JP3784945B2 - Taxol derivative - Google Patents
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- JP3784945B2 JP3784945B2 JP31780997A JP31780997A JP3784945B2 JP 3784945 B2 JP3784945 B2 JP 3784945B2 JP 31780997 A JP31780997 A JP 31780997A JP 31780997 A JP31780997 A JP 31780997A JP 3784945 B2 JP3784945 B2 JP 3784945B2
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- 0 CC(C)(C(C1)(C(C([C@]2(C(C3C4*3)OC2)OC(*)=O)C4(*)C(C2*)=O)OC(I)=O)O)C2=C(C)C1OC(C(*)(*)C(*)NC(I)=O)=O Chemical compound CC(C)(C(C1)(C(C([C@]2(C(C3C4*3)OC2)OC(*)=O)C4(*)C(C2*)=O)OC(I)=O)O)C2=C(C)C1OC(C(*)(*)C(*)NC(I)=O)=O 0.000 description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N CN1CCOCC1 Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N Cc1ccc(C=O)cc1 Chemical compound Cc1ccc(C=O)cc1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- VYJNGXULDIULEC-SNVBAGLBSA-N Cc1ccc([C@@H](C2=C)NC2=O)cc1 Chemical compound Cc1ccc([C@@H](C2=C)NC2=O)cc1 VYJNGXULDIULEC-SNVBAGLBSA-N 0.000 description 1
- LQXUYPKOOOUVJB-UHFFFAOYSA-N O=CC1=CC=CCC1 Chemical compound O=CC1=CC=CCC1 LQXUYPKOOOUVJB-UHFFFAOYSA-N 0.000 description 1
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Description
【０００１】
【産業上の利用分野】
本発明は抗腫瘍作用を有する新規タキソール誘導体に関するものである。
【０００２】
【従来の技術】
タキソールは次の化学構造式で表される天然物で、西洋イチイの幹などから微量得られる。
【０００３】
【化１１】
【０００４】
これまでは、タキソールは天然から極く微量しか得られなかった。しかし、近年になって、イチイ類の葉等から比較的多量に得ることのできるタキソール前駆体である１０−Ｏ−デアセチルバッカチン III
【０００５】
【化１２】
【０００６】
【化１３】
【発明が解決しようとする課題】
このようにタキソールやタキソテールで表される誘導体は抗腫瘍剤として有望なものである。しかしながら、臨床試験で消化器癌、特に大腸癌等に対する有効性は低いことが判明し、より強い抗腫瘍効果を持つ誘導体が望まれている。
【０００８】
【課題を解決するための手段】
従来、タキソール誘導体の１０位置換基としては、アセトキシ基や水酸基、およびその水酸基をさらにアシル基、アルキルアミノカルボニル基（ＥＰ５２４０９３）等で置換したものが報告されており、また１０位が水素原子置換となった誘導体（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，３４，４９２１（１９９３））も知られている。本発明者等は鋭意検討した結果、１０位にアルキル基または置換基を有するアルキル基を導入した誘導体が強い抗腫瘍活性を有することを見いだし本発明を完成した。
【０００９】
本発明は、一般式（Ｉ）
【００１０】
【化１４】
［式中、
Ｒ1 はフェニル基を意味し、該フェニル基はハロゲン原子、アルキル基およびアルコキシル基からなる群から選ばれる基を置換基として１個または複数個有していてもよい。
【００１２】
Ｒ2 はアルキル基、アルケニル基、アルキニル基、シクロアルキル基またはアルコキシル基を意味し、これらアルキル基、アルケニル基、アルキニル基、シクロアルキル基およびアルコキシル基は、ハロゲン原子、水酸基、カルボキシル基、アルコキシル基、アリールオキシ基、フェニル基、アミノ基、アルキルアミノ基、アルコキシカルボニル基、アリールオキシカルボニル基、アシル基、アシルアミノ基およびアシルオキシ基からなる群から選ばれる基を置換基として１個または複数個有していてもよい。
【００１３】
Ｒ3 はアルキル基およびアシル基からなる群から選ばれる基を置換基として１個または２個有するアミノ基、水素原子、水酸基、ハロゲン原子、アルコキシル基、アジド基またはアシルオキシ基を意味する。
【００１４】
Ｒ4 はアルキル基およびアシル基からなる群から選ばれる基を置換基として１個または２個有するアミノ基、水素原子、水酸基、ハロゲン原子、アルコキシル基、アジド基またはアシルオキシ基を意味し、該アルコキシル基およびアシルオキシ基は、ハロゲン原子、水酸基、カルボキシル基、シクロアルキル基、アルコキシル基、アリール基、アリールオキシ基、アミノ基、アルキルアミノ基、アルコキシカルボニル基、アリールオキシカルボニル基、アシル基、アシルアミノ基、アシルオキシ基および複素環基（該複素環基は、その環の構成原子上にアルキル基を１個または複数個有してもよい。）からなる群から選ばれる基を置換基として１個または複数個有してもよい。
また、Ｒ3 とＲ4 は一緒になって式
【００１５】
【化１５】
で表される構造を形成してもよい。
【００１６】
Ｒ5 はメチル基を意味するか、
または、Ｒ4 と一緒になって、Ｒ4 とＲ5 のそれぞれが結合している炭素原子と共に３員環を形成した構造となってもよい。
【００１７】
Ｒ6 はアルキル基、アルケニル基またはアルキニル基を意味し、
これらアルキル基、アルケニル基およびアルキニル基は、カルボキシル基、アルコキシル基、アリールオキシ基、アルコキシカルボニル基、アリールオキシカルボニル基、シアノ基、水酸基、アミノ基、アルキルアミノ基、アシル基、アシルアミノ基、アシルオキシ基、アルコキシカルボニルアミノ基、アルキルチオ基、アルキルスルフィニル基、アルキルスルホニル基および式
【００１８】
【化１６】
【００１９】
Ｚ1 は水素原子、水酸基、ハロゲン原子またはアルキル基を意味し、
Ｚ2 は水素原子、水酸基、ハロゲン原子またはアルキル基を意味し、
Ｚ3 はアルキル基、アルケニル基、アルキニル基、シクロアルキル基、アリール基または複素環基を意味し、これらアルキル基、アルケニル基、アルキニル基、シクロアルキル基、アリール基および複素環基は、ハロゲン原子、水酸基、カルボキシル基、アルキル基、アルコキシル基、フェニル基、アミノ基、アルキルアミノ基、アミノアルキル基、アルキルアミノアルキル基、アルコキシカルボニル基、アリールオキシカルボニル基、アシル基、アシルアミノ基およびアシルオキシ基からなる群から選ばれる基を置換基として１個または複数個有してもよい。
【００２０】
Ｚ4 はアルキル基、アリール基またはアルコキシル基を意味し、これらアルキル基、アリール基およびアルコキシル基は、ハロゲン原子、水酸基、カルボキシル基、アルキル基、アルコキシル基、フェニル基、アミノ基、アルキルアミノ基、アミノアルキル基、アルキルアミノアルキル基、アルコキシカルボニル基、アリールオキシカルボニル基、アシル基、アシルアミノ基およびアシルオキシ基からなる群から選ばれる基を置換基として１個または複数個有してもよい。
【００２１】
なお、
【００２２】
【化１７】
【００２３】
次に、本明細書で用いる用語について説明する。
【００２４】
“Ｃ1 〜Ｃ6 ”とは炭素数１から６のものという意味で、例えば、“Ｃ2 〜Ｃ6 アルケニル基”は炭素数が２から６のアルケニル基を意味する。
【００２５】
“アルキル基”、“アルケニル基”および“アルキニル基”は直鎖でも分枝鎖でもよく、炭素数１（アルケニル基およびアルキニル基の場合は炭素数２）から炭素数６までのものが好ましい。
【００２６】
“アルコキシル基”とは、基−Ｏ−にアルキル基が結合したものを意味するが、該アルキル基にフェニル基（置換基を有していてもよい。）が置換してもよく、この様な例としてはベンジルオキシ、フェネチルオキシ、ｐ−メトキシベンジルオキシ等が挙げられる。なお、アルキル部分は炭素数１から６のものが好ましい。
【００２７】
“アルコキシカルボニル基”とは、基−ＣＯＯ−の酸素原子にアルキル基が結合したものを意味するが、該アルキル基にフェニル基（置換基を有していてもよい。）が置換してもよく、この様な例としては、ベンジルオキシカルボニル、フェネチルオキシカルボニル、ｐ−メトキシベンジルオキシカルボニル等が挙げられる。なお、アルキル部分は炭素数１から６のものが好ましい。
【００２８】
“アリール基”とは、芳香族炭化水素の核から水素原子１個を除いた１価基のことを意味し、例えば、フェニル、トリル、ビフェニリル、ナフチル等が挙げられる。
【００２９】
“アミノアルキル基”のアミノ基の結合位置はアルキル基のどの位置でもよい。また、アルキル基の炭素数は１から６が好ましい。
【００３０】
“アルキルアミノ基”とは、アミノ基にアルキル基が１個置換したもの、あるいはアミノ基にアルキル基が２個置換したもの（２個のアルキル基は同一でも異なっても良い。）を意味する。また、アルキル基の炭素数は１から６が好ましい。
【００３１】
“アシル基”とは、カルボニル基（−ＣＯ−）に水素原子、アルキル基またはアリール基が結合したものを意味し、例えば、ホルミル、アセチル、プロパノイル、ベンゾイル等が挙げられる。なお結合するアルキル基としては、炭素数１から６のものが好ましく、結合するアリール基としてはフェニル基が好ましい。
【００３２】
“複素環基”とは、環構造の構成原子として酸素原子、窒素原子および硫黄原子からなる群から選ばれる原子の１種以上を１個または複数個含む、単環性あるいは二環性の飽和もしくは不飽和の複素環化合物から導かれる置換基を意味し、これら複素環基はいずれの位置で結合してもよい。単環性の複素環基としては、例えば、ピロール、フラン、チオフェン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、イミダゾール、ピラゾール、イミダゾリジン、ピラゾリジン、オキサゾール、チアゾール、オキサジアゾール、チアジアゾール、ピリジン、ジヒドロピリジン、テトラヒドロピラン、ピペリジン、ピリダジン、ピリミジン、ピラジン、ピペラジン、ジオキサン、ピラン、モルホリン等の単環性の複素環化合物から導かれる置換基が挙げられる。二環性の複素環基としては、ベンゾフラン、インドリジン、ベンゾチオフェン、インドール、ナフチリジン、キノキサリン、キナゾリン、クロマン等の二環性の複素環化合物から導かれる置換基が挙げられる。
【００３３】
“含窒素複素環基”とは、複素環基の構成原子として必ず窒素原子を１個含み、他に構成原子として酸素原子、窒素原子および硫黄原子からなる群から選ばれる原子の１種以上を１個または複数個含むこともある飽和または不飽和の複素環化合物から導かれる置換基を意味する。例えば、ピロール、ピロリジン、イミダゾール、ピラゾール、イミダゾリジン、ピラゾリジン、オキサゾール、チアゾール、オキサジアゾール、チアジアゾール、ピリジン、ジヒドロピリジン、ピペリジン、ピリダジン、ピリミジン、ピラジン、ピペラジン、モルホリン、チオモルホリン等が挙げられる。
【００３４】
“式
【００３５】
【化１８】
（Ｘは酸素原子、硫黄原子、ＣＨ２、ＣＨ−Ｙ、ＮＨまたはＮ−Ｙを意味し、Ｙはアルキル基を意味する。）
で表される、窒素原子を含む５員環から６員環の大きさの飽和の複素環基（該複素環基は、その環の構成原子である炭素原子上にアルキル基を１個または複数個有してもよい。）”とは、複素環基の構成原子として必ず窒素原子を１個含む５員環から６員環の大きさの飽和の複素環化合物から導かれる置換基を意味し、例えば、ピロリジン、イミダゾリジン、ピラゾリジン、オキサゾリジン、チアゾリジン、イソオキサゾリジン、イソチアゾリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリン等が挙げられる。
【００３７】
Ｒ3 とＲ4 が一緒になって式
【００３８】
【化１９】
で表される構造を形成するとは、６位および７位部分が次の構造となることを意味している。
【００３９】
【化２０】
Ｒ4 とＲ5 が一緒になって、それぞれが結合している炭素原子と共に３員環を形成するとは、７位および８位部分が次の構造となること意味している。
【００４１】
【化２１】
次に、一般式（Ｉ）中の各置換基について説明する。
【００４３】
Ｒ1 のフェニル基の置換基としての“アルキル基”、“アルコキシル基”は炭素数１から３のものが好ましい。
【００４４】
Ｒ1 のフェニル基の置換基の数としては、１または２が好ましく、置換基の置換位置は、メタ位が好ましい。
【００４５】
Ｒ1 としては、無置換のフェニル基が好ましい。また、フッ素原子、塩素原子、メチル基もしくはメトキシ基が１個または２個メタ位に置換したフェニル基も好ましいものとして挙げられる。
【００４６】
Ｒ2 としては、アルキル基、アルコキシル基およびシクロアルキル基が好ましい。
【００４７】
Ｒ2 の“アルキル基”としては、Ｃ1 〜Ｃ6 アルキル基が好ましく、特にメチル基、エチル基、プロピル基が好ましい。
【００４８】
Ｒ2 の“アルコキシル基”としては、Ｃ1 〜Ｃ6 アルコキシル基が好ましく、特にメトキシ基、エトキシ基が好ましい。
【００４９】
Ｒ2 の“シクロアルキル基”としては、Ｃ3 〜Ｃ6 シクロアルキル基が好ましく、特にシクロプロピル基が好ましい。
【００５０】
Ｒ2 としては、メチル基、エチル基、プロピル基、メトキシ基、エトキシ基またはシクロプロピル基が特に好ましい。
【００５１】
Ｒ3 としては水素原子が好ましい（ただしＲ4 が水素原子または水酸基で、Ｒ3 が結合する炭素原子とＲ4 が結合する炭素原子の間の結合が単結合のものを除く。）。
【００５２】
Ｒ4 としては、ハロゲン原子、アルコキシル基、水素原子または水酸基が好ましい（ただし、Ｒ4 が水素原子または水酸基の場合、Ｒ3 が水素原子で、Ｒ3 が結合する炭素原子とＲ4 が結合する炭素原子の間の結合が単結合のものを除く。）。
【００５３】
Ｒ4 の“ハロゲン原子”としては、フッ素原子が好ましい。
【００５４】
Ｒ4 の“アルコキシル基”としては、メトキシ基が好ましい。
【００５５】
Ｒ4 としては水素原子、フッ素原子、水酸基またはメトキシ基が特に好ましい（ただし、Ｒ4 が水素原子または水酸基の場合、Ｒ3 が水素原子で、Ｒ3 が結合する炭素原子とＲ4 が結合する炭素原子の間の結合が単結合のものを除く。）。
【００５６】
またＲ3 とＲ4 が一緒になって式
【００５７】
【化２２】
で表される構造を形成した、一般式（Ｉ−１）
【００５８】
【化２３】
【００５９】
【化２４】
【００６０】
Ｒ5 としては、メチル基の場合、またはＲ4 と一緒になってＲ4 とＲ5 のそれぞれが結合している炭素原子（７位と８位）と共に３員環を形成したもの、すなわち７位および８位部分が次の構造となった
【００６１】
【化２５】
【００６２】
【化２６】
【００６３】
Ｒ6 としては、アルキル基またはアルケニル基が好ましく、
該アルキル基は、カルボキシル基、アルコキシル基、アリールオキシ基、アルコキシカルボニル基、アリールオキシカルボニル基、シアノ基、水酸基、アミノ基、アルキルアミノ基、アシル基、アシルアミノ基、アシルオキシ基、アルコキシカルボニルアミノ基、アルキルチオ基、アルキルスルフィニル基、アルキルスルホニル基および式
【００６４】
【化２７】
で表される、３員環から８員環の大きさの窒素原子を含む飽和または不飽和の複素環基（該複素環基は、その環の構成原子である炭素原子上にアルキル基を１個または複数個有してもよい。）からなる群から選ばれる基を置換基として１個または複数個有してもよい。なお、置換基の結合位置は該アルキル基のどの位置でもよい。
【００６５】
Ｒ6 のアルキル基としては、Ｃ1 〜Ｃ6 アルキル基が好ましく、特にメチル基、エチル基、プロピル基、ブチル基が好ましい。
【００６６】
Ｒ6 のアルケニル基としては、Ｃ2 〜Ｃ6 アルケニル基が好ましく、特にアリル基が好ましい。
【００６７】
Ｒ6 のアルキル基の置換基としては、アルコキシカルボニル基、水酸基、シアノ基、アシル基、アルキルアミノ基、アルキルチオ基または式
【００６８】
【化２８】
で表される、５員環または６員環の大きさの窒素原子を含む飽和または不飽和の複素環基（該複素環基は、その環の構成原子である炭素原子上にアルキル基を１個または複数個有してもよい。）が好ましい。
【００６９】
最も好ましい置換基としては、式
【００７０】
【化２９】
【００７１】
なお、複素環基の環の構成原子である炭素原子上に置換するアルキル基としては、メチル基が好ましい。
【００７２】
Ｒ6 としては、特に置換基として式
【００７３】
【化３０】
で表される、５員環から６員環の大きさの窒素原子を含む飽和の複素環基（該複素環基は、その環の構成原子である炭素原子上にアルキル基を１個または複数個有してもよい。）を有する炭素数１から３のアルキル基、またはアリル基が好ましい。
【００７４】
Ｒ6 としては、モルホリンまたはチオモルホリン（該モルホリンまたはチオモルホリンは、その環の構成原子である炭素原子上にメチル基を１個または複数個有していてもよい。）を置換基として有している炭素数１から３のアルキル基、またはアリル基が最も好ましい。
【００７５】
Ｚ1 およびＺ2 の“ハロゲン原子”としては、フッ素原子、塩素原子および臭素原子が好ましい。
【００７６】
Ｚ1 およびＺ2 の“アルキル基”としては、メチル基、エチル基、プロピル基が好ましい。
【００７７】
Ｚ1 としては、ハロゲン原子、水酸基が好ましく、ハロゲン原子の中では、特にフッ素原子が好ましい。
【００７８】
Ｚ2 としては、ハロゲン原子、水素原子またはアルキル基が好ましい。ハロゲン原子の中では、特にフッ素原子が好ましい。アルキル基の中では、特にメチル基が好ましい。
【００７９】
Ｚ1 およびＺ2 として最も好ましいのは、Ｚ1 がフッ素原子、Ｚ2 がフッ素原子の組み合わせのもの、Ｚ1 が水酸基、Ｚ2 が水素原子の組み合わせのもの、あるいはＺ1 が水酸基、Ｚ2 がメチル基の組み合わせのものが挙げられる。
【００８０】
Ｚ3 としてはアリール基、複素環基、アルケニル基が好ましい。
【００８１】
Ｚ3 の“アリール基”としては、フェニル基が好ましい。
【００８２】
Ｚ3 の“アルケニル基”としては、２−メチル−１−プロペニル基が好ましい。
【００８３】
Ｚ3 の複素環基としては、単環性の複素環基が好ましく、さらには、単環性の５員環または６員環の複素環基が好ましく、例えば、ピロール、フラン、チオフェン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、イミダゾール、ピラゾール、イミダゾリジン、ピラゾリジン、オキサゾール、チアゾール、オキサジアゾール、チアジアゾール、ピリジン、ジヒドロピリジン、テトラヒドロピラン、ピペリジン、ピリダジン、ピリミジン、ピラジン、ピペラジン、ジオキサン、ピラン、モルホリン等から導かれる置換基が挙げられる。
【００８４】
Ｚ3 の複素環基の中では、単環性の５員環または６員環の複素環基で環構造の構成原子として酸素原子、窒素原子または硫黄原子を１個含む複素環基が特に好ましく、例えば、ピロール、フラン、チオフェン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピリジン、ジヒドロピリジン、テトラヒドロピラン、ピペリジン、ピラン等から導かれる置換基が挙げられる。
【００８５】
Ｚ3 の複素環基の中では、単環性の５員環または６員環の複素環基で環構造の構成原子として酸素原子、窒素原子または硫黄原子を１個含む不飽和の複素環基が最も好ましいものとして挙げられ、具体的には、フラン、ピリジン、ピロールから導かれる置換基が最も好ましい。
【００８６】
Ｚ3 としては、２−メチル−１−プロペニル基、フェニル基、フリル基、ピリジル基、ピロリル基が特に好ましい。
【００８７】
Ｚ4 はアリール基またはアルコキシル基が好ましい。
【００８８】
Ｚ4 の“アリール基”としては、フェニル基が好ましい。
【００８９】
Ｚ4 の“アルコキシル基”としては、第三級ブトキシが好ましい。
【００９０】
Ｚ4 としては、フェニル基、第三級ブトキシ基が特に好ましい。
【００９１】
なお
【００９２】
【化３１】
【００９３】
【化３２】
【００９４】
本発明においては、次に示す立体配置のものが好ましい。
【００９５】
【化３３】
置換基Ｚ3 の結合している３’位の立体配置は、どちらの立体配置のものも含まれるが、天然のタキソールと同じ立体配置のものがより好ましい。
【００９７】
本発明のタキソール誘導体は遊離体のままでもよいが、酸付加塩としてあるいはカルボキシル基の塩としてもよい。酸付加塩とする場合の例としては、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩等の無機酸塩類、あるいは酢酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、クエン酸塩、マレイン酸塩、フマル酸塩、乳酸塩等の有機酸塩類を挙げることができる。
【００９８】
また、カルボキシル基の塩としては、例えばリチウム塩、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アンモニウム塩、またトリエチルアミン塩やＮ−メチルグルカミン塩、トリス−（ヒドロキシルメチル）アミノメタン塩等で無機塩類、有機塩類の何れでもよい。
【００９９】
本発明化合物の製造法を説明する。なお、反応に際しては、必要に応じて置換基を保護基で保護して行ない、各置換基の変換順序は、特に限定されない。
【０１００】
【化３４】
［式中、Ｒ41は、保護基で保護された水酸基を意味する。
Ｒ13は、水素原子あるいは水酸基の保護基を意味する。
Ｒ61は、Ｒ6 、または保護基で保護されたＲ6 （置換基として、水酸基、アミノ基を有する場合）を意味する。
水酸基またはアミノ基の保護基としては、トリエチルシリル基、第三ブチルジメチルシリル基などのシリル系の保護基や２、２、２−トリクロロエトキシカルボニル基、ベンジルオキシカルボニル基、ベンジル基などが挙げられる。］
【０１０２】
まず、式（１）で表わされる化合物（以下、化合物（１）と表わし、その他の番号で表わされる化合物も同様に表わす。）とアクロレインを溶媒中、ラジカル開始剤の存在下に、水素化トリス（トリメチルシリル）シラン、水素化トリブチルスズあるいは水素化トリフェニルスズを加え、化合物（２）を得る。
【０１０３】
この反応で用いる溶媒は、反応に不活性な溶媒であればよく、例えば、トルエン、ベンゼン、ジオキサンが挙げられる。
【０１０４】
反応で用いるラジカル開始剤としては、例えば、２’，２’−アゾビス（イソブチロニトリル）、過酸化ベンゾイル、２、２、６、６−テトラメチル−１−ピペラジニルオキシ フリーラジカル等が挙げられ、ラジカル開始剤の使用量は、触媒量で良い。
【０１０５】
反応温度は、通常５０℃から１５０℃の範囲で行なえばよく、攪拌して行なうのが好ましい。
【０１０６】
アクロレインは、化合物（１）に対して５から５０当量用い、水素化トリス（トリメチルシリル）シラン等は、化合物（１）に対して２から１０当量程度用いる。
【０１０７】
こうして得られた１０位が２−ホルミルエチル基である化合物（２）から１０位がＲ61である化合物（３）への変換は、通常の有機化学的方法によって行えば良い。
【０１０８】
例えば、ホルミルエチル基のホルミル基を、二級アミンと還元条件下で反応させることにより三級アミンの結合したプロピオニル基に変換できる。
【０１０９】
また、ホルミル基を水素化ホウ素ナトリウム等で還元することにより、アルコール型の水酸基に変換できる。
【０１１０】
Ｒ61がアルコール型の水酸基となったものは、アシルオキシ基、アルコキシル基、アミノ基、アルキルアミノ基、アルキルチオ基、フェニルゼレノ基等に変換できる。
【０１１１】
さらに、Ｒ61がアミノ基となったものは、アシルアミノ基、アルコキシルカルボニルアミノ基、アルキルアミノ基に変換できる。
【０１１２】
また、Ｒ61がフェニルゼレノ基となったものは、酸化反応によりオレフィン型の置換基に変換でき、変換されたオレフィン型の置換基は、酸化反応によりジオール型に変換でき、また酸化的開裂反応によって炭素原子数の減った置換基、例えば、ホルミルメチル基、カルボキシルメチル基に変換することもできる。
【０１１３】
なお、Ｒ61がホルミルメチル基となった場合、ホルミルエチル基のホルミル基と同様に変換が可能であり、例えば二級アミンと還元条件下で反応させることにより三級アミンの結合したエチル基に変換できる。
【０１１４】
【化３５】
［式中、Ｒ1 、Ｒ2 、Ｒ3 、Ｒ41 、Ｒ5 、Ｒ61 およびＲ13は、前記と同じ。
【０１１６】
Ｚ11は、水素原子、ハロゲン原子、保護基で保護された水酸基、アルキル基を意味し、
Ｚ21は、水素原子、ハロゲン原子、保護基で保護された水酸基、アルキル基を意味し、
Ｚ31は、Ｚ3 、または保護基で保護されたＺ3 （置換基として、水酸基、アミノ基、カルボキシル基を有する場合）を意味し、
Ｚ41は、Ｚ4 、または保護基で保護されたＺ4 （置換基として、水酸基、アミノ基、カルボキシル基を有する場合）を意味する。
水酸基およびアミノ基の保護基としてはトリエチルシリル基、第三ブチルジメチルシリル基等のシリル系の保護基や１−エトキシエチル基、２，２，２−トリクロロエトキシカルボニル基、ベンジル基等が挙げられる。
カルボキシル基の保護基としては、メチル基、エチル基、ベンジル基、第三級ブチル基、２，２，２−トリクロロエチル基等が挙げられる。］
【０１１７】
得られた化合物（３）の各置換基を必要に応じて変換、脱保護して、化合物（４）を得ることができる。例えば、２位のベンゾイル基をＣＯＲ1 に、４位のアセチル基をＣＯＲ2 に、７位のＲ41をＲ3 またはＲ5 と一緒にし環構造を形成させる等の変換を行い種々の置換基を有する化合物（４）を得ることができる。
【０１１８】
目的化合物（Ｉ）は、化合物（３）あるいは化合物（４）を化合物（Ａ）と反応させ、最後に保護基の除去、必要ならＲ61をＲ6 に、Ｚ11、Ｚ21、Ｚ31およびＺ41をそれぞれＺ1 、Ｚ2 、Ｚ3 およびＺ4 に変換することにより得ることができる。
【０１１９】
これらの変換および脱保護は、通常の有機化学的方法を用いて行なうことができるが、以下に例を挙げる。
【０１２０】
２位のベンゾイル基をＣＯＲ1 に変換する方法としては、例えば、文献（Tetrahedron Lett., 35, 8931(1994)）記載の方法に従って２位のベンゾイル基を選択的に加水分解した後、アシル化する方法があり、Ｒ1 がフェニル基以外の化合物を得ることができる。
【０１２１】
４位のアセチル基をＣＯＲ2 に変換する方法としては、例えば、文献（J. Med. Chem.,38, 2263 (1995) ）記載の方法に従って４位のアセチル基を選択的に加水分解した後、アシル化する方法があり、Ｒ2 がメチル基以外の化合物を得ることができる。
【０１２２】
６位のＲ3 、７位のＲ4 、８位のＲ5 の変換はＲ3 、Ｒ4 およびＲ5 のタイプにより種々の方法がある。
【０１２３】
例えば、Ｒ3 、Ｒ4 が水素原子であり６位と７位の結合が、二重結合である化合物（４）を得るには、まず、Ｒ41の保護基を除去し、７位が水酸基である化合物にした後、７位の水酸基を、例えば、メチレンクロリド中、トルフルオロメタンスルフォン酸無水物を反応させることにより、トリフルオロメタンスルフォニル化し、次いでベンゼン、テトラヒドロフランなどの溶媒中、１，８−ジアザビシクロ［５，４，０］−７−ウンデセン等で処理することにより得ることができる。
【０１２４】
変換された６、７位のオレフィン型置換基は、メタクロロ過安息香酸などを用いた酸化反応によりエポキシ型に変換できる。
【０１２５】
またエポキシ型の置換基の場合、さらに様々な変換反応が可能であり、たとえばアジ化ナトリウムなどを用いた開環反応によってＲ3 あるいはＲ4 のどちらか一方が水酸基であり、もう一方がアジド基である化合物（４）を得ることも可能である。
【０１２６】
Ｒ4 およびＲ5 が一緒になって３員環を形成した構造となった化合物（４）を得るには、Ｒ41の保護基を除去し７位を水酸基にした後、この水酸基をトリフルオロメタンスルホニル化し、次いで溶媒中（アセトニトリル、テトラヒドロフラン、エチレンジクロリド等、またはこれらの混合溶媒中）でシリカゲルで処理することにより得ることができる。
【０１２７】
Ｒ4 がフッ素原子である化合物（４）を得るには、７位が水酸基である化合物を溶媒中（テトラヒドロフラン、メチレンクロリド、エチルエーテル、トルエン、１，１，−ジメトキシエタン等、またはこれらの混合溶媒中）でジエチルアミノスルファートトリフルオライドで処理することにより得ることができる。
【０１２８】
Ｒ4 がメトキシ基である化合物（４）を得るには、化合物（３）のＲ41の保護基を除去し、７位が水酸基である化合物を合成した後、ジメチルスルホキシドを溶媒として用い、無水酢酸を作用させメチルチオメチル化した後、アルコール系溶媒中、ラネーニッケルにより脱硫することにより得ることができる。
【０１２９】
得られた化合物（３）または（４）から、化合物（Ｉ）を得るには、まず化合物（３）または化合物（４）の１３位の置換基Ｒ13が保護基で保護されている場合は、脱保護し１３位が水酸基である化合物とした後、化合物（Ａ）とナトリウムヘキサメチルジシラジドやリチウムヘキサメチルジシラジド等の塩基を用い縮合させ、最後に各置換基の変換や脱保護を実施すればよい。
【０１３０】
製造原料である化合物（１）は、１０−Ｏ−デアセチルバッカチン IIIから合成でき、Ｒ41がトリエチルシリル基で保護された水酸基である化合物などが知られている（Tetrahedron Lett., 34, 4921 (1993)）。
【０１３１】
製造原料である、化合物（Ａ）は、文献（Tetrahedron Lett., 34, 4149 (1993)）記載の方法に従って合成できる。
【０１３２】
本発明化合物は、例えば、肺癌、消化器癌、卵巣癌、子宮癌、乳癌、肝癌、頭頚部癌、血液癌、腎癌、コウ丸腫瘍等の各種癌の治療に用いることができる。
【０１３３】
本発明化合物は、静脈内注射、筋肉内注射、皮下注射等の各種注射剤として、あるいは経口投与、経皮投与等の種々の方法によって投与することができる。これらの投与法の中では水性製剤による静脈内投与、及び経口投与が好ましい。水性製剤は薬理学的に許容される酸と酸付加物を形成させるか、ナトリウム等のアルカリ金属塩とすることで調製できる。経口投与の場合では遊離体のままでも、塩の型のいずれでも良い。
【０１３４】
製剤の調製方法としては投与法に応じ適当な製剤を選択し、通常用いられている各種製剤の調製法にて調製できる。本発明の抗腫瘍剤の剤型のうち経口用製剤としては例えば錠剤、散剤、顆粒剤、カプセル剤や、溶液剤、シロップ剤、エリキシル剤、油性ないし水性の懸濁液等を例示できる。注射剤の場合は製剤中に安定剤、防腐剤、溶解補助剤等を使用することもできる。これらの補助剤等を含むこともある溶液を容器に収納後、凍結乾燥等によって固形製剤として用時調製の製剤としても良い。
【０１３５】
液体製剤としては、溶液、懸濁液、乳液剤等を挙げることができるが、これらの製剤を調製する際、添加剤として懸濁化剤、乳化剤等を使用することもできる。
【０１３６】
本発明化合物は、哺乳類、特にヒトの癌治療に用いることができ、ヒトに投与する場合、１日あたり１回投与し、適当な間隔で繰り返すのが好ましい。
【０１３７】
投与量としては、体表面積１ｍ2 につき約 0.5 mg から 50 mg、好ましくは約 1 mg から 20 mgの範囲で投与するのが望ましい。
【０１３８】
次に実施例および参考例で詳しく説明する。
【０１３９】
実施例中では以下の略語を用いることがある。
ＴＭＳ：トリメチルシリル基、Ｂｏｃ：ｔｅｒｔ−ブトキシカルボニル基、ＴＢＳ：ｔｅｒｔ−ブチルジメチルシリル基、Ｂｚ：ベンゾイル基、Ａｃ：アセチル基、ＴＥＳ：トリエチルシリル基、Ｔｒｏｃ：２，２，２−トリクロロエトキシカルボニル基、Ｔｆ：トリフルオロメタンスルホニル基、ＤＭＳ：ジメチルシリル基、ＴＩＰＳ：トリイソプロピルシリル基、Ｍｅ：メチル基、Ｅｔ：エチル基、ＭＴＭ：メチルチオメチル基
【０１４０】
【実施例】
参考例１
【０１４１】
【化３６】
工程１：シス-3-メチル -4-フェニル-3-(トリメチルシリル)オキシ-2-アゼチジノン
リチウムビス( トリメチルシリル) アミド（１Ｍテトラヒドロフラン溶液）16.9 ml の溶液を -78℃に冷却し窒素下、ベンズアルデヒド 1.50 gのテトラヒドロフラン溶液 15ml を滴下し５分後、 0℃にし３０分攪拌した。次いで、塩化トリメチルシラン 2.26 mlを加え３０分攪拌した。一方、ジイソプロピルアミン 2.22 mlのテトラヒドロフラン溶液25mlを氷冷し n-ブチルリチウム（1.70 Mヘキサン溶液、9.95 ml）を滴下し１５分攪拌した。次いで、-78 ℃に冷却し 2-(トリメチルシリルオキシ) プロピオン酸メチルエステル2.48g のテトラヒドロフラン溶液 25 mlを滴下し１５分攪拌した。先に調製したイミン溶液をカニューレを用い滴下し一晩かけて室温まで昇温した。反応液に飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：ヘキサン＝１：５〜１：３(v/v) ）で精製し標記化合物0.98 gを淡黄色結晶として得た。
【０１４３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.07 (s,9H), 1.66 (s,3H), 4.51 (s,1H), 6.10 (br,1H), 7.28-7.39 (m,5H).
【０１４４】
工程２：シス-1-(tert-ブトキシカルボニル)-3-メチル-4-フェニル-3-(トリメチルシリル) オキシ-2-アゼチジノン
上記工程１で得た化合物 860 mg をテトラヒドロフラン 8.6 ml に溶解し、氷冷下、二炭酸ジ-tert-ブチル 0.95 mlおよび 4-ジメチルアミノピリジン 20 mgを加え室温で１時間攪拌した。溶媒を減圧留去した後、得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：ヘキサン＝１：１０(v/v) ）で精製し標記化合物1.01 gを無色の結晶として得た。
【０１４５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.07 (s,9H), 1.40 (s,9H), 1.67 (s,3H), 4.73 (s,1H), 7.21-7.37 (m,5H).
【０１４６】
参考例２
【０１４７】
【化３７】
工程１：シス-4-(p-フルオロフェニル)-3-メチル-3-(トリメチルシリル)オキシ-2-アゼチジノン
参考例１の工程１と同様、ベンズアルデヒドの代わりにp-フルオロベンズアルデヒドを用い反応させ標記化合物を淡黄色結晶として得た。
【０１４９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.05 (s,9H), 1.64 (s,3H), 4.49 (s,1H), 6.15 (br,1H), 7.04-7.26 (m,4H).
【０１５０】
工程２：シス-1-(tert-ブトキシカルボニル)-4-p-フルオロフェニル-3-メチル-3-(トリメチルシリル) オキシ-2-アゼチジノン
上記工程１で得た化合物を参考例１の工程２と同様に反応させ標記化合物を無色の結晶として得た。
【０１５１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.04 (s,9H), 1.41 (s,9H), 1.66 (s,3H), 4.71 (s,1H), 7.03-7.22 (m,4H).
【０１５２】
参考例３
【０１５３】
【化３８】
工程１：シス-3-(tert-ブチルジメチルシリル) オキシ-3-メチル-4-フェニル-2-アゼチジノン
参考例１の工程１と同様、2-(トリメチルシリルオキシ) プロピオン酸メチルエステルの代わりに2-(tert-ブチルジメチルシリルオキシ) プロピオン酸メチルエステルを用い反応させ標記化合物を白色固体として得た。
【０１５５】
融点：102-104 ℃ (ペンタンから再結晶、無色プリズム晶)
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.17 (s,3H), 0.08 (s,3H), 0.51 (s,9H), 1.64 (s,3H), 4.53 (s,1H), 6.05 (br,1H), 7.24-7.36 (m,5H).
【０１５６】
工程２：シス-1-(tert-ブトキシカルボニル)-3-(tert-ブチルジメチルシリル) オキシ-3-メチル-4-フェニル-2-アゼチジノン
上記工程１で得た化合物を参考例１の工程２と同様に反応させ標記化合物を白色固体として得た。
【０１５７】
融点：93℃ (ペンタンから再結晶、無色プリズム晶)
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.01 (s,3H), 0.05 (s,3H), 0.51 (s,9H), 1.44 (s,9H), 1.65 (s,3H),4.77 (s,1H), 7.16-7.35 (m,5H).
【０１５８】
参考例４
【０１５９】
【化３９】
工程１：シス-3- メチル-4- フェニル-3-(トリエチルシリル) オキシ-2- アゼチジノン
参考例１の工程１と同様、 2-(トリメチルシリル) オキシプロピオン酸メチルエステルの代わりに 2-(トリエチルシリル) オキシプロピオン酸メチルエステルを用い反応させ標記化合物を白色固体として得た。
【０１６１】
1H-NMR CDCl3/
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.40-0.46 (m, 6H), 0.72 (t, 9H, J = 7 Hz), 1.66 (s, 3H), 4.52 (s, 1H),6.15 (br, 1H), 7.24-7.37 (m, 5H).
【０１６２】
工程２： (3R,4S)-3- メチル-4- フェニル-3-(トリエチルシリル) オキシ-2- アゼチジノン
上記工程１で得た化合物 500 mg を10% 2-プロパノール/ ヘキサン(v/v) 25 ml 溶解し、光学活性カラム（CHIRALCEL OD，溶出溶媒；10% 2-プロパノール/ ヘキサン(v/v) ）を用い分割し、第一ピークとして 3S,4R体（220 mg），第二ピークとして目的とする3R,4S 体（215 mg）をそれぞれ無色の結晶として得た。
【０１６３】
[ α]D 24 +77°(c 0.09 ，エタノール) ．
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.40-0.46 (m, 6H), 0.72 (t, 9H, J = 7 Hz), 1.66 (s, 3H), 4.52 (s, 1H),6.15 (br, 1H), 7.24-7.37 (m, 5H).
【０１６４】
工程３： (3R,4S)-1-(tert- ブトキシカルボニル)-3-メチル-4- フェニル-3-(トリエチルシリル) オキシ-2- アゼチジノン
上記工程２で得た化合物を参考例１の工程２と同様に反応させ標記化合物を無色の結晶として得た。
【０１６５】
[ α]D 24 +96°(c 0.13 ，エタノール) ．
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.45 (q, 6H, J = 8 Hz), 0.72 (t, 9H, J = 8 Hz), 1.43 (s, 9H), 1.67 (s, 3H), 4.80 (s, 1H), 7.19-7.34 (m, 5H).
【０１６６】
参考例５
【０１６７】
【化４０】
工程１：シス-3- メチル-4-(4-トリル)-3-( トリメチルシリル) オキシ-2- アゼチジノン
参考例１の工程１と同様、 ベンズアルデヒドの代わりに４- トルアルデヒドを用い反応させ標記化合物を白色固体として得た。
【０１６９】
1H-NMR (CDCl3/TMS) δ(ppm) ：
-0.06 (s, 9H), 1.64 (s, 3H), 2.36 (s, 3H), 4.47 (s, 1H), 6.06 (br, 1H), 7.16 (s, 4H).
【０１７０】
工程２：(3R,4S)-3-メチル-4-(4-トリル)-3-( トリメチルシリル) オキシ-2- アゼチジノン
上記工程１で得た化合物を参考例４の工程２と同様に分割し標記化合物を無色の結晶として得た。
【０１７１】
融点：55-56 ℃．
[ α]D 24 +58.0°(c 1.00 ，エタノール) ．
1H-NMR (CDCl3/TMS) δ(ppm) ：
-0.06 (s, 9H), 1.64 (s, 3H), 2.36 (s, 3H), 4.47 (s, 1H), 6.06 (br, 1H), 7.16 (s, 4H).
【０１７２】
工程３：(3R,4S)-1-(tert-ブトキシカルボニル)-3-メチル-4-(4-トリル)-3-( トリメチルシリル) オキシ-2- アゼチジノン
上記工程２で得た化合物を参考例１の工程２と同様に反応させ標記化合物を無色の結晶として得た。
【０１７３】
融点：75-78 ℃．
[ α]D 24 +103 °(c 1.25 ，エタノール) ．
1H-NMR (CDCl3/TMS) δ(ppm) ：
-0.06 (s, 9H), 1.40 (s, 9H), 1.65 (s, 3H), 2.35 (s, 3H), 4.69 (s, 1H),7.10-7.16 (m, 4H)．
【０１７４】
実施例１
【０１７５】
【化４１】
工程１：10-アリル-10-デアセトキシバッカチンIII
10-アリル-10-デアセトキシ-7-Ｏ-トリエチルシリルバッカチンIII360 mg をピリジン4.0 mlに溶解させ 0 ℃にてフッ化水素ピリジン 1.0 ml を加え室温で８時間撹拌後、反応液を撹拌された酢酸エチル 20 ml及び氷水 60 ml の混合液に注ぎ分液し、水層を酢酸エチル20mlで抽出した。有機層を合わせて飽和重曹水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分を再沈殿（クロロホルム−エーテル−ヘキサン）にて精製し標記化合物 267 mg を無色の非晶質固体として得るとともに、母液を濃縮した残分からもシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１：１(v/v) ）を用い精製し標記化合物 20.8 mgを無色の非晶質固体として得た。
【０１７７】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.06 (3H,s), 1.11 (3H,s), 1.44 (1H,d,J=7.3Hz), 1.64 (3H,s), 1.65 (1H,s), 1.80 (1H,ddd,J=2.4Hz,11.2Hz,14.2Hz), 1.92 (3H,d,J=1.0Hz),2.17-2.42 (3H,m), 2.28 (3H,s), 2.57 (1H,ddd,J=6.4Hz,9.8Hz,14.2Hz),2.88-2.98 (1H,m), 3.93 (1H,dd,J=6.4Hz,7.8Hz), 4.11 (1H,d,J=7.3Hz),4.19 (1H,d,J=8.4Hz), 4.31 (1H,d,J=8.4Hz), 4.30-4.42 (1H,m), 4.86 (1H,s), 4.95-5.05 (2H,m), 5.12 (1H,dd,J=16.9Hz,1.7Hz), 5.63 (1H,d,J=7.3Hz), 5.73-5.87 (1H,m), 7.48 (2H,t,J=7.8Hz), 7.60 (1H,t,J=7.8Hz), 8.11 (2H,d,J=7.8Hz).
【０１７８】
工程２：10-アリル-10-デアセトキシ-7-Ｏ-(2,2,2-トリクロロエトキシカルボニル) バッカチンIII
上記工程１で得た化合物 280 mg をピリジン 8.0mlに溶解させ 0 ℃にてクロロギ酸2,2,2-トリクロロエチル 75.0 mlを加え２時間撹拌後、反応液を撹拌された酢酸エチル 20 ml及び氷水 60 ml の混合液に注ぎ分液し、水層を酢酸エチル 20 mlで抽出した。有機層を合わせて１規定塩酸水溶液 50 ml、飽和重曹水溶液 50 ml及び飽和食塩水 50 ml で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝１：１(v/v))を用いて精製し標記化合物360 mgを無色の非晶質固体として得た。
【０１７９】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.06 (3H,s), 1.19 (3H,s), 1.78 (3H,s), 1.98 (3H,d,J=1.5Hz), 1.98-2.08 (1H,m), 2.18-2.35 (3H,m), 2.30 (3H,s),2.64 (1H,ddd,J=7.3Hz,9.8Hz,14.2Hz), 2.78-2.87 (1H,m), 4.09 (1H,t,J=7.8Hz), 4.19 (1H,d,J=5.9Hz), 4.20 (1H,d,J=8.3Hz), 4.33 (1H,d,J=8.3Hz), 4.68 (1H,d,J=11.7Hz), 4.75 (1H,d,J=11.7Hz), 4.85 (1H,s), 4.95-5.00 (2H,m),5.08 (1H,dd,J=16.9Hz,1.7Hz), 5.53 (1H,dd,J=7.1Hz,11.0Hz), 5.68-5.80 (1H,m), 7.48 (2H,t,J=7.8Hz), 7.61 (1H,t,J=7.8Hz), 8.10 (2H,d,J=7.8Hz).
【０１８０】
工程３：10-アリル-10-デアセトキシ-7-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-13-Ｏ-トリエチルシリルバッカチンIII
上記工程２で得た化合物 360 mg を塩化メチレン 15 mlに溶解させ -50℃にて2,6-ルチジン 100 ml及びトリエチルシリルトリフルオロメタンスルホネート 165 ml を加え 1.5時間撹拌後、さらに2,6-ルチジン 150 ml及びトリエチルシリルトリフルオロメタンスルホネート 240 ml を加え 2時間撹拌後、反応液に飽和重曹水溶液 50 ml及び酢酸エチル 50 ml を加え分液し、水層を酢酸エチル 20 mlで抽出した。有機層を合わせて飽和食塩水 50 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝５：１(v/v) ）を用いて精製し標記化合物 285 mg を無色透明ガラス状物質として得た。
【０１８１】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.60-0.73 (6H,m), 1.02 (9H,t,J=7.3Hz), 1.09 (3H,s), 1.12 (3H,s),1.61 (1H,s), 1.77 (3H,s), 1.93 (3H,d,J=1.5Hz), 1.99-2.14 (2H,m),2.20-2.33 (2H,m), 2.30 (3H,s), 2.62 (1H,ddd,J=6.8Hz,9.3Hz,14.2Hz),2.77-2.86 (1H,m), 4.08 (1H,t,J=6.8Hz), 4.12 (1H,d,J=7.1Hz), 4.20 (1H,d,J=8.1Hz), 4.32 (1H,d,J=8.1Hz), 4.67 (1H,d,J=11.7Hz), 4.75 (1H,d,J=11.7Hz), 4.91 (1H,dd,J=7.3Hz,8.3Hz), 4.94-5.02 (2H,m), 5.06 (1H,dd,J=1.5Hz,17.1Hz), 5.54 (1H,dd,J=7.1Hz,11.1Hz), 5.64 (1H,d,J=7.1Hz), 5.68-5.79 (1H,m), 7.48 (2H,t,J=7.3Hz), 7.61 (1H,t,J=7.3Hz), 8.09 (2H,d,J=7.3Hz).
【０１８２】
工程４：10-アリル-10-デアセトキシ-13-Ｏ-トリエチルシリルバッカチンIII
上記工程３で得た化合物 285 mg を酢酸エチル 30 mlに溶解させ室温にて亜鉛粉末 2.80 g 及び酢酸 1.90 mlを加え室温で 5 分撹拌後、反応混液を濾過し、濾液に飽和重曹水溶液 150 ml を加え分液し、水層を酢酸エチル 30 mlで抽出した。有機層を合わせて飽和食塩水 50 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝３：１(v/v) ）を用いて精製し標記化合物 215 mg を無色の非晶質固体として得た。
【０１８３】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.60-0.75 (6H,m), 1.01 (9H,t,J=7.8Hz), 1.10 (3H,s), 1.13 (3H,s),1.62 (3H,s), 1.65 (1H,s), 1.75-1.85 (1H,m), 1.87 (3H,d,J=1.0Hz),2.10 (1H,dd,J=8.3Hz,15.6Hz), 2.20-2.40 (2H,m), 2.29 (3H,s), 2.50-2.63 (1H,m), 2.88-2.98 (1H,m), 3.89 (1H,t,J=7.1Hz),4.02 (1H,d,J=7.1Hz), 4.19 (1H,d,J=8.8Hz), 4.28-4.40 (1H,m), 4.30 (1H,d,J=8.8Hz), 4.90 (1H,dd,J=7.1Hz,8.3Hz), 4.95-5.05 (2H,m),5.09 (1H,d,J=17.1Hz), 5.63 (1H,d,J=7.1Hz), 5.73-5.87 (1H,m),7.47 (2H,t,J=7.3Hz), 7.60 (1H,t,J=7.3Hz), 8.09 (2H,d,J=7.3Hz).
【０１８４】
工程５：10-アリル-10-デアセトキシ-13-Ｏ-トリエチルシリル-7-Ｏ-トリフルオロメタンスルホニルバッカチンIII
上記工程４で得た化合物 205 mg を塩化メチレン 15 mlに溶解させ 0℃にてピリジン 5.0 ml 及びトリフルオロメタンスルホン酸無水物 263 ml を加え室温で 1.5時間撹拌後、反応液を撹拌された酢酸エチル 50 ml 及び氷水 150 ml の混合液に注ぎ分液し、水層を酢酸エチルで抽出した。有機層を合わせて飽和重曹水溶液 50 ml及び飽和食塩水 50 ml で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：酢酸エチル＝４０：１〜１０：１(v/v) ）を用いて精製し標記化合物 226 mg を無色の非晶質固体として得た。
【０１８５】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.60-0.73 (6H,m), 1.01 (9H,t,J=7.8Hz), 1.12 (3H,s), 1.15 (3H,s),1.59 (1H,s), 1.79 (3H,s), 1.91 (3H,d,J=1.5Hz),2.11 (1H,dd,J=8.3Hz,15.1Hz), 2.16-2.28 (2H,m), 2.31 (3H,s), 2.40-2.50 (1H,m), 2.74-2.84 (1H,m), 2.83-2.90 (1H,m),
4.08-4.16 (2H,m), 4.18 (1H,d,J=8.3Hz), 4.33 (1H,d,J=8.3Hz), 4.88-4.98 (2H,m), 5.02 (1H,dd,J=2.0Hz,9.8Hz), 5.09 (1H, dd,J=1.5Hz,17.1Hz), 5.60 (1H,dd,J=7.3Hz,10.7Hz),5.65 (1H,d,J=6.8Hz), 5.68-5.80 (1H,m), 7.48 (2H,t,J=8.3Hz), 7.62 (1H,t,J=8.3Hz), 8.08 (2H,d,J=8.3Hz).
【０１８６】
工程６：10-アリル-10-デアセトキシ-7-デオキシ-6,7-ジデヒドロ-13-Ｏ-トリエチルシリルバッカチンIII
上記工程５で得た化合物 226 mg をテトラヒドロフラン 5.0mlに溶解させ室温にて1,8-ジアザビシクロ[5.4.0]-7-ウンデセン 0.50 ml を加え室温で 3時間加熱還流し放冷後、減圧下溶媒を留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；ベンゼン：酢酸エチル＝３：１(v/v) ）を用いて精製し標記化合物 180 mg を無色の非晶質固体として得た。
【０１８７】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.58-0.78 (6H,m), 1.00 (9H,t,J=7.8Hz), 1.08 (3H,s), 1.15 (3H,s),1.70 (1H,s), 1.78 (3H,d,J=1.5Hz), 1.82 (3H,s),2.10 (1H,dd,J=8.6Hz,14.8Hz), 2.17-2.30 (1H,m), 2.27 (1H,dd,J=8.3Hz,14.8Hz), 2.28 (3H,s), 2.93-3.04 (1H,m), 3.16 (1H,t,J=7.1Hz),4.18 (1H,d,J=6.3Hz), 4.28 (1H,d,J=7.8Hz), 4.43 (1H,d,J=7.8Hz), 4.92 (1H,t,J=7.6Hz), 5.01 (1H,dd,J=1.5Hz,9.3Hz), 5.05-5.13 (1H,m), 5.12 (1H,d,J=5.9Hz), 5.73 (1H,d,J=9.8Hz), 5.79 (1H,d,J=6.3Hz), 5.76-5.88 (1H,m), 6.01 (1H,dd,J=5.9,9.8Hz),7.49 (2H,t,J=7.8Hz), 7.62 (1H,t,J=7.8Hz), 8.14 (2H,d,J=7.8Hz).
【０１８８】
工程７：10-アリル-10-デアセトキシ-7-デオキシ-6,7-ジデヒドロバッカチン III
上記工程６で得た化合物 28.0 mgをピリジン 1.0 mlに溶解させ 0℃にてフッ化水素ピリジン 0.50 mlを加え室温で 7 時間撹拌後、反応液を撹拌された酢酸エチル 10 ml及び氷水 20 mlの混合液に注ぎ分液し、水層を酢酸エチル 10mlで抽出した。有機層を合わせて飽和重曹水溶液 10 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１：１(v/v) ）を用いて精製し標記化合物 16.9 mgを無色の非晶質固体として得た。
【０１８９】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.08 (3H,s), 1.09 (3H,s), 1.73 (1H,s), 1.82 (3H,s), 1.84 (3H,d,J=1.5Hz), 2.02 (1H,d,J=5.4Hz), 2.18-2.30 (3H,m), 2.30 (3H,s), 2.93-3.02 (1H,m), 3.68 (1H,t,J=7.1Hz), 4.29 (1H,d,J=6.9Hz), 4.31 (1H,d,J=8.3Hz), 4.42 (1H,d,J=8.3Hz),4.81-4.90 (1H,m), 4.98-5.05 (1H,m), 5.11 (1H,d,J=5.4Hz),5.07-5.14 (1H,m), 5.74 (1H,d,J=10.2Hz), 5.80 (1H,d,J=6.9Hz),5.78-5.90 (1H,m), 6.02 (1H,dd,J=5.4Hz,10.2Hz), 7.49 (2H,t,J=8.3Hz), 7.62 (1H,t,J=8.3Hz), 8.15 (2H,d,J=8.3Hz).
【０１９０】
工程８：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(te rt-ブチルジメチルシリル )オキシ-3-フェニルプロピオニル ]-10-デアセトキシ-7-デオキシ-6,7-ジデヒドロバッカチンIII
上記工程７で得た化合物 16.5 mgをテトラヒドロフラン 2.0 mlに溶解させ-45℃にてリチウムビス( トリメチルシリル) アミド（１Ｍテトラヒドロフラン溶液）40.0 ml を加え 30 分撹拌後、(3R,4S)-1-(tert-ブトキシカルボニル)-3-( tert- ブチルジメチルシリル) オキシ -4-フェニル-2- アゼチジノン23.0 mg のテトラヒドロフラン 1.0 ml 溶液を滴下し 0℃で 1 時間撹拌後、反応液に飽和塩化アンモニウム水溶液 10 ml及び酢酸エチル 10 ml を加え分液し、水層を酢酸エチル 10 mlで抽出した。有機層を合わせて飽和食塩水 10 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝４：１(v/v) ）を用いて精製し標記化合物 27.8 mgを無色透明ガラス状物質として得た。
【０１９１】
1H-NMR (CDCl3/TMS)δ(ppm) :
-0.35 (3H,s), -0.11 (3H,s), 0.75 (9H,s), 1.12 (3H,s), 1.27 (3H,s),1.32 (9H,s), 1.65 (1H,s), 1.70 (3H,d,J=1.0Hz), 1.86 (3H,s), 2.16 (1H,dd,J=7.8Hz,14.9Hz), 2.18-2.27 (1H,m),2.43 (1H,dd,J=9.8Hz,14.9Hz), 2.56 (3H,s), 2.99-3.06 (1H,m), 3.65 (1H,t,J=6.8Hz), 4.21 (1H,d,J=6.8Hz), 4.34 (1H,d,J=8.3Hz),4.44 (1H,d,J=8.3Hz), 4.50 (1H,s), 5.04 (1H,d,J=9.8Hz),5.21 (1H,d,J=5.5Hz), 5.22 (1H,dd,J=1.5Hz,17.1Hz), 5.32 (1H,d,J=9.3Hz),5.46 (1H,d,J=9.3Hz), 5.76 (1H,d,J=9.8Hz), 5.86 (1H,d,J=6.8Hz),5.78-5.90 (1H,m), 6.03 (1H,dd,J=5.5Hz,9.8Hz), 6.36 (1H,t,J=8.6Hz),7.50 (2H,t,J=7.3Hz), 7.60 (1H,t,J=7.3Hz), 8.17 (2H,d,J=7.3Hz).
【０１９２】
工程９：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル ]-10-デアセトキシ-7-デオキシ-6,7-ジデヒドロバッカチンIII
上記工程８で得た化合物 27.0 mgをピリジン 2.0 mlに溶解させ 0℃にてフッ化水素ピリジン 0.50 mlを加え室温で 4 時間撹拌後、反応液を撹拌された酢酸エチル 10 ml及び氷水 20 mlの混合液に注ぎ分液し、水層を酢酸エチル 10mlで抽出した。有機層を合わせて飽和重曹水溶液 10 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１：１(v/v) ）を用いて精製し標記化合物 22.3 mgを無色の非晶質固体として得た。
【０１９３】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.12 (3H,s), 1.24 (3H,s), 1.33 (9H,s), 1.64 (3H,s), 1.82 (1H,s),1.84 (3H,s), 2.18-2.40 (3H,m), 2.38 (3H,s), 2.93-3.04 (1H,m), 3.32 (1H,d,J=5.4Hz), 3.65 (1H,t,J=7.1Hz), 4.17 (1H,d,J=6.4Hz),4.32 (1H,d,J=8.3Hz), 4.42 (1H,d,J=8.3Hz), 4.60 (1H,s),
5.03 (1H,d,J=9.8Hz), 5.08 (1H,d,J=5.4Hz), 5.11 (1H,dd,J=1.5Hz,17.1Hz),5.28 (1H,d,J=9.8Hz), 5.40 (1H,d,J=9.8Hz), 5.74 (1H,d,J=9.8Hz),5.84 (1H,d,J=6.4Hz), 5.77-5.87 (1H,m), 6.02 (1H,dd,J=5.4Hz,9.8Hz),6.21 (1H,t,J=8.6Hz), 7.51 (2H,t,J=8.3Hz), 7.62 (1H,t,J=8.3Hz),8.15 (2H,d,J=8.3Hz).
【０１９４】
工程１０： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル ]-10-デアセトキシ-7-デオキシ-6,7-ジデヒドロ-10-(2-モルホリノエチル) バッカチンIII
上記工程９で得た化合物 22.0 mgをテトラヒドロフラン 2.0 mlに溶解させ室温にて四酸化オスミウム水溶液 (0.040 M 水溶液) 1.0 ml及び N-メチルモルホリン-N- オキシド50.0 mg を加えた後、室温で 1時間撹拌した。反応液に酢酸エチル 10 ml及び 10 %チオ硫酸ナトリウム水溶液 15 ml を加え 30 分撹拌後分液し、水層を酢酸エチル 10 mlで抽出した。有機層を合わせて飽和重曹水溶液 10 ml及び飽和食塩水 10 ml で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し残分 23.0 mgを得た。この残分をテトラヒドロフラン 2.0 mlに溶解させ、室温にてメタノール 2.0ml、水 2.0 ml及びメタ過ヨウ素酸ナトリウム 69.5 mgを加えた後、室温で 1 時間撹拌した。反応液に酢酸エチル 10 ml及び水 10 ml を加え３０分撹拌後分液し、水層を酢酸エチル 10 mlで抽出した。有機層を合わせて飽和食塩水 10 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し残分 22.7 mgを得た。この残分をエタノール 3.0 ml溶液に溶解させ、室温にてモルホリン 24.0ml、酢酸 15.5 ml及び水素化シアノホウ素ナトリウム 17.0 mgを加えた後、室温で 1 時間撹拌した。反応液に飽和重曹水溶液 10 ml、酢酸エチル 10 ml及び水 10 ml を加え 30 分撹拌後分液し、水層を酢酸エチル 10 mlで抽出した。有機層を合わせて飽和食塩水10 ml で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；クロロホルム：アセトン= ７：３(v/v)) を用いて精製し１，４−ジオキサン標記化合物22.7mgを無色の固体として得た。
【０１９５】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.10 (3H,s), 1.22 (3H,s), 1.33 (9H,s), 1.44-1.55 (1H,m), 1.72 (3H,s), 1.83 (3H,s), 2.23 (1H,dd,J=8.6Hz,14.9Hz), 2.30-2.60 (8H,m), 2.39 (3H,s), 3.68 (4H,t,J=4.7Hz), 3.78 (1H,dd,J=4.9Hz,6.8Hz), 4.19 (1H,d,J=6.6Hz), 4.31 (1H,d,J=8.1Hz), 4.42 (1H,d,J=8.1Hz),4.60 (1H,s), 5.11 (1H,d,J=5.7Hz), 5.27 (1H,d,J=9.3Hz),5.41 (1H,d,J=9.3Hz), 5.72 (1H,d,J=9.8Hz), 5.83 (1H,d,J=6.6Hz),6.02 (1H,dd,J=5.9Hz,9.8Hz), 6.18 (1H,t,J=8.6Hz), 7.51 (2H,t,J=7.3Hz), 7.62 (1H,t,J=7.3Hz), 8.16 (2H,d,J=7.3Hz).
融点；202.5-206.5 ℃
【０１９６】
実施例２
【０１９７】
【化４２】
工程１：10-アリル-10-デアセトキシ-7-デオキシ-6,7-ジデヒドロ-1-Ｏ-ジメチルシリル-13-Ｏ-トリエチルシリルバッカチンIII
実施例１の工程６で得た化合物 150 mg をN,N-ジメチルホルムアミド 3.0 mlに溶解させ 0℃にてイミダゾール 62.0 mg 及び塩化ジメチルシラン 100 ml を加え 20 分撹拌後、反応液に飽和重曹水溶液 20 ml及び酢酸エチル 10 ml を加え分液し、水層を酢酸エチル 10 mlで抽出した。有機層を合わせて水 10 ml及び飽和食塩水 10 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝４：１(v/v) ）にて精製し標記化合物162 mgを無色の非晶質固体として得た。
【０１９９】
1H-NMR (CDCl3/TMS)δ(ppm) :
-0.23 (3H,d,J=2.9Hz), 0.09 (3H,d,J=2.9Hz), 0.60-0.75 (6H,m),1.03 (9H,t,J=7.8Hz), 1.07 (3H,s), 1.10 (3H,s), 1.78 (3H,d,J=1.0Hz), 1.83 (3H,s), 2.16-2.26 (1H,m), 2.28 (3H,s), 2.28 (1H,dd,J=9.3Hz,15.6Hz), 2.38 (1H,dd,J=7.8Hz,15.6Hz), 2.93-3.03 (1H,m), 3.63 (1H,t,J=6.9Hz), 4.16 (1H,d,J=6.8Hz), 4.34 (1H,d,J=8.3Hz), 4.36 (1H,d,J=8.3Hz), 4.54-4.59 (1H,m), 4.95 (1H,t,J=7.8Hz), 5.00 (1H,d,J=10.7Hz),5.08 (1H,dd,J=1.5Hz,17.1Hz), 5.10 (1H,d,J=5.4Hz), 5.72 (1H,d,J=9.8Hz),5.84 (1H,d,J=6.8Hz), 5.75-5.90 (1H,m), 5.98 (1H,dd,J=5.4Hz,9.8Hz),7.48 (2H,t,J=7.3Hz), 7.59 (1H,t,J=7.3Hz), 8.14 (2H,d,J=7.3Hz).
【０２００】
工程２：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-6,7-ジデヒドロ-1-Ｏ-ジメチルシリル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程１で得た化合物 162 mg をテトラヒドロフラン 2.0mlに溶解させ 0 ℃にて水素化ビス(2- メトキシエトキシ) アルミニウムナトリウム336 mlを加え 3.5時間撹拌後、反応液に酢酸エチル 5.0 ml、飽和酒石酸カリウム水溶液 5.0 ml 及び水 5.0 ml を加え分液し、水層を酢酸エチル 10 mlで抽出した。有機層を合わせて無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１０：３(v/v) ）を用いて精製し標記化合物137 mgを無色の非晶質固体として得た。
【０２０１】
1H-NMR (CDCl3/TMS)δ(ppm) :
-0.23 (3H,d,J=2.4Hz), 0.05 (3H,d,J=2.9Hz), 0.66-0.86 (6H,m),0.99 (3H,s), 1.06 (9H,t,J=8.1Hz), 1.09 (3H,s), 1.72 (6H,s), 2.30-2.42 (1H,m), 2.57 (1H,dd,J=9.8Hz,15.3Hz),2.84 (1H,dd,J=2.4Hz,15.3Hz), 2.88-3.02 (1H,m), 3.67 (1H,t,J=7.1Hz), 3.82 (1H,s), 4.03 (1H,d,J=5.7Hz), 4.30 (1H,d,J=7.8Hz),4.33 (1H,d,J=7.8Hz), 4.55-4.65 (1H,m), 4.68 (1H,d,J=8.8Hz), 4.85 (1H,d,J=5.4Hz), 5.03 (1H,d,J=10.3Hz), 5.12 (1H,d,J=17.1Hz),5.68 (1H,d,J=9.1Hz), 5.73 (1H,d,J=5.7Hz), 5.74-5.89 (1H,m), 5.95 (1H,dd,J=5.4Hz,9.1Hz), 7.45 (2H,t,J=7.3Hz), 7.56 (1H,t,J=7.3Hz), 8.17 (2H,d,J=7.3Hz).
【０２０２】
工程３：10-アリル-4-Ｏ-(シクロプロパンカルボニル)-10-デアセトキシ-4-デアセチル-7-デオキシ-6,7-ジデヒドロ -1-Ｏ-ジメチルシリル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程２で得た化合物 137 mg をテトラヒドロフラン 3.0mlに溶解させ -20 ℃にてリチウムビス( トリメチルシリル) アミド（１Ｍテトラヒドロフラン溶液）800 mlを加え 15分撹拌後、塩化シクロプロパンカルボニル 72.0 ml を加え 30 分撹拌後、反応液に飽和重曹水溶液 10 ml及び酢酸エチル 10 ml を加え分液し、水層を酢酸エチル 10 mlで抽出した。有機層を合わせて飽和食塩水 10 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝５：１(v/v) ）を用いて精製し標記化合物122 mgを無色の非晶質固体として得た。
【０２０３】
1H-NMR (CDCl3/TMS)δ(ppm) :
-0.23 (3H,d,J=2.9Hz), 0.09 (3H,d,J=2.4Hz), 0.56-0.74 (6H,m),0.96-1.30 (4H,m), 1.02 (9H,t,J=7.8Hz), 1.08 (3H,s), 1.13 (3H,s),1.71-1.82 (1H,m), 1.79 (3H,d,J=1.0Hz), 1.83 (3H,s), 2.14-2.24 (1H,m), 2.34 (1H,dd,J=7.3Hz,15.4Hz), 2.42 (1H,dd,J=9.3Hz,15.4Hz), 2.91-3.01 (1H,m), 3.61 (1H,t,J=6.8Hz), 4.11 (1H,d,J=6.4Hz), 4.34 (1H,d,J=7.8Hz), 4.42 (1H,d,J=7.8Hz), 4.56-4.62 (1H,m), 4.98 (1H,t,J=7.8Hz), 4.99 (1H,dd,J=1.8Hz,10.2Hz), 5.05 (1H,d,J=5.4Hz),5.08 (1H,dd,J=1.8Hz,17.1Hz), 5.72 (1H,d,J=9.8Hz), 5.76-6.01 (1H,m), 5.94 (1H,d,J=6.4Hz), 5.97 (1H,dd,J=5.4Hz,9.8Hz), 7.47 (2H,t,J=7.3Hz), 7.59 (1H,t,J=7.3Hz), 8.12 (2H,d,J=7.3Hz).
【０２０４】
工程４：10-アリル-4-Ｏ-(シクロプロパンカルボニル)-10-デアセトキシ-4-デアセチル-7-デオキシ-6,7-ジデヒドロバッカチンIII
上記工程３で得た化合物 122 mg をピリジン 3.0mlに溶解させ 0 ℃にてフッ化水素ピリジン 1.0 ml を加え室温で 3.5時間撹拌後、反応液を撹拌された酢酸エチル 10 ml及び氷水 30 mlの混合液に注ぎ分液し、水層を酢酸エチル 10mlで抽出した。有機層を合わせ飽和重曹水溶液 10 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；ベンゼン：酢酸エチル＝３：１(v/v) ）を用いて精製し標記化合物 77.2 mgを無色の非晶質固体として得た。
【０２０５】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.00-1.18 (4H,m), 1.08 (3H,s), 1.11 (3H,s), 1.70-1.88 (3H,m), 1.83 (6H,s), 2.18-2.38 (3H,m), 2.90-3.02 (1H,m), 3.66 (1H,t,J=6.8Hz), 4.28 (1H,d,J=6.6Hz), 4.33 (1H,d,J=8.3Hz), 4.46 (1H,d,J=8.3Hz), 4.75-4.87 (1H,m), 4.98-5.05 (2H,m), 5.11 (1H,dd,J=1.2Hz,16.8Hz), 5.75 (1H,d,J=9.8Hz), 5.77-5.90 (1H,m), 5.82 (1H,d,J=6.6Hz), 6.00 (1H,dd,J=5.4Hz,9.8Hz), 7.49 (2H,t,J=7.3Hz), 7.62 (1H,t,J=7.3Hz), 8.15 (2H,d,J=7.3Hz).
【０２０６】
工程５：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-3-(トリイソプロピルシリル )オキシプロピオニル]-4-Ｏ-(シクロプロパンカルボニル)-10-デアセトキシ-4-デアセチル-7-デオキシ-6,7-ジデヒドロバッカチンIII
上記工程４で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-4-(2- フリル)-3-( トリイソプロピルシリル) オキシ -2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２０７】
1H-NMR (CDCl3/TMS)δ(ppm) :
-0.16 (3H,s), 0.03 (3H,s), 0.77 (9H,s), 1.08-1.41 (4H,m), 1.11 (3H,s),1.25 (3H,s), 1.37 (9H,s), 1.71 (3H,d,J=1.0Hz), 1.76 (1H,s), 1.85 (3H,s),1.91-1.98 (1H,m), 2.16-2.29 (2H,m), 2.56 (1H,dd,J=9.6Hz,15.2Hz),2.94-3.02 (1H,m), 3.66 (1H,t,J=6.8Hz), 4.21 (1H,d,J=6.8Hz), 4.32 (1H,d,J=8.3Hz), 4.44 (1H,d,J=8.3Hz), 4.79 (1H,d,J=1.5Hz),5.00-5.07 (2H,m), 5.11 (1H,dd,J=1.2Hz,16.9Hz), 5.25 (1H,d,J=9.8Hz), 5.38 (1H,d,J=9.8Hz), 5.75 (1H,d,J=9.7Hz), 5.78-5.90 (1H,m), 5.86 (1H,d,J=6.8Hz), 6.01 (1H,dd,J=5.6Hz,9.7Hz), 6.16 (1H,t,J=8.5Hz), 6.22 (1H,d,J=3.2Hz), 6.34 (1H,dd,J=3.2Hz,2.0Hz), 7.33 (1H,s), 7.50 (2H,t,J=7.3Hz), 7.61 (1H,t,J=7.3Hz), 8.12 (2H,d,J=7.3Hz).
【０２０８】
工程６：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-4-Ｏ-(シクロプロパンカルボニル)-10-デアセトキシ-4-デアセチル-7-デオキシ-6,7-ジデヒドロバッカチンIII
上記工程５で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２０９】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.94-1.40 (4H,m), 1.13 (3H,s), 1.25 (3H,s), 1.36 (9H,s), 1.57 (3H,s), 1.79 (1H,s), 1.84 (3H,s), 1.84-1.93 (1H,m), 2.20-2.37 (2H,m), 2.54 (1H,dd,J=9.5Hz,15.4Hz), 2.93-3.03 (1H,m), 3.26 (1H,d,J=5.4Hz), 3.66 (1H,t,J=7.1Hz), 4.19 (1H,d,J=6.6Hz), 4.30 (1H,d,J=8.3Hz),4.43 (1H,d,J=8.3Hz), 4.73 (1H,d,J=3.9Hz), 4.98-5.05 (2H,m), 5.11 (1H,d,J=16.6Hz), 5.17 (1H,d,J=10.0Hz), 5.37 (1H,d,J=10.0Hz), 5.74 (1H,d,J=9.7Hz), 5.75-5.88 (1H,m), 5.86 (1H,d,J=6.6Hz), 6.01 (1H,dd,J=5.7Hz,9.7Hz), 6.17 (1H,t,J=8.6Hz), 6.32 (1H,d,J=3.4Hz), 6.37 (1H,dd,J=3.4Hz,2.0Hz), 7.38 (1H,s), 7.51 (2H,t,J=7.3Hz), 7.62 (1H,t,J=7.3Hz), 8.14 (2H,d,J=7.3Hz).
【０２１０】
工程７： 13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-4-Ｏ-(シクロプロパンカルボニル)-10-デアセトキシ-4-デアセチル-7-デオキシ-6,7-ジデヒドロ-10-(2-モルホリノエチル)バッカチンIII
上記工程６で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の固体として得た。
【０２１１】
融点；124.0-129.0 ℃
1H-NMR (CDCl3/TMS)δ(ppm) :
1.00-1.95 (8H,m), 1.11 (3H,s), 1.23 (3H,s), 1.36 (9H,s), 1.77 (3H,d,J=1.0Hz), 1.83 (1H,s), 2.25-2.65 (8H,m), 3.26 (1H,s),3.68 (4H,t,J=4.4Hz), 3.81 (1H,t,J=6.1Hz), 4.20 (1H,d,J=6.4Hz),4.30 (1H,d,J=8.3Hz), 4.44 (1H,d,J=8.3Hz), 4.74 (1H,s),5.05 (1H,d,J=5.8Hz), 5.17 (1H,d,J=9.6Hz), 5.37 (1H,d,J=9.6Hz),5.72 (1H,d,J=9.8Hz), 5.85 (1H,d,J=6.4Hz), 6.01 (1H,dd,J=5.8Hz,9.8Hz), 6.14 (1H,t,J=8.5Hz), 6.32 (1H,d,J=3.1Hz), 6.37 (1H,dd,J=3.1Hz,1.8Hz), 7.38 (1H,d,J=1.8Hz), 7.50 (2H,t,J=7.3Hz), 7.62 (1H,t,J=7.3Hz),8.14 (2H,d,J=7.3Hz).
【０２１２】
実施例３
【０２１３】
【化４３】
工程１：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル )オキシ-3-(2-フリル)プロピオニル]-10-デアセトキシ-6,7-ジデヒドロバッカチンIII
実施例１の工程７で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル) -3-(2-フリル)-3-(tert-ブチルジメチルシリル)オキシ-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２１５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.18 (s,3H), 0.02 (s,3H), 0.79 (s,9H), 1.11 (s,3H), 1.22 (s,3H), 1.34 (s,9H), 1.70 (s,3H), 1.84 (s,3H), 2.15-2.29 (m,2H), 2.43 (m,1H), 2.49 (s,3H), 2.99 (m,1H), 3.66 (t,1H,J=6.8Hz), 4.21 (d,1H,J=6.5Hz), 4.32 (d,1H,J=8.5Hz), 4.42 (d,1H,J=8.5Hz), 4.71 (s,1H),5.03 (d,1H,J=9.9Hz), 5.11 (m,2H), 5.29 (d,1H,J=9.9Hz),5.34 (d,1H,J=9.9Hz), 5.75 (d,1H,J=6.8Hz), 5.83 (m,2H),6.02 (dd,1H,J=5.6Hz,9.9Hz), 6.19 (m,1H), 6.21 (m,1H), 6.34 (m,1H),7.38 (s,1H), 7.50 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz),8.15 (d,2H,J=7.5Hz).
MS-FAB：918 (MH+)
【０２１６】
工程２： 13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-(2-フリル) プロピオニル]-10-デアセトキシ-6,7-ジデヒドロ-10-(2-モルホリノエチル) バッカチンIII
上記工程１で得られた化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２１７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.17 (s,3H), 0.01 (s,3H), 0.79 (s,9H), 1.10 (s,3H), 1.21 (s,3H), 1.35 (s,9H), 1.78 (s,3H), 1.85 (s,3H), 2.20 (m,2H), 2.30-2.58 (m,8H), 2.50 (s,3H), 3.69 (m,4H), 3.79 (dd,3H,J=4.9Hz,7.0Hz), 4.23 (d,1H,J=6.6Hz), 4.33 (d,1H,J=8.1Hz), 4.43 (d,1H,J=8.1Hz),4.72 (s,1H), 5.12 (d,1H,J=5.8Hz), 5.28 (d,1H,J=10Hz), 5.35 (d,1H,J=9.9Hz), 5.73 (d,1H,J=9.9Hz), 5.85 (d,1H,J=6.6Hz),6.04 (dd,1H,J=5.8Hz,9.9Hz), 6.17 (m,1H), 6.22 (m,1H), 6.35 (m,1H),7.38 (s,1H), 7.50 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz),8.15 (d,2H,J=7.5Hz).
MS-FAB：991 (MH+）
【０２１８】
工程３： 13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル ]-10-デアセトキシ-6,7-ジデヒドロ-10-(2-モルホリノエチル) バッカチンIII
上記工程２で得られた化合物を実施例1 の工程9 と同様に反応させ標記化合物を無色の固体として得た。
【０２１９】
融点：125-130 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.10 (s,3H), 1.21 (s,3H), 1.36 (s,9H), 1.75 (s,3H), 1.84 (s,3H),2.25 (m,1H), 2.30-2.48 (m,8H), 2.42 (s,3H), 2.55 (m,1H), 3.69 (m,4H), 3.79 (m,1H), 4.21 (d,1H,J=6.9Hz), 4.32 (d,1H,J=8.5Hz),4.42 (d,1H,J=8.5Hz), 4.70 (m,1H), 5.12 (d,1H,J=5.5Hz),5.26 (d,1H, J=10Hz), 5.33 (d,1H,J=9.9Hz), 5.72 (d,1H,J=9.9Hz),5.83 (d,1H,J=6.9Hz), 6.03 (dd,1H,J=5.5Hz,9.9Hz), 6.18 (t,1H,J=9Hz), 6.32 (m,1H), 6.38 (m,1H), 7.41 (s,1H), 7.50 (t,2H,J=7.5Hz), 7.61 (t,1H,J=7.5Hz), 8.16 (d,2H,J=7.5Hz).
MS-FAB：877(MH+)
【０２２０】
実施例４
【０２２１】
【化４４】
工程１：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3-フェニル-2-(トリメチルシリル) オキシプロピオニル]-10-デアセトキシ-6,7-ジデヒドロ-10-(2-モルホリノエチル) バッカチンIII
実施例１の工程７で得た化合物 62 mgと参考例1 の工程２で得たシス-1-(tert-ブトキシカルボニル)-3-メチル-4-フェニル-3-(トリメチルシリル) オキシ-2-アゼチジノン 47 mgを 3 mlの乾燥したテトラヒドロフランに溶解し、-78 ℃においてナトリウムビス( トリメチルシリル) アミド452 mlを加え、そのままの温度で15分間反応した。これを実施例１の工程８と同様に後処理し、シリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝８５：１５ (v/v)）により精製し 10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3-フェニル-2-(トリメチルシリル) オキシプロピオニル]-10-デアセトキシ-6,7-ジデヒドロバッカチン IIIおよび10-アリル-13-Ｏ-(tert-ブトキシカルボニル)-10-デアセトキシ-6,7-ジデヒドロバッカチンIII の混合物46 mg を得た。 得られた混合物を実施例１の工程１０と同様に反応させ、後処理しシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝７：３ (v/v)）により分離精製し標記化合物 26 mgを無色の非晶質固体として得た。
【０２２３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.10 (s,9H), 1.10 (s,3H), 1.19 (s,9H), 1.30 (s,3H), 1.39 (s,3H),1.76 (s,3H), 1.88 (s,3H), 2.10 (m,1H), 2.30-2.45 (m,8H), 2.56 (m,1H), 2.70 (s,3H), 3.69 (m,4H), 3.78 (m,1H), 4.19 (d,1H,J=6.7Hz), 4.38 (d,1H,J=8.5Hz), 4.44 (d,1H,J=8.5Hz), 4.99 (d,1H,J=10Hz), 5.13 (d,1H,J=5.6Hz), 5.50 (d,1H,J=9.9Hz), 5.75 (d,1H,J=9.9Hz),5.85 (d,1H,J=6.7Hz), 6.03 (dd,1H,J=5.7Hz,10.0Hz), 6.32 (t,1H,J=9Hz),7.27-7.38 (m,5H), 7.52 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.19 (d,2H,J=7.5Hz).
MS-FAB：973 (MH+)
【０２２４】
工程２：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-6,7-ジデヒドロ-10-(2-モルホリノエチル) バッカチンIII
上記工程１で得られた化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０２２５】
融点：165-170 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.11 (s,3H), 1.23 (s,9H), 1.28 (s,3H), 1.36 (s,3H), 1.86 (s,3H),2.20 (m,1H), 2.35 (m,4H), 2.44 (m,4H), 2.57 (m,1H), 2.65 (s,3H),3.69 (m,4H), 3.79 (t,1H,J=5.5Hz), 4.20 (d,1H,J=6.6Hz),4.35 (d,1H,J=8.2Hz), 4.44 (d,1H,J=8.2Hz), 5.03 (d,1H,J=10.2Hz), 5.11 (d,1H,J=5.6Hz), 5.51 (d,1H,J=10.2Hz), 5.72 (d,1H,J=9.9Hz), 5.85 (d,1H,J=7.7Hz), 6.03 (dd,1H,J=5.6Hz,10.0Hz), 6.30 (m,1H),7.30-7.40 (m,5H), 7.51 (t,2H,J=7.5Hz), 7.61 (t,1H,J=7.5Hz), 8.18 (d,2H,J=7.5Hz).
