6, 137.7, 156.3
Mass spectrum (ESI) 371.2 (MH +)
[0069]
Example 214-Nitro-N-((2′R (syn), 3 ′S) -3 ′-(N-benzyloxycarbonyl) amino-2′-hydroxy-4′-phenylbutyl) -N-isobutyl-benzenesulfone Amide (IXb) Manufacturing of
(2R, 3S) -3- (N-benzyloxycarbonylamino) -2-hydroxy-1- (N-isobutylamino) -4-phenylbutane (IXa) ((2R, 3S) / (2S, 3S) = 84/16, 6.08 g, 15.0 mmol) was dissolved in methylene chloride (40 ml). A solution of sodium carbonate (2.55 g, 24.1 mmol) in water (20 ml) was added to the above solution to prepare a two-layered solution. To this solution, a solution of 4-nitrobenzenesulfonyl chloride (4.0 g, 18.0 mmol) in methylene chloride (5 ml) was added over about 10 minutes under ice-cooling, and the reaction solution was returned to room temperature and reacted for another 3 hours. The organic layer was separated and concentrated to give a mixture (84:16) of the title compound and its diastereomer (2'S, 3'S) as white crystals. The crystals were recrystallized from ethanol (100 ml). The recrystallization melted at 70 ° C., crystallized at about 55 ° C., aged at that temperature for 1 hour, and finally cooled to 20 ° C. The separated crystals were washed with ethanol (30 ml) and dried to give the title compound (6.07 g, 10.9 mmol, 96.4% de) as white crystals.
1H-NMR (300MHz, CDCl3)
((2'R (syn), 3'S) body) δ: 0.84 (d, J = 6.1Hz, 3H), 0.86 (d, J = 6.3Hz, 3H), 1.75-1.95 (m, 1H), 2.88 ( dd, J = 7.5,14.1Hz, 2H), 2.96 (d, J = 6.8Hz, 2H), 3.00 (dd, J = 4.7,14.1Hz, 1H), 2.90 (bs, 1H), 3.12-3.26 (m , 2H), 3.80-3.91 (m, 2H), 4.99 (bd, J = 8.7Hz, 1H), 5.01 (s, 2H), 7.21-7.32 (m, 10H), 7.92 (d, J = 8.7Hz, 2H), 8.29 (d, J = 8.7Hz, 2H)
13C-NMR (75MHz, CDCl3)
((2'R (syn), 3S)) δ: 19.8, 19.9, 35.5, 52.4, 57.7, 66.9, 72.1, 124.3, 126.7, 127.8, 128.2, 128.5, 128.5, 128.6, 129.3, 136.1, 137.2, 144.6 , 150.0, 156.5
[0070]
Example 224-nitro-N-((2′R (syn), 3 ′S) -3 ′-(Nt-butyloxycarbonyl) amino-2′-hydroxy-4′-phenyl Chill) -N-isobutyl-benzenesulfonamide (IXc) Manufacturing of
4-Nitro-N-((2′R (syn), 3 ′S) -3 ′-(N-benzyloxycarbonylamino) -2′-hydroxy-4′-phenylbutyl) -N-isobutyl-benzenesulfone Amide (IXb) (13.0 g, 23.4 mmol, 96% de) was dissolved in methylene chloride (77 ml) and methanol (2 ml, 46.8 mmol) was added. Under ice cooling, a 30% hydrobromic acid / acetic acid solution (19.3 ml, HBr 93.6 mmol) was added, and the mixture was returned to room temperature and stirred for 3 hours. A 10% aqueous sodium carbonate solution (300 ml) was added to the reaction solution to make it alkaline, and further methylene chloride (100 ml) was added. The organic layer was separated, and di-tert-butyl dicarbonate (5.62 g, 25.7 mmol) in methylene chloride (50 ml) was added thereto and reacted at room temperature for 2 hours. The reaction mixture was concentrated to about 100 ml, methanol (100 ml) and potassium carbonate (3.23 g, 23.4 mmol) were added thereto, and the mixture was stirred at room temperature. In the middle of the reaction, the reaction was followed by HPLC. After 3 hours, when the Ac compound at the 2-position disappeared, acetic acid (1.34 ml, 23.4 mmol) was added to stop the reaction. The reaction mixture was concentrated, water (50 ml) was added, and the mixture was extracted with methylene chloride (200 ml). The organic layer was concentrated to obtain crude crystals of the title compound. The crystals were recrystallized from ethanol (550 ml). The recrystallization melted at 55 ° C., crystallized at about 40 ° C., and finally cooled to 5 ° C. The separated crystals were washed with ethanol (100 ml) and dried to give the title compound (8.71 g, 16.7 mmol, 100% de) as white crystals.
1H-NMR (300MHz, CDCl3)
((2R '(syn), 3'S) body) δ: 0.87 (d, J = 6.6Hz, 3H), 0.88 (d, J = 6.6Hz, 3H), 1.36 (s, 9H), 1.81-1.96 (m , 1H), 2.83-2.2.96 (m, 2H), 2.99 (d, J = 7.5Hz, 2H), 3.20 (d, J = 5.3Hz, 2H), 3.70-3.85 (m, 2H), 3.82 ( bs, 1H), 4.64 (bd, J = 7.6Hz, 1H), 7.21-7.33 (m, 10H), 7.96 (d, J = 8.8Hz, 2H), 8.33 (d, J = 8.8Hz, 2H)
13C-NMR (75MHz, CDCl3)
((2R '(syn), 3S)) δ: 19.8, 20.0, 26.9, 28.2, 35.6, 52.5, 55.2, 57.5, 72.2, 80.1, 124.3, 126.6, 128.5, 128.6, 129.4, 137.5, 144.8, 150.0, 156.3
Mass spectrum (ESI) 522.3 (MH +), 544.5 (MNa +), 560.4 (MK +)
[0071]
Example 23N- (S) -tetrahydrofuran-3-yloxycarbonyl-L-phenylalanine methyl ester (Ie) Manufacturing of
(S) -3-hydroxytetrahydrofuran (0.881 g, 10 mmol) was dissolved in methylene chloride (10 ml), and triphosgene (1.34 g, 4.5 mmol) was added and dissolved. The solution was cooled to −40 ° C., and a solution of pyridine (1.04 ml, 13.5 mmol) in methylene chloride (5 ml) was added dropwise over about 15 minutes. After the dropwise addition, the mixture was reacted at room temperature for 3.5 hours to prepare a chloroformate.
