JP4335390B2 - Method for producing optically active oxazolidinone derivative - Google Patents

Method for producing optically active oxazolidinone derivative Download PDF

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JP4335390B2
JP4335390B2 JP34762999A JP34762999A JP4335390B2 JP 4335390 B2 JP4335390 B2 JP 4335390B2 JP 34762999 A JP34762999 A JP 34762999A JP 34762999 A JP34762999 A JP 34762999A JP 4335390 B2 JP4335390 B2 JP 4335390B2
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optically active
mmol
reaction
optical purity
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JP2000229956A (en
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賢三 鷲見
隆 今井
茂 三橋
秀樹 奈良
孝志 三浦
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Takasago International Corp
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Takasago International Corp
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Description

【0001】
【発明の属する技術分野】
本発明は、医薬原料として、又は光学活性アミノアルコールの原料として有用な光学活性オキサゾリジノンの製造法に関する。
【0002】
【従来の技術】
光学活性なオキサゾリジノンは、β−ブロッカー(S.Hamaguchi et al., Agric. Biol. Chem., 48, 2055, 2331 (1984); idem, ibid., 49, 1509, 1661, 1669 (1985)、抗うつ病薬( 特開平3−218367号公報) 、抗バクテリア剤(Drugs Fut., 21,1116(1996); EP0789025A1)の重要中間体として知られており、安価な製造法が望まれている。
【0003】
従来の製造方法としては、例えば、1)光学活性エポキシドより得られるアミノアルコールとジアルキルカーボナートとの閉環反応により得る方法(J. Med. Chem., 32, 1673 (1989)、あるいは、2)イソシアネート又はアシルアジドによる光学活性エポキシドの開環反応による方法(J. Med. Chem., 32, 1673 (1989)) 、3)D−マンニトール、L−アスコルビン酸、(R)-又は(S)-リンゴ酸を用いて合成する方法(Tetrahedron:Asymmetry, 6, 1181 (1995))、等がある。
【0004】
この他、ラセミ体のオキサゾリジノンを合成する方法として、4)β−ヒドロキシカルボン酸にジフェニルホスホリルアジドを作用させて環化する方法(Kor. J. Med. Chem., 4. 52 (1994)) 、Bull. Korean Chem. Soc., 15, 525 (1996))、更には、5)β−ヒドロキシプロピオノヒドラジドのCurtius 転位反応により得る方法(Heterocycles, 6, 1604 (1977)) 、Tetrahedron:Asymmetry, 8, 477 (1997)、Liebigs Ann. Chem., 150 (1979)) 等がある。
【0005】
しかしながら、これらの各方法は、それぞれ、次のような問題点を有している。
(1)方法1
J. Med. Chem., 32, 1673 (1989)
アニリンとエポキシドより得られるアミノアルコールをマンデル酸により光学分割をし、得られた光学活性アミノアルコールに炭酸ジエチルを作用させ、オキサゾリジノンを得る。マンデル酸により光学分割する際、アミノアルコールの一方の対象体を捨てるため、経済効率が悪い。
【0006】
【化4】

Figure 0004335390
【0007】
(2)方法2
J. Med. Chem., 32, 1673 (1989)
酵素的光学分割により光学活性エポキシドを得、それとイソシアナートより光学活性オキサゾリジノンが得られる。光学活性エポキシドを取得する手段として、光学活性C3クロルヒドリン型化合物の微生物的分割法による光学活性体の製造がなされている。しかし、多量の溶媒を必要とし、かつ、酵素的光学分割であるが故に不用の立体異性体が等量副生する等、生産効率に問題がある。
【0008】
【化5】
Figure 0004335390
【0009】
(3)方法3
Tetrahedron:Asymmetry, 6, 1181 (1995)
D-マンニトール、L-アスコルビン酸、 (R)- または(S)-リンゴ酸を用いて合成する方法が、報告されている。
D-マンニトールを出発物質として光学活性オキサゾリジノンが得られるが、下記のように、多段階を要する。
【0010】
【化6】
Figure 0004335390
【0011】
また、L-アスコルビン酸を用いる方法も、また、D-(S)-リンゴ酸を出発物質とする方法も、いずれも、反応段階が長く、しかも、D-(S)-リンゴ酸を出発物質とする方法では高価なジフェニルホスホリルアジドが用いられている。
【0012】
(4)方法4
Kor. J. Med. Chem., 4. 52 (1994)
β- ヒドロキシカルボン酸にジフェニルホスホリルアジドを作用させて、Curtius 転位反応を行いラセミ体のオキサゾリジノンを得ている。前記と同様に、ジフェニルホスホリルアジドは高価であり、反応は80℃で行われ爆発の危険性をもち工業的には不適当である。
【0013】
【化7】
Figure 0004335390
【0014】
他のBull. Korean Chem. Soc., 15, 525 (1996) も、高価なジフェニルホスホリルアジドが必要となり、また反応は80℃で行われ、爆発の危険性をもつ。
【0015】
(5)方法5
Tetrahedron:Asymmetry, 8, 477 (1997)
Lipaseによる光学分割により得られたβ- ヒドロキシエステルをヒドラジドとし、Curtius 転位反応により光学活性オキサゾリジノンが得られている。5℃以下でアシルアジドを発生させ、その反応液を室温まで昇温し一晩攪拌することにより、オキサゾリジノンが得られている。この際、室温でCurtius 転位反応を行うため、長時間を要し、また長時間アシルアジドを室温下で放置するため爆発の危険性を含み工業的に適さない。
【0016】
【化8】
Figure 0004335390
【0017】
他のHeterocycles, 6, 1604 (1977)、Liebigs Ann. Chem., 150 (1979)も、低温下で中間体のアシルアジドを発生させ、そのまま加熱し転位反応を行うため、反応を大量に行う場合、爆発の危険性がある。
【0018】
【発明が解決しようとする課題】
本発明の課題は、前記した従来の方法における種々の問題点を解決し、しかも、高収率、高い光学純度をもつ光学活性オキサゾリジノン誘導体を取得する新規な製造方法を提供するものである。
【0019】
【課題を解決するための手段】
本発明者らは、前記した実状に鑑み、効果的且つ経済的に優れた光学活性オキサゾリジノン誘導体の製造方法について鋭意検討した結果、生産効率が高く、工程の繁雑さがなく、しかも高収率で高い光学純度の光学活性オキサゾリジノン誘導体が得られることを見出し、本発明を完成するに至った。
【0020】
すなわち、本発明は、次に示す(1)乃至(3)のとおりである。
(1) 一般式(1)
【0021】
【化9】
Figure 0004335390
【0022】
(式中、R1は炭素数1乃至4の低級アルキル基、フェニル基、メトキシメチル基、ベンジルオキシメチル基、ベンゼン環が置換されてもよいベンジルオキシカルボニルアミノメチル基、炭素数3乃至10のアシルアミノメチル基、炭素数3乃至6のアルコキシカルボニルアミノメチル基を示し、R2,R3 は、同一又は異なってもよくそれぞれ水素原子、炭素数1乃至4の低級アルキル基、フェニル基、アセチルアミノメチル基、ベンゾイルアミノメチル基、ベンジル基を示し、R4は炭素数1乃至4の低級アルキル基を示す。*印は不斉炭素原子を意味する。)
で表される3位に水酸基を持つ光学活性酸エステルに、ヒドラジンを作用させ、一般式(2)
【0023】
【化10】
Figure 0004335390
【0024】
(式中、R1,R2,R3及び*印は前記と同一なものを意味する。)で表される3位に水酸基を持つ光学活性ヒドラジド誘導体となし、次いで、Curtius 転位反応を行うことを特徴とする、一般式(3)
【0025】
【化11】
Figure 0004335390
【0026】
(式中、R1,R2,R3及び*印は前記と同一なものを意味する。)で表される光学活性オキサゾリジノン誘導体の製造方法。
【0027】
(2) 3位に水酸基を持つ光学活性ヒドラジド誘導体を再結晶化することにより高純度の3位に水酸基を持つ光学活性ヒドラジド誘導体を得ることを特徴とする前記第1項記載の高純度の光学活性オキサゾリジノン誘導体の製造方法。
【0028】
(3) 前記1の一般式(1)で表される3位に水酸基を持つ光学活性酸エステルにおいて、R1がメチル基、フェニル基、メトキシメチル基、ベンジルオキシメチル基、ベンジルオキシカルボニルアミノメチル基、アセチルアミノメチル基、へキサノイルアミノメチル基、t−ブトキシカルボニルアミノメチル基を示し、R2,R3 が同一の水素原子又は水素原子とアセチルアミノメチル基、ベンジルアミノメチル基、ベンジル基を示し、R4は炭素数1乃至4の低級アルキル基を示すことを特徴とする請求項1または請求項2記載の光学活性オキサゾリジノン誘導体の製造方法。
【0029】
以下、本発明について、更に詳しく説明する。
本発明の出発物質として使用する一般式(1)で表される3位に水酸基を持つ光学活性酸エステル誘導体(1)は、一般式(4)
【0030】
【化12】
Figure 0004335390
【0031】
(式中、R1は炭素数1乃至4の低級アルキル基、フェニル基、メトキシメチル基、ベンジルオキシメチル基、ベンゼン環が置換されてもよいベンジルオキシカルボニルアミノメチル基、炭素数3乃至10のアシルアミノメチル基、炭素数3乃至6のアルコキシカルボニルアミノメチル基を示し、R2,R3 は、同一又は異なってもよくそれぞれ水素原子、炭素数1乃至4の低級アルキル基、フェニル基、アセチルアミノメチル基、ベンゾイルアミノメチル基、ベンジル基を示し、R4は炭素数1乃至4の低級アルキル基を示す。*印は不斉炭素原子を意味する。)で表されるβ−ケトエステル(4)を、不斉水素化して調製される。
【0032】
原料となるβ−ケトエステル(4)は、以下の方法に準じて合成することができる。
R1が炭素数1乃至4の低級アルキル基又はフェニル基であるβ−ケトエステル(4)は、容易に入手できる3−オキソブタン酸エステルより、既知の方法、例えば、外口らの特開平10−53561号公報に記載されている方法でアセト酢酸エステルと酸ハロゲン化物を反応させて合成する。R1がメトキシメチル基、ベンジルオキシメチル基などのアルコキシメチル基である4−アルコキシ−3−オキソブタン酸エステルは、容易に入手できる4−ハロゲノ−3−オキソプロピオン酸エステルより、既知の方法、例えば、R.M.Kellogg ら(J. Chem. Soc., Chem. Commun., 932 (1997)); D. Seebachら(Synthesis, 37 (1986) に記載されている方法で合成される。又、R1がN上に保護基を持つアミノメチル基を有するβ−ケトエステル(4)の調製は、例えば、ベンジルオキシカルボニルアミノメチル基の場合は、容易に入手できるベンジルオキシカルボニルグリシンを用い、既知の方法、例えば、NatsugariらのSynthesis, 403 (1992) に記載されている方法で合成される。
【0033】
R1に含まれるアミノ基の保護基としては、ベンジルオキシカルボニル基、アシル基、アルコキシカルボニル基が好ましく用いられる。
ベンジルオキシカルボニル基のベンゼン環への置換基としては、炭素数1乃至4の低級アルキル基、好ましくはメチル基、t−ブチル基等、炭素数1乃至4の低級アルコキシル基、好ましくはメトキシ基、又はハロゲン原子、好ましくは塩素原子である。これらの例としては、p−メトキシベンジル、2,4−ジメチルベンジル、p−メチルベンジル、3,5−ジメチルベンジル、p−クロロベンジル、p−t−ブチルベンジル等を用いることができる。
アシル基の例としては、アセチル基、プロパノイル基、ブタノイル基、ペンタノイル基、ヘキサノイル基、ヘプタノイル基、オクタノイル基、ノナノイル基、デカノイル基等を用いることができる。
アルコキシカルボニル基の例としては、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、ブトキシカルボニル基、t −ブトキシカルボニル基等を用いることができる。
【0034】
2位の置換基を有するβ−ケトエステル(4)の調製は、例えば、R2,R3がアセチルアミノメチル基、ベンゾイルアミノメチル基、ベンジル基の場合は、特開平2−231471号公報に記載されている方法により合成される。
原料としてのβ−ケトエステル(4)のR4は、炭素数1乃至4の低級アルキル基を用いることができる。
【0035】
β−ケトエステル(4)の不斉水素化は、特開平2−289537号公報記載の方法に準じて、触媒量のルテニウム−ホスフィン錯体の存在下、アルコール類を溶媒に用い、水素圧5乃至100気圧、反応温度10乃至100℃、反応時間5乃至20時間の条件で実施される。
【0036】
好ましく用いられるルテニウム−光学活性ホスフィン錯体としては、例えば、特開昭61−63690号公報に記載されている下記の一般式(5)
【0037】
【化13】
Figure 0004335390
【0038】
(式中、R5−BINAPは一般式(6)
【0039】
【化14】
Figure 0004335390
【0040】
で表される第3級ホスフィンを示し、R5は水素原子、メチル基、t−ブチル基又はメトキシ基を示し、Tは第3級アミンを示し、bが1のとき、aは1、cは1、dは0を示し、bが0のとき、aは2、cは4、dは1を示す。)で表される錯体や、特開昭62−265293号公報に記載されている下記一般式(7)
【0041】
【化15】
Figure 0004335390
【0042】
(式中、R5−BINAPは上記式(6)と同一の第3級ホスフィンを示し、R6は低級アルキル基又はトリフルオロメチル基を示す。)で表される下記の錯体等を挙げることができる。
【0043】
一般式(6)で表される第3級ホスフィンの具体例としては、次のものを挙げることができる。
ホスフィン1: 2,2'- ビス( ジフェニルホスフィノ)-1,1'- ビナフチル( 「BINAP 」と略記する。)
ホスフィン2: 2,2'- ビス[ ジ(p- トリル) ホスフィノ]-1,1'- ビナフチル( 「Tol-BINAP 」と略記する。)
ホスフィン3: 2,2'- ビス[ ジ(p-tert-ブチルフェニル) ホスフィノ]-1,1'- ビナフチル( 「t-Bu-BINAP」と略記する。)
ホスフィン4: 2,2'- ビス[ ジ(p- メトキシフェニル) ホスフィノ]-1,1'- ビナフチル( 「Methoxy-BINAP 」と略記する。)
【0044】
これらの第3級ホスフィン(6)は、いずれも(+)- 体及び(−)- 体が存在するので、目的とする光学活性な化合物(2)の絶対配置に応じて何れかを選択すればよい。すなわち、(3R)体を得るには(+)- 体を用い、(3S)体を得るには(−)- 体を用いればよい。
【0045】
一般式(5)中、Tで表される第3級アミンとしては、トリエチルアミン、トリブチルアミン、エチルイソプロピルアミン、1,8-ビス( ジメチルアミノ) ナフタレン、ジメチルアニリン、ビリジン、N-メチルピペリジン等が挙げられるが、中でもトリエチルアミンが好ましい。
【0046】
一般式(5)で表される錯体の具体例としては、次のものを挙げることができる。なお、第3級ホスフィンの絶対配置の表記は省略した。Etはエチル基を、Tol はトリル基置換を、また、t-Buはtert-ブチル基を示す。
錯体1: Ru2Cl4(BINAP)2NEt3
錯体2: Ru2Cl4(Tol-BINAP)2NEt3
錯体3: Ru2Cl4(t-Bu-BINAP)2NEt3
錯体4: Ru2Cl4(Methoxy-BINAP)2NEt3
錯体5: RuHCl(BINAP)2
錯体6: RuHCl(Tol-BINAP)2
錯体7: RuHCl(t-Bu-BINAP)2
錯体8: RuHCl(Methoxy-BINAP)2
【0047】
一般式(7)で表される錯体の具体例としては、次のものを挙げることができる。なお、第3級ホスフィンの絶対配置の表記は省略した。
錯体9: Ru(BINAP)(O2CCH3)2
錯体10: Ru(Tol-BINAP)(O2CCH3)2
錯体11: Ru(t-Bu-BINAP)(O2CCH3)2
錯体12: Ru(Methoxy-BINAP)(O2CCH3)2
錯体13: Ru(BINAP)(O2CCF3)2
錯体14: Ru(Tol-BINAP)(O2CCF3)2
錯体15: Ru(t-Bu-BINAP)(O2CCF3)2
錯体16: Ru(Methoxy-BINAP)(O2CCF3)2
【0048】
上記のルテニウム−光学活性ホスフィン錯体の使用量は、基質であるβ−ケトエステルに対して、1/100乃至1/10000倍モル、好ましくは1/500乃至1/4000倍モルである。水素化反応の溶媒としては、アルコール類が好ましく、中でもメチルアルコール、エチルアルコール、イソプロピルアルコールが良く、特にエチルアルコールが好ましい。溶媒の量は、通常は、基質に対して1乃至5倍(容量/重量)量を用いる。
【0049】
3位に水酸基を持つ光学活性酸エステル(1)を調製する第2の方法を以下説明する。
まず、β−オキソ酸エステルの不斉水素化物から光学活性なβ−ヒドロキシ酸エステルのアジド体を得る。ついで、アジド体を常法によりアシル化した後、還元的転位反応によりアシルアミドを得る。その他上記アジド体をターシャリーブチルジカーボネート(Di-tert-butyldicarbonate:((Boc)2O))などのアミノ基などを保護する官能基を有する化合物の共存下還元的転位反応させてアミノ基が保護された光学活性なβ−ヒドロキシ酸エステル(1)を得る。
【0050】
煩雑さを避けるためにこの方法を具体的な化合物を用いて説明するが、本発明はこの例に限定されるものではない。
例えば、4−クロロ−3−オキソブタン酸エチルを常法にて不斉水素化し、アジ化ナトリウムを作用させることにより光学活性な3−ヒドロキシブタン酸エチルのアジド体を得る(例えば、特開平8−119935号公報の方法による)。
該アジド体をアシルクロリドによりアシル化し、パラジウム・炭素(Pd−C)共存下還元的転位反応により光学活性な3−ヒドロキシブタン酸エチルのアシルアミドを得る(例えば、J.Org.Chem.,58,1287(1993)の方法による)。
あるいは、上記アジド体をターシャリーブチルジカーボネート(Di-tert-butyldicarbonate:((Boc)2O))の共存下還元的転位反応させてアミノ基が保護された光学活性な3−ヒドロキシブタン酸エチルを得る(例えば、Tetrahedron Lett.,30,837(1989)の方法による)。
【0051】
本発明の3位に水酸基を持つ光学活性ヒドラジド(2)の合成は、上記の不斉水素化で得られた3位に水酸基を持つ光学活性酸エステル(1)にアルコール溶媒中ヒドラジンを作用させることにより得られ、一般には0乃至100℃、好ましくは30乃至70℃の温度加熱することにより行われる。
【0052】
アルコール溶媒としては、メチルアルコール、エチルアルコール、イソプロピルアルコールが好ましい。又、用いられるヒドラジンの量は、化合物(1)1モルに対し1乃至5モル、好ましくは1.1乃至1.5モルで用いられる。反応後、得られた粗製の3位に水酸基を持つ光学活性ヒドラジドは、メタノール中にイソプロピルアルコールを加え、溶解、晶析、濾過を行って、高収率、且つ光学的に純粋な3位に水酸基を持つ光学活性ヒドラジド(2)が得られる。
【0053】
