JP3921252B2 - Ether derivatives - Google Patents

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Publication number
JP3921252B2
JP3921252B2 JP01627896A JP1627896A JP3921252B2 JP 3921252 B2 JP3921252 B2 JP 3921252B2 JP 01627896 A JP01627896 A JP 01627896A JP 1627896 A JP1627896 A JP 1627896A JP 3921252 B2 JP3921252 B2 JP 3921252B2
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alkyl
alkoxyl
atom
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JPH08301861A (en
Inventor
弘文 寺沢
恒彦 曽我
浩一 魚戸
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第一製薬株式会社
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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】
タキソールは化3に示す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3】

Figure 0003921252
【0004】
タキソールは抗腫瘍活性を有することが知られており、その作用機作は細胞分裂における微小管の解重合阻害作用に基づくものとされており、従来の抗腫瘍剤とは異なるタイプの抗腫瘍剤としてその臨床応用が期待されている。
【0005】
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化4で表され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
【0006】
【化4】
Figure 0003921252
【0007】
を原料として用いて半合成したタキソール誘導体が報告され始めている(特開平03−505725)。なかでも化5で表される構造を有する化合物(タキソテール)は、タキソールと同等以上の抗腫瘍活性を有する化合物として注目され、現在抗腫瘍剤としての開発が進められている。
【0008】
【化5】
Figure 0003921252
【0009】
【発明が解決しようとする課題】
しかしながら、タキソールや化5で表される誘導体は抗腫瘍剤として有望なものではあるが、臨床試験では消化器癌、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。また、タキソールや化5で表される誘導体は水溶性が低いことも知られている。
【0010】
【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位に置換基を持たない誘導体(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位にエーテル型置換基を導入した誘導体が強い抗腫瘍活性を有すると共に水溶性を改善できることを見いだし本発明を完成した。
【0011】
本発明は、一般式(I)
【0012】
【化6】
Figure 0003921252
[式中、
1 はフェニル基
(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もよい。)
を意味する。
【0013】
2 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
(これらアルキル基、アルケニル基、アルキニル基、シクロアルキル基またはアルコキシル基は、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もよい。なお、置換基の置換位置は該アルキル基、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のいずれの位置でもよい。)
を意味する。
【0014】
3 は水酸基、水素原子またはハロゲン原子を意味する。また、R3 は8位に結合しているメチル基と一緒になって次の部分構造を形成してもよい。
【0015】
【化7】
Figure 0003921252
【0016】
4 はアルキル基、アルケニル基またはアルキニル基
(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、アリール基および複素環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、置換基の置換位置は該アルキル基、アルケニル基およびアルキニル基のいずれの位置でもよい。また、アリール基および複素環基はさらにカルボキシル基、アルキル基、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、アミノアルキル基、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およびアルキルスルホニ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もよい。なお、置換基の置換位置は該アリール基および複素環基のいずれの位置でもよい。)
を意味する。
【0017】
5 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する。
6 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する。
【0018】
7 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
(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、または複素環基は、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、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、置換基の置換位置は該アルキル基、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のいずれの位置でもよい。)
を意味する。
【0019】
8 はアルキル基、アリール基またはアルコキシル基
(これらアルキル基、アリール基またはアルコキシル基は、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、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、置換基の置換位置は該アルキル基、アリール基およびアルコキシル基のいずれの位置でもよい。)
を意味する。]
で表される化合物およびその塩に関する。
【0020】
次に、本明細書で用いる用語について説明する。
ここで用いられる、“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。
【0021】
“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。
【0022】
“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。)が置換したものでもよく、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。
【0023】
“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。)が置換したものでもよく、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。
【0024】
“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。
【0025】
“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。
【0026】
“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。
【0027】
“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。
【0028】
“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。
【0029】
“式
【0030】
【化8】
Figure 0003921252
【0031】
(Xは酸素原子、硫黄原子、S=O、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、チオモルホリン−1−オキサイド等が挙げられる。
【0032】
次に、一般式(I)中の各置換基の好ましいものを挙げる。
【0033】
1 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。
【0034】
1 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。
【0035】
1 としては、フッ素原子、塩素原子、メチル基またはメトキシ基が1個または2個メタ位に置換したフェニル基、または無置換のフェニル基が好ましい。
【0036】
2 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。
【0037】
2 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。
【0038】
2 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。
【0039】
2 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。
【0040】
2 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。
【0041】
3 の“ハロゲン原子”としては、フッ素原子が好ましい。
【0042】
3 としては、水素原子または水酸基が好ましい。
【0043】
4 としてはアルケニル基、アルキル基が好ましい。(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、アリール基および複素環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、アリール基および複素環基は、さらにカルボキシル基、アルキル基、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およびアルキルスルホニ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もよい。)
4 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。
【0044】
4 における“アルケニル基”としては、C3 〜C6 アルケニル基が好ましく、特にアリル基が好ましい。
【0045】
4 のアルキル基の置換基としては、アルキルアミノ基または複素環基が好ましい。
【0046】
複素環基の中では式
【0047】
【化9】
Figure 0003921252
【0048】
(Xは酸素原子、硫黄原子、S=O、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員環または6員環の大きさの飽和の複素環基(該複素環基は、その環の構成成分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。
【0049】
アルキルアミノ基のアルキル部分はC1 〜C3 アルキル基が好ましく、ジアルキル置換でもよい。(ジアルキル置換の場合、その2つのアルキル基は同一でも異なっていてもよい。)

【0050】
【化10】
Figure 0003921252
【0051】
(Xは酸素原子、硫黄原子、S=O、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員環または6員環の大きさの飽和の複素環基(該複素環基は、その環の構成成分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。)の中では、ピロリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリンから導かれる基が特に好ましい。また、YはC1 〜C3 アルキル基が好ましい。
【0052】
また、複素環基の環の構成成分である炭素原子上に置換するアルキル基としては、C1 〜C3 アルキル基が好ましく、特にメチル基が好ましい。
【0053】
4 としては、アリル基、モルホリノエチル基、チオモルホリノエチル基が最も好ましい。
【0054】
5 およびR6 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。
【0055】
5 およびR6 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。
【0056】
5 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。
【0057】
6 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。
【0058】
5 およびR6 として最も好ましいのは、R5 がフッ素原子、R6 がフッ素原子の組み合わせのもの、R5 が水酸基、R6 が水素原子の組み合わせのもの、あるいはR5 が水酸基、R6 がメチル基の組み合わせのものが挙げられる。
【0059】
7 としてはアリール基、複素環基、アルケニル基が好ましい。
【0060】
7 の“アリール基”としては、フェニル基が好ましい。
【0061】
7 の“アルケニル基”としては、2−メチル−1−プロペニルが好ましい。
【0062】
7 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、モルホリン等が挙げられる。
【0063】
7 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基が挙げられる。
【0064】
7 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基が最も好ましい。
【0065】
7 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。
【0066】
8 はアリール基またはアルコキシル基が好ましい。
【0067】
8 の“アリール基”としては、フェニル基が好ましい。
【0068】
8 の“アルコキシル基”としては、第三級ブトキシが好ましい。
【0069】
8 としては、フェニル基、第三級ブトキシ基が特に好ましい。
【0070】
本願に含まれる化合物としてはR1 がフェニル基、R2 がメチル基、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、R3 が水素原子または水酸基、R4 がアリル基、モルホリノエチル基またはチオモルホリノエチル基、R5 が水酸基、R6 が水素原子、R7 がフェニル基、フリル基または2−メチル−1−プロペニル基、R8 が第三級ブトキシ基である化合物が最も好ましい。
【0071】
本発明においては、化11に示す立体配置のものが好ましい。
【0072】
【化11】
Figure 0003921252
【0073】
また、置換基R7 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。
【0074】
本発明化合物においては、次の構造を有するものも好ましい例としてあげることができる。
【0075】
【化12】
Figure 0003921252
【0076】
および
【0077】
【化13】
Figure 0003921252
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。
【0078】
本発明化合物の製造法を説明する。
【0079】
【化14】
Figure 0003921252
【0080】
(上記反応式中、R21はR2 および保護基によって保護されているR2 (R2 が水酸基やアミノ基等で置換されている場合)を意味する。
【0081】
31は水素原子、ハロゲン原子または保護された水酸基を意味する。
【0082】
41は水素原子、アルキル基、アルケニル基、アリール基、アルコキシカルボニル基等を意味し、ビニル基、フェニル基等が好ましい。
【0083】
Xはヨウ素、臭素等のハロゲン原子またはメタンスルホニルオキシ基やp−トルエンスルホニルオキシ基等の脱離基として作用するものを意味する。
【0084】
51は水素原子、保護された水酸基、ハロゲン原子またはアルキル基を意味する。
【0085】
61は水素原子、保護された水酸基、ハロゲン原子またはアルキル基を意味する。
【0086】
71はR7 および保護基によって保護されているR7 (R7 が水酸基やアミノ基等で置換されている場合)を意味する。
【0087】
81はR8 および保護基によって保護されているR8 (R8 が水酸基やアミノ基等で置換されている場合)を意味する。
【0088】
9 およびR10はそれぞれ独立して水素原子、アルキル基、アリール基等を意味し、両方ともメチル基であるものや一方がp−メトキシフェニル基で他方が水素原子であるものが好ましい。
【0089】
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。)
まず、式(1)で表される化合物(以下、化合物(1)と表し、その他の番号で表される化合物も同様に表す。)と化合物(2)を溶媒中、塩基の存在下で処理し、10位水酸基を選択的にエーテル化することにより化合物(3)が得られる。
【0090】
溶媒としては、反応に不活性なものが良く、例えば、テトラヒドロフラン、N,N−ジメチルホルムアミド、ジメチルスルホキシド等が挙げられる。
【0091】
塩基としてはノルマルブチルリチウムや水素化ナトリウム等が挙げられる。
【0092】
次いで、化合物(3)に対し、化合物(4)、化合物(5)または化合物(6)を当該分野で知られている種々の方法で縮合させ、必要ならさらに変換反応を実施することにより化合物(7)を得ることができる。
【0093】
化合物(4)または(5)を用いる縮合反応としては、4−ジメチルアミノピリジン等の塩基触媒の存在下、ジ(2−ピリジル)カルボネートやジシクロヘキシルカルボジイミドのようなカルボン酸の活性化剤を用いる方法がある。なお、化合物(4)を用いた場合は、R51およびR61は水素原子と水酸基の組合せとなる。
【0094】
化合物(6)を用いる縮合反応としては、ナトリウムヘキサメチルジシラジド等の塩基を用いる方法がある。
【0095】
最後に、必要ならば一般的な有機化学的変換反応によって化合物(7)のR41を変換し(化合物(3)を化合物(4)、化合物(5)または化合物(6)と縮合させる前に、化合物(3)のR41 を変換してもよい。)、各種保護基を脱離することにより、目的物を得ることができる。
【0096】
3 が水素原子である目的化合物を得るには、例えば、R31が保護された水酸基である化合物(3)を得た後、保護基を除去し、R31を水酸基に変換し、水酸基を文献上知られている方法(例えば、J. Org. Chem., 58, 5028 (1993))で除去して、R3 が水素原子である化合物(3)を得た後、上記と同様の方法で、化合物(4)、(5)または(6)との縮合反応、必要なら10位部分の変換、さらに脱保護反応を実施すればよい。なお、初めにR31が水素原子である化合物(1)を合成した後、化合物(3)に変換し、縮合反応、10位部分の変換を行い目的物を得る方法もある。
【0097】
3 がハロゲン原子である目的化合物、例えば、R3 がフッ素原子である化合物を得るには、R31が保護された水酸基である化合物(3)を得た後、保護基を除去し、R31を水酸基に変換する。その後、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リフルオライドで処理し、R3 がフッ素原子である化合物(3)を得、さらに上記と同様の方法で、化合物(4)、(5)または(6)との縮合反応、必要なら10位部分の変換、さらに脱保護反応を実施すればよい。なお、初めにR31がフッ素原子である化合物(1)を合成した後、化合物(3)に変換し、縮合反応、10位部分の変換を行い目的物を得る方法もある。
【0098】
また、R1 が置換基を有するフェニル基である化合物は、例えば、文献(Tetrahedron Lett., 35, 8931(1994))記載の方法に従って、得られた化合物(7)の2位のエステルを選択的に加水分解した後、アシル化することにより得られる。
【0099】
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、R1 がフェニル基、R21 がメチル基である化合物が文献上知られている(例えば、J. Am. Chem. Soc., 110, 5917 (1988) )。
【0100】
なお、R2 がメチル基以外のアルキル基である化合物(1)は、次のようにして製造できる。
【0101】
【化15】
Figure 0003921252
【0102】
(式中、R40は水酸基の保護基を意味し、トリエチルシリル基、2,2,2−トリクロロエトキシカルボニル基、ベンジル基が好ましい。
1 およびR31は前記と同じ。)
まず、化合物(8)を酸化(不活性な溶媒中(ジオキサン等)で、二酸化マンガンと室温、あるいは加熱下で処理する等)し、化合物(9)を得る。
【0103】
次に、化合物(9)を反応に不活性な溶媒(テトラヒドロフラン等)中、反応温度−100℃から0℃で塩基と反応させた後、R22−Z(R22は、アルキル基を意味し、Zはヨウ素原子、臭素原子等のハロゲン原子、あるいはメタンスルホニル基やパラトルエンスルホニル基等の脱離基を意味する。)で表わされる化合物と−100℃から室温で反応させることにより、化合物(10)が得られる。
【0104】
使用する塩基としては、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、リチウムジイソプロピルアミド、第三級ブトキシカリウム、水素化ナトリウム等が挙げられ、塩基の使用量は、化合物(9)に対して1から10当量用いればよい。
【0105】
得られた化合物(10)を還元{溶媒(メタノールやテトラヒドロフラン等)中で、還元剤(水素化ホウ素ナトリウム等)で処理する等}し、化合物(11)を得ることができる。
【0106】
化合物(11)の10位の保護基をはずすことにより、R2 がメチル基以外のアルキル基である化合物(1)を得ることができる。
【0107】
製造原料である、化合物(4)、化合物(5)および化合物(6)は、化合物(4)は、テトラヘドロン レター,33,5185(1992)記載の方法に従って、化合物(5)は、ジャーナル オブ アメリカン ケミカル ソサエティー,110,5917(1988)記載の方法に従って、化合物(6)は、テトラヘドロン レター,34,4149(1993)記載の方法に従って、それぞれ合成できる。
【0108】
次に実施例で詳しく説明する。なお、実施例においては次の略号を用いる。
【0109】
TES :トリエチルシリル基
Bz :ベンジル基
Boc :tert−ブトキシカルボニル基
Ph :フェニル基
Troc:2,2,2−トリクロロエトキシカルボニル基
TBS :tert−ブチルジメチルシリル基
Tf :トリフルオロメタンスルホニル基
TIPS:トリイソプロピルシリル基
MP :p−メトキシフェニル基
Ts :p−トルエンスルホニル基
DMS :ジメチルシリル基
【0110】
【実施例】
実施例1
【0111】
【化16】
Figure 0003921252
【0112】
工程1:10−O−アリル-10-デアセチル-7−O−トリエチルシリルバッカチン III
200 mgの 10-デアセチル-7−O−トリエチルシリルバッカチン IIIを乾燥したテトラヒドロフラン 2 ml に溶解し、 -78 ℃に冷却した。 そこに、 n-ブチルリチウム(1.64 M n−ヘキサン溶液、 0.277 ml)を滴下し、15分間撹拌した後、 ヨウ化アリル 0.041 ml をジメチルスルホキシド 0.5 ml に溶かした溶液を滴下し、 0℃で 3時間撹拌した。 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し、 水、 飽和食塩水で洗浄後、 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=40:1(v/v))にて精製し、標記化合物 156 mg を白色結晶として得た。
【0113】
融点:205-209 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.64(m,6H), 0.95(t,9H,J=7Hz), 1.06(s,3H), 1.20(s,3H),
1.67(s,3H), 1.85-1.92(m,1H), 2.08(s,3H), 2.26-2.29(m,2H),
2.28(s,3H), 2.46-2.53(m,1H), 3.88(d,1H,J=7Hz), 4.01-4.10(m,2H),
4.15(d,1H,J=8Hz), 4.30(d,1H,J=8Hz), 4.43(dd,1H,J=7Hz,10Hz),
4.87-4.90(m,1H), 4.96(d,1H,J=8Hz), 5.03(s,1H), 5.20(d,1H,J=10Hz),
5.32(dd,1H,J=1.5Hz,10Hz), 5.61(d,1H,J=7Hz), 5.95-6.04(m,1H),
7.47(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
IR(KBr) :3488, 3080, 2956, 2884, 2744, 1724, 1652, 1604, 1586 cm-1
MS-FAB:699(MH+)
【0114】
工程2:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-フェニル-2-(トリエチルシリルオキシ) プロピオニル]-10−O−アリル-10-デアセチル-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 100 mg および (3R,4S)-1-tert-ブトキシカルボニル-4−フェニル-3-(トリエチルシリルオキシ) アゼチジン-2−オン 108mgを乾燥したテトラヒドロフラン 2 ml に溶解し -40℃に冷却した。 次いで、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、0.572 ml) を滴下し、 15 分間撹拌した。 飽和塩化アンモニウム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した。 溶媒を減圧留去し、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;酢酸エチル:ヘキサン=1:4(v/v) )で精製し、標記化合物 126 mg を無色の非晶質固体として得た。
【0115】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.31-0.52(m,6H), 0.54-0.62(m,6H), 0.79(t,9H,J=7Hz),
0.96(t,9H,J=7Hz), 1.24(s,6H), 1.32(s,9H), 1.69(s,3H), 1.90(s,3H),
2.15-2.22(m,1H), 2.34-2.41(m,1H), 2.45-2.54(m,1H), 2.53(s,3H),
3.85(d,1H,J=7Hz), 4.00-4.13(m,2H), 4.19(d,1H,J=8Hz),
4.31(d,1H,J=8Hz), 4.41(dd,1H,J=7Hz,10Hz), 4.56(s,1H),
4.95(d,1H,J=8Hz), 4.98(s,1H), 5.20(d,1H,J=12Hz), 5.29(br,1H),
5.32(dd,1H,J=1.5Hz,12Hz), 5.47(br,1H), 5.68(d,1H,J=7Hz),
5.94-6.02(m,1H), 6.31(t,1H,J=8Hz), 7.27-7.31(m,3H),
7.37(t,2H,J=8Hz), 7.48(t,2H,J=8Hz), 7.58(t,1H,J=8Hz),
8.12(d,2H,J=8Hz)
【0116】
工程3:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3−フェニルプロピオニル]-10−O−アリル-10-デアセチルバッカチン III
上記工程2で得られた化合物 45.5 mgをアセトニトリル 2 ml に溶解し -10℃に冷却した。次いで、12規定塩酸水溶液 0.035 ml を滴下し 1時間撹拌した。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した。溶媒を減圧留去し、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=20:1(v/v))で精製し、標記化合物 23.5 mgを白色の固体として得た。
【0117】
融点:156-160 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
1.22(s,6H), 1.35(s,9H), 1.69(s,3H), 1.80-1.82(m,1H), 1.83(s,3H),
2.28(m,2H), 2.36(s,3H), 2.53-2.61(m,1H), 3.39(br,1H),
3.86(d,1H,J=7Hz), 4.05(dd,1H,J=6Hz, 13Hz), 4.16-4.20(m,3H),
4.30(d,1H,J=8Hz), 4.62(s,1H), 4.94(d,1H,J=8Hz), 5.04(s,1H),
5.22(dd,1H,J=1.5Hz,10Hz), 5.26(br,1H), 5.32(dd,1H,J=1.5Hz,17.5Hz),
5.40(brd,1H,J=10Hz), 5.68(d,1H,J=7Hz), 5.89-5.99(m,1H),
6.22(t,1H,J=8Hz), 7.30-7.42(m,5H), 7.49(t,2H,J=8Hz),
7.61(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
IR(KBr) :3464, 3076, 2984, 2944, 2904, 1720, 1604, 1586 cm-1
MS-FAB:849(MH+)
【0118】
実施例2
【0119】
【化17】
Figure 0003921252
【0120】
工程1:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-フェニル-2-(トリエチルシリルオキシ) プロピオニル]-10−デアセチル-10-O−ホルミルメチル-7−O−トリエチルシリルバッカチン III
実施例1の工程2で得た化合物 126 mg および N−メチルモルホリン-N−オキサイド 41.0 mgをアセトン 10 mlと水 3 ml の混合溶媒に加え室温下、四酸化オスミウム 0.6 mg を加え 2時間撹拌した。亜硫酸ナトリウムを加え 15 分間撹拌し、さらに無水硫酸ナトリウムを加え 30 分撹拌した後、不溶物を濾去した。溶媒を減圧留去し得られた残分をメタノール 4 ml に溶解し氷冷下、メタ過よう素酸ナトリウム 50.0 mgを水 1 ml に溶かした溶液を滴下し 30 分間撹拌した。飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。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=40:1(v/v))で精製し、標記化合物 98.5 mgを無色の非晶質固体として得た。
【0121】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.31-0.48(m,6H), 0.54-0.61(m,6H), 0.79(t,9H,J=7Hz),
0.96(t,9H,J=7Hz), 1.25(s,3H),1.26(s,3H), 1.31(s,9H), 1.70(s,3H),
1.91(s,3H), 2.15-2.22(m,1H), 2.34-2.40(m,1H), 2.45-2.53(m,1H),
2.53(s,3H), 3.48(s,1H), 3.81(d,1H,J=7Hz), 4.18(s,1H),
4.19(d,1H,J=8Hz), 4.32(d,1H,J=8Hz), 4.44(dd,1H,J=7Hz,10Hz),
4.56(s,1H), 4.95(d,1H,J=8Hz), 5.12(s,1H), 5.30(br,1H), 5.47(br,1H),
5.68(d,1H,J=7Hz), 6.31(t,1H,J=8Hz), 7.29-7.39(m,3H),
7.37(t,2H,J=8Hz), 7.48(t,2H,J=8Hz), 7.59(t,1H,J=8Hz),
8.12(d,2H,J=8Hz), 9.85(s,1H)
【0122】
工程2:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-フェニル-2-(トリエチルシリルオキシ) プロピオニル]-10−デアセチル-10-O-(2-モルホリノエチル)-7-O−トリエチルシリルバッカチン III
上記工程1で得られた化合物 98.5 mg、 モルホリン 0.080 ml および酢酸 0.052 ml をエタノール 8 ml に溶解し、水素化シアノホウ素ナトリウム 57.0 mg加え室温で 1時間撹拌した。クロロホルムで希釈し、飽和重曹水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、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;クロロホルム: メタノール=40:1(v/v))で精製し、標記化合物 91.6 mgを無色の非晶質固体として得た。
【0123】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.31-0.49(m,6H), 0.52-0.64(m,6H), 0.79(t,9H,J=7Hz),
0.95(t,9H,J=7Hz), 1.21(s,3H), 1.22(s,3H), 1.32(s,9H), 1.68(s,3H),
1.91(s,3H), 1.88-1.94(m,1H), 2.15-2.22(m,1H), 2.34-2.40(m,1H),
2.44-2.50(m,1H), 2.53(s,3H), 2.56-2.59(m,4H), 2.68(t,2H,J=6Hz),
3.62(t,2H,J=6Hz), 3.73(t,4H,J=5Hz), 3.84(d,1H,J=7Hz),
4.18(d,1H,J=8Hz), 4.31(d, 1H,J=8Hz), 4.41(dd,1H,J=7Hz,10Hz),
4.56(s,1H), 4.94(s,1H), 4.95(d,1H,J=8Hz), 5.30(br,1H), 5.48(br,1H),
5.67(d,1H,J=7Hz), 6.30(t,1H,J=8Hz), 7.28-7.32(m,3H),
7.37(t,2H,J=8Hz), 7.48(t,2H,J=8Hz), 7.58(t,1H,J=8Hz),
8.12(d,2H,J=8Hz)
【0124】
工程3:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3−フェニルプロピオニル]-10−デアセチル-10-O-(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 91.6 mgをアセトニトリル 4 ml に溶解し、氷冷下、ピリジン 0.20 mlおよび 48 %フッ化水素水溶液 0.60 mlを加え、0 ℃で 2時間、室温で一晩反応させた。反応液を氷冷し、飽和重曹水溶液で弱アルカリ性にした。酢酸エチルで 3 回抽出し飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。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=10:1(v/v))で精製し、標記化合物 52.1 mgを白色の固体として得た。
【0125】
融点:143-147 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.20(s,3H), 1.34(s,9H), 1.67(s,3H), 1.78-1.85(m,1H),
1.88(s,3H), 2.27(m,2H), 2.36(s,3H), 2.51-2.68(m,7H),
3.63-3.80(m,6H), 3.84(d,1H,J=7Hz), 4.12(d,1H,J=8Hz),
4.22(dd,1H,J=7Hz,10Hz), 4.29(d,1H,J=8Hz), 4.62(s,1H),
4.94(d,1H,J=8Hz), 5.09(s,1H), 5.27(brd,1H,J=10Hz), 5.44(br,1H),
5.66(d,1H,J=7Hz), 6.21(t,1H,J=8Hz), 7.29-7.42(m,5H),
7.49(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.09(d,2H,J=8Hz)
IR(KBr) :3456, 3068, 2976, 2940, 1986, 1722, 1606, 1586 cm-1
MS-FAB:921(MH+)
【0126】
実施例3
【0127】
【化18】
Figure 0003921252
【0128】
工程1:4,10−ジデアセチル-4−O−プロピオニル-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
2.00 gの 4,10-ジデアセチル-4−O−プロピオニル-13-デオキシ-13-オキソ-7−O−トリエチルシリルバッカチン IIIをピリジン 40 ml に溶解し氷冷下、クロロギ酸 2,2,2−トリクロロエチル 1.03 mlをジクロロメタン 4 ml に溶かした溶液を滴下し 30 分間撹拌した。反応液を氷水に注ぎ酢酸エチルで抽出した。冷 0.5規定塩酸水溶液、水、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。得られた残分をテトラヒドロフラン 60ml に溶解し氷冷下、テトラヒドロホウ酸ナトリウム 282 mg を加え 5分後、メタノール 3 ml を加え 2.5時間撹拌した。反応液をクロロホルムで希釈し飽和塩化アンモニウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、残分をシリカゲルクロマトグラフィー(溶出溶媒;酢酸エチル:n−ヘキサン=1:2(v/v) )にて精製し標記化合物 2.05 g を白色結晶として得た。
【0129】
融点:227-228 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
0.56-0.62(m,6H), 0.93(t,9H,J=8Hz), 1.07(s,3H), 1.21(s,3H),
1.23(t,3H,J=7Hz), 1.70(s,3H), 1.85-1.92(m,1H), 2.19(s,3H),
2.26-2.28(m,2H), 2.51-2.67(m,3H), 3.72(d,1H,J=7Hz),
4.16(d,1H,J=8Hz), 4.31(d,1H,J=8Hz), 4.50(dd,1H,J=7Hz,10Hz),
4.81(AB type d,2H,J=2Hz), 4.85(br,1H), 4.91(d,1H,J=8Hz),
5.63(d,1H,J=7Hz), 6.30(s,1H), 7.47(t,2H,J=8Hz), 7.60(t,1H,J=8Hz),
8.12(d,2H,J=8Hz)
IR(KBr) :3560, 2960, 2888, 1764, 1728, 1604, 1586 cm-1
MS-FAB:849(MH+)
【0130】
工程2:4,10−ジデアセチル-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1で得た化合物 500 mg をメタノール 16 mlおよび酢酸 4 ml の混合溶媒に溶かし活性亜鉛末 1 gを加え 50 ℃で 15 分間撹拌した。放冷後、不溶物を濾去し溶媒を減圧留去した。残分に酢酸エチルおよび飽和重曹水溶液を加え有機層を無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。得られた油状物質をヘキサンより結晶化し標記化合物 370 mg を白色結晶として得た。
【0131】
融点:202-204 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
0.48-0.63(m,6H), 0.94(t,9H,J=8Hz), 1.07(s,3H), 1.24(t,3H,J=7Hz),
1.26(s,3H), 1.73(s,3H), 1.86-1.93(m,1H), 2.07(s,3H),
2.22-2.28(m,2H), 2.45-2.51(m,1H), 2.52-2.67(m,2H), 3.94(d,1H,J=7Hz),
4.16(d,1H,J=8Hz), 4.27(d,1H,J=2Hz), 4.31(d,1H,J=8Hz),
4.42(dd,1H,J=7Hz,10Hz), 4.84(t,1H,J=8Hz), 4.91(d,1H,J=8Hz),
5.18(s,3H), 5.59(d,1H,J=7Hz), 7.46(t,2H,J=8Hz), 7.60(t,1H,J=8Hz),
8.10-8.12(m,2H)
IR(KBr) :3476, 3072, 2960, 2888, 1986, 1728, 1712, 1604, 1586 cm-1
MS-FAB:673(MH+)
【0132】
工程3:10−O−アリル-4,10-ジデアセチル-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2で得た化合物を実施例1の工程1と同様に反応させ標記化合物を白色結晶として得た。
【0133】
融点:204-207 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.65(m,6H), 0.95(t,9H,J=7Hz), 1.06(s,3H), 1.20(s,3H),
1.24(t,3H,J=7Hz), 1.68(s,3H), 1.85-1.92(m,1H), 2.07(s,3H),
2.26(d,2H,J=8Hz), 2.47-2.57(m,1H), 2.58-2.67(m,2H),
3.88(d,1H,J=7Hz), 4.05-4.07(m,2H), 4.15(d,1H,J=8Hz),
4.29(d,1H,J=8Hz), 4.44(dd,1H,J=7Hz,10Hz), 4.88-4.92(m,2H),
5.04(s,1H), 5.20(dd,1H,J=1.5Hz,10Hz), 5.31(dd,1H,J=1.5Hz,17Hz),
5.60(d,1H,J=7Hz), 5.95-6.04(m,1H), 7.46(t,2H,J=8Hz),
7.59(t,1H,J=8Hz), 8.10-8.12(m,2H)
IR(KBr) :3496, 3080, 2956, 2884, 2744, 1724, 1650, 1604, 1586 cm-1
MS-FAB:713(MH+)
【0134】
工程4:10−O−アリル-13-O-[(2R,3S)-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]-4,10−ジデアセチル-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3で得られた化合物 50 mg および (3R,4S)-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) アゼチジン-2−オン 43 mgをテトラヒドロフラン 2 ml に溶解し -78℃に冷却した。 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、0.280 ml)を滴下し 15 分間撹拌した。飽和塩化アンモニウム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した。溶媒を減圧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;酢酸エチル:n−ヘキサン=1:4(v/v) )で精製し、標記化合物 67.8 mg を無色の非晶質固体として得た。
【0135】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.52-0.62(m,6H), 0.94-1.01(m,30H), 1.21(s,3H), 1.24(s,3H),
1.35(s,9H), 1.37(t,3H,J=7Hz), 1.69(s,3H), 1.92(s,3H),
1.87-1.94(m,1H), 2.31-2.36(m,2H), 2.46-2.56(m,1H), 2.71-2.79(m,2H),
3.84(d,1H,J=7Hz), 4.00-4.11(m,2H), 4.19(d,1H,J=8Hz),
4.31(d,1H,J=8Hz), 4.42(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz),
4.99(s,1H), 5.20(d,1H,J=11Hz), 5.24-5.34(m,3H), 5.68(d,1H,J=7Hz),
5.95-6.02(m,1H), 6.21(t,1H,J=8Hz), 6.27(d,1H,J=3.5Hz),
6.37(dd,1H,J=2Hz,3.5Hz), 7.39(s,1H), 7.46(t,2H,J=8Hz),
7.57(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0136】
工程5:13−O-[(2R,3S)-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]-4,10−ジデアセチル-10-O−ホルミルメチル-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。
【0137】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.53-0.63(m,6H), 0.94-1.01(m,30H), 1.22(s,3H), 1.25(s,3H),
1.34(s,9H), 1.36(t,3H,J=7Hz), 1.69(s,3H), 1.92(s,3H),
2.32-2.36(m,2H), 2.46-2.53(m,1H), 2.69-2.78(m,2H), 3.47(s,1H),
3.80(d,1H,J=7Hz), 4.16(s,1H), 4.18(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.43(dd,1H,J=7Hz,10Hz), 4.90(d,1H,J=8Hz), 4.98(s,1H), 5.13(s,1H),
5.24-5.30(m,2H), 5.68(d,1H,J=7Hz), 6.20(t,1H,J=8Hz),
6.27(d,1H,J=3.5Hz), 6.37(dd,1H,J=2Hz,3.5Hz), 7.39(s,1H),
7.47(t,2H,J=8Hz), 7.57(t,1H,J=8Hz), 8.11(d,2H,J=8Hz), 9.85(s,1H)
【0138】
工程6:13−O-[(2R,3S)-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]-4,10−ジデアセチル-10-O-(2-モルホリノエチル)-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5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。
【0139】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.65(m,6H), 0.93-1.01(m,30H), 1.19(s,3H), 1.21(s,3H),
1.35(s,9H), 1.37(t,3H,J=7Hz), 1.67(s,3H), 1.93(s,3H),
2.26-2.39(m,2H), 2.45-2.53(m,1H), 2.57-2.60(m,4H), 2.64-2.69(m,2H),
2.71-2.81(m,2H), 3.62(t,2H,J=6Hz), 3.73(t,4H,J=5Hz),
3.83(d,1H,J=7Hz), 4.18(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.41(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz), 4.95(s,1H), 4.99(s,1H),
5.24-5.31(m,2H), 5.67(d,1H,J=7Hz), 6.20(t,1H,J=8Hz),
6.27(d,1H,J=3.5Hz), 6.37(dd,1H,J=2Hz,3.5Hz), 7.39(s,1H),
7.48(t,2H,J=8Hz), 7.57(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0140】
工程7:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(2−フリル)-2-ハイドロキシプロピオニル]-4,10−ジデアセチル-10-O-(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6で得た化合物 50.6 mgをピリジン 2 ml に溶解し氷冷下、フッ化水素ピリジン 0.40 mlを加え 0℃で 10 分間撹拌後、室温で一晩反応させた。反応液を氷冷し飽和重曹水溶液で弱アルカリ性にした。酢酸エチルで 3回抽出し、無水硫酸ナトリウムで乾燥し溶媒を減圧留去した。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=10:1(v/v))で精製し、標記化合物 27.6 mgを白色固体として得た。
【0141】
融点:139-142 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.21(s,3H), 1.29(t,3H,J=7Hz), 1.34(s,9H), 1.67(s,3H),
1.78-1.85(m,1H), 1.93(s,3H), 2.26-2.40(m,2H), 2.52-2.73(m,9H),
3.64-3.80(m,6H), 3.86(d,1H,J=7Hz), 4.18(d,1H,J=8Hz),
4.27(dd,1H,J=7Hz,10Hz), 4.31(d,1H,J=8Hz), 4.70(s,1H),
4.91(d,1H,J=8Hz), 5.09(s,1H), 5.23(d,1H,J=10Hz),
5.31(brd,1H,J=10Hz), 5.68 (d,1H,J=7Hz), 6.23(t,1H,J=8Hz),
6.34(d,1H,J=3.5Hz), 6.39(dd,1H,J=2Hz,3.5Hz), 7.43(s,1H),
7.48(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.12(d,2H,J=8Hz)
IR(KBr) :3464, 2980, 2944, 2356, 1972, 1722, 1604, 1496 cm-1
MS-FAB:925(MH+)
【0142】
実施例4
【0143】
【化19】
Figure 0003921252
【0144】
工程1:4-O−ブタノイル-4,10-ジデアセチル-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
4-O−ブタノイル-13-デオキシ-4,10-ジデアセチル-13-オキソ-7−O−トリエチルシリルバッカチン IIIを実施例3の工程1と同様に反応させ標記化合物を白色結晶として得た。
【0145】
融点:227-228 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
0.52-0.62(m,6H), 0.93(t,9H,J=8Hz), 1.06(t,3H,J=7Hz), 1.07(s,3H),
1.21(s,3H), 1.70(s,3H), 1.78(q,2H,J=7Hz), 1.85-1.92(m,1H),
2.19(s,3H), 2.28(d,2H,J=8Hz), 2.56(t,2H,J=7Hz), 2.51-2.59(m,1H),
3.83(d,1H,J=7Hz), 4.15(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.49(dd,1H,J=7Hz,10Hz), 4.81(AB type d,2H,J=2Hz), 4.85(br,1H),
4.92(d,1H,J=8Hz), 5.63(d,1H,J=7Hz), 6.30(s,1H), 7.47(t,2H,J=8Hz),
7.61(t,1H,J=8Hz), 8.11(m,2H)
IR(KBr) :3560, 2960, 2888, 1764, 1728, 1604, 1586 cm-1
MS-FAB:849(MH+)
【0146】
工程2:4-O−ブタノイル-4,10-ジデアセチル-7−O−トリエチルシリルバッカチン III
上記工程1で得た化合物を実施例3の工程2と同様に反応させ標記化合物を白色結晶として得た。
【0147】
融点:160-163 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
0.48-0.63(m,6H), 0.94(t,9H,J=8Hz), 1.05(t,3H,J=3Hz), 1.08(s,6H),
1.74(s,3H), 1.76-1.78(m,2H), 1.80-1.92(m,1H), 2.07(s,3H),
2.25(d,2H,J=8Hz), 2.45-2.53(m,1H), 2.56(t,2H,J=7Hz),
3.94(d,1H,J=7Hz), 4.17(d,1H,J=8Hz), 4.25(d,1H,J=2Hz),
4.31(d,1H,J=8Hz), 4.42(dd,1H,J=7Hz,10Hz), 4.86(br,1H),
4.91(d,1H,J=8Hz), 5.17(s,3H), 5.59(d,1H,J=7Hz), 7.47(t,2H,J=8Hz),
7.61(t,1H,J=8Hz), 8.11-8.14(m,2H)
IR(KBr) :3484, 3076, 2968, 2888, 2744, 1714, 1606, 1586 cm-1
MS-FAB:687(MH+)
【0148】
工程3:10−O−アリル-4−O−ブタノイル-4,10-ジデアセチル-7−O−トリエチルシリルバッカチン III
上記工程2で得た化合物を実施例1の工程1と同様に反応させ標記化合物を白色結晶として得た。
【0149】
融点:200-204 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.65(m,6H), 0.96(t,9H,J=7Hz), 1.05(t,3H,J=7Hz), 1.06(s,3H),
1.20(s,3H), 1.67(s,3H), 1.78(q,2H,J=7Hz), 1.82-1.91(m,1H),
2.06(s,3H), 2.26(d,2H,J=8Hz), 2.47-2.57(m,1H), 2.55(t,2H,J=7Hz),
3.88(d,1H,J=7Hz), 4.01-4.13(m,2H), 4.15(d,1H,J=8Hz),
4.29(d,1H,J=8Hz), 4.43(dd,1H,J=7Hz,10Hz), 4.87-4.92(m,2H),
5.03(s,1H), 5.19(dd,1H,J=1.5Hz,10Hz), 5.31(dd,1H,J=1.5Hz,17Hz),
5.60(d,1H,J=7Hz), 5.95-6.04(m,1H), 7.46(t,2H,J=8Hz),
7.59(t,1H,J=8Hz), 8.10-8.12(m,2H)
IR(KBr) :3504, 3076, 2964, 2884, 2744, 1718, 1650, 1604, 1586 cm-1
MS-FAB:727(MH+)
【0150】
工程4:10−O−アリル-13-O-[(2R,3S)-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−ブタノイル-4,10-ジデアセチル-7−O−トリエチルシリルバッカチン III
上記工程3で得た化合物を実施例3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。
【0151】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.52-0.63(m,6H), 0.94-1.01(m,30H), 1.05(t,3H,J=7Hz), 1.20(s,3H),
1.24(s,3H), 1.35(s,9H), 1.69(s,3H), 1.92(s,3H), 1.83-1.95(m,1H),
2.25-2.36(m,2H), 2.46-2.56(m,1H), 2.58-2.63(m,2H), 2.76-2.80(m,1H),
3.85(d,1H,J=7Hz), 3.99-4.11(m,2H), 4.18(d,1H,J=8Hz),
4.29(d,1H,J=8Hz), 4.41(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz),
5.00(s,1H), 5.18-5.34(m,4H), 5.67(d,1H,J=7Hz), 5.94-6.02(m,1H),
6.20(t,1H,J=8Hz), 6.27(d,1H,J=3.5Hz), 6.37(dd,1H,J=2Hz,3.5Hz),
7.37(s,1H), 7.46(t,2H,J=8Hz), 7.57(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0152】
工程5:13−O-[(2R,3S)-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−ブタノイル-4,10-ジデアセチル-10-O−ホルミルメチル-7−O−トリエチルシリルバッカチン III
上記工程4で得られた化合物を実施例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。
【0153】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.53-0.65(m,6H), 0.94-1.01(m,30H), 1.05(t,3H,J=7Hz), 1.22(s,3H),
1.25(s,3H), 1.34(s,9H), 1.69(s,3H), 1.83-1.94(m,3H), 1.92(s,3H),
2.27-2.39(m,2H), 2.48-2.53(m,1H), 2.54-2.63(m,1H), 2.74-2.81(m,1H),
3.47(s,1H), 3.81(d,1H,J=7Hz), 4.16(s,1H), 4.18(d,1H,J=8Hz),
4.30(d,1H,J=8Hz), 4.44(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz),
4.99(s,1H), 5.14(s,1H), 5.25(d,1H,J=10Hz), 5.31(d,1H,J=10Hz),
5.67(d,1H,J=7Hz), 6.19(t,1H,J=8Hz), 6.27(d,1H,J=3.5Hz),
6.36(dd,1H,J=2Hz,3.5Hz), 7.37(s,1H), 7.47(t,2H,J=8Hz),
7.58(t,1H,J=8Hz), 8.11(d,2H,J=8Hz), 9.85(s,1H)
【0154】
工程6:13−O-[(2R,3S)-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−ブタノイル-4,10-ジデアセチル-10-O-(2-モルホリノエチル)-7-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。
【0155】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.64(m,6H), 0.94-1.03(m,30H), 1.05(t,3H,J=7Hz), 1.19(s,3H),
1.21(s,3H), 1.35(s,9H), 1.67(s,3H), 1.93(s,3H), 1.83-1.93(m,3H),
2.25-2.39(m,2H), 2.45-2.53(m,1H), 2.57-2.81(m,8H), 3.62(t,2H,J=6Hz),
3.73(t,4H,J=5Hz), 3.84(d,1H,J=7Hz), 4.18(d,1H,J=8Hz),
4.30(d,1H,J=8Hz), 4.41(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz),
4.96(s,1H), 5.00(s,1H), 5.24(d,1H,J=10Hz), 5.32(d,1H,J=10Hz),
5.66(d,1H,J=7Hz), 6.18(t,1H,J=8Hz), 6.27(d,1H,J=3.5Hz),
6.36(dd,1H,J=2Hz,3.5Hz), 7.37(s,1H), 7.46(t,2H,J=8Hz),
7.57(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0156】