The reaction solution obtained above was ice-cooled, and a solution obtained by dissolving L-phenylalanine methyl ester hydrochloride (1.94 g, 9 mmol) in methylene chloride (5 ml) was added. Further, an aqueous solution (20 ml) in which sodium carbonate (2.12 g, 20 mmol) was dissolved was added dropwise over about 15 minutes under ice cooling. After dropping, the reaction was allowed to proceed at room temperature for 2.5 hours. When the pH of the aqueous layer of the reaction solution after the reaction was measured, it was alkaline. The aqueous layer was separated, and the organic layer was washed twice with 1N hydrochloric acid (10 ml) and further washed with water (10 ml). The solvent was distilled off to give the title compound (2.10 g, 7.2 mmol) as a yellow oil.
1H-NMR (300MHz, CDCl3)
δ: 1.96-2.15 (m, 2H), 3.05 (dd, J = 5.6,13.9Hz, 1H), 3.13 (dd, J = 6.4,13.9Hz, 1H), 3.72 (s, 3H), 3.75-3.91 ( m, 4H), 4.62 (bq, J = approx.6Hz, 1H), 5.19-5.23 (m, 1H), 5.26 (bq, J = 8.7Hz, 1H), 7.10-7.29 (m, 5H)
13C-NMR (75MHz, CDCl3)
δ: 32.7, 38.2, 52.3, 54.7, 66.9, 73.2, 75.5, 127.1, 128.6, 129.2, 135.7, 155.3, 172.0
Mass spectrum (FAB) 294 (MH +)
[0072]
Example 24(4S) -4- (N- (S) -Tetrahydrofuran-3'-yloxycarbonyl) amino-5-phenyl-3-oxo-pentanoic acid tert-butyl (IIe) Manufacturing of
Under an argon atmosphere, a solution of LDA in heptane, THF, and ethylbenzene (2.0 M) (9 ml, 18 mmol) was dissolved in anhydrous THF (20 ml) and cooled to −50 ° C. To this solution, a solution of tert-butyl acetate (2.3 g, 20 mmol) in THF (3 ml) was added dropwise over about 10 minutes while maintaining the temperature at −45 to −50 ° C. After dropping, the mixture was stirred at −45 ° C. for 30 minutes, and then N— (S) -tetrahydrofuran-3′-yloxycarbonyl-L-phenylalanine methyl ester (Ie) (1.75 g, 5.3 mmol) was added to this solution. ) In THF (3 ml) was added dropwise in about 10 minutes while maintaining the temperature at -40 to -45 ° C. After dropping, the reaction solution was stirred at −45 ° C. for 60 minutes, and then acetic acid (2.3 ml, 40 mmol) was added to the reaction solution to stop the reaction. Water (20 ml) and toluene (50 ml) were added to the reaction solution for extraction, and the mixture was washed with a 5% aqueous sodium hydrogen carbonate solution (10 ml) and water (10 ml) in this order. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated to give the crude title compound (1.95 g, 5.2 mmol).
1H-NMR (300MHz, CDCl3)
δ: 1.46 (s, 9H), 1.96-2.17 (m, 2H), 2.97 (dd, J = 7.3,14.2Hz, 1H), 3.17 (dd, J = 6.2,14.2Hz, 1H), 3.39 (bs, 2H), 3.70-3.90 (m, 4H), 4.66 (bq, J = approx.6.5Hz, 1H), 5.15-5.23 (m, 1H), 5.34 (bd, J = 7.8Hz, 1H), 7.15-7.31 (m, 5H)
13C-NMR (75MHz, CDCl3)
δ: 27.9, 32.7, 37.1, 48.2, 60.6, 66.9, 73.2, 75.6, 82.3, 127.1, 128.7, 129.2, 135.7, 155.4, 165.8, 201.6
[0073]
Example 25(4S) -4- (N- (S) -Tetrahydrofuran-3'-yloxycarbonyl) amino-2-chloro-5-phenyl-3-oxo-pentanoic acid tert-butyl (IIIe) Manufacturing of
(4S) -4- (N- (S) -Tetrahydrofuran-3'-yloxycarbonyl) amino-5-phenyl-3-oxo-pentanoic acid tert-butyl (IIe) (1.8 g, 4.7 mmol) Dissolved in methylene chloride (5 ml). Sulfuryl chloride (0.39 mmol, 4.7 mmol) was added while stirring under ice cooling, and the mixture was stirred at room temperature for 60 minutes. The reaction solution was concentrated at 30 ° C. or lower to obtain a crude title compound.
1H-NMR (300MHz, CDCl3)
δ: 1.40 (s, 9H), 1.95-2.17 (m, 2H), 2.92-3.02 (m, 1H), 3.17-3.25 (m, 1H), 3.67-3.90 (m, 4H), 4.90 (d, J = 13.5Hz, 1H), 4.98 (bq, J = approx.6.0Hz, 1H), 5.15-5.19 (m, 1H), 5.27 (bd, J = 8.3Hz, 1H), 7.18-7.30 (m, 5H)
13C-NMR (75MHz, CDCl3)
δ: 27.7, 32.7, 37.6, 59.1, 60.9, 66.9, 73.0, 75.9, 84.8, 127.3, 128.8, 129.3, 135.3, 155.3, 163.3, 197.4
[0074]
Example 26(3S) -1-Chloro-2-oxo-3- (N- (S) -tetrahydrofuran-3'-yloxycarbonyl) amino-4-phenylbutane (Vd) Manufacturing of
Formic acid (5 ml) was added to the solid (IIIe) obtained in Example 25 and stirred at 80 ° C. for 15 minutes. When formic acid was distilled off and isopropanol (10 ml) was added to the resulting residue, crystallization occurred. The crystals were dissolved at 60 ° C. and crystallized at room temperature for 2 hours and at 5 ° C. for 30 minutes to separate crystals. The crystals were washed with isopropanol (2 ml) and dried to give the title compound (0.854 g, 2.7 mmol) as white crystals.
1H-NMR (300MHz, CDCl3)
δ: 1.93-2.03 (m, 1H), 2.08-2.20 (m, 1H), 3.00 (dd, J = 7.1, 13.8Hz, 1H), 3.10 (dd, J = 6.8, 13.8Hz, 1H), 3.75- 3.92 (m, 4H), 3.98 (d, J = 16.2Hz, 1H), 4.16 (d, J = 16.2Hz, 1H), 4.75 (bq, J = approx.7.5Hz, 1H), 5.17-5.22 (m , 1H), 5.36 (bd, J = 7.14Hz, 1H), 5.15-5.21 (m, 1H), 7.20-7.34 (m, 5H)