MS-FAB : 901 (MH+)
【０２２６】
実施例５
【０２２７】
【化４５】
工程１：10-アリル-7,13-Ｏ-ビス(トリエチルシリル)-10-デアセトキシバッカチンIII
10-アリル-10-デアセトキシ-7-Ｏ-トリエチルシリルバッカチンIII を実施例１の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２２９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.49-0.71 (m,12H), 0.94-1.03 (m,18H), 1.12 (s,3H), 1.14 (s,3H), 1.62 (s,3H), 1.87 (s,3H), 1.84-1.91 (m,1H), 2.05-2.11 (m,1H), 2.20-2.56 (m,1H), 2.29 (s,3H), 2.42-2.50 (m,2H), 2.78-2.82 (m,1H),3.87 (dd,1H,J=4.5Hz,10Hz), 3.97 (d,1H,J=7Hz), 4.16 (d,1H,J=8Hz),4.29 (d,1H,J=8Hz), 4.53 (dd,1H,J=7Hz,10Hz), 4.90-5.10 (m,4H), 5.61 (d,1H,J=7Hz), 5.71-5.82 (m,1H), 7.46 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０２３０】
工程２：10-アリル-10-デアセトキシ-13-Ｏ-トリエチルシリルバッカチンIII
上記工程１で得た化合物 209 mg をメタノール 21 mlに溶解し p-トルエンスルホン酸5 mgを加え室温で一晩攪拌した。p-トルエンスルホン酸 2 mgをさらに加え４時間攪拌後、トリエチルアミン 0.10 mlを加え反応液を濃縮した。得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：２(v/v) ）で精製し標記化合物135 mgを無色の非晶質固体として得た。
【０２３１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.61-0.72 (m,6H), 1.01 (t,9H,J=7Hz), 1.10 (s,3H), 1.13 (s,3H),1.63 (s,3H), 1.87 (s,3H), 1.75-1.84 (m,1H), 2.06-2.12 (m,1H), 2.22-2.34 (m,2H), 2.28 (s,3H), 2.53-2.61 (m,1H), 2.90-2.97 (m,1H),3.89 (t,1H,J=7Hz), 4.02 (d,1H,J=7Hz), 4.19 (d,1H,J=8Hz),4.30 (d,1H,J=8Hz), 4.33-4.36 (m,1H), 4.90 (t,1H,J=8Hz), 4.98-5.02 (m,2H), 5.10 (d,1H,J=17Hz), 5.63 (d,1H,J=7Hz),5.75-5.84 (m,1H), 7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０２３２】
工程３：10-アリル-10-デアセトキシ-7-デオキシ-7-α-フルオロ-13-Ｏ-トリエチルシリルバッカチンIII
上記工程２で得た化合物 188 mg をジクロロメタン 10 mlに溶解し -78 ℃に冷却した。次いで、ジエチルアミノ硫黄トリフルオリド 0.025 ml を加え同温で１５分、０℃で３０分攪拌した。反応液をふたたび -78℃に冷却しジエチルアミノ硫黄トリフルオリド 0.035 ml を加え同温で１５分、０℃で４０分攪拌した。反応液に飽和重曹水溶液を加え１０分攪拌した後、ジクロロメタン層を水、飽和食塩水の順に洗浄し無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：４(v/v) ）で精製し標記化合物94 mg を無色の非晶質固体として得た。
【０２３３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.59-0.74 (m,6H), 1.01 (t,9H,J=7Hz), 1.03 (s,3H), 1.07 (s,3H),1.66 (s,3H), 1.83 (s,3H), 2.07-2.37 (m,4H), 2.30 (s,3H),2.50-2.62 (m,1H), 2.99-3.07 (m,1H), 4.11 (dd,1H,J=5.5Hz,8Hz), 4.18 (d,1H,J=7Hz), 4.34 (AB type d, each 1H, J=8Hz),4.53 (dd,1H,J=3.5Hz,47Hz), 4.90 (t,1H,J=8Hz), 4.99 (d,1H,J=10Hz), 5.05 (s,1H), 5.08 (dd,1H,J=1.5Hz,17Hz), 5.69 (d,1H,J=7Hz),5.73-5.84 (m,1H), 7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz).
【０２３４】
工程４：10-アリル-10-デアセトキシ-7-デオキシ-7-α-フルオロバッカチン III上記工程３で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２３５】
融点：236-238 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.07 (s,6H), 1.67 (s,3H), 1.87 (s,3H), 2.18-2.39 (m,4H), 2.30 (s,3H), 2.50-2.63 (m,1H), 2.99-3.06 (m,1H), 4.12 (dd,1H,J=5.5Hz,8Hz), 4.30 (d,1H,J=7Hz), 4.35 (s,2H), 4.53 (dd,1H,J=3Hz,47Hz), 4.83 (br,1H),4.99-5.11 (m,3H), 5.70 (d,1H,J=7Hz), 5.74-5.85 (m,1H),7.49 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
IR (KBr)：3824, 3548, 3448, 3072, 2984, 2952, 1974, 1910, 1732, 1712, 1690, 1642, 1602, 1584 cm-1
MS-FAB：571 (MH+)
【０２３６】
工程５：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル )オキシ-3-(2-フリル)プロピオニル ]-10-デアセトキシ-7-デオキシ-7-α-フルオロバッカチンIII
上記工程４で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-3-(te rt-ブチルジメチルシリル )オキシ-4-(2-フリル)-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２３７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.18 (s,3H), -0.02 (s,3H), 0.77 (s,9H), 1.09 (s,3H), 1.19 (s,3H),1.32 (s,9H), 1.67 (s,3H), 1.71 (s,3H), 2.12-2.28 (m,3H), 2.47 (s,3H), 2.48-2.52 (m,2H), 2.99-3.05 (m,1H), 4.06-4.11 (m,1H), 4.21 (d,1H,J=7Hz), 4.35 (s,2H), 4.53 (dd,1H,J=3Hz,47Hz),4.71 (d,1H,J=1.5Hz), 4.99-5.10 (m,3H), 5.26 (d,1H,J=10Hz),5.36 (d,1H,J=10Hz), 5.73 (d,1H,J=7Hz), 5.75-5.82 (m,1H),6.19 (t,1H,J=8Hz), 6.21 (d,1H,J=3Hz), 6.33 (dd,1H,J=1.5Hz,3Hz), 7.36 (s,1H), 7.48 (t,2H,J=8Hz), 7.57 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
【０２３８】
工程６：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-(2-フリル) プロピオニル]-10-デアセトキシ-7-デオキシ-7-α-フルオロ-10-(2-モルホリノエチル) バッカチンIII
上記工程５で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２３９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.18 (s,3H), -0.01 (s,3H), 0.78 (s,9H), 1.08 (s,3H), 1.18 (s,3H),1.34 (s,9H), 1.68 (s,3H), 1.83 (s,3H), 2.16-2.62 (m,12H), 2.48 (s,3H),3.64-3.72 (m,4H), 4.21-4.23 (m,2H), 4.36 (AB type d,each 1H,J=8Hz), 4.53 (dd,1H,J=3Hz,47Hz), 4.73 (d,1H,J=1.5Hz), 5.04 (dd,1H,J=2Hz,9Hz), 5.27 (d,1H,J=10Hz), 5.37 (d,1H,J=10Hz), 5.75 (d,1H,J=7Hz),6.18 (t,1H,J=8Hz), 6.22 (d,1H,J=3Hz), 6.34 (dd,1H,J=2Hz,3Hz), 7.37 (d,1H,J=1Hz), 7.49 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz),8.13 (d,2H,J=8Hz).
【０２４０】
工程７：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-10-デアセトキシ-7-デオキシ-7-α-フルオロ-10-(2-モルホリノエチル) バッカチンIII
上記工程６で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０２４１】
融点：127-133 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.20 (s,3H), 1.35 (s,9H), 1.68 (s,3H), 1.82 (s,3H),2.37 (s,3H), 2.17-2.65 (m,12H), 3.66-3.71 (m,4H), 4.21-4.25 (m,2H), 4.35 (AB type d,each 1H,J=8Hz), 4.53 (dd,1H,J=3Hz,47Hz),4.70 (d,1H,J=2Hz), 5.03 (dd,1H,J=2Hz,9Hz), 5.26 (d,1H,J=10Hz),5.37 (d,1H,J=10Hz), 5.75 (d,1H,J=7Hz), 6.19 (t,1H,J=8Hz), 6.32 (d,1H,J=3Hz), 6.37 (dd,1H,J=2Hz,3Hz), 7.41 (d,1H,J=2Hz), 7.51 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.15 (d,2H,J=8Hz).
IR (KBr)：3448, 2976, 2860, 2812, 1742, 1720, 1604, 1496 cm-1
MS-FAB：897 (MH+)
【０２４２】
実施例６
【０２４３】
【化４６】
工程１：4,10-ビス(デアセチル)-10-Ｏ-(メチルチオ) チオカルボニル-4-Ｏ-プロピオニル-7-Ｏ-トリエチルシリルバッカチンIII
4,10-ビス(デアセチル)-4-Ｏ-プロピオニル-7-Ｏ-トリエチルシリルバッカチンIII 3.00 gをテトラヒドロフラン 24 ml に溶解し、-55 ℃に冷却した。次いで、n-ブチルリチウム (1.69 Mヘキサン溶液、3.44 ml) を滴下し１０分後、二硫化炭素 0.34 mlおよびヨウ化メチル 0.34 ml を加え -55℃で１時間、0 ℃で１時間攪拌した。反応液を飽和塩化アンモニウム水溶液に注ぎ酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分を酢酸エチルおよびn-ヘキサンより再結晶し標記化合物 3.07 g を淡黄色結晶として得た。
【０２４５】
融点：206-209 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.55-0.61 (m,6H), 0.92 (t,9H,J=7Hz), 1.06 (s,3H), 1.23-1.27 (m,6H), 1.71 (s,3H), 1.88-1.92 (m,1H), 2.26-2.28 (m,2H), 2.29 (s,3H), 2.53-2.64 (m,3H), 2.65 (s,3H), 3.87 (d,1H,J=7Hz), 4.16 (d,1H,J=8Hz),4.31 (d,1H,J=8Hz), 4.53 (dd,1H,J=7Hz,10Hz), 4.84 (br,1H), 4.92 (d,1H,J=8Hz), 5.67 (d,1H,J=7Hz), 7.26 (s,1H), 7.47 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz).
IR (KBr)：3884, 3480, 3068, 2948, 2880, 2744, 2424, 2272, 1912, 1716, 1602 cm-1
MS-FAB：763 (MH+)
【０２４６】
工程２：10-デアセトキシ-4-デアセチル-10-(2-ホルミルエチル)-4-Ｏ-プロピオニル-7-Ｏ-トリエチルシリルバッカチンIII
上記工程１で得た化合物 1.50 g、アクロレイン1.42 ml、水素化トリス( トリメチルシリル) シランおよび2', 2'-アゾビス(イソブチロニトリル)63 mgをベンゼン 22.5 mlに加え、窒素下、130 ℃で５時間加熱還流した（同スケールで２回）。反応液を放冷後、減圧濃縮して得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：ヘキサン＝１：２(v/v) ）で精製し、標記化合物1.64 gを無色の非晶質固体として得た。
【０２４７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.52-0.64 (m,6H), 0.96 (t,9H,J=7Hz), 1.05 (s,3H), 1.12 (s,3H),1.24 (t,3H,J=7Hz), 1.63 (s,3H), 1.94 (s,3H), 1.85-2.67 (m,10H), 3.81-3.84 (m,1H), 4.01 (d,1H,J=7Hz), 4.17 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.55 (dd,1H,J=7Hz,10Hz), 4.84 (br,1H), 4.92 (d,1H,J=8Hz), 5.60 (d,1H,J=7Hz), 7.46 (t,2H,J=8Hz),7.60 (t,1H,J=8Hz), 8.11 (d,2H,J=8Hz), 9.80 (s,1H).
【０２４８】
工程３：10-デアセトキシ-4-デアセチル-10-(3-ヒドロキシプロピル)-4-Ｏ-プロピオニル-7-Ｏ-トリエチルシリルバッカチンIII
上記工程２で得た化合物 1.90 g をテトラヒドロフラン 38 mlに溶解し氷冷下、水素化ホウ素ナトリウム 295 mg を加え５０分攪拌した。１規定塩酸水溶液で酸性にし酢酸エチルで２回抽出した。飽和重曹水溶液、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール＝５０：１〜２０：１(v/v) ）で精製し標記化合物1.63 gを無色の非晶質固体として得た。
【０２４９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.49-0.63 (m,6H), 0.95 (t,9H,J=7Hz), 1.05 (s,3H), 1.11 (s,3H),1.24 (t,3H,J=7Hz), 1.63 (s,3H), 1.97 (s,3H), 1.70-2.68 (m,10H), 3.64-3.71 (m,1H), 3.83 (dd,1H,J=3.5Hz,9Hz), 4.06 (d,1H,J=7Hz),4.17 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.55 (dd,1H,J=7Hz,10Hz),4.84 (br,1H), 4.92 (dd,1H,J=2Hz,9Hz), 5.60 (d,1H,J=7Hz),7.46 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz),9.80 (s,1H).
【０２５０】
工程４：10-デアセトキシ-4-デアセチル-10-[3-(2-ニトロフェニルゼレノ)プロピル]-4-Ｏ-プロピオニル-7-Ｏ-トリエチルシリルバッカチンIII
上記工程３で得た化合物 1.63 g をテトラヒドロフラン 33 mlに溶解し室温下、2-ニトロフェニルゼレノシアネート 631 mg を加え１時間攪拌した。濃縮後、得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：ヘキサン＝１：２(v/v) ）で精製し標記化合物1.31 gを黄色の非晶質固体として得た。
【０２５１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.48-0.61 (m,6H), 0.93 (t,9H,J=7Hz), 1.03 (s,3H), 1.12 (s,3H),1.24 (t,3H,J=7Hz), 1.63 (s,3H), 1.94 (s,3H), 1.75-2.67 (m,10H), 2.89-3.05 (m,2H), 3.83 (dd,1H,J=3.5Hz,9Hz), 4.03 (d,1H,J=7Hz),4.16 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.55 (dd,1H,J=7Hz,10Hz),4.82 (br,1H), 4.91 (d,1H,J=8Hz), 5.59 (d,1H,J=7Hz), 7.30-7.35 (m,1H), 7.46 (t,2H,J=8Hz), 7.52 (d,1H,J=4Hz), 7.60 (t,1H,J=8Hz),8.12 (d,2H,J=8Hz), 8.29 (d,1H,J=8Hz).
【０２５２】
工程５：10-アリル-10-デアセトキシ-4-デアセチル-4-Ｏ-プロピオニル-7-Ｏ-トリエチルシリルバッカチンIII
上記工程４で得た化合物 1.15 g をテトラヒドロフラン 20 mlに溶解し氷冷下、メタクロロ過安息香酸 243 mg を加え室温に戻し１時間攪拌した。飽和重曹水溶液を加え、酢酸エチルで抽出し飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：アセトン＝５０：１(v/v) ）で精製し標記化合物615 mgを淡黄色の非晶質固体として得た。
【０２５３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.50-0.64 (m,6H), 0.96 (t,9H,J=7Hz), 1.07 (s,3H), 1.13 (s,3H),1.24 (t,3H,J=7Hz), 1.63 (s,3H), 1.92 (s,3H), 1.75-1.87 (m,1H),2.20-2.30 (m,2H), 2.45-2.70 (m,4H), 2.76-2.83 (m,1H), 3.90 (dd,1H,J=4.5Hz,10Hz), 4.05 (d,1H,J=7Hz), 4.18 (d,1H,J=8Hz),4.30 (d,1H,J=8Hz), 4.55 (dd,1H,J=7Hz,10Hz), 4.83 (br,1H), 4.92 (d,1H,J=8Hz), 5.02 (d,1H,J=10Hz), 5.09 (d,1H,J=17Hz),5.60 (d,1H,J=7Hz), 5.73-5.84 (m,1H), 7.46 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz).
【０２５４】
工程６：10-アリル-7,13-Ｏ-ビス (トリエチルシリル)-10-デアセトキシ-4-デアセチル-4-Ｏ-プロピオニルバッカチンIII
上記工程５で得た化合物を実施例１の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２５５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.49-0.70 (m,12H), 0.94-1.02 (m,18H), 1.12 (s,3H), 1.15 (s,3H), 1.27 (t,3H,J=7Hz), 1.62 (s,3H), 1.85 (s,3H), 1.84-1.91 (m,1H),2.02-2.23 (m,2H), 2.41-2.51 (m,2H), 2.61 (q,2H,J=7Hz),2.77-2.84 (m,1H), 3.85 (dd,1H,J=4Hz,10Hz), 3.94 (d,1H,J=7Hz), 4.17 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.54 (dd,1H,J=7Hz,10Hz),4.91-4.94 (m,2H), 5.01 (d,1H,J=10Hz), 5.07 (d,1H,J=17Hz), 5.61 (d,1H,J=7Hz), 5.71-5.82 (m,1H), 7.46 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.11 (d,2H,J=8Hz).
【０２５６】
工程７：10-アリル-10-デアセトキシ-4-デアセチル-4-Ｏ-プロピオニル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程６で得た化合物を実施例５の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２５７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.61-0.73 (m,6H), 1.00 (t,9H,J=7Hz), 1.10 (s,3H), 1.14 (s,3H),1.26 (t,3H,J=7Hz), 1.63 (s,3H), 1.85 (s,3H), 1.75-1.84 (m,1H),2.04-2.10 (m,1H), 2.20-2.33 (m,2H), 2.54-2.70 (m,3H), 2.90-2.97 (m,1H), 3.88 (t,1H,J=7Hz), 3.99 (d,1H,J=7Hz), 4.20 (d,1H,J=8Hz), 4.32 (d,1H,J=8Hz), 4.34-4.40 (m,1H), 4.87-5.02(m,3H), 5.09 (dd,1H,J=1.5Hz,17Hz), 5.64 (d,1H,J=7Hz),5.75-5.85 (m,1H), 7.47 (t,2H,J=8Hz), 7.62 (t,1H,J=8Hz), 8.11 (d,2H,J=8Hz).
【０２５８】
工程８：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロ-4-Ｏ-プロピオニル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程７で得た化合物を実施例５の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２５９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.62-0.73 (m,6H), 1.00 (t,9H,J=7Hz), 1.07 (s,3H), 1.14 (s,3H),1.27 (t,3H,J=7Hz), 1.67 (s,3H), 1.82 (s,3H), 2.07-2.35 (m,4H),2.49-2.70 (m,3H), 2.98-3.05 (m,1H), 4.10 (dd,1H,J=5.5Hz,8Hz), 4.14 (d,1H,J=7Hz), 4.34 (AB type d, each 1H, J=8Hz),4.54 (dd,1H,J=3.5Hz,47Hz), 4.91 (t,1H,J=8Hz), 4.98-5.09 (m,3H), 5.70 (d,1H,J=7Hz), 5.72-5.81 (m,1H), 7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
【０２６０】
工程９：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロ-4-Ｏ-プロピオニルバッカチンIII
上記工程８で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２６１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.07 (s,6H), 1.21 (t,3H,J=7Hz), 1.67 (s,3H), 1.87 (s,3H), 2.16-2.38 (m,4H), 2.51-2.73 (m,3H), 2.97-3.06 (m,1H), 4.13 (dd,1H,J=5.5Hz,8Hz), 4.30 (d,1H,J=7Hz), 4.35 (s,2H), 4.54 (dd,1H,J=3.5Hz,47Hz), 4.81 (br,1H), 4.99-5.11 (m,3H),5.70 (d,1H,J=7Hz), 5.74-5.89 (m,1H), 7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
【０２６２】
工程１０：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-( tert-ブチルジメチルシリル )オキシ-3-(2-フリル)プロピオニル ]-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロ-4-Ｏ-プロピオニルバッカチン III
上記工程９で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-3-(te rt-ブチルジメチルシリル )オキシ-4-(2-フリル)-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２６３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.19 (s,3H), -0.01 (s,3H), 0.77 (s,9H), 1.10 (s,3H), 1.19 (s,3H),1.24 (t,3H,J=7Hz), 1.32 (s,9H), 1.67 (s,3H), 1.72 (s,3H), 2.15-2.28 (m,3H), 2.48-2.52 (m,2H), 2.75-2.80 (m,2H), 3.00-3.06 (m,1H), 4.06-4.11 (m,1H), 4.18 (d,1H,J=7Hz),4.36 (AB type d,each 1H,J=8Hz), 4.55 (dd,1H,J=3.5Hz,47Hz),4.72 (s,1H), 5.00-5.10 (m,3H), 5.25 (d,1H,J=10Hz), 5.32 (d,1H,J=10Hz),5.72-5.83 (m,2H), 6.15 (t,1H,J=8Hz), 6.23 (d,1H,J=3Hz), 6.35 (dd,1H,J=1.5Hz,3Hz), 7.38 (s,1H), 7.48 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
【０２６４】
工程１１：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-(2-フリル) プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロ-10-(2-モルホリノエチル)-4-Ｏ-プロピオニルバッカチン III
上記工程１０で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２６５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.18 (s,3H), -0.01 (s,3H), 0.78 (s,9H), 1.08 (s,3H), 1.19 (s,3H),1.23 (t,3H,J=7Hz), 1.34 (s,9H), 1.68 (s,3H), 1.83 (s,3H), 2.18-2.58 (m,12H), 2.77-2.79 (m,2H), 3.66-3.73 (m,4H),4.18-4.23 (m,2H), 4.36 (AB type d,each 1H,J=8Hz), 4.54 (dd,1H,J=3.5Hz,47Hz), 4.73 (s,1H), 5.02 (d,1H,J=8Hz),5.26 (d,1H,J=10Hz), 5.32 (d,1H,J=10Hz), 5.76 (d,1H,J=7Hz),6.15 (t,1H,J=8Hz), 6.24 (d,1H,J=3Hz), 6.36 (d,1H,J=3Hz), 7.39 (s,1H), 7.49 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.14 (d,2H,J=8Hz).
【０２６６】
工程１２：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロ-10-(2-モルホリノエチル)-4-Ｏ-プロピオニルバッカチンIII
上記工程１１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０２６７】
融点：130-134 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.21 (s,3H), 1.26 (t,3H,J=7Hz), 1.33 (s,9H), 1.68 (s,3H),1.82 (s,3H), 2.18-2.76 (m,14H), 3.65-3.69 (m,4H), 4.18 (d,1H,J=7Hz),4.24 (t,1H,J=5.5Hz), 4.36 (AB type d,each 1H,J=8Hz),4.54 (dd,1H,J=3.5Hz,47Hz), 4.70 (d,1H,J=1.5Hz), 5.00 (dd,1H,J=2Hz,9Hz), 5.19 (d,1H,J=10Hz), 5.33 (d,1H,J=10Hz), 5.75 (d,1H,J=7Hz), 6.20 (t,1H,J=8Hz), 6.33 (d,1H,J=3.5Hz),6.38 (dd,1H,J=2Hz,3.5Hz), 7.43 (s,1H), 7.50 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.16 (d,2H,J=8Hz).
IR (KBr)：3456, 2976, 2812, 1718, 1604, 1494 cm-1
MS-FAB：911 (MH+)
【０２６８】
実施例７
【０２６９】
【化４７】
工程１：10-アリル-7,13-Ｏ-ビス(トリエチルシリル)-10-デアセトキシ-1-Ｏ-ジメチルシリルバッカチンIII
実施例５の工程１で得た化合物を実施例２の工程１と同様に反応させ、標記化合物を無色の結晶として得た。
【０２７１】
融点：122 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.28 (d,3H,J=2.7Hz), 0.06 (d,3H,J=2.7Hz), 0.55 (m,6H), 0.69 (m,6H),0.95 (m,9H), 1.03 (m,9H), 1.10 (s,3H), 1.13 (s,3H), 1.61 (s,3H),1.85 (m,1H), 1.87 (s,3H), 2.27 (m,1H), 2.29 (s,3H), 2.30 (m,1H),2.44 (m,2H), 2.81 (m,1H), 3.83 (dd,1H,J=4.0Hz,10.0Hz),3.95 (d,1H,J=7.3Hz), 4.24 (m,2H), 4.47-4.55 (m,2H), 4.94-5.09 (m,3H), 5.68 (d,1H,J=7.3Hz), 5.77 (m,1H), 7.45 (t,2H,J=7.5Hz),7.57 (t,1H,J=7.5Hz), 8.09 (m,2H).
MS-FAB：855 (MH+)
【０２７２】
工程２：10-アリル-7,13-Ｏ-ビス (トリエチルシリル)-10-デアセトキシ-4-デアセチル-1-Ｏ-ジメチルシリルバッカチンIII
上記工程１で得た化合物を実施例２の工程２と同様に反応させ、標記化合物を無色の結晶として得た。
【０２７３】
融点：158-160 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (d,3H,J=2.7Hz), 0.00 (d,3H,J=2.7Hz), 0.53 (m,6H), 0.78 (m,6H),0.92 (m,12H), 1.22 (m,12H), 1.51 (s,3H), 1.85 (s,3H), 1.97 (m,1H),2.35 (m,1H), 2.52 (m,1H), 2.63 (m,1H), 2.73 (m,1H), 2.81 (m,1H),3.67 (s,1H), 3.70 (d,1H,J=6.0Hz), 3.88 (dd,1H,J=5.0Hz,10.0Hz),4.06 (dd,1H,J=6.0Hz,12.0Hz), 4.19 (d,1H,J=8.3Hz), 4.30 (d,1H,J=8.3Hz),4.55 (m,1H), 4.66 (m,2H), 5.03 (m,2H), 5.55 (d,1H,J=6.0Hz), 5.77 (m,1H), 7.42 (t,2H,J=7.5Hz), 7.53 (t,1H,J=7.5Hz),8.10 (d,2H,J=7.5Hz).
MS-FAB：813 (MH+)
【０２７４】
工程３：10-アリル-7,13-Ｏ-ビス(トリエチルシリル)-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-1-Ｏ-ジメチルシリルバッカチンIII
上記工程２で得た化合物を実施例２の工程３と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０２７５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.28 (d,3H,J=2.5Hz), 0.07 (d,3H,J=2.5Hz), 0.49-0.72 (m,12H), 0.94 (t,9H,J=7Hz), 1.02 (t,9H,J=7Hz), 1.12 (s,3H), 1.13 (s,3H), 0.97-1.27 (m,4H), 1.61 (s,3H), 1.67-1.89 (m,2H), 1.87 (d,3H,J=1.5Hz), 2.28-2.85 (m,4H), 3.82 (dd,1H,J=4.0Hz,10.0Hz), 3.95 (d,1H,J=7Hz), 4.20 (AB type d,2H,J=9Hz), 4.48 (dd,1H,J=7Hz,10Hz), 4.55 (t,1H,J=1.5Hz), 4.83 (dd,1H,J=2.5Hz,10Hz), 4.96-5.09 (m,3H), 5.69 (d,1H,J=7Hz), 5.72-5.82 (m,1H), 7.46 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０２７６】
工程４：10-アリル-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程３で得た化合物を実施例５の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２７７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.61-0.71 (m,6H), 1.00 (t,9H,J=7Hz), 1.10 (s,3H), 1.16 (s,3H),0.98-1.27 (m,4H), 1.63 (s,3H), 1.69-1.82 (m,2H), 1.87 (s,3H), 2.02-2.08 (m,1H), 2.23-2.33 (m,2H), 2.49-2.57 (m,1H), 2.89-2.95 (m,1H), 3.87 (t,1H,J=7Hz), 4.02 (d,1H,J=7Hz), 4.19 (d,1H,J=8Hz), 4.27 (d,1H,J=8Hz), 4.34 (br,1H), 4.85 (dd,1H,J=2Hz,9Hz), 4.93 (t,1H,J=8Hz), 4.99 (d,1H,J=10Hz),5.08 (dd,1H,J=1.5Hz,17Hz), 5.64 (d,1H,J=7Hz), 5.75-5.85 (m,1H), 7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０２７８】
工程５：10-アリル-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロ-13-Ｏ-トリエチルシリルバッカチンIII
上記工程４で得た化合物を実施例５の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２７９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.62-0.71 (m,6H), 1.00 (t,9H,J=7Hz), 0.98-1.28 (m,4H), 1.07 (s,3H), 1.17 (s,3H), 1.69 (s,3H), 1.74-1.81 (m,1H), 1.83 (s,3H),2.03-2.27 (m,4H), 2.43-2.57 (m,1H), 2.96-3.06 (m,1H), 4.07-4.13 (m,1H), 4.15 (d,1H,J=8Hz), 4.32 (d,1H,J=9Hz), 4.45 (d,1H,J=9Hz), 4.54 (dd,1H,J=3Hz,47Hz), 4.90-5.09 (m,4H), 5.70 (d,1H,J=7Hz), 5.75-5.83 (m,1H), 7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz).
【０２８０】
工程６：10-アリル-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロバッカチンIII
上記工程５で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２８１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.00-1.27 (m,4H), 1.08 (s,3H), 1.09 (s,3H), 1.67 (s,3H),1.80-1.85 (m,1H), 1.87 (s,3H), 2.12-2.39 (m,4H), 2.48-2.60 (m,1H),2.95-3.06 (m,1H), 4.10 (dd,1H,J=5.5Hz,8Hz), 4.30 (d,1H,J=7Hz),4.38 (AB type d,each 1H,J=9Hz), 4.53 (dd,1H,J=3.5Hz,47Hz),4.81 (br,1H), 4.95-5.11 (m,3H), 5.72 (d,1H,J=7Hz), 5.81-5.85 (m,1H),7.49 (t,2H,J=8Hz), 7.62 (t,1H,J=8Hz), 8.15 (d,2H,J=8Hz).
【０２８２】
工程７：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル )オキシ-3-(2-フリル)プロピオニル]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロバッカチンIII
上記工程６で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-3-(te rt-ブチルジメチルシリル )オキシ-4-(2-フリル)-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２８３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.20 (s,3H), -0.03 (s,3H), 0.74 (s,9H), 1.07 (s,3H), 1.18 (s,3H),1.04-1.21 (m,4H), 1.32 (s,9H), 1.65 (s,3H), 1.72 (s,3H),1.92-1.97 (m,1H), 2.10-2.27 (m,3H), 2.44-2.65 (m,2H), 2.97-3.04 (m,1H), 4.03-4.06 (m,1H), 4.17 (d,1H,J=7Hz),4.32 (d,1H,J=8Hz), 4.37 (d,1H,J=8Hz), 4.51 (dd,1H,J=3Hz,47Hz),4.77 (d,1H,J=2Hz), 4.96-5.00 (m,2H), 5.06 (dd,1H,J=1.5Hz,17Hz), 5.22 (d,1H,J=10Hz), 5.35 (d,1H,J=10Hz), 5.72-5.81 (m,2H), 6.14 (t,1H,J=8Hz), 6.19 (d,1H,J=3Hz), 6.31 (dd,1H,J=1.5Hz,3Hz), 7.30 (s,1H), 7.46 (t,2H,J=8Hz), 7.55 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０２８４】
工程８：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル) オキシ-3-(2-フリル) プロピオニル ]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロ-10-(2-モルホリノエチル) バッカチンIII
上記工程７で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２８５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.16 (s,3H), 0.02 (s,3H), 0.78 (s,9H), 1.09 (s,3H), 1.21 (s,3H), 1.08-1.22 (m,4H), 1.34 (s,9H), 1.68 (s,3H), 1.85 (s,3H),1.96-2.01 (m,1H), 2.14-2.61 (m,12H), 3.65-3.69 (m,4H),4.20-4.22 (m,2H), 4.34 (d,1H,J=8Hz), 4.40 (d,1H,J=8Hz), 4.52 (dd,1H,J=3Hz,47Hz), 4.80 (d,1H,J=1.5Hz), 5.00 (d,1H,J=8Hz),5.25 (d,1H,J=10Hz), 5.38 (d,1H,J=10Hz), 5.76 (d,1H,J=7Hz),6.15 (t,1H,J=8Hz), 6.22 (d,1H,J=3Hz), 6.34 (dd,1H,J=2Hz,3Hz), 7.34 (s,1H), 7.50 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
【０２８６】
工程９：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7-α-フルオロ-10-(2-モルホリノエチル) バッカチン III
上記工程８で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０２８７】
融点：132-137 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.97-1.24 (m,4H), 1.10 (s,3H), 1.22 (s,3H), 1.35 (s,9H), 1.68 (s,3H), 1.83 (s,3H), 1.91-1.95 (m,1H), 2.13-2.67 (m,12H), 3.66-3.71 (m,4H), 4.19-4.25 (m,2H), 4.32 (d,1H,J=8Hz), 4.40 (d,1H,J=8Hz), 4.53 (dd,1H,J=3Hz,47Hz), 4.75 (d,1H,J=1.5Hz), 4.98 (d,1H,J=8Hz),5.18 (d,1H,J=10Hz), 5.38 (d,1H,J=10Hz), 5.76 (d,1H,J=7Hz),6.17 (t,1H,J=8Hz), 6.32 (d,1H,J=3.5Hz), 6.37 (dd,1H,J=2Hz,3Hz), 7.39 (s,1H), 7.51 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.14 (d,2H,J=8Hz).
IR (KBr)：3452, 2976, 2812, 1724, 1624, 1494, 1454 cm-1
MS-FAB：923 (MH+)
【０２８８】
実施例８
【０２８９】
【化４８】
工程１：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル )オキシ-3-フェニルプロピオニル]-10-デアセトキシ-7-デオキシ-7-α-フルオロバッカチンIII
実施例５の工程４で得た化合物を実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２９１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.37 (s,3H), -0.10 (s,3H), 0.72 (s,9H), 1.11 (s,3H), 1.23 (s,3H),1.31 (s,9H), 1.69 (s,3H), 1.73 (s,3H), 2.12-2.34 (m,3H), 2.55 (s,3H), 2.50-2.65 (m,2H), 3.00-3.10 (m,1H), 4.05-4.09 (m,1H), 4.22 (d,1H,J=7Hz), 4.38 (s,2H), 4.52 (s,1H), 4.56 (dd,1H,J=3Hz,47Hz), 5.00-5.12 (m,3H), 5.34 (d,1H,J=10Hz), 5.45 (d,1H,J=10Hz), 5.75 (d,1H,J=7Hz), 5.76-5.85 (m,1H), 6.30 (t,1H,J=8Hz), 7.30-7.40 (m,5H), 7.49 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
【０２９２】
工程２：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-フェニルプロピオニル]-10-デアセトキシ-7-デオキシ-7-α-フルオロ-10-(2-モルホリノエチル) バッカチンIII
上記工程１で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２９３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.35 (s,3H), -0.11 (s,3H), 0.74 (s,9H), 1.09 (s,3H), 1.23 (s,3H),1.31 (s,9H), 1.69 (s,3H), 1.83 (s,3H), 2.04-2.63 (m,13H), 2.55 (s,3H),3.67 (m,4H), 4.21-4.23 (m,2H), 4.35, 4.38 (each d,total 2H,J=9Hz),4.52 (s,1H), 4.54 (dd,1H,J=3Hz,47Hz), 5.06 (d,1H,J=7Hz),5.35 (d,1H,J=10Hz), 5.46 (d,1H,J=10Hz), 5.75 (d,1H,J=7Hz),6.25 (t,1H,J=8Hz), 7.28-7.39 (m,5H), 7.50 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.14 (d,2H,J=8Hz).
【０２９４】
工程３：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル]-10-デアセトキシ-7-デオキシ-7-α-フルオロ-10-(2-モルホリノエチル) バッカチンIII
上記工程２で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０２９５】
融点：145-149 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.21 (s,3H), 1.33 (s,9H), 1.68 (s,3H), 1.77 (s,3H),2.40 (s,3H), 2.14-2.65 (m,13H), 3.68 (m,4H), 4.20-4.24 (m,2H),4.33, 4.36 (each d,total 2H,J=9Hz), 4.52 (dd,1H,J=3Hz,47Hz),4.61 (s,1H), 5.02 (dd,1H,J=2Hz,9Hz), 5.30 (d,1H,J=10Hz),5.41 (d,1H,J=10Hz), 5.74 (d,1H,J=7Hz), 6.19 (t,1H,J=8Hz), 7.40-7.42 (m,5H), 7.51 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.14 (d,2H,J=8Hz).
MS-FAB：907 (MH+)
【０２９６】
実施例９
【０２９７】
【化４９】
工程１：7,13-Ｏ-ビス (トリエチルシリル)-10-デアセトキシ-10-(2-モルホリノエチル) バッカチンIII
実施例５の工程１で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０２９９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.49-0.72 (m,12H), 0.94-1.03 (m,18H), 1.11 (s,3H), 1.12 (s,3H), 1.62 (s,3H), 1.96 (s,3H), 1.75-2.52 (m,12H), 2.29 (d,3H,J=2Hz), 3.72 (m,4H), 3.80-3.82 (m,1H), 3.97 (d,1H,J=7Hz), 4.16 (d,1H,J=8Hz),4.29 (d,1H,J=8Hz), 4.53 (dd,1H,J=7Hz,10Hz), 4.92 (t,1H,J=8Hz),4.98 (d,1H,J=9Hz), 5.60 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz),7.59 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３００】
工程２：7,13-Ｏ-ビス(トリエチルシリル)-10-デアセトキシ-4-デアセチル-1-Ｏ-ジメチルシリル-10-(2-モルホリノエチル) バッカチンIII
上記工程１で得た化合物 81.5 mgを N,N-ジメチルホルムアミド 2 ml に溶解し、イミダゾール 19 mgおよび塩化ジメチルシラン 0.031 mlを加え室温で１５分攪拌した。反応液を氷水に注ぎ酢酸エチルで抽出後、水（２回）、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をテトラヒドロフラン 2 ml に溶解し氷冷下、水素化ビス(2-メトキシエトキシ)アルミニウムナトリウム(65%wt、トルエン溶液）0.13 mlを滴下し２０分攪拌した。飽和酒石酸カリウム水溶液 1 ml を加え（約５分攪拌）酢酸エチルで抽出した後、水、飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：３(v/v) ）で精製し標記化合物68 mg を無色の非晶質固体として得た。
【０３０１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (d,3H,J=3Hz), 0.01 (d,3H,J=3Hz), 0.45-0.60 (m,6H),0.71-0.86 (m,6H), 0.92 (t,9H,J=7Hz), 1.09 (m,15H), 1.50 (s,3H), 1.95 (s,3H), 1.84-2.56 (m,11H), 2.80 (dd,1H,J=2.5Hz,15Hz),3.66-3.73 (m,6H), 3.85-3.88 (m,1H), 4.10 (dd,1H,J=7Hz,10Hz),4.20 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.54-4.57 (m,1H), 4.66-4.69 (m,2H), 5.54 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３０２】
工程３：7,13-Ｏ-ビス(トリエチルシリル)-10-デアセトキシ-4-デアセチル-1-Ｏ-ジメチルシリル-4-Ｏ-エトキシカルボニル-10-(2-モルホリノエチル)バッカチンIII
上記工程２で得た化合物 68 mgをテトラヒドロフラン 2 mlに溶解し氷冷下、リチウムビス( トリメチルシリル) アミド（１Ｍテトラヒドロフラン溶液） 0.23 mlを加え５分攪拌した後、クロロギ酸エチル 0.025 mlを加え１時間攪拌した。反応液を飽和重曹水溶液に注ぎ酢酸エチルで抽出後、水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：３(v/v) ）で精製し標記化合物49.5 mg を無色の非晶質固体として得た。
【０３０３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (d,3H,J=3Hz), 0.05 (d,3H,J=3Hz), 0.50-0.72 (m,12H), 0.95 (t,9H,J=7Hz), 1.02 (t,9H,J=7Hz), 1.10 (s,3H), 1.12 (s,3H), 1.40 (t,3H,J=7Hz), 1.61 (s,3H), 1.95 (s,3H), 1.71-2.49 (m,12H), 3.70-3.83 (m,5H), 3.97 (d,1H,J=7Hz), 4.14-4.27 (m,3H),4.39-4.55 (m,3H), 4.92-4.99 (m,2H), 5.69 (d,1H,J=7Hz),7.45 (t,2H,J=8Hz), 7.56 (t,1H,J=8Hz), 8.05 (d,2H,J=8Hz).
【０３０４】
工程４：10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリルバッカチンIII
上記工程３で得た化合物を実施例５の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３０５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.62-0.68 (m,6H), 1.00 (t,9H,J=7Hz), 1.07 (s,3H), 1.14 (s,3H),1.42 (t,3H,J=7Hz), 1.61 (s,3H), 1.93 (s,3H), 1.84-2.78 (m,12H), 3.68-3.70 (m,4H), 3.97-4.00 (m,2H), 4.11-4.17 (m,1H), 4.19 (d,1H,J=8Hz), 4.31 (d,1H,J=8Hz), 4.40-4.51 (m,2H), 4.90 (t,1H,J=8Hz), 5.00 (dd,1H,J=2Hz,9Hz), 5.61 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３０６】
工程５：10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチルチオメチル-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリルバッカチン III上記工程４で得た化合物 23 mgをジメチルスルホキシド 0.5 mlおよび無水酢酸 0.5 ml に溶解し室温で 17 時間攪拌した。反応液に飽和重曹水溶液を加え酢酸エチルで抽出し、水（２回）、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；クロロホルム：メタノール＝５０：１(v/v) ）で精製し標記化合物12 mg を無色の非晶質固体として得た。
【０３０７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.63-0.69 (m,6H), 1.00 (t,9H,J=7Hz), 1.12 (s,3H), 1.15 (s,3H),1.41 (t,3H,J=7Hz), 1.68 (s,3H), 2.01 (s,3H), 2.20 (s,3H), 1.73-2.77 (m,12H), 3.69-3.75 (m,4H), 4.07 (d,1H,J=7Hz), 4.10-4.17 (m,1H), 4.18 (d,1H,J=8Hz), 4.31 (d,1H,J=8Hz), 4.31-4.36 (m,1H), 4.40-4.48 (m,1H), 4.56, 4.65 (each d,total 2H,J=12Hz), 4.92-4.98 (m,2H), 5.63 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３０８】
工程６：10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチル-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリルバッカチンIII
上記工程５で得た化合物 9.0 mg をエタノール 2 ml に溶解し、ラネーニッケル 0.2 gを加え２０分加熱還流した。反応液を放冷後、不溶物をセライト濾過し濾液を濃縮した。得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；クロロホルム：メタノール＝５０：１(v/v) ）で精製し標記化合物5.7 mgを無色の非晶質固体として得た。
【０３０９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.63-0.69 (m,6H), 1.01 (t,9H,J=7Hz), 1.10 (s,3H), 1.14 (s,3H),1.42 (t,3H,J=7Hz), 1.66 (s,3H), 2.01 (s,3H), 1.68-2.74 (m,12H), 3.27 (s,3H), 3.69-3.73 (m,4H), 3.93 (t,1H,J=7Hz), 4.00 (dd,1H,J=6Hz,10Hz), 4.04 (d,1H,J=7Hz), 4.14-4.22 (m,2H), 4.31 (d,1H,J=8Hz), 4.40-4.48 (m,1H), 4.93 (t,1H,J=8Hz), 5.01 (d,1H,J=8Hz), 5.61 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz),7.58 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３１０】
工程７：10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程６で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３１１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.04 (s,3H), 1.10 (s,3H), 1.40 (t,3H,J=7Hz), 1.65 (s,3H), 2.09 (d,3H,J=1Hz), 1.73-2.78 (m,12H), 3.28 (s,3H), 3.63-3.78 (m,4H),3.98-4.02 (m,2H), 4.11-4.40 (m,5H), 4.83 (t,1H,J=8Hz),5.06 (d,1H,J=8Hz), 5.60 (d,1H,J=7Hz), 7.48 (t,2H,J=8Hz),7.59 (t,1H,J=8Hz), 8.11 (d,2H,J=8Hz).
【０３１２】
工程８：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-(2-チエニル) プロピオニル]-10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチル-10-(2-モルホリノエチル )バッカチンIII
上記工程７で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-3-(te rt-ブチルジメチルシリル )オキシ-4-(2-チエニル)-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３１３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.15 (s,3H), 0.02 (s,3H), 0.83 (s,9H), 1.14 (s,3H), 1.20 (s,3H), 1.33-1.37 (m,12H), 1.68 (s,3H), 1.94 (s,3H), 1.75-2.77 (m,12H), 3.27 (s,3H), 3.68 (m,4H), 3.95-4.03 (m,2H), 4.08 (d,1H,J=7Hz),4.14 (d,1H,J=8Hz), 4.34 (d,1H,J=8Hz), 4.36-4.42 (m,1H), 4.50-4.58 (m,2H), 5.02 (d,1H,J=8Hz), 5.37 (d,1H,J=10Hz),5.57 (d,1H,J=10Hz), 5.67 (d,1H,J=7Hz), 6.15 (t,1H,J=8Hz), 7.00-7.04 (m,2H), 7.22-7.25 (m,1H), 7.47 (t,2H,J=8Hz),7.58 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz).
【０３１４】
工程９：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-(2-チエニル )プロピオニル]-10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程８で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０３１５】
融点：140-145 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,3H), 1.17 (s,3H), 1.32 (t,3H,J=7Hz), 1.37 (s,9H), 1.67 (s,3H),1.90 (s,3H), 1.75-2.75 (m,12H), 3.26 (s,3H), 3.69 (m,4H), 3.90-4.05 (m,3H), 4.18-4.24 (m,2H), 4.35 (d,1H,J=8Hz),4.40-4.48 (m,1H), 4.63 (s,1H), 5.03 (d,1H,J=8Hz), 5.36 (d,1H,J=10Hz), 5.52 (d,1H,J=10Hz), 5.66 (d,1H,J=7Hz), 6.10 (t,1H,J=8Hz), 7.00 (dd,1H,J=3.5Hz,5Hz), 7.15 (s,1H), 7.27-7.30 (m,1H),7.47 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
MS-FAB：955 (MH+)
【０３１６】
実施例１０
【０３１７】
【化５０】
工程１：10-デアセトキシ-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリルバッカチンIII
実施例９の工程１で得た化合物を実施例５の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３１９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.63-0.70 (m,6H), 1.01 (t,9H,J=7Hz), 1.07 (s,3H), 1.11 (s,3H),1.60 (s,3H), 1.92 (s,3H), 2.29 (s,3H), 1.83-2.78 (m,12H), 3.69 (m,4H),3.95 (d,1H,J=7Hz), 3.98 (d,1H,J=8Hz), 4.18 (d,1H,J=8Hz),4.30 (d,1H,J=8Hz), 4.51 (dd,1H,J=7Hz,10Hz), 4.88 (t,1H,J=8Hz),5.04 (d,1H,J=8Hz), 5.69 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz),7.60 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３２０】
工程２：10-デアセトキシ-7-Ｏ-メチルチオメチル-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリルバッカチンIII
上記工程１で得た化合物を実施例９の工程５と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３２１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.62-0.72 (m,6H), 1.02 (t,9H,J=7Hz), 1.12 (s,3H), 1.13 (s,3H),1.68 (s,3H), 2.00 (s,3H), 2.21 (s,3H), 2.30 (s,3H), 1.78-2.77 (m,12H),3.70-3.72 (m,4H), 4.04 (d,1H,J=7Hz), 4.11-4.14 (m,1H),4.17 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.38 (dd,1H,J=7Hz,10Hz),4.55, 4.65 (each d,total 2H,J=12Hz), 4.93 (t,1H,J=8Hz), 4.99 (d,1H,J=8Hz), 5.61 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz),7.60 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３２２】
工程３：10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリルバッカチンIII
上記工程２で得た化合物を実施例９の工程６と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３２３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.64-0.74 (m,6H), 1.02 (t,9H,J=7Hz), 1.09 (s,3H), 1.10 (s,3H),1.65 (s,3H), 2.00 (s,3H), 2.30 (s,3H), 1.78-2.75 (m,12H), 3.26 (s,3H),3.68-3.74 (m,4H), 3.95 (dd,1H,J=5.5Hz,7Hz), 3.99-4.04 (m,2H), 4.16 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.91 (t,1H,J=8Hz),5.03 (dd,1H,J=2Hz,9Hz), 5.58 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３２４】
工程４：10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル)バッカチン III
上記工程３で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３２５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.06 (s,3H), 1.10 (s,3H), 1.66 (s,3H), 2.06 (s,3H), 2.30 (s,3H),1.72-2.76 (m,12H), 3.27 (s,3H), 3.63-3.72 (m,4H), 3.96-4.04 (m,2H), 4.08 (d,1H,J=7Hz), 4.16 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz),4.83 (t,1H,J=8Hz), 5.02 (d,1H,J=8Hz), 5.58 (d,1H,J=7Hz),7.47 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３２６】
工程５：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3-フェニル-2-(トリメチルシリル)オキシプロピオニル]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程４で得た化合物 43 mgおよび参考例１の工程２で得た化合物 49.5 mg をテトラヒドロフラン 4 ml に溶解し、-78 ℃に冷却した（窒素下）。次いで、ナトリウムビス(トリメチルシリル) アミド（１Ｍテトラヒドロフラン溶液,0.26 ml）を滴下し１０分撹拌した。反応液に飽和重曹水溶液を加えた後、室温に戻し酢酸エチルを加え抽出し、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後溶媒を減圧留去し得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；クロロホルム：メタノール＝５０：１(v/v) ）で精製し標記化合物48.5 mg を無色の非晶質固体として得た。
【０３２７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.08 (s,9H), 1.12 (s,3H), 1.16 (s,9H), 1.25 (s,3H), 1.38 (s,3H),1.67 (s,3H), 1.87 (s,3H), 2.68 (s,3H), 1.82-2.72 (m,12H), 3.24 (s,3H),3.65 (m,4H), 3.92-3.99 (m,3H), 4.19 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz),4.96-5.01 (m,2H), 5.47 (d,1H,J=10Hz), 5.64 (d,1H,J=7Hz),6.32 (t,1H,J=8Hz), 7.26-7.35 (m,5H), 7.47 (t,2H,J=8Hz), 7.56 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz).
【０３２８】
工程６：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程５で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０３２９】
融点：156-160 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,3H), 1.23 (s,12H), 1.40 (s,3H), 1.69 (s,3H), 1.79 (s,3H), 2.63 (s,3H), 1.75-2.75 (m,12H), 3.25 (s,3H), 3.68 (m,4H), 3.94-4.00 (m,3H), 4.20 (d,1H,J=8Hz), 4.32 (d,1H,J=8Hz), 5.00-5.05 (m,2H), 5.56 (d,1H,J=10Hz), 5.65 (d,1H,J=7Hz),6.29 (t,1H,J=8Hz), 7.31-7.38 (m,5H), 7.49 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
MS-FAB：933 (MH+)
【０３３０】
実施例１１
【０３３１】
【化５１】
工程１：10-デアセチル-10-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-13-Ｏ-トリエチルシリルバッカチンIII
10-デアセチル-10-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-Ｏ-トリエチルシリルバッカチンIII 28.5 gおよびイミダゾール 5.80 gを N,N-ジメチルホルムアミド 57 mlに溶解し塩化トリエチルシラン 14.3 mlを加え室温下、一晩攪拌した。反応液を氷水に注ぎ酢酸エチルで２回抽出し水（２回）、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をメタノール：テトラヒドロフラン＝１：１（v/v ）320ml に溶解しp-トルエンスルホン酸 963 mg を加え室温で４時間攪拌した。トリエチルアミン 5 ml を加え反応液を濃縮した。得られた残分に酢酸エチルおよび水を加え分液し、水層を酢酸エチルで抽出、有機層をあわせ水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：ヘキサン＝１：４〜１：１ (v/v)）で精製し標記化合物 23.5 g を無色の非晶質固体として得た。
【０３３３】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.62-0.73 (m,6H), 1.02 (t,9H,J=7Hz), 1.14 (s,3H), 1.20 (s,3H),1.68 (s,3H), 1.83-1.90 (m,1H), 2.04 (s,3H), 2.13-2.28 (m,2H), 2.29 (s,3H), 2.52-2.60 (m,1H), 3.77 (d,1H,J=7Hz), 4.16 (d,1H,J=8Hz),4.31 (d,1H,J=8Hz), 4.41-4.45 (m,1H), 4.77,4.91 (each d, total 2H, J=12Hz), 4.95-4.99 (m,2H), 5.64 (d,1H,J=7Hz), 6.17 (s,1H), 7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３３４】
工程２：10-デアセチル-7-Ｏ-メチルチオメチル-10-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-13-Ｏ-トリエチルシリルバッカチンIII
上記工程１で得た化合物を実施例９の工程５と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３３５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.65-0.73 (m,6H), 1.02 (t,9H,J=7Hz), 1.16 (s,3H), 1.20 (s,3H),1.76 (s,3H), 1.81-1.88 (m,1H), 2.15 (s,3H), 2.18 (s,3H),2.10-2.28 (m,2H), 2.30 (s,3H), 2.78-2.85 (m,1H), 3.85 (d,1H,J=7Hz), 4.15 (d,1H,J=8Hz), 4.31-4.36 (m,2H), 4.65,4.71 (each d, total 2H, J=12Hz), 4.75,4.87 (each d, total 2H, J=12Hz), 4.94-4.99 (m,2H), 5.65 (d,1H,J=7Hz), 6.47 (s,1H), 7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３３６】
工程３：10-デアセチル-7-Ｏ-メチルチオメチル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程２で得た化合物 14.5 g をメタノール：酢酸：テトラヒドロフラン＝１：１：１(v/v/v) 217.5 mlの混合溶媒に溶解し、亜鉛末 50 gを加え、６０℃で１５分攪拌した。放冷後、不溶物を濾去し濾液を濃縮、トルエンで共沸した。残分に１規定塩酸および酢酸エチルを加え分配し、有機層を飽和重曹水溶液、飽和食塩水の順に洗浄、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。次いで、得られた残分を酢酸エチル−ヘキサンより再結晶し標記化合物 10.7 g を無色の結晶として得た。
【０３３７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.63-0.73 (m,6H), 1.02 (t,9H,J=7Hz), 1.10 (s,3H), 1.17 (s,3H),1.80 (s,3H), 1.76-1.82 (m,1H), 2.11 (s,6H), 2.13-2.26 (m,2H), 2.30 (s,3H), 2.62-2.70 (m,1H), 3.96 (d,1H,J=7Hz), 4.17 (d,1H,J=8Hz),4.24 (d,1H,J=2.5Hz), 4.32 (d,1H,J=8Hz), 4.35 (dd,1H,J=7Hz,10Hz), 4.51,4.68 (each d, total 2H, J=12Hz), 4.96-5.00 (m,2H), 5.60-5.63 (m,2H),7.48 (t,2H,J=8Hz), 7.61 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３３８】
工程４：10-デアセチル-7-Ｏ-メチル-13-Ｏ-トリエチルシリルバッカチン III
上記工程３で得た化合物を実施例９の工程６と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３３９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.63-0.73 (m,6H), 1.02 (t,9H,J=7Hz), 1.09 (s,3H), 1.16 (s,3H),1.76 (s,3H), 1.73-1.81 (m,1H), 2.06 (d,3H,J=1Hz), 2.10-2.24 (m,2H), 2.30 (s,3H), 2.67-2.75 (m,1H), 3.26 (s,3H), 3.87-3.92 (m,2H), 4.16 (d,1H,J=8Hz), 4.28 (d,1H,J=2Hz), 4.31 (d,1H,J=8Hz),4.94-5.02 (m,2H), 5.18 (d,1H,J=2Hz), 5.60 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz), 8.08 (d,2H,J=8Hz).
【０３４０】
工程５：10-デアセチル-7-Ｏ-メチル-10-Ｏ-(メチルチオ) チオカルボニル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程４で得た化合物を実施例６の工程１と同様に反応させ標記化合物を淡黄色の非晶質固体として得た。
【０３４１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.64-0.71 (m,6H), 1.02 (t,9H,J=7Hz), 1.17 (s,3H), 1.24 (s,3H),1.72 (s,3H), 1.71-1.78 (m,1H), 2.15 (d,3H,J=1Hz), 2.13-2.25 (m,2H), 2.30 (s,3H), 2.64 (s,3H), 2.71-2.79 (m,1H), 3.29 (s,3H),3.85 (d,1H,J=7Hz), 3.96 (dd,1H,J=7Hz,10Hz), 4.14 (d,1H,J=8Hz),4.31 (d,1H,J=8Hz), 4.96 (t,1H,J=8Hz), 5.00 (d,1H,J=8Hz),5.66 (d,1H,J=7Hz), 7.48 (t,2H,J=8Hz), 7.50 (s,1H), 7.61 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３４２】
工程６：10-デアセトキシ-10-(2-ホルミルエチル)-7-Ｏ-メチル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程５で得た化合物を実施例６の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３４３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.60-0.72 (m,6H), 1.02 (t,9H,J=7Hz), 1.10 (s,3H), 1.11 (s,3H),1.64 (s,3H), 1.70-2.73 (m,8H), 1.97 (d,3H,J=1Hz), 2.29 (s,3H),3.24 (s,3H), 3.77-3.80 (m,1H), 3.95 (d,1H,J=7Hz), 4.00 (dd,1H,J=7Hz,10Hz), 4.16 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz),4.90 (t,1H,J=8Hz), 5.01 (d,1H,J=8Hz), 5.58 (d,1H,J=7Hz),7.47 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz), 8.08 (d,2H,J=8Hz), 9.80 (s,1H).
【０３４４】
工程７：10-デアセトキシ-10-(3-ヒドロキシプロピル)-7-Ｏ-メチル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程６で得た化合物を実施例６の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３４５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.62-0.70 (m,6H), 1.02 (t,9H,J=7Hz), 1.09 (s,3H), 1.11 (s,3H),1.65 (s,3H), 1.50-2.74 (m,8H), 1.94 (d,3H,J=1Hz), 2.30 (s,3H),3.26 (s,3H), 3.67-3.73 (m,3H), 4.00-4.05 (m,2H), 4.16 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.90 (t,1H,J=8Hz), 5.02 (d,1H,J=8Hz),5.58 (d,1H,J=7Hz), 7.47 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz),8.09 (d,2H,J=8Hz).
【０３４６】
工程８：10-デアセトキシ-7-Ｏ-メチル-10-[3-(2-ニトロフェニルゼレノ) プロピル]-13-Ｏ-トリエチルシリルバッカチンIII
上記工程７で得た化合物を実施例６の工程４と同様に反応させ標記化合物を黄色の非晶質固体として得た。
【０３４７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.64-0.70 (m,6H), 1.02 (t,9H,J=7Hz), 1.09 (s,6H), 1.65 (s,3H),1.53-3.08 (m,10H), 1.91 (d,3H,J=1Hz), 2.29 (s,3H), 3.20 (s,3H), 3.70 (dd,1H,J=5Hz,7Hz), 3.97 (d,1H,J=7Hz), 4.00 (dd,1H,J=7Hz,10Hz), 4.16 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.89 (t,1H,J=8Hz),5.01 (d,1H,J=8Hz), 5.58 (d,1H,J=7Hz), 7.41-7.62 (m,6H), 8.09 (d,2H,J=8Hz), 8.28 (d,1H,J=8Hz).
【０３４８】
工程９：10-アリル-10-デアセトキシ-7-Ｏ-メチル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程８で得た化合物を実施例６の工程５と同様に反応させ標記化合物を淡黄色の非晶質固体として得た。
【０３４９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.62-0.72 (m,6H), 1.02 (t,9H,J=7Hz), 1.11 (s,3H), 1.12 (s,3H),1.65 (s,3H), 1.71-1.78 (m,1H), 1.92 (s,3H), 2.04-2.26 (m,3H),2.29 (s,3H), 2.65-2.72 (m,1H), 2.94-3.00 (m,1H), 3.25 (s,3H),3.80 (t,1H,J=7Hz), 3.97-4.01 (m,2H), 4.16 (d,1H,J=8Hz),4.30 (d,1H,J=8Hz), 4.91 (t,1H,J=8Hz), 4.97-5.11 (m,3H),5.59 (d,1H,J=7Hz), 5.78-5.89 (m,1H), 7.47 (t,2H,J=8Hz),7.60 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３５０】
工程１０：10-アリル-10-デアセトキシ-7-Ｏ-メチルバッカチンIII
上記工程９で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３５１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.06 (s,3H), 1.11 (s,3H), 1.66 (s,3H), 1.73-1.80 (m,1H), 1.97 (s,3H), 2.24-2.33 (m,3H), 2.29 (s,3H), 2.66-2.74 (m,1H), 2.94-3.01 (m,1H),3.26 (s,3H), 3.83 (t,1H,J=7Hz), 3.99 (dd,1H,J=7Hz,10Hz),4.06 (d,1H,J=7Hz), 4.17 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.84 (m,1H), 4.99-5.12 (m,3H), 5.59 (d,1H,J=7Hz), 5.78-5.89 (m,1H),7.47 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３５２】
工程１１：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3-フェニル-2-(トリメチルシリル) オキシプロピオニル ]-10-デアセトキシ-7-Ｏ-メチルバッカチンIII
上記工程１０で得た化合物および参考例１の工程２で得た化合物を実施例１０の工程５と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３５３】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.10 (s,9H), 1.15 (s,3H), 1.17 (s,9H), 1.28 (s,3H), 1.39 (s,3H),1.70 (s,3H), 1.79 (s,3H), 1.76-1.86 (m,1H), 2.06-2.10 (m,1H), 2.20-2.37 (m,2H), 2.65-2.71 (m,1H), 2.70 (s,3H), 2.97-3.04 (m,1H),3.25 (s,3H), 3.76 (t,1H,J=7Hz), 3.93-3.98 (m,2H), 4.21 (d,1H,J=8Hz),4.31 (d,1H,J=8Hz), 4.98-5.12 (m,4H), 5.49 (d,1H,J=10Hz),5.65 (d,1H,J=7Hz), 5.80-5.90 (m,1H), 6.37 (t,1H,J=8Hz), 7.25-7.37 (m,5H), 7.48 (t,2H,J=8Hz), 7.56 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
【０３５４】
工程１２：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-7-Ｏ-メチルバッカチンIII
上記工程１１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３５５】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.16 (s,3H), 1.23 (s,9H), 1.26 (s,3H), 1.37 (s,3H), 1.69 (s,3H),1.72 (s,3H), 1.76-1.86 (m,1H), 2.15-2.34 (m,3H), 2.62 (s,3H), 2.65-2.73 (m,1H), 2.94-3.010 (m,1H), 3.25 (s,3H), 3.62 (s,3H),3.77 (t,1H,J=7Hz), 3.93 (dd,1H,J=7Hz,10Hz), 3.98 (d,1H,J=7Hz),4.21 (d,1H,J=8Hz), 4.32 (d,1H,J=8Hz), 4.99-5.11 (m,4H), 5.55 (d,1H,J=10Hz), 5.65 (d,1H,J=7Hz), 5.76-5.86 (m,1H),6.31 (t,1H,J=8Hz), 7.32-7.37 (m,5H), 7.48 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３５６】
工程１３：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程１２で得た化合物を実施例１の工程１０と同様に反応させ標記化合物（実施例１０の工程６で得た化合物）を無色の固体として得た。
【０３５７】
実施例１２
【０３５８】
【化５２】
工程１：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(p-フルオロフェニル)-2-メチル-2-(トリメチルシリル) オキシプロピオニル]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
実施例１０の工程４で得た化合物および参考例２の工程２で得た化合物を実施例１０の工程５と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３６０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.12 (s,9H), 1.14 (s,3H), 1.19 (s,9H), 1.27 (s,3H), 1.39 (s,3H),1.69 (s,3H), 1.88 (s,3H), 2.68 (s,3H), 1.85-2.75 (m,12H), 3.26 (s,3H),3.68 (m,4H), 3.95-4.00 (m,3H), 4.21 (d,1H,J=8Hz), 4.32 (d,1H,J=8Hz),4.97 (d,1H,J=10Hz), 5.02 (d,1H,J=8Hz), 5.44 (d,1H,J=10Hz),5.66 (d,1H,J=7Hz), 6.34 (t,1H,J=8Hz), 7.05 (t,2H,J=8Hz),7.26 (t,2H,J=8Hz), 7.49 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz),8.13 (d,2H,J=8Hz).
【０３６１】
工程２：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(p-フルオロフェニル)-2-ヒドロキシ-2-メチルプロピオニル ]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０３６２】
融点：147-150 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,3H), 1.22 (s,9H), 1.23 (s,3H), 1.38 (s,3H), 1.68 (s,3H),1.81 (s,3H), 2.62 (s,3H), 1.73-2.76 (m,12H), 3.26 (s,3H), 3.68 (m,4H),3.94-4.01 (m,3H), 4.20 (d,1H,J=8Hz), 4.32 (d,1H,J=8Hz), 4.99-5.04 (m,2H), 5.49 (d,1H,J=10Hz), 5.65 (d,1H,J=7Hz),6.30 (t,1H,J=8Hz), 7.06 (t,2H,J=8Hz), 7.36 (t,2H,J=8Hz),7.49 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.13 (d,2H,J=8Hz).
MS-FAB：951 (MH+)
【０３６３】
実施例１３
【０３６４】
【化５３】
工程１：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル) オキシ-3-(2-フリル) プロピオニル ]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
実施例１０の工程４で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-3-(tert-ブチルジメチルシリル) オキシ-4-(2-フリル)-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３６６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.15 (s,3H), 0.02 (s,3H), 0.80 (s,9H), 1.13 (s,3H), 1.18 (s,3H), 1.36 (s,9H), 1.68 (s,3H), 1.91 (s,3H), 2.50 (s,3H), 1.78-2.77 (m,12H),3.27 (s,3H), 3.68 (m,4H), 3.93-4.04 (m,3H), 4.20 (d,1H,J=8Hz),4.31 (d,1H,J=8Hz), 4.74 (s,1H), 5.01 (d,1H,J=9Hz), 5.26 (d,1H,J=10Hz),5.36 (d,1H,J=10Hz), 5.65 (d,1H,J=7Hz), 6.19 (t,1H,J=8Hz), 6.24 (s,1H),6.35 (s,1H), 7.38 (s,1H), 7.48 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz), 8.11 (d,2H,J=8Hz).
【０３６７】
工程２：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０３６８】
融点：138-142 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,3H), 1.18 (s,3H), 1.36 (s,9H), 1.67 (s,3H), 1.90 (d,3H,J=1Hz),2.41 (s,3H), 1.75-2.76 (m,12H), 3.26 (s,3H), 3.68 (m,4H), 3.95-4.02 (m,3H), 4.18 (d,1H,J=8Hz), 4.31 (d,1H,J=8Hz), 4.70 (d,1H,J=2.5Hz), 4.99 (d,1H,J=8Hz), 5.25 (d,1H,J=10Hz), 5.35 (d,1H,J=10Hz), 5.64 (d,1H,J=7Hz), 6.18 (t,1H,J=8Hz), 6.32 (d,1H,J=3.5Hz), 6.38 (dd,1H,J=2Hz,3.5Hz), 7.42 (d,1H,J=1Hz), 7.49 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz), 8.11 (d,2H,J=8Hz).
MS-FAB：909 (MH+)
【０３６９】
実施例１４
【０３７０】
【化５４】
工程１：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル) オキシ-3-フェニルプロピオニル]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
実施例１０の工程４で得た化合物を実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３７２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.12 (s,3H), 0.09 (s,3H), 0.75 (s,9H), 1.13 (s,3H), 1.21 (s,3H), 1.32 (s,9H), 1.68 (s,3H), 1.89 (s,3H), 2.56 (s,3H), 1.73-2.78 (m,12H),3.27 (s,3H), 3.69 (m,4H), 3.93-4.04 (m,3H), 4.20 (d,1H,J=8Hz),4.32 (d,1H,J=8Hz), 4.52 (s,1H), 5.02 (d,1H,J=8Hz), 5.28 (d,1H,J=10Hz),5.43 (d,1H,J=10Hz), 5.65 (d,1H,J=7Hz), 6.24 (t,1H,J=8Hz), 7.27-7.39 (m,5H), 7.48 (t,2H,J=8Hz), 7.59 (t,1H,J=8Hz), 8.11 (d,2H,J=8Hz).
【０３７３】
工程２：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル]-10-デアセトキシ-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の固体として得た。
【０３７４】
融点：151-155 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,3H), 1.19 (s,3H), 1.35 (s,9H), 1.67 (s,3H), 1.85 (d,3H,J=1Hz),2.37 (s,3H), 1.73-2.75 (m,12H), 3.25 (s,3H), 3.68 (m,4H), 3.93-4.01 (m,3H), 4.18 (d,1H,J=8Hz), 4.30 (d,1H,J=8Hz), 4.61 (s,1H), 4.99 (d,1H,J=8Hz), 5.27 (d,1H,J=10Hz), 5.42 (d,1H,J=10Hz), 5.63 (d,1H,J=7Hz), 6.16 (t,1H,J=8Hz), 7.29-7.42 (m,5H), 7.49 (t,2H,J=8Hz), 7.60 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
MS-FAB：919 (MH+)
【０３７５】
実施例１５
【０３７６】
【化５５】
工程１：10-アリル-10-デアセトキシ-1-Ｏ-ジメチルシリル-7-Ｏ-メチル-13-Ｏ-トリエチルシリルバッカチンIII
実施例１１の工程９で得た化合物を実施例２の工程１と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３７８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (d,3H,J=3Hz), 0.06 (d,3H,J=3Hz), 0.62-0.74 (m,6H),1.04 (t,9H,J=7Hz), 1.08 (s,3H), 1.11 (s,3H), 1.65 (s,3H), 1.71-1.78 (m,1H), 1.92 (s,3H), 2.19-2.39 (m,3H), 2.29 (s,3H), 2.63-2.70 (m,1H), 2.95-3.01 (m,1H), 3.24 (s,3H), 3.77 (t,1H,J=7Hz), 3.93-3.98 (m,2H), 4.24 (s,2H), 4.53 (t,1H,J=3Hz), 4.92-5.10 (m,4H), 5.67 (d,1H,J=7Hz), 5.79-5.90 (m,1H), 7.46 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３７９】
工程２：10-アリル-10-デアセトキシ-4-デアセチル-1-Ｏ-ジメチルシリル-7-Ｏ-メチル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程１で得た化合物を実施例２の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３８０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (d,3H,J=3Hz), 0.02 (d,3H,J=3Hz), 0.76-0.83 (m,6H), 0.97 (s,3H), 1.10 (t,9H,J=7Hz), 1.12 (s,3H), 1.55 (s,3H), 1.76-1.86 (m,1H),1.92 (s,3H), 2.34-2.42 (m,1H), 2.51-2.64 (m,2H),2.79 (dd,1H,J=2.5Hz,15Hz), 2.93-2.98 (m,1H), 3.23 (s,3H), 3.52 (dd,1H,J=5Hz,12Hz), 3.66 (s,1H), 3.73 (d,1H,J=5.5Hz),3.83 (t,1H,J=7Hz), 4.21 (d,1H,J=8Hz), 4.31 (d,1H,J=8Hz),4.57 (t,1H,J=3Hz), 4.69 (d,1H,J=9Hz), 4.74 (dd,1H,J=4.5Hz,10Hz),5.00 (d,1H,J=8Hz), 5.10 (d,1H,J=17Hz), 5.55 (d,1H,J=7Hz), 5.76-5.87 (m,1H), 7.43 (t,2H,J=8Hz), 7.55 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz).
【０３８１】
工程３：10-アリル-10-デアセトキシ-4-デアセチル-1-Ｏ-ジメチルシリル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチル-13-Ｏ-トリエチルシリルバッカチンIII
上記工程２で得た化合物を実施例９の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３８２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (d,3H,J=3Hz), 0.06 (d,3H,J=3Hz), 0.65-0.73 (m,6H),1.03 (t,9H,J=7Hz),1.11 (s,6H), 1.41 (t,3H,J=7Hz), 1.65 (s,3H), 1.70-1.80 (m,1H),1.93 (s,3H), 2.19-2.30 (m,3H), 2.62-2.70 (m,1H), 2.94-3.01 (m,1H),3.25 (s,3H), 3.76 (t,1H,J=7Hz), 3.93 (dd,1H,J=7Hz,10Hz),4.00 (d,1H,J=7Hz), 4.10-4.23 (m,1H), 4.19 (s,2H), 4.39-4.47 (m,1H), 4.55 (t,1H,J=3Hz), 4.95-5.10 (m,4H), 5.69 (d,1H,J=7Hz), 5.80-5.91 (m,1H), 7.46 (t,2H,J=8Hz), 7.56 (t,1H,J=8Hz), 8.10 (d,2H,J=8Hz).
【０３８３】
工程４：10-アリル-10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチルバッカチンIII
上記工程３で得た化合物を実施例２の工程４と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３８４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.05 (s,3H), 1.11 (s,3H), 1.39 (t,3H,J=7Hz), 1.65 (s,3H), 1.73-1.79 (m,1H), 1.99 (s,3H), 2.20-2.33 (m,3H), 2.67-2.74 (m,1H),2.94-3.01 (m,1H), 3.26 (s,3H), 3.84 (t,1H,J=7Hz), 3.97 (dd,1H,J=7Hz,10Hz), 4.09 (d,1H,J=7Hz), 4.15 (d,1H,J=8Hz),4.16-4.20 (m,1H), 4.22-4.26 (m,2H), 4.82 (t,1H,J=8Hz),4.98-5.13 (m,3H), 5.60 (d,1H,J=7Hz), 5.79-5.89 (m,1H),7.47 (t,2H,J=8Hz), 7.58 (t,1H,J=8Hz), 8.11 (d,2H,J=8Hz).
【０３８５】
工程５：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3-フェニル-2-(トリメチルシリル) オキシプロピオニル]-10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチルバッカチンIII
上記工程４で得た化合物および参考例１の工程２で得た化合物を実施例１０の工程５と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３８６】
1H-NMR (CDCl3/TMS) δ(ppm):
0.06 (s,9H), 1.15 (s,3H), 1.25 (s,3H), 1.26 (s,9H), 1.41 (t,3H,J=7Hz),1.45 (s,3H), 1.70 (s,3H), 1.84 (s,3H), 1.81-1.87 (m,1H),2.08-2.15 (m,1H), 2.26-2.31 (m,1H), 2.38-2.44 (m,1H), 2.67-2.74 (m,1H), 2.97-3.02 (m,1H), 3.25 (s,3H), 3.81 (t,1H,J=7Hz), 3.93 (dd,1H,J=7Hz,10Hz), 4.16 (d,1H,J=7Hz), 4.30 (s,2H),4.65-4.77 (m,2H), 5.00-5.16 (m,4H), 5.53 (d,1H,J=10Hz), 5.67 (d,1H,J=7Hz), 5.79-5.90 (m,1H), 6.30 (t,1H,J=8Hz), 7.30-7.45 (m,7H), 7.56 (t,1H,J=8Hz), 8.12 (d,2H,J=8Hz).
【０３８７】
工程６：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-4- Ｏ-エトキシカルボニル-7-Ｏ-メチルバッカチンIII
上記工程５で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０３８８】
1H-NMR (CDCl3/TMS) δ(ppm):
1.16 (s,3H), 1.22 (s,3H), 1.32 (s,9H), 1.40 (s,3H), 1.42 (t,3H,J=7Hz),1.69 (s,3H), 1.74 (s,3H), 1.78-1.85 (m,1H), 2.20-2.37 (m,3H), 2.66-2.73 (m,1H), 2.94-3.01 (m,1H), 3.25 (s,3H), 3.62 (s,3H), 3.80 (t,1H,J=7Hz), 3.89 (dd,1H,J=7Hz,10Hz), 4.07 (d,1H,J=7Hz),4.24 (d,1H,J=8Hz), 4.34 (d,1H,J=8Hz), 4.52-4.65 (m,2H), 5.00-5.15 (m,4H), 5.66-5.70 (m,2H), 5.76-5.86 (m,1H), 6.21 (t,1H,J=8Hz), 7.30-7.46 (m,7H), 7.58 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３８９】
工程７：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル ]-10-デアセトキシ-4-デアセチル-10-(2,3-ジヒドロキシプロピル)-4-Ｏ-エトキシカルボニル-7-Ｏ-メチルバッカチン III
上記工程６で得た化合物 98 mgをテトラヒドロフラン：アセトン：水＝１：１：１(v/v/v) 12 ml に溶解しN-メチルモルホリン-N- オキシド 65 mgおよび四酸化オスミウム 10 mgを加え１時間攪拌した。反応液を酢酸エチルで希釈し飽和亜硫酸ナトリウム水溶液、飽和塩化アンモニウム水溶液、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；クロロホルム：メタノール＝１０：１(v/v) ）で精製し標記化合物81.5 mg を無色の非晶質固体として得た。
【０３９０】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.11, 1.13 (each s,total 3H), 1.20, 1.21 (each s,total 3H), 1.31 (s,9H), 1.41 (s,3H), 1.42 (t,3H,J=7Hz), 1.69,1.70 (each s,total 3H), 1.83, 1.87 (each s,total 3H), 1.81-2.73 (m,6H), 3.28, 3.29 (each s,total 3H), 3.46-3.76 (m,3H), 3.88-3.95 (m,1H), 4.11-4.18 (m,2H), 4.24 (d,1H,J=8Hz),4.34 (d,1H,J=8Hz), 4.52-4.65 (m,2H), 5.04 (d,1H,J=9Hz), 5.14 (d,1H,J=10Hz), 5.66-5.68 (m,2H), 6.19 (m,1H), 7.32-7.47 (m,7H),7.58 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
【０３９１】
工程８：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチル-10-(2-モルホリノエチル) バッカチンIII
上記工程７で得た化合物 40 mgをテトラヒドロフラン：メタノール＝１：１(v/v) 4 mlに溶解し氷冷下、メタ過よう素酸ナトリウム 92.5 mg を水 2 ml に溶かした溶液を滴下し室温で２時間攪拌した。水を加え酢酸エチルで抽出後、水、飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をエタノール 4 ml に溶解し酢酸 0.024 ml およびモルホリン 0.037 ml を加え、さらにシアン化ホウ素ナトリウム 26 mgを添加し１５分攪拌した。飽和重曹水溶液を加え酢酸エチルで抽出後、飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲル薄相クロマトグラフィー（展開溶媒；クロロホルム：メタノール＝１５：１(v/v) ）で精製後、1,4-ジオキサンより凍結乾燥し標記化合物 36.7 mgを無色の固体として得た。
【０３９２】
融点：150-152 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.15 (s,3H), 1.20 (s,3H), 1.32 (s,9H), 1.41-1.44 (m,6H), 1.69 (s,3H), 1.82 (s,3H), 1.80-2.76 (m,12H), 3.25 (s,3H), 3.60 (s,1H), 3.66-3.68 (m,4H), 3.91 (dd,1H,J=7Hz,10Hz), 4.00 (t,1H,J=6Hz), 4.09 (d,1H,J=7Hz), 4.24 (d,1H,J=8Hz), 4.34 (d,1H,J=8Hz),4.54-4.62 (m,2H), 5.04 (d,1H,J=9Hz), 5.14 (d,1H,J=10Hz),5.60-5.70 (m,2H), 6.19 (t,1H,J=8Hz), 7.29-7.46 (m,7H),7.58 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
MS-FAB：963 (MH+)
【０３９３】
実施例１６
【０３９４】
【化５６】
13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチル-10-[2-(4-メチルピペラジニル) エチル] バッカチンIII
実施例１５の工程７で得た化合物を実施例１５の工程８と同様に、モルホリンの代わりにN-メチルピペラジンを用い反応させ標記化合物を無色の固体として得た。
【０３９６】
融点：143-147 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.15 (s,3H), 1.19 (s,3H), 1.32 (s,9H), 1.41-1.45 (m,6H), 1.69 (s,3H), 1.81 (s,3H), 1.79-2.72 (m,16H), 2.27 (s,3H), 3.26 (s,3H), 3.60 (br,1H), 3.90 (dd,1H,J=7Hz,10Hz), 4.00 (t,1H,J=6Hz), 4.09 (d,1H,J=7Hz), 4.24 (d,1H,J=8Hz), 4.34 (d,1H,J=8Hz),4.53-4.60 (m,2H), 5.04 (d,1H,J=9Hz), 5.14 (d,1H,J=10Hz),5.66 (d,1H,J=7Hz), 5.69 (d,1H,J=10Hz), 6.18 (t,1H,J=8Hz), 7.31-7.46 (m,7H), 7.58 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
MS-FAB：976 (MH+)
【０３９７】
実施例１７
【０３９８】
【化５７】
13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-4-Ｏ-エトキシカルボニル-7-Ｏ-メチル-10-(2-ピペリジノエチル) バッカチンIII
実施例１５の工程７で得た化合物を実施例１５の工程８と同様に、モルホリンの代わりにピペリジンを用い反応させ標記化合物を無色の固体として得た。
【０４００】
融点：130-134 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,3H), 1.20 (s,3H), 1.32 (s,9H), 1.68 (s,3H), 1.80 (s,3H),1.41-2.75 (m,24H), 3.27 (s,3H), 3.60 (br,1H), 3.89 (dd,1H,J=7Hz,10Hz),3.98 (m,1H), 4.08 (d,1H,J=7Hz), 4.24 (d,1H,J=8Hz), 4.34 (d,1H,J=8Hz), 4.55-4.60 (m,2H), 5.04 (d,1H,J=9Hz), 5.13 (d,1H,J=10Hz),5.66 (d,1H,J=7Hz), 5.71 (d,1H,J=10Hz), 6.18 (t,1H,J=8Hz), 7.29-7.46 (m,7H), 7.58 (t,1H,J=8Hz), 8.09 (d,2H,J=8Hz).
MS-FAB：961 (MH+)
【０４０１】
実施例１８
【０４０２】
【化５８】
工程１：10-アリル-10-デアセトキシ-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル) バッカチンIII
10-アリル-10-デアセトキシ-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-O-トリエチルシリルバッカチンIII を実施例１の工程１と同様に反応させて、標記化合物を無色の結晶として得た。
【０４０４】
融点：195 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,6H), 1.63 (s,3H), 1.82 (m,1H), 1.87 (s,3H), 2.35-2.40 (m,4H), 2.38 (s,3H), 2.59 (m,1H), 2.95 (m,1H), 3.94 (t,1H,J=8Hz), 4.10 (d,1H,J=7.0Hz), 4.18 (d,1H,J=8.0Hz), 4.32 (d,1H,J=8.0Hz),4.39 (m,1H), 4.35 (AB type d,2H,J=12Hz), 4.96 (d,1H,J=8.0Hz), 5.02 (d,1H,J=9.9Hz), 5.13 (d,1H,J=17Hz), 5.68 (d,1H,J=7.0Hz), 5.78 (m,1H), 5.94 (m,1H), 7.49 (t,2H,J=7.5Hz), 7.62 (t,1H,J=7.5Hz), 8.09 (d,2H,J=7.5Hz).
MS-FAB : 744 (MH+)
IR (KBr)：3484, 3160, 3070, 2956, 2902, 2452, 2260, 1969, 1764, 1731, 1713, 1644 cm-1
【０４０５】
工程２：10-アリル-10-デアセトキシ-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-Ｏ-トリフルオロメタンスルホニルバッカチンIII
上記工程１で得た化合物を実施例１の工程５と同様に反応させ標記化合物を無色の非晶質固体無色として得た。
【０４０６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.15 (s,3H), 1.16 (s,3H), 1.80 (s,3H), 1.90 (d,3H,J=1Hz), 1.91 (m,1H),2.22 (m,1H), 2.38 (m,1H), 2.40 (s,3H), 2.52 (m,1H), 2.80-2.90 (m,2H), 4.18 (m,3H), 4.35 (d,1H,J=8.0Hz), 4.85 (AB type d,2H,J=12Hz), 4.93 (d,1H,J=8.0Hz), 5.05 (dd,1H,J=2.0Hz,12Hz), 5.13 (dd,1H,J=2.0Hz,17Hz), 5.60 (dd,1H,J=7.0Hz,11Hz), 5.68 (d,1H,J=7.0Hz), 5.73 (m,1H), 5.96 (t,1H,J=7.0Hz),7.49 (t,2H,J=7.5Hz), 7.63 (m,1H), 8.07 (m,2H).
MS-FAB：875 (MH+)
【０４０７】
工程３：10-アリル-10-デアセトキシ-7-デオキシ-7β,8β-メチレン-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-19-ノルバッカチンIII
上記工程２で得た化合物 20 mgを6 ml のジクロロメタンと 5 ml のアセトニトリルの混合溶媒に溶解し、シリカゲル（メッシュ40-63 mm）を大過剰加えて 80 ℃で1.5 時間攪拌した。シリカゲルを濾去し、濾液を濃縮後、得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；塩化メチレン：ヘキサン：アセトン＝７０：３０：３(v/v/v) ）により精製し、標記化合物13.2 mg を無色の非晶質固体として得た。
【０４０８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,3H), 1.19 (s,3H), 1.53 (t,1H,J=6.0Hz), 1.82 (s,3H), 1.90 (br,1H), 2.10 (d,1H,J=17Hz), 2.22 (m,2H), 2.34 (s,3H), 2.40 (m,2H), 2.46 (m,1H), 3.00 (m,1H), 3.71 (d,1H,J=7.0Hz), 4.02 (d,1H,J=8.0Hz), 4.29 (d,1H,J=8.0Hz), 4.33 (d,1H,J=7.0Hz),4.74 (d,1H,J=1.0Hz), 4.84 (AB type d,2H,J=12Hz), 5.01 (d,1H,J=10.0Hz),5.10 (d,1H,J=17Hz), 5.61 (d,1H,J=7.0Hz), 5.81 (m,1H), 5.88 (m,1H),7.49 (t,2H,J=7.5Hz), 7.61 (t,1H,J=7.5Hz), 8.10 (d,2H,J=7.5Hz).
