JP4012293B2 - 16-ene-vitamin D derivative - Google Patents
16-ene-vitamin D derivative Download PDFInfo
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- JP4012293B2 JP4012293B2 JP35093897A JP35093897A JP4012293B2 JP 4012293 B2 JP4012293 B2 JP 4012293B2 JP 35093897 A JP35093897 A JP 35093897A JP 35093897 A JP35093897 A JP 35093897A JP 4012293 B2 JP4012293 B2 JP 4012293B2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Description
【0001】
【発明が属する技術分野】
本発明は、ビタミンDレセプターに対する結合能が高く、カルシウム上昇作用の弱い、新規なビタミンD誘導体に関し、抗腫瘍剤、抗リウマチ剤等の医薬として有用な化合物および該化合物の合成に有用な新規合成中間体に関する。
【0002】
【従来の技術】
1α,25−ジヒドロキシビタミンD3をはじめとする活性型ビタミンD3はカルシウム代謝調節作用の他、腫瘍細胞の増殖抑制作用や分化誘導作用、免疫調節作用など多くの生理活性を有することが知られている。しかしながら、活性型ビタミンD3のなかには、長期かつ連続的な投与により、高カルシウム血症を起こすという欠点を有している化合物が存在し、このような化合物は抗腫瘍剤、抗リウマチ剤等の使用には適さない。したがって、これらビタミンD類の作用の分離を目的として数多くのビタミンD誘導体が合成が研究されている。
【0003】
このような化合物として、例えば特開昭61−267550号公報には1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルオキシ)−9,10−セコプレグナ−5,7,10(19)−トリエンが、また特開平7−330714号公報には、22位が硫黄原子で置換されたビタミンD誘導体等が開示されている。
【0004】
また特開平2−9861号公報、同3−17019号公報、同7−188159号公報、同6−40975号公報、同7−179418号公報、米国特許5087619号公報および同5145846号公報等には、ビタミンD誘導体の16位に二重結合を有する種々の化合物が記載されている。しかしながら、これらの化合物がカルシウム上昇作用が弱い旨の記載は何らなされていない。
【0005】
【発明が解決しようとする課題】
これら公知のビタミンD化合物は、いずれもビタミンDレセプターに対する結合能力は高いが、同時にカルシウム上昇作用も高いものであったり、逆にカルシウム上昇作用は低いが、ビタミンDレセプターに対する結合能力が満足のいけるものではないものが多く、ビタミンDレセプターに対する結合能力が高く、かつカルシウム上昇作用が低い、有望な化合物の出現が望まれている。
【0006】
【発明を解決するための手段】
本発明者等はこれらの課題に鑑み、ビタミンDレセプターに対する結合能力が高く、かつカルシウム上昇作用が低い化合物について鋭意研究を重ねた結果、一般式(1):
【化14】
(式中、Xは酸素原子またはイオウ原子を示し、R11は水酸基または保護された水酸基で置換されていてもよい飽和または不飽和の脂肪族炭化水素基、あるいは−COR12基(式中R12はアルキル基、アリール基またはアルコキシ基を示す)を意味し、R2は−OR9又は水素原子を示し、R9およびR10は同一または異なって水素原子または保護基を示す)で表される化合物が高いビタミンDレセプター結合能をもち、カルシウム上昇作用も低いことを見出し、本発明に至った。
【0007】
本発明の一つの側面によれば、一般式(1):
【化15】
(式中、Xは酸素原子またはイオウ原子を示し、R11は水酸基又は保護された水酸基で置換されていてもよい飽和または不飽和の脂肪族炭化水素基、あるいは−COR12基(式中R12はアルキル基、アリール基またはアルコキシ基を示す)を意味し、R2は−OR9又は水素原子を示し、R9およびR10は同一または異なって水素原子または保護基を示す)で表されるビタミンD誘導体が提供される。
【0008】
一般式(1)において、好ましくはR2は−OR9である。
一般式(1)において、好ましくはR11は水酸基で置換されていてもよい炭素数1〜15の飽和の脂肪族炭化水素基である。
一般式(1)において、好ましくはR11は水酸基で置換されていてもよい炭素数2〜15の不飽和の脂肪族炭化水素基である。
【0009】
一般式(1)において、好ましくはR11は基(2):
【化16】
(式中、R3およびR4は同一または異なって水素原子または水酸基を示すか、一緒になって、酸素原子を有し=Oを示す。ただし、R3とR4が同時に水酸基となることはない。R5およびR6は水素原子または水酸基を示すが、R6はR3またはR4と同時に水酸基となることはない。mは1〜4の整数を示し、nは0〜2の整数を示す)または基(3):
【化17】
(式中R5およびR6は同一または異なって水素原子または水酸基を示す。R7およびR8は水素原子または一緒になって共有結合を示す。pは1〜3の整数を示し、qは0〜2の整数を示す)である。
【0010】
一般式(1)において、特に好ましくはR11は3−ヒドロキシ−3−メチルブチル基である。
一般式(1)で表される化合物の一つの態様では、20位がS配置である。
一般式(1)で表される化合物の別の態様では、20位がR配置である。
【0011】
一般式(1)で表される化合物の具体例としては、1,3−ジヒドロキシ−20−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンがある。この化合物のさらに立体的に特定された具体例としては、1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンおよび1α,3β−ジヒドロキシ−20(R)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンがある。
一般式(1)で表される化合物の別の具体例としては、1α,3β−ジヒドロキシ−20(R)−((E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンおよび1α,3β−ジヒドロキシ−20(R)−((E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンがある。
一般式(1)で表される化合物の別の具体例としては、1α,3β−ジヒドロキシ−20(S)−(2−ヒドロキシ−2−メチルプロピルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(R)−(2−ヒドロキシ−2−メチルプロピルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(S)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(S)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(S)−(2−エチル−2−ヒドロキシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(R)−(2−エチル−2−ヒドロキシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンがある。
【0012】
本発明の別の側面によれば、一般式(4):
【化18】
(式中、Xは酸素原子またはイオウ原子を示し、R11は水酸基または保護された水酸基で置換されていてもよい飽和または不飽和の脂肪族炭化水素基、あるいは−COR12基(式中、R12はアルキル基、アリール基またはアルコキシ基を示す)を意味し、R9およびR10は同一または異なって、水素原子または保護基を示す)で表される化合物が提供される。
【0013】
一般式(4)において、好ましくはR11は水酸基で置換されていてもよい炭素数1〜15の飽和の脂肪族炭化水素基である。
一般式(4)において、好ましくはR11は水酸基で置換されていてもよい炭素数2〜15の不飽和の脂肪族炭化水素基である。
【0014】
一般式(4)において、好ましくはR11は基(2):
【化19】
(式中、R3およびR4は同一または異なって水素原子または水酸基を示すか、一緒になって、酸素原子を有し=Oを示す。ただし、R3とR4が同時に水酸基となることはない。R5およびR6は水素原子または水酸基を示すが、R6はR3またはR4と同時に水酸基となることはない。mは1〜4の整数を示し、nは0〜2の整数を示す)または基(3):
【化20】
(式中R5およびR6は同一または異なって水素原子または水酸基を示す。R7およびR8は水素原子または一緒になって共有結合を示す。pは1〜3の整数を示し、qは0〜2の整数を示す)である。
一般式(4)において、特に好ましくはR11は3−ヒドロキシ−3−メチルブチル基である。
【0015】
本発明の別の側面によれば、一般式(24):
【化21】
(式中、R9およびR10は同一または異なって水素原子または保護基を示す)で表される化合物が提供される。
本発明のさらに別の側面によれば、一般式(5):
【化22】
(式中、R9およびR10は同一または異なって水素原子または保護基を示し、式中の共役二重結合は保護基により保護されていてもよい)で表される化合物が提供される。
【0016】
本発明のさらに別の側面によれば、一般式(6):
【化23】
(式中、R9およびR10は同一または異なって水素原子または保護基を示す)で表される化合物が提供される。
【0017】
本発明のさらに別の側面によれば、一般式(7):
【化24】
(式中、R9およびR10は同一または異なって水素原子または保護基を示す)で表される化合物が提供される。
【0018】
本発明のさらに別の側面によれば、一般式(4a):
【化25】
(式中、Xは酸素原子またはイオウ原子を示し、R1は保護基を有していてもよい水酸基で置換されていてもよい飽和または不飽和の脂肪族炭化水素基、あるいは−COR12基(式中R12はアルキル基、アリール基またはアルコキシ基を示す)を意味し、R9およびR10は同一または異なって、水素原子または保護基を示す)で表される化合物を光反応、熱異性化反応および脱保護反応に付すことを特徴とする、一般式(1):
【化26】
(式中、Xは酸素原子又はイオウ原子を示し、R11は水酸基又は保護された水酸基で置換されていてもよい飽和または不飽和の脂肪族炭化水素基、あるいは−COR12基(式中R12はアルキル基、アリール基又はアルコキシ基を示す)を意味し、R2は−OR9又は水素原子を示し、R9及びR10は同一又は異なって水素原子又は保護基を示す)で表されるビタミンD誘導体の製造方法が提供される。
本発明のさらに別の側面によれば、上記一般式(1)で表されるビタミンD誘導体を含むことを特徴とする医薬が提供される。
【0019】
【発明の実施の形態】
本発明において使用される用語は、特別に定義しないかぎり、以下の意味を表す。
飽和の脂肪族炭化水素基とは、一般的には炭素数1〜15の直鎖または分岐鎖状のアルキル基を示し、例えばメチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、s−ブチル基、i−ブチル基、t−ブチル基のほか、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デカニル基等が挙げられ、好ましくは3−メチルブチル基、3−エチルペンチル基、4−メチルペンチル基、3−(n−プロピル)ヘキシル基、4−エチルヘキシル基、5−メチルヘキシル基、6−メチルヘプチル基、5−エチルヘプチル基、4−(n−プロピル)ヘプチル基などが挙げられ、さらに好ましくは3−メチルブチル基、3−エチルペンチル基、4−メチルペンチル基などが挙げられる。
【0020】
不飽和の脂肪族炭化水素基とは、一般的には炭素数2〜15の直鎖または分岐鎖のアルケニル基またはアルキニル基を示し、例えば、2−プロペニル基、2−ブテニル基、3−ブテニル基、2−ペンテニル基、3−ペンテニル基、4−ペンテニル基、2−ヘキセニル基、3−ヘキセニル基、4−ヘキセニル基、5−ヘキセニル基、2−ヘプテニル基、3−ヘプテニル基、4−ヘプテニル基、5−ヘプテニル基、6−ヘプテニル基、2−プロピニル基、2−ブチニル基、3−ブチニル基、2−ペンチニル基、3−ペンチニル基、4−ペンチニル基、2−ヘキシニル基、3−ヘキシニル基、4−ヘキシニル基、5−ヘキシニル基、2−ヘプチニル基、3−ヘプチニル基、4−ヘプチニル基、5−ヘプチニル基、6−ヘプチニル基等が挙げられ、任意の水素原子が1以上の前述したアルキル基で置換されていてもよく、二重結合に関してはシスまたはトランス何れでもよい。好ましくは、4−メチル−2−ペンチニル基、4−エチル−2−ヘキシニル基、4−メチル−2−ペンテニル基、4−エチル−2−ヘキセニル基などが挙げられる。
【0021】
また水酸基で置換されていてもよい飽和または不飽和の脂肪族炭化水素基とは、前記の飽和または不飽和の炭化水素基の任意の水素原子が1以上の水酸基で置換されていてもよい基を意味し、置換している水酸基の数の例としては、0,1,2,3などが挙げられ、好ましくは1または2であり、さらに好ましくは1である。具体的な例としては前記の脂肪族炭化水素基の他、2−ヒドロキシ−2−メチルプロピル基、3−ヒドロキシ−2−メチルプロピル基、2、3−ジヒドロキシ−2−メチルプロピル基、2−エチル−2−ヒドロキシブチル基、2−エチル−3−ヒドロキシブチル基、2−エチル−2、3−ジヒドロキシブチル基、2−ヒドロキシ−2−(n−プロピル)ペンチル基、3−ヒドロキシ−2−(n−プロピル)ペンチル基、2、3−ジヒドロキシ−2−(n−プロピル)ペンチル基、2−ヒドロキシ−3−メチルブチル基、3−ヒドロキシ−3−メチルブチル基、4−ヒドロキシ−3−メチルブチル基、2、3−ジヒドロキシ−3−メチルブチル基、2、4−ジヒドロキシ−3−メチルブチル基、3、4−ジヒドロキシ−3−メチルブチル基、3−エチル−2−ヒドロキシペンチル基、3−エチル−3−ヒドロキシペンチル基、3−エチル−4−ヒドロキシペンチル基、3−エチル−2、3−ジヒドロキシペンチル基、3−エチル−2、4−ジヒドロキシペンチル基、3−エチル−3、4−ジヒドロキシペンチル基、2−ヒドロキシ−3−(n−プロピル)ヘキシル基、3−ヒドロキシ−3−(n−プロピル)ヘキシル基、4−ヒドロキシ−3−(n−プロピル)ヘキシル基、2、3−ジヒドロキシ−3−(n−プロピル)ヘキシル基、2、4−ジヒドロキシ−3−(n−プロピル)ヘキシル基、3、4−ジヒドロキシ−3−(n−プロピル)ヘキシル基、3−ヒドロキシ−4−メチルペンチル基、4−ヒドロキシ−4−メチルペンチル基、5−ヒドロキシ−4−メチルペンチル基、3、4−ジヒドロキシ−4−メチルペンチル基、3、5−ジヒドロキシ−4−メチルペンチル基、4、5−ジヒドロキシ−4−メチルペンチル基、4−エチル−3−ヒドロキシヘキシル基、4−エチル−4−ヒドロキシヘキシル基、4−エチル−5−ヒドロキシヘキシル基、4−エチル−3、4−ジヒドロキシヘキシル基、4−エチル−3、5−ジヒドロキシヘキシル基、4−エチル−4、5−ジヒドロキシヘキシル基、3−ヒドロキシ−4−(n−プロピル)ヘプチル基、4−ヒドロキシ−4−(n−プロピル)ヘプチル基、5−ヒドロキシ−4−(n−プロピル)ヘプチル基、3、4−ジヒドロキシ−4−(n−プロピル)ヘプチル基、3、5−ジヒドロキシ−4−(n−プロピル)ヘプチル基、4、5−ジヒドロキシ−4−(n−プロピル)ヘプチル基、4−ヒドロキシ−5−メチルヘキシル基、5−ヒドロキシ−5−メチルヘキシル基、6−ヒドロキシ−5−メチルヘキシル基、4、5−ジヒドロキシ−5−メチルヘキシル基、4、6−ジヒドロキシ−5−メチルヘキシル基、5、6−ジヒドロキシ−5−メチルヘキシル基、5−エチル−4−ヒドロキシヘプチル基、5−エチル−5−ヒドロキシヘプチル基、5−エチル−6−ヒドロキシヘプチル基、5−エチル−4、5−ジヒドロキシヘプチル基、5−エチル−4、6−ジヒドロキシヘプチル基、5−エチル−5、6−ジヒドロキシヘプチル基、4−ヒドロキシ−5−(n−プロピル)オクチル基、5−ヒドロキシ−5−(n−プロピル)オクチル基、6−ヒドロキシ−5−(n−プロピル)オクチル基、4、5−ジヒドロキシ−5−(n−プロピル)オクチル基、4、6−ジヒドロキシ−5−(n−プロピル)オクチル基、5、6−ジヒドロキシ−5−(n−プロピル)オクチル基、5−ヒドロキシ−6−メチルヘプチル基、6−ヒドロキシ−6−メチルヘプチル基、7−ヒドロキシ−6−メチルヘプチル基、5、6−ジヒドロキシ−6−メチルヘプチル基、5、7−ジヒドロキシ−6−メチルヘプチル基、6、7−ジヒドロキシ−6−メチルヘプチル基、6−エチル−5−ヒドロキシオクチル基、6−エチル−6−ヒドロキシオクチル基、6−エチル−7−ヒドロキシオクチル基、6−エチル−5、6−ヒドロキシオクチル基、6−エチル−5、7−ヒドロキシオクチル基、6−エチル−6、7−ヒドロキシオクチル基、5−ヒドロキシ−6−(n−プロピル)ノニル基、6−ヒドロキシ−6−(n−プロピル)ノニル基、7−ヒドロキシ−6−(n−プロピル)ノニル基、5、6−ジヒドロキシ−6−(n−プロピル)ノニル基、5、7−ジヒドロキシ−6−(n−プロピル)ノニル基、6、7−ジヒドロキシ−6−(n−プロピル)ノニル基等の飽和脂肪族炭化水素基のもの、また4−ヒドロキシ−4−メチル−2−ペンテニル基、5−ヒドロキシ−4−メチル−2−ペンテニル基、4、5−ジヒドロキシ−4−メチル−2−ペンテニル基、4−エチル−4−ヒドロキシ−2−ヘキセニル基、4−エチル−5−ヒドロキシ−2−ヘキセニル基、4−エチル−4、5−ジヒドロキシ−2−ヘキセニル基、4−ヒドロキシ−4−(n−プロピル)−2−ヘプテニル基、5−ヒドロキシ−4−(n−プロピル)−2−ヘプテニル基、4、5−ジヒドロキシ−4−(n−プロピル)−2−ヘプテニル基、5−ヒドロキシ−5−メチル−3−ヘキセニル基、6−ヒドロキシ−5−メチル−3−ヘキセニル基、5、6−ジヒドロキシ−5−メチル−3−ヘキセニル基、5−エチル−5−ヒドロキシ−3−ヘプテニル基、5−エチル−6−ヒドロキシ−3−ヘプテニル基、5−エチル−5、6−ジヒドロキシ−3−ヘプテニル基、5−ヒドロキシ−5−(n−プロピル)−3−オクテニル基、6−ヒドロキシ−5−(n−プロピル)−3−オクテニル基、5、6−ジヒドロキシ−5−(n−プロピル)−3−オクテニル基、4−ヒドロキシ−5−メチル−2−ヘキセニル基、5−ヒドロキシ−5−メチル−2−ヘキセニル基、6−ヒドロキシ−5−メチル−2−ヘキセニル基、4、5−ジヒドロキシ−5−メチル−2−ヘキセニル基、4、6−ジヒドロキシ−5−メチル−2−ヘキセニル基、5、6−ジヒドロキシ−5−メチル−2−ヘキセニル基、5−エチル−4−ヒドロキシ−2−ヘプテニル基、5−エチル−5−ヒドロキシ−2−ヘプテニル基、5−エチル−6−ヒドロキシ−2−ヘプテニル基、5−エチル−4、5−ジヒドロキシ−2−ヘプテニル基、5−エチル−4、6−ジヒドロキシ−2−ヘプテニル基、5−エチル−5、6−ジヒドロキシ−2−ヘプテニル基、4−ヒドロキシ−5−(n−プロピル)−2−オクテニル基、5−ヒドロキシ−5−(n−プロピル)−2−オクテニル基、6−ヒドロキシ−5−(n−プロピル)−2−オクテニル基、4、5−ジヒドロキシ−5−(n−プロピル)−2−オクテニル基、4、6−ジヒドロキシ−5−(n−プロピル)−2−オクテニル基、5、6−ジヒドロキシ−5−(n−プロピル)−2−オクテニル基、6−ヒドロキシ−6−メチル−4−ヘプテニル基、7−ヒドロキシ−6−メチル−4−ヘプテニル基、6、7−ジヒドロキシ−6−メチル−4−ヘプテニル基、6−エチル−6−ヒドロキシ−4−オクテニル基、6−エチル−7−ヒドロキシ−4−オクテニル基、6−エチル−6、7−ジヒドロキシ−4−オクテニル基、6−ヒドロキシ−6−(n−プロピル)−4−ノネニル基、7−ヒドロキシ−6−(n−プロピル)−4−ノネニル基、6、7−ジヒドロキシ−6−(n−プロピル)−4−ノネニル基、5−ヒドロキシ−6−メチル−3−ヘプテニル基、6−ヒドロキシ−6−メチル−3−ヘプテニル基、7−ヒドロキシ−6−メチル−3−ヘプテニル基、5、6−ジヒドロキシ−6−メチル−3−ヘプテニル基、5、7−ジヒドロキシ−6−メチル−3−ヘプテニル基、6、7−ジヒドロキシ−6−メチル−3−ヘプテニル基、6−エチル−5−ヒドロキシ−3−オクテニル基、6−エチル−6−ヒドロキシ−3−オクテニル基、6−エチル−7−ヒドロキシ−3−オクテニル基、6−エチル−5、6−ジヒドロキシ−3−オクテニル基、6−エチル−5、7−ジヒドロキシ−3−オクテニル基、6−エチル−6、7−ジヒドロキシ−3−オクテニル基、5−ヒドロキシ−6−(n−プロピル)−3−ノネニル基、6−ヒドロキシ−6−(n−プロピル)−3−ノネニル基、7−ヒドロキシ−6−(n−プロピル)−3−ノネニル基、5、6−ジヒドロキシ−6−(n−プロピル)−3−ノネニル基、5、7−ジヒドロキシ−6−(n−プロピル)−3−ノネニル基、6、7−ジヒドロキシ−6−(n−プロピル)−3−ノネニル基、5−ヒドロキシ−6−メチル−2−ヘプテニル基、6−ヒドロキシ−6−メチル−2−ヘプテニル基、7−ヒドロキシ−6−メチル−2−ヘプテニル基、5、6−ジヒドロキシ−6−メチル−2−ヘプテニル基、5、7−ジヒドロキシ−6−メチル−2−ヘプテニル基、6、7−ジヒドロキシ−6−メチル−2−ヘプテニル基、6−エチル−5−ヒドロキシ−2−オクテニル基、6−エチル−6−ヒドロキシ−2−オクテニル基、6−エチル−7−ヒドロキシ−2−オクテニル基、6−エチル−5、6−ジヒドロキシ−2−オクテニル基、6−エチル−5、7−ジヒドロキシ−2−オクテニル基、6−エチル−6、7−ジヒドロキシ−2−オクテニル基、5−ヒドロキシ−6−(n−プロピル)−2−ノネニル基、6−ヒドロキシ−6−(n−プロピル)−2−ノネニル基、7−ヒドロキシ−6−(n−プロピル)−2−ノネニル基、5、6−ジヒドロキシ−6−(n−プロピル)−2−ノネニル基、5、7−ジヒドロキシ−6−(n−プロピル)−2−ノネニル基、6、7−ジヒドロキシ−6−(n−プロピル)−2−ノネニル基、4−ヒドロキシ−4−メチル−2−ペンチニル基、5−ヒドロキシ−4−メチル−2−ペンチニル基、4、5−ジヒドロキシ−4−メチル−2−ペンチニル基、4−エチル−4−ヒドロキシ−2−ヘキシニル基、4−エチル−5−ヒドロキシ−2−ヘキシニル基、4−エチル−4、5−ジヒドロキシ−2−ヘキシニル基、4−ヒドロキシ−4−(n−プロピル)−2−ヘプチニル基、5−ヒドロキシ−4−(n−プロピル)−2−ヘプチニル基、4、5−ジヒドロキシ−4−(n−プロピル)−2−ヘプチニル基、5−ヒドロキシ−5−メチル−3−ヘキシニル基、6−ヒドロキシ−5−メチル−3−ヘキシニル基、5、6−ジヒドロキシ−5−メチル−3−ヘキシニル基、5−エチル−5−ヒドロキシ−3−ヘプチニル基、5−エチル−6−ヒドロキシ−3−ヘプチニル基、5−エチル−5、6−ジヒドロキシ−3−ヘプチニル基、5−ヒドロキシ−5−(n−プロピル)−3−オクチニル基、6−ヒドロキシ−5−(n−プロピル)−3−オクチニル基、5、6−ジヒドロキシ−5−(n−プロピル)−3−オクチニル基、4−ヒドロキシ−5−メチル−2−ヘキシニル基、5−ヒドロキシ−5−メチル−2−ヘキシニル基、6−ヒドロキシ−5−メチル−2−ヘキシニル基、4、5−ジヒドロキシ−5−メチル−2−ヘキシニル基、4、6−ジヒドロキシ−5−メチル−2−ヘキシニル基、5、6−ジヒドロキシ−5−メチル−2−ヘキシニル基、5−エチル−4−ヒドロキシ−2−ヘプチニル基、5−エチル−5−ヒドロキシ−2−ヘプチニル基、5−エチル−6−ヒドロキシ−2−ヘプチニル基、5−エチル−4、5−ジヒドロキシ−2−ヘプチニル基、5−エチル−4、6−ジヒドロキシ−2−ヘプチニル基、5−エチル−5、6−ジヒドロキシ−2−ヘプチニル基、4−ヒドロキシ−5−(n−プロピル)−2−オクチニル基、5−ヒドロキシ−5−(n−プロピル)−2−オクチニル基、6−ヒドロキシ−5−(n−プロピル)−2−オクチニル基、4、5−ジヒドロキシ−5−(n−プロピル)−2−オクチニル基、4、6−ジヒドロキシ−5−(n−プロピル)−2−オクチニル基、5、6−ジヒドロキシ−5−(n−プロピル)−2−オクチニル基、6−ヒドロキシ−6−メチル−4−ヘプチニル基、7−ヒドロキシ−6−メチル−4−ヘプチニル基、6、7−ジヒドロキシ−6−メチル−4−ヘプチニル基、6−エチル−6−ヒドロキシ−4−オクチニル基、6−エチル−7−ヒドロキシ−4−オクチニル基、6−エチル−6、7−ジヒドロキシ−4−オクチニル基、6−ヒドロキシ−6−(n−プロピル)−4−ノニニル基、7−ヒドロキシ−6−(n−プロピル)−4−ノニニル基、6、7−ジヒドロキシ−6−(n−プロピル)−4−ノニニル基、5−ヒドロキシ−6−メチル−3−ヘプチニル基、6−ヒドロキシ−6−メチル−3−ヘプチニル基、7−ヒドロキシ−6−メチル−3−ヘプチニル基、5、6−ジヒドロキシ−6−メチル−3−ヘプチニル基、5、7−ジヒドロキシ−6−メチル−3−ヘプチニル基、6、7−ジヒドロキシ−6−メチル−3−ヘプチニル基、6−エチル−5−ヒドロキシ−3−オクチニル基、6−エチル−6−ヒドロキシ−3−オクチニル基、6−エチル−7−ヒドロキシ−3−オクチニル基、6−エチル−5、6−ジヒドロキシ−3−オクチニル基、6−エチル−5、7−ジヒドロキシ−3−オクチニル基、6−エチル−6、7−ジヒドロキシ−3−オクチニル基、5−ヒドロキシ−6−(n−プロピル)−3−ノニニル基、6−ヒドロキシ−6−(n−プロピル)−3−ノニニル基、7−ヒドロキシ−6−(n−プロピル)−3−ノニニル基、5、6−ジヒドロキシ−6−(n−プロピル)−3−ノニニル基、5、7−ジヒドロキシ−6−(n−プロピル)−3−ノニニル基、6、7−ジヒドロキシ−6−(n−プロピル)−3−ノニニル基、5−ヒドロキシ−6−メチル−2−ヘプチニル基、6−ヒドロキシ−6−メチル−2−ヘプチニル基、7−ヒドロキシ−6−メチル−2−ヘプチニル基、5、6−ジヒドロキシ−6−メチル−2−ヘプチニル基、5、7−ジヒドロキシ−6−メチル−2−ヘプチニル基、6、7−ジヒドロキシ−6−メチル−2−ヘプチニル基、6−エチル−5−ヒドロキシ−2−オクチニル基、6−エチル−6−ヒドロキシ−2−オクチニル基、6−エチル−7−ヒドロキシ−2−オクチニル基、6−エチル−5、6−ジヒドロキシ−2−オクチニル基、6−エチル−5、7−ジヒドロキシ−2−オクチニル基、6−エチル−6、7−ジヒドロキシ−2−オクチニル基、5−ヒドロキシ−6−(n−プロピル)−2−ノニニル基、6−ヒドロキシ−6−(n−プロピル)−2−ノニニル基、7−ヒドロキシ−6−(n−プロピル)−2−ノニニル基、5、6−ジヒドロキシ−6−(n−プロピル)−2−ノニニル基、5、7−ジヒドロキシ−6−(n−プロピル)−2−ノニニル基、6、7−ジヒドロキシ−6−(n−プロピル)−2−ノニニル基等が挙げられ、好ましくは3−ヒドロキシ−3−メチルブチル基、4−ヒドロキシ−3−メチルブチル基、3、4−ジヒドロキシ−3−メチルブチル基、3−エチル−3−ヒドロキシペンチル基、3−エチル−4−ヒドロキシペンチル基、3−エチル−3、4−ジヒドロキシペンチル基、4−ヒドロキシ−4−メチルペンチル基、5−ヒドロキシ−4−メチルペンチル基、4、5−ジヒドロキシ−4−メチルペンチル基、4−エチル−4−ヒドロキシヘキシル基、4−エチル−5−ヒドロキシヘキシル基、4−エチル−4、5−ジヒドロキシヘキシル基、4−ヒドロキシ−4−メチル−2−ペンテニル基、5−ヒドロキシ−4−メチル−2−ペンテニル基、4、5−ジヒドロキシ−4−メチル−2−ペンテニル基、4−エチル−4−ヒドロキシ−2−ヘキセニル基、4−エチル−5−ヒドロキシ−2−ヘキセニル基、4−エチル−4、5−ジヒドロキシ−2−ヘキセニル基、4−ヒドロキシ−4−メチル−2−ペンチニル基、5−ヒドロキシ−4−メチル−2−ペンチニル基、4、5−ジヒドロキシ−4−メチル−2−ペンチニル基、4−エチル−4−ヒドロキシ−2−ヘキシニル基、4−エチル−5−ヒドロキシ−2−ヘキシニル基、4−エチル−4、5−ジヒドロキシ−2−ヘキシニル基等が挙げられる。