最後に、本発明では3位に水酸基を持つ光学活性ヒドラジド誘導体をCurtius転位反応により光学活性オキサゾリジノン誘導体とする。本発明におけるCurtius 転位反応は、文献(P.A.S. Smith, Organic Reactions,II, 337 (1946))の方法と異なり、3位に水酸基を持つ光学活性ヒドラジド(2)に、酸存在下、0〜5℃で亜硝酸ナトリウムを作用せしめて、中間体のアシルアジドを発生させ、この溶液をこのまま放置するかもしくは加熱した溶媒中に滴下することにより安全に目的とする光学活性オキサゾリジノン誘導体(3)へ導くことができる。
【0054】
亜硝酸ナトリウムの量は、化合物(2)1モルに対し1乃至2モル、好ましくは1.1乃至1.3モルで用いられる。本反応において、Curtius 転位反応に用いられる酸としては、塩酸、硫酸、燐酸、酢酸、スルホン酸、メタスルホン酸、p-トルエンスルホン酸等を用いることができ、塩酸、硫酸、酢酸が特に好ましい。反応に用いる溶媒は、塩化メチレン、クロロホルム等のハロゲン化炭化水素類、アセトン等のケトン類、酢酸エチル、酢酸ブチル等のエステル類、ジエチルエーテル、ジイソプロピルエーテル等のエーテル類、メタノール、エタノール、ブタノール等のアルコール類、ヘキサン、ヘプタン、トルエン、ベンゼン等の炭化水類、水及びこれらの混合物を用いる事ができ、水又は水とエーテル類の混合溶媒が特に好ましい。本反応における反応温度は、一般には20乃至100℃で、好ましくは30℃乃至50℃の温度で行われる。なお、本発明方法によれば、原料化合物(2)が光学活性であっても、その立体は保持されたまま、光学活性な本発明化合物(3)を得ることができる。
【0055】
なお、上記式(2)または式(3)で表される化合物のなかで、R1が炭素数3乃至10のアシルアミノメチル基あるいは炭素数3乃至6のアルコキシカルボニルアミノメチル基であり、R2やR3が水素原子である化合物は新規な化合物である。これら新規な化合物は、医薬製造中間体として、また、光学活性アミノアルコールの製造原料として有用である。とくに式(31)で表される新規化合物は抗菌剤として有用なリネゾリド(linezolid)(ファルマシアアップジョン社:Pharmacia&Upjohn Corp.)の製造中間体として有用である。
上記新規な化合物の製法の代表例は下記のような方法である。
3位に水酸基を持つ光学活性酸エステル(1)を第2の方法を用いて調製し、すでに述べたとおり、この酸エステル(1)にヒドラジンを作用させてヒドラジド(2)を得、Curtius転位反応させて新規光学活性なオキサゾリジノンを得ることができる。
【0056】
【化16】
Figure 0004335390
【0057】
【発明の効果】
本発明によれば、生産効率が高く、工程の繁雑さがない新規な光学活性オキサゾリジノン誘導体の製造方法を提供することができる。また、高収率で光学純度の高い光学活性オキサゾリジノン誘導体の新規な製造方法を提供することができる。
【0058】
【実施例】
以下に、実施例を挙げて本発明をさらに詳細に説明するが、本発明はこれらによって何ら限定されるものではない。
なお、実施例における物性の測定に使用した機器、条件は、特に断る以外は以下のとおりのものを採用した。
【0059】
核磁気共鳴スペクトル
1.核磁気共鳴スペクトル( 1H−NMR): ジェミニ−2000型(200MHz)(バリアン社製)
内部標準物質 : テトラメチルシラン
2.核磁気共鳴スペクトル(13C−NMR): ジェミニ−2000型(50MHz)(バリアン社製)
内部標準物質 : テトラメチルシラン
3.核磁気共鳴スペクトル( 1H−NMR): DRX500(500MHz)(ブルーカージャパン社製)
内部標準物質 : テトラメチルシラン
4.核磁気共鳴スペクトル(13C−NMR): DRX500(126MHz)(ブルーカージャパン社製)
内部標準物質 : テトラメチルシラン
融点 : MP−S3型(柳本商事株式会社)
高速液体クロマトグラフィー HPLC : 日立液体クロマトグラフィー L−600
ガスクロマトグラフィー GLC : Hewlett Packard 5890−II
【0060】
なお、光学純度の決定のためにMTPAエステルまたはMTPAアミドに誘導したが、このMTPAとは(R)−または(S)−α−methoxy−α−(trifluoromethyl)phenylacetic acidである。
【0061】
【参考例1】
(R)−4−メトキシ−3−ヒドロキシブタン酸メチルエステルの合成
2Lの4つ口フラスコに窒素気流下、水素化ナトリウム(60%)88.0g(2.2mol)、テトラヒドロフラン(753ml)を加え、ここに、4−クロロ−3−オキソ−ブタン酸メチルエステル150.6g(1.0mmol)、メタノール35.2g(1.1mol)の混合液を室温下(22〜24℃)で滴下し、滴下終了後室温下(22〜24℃)で1時間攪拌する。反応液を氷冷し2N塩酸600ml(1.2mol)を滴下する。反応物より、テトラヒドロフランを回収し、残渣にトルエン(400ml)を加え、水相をトルエン(200ml)で3回抽出する。有機相を5%食塩水で洗い、溶媒減圧留去後、残渣を減圧蒸留(沸点90℃/1000Pa)し、4−メトキシ−3−オキソブタン酸メチルエステル107.7g(液体)(74%)を得た。
【0062】
1H−NMR(200MHz,CDCl3 ,δppm): 4.08(s,2H),3.74(s,3H),3.52(s,2H),3.42(s,3H)
【0063】
10Lオートクレーブに窒素気流下、4−メトキシ−3−オキソブタン酸メチルエステル1473g(10.08mol)、エタノール2210ml、Ru2 Cl4 ((S)−tol−BINAP)2 ・NEt3 4.59g(5.09mmol)を入れ反応温度100℃、水素圧4000kPaで4時間不斉水素化を行った(転化率100%)。溶剤を減圧留去して表記化合物1490g(液体)を得た。
【0064】
1H−NMR(200MHz,CDCl3 ,δppm): 4.3−4.1(m,1H),3.70(s,3H),3.42(dd,J=4.6,12.2Hz,1H),3.36(dd,J=6.0,12.2Hz,1H),3.38(s,3H),2.52(d,J=6.4Hz,2H)
【0065】
なお、光学純度の測定は、次の条件で行った。
表記化合物を(R)−MTPAエステル誘導体としてHPLC分析し、光学純度は94%と算出した。
カラム: Cosmosil 5SL 4.6mm×250mm(Nacalai Tesque Inc.)
溶媒 : ヘキサン/エーテル=3/1(容量比)
流速 : 1.0ml/分
検出 : 254nm
【0066】
【実施例1】
(R)−4−メトキシ−3−ヒドロキシブタノヒドラジドの合成
10L4つ口フラスコに窒素気流下、(R)−4−メトキシ−3−ヒドロキシブタン酸メチルエステル(光学純度94%ee)1036g(6.99mol)、エタノール4140mlを加え、続いて、室温下20分かけてヒドラジン1水和物525g(10.49mol)を加えた。70℃で6時間攪拌した。反応液を室温(22〜24℃)まで冷却し、イソプロピルアルコール2Lを反応液に加え5℃に冷却する。1時間攪拌晶析し、濾過を行い、結晶の洗いにはイソプロピルアルコールを0.45L用いて、第一晶626.5gを得た。第一母液にメタノール1L、イソプロピルアルコール0.5Lを加え、同様に晶析を行い、第二結晶225.2gを得た。第一、第二結晶を合わせて表記化合物は、851.7g、収率は、82%であった(mp101.4℃、光学純度>99.9%ee)。
【0067】
1H−NMR(200MHz,CD3 OD,δppm): 4.2−4.0(m,1H),3.4−3.2(m,2H),3.37(s,3H),2.37(dd,J=5.0,14.2Hz,1H),2.20(dd,J=7.7,14.2Hz,1H)
【0068】
なお、次の反応を行い生成物の光学純度を測定した。
得られた(R)−4−メトキシ−3−ヒドロキシブタノヒドラジド40mg(0.27mmol)の酢酸溶液1mlを5℃に冷却し、亜硝酸ナトリウム28mg(0.40mmol)を加えた。反応液を室温(22〜24℃)で1時間攪拌し、80℃まで昇温し80℃で1時間攪拌する。反応液の酢酸を減圧留去し、粗生成物の光学純度をガスクロマトグラフィーにより測定した。
カラム : ALPHA DEX 120(0.25mm×30m)(SUPELCO製)
注入温度 : 200℃
カラム温度: 100℃から250℃
検知温度 : 250℃
昇温温度 : 5℃/分
【0069】
【実施例2】
(R)−5−メトキシメチル−2−オキサゾリジノンの合成
4つ口500mlのフラスコに、窒素気流下、実施例1で得られた(R)−4−メトキシ−3−ヒドロキシブタノヒドラジド(光学純度>99.9%ee)100.0g(0.675mol)、水150mlを加え、氷冷下(0〜5℃)35%濃塩酸64.5ml(0.742mol)を35分かけて加えた。滴下終了後、氷零下(0〜5℃)、亜硝酸ナトリウム51.2g(0.742mol)の水溶液(130ml)を2時間25分かけて加えた。滴下後、氷零下(0〜5℃)1時間攪拌した。別に、4つ口1Lのフラスコに、窒素気流下、水100mlを加え50℃に加温し、そこに、先に調整した反応液を2時間10分かけて滴下した。この際、激しく窒素ガスが発生し反応温度は55℃まで上昇した。先の反応液を30ml、20mlの水で2回洗浄して後者のフラスコに加えた。その反応液を50℃で2時間攪拌した。反応液の水を減圧留去し、反応残渣にメタノール100mlを加え、濾過して塩化ナトリウムを除いた。母液のメタノールを減圧留去し、残渣にメタノール100mlを加え、濾過して塩化ナトリウムを除いた。母液のメタノールを減圧留去し残渣を減圧蒸留(141℃/100Pa)し、81.1gの表題化合物を得た。収率は92%、光学純度は99.9%ee以上であった。
【0070】
1H−NMR(200MHz,CDCl3 ,δppm ): 4.76(ddt,J=6.6,8.8,4.8Hz,1H),3.66(ddd,J=8.8,8.4,4.4Hz,1H),3.59(d,J=4.8Hz,1H),3.50(ddd,J=6.6,8,4,1.0Hz,1H),3.43(s,3H)
13C−NMR(50MHz,CDCl3 ,δppm):159.96,72.59,59.04,42.09
【0071】
なお、光学純度の測定はガスクロマトグラフィーを用いて行った。
カラム : ALPHA DEX 120(0.25mm×30m)(SUPELCO製)
注入温度 : 200℃
カラム温度: 100℃から250℃
検知温度 : 250℃
昇温温度 : 5℃/分
【0072】
【参考例2】
(S)−4−ベンジルオキシ−3−ヒドロキシブタン酸エチルエステルの合成
60%水素化ナトリウム82.9g(2.07mol)にテトラヒドロフラン775mlを加えた懸濁液に、ベンジルアルコール112g(1.04mol)と4−クロロ−3−オキソブタン酸エチルエステル155g(0.94mol)の混合液を35〜40℃で滴下する。滴下終了後、40℃で1時間攪拌する。反応物より、テトラヒドロフランを回収し、ヘプタン500mlを加える。この溶液を水800mlに滴下し、結晶を析出させる。結晶を室温で分離し、ヘプタンで洗浄する。結晶に酢酸ブチルエステル800ml、1N−HCl1000mlを加え、抽出する。有機相を5%食塩水500ml、5%NaHCO3 水500ml、5%食塩水で洗浄し、pH6〜7とする。酢酸ブチルエステルを回収し、ヘプタン100mlを加え、攪拌後分液し、4−ベンジルオキシ−3−オキソブタン酸エチルエステル173g(78%収率)を得た。
【0073】
1H−NMR(200MHz,CDCl3 ,δppm): 7.6−7.2(m,5H),5.16(s,2H),4.15(q,J=7.2 Hz,2H),3.45(s,2H),1.21(t,J=7.2Hz,3H)
【0074】
100mlのオートクレーブに4−ベンジルオキシ−3−オキソブタン酸エチルエステル20.0g(84.7mmol)、エタノール16ml、Ru2 Cl4 ((R)−tol−BINAP)2 ・NEt3 31mg(0.034mmol)を入れ反応温度100℃、水素圧10atmで3時間不斉水素化を行った(転化率100%)。溶剤を減圧留去して表記化合物18.0g(液体)を得た。
【0075】
1H−NMR(200MHz,CDCl3 ,δppm ): 7.4−7.2(m,5H),4.56(s,2H),4.3−4.1(m,1H),4.15(q,J=7.1Hz,2H),3.53(dd,J=4.6,9.5Hz,1H),3.46(dd,J=5.9,9.5Hz,1H),3.00(bs,1H),2.54(d,J=6.2Hz,2H),1.25(t,J=7.1Hz,3H)
【0076】
なお、光学純度の測定は、次の条件で行った。
表記化合物を(R)−MTPAエステル誘導体としてHPLC分析し、光学純度は89%eeと算出した。
カラム: Cosmosil 5SL 4.6mm×250mm(Nacalai Tesque Inc.)
溶媒 : ヘキサン/エーテル=9/1(容量比)
流速 : 1.0ml/分
検出 : 254nm
【0077】
【実施例3】
(S)−4−ベンジルオキシ−3−ヒドロキシブタノヒドラジドの合成
100mlのフラスコに、窒素気流下、参考例2で得られた(S)−4−ベンジルオキシ−3−ヒドロキシブタン酸エチルエステル(光学純度89%ee)4.15g(17.4mmol)、エタノール20ml、ヒドラジン1水和物2.62g(52.2mmol)を加え、20時間加熱還流した。反応液を室温(22〜24℃)まで冷却し、反応液のエタノールを減圧留去し、残渣に、エーテル40ml加え加熱還流して粗結晶を溶解し、5℃に冷却する。1時間攪拌晶析し、濾過を行い、結晶の洗いにはエーテル10mlを用いて、2.90gの表題化合物を得た。収率は74%であった(mp96.9℃、光学純度>99.9%ee)。
【0078】
1H−NMR(200MHz,CDCl3 ,δppm): 7.4−7.2(m,5H),4.56(s,2H),4.3−4.1(m,1H),4.0−3.8(bs,2H),3.51(dd,J=4.6,9.6Hz,1H),3.44(dd,J=6.4,9.4Hz,1H),2.41(dd,J=4.8,15.4Hz,1H),2.31(dd,J=7.4,15.4Hz,1H),1.8−1.5(bs,1H)
【0079】
なお、次の反応を行い生成物の光学純度を測定した。
得られた(S)−4−ベンジルオキシ−3−ヒドロキシブタノヒドラジド50mg(0.22mmol)の酢酸溶液1mlを5℃に冷却し、亜硝酸ナトリウム23mg(0.33mmol)を加えた。反応液を室温(22〜24℃)で1時間攪拌し、80℃まで昇温し80℃で1時間攪拌する。反応液の酢酸を減圧留去し、粗生成物を(R)−MTPAアミド誘導体としてHPLC分析した。
カラム: Cosmosil 5SL 4.6mm×250mm(Nacalai Tesque Inc.)
溶媒 : ヘキサン/エーテル=3/7(容量比)
流速 : 1.0ml/分
検出 : 254nm
【0080】
【実施例4】
(S)−5−ベンジルオキシメチル−2−オキサゾリジノンの合成
2つ口20mlのフラスコに、窒素気流下、実施例3で得られた(S)−4−ベンジルオキシ−3−ヒドロキシブタノヒドラジド(光学純度>99.9%ee)150mg(0.67mmol)、水2mlを加え、氷冷下(0〜5℃)35%濃塩酸85ml(1.01mmol)を3分かけて加えた。滴下終了後、氷零下(0〜5℃)エーテル1mlを加え、続いて亜硝酸ナトリウム69mg(1.01mmol)を3分かけて加えた。反応液を氷零下(0〜5℃)1時間攪拌した後、反応液に飽和炭酸水素ナトリウム水溶液を1ml加え、酢酸ブチルエステル10mlにて抽出し、有機相を5%食塩水2mlで洗う。別に、2つ口20mlのフラスコに窒素気流下、酢酸ブチルエステル1mlを加え100℃に加温し、そこに、先に抽出した酢酸ブチルエステル反応液を、10分かけて滴下した。この際、激しく窒素ガスが発生した。先の反応液を0.5ml、0.2mlの酢酸ブチルエステルで2回洗浄して後者のフラスコに加えた。その反応液を100℃で4時間攪拌した。反応液の酢酸ブチルエステルを減圧留去し、反応残渣をカラムクロマトにより精製し、137mgの表題化合物を得た。収率は99%、光学純度は99.9%ee以上であった。
【0081】
1H−NMR(200MHz,CDCl3 ,δppm ): 7.4−7.2(m,5H),6.6−6.4(m,1H),4.9−4.6(m,1H),4.58(s,2H),3.61(dd,J=8.0,8.4,1H),3.62(d,J=4.8Hz,2H),3.42(dd,J=6.6,8.4HZ,1H)
【0082】
なお、光学純度の測定は、次の条件で行った。
表記化合物を(R)−MTPAアミド誘導体としてHPLC分析した。
カラム: Cosmosil 5SL 4.6mm×250mm(Nacalai Tesque Inc.)
溶媒 : ヘキサン/エーテル=3/7(容量比)
流速 : 1.0ml/分
検出 : 254nm
【0083】
【参考例3】
(S)−4−ベンジルオキシカルボニルアミノ−3−ヒドロキシブタン酸エチルエステルの合成
1Lの4つ口フラスコに、窒素気流下で、N−ベンジルオキソカルボニル−グリシン50g(0.24mol)、アセトニトリル300mlを入れ、30分かけて1,1’−カルボニルジイミダゾール39.5g(0.24mol)を加え、室温(22〜24℃)で2時間攪拌した。7℃まで冷却後、マロン酸カリウムエチルエステル61.0g(0.36mol)を5分で加え、その後、塩化マグネシウム23.0g(0.24mol)を30分かけて加え、室温で30分攪拌した後、50℃で2時間攪拌して反応を終了させた。アセトニトリルを減圧留去し、5%塩酸水溶液550mlを加え、酢酸ブチル180mlで抽出、洗浄し、有機相をさらに5%塩酸水溶液100mlで洗浄後、8%炭酸ナトリウム水溶液100mlで中和、水100mlで洗浄後、溶剤を減圧留去して4−ベンジルオキシカルボニルアミノ−3−オキソブタン酸エチルエステル67.1g(液体)を得た。カラムクロマトにより単離精製したところ、収率は90%であった。
【0084】
1H−NMR(200MHz,CDCl3 ,δppm): 7.4〜7.2(m,5H),5.63(s,1H),5.10(s,2H),4.1〜4.2(m,4H),3.46(s,2H),1.26(t,J=7.1Hz,3H)
【0085】
200mlのオートクレーブに、窒素気流下、4−ベンジルオキシカルボニルアミノ−3−オキソブタン酸エチルエステル40g(0.13mol)、エタノール120ml、Ru2 Cl4 ((R)−tol−BINAP)2 ・NEt3 173mg(0.102mmol)を入れ、50℃、水素圧30atmで17時間不斉水素化を行った(転化率98.4%、光学純度94%ee)。エタノールを減圧留去して、表記化合物38.9g(液体)を得た。この一部をカラムクロマトにより単離精製したところ、収率は91%であった。
【0086】
1H−NMR(200MHz,CDCl3 ,δppm ): 7.4−7.2(m,5H),5.48(s,1H),5.09(s,2H),4.2−4.0(m,4H),3.4−3.1(m,2H),2.5−2.4(m,2H),1.26(t,J=7.1Hz,3H)
【0087】
なお、光学純度の測定は、次の条件で行った。
カラム: キラルセル(Chiralcel)OD−H、4.6mm×250mm(ダイセル(株)製)
溶媒 : ヘキサン/イソプロピルアルコール=9/1(容量比)
流速 : 1.0ml/分
検出 : 210nm
【0088】
【実施例5】
(S)−4−ベンジルオキシカルボニルアミノ−3−ヒドロキシブタノヒドラジドの合成
100mlのフラスコに窒素気流下、参考例3で得られた(S)−4−ベンジルオキシカルボニルアミノ−3−ヒドロキシブタン酸エチルエステル(光学純度94%ee)2.70g(9.60mmol)、エタノール40ml、ヒドラジン1水和物2.40g(48.0mmol)を加え、20時間加熱還流した。反応液を室温(22〜24℃)まで冷却し、反応液のエタノールを減圧留去し、残渣に、メタノール30ml加え加熱還流して粗結晶を溶解し、5℃に冷却する。1時間攪拌晶析し、濾過を行い、結晶の洗いにはエーテル10mlを用いて、1.42gの表題化合物を得た。収率は52%であった(mp135.4℃、光学純度>99.9%ee)。
【0089】
1H−NMR(200MHz,CD3 OD,δppm): 7.4−7.2(m,5H),5.07(s,2H),4.2−3.9(m,1H),3.22(dd,J=5.4,14.0,1H),3.13(dd,J=6.3,14.0Hz,1H),2.32(dd,J=4.8,14.4Hz,1H),2.21(dd,J=8.2,14.4Hz,1H)
【0090】
なお、次の反応を行い生成物の光学純度を測定した。
得られた(S)−4−ベンジルオキシカルボニルアミノ−3−ヒドロキシブタノヒドラジド50mg(0.19mmol)の酢酸溶液1mlを5℃に冷却し、亜硝酸ナトリウム19mg(0.28mmol)を加えた。反応液を室温(22〜24℃)で1時間攪拌し、80℃まで昇温し80℃で1時間攪拌する。反応液の酢酸を減圧留去し、粗生成物を(R)−MTPAアミド誘導体としてHPLC分析した。
【0091】
カラム: Cosmosil 5SL 4.6mm×250mm(Nacalai Tesque Inc.)