工程7:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(2−フリル)-2-ハイドロキシプロピオニル]-4-O−ブタノイル-4,10-ジデアセチル-10-O-(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3の工程7と同様に反応させ標記化合物を白色の固体として得た。
【0157】
融点:135-137 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
0.99(t,3H,J=7Hz), 1.19(s,3H), 1.21(s,3H), 1.35(s,9H), 1.68(s,3H),
1.78-1.84(m,3H), 1.93(s,3H), 2.30-2.38(m,2H), 2.53-2.68(m,9H),
3.65-3.78(m,6H), 3.88(d,1H,J=7Hz), 4.18(d,1H,J=8Hz),
4.26(dd,1H,J=7Hz,10Hz), 4.30(d,1H,J=8Hz), 4.70(s,1H),
4.90(d,1H,J=8Hz), 5.10(s,1H), 5.22(d,1H,J=10Hz),
5.31(brd,1H,J=10Hz), 5.67(d,1H,J=7Hz), 6.20(t,1H,J=8Hz),
6.35(d,1H,J=3.5Hz), 6.38(dd,1H,J=2Hz,3.5Hz), 7.42(s,1H),
7.49(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
IR(KBr) :3456, 2972, 2944, 1720, 1604, 1498 cm-1
MS-FAB:939(MH+)
【0158】
実施例5
【0159】
【化20】
Figure 0003921252
【0160】
工程1:13−O-[(2R,3S)-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]-4,10−ジデアセチル-10-O-[2-( N, N−ジエチルアミノ) 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
実施例3の工程5で得た化合物 46.0 mg、 ジエチルアミン 0.042 ml および酢酸 0.024 ml をエタノール 4 ml に溶解し水素化シアノホウ素ナトリウム 26.0 mgを加え室温で一晩撹拌した。クロロホルムで希釈し飽和重曹水溶液で洗浄し無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、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;クロロホルム: メタノール=20:1(v/v))で精製し、標記化合物 26.0 mgを無色の非晶質固体として得た。
【0161】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.65(m,6H), 0.94-1.01(m,30H), 1.18-1.23(m,6H), 1.34(s,9H),
1.36(t,3H,J=7Hz), 1.68(s,3H), 1.87-1.92(m,1H), 1.93(s,3H),
2.26-2.39(m,2H), 2.46-2.55(m,1H), 2.71-2.81(m,2H), 2.91(br,4H),
3.02(br,2H), 3.60-3.73(m,2H), 3.81(d,1H,J=7Hz), 4.18(d,1H,J=8Hz),
4.31(d,1H,J=8Hz), 4.44(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz),
4.95(s,1H), 4.98(s,1H), 5.24-5.30(m,2H), 5.67(d,1H,J=7Hz),
6.20(t,1H,J=8Hz), 6.27(d,1H,J=3.5Hz), 6.37(dd,1H,J=2Hz,3.5Hz),
7.39(s,1H), 7.47(t,2H,J=8Hz), 7.57(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0162】
工程2:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(2−フリル)-2-ハイドロキシプロピオニル]-4,10−ジデアセチル-10-O-[2-( N, N−ジエチルアミノ) エチル]-4-O−プロピオニルバッカチン III
上記工程1で得た化合物を実施例3の工程7と同様に反応させ標記化合物を白色固体として得た。
【0163】
融点:128-132 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
1.10(t,6H,J=7Hz), 1.20(s,3H), 1.22(s,3H), 1.29(t,3H,J=7Hz),
1.34(s,9H), 1.68(s,3H), 1.82-1.90(m,1H), 1.94(s,3H),
2.28-2.36(m,2H), 2.51-2.60(m,1H), 2.70-2.80(m,6H),
2.84-2.90(m,2H), 3.70-3.73(m,1H), 3.85-3.89(m,2H), 4.17(d,1H,J=8Hz),
4.30−4.33(m,2H), 4.71(s,1H), 4.91(d,1H,J=8Hz), 5.19(s,1H),
5.23(d,1H,J=10Hz), 5.31(brd,1H,J=10Hz), 5.68(d,1H,J=7Hz),
6.22(t,1H,J=8Hz), 6.35(d,1H,J=3.5Hz), 6.39(dd,1H,J=2Hz,3.5Hz),
7.43(s,1H), 7.48(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.13(d,2H,J=8Hz)
IR(KBr) :3456, 2980, 1720, 1496 cm-1
MS-FAB:911(MH+)
【0164】
実施例6
【0165】
【化21】
Figure 0003921252
【0166】
工程1:13−O-[(2R,3S)-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]-4,10−ジデアセチル-4−O−プロピオニル-10-O-(2-チオモルホリノエチル)-7-O−トリエチルシリルバッカチン III
実施例3の工程5で得た化合物 50.5 mg、 チオモルホリン 0.045 ml および酢酸 0.026 ml をエタノール 4 ml に溶解し、水素化シアノホウ素ナトリウム 28.0 mgを加え室温で 30 分間撹拌した。クロロホルムで希釈し飽和重曹水溶液で洗浄し無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、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;クロロホルム:メタノール=40:1(v/v))で精製し、標記化合物 43.5 mgを無色の非晶質固体として得た。
【0167】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.65(m,6H), 0.94-1.01(m,30H), 1.19(s,3H), 1.20(s,3H),
1.35(s,9H), 1.37(t,3H,J=7Hz), 1.67(s,3H), 1.93(s,3H),
2.31-2.39(m,2H), 2.45-2.53(m,1H), 2.67-2.81(m,9H), 2.84-2.86(m,4H),
3.59(t,2H,J=6Hz), 3.82(d,1H,J=7Hz), 4.18(d,1H,J=8Hz),
4.31(d,1H,J=8Hz), 4.42(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz),
4.94(s,1H), 4.99(s,1H), 5.24-5.31(m,2H), 5.67(d,1H,J=7Hz),
6.20(t,1H,J=8Hz), 6.27(d,1H,J=3.5Hz), 6.37(dd,1H,J=2Hz,3.5Hz),
7.39(s,1H), 7.46(t,2H,J=8Hz), 7.57(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0168】
工程2:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(2−フリル)-2-ハイドロキシプロピオニル]-4,10−ジデアセチル-4−O−プロピオニル-10-O-(2-チオモルホリノエチル) バッカチン III
上記工程1で得た化合物を実施例3の工程7と同様に反応させ標記化合物を白色固体として得た。
【0169】
融点:145-148 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.21(s,3H), 1.29(t,3H,J=7Hz), 1.34(s,9H), 1.67(s,3H),
1.78-1.85(m,1H), 1.92(s,3H), 2.25-2.40(m,2H), 2.53-2.61(m,1H),
2.66-2.72(m,8H), 2.78-2.90(m,4H), 3.61-3.67(m,1H), 3.72-3.78(m,1H),
3.86(d,1H,J=7Hz), 4.17(d,1H,J=8Hz), 4.27(dd,1H,J=7Hz,10Hz),
4.31(d,1H,J=8Hz), 4.71(s,1H), 4.81(d,1H,J=8Hz), 5.05(s,1H),
5.22(d,1H,J=10Hz), 5.31(br,1H,J=10Hz), 5.68 (d,1H,J=7Hz),
6.23(t,1H,J=8Hz), 6.34(d,1H,J=3.5Hz), 6.39(dd,1H,J=2Hz,3.5Hz),
7.43(s,1H), 7.48(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.12(d,2H,J=8Hz)
IR(KBr) :3456, 2980, 2944, 2824, 1722, 1602, 1586, 1496 cm-1
MS-FAB:941(MH+)
【0170】
実施例7
【0171】
【化22】
Figure 0003921252
【0172】
工程1:10−O−アリル-13-O-[(2R,3S)-N-(tert−ブトキシカルボニル)-2,3-N, O−イソプロピリデン-3−フェニルイソセリニル]-10−デアセチル-7−O−トリエチルシリルバッカチン III
実施例1の工程1で得た化合物 150 mg および (2R,3S)-N-(tert−ブトキシカルボニル)-2,3-N, O−イソプロピリデン-3−フェニルイソセリン 207 mg をトルエン 4 ml に溶解し 0℃に冷却した。次いで、ジシクロヘキシルカルボジイミド 146 mg を加え 15 分間撹拌した後、4-ジメチルアミノピリジン 26 mgを加え 80 ℃で 15 分間撹拌した。放冷後、酢酸エチルで希釈し1規定塩酸水溶液、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した。溶媒を減圧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:アセトン=50:1(v/v))で精製し、標記化合物 215 mg を無色の非晶質固体として得た。
【0173】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.62(m,6H), 0.94(t,9H,J=7Hz), 1.10(brs,9H), 1.22(s,6H),
1.65(s,3H), 1.78(s,6H), 1.82(s,3H), 1.93(s,3H), 2.13-2.17(m,2H),
2.41-2.48(m,1H), 3.76(d,1H,J=7Hz), 3.98-4.15(m,2H),
4.09(d,1H,J=8Hz), 4.23(d,1H,J=8Hz), 4.36(dd,1H,J=7Hz,10Hz),
4.47(d,1H,J=7Hz), 4.86(d,1H,J=8Hz), 4.97(s,1H), 5.10(br,1H),
5.20(d,1H,J=11Hz), 5.29(dd,1H,J=1.5Hz,11Hz), 5.62(d,1H,J=7Hz),
5.92-6.02(m,1H), 6.30(t,1H,J=8Hz), 7.33-7.39(m,5H),
7.50(t,2H,J=8Hz), 7.61-7.65(m,1H), 8.03-8.05(m,2H)
【0174】
工程2:13−O-[(2R,3S)-N-(tert−ブトキシカルボニル)-2,3-N, O−イソプロピリデン-3−フェニルイソセリニル]-10−デアセチル-10-O−ホルミルメチル-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。
【0175】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.51-0.59(m,6H), 0.95(t,9H,J=7Hz), 1.11(brs,9H), 1.23(s,6H),
1.65(s,3H), 1.77(s,3H), 1.81(s,3H), 1.84(s,3H), 1.94(s,3H),
2.14-2.17(m,2H), 2.43-2.51(m,1H), 3.73(d,1H,J=7Hz),
4.10(d,1H,J=8Hz), 4.17(d,2H,J=2.5Hz), 4.24(d,1H,J=8Hz),
4.40(dd,1H,J=7Hz,10Hz), 4.46(d,1H,J=7Hz), 4.86(d,1H,J=8Hz),
5.05-5.13(m,1H), 5.11(s,1H), 5.62(d,1H,J=7Hz), 6.28(t,1H,J=8Hz),
7.34-7.40(m,5H), 7.49(t,2H,J=8Hz), 7.62(t,1H,J=8Hz),
8.03(d,2H,J=8Hz), 9.83(s,1H)
【0176】
工程3:13−O-[(2R,3S)-N-(tert−ブトキシカルボニル)-2,3-N, O−イソプロピリデン-3−フェニルイソセリニル]-10−デアセチル-10-O-(2-ピペリジノエチル)-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 52.4 mg、 ピペリジン 0.051 ml および酢酸 0.030 ml をエタノール 4 ml に溶解し、水素化シアノホウ素ナトリウム 33.0 mgを加え室温で 1時間撹拌した。クロロホルムで希釈し飽和重曹水溶液で洗浄し無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、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;クロロホルム:メタノール=10:1(v/v))で精製し、標記化合物 46.3 mgを無色の非晶質固体として得た。
【0177】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.50-0.60(m,6H), 0.94(t,9H,J=7Hz), 1.10(brs,9H), 1.19(s,3H),
1.21(s,3H), 1.47(br,2H), 1.64(s,3H), 1.76-1.89(m,4H), 1.78(s,3H),
1.80(s,3H), 1.82(s,3H), 1.95(s,3H), 2.13-2.15(m,2H),
2.40-2.48(m,1H), 2.58(br,4H), 2.73(t,2H,J=6Hz), 3.63(t,2H,J=6Hz),
3.76(d,1H,J=7Hz), 4.09(d,1H,J=8Hz), 4.23(d,1H,J=8Hz),
4.37(dd,1H,J=7Hz,10Hz), 4.46(d,1H,J=7Hz), 4.86(d,1H,J=8Hz),
4.94(s,1H), 5.05(br,1H), 5.61(d,1H,J=7Hz), 6.28(t,1H,J=8Hz),
7.34-7.38(m,5H), 7.49(t,2H,J=8Hz), 7.63(t,1H,J=8Hz), 8.03(d,2H,J=8Hz)
【0178】
工程4:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3−フェニルプロピオニル]-10−デアセチル-10-O-(2-ピペリジノエチル) バッカチン III
【0179】
上記工程3で得た化合物 46.3 mgをギ酸 4 ml に溶解し室温で 80 分間反応させた。反応液を濃縮、残分をクロロホルムで希釈し飽和重曹水で洗浄後、無水硫酸ナトリウムで乾燥、溶媒を減圧留去した。残分をテトラヒドロフラン 4 ml に溶解し、二炭酸ジ-tert-ブチル 0.040 ml を加え室温で 3 時間反応させた。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;クロロホルム:メタノール:水=8:3:1(v/v) 、下層)で精製し、標記化合物 13.6 mg白色固体として得た。
【0180】
融点:134-140 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.20(s,3H), 1.34(s,9H), 1.46(br,2H), 1.67(s,3H),
1.85-1.89(m,1H), 1.90(s,3H), 2.23-2.28(m,2H), 2.36(s,3H),
2.45-2.73(m,7H), 3.74-3.84(m,3H), 4.17(d,1H,J=8Hz),
4.25(dd,1H,J=7Hz,10Hz), 4.29(d,1H,J=8Hz), 4.62(s,1H),
4.94(d,1H,J=8Hz), 5.20(s,1H), 5.25(br,1H), 5.45(br,1H),
5.66 (d,1H,J=7Hz), 6.21(t,1H,J=8Hz), 7.31-7.39(m,5H),
7.49(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
IR(KBr) :3440, 2940, 1722, 1604, 1496 cm-1
MS-FAB:920(MH+)
【0181】
実施例8
【0182】
【化23】
Figure 0003921252
【0183】
工程1:13−O-[(2R,3S)-N-(tert−ブトキシカルボニル)-2,3-N, O−イソプロピリデン-3−フェニルイソセリニル]-10−デアセチル-10-O-[2-( N−ピロリジノ) エチル]-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 54.4 mg、 ピロリジン 0.045 ml および酢酸 0.031 ml をエタノール 4 ml に溶解し、水素化シアノホウ素ナトリウム 34.0 mgを加え室温で 1時間撹拌した。クロロホルムで希釈し飽和重曹水溶液で洗浄し無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、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;クロロホルム:メタノール=10:1(v/v))で精製し、標記化合物 34.6 mgを無色の非晶質固体として得た。
【0184】
1H-NMR (CDCl3/TMS) δ(ppm) :
0.48-0.63(m,6H), 0.94(t,9H,J=7Hz), 1.12(brs,9H), 1.20(s,3H),
1.21(s,3H), 1.64(s,3H), 1.77(s,3H), 1.81(s,3H), 1.85(s,3H),
1.95(s,3H), 2.13-2.15(m,2H), 2.41-2.48(m,1H), 2.75(br,4H),
2.90(t,2H,J=6Hz), 3.67(t,2H,J=6Hz), 3.76(d,1H,J=7Hz),
4.09(d,1H,J=8Hz), 4.23(d,1H,J=8Hz), 4.38(dd,1H,J=7Hz,10Hz),
4.46(d,1H,J=7Hz), 4.86(d,1H,J=8Hz), 4.96(s,1H), 5.08(br,1H),
5.61(d,1H,J=7Hz), 6.28(t,1H,J=8Hz), 7.34-7.38(m,5H),
7.48(t,2H,J=8Hz), 7.62(t,1H,J=8Hz), 8.03(d,2H,J=8Hz)
【0185】
工程2:13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3−フェニルプロピオニル]-10−デアセチル-10-O-[2-( N−ピロリジノ) エチル] バッカチン III
上記工程1で得た化合物を実施例7の工程4と同様に反応させ標記化合物を白色固体として得た。
【0186】
融点:136-142 ℃
1H-NMR (CDCl3/TMS) δ(ppm) :
1.21(s,6H), 1.34(s,9H), 1.67(s,3H), 1.80(br,4H), 1.90(s,3H),
2.23-2.28(m,2H), 2.36(s,3H), 2.45-2.53(m,1H), 2.70(br,4H),
2.85(br,2H), 3.74-3.81(m,2H), 3.83(d,1H,J=7Hz), 4.17(d,1H,J=8Hz),
4.24(dd,1H,J=7Hz,10Hz), 4.29(d,1H,J=8Hz), 4.61(s,1H),
4.94(d,1H,J=8Hz), 5.20(s,1H), 5.25(br,1H), 5.45(br,1H),
5.66(d,1H,J=7Hz), 6.21(t,1H,J=8Hz), 7.31-7.40(m,5H),
7.49(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
IR(KBr) :3448, 2976, 2820, 1852, 1720, 1634, 1604, 1588 cm-1
MS-FAB:905(MH+)
【0187】
実施例9
【0188】
【化24】
Figure 0003921252
【0189】
工程1:10−O−アリル-10-デアセチルバッカチン III
実施例1の工程2で得た化合物 292 mg を蒸留したピリジン 5 ml に溶解し 0℃に冷却した。次いで、同温度にてフッ化水素−ピリジン溶液 1 ml を滴下した。滴下終了後、室温まで昇温させ1夜間撹拌した。反応液を酢酸エチルで希釈後、水で洗浄した。さらに飽和食塩水で洗浄後、 無水硫酸マグネシウムで乾燥させたのち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=95:5 (v/v)) にて精製することにより標記化合物 210 mg を得た。
【0190】
1H-NMR (CDCl3/TMS) δ(ppm) :
1.07(3H,s), 1.19(3H,s), 1.68(3H,s), 1.75-1.83(1H,m),
2.04(3H,d,J=1.5Hz), 2.27-2.30(1H,m), 2.29(3H,s), 2.55-2.63(1H,m),
3.95(1H,d,J=7.5Hz), 4.06(1H,dd,J=4.5Hz,7.5Hz), 4.16(1H,d,J=8.5Hz),
4.21(1H,dd,J=5Hz,8.5Hz), 4.24-4.31(1H,m), 4.31(1H,d,J=8.5Hz),
4.85-4.91(1H,m), 4.98(1H,d,J=8Hz), 5.09(1H,s),
5.23(1H,dd,J=1.5Hz,9.5Hz), 5.33(1H,dd,J=1.5Hz,15.5Hz),
5.64(1H,d,J=7.5Hz), 5.91-6.02(1H,m), 7.48(2H,t,J=7.5Hz),
7.61(1H,t,J=7.5Hz), 8.11(2H,d,J=7.5Hz).
【0191】
工程2:10−O−アリル-10-デアセチル-7−デオキシバッカチン III
水素化ナトリウム(ca 60% oil suspension (w/w)) 20 mg をテトラヒドロフラン 2 ml に懸濁させ、工程1で得た化合物 219 mg をテトラヒドロフラン 2 ml に溶かした溶液を -45℃にて滴下した。同温度にて 10 分間撹拌後、0.03 ml の二硫化炭素および 0.03 mlのヨウ化メチルを加えたのち 0℃まで昇温させて1 夜間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた後、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 = 97:3(v/v)) にて精製することにより 10-O−アリル-10-デアセチル-7−O-[( メチルチオ) チオカルボニル] バッカチン III 145 mg を得た。この化合物を、窒素雰囲気下にて脱気したジオキサン 2 ml に溶解し、10 mg の 2,2'-アゾビス( イソブチロニトリル) と 0.25 ml の水素化トリブチルスズを加え 70 ℃ にて1 夜間撹拌した。反応液を冷却後、溶媒を減圧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 = 2:1(v/v)) にて精製することにより標記化合物 63 mg を得た。
【0192】
1H-NMR (CDCl3/TMS) δ(ppm) :
1.06(3H,s), 1.15(3H,s), 1.22-1.72(3H,m), 1.74(3H,s),
1.90-2.10(1H,m), 2.02(3H,s), 2.19-2.37(2H,m), 2.28(3H,s),
3.86(1H,d,J=7.5Hz), 4.05-4.17(2H,m), 4.20(1H,d,J=8.5Hz),
4.31(1H,d,J=8.5Hz), 4.81-4.90(1H,br), 4.96(1H,d,J=10Hz), 5.07(1H,s),
5.22(1H,d,J=11Hz), 5.31(1H,d,J=17Hz), 5.62(1H,d,J=7.5Hz),
5.91-6.01(1H,m), 7.48(2H,t,J=7.5Hz), 7.60(1H,t,J=7.5Hz),
8.12(2H,d,J=7.5Hz)
【0193】
工程3:10-O-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-デアセチル-7−デオキシバッカチン III
水素化ナトリウム(ca 60% oil suspension (w/w)) 96 mg をテトラヒドロフラン 2 ml に懸濁させ、上記工程2で得た化合物 46 mgを乾燥したテトラヒドロフラン 1 ml に溶解し 0℃にて加えた。次いで、(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-フェニルアゼチジン-2−オン 61 mgを加え同温度にて3時間撹拌した。反応液に飽和塩化アンモニウム溶液を加えた後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させたのち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 = 2:1(v/v)) にて精製することにより標記化合物 35 mgを得た。
【0194】
1H-NMR (CDCl3/TMS) δ(ppm) :
-0.12(6H,s), 0.75(9H,s), 1.19(3H,s), 1.23(3H,s), 1.26(6H,s),
1.29(9H,s), 1.38-1.48(1H,m), 1.52-1.58(1H,m), 1.76(3H,s),
1.86(3H,s), 1.89-2.02(1H,m), 2.08-2.28(2H,m), 2.35-2.47(1H,m),
2.55(3H,s), 3.80(1H,d,J=7.5Hz), 4.09-4.16(2H,m), 4.23(1H,d,J=8.5Hz),
4.33(1H,d,J=9Hz), 4.51(1H,brs), 4.96(1H,d,J=8.5Hz), 5.03(1H,s),
5.22(1H,d,J=10.5Hz), 5.28-5.36(1H,m), 5.31(1H,d,J=19Hz),
5.41-5.47(1H,m), 5.68(1H,d,J=7.5Hz), 5.90-5.99(1H,m),
6.29-6.35(1H,m), 7.26-7.30(5H,m), 7.49(2H,t,J=7.5Hz),
7.58(1H,t,J=7.5Hz), 8.13(2H,d,J=7.5Hz)
【0195】
工程4:10-O-アリル-13-O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3−フェニルプロピオニル]-10-デアセチル-7−デオキシバッカチン III
上記工程3で得た化合物 35mg を蒸留したピリジン 2 ml に溶解し、 0 ℃にて 0.4 ml のフッ化水素−ピリジンを加えた。滴下終了後、室温まで昇温させて1 夜間撹拌した。反応液を水で希釈後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させたのち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)) にて精製することにより標記化合物 21 mgを得た。
【0196】
1H-NMR (CDCl3/TMS) δ(ppm) :
1.19(3H,s), 1.21(3H,s), 1.33(9H,s), 1.51-1.56(1H,m),
1.64-1.67(1H,m), 1.75(3H,s), 1.82(3H,s), 1.89-2.04(2H,m),
2.19-2.27(1H,m), 2.31-2.40(1H,m), 2.38(3H,s), 3.36(1H,brs),
3.77(1H,d,J=7.5Hz), 4.10-4.13(2H,m), 4.21(1H,d,J=8.5Hz),
4.31(1H,d,J=8.5Hz), 4.61(1H,brs), 4.93(1H,d,J=8.5Hz), 5.02(1H,s),
5.23(1H,dd,J=1.5Hz,9Hz), 5.23-5.29(1H,m),
5.31(1H,dd,J=1.5Hz,15.5Hz), 5.39(1H,d,J=9.5Hz), 5.67(1H,d,J=7.5Hz),
5.90-6.00(1H,m), 6.22-6.27(1H,m), 7.25-7.40(5H,m),
7.50(2H,t,J=7.5Hz), 7.61(1H,t,J=7.5Hz), 8.13(2H,d,J=7.5Hz)
【0197】
実施例10
13−O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(2−フリル)-2-ハイドロキシプロピオニル]-4,10−ジデアセチル-10-O-(2-モルホリノエチル)-4-O−プロピオニルバッカチン III・ メタンスルホン酸塩
実施例3の工程7で得た化合物 59 mgを t−ブタノール 2 ml および水 1.5 ml に溶解し約 5℃に冷却した。次いで、1当量のメタンスルホン酸(0.02 M 溶液、3.1 ml)を滴下し同温で 2分間撹拌した。得られた溶液をミリポアフィルターに通導後、凍結乾燥し標記化合物 51 mgを白色固体として得た。
【0198】
融点:157-161 ℃
1H-NMR (CDCl3/TMS)δ(ppm) :
1.17(s,3H), 1.20(s,3H), 1.27(t,3H,J=7Hz), 1.34(s,9H), 1.67(s,3H),
1.85-1.92(m,1H), 2.04(s,3H), 2.21-2.40(m,2H), 2.45-2.56(m,1H),
2.65-2.70(m,2H), 2.78(s,3H), 3.04(m,4H), 3.29(br,2H),
3.81(d,1H,J=7Hz), 3.92-4.10(m,6H), 4.16(d,1H,J=8Hz),
4.30(d,1H,J=8Hz), 4.35(dd,1H,J=7Hz,10Hz), 4.70(s,1H),
4.91(d,1H,J=8Hz), 5.25-5.30(m,2H), 5.54(s,1H), 5.67(d,1H,J=7Hz),
6.21(t,1H,J=8Hz), 6.34(d,1H,J=3.5Hz), 6.37(dd,1H,J=2Hz,3.5Hz),
7.43(s,1H), 7.48(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.12(d,2H,J=8Hz)
IR(KBr) :3432, 2968, 2940, 1980, 1720, 1602, 1584 cm-1
MS-FAB:925 (MH+)
【0199】
実施例11
【0200】
【化25】
Figure 0003921252
【0201】
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-デアセチル-7-デオキシ-10-O-(2-モルホリノエチル) バッカチン III
実施例9の工程3で得た化合物を実施例2の工程1と同様に反応させ、次いで、実施例2の工程2と同様に反応させ標記化合物を得た。
【0202】
1H-NMR (CDCl3/TMS) δ(ppm) :
-0.32(3H,s), -0.11(3H,s), 0.75(9H,s), 1.16(3H,s), 1.23(3H,s),
1.29(9H,s), 1.52-1.82(2H,m), 1.75(3H,s), 1.89(3H,s),
1.95-2.46(4H,m), 2.55(3H,s), 2.46-2.66(4H,m), 2.65-2.71(2H,m),
3.66-3.78(6H,m), 3.80(1H,d,J=7Hz), 4.23(1H,d,J=8Hz),
4.33(1H,d,J=8Hz), 4.52(1H,s), 4.96(1H,d,J=9Hz), 5.04(1H,s),
5.29-5.35(1H,m), 5.40-5.45(1H,m), 5.67(1H,d,J=7Hz), 6.31(1H,m),
7.27-7.46(5H,m), 7.49(2H,t,J=8Hz), 7.58(1H,t,J=7Hz),
8.13(2H,d,J=8Hz).
【0203】
工程2:13-O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3-フェニルプロピオニル]-10-デアセチル-7-デオキシ-10-O-(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9の工程1と同様に反応させ、標記化合物を得た。
【0204】
1H-NMR (CDCl3/TMS) δ(ppm) :
1.17(3H,s), 1.21(3H,s), 1.33(9H,s), 1.50-1.74(2H,m), 1.74(3H,s),
1.86(3H,s), 1.90-2.41(4H,m), 2.38(3H,s), 2.50-2.65(4H,m),
2.68(2H,m), 3.61-3.76(6H,m), 3.77(1H,d,J=7Hz), 4.21(1H,d,J=8Hz),
4.31(1H,d,J=8Hz), 4.46(1H,s), 4.93(1H,d,J=8Hz), 5.05(1H,s),
5.24-5.30(1H,m), 5.30-5.35(1H,m), 5.66(1H,d,J=7Hz), 6.22(1H,m),
7.27-7.41(5H,m), 7.50(2H,t,J=8Hz), 7.59(1H,t,J=8Hz),
8.13(2H,d,J=8Hz).
【0205】
実施例12
【0206】
【化26】
Figure 0003921252
【0207】
工程1:10- O- アリル-13-O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-フェニル-2-(トリエチルシリルオキシ) プロピオニル]-4,10- ジデアセチル-4- O- プロピオニル-7- O- トリエチルシリルバッカチンIII
実施例3の工程3で得た化合物および (3R,4S)-1-tert-( ブトキシカルボニル)-4-フェニル-3-(トリエチルシリルオキシ) アゼチジン-2- オンを実施例3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。
【0208】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.33-0.49(m,6H), 0.52-0.62(m,6H), 0.79(t,9H,J=8Hz), 0.96(t,9H,J=8Hz),
1.24(s,6H),1.34(s,9H), 1.38(t,3H,J=7Hz), 1.69(s,3H), 1.90(s,3H),
1.88-1.92(m,1H), 2.18-2.27(m,1H), 2.33-2.41(m,1H), 2.45-2.52(m,1H),
2.73-2.85(m,2H), 3.83(d,1H,J=7Hz), 4.05(dq,2H,J=5Hz,12.5Hz),
4.20(d,1H,J=8Hz), 4.33(d,1H,J=8Hz), 4.43(dd,1H,J=7Hz,10Hz),
4.54(s,1H), 4.90(d,1H,J=8Hz), 4.99(s,1H), 5.20(d,1H,J=10.5Hz),
5.23(d,1H,J=10Hz), 5.32(dd,1H,J=1.5Hz,17Hz), 5.47(d,1H,J=10Hz),
5.69(d,1H,J=7Hz), 5.94-6.02(m,1H), 6.26(t,1H,J=8Hz), 7.28-7.40(m,5H),
7.48(t,2H,J=8Hz), 7.59(t,1H,J=8Hz), 8.13(d,2H,J=8Hz)
【0209】
工程2:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-フェニル-2-(トリエチルシリルオキシ) プロピオニル]-4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル)-7-O- トリエチルシリルバッカチンIII 上記工程1で得た化合物を実施例2の工程1と同様に反応させ、次いで実施例2の工程2のモリホリンの代わりにチオモルホリンを用いて反応させ、標記化合物を無色の非晶質固体として得た。
【0210】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.34-0.49(m,6H), 0.52-0.63(m,6H), 0.79(t,9H,J=8Hz), 0.96(t,9H,J=8Hz),
1.21(s,3H),1.23(s,3H), 1.33(s,9H), 1.38(t,3H,J=7Hz), 1.67(s,3H),
1.91(s,3H), 1.89-1.94(m,1H), 2.17-2.24(m,1H), 2.32-2.40(m,1H),
2.45-2.52(m,1H), 2.67-2.76(m,8H), 2.82-2.90(m,4H), 3.59(t,2H,J=6Hz),
3.82(d,1H,J=7Hz), 4.19(d,1H,J=8Hz), 4.32(d,1H,J=8Hz),
4.43(dd,1H,J=7Hz,10Hz), 4.53(s,1H), 4.90(d,1H,J=8Hz), 4.93(s,1H),
5.22(d,1H,J=10Hz), 5.46(d,1H,J=10Hz), 5.68(d,1H,J=7Hz),
6.25(t,1H,J=8Hz), 7.28-7.40(m,5H), 7.48(t,2H,J=8Hz), 7.59(t,1H,J=8Hz),
8.13(d,2H,J=8Hz)
【0211】
工程3:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル) バッカチンIII
上記工程2で得た化合物を実施例3の工程7と同様に反応させ、標記化合物を白色固体として得た。
【0212】
融点:142-146 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.21(t,3H,J=7Hz), 1.22(s,3H), 1.34(s,9H), 1.67(s,3H),
1.76-1.88(m,1H), 1.89(s,3H), 2.29(m,2H), 2.53-2.59(m,3H),
2.64-2.78(m,6H), 2.79-2.89(m,4H), 3.62-3.67(m,1H), 3.71-3.85(m,1H),
3.84(d,1H,J=7Hz), 4.17(d,1H,J=8Hz), 4.26(dd,1H,J=7Hz,10Hz),
4.31(d,1H,J=8Hz), 4.62(s,1H), 4.89(d,1H,J=8Hz), 5.05(s,1H),
5.23(br,1H), 5.32(d,1H,J=9Hz), 5.67(d,1H,J=7Hz), 6.21(t,1H,J=8Hz),
7.31-7.42(m,5H), 7.50(t,2H,J=8Hz), 7.62(t,1H,J=8Hz), 8.12(d,2H,J=8Hz)
IR (KBr):3456, 3068, 2980, 2944, 2820, 1968, 1818, 1722, 1604,
1584 cm-1
MS-FAB:951(MH+)
【0213】
実施例13
【0214】
【化27】
Figure 0003921252
【0215】
工程1:10- O- アリル-10-デアセチル-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1の工程1で得た化合物 200 mg をピリジン 4 ml に溶解し、 クロロギ酸 2,2,2- トリクロロエチル 0.20 mlを加え、 80℃で 30 分加熱撹拌した。 放冷後、 氷水に注ぎ酢酸エチルで抽出し、 1規定塩酸、 飽和重曹水溶液、 飽和食塩水の順に洗浄した。 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;クロロホルム:アセトン= 40:1 (v/v) )で展開精製し標記化合物 220 mg を無色の非晶質固体として得た。
【0216】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.50-0.64(m,6H), 0.95(t,9H,J=8Hz), 1.14(s,3H), 1.23(s,3H), 1.67(s,3H),
1.85-1.92(m,1H), 2.00(s,3H), 2.37(d,2H,J=8Hz), 2.39(s,3H),
2.45-2.53(m,1H), 3.87(d,1H,J=7Hz), 4.05-4.11(m,2H),
4.13(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.43(dd,1H,J=7Hz,10Hz)4.84 and 4.89(each d,each 1H,J=12Hz),
4.95(d,1H,J=8Hz), 5.02(s,1H), 5.21(dd,1H,J=1.5Hz,10.5Hz),
5.32(dd,1H,J=1.5Hz,17Hz), 5.63(d,1H,J=7Hz), 5.93-6.00(m,1H),
6.02(t,1H,J=8Hz), 7.48(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.07-8.09(m,2H)
【0217】
工程2:10- デアセチル-10-O-(2-チオモルホリノエチル)-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で得た化合物を実施例2の工程1と同様に反応させ、次いで、実施例2の工程2と同様にモルホリンの代わりにチオモルホリン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。
【0218】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.49-0.64(m,6H), 0.95(t,9H,J=8Hz), 1.13(s,3H), 1.20(s,3H), 1.67(s,3H),
1.85-1.99(m,1H), 2.01(s,3H), 2.33-2.39(m,2H), 2.38(s,3H),
2.45-2.54(m,1H), 2.66-2.79(m,6H), 2.82-2.85(m,4H), 3.53-3.62(m,1H),
3.64-3.68(m,1H), 3.86(d,1H,J=7Hz), 4.12(d,1H,J=8Hz), 4.15(s,1H),
4.31(d,1H,J=8Hz), 4.44(dd,1H,J=7Hz,10Hz),
4.83 and 4.88(each d,each 1H,J=12Hz), 4.94(d,1H,J=8Hz), 4.97(s,1H),
5.62(d,1H,J=7Hz), 6.01(t,1H,J=8Hz), 7.48(t,2H,J=8Hz),
7.61(t,1H,J=8Hz), 8.09(d,2H,J=8Hz)
【0219】
工程3:10- デアセチル-10-O-(2-チオモルホリノエチル)-7-O- トリエチルシリルバッカチンIII
上記工程2で得た化合物を実施例3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。
【0220】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.50-0.65(m,6H), 0.96(t,9H,J=8Hz), 1.05(s,3H), 1.17(s,3H), 1.66(s,3H),
1.85-1.97(m,1H), 2.08(s,3H), 2.26(d,2H,J=9Hz), 2.28(s,3H),
2.45-2.53(m,2H), 2.66-2.74(m,6H), 2.83-2.85(m,4H), 3.54-3.60(m,1H),
3.62-3.68(m,1H), 3.87(d,1H,J=7Hz), 4.14(d,1H,J=8Hz), 4.30(d,1H,J=8Hz),
4.43(dd,1H,J=7Hz,10Hz), 4.87(br,1H), 4.96(d,1H,J=8Hz), 4.97(s,1H),
5.60(d,1H,J=7Hz), 7.47(t,2H,J=8Hz), 7.59(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
【0221】
工程4:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-フェニル-2-(トリエチルシリルオキシ) プロピオニル]-10- デアセチル-10-O-(2-チオモルホリノエチル)-7-O- トリエチルシリルバッカチンIII
上記工程3で得た化合物および (3R,4S)-1-(tert- ブトキシカルボニル)-4-フェニル-3-(トリエチルシリルオキシ) アゼチジン-2- オンを実施例3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。
【0222】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.33-0.48(m,6H), 0.52-0.62(m,6H), 0.79(t,9H,J=8Hz), 0.96(t,9H,J=8Hz),
1.20(s,3H), 1.23(s,3H), 1.32(s,9H), 1.68(s,3H), 1.91(s,3H),
1.89-1.94(m,1H), 2.15-2.22(m,1H), 2.31-2.40(m,1H), 2.44-2.51(m,1H),
2.52(s,3H), 2.67-2.73(m,6H), 2.84-2.86(m,4H), 3.58-3.60(m,2H),
3.83(d,1H,J=7Hz), 4.18(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.41(dd,1H,J=7Hz,10Hz), 4.56(s,1H), 4.93(s,1H), 4.94(d,1H,J=8Hz),
5.30(br,1H), 5.46(br,1H), 5.67(d,1H,J=7Hz), 6.30(t,1H,J=8Hz),
7.28-7.46(m,5H), 7.48(t,2H,J=8Hz), 7.58(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0223】
工程5:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-10- デアセチル-10-O-(2-チオモルホリノエチル) バッカチンIII
上記工程4で得た化合物を実施例3の工程7と同様に反応させ標記化合物を無色の固体として得た。
【0224】
融点:152-156 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.21(s,3H), 1.35(s,9H), 1.68(s,3H), 1.85-1.92(m,1H),
1.88(s,3H), 2.22-2.27(m,2H), 2.37(s,3H), 2.52-2.58(m,1H),
2.67-2.73(m,6H), 2.82-2.90(m,4H), 3.63-3.66(m,1H), 3.75-3.78(m,1H),
3.85(d,1H,J=7Hz), 4.17(d,1H,J=8Hz), 4.22(dd,1H,J=7Hz,10Hz),
4.30(d,1H,J=8Hz), 4.62(s,1H), 4.94(d,1H,J=8Hz), 5.06(s,1H),
5.25(br,1H), 5.39(d,1H,J=10Hz), 5.66(d,1H,J=7Hz), 6.22(t,1H,J=8Hz),
7.31-7.42(m,5H), 7.49(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
IR (KBr):3456, 3068, 2980, 2944, 2820, 1968, 1818, 1722, 1604,
1584 cm-1
MS-FAB:937 (MH+)
【0225】
実施例14
【0226】
【化28】
Figure 0003921252
【0227】
工程1:10- O- 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- デアセチル-7- O- トリエチルシリルバッカチンIII
実施例1の工程1で得た化合物および (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-フェニルアゼチジン-2- オンを実施例3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。
【0228】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.10(s,3H), 0.54-0.61(m,6H), 0.76(s,9H),
0.96(t,9H,J=8Hz), 1.24(s,6H), 1.32(s,9H), 1.69(s,3H), 1.90(s,3H),
1.89-1.94(m,1H), 2.14-2.21(m,1H), 2.32-2.42(m,1H), 2.45-2.54(m,1H),
2.56(s,3H), 3.85(d,1H,J=7Hz), 4.00-4.10(m,2H), 4.19(d,1H,J=8Hz),
4.31(d,1H,J=8Hz), 4.41(dd,1H,J=7Hz,10Hz), 4.54(s,1H),
4.95(d,1H,J=8Hz), 4.98(s,1H), 5.20(d,1H,J=12Hz),
5.32(dd,1H,J=2Hz,17.5Hz), 5.33(d,1H,J=10Hz),5.42(d,1H,J=10Hz),
5.68(d,1H,J=7Hz), 5.93-6.01(m,1H), 6.34(t,1H,J=8Hz), 7.28-7.39(m,5H),
7.47(t,2H,J=8Hz), 7.59(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0229】
工程2:10- O- 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- デアセチルバッカチンIII
上記工程1で得た化合物 198 mg をアセトニトリル 4 ml に溶解し -10℃に冷却した。 次いで、 12規定塩酸 0.050 ml を滴下し1時間撹拌した。 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した。 溶媒を減圧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= 40:1 (v/v) )で展開精製し標記化合物 136
mg を無色の非晶質固体として得た。
【0230】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.10(s,3H), 0.75(s,9H), 1.22(s,3H), 1.24(s,3H),
1.31(s,9H), 1.70(s,3H), 1.79-1.82(m,1H), 1.88(s,3H), 2.17(m,1H),
2.35-2.41(m,1H), 2.66(s,3H), 2.66-2.81(m,1H), 3.90(d,1H,J=7Hz),
4.04-4.09(m,1H), 4.16-4.23(m,3H), 4.31(d,1H,J=8Hz), 4.52(s,1H),
4.97(d,1H,J=8Hz), 5.04(s,1H), 5.21(d,1H,J=12Hz), 5.28(br,1H),
5.31(d,1H,J=17Hz), 5.53(br,1H), 5.70(d,1H,J=7Hz), 5.90-5.98(m,1H),
6.32(t,1H,J=8Hz),7.27-7.34(m,5H), 7.48(t,2H,J=8Hz), 7.59(t,1H,J=8Hz),
8.11(d,2H,J=8Hz)
【0231】
工程3:10- O- 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- デアセチル-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2で得た化合物 136 mg を塩化メチレン 3 ml およびピリジン 3 ml に溶解し、-30℃に冷却した。 次いで、 無水トリフルオロメタンスルホン酸 0.059 ml を滴下し、3時間かけて室温まで昇温した。飽和塩化アンモニウム水溶液を加え、 酢酸エチルで抽出し、 1規定硫酸水素ナトリウム水溶液、飽和重曹水溶液の順に洗浄した。 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薄層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))で展開精製し標記化合物 123 mg を淡黄色の非晶質固体として得た。
【0232】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.31(s,3H), -0.12(s,3H), 0.76(s,9H), 1.24(s,3H), 1.25(s,3H),
1.33(s,9H), 1.89(s,3H), 1.93(s,3H), 2.17-2.28(m,2H), 2.35-2.41(m,1H),
2.58(s,3H), 2.78-2.85(m,1H), 3.98(d,1H,J=7Hz), 4.06-4.21(m,4H),
4.34(d,1H,J=8Hz), 4.53(s,1H), 4.93(d,1H,J=8Hz), 5.18(s,1H),
5.20(d,1H,J=12Hz), 5.28(br,1H), 5.31(d,1H,J=17Hz), 5.42-5.49(m,2H),
5.72(d,1H,J=7Hz), 5.91-6.01(m,1H), 6.32(t,1H,J=8Hz), 7.27-7.40(m,5H),
7.49(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.09(d,2H,J=8Hz)
【0233】
工程4:10- O- 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- デアセチル-7- デオキシ-7β,8β- メタノバッカチンIII
上記工程3で得た化合物 123 mg を 1,4- ジオキサン 3 ml に溶解し、 アジ化ナトリウム 100 mg を水 0.60ml に溶かした溶液を加え、 窒素雰囲気下 1時間加熱還流した。 放冷後、 酢酸エチルで希釈し、 水、 飽和食塩水の順で洗浄した。 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薄層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))で展開精製し標記化合物 58.6 mgを無色の非晶質固体として得た。
【0234】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.33(s,3H), -0.12(s,3H), 0.74(s,9H), 1.25(s,9H), 1.29(s,3H),
1.30(s,3H), 1.66-1.69(m,1H), 1.84(s,3H), 2.10-2.19(m,2H),
2.28-2.31(m,1H), 2.41-2.47(m,2H), 2.53(s,3H), 4.05(d,1H,J=9Hz),
4.11-4.14(m,2H), 4.32(d,1H,J=8Hz), 4.51(s,1H), 4.75(d,1H,J=3.5Hz),
4.83(s,1H), 5.21(dd,1H,J=1.5Hz,10Hz), 5.30-5.35(m,2H), 5.40(br,1H),
5.68(d,1H,J=7Hz), 5.91-6.01(m,1H), 6.36(t,1H,J=8Hz), 7.26-7.39(m,5H),
7.48(t,2H,J=8Hz), 7.58(t,1H,J=8Hz), 8.14(d,2H,J=8Hz)
【0235】
工程5:13- 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- デアセチル-7- デオキシ-7β,8β- メタノ-10-O-(2-チオモルホリノエチル) バッカチンIII
上記工程4で得た化合物を実施例2の工程1と同様に反させ、次いで実施例2の工程2と同様に、モルホリンの代わりにチオモルホリン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。
【0236】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.32(s,3H), -0.11(s,3H), 0.74(s,9H), 1.25(s,3H), 1.26(s,9H),
1.29(s,3H), 1.61-1.64(m,1H), 1.87(s,3H), 2.10-2.18(m,2H),
2.26-2.31(m,1H), 2.36-2.47(m,2H), 2.52(s,3H), 2.64-2.72(m,6H),
2.82-2.85(m,4H), 3.61-3.74(m,2H), 4.05(d,1H,J=9Hz), 4.10(d,1H,J=8Hz),
4.31(d,1H,J=8Hz), 4.51(s,1H), 4.75(d,1H,J=3.5Hz), 4.83(s,1H),
5.32(d,1H,J=10Hz), 5.44(d,1H,J=10Hz), 5.66(d,1H,J=7Hz),
6.35(t,1H,J=8Hz), 7.26-7.39(m,5H), 7.48(t,2H,J=8Hz), 7.58(t,1H,J=8Hz),
8.14(d,2H,J=8Hz)
【0237】
工程6:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2- ハイドロキシ-3- フェニルプロピオニル]-10- デアセチル-7- デオキシ-7β,8β- メタノ-10-O-(2-チオモルホリノエチル) バッカチンIII
上記工程5で得た化合物を実施例3の工程7と同様に反応させ標記化合物を無色の固体として得た。
【0238】
融点:139-144 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.22(s,3H), 1.27(s,9H), 1.29(s,3H), 1.61-1.64(m,1H), 1.85(s,3H),
2.13-2.40(m,5H), 2.37(s,3H), 2.66-2.72(m,6H), 2.81-2.84(m,4H),
3.60-3.75(m,2H), 4.03(d,1H,J=8Hz), 4.08(d,1H,J=7Hz), 4.30(d,1H,J=8Hz),
4.61(s,1H), 4.72(d,1H,J=3.5Hz), 4.83(s,1H), 5.30(br,1H),
5.35(d,1H,J=10Hz), 5.73(d,1H,J=7Hz), 6.29(t,1H,J=8Hz),
7.29-7.42(m,5H), 7.50(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.14(d,2H,J=8Hz)
IR (KBr):3452, 3068, 2976, 2936, 2820, 2100, 1866, 1716, 1602,
1586 cm-1
MS-FAB:919 (MH+)
【0239】
実施例15
【0240】
【化29】
Figure 0003921252
【0241】
工程1:10- O- アリル-4,10-ジデアセチル-4- O- プロピオニルバッカチンIII
実施例3の工程3で得た化合物を実施例3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。
【0242】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.07(s,3H), 1.19(s,3H), 1.23(t,3H,J=7Hz), 1.68(s,3H), 1.76-1.83(m,1H),
1.95(d,1H,J=5Hz), 2.04(s,3H), 2.26-2.28(m,2H), 2.53-2.71(m,3H),
3.95(d,1H,J=7Hz), 4.03-4.08(m,1H), 4.16(d,1H,J=8Hz), 4.18-4.23(m,1H),
4.27-4.34(m,2H), 4.87(m,1H), 4.94(d,1H,J=8Hz), 5.09(s,1H),