【0022】
本明細書中において、アルキル基とは一般的には炭素数1〜15、好ましくは炭素数1〜8の直鎖または分枝鎖のアルキル基を意味し、アリール基とは一般的には炭素数6〜20、好ましくは炭素数6〜14のアリール基を意味し、アルコキシ基とは一般的には炭素数1〜15、好ましくは炭素数1〜8の直鎖または分枝鎖のアルコキシ基を意味する。
【0023】
保護基とは、アシル基、置換シリル基、置換アルキル基などが挙げられ、好ましくはアシル基、置換シリル基である。
アシル基とは、置換されたカルボニル基を意味し、ここでいうカルボニル基の置換基とは、水素原子、置換基を有していてもよい低級アルキル基、置換基を有していてもよいアリール基、置換基を有していてもよい低級アルキルオキシ基、置換基を有していてもよいアリールオキシ基、置換基を有していてもよいアラルキルオキシ基等を意味する。アシル基は、好ましくはホルミル基、低級アルキルカルボニル基、置換基を有していてもよいフェニルカルボニル基、低級アルキルオキシカルボニル基、置換基を有していてもよいフェニルアルキルオキシカルボニル基などを示し、さらに好ましくはホルミル基、アセチル基、プロピオニル基、ブチリル基、ピバロイル基、ベンゾイル基、メトキシカルボニル基、エトキシカルボニル基、t−ブトキシカルボニル基、ベンジルオキシカルボニル基等を示す。
【0024】
置換シリル基とは、1以上の置換基を有していてもよい低級アルキル基または置換基を有していてもよいアリール基などで置換されたシリル基を意味し、好ましくは3置換されたシリル基を示す。置換シリル基の好ましい例としては、トリメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、t−ブチルジフェニルシリル基、t−ブチルジメチルシリル基などが挙げられる。
【0025】
置換アルキル基とは1以上の置換基で置換されているアルキル基を示し、ここで置換基の好ましい例としては、置換基を有していてもよいアルキルオキシ基や置換基を有していてもよいアリール基が挙げられ、特に置換基を有していてもよいアルキルオキシ基が挙げられる。アルキルオキシ基などの置換基を有していてもよいアルキルオキシ基で置換された置換アルキル基としては、例えばメトキシメチル基、2−メトキシエトキシメチル基の他にテトラヒドロピラン−2−イル基などが挙げられる。また置換基の例としては、ハロゲン原子、シアノ基、ニトロ基、アミノ基、水酸基、アルキル基、アルキルオキシ基、アシルオキシ基、スルホニル基等が挙げられる。
【0026】
本発明の一般式(1)で表される化合物のうち、Xがイオウ原子である化合物は、例えば以下に式示するように、特開平7−330714号公報に記載された式(8)で表される化合物から製造することができる。
【化27】
(式中、TBSはt−ブチルジメチルシリル基を意味し、R12はアルキル基、アリール基またはアルコキシ基を、R1aは水酸基または保護された水酸基で置換されていてもよい飽和または不飽和の脂肪族炭化水素基を示し、R1bは水酸基で置換された飽和または不飽和の脂肪族炭化水素基を示す)
【0027】
上式において、特開平7−330714号公報に記載された方法と同様にして得られた式(8)で示される化合物から、適当な溶媒中、塩基の存在下でアルキルハロチオホルメートまたはアリールハロチオホルメートと反応させることにより、O−アルキルチオカルボネートまたはアルキルジチオカルボネートを経て、一般式(9)で示される化合物を得ることができる(工程1)。
【0028】
上記工程1で用いられるアルキルハロチオホルメートまたはアリールハロチオホルメートとしては、例えばフェニルクロロチオノホルメート、トリルクロロチオノホルメート、4−tert−ブチルフェニルクロロチオノホルメート、4−フルオロフェニルクロロチオノホルメート、3−クロロフェニルクロロチオノホルメート、4−クロロフェニルクロロチオノホルメート、3,4−ジクロロフェニルクロロチオノホルメート、2,4,6−トリクロロフェニルクロロチオノホルメート、ペンタフルオロフェニルクロロチオノホルメート、メチルクロロジチオホルメート、エチルクロロジチオホルメート、イソプロピルクロロジチオホルメート、フェニルクロロジチオホルメート、トリルクロロジチオホルメート、2,4,6−トリメチルフェニルクロロジチオホルメート、4−フルオロフェニルクロロジチオホルメート、ペンタフルオロフェニルクロロジチオホルメート、2−クロロフェニルクロロジチオホルメート、3−クロロフェニルクロロジチオホルメート、4−クロロフェニルクロロジチオホルメート、2,4,5−トリクロロフェニルクロロジチオホルメート、ペンタクロロクロロジチオホルメート、4−メトキシフェニルクロロジチオホルメート、4−シアノフェニルクロロジチオホルメート、4−ニトロフェニルクロロジチオホルメート等が挙げられ、好ましくはフェニルクロロチオノホルメート、トリルクロロチオノホルメート、4−tert−ブチルフェニルクロロチオノホルメート、4−フルオロフェニルクロロチオノホルメート、4−クロロフェニルクロロチオノホルメート、2,4,6−トリクロロフェニルクロロチオノホルメート、ペンタフルオロフェニルクロロチオノホルメート、フェニルクロロジチオホルメート等が挙げられ、さらに好ましくはフェニルクロロチオノホルメートが挙げられる。
【0029】
上記工程1で用いられる溶媒としては、炭化水素系、エーテル系、ハロゲン系溶媒等が挙げられ、例えばベンゼン、トルエン、ジエチルエーテル、テトラヒドロフラン、1,2−ジメトキシエタン、ジクロロメタン、クロロホルム、四塩化炭素等が挙げられ、好ましくはジクロロメタン、トルエン等が挙げられ、さらに好ましくはジクロロメタンが使用できる。
【0030】
上記工程1で用いられる塩基としてはピリジン系化合物、アミン系化合物、イミダゾール系化合物、アルカリ金属水酸化物、金属水素化物、アルカリ金属化合物、金属アミド等が挙げられ、例えばピリジン、コリジン、ルチジン、2,6−ジ−tert−ブチルピリジン、4−メチル−2,6−ジ−tert−ブチルピリジン、4−ジメチルアミノピリジン、トリエチルアミン、ジイソプロピルエチルアミン、イミダゾール、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、水素化カリウム、メチルリチウム、n−ブチルリチウム、エチルマグネシウムブロマイド、リチウムジイソプロピルアミド、リチウムビストリメチルシリルアミド等が挙げられ、好ましくはピリジン、コリジン、ルチジン、2,6−ジ−tert−ブチルピリジン、4−メチル−2,6−ジ−tert−ブチルピリジン、4−ジメチルアミノピリジン、トリエチルアミン、ジイソプロピルエチルアミンが挙げられ、さらに好ましくはピリジンが用いられる。
【0031】
上記工程1の反応温度は進行する温度であれば特に制限はないが、0〜100℃の範囲、好ましくは室温で進行する。なお、本反応においては16α−OH体からは20Sの立体を有するチオールカルボネートが、また16β−OH体からは20Rの立体を有するチオールカルボネートがそれぞれ選択的に合成することができる。
この一般式(9)で示される化合物は、一般式(4)で示される中間体の一部を構成する。
【0032】
一般式(9)で示される化合物から、アルカリ加溶媒分解と同時にS−アルキル化を行うことにより、側鎖の導入された一般式(10)で示される化合物を得ることができる(工程2)。
【0033】
上記工程2のアルカリ加溶媒分解およびS−アルキル化に用いる塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、ナトリウムメトキシド、カリウム−tert−ブトキシド等が挙げられ、好ましくは水酸化ナトリウム、水酸化カリウム、ナトリウムメトキシド等が用いられる。反応は水またはアルコール系溶媒、例えばメタノール、エタノール、プロパノール、ブタノール等を単独もしくはエーテル系溶媒、例えばジエチルエーテル、テトラヒドロフラン、1,2−ジメトキシエタン、1,4−ジオキサン、ジグリム等との混合溶媒系で行うことができる。
【0034】
また使用するアルキル化剤としては、側鎖に対応する一般式(13):
Y−R1a (13)
(式中、Yはハロゲン原子、メシルオキシ基、トシルオキシ基、トリフルオロメタンスルホニルオキシ基等の脱離基を示し、R1aは前記と同一の意味を示す)またはイソブチレンオキサイド、1,2−エポキシ−2−エチルブタン、1,2−エポキシ−3−メチルブタン、1,2−エポキシ−3−エチルペンタン等のエポキシドなどが挙げられる。
この一般式(10)で示される化合物は、一般式(4)で示される中間体の一部を構成する。
【0035】
一般式(13)で示される化合物としては、例えば4−ブロモ−2−メチル−2−ブタノール、1−ブロモ−4−メチル−4−トリエチルシリルオキシペンタン、6−ブロモ−2−メチル−2−ヘキサノール、5−ブロモ−3−エチル−3−ペンタノール、6−ブロモ−3−エチル−3−ヘキサノール等、一般式(1)で示される本発明化合物のR1に相当するアルキル化剤が用いられる。
上記工程2の反応は−40から100℃で行われ、好ましくは0〜50℃、さらに好ましくは室温で行われる。
【0036】
一般式(10)で示される化合物は常法の脱保護により、一般式(11)で示される化合物とすることができる(工程3)。
上記工程3の反応に用いる試薬としては、塩酸、酸性イオン交換樹脂、テトラブチルアンモニウムフルオライド、フッ化水素/ピリジン、フッ化水素/トリエチルアミン、フッ化水素酸が用いられ、好ましくはテトラブチルアンモニウムフルオライドが用いられる。
【0037】
上記工程3で用いる溶媒としては通常エーテル系溶媒が用いられ、好ましくはテトラヒドロフランが用いられる。
反応温度は基質によって異なるが、室温から65℃の範囲で行われる。
この脱保護された一般式(11)の化合物もまた一般式(4)で示される中間体の一部を構成する。
【0038】
一般式(11)で示される化合物に光反応、熱異性化反応を施すことにより、本発明の一般式(1)で示される化合物のうち、Xがイオウ原子であり、かつR1が水酸基で置換されていてもよい飽和の脂肪族炭化水素基である化合物(12)を製造することができる(工程4)。ここで行われる光反応および熱異性化反応は常法により行える。
【0039】
また光反応および熱異性化反応を脱保護する前の一般式(9)の化合物に施すことにより、水酸基が保護された一般式(1)で示される化合物を得ることができる。さらに工程1、2、3および4を行う順序は特に限定しないが、工程2が工程1より先に行われることはない。また工程4→3→1→2の順序で行われることもない。さらにまた側鎖に保護基を有する場合は必要に応じて、工程3を行うことができる。
【0040】
また本発明の一般式(1)で表される化合物のうち、Xが酸素原子である化合物は、例えば特開平7−330714号公報に記載された公知の化合物(14)から以下に式示するようにして得ることができる。
【化28】
(式中、TBSはt−ブチルジメチルシリル基を意味する)
【0041】
上式において、特開平7−330714号公報に記載された方法と同様にして得られた式(14)で示される化合物を酸化することにより、式(15)で示される化合物を得ることができる(工程1)。
上記工程1で用いられる酸化剤としてはm−クロロ過安息香酸、マグネシウムモノパーオキシフタレート、過酸化水素などが挙げられ、好ましくはm−クロロ過安息香酸が適している。
【0042】
上記工程1の溶媒としては例えばトルエン、ベンゼン、ジクロロメタン、クロロホルム、四塩化炭素等があげられ、好ましくはトルエンまたはジクロロメタンが用いられる。また反応系中に炭酸水素ナトリウムやリン酸二水素ナトリウムなどの中和剤を存在させて反応を行ってもよい。
上記工程1の反応温度は−78〜110℃、好ましくは−40℃〜室温で行われる。
【0043】
式(15)で示される化合物は、例えばジャーナル・オブ・オーガニック・ケミストリー(Journal of Organic Chemstry),57,5019(1992)等に記載されている常法に従い、脱保護反応に付すことにより式(16)で示される化合物を得ることできる(工程2)。
式(15)または式(16)で示される化合物は、一般式(5)で示される化合物の一部を構成する。
【0044】
式(16)で示される化合物から式(17)で示される20S−アリルアルコール中間体を得る工程(工程3)は、リチウムジエチルアミド等の単純な金属アミドなどによっても行えるが、脱プロトン化反応における位置選択性が良くないため、不活性溶媒中、対応する金属アミドおよびジアルキルアルミニウムハライドから調製されるジアルキルアルミニウムジアルキルアミドを用いて反応を行うと目的化合物が収率よく得られる。
【0045】
上記工程3で使用される金属アミドとしては、リチウムジエチルアミド、リチウムジイソプロピルアミド、リチウムビストリメチルシリルアミド、ナトリウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミド、リチウム−2,2,6,6−テトラメチルピペリジドなどが挙げられ、好ましくはリチウムジイソプロピルアミド、リチウムビストリメチルシリルアミド、さらに好ましくはリチウムジイソプロピルアミドが挙げられる。ジアルキルアルミニウムハライドとしてはジメチルアルミニウムクロライド、ジエチルアルミニウムクロライド、ジイソブチルアルミニウムクロライド、ジエチルアルミニウムヨーダイドなどが挙げられ、好ましくはジメチルアルミニウムクロライド、ジエチルアルミニウムクロライド、ジイソブチルアルミニウムクロライド、さらに好ましくはジエチルアルミニウムクロライドが挙げられる。
【0046】
上記工程3で用いる溶媒としては、炭化水素系溶媒、ハロゲン系溶媒などが挙げられ、例えばヘキサン、ベンゼン、トルエン、ジクロロメタン、クロロホルムなどが、好ましくはベンゼン、トルエンが挙げられる。反応温度は−40〜50℃、好ましくは0℃〜室温で、さらに好ましくは0℃で行われる。
【0047】
式(17)で示される20S−アリルアルコール中間体は酸化反応により、式(18)で示される化合物を経て(工程4)、さらに還元反応を行うことによって、式(19)で示される20R−アリルアルコール中間体を製造することができる(工程5)。
式(17)および式(19)で示される化合物は一般式(6)で示される化合物の一部を構成し、式(18)で示される化合物は一般式(7)で示される化合物の一部を構成する。
【0048】
上記工程4の酸化反応において、酸化条件としてはクロム化合物、マンガン化合物、オスミウム化合物、ルテニウム化合物など金属酸化剤を用いる方法のほか、ジメチルスルホキシドを用いる方法、カルボニル化合物を用いる方法(Oppenauer酸化)、キノン化合物を用いる方法などが挙げられる。具体的にはピリジニウムクロロクロメート、ピリジニウムジクロメート、二酸化マンガン、四酸化オスミウム、三塩化ルテニウム、過ルテニウム酸テトラプロピルアンモニウム、オギザリルクロリド/ジメチルスルホキシド、トリホスゲン/ジメチルスルホキシド、三酸化硫黄ピリジン錯体/ジメチルスルホキシド、アセトン/アルミニウムトリイソプロポキシド、シクロヘキサノン/アルミニウムトリイソプロポキシド等が挙げられ、好ましくはピリジニウムクロロクロメート、ピリジニウムジクロメート、二酸化マンガン、過ルテニウム酸テトラプロピルアンモニウム(触媒)/4−メチルモルホリン N−オキシド、オギザリルクロリド/ジメチルスルホキシド等が挙げられる。
【0049】
また上記工程5の還元反応において、還元条件としては金属水素化物、金属水素錯化合物等が挙げられる。具体的にはボラン、テキシルボラン、9−ボラビシクロ[3,3,1]ノナン、カテコールボラン、ジイソブチルアルミニウムヒドリド、水素化ホウ素リチウム、水素化ホウ素亜鉛、水素化ホウ素ナトリウム、トリメトキシ水素化ホウ素ナトリウム、シアン化水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化トリ−s−ブチルホウ素リチウム、水素化トリ−s−ブチルホウ素カリウム、水素化トリシアミルホウ素リチウム、水素化トリシアミルホウ素カリウム、水素化トリエチルホウ素リチウム、水素化トリフェニルホウ素カリウム、水素化n−ブチルホウ素リチウム、水素化アルミニウムリチウム、水素化トリメトキシアルミニウムリチウム、水素化トリ−t−ブトキシアルミニウムリチウム、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等が挙げられ、好ましくはジイソブチルアルミニウムヒドリド、水素化ホウ素ナトリウム/塩化セリウム、水素化n−ブチルホウ素リチウム、水素化トリエチルホウ素リチウム、水素化トリ−t−ブトキシアルミニウムリチウム等が挙げられ、さらに好ましくは水素化ホウ素ナトリウム/塩化セリウム、水素化n−ブチルホウ素リチウム、水素化トリエチルホウ素リチウムが挙げられる。
【0050】
このようにして得られた20S−および20R−アリルアルコール中間体に一般式(1)または一般式(4)で示される化合物に対応する側鎖を導入して、一連の反応に付すことにより、下記に示すように一般式(23)で示される本発明化合物を得ることができる。
【化29】
(式中、TBSはt−ブチルジメチルシリル基を意味し、R1aは水酸基または保護された水酸基で置換されていてもよい飽和または不飽和の脂肪族炭化水素基を示し、R1bは水酸基で置換された飽和または不飽和の脂肪族炭化水素基を示す)
【0051】
一般式(20)で示される20S−または20R−アリルアルコールに側鎖を導入することにより、一般式(21)で示される化合物を得ることができる(工程6)。側鎖導入の方法としては側鎖に対応する一般式(13):R1a−Y(式中、R1aおよびYは前記と同一の意味を示す)を塩基存在下、前述のアリルアルコール中間体と反応させることにより達成できる。
【0052】
上記工程6で用いる塩基としてはアルカリ金属水素化物、アルカリ金属アルコキシド、金属ジアルキルアミド、アルキル金属などがあげられ、好ましくは水素化ナトリウム、水素化カリウム、t−ブトキシカリウム、リチウム ジイソプロピルアミド、リチウム ビストリメチルシリルアミド、メチルリチウム、n−ブチルリチウム、エチルマグネシウムブロミド等が挙げられ、さらに好ましくは水素化ナトリウム、水素化カリウムが挙げられる。また、本反応は触媒量のクラウンエーテル存在下で反応を行ってもよい。クラウンエーテルとしては15−クラウン−5、18−クラウン−6、ジベンゾ−18−クラウン−6等が挙げられ、好ましくは15−クラウン−5が挙げられる。
【0053】
上記工程6で用いられる溶媒としては炭化水素系、エーテル系、アミド系溶媒が挙げられ、たとえばベンゼン、トルエン、ジエチルエーテル、テトラヒドロフラン、1,2−ジメトキシエタン、1,4−ジオキサン、N,N−ジメチルアセトアミド、N,N−ジメチルホルムアミド、1,3−ジメチル−2−イミダゾリジノン、1,3−ジメチル−3,4,5,6−テトラヒドロ−2(1H)−ピリミジノン等が挙げられ、好ましくはテトラヒドロフラン、1,2−ジメトキシエタン、N,N−ジメチルホルムアミド、1,3−ジメチル−2−イミダゾリジノンが挙げられ、さらに好ましくはテトラヒドロフランが挙げられる。
上記工程6の反応温度は0℃〜使用する溶媒の沸点または分解点以下で行なわれ、好ましくは室温〜100℃、さらに好ましくは50〜80℃程度である。
【0054】
また側鎖導入に際しては上記方法のほか、アルキルハライドとしてたとえば1−ブロモ−2,3−エポキシ−3−メチルブタンを用い、上記塩基存在下にてアルキル化を行った後還元剤、たとえば水素化リチウムアルミニウムヒドリド、水素化ホウ素リチウム、水素化トリ−s−ブチルホウ素リチウム、水素化トリエチルホウ素リチウム等によりエポキシドを開環することによっても行うことができる。この方法は2段階で行っても1段階で行ってもよい。
また、側鎖導入に際してはアルキルハライドのかわりに、イソブチレンオキサイド、1,2−エポキシ−2−エチルブタン、1,2−エポキシ−3−メチルブタン、1,2−エポキシ−3−エチルペンタン等のエポキシドを用いてもよい。反応条件は、例えば、特開平6−80626号(特願平4−158483号)に記載されている条件を使用することができ、好ましくは、カリウムt−ブトキシドを塩基として用い、ジベンゾ−18−クラウン−6存在下、トルエン中100〜110℃で行うことができる。
【0055】
一般式(21)で示される化合物も本発明化合物に含まれるが、さらに脱保護反応を付すことにより、一般式(22)で示される化合物に変換することができる(工程7)。このt−ブチルジメチルシリル基の除去は常法により行われる。すなわち、反応に用いる試薬としては塩酸、酸性イオン交換樹脂、テトラブチルアンモニウムフルオリド、フッ化水素/ピリジン、フッ化水素/トリエチルアミン、フッ化水素酸が用いられ、好ましくはテトラブチルアンモニウムフルオリドが用いられる。溶媒としては通常エーテル系溶媒が用いられ、好ましくはテトラヒドロフランが用いられる。反応温度は基質によって異なるが、通常、室温〜65℃の範囲で行われる。
【0056】
さらに一般式(22)で示される化合物は常法の光反応・熱異性化を行うことにより、一般式(23)で示される化合物を得ることができる(工程8)。
なお、工程6、7、8は上記の順で反応を行うほか、工程6→工程8→工程7あるいは工程8→工程6→工程7の順で行っても良い(つまり、順序については特に限定しないが、工程7が工程6より先に行われることはない)。
【0057】
上述してきた製造工程において、各中間体および最終物質はシリカゲルカラムクロマトグラフィー、薄層クロマトグラフィー、再結晶等の通常の手段により、精製、単離することができる。
このようにして得られた一般式(1)の化合物は、後記実施例に示すように、カルシウム上昇作用の低い、抗腫瘍剤、抗リウマチ剤等の医薬として有用な化合物である。
【0058】
本発明の一般式(1)で示される化合物において、20位の立体配置、水酸基の立体配置はR、Sあるいはα、βの何れの化合物も本発明に含まれる。さらに一般式(1)中のR1が水酸基で置換されていてもよい不飽和の脂肪族炭化水素基を示す場合であって、二重結合を含む場合、それにより生じるシス、トランスの幾何異性体もまた本発明に含まれ、その他、考えられる光学異性体、幾何異性体も本発明に含まれる。
【0059】
本発明の一般式(1)で示される化合物のうち、より好ましい化合物としてはR1が水酸基で置換されたアルキル基、特に3−ヒドロキシ−3−メチルブチル基である化合物が挙げられる。また1位は水酸基で置換されているものが好ましく、その水酸基はα配位のものがより好ましい。さらに20位がR配置である化合物も、強い分化誘導作用を示すことから好ましい。さらにまたXがイオウ原子の化合物も好ましい態様の1つとして挙げられる。
【0060】
また本発明の一般式(1)で示される化合物に含まれる具体的な化合物としては、1,3−ジヒドロキシ−20−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(R)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン等がより好ましい化合物として含まれる。
また本発明の一般式(1)で示される、より好ましい具体的化合物としては、1α,3β−ジヒドロキシ−20(R)−((E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンおよび1α,3β−ジヒドロキシ−20(R)−((E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(S)−(2−ヒドロキシ−2−メチルプロピルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(R)−(2−ヒドロキシ−2−メチルプロピルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(S)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(S)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(S)−(2−エチル−2−ヒドロキシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン、1α,3β−ジヒドロキシ−20(R)−(2−エチル−2−ヒドロキシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンなどが挙げられる。
【0061】
これらの好ましい化合物を製造するための一般式(4)〜(7)で示される化合物も合成中間体として、より好ましい有用な化合物といえる。
【0062】
本発明化合物は、製薬上許容しうる担体、賦型剤、崩壊剤、滑沢剤、結合剤、香料、着色剤等とともに、適当な剤型に製剤化して用いるのが好ましく、そのような剤型としては、錠剤、顆粒剤、細粒剤、カプセル剤、散剤、注射剤、溶液剤、懸濁剤、乳剤、経皮吸収剤、坐剤等が挙げられる。
【0063】
本発明化合物の投与量は、対象疾患、患者の状態、体型、体質、年齢、性別、また投与経路、剤型等により適宜選択することができるが、一般に投与量の下限として、1日0.001μg〜0.1μgの範囲、好ましくは0.01μg前後で、投与量の上限としては1日100μg〜10000μgの範囲、好ましくは200μg〜1000μgの範囲内で選択でき、1日1〜3回に分けて投与することができる。
【0064】
【実施例】
以下に実施例を挙げて、本発明をさらに詳細に説明するが、本発明はこれらに何ら限定されるものではない。
本実施例に際して、赤外吸収スペクトル(IR)は HITACHI 270-30で測定した。1H NMRはJEOL FX-200(200MHz)、またはJEOL EX-270(270MHz)で測定し、CDCl3溶媒中、テトラメチルシランを内部標準として用いた。マススペクトル(MS)は、SHIMADZU GCMS-QP 1000でEIモード、イオン化電圧70eVで測定した。紫外吸収スペクトル(UV)はSHIMADZU UV-240 によりエタノール中で測定を行った。カラムクロマトグラフィーにはMerck Kieselgel 60 F254 Art. 9385を、また分取用薄層クロマトグラフィーにはMerck Kieselgel 60 F254 Art. 5744(シリカゲル厚 0.5mm、20×20cm)または同 Art. 5715(シリカゲル厚 0.25mm、20×20cm)を用いた。
【0065】
実施例1
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16α−ヒドロキシプレグナ−5,7,17(E)−トリエン(150mg,0.27mmol)のジクロロメタン(5ml)溶液にピリジン(0.13ml,1.61mmol)とフェニルクロロチオノホルメート(0.11ml,0.81mmol)を加え室温で1時間撹拌後、減圧下濃縮した。残渣をヘキサンで希釈し、氷冷1N−塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄し、有機層を硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、得られた残渣を分取用薄層クロマトグラフィー(0.5mm×4枚、ヘキサン:酢酸エチル=9:1、1回展開)で精製し、無色固体の標記化合物を得た(160mg,85%)を得た。
【0066】
IR (KBr): 2920, 2850, 1720, 1490, 1460, 1370, 1245, 1180, 1155, 1095, 1000cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.89 (s, 21H), 0.95 (s, 3H), 1.60 (d, J = 7.3Hz, 3H), 3.72 (brs, 1H), 3.94-4.24 (m, 2H), 5.41 (brs, 1H), 5.61 (d, J = 5.4Hz, 1H), 5.77 (brs, 1H), 7.09-7.44 (m, 5H). MS m/z: 694 (M+), 505 (100%). UV λmax nm: 205, 270, 282, 293.