13C-NMR (75MHz, CDCl3)
δ: 32.7, 37.7, 47.3, 58.5, 66.9, 73.1, 75.9, 127.5, 129.0, 129.0, 135.2, 155.4, 201.0
[0075]
Example 27(2S, 3S) -1-Chloro-2-hydroxy-3- (N- (S) -tetrahydrofuran-3'-yloxycarbonylamino) -4-phenylbutane (VId) Manufacturing of
(3S) -1-chloro-2-oxo-3- (N- (S) -tetrahydrofuran-3′-yloxycarbonylamino) -4-phenylbutane (Vd) (0.706 g, 2.26 mmol) was salified. Dissolved in methylene (8 ml) and further methanol (80 ml) was added. To this solution, sodium borohydride (60 mg, 1.6 mmol) was added at −3 ° C. over about 5 minutes, and the mixture was further stirred at −3 ° C. for 60 minutes for reaction. Acetic acid (0.385 ml, 6.72 mmol) was added to the reaction solution to stop the reaction, and then methanol was distilled off under reduced pressure. Water (5 ml) was added to this solution, and extracted twice with methylene chloride (20 ml + 10 ml). The organic layer was concentrated to give a mixture (83:17) of the title compound and its diastereomer ((2R, 3S) form) as white crystals.
1H-NMR (300MHz, CDCl3)
δ: (2S, 3S): 1.90-2.00 (m, 1H), 2.05-2.18 (m, 1H), 2.80 (dd, J = 9.3,14.0Hz, 1H), 3.01 (dd, J = 4.3,14.0Hz , 1H), 3.54 (bs, 1H), 3.52-3.66 (m, 2H), 3.67-3.90 (m, 5H), 3.94-4.03 (m, 1H), 5.08-5.16 (m, 1H), 5.64 (bd , J = 9.4Hz, 1H), 7.20-7.30 (m, 5H)
13C-NMR (75MHz, CDCl3)
δ: (2S, 3S): 32.4, 35.1, 46.8, 54.2, 66.5, 72.9, 73.0, 74.7, 126.0, 128.0, 129.1, 137.6, 155.5
Mass spectrum (ESI) 314.3 (MH +)
[0076]
Example 28(2S, 3S) -3- (N- (S) -Tetrahydrofuran-3'-yloxycarbonylamino) -4-phenylbutane-1,2-epoxide (VIIc) Manufacturing of
The crystal (VId) obtained in Example 27 was suspended in methanol (20 ml), potassium carbonate (624 mg, 4.52 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours to be reacted. The reaction solution was filtered to remove salts, and then the filtrate was concentrated at 35 ° C. or lower. The concentrate was acidified with 0.5N hydrochloric acid (10 ml), and extracted twice with methylene chloride (10 ml + 10 ml). The organic layer was concentrated at 40 ° C. or lower to obtain a mixture (83:17) of the title compound and its diastereomer ((2R, 3S) form) as white crystals (0.58 g, 2.1 mmol).
1H-NMR (300MHz, CDCl3)
δ: (1S, 1'S): 2.72-2.78 (m, 2H), 2.78-2.83 (m, 1H), 2.86-3.02 (m, 2H), 3.70-3.90 (m, 5H), 4.65-4.68 (b, 1H), 5.15-5.21 (m, 1H), 7.20-7.34 (m, 5H)
13C-NMR (75MHz, CDCl3)
δ: (1S, 1'S): 32.7, 37.5, 46.7, 53.0, 53.0, 66.9, 73.2, 75.4, 126.9, 128.7, 129.4, 136.3, 155.5
Mass spectrum (ESI) 278.2 (MH +)
[0077]
Example 29(2R, 3S) -3- (N- (S) -Tetrahydrofuran-3'-yloxycarbonylamino) -2-hydroxy-1-N-isobutylamino-4-phenylbutane (IXd) Manufacturing of
(2S, 3S) -3- (N- (S) -Tetrahydrofuran-3′-yloxycarbonylamino) -4-phenylbutane-1,2-epoxide (VIIc) ((2S, 3S): (2R, 3S ) = 83: 17, 0.58 g, 2.1 mmol) was suspended in ethanol (4 ml) and added to isobutylamine (3.4 ml, 33.9 mmol). This solution was heated to 70 ° C. and reacted for 60 minutes. The reaction mixture was concentrated to give a mixture (83:17) of the title compound and its diastereomer ((2S, 3S) form) as white crystals.
1H-NMR (300MHz, CDCl3)
δ: (2R, 3S): 0.91 (d, J = 6.6Hz, 6H), 1.72 (hep, J = 6.6Hz, 1H), 1.80-1.95 (m, 1H), 2.02-2.14 (m, 1H), 2.37-2.44 (m, 2H), 2.64-2.99 (m, 5H), 3.55-3.86 (m, 5H), 5.11 (b, 1H), 5.43 (bd, J = 8.7Hz, 1H), 7.19-7.28 ( m, 5H)
13C-NMR (75MHz, CDCl3)
δ: (2R, 3S): 20.4, 28.2, 32.7, 36.6, 51.4, 55.2, 57.7, 66.8, 70.3, 73.2, 75.0, 126.3, 128.3, 129.3, 137.7, 155.9
Mass spectrum (ESI) 351.3 (MH +)
[0078]
Example 304-Nitro-N-((2'R (syn), 3'S) -2'-hydroxy-4'-phenyl-3 '-(N- (S) -tetrahydrofuran-3 "-yloxycarbonyl) amino -Butyl) -N-isobutyl-benzenesulfone Mid (IXe) Manufacturing of
The crystal (IXd) obtained in Example 29 was dissolved in methylene chloride (2 ml). A solution of sodium carbonate (0.233 g, 2.2 mmol) in water (2 ml) was added to the above solution to prepare a two-layered solution. To this solution, a solution of 4-nitrobenzenesulfonyl chloride (0.488 g, 2.2 mmol) in methylene chloride (1 ml) was added over about 2 minutes under ice-cooling, and the reaction solution was returned to room temperature and reacted for another 3 hours. During the reaction, crystals precipitated and stirring became difficult, so methylene chloride (6 ml) and water (2 ml) were added. The organic layer was separated and concentrated to give a mixture (83:17, 0.974 g) of the title compound and its diastereomer ((2S (anti), 3S) form) as white crystals. The crystals were recrystallized from ethanol (60 ml). The recrystallization was dissolved at 70 ° C., crystallized at about 55 ° C., cooled to 5 ° C. and crystallized. The separated crystals were washed with ethanol (5 ml) and dried to give the title compound (0.642 g, 96.4% de) as white crystals.