溶媒 : ヘキサン/エーテル=3/7(容量比)
流速 : 1.0ml/分
検出 : 254nm
【0092】
【実施例6】
(R)−5−ベンジルオキシカルボニルアミノメチル−2−オキサゾリジノンの合成
2つ口20mlのフラスコに、窒素気流下、実施例5で得られた(S)−4−ベンジルオキシカルボニルアミノ−3−ヒドロキシブタノヒドラジド(光学純度>99.9%ee)103mg(0.39mmol)、水1mlを加え、氷零下(0〜5℃)35%濃塩酸49ml(0.59mmol)を3分かけて加えた。滴下終了後、氷冷下(0〜5℃)ジイソプロピルエーテル1mlを加え、続いて亜硝酸ナトリウム40mg(0.59mmol)を3分かけて加えた。反応液を氷冷下(0〜5℃)1時間攪拌した後、反応液に飽和炭酸水素ナトリウム水溶液を1ml加え、酢酸ブチルエステル10mlにて抽出し、有機相を5%食塩水2mlで洗う。別に、2つ口20mlのフラスコに窒素気流下、酢酸ブチルエステル1mlを加え110℃に加温し、そこに、先に抽出した酢酸ブチルエステル反応液を、10分かけて滴下した。この際、激しく窒素ガスが発生した。先の反応液を0.5ml、0.2mlの酢酸ブチルエステルで2回洗浄して後者のフラスコに加えた。その反応液を100℃で4時間攪拌した。反応液の酢酸ブチルエステルを減圧留去し、反応残渣をカラムクロマトにより精製し、95mgの表題化合物を得た。収率は99%、光学純度は99.9%ee以上であった。
【0093】
1H−NMR(200MHz,CDCl3 ,δppm): 7.4−7.2(m,5H),6.14(bs,1H),5.7−5.5(m,1H),5.10(s,2H),4.8−4.6(m,1H),3.7−3.2(m,4H)
13C−NMR(200MHz,CDCl3 ,δppm): 159.78,156.85,136.18,128.43,128.09,127.90,75.34,66.78,43.58,42.67
【0094】
なお、光学純度の測定は、次の条件で行った。
表記化合物を(R)−MTPAアミド誘導体としてHPLC分析した。
カラム: Cosmosil 5SL 4.6mm×250mm(Nacalai Tesque Inc.)
溶媒 : ヘキサン/エーテル=3/7(容量比)
流速 : 1.0ml/分
検出 : 254nm
【0095】
【参考例4】
(2S,3R)−2−(N−ベンゾイルアミノ)メチル−3−ヒドロキシブタン酸メチルエステルの合成
窒素気流下、100mlのオートクレーブに、2−(N−ベンゾイルアミノ)メチル−3−オキソブタン酸メチルエステル2.5g(10mmol)とRu2 Cl4 ((R)−BINAP)2 ・NEt3 173mg(0.102mmol)を塩化メチレン17.5mlに溶かしたものを加え、50℃、水素圧100atmで20時間攪拌した。溶媒を減圧留去し、残渣をカラムクロマトにより単離精製し、2.25gの表題化合物を得た。収率90%、光学純度98%ee。
【0096】
1H−NMR(200MHz,CDCl3 ,δppm): 7.8−7.4(m,5H),7.02(bs,1H),4.2−4.1(m,1H),4.1−4.0(m,1H),3.73(s,3H),3,7−3.5(m,1H),2.7−2.5(m,1H),1.26(d,J=6.3Hz,3H)
【0097】
(R)−MTPAエステルに誘導した後、下記条件にて高速液体クロマトグラフィーを使用して光学純度を決定した。
カラム: Develosil 100−3 4.6mm×250mm(野村化学(株)製)
溶媒 : ヘキサン/エーテル=9/1(容量比)
流速 : 1.0ml/分
検出 : 254nm
【0098】
【実施例7】
(2S,3R)−2−(N−ベンゾイルアミノ)メチル−3−ヒドロキシブタノヒドラジドの合成
100mlのフラスコに、窒素気流下、参考例4で得られた(2S,3R)−2−(N−ベンゾイルアミノ)メチル−3−ヒドロキシブタン酸メチルエステル(光学純度98%ee)3.80g(15.1mmol)、メタノール38ml、ヒドラジン1水和物4.54g(90.74mmol)を加え、10時間加熱還流した。反応液を5℃に冷却する。1時間攪拌晶析し、濾過を行い、結晶の洗いにはエーテル10mlを用いて、2.35gの表題化合物を得た。収率は62%であった(mp185.4℃、光学純度>99.9%ee)。
【0099】
1H−NMR(200MHz,CD3 OD,δppm): 7.8−7.7(m,2H),7.6−7.3(m,3H),3.92(dq,J=8.2,6.2Hz,1H),3.79(dd,J=4.8,13.6Hz,1H),3.63(dd,J=8.2,13.6Hz,1H),2.49(ddd,J=4.8,8.2,8.2Hz,1H),1.19(d,J=6.2Hz,3H)
【0100】
なお、次の反応を行い生成物の光学純度を測定した。
得られた(2S,3R)−2−(N−ベンゾイルアミノ)メチル−3−ヒドロキシブタノヒドラジド50mg(0.20mmol)の酢酸溶液1mlを5℃に冷却し、亜硝酸ナトリウム21mg(0.30mmol)を加えた。反応液を室温(22〜24℃)で1時間攪拌し、80℃まで昇温し80℃で1時間攪拌する。反応液の酢酸を減圧留去し、粗生成物を(R)−MTPAアミド誘導体としてHPLC分析した。
【0101】
カラム: Cosmosil 5SL 4.6mm×250mm(Nacalai Tesque Inc.)
溶媒 : エーテル
流速 : 1.0ml/分
検出 : 254nm
【0102】
【実施例8】
(5R,4R)−5−メチル−4−(N−ベンゾイルアミノ)メチル−2−オキサゾリジノンの合成
2つ口50mlのフラスコに、窒素気流下、亜硝酸ナトリウム412mg(5.97 mmol)、水2mlを加え、氷零下(0〜5℃)、実施例7で得られた(2S,3R)−2−(N−ベンゾイルアミノ)メチル−3−ヒドロキシブタノヒドラジド(光学純度>99.9%ee)1.00g(3.98mmol)の酢酸6ml溶液を5分かけて加えた。別に、2つ口50mlのフラスコに窒素気流下、水1mlを加え50℃に加温し、そこに、先に調整した反応液を10分かけて滴下した。先の反応液を0.5mlの水で2回洗浄して後者のフラスコに加えた。その反応液を50℃で2時間攪拌した。反応液の水を減圧留去し、反応残渣に酢酸ブチルエステル10mlを加え、濾過して酢酸ナトリウムを除いた。濾別した酢酸ナトリウムを5mlの酢酸ブチルエステルで2回洗浄し、得られた母液の酢酸ブチルエステルを減圧留去し、反応残渣をカラムクロマトにより精製し、451mgの表題化合物を得た。収率は48%、光学純度は99.9%ee以上であった。
【0103】
mp : 156.7℃
1H−NMR(200MHz,CDCl3 ,δppm): 7.9−7.7(m,2H),7.6−7.3(m,3H),6.99(bs,1H),4.74(dq,J=7.0,6.6Hz,1H),4.1−3.8(m,2H),3.2−3.0(m,1H),1.39(d,J=6.6Hz,3H)
13C−NMR(50MHz,CDCl3 ,δppm): 168.42,160.36,133.73,131.66,128.42,127.30,75.62,54.97,40.32,14,35
【0104】
なお、光学純度の測定は、次の条件で行った。
表記化合物を(R)−MTPAアミド誘導体としてHPLC分析した。
カラム: Cosmosil 5SL 4.6mm×250mm(Nacalai Tesque Inc.)
溶媒 : エーテル
流速 : 1.0ml/分
検出 : 254nm
【0105】
【参考例5】
(S)−3−ヒドロキシ−3−フェニルプロピオン酸メチルエステルの合成
1Lのオートクレーブに、窒素気流下、Ru2 Cl4 ((R)−tol−BINAP)2 ・NEt3 0.84g(1.0mmol)、ベンゾイル酢酸メチルエステル178g(1.00mol)、メタノール500mlの混合液を、50℃、水素圧100atmで16時間攪拌した。溶剤を減圧留去して残渣を減圧蒸留(99℃/100Pa)し、表記化合物171g(液体)を得た。収率は95%
であった(光学純度87%ee)。
【0106】
1H−NMR(200MHz,CDCl3 ,δppm): 7.5−7.2(m,5H),5.2−5.0(m,1H),3,71(s,3H),3.29(bs,1H),2.77(dd,J=9.2,16.3Hz,1H),2.70(dd,J=3.8,16.3Hz,1H)
【0107】
光学純度は下記の条件で測定した。
カラム: キラルセル(Chiralcel)OD−H、4.6mm×250mm(ダイセル(株)製)
溶媒 : ヘキサン/イソプロピルアルコール=95/5(容量比)
流速 : 1.0ml/分
検出 : 254nm
【0108】
【実施例9】
(S)−3−ヒドロキシ−3−フェニルプロピオノヒドラジドの合成
1Lの4つ口フラスコに(S)−3−ヒドロキシ−3−フェニルプロピオン酸メチルエステル(光学純度87%ee)200g(1.11mol)、ヒドラジン一水和物77.8g(1.56mol)、メタノール400mlを仕込み、70℃で3時間加熱撹拌した。後氷水で5℃に冷却しろ過、結晶をメタノール4.7Lに熱時溶解し、5℃に冷却して析出した結晶をろ過、乾燥して148gの目的物を得た。収率は74%であった(mp179.5℃、光学純度>99.9%ee)。
【0109】
1H−NMR(200MHz,D2 O,δppm): 7.5−7.2(m,5H),5.1−5.0(m,1H),2.69(dd,J=8.2,14.2Hz,1H),2.59(dd,J =6.0,14.2Hz,1H)
13C−NMR(200MHz,CDCl3 ,δppm): 172.28, 142.56,129.20,128.65,126.32,71.11,43.30
【0110】
光学純度測定用試料の合成は、次のように行った。
上記(S)−3−ヒドロキシ−3−フェニルプロピオノヒドラジド100mg(0.55mmol)、ピリジン5ml、酢酸エチルエステル2mlの混合物を室温下3時間攪拌した。その後、反応液を水にあけ、酢酸エチルエステルで抽出し、酢酸エチルエステル層を1N塩酸水溶液で洗浄、5%食塩水で2回洗浄後、無水硫酸ナトリウムで乾燥し、溶媒留去後、0.25gの粗生成物を得た。この物を下記の条件で分析し、99.9%ee以上の光学純度であった。
【0111】
カラム: キラルセル(Chiralcel) OD−H、4.6mm×250mm(ダイセル(株)製)
溶媒 : ヘキサン/イソプロピルアルコール=7/3(容量比)
流速 : 1.0ml/分
検出 : 210nm
【0112】
【実施例10】
(R)−5−フェニル−2−オキサゾリジノンの合成
1Lの4つ口フラスコに(S)−3−ヒドロキシ−3−フェニルプロピオノヒドラジド(光学純度>99.9%ee)150g(0.83mol)、35%濃塩酸150g(1.44mol)、水220ml、酢酸エチルエステル100mlを加え、5℃に冷却し、これに亜硝酸ナトリウム57.5g(0.83mol)の水溶液(水80ml)を5℃で1時間かけて滴下した。同温下で30分攪拌した後、反応液の水層を酢酸エチルエステル100mlで抽出し、反応液の酢酸エチルエステル層と合わせ、5%食塩水で2回洗浄した。酢酸エチルエステル層を100℃に加熱した水100ml中に滴下し、熱分解を行うと同時に酢酸エチルエステルを回収した。滴下後残留物を室温に冷却し、酢酸エチルエステル200mlを加えて、無水硫酸ナトリウムで乾燥、溶媒留去後、123.5gの粗生成物を得た。このものを水150ml、メタノール90mlに加熱溶解し、5℃で晶析して、113.1gの(R)−5−フェニル−2−オキサゾリジノンを得た。収率は83%であった(mp96.4℃、光学純度>99.9%ee)。
【0113】
1H−NMR(200MHz,CDCl3 ,δppm): 7.5−7.3(m,5H),5.64(t,J=8.2Hz,1H),5.14(bs,1H),3.99(dd,J=8.2,8.6Hz,1H),3.55(d,J=8.2Hz,8.6Hz,1H)
13C−NMR(50MHz,CDCl3 ,δppm): 162.16,140.57,129.91,129.83,126.81,79.36,49.30
【0114】
なお、光学純度は、下記の条件で測定した。
カラム: キラルセル(Chiralcel) OD−H、4.6mm×250mm(ダイセル(株)製)
溶媒 : ヘキサン/イソプロピルアルコール=95/5(容量比)
流速 : 1.0ml/分
検出 : 210nm
【0115】
【参考例6】
(R)−4−クロロ−3−ヒドロキシブタン酸エチルの合成
200 mlのオートクレーブに4-クロロ-3- オキソブタン酸エチル 40.0 g (0.24 mol)、Ru2Cl4((S)-tol-BINAP)2・NEt3 20 mg、エタノール40 ml を投入し、100 ℃、水素圧3 気圧、5 時間反応した。溶媒を除去後、反応液の蒸留 (60℃/200Pa)を行い、30.3 gの表題化合物を得た。光学純度 95% ee 。
【0116】
【参考例7】
(R)−4−アジド−3−ヒドロキシブタン酸エチルの合成
200 mlの4 つ口フラスコに(R)-4-クロロ-3- ヒドロキシブタン酸エチル 20.0 g (0.12 mol), アジ化ナトリウム 15.6 g (0.24 mol), DMF 80 ml をいれ、反応温度約100 ℃、24 h撹拌を行った。反応液を冷却後、トルエン100 mlを加え、水50 mlで洗浄した後濃縮を行い、16.5 gの表題化合物を得た。収率は79% であった。
【0117】
【参考例8】
(R)−4−アジド−3−アセトキシブタン酸エチルの合成
100 mlの4 つ口フラスコに(R)-4-アジド-3- ヒドロキシブタン酸エチル 5.0 g (28.8 mmol), トリエチルアミン 3.5 g (34.6 mmol), 4-ジメチルアミノピリジン 0.11 g (0.900 mmol), テトラヒドロフラン50 ml を仕込み、0 ℃まで冷却後窒素気流下、塩化アセチル2.50 g (31.8 mmol)をゆっくり滴下した。滴下終了後室温で一晩撹拌後、溶媒を減圧留去し濃縮物4.94 gを得た。この濃縮物のカラムクロマトグラフィー (酢酸エチル/ ヘキサン = 1/10 ) により、4.50 gの表題化合物を得た。収率は73% であった。
【0118】
【参考例9】
(R)−4−アセチルアミノ−3−ヒドロキシブタン酸エチルの合成
200 mlのオートクレーブに (R)-4- アジド-3- アセトキシブタン酸エチル 4.50 g (20.9 mmol) , 5% Pd-C 0.02 g , 酢酸エチル 5 ml を仕込み、水素圧1000kPa、室温にて一晩撹拌を行った。触媒を除去し、濃縮を行い、3.20 gの表題化合物を得た。収率は81% であった。
【0119】
【実施例11】
(R)−4−アセチルアミノ−3−ヒドロキシブタノヒドラジドの合成
(R)-4-アセチルアミノ-3- ヒドロキシブタン酸エチル(光学純度 95% ee )5.00 g (26.4 mmol)をメタノール20 ml に溶解し、ヒドラジン1 水和物2.00 g (39.6 mmol)を室温にて、滴下した。滴下終了後65℃まで加熱を行い一晩撹拌した。室温まで冷却後メタノール20 ml を加え10℃にて晶析を行い、3.90 gの表題化合物を得た。収率は84% であった(mp 177.5℃、光学純度 >99.9% ee)。
【0120】
1H-NMR (500 MHz, CD3SOCD3, δppm): 1.81 (s, 3H), 2.07 (dd, J = 8.0, 14.2 Hz, 1H), 2.14 (dd, J = 4.8, 14.2 Hz, 1H), 2.97-3.06 (m, 1H), 3.06-3.11 (m, 1H), 3.86 (bs, 1H), 4.14 (bs, 2H), 4.77 (d, J = 4.4 Hz, 1H), 7.69 (bs, 1H), 8.85 (bs, 1H)
13C-NMR (126 MHz, CD3OD, δppm): 22.54, 40.37, 46.17, 68.59, 172.81, 173.73
【0121】
なお、次の反応を行い生成物の光学純度を測定した。
得られた (R)-4- アセチルアミノ-3- ヒドロキシブタノヒドラジド 36 mg (0.19 mmol)の酢酸溶液 1 ml を 5℃に冷却し、亜硝酸ナトリウム 19 mg (0.28 mmol)を加えた。反応液を室温 (22〜24℃) で 1時間撹拌し、80℃まで昇温し 80 ℃で 1時間撹拌する。反応液の酢酸を減圧留去し、粗生成物を 4- クロロベンゾイルアミド誘導体として下記の条件で HPLC 分析した。
【0122】
カラム: CHIRALPAC- AD 4.6 mm X 250 mm (ダイセル化学工業製)
溶媒 : ヘキサン / 2- プロパノール = 9 / 1
流速 : 1.0 ml /分
検出 : 254 nm
【0123】
【実施例12】
(S)−5−アセチルアミノメチル−2−オキサゾリジノンの合成
(R)-4-アセチルアミノ-3- ヒドロキシブタノヒドラジド( 光学純度 >99.9% ee) 3.50 g (20.0 mmol)に水14 ml を加え0 ℃まで冷却する。35 % HCl 2.29 g (22.0 mmol) を10 minかけて滴下後、亜硝酸ナトリウム1.52 g (22.0 mmol)を水 3.5 ml に溶解させた水溶液をゆっくり滴下した。そのままの温度にて1 時間撹拌後50℃の温水10 ml に先に調製した反応液を2 時間かけて滴下した。滴下終了後1 時間撹拌を行い、水を除去しメタノール30 ml を加え、塩を除去し粗表題化合物3.30 gを得た。この物をエタノール10 ml にて晶析を行い、2.75 gの表題化合物を得た。収率は87% であった(mp 137.5℃、光学純度 >99.9% ee)。
【0124】
1H-NMR (500 MHz, CD3SOCD3, δppm): 1.84 (s, 3H), 3.14-3.18 (m, 1H), 3.29 (t, J = 5.7 Hz, 2H), 3.49 (t, J = 8.8 Hz, 1H), 4.52-4.58 (m, 1H), 7.32 (bs, 1H), 8.05 (bs, 1H)
13C-NMR (126 MHz, CD3OD, δppm): 22.15, 41.46, 42.43, 73.91, 158.30, 169.55
【0125】
この生成物を4-クロロベンゾイルアミド誘導体として下記の条件で HPLC 分析した。
カラム: CHIRALPAC- AD 4.6 mm X 250 mm (ダイセル化学工業製)
溶媒 : ヘキサン / 2- プロパノール = 9 / 1
流速 : 1ml / 分
検出 : 254 nm
【0126】
【参考例10】
(R)−4−アジド−3−ヘキサノイルオキシブタン酸エチルの合成
100 mlの4 つ口フラスコに(R)-4-アジド-3- ヒドロキシブタン酸エチル 6.0 g (34.6 mmol),トリエチルアミン 4.2 g (41.5 mmol), 4-ジメチルアミノピリジン 0.12 g (1.04 mmol),テトラヒドロフラン60 ml を仕込み0 ℃まで冷却後窒素気流下、塩化ヘキサノイル5.10 g (38.1 mmol)をゆっくり滴下した。滴下終了後室温で5 時間撹拌後、5%塩酸14 ml を加え分液後5%食塩水30 ml で3 回洗浄し濃縮を行い、8.75 gの表題化合物を得た。収率は93% であった。