【0067】
実施例2
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16α−ヒドロキシプレグナ−5,7,17(E)−トリエン(1.50g,2.68mmol)、ピリジン(1.30ml,16.1mmol)、フェニルチオノクロロホルメート(1.11ml,8.04mmol)、ジクロロメタン(50ml)を実施例1と同様に反応、後処理を行った後、精製せずにテトラヒドロフラン(50ml)に溶解しアンバーリスト15(3.00g)を加え室温で36時間撹拌した。樹脂をろ過、テトラヒドロフランで洗浄後、ろ液を減圧下濃縮し、カラムクロマトグラフィー(ヘキサン:酢酸エチル=7:1→5:1)で精製して無色油状の標記化合物(1.07g,69%)を得た。
【0068】
IR (neat): 3250, 2920, 2850, 1720, 1490, 1460, 1370, 1260, 1190, 1165, 1100cm-1. 1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.95 (s, 3H), 0.96 (s, 3H), 1.60 (d, J = 6.8Hz, 3H), 3.76 (brs, 1H), 3.99-4.24 (m, 2H), 5.37-5.46 (m, 1H), 5.60-5.68 (m, 1H), 5.78 (brs, 1H), 7.12-7.45 (m, 5H). MS m/z: 580 (M+), 277 (100%). UV λmax nm: 205, 270, 282, 293.
【0069】
実施例3
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(81.6mg,0.140mmol)、4−ブロモ−2−メチル−2−ブタノール(117mg,0.700mmol)のテトラヒドロフラン(1ml)溶液に1M−KOH メタノール溶液(1ml)を加え室温で30分間撹拌後、減圧下濃縮した。残渣をヘキサンで希釈し、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した後減圧下溶媒を留去した。得られた残渣を分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:酢酸エチル=8:1、1回展開)で精製し無色油状の標記化合物(60.3mg,79%)を得た。
【0070】
IR (neat): 3400, 2950, 2850, 1460, 1370, 1250, 1200, 1150, 1060cm-1. 1H NMR δ: 0.08 (s, 3H), 0.13 (s, 3H), 0.88 (s, 9H), 0.93 (s, 3H), 0.94 (s,3H), 1.22 (s, 6H), 1.43 (d, J = 6.9Hz, 3H), 3.51 (q, J = 6.9Hz, 1H), 3.75 (brs, 1H), 3.95-4.17 (m, 1H), 5.37-5.45 (br, 1H), 5.59-5.69 (br, 2H). MS m/z: 546 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
【0071】
実施例4
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−メチル−4−トリエチルシリルオキシペンチルチオ)−プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(82.4mg,0.142mmol)、1−ブロモ−4−メチル−4−トリエチルシリルオキシペンタン(209mg,0.709mmol)、テトラヒドロフラン(1ml)、1M−KOH メタノール溶液(1ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=3:2、1回展開)で精製し無色油状の標記化合物(56.1mg,59%)を得た。
【0072】
IR (neat): 3350, 2950, 2850, 1460, 1365, 1255, 1150, 1050cm-1. 1H NMR δ: 0.08 (s, 3H), 0.13 (s, 3H), 0.56 (q, J = 7.7Hz, 6H), 0.81-1.03 (m, 24H), 1.19 (s, 6H), 1.42 (d, J = 6.9Hz, 3H), 3.46 (q, J = 6.9Hz, 1H), 3.76 (brs, 1H), 4.00-4.16 (m, 1H), 5.39-5.47 (m, 1H), 5.59-5.71 (m, 2H). MS m/z: 674 (M+), 277 (100%). UV λmax nm: 270, 281, 293.
【0073】
実施例5
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(5−ヒドロキシ−5−メチルヘキシルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(82.6mg,0.142mmol)、6−ブロモ−2−メチル−2−ヘキサノール(139mg,0.710mmol)、テトラヒドロフラン(1ml)、1M−KOH メタノール溶液(1ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:酢酸エチル=8:1、1回展開)で精製し、87.2mgの生成物を得たが、6−ブロモ−2−メチル−2−ヘキサノールとの分離が困難であったため、そのまま次の反応に使用した。
【0074】
実施例6
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(2−ヒドロキシ−2−メチルプロピルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(83.0mg,0.143mmol)、イソブチレンオキシド(113mg,1.56mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=1:1、1回展開)で精製し無色油状の標記化合物(62.3mg,82%)を得た。
【0075】
IR (neat): 3400, 2950, 2850, 1460, 1370, 1250, 1200, 1150, 1060cm-1. 1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.94 (s, 6H), 1.26 (s, 3H), 1.27 (s, 3H), 1.44 (d, J = 6.9Hz, 3H), 3.49 (q, J = 6.9Hz, 1H), 3.76 (brs, 1H), 4.00-4.17 (m, 1H), 5.36-5.47 (m, 1H), 5.59-5.69 (m, 2H). MS m/z: 532 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
【0076】
実施例7
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(3−エチル−3−ヒドロキシペンチルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(82.8mg,0.143mmol)、5−ブロモ−3−エチル−3−ペンタノール(139mg,0.715mmol)、テトラヒドロフラン(1ml)、1M−KOH メタノール溶液(1ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:酢酸エチル=8:1、1回展開)で精製し、99.6mgの生成物を得たが、5−ブロモ−3−エチル−3−ペンタノールとの分離が困難であったため、そのまま次の反応に使用した。
【0077】
実施例8
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−エチル−4−ヒドロキシヘキシルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(84.3mg,0.145mmol)、6−ブロモ−3−エチル−3−ヘキサノール(152mg,0.725mmol)、テトラヒドロフラン(1ml)、1M−KOH メタノール溶液(1ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=2:1、2回展開)で精製し、76.4mgの生成物を得たが、6−ブロモ−3−エチル−3−ヘキサノールとの分離が困難であったため、そのまま次の反応に使用した。
【0078】
実施例9
1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)プレグナ−5,7,16−トリエン(58.5mg,0.107mmol)のテトラヒドロフラン(3ml)溶液に1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を加え4時間加熱還流した。反応終了後、反応溶液を酢酸エチルで希釈し、氷冷0.5N−塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄し、有機層を硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、得られた残渣を分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=7:1、1回展開)で精製し、薄黄色油状の標記化合物(41.8mg,90%)を得た。
【0079】
IR (neat): 3400, 2950, 1460, 1370, 1210, 1150, 1060cm-1. 1H NMR δ: 0.93 (s, 3H), 0.96 (s, 3H), 1.22 (s, 6H), 1.42 (d, J = 6.8Hz, 3H), 3.52 (q, J = 6.8Hz, 1H), 3.77 (brs, 1H), 3.96-4.16 (m, 1H), 5.38-5.48 (m, 1H), 5.59-5.65 (brs, 1H), 5.66-5.76 (m, 1H). MS m/z: 432 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
【0080】
実施例10
1α,3β−ジヒドロキシ−20(S)−(4−ヒドロキシ−4−メチルペンチルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−メチル−4−トリエチルシリルオキシペンチルチオ)−プレグナ−5,7,16−トリエン(55.7mg,0.0825mmol)、テトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例9と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=7:1、1回展開)で精製し、無色油状の標記化合物(34.1mg,92%)を得た。
【0081】
IR (neat): 3400, 2950, 2850, 1460, 1370, 1200, 1150, 1100, 1160cm-1. 1H NMR δ: 0.92 (s, 3H), 0.97 (s, 3H), 1.21 (s, 6H), 1.42 (d, J = 6.9Hz, 3H), 3.47 (q, J = 6.9Hz, 1H), 3.77 (brs, 1H), 3.98-4.16 (m, 1H), 5.39-5.50 (m, 1H), 5.62 (brs, 1H), 5.69-5.77 (m, 1H). MS m/z: 446 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
【0082】
実施例11
1α,3β−ジヒドロキシ−20(S)−(5−ヒドロキシ−5−メチルヘキシルチオ)プレグナ−5,7,16−トリエンの製造
実施例5で得られた粗1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(5−ヒドロキシ−5−メチルヘキシルチオ)プレグナ−5,7,16−トリエン(73.2mg)、テトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例9と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=7:1、1回展開)で精製し、薄黄色油状の標記化合物(36.1mg,55%,2工程)を得た。
【0083】
IR (neat): 3400, 2950, 1460, 1370, 1200, 1145, 1050cm-1. 1H NMR δ: 0.93 (s, 3H), 0.98 (s, 3H), 1.08 (s, 6H), 1.42 (d, J = 6.9Hz, 3H), 3.46 (q, J = 6.9Hz, 1H), 3.78 (brs, 1H), 3.98-4.16 (m, 1H), 5.41-5.50 (m, 1H), 5.61 (brs, 1H), 5.69-5.78 (m, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
【0084】
実施例12
1α,3β−ジヒドロキシ−20(S)−(2−ヒドロキシ−2−メチルプロピルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(5−ヒドロキシ−5−メチルヘキシルチオ)プレグナ−5,7,16−トリエン(60.1mg,0.113mmol)、テトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例9と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=7:1、1回展開)で精製し、無色油状の標記化合物(36.3mg,77%)を得た。
【0085】
IR (neat): 3400, 2950, 1460, 1370, 1250, 1210, 1150, 1060cm-1. 1H NMR δ: 0.94 (s, 3H), 0.97 (s, 3H), 1.26 (s, 3H), 1.27 (s, 3H), 1.43 (d, J = 6.8Hz, 3H), 3.50 (q, J = 6.8Hz, 1H), 3.77 (brs, 1H), 3.96-4.16 (m, 1H), 5.40-5.51 (m, 1H), 5.64 (brs, 1H), 5.68-5.98 (m, 1H). MS m/z: 418 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
【0086】
実施例13
1α,3β−ジヒドロキシ−20(S)−(3−エチル−3−ヒドロキシペンチルチオ)プレグナ−5,7,16−トリエンの製造
実施例7で得られた粗1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(3−エチル−3−ヒドロキシペンチルチオ)プレグナ−5,7,16−トリエン、テトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例9と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=7:1、1回展開)で精製し、無色油状の標記化合物(42.0mg,64%,2工程)を得た。
【0087】
IR (neat): 3400, 2950, 1460, 1370, 1150, 1060cm-1. 1H NMR δ: 0.85 (t, J = 7.3Hz, 6H), 0.94 (s, 3H), 0.96 (s, 3H), 1.43 (d, J = 6.8Hz, 3H), 1.46 (q, J = 7.3Hz, 4H), 3.51 (q, J = 6.8Hz, 1H), 3.78 (brs, 1H), 3.90-4.09 (m, 1H), 5.38-5.49 (m, 1H), 5.63 (brs, 1H), 5.66-5.78 (m, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
【0088】
実施例14
1α,3β−ジヒドロキシ−20(S)−(4−エチル−4−ヒドロキシヘキシルチオ)プレグナ−5,7,16−トリエンの製造
実施例8で得られた粗1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−エチル−4−ヒドロキシヘキシルチオ)プレグナ−5,7,16−トリエン(71.4mg)、テトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例9と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=7:1、1回展開)で精製し、無色油状の標記化合物(45.8mg,67%,2工程)を得た。
【0089】
IR (neat): 3400, 2950, 1450, 1370, 1050cm-1. 1H NMR δ: 0.85 (t, J = 7.3Hz, 6H), 0.94 (s, 3H), 0.98 (s, 3H), 3.51 (q, J = 6.8Hz, 1H), 3.78 (brs, 1H), 3.98-4.16 (m, 1H), 5.38-5.50 (m, 1H), 5.63 (brs, 1H), 5.69-5.78 (m, 1H). MS m/z: 474 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
【0090】
実施例15
1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)プレグナ−5,7,16−トリエン(40.2mg,0.0929mmol)をエタノール(200ml)に溶解し、0℃で撹拌下アルゴンをバブリングしながら、400W高圧水銀灯バイコールフィルター透過光により、3.5分間光照射を行った後、1.5時間加熱還流を行った。室温に冷却後、減圧下溶媒を除去し、得られた残渣を分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:エタノール=7:1、1回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=10:10:1、3回展開)で精製し、無色油状の標記化合物(3.66mg,9.1%)を得た。
【0091】
IR (neat): 3400, 2920, 1440, 1365, 1200, 1140, 1060cm-1. 1H NMR δ: 0.83 (s, 3H), 1.23 (s, 6H), 1.42 (d, J = 7.3Hz, 3H), 3.49 (q, J = 7.3Hz, 1H), 4.18-4.32 (m, 1H), 4.39-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 432 (M+), 312 (100%). UV λmax nm: 263.
【0092】
実施例16
1α,3β−ジヒドロキシ−20(S)−(4−ヒドロキシ−4−メチルペンチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(4−ヒドロキシ−4−メチルペンチルチオ)プレグナ−5,7,16−トリエン(33.4mg,0.0748mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=7:1、1回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=10:10:1、3回展開)で精製し、無色油状の標記化合物(3.10mg,9.3%)を得た。
【0093】
IR (neat): 3400, 2930, 1450, 1370, 1220, 1150, 1060cm-1. 1H NMR δ: 0.83 (s, 3H), 1.21 (s, 6H), 1.41 (d, J = 6.8Hz, 3H), 3.44 (q, J = 6.8Hz, 1H), 4.18-4.32 (m, 1H), 4.40-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 446 (M+), 312 (100%). UV λmax nm: 263.
【0094】
実施例17
1α,3β−ジヒドロキシ−20(S)−(5−ヒドロキシ−5−メチルヘキシルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(5−ヒドロキシ−5−メチルヘキシルチオ)プレグナ−5,7,16−トリエン(35.7mg,0.0749mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2.75分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=8:1、1回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(2.94mg,8.2%)を得た。
【0095】
IR (neat): 3400, 2930, 1460, 1370, 1200, 1140, 1050cm-1. 1H NMR δ: 0.83 (s, 3H), 1.21 (s, 6H), 1.41 (d, J = 6.8Hz, 3H), 3.44 (q, J = 6.8Hz, 1H), 4.18-4.32 (m, 1H), 4.40-4.52 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 263.
【0096】
実施例18
1α,3β−ジヒドロキシ−20(S)−(2−ヒドロキシ−2−メチルプロピルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(2−ヒドロキシ−2−メチルプロピルチオ)プレグナ−5,7,16−トリエン(36.0mg,0.0860mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2.75分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:エタノール=7:1、1回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=10:10:1、3回展開)で精製し、無色油状の標記化合物(2.60mg,7.2%)を得た。
【0097】
IR (neat): 3400, 2930, 1460, 1370, 1200, 1140, 1060cm-1. 1H NMR δ: 0.84 (s, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.43 (d, J = 6.9Hz, 3H), 3.47 (q, J = 6.9Hz, 1H), 4.16-4.30 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 418 (M+), 312 (100%). UV λmax nm: 263.
【0098】
実施例19
1α,3β−ジヒドロキシ−20(S)−(3−エチル−3−ヒドロキシペンチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(3−エチル−3−ヒドロキシペンチルチオ)プレグナ−5,7,16−トリエン(41.7mg,0.0905mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2.25分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:エタノール=7:1、1回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開、さらに0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=28:12:1)で精製し、無色油状の標記化合物(3.78mg,9.1%)を得た。
【0099】
IR (neat): 3400, 2930, 1450, 1370, 1060cm-1. 1H NMR δ: 0.83 (s, 3H), 0.86 (t, J = 7.3Hz, 6H), 1.42 (d, J = 6.8Hz, 3H), 1.47 (q, J = 7.3Hz, 4H), 3.49 (q, J = 6.8Hz, 1H), 4.27-4.32 (m, 1H), 4.38-4.52 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 263.
【0100】
実施例20
1α,3β−ジヒドロキシ−20(S)−(4−エチル−4−ヒドロキシヘキシルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(4−エチル−4−ヒドロキシヘキシルチオ)プレグナ−5,7,16−トリエン(44.7mg,0.0942mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2.25分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:酢酸エチル:エタノール=14:6:1、3回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(3.62mg,8.1%)を得た。
【0101】
IR (neat): 3400, 2930, 1450, 1370, 1050cm-1. 1H NMR δ: 0.83 (s, 3H), 0.91 (t, J = 7.3Hz, 6H), 3.48 (q, J = 6.8Hz, 1H), 4.18-4.36 (m, 1H), 4.38-4.53 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 474 (M+), 312 (100%). UV λmax nm: 263.
【0102】
実施例21
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−ヒドロキシ−4−メチル−2−ペンチニルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(59.4mg,0.102mmol)、5−ブロモ−2−メチル−3−ペンチン−2−オル(90.5mg,0.511mmol)、テトラヒドロフラン(1ml)、1M−KOH メタノール溶液(1ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:酢酸エチル=5:1、2回展開)で精製し無色油状の標記化合物(41.6mg,73%)を得た。
【0103】
IR (neat): 3400, 2950, 2850, 1460, 1370, 1250, 1150, 1060cm-1. 1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.93 (s, 3H), 0.94 (s, 3H), 1.46 (d, J = 7.3Hz, 3H), 1.51 (s, 6H), 3.18 (d, J = 16.6Hz, 1H), 3.22 (d, J = 16.6Hz, 1H), 3.67 (q, J = 7.3Hz, 1H), 3.76 (brs, 1H), 3.96-4.10 (m, 1H), 5.32-5.44 (m, 1H), 5.56-5.71 (m, 2H). MS m/z: 556 (M+), 188 (100%). UV λmax nm: 270, 281, 293.
【0104】
実施例22
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ}−プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(33.5mg,0.0577mmol)、(E)−5−ブロモ−2−メチル−3−ペンテン−2−オル(41.2mg,0.230mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル=5:1、2回展開)で精製し、26.2mgの生成物を得たが、(E)−5−ブロモ−2−メチル−3−ペンテン−2−オルとの分離が困難であったため、そのまま次の反応に使用した。
【0105】
実施例23
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)− {(Z)−4−メチル−4−トリエチルシリルオキシ−2−ペンテニルチオ}−プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(91.2mg,0.131mmol)、(Z)−1−ブロモ−4−メチル−4−トリエチルシリルオキシ−2−ペンテン(192mg,0.655mmol)、テトラヒドロフラン(1.5ml)、1M−KOH メタノール溶液(1.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:ジクロロメタン:酢酸エチル=160:40:1、1回展開)で精製し無色油状の標記化合物(66.3mg,64%)を得た。
【0106】
IR (neat): 2950, 2850, 1460, 1170, 1250, 1160, 1080cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.60 (q, J = 7.3Hz, 6H), 0.89 (s, 18H), 0.90-1.04 (m, 15H), 1.37 (s, 6H), 1.44 (d, J = 6.8Hz, 3H), 3.33 (dd, J = 13.0, 6.8Hz, 1H), 3.41-3.60 (m, 2H), 3.72 (brs, 1H), 3.96-4.16 (m, 1H), 5.23-5.52 (m, 3H), 5.55-5.68 (m, 2H). MS m/z: 786 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
【0107】
実施例24
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−エチル−4−ヒドロキシ−2−ヘキシニルチオ)プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(60.8mg,0.105mmol)、6−ブロモ−3−エチル−4−ヘキシン−3−オル(108mg,0.525mmol)、テトラヒドロフラン(1ml)、1M−KOH メタノール溶液(1ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:酢酸エチル=5:1、2回展開)で精製し無色油状の標記化合物(38.4mg,63%)を得た。
【0108】
IR (neat): 3400, 2950, 2850, 1460, 1370, 1250, 1150, 1060cm-1. 1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.92 (s, 3H), 0.94 (s, 3H), 1.03 (t, J = 7.3Hz, 6H), 1.46 (d, J = 6.8Hz, 3H), 1.66 (q, J = 7.3Hz, 4H), 3.20 (d, J = 16.6Hz, 1H), 3.24 (d, J = 16.6Hz, 1H), 3.68 (q, J = 6.8Hz, 1H), 3.75 (brs, 1H), 3.96-4.12 (m, 1H), 5.35-5.44 (m, 1H), 5.57-5.71 (m, 2H). MS m/z: 566 (M+- H2O), 187 (100%). UV λmax nm: 270, 281, 293.
【0109】
実施例25
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ}−プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(33.1mg,0.0570mmol)、(E)−6−ブロモ−3−エチル−4−ヘキセン−3−オル(47.4mg,0.229mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル=5:1、2回展開)で精製し無色油状の標記化合物(28.2mg,84%)を得た。
【0110】
IR (neat): 3400, 2920, 2850, 1460, 1370, 1250, 1150, 1060cm-1. 1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.87 (t, J = 7.3Hz, 6H), 0.88 (s, 9H), 1.42 (d, J = 6.8Hz, 3H), 1.54 (q, J = 7.3Hz, 4H), 3.10 (dd, J = 12.6, 5.5Hz, 1H), 3.12 (dd, J = 12.6, 5.5Hz, 1H), 3.45 (q, J = 6.8Hz, 1H), 3.75 (brs, 1H), 3.96-4.15 (m, 1H), 5.35-5.44 (m, 1H), 5.45-5.73 (m, 4H). MS m/z: 586 (M+), 277 (100%). UV λmax nm: 270, 281, 293.