5.23(d,1H,J=10Hz), 5.33(dd,1H,J=1.5Hz,17Hz), 5.64(d,1H,J=7Hz),
5.92-6.01(m,1H), 7.47(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.12(d,2H,J=8Hz)
【0243】
工程2:10- O- アリル-4,10-ジデアセチル-7- O-(1-イミダゾリルチオカルボニル)-4-O- プロピオニルバッカチンIII
上記工程1で得た化合物 758 mg をトルエン 75 mlに溶解し、1,1'- チオカルボニルジイミダゾール 500 mg および 4- ジメチルアミノピリジン 154 mg を加え 80 ℃で一晩撹拌した。トルエンを減圧留去し残分を酢酸エチルで希釈し、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 (v/v) )で精製し標記化合物 790 mg を淡黄色固体として得た。
【0244】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.06(s,3H), 1.17(s,3H), 1.27(t,3H,J=7Hz), 1.62(s,3H), 1.89-1.93(m,1H),
1.96(s,3H), 2.07(s,3H), 2,28-2.35(m,2H), 2.59-2.74(m,2H),
2.92-3.00(m,2H), 3.78-3.90(m,2H), 4.09(d,1H,J=7Hz), 4.21(d,1H,J=8Hz),
4.37(d,1H,J=8Hz), 4.87(br,1H), 4.96-5.02(m,4H), 5.58-5.69(m,2H),
6.16(dd,1H,J=7Hz,10Hz), 7.04(s,1H), 7.48(t,2H,J=8Hz), 7.54(s,1H),
7.62(t,1H,J=8Hz), 8.13(d,2H,J=8Hz), 8.30(s,1H)
工程3:10- O- アリル-7- デオキシ-4,10-ジデアセチル-4- O- プロピオニルバッカチンIII
上記工程2で得た化合物 780 mg をトルエン 15 mlおよび 1,4- ジオキサン 15 mlに溶解し、α, α´-アゾビスイソブチロニトリル 20 mgを加え十分に脱気し窒素置換した。次いで、水素化トリブチルスズ 0.712 ml を加え 90 ℃で30分撹拌した。反応液を濃縮し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= 40:1 (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。
【0245】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.06(s,3H), 1.15(s,3H), 1.22(t,3H,J=7Hz), 1.74(s,3H), 2.02(s,3H),
1.92-2.10(m,2H), 2.19-2.36(m,4H), 2.54-2.70(m,2H), 3.86(d,1H,J=7Hz),
4.10-4.17(m,2H), 4.20(d,1H,J=8Hz), 4.31(d,1H,J=8Hz), 4.87(m,1H),
4.92(d,1H,J=8Hz), 5.07(s,1H), 5.22(d,1H,J=10Hz),
5.30(dd,1H,J=1.5Hz,17Hz), 5.62(d,1H,J=7Hz), 5.92-6.02(m,1H),
7.47(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.13(d,2H,J=8Hz)
工程4:10- O- 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]-7-デオキシ-4,10-ジデアセチル-4- O- プロピオニルバッカチンIII
上記工程3で得た化合物および (3R,4S)-1-(tert- ブトキシカルボニル)-4-フェニル-3-(トリエチルシリルオキシ) アゼチジン-2- オンを実施例3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。
【0246】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.13(s,3H), 0.76(s,9H), 1.19(s,3H), 1.23(s,3H),
1.31(s,9H), 1.38(t,3H,J=7Hz), 1.51-1.58(m,1H), 1.76(s,3H), 1.86(s,3H),
1.91-2.07(m,3H), 2.16-2.28(m,1H), 2.37-2.46(m,1H), 2.74-2.96(m,2H),
3.78(d,1H,J=7Hz), 4.11(d,2H,J=5Hz), 4.24(d,1H,J=8Hz),
4.34(d,1H,J=8Hz), 4.48(s,1H), 4.92(d,1H,J=8Hz), 5.03(s,1H),
5.22(d,1H,J=10Hz), 5.26(br,1H), 5.31(d,1H,J=17Hz), 5.46(br,1H),
5.69(d,1H,J=7Hz), 5.91-6.00(m,1H), 6.25(t,1H,J=8Hz), 7.28-7.41(m,5H),
7.49(t,2H,J=8Hz), 7.59(t,1H,J=8Hz), 8.14(d,2H,J=8Hz)
【0247】
工程5:13- 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]-7-デオキシ-4,10-ジデアセチル-4- O- プロピオニル-10-O-(2-チオモリホリノエチル) バッカチンIII
上記工程4で得た化合物を実施例2の工程1と同様に反応させ、次いで、実施例2の工程2と同様にモルホリンの代わりにチオモルホリン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。
【0248】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.13(s,3H), 0.76(s,9H), 1.16(s,3H), 1.22(s,3H),
1.31(s,9H), 1.38(t,3H,J=7Hz), 1.53-1.57(m,1H), 1.75(s,3H), 1.89(s,3H),
1.95(m,2H), 2.04-2.12(m,1H), 2.21-2.28(m,1H), 2.39-2.45(m,1H),
2.67-2.75(m,6H), 2.77-2.90(m,6H), 3.59-3.76(m,2H), 3.78(d,1H,J=7Hz),
4.24(d,1H,J=8Hz), 4.35(d,1H,J=8Hz), 4.48(s,1H), 4.91(d,1H,J=8Hz),
5.01(s,1H), 5.28(d,1H,J=10Hz), 5.43(br,1H), 5.68(d,1H,J=7Hz),
6.25(t,1H,J=8Hz), 7.28-7.41(m,5H), 7.49(t,2H,J=8Hz), 7.59(t,1H,J=8Hz),
8.14(d,2H,J=8Hz)
【0249】
工程6:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-7-デオキシ-4,10-ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル) バッカチンIII
上記工程5で得た化合物を実施例3の工程7と同様に反応させ標記化合物を無色の固体として得た。
【0250】
融点:127-131 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.16(s,3H), 1.21(s,3H), 1.21(t,3H,J=7Hz), 1.32(s,9H), 1.51-1.55(m,1H),
1.74(s,3H), 1.86(s,3H), 1.90-2.09(m,2H), 2.19-2.29(m,2H),
2.33-2.39(m,1H), 2.61-2.73(m,8H), 2.79-2.89(m,4H), 3.58-3.72(m,2H),
3.75(d,1H,J=7Hz), 4.21(d,1H,J=8Hz), 4.32(d,1H,J=8Hz), 4.61(s,1H),
4.88(d,1H,J=8Hz), 5.01(s,1H), 5.24(br,1H), 5.31(d,1H,J=10Hz),
5.66(d,1H,J=7Hz), 6.23(t,1H,J=8Hz), 7.30-7.43(m,5H), 7.50(t,2H,J=8Hz),
7.61(t,1H,J=8Hz), 8.14(d,2H,J=8Hz)
IR (KBr):3460, 3068, 2984, 2936, 2820, 1718, 1604, 1586 cm-1
MS-FAB:935 (MH+)
【0251】
実施例16
【0252】
【化30】
Figure 0003921252
【0253】
工程1:13- O-[(2R,3S)-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]-4,10- ジデアセチル-4- O- プロピオニル-10-O-[2-( チオモルホリノ-1- オキシド) エチル]-7-O- トリエチルシリルバッカチンIII
実施例6の工程1で得た化合物 30 mgをメタノール 3 ml に溶解し、 氷冷下 0.1Mメタ過ヨウ素酸ナトリウム水溶液 0.271 ml を加え、 0 ℃で2時間、 室温で4時間撹拌した。 反応液を水で希釈し、 クロロホルムで抽出した。 有機層を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= 40:1 (v/v) )で展開精製し標記化合物 18.2 mgを無色の非晶質固体として得た。
【0254】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.52-0.63(m,6H), 0.96-1.01(m,30H), 1.19(s,3H), 1.20(s,3H), 1.35(s,9H),
1.37(t,3H,J=7Hz), 1.67(s,3H), 1.87(m,1H), 1.93(s,3H), 2.32-2.36(m,2H),
2.45-2.52(m,1H), 2.75-2.89(m,10H), 3.19-3.25(m,2H), 3.60(t,2H,J=6Hz),
3.82(d,1H,J=7Hz), 4.18(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.42(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz), 4.94(s,1H), 4.99(s,1H),
5.24(d,1H,J=10Hz), 5.30(d,1H,J=10Hz), 5.67(d,1H,J=7Hz),
6.18(t,1H,J=8Hz), 6.27(d,1H,J=3.5Hz), 6.37(s,1H), 7.40(s,1H),
7.47(t,2H,J=8Hz), 7.58(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0255】
工程2:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(2- フリル)-2-ハイドロキシプロピオニル]-4,10- ジデアセチル-4- O- プロピオニル-10-O-[2-( チオモルホリノ-1- オキシド) エチル] バッカチンIII
上記工程1で得た化合物を実施例3の工程7と同様に反応させ標記化合物を無色の固体として得た。
【0256】
融点:147-151 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.21(s,3H), 1.30(t,3H,J=7Hz), 1.34(s,9H), 1.67(s,3H),
1.77-1.84(m,1H), 1.93(s,3H), 2.28-2.37(m,2H), 2.46-2.54(m,1H),
2.69-2.76(m,2H), 2.78-2.92(m,8H), 3.20-3.27(m,2H), 3.61-3.66(m,1H),
3.73-3.81(m,1H), 3.85(d,1H,J=7Hz), 4.17(d,1H,J=8Hz),
4.26(dd,1H,J=7Hz,10Hz), 4.31(d,1H,J=8Hz), 4.70(d,1H,J=2Hz),
4.90(d,1H,J=8Hz), 5.09(s,1H), 5.31(d,1H,J=10Hz), 5.40(d,1H,J=10Hz),
5.67 (d,1H,J=7Hz), 6.20(t,1H,J=8Hz), 6.34(d,1H,J=3Hz),
6.38(dd,1H,J=2Hz,3Hz), 7.43(s,1H), 7.49(t,2H,J=8Hz), 7.60(t,1H,J=8Hz),
8.12(d,2H,J=8Hz)
IR (KBr):3896, 3448, 2980, 2940, 1722, 1632, 1604, 1496 cm-1
MS-FAB:957 (MH+)
【0257】
実施例17
【0258】
【化31】
Figure 0003921252
【0259】
工程1:10- O- アリル-10-デアセチル-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
実施例13の工程1で得た化合物 563 mg をアセトニトリル 50 mlに溶解し、 ピリジン 2.5 ml 及び 48 %フッ化水素酸 7.5 ml を氷冷下加え、 室温で 2 時間撹拌した。 濃縮後、 酢酸エチルで希釈し、 飽和重曹水溶液、 1 規定塩酸の順に洗浄した。 無色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= 40:1 (v/v) )で展開精製し標記化合物 415 mg を無色の非晶質固体として得た。
【0260】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.15(s,3H), 1.22(s,3H), 1.68(s,3H), 1.76-1.82(m,1H), 1.98(s,3H),
2.38(s,3H), 2.35-2.42(m,2H), 2.54-2.62(m,1H), 3.93(d,1H,J=7Hz),
4.04-4.08(m,2H), 4.13(d,1H,J=8Hz), 4.32(d,1H,J=8Hz),
4.86(s,2H), 4.96(d,1H,J=8Hz), 5.08(s,1H), 5.23(d,1H,J=10.5Hz),
5.32(d,1H,J=17Hz), 5.66(d,1H,J=7Hz), 5.91-6.00(m,2H),
7.48(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.09(d,2H,J=8Hz)
【0261】
工程2:10- O- アリル-10-デアセチル-7- デオキシ-7- α- フルオロ-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1で得た化合物 320 mg を塩化メチレン 30 mlに溶解し、 -78 ℃に冷却した。 次いで、 ジエチルアミノスルファートリフルオライド 0.040 ml を加え、-78 ℃で 15 分、 室温で 30 分撹拌した。 反応液を再び -78℃に冷却しジエチルアミノスルファートリフルオライド 0.080 ml を加え、-78 ℃で 15 分、 室温で 60 分撹拌した。原料の消失を確認後、 反応液を水で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= 40:1 (v/v) )で展開精製し標記化合物 185 mg を無色の固体として得た。
【0262】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.14(s,3H), 1.20(s,3H), 1.71(s,3H), 1.90(s,3H), 2.12-2.62(m,4H),
2.39(s,3H), 4.07(d,1H,J=7Hz), 4.11-4.14(m,2H), 4.23(d,1H,J=8Hz),
4.37(d,1H,J=8Hz), 4.57(dd,1H,J=5Hz,47Hz), 4.85(s,2H),
5.02(d,1H,J=9Hz), 5.12(s,1H), 5.22(d,1H,J=10.5Hz), 5.31(d,1H,J=17Hz),
5.74(d,1H,J=7Hz), 5.90-6.00(m,2H), 7.49(t,2H,J=8Hz) ,
7.62(t,1H,J=8Hz), 8.12(d,2H,J=8Hz)
【0263】
工程3:10- O- アリル-10-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2で得た化合物 185.0 mg をメタノール:酢酸=1 :1(v/v)の混合溶媒 20 mlに溶解し、 活性亜鉛末 1 gを加え 60 ℃で 30 分撹拌した。 不溶物を濾去し、 溶媒を減圧留去した後、トルエンで共沸した。 得られた残分を酢酸エチルで希釈し、 飽和重曹水溶液で洗浄、 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= 40:1 (v/v) )で展開精製し標記化合物 130 mg を無色の固体として得た。
【0264】
融点:193-195 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.06(s,3H), 1.17(s,3H), 1.71(s,3H), 1.96(s,3H), 2.12(m,1H),
2.25-2,39(m,2H), 2.30(s,3H), 2.48-2.61(m,1H), 4.10-4.13(m,3H),
4.27(d,1H,J=8Hz), 4.35(d,1H,J=8Hz), 4.55(dd,1H,J=4.5Hz,47.5Hz),
4.86(br,1H), 5.02(d,1H,J=8Hz), 5.11(s,1H), 5.27(d,1H,J=10.5Hz),
5.32(d,1H,J=17Hz), 5.72(d,1H,J=7Hz), 5.92-6.02(m,1H),
7.48(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.13(d,2H,J=8Hz)
IR (KBr):3536, 3076, 2992, 2944, 2904, 1744, 1712, 1648, 1602 cm-1
MS-FAB:587 (MH+)
【0265】
工程4:10- O- 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- デアセチル-7- デオキシ-7- α- フルオロバッカチンIII
上記工程3で得た化合物および (3R,4S)-1-tert-ブトキシカルボニル-4- フェニル-3-(トリエチルシリルオキシ) アゼチジン-2- オンを実施例3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。
【0266】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.11(s,3H), 0.74(s,9H), 1.21(s,3H), 1.23(s,3H),
1.31(s,9H), 1.75(s,3H), 1.83(s,3H), 2.17-2.60(m,4H), 2.56(s,3H),
4.05(d,1H,J=7Hz), 4.12(d,1H,J=5.5Hz), 4.30(d,1H,J=8Hz),
4.38(d,1H,J=8Hz), 4.53(s,1H), 4.59(dd,1H,J=4Hz,47Hz),
5.04(d,1H,J=8Hz), 5.09(d,1H,.J=2Hz), 5.21(dd,1H,J=1.5Hz,10.5Hz),
5.32(dd,1H,J=1.5Hz,17Hz), 5.36(d,1H,J=10Hz), 5.45(d,1H,J=10Hz),
5.78(d,1H,J=7Hz), 5.91-6.00(m,1H), 6.32(t,1H,J=8Hz), 7.28-7.40(m,5H),
7.50(t,2H,J=8Hz), 7.59(t,1H,J=8Hz), 8.15(d,2H,J=8Hz)
【0267】
工程5:13- 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- デアセチル-7- デオキシ-7- α- フルオロ-10-O-(2-チオモルホリノエチル) バッカチンIII
上記工程4で得た化合物を実施例2の工程1と同様に反応させ、次いで、実施例2の工程2と同様にモルホリンの代わりにチオモルホリン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。
【0268】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.32(s,3H), -0.11(s,3H), 0.74(s,9H), 1.18(s,3H), 1.22(s,3H),
1.31(s,9H), 1.74(s,3H), 1.85(s,3H), 2.12-2.59(m,4H), 2.56(s,3H),
2.67-2.72(m,6H), 2.82-2.85(m,4H), 3.62-3.70(m,2H), 4.04(d,1H,J=7Hz),
4.30(d,1H,J=8Hz), 4.37(d,1H,J=8Hz), 4.52(s,1H), 4.59(dd,1H,J=4Hz,47Hz),
5.03(d,1H,J=8Hz), 5.08(s,1H), 5.35(d,1H,J=10Hz), 5.48(d,1H,J=10Hz),
5.77(d,1H,J=7Hz), 6.31(t,1H,J=8Hz), 7.28-7.40(m,5H),
7.50(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.14(d,2H,J=8Hz)
【0269】
工程6:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-10- デアセチル-7- デオキシ-7- α- フルオロ-10-O-(2-チオモルホリノエチル) バッカチンIII
上記工程5で得た化合物を実施例3の工程7と同様に反応させ標記化合物を無色の固体として得た。
【0270】
融点:142-146 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.17(s,3H), 1.20(s,3H), 1.34(s,9H), 1.72(s,3H), 1.80(s,3H),
2.15-2.60(m,4H), 2.38(s,3H), 2.66-2.72(m,6H), 2.79-2.84(m,4H),
3.59-3.72(m,2H), 4.02(d,1H,J=7Hz), 4.27(d,1H,J=8Hz), 4.35(d,1H,J=8Hz),
4.62(s,1H), 4.56(dd,1H,J=4Hz,47Hz), 5.00(d,1H,J=8Hz), 5.07(s,1H),
5.30(d,1H,J=10Hz), 5.40(d,1H,J=10Hz), 5.75(d,1H,J=7Hz),
6.23(t,1H,J=8Hz), 7.32-7.39(m,5H), 7.50(t,2H,J=8Hz), 7.61(t,1H,J=8Hz),
8.13(d,2H,J=8Hz)
IR (KBr):3452, 3068, 2940, 2816, 1742, 1714, 1604, 1586 cm-1
MS-FAB:939 (MH+)
【0271】
実施例18
【0272】
【化32】
Figure 0003921252
【0273】
工程1:10- O- アリル-4,10-ジデアセチル-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3の工程3で得た化合物を実施例13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。
【0274】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.50-0.64(m,6H), 0.95(t,9H,J=8Hz), 1.16(s,3H), 1.23(s,3H),
1.33(t,3H,J=7Hz), 1.67(s,3H), 1.85-1.91(m,1H), 1.99(s,3H),
2.30-2.41(m,2H), 2.46-2.54(m,1H), 2.64-2.76(m,2H), 3.87(d,1H,J=7Hz),
4.10-4.14(m,2H), 4.13(d,1H,J=8Hz), 4.32(d,1H,J=8Hz),
4.45(dd,1H,J=7Hz,10Hz), 4.84 and 4.88(each d,each 1H,J=12Hz),
4.89(d,1H,J=8Hz), 5.02(s,1H), 5.21(dd,1H,J=1.5Hz,10Hz),
5.30(dd,1H,J=1.5Hz,17Hz), 5.64(d,1H,J=7Hz), 5.94-6.02(m,1H),
6.05(t,1H,J=8Hz), 7.47(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
【0275】
工程2:4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル)-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で得た化合物を実施例13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。
【0276】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.52-0.64(m,6H), 0.96(t,9H,J=8Hz), 1.14(s,3H), 1.20(s,3H),
1.33(t,3H,J=7Hz), 1.67(s,3H), 1.85-1.91(m,1H), 2.00(s,3H),
2.33-2.40(m,2H), 2.46-2.53(m,1H), 2.67-2.76(m,8H), 2.83(m,4H),
3.48-3.66(m,2H), 3.85(d,1H,J=7Hz), 4.13(d,1H,J=8Hz), 4.15(s,1H),
4.32(d,1H,J=8Hz), 4.45(dd,1H,J=7Hz,10Hz),
4.83 and 4.88(each d,each 1H,J=12Hz), 4.87(d,1H,J=8Hz), 4.96(s,1H),
5.63(d,1H,J=7Hz), 6.04(t,1H,J=8Hz), 7.47(t,2H,J=8Hz),
7.61(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
【0277】
工程3:4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル)-7-O- トリエチルシリルバッカチンIII
上記工程2で得た化合物を実施例13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。
【0278】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.50-0.65(m,6H), 0.96(t,9H,J=8Hz), 1.05(s,3H), 1.17(s,3H),
1.24(t,3H,J=7Hz), 1.66(s,3H), 1.85-1.91(m,1H), 2.07(s,3H),
2.24(d,2H,J=9Hz), 2.46-2.55(m,2H), 2.57-2.64(m,2H), 2.66-2.74(m,6H),
2.84-2.89(m,4H), 3.55-3.67(m,2H), 3.87(d,1H,J=7Hz), 4.14(d,1H,J=8Hz),
4.29(d,1H,J=8Hz), 4.44(dd,1H,J=7Hz,10Hz), 4.86(br,1H),
4.91(d,1H,J=8Hz), 4.98(s,1H), 5.60(d,1H,J=7Hz), 7.46(t,2H,J=8Hz),
7.59(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0279】
工程4:13- O-[(2,3- スレオ)-3-(tert-ブトキシカルボニルアミノ)-5-メチル-2-(トリエチルシリルオキシ)-4-ヘキセノイル]-4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル)-7-O- トリエチルシリルバッカチ
ンIII
【0280】
上記工程3で得た化合物および (3,4 −シス)-1-tert- ブトキシカルボニル-4- イソブテニル-3-(トリエチルシリルオキシ) アゼチジン-2- オンを実施例3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。
【0281】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.53-0.70(m,12H), 0.93-1.03(m,18H), 1.19(s,6H), 1.26-1.32(m,3H),
1.35 and 1.39(each s,total 9H), 1.67(s,3H), 1.77(s,3H), 1.81(s,3H),
1.86 and 1.89(each s,total 3H), 2.12(m,2H), 2.34-2.47(m,3H),
2.65-2.70(m,6H), 2.83(m,4H), 3.56-3.60(m,2H),
3.80 and 3.84(each d,total 1H,J=7Hz), 4.18-4.31(m,3H), 4.41(m,1H),
4.75 and 5.02(each br,total 1H), 4.85(m,2H),
4.92 and 4.97(each s,total 1H), 5.26 and 5.31(each d,total 1H,J=10Hz),
5.64-5.66(m,1H), 6.11(m,1H), 7.42-7.60(m,3H),
8.06 and 8.11(each d,total 2H,J=8Hz)
【0282】
工程5:13- O-[(2S,3R)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-5- メチル-4- ヘキセノイル]-4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル) バッカチンIII および 13-O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-5- メチル-4- ヘキセノイル]-4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル) バッカチ
ンIII
【0283】
上記工程4で得た化合物を実施例3の工程7と同様に反応させ、標記化合物をそれぞれ無色の固体として得た。
【0284】
(2S,3R) 体
融点:142-145 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.18(s,6H), 1.28(t,3H,J=7Hz), 1.39(s,9H), 1.68(s,3H), 1.79(s,3H),
1.82(s,3H), 2.00(m,1H), 2.11-2.16(m,2H), 2.15(s,3H), 2.38-2.62(m,3H),
2.67-2.73(m,6H), 2.79-2.87(m,4H), 3.63-3.65(m,1H), 3.76-3.79(m,1H),
3.89(d,1H,J=7Hz), 4.08(s,1H), 4.16(d,1H,J=8Hz), 4.29(d,1H,J=8Hz),
4.30(dd,1H,J=7Hz,10Hz), 4.78(s,1H), 4.76-4.80(m,1H), 4.90(d,1H,J=8Hz),
5.07(s,1H), 5.29(d,1H,J=7Hz), 5.66(d,1H,J=7Hz), 6.01(t,1H,J=8Hz),
7.46(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.05(d,2H,J=8Hz)
IR (KBr):3460, 2980, 2940, 2824, 2352, 1722, 1604, 1586 cm-1
MS-FAB:929 (MH+)
【0285】
(2R,3S) 体
融点:146-149 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.20(s,3H), 1.27(t,3H,J=7Hz), 1.35(s,9H), 1.67(s,3H),
1.78(s,6H), 1.84(m,1H), 1.93(s,3H), 2.35-2.37(m,2H), 2.53-2.71(m,9H),
2.79-2.89(m,4H), 3.63-3.66(m,1H), 3.72-3.76(m,1H), 3.86(d,1H,J=7Hz),
4.16(s,1H), 4.17(d,1H,J=8Hz), 4.27(dd,1H,J=7Hz,10Hz),
4.31(d,1H,J=8Hz), 4.70-4.79(m,2H), 4.91(d,1H,J=8Hz), 5.06(s,1H),
5.36(d,1H,J=7Hz), 5.67(d,1H,J=7Hz), 6.14(t,1H,J=8Hz),
7.46(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
IR (KBr):3464, 3068, 2980, 2940, 2820, 1716, 1604, 1584 cm-1
MS-FAB:929 (MH+)
【0286】
実施例19
【0287】
【化33】
Figure 0003921252
【0288】
工程1:10- O- アリル-13-O-[3-(tert-ブトキシカルボニルアミノ)-2,2-ジフルオロ-3-(2-フリル) プロピオニル]-4,10- ジデアセチル-4- O- プロピオニル-7- O- トリエチルシリルバッカチンIII (アイソマーA、アイソマーB)
【0289】
3-(tert-ブトキシカルボニルアミノ)-2,2-ジフルオロ-3-(2-フリル) プロピオン酸 245 mg および 2,2'-ジピリジルカーボネート 182 mg をトルエン 6 ml に溶解し室温で10分撹拌した。次いで、実施例3の工程3で得た化合物 100 mg ??? 4- ジメチルアミノピリジン 17 mgを加え、70℃で一晩加熱撹拌した。放冷後、反応液を酢酸エチルで希釈し、1規定塩酸、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、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;エチルエーテル:ヘキサン= 1:1 (v/v))で 2 回展開することにより精製し2つのアイソマーA(低極性化合物)56.3 mg およびアイソマーB(高極性化合物)51.0 mg をそれぞれ得た。
【0290】
アイソマーA
1H-NMR(CDCl3/TMS) δ(ppm) :
0.51-0.64(m,6H), 0.95(t,9H,J=8Hz), 1.21(s,3H), 1.24(s,3H),
1.31(t,3H,J=7Hz), 1.42(s,9H), 1.68(s,3H), 1.87(s,3H), 1.85-1.92(m,1H),
2.25-2.27(m,2H), 2.45-2.53(m,1H), 2.59-2.61(m,2H), 3.79(d,1H,J=7Hz),
3.99-4.07(m,2H), 4.15(d,1H,J=8Hz), 4.30(d,1H,J=8Hz),
4.41(dd,1H,J=7Hz,10Hz), 4.87(d,1H,J=8Hz), 4.96(s,1H),
5.19(d,1H,J=9Hz), 5.29(dd,1H,J=1.5Hz,17Hz), 5.38(d,1H,J=10Hz),
5.62(m,1H), 5.66(d,1H,J=7Hz), 5.92-6.02(m,1H), 6.27(t,1H,J=8Hz),
6.40-6.44(m,2H), 7.45-7.50(m,3H), 7.61(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0291】
アイソマーB
1H-NMR(CDCl3/TMS) δ(ppm) :
0.51-0.64(m,6H), 0.95(t,9H,J=8Hz), 1.21(s,3H), 1.24(s,3H),
1.29(t,3H,J=7Hz), 1.45(s,9H), 1.68(s,3H), 1.90(s,3H), 1.87-1.93(m,1H),
2.26(d,2H,J=9Hz), 2.45-2.60(m,3H), 3.79(d,1H, J=7Hz), 3.99-4.09(m,2H),
4.14(d,1H,J=8Hz), 4.30(d,1H,J=8Hz), 4.41(dd,1H,J=7Hz,10Hz),
4.87(d,1H,J=8Hz), 4.97(s,1H), 5.19(dd,1H,J=1.5Hz,10.5Hz),
5.29(dd,1H,J=1.5Hz,17Hz), 5.38(d,1H,J=10Hz), 5.60(m,1H),
5.66(d,1H,J=7Hz), 5.93-6.03(m,1H), 6.23(t,1H,J=8Hz), 6.39-6.45(m,2H),
7.43(d,1H,J=1.5Hz), 7.48(t,2H,J=8Hz), 7.61(t,1H,J=8Hz),
8.09(d,2H,J=8Hz)
【0292】
工程2:13- O-[3-(tert-ブトキシカルボニルアミノ)-2,2-ジフルオロ-3-(2-フリル) プロピオニル]-4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル)-7-O- トリエチルシリルバッカチンIII (アイソマーA,アイソマーB)
【0293】
上記工程1でそれぞれ得た化合物を実施例2の工程1と同様に反応させ、次いで、実施例2の工程2と同様にモルホリンの代わりにチオモルホリンを用い反応させ標記化合物(アイソマーA、アイソマーB)をそれぞれ非晶質固体として得た。
【0294】
アイソマーA
1H-NMR(CDCl3/TMS) δ(ppm) :
0.49-0.64(m,6H), 0.96(t,9H,J=8Hz), 1.20(s,6H), 1.30(t,3H,J=7Hz),
1.42(s,9H), 1.67(s,3H), 1.87(s,3H), 1.89-1.93(m,1H), 2.24-2.30(m,2H),
2.44-2.52(m,1H), 2.59-2.61(m,2H), 2.66-2.73(m,8H), 2.83-2.95(m,4H),
3.48-3.65(m,2H), 3.78(d,1H,J=7Hz), 4.15(d,1H,J=8Hz), 4.30(d,1H,J=8Hz),
4.42(dd,1H,J=7Hz,10Hz), 4.87(d,1H,J=8Hz), 4.91(s,1H),
5.36(d,1H,J=10Hz), 5.55-5.63(m,1H), 5.65(d,1H,J=7Hz),
6.25(t,1H,J=8Hz), 6.40-6.43(m,2H), 7.45-7.49(m,3H), 7.61(t,1H,J=8Hz),
8.10(d,2H,J=8Hz)
【0295】
アイソマーB
1H-NMR(CDCl3/TMS) δ(ppm) :
0.49-0.64(m,6H), 0.96(t,9H,J=8Hz), 1.19(s,3H), 1.20(s,3H),
1.29(t,3H,J=7Hz), 1.45(s,9H), 1.67(s,3H), 1.90(s,3H), 1.87-1.91(m,1H),
2.25(d,2H,J=9Hz), 2.44-2.61(m,3H), 2.66-2.73 (m,8H), 2.83-2.85(m,4H),
3.48-3.65(m,2H), 3.78(d,1H,J=7Hz), 4.14(d,1H,J=8Hz), 4.30(d,1H,J=8Hz),
4.43(dd,1H,J=7Hz,10Hz), 4.87(d,1H,J=8Hz), 4.92(s,1H),
5.37(d,1H,J=10Hz), 5.58-5.61(m,1H), 5.65(d,1H,J=7Hz),
6.21(t,1H,J=8Hz), 6.39-6.44(m,2H), 7.43-7.50(m,3H), 7.61(t,1H,J=8Hz),
8.09(d,2H,J=8Hz)
【0296】
工程3:13- O-[3-(tert-ブトキシカルボニルアミノ)-2,2-ジフルオロ-3-(2-フリル) プロピオニル]-4,10- ジデアセチル-4- O- プロピオニル-10-O-(2-チオモルホリノエチル) バッカチンIII (アイソマーA、アイソマーB)
上記工程2でそれぞれ得た化合物を実施例3の工程7と同様に反応させ標記化合物(アイソマーA、アイソマーB)をそれぞれ無色の固体として得た。
【0297】
アイソマーA
融点:136-139 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.21(s,3H), 1.29(t,3H,J=7Hz), 1.41(s,9H), 1.67(s,3H),
1.87(s,3H), 1.81-1.84 (m,1H), 2.21-2.32(m,2H), 2.54-2.62(m,3H),
2.66-2.71 (m,8H), 2.78-2.90(m,4H), 3.60-3.65 (m,1H), 3.71-3.79(m,1H),
3.84(d,1H,J=7Hz), 4.13(d,1H,J=8Hz), 4.28(dd,1H,J=7Hz,10Hz),
4.31(d,1H,J=8Hz), 4.89(d,1H,J=8Hz), 5.02(s,1H), 5.36(d,1H, J=10Hz),
5.57-5.63(m,1H), 5.67(d,1H,J=7Hz), 6.25(t,1H,J=8Hz), 6.40-6.43(m,2H),
7.45-7.50(m,3H), 7.61(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
IR (KBr):3464, 2984, 2944, 2816, 1768, 1724, 1604, 1500 cm-1
MS-FAB:961 (MH+)
【0298】
アイソマーB
融点:138-142 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.19(s,3H), 1.20(s,3H), 1.27(t,3H,J=7Hz), 1.45(s,9H), 1.67(s,3H),
1.90(s,3H), 1.77-1.84 (m,1H), 2.25(d,2H,J=9Hz), 2.50-2.61(m,3H),
2.66-2.72 (m,8H), 2.77-2.89(m,4H), 3.60-3.65 (m,1H), 3.74-3.79(m,1H),
3.82(d,1H,J=7Hz), 4.15(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.27(dd,1H,J=7Hz,10Hz), 4.89(d,1H,J=8Hz), 5.03(s,1H),
5.37(d,1H,J=10Hz), 5.55-5.61(m,1H), 5.67(d,1H,J=7Hz),
6.19(t,1H,J=8Hz), 6.39-6.43(m,2H), 7.43(d,1H,J=1.5Hz),
7.48(t,2H,J=8Hz), 7.62(t,1H,J=8Hz), 8.09(d,2H,J=8Hz)
IR (KBr):3464, 2980, 2944, 2820, 1766, 1722, 1604, 1500 cm-1
MS-FAB:961 (MH+)
【0299】
実施例20
【0300】
【化34】
Figure 0003921252
【0301】
工程1:10- デアセチル-10-O-(2-ピリジルメチル)-7-O- トリエチルシリルバッカチンIII
7-O- トリエチルシリルバッカチンIII 100 mgをテトラヒドロフラン 4 ml に溶解し、-78 ℃に冷却した。次いで、n-ブチルリチウム (1.61 Mヘキサン溶液) 0.378 ml を滴下した。15分後、2-ピリジルメチルブロマイド臭酸塩 57.7 mgをジメチルスルホキシド 1 ml に溶かした溶液を滴下し、 0 ℃に昇温し1時間撹拌した。飽和重曹水溶液を加え酢酸エチルで抽出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= 20:1 (v/v) )で展開精製し標記化合物 25.1 mgを無色の非晶質固体として得た。
【0302】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.47-0.61(m,6H), 0.92(t,9H,J=8Hz), 1.06(s,3H), 1.24(s,3H), 1.70(s,3H),
1.86-1.93(m,1H), 2.09(s,3H), 2.21-2.33(m,2H), 2.28(s,3H),
2.46-2.54(m,1H), 3.91(d,1H,J=7Hz), 4.16(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.45(dd,1H,J=7Hz,10Hz), 4.71(AB type d,each 1H,J=13Hz), 4.88(br,1H),
4.96(d,1H,J=8Hz), 5.22(s,1H), 5.64(d,1H,J=7Hz), 7.18-7.21(m,1H),
7.47(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 7.72-7.76(m,2H), 8.10-8.12(m,2H),
8.50(d,1H,J=5Hz)
【0303】
工程2:13- O-[(2R,3S)-N-(tert- ブトキシカルボニル)-2,3-N, O-(4-メトキシベンジリデン)-3-フェニルイソセリニル]-10- デアセチル-10-O-(2-ピリジルメチル)-7-O- トリエチルシリルバッカチンIII
【0304】
(4S,5R)-3-tert- ブトキシカルボニル-2-(4-メトキシフェニル)-オキサゾリジン-5- カルボン酸 80.0 mgを酢酸エチル 2 ml に溶解しジシクロヘキシルカルボジイミド 49.5 mgを加え室温で15分撹拌した。次いで、上記工程1で得た化合物 50.0 mgおよび 2- ジメチルアミノピリジンを加え1時間撹拌した。不溶物を濾去した後、母液を飽和重曹水溶液、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。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= 40:1 (v/v) )で展開精製し標記化合物 65.1 mgを無色の非晶質固体として得た。
【0305】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.45-0.55(m,6H), 0.89(t,9H,J=8Hz), 1.05(s,9H), 1.19(s,3H), 1.25(s,3H),
1.58(br,3H), 1.65(s,3H), 1.84(br,3H), 1.87-1.91(m,1H),
2.05-2.17(m,2H), 2.41-2.45(m,1H), 3.72(d,1H,J=7Hz), 3.77(s,3H),
4.09(d,1H,J=8Hz), 4.22(d,1H,J=8Hz), 4.33(dd,1H,J=7Hz,10Hz),
4.56(d,1H,J=5Hz), 4.65(AB type d,each 1H,J=14Hz), 4.84(d,1H,J=8Hz),
5.08(s,1H), 5.40(br,1H), 5.63(d,1H,J=7Hz), 6.15(br,1H), 6.40(br,1H),
6.93(d,2H,J=9Hz), 7.17-7.21(m,1H), 7.41-7.50(m,9H), 7.60-7.64(m,2H),
7.69-7.73(m,1H), 8.03(d,2H,J=8Hz), 8.51(d,1H,J=4.5Hz)
【0306】
工程3:13- O-[(2R,3S)-N-(tert- ブトキシカルボニル)-2,3-N, O-(4-メトキシベンジリデン)-3-フェニルイソセリニル]-10- デアセチル-10-O-(2-ピリジルメチル)バッカチンIII
上記工程2で得た化合物を実施例3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。
【0307】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.81(br,3H), 1.03(s,9H), 1.18(s,3H), 1.20(s,3H), 1.66(s,3H),
1.74(br,3H), 1.86-1.94(m,1H), 1.97-2.15(m,2H), 2.45-2.52(m,1H),
3.59(d,1H,J=7Hz), 3.82(s,3H), 4.10(d,1H,J=8Hz),
4.16(dd,1H,J=7Hz,10Hz), 4.21(d,1H,J=8Hz), 4.50(s,1H),
4.75(d,1H,J=13Hz), 4.87(d,1H,J=13Hz), 4.88(d,1H,J=8Hz), 5.03(s,1H),
5.35(br,1H), 5.60(d,1H,J=7Hz), 6.04(br,1H), 6.35(br,1H),
6.86(d,2H,J=8Hz), 7.29-7.39(m,8H), 7.47(t,2H,J=8Hz), 7.54-7.61(m,2H),
7.82(t,1H,J=8Hz), 8.01(d,2H,J=8Hz), 8.48(d,1H,J=4.5Hz)
【0308】
工程4:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-10- デアセチル-10-O-(2-ピリジルメチル) バッカチンIII
上記工程3で得た化合物 34.1 mgをメタノール 4 ml に溶解し、室温下トシル酸 16.2 mgを加え、2時間撹拌した。飽和重曹水溶液で希釈し酢酸エチル抽出、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= 20:1 (v/v) )で展開精製後 1,4- ジオキサンより凍結乾燥し標記化合物 28.3 mgを白色固体として得た。
【0309】
融点:152-157 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.15(s,3H), 1.20(s,3H), 1.25(s,3H), 1.32(s,9H), 1.73(s,3H),
1.92-1.99(m,1H), 2.21(d,2H,J=8Hz), 2.32(s,3H), 2.50-2.58(m,1H),
3.71(d,1H,J=7Hz), 4.19(d,1H,J=8Hz), 4.25(dd,1H,J=7Hz,10Hz),
4.29(d,1H,J=8Hz), 4.52(s,1H), 4.89(d,1H,J=12Hz), 4.92(d,1H,J=12Hz),
4.95(d,1H,J=8Hz), 5.18(s,1H), 5.21(d,1H,J=10Hz), 5.36(d,1H,J=10Hz),
5.66(d,1H,J=7Hz), 6.12(t,1H,J=8Hz), 7.29-7.39(m,6H), 7.48(t,2H,J=8Hz),
7.59(d,2H,J=7Hz), 7.81(t,1H,J=8Hz), 8.09(d,2H,J=8Hz), 8.51(d,1H,J=5Hz)
IR (KBr):3452, 3068, 2980, 2940, 2504, 1722, 1600 cm-1
MS-FAB:899 (MH+)
【0310】
実施例21
【0311】
【化35】
Figure 0003921252
【0312】
工程1:10- デアセチル-10-O-(3-ピリジルメチル)-7-O- トリエチルシリルバッカチンIII
実施例20の工程1と同様に 2- ピリジルメチルブロマイド臭酸塩の代わりに3-ピリジルメチルブロマイド臭酸塩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。
【0313】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.49-0.63(m,6H), 0.95(t,9H,J=8Hz), 1.07(s,3H), 1.21(s,3H), 1.69(s,3H),
1.82-1.93(m,1H), 2.07(s,3H), 2.25-2.31(m,2H), 2.29(s,3H),
2.44-2.55(m,1H), 3.89(d,1H,J=7Hz), 4.16(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.46(dd,1H,J=7Hz,10Hz), 4.55(d,1H,J=12Hz), 4.68(d,1H,J=12Hz),
4.91(t,1H,J=8Hz), 4.97(d,1H,J=8Hz), 5.13(s,1H), 5.63(d,1H,J=7Hz),
7.29-7.33(m,1H), 7.47(t,2H,J=8Hz), 7.60(t,1H,J=8Hz), 7.83(d,1H,J=8Hz),
8.11(d,2H,J=8Hz), 8.53-8.59(m,2H)
【0314】
工程2:13- O-[(2R,3S)-N-(tert- ブトキシカルボニル)-2,3-N, O-(4-メトキシベンジリデン)-3-フェニルイソセリニル]-10- デアセチル-10-O-(3-ピリジルメチル)-7-O- トリエチルシリルバッカチンIII
上記工程1で得た化合物を実施例20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。
【0315】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.45-0.59(m,6H), 0.93(t,9H,J=8Hz), 1.06(s,9H), 1.19(s,3H), 1.21(s,3H),
1.56(br,3H), 1.64(s,3H), 1.85(br,3H), 1.86-1.92(m,1H),
2.04-2.24(m,2H), 2.39-2.47(m,1H), 3.70(d,1H,J=7Hz), 3.77(s,3H),
4.08(d,1H,J=8Hz), 4.22(d,1H,J=8Hz), 4.35(dd,1H,J=7Hz,10Hz),
4.48(d,1H,J=11Hz), 4.56(d,1H,J=11Hz), 4.57(s,1H), 4.84(d,1H,J=8Hz),
4.98(s,1H), 5.42(br,1H), 5.61(d,1H,J=7Hz), 6.12(br,1H), 6.39(br,1H),
6.93(d,2H,J=9Hz), 7.29-7.32(m,1H), 7.38-7.50(m,9H), 7.62(t,1H,J=8Hz),
7.78(d,1H,J=8Hz), 8.02(d,2H,J=8Hz), 8.54-8.59(m,2H)
【0316】
工程3:13- O-[(2R,3S)-N-(tert- ブトキシカルボニル)-2,3-N, O-(4-メトキシベンジリデン)-3-フェニルイソセリニル]-10- デアセチル-10-O-(3-ピリジルメチル) バッカチンIII
上記工程2で得た化合物を実施例20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。
【0317】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.05(s,9H), 1.19(s,3H), 1.21(s,3H), 1.34(s,3H), 1.65(s,3H),
1.73(br,4H), 2.03-2.22(m,2H), 2.46-2.53(m,1H), 3.71(d,1H,J=7Hz),
3.80(s,3H), 4.09(d,1H,J=8Hz), 4.15(dd,1H,J=7Hz,10Hz),
4.21(d,1H,J=8Hz), 4.55(s,1H), 4.56(d,1H,J=13Hz), 4.73(d,1H,J=13Hz),
4.85(d,1H,J=8Hz), 4.93(s,1H), 5.39(br,1H), 5.62(d,1H,J=7Hz),
6.09(br,1H), 6.36(br,1H), 6.93(d,2H,J=8Hz), 7.30(dd,2H,J=5Hz,8Hz),
7.37-7.44(m,6H), 7.48(t,2H,J=8Hz), 7.62(t,1H,J=8Hz), 7.77(d,1H,J=8Hz),
8.00-8.03(m,2H), 8.52(dd,1H,J=1.5Hz,5Hz), 8.57(d,1H,J=1.5Hz)
【0318】
工程4:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-10- デアセチル−10- O-(3-ピリジルメチル) バッカチンIII
上記工程3で得た化合物を実施例20の工程4と同様に反応させ標記化合物を無色の固体として得た。
【0319】
融点:158-163 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.22(s,3H), 1.25(s,3H), 1.34(s,9H), 1.61(s,3H), 1.71(s,3H),
1.81-1.87(m,1H), 2.26(m,2H), 2.34(s,3H), 2.51-2.55(m,1H),
3.81(d,1H,J=7Hz), 4.17(d,1H,J=8Hz), 4.21(dd,1H,J=7Hz,10Hz),
4.30(d,1H,J=8Hz), 4.59(d,1H,J=12Hz), 4.60(s,1H), 4.77(d,1H,J=12Hz),
4.93(d,1H,J=8Hz), 5.03(s,1H), 5.25(d,1H,J=10Hz), 5.45(d,1H,J=10Hz),
5.68(d,1H,J=7Hz), 6.20(t,1H,J=8Hz), 7.28-7.39(m,6H), 7.49(t,2H,J=8Hz),
7.61(d,2H,J=8Hz), 7.81(d,1H,J=8Hz), 8.10(d,2H,J=8Hz), 8.48-8.49(m,1H),
8.55(s,1H)
IR (KBr):3448, 3068, 2980, 2940, 2356, 1720, 1602 cm-1
MS-FAB:899 (MH+)
【0320】
実施例22
【0321】
【化36】
Figure 0003921252
【0322】
工程1:10- デアセチル-10-O-(4-ピリジルメチル)-7-O- トリエチルシリルバッカチンIII
実施例20の工程1と同様に 2- ピリジルメチルブロマイド臭酸塩の代わりに 4- ピリジルメチルブロマイド臭酸塩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。
【0323】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.51-0.63(m,6H), 0.94(t,9H,J=8Hz), 1.09(s,3H), 1.24(s,3H), 1.69(s,3H),
1.87-1.93(m,1H), 2.06(s,3H), 2.27-2.31(m,2H), 2.28(s,3H),
2.47-2.55(m,1H), 3.89(d,1H,J=7Hz), 4.16(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.47(dd,1H,J=7Hz,10Hz), 4.54(d,1H,J=13Hz), 4.73(d,1H,J=13Hz),
4.91(t,1H,J=8Hz), 4.97(d,1H,J=8Hz), 5.11(s,1H), 5.64(d,1H,J=7Hz),
7.34(d,2H,J=6Hz), 7.47(t,2H,J=8Hz), 7.60(t,1H,J=8Hz),
8.11(d,2H,J=8Hz), 8.57(d,2H,J=6Hz)
【0324】
工程2:13- O-[(2R,3S)-N-(tert- ブトキシカルボニル)-2,3-N, O-(4-メトキシベンジリデン)-3-フェニルイソセリニル]-10- デアセチル-10-O-(4-ピリジルメチル)-7-O- トリエチルシリルバッカチンIII
上記工程1で得た化合物を実施例20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。
【0325】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.49-0.53(m,6H), 0.91(t,9H,J=8Hz), 1.06(s,9H), 1.19(s,3H), 1.23(s,3H),
1.54(br,3H), 1.64(s,3H), 1.78(br,3H), 1.85-1.90(m,1H),
2.05-2.21(m,2H), 2.39-2.48(m,1H), 3.70(d,1H,J=7Hz), 3.77(s,3H),
4.09(d,1H,J=8Hz), 4.22(d,1H,J=8Hz), 4.33(dd,1H,J=7Hz,10Hz),
4.48(d,1H,J=13Hz), 4.57(s,1H), 4.60(d,1H,J=13Hz), 4.84(d,1H,J=8Hz),
4.96(s,1H), 5.40(br,1H), 5.62(d,1H,J=7Hz), 6.10(br,1H), 6.39(br,1H),
6.93(d,2H,J=9Hz), 7.31-7.50(m,11H), 7.62(t,1H,J=8Hz),
8.03(d,2H,J=8Hz), 8.59(d,2H,J=6Hz)
【0326】
工程3:13- O-[(2R,3S)-N-(tert- ブトキシカルボニル)-2,3-N, O-(4-メトキシベンジリデン)-3-フェニルイソセリニル]-10- デアセチル-10-O-(4-ピリジルメチル) バッカチンIII
上記工程2で得た化合物を実施例20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。
【0327】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.05(s,9H), 1.21(s,3H), 1.23(s,3H), 1.40(s,3H), 1.65(s,3H),