MS-FAB：725 (MH+)
【０４０９】
工程４: 10-アリル-10-デアセトキシ-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
上記工程３で得た化合物 13 mgを 3 mlの酢酸と 3 mlのメタノールの混合溶媒に溶解し、亜鉛粉末 100 mg を加えて 60 ℃で 10分間攪拌した。亜鉛を濾去し、濾液を濃縮後、得られた残分を酢酸エチルで希釈し飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を減圧留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；クロロホルム：アセトン＝９５：５(v/v) ）により精製し、標記化合物7 mgを無色の非晶質固体として得た。
【０４１０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.17 (s,3H), 1.26 (m,1H), 1.53 (m,1H), 1.88 (d,1H,J=1.0Hz), 1.94 (br,1H), 2.09 (d,1H,J=16Hz), 2.22 (m,1H), 2.26 (m,2H), 2.27 (s,3H), 2.36 (dd,1H,J=7.0Hz,16Hz),2.43 (dt,1H,J=4.5Hz,16Hz), 3.00 (m,1H), 3.71 (dd,1H,J=6.0Hz,8.0Hz), 4.02 (d,1H,J=8.0Hz), 4.30 (d,1H,J=8.0Hz), 4.36 (d,1H,J=7.0Hz),4.72 (d,1H,J=4.0Hz), 4.82 (m,1H), 5.01 (d,1H,J=10.0Hz), 5.10 (dd,1H,J=1.5Hz,17Hz), 5.60 (d,1H,J=7.0Hz), 5.82 (m,1H),7.49 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.11 (d,2H,J=7.5Hz).
MS-FAB：550 (MH+)
【０４１１】
工程５：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル )オキシ-3-フェニルプロピオニル ]-10-デアセトキシ-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
上記工程４で得た化合物を実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０４１２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.35 (s,3H), -0.12 (s,3H), 0.71 (s,9H), 1.21 (s,3H), 1.22 (s,9H),1.24 (s,3H), 1.55 (m,1H), 1.71 (s,3H), 1.83 (br,1H),2.10-2.21 (m,4H), 2.43 (m,3H), 2.50 (s,3H), 2.99 (m,1H), 3.68(t,1H,J=7.0Hz),4.03(d,1H,J=8.0Hz), 4.26(d,1H,J=7.0Hz), 4.29(d,1H,J=8.0Hz), 4.47 (s,1H), 4.78 (d,1H,J=4.0Hz), 5.03 (d,1H,J=8.0Hz),5.10 (d,1H,J=17Hz), 5.30 (m,1H), 5.42 (m,1H), 5.65 (d,1H,J=7.0Hz),5.82 (m,1H), 6.29 (m,1H), 7.25-7.36 (m,5H), 7.48 (t,2H,J=7.5Hz),7.56 (t,1H,J=7.5Hz), 8.14 (d,2H,J=7.5Hz).
MS-FAB：928 (MH+)
【０４１３】
工程６：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-フェニルプロピオニル]-10-デアセトキシ-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程５で得た化合物を実施例１の工程１０と同様に反応させて、 標記化合物を無色の非晶質固体として得た。
【０４１４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.33 (s,3H), -0.12 (s,3H), 0.74 (s,9H), 1.20 (s,3H), 1.22 (s,3H),1.25 (s,9H), 1.57 (m,1H), 1.80 (s,3H), 2.12 (m,2H), 2.20 (m,1H),2.35 (m,2H), 2.44 (m,6H), 2.52 (s,3H), 2.55 (m,1H), 3.70 (m,4H),3.75 (m,1H), 4.06 (d,1H,J=8.5Hz), 4.28 (d,1H,J=7.0Hz),4.31 (d,1H,J=7.0Hz), 4.50 (s,1H), 4.79 (d,1H,J=3.0Hz),5.32 (d,1H,J=10.0Hz), 4.43 (d,1H,J=10Hz), 5.68 (d,1H,J=7.0Hz),6.28 (t,1H,J=7.0Hz), 7.28-7.35 (m,5H), 7.48 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：1001 (MH+)
【０４１５】
工程７：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル]-10-デアセトキシ-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程６で得た化合物を実施例１の工程９と同様に反応させて、 標記化合物を無色の固体として得た。
【０４１６】
融点：120-125 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.20 (s,3H), 1.22 (s,3H), 1.27 (s,9H), 1.56 (t,1H,J=7.0Hz), 1.79 (s,3H), 1.88 (s,1H), 2.12 (m,1H), 2.20 (m,3H), 2.35-2.48 (m,12H),2.43 (m,6H), 2.55 (m,1H), 3.71 (m,4H), 3.75 (m,1H), 4.04 (d,1H,J=8.5Hz), 4.27 (d,1H,J=7.0Hz), 4.29 (d,1H,J=7.0Hz),4.60 (s,1H), 4.75 (d,1H,J=3.0Hz), 5.29 (m,1H), 5.35 (d,1H,J=10.0Hz),5.65 (d,1H,J=7.0Hz), 6.22 (m,1H), 7.30-7.44 (m,5H), 7.50 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.16 (d,2H,J=7.5Hz).
MS-FAB：887 (MH+)
IR (KBr)：3448, 3068, 2972, 2932, 2860, 2812, 1720, 1684, 1604, 1586, 1494 cm-1
【０４１７】
実施例１９
【０４１８】
【化５９】
工程１： 10-アリル-10-デアセトキシ-7-デオキシ-7β,8β-メチレン-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
実施例１の工程５で得た化合物 182 mg を 10 mlの乾燥したテトラヒドロフランと 10ml の乾燥したアセトニトリルの混合溶媒に溶解し、シリカゲル（メッシュ40-63 mm）を5.5 g 加えて55℃で 16時間攪拌した。シリカゲルを濾去し、濾液を濃縮後、得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；塩化メチレン：ヘキサン：アセトン＝７０：３０：３(v/v/v) ）により精製し、標記化合物 107 mg を無色の非晶質固体として得た。
【０４２０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.66 (m,6H), 1.01 (t,9H,J=8.0Hz), 1.13 (s,3H), 1.17 (s,3H), 1.52 (dd,1H,J=5.0Hz,7.0Hz), 1.83 (d,3H,J=1Hz), 2.08 (d,1H,J=16Hz),2.17 (m,3H), 2.26 (s,3H), 2.30 (m,1H), 2.45 (dt,1H,J=2Hz,6Hz),2.99 (m,1H), 3.70 (dd,1H,J=6.0Hz,8.0Hz), 4.05 (d,1H,J=8.5Hz), 4.26 (d,1H,J=8.0Hz), 4.29 (d,1H,J=8.5Hz), 4.76 (d,1H,J=4.0Hz),4.87 (t,1H,J=7Hz), 5.01 (d,1H,J=10.0Hz), 5.10 (dd,1H,J=1.5Hz,17Hz), 5.59 (d,1H,J=8.0Hz), 5.81 (m,1H), 7.47 (t,2H,J=7.5Hz),7.60 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：664 (MH+)
【０４２１】
工程２：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-1-Ｏ-ジメチルシリル-7β,8β-メチレン-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
上記工程１で得た化合物を実施例９の工程２と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４２２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.23 (d,3H,J=2.7Hz), 0.08 (d,3H,J=2.7Hz), 0.77 (m,6H), 1.06 (s,3H),1.07 (t,9H,J=8.0Hz), 1.18 (s,3H), 1.54 (t,1H,J=6.0Hz), 1.82 (s,3H), 2.05-2.18 (m,4H), 2.31 (m,1H), 2.55 (dd,1H,J=8.8Hz,15.0Hz), 2.68 (dd,1H,J=3.3Hz,15.0Hz), 2.99 (m,1H), 3.46 (s,1H),3.62 (dd,1H,J=5.7Hz,8.2Hz), 3.99 (d,1H,J=7.3Hz), 4.12 (d,1H,J=7.9Hz), 4.15 (d,1H,J=7.9Hz), 4.57 (m,1H), 4.68 (m,2H), 5.02 (d,1H,J=10.0Hz),5.12 (dd,1H,J=1.3Hz,17Hz), 5.76 (d,1H,J=7.3Hz), 5.82 (m,1H),7.45 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：681 (MH+)
【０４２３】
工程３：10-アリル-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-1-Ｏ-ジメチルシリル-7β,8β-メチレン-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
上記工程２で得た化合物を実施例２の工程３と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４２４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.24 (d,3H,J=2.7Hz), 0.11 (d,3H,J=2.7Hz), 0.68 (m,6H), 1.00 (m,9H),1.12 (s,3H), 1.19 (s,3H), 1.24 (m,4H), 1.51 (t,1H,J=7.0Hz), 1.61 (m,1H), 1.72 (m,1H), 1.80 (s,3H), 2.05 (m,1H), 2.16 (m,1H),2.31-2.40 (m,4H), 2.96 (m,1H), 3.62 (m,1H), 4.13 (d,1H,J=8.0Hz),4.19 (d,1H,J=8.0Hz), 4.21 (d,1H,J=8.0Hz), 4.54 (m,1H),4.62 (d,1H,J=3.8Hz), 4.98 (d,1H,J=10.0Hz), 5.08 (d,1H,J=17Hz),5.69 (d,1H,J=7.0Hz), 5.81 (m,1H), 7.46 (t,2H,J=7.5Hz),7.58 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：749 (MH+)
【０４２５】
工程４：10-アリル-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
上記工程３で得た化合物を実施例１の工程７と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４２６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.02 (m, 2H), 1.10 (s,3H), 1.17 (s,3H), 1.20-1.27 (m,2H), 1.53 (m,1H),1.65 (m,1H), 1.77 (m,1H), 1.85 (s,3H), 2.06 (d,1H,J=17.1Hz),2.19 (m,2H), 2.25-2.30 (m,2H), 2.39 (m,1H), 2.99 (m,1H),3.68 (dd,1H,J=6.3Hz,7.8Hz), 4.06 (d,1H,J=8.5Hz), 4.30 (d,1H,J=8.5Hz), 4.32 (d,1H,J=7.8Hz), 4.68 (d,1H,J=3.9Hz), 4.80 (br,1H), 4.00 (dd,1H,J=1.0Hz,9.8Hz), 5.09 (dd,1H,J=1.5Hz,17.1Hz),5.62 (d,1H,J=7.8Hz), 5.82 (m,1H), 7.48 (t,2H,J=7.5Hz),7.61 (t,1H,J=7.5Hz), 8.14 (m,2H).
MS-FAB：576 (MH+)
【０４２７】
工程５：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-（トリイソプロピルシリル)オキシプロピオニル]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
上記工程４で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-4-(2- フリル)-3-(トリイソプロピルシリル) オキシ-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０４２８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.00 (m,21H), 1.21 (s,3H), 1.24 (s,3H), 1.27 (s,9H), 1.10-1.30 (m,4H),1.52 (m,1H), 1.73 (s,3H), 1.79 (m,1H), 1.90 (m,1H), 2.08 (d,1H,J=17.1Hz), 2.19 (m,3H), 2.38 (dt,1H,J=4.4Hz,17.1Hz), 2.48 (dd,1H,J=9.6Hz,17.4Hz), 2.99 (m,1H), 3.69 (t,1H,J=6.9Hz),4.05 (d,1H,J=8.6Hz), 4.29 (m,2H), 4.62 (m,1H), 5.02 (m,2H), 5.10 (d,1H,J=17.1Hz), 5.23 (d,1H,J=10.0Hz), 5.35 (d,1H,J=10.0Hz), 5.68 (d,1H,J=7.8Hz), 5.83 (m,1H), 6.22 (m,2H), 6.34 (m,1H), 7.34 (s,1H), 7.49 (t,2H,J=7.5Hz), 7.56 (t,1H,J=7.5Hz),8.15 (d,2H,J=7.5Hz).
MS-FAB：986 (MH+)
【０４２９】
工程６： 13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-(トリイソプロピルシリル)オキシプロピオニル]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程５で得られた化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４３０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.95-1.00 (m,21H), 1.19 (s,3H), 1.22 (s,3H), 1.18-1.23 (m,4H),1.29 (s,9H), 1.47 (m,1H), 1.54 (m,1H), 1.84 (s,3H), 1.90 (m,1H),2.08 (d,1H,J=16.1Hz), 2.19 (m,2H), 2.33 (m,1H), 2.40 (m,1H),2.43 (m,4H), 2.48-2.53 (m,2H), 3.69 (m,4H), 3.74 (m,1H),4.07 (d,1H,J=8.8Hz), 4.29 (m,2H), 4.63 (m,1H), 5.02 (s,1H), 5.23 (d,1H,J=9.7Hz), 5.36 (d,1H,J=9.7Hz), 5.67 (d,1H,J=7.8Hz),6.20 (d,1H,J=8.5Hz), 6.24 (m,1H), 6.35 (m,1H), 7.33 (m,1H), 7.49 (t,2H,J=7.5Hz), 7.56 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：1059(MH+)
【０４３１】
工程７： 13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程６で得られた化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０４３２】
融点：120-125 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.02 (m,2H), 1.16 (m,2H), 1.20 (s,3H), 1.23 (s,3H), 1.28 (s,9H),1.47 (m,1H), 1.53 (m,1H), 1.80 (s,3H), 1.90 (m,1H), 2.04 (d,1H,J=13.1Hz), 2.20 (m,2H), 2.37 (m,2H), 2.75-2.42 (m,6H), 2.44 (m,4H), 3.70 (m,4H), 3.75 (m,1H), 4.79 (AB type d,2H,J=8.5Hz), 4.63 (d,1H,J=3.4Hz), 4.76 (m,1H), 5.15 (d,1H,J=9.7Hz),5.39 (d,1H,J=9.7Hz), 5.64 (d,1H,J=7.8Hz), 6.23 (t,1H,J=8.3Hz),6.30 (m,1H), 6.37 (m,1H), 7.39 (s,1H), 7.51 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.17 (d,2H,J=7.5Hz).
MS-FAB：903 (MH+)
【０４３３】
実施例２０
【０４３４】
【化６０】
工程１：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-フェニルプロピオニル]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
実施例１９の工程４で得た化合物を実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０４３６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (s,3H), -0.09 (s,3H), 0.74 (s,9H), 1.00 (m,2H), 1.09 (m,2H),1.21 (s,3H), 1.28 (s,9H), 1.29 (s,3H), 1.56 (m,1H), 1.71 (s,3H),1.82 (br,1H), 1.90 (m,1H), 2.10 (d,1H,J=15.9Hz), 2.14-2.24 (m,3H),2.39 (dt,1H,J=4.4Hz,15.9Hz), 2.50 (dd,1H,J=10.1Hz,15.1Hz),2.99 (m,1H), 3.68 (t,1H,J=6.9Hz), 4.08 (d,1H,J=8.5Hz), 4.54 (s,1H), 4.64 (d,1H,J=4.0Hz), 5.02 (d,1H,J=10.0Hz),5.08 (dd,1H,J=1.4Hz,17.1Hz), 5.30 (d,1H,J=8.8Hz), 5.43 (d,1H,J=8.8Hz),5.66 (d,1H,J=7.8Hz), 5.86 (m,1H), 6.25 (t,1H,J=8.3Hz),7.24-7.37 (m,5H), 7.50 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：954 (MH+)
【０４３７】
工程２： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル) オキシ-3-フェニルプロピオニル]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程１で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４３８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (s,3H), -0.09 (s,3H), 0.76 (s,9H), 1.02 (m,2H), 1.12 (m,2H), 1.21 (s,3H), 1.25 (s,3H), 1.31 (s,9H), 1.48 (m,1H),1.57 (t,1H,J=6.0Hz), 1.80 (s,3H), 1.91 (m,1H), 2.10 (d,1H,J=15.9Hz),2.18 (m,2H), 2.34 (m,2H), 2.42 (m,4H), 2.50 (m,4H), 3.70 (m,5H),4.08 (d,1H,J=8.5Hz), 4.26 (d,1H,J=7.7Hz), 4.30 (d,1H,J=8.5Hz),4.54 (s,1H), 4.67 (d,1H,J=3.6Hz), 5.31 (d,1H,J=9.0Hz),5.44 (d,1H,J=9.0Hz), 5.68 (d,1H,J=7.7Hz), 6.21 (t,1H,J=8.4Hz),7.24-7.37 (m,5H), 7.50 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：1026 (MH+)
【０４３９】
工程３： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル]-4-Ｏ-シクロプロパンカルボニル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2- モルホリノエチル)-19-ノルバッカチンIII
上記工程２で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０４４０】
融点：130-135 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.82 (m,2H), 0.92 (m,2H), 1.20 (s,3H), 1.24 (s,3H), 1.29 (s,9H),1.46 (m,1H), 1.54 (m,1H), 1.77 (s,3H), 1.82 (m,1H), 2.10 (m,1H),2.20-2.24 (m,2H), 2.33-2.48 (m,9H), 2.58 (m,1H), 3.70 (m,4H), 3.74 (m,1H), 4.05 (d,1H,J=8.5Hz), 4.26 (d,1H,J=7.7Hz),4.30 (d,1H,J=8.5Hz), 4.61 (d,1H,J=3.3Hz), 4.69 (br,1H), 5.29 (s,2H), 5.66 (d,1H,J=7.7Hz), 6.18 (m,1H), 7.30-7.39 (m,5H),7.52 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.17 (d,2H,J=7.5Hz).
MS-FAB：913 (MH+)
【０４４１】
実施例２１
【０４４２】
【化６１】
工程１：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル-1-Ｏ-ジメチルシリル-7β,8β-メチレン-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
実施例１９の工程２で得た化合物を実施例９の工程３と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４４４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.24 (d,3H,J=2.7Hz), 0.11 (d,3H,J=2.7Hz), 0.68 (m,6H), 1.02 (t,9H,J=8.0Hz), 1.12 (s,3H), 1.19 (s,3H), 1.24 (m,1H), 1.39 (t,3H,J=7.2Hz), 1.49 (dd,1H,J=5.3Hz,7.0Hz), 1.84 (s,3H), 2.09 (d,1H,J=15.9Hz), 2.16 (m,2H), 2.32 (m,2H), 2.38 (m,1H),2.99 (m,1H), 3.66 (dd,1H,J=6.6Hz,7.2Hz), 4.12 (m,2H), 4.24 (d,1H,J=8.6Hz), 4.28 (d,1H,J=7.7Hz), 4.38 (m,1H), 4.53 (m,1H), 4.73 (d,1H,J=4.2Hz), 4.93 (t,1H,J=8.1Hz), 4.99 (dd,1H,J=1.7Hz,10.1Hz),5.09 (dd,1H,J=1.7Hz,17.0Hz), 5.69 (d,1H,J=7.7Hz), 5.85 (m,1H),7.46 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.12 (m,2H).
MS-FAB：753 (MH+)
【０４４５】
工程２：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル-7β,8β-メチレン-19-ノルバッカチンIII
上記工程１で得た化合物を実施例２の工程４と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４４６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.99 (s,3H), 1.17 (s,3H), 1.37 (t,3H,J=7.5Hz), 1.51 (m,1H), 1.89 (d,3H,J=15.9Hz), 2.13 (d,1H,J=15.9Hz), 2.23 (m,2H),2.28 (d,1H,J=9.0Hz), 2.37 (dd,1H,J=6.9Hz,15.7Hz), 2.43 (dt,1H,J=4.5Hz,15.9Hz), 3.00 (m,1H), 3.72 (dd,1H,J=6.3Hz,7.6Hz), 4.05 (d,1H,J=8.6Hz), 4.21 (m,1H), 4.31 (m,2H), 4.42 (d,1H,J=7.6Hz), 4.80 (m,2H), 5.02 (d,1H,J=10.1Hz), 5.10 (dd,1H,J=1.6Hz,17.1Hz), 5.63 (d,1H,J=7.6Hz), 5.84 (m,1H), 7.49 (t,2H,J=7.5Hz),7.60 (t,1H,J=7.5Hz), 8.14 (m,2H).
MS-FAB：580 (MH+)
【０４４７】
工程３：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(te rt-ブチルジメチルシリル）オキシ-3-(2-フリル)プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル-7β,8β-メチレン-19-ノルバッカチンIII
上記工程２で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-4-(2- フリル)-3-(tert-ブチルジメチルシリル)オキシ -2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０４４８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.14 (s,3H), 0.04 (s,3H), 0.89 (s,9H), 1.21 (s,3H), 1.24 (s,3H), 1.29 (s,9H), 1.38 (t,1H,J=6.9Hz), 1.54 (m,1H), 1.74 (s,3H), 1.82 (br,1H), 2.14 (d,1H,J=15.9Hz), 2.10-2.25 (m,3H), 2.40 (m,1H),2.48 (m,1H), 2.99 (m,1H), 3.69 (t,1H,J=6.9Hz), 4.06 (d,1H,J=8.7Hz), 4.31 (m,3H), 4.52 (m,1H), 4.71 (m,1H), 4.78 (d,1H,J=4.0Hz), 5.02 (d,1H,J=10.0Hz), 5.12 (dd,1H,J=1.7Hz,17.1Hz),5.21 (d,1H,J=8.5Hz), 5.33 (d,1H,J=8.5Hz), 5.69 (d,1H,J=7.5Hz),5.82 (m,1H), 6.19 (m,1H), 6.23 (m,1H), 6.35 (m,1H), 7.38 (m,1H),7.50 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.16 (d,2H,J=7.5Hz).
MASS-FAB：948 (MH+)
【０４４９】
工程４：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-(2-フリル) プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程３で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４５０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.14 (s,3H), 0.04 (s,3H), 0.79 (s,9H), 1.21 (s,3H), 1.22 (s,3H), 1.31 (s,9H), 1.40 (t,3H,J=7.5Hz), 1.54 (m,1H), 1.73 (s,4H), 2.14 (d,1H,J=15.9Hz), 2.14 (m,1H), 2.20 (m,1H), 2.30-2.60 (m,8H), 3.69 (m,4H), 3.75 (t,1H,J=6.6Hz), 4.06 (d,1H,J=8.5Hz), 4.31 (m,3H), 4.54 (m,1H), 4.72 (m,1H), 4.78 (d,1H,J=4.0Hz), 5.21 (d,1H,J=10.0Hz),5.33 (d,1H,J=10.0Hz), 5.69 (d,1H,J=7.6Hz), 6.17 (t,1H,J=8.0Hz), 6.24 (m,1H), 6.36 (m,1H), 7.38 (m,1H), 7.50 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.16 (d,2H,J=7.5Hz).
MS-FAB：1021 (MH+)
【０４５１】
工程５： 13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程４で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０４５２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.21 (s,6H), 1.26 (m,3H), 1.33 (s,9H), 1.48 (m,1H), 1.53 (m,1H),1.82 (s,3H), 1.88 (s,1H), 2.14 (d,1H,J=15.9Hz), 2.16-2.22 (m,3H), 2.37-2.57 (m,9H), 3.70 (s,4H), 3.74 (m,1H), 4.06 (d,1H,J=8.5Hz),4.20 (m,1H), 4.31 (d,1H,J=7.6Hz), 4.34 (d,1H,J=8.5Hz), 4.46 (m,1H), 4.68 (d,1H,J=3.4Hz), 4.78 (s,1H), 5.21 (d,1H,J=9.7Hz),5.31 (d,1H,J=9.7Hz), 5.69 (d,1H,J=7.6Hz), 6.14 (t,1H,J=8.4Hz),6.35 (m,2H), 7.43 (s,1H), 7.50 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.16 (d,2H,J=7.5Hz).
MS-FAB：907 (MH+)
【０４５３】
実施例２２
【０４５４】
【化６２】
工程１：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-1-Ｏ-ジメチルシリル-4-Ｏ-メトキシアセチル-7β,8β-メチレン-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
実施例１９の工程２で得た化合物を実施例２の工程３の塩化シクロプロパンカルボニルを塩化メトキシアセチルに代えて同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４５６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.24 (d,3H,J=2.7Hz), 0.11 (d,3H,J=2.7Hz), 0.68 (m,6H), 1.02 (t,9H,J=8.0Hz), 1.10 (s,3H), 1.19 (s,3H), 1.22 (m,1H), 1.52 (m,1H), 1.80 (s,3H), 2.09 (d,1H,J=15.9Hz), 2.18 (m,2H),2.32 (m,2H), 2.46 (dt,1H,J=4.5Hz,16.0Hz), 2.99 (m,1H), 3.55 (s,3H), 3.66 (m,1H), 4.12 (m,2H), 4.16 (d,1H,J=16.1Hz), 4.17 (d,1H,J=8.5Hz),4.22 (d,1H,J=7.6Hz), 4.28 (d,1H,J=8.5Hz), 4.35 (d,1H,J=16.1Hz), 4.53 (m,1H), 4.79 (d,1H,J=3.7Hz), 4.92 (t,1H,J=8.1Hz),5.00 (d,1H,J=10.1Hz), 5.09 (d,1H,J=17.0Hz), 5.67 (d,1H,J=7.6Hz),5.83 (m,1H), 7.46 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.18 (m,2H).
MS-FAB：753 (MH+)
【０４５７】
工程２：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-メトキシアセチル-7β,8β-メチレン-19-ノルバッカチンIII
上記工程１で得た化合物を実施例２の工程４と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４５８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.17 (s,3H), 1.54 (m,1H), 1.87 (s,3H), 2.14 (m,2H),2.20-2.27 (m,3H), 2.32 (dd,1H,J=7.0Hz,16.0Hz),2.48 (dt,1H,J=4.5Hz,16.0Hz), 2.99 (m,1H), 3.57 (s,3H),3.71 (dd,1H,J=6.1Hz,7.9Hz), 4.08 (m,1H), 4.24 (AB type q,2H,J=15.7Hz),4.31 (d,1H,J=8.6Hz), 4.37 (d,1H,J=7.7Hz), 4.79 (m,2H),5.01 (d,1H,J=10.1Hz), 5.10 (dd,1H,J=1.7Hz,17.0Hz),5.62 (d,1H,J=7.7Hz), 5.84 (m,1H), 7.48 (t,2H,J=7.5Hz),7.61 (t,1H,J=7.5Hz), 8.16 (m,2H).
MS-FAB：580 (MH+)
【０４５９】
工程３：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-(2-フリル)プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-メトキシアセチル-7β,8β-メチレン-19-ノルバッカチンIII
上記工程２で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-4-(2- フリル)-3-(tert-ブチルジメチルシリル)オキシ-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０４６０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.13 (s,3H), -0.03 (s,3H), 0.80 (s,9H), 1.21 (s,6H), 1.31 (s,9H),1.54 (m,1H), 1.60 (s,1H), 1.72 (s,3H), 2.14 (d,1H,J=15.9Hz),2.14-2.25 (m,3H), 2.41 (dd,1H,J=9.3Hz,15.5Hz),2.48 (dt,1H,J=4.5Hz,15.9Hz), 2.99 (m,1H), 3.69 (t,1H,J=7.0Hz),4.08-4.15 (m,2H), 4.31 (m,2H), 4.79 (m,3H), 5.02 (d,1H,J=10.1Hz), 5.12 (d,1H,J=17.1Hz), 5.36 (d,1H,J=9.6Hz), 5.65 (m,2H), 5.83 (m,1H),6.20 (m,1H), 6.22 (m,1H), 6.35 (m,1H), (d,1H,J=8.5Hz),5.69 (d,1H,J=7.5Hz), 5.82 (m,1H), 6.19 (m,1H), 6.23 (m,1H), 6.35 (m,1H), 7.39 (s,1H), 7.48 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：948(MH+)
【０４６１】
工程４： 13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-(2-フリル) プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-メトキシアセチル-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程３で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４６２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.12 (s,3H), -0.03 (s,3H), 0.80 (s,9H), 1.19 (s,6H), 1.31 (s,9H),1.48 (m,1H), 1.54 (m,1H), 1.78 (s,1H), 1.80 (s,3H), 2.10-2.18 (m,2H), 2.22 (m,1H), 2.30-2.60 (m,10H), 3.53 (s,3H), 3.69 (m,4H), 3.78 (t,1H,J=6.0Hz), 4.07-4.17 (m,2H), 4.30 (m,3H), 4.79 (m,2H),4.82 (d,1H,J=16.0Hz), 5.33 (d,1H,J=10.0Hz), 5.59 (d,1H,J=10.0Hz), 5.65 (d,1H,J=7.5Hz), 6.18 (t,1H,J=8.5Hz), 6.22 (m,1H), 6.35 (m,1H), 7.38 (m,1H), 7.48 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz),8.12 (d,2H,J=7.5Hz).
MS-FAB：1021 (MH+)
【０４６３】
工程５： 13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-メトキシアセチル-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチン III
上記工程４で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０４６４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.19 (s,6H), 1.33 (s,9H), 1.48 (m,1H), 1.56 (m,1H), 1.80 (s,3H),2.13 (d,1H,J=16.0Hz), 2.22 (m,3H), 2.30-2.60 (m,10H), 3.50 (s,3H),3.70 (m,4H), 3.78 (m,1H), 4.06 (d,1H,J=8.6Hz), 4.12 (d,1H,J=17.0Hz),4.30 (d,1H,J=7.6Hz), 4.31 (m,1H), 4.62 (d,1H,J=17.0Hz), 4.76 (s,1H),4.79 (s,1H), 5.37 (s,2H), 5.66 (d,1H,J=7.6Hz), 6.19 (br,1H),6.32 (s,1H), 6.36 (m,1H), 7.41 (m,1H), 7.48 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：907 (MH+)
【０４６５】
実施例２３
【０４６６】
【化６３】
工程１：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-1-Ｏ-ジメチルシリル-7β,8β-メチレン-4-Ｏ-プロピオニル-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
実施例１９の工程２で得た化合物を実施例２の工程３の塩化シクロプロパンカルボニルを塩化プロピオニルに代えて同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４６８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.23 (d,3H,J=2.7Hz), 0.10 (d,3H,J=2.7Hz), 0.68 (m,6H), 1.02 (t,9H,J=8.0Hz), 1.11 (s,3H), 1.19 (s,3H), 1.22 (t,3H,J=7.5Hz), 1.25 (m,1H), 1.48 (m,1H), 1.81 (s,3H), 2.07 (d,1H,J=15.9Hz),2.18 (m,2H), 2.33 (m,2H), 2.45 (dt,1H,J=4.5Hz,15.8Hz), 2.60 (m,2H), 2.99 (m,1H), 3.66 (t,1H,J=6.9Hz), 4.12 (d,1H,J=8.5Hz),4.20 (d,1H,J=7.6Hz), 4.24 (d,1H,J=8.5Hz), 4.53 (m,1H),4.70 (d,1H,J=4.0Hz), 4.92 (t,1H,J=8.2Hz), 4.99 (d,1H,J=10.1Hz), 5.09 (d,1H,J=17.0Hz), 5.67 (d,1H,J=7.6Hz), 5.83 (m,1H), 7.46 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：737 (MH+)
【０４６９】
工程２：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程１で得た化合物を実施例２の工程４と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４７０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.17 (s,3H), 1.26 (t,3H,J=7.1Hz), 1.53 (m,1H), 1.87 (s,3H), 1.99 (s,1H), 2.09 (d,1H,J=15.9Hz), 2.20 (m,3H),2.34 (dd,1H,J=7.0Hz,15.9Hz), 2.57 (m,1H), 2.65 (m,1H), 2.99 (m,1H), 3.71 (m,1H), 4.06 (d,1H,J=8.5Hz), 4.29 (d,1H,J=8.5Hz),4.36 (d,1H,J=7.6Hz), 4.71 (d,1H,J=3.2Hz), 4.83 (br,1H), 4.99 (d,1H,J=9.9Hz), 5.09 (d,1H,J=17.0Hz), 5.61 (d,1H,J=7.6Hz), 5.83 (m,1H), 7.46 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz),8.14 (d,2H,J=7.5Hz).
MS-FAB：564 (MH+)
【０４７１】
工程３：10-アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-(2-フリル)プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程２で得た化合物および(3R,4R)-1-(tert-ブトキシカルボニル)-4-(2- フリル)-3-(tert-ブチルジメチルシリル)オキシ-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０４７２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.17 (s,3H), 0.02 (s,3H), 0.80 (s,9H), 1.21 (s,3H), 1.22 (s,3H), 1.27 (s,9H), 1.32 (t,3H,J=7.5Hz), 1.55 (m,1H), 1.72 (s,3H), 1.80 (br,1H), 2.12 (d,1H,J=15.9Hz), 2.14-2.25 (m,3H), 2.42 (m,1H),2.46 (m,1H), 2.74 (m,2H), 2.99 (m,1H), 3.69 (t,1H,J=7.0Hz), 4.06 (d,1H,J=8.5Hz), 4.24 (d,1H,J=7.6Hz), 4.30 (d,1H,J=8.5Hz),4.70 (s,2H), 5.04 (d,1H,J=10.1Hz), 5.11 (dd,1H,J=1.7Hz,17.1Hz), 5.22 (d,1H,J=10.0Hz), 5.31 (d,1H,J=10.0Hz), 5.66 (d,1H,J=7.6Hz),5.82 (m,1H), 6.22 (m,2H), 6.36 (m,1H), 7.39 (s,1H), 7.48 (t,2H,J=7.5Hz), 7.57 (t,1H, J=7.5Hz), 8.16 (d,2H,J=7.5Hz).
MS-FAB：932 (MH+)
【０４７３】
工程４：13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-(2-フリル)プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程３で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４７４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.17 (s,3H), 0.02 (s,3H), 0.80 (s,9H), 1.20 (s,3H), 1.21 (s,3H), 1.28 (s,9H), 1.34 (t,3H,J=7.5Hz), 1.48 (m,1H), 1.55 (m,1H), 1.78 (s,1H), 1.80 (s,3H), 2.12 (d,1H,J=15.9Hz), 2.13-2.21 (m,2H), 2.30-2.54 (m,10H), 2.75 (m,2H), 3.70 (m,4H), 3.74 (m,1H), 4.06 (d,1H,J=8.5Hz), 4.26 (d,1H,J=7.6Hz), 4.30 (d,1H,J=8.5Hz),4.72 (s,2H), 5.23 (d,1H,J=10.0Hz), 5.31 (d,1H,J=10.0Hz),5.66 (d,1H,J=7.6Hz), 6.21 (m,1H), 6.23 (m,1H), 6.36 (s,1H), 7.39 (s,1H), 7.48 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz),8.15 (d,2H,J=7.5Hz).
MS-FAB：1004 (MH+)
【０４７５】
工程５：13-O-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-4-Ｏ-プロピオニル-19-ノルバッカチンIII 上記工程４で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０４７６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.21 (s,3H), 1.23 (s,3H), 1.27 (s,9H), 1.48 (m,1H), 1.55 (m,1H),1.81 (s,3H), 1.88 (br,1H), 2.14 (d,1H,J=16.0Hz), 2.19 (m,2H), 2.30-2.60 (m,10H), 2.72 (m,2H), 3.72 (m,5H), 4.03 (d,1H,J=8.5Hz), 4.23 (d,1H,J=7.6Hz), 4.30 (d,1H,J=8.5Hz), 4.70 (s,2H),5.19 (d,1H,J=10.0Hz), 5.31 (d,1H,J=10.0Hz), 5.64 (d,1H,J=7.6Hz),6.23 (m,1H), 6.31 (br,1H), 6.38 (s,1H), 7.43 (s,1H),7.48 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.18 (d,2H,J=7.5Hz).
MS-FAB：891 (MH+)
【０４７７】
実施例２４
【０４７８】
【化６４】
工程１：10-アリル-4-Ｏ-ブタノイル-10-デアセトキシ-4-デアセチル-7-デオキシ-1-Ｏ-ジメチルシリル-7β,8β-メチレン-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
実施例１９の工程２で得た化合物を実施例２の工程３の塩化シクロプロパンカルボニルを塩化n-ブチリルに代えて同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４８０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.23 (d,3H,J=2.7Hz), 0.10 (d,3H,J=2.7Hz), 0.68 (m,6H), 1.02 (t,9H,J=8.0Hz), 1.04 (t,3H,J=7.5Hz), 1.10 (s,3H), 1.19 (s,3H), 1.22 (m,1H), 1.48 (m,1H), 1.78 (m,2H), 1.80 (s,3H), 2.09 (d,1H,J=15.9Hz), 2.18 (m,2H), 2.33 (m,2H), 2.45 (dt,1H,J=4.5Hz,15.9Hz), 2.52 (m,2H), 2.99 (m,1H), 3.67 (m,1H), 4.12 (d,1H,J=8.5Hz), 4.22 (d,1H,J=8.1Hz), 4.24 (d,1H,J=8.5Hz),4.53 (m,1H), 4.70 (d,1H,J=3.9Hz), 4.92 (t,1H,J=8.2Hz),4.99 (d,1H,J=10.1Hz), 5.09 (d,1H,J=17.0Hz), 5.67 (d,1H,J=8.1Hz),5.83 (m,1H), 7.46 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz),8.12 (d,2H,J=7.5Hz).
MS-FAB：751 (MH+)
【０４８１】
工程２：10-アリル-4-Ｏ-ブタノイル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
上記工程１で得た化合物を実施例２の工程４と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４８２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.17 (s,3H), 1.28 (t,3H,J=7.5Hz), 1.53 (m,1H), 1.74 (m,2H), 1.86 (d,3H,J=1.1Hz), 1.92 (m,1H), 2.09 (d,1H,J=15.9Hz),2.18-2.27 (m,3H), 2.34 (dd,1H,J=7.0Hz,15.6Hz),2.46 (dt,1H,J=4.5Hz,15.6Hz), 2.53 (m,1H), 2.59 (m,1H), 2.99 (m,1H), 3.71 (m,1H), 4.06 (d,1H,J=8.5Hz), 4.29 (d,1H,J=8.5Hz),4.36 (d,1H,J=7.6Hz), 4.71 (d,1H,J=3.9Hz), 4.83 (br,1H), 5.01 (d,1H,J=9.9Hz), 5.10 (dd,1H,J=1.7Hz,17.0Hz), 5.61 (d,1H,J=7.6Hz),5.83 (m,1H), 7.48 (t,2H,J=7.5Hz), 7.61 (t,1H,J=7.5Hz),8.15 (d,2H,J=7.5Hz).
MS-FAB：578 (MH+)
【０４８３】
工程３：10-アリル-4-Ｏ-ブタノイル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-(2-フリル)プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
上記工程２で得た化合物および (3R,4R)-1-(tert-ブトキシカルボニル)-3-(2-フリル)-3-(tert-ブチルジメチルシリル)オキシ-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０４８４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.17 (s,3H), 0.02 (s,3H), 0.80 (s,9H), 1.01 (t,3H,J=7.5Hz),1.21 (s,3H), 1.23 (s,3H), 1.28 (s,9H), 1.55 (t,1H,J=7.5Hz), 1.72 (s,3H), 1.78-1.87 (m,3H), 2.14 (d,1H,J=15.9Hz), 2.11-2.24 (m,3H),2.39-2.48 (m,2H), 2.65 (m,1H), 2.72 (m,1H), 2.99 (m,1H),3.69 (t,1H,J=6.8Hz), 4.06 (d,1H,J=8.5Hz), 4.28 (d,1H,J=7.6Hz),4.31 (d,1H,J=8.5Hz), 4.72 (s,2H), 5.03 (d,1H,J=10.0Hz), 5.12 (d,1H,J=17.1Hz), 5.23 (d,1H,J=10.0Hz), 5.33 (d,1H,J=10.0Hz), 5.65 (d,1H,J=7.6Hz), 5.83 (m,1H), 6.21 (m,2H), 6.37 (m,1H), 7.37 (s,1H), 7.48 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz),8.15 (d,2H,J=7.5Hz).
MS-FAB：946 (MH+)
【０４８５】
工程４：4-Ｏ-ブタノイル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ) -2-(tert-ブチルジメチルシリル）オキシ-3-(2-フリル)プロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程３で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４８６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.15 (s,3H), 0.02 (s,3H), 0.80 (s,9H), 1.01 (t,3H,J=7.5Hz),1.19 (s,3H), 1.20 (s,3H), 1.29 (s,9H), 1.48 (m,1H), 1.55 (m,1H),1.81 (s,3H), 1.82 (m,2H), 2.08-2.20 (m,3H), 2.30-2.55 (m,10H),2.66-2.72 (m,2H), 3.70 (s,4H), 3.75 (m,1H), 4.06 (d,1H,J=8.5Hz),4.28 (d,1H,J=7.3Hz), 4.31 (d,1H,J=8.5Hz), 4.72 (s,2H),5.22 (d,1H,J=10.0Hz), 5.34 (d,1H,J=10.0Hz), 5.64 (d,1H,J=7.3Hz),6.19 (m,1H), 6.21 (s,1H), 6.35 (m,1H), 7.38 (s,1H), 7.48 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：1018 (MH+)
【０４８７】
工程５：4-Ｏ-ブタノイル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2-フリル)-2-ヒドロキシプロピオニル]-10-デアセトキシ-4-デアセチル-7- デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチン III上記工程４で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０４８８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.98 (t,3H,J=7.5Hz), 1.21 (s,6H), 1.28 (s,9H), 1.48 (m,1H), 1.55 (m,1H), 1.77 (m,2H), 1.80 (s,3H), 1.88 (s,1H), 2.10 (d,1H,J=15.6Hz), 2.20 (m,2H), 2.30-2.70 (m,12H), 3.70 (s,4H),3.74 (m,1H), 4.06 (d,1H,J=8.5Hz), 4.28 (d,1H,J=7.5Hz),4.29 (d,1H,J=8.5Hz), 4.69 (s,2H), 5.18 (d,1H,J=10.0Hz), 5.32 (d,1H,J=10.0Hz), 5.64 (d,1H,J=7.5Hz), 6.21 (m,1H), 6.32 (s,1H),6.36 (s,1H), 7.41 (s,1H), 7.49 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.17 (d,2H,J=7.5Hz).
MS-FAB：904 (MH+)
【０４８９】
実施例２５
【０４９０】
【化６５】
工程１：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(te rt-ブチルジメチルシリル）オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル-7β,8β-メチレン-19-ノルバッカチンIII
実施例２１の工程２で得た化合物を実施例１の工程８と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４９２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (s,3H), -0.10 (s,3H), 0.77 (s,9H), 1.22 (s,3H), 1.24 (s,3H),1.31 (s,9H), 1.33 (m,3H), 1.54 (m,1H), 1.59 (s,1H), 1.74 (s,3H),1.83 (br,1H), 2.14 (d,1H,J=15.9Hz), 2.18-2.27 (m,3H), 2.42 (dt,1H,J=4.5Hz,15.9Hz), 2.55 (dd,1H,J=9.3Hz,15.5Hz), 3.00 (m,1H),3.69 (t,1H,J=6.9Hz), 4.11 (d,1H,J=8.5Hz), 4.27 (m,1H), 4.32 (m,2H), 4.46 (s,1H), 4.49 (m,1H), 4.77 (d,1H,J=4.0Hz), 5.03 (d,1H,J=10.0Hz),5.10 (d,1H,J=17.1Hz), 5.28 (d,1H,J=10.0Hz), 5.43 (d,1H,J=10.0Hz), 5.68 (d,1H,J=7.6Hz), 5.82 (m,1H), 6.18 (m,1H), 7.28-7.40 (m,5H),7.46 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：958 (MH+)
【０４９３】
工程２： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程１で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０４９４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (s,3H), -0.12 (s,3H), 0.77 (s,9H), 1.20 (s,3H), 1.21 (s,3H),1.31 (s,9H), 1.35 (m,3H), 1.50 (m,1H), 1.54 (s,1H), 1.82 (s,4H),2.12-2.20 (m,4H), 2.30-2.59 (m,9H), 3.70 (s,4H), 3.75 (m,1H), 4.10 (m,1H), 4.29 (m,1H), 4.33 (m,2H), 4.46 (s,1H), 4.52 (m,1H),4.79 (s,1H), 5.29 (m,1H), 5.42 (m,1H), 5.68 (d,1H,J=7.6Hz), 6.16 (m,1H), 7.28-7.37 (m,5H), 7.46 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：1031 (MH+)
【０４９５】
工程３：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程２で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０４９６】
融点：115-120 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.20 (s,3H), 1.23 (s,3H), 1.31 (s,9H), 1.49 (m,1H), 1.52 (m,1H),1.77 (s,3H), 1.76 (s,1H), 2.14 (d,1H,J=15.9Hz), 2.20 (m,3H),2.31-2.59 (m,9H), 3.70 (s,4H), 3.73 (m,1H), 4.08 (d,1H,J=8.5Hz),4.10 (m,1H), 4.32 (m,3H), 4.58 (s,1H), 4.78 (s,1H), 5.26 (m,1H),5.36 (m,1H), 5.68 (d,1H,J=7.6Hz), 6.09 (s,1H), 7.28-7.45 (m,5H),7.49 (t,2H,J=7.5Hz), 7.59 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：917 (MH+)
【０４９７】
実施例２６
【０４９８】
【化６６】
工程１：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-メトキシアセチル-7β,8β-メチレン-19-ノルバッカチンIII
実施例２２の工程２で得た化合物を実施例１の工程８と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５００】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (s,3H), -0.28 (s,3H), 0.73 (s,9H), 1.22 (s,3H), 1.24 (s,3H),1.31 (s,9H), 1.54 (m,1H), 1.58 (s,1H), 1.76 (s,3H), 1.79 (br,1H), 2.14 (m,2H), 2.22 (m,2H), 2.43 (dd,1H,J=7.7Hz,15.4Hz), 2.49 (m,1H), 2.99 (m,1H), 3.59 (s,3H), 3.70 (m,1H), 4.11 (d,1H,J=8.5Hz), 4.12 (d,1H,J=16.0Hz), 4.30 (d,1H,J=7.6Hz), 4.31 (d,1H,J=8.5Hz), 4.62 (s,1H), 4.80 (d,1H,J=2.5Hz), 4.91 (d,1H,J=16.0Hz), 5.03 (d,1H,J=10.0Hz), 5.10 (d,1H,J=17.1Hz), 5.29 (d,1H,J=10.0Hz), 5.68 (d,1H,J=7.6Hz), 5.82 (m,1H), 6.09 (m,1H), 6.21 (m,1H), 7.28-7.36 (m,5H), 7.48 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.10 (d,2H,J=7.5Hz).
MS-FAB：958 (MH+)
【０５０１】
工程２：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-メトキシアセチル-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程１で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５０２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (s,3H), -0.28 (s,3H), 0.73 (s,9H), 1.19 (s,3H), 1.20 (s,3H),1.31 (s,9H), 1.49 (m,1H), 1.53 (m,1H), 1.80 (s,1H), 1.83 (s,3H),2.05-2.23 (m,4H), 2.30-2.60 (m,9H), 3.59 (s,3H), 3.70 (s,4H), 3.78 (m,1H), 4.09 (d,1H,J=8.5Hz), 4.17 (d,1H,J=17.3Hz), 4.32 (m,2H),4.62 (s,1H), 4.82 (m,1H), 4.93 (d,1H,J=17.3Hz), 5.29 (d,1H,J=10.0Hz), 5.68 (d,1H,J=7.6Hz), 6.03 (m,1H), 6.20 (t,1H,J=8.0Hz),7.35-7.36 (m,5H), 7.48 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.10 (d,2H,J=7.5Hz).
MS-FAB：1031 (MH+)
【０５０３】
工程３：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-メトキシアセチル-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチン III
上記工程２で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０５０４】
融点 :115-120 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.19 (s,6H), 1.31 (s,9H), 1.49 (m,1H), 1.55 (m,1H), 1.80 (s,4H),2.14 (d,1H,J=15.9Hz), 2.22 (m,3H), 2.30-2.60 (m,9H), 3.50 (s,3H), 3.70 (s,4H), 3.78 (m,1H), 4.09 (d,1H,J=8.5Hz), 4.12 (m,1H), 4.30 (s,2H), 4.64 (m,1H), 4.68 (s,1H), 4.78 (s,1H), 5.31 (br,1H), 5.55 (d,1H,J=10.0Hz), 5.68 (d,1H,J=7.6Hz), 6.19 (m,1H), 7.28-7.43 (m,5H), 7.48 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.10 (d,2H,J=7.5Hz).
MS-FAB：917 (MH+)
【０５０５】
実施例２７
【０５０６】
【化６７】
工程１：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-4-Ｏ-プロピオニル-19-ノルバッカチンIII
実施例２３の工程２で得た化合物を実施例１の工程８と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５０８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.32 (s,3H), -0.14 (s,3H), 0.73 (s,9H), 1.22 (s,6H), 1.24 (s,9H),1.36 (t,1H,J=7.5Hz), 1.54 (m,1H), 1.62 (s,1H), 1.72 (s,3H), 1.84 (br,1H), 2.08 (m,1H), 2.20 (m,3H), 2.41-2.48 (m,2H), 2.78 (m,2H),2.99 (m,1H), 3.68 (m,1H), 4.08 (d,1H,J=8.5Hz), 4.24 (d,1H,J=7.6Hz), 4.31 (d,1H,J=8.5Hz), 4.47 (s,1H), 4.72 (s,1H), 5.03 (d,1H,J=10.0Hz),5.10 (d,1H,J=17.1Hz), 5.29 (m,1H), 5.42 (m,1H), 5.68 (d,1H,J=7.6Hz),5.82 (m,1H), 6.25 (br,1H), 7.28-7.40 (m,5H), 7.48 (t,2H,J=7.5Hz), 7.58 (m,1H), 8.15 (d,2H,J=7.5Hz).
MS-FAB：942(MH+)
【０５０９】
工程２：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル )-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程１で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５１０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.32 (s,3H), -0.14 (s,3H), 0.75 (s,9H), 1.20 (s,3H), 1.23 (s,3H),1.26 (s,9H), 1.36 (t,1H,J=7.5Hz), 1.49 (m,1H), 1.54 (m,1H), 1.80 (s,3H), 1.84 (br,1H), 2.09-2.20 (m,4H), 2.30-2.56 (m,9H),2.78 (m,2H), 3.70 (s,4H), 3.72 (m,1H), 4.08 (d,1H,J=8.5Hz), 4.26 (d,1H,J=7.6Hz), 4.31 (d,1H,J=8.5Hz), 4.47 (s,1H), 4.72 (s,1H), 5.26 (m,1H), 5.41 (m,1H), 5.61 (d,1H,J=7.6Hz), 6.22 (m,1H), 7.28-7.40 (m,5H), 7.48 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：1015 (MH+)
【０５１１】
工程３：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程２で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０５１２】
融点：120-125 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.20 (s,3H), 1.23 (s,3H), 1.25 (m,3H), 1.26 (s,9H), 1.49 (m,1H),1.54 (m,1H), 1.78 (s,3H), 1.87 (s,1H), 2.09-2.20 (m,4H),2.30-2.59 (m,9H), 2.68 (m,2H), 3.70 (m,4H), 3.72 (m,1H),4.05 (d,1H,J=8.5Hz), 4.22 (d,1H,J=7.6Hz), 4.31 (d,1H,J=8.5Hz),4.60 (s,1H), 4.70 (s,1H), 5.26 (m,1H), 5.64 (d,1H,J=7.6Hz), 6.22 (m,1H), 7.31-7.39 (m,5H), 7.50 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.17 (d,2H,J=7.5Hz).
MS-FAB：901 (MH+)
【０５１３】
実施例２８
【０５１４】
【化６８】
工程１：10-アリル-4-Ｏ-ブタノイル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
実施例２４の工程２で得た化合物を実施例１の工程８と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５１６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.32 (s,3H), -0.12 (s,3H), 0.73 (s,9H), 1.04 (t,3H,J=7.5Hz), 1.22 (s,6H), 1.26 (s,12H), 1.55 (m,1H), 1.58 (m,1H), 1.72 (s,3H), 1.78-1.92 (m,3H), 2.10-2.25 (m,4H), 2.41-2.49 (m,2H), 2.64 (m,1H),2.80 (m,1H), 2.99 (m,1H), 3.69 (t,1H,J=6.7Hz), 4.08 (d,1H,J=8.5Hz), 4.29 (d,1H,J=7.6Hz), 4.31 (d,1H,J=8.5Hz), 4.48 (s,1H), 4.72 (s,1H), 5.03 (d,1H,J=10.0Hz), 5.10 (d,1H,J=17.1Hz), 5.29 (m,1H), 5.42 (m,1H), 5.65 (d,1H,J=7.6Hz), 5.82 (m,1H), 6.23 (m,1H), 7.28-7.40 (m,5H),7.48 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：956 (MH+)
【０５１７】
工程２：4-Ｏ-ブタノイル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程１で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５１８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.32 (s,3H), -0.12 (s,3H), 0.73 (s,9H), 1.06 (t,3H,J=7.5Hz), 1.20 (s,3H), 1.23 (s,3H), 1.27 (s,9H), 1.48 (m,1H), 1.56 (m,1H),1.80 (s,3H), 1.82-1.98 (m,3H), 2.08-2.23 (m,4H), 2.30-2.58 (m,9H),2.68 (m,1H), 2.80 (m,1H), 3.69 (s,4H), 3.75 (m,1H), 4.09 (d,1H,J=8.5Hz), 4.29 (d,1H,J=7.6Hz), 4.31 (d,1H,J=8.5Hz),4.48 (s,1H), 4.72 (d,1H,J=4.0Hz), 5.29 (m,1H), 5.41 (d,1H,J=8.6Hz), 5.66 (d,1H,J=7.6Hz), 6.21 (m,1H), 7.28-7.40 (m,5H), 7.48 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：1029 (MH+)
【０５１９】
工程３：4-Ｏ-ブタノイル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ) -2-ヒドロキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程２で得た化合物を実施例１の工程９と同様に反応させ、標記化合物を無色の固体として得た。
【０５２０】
融点 :115-120 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.93 (m,3H), 1.20 (s,3H), 1.21 (s,3H), 1.28 (s,9H), 1.46 (m,1H),1.55 (m,1H), 1.64-1.75 (m,2H), 1.76 (s,3H), 1.88 (br,1H), 2.10-2.22 (m,4H), 2.30-2.60 (m,9H), 2.65 (m,2H), 3.70 (s,4H), 3.72 (m,1H), 4.05 (d,1H,J=8.5Hz), 4.26 (d,1H,J=7.6Hz),4.29 (d,1H,J=8.5Hz), 4.60 (s,1H), 4.70 (s,1H), 4.76 (br,1H),4.79 (br,1H), 5.64 (d,1H,J=7.6Hz), 6.19 (m,1H), 7.28-7.40 (m,5H), 7.50 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.17 (d,2H,J=7.5Hz).
MS-FAB：915 (MH+)
【０５２１】
実施例２９
【０５２２】
【化６９】
工程１：10-デアセトキシ-7-デオキシ-7β,８β-メチレン-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
実施例１９の工程１で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５２４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.66 (6H,q,J=7.8Hz), 1.01 (9H,t,J=7.8Hz), 1.12 (3H,s), 1.15 (3H,s), 1.25-1.56 (3H,m), 1.77 (1H,s), 1.89 (3H,d,J=1.0Hz), 2.27 (3H,s),2.04-2.63 (12H,m), 3.71 (4H,m), 4.16 (2H,ABq,J=8.3Hz),4.29 (1H,d,J=8.8Hz), 4.53 (1H,d,J=3.9Hz), 4.87 (1H,t,J=7.3Hz),7.47 (2H,t,J=7.8Hz), 7.60 (1H,t,J=7.3Hz), 8.11 (2H,d,J=6.8Hz).
【０５２５】
工程２：10-デアセトキシ-7-デオキシ-1-Ｏ-ジメチルシリル-7β,8β-メチレン -10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII 上記工程１で得た化合物を実施例２の工程１と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５２６】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.22 (d,3H,J=2.7Hz), 1.10 (d,3H,J=2.7Hz), 0.69 (m,6H), 1.27 (t,9H,J=7.5Hz), 1.09 (s,3H), 1.18 (s,3H), 1.26 (m,1H), 1.49 (m,2H), 1.89 (s,3H), 2.05 (d,1H,J=15.9Hz), 2.19 (m,1H),2.28 (s,3H), 2.35 (m,4H), 2.46 (m,6H), 2.53 (m,1H), 3.68 (m,1H),3.71 (m,4H), 4.12 (d,1H,J=8.5Hz), 4.24 (m,2H), 4.53 (m,1H), 4.75 (d,1H,J=4.0Hz), 4.91 (t,1H,J=8.0Hz), 5.69 (d,1H,J=7.8Hz),7.45 (t,2H,J=7.5Hz), 7.57 (t,1H,J=7.5Hz), 8.10 (m,2H).
MS-FAB：796 (MH+)
【０５２７】
工程３：10-デアセトキシ-4-デアセチル-7-デオキシ-1-Ｏ-ジメチルシリル-7β,8β-メチレン-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
上記工程２で得た化合物を実施例２の工程２と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５２８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.24 (d,3H,J=2.7Hz), 0.11 (d,3H,J=2.7Hz), 0.78 (m,6H), 1.03 (s,3H),1.08 (t,9H,J=7.5Hz), 1.18 (s,3H), 1.55 (m,1H), 1.90 (s,3H), 2.15 (m,3H), 2.35-2.50 (m,7H), 2.55 (m,3H), 2.68 (dd,1H,J=2.9Hz,15.3Hz), 3.49 (s,1H), 3.70 (m,5H),4.00 (d,1H,J=7.2Hz), 4.12 (d,1H,J=7.5Hz), 4.17 (d,1H,J=7.5Hz),4.57 (m,1H), 4.68 (m,1H), 5.77 (d,1H,J=7.2Hz), 7.46 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：754 (MH+)
【０５２９】
工程４：10-デアセトキシ-4-デアセチル-7-デオキシ-1-Ｏ-ジメチルシリル-7β,8β-メチレン-10-(2-モルホリノエチル)-4-Ｏ-プロピオニル-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
上記工程３で得た化合物を実施例２の工程３の塩化シクロプロパンカルボニルを塩化プロピオニルに代えて同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５３０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.24 (d,3H,J=2.7Hz), 0.11 (d,3H,J=2.7Hz), 0.69 (m,6H), 1.02 (t,9H,J=7.5Hz), 1.09 (s,3H), 1.18 (s,3H), 1.24 (t,3H,J=7.5Hz), 1.48 (m,2H), 2.07 (d,1H,J=15.8Hz), 2.17 (m,1H), 2.34 (m,3H),2.46 (m,7H), 2.54 (m,1H), 2.62 (m,2H), 2.67 (m,1H), 3.68 (t,1H,J=6.0Hz), 3.72 (m,4H), 4.13 (d,1H,J=8.3Hz),4.21 (d,1H,J=7.7Hz), 4.24 (d,1H,J=8.3Hz), 4.52 (m,1H),4.71 (d,1H,J=4.0Hz), 4.91 (t,1H,J=8.2Hz), 5.69 (d,1H,J=7.7Hz),7.46 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：810 (MH+)
【０５３１】
工程５：10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程４で得た化合物を実施例２の工程４と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５３２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.07 (s,3H), 1.15 (s,3H), 1.21 (t,3H,J=7.5Hz), 1.52 (m,1H), 1.92 (s,3H),2.10 (d,1H,J=15.8Hz), 2.22 (m,2H), 2.32-2.70 (m,13H), 3.70 (m,5H),4.03 (d,1H,J=8.5Hz), 4.30 (d,1H,J=8.5Hz), 4.37 (d,1H,J=7.8Hz),4.71 (d,1H,J=3.9Hz), 4.81 (d,1H,J=7.5Hz), 5.61 (d,1H,J=7.8Hz),7.48 (t,2H,J=7.5Hz), 7.61 (t,1H,J=7.5Hz), 8.14 (m,2H).
MS-FAB：637 (MH+)
【０５３３】
工程６：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程５で得た化合物を実施例１０の工程５と同様に反応させ、次いで実施例１の工程９と同様に反応させて標記化合物を無色の固体として得た。
【０５３４】
融点 :135-140 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,9H), 1.21 (s,3H), 1.26 (s,3H), 1.33 (s,3H), 1.44 (t,3H,J=7.5Hz), 1.57 (m,1H), 1.72 (s,3H), 2.13 (d,1H,J=15.6Hz),2.18 (m,2H), 2.30-2.49 (m,10H), 2.57 (m,1H), 2.77 (m,1H), 2.94 (m,1H),3.70 (m,4H), 3.72 (m,1H), 4.08 (d,1H,J=8.3Hz), 4.23 (d,1H,J=7.6Hz), 4.33 (d,1H,J=8.3Hz), 4.72 (m,1H), 4.99 (d,1H,J=9.9Hz),5.49 (d,1H,J=9.9Hz), 5.67 (d,1H,J=7.6Hz), 6.31 (m,1H),7.33-7.40 (m,5H), 7.50 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.19 (d,2H,J=7.5Hz).
MS-FAB：915(MH+)
【０５３５】
実施例３０
【０５３６】
【化７０】
工程１：10-アリル-10-デアセトキシ-4-デアセチル-4-Ｏ-プロピオニル-13-Ｏ-トリエチルシリル-7-Ｏ-トリフルオロメタンスルホニルバッカチンIII
実施例６の工程７で得た化合物を実施例１の工程５と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０５３８】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.65 (m,6H), 0.99 (m,9H), 1.13 (s,3H), 1.10 (s,3H), 1.13 (s,3H),1.28 (t,3H,J=7.5Hz), 1.80 (s,3H), 1.88 (s,3H), 2.08 (m,1H), 2.20 (m,2H), 2.42 (m,1H), 2.62 (m,2H), 2.80 (m,2H), 4.10 (m,2H),4.18 (d,1H,J=8.3Hz), 4.30 (d,1H,J=8.3Hz), 4.90 (m,2H),5.00 (d,1H,J=10.0Hz), 5.08 (d,1H,J=17.0Hz), 5.60 (dd,1H,J=7.3Hz,10.7Hz), 5.65 (d,1H,J=7.4Hz), 5.75 (m,1H),7.46 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.09 (d,2H,J=7.5Hz).
【０５３９】
工程２：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-4-Ｏ-プロピオニル-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
上記工程１で得た化合物を実施例1 ８の工程３と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５４０】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.65 (m,6H), 1.00 (t,9H,J=7.8Hz), 1.13 (s,3H), 1.15 (s,3H), 1.23 (t,3H,J=7.4Hz), 1.50 (m,1H), 1.80 (s,3H), 2.08-2.21 (m,5H),2.28 (dd,1H,J=8.8Hz,15.1Hz), 2.46 (dt,1H,J=4.4Hz, 15.6Hz),2.60 (m,2H), 2.96 (m,1H), 3.69 (m,1H), 4.06 (d,1H,J=8.5Hz), 4.21 (d,1H,J=7.8Hz), 4.29 (d,1H,J=8.5Hz), 4.70 (d,1H,J=3.9Hz),4.88 (t,1H,J=8.0Hz), 4.99 (d,1H,J=9.7Hz), 5.08 (dd,1H,J=2.0Hz,17.1Hz),5.57 (d,1H,J=7.8Hz), 5.80 (m,1H), 7.46 (t,2H,J=7.5Hz),7.60 (t,1H,J=7.5Hz), 8.11 (d,2H,J=7.5Hz).
MS-FAB：678 (MH+)
【０５４１】
工程３：10-アリル-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程２で得た化合物を実施例１の工程７と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５４２】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.15 (s,3H), 1.26 (t,3H,J=7.4Hz), 1.50 (m,1H), 1.86 (s,3H), 2.08 (d,1H,J=16.1Hz), 2.21 (m,3H), 2.31 (dd,1H,J=7.3Hz,15.6Hz), 2.46 (dt,1H,J=4.4Hz,16.1Hz), 2.68 (m,1H),2.72 (m,1H), 2.99 (m,1H), 3.70 (dd,1H,J=6.2Hz,7.5Hz), 4.05 (d,1H,J=8.5Hz), 4.31 (d,1H,J=8.5Hz), 4.35 (d,1H,J=7.2Hz),4.70 (d,1H,J=3.9Hz), 4.82 (br,1H), 4.99 (d,1H,J=9.7Hz), 5.08 (d,1H,J=17.1Hz), 5.60 (d,1H,J=7.2Hz), 5.83 (m,1H), 7.46 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.14 (d,2H,J=7.5Hz).
MS-FAB：564 (MH+)
【０５４３】
工程４：10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7- デオキシ-7β,8β-メチレン-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程３で得た化合物および参考例３の工程２で得た化合物を実施例１０の工程５と同様に反応させた後、得られた10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル)オキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-4-Ｏ-プロピオニル-19-ノルバッカチン IIIと10-アリル-13-Ｏ-(tert-ブトキシカルボニル)-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-4-Ｏ-プロピオニル-19-ノルバッカチン IIIの混合物をテトラヒドロフラン5 mlに溶解し、テトラ-n-ブチルアンモニウムフルオリド（１Ｍテトラヒドロフラン溶液） 345 ml を０℃で加えて同温で10分間反応した。反応液を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝３：７( v/v)）により精製し標記化合物 50 mgを無色の非晶質固体として得た。
【０５４４】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.12 (s,9H), 1.23 (s,3H), 1.32 (s,3H), 1.43 (t,3H,J=7.3Hz), 1.58 (m,1H), 1.65 (s,3H), 2.12 (d,1H,J=15.9Hz), 2.17 (m,2H),2.42 (m,3H), 2.73 (m,1H), 2.98 (m,2H), 3.59 (br,1H), 3.68 (m,1H), 4.05 (d,1H,J=8.5Hz), 4.21 (d,1H,J=7.8Hz), 4.32 (d,1H,J=8.5Hz),4.70 (d,1H,J=3.9Hz), 4.98 (m,2H), 5.06 (d,1H,J=17.1Hz), 5.50 (d,1H,J=9.8Hz), 5.62 (d,1H,J=7.8Hz), 5.78 (m,1H),6.31 (m,1H), 7.33 (m,5H), 7.49 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.19 (d,2H,J=7.5Hz).
MS-FAB：842 (MH+)
【０５４５】
工程５：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程４で得た化合物を実施例１の工程１０と同様に反応させ、標記化合物（実施例２９の工程６で得た化合物）を無色の固体として得た。
【０５４６】
実施例３１
【０５４７】
【化７１】
工程１：10-デアセトキシ-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
実施例２９の工程１で得た化合物を実施例１の工程７と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５４９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.11 (s,3H), 1.52 (m,1H), 1.92 (s,3H), 2.00-2.10 (m,2H), 2.18 (m,1H), 2.23 (m,1H), 2.30-2.60 (m,10H), 3.68 (m,4H), 3.71 (m,1H),4.02 (d,1H,J=8.3Hz), 4.28 (d,1H,J=7.6Hz), 4.36 (d,1H,J=8.3Hz),4.71 (m,1H), 4.80 (t,1H,J=7.5Hz), 5.60 (d,1H,J=7.6Hz),7.49 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：623 (MH+)
【０５５０】
工程２：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-7-デオキシ-7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程１で得た化合物を実施例１０の工程５と同様に反応させ、次いで実施例１の工程９と同様に反応させて標記化合物を無色の固体として得た。
【０５５１】
融点 :140-145 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.10 (s,9H), 1.19 (s,3H), 1.21 (s,3H), 1.30 (s,3H), 1.59 (m,1H),1.70 (s,3H), 2.10 (d,1H,J=15.6Hz), 2.17 (m,2H), 2.30-2.45 (m,10H),2.57 (m,2H), 2.60 (s,3H), 2.30-2.45 (m,10H), 3.65 (m,4H), 3.70 (m,1H),4.02 (d,1H,J=8.3Hz), 4.26 (d,1H,J=7.6Hz), 4.30 (d,1H,J=8.3Hz),4.76 (m,1H), 5.00 (d,1H,J=9.9Hz), 5.49 (d,1H,J=9.9Hz),5.63 (d,1H,J=7.6Hz), 6.31 (m,1H), 7.31 (m,5H), 7.49 (t,2H,J=7.5Hz), 7.53 (t,1H,J=7.5Hz), 8.16 (d,2H,J=7.5Hz).
MS-FAB：901 (MH+)
【０５５２】
実施例３２
【０５５３】
【化７２】
工程１：10-デアセトキシ-4-デアセチル-7-デオキシ-1-Ｏ-ジメチルシリル-4-Ｏ-エトキシカルボニル-7β,8β-メチレン-10-(2-モルホリノエチル)-13-Ｏ-トリエチルシリル-19-ノルバッカチンIII
実施例２９の工程３で得た化合物を実施例９の工程３と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５５５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.24 (d,3H,J=2.7Hz), 0.11 (d,3H,J=2.7Hz), 0.69 (m,6H), 1.02 (t,9H,J=7.5Hz), 1.09 (s,3H), 1.18 (s,3H), 1.40 (t,3H,J=7.2Hz), 1.50 (m,1H), 1.72 (br,1H), 1.90 (s,3H), 2.10 (d,1H,J=15.8Hz), 2.17 (m,1H), 2.30-2.60 (m,12H), 3.68 (t,1H,J=4.5Hz), 3.72 (m,4H), 4.13 (m,1H), 4.24 (d,1H,J=8.5Hz), 4.29 (d,1H,J=7.7Hz), 4.40 (m,1H), 4.53 (m,1H), 4.75 (d,1H,J=4.0Hz), 4.91 (t,1H,J=8.0Hz),5.69 (d,1H,J=7.7Hz), 7.46 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz),8.12 (d,2H,J=7.5Hz).
MS-FAB：826 (MH+)
【０５５６】
工程２：10-デアセトキシ-4-デアセチル-7-デオキシ-4-Ｏ-エトキシカルボニル -7β,8β-メチレン-10-(2-モルホリノエチル)-19-ノルバッカチンIII
上記工程１で得た化合物を実施例２の工程４と同様に反応させ、標記化合物を無色の非晶質固体として得た。
【０５５７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.06 (s,3H), 1.15 (s,3H), 1.38 (t,3H,J=7.3Hz), 1.50 (m,2H), 1.94 (s,3H), 2.12 (d,1H,J=15.6Hz), 2.19 (m,1H), 2.28-2.55 (m,12H),3.71 (m,4H), 3.76 (m,1H), 4.03 (d,1H,J=8.7Hz), 4.20 (m,1H), 4.30 (m,2H), 4.41 (d,1H,J=7.8Hz), 4.79 (m,2H), 5.61 (d,1H,J=7.8Hz), 7.49 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.14 (m,2H).
【０５５８】
工程３： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2-メチル-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ -4-Ｏ-エトキシカルボニル-7β,8β-メチレン-10-(2-モルホリノエチル )-19-ノルバッカチンIII
上記工程２で得た化合物を実施例１０の工程５と同様に反応させ、次いで実施例１の工程９と同様に反応させて標記化合物を無色の固体として得た。
【０５５９】
融点 :130-135 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.20 (s,3H), 1.21 (s,3H), 1.26 (s,3H), 1.27 (s,9H), 1.39 (m,3H),1.48 (m,1H), 1.52 (m,1H), 1.70 (s,3H), 2.13 (d,1H,J=16.1Hz),2.20-2.48 (m,12H), 2.53 (m,1H), 3.69 (m,4H), 3.72 (m,1H), 4.09 (m,1H),4.12 (m,1H), 4.29 (d,1H,J=6.9Hz), 4.35 (d,1H,J=8.8Hz), 4.43 (m,1H), 4.79 (s,1H), 5.04 (d,1H,J=9.9Hz), 5.65 (d,1H,J=10.3Hz), 5.67 (d,1H,J=6.9Hz), 6.11 (br,1H), 7.29-7.40 (m,5H),7.47 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.14 (d,2H,J=7.5Hz).
MS-FAB：931 (MH+)
【０５６０】
実施例３３
【０５６１】
【化７３】
10-アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル ]-10-デアセトキシ-7-デオキシ-7β,8β-メチレン-19-ノルバッカチンIII
実施例１８の工程５で得た化合物を実施例１の工程９と同様に反応させて、 標記化合物を無色の固体として得た。
【０５６３】
融点 :130-135 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.24 (s,3H), 1.26 (s,3H), 1.27 (s,9H), 1.55 (m,1H), 1.71 (s,3H),2.08 (d,1H,J=16.1Hz), 2.20 (m,2H), 2.38 (s,3H), 2.40 (m,2H),2.99 (m,1H), 3.30 (br,1H), 3.69 (dd,1H,J=6.0Hz,8.0Hz),4.03 (d,1H,J=8.5Hz), 4.21 (d,1H,J=7.8Hz), 4.29 (d,1H,J=8.5Hz),4.59 (s,1H), 4.73 (d,1H,J=3.5Hz), 5.00 (d,1H,J=10.0Hz), 5.12 (d,1H,J=17.0Hz), 5.28 (m,1H), 5.38 (d,1H,J=9.0Hz), 5.65 (d,1H,J=6.8Hz), 5.80 (m,1H), 6.25 (m,1H), 7.28-7.36 (m,5H),7.48 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.12 (d,2H,J=7.5Hz).
MS-FAB：813 (MH+)
【０５６４】
実施例３４
【０５６５】
【化７４】
工程１：10-アリル-10-デアセトキシ-4-デアセチル-4-Ｏ-プロピオニル-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-Ｏ-トリエチルシリルバッカチンIII
実施例７の工程２で得た化合物 400 mg を実施例２３の工程１と同様に反応させ４位にプロピオニル基を導入した。得られた化合物を実施例２の工程４と同様に反応し、シリカゲル薄層クロマトグラフィー( 展開溶媒；クロロホルム：メタノール＝９５：５(v/v) ）で精製し10-アリル-10-デアセトキシ-4-デアセチル-4-Ｏ-プロピオニルバッカチン IIIを得た。これを6 mlの乾燥した N,N-ジメチルホルムアミドに溶解し、イミダゾール 140mgと塩化トリエチルシラン 0.345 mlを０℃で加えて同温で60分間反応した。反応液を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液、飽和食塩水の順で洗浄し、無水硫酸マグネシウムで乾燥して溶媒を留去した。得られた残分を乾燥した12 ml のピリジンに溶解し、クロロギ酸2,2,2-トリクロロエチル 0.345 mlを加えて60℃で１時間攪拌した。０℃にて、酢酸エチルで希釈し、飽和塩化アンモニウム水溶液、飽和食塩水の順で洗浄し、無水硫酸マグネシウムで乾燥して溶媒を留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝８：２(v/v) ）で精製し標記化合物372 mgを無色の非晶質固体として得た。
【０５６７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.57 (m,6H), 0.97 (t,9H,J=7.5Hz), 1.16 (s,6H), 1.31 (t,3H,J=7.5Hz), 1.62 (s,3H), 1.85 (s,3H), 1.89 (m,1H), 2.31 (m,1H), 2.37 (m,1H),2.50 (m,2H), 2.70 (m,2H), 2.81 (m,1H), 3.91 (dd,1H,J=4.3Hz,10.4Hz), 4.01 (d,1H,J=7.1Hz), 4.18 (d,1H,J=8.5Hz), 4.30 (d,1H,J=8.5Hz),4.58 (dd,1H,J=6.5Hz,10.7Hz), 4.85 (AB type d,2H,J=11.9Hz),4.91 (dd,1H,J=2.0Hz,9.5Hz), 5.02 (dd,1H,J=1.6Hz,9.9Hz), 5.10 (dd,1H,J=1.6Hz,16.9Hz),5.63 (d,1H,J=7.2Hz), 5.77 (m,1H), 5.98 (m,1H), 7.47 (t,2H,J=7.5Hz), 7.61 (t,1H,J=7.5Hz),8.10 (d,2H,J=7.5Hz).
MS-FAB：871(MH+)
【０５６８】
工程２：10-デアセトキシ-4-デアセチル-10-(2-ヒドロキシエチル)-4-Ｏ-プロピオニル-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-Ｏ-トリエチルシリルバッカチンIII
上記工程１で得た化合物 11.4 g を 150 ml のテトラヒドロフラン、100 mlのメタノール、50 mlの水の混合溶媒に溶解し、N-メチルモルホリン-N-オキシド 7.67 g、四酸化オスミウム水溶液(0.1 M 溶液) 13 mlを加えて室温で 15 時間攪拌した。反応液を酢酸エチルで希釈し、チオ硫酸ナトリウム水溶液、１規定塩酸、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥して溶媒を留去した。残分を 100 ml のテトラヒドロフラン、100 ml のメタノール、100 ml の水の混合溶媒に溶解し、メタ過ヨウ素酸ナトリウム 14 g を加えて室温で３時間攪拌した。反応液を酢酸エチルで希釈し、水、飽和重曹水溶液、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥して溶媒を留去した。得られた残分を乾燥した 230 ml のメタノールに溶解し、水素化ホウ酸ナトリウム 495 mg を０℃で加えて同温で30分間攪拌し、さらに水素化ホウ酸ナトリウム 495 ml を０℃で加えて同温で３０分間攪拌した。反応液を酢酸エチルで希釈し、冷飽和塩化アンモニウム水溶液に注いだ。水層を酢酸エチルで抽出し、あわせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して溶媒を留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝８：２(v/v) ）で精製し標記化合物 7.91 gを無色の非晶質固体として得た。
【０５６９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.60 (m,6H), 0.99 (s,9H), 1.14 (s,6H), 1.32 (m,3H), 1.65 (s,3H),1.90 (m,3H), 1.95 (s,3H), 2.31 (m,1H), 2.40 (m,1H), 2.51 (m,1H),2.70 (m,2H), 3.61 (m,1H), 3.73 (m,1H), 4.06 (m,2H), 4.18 (d,1H,J=8.5Hz), 4.32 (d,1H,J=8.5Hz), 4.59 (dd,1H,J=6.5Hz,10.7Hz),4.82 (AB type d,2H,J=12.0Hz), 4.91 (d,1H,J=9.7Hz),5.63 (d,1H,J=7.3Hz), 5.99 (t,1H,J=8.3Hz), 7.47 (t,2H,J=7.5Hz),7.61 (t,1H,J=7.5Hz), 8.11 (m,2H).
MS-FAB：875 (MH+)
【０５７０】
工程３：10-デアセトキシ-4-デアセチル-4-Ｏ-プロピオニル-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-Ｏ-トリエチルシリル-10-ビニルバッカチンIII
上記工程２で得た化合物を実施例６の工程４と同様に反応させ、次いで実施例６の工程５と同様に反応し、標記化合物を無色の非晶質固体として得た。
【０５７１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.56 (m,6H), 0.94 (t,9H,J=7.8Hz), 1.04 (s,3H), 1.16 (s,3H), 1.33 (t,3H,J=7.5Hz), 1.65 (s,3H), 1.90 (d,3H,J=1.0Hz), 1.91 (m,1H), 2.32 (m,1H), 2.38 (m,1H), 2.49 (m,1H), 2.71 (m,2H), 4.08 (d,1H,J=7.3Hz), 4.16 (d,1H,J=8.3Hz), 4.32 (d,1H,J=8.3Hz),4.51 (d,1H,J=2.5Hz), 4.56 (dd,1H,J=6.3Hz,10.7Hz), 4.86 (AB type d,2H,J=12.0Hz), 4.90 (d,1H,J=9.0Hz),5.06 (d,1H,J=17.5Hz), 5.25 (m,1H), 5.63 (d,1H,J=7.3Hz), 6.04 (t,1H,J=8.0Hz), 6.60 (m,1H), 7.47 (t,2H,J=7.5Hz),7.61 (t,1H,J=7.5Hz), 8.10 (m,2H).
MS-FAB：857(MH+)
【０５７２】
工程４：10-デアセトキシ-4-デアセチル-10-ホルミル-4-Ｏ-プロピオニル-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-Ｏ-トリエチルシリルバッカチン III
上記工程３で得た化合物 4.5 g を 80 ml のテトラヒドロフラン、80 ml のメタノール、80 ml の水の混合溶媒に溶解し、N-メチルモルホリン-N-オキシド 3.07 g、四酸化オスミウム水溶液（0.1 M 溶液） 15.7 mlを加えて室温で 12 時間攪拌した。反応液を酢酸エチルで希釈し、チオ硫酸ナトリウム水溶液、１規定塩酸、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥して溶媒を留去した。得られた残分を 80 ml のテトラヒドロフラン、80 ml のメタノール、80 ml の水の混合溶媒に溶解し、メタ過ヨウ素酸ナトリウム 5.6 g を加えて室温で３時間攪拌した。反応液を酢酸エチルで希釈し、水、飽和重曹水溶液、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥して溶媒を留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝９：１(v/v) ）で精製し標記化合物 3.09 g を無色の非晶質固体として得た。
【０５７３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.60 (m,6H), 0.96 (s,3H), 0.97 (m,9H), 1.05 (s,3H), 1.32 (t,3H,J=7.5Hz), 1.62 (s,3H), 1.84 (s,3H), 1.91 (m,1H), 2.32 (m,2H), 2.52 (m,1H), 2.70 (m,2H), 3.48 (m,1H), 3.95 (d,3H,J=6.8Hz), 4.19 (m,1H), 4.32 (d,1H,J=8.3Hz),4.60 (dd,1H,J=6.3Hz,10.5Hz), 4.84 (AB type d,2H,J=12.0Hz),4.90 (m,1H), 5.63 (d,1H,J=5.6Hz), 6.04 (t,1H,J=8.0Hz),7.47 (t,2H,J=7.5Hz), 7.61 (t,1H,J=7.5Hz), 8.10 (m,2H), 10.23 (s,1H).
MS-FAB：859 (MH+)
【０５７４】
工程５：10-デアセトキシ-4-デアセチル-10-モルホリノメチル-4-Ｏ-プロピオニル-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-Ｏ-トリエチルシリルバッカチンIII
上記工程４で得た化合物 3.08 g を乾燥した 308 ml のエタノールに溶解し、モルホリン 0.624ml、酢酸 0.41 ml を -20℃で加えた。この溶液に水素化シアノホウ酸ナトリウム 55 mgを５分間隔で４回に分けて加えた。-20 ℃で25分間攪拌した後にモルホリン 0.936ml、酢酸 0.625 mlを -20 ℃で加え、６℃で15時間攪拌した。水素化シアノホウ酸ナトリウム 225 mg さらにを加え、室温で３時間反応した。０℃で反応液を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液、飽和食塩水の順に洗浄し無水硫酸マグネシウムで乾燥して溶媒を減圧留去した。得られた残分をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝８：２(v/v) ）で精製し、標記化合物1.51 gを無色の非晶質固体として得た。
【０５７５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.60 (m,6H), 0.97 (t,9H,J=7.5Hz), 1.12 (s,3H), 1.18 (s,3H), 1.32 (t,3H,J=7.5Hz), 1.62 (s,3H), 1.88 (m,1H), 1.98 (s,3H), 2.30-2.40 (m,2H), 2.49 (m,4H), 2.70 (m,4H), 3.15 (dd,1H,J=3.5Hz,13.5Hz), 3.64 (m,4H), 4.05 (d,1H,J=7.3Hz),4.08-4.16 (m,2H), 4.32 (d,1H,J=8.3Hz), 4.60 (dd,1H,J=6.5Hz,10.5Hz), 4.84 (AB type d,2H,J=11.7Hz), 4.90 (d,1H,J=10.0Hz), 5.61 (d,1H,J=6.8Hz), 5.96 (t,1H,J=8.0Hz), 7.47 (t,2H,J=7.5Hz),7.61 (t,1H,J=7.5Hz), 8.10 (d,2H,J=7.5Hz).
MS-FAB：930 (MH+)
【０５７６】
工程６：10-デアセトキシ-4-デアセチル-10-モルホリノメチル-4-Ｏ-プロピオニル-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル) バッカチンIII
上記工程５で得た化合物を実施例１の工程７と同様に反応し、標記化合物を無色の非晶質固体として得た。
【０５７７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.06 (s,3H), 1.12 (s,3H), 1.32 (t,3H,J=7.5Hz), 1.72 (s,3H), 1.82 (m,1H), 1.91 (s,3H), 2.10 (m,1H), 2.32 (m,3H), 2.59 (m,4H),2.70 (m,2H), 3.40 (dd,1H,J=8.0Hz,13.0Hz), 3.61 (m,4H), 4.00 (m,2H), 4.19 (d,1H,J=8.5Hz), 4.31 (d,1H,J=8.5Hz), 4.49 (m,1H),4.82 (AB type d,2H,J=11.7Hz), 4.94 (d,1H,J=7.8Hz),5.61 (d,1H,J=7.3Hz), 5.96 (m,1H), 7.47 (t,2H,J=7.5Hz),7.61 (t,1H,J=7.5Hz), 8.10 (d,2H,J=7.5Hz).
【０５７８】
工程７：10-デアセトキシ-4-デアセチル-10-モルホリノメチル-4-Ｏ-プロピオニル-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-7-Ｏ-トリフルオロメタンスルホニルバッカチンIII
上記工程６で得た化合物を実施例１の工程５と同様に反応し、標記化合物を無色の非晶質固体として得た。
【０５７９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.12 (s,3H), 1.19 (s,3H), 1.31 (t,3H,J=7.3Hz), 1.79 (s,3H), 1.99 (s,3H), 2.20 (m,1H), 2.35 (m,2H), 2.42 (m,2H), 2.59 (m,2H),2.70 (m,3H), 2.81 (m,1H), 3.18 (dd,1H,J=4.0Hz,14.0Hz), 3.62 (m,4H), 4.19 (m,2H), 4.27 (dd,1H,J=4.3Hz,8.3Hz), 4.35 (d,1H,J=8.3Hz), 4.86 (AB type d,2H,J=12.0Hz), 4.88 (m,1H), 5.66 (m,1H), 5.98 (t,1H,J=8.3Hz), 7.49 (t,2H,J=7.5Hz), 7.63 (t,1H,J=7.5Hz),8.08 (d,2H,J=7.5Hz).