【0127】
【参考例11】
(R)−4−ヘキサノイルアミノ−3−ヒドロキシブタン酸エチルの合成
200 mlのオートクレーブに(R)-4-アジド-3- ヘキサノイルオキシブタン酸エチル 8.50 g (29.5 mmol) , 5% Pd-C 0.20 g ,酢酸エチル 16 mlを仕込み、水素圧10気圧、室温にて7 時間撹拌を行った。触媒を除去し、濃縮を行い、7.07 gの表題化合物を得た。収率は87% であった。
【0128】
【実施例13】
(R)−4−ヘキサノイルアミノ−3−ヒドロキシブタノヒドラジドの合成
(R)- 4- ヘキサノイルアミノ-3- ヒドロキシブタン酸エチル(光学純度 95% ee )6.50 g (24.9 mmol) をメタノール26 ml に溶解し、ヒドラジン1 水和物1.87 g (37.3 mmol)を室温にて、滴下した。滴下終了後65℃まで加熱を行い2 時間撹拌した。室温まで冷却後一晩撹拌を行い、析出した4.09 gの表題化合物を得た。収率は66% であった(mp 172.5℃、光学純度 >99.9% ee)。
【0129】
1H-NMR (500 MHz, CD3SOCD3, δppm): 0.86 (t, J = 7.0 Hz, 3H), 1.21-1.28 (m, 4H), 1.47-1.52 (m, 2H), 2.03-2.08 (m, 3H), 2.13 (dd, J = 4.8, 14.1 Hz, 1H), 3.00-3.03 (m, 1H), 3.07-3.10 (m, 1H), 3.84-3.87 ( m, 1H), 4.13(bs, 2H), 4.76 (d, J = 4.9 Hz, 1H), 7.62 (bs, 1H), 8.86 (bs, 1H)
13C-NMR (126 MHz, CD3OD, δppm): 14.26, 23.43, 26.66, 32.56, 37.04, 40.43, 46.06,68.69, 172.83, 176.76
【0130】
なお、次の反応を行い生成物の光学純度を測定した。
得られた (R)-4- ヘキサノイルアミノ-3- ヒドロキシブタノヒドラジド 47 mg (0.19 mmol)の酢酸溶液 1 ml を 5℃に冷却し、亜硝酸ナトリウム 19 mg (0.28 mmol)を加えた。反応液を室温 (22〜24℃) で 1時間撹拌し、80℃まで昇温し 80 ℃で 1時間撹拌する。反応液の酢酸を減圧留去し、粗生成物を MTPA アミド誘導体として下記の条件で HPLC 分析した。
【0131】
カラム: Cosmosil 5SL 4.6 mm X 250 mm(Nacalai Tesque Inc. 製)
溶媒 : ヘキサン / 2- プロパノール = 95 / 5
流速 : 1.0 ml /分
検出 : 254 nm
【0132】
【実施例14】
(S)−5−ヘキサノイルアミノメチル−2−オキサゾリジノンの合成
(R)-4-ヘキサノイルアミノ-3- ヒドロキシブタノヒドラジド( 光学純度 >99.9% ee) 2.50 g (10.1 mmol)に水33 ml を加え0 ℃まで冷却する。35 % HCl 1.16g (11.1mmol) を10 minかけて滴下後、亜硝酸ナトリウム0.77 g(11.1 mmol) を水 2.5 ml に溶解させた水溶液をゆっくり滴下した。そのままの温度にて2 時間撹拌後50℃の温水10 ml に先に調製した反応液を1 時間かけて滴下した。滴下終了後1 時間撹拌後、室温まで冷却し酢酸エチル20 ml で3 回抽出をおこなった。抽出した酢酸エチルを濃縮し、粗表題化合物を2.05 gを得た。カラムクロマトグラフィー(酢酸エチル/ ヘキサン = 1/1)により、0.96 gの表題化合物を得た。収率は85% であった(mp 124.1℃、光学純度 >99.9% ee)。
【0133】
1H-NMR (500 MHz, CD3SOCD3, δppm): 0.91 (t, J = 7.2Hz, 3H), 1.26-1.36 (m, 4H), 1.52-1.58 (m, 2H), 2.10-2.17 (m, 2H), 3.18-3.20 (m, 3H), 3.53 (t, J = 8.3Hz, 1H), 4.63-4.58 (m, 1H), 7.34 (bs, 1H), 7.97 (bs, 1H)
13C-NMR (126 MHz, CD3OD, δppm): 13.45, 21.49, 24.60, 30.57, 35.00, 41.31, 42.33,73.96, 158.29, 172.57
【0134】
光学純度は、MTPAアミド誘導体として下記の条件で HPLC 分析した。
カラム: Cosmosil 5SL 4.6 mm X 250 mm(Nacalai Tesque Inc. )
溶媒 : ヘキサン / 2- プロパノール = 95 / 5
流速 : 1.0 ml /分
検出 : 254 nm
【0135】
【参考例12】
(R)−4−t−ブトキシカルボニルアミノ−3−ヒドロキシブタン酸エチルの合成
200 mlのオートクレーブに (R)-4- アジド-3- ヒドロキシブタン酸エチル 4.90 g (28.2 mmol) , 5% Pd-C 0.25 g , (Boc)2O 6.47 g (29.6 mmol) 、酢酸エチル 5 ml を仕込み、水素圧1000kPa、室温にて8 時間撹拌を行った。触媒を除去し、濃縮を行い、5.26 g の表題化合物を得た。収率は75% であった。
【0136】
【実施例15】
(R)−4−t−ブトキシカルボニルアミノ−3−ヒドロキシブタノヒドラジドの合成
(R)-4-t-ブトキシカルボニルアミノ-3- ヒドロキシブタン酸エチル(光学純度 95% ee )6.50 g (26.1 mmol)をメタノール26 ml に溶解し、ヒドラジン1 水和物1.96 g (39.1 mmol)を室温にて、滴下した。滴下終了後65℃まで加熱を行い5 時間撹拌し、室温まで冷却後一晩撹拌を行い、4.27 gの表題化合物を得た。収率は70% であった(mp 143.6℃、光学純度 >99.9% ee)。
【0137】
1H-NMR (500 MHz, CD3SOCD3, δppm): 1.38 (s, 9H), 2.04 (dd, J = 8.2, 14.2 Hz, 1H), 2.14 (dd, J = 4.5, 14.2 Hz, 1H), 2.87-2.98 (m, 2H), 3.80-3.87 (m, 1H), 4.11 (bs, 1H), 4.69 (d, J = 5.0 Hz, 1H), 6.53 (bs, 1H), 8.84 (bs, 1H)
13C-NMR (126 MHz, CD3OD, δppm): 28.73, 40.29, 47.05, 68.98, 80.72, 158.62, 172.96
【0138】
なお、次の反応を行い表題化合物の光学純度を測定した。
得られた (R)-4- ブトキシカルボニルアミノ-3- ヒドロキシブタノヒドラジド 44 mg (0.19 mmol)の酢酸溶液 1 ml を 5℃に冷却し、亜硝酸ナトリウム 19 mg (0.28 mmol)を加えた。反応液を室温 (22〜24℃) で 1時間撹拌し、80℃まで昇温し 80 ℃で 1時間撹拌する。反応液の酢酸を減圧留去し、粗生成物を MTPA アミド誘導体として下記の条件で HPLC 分析した。
カラム: Inertsi SIL 100-5 4.6 mm X 250 mm(ジーエルサイエンス株式会社製)
溶媒 : ヘキサン / 2- プロパノール = 95 / 5
流速 : 0.5 ml /分
検出 : 254 nm
【0139】
【実施例16】
(S)−5−t−ブトキシカルボニルアミノメチル−2−オキサゾリジノンの合成
(R)-4-t-ブトキシカルボニルアミノ-3- ヒドロキシブタノヒドラジド( 光学純度 >99.9% ee) 2.00 g (8.57 mmol)に水10 ml を加え0 ℃まで冷却する。35 % HCl 0.89 g (8.57 mmol) を10分かけて滴下後、亜硝酸ナトリウム0.59 g (8.57 mmol)を水 2.0 ml に溶解させた水溶液をゆっくり滴下した。そのままの温度にて1 時間撹拌後50℃の温水10 ml に先に調製した反応液を1 時間かけて滴下した。滴下終了後1 時間撹拌後、室温まで冷却し酢酸エチル20 ml で3 回抽出をおこなった。抽出した酢酸エチルを濃縮し粗表題化合物1.06 gを得た。カラムクロマトグラフィー(酢酸エチル)により、0.96 gの表題化合物を得た。収率は52% であった(mp 115.5℃、光学純度 >99.9% ee)。
【0140】
1H-NMR (500 MHz, CD3SOCD3, δppm): 1.43 (s, 9H), 3.18-3.24 (m, 3H), 3.5 (t, J = 8.8Hz, 1H), 4.54-4.59 ( m,1H), 6.49 (bs, 1H), 7.32 (bs, 1H)
13C-NMR (126 MHz, CD3OD, δppm): 28.69, 43.99, 44.12, 76.98, 80.36, 158.44, 161.81
【0141】
光学純度は、MTPAアミド誘導体として下記の条件で HPLC 分析した。
カラム: Inertsi SIL 100-5 4.6 mm X 250 mm(ジーエルサイエンス株式会社製)
溶媒 : ヘキサン / 2- プロパノール = 95 / 5
流速 : 0.5 ml /分
検出 : 254 nm
【0142】
【参考例13】
(2S,3S)−2−ベンジル−3−ヒドロキシブタン酸メチルの合成
500 mlオートクレーブに窒素気流下、アセト酢酸メチル100 g(861 mmol), Ru2Cl4((S)-binap)2 ・NEt3 50 mg (0.0592 mmol), メタノール100 mlを入れ、50℃, 水素圧500kPaで45時間水素化を行った。反応終了後メタノールを回収し、減圧蒸留を行い(S)-3-ヒドロキシブタン酸メチル 91.56 g ( 65 ℃/1300Pa, 96% ee)を得た。
続いて、50 ml のフラスコにジイソプロピルアミン 3.3 g (30.0 mmol) とテトラヒドロフラン 10ml をいれ、窒素気流下、氷浴上n-ブチルリチウム1.5Mヘキサン溶液16.6 ml (24.9 mmol) を滴下、同温下で1h撹拌した。更に反応液を-40 ℃まで冷却し、先の (S)-3- ヒドロキシブタン酸メチル1.40 g (11.9mmol)を滴下し、0.5 時間撹拌後ヘキサメチルホスホルアミド 6mlに溶解させた臭化ベンジル3.00 g(17.5 mmol) を-10 ℃を越えないように滴下した。滴下終了後0 ℃まで上げて15分撹拌後、氷水に注ぎ酢酸エチルエステルにて抽出を行った。酢酸エチルエステルを濃縮し3.90 gの粗表題化合物を得た。カラムクロマトグラフィー( ヘキサン/ 酢酸エチル = 4/1 )により、表題化合物1.50 g (anti/syn = 98/2)を得た。収率は61% であった。
【0143】
【実施例17】
(2S,3S)−2−ベンジル−3−ヒドロキシブタノヒドラジドの合成
(2S, 3S)-2- ベンジル-3- ヒドロキシブタン酸メチル (96% ee、anti/syn = 98/2) 0.70 g (3.36 mmol) を2-プロパノール 1 ml に溶解し、ヒドラジン1 水和物0.34 g (6.72 mmol)を室温にて、滴下する。滴下終了後8 時間還流し一晩撹拌後濃縮する。濃縮物を酢酸エチル- ヘキサン混合溶媒にて晶析を行い、0.45 gの表題化合物を得た。収率は64% であった(mp 167.1℃、光学純度 >99.9% ee、anti/syn > 99/1 )。
【0144】
1H-NMR (500 MHz, CD3SOCD3, δppm): 1.10 (d, J = 6.4 Hz, 3H), 2.38-2.42 (m, 1H), 2.73 (dd, J = 4.8, 13.6 Hz, 1H), 2.83 (dd, J = 9.8, 13.6 Hz, 1H), 3.65-3.75 (m, 1H), 4.08 (s, 2H), 4.51 (d, J = 5.6Hz, 1H), 7.12-7.15 (m, 3H), 7.21-7.24 (m, 2H), 8.77 (bs, 1H)
13C-NMR (126 MHz, CD3OD, δppm): 20.95, 33.32, 52.80, 66.88, 125.53, 127.83, 128.54, 140.07, 172.06
【0145】
なお、次の反応を行い表題化合物の光学純度およびジアステレオマー比を測定した。
得られた (2S, 3S)-2-ベンジル-3- ヒドロキシ1-ブタノヒドラジド40 mg (0.19 mmol) の酢酸溶液 1 ml を 5℃に冷却し、亜硝酸ナトリウム 19 mg (0.28 mmol)を加えた。反応液を室温 (22〜24℃) で 1時間撹拌し、80℃まで昇温し 80 ℃で 1時間撹拌する。反応液の酢酸を減圧留去し、粗生成物を下記の条件で GLC分析した。
【0146】
光学純度は下記の条件で GLCにより測定した。
カラム : CHIRALSIL- DEX CB 0.25 mm X 25 m(Chrompack Inc.製)
注入温度 : 200 ℃
カラム温度: 165 ℃
検知温度 : 250 ℃
【0147】
ジアステレオマー比は下記の条件でGLC により測定した。
カラム : Neutra Bond-I 0.25 mm X 30 m(ジーエルサイエンス株式会社製)
注入温度 : 200 ℃
カラム温度: 150 ℃から 180℃
検知温度 : 250 ℃
昇温温度 : 2 ℃/ 分
【0148】
【実施例18】
(4S,5S)−4−ベンジル−5−メチル−2−オキサゾリジノンの合成
(2S, 3S)-2- ベンジル-3- ヒドロキシブタノヒドラジド( 光学純度 >99.9% ee、anti/syn > 99/1 )0.50 g (2.40 mmol)に水5.5 mlを加え0 ℃まで冷却する。35 % HCl 0.30 g (2.88 mmol) を滴下後、亜硝酸ナトリウム0.20 g(2.88 mmol) を水 1.0 ml に溶解させた水溶液をゆっくり滴下した。そのままの温度にて1 時間撹拌後50℃の温水10 ml に先に調製した反応液を0.5 時間かけて滴下した。滴下終了後1 時間撹拌、室温まで冷却しトルエン10 ml で3 回抽出をおこなった。抽出したトルエンを濃縮し粗表題化合物0.33 gを得た。カラムクロマトグラフィー精製( ヘキサン/ 酢酸エチル= 1/1)により、0.25 gの表題化合物を得た。収率は52% であった(mp 115.5℃、光学純度 >99.9% ee、anti/syn > 99/1 )。
【0149】
1H-NMR (500 MHz, CD3SOCD3, δppm): 1.07 (d, J = 6.3Hz, 3H), 2.73 (dd , J = 7.2, 13.6 Hz, 1H), 2.83 (dd, J = 5.6, 13.6 Hz, 1H), 3.53-3.59 (m, 1H), 4.23-4.26 (m, 1H), 7.22-7.23 (m, 3H), 7.27-7.30 (m, 2H), 7.59 (bs, 1H)
13C-NMR (126 MHz, CD3OD, δppm): 19.97, 40.16, 59.53, 76.38, 126.46, 128.30, 129.32, 136.47, 157.69
【0150】
光学純度は下記の条件で GLCにより測定した。
カラム : CHIRALSIL- DEX CB 0.25 mm X 25 m(Chrompack Inc.製)
注入温度 : 200 ℃
カラム温度: 165 ℃
検知温度 : 250 ℃
【0151】
ジアステレオマー比は下記の条件でGLC により測定した。
カラム: Neutra Bond-I 0.25 mm X 30 m(ジーエルサイエンス株式会社製)
注入温度 : 200 ℃
カラム温度: 150 ℃から 180℃
検知温度 : 250 ℃
昇温温度 : 2 ℃/ 分[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing an optically active oxazolidinone useful as a pharmaceutical raw material or a raw material for optically active amino alcohols.
[0002]
[Prior art]
Optically active oxazolidinones are β-blockers (S. Hamaguchi et al., Agric. Biol. Chem., 48, 2055, 2331 (1984); idem, ibid., 49, 1509, 1661, 1669 (1985), anti- It is known as an important intermediate for depression drugs (JP-A-3-218367) and antibacterial agents (Drugs Fut., 21,1116 (1996); EP0789025A1), and an inexpensive production method is desired.
[0003]
Conventional production methods include, for example, 1) a method obtained by a ring-closing reaction between an amino alcohol obtained from an optically active epoxide and a dialkyl carbonate (J. Med. Chem., 32, 1673 (1989), or 2) an isocyanate. Or a method by ring-opening reaction of an optically active epoxide with acyl azide (J. Med. Chem., 32, 1673 (1989)), 3) D-mannitol, L-ascorbic acid, (R)-or (S) -malic acid (Tetrahedron: Asymmetry, 6, 1181 (1995)), etc.
[0004]
In addition, as a method for synthesizing racemic oxazolidinone, 4) a method in which β-hydroxycarboxylic acid is reacted with diphenylphosphoryl azide (Kor. J. Med. Chem., 4.52 (1994)), Bull. Korean Chem. Soc., 15, 525 (1996)), and 5) a method obtained by the Curtius rearrangement reaction of β-hydroxypropionohydrazide (Heterocycles, 6, 1604 (1977)), Tetrahedron: Asymmetry, 8 477 (1997), Liebigs Ann. Chem., 150 (1979)).