1.75(br,3H), 1.79(m,1H), 2.05-2.24(m,2H), 2.45-2.53(m,1H),
3.72(d,1H,J=7Hz), 3.79(s,3H), 4.09(d,1H,J=8Hz),
4.13(dd,1H,J=7Hz,10Hz), 4.22(d,1H,J=8Hz), 4.54(d,1H,J=14Hz),
4.55(s,1H), 4.70(d,1H,J=14Hz), 4.85(d,1H,J=8Hz), 4.94(s,1H),
5.41(br,1H), 5.63(d,1H,J=7Hz), 6.12(br,1H), 6.37(br,1H),
6.92(d,2H,J=8Hz), 7.29(d,2H,J=5.5Hz), 7.41-7.43(m,7H),
7.48(t,2H,J=8Hz), 7.62(t,1H,J=8Hz), 8.02(d,2H,J=8Hz),
8.56(d,2H,J=5.5Hz)
【0328】
工程4:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-10- デアセチル−10- O-(4-ピリジルメチル) バッカチンIII
上記工程3で得た化合物を実施例20の工程4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:160-165 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.20(s,3H), 1.28(s,3H), 1.33(s,9H), 1.66(s,3H), 1.73(s,3H),
1.83-1.89(m,1H), 2.29(d,2H,J=8Hz), 2.36(s,3H), 2.49-2.57(m,1H),
3.83(d,1H,J=7Hz), 4.17(d,1H,J=8Hz), 4.25(dd,1H,J=7Hz,10Hz),
4.31(d,1H,J=8Hz), 4.60(d,1H,J=14Hz), 4.65(s,1H), 4.82(d,1H,J=14Hz),
4.94(d,1H,J=8Hz), 5.02(s,1H), 5.27(d,1H,J=10Hz), 5.44(d,1H,J=10Hz),
5.69(d,1H,J=7Hz), 6.22(t,1H,J=8Hz), 7.27-7.39(m,7H), 7.50(t,2H,J=8Hz),
7.61(d,2H,J=8Hz), 8.10(d,2H,J=8Hz), 8.48(d,2H,J=6Hz)
IR (KBr):3444, 3072, 2984, 2940, 1948, 1726, 1606 cm-1
MS-FAB:899 (MH+)
【0330】
実施例23
【0331】
【化37】
Figure 0003921252
【0332】
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- デアセチル-10-O-[2-(3- チアゾリジノ) エチル]-7-O- トリエチルシリルバッカチンIII
実施例14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、次いで、実施例2の工程2と同様に、モルホリンの代わりにチアゾリジン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。
【0333】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.09(s,3H), 0.52-0.62(m,6H), 0.75(s,9H),
0.96(t,3H,J=7Hz), 1.20(s,3H), 1.23(s,3H), 1.31(s,9H), 1.68(s,3H),
1.90-1.93(m,1H), 1.91(s,3H), 2.13-2.21(m,1H), 2.35-2.54(m,2H),
2.56(s,3H), 2.68(t,2H,J=6Hz), 2.91(t,2H,J=6Hz), 3.09-3.22(m,2H),
3.62-3.64(m,2H), 3.84(d,1H,J=7Hz), 4.11-4.20(m,3H), 4.31(d,1H,J=8Hz),
4.42(dd,1H,J=7Hz,10Hz), 4.54(s,1H), 4.95(d,1H,J=8Hz), 5.34(br,1H),
5.41(br,1H), 5.67(d,1H,J=7Hz), 6.33(t,1H,J=8Hz), 7.27-7.37(m,5H),
7.47(t,2H,J=8Hz), 7.58(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0334】
工程2:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-10- デアセチル-10-O-[2-(3- チアゾリジノ) エチル] バッカチンIII
上記工程1で得た化合物を実施例3の工程7と同様に反応させ標記化合物を無色の固体として得た。
【0335】
融点:147-153 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.20(s,3H), 1.21(s,3H), 1.35(s,9H), 1.68(s,3H), 1.78-1.85(m,1H),
1.87(s,3H), 2.28(m,2H), 2.36(s,3H), 2.51-2.59(m,1H),
2.68(t,2H,J=5.5Hz), 2.90(t,2H,J=5.5Hz), 3.10-3.19(m,2H),
3.66-3.70(m,1H), 3.77-3.80(m,1H), 3.85(d,1H,J=7Hz), 4.12(s,2H),
4.17(d,1H,J=8Hz), 4.21(dd,1H,J=7Hz,10Hz), 4.30(d,1H,J=8Hz),
4.62(s,1H), 4.94(d,1H,J=8Hz), 5.10(s,1H), 5.25(br,1H),
5.40(d,1H,J=10Hz), 5.67(d,1H,J=7Hz), 6.22(t,1H,J=8Hz),
7.32-7.40(m,5H), 7.49(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.10(d,2H,J=8Hz)
IR (KBr):3456, 2980, 2940, 1722, 1768, 1604, 1586 cm-1
MS-FAB:923 (MH+)
【0336】
実施例24
【0337】
【化38】
Figure 0003921252
【0338】
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- デアセチル-10-O-(2-ハイドロキシエチル)-7-O- トリエチルシリルバッカチンIII
実施例14の工程1で得た化合物 550 mg および N- メチルモルホリン-N- オキサイド 180 mg をアセトン 40 mlと水 10 mlの混合溶媒に溶解し室温下、四酸化オスミウム 5 mg を加え、3時間撹拌した。亜硫酸ナトリウムを加え15分さらに無水硫酸ナトリウムを加え30分撹拌した後、不溶物を濾去し溶媒を減圧留去した。得られた残分をメタノール 40 mlに溶解し氷冷下、メタ過ヨウ素酸ナトリウム 219 mg を水 10 mlに溶かした溶液を滴下し1時間撹拌した。飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出し無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。得られた残分をテトラヒドロフラン 20 mlに溶解し、水素化ホウ素ナトリウム 48 mgを加え、氷冷下で15分撹拌した。1規定塩酸を発泡しなくなるまで加え水で希釈し酢酸エチルで抽出した。飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、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;酢酸エチル:ヘキサン= 1:2 (v/v))で精製し標記化合物 278 mg を無色の非晶質固体として得た。
【0339】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.10(s,3H), 0.53-0.63(m,6H), 0.75(s,9H),
0.96(t,3H,J=7Hz), 1.21(s,3H), 1.25(s,3H), 1.31(s,9H), 1.69(s,3H),
1.90-1.93(m,1H), 1.91(s,3H), 2.15-2.20(m,1H), 2.31-2.40(m,1H),
2.45-2.53(m,1H), 2.56(s,3H), 2.92(br,1H), 3.54-3.58(m,1H),
3.66-3.70(m,1H), 3.79(m,2H), 4.19(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.44(dd,1H,J=7Hz,10Hz), 4.53(s,1H), 4.95(d,1H,J=8Hz), 5.01(s,1H),
5.33(br,1H), 5.41(br,1H), 5.67(d,1H,J=7Hz), 6.33(t,1H,J=8Hz),
7.27-7.39(m,5H), 7.48(t,2H,J=8Hz), 7.58(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0340】
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- デアセチル-10-O-[2-(p- トルエンスルホニルオキシ) エチル]-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 260 mg およびトリエチルアミン 0.067 ml を塩化メチレン 10 mlに溶解し室温下、無水トシル酸 118 mg を加え2時間撹拌した。反応液を飽和重曹水溶液、飽和食塩水の順に洗浄し無水硫酸ナトリウムで乾燥、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;酢酸エチル:ヘキサン= 1:4 (v/v))で精製し標記化合物 257 mg を無色の非晶質固体として得た。
【0341】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.08(s,3H), 0.52-0.60(m,6H), 0.75(s,9H),
0.94(t,3H,J=7Hz), 1.10(s,3H), 1.16(s,3H), 1.31(s,9H), 1.66(s,3H),
1.87-1.90(m,1H), 1.89(s,3H), 2.10-2.19(m,1H), 2.32-2.40(m,1H),
2.45(s,3H), 2.45-2.49(m,1H), 2.55(s,3H), 3.66-3.69(m,1H),
3.77-3.80(m,2H), 4.12(d,1H,J=8Hz), 4.16-4.24(m,2H), 4.30(d,1H,J=8Hz),
4.41(dd,1H,J=7Hz,10Hz), 4.54(s,1H), 4.94(d,1H,J=8Hz), 4.95(s,1H),
5.33(br,1H), 5.42(br,1H), 5.63(d,1H,J=7Hz), 6.32(t,1H,J=8Hz),
7.28-7.39(m,7H), 7.47(t,2H,J=8Hz), 7.58(t,1H,J=8Hz), 7.82(d,2H,J=8Hz),
8.11(d,2H,J=8Hz)
【0342】
工程3:13- 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- デアセチル-10-O-(2-ヨードエチル)-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 200 mg をアセトニトリル 5 ml に溶解し、ヨウ化ナトリウム121 mgを加え2時間加熱還流した。反応液を氷水に注ぎ酢酸エチルで抽出した。飽和食塩水で洗浄、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薄層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 184 mg を無色の非晶質固体として得た。
【0343】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.09(s,3H), 0.56-0.61(m,6H), 0.75(s,9H),
0.97(t,3H,J=7Hz), 1.22(s,3H), 1.26(s,3H), 1.31(s,9H), 1.68(s,3H),
1.89-1.92(m,1H), 1.90(s,3H), 2.11-2.20(m,1H), 2.33-2.41(m,1H),
2.46-2.56(m,1H), 2.57(s,3H), 3.30-3.37(m,2H), 3.66-3.70(m,1H),
3.82(d,1H,J=7Hz), 3.85-3.88(m,1H), 4.19(d,1H,J=8Hz), 4.31(d,1H,J=8Hz),
4.44(dd,1H,J=7Hz,10Hz), 4.54(s,1H), 4.95(d,1H,J=8Hz), 5.00(s,1H),
5.31(br,1H), 5.43(br,1H), 5.67(d,1H,J=7Hz), 6.34(t,1H,J=8Hz),
7.28-7.37(m,5H), 7.47(t,2H,J=8Hz), 7.58(t,1H,J=8Hz), 8.11(d,2H,J=8Hz)
【0344】
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- デアセチル-10-O-[2-(1- イミダゾリル) エチル]-7-O- トリエチルシリルバッカチンIII
【0345】
A法
上記工程3で得た化合物 184 mg をアセトニトリル 5 ml に溶解し、N-アセチルイミダゾール 20.4 mgを加え封管し 100 ℃で24時間撹拌した。反応液を放冷後、飽和重曹水溶液 2 ml を加え20分撹拌した。酢酸エチルおよび飽和重曹水溶液 20 mlを加え有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し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:メタノール= 20:1(v/v))で精製し標記化合物 26.5 mgを無色の非晶質固体として得た。
【0346】
B法
N,N-ジメチルホルムアミド 0.5 ml に水素化ナトリウム 2.8 mg を加え窒素下、イミダゾール 7.8 mg を加え 90 ℃で30分撹拌した。次いで、上記工程3で得た化合物 115 mg を N,N- ジメチルホルムアミド 2 ml に溶解した溶液を滴下し同温で40分撹拌した。反応液を氷水に注ぎ酢酸エチルで抽出し、水、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= 20:1(v/v))で展開精製し標記化合物 35.5 mgを無色の非晶質固体として得た。
【0347】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.30(s,3H), -0.10(s,3H), 0.48-0.59(m,6H), 0.75(s,9H),
0.93(t,3H,J=7Hz), 1.09(s,3H), 1.13(s,3H), 1.30(s,9H), 1.68(s,3H),
1.88-1.94(m,1H), 1.85(s,3H), 2.09-2.19(m,1H), 2.32-2.38(m,1H),
2.44-2.49(m,1H), 2.56(s,3H), 3.66-3.73(m,1H), 3.79(m,2H),
4.15-4.25(m,2H), 4.30(d,1H,J=8Hz), 4.40(dd,1H,J=7Hz,10Hz), 4.52(s,1H),
4.93(s,1H), 4.94(d,1H,J=8Hz), 5.32(br,1H), 5.42(br,1H),
5.65(d,1H,J=7Hz), 6.28(t,1H,J=8Hz), 7.04(s,1H), 7.11(s,3H),
7.26-7.39(m,5H), 7.47(t,2H,J=8Hz), 7.57-7.60(m,2H), 8.10(d,2H,J=8Hz)
【0348】
工程5:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-10- デアセチル-10-O-[2-(1- イミダゾリル) エチル] バッカチンIII
上記工程4で得た化合物を実施例3の工程7と同様に反応させ標記化合物を無色の固体として得た。
【0349】
融点:163-169 ℃
1H-NMR(CDCl3/TMS) δ(ppm) :
1.11(s,3H), 1.14(s,3H), 1.33(s,9H), 1.67(s,3H), 1.69(s,3H),
1.85-1.90(m,1H), 2.25(m,2H), 2.33(s,3H), 2.45-2.54(m,1H), 3.60(m,1H),
3.77(d,1H,J=7Hz), 3.93(m,1H), 4.10-4.24(m,4H), 4.27(d,1H,J=8Hz),
4.61(s,1H), 4.86(s,1H), 4.93(d,1H,J=8Hz), 5.20(br,1H),
5.55(d,1H,J=10Hz), 5.63(d,1H,J=7Hz), 6.17(t,1H,J=8Hz), 6.97(s,1H),
7.02(s,1H), 7.29-7.38(m,5H), 7.48(t,2H,J=8Hz), 7.55(s,1H),
7.60(t,1H,J=8Hz), 8.08(d,2H,J=8Hz)
IR (KBr):3444, 3120, 3072, 2980, 2940, 1724, 1604, 1586 cm-1
MS-FAB:902 (MH+)
【0350】
実施例25
【0351】
【化39】
Figure 0003921252
【0352】
10- O- アリル-13-O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-2-ハイドロキシ-3- フェニルプロピオニル]-4,10- ジデアセチル-7- デオキシ-4- O- プロピオニルバッカチンIII
実施例15の工程4で得た化合物を実施例3の工程7と同様に反応させ標記化合物を無色の固体として得た。
【0353】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.20-1.25(m,9H), 1.34(s,9H), 1.69(s,3H), 1.80-1.82(m,1H), 1.84(s,3H),
2.28(m,2H),2.54-2.65(m,3H), 3.30(br,1H), 3.85(d,1H,J=7Hz),
4.06(dd,1H,J=6Hz,13Hz), 4.16-4.21(m,3H), 4.31(d,1H,J=8Hz), 4.62(s,1H),
4.89(d,1H,J=8Hz), 5.03(s,1H), 5.22(d,1H,J=10Hz), 5.24(br,1H),
5.29-5.40(m,2H), 5.69(d,1H,J=7Hz), 5.89-5.99(m,1H), 6.22(t,1H,J=8Hz),
7.32-7.41(m,5H), 7.49(t,2H,J=8Hz), 7.61(t,1H,J=8Hz), 8.12(d,2H,J=8Hz)
【0354】
実施例26
【0355】
【化40】
Figure 0003921252
【0356】
工程1:10- O- アリル-10-デアセチル-7- デオキシバッカチンIII
10- デアセチル-7- デオキシバッカチンIII を実施例1の工程1と同様に反応させ標記化合物を白色固体として得た。
【0357】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.07(s,3H), 1.16(s,3H), 1.52(dd,J=4.0Hz,12.0Hz,1H), 1.68(s,1H),
1.74(s,3H), 2.02(s,3H), 1.19-2.12(m,4H), 2.24(dd,J=6.4Hz,15.6Hz,1H),
2.28(s,3H), 2.33(dd,J=6.8Hz,15.6Hz,1H), 3.87(d,J=7.3Hz,1H),
4.06-4.18(m,2H), 4.20(d,J=8.3Hz,1H), 4.31(d,J=8.3Hz,1H), 4.89(s,1H),
4.96(dd,J=2.5Hz, 9.5Hz,1H), 5.22(d,J=10.2Hz,1H), 5.07(s,1H),
5.31(d,J=15.6Hz,1H), 5.63(d,J=7.3Hz,1H), 5.90-6.03(m,1H),
7.48(t,J=7.3Hz,2H), 7.60(t,J=7.3Hz,1H), 8.12(d,J=7.3Hz,2H)
【0358】
工程2:10- O- アリル-10-デアセチル-7- デオキシ-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 1.60 g の N,N−ジメチルホルムアミド 24 ml溶液に、室温にて、イミダゾール 1.91 g およびトリエチルクロロシラン 4.71 mlを加え、25時間撹拌した。反応混液に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、分液し、水層を酢酸エチルで抽出した。有機層を合わせて、水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。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 〜 3:1 (v/v))を用いて精製し標記化合物 1.75 g を白色固体として得た。
【0359】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.67(q,J=7.8Hz,6H), 1.02(t,J=7.8Hz,9H), 1.12(s,3H), 1.15(s,3H),
1.52(dd,J=4.9Hz, 11.7Hz,1H), 1.62(s,1H), 1.74(s,3H), 1.97(s,3H),
1.90-2.33(m,5H), 2.28(s,3H), 3.78(d,J=7.3Hz,1H), 4.06-4.17(m,2H),
4.20(d,J=8.3Hz,1H), 4.31(d,J=8.3Hz,1H), 4.95(t,J=9.8Hz,1H),
4.96(dd,J=2.5Hz, 9.5Hz,1H), 5.05(s,1H), 5.22(d,J=12.2Hz,1H),
5.30(d,J=16.9Hz,1H), 5.61(d,J=7.3Hz,1H), 5.90-6.04(m,1H),
7.47(t,J=7.3Hz,2H), 7.59(t,J=7.3Hz,1H), 8.10(d,J=7.3Hz,2H)
【0360】
工程3:10- O- アリル-10-デアセチル-1- O- ジメチルシリル-7- デオキシ-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 460 mg の N,N−ジメチルホルムアミド 9.0 ml 溶液に、0 ℃にて、イミダゾール 183 mg およびジメチルクロロシラン 300μl を加え、20分間撹拌した。反応混液に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、分液し、水層を酢酸エチルで抽出した。有機層を合わせて、飽和食塩水 20 mlで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。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465 mgを白色固体として得た。
【0361】
1H-NMR(CDCl3/TMS) δ(ppm) :
-0.27(d,J=2.9Hz,3H), 0.08(d,J=2.9Hz,3H), 0.70(q,J=7.8Hz,6H),
1.04(t,J=7.8Hz,9H), 1.15(s,3H), 1.08(s,3H), 1.85(s,3H),
1.96(s,3H), 1.40-2.50(m,6H), 2.28(s,3H), 3.70-3.79(m,1H),
4.05-4.18(m,2H), 4.25(d,J=8.3Hz,1H), 4.29(d,J=8.3Hz,1H),
4.50-4.57(m,1H), 4.92-5.01(m,1H), 5.01(s,1H), 5.21(d,J=10.5Hz,1H),
5.30(d,J=15.6Hz,1H), 5.69(d,J=7.3Hz,1H), 5.90-6.05(m,1H),
7.58(t,J=7.3Hz,1H), 8.10(d,J=7.3Hz,2H)
【0362】
工程4:10- O- アリル-7- デオキシ-4,10-ジデアセチル-4- O- プロピオニルバッカチンIII
上記工程3で得た化合物 465 mg のテトラヒドロフラン 9.0 ml 溶液に、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 65%(w/v) トルエン溶液 940μl を加え、2時間撹拌した。反応混液に酢酸エチル、酒石酸ナトリウムカリウム水溶液および水を加え15分撹拌後、分液し、水層を酢酸エチルで抽出した。有機層を合わせて、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。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= 4:1 (v/v))を用いて粗精製し、粗生成物 240 mg を白色固体として得た。その粗生成物 240 mg のテトラヒドロフラン 6.0 ml 溶液に、-48 ℃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 550μl を加え15分間撹拌後、プロピオニルクロライド 47.0 μl を加え1時間撹拌した。反応混液に飽和塩化アンモニウム水溶液および酢酸エチルを加え分液し、水層を酢酸エチルで抽出した。有機層を合わせて、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去し、残分 285 mg を得た。得られた残分 285 mg のピリジン 4.0 ml 溶液に、0 ℃にて、フッ化水素ピリジン 1.0 ml を加え、室温で18時間撹拌した。撹拌している酢酸エチルおよび氷水の混合液に反応混液を注ぎ、分液し、水層を酢酸エチルで抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。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))を用いて標記化合物 37.0 mgを白色固体として得た。
【0363】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.10-1.40(m,3H), 1.09(s,3H), 1.07(s,3H), 1.74(s,3H), 2.02(s,3H),
1.50-2.40(m,7H), 2.52-2.76(m,2H), 3.87(d,J=7.3Hz,1H), 4.05-4.18(m,2H),
4.20(d,J=8.3Hz,1H), 4.32(d,J=8.3Hz,1H), 4.82(s,1H), 4.88(s,1H),
4.92(d,J=9.3Hz,1H), 5.07(s,1H), 5.22(d,J=10.3Hz,1H),
5.30(d,J=17.1Hz,1H), 5.63(d,J=7.3Hz,1H), 5.85-6.05(m,1H),
7.47(t,J=7.3Hz,2H), 7.60(t,J=7.3Hz,1H), 8.13(d,J=7.3Hz,2H)
【0364】
工程5:10- O- アリル-13-O-[(2R,3S)-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]-4,10- ジデアセチル-7- デオキシ-4- O- プロピオニルバッカチンIII
上記工程4で得た化合物および (3R,4S)-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) アゼチジン-2- オンを実施例3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。
【0365】
1H-NMR(CDCl3/TMS) δ(ppm) :
0.90-1.05(m,18H), 1.15-1.40(m,12H), 1.33(s,9H), 1.73(s,1H), 1.76(s,3H),
1.50-1.80(m,2H), 1.88(s,3H), 1.95-2.12(m,2H), 2.18-2.45(m,2H),
2.75(q,J=7.3Hz,2H), 3.80(d,J=7.3Hz,1H), 4.08-4.16(m,2H),
4.24(d,J=7.8Hz,1H), 4.33(d,J=7.8Hz,1H), 4.92(d,J=7.3Hz,1H), 4.98(s,1H),
5.04(s,1H), 5.18-5.37(m,4H), 5.69(d,J=7.3Hz,1H), 5.90-6.03(m,1H),
6.15-6.25(m,1H), 6.27(d,J=2.5Hz,1H), 6.37(d,J=2.5Hz,1H), 7.40(s,1H),
7.47(t,J=7.3Hz,2H), 7.57(t,J=7.3Hz,1H), 8.13(d,J=7.3Hz,2H)
【0366】
工程6:10- O- アリル-13-O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(2- フリル)-2-ハイドロキシプロピオニル]-4,10- ジデアセチル-7- デオキシ-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3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。
【0367】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.18-1.30(m,3H), 1.22(s,3H), 1.26(s,3H), 1.32(s,9H),
1.54(dd,J=4.6Hz,12.3Hz,1H), 1.73(s,1H), 1.76(s,3H), 1.86(s,3H),
1.77-2.12(m,2H), 2.17-2.32(m,2H), 2.43(dd,J=9.3Hz, 15.1Hz,1H),
2.62-2.80(m,2H), 3.39(d,J=5.9Hz,1H), 3.77(d,J=7.3Hz,1H), 4.07-4.17(m,2H)
,
4.22(d,J=8.5Hz,1H), 4.33(d,J=8.5Hz,1H), 4.70(d,J=7.3Hz,1H),
4.90(dd,J=2.2Hz,9.5Hz,1H), 5.03(s,1H), 5.15-5.35(m,4H),
5.68(d,J=7.3Hz,1H), 5.90-6.02(m,1H), 6.37(t,J=8.8Hz,1H),
6.44(d,J=2.9Hz,1H), 6.49(dd,J=1.9Hz,2.9Hz,1H), 7.44(brs,1H),
7.49(t,J=7.8Hz,2H), 7.60(t,J=7.8Hz,1H), 8.15(d,J=7.8Hz,2H).
【0368】
工程7:13- O-[(2R,3S)-3-(tert-ブトキシカルボニルアミノ)-3-(2- フリル)-2-ハイドロキシプロピオニル]-4,10- ジデアセチル-7- デオキシ-4- O- プロピオニル-10-O-(2-チオモルホリノエチル) バッカチンIII
上記工程6で得た化合物を実施例2の工程1と同様に反応させ、次いで、実施例2の工程2と同様にモルホリンの代わりにチオモルホリンを用い反応させ標記化合物を無色の固体として得た。
【0369】
1H-NMR(CDCl3/TMS) δ(ppm) :
1.18-1.32(m,3H), 1.17(s,3H), 1.21(s,3H), 1.32(s,9H),
1.54(dd,J=5.7Hz,11.9Hz), 1.73(s,1H), 1.75(s,3H), 1.89(s,3H),
1.92-2.12(m,2H), 2.19-2.32(m,2H), 2.42(dd,J=9.3Hz,15.1Hz,1H),
2.62-2.78(m,8H), 2.78-2.90(m,4H), 3.56-3.74(m,2H), 3.77(d,J=7.3Hz,1H),
4.22(d,J=8.3Hz,1H), 4.33(d,J=8.3Hz,1H), 4.71(d,J=2.0Hz,1H),
4.89(dd,J=2.2Hz,9.6Hz,1H), 5.03(s,1H), 5.18(d,J=9.8Hz,1H),
5.32(d,J=10.7Hz,1H), 5.67(d,J=7.3Hz,1H), 6.26(t,J=8.8Hz,1H),
6.45(d,J=2.9Hz,1H), 6.49(dd,J=1.5Hz,2.9Hz,1H), 7.44(brs,1H),
7.49(t,J=7.8Hz,2H), 7.60(t,J=7.8Hz,1H), 8.15(d,J=7.8Hz,2H)
【0370】
【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。
【0371】
【表1】
Figure 0003921252
【0372】
本発明化合物は、強い抗腫瘍効果を示すだけでなく、その水溶性も優れ、1mlの水に対する溶解性は、次のとおりである(当社実験データ)。
【0373】
タキソテール 約 0.003 mg/ml
実施例10の化合物 13.0 mg/ml[0001]
[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 chemical structural formula shown in Chemical Formula 3 and can be obtained in a trace amount from the trunk of yew or the like.
[0003]
[Chemical Formula 3]
Figure 0003921252
[0004]
Taxol is known to have antitumor activity, and its mechanism of action is based on the depolymerization inhibitory action of microtubules in cell division, and is a different type of antitumor agent Its clinical application is expected.
[0005]
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 represented by Chemical formula 4 that can be obtained in relatively large amounts from leaves of yews and the like.
[0006]
[Formula 4]
Figure 0003921252
[0007]
A taxol derivative semi-synthesized using as a raw material has begun to be reported (Japanese Patent Laid-Open No. 03-505725). Among them, a compound having a structure represented by Chemical Formula 5 (Taxotere) has been attracting attention as a compound having an antitumor activity equivalent to or higher than that of Taxol, and is currently being developed as an antitumor agent.
[0008]
[Chemical formula 5]
Figure 0003921252
[0009]
[Problems to be solved by the invention]
However, taxol and derivatives represented by Chemical Formula 5 are promising as antitumor agents, but clinical trials have proved to be less effective against digestive organ cancer, particularly colon cancer, and have a stronger antitumor effect. Derivatives possessed are desired. Taxol and derivatives represented by Chemical formula 5 are also known to have low water solubility.
[0010]
[Means for Solving the Problems]
Conventionally, as a 10-position substituent of a taxol derivative, an acetoxy group, a hydroxyl group, and a hydroxyl group further substituted with an acyl group, an alkylaminocarbonyl group (EP 524093), etc. have been reported. Derivatives without (Tetrahedron Lett.,344921 (1993)) is also known. As a result of intensive studies, the present inventors have found that a derivative having an ether-type substituent introduced at the 10-position has strong antitumor activity and can improve water solubility, thereby completing the present invention.
[0011]
The present invention relates to general formula (I)
[0012]
[Chemical 6]
Figure 0003921252
[Where:
R1 Is a phenyl group
(The phenyl group may have one or more groups as substituents selected from the group consisting of halogen atoms, alkyl groups and alkoxyl groups.)
Means.
[0013]
R2 Is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group or alkoxyl group
(These alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups or alkoxyl groups are halogen atoms, hydroxyl groups, carboxyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, alkylamino groups, alkoxycarbonyl groups, aryloxy groups. One or more groups selected from the group consisting of a carbonyl group, an acyl group, an acylamino group, and an acyloxy group may be present as a substituent, and the substitution position of the substituent is the alkyl group, alkenyl group, or alkynyl group. , Any position of a cycloalkyl group and an alkoxyl group may be used.)
Means.
[0014]
RThree Means a hydroxyl group, a hydrogen atom or a halogen atom. RThree May form the following partial structure together with a methyl group bonded to the 8-position.
[0015]
[Chemical 7]
Figure 0003921252
[0016]
RFour Is an alkyl, alkenyl or alkynyl group
(These alkyl groups, alkenyl groups and alkynyl groups are carboxyl groups, alkoxyl groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, cyano groups, hydroxyl groups, amino groups, alkylamino groups, acyl groups, acylamino groups, acyloxy groups. One or more groups selected from the group consisting of a group, an alkoxycarbonylamino group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an aryl group and a heterocyclic group may be present as a substituent. The substitution position may be any position of the alkyl group, alkenyl group, and alkynyl group, and the aryl group and heterocyclic group may further be a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, an alkoxycarbonyl group, an aryloxycarbo- yl group. D A group selected from the group consisting of a group, a cyano group, a hydroxyl group, an amino group, an alkylamino group, an aminoalkyl group, an acyl group, an acylamino group, an acyloxy group, an alkoxycarbonylamino group, an alkylthio group, an alkylsulfinyl group, and an alkylsulfonyl group. One or more substituents may be present, and the substituent may be substituted at any position of the aryl group or heterocyclic group.)
Means.
[0017]
RFive Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
R6 Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
[0018]
R7 Is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group or heterocyclic group
(These alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, or heterocyclic groups are halogen atoms, hydroxyl groups, carboxyl groups, alkyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, alkylaminos. One or a plurality of groups selected from the group consisting of a group, 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. The substitution position of the substituent may be any position of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heterocyclic group.
Means.
[0019]
R8 Is an alkyl group, aryl group or alkoxyl group
(These alkyl groups, aryl groups or alkoxyl groups are halogen atoms, hydroxyl groups, carboxyl groups, alkyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, alkylamino groups, aminoalkyl groups, alkylaminoalkyl groups, alkoxy groups. One or a plurality of substituents selected from the group consisting of a carbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group may be included. (Any position of aryl group and alkoxyl group may be used.)
Means. ]
And a salt thereof.
[0020]
Next, terms used in this specification will be described.
As used here, “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.
[0021]
The “alkyl group”, “alkenyl group” and “alkynyl group” may be linear or branched, and preferably have 1 to 6 carbon atoms (in the case of alkenyl and alkynyl groups) to 6 carbon atoms.
[0022]
The “alkoxyl group” means a group in which an alkyl group is bonded to the group —O—, but 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.
[0023]
“Alkoxycarbonyl group” means an alkyl group bonded to an oxygen atom of a group —COO—, but the 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.
[0024]
“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.
[0025]
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.
[0026]
“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.
[0027]
“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.
[0028]
“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 the monocyclic heterocyclic group 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.
[0029]
"formula
[0030]
[Chemical 8]
Figure 0003921252
[0031]
(X is an oxygen atom, a sulfur atom, S = O, 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. And pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, thiazolidine, isoxazolidine, isothiazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1-oxide, and the like.
[0032]
Next, the preferable thing of each substituent in general formula (I) is mentioned.
[0033]
R1 The “alkyl group” and the “alkoxyl group” as the substituent of the phenyl group preferably have 1 to 3 carbon atoms.
[0034]
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.
[0035]
R1 As for, a phenyl group in which one or two fluorine atoms, chlorine atoms, methyl groups or methoxy groups are substituted at the meta position, or an unsubstituted phenyl group is preferable.
[0036]
R2 As these, an alkyl group, an alkoxyl group and a cycloalkyl group are preferable.
[0037]
R2 As the “alkyl group” of C,1 ~ C6 Alkyl groups are preferred, especially methyl and ethyl groups. A propyl group is preferred.
[0038]
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.
[0039]
R2 As the “cycloalkyl group”,Three ~ C6 A cycloalkyl group is preferred, and a cyclopropyl group is particularly preferred.
[0040]
R2 As a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group or a cyclopropyl group is particularly preferable.
[0041]
RThree As the “halogen atom”, a fluorine atom is preferable.
[0042]
RThree Is preferably a hydrogen atom or a hydroxyl group.
[0043]
RFour Is preferably an alkenyl group or an alkyl group. (This 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. , An alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an aryl group and a heterocyclic group may have one or more substituents selected from the group consisting of an aryl group and a heterocyclic group, Further, carboxyl group, alkyl 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, Kiruchio group, a group selected from alkylsulfinyl group consisting Le group and an alkylsulfonyl group which may have one or more as a substituent.)
RFour As the “alkyl group” of C,1 ~ C6An alkyl group is preferable, and a methyl group, an ethyl group, and a propyl group are particularly preferable.
[0044]
RFour As the “alkenyl group” inThree ~ C6 Alkenyl groups are preferred, and allyl groups are particularly preferred.
[0045]
RFour As the substituent of the alkyl group, an alkylamino group or a heterocyclic group is preferable.
[0046]
Within a heterocyclic group, the formula
[0047]
[Chemical 9]
Figure 0003921252
[0048]
(X is an oxygen atom, a sulfur atom, S = O, CH2 , CH—Y, NH or N—Y, Y represents an alkyl group. )
A saturated heterocyclic group having a size of a 5-membered or 6-membered ring containing a nitrogen atom (wherein the heterocyclic group includes one or more alkyl groups on the carbon atom that is a component of the ring) May be included).
[0049]
The alkyl part of the alkylamino group is C1 ~ CThree Alkyl groups are preferred and may be dialkyl substituted. (In the case of dialkyl substitution, the two alkyl groups may be the same or different.)
formula
[0050]
[Chemical Formula 10]
Figure 0003921252
[0051]
(X is an oxygen atom, a sulfur atom, S = O, CH2 , CH—Y, NH or N—Y, Y represents an alkyl group. )
A saturated heterocyclic group having a size of a 5-membered or 6-membered ring containing a nitrogen atom (wherein the heterocyclic group includes one or more alkyl groups on the carbon atom that is a component of the ring) Among them, a group derived from pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine is particularly preferable. Y is C1 ~ CThree Alkyl groups are preferred.
[0052]
In addition, as an alkyl group substituted on a carbon atom that is a constituent component of a ring of a heterocyclic group, C1 ~ CThree An alkyl group is preferable, and a methyl group is particularly preferable.
[0053]
RFour The most preferred are allyl group, morpholinoethyl group, and thiomorpholinoethyl group.
[0054]
RFive And R6 As the “halogen atom”, a fluorine atom, a chlorine atom and a bromine atom are preferable.
[0055]
RFive And R6 As the “alkyl group”, a methyl group, an ethyl group, or a propyl group is preferable.
[0056]
RFive Is preferably a halogen atom or a hydroxyl group, and among the halogen atoms, a fluorine atom is particularly preferred.
[0057]
R6 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.
[0058]
RFive And R6 Most preferred as RFive Is a fluorine atom, R6 Is a combination of fluorine atoms, RFive Is a hydroxyl group, R6 Is a combination of hydrogen atoms, or RFiveIs a hydroxyl group, R6Is a combination of methyl groups.
[0059]
R7 Is preferably an aryl group, a heterocyclic group or an alkenyl group.
[0060]
R7 As the “aryl group”, a phenyl group is preferable.
[0061]
R7As the “alkenyl group”, 2-methyl-1-propenyl is preferable.
[0062]
R7 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, Examples include tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine and the like.
[0063]
R7 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.
[0064]
R7 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 groups derived from furan, pyridine, and pyrrole.
[0065]
R7 As such, 2-methyl-1-propenyl group, phenyl group, furyl group, pyridyl group and pyrrolyl group are particularly preferable.
[0066]
R8 Is preferably an aryl group or an alkoxyl group.
[0067]
R8As the “aryl group”, a phenyl group is preferable.
[0068]
R8 As the “alkoxyl group”, tertiary butoxy is preferable.
[0069]
R8 Are particularly preferably a phenyl group and a tertiary butoxy group.
[0070]
Compounds included in this application include R1Is a phenyl group, R2Is methyl, ethyl, propyl, methoxy, ethoxy or cyclopropyl, RThreeIs a hydrogen atom or a hydroxyl group, RFourIs an allyl group, morpholinoethyl group or thiomorpholinoethyl group, RFiveIs a hydroxyl group, R6Is a hydrogen atom, R7Is a phenyl group, a furyl group or a 2-methyl-1-propenyl group, R8A compound in which is a tertiary butoxy group is most preferred.