MS-FAB：948 (MH+)
【０５８０】
工程８：10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-モルホリノメチル-4-Ｏ-プロピオニル-13-Ｏ-(2,2,2-トリクロロエトキシカルボニル)-19-ノルバッカチンIII
上記工程７で得た化合物を実施例１８の工程３と同様に反応し、標記化合物を無色の非晶質固体として得た。
【０５８１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s,3H), 1.16 (s,3H), 1.28 (t,3H,J=7.3Hz),1.51 (dd,1H,J=5.4Hz,6.8Hz), 1.91 (s,3H), 1.95 (s,1H), 2.10 (d,1H,J=16.1Hz), 2.18 (m,1H), 2.35-2.50 (m,8H), 2.60-2.72 (m,2H),3.36 (dd,1H,J=4.4Hz,13.2Hz), 3.64 (m,4H), 3.80 (t,1H,J=5.4Hz),4.03 (d,1H,J=8.3Hz), 4.31 (d,1H,J=8.3Hz), 4.35 (d,1H,J=7.8Hz),4.69 (d,1H,J=3.9Hz), 4.82 (d,1H,J=12.2Hz), 4.88 (d,1H,J=12.2Hz),5.60 (d,1H,J=7.8Hz), 5.90 (t,1H,J=7.8Hz), 7.49 (t,2H,J=7.5Hz),7.63 (t,1H,J=7.5Hz), 8.11 (m,2H).
MS-FAB：799 (MH+)
【０５８２】
工程９：10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-モルホリノメチル-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程８で得た化合物を実施例１の工程４と同様に反応し、標記化合物を無色の非晶質固体として得た。
【０５８３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.09 (s,3H), 1.26 (t,3H,J=7.3Hz), 1.52 (m,1H), 1.80 (s,1H), 1.96 (s,3H), 2.10 (d,1H,J=16.1Hz), 2.22 (m,2H), 2.32 (m,2H),2.45-2.70 (m,7H), 3.32 (dd,1H,J=4.9Hz,12.7Hz), 3.65 (m,4H), 3.80 (m,1H), 4.05 (d,1H,J=8.8Hz), 4.30 (d,1H,J=8.8Hz),4.38 (d,1H,J=7.8Hz), 4.71 (s,1H), 4.79 (br,1H), 5.59 (d,1H,J=7.8Hz),7.49 (t,2H,J=7.5Hz), 7.61 (t,1H,J=7.5Hz), 8.14 (d,2H,J=7.5Hz).
MS-FAB：623 (MH+)
【０５８４】
工程１０：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-モルホリノメチル-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程９で得た化合物を実施例１の工程８と同様に反応し、標記化合物を無色の非晶質固体として得た。
【０５８５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.31 (s,3H), -0.13 (s,3H), 0.75 (s,9H), 1.18 (s,3H), 1.26 (s,3H),1.28 (s,9H), 1.37 (t,3H,J=7.5Hz), 1.54 (m,1H), 1.81 (s,3H), 1.92 (br,1H), 2.14 (d,1H,J=16.1Hz), 2.18 (m,2H),2.36 (dd,1H,J=5.0Hz,13.1Hz), 2.46 (m,2H), 2.53 (m,4H), 2.79 (m,2H), 3.37 (dd,1H,J=5.2Hz,13.1Hz), 3.66 (m,4H), 3.78 (m,1H),4.07 (d,1H,J=8.5Hz), 4.28 (d,1H,J=7.8Hz), 4.34 (d,1H,J=8.5Hz),4.48 (s,1H), 4.72 (d,1H,J=3.9Hz), 5.26 (br,1H), 5.47 (d,1H,J=9.3Hz),5.66 (d,1H,J=7.8Hz), 6.24 (t,1H,J=8.8Hz), 7.29-7.40 (m,5H), 7.49 (t,2H,J=7.5Hz), 7.58 (t,1H,J=7.5Hz), 8.15 (d,2H,J=7.5Hz).
MS-FAB：1001 (MH+)
【０５８６】
工程１１：13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3-フェニルプロピオニル]-10-デアセトキシ-4-デアセチル-7-デオキシ-7β,8β-メチレン-10-モルホリノメチル-4-Ｏ-プロピオニル-19-ノルバッカチンIII
上記工程１０で得た化合物を実施例１の工程９と同様に反応し、標記化合物を無色の固体として得た。
【０５８７】
融点 :150-155 ℃
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.16 (s,3H), 1.24 (s,3H), 1.26 (m,3H), 1.27 (s,9H), 1.52 (m,1H),1.79 (s,3H), 1.92 (s,1H), 2.08 (d,1H,J=16.1Hz), 2.19 (m,2H),2.38-2.42 (m,4H), 2.50 (m,4H), 2.65 (m,2H), 3.35 (dd,1H,J=5.0Hz,13.1Hz), 3.65 (m,4H), 3.76 (m,1H),4.04 (d,1H,J=8.8Hz), 4.23 (d,1H,J=7.8Hz), 4.31 (d,1H,J=8.8Hz),4.61 (br,1H), 4.69 (d,1H,J=3.9Hz), 5.26 (br,1H), 5.34 (d,1H,J=9.3Hz), 5.62 (d,1H,J=7.8Hz), 6.23 (br,1H), 7.31-7.41 (m,5H),7.51 (t,2H,J=7.5Hz), 7.60 (t,1H,J=7.5Hz), 8.16 (d,2H,J=7.5Hz).
MS-FAB：887 (MH+)
【０５８８】
実施例３５
【０５８９】
【化７５】
工程１：10- アリル-10-デアセトキシ-4- デアセチル-7- デオキシ-6,7- ジデヒドロ-1- Ｏ- ジメチルシリル-4- Ｏ-(エトキシカルボニル)-13- Ｏ- トリエチルシリルバッカチンIII
実施例２の工程２で得た化合物を実施例２の工程３と同様に塩化シクロプロパンカルボニルの代わりにクロロぎ酸エチルを用い反応させ標記化合物を無色の非晶質固体として得た。
【０５９１】
1H-NMR (CDCl3/TMS)δ(ppm) :
-0.26 (d, 3H, J = 3 Hz), 0.09 (d, 3H, J = 3 Hz), 0.68 (m, 6H), 1.02 (t, 9H, J = 7 Hz), 1.08 (s, 3H), 1.13 (s, 3H), 1.39 (t, 3H, J = 7 Hz),1.80 (s, 3H), 1.84 (s, 3H), 2.20 (m, 1H), 2.30 (d, 1H, J = 9 Hz), 2.99 (m, 1H), 3.61 (t, 1H, J = 7 Hz), 4.14 (m, 2H), 4.36 (m, 2H), 4.59 (m, 1H), 4.99 (m, 2H), 5.09 (m, 2H), 5.72 (d, 1H, J = 10 Hz), 5.83 (m, 1H), 5.85 (d, 1H, J = 7 Hz), 6.00 (dd, 1H, J = 6, 10 Hz), 7.48 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.15 (d, 2H, J = 8 Hz).
MS-FAB : 753 (MH+).
【０５９２】
工程２：10- アリル-10-デアセトキシ-4- デアセチル-7- デオキシ-6,7- ジデヒドロ-4- Ｏ-(エトキシカルボニル) バッカチンIII
上記工程１で得た化合物を実施例２の工程４と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０５９３】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.08 (s, 3H), 1.10 (s, 3H), 1.39 (t, 3H, J = 7 Hz), 1.82 (s, 3H), 1.85 (d, 3H, J = 1.5 Hz), 2.05 (s, 3H), 2.23-2.32 (m, 2H), 2.36 (dd, 1H, J = 7, 16 Hz), 2.99 (m, 1H), 3.68 (m, 1H), 4.22 (m, 1H), 4.29 (m, 2H), 4.33 (m, 1H), 4.52 (d, 1H, J = 8 Hz), 4.82 (br, 1H), 5.02 (d, 1H, J = 10 Hz), 5.10 (dd, 1H, J = 1.5, 17 Hz), 5.19 (d, 1H, J = 6 Hz), 5.77 (d, 1H, J = 10 Hz), 5.82 (d, 1H, J = 7 Hz), 5.83 (m, 1H), 6.01 (dd, 1H, J = 6 , 10 Hz), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.14 (m, 2H).
MS-FAB : 580 (MH+).
【０５９４】
工程３：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル) オキシ-3- フェニルプロピオニル]-10- デアセトキシ-4- デアセチル-7- デオキシ-6,7- ジデヒドロ-4- Ｏ-(エトキシカルボニル) バッカチンIII
上記工程２で得た化合物を実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０５９５】
1H-NMR (CDCl3/TMS)δ(ppm) :
-0.33 (s, 3H), -0.12 (s, 3H), 0.74 (s, 9H), 1.12 (s, 3H), 1.26 (s, 3H), 1.33 (m, 3H), 1.35 (s, 9H), 1.72 (s, 3H), 1.88 (s, 3H), 2.18 (m, 1H), 2.28 (m, 1H), 2.58 (dd, 1H, J = 7, 15 Hz), 2.99 (m, 1H), 3.65 (t, 1H, J = 7 Hz), 4.21 (d, 1H, J = 7 Hz), 4.32 (m, 1H), 4.38 (d, 1H, J = 9 Hz), 4.45-4.53 (m, 3H), 5.02(d, 1H, J = 10 Hz), 5.03 (dd, 1H, J = 1.5, 17 Hz), 5.19 (d, 1H, J = 5 Hz), 5.36 (d, 1H, J = 10 Hz), 5.46 (d, 1H, J = 10 Hz), 5.80 (d, 1H, J = 10 Hz), 5.86 (m, 1H), 5.89 (d, 1H, J = 7 Hz), 6.02 (dd, 1H, J = 6, 10 Hz), 6.19 (t, 1H, J = 8 Hz), 7.29-7.38 (m, 5H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.18 (d, 2H, J = 8 Hz)．
MS-FAB : 958 (MH+).
【０５９６】
工程４：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル) オキシ-3- フェニルプロピオニル]-10- デアセトキシ-4- デアセチル-7- デオキシ-6,7- ジデヒドロ-4- Ｏ-(エトキシカルボニル)-10-(2-モルホリノエチル) バッカチンIII
上記工程３で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０５９７】
1H-NMR (CDCl3/TMS)δ(ppm) :
-0.33 (s, 3H), -0.12 (s, 3H), 0.74 (s, 9H), 1.12 (s, 3H), 1.24 (s, 3H), 1.33 (m, 3H), 1.35 (s, 9H), 1.79 (s, 3H), 1.88 (s, 4H), 2.10-2.64 (m, 11H), 3.69 (m, 4H), 3.80 (dd, 1H, J = 5, 7 Hz), 4.21 (d, 1H, J = 7 Hz), 4.32 (m, 1H), 4.38 (d, 1H, J = 8 Hz), 4.49-4.54 (m, 3H), 5.20 (d, 1H, J = 6 Hz), 5.37 (br, 1H), 5.47 (d, 1H, J = 10 Hz), 5.77 (d, 1H, J = 10 Hz), 5.89 (d, 1H, J = 7 Hz), 6.33 (dd, 1H, J = 6, 10 Hz), 6.16 (t, 1H, J = 8 Hz), 7.29-7.38 (m, 5H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.18 (d, 2H, J = 8 Hz)．
MS-FAB : 1031 (MH+).
【０５９８】
工程５： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3- フェニルプロピオニル]-10- デアセトキシ-4- デアセチル-7- デオキシ-6,7- ジデヒドロ-4- Ｏ-(エトキシカルボニル)-10-(2-モルホリノエチル) バッカチンIII
上記工程４で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０５９９】
融点：115-120 ℃．
1H-NMR (CDCl3/TMS)δ(ppm) :
1.10 (s, 3H), 1.20 (s, 3H), 1.26 (t, 3H, J = 7 Hz), 1.37 (s, 9H), 1.68 (s, 3H), 1.80 (s, 1H), 1.83 (s, 3H), 2.25-2.60 (m, 11H), 3.68 (m, 4H), 3.79 (m, 1H), 4.10 (m, 1H), 4.19 (m, 1H), 4.31 (d, 1H, J = 8 Hz), 4.38 (m, 1H), 4.60 (m, 2H), 5.21 (m, 1H), 5.28 (br, 1H), 5.48 (d, 1H, J = 10 Hz), 5.74 (d, 1H, J = 10 Hz), 6.08 (t, 1H, J = 8 Hz), 7.29-7.46 (m, 5H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.11 (d, 2H, J = 8 Hz).
MS-FAB : 917 (MH+).
【０６００】
実施例３６
【０６０１】
【化７６】
工程１：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3- フェニル-2-(トリエチルシリル) オキシプロピオニル]-10- デアセトキシ-4- デアセチル-7- デオキシ-6,7- ジデヒドロ-4- Ｏ-(エトキシカルボニル) バッカチンIII
実施例３５の工程２で得た化合物を実施例４の工程１と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６０３】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.47-0.69 (m, 6H), 0.85 (t, 9H, J = 7 Hz), 1.12 (s, 3H), 1.24 (s, 3H),1.28 (s, 9H), 1.39 (t, 3H, J = 7 Hz), 1.41 (s, 3H), 1.71 (s, 3H), 1.89 (s, 3H), 2.13-2.29 (m, 2H), 2.54-2.60 (m, 1H), 2.96-3.03 (m, 1H),3.66 (t, 1H, J = 7 Hz), 4.24 (d, 1H, J = 7 Hz), 4.43 (d, 1H, J = 8 Hz), 4.50 (d, 1H, J = 8 Hz), 4.57-4.67 (m, 2H), 5.03-5.19 (m, 3H), 5.55 (d, 1H, J = 10 Hz), 5.78 (d, 1H, J = 10 Hz), 5.81-5.91 (m, 1H), 6.02 (dd, 1H, J = 6, 10 Hz), 6.26 (t, 1H, J = 8 Hz), 7.28-7.47 (m, 7H), 7.57 (t, 1H, J = 8 Hz), 8.15 (d, 2H, J = 8 Hz).
【０６０４】
工程２：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-4- デアセチル-7- デオキシ-6,7- ジデヒドロ-4- Ｏ-(エトキシカルボニル) バッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６０５】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.13 (s, 3H), 1.24 (s, 3H), 1.33 (s, 9H), 1.39 (t, 3H, J = 7 Hz), 1.41 (s, 3H), 1.59 (s, 3H), 1.86 (s, 3H), 2.22-2.32 (m, 2H), 2.54-2.60 (m, 1H), 2.95-3.02 (m, 1H), 3.61-3.64 (m, 2H), 4.12 (d, 1H, J = 7 Hz), 4.35 (d, 1H, J = 8 Hz), 4.45-4.50 (m, 2H), 4.47 (d, 1H, J = 8 Hz), 5.02-5.13 (m, 3H), 5.69 (d, 1H, J = 10 Hz), 5.75-5.85 (m, 2H), 5.87 (d, 1H, J = 7 Hz), 6.02 (dd, 1H, J = 6, 10 Hz), 6.17 (t, 1H, J = 8 Hz), 7.28-7.48 (m, 7H), 7.60 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
【０６０６】
工程３： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-4- デアセチル-7- デオキシ-6,7- ジデヒドロ-4- Ｏ-(エトキシカルボニル)-10-(2-モルホリノエチル) バッカチンIII
上記工程２で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６０７】
融点: 125-130 ℃．
1H-NMR (CDCl3/TMS)δ(ppm) :
1.10 (s, 3H), 1.20 (s, 3H), 1.30 (s, 9H), 1.36 (t, 3H, J = 7.5 Hz), 1.62 (s, 3H),1.80 (s, 3H), 2.20-2.60 (m, 10H), 3.65 (s, 4H), 3.79 (m, 1H), 4.10 (m, 1H), 4.32 (d, 1H, J = 8.5 Hz), 4.48 (m, 2H), 4.62 (d, 1H, J = 8.5 Hz), 5.09 (d, 1H, J = 10 Hz), 5.28 (d, 1H, J = 5 Hz), 5.70 (d, 1H, J = 10 Hz), 5.76 (d, 1H, J = 10 Hz), 5.85 (d, 1H, J = 7 Hz), 6.01 (dd, 1H, J = 5, 10 Hz), 6.13 (br, 1H), 7.29-7.42 (m, 5H), 7.46 (t, 2H, J = 7.5 Hz), 7.59 (t, 1H, J = 7.5 Hz), 8.09 (d, 2H, J = 7.5 Hz)
MS-FAB : 931(MH+).
【０６０８】
実施例３７
【０６０９】
【化７７】
工程１：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3- フェニル-2-(トリメチルシリル) オキシプロピオニル]-10- デアセトキシ-7- デオキシ-7α- フルオロバッカチンIII
実施例５の工程４で得た化合物を実施例４の工程１と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６１１】
1H-NMR (CDCl3/TMS)δ(ppm) :
0.09 (s, 9H), 1.11 (s, 3H), 1.18 (s, 9H), 1.28 (s, 3H), 1.37 (s, 3H), 1.62 (s, 3H), 1.71 (s, 3H), 2.32 (s, 3H), 2.08-3.03 (m, 6H), 4.06 (t, 1H, J = 7 Hz), 4.20 (d, 1H, J = 7 Hz), 4.38 (s, 2H), 4.56 (dd, 1H, J = 3, 47Hz), 4.99-5.12 (m, 4H), 5.50 (d, 1H, J = 10 Hz), 5.74-5.81 (m, 2H), 6.35 (t, 1H, J = 8 Hz), 7.29-7.41 (m, 5H), 7.50 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.18 (d, 2H, J = 8 Hz).
【０６１２】
工程２：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-7- デオキシ-7α- フルオロバッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６１３】
1H-NMR (CDCl3/TMS)δ(ppm) :
1.12 (s, 3H), 1.22 (s, 9H), 1.26 (s, 3H), 1.34 (s, 3H), 1.66 (s, 3H), 1.70 (s, 3H), 2.62 (s, 3H), 2.15-3.06 (m, 6H), 3.61 (br, 1H), 4.08 (dd, 1H, J = 5.5, 8 Hz), 4.21 (d, 1H, J = 7 Hz), 4.37 (AB type d, 2H, J = 8.5 Hz), 4.55 (dd, 1H, J = 3, 47 Hz), 5.05-5.11 (m, 4H), 5.52 (d, 1H, J = 10 Hz), 5.71-5.81 (m, 2H), 6.31 (t, 1H, J = 8 Hz), 7.32-7.36 (m, 5H), 7.50 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.17 (d, 2H, J = 8 Hz).
【０６１４】
工程３： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-7- デオキシ-7α- フルオロ-10-(2- モルホリノエチル) バッカチンIII
上記工程２で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６１５】
融点：147-151 ℃.
1H-NMR (CDCl3/TMS) δ(ppm) ：
1.10 (s, 3H), 1.22 (s, 9H), 1.25 (s, 3H), 1.36 (s, 3H), 1.70 (s, 3H),1.75 (s, 3H), 2.65 (s, 3H), 2.14-2.60 (m, 12H), 3.66-3.69 (m, 4H), 4.22-4.23 (m, 2H), 4.37 (AB type d, 2H,J = 8 Hz), 4.53 (dd, 1H, J = 3, 47 Hz), 5.03-5.07 (m, 2H), 5.53 (d, 1H, J = 10 Hz), 5.75 (d, 1H, J = 7 Hz), 6.30 (t, 1H, J = 8 Hz), 7.32-7.37 (m, 5H), 7.50 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.17 (d, 2H, J = 8 Hz) ．
MS-FAB：921 (MH+) ．
【０６１６】
実施例３８
【０６１７】
【化７８】
工程１：10- アリル-10-デアセトキシ-4- デアセチル-4- Ｏ- エトキシカルボニル-13-Ｏ- トリエチルシリルバッカチンIII
10- アリル-7,13-ビス( トリエチルシリル)-10- デアセトキシ-4- デアセチル-1- Ｏ- ジメチルシリル-4- Ｏ- エトキシカルボニルバッカチンIII を実施例５の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６１９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.63-0.68 (m, 6H), 1.00 (t, 9H, J = 7 Hz),1.10 (s, 3H), 1.15 (s, 3H),1.40 (t, 3H, J = 7 Hz), 1.63 (s, 3H), 1.82-1.87 (m, 1H), 1.89 (s, 3H),2.04-2.09 (m, 1H), 2.24-2.30 (m, 2H), 2.51-2.57 (m, 1H), 2.91-2.96 (m, 1H), 3.87 (t, 1H, J = 8 Hz), 4.07 (d, 1H, J = 7 Hz), 4.20 (d, 1H, J = 8 Hz), 4.30-4.45 (m, 3H), 4.92-5.12 (m, 4H), 5.65 (d, 1H, J = 7 Hz), 5.80-5.86 (m, 1H), 7.47 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
【０６２０】
工程２：10- アリル-10-デアセトキシ-4- デアセチル-7- デオキシ-4- Ｏ- エトキシカルボニル-7α- フルオロ-13-Ｏ- トリエチルシリルバッカチンIII
上記工程１で得た化合物を実施例５の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６２１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.62-0.68 (m, 6H), 1.00 (t, 9H, J = 7 Hz), 1.07 (s, 3H), 1.15 (s, 3H),1.39 (t, 3H, J = 7 Hz), 1.67 (s, 3H), 1.84 (s, 3H), 2.07-3.05 (m, 6H),2.49-2.70 (m, 3H), 4.07-4.21 (m, 4H),4.32-4.44 (m, 2H), 4.55 (dd, 1H, J = 3, 47 Hz), 4.92 (t, 1H, J = 8 Hz), 4.98-5.09 (m, 3H), 5.70 (d, 1H, J = 7 Hz), 5.72-5.81 (m, 1H), 7.48 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.14 (d, 2H, J = 8 Hz).
【０６２２】
工程３：10- アリル-10-デアセトキシ-4- デアセチル-7- デオキシ-4- Ｏ- エトキシカルボニル-7α- フルオロバッカチンIII
上記工程２で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６２３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.08 (s, 6H), 1.39 (t, 3H, J = 7 Hz), 1.65 (s, 3H), 1.89 (s, 3H), 2.12-3.06 (m, 6H), 4.10-4.44 (m, 6H), 4.55 (ddd, 1H, J = 2, 4.5, 9 Hz), 4.80 (br, 1H), 5.00 (dd, 1H, J = 1.5, 9 Hz), 5.07-5.13 (m, 2H), 5.75-5.93 (m, 1H), 7.51 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
【０６２４】
工程４：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-4- デアセチル-7- デオキシ-4- Ｏ- エトキシカルボニル-7α- フルオロバッカチンIII
上記工程３で得た化合物を実施例４の工程１と同様に反応し、ついで実施例１の工程９と同様に反応させて標記化合物を無色の非晶質固体として得た。
【０６２５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.11 (s, 3H), 1.20 (s, 3H), 1.34 (s, 9H), 1.37-1.39 (m, 6H), 1.63 (s, 3H), 1.68 (s, 3H), 2.20-3.07 (m, 6H), 3.70 (s, 1H), 4.06 (dd, 1H, J = 4, 8 Hz), 4.12 (d, 1H, J = 7 Hz), 4.33-4.62 (m, 5H), 5.02 (d, 1H, J = 10 Hz), 5.07-5.13 (m, 2H), 5.20 (d, 1H, J = 10 Hz), 5.66-5.82 (m, 3H), 6.11 (t, 1H, J = 8 Hz), 7.28-7.48 (m, 7H), 7.59 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
【０６２６】
工程５：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-4- デアセチル-7- デオキシ-4- Ｏ- エトキシカルボニル-7α- フルオロ-10-(2- モルホリノエチル) バッカチンIII
上記工程４で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の固体として得た。
【０６２７】
融点：130-132 ℃．
1H-NMR (CDCl3/TMS) δ(ppm) ：
1.09 (s, 3H), 1.19 (s, 3H), 1.33 (s, 9H), 1.36-1.41 (m, 6H), 1.67 (s, 3H), 1.73 (s, 3H), 2.16-2.64 (m, 12H), 3.63-3.68 (m, 4H), 4.13 (d, 1H, J = 7 Hz), 4.19 (t, 1H, J = 5.5 Hz), 4.33-4.58 (m, 5H), 5.08 (d, 1H, J = 10 Hz), 5.20 (d, 1H, J = 7 Hz), 5.75-5.77 (m, 2H), 6.10 (t, 1H, J = 8 Hz), 7.29-7.48 (m, 7H), 7.59 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz)．
MS-FAB：951 (MH+).
【０６２８】
実施例３９
【０６２９】
【化７９】
工程１： 13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル) オキシ-3- フェニルプロピオニル]-10- デアセトキシ-2- デベンゾイル-7- デオキシ-7β,8β- メチレン-10-(2- モルホリノエチル)-19- ノルバッカチンIII
実施例１８の工程６で得た化合物 89 mg を4.5 ml の乾燥したジクロロメタンに溶解し、Triton B (89 ml, 40% w/wメタノール溶液) を -78 ℃ にて加えて同温で5 分間、-10 ℃ で7 分間撹拌した。 反応液を酢酸エチルで希釈後、1 規定塩酸（10 ml ）を加え反応を停止し、酢酸エチルで抽出操作を行ない、飽和重曹水、飽和食塩水の順で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を留去し、得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒、 クロロホルム：メタノール＝ ９５：５(v/v) ）で精製し標記化合物 41 mg を無色の非晶質固体として得た。
【０６３１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.34 (s, 3H), -0.12 (s, 3H), 0.76 (s, 9H), 1.10 (s, 3H), 1.24 (s, 3H), 1.44 (s, 9H), 1.61 (m, 1H), 1.77 (s, 3H), 1.90 (br, 1H),2.08-2.22 (m, 2H), 2.38-2.58 (m, 14H), 3.69 (m, 5H), 3.81 (d, 1H, J = 8 Hz), 3.98 (br, 1H), 4.42 (s, 1H), 4.52 (d, 1H, J = 9.5 Hz), 4.65 (d, 1H, J = 9.5 Hz), 4.79 (d, 1H, J = 4 Hz), 5.22 (d, 1H, J = 10 Hz), 5.50 (d, 1H, J = 10 Hz), 6.21 (m, 1H), 7.23 (t, 1H, J = 8 Hz), 7.28 (m, 1H), 7.36 (m, 2H)
MS-FAB : 897(MH+).
【０６３２】
工程２：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3- フェニルプロピオニル]-10- デアセトキシ-2- デベンゾイル-7- デオキシ-2- Ｏ-(3-メトキシベンゾイル)-7 β,8β- メチレン-10-(2- モルホリノエチル)-19- ノルバッカチンIII
上記工程１で得た化合物13 mg を0.4 ml の乾燥したテトラヒドロフランに溶解した。 ついで、 -78 ℃ にてリチウムビス( トリメチルシリル) アミド( １Ｍテトラヒドロフラン溶液、73 ml ）および３- メトキシベンゾイルクロライド10 ml を加えて同温で 120 分間撹拌した。 反応液を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液を加えて反応を停止後、 有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、溶媒を留去し、得られた残分をシリカゲル薄層クロマトグラフィー( 展開溶媒；ヘキサン：酢酸エチル＝４：１(v/v)) で精製した。得られた化合物を実施例１の工程９と同様に反応させ標記化合物4 mgを白色固体として得た。
【０６３３】
融点：110-115 ℃.
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.20 (s, 3H), 1.22 (s, 3H), 1.28 (s, 9H), 1.56 (m, 1H), 1.80 (s, 3H), 2.12 (d, 1H, J = 16 Hz), 2.20 (m, 2H), 2.37-2.49 (m, 12H), 2.56 (m, 1H), 3.72 (s, 4H), 3.75 (m, 1H), 3.90 (s, 3H), 4.03 (d, 1H, J = 8.5 Hz), 4.28 (d, 1H, J = 7.5 Hz), 4.38 (d, 1H, J = 8.5 Hz), 4.59 (s, 1H), 4.75 (d, 1H, J = 3.5 Hz), 5.28 (br, 1H), 5.33 (d, 1H, J = 9 Hz), 5.65 (d, 1H, J = 7 Hz), 6.22 (m, 1H), 7.13 (dd, 1H, J = 2.5, 8 Hz), 7.30-7.43 (m, 6H), 7.69 (br, 1H), 7.76 (d, 1H, J = 8 Hz).
MS-FAB : 917 (MH+).
【０６３４】
実施例４０
【０６３５】
【化８０】
工程１：10- アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-(2-フリル) プロピオニル]-10- デアセトキシ-7- デオキシ-7β,8β- メチレン-19-ノルバッカチンIII
実施例１８の工程４で得た化合物および (3R,4R)-1-(tert- ブトキシカルボニル)-3-(tert-ブチルジメチルシリル) オキシ-4-(2-フリル)-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６３７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.16 (s, 3H), 0.02 (s, 3H), 0.79 (s, 9H), 1.21 (s, 3H), 1.22 (s, 3H),1.28 (s, 9H), 1.55 (m, 1H), 1.73 (s, 3H), 1.83 (br, 1H), 2.10-2.25 (m, 4H), 2.42-2.48 (m, 2H), 2.45 (s, 3H), 2.99 (m, 1H), 3.69 (t, 1H, J = 7 Hz), 4.05 (d, 1H, J = 9 Hz), 4.29 (m, 2H), 4.70 (d, 1H, J = 2 Hz), 4.76 (d, 1H, J = 3.5 Hz), 5.03 (d, 1H, J = 10 Hz), 5.10 (dd, 1H, J = 1.5, 17 Hz), 5.24 (d, 1H, J = 10 Hz), 5.38 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 8 Hz), 5.83 (m, 1H), 6.21 (m, 1H), 6.26 (t, 1H, J = 6 Hz), 6.35 (m, 1H), 7.37 (s, 1H), 7.49 (t, 2H, J = 7.5 Hz), 7.57 (t, 1H, J = 7.5 Hz), 8.14 (d, 2H, J = 7.5 Hz)
MS-FAB : 918(MH+).
【０６３８】
工程２：13- Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2- フリル)-2-ヒドロキシプロピオニル]-10- デアセトキシ-7- デオキシ-7β,8β- メチレン-10-(2- モルホリノエチル)-19- ノルバッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ、次いで実施例１の工程１０と同様に反応させて標記化合物を無色の固体として得た。
【０６３９】
融点：130-135 ℃.
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.20 (s, 6H), 1.30 (s, 9H), 1.57 (m, 1H),1.82 (s, 3H), 1.87 (br, 1H),2.10 (d, 1H, J = 16 Hz), 2.22 (m, 2H), 2.30-2.60 (m, 10H), 2.38 (s, 3H), 3.70 (m, 4H),4.71 (m, 1H), 4.76 (m, 1H), 4.05 (d, 1H, J = 8.5 Hz), 4.29 (m, 2H), 4.69 (s, 1H), 4.75 (d, 1H, J = 3 Hz), 5.22 (d, 1H, J = 10 Hz), 5.35(d, 1H, J = 10 Hz), 5.68 (d, 1H, J = 8 Hz), 6.22 (t, 1H, J = 9 Hz), 6.32 (m, 1H), 6.39 (m, 1H), 7.42 (s, 1H), 7.49 (t, 2H, J = 7.5 Hz), 7.59(t, 1H, J = 7.5 Hz), 8.16 (d, 2H, J = 7.5Hz) ．
MS-FAB : 877(MH+) ．
【０６４０】
実施例４１
【０６４１】
【化８１】
工程１：10- アリル-10-デアセトキシ-2- デベンゾイル-7- デオキシ-7β,8β- メチレン-19-ノルバッカチンIII
実施例１９の工程１で得た化合物 100 mg を 1.5 ml の乾燥したテトラヒドロフランに溶解し、水素化ビス（２−メトキシエトキシ）アルミニウムナトリウム 180μl を加え 0℃で２０分間攪拌した。反応混液に酢酸エチル、飽和酒石酸カリウム水溶液、及び水を加え分液し、水層を酢酸エチルで抽出した。有機層を合わせて無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残分をシリカゲル薄層クロマトグラフィ−（展開溶媒；ヘキサン：酢酸エチル＝３：２（ｖ／ｖ））を用いて精製し、標記化合物 70 mgを無色の非晶質固体として得た。
【０６４３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.68 (m, 6H), 0.99 (m, 9H), 1.10 (s, 3H), 1.19 (s, 3H), 1.56 (dd, 1H, J = 5, 7 Hz), 1.65 (br, 1H), 1.76 (s, 3H), 1.92 (dd, 1H, J = 8, 15 Hz), 2.05-2.20 (m, 7H), 2.34 (d, 1H, J = 7 Hz), 2.45 (m, 1H), 2.94 (m, 1H), 3.61 (dd, 1H, J = 6, 8 Hz), 3.77 (d, 1H, J = 7 Hz), 3.94 (t, 1H, J = 7 Hz), 4.51 (d, 1H, J = 9 Hz), 4.60 (d, 1H, J = 9 Hz), 4.77 (d, 1H, J = 4 Hz), 4.93 (t, 1H, J = 8 Hz), 4.96 (m, 1H), 5.05 (dd, 1H, J = 1.5, 17 Hz), 5.81 (m, 1H)．
MS-FAB : 560 (MH+).
【０６４４】
工程２：10- アリル-2- Ｏ-(3-クロロベンゾイル)-10- デアセトキシ-2- デベンゾイル-7- デオキシ-7β,8β- メチレン-19-ノルバッカチンIII
上記工程１で得た化合物 35 mgを1.05 ml の乾燥したトルエンに溶解し、室温にて３−クロロ安息香酸196 mg、ジシクロヘキシルカルボジイミド258 mg、４−ジメチルアミノピリジン153 mgを加え60℃で1 日間攪拌した。反応液を酢酸エチルで希釈し氷冷下、飽和酒石酸水溶液を加えて反応を停止後、 有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し溶媒を減圧留去した。 得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝４：１(v/v)) で精製した。次いで、得られた化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６４５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.10 (s, 3H), 1.18 (s, 3H), 1.52 (t, 1H, J = 6 Hz), 1.78 (s, 1H), 1.89 (s, 3H), 2.12 (d, 1H, J = 16 Hz), 2.20-2.32 (m, 4H), 2.28 (s, 3H), 2.46 (dt, 1H, J = 4.5, 16 Hz), 3.00 (m, 1H), 3.71 (dd, 1H, J = 6, 8 Hz), 4.02 (d, 1H, J = 9 Hz), 4.27 (d, 1H, J = 8 Hz), 4.36 (d, 1H, J = 8 Hz), 4.77 (d, 1H, J = 4 Hz), 4.82 (t, 1H, J = 7 Hz), 5.01 (d, 1H, J = 10 Hz), 5.09 (dd, 1H, J = 1.5, 17 Hz), 5.56 (d, 1H, J = 8 Hz), 5.82 (m, 1H), 7.43 (d, 1H, J = 8 Hz), 7.57 (m, 1H), 8.00 (d, 1H, J = 8 Hz), 8.16 (m, 1H) ．
MS-FAB : 585 (MH+).
【０６４６】
工程３：10- アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-(2-フリル) プロピオニル]-2-Ｏ-(3-クロロベンゾイル)-10- デアセトキシ-2- デベンゾイル-7- デオキシ-7β,8β- メチレン-19-ノルバッカチンIII
上記工程２で得た化合物および (3R,4R)-1-(tert- ブトキシカルボニル)-3-(tert-ブチルジメチルシリル) オキシ-4-(2-フリル)-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６４７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.16 (s, 3H), 0.02 (s, 3H), 0.79 (s, 9H), 1.21 (s, 3H), 1.22 (s, 3H),1.28 (s, 9H), 1.55 (m, 1H), 1.73 (s, 3H), 1.77 (br, 1H), 2.10-2.25 (m, 4H), 2.38-2.49 (m, 2H), 2.45 (s, 3H), 3.00 (m, 1H), 3.69 (m, 1H), 4.03 (d, 1H, J = 8 Hz), 4.29(m, 2H), 4.70 (m, 1H), 4.76 (d, 1H, J = 4 Hz), 5.03 (d, 1H, J = 10 Hz), 5.10 (dd, 1H, J = 1.5, 17 Hz), 5.24 (d, 1H, J = 10 Hz), 5.35 (d, 1H, J = 10 Hz), 5.61 (d, 1H, J = 8 Hz), 5.83 (m, 1H), 6.21 (m, 1H), 6.23 (m, 1H), 6.35 (m, 1H), 7.37 (m, 1H), 7.45 (t, 1H, J = 8 Hz), 7.54 (d, 1H, J = 8 Hz), 8.03 (d, 1H, J = 8 Hz), 8.15 (m, 1H) ．
MS-FAB : 952(MH+).
【０６４８】
工程４：13- Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2- フリル)-2-ヒドロキシプロピオニル]-2-Ｏ-(3-クロロベンゾイル)-10- デアセトキシ-2- デベンゾイル-7- デオキシ-7β,8β- メチレン-10-(2- モルホリノエチル)-19- ノルバッカチンIII
上記工程3 で得た化合物を実施例１の工程９と同様に反応させ、次いで実施例１の工程１０と同様に反応させて標記化合物を無色の固体として得た。
【０６４９】
融点：125-130 ℃．
1H-NMR(CDCl3/TMS) δ(ppm) ：
1.20 (s, 3H), 1.30 (s, 9H), 1.57 (m, 1H), 1.82 (s, 4H), 2.12 (d, 1H, J = 16 Hz), 2.22 (m, 2H), 2.30-2.60 (m, 7H), 2.38 (s, 3H), 3.70 (m, 4H), 3.77 (t, 1H, J = 6 Hz), 4.02 (d, 1H, J = 8.5 Hz), 4.29 (m, 2H), 4.68 (d, 1H, J = 2.5 Hz), 4.78 (d, 1H, J = 3.5 Hz), 5.22 (d, 1H, J = 10 Hz), 5.32 (br, 1H), 5.61 (d, 1H, J = 8 Hz), 6.20 (t, 1H, J = 8.5 Hz), 6.30 (d, 1H, J = 3.5 Hz), 6.37 (m, 1H), 7.42 (s, 1H), 7.45 (t, 1H, J = 8 Hz), 7.57 (m, 1H), 8.04 (d, 1H, J = 8 Hz), 8.17 (s, 1H) ．
MS-FAB : 911 (MH+).
【０６５０】
実施例４２
【０６５１】
【化８２】
工程１：10- アリル-10-デアセトキシ-2- デベンゾイル-7- デオキシ-2- Ｏ-(3-メトキシベンゾイル)-7 β,8β- メチレン-19-ノルバッカチンIII
実施例４１の工程１で得た化合物を実施例４１の工程２と同様に、３−クロロ安息香酸の代わりに３−メトキシ安息香酸を用い反応させ、次いで実施例１の工程７と同様に反応させて標記化合物を無色の非晶質固体として得た。
【０６５３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.10 (s, 3H), 1.16 (s, 3H), 1.52 (dd, 1H, J = 5, 7 Hz), 1.82 (br, 1H),1.89 (s, 3H), 2.10 (d, 1H, J = 16 Hz), 2.20-2.25 (m, 3H), 2.25 (s, 3H), 2.35 (dd, 1H, J = 7, 16 Hz), 2.44 (dt, 1H, J = 4.5, 16 Hz), 3.00 (m, 1H), 3.71 (dd, 1H, J = 6, 8 Hz), 3.87 (s, 3H), 4.04 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.36 (d, 1H, J = 8 Hz), 4.75 (d, 1H, J = 4.5 Hz), 4.83 (d, 1H, J = 8 Hz), 5.01 (m, 1H), 5.08 (dd, 1H, J = 1.5, 17 Hz), 5.60 (d, 1H, J = 7 Hz), 5.82 (m, 1H), 7.15 (m, 1H), 7.39 (m, 1H), 7.67 (m, 1H), 7.73 (d, 1H, J = 8 Hz)．
MS-FAB : 580 (MH+).
【０６５４】
工程２：10- アリル-13-Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3-(2-フリル) プロピオニル]-10- デアセトキシ-2- デベンゾイル-7- デオキシ-2- Ｏ-(3-メトキシベンゾイル)-7 β,8β- メチレン-19-ノルバッカチンIII
上記工程１で得た化合物および (3R,4R)-1-(tert- ブトキシカルボニル)-3-(tert-ブチルジメチルシリル) オキシ-4-(2-フリル)-2-アゼチジノンを実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６５５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.16 (s, 3H), 0.02 (s, 3H), 0.79 (s, 9H), 1.21 (s, 3H), 1.22 (s, 3H),1.28 (s, 9H), 1.55 (m, 1H), 1.73 (s, 3H), 1.84 (br, 1H), 2.10-2.25 (m, 4H), 2.43 (s,3H), 2.40-2.48 (m, 2H), 2.99 (m, 1H), 3.69 (m, 1H), 3.84 (s, 3H), 4.05 (d, 1H, J = 8 Hz), 4.29 (d, 1H, J = 8 Hz), 4.35 (d, 1H, J = 8 Hz), 4.69 (m, 1H), 4.75 (d, 1H, J = 4 Hz), 5.03 (d, 1H, J = 10 Hz), 5.12 (dd, 1H, J = 1.5, 17 Hz), 5.24 (d, 1H, J = 10 Hz), 5.31 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 8 Hz), 5.83 (m, 1H), 6.21 (m, 1H), 6.23 (m, 1H), 6.33 (m, 1H), 7.12 (m, 1H), 7.37 (s, 1H),7.39 (t, 2H, J = 8 Hz), 7.67 (m, 1H), 7.77 (d, 2H, J = 8 Hz).
MS-FAB : 948 (MH+).
【０６５６】
工程３：13- Ｏ-[(2R,3R)-3-(tert-ブトキシカルボニルアミノ)-3-(2- フリル)-2-ヒドロキシプロピオニル]-10- デアセトキシ-2- デベンゾイル-7- デオキシ-2- Ｏ-(3-メトキシベンゾイル)-7 β,8β- メチレン-10-(2- モルホリノエチル)-19- ノルバッカチンIII
上記工程2 で得た化合物を実施例１の工程９と同様に反応させ、次いで実施例１の工程１０と同様に反応させて標記化合物を無色の固体として得た。
【０６５７】
融点:120-125℃．
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.20 (s, 3H), 1.28 (s, 9H), 1.55 (m, 1H),1.80 (s, 3H), 1.88 (s, 3H), 2.12 (d, 1H, J = 16 Hz), 2.20 (m, 2H), 2.30-2.60 (m, 7H), 2.38 (s,3H),3.70 (m, 4H), 3.77 (d, 1H, J = 8 Hz), 4.89 (s,3H), 4.04 (d, 1H, J = 8 Hz), 4.28 (d, 1H, J = 8 Hz), 4.35 (d, 1H, J = 8 Hz), 4.68 (s, 1H), 4.76 (d, 1H, J = 4 Hz), 5.20 (d, 1H, J = 10 Hz), 5.32 (br, 1H), 6.21 (t, 1H, J = 8 Hz), 6.30 (d, 1H, J = 3 Hz), 6.37 (m, 1H), 7.14 (dd, 1H, J = 3, 8 Hz), 7.41 (t, 1H, J = 8 Hz), 7.42 (s, 1H), 7.68 (br, 1H), 7.76 (d, 1H, J = 8 Hz) ．
MS-FAB : 907 (MH+).
【０６５８】
実施例４３
【０６５９】
【化８３】
工程１：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル）オキシ-3- フェニルプロピオニル]-2-Ｏ-(3-クロロベンゾイル)-10- デアセトキシ-2- デベンゾイル-7- デオキシ-7β,8β- メチレン-19-ノルバッカチンIII
実施例４１の工程２で得た化合物を実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６６１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.32 (s, 3H), -0.12 (s, 3H), 0.73 (s, 9H), 1.21 (s, 3H), 1.25 (s, 3H), 1.26 (s, 9H), 1.55 (m, 1H), 1.73 (s, 3H), 1.80 (br, 1H),2.18-2.25 (m, 4H), 2.38-2.49 (m, 2H), 2.51 (s, 3H), 2.99 (m, 1H), 3.69 (t, 1H, J = 8 Hz), 4.03 (d, 1H, J = 8 Hz), 4.28 (d, 1H, J = 7 Hz), 4.30 (d, 1H, J = 8 Hz), 4.49 (s, 1H), 4.79 (m, 1H), 5.02 (d, 1H, J = 10 Hz), 5.12 (d, 1H, J = 17 Hz), 5.30 (br, 1H), 5.41 (br, 1H), 5.61 (d, 1H, J = 7 Hz), 5.82 (m, 1H), 6.25 (t, 1H, J = 9 Hz), 7.25-7.36 (m, 5H), 7.44 (t, 2H, J = 8 Hz), 7.56 (d, 1H, J = 8 Hz), 8.03 (d, 1H, J = 8 Hz), 8.17 (s, 1H).
MS-FAB : 962 (MH+).
【０６６２】
工程２：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3- フェニルプロピオニル]-2-Ｏ-(3-クロロベンゾイル)-10- デアセトキシ-2- デベンゾイル-7- デオキシ-7β,8β- メチレン-10-(2- モルホリノエチル)-19- ノルバッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ、次いで実施例１の工程１０と同様に反応させて標記化合物を無色の固体として得た。
【０６６３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.20 (s, 3H), 1.21 (s, 3H), 1.28 (s, 9H), 1.55 (m, 1H), 1.80 (s, 4H),2.08-2.23 (m, 3H), 2.30-2.60 (m, 10H), 2.37 (s, 3H), 3.70 (m, 4H), 3.76 (t, 1H, J = 6 Hz), 4.02 (d, 1H, J = 9 Hz), 4.29 (m, 2H), 4.57 (s, 1H), 4.76 (d, 1H, J = 3.5 Hz), 5.28 (br, 1H), 5.31 (d, 1H, J = 10 Hz), 5.60 (d, 1H, J = 7 Hz), 6.20 (br, 1H), 7.29-7.40 (m, 5H), 7.46 (t, 2H, J = 8 Hz), 7.58 (d, 1H, J = 8 Hz), 8.03 (d, 1H, J = 8 Hz), 8.18 (s, 1H)．
MS-FAB : 921 (MH+).
【０６６４】
実施例４４
【０６６５】
【化８４】
工程１：10- デアセトキシ-2- デベンゾイル-7- Ｏ- メチル-10-(2- モルホリノエチル)-13- Ｏ- トリエチルシリルバッカチンIII
実施例１０の工程３で得た化合物を実施例４１の工程１と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６６７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.65 (m, 6H), 1.00 (t, 9H, J = 8 Hz), 1.02 (s, 3H), 1.12 (s, 3H), 1.60 (s, 3H), 1.76 (m, 1H), 1.91 (s, 3H), 2.02 (m, 1H), 2,18 (s, 3H),2.22-2.75 (m, 10H), 3.24 (s, 3H), 3.59 (d, 1H, J = 7 Hz), 3.70 (m, 4H), 3.82 (d, 1H, J = 7 Hz), 3.95 (m, 1H), 4.68 (d, 1H, J = 7 Hz), 4.62 (d, 1H, J = 7 Hz), 4.92 (t, 1H, J = 8 Hz), 5.02 (d, 1H, J = 7 Hz).
MS-FAB : 665 (MH+).
【０６６８】
工程２：10- デアセトキシ-2- デベンゾイル-2- Ｏ-(3-メトキシベンゾイル)-7-Ｏ- メチル-10-(2- モルホリノエチル)-13- Ｏ- トリエチルシリルバッカチンIII
上記工程１で得た化合物を実施例４１の工程２と同様に、３−クロロ安息香酸の代わりに３−メトキシ安息香酸を用い反応させ標記化合物を無色の非晶質固体として得た。
【０６６９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.67 (m, 6H), 1.01 (t, 9H, J = 7 Hz), 1.10 (s, 6H), 1.66 (s, 3H), 1.70-2.80 (m, 12H), 1.88 (s, 3H), 2.28 (s, 3H), 3.25 (s, 3H), 3.64 (m, 1H), 3.69 (m, 4H), 3.85 (s, 3H), 3.94 (m, 1H), 4.00 (m, 1H),4.18 (d, 1H, J = 8.5 Hz), 4.28 (dd, 1H, J = 6.5, 10.5 Hz), 4.33 (d, 1H, J = 8.5 Hz), 4.91 (t, 1H, J = 8 Hz), 5.03 (d, 1H, J = 8 Hz), 5.59 (d, 1H, J = 7 Hz), 7.14 (m, 1H), 7.37 (t, 1H, J = 8 Hz), 7.63 (s, 1H), 7.69 (d, 1H, J = 8 Hz).
MS-FAB : 800 (MH+).
【０６７０】
工程３：10- デアセトキシ-2- デベンゾイル-2- Ｏ-(3-メトキシベンゾイル)-7-Ｏ- メチル-10-(2- モルホリノエチル) バッカチンIII
上記工程２で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６７１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.06 (s, 3H), 1.12 (s, 3H), 1.66 (s, 3H), 1.75 (m, 1H), 2.05 (s, 3H), 2.26 (s, 3H), 2.30-2.75 (m, 11H), 3.26 (s, 3H), 3.64 (m, 1H), 3.69 (m, 4H), 3.85 (s, 3H), 3.99 (m, 1H), 4.09 (d, 1H, J = 7 Hz), 4.16 (d, 1H, J = 8.5 Hz), 4.32 (d, 1H, J = 8.5 Hz), 4.81 (br, 1H), 5.00 (d, 1H, J = 7 Hz), 5.59 (d, 1H, J = 7 Hz), 7.12 (dd, 1H, J = 3, 8.5 Hz), 7.36 (t, 1H, J = 8 Hz), 7.64 (d, 1H, J = 2 Hz), 7.70 (d, 1H, J = 8 Hz).
【０６７２】
工程４：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-2- デベンゾイル-2- Ｏ-(3-メトキシベンゾイル)-7-Ｏ- メチル-10-(2- モルホリノエチル) バッカチンIII
上記工程３および参考例４の工程３で得た化合物を実施例４の工程１と同様に反応させ、次いで実施例１の工程９と同様に反応させて標記化合物を無色の固体として得た。
【０６７３】
融点:125-130 ℃．
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.14 (s, 3H), 1.22 (s, 9H), 1.24 (s, 3H), 1.25 (s, 3H), 1.68 (s,3H), 1.79 (s, 3H), 1.79 (m, 1H), 2.17-2.75 (m, 11H), 2.62 (s, 3H), 3.27 (s,3H), 3.59 (br, 1H), 3.65 (m, 1H), 3.67 (br, 4H), 3.89 (s, 3H),3.97 (m, 2H), 4.19 (d, 1H, J = 8.5 Hz), 4.38 (d, 1H, J = 8.5 Hz), 5.01 (m, 2H), 5.54 (d, 1H, J = 10 Hz), 5.64 (d, 1H, J = 7 Hz), 6.29 (t, 1H, J = 8 Hz), 7.13 (dd, 1H, J = 2, 8 Hz), 7.36 (m, 5H), 7.38 (m, 1H), 7.66 (m, 1H), 7.74 (d, 1H, J = 8 Hz).
MS-FAB : 963 (MH+).
【０６７４】
実施例４５
【０６７５】
【化８５】
工程１：10- デアセトキシ-2- デベンゾイル-2- Ｏ-(3,5-ジフルオロベンゾイル)-7-Ｏ- メチル-10-(2- モルホリノエチル)-13- Ｏ- トリエチルシリルバッカチンIII
実施例４４の工程１で得た化合物を実施例４１の工程２と同様に、３−クロロ安息香酸の代わりに３，５−ジフルオロ安息香酸を用い反応させ標記化合物を無色の非晶質固体として得た。
【０６７７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.67 (m, 6H), 1.01 (t, 9H, J = 7 Hz), 1.08 (s, 3H), 1.10 (s, 3H), 1.66 (s,3H), 1.75 (m, 1H), 1.99 (s, 3H), 2.10-2.75 (m, 11H), 2.29 (s, 3H), 3.26 (s, 3H), 3.64 (m, 1H), 3.69 (m, 4H), 3.95 (m, 1H),4.01 (d, 1H, J = 7 Hz), 4.14 (d, 1H, J = 8.5 Hz), 4.28 (d, 1H, J = 8.5 Hz), 4.90 (t, 1H, J = 8 Hz), 5.03 (d, 1H, J = 8 Hz), 5.52 (d, 1H, J = 7 Hz), 7.06 (m, 1H), 7.60 (d, 2H, J = 5.5 Hz)．
MS-FAB : 806 (MH+).
【０６７８】
工程２：10- デアセトキシ-2- デベンゾイル-2- Ｏ-(3,5-ジフルオロベンゾイル)-7-Ｏ- メチル-10-(2- モルホリノエチル) バッカチンIII
上記工程１で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６７９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.06 (s, 3H), 1.10 (s, 3H), 1.68 (s, 3H), 2.08 (s, 3H), 1.70-2.72 (m, 12H), 2.30 (s, 3H), 3.28 (s, 3H), 3.69 (s, 5H), 4.00 (m, 1H), 4.10 (m, 1H), 4.13 (d, 1H, J = 8.5 Hz), 4.29 (d, 1H, J = 8.5 Hz), 4.82 (br, 1H), 5.00 (d, 1H, J = 8 Hz), 5.52 (d, 1H, J = 7 Hz), 7.02 (m, 1H), 7.60 (d, 1H, J = 5.5 Hz) ．
【０６８０】
工程３：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-2- デベンゾイル-2- Ｏ-(3,5-ジフルオロベンゾイル)-7-Ｏ- メチル-10-(2- モルホリノエチル) バッカチンIII
上記工程２および参考例４の工程３で得た化合物を実施例４の工程１と同様に反応させ、次いで実施例１の工程９と同様に反応させて標記化合物を無色の固体として得た。
【０６８１】
融点:130-135 ℃．
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.12 (s, 3H), 1.22 (s, 9H), 1.23 (s, 3H), 1.38 (s, 3H), 1.69 (s, 3H),1.78 (s, 3H), 1.78 (m, 1H), 2.10-2.72 (m, 11H), 2.61 (s, 3H), 3.25 (s, 3H), 3.68 (br, 4H), 3.95 (m, 3H), 4.15 (d, 1H, J = 8.5 Hz), 4.31 (d, 1H, J = 8.5 Hz), 5.00 (m, 2H), 5.50 (d, 1H, J = 10 Hz), 5.59 (d, 1H, J = 7 Hz), 6.26 (m, 1H), 7.03 (m, 1H), 7.18-7.33 (m, 5H), 7.66 (m, 2H) ．
MS-FAB : 969 (MH+).
【０６８２】
実施例４６
【０６８３】
【化８６】
工程１：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3-(4-トリル)-2-( トリメチルシリル) オキシプロピオニル]-10- デアセトキシ-7- Ｏ- メチルバッカチンIII
実施例１１の工程１０で得た化合物および参考例５の工程３で得た化合物を実施例４の工程１と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６８５】
1H-NMR(CDCl3/TMS) δ(ppm) ：
0.11 (s, 9H), 1.14 (s, 3H), 1.16 (s, 9H), 1.28 (s, 3H), 1.38 (s, 3H), 1.69 (s, 3H), 1.79 (s, 3H), 1.76-1.82 (m, 1H), 2.03-2.09 (m, 1H), 2.22-2.34 (m, 2H), 2.35 (s, 3H), 2.67-2.72 (m, 1H), 2.69 (s, 3H), 2.96-3.04 (m, 1H), 3.24 (s, 3H), 3.76 (t, 1H, J = 7 Hz), 3.92-3.98 (m, 2H), 4.21 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.94-5.08 (m, 3H), 5.45 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 7 Hz), 5.80-5.90 (m, 1H), 6.36 (t, 1H, J = 8 Hz), 7.15 (s, 4H), 7.47 (t, 2H, J = 8 Hz), 7.56 (t, 1H, J = 8 Hz), 8.14 (d, 2H, J = 8 Hz).
【０６８６】
工程２：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3-(4-トリル) プロピオニル]-10- デアセトキシ-7- Ｏ- メチルバッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６８７】
1H-NMR(CDCl3/TMS) δ(ppm) ：
1.15 (s, 3H), 1.23 (s, 9H), 1.25 (s, 3H), 1.37 (s, 3H), 1.68 (s, 3H),1.70 (s, 3H), 1.75-1.82 (m, 1H), 2.15-2.31 (m, 3H), 2.36 (s, 3H), 2.61 (s, 3H), 2.65-2.73 (m, 1H), 2.93-3.00 (m, 1H), 3.25 (s, 3H), 3.56 (br, 1H), 3.77 (t, 1H, J = 7 Hz), 3.93 (dd, 1H, J = 7, 10 Hz), 3.98 (d, 1H, J = 7 Hz), 4.21 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.99-5.11 (m, 3H), 5.50 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 7 Hz), 5.75-5.86 (m, 1H), 6.29 (t, 1H, J = 8 Hz), 7.17 (d, 2H, J = 8 Hz), 7.25 (d, 2H, J = 8 Hz), 7.48 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
【０６８８】
工程３：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3-(4-トリル) プロピオニル]-10- デアセトキシ-7- Ｏ- メチル-10-(2- モルホリノエチル) バッカチンIII
上記工程２で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の固体として得た。
【０６８９】
融点：158-162 ℃．
1H-NMR(CDCl3/TMS) δ(ppm) ：
1.14 (s, 3H), 1.22 (s, 9H), 1.24 (s, 3H), 1.37 (s, 3H), 1.69 (s, 3H),1.84 (s, 3H), 1.75-1.82 (m, 1H), 2.14-2.75 (m, 11H), 2.36 (s, 3H), 2.64 (s, 3H), 3.26 (s, 3H), 3.60 (br, 1H), 3.67 (s, 4H), 3.95-4.02 (m, 3H), 4.21 (d, 1H, J = 8 Hz), 4.32 (d, 1H, J = 8 Hz), 5.00-5.02 (m, 2H), 5.48 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 7 Hz), 6.31 (t, 1H, J = 8 Hz), 7.18 (d, 2H, J = 8 Hz), 7.25 (d, 2H, J = 8 Hz), 7.48 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
MS-FAB：947 (MH+).
【０６９０】
実施例４７
【０６９１】
【化８７】
13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10-[2-( シクロプロピルアミノ) エチル] −10- デアセトキシ-7- Ｏ- メチルバッカチンIII
実施例１１の工程１２で得た化合物を実施例１の工程１０と同様にモルホリンの代わりにシクロプロピルアミンを用い反応させ標記化合物を無色の固体として得た。
【０６９３】
融点：140-143 ℃．
1H-NMR(CDCl3/TMS) δ(ppm) ：
0.32-0.33 (m, 2H), 0.43-0.44 (m, 2H), 1.14 (s, 3H), 1.23 (s, 9H), 1.39 (s, 3H), 1.58-2.75 (m, 7H), 1.69 (s, 3H), 1.76 (s, 3H), 2.62 (s, 3H), 3.27 (s, 3H), 3.85 (t, 1H, J = 6 Hz), 3.94 (dd, 1H, J = 10, 7 Hz), 3.99 (d, 1H, J = 7.5 Hz), 4.20 (d, 1H, J = 9 Hz), 4.31 (d, 1H, J = 9 Hz), 4.99-5.05 (m, 2H), 5.55 (d, 1H, J = 10 Hz), 5.64 (d, 1H, J = 7 Hz), 6.29 (t, 1H, J = 8 Hz), 7.33-7.37 (m, 5H), 7.48 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz) ．
MS-FAB：903 (MH+).
【０６９４】
実施例４８
【０６９５】
【化８８】
工程１：13- Ｏ- トリエチルシリルバッカチンIII
7,13- Ｏ- ビス( トリエチルシリル) バッカチンIII を実施例５の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６９７】
1H-NMR(CDCl3/TMS) δ(ppm) ：
0.61-0.73 (m, 6H), 1.02 (t, 9H, J = 8 Hz), 1.11 (s, 3H), 1.18 (s, 3H),1.80 (s, 3H), 1.83-1.90 (m, 1H), 2.00 (s, 3H), 2.12-2.26 (m, 2H), 2.24 (s, 3H), 2.29 (s, 3H), 2.51 (d, 1H, J = 4 Hz), 2.52-2.59 (m, 1H),3.80 (d, 1H, J = 7 Hz), 4.15 (d, 1H, J = 8 Hz), 4.30 (d, 1H, J = 8 Hz), 4.44-4.49 (m, 1H), 4.94-5.00 (m, 2H), 5.62 (d, 1H, J = 7 Hz), 6.31 (s, 1H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
【０６９８】
工程２：7-Ｏ- メチルチオメチル-13-Ｏ- トリエチルシリルバッカチンIII
上記工程１で得た化合物を実施例９の工程５と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０６９９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.63-0.75 (m, 6H), 1.02 (t, 9H, J = 8 Hz), 1.13 (s, 3H), 1.19 (s, 3H),1.74 (s, 3H), 1.81-1.89 (m, 1H), 2.12 (s, 3H), 2.15 (s, 3H), 2.19 (s, 3H), 2.17-2.28 (m, 2H), 2.30 (s, 3H), 2.80-2.87 (m, 1H), 3.89 (d, 1H, J = 7 Hz), 4.15 (d, 1H, J = 8 Hz), 4.30-4.38 (m, 2H), 4.67 (s, 2H), 4.93 (t, 1H, J = 9 Hz), 4.98 (d, 1H, J = 9.5 Hz), 5.64 (d, 1H, J = 7 Hz), 6.56 (s, 1H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
【０７００】
工程３：7-Ｏ- フルオロメチル-13-Ｏ- トリエチルシリルバッカチンIII
上記工程２で得た化合物 100 mg をジクロロメタン 2 ml に溶解し氷冷した。次いで、Ｎ- ヨードスクシンイミド 45 mg およびジエチルアミノ硫黄トリフルオリド 0.035 ml を加え１時間攪拌した。反応液に飽和重曹水溶液を加え、約５分激しく攪拌した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲル薄層クロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝４：１(v/v) ）で展開精製し標記化合物 61.5 mg を無色結晶として得た。
【０７０１】
1H-NMR(CDCl3/TMS) δ(ppm) ：
0.63-0.73 (m, 6H), 1.02 (t, 9H, J = 8 Hz), 1.15 (s, 6H), 1.75 (s, 3H),1.99-2.03 (m, 1H), 2.04 (s, 3H), 2.14-2.27 (m, 2H), 2.21 (s, 3H), 2.30 (s, 3H), 2.70-2.78 (m, 1H), 3.87 (d, 1H, J = 7 Hz), 4.14 (d, 1H, J = 8 Hz), 4.27-4.32 (m, 2H), 4.92-4.97 (m, 2H), 5.27 (dd, 1H, J = 3.5, 43 Hz), 5.36 (dd, 1H, J = 3.5, 38.5 Hz), 5.62 (d, 1H, J = 7 Hz), 6.35 (s, 1H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.08 (d, 2H, J = 8 Hz).
【０７０２】
工程４：7-Ｏ- フルオロメチルバッカチンIII
上記工程３で得た化合物を実施例１の工程７と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７０３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.08 (s, 3H), 1.15 (s, 3H), 1.76 (s, 3H), 1.99-2.05 (m, 1H), 2.10 (s, 3H), 2.21 (s, 3H), 2.27-2.30 (m, 2H), 2.29 (s, 3H), 2.71-2.79 (m, 1H), 3.92 (d, 1H, J = 7 Hz), 4.14 (d, 1H, J = 8 Hz), 4.28-4.32 (m, 2H), 4.86 (br, 1H), 4.97 (d, 1H, J = 9 Hz), 5.23 (dd, 1H, J = 3, 44 Hz), 5.37 (dd, 1H, J = 3, 40 Hz), 5.63 (d, 1H, J = 7 Hz), 6.36 (s, 1H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
【０７０４】
工程５：10−デアセチル-7- Ｏ- フルオロメチルバッカチンIII
上記工程４で得た化合物3.10 gをエタノール60 ml およびテトラヒドロフラン20 ml の混合溶媒に溶解し氷冷下、ヒドラジン・1 水和物19 ml を加え室温で90分撹拌した。反応液を氷水に注ぎ酢酸エチルで抽出し、１規定塩酸水溶液（2 回）、飽和重曹水溶液、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた残分をシリカゲルクロマトグラフィー（溶出溶媒、クロロホルム：メタノール＝100:1(v/v)）にて精製し標記化合物2.80 g を無色の非晶質固体として得た。
【０７０５】
1H-NMR(CDCl3/TMS) δ(ppm) ：
1.09 (s, 3H), 1.10 (s, 3H), 1.81 (s, 3H), 1.84-1.98 (m, 1H), 2.09 (d, 3H, J = 1.5 Hz), 2.26-2.29 (m, 2H), 2.30 (s, 3H), 2.63-2.70 (m, 1H), 4.00 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.35 (dd, 1H, J = 7, 10 Hz), 4.88 (d, 1H, J = 8 Hz), 4.98 (d, 1H, J = 8 Hz), 5.12 (dd, 1H, J = 3, 22 Hz), 5.26 (dd, 1H, J = 3, 27 Hz), 5.31 (s, 1H), 5.62 (d, 1H, J = 7 Hz), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8Hz).
【０７０６】
工程６：10- デアセチル-7- Ｏ- フルオロメチル-10-Ｏ-(メチルチオ) チオカルボニルバッカチンIII
上記工程５で得た化合物を実施例６の工程１と同様に反応させ標記化合物を淡黄色の非晶質固体として得た。
【０７０７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.10 (s, 3H), 1.24 (s, 3H), 1.78 (s, 3H), 2.00-2.32 (m, 3H), 2.19 (s, 3H), 2.30 (s, 3H), 2.64 (s, 3H), 2.74-2.82 (m, 1H), 3.92 (d, 1H, J = 7 Hz), 4.15 (d, 1H, J = 8 Hz), 4.29-4.34 (m, 2H), 4.88 (t, 1H, J = 8 Hz), 4.97 (d, 1H, J = 8 Hz), 5.20 (dd, 1H, J = 3, 24 Hz), 5.35 (dd, 1H, J = 3, 20 Hz), 5.67 (d, 1H, J = 7 Hz), 7.42 (s, 1H), 7.49 (t, 2H, J = 8 Hz), 7.62 (t, 1H, J = 8 Hz), 8.11 (d, 2H, J = 8 Hz).
【０７０８】
工程７：10- デアセトキシ-7- Ｏ- フルオロメチル-10-(2- ホルミルエチル) バッカチンIII
上記工程６で得た化合物を実施例６の工程２と同様に反応させ標記化合物を無色の非晶質結晶として得た。
【０７０９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.06 (s, 3H), 1.11 (s, 3H), 1.70 (s, 3H), 1.78-1.93 (m, 2H), 1.98 (d, 3H, J = 1 Hz), 2.24-2.27 (m, 2H), 2.29 (s, 3H), 2.44-2.70 (m, 4H), 3.91 (dd, 1H, J = 5, 7 Hz), 4.07 (d, 1H, J = 7 Hz),4.18 (d, 1H, J = 8 Hz), 4.32 (d, 1H, J = 8 Hz), 4.48 (dd, 1H, J = 7, 10 Hz), 4.84 (t, 1H, J = 8 Hz), 4.99 (d, 1H, J = 8 Hz), 5.14 (dd, 1H, J = 3, 24 Hz), 5.28 (dd, 1H, J = 3, 22 Hz), 5.60 (d, 1H, J = 7 Hz), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz), 9.78 (s, 1H).
【０７１０】
工程８：10- デアセトキシ-7- Ｏ- フルオロメチル-10-(3- ヒドロキシプロピオニル) バッカチンIII
上記工程７で得た化合物を実施例６の工程３と同様に反応させ標記化合物を無色の非晶質結晶として得た。
【０７１１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.05 (s, 3H), 1.11 (s, 3H), 1.51-1.61 (m, 4H), 1.70 (s, 3H), 1.87-1.93 (m, 1H), 1.98 (s, 3H), 2.20-2.27 (m, 2H), 2.30 (s, 3H),2.63-2.70 (m, 2H), 3.62-3.72 (m, 2H), 3.93 (t, 1H, J = 6 Hz), 4.10 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.32 (d, 1H, J = 8 Hz), 4.50 (dd, 1H, J = 7, 10 Hz), 4.84 (t, 1H, J = 8 Hz), 5.00 (d, 1H, J = 8 Hz), 5.14 (dd, 1H, J = 3, 22 Hz), 5.28 (dd, 1H, J = 3, 29 Hz), 5.61 (d, 1H, J = 7 Hz), 7.48 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
【０７１２】
工程９：10- アリル-10-デアセトキシ-7- Ｏ- フルオロメチルバッカチンIII
上記工程８で得た化合物を実施例６の工程４と同様に反応させ、次いで実施例６の工程５と同様に反応させて標記化合物を淡黄色の非晶質固体として得た。
【０７１３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.07 (s, 3H), 1.12 (s, 3H), 1.71 (s, 3H), 1.89-1.93 (m, 1H), 1.95 (d, 3H, J = 1 Hz), 2.20-2.27 (m, 2H), 2.29 (s, 3H), 2.31-2.45 (m, 1H), 2.61-2.68 (m, 1H), 2.85-2.92 (m, 1H), 4.00 (dd, 1H, J = 6, 8 Hz), 4.10 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.45 (dd, 1H, J = 7, 10 Hz), 4.85 (t, 1H, J = 8 Hz), 4.98-5.11 (m, 3H), 5.12 (dd, 1H, J = 3, 20 Hz), 5.26 (dd, 1H, J = 3, 28 Hz), 5.61 (d, 1H, J = 7 Hz), 5.73-5.83 (m, 1H), 7.47 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
【０７１４】
工程１０：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-(tert-ブチルジメチルシリル) オキシ-3- フェニルプロピオニル]-10- デアセトキシ-7- Ｏ- フルオロメチルバッカチンIII
上記工程９で得た化合物を実施例１の工程８と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７１５】
1H-NMR(CDCl3/TMS) δ(ppm) ：
-0.31 (s, 3H), -0.11 (s, 3H), 0.75 (s, 9H), 1.16 (s, 3H), 1.24 (s, 3H), 1.31 (s, 9H), 1.73 (s, 3H), 1.79 (s, 3H), 1.85-1.99 (m, 1H), 2.14-2.38 (m, 3H), 2.56 (s, 3H), 2.64 (m, 1H), 2.89-2.95 (m, 1H), 3.96 (t, 1H, J = 6 Hz), 4.03 (d, 1H, J = 7 Hz), 4.22 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.43 (dd, 1H, J = 7, 10 Hz), 4.51 (s, 1H), 4.98-5.29 (m, 6H), 5.44 (d, 1H, J = 10 Hz), 5.77 (d, 1H, J = 7 Hz), 5.79-5.85 (m, 1H), 6.26 (t, 1H, J = 8 Hz), 7.25-7.39 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.11 (d, 2H, J = 8 Hz).
【０７１６】
工程１１：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3- フェニルプロピオニル]-10- デアセトキシ-7- Ｏ- フルオロメチルバッカチンIII
上記工程１０で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７１７】
1H-NMR(CDCl3/TMS) δ(ppm) ：
1.16 (s, 3H), 1.22 (s, 3H), 1.34 (s, 9H), 1.72 (s, 3H), 1.75 (s, 3H),1.90-1.97 (m, 1H), 2.20-2.28 (m, 2H), 2.37 (s, 3H), 2.33-2.41 (m, 1H),2.59-2.67 (m, 1H), 2.86-2.92 (m, 1H), 3.32 (d, 1H, J = 5 Hz), 3.96-4.01 (m, 2H), 4.20 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.40 (dd, 1H, J = 7, 10 Hz), 4.61 (s, 1H), 4.94-5.13 (m, 4H), 5.21-5.28 (m, 2H), 5.39 (d, 1H, J = 10 Hz), 5.66 (d, 1H, J = 7 Hz), 5.70-5.80 (m, 1H), 6.19 (t, 1H, J = 8 Hz), 7.30-7.42 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
【０７１８】
工程１２：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-3- フェニルプロピオニル]-10- デアセトキシ-7- Ｏ- フルオロメチル-10-(2- モルホリノエチル) バッカチンIII
上記工程１１で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の固体として得た。
【０７１９】
融点：142-146 ℃.
1H-NMR (CDCl3/TMS) δ(ppm) ：
1.15 (s, 3H), 1.20 (s, 3H), 1.34 (s, 9H), 1.72 (s, 3H), 1.85 (s, 3H),2.38 (s, 3H), 1.60-2.70 (m, 12H), 3.68 (m, 4H), 4.00-4.06 (m, 2H), 4.19 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.41 (dd, 1H, J = 7, 10 Hz), 4.60 (s, 1H), 4.96 (d, 1H, J = 8 Hz), 5.11 (dd, 1H, J = 3, 27.5 Hz), 5.22-5.28 (m, 2H), 5.41 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 7 Hz), 6.17 (t, 1H, J = 8 Hz), 7.30-7.42 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
MS-FAB：937 (MH+) ．
【０７２０】
実施例４９
【０７２１】
【化８９】
工程１：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3- フェニル-2-(トリエチルシリル) オキシプロピオニル]-10- デアセトキシ-7- Ｏ- フルオロメチルバッカチンIII
実施例４８の工程９および参考例４の工程３で得た化合物を実施例４の工程１と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７２３】
1H-NMR(CDCl3/TMS) δ(ppm) ：
0.50-0.74 (m, 6H), 0.86 (t, 9H, J = 7 Hz), 1.17 (s, 12H), 1.30 (s, 3H), 1.38 (s, 3H), 1.74 (s, 3H), 1.78 (s, 3H), 1.93-2.11 (m, 2H), 2.29-2.36 (m, 2H), 2.60-2.66 (m, 1H), 2.70 (s, 3H),2.90-2.97 (m, 1H), 3.93 (t, 1H, J = 7 Hz), 4.01 (d, 1H, J = 7 Hz), 4.23 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.41 (dd, 1H, J = 7, 10 Hz), 4.97-5.13 (m, 4H), 5.25 (dd, 1H, J = 2.5, 26 Hz), 5.49 (d, 1H, J = 10 Hz), 5.69 (d, 1H, J = 7 Hz), 5.77-5.85 (m, 1H), 6.37 (t, 1H, J = 8 Hz), 7.31-7.36 (m, 5H), 7.50 (t, 2H, J = 8 Hz), 7.57 (t, 1H, J = 8 Hz), 8.14 (d, 2H, J = 8 Hz).
【０７２４】
工程２：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-7- Ｏ- フルオロメチルバッカチンIII
上記工程１で得た化合物を実施例１の工程９と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７２５】
1H-NMR(CDCl3/TMS) δ(ppm) ：
1.17 (s, 3H), 1.23 (s, 9H), 1.27 (s, 3H), 1.36 (s, 3H), 1.70 (s, 3H),1.73 (s, 3H), 1.89-1.98 (m, 1H), 2.15-2.40 (m, 3H), 2.62 (s, 3H), 2.60-2.67 (m, 1H), 2.86-2.93 (m, 1H), 3.60 (s, 3H), 3.97 (dd, 1H, J = 6, 8.5 Hz), 4.01 (d, 1H, J = 7 Hz), 4.21 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.40 (dd, 1H, J = 7, 10 Hz), 4.97-5.13 (m, 4H), 5.25 (dd, 1H, J = 3, 24 Hz), 5.54 (d, 1H, J = 10 Hz), 5.67 (d, 1H, J = 7 Hz), 5.71-5.80 (m, 1H), 6.31 (t, 1H, J = 8 Hz), 7.32-7.36 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
【０７２６】
工程３：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-7- Ｏ- フルオロメチル-10-(2- モルホリノエチル) バッカチンIII
上記工程２で得た化合物を実施例１の工程１０と同様に反応させ標記化合物を無色の固体として得た。
【０７２７】
融点：152-155 ℃．
1H-NMR (CDCl3/TMS) δ(ppm) ：
1.16 (s, 3H), 1.23 (s, 9H), 1.25 (s, 3H), 1.39 (s, 3H), 1.73 (s, 3H),
1.79 (s, 3H), 2.64 (s, 3H), 1.90-2.70 (m, 12H), 3.68 (m, 4H), 4.01-4.04 (m, 2H), 4.21 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.42 (dd, 1H, J = 7, 10 Hz), 4.98-5.13 (m, 4H), 5.25 (dd, 1H, J = 3, 20 Hz), 5.54 (d, 1H, J = 10 Hz), 5.67 (d, 1H, J = 7 Hz), 6.30 (t, 1H, J = 8 Hz), 7.32-7.40 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
MS-FAB：951 (MH+) ．
【０７２８】
実施例５０
【０７２９】
【化９０】
工程１：10- アリル-10-デアセトキシ-7- Ｏ- フルオロメチル-13-Ｏ- トリエチルシリルバッカチンIII
実施例４８の工程９で得た化合物を実施例１の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７３１】
1H-NMR (CDCl3/TMS)δ(ppm) ：
0.64-0.70 (m, 6H), 1.02 (t, 9H, J = 7 Hz), 1.12 (s, 3H), 1.13 (s, 3H),1.70 (s, 3H), 1.90-1.96 (m, 1H), 1.90 (s, 3H), 2.10-2.37 (m, 4H), 2.29 (s, 3H), 2.59-2.67 (m, 1H), 2.86-2.91 (m, 1H), 3.96 (dd, 1H, J = 6, 8 Hz), 4.03 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.44 (dd, 1H, J = 7, 10 Hz), 4.91 (t, 1H, J = 9 Hz), 4.98-5.09 (m, 3H), 5.10 (dd, 1H, J = 3, 25 Hz), 5.24 (dd, 1H, J = 3, 30 Hz), 5.61 (d, 1H, J = 7 Hz), 5.72-5.83 (m, 1H), 7.47 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
【０７３２】
工程２：10- アリル-10-デアセトキシ-1- Ｏ- ジメチルシリル-7- Ｏ- フルオロメチル-13-Ｏ- トリエチルシリルバッカチンIII
上記工程１で得た化合物を実施例２の工程１と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７３３】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.25 (d, 3H,J = 2.5 Hz), 0.06 (d, 3H, J = 2.5 Hz), 0.66-0.73 (m, 6H),1.03 (t, 9H, J = 7 Hz), 1.08 (s, 3H), 1.12 (s, 3H), 1.69 (s, 3H), 1.89 (s, 3H), 1.90-1.95 (m, 1H), 2.22-2.39 (m, 3H), 2.30 (s, 3H), 2.57-2.65 (m, 1H), 2.87-2.93 (m, 1H), 3.93 (dd, 1H, J = 6, 8 Hz), 4.01 (d, 1H, J = 7 Hz), 4.25 (AB type d, each 1H, J = 9 Hz), 4.40 (dd, 1H, J = 7, 10 Hz), 4.53 (m, 1H), 4.92-4.99 (m, 3H),5.05-5.13 (m, 2H), 5.23 (dd, 1H, J = 3, 30 Hz), 5.69 (d, 1H, J = 7 Hz), 5.75-5.85 (m, 1H), 7.47 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
【０７３４】
工程３：10- アリル-10-デアセトキシ-4- デアセチル-1- Ｏ- ジメチルシリル-7- Ｏ- フルオロメチル-13-Ｏ- トリエチルシリルバッカチンIII
上記工程２で得た化合物を実施例２の工程２と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７３５】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.28 (d, 3H,J = 3 Hz), 0.02 (d, 3H, J = 3Hz), 0.74-0.85 (m, 6H), 0.97 (s, 3H), 1.08-1.13 (m, 12H), 1.59 (s, 3H), 1.90 (s, 3H), 1.94-2.02 (m, 1H), 2.46-2.59 (m, 3H), 2.80 (dd, 1H, J = 2, 13 Hz), 2.84-2.89 (m, 1H), 3.76-3.80 (m, 1H), 4.00-4.06 (m, 1H), 4.24 (d, 1H, J = 9 H), 4.32 (d, 1H, J = 9 Hz), 4.56-4.58 (m, 1H), 4.67-4.75 (m, 2H), 5.00-5.13 (m, 3H), 5.25 (dd, 1H, J = 3, 24 Hz ), 5.57 (d, 1H, J = 7 Hz), 5.75-5.83 (m, 1H), 7.44 (t, 2H, J = 8 Hz), 7.56 (t, 1H, J = 8 Hz), 8.12 (d, 2H, J = 8 Hz).
【０７３６】
工程４：10- アリル-10-デアセトキシ-4- デアセチル-1- Ｏ- ジメチルシリル-4- Ｏ- エトキシカルボニル-7- Ｏ- フルオロメチル-13-Ｏ- トリエチルシリルバッカチンIII
上記工程３で得た化合物を実施例９の工程３と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７３７】
1H-NMR (CDCl3/TMS)δ(ppm) ：
-0.30 (d, 3H, J = 3 Hz), 0.06 (d, 3H, J = 3 Hz), 0.64-0.70 (m, 6H), 1.02 (t, 9H, J = 7 Hz), 1.12 (s, 6 H), 1.41 (t, 3H, J = 7 Hz), 1.69 (s, 3H), 1.90 (s, 3H), 1.92-1.97 (m, 1H), 2.22-2.34 (m, 2H), 2.57-2.64 (m, 1H), 2.87-2.94 (m, 1H), 3.91 (dd, 1H, J = 6, 8 Hz), 4.04 (d, 1H, J = 7 Hz), 4.13-4.21 (m, 1H), 4.26 (AB type d, each 1H, J = 9 Hz), 4.35-4.43 (m, 2H), 4.53-4.56 (m, 1H), 4.94-5.14 (m, 4H), 5.25 (dd, 1H, J = 3, 30 Hz), 5.71 (d, 1H, J = 7 Hz), 5.74-5.84 (m, 1H), 7.46 (t, 2H, J = 8 Hz), 7.57(t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
【０７３８】
工程５：10- アリル-10-デアセトキシ-4- デアセチル-4- Ｏ- エトキシカルボニル-7- Ｏ- フルオロメチルバッカチンIII
上記工程４で得た化合物を実施例２の工程４と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７３９】
1H-NMR (CDCl3/TMS)δ(ppm) ：
1.07 (s, 3H), 1.13 (s, 3H), 1.39 (t, 3H, J = 7 Hz), 1.70 (s, 3H), 1.90-1.94 (m, 1H), 1.97 (s, 3H), 2.22-2.43 (m, 2H), 2.62-2.69 (m, 1H),2.86-2.93 (m, 1H), 4.02 (dd, 1H, J = 6, 8 Hz), 4.13-4.25 (m, 3H), 4.31-4.39 (m, 3H), 4.84 (br, 1H), 4.98-5.15 (m, 4H), 5.26 (dd, 1H, J = 3, 30 Hz), 5.63 (d, 1H, J = 7 Hz), 5.74-5.83 (m, 1H), 7.48 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.11 (d, 2H, J = 8 Hz).
【０７４０】
工程６：10- アリル-13-Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-メチル-3- フェニル-2-(トリエチルシリル) オキシプロピオニル]-10- デアセトキシ-4- デアセチル-4- Ｏ- エトキシカルボニル-7- Ｏ- フルオロメチルバッカチンIII
上記工程５で得た化合物および参考例４の工程３で得た化合物を実施例４の工程１と同様に反応させ標記化合物を無色の非晶質固体として得た。
【０７４１】
1H-NMR(CDCl3/TMS) δ(ppm) ：
0.43-0.86 (m, 6H), 0.84 (t, 9H, J = 7 Hz), 1.17 (s, 3H), 1.24 (s, 3H),1.27 (s, 9H), 1.39 (t, 3H, J = 7 Hz), 1.44 (s, 3H), 1.76 (s, 3H), 1.83 (s, 3H), 1.92-1.98 (m, 1H), 2.10-2.16 (m, 1H), 2.35-2.44 (m, 2H),2.61-2.69 (m, 1H), 2.91-2.95 (m, 1H), 3.99 (t, 1H, J = 7 Hz), 4.20 (d, 1H, J = 7 Hz), 4.30 (s, 2H), 4.40 (dd, 1H, J = 7, 10 HZ), 4.64-4.73 (m, 2H), 4.98-5.15 (m, 4H), 5.24 (dd, 1H, J = 3, 30 Hz),5.54 (d, 1H, J = 10 Hz), 5.69 (d, 1H, J = 7 Hz), 5.76-5.83 (m, 1H), 6.29 (t, 1H, J = 8 Hz), 7.30-7.45 (m, 7H), 7.56 (t, 1H, J = 8 Hz), 8.12 (d, 2H, J = 8 Hz).