【0111】
実施例26
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(Z)−4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルチオ}プレグナ−5,7,16−トリエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−フェノキシカルボニルチオプレグナ−5,7,16−トリエン(33.0mg,0.0568mmol)、(Z)−1−ブロモ−4−エチル−4−トリエチルシリルオキシ−2−ヘキセン(91.0mg,0.284mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル=2:1、1回展開)で精製し薄黄色油状の標記化合物(23.8mg,60%)を得た。
【0112】
IR (neat): 3400, 2950, 2850, 1460, 1350, 1250, 1140, 1060cm-1. 1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.62 (q, J = 7.5Hz, 6H), 0.80-1.05 (m, 30H), 1.44 (d, J = 6.8Hz, 3H), 1.57 (q, J = 7.3Hz, 4H), 3.28-3.59 (m, 3H), 3.76 (brs, 1H), 3.97-4.28 (m, 1H), 5.23 (d, J = 11.2Hz, 1H), 5.35-5.53 (m, 2H), 5.56-5.72 (m, 2H). MS m/z: 700 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
【0113】
実施例27
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−ヒドロキシ−4−メチル−2−ペンチニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−ヒドロキシ−4−メチル−2−ペンチニルチオ)プレグナ−5,7,16−トリエン(41.6mg,0.0747mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2分間、加熱還流1.5時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル=6:1、3回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル=3:1、3回展開)で精製し、無色油状の標記化合物(3.8mg,9.1%)を得た。
【0114】
IR (neat): 3400, 2930, 2850, 1460, 1360, 1245, 1160, 1060cm-1. 1H NMR δ: 0.09 (s, 6H), 0.82 (s, 3H), 0.90 (s, 9H), 1.45 (d, J = 7.3Hz, 3H), 1.51 (s, 6H), 3.18 (d, J = 16.6Hz, 1H), 3.21 (d, J = 16.6Hz, 1H), 3.66 (q, J = 7.3Hz, 1H), 4.16-4.28 (m, 1H), 4.34-4.43 (m, 1H), 4.92 (brs, 1H), 5.27 (brs, 1H), 5.64 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.32 (d, J = 11.2Hz, 1H). MS m/z: 556 (M+), 248 (100%). UV λmax nm: 264.
【0115】
実施例28
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
実施例22で得られた粗1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ}−プレグナ−5,7,16−トリエン(25.8mg)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル=6:1、4回展開)により、粗精製物(3.1mg)および原料回収(10.5mg)を得た。回収した原料(10.5mg)を再度光照射2分間、加熱還流2時間反応を行い、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル=6:1、4回展開)により、粗精製物(1.8mg)を得た。先に得られたものとあわせ、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル=4:1、4回展開)で精製し、無色油状の標記化合物(2.0mg,6.2%,2工程)を得た。
【0116】
IR (neat): 3400, 2930, 1460, 1370, 1250, 1060cm-1. 1H NMR δ: 0.09 (s, 6H), 0.82 (s, 3H), 0.90 (s, 9H), 1.32 (s, 6H), 1.41 (d, J = 6.8Hz, 3H), 2.99-3.19 (m, 2H), 3.41 (q, J = 6.8Hz, 1H), 4.16-4.28 (m, 1H), 4.32-4.43 (m, 1H), 4.93 (brs,1H), 5.27 (brs, 1H), 5.58 (brs, 1H), 5.10-5.78 (m, 2H), 6.10 (d, J = 11.2Hz, 1H), 6.33 (d, J = 11.2Hz, 1H). MS m/z: 558 (M+), 160 (100%). UV λmax nm: 263.
【0117】
実施例29
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(Z)−4−メチル−4−トリエチルシリルオキシ−2−ペンテニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(Z)−4−メチル−4−トリエチルシリルオキシ−2−ペンテニルチオ}−プレグナ−5,7,16−トリエン(66.1mg,0.0839mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×3枚、ヘキサン:ジクロロメタン=4:1、2回展開)で精製し、20.9mgの化合物を得たが、原料との分離が困難であったため、そのまま次の反応に使用した。
【0118】
実施例30
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−エチル−4−ヒドロキシ−2−ヘキシニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−エチル−4−ヒドロキシ−2−ヘキシニルチオ)プレグナ−5,7,16−トリエン(21.9mg,0.0374mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.45分間、加熱還流1.5時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル=6:1、2回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル=3:1、4回展開)で精製し、無色油状の標記化合物(1.8mg,8.2%)を得た。
【0119】
IR (neat): 3400, 2930, 2850, 1460, 1370, 1250, 1060cm-1. 1H NMR δ: 0.09 (s, 3H), 0.81 (s, 3H), 0.89 (s, 9H), 1.03 (t, J = 7.3Hz, 6H), 1.45 (d, J = 6.8Hz, 3H), 1.67 (q, J = 7.3Hz, 4H), 3.20 (d, J = 16.8Hz, 1H), 3.23 (d, J = 16.8Hz, 1H), 3.67 (q, J = 6.8Hz, 1H), 4.14-4.28 (m, 1H), 4.32-4.43 (m, 1H), 4.93 (brs, 1H), 5.27 (brs, 1H), 5.63 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.32 (d, J = 11.2Hz, 1H). MS m/z: 584 (M+), 248 (100%). UV λmax nm: 264.
【0120】
実施例31
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ}−プレグナ−5,7,16−トリエン(26.3mg,0.0448mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3分間、加熱還流1.5時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル=6:1、3回展開、さらに0.5mm×1枚、ヘキサン:酢酸エチル=3:1、3回展開)で精製し、無色油状の標記化合物(2.1mg,8.0%)を得た。
【0121】
IR (neat): 3400, 2930, 2850, 1460, 1375, 1255, 1060cm-1. 1H NMR δ: 0.09 (s, 6H), 0.82 (s, 3H), 0.84-0.98 (m, 15H), 1.41 (d, J = 6.8Hz, 3H), 1.54 (q, J = 7.3Hz, 4H), 3.07-3.18 (m, 2H), 3.42 (q, J = 6.8Hz, 1H), 4.15-4.29 (m, 1H), 4.33-4.44 (m, 1H), 4.93 (brs, 1H), 5.27 (brs, 1H), 5.44-5.76 (m, 3H), 6.10 (d, J = 11.2Hz, 1H), 6.32 (d, J = 11.2Hz, 1H). MS m/z: 586 (M+), 426 (100%). UV λmax nm: 263.
【0122】
実施例32
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(Z)−4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(Z)−4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルチオ}プレグナ−5,7,16−トリエン(23.7mg,0.0338mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.5分間、加熱還流1.5時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル=6:1、3回展開)で精製し、無色油状の標記化合物(1.3mg,5.5%)を得た。
【0123】
IR (neat): 3400, 2925, 2850, 1460, 1370, 1250, 1050cm-1. 1H NMR δ: 0.09 (s, 6H), 0.62 (q, J = 7.5Hz, 6H), 0.76-1.05 (m, 27H), 1.43 (d, J = 6.8Hz, 3H), 1.56 (q, J = 7.5Hz, 4H), 3.28-3.60 (m, 3H), 4.16-4.29 (m, 1H), 4.32-4.43 (m, 1H), 4.93 (brs, 1H), 5.18-5.30 (m, 2H), 5.32-5.55 (m, 1H), 5.59 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.32 (d, J = 11.2Hz, 1H). MS m/z: 700 (M+), 202 (100%). UV λmax nm: 263.
【0124】
実施例33
1α,3β−ジヒドロキシ−20(S)−(4−ヒドロキシ−4−メチル−2−ペンチニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−ヒドロキシ−4−メチル−2−ペンチニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン(3.4mg,0.00611mmol)のテトラヒドロフラン(2ml)溶液に1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(1ml)を加え室温で13時間反応した。反応溶液を酢酸エチルで希釈し、氷冷0.5N−塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄、硫酸マグネシウムで乾燥後減圧下溶媒を除去した。得られた残渣を分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(0.653mg,24%)を得た。
【0125】
IR (neat): 3400, 2930, 1450, 1370, 1250, 1160, 1050cm-1. 1H NMR δ: 0.84 (s, 3H), 1.45 (d, J = 7.3Hz, 3H), 1.51 (s, 6H), 3.17 (d, J = 16.6Hz, 1H), 3.20 (d, J = 16.6Hz, 1H), 3.66 (q, J = 7.3Hz, 1H), 4.28-4.31 (m, 1H), 4.38-4.49 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.65 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 442 (M+), 311 (100%). UV λmax nm: 263.
【0126】
実施例34
1α,3β−ジヒドロキシ−20(S)−{(E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン(2.0mg,0.00358mmol)、テトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.5ml)を実施例33と同操作で反応(3日間)、後処理を行い、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(0.744mg,47%)を得た。
【0127】
IR (neat): 3400, 2920, 1460, 1370, 1060cm-1. 1H NMR δ: 0.88 (s, 3H), 1.32 (s, 6H), 1.41 (d, J = 6.8Hz, 3H), 2.96-3.20 (m, 2H), 3.40 (d, J = 6.8Hz, 1H), 4.17-4.32 (m, 1H), 4.39-4.49 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.60-5.77 (m, 2H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 426 (M+- H2O), 105 (100%). UV λmax nm: 264.
【0128】
実施例35
1α,3β−ジヒドロキシ−20(S)−{(Z)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
実施例29で得られた粗1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(Z)−4−メチル−4−トリエチルシリルオキシ−2−ペンテニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン(20.9mg)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例33と同操作で反応(40時間)、後処理を行い、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、5回展開)で精製し、無色油状の標記化合物(1.67mg,14%,2工程)を得た。
【0129】
IR (neat): 3400, 2930, 1450, 1370, 1210, 1150, 1060cm-1. 1H NMR δ: 0.84 (s, 3H), 1.36 (s, 6H), 1.44 (d, J = 7.3Hz, 3H), 3.34 (dd, J = 12.2, 6.8Hz, 1H), 3.62-3.77 (m, 2H), 4.17-4.32 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.35-5.58 (m, 2H), 5.60 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 444 (M+), 312 (100%). UV λmax nm: 264.
【0130】
実施例36
1α,3β−ジヒドロキシ−20(S)−(4−エチル−4−ヒドロキシ−2−ヘキシニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−(4−エチル−4−ヒドロキシ−2−ヘキシニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン(1.8mg,0.00308mmol)、テトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例33と同操作で反応(40時間)、後処理を行い、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(0.699mg,48%)を得た。
【0131】
IR (neat): 3400, 2930, 1450, 1370, 1230, 1150, 1060cm-1. 1H NMR δ: 0.82 (s, 3H), 1.02 (t, J = 7.3Hz, 6H), 1.44 (d, J = 6.8Hz, 3H), 1.65 (q, J = 7.3Hz, 4H), 3.28 (d, J = 16.7Hz, 1H), 3.32 (d, J = 16.7Hz, 1H), 3.66 (q, J = 6.8Hz, 1H), 4.16-4.31 (m, 1H), 4.36-4.52 (m, 1H), 4.99 (brs, 1H), 5.32 (brs, 1H), 5.61 (brs, 1H), 6.07 (d, J = 11.2Hz, 1H), 6.35 (d, J = 11.2Hz, 1H). MS m/z: 452 (M+- H2O), 91 (100%). UV λmax nm: 264.
【0132】
実施例37
1α,3β−ジヒドロキシ−20(S)−{(E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン(1.9mg,0.00324mmol)、テトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例33と同操作で反応(40時間)、後処理を行い、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(0.748mg,49%)を得た。
【0133】
IR (neat): 3400, 2920, 1450, 1370, 1270, 1050cm-1. 1H NMR δ: 0.86 (t, J = 7.3Hz, 6H), 0.88 (s, 3H), 1.41 (d, J = 6.8Hz, 3H), 1.53 (q, J = 7.3Hz, 4H), 3.07-3.17 (m, 2H), 3.42 (q, J = 6.8Hz, 1H), 4.17-4.29 (m, 1H), 4.38-4.50 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.43-5.80 (m, 3H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 454 (M+- H2O), 161 (100%). UV λmax nm: 264.
【0134】
実施例38
1α,3β−ジヒドロキシ−20(S)−{(Z)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α−(tert−ブチルジメチルシリルオキシ)−3β−ヒドロキシ−20(S)−{(Z)−4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン(1.2mg,0.00171mmol)、テトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例33と同操作で反応(40時間)、後処理を行い、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、2回展開)で精製し、無色油状の標記化合物(0.357mg,44%)を得た。
【0135】
IR (neat): 3400, 2920, 1450, 1370, 1060cm-1. 1H NMR δ: 0.84 (s, 3H), 0.91 (t, J = 7.5Hz, 6H), 1.44 (d, J = 6.8Hz, 3H), 1.57 (q, J = 7.5Hz, 4H), 3.27-3.58 (m, 3H), 4.17-4.31 (m, 1H), 4.40-4.52 (m, 1H), 5.01 (brs, 1H), 5.23-5.37 (m, 2H), 5.44-5.70 (m, 2H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 454 (M+- H2O), 312 (100%). UV λmax nm: 263.
【0136】
実施例39
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16α−ヒドロキシ−9,10−セコプレグナ−5,7,10(19),17(E)−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16α−ヒドロキシプレグナ−5,7,17(E)−トリエン(103mg,0.184mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×3枚、ヘキサン:酢酸エチル=9:1、4回展開、さらに0.5mm×2枚、ヘキサン:酢酸エチル=9:1、4回展開)で精製し、無色油状の標記化合物(24.1mg,23%)を得た。
【0137】
IR (neat): 3350, 2930, 2855, 1460, 1380, 1255, 1080cm-1. 1H NMR δ: 0.06 (s, 12H), 0.74 (s, 3H), 0.88 (s, 18H), 1.74 (d, J = 7.3Hz, 3H), 4.12-4.28 (m, 1H), 4.32-4.52 (m, 2H), 4.86 (d, J = 2.0Hz, 1H), 5.19 (d, J = 2.0Hz, 1H), 5.64 (q, J = 7.3Hz, 1H), 6.00 (d, J = 11.2Hz, 1H), 6.23 (d, J = 11.2Hz, 1H). MS m/z: 558 (M+), 248 (100%). UV λmax nm: 262.
【0138】
実施例40
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16α−ヒドロキシ−9,10−セコプレグナ−5,7,10(19),17(E)−テトラエン(24.0mg,0.0430mmol)、ジクロロメタン(2.5ml)、ピリジン(0.0209ml,0.258mmol)、フェニルクロロチオノホルメート(0.0178ml,0.129mmol)を実施例1と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル=9:1、1回展開)で精製し、無色油状の標記化合物(17.9mg,60%)を得た。
【0139】
IR (neat): 2925, 2850, 1730, 1490, 1470, 1255, 1190, 1160, 1100cm-1. 1H NMR δ: 0.07 (s, 12H), 0.85 (s, 3H), 0.88 (s, 18H), 1.59 (d, J = 6.8Hz, 3H), 4.04-4.28 (m, 2H), 4.39 (t, J = 4.9Hz, 1H), 4.88 (d, J = 2.0Hz, 1H), 5.19 (d, J = 2.0Hz, 1H), 5.74 (brs, 1H), 6.09 (d, J = 11.2Hz, 1H), 6.24 (d, J = 11.2Hz, 1H), 7.12-7.44 (m, 5H). MS m/z: 694 (M+), 248 (100%). UV λmax nm: 210, 263.
【0140】
実施例41
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(2.0mg,0.00288mmol)、4−ブロモ−2−メチル−2−ブタノール(2.4mg,0.0144mmol)、テトラヒドロフラン(0.25ml)、1M−KOH メタノール溶液(0.25ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し無色油状の標記化合物(1.5mg,79%)を得た。
【0141】
IR (neat): 3400, 2920, 2850, 1460, 1360, 1250, 1080cm-1. 1H NMR δ: 0.07 (s, 12H), 0.81 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.23 (s, 6H), 1.42 (d, J = 6.8Hz, 3H), 3.49 (q, J = 6.8Hz, 1H), 4.11-4.24 (m, 1H), 4.26-4.31 (m, 1H), 4.84 (brs, 1H), 5.19 (brs, 1H), 5.60 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.24 (d, J = 11.2Hz, 1H). MS m/z: 660 (M+), 248 (100%). UV λmax nm: 263.
【0142】
実施例42
1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン(1.5mg,0.00227mmol)、テトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.5ml)を実施例9と同操作で反応(1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状物の標記化合物(0.511mg,52%)を得た。ここで得られた化合物の各スペクトルは、実施例15で得られた化合物のそれと一致した。
【0143】
実施例43
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16−オキソプレグナ−5,7,17(E)−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16α−ヒドロキシプレグナ−5,7,17(E)−トリエン(2.01g,3.60mmol)のクロロホルム(150ml)溶液に二酸化マンガン(40g)を加え、超音波照射下2時間反応した。反応溶液をろ過、濃縮後、カラムクロマトグラフィー(ヘキサン:ジクロロメタン:酢酸エチル=18:2:1)で精製して無色固体の標記化合物(1.45g,73%)を得た。
【0144】
IR (KBr): 2950, 2850, 1730, 1650, 1460, 1380, 1255, 1100cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 3H), 0.08 (s, 3H), 0.12 (s, 3H), 0.89 (s, 18H), 0.97 (s, 3H), 0.99 (s, 3H), 1.88 (d, J = 7.3Hz, 3H), 3.73 (brs, 1H), 3.96-4.16 (m, 1H), 5.30-5.39 (m, 1H), 5.56-5.65 (m, 1H), 6.56 (q, J = 7.3Hz, 1H). MS m/z: 556 (M+), 367 (100%). UV λmax nm: 242, 258, 270, 281, 293.
【0145】
実施例44
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16β−ヒドロキシプレグナ−5,7,17(E)−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16−オキソプレグナ−5,7,17(E)−トリエン(1.45g,2.60mmol)および塩化セリウム(III)・7水和物(1.45g,3.90mmol)のメタノール(20ml)、テトラヒドロフラン(80ml)溶液を0℃に冷却し、水素化ホウ素ナトリウム(490mg,13.0mmol)を少しずつ加えた。反応溶液を室温で1時間撹拌後、減圧下で濃縮し、残渣を水にあけ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:1)で精製して無色固体の標記化合物(1.29g,89%)および1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16α−ヒドロキシプレグナ−5,7,17(E)−トリエン(85mg,5.8%)を得た。
【0146】
標記化合物 IR (KBr): 3300, 2950, 2850, 1460, 1370, 1245, 1100, 1000cm-1. 1H NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.88 (s, 18H), 0.93 (s, 3H), 1.00 (s, 3H), 1.76 (dd, J = 7.3, 2.0Hz, 3H), 3.71 (brs, 1H), 3.93-4.16 (m, 1H), 4.49 (t, J = 7.8Hz, 1H), 5.33-5.42 (m, 1H), 5.47-5.64 (m, 2H). MS m/z: 558 (M+), 369 (100%). UV λmax nm: 270, 281, 293.
【0147】
実施例45
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16β−ヒドロキシ−9,10−セコプレグナ−5,7,10(19),17(E)−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16β−ヒドロキシプレグナ−5,7,17(E)−トリエン(115mg,0.205mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射5.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×3枚、ヘキサン:酢酸エチル=8:1、3回展開)で精製し、無色油状の標記化合物(27.0mg,23%)を得た。
【0148】
IR (neat): 3400, 2950, 2850, 1470, 1370, 1250, 1075cm-1. 1H NMR δ: 0.06 (s, 6H), 0.07 (s, 6H), 0.88 (s, 18H), 0.91 (s, 3H), 1.74 (dd, J = 6.8, 1.5Hz, 3H), 4.13-4.29 (m, 1H), 4.32-4.55 (m, 2H), 4.87 (d, J = 1.9Hz, 1H), 5.20 (d, J = 1.9Hz, 1H), 5.57 (dq, J = 6.8, 1.5Hz, 1H), 6.04 (d, J = 11.2Hz, 1H), 6.21 (d, J = 11.2Hz, 1H). MS m/z: 558 (M+), 427 (100%). UV λmax nm: 263.
【0149】
実施例46
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−16β−ヒドロキシ−9,10−セコプレグナ−5,7,10(19),17(E)−テトラエン(53.1mg,0.0950mmol)、ジクロロメタン(5ml)、ピリジン(0.0461ml,0.570mmol)、フェニルクロロチオノホルメート(0.0394ml,0.285mmol)を実施例1と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=8:1、1回展開)で精製し、無色油状の標記化合物(55.4mg,84%)を得た。
【0150】
IR (neat): 2930, 2850, 1730, 1490, 1470, 1370, 1255, 1190, 1160, 1100, 1010cm-1. 1H NMR δ: 0.06 (s, 12H), 0.73 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.61 (d, J = 6.8Hz, 3H), 4.08 (q, J = 6.8Hz, 1H), 4.12-4.28 (m, 1H), 4.32-4.44 (m, 1H), 4.88 (d, J = 1.9Hz, 1H), 5.19 (d, J = 1.9Hz, 1H), 5.72 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.24 (d, J = 11.2Hz, 1H), 7.07-7.48 (m, 5H). MS m/z: 694 (M+), 248 (100%). UV λmax nm: 215, 263.
【0151】
実施例47
1α,3β−ジヒドロキシ−20(R)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(3.3mg,0.00475mmol)、4−ブロモ−2−メチル−2−ブタノール(4.0mg,0.0238mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、3.6mgの生成物を得た。これにテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例9と同操作で反応(1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(1.15mg,56%)を得た。
【0152】
IR (neat): 3400, 2920, 1450, 1370, 1200, 1060cm-1. 1H NMR δ: 0.74 (s, 3H), 1.24 (s, 6H), 1.47 (d, J = 6.8Hz, 3H), 3.40 (q, J = 6.8Hz, 1H), 4.14-4.29 (m, 1H), 4.34-4.48 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.29 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 432 (M+), 312 (100%). UV λmax nm: 263.
【0153】
実施例48
1α,3β−ジヒドロキシ−20(R)−(4−ヒドロキシ−4−メチルペンチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(3.9mg,0.00561mmol)、1−ブロモ−4−メチル−4−トリエチルシリルオキシペンタン(8.3mg,0.0281mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:ジクロロメタン:酢酸エチル=160:40:1、1回展開)で精製し、3.1mgの生成物を得た。これにテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.5ml)を加え、実施例9と同操作で反応(1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、2回展開)で精製し、無色油状の標記化合物(0.614mg,24%)を得た。
【0154】
IR (neat): 3400, 2920, 1450, 1370, 1270, 1200, 1050cm-1. 1H NMR δ: 0.74 (s, 3H), 1.22 (s, 6H), 1.45 (d, J = 6.9Hz, 3H), 3.36 (q, J = 6.9Hz, 1H), 4.18-4.30 (m, 1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.57 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 428 (M+- H2O), 312 (100%). UV λmax nm: 264.
【0155】
実施例49
1α,3β−ジヒドロキシ−20(R)−(5−ヒドロキシ−5−メチルヘキシルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(3.8mg,0.00547mmol)、6−ブロモ−2−メチル−2−ヘキサノール(5.3mg,0.0274mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、3.1mgの生成物を得た。これにテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例9と同操作で反応(1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(1.34mg,60%)を得た。
【0156】
IR (neat): 3400, 2920, 1450, 1370, 1200, 1060cm-1. 1H NMR δ: 0.73 (s, 3H), 1.21 (s, 6H), 1.45 (d, J = 6.8Hz, 3H), 3.34 (q, J = 6.8Hz, 1H), 4.28-4.32 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.56 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 442 (M+- H2O), 312 (100%). UV λmax nm: 264.
【0157】
実施例50
1α,3β−ジヒドロキシ−20(R)−(2−ヒドロキシ−2−メチルプロピルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(3.9mg,0.00561mmol)、イソブチレンオキシド(2.0mg,0.0281mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、2.2mgの生成物を得た。これにテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例9と同操作で反応(1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(0.929mg,40%)を得た。
【0158】
IR (neat): 3400, 2920, 1450, 1370, 1200, 1145, 1055cm-1. 1H NMR δ: 0.73 (s, 3H), 1.26 (s, 3H), 1.27 (s, 3H), 1.46 (d, J = 6.9Hz, 3H), 3.39 (q, J = 6.9Hz, 1H), 4.18-4.29 (m, 1H), 4.41-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 418 (M+), 91 (100%). UV λmax nm: 264.
【0159】
実施例51
1α,3β−ジヒドロキシ−20(R)−(3−エチル−3−ヒドロキシペンチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(4.0mg,0.00575mmol)、5−ブロモ−3−エチル−3−ペンタノール(5.6mg,0.0288mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液 (0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、3.0mgの生成物を得た。これにテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例9と同操作で反応(1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(1.48mg,56%)を得た。
【0160】
IR (neat): 3400, 2920, 1465, 1370, 1200, 1060cm-1. 1H NMR δ: 0.74 (s, 3H), 0.86 (t, J = 7.4Hz, 6H), 1.40-1.53 (m, 7H), 3.39 (q, J = 6.9Hz, 1H), 4.18-4.30 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 264.
【0161】
実施例52
1α,3β−ジヒドロキシ−20(R)−(4−エチル−4−ヒドロキシヘキシルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(5.0mg,0.00719mmol)、6−ブロモ−3−エチル−3−ヘキサノール(7.5mg,0.0360mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、4.2mgの生成物を得た。これにテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例9と同操作で反応(1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(1.14mg,33%)を得た。
【0162】
IR (neat): 3400, 2920, 1455, 1370, 1250, 1140, 1050cm-1. 1H NMR δ: 0.74 (s, 3H), 0.92 (t, J = 6.9Hz, 6H), 3.39 (q, J = 6.8Hz, 1H), 4.18-4.32 (m, 1H), 4.39-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 456 (M+- H2O), 312 (100%). UV λmax nm: 264.
【0163】
実施例53
1α,3β−ジヒドロキシ−20(R)−(4−ヒドロキシ−4−メチル−2−ペンチニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(4.3mg,0.00619mmol)、5−ブロモ−2−メチル−3−ペンチン−2−オル(5.5mg,0.0309mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、3.3mgの生成物を得た。これにテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例33と同操作で反応(2日間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(1.17mg,43%)を得た。
【0164】
IR (neat): 3400, 2920, 1455, 1370, 1250, 1170, 1055cm-1. 1H NMR δ: 0.74 (s, 3H), 1.45 (d, J = 6.8Hz, 3H), 1.48 (s, 6H), 3.20 (d, J = 16.6Hz, 1H), 3.30 (d, J = 16.6Hz, 1H), 3.56 (q, J = 6.8Hz, 1H), 4.18-4.32 (m, 1H), 4.37-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 442 (M+), 312 (100%). UV λmax nm: 264.