[0005]
However, each of these methods has the following problems.
(1) Method 1
J. Med. Chem., 32, 1673 (1989)
An amino alcohol obtained from aniline and epoxide is optically resolved with mandelic acid, and diethyl carbonate is allowed to act on the obtained optically active amino alcohol to obtain oxazolidinone. When optically resolving with mandelic acid, one of the objects of amino alcohol is discarded, so that the economic efficiency is poor.
[0006]
[Formula 4]
Figure 0004335390
[0007]
(2) Method 2
J. Med. Chem., 32, 1673 (1989)
An optically active epoxide is obtained by enzymatic optical resolution, and an optically active oxazolidinone is obtained from it and an isocyanate. As a means for obtaining an optically active epoxide, an optically active substance is produced by a microbial resolution method of an optically active C3 chlorohydrin type compound. However, there is a problem in production efficiency such that a large amount of solvent is required and an equal amount of unnecessary stereoisomers are by-produced due to enzymatic optical resolution.
[0008]
[Chemical formula 5]
Figure 0004335390
[0009]
(3) Method 3
Tetrahedron: Asymmetry, 6, 1181 (1995)
A synthesis method using D-mannitol, L-ascorbic acid, (R)-or (S) -malic acid has been reported.
Optically active oxazolidinone can be obtained using D-mannitol as a starting material, but it requires multiple steps as described below.
[0010]
[Chemical 6]
Figure 0004335390
[0011]
In addition, both the method using L-ascorbic acid and the method starting from D- (S) -malic acid have a long reaction stage, and D- (S) -malic acid is used as the starting material. In this method, expensive diphenylphosphoryl azide is used.
[0012]
(4) Method 4
Kor. J. Med. Chem., 4. 52 (1994)
Racemic oxazolidinone is obtained by reacting β-hydroxycarboxylic acid with diphenylphosphoryl azide and carrying out Curtius rearrangement reaction. As before, diphenylphosphoryl azide is expensive, the reaction is carried out at 80 ° C., has an explosion risk and is unsuitable industrially.
[0013]
[Chemical 7]
Figure 0004335390
[0014]
Other Bull. Korean Chem. Soc., 15, 525 (1996) also requires expensive diphenylphosphoryl azide, and the reaction is carried out at 80 ° C. and has an explosion risk.
[0015]
(5) Method 5
Tetrahedron: Asymmetry, 8, 477 (1997)
An optically active oxazolidinone is obtained by Curtius rearrangement reaction using β-hydroxyester obtained by optical resolution with Lipase as hydrazide. Oxazolidinone is obtained by generating acyl azide at 5 ° C. or lower and heating the reaction solution to room temperature and stirring overnight. At this time, since Curtius rearrangement reaction is performed at room temperature, it takes a long time, and acyl azide is allowed to stand at room temperature for a long time.
[0016]
[Chemical 8]
Figure 0004335390
[0017]
Other Heterocycles, 6, 1604 (1977) and Liebigs Ann. Chem., 150 (1979) also generate an intermediate acyl azide at low temperature and perform the rearrangement reaction by heating as it is. There is a risk of explosion.
[0018]
[Problems to be solved by the invention]
An object of the present invention is to solve various problems in the conventional methods described above, and to provide a novel production method for obtaining an optically active oxazolidinone derivative having high yield and high optical purity.
[0019]
[Means for Solving the Problems]
In light of the above circumstances, the present inventors have intensively studied an effective and economical method for producing an optically active oxazolidinone derivative. As a result, the production efficiency is high, the process is not complicated, and the yield is high. The inventors have found that an optically active oxazolidinone derivative having a high optical purity can be obtained, and have completed the present invention.
[0020]
That is, the present invention is as follows (1) to (3).
(1) General formula (1)
[0021]
[Chemical 9]
Figure 0004335390
[0022]
(Where R1Is a lower alkyl group having 1 to 4 carbon atoms, phenyl group, methoxymethyl group, benzyloxymethyl group, benzyloxycarbonylaminomethyl group in which the benzene ring may be substituted, acylaminomethyl group having 3 to 10 carbon atoms, carbon Represents an alkoxycarbonylaminomethyl group of formula 3 to 6, and R2, RThree May be the same or different and each represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, an acetylaminomethyl group, a benzoylaminomethyl group, or a benzyl group;FourRepresents a lower alkyl group having 1 to 4 carbon atoms. * Means an asymmetric carbon atom. )
Hydrazine is allowed to act on an optically active acid ester having a hydroxyl group at the 3-position represented by formula (2)
[0023]
[Chemical Formula 10]
Figure 0004335390
[0024]
(Where R1, R2, RThreeAnd * mark means the same thing as the above. ), An optically active hydrazide derivative having a hydroxyl group at the 3-position, and then carrying out a Curtius rearrangement reaction.
[0025]
Embedded image
Figure 0004335390
[0026]
(Where R1, R2, RThreeAnd * mark means the same thing as the above. The manufacturing method of the optically active oxazolidinone derivative represented by this.
[0027]
(2) An optically active hydrazide derivative having a hydroxyl group at the 3-position is obtained by recrystallizing an optically active hydrazide derivative having a hydroxyl group at the 3-position. A method for producing an active oxazolidinone derivative.
[0028]
(3) In the optically active acid ester having a hydroxyl group at the 3-position represented by the general formula (1) of 1,1Represents methyl group, phenyl group, methoxymethyl group, benzyloxymethyl group, benzyloxycarbonylaminomethyl group, acetylaminomethyl group, hexanoylaminomethyl group, t-butoxycarbonylaminomethyl group, R2, RThree Represents the same hydrogen atom or a hydrogen atom and an acetylaminomethyl group, benzylaminomethyl group, benzyl group, RFourThe method for producing an optically active oxazolidinone derivative according to claim 1 or 2, wherein represents a lower alkyl group having 1 to 4 carbon atoms.
[0029]
Hereinafter, the present invention will be described in more detail.
The optically active acid ester derivative (1) having a hydroxyl group at the 3-position represented by the general formula (1) used as a starting material of the present invention is represented by the general formula (4).
[0030]
Embedded image
Figure 0004335390
[0031]
(Where R1Is a lower alkyl group having 1 to 4 carbon atoms, phenyl group, methoxymethyl group, benzyloxymethyl group, benzyloxycarbonylaminomethyl group in which the benzene ring may be substituted, acylaminomethyl group having 3 to 10 carbon atoms, carbon Represents an alkoxycarbonylaminomethyl group of formula 3 to 6, and R2, RThree May be the same or different and each represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, an acetylaminomethyl group, a benzoylaminomethyl group, or a benzyl group;FourRepresents a lower alkyl group having 1 to 4 carbon atoms. * Means an asymmetric carbon atom. The β-ketoester (4) represented by the above formula is prepared by asymmetric hydrogenation.
[0032]
The β-ketoester (4) as a raw material can be synthesized according to the following method.
R1Β-ketoester (4), in which is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group, is obtained by a known method from 3-oxobutanoic acid ester which is readily available, for example, JP-A-10-53561 by Soguchi et al. It is synthesized by reacting acetoacetate with an acid halide by the method described in the publication. R14-alkoxy-3-oxobutanoic acid ester in which is an alkoxymethyl group such as methoxymethyl group, benzyloxymethyl group, etc. is obtained by a known method, for example, RM, from 4-halogeno-3-oxopropionic acid ester, which is readily available. Kellogg et al. (J. Chem. Soc., Chem. Commun., 932 (1997)); D. Seebach et al. (Synthesis, 37 (1986)).1Preparation of β-ketoester (4) having an aminomethyl group having a protecting group on N is, for example, in the case of benzyloxycarbonylaminomethyl group, using benzyloxycarbonylglycine which is easily available, For example, it is synthesized by the method described in Natsugari et al., Synthesis, 403 (1992).
[0033]
R1As the protecting group for the amino group contained in benzyloxycarbonyl, acyl, and alkoxycarbonyl are preferably used.
As a substituent for the benzene ring of the benzyloxycarbonyl group, a lower alkyl group having 1 to 4 carbon atoms, preferably a methyl group, a t-butyl group or the like, or a lower alkoxyl group having 1 to 4 carbon atoms, preferably a methoxy group, Or a halogen atom, preferably a chlorine atom. As these examples, p-methoxybenzyl, 2,4-dimethylbenzyl, p-methylbenzyl, 3,5-dimethylbenzyl, p-chlorobenzyl, pt-butylbenzyl and the like can be used.
Examples of the acyl group include acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group, heptanoyl group, octanoyl group, nonanoyl group, decanoyl group and the like.
As examples of the alkoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a t-butoxycarbonyl group, and the like can be used.
[0034]
The preparation of the β-ketoester (4) having a substituent at the 2-position is, for example, R2, RThreeIs an acetylaminomethyl group, benzoylaminomethyl group, or benzyl group, they are synthesized by the method described in JP-A-2-231471.
R of β-ketoester (4) as raw materialFourCan be a lower alkyl group having 1 to 4 carbon atoms.
[0035]
The asymmetric hydrogenation of β-ketoester (4) is carried out in accordance with the method described in JP-A-2-289537 using an alcohol as a solvent in the presence of a catalytic amount of a ruthenium-phosphine complex and a hydrogen pressure of 5 to 100. The reaction is carried out under the conditions of atmospheric pressure, reaction temperature of 10 to 100 ° C., and reaction time of 5 to 20 hours.
[0036]
As the ruthenium-optically active phosphine complex preferably used, for example, the following general formula (5) described in JP-A No. 61-63690 is described.
[0037]
Embedded image
Figure 0004335390
[0038]
(Where RFive-BINAP is the general formula (6)
[0039]
Embedded image
Figure 0004335390
[0040]
Represents a tertiary phosphine represented by RFiveRepresents a hydrogen atom, a methyl group, a t-butyl group or a methoxy group, T represents a tertiary amine, and when b is 1, a is 1, c is 1, d is 0, and b is 0. Where a is 2, c is 4, and d is 1. And the following general formula (7) described in JP-A-62-265293
[0041]
Embedded image
Figure 0004335390
[0042]
(Where RFive-BINAP represents the same tertiary phosphine as the above formula (6), and R6Represents a lower alkyl group or a trifluoromethyl group. And the following complexes represented by:
[0043]
Specific examples of the tertiary phosphine represented by the general formula (6) include the following.
Phosphine 1: 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (abbreviated as "BINAP")
Phosphine 2: 2,2'-bis [di (p-tolyl) phosphino] -1,1'-binaphthyl (abbreviated as "Tol-BINAP")
Phosphine 3: 2,2'-bis [di (p-tert-butylphenyl) phosphino] -1,1'-binaphthyl (abbreviated as "t-Bu-BINAP")
Phosphine 4: 2,2′-bis [di (p-methoxyphenyl) phosphino] -1,1′-binaphthyl (abbreviated as “Methoxy-BINAP”)
[0044]
Since these tertiary phosphines (6) are both in the (+)-and (-)-isomers, either one is selected according to the absolute configuration of the target optically active compound (2). That's fine. That is, the (+)-isomer is used to obtain the (3R) isomer, and the (-)-isomer is used to obtain the (3S) isomer.
[0045]
In the general formula (5), the tertiary amine represented by T includes triethylamine, tributylamine, ethylisopropylamine, 1,8-bis (dimethylamino) naphthalene, dimethylaniline, pyridine, N-methylpiperidine and the like. Among them, triethylamine is preferable.
[0046]
Specific examples of the complex represented by the general formula (5) include the following. In addition, the description of the absolute configuration of the tertiary phosphine was omitted. Et represents an ethyl group, Tol represents a tolyl group substitution, and t-Bu represents a tert-butyl group.
Complex 1: Ru2ClFour(BINAP)2NEtThree
Complex 2: Ru2ClFour(Tol-BINAP)2NEtThree
Complex 3: Ru2ClFour(t-Bu-BINAP)2NEtThree
Complex 4: Ru2ClFour(Methoxy-BINAP)2NEtThree
Complex 5: RuHCl (BINAP)2
Complex 6: RuHCl (Tol-BINAP)2
Complex 7: RuHCl (t-Bu-BINAP)2
Complex 8: RuHCl (Methoxy-BINAP)2
[0047]
Specific examples of the complex represented by the general formula (7) include the following. The absolute configuration of the tertiary phosphine is not shown.
Complex 9: Ru (BINAP) (O2CCHThree)2
Complex 10: Ru (Tol-BINAP) (O2CCHThree)2
Complex 11: Ru (t-Bu-BINAP) (O2CCHThree)2
Complex 12: Ru (Methoxy-BINAP) (O2CCHThree)2
Complex 13: Ru (BINAP) (O2CCFThree)2
Complex 14: Ru (Tol-BINAP) (O2CCFThree)2
Complex 15: Ru (t-Bu-BINAP) (O2CCFThree)2
Complex 16: Ru (Methoxy-BINAP) (O2CCFThree)2
[0048]
The ruthenium-optically active phosphine complex is used in an amount of 1/100 to 1/10000 times mol, preferably 1/500 to 1/4000 times mol, of the β-ketoester as the substrate. As the solvent for the hydrogenation reaction, alcohols are preferable, and methyl alcohol, ethyl alcohol, and isopropyl alcohol are particularly preferable, and ethyl alcohol is particularly preferable. The amount of the solvent is usually 1 to 5 times (volume / weight) with respect to the substrate.
[0049]
A second method for preparing the optically active acid ester (1) having a hydroxyl group at the 3-position will be described below.
First, an azide of an optically active β-hydroxy acid ester is obtained from an asymmetric hydride of β-oxo acid ester. Next, after acylating the azide form by a conventional method, acylamide is obtained by a reductive rearrangement reaction. In addition, the above azides are converted into tertiary butyldicarbonate: ((Boc)2An optically active β-hydroxy acid ester (1) in which the amino group is protected is obtained by reductive rearrangement reaction in the presence of a compound having a functional group protecting the amino group such as O)).
[0050]
In order to avoid complexity, this method will be described using specific compounds, but the present invention is not limited to this example.
For example, an optically active azide of ethyl 3-hydroxybutanoate is obtained by asymmetric hydrogenation of ethyl 4-chloro-3-oxobutanoate and allowing sodium azide to act (for example, see JP-A 8- 119935 method).
The azide compound is acylated with acyl chloride, and optically active acylamide of ethyl 3-hydroxybutanoate is obtained by reductive rearrangement reaction in the presence of palladium-carbon (Pd-C) (for example, J. Org. Chem., 58, 1287 (1993)).
Alternatively, the above azide compound is converted into tertiary butyldicarbonate: ((Boc)2In the presence of O)), reductive rearrangement reaction is performed to obtain an optically active ethyl 3-hydroxybutanoate having a protected amino group (for example, according to the method of Tetrahedron Lett., 30, 837 (1989)).
[0051]
In the synthesis of the optically active hydrazide (2) having a hydroxyl group at the 3-position according to the present invention, hydrazine in an alcohol solvent is allowed to act on the optically active acid ester (1) having a hydroxyl group at the 3-position obtained by the asymmetric hydrogenation. In general, it is carried out by heating at a temperature of 0 to 100 ° C., preferably 30 to 70 ° C.
[0052]
As the alcohol solvent, methyl alcohol, ethyl alcohol, and isopropyl alcohol are preferable. The amount of hydrazine used is 1 to 5 mol, preferably 1.1 to 1.5 mol, per 1 mol of compound (1). After the reaction, the obtained optically active hydrazide having a hydroxyl group at the 3-position is obtained by adding isopropyl alcohol to methanol, dissolving, crystallizing, and filtering to obtain a high yield and optically pure 3-position. An optically active hydrazide (2) having a hydroxyl group is obtained.
[0053]
  Finally, in the present invention, an optically active hydrazide derivative having a hydroxyl group at the 3-position is converted into an optically active oxazolidinone derivative by Curtius rearrangement reaction. Unlike the method of the literature (P.A.S. Smith, Organic Reactions, II, 337 (1946)), the Curtius rearrangement reaction in the present invention is carried out in the presence of an acid in the optically active hydrazide (2) having a hydroxyl group at the 3-position.At 0-5 ° CBy reacting sodium nitrite to generate an intermediate acyl azide, this solution can be left as it is or dropped into a heated solvent to safely lead to the target optically active oxazolidinone derivative (3). .
[0054]
The amount of sodium nitrite is 1 to 2 mol, preferably 1.1 to 1.3 mol, per 1 mol of compound (2). In this reaction, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sulfonic acid, metasulfonic acid, p-toluenesulfonic acid and the like can be used as the acid used in the Curtius rearrangement reaction, and hydrochloric acid, sulfuric acid and acetic acid are particularly preferable. Solvents used in the reaction include halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone, esters such as ethyl acetate and butyl acetate, ethers such as diethyl ether and diisopropyl ether, methanol, ethanol, butanol, etc. Alcohol, hexane, heptane, toluene, benzene and other hydrocarbons, water and mixtures thereof can be used, and water or a mixed solvent of water and ethers is particularly preferred. The reaction temperature in this reaction is generally 20 to 100 ° C., preferably 30 to 50 ° C. According to the method of the present invention, even if the raw material compound (2) is optically active, the optically active compound (3) of the present invention (3) can be obtained while maintaining its stericity.
[0055]
Among the compounds represented by the above formula (2) or formula (3), R1Is an acylaminomethyl group having 3 to 10 carbon atoms or an alkoxycarbonylaminomethyl group having 3 to 6 carbon atoms, and R2Or RThreeA compound in which is a hydrogen atom is a novel compound. These novel compounds are useful as pharmaceutical production intermediates and as raw materials for producing optically active amino alcohols. In particular, the novel compound represented by the formula (31) is useful as an intermediate for production of linezolid (Pharmacia & Upjohn Corp.) useful as an antibacterial agent.
A typical example of the production method of the novel compound is as follows.
An optically active acid ester (1) having a hydroxyl group at the 3-position was prepared using the second method, and, as already described, hydrazine was allowed to act on this acid ester (1) to obtain hydrazide (2), and the Curtius rearrangement A new optically active oxazolidinone can be obtained by reaction.
[0056]
Embedded image
Figure 0004335390
[0057]
【The invention's effect】
According to the present invention, it is possible to provide a method for producing a novel optically active oxazolidinone derivative having high production efficiency and no complicated processes. In addition, a novel method for producing an optically active oxazolidinone derivative with high yield and high optical purity can be provided.
[0058]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
The equipment and conditions used for measuring the physical properties in the examples were as follows unless otherwise specified.
[0059]
Nuclear magnetic resonance spectrum
1. Nuclear magnetic resonance spectrum (1H-NMR): Gemini-2000 type (200 MHz) (manufactured by Varian)
Internal standard substance: Tetramethylsilane
2. Nuclear magnetic resonance spectrum (13C-NMR): Gemini-2000 type (50 MHz) (manufactured by Varian)
Internal standard substance: Tetramethylsilane
3. Nuclear magnetic resonance spectrum (1H-NMR): DRX500 (500 MHz) (manufactured by Blue Car Japan)
Internal standard substance: Tetramethylsilane
4). Nuclear magnetic resonance spectrum (13C-NMR): DRX500 (126 MHz) (manufactured by Blue Car Japan)
Internal standard substance: Tetramethylsilane
Melting point: MP-S3 type (Yanamoto Shoji Co., Ltd.)
High performance liquid chromatography HPLC: Hitachi Liquid Chromatography L-600
Gas chromatography GLC: Hewlett Packard 5890-II
[0060]
In addition, although it induced | guided | derived to MTPA ester or MTPA amide for determination of optical purity, this MTPA is (R)-or (S)-(alpha) -methoxy- (alpha)-(trifluoromethyl) phenetic acid.