【０７４２】
工程７：13- Ｏ-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ヒドロキシ-2- メチル-3- フェニルプロピオニル]-10- デアセトキシ-4- デアセチル-4- Ｏ- エトキシカルボニル-7- Ｏ- フルオロメチル-10-(2- モルホリノエチル) バッカチンIII
上記工程６で得た化合物を実施例１の工程９と同様に反応させ、ついで実施例１の工程１０と同様に反応させて標記化合物を無色の固体として得た。
【０７４３】
融点：143-146 ℃．
1H-NMR (CDCl3/TMS) δ(ppm) ：
1.16 (s, 3H), 1.21 (s, 3H), 1.32 (s, 9H), 1.42-1.44 (m, 6H), 1.73 (s, 3H), 1.80 (s, 3H), 1.92-1.98 (m, 1H), 2.20-2.71 (m, 11H), 3.61 (br, 1H), 3.68 (m, 4H), 4.05 (t, 1H, J = 7 Hz), 4.10 (d, 1H, J = 7 Hz), 4.24 (d, 1H, J = 8 Hz), 4.33-4.38 (m, 2H), 4.56-4.60 (m, 2H), 5.00-5.13 (m, 4H), 5.24 (dd, 1H, J = 3, 20 Hz), 5.68-5.72 (m, 2H), 6.18 (t, 1H, J = 8 Hz), 7.27-7.47 (m, 7H), 7.58 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).MS-FAB：981 (MH+) ．
【０７４４】
【発明の効果】
次の実験例により、本発明化合物の抗腫瘍効果を示す。
実験例
３種の腫瘍細胞、P388、PC-6および PC-12をそれぞれ、P388は 5.0×102 cells/150 μl/well、PC-6は 5.0×103 cells/150 μl/well、 PC-12 は 1.0×103 cells/150 μl/wellになるように 96 ウェル−マイクロプレートに播種し、P388は２時間後、ほかの２つは、24時間後に検体を 50 μl/well添加した。その後、３日間培養し、ＭＴＴ[3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide]の 5 mg/ml溶液を 20 μl/well添加した。４時間後培養液を除去し、ジメチルスルホキシドを 150μl/well加え、吸光度を 540 nm にて測定した。抗腫瘍効果は薬剤添加群の細胞増殖を対照群の 50 % にする薬剤濃度を GI50 値 (ng/ml)として示した。
【０７４５】
【表１】
[Industrial application fields]
The present invention relates to a novel taxol derivative having antitumor activity.
[0002]
[Prior art]
Taxol is a natural product represented by the following chemical structural formula, and is obtained in trace amounts from the trunk of the yew.
[0003]
Embedded image
[0004]
Until now, only a very small amount of taxol was obtained from nature. However, in recent years, 10-O-deacetylbaccatin III, which is a taxol precursor that can be obtained in relatively large amounts from the leaves of yews, etc.
[0005]
Embedded image
[0006]
Embedded image
[Problems to be solved by the invention]
Thus, derivatives represented by taxol and taxotere are promising as antitumor agents. However, clinical trials have proved to be less effective for digestive organ cancer, particularly colon cancer, and a derivative having a stronger antitumor effect is desired.
[0008]
[Means for Solving the Problems]
Conventionally, as a substituent at the 10-position of a taxol derivative, an acetoxy group, a hydroxyl group, and those obtained by further substituting the hydroxyl group with an acyl group, an alkylaminocarbonyl group (EP 524093), etc. have been reported. Derivatives (Tetrahedron Lett.,344921 (1993)) is also known. As a result of intensive studies, the present inventors have found that a derivative into which an alkyl group having a substituent or a substituent is introduced at the 10-position has a strong antitumor activity and completed the present invention.
[0009]
The present invention relates to general formula (I)
[0010]
Embedded image
[Where:
R1 Means a phenyl group, and the phenyl group may have one or more substituents selected from the group consisting of a halogen atom, an alkyl group and an alkoxyl group.
[0012]
R2 Means an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or an alkoxyl group. These alkyl group, alkenyl group, alkynyl group, cycloalkyl group and alkoxyl group are a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryl group. It has one or more substituents selected from the group consisting of oxy group, phenyl group, amino group, alkylamino group, alkoxycarbonyl group, aryloxycarbonyl group, acyl group, acylamino group and acyloxy group. Also good.
[0013]
RThree Means an amino group, a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group, an azido group or an acyloxy group having one or two groups selected from the group consisting of an alkyl group and an acyl group as a substituent.
[0014]
RFour Means an amino group, a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group, an azido group or an acyloxy group having one or two groups selected from the group consisting of an alkyl group and an acyl group as a substituent. Acyloxy group is a halogen atom, hydroxyl group, carboxyl group, cycloalkyl group, alkoxyl group, aryl group, aryloxy group, amino group, alkylamino group, alkoxycarbonyl group, aryloxycarbonyl group, acyl group, acylamino group, acyloxy group And a heterocyclic group (the heterocyclic group may have one or more alkyl groups on the constituent atoms of the ring), and a substituent selected from a group selected from the group consisting of May be.
RThree And RFour Together
[0015]
Embedded image
You may form the structure represented by these.
[0016]
RFive Means a methyl group,
Or RFour Together with RFour And RFive A structure in which a three-membered ring is formed together with the carbon atom to which each of these is bonded may be used.
[0017]
R6 Means an alkyl group, an alkenyl group or an alkynyl group,
These alkyl group, alkenyl group and alkynyl group are carboxyl group, alkoxyl group, aryloxy group, alkoxycarbonyl group, aryloxycarbonyl group, cyano group, hydroxyl group, amino group, alkylamino group, acyl group, acylamino group, acyloxy group. , Alkoxycarbonylamino group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group and formula
[0018]
Embedded image
[0019]
Z1 Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group,
Z2 Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group,
ZThree Means an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group. These alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heterocyclic group are a halogen atom, a hydroxyl group , Carboxyl group, alkyl group, alkoxyl group, phenyl group, amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxycarbonyl group, aryloxycarbonyl group, acyl group, acylamino group, and acyloxy group One or more selected groups may be substituted.
[0020]
ZFour Means an alkyl group, an aryl group or an alkoxyl group. These alkyl group, aryl group and alkoxyl group are a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group. One or a plurality of groups selected from the group consisting of a group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group may be included.
[0021]
In addition,
[0022]
Embedded image
[0023]
Next, terms used in this specification will be described.
[0024]
“C1 ~ C6 "Means one having 1 to 6 carbon atoms, for example," C2 ~ C6 “Alkenyl group” means an alkenyl group having 2 to 6 carbon atoms.
[0025]
The “alkyl group”, “alkenyl group” and “alkynyl group” may be linear or branched, and those having 1 to 6 carbon atoms (in the case of alkenyl and alkynyl groups) to 6 carbon atoms are preferred.
[0026]
An “alkoxyl group” means a group in which an alkyl group is bonded to the group —O—, and the alkyl group may be substituted with a phenyl group (which may have a substituent). Specific examples include benzyloxy, phenethyloxy, p-methoxybenzyloxy and the like. The alkyl moiety preferably has 1 to 6 carbon atoms.
[0027]
“Alkoxycarbonyl group” means an alkyl group bonded to an oxygen atom of a group —COO—, and this alkyl group may be substituted with a phenyl group (which may have a substituent). Often, such examples include benzyloxycarbonyl, phenethyloxycarbonyl, p-methoxybenzyloxycarbonyl, and the like. The alkyl moiety preferably has 1 to 6 carbon atoms.
[0028]
“Aryl group” means a monovalent group obtained by removing one hydrogen atom from an aromatic hydrocarbon nucleus, and examples thereof include phenyl, tolyl, biphenylyl, naphthyl and the like.
[0029]
The bonding position of the amino group of the “aminoalkyl group” may be any position of the alkyl group. Further, the alkyl group preferably has 1 to 6 carbon atoms.
[0030]
“Alkylamino group” means an amino group substituted with one alkyl group, or an amino group substituted with two alkyl groups (the two alkyl groups may be the same or different). . Further, the alkyl group preferably has 1 to 6 carbon atoms.
[0031]
“Acyl group” means a carbonyl group (—CO—) bonded with a hydrogen atom, an alkyl group or an aryl group, and examples thereof include formyl, acetyl, propanoyl, benzoyl and the like. The alkyl group to be bonded preferably has 1 to 6 carbon atoms, and the aryl group to be bonded is preferably a phenyl group.
[0032]
“Heterocyclic group” means a monocyclic or bicyclic saturated group containing one or more atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms as constituent atoms of the ring structure. Alternatively, it means a substituent derived from an unsaturated heterocyclic compound, and these heterocyclic groups may be bonded at any position. Examples of monocyclic heterocyclic groups include pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran And substituents derived from monocyclic heterocyclic compounds such as piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran and morpholine. Examples of the bicyclic heterocyclic group include substituents derived from bicyclic heterocyclic compounds such as benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, and chroman.
[0033]
“Nitrogen-containing heterocyclic group” means that at least one nitrogen atom is included as a constituent atom of the heterocyclic group, and at least one atom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom is included as a constituent atom. It means a substituent derived from a saturated or unsaturated heterocyclic compound which may contain one or more. Examples include pyrrole, pyrrolidine, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, thiomorpholine, and the like.
[0034]
"formula
[0035]
Embedded image
(X is oxygen atom, sulfur atom, CH2, CH—Y, NH or N—Y, Y represents an alkyl group. )
And a saturated heterocyclic group having a size of 5 to 6-membered ring containing a nitrogen atom (wherein the heterocyclic group has one or more alkyl groups on a carbon atom that is a constituent atom of the ring) The term "" means a substituent derived from a saturated heterocyclic compound having a size of 5 to 6 members and always containing one nitrogen atom as a constituent atom of the heterocyclic group. Examples thereof include pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, thiazolidine, isoxazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, and the like.
[0037]
RThree And RFour Together
[0038]
Embedded image
The formation of the structure represented by the formula means that the 6-position and 7-position are the following structures.
[0039]
Embedded image
RFour And RFive Together, forming a three-membered ring with the carbon atoms to which they are attached, means that the 7- and 8-position moieties have the following structure.
[0041]
Embedded image
Next, each substituent in the general formula (I) will be described.
[0043]
R1 The “alkyl group” and the “alkoxyl group” as the substituent of the phenyl group are preferably those having 1 to 3 carbon atoms.
[0044]
R1 The number of substituents of the phenyl group is preferably 1 or 2, and the substitution position of the substituent is preferably the meta position.
[0045]
R1 Is preferably an unsubstituted phenyl group. In addition, a phenyl group in which one or two fluorine atom, chlorine atom, methyl group or methoxy group is substituted at the meta position is also preferable.
[0046]
R2 As these, an alkyl group, an alkoxyl group and a cycloalkyl group are preferable.
[0047]
R2 As the “alkyl group” of C,1 ~ C6 An alkyl group is preferable, and a methyl group, an ethyl group, and a propyl group are particularly preferable.
[0048]
R2 As the “alkoxyl group” of C,1 ~ C6 An alkoxyl group is preferable, and a methoxy group and an ethoxy group are particularly preferable.
[0049]
R2 As the “cycloalkyl group”,Three ~ C6 A cycloalkyl group is preferred, and a cyclopropyl group is particularly preferred.
[0050]
R2 As a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group or a cyclopropyl group is particularly preferable.
[0051]
RThree Is preferably a hydrogen atom (however, RFour Is a hydrogen atom or a hydroxyl group and RThree Carbon atom to which R is bonded and RFourThe bond between the carbon atoms to which is bonded is not a single bond. ).
[0052]
RFour Is preferably a halogen atom, an alkoxyl group, a hydrogen atom or a hydroxyl group (however, RFour R is a hydrogen atom or a hydroxyl group, RThree Is a hydrogen atom and RThree Carbon atom to which R is bonded and RFourThe bond between the carbon atoms to which is bonded is not a single bond. ).
[0053]
RFour As the “halogen atom”, a fluorine atom is preferable.
[0054]
RFour As the “alkoxyl group”, a methoxy group is preferable.
[0055]
RFour Is particularly preferably a hydrogen atom, a fluorine atom, a hydroxyl group or a methoxy group (provided that RFour R is a hydrogen atom or a hydroxyl group, RThree Is a hydrogen atom and RThree Carbon atom to which R is bonded and RFourThe bond between the carbon atoms to which is bonded is not a single bond. ).
[0056]
Also RThree And RFour Together
[0057]
Embedded image
The structure represented by general formula (I-1)
[0058]
Embedded image
[0059]
Embedded image
[0060]
RFive In the case of a methyl group, or RFour Together with RFour And RFive Formed a three-membered ring with the carbon atoms (7th and 8th positions) to which each is bonded, that is, the 7th and 8th positions have the following structure
[0061]
Embedded image
[0062]
Embedded image
[0063]
R6 Is preferably an alkyl group or an alkenyl group,
The alkyl group is a carboxyl group, alkoxyl group, aryloxy group, alkoxycarbonyl group, aryloxycarbonyl group, cyano group, hydroxyl group, amino group, alkylamino group, acyl group, acylamino group, acyloxy group, alkoxycarbonylamino group, Alkylthio, alkylsulfinyl, alkylsulfonyl and formulas
[0064]
Embedded image
And a saturated or unsaturated heterocyclic group containing a nitrogen atom having a size of 3 to 8 members (the heterocyclic group is an alkyl group on the carbon atom that is a constituent atom of the ring). Or a group selected from the group consisting of 1 or more as substituents. In addition, the bonding position of the substituent may be any position of the alkyl group.
[0065]
R6 As the alkyl group,1 ~ C6 An alkyl group is preferable, and a methyl group, an ethyl group, a propyl group, and a butyl group are particularly preferable.
[0066]
R6 As the alkenyl group,2 ~ C6 Alkenyl groups are preferred, and allyl groups are particularly preferred.
[0067]
R6 As the substituent of the alkyl group, an alkoxycarbonyl group, a hydroxyl group, a cyano group, an acyl group, an alkylamino group, an alkylthio group, or a formula
[0068]
Embedded image
Or a saturated or unsaturated heterocyclic group containing a nitrogen atom having a size of 5 or 6 members, wherein the heterocyclic group is an alkyl group on a carbon atom that is a constituent atom of the ring. Or a plurality of them may be present).
[0069]
Most preferred substituents include those of the formula
[0070]
Embedded image
[0071]
In addition, as an alkyl group substituted on the carbon atom which is a member atom of the ring of a heterocyclic group, a methyl group is preferable.
[0072]
R6Especially as a substituent
[0073]
Embedded image
And a saturated heterocyclic group containing a nitrogen atom having a size of 5 to 6 members (wherein the heterocyclic group includes one or more alkyl groups on a carbon atom that is a constituent atom of the ring). Preferably an alkyl group having 1 to 3 carbon atoms or an allyl group.
[0074]
R6As a substituent, such as morpholine or thiomorpholine (the morpholine or thiomorpholine may have one or more methyl groups on the carbon atoms that constitute the ring). An alkyl group having 1 to 3 carbon atoms or an allyl group is most preferable.
[0075]
Z1 And Z2 As the “halogen atom”, a fluorine atom, a chlorine atom and a bromine atom are preferable.
[0076]
Z1 And Z2 As the “alkyl group”, a methyl group, an ethyl group, or a propyl group is preferable.
[0077]
Z1 Is preferably a halogen atom or a hydroxyl group, and among the halogen atoms, a fluorine atom is particularly preferred.
[0078]
Z2 Is preferably a halogen atom, a hydrogen atom or an alkyl group. Of the halogen atoms, a fluorine atom is particularly preferable. Among the alkyl groups, a methyl group is particularly preferable.
[0079]
Z1 And Z2 Most preferred as Z1 Is a fluorine atom, Z2 Is a combination of fluorine atoms, Z1 Is a hydroxyl group, Z2 Is a combination of hydrogen atoms, or Z1Is a hydroxyl group, Z2Is a combination of methyl groups.
[0080]
ZThree Is preferably an aryl group, a heterocyclic group or an alkenyl group.
[0081]
ZThree As the “aryl group”, a phenyl group is preferable.
[0082]
ZThreeAs the “alkenyl group”, 2-methyl-1-propenyl group is preferable.
[0083]
ZThree The heterocyclic group is preferably a monocyclic heterocyclic group, more preferably a monocyclic 5-membered or 6-membered heterocyclic group, such as pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, Substituents derived from tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine, etc. Is mentioned.
[0084]
ZThree Among these heterocyclic groups, a monocyclic five-membered or six-membered heterocyclic group, particularly preferably a heterocyclic group containing one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure, , Pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyran and the like.
[0085]
ZThree Among the heterocyclic groups, the monocyclic 5-membered or 6-membered heterocyclic group is most preferably an unsaturated heterocyclic group containing one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure. Specific examples thereof include substituents derived from furan, pyridine, and pyrrole.
[0086]
ZThree As such, 2-methyl-1-propenyl group, phenyl group, furyl group, pyridyl group and pyrrolyl group are particularly preferable.
[0087]
ZFour Is preferably an aryl group or an alkoxyl group.
[0088]
ZFourAs the “aryl group”, a phenyl group is preferable.
[0089]
ZFour As the “alkoxyl group”, tertiary butoxy is preferable.
[0090]
ZFour Are particularly preferably a phenyl group and a tertiary butoxy group.
[0091]
In addition
[0092]
Embedded image
[0093]
Embedded image
[0094]
In the present invention, the following configuration is preferable.
[0095]
Embedded image
Substituent ZThreeThe configuration at the 3 'position to which is attached includes both configurations, but the configuration having the same configuration as natural taxol is more preferable.
[0097]
The taxol derivative of the present invention may be a free form, but may be an acid addition salt or a carboxyl group salt. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, acetate, methanesulfonate, benzene Examples thereof include organic acid salts such as sulfonate, toluenesulfonate, citrate, maleate, fumarate, and lactate.
[0098]
Examples of the carboxyl group salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N-methylglucamine salt. Any of inorganic salts and organic salts such as tris- (hydroxylmethyl) aminomethane salt may be used.
[0099]
A method for producing the compound of the present invention will be described. In the reaction, the substituent is protected with a protecting group as necessary, and the conversion order of each substituent is not particularly limited.
[0100]
Embedded image
[Wherein R41Means a hydroxyl group protected by a protecting group.
R13Means a hydrogen atom or a protecting group for a hydroxyl group.
R61Is R6 Or R protected with a protecting group6 (When it has a hydroxyl group or an amino group as a substituent).
Examples of the protecting group for hydroxyl group or amino group include silyl-based protecting groups such as triethylsilyl group and tert-butyldimethylsilyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, benzyl group and the like. . ]
[0102]
First, a compound represented by the formula (1) (hereinafter referred to as a compound (1), and compounds represented by other numbers are also represented in the same manner) and acrolein in a solvent in the presence of a radical initiator, trishydride. (Trimethylsilyl) silane, tributyltin hydride or triphenyltin hydride is added to obtain compound (2).
[0103]
The solvent used in this reaction may be any solvent inert to the reaction, and examples thereof include toluene, benzene, and dioxane.
[0104]
Examples of the radical initiator used in the reaction include 2 ′, 2′-azobis (isobutyronitrile), benzoyl peroxide, 2,2,6,6-tetramethyl-1-piperazinyloxy free radical, and the like. The amount of radical initiator used may be a catalytic amount.
[0105]
The reaction temperature may usually be in the range of 50 ° C. to 150 ° C., preferably with stirring.
[0106]
Acrolein is used in an amount of 5 to 50 equivalents relative to compound (1), and hydrogenated tris (trimethylsilyl) silane or the like is used in an amount of about 2 to 10 equivalents relative to compound (1).
[0107]
From the thus obtained compound (2) in which the 10-position is a 2-formylethyl group, the 10-position is R61Conversion to the compound (3) can be carried out by a common organic chemical method.
[0108]
For example, a formyl group of a formylethyl group can be converted to a propionyl group to which a tertiary amine is bound by reacting with a secondary amine under reducing conditions.
[0109]
Further, the formyl group can be converted to an alcohol-type hydroxyl group by reduction with sodium borohydride or the like.
[0110]
R61Can be converted into an acyloxy group, an alkoxyl group, an amino group, an alkylamino group, an alkylthio group, a phenylzeleno group, or the like.
[0111]
In addition, R61Can be converted into an acylamino group, an alkoxylcarbonylamino group, or an alkylamino group.
[0112]
R61Can be converted to an olefin type substituent by an oxidation reaction, the converted olefin type substituent can be converted to a diol type by an oxidation reaction, and the number of carbon atoms can be converted by an oxidative cleavage reaction. It can also be converted to a reduced substituent, for example a formylmethyl group, a carboxylmethyl group.
[0113]
R61Can be converted into a formylmethyl group in the same manner as the formyl group of the formylethyl group, and can be converted into an ethyl group to which a tertiary amine is bonded by, for example, reacting with a secondary amine under reducing conditions.
[0114]
Embedded image
[Wherein R1 , R2 , RThree , R41 , RFive , R61 And R13Is the same as above.
[0116]
Z11Means a hydrogen atom, a halogen atom, a hydroxyl group protected with a protecting group, an alkyl group,
Ztwenty oneMeans a hydrogen atom, a halogen atom, a hydroxyl group protected with a protecting group, an alkyl group,
Z31Is ZThree Or Z protected with a protecting groupThree (When it has a hydroxyl group, an amino group or a carboxyl group as a substituent),
Z41Is ZFour Or Z protected with a protecting groupFour (When it has a hydroxyl group, an amino group or a carboxyl group as a substituent).
Examples of protecting groups for hydroxyl and amino groups include silyl-based protecting groups such as triethylsilyl group and tert-butyldimethylsilyl group, 1-ethoxyethyl group, 2,2,2-trichloroethoxycarbonyl group, benzyl group and the like. .
Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, a benzyl group, a tertiary butyl group, and a 2,2,2-trichloroethyl group. ]
[0117]
Each substituent of the obtained compound (3) can be converted and deprotected as necessary to obtain the compound (4). For example, the benzoyl group at position 21 And the acetyl group at position 42 7th place R41RThree Or RFiveA compound (4) having various substituents can be obtained by performing a transformation such as forming a ring structure together with the compound.
[0118]
The target compound (I) is obtained by reacting the compound (3) or the compound (4) with the compound (A) and finally removing the protecting group, and if necessary, R61R6 And Z11, Ztwenty one, Z31And Z41Each Z1 , Z2 , ZThree And ZFour Can be obtained by converting to
[0119]
These transformations and deprotections can be carried out using ordinary organic chemical methods, but examples are given below.
[0120]
The benzoyl group at the 2-position is COR1 As a method for converting to, there is, for example, a method of selectively hydrolyzing the benzoyl group at the 2-position according to the method described in the literature (Tetrahedron Lett., 35, 8931 (1994)) and then acylating.1 Can obtain compounds other than phenyl groups.
[0121]
The acetyl group at position 4 is COR2 As a method for converting to, there is, for example, a method of selectively hydrolyzing the acetyl group at the 4-position according to the method described in the literature (J. Med. Chem., 38, 2263 (1995)), and then acylating. R2 Can obtain compounds other than methyl groups.
[0122]
6th RThree , 7th place RFour , 8th place RFive Conversion of RThree , RFour And RFive There are various methods depending on the type.
[0123]
For example, RThree , RFour In order to obtain a compound (4) in which is a hydrogen atom and the bond at the 6-position and the 7-position is a double bond, first, R41The 7-position hydroxyl group is converted into a compound having a hydroxyl group at the 7-position, and the 7-position hydroxyl group is converted to trifluoromethane sulfonate by reacting, for example, trifluoromethanesulfonic anhydride in methylene chloride. And 1,8-diazabicyclo [5,4,0] -7-undecene or the like in a solvent such as tetrahydrofuran.
[0124]
The converted olefin type substituents at the 6th and 7th positions can be converted into an epoxy type by an oxidation reaction using metachloroperbenzoic acid or the like.
[0125]
In the case of an epoxy-type substituent, various conversion reactions are possible. For example, R may be obtained by a ring-opening reaction using sodium azide.Three Or RFour It is also possible to obtain a compound (4) in which either one is a hydroxyl group and the other is an azide group.
[0126]
RFour And RFive In order to obtain a compound (4) having a structure in which a three-membered ring is formed by combining R41Is obtained by removing the protecting group and converting the 7-position to a hydroxyl group, converting the hydroxyl group to trifluoromethanesulfonyl, and then treating with silica gel in a solvent (acetonitrile, tetrahydrofuran, ethylene dichloride, etc., or a mixed solvent thereof). Can do.
[0127]
RFour In order to obtain the compound (4) in which is a fluorine atom, the compound in which the 7-position is a hydroxyl group is dissolved in a solvent (tetrahydrofuran, methylene chloride, ethyl ether, toluene, 1,1, -dimethoxyethane, etc., or a mixed solvent thereof) ) With diethylaminosulfur trifluoride.
[0128]
RFour In order to obtain the compound (4) in which is a methoxy group, R of the compound (3)41Is obtained by removing the protecting group, synthesizing a compound in which the 7-position is a hydroxyl group, dimethyl sulfoxide as a solvent, reacting with acetic anhydride to methylthiomethylate, and desulfurizing with Raney nickel in an alcohol solvent. Can do.
[0129]
In order to obtain compound (I) from the obtained compound (3) or (4), first, the substituent R at the 13-position of compound (3) or compound (4) is used.13Is protected with a protecting group, the compound is deprotected to form a compound having a hydroxyl group at position 13, and then condensed with a base such as compound (A) and sodium hexamethyldisilazide or lithium hexamethyldisilazide. Finally, each substituent may be converted or deprotected.
[0130]
Compound (1), which is a production raw material, can be synthesized from 10-O-deacetylbaccatin III, R41A compound in which is a hydroxyl group protected with a triethylsilyl group is known (Tetrahedron Lett., 34, 4921 (1993)).
[0131]
Compound (A), which is a raw material for production, can be synthesized according to the method described in the literature (Tetrahedron Lett., 34, 4149 (1993)).
[0132]
The compound of the present invention can be used, for example, for the treatment of various cancers such as lung cancer, digestive organ cancer, ovarian cancer, uterine cancer, breast cancer, liver cancer, head and neck cancer, blood cancer, renal cancer, and kobo-maru tumor.
[0133]
The compound of the present invention can be administered as various injections such as intravenous injection, intramuscular injection and subcutaneous injection, or by various methods such as oral administration and transdermal administration. Among these administration methods, intravenous administration by an aqueous preparation and oral administration are preferable. The aqueous preparation can be prepared by forming an acid adduct with a pharmacologically acceptable acid or by forming an alkali metal salt such as sodium. In the case of oral administration, it may be in the free form or in the salt form.
[0134]
As a preparation method of the preparation, an appropriate preparation can be selected according to the administration method, and it can be prepared by various commonly used preparation methods. Among the dosage forms of the antitumor agent of the present invention, examples of the oral preparation include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. In the case of injections, stabilizers, preservatives, solubilizing agents and the like can also be used in the preparation. A solution that may contain these adjuvants and the like may be stored in a container and then used as a solid preparation by freeze-drying or the like.
[0135]
Examples of liquid preparations include solutions, suspensions, emulsions, and the like. When these preparations are prepared, suspending agents, emulsifiers, and the like can be used as additives.
[0136]
The compound of the present invention can be used for the treatment of cancer in mammals, particularly humans, and when administered to humans, it is preferably administered once a day and repeated at appropriate intervals.
[0137]
As a dosage, body surface area 1m2 It is desirable to administer about 0.5 mg to 50 mg per dose, preferably about 1 mg to 20 mg.
[0138]
Next, examples and reference examples are described in detail.
[0139]
In the examples, the following abbreviations may be used.
TMS: trimethylsilyl group, Boc: tert-butoxycarbonyl group, TBS: tert-butyldimethylsilyl group, Bz: benzoyl group, Ac: acetyl group, TES: triethylsilyl group, Troc: 2,2,2-trichloroethoxycarbonyl group , Tf: trifluoromethanesulfonyl group, DMS: dimethylsilyl group, TIPS: triisopropylsilyl group, Me: methyl group, Et: ethyl group, MTM: methylthiomethyl group
[0140]
【Example】
Reference example 1
[0141]
Embedded image
Step 1: cis-3-methyl-4-phenyl-3- (trimethylsilyl) oxy-2-azetidinone
A solution of 16.9 ml of lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution) was cooled to −78 ° C., 15 ml of a tetrahydrofuran solution of 1.50 g of benzaldehyde was added dropwise under nitrogen, and after 5 minutes, the mixture was brought to 0 ° C. and stirred for 30 minutes. Next, 2.26 ml of trimethylsilane chloride was added and stirred for 30 minutes. On the other hand, 25 ml of a tetrahydrofuran solution of 2.22 ml of diisopropylamine was ice-cooled, and n-butyllithium (1.70 M hexane solution, 9.95 ml) was added dropwise, followed by stirring for 15 minutes. Next, the mixture was cooled to −78 ° C., and 25 ml of a tetrahydrofuran solution containing 2.48 g of 2- (trimethylsilyloxy) propionic acid methyl ester was added dropwise and stirred for 15 minutes. The previously prepared imine solution was added dropwise using a cannula and the temperature was raised to room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 5 to 1: 3 (v / v)) to obtain 0.98 g of the title compound as pale yellow crystals.
[0143]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.07 (s, 9H), 1.66 (s, 3H), 4.51 (s, 1H), 6.10 (br, 1H), 7.28-7.39 (m, 5H).
[0144]
Step 2: cis-1- (tert-butoxycarbonyl) -3-methyl-4-phenyl-3- (trimethylsilyl) oxy-2-azetidinone
860 mg of the compound obtained in the above step 1 was dissolved in 8.6 ml of tetrahydrofuran, 0.95 ml of di-tert-butyl dicarbonate and 20 mg of 4-dimethylaminopyridine were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 10 (v / v)) to obtain 1.01 g of the title compound as colorless crystals. .
[0145]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.07 (s, 9H), 1.40 (s, 9H), 1.67 (s, 3H), 4.73 (s, 1H), 7.21-7.37 (m, 5H).
[0146]
Reference example 2
[0147]
Embedded image
Step 1: cis-4- (p-fluorophenyl) -3-methyl-3- (trimethylsilyl) oxy-2-azetidinone
In the same manner as in Step 1 of Reference Example 1, the title compound was obtained as pale yellow crystals by reaction using p-fluorobenzaldehyde instead of benzaldehyde.
[0149]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.05 (s, 9H), 1.64 (s, 3H), 4.49 (s, 1H), 6.15 (br, 1H), 7.04-7.26 (m, 4H).
[0150]
Step 2: cis-1- (tert-butoxycarbonyl) -4-p-fluorophenyl-3-methyl-3- (trimethylsilyl) oxy-2-azetidinone
The compound obtained in Step 1 was reacted in the same manner as in Step 2 of Reference Example 1 to obtain the title compound as colorless crystals.
[0151]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.04 (s, 9H), 1.41 (s, 9H), 1.66 (s, 3H), 4.71 (s, 1H), 7.03-7.22 (m, 4H).
[0152]
Reference example 3
[0153]
Embedded image
Step 1: cis-3- (tert-butyldimethylsilyl) oxy-3-methyl-4-phenyl-2-azetidinone
As in Step 1 of Reference Example 1, 2- (tert-butyldimethylsilyloxy) propionic acid methyl ester was used in place of 2- (trimethylsilyloxy) propionic acid methyl ester to give the title compound as a white solid.
[0155]
Melting point: 102-104 ℃ (Recrystallized from pentane, colorless prisms)
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.17 (s, 3H), 0.08 (s, 3H), 0.51 (s, 9H), 1.64 (s, 3H), 4.53 (s, 1H), 6.05 (br, 1H), 7.24-7.36 (m, 5H ).
[0156]
Step 2: cis-1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyl) oxy-3-methyl-4-phenyl-2-azetidinone
The compound obtained in Step 1 was reacted in the same manner as in Step 2 of Reference Example 1 to obtain the title compound as a white solid.
[0157]
Melting point: 93 ° C (recrystallized from pentane, colorless prisms)
1H-NMR (CDClThree/ TMS) δ (ppm):
0.01 (s, 3H), 0.05 (s, 3H), 0.51 (s, 9H), 1.44 (s, 9H), 1.65 (s, 3H), 4.77 (s, 1H), 7.16-7.35 (m, 5H) .
[0158]
Reference example 4
[0159]
Embedded image
Step 1: cis-3-methyl-4-phenyl-3- (triethylsilyl) oxy-2-azetidinone
In the same manner as in Step 1 of Reference Example 1, 2- (triethylsilyl) oxypropionic acid methyl ester was used in place of 2- (trimethylsilyl) oxypropionic acid methyl ester to give the title compound as a white solid.
[0161]
1H-NMR CDClThree/
1H-NMR (CDClThree/ TMS) δ (ppm):
0.40-0.46 (m, 6H), 0.72 (t, 9H, J = 7 Hz), 1.66 (s, 3H), 4.52 (s, 1H), 6.15 (br, 1H), 7.24-7.37 (m, 5H) .
[0162]
Step 2: (3R, 4S) -3-Methyl-4-phenyl-3- (triethylsilyl) oxy-2-azetidinone
Dissolve 25 ml of 10% 2-propanol / hexane (v / v) in 500 mg of the compound obtained in the above step 1, and optically active column (CHIRALCEL OD, elution solvent; 10% 2-propanol / hexane (v / v)) To obtain 3S, 4R isomer (220 mg) as the first peak and the desired 3R, 4S isomer (215 mg) as the second peak, respectively, as colorless crystals.
[0163]
[α]D twenty four + 77 ° (c 0.09, ethanol).
1H-NMR (CDClThree/ TMS) δ (ppm):
0.40-0.46 (m, 6H), 0.72 (t, 9H, J = 7 Hz), 1.66 (s, 3H), 4.52 (s, 1H), 6.15 (br, 1H), 7.24-7.37 (m, 5H) .
[0164]
Step 3: (3R, 4S) -1- (tert-butoxycarbonyl) -3-methyl-4-phenyl-3- (triethylsilyl) oxy-2-azetidinone
The compound obtained in Step 2 was reacted in the same manner as in Step 2 of Reference Example 1 to obtain the title compound as colorless crystals.
[0165]
[α]D twenty four + 96 ° (c 0.13, ethanol).
1H-NMR (CDClThree/ TMS) δ (ppm):
0.45 (q, 6H, J = 8 Hz), 0.72 (t, 9H, J = 8 Hz), 1.43 (s, 9H), 1.67 (s, 3H), 4.80 (s, 1H), 7.19-7.34 (m , 5H).
[0166]
Reference Example 5
[0167]
Embedded image
Step 1: cis-3-methyl-4- (4-tolyl) -3- (trimethylsilyl) oxy-2-azetidinone
In the same manner as in Step 1 of Reference Example 1, 4-tolualdehyde was used in place of benzaldehyde, and the title compound was obtained as a white solid.
[0169]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.06 (s, 9H), 1.64 (s, 3H), 2.36 (s, 3H), 4.47 (s, 1H), 6.06 (br, 1H), 7.16 (s, 4H).
[0170]
Step 2: (3R, 4S) -3-Methyl-4- (4-tolyl) -3- (trimethylsilyl) oxy-2-azetidinone
The compound obtained in Step 1 was divided in the same manner as in Step 2 of Reference Example 4 to obtain the title compound as colorless crystals.
[0171]
Melting point: 55-56 ° C.
[α]D twenty four + 58.0 ° (c 1.00, ethanol).
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.06 (s, 9H), 1.64 (s, 3H), 2.36 (s, 3H), 4.47 (s, 1H), 6.06 (br, 1H), 7.16 (s, 4H).
[0172]
Step 3: (3R, 4S) -1- (tert-butoxycarbonyl) -3-methyl-4- (4-tolyl) -3- (trimethylsilyl) oxy-2-azetidinone
The compound obtained in Step 2 was reacted in the same manner as in Step 2 of Reference Example 1 to obtain the title compound as colorless crystals.
[0173]
Melting point: 75-78 ° C.
[α]D twenty four + 103 ° (c 1.25, ethanol).
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.06 (s, 9H), 1.40 (s, 9H), 1.65 (s, 3H), 2.35 (s, 3H), 4.69 (s, 1H), 7.10-7.16 (m, 4H).
[0174]
Example 1
[0175]
Embedded image
Step 1: 10-allyl-10-deacetoxybaccatin III
After dissolving 360 mg of 10-allyl-10-deacetoxy-7-O-triethylsilylbaccatin III in 4.0 ml of pyridine, adding 1.0 ml of hydrogen fluoride pyridine at 0 ° C. and stirring at room temperature for 8 hours, the reaction solution was stirred. The mixture was poured into a mixture of 20 ml of ethyl acetate and 60 ml of ice water, and the phases were separated. The aqueous layer was extracted with 20 ml of ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reprecipitation (chloroform-ether-hexane) to obtain 267 mg of the title compound as a colorless amorphous solid, and the silica gel thin layer chromatography (developing solvent; Purification using hexane: ethyl acetate = 1: 1 (v / v)) gave 20.8 mg of the title compound as a colorless amorphous solid.
[0177]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (3H, s), 1.11 (3H, s), 1.44 (1H, d, J = 7.3Hz), 1.64 (3H, s), 1.65 (1H, s), 1.80 (1H, ddd, J = 2.4Hz , 11.2Hz, 14.2Hz), 1.92 (3H, d, J = 1.0Hz), 2.17-2.42 (3H, m), 2.28 (3H, s), 2.57 (1H, ddd, J = 6.4Hz, 9.8Hz, 14.2Hz), 2.88-2.98 (1H, m), 3.93 (1H, dd, J = 6.4Hz, 7.8Hz), 4.11 (1H, d, J = 7.3Hz), 4.19 (1H, d, J = 8.4Hz) ), 4.31 (1H, d, J = 8.4Hz), 4.30-4.42 (1H, m), 4.86 (1H, s), 4.95-5.05 (2H, m), 5.12 (1H, dd, J = 16.9Hz, 1.7Hz), 5.63 (1H, d, J = 7.3Hz), 5.73-5.87 (1H, m), 7.48 (2H, t, J = 7.8Hz), 7.60 (1H, t, J = 7.8Hz), 8.11 (2H, d, J = 7.8Hz).
[0178]
Process 2: 10-allyl-10-deacetoxy-7-O- (2,2,2-trichloroethoxycarbonyl) baccatin III
280 mg of the compound obtained in the above step 1 was dissolved in 8.0 ml of pyridine, 75.0 ml of 2,2,2-trichloroethyl chloroformate was added at 0 ° C. and stirred for 2 hours, and then the reaction solution was stirred with 20 ml of ethyl acetate and The mixture was poured into a mixture of 60 ml of ice water and separated, and the aqueous layer was extracted with 20 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of 1N hydrochloric acid aqueous solution, 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 1 (v / v)) to obtain 360 mg of the title compound as a colorless amorphous solid.
[0179]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (3H, s), 1.19 (3H, s), 1.78 (3H, s), 1.98 (3H, d, J = 1.5Hz), 1.98-2.08 (1H, m), 2.18-2.35 (3H, m) , 2.30 (3H, s), 2.64 (1H, ddd, J = 7.3Hz, 9.8Hz, 14.2Hz), 2.78-2.87 (1H, m), 4.09 (1H, t, J = 7.8Hz), 4.19 (1H , d, J = 5.9Hz), 4.20 (1H, d, J = 8.3Hz), 4.33 (1H, d, J = 8.3Hz), 4.68 (1H, d, J = 11.7Hz), 4.75 (1H, d , J = 11.7Hz), 4.85 (1H, s), 4.95-5.00 (2H, m), 5.08 (1H, dd, J = 16.9Hz, 1.7Hz), 5.53 (1H, dd, J = 7.1Hz, 11.0 Hz), 5.68-5.80 (1H, m), 7.48 (2H, t, J = 7.8Hz), 7.61 (1H, t, J = 7.8Hz), 8.10 (2H, d, J = 7.8Hz).
[0180]
Step 3: 10-allyl-10-deacetoxy-7-O- (2,2,2-trichloroethoxycarbonyl) -13-O-triethylsilylbaccatin III
Dissolve 360 mg of the compound obtained in Step 2 above in 15 ml of methylene chloride, add 100 ml of 2,6-lutidine and 165 ml of triethylsilyl trifluoromethanesulfonate at -50 ° C, stir for 1.5 hours, and then add 2,6-lutidine. 150 ml and 240 ml of triethylsilyl trifluoromethanesulfonate were added and stirred for 2 hours, 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of ethyl acetate were added to the reaction solution and the phases were separated, and the aqueous layer was extracted with 20 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 5: 1 (v / v)) to obtain 285 mg of the title compound as a colorless transparent glassy substance.
[0181]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.60-0.73 (6H, m), 1.02 (9H, t, J = 7.3Hz), 1.09 (3H, s), 1.12 (3H, s), 1.61 (1H, s), 1.77 (3H, s), 1.93 (3H, d, J = 1.5Hz), 1.99-2.14 (2H, m), 2.20-2.33 (2H, m), 2.30 (3H, s), 2.62 (1H, ddd, J = 6.8Hz, 9.3Hz, 14.2Hz), 2.77-2.86 (1H, m), 4.08 (1H, t, J = 6.8Hz), 4.12 (1H, d, J = 7.1Hz), 4.20 (1H, d, J = 8.1Hz), 4.32 (1H, d, J = 8.1Hz), 4.67 (1H, d, J = 11.7Hz), 4.75 (1H, d, J = 11.7Hz), 4.91 (1H, dd, J = 7.3Hz, 8.3Hz), 4.94-5.02 (2H, m), 5.06 (1H, dd, J = 1.5Hz, 17.1Hz), 5.54 (1H, dd, J = 7.1Hz, 11.1Hz), 5.64 (1H, d, J = 7.1Hz) , 5.68-5.79 (1H, m), 7.48 (2H, t, J = 7.3Hz), 7.61 (1H, t, J = 7.3Hz), 8.09 (2H, d, J = 7.3Hz).
[0182]
Process 4: 10-allyl-10-deacetoxy-13-O-triethylsilylbaccatin III
Dissolve 285 mg of the compound obtained in the above step 3 in 30 ml of ethyl acetate, add 2.80 g of zinc powder and 1.90 ml of acetic acid at room temperature, and stir at room temperature for 5 minutes. Was added to separate the layers, and the aqueous layer was extracted with 30 ml of ethyl acetate. The organic layers were combined, washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1 (v / v)) to obtain 215 mg of the title compound as a colorless amorphous solid.
[0183]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.60-0.75 (6H, m), 1.01 (9H, t, J = 7.8Hz), 1.10 (3H, s), 1.13 (3H, s), 1.62 (3H, s), 1.65 (1H, s), 1.75 -1.85 (1H, m), 1.87 (3H, d, J = 1.0Hz), 2.10 (1H, dd, J = 8.3Hz, 15.6Hz), 2.20-2.40 (2H, m), 2.29 (3H, s) , 2.50-2.63 (1H, m), 2.88-2.98 (1H, m), 3.89 (1H, t, J = 7.1Hz), 4.02 (1H, d, J = 7.1Hz), 4.19 (1H, d, J = 8.8Hz), 4.28-4.40 (1H, m), 4.30 (1H, d, J = 8.8Hz), 4.90 (1H, dd, J = 7.1Hz, 8.3Hz), 4.95-5.05 (2H, m), 5.09 (1H, d, J = 17.1Hz), 5.63 (1H, d, J = 7.1Hz), 5.73-5.87 (1H, m), 7.47 (2H, t, J = 7.3Hz), 7.60 (1H, t , J = 7.3Hz), 8.09 (2H, d, J = 7.3Hz).
[0184]
Step 5: 10-allyl-10-deacetoxy-13-O-triethylsilyl-7-O-trifluoromethanesulfonylbaccatin III
Dissolve 205 mg of the compound obtained in the above Step 4 in 15 ml of methylene chloride, add 5.0 ml of pyridine and 263 ml of trifluoromethanesulfonic anhydride at 0 ° C. and stir at room temperature for 1.5 hours. The mixture was poured into a mixture of 50 ml and ice water 150 ml, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 40: 1 to 10: 1 (v / v)) to obtain 226 mg of the title compound as a colorless amorphous solid. It was.
[0185]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.60-0.73 (6H, m), 1.01 (9H, t, J = 7.8Hz), 1.12 (3H, s), 1.15 (3H, s), 1.59 (1H, s), 1.79 (3H, s), 1.91 (3H, d, J = 1.5Hz), 2.11 (1H, dd, J = 8.3Hz, 15.1Hz), 2.16-2.28 (2H, m), 2.31 (3H, s), 2.40-2.50 (1H, m) , 2.74-2.84 (1H, m), 2.83-2.90 (1H, m),
4.08-4.16 (2H, m), 4.18 (1H, d, J = 8.3Hz), 4.33 (1H, d, J = 8.3Hz), 4.88-4.98 (2H, m), 5.02 (1H, dd, J = 2.0Hz, 9.8Hz), 5.09 (1H, dd, J = 1.5Hz, 17.1Hz), 5.60 (1H, dd, J = 7.3Hz, 10.7Hz), 5.65 (1H, d, J = 6.8Hz), 5.68 -5.80 (1H, m), 7.48 (2H, t, J = 8.3Hz), 7.62 (1H, t, J = 8.3Hz), 8.08 (2H, d, J = 8.3Hz).
[0186]
Step 6: 10-allyl-10-deacetoxy-7-deoxy-6,7-didehydro-13-O-triethylsilylbaccatin III
226 mg of the compound obtained in the above step 5 was dissolved in 5.0 ml of tetrahydrofuran, 0.58 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was added at room temperature, and the mixture was heated to reflux at room temperature for 3 hours and allowed to cool, then under reduced pressure. The solvent was distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent; benzene: ethyl acetate = 3: 1 (v / v)) to obtain 180 mg of the title compound as a colorless amorphous solid.
[0187]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.58-0.78 (6H, m), 1.00 (9H, t, J = 7.8Hz), 1.08 (3H, s), 1.15 (3H, s), 1.70 (1H, s), 1.78 (3H, d, J = 1.5Hz), 1.82 (3H, s), 2.10 (1H, dd, J = 8.6Hz, 14.8Hz), 2.17-2.30 (1H, m), 2.27 (1H, dd, J = 8.3Hz, 14.8Hz), 2.28 (3H, s), 2.93-3.04 (1H, m), 3.16 (1H, t, J = 7.1Hz), 4.18 (1H, d, J = 6.3Hz), 4.28 (1H, d, J = 7.8Hz ), 4.43 (1H, d, J = 7.8Hz), 4.92 (1H, t, J = 7.6Hz), 5.01 (1H, dd, J = 1.5Hz, 9.3Hz), 5.05-5.13 (1H, m), 5.12 (1H, d, J = 5.9Hz), 5.73 (1H, d, J = 9.8Hz), 5.79 (1H, d, J = 6.3Hz), 5.76-5.88 (1H, m), 6.01 (1H, dd , J = 5.9,9.8Hz), 7.49 (2H, t, J = 7.8Hz), 7.62 (1H, t, J = 7.8Hz), 8.14 (2H, d, J = 7.8Hz).
[0188]
Step 7: 10-allyl-10-deacetoxy-7-deoxy-6,7-didehydrobaccatin III
28.0 mg of the compound obtained in the above Step 6 was dissolved in 1.0 ml of pyridine, 0.50 ml of hydrogen fluoride pyridine was added at 0 ° C. and stirred at room temperature for 7 hours, and then the reaction solution was stirred with 10 ml of stirred ethyl acetate and 20 ml of ice water. The mixture was poured into a mixture and separated, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layers were combined, washed with 10 ml of a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 1: 1 (v / v)) to obtain 16.9 mg of the title compound as a colorless amorphous solid.
[0189]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.08 (3H, s), 1.09 (3H, s), 1.73 (1H, s), 1.82 (3H, s), 1.84 (3H, d, J = 1.5Hz), 2.02 (1H, d, J = 5.4Hz ), 2.18-2.30 (3H, m), 2.30 (3H, s), 2.93-3.02 (1H, m), 3.68 (1H, t, J = 7.1Hz), 4.29 (1H, d, J = 6.9Hz) , 4.31 (1H, d, J = 8.3Hz), 4.42 (1H, d, J = 8.3Hz), 4.81-4.90 (1H, m), 4.98-5.05 (1H, m), 5.11 (1H, d, J = 5.4Hz), 5.07-5.14 (1H, m), 5.74 (1H, d, J = 10.2Hz), 5.80 (1H, d, J = 6.9Hz), 5.78-5.90 (1H, m), 6.02 (1H , dd, J = 5.4Hz, 10.2Hz), 7.49 (2H, t, J = 8.3Hz), 7.62 (1H, t, J = 8.3Hz), 8.15 (2H, d, J = 8.3Hz).
[0190]
Step 8: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy- 7-Deoxy-6,7-didehydrobaccatin III
16.5 mg of the compound obtained in the above Step 7 was dissolved in 2.0 ml of tetrahydrofuran, 40.0 ml of lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution) was added at −45 ° C., and the mixture was stirred for 30 minutes, and then (3R, 4S) -1- ( tert-Butoxycarbonyl) -3- (tert-Butyldimethylsilyl) oxy-4-phenyl-2-azetidinone 23.0 mg of tetrahydrofuran in 1.0 ml was added dropwise and stirred at 0 ° C for 1 hour. ml and 10 ml of ethyl acetate were added for liquid separation, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layers were combined, washed with 10 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 4: 1 (v / v)) to obtain 27.8 mg of the title compound as a colorless transparent glassy substance.
[0191]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.35 (3H, s), -0.11 (3H, s), 0.75 (9H, s), 1.12 (3H, s), 1.27 (3H, s), 1.32 (9H, s), 1.65 (1H, s) , 1.70 (3H, d, J = 1.0Hz), 1.86 (3H, s), 2.16 (1H, dd, J = 7.8Hz, 14.9Hz), 2.18-2.27 (1H, m), 2.43 (1H, dd, J = 9.8Hz, 14.9Hz), 2.56 (3H, s), 2.99-3.06 (1H, m), 3.65 (1H, t, J = 6.8Hz), 4.21 (1H, d, J = 6.8Hz), 4.34 (1H, d, J = 8.3Hz), 4.44 (1H, d, J = 8.3Hz), 4.50 (1H, s), 5.04 (1H, d, J = 9.8Hz), 5.21 (1H, d, J = 5.5Hz), 5.22 (1H, dd, J = 1.5Hz, 17.1Hz), 5.32 (1H, d, J = 9.3Hz), 5.46 (1H, d, J = 9.3Hz), 5.76 (1H, d, J = 9.8Hz), 5.86 (1H, d, J = 6.8Hz), 5.78-5.90 (1H, m), 6.03 (1H, dd, J = 5.5Hz, 9.8Hz), 6.36 (1H, t, J = 8.6 Hz), 7.50 (2H, t, J = 7.3Hz), 7.60 (1H, t, J = 7.3Hz), 8.17 (2H, d, J = 7.3Hz).
[0192]
Step 9: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-7-deoxy-6,7- Didehydrobaccatin III
27.0 mg of the compound obtained in the above step 8 was dissolved in 2.0 ml of pyridine, 0.50 ml of hydrogen fluoride pyridine was added at 0 ° C. and stirred at room temperature for 4 hours, and then the reaction solution was stirred with 10 ml of stirred ethyl acetate and 20 ml of ice water. The mixture was poured into a mixture and separated, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layers were combined, washed with 10 ml of a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 1: 1 (v / v)) to obtain 22.3 mg of the title compound as a colorless amorphous solid.
[0193]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.12 (3H, s), 1.24 (3H, s), 1.33 (9H, s), 1.64 (3H, s), 1.82 (1H, s), 1.84 (3H, s), 2.18-2.40 (3H, m) , 2.38 (3H, s), 2.93-3.04 (1H, m), 3.32 (1H, d, J = 5.4Hz), 3.65 (1H, t, J = 7.1Hz), 4.17 (1H, d, J = 6.4 Hz), 4.32 (1H, d, J = 8.3Hz), 4.42 (1H, d, J = 8.3Hz), 4.60 (1H, s),
5.03 (1H, d, J = 9.8Hz), 5.08 (1H, d, J = 5.4Hz), 5.11 (1H, dd, J = 1.5Hz, 17.1Hz), 5.28 (1H, d, J = 9.8Hz) , 5.40 (1H, d, J = 9.8Hz), 5.74 (1H, d, J = 9.8Hz), 5.84 (1H, d, J = 6.4Hz), 5.77-5.87 (1H, m), 6.02 (1H, dd, J = 5.4Hz, 9.8Hz), 6.21 (1H, t, J = 8.6Hz), 7.51 (2H, t, J = 8.3Hz), 7.62 (1H, t, J = 8.3Hz), 8.15 (2H , d, J = 8.3Hz).
[0194]
Step 10: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-7-deoxy-6,7-didehydro-10- (2-morpholinoethyl) baccatin III
22.0 mg of the compound obtained in Step 9 above was dissolved in 2.0 ml of tetrahydrofuran, and 1.0 ml of an osmium tetroxide aqueous solution (0.040 M aqueous solution) and 50.0 mg of N-methylmorpholine-N-oxide were added at room temperature, and then at room temperature for 1 hour. Stir. To the reaction solution were added 10 ml of ethyl acetate and 15 ml of 10% aqueous sodium thiosulfate solution, and the mixture was stirred for 30 minutes and separated. The aqueous layer was extracted with 10 ml of ethyl acetate. The organic layers were combined, washed with 10 ml of saturated aqueous sodium bicarbonate solution and 10 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 23.0 mg of the residue. This residue was dissolved in 2.0 ml of tetrahydrofuran, and 2.0 ml of methanol, 2.0 ml of water and 69.5 mg of sodium metaperiodate were added at room temperature, followed by stirring at room temperature for 1 hour. To the reaction solution were added 10 ml of ethyl acetate and 10 ml of water, and the mixture was stirred for 30 minutes and separated. The aqueous layer was extracted with 10 ml of ethyl acetate. The organic layers were combined, washed with 10 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 22.7 mg of the residue. This residue was dissolved in a 3.0 ml ethanol solution, 24.0 ml morpholine, 15.5 ml acetic acid and 17.0 mg sodium cyanoborohydride were added at room temperature, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (10 ml), ethyl acetate (10 ml) and water (10 ml) were added to the reaction mixture, and the mixture was stirred for 30 minutes and separated. The aqueous layer was extracted with ethyl acetate (10 ml). The organic layers were combined, washed with 10 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel thin layer chromatography (developing solvent; chloroform: acetone = 7: 3 (v / v)) to obtain 22.7 mg of 1,4-dioxane title compound as a colorless solid.
[0195]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (3H, s), 1.22 (3H, s), 1.33 (9H, s), 1.44-1.55 (1H, m), 1.72 (3H, s), 1.83 (3H, s), 2.23 (1H, dd, J = 8.6Hz, 14.9Hz), 2.30-2.60 (8H, m), 2.39 (3H, s), 3.68 (4H, t, J = 4.7Hz), 3.78 (1H, dd, J = 4.9Hz, 6.8Hz ), 4.19 (1H, d, J = 6.6Hz), 4.31 (1H, d, J = 8.1Hz), 4.42 (1H, d, J = 8.1Hz), 4.60 (1H, s), 5.11 (1H, d , J = 5.7Hz), 5.27 (1H, d, J = 9.3Hz), 5.41 (1H, d, J = 9.3Hz), 5.72 (1H, d, J = 9.8Hz), 5.83 (1H, d, J = 6.6Hz), 6.02 (1H, dd, J = 5.9Hz, 9.8Hz), 6.18 (1H, t, J = 8.6Hz), 7.51 (2H, t, J = 7.3Hz), 7.62 (1H, t, J = 7.3Hz), 8.16 (2H, d, J = 7.3Hz).
Melting point: 202.5-206.5 ℃
[0196]
Example 2
[0197]
Embedded image
Step 1: 10-allyl-10-deacetoxy-7-deoxy-6,7-didehydro-1-O-dimethylsilyl-13-O-triethylsilylbaccatin III
150 mg of the compound obtained in Step 6 of Example 1 was dissolved in 3.0 ml of N, N-dimethylformamide, 62.0 mg of imidazole and 100 ml of dimethylsilane chloride were added at 0 ° C., and the mixture was stirred for 20 minutes. 20 ml and 10 ml of ethyl acetate were added for liquid separation, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layers were combined, washed with 10 ml of water and 10 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 4: 1 (v / v)) to obtain 162 mg of the title compound as a colorless amorphous solid.
[0199]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.23 (3H, d, J = 2.9Hz), 0.09 (3H, d, J = 2.9Hz), 0.60-0.75 (6H, m), 1.03 (9H, t, J = 7.8Hz), 1.07 (3H, s), 1.10 (3H, s), 1.78 (3H, d, J = 1.0Hz), 1.83 (3H, s), 2.16-2.26 (1H, m), 2.28 (3H, s), 2.28 (1H, dd , J = 9.3Hz, 15.6Hz), 2.38 (1H, dd, J = 7.8Hz, 15.6Hz), 2.93-3.03 (1H, m), 3.63 (1H, t, J = 6.9Hz), 4.16 (1H, d, J = 6.8Hz), 4.34 (1H, d, J = 8.3Hz), 4.36 (1H, d, J = 8.3Hz), 4.54-4.59 (1H, m), 4.95 (1H, t, J = 7.8 Hz), 5.00 (1H, d, J = 10.7Hz), 5.08 (1H, dd, J = 1.5Hz, 17.1Hz), 5.10 (1H, d, J = 5.4Hz), 5.72 (1H, d, J = 9.8Hz), 5.84 (1H, d, J = 6.8Hz), 5.75-5.90 (1H, m), 5.98 (1H, dd, J = 5.4Hz, 9.8Hz), 7.48 (2H, t, J = 7.3Hz ), 7.59 (1H, t, J = 7.3Hz), 8.14 (2H, d, J = 7.3Hz).
[0200]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-6,7-didehydro-1-O-dimethylsilyl-13-O-triethylsilylbaccatin III
162 mg of the compound obtained in the above step 1 was dissolved in 2.0 ml of tetrahydrofuran, 336 ml of bis (2-methoxyethoxy) aluminum sodium hydride was added at 0 ° C. and stirred for 3.5 hours, and then 5.0 ml of ethyl acetate and saturated tartaric acid A potassium aqueous solution (5.0 ml) and water (5.0 ml) were added for liquid separation, and the aqueous layer was extracted with ethyl acetate (10 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 10: 3 (v / v)) to obtain 137 mg of the title compound as a colorless amorphous solid.
[0201]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.23 (3H, d, J = 2.4Hz), 0.05 (3H, d, J = 2.9Hz), 0.66-0.86 (6H, m), 0.99 (3H, s), 1.06 (9H, t, J = 8.1 Hz), 1.09 (3H, s), 1.72 (6H, s), 2.30-2.42 (1H, m), 2.57 (1H, dd, J = 9.8Hz, 15.3Hz), 2.84 (1H, dd, J = 2.4 Hz, 15.3Hz), 2.88-3.02 (1H, m), 3.67 (1H, t, J = 7.1Hz), 3.82 (1H, s), 4.03 (1H, d, J = 5.7Hz), 4.30 (1H, d, J = 7.8Hz), 4.33 (1H, d, J = 7.8Hz), 4.55-4.65 (1H, m), 4.68 (1H, d, J = 8.8Hz), 4.85 (1H, d, J = 5.4 Hz), 5.03 (1H, d, J = 10.3Hz), 5.12 (1H, d, J = 17.1Hz), 5.68 (1H, d, J = 9.1Hz), 5.73 (1H, d, J = 5.7Hz) , 5.74-5.89 (1H, m), 5.95 (1H, dd, J = 5.4Hz, 9.1Hz), 7.45 (2H, t, J = 7.3Hz), 7.56 (1H, t, J = 7.3Hz), 8.17 (2H, d, J = 7.3Hz).
[0202]
Step 3: 10-allyl-4-O- (cyclopropanecarbonyl) -10-deacetoxy-4-deacetyl-7-deoxy-6,7-didehydro-1-O-dimethylsilyl-13-O-triethylsilylbaccatin III
Dissolve 137 mg of the compound obtained in the above step 2 in 3.0 ml of tetrahydrofuran, add 800 ml of lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution) at -20 ° C and stir for 15 minutes, then add 72.0 ml of cyclopropanecarbonyl chloride and add 30 ml. After stirring for 10 minutes, 10 ml of a saturated aqueous sodium bicarbonate solution and 10 ml of ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layers were combined, washed with 10 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 5: 1 (v / v)) to obtain 122 mg of the title compound as a colorless amorphous solid.
[0203]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.23 (3H, d, J = 2.9Hz), 0.09 (3H, d, J = 2.4Hz), 0.56-0.74 (6H, m), 0.96-1.30 (4H, m), 1.02 (9H, t, J = 7.8Hz), 1.08 (3H, s), 1.13 (3H, s), 1.71-1.82 (1H, m), 1.79 (3H, d, J = 1.0Hz), 1.83 (3H, s), 2.14-2.24 (1H, m), 2.34 (1H, dd, J = 7.3Hz, 15.4Hz), 2.42 (1H, dd, J = 9.3Hz, 15.4Hz), 2.91-3.01 (1H, m), 3.61 (1H, t , J = 6.8Hz), 4.11 (1H, d, J = 6.4Hz), 4.34 (1H, d, J = 7.8Hz), 4.42 (1H, d, J = 7.8Hz), 4.56-4.62 (1H, m ), 4.98 (1H, t, J = 7.8Hz), 4.99 (1H, dd, J = 1.8Hz, 10.2Hz), 5.05 (1H, d, J = 5.4Hz), 5.08 (1H, dd, J = 1.8 Hz, 17.1Hz), 5.72 (1H, d, J = 9.8Hz), 5.76-6.01 (1H, m), 5.94 (1H, d, J = 6.4Hz), 5.97 (1H, dd, J = 5.4Hz, 9.8Hz), 7.47 (2H, t, J = 7.3Hz), 7.59 (1H, t, J = 7.3Hz), 8.12 (2H, d, J = 7.3Hz).
[0204]
Step 4: 10-allyl-4-O- (cyclopropanecarbonyl) -10-deacetoxy-4-deacetyl-7-deoxy-6,7-didehydrobaccatin III
122 mg of the compound obtained in the above step 3 was dissolved in 3.0 ml of pyridine, 1.0 ml of hydrogen fluoride pyridine was added at 0 ° C. and stirred at room temperature for 3.5 hours, and then the reaction solution was stirred with 10 ml of stirred ethyl acetate and 30 ml of ice water. The mixture was poured into a mixture and separated, and the aqueous layer was extracted with 10 ml of ethyl acetate. The organic layers were combined, washed with 10 ml of a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 3: 1 (v / v)) to obtain 77.2 mg of the title compound as a colorless amorphous solid.
[0205]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.00-1.18 (4H, m), 1.08 (3H, s), 1.11 (3H, s), 1.70-1.88 (3H, m), 1.83 (6H, s), 2.18-2.38 (3H, m), 2.90- 3.02 (1H, m), 3.66 (1H, t, J = 6.8Hz), 4.28 (1H, d, J = 6.6Hz), 4.33 (1H, d, J = 8.3Hz), 4.46 (1H, d, J = 8.3Hz), 4.75-4.87 (1H, m), 4.98-5.05 (2H, m), 5.11 (1H, dd, J = 1.2Hz, 16.8Hz), 5.75 (1H, d, J = 9.8Hz), 5.77-5.90 (1H, m), 5.82 (1H, d, J = 6.6Hz), 6.00 (1H, dd, J = 5.4Hz, 9.8Hz), 7.49 (2H, t, J = 7.3Hz), 7.62 ( 1H, t, J = 7.3Hz), 8.15 (2H, d, J = 7.3Hz).
[0206]
Step 5: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -3- (triisopropylsilyl) oxypropionyl] -4-O -(Cyclopropanecarbonyl) -10-deacetoxy-4-deacetyl-7-deoxy-6,7-didehydrobaccatin III
The compound obtained in Step 4 above and (3R, 4R) -1- (tert-butoxycarbonyl) -4- (2-furyl) -3- (triisopropylsilyl) oxy-2-azetidinone were used in Step 8 of Example 1. To give the title compound as a colorless amorphous solid.
[0207]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.16 (3H, s), 0.03 (3H, s), 0.77 (9H, s), 1.08-1.41 (4H, m), 1.11 (3H, s), 1.25 (3H, s), 1.37 (9H, s ), 1.71 (3H, d, J = 1.0Hz), 1.76 (1H, s), 1.85 (3H, s), 1.91-1.98 (1H, m), 2.16-2.29 (2H, m), 2.56 (1H, dd, J = 9.6Hz, 15.2Hz), 2.94-3.02 (1H, m), 3.66 (1H, t, J = 6.8Hz), 4.21 (1H, d, J = 6.8Hz), 4.32 (1H, d, J = 8.3Hz), 4.44 (1H, d, J = 8.3Hz), 4.79 (1H, d, J = 1.5Hz), 5.00-5.07 (2H, m), 5.11 (1H, dd, J = 1.2Hz, 16.9Hz), 5.25 (1H, d, J = 9.8Hz), 5.38 (1H, d, J = 9.8Hz), 5.75 (1H, d, J = 9.7Hz), 5.78-5.90 (1H, m), 5.86 (1H, d, J = 6.8Hz), 6.01 (1H, dd, J = 5.6Hz, 9.7Hz), 6.16 (1H, t, J = 8.5Hz), 6.22 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = 3.2Hz, 2.0Hz), 7.33 (1H, s), 7.50 (2H, t, J = 7.3Hz), 7.61 (1H, t, J = 7.3Hz), 8.12 (2H, d, J = 7.3Hz).
[0208]
Step 6: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4-O- (cyclopropanecarbonyl ) -10-deacetoxy-4-deacetyl-7-deoxy-6,7-didehydrobaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0209]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.94-1.40 (4H, m), 1.13 (3H, s), 1.25 (3H, s), 1.36 (9H, s), 1.57 (3H, s), 1.79 (1H, s), 1.84 (3H, s) , 1.84-1.93 (1H, m), 2.20-2.37 (2H, m), 2.54 (1H, dd, J = 9.5Hz, 15.4Hz), 2.93-3.03 (1H, m), 3.26 (1H, d, J = 5.4Hz), 3.66 (1H, t, J = 7.1Hz), 4.19 (1H, d, J = 6.6Hz), 4.30 (1H, d, J = 8.3Hz), 4.43 (1H, d, J = 8.3 Hz), 4.73 (1H, d, J = 3.9Hz), 4.98-5.05 (2H, m), 5.11 (1H, d, J = 16.6Hz), 5.17 (1H, d, J = 10.0Hz), 5.37 ( 1H, d, J = 10.0Hz), 5.74 (1H, d, J = 9.7Hz), 5.75-5.88 (1H, m), 5.86 (1H, d, J = 6.6Hz), 6.01 (1H, dd, J = 5.7Hz, 9.7Hz), 6.17 (1H, t, J = 8.6Hz), 6.32 (1H, d, J = 3.4Hz), 6.37 (1H, dd, J = 3.4Hz, 2.0Hz), 7.38 (1H , s), 7.51 (2H, t, J = 7.3Hz), 7.62 (1H, t, J = 7.3Hz), 8.14 (2H, d, J = 7.3Hz).
[0210]
Step 7: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4-O- (cyclopropanecarbonyl) -10- Deacetoxy-4-deacetyl-7-deoxy-6,7-didehydro-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 6 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0211]
Melting point: 124.0-129.0 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.00-1.95 (8H, m), 1.11 (3H, s), 1.23 (3H, s), 1.36 (9H, s), 1.77 (3H, d, J = 1.0Hz), 1.83 (1H, s), 2.25 -2.65 (8H, m), 3.26 (1H, s), 3.68 (4H, t, J = 4.4Hz), 3.81 (1H, t, J = 6.1Hz), 4.20 (1H, d, J = 6.4Hz) , 4.30 (1H, d, J = 8.3Hz), 4.44 (1H, d, J = 8.3Hz), 4.74 (1H, s), 5.05 (1H, d, J = 5.8Hz), 5.17 (1H, d, J = 9.6Hz), 5.37 (1H, d, J = 9.6Hz), 5.72 (1H, d, J = 9.8Hz), 5.85 (1H, d, J = 6.4Hz), 6.01 (1H, dd, J = 5.8Hz, 9.8Hz), 6.14 (1H, t, J = 8.5Hz), 6.32 (1H, d, J = 3.1Hz), 6.37 (1H, dd, J = 3.1Hz, 1.8Hz), 7.38 (1H, d, J = 1.8Hz), 7.50 (2H, t, J = 7.3Hz), 7.62 (1H, t, J = 7.3Hz), 8.14 (2H, d, J = 7.3Hz).
[0212]
Example 3
[0213]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10 -Deacetoxy-6,7-didehydrobaccatin III
Conducting the compound obtained in Step 7 of Example 1 and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (2-furyl) -3- (tert-butyldimethylsilyl) oxy-2-azetidinone Reaction was carried out in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0215]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.18 (s, 3H), 0.02 (s, 3H), 0.79 (s, 9H), 1.11 (s, 3H), 1.22 (s, 3H), 1.34 (s, 9H), 1.70 (s, 3H), 1.84 (s, 3H), 2.15-2.29 (m, 2H), 2.43 (m, 1H), 2.49 (s, 3H), 2.99 (m, 1H), 3.66 (t, 1H, J = 6.8Hz), 4.21 (d, 1H, J = 6.5Hz), 4.32 (d, 1H, J = 8.5Hz), 4.42 (d, 1H, J = 8.5Hz), 4.71 (s, 1H), 5.03 (d, 1H, J = 9.9Hz), 5.11 (m, 2H), 5.29 (d, 1H, J = 9.9Hz), 5.34 (d, 1H, J = 9.9Hz), 5.75 (d, 1H, J = 6.8Hz), 5.83 (m , 2H), 6.02 (dd, 1H, J = 5.6Hz, 9.9Hz), 6.19 (m, 1H), 6.21 (m, 1H), 6.34 (m, 1H), 7.38 (s, 1H), 7.50 (t , 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 918 (MH+)
[0216]
Step 2: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10-deacetoxy-6 , 7-didehydro-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0217]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.17 (s, 3H), 0.01 (s, 3H), 0.79 (s, 9H), 1.10 (s, 3H), 1.21 (s, 3H), 1.35 (s, 9H), 1.78 (s, 3H), 1.85 (s, 3H), 2.20 (m, 2H), 2.30-2.58 (m, 8H), 2.50 (s, 3H), 3.69 (m, 4H), 3.79 (dd, 3H, J = 4.9Hz, 7.0Hz ), 4.23 (d, 1H, J = 6.6Hz), 4.33 (d, 1H, J = 8.1Hz), 4.43 (d, 1H, J = 8.1Hz), 4.72 (s, 1H), 5.12 (d, 1H , J = 5.8Hz), 5.28 (d, 1H, J = 10Hz), 5.35 (d, 1H, J = 9.9Hz), 5.73 (d, 1H, J = 9.9Hz), 5.85 (d, 1H, J = 6.6Hz), 6.04 (dd, 1H, J = 5.8Hz, 9.9Hz), 6.17 (m, 1H), 6.22 (m, 1H), 6.35 (m, 1H), 7.38 (s, 1H), 7.50 (t , 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 991 (MH+)
[0218]
Step 3: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-6,7-didehydro-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0219]
Melting point: 125-130 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (s, 3H), 1.21 (s, 3H), 1.36 (s, 9H), 1.75 (s, 3H), 1.84 (s, 3H), 2.25 (m, 1H), 2.30-2.48 (m, 8H) , 2.42 (s, 3H), 2.55 (m, 1H), 3.69 (m, 4H), 3.79 (m, 1H), 4.21 (d, 1H, J = 6.9Hz), 4.32 (d, 1H, J = 8.5 Hz), 4.42 (d, 1H, J = 8.5Hz), 4.70 (m, 1H), 5.12 (d, 1H, J = 5.5Hz), 5.26 (d, 1H, J = 10Hz), 5.33 (d, 1H , J = 9.9Hz), 5.72 (d, 1H, J = 9.9Hz), 5.83 (d, 1H, J = 6.9Hz), 6.03 (dd, 1H, J = 5.5Hz, 9.9Hz), 6.18 (t, 1H, J = 9Hz), 6.32 (m, 1H), 6.38 (m, 1H), 7.41 (s, 1H), 7.50 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz ), 8.16 (d, 2H, J = 7.5Hz).
MS-FAB: 877 (MH+)
[0220]
Example 4
[0221]
Embedded image
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3-phenyl-2- (trimethylsilyl) oxypropionyl] -10-deacetoxy-6,7-didehydro -10- (2-morpholinoethyl) baccatin III
62 mg of the compound obtained in Step 7 of Example 1 and cis-1- (tert-butoxycarbonyl) -3-methyl-4-phenyl-3- (trimethylsilyl) oxy-2-yl obtained in Step 2 of Reference Example 1 47 mg of azetidinone was dissolved in 3 ml of dry tetrahydrofuran, 452 ml of sodium bis (trimethylsilyl) amide was added at −78 ° C., and the mixture was reacted at the same temperature for 15 minutes. This was post-treated in the same manner as in Step 8 of Example 1, purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 85: 15 (v / v)), and 10-allyl-13-O— [ (2R, 3S) -3- (tert-Butoxycarbonylamino) -2-methyl-3-phenyl-2- (trimethylsilyl) oxypropionyl] -10-deacetoxy-6,7-didehydrobaccatin III and 10-allyl 46 mg of a mixture of -13-O- (tert-butoxycarbonyl) -10-deacetoxy-6,7-didehydrobaccatin III was obtained. The resulting mixture was reacted in the same manner as in Step 10 of Example 1, post-treated, separated and purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 7: 3 (v / v)), and the title compound 26 mg was obtained as a colorless amorphous solid.
[0223]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.10 (s, 9H), 1.10 (s, 3H), 1.19 (s, 9H), 1.30 (s, 3H), 1.39 (s, 3H), 1.76 (s, 3H), 1.88 (s, 3H), 2.10 (m, 1H), 2.30-2.45 (m, 8H), 2.56 (m, 1H), 2.70 (s, 3H), 3.69 (m, 4H), 3.78 (m, 1H), 4.19 (d, 1H, J = 6.7Hz), 4.38 (d, 1H, J = 8.5Hz), 4.44 (d, 1H, J = 8.5Hz), 4.99 (d, 1H, J = 10Hz), 5.13 (d, 1H, J = 5.6Hz) ), 5.50 (d, 1H, J = 9.9Hz), 5.75 (d, 1H, J = 9.9Hz), 5.85 (d, 1H, J = 6.7Hz), 6.03 (dd, 1H, J = 5.7Hz, 10.0 Hz), 6.32 (t, 1H, J = 9Hz), 7.27-7.38 (m, 5H), 7.52 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.19 (d , 2H, J = 7.5Hz).
MS-FAB: 973 (MH+)
[0224]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-6,7-didehydro-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0225]
Melting point: 165-170 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.11 (s, 3H), 1.23 (s, 9H), 1.28 (s, 3H), 1.36 (s, 3H), 1.86 (s, 3H), 2.20 (m, 1H), 2.35 (m, 4H), 2.44 (m, 4H), 2.57 (m, 1H), 2.65 (s, 3H), 3.69 (m, 4H), 3.79 (t, 1H, J = 5.5Hz), 4.20 (d, 1H, J = 6.6Hz) , 4.35 (d, 1H, J = 8.2Hz), 4.44 (d, 1H, J = 8.2Hz), 5.03 (d, 1H, J = 10.2Hz), 5.11 (d, 1H, J = 5.6Hz), 5.51 (d, 1H, J = 10.2Hz), 5.72 (d, 1H, J = 9.9Hz), 5.85 (d, 1H, J = 7.7Hz), 6.03 (dd, 1H, J = 5.6Hz, 10.0Hz), 6.30 (m, 1H), 7.30-7.40 (m, 5H), 7.51 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.18 (d, 2H, J = 7.5Hz) ).
MS-FAB: 901 (MH+)
[0226]
Example 5
[0227]
Embedded image
Step 1: 10-allyl-7,13-O-bis (triethylsilyl) -10-deacetoxybaccatin III
10-Allyl-10-deacetoxy-7-O-triethylsilylbaccatin III was reacted in the same manner as in Step 3 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0229]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.71 (m, 12H), 0.94-1.03 (m, 18H), 1.12 (s, 3H), 1.14 (s, 3H), 1.62 (s, 3H), 1.87 (s, 3H), 1.84-1.91 ( m, 1H), 2.05-2.11 (m, 1H), 2.20-2.56 (m, 1H), 2.29 (s, 3H), 2.42-2.50 (m, 2H), 2.78-2.82 (m, 1H), 3.87 ( dd, 1H, J = 4.5Hz, 10Hz), 3.97 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.29 (d, 1H, J = 8Hz), 4.53 (dd, 1H , J = 7Hz, 10Hz), 4.90-5.10 (m, 4H), 5.61 (d, 1H, J = 7Hz), 5.71-5.82 (m, 1H), 7.46 (t, 2H, J = 8Hz), 7.59 ( t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0230]
Process 2: 10-allyl-10-deacetoxy-13-O-triethylsilylbaccatin III
209 mg of the compound obtained in the above step 1 was dissolved in 21 ml of methanol, 5 mg of p-toluenesulfonic acid was added, and the mixture was stirred overnight at room temperature. After further adding 2 mg of p-toluenesulfonic acid and stirring for 4 hours, 0.10 ml of triethylamine was added and the reaction solution was concentrated. The obtained residue was purified by silica gel thin phase chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v)) to obtain 135 mg of the title compound as a colorless amorphous solid.
[0231]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.61-0.72 (m, 6H), 1.01 (t, 9H, J = 7Hz), 1.10 (s, 3H), 1.13 (s, 3H), 1.63 (s, 3H), 1.87 (s, 3H), 1.75- 1.84 (m, 1H), 2.06-2.12 (m, 1H), 2.22-2.34 (m, 2H), 2.28 (s, 3H), 2.53-2.61 (m, 1H), 2.90-2.97 (m, 1H), 3.89 (t, 1H, J = 7Hz), 4.02 (d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.33-4.36 (m, 1H), 4.90 (t, 1H, J = 8Hz), 4.98-5.02 (m, 2H), 5.10 (d, 1H, J = 17Hz), 5.63 (d, 1H, J = 7Hz), 5.75-5.84 (m , 1H), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
[0232]
Step 3: 10-allyl-10-deacetoxy-7-deoxy-7-α-fluoro-13-O-triethylsilylbaccatin III
188 mg of the compound obtained in the above step 2 was dissolved in 10 ml of dichloromethane and cooled to -78 ° C. Next, 0.025 ml of diethylaminosulfur trifluoride was added, and the mixture was stirred at the same temperature for 15 minutes and at 0 ° C. for 30 minutes. The reaction solution was cooled again to -78 ° C., 0.035 ml of diethylaminosulfur trifluoride was added, and the mixture was stirred at the same temperature for 15 minutes and at 0 ° C. for 40 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture and stirred for 10 minutes. The dichloromethane layer was washed with water and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin phase chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to obtain 94 mg of the title compound as a colorless amorphous solid.
[0233]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.59-0.74 (m, 6H), 1.01 (t, 9H, J = 7Hz), 1.03 (s, 3H), 1.07 (s, 3H), 1.66 (s, 3H), 1.83 (s, 3H), 2.07- 2.37 (m, 4H), 2.30 (s, 3H), 2.50-2.62 (m, 1H), 2.99-3.07 (m, 1H), 4.11 (dd, 1H, J = 5.5Hz, 8Hz), 4.18 (d, 1H, J = 7Hz), 4.34 (AB type d, each 1H, J = 8Hz), 4.53 (dd, 1H, J = 3.5Hz, 47Hz), 4.90 (t, 1H, J = 8Hz), 4.99 (d, 1H, J = 10Hz), 5.05 (s, 1H), 5.08 (dd, 1H, J = 1.5Hz, 17Hz), 5.69 (d, 1H, J = 7Hz), 5.73-5.84 (m, 1H), 7.48 ( t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).
[0234]
Step 4: 10-allyl-10-deacetoxy-7-deoxy-7-α-fluorobaccatin III The compound obtained in Step 3 above is reacted in the same manner as in Step 7 of Example 1 to give the title compound as a colorless amorphous substance. Obtained as a solid.
[0235]
Melting point: 236-238 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.07 (s, 6H), 1.67 (s, 3H), 1.87 (s, 3H), 2.18-2.39 (m, 4H), 2.30 (s, 3H), 2.50-2.63 (m, 1H), 2.99-3.06 ( m, 1H), 4.12 (dd, 1H, J = 5.5Hz, 8Hz), 4.30 (d, 1H, J = 7Hz), 4.35 (s, 2H), 4.53 (dd, 1H, J = 3Hz, 47Hz), 4.83 (br, 1H), 4.99-5.11 (m, 3H), 5.70 (d, 1H, J = 7Hz), 5.74-5.85 (m, 1H), 7.49 (t, 2H, J = 8Hz), 7.61 (t , 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
IR (KBr): 3824, 3548, 3448, 3072, 2984, 2952, 1974, 1910, 1732, 1712, 1690, 1642, 1602, 1584 cm-1
MS-FAB: 571 (MH+)
[0236]
Step 5: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10 -Deacetoxy-7-deoxy-7-α-fluorobaccatin III
The compound obtained in the above Step 4 and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (ter tert-butyldimethylsilyl) oxy-4- (2-furyl) -2-azetidinone were used in Example 1. In the same manner as in Step 8, the title compound was obtained as a colorless amorphous solid.
[0237]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.18 (s, 3H), -0.02 (s, 3H), 0.77 (s, 9H), 1.09 (s, 3H), 1.19 (s, 3H), 1.32 (s, 9H), 1.67 (s, 3H) , 1.71 (s, 3H), 2.12-2.28 (m, 3H), 2.47 (s, 3H), 2.48-2.52 (m, 2H), 2.99-3.05 (m, 1H), 4.06-4.11 (m, 1H) , 4.21 (d, 1H, J = 7Hz), 4.35 (s, 2H), 4.53 (dd, 1H, J = 3Hz, 47Hz), 4.71 (d, 1H, J = 1.5Hz), 4.99-5.10 (m, 3H), 5.26 (d, 1H, J = 10Hz), 5.36 (d, 1H, J = 10Hz), 5.73 (d, 1H, J = 7Hz), 5.75-5.82 (m, 1H), 6.19 (t, 1H , J = 8Hz), 6.21 (d, 1H, J = 3Hz), 6.33 (dd, 1H, J = 1.5Hz, 3Hz), 7.36 (s, 1H), 7.48 (t, 2H, J = 8Hz), 7.57 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
[0238]
Step 6: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10-deacetoxy-7 -Deoxy-7-α-fluoro-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 5 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0239]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.18 (s, 3H), -0.01 (s, 3H), 0.78 (s, 9H), 1.08 (s, 3H), 1.18 (s, 3H), 1.34 (s, 9H), 1.68 (s, 3H) , 1.83 (s, 3H), 2.16-2.62 (m, 12H), 2.48 (s, 3H), 3.64-3.72 (m, 4H), 4.21-4.23 (m, 2H), 4.36 (AB type d, each 1H , J = 8Hz), 4.53 (dd, 1H, J = 3Hz, 47Hz), 4.73 (d, 1H, J = 1.5Hz), 5.04 (dd, 1H, J = 2Hz, 9Hz), 5.27 (d, 1H, J = 10Hz), 5.37 (d, 1H, J = 10Hz), 5.75 (d, 1H, J = 7Hz), 6.18 (t, 1H, J = 8Hz), 6.22 (d, 1H, J = 3Hz), 6.34 (dd, 1H, J = 2Hz, 3Hz), 7.37 (d, 1H, J = 1Hz), 7.49 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.13 (d, 2H , J = 8Hz).
[0240]
Step 7: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-7-deoxy-7-α- Fluoro-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 6 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0241]
Melting point: 127-133 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.20 (s, 3H), 1.35 (s, 9H), 1.68 (s, 3H), 1.82 (s, 3H), 2.37 (s, 3H), 2.17-2.65 (m, 12H) , 3.66-3.71 (m, 4H), 4.21-4.25 (m, 2H), 4.35 (AB type d, each 1H, J = 8Hz), 4.53 (dd, 1H, J = 3Hz, 47Hz), 4.70 (d, 1H, J = 2Hz), 5.03 (dd, 1H, J = 2Hz, 9Hz), 5.26 (d, 1H, J = 10Hz), 5.37 (d, 1H, J = 10Hz), 5.75 (d, 1H, J = 7Hz), 6.19 (t, 1H, J = 8Hz), 6.32 (d, 1H, J = 3Hz), 6.37 (dd, 1H, J = 2Hz, 3Hz), 7.41 (d, 1H, J = 2Hz), 7.51 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.15 (d, 2H, J = 8Hz).