【0165】
実施例54
1α,3β−ジヒドロキシ−20(R)−{(E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(5.0mg,0.00719mmol)、(E)−5−ブロモ−2−メチル−3−ペンテン−2−オル(6.4mg,0.0360mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、4.8mgの生成物を得た。これにテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例33と同操作で反応(2日間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、2回展開)で精製し、無色油状の標記化合物(1.88mg,59%)を得た。
【0166】
IR (neat): 3400, 2920, 1450, 1370, 1205, 1140, 1050cm-1. 1H NMR δ: 0.73 (s, 3H), 1.33 (s, 6H), 1.44 (d, J = 6.8Hz, 3H), 3.02-3.22 (m, 2H), 3.33 (q, J = 6.8Hz, 1H), 4.16-4.31 (m, 1H), 4.39-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 5.63-5.79 (m, 2H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 426 (M+- H2O), 352 (100%). UV λmax nm: 264.
【0167】
実施例55
1α,3β−ジヒドロキシ−20(R)−{(Z)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(4.8mg,0.00690mmol)、(Z)−1−ブロモ−4−メチル−4−トリエチルシリルオキシ−2−ペンテン(10.1mg,0.0345mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を、実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:ジクロロメタン:酢酸エチル=160:40:1、1回展開)で精製し、4.2mgの生成物を得た。これにテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例33と同操作で反応(2日間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、2回展開)で精製し、無色油状の標記化合物(1.87mg,61%)を得た。
【0168】
IR (neat): 3400, 2920, 1450, 1370, 1200, 1140, 1055cm-1. 1H NMR δ: 0.73 (s, 3H), 1.36 (s, 6H), 1.48 (d, J = 6.9Hz, 3H), 3.32-3.61 (m, 3H), 4.17-4.33 (m, 1H), 4.37-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.37-5.63 (m, 3H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 444 (M+), 294 (100%). UV λmax nm: 264.
【0169】
実施例56
1α,3β−ジヒドロキシ−20(R)−(4−エチル−4−ヒドロキシ−2−ヘキシニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(4.3mg,0.00619mmol)、6−ブロモ−3−エチル−4−ヘキシン−3−オル(6.4mg,0.0309mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、4.2mgの生成物を得た。これにテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例33と同操作で反応(2日間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(1.17mg,43%)を得た。
【0170】
IR (neat): 3400, 2920, 1455, 1370, 1240, 1150, 1055cm-1. 1H NMR δ: 0.74 (s, 3H), 1.03 (t, J = 7.3Hz, 6H), 1.49 (d, J = 6.8Hz, 3H), 1.66 (q, J = 7.3Hz, 4H), 3.23 (d, J = 16.6Hz, 1H), 3.29 (d, J = 16.6Hz, 1H), 3.59 (q, J = 6.8Hz, 1H), 4.18-4.33 (m, 1H), 4.39-4.53 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.34 (d, J = 11.2Hz, 1H). MS m/z: 470 (M+), 312 (100%). UV λmax nm: 264.
【0171】
実施例57
1α,3β−ジヒドロキシ−20(R)−{(E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(5.0mg,0.00719mmol)、(E)−6−ブロモ−3−エチル−4−ヘキセン−3−オル(7.5mg,0.0360mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)で精製し、4.6mgの生成物を得た。これにテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例33と同操作で反応(2日間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、2回展開)で精製し、無色油状の標記化合物(2.40mg,71%)を得た。
【0172】
IR (neat): 3400, 2920, 1450, 1370, 1220, 1140, 1055cm-1. 1H NMR δ: 0.73 (s, 3H), 0.87 (t, J = 7.3Hz, 6H), 1.44 (d, J = 6.8Hz, 3H), 1.54 (q, J = 7.3Hz, 4H), 3.04-3.27 (m, 2H), 3.35 (q, J = 6.8Hz, 1H), 4.26-4.32 (m, 1H), 4.39-4.53 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.45-5.78 (m, 3H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 454 (M+- H2O), 380 (100%). UV λmax nm: 264.
【0173】
実施例58
1α,3β−ジヒドロキシ−20(R)−{(Z)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(5.0mg,0.00719mmol)、(Z)−1−ブロモ−4−エチル−4−トリエチルシリルオキシ−2−ヘキセン(11.6mg,0.0360mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:ジクロロメタン:酢酸エチル=160:40:1、1回展開)で精製し、4.2mgの生成物を得た。これにテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を加え、実施例33と同操作で反応(2日間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)で精製し、無色油状の標記化合物(1.74mg,51%)を得た。
【0174】
IR (neat): 3400, 2925, 1450, 1365, 1210, 1055cm-1. 1H NMR δ: 0.72 (s, 3H), 0.91 (t, J = 7.3Hz, 6H), 1.48 (d, J = 6.8Hz, 3H), 1.52 (q, J = 7.3Hz, 4H), 3.32-3.64 (m, 3H), 4.16-4.32 (m, 1H), 4.39-4.51 (m, 1H), 5.01 (brs, 1H), 5.25-5.37 (m, 2H), 5.50-5.69 (m, 2H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 454 (M+- H2O), 312 (100%). UV λmax nm: 263.
【0175】
実施例59
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−17α,20α−エポキシプレグナ−5,7−ジエン PTAD付加体の製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)プレグナ−5,7,17(Z)−トリエン PTAD付加体(1.00g,1.39mmol)及び炭酸水素ナトリウム(290mg,3.48mmol)のジクロロメタン(20ml)混合液を0℃に冷却し、70%−m−クロロ過安息香酸(412mg,1.67mmol)を加えた。反応混合液を同温下0.5時間撹拌後、ジクロロメタンで希釈し飽和炭酸水素ナトリウム水溶液、飽和亜硫酸水素ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル=5:1)により精製し、無色固体の標記化合物(920mg,90%)を得た。
【0176】
1H-NMR δ: 0.08 (s, 3H), 0.09 (s, 3H), 0.11 (s, 3H), 0.15 (s, 3H), 0.89 (s, 9H), 0.91 (s, 12H), 1.01 (s, 3H), 1.41 (d, 3H, J=5.6Hz), 3.00 (q, 1H, J=5.6Hz), 3.11-3.28 (m, 1H), 3.85 (brs, 1H), 4.69-4.85 (m, 1H), 6.13 (d, 1H, J=8.3Hz), 6.28 (d, 1H, J=7.9Hz), 7.15 (dd, 1H, J=7.3, 7.6Hz), 7.28 (dd, 2H, J=7.6, 7.9Hz), 7.38 (d, 2H, J=7.6Hz). UV λmaxnm: 260.
【0177】
実施例60
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−17α,20α−エポキシプレグナ−5,7−ジエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−17α,20α−エポキシプレグナ−5,7−ジエン PTAD付加体(613mg,0.835mmol)を1,3−ジメチル−2−イミダゾリジノン(60ml)に溶解し、140℃で5時間加熱攪拌した。これを水にあけ、酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル=20:1)により精製し、無色固体の標記化合物(328mg,70%)を得た。
【0178】
1H-NMR δ: 0.04 (s, 9H), 0.08 (s, 3H), 0.81 (s, 3H), 0.86 (s, 18H), 0.88 (s, 3H), 1.36 (d, 3H, J=5.6Hz), 2.95 (q, 1H, J=5.6Hz), 3.67 (brs, 1H), 3.95-4.10 (m, 1H), 5.33-5.44 (m, 1H), 5.57 (d, 1H, J=5.3Hz). UV λmaxnm: 269, 281, 293 .
【0179】
実施例61
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエンの製造
1.5M−リチウムジイソプロピルアミド シクロヘキサン溶液(4.7ml,7.05mmol)のトルエン(3ml)溶液を0℃に冷却し、0.95M−塩化ジエチルアルミニウム ヘキサン溶液(4.95ml,4.70mmol)を加えた。反応溶液を同温下、0.5時間撹拌後、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−17α,20α−エポキシプレグナ−5,7−ジエン(328mg,0.587mmol)のトルエン(5ml)溶液を加えさらに同温下3時間撹拌し、飽和炭酸水素ナトリウム水溶液及び酢酸エチルを加えてセライト濾過した。有機層を飽和食塩水で洗浄、硫酸マグネシウムで乾燥し、減圧下溶媒留去後得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:1)により精製し、無色固体の標記化合物(277mg,84%)を得た。
【0180】
1H-NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.88 (s, 21H), 0.95 (s, 3H), 1.36 (d, 3H, J=6.3Hz), 3.71 (brs, 1H), 3.97-4.12 (m, 1H), 4.39 (q, 1H, J=6.3Hz), 5.35-5.44 (m, 1H), 5.61 (d, 1H, J=5.3Hz), 5.67 (s, 1H). UV λmaxnm: 270, 281, 293 .
【0181】
実施例62
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(3−ヒドロキシ−3−メチルブチルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(97mg,0.175mmol)、水素化ナトリウム(50mg,2.08mmol)及び4−ブロモ−2,3−エポキシ−2−メチルブタン(145mg,0.877mmol)のテトラヒドロフラン(2ml)溶液を12時間加熱還流後、1M−水素化トリ−s−ブチルホウ素リチウム テトラヒドロフラン溶液(1.8ml,1.80mmol)を加え45分間加熱還流した。反応溶液に3N−水酸化ナトリウム水溶液及び30%−過酸化水素水を加え室温で30分間撹拌後、酢酸エチルで希釈、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:1)により精製し、無色油状の標記化合物(113mg,100%)を得た。
【0182】
IR (neat): 3500, 2960, 2860, 1463, 1375, 1260, 1105cm-1. 1H-NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.88 (s, 21H), 0.94 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.31 (d, 3H, J=6.6Hz), 3.47-3.59 (m, 1H), 3.59-3.78 (m, 1H), 3.70 (brs, 1H), 3.93 (q, 1H, J=6.6Hz), 3.98-4.12 (m, 1H), 5.34-5.45 (m, 1H), 5.57-5.70 (m, 2H). UV λmaxnm: 269, 281, 293.
【0183】
実施例63
1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(3−ヒドロキシ−3−メチルブチルオキシ)プレグナ−5,7,16−トリエン(27mg,0.0419mmol)のテトラヒドロフラン(1ml)溶液に1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.25ml,0.25mmol)を加え室温下20時間、加熱還流下2時間撹拌した。反応溶液を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄し、有機層を硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣を分取用薄層クロマトグラフィー(0.5mm×1枚及び0.25mm×1枚、ジクロロメタン:エタノール=20:1、2回展開)により精製し、無色油状の標記化合物(17.3mg,99%)を得た。
【0184】
IR (neat): 3420, 2940, 1735, 1660, 1460, 1365, 1270, 1150, 1055cm-1. 1H-NMR δ: 0.88 (s, 3H), 0.96 (s, 3H), 1.22 (s, 3H), 1.23 (s, 3H), 1.30 (d, 3H, J=6.6Hz), 3.45-3.58 (m, 1H), 3.58-3.72 (m, 2H), 3.76 (brs, 1H), 3.94 (q, 1H, J=6.6Hz), 3.98-4.14 (m, 1H), 5.37-5.48 (m, 1H), 5.62 (s, 1H), 5.72 (d, 1H, J=3.6Hz) . UV λmaxnm: 270, 281, 293.
【0185】
実施例64
1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルオキシ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルオキシ)プレグナ−5,7,16−トリエン(11mg,0.0264mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射1分50秒間、加熱還流2時間)、減圧下溶媒を留去し、得られた残渣を分取用薄層クロマトグラフィー(0.25mm×1枚、ジクロロメタン:酢酸エチル=20:1、2回展開、さらに0.25mm×0.5枚、ヘキサン:酢酸エチル:エタノール=10:5:1、3回展開)により精製し、無色油状の標記化合物(0.890mg,8.1%)を得た。
【0186】
IR (neat): 3400, 2980, 2940, 1450, 1370, 1160, 1060cm-1. 1H-NMR δ: 0.78 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.31 (d, 3H, J=6.6Hz), 3.47-3.58 (m, 1H), 3.63 (s, 1H), 3.61-3.73 (m, 1H), 3.91 (q, 1H, J=6.6Hz), 4.18-4.30 (m, 1H), 4.39-4.51 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.59 (brs, 1H), 6.10 (d, 1H, J=11.6Hz), 6.37 (d, 1H, J=11.6Hz). UV λmaxnm: 263.
【0187】
実施例65
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20−オキソプレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(600mg,1.07mmol)、ピリジニウムジクロメート(610mg,1.61mmol)及びフロリジル(3g)のジクロロメタン(10ml)懸濁液を1.5時間室温下撹拌後 2.5時間超音波照射した。減圧下溶媒を留去し得られた残渣をジエチルエーテルで希釈しセライト濾過した。減圧下溶媒を留去し得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル=15:1)により精製し、無色固体の標記化合物(343mg,57%)を得た。
【0188】
IR (KBr): 2920, 2850, 1655, 1585, 1460, 1370, 1250, 1225, 1100, 1075, 1060cm-1. 1H-NMR δ: 0.06 (s, 6H), 0.07 (s, 3H), 0.11 (s, 3H), 0.87 (s, 9H), 0.89 (s, 12H), 0.95 (s,3H), 2.28 (s, 3H), 3.72 (brs, 1H), 3.95-4.15 (m, 1H), 5.36-5.44 (m,1H), 5.57-5.67 (m, 1H), 6.74 (brs, 1H). MS m/z: 556 (M+), 367 (100%). UV λmaxnm: 238, 270, 281, 293.
【0189】
実施例66
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20−オキソプレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(50.0mg,0.0894mmol)及び4−メチルモルホリン−N−オキシド(15.7mg,0.134mmol)のジクロロメタン(1ml)溶液に粉末状モレキュラーシーブ4Aを加え室温で10分間撹拌した。これに過ルテニウム酸テトラ−n−ブチルアンモニウム(1.6mg,0.00447mmol)を加え室温で30分間撹拌した。反応溶液を濾過後、ジクロロメタンで希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水、飽和硫酸銅水溶液の順で有機層を洗浄し、硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、得られた残渣を分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル=5:1、1回展開)により精製し、無色固体の標記化合物(37.1mg,74%)を得た。
【0190】
実施例67
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20−オキソプレグナ−5,7,16−トリエン(93mg,0.167mmol)及び塩化セリウム(III)・7水和物(93mg,0.251mmol)のメタノール(1.5ml)、テトラヒドロフラン(6ml)溶液を0℃に冷却し、水素化ホウ素ナトリウム(32mg,0.835mmol)を徐々に加えた。反応溶液を室温で1時間撹拌後、減圧下濃縮し残渣を水にあけ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下溶媒留去した。得られた残渣を分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=10:1、3回展開)により精製し、無色固体の標記化合物(68.2mg,73%)及び1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(17.0mg,18%)を得た。
【0191】
標記化合物 1H-NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.85 (s, 3H), 0.89 (s, 18H), 0.95 (s, 3H), 1.37 (d, 3H, J=6.6Hz), 3.70 (brs, 1H), 3.96-4.12 (m, 1H), 4.31-4.44 (m, 1H), 5.31-5.43 (m, 1H), 5.61 (d, 1H, J=5.3Hz), 5.66 (brs, 1H). UV λmaxnm: 270, 281, 293.
【0192】
実施例68
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−(3−ヒドロキシ−3−メチルブチルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(51mg,0.0911mmol)、水素化ナトリウム(50mg,2.08mmol)及び4−ブロモ−2,3−エポキシ−2−メチルブタン(75mg,0.455mmol)のテトラヒドロフラン(2ml)溶液を1.5時間加熱還流し、1M−水素化トリ−s−ブチルホウ素リチウム テトラヒドロフラン溶液(0.9ml,0.900mmol)を加え20分間加熱還流した。反応溶液に3N−水酸化ナトリウム水溶液及び30%−過酸化水素水を加え室温で30分間撹拌後、酢酸エチルで希釈、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣を分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル=10:1、2回展開)により精製し、無色油状の標記化合物(48.6mg,83%)を得た。
【0193】
IR (neat): 3500, 2950, 2870, 1470, 1380, 1260cm-1. 1H-NMR δ: 0.05 (s, 3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.11 (s, 3H), 0.85 (s, 3H), 0.88 (s, 18H), 0.94 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.32 (d, 3H, J=6.6Hz), 1.73 (t, 2H, J=5.6Hz), 3.53 (s, 1H), 3.57-3.70 (m, 2H), 3.70 (brs, 1H), 3.93-4.11 (m, 2H), 5.31-5.42 (m, 1H), 5.60 (d, 1H, J=5.6Hz), 5.64 (s, 1H). UV λmaxnm: 270, 281, 293.
【0194】
実施例69
1α,3β−ジヒドロキシ−20(R)−(3−ヒドロキシ−3−メチルブチルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−(3−ヒドロキシ−3−メチルブチルオキシ)プレグナ−5,7,16−トリエン(50mg,0.0775mmol)のテトラヒドロフラン(1ml)溶液に1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.5ml)を加え室温下12時間、加熱還流下5時間撹拌した。反応溶液を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄し、有機層を硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣を分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=20:1、2回展開)により精製し、無色油状の標記化合物(23.8mg,74%)、および原料回収(6mg,12%)を得た。
【0195】
IR (neat): 3420, 2970, 2940, 1460, 1370, 1160, 1088, 1060cm-1. 1H-NMR δ: 0.84 (s, 3H), 0.97 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.73 (d, 3H, J=6.6Hz), 3.59-3.72 (m, 3H), 3.77 (brs, 1H), 4.00 (q, 1H J=6.6Hz), 4.06-4.20 (m, 1H), 5.41-5.51 (m, 1H), 5.65 (s, 1H), 5.73 (d, 1H, J=4.0Hz). UV λmaxnm: 270, 281, 292.
【0196】
実施例70
1α,3β−ジヒドロキシ−20(R)−(3−ヒドロキシ−3−メチルブチルオキシ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−(3−ヒドロキシ−3−メチルブチルオキシ)プレグナ−5,7,16−トリエン(12.2mg,0.0293mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射1分30秒間、加熱還流2時間)、減圧化溶媒を留去し、得られた残渣を分取用薄層クロマトグラフィー(0.25mm×1枚、ジクロロメタン:エタノール=10:1、1回展開、さらに0.25mm×0.5枚、ヘキサン:酢酸エチル:エタノール=10:5:1、3回展開)により精製し、無色油状の標記化合物(1.11mg,9.1%)を得た。
【0197】
IR (neat): 3380, 2940, 2850, 1370, 1160, 1055cm-1. 1H-NMR δ: 0.75 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.32 (d, 3H, J=6.6Hz), 1.75 (t, 2H, J=5.9Hz), 3.58 (s, 1H), 3.65 (t, 2H, J=5.9Hz), 3.97 (q, 1H, J=6.6Hz), 4.20-4.25 (m, 1H), 4.40-4.51 (m, 1H), 5.00 (s, 1H), 5.33 (s, 1H), 5.62 (s, 1H), 6.10 (d, 1H, J=11.6Hz), 6.37 (d, 1H, J=11.6Hz). UV λmaxnm: 264.
【0198】
実施例71
1α,3β−ジヒドロキシ−20(S)−(2−エチル−2−ヒドロキシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(6.8mg,0.00978mmol)、1,2−エポキシ−2−エチルブタン(9.8mg,0.0978mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例3と同条件で反応後、減圧下濃縮した。残渣を酢酸エチルで希釈して水、飽和食塩水の順に洗浄、硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、得られた残渣を分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=4:1、1回展開)により精製し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(2−エチル−2−ヒドロキシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンを含む画分を得た。これとテトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(1ml)を実施例9と同操作で反応(60℃、1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)により精製し、無色油状の標記化合物(2.05mg,47%)を得た。
【0199】
IR (neat): 3369, 2964, 2929, 2879, 2848, 1446, 1369, 1055cm-1. 1H NMR δ: 0.84 (s, 3H), 1.42 (d, J = 7.3Hz, 3H), 2.76-2.87 (m, 1H), 3.43 (q, J = 6.8Hz, 1H), 4.18-4.30 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0200】
実施例72
1α,3β−ジヒドロキシ−20(R)−(2−エチル−2−ヒドロキシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(6.9mg,0.00993mmol)、1,2−エポキシ−2−エチルブタン(9.9mg,0.0993mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例71と同条件でアルキル化反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=4:1、1回展開)により精製し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−(2−エチル−2−ヒドロキシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンを含む画分を得た。これとテトラヒドロフラン(2ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(1ml)を実施例9と同操作で反応(60℃、1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)により精製し、無色油状の標記化合物(2.64mg,59%)を得た。
【0201】
IR (neat): 3369, 2929, 2909, 2879, 2848, 1446, 1371, 1055cm-1. 1H NMR δ: 0.73 (s, 3H), 0.87 (t, J = 7.4Hz, 3H), 0.88 (t, J = 7.4Hz, 3H), 1.46 (d, J = 6.9Hz, 3H), 2.77-2.87 (m, 1H), 3.35 (q, J = 6.9Hz, 1H), 4.18-4.31 (m, 1H), 4.39-4.01 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0202】
実施例73
1α,3β−ジヒドロキシ−20(S)−{2(S)−ヒドロキシ−3−メチルブチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(5.7mg,0.00820mmol)、(S)−(+)−1,2−エポキシ−3−メチルブタン(3.53mg,0.0410mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例71と同条件でアルキル化反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)により精製し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{2(S)−ヒドロキシ−3−メチルブチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンを含む画分を得た。これとテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を実施例9と同操作で反応(60℃、2時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)により精製し無色油状の標記化合物(1.36mg,38%)を得た。
【0203】
IR (neat): 3400, 2950, 2920, 2860, 2845, 1450, 1370, 1050cm-1. 1H NMR δ: 0.85 (s, 3H), 0.93 (d, J = 7.4Hz, 3H), 0.96 (d, J = 7.4Hz, 3H), 1.43 (d, J = 6.9Hz, 3H), 2.53-2.66 (m, 1H), 2.73 (dd, J = 13.4, 3.2Hz, 1H), 2.76-2.88 (m, 1H), 3.32-3.54 (m, 2H), 4.16-4.30 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0204】
実施例74
1α,3β−ジヒドロキシ−20(S)−{2(R)−ヒドロキシ−3−メチルブチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(5.1mg,0.00734mmol)、(R)−(−)−1,2−エポキシ−3−メチルブタン(3.16mg,0.0367mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例71と同条件でアルキル化反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=3:1、1回展開)により精製し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{2(R)−ヒドロキシ−3−メチルブチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンを含む画分を得た。これとテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を実施例9と同操作で反応(60℃、2時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)により精製し、無色油状の標記化合物(1.34mg,42%)を得た。
【0205】
IR (neat): 3400, 2958, 2929, 2850, 1446, 1369, 1254, 1213, 1053cm-1. 1H NMR δ: 0.81 (s, 3H), 0.92 (d, J = 6.8Hz, 3H), 0.96 (d, J = 6.8Hz, 3H), 1.41 (d, J = 6.8Hz, 3H), 2.56-2.66 (m, 1H), 2.70 (dd, J = 13.4, 2.8Hz, 1H), 2.76-2.88 (m, 1H), 3.31-3.42 (m, 1H), 3.51 (q, J = 6.8Hz, 1H), 4.18-4.30 (m, 1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 264.
【0206】
実施例75
1α,3β−ジヒドロキシ−20(R)−{2(S)−ヒドロキシ−3−メチルブチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(7.1mg,0.0102mmol)、(S)−(+)−1,2−エポキシ−3−メチルブタン(4.4mg,0.0510mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例71と同条件でアルキル化反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=4:1、1回展開)により精製し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{2(S)−ヒドロキシ−3−メチルブチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンを含む画分を得た。これとテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を実施例9と同操作で反応(60℃、2時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)により精製し、無色油状の標記化合物(1.24mg,28%)を得た。
【0207】
IR (neat): 3367, 2956, 2929, 2850, 1446, 1369, 1215, 1055cm-1. 1H NMR δ: 0.75 (s, 3H), 0.93 (d, J = 6.9Hz, 3H), 0.96 (d, J = 6.9Hz, 3H), 1.46 (d, J = 6.9Hz, 3H), 2.56-2.66 (m, 1H), 2.74 (dd, J = 13.2, 3.0Hz, 1H), 2.78-2.88 (m,1H), 3.32-3.48 (m, 2H), 4.16-4.29 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0208】
実施例76
1α,3β−ジヒドロキシ−20(R)−{2(R)−ヒドロキシ−3−メチルブチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(6.7mg,0.00964mmol)、(R)−(−)−1,2−エポキシ−3−メチルブタン(4.2mg,0.0482mmol)、テトラヒドロフラン(0.5ml)、1M−KOH メタノール溶液(0.5ml)を実施例71と同条件でアルキル化反応、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル=4:1、1回展開)により精製し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{2(R)−ヒドロキシ−3−メチルブチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンを含む画分を得た。これとテトラヒドロフラン(0.5ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.3ml)を実施例9と同操作で反応(60℃、2時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)により精製し、無色油状の標記化合物(0.754mg,18%)を得た。
【0209】
IR (neat): 3340, 2922, 2846, 1456, 1369, 1290, 1238, 1043cm-1. 1H NMR δ: 0.72 (s, 3H), 0.94 (d, J = 6.9Hz, 3H), 0.97 (d, J = 6.9Hz, 3H), 1.47 (d, J = 6.9Hz, 3H), 2.56-2.68 (m, 1H), 2.75-2.88 (m, 2H), 3.32-3.45 (m, 2H), 4.18-4.30 (m, 1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UVλmax nm: 263.