The crystals were further recrystallized from ethanol (50 ml) and dried to give the title compound (0.583 g, 100 de).
1H-NMR (300MHz, CDCl3)
(2R '(syn), 3S body) δ: 0.87 (d, J = 7.0Hz, 3H), 0.89 (d, J = 7.0Hz, 3H), 1.89 (hep, J = 6.8Hz, 1H), 1.90- 1.94 (m, 1H), 2.08-2.15 (m, 1H), 2.86-3.04 (m, 4H), 3.11-3.24 (m, 2H), 3.58 (bs, 6H), 3.65-3.87 (m, 6H), 4.85 (bd, J = 5.2Hz, 1H), 5.10-5.18 (m, 1H), 7.20-7.37 (m, 5H), 7.95 (d, J = 8.9Hz, 2H), 8.34 (d, J = 8.9Hz , 2H)
13C-NMR (75MHz, CDCl3)
(2R '(syn), 3S form) δ: 19.8, 19.9, 27.0, 32.7, 35.4, 52.7, 55.3, 57.8, 66.8, 72.1, 73.1, 75.6, 124.3, 126.7, 128.5, 128.6, 129.3, 137.2, 144.7, 150.0, 156.2
Mass spectrum (FAB) 536 (MH +)
[0079]
Example 31(4R) -4- (N-benzyloxycarbonyl) amino-3-oxo-5-phenylthiopentanoic acid t-butyl (IIf) Manufacturing of
Under argon atmosphere, 420 ml (840 mmol) of 2.0 M heptane of lithium diisopropylamide, tetrahydrofuran and ethylbenzene was added to 800 ml of tetrahydrofuran, and the mixture was cooled to -66 ° C. To this solution, a solution of 99.54 g (856.9 mmol) of t-butyl acetate in 53 ml of tetrahydrofuran was dropped over 45 minutes while maintaining at -66 ° C to -71 ° C, and then stirred at -69 ° C to -74 ° C for 1 hour. did. To this solution was added a solution of 80.00 g (231.6 mmol) of N-benzyloxycarbonyl- (S-phenyl) -L-cysteine methyl ester (If) in 135 ml of tetrahydrofuran over 45 minutes while maintaining at -69 ° C to -74 ° C. It was dripped. After stirring at −69 ° C. to −73 ° C. for 2 hours and 30 minutes, the reaction solution was poured into a solution of 36% hydrochloric acid 150 ml of water 750 ml. After adding 80 ml of ethyl acetate and separating the layers, the aqueous layer was extracted with 550 ml of ethyl acetate. The organic layers were combined and washed with 300 ml of 1N hydrochloric acid, and then washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine. After drying over anhydrous sodium sulfate, filtration and concentration were performed to obtain 108.04 g (purity 79.9%, 86.33 g) of the title compound (yield 86.8%).
1H-NMR (300 MHz, CDCl_Three)
δ: 3.28 (dd, 1H), 3.36-3.52 (m, 3H), 4.60 (dd, 1H), 5.07 (d, 1H), 5.10 (d, 1H) , 5.58 (bd.d, 1H), 7.19-7.40 (m, 10H).
Mass spectrum (ESI) 452 (M + Na⁺)
[0080]
Example 32(3R) -3- (N-benzyloxycarbonyl) amino-1-chloro-2-oxo-4-phenylthiobutane (Ve) Manufacturing of
108.04 g of t-butyl (IIf) (4R) -4- (N-benzyloxycarbonyl) amino-3-oxo-5-phenylthiopentanoate (IIf) obtained according to Example 31 (purity 79.9%, 86. 33 g, 201.0 mmol) was dissolved in 320 ml of dichloromethane and cooled to -32 ° C. To this solution, a solution of 34.38 g (254.7 mmol) of sulfuryl chloride in 22 ml of dichloromethane was added dropwise over 1 hour and 20 minutes while maintaining the temperature at -32 ° C to -31 ° C. After stirring at -32 ° C to -31 ° C for 1 hour and 20 minutes, 300 ml of water was added and the layers were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, further washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtration and concentration, 192 ml of formic acid was added to the resulting residue, and the mixture was stirred at 50 to 52 ° C. for 4 hours. The obtained reaction liquid was concentrated, and 200 ml of isopropyl alcohol was added and further concentrated. 400 ml of isopropyl alcohol was added and heated to 52 ° C. to dissolve the solid, then cooled to 5 ° C., and the resulting crystals were collected by filtration and washed with 150 ml of isopropyl alcohol. The crystals were vacuum-dried to obtain 51.5 g (purity 98.0%, 50.47 g) of the title compound (yield 59.9%). 1H-NMR (300 MHz, CDCl_Three)
δ: 3.32 (dd, 1H), 3.42 (dd, 1H), 4.13 (d, 1H), 4.72 (d, 1H), 4.73 (dd, 1H), 5.00 (S, 2H), 5.57 (br.d, 1H), 7.22-7.40 (m, 10H).
Mass spectrum (ESI) 364 (MH⁺)
[0081]
Example 33(2S, 3R) -3- (N-benzyloxycarbonyl) amino-1-chloro-2-hydroxy-4-phenylthiobutane (VIe) Manufacturing of
51.5 g (purity 98.0%, 50.47 g, 138.7 mmol) of (3R) -3- (N-benzyloxycarbonyl) amino-1-chloro-2-oxo-4-phenylthiobutane (Ve) Dissolved in 300 ml dichloromethane and 187 ml methanol and cooled to -10 ° C. To this, 3.64 g (96.2 mmol) of sodium borohydride was added over 1 hour while maintaining at -11 ° C to -9 ° C. After stirring at −12 ° C. to −9 ° C. for 40 minutes, 48 ml of 2N hydrochloric acid was added, and the reaction solution was concentrated. To the concentrated residue were added 500 ml of dichloromethane and 300 ml of water, and the layers were separated. The organic layer was washed with 300 ml of saturated brine. After drying over anhydrous sodium sulfate, this was concentrated by filtration. As a result of HPLC analysis, the obtained compound was a diastereo mixture of (2S, 3R) :( 2R: 3R) = 83: 17. To this mixture, 200 ml of ethyl acetate and 300 ml of hexane were added, dissolved by heating to 60 ° C., and gradually cooled to 5 ° C. The obtained crystals were collected by filtration and washed with 170 ml of a solution of ethyl acetate / hexane = 1/2. The crystals were vacuum-dried to obtain 38.77 g ((2S, 3R) :( 2R, 3R) = 99.3: 0.7) of the title compound (yield 76.4%).