IR (KBr): 3448, 2976, 2860, 2812, 1742, 1720, 1604, 1496 cm-1
MS-FAB: 897 (MH+)
[0242]
Example 6
[0243]
Embedded image
Step 1: 4,10-bis (deacetyl) -10-O- (methylthio) thiocarbonyl-4-O-propionyl-7-O-triethylsilylbaccatin III
3.00 g of 4,10-bis (deacetyl) -4-O-propionyl-7-O-triethylsilylbaccatin III was dissolved in 24 ml of tetrahydrofuran and cooled to -55 ° C. Then, n-butyllithium (1.69 M hexane solution, 3.44 ml) was added dropwise, and after 10 minutes, 0.34 ml of carbon disulfide and 0.34 ml of methyl iodide were added, and the mixture was stirred at -55 ° C for 1 hour and stirred at 0 ° C for 1 hour. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate and n-hexane to obtain 3.07 g of the title compound as pale yellow crystals.
[0245]
Melting point: 206-209 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
0.55-0.61 (m, 6H), 0.92 (t, 9H, J = 7Hz), 1.06 (s, 3H), 1.23-1.27 (m, 6H), 1.71 (s, 3H), 1.88-1.92 (m, 1H ), 2.26-2.28 (m, 2H), 2.29 (s, 3H), 2.53-2.64 (m, 3H), 2.65 (s, 3H), 3.87 (d, 1H, J = 7Hz), 4.16 (d, 1H , J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.53 (dd, 1H, J = 7Hz, 10Hz), 4.84 (br, 1H), 4.92 (d, 1H, J = 8Hz), 5.67 ( d, 1H, J = 7Hz), 7.26 (s, 1H), 7.47 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).
IR (KBr): 3884, 3480, 3068, 2948, 2880, 2744, 2424, 2272, 1912, 1716, 1602 cm-1
MS-FAB: 763 (MH+)
[0246]
Step 2: 10-deacetoxy-4-deacetyl-10- (2-formylethyl) -4-O-propionyl-7-O-triethylsilylbaccatin III
1.50 g of the compound obtained in Step 1 above, 1.42 ml of acrolein, 63 mg of tris (trimethylsilyl) silane silane and 2 ', 2'-azobis (isobutyronitrile) are added to 22.5 ml of benzene, and at 130 ° C. under nitrogen. Heated to reflux for 5 hours (twice on the same scale). The reaction mixture is allowed to cool and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 2 (v / v)) to give 1.64 g of the title compound as a colorless compound. Obtained as an amorphous solid.
[0247]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.52-0.64 (m, 6H), 0.96 (t, 9H, J = 7Hz), 1.05 (s, 3H), 1.12 (s, 3H), 1.24 (t, 3H, J = 7Hz), 1.63 (s, 3H ), 1.94 (s, 3H), 1.85-2.67 (m, 10H), 3.81-3.84 (m, 1H), 4.01 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.55 (dd, 1H, J = 7Hz, 10Hz), 4.84 (br, 1H), 4.92 (d, 1H, J = 8Hz), 5.60 (d, 1H, J = 7Hz ), 7.46 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz), 9.80 (s, 1H).
[0248]
Step 3: 10-deacetoxy-4-deacetyl-10- (3-hydroxypropyl) -4-O-propionyl-7-O-triethylsilylbaccatin III
1.90 g of the compound obtained in the above Step 2 was dissolved in 38 ml of tetrahydrofuran, 295 mg of sodium borohydride was added under ice cooling, and the mixture was stirred for 50 minutes. The mixture was acidified with 1N aqueous hydrochloric acid and extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 50: 1 to 20: 1 (v / v)) to obtain 1.63 g of the title compound as a colorless amorphous solid.
[0249]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.63 (m, 6H), 0.95 (t, 9H, J = 7Hz), 1.05 (s, 3H), 1.11 (s, 3H), 1.24 (t, 3H, J = 7Hz), 1.63 (s, 3H ), 1.97 (s, 3H), 1.70-2.68 (m, 10H), 3.64-3.71 (m, 1H), 3.83 (dd, 1H, J = 3.5Hz, 9Hz), 4.06 (d, 1H, J = 7Hz ), 4.17 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.55 (dd, 1H, J = 7Hz, 10Hz), 4.84 (br, 1H), 4.92 (dd, 1H, J = 2Hz, 9Hz), 5.60 (d, 1H, J = 7Hz), 7.46 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz) , 9.80 (s, 1H).
[0250]
Step 4: 10-deacetoxy-4-deacetyl-10- [3- (2-nitrophenylzeleno) propyl] -4-O-propionyl-7-O-triethylsilylbaccatin III
1.63 g of the compound obtained in the above Step 3 was dissolved in 33 ml of tetrahydrofuran, and 631 mg of 2-nitrophenyl zelenocyanate was added at room temperature, followed by stirring for 1 hour. After concentration, the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 2 (v / v)) to obtain 1.31 g of the title compound as a yellow amorphous solid.
[0251]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.48-0.61 (m, 6H), 0.93 (t, 9H, J = 7Hz), 1.03 (s, 3H), 1.12 (s, 3H), 1.24 (t, 3H, J = 7Hz), 1.63 (s, 3H ), 1.94 (s, 3H), 1.75-2.67 (m, 10H), 2.89-3.05 (m, 2H), 3.83 (dd, 1H, J = 3.5Hz, 9Hz), 4.03 (d, 1H, J = 7Hz ), 4.16 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.55 (dd, 1H, J = 7Hz, 10Hz), 4.82 (br, 1H), 4.91 (d, 1H, J = 8Hz), 5.59 (d, 1H, J = 7Hz), 7.30-7.35 (m, 1H), 7.46 (t, 2H, J = 8Hz), 7.52 (d, 1H, J = 4Hz), 7.60 (t , 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz), 8.29 (d, 1H, J = 8Hz).
[0252]
Step 5: 10-allyl-10-deacetoxy-4-deacetyl-4-O-propionyl-7-O-triethylsilylbaccatin III
1.15 g of the compound obtained in the above Step 4 was dissolved in 20 ml of tetrahydrofuran, 243 mg of metachloroperbenzoic acid was added under ice cooling, and the mixture was returned to room temperature and stirred for 1 hour. A saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: acetone = 50: 1 (v / v)) to obtain 615 mg of the title compound as a pale yellow amorphous solid.
[0253]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.64 (m, 6H), 0.96 (t, 9H, J = 7Hz), 1.07 (s, 3H), 1.13 (s, 3H), 1.24 (t, 3H, J = 7Hz), 1.63 (s, 3H ), 1.92 (s, 3H), 1.75-1.87 (m, 1H), 2.20-2.30 (m, 2H), 2.45-2.70 (m, 4H), 2.76-2.83 (m, 1H), 3.90 (dd, 1H , J = 4.5Hz, 10Hz), 4.05 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.55 (dd, 1H, J = 7Hz, 10Hz), 4.83 (br, 1H), 4.92 (d, 1H, J = 8Hz), 5.02 (d, 1H, J = 10Hz), 5.09 (d, 1H, J = 17Hz), 5.60 (d, 1H , J = 7Hz), 5.73-5.84 (m, 1H), 7.46 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).
[0254]
Step 6: 10-allyl-7,13-O-bis (triethylsilyl) -10-deacetoxy-4-deacetyl-4-O-propionylbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 3 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0255]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.70 (m, 12H), 0.94-1.02 (m, 18H), 1.12 (s, 3H), 1.15 (s, 3H), 1.27 (t, 3H, J = 7Hz), 1.62 (s, 3H), 1.85 (s, 3H), 1.84-1.91 (m, 1H), 2.02-2.23 (m, 2H), 2.41-2.51 (m, 2H), 2.61 (q, 2H, J = 7Hz), 2.77-2.84 (m , 1H), 3.85 (dd, 1H, J = 4Hz, 10Hz), 3.94 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.54 (dd, 1H, J = 7Hz, 10Hz), 4.91-4.94 (m, 2H), 5.01 (d, 1H, J = 10Hz), 5.07 (d, 1H, J = 17Hz), 5.61 (d, 1H, J = 7Hz), 5.71-5.82 (m, 1H), 7.46 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz).
[0256]
Step 7: 10-allyl-10-deacetoxy-4-deacetyl-4-O-propionyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 6 was reacted in the same manner as in Step 2 of Example 5 to obtain the title compound as a colorless amorphous solid.
[0257]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.61-0.73 (m, 6H), 1.00 (t, 9H, J = 7Hz), 1.10 (s, 3H), 1.14 (s, 3H), 1.26 (t, 3H, J = 7Hz), 1.63 (s, 3H ), 1.85 (s, 3H), 1.75-1.84 (m, 1H), 2.04-2.10 (m, 1H), 2.20-2.33 (m, 2H), 2.54-2.70 (m, 3H), 2.90-2.97 (m , 1H), 3.88 (t, 1H, J = 7Hz), 3.99 (d, 1H, J = 7Hz), 4.20 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 4.34- 4.40 (m, 1H), 4.87-5.02 (m, 3H), 5.09 (dd, 1H, J = 1.5Hz, 17Hz), 5.64 (d, 1H, J = 7Hz), 5.75-5.85 (m, 1H), 7.47 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz).
[0258]
Step 8: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-7-α-fluoro-4-O-propionyl-13-O-triethylsilylbaccatin III
The compound obtained in the above Step 7 was reacted in the same manner as in Step 3 of Example 5 to obtain the title compound as a colorless amorphous solid.
[0259]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.62-0.73 (m, 6H), 1.00 (t, 9H, J = 7Hz), 1.07 (s, 3H), 1.14 (s, 3H), 1.27 (t, 3H, J = 7Hz), 1.67 (s, 3H ), 1.82 (s, 3H), 2.07-2.35 (m, 4H), 2.49-2.70 (m, 3H), 2.98-3.05 (m, 1H), 4.10 (dd, 1H, J = 5.5Hz, 8Hz), 4.14 (d, 1H, J = 7Hz), 4.34 (AB type d, each 1H, J = 8Hz), 4.54 (dd, 1H, J = 3.5Hz, 47Hz), 4.91 (t, 1H, J = 8Hz), 4.98-5.09 (m, 3H), 5.70 (d, 1H, J = 7Hz), 5.72-5.81 (m, 1H), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz) , 8.13 (d, 2H, J = 8Hz).
[0260]
Step 9: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-7-α-fluoro-4-O-propionylbaccatin III
The compound obtained in Step 8 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0261]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.07 (s, 6H), 1.21 (t, 3H, J = 7Hz), 1.67 (s, 3H), 1.87 (s, 3H), 2.16-2.38 (m, 4H), 2.51-2.73 (m, 3H), 2.97-3.06 (m, 1H), 4.13 (dd, 1H, J = 5.5Hz, 8Hz), 4.30 (d, 1H, J = 7Hz), 4.35 (s, 2H), 4.54 (dd, 1H, J = 3.5 Hz, 47Hz), 4.81 (br, 1H), 4.99-5.11 (m, 3H), 5.70 (d, 1H, J = 7Hz), 5.74-5.89 (m, 1H), 7.48 (t, 2H, J = 8Hz ), 7.61 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
[0262]
Step 10: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10 -Deacetoxy-4-deacetyl-7-deoxy-7-α-fluoro-4-O-propionylbaccatin III
The compound obtained in the above Step 9 and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyl) oxy-4- (2-furyl) -2-azetidinone were used in Example 1. In the same manner as in Step 8, the title compound was obtained as a colorless amorphous solid.
[0263]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.19 (s, 3H), -0.01 (s, 3H), 0.77 (s, 9H), 1.10 (s, 3H), 1.19 (s, 3H), 1.24 (t, 3H, J = 7Hz), 1.32 ( s, 9H), 1.67 (s, 3H), 1.72 (s, 3H), 2.15-2.28 (m, 3H), 2.48-2.52 (m, 2H), 2.75-2.80 (m, 2H), 3.00-3.06 ( m, 1H), 4.06-4.11 (m, 1H), 4.18 (d, 1H, J = 7Hz), 4.36 (AB type d, each 1H, J = 8Hz), 4.55 (dd, 1H, J = 3.5Hz, 47Hz), 4.72 (s, 1H), 5.00-5.10 (m, 3H), 5.25 (d, 1H, J = 10Hz), 5.32 (d, 1H, J = 10Hz), 5.72-5.83 (m, 2H), 6.15 (t, 1H, J = 8Hz), 6.23 (d, 1H, J = 3Hz), 6.35 (dd, 1H, J = 1.5Hz, 3Hz), 7.38 (s, 1H), 7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
[0264]
Step 11: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10-deacetoxy-4 -Deacetyl-7-deoxy-7-α-fluoro-10- (2-morpholinoethyl) -4-O-propionylbaccatin III
The compound obtained in Step 10 was reacted in the same manner as in Step 1 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0265]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.18 (s, 3H), -0.01 (s, 3H), 0.78 (s, 9H), 1.08 (s, 3H), 1.19 (s, 3H), 1.23 (t, 3H, J = 7Hz), 1.34 ( s, 9H), 1.68 (s, 3H), 1.83 (s, 3H), 2.18-2.58 (m, 12H), 2.77-2.79 (m, 2H), 3.66-3.73 (m, 4H), 4.18-4.23 ( m, 2H), 4.36 (AB type d, each 1H, J = 8Hz), 4.54 (dd, 1H, J = 3.5Hz, 47Hz), 4.73 (s, 1H), 5.02 (d, 1H, J = 8Hz) , 5.26 (d, 1H, J = 10Hz), 5.32 (d, 1H, J = 10Hz), 5.76 (d, 1H, J = 7Hz), 6.15 (t, 1H, J = 8Hz), 6.24 (d, 1H , J = 3Hz), 6.36 (d, 1H, J = 3Hz), 7.39 (s, 1H), 7.49 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.14 (d, (2H, J = 8Hz).
[0266]
Step 12: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 7-α-Fluoro-10- (2-morpholinoethyl) -4-O-propionylbaccatin III
The compound obtained in the above Step 11 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0267]
Melting point: 130-134 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.21 (s, 3H), 1.26 (t, 3H, J = 7Hz), 1.33 (s, 9H), 1.68 (s, 3H), 1.82 (s, 3H), 2.18-2.76 ( m, 14H), 3.65-3.69 (m, 4H), 4.18 (d, 1H, J = 7Hz), 4.24 (t, 1H, J = 5.5Hz), 4.36 (AB type d, each 1H, J = 8Hz) , 4.54 (dd, 1H, J = 3.5Hz, 47Hz), 4.70 (d, 1H, J = 1.5Hz), 5.00 (dd, 1H, J = 2Hz, 9Hz), 5.19 (d, 1H, J = 10Hz) , 5.33 (d, 1H, J = 10Hz), 5.75 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 8Hz), 6.33 (d, 1H, J = 3.5Hz), 6.38 (dd, 1H, J = 2Hz, 3.5Hz), 7.43 (s, 1H), 7.50 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.16 (d, 2H, J = 8Hz).
IR (KBr): 3456, 2976, 2812, 1718, 1604, 1494 cm-1
MS-FAB: 911 (MH+)
[0268]
Example 7
[0269]
Embedded image
Step 1: 10-allyl-7,13-O-bis (triethylsilyl) -10-deacetoxy-1-O-dimethylsilylbaccatin III
The compound obtained in Step 1 of Example 5 was reacted in the same manner as in Step 1 of Example 2 to obtain the title compound as colorless crystals.
[0271]
Melting point: 122 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.28 (d, 3H, J = 2.7Hz), 0.06 (d, 3H, J = 2.7Hz), 0.55 (m, 6H), 0.69 (m, 6H), 0.95 (m, 9H), 1.03 (m, 9H), 1.10 (s, 3H), 1.13 (s, 3H), 1.61 (s, 3H), 1.85 (m, 1H), 1.87 (s, 3H), 2.27 (m, 1H), 2.29 (s, 3H ), 2.30 (m, 1H), 2.44 (m, 2H), 2.81 (m, 1H), 3.83 (dd, 1H, J = 4.0Hz, 10.0Hz), 3.95 (d, 1H, J = 7.3Hz), 4.24 (m, 2H), 4.47-4.55 (m, 2H), 4.94-5.09 (m, 3H), 5.68 (d, 1H, J = 7.3Hz), 5.77 (m, 1H), 7.45 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.09 (m, 2H).
MS-FAB: 855 (MH+)
[0272]
Step 2: 10-allyl-7,13-O-bis (triethylsilyl) -10-deacetoxy-4-deacetyl-1-O-dimethylsilylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 2 of Example 2 to obtain the title compound as colorless crystals.
[0273]
Melting point: 158-160 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (d, 3H, J = 2.7Hz), 0.00 (d, 3H, J = 2.7Hz), 0.53 (m, 6H), 0.78 (m, 6H), 0.92 (m, 12H), 1.22 (m, 12H), 1.51 (s, 3H), 1.85 (s, 3H), 1.97 (m, 1H), 2.35 (m, 1H), 2.52 (m, 1H), 2.63 (m, 1H), 2.73 (m, 1H ), 2.81 (m, 1H), 3.67 (s, 1H), 3.70 (d, 1H, J = 6.0Hz), 3.88 (dd, 1H, J = 5.0Hz, 10.0Hz), 4.06 (dd, 1H, J = 6.0Hz, 12.0Hz), 4.19 (d, 1H, J = 8.3Hz), 4.30 (d, 1H, J = 8.3Hz), 4.55 (m, 1H), 4.66 (m, 2H), 5.03 (m, 2H), 5.55 (d, 1H, J = 6.0Hz), 5.77 (m, 1H), 7.42 (t, 2H, J = 7.5Hz), 7.53 (t, 1H, J = 7.5Hz), 8.10 (d, (2H, J = 7.5Hz).
MS-FAB: 813 (MH+)
[0274]
Step 3: 10-allyl-7,13-O-bis (triethylsilyl) -4-O-cyclopropanecarbonyl-10-deacetoxy-4-deacetyl-1-O-dimethylsilylbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 3 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0275]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.28 (d, 3H, J = 2.5Hz), 0.07 (d, 3H, J = 2.5Hz), 0.49-0.72 (m, 12H), 0.94 (t, 9H, J = 7Hz), 1.02 (t, 9H , J = 7Hz), 1.12 (s, 3H), 1.13 (s, 3H), 0.97-1.27 (m, 4H), 1.61 (s, 3H), 1.67-1.89 (m, 2H), 1.87 (d, 3H , J = 1.5Hz), 2.28-2.85 (m, 4H), 3.82 (dd, 1H, J = 4.0Hz, 10.0Hz), 3.95 (d, 1H, J = 7Hz), 4.20 (AB type d, 2H, J = 9Hz), 4.48 (dd, 1H, J = 7Hz, 10Hz), 4.55 (t, 1H, J = 1.5Hz), 4.83 (dd, 1H, J = 2.5Hz, 10Hz), 4.96-5.09 (m, 3H), 5.69 (d, 1H, J = 7Hz), 5.72-5.82 (m, 1H), 7.46 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.09 (d, 2H , J = 8Hz).
[0276]
Step 4: 10-allyl-4-O-cyclopropanecarbonyl-10-deacetoxy-4-deacetyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 2 of Example 5 to obtain the title compound as a colorless amorphous solid.
[0277]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.61-0.71 (m, 6H), 1.00 (t, 9H, J = 7Hz), 1.10 (s, 3H), 1.16 (s, 3H), 0.98-1.27 (m, 4H), 1.63 (s, 3H), 1.69-1.82 (m, 2H), 1.87 (s, 3H), 2.02-2.08 (m, 1H), 2.23-2.33 (m, 2H), 2.49-2.57 (m, 1H), 2.89-2.95 (m, 1H ), 3.87 (t, 1H, J = 7Hz), 4.02 (d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.27 (d, 1H, J = 8Hz), 4.34 (br, 1H), 4.85 (dd, 1H, J = 2Hz, 9Hz), 4.93 (t, 1H, J = 8Hz), 4.99 (d, 1H, J = 10Hz), 5.08 (dd, 1H, J = 1.5Hz, 17Hz) ), 5.64 (d, 1H, J = 7Hz), 5.75-5.85 (m, 1H), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0278]
Step 5: 10-allyl-4-O-cyclopropanecarbonyl-10-deacetoxy-4-deacetyl-7-deoxy-7-α-fluoro-13-O-triethylsilylbaccatin III
The compound obtained in Step 4 was reacted in the same manner as in Step 3 of Example 5 to obtain the title compound as a colorless amorphous solid.
[0279]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.62-0.71 (m, 6H), 1.00 (t, 9H, J = 7Hz), 0.98-1.28 (m, 4H), 1.07 (s, 3H), 1.17 (s, 3H), 1.69 (s, 3H), 1.74-1.81 (m, 1H), 1.83 (s, 3H), 2.03-2.27 (m, 4H), 2.43-2.57 (m, 1H), 2.96-3.06 (m, 1H), 4.07-4.13 (m, 1H ), 4.15 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 9Hz), 4.45 (d, 1H, J = 9Hz), 4.54 (dd, 1H, J = 3Hz, 47Hz), 4.90- 5.09 (m, 4H), 5.70 (d, 1H, J = 7Hz), 5.75-5.83 (m, 1H), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).
[0280]
Step 6: 10-allyl-4-O-cyclopropanecarbonyl-10-deacetoxy-4-deacetyl-7-deoxy-7-α-fluorobaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0281]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.00-1.27 (m, 4H), 1.08 (s, 3H), 1.09 (s, 3H), 1.67 (s, 3H), 1.80-1.85 (m, 1H), 1.87 (s, 3H), 2.12-2.39 ( m, 4H), 2.48-2.60 (m, 1H), 2.95-3.06 (m, 1H), 4.10 (dd, 1H, J = 5.5Hz, 8Hz), 4.30 (d, 1H, J = 7Hz), 4.38 ( AB type d, each 1H, J = 9Hz), 4.53 (dd, 1H, J = 3.5Hz, 47Hz), 4.81 (br, 1H), 4.95-5.11 (m, 3H), 5.72 (d, 1H, J = 7Hz), 5.81-5.85 (m, 1H), 7.49 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.15 (d, 2H, J = 8Hz).
[0282]
Step 7: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -4 -O-cyclopropanecarbonyl-10-deacetoxy-4-deacetyl-7-deoxy-7-α-fluorobaccatin III
The compound obtained in Step 6 above and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyl) oxy-4- (2-furyl) -2-azetidinone were used in Example 1. In the same manner as in Step 8, the title compound was obtained as a colorless amorphous solid.
[0283]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.20 (s, 3H), -0.03 (s, 3H), 0.74 (s, 9H), 1.07 (s, 3H), 1.18 (s, 3H), 1.04-1.21 (m, 4H), 1.32 (s, 9H), 1.65 (s, 3H), 1.72 (s, 3H), 1.92-1.97 (m, 1H), 2.10-2.27 (m, 3H), 2.44-2.65 (m, 2H), 2.97-3.04 (m, 1H), 4.03-4.06 (m, 1H), 4.17 (d, 1H, J = 7Hz), 4.32 (d, 1H, J = 8Hz), 4.37 (d, 1H, J = 8Hz), 4.51 (dd, 1H , J = 3Hz, 47Hz), 4.77 (d, 1H, J = 2Hz), 4.96-5.00 (m, 2H), 5.06 (dd, 1H, J = 1.5Hz, 17Hz), 5.22 (d, 1H, J = 10Hz), 5.35 (d, 1H, J = 10Hz), 5.72-5.81 (m, 2H), 6.14 (t, 1H, J = 8Hz), 6.19 (d, 1H, J = 3Hz), 6.31 (dd, 1H , J = 1.5Hz, 3Hz), 7.30 (s, 1H), 7.46 (t, 2H, J = 8Hz), 7.55 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0284]
Step 8: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -4-O-cyclo Propanecarbonyl-10-deacetoxy-4-deacetyl-7-deoxy-7-α-fluoro-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 7 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0285]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.16 (s, 3H), 0.02 (s, 3H), 0.78 (s, 9H), 1.09 (s, 3H), 1.21 (s, 3H), 1.08-1.22 (m, 4H), 1.34 (s, 9H ), 1.68 (s, 3H), 1.85 (s, 3H), 1.96-2.01 (m, 1H), 2.14-2.61 (m, 12H), 3.65-3.69 (m, 4H), 4.20-4.22 (m, 2H ), 4.34 (d, 1H, J = 8Hz), 4.40 (d, 1H, J = 8Hz), 4.52 (dd, 1H, J = 3Hz, 47Hz), 4.80 (d, 1H, J = 1.5Hz), 5.00 (d, 1H, J = 8Hz), 5.25 (d, 1H, J = 10Hz), 5.38 (d, 1H, J = 10Hz), 5.76 (d, 1H, J = 7Hz), 6.15 (t, 1H, J = 8Hz), 6.22 (d, 1H, J = 3Hz), 6.34 (dd, 1H, J = 2Hz, 3Hz), 7.34 (s, 1H), 7.50 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
[0286]
Step 9: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4-O-cyclopropanecarbonyl-10-deacetoxy- 4-Deacetyl-7-deoxy-7-α-fluoro-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 8 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0287]
Melting point: 132-137 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
0.97-1.24 (m, 4H), 1.10 (s, 3H), 1.22 (s, 3H), 1.35 (s, 9H), 1.68 (s, 3H), 1.83 (s, 3H), 1.91-1.95 (m, 1H), 2.13-2.67 (m, 12H), 3.66-3.71 (m, 4H), 4.19-4.25 (m, 2H), 4.32 (d, 1H, J = 8Hz), 4.40 (d, 1H, J = 8Hz ), 4.53 (dd, 1H, J = 3Hz, 47Hz), 4.75 (d, 1H, J = 1.5Hz), 4.98 (d, 1H, J = 8Hz), 5.18 (d, 1H, J = 10Hz), 5.38 (d, 1H, J = 10Hz), 5.76 (d, 1H, J = 7Hz), 6.17 (t, 1H, J = 8Hz), 6.32 (d, 1H, J = 3.5Hz), 6.37 (dd, 1H, J = 2Hz, 3Hz), 7.39 (s, 1H), 7.51 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.14 (d, 2H, J = 8Hz).
IR (KBr): 3542, 2976, 2812, 1724, 1624, 1494, 1454 cm-1
MS-FAB: 923 (MH+)
[0288]
Example 8
[0289]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-7 -Deoxy-7-α-fluorobaccatin III
The compound obtained in Step 4 of Example 5 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0291]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.37 (s, 3H), -0.10 (s, 3H), 0.72 (s, 9H), 1.11 (s, 3H), 1.23 (s, 3H), 1.31 (s, 9H), 1.69 (s, 3H) , 1.73 (s, 3H), 2.12-2.34 (m, 3H), 2.55 (s, 3H), 2.50-2.65 (m, 2H), 3.00-3.10 (m, 1H), 4.05-4.09 (m, 1H) , 4.22 (d, 1H, J = 7Hz), 4.38 (s, 2H), 4.52 (s, 1H), 4.56 (dd, 1H, J = 3Hz, 47Hz), 5.00-5.12 (m, 3H), 5.34 ( d, 1H, J = 10Hz), 5.45 (d, 1H, J = 10Hz), 5.75 (d, 1H, J = 7Hz), 5.76-5.85 (m, 1H), 6.30 (t, 1H, J = 8Hz) , 7.30-7.40 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
[0292]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-7-deoxy-7 -α-Fluoro-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0293]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.35 (s, 3H), -0.11 (s, 3H), 0.74 (s, 9H), 1.09 (s, 3H), 1.23 (s, 3H), 1.31 (s, 9H), 1.69 (s, 3H) , 1.83 (s, 3H), 2.04-2.63 (m, 13H), 2.55 (s, 3H), 3.67 (m, 4H), 4.21-4.23 (m, 2H), 4.35, 4.38 (each d, total 2H, J = 9Hz), 4.52 (s, 1H), 4.54 (dd, 1H, J = 3Hz, 47Hz), 5.06 (d, 1H, J = 7Hz), 5.35 (d, 1H, J = 10Hz), 5.46 (d , 1H, J = 10Hz), 5.75 (d, 1H, J = 7Hz), 6.25 (t, 1H, J = 8Hz), 7.28-7.39 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.14 (d, 2H, J = 8Hz).
[0294]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-7-deoxy-7-α-fluoro-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0295]
Melting point: 145-149 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.21 (s, 3H), 1.33 (s, 9H), 1.68 (s, 3H), 1.77 (s, 3H), 2.40 (s, 3H), 2.14-2.65 (m, 13H) , 3.68 (m, 4H), 4.20-4.24 (m, 2H), 4.33, 4.36 (each d, total 2H, J = 9Hz), 4.52 (dd, 1H, J = 3Hz, 47Hz), 4.61 (s, 1H ), 5.02 (dd, 1H, J = 2Hz, 9Hz), 5.30 (d, 1H, J = 10Hz), 5.41 (d, 1H, J = 10Hz), 5.74 (d, 1H, J = 7Hz), 6.19 ( t, 1H, J = 8Hz), 7.40-7.42 (m, 5H), 7.51 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.14 (d, 2H, J = 8Hz) .
MS-FAB: 907 (MH+)
[0296]
Example 9
[0297]
Embedded image
Step 1: 7,13-O-bis (triethylsilyl) -10-deacetoxy-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 1 of Example 5 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0299]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.72 (m, 12H), 0.94-1.03 (m, 18H), 1.11 (s, 3H), 1.12 (s, 3H), 1.62 (s, 3H), 1.96 (s, 3H), 1.75-2.52 ( m, 12H), 2.29 (d, 3H, J = 2Hz), 3.72 (m, 4H), 3.80-3.82 (m, 1H), 3.97 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.29 (d, 1H, J = 8Hz), 4.53 (dd, 1H, J = 7Hz, 10Hz), 4.92 (t, 1H, J = 8Hz), 4.98 (d, 1H, J = 9Hz), 5.60 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
[0300]
Step 2: 7,13-O-bis (triethylsilyl) -10-deacetoxy-4-deacetyl-1-O-dimethylsilyl-10- (2-morpholinoethyl) baccatin III
81.5 mg of the compound obtained in the above step 1 was dissolved in 2 ml of N, N-dimethylformamide, 19 mg of imidazole and 0.031 ml of dimethylsilane chloride were added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed successively with water (twice) and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 2 ml of tetrahydrofuran, and 0.13 ml of sodium bis (2-methoxyethoxy) aluminum hydride (65% wt, toluene solution) was added dropwise under ice cooling, followed by stirring for 20 minutes. 1 ml of a saturated aqueous potassium tartrate solution was added (stirred for about 5 minutes), extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin phase chromatography (developing solvent; ethyl acetate: hexane = 1: 3 (v / v)) to obtain 68 mg of the title compound as a colorless amorphous solid.
[0301]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (d, 3H, J = 3Hz), 0.01 (d, 3H, J = 3Hz), 0.45-0.60 (m, 6H), 0.71-0.86 (m, 6H), 0.92 (t, 9H, J = 7Hz ), 1.09 (m, 15H), 1.50 (s, 3H), 1.95 (s, 3H), 1.84-2.56 (m, 11H), 2.80 (dd, 1H, J = 2.5Hz, 15Hz), 3.66-3.73 ( m, 6H), 3.85-3.88 (m, 1H), 4.10 (dd, 1H, J = 7Hz, 10Hz), 4.20 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.54 -4.57 (m, 1H), 4.66-4.69 (m, 2H), 5.54 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
[0302]
Step 3: 7,13-O-bis (triethylsilyl) -10-deacetoxy-4-deacetyl-1-O-dimethylsilyl-4-O-ethoxycarbonyl-10- (2-morpholinoethyl) baccatin III
68 mg of the compound obtained in the above step 2 was dissolved in 2 ml of tetrahydrofuran, and 0.23 ml of lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution) was added under ice cooling, followed by stirring for 5 minutes, and then 0.025 ml of ethyl chloroformate was added for 1 hour. Stir. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin phase chromatography (developing solvent; ethyl acetate: hexane = 1: 3 (v / v)) to obtain 49.5 mg of the title compound as a colorless amorphous solid.
[0303]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (d, 3H, J = 3Hz), 0.05 (d, 3H, J = 3Hz), 0.50-0.72 (m, 12H), 0.95 (t, 9H, J = 7Hz), 1.02 (t, 9H, J = 7Hz), 1.10 (s, 3H), 1.12 (s, 3H), 1.40 (t, 3H, J = 7Hz), 1.61 (s, 3H), 1.95 (s, 3H), 1.71-2.49 (m, 12H ), 3.70-3.83 (m, 5H), 3.97 (d, 1H, J = 7Hz), 4.14-4.27 (m, 3H), 4.39-4.55 (m, 3H), 4.92-4.99 (m, 2H), 5.69 (d, 1H, J = 7Hz), 7.45 (t, 2H, J = 8Hz), 7.56 (t, 1H, J = 8Hz), 8.05 (d, 2H, J = 8Hz).
[0304]
Step 4: 10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl-10- (2-morpholinoethyl) -13-O-triethylsilylbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 2 of Example 5 to obtain the title compound as a colorless amorphous solid.
[0305]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.62-0.68 (m, 6H), 1.00 (t, 9H, J = 7Hz), 1.07 (s, 3H), 1.14 (s, 3H), 1.42 (t, 3H, J = 7Hz), 1.61 (s, 3H ), 1.93 (s, 3H), 1.84-2.78 (m, 12H), 3.68-3.70 (m, 4H), 3.97-4.00 (m, 2H), 4.11-4.17 (m, 1H), 4.19 (d, 1H , J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.40-4.51 (m, 2H), 4.90 (t, 1H, J = 8Hz), 5.00 (dd, 1H, J = 2Hz, 9Hz), 5.61 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
[0306]
Step 5: 10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl-7-O-methylthiomethyl-10- (2-morpholinoethyl) -13-O-triethylsilylbaccatin III Compound obtained in Step 4 above 23 mg was dissolved in dimethyl sulfoxide 0.5 ml and acetic anhydride 0.5 ml and stirred at room temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained residue was purified by silica gel thin phase chromatography (developing solvent; chloroform: methanol = 50: 1 (v / v)) to obtain 12 mg of the title compound as a colorless amorphous solid.
[0307]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.63-0.69 (m, 6H), 1.00 (t, 9H, J = 7Hz), 1.12 (s, 3H), 1.15 (s, 3H), 1.41 (t, 3H, J = 7Hz), 1.68 (s, 3H ), 2.01 (s, 3H), 2.20 (s, 3H), 1.73-2.77 (m, 12H), 3.69-3.75 (m, 4H), 4.07 (d, 1H, J = 7Hz), 4.10-4.17 (m , 1H), 4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.31-4.36 (m, 1H), 4.40-4.48 (m, 1H), 4.56, 4.65 (each d , total 2H, J = 12Hz), 4.92-4.98 (m, 2H), 5.63 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz) , 8.10 (d, 2H, J = 8Hz).
[0308]
Step 6: 10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl-7-O-methyl-10- (2-morpholinoethyl) -13-O-triethylsilylbaccatin III
9.0 mg of the compound obtained in the above step 5 was dissolved in 2 ml of ethanol, 0.2 g of Raney nickel was added and the mixture was heated to reflux for 20 minutes. The reaction solution was allowed to cool, the insoluble material was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel thin phase chromatography (developing solvent; chloroform: methanol = 50: 1 (v / v)) to obtain 5.7 mg of the title compound as a colorless amorphous solid.
[0309]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.63-0.69 (m, 6H), 1.01 (t, 9H, J = 7Hz), 1.10 (s, 3H), 1.14 (s, 3H), 1.42 (t, 3H, J = 7Hz), 1.66 (s, 3H ), 2.01 (s, 3H), 1.68-2.74 (m, 12H), 3.27 (s, 3H), 3.69-3.73 (m, 4H), 3.93 (t, 1H, J = 7Hz), 4.00 (dd, 1H , J = 6Hz, 10Hz), 4.04 (d, 1H, J = 7Hz), 4.14-4.22 (m, 2H), 4.31 (d, 1H, J = 8Hz), 4.40-4.48 (m, 1H), 4.93 ( t, 1H, J = 8Hz), 5.01 (d, 1H, J = 8Hz), 5.61 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
[0310]
Step 7: 10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl-7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 6 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0311]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.04 (s, 3H), 1.10 (s, 3H), 1.40 (t, 3H, J = 7Hz), 1.65 (s, 3H), 2.09 (d, 3H, J = 1Hz), 1.73-2.78 (m, 12H ), 3.28 (s, 3H), 3.63-3.78 (m, 4H), 3.98-4.02 (m, 2H), 4.11-4.40 (m, 5H), 4.83 (t, 1H, J = 8Hz), 5.06 (d , 1H, J = 8Hz), 5.60 (d, 1H, J = 7Hz), 7.48 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz) ).
[0312]
Step 8: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-thienyl) propionyl] -10-deacetoxy-4 -Deacetyl-4-O-ethoxycarbonyl-7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 7 and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyl) oxy-4- (2-thienyl) -2-azetidinone were used in Example 1. In the same manner as in Step 8, the title compound was obtained as a colorless amorphous solid.
[0313]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.15 (s, 3H), 0.02 (s, 3H), 0.83 (s, 9H), 1.14 (s, 3H), 1.20 (s, 3H), 1.33-1.37 (m, 12H), 1.68 (s, 3H ), 1.94 (s, 3H), 1.75-2.77 (m, 12H), 3.27 (s, 3H), 3.68 (m, 4H), 3.95-4.03 (m, 2H), 4.08 (d, 1H, J = 7Hz ), 4.14 (d, 1H, J = 8Hz), 4.34 (d, 1H, J = 8Hz), 4.36-4.42 (m, 1H), 4.50-4.58 (m, 2H), 5.02 (d, 1H, J = 8Hz), 5.37 (d, 1H, J = 10Hz), 5.57 (d, 1H, J = 10Hz), 5.67 (d, 1H, J = 7Hz), 6.15 (t, 1H, J = 8Hz), 7.00-7.04 (m, 2H), 7.22-7.25 (m, 1H), 7.47 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).
[0314]
Step 9: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2-hydroxy-3- (2-thienyl) propionyl] -10-deacetoxy-4-deacetyl-4-O- Ethoxycarbonyl-7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 8 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0315]
Melting point: 140-145 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.17 (s, 3H), 1.32 (t, 3H, J = 7Hz), 1.37 (s, 9H), 1.67 (s, 3H), 1.90 (s, 3H), 1.75-2.75 ( m, 12H), 3.26 (s, 3H), 3.69 (m, 4H), 3.90-4.05 (m, 3H), 4.18-4.24 (m, 2H), 4.35 (d, 1H, J = 8Hz), 4.40- 4.48 (m, 1H), 4.63 (s, 1H), 5.03 (d, 1H, J = 8Hz), 5.36 (d, 1H, J = 10Hz), 5.52 (d, 1H, J = 10Hz), 5.66 (d , 1H, J = 7Hz), 6.10 (t, 1H, J = 8Hz), 7.00 (dd, 1H, J = 3.5Hz, 5Hz), 7.15 (s, 1H), 7.27-7.30 (m, 1H), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
MS-FAB: 955 (MH+)
[0316]
Example 10
[0317]
Embedded image
Step 1: 10-deacetoxy-10- (2-morpholinoethyl) -13-O-triethylsilylbaccatin III
The compound obtained in Step 1 of Example 9 was reacted in the same manner as in Step 2 of Example 5 to obtain the title compound as a colorless amorphous solid.
[0319]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.63-0.70 (m, 6H), 1.01 (t, 9H, J = 7Hz), 1.07 (s, 3H), 1.11 (s, 3H), 1.60 (s, 3H), 1.92 (s, 3H), 2.29 ( s, 3H), 1.83-2.78 (m, 12H), 3.69 (m, 4H), 3.95 (d, 1H, J = 7Hz), 3.98 (d, 1H, J = 8Hz), 4.18 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.51 (dd, 1H, J = 7Hz, 10Hz), 4.88 (t, 1H, J = 8Hz), 5.04 (d, 1H, J = 8Hz), 5.69 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0320]
Step 2: 10-deacetoxy-7-O-methylthiomethyl-10- (2-morpholinoethyl) -13-O-triethylsilylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 5 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0321]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.62-0.72 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.12 (s, 3H), 1.13 (s, 3H), 1.68 (s, 3H), 2.00 (s, 3H), 2.21 ( s, 3H), 2.30 (s, 3H), 1.78-2.77 (m, 12H), 3.70-3.72 (m, 4H), 4.04 (d, 1H, J = 7Hz), 4.11-4.14 (m, 1H), 4.17 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.38 (dd, 1H, J = 7Hz, 10Hz), 4.55, 4.65 (each d, total 2H, J = 12Hz), 4.93 (t, 1H, J = 8Hz), 4.99 (d, 1H, J = 8Hz), 5.61 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0322]
Step 3: 10-deacetoxy-7-O-methyl-10- (2-morpholinoethyl) -13-O-triethylsilylbaccatin III
The compound obtained in Step 2 was reacted in the same manner as in Step 6 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0323]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.64-0.74 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.09 (s, 3H), 1.10 (s, 3H), 1.65 (s, 3H), 2.00 (s, 3H), 2.30 ( s, 3H), 1.78-2.75 (m, 12H), 3.26 (s, 3H), 3.68-3.74 (m, 4H), 3.95 (dd, 1H, J = 5.5Hz, 7Hz), 3.99-4.04 (m, 2H), 4.16 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.91 (t, 1H, J = 8Hz), 5.03 (dd, 1H, J = 2Hz, 9Hz), 5.58 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0324]
Step 4: 10-deacetoxy-7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0325]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.10 (s, 3H), 1.66 (s, 3H), 2.06 (s, 3H), 2.30 (s, 3H), 1.72-2.76 (m, 12H), 3.27 (s, 3H) , 3.63-3.72 (m, 4H), 3.96-4.04 (m, 2H), 4.08 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz ), 4.83 (t, 1H, J = 8Hz), 5.02 (d, 1H, J = 8Hz), 5.58 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
[0326]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3-phenyl-2- (trimethylsilyl) oxypropionyl] -10-deacetoxy-7-O-methyl -10- (2-morpholinoethyl) baccatin III
43 mg of the compound obtained in the above Step 4 and 49.5 mg of the compound obtained in Step 2 of Reference Example 1 were dissolved in 4 ml of tetrahydrofuran and cooled to −78 ° C. (under nitrogen). Then, sodium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 0.26 ml) was added dropwise and stirred for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was returned to room temperature, extracted with ethyl acetate, and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin phase chromatography (developing solvent; chloroform: methanol = 50: 1 (v / v)) to purify 48.5 mg of the title compound as colorless Obtained as an amorphous solid.
[0327]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.08 (s, 9H), 1.12 (s, 3H), 1.16 (s, 9H), 1.25 (s, 3H), 1.38 (s, 3H), 1.67 (s, 3H), 1.87 (s, 3H), 2.68 (s, 3H), 1.82-2.72 (m, 12H), 3.24 (s, 3H), 3.65 (m, 4H), 3.92-3.99 (m, 3H), 4.19 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.96-5.01 (m, 2H), 5.47 (d, 1H, J = 10Hz), 5.64 (d, 1H, J = 7Hz), 6.32 (t, 1H, J = 8Hz ), 7.26-7.35 (m, 5H), 7.47 (t, 2H, J = 8Hz), 7.56 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).
[0328]
Step 6: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 5 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0329]
Melting point: 156-160 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.23 (s, 12H), 1.40 (s, 3H), 1.69 (s, 3H), 1.79 (s, 3H), 2.63 (s, 3H), 1.75-2.75 (m, 12H) , 3.25 (s, 3H), 3.68 (m, 4H), 3.94-4.00 (m, 3H), 4.20 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 5.00-5.05 ( m, 2H), 5.56 (d, 1H, J = 10Hz), 5.65 (d, 1H, J = 7Hz), 6.29 (t, 1H, J = 8Hz), 7.31-7.38 (m, 5H), 7.49 (t , 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
MS-FAB: 933 (MH+)
[0330]
Example 11
[0331]
Embedded image
Step 1: 10-deacetyl-10-O- (2,2,2-trichloroethoxycarbonyl) -13-O-triethylsilylbaccatin III
10-deacetyl-10-O- (2,2,2-trichloroethoxycarbonyl) -7-O-triethylsilylbaccatin III 28.5 g and imidazole 5.80 g are dissolved in N, N-dimethylformamide 57 ml and triethylsilane chloride 14.3 ml was added and stirred overnight at room temperature. The reaction solution was poured into ice water, extracted twice with ethyl acetate, washed successively with water (twice) and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 320 ml of methanol: tetrahydrofuran = 1 (v / v), 963 mg of p-toluenesulfonic acid was added, and the mixture was stirred at room temperature for 4 hours. 5 ml of triethylamine was added and the reaction solution was concentrated. Ethyl acetate and water are added to the residue obtained, and the mixture is separated. The aqueous layer is extracted with ethyl acetate. The organic layer is combined, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. did. The obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 4 to 1: 1 (v / v)) to obtain 23.5 g of the title compound as a colorless amorphous solid.
[0333]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.62-0.73 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.14 (s, 3H), 1.20 (s, 3H), 1.68 (s, 3H), 1.83-1.90 (m, 1H), 2.04 (s, 3H), 2.13-2.28 (m, 2H), 2.29 (s, 3H), 2.52-2.60 (m, 1H), 3.77 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.41-4.45 (m, 1H), 4.77,4.91 (each d, total 2H, J = 12Hz), 4.95-4.99 (m, 2H), 5.64 ( d, 1H, J = 7Hz), 6.17 (s, 1H), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0334]
Step 2: 10-deacetyl-7-O-methylthiomethyl-10-O- (2,2,2-trichloroethoxycarbonyl) -13-O-triethylsilylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 5 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0335]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.65-0.73 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.16 (s, 3H), 1.20 (s, 3H), 1.76 (s, 3H), 1.81-1.88 (m, 1H), 2.15 (s, 3H), 2.18 (s, 3H), 2.10-2.28 (m, 2H), 2.30 (s, 3H), 2.78-2.85 (m, 1H), 3.85 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.31-4.36 (m, 2H), 4.65,4.71 (each d, total 2H, J = 12Hz), 4.75,4.87 (each d, total 2H, J = 12Hz), 4.94-4.99 (m, 2H), 5.65 (d, 1H, J = 7Hz), 6.47 (s, 1H), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0336]
Step 3: 10-deacetyl-7-O-methylthiomethyl-13-O-triethylsilylbaccatin III
14.5 g of the compound obtained in the above step 2 is dissolved in a mixed solvent of methanol: acetic acid: tetrahydrofuran = 1: 1: 1 (v / v / v) 217.5 ml, added with 50 g of zinc dust, and stirred at 60 ° C. for 15 minutes. did. After standing to cool, insolubles were removed by filtration, and the filtrate was concentrated and azeotroped with toluene. 1N Hydrochloric acid and ethyl acetate were added to the residue for partitioning, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Subsequently, the obtained residue was recrystallized from ethyl acetate-hexane to obtain 10.7 g of the title compound as colorless crystals.
[0337]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.63-0.73 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.10 (s, 3H), 1.17 (s, 3H), 1.80 (s, 3H), 1.76-1.82 (m, 1H), 2.11 (s, 6H), 2.13-2.26 (m, 2H), 2.30 (s, 3H), 2.62-2.70 (m, 1H), 3.96 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.24 (d, 1H, J = 2.5Hz), 4.32 (d, 1H, J = 8Hz), 4.35 (dd, 1H, J = 7Hz, 10Hz), 4.51,4.68 (each d, total 2H, J = 12Hz), 4.96-5.00 (m, 2H), 5.60-5.63 (m, 2H), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H , J = 8Hz).
[0338]
Process 4: 10-deacetyl-7-O-methyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 3 above was reacted in the same manner as in Step 6 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0339]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.63-0.73 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.09 (s, 3H), 1.16 (s, 3H), 1.76 (s, 3H), 1.73-1.81 (m, 1H), 2.06 (d, 3H, J = 1Hz), 2.10-2.24 (m, 2H), 2.30 (s, 3H), 2.67-2.75 (m, 1H), 3.26 (s, 3H), 3.87-3.92 (m, 2H ), 4.16 (d, 1H, J = 8Hz), 4.28 (d, 1H, J = 2Hz), 4.31 (d, 1H, J = 8Hz), 4.94-5.02 (m, 2H), 5.18 (d, 1H, J = 2Hz), 5.60 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.08 (d, 2H, J = 8Hz).
[0340]
Step 5: 10-deacetyl-7-O-methyl-10-O- (methylthio) thiocarbonyl-13-O-triethylsilylbaccatin III
The compound obtained in the above Step 4 was reacted in the same manner as in Step 1 of Example 6 to obtain the title compound as a pale yellow amorphous solid.
[0341]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.64-0.71 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.17 (s, 3H), 1.24 (s, 3H), 1.72 (s, 3H), 1.71-1.78 (m, 1H), 2.15 (d, 3H, J = 1Hz), 2.13-2.25 (m, 2H), 2.30 (s, 3H), 2.64 (s, 3H), 2.71-2.79 (m, 1H), 3.29 (s, 3H), 3.85 (d, 1H, J = 7Hz), 3.96 (dd, 1H, J = 7Hz, 10Hz), 4.14 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.96 (t, 1H, J = 8Hz), 5.00 (d, 1H, J = 8Hz), 5.66 (d, 1H, J = 7Hz), 7.48 (t, 2H, J = 8Hz), 7.50 (s, 1H), 7.61 (t , 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
[0342]
Step 6: 10-deacetoxy-10- (2-formylethyl) -7-O-methyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 2 of Example 6 to obtain the title compound as a colorless amorphous solid.
[0343]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.60-0.72 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.10 (s, 3H), 1.11 (s, 3H), 1.64 (s, 3H), 1.70-2.73 (m, 8H), 1.97 (d, 3H, J = 1Hz), 2.29 (s, 3H), 3.24 (s, 3H), 3.77-3.80 (m, 1H), 3.95 (d, 1H, J = 7Hz), 4.00 (dd, 1H , J = 7Hz, 10Hz), 4.16 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.90 (t, 1H, J = 8Hz), 5.01 (d, 1H, J = 8Hz) ), 5.58 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.08 (d, 2H, J = 8Hz), 9.80 (s, 1H).
[0344]
Step 7: 10-deacetoxy-10- (3-hydroxypropyl) -7-O-methyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 6 was reacted in the same manner as in Step 3 of Example 6 to obtain the title compound as a colorless amorphous solid.
[0345]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.62-0.70 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.09 (s, 3H), 1.11 (s, 3H), 1.65 (s, 3H), 1.50-2.74 (m, 8H), 1.94 (d, 3H, J = 1Hz), 2.30 (s, 3H), 3.26 (s, 3H), 3.67-3.73 (m, 3H), 4.00-4.05 (m, 2H), 4.16 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.90 (t, 1H, J = 8Hz), 5.02 (d, 1H, J = 8Hz), 5.58 (d, 1H, J = 7Hz), 7.47 ( t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0346]
Step 8: 10-deacetoxy-7-O-methyl-10- [3- (2-nitrophenylzeleno) propyl] -13-O-triethylsilylbaccatin III
The compound obtained in Step 7 was reacted in the same manner as in Step 4 of Example 6 to obtain the title compound as a yellow amorphous solid.
[0347]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.64-0.70 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.09 (s, 6H), 1.65 (s, 3H), 1.53-3.08 (m, 10H), 1.91 (d, 3H, J = 1Hz), 2.29 (s, 3H), 3.20 (s, 3H), 3.70 (dd, 1H, J = 5Hz, 7Hz), 3.97 (d, 1H, J = 7Hz), 4.00 (dd, 1H, J = 7Hz, 10Hz), 4.16 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.89 (t, 1H, J = 8Hz), 5.01 (d, 1H, J = 8Hz), 5.58 (d, 1H, J = 7Hz), 7.41-7.62 (m, 6H), 8.09 (d, 2H, J = 8Hz), 8.28 (d, 1H, J = 8Hz).
[0348]
Process 9: 10-allyl-10-deacetoxy-7-O-methyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 8 was reacted in the same manner as in Step 5 of Example 6 to obtain the title compound as a pale yellow amorphous solid.
[0349]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.62-0.72 (m, 6H), 1.02 (t, 9H, J = 7Hz), 1.11 (s, 3H), 1.12 (s, 3H), 1.65 (s, 3H), 1.71-1.78 (m, 1H), 1.92 (s, 3H), 2.04-2.26 (m, 3H), 2.29 (s, 3H), 2.65-2.72 (m, 1H), 2.94-3.00 (m, 1H), 3.25 (s, 3H), 3.80 ( t, 1H, J = 7Hz), 3.97-4.01 (m, 2H), 4.16 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.91 (t, 1H, J = 8Hz) , 4.97-5.11 (m, 3H), 5.59 (d, 1H, J = 7Hz), 5.78-5.89 (m, 1H), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz ), 8.09 (d, 2H, J = 8Hz).
[0350]
Process 10: 10-allyl-10-deacetoxy-7-O-methylbaccatin III
The compound obtained in Step 9 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0351]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.11 (s, 3H), 1.66 (s, 3H), 1.73-1.80 (m, 1H), 1.97 (s, 3H), 2.24-2.33 (m, 3H), 2.29 (s, 3H), 2.66-2.74 (m, 1H), 2.94-3.01 (m, 1H), 3.26 (s, 3H), 3.83 (t, 1H, J = 7Hz), 3.99 (dd, 1H, J = 7Hz, 10Hz ), 4.06 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.84 (m, 1H), 4.99-5.12 (m, 3H) , 5.59 (d, 1H, J = 7Hz), 5.78-5.89 (m, 1H), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
[0352]
Step 11: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3-phenyl-2- (trimethylsilyl) oxypropionyl] -10-deacetoxy-7 -O-Methylbaccatin III
The compound obtained in Step 10 above and the compound obtained in Step 2 of Reference Example 1 were reacted in the same manner as in Step 5 of Example 10 to obtain the title compound as a colorless amorphous solid.
[0353]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.10 (s, 9H), 1.15 (s, 3H), 1.17 (s, 9H), 1.28 (s, 3H), 1.39 (s, 3H), 1.70 (s, 3H), 1.79 (s, 3H), 1.76 -1.86 (m, 1H), 2.06-2.10 (m, 1H), 2.20-2.37 (m, 2H), 2.65-2.71 (m, 1H), 2.70 (s, 3H), 2.97-3.04 (m, 1H) , 3.25 (s, 3H), 3.76 (t, 1H, J = 7Hz), 3.93-3.98 (m, 2H), 4.21 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.98-5.12 (m, 4H), 5.49 (d, 1H, J = 10Hz), 5.65 (d, 1H, J = 7Hz), 5.80-5.90 (m, 1H), 6.37 (t, 1H, J = 8Hz) , 7.25-7.37 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.56 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
[0354]
Step 12: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-7-O- Methylbaccatin III
The compound obtained in the above Step 11 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0355]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.16 (s, 3H), 1.23 (s, 9H), 1.26 (s, 3H), 1.37 (s, 3H), 1.69 (s, 3H), 1.72 (s, 3H), 1.76-1.86 (m, 1H) , 2.15-2.34 (m, 3H), 2.62 (s, 3H), 2.65-2.73 (m, 1H), 2.94-3.010 (m, 1H), 3.25 (s, 3H), 3.62 (s, 3H), 3.77 (t, 1H, J = 7Hz), 3.93 (dd, 1H, J = 7Hz, 10Hz), 3.98 (d, 1H, J = 7Hz), 4.21 (d, 1H, J = 8Hz), 4.32 (d, 1H , J = 8Hz), 4.99-5.11 (m, 4H), 5.55 (d, 1H, J = 10Hz), 5.65 (d, 1H, J = 7Hz), 5.76-5.86 (m, 1H), 6.31 (t, 1H, J = 8Hz), 7.32-7.37 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0356]
Step 13: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 12 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound (compound obtained in Step 6 of Example 10) as a colorless solid.
[0357]
Example 12
[0358]
Embedded image
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (p-fluorophenyl) -2-methyl-2- (trimethylsilyl) oxypropionyl] -10-deacetoxy- 7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 4 of Example 10 and the compound obtained in Step 2 of Reference Example 2 were reacted in the same manner as in Step 5 of Example 10 to obtain the title compound as a colorless amorphous solid.
[0360]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.12 (s, 9H), 1.14 (s, 3H), 1.19 (s, 9H), 1.27 (s, 3H), 1.39 (s, 3H), 1.69 (s, 3H), 1.88 (s, 3H), 2.68 (s, 3H), 1.85-2.75 (m, 12H), 3.26 (s, 3H), 3.68 (m, 4H), 3.95-4.00 (m, 3H), 4.21 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 4.97 (d, 1H, J = 10Hz), 5.02 (d, 1H, J = 8Hz), 5.44 (d, 1H, J = 10Hz), 5.66 (d, 1H, J = 7Hz), 6.34 (t, 1H, J = 8Hz), 7.05 (t, 2H, J = 8Hz), 7.26 (t, 2H, J = 8Hz), 7.49 (t, 2H, J = 8Hz), 7.58 ( t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
[0361]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (p-fluorophenyl) -2-hydroxy-2-methylpropionyl] -10-deacetoxy-7-O -Methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0362]
Melting point: 147-150 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.22 (s, 9H), 1.23 (s, 3H), 1.38 (s, 3H), 1.68 (s, 3H), 1.81 (s, 3H), 2.62 (s, 3H), 1.73 -2.76 (m, 12H), 3.26 (s, 3H), 3.68 (m, 4H), 3.94-4.01 (m, 3H), 4.20 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 4.99-5.04 (m, 2H), 5.49 (d, 1H, J = 10Hz), 5.65 (d, 1H, J = 7Hz), 6.30 (t, 1H, J = 8Hz), 7.06 (t, 2H , J = 8Hz), 7.36 (t, 2H, J = 8Hz), 7.49 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz).
MS-FAB: 951 (MH+)
[0363]
Example 13
[0364]
Embedded image
Step 1: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10-deacetoxy-7 -O-methyl-10- (2-morpholinoethyl) baccatin III
Carry out the compound obtained in Step 4 of Example 10 and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyl) oxy-4- (2-furyl) -2-azetidinone Reaction was carried out in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0366]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.15 (s, 3H), 0.02 (s, 3H), 0.80 (s, 9H), 1.13 (s, 3H), 1.18 (s, 3H), 1.36 (s, 9H), 1.68 (s, 3H), 1.91 (s, 3H), 2.50 (s, 3H), 1.78-2.77 (m, 12H), 3.27 (s, 3H), 3.68 (m, 4H), 3.93-4.04 (m, 3H), 4.20 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.74 (s, 1H), 5.01 (d, 1H, J = 9Hz), 5.26 (d, 1H, J = 10Hz), 5.36 (d , 1H, J = 10Hz), 5.65 (d, 1H, J = 7Hz), 6.19 (t, 1H, J = 8Hz), 6.24 (s, 1H), 6.35 (s, 1H), 7.38 (s, 1H) , 7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz).
[0367]
Step 2: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0368]
Melting point: 138-142 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.18 (s, 3H), 1.36 (s, 9H), 1.67 (s, 3H), 1.90 (d, 3H, J = 1Hz), 2.41 (s, 3H), 1.75-2.76 ( m, 12H), 3.26 (s, 3H), 3.68 (m, 4H), 3.95-4.02 (m, 3H), 4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.70 (d, 1H, J = 2.5Hz), 4.99 (d, 1H, J = 8Hz), 5.25 (d, 1H, J = 10Hz), 5.35 (d, 1H, J = 10Hz), 5.64 (d, 1H , J = 7Hz), 6.18 (t, 1H, J = 8Hz), 6.32 (d, 1H, J = 3.5Hz), 6.38 (dd, 1H, J = 2Hz, 3.5Hz), 7.42 (d, 1H, J = 1Hz), 7.49 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz).
MS-FAB: 909 (MH+)
[0369]
Example 14
[0370]
Embedded image
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-7-O-methyl -10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 4 of Example 10 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0372]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.12 (s, 3H), 0.09 (s, 3H), 0.75 (s, 9H), 1.13 (s, 3H), 1.21 (s, 3H), 1.32 (s, 9H), 1.68 (s, 3H), 1.89 (s, 3H), 2.56 (s, 3H), 1.73-2.78 (m, 12H), 3.27 (s, 3H), 3.69 (m, 4H), 3.93-4.04 (m, 3H), 4.20 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 4.52 (s, 1H), 5.02 (d, 1H, J = 8Hz), 5.28 (d, 1H, J = 10Hz), 5.43 (d , 1H, J = 10Hz), 5.65 (d, 1H, J = 7Hz), 6.24 (t, 1H, J = 8Hz), 7.27-7.39 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz).
[0373]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-7-O-methyl-10- (2-morpholino Ethyl) Baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0374]
Melting point: 151-155 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.19 (s, 3H), 1.35 (s, 9H), 1.67 (s, 3H), 1.85 (d, 3H, J = 1Hz), 2.37 (s, 3H), 1.73-2.75 ( m, 12H), 3.25 (s, 3H), 3.68 (m, 4H), 3.93-4.01 (m, 3H), 4.18 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.61 (s, 1H), 4.99 (d, 1H, J = 8Hz), 5.27 (d, 1H, J = 10Hz), 5.42 (d, 1H, J = 10Hz), 5.63 (d, 1H, J = 7Hz) , 6.16 (t, 1H, J = 8Hz), 7.29-7.42 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz).
MS-FAB: 919 (MH+)
[0375]
Example 15
[0376]
Embedded image
Step 1: 10-allyl-10-deacetoxy-1-O-dimethylsilyl-7-O-methyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 9 of Example 11 was reacted in the same manner as in Step 1 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0378]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (d, 3H, J = 3Hz), 0.06 (d, 3H, J = 3Hz), 0.62-0.74 (m, 6H), 1.04 (t, 9H, J = 7Hz), 1.08 (s, 3H), 1.11 (s, 3H), 1.65 (s, 3H), 1.71-1.78 (m, 1H), 1.92 (s, 3H), 2.19-2.39 (m, 3H), 2.29 (s, 3H), 2.63-2.70 ( m, 1H), 2.95-3.01 (m, 1H), 3.24 (s, 3H), 3.77 (t, 1H, J = 7Hz), 3.93-3.98 (m, 2H), 4.24 (s, 2H), 4.53 ( t, 1H, J = 3Hz), 4.92-5.10 (m, 4H), 5.67 (d, 1H, J = 7Hz), 5.79-5.90 (m, 1H), 7.46 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0379]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-1-O-dimethylsilyl-7-O-methyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 2 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0380]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (d, 3H, J = 3Hz), 0.02 (d, 3H, J = 3Hz), 0.76-0.83 (m, 6H), 0.97 (s, 3H), 1.10 (t, 9H, J = 7Hz), 1.12 (s, 3H), 1.55 (s, 3H), 1.76-1.86 (m, 1H), 1.92 (s, 3H), 2.34-2.42 (m, 1H), 2.51-2.64 (m, 2H), 2.79 ( dd, 1H, J = 2.5Hz, 15Hz), 2.93-2.98 (m, 1H), 3.23 (s, 3H), 3.52 (dd, 1H, J = 5Hz, 12Hz), 3.66 (s, 1H), 3.73 ( d, 1H, J = 5.5Hz), 3.83 (t, 1H, J = 7Hz), 4.21 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.57 (t, 1H, J = 3Hz), 4.69 (d, 1H, J = 9Hz), 4.74 (dd, 1H, J = 4.5Hz, 10Hz), 5.00 (d, 1H, J = 8Hz), 5.10 (d, 1H, J = 17Hz) , 5.55 (d, 1H, J = 7Hz), 5.76-5.87 (m, 1H), 7.43 (t, 2H, J = 8Hz), 7.55 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).
[0381]
Step 3: 10-allyl-10-deacetoxy-4-deacetyl-1-O-dimethylsilyl-4-O-ethoxycarbonyl-7-O-methyl-13-O-triethylsilylbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 3 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0382]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (d, 3H, J = 3Hz), 0.06 (d, 3H, J = 3Hz), 0.65-0.73 (m, 6H), 1.03 (t, 9H, J = 7Hz), 1.11 (s, 6H), 1.41 (t, 3H, J = 7Hz), 1.65 (s, 3H), 1.70-1.80 (m, 1H), 1.93 (s, 3H), 2.19-2.30 (m, 3H), 2.62-2.70 (m, 1H ), 2.94-3.01 (m, 1H), 3.25 (s, 3H), 3.76 (t, 1H, J = 7Hz), 3.93 (dd, 1H, J = 7Hz, 10Hz), 4.00 (d, 1H, J = 7Hz), 4.10-4.23 (m, 1H), 4.19 (s, 2H), 4.39-4.47 (m, 1H), 4.55 (t, 1H, J = 3Hz), 4.95-5.10 (m, 4H), 5.69 ( d, 1H, J = 7Hz), 5.80-5.91 (m, 1H), 7.46 (t, 2H, J = 8Hz), 7.56 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz) .
[0383]
Step 4: 10-allyl-10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl-7-O-methylbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0384]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.05 (s, 3H), 1.11 (s, 3H), 1.39 (t, 3H, J = 7Hz), 1.65 (s, 3H), 1.73-1.79 (m, 1H), 1.99 (s, 3H), 2.20- 2.33 (m, 3H), 2.67-2.74 (m, 1H), 2.94-3.01 (m, 1H), 3.26 (s, 3H), 3.84 (t, 1H, J = 7Hz), 3.97 (dd, 1H, J = 7Hz, 10Hz), 4.09 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.16-4.20 (m, 1H), 4.22-4.26 (m, 2H), 4.82 (t, 1H, J = 8Hz), 4.98-5.13 (m, 3H), 5.60 (d, 1H, J = 7Hz), 5.79-5.89 (m, 1H), 7.47 (t, 2H, J = 8Hz), 7.58 (t , 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz).
[0385]
Step 5: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3-phenyl-2- (trimethylsilyl) oxypropionyl] -10-deacetoxy-4 -Deacetyl-4-O-ethoxycarbonyl-7-O-methylbaccatin III
The compound obtained in Step 4 above and the compound obtained in Step 2 of Reference Example 1 were reacted in the same manner as in Step 5 of Example 10 to obtain the title compound as a colorless amorphous solid.
[0386]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.06 (s, 9H), 1.15 (s, 3H), 1.25 (s, 3H), 1.26 (s, 9H), 1.41 (t, 3H, J = 7Hz), 1.45 (s, 3H), 1.70 (s, 3H), 1.84 (s, 3H), 1.81-1.87 (m, 1H), 2.08-2.15 (m, 1H), 2.26-2.31 (m, 1H), 2.38-2.44 (m, 1H), 2.67-2.74 ( m, 1H), 2.97-3.02 (m, 1H), 3.25 (s, 3H), 3.81 (t, 1H, J = 7Hz), 3.93 (dd, 1H, J = 7Hz, 10Hz), 4.16 (d, 1H , J = 7Hz), 4.30 (s, 2H), 4.65-4.77 (m, 2H), 5.00-5.16 (m, 4H), 5.53 (d, 1H, J = 10Hz), 5.67 (d, 1H, J = 7Hz), 5.79-5.90 (m, 1H), 6.30 (t, 1H, J = 8Hz), 7.30-7.45 (m, 7H), 7.56 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz).
[0387]
Step 6: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl- 4-O-Ethoxycarbonyl-7-O-methylbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0388]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.16 (s, 3H), 1.22 (s, 3H), 1.32 (s, 9H), 1.40 (s, 3H), 1.42 (t, 3H, J = 7Hz), 1.69 (s, 3H), 1.74 (s, 3H), 1.78-1.85 (m, 1H), 2.20-2.37 (m, 3H), 2.66-2.73 (m, 1H), 2.94-3.01 (m, 1H), 3.25 (s, 3H), 3.62 (s, 3H), 3.80 (t, 1H, J = 7Hz), 3.89 (dd, 1H, J = 7Hz, 10Hz), 4.07 (d, 1H, J = 7Hz), 4.24 (d, 1H, J = 8Hz), 4.34 (d, 1H, J = 8Hz), 4.52-4.65 (m, 2H), 5.00-5.15 (m, 4H), 5.66-5.70 (m, 2H), 5.76-5.86 (m, 1H), 6.21 (t, 1H, J = 8Hz), 7.30-7.46 (m, 7H), 7.58 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0389]
Step 7: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-10- (2 , 3-Dihydroxypropyl) -4-O-ethoxycarbonyl-7-O-methylbaccatin III
98 mg of the compound obtained in the above step 6 was dissolved in 12 ml of tetrahydrofuran: acetone: water = 1: 1: 1 (v / v / v), and 65 mg of N-methylmorpholine-N-oxide and 10 mg of osmium tetroxide were added. The mixture was further stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with a saturated aqueous sodium sulfite solution, a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin phase chromatography (developing solvent; chloroform: methanol = 10: 1 (v / v)) to obtain 81.5 mg of the title compound as a colorless amorphous solid.
[0390]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.11, 1.13 (each s, total 3H), 1.20, 1.21 (each s, total 3H), 1.31 (s, 9H), 1.41 (s, 3H), 1.42 (t, 3H, J = 7Hz), 1.69,1.70 (each s, total 3H), 1.83, 1.87 (each s, total 3H), 1.81-2.73 (m, 6H), 3.28, 3.29 (each s, total 3H), 3.46-3.76 (m, 3H), 3.88- 3.95 (m, 1H), 4.11-4.18 (m, 2H), 4.24 (d, 1H, J = 8Hz), 4.34 (d, 1H, J = 8Hz), 4.52-4.65 (m, 2H), 5.04 (d , 1H, J = 9Hz), 5.14 (d, 1H, J = 10Hz), 5.66-5.68 (m, 2H), 6.19 (m, 1H), 7.32-7.47 (m, 7H), 7.58 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
[0390]
Step 8: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-4-O- Ethoxycarbonyl-7-O-methyl-10- (2-morpholinoethyl) baccatin III
40 mg of the compound obtained in the above step 7 was dissolved in 4 ml of tetrahydrofuran: methanol = 1: 1 (v / v), and a solution of 92.5 mg of sodium metaperiodate in 2 ml of water was added dropwise under ice cooling. Stir at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 4 ml of ethanol, 0.024 ml of acetic acid and 0.037 ml of morpholine were added, 26 mg of sodium cyanoborohydride was further added, and the mixture was stirred for 15 minutes. A saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin phase chromatography (developing solvent; chloroform: methanol = 15: 1 (v / v)) and then lyophilized from 1,4-dioxane to give 36.7 mg of the title compound as a colorless solid. Obtained.
[0392]
Melting point: 150-152 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.15 (s, 3H), 1.20 (s, 3H), 1.32 (s, 9H), 1.41-1.44 (m, 6H), 1.69 (s, 3H), 1.82 (s, 3H), 1.80-2.76 (m, 12H), 3.25 (s, 3H), 3.60 (s, 1H), 3.66-3.68 (m, 4H), 3.91 (dd, 1H, J = 7Hz, 10Hz), 4.00 (t, 1H, J = 6Hz), 4.09 (d, 1H, J = 7Hz), 4.24 (d, 1H, J = 8Hz), 4.34 (d, 1H, J = 8Hz), 4.54-4.62 (m, 2H), 5.04 (d, 1H, J = 9Hz), 5.14 (d, 1H, J = 10Hz), 5.60-5.70 (m, 2H), 6.19 (t, 1H, J = 8Hz), 7.29-7.46 (m, 7H), 7.58 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
MS-FAB: 963 (MH+)
[0393]
Example 16
[0394]
Embedded image
13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl- 7-O-methyl-10- [2- (4-methylpiperazinyl) ethyl] baccatin III
The compound obtained in Step 7 of Example 15 was reacted in the same manner as in Step 8 of Example 15 using N-methylpiperazine instead of morpholine to obtain the title compound as a colorless solid.
[0396]
Melting point: 143-147 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.15 (s, 3H), 1.19 (s, 3H), 1.32 (s, 9H), 1.41-1.45 (m, 6H), 1.69 (s, 3H), 1.81 (s, 3H), 1.79-2.72 (m, 16H), 2.27 (s, 3H), 3.26 (s, 3H), 3.60 (br, 1H), 3.90 (dd, 1H, J = 7Hz, 10Hz), 4.00 (t, 1H, J = 6Hz), 4.09 ( d, 1H, J = 7Hz), 4.24 (d, 1H, J = 8Hz), 4.34 (d, 1H, J = 8Hz), 4.53-4.60 (m, 2H), 5.04 (d, 1H, J = 9Hz) , 5.14 (d, 1H, J = 10Hz), 5.66 (d, 1H, J = 7Hz), 5.69 (d, 1H, J = 10Hz), 6.18 (t, 1H, J = 8Hz), 7.31-7.46 (m , 7H), 7.58 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz).
MS-FAB: 976 (MH+)
[0397]
Example 17
[0398]
Embedded image
13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl- 7-O-methyl-10- (2-piperidinoethyl) baccatin III
The compound obtained in Step 7 of Example 15 was reacted in the same manner as in Step 8 of Example 15 using piperidine instead of morpholine to obtain the title compound as a colorless solid.
[0400]
Melting point: 130-134 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.20 (s, 3H), 1.32 (s, 9H), 1.68 (s, 3H), 1.80 (s, 3H), 1.41-2.75 (m, 24H), 3.27 (s, 3H) , 3.60 (br, 1H), 3.89 (dd, 1H, J = 7Hz, 10Hz), 3.98 (m, 1H), 4.08 (d, 1H, J = 7Hz), 4.24 (d, 1H, J = 8Hz), 4.34 (d, 1H, J = 8Hz), 4.55-4.60 (m, 2H), 5.04 (d, 1H, J = 9Hz), 5.13 (d, 1H, J = 10Hz), 5.66 (d, 1H, J = 7Hz), 5.71 (d, 1H, J = 10Hz), 6.18 (t, 1H, J = 8Hz), 7.29-7.46 (m, 7H), 7.58 (t, 1H, J = 8Hz), 8.09 (d, 2H , J = 8Hz).
MS-FAB: 961 (MH+)
[0401]
Example 18
[0402]
Embedded image
Step 1: 10-allyl-10-deacetoxy-13-O- (2,2,2-trichloroethoxycarbonyl) baccatin III
10-allyl-10-deacetoxy-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O-triethylsilylbaccatin III is reacted in the same manner as in Step 1 of Example 1 to give the title compound. Obtained as colorless crystals.
[0404]
Melting point: 195 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 6H), 1.63 (s, 3H), 1.82 (m, 1H), 1.87 (s, 3H), 2.35-2.40 (m, 4H), 2.38 (s, 3H), 2.59 (m, 1H) , 2.95 (m, 1H), 3.94 (t, 1H, J = 8Hz), 4.10 (d, 1H, J = 7.0Hz), 4.18 (d, 1H, J = 8.0Hz), 4.32 (d, 1H, J = 8.0Hz), 4.39 (m, 1H), 4.35 (AB type d, 2H, J = 12Hz), 4.96 (d, 1H, J = 8.0Hz), 5.02 (d, 1H, J = 9.9Hz), 5.13 (d, 1H, J = 17Hz), 5.68 (d, 1H, J = 7.0Hz), 5.78 (m, 1H), 5.94 (m, 1H), 7.49 (t, 2H, J = 7.5Hz), 7.62 ( t, 1H, J = 7.5Hz), 8.09 (d, 2H, J = 7.5Hz).
MS-FAB: 744 (MH+)
IR (KBr): 3484, 3160, 3070, 2956, 2902, 2452, 2260, 1969, 1764, 1731, 1713, 1644 cm-1
[0405]
Step 2: 10-allyl-10-deacetoxy-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O-trifluoromethanesulfonylbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 5 of Example 1 to obtain the title compound as a colorless amorphous solid colorless.
[0406]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.15 (s, 3H), 1.16 (s, 3H), 1.80 (s, 3H), 1.90 (d, 3H, J = 1Hz), 1.91 (m, 1H), 2.22 (m, 1H), 2.38 (m, 1H), 2.40 (s, 3H), 2.52 (m, 1H), 2.80-2.90 (m, 2H), 4.18 (m, 3H), 4.35 (d, 1H, J = 8.0Hz), 4.85 (AB type d , 2H, J = 12Hz), 4.93 (d, 1H, J = 8.0Hz), 5.05 (dd, 1H, J = 2.0Hz, 12Hz), 5.13 (dd, 1H, J = 2.0Hz, 17Hz), 5.60 ( dd, 1H, J = 7.0Hz, 11Hz), 5.68 (d, 1H, J = 7.0Hz), 5.73 (m, 1H), 5.96 (t, 1H, J = 7.0Hz), 7.49 (t, 2H, J = 7.5Hz), 7.63 (m, 1H), 8.07 (m, 2H).
MS-FAB: 875 (MH+)
[0407]
Step 3: 10-allyl-10-deacetoxy-7-deoxy-7β, 8β-methylene-13-O- (2,2,2-trichloroethoxycarbonyl) -19-norbaccatin III
20 mg of the compound obtained in Step 2 above was dissolved in a mixed solvent of 6 ml of dichloromethane and 5 ml of acetonitrile, silica gel (mesh 40-63 mm) was added in large excess, and the mixture was stirred at 80 ° C. for 1.5 hours. The silica gel was removed by filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent; methylene chloride: hexane: acetone = 70: 30: 3 (v / v / v)), The title compound (13.2 mg) was obtained as a colorless amorphous solid.
[0408]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.19 (s, 3H), 1.53 (t, 1H, J = 6.0Hz), 1.82 (s, 3H), 1.90 (br, 1H), 2.10 (d, 1H, J = 17Hz) , 2.22 (m, 2H), 2.34 (s, 3H), 2.40 (m, 2H), 2.46 (m, 1H), 3.00 (m, 1H), 3.71 (d, 1H, J = 7.0Hz), 4.02 ( d, 1H, J = 8.0Hz), 4.29 (d, 1H, J = 8.0Hz), 4.33 (d, 1H, J = 7.0Hz), 4.74 (d, 1H, J = 1.0Hz), 4.84 (AB type d, 2H, J = 12Hz), 5.01 (d, 1H, J = 10.0Hz), 5.10 (d, 1H, J = 17Hz), 5.61 (d, 1H, J = 7.0Hz), 5.81 (m, 1H) , 5.88 (m, 1H), 7.49 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.10 (d, 2H, J = 7.5Hz).
MS-FAB: 725 (MH+)
[0409]
Step 4: 10-allyl-10-deacetoxy-7-deoxy-7β, 8β-methylene-19-norbaccatin III
13 mg of the compound obtained in the above Step 3 was dissolved in a mixed solvent of 3 ml of acetic acid and 3 ml of methanol, 100 mg of zinc powder was added, and the mixture was stirred at 60 ° C. for 10 minutes. Zinc was filtered off and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: acetone = 95: 5 (v / v)) to obtain 7 mg of the title compound as a colorless amorphous solid.
[0410]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.17 (s, 3H), 1.26 (m, 1H), 1.53 (m, 1H), 1.88 (d, 1H, J = 1.0Hz), 1.94 (br, 1H), 2.09 (d , 1H, J = 16Hz), 2.22 (m, 1H), 2.26 (m, 2H), 2.27 (s, 3H), 2.36 (dd, 1H, J = 7.0Hz, 16Hz), 2.43 (dt, 1H, J = 4.5Hz, 16Hz), 3.00 (m, 1H), 3.71 (dd, 1H, J = 6.0Hz, 8.0Hz), 4.02 (d, 1H, J = 8.0Hz), 4.30 (d, 1H, J = 8.0 Hz), 4.36 (d, 1H, J = 7.0Hz), 4.72 (d, 1H, J = 4.0Hz), 4.82 (m, 1H), 5.01 (d, 1H, J = 10.0Hz), 5.10 (dd, 1H, J = 1.5Hz, 17Hz), 5.60 (d, 1H, J = 7.0Hz), 5.82 (m, 1H), 7.49 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5 Hz), 8.11 (d, 2H, J = 7.5Hz).
MS-FAB: 550 (MH+)
[0411]
Step 5: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-7 -Deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 4 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0412]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.35 (s, 3H), -0.12 (s, 3H), 0.71 (s, 9H), 1.21 (s, 3H), 1.22 (s, 9H), 1.24 (s, 3H), 1.55 (m, 1H) , 1.71 (s, 3H), 1.83 (br, 1H), 2.10-2.21 (m, 4H), 2.43 (m, 3H), 2.50 (s, 3H), 2.99 (m, 1H), 3.68 (t, 1H , J = 7.0Hz), 4.03 (d, 1H, J = 8.0Hz), 4.26 (d, 1H, J = 7.0Hz), 4.29 (d, 1H, J = 8.0Hz), 4.47 (s, 1H), 4.78 (d, 1H, J = 4.0Hz), 5.03 (d, 1H, J = 8.0Hz), 5.10 (d, 1H, J = 17Hz), 5.30 (m, 1H), 5.42 (m, 1H), 5.65 (d, 1H, J = 7.0Hz), 5.82 (m, 1H), 6.29 (m, 1H), 7.25-7.36 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.56 (t, 1H, J = 7.5Hz), 8.14 (d, 2H, J = 7.5Hz).
MS-FAB: 928 (MH+)
[0413]
Step 6: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-7-deoxy-7β , 8β-Methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0414]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.33 (s, 3H), -0.12 (s, 3H), 0.74 (s, 9H), 1.20 (s, 3H), 1.22 (s, 3H), 1.25 (s, 9H), 1.57 (m, 1H) , 1.80 (s, 3H), 2.12 (m, 2H), 2.20 (m, 1H), 2.35 (m, 2H), 2.44 (m, 6H), 2.52 (s, 3H), 2.55 (m, 1H), 3.70 (m, 4H), 3.75 (m, 1H), 4.06 (d, 1H, J = 8.5Hz), 4.28 (d, 1H, J = 7.0Hz), 4.31 (d, 1H, J = 7.0Hz), 4.50 (s, 1H), 4.79 (d, 1H, J = 3.0Hz), 5.32 (d, 1H, J = 10.0Hz), 4.43 (d, 1H, J = 10Hz), 5.68 (d, 1H, J = 7.0Hz), 6.28 (t, 1H, J = 7.0Hz), 7.28-7.35 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 1001 (MH+)
[0415]
Step 7: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 6 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0416]
Melting point: 120-125 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.22 (s, 3H), 1.27 (s, 9H), 1.56 (t, 1H, J = 7.0Hz), 1.79 (s, 3H), 1.88 (s, 1H), 2.12 (m , 1H), 2.20 (m, 3H), 2.35-2.48 (m, 12H), 2.43 (m, 6H), 2.55 (m, 1H), 3.71 (m, 4H), 3.75 (m, 1H), 4.04 ( d, 1H, J = 8.5Hz), 4.27 (d, 1H, J = 7.0Hz), 4.29 (d, 1H, J = 7.0Hz), 4.60 (s, 1H), 4.75 (d, 1H, J = 3.0 Hz), 5.29 (m, 1H), 5.35 (d, 1H, J = 10.0Hz), 5.65 (d, 1H, J = 7.0Hz), 6.22 (m, 1H), 7.30-7.44 (m, 5H), 7.50 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.16 (d, 2H, J = 7.5Hz).
MS-FAB: 887 (MH+)
IR (KBr): 3448, 3068, 2972, 2932, 2860, 2812, 1720, 1684, 1604, 1586, 1494 cm-1
[0417]
Example 19
[0418]
Embedded image
Step 1: 10-allyl-10-deacetoxy-7-deoxy-7β, 8β-methylene-13-O-triethylsilyl-19-norbaccatin III
182 mg of the compound obtained in Step 5 of Example 1 was dissolved in a mixed solvent of 10 ml of dry tetrahydrofuran and 10 ml of dry acetonitrile, and 5.5 g of silica gel (mesh 40-63 mm) was added thereto at 55 ° C. for 16 hours. Stir. The silica gel was removed by filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent; methylene chloride: hexane: acetone = 70: 30: 3 (v / v / v)), The title compound (107 mg) was obtained as a colorless amorphous solid.