【0210】
実施例77
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{3−エチル−2(S)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン及び1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{3−エチル−2(R)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(151.7mg,0.220mmol)、1,2−エポキシ−3−エチルペンタン(503mg,4.40mmol)、テトラヒドロフラン(1ml)、1M−KOH メタノール溶液(1ml)を実施例71と同条件でアルキル化反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×3枚、ヘキサン:酢酸エチル=4:1、1回展開)により精製し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(3−エチル−2−ヒドロキシペンチルチオ)プレグナ−5,7,16−トリエン(ジアステレオマー混合物)を得た。これをジクロロメタン(2ml)に溶解し、4−ジメチルアミノピリジン(117mg,0.956mmol)及び(1R)−(+)−カンファニッククロリド(104mg,0.478mmol)を加え室温で15分間攪拌後、減圧下溶媒を留去した。残渣を酢酸エチルで希釈し、氷冷0.5N−塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄し、硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、分取用薄層クロマトグラフィー(0.5mm×4枚、ヘキサン:ベンゼン:酢酸エチル=10:20:1、3回展開)で精製し、低極性成分及び高極性成分を分離した。次にそれぞれをテトラヒドロフラン(3ml)に溶解し、1M−ナトリウムメトキシド メタノール溶液(1ml)を加え、室温で2時間攪拌後、減圧下溶媒を留去した。残渣を酢酸エチルで希釈し、水、飽和食塩水の順で洗浄し、硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、得られた残渣を分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=4:1、1回展開)により精製し無色油状の1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{3−エチル−2(S)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン(57.9mg,44%)及び無色油状の1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{3−エチル−2(R)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン(56.7mg,43%)を得た。
【0211】
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{3−エチル−2(S)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン:
IR (neat): 2897, 2856, 1462, 1371, 1254, 1099, 1082cm-1. 1H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.88 (s, 18H), 1.44 (d, J = 6.9Hz, 3H), 2.47 (dd, J = 13.4, 9.6Hz, 1H), 2.72 (dd, J = 13.4, 3.0Hz, 1H), 2.79-2.91 (m, 1H), 3.49 (q, J = 6.7Hz, 1H), 3.60-3.73 (m, 2H), 3.95-4.13 (m, 1H), 5.34-5.42 (m, 1H), 5.56-5.62 (m, 1H), 5.66 (brs, 1H). MS m/z: 557 (M+-OSitBuMe2), 500 (100%). UV λmax nm: 270, 281, 293.
【0212】
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{3−エチル−2(R)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン:
IR (neat): 2956, 2929, 2856, 1462, 1371, 1254, 1099, 1082cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.89 (s, 18H), 1.43 (d, J = 6.9Hz, 3H), 2.68 (dd, J = 13.2, 3.0Hz, 1H), 2.78-2.92 (m, 1H), 3.53 (q, J = 6.8Hz, 1H), 3.56-3.66 (m, 1H), 3.71 (brs, 1H), 3.95-4.12 (m, 1H), 5.31-5.44 (m, 1H), 5.52-5.68 (m, 2H). MS m/z: 557 (M+-OSitBuMe2), 500 (100%). UV λmax nm: 270, 281, 293.
【0213】
実施例78
1α,3β−ジヒドロキシ−20(S)−{3−エチル−2(S)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{3−エチル−2(S)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン(55.3mg,0.0802mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例9と同操作で反応(加熱還流、5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=9:1、1回展開)により精製し、白色固体の標記化合物(35.5mg,96%)を得た。
【0214】
IR (KBr): 3390, 2950, 2920, 2870, 1460, 1365, 1045, 1030, 1020cm-1. 1H NMR (CDCl3/CD3OD) δ: 0.91 (t, J = 7.3Hz, 6H), 0.94 (s, 3H), 0.97 (s, 3H), 1.44 (d, J = 6.9Hz, 3H), 2.68 (dd, J = 13.4, 3.5Hz, 1H), 2.78-2.90 (m, 1H), 3.43-3.73 (m, 2H), 3.75 (brs, 1H), 3.92-4.08 (m, 1H), 5.40-5.49 (m, 1H), 5.66 (brs, 1H), 5.68-5.76 (m, 1H). MS m/z: 460 (M+), 315 (100%). UV λmax nm: 270, 281, 293.
【0215】
実施例79
1α,3β−ジヒドロキシ−20(S)−{3−エチル−2(R)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{3−エチル−2(R)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン(54.9mg,0.0797mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を実施例9と同操作で反応(加熱還流、5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ジクロロメタン:エタノール=9:1、1回展開)により精製し、無色油状の標記化合物(37.9mg,100%)を得た。
【0216】
IR (neat): 3400, 2962, 2929, 2873, 1460, 1369, 1055, 1030cm-1. 1H NMR δ: 0.90 (t, J = 7.3Hz, 6H), 0.92 (s, 3H), 0.98 (s, 3H), 1.43 (d, J = 6.9Hz, 3H), 2.68 (dd, J = 13.5, 3.0Hz, 1H), 2.75-2.87 (m, 1H), 3.55 (q, J = 6.9Hz, 1H), 3.56-3.67 (m, 1H), 3.79 (brs, 1H), 3.99-4.16 (m, 1H), 5.41-5.50 (m, 1H), 5.63 (brs, 1H), 5.70-5.79 (m, 1H). MS m/z: 460 (M+), 313 (100%). UV λmax nm: 270, 281, 293.
【0217】
実施例80
1α,3β−ジヒドロキシ−20(S)−{3−エチル−2(S)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−{3−エチル−2(S)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン(33.0mg,0.0716mmol)、エタノール(200ml)を用い、実施例15と同操作で反応(光照射3.25分、加熱還流2時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=14:6:1、2回展開、さらに0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=10:10:1、3回展開)で精製し、無色油状の標記化合物(1.81mg,5.5%)を得た。
【0218】
IR (neat): 3367, 2960, 2873, 1456, 1369, 1055cm-1. 1H NMR δ: 0.85 (s, 3H), 0.90 (t, J = 7.3Hz, 6H), 1.43 (d, J = 6.9Hz, 3H), 2.47 (dd, J = 13.3, 9.6Hz, 1H), 2.55-2.68 (m, 1H), 2.71 (dd, J = 13.3, 3.0Hz, 1H), 2.78-2.89 (m, 1H), 3.47 (q, J = 6.8Hz, 1H), 3.60-3.72 (m, 1H), 4.19-4.31 (m, 1H), 4.40-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 263.
【0219】
実施例81
1α,3β−ジヒドロキシ−20(S)−{3−エチル−2(R)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−{3−エチル−2(R)−ヒドロキシペンチルチオ}プレグナ−5,7,16−トリエン(34.1mg,0.0740mmol)、エタノール(200ml)を用い、実施例15と同操作で反応(光照射3.25分、加熱還流2時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=10:10:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=18:1、3回展開)で精製し、無色油状の標記化合物(2.13mg,6.2%)を得た。
【0220】
IR (neat): 3369, 2960, 2929, 2873, 1446, 1369, 1055cm-1. 1H NMR δ: 0.82 (s, 3H), 0.90 (t, J = 7.1Hz, 6H), 1.42 (d, J = 6.9Hz, 3H), 2.75-2.89 (m, 1H), 3.51 (q, J = 6.9Hz, 1H), 3.57-3.68 (m, 1H), 4.18-4.31 (m, 1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.37 (d, J =11.2Hz, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 263.
【0221】
実施例82
1α,3β−ジヒドロキシ−20(R)−{3−エチル−2(R)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン及び1α,3β−ジヒドロキシ−20(R)−{3−エチル−2(S)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−フェノキシカルボニルチオ−9,10−セコプレグナ−5,7,10(19),16−テトラエン(24.5mg,0.0352mmol)、1,2−エポキシ−3−エチルペンタン(80.4mg,0.704mmol)、テトラヒドロフラン(1ml)、1M−KOH メタノール溶液(1ml)を実施例71と同操作でアルキル化反応(室温、1時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル=4:1、1回展開)により精製し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−(3−エチル−2−ヒドロキシペンチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン(ジアステレオマー混合物、18.5mg)を得た。このうち17.2mgをジクロロメタン(1ml)に溶解し、4−ジメチルアミノピリジン(15.3mg,0.125mmol)及び(1S)−(−)−カンファニッククロリド(13.5mg,0.0625mmol)を加え室温で15分間攪拌後、減圧下溶媒を留去した。残渣を酢酸エチルで希釈し、氷冷0.5N−塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄し、硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:ベンゼン:酢酸エチル=10:20:1、2回展開)で精製し、低極性成分及び高極性成分を分離した。次にそれぞれをテトラヒドロフラン(1ml)に溶解し、1M−ナトリウムメトキシド メタノール溶液(0.5ml)を加え、室温で2時間攪拌後、減圧下溶媒を留去した。残渣を酢酸エチルで希釈し、水、飽和食塩水の順で洗浄し、硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、得られた残渣を分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル=4:1、1回展開)により精製し1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{3−エチル−2(R)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン及び1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{3−エチル−2(S)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンを得た。それぞれの化合物とテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.5ml)を実施例9と同操作で反応(60℃、2時間)、後処理後、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=12:8:1、3回展開)により精製し、無色油状の1α,3β−ジヒドロキシ−20(R)−{3−エチル−2(R)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン(3.09mg,20%)及び無色油状の1α,3β−ジヒドロキシ−20(R)−{3−エチル−2(S)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン(2.95mg,20%)を得た。
【0222】
1α,3β−ジヒドロキシ−20(R)−{3−エチル−2(R)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン:
IR (neat): 3361, 2960, 2929, 2873, 1446, 1371, 1290, 1217, 1055cm-1. 1H NMR δ: 0.72 (s, 3H), 0.91 (t, J = 7.1Hz, 6H), 1.47 (d, J = 6.9Hz, 3H), 2.54-2.67 (m, 1H), 2.72-2.90 (m, 2H), 3.37 (q, J = 6.9Hz, 1H), 3.58-3.70 (m, 1H), 4.18-4.29 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 263.
【0223】
1α,3β−ジヒドロキシ−20(R)−{3−エチル−2(S)−ヒドロキシペンチルチオ}−9,10−セコプレグナ−5,7,10(19),16−テトラエン:
IR (neat): 3369, 2960, 2929, 2873, 1448, 1371, 1290, 1211, 1055cm-1. 1H NMR δ: 0.75 (s, 3H), 0.90 (t, J =7.1Hz, 6H), 1.46 (d, J = 6.9Hz, 3H), 2.48 (dd, J = 13.5, 9.6Hz, 1H), 2.55-2.66 (m, 1H), 2.72 (dd, J = 13.5, 3.1Hz, 1H), 2.76-2.88 (m, 1H), 3.41 (q, J = 6.9Hz, 1H), 3.57-3.70 (m, 1H), 4.18-4.30 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m/z: 460 (M+), 312 (100%). UV λmax nm: 263.
【0224】
実施例83
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(4−メチル−4−トリエチルシリルオキシ−2−ペンチニルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)及び1−ブロモ−4−メチル−4−トリエチルシリルオキシ−2−ペンチン(109mg,0.375mmol)のテトラヒドロフラン(1ml)溶液を60℃で2時間攪拌した。室温に戻した後、水にあけ、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄、硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣を分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=40:1、1回展開)で精製し無色油状の標記化合物(82.4mg,99%)を得た。
【0225】
IR (neat): 2950, 2875, 1460, 1370, 1250, 1160, 1090, 1040cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.67 (q, J = 7.8Hz, 6H), 0.89 (s, 18H), 0.96 (t, J = 7.8Hz, 9H), 1.32 (d, J = 6.5Hz, 3H), 1.46 (s, 6H), 3.70 (brs, 1H), 3.76-3.83 (m, 1H), 3.94-4.39 (m, 3H), 5.35-5.44 (m, 1H), 5.56-5.66 (m, 2H). UV λmax nm: 270, 281, 293.
【0226】
実施例84
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(E)−(4−メチル−4−トリエチルシリルオキシ−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)及び(E)−1−ブロモ−4−メチル−4−トリエチルシリルオキシ−2−ペンテン(116mg,0.375mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=40:1、1回展開)で精製し無色油状の標記化合物(85.9mg,99%)を得た。
【0227】
IR (neat): 2950, 2850, 1460, 1370, 1250, 1150, 1040cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.57 (q, J = 7.8Hz, 6H), 0.89 (s, 18H), 0.94 (t, J = 7.8Hz, 9H), 1.31 (s, 6H), 3.72 (brs, 1H), 3.79-4.18 (m, 4H), 5.37-5.45 (m, 1H), 5.57-5.83 (m, 4H). UV λmax nm: 270, 281, 293.
【0228】
実施例85
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(Z)−(4−メチル−4−トリエチルシリルオキシ−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)及び(Z)−1−ブロモ−4−メチル−4−トリエチルシリルオキシ−2−ペンテン(125mg,0.428mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=30:1、1回展開)で精製し無色油状の標記化合物(80.7mg,98%)を得た。
【0229】
IR (neat): 2950, 2850, 1460, 1370, 1255, 1170, 1100, 1040cm-1. 1H NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.58 (q, J = 7,8Hz, 6H), 0.88 (s, 18H), 0.94 (t, J = 7.8Hz, 9H), 1.32 (s, 6H), 3.71 (brs, 1H), 3.93-4.14 (m, 2H), 4.16-4.36 (m, 2H), 5.29-5.44 (m, 3H), 5.57-5.66 (m, 2H). UV λmax nm: 270, 281, 293.
【0230】
実施例86
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキシニルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,21.0mg,0.525mmol)、15−クラウン−5(10μl)、1−ブロモ−4−エチル−4−トリエチルシリルオキシ−2−ヘキシン(134mg,0.420mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=40:1、1回展開)で精製し無色油状の標記化合物(79.0mg,92%)を得た。
【0231】
IR (neat): 2950, 2850, 1460, 1375, 1255, 1080, 1010cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.67 (q, J = 7.8Hz, 6H), 0.89 (s, 18H), 1.32 (d, J = 6.4Hz, 3H), 3.72 (brs, 1H), 3.95-4.32 (m, 4H), 5.36-5.44 (m, 1H), 5.58-5.68 (m, 2H). MS m/z: 796 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
【0232】
実施例87
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(E)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)、(E)−1−ブロモ−4−エチル−4−トリエチルシリルオキシ−2−ヘキセン(134mg,0.420mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=40:1、1回展開)で精製し無色油状の標記化合物(86.0mg,100%)を得た。
【0233】
IR (neat): 2950, 2850, 1460, 1375, 1255, 1100, 1000cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.58 (q, J = 7.8Hz, 6H), 0.89 (s, 18H), 1.31 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 3.70-4.19 (m, 4H), 5.37-5.45 (m, 1H), 5.49-5.76 (m, 4H). UV λmax nm: 270, 281, 293.
【0234】
実施例88
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(Z)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)、(Z)−1−ブロモ−4−エチル−4−トリエチルシリルオキシ−2−ヘキセン(103mg,0.321mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=40:1、1回展開)で精製し無色油状の標記化合物(83.6mg,98%)を得た。
【0235】
IR (neat): 2950, 2850, 1460, 1370, 1250 1100 1000cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.60 (q, J = 7.5Hz, 6H), 0.89 (s, 18H), 1.32 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 3.89-4.47 (m, 4H), 5.09-5.20 (m, 1H), 5.35-5.66 (m, 4H). MS m/z: 798 (M+), 277 (100%). UV λmax nm: 270, 281, 293.
【0236】
実施例89
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−(4−メチル−4−トリエチルシリルオキシ−2−ペンチニルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)、1−ブロモ−4−メチル−4−トリエチルシリルオキシ−2−ペンチン(109mg,0.375mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=40:1、1回展開)で精製し無色油状の標記化合物(76.4mg,93%)を得た。
【0237】
IR (neat): 2950, 2850, 1465, 1375, 1250, 1160, 1090, 1040cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.67 (q, J = 7.8Hz, 6H), 0.85 (s, 3H), 0.89 (s, 18H), 0.95 (s, 3H), 0.96 (t, J = 7.8Hz, 9H), 1.33 (d, J = 6.6Hz, 3H), 1.48 (s, 6H), 3.71 (brs, 1H), 3.93-4.32 (m, 4H), 5.36-5.45 (m, 1H), 5.58-5.66 (m, 1H), 5.60 (brs, 1H). UV λmax nm: 270, 281, 293.
【0238】
実施例90
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{(E)−(4−メチル−4−トリエチルシリルオキシ−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)及び(E)−1−ブロモ−4−メチル−4−トリエチルシリルオキシ−2−ペンテン(116mg,0.375mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=30:1、1回展開)で精製し無色油状の標記化合物(73.4mg,89%)を得た。
【0239】
IR (neat): 2950, 2850, 1460, 1370, 1250, 1150, 1095, 1040cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.58 (q, J = 7.8Hz, 6H), 0.85 (s, 3H), 0.88 (s, 9H), 0.89 (s, 9H), 0.94 (t, J = 7.8Hz, 9H), 0.94 (s, 3H), 1.30, (s, 6H), 1.33 (d, J = 5.1Hz, 3H), 3.71 (brs, 1H), 3.83-4.16 (m, 4H), 5.35-5.45 (m, 1H), 5.57-5.88 (m, 4H). UV λmax nm: 270, 281, 293.
【0240】
実施例91
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{(Z)−(4−メチル−4−トリエチルシリルオキシ−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)及び(Z)−1−ブロモ−4−メチル−4−トリエチルシリルオキシ−2−ペンテン(125mg,0.428mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=30:1、1回展開)で精製し無色油状の標記化合物(70.3mg,85%)を得た。
【0241】
IR (neat): 2950, 2850, 1460, 1375, 1255, 1170, 1100, 1040cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.59 (q, J = 7.9Hz, 6H), 0.86 (s, 3H), 0.88 (s, 9H), 0.89 (s, 9H), 0.95 (t, J = 7.9Hz, 9H), 0.95 (s, 3H), 1.32 (s, 6H), 1.33 (d, J = 4.9Hz, 3H), 3.71 (brs, 1H), 3.96-4.13 (m, 2H), 4.23-4.38 (m, 2H), 5.29-5.47 (m, 3H), 5.58-5.68 (m, 2H). UV λmax nm: 270, 281, 293.
【0242】
実施例92
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキシニルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(58.9mg,0.105mmol)、水素化ナトリウム(60%,21.0mg,0.525mmol)、15−クラウン−5(10μl)、1−ブロモ−4−エチル−4−トリエチルシリルオキシ−2−ヘキシン(134mg,0.420mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=19:1、1回展開)で精製し無色油状の標記化合物(60.2mg,72%)を得た。
【0243】
IR (neat): 2950, 2850, 1460, 1370, 1250, 1085cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.67 (q, J = 7.3Hz, 6H), 0.88 (s, 9H), 0.89 (s, 9H), 1.33 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 3.97-4.35 (m, 4H), 5.35-5.44 (m, 1H), 5.58-5.64 (m, 1H), 5.67 (brs, 1H). MS m/z: 796 (M+), 301 (100%). UV λmax nm: 270, 281, 293.
【0244】
実施例93
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{(E)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)、(E)−1−ブロモ−4−エチル−4−トリエチルシリルオキシ−2−ヘキセン(134mg,0.420mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=40:1、1回展開)で精製し無色油状の標記化合物(62.4mg,73%)を得た。
【0245】
IR (neat): 2950, 2870, 1460, 1375, 1255, 1070cm-1. 1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.58 (q, J = 7.8Hz, 6H), 0.88 (s, 9H), 0.89 (s, 9H), 1.32 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 3.88-4.14 (m, 4H), 5.36-5.44 (m, 1H), 5.54-5.76 (m, 4H). MS m/z: 798 (M+), 609 (100%). UV λmax nm: 270, 281, 293.
【0246】
実施例94
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{(Z)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(60.0mg,0.107mmol)、水素化ナトリウム(60%,17.1mg,0.428mmol)、15−クラウン−5(10μl)、(Z)−1−ブロモ−4−エチル−4−トリエチルシリルオキシ−2−ヘキセン(103mg,0.321mmol)、テトラヒドロフラン(1ml)を実施例83と同条件で反応、後処理後、分取用薄層クロマトグラフィー(0.5mm×2枚、ヘキサン:酢酸エチル=40:1、1回展開)で精製し無色油状の標記化合物(84.6mg,99%)を得た。
【0247】
IR (neat): 2950, 2850, 1460, 1375, 1255, 1100, 1070cm-1. 1H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.61 (q, J = 7.8Hz, 6H), 0.88 (s, 9H), 0.89 (s, 9H), 1.32 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 4.15-4.24 (m, 2H), 4.23-4.38 (m, 2H), 5.13 (dt, J = 12.5, 2.2Hz, 1H), 5.35-5.42 (m, 1H), 5.50 (dt, J = 12.2, 5.0Hz, 1H), 5.59-5.69 (m, 2H). MS m/z: 798 (M+), 610 (100%). UV λmax nm: 270, 281, 293.
【0248】
実施例95
1α,3β−ジヒドロキシ−20(S)−(4−ヒドロキシ−4−メチル−2−ペンチニルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(4−メチル−4−トリエチルシリルオキシ−2−ペンチニルオキシ)プレグナ−5,7,16−トリエン(80.0mg,0.104mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し薄黄色油状の標記化合物(14.0mg,32%)を得た。
【0249】
IR (neat): 3400, 2980, 2940, 2850, 1450, 1370, 1230, 1170, 1060cm-1. 1H NMR δ: 0.90 (s, 3H), 0.99 (s, 3H), 1.33 (d, J = 6.4Hz, 3H), 1.52 (s, 6H), 3.79 (brs, 1H), 3.98-4.23 (m, 4H), 5.43-5.50 (m, 1H), 5.66 (brs, 1H), 5.70-5.80 (m, 1H). UV λmax nm: 270, 281, 293.
【0250】
実施例96
1α,3β−ジヒドロキシ−20(S)−{(E)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(E)−(4−メチル−4−トリエチルシリルオキシ−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエン(83.0mg,0.108mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し薄黄色油状の標記化合物(15.9mg,34%)を得た。
【0251】
IR (neat): 3400, 2950, 2850, 1460, 1370, 1230, 1150, 1050cm-1. 1H NMR δ: 0.89 (s, 3H), 0.99 (s, 3H), 1.33 (s, 6H), 3.71-4.12 (m, 5H), 5.42-5.51 (m, 1H), 5.63 (brs, 1H), 5.66-5.92 (m, 3H). UV λmax nm: 270, 281, 293.
【0252】
実施例97
1α,3β−ジヒドロキシ−20(S)−{(Z)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(Z)−(4−メチル−4−トリエチルシリルオキシ−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエン(78.0mg,0.101mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し無色油状の標記化合物(32.0mg,74%)を得た。
【0253】
IR (neat): 3400, 2960, 2850, 1460, 1375, 1260, 1150, 1050cm-1. 1H NMR δ: 0.89 (s, 3H), 0.97 (s, 3H), 1.34 (s, 6H), 3.76 (brs, 1H), 3.96-4.24 (m, 4H), 5.35-5.51 (m, 2H), 5.59-5.78 (m, 3H). UV λmax nm: 270, 281, 293.
【0254】
実施例98
1α,3β−ジヒドロキシ−20(S)−(4−エチル−4−ヒドロキシ−2−ヘキシニルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキシニルオキシ)プレグナ−5,7,16−トリエン(79.0g、0.0991mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し無色油状の標記化合物(43.5mg,96%)を得た。
【0255】
IR (neat): 3400, 2960, 2930, 2850, 1460, 1370, 1260, 1195, 1150, 1050cm-1. 1H NMR δ: 0.90 (s, 3H), 0.99 (s, 3H), 1.03 (t, J = 7.8Hz, 6H), 1.33 (d, J = 6.6Hz, 3H), 3.79 (brs, 1H), 4.02-4.31 (m, 4H), 5.43-5.52 (m, 1H), 5.66 (brs, 1H), 5.72-5.80 (m, 1H). MS m/z: 454 (M+), 263 (100%). UV λmax nm: 270, 281, 293.
【0256】
実施例99
1α,3β−ジヒドロキシ−20(S)−{(E)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(E)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエン(84.0mg,0.105mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し無色油状の標記化合物(37.3mg,78%)を得た。
【0257】
IR (neat): 3400, 2960, 2925, 2850, 1460, 1371, 1255, 1200 1150, 1055cm-1. 1H NMR δ: 0.87 (t, J = 7.4Hz, 6H), 0.89 (s, 3H), 0.98 (s, 3H), 1.32 (d, J = 6.6Hz, 3H), 1.55 (q, J = 7.4Hz, 4H), 3.78 (brs, 1H), 3.86 (dd, J = 12.6, 5.3Hz, 1H), 3.94-4.09 (m, 3H), 5.41-5.51 (m, 1H), 5.58-5.73 (m, 4H). UV λmax nm: 270, 281, 293.
【0258】
実施例100
1α,3β−ジヒドロキシ−20(S)−{(Z)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{(Z)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエン(81.3mg,0.102mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し薄黄色油状の標記化合物(44.0mg,94%)を得た。
【0259】
IR (neat): 3400, 2965, 2930, 2850, 1460, 1370, 1275, 1150, 1050cm-1. 1H NMR δ: 0.89 (s, 3H), 0.90 (t, J = 7.4Hz, 6H), 0.98 (s, 3H), 1.33 (d, J = 6.6Hz, 3H), 1.54 (q, J = 7.4Hz, 4H), 3.78 (brs, 1H), 3.98-4.24 (m, 4H), 5.37-5.49 (m, 2H), 5.54-5.68 (m, 2H), 5.71-5.78 (m, 1H). UV λmax nm: 270, 281, 293.
【0260】
実施例101
1α,3β−ジヒドロキシ−20(R)−(4−ヒドロキシ−4−メチル−2−ペンチニルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−(4−メチル−4−トリエチルシリルオキシ−2−ペンチニルオキシ)プレグナ−5,7,16−トリエン(74.1mg,0.0963mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し薄黄色油状の標記化合物(21.0mg,51%)を得た。
【0261】
IR (neat): 3400, 2970, 2920, 2850, 1450, 1370, 1230, 1160, 1050cm-1. 1H NMR δ: 0.85 (s, 3H), 0.97 (s, 3H), 1.35 (d, J = 6.4Hz, 3H), 1.52 (s, 6H), 3.78 (m, 1H), 5.41-5.50 (m, 1H), 5.64-5.78 (m, 2H). UV λmax nm: 270, 281, 293.
【0262】
実施例102
1α,3β−ジヒドロキシ−20(R)−{(E)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{(E)−(4−メチル−4−トリエチルシリルオキシ−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエン(71.0mg,0.0920mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し無色油状の標記化合物(34.0mg,86%)を得た。
【0263】
IR (neat): 3400, 2960, 2925, 2850, 1460, 1370, 1240, 1150, 1055cm-1. 1H NMR δ: 0.85 (s, 3H), 0.97 (s, 3H), 1.32 (s, 6H), 3.77 (brs, 1H), 3.85-4.16 (m, 4H), 5.40-5.50 (m, 1H), 5.61-5.91 (m, 4H). UV λmax nm: 270, 281, 293.