[0071]
In the present invention, those having the configuration shown in Chemical Formula 11 are preferred.
[0072]
Embedded image
Figure 0003921252
[0073]
In addition, the substituent R7 The 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.
[0074]
Among the compounds of the present invention, those having the following structure can also be mentioned as preferred examples.
[0075]
Embedded image
Figure 0003921252
[0076]
and
[0077]
Embedded image
Figure 0003921252
The taxol derivative of the present invention may be in a free form or may be an acid addition 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.
[0078]
A method for producing the compound of the present invention will be described.
[0079]
Embedded image
Figure 0003921252
[0080]
(In the above reaction formula, Rtwenty oneIs R2 And R protected by a protecting group2 (R2 Is substituted with a hydroxyl group, an amino group or the like.
[0081]
R31Means a hydrogen atom, a halogen atom or a protected hydroxyl group.
[0082]
R41Means a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an alkoxycarbonyl group and the like, and a vinyl group, a phenyl group and the like are preferable.
[0083]
X means a halogen atom such as iodine or bromine, or one that acts as a leaving group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group.
[0084]
R51Means a hydrogen atom, a protected hydroxyl group, a halogen atom or an alkyl group.
[0085]
R61Means a hydrogen atom, a protected hydroxyl group, a halogen atom or an alkyl group.
[0086]
R71Is R7 And R protected by a protecting group7 (R7 Is substituted with a hydroxyl group, an amino group or the like.
[0087]
R81Is R8 And R protected by a protecting group8 (R8 Is substituted with a hydroxyl group, an amino group or the like.
[0088]
R9 And RTenEach independently represents a hydrogen atom, an alkyl group, an aryl group or the like, and preferably both are methyl groups or one is a p-methoxyphenyl group and the other is a hydrogen atom.
[0089]
Examples of the protecting group for hydroxyl group or amino group 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. . )
First, the compound represented by the formula (1) (hereinafter referred to as the compound (1), the compounds represented by other numbers are also represented in the same manner) and the compound (2) are treated in a solvent in the presence of a base. Then, the compound (3) is obtained by selectively etherifying the 10-position hydroxyl group.
[0090]
The solvent is preferably inert to the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like.
[0091]
Examples of the base include normal butyl lithium and sodium hydride.
[0092]
Next, the compound (3) is condensed with the compound (4), the compound (5) or the compound (6) by various methods known in the art, and if necessary, the compound (3) is further subjected to a conversion reaction. 7) can be obtained.
[0093]
As a condensation reaction using the compound (4) or (5), a method using a carboxylic acid activator such as di (2-pyridyl) carbonate or dicyclohexylcarbodiimide in the presence of a base catalyst such as 4-dimethylaminopyridine. There is. When compound (4) is used, R51And R61Is a combination of a hydrogen atom and a hydroxyl group.
[0094]
As a condensation reaction using the compound (6), there is a method using a base such as sodium hexamethyldisilazide.
[0095]
Finally, if necessary, the R41(The R of compound (3) before condensing compound (3) with compound (4), compound (5) or compound (6))41May be converted. ), By removing various protecting groups, the desired product can be obtained.
[0096]
RThree In order to obtain a target compound in which is a hydrogen atom, for example, R31After obtaining the compound (3) in which is a protected hydroxyl group, the protecting group is removed, and R31Is converted to a hydroxyl group, and the hydroxyl group is converted to a method known in the literature (for example, J. Org. Chem.,58, 5028 (1993)) and RThree After obtaining compound (3) in which is a hydrogen atom, in the same manner as described above, condensation reaction with compound (4), (5) or (6), conversion of the 10-position, if necessary, further deprotection reaction Should be implemented. First, R31There is also a method of synthesizing compound (1) in which is a hydrogen atom, then converting to compound (3), condensation reaction, conversion of the 10-position, and obtaining the desired product.
[0097]
RThree A target compound in which is a halogen atom, for example RThree To obtain a compound wherein is a fluorine atom, R31After obtaining the compound (3) in which is a protected hydroxyl group, the protecting group is removed, and R31Is converted to a hydroxyl group. Thereafter, it is treated with diethylaminosulfur trifluoride in tetrahydrofuran, methylene chloride, ethyl ether, toluene, 1,1-dimethoxyethane or a mixed solvent thereof, and RThree Is a fluorine atom, and in the same manner as above, a condensation reaction with the compound (4), (5) or (6), conversion of the 10-position, if necessary, and a deprotection reaction are carried out. Just do it. First, R31There is also a method of synthesizing a compound (1) in which is a fluorine atom and then converting it to a compound (3), followed by a condensation reaction and conversion of the 10-position moiety to obtain the desired product.
[0098]
R1Is a phenyl group having a substituent, for example, literature (Tetrahedron Lett.,358931 (1994)), the ester at the 2-position of the obtained compound (7) is selectively hydrolyzed and then acylated.
[0099]
Compound (1), which is a raw material for production, can be synthesized from 10-O-deacetylbaccatin III, and R1 Is a phenyl group, Rtwenty one Are compounds known in the literature (for example, J. Am. Chem. Soc.,110, 5917 (1988)).
[0100]
R2 Compound (1) in which is an alkyl group other than a methyl group can be produced as follows.
[0101]
Embedded image
Figure 0003921252
[0102]
(Wherein R40Means a protective group for a hydroxyl group, and a triethylsilyl group, a 2,2,2-trichloroethoxycarbonyl group or a benzyl group is preferred.
R1 And R31Is the same as above. )
First, compound (8) is oxidized (treated in an inert solvent (dioxane or the like) with manganese dioxide at room temperature or under heating) to obtain compound (9).
[0103]
Next, the compound (9) is reacted with a base at a reaction temperature of −100 ° C. to 0 ° C. in a solvent inert to the reaction (such as tetrahydrofuran), and then Rtwenty two-Z (Rtwenty twoMeans an alkyl group, and Z means a halogen atom such as an iodine atom or a bromine atom, or a leaving group such as a methanesulfonyl group or a paratoluenesulfonyl group. The compound (10) is obtained by reacting the compound represented by) at −100 ° C. at room temperature.
[0104]
Examples of the base to be used include lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, tertiary butoxypotassium, sodium hydride and the like. And 1 to 10 equivalents may be used relative to compound (9).
[0105]
The resulting compound (10) can be reduced {treated with a reducing agent (such as sodium borohydride) in a solvent (such as methanol or tetrahydrofuran)} to obtain compound (11).
[0106]
By removing the protecting group at position 10 of compound (11), R2 Compound (1) in which is an alkyl group other than a methyl group can be obtained.
[0107]
Compound (4), compound (5) and compound (6), which are raw materials for production, compound (4) is tetrahedron letter,335185 (1992), compound (5) is obtained from the Journal of American Chemical Society,110, 5917 (1988), the compound (6) is converted to tetrahedron letter,344149 (1993), respectively.
[0108]
Next, the embodiment will be described in detail. In the examples, the following abbreviations are used.
[0109]
TES: Triethylsilyl group
Bz: benzyl group
Boc: tert-butoxycarbonyl group
Ph: phenyl group
Troc: 2,2,2-trichloroethoxycarbonyl group
TBS: tert-butyldimethylsilyl group
Tf: trifluoromethanesulfonyl group
TIPS: Triisopropylsilyl group
MP: p-methoxyphenyl group
Ts: p-toluenesulfonyl group
DMS: Dimethylsilyl group
[0110]
【Example】
Example 1
[0111]
Embedded image
Figure 0003921252
[0112]
Step 1: 10-O-allyl-10-deacetyl-7-O-triethylsilylbaccatin III
200 mg of 10-deacetyl-7-O-triethylsilylbaccatin III was dissolved in 2 ml of dry tetrahydrofuran and cooled to -78 ° C. N-Butyllithium (1.64 M n-hexane solution, 0.277 ml) was added dropwise thereto, stirred for 15 minutes, and then a solution of 0.041 ml of allyl iodide dissolved in 0.5 ml of dimethyl sulfoxide was added dropwise at 0 ° C. for 3 minutes. Stir for hours. 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, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to obtain 156 mg of the title compound as white crystals.
[0113]
Melting point: 205-209 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.64 (m, 6H), 0.95 (t, 9H, J = 7Hz), 1.06 (s, 3H), 1.20 (s, 3H),
1.67 (s, 3H), 1.85-1.92 (m, 1H), 2.08 (s, 3H), 2.26-2.29 (m, 2H),
2.28 (s, 3H), 2.46-2.53 (m, 1H), 3.88 (d, 1H, J = 7Hz), 4.01-4.10 (m, 2H),
4.15 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.43 (dd, 1H, J = 7Hz, 10Hz),
4.87-4.90 (m, 1H), 4.96 (d, 1H, J = 8Hz), 5.03 (s, 1H), 5.20 (d, 1H, J = 10Hz),
5.32 (dd, 1H, J = 1.5Hz, 10Hz), 5.61 (d, 1H, J = 7Hz), 5.95-6.04 (m, 1H),
7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
IR (KBr): 3488, 3080, 2956, 2884, 2744, 1724, 1652, 1604, 1586 cm-1
MS-FAB: 699 (MH+)
[0114]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -10-O-allyl-10-deacetyl-7- O-Triethylsilylbaccatin III
100 mg of the compound obtained in the above step 1 and 108 mg of (3R, 4S) -1-tert-butoxycarbonyl-4-phenyl-3- (triethylsilyloxy) azetidin-2-one were dissolved in 2 ml of dry tetrahydrofuran- Cooled to 40 ° C. Next, lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 0.572 ml) was added dropwise, and the mixture was stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to give 126 mg of the title compound as a colorless amorphous product. Obtained as a solid.
[0115]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.31-0.52 (m, 6H), 0.54-0.62 (m, 6H), 0.79 (t, 9H, J = 7Hz),
0.96 (t, 9H, J = 7Hz), 1.24 (s, 6H), 1.32 (s, 9H), 1.69 (s, 3H), 1.90 (s, 3H),
2.15-2.22 (m, 1H), 2.34-2.41 (m, 1H), 2.45-2.54 (m, 1H), 2.53 (s, 3H),
3.85 (d, 1H, J = 7Hz), 4.00-4.13 (m, 2H), 4.19 (d, 1H, J = 8Hz),
4.31 (d, 1H, J = 8Hz), 4.41 (dd, 1H, J = 7Hz, 10Hz), 4.56 (s, 1H),
4.95 (d, 1H, J = 8Hz), 4.98 (s, 1H), 5.20 (d, 1H, J = 12Hz), 5.29 (br, 1H),
5.32 (dd, 1H, J = 1.5Hz, 12Hz), 5.47 (br, 1H), 5.68 (d, 1H, J = 7Hz),
5.94-6.02 (m, 1H), 6.31 (t, 1H, J = 8Hz), 7.27-7.31 (m, 3H),
7.37 (t, 2H, J = 8Hz), 7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz),
8.12 (d, 2H, J = 8Hz)
[0116]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-O-allyl-10-deacetylbaccatin III
45.5 mg of the compound obtained in the above step 2 was dissolved in 2 ml of acetonitrile and cooled to −10 ° C. Next, 0.035 ml of 12N aqueous hydrochloric acid solution was added dropwise and stirred for 1 hour. A saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 20: 1 (v / v)) to obtain 23.5 mg of the title compound as a white solid. .
[0117]
Melting point: 156-160 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.22 (s, 6H), 1.35 (s, 9H), 1.69 (s, 3H), 1.80-1.82 (m, 1H), 1.83 (s, 3H),
2.28 (m, 2H), 2.36 (s, 3H), 2.53-2.61 (m, 1H), 3.39 (br, 1H),
3.86 (d, 1H, J = 7Hz), 4.05 (dd, 1H, J = 6Hz, 13Hz), 4.16-4.20 (m, 3H),
4.30 (d, 1H, J = 8Hz), 4.62 (s, 1H), 4.94 (d, 1H, J = 8Hz), 5.04 (s, 1H),
5.22 (dd, 1H, J = 1.5Hz, 10Hz), 5.26 (br, 1H), 5.32 (dd, 1H, J = 1.5Hz, 17.5Hz),
5.40 (brd, 1H, J = 10Hz), 5.68 (d, 1H, J = 7Hz), 5.89-5.99 (m, 1H),
6.22 (t, 1H, J = 8Hz), 7.30-7.42 (m, 5H), 7.49 (t, 2H, J = 8Hz),
7.61 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
IR (KBr): 3464, 3076, 2984, 2944, 2904, 1720, 1604, 1586 cm-1
MS-FAB: 849 (MH+)
[0118]
Example 2
[0119]
Embedded image
Figure 0003921252
[0120]
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -10-deacetyl-10-O-formylmethyl-7 -O-Triethylsilylbaccatin III
126 mg of the compound obtained in Step 2 of Example 1 and 41.0 mg of N-methylmorpholine-N-oxide were added to a mixed solvent of 10 ml of acetone and 3 ml of water, 0.6 mg of osmium tetroxide was added at room temperature, and the mixture was stirred for 2 hours. . Sodium sulfite was added and the mixture was stirred for 15 minutes. Further, anhydrous sodium sulfate was added and the mixture was stirred for 30 minutes, and then insoluble matters were removed by filtration. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methanol (4 ml). Under ice cooling, a solution of sodium metaperiodate (50.0 mg) in water (1 ml) was added dropwise and stirred for 30 minutes. Saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to obtain 98.5 mg of the title compound as a colorless amorphous solid.
[0121]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.31-0.48 (m, 6H), 0.54-0.61 (m, 6H), 0.79 (t, 9H, J = 7Hz),
0.96 (t, 9H, J = 7Hz), 1.25 (s, 3H), 1.26 (s, 3H), 1.31 (s, 9H), 1.70 (s, 3H),
1.91 (s, 3H), 2.15-2.22 (m, 1H), 2.34-2.40 (m, 1H), 2.45-2.53 (m, 1H),
2.53 (s, 3H), 3.48 (s, 1H), 3.81 (d, 1H, J = 7Hz), 4.18 (s, 1H),
4.19 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 4.44 (dd, 1H, J = 7Hz, 10Hz),
4.56 (s, 1H), 4.95 (d, 1H, J = 8Hz), 5.12 (s, 1H), 5.30 (br, 1H), 5.47 (br, 1H),
5.68 (d, 1H, J = 7Hz), 6.31 (t, 1H, J = 8Hz), 7.29-7.39 (m, 3H),
7.37 (t, 2H, J = 8Hz), 7.48 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz),
8.12 (d, 2H, J = 8Hz), 9.85 (s, 1H)
[0122]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -10-deacetyl-10-O- (2-morpholino Ethyl) -7-O-triethylsilylbaccatin III
98.5 mg of the compound obtained in the above Step 1, 0.080 ml of morpholine and 0.052 ml of acetic acid were dissolved in 8 ml of ethanol, 57.0 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with chloroform, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to give 91.6 mg of the title compound as a colorless amorphous substance. Obtained as a solid.
[0123]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.31-0.49 (m, 6H), 0.52-0.64 (m, 6H), 0.79 (t, 9H, J = 7Hz),
0.95 (t, 9H, J = 7Hz), 1.21 (s, 3H), 1.22 (s, 3H), 1.32 (s, 9H), 1.68 (s, 3H),
1.91 (s, 3H), 1.88-1.94 (m, 1H), 2.15-2.22 (m, 1H), 2.34-2.40 (m, 1H),
2.44-2.50 (m, 1H), 2.53 (s, 3H), 2.56-2.59 (m, 4H), 2.68 (t, 2H, J = 6Hz),
3.62 (t, 2H, J = 6Hz), 3.73 (t, 4H, J = 5Hz), 3.84 (d, 1H, J = 7Hz),
4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.41 (dd, 1H, J = 7Hz, 10Hz),
4.56 (s, 1H), 4.94 (s, 1H), 4.95 (d, 1H, J = 8Hz), 5.30 (br, 1H), 5.48 (br, 1H),
5.67 (d, 1H, J = 7Hz), 6.30 (t, 1H, J = 8Hz), 7.28-7.32 (m, 3H),
7.37 (t, 2H, J = 8Hz), 7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz),
8.12 (d, 2H, J = 8Hz)
[0124]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- (2-morpholinoethyl) baccatin III
91.6 mg of the compound obtained in the above step 2 was dissolved in 4 ml of acetonitrile, 0.20 ml of pyridine and 0.60 ml of 48% aqueous hydrogen fluoride solution were added under ice cooling, and the mixture was reacted at 0 ° C. for 2 hours and at room temperature overnight. . The reaction solution was ice-cooled and made weakly alkaline with a saturated aqueous sodium bicarbonate solution. The mixture was extracted 3 times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 10: 1 (v / v)) to obtain 52.1 mg of the title compound as a white solid.
[0125]
Melting point: 143-147 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.20 (s, 3H), 1.34 (s, 9H), 1.67 (s, 3H), 1.78-1.85 (m, 1H),
1.88 (s, 3H), 2.27 (m, 2H), 2.36 (s, 3H), 2.51-2.68 (m, 7H),
3.63-3.80 (m, 6H), 3.84 (d, 1H, J = 7Hz), 4.12 (d, 1H, J = 8Hz),
4.22 (dd, 1H, J = 7Hz, 10Hz), 4.29 (d, 1H, J = 8Hz), 4.62 (s, 1H),
4.94 (d, 1H, J = 8Hz), 5.09 (s, 1H), 5.27 (brd, 1H, J = 10Hz), 5.44 (br, 1H),
5.66 (d, 1H, J = 7Hz), 6.21 (t, 1H, J = 8Hz), 7.29-7.42 (m, 5H),
7.49 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz)
IR (KBr): 3456, 3068, 2976, 2940, 1986, 1722, 1606, 1586 cm-1
MS-FAB: 921 (MH+)
[0126]
Example 3
[0127]
Embedded image
Figure 0003921252
[0128]
Step 1: 4,10-dideacetyl-4-O-propionyl-10-O- (2,2,2-trichloroethoxycarbonyl-7-O-triethylsilylbaccatin III
Dissolve 2.00 g of 4,10-dideacetyl-4-O-propionyl-13-deoxy-13-oxo-7-O-triethylsilylbaccatin III in 40 ml of pyridine and cool with chloroformate 2,2,2 -A solution of 1.03 ml of trichloroethyl dissolved in 4 ml of dichloromethane was added dropwise and stirred for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The mixture was washed with a cold 0.5N aqueous hydrochloric acid solution, water, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order, and dried over anhydrous sodium sulfate. The obtained residue was dissolved in 60 ml of tetrahydrofuran, and 282 mg of sodium tetrahydroborate was added under ice cooling. After 5 minutes, 3 ml of methanol was added and stirred for 2.5 hours. The reaction solution was diluted with chloroform, washed with a saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (elution solvent; ethyl acetate: n-hexane = 1: 2 (v / v)) to obtain 2.05 g of the title compound as white crystals.
[0129]
Melting point: 227-228 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
0.56-0.62 (m, 6H), 0.93 (t, 9H, J = 8Hz), 1.07 (s, 3H), 1.21 (s, 3H),
1.23 (t, 3H, J = 7Hz), 1.70 (s, 3H), 1.85-1.92 (m, 1H), 2.19 (s, 3H),
2.26-2.28 (m, 2H), 2.51-2.67 (m, 3H), 3.72 (d, 1H, J = 7Hz),
4.16 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.50 (dd, 1H, J = 7Hz, 10Hz),
4.81 (AB type d, 2H, J = 2Hz), 4.85 (br, 1H), 4.91 (d, 1H, J = 8Hz),
5.63 (d, 1H, J = 7Hz), 6.30 (s, 1H), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz),
8.12 (d, 2H, J = 8Hz)
IR (KBr): 3560, 2960, 2888, 1764, 1728, 1604, 1586 cm-1
MS-FAB: 849 (MH+)
[0130]
Step 2: 4,10-dideacetyl-4-O-propionyl-7-O-triethylsilylbaccatin III
500 mg of the compound obtained in the above step 1 was dissolved in a mixed solvent of 16 ml of methanol and 4 ml of acetic acid, 1 g of active zinc powder was added, and the mixture was stirred at 50 ° C. for 15 minutes. After standing to cool, the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained oily substance was crystallized from hexane to obtain 370 mg of the title compound as white crystals.
[0131]
Melting point: 202-204 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
0.48-0.63 (m, 6H), 0.94 (t, 9H, J = 8Hz), 1.07 (s, 3H), 1.24 (t, 3H, J = 7Hz),
1.26 (s, 3H), 1.73 (s, 3H), 1.86-1.93 (m, 1H), 2.07 (s, 3H),
2.22-2.28 (m, 2H), 2.45-2.51 (m, 1H), 2.52-2.67 (m, 2H), 3.94 (d, 1H, J = 7Hz),
4.16 (d, 1H, J = 8Hz), 4.27 (d, 1H, J = 2Hz), 4.31 (d, 1H, J = 8Hz),
4.42 (dd, 1H, J = 7Hz, 10Hz), 4.84 (t, 1H, J = 8Hz), 4.91 (d, 1H, J = 8Hz),
5.18 (s, 3H), 5.59 (d, 1H, J = 7Hz), 7.46 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz),
8.10-8.12 (m, 2H)
IR (KBr): 3476, 3072, 2960, 2888, 1986, 1728, 1712, 1604, 1586 cm-1
MS-FAB: 673 (MH+)
[0132]
Step 3: 10-O-allyl-4,10-dideacetyl-4-O-propionyl-7-O-triethylsilylbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 1 of Example 1 to obtain the title compound as white crystals.
[0133]
Melting point: 204-207 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.65 (m, 6H), 0.95 (t, 9H, J = 7Hz), 1.06 (s, 3H), 1.20 (s, 3H),
1.24 (t, 3H, J = 7Hz), 1.68 (s, 3H), 1.85-1.92 (m, 1H), 2.07 (s, 3H),
2.26 (d, 2H, J = 8Hz), 2.47-2.57 (m, 1H), 2.58-2.67 (m, 2H),
3.88 (d, 1H, J = 7Hz), 4.05-4.07 (m, 2H), 4.15 (d, 1H, J = 8Hz),
4.29 (d, 1H, J = 8Hz), 4.44 (dd, 1H, J = 7Hz, 10Hz), 4.88-4.92 (m, 2H),
5.04 (s, 1H), 5.20 (dd, 1H, J = 1.5Hz, 10Hz), 5.31 (dd, 1H, J = 1.5Hz, 17Hz),
5.60 (d, 1H, J = 7Hz), 5.95-6.04 (m, 1H), 7.46 (t, 2H, J = 8Hz),
7.59 (t, 1H, J = 8Hz), 8.10-8.12 (m, 2H)
IR (KBr): 3496, 3080, 2956, 2884, 2744, 1724, 1650, 1604, 1586 cm-1
MS-FAB: 713 (MH+)
[0134]
Step 4: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4 , 10-dideacetyl-4-O-propionyl-7-O-triethylsilylbaccatin III
50 mg of the compound obtained in the above Step 3 and 43 mg of (3R, 4S) -1-tert-butoxycarbonyl-4- (2-furyl) -3- (triisopropylsilyloxy) azetidin-2-one were added to tetrahydrofuran 2 Dissolved in ml and cooled to -78 ° C. Then, sodium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 0.280 ml) was added dropwise and stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: n-hexane = 1: 4 (v / v)) to give 67.8 mg of the title compound as colorless amorphous Obtained as a fine solid.
[0135]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.52-0.62 (m, 6H), 0.94-1.01 (m, 30H), 1.21 (s, 3H), 1.24 (s, 3H),
1.35 (s, 9H), 1.37 (t, 3H, J = 7Hz), 1.69 (s, 3H), 1.92 (s, 3H),
1.87-1.94 (m, 1H), 2.31-2.36 (m, 2H), 2.46-2.56 (m, 1H), 2.71-2.79 (m, 2H),
3.84 (d, 1H, J = 7Hz), 4.00-4.11 (m, 2H), 4.19 (d, 1H, J = 8Hz),
4.31 (d, 1H, J = 8Hz), 4.42 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz),
4.99 (s, 1H), 5.20 (d, 1H, J = 11Hz), 5.24-5.34 (m, 3H), 5.68 (d, 1H, J = 7Hz),
5.95-6.02 (m, 1H), 6.21 (t, 1H, J = 8Hz), 6.27 (d, 1H, J = 3.5Hz),
6.37 (dd, 1H, J = 2Hz, 3.5Hz), 7.39 (s, 1H), 7.46 (t, 2H, J = 8Hz),
  7.57 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0136]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4,10-dideacetyl-10 -O-formylmethyl-4-O-propionyl-7-O-triethylsilylbaccatin III
The compound obtained in Step 4 was reacted in the same manner as in Step 1 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0137]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.53-0.63 (m, 6H), 0.94-1.01 (m, 30H), 1.22 (s, 3H), 1.25 (s, 3H),
1.34 (s, 9H), 1.36 (t, 3H, J = 7Hz), 1.69 (s, 3H), 1.92 (s, 3H),
2.32-2.36 (m, 2H), 2.46-2.53 (m, 1H), 2.69-2.78 (m, 2H), 3.47 (s, 1H),
3.80 (d, 1H, J = 7Hz), 4.16 (s, 1H), 4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.43 (dd, 1H, J = 7Hz, 10Hz), 4.90 (d, 1H, J = 8Hz), 4.98 (s, 1H), 5.13 (s, 1H),
5.24-5.30 (m, 2H), 5.68 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 8Hz),
6.27 (d, 1H, J = 3.5Hz), 6.37 (dd, 1H, J = 2Hz, 3.5Hz), 7.39 (s, 1H),
7.47 (t, 2H, J = 8Hz), 7.57 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz), 9.85 (s, 1H)
[0138]
Step 6: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4,10-dideacetyl-10 -O- (2-morpholinoethyl) -4-O-propionyl-7-O-triethylsilylbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 2 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0139]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.65 (m, 6H), 0.93-1.01 (m, 30H), 1.19 (s, 3H), 1.21 (s, 3H),
1.35 (s, 9H), 1.37 (t, 3H, J = 7Hz), 1.67 (s, 3H), 1.93 (s, 3H),
2.26-2.39 (m, 2H), 2.45-2.53 (m, 1H), 2.57-2.60 (m, 4H), 2.64-2.69 (m, 2H),
2.71-2.81 (m, 2H), 3.62 (t, 2H, J = 6Hz), 3.73 (t, 4H, J = 5Hz),
3.83 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.41 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz), 4.95 (s, 1H), 4.99 (s, 1H),
5.24-5.31 (m, 2H), 5.67 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 8Hz),
6.27 (d, 1H, J = 3.5Hz), 6.37 (dd, 1H, J = 2Hz, 3.5Hz), 7.39 (s, 1H),
7.48 (t, 2H, J = 8Hz), 7.57 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0140]
Step 7: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4,10-dideacetyl-10-O- (2 -Morpholinoethyl) -4-O-propionylbaccatin III
50.6 mg of the compound obtained in the above Step 6 was dissolved in 2 ml of pyridine, 0.40 ml of hydrogen fluoride pyridine was added under ice cooling, and the mixture was stirred at 0 ° C. for 10 minutes, and then reacted at room temperature overnight. The reaction solution was ice-cooled and made weakly alkaline with a saturated aqueous sodium bicarbonate solution. The mixture was extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 10: 1 (v / v)) to obtain 27.6 mg of the title compound as a white solid.
[0141]
Melting point: 139-142 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.21 (s, 3H), 1.29 (t, 3H, J = 7Hz), 1.34 (s, 9H), 1.67 (s, 3H),
1.78-1.85 (m, 1H), 1.93 (s, 3H), 2.26-2.40 (m, 2H), 2.52-2.73 (m, 9H),
3.64-3.80 (m, 6H), 3.86 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz),
4.27 (dd, 1H, J = 7Hz, 10Hz), 4.31 (d, 1H, J = 8Hz), 4.70 (s, 1H),
4.91 (d, 1H, J = 8Hz), 5.09 (s, 1H), 5.23 (d, 1H, J = 10Hz),
5.31 (brd, 1H, J = 10Hz), 5.68 (d, 1H, J = 7Hz), 6.23 (t, 1H, J = 8Hz),
6.34 (d, 1H, J = 3.5Hz), 6.39 (dd, 1H, J = 2Hz, 3.5Hz), 7.43 (s, 1H),
7.48 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz)
IR (KBr): 3464, 2980, 2944, 2356, 1972, 1722, 1604, 1496 cm-1
MS-FAB: 925 (MH+)
[0142]
Example 4
[0143]
Embedded image
Figure 0003921252
[0144]
Step 1: 4-O-butanoyl-4,10-dideacetyl-10-O- (2,2,2-trichloroethoxycarbonyl) -7-O-triethylsilylbaccatin III
4-O-butanoyl-13-deoxy-4,10-dideacetyl-13-oxo-7-O-triethylsilylbaccatin III was reacted in the same manner as in Step 3 of Example 3 to obtain the title compound as white crystals.
[0145]
Melting point: 227-228 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
0.52-0.62 (m, 6H), 0.93 (t, 9H, J = 8Hz), 1.06 (t, 3H, J = 7Hz), 1.07 (s, 3H),
1.21 (s, 3H), 1.70 (s, 3H), 1.78 (q, 2H, J = 7Hz), 1.85-1.92 (m, 1H),
2.19 (s, 3H), 2.28 (d, 2H, J = 8Hz), 2.56 (t, 2H, J = 7Hz), 2.51-2.59 (m, 1H),
3.83 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.49 (dd, 1H, J = 7Hz, 10Hz), 4.81 (AB type d, 2H, J = 2Hz), 4.85 (br, 1H),
4.92 (d, 1H, J = 8Hz), 5.63 (d, 1H, J = 7Hz), 6.30 (s, 1H), 7.47 (t, 2H, J = 8Hz),
7.61 (t, 1H, J = 8Hz), 8.11 (m, 2H)
IR (KBr): 3560, 2960, 2888, 1764, 1728, 1604, 1586 cm-1
MS-FAB: 849 (MH+)
[0146]
Step 2: 4-O-butanoyl-4,10-dideacetyl-7-O-triethylsilylbaccatin III
The compound obtained in Step 1 was reacted in the same manner as in Step 2 of Example 3 to obtain the title compound as white crystals.
[0147]
Melting point: 160-163 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
0.48-0.63 (m, 6H), 0.94 (t, 9H, J = 8Hz), 1.05 (t, 3H, J = 3Hz), 1.08 (s, 6H),
1.74 (s, 3H), 1.76-1.78 (m, 2H), 1.80-1.92 (m, 1H), 2.07 (s, 3H),
2.25 (d, 2H, J = 8Hz), 2.45-2.53 (m, 1H), 2.56 (t, 2H, J = 7Hz),
3.94 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.25 (d, 1H, J = 2Hz),
4.31 (d, 1H, J = 8Hz), 4.42 (dd, 1H, J = 7Hz, 10Hz), 4.86 (br, 1H),
4.91 (d, 1H, J = 8Hz), 5.17 (s, 3H), 5.59 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz),
7.61 (t, 1H, J = 8Hz), 8.11-8.14 (m, 2H)
IR (KBr): 3484, 3076, 2968, 2888, 2744, 1714, 1606, 1586 cm-1
MS-FAB: 687 (MH+)
[0148]
Step 3: 10-O-allyl-4-O-butanoyl-4,10-dideacetyl-7-O-triethylsilylbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 1 of Example 1 to obtain the title compound as white crystals.
[0149]
Melting point: 200-204 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.65 (m, 6H), 0.96 (t, 9H, J = 7Hz), 1.05 (t, 3H, J = 7Hz), 1.06 (s, 3H),
1.20 (s, 3H), 1.67 (s, 3H), 1.78 (q, 2H, J = 7Hz), 1.82-1.91 (m, 1H),
2.06 (s, 3H), 2.26 (d, 2H, J = 8Hz), 2.47-2.57 (m, 1H), 2.55 (t, 2H, J = 7Hz),
3.88 (d, 1H, J = 7Hz), 4.01-4.13 (m, 2H), 4.15 (d, 1H, J = 8Hz),
4.29 (d, 1H, J = 8Hz), 4.43 (dd, 1H, J = 7Hz, 10Hz), 4.87-4.92 (m, 2H),
  5.03 (s, 1H), 5.19 (dd, 1H, J = 1.5Hz, 10Hz), 5.31 (dd, 1H, J = 1.5Hz, 17Hz),
5.60 (d, 1H, J = 7Hz), 5.95-6.04 (m, 1H), 7.46 (t, 2H, J = 8Hz),
7.59 (t, 1H, J = 8Hz), 8.10-8.12 (m, 2H)
IR (KBr): 3504, 3076, 2964, 2884, 2744, 1718, 1650, 1604, 1586 cm-1
MS-FAB: 727 (MH+)
[0150]
Step 4: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4 -O-butanoyl-4,10-dideacetyl-7-O-triethylsilylbaccatin III
The compound obtained in Step 3 was reacted in the same manner as in Step 4 of Example 3 to obtain the title compound as a colorless amorphous solid.
[0151]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.52-0.63 (m, 6H), 0.94-1.01 (m, 30H), 1.05 (t, 3H, J = 7Hz), 1.20 (s, 3H),
1.24 (s, 3H), 1.35 (s, 9H), 1.69 (s, 3H), 1.92 (s, 3H), 1.83-1.95 (m, 1H),
2.25-2.36 (m, 2H), 2.46-2.56 (m, 1H), 2.58-2.63 (m, 2H), 2.76-2.80 (m, 1H),
3.85 (d, 1H, J = 7Hz), 3.99-4.11 (m, 2H), 4.18 (d, 1H, J = 8Hz),
4.29 (d, 1H, J = 8Hz), 4.41 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz),
5.00 (s, 1H), 5.18-5.34 (m, 4H), 5.67 (d, 1H, J = 7Hz), 5.94-6.02 (m, 1H),
6.20 (t, 1H, J = 8Hz), 6.27 (d, 1H, J = 3.5Hz), 6.37 (dd, 1H, J = 2Hz, 3.5Hz),
7.37 (s, 1H), 7.46 (t, 2H, J = 8Hz), 7.57 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0152]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4-O-butanoyl-4 , 10-dideacetyl-10-O-formylmethyl-7-O-triethylsilylbaccatin III
The compound obtained in the above Step 4 was reacted in the same manner as in Step 1 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0153]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.53-0.65 (m, 6H), 0.94-1.01 (m, 30H), 1.05 (t, 3H, J = 7Hz), 1.22 (s, 3H),
1.25 (s, 3H), 1.34 (s, 9H), 1.69 (s, 3H), 1.83-1.94 (m, 3H), 1.92 (s, 3H),
2.27-2.39 (m, 2H), 2.48-2.53 (m, 1H), 2.54-2.63 (m, 1H), 2.74-2.81 (m, 1H),
3.47 (s, 1H), 3.81 (d, 1H, J = 7Hz), 4.16 (s, 1H), 4.18 (d, 1H, J = 8Hz),
4.30 (d, 1H, J = 8Hz), 4.44 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz),
4.99 (s, 1H), 5.14 (s, 1H), 5.25 (d, 1H, J = 10Hz), 5.31 (d, 1H, J = 10Hz),
5.67 (d, 1H, J = 7Hz), 6.19 (t, 1H, J = 8Hz), 6.27 (d, 1H, J = 3.5Hz),
6.36 (dd, 1H, J = 2Hz, 3.5Hz), 7.37 (s, 1H), 7.47 (t, 2H, J = 8Hz),
7.58 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz), 9.85 (s, 1H)
[0154]
Step 6: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4-O-butanoyl-4 , 10-dideacetyl-10-O- (2-morpholinoethyl) -7-O-triethylsilylbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 2 of Example 2 to obtain the title compound as a colorless amorphous solid.
[0155]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.64 (m, 6H), 0.94-1.03 (m, 30H), 1.05 (t, 3H, J = 7Hz), 1.19 (s, 3H),
1.21 (s, 3H), 1.35 (s, 9H), 1.67 (s, 3H), 1.93 (s, 3H), 1.83-1.93 (m, 3H),
2.25-2.39 (m, 2H), 2.45-2.53 (m, 1H), 2.57-2.81 (m, 8H), 3.62 (t, 2H, J = 6Hz),
3.73 (t, 4H, J = 5Hz), 3.84 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz),
4.30 (d, 1H, J = 8Hz), 4.41 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz),
4.96 (s, 1H), 5.00 (s, 1H), 5.24 (d, 1H, J = 10Hz), 5.32 (d, 1H, J = 10Hz),
5.66 (d, 1H, J = 7Hz), 6.18 (t, 1H, J = 8Hz), 6.27 (d, 1H, J = 3.5Hz),
6.36 (dd, 1H, J = 2Hz, 3.5Hz), 7.37 (s, 1H), 7.46 (t, 2H, J = 8Hz),
7.57 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0156]
Step 7: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4-O-butanoyl-4,10-dideacetyl- 10-O- (2-morpholinoethyl) -baccatin III
The compound obtained in Step 6 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a white solid.
[0157]
Melting point: 135-137 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
0.99 (t, 3H, J = 7Hz), 1.19 (s, 3H), 1.21 (s, 3H), 1.35 (s, 9H), 1.68 (s, 3H),
1.78-1.84 (m, 3H), 1.93 (s, 3H), 2.30-2.38 (m, 2H), 2.53-2.68 (m, 9H),
3.65-3.78 (m, 6H), 3.88 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz),
4.26 (dd, 1H, J = 7Hz, 10Hz), 4.30 (d, 1H, J = 8Hz), 4.70 (s, 1H),
4.90 (d, 1H, J = 8Hz), 5.10 (s, 1H), 5.22 (d, 1H, J = 10Hz),
5.31 (brd, 1H, J = 10Hz), 5.67 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 8Hz),
6.35 (d, 1H, J = 3.5Hz), 6.38 (dd, 1H, J = 2Hz, 3.5Hz), 7.42 (s, 1H),
7.49 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
IR (KBr): 3456, 2972, 2944, 1720, 1604, 1498 cm-1
MS-FAB: 939 (MH+)
[0158]
Example 5
[0159]
Embedded image
Figure 0003921252
[0160]
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4,10-dideacetyl-10 -O- [2- (N, N-diethylamino) ethyl] -4-O-propionyl-7-O-triethylsilylbaccatin III
46.0 mg of the compound obtained in Step 5 of Example 3, 0.042 ml of diethylamine and 0.024 ml of acetic acid were dissolved in 4 ml of ethanol. The mixture was diluted with chloroform, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 20: 1 (v / v)) to give 26.0 mg of the title compound as a colorless amorphous substance. Obtained as a solid.
[0161]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.65 (m, 6H), 0.94-1.01 (m, 30H), 1.18-1.23 (m, 6H), 1.34 (s, 9H),
1.36 (t, 3H, J = 7Hz), 1.68 (s, 3H), 1.87-1.92 (m, 1H), 1.93 (s, 3H),
2.26-2.39 (m, 2H), 2.46-2.55 (m, 1H), 2.71-2.81 (m, 2H), 2.91 (br, 4H),
3.02 (br, 2H), 3.60-3.73 (m, 2H), 3.81 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz),
4.31 (d, 1H, J = 8Hz), 4.44 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz),
4.95 (s, 1H), 4.98 (s, 1H), 5.24-5.30 (m, 2H), 5.67 (d, 1H, J = 7Hz),
6.20 (t, 1H, J = 8Hz), 6.27 (d, 1H, J = 3.5Hz), 6.37 (dd, 1H, J = 2Hz, 3.5Hz),
7.39 (s, 1H), 7.47 (t, 2H, J = 8Hz), 7.57 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0162]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4,10-dideacetyl-10-O- [2 -(N, N-diethylamino) ethyl] -4-O-propionylbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a white solid.
[0163]
Melting point: 128-132 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10 (t, 6H, J = 7Hz), 1.20 (s, 3H), 1.22 (s, 3H), 1.29 (t, 3H, J = 7Hz),
1.34 (s, 9H), 1.68 (s, 3H), 1.82-1.90 (m, 1H), 1.94 (s, 3H),
2.28-2.36 (m, 2H), 2.51-2.60 (m, 1H), 2.70-2.80 (m, 6H),
2.84-2.90 (m, 2H), 3.70-3.73 (m, 1H), 3.85-3.89 (m, 2H), 4.17 (d, 1H, J = 8Hz),
4.30−4.33 (m, 2H), 4.71 (s, 1H), 4.91 (d, 1H, J = 8Hz), 5.19 (s, 1H),
5.23 (d, 1H, J = 10Hz), 5.31 (brd, 1H, J = 10Hz), 5.68 (d, 1H, J = 7Hz),
6.22 (t, 1H, J = 8Hz), 6.35 (d, 1H, J = 3.5Hz), 6.39 (dd, 1H, J = 2Hz, 3.5Hz),
7.43 (s, 1H), 7.48 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz)
IR (KBr): 3456, 2980, 1720, 1496 cm-1
MS-FAB: 911 (MH+)
[0164]
Example 6
[0165]
Embedded image
Figure 0003921252
[0166]
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4,10-dideacetyl-4 -O-propionyl-10-O- (2-thiomorpholinoethyl) -7-O-triethylsilylbaccatin III
50.5 mg of the compound obtained in Step 5 of Example 3, 0.045 ml of thiomorpholine and 0.026 ml of acetic acid were dissolved in 4 ml of ethanol. The mixture was diluted with chloroform, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to give 43.5 mg of the title compound as a colorless amorphous substance. Obtained as a solid.
[0167]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.65 (m, 6H), 0.94-1.01 (m, 30H), 1.19 (s, 3H), 1.20 (s, 3H),
1.35 (s, 9H), 1.37 (t, 3H, J = 7Hz), 1.67 (s, 3H), 1.93 (s, 3H),
2.31-2.39 (m, 2H), 2.45-2.53 (m, 1H), 2.67-2.81 (m, 9H), 2.84-2.86 (m, 4H),
3.59 (t, 2H, J = 6Hz), 3.82 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz),
4.31 (d, 1H, J = 8Hz), 4.42 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz),
4.94 (s, 1H), 4.99 (s, 1H), 5.24-5.31 (m, 2H), 5.67 (d, 1H, J = 7Hz),
6.20 (t, 1H, J = 8Hz), 6.27 (d, 1H, J = 3.5Hz), 6.37 (dd, 1H, J = 2Hz, 3.5Hz),
7.39 (s, 1H), 7.46 (t, 2H, J = 8Hz), 7.57 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0168]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4,10-dideacetyl-4-O-propionyl- 10-O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a white solid.
[0169]
Melting point: 145-148 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.21 (s, 3H), 1.29 (t, 3H, J = 7Hz), 1.34 (s, 9H), 1.67 (s, 3H),
1.78-1.85 (m, 1H), 1.92 (s, 3H), 2.25-2.40 (m, 2H), 2.53-2.61 (m, 1H),
2.66-2.72 (m, 8H), 2.78-2.90 (m, 4H), 3.61-3.67 (m, 1H), 3.72-3.78 (m, 1H),
3.86 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.27 (dd, 1H, J = 7Hz, 10Hz),
4.31 (d, 1H, J = 8Hz), 4.71 (s, 1H), 4.81 (d, 1H, J = 8Hz), 5.05 (s, 1H),
5.22 (d, 1H, J = 10Hz), 5.31 (br, 1H, J = 10Hz), 5.68 (d, 1H, J = 7Hz),
6.23 (t, 1H, J = 8Hz), 6.34 (d, 1H, J = 3.5Hz), 6.39 (dd, 1H, J = 2Hz, 3.5Hz),
7.43 (s, 1H), 7.48 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz)
IR (KBr): 3456, 2980, 2944, 2824, 1722, 1602, 1586, 1496 cm-1
MS-FAB: 941 (MH+)
[0170]
Example 7
[0171]
Embedded image
Figure 0003921252
[0172]
Step 1: 10-O-allyl-13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O-isopropylidene-3-phenylisoserinyl] -10- Deacetyl-7-O-triethylsilylbaccatin III
150 ml of the compound obtained in Step 1 of Example 1 and 207 mg of (2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O-isopropylidene-3-phenylisoserine were added to 4 ml of toluene. And then cooled to 0 ° C. Next, after adding 146 mg of dicyclohexylcarbodiimide and stirring for 15 minutes, 26 mg of 4-dimethylaminopyridine was added and stirred at 80 ° C. for 15 minutes. After allowing to cool, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid aqueous solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: acetone = 50: 1 (v / v)) to give 215 mg of the title compound as a colorless amorphous solid. Obtained.