1H-NMR (300 MHz, CDCl_Three)
δ: 3.29 (d, 2H), 3.60 (dd, 1H), 3.68 (dd, 1H), 3.88-3.96 (m, 2H), 5.07 (s, 2H) 5.15 (br., 2H), 7.18-7.39 (m, 10H).
[0082]
Example 34(3S) -3- (N-benzyloxycarbonyl) amino-3-benzyl-2-oxo-1-chloropropane (Vb) Manufacturing of
Under an argon atmosphere, N-benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester ester (Ig) (1.00 g, 2.38 mmol) and trimethylsilyl chloroacetate (IVb) (1.45 ml, 9.38 mmol) were dissolved in anhydrous THF. (10 ml) and cooled to -70 ° C. To this solution, a solution of LDA in heptane, THF, ethylbenzene (2.0 M) (4.52 ml, 9.04 mmol) dissolved in anhydrous THF (4 ml) was heated at a temperature of −72 to −65 in about 1 hour and 15 minutes. The solution was added dropwise while maintaining at ° C. After dropping, the mixture was stirred at −72 ° C. for 3 hours, and 10% aqueous citric acid solution (35 ml) was added to stop the reaction. The mixture was returned to room temperature and ethyl acetate (20 ml) was added, and then the organic layer was separated and washed twice with water (10 ml). The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated to obtain the crude title compound (Vb). As a result of HPLC analysis, this crude product was found to contain 316.6 mg (0.954 mmol, 40.1% yield) of the title compound (Vb) and the starting material N-benzylloxycarbonyl-L-phenylalanine p-nitrophenyl ester ester. (Ig) It contained 398.8 mg (0.949 mmol, 39.9%).
[0083]
Example 35(3S) -3- (N-tert-butyloxycarbonyl) amino-3-benzyl-2-oxo-1-chloropropane (Vf) Manufacturing of
Under an argon atmosphere, N-tert-butyloxycarbonyl-L-phenylalanine p-nitrophenyl ester ester (Ih) (1.002 g, 2.594 mmol) and trimethylsilyl chloroacetate (IVb) (2.04 ml, 12.96 mmol) were added. Dissolved in anhydrous THF (10 ml) and cooled to -70 ° C. To this solution, a solution of LDA in heptane, THF, ethylbenzene (2.0 M) (6.47 ml, 12.95 mmol) in anhydrous THF (9 ml) was dissolved in anhydrous THF (9 ml) at a temperature of −70 to −68 in about 1 hour and 10 minutes. The solution was added dropwise while maintaining at ° C. After dropping, the mixture was stirred at −70 ° C. for 3 hours, and 10% aqueous citric acid solution (54 ml) was added to stop the reaction. The mixture was returned to room temperature, ethyl acetate (20 ml) was added, the organic layer was separated, and washed twice with water (10 ml). The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated to give the crude title compound (Vf). As a result of HPLC analysis, this crude product was found to contain 413.5 mg (1.389 mmol, yield 53.5%) of the title compound (Vf) and N-tert-butyloxycarbonyl-L-phenylalanine p-nitrophenyl ester as starting materials. It contained 164 mg (0.425 mmol, 16.4%) of ester (Ih).
[0084]
Example 36(3S) -3- (N-tert-butyloxycarbonyl) amino-3-benzyl-2-oxo-1-chloropropane (Vf) Manufacturing of
Under an argon atmosphere, a solution of LDA in heptane, THF, and ethylbenzene (2.0 M) (4.9 ml, 9.8 mmol) was dissolved in anhydrous THF (10 ml) and cooled to -75 ° C. To this solution, a solution of chloroacetic acid (IVc) (463 mg, 4.9 mmol) in THF (3.5 ml) was added dropwise while maintaining the temperature at −75 to −70 ° C. over about 20 minutes. After the dropwise addition, the mixture was stirred at -75 to -70 ° C for 30 minutes, and then N-tert-butyloxycarbonyl-L-phenylalanine p-nitrophenyl ester ester (Ih) (500 mg, 1.29 mmol) was added to this solution. A THF (4 ml) solution was added dropwise over about 15 minutes while maintaining the temperature at -75 to -70 ° C. After the dropwise addition, the reaction solution was stirred at −75 to −70 ° C. for 3 hours, and 10% aqueous citric acid solution (20 ml) was added to stop the reaction. The mixture was returned to room temperature, ethyl acetate (20 ml) was added, the organic layer was separated, and washed with saturated aqueous sodium hydrogencarbonate (20 ml, 10 ml) and saturated brine (20 ml) in this order. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated to give the crude title compound (Vf). As a result of HPLC analysis, this crude product contained 186 mg (0.625 mmol) of the title compound (Vf) (yield 48.4%).
[0085]
The compounds used or synthesized in the above production examples and examples are shown below.
[0086]
Embedded image