【0264】
実施例103
1α,3β−ジヒドロキシ−20(R)−{(Z)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{(Z)−(4−メチル−4−トリエチルシリルオキシ−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエン(67.9mg,0.0880mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し白色固体の標記化合物(32.0mg,85%)を得た。
【0265】
IR (KBr): 3400, 2960, 2920, 2850, 1460, 1370, 1200, 1170, 1135, 1080, 1060, 1035cm-1. 1H NMR (CDCl3/CD3OD) δ: 0.86 (s, 3H), 0.96 (s, 3H), 1.33 (s, 6H), 1.37 (d, J = 6.6Hz, 3H), 3.74 (brs, 1H), 3.90-4.27 (m, 4H), 5.36-5.50 (m, 2H), 5.55-5.76 (m, 3H). UV λmax nm: 270, 281, 293.
【0266】
実施例104
1α,3β−ジヒドロキシ−20(R)−(4−エチル−4−ヒドロキシ−2−ヘキシニルオキシ)プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキシニルオキシ)プレグナ−5,7,16−トリエン(58.2mg,0.0730mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し無色油状の標記化合物(33.5mg,100%)を得た。
【0267】
IR (neat): 3400, 2960, 2930, 2850, 1460, 1370, 1325, 1260, 1195, 1150, 1060, 1035cm-1. 1H NMR δ: 0.85 (s, 3H), 0.98 (s, 3H), 1.03 (t, J = 7.4Hz, 6H), 1.34 (d, J = 6.6Hz, 3H), 3.78 (brs, 1H), 4.00-4.32 (m, 4H), 5.41-5.50 (m, 1H), 5.68 (brs, 1H), 5.71-5.80 (m, 1H). UV λmax nm: 270, 281, 293.
【0268】
実施例105
1α,3β−ジヒドロキシ−20(R)−{(E)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{(E)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエン(60.3mg,0.0754mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し薄黄色油状の標記化合物(14.5mg,42%)を得た。
【0269】
IR (neat): 3400, 2960, 2930, 2850, 1460, 1375, 1330, 1270, 1150, 1060, 1035cm-1. 1H NMR δ: 0.86 (s, 3H), 0.86 (t, J = 7.3Hz, 6H), 0.98 (s, 3H), 1.33 (d, J = 6.6Hz, 3H), 1.55 (q, J = 7.6Hz, 4H), 3.78 (brs, 1H), 3.91-4.20 (m, 4H), 5.42-5.52 (m, 1H), 5.58-5.82 (m, 4H). UV λmax nm: 270, 281, 293.
【0270】
実施例106
1α,3β−ジヒドロキシ−20(R)−{(Z)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{(Z)−(4−エチル−4−トリエチルシリルオキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエン(82.0mg,0.103mmol)、テトラヒドロフラン(3ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(2ml)を用い、実施例9と同操作で反応(加熱還流、5.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=20:80:1、1回展開)で精製し白色固体の標記化合物(46.1mg,98%)を得た。
【0271】
IR (KBr): 3400, 2960, 2930, 2850, 1460, 1370, 1325, 1270, 1250, 1200, 1150, 1060cm-1. 1H NMR δ: 0.86 (s, 3H), 0.90 (t, J = 7.4Hz, 6H), 0.98 (s, 3H), 1.36 (d, J = 6.4Hz, 3H), 1.54 (q, J = 7.4Hz, 4H), 3.77 (brs, 1H), 3.99-4.22 (m, 4H), 5.35-5.49 (m, 2H), 5.55-5.70 (m, 2H), 5.71-5.79 (m, 1H). UV λmax nm: 270, 281, 293.
【0272】
実施例107
1α,3β−ジヒドロキシ−20(S)−(4−ヒドロキシ−4−メチル−2−ペンチニルオキシ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(4−ヒドロキシ−4−メチル−2−ペンチニルオキシ)プレグナ−5,7,16−トリエン(13.0mg,0.0305mmol)、エタノール(200ml)を用い、実施例15と同操作で反応(光照射2.5分間、加熱還流1.5時間)、後処理後、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、0.25mm×1枚、ジクロロメタン:酢酸エチル:エタノール=10:10:1、2回展開、さらにジクロロメタン:エタノール=19:1、3回展開)で精製し、無色油状の標記化合物(0.758mg,5.8%)を得た。
【0273】
IR (neat): 3369, 2929, 2852, 1442, 1369, 1234, 1167, 1060cm-1. 1H NMR δ: 0.79 (s, 3H), 1.33 (d, J = 6.6Hz, 3H), 1.52 (s, 6H), 4.03 (d, J = 15.4Hz, 1H), 4.14 (m, 1H), 4.15 (d, J = 15.4Hz, 1H), 4.19-4.30 (m, 1H), 4.41-4.51 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 367 (M+-C(CH3)2OH), 129 (100%). UV λmax nm: 264.
【0274】
実施例108
1α,3β−ジヒドロキシ−20(S)−(E)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−{(E)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエン(14.5mg,0.0338mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ジクロロメタン:酢酸エチル:エタノール=10:10:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=18:1、3回展開)で精製し、無色油状の標記化合物(1.41mg,9.7%)を得た。
【0275】
IR (neat): 3400, 2929, 2850, 1446, 1369, 1220, 1153, 1101, 1055cm-1. 1H NMR δ: 0.79 (s, 3H), 1.33 (s, 6H), 3.81 (dd, J = 6.3, 5.6Hz, 1H), 3.89-4.04 (m, 2H), 4.17-4.30 (m, 1H), 4.38-4.50 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.27 (d, J = 11.2Hz, 1H). MS m/z: 410 (M+-H2O), 134 (100%). UV λmax nm: 264.
【0276】
実施例109
1α,3β−ジヒドロキシ−20(S)−{(Z)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−{(Z)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエン(30.0mg,0.0700mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、さらに0.25mm×1枚ジクロロメタン:エタノール=16:1、3回展開)で精製し、無色油状の標記化合物(3.04mg,10%)を得た。
【0277】
IR (neat): 3369, 2972, 2929, 2850, 1446, 1371, 1169, 1055cm-1. 1H NMR δ: 0.78 (s, 3H), 1.34 (s, 6H), 2.54-2.68 (m, 1H), 2.75-2.88 (m, 1H), 3.95-4.30 (m, 4H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.44 (dt, J =12.2, 5.6Hz, 1H), 5.58-5.70 (m, 2H), 6.11 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0278】
実施例110
1α,3β−ジヒドロキシ−20(S)−(4−エチル−4−ヒドロキシ−2−ヘキシニルオキシ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−(4−エチル−4−ヒドロキシ−2−ヘキシニルオキシ)プレグナ−5,7,16−トリエン(40.0mg,0.0880mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=19:1、3回展開)で精製し、無色油状の標記化合物(2.76mg,6.9%)を得た。
【0279】
IR (neat): 3369, 2970, 2931, 2850, 1442, 1369, 1263, 1182, 1146, 1057cm-1. 1H NMR δ: 0.79 (s, 3H), 1.03 (t, J = 7.4Hz, 6H), 1.32 (d, J = 6.3Hz, 3H), 2.55-2.65 (m, 1H), 2.77-2.88 (m, 1H), 4.06 (d, J = 15.5Hz, 1H), 4.14-4.31 (m, 3H), 4.38-4.53 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). UV λmax nm: 264.
【0280】
実施例111
1α,3β−ジヒドロキシ−20(S)−{(E)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−{(E)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエン(35.0mg,0.0766mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=16:1、3回展開)で精製し、無色油状の標記化合物(3.94mg,11%)を得た。
【0281】
IR (neat): 3400, 2968, 2931, 2850, 1446, 1369, 1101, 1055cm-1. 1H NMR δ: 0.79 (s, 3H), 0.86 (t, J = 7.4Hz, 6H), 2.55-2.68 (m, 1H), 2.77-2.89 (m, 1H), 3.86 (dd, J = 12.4, 5.4 Hz, 1H), 3.93-4.06 (m, 2H), 4.18-4.31 (m, 1H), 4.39-4.52 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). MS m/z: 456 (M+), 134 (100%). UV λmax nm: 263.
【0282】
実施例112
1α,3β−ジヒドロキシ−20(S)−{(Z)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−{(Z)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエン(41.0mg,0.0898mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.75分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=16:1、3回展開)で精製し、無色油状の標記化合物(1.58mg,3.9%)を得た。
【0283】
IR (neat): 3400, 2968, 2929, 2850, 1448, 1371, 1055cm-1. 1H NMR δ: 0.78 (s, 3H), 0.90 (t, J = 7.4Hz, 3H), 0.91 (t, J = 7.4Hz, 3H), 1.34 (d, J = 6.3Hz, 3H), 2.55-2.65 (m, 1H), 2.78-2.88 (m, 1H), 3.95-4.31 (m, 4H), 4.39-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.42 (d, J = 12.5Hz, 1H), 5.55-5.69 (m, 2H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0284】
実施例113
1α,3β−ジヒドロキシ−20(R)−(4−ヒドロキシ−4−メチル−2−ペンチニルオキシ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−(4−ヒドロキシ−4−メチル−2−ペンチニルオキシ)プレグナ−5,7,16−トリエン(20.0mg,0.0469mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、0.25mm×1枚、ジクロロメタン:酢酸エチル:エタノール=10:10:1、2回展開、さらにジクロロメタン:エタノール=19:1、3回展開)で精製し、無色油状の標記化合物(1.19mg,5.9%)を得た。
【0285】
IR (neat): 3400, 2976, 2929, 2852, 1444, 1373, 1234, 1167, 1063cm-1. 1H NMR δ: 0.75 (s, 3H), 1.33 (d, J = 6.3Hz, 3H), 1.52 (s, 6H), 2.55-2.66 (m, 1H), 2.76-2.86 (m, 1H), 4.03-4.31 (m, 4H), 4.40-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.56 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 264.
【0286】
実施例114
1α,3β−ジヒドロキシ−20(R)−{(E)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−{(E)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエン(31.8mg,0.0742mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=10:10:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=18:1、3回展開)で精製し、無色油状の標記化合物(3.03mg,9.5%)を得た。
【0287】
IR (neat): 3390, 2972, 2931, 2850, 1448, 1371, 1217, 1153, 1095, 1057cm-1. 1H NMR δ: 0.75 (s, 3H), 1.33 (s, 6H), 2.56-2.68 (m, 1H), 2.78-2.88 (m, 1H), 3.85-4.08 (m, 3H), 4.18-4.30 (m, 1H), 4.39-5.00 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H), 5.73 (dt, J = 15.8, 5.3Hz, 1H), 5.85 (d, J = 15.8Hz, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0288】
実施例115
1α,3β−ジヒドロキシ−20(R)−{(Z)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−{(Z)−(4−ヒドロキシ−4−メチル−2−ペンテニルオキシ)}プレグナ−5,7,16−トリエン(30.0mg,0.0700mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=16:1、3回展開)で精製し、無色油状の標記化合物(3.04mg,10%)を得た。
【0289】
IR (neat): 3350, 2972, 2929, 2850, 1448, 1371, 1167, 1063cm-1. 1H NMR δ: 0.75 (s, 3H), 1.34 (s, 6H), 2.55-2.67 (m, 1H), 2.75-2.87 (m, 1H), 4.06 (q, J = 6.3Hz, 1H), 4.11-4.30 (m, 3H), 4.38-4.50 (m, 1H), 5.01(brs, 1H), 5.34 (brs, 1H), 5.45 (dt, J = 12.5, 5.3Hz, 1H), 5.58 (m, 2H), 6.01 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0290】
実施例116
1α,3β−ジヒドロキシ−20(R)−(4−エチル−4−ヒドロキシ−2−ヘキシニルオキシ)−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−(4−エチル−4−ヒドロキシ−2−ヘキシニルオキシ)プレグナ−5,7,16−トリエン(30.8mg,0.0677mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=19:1、3回展開)で精製し、無色油状の標記化合物(1.83mg,5.9%)を得た。
【0291】
IR (neat): 3390, 2970, 2933, 2852, 1450, 1371, 1265, 1146, 1061cm-1. 1H NMR δ: 0.75 (s, 3H), 1.03 (t, J = 7.4Hz, 6H), 1.33 (d, J = 6.6Hz, 3H), 2.56-2.65 (m, 1H), 2.75-2.85 (m, 1H), 4.08-4.29 (m, 4H), 4.39-4.53 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). UV λmax nm: 264.
【0292】
実施例117
1α,3β−ジヒドロキシ−20(R)−{(E)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−{(E)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエン(13.0mg,0.0285mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射2.5分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=16:1、3回展開)で精製し、無色油状の標記化合物(0.888mg,6.8%)を得た。
【0293】
IR (neat): 3378, 2964, 2925, 2852, 1452, 1385, 1057cm-1. 1H NMR δ: 0.75 (s, 3H), 0.86 (t, J = 7.4Hz, 6H), 1.32 (d, J = 6.6Hz, 3H), 2.55-2.66 (m, 1H), 2.76-2.87 (m, 1H), 3.90-4.10 (m, 3H), 4.18-4.31 (m, 1H), 4.39-4.51 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.57-5.81 (m, 3H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0294】
実施例118
1α,3β−ジヒドロキシ−20(R)−{(Z)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−{(Z)−(4−エチル−4−ヒドロキシ−2−ヘキセニルオキシ)}プレグナ−5,7,16−トリエン(42.1mg,0.0922mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射3.75分間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.5mm×1枚、ヘキサン:酢酸エチル:エタノール=8:12:1、2回展開、さらに0.25mm×1枚、ジクロロメタン:エタノール=16:1、3回展開)で精製し、無色油状の標記化合物(2.09mg,5.0%)を得た。
【0295】
IR (neat): 3400, 2968, 2931, 2852, 1456, 1371, 1059cm-1. 1H NMR δ: 0.75 (s, 3H), 0.90 (t, J = 7.4Hz, 6H), 1.34 (d, J = 6.6Hz, 3H), 2.55-2.66 (m, 1H), 2.73-2.89 (m, 1H), 3.98-4.31 (m, 4H), 4.39-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.41 (d, J = 12.5Hz, 1H), 5.55-5.71 (m, 2H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
【0296】
実施例119
1α,3β−ジヒドロキシ−20(S)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(97.9mg,0.175mmol)、カリウム t−ブトキシド(230mg,2.05mmol)、ジベンゾ−18−クラウン−6(45.0mg,0.125mmol)のトルエン(6ml)溶液に、室温下で(S)−(+)−1,2−エポキシ−3−メチルブタン(0.18ml,1.72mmol)を加え、106℃で1時間攪拌した。反応溶液をジエチルエーテルで希釈、飽和食塩水で洗浄後、有機層を硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣を分取用薄層クロマトグラフィー(0.5mm×4枚、ヘキサン:ジクロロメタン:酢酸エチル=45:5:2、3回展開)により分離し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエンを含む画分(67.5mg)を得た。このうち52.6mgをテトラヒドロフラン(1.5ml)に溶解し、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.5ml)を加え、外温71℃条件下で10時間攪拌した。反応終了後、反応溶液を酢酸エチルで希釈し、1N−塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄し、有機層を硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣を分取用薄層クロマトグラフィー(0.25mm×2枚、ジクロロメタン:エタノール=15:1、2回展開)により精製し、無色油状の標記化合物(20.6mg,36%)を得た。
【0297】
IR (neat): 3416, 2924, 1462, 1370, 1056, 1196cm-1. 1H NMR δ: 0.88 (s, 3H), 0.90 (d, J = 6.9Hz, 3H), 0.97 (s, 3H), 1.31 (d, J = 6.6Hz, 3H), 2.72-2.86 (m, 1H), 3.10-3.24 (m, 1H), 3.39-3.53 (m, 2H), 3.77 (brs, 1H), 3.96 (q, J = 6.6Hz, 1H), 4.00-4.16 (m, 1H), 5.40-5.49 (m, 1H), 5.60 (s, 1H), 5.68-5.80 (m, 1H). MS m/z: 312 (M+-HOCH2CH(OH)iPr), 223 (100%). UV λmax nm: 269, 281, 292.
【0298】
実施例120
1α,3β−ジヒドロキシ−20(S)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−ヒドロキシプレグナ−5,7,16−トリエン(71.5mg,0.128mmol)、カリウム t−ブトキシド(170mg,1.52mmol)、ジベンゾ−18−クラウン−6(32.0mg,0.0888mmol)、トルエン(4.5ml)、(R)−(−)−1,2−エポキシ−3−メチルブタン(0.13ml,1.24mmol)を用い、実施例119と同操作でアルキル化反応(108℃、1時間)及び後処理を行った後、分取用薄層クロマトグラフィー(0.5mm×3枚、ヘキサン:ジクロロメタン:酢酸エチル=45:5:2、3回展開)により分離し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(S)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエンを含む画分(26.8mg)を得た。これとテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.4ml)を用い、実施例119と同操作で脱保護反応(反応温度74℃、反応時間12時間)及び後処理を行った後、分取用薄層クロマトグラフィー(0.25mm×1枚、ジクロロメタン:エタノール=15:1、2回展開)により精製し、無色油状の標記化合物(12.0mg,23%)を得た。
【0299】
IR (neat): 3420, 2924, 1460, 1368, 1056cm-1. 1H NMR δ: 0.89 (s, 3H), 0.89 (d, J = 6.6Hz, 3H), 0.98 (s, 3H), 1.32 (d, J = 6.6Hz, 3H), 2.49-2.62 (m, 1H), 2.72-2.87 (m, 1H), 3.26-3.54 (m, 3H), 3.77 (brs, 1H), 3.93-4.18 (m, 2H), 5.41-5.50 (m, 1H), 5.63 (s, 1H), 5.70-5.80 (m, 1H). MS m/z: 312 (M+-HOCH2CH(OH)iPr, 100%). UV λmax nm: 269, 280, 292.
【0300】
実施例121
1α,3β−ジヒドロキシ−20(R)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(79.0mg,0.141mmol)、カリウム t−ブトキシド(190mg,1.69mmol)、ジベンゾ−18−クラウン−6(25.0mg,0.0694mmol)、トルエン(4.5ml)、(S)−(+)−1,2−エポキシ−3−メチルブタン(0.15ml,1.43mmol)を用い、実施例119と同操作でアルキル化反応(108℃、1時間)及び後処理を行った後、分取用薄層クロマトグラフィー(0.5mm×3枚、ヘキサン:ジクロロメタン:酢酸エチル=45:5:2、3回展開)により分離し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエンを含む画分(27.8mg)を得た。これとテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.25ml)を用い、実施例119と同操作で脱保護反応(反応温度76℃、反応時間13時間)及び後処理を行った後、分取用薄層クロマトグラフィー(0.25mm×1枚、ジクロロメタン:エタノール=15:1、2回展開)により精製し、無色油状の標記化合物(11.0mg,19%)を得た。
【0301】
IR (neat): 3416, 3036, 2928, 1462, 1370, 1270, 1196, 1056cm-1. 1H NMR δ: 0.84 (s, 3H), 0.90 (d, J = 6.9Hz, 3H), 0.97 (s, 3H), 1.34 (d, J = 6.6Hz, 3H), 2.72-2.88 (m, 1H), 3.19-3.34 (m, 1H), 3.40-3.60 (m, 2H), 3.77 (brs, 1H), 3.93-4.16 (m, 2H), 5.40-5.50 (m, 1H), 5.67 (s, 1H), 5.71-5.80 (m, 1H). MS m/z: 312 (M+-HOCH2CH(OH)iPr, 100%). UV λmax nm: 270, 281, 293.
【0302】
実施例122
1α,3β−ジヒドロキシ−20(R)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエンの製造
1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−ヒドロキシプレグナ−5,7,16−トリエン(69.7mg,0.125mmol)、カリウム t−ブトキシド(170mg,1.52mmol)、ジベンゾ−18−クラウン−6(22.0mg,0.0610mmol)、トルエン(4ml)、(R)−(−)−1,2−エポキシ−3−メチルブタン(0.13ml,1.24mmol)を用い、実施例119と同操作でアルキル化反応(109℃、1時間)及び後処理を行った後、分取用薄層クロマトグラフィー(0.5mm×3枚、ヘキサン:ジクロロメタン:酢酸エチル=45:5:2、3回展開)により分離し、1α,3β−ビス(tert−ブチルジメチルシリルオキシ)−20(R)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエンを含む画分(23.6mg)を得た。このうち21.1mgとテトラヒドロフラン(1ml)、1M−テトラ−n−ブチルアンモニウムフルオリド テトラヒドロフラン溶液(0.2ml)を用い、実施例119と同操作で脱保護反応(反応温度76℃、反応時間13時間)及び後処理を行った後、分取用薄層クロマトグラフィー(0.25mm×1枚、ジクロロメタン:エタノール=15:1、2回展開)により精製し、無色油状の標記化合物(9.4mg,20%)を得た。
【0303】
IR (neat): 3404, 2960, 2928, 1462, 1370, 1272, 1196, 1056cm-1. 1H NMR δ: 0.85 (s, 3H), 0.90 (d, J = 6.9Hz, 3H), 0.98 (s, 3H), 1.33 (d, J = 6.3Hz, 3H), 2.49-2.61 (m, 1H), 2.74-2.87 (m, 1H), 3.21-3.35 (m, 1H), 3.39-3.56 (m, 2H), 3.78 (brs, 1H), 3.93-4.15 (m, 2H), 5.40-5.50 (m, 1H), 5.65 (s, 1H), 5.70-5.81 (m, 1H). MS m/z: 312 (M+-HOCH2CH(OH)iPr, 100%). UV λmax nm: 269, 281, 293.
【0304】
実施例123
1α,3β−ジヒドロキシ−20(S)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエン(9.7mg,0.0233mmol)、エタノール(200ml)を用いて、実施例15と同操作で反応を行った後(光照射1分40秒間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.25mm×1枚、ジクロロメタン:エタノール=20:1、2回展開、さらに0.25mm×0.5枚、ヘキサン:酢酸エチル:エタノール=10:5:1、2回展開)により精製し、無色油状の標記化合物(1.06mg,11%)を得た。
【0305】
IR (neat): 3400, 2928, 1444, 1368, 1056cm-1. 1H NMR δ: 0.78 (s, 3H), 0.90 (d, J = 6.9Hz, 3H), 0.96 (d, J = 6.9Hz, 3H), 1.31 (d, J = 6.6Hz, 3H), 2.53-2.68 (m, 1H), 2.76-2.90 (m, 1H), 3.09-3.24 (m, 1H), 3.40-3.55 (m, 2H), 3.88-4.01 (m, 1H), 4.18-4.30 (m, 1H), 4.40-4.50 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.57 (s,1H), 6.10 (d, J = 11.4Hz, 1H), 6.37 (d, J = 11.4Hz, 1H). MS m/z: 312 (M+-HOCH2CH(OH)iPr), 149 (100%). UV λmax nm: 262.
【0306】
実施例124
1α,3β−ジヒドロキシ−20(S)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(S)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエン(12.0mg,0.0288mmol)及びエタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射1分40秒間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=10:5:1、1回展開、さらに0.25mm×0.5枚、ジクロロメタン:エタノール=30:1、2回展開、次いでジクロロメタン:エタノール=10:1、2回展開)により精製し、無色油状の標記化合物(1.45mg,12%)を得た。
【0307】
IR (neat): 3400, 2928, 1444, 1370, 1056cm-1. 1H NMR δ: 0.78 (s, 3H), 0.89 (d, J = 6.9Hz, 3H), 0.97 (d, J = 6.9Hz, 3H), 1.31 (d, J = 6.6Hz, 3H), 2.54-2.67 (m, 1H), 2.74-2.90 (m, 1H), 3.25-3.53 (m, 3H), 3.95 (q, J = 6.6Hz, 1H), 4.19-4.32 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.58 (s, 1H), 6.11 (d, J = 11.4Hz, 1H), 6.37 (d, J = 11.4Hz, 1H). MS m/z: 312 (M+-HOCH2CH(OH)iPr), 149 (100%). UV λmax nm: 263.
【0308】
実施例125
1α,3β−ジヒドロキシ−20(R)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−{2(S)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエン(9.9mg,0.0238mmol)及びエタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射1分40秒間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.25mm×1枚、ヘキサン:酢酸エチル:エタノール=10:5:1、2回展開、さらに0.25mm×0.5枚、ジクロロメタン:エタノール=15:1、2回展開)により精製し、無色油状の標記化合物(0.786mg,7.9%)を得た。
【0309】
IR (neat): 3392, 2928, 1452, 1370, 1264, 1056cm-1. 1H NMR δ: 0.74 (s, 3H), 0.90 (d, J = 6.6Hz, 3H), 0.97 (d, J = 6.6Hz, 3H), 1.33 (d, J = 6.3Hz, 3H), 2.55-2.68 (m, 1H), 2.77-2.90 (m, 1H), 3.21-3.34 (m, 1H), 3.41-3.56 (m, 2H), 3.98 (q, J = 6.3Hz, 1H), 4.18-4.31 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.63 (s, 1H), 6.10 (d, J = 11.4Hz, 1H), 6.37 (d, J = 11.4Hz, 1H). MS m/z: 312 (M+-HOCH2CH(OH)iPr), 149 (100%). UV λmax nm: 262.
【0310】
実施例126
1α,3β−ジヒドロキシ−20(R)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}−9,10−セコプレグナ−5,7,10(19),16−テトラエンの製造
1α,3β−ジヒドロキシ−20(R)−{2(R)−ヒドロキシ−3−メチルブチルオキシ}プレグナ−5,7,16−トリエン(8.5mg,0.0204mmol)、エタノール(200ml)を用い、実施例15と同操作で反応を行った後(光照射1分40秒間、加熱還流2時間)、分取用薄層クロマトグラフィー(0.25mm×1枚、ジクロロメタン:エタノール=15:1、2回展開、さらに0.25mm×0.5枚、ヘキサン:酢酸エチル:エタノール=10:5:1、2回展開)により精製し、無色油状の標記化合物(0.400mg,4.7%)を得た。
【0311】
IR (neat): 3416, 2924, 1452, 1370, 1262, 1066cm-1. 1H NMR δ: 0.75 (s, 3H), 0.91 (d, J = 6.6Hz, 3H), 0.97 (d, J = 6.6Hz, 3H), 1.32 (d, J = 6.3Hz, 3H), 2.55-2.67 (m, 1H), 2.77-2.88 (m, 1H), 3.21-3.33 (m, 1H), 3.36-3.57 (m, 2H), 3.92-4.06 (m, 1H), 4.19-4.30 (m, 1H), 4.40-4.50 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.60 (s, 1H), 6.10 (d, J = 11.4Hz, 1H), 6.37 (d, J = 11.4Hz, 1H). UV λmax nm: 260.