[0061]
[Reference Example 1]
Synthesis of (R) -4-methoxy-3-hydroxybutanoic acid methyl ester
Sodium hydride (60%) 88.0 g (2.2 mol) and tetrahydrofuran (753 ml) were added to a 2 L four-necked flask under a nitrogen stream, and 4-chloro-3-oxo-butanoic acid methyl ester 150 was added thereto. 1.6 g (1.0 mmol) and 35.2 g (1.1 mol) of methanol are added dropwise at room temperature (22-24 ° C.), and the mixture is stirred at room temperature (22-24 ° C.) for 1 hour after completion of the addition. The reaction solution is ice-cooled, and 600 ml (1.2 mol) of 2N hydrochloric acid is added dropwise. Tetrahydrofuran is recovered from the reaction product, toluene (400 ml) is added to the residue, and the aqueous phase is extracted three times with toluene (200 ml). The organic phase was washed with 5% brine and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure (boiling point 90 ° C./1000 Pa) to give 107.7 g (liquid) (74%) of 4-methoxy-3-oxobutanoic acid methyl ester. Obtained.
[0062]
1H-NMR (200 MHz, CDClThree , Δ ppm): 4.08 (s, 2H), 3.74 (s, 3H), 3.52 (s, 2H), 3.42 (s, 3H)
[0063]
In a 10 L autoclave under a nitrogen stream, 1473 g (10.08 mol) of 4-methoxy-3-oxobutanoic acid methyl ester, 2210 ml of ethanol, Ru2 ClFour ((S) -tol-BINAP)2 ・ NEtThree 4.59 g (5.09 mmol) was added, and asymmetric hydrogenation was performed at a reaction temperature of 100 ° C. and a hydrogen pressure of 4000 kPa for 4 hours (conversion rate: 100%). The solvent was distilled off under reduced pressure to obtain 1490 g (liquid) of the title compound.
[0064]
1H-NMR (200 MHz, CDClThree , Δ ppm): 4.3-4.1 (m, 1H), 3.70 (s, 3H), 3.42 (dd, J = 4.6, 12.2 Hz, 1H), 3.36 (dd , J = 6.0, 12.2 Hz, 1H), 3.38 (s, 3H), 2.52 (d, J = 6.4 Hz, 2H)
[0065]
The optical purity was measured under the following conditions.
The title compound was analyzed by HPLC as the (R) -MTPA ester derivative, and the optical purity was calculated to be 94%.
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: hexane / ether = 3/1 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 254 nm
[0066]
[Example 1]
Synthesis of (R) -4-methoxy-3-hydroxybutanohydrazide
Under a nitrogen stream, 1036 g (6.99 mol) of (R) -4-methoxy-3-hydroxybutanoic acid methyl ester (optical purity 94% ee) and 4140 ml of ethanol were added to a 10 L four-necked flask, followed by 20 minutes at room temperature. Over the course of 525 g (10.49 mol) of hydrazine monohydrate. The mixture was stirred at 70 ° C. for 6 hours. The reaction solution is cooled to room temperature (22-24 ° C.), and 2 L of isopropyl alcohol is added to the reaction solution and cooled to 5 ° C. Crystallization was carried out with stirring for 1 hour, followed by filtration. To wash the crystals, 0.45 L of isopropyl alcohol was used to obtain 626.5 g of a first crystal. 1 L of methanol and 0.5 L of isopropyl alcohol were added to the first mother liquor, and crystallization was performed in the same manner to obtain 225.2 g of second crystals. The title compound combined with the first and second crystals was 851.7 g, and the yield was 82% (mp 101.4 ° C., optical purity> 99.9% ee).
[0067]
1H-NMR (200 MHz, CDThree OD, δ ppm): 4.2-4.0 (m, 1H), 3.4-3.2 (m, 2H), 3.37 (s, 3H), 2.37 (dd, J = 5. 0, 14.2 Hz, 1 H), 2.20 (dd, J = 7.7, 14.2 Hz, 1 H)
[0068]
In addition, the following reaction was performed and the optical purity of the product was measured.
1 ml of an acetic acid solution of 40 mg (0.27 mmol) of (R) -4-methoxy-3-hydroxybutanohydrazide obtained was cooled to 5 ° C., and 28 mg (0.40 mmol) of sodium nitrite was added. The reaction solution is stirred at room temperature (22-24 ° C.) for 1 hour, heated to 80 ° C. and stirred at 80 ° C. for 1 hour. Acetic acid in the reaction solution was distilled off under reduced pressure, and the optical purity of the crude product was measured by gas chromatography.
Column: ALPHA DEX 120 (0.25 mm x 30 m) (supplico)
Injection temperature: 200 ° C
Column temperature: 100 ° C to 250 ° C
Detection temperature: 250 ° C
Temperature rising temperature: 5 ° C / min
[0069]
[Example 2]
Synthesis of (R) -5-methoxymethyl-2-oxazolidinone
(R) -4-methoxy-3-hydroxybutanohydrazide (optical purity> 99.9% ee) obtained in Example 1 was placed in a four-necked 500 ml flask under a nitrogen stream in an amount of 100.0 g (0.675 mol). ), 150 ml of water was added, and 64.5 ml (0.742 mol) of 35% concentrated hydrochloric acid was added over 35 minutes under ice-cooling (0 to 5 ° C.). After completion of dropping, an aqueous solution (130 ml) of 51.2 g (0.742 mol) of sodium nitrite was added over 2 hours and 25 minutes under ice zero (0 to 5 ° C.). After dropping, the mixture was stirred for 1 hour under ice zero (0 to 5 ° C.). Separately, 100 ml of water was added to a four-necked 1 L flask under a nitrogen stream and heated to 50 ° C., and the previously prepared reaction solution was added dropwise over 2 hours and 10 minutes. At this time, nitrogen gas was generated vigorously, and the reaction temperature rose to 55 ° C. The previous reaction solution was washed twice with 30 ml and 20 ml of water and added to the latter flask. The reaction was stirred at 50 ° C. for 2 hours. Water in the reaction solution was distilled off under reduced pressure, and 100 ml of methanol was added to the reaction residue, followed by filtration to remove sodium chloride. Methanol in the mother liquor was distilled off under reduced pressure, and 100 ml of methanol was added to the residue, followed by filtration to remove sodium chloride. The mother liquor of methanol was distilled off under reduced pressure, and the residue was distilled under reduced pressure (141 ° C./100 Pa) to obtain 81.1 g of the title compound. The yield was 92%, and the optical purity was 99.9% ee or higher.
[0070]
1H-NMR (200 MHz, CDClThree , Δ ppm): 4.76 (ddt, J = 6.6, 8.8, 4.8 Hz, 1H), 3.66 (ddd, J = 8.8, 8.4, 4.4 Hz, 1H), 3.59 (d, J = 4.8 Hz, 1H), 3.50 (ddd, J = 6.6, 8, 4, 1.0 Hz, 1H), 3.43 (s, 3H)
13C-NMR (50 MHz, CDClThree , Δ ppm): 159.96, 72.59, 59.04, 42.09
[0071]
The optical purity was measured using gas chromatography.
Column: ALPHA DEX 120 (0.25 mm x 30 m) (supplico)
Injection temperature: 200 ° C
Column temperature: 100 ° C to 250 ° C
Detection temperature: 250 ° C
Temperature rising temperature: 5 ° C / min
[0072]
[Reference Example 2]
Synthesis of (S) -4-benzyloxy-3-hydroxybutanoic acid ethyl ester
To a suspension obtained by adding 775 ml of tetrahydrofuran to 82.9 g (2.07 mol) of 60% sodium hydride, 112 g (1.04 mol) of benzyl alcohol and 155 g (0.94 mol) of 4-chloro-3-oxobutanoic acid ethyl ester were added. The mixture is added dropwise at 35-40 ° C. After completion of dropping, the mixture is stirred at 40 ° C. for 1 hour. Tetrahydrofuran is recovered from the reaction product, and 500 ml of heptane is added. This solution is dropped into 800 ml of water to precipitate crystals. The crystals are separated at room temperature and washed with heptane. The crystals are extracted by adding 800 ml of acetic acid butyl ester and 1000 ml of 1N HCl. The organic phase is 500 ml 5% brine, 5% NaHCO 3.Three Wash with 500 ml of water and 5% saline to adjust the pH to 6-7. The butyl acetate was recovered, 100 ml of heptane was added, and the mixture was stirred and separated to obtain 173 g (78% yield) of 4-benzyloxy-3-oxobutanoic acid ethyl ester.
[0073]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.6-7.2 (m, 5H), 5.16 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.45 (s, 2H) 1.21 (t, J = 7.2 Hz, 3H)
[0074]
To a 100 ml autoclave, 20.0 g (84.7 mmol) of 4-benzyloxy-3-oxobutanoic acid ethyl ester, 16 ml of ethanol, Ru2 ClFour ((R) -tol-BINAP)2 ・ NEtThree 31 mg (0.034 mmol) was added, and asymmetric hydrogenation was performed for 3 hours at a reaction temperature of 100 ° C. and a hydrogen pressure of 10 atm (conversion rate: 100%). The solvent was distilled off under reduced pressure to obtain 18.0 g (liquid) of the title compound.
[0075]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.4-7.2 (m, 5H), 4.56 (s, 2H), 4.3-4.1 (m, 1H), 4.15 (q, J = 7.1 Hz) , 2H), 3.53 (dd, J = 4.6, 9.5 Hz, 1H), 3.46 (dd, J = 5.9, 9.5 Hz, 1H), 3.00 (bs, 1H) , 2.54 (d, J = 6.2 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H)
[0076]
The optical purity was measured under the following conditions.
The title compound was analyzed by HPLC as the (R) -MTPA ester derivative, and the optical purity was calculated to be 89% ee.
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: Hexane / ether = 9/1 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 254 nm
[0077]
[Example 3]
Synthesis of (S) -4-benzyloxy-3-hydroxybutanohydrazide
In a 100 ml flask, under a nitrogen stream, 4.15 g (17.4 mmol) of (S) -4-benzyloxy-3-hydroxybutanoic acid ethyl ester (optical purity 89% ee) obtained in Reference Example 2 and 20 ml of ethanol Then, 2.62 g (52.2 mmol) of hydrazine monohydrate was added, and the mixture was heated to reflux for 20 hours. The reaction solution is cooled to room temperature (22-24 ° C.), ethanol in the reaction solution is distilled off under reduced pressure, 40 ml of ether is added to the residue and heated to reflux to dissolve the crude crystals, and cooled to 5 ° C. Crystallization was carried out with stirring for 1 hour, followed by filtration. To wash the crystals, 10 ml of ether was used to obtain 2.90 g of the title compound. The yield was 74% (mp 96.9 ° C., optical purity> 99.9% ee).
[0078]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.4-7.2 (m, 5H), 4.56 (s, 2H), 4.3-4.1 (m, 1H), 4.0-3.8 (bs, 2H) ), 3.51 (dd, J = 4.6, 9.6 Hz, 1H), 3.44 (dd, J = 6.4, 9.4 Hz, 1H), 2.41 (dd, J = 4. 8, 15.4 Hz, 1 H), 2.31 (dd, J = 7.4, 15.4 Hz, 1 H), 1.8-1.5 (bs, 1 H)
[0079]
In addition, the following reaction was performed and the optical purity of the product was measured.
1 ml of an acetic acid solution of 50 mg (0.22 mmol) of (S) -4-benzyloxy-3-hydroxybutanohydrazide obtained was cooled to 5 ° C., and 23 mg (0.33 mmol) of sodium nitrite was added. The reaction solution is stirred at room temperature (22-24 ° C.) for 1 hour, heated to 80 ° C. and stirred at 80 ° C. for 1 hour. Acetic acid in the reaction solution was distilled off under reduced pressure, and the crude product was subjected to HPLC analysis as a (R) -MTPA amide derivative.
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: Hexane / ether = 3/7 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 254 nm
[0080]
[Example 4]
Synthesis of (S) -5-benzyloxymethyl-2-oxazolidinone
150 mg (0.67 mmol) of (S) -4-benzyloxy-3-hydroxybutanohydrazide (optical purity> 99.9% ee) obtained in Example 3 in a two-necked 20 ml flask under a nitrogen stream Then, 2 ml of water was added, and 85 ml (1.01 mmol) of 35% concentrated hydrochloric acid was added over 3 minutes under ice cooling (0 to 5 ° C.). After completion of the dropwise addition, 1 ml of ether was added under zero ice (0 to 5 ° C.), and then 69 mg (1.01 mmol) of sodium nitrite was added over 3 minutes. The reaction mixture is stirred for 1 hour under ice freezing (0 to 5 ° C.), 1 ml of a saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and extracted with 10 ml of butyl acetate, and the organic phase is washed with 2 ml of 5% brine. Separately, 1 ml of butyl acetate was added to a two-necked 20 ml flask under a nitrogen stream and heated to 100 ° C., and the previously extracted acetate butyl ester reaction solution was added dropwise over 10 minutes. At this time, nitrogen gas was vigorously generated. The previous reaction solution was washed twice with 0.5 ml and 0.2 ml of butyl acetate and added to the latter flask. The reaction was stirred at 100 ° C. for 4 hours. The butyl acetate in the reaction solution was distilled off under reduced pressure, and the reaction residue was purified by column chromatography to obtain 137 mg of the title compound. The yield was 99%, and the optical purity was 99.9% ee or higher.
[0081]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.4-7.2 (m, 5H), 6.6-6.4 (m, 1H), 4.9-4.6 (m, 1H), 4.58 (s, 2H) ), 3.61 (dd, J = 8.0, 8.4, 1H), 3.62 (d, J = 4.8 Hz, 2H), 3.42 (dd, J = 6.6, 8.. 4HZ, 1H)
[0082]
The optical purity was measured under the following conditions.
The title compound was analyzed by HPLC as the (R) -MTPA amide derivative.
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: Hexane / ether = 3/7 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 254 nm
[0083]
[Reference Example 3]
Synthesis of (S) -4-benzyloxycarbonylamino-3-hydroxybutanoic acid ethyl ester
In a 1 L four-necked flask, 50 g (0.24 mol) of N-benzyloxocarbonyl-glycine and 300 ml of acetonitrile were placed under a nitrogen stream, and 39.5 g (0. 1 of 1,1′-carbonyldiimidazole was added over 30 minutes). 24 mol) was added, and the mixture was stirred at room temperature (22-24 ° C.) for 2 hours. After cooling to 7 ° C., 61.0 g (0.36 mol) of malonic acid potassium ethyl ester was added over 5 minutes, then 23.0 g (0.24 mol) of magnesium chloride was added over 30 minutes, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction was terminated by stirring at 50 ° C. for 2 hours. Acetonitrile was distilled off under reduced pressure, 550 ml of 5% aqueous hydrochloric acid solution was added, extracted and washed with 180 ml of butyl acetate, the organic phase was further washed with 100 ml of 5% aqueous hydrochloric acid solution, neutralized with 100 ml of 8% aqueous sodium carbonate solution, and then with 100 ml of water. After washing, the solvent was distilled off under reduced pressure to obtain 67.1 g (liquid) of 4-benzyloxycarbonylamino-3-oxobutanoic acid ethyl ester. When isolated and purified by column chromatography, the yield was 90%.
[0084]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.4 to 7.2 (m, 5H), 5.63 (s, 1H), 5.10 (s, 2H), 4.1 to 4.2 (m, 4H), 3. 46 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H)
[0085]
In a 200 ml autoclave, under a nitrogen stream, 4-benzyloxycarbonylamino-3-oxobutanoic acid ethyl ester 40 g (0.13 mol), ethanol 120 ml, Ru2 ClFour ((R) -tol-BINAP)2 ・ NEtThree 173 mg (0.102 mmol) was added, and asymmetric hydrogenation was carried out at 50 ° C. and a hydrogen pressure of 30 atm for 17 hours (conversion rate 98.4%, optical purity 94% ee). Ethanol was distilled off under reduced pressure to obtain 38.9 g (liquid) of the title compound. A part of this was isolated and purified by column chromatography, and the yield was 91%.
[0086]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.4-7.2 (m, 5H), 5.48 (s, 1H), 5.09 (s, 2H), 4.2-4.0 (m, 4H), 3. 4-3.1 (m, 2H), 2.5-2.4 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H)
[0087]
The optical purity was measured under the following conditions.
Column: Chiralcel OD-H, 4.6 mm × 250 mm (manufactured by Daicel Corporation)
Solvent: Hexane / Isopropyl alcohol = 9/1 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 210nm
[0088]
[Example 5]
Synthesis of (S) -4-benzyloxycarbonylamino-3-hydroxybutanohydrazide
2.70 g (9.60 mmol) of (S) -4-benzyloxycarbonylamino-3-hydroxybutanoic acid ethyl ester (optical purity 94% ee) obtained in Reference Example 3 in a 100 ml flask under a nitrogen stream, ethanol 40 ml of hydrazine monohydrate 2.40 g (48.0 mmol) was added, and the mixture was heated to reflux for 20 hours. The reaction solution is cooled to room temperature (22 to 24 ° C.), and ethanol in the reaction solution is distilled off under reduced pressure. Crystallization was carried out with stirring for 1 hour, followed by filtration. To wash the crystals, 10 ml of ether was used to obtain 1.42 g of the title compound. The yield was 52% (mp 135.4 ° C., optical purity> 99.9% ee).
[0089]
1H-NMR (200 MHz, CDThree OD, δ ppm): 7.4-7.2 (m, 5H), 5.07 (s, 2H), 4.2-3.9 (m, 1H), 3.22 (dd, J = 5. 4, 14.0, 1H), 3.13 (dd, J = 6.3, 14.0 Hz, 1H), 2.32 (dd, J = 4.8, 14.4 Hz, 1H), 2.21 (Dd, J = 8.2, 14.4 Hz, 1H)
[0090]
In addition, the following reaction was performed and the optical purity of the product was measured.
1 ml of acetic acid solution of 50 mg (0.19 mmol) of the obtained (S) -4-benzyloxycarbonylamino-3-hydroxybutanohydrazide was cooled to 5 ° C., and 19 mg (0.28 mmol) of sodium nitrite was added. The reaction solution is stirred at room temperature (22-24 ° C.) for 1 hour, heated to 80 ° C. and stirred at 80 ° C. for 1 hour. Acetic acid in the reaction solution was distilled off under reduced pressure, and the crude product was subjected to HPLC analysis as a (R) -MTPA amide derivative.
[0091]
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: Hexane / ether = 3/7 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 254 nm
[0092]
[Example 6]
Synthesis of (R) -5-benzyloxycarbonylaminomethyl-2-oxazolidinone
(S) -4-benzyloxycarbonylamino-3-hydroxybutanohydrazide (optical purity> 99.9% ee) 103 mg (0. 0%) obtained in Example 5 was placed in a two-necked 20 ml flask under a nitrogen stream. 39 mmol) and 1 ml of water were added, and 49 ml (0.59 mmol) of 35% concentrated hydrochloric acid was added over 3 minutes under ice zero (0 to 5 ° C.). After completion of the dropwise addition, 1 ml of diisopropyl ether was added under ice cooling (0 to 5 ° C.), and then 40 mg (0.59 mmol) of sodium nitrite was added over 3 minutes. The reaction solution is stirred for 1 hour under ice-cooling (0 to 5 ° C.), then 1 ml of a saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, extracted with 10 ml of butyl acetate, and the organic phase is washed with 2 ml of 5% brine. Separately, 1 ml of butyl acetate was added to a two-necked 20 ml flask under a nitrogen stream and heated to 110 ° C., and the previously extracted acetate butyl ester reaction solution was added dropwise over 10 minutes. At this time, nitrogen gas was vigorously generated. The previous reaction solution was washed twice with 0.5 ml and 0.2 ml of butyl acetate and added to the latter flask. The reaction was stirred at 100 ° C. for 4 hours. The butyl acetate in the reaction solution was distilled off under reduced pressure, and the reaction residue was purified by column chromatography to obtain 95 mg of the title compound. The yield was 99%, and the optical purity was 99.9% ee or higher.