[0420]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.66 (m, 6H), 1.01 (t, 9H, J = 8.0Hz), 1.13 (s, 3H), 1.17 (s, 3H), 1.52 (dd, 1H, J = 5.0Hz, 7.0Hz), 1.83 ( d, 3H, J = 1Hz), 2.08 (d, 1H, J = 16Hz), 2.17 (m, 3H), 2.26 (s, 3H), 2.30 (m, 1H), 2.45 (dt, 1H, J = 2Hz , 6Hz), 2.99 (m, 1H), 3.70 (dd, 1H, J = 6.0Hz, 8.0Hz), 4.05 (d, 1H, J = 8.5Hz), 4.26 (d, 1H, J = 8.0Hz), 4.29 (d, 1H, J = 8.5Hz), 4.76 (d, 1H, J = 4.0Hz), 4.87 (t, 1H, J = 7Hz), 5.01 (d, 1H, J = 10.0Hz), 5.10 (dd , 1H, J = 1.5Hz, 17Hz), 5.59 (d, 1H, J = 8.0Hz), 5.81 (m, 1H), 7.47 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 664 (MH+)
[0421]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-1-O-dimethylsilyl-7β, 8β-methylene-13-O-triethylsilyl-19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 2 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0422]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.23 (d, 3H, J = 2.7Hz), 0.08 (d, 3H, J = 2.7Hz), 0.77 (m, 6H), 1.06 (s, 3H), 1.07 (t, 9H, J = 8.0Hz) , 1.18 (s, 3H), 1.54 (t, 1H, J = 6.0Hz), 1.82 (s, 3H), 2.05-2.18 (m, 4H), 2.31 (m, 1H), 2.55 (dd, 1H, J = 8.8Hz, 15.0Hz), 2.68 (dd, 1H, J = 3.3Hz, 15.0Hz), 2.99 (m, 1H), 3.46 (s, 1H), 3.62 (dd, 1H, J = 5.7Hz, 8.2Hz ), 3.99 (d, 1H, J = 7.3Hz), 4.12 (d, 1H, J = 7.9Hz), 4.15 (d, 1H, J = 7.9Hz), 4.57 (m, 1H), 4.68 (m, 2H ), 5.02 (d, 1H, J = 10.0Hz), 5.12 (dd, 1H, J = 1.3Hz, 17Hz), 5.76 (d, 1H, J = 7.3Hz), 5.82 (m, 1H), 7.45 (t , 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 681 (MH+)
[0423]
Step 3: 10-allyl-4-O-cyclopropanecarbonyl-10-deacetoxy-4-deacetyl-7-deoxy-1-O-dimethylsilyl-7β, 8β-methylene-13-O-triethylsilyl-19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 3 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0424]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.24 (d, 3H, J = 2.7Hz), 0.11 (d, 3H, J = 2.7Hz), 0.68 (m, 6H), 1.00 (m, 9H), 1.12 (s, 3H), 1.19 (s, 3H), 1.24 (m, 4H), 1.51 (t, 1H, J = 7.0Hz), 1.61 (m, 1H), 1.72 (m, 1H), 1.80 (s, 3H), 2.05 (m, 1H), 2.16 (m, 1H), 2.31-2.40 (m, 4H), 2.96 (m, 1H), 3.62 (m, 1H), 4.13 (d, 1H, J = 8.0Hz), 4.19 (d, 1H, J = 8.0Hz), 4.21 (d, 1H, J = 8.0Hz), 4.54 (m, 1H), 4.62 (d, 1H, J = 3.8Hz), 4.98 (d, 1H, J = 10.0Hz), 5.08 (d , 1H, J = 17Hz), 5.69 (d, 1H, J = 7.0Hz), 5.81 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz) , 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 749 (MH+)
[0425]
Step 4: 10-allyl-4-O-cyclopropanecarbonyl-10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0426]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.02 (m, 2H), 1.10 (s, 3H), 1.17 (s, 3H), 1.20-1.27 (m, 2H), 1.53 (m, 1H), 1.65 (m, 1H), 1.77 (m, 1H) , 1.85 (s, 3H), 2.06 (d, 1H, J = 17.1Hz), 2.19 (m, 2H), 2.25-2.30 (m, 2H), 2.39 (m, 1H), 2.99 (m, 1H), 3.68 (dd, 1H, J = 6.3Hz, 7.8Hz), 4.06 (d, 1H, J = 8.5Hz), 4.30 (d, 1H, J = 8.5Hz), 4.32 (d, 1H, J = 7.8Hz) , 4.68 (d, 1H, J = 3.9Hz), 4.80 (br, 1H), 4.00 (dd, 1H, J = 1.0Hz, 9.8Hz), 5.09 (dd, 1H, J = 1.5Hz, 17.1Hz), 5.62 (d, 1H, J = 7.8Hz), 5.82 (m, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.14 (m, 2H).
MS-FAB: 576 (MH+)
[0427]
Step 5: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyl) oxypropionyl] -4-O -Cyclopropanecarbonyl-10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 4 above and (3R, 4R) -1- (tert-butoxycarbonyl) -4- (2-furyl) -3- (triisopropylsilyl) oxy-2-azetidinone were used in Step 8 of Example 1. To give the title compound as a colorless amorphous solid.
[0428]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.00 (m, 21H), 1.21 (s, 3H), 1.24 (s, 3H), 1.27 (s, 9H), 1.10-1.30 (m, 4H), 1.52 (m, 1H), 1.73 (s, 3H) , 1.79 (m, 1H), 1.90 (m, 1H), 2.08 (d, 1H, J = 17.1Hz), 2.19 (m, 3H), 2.38 (dt, 1H, J = 4.4Hz, 17.1Hz), 2.48 (dd, 1H, J = 9.6Hz, 17.4Hz), 2.99 (m, 1H), 3.69 (t, 1H, J = 6.9Hz), 4.05 (d, 1H, J = 8.6Hz), 4.29 (m, 2H ), 4.62 (m, 1H), 5.02 (m, 2H), 5.10 (d, 1H, J = 17.1Hz), 5.23 (d, 1H, J = 10.0Hz), 5.35 (d, 1H, J = 10.0Hz) ), 5.68 (d, 1H, J = 7.8Hz), 5.83 (m, 1H), 6.22 (m, 2H), 6.34 (m, 1H), 7.34 (s, 1H), 7.49 (t, 2H, J = 7.5Hz), 7.56 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 986 (MH+)
[0429]
Step 6: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyl) oxypropionyl] -4-O-cyclopropanecarbonyl -10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0430]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.95-1.00 (m, 21H), 1.19 (s, 3H), 1.22 (s, 3H), 1.18-1.23 (m, 4H), 1.29 (s, 9H), 1.47 (m, 1H), 1.54 (m, 1H), 1.84 (s, 3H), 1.90 (m, 1H), 2.08 (d, 1H, J = 16.1Hz), 2.19 (m, 2H), 2.33 (m, 1H), 2.40 (m, 1H), 2.43 (m, 4H), 2.48-2.53 (m, 2H), 3.69 (m, 4H), 3.74 (m, 1H), 4.07 (d, 1H, J = 8.8Hz), 4.29 (m, 2H), 4.63 (m, 1H), 5.02 (s, 1H), 5.23 (d, 1H, J = 9.7Hz), 5.36 (d, 1H, J = 9.7Hz), 5.67 (d, 1H, J = 7.8Hz), 6.20 (d, 1H, J = 8.5Hz), 6.24 (m, 1H), 6.35 (m, 1H), 7.33 (m, 1H), 7.49 (t, 2H, J = 7.5Hz), 7.56 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 1059 (MH+)
[0431]
Step 7: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4-O-cyclopropanecarbonyl-10-deacetoxy- 4-deacetyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 6 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0432]
Melting point: 120-125 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.02 (m, 2H), 1.16 (m, 2H), 1.20 (s, 3H), 1.23 (s, 3H), 1.28 (s, 9H), 1.47 (m, 1H), 1.53 (m, 1H), 1.80 (s, 3H), 1.90 (m, 1H), 2.04 (d, 1H, J = 13.1Hz), 2.20 (m, 2H), 2.37 (m, 2H), 2.75-2.42 (m, 6H), 2.44 ( m, 4H), 3.70 (m, 4H), 3.75 (m, 1H), 4.79 (AB type d, 2H, J = 8.5Hz), 4.63 (d, 1H, J = 3.4Hz), 4.76 (m, 1H ), 5.15 (d, 1H, J = 9.7Hz), 5.39 (d, 1H, J = 9.7Hz), 5.64 (d, 1H, J = 7.8Hz), 6.23 (t, 1H, J = 8.3Hz), 6.30 (m, 1H), 6.37 (m, 1H), 7.39 (s, 1H), 7.51 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.17 (d, 2H , J = 7.5Hz).
MS-FAB: 903 (MH+)
[0433]
Example 20
[0434]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -4-O-cyclo Propanecarbonyl-10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 4 of Example 19 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0436]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.09 (s, 3H), 0.74 (s, 9H), 1.00 (m, 2H), 1.09 (m, 2H), 1.21 (s, 3H), 1.28 (s, 9H) , 1.29 (s, 3H), 1.56 (m, 1H), 1.71 (s, 3H), 1.82 (br, 1H), 1.90 (m, 1H), 2.10 (d, 1H, J = 15.9Hz), 2.14- 2.24 (m, 3H), 2.39 (dt, 1H, J = 4.4Hz, 15.9Hz), 2.50 (dd, 1H, J = 10.1Hz, 15.1Hz), 2.99 (m, 1H), 3.68 (t, 1H, J = 6.9Hz), 4.08 (d, 1H, J = 8.5Hz), 4.54 (s, 1H), 4.64 (d, 1H, J = 4.0Hz), 5.02 (d, 1H, J = 10.0Hz), 5.08 (dd, 1H, J = 1.4Hz, 17.1Hz), 5.30 (d, 1H, J = 8.8Hz), 5.43 (d, 1H, J = 8.8Hz), 5.66 (d, 1H, J = 7.8Hz), 5.86 (m, 1H), 6.25 (t, 1H, J = 8.3Hz), 7.24-7.37 (m, 5H), 7.50 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz ), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 954 (MH+)
[0437]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -4-O-cyclopropanecarbonyl-10 -Deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0438]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.09 (s, 3H), 0.76 (s, 9H), 1.02 (m, 2H), 1.12 (m, 2H), 1.21 (s, 3H), 1.25 (s, 3H) , 1.31 (s, 9H), 1.48 (m, 1H), 1.57 (t, 1H, J = 6.0Hz), 1.80 (s, 3H), 1.91 (m, 1H), 2.10 (d, 1H, J = 15.9 Hz), 2.18 (m, 2H), 2.34 (m, 2H), 2.42 (m, 4H), 2.50 (m, 4H), 3.70 (m, 5H), 4.08 (d, 1H, J = 8.5Hz), 4.26 (d, 1H, J = 7.7Hz), 4.30 (d, 1H, J = 8.5Hz), 4.54 (s, 1H), 4.67 (d, 1H, J = 3.6Hz), 5.31 (d, 1H, J = 9.0Hz), 5.44 (d, 1H, J = 9.0Hz), 5.68 (d, 1H, J = 7.7Hz), 6.21 (t, 1H, J = 8.4Hz), 7.24-7.37 (m, 5H), 7.50 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 1026 (MH+)
[0439]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -4-O-cyclopropanecarbonyl-10-deacetoxy-4-deacetyl- 7-Deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0440]
Melting point: 130-135 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
0.82 (m, 2H), 0.92 (m, 2H), 1.20 (s, 3H), 1.24 (s, 3H), 1.29 (s, 9H), 1.46 (m, 1H), 1.54 (m, 1H), 1.77 (s, 3H), 1.82 (m, 1H), 2.10 (m, 1H), 2.20-2.24 (m, 2H), 2.33-2.48 (m, 9H), 2.58 (m, 1H), 3.70 (m, 4H ), 3.74 (m, 1H), 4.05 (d, 1H, J = 8.5Hz), 4.26 (d, 1H, J = 7.7Hz), 4.30 (d, 1H, J = 8.5Hz), 4.61 (d, 1H , J = 3.3Hz), 4.69 (br, 1H), 5.29 (s, 2H), 5.66 (d, 1H, J = 7.7Hz), 6.18 (m, 1H), 7.30-7.39 (m, 5H), 7.52 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.17 (d, 2H, J = 7.5Hz).
MS-FAB: 913 (MH+)
[0441]
Example 21
[0442]
Embedded image
Step 1: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-4-O-ethoxycarbonyl-1-O-dimethylsilyl-7β, 8β-methylene-13-O-triethylsilyl-19-norbaccatin III
The compound obtained in Step 2 of Example 19 was reacted in the same manner as in Step 3 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0444]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.24 (d, 3H, J = 2.7Hz), 0.11 (d, 3H, J = 2.7Hz), 0.68 (m, 6H), 1.02 (t, 9H, J = 8.0Hz), 1.12 (s, 3H) , 1.19 (s, 3H), 1.24 (m, 1H), 1.39 (t, 3H, J = 7.2Hz), 1.49 (dd, 1H, J = 5.3Hz, 7.0Hz), 1.84 (s, 3H), 2.09 (d, 1H, J = 15.9Hz), 2.16 (m, 2H), 2.32 (m, 2H), 2.38 (m, 1H), 2.99 (m, 1H), 3.66 (dd, 1H, J = 6.6Hz, 7.2Hz), 4.12 (m, 2H), 4.24 (d, 1H, J = 8.6Hz), 4.28 (d, 1H, J = 7.7Hz), 4.38 (m, 1H), 4.53 (m, 1H), 4.73 (d, 1H, J = 4.2Hz), 4.93 (t, 1H, J = 8.1Hz), 4.99 (dd, 1H, J = 1.7Hz, 10.1Hz), 5.09 (dd, 1H, J = 1.7Hz, 17.0 Hz), 5.69 (d, 1H, J = 7.7Hz), 5.85 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.12 (m, 2H).
MS-FAB: 753 (MH+)
[0445]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-4-O-ethoxycarbonyl-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0446]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.99 (s, 3H), 1.17 (s, 3H), 1.37 (t, 3H, J = 7.5Hz), 1.51 (m, 1H), 1.89 (d, 3H, J = 15.9Hz), 2.13 (d, 1H , J = 15.9Hz), 2.23 (m, 2H), 2.28 (d, 1H, J = 9.0Hz), 2.37 (dd, 1H, J = 6.9Hz, 15.7Hz), 2.43 (dt, 1H, J = 4.5 Hz, 15.9Hz), 3.00 (m, 1H), 3.72 (dd, 1H, J = 6.3Hz, 7.6Hz), 4.05 (d, 1H, J = 8.6Hz), 4.21 (m, 1H), 4.31 (m , 2H), 4.42 (d, 1H, J = 7.6Hz), 4.80 (m, 2H), 5.02 (d, 1H, J = 10.1Hz), 5.10 (dd, 1H, J = 1.6Hz, 17.1Hz), 5.63 (d, 1H, J = 7.6Hz), 5.84 (m, 1H), 7.49 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.14 (m, 2H).
MS-FAB: 580 (MH+)
[0447]
Step 3: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl]- 10-deacetoxy-4-deacetyl-7-deoxy-4-O-ethoxycarbonyl-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 2 above and (3R, 4R) -1- (tert-butoxycarbonyl) -4- (2-furyl) -3- (tert-butyldimethylsilyl) oxy-2-azetidinone were used in Example 1. The reaction was conducted in the same manner as in Step 8 to obtain the title compound as a colorless amorphous solid.
[0448]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.14 (s, 3H), 0.04 (s, 3H), 0.89 (s, 9H), 1.21 (s, 3H), 1.24 (s, 3H), 1.29 (s, 9H), 1.38 (t, 1H, J = 6.9Hz), 1.54 (m, 1H), 1.74 (s, 3H), 1.82 (br, 1H), 2.14 (d, 1H, J = 15.9Hz), 2.10-2.25 (m, 3H), 2.40 (m , 1H), 2.48 (m, 1H), 2.99 (m, 1H), 3.69 (t, 1H, J = 6.9Hz), 4.06 (d, 1H, J = 8.7Hz), 4.31 (m, 3H), 4.52 (m, 1H), 4.71 (m, 1H), 4.78 (d, 1H, J = 4.0Hz), 5.02 (d, 1H, J = 10.0Hz), 5.12 (dd, 1H, J = 1.7Hz, 17.1Hz ), 5.21 (d, 1H, J = 8.5Hz), 5.33 (d, 1H, J = 8.5Hz), 5.69 (d, 1H, J = 7.5Hz), 5.82 (m, 1H), 6.19 (m, 1H ), 6.23 (m, 1H), 6.35 (m, 1H), 7.38 (m, 1H), 7.50 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.16 (d , 2H, J = 7.5Hz).
MASS-FAB: 948 (MH+)
[0449]
Step 4: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10-deacetoxy-4 -Deacetyl-7-deoxy-4-O-ethoxycarbonyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0450]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.14 (s, 3H), 0.04 (s, 3H), 0.79 (s, 9H), 1.21 (s, 3H), 1.22 (s, 3H), 1.31 (s, 9H), 1.40 (t, 3H, J = 7.5Hz), 1.54 (m, 1H), 1.73 (s, 4H), 2.14 (d, 1H, J = 15.9Hz), 2.14 (m, 1H), 2.20 (m, 1H), 2.30-2.60 (m , 8H), 3.69 (m, 4H), 3.75 (t, 1H, J = 6.6Hz), 4.06 (d, 1H, J = 8.5Hz), 4.31 (m, 3H), 4.54 (m, 1H), 4.72 (m, 1H), 4.78 (d, 1H, J = 4.0Hz), 5.21 (d, 1H, J = 10.0Hz), 5.33 (d, 1H, J = 10.0Hz), 5.69 (d, 1H, J = 7.6Hz), 6.17 (t, 1H, J = 8.0Hz), 6.24 (m, 1H), 6.36 (m, 1H), 7.38 (m, 1H), 7.50 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.16 (d, 2H, J = 7.5Hz).
MS-FAB: 1021 (MH+)
[0451]
Step 5: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 4-O-Ethoxycarbonyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 4 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0452]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.21 (s, 6H), 1.26 (m, 3H), 1.33 (s, 9H), 1.48 (m, 1H), 1.53 (m, 1H), 1.82 (s, 3H), 1.88 (s, 1H), 2.14 (d, 1H, J = 15.9Hz), 2.16-2.22 (m, 3H), 2.37-2.57 (m, 9H), 3.70 (s, 4H), 3.74 (m, 1H), 4.06 (d, 1H, J = 8.5Hz), 4.20 (m, 1H), 4.31 (d, 1H, J = 7.6Hz), 4.34 (d, 1H, J = 8.5Hz), 4.46 (m, 1H), 4.68 (d, 1H, J = 3.4Hz), 4.78 (s, 1H), 5.21 (d, 1H, J = 9.7Hz), 5.31 (d, 1H, J = 9.7Hz), 5.69 (d, 1H, J = 7.6Hz), 6.14 ( t, 1H, J = 8.4Hz), 6.35 (m, 2H), 7.43 (s, 1H), 7.50 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.16 ( d, 2H, J = 7.5Hz).
MS-FAB: 907 (MH+)
[0453]
Example 22
[0454]
Embedded image
Step 1: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-1-O-dimethylsilyl-4-O-methoxyacetyl-7β, 8β-methylene-13-O-triethylsilyl-19-norbaccatin III
The compound obtained in Step 2 of Example 19 was reacted in the same manner except that cyclopropanecarbonyl chloride in Step 3 of Example 2 was replaced with methoxyacetyl chloride to obtain the title compound as a colorless amorphous solid.
[0456]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.24 (d, 3H, J = 2.7Hz), 0.11 (d, 3H, J = 2.7Hz), 0.68 (m, 6H), 1.02 (t, 9H, J = 8.0Hz), 1.10 (s, 3H) , 1.19 (s, 3H), 1.22 (m, 1H), 1.52 (m, 1H), 1.80 (s, 3H), 2.09 (d, 1H, J = 15.9Hz), 2.18 (m, 2H), 2.32 ( m, 2H), 2.46 (dt, 1H, J = 4.5Hz, 16.0Hz), 2.99 (m, 1H), 3.55 (s, 3H), 3.66 (m, 1H), 4.12 (m, 2H), 4.16 ( d, 1H, J = 16.1Hz), 4.17 (d, 1H, J = 8.5Hz), 4.22 (d, 1H, J = 7.6Hz), 4.28 (d, 1H, J = 8.5Hz), 4.35 (d, 1H, J = 16.1Hz), 4.53 (m, 1H), 4.79 (d, 1H, J = 3.7Hz), 4.92 (t, 1H, J = 8.1Hz), 5.00 (d, 1H, J = 10.1Hz) , 5.09 (d, 1H, J = 17.0Hz), 5.67 (d, 1H, J = 7.6Hz), 5.83 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.18 (m, 2H).
MS-FAB: 753 (MH+)
[0457]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-4-O-methoxyacetyl-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0458]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.17 (s, 3H), 1.54 (m, 1H), 1.87 (s, 3H), 2.14 (m, 2H), 2.20-2.27 (m, 3H), 2.32 (dd, 1H, J = 7.0Hz, 16.0Hz), 2.48 (dt, 1H, J = 4.5Hz, 16.0Hz), 2.99 (m, 1H), 3.57 (s, 3H), 3.71 (dd, 1H, J = 6.1Hz, 7.9 Hz), 4.08 (m, 1H), 4.24 (AB type q, 2H, J = 15.7Hz), 4.31 (d, 1H, J = 8.6Hz), 4.37 (d, 1H, J = 7.7Hz), 4.79 ( m, 2H), 5.01 (d, 1H, J = 10.1Hz), 5.10 (dd, 1H, J = 1.7Hz, 17.0Hz), 5.62 (d, 1H, J = 7.7Hz), 5.84 (m, 1H) , 7.48 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.16 (m, 2H).
MS-FAB: 580 (MH+)
[0459]
Step 3: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10 -Deacetoxy-4-deacetyl-7-deoxy-4-O-methoxyacetyl-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 2 above and (3R, 4R) -1- (tert-butoxycarbonyl) -4- (2-furyl) -3- (tert-butyldimethylsilyl) oxy-2-azetidinone were used in Example 1. The reaction was conducted in the same manner as in Step 8 to obtain the title compound as a colorless amorphous solid.
[0460]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.13 (s, 3H), -0.03 (s, 3H), 0.80 (s, 9H), 1.21 (s, 6H), 1.31 (s, 9H), 1.54 (m, 1H), 1.60 (s, 1H) , 1.72 (s, 3H), 2.14 (d, 1H, J = 15.9Hz), 2.14-2.25 (m, 3H), 2.41 (dd, 1H, J = 9.3Hz, 15.5Hz), 2.48 (dt, 1H, J = 4.5Hz, 15.9Hz), 2.99 (m, 1H), 3.69 (t, 1H, J = 7.0Hz), 4.08-4.15 (m, 2H), 4.31 (m, 2H), 4.79 (m, 3H) , 5.02 (d, 1H, J = 10.1Hz), 5.12 (d, 1H, J = 17.1Hz), 5.36 (d, 1H, J = 9.6Hz), 5.65 (m, 2H), 5.83 (m, 1H) , 6.20 (m, 1H), 6.22 (m, 1H), 6.35 (m, 1H), (d, 1H, J = 8.5Hz), 5.69 (d, 1H, J = 7.5Hz), 5.82 (m, 1H ), 6.19 (m, 1H), 6.23 (m, 1H), 6.35 (m, 1H), 7.39 (s, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 948 (MH+)
[0461]
Step 4: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10-deacetoxy-4 -Deacetyl-7-deoxy-4-O-methoxyacetyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0462]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.12 (s, 3H), -0.03 (s, 3H), 0.80 (s, 9H), 1.19 (s, 6H), 1.31 (s, 9H), 1.48 (m, 1H), 1.54 (m, 1H) , 1.78 (s, 1H), 1.80 (s, 3H), 2.10-2.18 (m, 2H), 2.22 (m, 1H), 2.30-2.60 (m, 10H), 3.53 (s, 3H), 3.69 (m , 4H), 3.78 (t, 1H, J = 6.0Hz), 4.07-4.17 (m, 2H), 4.30 (m, 3H), 4.79 (m, 2H), 4.82 (d, 1H, J = 16.0Hz) , 5.33 (d, 1H, J = 10.0Hz), 5.59 (d, 1H, J = 10.0Hz), 5.65 (d, 1H, J = 7.5Hz), 6.18 (t, 1H, J = 8.5Hz), 6.22 (m, 1H), 6.35 (m, 1H), 7.38 (m, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 1021 (MH+)
[0463]
Step 5: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 4-O-methoxyacetyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 4 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0464]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 6H), 1.33 (s, 9H), 1.48 (m, 1H), 1.56 (m, 1H), 1.80 (s, 3H), 2.13 (d, 1H, J = 16.0Hz), 2.22 (m , 3H), 2.30-2.60 (m, 10H), 3.50 (s, 3H), 3.70 (m, 4H), 3.78 (m, 1H), 4.06 (d, 1H, J = 8.6Hz), 4.12 (d, 1H, J = 17.0Hz), 4.30 (d, 1H, J = 7.6Hz), 4.31 (m, 1H), 4.62 (d, 1H, J = 17.0Hz), 4.76 (s, 1H), 4.79 (s, 1H), 5.37 (s, 2H), 5.66 (d, 1H, J = 7.6Hz), 6.19 (br, 1H), 6.32 (s, 1H), 6.36 (m, 1H), 7.41 (m, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 907 (MH+)
[0465]
Example 23
[0466]
Embedded image
Step 1: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-1-O-dimethylsilyl-7β, 8β-methylene-4-O-propionyl-13-O-triethylsilyl-19-norbaccatin III
The compound obtained in Step 2 of Example 19 was reacted in the same manner by replacing cyclopropanecarbonyl chloride in Step 3 of Example 2 with propionyl chloride to obtain the title compound as a colorless amorphous solid.
[0468]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.23 (d, 3H, J = 2.7Hz), 0.10 (d, 3H, J = 2.7Hz), 0.68 (m, 6H), 1.02 (t, 9H, J = 8.0Hz), 1.11 (s, 3H) , 1.19 (s, 3H), 1.22 (t, 3H, J = 7.5Hz), 1.25 (m, 1H), 1.48 (m, 1H), 1.81 (s, 3H), 2.07 (d, 1H, J = 15.9 Hz), 2.18 (m, 2H), 2.33 (m, 2H), 2.45 (dt, 1H, J = 4.5Hz, 15.8Hz), 2.60 (m, 2H), 2.99 (m, 1H), 3.66 (t, 1H, J = 6.9Hz), 4.12 (d, 1H, J = 8.5Hz), 4.20 (d, 1H, J = 7.6Hz), 4.24 (d, 1H, J = 8.5Hz), 4.53 (m, 1H) , 4.70 (d, 1H, J = 4.0Hz), 4.92 (t, 1H, J = 8.2Hz), 4.99 (d, 1H, J = 10.1Hz), 5.09 (d, 1H, J = 17.0Hz), 5.67 (d, 1H, J = 7.6Hz), 5.83 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 737 (MH+)
[0469]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-4-O-propionyl-19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0470]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.17 (s, 3H), 1.26 (t, 3H, J = 7.1Hz), 1.53 (m, 1H), 1.87 (s, 3H), 1.99 (s, 1H), 2.09 (d , 1H, J = 15.9Hz), 2.20 (m, 3H), 2.34 (dd, 1H, J = 7.0Hz, 15.9Hz), 2.57 (m, 1H), 2.65 (m, 1H), 2.99 (m, 1H ), 3.71 (m, 1H), 4.06 (d, 1H, J = 8.5Hz), 4.29 (d, 1H, J = 8.5Hz), 4.36 (d, 1H, J = 7.6Hz), 4.71 (d, 1H , J = 3.2Hz), 4.83 (br, 1H), 4.99 (d, 1H, J = 9.9Hz), 5.09 (d, 1H, J = 17.0Hz), 5.61 (d, 1H, J = 7.6Hz), 5.83 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.14 (d, 2H, J = 7.5Hz).
MS-FAB: 564 (MH+)
[0471]
Step 3: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10 -Deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-4-O-propionyl-19-norbaccatin III
The compound obtained in Step 2 above and (3R, 4R) -1- (tert-butoxycarbonyl) -4- (2-furyl) -3- (tert-butyldimethylsilyl) oxy-2-azetidinone were used in Example 1. The reaction was conducted in the same manner as in Step 8 to obtain the title compound as a colorless amorphous solid.
[0472]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.17 (s, 3H), 0.02 (s, 3H), 0.80 (s, 9H), 1.21 (s, 3H), 1.22 (s, 3H), 1.27 (s, 9H), 1.32 (t, 3H, J = 7.5Hz), 1.55 (m, 1H), 1.72 (s, 3H), 1.80 (br, 1H), 2.12 (d, 1H, J = 15.9Hz), 2.14-2.25 (m, 3H), 2.42 (m , 1H), 2.46 (m, 1H), 2.74 (m, 2H), 2.99 (m, 1H), 3.69 (t, 1H, J = 7.0Hz), 4.06 (d, 1H, J = 8.5Hz), 4.24 (d, 1H, J = 7.6Hz), 4.30 (d, 1H, J = 8.5Hz), 4.70 (s, 2H), 5.04 (d, 1H, J = 10.1Hz), 5.11 (dd, 1H, J = 1.7Hz, 17.1Hz), 5.22 (d, 1H, J = 10.0Hz), 5.31 (d, 1H, J = 10.0Hz), 5.66 (d, 1H, J = 7.6Hz), 5.82 (m, 1H), 6.22 (m, 2H), 6.36 (m, 1H), 7.39 (s, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.16 (d, 2H , J = 7.5Hz).
MS-FAB: 932 (MH+)
[0473]
Step 4: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10-deacetoxy-4 -Deacetyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -4-O-propionyl-19-norbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0474]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.17 (s, 3H), 0.02 (s, 3H), 0.80 (s, 9H), 1.20 (s, 3H), 1.21 (s, 3H), 1.28 (s, 9H), 1.34 (t, 3H, J = 7.5Hz), 1.48 (m, 1H), 1.55 (m, 1H), 1.78 (s, 1H), 1.80 (s, 3H), 2.12 (d, 1H, J = 15.9Hz), 2.13-2.21 (m , 2H), 2.30-2.54 (m, 10H), 2.75 (m, 2H), 3.70 (m, 4H), 3.74 (m, 1H), 4.06 (d, 1H, J = 8.5Hz), 4.26 (d, 1H, J = 7.6Hz), 4.30 (d, 1H, J = 8.5Hz), 4.72 (s, 2H), 5.23 (d, 1H, J = 10.0Hz), 5.31 (d, 1H, J = 10.0Hz) , 5.66 (d, 1H, J = 7.6Hz), 6.21 (m, 1H), 6.23 (m, 1H), 6.36 (s, 1H), 7.39 (s, 1H), 7.48 (t, 2H, J = 7.5 Hz), 7.57 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 1004 (MH+)
[0475]
Step 5: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 7β, 8β-Methylene-10- (2-morpholinoethyl) -4-O-propionyl-19-norbaccatin III The compound obtained in Step 4 above was reacted in the same manner as in Step 9 of Example 1 to give the title compound as colorless Obtained as a solid.
[0476]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.21 (s, 3H), 1.23 (s, 3H), 1.27 (s, 9H), 1.48 (m, 1H), 1.55 (m, 1H), 1.81 (s, 3H), 1.88 (br, 1H), 2.14 (d, 1H, J = 16.0Hz), 2.19 (m, 2H), 2.30-2.60 (m, 10H), 2.72 (m, 2H), 3.72 (m, 5H), 4.03 (d, 1H, J = 8.5 Hz), 4.23 (d, 1H, J = 7.6Hz), 4.30 (d, 1H, J = 8.5Hz), 4.70 (s, 2H), 5.19 (d, 1H, J = 10.0Hz), 5.31 (d, 1H, J = 10.0Hz), 5.64 (d, 1H, J = 7.6Hz), 6.23 (m, 1H), 6.31 (br, 1H), 6.38 (s, 1H), 7.43 (s, 1H), 7.48 ( t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.18 (d, 2H, J = 7.5Hz).
MS-FAB: 891 (MH+)
[0477]
Example 24
[0478]
Embedded image
Step 1: 10-allyl-4-O-butanoyl-10-deacetoxy-4-deacetyl-7-deoxy-1-O-dimethylsilyl-7β, 8β-methylene-13-O-triethylsilyl-19-norbaccatin III
The compound obtained in Step 2 of Example 19 was reacted in the same manner except that cyclopropanecarbonyl chloride in Step 3 of Example 2 was replaced with n-butyryl chloride to obtain the title compound as a colorless amorphous solid.
[0480]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.23 (d, 3H, J = 2.7Hz), 0.10 (d, 3H, J = 2.7Hz), 0.68 (m, 6H), 1.02 (t, 9H, J = 8.0Hz), 1.04 (t, 3H, J = 7.5Hz), 1.10 (s, 3H), 1.19 (s, 3H), 1.22 (m, 1H), 1.48 (m, 1H), 1.78 (m, 2H), 1.80 (s, 3H), 2.09 ( d, 1H, J = 15.9Hz), 2.18 (m, 2H), 2.33 (m, 2H), 2.45 (dt, 1H, J = 4.5Hz, 15.9Hz), 2.52 (m, 2H), 2.99 (m, 1H), 3.67 (m, 1H), 4.12 (d, 1H, J = 8.5Hz), 4.22 (d, 1H, J = 8.1Hz), 4.24 (d, 1H, J = 8.5Hz), 4.53 (m, 1H), 4.70 (d, 1H, J = 3.9Hz), 4.92 (t, 1H, J = 8.2Hz), 4.99 (d, 1H, J = 10.1Hz), 5.09 (d, 1H, J = 17.0Hz) , 5.67 (d, 1H, J = 8.1Hz), 5.83 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 751 (MH+)
[0481]
Step 2: 10-allyl-4-O-butanoyl-10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0482]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.17 (s, 3H), 1.28 (t, 3H, J = 7.5Hz), 1.53 (m, 1H), 1.74 (m, 2H), 1.86 (d, 3H, J = 1.1Hz ), 1.92 (m, 1H), 2.09 (d, 1H, J = 15.9Hz), 2.18-2.27 (m, 3H), 2.34 (dd, 1H, J = 7.0Hz, 15.6Hz), 2.46 (dt, 1H , J = 4.5Hz, 15.6Hz), 2.53 (m, 1H), 2.59 (m, 1H), 2.99 (m, 1H), 3.71 (m, 1H), 4.06 (d, 1H, J = 8.5Hz), 4.29 (d, 1H, J = 8.5Hz), 4.36 (d, 1H, J = 7.6Hz), 4.71 (d, 1H, J = 3.9Hz), 4.83 (br, 1H), 5.01 (d, 1H, J = 9.9Hz), 5.10 (dd, 1H, J = 1.7Hz, 17.0Hz), 5.61 (d, 1H, J = 7.6Hz), 5.83 (m, 1H), 7.48 (t, 2H, J = 7.5Hz) , 7.61 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 578 (MH+)
[0483]
Step 3: 10-allyl-4-O-butanoyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2- Furyl) propionyl] -10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 2 above and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (2-furyl) -3- (tert-butyldimethylsilyl) oxy-2-azetidinone were used in Example 1. The reaction was carried out in the same manner as in Step 8 to obtain the title compound as a colorless amorphous solid.
[0484]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.17 (s, 3H), 0.02 (s, 3H), 0.80 (s, 9H), 1.01 (t, 3H, J = 7.5Hz), 1.21 (s, 3H), 1.23 (s, 3H), 1.28 ( s, 9H), 1.55 (t, 1H, J = 7.5Hz), 1.72 (s, 3H), 1.78-1.87 (m, 3H), 2.14 (d, 1H, J = 15.9Hz), 2.11-2.24 (m , 3H), 2.39-2.48 (m, 2H), 2.65 (m, 1H), 2.72 (m, 1H), 2.99 (m, 1H), 3.69 (t, 1H, J = 6.8Hz), 4.06 (d, 1H, J = 8.5Hz), 4.28 (d, 1H, J = 7.6Hz), 4.31 (d, 1H, J = 8.5Hz), 4.72 (s, 2H), 5.03 (d, 1H, J = 10.0Hz) , 5.12 (d, 1H, J = 17.1Hz), 5.23 (d, 1H, J = 10.0Hz), 5.33 (d, 1H, J = 10.0Hz), 5.65 (d, 1H, J = 7.6Hz), 5.83 (m, 1H), 6.21 (m, 2H), 6.37 (m, 1H), 7.37 (s, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz) , 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 946 (MH+)
[0485]
Step 4: 4-O-butanoyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0486]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.15 (s, 3H), 0.02 (s, 3H), 0.80 (s, 9H), 1.01 (t, 3H, J = 7.5Hz), 1.19 (s, 3H), 1.20 (s, 3H), 1.29 ( s, 9H), 1.48 (m, 1H), 1.55 (m, 1H), 1.81 (s, 3H), 1.82 (m, 2H), 2.08-2.20 (m, 3H), 2.30-2.55 (m, 10H) , 2.66-2.72 (m, 2H), 3.70 (s, 4H), 3.75 (m, 1H), 4.06 (d, 1H, J = 8.5Hz), 4.28 (d, 1H, J = 7.3Hz), 4.31 ( d, 1H, J = 8.5Hz), 4.72 (s, 2H), 5.22 (d, 1H, J = 10.0Hz), 5.34 (d, 1H, J = 10.0Hz), 5.64 (d, 1H, J = 7.3 Hz), 6.19 (m, 1H), 6.21 (s, 1H), 6.35 (m, 1H), 7.38 (s, 1H), 7.48 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 1018 (MH+)
[0487]
Step 5: 4-O-butanoyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-4- Deacetyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III The compound obtained in Step 4 above was reacted in the same manner as in Step 9 of Example 1 to give the title compound as colorless Obtained as a solid.
[0488]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.98 (t, 3H, J = 7.5Hz), 1.21 (s, 6H), 1.28 (s, 9H), 1.48 (m, 1H), 1.55 (m, 1H), 1.77 (m, 2H), 1.80 (s , 3H), 1.88 (s, 1H), 2.10 (d, 1H, J = 15.6Hz), 2.20 (m, 2H), 2.30-2.70 (m, 12H), 3.70 (s, 4H), 3.74 (m, 1H), 4.06 (d, 1H, J = 8.5Hz), 4.28 (d, 1H, J = 7.5Hz), 4.29 (d, 1H, J = 8.5Hz), 4.69 (s, 2H), 5.18 (d, 1H, J = 10.0Hz), 5.32 (d, 1H, J = 10.0Hz), 5.64 (d, 1H, J = 7.5Hz), 6.21 (m, 1H), 6.32 (s, 1H), 6.36 (s, 1H), 7.41 (s, 1H), 7.49 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.17 (d, 2H, J = 7.5Hz).
MS-FAB: 904 (MH+)
[0489]
Example 25
[0490]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy- 4-deacetyl-7-deoxy-4-O-ethoxycarbonyl-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 2 of Example 21 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0492]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.10 (s, 3H), 0.77 (s, 9H), 1.22 (s, 3H), 1.24 (s, 3H), 1.31 (s, 9H), 1.33 (m, 3H) , 1.54 (m, 1H), 1.59 (s, 1H), 1.74 (s, 3H), 1.83 (br, 1H), 2.14 (d, 1H, J = 15.9Hz), 2.18-2.27 (m, 3H), 2.42 (dt, 1H, J = 4.5Hz, 15.9Hz), 2.55 (dd, 1H, J = 9.3Hz, 15.5Hz), 3.00 (m, 1H), 3.69 (t, 1H, J = 6.9Hz), 4.11 (d, 1H, J = 8.5Hz), 4.27 (m, 1H), 4.32 (m, 2H), 4.46 (s, 1H), 4.49 (m, 1H), 4.77 (d, 1H, J = 4.0Hz) , 5.03 (d, 1H, J = 10.0Hz), 5.10 (d, 1H, J = 17.1Hz), 5.28 (d, 1H, J = 10.0Hz), 5.43 (d, 1H, J = 10.0Hz), 5.68 (d, 1H, J = 7.6Hz), 5.82 (m, 1H), 6.18 (m, 1H), 7.28-7.40 (m, 5H), 7.46 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 958 (MH+)
[0493]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7 -Deoxy-4-O-ethoxycarbonyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0494]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.12 (s, 3H), 0.77 (s, 9H), 1.20 (s, 3H), 1.21 (s, 3H), 1.31 (s, 9H), 1.35 (m, 3H) , 1.50 (m, 1H), 1.54 (s, 1H), 1.82 (s, 4H), 2.12-2.20 (m, 4H), 2.30-2.59 (m, 9H), 3.70 (s, 4H), 3.75 (m , 1H), 4.10 (m, 1H), 4.29 (m, 1H), 4.33 (m, 2H), 4.46 (s, 1H), 4.52 (m, 1H), 4.79 (s, 1H), 5.29 (m, 1H), 5.42 (m, 1H), 5.68 (d, 1H, J = 7.6Hz), 6.16 (m, 1H), 7.28-7.37 (m, 5H), 7.46 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 1031 (MH+)
[0495]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy-4-O- Ethoxycarbonyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0496]
Melting point: 115-120 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.23 (s, 3H), 1.31 (s, 9H), 1.49 (m, 1H), 1.52 (m, 1H), 1.77 (s, 3H), 1.76 (s, 1H), 2.14 (d, 1H, J = 15.9Hz), 2.20 (m, 3H), 2.31-2.59 (m, 9H), 3.70 (s, 4H), 3.73 (m, 1H), 4.08 (d, 1H, J = 8.5 Hz), 4.10 (m, 1H), 4.32 (m, 3H), 4.58 (s, 1H), 4.78 (s, 1H), 5.26 (m, 1H), 5.36 (m, 1H), 5.68 (d, 1H , J = 7.6Hz), 6.09 (s, 1H), 7.28-7.45 (m, 5H), 7.49 (t, 2H, J = 7.5Hz), 7.59 (t, 1H, J = 7.5Hz), 8.15 (d , 2H, J = 7.5Hz).
MS-FAB: 917 (MH+)
[0497]
Example 26
[0498]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4 -Deacetyl-7-deoxy-4-O-methoxyacetyl-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 2 of Example 22 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0500]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.28 (s, 3H), 0.73 (s, 9H), 1.22 (s, 3H), 1.24 (s, 3H), 1.31 (s, 9H), 1.54 (m, 1H) , 1.58 (s, 1H), 1.76 (s, 3H), 1.79 (br, 1H), 2.14 (m, 2H), 2.22 (m, 2H), 2.43 (dd, 1H, J = 7.7Hz, 15.4Hz) , 2.49 (m, 1H), 2.99 (m, 1H), 3.59 (s, 3H), 3.70 (m, 1H), 4.11 (d, 1H, J = 8.5Hz), 4.12 (d, 1H, J = 16.0 Hz), 4.30 (d, 1H, J = 7.6Hz), 4.31 (d, 1H, J = 8.5Hz), 4.62 (s, 1H), 4.80 (d, 1H, J = 2.5Hz), 4.91 (d, 1H, J = 16.0Hz), 5.03 (d, 1H, J = 10.0Hz), 5.10 (d, 1H, J = 17.1Hz), 5.29 (d, 1H, J = 10.0Hz), 5.68 (d, 1H, J = 7.6Hz), 5.82 (m, 1H), 6.09 (m, 1H), 6.21 (m, 1H), 7.28-7.36 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.57 ( t, 1H, J = 7.5Hz), 8.10 (d, 2H, J = 7.5Hz).
MS-FAB: 958 (MH+)
[0501]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7 -Deoxy-4-O-methoxyacetyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0502]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.28 (s, 3H), 0.73 (s, 9H), 1.19 (s, 3H), 1.20 (s, 3H), 1.31 (s, 9H), 1.49 (m, 1H) , 1.53 (m, 1H), 1.80 (s, 1H), 1.83 (s, 3H), 2.05-2.23 (m, 4H), 2.30-2.60 (m, 9H), 3.59 (s, 3H), 3.70 (s , 4H), 3.78 (m, 1H), 4.09 (d, 1H, J = 8.5Hz), 4.17 (d, 1H, J = 17.3Hz), 4.32 (m, 2H), 4.62 (s, 1H), 4.82 (m, 1H), 4.93 (d, 1H, J = 17.3Hz), 5.29 (d, 1H, J = 10.0Hz), 5.68 (d, 1H, J = 7.6Hz), 6.03 (m, 1H), 6.20 (t, 1H, J = 8.0Hz), 7.35-7.36 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.10 (d, 2H, J = 7.5Hz).
MS-FAB: 1031 (MH+)
[0503]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy-4-O- Methoxyacetyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0504]
Melting point : 115-120 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 6H), 1.31 (s, 9H), 1.49 (m, 1H), 1.55 (m, 1H), 1.80 (s, 4H), 2.14 (d, 1H, J = 15.9Hz), 2.22 (m , 3H), 2.30-2.60 (m, 9H), 3.50 (s, 3H), 3.70 (s, 4H), 3.78 (m, 1H), 4.09 (d, 1H, J = 8.5Hz), 4.12 (m, 1H), 4.30 (s, 2H), 4.64 (m, 1H), 4.68 (s, 1H), 4.78 (s, 1H), 5.31 (br, 1H), 5.55 (d, 1H, J = 10.0Hz), 5.68 (d, 1H, J = 7.6Hz), 6.19 (m, 1H), 7.28-7.43 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz ), 8.10 (d, 2H, J = 7.5Hz).
MS-FAB: 917 (MH+)
[0505]
Example 27
[0506]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4 -Deacetyl-7-deoxy-7β, 8β-methylene-4-O-propionyl-19-norbaccatin III
The compound obtained in Step 2 of Example 23 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0508]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.32 (s, 3H), -0.14 (s, 3H), 0.73 (s, 9H), 1.22 (s, 6H), 1.24 (s, 9H), 1.36 (t, 1H, J = 7.5Hz), 1.54 (m, 1H), 1.62 (s, 1H), 1.72 (s, 3H), 1.84 (br, 1H), 2.08 (m, 1H), 2.20 (m, 3H), 2.41-2.48 (m, 2H), 2.78 (m, 2H), 2.99 (m, 1H), 3.68 (m, 1H), 4.08 (d, 1H, J = 8.5Hz), 4.24 (d, 1H, J = 7.6Hz), 4.31 (d, 1H , J = 8.5Hz), 4.47 (s, 1H), 4.72 (s, 1H), 5.03 (d, 1H, J = 10.0Hz), 5.10 (d, 1H, J = 17.1Hz), 5.29 (m, 1H ), 5.42 (m, 1H), 5.68 (d, 1H, J = 7.6Hz), 5.82 (m, 1H), 6.25 (br, 1H), 7.28-7.40 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.58 (m, 1H), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 942 (MH+)
[0509]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7 -Deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -4-O-propionyl-19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0510]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.32 (s, 3H), -0.14 (s, 3H), 0.75 (s, 9H), 1.20 (s, 3H), 1.23 (s, 3H), 1.26 (s, 9H), 1.36 (t, 1H, J = 7.5Hz), 1.49 (m, 1H), 1.54 (m, 1H), 1.80 (s, 3H), 1.84 (br, 1H), 2.09-2.20 (m, 4H), 2.30-2.56 (m, 9H ), 2.78 (m, 2H), 3.70 (s, 4H), 3.72 (m, 1H), 4.08 (d, 1H, J = 8.5Hz), 4.26 (d, 1H, J = 7.6Hz), 4.31 (d , 1H, J = 8.5Hz), 4.47 (s, 1H), 4.72 (s, 1H), 5.26 (m, 1H), 5.41 (m, 1H), 5.61 (d, 1H, J = 7.6Hz), 6.22 (m, 1H), 7.28-7.40 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz) .
MS-FAB: 1015 (MH+)
[0511]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β- Methylene-10- (2-morpholinoethyl) -4-O-propionyl-19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0512]
Melting point: 120-125 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.23 (s, 3H), 1.25 (m, 3H), 1.26 (s, 9H), 1.49 (m, 1H), 1.54 (m, 1H), 1.78 (s, 3H), 1.87 (s, 1H), 2.09-2.20 (m, 4H), 2.30-2.59 (m, 9H), 2.68 (m, 2H), 3.70 (m, 4H), 3.72 (m, 1H), 4.05 (d, 1H , J = 8.5Hz), 4.22 (d, 1H, J = 7.6Hz), 4.31 (d, 1H, J = 8.5Hz), 4.60 (s, 1H), 4.70 (s, 1H), 5.26 (m, 1H ), 5.64 (d, 1H, J = 7.6Hz), 6.22 (m, 1H), 7.31-7.39 (m, 5H), 7.50 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.17 (d, 2H, J = 7.5Hz).
MS-FAB: 901 (MH+)
[0513]
Example 28
[0514]
Embedded image
Step 1: 10-allyl-4-O-butanoyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 2 of Example 24 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0516]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.32 (s, 3H), -0.12 (s, 3H), 0.73 (s, 9H), 1.04 (t, 3H, J = 7.5Hz), 1.22 (s, 6H), 1.26 (s, 12H), 1.55 (m, 1H), 1.58 (m, 1H), 1.72 (s, 3H), 1.78-1.92 (m, 3H), 2.10-2.25 (m, 4H), 2.41-2.49 (m, 2H), 2.64 (m , 1H), 2.80 (m, 1H), 2.99 (m, 1H), 3.69 (t, 1H, J = 6.7Hz), 4.08 (d, 1H, J = 8.5Hz), 4.29 (d, 1H, J = 7.6Hz), 4.31 (d, 1H, J = 8.5Hz), 4.48 (s, 1H), 4.72 (s, 1H), 5.03 (d, 1H, J = 10.0Hz), 5.10 (d, 1H, J = 17.1Hz), 5.29 (m, 1H), 5.42 (m, 1H), 5.65 (d, 1H, J = 7.6Hz), 5.82 (m, 1H), 6.23 (m, 1H), 7.28-7.40 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 956 (MH+)
[0517]
Step 2: 4-O-butanoyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy -4-deacetyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0518]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.32 (s, 3H), -0.12 (s, 3H), 0.73 (s, 9H), 1.06 (t, 3H, J = 7.5Hz), 1.20 (s, 3H), 1.23 (s, 3H), 1.27 (s, 9H), 1.48 (m, 1H), 1.56 (m, 1H), 1.80 (s, 3H), 1.82-1.98 (m, 3H), 2.08-2.23 (m, 4H), 2.30-2.58 (m , 9H), 2.68 (m, 1H), 2.80 (m, 1H), 3.69 (s, 4H), 3.75 (m, 1H), 4.09 (d, 1H, J = 8.5Hz), 4.29 (d, 1H, J = 7.6Hz), 4.31 (d, 1H, J = 8.5Hz), 4.48 (s, 1H), 4.72 (d, 1H, J = 4.0Hz), 5.29 (m, 1H), 5.41 (d, 1H, J = 8.6Hz), 5.66 (d, 1H, J = 7.6Hz), 6.21 (m, 1H), 7.28-7.40 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 1029 (MH+)
[0519]
Step 3: 4-O-butanoyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7- Deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0520]
Melting point : 115-120 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
0.93 (m, 3H), 1.20 (s, 3H), 1.21 (s, 3H), 1.28 (s, 9H), 1.46 (m, 1H), 1.55 (m, 1H), 1.64-1.75 (m, 2H) , 1.76 (s, 3H), 1.88 (br, 1H), 2.10-2.22 (m, 4H), 2.30-2.60 (m, 9H), 2.65 (m, 2H), 3.70 (s, 4H), 3.72 (m , 1H), 4.05 (d, 1H, J = 8.5Hz), 4.26 (d, 1H, J = 7.6Hz), 4.29 (d, 1H, J = 8.5Hz), 4.60 (s, 1H), 4.70 (s , 1H), 4.76 (br, 1H), 4.79 (br, 1H), 5.64 (d, 1H, J = 7.6Hz), 6.19 (m, 1H), 7.28-7.40 (m, 5H), 7.50 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.17 (d, 2H, J = 7.5Hz).
MS-FAB: 915 (MH+)
[0521]
Example 29
[0522]
Embedded image
Step 1: 10-deacetoxy-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -13-O-triethylsilyl-19-norbaccatin III
The compound obtained in Step 1 of Example 19 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0524]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.66 (6H, q, J = 7.8Hz), 1.01 (9H, t, J = 7.8Hz), 1.12 (3H, s), 1.15 (3H, s), 1.25-1.56 (3H, m), 1.77 (1H , s), 1.89 (3H, d, J = 1.0Hz), 2.27 (3H, s), 2.04-2.63 (12H, m), 3.71 (4H, m), 4.16 (2H, ABq, J = 8.3Hz) , 4.29 (1H, d, J = 8.8Hz), 4.53 (1H, d, J = 3.9Hz), 4.87 (1H, t, J = 7.3Hz), 7.47 (2H, t, J = 7.8Hz), 7.60 (1H, t, J = 7.3Hz), 8.11 (2H, d, J = 6.8Hz).
[0525]
Step 2: 10-deacetoxy-7-deoxy-1-O-dimethylsilyl-7β, 8β-methylene-10- (2-morpholinoethyl) -13-O-triethylsilyl-19-norbaccatin III obtained in step 1 above The compound was reacted in the same manner as in Step 1 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0526]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.22 (d, 3H, J = 2.7Hz), 1.10 (d, 3H, J = 2.7Hz), 0.69 (m, 6H), 1.27 (t, 9H, J = 7.5Hz), 1.09 (s, 3H) , 1.18 (s, 3H), 1.26 (m, 1H), 1.49 (m, 2H), 1.89 (s, 3H), 2.05 (d, 1H, J = 15.9Hz), 2.19 (m, 1H), 2.28 ( s, 3H), 2.35 (m, 4H), 2.46 (m, 6H), 2.53 (m, 1H), 3.68 (m, 1H), 3.71 (m, 4H), 4.12 (d, 1H, J = 8.5Hz ), 4.24 (m, 2H), 4.53 (m, 1H), 4.75 (d, 1H, J = 4.0Hz), 4.91 (t, 1H, J = 8.0Hz), 5.69 (d, 1H, J = 7.8Hz) ), 7.45 (t, 2H, J = 7.5Hz), 7.57 (t, 1H, J = 7.5Hz), 8.10 (m, 2H).
MS-FAB: 796 (MH+)
[0527]
Step 3: 10-deacetoxy-4-deacetyl-7-deoxy-1-O-dimethylsilyl-7β, 8β-methylene-10- (2-morpholinoethyl) -13-O-triethylsilyl-19-norbaccatin III
The compound obtained in Step 2 was reacted in the same manner as in Step 2 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0528]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.24 (d, 3H, J = 2.7Hz), 0.11 (d, 3H, J = 2.7Hz), 0.78 (m, 6H), 1.03 (s, 3H), 1.08 (t, 9H, J = 7.5Hz) , 1.18 (s, 3H), 1.55 (m, 1H), 1.90 (s, 3H), 2.15 (m, 3H), 2.35-2.50 (m, 7H), 2.55 (m, 3H), 2.68 (dd, 1H , J = 2.9Hz, 15.3Hz), 3.49 (s, 1H), 3.70 (m, 5H), 4.00 (d, 1H, J = 7.2Hz), 4.12 (d, 1H, J = 7.5Hz), 4.17 ( d, 1H, J = 7.5Hz), 4.57 (m, 1H), 4.68 (m, 1H), 5.77 (d, 1H, J = 7.2Hz), 7.46 (t, 2H, J = 7.5Hz), 7.58 ( t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 754 (MH+)
[0529]
Step 4: 10-deacetoxy-4-deacetyl-7-deoxy-1-O-dimethylsilyl-7β, 8β-methylene-10- (2-morpholinoethyl) -4-O-propionyl-13-O-triethylsilyl- 19-norbaccatin III
The compound obtained in the above Step 3 was reacted in the same manner except that the cyclopropanecarbonyl chloride in Step 3 of Example 2 was replaced with propionyl chloride to obtain the title compound as a colorless amorphous solid.
[0530]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.24 (d, 3H, J = 2.7Hz), 0.11 (d, 3H, J = 2.7Hz), 0.69 (m, 6H), 1.02 (t, 9H, J = 7.5Hz), 1.09 (s, 3H) , 1.18 (s, 3H), 1.24 (t, 3H, J = 7.5Hz), 1.48 (m, 2H), 2.07 (d, 1H, J = 15.8Hz), 2.17 (m, 1H), 2.34 (m, 3H), 2.46 (m, 7H), 2.54 (m, 1H), 2.62 (m, 2H), 2.67 (m, 1H), 3.68 (t, 1H, J = 6.0Hz), 3.72 (m, 4H), 4.13 (d, 1H, J = 8.3Hz), 4.21 (d, 1H, J = 7.7Hz), 4.24 (d, 1H, J = 8.3Hz), 4.52 (m, 1H), 4.71 (d, 1H, J = 4.0Hz), 4.91 (t, 1H, J = 8.2Hz), 5.69 (d, 1H, J = 7.7Hz), 7.46 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5 Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 810 (MH+)
[0531]
Step 5: 10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -4-O-propionyl-19-norbaccatin III
The compound obtained in Step 4 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0532]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.07 (s, 3H), 1.15 (s, 3H), 1.21 (t, 3H, J = 7.5Hz), 1.52 (m, 1H), 1.92 (s, 3H), 2.10 (d, 1H, J = 15.8Hz ), 2.22 (m, 2H), 2.32-2.70 (m, 13H), 3.70 (m, 5H), 4.03 (d, 1H, J = 8.5Hz), 4.30 (d, 1H, J = 8.5Hz), 4.37 (d, 1H, J = 7.8Hz), 4.71 (d, 1H, J = 3.9Hz), 4.81 (d, 1H, J = 7.5Hz), 5.61 (d, 1H, J = 7.8Hz), 7.48 (t , 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.14 (m, 2H).
MS-FAB: 637 (MH+)
[0533]
Step 6: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 7β, 8β-Methylene-10- (2-morpholinoethyl) -4-O-propionyl-19-norbaccatin III
The compound obtained in the above Step 5 was reacted in the same manner as in Step 5 of Example 10, and then reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0534]
Melting point : 135-140 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 9H), 1.21 (s, 3H), 1.26 (s, 3H), 1.33 (s, 3H), 1.44 (t, 3H, J = 7.5Hz), 1.57 (m, 1H), 1.72 (s , 3H), 2.13 (d, 1H, J = 15.6Hz), 2.18 (m, 2H), 2.30-2.49 (m, 10H), 2.57 (m, 1H), 2.77 (m, 1H), 2.94 (m, 1H), 3.70 (m, 4H), 3.72 (m, 1H), 4.08 (d, 1H, J = 8.3Hz), 4.23 (d, 1H, J = 7.6Hz), 4.33 (d, 1H, J = 8.3 Hz), 4.72 (m, 1H), 4.99 (d, 1H, J = 9.9Hz), 5.49 (d, 1H, J = 9.9Hz), 5.67 (d, 1H, J = 7.6Hz), 6.31 (m, 1H), 7.33-7.40 (m, 5H), 7.50 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.19 (d, 2H, J = 7.5Hz).
MS-FAB: 915 (MH+)
[0535]
Example 30
[0536]
Embedded image
Step 1: 10-allyl-10-deacetoxy-4-deacetyl-4-O-propionyl-13-O-triethylsilyl-7-O-trifluoromethanesulfonylbaccatin III
The compound obtained in Step 7 of Example 6 was reacted in the same manner as in Step 5 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0538]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.65 (m, 6H), 0.99 (m, 9H), 1.13 (s, 3H), 1.10 (s, 3H), 1.13 (s, 3H), 1.28 (t, 3H, J = 7.5Hz), 1.80 (s , 3H), 1.88 (s, 3H), 2.08 (m, 1H), 2.20 (m, 2H), 2.42 (m, 1H), 2.62 (m, 2H), 2.80 (m, 2H), 4.10 (m, 2H), 4.18 (d, 1H, J = 8.3Hz), 4.30 (d, 1H, J = 8.3Hz), 4.90 (m, 2H), 5.00 (d, 1H, J = 10.0Hz), 5.08 (d, 1H, J = 17.0Hz), 5.60 (dd, 1H, J = 7.3Hz, 10.7Hz), 5.65 (d, 1H, J = 7.4Hz), 5.75 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.09 (d, 2H, J = 7.5Hz).
[0539]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-4-O-propionyl-13-O-triethylsilyl-19-norbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 18 of Example 18 to obtain the title compound as a colorless amorphous solid.
[0540]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.65 (m, 6H), 1.00 (t, 9H, J = 7.8Hz), 1.13 (s, 3H), 1.15 (s, 3H), 1.23 (t, 3H, J = 7.4Hz), 1.50 (m, 1H ), 1.80 (s, 3H), 2.08-2.21 (m, 5H), 2.28 (dd, 1H, J = 8.8Hz, 15.1Hz), 2.46 (dt, 1H, J = 4.4Hz, 15.6Hz), 2.60 ( m, 2H), 2.96 (m, 1H), 3.69 (m, 1H), 4.06 (d, 1H, J = 8.5Hz), 4.21 (d, 1H, J = 7.8Hz), 4.29 (d, 1H, J = 8.5Hz), 4.70 (d, 1H, J = 3.9Hz), 4.88 (t, 1H, J = 8.0Hz), 4.99 (d, 1H, J = 9.7Hz), 5.08 (dd, 1H, J = 2.0 Hz, 17.1Hz), 5.57 (d, 1H, J = 7.8Hz), 5.80 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.11 (d, 2H, J = 7.5Hz).
MS-FAB: 678 (MH+)
[0541]
Step 3: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-4-O-propionyl-19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0542]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.15 (s, 3H), 1.26 (t, 3H, J = 7.4Hz), 1.50 (m, 1H), 1.86 (s, 3H), 2.08 (d, 1H, J = 16.1Hz ), 2.21 (m, 3H), 2.31 (dd, 1H, J = 7.3Hz, 15.6Hz), 2.46 (dt, 1H, J = 4.4Hz, 16.1Hz), 2.68 (m, 1H), 2.72 (m, 1H), 2.99 (m, 1H), 3.70 (dd, 1H, J = 6.2Hz, 7.5Hz), 4.05 (d, 1H, J = 8.5Hz), 4.31 (d, 1H, J = 8.5Hz), 4.35 (d, 1H, J = 7.2Hz), 4.70 (d, 1H, J = 3.9Hz), 4.82 (br, 1H), 4.99 (d, 1H, J = 9.7Hz), 5.08 (d, 1H, J = 17.1Hz), 5.60 (d, 1H, J = 7.2Hz), 5.83 (m, 1H), 7.46 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.14 (d , 2H, J = 7.5Hz).
MS-FAB: 564 (MH+)
[0543]
Step 4: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl- 7-Deoxy-7β, 8β-methylene-4-O-propionyl-19-norbaccatin III
The compound obtained in Step 3 above and the compound obtained in Step 2 of Reference Example 3 were reacted in the same manner as in Step 5 of Example 10, and then obtained 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene- 4-O-propionyl-19-norbaccatin III and 10-allyl-13-O- (tert-butoxycarbonyl) -10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-4-O-propionyl- A mixture of 19-norbaccatin III was dissolved in 5 ml of tetrahydrofuran, and 345 ml of tetra-n-butylammonium fluoride (1M tetrahydrofuran solution) was added at 0 ° C. and reacted at the same temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 3: 7 (v / v)) to obtain 50 mg of the title compound as a colorless amorphous solid.
[0544]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.12 (s, 9H), 1.23 (s, 3H), 1.32 (s, 3H), 1.43 (t, 3H, J = 7.3Hz), 1.58 (m, 1H), 1.65 (s, 3H), 2.12 (d , 1H, J = 15.9Hz), 2.17 (m, 2H), 2.42 (m, 3H), 2.73 (m, 1H), 2.98 (m, 2H), 3.59 (br, 1H), 3.68 (m, 1H) , 4.05 (d, 1H, J = 8.5Hz), 4.21 (d, 1H, J = 7.8Hz), 4.32 (d, 1H, J = 8.5Hz), 4.70 (d, 1H, J = 3.9Hz), 4.98 (m, 2H), 5.06 (d, 1H, J = 17.1Hz), 5.50 (d, 1H, J = 9.8Hz), 5.62 (d, 1H, J = 7.8Hz), 5.78 (m, 1H), 6.31 (m, 1H), 7.33 (m, 5H), 7.49 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.19 (d, 2H, J = 7.5Hz).
MS-FAB: 842 (MH+)
[0545]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 7β, 8β-Methylene-10- (2-morpholinoethyl) -4-O-propionyl-19-norbaccatin III
The compound obtained in Step 4 above was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound (compound obtained in Step 6 of Example 29) as a colorless solid.
[0546]
Example 31
[0547]
Embedded image
Step 1: 10-deacetoxy-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 1 of Example 29 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0549]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.11 (s, 3H), 1.52 (m, 1H), 1.92 (s, 3H), 2.00-2.10 (m, 2H), 2.18 (m, 1H), 2.23 (m, 1H) , 2.30-2.60 (m, 10H), 3.68 (m, 4H), 3.71 (m, 1H), 4.02 (d, 1H, J = 8.3Hz), 4.28 (d, 1H, J = 7.6Hz), 4.36 ( d, 1H, J = 8.3Hz), 4.71 (m, 1H), 4.80 (t, 1H, J = 7.5Hz), 5.60 (d, 1H, J = 7.6Hz), 7.49 (t, 2H, J = 7.5 Hz), 7.60 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 623 (MH+)
[0550]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-7-deoxy-7β, 8β- Methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 5 of Example 10, and then reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0551]
Melting point : 140-145 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (s, 9H), 1.19 (s, 3H), 1.21 (s, 3H), 1.30 (s, 3H), 1.59 (m, 1H), 1.70 (s, 3H), 2.10 (d, 1H, J = 15.6Hz), 2.17 (m, 2H), 2.30-2.45 (m, 10H), 2.57 (m, 2H), 2.60 (s, 3H), 2.30-2.45 (m, 10H), 3.65 (m, 4H), 3.70 (m, 1H), 4.02 (d, 1H, J = 8.3Hz), 4.26 (d, 1H, J = 7.6Hz), 4.30 (d, 1H, J = 8.3Hz), 4.76 (m, 1H), 5.00 (d, 1H, J = 9.9Hz), 5.49 (d, 1H, J = 9.9Hz), 5.63 (d, 1H, J = 7.6Hz), 6.31 (m, 1H), 7.31 (m, 5H), 7.49 (t, 2H, J = 7.5Hz), 7.53 (t, 1H, J = 7.5Hz), 8.16 (d, 2H, J = 7.5Hz).
MS-FAB: 901 (MH+)
[0552]
Example 32
[0553]
Embedded image
Step 1: 10-deacetoxy-4-deacetyl-7-deoxy-1-O-dimethylsilyl-4-O-ethoxycarbonyl-7β, 8β-methylene-10- (2-morpholinoethyl) -13-O-triethylsilyl -19-Norbaccatin III
The compound obtained in Step 3 of Example 29 was reacted in the same manner as in Step 3 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0555]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.24 (d, 3H, J = 2.7Hz), 0.11 (d, 3H, J = 2.7Hz), 0.69 (m, 6H), 1.02 (t, 9H, J = 7.5Hz), 1.09 (s, 3H) , 1.18 (s, 3H), 1.40 (t, 3H, J = 7.2Hz), 1.50 (m, 1H), 1.72 (br, 1H), 1.90 (s, 3H), 2.10 (d, 1H, J = 15.8 Hz), 2.17 (m, 1H), 2.30-2.60 (m, 12H), 3.68 (t, 1H, J = 4.5Hz), 3.72 (m, 4H), 4.13 (m, 1H), 4.24 (d, 1H , J = 8.5Hz), 4.29 (d, 1H, J = 7.7Hz), 4.40 (m, 1H), 4.53 (m, 1H), 4.75 (d, 1H, J = 4.0Hz), 4.91 (t, 1H , J = 8.0Hz), 5.69 (d, 1H, J = 7.7Hz), 7.46 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 826 (MH+)
[0556]
Step 2: 10-deacetoxy-4-deacetyl-7-deoxy-4-O-ethoxycarbonyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0557]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.15 (s, 3H), 1.38 (t, 3H, J = 7.3Hz), 1.50 (m, 2H), 1.94 (s, 3H), 2.12 (d, 1H, J = 15.6Hz ), 2.19 (m, 1H), 2.28-2.55 (m, 12H), 3.71 (m, 4H), 3.76 (m, 1H), 4.03 (d, 1H, J = 8.7Hz), 4.20 (m, 1H) , 4.30 (m, 2H), 4.41 (d, 1H, J = 7.8Hz), 4.79 (m, 2H), 5.61 (d, 1H, J = 7.8Hz), 7.49 (t, 2H, J = 7.5Hz) , 7.60 (t, 1H, J = 7.5Hz), 8.14 (m, 2H).
[0558]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 4-O-Ethoxycarbonyl-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 5 of Example 10, and then reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0559]
Melting point : 130-135 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.21 (s, 3H), 1.26 (s, 3H), 1.27 (s, 9H), 1.39 (m, 3H), 1.48 (m, 1H), 1.52 (m, 1H), 1.70 (s, 3H), 2.13 (d, 1H, J = 16.1Hz), 2.20-2.48 (m, 12H), 2.53 (m, 1H), 3.69 (m, 4H), 3.72 (m, 1H), 4.09 ( m, 1H), 4.12 (m, 1H), 4.29 (d, 1H, J = 6.9Hz), 4.35 (d, 1H, J = 8.8Hz), 4.43 (m, 1H), 4.79 (s, 1H), 5.04 (d, 1H, J = 9.9Hz), 5.65 (d, 1H, J = 10.3Hz), 5.67 (d, 1H, J = 6.9Hz), 6.11 (br, 1H), 7.29-7.40 (m, 5H ), 7.47 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.14 (d, 2H, J = 7.5Hz).
MS-FAB: 931 (MH+)
[0560]
Example 33
[0561]
Embedded image
10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-7-deoxy-7β, 8β-methylene-19 -Norbaccatin III
The compound obtained in Step 5 of Example 18 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0563]
Melting point : 130-135 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.24 (s, 3H), 1.26 (s, 3H), 1.27 (s, 9H), 1.55 (m, 1H), 1.71 (s, 3H), 2.08 (d, 1H, J = 16.1Hz), 2.20 (m , 2H), 2.38 (s, 3H), 2.40 (m, 2H), 2.99 (m, 1H), 3.30 (br, 1H), 3.69 (dd, 1H, J = 6.0Hz, 8.0Hz), 4.03 (d , 1H, J = 8.5Hz), 4.21 (d, 1H, J = 7.8Hz), 4.29 (d, 1H, J = 8.5Hz), 4.59 (s, 1H), 4.73 (d, 1H, J = 3.5Hz ), 5.00 (d, 1H, J = 10.0Hz), 5.12 (d, 1H, J = 17.0Hz), 5.28 (m, 1H), 5.38 (d, 1H, J = 9.0Hz), 5.65 (d, 1H , J = 6.8Hz), 5.80 (m, 1H), 6.25 (m, 1H), 7.28-7.36 (m, 5H), 7.48 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.12 (d, 2H, J = 7.5Hz).
MS-FAB: 813 (MH+)
[0564]
Example 34
[0565]
Embedded image
Step 1: 10-allyl-10-deacetoxy-4-deacetyl-4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O-triethylsilylbaccatin III
400 mg of the compound obtained in Step 2 of Example 7 was reacted in the same manner as in Step 1 of Example 23 to introduce a propionyl group at the 4-position. The obtained compound was reacted in the same manner as in Step 4 of Example 2, and purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 95: 5 (v / v)) to obtain 10-allyl-10-deacetoxy- 4-deacetyl-4-O-propionylbaccatin III was obtained. This was dissolved in 6 ml of dry N, N-dimethylformamide, 140 mg of imidazole and 0.345 ml of triethylsilane chloride were added at 0 ° C., and the mixture was reacted at the same temperature for 60 minutes. The reaction solution was diluted with ethyl acetate, washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 12 ml of dried pyridine, 0.345 ml of 2,2,2-trichloroethyl chloroformate was added, and the mixture was stirred at 60 ° C. for 1 hour. The mixture was diluted with ethyl acetate at 0 ° C., washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 8: 2 (v / v)) to obtain 372 mg of the title compound as a colorless amorphous solid.
[0567]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.57 (m, 6H), 0.97 (t, 9H, J = 7.5Hz), 1.16 (s, 6H), 1.31 (t, 3H, J = 7.5Hz), 1.62 (s, 3H), 1.85 (s, 3H ), 1.89 (m, 1H), 2.31 (m, 1H), 2.37 (m, 1H), 2.50 (m, 2H), 2.70 (m, 2H), 2.81 (m, 1H), 3.91 (dd, 1H, J = 4.3Hz, 10.4Hz), 4.01 (d, 1H, J = 7.1Hz), 4.18 (d, 1H, J = 8.5Hz), 4.30 (d, 1H, J = 8.5Hz), 4.58 (dd, 1H , J = 6.5Hz, 10.7Hz), 4.85 (AB type d, 2H, J = 11.9Hz), 4.91 (dd, 1H, J = 2.0Hz, 9.5Hz), 5.02 (dd, 1H, J = 1.6Hz, 9.9Hz), 5.10 (dd, 1H, J = 1.6Hz, 16.9Hz), 5.63 (d, 1H, J = 7.2Hz), 5.77 (m, 1H), 5.98 (m, 1H), 7.47 (t, 2H , J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.10 (d, 2H, J = 7.5Hz).
MS-FAB: 871 (MH+)
[0568]
Step 2: 10-deacetoxy-4-deacetyl-10- (2-hydroxyethyl) -4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O-triethylsilylbaccatin III
11.4 g of the compound obtained in the above step 1 is dissolved in a mixed solvent of 150 ml of tetrahydrofuran, 100 ml of methanol and 50 ml of water, 7.67 g of N-methylmorpholine-N-oxide, an osmium tetroxide aqueous solution (0.1 M solution) ) 13 ml was added and stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium thiosulfate solution, 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in a mixed solvent of 100 ml of tetrahydrofuran, 100 ml of methanol, and 100 ml of water, 14 g of sodium metaperiodate was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed successively with water, a saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 230 ml of dried methanol, 495 mg of sodium borohydride was added at 0 ° C and stirred at the same temperature for 30 minutes, and 495 ml of sodium borohydride was added at 0 ° C. And stirred at the same temperature for 30 minutes. The reaction was diluted with ethyl acetate and poured into cold saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 8: 2 (v / v)) to obtain 7.91 g of the title compound as a colorless amorphous solid.
[0569]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.60 (m, 6H), 0.99 (s, 9H), 1.14 (s, 6H), 1.32 (m, 3H), 1.65 (s, 3H), 1.90 (m, 3H), 1.95 (s, 3H), 2.31 (m, 1H), 2.40 (m, 1H), 2.51 (m, 1H), 2.70 (m, 2H), 3.61 (m, 1H), 3.73 (m, 1H), 4.06 (m, 2H), 4.18 ( d, 1H, J = 8.5Hz), 4.32 (d, 1H, J = 8.5Hz), 4.59 (dd, 1H, J = 6.5Hz, 10.7Hz), 4.82 (AB type d, 2H, J = 12.0Hz) , 4.91 (d, 1H, J = 9.7Hz), 5.63 (d, 1H, J = 7.3Hz), 5.99 (t, 1H, J = 8.3Hz), 7.47 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.11 (m, 2H).
MS-FAB: 875 (MH+)
[0570]
Step 3: 10-deacetoxy-4-deacetyl-4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O-triethylsilyl-10-vinylbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 4 of Example 6 and then in the same manner as in Step 5 of Example 6 to obtain the title compound as a colorless amorphous solid.
[0571]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.56 (m, 6H), 0.94 (t, 9H, J = 7.8Hz), 1.04 (s, 3H), 1.16 (s, 3H), 1.33 (t, 3H, J = 7.5Hz), 1.65 (s, 3H ), 1.90 (d, 3H, J = 1.0Hz), 1.91 (m, 1H), 2.32 (m, 1H), 2.38 (m, 1H), 2.49 (m, 1H), 2.71 (m, 2H), 4.08 (d, 1H, J = 7.3Hz), 4.16 (d, 1H, J = 8.3Hz), 4.32 (d, 1H, J = 8.3Hz), 4.51 (d, 1H, J = 2.5Hz), 4.56 (dd , 1H, J = 6.3Hz, 10.7Hz), 4.86 (AB type d, 2H, J = 12.0Hz), 4.90 (d, 1H, J = 9.0Hz), 5.06 (d, 1H, J = 17.5Hz), 5.25 (m, 1H), 5.63 (d, 1H, J = 7.3Hz), 6.04 (t, 1H, J = 8.0Hz), 6.60 (m, 1H), 7.47 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.10 (m, 2H).
MS-FAB: 857 (MH+)
[0572]
Step 4: 10-deacetoxy-4-deacetyl-10-formyl-4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O-triethylsilylbaccatin III
4.5 g of the compound obtained in the above step 3 is dissolved in a mixed solvent of 80 ml of tetrahydrofuran, 80 ml of methanol and 80 ml of water, 3.07 g of N-methylmorpholine-N-oxide, an osmium tetroxide aqueous solution (0.1 M solution) 15.7 ml was added and stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium thiosulfate solution, 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in a mixed solvent of 80 ml of tetrahydrofuran, 80 ml of methanol and 80 ml of water, 5.6 g of sodium metaperiodate was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed successively with water, a saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 9: 1 (v / v)) to obtain 3.09 g of the title compound as a colorless amorphous solid.
[0573]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.60 (m, 6H), 0.96 (s, 3H), 0.97 (m, 9H), 1.05 (s, 3H), 1.32 (t, 3H, J = 7.5Hz), 1.62 (s, 3H), 1.84 (s , 3H), 1.91 (m, 1H), 2.32 (m, 2H), 2.52 (m, 1H), 2.70 (m, 2H), 3.48 (m, 1H), 3.95 (d, 3H, J = 6.8Hz) , 4.19 (m, 1H), 4.32 (d, 1H, J = 8.3Hz), 4.60 (dd, 1H, J = 6.3Hz, 10.5Hz), 4.84 (AB type d, 2H, J = 12.0Hz), 4.90 (m, 1H), 5.63 (d, 1H, J = 5.6Hz), 6.04 (t, 1H, J = 8.0Hz), 7.47 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.10 (m, 2H), 10.23 (s, 1H).
MS-FAB: 859 (MH+)
[0574]
Step 5: 10-deacetoxy-4-deacetyl-10-morpholinomethyl-4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O-triethylsilylbaccatin III
3.08 g of the compound obtained in the above Step 4 was dissolved in 308 ml of dry ethanol, and 0.624 ml of morpholine and 0.41 ml of acetic acid were added at -20 ° C. To this solution, 55 mg of sodium cyanoborohydride was added in 4 portions at 5-minute intervals. After stirring at -20 ° C for 25 minutes, 0.936 ml of morpholine and 0.625 ml of acetic acid were added at -20 ° C and stirred at 6 ° C for 15 hours. Sodium cyanoborate 225 mg was further added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate at 0 ° C., washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 8: 2 (v / v)) to obtain 1.51 g of the title compound as a colorless amorphous solid.
[0575]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.60 (m, 6H), 0.97 (t, 9H, J = 7.5Hz), 1.12 (s, 3H), 1.18 (s, 3H), 1.32 (t, 3H, J = 7.5Hz), 1.62 (s, 3H ), 1.88 (m, 1H), 1.98 (s, 3H), 2.30-2.40 (m, 2H), 2.49 (m, 4H), 2.70 (m, 4H), 3.15 (dd, 1H, J = 3.5Hz, 13.5Hz), 3.64 (m, 4H), 4.05 (d, 1H, J = 7.3Hz), 4.08-4.16 (m, 2H), 4.32 (d, 1H, J = 8.3Hz), 4.60 (dd, 1H, J = 6.5Hz, 10.5Hz), 4.84 (AB type d, 2H, J = 11.7Hz), 4.90 (d, 1H, J = 10.0Hz), 5.61 (d, 1H, J = 6.8Hz), 5.96 (t , 1H, J = 8.0Hz), 7.47 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.10 (d, 2H, J = 7.5Hz).
MS-FAB: 930 (MH+)
[0576]
Step 6: 10-deacetoxy-4-deacetyl-10-morpholinomethyl-4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) baccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0577]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.12 (s, 3H), 1.32 (t, 3H, J = 7.5Hz), 1.72 (s, 3H), 1.82 (m, 1H), 1.91 (s, 3H), 2.10 (m , 1H), 2.32 (m, 3H), 2.59 (m, 4H), 2.70 (m, 2H), 3.40 (dd, 1H, J = 8.0Hz, 13.0Hz), 3.61 (m, 4H), 4.00 (m , 2H), 4.19 (d, 1H, J = 8.5Hz), 4.31 (d, 1H, J = 8.5Hz), 4.49 (m, 1H), 4.82 (AB type d, 2H, J = 11.7Hz), 4.94 (d, 1H, J = 7.8Hz), 5.61 (d, 1H, J = 7.3Hz), 5.96 (m, 1H), 7.47 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.10 (d, 2H, J = 7.5Hz).
[0578]
Step 7: 10-deacetoxy-4-deacetyl-10-morpholinomethyl-4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O-trifluoromethanesulfonylbaccatin III
The compound obtained in the above Step 6 was reacted in the same manner as in Step 5 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0579]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.12 (s, 3H), 1.19 (s, 3H), 1.31 (t, 3H, J = 7.3Hz), 1.79 (s, 3H), 1.99 (s, 3H), 2.20 (m, 1H), 2.35 (m , 2H), 2.42 (m, 2H), 2.59 (m, 2H), 2.70 (m, 3H), 2.81 (m, 1H), 3.18 (dd, 1H, J = 4.0Hz, 14.0Hz), 3.62 (m , 4H), 4.19 (m, 2H), 4.27 (dd, 1H, J = 4.3Hz, 8.3Hz), 4.35 (d, 1H, J = 8.3Hz), 4.86 (AB type d, 2H, J = 12.0Hz ), 4.88 (m, 1H), 5.66 (m, 1H), 5.98 (t, 1H, J = 8.3Hz), 7.49 (t, 2H, J = 7.5Hz), 7.63 (t, 1H, J = 7.5Hz) ), 8.08 (d, 2H, J = 7.5Hz).
MS-FAB: 948 (MH+)
[0580]
Step 8: 10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-10-morpholinomethyl-4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) -19- Norbaccatin III
The compound obtained in the above Step 7 was reacted in the same manner as in Step 3 of Example 18 to obtain the title compound as a colorless amorphous solid.
[0581]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.16 (s, 3H), 1.28 (t, 3H, J = 7.3Hz), 1.51 (dd, 1H, J = 5.4Hz, 6.8Hz), 1.91 (s, 3H), 1.95 ( s, 1H), 2.10 (d, 1H, J = 16.1Hz), 2.18 (m, 1H), 2.35-2.50 (m, 8H), 2.60-2.72 (m, 2H), 3.36 (dd, 1H, J = 4.4Hz, 13.2Hz), 3.64 (m, 4H), 3.80 (t, 1H, J = 5.4Hz), 4.03 (d, 1H, J = 8.3Hz), 4.31 (d, 1H, J = 8.3Hz), 4.35 (d, 1H, J = 7.8Hz), 4.69 (d, 1H, J = 3.9Hz), 4.82 (d, 1H, J = 12.2Hz), 4.88 (d, 1H, J = 12.2Hz), 5.60 ( d, 1H, J = 7.8Hz), 5.90 (t, 1H, J = 7.8Hz), 7.49 (t, 2H, J = 7.5Hz), 7.63 (t, 1H, J = 7.5Hz), 8.11 (m, 2H).
MS-FAB: 799 (MH+)
[0582]
Step 9: 10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β-methylene-10-morpholinomethyl-4-O-propionyl-19-norbaccatin III
The compound obtained in Step 8 was reacted in the same manner as in Step 4 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0583]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.26 (t, 3H, J = 7.3Hz), 1.52 (m, 1H), 1.80 (s, 1H), 1.96 (s, 3H), 2.10 (d, 1H, J = 16.1Hz ), 2.22 (m, 2H), 2.32 (m, 2H), 2.45-2.70 (m, 7H), 3.32 (dd, 1H, J = 4.9Hz, 12.7Hz), 3.65 (m, 4H), 3.80 (m , 1H), 4.05 (d, 1H, J = 8.8Hz), 4.30 (d, 1H, J = 8.8Hz), 4.38 (d, 1H, J = 7.8Hz), 4.71 (s, 1H), 4.79 (br , 1H), 5.59 (d, 1H, J = 7.8Hz), 7.49 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5Hz), 8.14 (d, 2H, J = 7.5Hz) ).