[0087]
【The invention's effect】
According to the present invention, 3-amino which can be easily converted into 3-amino-1,2-epoxypropanes which are important units as pharmaceutical intermediates including various HIV protease inhibitors or certain enzyme inhibitors A 2-oxo-1-halogenopropane derivative can be industrially produced in a short process with a high yield and a safe process.

Claims

下記一般式(I)で示される化合物に、

（式中のＲｓは水素、それぞれ置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基もしくは炭素数７〜２０のアラルキル基、又はこれらの炭素骨格中にヘテロ原子を含む置換基を、Ｐ₁、Ｐ₂は互いに独立して水素もしくはアミノ保護基、又はＰ₁及びＰ₂は一体となって二官能性のアミノ保護基を、Ｅ₁ はカルボキシ末端として、炭素数１〜１０のアルコキシのエステル残基、それぞれ環上に置換基を有していてもよいフェノキシ基もしくはベンジルオキシ基、Ｎ−オキシコハク酸イミドもしくは１−オキシベンゾトリアゾールの活性エステル残基、活性チオエステル残基、イミダゾリル基、酸ハロゲン化物、酸無水物、又は酸アジドを形成しうる残基を表す。）
酢酸のエステルのアルカリ金属エノラートを反応させて下記一般式(II)で示される化合物を得、

（式中のRｓ、Ｐ₁、Ｐ₂、は上記した意味を有し、Ｒ₁は置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基、炭素数７〜２０のアラルキル基、炭素数４〜１０のトリアルキルシリル基、炭素数８〜１０のフェニルジアルキルシリル基または炭素数１３〜１５のジフェニルアルキルシリル基を表す。）
これに、ハロゲン化試剤を作用させ、２位をハロゲン化して下記一般式(III)で示される４−アミノ−３−オキソ−２−ハロゲノブタン酸エステル誘導体を製造し、