[0173]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.62 (m, 6H), 0.94 (t, 9H, J = 7Hz), 1.10 (brs, 9H), 1.22 (s, 6H),
1.65 (s, 3H), 1.78 (s, 6H), 1.82 (s, 3H), 1.93 (s, 3H), 2.13-2.17 (m, 2H),
2.41-2.48 (m, 1H), 3.76 (d, 1H, J = 7Hz), 3.98-4.15 (m, 2H),
4.09 (d, 1H, J = 8Hz), 4.23 (d, 1H, J = 8Hz), 4.36 (dd, 1H, J = 7Hz, 10Hz),
4.47 (d, 1H, J = 7Hz), 4.86 (d, 1H, J = 8Hz), 4.97 (s, 1H), 5.10 (br, 1H),
5.20 (d, 1H, J = 11Hz), 5.29 (dd, 1H, J = 1.5Hz, 11Hz), 5.62 (d, 1H, J = 7Hz),
5.92-6.02 (m, 1H), 6.30 (t, 1H, J = 8Hz), 7.33-7.39 (m, 5H),
7.50 (t, 2H, J = 8Hz), 7.61-7.65 (m, 1H), 8.03-8.05 (m, 2H)
[0174]
Step 2: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O-isopropylidene-3-phenylisoserinyl] -10-deacetyl-10-O- Formylmethyl-7-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.
[0175]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.51-0.59 (m, 6H), 0.95 (t, 9H, J = 7Hz), 1.11 (brs, 9H), 1.23 (s, 6H),
1.65 (s, 3H), 1.77 (s, 3H), 1.81 (s, 3H), 1.84 (s, 3H), 1.94 (s, 3H),
2.14-2.17 (m, 2H), 2.43-2.51 (m, 1H), 3.73 (d, 1H, J = 7Hz),
4.10 (d, 1H, J = 8Hz), 4.17 (d, 2H, J = 2.5Hz), 4.24 (d, 1H, J = 8Hz),
4.40 (dd, 1H, J = 7Hz, 10Hz), 4.46 (d, 1H, J = 7Hz), 4.86 (d, 1H, J = 8Hz),
5.05-5.13 (m, 1H), 5.11 (s, 1H), 5.62 (d, 1H, J = 7Hz), 6.28 (t, 1H, J = 8Hz),
7.34-7.40 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz),
8.03 (d, 2H, J = 8Hz), 9.83 (s, 1H)
[0176]
Step 3: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O-isopropylidene-3-phenylisoserinyl] -10-deacetyl-10-O- (2-Piperidinoethyl) -7-O-triethylsilylbaccatin III
52.4 mg of the compound obtained in the above Step 2, 0.051 ml of piperidine and 0.030 ml of acetic acid were dissolved in 4 ml of ethanol, 33.0 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with chloroform, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 10: 1 (v / v)) to give 46.3 mg of the title compound as a colorless amorphous substance. Obtained as a solid.
[0177]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.60 (m, 6H), 0.94 (t, 9H, J = 7Hz), 1.10 (brs, 9H), 1.19 (s, 3H),
1.21 (s, 3H), 1.47 (br, 2H), 1.64 (s, 3H), 1.76-1.89 (m, 4H), 1.78 (s, 3H),
1.80 (s, 3H), 1.82 (s, 3H), 1.95 (s, 3H), 2.13-2.15 (m, 2H),
2.40-2.48 (m, 1H), 2.58 (br, 4H), 2.73 (t, 2H, J = 6Hz), 3.63 (t, 2H, J = 6Hz),
3.76 (d, 1H, J = 7Hz), 4.09 (d, 1H, J = 8Hz), 4.23 (d, 1H, J = 8Hz),
4.37 (dd, 1H, J = 7Hz, 10Hz), 4.46 (d, 1H, J = 7Hz), 4.86 (d, 1H, J = 8Hz),
4.94 (s, 1H), 5.05 (br, 1H), 5.61 (d, 1H, J = 7Hz), 6.28 (t, 1H, J = 8Hz),
7.34-7.38 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.63 (t, 1H, J = 8Hz), 8.03 (d, 2H, J = 8Hz)
[0178]
Step 4: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- (2-piperidinoethyl) baccatin III
[0179]
46.3 mg of the compound obtained in the above Step 3 was dissolved in 4 ml of formic acid and reacted at room temperature for 80 minutes. The reaction mixture was concentrated, the residue was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 4 ml of tetrahydrofuran, 0.040 ml of di-tert-butyl dicarbonate was added and reacted at room temperature for 3 hours. After concentration, the resulting residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol: water = 8: 3: 1 (v / v), lower layer) to obtain 13.6 mg of the title compound as a white solid. .
[0180]
Melting point: 134-140 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.20 (s, 3H), 1.34 (s, 9H), 1.46 (br, 2H), 1.67 (s, 3H),
1.85-1.89 (m, 1H), 1.90 (s, 3H), 2.23-2.28 (m, 2H), 2.36 (s, 3H),
2.45-2.73 (m, 7H), 3.74-3.84 (m, 3H), 4.17 (d, 1H, J = 8Hz),
4.25 (dd, 1H, J = 7Hz, 10Hz), 4.29 (d, 1H, J = 8Hz), 4.62 (s, 1H),
4.94 (d, 1H, J = 8Hz), 5.20 (s, 1H), 5.25 (br, 1H), 5.45 (br, 1H),
5.66 (d, 1H, J = 7Hz), 6.21 (t, 1H, J = 8Hz), 7.31-7.39 (m, 5H),
7.49 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
IR (KBr): 3440, 2940, 1722, 1604, 1496 cm-1
MS-FAB: 920 (MH+)
[0181]
Example 8
[0182]
Embedded image
Figure 0003921252
[0183]
Step 1: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O-isopropylidene-3-phenylisoserinyl] -10-deacetyl-10-O- [2- (N-pyrrolidino) ethyl] -7-O-triethylsilylbaccatin III
54.4 mg of the compound obtained in Step 2 of Example 7, 0.045 ml of pyrrolidine and 0.031 ml of acetic acid were dissolved in 4 ml of ethanol, 34.0 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with chloroform, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 10: 1 (v / v)) to give 34.6 mg of the title compound as a colorless amorphous substance. Obtained as a solid.
[0184]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.48-0.63 (m, 6H), 0.94 (t, 9H, J = 7Hz), 1.12 (brs, 9H), 1.20 (s, 3H),
1.21 (s, 3H), 1.64 (s, 3H), 1.77 (s, 3H), 1.81 (s, 3H), 1.85 (s, 3H),
1.95 (s, 3H), 2.13-2.15 (m, 2H), 2.41-2.48 (m, 1H), 2.75 (br, 4H),
2.90 (t, 2H, J = 6Hz), 3.67 (t, 2H, J = 6Hz), 3.76 (d, 1H, J = 7Hz),
4.09 (d, 1H, J = 8Hz), 4.23 (d, 1H, J = 8Hz), 4.38 (dd, 1H, J = 7Hz, 10Hz),
4.46 (d, 1H, J = 7Hz), 4.86 (d, 1H, J = 8Hz), 4.96 (s, 1H), 5.08 (br, 1H),
5.61 (d, 1H, J = 7Hz), 6.28 (t, 1H, J = 8Hz), 7.34-7.38 (m, 5H),
7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.03 (d, 2H, J = 8Hz)
[0185]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- [2- (N-pyrrolidino) Ethyl] Baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 4 of Example 7 to obtain the title compound as a white solid.
[0186]
Melting point: 136-142 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.21 (s, 6H), 1.34 (s, 9H), 1.67 (s, 3H), 1.80 (br, 4H), 1.90 (s, 3H),
2.23-2.28 (m, 2H), 2.36 (s, 3H), 2.45-2.53 (m, 1H), 2.70 (br, 4H),
2.85 (br, 2H), 3.74-3.81 (m, 2H), 3.83 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz),
4.24 (dd, 1H, J = 7Hz, 10Hz), 4.29 (d, 1H, J = 8Hz), 4.61 (s, 1H),
4.94 (d, 1H, J = 8Hz), 5.20 (s, 1H), 5.25 (br, 1H), 5.45 (br, 1H),
5.66 (d, 1H, J = 7Hz), 6.21 (t, 1H, J = 8Hz), 7.31-7.40 (m, 5H),
7.49 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
IR (KBr): 3448, 2976, 2820, 1852, 1720, 1634, 1604, 1588 cm-1
MS-FAB: 905 (MH+)
[0187]
Example 9
[0188]
Embedded image
Figure 0003921252
[0189]
Step 1: 10-O-allyl-10-deacetylbaccatin III
292 mg of the compound obtained in Step 2 of Example 1 was dissolved in 5 ml of distilled pyridine and cooled to 0 ° C. Then, 1 ml of hydrogen fluoride-pyridine solution was added dropwise at the same temperature. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. Further, after washing with a saturated saline solution and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: acetone = 95: 5 (v / v)) to obtain 210 mg of the title compound.
[0190]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.07 (3H, s), 1.19 (3H, s), 1.68 (3H, s), 1.75-1.83 (1H, m),
2.04 (3H, d, J = 1.5Hz), 2.27-2.30 (1H, m), 2.29 (3H, s), 2.55-2.63 (1H, m),
3.95 (1H, d, J = 7.5Hz), 4.06 (1H, dd, J = 4.5Hz, 7.5Hz), 4.16 (1H, d, J = 8.5Hz),
4.21 (1H, dd, J = 5Hz, 8.5Hz), 4.24-4.31 (1H, m), 4.31 (1H, d, J = 8.5Hz),
4.85-4.91 (1H, m), 4.98 (1H, d, J = 8Hz), 5.09 (1H, s),
5.23 (1H, dd, J = 1.5Hz, 9.5Hz), 5.33 (1H, dd, J = 1.5Hz, 15.5Hz),
5.64 (1H, d, J = 7.5Hz), 5.91-6.02 (1H, m), 7.48 (2H, t, J = 7.5Hz),
7.61 (1H, t, J = 7.5Hz), 8.11 (2H, d, J = 7.5Hz).
[0191]
Step 2: 10-O-allyl-10-deacetyl-7-deoxybaccatin III
20 mg of sodium hydride (ca 60% oil suspension (w / w)) was suspended in 2 ml of tetrahydrofuran, and a solution of 219 mg of the compound obtained in step 1 dissolved in 2 ml of tetrahydrofuran was added dropwise at -45 ° C. . After stirring at the same temperature for 10 minutes, 0.03 ml of carbon disulfide and 0.03 ml of methyl iodide were added, and the mixture was warmed to 0 ° C. and stirred overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract 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 column chromatography (elution solvent; chloroform: methanol = 97: 3 (v / v)) to give 10-O-allyl-10-deacetyl-7-O-[(methylthio ) Thiocarbonyl] Baccatin III 145 mg was obtained. Dissolve this compound in 2 ml of dioxane degassed under a nitrogen atmosphere, add 10 mg of 2,2'-azobis (isobutyronitrile) and 0.25 ml of tributyltin hydride, and stir at 70 ° C overnight. did. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 2: 1 (v / v)) to give the title compound 63 mg was obtained.
[0192]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (3H, s), 1.15 (3H, s), 1.22-1.72 (3H, m), 1.74 (3H, s),
1.90-2.10 (1H, m), 2.02 (3H, s), 2.19-2.37 (2H, m), 2.28 (3H, s),
3.86 (1H, d, J = 7.5Hz), 4.05-4.17 (2H, m), 4.20 (1H, d, J = 8.5Hz),
4.31 (1H, d, J = 8.5Hz), 4.81-4.90 (1H, br), 4.96 (1H, d, J = 10Hz), 5.07 (1H, s),
5.22 (1H, d, J = 11Hz), 5.31 (1H, d, J = 17Hz), 5.62 (1H, d, J = 7.5Hz),
5.91-6.01 (1H, m), 7.48 (2H, t, J = 7.5Hz), 7.60 (1H, t, J = 7.5Hz),
8.12 (2H, d, J = 7.5Hz)
[0193]
Step 3: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl -7-Deoxybaccatin III
96 mg of sodium hydride (ca 60% oil suspension (w / w)) was suspended in 2 ml of tetrahydrofuran, and 46 mg of the compound obtained in the above step 2 was dissolved in 1 ml of dry tetrahydrofuran and added at 0 ° C. . Next, 61 mg of (3R, 4S) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyloxy) -4-phenylazetidin-2-one was added and stirred at the same temperature for 3 hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 2: 1 (v / v)) to obtain 35 mg of the title compound.
[0194]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.12 (6H, s), 0.75 (9H, s), 1.19 (3H, s), 1.23 (3H, s), 1.26 (6H, s),
1.29 (9H, s), 1.38-1.48 (1H, m), 1.52-1.58 (1H, m), 1.76 (3H, s),
1.86 (3H, s), 1.89-2.02 (1H, m), 2.08-2.28 (2H, m), 2.35-2.47 (1H, m),
2.55 (3H, s), 3.80 (1H, d, J = 7.5Hz), 4.09-4.16 (2H, m), 4.23 (1H, d, J = 8.5Hz),
4.33 (1H, d, J = 9Hz), 4.51 (1H, brs), 4.96 (1H, d, J = 8.5Hz), 5.03 (1H, s),
5.22 (1H, d, J = 10.5Hz), 5.28-5.36 (1H, m), 5.31 (1H, d, J = 19Hz),
5.41-5.47 (1H, m), 5.68 (1H, d, J = 7.5Hz), 5.90-5.99 (1H, m),
6.29-6.35 (1H, m), 7.26-7.30 (5H, m), 7.49 (2H, t, J = 7.5Hz),
7.58 (1H, t, J = 7.5Hz), 8.13 (2H, d, J = 7.5Hz)
[0195]
Step 4: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-7-deoxybaccatin III
35 mg of the compound obtained in the above step 3 was dissolved in 2 ml of distilled pyridine, and 0.4 ml of hydrogen fluoride-pyridine was added at 0 ° C. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract 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; chloroform: acetone = 95: 5 (v / v)) to obtain 21 mg of the title compound.
[0196]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (3H, s), 1.21 (3H, s), 1.33 (9H, s), 1.51-1.56 (1H, m),
1.64-1.67 (1H, m), 1.75 (3H, s), 1.82 (3H, s), 1.89-2.04 (2H, m),
2.19-2.27 (1H, m), 2.31-2.40 (1H, m), 2.38 (3H, s), 3.36 (1H, brs),
3.77 (1H, d, J = 7.5Hz), 4.10-4.13 (2H, m), 4.21 (1H, d, J = 8.5Hz),
4.31 (1H, d, J = 8.5Hz), 4.61 (1H, brs), 4.93 (1H, d, J = 8.5Hz), 5.02 (1H, s),
5.23 (1H, dd, J = 1.5Hz, 9Hz), 5.23-5.29 (1H, m),
5.31 (1H, dd, J = 1.5Hz, 15.5Hz), 5.39 (1H, d, J = 9.5Hz), 5.67 (1H, d, J = 7.5Hz),
5.90-6.00 (1H, m), 6.22-6.27 (1H, m), 7.25-7.40 (5H, m),
7.50 (2H, t, J = 7.5Hz), 7.61 (1H, t, J = 7.5Hz), 8.13 (2H, d, J = 7.5Hz)
[0197]
Example 10
13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4,10-dideacetyl-10-O- (2-morpholinoethyl ) -4-O-propionylbaccatin III methanesulfonate
59 mg of the compound obtained in Step 7 of Example 3 was dissolved in 2 ml of t-butanol and 1.5 ml of water and cooled to about 5 ° C. Then, 1 equivalent of methanesulfonic acid (0.02 M solution, 3.1 ml) was added dropwise and stirred at the same temperature for 2 minutes. The resulting solution was passed through a Millipore filter and then lyophilized to obtain 51 mg of the title compound as a white solid.
[0198]
Melting point: 157-161 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.17 (s, 3H), 1.20 (s, 3H), 1.27 (t, 3H, J = 7Hz), 1.34 (s, 9H), 1.67 (s, 3H),
1.85-1.92 (m, 1H), 2.04 (s, 3H), 2.21-2.40 (m, 2H), 2.45-2.56 (m, 1H),
2.65-2.70 (m, 2H), 2.78 (s, 3H), 3.04 (m, 4H), 3.29 (br, 2H),
3.81 (d, 1H, J = 7Hz), 3.92-4.10 (m, 6H), 4.16 (d, 1H, J = 8Hz),
4.30 (d, 1H, J = 8Hz), 4.35 (dd, 1H, J = 7Hz, 10Hz), 4.70 (s, 1H),
4.91 (d, 1H, J = 8Hz), 5.25-5.30 (m, 2H), 5.54 (s, 1H), 5.67 (d, 1H, J = 7Hz),
6.21 (t, 1H, J = 8Hz), 6.34 (d, 1H, J = 3.5Hz), 6.37 (dd, 1H, J = 2Hz, 3.5Hz),
7.43 (s, 1H), 7.48 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz)
IR (KBr): 3432, 2968, 2940, 1980, 1720, 1602, 1584 cm-1
MS-FAB: 925 (MH+)
[0199]
Example 11
[0200]
Embedded image
Figure 0003921252
[0201]
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-7-deoxy-10 -O- (2-morpholinoethyl) baccatin III
The compound obtained in Step 3 of Example 9 was reacted in the same manner as in Step 1 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 to obtain the title compound.
[0202]
1H-NMR (CDClThree/ TMS) δ (ppm):
  -0.32 (3H, s), -0.11 (3H, s), 0.75 (9H, s), 1.16 (3H, s), 1.23 (3H, s),
1.29 (9H, s), 1.52-1.82 (2H, m), 1.75 (3H, s), 1.89 (3H, s),
1.95-2.46 (4H, m), 2.55 (3H, s), 2.46-2.66 (4H, m), 2.65-2.71 (2H, m),
3.66-3.78 (6H, m), 3.80 (1H, d, J = 7Hz), 4.23 (1H, d, J = 8Hz),
4.33 (1H, d, J = 8Hz), 4.52 (1H, s), 4.96 (1H, d, J = 9Hz), 5.04 (1H, s),
5.29-5.35 (1H, m), 5.40-5.45 (1H, m), 5.67 (1H, d, J = 7Hz), 6.31 (1H, m),
7.27-7.46 (5H, m), 7.49 (2H, t, J = 8Hz), 7.58 (1H, t, J = 7Hz),
8.13 (2H, d, J = 8Hz).
[0203]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-7-deoxy-10-O- (2-morpholino Ethyl) baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 1 of Example 9 to obtain the title compound.
[0204]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.17 (3H, s), 1.21 (3H, s), 1.33 (9H, s), 1.50-1.74 (2H, m), 1.74 (3H, s),
1.86 (3H, s), 1.90-2.41 (4H, m), 2.38 (3H, s), 2.50-2.65 (4H, m),
2.68 (2H, m), 3.61-3.76 (6H, m), 3.77 (1H, d, J = 7Hz), 4.21 (1H, d, J = 8Hz),
4.31 (1H, d, J = 8Hz), 4.46 (1H, s), 4.93 (1H, d, J = 8Hz), 5.05 (1H, s),
5.24-5.30 (1H, m), 5.30-5.35 (1H, m), 5.66 (1H, d, J = 7Hz), 6.22 (1H, m),
7.27-7.41 (5H, m), 7.50 (2H, t, J = 8Hz), 7.59 (1H, t, J = 8Hz),
8.13 (2H, d, J = 8Hz).
[0205]
Example 12
[0206]
Embedded image
Figure 0003921252
[0207]
Step 1: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -4,10-dideacetyl- 4-O-propionyl-7-O-triethylsilylbaccatin III
The compound obtained in Step 3 of Example 3 and (3R, 4S) -1-tert- (butoxycarbonyl) -4-phenyl-3- (triethylsilyloxy) azetidin-2-one were combined with Step 4 of Example 3. The same reaction was carried out to obtain the title compound as a colorless amorphous solid.
[0208]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.33-0.49 (m, 6H), 0.52-0.62 (m, 6H), 0.79 (t, 9H, J = 8Hz), 0.96 (t, 9H, J = 8Hz),
1.24 (s, 6H), 1.34 (s, 9H), 1.38 (t, 3H, J = 7Hz), 1.69 (s, 3H), 1.90 (s, 3H),
1.88-1.92 (m, 1H), 2.18-2.27 (m, 1H), 2.33-2.41 (m, 1H), 2.45-2.52 (m, 1H),
2.73-2.85 (m, 2H), 3.83 (d, 1H, J = 7Hz), 4.05 (dq, 2H, J = 5Hz, 12.5Hz),
4.20 (d, 1H, J = 8Hz), 4.33 (d, 1H, J = 8Hz), 4.43 (dd, 1H, J = 7Hz, 10Hz),
4.54 (s, 1H), 4.90 (d, 1H, J = 8Hz), 4.99 (s, 1H), 5.20 (d, 1H, J = 10.5Hz),
5.23 (d, 1H, J = 10Hz), 5.32 (dd, 1H, J = 1.5Hz, 17Hz), 5.47 (d, 1H, J = 10Hz),
5.69 (d, 1H, J = 7Hz), 5.94-6.02 (m, 1H), 6.26 (t, 1H, J = 8Hz), 7.28-7.40 (m, 5H),
7.48 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz)
[0209]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -4,10-dideacetyl-4-O-propionyl- 10-O- (2-thiomorpholinoethyl) -7-O-triethylsilylbaccatin III The compound obtained in Step 1 above was reacted in the same manner as in Step 1 of Example 2, and then morpholine in Step 2 of Example 2 was used. Reaction with thiomorpholine instead of gave the title compound as a colorless amorphous solid.
[0210]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.34-0.49 (m, 6H), 0.52-0.63 (m, 6H), 0.79 (t, 9H, J = 8Hz), 0.96 (t, 9H, J = 8Hz),
1.21 (s, 3H), 1.23 (s, 3H), 1.33 (s, 9H), 1.38 (t, 3H, J = 7Hz), 1.67 (s, 3H),
1.91 (s, 3H), 1.89-1.94 (m, 1H), 2.17-2.24 (m, 1H), 2.32-2.40 (m, 1H),
2.45-2.52 (m, 1H), 2.67-2.76 (m, 8H), 2.82-2.90 (m, 4H), 3.59 (t, 2H, J = 6Hz),
3.82 (d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz),
4.43 (dd, 1H, J = 7Hz, 10Hz), 4.53 (s, 1H), 4.90 (d, 1H, J = 8Hz), 4.93 (s, 1H),
5.22 (d, 1H, J = 10Hz), 5.46 (d, 1H, J = 10Hz), 5.68 (d, 1H, J = 7Hz),
6.25 (t, 1H, J = 8Hz), 7.28-7.40 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz),
8.13 (d, 2H, J = 8Hz)
[0211]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -4,10-dideacetyl-4-O-propionyl-10-O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a white solid.
[0212]
Melting point: 142-146 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.21 (t, 3H, J = 7Hz), 1.22 (s, 3H), 1.34 (s, 9H), 1.67 (s, 3H),
1.76-1.88 (m, 1H), 1.89 (s, 3H), 2.29 (m, 2H), 2.53-2.59 (m, 3H),
2.64-2.78 (m, 6H), 2.79-2.89 (m, 4H), 3.62-3.67 (m, 1H), 3.71-3.85 (m, 1H),
3.84 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.26 (dd, 1H, J = 7Hz, 10Hz),
4.31 (d, 1H, J = 8Hz), 4.62 (s, 1H), 4.89 (d, 1H, J = 8Hz), 5.05 (s, 1H),
5.23 (br, 1H), 5.32 (d, 1H, J = 9Hz), 5.67 (d, 1H, J = 7Hz), 6.21 (t, 1H, J = 8Hz),
7.31-7.42 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz)
IR (KBr): 3456, 3068, 2980, 2944, 2820, 1968, 1818, 1722, 1604,
1584 cm-1
MS-FAB: 951 (MH+)
[0213]
Example 13
[0214]
Embedded image
Figure 0003921252
[0215]
Step 1: 10-O-allyl-10-deacetyl-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O- triethylsilylbaccatin III
200 mg of the compound obtained in Step 1 of Example 1 was dissolved in 4 ml of pyridine, 0.20 ml of 2,2,2-trichloroethyl chloroformate was added, and the mixture was stirred with heating at 80 ° C. for 30 minutes. After allowing to cool, the mixture was poured into ice water, extracted with ethyl acetate, and washed with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and saturated brine in this order. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; chloroform: acetone = 40: 1 (v / v)) to obtain 220 mg of the title compound as a colorless amorphous solid.
[0216]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.64 (m, 6H), 0.95 (t, 9H, J = 8Hz), 1.14 (s, 3H), 1.23 (s, 3H), 1.67 (s, 3H),
1.85-1.92 (m, 1H), 2.00 (s, 3H), 2.37 (d, 2H, J = 8Hz), 2.39 (s, 3H),
2.45-2.53 (m, 1H), 3.87 (d, 1H, J = 7Hz), 4.05-4.11 (m, 2H),
4.13 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.43 (dd, 1H, J = 7Hz, 10Hz) 4.84 and 4.89 (each d, each 1H, J = 12Hz),
4.95 (d, 1H, J = 8Hz), 5.02 (s, 1H), 5.21 (dd, 1H, J = 1.5Hz, 10.5Hz),
5.32 (dd, 1H, J = 1.5Hz, 17Hz), 5.63 (d, 1H, J = 7Hz), 5.93-6.00 (m, 1H),
6.02 (t, 1H, J = 8Hz), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.07-8.09 (m, 2H)
[0217]
Step 2: 10-deacetyl-10-O- (2-thiomorpholinoethyl) -13-O- (2,2,2-trichloroethoxycarbonyl) -7-O- triethylsilylbaccatin III
The compound obtained in the above Step 1 is reacted in the same manner as in Step 1 of Example 2, and then reacted using thiomorpholine instead of morpholine in the same manner as in Step 2 of Example 2 to give the title compound as a colorless amorphous solid. Got as.
[0218]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.64 (m, 6H), 0.95 (t, 9H, J = 8Hz), 1.13 (s, 3H), 1.20 (s, 3H), 1.67 (s, 3H),
1.85-1.99 (m, 1H), 2.01 (s, 3H), 2.33-2.39 (m, 2H), 2.38 (s, 3H),
2.45-2.54 (m, 1H), 2.66-2.79 (m, 6H), 2.82-2.85 (m, 4H), 3.53-3.62 (m, 1H),
3.64-3.68 (m, 1H), 3.86 (d, 1H, J = 7Hz), 4.12 (d, 1H, J = 8Hz), 4.15 (s, 1H),
4.31 (d, 1H, J = 8Hz), 4.44 (dd, 1H, J = 7Hz, 10Hz),
4.83 and 4.88 (each d, each 1H, J = 12Hz), 4.94 (d, 1H, J = 8Hz), 4.97 (s, 1H),
5.62 (d, 1H, J = 7Hz), 6.01 (t, 1H, J = 8Hz), 7.48 (t, 2H, J = 8Hz),
7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz)
[0219]
Step 3: 10-deacetyl-10-O- (2-thiomorpholinoethyl) -7-O-triethylsilylbaccatin III
The compound obtained in Step 2 was reacted in the same manner as in Step 2 of Example 3 to obtain the title compound as a colorless amorphous solid.
[0220]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.65 (m, 6H), 0.96 (t, 9H, J = 8Hz), 1.05 (s, 3H), 1.17 (s, 3H), 1.66 (s, 3H),
1.85-1.97 (m, 1H), 2.08 (s, 3H), 2.26 (d, 2H, J = 9Hz), 2.28 (s, 3H),
2.45-2.53 (m, 2H), 2.66-2.74 (m, 6H), 2.83-2.85 (m, 4H), 3.54-3.60 (m, 1H),
3.62-3.68 (m, 1H), 3.87 (d, 1H, J = 7Hz), 4.14 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz),
4.43 (dd, 1H, J = 7Hz, 10Hz), 4.87 (br, 1H), 4.96 (d, 1H, J = 8Hz), 4.97 (s, 1H),
5.60 (d, 1H, J = 7Hz), 7.47 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
[0221]
Step 4: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -10-deacetyl-10-O- (2-thiol Morpholinoethyl) -7-O-triethylsilylbaccatin III
The compound obtained in Step 3 above and (3R, 4S) -1- (tert-butoxycarbonyl) -4-phenyl-3- (triethylsilyloxy) azetidin-2-one are reacted in the same manner as in Step 4 of Example 3. The title compound was obtained as a colorless amorphous solid.
[0222]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.33-0.48 (m, 6H), 0.52-0.62 (m, 6H), 0.79 (t, 9H, J = 8Hz), 0.96 (t, 9H, J = 8Hz),
1.20 (s, 3H), 1.23 (s, 3H), 1.32 (s, 9H), 1.68 (s, 3H), 1.91 (s, 3H),
1.89-1.94 (m, 1H), 2.15-2.22 (m, 1H), 2.31-2.40 (m, 1H), 2.44-2.51 (m, 1H),
2.52 (s, 3H), 2.67-2.73 (m, 6H), 2.84-2.86 (m, 4H), 3.58-3.60 (m, 2H),
3.83 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.41 (dd, 1H, J = 7Hz, 10Hz), 4.56 (s, 1H), 4.93 (s, 1H), 4.94 (d, 1H, J = 8Hz),
5.30 (br, 1H), 5.46 (br, 1H), 5.67 (d, 1H, J = 7Hz), 6.30 (t, 1H, J = 8Hz),
7.28-7.46 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0223]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in Step 4 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0224]
Melting point: 152-156 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.21 (s, 3H), 1.35 (s, 9H), 1.68 (s, 3H), 1.85-1.92 (m, 1H),
1.88 (s, 3H), 2.22-2.27 (m, 2H), 2.37 (s, 3H), 2.52-2.58 (m, 1H),
2.67-2.73 (m, 6H), 2.82-2.90 (m, 4H), 3.63-3.66 (m, 1H), 3.75-3.78 (m, 1H),
3.85 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.22 (dd, 1H, J = 7Hz, 10Hz),
4.30 (d, 1H, J = 8Hz), 4.62 (s, 1H), 4.94 (d, 1H, J = 8Hz), 5.06 (s, 1H),
5.25 (br, 1H), 5.39 (d, 1H, J = 10Hz), 5.66 (d, 1H, J = 7Hz), 6.22 (t, 1H, J = 8Hz),
7.31-7.42 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
IR (KBr): 3456, 3068, 2980, 2944, 2820, 1968, 1818, 1722, 1604,
1584 cm-1
MS-FAB: 937 (MH+)
[0225]
Example 14
[0226]
Embedded image
Figure 0003921252
[0227]
Step 1: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl -7- O- Triethylsilylbaccatin III
The compound obtained in Step 1 of Example 1 and (3R, 4S) -1- (tert-butoxycarbonyl) -3- (tert-butyldimethylsilyloxy) -4-phenylazetidin-2-one were used in Example 3. In the same manner as in Step 4, the title compound was obtained as a colorless amorphous solid.
[0228]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.10 (s, 3H), 0.54-0.61 (m, 6H), 0.76 (s, 9H),
0.96 (t, 9H, J = 8Hz), 1.24 (s, 6H), 1.32 (s, 9H), 1.69 (s, 3H), 1.90 (s, 3H),
1.89-1.94 (m, 1H), 2.14-2.21 (m, 1H), 2.32-2.42 (m, 1H), 2.45-2.54 (m, 1H),
2.56 (s, 3H), 3.85 (d, 1H, J = 7Hz), 4.00-4.10 (m, 2H), 4.19 (d, 1H, J = 8Hz),
4.31 (d, 1H, J = 8Hz), 4.41 (dd, 1H, J = 7Hz, 10Hz), 4.54 (s, 1H),
4.95 (d, 1H, J = 8Hz), 4.98 (s, 1H), 5.20 (d, 1H, J = 12Hz),
5.32 (dd, 1H, J = 2Hz, 17.5Hz), 5.33 (d, 1H, J = 10Hz), 5.42 (d, 1H, J = 10Hz),
5.68 (d, 1H, J = 7Hz), 5.93-6.01 (m, 1H), 6.34 (t, 1H, J = 8Hz), 7.28-7.39 (m, 5H),
7.47 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0229]
Step 2: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-de Acetylbaccatin III
198 mg of the compound obtained in the above step 1 was dissolved in 4 ml of acetonitrile and cooled to −10 ° C. Next, 0.050 ml of 12N hydrochloric acid was added dropwise and stirred for 1 hour. A saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to give the title compound 136
mg was obtained as a colorless amorphous solid.
[0230]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.10 (s, 3H), 0.75 (s, 9H), 1.22 (s, 3H), 1.24 (s, 3H),
1.31 (s, 9H), 1.70 (s, 3H), 1.79-1.82 (m, 1H), 1.88 (s, 3H), 2.17 (m, 1H),
2.35-2.41 (m, 1H), 2.66 (s, 3H), 2.66-2.81 (m, 1H), 3.90 (d, 1H, J = 7Hz),
4.04-4.09 (m, 1H), 4.16-4.23 (m, 3H), 4.31 (d, 1H, J = 8Hz), 4.52 (s, 1H),
4.97 (d, 1H, J = 8Hz), 5.04 (s, 1H), 5.21 (d, 1H, J = 12Hz), 5.28 (br, 1H),
5.31 (d, 1H, J = 17Hz), 5.53 (br, 1H), 5.70 (d, 1H, J = 7Hz), 5.90-5.98 (m, 1H),
6.32 (t, 1H, J = 8Hz), 7.27-7.34 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz),
8.11 (d, 2H, J = 8Hz)
[0231]
Step 3: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl -7- O-Trifluoromethanesulfonylbaccatin III
136 mg of the compound obtained in the above step 2 was dissolved in 3 ml of methylene chloride and 3 ml of pyridine, and cooled to -30 ° C. Next, 0.059 ml of trifluoromethanesulfonic anhydride was added dropwise, and the temperature was raised to room temperature over 3 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, and washed with a 1N aqueous sodium hydrogen sulfate solution and a saturated aqueous sodium bicarbonate solution in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to obtain 123 mg of the title compound as a pale yellow amorphous solid.
[0232]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.31 (s, 3H), -0.12 (s, 3H), 0.76 (s, 9H), 1.24 (s, 3H), 1.25 (s, 3H),
1.33 (s, 9H), 1.89 (s, 3H), 1.93 (s, 3H), 2.17-2.28 (m, 2H), 2.35-2.41 (m, 1H),
2.58 (s, 3H), 2.78-2.85 (m, 1H), 3.98 (d, 1H, J = 7Hz), 4.06-4.21 (m, 4H),
4.34 (d, 1H, J = 8Hz), 4.53 (s, 1H), 4.93 (d, 1H, J = 8Hz), 5.18 (s, 1H),
5.20 (d, 1H, J = 12Hz), 5.28 (br, 1H), 5.31 (d, 1H, J = 17Hz), 5.42-5.49 (m, 2H),
5.72 (d, 1H, J = 7Hz), 5.91-6.01 (m, 1H), 6.32 (t, 1H, J = 8Hz), 7.27-7.40 (m, 5H),
7.49 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz)
[0233]
Step 4: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl -7-Deoxy-7β, 8β-methanobaccatin III
123 mg of the compound obtained in Step 3 above was dissolved in 3 ml of 1,4-dioxane, a solution of 100 mg of sodium azide in 0.60 ml of water was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. The mixture was allowed to cool, diluted with ethyl acetate, and washed with water and then saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v)) to obtain 58.6 mg of the title compound as a colorless amorphous solid.
[0234]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.33 (s, 3H), -0.12 (s, 3H), 0.74 (s, 9H), 1.25 (s, 9H), 1.29 (s, 3H),
1.30 (s, 3H), 1.66-1.69 (m, 1H), 1.84 (s, 3H), 2.10-2.19 (m, 2H),
2.28-2.31 (m, 1H), 2.41-2.47 (m, 2H), 2.53 (s, 3H), 4.05 (d, 1H, J = 9Hz),
4.11-4.14 (m, 2H), 4.32 (d, 1H, J = 8Hz), 4.51 (s, 1H), 4.75 (d, 1H, J = 3.5Hz),
4.83 (s, 1H), 5.21 (dd, 1H, J = 1.5Hz, 10Hz), 5.30-5.35 (m, 2H), 5.40 (br, 1H),
5.68 (d, 1H, J = 7Hz), 5.91-6.01 (m, 1H), 6.36 (t, 1H, J = 8Hz), 7.26-7.39 (m, 5H),
7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.14 (d, 2H, J = 8Hz)
[0235]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-7-deoxy-7β , 8β-Methano-10-O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 4 was reacted in the same manner as in Step 1 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 using thiomorpholine instead of morpholine to give the title compound as a colorless amorphous solid. Got as.
[0236]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.32 (s, 3H), -0.11 (s, 3H), 0.74 (s, 9H), 1.25 (s, 3H), 1.26 (s, 9H),
1.29 (s, 3H), 1.61-1.64 (m, 1H), 1.87 (s, 3H), 2.10-2.18 (m, 2H),
2.26-2.31 (m, 1H), 2.36-2.47 (m, 2H), 2.52 (s, 3H), 2.64-2.72 (m, 6H),
2.82-2.85 (m, 4H), 3.61-3.74 (m, 2H), 4.05 (d, 1H, J = 9Hz), 4.10 (d, 1H, J = 8Hz),
4.31 (d, 1H, J = 8Hz), 4.51 (s, 1H), 4.75 (d, 1H, J = 3.5Hz), 4.83 (s, 1H),
5.32 (d, 1H, J = 10Hz), 5.44 (d, 1H, J = 10Hz), 5.66 (d, 1H, J = 7Hz),
6.35 (t, 1H, J = 8Hz), 7.26-7.39 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz),
8.14 (d, 2H, J = 8Hz)
[0237]
Step 6: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-7-deoxy-7β, 8β-methano-10- O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 5 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0238]
Melting point: 139-144 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.22 (s, 3H), 1.27 (s, 9H), 1.29 (s, 3H), 1.61-1.64 (m, 1H), 1.85 (s, 3H),
2.13-2.40 (m, 5H), 2.37 (s, 3H), 2.66-2.72 (m, 6H), 2.81-2.84 (m, 4H),
3.60-3.75 (m, 2H), 4.03 (d, 1H, J = 8Hz), 4.08 (d, 1H, J = 7Hz), 4.30 (d, 1H, J = 8Hz),
4.61 (s, 1H), 4.72 (d, 1H, J = 3.5Hz), 4.83 (s, 1H), 5.30 (br, 1H),
5.35 (d, 1H, J = 10Hz), 5.73 (d, 1H, J = 7Hz), 6.29 (t, 1H, J = 8Hz),
7.29-7.42 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.14 (d, 2H, J = 8Hz)
IR (KBr): 3542, 3068, 2976, 2936, 2820, 2100, 1866, 1716, 1602,
1586 cm-1
MS-FAB: 919 (MH+)
[0239]
Example 15
[0240]
Embedded image
Figure 0003921252
[0241]
Step 1: 10-O-allyl-4,10-dideacetyl-4-O-propionylbaccatin III
The compound obtained in Step 3 of Example 3 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless amorphous solid.
[0242]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.07 (s, 3H), 1.19 (s, 3H), 1.23 (t, 3H, J = 7Hz), 1.68 (s, 3H), 1.76-1.83 (m, 1H),
1.95 (d, 1H, J = 5Hz), 2.04 (s, 3H), 2.26-2.28 (m, 2H), 2.53-2.71 (m, 3H),
3.95 (d, 1H, J = 7Hz), 4.03-4.08 (m, 1H), 4.16 (d, 1H, J = 8Hz), 4.18-4.23 (m, 1H),
4.27-4.34 (m, 2H), 4.87 (m, 1H), 4.94 (d, 1H, J = 8Hz), 5.09 (s, 1H),
5.23 (d, 1H, J = 10Hz), 5.33 (dd, 1H, J = 1.5Hz, 17Hz), 5.64 (d, 1H, J = 7Hz),
5.92-6.01 (m, 1H), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz)
[0243]
Step 2: 10-O-allyl-4,10-dideacetyl-7-O- (1-imidazolylthiocarbonyl) -4-O-propionylbaccatin III
758 mg of the compound obtained in the above step 1 was dissolved in 75 ml of toluene, 500 mg of 1,1′-thiocarbonyldiimidazole and 154 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at 80 ° C. overnight. Toluene was distilled off under reduced pressure, and the residue was diluted with ethyl acetate, 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 purified by silica gel chromatography (elution solvent; chloroform: methanol = 50: 1 (v / v)) to obtain 790 mg of the title compound as a pale yellow solid.
[0244]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.17 (s, 3H), 1.27 (t, 3H, J = 7Hz), 1.62 (s, 3H), 1.89-1.93 (m, 1H),
1.96 (s, 3H), 2.07 (s, 3H), 2,28-2.35 (m, 2H), 2.59-2.74 (m, 2H),
2.92-3.00 (m, 2H), 3.78-3.90 (m, 2H), 4.09 (d, 1H, J = 7Hz), 4.21 (d, 1H, J = 8Hz),
4.37 (d, 1H, J = 8Hz), 4.87 (br, 1H), 4.96-5.02 (m, 4H), 5.58-5.69 (m, 2H),
6.16 (dd, 1H, J = 7Hz, 10Hz), 7.04 (s, 1H), 7.48 (t, 2H, J = 8Hz), 7.54 (s, 1H),
7.62 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz), 8.30 (s, 1H)
Step 3: 10-O-allyl-7-deoxy-4,10-dideacetyl-4-O-propionylbaccatin III
780 mg of the compound obtained in the above Step 2 was dissolved in 15 ml of toluene and 15 ml of 1,4-dioxane, 20 mg of α, α′-azobisisobutyronitrile was added, and the mixture was sufficiently deaerated and purged with nitrogen. Next, 0.712 ml of tributyltin hydride was added and stirred at 90 ° C. for 30 minutes. The residue obtained by concentrating the reaction solution was purified by silica gel chromatography (elution solvent; chloroform: methanol = 40: 1 (v / v)) to obtain 94 mg of the title compound as a colorless amorphous solid.
[0245]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.15 (s, 3H), 1.22 (t, 3H, J = 7Hz), 1.74 (s, 3H), 2.02 (s, 3H),
1.92-2.10 (m, 2H), 2.19-2.36 (m, 4H), 2.54-2.70 (m, 2H), 3.86 (d, 1H, J = 7Hz),
4.10-4.17 (m, 2H), 4.20 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.87 (m, 1H),
4.92 (d, 1H, J = 8Hz), 5.07 (s, 1H), 5.22 (d, 1H, J = 10Hz),
5.30 (dd, 1H, J = 1.5Hz, 17Hz), 5.62 (d, 1H, J = 7Hz), 5.92-6.02 (m, 1H),
7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz)
Step 4: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -7-deoxy -4,10-dideacetyl-4-O-propionylbaccatin III
The compound obtained in Step 3 above and (3R, 4S) -1- (tert-butoxycarbonyl) -4-phenyl-3- (triethylsilyloxy) azetidin-2-one are reacted in the same manner as in Step 4 of Example 3. The title compound was obtained as a colorless amorphous solid.