[0093]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.4-7.2 (m, 5H), 6.14 (bs, 1H), 5.7-5.5 (m, 1H), 5.10 (s, 2H), 4. 8-4.6 (m, 1H), 3.7-3.2 (m, 4H)
13C-NMR (200 MHz, CDCl 3, δ ppm): 159.78, 156.85, 136.18, 128.43, 128.09, 127.90, 75.34, 66.78, 43.58, 42.67
[0094]
The optical purity was measured under the following conditions.
The title compound was analyzed by HPLC as the (R) -MTPA amide derivative.
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: Hexane / ether = 3/7 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 254 nm
[0095]
[Reference Example 4]
Synthesis of (2S, 3R) -2- (N-benzoylamino) methyl-3-hydroxybutanoic acid methyl ester
In a 100 ml autoclave under a nitrogen stream, 2.5 g (10 mmol) of 2- (N-benzoylamino) methyl-3-oxobutanoic acid methyl ester and Ru2 ClFour ((R) -BINAP)2 ・ NEtThree A solution prepared by dissolving 173 mg (0.102 mmol) in 17.5 ml of methylene chloride was added, and the mixture was stirred at 50 ° C. and a hydrogen pressure of 100 atm for 20 hours. The solvent was distilled off under reduced pressure, and the residue was isolated and purified by column chromatography to obtain 2.25 g of the title compound. Yield 90%, optical purity 98% ee.
[0096]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.8-7.4 (m, 5H), 7.02 (bs, 1H), 4.2-4.1 (m, 1H), 4.1-4.0 (m, 1H) ), 3.73 (s, 3H), 3, 7-3.5 (m, 1H), 2.7-2.5 (m, 1H), 1.26 (d, J = 6.3 Hz, 3H) )
[0097]
After derivatization to (R) -MTPA ester, optical purity was determined using high performance liquid chromatography under the following conditions.
Column: Develosil 100-3 4.6 mm × 250 mm (manufactured by Nomura Chemical Co., Ltd.)
Solvent: Hexane / ether = 9/1 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 254 nm
[0098]
[Example 7]
Synthesis of (2S, 3R) -2- (N-benzoylamino) methyl-3-hydroxybutanohydrazide
(2S, 3R) -2- (N-benzoylamino) methyl-3-hydroxybutanoic acid methyl ester (optical purity 98% ee) 3.80 g obtained in Reference Example 4 in a 100 ml flask under a nitrogen stream ( 15.1 mmol), 38 ml of methanol, and 4.54 g (90.74 mmol) of hydrazine monohydrate were added and heated to reflux for 10 hours. Cool the reaction to 5 ° C. Crystallization was carried out with stirring for 1 hour, followed by filtration. 2.35 g of the title compound was obtained using 10 ml of ether for washing the crystals. The yield was 62% (mp 185.4 ° C., optical purity> 99.9% ee).
[0099]
1H-NMR (200 MHz, CDThree OD, δ ppm): 7.8-7.7 (m, 2H), 7.6-7.3 (m, 3H), 3.92 (dq, J = 8.2, 6.2 Hz, 1H), 3.79 (dd, J = 4.8, 13.6 Hz, 1H), 3.63 (dd, J = 8.2, 13.6 Hz, 1H), 2.49 (ddd, J = 4.8, 8.2, 8.2 Hz, 1H), 1.19 (d, J = 6.2 Hz, 3H)
[0100]
In addition, the following reaction was performed and the optical purity of the product was measured.
1 ml of an acetic acid solution of 50 mg (0.20 mmol) of (2S, 3R) -2- (N-benzoylamino) methyl-3-hydroxybutanohydrazide obtained was cooled to 5 ° C., and 21 mg (0.30 mmol) of sodium nitrite ) Was added. The reaction solution is stirred at room temperature (22-24 ° C.) for 1 hour, heated to 80 ° C. and stirred at 80 ° C. for 1 hour. Acetic acid in the reaction solution was distilled off under reduced pressure, and the crude product was subjected to HPLC analysis as a (R) -MTPA amide derivative.
[0101]
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: Ether
Flow rate: 1.0 ml / min
Detection: 254 nm
[0102]
[Example 8]
Synthesis of (5R, 4R) -5-methyl-4- (N-benzoylamino) methyl-2-oxazolidinone
To a two-necked 50 ml flask, 412 mg (5.97 mmol) of sodium nitrite and 2 ml of water were added under a nitrogen stream, and the mixture was obtained in Example 7 under ice zero (0-5 ° C.) (2S, 3R) − A solution of 1.00 g (3.98 mmol) of 2- (N-benzoylamino) methyl-3-hydroxybutanohydrazide (optical purity> 99.9% ee) in 6 ml of acetic acid was added over 5 minutes. Separately, 1 ml of water was added to a two-necked 50 ml flask under a nitrogen stream and heated to 50 ° C., and the previously prepared reaction solution was added dropwise over 10 minutes. The previous reaction was washed twice with 0.5 ml of water and added to the latter flask. The reaction was stirred at 50 ° C. for 2 hours. Water in the reaction solution was distilled off under reduced pressure, and 10 ml of butyl acetate was added to the reaction residue, followed by filtration to remove sodium acetate. The sodium acetate separated by filtration was washed twice with 5 ml of butyl acetate, the resulting mother liquor was distilled off under reduced pressure, and the reaction residue was purified by column chromatography to obtain 451 mg of the title compound. The yield was 48%, and the optical purity was 99.9% ee or higher.
[0103]
mp: 156.7 ° C
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.9-7.7 (m, 2H), 7.6-7.3 (m, 3H), 6.99 (bs, 1H), 4.74 (dq, J = 7.0) , 6.6 Hz, 1H), 4.1-3.8 (m, 2H), 3.2-3.0 (m, 1H), 1.39 (d, J = 6.6 Hz, 3H)
13C-NMR (50 MHz, CDClThree , Δ ppm): 168.42, 160.36, 133.73, 131.66, 128.42, 127.30, 75.62, 54.97, 40.32, 14, 35
[0104]
The optical purity was measured under the following conditions.
The title compound was analyzed by HPLC as the (R) -MTPA amide derivative.
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: Ether
Flow rate: 1.0 ml / min
Detection: 254 nm
[0105]
[Reference Example 5]
Synthesis of (S) -3-hydroxy-3-phenylpropionic acid methyl ester
In a 1L autoclave, under a nitrogen stream, Ru2 ClFour ((R) -tol-BINAP)2 ・ NEtThree A mixture of 0.84 g (1.0 mmol), benzoylacetic acid methyl ester 178 g (1.00 mol), and methanol 500 ml was stirred at 50 ° C. and hydrogen pressure 100 atm for 16 hours. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure (99 ° C./100 Pa) to obtain 171 g (liquid) of the title compound. Yield 95%
(Optical purity 87% ee).
[0106]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.5-7.2 (m, 5H), 5.2-5.0 (m, 1H), 3, 71 (s, 3H), 3.29 (bs, 1H), 2. 77 (dd, J = 9.2, 16.3 Hz, 1H), 2.70 (dd, J = 3.8, 16.3 Hz, 1H)
[0107]
The optical purity was measured under the following conditions.
Column: Chiralcel OD-H, 4.6 mm × 250 mm (manufactured by Daicel Corporation)
Solvent: hexane / isopropyl alcohol = 95/5 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 254 nm
[0108]
[Example 9]
Synthesis of (S) -3-hydroxy-3-phenylpropionohydrazide
In a 1 L four-necked flask, 200 g (1.11 mol) of (S) -3-hydroxy-3-phenylpropionic acid methyl ester (optical purity 87% ee), 77.8 g (1.56 mol) of hydrazine monohydrate, 400 ml of methanol was charged, and heated and stirred at 70 ° C. for 3 hours. Thereafter, the mixture was cooled to 5 ° C. with ice water and filtered. The crystals were dissolved in 4.7 L of methanol while hot, cooled to 5 ° C., and the precipitated crystals were filtered and dried to obtain 148 g of the desired product. The yield was 74% (mp 179.5 ° C., optical purity> 99.9% ee).
[0109]
1H-NMR (200 MHz, D2 O, δ ppm): 7.5-7.2 (m, 5H), 5.1-5.0 (m, 1H), 2.69 (dd, J = 8.2, 14.2 Hz, 1H), 2.59 (dd, J = 6.0, 14.2 Hz, 1H)
13C-NMR (200 MHz, CDClThree , Δ ppm): 172.28, 142.56, 129.20, 128.65, 126.32, 71.11, 43.30
[0110]
The sample for optical purity measurement was synthesized as follows.
A mixture of the above (S) -3-hydroxy-3-phenylpropionohydrazide 100 mg (0.55 mmol), pyridine 5 ml, and acetic acid ethyl ester 2 ml was stirred at room temperature for 3 hours. Thereafter, the reaction solution was poured into water and extracted with ethyl acetate, and the ethyl acetate layer was washed with 1N aqueous hydrochloric acid, washed twice with 5% brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. .25 g of crude product was obtained. This product was analyzed under the following conditions, and the optical purity was 99.9% ee or higher.
[0111]
Column: Chiralcel OD-H, 4.6 mm × 250 mm (manufactured by Daicel Corporation)
Solvent: Hexane / Isopropyl alcohol = 7/3 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 210nm
[0112]
[Example 10]
Synthesis of (R) -5-phenyl-2-oxazolidinone
In a 1 L four-necked flask, 150 g (0.83 mol) of (S) -3-hydroxy-3-phenylpropionohydrazide (optical purity> 99.9% ee), 150 g of 35% concentrated hydrochloric acid (1.44 mol), 220 ml of water 100 ml of acetic acid ethyl ester was added and cooled to 5 ° C., and an aqueous solution (water 80 ml) of 57.5 g (0.83 mol) of sodium nitrite was added dropwise thereto at 5 ° C. over 1 hour. After stirring at the same temperature for 30 minutes, the aqueous layer of the reaction solution was extracted with 100 ml of ethyl acetate, combined with the ethyl acetate layer of the reaction, and washed twice with 5% brine. The ethyl acetate layer was dropped into 100 ml of water heated to 100 ° C. to perform thermal decomposition, and at the same time, the ethyl acetate was recovered. After dropping, the residue was cooled to room temperature, 200 ml of ethyl acetate was added, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 123.5 g of a crude product. This was heated and dissolved in 150 ml of water and 90 ml of methanol and crystallized at 5 ° C. to obtain 113.1 g of (R) -5-phenyl-2-oxazolidinone. The yield was 83% (mp 96.4 ° C., optical purity> 99.9% ee).
[0113]
1H-NMR (200 MHz, CDClThree , Δ ppm): 7.5-7.3 (m, 5H), 5.64 (t, J = 8.2 Hz, 1H), 5.14 (bs, 1H), 3.99 (dd, J = 8 .2, 8.6 Hz, 1 H), 3.55 (d, J = 8.2 Hz, 8.6 Hz, 1 H)
13C-NMR (50 MHz, CDClThree , Δ ppm): 162.16, 140.57, 129.91, 129.83, 126.81, 79.36, 49.30
[0114]
The optical purity was measured under the following conditions.
Column: Chiralcel OD-H, 4.6 mm × 250 mm (manufactured by Daicel Corporation)
Solvent: hexane / isopropyl alcohol = 95/5 (volume ratio)
Flow rate: 1.0 ml / min
Detection: 210nm
[0115]
[Reference Example 6]
Synthesis of ethyl (R) -4-chloro-3-hydroxybutanoate
In a 200 ml autoclave 40.0 g (0.24 mol) ethyl 4-chloro-3-oxobutanoate, Ru2ClFour((S) -tol-BINAP)2・ NEtThree 20 mg and 40 ml of ethanol were added and reacted at 100 ° C., hydrogen pressure of 3 atm for 5 hours. After removing the solvent, the reaction solution was distilled (60 ° C./200 Pa) to obtain 30.3 g of the title compound. Optical purity 95% ee.
[0116]
[Reference Example 7]
Synthesis of ethyl (R) -4-azido-3-hydroxybutanoate
Add 200 ml of (R) -4-chloro-3-hydroxybutanoate (20.0 g, 0.12 mol), sodium azide (15.6 g, 0.24 mol), and DMF (80 ml) into a 200 ml four-necked flask. For 24 hours. After cooling the reaction solution, 100 ml of toluene was added, washed with 50 ml of water and concentrated to obtain 16.5 g of the title compound. The yield was 79%.
[0117]
[Reference Example 8]
Synthesis of ethyl (R) -4-azido-3-acetoxybutanoate
(R) -4-azido-3-hydroxybutanoic acid ethyl 5.0 g (28.8 mmol), triethylamine 3.5 g (34.6 mmol), 4-dimethylaminopyridine 0.11 g (0.900 mmol), tetrahydrofuran in a 100 ml four-necked flask 50 ml was charged and cooled to 0 ° C., and then 2.50 g (31.8 mmol) of acetyl chloride was slowly added dropwise under a nitrogen stream. After completion of the dropwise addition, the mixture was stirred overnight at room temperature, and the solvent was distilled off under reduced pressure to obtain 4.94 g of a concentrate. Column chromatography of this concentrate (ethyl acetate / hexane = 1/10) gave 4.50 g of the title compound. The yield was 73%.
[0118]
[Reference Example 9]
Synthesis of ethyl (R) -4-acetylamino-3-hydroxybutanoate
A 200 ml autoclave was charged with 4.50 g (20.9 mmol) of ethyl (R) -4-azido-3-acetoxybutanoate, 0.02 g of 5% Pd-C and 5 ml of ethyl acetate, and hydrogen pressure 1000 kPa at room temperature overnight Stirring was performed. The catalyst was removed and concentrated to give 3.20 g of the title compound. The yield was 81%.
[0119]
Example 11
Synthesis of (R) -4-acetylamino-3-hydroxybutanohydrazide
Dissolve 5.00 g (26.4 mmol) of ethyl (R) -4-acetylamino-3-hydroxybutanoate (95% ee optical purity) in 20 ml of methanol and add 2.00 g (39.6 mmol) of hydrazine monohydrate to room temperature. And dripped. After completion of dropping, the mixture was heated to 65 ° C. and stirred overnight. After cooling to room temperature, 20 ml of methanol was added and crystallization was performed at 10 ° C. to obtain 3.90 g of the title compound. The yield was 84% (mp 177.5 ° C., optical purity> 99.9% ee).
[0120]
1H-NMR (500 MHz, CDThreeSOCDThree, δppm): 1.81 (s, 3H), 2.07 (dd, J = 8.0, 14.2 Hz, 1H), 2.14 (dd, J = 4.8, 14.2 Hz, 1H), 2.97-3.06 (m, 1H), 3.06- 3.11 (m, 1H), 3.86 (bs, 1H), 4.14 (bs, 2H), 4.77 (d, J = 4.4 Hz, 1H), 7.69 (bs, 1H), 8.85 (bs, 1H)
13C-NMR (126 MHz, CDThree(OD, δppm): 22.54, 40.37, 46.17, 68.59, 172.81, 173.73
[0121]
In addition, the following reaction was performed and the optical purity of the product was measured.
1 ml of acetic acid solution of 36 mg (0.19 mmol) of the obtained (R) -4-acetylamino-3-hydroxybutanohydrazide was cooled to 5 ° C., and 19 mg (0.28 mmol) of sodium nitrite was added. Stir the reaction at room temperature (22-24 ° C) for 1 hour, warm to 80 ° C and stir at 80 ° C for 1 hour. Acetic acid in the reaction solution was distilled off under reduced pressure, and the crude product was subjected to HPLC analysis as a 4-chlorobenzoylamide derivative under the following conditions.
[0122]
Column: CHIRALPAC- AD 4.6 mm X 250 mm (Daicel Chemical Industries)
Solvent: Hexane / 2-propanol = 9/1
Flow rate: 1.0 ml / min
Detection: 254 nm
[0123]
Example 12
Synthesis of (S) -5-acetylaminomethyl-2-oxazolidinone
(R) -4-acetylamino-3-hydroxybutanohydrazide (optical purity> 99.9% ee) To 3.50 g (20.0 mmol), add 14 ml of water and cool to 0 ° C. 35% HCl 2.29 g (22.0 mmol) was added dropwise over 10 min, and then an aqueous solution of sodium nitrite 1.52 g (22.0 mmol) dissolved in water 3.5 ml was slowly added dropwise. After stirring at the same temperature for 1 hour, the previously prepared reaction solution was added dropwise to 10 ml of hot water at 50 ° C. over 2 hours. After completion of the dropwise addition, the mixture was stirred for 1 hour, water was removed and 30 ml of methanol was added to remove the salt to obtain 3.30 g of the crude title compound. This product was crystallized from 10 ml of ethanol to obtain 2.75 g of the title compound. The yield was 87% (mp 137.5 ° C., optical purity> 99.9% ee).
[0124]
1H-NMR (500 MHz, CDThreeSOCDThree, δppm): 1.84 (s, 3H), 3.14-3.18 (m, 1H), 3.29 (t, J = 5.7 Hz, 2H), 3.49 (t, J = 8.8 Hz, 1H), 4.52-4.58 (m, 1H), 7.32 (bs, 1H), 8.05 (bs, 1H)
13C-NMR (126 MHz, CDThree(OD, δppm): 22.15, 41.46, 42.43, 73.91, 158.30, 169.55
[0125]
This product was analyzed by HPLC as a 4-chlorobenzoylamide derivative under the following conditions.
Column: CHIRALPAC- AD 4.6 mm X 250 mm (Daicel Chemical Industries)
Solvent: Hexane / 2-propanol = 9/1
Flow rate: 1ml / min
Detection: 254 nm
[0126]
[Reference Example 10]
Synthesis of ethyl (R) -4-azido-3-hexanoyloxybutanoate
(R) -4-azido-3-hydroxybutanoic acid 6.0 g (34.6 mmol), triethylamine 4.2 g (41.5 mmol), 4-dimethylaminopyridine 0.12 g (1.04 mmol), tetrahydrofuran in a 100 ml four-necked flask After 60 ml was charged and cooled to 0 ° C., 5.10 g (38.1 mmol) of hexanoyl chloride was slowly added dropwise under a nitrogen stream. After completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours, 14 ml of 5% hydrochloric acid was added, and the mixture was separated, washed 3 times with 30 ml of 5% brine, and concentrated to obtain 8.75 g of the title compound. The yield was 93%.
[0127]
[Reference Example 11]
Synthesis of ethyl (R) -4-hexanoylamino-3-hydroxybutanoate
A 200 ml autoclave was charged with 8.50 g (29.5 mmol) of ethyl (R) -4-azido-3-hexanoyloxybutanoate, 0.20 g of 5% Pd-C and 16 ml of ethyl acetate, and the hydrogen pressure was adjusted to 10 atm and room temperature. The mixture was stirred for 7 hours. The catalyst was removed and concentrated to give 7.07 g of the title compound. The yield was 87%.