（式中のＲｓ、Ｐ₁、Ｐ₂、Ｒ₁は上記した意味を有し、Ｘはフッ素以外のハロゲン原子を表す。）
さらに得られた(III)の加水分解を行い、脱炭酸を行うことを特徴とする下記一般式(V)で示される３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体またはその塩の製造方法、

（式中のＲｓ、Ｐ₁、Ｐ₂、Ｘは上記した意味を有する。）In the compound represented by the following general formula (I),

(In the formula, Rs is hydrogen, an alkyl group having 1 to 10 carbon atoms which may have a substituent, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, or a carbon skeleton thereof. P ₁ and P ₂ are independently of each other hydrogen or an amino protecting group, or P ₁ and P ₂ are combined to form a bifunctional amino protecting group, and E ₁ is a carboxyl group. As ruruboxy terminal , an alkoxy ester residue having 1 to 10 carbon atoms, an active ester of phenoxy group or benzyloxy group, N-oxysuccinimide or 1-oxybenzotriazole each optionally having a substituent on the ring Represents a residue that can form a residue, an active thioester residue, an imidazolyl group, an acid halide, an acid anhydride, or an acid azide.)
A compound represented by the following general formula (II) is obtained by reacting an alkali metal enolate of an ester of acetic acid,

(In the formula, Rs, P ₁ and P ₂ have the above-mentioned meanings, and R ₁ is an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, A aralkyl group having 7 to 20 carbon atoms, a trialkylsilyl group having 4 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms, or a diphenylalkylsilyl group having 13 to 15 carbon atoms.)
A halogenated reagent is allowed to act on this to produce a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative represented by the following general formula (III) by halogenating the 2-position,

(In the formula, Rs, P ₁ , P ₂ and R ₁ have the above-mentioned meanings, and X represents a halogen atom other than fluorine.)
The method for producing a 3-amino-2-oxo-1-halogenopropane derivative represented by the following general formula (V) or a salt thereof, wherein the obtained (III) is further hydrolyzed and decarboxylated ,

(Rs, P ₁ , P ₂ and X in the formula have the above-mentioned meanings.)

下記一般式(I)で示される化合物に、

（式中のＲｓは水素、それぞれ置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基もしくは炭素数７〜２０のアラルキル基、又はこれらの炭素骨格中にヘテロ原子を含む置換基を、Ｐ₁、Ｐ₂は互いに独立して水素もしくはアミノ保護基、又はＰ₁及びＰ₂は一体となって二官能性のアミノ保護基を、Ｅ₁ はカルボキシ末端として、炭素数１〜１０のアルコキシのエステル残基、それぞれ環上に置換基を有していてもよいフェノキシ基もしくはベンジルオキシ基、Ｎ−オキシコハク酸イミドもしくは１−オキシベンゾトリアゾールの活性エステル残基、活性チオエステル残基、イミダゾリル基、酸ハロゲン化物、酸無水物、又は酸アジドを形成しうる残基を表す。）
下記一般式(IV)で示される化合物のアルカリ金属エノラート又はジアニオンを反応させて、

（式中のＲ₂は水素、置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基、炭素数７〜２０のアラルキル基、炭素数３〜１０のトリアルキルシリル基、炭素数８〜１０のフェニルジアルキルシリル基または炭素数１３〜１５のジフェニルアルキルシリル基を、Ｘはフッ素以外のハロゲン原子を表す。）
下記一般式(III')で示される４−アミノ−３−オキソ−２−ハロゲノブタン酸エステルまたは塩の誘導体を製造し、

（式中のＲｓ、Ｐ₁、Ｐ₂は上記した意味を有し、Ｒ₃はアルカリ金属、置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基、炭素数７〜２０のアラルキル基、炭素数３〜１０のトリアルキルシリル基、炭素数８〜１０のフェニルジアルキルシリル基または炭素数１３〜１５のジフェニルアルキルシリル基を表す。Ｘは上記した意味を有する。）
さらに得られた(III')の加水分解を行い、脱炭酸を行うことを特徴とする下記一般式(V)で示される３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体またはその塩の製造方法、

(In the formula, Rs is hydrogen, an alkyl group having 1 to 10 carbon atoms which may have a substituent, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, or a carbon skeleton thereof. P ₁ and P ₂ are independently of each other hydrogen or an amino protecting group, or P ₁ and P ₂ are combined to form a bifunctional amino protecting group, and E ₁ is a carboxyl group. As ruruboxy terminal , an alkoxy ester residue having 1 to 10 carbon atoms, an active ester of phenoxy group or benzyloxy group, N-oxysuccinimide or 1-oxybenzotriazole each optionally having a substituent on the ring Represents a residue that can form a residue, an active thioester residue, an imidazolyl group, an acid halide, an acid anhydride, or an acid azide.)
Reaction with an alkali metal enolate or dianion of a compound represented by the following general formula (IV),

(In the formula, R ₂ is hydrogen, an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or 3 to 10 carbon atoms. X represents a halogen atom other than fluorine.) A trialkylsilyl group, a phenyldialkylsilyl group having 8 to 10 carbon atoms or a diphenylalkylsilyl group having 13 to 15 carbon atoms.
A 4-amino-3-oxo-2-halogenobutanoic acid ester or salt derivative represented by the following general formula (III ′):

(In the formula, Rs, P ₁ and P ₂ have the above-mentioned meanings, R ₃ is an alkali metal, an optionally substituted alkyl group having 1 to 10 carbon atoms, and an aryl group having 6 to 15 carbon atoms. Group, an aralkyl group having 7 to 20 carbon atoms, a trialkylsilyl group having 3 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms, or a diphenylalkylsilyl group having 13 to 15 carbon atoms, X is as described above. Has meaning.)
Furthermore, the obtained (III ′) is hydrolyzed and decarboxylated to produce a 3-amino-2-oxo-1-halogenopropane derivative represented by the following general formula (V) or a salt thereof Method,

(Rs, P ₁ , P ₂ and X in the formula have the above-mentioned meanings.)