MS-FAB: 623 (MH+)
[0584]
Step 10: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7 -Deoxy-7β, 8β-methylene-10-morpholinomethyl-4-O-propionyl-19-norbaccatin III
The compound obtained in the above Step 9 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0585]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.31 (s, 3H), -0.13 (s, 3H), 0.75 (s, 9H), 1.18 (s, 3H), 1.26 (s, 3H), 1.28 (s, 9H), 1.37 (t, 3H, J = 7.5Hz), 1.54 (m, 1H), 1.81 (s, 3H), 1.92 (br, 1H), 2.14 (d, 1H, J = 16.1Hz), 2.18 (m, 2H), 2.36 (dd, 1H, J = 5.0Hz, 13.1Hz), 2.46 (m, 2H), 2.53 (m, 4H), 2.79 (m, 2H), 3.37 (dd, 1H, J = 5.2Hz, 13.1Hz), 3.66 (m , 4H), 3.78 (m, 1H), 4.07 (d, 1H, J = 8.5Hz), 4.28 (d, 1H, J = 7.8Hz), 4.34 (d, 1H, J = 8.5Hz), 4.48 (s , 1H), 4.72 (d, 1H, J = 3.9Hz), 5.26 (br, 1H), 5.47 (d, 1H, J = 9.3Hz), 5.66 (d, 1H, J = 7.8Hz), 6.24 (t , 1H, J = 8.8Hz), 7.29-7.40 (m, 5H), 7.49 (t, 2H, J = 7.5Hz), 7.58 (t, 1H, J = 7.5Hz), 8.15 (d, 2H, J = 7.5Hz).
MS-FAB: 1001 (MH+)
[0586]
Step 11: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy-7β, 8β- Methylene-10-morpholinomethyl-4-O-propionyl-19-norbaccatin III
The compound obtained in Step 10 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0587]
Melting point : 150-155 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.16 (s, 3H), 1.24 (s, 3H), 1.26 (m, 3H), 1.27 (s, 9H), 1.52 (m, 1H), 1.79 (s, 3H), 1.92 (s, 1H), 2.08 (d, 1H, J = 16.1Hz), 2.19 (m, 2H), 2.38-2.42 (m, 4H), 2.50 (m, 4H), 2.65 (m, 2H), 3.35 (dd, 1H, J = 5.0 Hz, 13.1Hz), 3.65 (m, 4H), 3.76 (m, 1H), 4.04 (d, 1H, J = 8.8Hz), 4.23 (d, 1H, J = 7.8Hz), 4.31 (d, 1H, J = 8.8Hz), 4.61 (br, 1H), 4.69 (d, 1H, J = 3.9Hz), 5.26 (br, 1H), 5.34 (d, 1H, J = 9.3Hz), 5.62 (d, 1H, J = 7.8Hz), 6.23 (br, 1H), 7.31-7.41 (m, 5H), 7.51 (t, 2H, J = 7.5Hz), 7.60 (t, 1H, J = 7.5Hz), 8.16 (d, (2H, J = 7.5Hz).
MS-FAB: 887 (MH+)
[0588]
Example 35
[0589]
Embedded image
Step 1: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-6,7-didehydro-1-O-dimethylsilyl-4-O- (ethoxycarbonyl) -13-O-triethylsilylbaccatin III
The compound obtained in Step 2 of Example 2 was reacted in the same manner as in Step 3 of Example 2 using ethyl chloroformate instead of cyclopropanecarbonyl chloride to obtain the title compound as a colorless amorphous solid.
[0591]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.26 (d, 3H, J = 3 Hz), 0.09 (d, 3H, J = 3 Hz), 0.68 (m, 6H), 1.02 (t, 9H, J = 7 Hz), 1.08 (s, 3H) , 1.13 (s, 3H), 1.39 (t, 3H, J = 7 Hz), 1.80 (s, 3H), 1.84 (s, 3H), 2.20 (m, 1H), 2.30 (d, 1H, J = 9 Hz), 2.99 (m, 1H), 3.61 (t, 1H, J = 7 Hz), 4.14 (m, 2H), 4.36 (m, 2H), 4.59 (m, 1H), 4.99 (m, 2H), 5.09 (m, 2H), 5.72 (d, 1H, J = 10 Hz), 5.83 (m, 1H), 5.85 (d, 1H, J = 7 Hz), 6.00 (dd, 1H, J = 6, 10 Hz ), 7.48 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.15 (d, 2H, J = 8 Hz).
MS-FAB: 753 (MH+).
[0592]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-6,7-didehydro-4-O- (ethoxycarbonyl) baccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0593]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.08 (s, 3H), 1.10 (s, 3H), 1.39 (t, 3H, J = 7 Hz), 1.82 (s, 3H), 1.85 (d, 3H, J = 1.5 Hz), 2.05 (s, 3H ), 2.23-2.32 (m, 2H), 2.36 (dd, 1H, J = 7, 16 Hz), 2.99 (m, 1H), 3.68 (m, 1H), 4.22 (m, 1H), 4.29 (m, 2H), 4.33 (m, 1H), 4.52 (d, 1H, J = 8 Hz), 4.82 (br, 1H), 5.02 (d, 1H, J = 10 Hz), 5.10 (dd, 1H, J = 1.5 , 17 Hz), 5.19 (d, 1H, J = 6 Hz), 5.77 (d, 1H, J = 10 Hz), 5.82 (d, 1H, J = 7 Hz), 5.83 (m, 1H), 6.01 ( dd, 1H, J = 6, 10 Hz), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.14 (m, 2H).
MS-FAB: 580 (MH+).
[0594]
Step 3: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4 -Deacetyl-7-deoxy-6,7-didehydro-4- O- (ethoxycarbonyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0595]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.33 (s, 3H), -0.12 (s, 3H), 0.74 (s, 9H), 1.12 (s, 3H), 1.26 (s, 3H), 1.33 (m, 3H), 1.35 (s, 9H) , 1.72 (s, 3H), 1.88 (s, 3H), 2.18 (m, 1H), 2.28 (m, 1H), 2.58 (dd, 1H, J = 7, 15 Hz), 2.99 (m, 1H), 3.65 (t, 1H, J = 7 Hz), 4.21 (d, 1H, J = 7 Hz), 4.32 (m, 1H), 4.38 (d, 1H, J = 9 Hz), 4.45-4.53 (m, 3H ), 5.02 (d, 1H, J = 10 Hz), 5.03 (dd, 1H, J = 1.5, 17 Hz), 5.19 (d, 1H, J = 5 Hz), 5.36 (d, 1H, J = 10 Hz) ), 5.46 (d, 1H, J = 10 Hz), 5.80 (d, 1H, J = 10 Hz), 5.86 (m, 1H), 5.89 (d, 1H, J = 7 Hz), 6.02 (dd, 1H , J = 6, 10 Hz), 6.19 (t, 1H, J = 8 Hz), 7.29-7.38 (m, 5H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.18 (d, 2H, J = 8 Hz).
MS-FAB: 958 (MH+).
[0596]
Step 4: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7 -Deoxy-6,7-didehydro-4-O- (ethoxycarbonyl) -10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0597]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.33 (s, 3H), -0.12 (s, 3H), 0.74 (s, 9H), 1.12 (s, 3H), 1.24 (s, 3H), 1.33 (m, 3H), 1.35 (s, 9H) , 1.79 (s, 3H), 1.88 (s, 4H), 2.10-2.64 (m, 11H), 3.69 (m, 4H), 3.80 (dd, 1H, J = 5, 7 Hz), 4.21 (d, 1H , J = 7 Hz), 4.32 (m, 1H), 4.38 (d, 1H, J = 8 Hz), 4.49-4.54 (m, 3H), 5.20 (d, 1H, J = 6 Hz), 5.37 (br , 1H), 5.47 (d, 1H, J = 10 Hz), 5.77 (d, 1H, J = 10 Hz), 5.89 (d, 1H, J = 7 Hz), 6.33 (dd, 1H, J = 6, 10 Hz), 6.16 (t, 1H, J = 8 Hz), 7.29-7.38 (m, 5H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.18 (d, 2H, J = 8 Hz).
MS-FAB: 1031 (MH+).
[0598]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy-6,7- Didehydro-4-O- (ethoxycarbonyl) -10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 4 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0599]
Melting point: 115-120 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (s, 3H), 1.20 (s, 3H), 1.26 (t, 3H, J = 7 Hz), 1.37 (s, 9H), 1.68 (s, 3H), 1.80 (s, 1H), 1.83 (s , 3H), 2.25-2.60 (m, 11H), 3.68 (m, 4H), 3.79 (m, 1H), 4.10 (m, 1H), 4.19 (m, 1H), 4.31 (d, 1H, J = 8 Hz), 4.38 (m, 1H), 4.60 (m, 2H), 5.21 (m, 1H), 5.28 (br, 1H), 5.48 (d, 1H, J = 10 Hz), 5.74 (d, 1H, J = 10 Hz), 6.08 (t, 1H, J = 8 Hz), 7.29-7.46 (m, 5H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.11 (d, 2H, J = 8 Hz).
MS-FAB: 917 (MH+).
[0600]
Example 36
[0601]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3-phenyl-2- (triethylsilyl) oxypropionyl] -10-deacetoxy- 4-deacetyl-7-deoxy-6,7-didehydro-4-O- (ethoxycarbonyl) baccatin III
The compound obtained in Step 2 of Example 35 was reacted in the same manner as in Step 1 of Example 4 to obtain the title compound as a colorless amorphous solid.
[0603]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.47-0.69 (m, 6H), 0.85 (t, 9H, J = 7 Hz), 1.12 (s, 3H), 1.24 (s, 3H), 1.28 (s, 9H), 1.39 (t, 3H, J = 7 Hz), 1.41 (s, 3H), 1.71 (s, 3H), 1.89 (s, 3H), 2.13-2.29 (m, 2H), 2.54-2.60 (m, 1H), 2.96-3.03 (m, 1H ), 3.66 (t, 1H, J = 7 Hz), 4.24 (d, 1H, J = 7 Hz), 4.43 (d, 1H, J = 8 Hz), 4.50 (d, 1H, J = 8 Hz), 4.57-4.67 (m, 2H), 5.03-5.19 (m, 3H), 5.55 (d, 1H, J = 10 Hz), 5.78 (d, 1H, J = 10 Hz), 5.81-5.91 (m, 1H) , 6.02 (dd, 1H, J = 6, 10 Hz), 6.26 (t, 1H, J = 8 Hz), 7.28-7.47 (m, 7H), 7.57 (t, 1H, J = 8 Hz), 8.15 ( d, 2H, J = 8 Hz).
[0604]
Step 2: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl- 7-Deoxy-6,7-didehydro-4-O- (ethoxycarbonyl) baccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0605]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.13 (s, 3H), 1.24 (s, 3H), 1.33 (s, 9H), 1.39 (t, 3H, J = 7 Hz), 1.41 (s, 3H), 1.59 (s, 3H), 1.86 (s , 3H), 2.22-2.32 (m, 2H), 2.54-2.60 (m, 1H), 2.95-3.02 (m, 1H), 3.61-3.64 (m, 2H), 4.12 (d, 1H, J = 7 Hz ), 4.35 (d, 1H, J = 8 Hz), 4.45-4.50 (m, 2H), 4.47 (d, 1H, J = 8 Hz), 5.02-5.13 (m, 3H), 5.69 (d, 1H, J = 10 Hz), 5.75-5.85 (m, 2H), 5.87 (d, 1H, J = 7 Hz), 6.02 (dd, 1H, J = 6, 10 Hz), 6.17 (t, 1H, J = 8 Hz), 7.28-7.48 (m, 7H), 7.60 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
[0606]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 6,7-didehydro-4-O- (ethoxycarbonyl) -10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0607]
Melting point: 125-130 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (s, 3H), 1.20 (s, 3H), 1.30 (s, 9H), 1.36 (t, 3H, J = 7.5 Hz), 1.62 (s, 3H), 1.80 (s, 3H), 2.20-2.60 (m, 10H), 3.65 (s, 4H), 3.79 (m, 1H), 4.10 (m, 1H), 4.32 (d, 1H, J = 8.5 Hz), 4.48 (m, 2H), 4.62 (d, 1H, J = 8.5 Hz), 5.09 (d, 1H, J = 10 Hz), 5.28 (d, 1H, J = 5 Hz), 5.70 (d, 1H, J = 10 Hz), 5.76 (d, 1H, J = 10 Hz), 5.85 (d, 1H, J = 7 Hz), 6.01 (dd, 1H, J = 5, 10 Hz), 6.13 (br, 1H), 7.29-7.42 (m, 5H), 7.46 ( t, 2H, J = 7.5 Hz), 7.59 (t, 1H, J = 7.5 Hz), 8.09 (d, 2H, J = 7.5 Hz)
MS-FAB: 931 (MH+).
[0608]
Example 37
[0609]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3-phenyl-2- (trimethylsilyl) oxypropionyl] -10-deacetoxy-7 -Deoxy-7α-fluorobaccatin III
The compound obtained in Step 4 of Example 5 was reacted in the same manner as in Step 1 of Example 4 to obtain the title compound as a colorless amorphous solid.
[0611]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.09 (s, 9H), 1.11 (s, 3H), 1.18 (s, 9H), 1.28 (s, 3H), 1.37 (s, 3H), 1.62 (s, 3H), 1.71 (s, 3H), 2.32 (s, 3H), 2.08-3.03 (m, 6H), 4.06 (t, 1H, J = 7 Hz), 4.20 (d, 1H, J = 7 Hz), 4.38 (s, 2H), 4.56 (dd, 1H, J = 3, 47Hz), 4.99-5.12 (m, 4H), 5.50 (d, 1H, J = 10 Hz), 5.74-5.81 (m, 2H), 6.35 (t, 1H, J = 8 Hz) , 7.29-7.41 (m, 5H), 7.50 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.18 (d, 2H, J = 8 Hz).
[0612]
Step 2: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-7-deoxy- 7α-Fluorobaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0613]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.12 (s, 3H), 1.22 (s, 9H), 1.26 (s, 3H), 1.34 (s, 3H), 1.66 (s, 3H), 1.70 (s, 3H), 2.62 (s, 3H), 2.15 -3.06 (m, 6H), 3.61 (br, 1H), 4.08 (dd, 1H, J = 5.5, 8 Hz), 4.21 (d, 1H, J = 7 Hz), 4.37 (AB type d, 2H, J = 8.5 Hz), 4.55 (dd, 1H, J = 3, 47 Hz), 5.05-5.11 (m, 4H), 5.52 (d, 1H, J = 10 Hz), 5.71-5.81 (m, 2H), 6.31 (t, 1H, J = 8 Hz), 7.32-7.36 (m, 5H), 7.50 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.17 (d, 2H, J = 8 Hz).
[0614]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-7-deoxy-7α-fluoro- 10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0615]
Melting point: 147-151 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (s, 3H), 1.22 (s, 9H), 1.25 (s, 3H), 1.36 (s, 3H), 1.70 (s, 3H), 1.75 (s, 3H), 2.65 (s, 3H), 2.14 -2.60 (m, 12H), 3.66-3.69 (m, 4H), 4.22-4.23 (m, 2H), 4.37 (AB type d, 2H, J = 8 Hz), 4.53 (dd, 1H, J = 3, 47 Hz), 5.03-5.07 (m, 2H), 5.53 (d, 1H, J = 10 Hz), 5.75 (d, 1H, J = 7 Hz), 6.30 (t, 1H, J = 8 Hz), 7.32 -7.37 (m, 5H), 7.50 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.17 (d, 2H, J = 8 Hz).
MS-FAB: 921 (MH+).
[0616]
Example 38
[0617]
Embedded image
Step 1: 10-allyl-10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl-13-O-triethylsilylbaccatin III
10-allyl-7,13-bis (triethylsilyl) -10-deacetoxy-4-deacetyl-1-O-dimethylsilyl-4-O-ethoxycarbonylbaccatin III was reacted in the same manner as in Step 2 of Example 5. The title compound was obtained as a colorless amorphous solid.
[0619]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.63-0.68 (m, 6H), 1.00 (t, 9H, J = 7 Hz), 1.10 (s, 3H), 1.15 (s, 3H), 1.40 (t, 3H, J = 7 Hz), 1.63 (s , 3H), 1.82-1.87 (m, 1H), 1.89 (s, 3H), 2.04-2.09 (m, 1H), 2.24-2.30 (m, 2H), 2.51-2.57 (m, 1H), 2.91-2.96 (m, 1H), 3.87 (t, 1H, J = 8 Hz), 4.07 (d, 1H, J = 7 Hz), 4.20 (d, 1H, J = 8 Hz), 4.30-4.45 (m, 3H) , 4.92-5.12 (m, 4H), 5.65 (d, 1H, J = 7 Hz), 5.80-5.86 (m, 1H), 7.47 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
[0620]
Step 2: 10-allyl-10-deacetoxy-4-deacetyl-7-deoxy-4-O-ethoxycarbonyl-7α-fluoro-13-O-triethylsilylbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 3 of Example 5 to obtain the title compound as a colorless amorphous solid.
[0621]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.62-0.68 (m, 6H), 1.00 (t, 9H, J = 7 Hz), 1.07 (s, 3H), 1.15 (s, 3H), 1.39 (t, 3H, J = 7 Hz), 1.67 (s , 3H), 1.84 (s, 3H), 2.07-3.05 (m, 6H), 2.49-2.70 (m, 3H), 4.07-4.21 (m, 4H), 4.32-4.44 (m, 2H), 4.55 (dd , 1H, J = 3, 47 Hz), 4.92 (t, 1H, J = 8 Hz), 4.98-5.09 (m, 3H), 5.70 (d, 1H, J = 7 Hz), 5.72-5.81 (m, 1H), 7.48 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.14 (d, 2H, J = 8 Hz).
[0622]
Step 3: 10-Allyl-10-deacetoxy-4-deacetyl-7-deoxy-4-O-ethoxycarbonyl-7α-fluorobaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0623]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.08 (s, 6H), 1.39 (t, 3H, J = 7 Hz), 1.65 (s, 3H), 1.89 (s, 3H), 2.12-3.06 (m, 6H), 4.10-4.44 (m, 6H) , 4.55 (ddd, 1H, J = 2, 4.5, 9 Hz), 4.80 (br, 1H), 5.00 (dd, 1H, J = 1.5, 9 Hz), 5.07-5.13 (m, 2H), 5.75-5.93 (m, 1H), 7.51 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
[0624]
Step 4: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl- 7-Deoxy-4-O-ethoxycarbonyl-7α-fluorobaccatin III
The compound obtained in the above Step 3 was reacted in the same manner as in Step 1 of Example 4, and then reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0625]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.11 (s, 3H), 1.20 (s, 3H), 1.34 (s, 9H), 1.37-1.39 (m, 6H), 1.63 (s, 3H), 1.68 (s, 3H), 2.20-3.07 (m, 6H), 3.70 (s, 1H), 4.06 (dd, 1H, J = 4, 8 Hz), 4.12 (d, 1H, J = 7 Hz), 4.33-4.62 (m, 5H), 5.02 (d, 1H , J = 10 Hz), 5.07-5.13 (m, 2H), 5.20 (d, 1H, J = 10 Hz), 5.66-5.82 (m, 3H), 6.11 (t, 1H, J = 8 Hz), 7.28 -7.48 (m, 7H), 7.59 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
[0626]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-7-deoxy- 4-O-Ethoxycarbonyl-7α-fluoro-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 4 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0627]
Melting point: 130-132 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.19 (s, 3H), 1.33 (s, 9H), 1.36-1.41 (m, 6H), 1.67 (s, 3H), 1.73 (s, 3H), 2.16-2.64 (m, 12H), 3.63-3.68 (m, 4H), 4.13 (d, 1H, J = 7 Hz), 4.19 (t, 1H, J = 5.5 Hz), 4.33-4.58 (m, 5H), 5.08 (d, 1H , J = 10 Hz), 5.20 (d, 1H, J = 7 Hz), 5.75-5.77 (m, 2H), 6.10 (t, 1H, J = 8 Hz), 7.29-7.48 (m, 7H), 7.59 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
MS-FAB: 951 (MH+).
[0628]
Example 39
[0629]
Embedded image
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-2-debenzoyl-7 -Deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
89 mg of the compound obtained in Step 6 of Example 18 was dissolved in 4.5 ml of dry dichloromethane, Triton B (89 ml, 40% w / w methanol solution) was added at −78 ° C., and the same temperature was maintained for 5 minutes. The mixture was stirred at -10 ° C for 7 minutes. The reaction mixture was diluted with ethyl acetate, 1N hydrochloric acid (10 ml) was added to stop the reaction, extraction was performed with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent, chloroform: methanol = 95: 5 (v / v)) to give the title compound 41 mg was obtained as a colorless amorphous solid.
[0631]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.34 (s, 3H), -0.12 (s, 3H), 0.76 (s, 9H), 1.10 (s, 3H), 1.24 (s, 3H), 1.44 (s, 9H), 1.61 (m, 1H) , 1.77 (s, 3H), 1.90 (br, 1H), 2.08-2.22 (m, 2H), 2.38-2.58 (m, 14H), 3.69 (m, 5H), 3.81 (d, 1H, J = 8 Hz ), 3.98 (br, 1H), 4.42 (s, 1H), 4.52 (d, 1H, J = 9.5 Hz), 4.65 (d, 1H, J = 9.5 Hz), 4.79 (d, 1H, J = 4 Hz ), 5.22 (d, 1H, J = 10 Hz), 5.50 (d, 1H, J = 10 Hz), 6.21 (m, 1H), 7.23 (t, 1H, J = 8 Hz), 7.28 (m, 1H ), 7.36 (m, 2H)
MS-FAB: 897 (MH+).
[0632]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-2-debenzoyl-7-deoxy-2-O- (3-Methoxybenzoyl) -7 β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
13 mg of the compound obtained in the above step 1 was dissolved in 0.4 ml of dry tetrahydrofuran. Subsequently, lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 73 ml) and 10 ml of 3-methoxybenzoyl chloride were added at −78 ° C., and the mixture was stirred at the same temperature for 120 minutes. The reaction solution was diluted with ethyl acetate, and the reaction was stopped by adding saturated aqueous ammonium chloride solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was diluted with silica gel. Purification by layer chromatography (developing solvent; hexane: ethyl acetate = 4: 1 (v / v)). The obtained compound was reacted in the same manner as in Step 9 of Example 1 to obtain 4 mg of the title compound as a white solid.
[0633]
Melting point: 110-115 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.22 (s, 3H), 1.28 (s, 9H), 1.56 (m, 1H), 1.80 (s, 3H), 2.12 (d, 1H, J = 16 Hz), 2.20 (m , 2H), 2.37-2.49 (m, 12H), 2.56 (m, 1H), 3.72 (s, 4H), 3.75 (m, 1H), 3.90 (s, 3H), 4.03 (d, 1H, J = 8.5 Hz), 4.28 (d, 1H, J = 7.5 Hz), 4.38 (d, 1H, J = 8.5 Hz), 4.59 (s, 1H), 4.75 (d, 1H, J = 3.5 Hz), 5.28 (br, 1H), 5.33 (d, 1H, J = 9 Hz), 5.65 (d, 1H, J = 7 Hz), 6.22 (m, 1H), 7.13 (dd, 1H, J = 2.5, 8 Hz), 7.30- 7.43 (m, 6H), 7.69 (br, 1H), 7.76 (d, 1H, J = 8 Hz).
MS-FAB: 917 (MH+).
[0634]
Example 40
[0635]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10 -Deacetoxy-7-deoxy-7β, 8β-methylene-19-norbaccatin III
Carry out the compound obtained in Step 4 of Example 18 and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyl) oxy-4- (2-furyl) -2-azetidinone Reaction was carried out in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0637]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.16 (s, 3H), 0.02 (s, 3H), 0.79 (s, 9H), 1.21 (s, 3H), 1.22 (s, 3H), 1.28 (s, 9H), 1.55 (m, 1H), 1.73 (s, 3H), 1.83 (br, 1H), 2.10-2.25 (m, 4H), 2.42-2.48 (m, 2H), 2.45 (s, 3H), 2.99 (m, 1H), 3.69 (t, 1H, J = 7 Hz), 4.05 (d, 1H, J = 9 Hz), 4.29 (m, 2H), 4.70 (d, 1H, J = 2 Hz), 4.76 (d, 1H, J = 3.5 Hz) , 5.03 (d, 1H, J = 10 Hz), 5.10 (dd, 1H, J = 1.5, 17 Hz), 5.24 (d, 1H, J = 10 Hz), 5.38 (d, 1H, J = 10 Hz) , 5.65 (d, 1H, J = 8 Hz), 5.83 (m, 1H), 6.21 (m, 1H), 6.26 (t, 1H, J = 6 Hz), 6.35 (m, 1H), 7.37 (s, 1H), 7.49 (t, 2H, J = 7.5 Hz), 7.57 (t, 1H, J = 7.5 Hz), 8.14 (d, 2H, J = 7.5 Hz)
MS-FAB: 918 (MH+).
[0638]
Step 2: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-7-deoxy-7β, 8β- Methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 9 of Example 1, and then reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0639]
Melting point: 130-135 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 6H), 1.30 (s, 9H), 1.57 (m, 1H), 1.82 (s, 3H), 1.87 (br, 1H), 2.10 (d, 1H, J = 16 Hz), 2.22 (m , 2H), 2.30-2.60 (m, 10H), 2.38 (s, 3H), 3.70 (m, 4H), 4.71 (m, 1H), 4.76 (m, 1H), 4.05 (d, 1H, J = 8.5 Hz), 4.29 (m, 2H), 4.69 (s, 1H), 4.75 (d, 1H, J = 3 Hz), 5.22 (d, 1H, J = 10 Hz), 5.35 (d, 1H, J = 10 Hz), 5.68 (d, 1H, J = 8 Hz), 6.22 (t, 1H, J = 9 Hz), 6.32 (m, 1H), 6.39 (m, 1H), 7.42 (s, 1H), 7.49 ( t, 2H, J = 7.5 Hz), 7.59 (t, 1H, J = 7.5 Hz), 8.16 (d, 2H, J = 7.5 Hz).
MS-FAB: 877 (MH+).
[0640]
Example 41
[0641]
Embedded image
Step 1: 10-allyl-10-deacetoxy-2-debenzoyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
100 mg of the compound obtained in Step 1 of Example 19 was dissolved in 1.5 ml of dry tetrahydrofuran, 180 μl of sodium bis (2-methoxyethoxy) aluminum hydride was added, and the mixture was stirred at 0 ° C. for 20 minutes. Ethyl acetate, saturated aqueous potassium tartrate solution, and water were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 3: 2 (v / v)) to obtain 70 mg of the title compound as a colorless amorphous solid.
[0643]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.68 (m, 6H), 0.99 (m, 9H), 1.10 (s, 3H), 1.19 (s, 3H), 1.56 (dd, 1H, J = 5, 7 Hz), 1.65 (br, 1H), 1.76 (s, 3H), 1.92 (dd, 1H, J = 8, 15 Hz), 2.05-2.20 (m, 7H), 2.34 (d, 1H, J = 7 Hz), 2.45 (m, 1H), 2.94 ( m, 1H), 3.61 (dd, 1H, J = 6, 8 Hz), 3.77 (d, 1H, J = 7 Hz), 3.94 (t, 1H, J = 7 Hz), 4.51 (d, 1H, J = 9 Hz), 4.60 (d, 1H, J = 9 Hz), 4.77 (d, 1H, J = 4 Hz), 4.93 (t, 1H, J = 8 Hz), 4.96 (m, 1H), 5.05 ( dd, 1H, J = 1.5, 17 Hz), 5.81 (m, 1H).
MS-FAB: 560 (MH+).
[0644]
Step 2: 10-allyl-2-O- (3-chlorobenzoyl) -10-deacetoxy-2-debenzoyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
35 mg of the compound obtained in the above step 1 was dissolved in 1.05 ml of dry toluene, and 196 mg of 3-chlorobenzoic acid, 258 mg of dicyclohexylcarbodiimide and 153 mg of 4-dimethylaminopyridine were added at room temperature for 1 day at 60 ° C. Stir. The reaction solution was diluted with ethyl acetate, saturated aqueous tartaric acid solution was added under ice cooling to stop the reaction, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 4: 1 (v / v)). The resulting compound was then reacted in the same manner as in Step 1 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0645]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (s, 3H), 1.18 (s, 3H), 1.52 (t, 1H, J = 6 Hz), 1.78 (s, 1H), 1.89 (s, 3H), 2.12 (d, 1H, J = 16 Hz ), 2.20-2.32 (m, 4H), 2.28 (s, 3H), 2.46 (dt, 1H, J = 4.5, 16 Hz), 3.00 (m, 1H), 3.71 (dd, 1H, J = 6, 8 Hz), 4.02 (d, 1H, J = 9 Hz), 4.27 (d, 1H, J = 8 Hz), 4.36 (d, 1H, J = 8 Hz), 4.77 (d, 1H, J = 4 Hz) , 4.82 (t, 1H, J = 7 Hz), 5.01 (d, 1H, J = 10 Hz), 5.09 (dd, 1H, J = 1.5, 17 Hz), 5.56 (d, 1H, J = 8 Hz) , 5.82 (m, 1H), 7.43 (d, 1H, J = 8 Hz), 7.57 (m, 1H), 8.00 (d, 1H, J = 8 Hz), 8.16 (m, 1H).
MS-FAB: 585 (MH+).
[0646]
Step 3: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -2 -O- (3-Chlorobenzoyl) -10-deacetoxy-2-debenzoyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 2 above and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyl) oxy-4- (2-furyl) -2-azetidinone were used in Example 1. The reaction was carried out in the same manner as in Step 8 to obtain the title compound as a colorless amorphous solid.
[0647]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.16 (s, 3H), 0.02 (s, 3H), 0.79 (s, 9H), 1.21 (s, 3H), 1.22 (s, 3H), 1.28 (s, 9H), 1.55 (m, 1H), 1.73 (s, 3H), 1.77 (br, 1H), 2.10-2.25 (m, 4H), 2.38-2.49 (m, 2H), 2.45 (s, 3H), 3.00 (m, 1H), 3.69 (m, 1H), 4.03 (d, 1H, J = 8 Hz), 4.29 (m, 2H), 4.70 (m, 1H), 4.76 (d, 1H, J = 4 Hz), 5.03 (d, 1H, J = 10 Hz), 5.10 (dd, 1H, J = 1.5, 17 Hz), 5.24 (d, 1H, J = 10 Hz), 5.35 (d, 1H, J = 10 Hz), 5.61 (d, 1H, J = 8 Hz), 5.83 (m, 1H), 6.21 (m, 1H), 6.23 (m, 1H), 6.35 (m, 1H), 7.37 (m, 1H), 7.45 (t, 1H, J = 8 Hz), 7.54 (d, 1H, J = 8 Hz), 8.03 (d, 1H, J = 8 Hz), 8.15 (m, 1H).
MS-FAB: 952 (MH+).
[0648]
Step 4: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -2-O- (3-chlorobenzoyl) -10 -Deacetoxy-2-debenzoyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in Step 3 above was reacted in the same manner as in Step 9 of Example 1, and then reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0649]
Melting point: 125-130 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.30 (s, 9H), 1.57 (m, 1H), 1.82 (s, 4H), 2.12 (d, 1H, J = 16 Hz), 2.22 (m, 2H), 2.30-2.60 (m, 7H), 2.38 (s, 3H), 3.70 (m, 4H), 3.77 (t, 1H, J = 6 Hz), 4.02 (d, 1H, J = 8.5 Hz), 4.29 (m, 2H) , 4.68 (d, 1H, J = 2.5 Hz), 4.78 (d, 1H, J = 3.5 Hz), 5.22 (d, 1H, J = 10 Hz), 5.32 (br, 1H), 5.61 (d, 1H, J = 8 Hz), 6.20 (t, 1H, J = 8.5 Hz), 6.30 (d, 1H, J = 3.5 Hz), 6.37 (m, 1H), 7.42 (s, 1H), 7.45 (t, 1H, J = 8 Hz), 7.57 (m, 1H), 8.04 (d, 1H, J = 8 Hz), 8.17 (s, 1H).
MS-FAB: 911 (MH+).
[0650]
Example 42
[0651]
Embedded image
Step 1: 10-allyl-10-deacetoxy-2-debenzoyl-7-deoxy-2-O- (3-methoxybenzoyl) -7 β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 1 of Example 41 was reacted in the same manner as in Step 2 of Example 41 using 3-methoxybenzoic acid instead of 3-chlorobenzoic acid, and then reacted in the same manner as in Step 7 of Example 1. To give the title compound as a colorless amorphous solid.
[0653]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (s, 3H), 1.16 (s, 3H), 1.52 (dd, 1H, J = 5, 7 Hz), 1.82 (br, 1H), 1.89 (s, 3H), 2.10 (d, 1H, J = 16 Hz), 2.20-2.25 (m, 3H), 2.25 (s, 3H), 2.35 (dd, 1H, J = 7, 16 Hz), 2.44 (dt, 1H, J = 4.5, 16 Hz), 3.00 ( m, 1H), 3.71 (dd, 1H, J = 6, 8 Hz), 3.87 (s, 3H), 4.04 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.36 (d, 1H, J = 8 Hz), 4.75 (d, 1H, J = 4.5 Hz), 4.83 (d, 1H, J = 8 Hz), 5.01 (m, 1H), 5.08 (dd, 1H, J = 1.5, 17 Hz), 5.60 (d, 1H, J = 7 Hz), 5.82 (m, 1H), 7.15 (m, 1H), 7.39 (m, 1H), 7.67 (m, 1H), 7.73 (d , 1H, J = 8 Hz).
MS-FAB: 580 (MH+).
[0654]
Step 2: 10-allyl-13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3- (2-furyl) propionyl] -10 -Deacetoxy-2-debenzoyl-7-deoxy-2-O- (3-methoxybenzoyl) -7 β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 1 above and (3R, 4R) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyl) oxy-4- (2-furyl) -2-azetidinone were used in Example 1. The reaction was carried out in the same manner as in Step 8 to obtain the title compound as a colorless amorphous solid.
[0655]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.16 (s, 3H), 0.02 (s, 3H), 0.79 (s, 9H), 1.21 (s, 3H), 1.22 (s, 3H), 1.28 (s, 9H), 1.55 (m, 1H), 1.73 (s, 3H), 1.84 (br, 1H), 2.10-2.25 (m, 4H), 2.43 (s, 3H), 2.40-2.48 (m, 2H), 2.99 (m, 1H), 3.69 (m, 1H), 3.84 (s, 3H), 4.05 (d, 1H, J = 8 Hz), 4.29 (d, 1H, J = 8 Hz), 4.35 (d, 1H, J = 8 Hz), 4.69 (m, 1H), 4.75 (d, 1H, J = 4 Hz), 5.03 (d, 1H, J = 10 Hz), 5.12 (dd, 1H, J = 1.5, 17 Hz), 5.24 (d, 1H, J = 10 Hz), 5.31 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 8 Hz), 5.83 (m, 1H), 6.21 (m, 1H), 6.23 (m, 1H), 6.33 ( m, 1H), 7.12 (m, 1H), 7.37 (s, 1H), 7.39 (t, 2H, J = 8 Hz), 7.67 (m, 1H), 7.77 (d, 2H, J = 8 Hz).
MS-FAB: 948 (MH+).
[0656]
Step 3: 13-O-[(2R, 3R) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -10-deacetoxy-2-debenzoyl-7-deoxy- 2-O- (3-methoxybenzoyl) -7 β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 9 of Example 1, and then reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0657]
Melting point: 120-125 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.28 (s, 9H), 1.55 (m, 1H), 1.80 (s, 3H), 1.88 (s, 3H), 2.12 (d, 1H, J = 16 Hz), 2.20 (m , 2H), 2.30-2.60 (m, 7H), 2.38 (s, 3H), 3.70 (m, 4H), 3.77 (d, 1H, J = 8 Hz), 4.89 (s, 3H), 4.04 (d, 1H, J = 8 Hz), 4.28 (d, 1H, J = 8 Hz), 4.35 (d, 1H, J = 8 Hz), 4.68 (s, 1H), 4.76 (d, 1H, J = 4 Hz) , 5.20 (d, 1H, J = 10 Hz), 5.32 (br, 1H), 6.21 (t, 1H, J = 8 Hz), 6.30 (d, 1H, J = 3 Hz), 6.37 (m, 1H) , 7.14 (dd, 1H, J = 3, 8 Hz), 7.41 (t, 1H, J = 8 Hz), 7.42 (s, 1H), 7.68 (br, 1H), 7.76 (d, 1H, J = 8 Hz).
MS-FAB: 907 (MH+).
[0658]
Example 43
[0659]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -2-O- ( 3-Chlorobenzoyl) -10-deacetoxy-2-debenzoyl-7-deoxy-7β, 8β-methylene-19-norbaccatin III
The compound obtained in Step 2 of Example 41 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0661]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.32 (s, 3H), -0.12 (s, 3H), 0.73 (s, 9H), 1.21 (s, 3H), 1.25 (s, 3H), 1.26 (s, 9H), 1.55 (m, 1H) , 1.73 (s, 3H), 1.80 (br, 1H), 2.18-2.25 (m, 4H), 2.38-2.49 (m, 2H), 2.51 (s, 3H), 2.99 (m, 1H), 3.69 (t , 1H, J = 8 Hz), 4.03 (d, 1H, J = 8 Hz), 4.28 (d, 1H, J = 7 Hz), 4.30 (d, 1H, J = 8 Hz), 4.49 (s, 1H ), 4.79 (m, 1H), 5.02 (d, 1H, J = 10 Hz), 5.12 (d, 1H, J = 17 Hz), 5.30 (br, 1H), 5.41 (br, 1H), 5.61 (d , 1H, J = 7 Hz), 5.82 (m, 1H), 6.25 (t, 1H, J = 9 Hz), 7.25-7.36 (m, 5H), 7.44 (t, 2H, J = 8 Hz), 7.56 (d, 1H, J = 8 Hz), 8.03 (d, 1H, J = 8 Hz), 8.17 (s, 1H).
MS-FAB: 962 (MH+).
[0662]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -2-O- (3-chlorobenzoyl) -10-deacetoxy-2 -Debenzoyl-7-deoxy-7β, 8β-methylene-10- (2-morpholinoethyl) -19-norbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 9 of Example 1, and then reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0663]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.21 (s, 3H), 1.28 (s, 9H), 1.55 (m, 1H), 1.80 (s, 4H), 2.08-2.23 (m, 3H), 2.30-2.60 (m, 10H), 2.37 (s, 3H), 3.70 (m, 4H), 3.76 (t, 1H, J = 6 Hz), 4.02 (d, 1H, J = 9 Hz), 4.29 (m, 2H), 4.57 ( s, 1H), 4.76 (d, 1H, J = 3.5 Hz), 5.28 (br, 1H), 5.31 (d, 1H, J = 10 Hz), 5.60 (d, 1H, J = 7 Hz), 6.20 ( br, 1H), 7.29-7.40 (m, 5H), 7.46 (t, 2H, J = 8 Hz), 7.58 (d, 1H, J = 8 Hz), 8.03 (d, 1H, J = 8 Hz), 8.18 (s, 1H).
MS-FAB: 921 (MH+).
[0664]
Example 44
[0665]
Embedded image
Step 1: 10-deacetoxy-2-debenzoyl-7-O-methyl-10- (2-morpholinoethyl) -13-O-triethylsilylbaccatin III
The compound obtained in Step 3 of Example 10 was reacted in the same manner as in Step 1 of Example 41 to obtain the title compound as a colorless amorphous solid.
[0667]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.65 (m, 6H), 1.00 (t, 9H, J = 8 Hz), 1.02 (s, 3H), 1.12 (s, 3H), 1.60 (s, 3H), 1.76 (m, 1H), 1.91 (s , 3H), 2.02 (m, 1H), 2,18 (s, 3H), 2.22-2.75 (m, 10H), 3.24 (s, 3H), 3.59 (d, 1H, J = 7 Hz), 3.70 ( m, 4H), 3.82 (d, 1H, J = 7 Hz), 3.95 (m, 1H), 4.68 (d, 1H, J = 7 Hz), 4.62 (d, 1H, J = 7 Hz), 4.92 ( t, 1H, J = 8 Hz), 5.02 (d, 1H, J = 7 Hz).
MS-FAB: 665 (MH+).
[0668]
Step 2: 10-deacetoxy-2-debenzoyl-2-O- (3-methoxybenzoyl) -7-O-methyl-10- (2-morpholinoethyl) -13-O- triethylsilylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 2 of Example 41 using 3-methoxybenzoic acid instead of 3-chlorobenzoic acid to obtain the title compound as a colorless amorphous solid.
[0669]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.67 (m, 6H), 1.01 (t, 9H, J = 7 Hz), 1.10 (s, 6H), 1.66 (s, 3H), 1.70-2.80 (m, 12H), 1.88 (s, 3H), 2.28 (s, 3H), 3.25 (s, 3H), 3.64 (m, 1H), 3.69 (m, 4H), 3.85 (s, 3H), 3.94 (m, 1H), 4.00 (m, 1H), 4.18 ( d, 1H, J = 8.5 Hz), 4.28 (dd, 1H, J = 6.5, 10.5 Hz), 4.33 (d, 1H, J = 8.5 Hz), 4.91 (t, 1H, J = 8 Hz), 5.03 ( d, 1H, J = 8 Hz), 5.59 (d, 1H, J = 7 Hz), 7.14 (m, 1H), 7.37 (t, 1H, J = 8 Hz), 7.63 (s, 1H), 7.69 ( d, 1H, J = 8 Hz).
MS-FAB: 800 (MH+).
[0670]
Step 3: 10-deacetoxy-2-debenzoyl-2-O- (3-methoxybenzoyl) -7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0671]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.12 (s, 3H), 1.66 (s, 3H), 1.75 (m, 1H), 2.05 (s, 3H), 2.26 (s, 3H), 2.30-2.75 (m, 11H) , 3.26 (s, 3H), 3.64 (m, 1H), 3.69 (m, 4H), 3.85 (s, 3H), 3.99 (m, 1H), 4.09 (d, 1H, J = 7 Hz), 4.16 ( d, 1H, J = 8.5 Hz), 4.32 (d, 1H, J = 8.5 Hz), 4.81 (br, 1H), 5.00 (d, 1H, J = 7 Hz), 5.59 (d, 1H, J = 7 Hz), 7.12 (dd, 1H, J = 3, 8.5 Hz), 7.36 (t, 1H, J = 8 Hz), 7.64 (d, 1H, J = 2 Hz), 7.70 (d, 1H, J = 8 Hz).
[0672]
Step 4: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-2-debenzoyl-2-O- (3-Methoxybenzoyl) -7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 3 of the above Step 3 and Reference Example 4 was reacted in the same manner as in Step 1 of Example 4, and then reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0673]
Melting point: 125-130 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.22 (s, 9H), 1.24 (s, 3H), 1.25 (s, 3H), 1.68 (s, 3H), 1.79 (s, 3H), 1.79 (m, 1H), 2.17 -2.75 (m, 11H), 2.62 (s, 3H), 3.27 (s, 3H), 3.59 (br, 1H), 3.65 (m, 1H), 3.67 (br, 4H), 3.89 (s, 3H), 3.97 (m, 2H), 4.19 (d, 1H, J = 8.5 Hz), 4.38 (d, 1H, J = 8.5 Hz), 5.01 (m, 2H), 5.54 (d, 1H, J = 10 Hz), 5.64 (d, 1H, J = 7 Hz), 6.29 (t, 1H, J = 8 Hz), 7.13 (dd, 1H, J = 2, 8 Hz), 7.36 (m, 5H), 7.38 (m, 1H ), 7.66 (m, 1H), 7.74 (d, 1H, J = 8 Hz).
MS-FAB: 963 (MH+).
[0674]
Example 45
[0675]
Embedded image
Step 1: 10-deacetoxy-2-debenzoyl-2-O- (3,5-difluorobenzoyl) -7-O-methyl-10- (2-morpholinoethyl) -13-O- triethylsilylbaccatin III
The compound obtained in Step 1 of Example 44 was reacted in the same manner as in Step 2 of Example 41 using 3,5-difluorobenzoic acid in place of 3-chlorobenzoic acid to give the title compound as a colorless amorphous solid. Obtained.
[0677]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.67 (m, 6H), 1.01 (t, 9H, J = 7 Hz), 1.08 (s, 3H), 1.10 (s, 3H), 1.66 (s, 3H), 1.75 (m, 1H), 1.99 (s , 3H), 2.10-2.75 (m, 11H), 2.29 (s, 3H), 3.26 (s, 3H), 3.64 (m, 1H), 3.69 (m, 4H), 3.95 (m, 1H), 4.01 ( d, 1H, J = 7 Hz), 4.14 (d, 1H, J = 8.5 Hz), 4.28 (d, 1H, J = 8.5 Hz), 4.90 (t, 1H, J = 8 Hz), 5.03 (d, 1H, J = 8 Hz), 5.52 (d, 1H, J = 7 Hz), 7.06 (m, 1H), 7.60 (d, 2H, J = 5.5 Hz).
MS-FAB: 806 (MH+).
[0678]
Step 2: 10-deacetoxy-2-debenzoyl-2-O- (3,5-difluorobenzoyl) -7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0679]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.10 (s, 3H), 1.68 (s, 3H), 2.08 (s, 3H), 1.70-2.72 (m, 12H), 2.30 (s, 3H), 3.28 (s, 3H) , 3.69 (s, 5H), 4.00 (m, 1H), 4.10 (m, 1H), 4.13 (d, 1H, J = 8.5 Hz), 4.29 (d, 1H, J = 8.5 Hz), 4.82 (br, 1H), 5.00 (d, 1H, J = 8 Hz), 5.52 (d, 1H, J = 7 Hz), 7.02 (m, 1H), 7.60 (d, 1H, J = 5.5 Hz).
[0680]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-2-debenzoyl-2-O- (3,5-Difluorobenzoyl) -7-O-methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 2 and Step 3 of Reference Example 4 was reacted in the same manner as in Step 1 of Example 4, and then reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless solid.
[0681]
Melting point: 130-135 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.12 (s, 3H), 1.22 (s, 9H), 1.23 (s, 3H), 1.38 (s, 3H), 1.69 (s, 3H), 1.78 (s, 3H), 1.78 (m, 1H), 2.10 -2.72 (m, 11H), 2.61 (s, 3H), 3.25 (s, 3H), 3.68 (br, 4H), 3.95 (m, 3H), 4.15 (d, 1H, J = 8.5 Hz), 4.31 ( d, 1H, J = 8.5 Hz), 5.00 (m, 2H), 5.50 (d, 1H, J = 10 Hz), 5.59 (d, 1H, J = 7 Hz), 6.26 (m, 1H), 7.03 ( m, 1H), 7.18-7.33 (m, 5H), 7.66 (m, 2H).
MS-FAB: 969 (MH+).
[0682]
Example 46
[0683]
[Chemical Formula 86]
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3- (4-tolyl) -2- (trimethylsilyl) oxypropionyl] -10 -Deacetoxy-7-O-methylbaccatin III
The compound obtained in Step 10 of Example 11 and the compound obtained in Step 3 of Reference Example 5 were reacted in the same manner as in Step 1 of Example 4 to obtain the title compound as a colorless amorphous solid.
[0685]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.11 (s, 9H), 1.14 (s, 3H), 1.16 (s, 9H), 1.28 (s, 3H), 1.38 (s, 3H), 1.69 (s, 3H), 1.79 (s, 3H), 1.76 -1.82 (m, 1H), 2.03-2.09 (m, 1H), 2.22-2.34 (m, 2H), 2.35 (s, 3H), 2.67-2.72 (m, 1H), 2.69 (s, 3H), 2.96 -3.04 (m, 1H), 3.24 (s, 3H), 3.76 (t, 1H, J = 7 Hz), 3.92-3.98 (m, 2H), 4.21 (d, 1H, J = 8 Hz), 4.31 ( d, 1H, J = 8 Hz), 4.94-5.08 (m, 3H), 5.45 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 7 Hz), 5.80-5.90 (m, 1H ), 6.36 (t, 1H, J = 8 Hz), 7.15 (s, 4H), 7.47 (t, 2H, J = 8 Hz), 7.56 (t, 1H, J = 8 Hz), 8.14 (d, 2H , J = 8 Hz).
[0686]
Step 2: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3- (4-tolyl) propionyl] -10-deacetoxy- 7- O-Methylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0687]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.15 (s, 3H), 1.23 (s, 9H), 1.25 (s, 3H), 1.37 (s, 3H), 1.68 (s, 3H), 1.70 (s, 3H), 1.75-1.82 (m, 1H) , 2.15-2.31 (m, 3H), 2.36 (s, 3H), 2.61 (s, 3H), 2.65-2.73 (m, 1H), 2.93-3.00 (m, 1H), 3.25 (s, 3H), 3.56 (br, 1H), 3.77 (t, 1H, J = 7 Hz), 3.93 (dd, 1H, J = 7, 10 Hz), 3.98 (d, 1H, J = 7 Hz), 4.21 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.99-5.11 (m, 3H), 5.50 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 7 Hz) , 5.75-5.86 (m, 1H), 6.29 (t, 1H, J = 8 Hz), 7.17 (d, 2H, J = 8 Hz), 7.25 (d, 2H, J = 8 Hz), 7.48 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
[0688]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3- (4-tolyl) propionyl] -10-deacetoxy-7-O- Methyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0689]
Melting point: 158-162 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.22 (s, 9H), 1.24 (s, 3H), 1.37 (s, 3H), 1.69 (s, 3H), 1.84 (s, 3H), 1.75-1.82 (m, 1H) , 2.14-2.75 (m, 11H), 2.36 (s, 3H), 2.64 (s, 3H), 3.26 (s, 3H), 3.60 (br, 1H), 3.67 (s, 4H), 3.95-4.02 (m , 3H), 4.21 (d, 1H, J = 8 Hz), 4.32 (d, 1H, J = 8 Hz), 5.00-5.02 (m, 2H), 5.48 (d, 1H, J = 10 Hz), 5.65 (d, 1H, J = 7 Hz), 6.31 (t, 1H, J = 8 Hz), 7.18 (d, 2H, J = 8 Hz), 7.25 (d, 2H, J = 8 Hz), 7.48 (t , 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
MS-FAB: 947 (MH+).
[0690]
Example 47
[0691]
Embedded image
13- O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10- [2- (cyclopropylamino) ethyl] -10- Deacetoxy-7-O-methylbaccatin III
The compound obtained in Step 12 of Example 11 was reacted with cyclopropylamine instead of morpholine in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0693]
Melting point: 140-143 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
0.32-0.33 (m, 2H), 0.43-0.44 (m, 2H), 1.14 (s, 3H), 1.23 (s, 9H), 1.39 (s, 3H), 1.58-2.75 (m, 7H), 1.69 ( s, 3H), 1.76 (s, 3H), 2.62 (s, 3H), 3.27 (s, 3H), 3.85 (t, 1H, J = 6 Hz), 3.94 (dd, 1H, J = 10, 7 Hz ), 3.99 (d, 1H, J = 7.5 Hz), 4.20 (d, 1H, J = 9 Hz), 4.31 (d, 1H, J = 9 Hz), 4.99-5.05 (m, 2H), 5.55 (d , 1H, J = 10 Hz), 5.64 (d, 1H, J = 7 Hz), 6.29 (t, 1H, J = 8 Hz), 7.33-7.37 (m, 5H), 7.48 (t, 2H, J = 8 Hz), 7.58 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
MS-FAB: 903 (MH+).
[0694]
Example 48
[0695]
Embedded image
Step 1: 13-O-triethylsilylbaccatin III
7,13-O-bis (triethylsilyl) baccatin III was reacted in the same manner as in Step 2 of Example 5 to obtain the title compound as a colorless amorphous solid.
[0697]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.61-0.73 (m, 6H), 1.02 (t, 9H, J = 8 Hz), 1.11 (s, 3H), 1.18 (s, 3H), 1.80 (s, 3H), 1.83-1.90 (m, 1H) , 2.00 (s, 3H), 2.12-2.26 (m, 2H), 2.24 (s, 3H), 2.29 (s, 3H), 2.51 (d, 1H, J = 4 Hz), 2.52-2.59 (m, 1H ), 3.80 (d, 1H, J = 7 Hz), 4.15 (d, 1H, J = 8 Hz), 4.30 (d, 1H, J = 8 Hz), 4.44-4.49 (m, 1H), 4.94-5.00 (m, 2H), 5.62 (d, 1H, J = 7 Hz), 6.31 (s, 1H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
[0698]
Step 2: 7-O-methylthiomethyl-13-O- triethylsilylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 5 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0699]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.63-0.75 (m, 6H), 1.02 (t, 9H, J = 8 Hz), 1.13 (s, 3H), 1.19 (s, 3H), 1.74 (s, 3H), 1.81-1.89 (m, 1H) , 2.12 (s, 3H), 2.15 (s, 3H), 2.19 (s, 3H), 2.17-2.28 (m, 2H), 2.30 (s, 3H), 2.80-2.87 (m, 1H), 3.89 (d , 1H, J = 7 Hz), 4.15 (d, 1H, J = 8 Hz), 4.30-4.38 (m, 2H), 4.67 (s, 2H), 4.93 (t, 1H, J = 9 Hz), 4.98 (d, 1H, J = 9.5 Hz), 5.64 (d, 1H, J = 7 Hz), 6.56 (s, 1H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
[0700]
Step 3: 7-O-fluoromethyl-13-O- triethylsilylbaccatin III
100 mg of the compound obtained in the above step 2 was dissolved in 2 ml of dichloromethane and cooled on ice. Next, 45 mg of N-iodosuccinimide and 0.035 ml of diethylaminosulfur trifluoride were added and stirred for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was vigorously stirred for about 5 minutes. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 4: 1 (v / v)) to obtain 61.5 mg of the title compound as colorless crystals.
[0701]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.63-0.73 (m, 6H), 1.02 (t, 9H, J = 8 Hz), 1.15 (s, 6H), 1.75 (s, 3H), 1.99-2.03 (m, 1H), 2.04 (s, 3H) , 2.14-2.27 (m, 2H), 2.21 (s, 3H), 2.30 (s, 3H), 2.70-2.78 (m, 1H), 3.87 (d, 1H, J = 7 Hz), 4.14 (d, 1H , J = 8 Hz), 4.27-4.32 (m, 2H), 4.92-4.97 (m, 2H), 5.27 (dd, 1H, J = 3.5, 43 Hz), 5.36 (dd, 1H, J = 3.5, 38.5 Hz), 5.62 (d, 1H, J = 7 Hz), 6.35 (s, 1H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.08 (d, 2H, J = 8 Hz).
[0702]
Process 4: 7-O-fluoromethylbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 7 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0703]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.08 (s, 3H), 1.15 (s, 3H), 1.76 (s, 3H), 1.99-2.05 (m, 1H), 2.10 (s, 3H), 2.21 (s, 3H), 2.27-2.30 (m, 2H), 2.29 (s, 3H), 2.71-2.79 (m, 1H), 3.92 (d, 1H, J = 7 Hz), 4.14 (d, 1H, J = 8 Hz), 4.28-4.32 (m, 2H ), 4.86 (br, 1H), 4.97 (d, 1H, J = 9 Hz), 5.23 (dd, 1H, J = 3, 44 Hz), 5.37 (dd, 1H, J = 3, 40 Hz), 5.63 (d, 1H, J = 7 Hz), 6.36 (s, 1H), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
[0704]
Step 5: 10-deacetyl-7-O-fluoromethylbaccatin III
3.10 g of the compound obtained in the above Step 4 was dissolved in a mixed solvent of 60 ml of ethanol and 20 ml of tetrahydrofuran, 19 ml of hydrazine monohydrate was added under ice cooling, and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with 1N hydrochloric acid aqueous solution (twice), saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent, chloroform: methanol = 100: 1 (v / v)) to obtain 2.80 g of the title compound as a colorless amorphous solid.
[0705]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.09 (s, 3H), 1.10 (s, 3H), 1.81 (s, 3H), 1.84-1.98 (m, 1H), 2.09 (d, 3H, J = 1.5 Hz), 2.26-2.29 (m, 2H) , 2.30 (s, 3H), 2.63-2.70 (m, 1H), 4.00 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.35 (dd, 1H, J = 7, 10 Hz), 4.88 (d, 1H, J = 8 Hz), 4.98 (d, 1H, J = 8 Hz), 5.12 (dd, 1H, J = 3 , 22 Hz), 5.26 (dd, 1H, J = 3, 27 Hz), 5.31 (s, 1H), 5.62 (d, 1H, J = 7 Hz), 7.48 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
[0706]
Step 6: 10-deacetyl-7-O-fluoromethyl-10-O- (methylthio) thiocarbonylbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 1 of Example 6 to obtain the title compound as a pale yellow amorphous solid.
[0707]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (s, 3H), 1.24 (s, 3H), 1.78 (s, 3H), 2.00-2.32 (m, 3H), 2.19 (s, 3H), 2.30 (s, 3H), 2.64 (s, 3H) , 2.74-2.82 (m, 1H), 3.92 (d, 1H, J = 7 Hz), 4.15 (d, 1H, J = 8 Hz), 4.29-4.34 (m, 2H), 4.88 (t, 1H, J = 8 Hz), 4.97 (d, 1H, J = 8 Hz), 5.20 (dd, 1H, J = 3, 24 Hz), 5.35 (dd, 1H, J = 3, 20 Hz), 5.67 (d, 1H , J = 7 Hz), 7.42 (s, 1H), 7.49 (t, 2H, J = 8 Hz), 7.62 (t, 1H, J = 8 Hz), 8.11 (d, 2H, J = 8 Hz).
[0708]
Step 7: 10-deacetoxy-7-O-fluoromethyl-10- (2-formylethyl) baccatin III
The compound obtained in Step 6 was reacted in the same manner as in Step 2 of Example 6 to obtain the title compound as colorless amorphous crystals.
[0709]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.11 (s, 3H), 1.70 (s, 3H), 1.78-1.93 (m, 2H), 1.98 (d, 3H, J = 1 Hz), 2.24-2.27 (m, 2H) , 2.29 (s, 3H), 2.44-2.70 (m, 4H), 3.91 (dd, 1H, J = 5, 7 Hz), 4.07 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.32 (d, 1H, J = 8 Hz), 4.48 (dd, 1H, J = 7, 10 Hz), 4.84 (t, 1H, J = 8 Hz), 4.99 (d, 1H, J = 8 Hz), 5.14 (dd, 1H, J = 3, 24 Hz), 5.28 (dd, 1H, J = 3, 22 Hz), 5.60 (d, 1H, J = 7 Hz), 7.48 (t, 2H , J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz), 9.78 (s, 1H).
[0710]
Step 8: 10-deacetoxy-7-O-fluoromethyl-10- (3-hydroxypropionyl) baccatin III
The compound obtained in the above Step 7 was reacted in the same manner as in Step 3 of Example 6 to obtain the title compound as colorless amorphous crystals.
[0711]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.05 (s, 3H), 1.11 (s, 3H), 1.51-1.61 (m, 4H), 1.70 (s, 3H), 1.87-1.93 (m, 1H), 1.98 (s, 3H), 2.20-2.27 ( m, 2H), 2.30 (s, 3H), 2.63-2.70 (m, 2H), 3.62-3.72 (m, 2H), 3.93 (t, 1H, J = 6 Hz), 4.10 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.32 (d, 1H, J = 8 Hz), 4.50 (dd, 1H, J = 7, 10 Hz), 4.84 (t, 1H, J = 8 Hz), 5.00 (d, 1H, J = 8 Hz), 5.14 (dd, 1H, J = 3, 22 Hz), 5.28 (dd, 1H, J = 3, 29 Hz), 5.61 (d, 1H, J = 7 Hz), 7.48 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
[0712]
Process 9: 10-allyl-10-deacetoxy-7-O-fluoromethylbaccatin III
The compound obtained in the above Step 8 was reacted in the same manner as in Step 4 of Example 6, and then reacted in the same manner as in Step 5 of Example 6 to obtain the title compound as a pale yellow amorphous solid.
[0713]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.07 (s, 3H), 1.12 (s, 3H), 1.71 (s, 3H), 1.89-1.93 (m, 1H), 1.95 (d, 3H, J = 1 Hz), 2.20-2.27 (m, 2H) , 2.29 (s, 3H), 2.31-2.45 (m, 1H), 2.61-2.68 (m, 1H), 2.85-2.92 (m, 1H), 4.00 (dd, 1H, J = 6, 8 Hz), 4.10 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.45 (dd, 1H, J = 7, 10 Hz), 4.85 (t, 1H, J = 8 Hz), 4.98-5.11 (m, 3H), 5.12 (dd, 1H, J = 3, 20 Hz), 5.26 (dd, 1H, J = 3, 28 Hz), 5.61 ( d, 1H, J = 7 Hz), 5.73-5.83 (m, 1H), 7.47 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
[0714]
Step 10: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyl) oxy-3-phenylpropionyl] -10-deacetoxy-7 -O-Fluoromethylbaccatin III
The compound obtained in Step 9 was reacted in the same manner as in Step 8 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0715]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.31 (s, 3H), -0.11 (s, 3H), 0.75 (s, 9H), 1.16 (s, 3H), 1.24 (s, 3H), 1.31 (s, 9H), 1.73 (s, 3H) , 1.79 (s, 3H), 1.85-1.99 (m, 1H), 2.14-2.38 (m, 3H), 2.56 (s, 3H), 2.64 (m, 1H), 2.89-2.95 (m, 1H), 3.96 (t, 1H, J = 6 Hz), 4.03 (d, 1H, J = 7 Hz), 4.22 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.43 (dd , 1H, J = 7, 10 Hz), 4.51 (s, 1H), 4.98-5.29 (m, 6H), 5.44 (d, 1H, J = 10 Hz), 5.77 (d, 1H, J = 7 Hz) , 5.79-5.85 (m, 1H), 6.26 (t, 1H, J = 8 Hz), 7.25-7.39 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.11 (d, 2H, J = 8 Hz).
[0716]
Step 11: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-7-O-fluoromethylbaccatin III
The compound obtained in Step 10 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0717]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.16 (s, 3H), 1.22 (s, 3H), 1.34 (s, 9H), 1.72 (s, 3H), 1.75 (s, 3H), 1.90-1.97 (m, 1H), 2.20-2.28 (m, 2H), 2.37 (s, 3H), 2.33-2.41 (m, 1H), 2.59-2.67 (m, 1H), 2.86-2.92 (m, 1H), 3.32 (d, 1H, J = 5 Hz), 3.96 -4.01 (m, 2H), 4.20 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.40 (dd, 1H, J = 7, 10 Hz), 4.61 (s, 1H), 4.94-5.13 (m, 4H), 5.21-5.28 (m, 2H), 5.39 (d, 1H, J = 10 Hz), 5.66 (d, 1H, J = 7 Hz), 5.70-5.80 (m , 1H), 6.19 (t, 1H, J = 8 Hz), 7.30-7.42 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
[0718]
Step 12: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetoxy-7-O-fluoromethyl-10- (2- Morpholinoethyl) Baccatin III
The compound obtained in Step 11 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0719]
Melting point: 142-146 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.15 (s, 3H), 1.20 (s, 3H), 1.34 (s, 9H), 1.72 (s, 3H), 1.85 (s, 3H), 2.38 (s, 3H), 1.60-2.70 (m, 12H) , 3.68 (m, 4H), 4.00-4.06 (m, 2H), 4.19 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.41 (dd, 1H, J = 7 , 10 Hz), 4.60 (s, 1H), 4.96 (d, 1H, J = 8 Hz), 5.11 (dd, 1H, J = 3, 27.5 Hz), 5.22-5.28 (m, 2H), 5.41 (d , 1H, J = 10 Hz), 5.65 (d, 1H, J = 7 Hz), 6.17 (t, 1H, J = 8 Hz), 7.30-7.42 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.61 (t, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz).
MS-FAB: 937 (MH+).
[0720]
Example 49
[0721]
Embedded image
Step 1: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3-phenyl-2- (triethylsilyl) oxypropionyl] -10-deacetoxy- 7- O- Fluoromethylbaccatin III
The compound obtained in Step 9 of Example 48 and Step 3 of Reference Example 4 was reacted in the same manner as in Step 1 of Example 4 to obtain the title compound as a colorless amorphous solid.
[0723]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.74 (m, 6H), 0.86 (t, 9H, J = 7 Hz), 1.17 (s, 12H), 1.30 (s, 3H), 1.38 (s, 3H), 1.74 (s, 3H), 1.78 (s, 3H), 1.93-2.11 (m, 2H), 2.29-2.36 (m, 2H), 2.60-2.66 (m, 1H), 2.70 (s, 3H), 2.90-2.97 (m, 1H), 3.93 (t, 1H, J = 7 Hz), 4.01 (d, 1H, J = 7 Hz), 4.23 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.41 (dd , 1H, J = 7, 10 Hz), 4.97-5.13 (m, 4H), 5.25 (dd, 1H, J = 2.5, 26 Hz), 5.49 (d, 1H, J = 10 Hz), 5.69 (d, 1H, J = 7 Hz), 5.77-5.85 (m, 1H), 6.37 (t, 1H, J = 8 Hz), 7.31-7.36 (m, 5H), 7.50 (t, 2H, J = 8 Hz), 7.57 (t, 1H, J = 8 Hz), 8.14 (d, 2H, J = 8 Hz).
[0724]
Step 2: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-7-O- Fluoromethylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 9 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0725]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.17 (s, 3H), 1.23 (s, 9H), 1.27 (s, 3H), 1.36 (s, 3H), 1.70 (s, 3H), 1.73 (s, 3H), 1.89-1.98 (m, 1H) , 2.15-2.40 (m, 3H), 2.62 (s, 3H), 2.60-2.67 (m, 1H), 2.86-2.93 (m, 1H), 3.60 (s, 3H), 3.97 (dd, 1H, J = 6, 8.5 Hz), 4.01 (d, 1H, J = 7 Hz), 4.21 (d, 1H, J = 8 Hz), 4.33 (d, 1H, J = 8 Hz), 4.40 (dd, 1H, J = 7, 10 Hz), 4.97-5.13 (m, 4H), 5.25 (dd, 1H, J = 3, 24 Hz), 5.54 (d, 1H, J = 10 Hz), 5.67 (d, 1H, J = 7 Hz), 5.71-5.80 (m, 1H), 6.31 (t, 1H, J = 8 Hz), 7.32-7.36 (m, 5H), 7.49 (t, 2H, J = 8 Hz), 7.59 (t, 1H , J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
[0726]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-7-O-fluoromethyl-10 -(2-morpholinoethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0727]
Melting point: 152-155 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.16 (s, 3H), 1.23 (s, 9H), 1.25 (s, 3H), 1.39 (s, 3H), 1.73 (s, 3H),
1.79 (s, 3H), 2.64 (s, 3H), 1.90-2.70 (m, 12H), 3.68 (m, 4H), 4.01-4.04 (m, 2H), 4.21 (d, 1H, J = 8 Hz) , 4.33 (d, 1H, J = 8 Hz), 4.42 (dd, 1H, J = 7, 10 Hz), 4.98-5.13 (m, 4H), 5.25 (dd, 1H, J = 3, 20 Hz), 5.54 (d, 1H, J = 10 Hz), 5.67 (d, 1H, J = 7 Hz), 6.30 (t, 1H, J = 8 Hz), 7.32-7.40 (m, 5H), 7.49 (t, 2H , J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.13 (d, 2H, J = 8 Hz).
MS-FAB: 951 (MH+).
[0728]
Example 50
[0729]
Embedded image
Step 1: 10-allyl-10-deacetoxy-7-O-fluoromethyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 9 of Example 48 was reacted in the same manner as in Step 3 of Example 1 to obtain the title compound as a colorless amorphous solid.
[0731]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.64-0.70 (m, 6H), 1.02 (t, 9H, J = 7 Hz), 1.12 (s, 3H), 1.13 (s, 3H), 1.70 (s, 3H), 1.90-1.96 (m, 1H) , 1.90 (s, 3H), 2.10-2.37 (m, 4H), 2.29 (s, 3H), 2.59-2.67 (m, 1H), 2.86-2.91 (m, 1H), 3.96 (dd, 1H, J = 6, 8 Hz), 4.03 (d, 1H, J = 7 Hz), 4.18 (d, 1H, J = 8 Hz), 4.31 (d, 1H, J = 8 Hz), 4.44 (dd, 1H, J = 7, 10 Hz), 4.91 (t, 1H, J = 9 Hz), 4.98-5.09 (m, 3H), 5.10 (dd, 1H, J = 3, 25 Hz), 5.24 (dd, 1H, J = 3 , 30 Hz), 5.61 (d, 1H, J = 7 Hz), 5.72-5.83 (m, 1H), 7.47 (t, 2H, J = 8 Hz), 7.60 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
[0732]
Step 2: 10-allyl-10-deacetoxy-1-O-dimethylsilyl-7-O-fluoromethyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 1 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0733]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.25 (d, 3H, J = 2.5 Hz), 0.06 (d, 3H, J = 2.5 Hz), 0.66-0.73 (m, 6H), 1.03 (t, 9H, J = 7 Hz), 1.08 (s, 3H), 1.12 (s, 3H), 1.69 (s, 3H), 1.89 (s, 3H), 1.90-1.95 (m, 1H), 2.22-2.39 (m, 3H), 2.30 (s, 3H), 2.57 -2.65 (m, 1H), 2.87-2.93 (m, 1H), 3.93 (dd, 1H, J = 6, 8 Hz), 4.01 (d, 1H, J = 7 Hz), 4.25 (AB type d, each 1H, J = 9 Hz), 4.40 (dd, 1H, J = 7, 10 Hz), 4.53 (m, 1H), 4.92-4.99 (m, 3H), 5.05-5.13 (m, 2H), 5.23 (dd , 1H, J = 3, 30 Hz), 5.69 (d, 1H, J = 7 Hz), 5.75-5.85 (m, 1H), 7.47 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.09 (d, 2H, J = 8 Hz).
[0734]
Step 3: 10-allyl-10-deacetoxy-4-deacetyl-1-O-dimethylsilyl-7-O-fluoromethyl-13-O-triethylsilylbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 2 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0735]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.28 (d, 3H, J = 3 Hz), 0.02 (d, 3H, J = 3Hz), 0.74-0.85 (m, 6H), 0.97 (s, 3H), 1.08-1.13 (m, 12H), 1.59 (s, 3H), 1.90 (s, 3H), 1.94-2.02 (m, 1H), 2.46-2.59 (m, 3H), 2.80 (dd, 1H, J = 2, 13 Hz), 2.84-2.89 (m , 1H), 3.76-3.80 (m, 1H), 4.00-4.06 (m, 1H), 4.24 (d, 1H, J = 9 H), 4.32 (d, 1H, J = 9 Hz), 4.56-4.58 ( m, 1H), 4.67-4.75 (m, 2H), 5.00-5.13 (m, 3H), 5.25 (dd, 1H, J = 3, 24 Hz), 5.57 (d, 1H, J = 7 Hz), 5.75 -5.83 (m, 1H), 7.44 (t, 2H, J = 8 Hz), 7.56 (t, 1H, J = 8 Hz), 8.12 (d, 2H, J = 8 Hz).
[0736]
Step 4: 10-allyl-10-deacetoxy-4-deacetyl-1-O-dimethylsilyl-4-O-ethoxycarbonyl-7-O-fluoromethyl-13-O-triethylsilylbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 9 of Example 9 to obtain the title compound as a colorless amorphous solid.
[0737]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (d, 3H, J = 3 Hz), 0.06 (d, 3H, J = 3 Hz), 0.64-0.70 (m, 6H), 1.02 (t, 9H, J = 7 Hz), 1.12 (s, 6 H), 1.41 (t, 3H, J = 7 Hz), 1.69 (s, 3H), 1.90 (s, 3H), 1.92-1.97 (m, 1H), 2.22-2.34 (m, 2H), 2.57- 2.64 (m, 1H), 2.87-2.94 (m, 1H), 3.91 (dd, 1H, J = 6, 8 Hz), 4.04 (d, 1H, J = 7 Hz), 4.13-4.21 (m, 1H) , 4.26 (AB type d, each 1H, J = 9 Hz), 4.35-4.43 (m, 2H), 4.53-4.56 (m, 1H), 4.94-5.14 (m, 4H), 5.25 (dd, 1H, J = 3, 30 Hz), 5.71 (d, 1H, J = 7 Hz), 5.74-5.84 (m, 1H), 7.46 (t, 2H, J = 8 Hz), 7.57 (t, 1H, J = 8 Hz ), 8.10 (d, 2H, J = 8 Hz).
[0738]
Step 5: 10-allyl-10-deacetoxy-4-deacetyl-4-O-ethoxycarbonyl-7-O-fluoromethylbaccatin III
The compound obtained in the above Step 4 was reacted in the same manner as in Step 4 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0739]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.07 (s, 3H), 1.13 (s, 3H), 1.39 (t, 3H, J = 7 Hz), 1.70 (s, 3H), 1.90-1.94 (m, 1H), 1.97 (s, 3H), 2.22 -2.43 (m, 2H), 2.62-2.69 (m, 1H), 2.86-2.93 (m, 1H), 4.02 (dd, 1H, J = 6, 8 Hz), 4.13-4.25 (m, 3H), 4.31 -4.39 (m, 3H), 4.84 (br, 1H), 4.98-5.15 (m, 4H), 5.26 (dd, 1H, J = 3, 30 Hz), 5.63 (d, 1H, J = 7 Hz), 5.74-5.83 (m, 1H), 7.48 (t, 2H, J = 8 Hz), 7.59 (t, 1H, J = 8 Hz), 8.11 (d, 2H, J = 8 Hz).
[0740]
Step 6: 10-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-methyl-3-phenyl-2- (triethylsilyl) oxypropionyl] -10-deacetoxy- 4-Deacetyl-4-O-ethoxycarbonyl-7-O-fluoromethylbaccatin III
The compound obtained in Step 5 above and the compound obtained in Step 3 of Reference Example 4 were reacted in the same manner as in Step 1 of Example 4 to obtain the title compound as a colorless amorphous solid.
[0741]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.43-0.86 (m, 6H), 0.84 (t, 9H, J = 7 Hz), 1.17 (s, 3H), 1.24 (s, 3H), 1.27 (s, 9H), 1.39 (t, 3H, J = 7 Hz), 1.44 (s, 3H), 1.76 (s, 3H), 1.83 (s, 3H), 1.92-1.98 (m, 1H), 2.10-2.16 (m, 1H), 2.35-2.44 (m, 2H ), 2.61-2.69 (m, 1H), 2.91-2.95 (m, 1H), 3.99 (t, 1H, J = 7 Hz), 4.20 (d, 1H, J = 7 Hz), 4.30 (s, 2H) , 4.40 (dd, 1H, J = 7, 10 HZ), 4.64-4.73 (m, 2H), 4.98-5.15 (m, 4H), 5.24 (dd, 1H, J = 3, 30 Hz), 5.54 (d , 1H, J = 10 Hz), 5.69 (d, 1H, J = 7 Hz), 5.76-5.83 (m, 1H), 6.29 (t, 1H, J = 8 Hz), 7.30-7.45 (m, 7H) , 7.56 (t, 1H, J = 8 Hz), 8.12 (d, 2H, J = 8 Hz).
[0741]
Step 7: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-2-methyl-3-phenylpropionyl] -10-deacetoxy-4-deacetyl-4-O- Ethoxycarbonyl-7-O-fluoromethyl-10- (2-morpholinoethyl) baccatin III
The compound obtained in the above Step 6 was reacted in the same manner as in Step 9 of Example 1, and then reacted in the same manner as in Step 10 of Example 1 to obtain the title compound as a colorless solid.
[0743]
Melting point: 143-146 ° C.
1H-NMR (CDClThree/ TMS) δ (ppm):
1.16 (s, 3H), 1.21 (s, 3H), 1.32 (s, 9H), 1.42-1.44 (m, 6H), 1.73 (s, 3H), 1.80 (s, 3H), 1.92-1.98 (m, 1H), 2.20-2.71 (m, 11H), 3.61 (br, 1H), 3.68 (m, 4H), 4.05 (t, 1H, J = 7 Hz), 4.10 (d, 1H, J = 7 Hz), 4.24 (d, 1H, J = 8 Hz), 4.33-4.38 (m, 2H), 4.56-4.60 (m, 2H), 5.00-5.13 (m, 4H), 5.24 (dd, 1H, J = 3, 20 Hz), 5.68-5.72 (m, 2H), 6.18 (t, 1H, J = 8 Hz), 7.27-7.47 (m, 7H), 7.58 (t, 1H, J = 8 Hz), 8.09 (d, 2H , J = 8 Hz). MS-FAB: 981 (MH+).
[0744]
【The invention's effect】
The following experimental examples show the antitumor effect of the compounds of the present invention.
Experimental example
Three tumor cells, P388, PC-6 and PC-12, respectively,2 cells / 150 μl / well, PC-6 is 5.0 × 10Three cells / 150 μl / well, PC-12 is 1.0 × 10Three A 96-well microplate was seeded at cells / 150 μl / well, and P388 was added 2 hours later, and the other two samples were added 50 μl / well after 24 hours. Thereafter, the cells were cultured for 3 days, and a 5 mg / ml solution of MTT [3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyl-2H-tetrazolium bromide] was added at 20 μl / well. After 4 hours, the culture solution was removed, dimethyl sulfoxide was added at 150 μl / well, and the absorbance was measured at 540 nm. The antitumor effect is determined by the drug concentration at which the cell growth of the drug-added group is 50% of the control group50 It was shown as a value (ng / ml).
[0745]
[Table 1]
Claims (27)
Ｒ1 はフェニル基を意味し、該フェニル基はハロゲン原子、アルキル基およびアルコキシル基からなる群から選ばれる基を置換基として１個または複数個有していてもよい。
Ｒ2 はアルキル基、アルケニル基、アルキニル基、シクロアルキル基またはアルコキシル基を意味し、これらアルキル基、アルケニル基、アルキニル基、シクロアルキル基およびアルコキシル基は、ハロゲン原子、水酸基、カルボキシル基、アルコキシル基、アリールオキシ基、フェニル基、アミノ基、アルキルアミノ基、アルコキシカルボニル基、アリールオキシカルボニル基、アシル基、アシルアミノ基およびアシルオキシ基からなる群から選ばれる基を置換基として１個または複数個有していてもよい。
Ｒ3 はアルキル基およびアシル基からなる群から選ばれる基を置換基として１個または２個有するアミノ基、水素原子、水酸基、ハロゲン原子、アルコキシル基、アジド基またはアシルオキシ基を意味する。
Ｒ4 はアルキル基およびアシル基からなる群から選ばれる基を置換基として１個または２個有するアミノ基、水素原子、水酸基、ハロゲン原子、アルコキシル基、アジド基またはアシルオキシ基を意味し、該アルコキシル基およびアシルオキシ基は、ハロゲン原子、水酸基、カルボキシル基、シクロアルキル基、アルコキシル基、アリール基、アリールオキシ基、アミノ基、アルキルアミノ基、アルコキシカルボニル基、アリールオキシカルボニル基、アシル基、アシルアミノ基、アシルオキシ基および複素環基（該複素環基は、その環の構成原子上にアルキル基を１個または複数個有してもよい。）からなる群から選ばれる基を置換基として１個または複数個有してもよい。
また、Ｒ3 とＲ4 は一緒になって式
で表される構造を形成してもよい。
Ｒ5 はメチル基を意味するか、
または、Ｒ4 と一緒になって、Ｒ4 とＲ5 のそれぞれが結合している炭素原子と共に３員環を形成した構造となってもよい。
Ｒ6 はアルキル基、アルケニル基またはアルキニル基を意味し、
これらアルキル基、アルケニル基およびアルキニル基は、カルボキシル基、アルコキシル基、アリールオキシ基、アルコキシカルボニル基、アリールオキシカルボニル基、シアノ基、水酸基、アミノ基、アルキルアミノ基、アシル基、アシルアミノ基、アシルオキシ基、アルコキシカルボニルアミノ基、アルキルチオ基、アルキルスルフィニル基、アルキルスルホニル基および式
Ｚ1 は水素原子、水酸基、ハロゲン原子またはアルキル基を意味し、
Ｚ2 は水素原子、水酸基、ハロゲン原子またはアルキル基を意味し、
Ｚ3 はアルキル基、アルケニル基、アルキニル基、シクロアルキル基、アリール基または複素環基を意味し、これらアルキル基、アルケニル基、アルキニル基、シクロアルキル基、アリール基および複素環基は、ハロゲン原子、水酸基、カルボキシル基、アルキル基、アルコキシル基、フェニル基、アミノ基、アルキルアミノ基、アミノアルキル基、アルキルアミノアルキル基、アルコキシカルボニル基、アリールオキシカルボニル基、アシル基、アシルアミノ基およびアシルオキシ基からなる群から選ばれる基を置換基として１個または複数個有してもよい。Ｚ4 はアルキル基、アリール基またはアルコキシル基を意味し、これらアルキル基、アリール基およびアルコキシル基は、ハロゲン原子、水酸基、カルボキシル基、アルキル基、アルコキシル基、フェニル基、アミノ基、アルキルアミノ基、アミノアルキル基、アルキルアミノアルキル基、アルコキシカルボニル基、アリールオキシカルボニル基、アシル基、アシルアミノ基およびアシルオキシ基からなる群から選ばれる基を置換基として１個または複数個有してもよい。
なお、
R 1 means a phenyl group, and the phenyl group may have one or more substituents selected from the group consisting of a halogen atom, an alkyl group and an alkoxyl group.
R 2 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or an alkoxyl group. These alkyl group, alkenyl group, alkynyl group, cycloalkyl group and alkoxyl group are each a halogen atom, a hydroxyl group, a carboxyl group or an alkoxyl group. , An aryloxy group, a phenyl group, an amino group, an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group having one or more substituents as a substituent It may be.
R 3 represents an amino group, a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group, an azido group or an acyloxy group having one or two groups selected from the group consisting of an alkyl group and an acyl group as a substituent.
R 4 represents an amino group, a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group, an azide group or an acyloxy group having one or two groups selected from the group consisting of an alkyl group and an acyl group as a substituent. Group and acyloxy group are halogen atom, hydroxyl group, carboxyl group, cycloalkyl group, alkoxyl group, aryl group, aryloxy group, amino group, alkylamino group, alkoxycarbonyl group, aryloxycarbonyl group, acyl group, acylamino group, One or a plurality of substituents selected from a group selected from the group consisting of an acyloxy group and a heterocyclic group (the heterocyclic group may have one or more alkyl groups on the constituent atoms of the ring) You may have.
R 3 and R 4 together form the formula
You may form the structure represented by these.
R 5 represents a methyl group or
Or it may be a structure in which a three-membered ring is formed together with the carbon atom to which each of R 4 and R 5 is bonded together with R 4 .
R 6 represents an alkyl group, an alkenyl group or an alkynyl group,
These alkyl group, alkenyl group and alkynyl group are carboxyl group, alkoxyl group, aryloxy group, alkoxycarbonyl group, aryloxycarbonyl group, cyano group, hydroxyl group, amino group, alkylamino group, acyl group, acylamino group, acyloxy group. , Alkoxycarbonylamino group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group and formula
Z 1 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group,
Z 2 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group,
Z 3 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group, and these alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heterocyclic group are each a halogen atom. , Hydroxyl group, carboxyl group, alkyl group, alkoxyl group, phenyl group, amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxycarbonyl group, aryloxycarbonyl group, acyl group, acylamino group and acyloxy group One or more groups selected from the group may be substituted. Z 4 means an alkyl group, an aryl group or an alkoxyl group, and these alkyl group, aryl group and alkoxyl group are a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, a phenyl group, an amino group, an alkylamino group, One or more groups selected from the group consisting of an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group may be included as a substituent.
In addition,
で表される構造を形成した、一般式（Ｉ−１）で表わされる請求項１記載の化合物およびその塩
The compound of Claim 1 and its salt which are represented by general formula (I-1) which formed the structure represented by these
で表される、５員環または６員環の大きさの窒素原子を含む飽和の複素環基（該複素環基は、その環の構成原子である炭素原子上にアルキル基を１個または複数個有してもよい。）を有する炭素数１から３のアルキル基、またはアリル基である請求項１から３のいずれか一項に記載の化合物およびその塩R 6 is a substituent as a formula
And a saturated heterocyclic group containing a nitrogen atom having a size of a 5-membered ring or a 6-membered ring (wherein the heterocyclic group has one or more alkyl groups on the carbon atom which is a constituent atom of the ring) The compound and the salt thereof according to any one of claims 1 to 3, which may be an alkyl group having 1 to 3 carbon atoms or an allyl group.
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