[0128]
Example 13
Synthesis of (R) -4-hexanoylamino-3-hydroxybutanohydrazide
Dissolve 6.50 g (24.9 mmol) of ethyl (R) -4-hexanoylamino-3-hydroxybutanoate (optical purity 95% ee) in 26 ml of methanol, and add 1.87 g (37.3 mmol) of hydrazine monohydrate to room temperature. And then dripped. After completion of dropping, the mixture was heated to 65 ° C. and stirred for 2 hours. After cooling to room temperature, the mixture was stirred overnight to obtain 4.09 g of the title compound. The yield was 66% (mp 172.5 ° C., optical purity> 99.9% ee).
[0129]
1H-NMR (500 MHz, CDThreeSOCDThree, δppm): 0.86 (t, J = 7.0 Hz, 3H), 1.21-1.28 (m, 4H), 1.47-1.52 (m, 2H), 2.03-2.08 (m, 3H), 2.13 (dd, J = 4.8 , 14.1 Hz, 1H), 3.00-3.03 (m, 1H), 3.07-3.10 (m, 1H), 3.84-3.87 (m, 1H), 4.13 (bs, 2H), 4.76 (d, J = 4.9 Hz, 1H), 7.62 (bs, 1H), 8.86 (bs, 1H)
13C-NMR (126 MHz, CDThree(OD, δppm): 14.26, 23.43, 26.66, 32.56, 37.04, 40.43, 46.06,68.69, 172.83, 176.76
[0130]
In addition, the following reaction was performed and the optical purity of the product was measured.
1 ml of acetic acid solution of the obtained (R) -4-hexanoylamino-3-hydroxybutanohydrazide 47 mg (0.19 mmol) was cooled to 5 ° C., and 19 mg (0.28 mmol) of sodium nitrite was added. Stir the reaction at room temperature (22-24 ° C) for 1 hour, warm to 80 ° C and stir at 80 ° C for 1 hour. Acetic acid in the reaction solution was distilled off under reduced pressure, and the crude product was analyzed by HPLC under the following conditions as an MTPA amide derivative.
[0131]
Column: Cosmosil 5SL 4.6 mm x 250 mm (manufactured by Nacalai Tesque Inc.)
Solvent: Hexane / 2-propanol = 95/5
Flow rate: 1.0 ml / min
Detection: 254 nm
[0132]
Example 14
Synthesis of (S) -5-hexanoylaminomethyl-2-oxazolidinone
(R) -4-Hexanoylamino-3-hydroxybutanohydrazide (optical purity> 99.9% ee) 2.50 g (10.1 mmol) is added with 33 ml of water and cooled to 0 ° C. After 35% HCl 1.16 g (11.1 mmol) was added dropwise over 10 min, an aqueous solution in which 0.77 g (11.1 mmol) of sodium nitrite was dissolved in 2.5 ml of water was slowly added dropwise. After stirring at the same temperature for 2 hours, the previously prepared reaction solution was added dropwise to 10 ml of hot water at 50 ° C. over 1 hour. After completion of dropping, the mixture was stirred for 1 hour, cooled to room temperature, and extracted three times with 20 ml of ethyl acetate. The extracted ethyl acetate was concentrated to obtain 2.05 g of the crude title compound. Column chromatography (ethyl acetate / hexane = 1/1) gave 0.96 g of the title compound. The yield was 85% (mp 124.1 ° C., optical purity> 99.9% ee).
[0133]
1H-NMR (500 MHz, CDThreeSOCDThree, δppm): 0.91 (t, J = 7.2Hz, 3H), 1.26-1.36 (m, 4H), 1.52-1.58 (m, 2H), 2.10-2.17 (m, 2H), 3.18-3.20 (m, 3H ), 3.53 (t, J = 8.3Hz, 1H), 4.63-4.58 (m, 1H), 7.34 (bs, 1H), 7.97 (bs, 1H)
13C-NMR (126 MHz, CDThree(OD, δppm): 13.45, 21.49, 24.60, 30.57, 35.00, 41.31, 42.33,73.96, 158.29, 172.57
[0134]
The optical purity was analyzed by HPLC under the following conditions as an MTPA amide derivative.
Column: Cosmosil 5SL 4.6 mm x 250 mm (Nacalai Tesque Inc.)
Solvent: Hexane / 2-propanol = 95/5
Flow rate: 1.0 ml / min
Detection: 254 nm
[0135]
[Reference Example 12]
Synthesis of ethyl (R) -4-t-butoxycarbonylamino-3-hydroxybutanoate
In a 200 ml autoclave, ethyl (R) -4-azido-3-hydroxybutanoate 4.90 g (28.2 mmol), 5% Pd-C 0.25 g, (Boc)2O 6.47 g (29.6 mmol) and ethyl acetate 5 ml were charged, and the mixture was stirred at a hydrogen pressure of 1000 kPa at room temperature for 8 hours. The catalyst was removed and concentrated to give 5.26 g of the title compound. The yield was 75%.
[0136]
Example 15
Synthesis of (R) -4-t-butoxycarbonylamino-3-hydroxybutanohydrazide
(R) -4-t-Butoxycarbonylamino-3-hydroxybutanoic acid ethyl (optical purity 95% ee) 6.50 g (26.1 mmol) was dissolved in methanol 26 ml, hydrazine monohydrate 1.96 g (39.1 mmol) Was added dropwise at room temperature. After completion of the dropwise addition, the mixture was heated to 65 ° C. and stirred for 5 hours. After cooling to room temperature, the mixture was stirred overnight to obtain 4.27 g of the title compound. The yield was 70% (mp 143.6 ° C., optical purity> 99.9% ee).
[0137]
1H-NMR (500 MHz, CDThreeSOCDThree, δppm): 1.38 (s, 9H), 2.04 (dd, J = 8.2, 14.2 Hz, 1H), 2.14 (dd, J = 4.5, 14.2 Hz, 1H), 2.87-2.98 (m, 2H), 3.80- 3.87 (m, 1H), 4.11 (bs, 1H), 4.69 (d, J = 5.0 Hz, 1H), 6.53 (bs, 1H), 8.84 (bs, 1H)
13C-NMR (126 MHz, CDThree(OD, δppm): 28.73, 40.29, 47.05, 68.98, 80.72, 158.62, 172.96
[0138]
In addition, the following reaction was performed and the optical purity of the title compound was measured.
1 ml of acetic acid solution of 44 mg (0.19 mmol) of the obtained (R) -4-butoxycarbonylamino-3-hydroxybutanohydrazide was cooled to 5 ° C., and 19 mg (0.28 mmol) of sodium nitrite was added. Stir the reaction at room temperature (22-24 ° C) for 1 hour, warm to 80 ° C and stir at 80 ° C for 1 hour. Acetic acid in the reaction solution was distilled off under reduced pressure, and the crude product was analyzed by HPLC under the following conditions as an MTPA amide derivative.
Column: Inertsi SIL 100-5 4.6 mm X 250 mm (manufactured by GL Sciences Inc.)
Solvent: Hexane / 2-propanol = 95/5
Flow rate: 0.5 ml / min
Detection: 254 nm
[0139]
Example 16
Synthesis of (S) -5-t-butoxycarbonylaminomethyl-2-oxazolidinone
Add 10 ml of water to 2.00 g (8.57 mmol) of (R) -4-t-butoxycarbonylamino-3-hydroxybutanohydrazide (optical purity> 99.9% ee) and cool to 0 ° C. 35% HCl 0.89 g (8.57 mmol) was added dropwise over 10 minutes, and then an aqueous solution of sodium nitrite 0.59 g (8.57 mmol) dissolved in water 2.0 ml was slowly added dropwise. After stirring at the same temperature for 1 hour, the previously prepared reaction solution was added dropwise to 10 ml of warm water at 50 ° C. over 1 hour. After completion of dropping, the mixture was stirred for 1 hour, cooled to room temperature, and extracted three times with 20 ml of ethyl acetate. The extracted ethyl acetate was concentrated to obtain 1.06 g of the crude title compound. Column chromatography (ethyl acetate) gave 0.96 g of the title compound. The yield was 52% (mp 115.5 ° C., optical purity> 99.9% ee).
[0140]
1H-NMR (500 MHz, CDThreeSOCDThree, δppm): 1.43 (s, 9H), 3.18-3.24 (m, 3H), 3.5 (t, J = 8.8Hz, 1H), 4.54-4.59 (m, 1H), 6.49 (bs, 1H), 7.32 ( bs, 1H)
13C-NMR (126 MHz, CDThree(OD, δppm): 28.69, 43.99, 44.12, 76.98, 80.36, 158.44, 161.81
[0141]
The optical purity was analyzed by HPLC under the following conditions as an MTPA amide derivative.
Column: Inertsi SIL 100-5 4.6 mm X 250 mm (manufactured by GL Sciences Inc.)
Solvent: Hexane / 2-propanol = 95/5
Flow rate: 0.5 ml / min
Detection: 254 nm
[0142]
[Reference Example 13]
Synthesis of methyl (2S, 3S) -2-benzyl-3-hydroxybutanoate
In a 500 ml autoclave under a nitrogen stream, methyl acetoacetate 100 g (861 mmol), Ru2ClFour((S) -binap)2 ・ NEtThree 50 mg (0.0592 mmol) and 100 ml of methanol were added, and hydrogenated at 50 ° C. and hydrogen pressure of 500 kPa for 45 hours. After completion of the reaction, methanol was collected and distilled under reduced pressure to obtain 91.56 g (65 ° C./1300 Pa, 96% ee) of methyl (S) -3-hydroxybutanoate.
Subsequently, 3.3 g (30.0 mmol) of diisopropylamine and 10 ml of tetrahydrofuran were placed in a 50 ml flask, and 16.6 ml (24.9 mmol) of n-butyllithium 1.5M hexane solution was added dropwise to the ice bath under a nitrogen stream. Stir for 1 h. The reaction solution was further cooled to −40 ° C., and 1.40 g (11.9 mmol) of methyl (S) -3-hydroxybutanoate was added dropwise, stirred for 0.5 hour, and then dissolved in 6 ml of hexamethylphosphoramide. 3.00 g (17.5 mmol) was added dropwise so as not to exceed −10 ° C. After completion of the dropwise addition, the mixture was raised to 0 ° C. and stirred for 15 minutes, poured into ice water and extracted with acetic acid ethyl ester. The ethyl acetate was concentrated to give 3.90 g of the crude title compound. Column chromatography (hexane / ethyl acetate = 4/1) gave 1.50 g (anti / syn = 98/2) of the title compound. The yield was 61%.
[0143]
[Example 17]
Synthesis of (2S, 3S) -2-benzyl-3-hydroxybutanohydrazide
Hydrazine monohydrate is obtained by dissolving 0.70 g (3.36 mmol) of methyl (2S, 3S) -2-benzyl-3-hydroxybutanoate (96% ee, anti / syn = 98/2) in 1 ml of 2-propanol. 0.34 g (6.72 mmol) is added dropwise at room temperature. Reflux for 8 hours after completion of the dropwise addition, stir overnight and concentrate. The concentrate was crystallized with an ethyl acetate-hexane mixed solvent to obtain 0.45 g of the title compound. The yield was 64% (mp 167.1 ° C., optical purity> 99.9% ee, anti / syn> 99/1).
[0144]
1H-NMR (500 MHz, CDThreeSOCDThree, δppm): 1.10 (d, J = 6.4 Hz, 3H), 2.38-2.42 (m, 1H), 2.73 (dd, J = 4.8, 13.6 Hz, 1H), 2.83 (dd, J = 9.8, 13.6 Hz, 1H), 3.65-3.75 (m, 1H), 4.08 (s, 2H), 4.51 (d, J = 5.6Hz, 1H), 7.12-7.15 (m, 3H), 7.21-7.24 (m, 2H), 8.77 (bs, 1H)
13C-NMR (126 MHz, CDThree(OD, δppm): 20.95, 33.32, 52.80, 66.88, 125.53, 127.83, 128.54, 140.07, 172.06
[0145]
In addition, the following reaction was performed and the optical purity and diastereomer ratio of the title compound were measured.
1 ml of acetic acid solution of 40 mg (0.19 mmol) of (2S, 3S) -2-benzyl-3-hydroxy 1-butanohydrazide obtained was cooled to 5 ° C, and 19 mg (0.28 mmol) of sodium nitrite was added. It was. Stir the reaction at room temperature (22-24 ° C) for 1 hour, warm to 80 ° C and stir at 80 ° C for 1 hour. Acetic acid in the reaction solution was distilled off under reduced pressure, and the crude product was subjected to GLC analysis under the following conditions.
[0146]
The optical purity was measured by GLC under the following conditions.
Column: CHIRALSIL-DEX CB 0.25 mm x 25 m (Chrompack Inc.)
Injection temperature: 200 ° C
Column temperature: 165 ° C
Detection temperature: 250 ℃
[0147]
The diastereomeric ratio was measured by GLC under the following conditions.
Column: Neutra Bond-I 0.25 mm X 30 m (manufactured by GL Sciences Inc.)
Injection temperature: 200 ° C
Column temperature: 150 ° C to 180 ° C
Detection temperature: 250 ℃
Temperature rise: 2 ° C / min
[0148]
Example 18
Synthesis of (4S, 5S) -4-benzyl-5-methyl-2-oxazolidinone
Add 5.5 ml of water to 0.50 g (2.40 mmol) of (2S, 3S) -2-benzyl-3-hydroxybutanohydrazide (optical purity> 99.9% ee, anti / syn> 99/1) and cool to 0 ° C. After dropwise addition of 0.30 g (2.88 mmol) of 35% HCl, an aqueous solution in which 0.20 g (2.88 mmol) of sodium nitrite was dissolved in 1.0 ml of water was slowly added dropwise. After stirring at the same temperature for 1 hour, the previously prepared reaction solution was added dropwise to 10 ml of warm water at 50 ° C. over 0.5 hour. After completion of the dropwise addition, the mixture was stirred for 1 hour, cooled to room temperature, and extracted three times with 10 ml of toluene. The extracted toluene was concentrated to obtain 0.33 g of the crude title compound. Column chromatography purification (hexane / ethyl acetate = 1/1) gave 0.25 g of the title compound. The yield was 52% (mp 115.5 ° C., optical purity> 99.9% ee, anti / syn> 99/1).
[0149]
1H-NMR (500 MHz, CDThreeSOCDThree, δppm): 1.07 (d, J = 6.3Hz, 3H), 2.73 (dd, J = 7.2, 13.6 Hz, 1H), 2.83 (dd, J = 5.6, 13.6 Hz, 1H), 3.53-3.59 (m, 1H), 4.23-4.26 (m, 1H), 7.22-7.23 (m, 3H), 7.27-7.30 (m, 2H), 7.59 (bs, 1H)
13C-NMR (126 MHz, CDThree(OD, δppm): 19.97, 40.16, 59.53, 76.38, 126.46, 128.30, 129.32, 136.47, 157.69
[0150]
The optical purity was measured by GLC under the following conditions.
Column: CHIRALSIL-DEX CB 0.25 mm x 25 m (Chrompack Inc.)
Injection temperature: 200 ° C
Column temperature: 165 ° C
Detection temperature: 250 ℃
[0151]
The diastereomeric ratio was measured by GLC under the following conditions.
Column: Neutra Bond-I 0.25 mm X 30 m (manufactured by GL Sciences Inc.)
Injection temperature: 200 ° C
Column temperature: 150 ° C to 180 ° C
Detection temperature: 250 ℃
Temperature rise: 2 ° C / min

Claims (3)

一般式(1)
Figure 0004335390
(式中、R1は、炭素数1乃至4の低級アルキル基、フェニル基、メトキシメチル基、ベンジルオキシメチル基、ベンゼン環が置換されてもよいベンジルオキシカルボニルアミノメチル基、炭素数3乃至10のアシルアミノメチル基、炭素数3乃至6のアルコキシカルボニルアミノメチル基を示し、R2,R3は、同一又は異なってもよくそれぞれ水素原子、炭素数1乃至4の低級アルキル基、フェニル基、アセチルアミノメチル基、ベンゾイルアミノメチル基、ベンジル基を示し、R4は炭素数1乃至4の低級アルキル基を示す。*印は不斉炭素原子を意味する。)で表される3位に水酸基を持つ光学活性酸エステルに、ヒドラジンを作用させ、一般式(2)
Figure 0004335390
(式中、R1,R2,R3及び*印は前記と同一なものを意味する。)で表される3位に水酸基を持つ光学活性ヒドラジド誘導体となし、次いで、酸存在下、0〜5℃で亜硝酸ナトリウムを作用せしめて、中間体のアシルアジドを発生させ、この溶液を加熱した溶媒中に滴下してCurtius 転位反応を行うことを特徴とする、一般式(3)
Figure 0004335390
( 式中、R1,R2,R3及び*印は前記と同一なものを意味する。)で表される光学活性オキサゾリジノン誘導体の製造方法。
General formula (1)
Figure 0004335390
(In the formula, R 1 represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, a methoxymethyl group, a benzyloxymethyl group, a benzyloxycarbonylaminomethyl group on which a benzene ring may be substituted, or 3 to 10 carbon atoms. An acylaminomethyl group, an alkoxycarbonylaminomethyl group having 3 to 6 carbon atoms, wherein R 2 and R 3 may be the same or different and each is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, An acetylaminomethyl group, a benzoylaminomethyl group, and a benzyl group, R 4 represents a lower alkyl group having 1 to 4 carbon atoms, and * represents a chiral carbon atom.) Hydrazine is allowed to act on an optically active acid ester having a general formula (2)
Figure 0004335390
(Wherein R 1 , R 2 , R 3 and * means the same as those described above), an optically active hydrazide derivative having a hydroxyl group at the 3-position, and then in the presence of an acid, 0 Sodium nitrite is allowed to act at ˜5 ° C. to generate an intermediate acyl azide, and this solution is dropped into a heated solvent to carry out Curtius rearrangement reaction.
Figure 0004335390
(Wherein R 1 , R 2 , R 3, and * are the same as those described above.) A process for producing an optically active oxazolidinone derivative represented by the formula:
3位に水酸基を持つ光学活性ヒドラジド誘導体を再結晶化することにより高純度の3位に水酸基を持つ光学活性ヒドラジド誘導体を得ることを特徴とする請求項1記載の高純度の光学活性オキサゾリジノン誘導体の製造方法。 2. An optically active oxazolidinone derivative having a high purity according to claim 1, wherein an optically active hydrazide derivative having a hydroxyl group at the 3-position is obtained by recrystallization of the optically active hydrazide derivative having a hydroxyl group at the 3-position. Production method. 請求項1の一般式(1)で表される3位に水酸基を持つ光学活性酸エステルにおいて、R1がメチル基、フェニル基、メトキシメチル基、ベンジルオキシメチル基、ベンジルオキシカルボニルアミノメチル基、アセチルアミノメチル基、へキサノイルアミノメチル基、t−ブトキシカルボニルアミノメチル基を示し、R2,R3 が同一の水素原子又は水素原子とアセチルアミノメチル基、ベンゾイルアミノメチル基、ベンジル基を示し、R4は炭素数1乃至4の低級アルキル基を示すことを特徴とする請求項1または請求項2記載の光学活性オキサゾリジノン誘導体の製造方法。In the optically active acid ester having a hydroxyl group at the 3-position represented by the general formula (1) of claim 1, R 1 is a methyl group, a phenyl group, a methoxymethyl group, a benzyloxymethyl group, a benzyloxycarbonylaminomethyl group, Acetylaminomethyl group, hexanoylaminomethyl group, t-butoxycarbonylaminomethyl group, R 2 and R 3 are the same hydrogen atom or hydrogen atom and acetylaminomethyl group, benzoylaminomethyl group, benzyl group , R 4 represents a lower alkyl group having 1 to 4 carbon atoms, The method for producing an optically active oxazolidinone derivative according to claim 1 or 2.
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