一般式(I)で示される化合物のアミノ基の根元の炭素原子がＳ配置である請求項１または２に記載の方法、但し、(I)式中のＲｓが水素である場合を除く。 The method according to claim 1 or 2, wherein the carbon atom at the base of the amino group of the compound represented by the general formula (I) is in S configuration, except that Rs in the formula (I) is hydrogen.

一般式(I)で示される化合物のアミノ基の根元の炭素原子がＲ配置である請求項１または２に記載の方法、但し、(I)式中のＲｓが水素である場合を除く。 The method according to claim 1 or 2, wherein the carbon atom at the base of the amino group of the compound represented by formula (I) is in the R configuration, except that Rs in formula (I) is hydrogen.

請求項１乃至４の製造方法に従って、一般式According to the manufacturing method of claims 1 to 4, the general formula (V)(V) で示される３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体またはその塩を得た後、該誘導体またはその塩を還元反応によりハロヒドリンとすることを特徴とする下記一般式A 3-amino-2-oxo-1-halogenopropane derivative represented by the following formula or a salt thereof, and then the derivative or the salt thereof is converted into a halohydrin by a reduction reaction: (VI)(VI) で示されるハロヒドリンの製造方法。The manufacturing method of halohydrin shown by these.

（式中のＲｓ、Ｐ(Rs in the formula, P ₁₁ 、Ｐ, P ₂₂ 、Ｘは上記した意味を有する。）, X has the meaning described above. )

請求項１乃至４の製造方法に従って、一般式(V)で示される３−アミノ−２−オキソ−１−ハロゲノプロパン誘導体またはその塩を得た後、該誘導体またはその塩を還元反応により下記一般式(VI)で示されるハロヒドリンとし、

（式中のＲｓ、Ｐ₁、Ｐ₂、Ｘは上記した意味を有する。）
さらに該ハロヒドリンをエポキシ化することを特徴とする下記一般式(VII)で示される化合物の製造方法。

（式中のＲｓ、Ｐ₁、Ｐ₂は上記した意味を有する。）After obtaining the 3-amino-2-oxo-1-halogenopropane derivative represented by the general formula (V) or a salt thereof according to the production method of claims 1 to 4, the derivative or the salt thereof is reduced by the following general reaction. A halohydrin represented by formula (VI),

(Rs, P ₁ , P ₂ and X in the formula have the above-mentioned meanings.)
Furthermore, the method for producing a compound represented by the following general formula (VII), wherein the halohydrin is epoxidized.

(Rs, P ₁ and P ₂ in the formula have the above-mentioned meanings.)

下記一般式(I)で示される化合物に、

（式中のＲｓは水素、それぞれ置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基もしくは炭素数７〜２０のアラルキル基、又はこれらの炭素骨格中にヘテロ原子を含む置換基を、Ｐ₁、Ｐ₂は互いに独立して水素もしくはアミノ保護基、又はＰ₁及びＰ₂は一体となって二官能性のアミノ保護基を、Ｅ₁はカルボキシ末端として、メトキシ又はエトキシのエステル残基を表す。）
酢酸のエステルのアルカリ金属エノラートを反応させることを特徴とする下記一般式(II)で示される化合物の製造方法。

（式中のRｓ、Ｐ₁、Ｐ₂、は上記した意味を有し、Ｒ₁は置換基を有していてもよい炭素数１〜１０のアルキル基、炭素数６〜１５のアリール基、炭素数７〜２０のアラルキル基、炭素数４〜１０のトリアルキルシリル基、炭素数８〜１０のフェニルジアルキルシリル基または炭素数１３〜１５のジフェニルアルキルシリル基を表す。）In the compound represented by the following general formula (I),

(In the formula, Rs is hydrogen, an alkyl group having 1 to 10 carbon atoms which may have a substituent, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, or a carbon skeleton thereof. a substituent containing a hetero atom in the P _1, P ₂ independently of one another are hydrogen or an amino protecting group, or P ₁ and P ₂ are amino protecting groups of the bifunctional together, E ₁ is Ca Represents a methoxy or ethoxy ester residue as the ruboxy end .)
A method for producing a compound represented by the following general formula (II), wherein an alkali metal enolate of an ester of acetic acid is reacted.

(In the formula, Rs, P ₁ and P ₂ have the above-mentioned meanings, and R ₁ is an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, A aralkyl group having 7 to 20 carbon atoms, a trialkylsilyl group having 4 to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10 carbon atoms, or a diphenylalkylsilyl group having 13 to 15 carbon atoms.)

一般式(I)で示される化合物のアミノ基の根元の炭素原子がＳ配置である請求項９に記載の方法、但し、(I)式中のＲｓが水素である場合を除く。 The method according to claim 9, wherein the carbon atom at the base of the amino group of the compound represented by the general formula (I) is in S configuration, except that Rs in the formula (I) is hydrogen.

一般式(I)で示される化合物のアミノ基の根元の炭素原子がＲ配置である請求項９に記載の方法、但し、(I)式中のＲｓが水素である場合を除く。 The method according to claim 9, wherein the base carbon atom of the amino group of the compound represented by the general formula (I) is in the R configuration, except that Rs in the formula (I) is hydrogen.