[0246]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.13 (s, 3H), 0.76 (s, 9H), 1.19 (s, 3H), 1.23 (s, 3H),
1.31 (s, 9H), 1.38 (t, 3H, J = 7Hz), 1.51-1.58 (m, 1H), 1.76 (s, 3H), 1.86 (s, 3H),
1.91-2.07 (m, 3H), 2.16-2.28 (m, 1H), 2.37-2.46 (m, 1H), 2.74-2.96 (m, 2H),
3.78 (d, 1H, J = 7Hz), 4.11 (d, 2H, J = 5Hz), 4.24 (d, 1H, J = 8Hz),
4.34 (d, 1H, J = 8Hz), 4.48 (s, 1H), 4.92 (d, 1H, J = 8Hz), 5.03 (s, 1H),
5.22 (d, 1H, J = 10Hz), 5.26 (br, 1H), 5.31 (d, 1H, J = 17Hz), 5.46 (br, 1H),
5.69 (d, 1H, J = 7Hz), 5.91-6.00 (m, 1H), 6.25 (t, 1H, J = 8Hz), 7.28-7.41 (m, 5H),
7.49 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.14 (d, 2H, J = 8Hz)
[0247]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -7-deoxy-4,10-dideacetyl -4- O-propionyl-10-O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 4 is reacted in the same manner as in Step 2 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 using thiomorpholine instead of morpholine to give the title compound as a colorless amorphous solid. Got as.
[0248]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.13 (s, 3H), 0.76 (s, 9H), 1.16 (s, 3H), 1.22 (s, 3H),
1.31 (s, 9H), 1.38 (t, 3H, J = 7Hz), 1.53-1.57 (m, 1H), 1.75 (s, 3H), 1.89 (s, 3H),
1.95 (m, 2H), 2.04-2.12 (m, 1H), 2.21-2.28 (m, 1H), 2.39-2.45 (m, 1H),
2.67-2.75 (m, 6H), 2.77-2.90 (m, 6H), 3.59-3.76 (m, 2H), 3.78 (d, 1H, J = 7Hz),
4.24 (d, 1H, J = 8Hz), 4.35 (d, 1H, J = 8Hz), 4.48 (s, 1H), 4.91 (d, 1H, J = 8Hz),
5.01 (s, 1H), 5.28 (d, 1H, J = 10Hz), 5.43 (br, 1H), 5.68 (d, 1H, J = 7Hz),
6.25 (t, 1H, J = 8Hz), 7.28-7.41 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz),
8.14 (d, 2H, J = 8Hz)
[0249]
Step 6: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -7-deoxy-4,10-dideacetyl-4-O-propionyl- 10-O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 5 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0250]
Melting point: 127-131 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.16 (s, 3H), 1.21 (s, 3H), 1.21 (t, 3H, J = 7Hz), 1.32 (s, 9H), 1.51-1.55 (m, 1H),
1.74 (s, 3H), 1.86 (s, 3H), 1.90-2.09 (m, 2H), 2.19-2.29 (m, 2H),
2.33-2.39 (m, 1H), 2.61-2.73 (m, 8H), 2.79-2.89 (m, 4H), 3.58-3.72 (m, 2H),
3.75 (d, 1H, J = 7Hz), 4.21 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 4.61 (s, 1H),
4.88 (d, 1H, J = 8Hz), 5.01 (s, 1H), 5.24 (br, 1H), 5.31 (d, 1H, J = 10Hz),
5.66 (d, 1H, J = 7Hz), 6.23 (t, 1H, J = 8Hz), 7.30-7.43 (m, 5H), 7.50 (t, 2H, J = 8Hz),
7.61 (t, 1H, J = 8Hz), 8.14 (d, 2H, J = 8Hz)
IR (KBr): 3460, 3068, 2984, 2936, 2820, 1718, 1604, 1586 cm-1
MS-FAB: 935 (MH+)
[0251]
Example 16
[0252]
Embedded image
Figure 0003921252
[0253]
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4,10-dideacetyl-4 -O-propionyl-10-O- [2- (thiomorpholino-1-oxide) ethyl] -7-O-triethylsilylbaccatin III
30 mg of the compound obtained in Step 1 of Example 6 was dissolved in 3 ml of methanol, 0.271 ml of 0.1M aqueous sodium metaperiodate was added under ice cooling, and the mixture was stirred at 0 ° C. for 2 hours and at room temperature for 4 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to obtain 18.2 mg of the title compound as a colorless amorphous solid.
[0254]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.52-0.63 (m, 6H), 0.96-1.01 (m, 30H), 1.19 (s, 3H), 1.20 (s, 3H), 1.35 (s, 9H),
1.37 (t, 3H, J = 7Hz), 1.67 (s, 3H), 1.87 (m, 1H), 1.93 (s, 3H), 2.32-2.36 (m, 2H),
2.45-2.52 (m, 1H), 2.75-2.89 (m, 10H), 3.19-3.25 (m, 2H), 3.60 (t, 2H, J = 6Hz),
3.82 (d, 1H, J = 7Hz), 4.18 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.42 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz), 4.94 (s, 1H), 4.99 (s, 1H),
5.24 (d, 1H, J = 10Hz), 5.30 (d, 1H, J = 10Hz), 5.67 (d, 1H, J = 7Hz),
6.18 (t, 1H, J = 8Hz), 6.27 (d, 1H, J = 3.5Hz), 6.37 (s, 1H), 7.40 (s, 1H),
7.47 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0255]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4,10-dideacetyl-4-O-propionyl- 10-O- [2- (thiomorpholino-1-oxide) ethyl] baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0256]
Melting point: 147-151 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.21 (s, 3H), 1.30 (t, 3H, J = 7Hz), 1.34 (s, 9H), 1.67 (s, 3H),
1.77-1.84 (m, 1H), 1.93 (s, 3H), 2.28-2.37 (m, 2H), 2.46-2.54 (m, 1H),
2.69-2.76 (m, 2H), 2.78-2.92 (m, 8H), 3.20-3.27 (m, 2H), 3.61-3.66 (m, 1H),
3.73-3.81 (m, 1H), 3.85 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz),
4.26 (dd, 1H, J = 7Hz, 10Hz), 4.31 (d, 1H, J = 8Hz), 4.70 (d, 1H, J = 2Hz),
4.90 (d, 1H, J = 8Hz), 5.09 (s, 1H), 5.31 (d, 1H, J = 10Hz), 5.40 (d, 1H, J = 10Hz),
5.67 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 8Hz), 6.34 (d, 1H, J = 3Hz),
6.38 (dd, 1H, J = 2Hz, 3Hz), 7.43 (s, 1H), 7.49 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz),
8.12 (d, 2H, J = 8Hz)
IR (KBr): 3896, 3448, 2980, 2940, 1722, 1632, 1604, 1496 cm-1
MS-FAB: 957 (MH+)
[0257]
Example 17
[0258]
Embedded image
Figure 0003921252
[0259]
Step 1: 10-O-allyl-10-deacetyl-13-O- (2,2,2-trichloroethoxycarbonyl) baccatin III
563 mg of the compound obtained in Step 1 of Example 13 was dissolved in 50 ml of acetonitrile, 2.5 ml of pyridine and 7.5 ml of 48% hydrofluoric acid were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. After concentration, the mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid. After drying with colorless sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to obtain 415 mg of the title compound as a colorless amorphous solid.
[0260]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.15 (s, 3H), 1.22 (s, 3H), 1.68 (s, 3H), 1.76-1.82 (m, 1H), 1.98 (s, 3H),
2.38 (s, 3H), 2.35-2.42 (m, 2H), 2.54-2.62 (m, 1H), 3.93 (d, 1H, J = 7Hz),
4.04-4.08 (m, 2H), 4.13 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz),
4.86 (s, 2H), 4.96 (d, 1H, J = 8Hz), 5.08 (s, 1H), 5.23 (d, 1H, J = 10.5Hz),
5.32 (d, 1H, J = 17Hz), 5.66 (d, 1H, J = 7Hz), 5.91-6.00 (m, 2H),
7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz)
[0261]
Step 2: 10-O-allyl-10-deacetyl-7-deoxy-7-α-fluoro-13-O- (2,2,2-trichloroethoxycarbonyl) baccatin III
320 mg of the compound obtained in the above step 1 was dissolved in 30 ml of methylene chloride and cooled to -78 ° C. Next, 0.040 ml of diethylaminosulfur trifluoride was added, and the mixture was stirred at -78 ° C for 15 minutes and at room temperature for 30 minutes. The reaction mixture was cooled again to -78 ° C, 0.080 ml of diethylaminosulfur trifluoride was added, and the mixture was stirred at -78 ° C for 15 minutes and at room temperature for 60 minutes. After confirming disappearance of the raw materials, the reaction solution was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; chloroform: acetone = 40: 1 (v / v)) to obtain 185 mg of the title compound as a colorless solid.
[0262]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.14 (s, 3H), 1.20 (s, 3H), 1.71 (s, 3H), 1.90 (s, 3H), 2.12-2.62 (m, 4H),
2.39 (s, 3H), 4.07 (d, 1H, J = 7Hz), 4.11-4.14 (m, 2H), 4.23 (d, 1H, J = 8Hz),
4.37 (d, 1H, J = 8Hz), 4.57 (dd, 1H, J = 5Hz, 47Hz), 4.85 (s, 2H),
5.02 (d, 1H, J = 9Hz), 5.12 (s, 1H), 5.22 (d, 1H, J = 10.5Hz), 5.31 (d, 1H, J = 17Hz),
5.74 (d, 1H, J = 7Hz), 5.90-6.00 (m, 2H), 7.49 (t, 2H, J = 8Hz),
7.62 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz)
[0263]
Step 3: 10-O-allyl-10-deacetyl-7-deoxy-7-α-fluorobaccatin III
185.0 mg of the compound obtained in the above step 2 was dissolved in 20 ml of a mixed solvent of methanol: acetic acid = 1: 1 (v / v), 1 g of active zinc powder was added and stirred at 60 ° C. for 30 minutes. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure, and then azeotroped with toluene. The obtained residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, 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; chloroform: acetone = 40: 1 (v / v)) to obtain 130 mg of the title compound as a colorless solid.
[0264]
Melting point: 193-195 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.06 (s, 3H), 1.17 (s, 3H), 1.71 (s, 3H), 1.96 (s, 3H), 2.12 (m, 1H),
2.25-2,39 (m, 2H), 2.30 (s, 3H), 2.48-2.61 (m, 1H), 4.10-4.13 (m, 3H),
4.27 (d, 1H, J = 8Hz), 4.35 (d, 1H, J = 8Hz), 4.55 (dd, 1H, J = 4.5Hz, 47.5Hz),
4.86 (br, 1H), 5.02 (d, 1H, J = 8Hz), 5.11 (s, 1H), 5.27 (d, 1H, J = 10.5Hz),
5.32 (d, 1H, J = 17Hz), 5.72 (d, 1H, J = 7Hz), 5.92-6.02 (m, 1H),
7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.13 (d, 2H, J = 8Hz)
IR (KBr): 3536, 3076, 2992, 2944, 2904, 1744, 1712, 1648, 1602 cm-1
MS-FAB: 587 (MH+)
[0265]
Step 4: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl -7-Deoxy-7-α-fluorobaccatin III
The compound obtained in Step 3 above and (3R, 4S) -1-tert-butoxycarbonyl-4-phenyl-3- (triethylsilyloxy) azetidin-2-one were reacted in the same manner as in Step 4 of Example 3 to give the title The compound was obtained as a colorless amorphous solid.
[0266]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.11 (s, 3H), 0.74 (s, 9H), 1.21 (s, 3H), 1.23 (s, 3H),
1.31 (s, 9H), 1.75 (s, 3H), 1.83 (s, 3H), 2.17-2.60 (m, 4H), 2.56 (s, 3H),
4.05 (d, 1H, J = 7Hz), 4.12 (d, 1H, J = 5.5Hz), 4.30 (d, 1H, J = 8Hz),
4.38 (d, 1H, J = 8Hz), 4.53 (s, 1H), 4.59 (dd, 1H, J = 4Hz, 47Hz),
5.04 (d, 1H, J = 8Hz), 5.09 (d, 1H, .J = 2Hz), 5.21 (dd, 1H, J = 1.5Hz, 10.5Hz),
5.32 (dd, 1H, J = 1.5Hz, 17Hz), 5.36 (d, 1H, J = 10Hz), 5.45 (d, 1H, J = 10Hz),
5.78 (d, 1H, J = 7Hz), 5.91-6.00 (m, 1H), 6.32 (t, 1H, J = 8Hz), 7.28-7.40 (m, 5H),
7.50 (t, 2H, J = 8Hz), 7.59 (t, 1H, J = 8Hz), 8.15 (d, 2H, J = 8Hz)
[0267]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-7-deoxy-7 -α-Fluoro-10-O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 4 is reacted in the same manner as in Step 2 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 using thiomorpholine instead of morpholine to give the title compound as a colorless amorphous solid. Got as.
[0268]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.32 (s, 3H), -0.11 (s, 3H), 0.74 (s, 9H), 1.18 (s, 3H), 1.22 (s, 3H),
1.31 (s, 9H), 1.74 (s, 3H), 1.85 (s, 3H), 2.12-2.59 (m, 4H), 2.56 (s, 3H),
2.67-2.72 (m, 6H), 2.82-2.85 (m, 4H), 3.62-3.70 (m, 2H), 4.04 (d, 1H, J = 7Hz),
4.30 (d, 1H, J = 8Hz), 4.37 (d, 1H, J = 8Hz), 4.52 (s, 1H), 4.59 (dd, 1H, J = 4Hz, 47Hz),
5.03 (d, 1H, J = 8Hz), 5.08 (s, 1H), 5.35 (d, 1H, J = 10Hz), 5.48 (d, 1H, J = 10Hz),
5.77 (d, 1H, J = 7Hz), 6.31 (t, 1H, J = 8Hz), 7.28-7.40 (m, 5H),
7.50 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.14 (d, 2H, J = 8Hz)
[0269]
Step 6: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-7-deoxy-7-α-fluoro-10- O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 5 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0270]
Melting point: 142-146 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.17 (s, 3H), 1.20 (s, 3H), 1.34 (s, 9H), 1.72 (s, 3H), 1.80 (s, 3H),
2.15-2.60 (m, 4H), 2.38 (s, 3H), 2.66-2.72 (m, 6H), 2.79-2.84 (m, 4H),
3.59-3.72 (m, 2H), 4.02 (d, 1H, J = 7Hz), 4.27 (d, 1H, J = 8Hz), 4.35 (d, 1H, J = 8Hz),
4.62 (s, 1H), 4.56 (dd, 1H, J = 4Hz, 47Hz), 5.00 (d, 1H, J = 8Hz), 5.07 (s, 1H),
5.30 (d, 1H, J = 10Hz), 5.40 (d, 1H, J = 10Hz), 5.75 (d, 1H, J = 7Hz),
6.23 (t, 1H, J = 8Hz), 7.32-7.39 (m, 5H), 7.50 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz),
8.13 (d, 2H, J = 8Hz)
IR (KBr): 3542, 3068, 2940, 2816, 1742, 1714, 1604, 1586 cm-1
MS-FAB: 939 (MH+)
[0271]
Example 18
[0272]
Embedded image
Figure 0003921252
[0273]
Step 1: 10-O-allyl-4,10-dideacetyl-4-O-propionyl-13-O- (2,2,2-trichloroethoxycarbonyl) -7-O- triethylsilylbaccatin III
The compound obtained in Step 3 of Example 3 was reacted in the same manner as in Step 1 of Example 13 to obtain the title compound as a colorless amorphous solid.
[0274]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.64 (m, 6H), 0.95 (t, 9H, J = 8Hz), 1.16 (s, 3H), 1.23 (s, 3H),
1.33 (t, 3H, J = 7Hz), 1.67 (s, 3H), 1.85-1.91 (m, 1H), 1.99 (s, 3H),
2.30-2.41 (m, 2H), 2.46-2.54 (m, 1H), 2.64-2.76 (m, 2H), 3.87 (d, 1H, J = 7Hz),
4.10-4.14 (m, 2H), 4.13 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz),
4.45 (dd, 1H, J = 7Hz, 10Hz), 4.84 and 4.88 (each d, each 1H, J = 12Hz),
4.89 (d, 1H, J = 8Hz), 5.02 (s, 1H), 5.21 (dd, 1H, J = 1.5Hz, 10Hz),
5.30 (dd, 1H, J = 1.5Hz, 17Hz), 5.64 (d, 1H, J = 7Hz), 5.94-6.02 (m, 1H),
6.05 (t, 1H, J = 8Hz), 7.47 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
[0275]
Step 2: 4,10-dideacetyl-4-O-propionyl-10-O- (2-thiomorpholinoethyl) -13-O- (2,2,2-trichloroethoxycarbonyl) -7-O- triethylsilylbacca Chin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 2 of Example 13 to obtain the title compound as a colorless amorphous solid.
[0276]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.52-0.64 (m, 6H), 0.96 (t, 9H, J = 8Hz), 1.14 (s, 3H), 1.20 (s, 3H),
1.33 (t, 3H, J = 7Hz), 1.67 (s, 3H), 1.85-1.91 (m, 1H), 2.00 (s, 3H),
2.33-2.40 (m, 2H), 2.46-2.53 (m, 1H), 2.67-2.76 (m, 8H), 2.83 (m, 4H),
3.48-3.66 (m, 2H), 3.85 (d, 1H, J = 7Hz), 4.13 (d, 1H, J = 8Hz), 4.15 (s, 1H),
4.32 (d, 1H, J = 8Hz), 4.45 (dd, 1H, J = 7Hz, 10Hz),
4.83 and 4.88 (each d, each 1H, J = 12Hz), 4.87 (d, 1H, J = 8Hz), 4.96 (s, 1H),
5.63 (d, 1H, J = 7Hz), 6.04 (t, 1H, J = 8Hz), 7.47 (t, 2H, J = 8Hz),
7.61 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
[0277]
Step 3: 4,10-dideacetyl-4-O-propionyl-10-O- (2-thiomorpholinoethyl) -7-O-triethylsilylbaccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 3 of Example 13 to obtain the title compound as a colorless amorphous solid.
[0278]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.50-0.65 (m, 6H), 0.96 (t, 9H, J = 8Hz), 1.05 (s, 3H), 1.17 (s, 3H),
1.24 (t, 3H, J = 7Hz), 1.66 (s, 3H), 1.85-1.91 (m, 1H), 2.07 (s, 3H),
2.24 (d, 2H, J = 9Hz), 2.46-2.55 (m, 2H), 2.57-2.64 (m, 2H), 2.66-2.74 (m, 6H),
2.84-2.89 (m, 4H), 3.55-3.67 (m, 2H), 3.87 (d, 1H, J = 7Hz), 4.14 (d, 1H, J = 8Hz),
4.29 (d, 1H, J = 8Hz), 4.44 (dd, 1H, J = 7Hz, 10Hz), 4.86 (br, 1H),
4.91 (d, 1H, J = 8Hz), 4.98 (s, 1H), 5.60 (d, 1H, J = 7Hz), 7.46 (t, 2H, J = 8Hz),
7.59 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0279]
Step 4: 13-O-[(2,3-threo) -3- (tert-butoxycarbonylamino) -5-methyl-2- (triethylsilyloxy) -4-hexenoyl] -4,10-dideacetyl-4 -O-propionyl-10-O- (2-thiomorpholinoethyl) -7-O- triethylsilylbaccati
III
[0280]
The compound obtained in Step 3 above and (3,4-cis) -1-tert-butoxycarbonyl-4-isobutenyl-3- (triethylsilyloxy) azetidin-2-one are reacted in the same manner as in Step 4 of Example 3. The title compound was obtained as a colorless amorphous solid.
[0281]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.53-0.70 (m, 12H), 0.93-1.03 (m, 18H), 1.19 (s, 6H), 1.26-1.32 (m, 3H),
1.35 and 1.39 (each s, total 9H), 1.67 (s, 3H), 1.77 (s, 3H), 1.81 (s, 3H),
1.86 and 1.89 (each s, total 3H), 2.12 (m, 2H), 2.34-2.47 (m, 3H),
2.65-2.70 (m, 6H), 2.83 (m, 4H), 3.56-3.60 (m, 2H),
3.80 and 3.84 (each d, total 1H, J = 7Hz), 4.18-4.31 (m, 3H), 4.41 (m, 1H),
4.75 and 5.02 (each br, total 1H), 4.85 (m, 2H),
4.92 and 4.97 (each s, total 1H), 5.26 and 5.31 (each d, total 1H, J = 10Hz),
5.64-5.66 (m, 1H), 6.11 (m, 1H), 7.42-7.60 (m, 3H),
8.06 and 8.11 (each d, total 2H, J = 8Hz)
[0282]
Step 5: 13-O-[(2S, 3R) -3- (tert-butoxycarbonylamino) -2-hydroxy-5-methyl-4-hexenoyl] -4,10-dideacetyl-4-O-propionyl-10 -O- (2-thiomorpholinoethyl) baccatin III and 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-5-methyl-4-hexenoyl] -4,10 -Dideacetyl-4-O-propionyl-10-O- (2-thiomorpholinoethyl)
III
[0283]
The compound obtained in Step 4 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0284]
(2S, 3R) body
Melting point: 142-145 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.18 (s, 6H), 1.28 (t, 3H, J = 7Hz), 1.39 (s, 9H), 1.68 (s, 3H), 1.79 (s, 3H),
1.82 (s, 3H), 2.00 (m, 1H), 2.11-2.16 (m, 2H), 2.15 (s, 3H), 2.38-2.62 (m, 3H),
2.67-2.73 (m, 6H), 2.79-2.87 (m, 4H), 3.63-3.65 (m, 1H), 3.76-3.79 (m, 1H),
3.89 (d, 1H, J = 7Hz), 4.08 (s, 1H), 4.16 (d, 1H, J = 8Hz), 4.29 (d, 1H, J = 8Hz),
4.30 (dd, 1H, J = 7Hz, 10Hz), 4.78 (s, 1H), 4.76-4.80 (m, 1H), 4.90 (d, 1H, J = 8Hz),
5.07 (s, 1H), 5.29 (d, 1H, J = 7Hz), 5.66 (d, 1H, J = 7Hz), 6.01 (t, 1H, J = 8Hz),
7.46 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.05 (d, 2H, J = 8Hz)
IR (KBr): 3460, 2980, 2940, 2824, 2352, 1722, 1604, 1586 cm-1
MS-FAB: 929 (MH+)
[0285]
(2R, 3S) body
Melting point: 146-149 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.20 (s, 3H), 1.27 (t, 3H, J = 7Hz), 1.35 (s, 9H), 1.67 (s, 3H),
1.78 (s, 6H), 1.84 (m, 1H), 1.93 (s, 3H), 2.35-2.37 (m, 2H), 2.53-2.71 (m, 9H),
2.79-2.89 (m, 4H), 3.63-3.66 (m, 1H), 3.72-3.76 (m, 1H), 3.86 (d, 1H, J = 7Hz),
4.16 (s, 1H), 4.17 (d, 1H, J = 8Hz), 4.27 (dd, 1H, J = 7Hz, 10Hz),
4.31 (d, 1H, J = 8Hz), 4.70-4.79 (m, 2H), 4.91 (d, 1H, J = 8Hz), 5.06 (s, 1H),
5.36 (d, 1H, J = 7Hz), 5.67 (d, 1H, J = 7Hz), 6.14 (t, 1H, J = 8Hz),
7.46 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
IR (KBr): 3464, 3068, 2980, 2940, 2820, 1716, 1604, 1584 cm-1
MS-FAB: 929 (MH+)
[0286]
Example 19
[0287]
Embedded image
Figure 0003921252
[0288]
Step 1: 10-O-allyl-13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionyl] -4,10-dideacetyl-4-O- Propionyl-7-O- triethylsilylbaccatin III (Isomer A, Isomer B)
[0289]
3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionic acid 245 mg and 2,2'-dipyridyl carbonate 182 mg were dissolved in toluene 6 ml and stirred at room temperature for 10 minutes. . Next, 100 mg of the compound obtained in Step 3 of Example 3 ??? 17 mg of 4-dimethylaminopyridine was added, and the mixture was stirred with heating at 70 ° C overnight. After allowing to cool, the reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, 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 thin layer chromatography (developing solvent; ethyl ether: hexane = 1: 1 (v / v)) twice and purified with two isomers A (low polarity compound) 56.3 mg and 51.0 mg of isomer B (high polarity compound) was obtained.
[0290]
Isomer A
1H-NMR (CDClThree/ TMS) δ (ppm):
0.51-0.64 (m, 6H), 0.95 (t, 9H, J = 8Hz), 1.21 (s, 3H), 1.24 (s, 3H),
1.31 (t, 3H, J = 7Hz), 1.42 (s, 9H), 1.68 (s, 3H), 1.87 (s, 3H), 1.85-1.92 (m, 1H),
2.25-2.27 (m, 2H), 2.45-2.53 (m, 1H), 2.59-2.61 (m, 2H), 3.79 (d, 1H, J = 7Hz),
3.99-4.07 (m, 2H), 4.15 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz),
4.41 (dd, 1H, J = 7Hz, 10Hz), 4.87 (d, 1H, J = 8Hz), 4.96 (s, 1H),
5.19 (d, 1H, J = 9Hz), 5.29 (dd, 1H, J = 1.5Hz, 17Hz), 5.38 (d, 1H, J = 10Hz),
5.62 (m, 1H), 5.66 (d, 1H, J = 7Hz), 5.92-6.02 (m, 1H), 6.27 (t, 1H, J = 8Hz),
6.40-6.44 (m, 2H), 7.45-7.50 (m, 3H), 7.61 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0291]
Isomer B
1H-NMR (CDClThree/ TMS) δ (ppm):
0.51-0.64 (m, 6H), 0.95 (t, 9H, J = 8Hz), 1.21 (s, 3H), 1.24 (s, 3H),
1.29 (t, 3H, J = 7Hz), 1.45 (s, 9H), 1.68 (s, 3H), 1.90 (s, 3H), 1.87-1.93 (m, 1H),
2.26 (d, 2H, J = 9Hz), 2.45-2.60 (m, 3H), 3.79 (d, 1H, J = 7Hz), 3.99-4.09 (m, 2H),
4.14 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz), 4.41 (dd, 1H, J = 7Hz, 10Hz),
4.87 (d, 1H, J = 8Hz), 4.97 (s, 1H), 5.19 (dd, 1H, J = 1.5Hz, 10.5Hz),
5.29 (dd, 1H, J = 1.5Hz, 17Hz), 5.38 (d, 1H, J = 10Hz), 5.60 (m, 1H),
5.66 (d, 1H, J = 7Hz), 5.93-6.03 (m, 1H), 6.23 (t, 1H, J = 8Hz), 6.39-6.45 (m, 2H),
7.43 (d, 1H, J = 1.5Hz), 7.48 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz),
8.09 (d, 2H, J = 8Hz)
[0292]
Step 2: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionyl] -4,10-dideacetyl-4-O-propionyl-10-O- (2-Thiomorpholinoethyl) -7-O-triethylsilylbaccatin III (Isomer A, Isomer B)
[0293]
The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Example 2, and then reacted using thiomorpholine instead of morpholine in the same manner as in Step 2 of Example 2 to give the title compounds (isomer A, isomer B). ) Were obtained as amorphous solids, respectively.
[0294]
Isomer A
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.64 (m, 6H), 0.96 (t, 9H, J = 8Hz), 1.20 (s, 6H), 1.30 (t, 3H, J = 7Hz),
1.42 (s, 9H), 1.67 (s, 3H), 1.87 (s, 3H), 1.89-1.93 (m, 1H), 2.24-2.30 (m, 2H),
2.44-2.52 (m, 1H), 2.59-2.61 (m, 2H), 2.66-2.73 (m, 8H), 2.83-2.95 (m, 4H),
3.48-3.65 (m, 2H), 3.78 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz),
4.42 (dd, 1H, J = 7Hz, 10Hz), 4.87 (d, 1H, J = 8Hz), 4.91 (s, 1H),
5.36 (d, 1H, J = 10Hz), 5.55-5.63 (m, 1H), 5.65 (d, 1H, J = 7Hz),
6.25 (t, 1H, J = 8Hz), 6.40-6.43 (m, 2H), 7.45-7.49 (m, 3H), 7.61 (t, 1H, J = 8Hz),
8.10 (d, 2H, J = 8Hz)
[0295]
Isomer B
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.64 (m, 6H), 0.96 (t, 9H, J = 8Hz), 1.19 (s, 3H), 1.20 (s, 3H),
1.29 (t, 3H, J = 7Hz), 1.45 (s, 9H), 1.67 (s, 3H), 1.90 (s, 3H), 1.87-1.91 (m, 1H),
2.25 (d, 2H, J = 9Hz), 2.44-2.61 (m, 3H), 2.66-2.73 (m, 8H), 2.83-2.85 (m, 4H),
3.48-3.65 (m, 2H), 3.78 (d, 1H, J = 7Hz), 4.14 (d, 1H, J = 8Hz), 4.30 (d, 1H, J = 8Hz),
4.43 (dd, 1H, J = 7Hz, 10Hz), 4.87 (d, 1H, J = 8Hz), 4.92 (s, 1H),
5.37 (d, 1H, J = 10Hz), 5.58-5.61 (m, 1H), 5.65 (d, 1H, J = 7Hz),
6.21 (t, 1H, J = 8Hz), 6.39-6.44 (m, 2H), 7.43-7.50 (m, 3H), 7.61 (t, 1H, J = 8Hz),
8.09 (d, 2H, J = 8Hz)
[0296]
Step 3: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionyl] -4,10-dideacetyl-4-O-propionyl-10-O- (2-thiomorpholinoethyl) baccatin III (Isomer A, Isomer B)
The compound obtained in Step 2 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compounds (Isomer A and Isomer B) as colorless solids.
[0297]
Isomer A
Melting point: 136-139 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.21 (s, 3H), 1.29 (t, 3H, J = 7Hz), 1.41 (s, 9H), 1.67 (s, 3H),
1.87 (s, 3H), 1.81-1.84 (m, 1H), 2.21-2.32 (m, 2H), 2.54-2.62 (m, 3H),
2.66-2.71 (m, 8H), 2.78-2.90 (m, 4H), 3.60-3.65 (m, 1H), 3.71-3.79 (m, 1H),
3.84 (d, 1H, J = 7Hz), 4.13 (d, 1H, J = 8Hz), 4.28 (dd, 1H, J = 7Hz, 10Hz),
4.31 (d, 1H, J = 8Hz), 4.89 (d, 1H, J = 8Hz), 5.02 (s, 1H), 5.36 (d, 1H, J = 10Hz),
5.57-5.63 (m, 1H), 5.67 (d, 1H, J = 7Hz), 6.25 (t, 1H, J = 8Hz), 6.40-6.43 (m, 2H),
7.45-7.50 (m, 3H), 7.61 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
IR (KBr): 3464, 2984, 2944, 2816, 1768, 1724, 1604, 1500 cm-1
MS-FAB: 961 (MH+)
[0298]
Isomer B
Melting point: 138-142 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.19 (s, 3H), 1.20 (s, 3H), 1.27 (t, 3H, J = 7Hz), 1.45 (s, 9H), 1.67 (s, 3H),
1.90 (s, 3H), 1.77-1.84 (m, 1H), 2.25 (d, 2H, J = 9Hz), 2.50-2.61 (m, 3H),
2.66-2.72 (m, 8H), 2.77-2.89 (m, 4H), 3.60-3.65 (m, 1H), 3.74-3.79 (m, 1H),
3.82 (d, 1H, J = 7Hz), 4.15 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.27 (dd, 1H, J = 7Hz, 10Hz), 4.89 (d, 1H, J = 8Hz), 5.03 (s, 1H),
5.37 (d, 1H, J = 10Hz), 5.55-5.61 (m, 1H), 5.67 (d, 1H, J = 7Hz),
6.19 (t, 1H, J = 8Hz), 6.39-6.43 (m, 2H), 7.43 (d, 1H, J = 1.5Hz),
7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz)
IR (KBr): 3464, 2980, 2944, 2820, 1766, 1722, 1604, 1500 cm-1
MS-FAB: 961 (MH+)
[0299]
Example 20
[0300]
Embedded image
Figure 0003921252
[0301]
Step 1: 10-deacetyl-10-O- (2-pyridylmethyl) -7-O-triethylsilylbaccatin III
100 mg of 7-O-triethylsilylbaccatin III was dissolved in 4 ml of tetrahydrofuran and cooled to -78 ° C. Next, 0.378 ml of n-butyllithium (1.61 M hexane solution) was added dropwise. After 15 minutes, a solution of 57.7 mg of 2-pyridylmethyl bromide bromide dissolved in 1 ml of dimethyl sulfoxide was added dropwise, and the temperature was raised to 0 ° C. and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, 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; chloroform: methanol = 20: 1 (v / v)) to obtain 25.1 mg of the title compound as a colorless amorphous solid.
[0302]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.47-0.61 (m, 6H), 0.92 (t, 9H, J = 8Hz), 1.06 (s, 3H), 1.24 (s, 3H), 1.70 (s, 3H),
1.86-1.93 (m, 1H), 2.09 (s, 3H), 2.21-2.33 (m, 2H), 2.28 (s, 3H),
2.46-2.54 (m, 1H), 3.91 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.45 (dd, 1H, J = 7Hz, 10Hz), 4.71 (AB type d, each 1H, J = 13Hz), 4.88 (br, 1H),
4.96 (d, 1H, J = 8Hz), 5.22 (s, 1H), 5.64 (d, 1H, J = 7Hz), 7.18-7.21 (m, 1H),
7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 7.72-7.76 (m, 2H), 8.10-8.12 (m, 2H),
8.50 (d, 1H, J = 5Hz)
[0303]
Step 2: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O- (4-methoxybenzylidene) -3-phenylisoserinyl] -10-deacetyl- 10-O- (2-pyridylmethyl) -7-O- triethylsilylbaccatin III
[0304]
80.0 mg of (4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -oxazolidine-5-carboxylic acid was dissolved in 2 ml of ethyl acetate, 49.5 mg of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 15 minutes. . Next, 50.0 mg of the compound obtained in the above Step 1 and 2-dimethylaminopyridine were added and stirred for 1 hour. The insoluble material was removed by filtration, and then the mother liquor 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. The resulting residue was developed and purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 40: 1 (v / v)) to obtain 65.1 mg of the title compound as a colorless amorphous solid.
[0305]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.45-0.55 (m, 6H), 0.89 (t, 9H, J = 8Hz), 1.05 (s, 9H), 1.19 (s, 3H), 1.25 (s, 3H),
1.58 (br, 3H), 1.65 (s, 3H), 1.84 (br, 3H), 1.87-1.91 (m, 1H),
2.05-2.17 (m, 2H), 2.41-2.45 (m, 1H), 3.72 (d, 1H, J = 7Hz), 3.77 (s, 3H),
4.09 (d, 1H, J = 8Hz), 4.22 (d, 1H, J = 8Hz), 4.33 (dd, 1H, J = 7Hz, 10Hz),
4.56 (d, 1H, J = 5Hz), 4.65 (AB type d, each 1H, J = 14Hz), 4.84 (d, 1H, J = 8Hz),
5.08 (s, 1H), 5.40 (br, 1H), 5.63 (d, 1H, J = 7Hz), 6.15 (br, 1H), 6.40 (br, 1H),
6.93 (d, 2H, J = 9Hz), 7.17-7.21 (m, 1H), 7.41-7.50 (m, 9H), 7.60-7.64 (m, 2H),
7.69-7.73 (m, 1H), 8.03 (d, 2H, J = 8Hz), 8.51 (d, 1H, J = 4.5Hz)
[0306]
Step 3: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O- (4-methoxybenzylidene) -3-phenylisoserinyl] -10-deacetyl- 10-O- (2-pyridylmethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless amorphous solid.
[0307]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.81 (br, 3H), 1.03 (s, 9H), 1.18 (s, 3H), 1.20 (s, 3H), 1.66 (s, 3H),
1.74 (br, 3H), 1.86-1.94 (m, 1H), 1.97-2.15 (m, 2H), 2.45-2.52 (m, 1H),
3.59 (d, 1H, J = 7Hz), 3.82 (s, 3H), 4.10 (d, 1H, J = 8Hz),
4.16 (dd, 1H, J = 7Hz, 10Hz), 4.21 (d, 1H, J = 8Hz), 4.50 (s, 1H),
4.75 (d, 1H, J = 13Hz), 4.87 (d, 1H, J = 13Hz), 4.88 (d, 1H, J = 8Hz), 5.03 (s, 1H),
5.35 (br, 1H), 5.60 (d, 1H, J = 7Hz), 6.04 (br, 1H), 6.35 (br, 1H),
6.86 (d, 2H, J = 8Hz), 7.29-7.39 (m, 8H), 7.47 (t, 2H, J = 8Hz), 7.54-7.61 (m, 2H),
7.82 (t, 1H, J = 8Hz), 8.01 (d, 2H, J = 8Hz), 8.48 (d, 1H, J = 4.5Hz)
[0308]
Step 4: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- (2-pyridylmethyl) baccatin III
34.1 mg of the compound obtained in the above Step 3 was dissolved in 4 ml of methanol, 16.2 mg of tosylic acid was added at room temperature, and the mixture was stirred for 2 hours. The mixture was diluted with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, 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; chloroform: methanol = 20: 1 (v / v)) and lyophilized from 1,4-dioxane to give 28.3 mg of the title compound as a white solid. It was.
[0309]
Melting point: 152-157 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.15 (s, 3H), 1.20 (s, 3H), 1.25 (s, 3H), 1.32 (s, 9H), 1.73 (s, 3H),
1.92-1.99 (m, 1H), 2.21 (d, 2H, J = 8Hz), 2.32 (s, 3H), 2.50-2.58 (m, 1H),
3.71 (d, 1H, J = 7Hz), 4.19 (d, 1H, J = 8Hz), 4.25 (dd, 1H, J = 7Hz, 10Hz),
4.29 (d, 1H, J = 8Hz), 4.52 (s, 1H), 4.89 (d, 1H, J = 12Hz), 4.92 (d, 1H, J = 12Hz),
4.95 (d, 1H, J = 8Hz), 5.18 (s, 1H), 5.21 (d, 1H, J = 10Hz), 5.36 (d, 1H, J = 10Hz),
5.66 (d, 1H, J = 7Hz), 6.12 (t, 1H, J = 8Hz), 7.29-7.39 (m, 6H), 7.48 (t, 2H, J = 8Hz),
7.59 (d, 2H, J = 7Hz), 7.81 (t, 1H, J = 8Hz), 8.09 (d, 2H, J = 8Hz), 8.51 (d, 1H, J = 5Hz)
IR (KBr): 3542, 3068, 2980, 2940, 2504, 1722, 1600 cm-1
MS-FAB: 899 (MH+)
[0310]
Example 21
[0311]
Embedded image
Figure 0003921252
[0312]
Step 1: 10-deacetyl-10-O- (3-pyridylmethyl) -7-O-triethylsilylbaccatin III
In the same manner as in Step 1 of Example 20, the reaction was carried out using 3-pyridylmethyl bromide bromide instead of 2-pyridylmethyl bromide bromide to obtain the title compound as a colorless amorphous solid.
[0313]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.63 (m, 6H), 0.95 (t, 9H, J = 8Hz), 1.07 (s, 3H), 1.21 (s, 3H), 1.69 (s, 3H),
1.82-1.93 (m, 1H), 2.07 (s, 3H), 2.25-2.31 (m, 2H), 2.29 (s, 3H),
2.44-2.55 (m, 1H), 3.89 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.46 (dd, 1H, J = 7Hz, 10Hz), 4.55 (d, 1H, J = 12Hz), 4.68 (d, 1H, J = 12Hz),
4.91 (t, 1H, J = 8Hz), 4.97 (d, 1H, J = 8Hz), 5.13 (s, 1H), 5.63 (d, 1H, J = 7Hz),
7.29-7.33 (m, 1H), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz), 7.83 (d, 1H, J = 8Hz),
8.11 (d, 2H, J = 8Hz), 8.53-8.59 (m, 2H)
[0314]
Step 2: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O- (4-methoxybenzylidene) -3-phenylisoserinyl] -10-deacetyl- 10-O- (3-pyridylmethyl) -7-O- triethylsilylbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 2 of Example 20 to obtain the title compound as a colorless amorphous solid.
[0315]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.45-0.59 (m, 6H), 0.93 (t, 9H, J = 8Hz), 1.06 (s, 9H), 1.19 (s, 3H), 1.21 (s, 3H),
1.56 (br, 3H), 1.64 (s, 3H), 1.85 (br, 3H), 1.86-1.92 (m, 1H),
2.04-2.24 (m, 2H), 2.39-2.47 (m, 1H), 3.70 (d, 1H, J = 7Hz), 3.77 (s, 3H),
4.08 (d, 1H, J = 8Hz), 4.22 (d, 1H, J = 8Hz), 4.35 (dd, 1H, J = 7Hz, 10Hz),
4.48 (d, 1H, J = 11Hz), 4.56 (d, 1H, J = 11Hz), 4.57 (s, 1H), 4.84 (d, 1H, J = 8Hz),
4.98 (s, 1H), 5.42 (br, 1H), 5.61 (d, 1H, J = 7Hz), 6.12 (br, 1H), 6.39 (br, 1H),
6.93 (d, 2H, J = 9Hz), 7.29-7.32 (m, 1H), 7.38-7.50 (m, 9H), 7.62 (t, 1H, J = 8Hz),
7.78 (d, 1H, J = 8Hz), 8.02 (d, 2H, J = 8Hz), 8.54-8.59 (m, 2H)
[0316]
Step 3: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O- (4-methoxybenzylidene) -3-phenylisoserinyl] -10-deacetyl- 10-O- (3-pyridylmethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 3 of Example 20 to obtain the title compound as a colorless amorphous solid.
[0317]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.05 (s, 9H), 1.19 (s, 3H), 1.21 (s, 3H), 1.34 (s, 3H), 1.65 (s, 3H),
1.73 (br, 4H), 2.03-2.22 (m, 2H), 2.46-2.53 (m, 1H), 3.71 (d, 1H, J = 7Hz),
3.80 (s, 3H), 4.09 (d, 1H, J = 8Hz), 4.15 (dd, 1H, J = 7Hz, 10Hz),
4.21 (d, 1H, J = 8Hz), 4.55 (s, 1H), 4.56 (d, 1H, J = 13Hz), 4.73 (d, 1H, J = 13Hz),
4.85 (d, 1H, J = 8Hz), 4.93 (s, 1H), 5.39 (br, 1H), 5.62 (d, 1H, J = 7Hz),
6.09 (br, 1H), 6.36 (br, 1H), 6.93 (d, 2H, J = 8Hz), 7.30 (dd, 2H, J = 5Hz, 8Hz),
7.37-7.44 (m, 6H), 7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 7.77 (d, 1H, J = 8Hz),
8.00-8.03 (m, 2H), 8.52 (dd, 1H, J = 1.5Hz, 5Hz), 8.57 (d, 1H, J = 1.5Hz)
[0318]
Step 4: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- (3-pyridylmethyl) baccatin III
The compound obtained in the above Step 3 was reacted in the same manner as in Step 4 of Example 20 to obtain the title compound as a colorless solid.
[0319]
Melting point: 158-163 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.22 (s, 3H), 1.25 (s, 3H), 1.34 (s, 9H), 1.61 (s, 3H), 1.71 (s, 3H),
1.81-1.87 (m, 1H), 2.26 (m, 2H), 2.34 (s, 3H), 2.51-2.55 (m, 1H),
3.81 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.21 (dd, 1H, J = 7Hz, 10Hz),
4.30 (d, 1H, J = 8Hz), 4.59 (d, 1H, J = 12Hz), 4.60 (s, 1H), 4.77 (d, 1H, J = 12Hz),
4.93 (d, 1H, J = 8Hz), 5.03 (s, 1H), 5.25 (d, 1H, J = 10Hz), 5.45 (d, 1H, J = 10Hz),
5.68 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 8Hz), 7.28-7.39 (m, 6H), 7.49 (t, 2H, J = 8Hz),
7.61 (d, 2H, J = 8Hz), 7.81 (d, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz), 8.48-8.49 (m, 1H),
8.55 (s, 1H)
IR (KBr): 3448, 3068, 2980, 2940, 2356, 1720, 1602 cm-1
MS-FAB: 899 (MH+)
[0320]
Example 22
[0321]
Embedded image
Figure 0003921252
[0322]
Step 1: 10-deacetyl-10-O- (4-pyridylmethyl) -7-O-triethylsilylbaccatin III
In the same manner as in Step 1 of Example 20, the reaction was carried out using 4-pyridylmethyl bromide bromide instead of 2-pyridylmethyl bromide bromide to obtain the title compound as a colorless amorphous solid.
[0323]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.51-0.63 (m, 6H), 0.94 (t, 9H, J = 8Hz), 1.09 (s, 3H), 1.24 (s, 3H), 1.69 (s, 3H),
1.87-1.93 (m, 1H), 2.06 (s, 3H), 2.27-2.31 (m, 2H), 2.28 (s, 3H),
2.47-2.55 (m, 1H), 3.89 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.47 (dd, 1H, J = 7Hz, 10Hz), 4.54 (d, 1H, J = 13Hz), 4.73 (d, 1H, J = 13Hz),
4.91 (t, 1H, J = 8Hz), 4.97 (d, 1H, J = 8Hz), 5.11 (s, 1H), 5.64 (d, 1H, J = 7Hz),
7.34 (d, 2H, J = 6Hz), 7.47 (t, 2H, J = 8Hz), 7.60 (t, 1H, J = 8Hz),
8.11 (d, 2H, J = 8Hz), 8.57 (d, 2H, J = 6Hz)
[0324]
Step 2: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O- (4-methoxybenzylidene) -3-phenylisoserinyl] -10-deacetyl- 10-O- (4-pyridylmethyl) -7-O- triethylsilylbaccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 2 of Example 20 to obtain the title compound as a colorless amorphous solid.
[0325]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.49-0.53 (m, 6H), 0.91 (t, 9H, J = 8Hz), 1.06 (s, 9H), 1.19 (s, 3H), 1.23 (s, 3H),
1.54 (br, 3H), 1.64 (s, 3H), 1.78 (br, 3H), 1.85-1.90 (m, 1H),
2.05-2.21 (m, 2H), 2.39-2.48 (m, 1H), 3.70 (d, 1H, J = 7Hz), 3.77 (s, 3H),
4.09 (d, 1H, J = 8Hz), 4.22 (d, 1H, J = 8Hz), 4.33 (dd, 1H, J = 7Hz, 10Hz),
4.48 (d, 1H, J = 13Hz), 4.57 (s, 1H), 4.60 (d, 1H, J = 13Hz), 4.84 (d, 1H, J = 8Hz),
4.96 (s, 1H), 5.40 (br, 1H), 5.62 (d, 1H, J = 7Hz), 6.10 (br, 1H), 6.39 (br, 1H),
6.93 (d, 2H, J = 9Hz), 7.31-7.50 (m, 11H), 7.62 (t, 1H, J = 8Hz),
8.03 (d, 2H, J = 8Hz), 8.59 (d, 2H, J = 6Hz)
[0326]
Step 3: 13-O-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O- (4-methoxybenzylidene) -3-phenylisoserinyl] -10-deacetyl- 10-O- (4-pyridylmethyl) baccatin III
The compound obtained in the above Step 2 was reacted in the same manner as in Step 3 of Example 20 to obtain the title compound as a colorless amorphous solid.
[0327]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.05 (s, 9H), 1.21 (s, 3H), 1.23 (s, 3H), 1.40 (s, 3H), 1.65 (s, 3H),
1.75 (br, 3H), 1.79 (m, 1H), 2.05-2.24 (m, 2H), 2.45-2.53 (m, 1H),
3.72 (d, 1H, J = 7Hz), 3.79 (s, 3H), 4.09 (d, 1H, J = 8Hz),
4.13 (dd, 1H, J = 7Hz, 10Hz), 4.22 (d, 1H, J = 8Hz), 4.54 (d, 1H, J = 14Hz),
4.55 (s, 1H), 4.70 (d, 1H, J = 14Hz), 4.85 (d, 1H, J = 8Hz), 4.94 (s, 1H),
5.41 (br, 1H), 5.63 (d, 1H, J = 7Hz), 6.12 (br, 1H), 6.37 (br, 1H),
6.92 (d, 2H, J = 8Hz), 7.29 (d, 2H, J = 5.5Hz), 7.41-7.43 (m, 7H),
7.48 (t, 2H, J = 8Hz), 7.62 (t, 1H, J = 8Hz), 8.02 (d, 2H, J = 8Hz),
8.56 (d, 2H, J = 5.5Hz)
[0328]
Step 4: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- (4-pyridylmethyl) baccatin III
The compound obtained in the above Step 3 was reacted in the same manner as in Step 4 of Example 20 to obtain the title compound as a colorless solid.
[0329]
Melting point: 160-165 ℃
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.28 (s, 3H), 1.33 (s, 9H), 1.66 (s, 3H), 1.73 (s, 3H),
1.83-1.89 (m, 1H), 2.29 (d, 2H, J = 8Hz), 2.36 (s, 3H), 2.49-2.57 (m, 1H),
3.83 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 8Hz), 4.25 (dd, 1H, J = 7Hz, 10Hz),
4.31 (d, 1H, J = 8Hz), 4.60 (d, 1H, J = 14Hz), 4.65 (s, 1H), 4.82 (d, 1H, J = 14Hz),
4.94 (d, 1H, J = 8Hz), 5.02 (s, 1H), 5.27 (d, 1H, J = 10Hz), 5.44 (d, 1H, J = 10Hz),
5.69 (d, 1H, J = 7Hz), 6.22 (t, 1H, J = 8Hz), 7.27-7.39 (m, 7H), 7.50 (t, 2H, J = 8Hz),
7.61 (d, 2H, J = 8Hz), 8.10 (d, 2H, J = 8Hz), 8.48 (d, 2H, J = 6Hz)
IR (KBr): 3444, 3072, 2984, 2940, 1948, 1726, 1606 cm-1
MS-FAB: 899 (MH+)
[0330]
Example 23
[0331]
Embedded image
Figure 0003921252
[0332]
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-10-O- [ 2- (3-Thiazolidino) ethyl] -7-O-triethylsilylbaccatin III
The compound obtained in Step 1 of Example 14 was reacted in the same manner as in Step 1 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 using thiazolidine instead of morpholine to give the title compound a colorless Obtained as a crystalline solid.
[0333]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.09 (s, 3H), 0.52-0.62 (m, 6H), 0.75 (s, 9H),
0.96 (t, 3H, J = 7Hz), 1.20 (s, 3H), 1.23 (s, 3H), 1.31 (s, 9H), 1.68 (s, 3H),
1.90-1.93 (m, 1H), 1.91 (s, 3H), 2.13-2.21 (m, 1H), 2.35-2.54 (m, 2H),
2.56 (s, 3H), 2.68 (t, 2H, J = 6Hz), 2.91 (t, 2H, J = 6Hz), 3.09-3.22 (m, 2H),
3.62-3.64 (m, 2H), 3.84 (d, 1H, J = 7Hz), 4.11-4.20 (m, 3H), 4.31 (d, 1H, J = 8Hz),
4.42 (dd, 1H, J = 7Hz, 10Hz), 4.54 (s, 1H), 4.95 (d, 1H, J = 8Hz), 5.34 (br, 1H),
5.41 (br, 1H), 5.67 (d, 1H, J = 7Hz), 6.33 (t, 1H, J = 8Hz), 7.27-7.37 (m, 5H),
7.47 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0334]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- [2- (3-thiazolidino) Ethyl] Baccatin III
The compound obtained in the above Step 1 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0335]
Melting point: 147-153 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20 (s, 3H), 1.21 (s, 3H), 1.35 (s, 9H), 1.68 (s, 3H), 1.78-1.85 (m, 1H),
1.87 (s, 3H), 2.28 (m, 2H), 2.36 (s, 3H), 2.51-2.59 (m, 1H),
2.68 (t, 2H, J = 5.5Hz), 2.90 (t, 2H, J = 5.5Hz), 3.10-3.19 (m, 2H),
3.66-3.70 (m, 1H), 3.77-3.80 (m, 1H), 3.85 (d, 1H, J = 7Hz), 4.12 (s, 2H),
4.17 (d, 1H, J = 8Hz), 4.21 (dd, 1H, J = 7Hz, 10Hz), 4.30 (d, 1H, J = 8Hz),
4.62 (s, 1H), 4.94 (d, 1H, J = 8Hz), 5.10 (s, 1H), 5.25 (br, 1H),
5.40 (d, 1H, J = 10Hz), 5.67 (d, 1H, J = 7Hz), 6.22 (t, 1H, J = 8Hz),
7.32-7.40 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.10 (d, 2H, J = 8Hz)
IR (KBr): 3456, 2980, 2940, 1722, 1768, 1604, 1586 cm-1
MS-FAB: 923 (MH+)
[0336]
Example 24
[0337]
Embedded image
Figure 0003921252
[0338]
Step 1: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-10-O- ( 2-Hydroxyethyl) -7-O-triethylsilylbaccatin III
550 mg of the compound obtained in Step 1 of Example 14 and 180 mg of N-methylmorpholine-N-oxide were dissolved in a mixed solvent of 40 ml of acetone and 10 ml of water, and 5 mg of osmium tetroxide was added at room temperature for 3 hours. Stir. Sodium sulfite was added, and anhydrous sodium sulfate was further added for 15 minutes. After stirring for 30 minutes, the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 40 ml of methanol, and a solution prepared by dissolving 219 mg of sodium metaperiodate in 10 ml of water was added dropwise under ice cooling, followed by stirring for 1 hour. A saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 20 ml of tetrahydrofuran, 48 mg of sodium borohydride was added, and the mixture was stirred for 15 minutes under ice cooling. 1N hydrochloric acid was added until it no longer foamed, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography (elution solvent; ethyl acetate: hexane = 1: 2 (v / v)) to give 278 mg of the title compound as a colorless amorphous solid. Obtained.
[0339]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.10 (s, 3H), 0.53-0.63 (m, 6H), 0.75 (s, 9H),
0.96 (t, 3H, J = 7Hz), 1.21 (s, 3H), 1.25 (s, 3H), 1.31 (s, 9H), 1.69 (s, 3H),
1.90-1.93 (m, 1H), 1.91 (s, 3H), 2.15-2.20 (m, 1H), 2.31-2.40 (m, 1H),
2.45-2.53 (m, 1H), 2.56 (s, 3H), 2.92 (br, 1H), 3.54-3.58 (m, 1H),
3.66-3.70 (m, 1H), 3.79 (m, 2H), 4.19 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.44 (dd, 1H, J = 7Hz, 10Hz), 4.53 (s, 1H), 4.95 (d, 1H, J = 8Hz), 5.01 (s, 1H),
5.33 (br, 1H), 5.41 (br, 1H), 5.67 (d, 1H, J = 7Hz), 6.33 (t, 1H, J = 8Hz),
7.27-7.39 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0340]
Step 2: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-10-O- [ 2- (p-Toluenesulfonyloxy) ethyl] -7-O-triethylsilylbaccatin III 260 mg of the compound obtained in the above step 2 and 0.067 ml of triethylamine are dissolved in 10 ml of methylene chloride and 118 mg of tosylic anhydride at room temperature. And stirred for 2 hours. The reaction solution was washed sequentially with a saturated aqueous sodium bicarbonate 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 chromatography (elution solvent; ethyl acetate: hexane = 1: 4 (v / v)) to obtain 257 mg of the title compound as a colorless amorphous solid.
[0341]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.08 (s, 3H), 0.52-0.60 (m, 6H), 0.75 (s, 9H),
0.94 (t, 3H, J = 7Hz), 1.10 (s, 3H), 1.16 (s, 3H), 1.31 (s, 9H), 1.66 (s, 3H),
1.87-1.90 (m, 1H), 1.89 (s, 3H), 2.10-2.19 (m, 1H), 2.32-2.40 (m, 1H),
2.45 (s, 3H), 2.45-2.49 (m, 1H), 2.55 (s, 3H), 3.66-3.69 (m, 1H),
3.77-3.80 (m, 2H), 4.12 (d, 1H, J = 8Hz), 4.16-4.24 (m, 2H), 4.30 (d, 1H, J = 8Hz),
4.41 (dd, 1H, J = 7Hz, 10Hz), 4.54 (s, 1H), 4.94 (d, 1H, J = 8Hz), 4.95 (s, 1H),
5.33 (br, 1H), 5.42 (br, 1H), 5.63 (d, 1H, J = 7Hz), 6.32 (t, 1H, J = 8Hz),
7.28-7.39 (m, 7H), 7.47 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 7.82 (d, 2H, J = 8Hz),
8.11 (d, 2H, J = 8Hz)
[0342]
Step 3: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-10-O- ( 2-Iodoethyl) -7-O- triethylsilylbaccatin III
200 mg of the compound obtained in the above step 2 was dissolved in 5 ml of acetonitrile, 121 mg of sodium iodide was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was 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 layer chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to obtain 184 mg of the title compound as a colorless amorphous solid.
[0343]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.09 (s, 3H), 0.56-0.61 (m, 6H), 0.75 (s, 9H),
0.97 (t, 3H, J = 7Hz), 1.22 (s, 3H), 1.26 (s, 3H), 1.31 (s, 9H), 1.68 (s, 3H),
1.89-1.92 (m, 1H), 1.90 (s, 3H), 2.11-2.20 (m, 1H), 2.33-2.41 (m, 1H),
2.46-2.56 (m, 1H), 2.57 (s, 3H), 3.30-3.37 (m, 2H), 3.66-3.70 (m, 1H),
3.82 (d, 1H, J = 7Hz), 3.85-3.88 (m, 1H), 4.19 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz),
4.44 (dd, 1H, J = 7Hz, 10Hz), 4.54 (s, 1H), 4.95 (d, 1H, J = 8Hz), 5.00 (s, 1H),
5.31 (br, 1H), 5.43 (br, 1H), 5.67 (d, 1H, J = 7Hz), 6.34 (t, 1H, J = 8Hz),
7.28-7.37 (m, 5H), 7.47 (t, 2H, J = 8Hz), 7.58 (t, 1H, J = 8Hz), 8.11 (d, 2H, J = 8Hz)
[0344]
Step 4: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-10-O- [ 2- (1-Imidazolyl) ethyl] -7-O-triethylsilylbaccatin III
[0345]
Method A
184 mg of the compound obtained in the above Step 3 was dissolved in 5 ml of acetonitrile, 20.4 mg of N-acetylimidazole was added and sealed, and stirred at 100 ° C. for 24 hours. The reaction solution was allowed to cool, 2 ml of a saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 20 minutes. Ethyl acetate and 20 ml of saturated aqueous sodium bicarbonate solution were added, the organic layer was 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 layer chromatography (developing solvent; chloroform: methanol = 20: 1 (v / v)) to obtain 26.5 mg of the title compound as a colorless amorphous solid.
[0346]
Method B
2.8 mg of sodium hydride was added to 0.5 ml of N, N-dimethylformamide, 7.8 mg of imidazole was added under nitrogen, and the mixture was stirred at 90 ° C. for 30 minutes. Next, a solution obtained by dissolving 115 mg of the compound obtained in the above Step 3 in 2 ml of N, N-dimethylformamide was added dropwise and stirred at the same temperature for 40 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water and saturated brine in that order, 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; chloroform: methanol = 20: 1 (v / v)) to obtain 35.5 mg of the title compound as a colorless amorphous solid.
[0347]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.30 (s, 3H), -0.10 (s, 3H), 0.48-0.59 (m, 6H), 0.75 (s, 9H),
0.93 (t, 3H, J = 7Hz), 1.09 (s, 3H), 1.13 (s, 3H), 1.30 (s, 9H), 1.68 (s, 3H),
1.88-1.94 (m, 1H), 1.85 (s, 3H), 2.09-2.19 (m, 1H), 2.32-2.38 (m, 1H),
2.44-2.49 (m, 1H), 2.56 (s, 3H), 3.66-3.73 (m, 1H), 3.79 (m, 2H),
4.15-4.25 (m, 2H), 4.30 (d, 1H, J = 8Hz), 4.40 (dd, 1H, J = 7Hz, 10Hz), 4.52 (s, 1H),
4.93 (s, 1H), 4.94 (d, 1H, J = 8Hz), 5.32 (br, 1H), 5.42 (br, 1H),
5.65 (d, 1H, J = 7Hz), 6.28 (t, 1H, J = 8Hz), 7.04 (s, 1H), 7.11 (s, 3H),
7.26-7.39 (m, 5H), 7.47 (t, 2H, J = 8Hz), 7.57-7.60 (m, 2H), 8.10 (d, 2H, J = 8Hz)
[0348]
Step 5: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-10-O- [2- (1-imidazolyl) Ethyl] Baccatin III
The compound obtained in Step 4 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0349]
Melting point: 163-169 ° C
1H-NMR (CDClThree/ TMS) δ (ppm):
1.11 (s, 3H), 1.14 (s, 3H), 1.33 (s, 9H), 1.67 (s, 3H), 1.69 (s, 3H),
1.85-1.90 (m, 1H), 2.25 (m, 2H), 2.33 (s, 3H), 2.45-2.54 (m, 1H), 3.60 (m, 1H),
3.77 (d, 1H, J = 7Hz), 3.93 (m, 1H), 4.10-4.24 (m, 4H), 4.27 (d, 1H, J = 8Hz),
4.61 (s, 1H), 4.86 (s, 1H), 4.93 (d, 1H, J = 8Hz), 5.20 (br, 1H),
5.55 (d, 1H, J = 10Hz), 5.63 (d, 1H, J = 7Hz), 6.17 (t, 1H, J = 8Hz), 6.97 (s, 1H),
7.02 (s, 1H), 7.29-7.38 (m, 5H), 7.48 (t, 2H, J = 8Hz), 7.55 (s, 1H),
7.60 (t, 1H, J = 8Hz), 8.08 (d, 2H, J = 8Hz)
IR (KBr): 3444, 3120, 3072, 2980, 2940, 1724, 1604, 1586 cm-1
MS-FAB: 902 (MH+)
[0350]
Example 25
[0351]
Embedded image
Figure 0003921252
[0352]
10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -4,10-dideacetyl-7-deoxy-4-O -Propionyl baccatin III
The compound obtained in Step 4 of Example 15 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless solid.
[0353]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.20-1.25 (m, 9H), 1.34 (s, 9H), 1.69 (s, 3H), 1.80-1.82 (m, 1H), 1.84 (s, 3H),
2.28 (m, 2H), 2.54-2.65 (m, 3H), 3.30 (br, 1H), 3.85 (d, 1H, J = 7Hz),
4.06 (dd, 1H, J = 6Hz, 13Hz), 4.16-4.21 (m, 3H), 4.31 (d, 1H, J = 8Hz), 4.62 (s, 1H),
4.89 (d, 1H, J = 8Hz), 5.03 (s, 1H), 5.22 (d, 1H, J = 10Hz), 5.24 (br, 1H),
5.29-5.40 (m, 2H), 5.69 (d, 1H, J = 7Hz), 5.89-5.99 (m, 1H), 6.22 (t, 1H, J = 8Hz),
7.32-7.41 (m, 5H), 7.49 (t, 2H, J = 8Hz), 7.61 (t, 1H, J = 8Hz), 8.12 (d, 2H, J = 8Hz)
[0354]
Example 26
[0355]
Embedded image
Figure 0003921252
[0356]
Step 1: 10-O-allyl-10-deacetyl-7-deoxybaccatin III
10-Deacetyl-7-deoxybaccatin III was reacted in the same manner as in Step 1 of Example 1 to obtain the title compound as a white solid.
[0357]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.07 (s, 3H), 1.16 (s, 3H), 1.52 (dd, J = 4.0Hz, 12.0Hz, 1H), 1.68 (s, 1H),
1.74 (s, 3H), 2.02 (s, 3H), 1.19-2.12 (m, 4H), 2.24 (dd, J = 6.4Hz, 15.6Hz, 1H),
2.28 (s, 3H), 2.33 (dd, J = 6.8Hz, 15.6Hz, 1H), 3.87 (d, J = 7.3Hz, 1H),
4.06-4.18 (m, 2H), 4.20 (d, J = 8.3Hz, 1H), 4.31 (d, J = 8.3Hz, 1H), 4.89 (s, 1H),
4.96 (dd, J = 2.5Hz, 9.5Hz, 1H), 5.22 (d, J = 10.2Hz, 1H), 5.07 (s, 1H),
5.31 (d, J = 15.6Hz, 1H), 5.63 (d, J = 7.3Hz, 1H), 5.90-6.03 (m, 1H),
7.48 (t, J = 7.3Hz, 2H), 7.60 (t, J = 7.3Hz, 1H), 8.12 (d, J = 7.3Hz, 2H)
[0358]
Step 2: 10-O-allyl-10-deacetyl-7-deoxy-13-O-triethylsilylbaccatin III
To a solution of 1.60 g of the compound obtained in the above Step 1 in 24 ml of N, N-dimethylformamide, 1.91 g of imidazole and 4.71 ml of triethylchlorosilane were added at room temperature, followed by stirring for 25 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (elution solvent; hexane: ethyl acetate = 5: 1-3: 1 (v / v)) to obtain 1.75 g of the title compound as a white solid.
[0359]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.67 (q, J = 7.8Hz, 6H), 1.02 (t, J = 7.8Hz, 9H), 1.12 (s, 3H), 1.15 (s, 3H),
1.52 (dd, J = 4.9Hz, 11.7Hz, 1H), 1.62 (s, 1H), 1.74 (s, 3H), 1.97 (s, 3H),
1.90-2.33 (m, 5H), 2.28 (s, 3H), 3.78 (d, J = 7.3Hz, 1H), 4.06-4.17 (m, 2H),
4.20 (d, J = 8.3Hz, 1H), 4.31 (d, J = 8.3Hz, 1H), 4.95 (t, J = 9.8Hz, 1H),
4.96 (dd, J = 2.5Hz, 9.5Hz, 1H), 5.05 (s, 1H), 5.22 (d, J = 12.2Hz, 1H),
5.30 (d, J = 16.9Hz, 1H), 5.61 (d, J = 7.3Hz, 1H), 5.90-6.04 (m, 1H),
7.47 (t, J = 7.3Hz, 2H), 7.59 (t, J = 7.3Hz, 1H), 8.10 (d, J = 7.3Hz, 2H)
[0360]
Step 3: 10-O-allyl-10-deacetyl-1-O-dimethylsilyl-7-deoxy-13-O-triethylsilylbaccatin III
To a solution of 460 mg of N, N-dimethylformamide in 460 mg obtained in Step 2 above, 183 mg of imidazole and 300 μl of dimethylchlorosilane were added at 0 ° C. and stirred for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 20 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 column chromatography (elution solvent; hexane: ethyl acetate = 3: 1 (v / v)) to obtain 465 mg of the title compound as a white solid.
[0361]
1H-NMR (CDClThree/ TMS) δ (ppm):
-0.27 (d, J = 2.9Hz, 3H), 0.08 (d, J = 2.9Hz, 3H), 0.70 (q, J = 7.8Hz, 6H),
1.04 (t, J = 7.8Hz, 9H), 1.15 (s, 3H), 1.08 (s, 3H), 1.85 (s, 3H),
1.96 (s, 3H), 1.40-2.50 (m, 6H), 2.28 (s, 3H), 3.70-3.79 (m, 1H),
4.05-4.18 (m, 2H), 4.25 (d, J = 8.3Hz, 1H), 4.29 (d, J = 8.3Hz, 1H),
4.50-4.57 (m, 1H), 4.92-5.01 (m, 1H), 5.01 (s, 1H), 5.21 (d, J = 10.5Hz, 1H),
5.30 (d, J = 15.6Hz, 1H), 5.69 (d, J = 7.3Hz, 1H), 5.90-6.05 (m, 1H),
7.58 (t, J = 7.3Hz, 1H), 8.10 (d, J = 7.3Hz, 2H)
[0362]
Step 4: 10-O-allyl-7-deoxy-4,10-dideacetyl-4-O-propionylbaccatin III
To a solution of 465 mg of the compound obtained in Step 3 above in 9.0 ml of tetrahydrofuran was added 940 μl of a bis (2-methoxyethoxy) aluminum hydride 65% (w / v) toluene solution at 0 ° C. and stirred for 2 hours. Ethyl acetate, an aqueous sodium potassium tartrate solution and water were added to the reaction mixture, and the mixture was stirred for 15 minutes and then separated. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified using silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4: 1 (v / v)) to obtain 240 mg of a crude product as a white solid. To a solution of 240 mg of the crude product in 6.0 ml of tetrahydrofuran, 550 μl of lithium bis (trimethylsilyl) amide 1M tetrahydrofuran solution was added at −48 ° C. and stirred for 15 minutes, and then 47.0 μl of propionyl chloride was added and stirred for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 285 mg of the residue. To a solution of 285 mg of the obtained residue in 4.0 ml of pyridine, 1.0 ml of hydrogen fluoride pyridine was added at 0 ° C. and stirred at room temperature for 18 hours. The reaction mixture was poured into a stirring mixture of ethyl acetate and ice water, the phases were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 1: 1 (v / v)) to obtain 37.0 mg of the title compound as a white solid.
[0363]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.10-1.40 (m, 3H), 1.09 (s, 3H), 1.07 (s, 3H), 1.74 (s, 3H), 2.02 (s, 3H),
1.50-2.40 (m, 7H), 2.52-2.76 (m, 2H), 3.87 (d, J = 7.3Hz, 1H), 4.05-4.18 (m, 2H),
4.20 (d, J = 8.3Hz, 1H), 4.32 (d, J = 8.3Hz, 1H), 4.82 (s, 1H), 4.88 (s, 1H),
4.92 (d, J = 9.3Hz, 1H), 5.07 (s, 1H), 5.22 (d, J = 10.3Hz, 1H),
5.30 (d, J = 17.1Hz, 1H), 5.63 (d, J = 7.3Hz, 1H), 5.85-6.05 (m, 1H),
7.47 (t, J = 7.3Hz, 2H), 7.60 (t, J = 7.3Hz, 1H), 8.13 (d, J = 7.3Hz, 2H)
[0364]
Step 5: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4 , 10-Dideacetyl-7-deoxy-4-O-propionylbaccatin III
The compound obtained in Step 4 above and (3R, 4S) -1- (tert-butoxycarbonyl) -4- (2-furyl) -3- (triisopropylsilyloxy) azetidin-2-one were used in the steps of Example 3. The reaction was carried out in the same manner as in 4 to give the title compound as a colorless amorphous solid.
[0365]
1H-NMR (CDClThree/ TMS) δ (ppm):
0.90-1.05 (m, 18H), 1.15-1.40 (m, 12H), 1.33 (s, 9H), 1.73 (s, 1H), 1.76 (s, 3H),
1.50-1.80 (m, 2H), 1.88 (s, 3H), 1.95-2.12 (m, 2H), 2.18-2.45 (m, 2H),
2.75 (q, J = 7.3Hz, 2H), 3.80 (d, J = 7.3Hz, 1H), 4.08-4.16 (m, 2H),
4.24 (d, J = 7.8Hz, 1H), 4.33 (d, J = 7.8Hz, 1H), 4.92 (d, J = 7.3Hz, 1H), 4.98 (s, 1H),
5.04 (s, 1H), 5.18-5.37 (m, 4H), 5.69 (d, J = 7.3Hz, 1H), 5.90-6.03 (m, 1H),
6.15-6.25 (m, 1H), 6.27 (d, J = 2.5Hz, 1H), 6.37 (d, J = 2.5Hz, 1H), 7.40 (s, 1H),
7.47 (t, J = 7.3Hz, 2H), 7.57 (t, J = 7.3Hz, 1H), 8.13 (d, J = 7.3Hz, 2H)
[0366]
Step 6: 10-O-allyl-13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4,10-dideacetyl- 7-Deoxy-4-O-propionylbaccatin III
The compound obtained in Step 5 was reacted in the same manner as in Step 7 of Example 3 to obtain the title compound as a colorless amorphous solid.
[0367]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.18-1.30 (m, 3H), 1.22 (s, 3H), 1.26 (s, 3H), 1.32 (s, 9H),
1.54 (dd, J = 4.6Hz, 12.3Hz, 1H), 1.73 (s, 1H), 1.76 (s, 3H), 1.86 (s, 3H),
1.77-2.12 (m, 2H), 2.17-2.32 (m, 2H), 2.43 (dd, J = 9.3Hz, 15.1Hz, 1H),
2.62-2.80 (m, 2H), 3.39 (d, J = 5.9Hz, 1H), 3.77 (d, J = 7.3Hz, 1H), 4.07-4.17 (m, 2H)
,
4.22 (d, J = 8.5Hz, 1H), 4.33 (d, J = 8.5Hz, 1H), 4.70 (d, J = 7.3Hz, 1H),
4.90 (dd, J = 2.2Hz, 9.5Hz, 1H), 5.03 (s, 1H), 5.15-5.35 (m, 4H),
5.68 (d, J = 7.3Hz, 1H), 5.90-6.02 (m, 1H), 6.37 (t, J = 8.8Hz, 1H),
6.44 (d, J = 2.9Hz, 1H), 6.49 (dd, J = 1.9Hz, 2.9Hz, 1H), 7.44 (brs, 1H),
7.49 (t, J = 7.8Hz, 2H), 7.60 (t, J = 7.8Hz, 1H), 8.15 (d, J = 7.8Hz, 2H).
[0368]
Step 7: 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxypropionyl] -4,10-dideacetyl-7-deoxy-4- O-propionyl-10-O- (2-thiomorpholinoethyl) baccatin III
The compound obtained in the above Step 6 was reacted in the same manner as in Step 1 of Example 2, and then reacted using thiomorpholine instead of morpholine in the same manner as in Step 2 of Example 2 to obtain the title compound as a colorless solid. .
[0369]
1H-NMR (CDClThree/ TMS) δ (ppm):
1.18-1.32 (m, 3H), 1.17 (s, 3H), 1.21 (s, 3H), 1.32 (s, 9H),
1.54 (dd, J = 5.7Hz, 11.9Hz), 1.73 (s, 1H), 1.75 (s, 3H), 1.89 (s, 3H),
1.92-2.12 (m, 2H), 2.19-2.32 (m, 2H), 2.42 (dd, J = 9.3Hz, 15.1Hz, 1H),
2.62-2.78 (m, 8H), 2.78-2.90 (m, 4H), 3.56-3.74 (m, 2H), 3.77 (d, J = 7.3Hz, 1H),
4.22 (d, J = 8.3Hz, 1H), 4.33 (d, J = 8.3Hz, 1H), 4.71 (d, J = 2.0Hz, 1H),
4.89 (dd, J = 2.2Hz, 9.6Hz, 1H), 5.03 (s, 1H), 5.18 (d, J = 9.8Hz, 1H),
5.32 (d, J = 10.7Hz, 1H), 5.67 (d, J = 7.3Hz, 1H), 6.26 (t, J = 8.8Hz, 1H),
6.45 (d, J = 2.9Hz, 1H), 6.49 (dd, J = 1.5Hz, 2.9Hz, 1H), 7.44 (brs, 1H),
7.49 (t, J = 7.8Hz, 2H), 7.60 (t, J = 7.8Hz, 1H), 8.15 (d, J = 7.8Hz, 2H)
[0370]
【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 that of the control group.50 It was shown as a value (ng / ml).
[0371]
[Table 1]
Figure 0003921252
[0372]
The compound of the present invention not only shows a strong antitumor effect, but also has excellent water solubility, and the solubility in 1 ml of water is as follows (our experimental data).
[0373]
Taxotere about 0.003 mg / ml
Compound of Example 10 13.0 mg / ml

Claims (23)

一般式(I)
Figure 0003921252
[式中、
はフェニル基
(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もよい。)を意味する。
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
(これらアルキル基、アルケニル基、アルキニル基、シクロアルキル基またはアルコキシル基は、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もよい。)
を意味する。
は水酸基、水素原子またはハロゲン原子を意味する。また、R は、8位に結合しているメチル基と一緒になって次の部分構造を形成してもよい。
Figure 0003921252
、C 〜C アルキル基(C 〜C アルキル基は、アミノ基、C 〜C アルキルアミノ基および複素環基(ここで、複素環基は、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、チアゾリジン、チオモルホリン、チオモルホリン−1−オキサイド、インドリジン、インドール、ナフチリジン、キノキサリンまたはキナゾリンから導かれる置換基からなる群から選択される。なお、複素環基はさらにC 〜C アルキル基を置換基として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個または複数個有する。)またはC 〜C アルケニル基を意味する。
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する。
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する。
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
(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、または複素環基は、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、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。)を意味する。
はアルキル基、アリール基またはアルコキシル基
(これらアルキル基、アリール基またはアルコキシル基は、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、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。)を意味する。]で表される化合物およびその塩
Formula (I)
Figure 0003921252
[Where:
R 1 represents a phenyl group (the phenyl group may have one or a plurality of substituents selected from the group consisting of a halogen atom, an alkyl group, and an alkoxyl group).
R 2 represents an alkyl group, alkenyl group, alkynyl group, cycloalkyl group or alkoxyl group (these alkyl group, alkenyl group, alkynyl group, cycloalkyl group or alkoxyl group are a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, One or a plurality of groups selected from the group consisting of a 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 may be included as a substituent. .)
Means.
R 3 means a hydroxyl group, a hydrogen atom or a halogen atom. R 3 may form the following partial structure together with a methyl group bonded to the 8-position.
Figure 0003921252
R 4 is a C 1 -C 3 alkyl group (C 1 -C 3 alkyl group is an amino group, C 1 -C 3 alkylamino group and a heterocyclic group (wherein the heterocyclic group is pyrrole, pyrrolidine, imidazole) , Pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, thiazolidine, thiomorpholine, thiomorpholine-1-oxide, indolizine, indole , Naphthyridine, quinoxaline or quinazoline, wherein the heterocyclic group may further have one or more C 1 -C 3 alkyl groups as substituents. A group selected from the group consisting of Or a C 3 -C 6 alkenyl group .
R 5 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
R 6 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
R 7 represents 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, or heterocyclic group are a halogen atom, Hydroxyl group, carboxyl group, alkyl group, alkoxyl group, aryloxy group, phenyl group, amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, alkoxycarbonyl group, aryloxycarbonyl group, acyl group, acylamino group and acyloxy Or a group selected from the group consisting of groups may have one or more substituents.
R 8 represents an alkyl group, an aryl group or an alkoxyl group (these alkyl group, aryl group or alkoxyl group are a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, or an alkylamino group. , An aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group may have one or more substituents as a substituent. Means. And a salt thereof
およびRがフッ素原子である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 5 and R 6 are fluorine atoms, and salts thereof. が水酸基であり、Rが水素原子である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 5 is a hydroxyl group, and R 6 is a hydrogen atom, and a salt thereof. が水酸基であり、Rがメチル基である請求項1記載の化合物およびその塩2. The compound according to claim 1, wherein R 5 is a hydroxyl group, and R 6 is a methyl group. がフェニル基である請求項1記載の化合物およびその塩The compound or a salt thereof according to claim 1, wherein R 8 is a phenyl group. が第三級ブトキシ基である請求項1記載の化合物およびその塩The compound or a salt thereof according to claim 1, wherein R 8 is a tertiary butoxy group. がフェニル基である請求項1記載の化合物およびその塩The compound or a salt thereof according to claim 1, wherein R 7 is a phenyl group. が複素環基である請求項1記載の化合物およびその塩The compound or a salt thereof according to claim 1, wherein R 7 is a heterocyclic group. が単環性の複素環基である請求項1記載の化合物およびその塩The compound or a salt thereof according to claim 1, wherein R 7 is a monocyclic heterocyclic group. が単環性の5員環または6員環の大きさの複素環基である請求項1記載の化合物およびその塩The compound or a salt thereof according to claim 1, wherein R 7 is a monocyclic heterocyclic group having a size of 5 or 6 members. が単環性の5員環または6員環の大きさで、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個含む複素環基である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 7 is a monocyclic 5-membered or 6-membered ring and a heterocyclic group containing one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure. Its salt が単環性の5員環または6員環の大きさで、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である請求項1記載の化合物およびその塩2. R 7 is a monocyclic 5-membered or 6-membered ring and an unsaturated heterocyclic group containing one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure. And its salts がフリル基、ピリジル基またはピロリル基である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 7 is a furyl group, a pyridyl group or a pyrrolyl group, and a salt thereof. が2−メチル−1−プロペニル基である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 7 is a 2-methyl-1-propenyl group, and a salt thereof. が炭素数1から6のアルキル基である請求項1記載の化合物およびその塩The compound and the salt thereof according to claim 1, wherein R 2 is an alkyl group having 1 to 6 carbon atoms. が炭素数1から6のアルコキシル基である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 2 is an alkoxyl group having 1 to 6 carbon atoms, and a salt thereof. が炭素数3から6のシクロアルキル基である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 2 is a cycloalkyl group having 3 to 6 carbon atoms. がメチル基、エチル基またはプロピル基である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 2 is a methyl group, an ethyl group or a propyl group, and a salt thereof. がメトキシ基またはエトキシ基である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 2 is a methoxy group or an ethoxy group, and a salt thereof. がシクロプロピル基である請求項1記載の化合物およびその塩The compound according to claim 1, wherein R 2 is a cyclopropyl group, and a salt thereof. がフェニル基、Rがメチル基、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、Rが水素原子または水酸基、Rがアリル基、モルホリノエチル基またはチオモルホリノエチル基、Rが水酸基、Rが水素原子、Rがフェニル基、フリル基または2−メチル−1−プロペニル基、Rが第三級ブトキシ基である請求項1記載の化合物およびその塩R 1 is phenyl group, R 2 is methyl group, ethyl group, propyl group, methoxy group, ethoxy group or cyclopropyl group, R 3 is hydrogen atom or hydroxyl group, R 4 is allyl group, morpholinoethyl group or thiomorpholinoethyl group Wherein R 5 is a hydroxyl group, R 6 is a hydrogen atom, R 7 is a phenyl group, a furyl group or a 2-methyl-1-propenyl group, and R 8 is a tertiary butoxy group, and a salt thereof 一般式(I)Formula (I)
Figure 0003921252
Figure 0003921252
[式中、[Where:
R 1 はフェニル基Is a phenyl group
(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もよい。)を意味する。(This phenyl group may have one or more groups selected from the group consisting of a halogen atom, an alkyl group and an alkoxyl group as a substituent).
R 2 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Is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group or alkoxyl group
(これらアルキル基、アルケニル基、アルキニル基、シクロアルキル基またはアルコキシル基は、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もよい。)(These alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups or alkoxyl groups are halogen atoms, hydroxyl groups, carboxyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, alkylamino groups, alkoxycarbonyl groups, aryloxy groups. (You may have one or more groups as substituents selected from the group consisting of a carbonyl group, an acyl group, an acylamino group, and an acyloxy group.)
を意味する。Means.
R 3 は水酸基、水素原子またはハロゲン原子を意味する。また、RMeans a hydroxyl group, a hydrogen atom or a halogen atom. R 3 は、8位に結合しているメチル基と一緒になって次の部分構造を形成してもよい。May form the following partial structure together with the methyl group bonded to the 8-position.
Figure 0003921252
Figure 0003921252
R 4 は、CIs C 1 〜C~ C 3 アルキル基(CAlkyl group (C 1 〜C~ C 3 アルキル基は、CThe alkyl group is C 1 〜C~ C 3 アルキルアミノ基および複素環基(ここで、複素環基は、式An alkylamino group and a heterocyclic group (wherein the heterocyclic group has the formula
Figure 0003921252
Figure 0003921252
(Xは酸素原子、硫黄原子、S=O、CH(X is an oxygen atom, a sulfur atom, S = O, CH 2 、CH−Y、NHまたはN−Yを意味し、YはC, CH-Y, NH or N-Y, where Y is C 1 〜C~ C 3 アルキル基を意味する。)で表される、窒素原子を含む5員環または6員環の大きさの飽和の複素環基(該複素環基は、その環の構成成分である炭素原子上にCAn alkyl group is meant. And a saturated heterocyclic group having a size of a 5- or 6-membered ring containing a nitrogen atom (the heterocyclic group is a C atom on a carbon atom that is a constituent of the ring). 1 〜C~ C 3 アルキル基を1個または複数個有していてもよい。)またはピリジル基を意味する。)からなる群から選ばれる基を置換基として1個または複数個有する。)またはCIt may have one or more alkyl groups. ) Or a pyridyl group. 1 or more as a substituent. ) Or C 3 〜C~ C 6 アルケニル基を意味する。An alkenyl group is meant.
R 5 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する。Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
R 6 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する。Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
R 7 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Is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, or heterocyclic group
(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、または複素環基は、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、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、アミノアルキル基、ア(These alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, or heterocyclic groups are halogen atoms, hydroxyl groups, carboxyl groups, alkyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, alkylamino groups. Group, aminoalkyl group, a 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。)を意味する。One or a plurality of groups selected from the group consisting of 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. ).
R 8 はアルキル基、アリール基またはアルコキシル基Is an alkyl group, aryl group or alkoxyl group
(これらアルキル基、アリール基またはアルコキシル基は、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、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。)を意味する。]で表される化合物およびその塩(These alkyl groups, aryl groups or alkoxyl groups are halogen atoms, hydroxyl groups, carboxyl groups, alkyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, alkylamino groups, aminoalkyl groups, alkylaminoalkyl groups, alkoxy groups. Or a group selected from the group consisting of a carbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group. And a salt thereof
一般式(I)Formula (I)
Figure 0003921252
Figure 0003921252
[式中、[Where:
R 1 はフェニル基Is a phenyl group
(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もよい。)を意味する。(This phenyl group may have one or more groups selected from the group consisting of a halogen atom, an alkyl group and an alkoxyl group as a substituent).
R 2 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Is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group or alkoxyl group
(これらアルキル基、アルケニル基、アルキニル基、シクロアルキル基またはアルコキシル基は、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もよい。)(These alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups or alkoxyl groups are halogen atoms, hydroxyl groups, carboxyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, alkylamino groups, alkoxycarbonyl groups, aryloxy groups. (You may have one or more groups as substituents selected from the group consisting of a carbonyl group, an acyl group, an acylamino group, and an acyloxy group.)
を意味する。Means.
R 3 は水酸基、水素原子またはハロゲン原子を意味する。また、RMeans a hydroxyl group, a hydrogen atom or a halogen atom. R 3 は、8位に結合しているメチル基と一緒になって次の部分構造を形成してもよい。May form the following partial structure together with the methyl group bonded to the 8-position.
Figure 0003921252
Figure 0003921252
R 4 は、CIs C 1 〜C~ C 3 アルキル基(CAlkyl group (C 1 〜C~ C 3 アルキル基は、CThe alkyl group is C 1 〜C~ C 3 アルキルアミノ基および複素環基(ここで、複素環基は、モルホリノ基、チオモルホリノ基、ピペリジノ基、ピロリジノ基、チオモルホリノ−1−オキシド基、ピリジル基、チアゾリジノ基またはイミダゾリル基を意味する。)からなる群から選ばれる基を置換基として1個または複数個有する。)またはアリル基を意味する。An alkylamino group and a heterocyclic group (wherein the heterocyclic group means a morpholino group, a thiomorpholino group, a piperidino group, a pyrrolidino group, a thiomorpholino-1-oxide group, a pyridyl group, a thiazolidino group or an imidazolyl group); It has one or more groups selected from the group consisting of as substituents. ) Or an allyl group.
R 5 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する。Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
R 6 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する。Means a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
R 7 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Is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, or heterocyclic group
(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、ま(These alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, たは複素環基は、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、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。)を意味する。Alternatively, the heterocyclic group includes a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxy group. One or more groups selected from the group consisting of a carbonyl group, an acyl group, an acylamino group, and an acyloxy group may be included as a substituent. ).
R 8 はアルキル基、アリール基またはアルコキシル基Is an alkyl group, aryl group or alkoxyl group
(これらアルキル基、アリール基またはアルコキシル基は、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、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。)を意味する。]で表される化合物およびその塩(These alkyl groups, aryl groups or alkoxyl groups are halogen atoms, hydroxyl groups, carboxyl groups, alkyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, alkylamino groups, aminoalkyl groups, alkylaminoalkyl groups, alkoxy groups. Or a group selected from the group consisting of a carbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, and an acyloxy group. And a salt thereof
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