【0312】
以下に化合物1(1α,3β−ジヒドロキシ−20(S)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン)、化合物2(1α,3β−ジヒドロキシ−20(R)−(3−ヒドロキシ−3−メチルブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン)、化合物3(1α,3β−ジヒドロキシ−20(R)−(4−ヒドロキシ−4−メチル−2−ペンチニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン)、化合物4(1α,3β−ジヒドロキシ−20(R)−(4−エチル−4−ヒドロキシ−2−ヘキシニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン)、化合物5(1α,3β−ジヒドロキシ−20(R)−((E)−4−ヒドロキシ−4−メチル−2−ペンテニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン)、化合物6(1α,3β−ジヒドロキシ−20(R)−((E)−4−エチル−4−ヒドロキシ−2−ヘキセニルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン)に関する活性の試験例を示す。
【0313】
試験例1
リン酸緩衝液に溶解した活性型ビタミンD3あるいは各ビタミンD3誘導体を8週齢雄性ddYマウスに投与量30μg/kgで静脈内投与した後、24時間目に血中のイオン化カルシウム値を測定した。実験は各群5例で実施し、結果は平均値±標準誤差で示した。活性型ビタミンD3および各ビタミンD3誘導体の持つ血中カルシウム上昇活性の評価は、同量のリン酸緩衝液のみを投与した対照群との比較により行った。結果は図1〜図3に示す。有意差検定にはDunnettのT検定を用い、図中*は5%、**は1%、***は0.1%の危険率で有意差があることを示す。
【0314】
試験例2
HL−60細胞は、10%ウシ胎児血清および20μg/mlゲンタミシンを含むRPMI−1640培地にて、5%CO2下、37℃で継代培養された。分化誘導作用は以下の方法で評価した。まず24ウェルプレートに様々な濃度の被験化合物を含む培養液に105個の細胞を播種し、上記培養条件にて4日間培養した。次にフォルボールミリステートアセテート(PMA)刺激により産生されるスーパーオキサイドの量をチトクロームC還元能として測定した。すなわち、培養上清を吸引除去後、被験化合物で処理した細胞を1.5mlの反応混合液(80μM ferricytochrome C,500ng/ml PMA)に懸濁し、37℃で1時間培養した後、培養上清の吸光度を日立二波長分光光度計を用いて、OD550−540にて測定した。結果を図4〜図6に示す。還元チトクロームCの濃度は分子吸光係数19.1×103cm-1を用いて計算した。
【0315】
【発明の効果】
本発明の一般式(1)で示される化合物は、カルシウム上昇作用の低い、抗腫瘍剤、抗リウマチ剤等の医薬として有用な化合物である。
【図面の簡単な説明】
【図1】図1は活性型ビタミンD3またはビタミンD3誘導体の投与後の血中イオン化カルシウム値の測定結果を示したグラフである。
【図2】図2は活性型ビタミンD3またはビタミンD3誘導体の投与後の血中イオン化カルシウム値の測定結果を示したグラフである。
【図3】図3は活性型ビタミンD3またはビタミンD3誘導体の投与後の血中イオン化カルシウム値の測定結果を示したグラフである。
【図4】図4は活性型ビタミンD3またはビタミンD3誘導体の分化誘導作用の評価試験の結果を示したグラフである。
【図5】図5は活性型ビタミンD3またはビタミンD3誘導体の分化誘導作用の評価試験の結果を示したグラフである。
【図6】図6は活性型ビタミンD3またはビタミンD3誘導体の分化誘導作用の評価試験の結果を示したグラフである。[0001]
[Technical field to which the invention belongs]
The present invention relates to a novel vitamin D derivative having a high binding ability to a vitamin D receptor and a weak calcium-elevating action, a compound useful as a pharmaceutical such as an antitumor agent and an antirheumatic agent, and a novel synthesis useful for the synthesis of the compound. Regarding intermediates.
[0002]
[Prior art]
1α, 25-dihydroxyvitamin DThreeAnd other active vitamin DThreeIs known to have many physiological activities such as tumor cell growth inhibitory action, differentiation inducing action, and immunoregulatory action in addition to calcium metabolism regulating action. However, active vitamin DThreeAmong these compounds, there are compounds having the disadvantage of causing hypercalcemia by long-term and continuous administration, and such compounds are not suitable for use as antitumor agents, antirheumatic agents and the like. Therefore, many vitamin D derivatives have been studied for the purpose of separating the actions of these vitamin Ds.
[0003]
As such a compound, for example, JP-A-61-267550 discloses 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7, 10 (19) -triene and JP-A-7-330714 disclose vitamin D derivatives substituted at the 22-position with a sulfur atom.
[0004]
JP-A-2-9861, JP-A-3-17019, JP-A-7-188159, JP-A-6-40975, JP-A-7-179418, US Pat. Nos. 5,087,619 and 5,145,846, etc. Various compounds having a double bond at position 16 of the vitamin D derivative have been described. However, there is no description that these compounds have a weak calcium-elevating action.
[0005]
[Problems to be solved by the invention]
All of these known vitamin D compounds have a high binding ability to the vitamin D receptor, but at the same time have a high calcium raising action, and conversely, the calcium raising action is low, but the binding ability to the vitamin D receptor is satisfactory. There are many that are not, and the appearance of promising compounds that have a high ability to bind to vitamin D receptors and a low calcium-elevating effect is desired.
[0006]
[Means for Solving the Invention]
In view of these problems, the present inventors have conducted extensive research on compounds having a high binding ability to vitamin D receptor and a low calcium-elevating action, and as a result, the general formula (1):
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(Wherein X represents an oxygen atom or a sulfur atom, R11Is a saturated or unsaturated aliphatic hydrocarbon group optionally substituted by a hydroxyl group or a protected hydroxyl group, or -COR12Group (wherein R12Represents an alkyl group, an aryl group or an alkoxy group), and R2Is -OR9Or a hydrogen atom, R9And RTenHave the same or different and each represents a hydrogen atom or a protecting group), and have found that they have a high vitamin D receptor binding ability and a low calcium-elevating action, leading to the present invention.
[0007]
According to one aspect of the present invention, the general formula (1):
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(Wherein X represents an oxygen atom or a sulfur atom, R11Is a saturated or unsaturated aliphatic hydrocarbon group optionally substituted by a hydroxyl group or a protected hydroxyl group, or -COR12Group (wherein R12Represents an alkyl group, an aryl group or an alkoxy group), and R2Is -OR9Or a hydrogen atom, R9And RTenAre the same or different and each represents a hydrogen atom or a protecting group).
[0008]
In general formula (1), preferably R2Is -OR9It is.
In general formula (1), preferably R11Is a saturated aliphatic hydrocarbon group having 1 to 15 carbon atoms which may be substituted with a hydroxyl group.
In general formula (1), preferably R11Is an unsaturated aliphatic hydrocarbon group having 2 to 15 carbon atoms which may be substituted with a hydroxyl group.
[0009]
In general formula (1), preferably R11Is the group (2):
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(Wherein RThreeAnd RFourAre the same or different and each represents a hydrogen atom or a hydroxyl group, or together, has an oxygen atom and represents = O. However, RThreeAnd RFourAre not simultaneously hydroxyl groups. RFiveAnd R6Represents a hydrogen atom or a hydroxyl group, but R6Is RThreeOr RFourAt the same time, it does not become a hydroxyl group. m represents an integer of 1 to 4 and n represents an integer of 0 to 2) or group (3):
Embedded image
(Where RFiveAnd R6Are the same or different and each represents a hydrogen atom or a hydroxyl group. R7And R8Represents a hydrogen atom or a covalent bond together. p represents an integer of 1 to 3, and q represents an integer of 0 to 2.
[0010]
In the general formula (1), particularly preferably R11Is a 3-hydroxy-3-methylbutyl group.
In one embodiment of the compound represented by the general formula (1), the 20-position is the S configuration.
In another aspect of the compounds represented by general formula (1),
[0011]
Specific examples of the compound represented by the general formula (1) include 1,3-dihydroxy-20- (3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19). 16-tetraene. Specific examples of the sterically specified compounds include 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 ( 19), 16-tetraene and 1α, 3β-dihydroxy-20 (R)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene .
Another specific example of the compound represented by the general formula (1) is 1α, 3β-dihydroxy-20 (R)-((E) -4-hydroxy-4-methyl-2-pentenylthio) -9, 10-secopregna-5,7,10 (19), 16-tetraene and 1α, 3β-dihydroxy-20 (R)-((E) -4-ethyl-4-hydroxy-2-hexenylthio) -9,10 -Secopregna-5,7,10 (19), 16-tetraene.
Another specific example of the compound represented by the general formula (1) is 1α, 3β-dihydroxy-20 (S)-(2-hydroxy-2-methylpropylthio) -9,10-secopregna-5,7. , 10 (19), 16-tetraene, 1α, 3β-dihydroxy-20 (R)-(2-hydroxy-2-methylpropylthio) -9,10-secopregna-5,7,10 (19), 16- Tetraene, 1α, 3β-dihydroxy-20 (S)-{2 (S) -hydroxy-3-methylbutyloxy} -9,10-secopregna-5,7,10 (19), 16-tetraene, 1α, 3β -Dihydroxy-20 (S)-{2 (R) -hydroxy-3-methylbutyloxy} -9,10-secopregna-5,7,10 (19), 16-tetraene, 1α, 3β-dihydroxy- 0 (S)-(2-ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene, 1α, 3β-dihydroxy-20 (R)-(2- Ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene.
[0012]
According to another aspect of the present invention, the general formula (4):
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(Wherein X represents an oxygen atom or a sulfur atom, R11Is a saturated or unsaturated aliphatic hydrocarbon group optionally substituted by a hydroxyl group or a protected hydroxyl group, or -COR12Group (wherein R12Represents an alkyl group, an aryl group or an alkoxy group), and R9And RTenAre the same or different and each represents a hydrogen atom or a protecting group.
[0013]
In general formula (4), preferably R11Is a saturated aliphatic hydrocarbon group having 1 to 15 carbon atoms which may be substituted with a hydroxyl group.
In general formula (4), preferably R11Is an unsaturated aliphatic hydrocarbon group having 2 to 15 carbon atoms which may be substituted with a hydroxyl group.
[0014]
In general formula (4), preferably R11Is the group (2):
Embedded image
(Wherein RThreeAnd RFourAre the same or different and each represents a hydrogen atom or a hydroxyl group, or together, has an oxygen atom and represents = O. However, RThreeAnd RFourAre not simultaneously hydroxyl groups. RFiveAnd R6Represents a hydrogen atom or a hydroxyl group, but R6Is RThreeOr RFourAt the same time, it does not become a hydroxyl group. m represents an integer of 1 to 4 and n represents an integer of 0 to 2) or group (3):
Embedded image
(Where RFiveAnd R6Are the same or different and each represents a hydrogen atom or a hydroxyl group. R7And R8Represents a hydrogen atom or a covalent bond together. p represents an integer of 1 to 3, and q represents an integer of 0 to 2.
In the general formula (4), particularly preferably R11Is a 3-hydroxy-3-methylbutyl group.
[0015]
According to another aspect of the present invention, the general formula (24):
Embedded image
(Wherein R9And RTenAre the same or different and each represents a hydrogen atom or a protecting group.
According to yet another aspect of the present invention, the general formula (5):
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(Wherein R9And RTenAre the same or different and each represents a hydrogen atom or a protecting group, and the conjugated double bond in the formula may be protected by a protecting group.
[0016]
According to yet another aspect of the present invention, the general formula (6):
Embedded image
(Wherein R9And RTenAre the same or different and each represents a hydrogen atom or a protecting group.
[0017]
According to yet another aspect of the present invention, the general formula (7):
Embedded image
(Wherein R9And RTenAre the same or different and each represents a hydrogen atom or a protecting group.
[0018]
According to yet another aspect of the present invention, the general formula (4a):
Embedded image
(Wherein X represents an oxygen atom or a sulfur atom, R1Is a saturated or unsaturated aliphatic hydrocarbon group which may be substituted with a hydroxyl group which may have a protecting group, or -COR12Group (wherein R12Represents an alkyl group, an aryl group or an alkoxy group), and R9And RTenAre the same or different and each represents a hydrogen atom or a protecting group), and is subjected to photoreaction, thermal isomerization reaction and deprotection reaction,
Embedded image
(In the formula, X represents an oxygen atom or a sulfur atom, R11Is a saturated or unsaturated aliphatic hydrocarbon group optionally substituted by a hydroxyl group or a protected hydroxyl group, or -COR12Group (wherein R12Represents an alkyl group, an aryl group or an alkoxy group), and R2Is -OR9Or a hydrogen atom, R9And RTenAre the same or different and each represents a hydrogen atom or a protecting group).
According to still another aspect of the present invention, there is provided a medicament comprising the vitamin D derivative represented by the general formula (1).
[0019]
DETAILED DESCRIPTION OF THE INVENTION
The terms used in the present invention have the following meanings unless otherwise defined.
The saturated aliphatic hydrocarbon group generally represents a linear or branched alkyl group having 1 to 15 carbon atoms, such as a methyl group, ethyl group, n-propyl group, i-propyl group, n In addition to -butyl group, s-butyl group, i-butyl group and t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decanyl group and the like can be mentioned, preferably 3-methylbutyl group, 3-ethylpentyl group, 4-methylpentyl group, 3- (n-propyl) hexyl group, 4-ethylhexyl group, 5-methylhexyl group, 6-methylheptyl group, 5-ethylheptyl group, 4- (n- Propyl) heptyl group and the like, more preferably 3-methylbutyl group, 3-ethylpentyl group, 4-methylpentyl group and the like.
[0020]
The unsaturated aliphatic hydrocarbon group generally represents a linear or branched alkenyl group or alkynyl group having 2 to 15 carbon atoms, for example, 2-propenyl group, 2-butenyl group, 3-butenyl group. Group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group Group, 5-heptenyl group, 6-heptenyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 2-hexynyl group, 3-hexynyl group Group, 4-hexynyl group, 5-hexynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 5-heptynyl group, 6-heptynyl group, etc. May be substituted with the aforementioned alkyl groups hydrogen atoms is 1 or more, may be either cis or trans with respect to the double bond. Preferably, 4-methyl-2-pentynyl group, 4-ethyl-2-hexynyl group, 4-methyl-2-pentenyl group, 4-ethyl-2-hexenyl group and the like can be mentioned.
[0021]
The saturated or unsaturated aliphatic hydrocarbon group which may be substituted with a hydroxyl group is a group in which any hydrogen atom of the saturated or unsaturated hydrocarbon group may be substituted with one or more hydroxyl groups , And examples of the number of substituted hydroxyl groups include 0, 1, 2, 3 and the like, preferably 1 or 2, and more preferably 1. Specific examples include the above aliphatic hydrocarbon group, 2-hydroxy-2-methylpropyl group, 3-hydroxy-2-methylpropyl group, 2,3-dihydroxy-2-methylpropyl group, 2- Ethyl-2-hydroxybutyl group, 2-ethyl-3-hydroxybutyl group, 2-ethyl-2, 3-dihydroxybutyl group, 2-hydroxy-2- (n-propyl) pentyl group, 3-hydroxy-2- (N-propyl) pentyl group, 2,3-dihydroxy-2- (n-propyl) pentyl group, 2-hydroxy-3-methylbutyl group, 3-hydroxy-3-methylbutyl group, 4-hydroxy-3-methylbutyl group 2,3-dihydroxy-3-methylbutyl group, 2,4-dihydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl group, 3 Ethyl-2-hydroxypentyl group, 3-ethyl-3-hydroxypentyl group, 3-ethyl-4-hydroxypentyl group, 3-ethyl-2, 3-dihydroxypentyl group, 3-ethyl-2, 4-dihydroxypentyl Group, 3-ethyl-3,4-dihydroxypentyl group, 2-hydroxy-3- (n-propyl) hexyl group, 3-hydroxy-3- (n-propyl) hexyl group, 4-hydroxy-3- (n -Propyl) hexyl group, 2,3-dihydroxy-3- (n-propyl) hexyl group, 2,4-dihydroxy-3- (n-propyl) hexyl group, 3,4-dihydroxy-3- (n-propyl) ) Hexyl group, 3-hydroxy-4-methylpentyl group, 4-hydroxy-4-methylpentyl group, 5-hydroxy-4-methylpentyl group, 3 4-dihydroxy-4-methylpentyl group, 3,5-dihydroxy-4-methylpentyl group, 4,5-dihydroxy-4-methylpentyl group, 4-ethyl-3-hydroxyhexyl group, 4-ethyl-4- Hydroxyhexyl group, 4-ethyl-5-hydroxyhexyl group, 4-ethyl-3, 4-dihydroxyhexyl group, 4-ethyl-3, 5-dihydroxyhexyl group, 4-ethyl-4, 5-dihydroxyhexyl group, 3-hydroxy-4- (n-propyl) heptyl group, 4-hydroxy-4- (n-propyl) heptyl group, 5-hydroxy-4- (n-propyl) heptyl group, 3,4-dihydroxy-4- (N-propyl) heptyl group, 3,5-dihydroxy-4- (n-propyl) heptyl group, 4,5-dihydroxy-4- (n-propyl) ) Heptyl group, 4-hydroxy-5-methylhexyl group, 5-hydroxy-5-methylhexyl group, 6-hydroxy-5-methylhexyl group, 4,5-dihydroxy-5-methylhexyl group, 4,6- Dihydroxy-5-methylhexyl group, 5,6-dihydroxy-5-methylhexyl group, 5-ethyl-4-hydroxyheptyl group, 5-ethyl-5-hydroxyheptyl group, 5-ethyl-6-hydroxyheptyl group, 5-ethyl-4,5-dihydroxyheptyl group, 5-ethyl-4,6-dihydroxyheptyl group, 5-ethyl-5,6-dihydroxyheptyl group, 4-hydroxy-5- (n-propyl) octyl group, 5-hydroxy-5- (n-propyl) octyl group, 6-hydroxy-5- (n-propyl) octyl group, 4,5-dihydro Ci-5- (n-propyl) octyl group, 4,6-dihydroxy-5- (n-propyl) octyl group, 5,6-dihydroxy-5- (n-propyl) octyl group, 5-hydroxy-6 Methyl heptyl group, 6-hydroxy-6-methylheptyl group, 7-hydroxy-6-methylheptyl group, 5,6-dihydroxy-6-methylheptyl group, 5,7-dihydroxy-6-methylheptyl group, 6, 7-dihydroxy-6-methylheptyl group, 6-ethyl-5-hydroxyoctyl group, 6-ethyl-6-hydroxyoctyl group, 6-ethyl-7-hydroxyoctyl group, 6-ethyl-5, 6-hydroxyoctyl Group, 6-ethyl-5,7-hydroxyoctyl group, 6-ethyl-6,7-hydroxyoctyl group, 5-hydroxy-6- (n-propyl) Nonyl group, 6-hydroxy-6- (n-propyl) nonyl group, 7-hydroxy-6- (n-propyl) nonyl group, 5,6-dihydroxy-6- (n-propyl) nonyl group, 5,7 Saturated aliphatic hydrocarbon groups such as -dihydroxy-6- (n-propyl) nonyl group, 6,7-dihydroxy-6- (n-propyl) nonyl group, and 4-hydroxy-4-methyl-2- Pentenyl group, 5-hydroxy-4-methyl-2-pentenyl group, 4,5-dihydroxy-4-methyl-2-pentenyl group, 4-ethyl-4-hydroxy-2-hexenyl group, 4-ethyl-5 Hydroxy-2-hexenyl group, 4-ethyl-4,5-dihydroxy-2-hexenyl group, 4-hydroxy-4- (n-propyl) -2-heptenyl group, 5-hydroxy-4- (n-pro Pyr) -2-heptenyl group, 4,5-dihydroxy-4- (n-propyl) -2-heptenyl group, 5-hydroxy-5-methyl-3-hexenyl group, 6-hydroxy-5-methyl-3- Hexenyl group, 5,6-dihydroxy-5-methyl-3-hexenyl group, 5-ethyl-5-hydroxy-3-heptenyl group, 5-ethyl-6-hydroxy-3-heptenyl group, 5-ethyl-5, 6-dihydroxy-3-heptenyl group, 5-hydroxy-5- (n-propyl) -3-octenyl group, 6-hydroxy-5- (n-propyl) -3-octenyl group, 5,6-dihydroxy-5 -(N-propyl) -3-octenyl group, 4-hydroxy-5-methyl-2-hexenyl group, 5-hydroxy-5-methyl-2-hexenyl group, 6-hydroxy-5-methyl 2-hexenyl group, 4,5-dihydroxy-5-methyl-2-hexenyl group, 4,6-dihydroxy-5-methyl-2-hexenyl group, 5,6-dihydroxy-5-methyl-2-hexenyl group 5-ethyl-4-hydroxy-2-heptenyl group, 5-ethyl-5-hydroxy-2-heptenyl group, 5-ethyl-6-hydroxy-2-heptenyl group, 5-ethyl-4, 5-dihydroxy- 2-heptenyl group, 5-ethyl-4,6-dihydroxy-2-heptenyl group, 5-ethyl-5,6-dihydroxy-2-heptenyl group, 4-hydroxy-5- (n-propyl) -2-octenyl Group, 5-hydroxy-5- (n-propyl) -2-octenyl group, 6-hydroxy-5- (n-propyl) -2-octenyl group, 4,5-dihydroxy-5- n-propyl) -2-octenyl group, 4,6-dihydroxy-5- (n-propyl) -2-octenyl group, 5,6-dihydroxy-5- (n-propyl) -2-octenyl group, 6- Hydroxy-6-methyl-4-heptenyl group, 7-hydroxy-6-methyl-4-heptenyl group, 6,7-dihydroxy-6-methyl-4-heptenyl group, 6-ethyl-6-hydroxy-4-octenyl Group, 6-ethyl-7-hydroxy-4-octenyl group, 6-ethyl-6,7-dihydroxy-4-octenyl group, 6-hydroxy-6- (n-propyl) -4-nonenyl group, 7-hydroxy -6- (n-propyl) -4-nonenyl group, 6,7-dihydroxy-6- (n-propyl) -4-nonenyl group, 5-hydroxy-6-methyl-3-heptenyl group, Droxy-6-methyl-3-heptenyl group, 7-hydroxy-6-methyl-3-heptenyl group, 5,6-dihydroxy-6-methyl-3-heptenyl group, 5,7-dihydroxy-6-methyl-3 -Heptenyl group, 6,7-dihydroxy-6-methyl-3-heptenyl group, 6-ethyl-5-hydroxy-3-octenyl group, 6-ethyl-6-hydroxy-3-octenyl group, 6-ethyl-7 -Hydroxy-3-octenyl group, 6-ethyl-5, 6-dihydroxy-3-octenyl group, 6-ethyl-5, 7-dihydroxy-3-octenyl group, 6-ethyl-6, 7-dihydroxy-3- Octenyl group, 5-hydroxy-6- (n-propyl) -3-nonenyl group, 6-hydroxy-6- (n-propyl) -3-nonenyl group, 7-hydroxy-6- ( -Propyl) -3-nonenyl group, 5,6-dihydroxy-6- (n-propyl) -3-nonenyl group, 5,7-dihydroxy-6- (n-propyl) -3-nonenyl group, 6,7 -Dihydroxy-6- (n-propyl) -3-nonenyl group, 5-hydroxy-6-methyl-2-heptenyl group, 6-hydroxy-6-methyl-2-heptenyl group, 7-hydroxy-6-methyl- 2-heptenyl group, 5,6-dihydroxy-6-methyl-2-heptenyl group, 5,7-dihydroxy-6-methyl-2-heptenyl group, 6,7-dihydroxy-6-methyl-2-heptenyl group, 6-ethyl-5-hydroxy-2-octenyl group, 6-ethyl-6-hydroxy-2-octenyl group, 6-ethyl-7-hydroxy-2-octenyl group, 6-ethyl-5,6-di Droxy-2-octenyl group, 6-ethyl-5,7-dihydroxy-2-octenyl group, 6-ethyl-6,7-dihydroxy-2-octenyl group, 5-hydroxy-6- (n-propyl) -2 -Nonenyl group, 6-hydroxy-6- (n-propyl) -2-nonenyl group, 7-hydroxy-6- (n-propyl) -2-nonenyl group, 5,6-dihydroxy-6- (n-propyl) ) -2-nonenyl group, 5,7-dihydroxy-6- (n-propyl) -2-nonenyl group, 6,7-dihydroxy-6- (n-propyl) -2-nonenyl group, 4-hydroxy-4 -Methyl-2-pentynyl group, 5-hydroxy-4-methyl-2-pentynyl group, 4,5-dihydroxy-4-methyl-2-pentynyl group, 4-ethyl-4-hydroxy-2-hexynyl group, 4 -Ethyl-5-hydroxy-2-hexynyl group, 4-ethyl-4,5-dihydroxy-2-hexynyl group, 4-hydroxy-4- (n-propyl) -2-heptynyl group, 5-hydroxy-4- (N-propyl) -2-heptynyl group, 4,5-dihydroxy-4- (n-propyl) -2-heptynyl group, 5-hydroxy-5-methyl-3-hexynyl group, 6-hydroxy-5-methyl -3-hexynyl group, 5,6-dihydroxy-5-methyl-3-hexynyl group, 5-ethyl-5-hydroxy-3-heptynyl group, 5-ethyl-6-hydroxy-3-heptynyl group, 5-ethyl -5,6-dihydroxy-3-heptynyl group, 5-hydroxy-5- (n-propyl) -3-octynyl group, 6-hydroxy-5- (n-propyl) -3-octynyl 5,6-dihydroxy-5- (n-propyl) -3-octynyl group, 4-hydroxy-5-methyl-2-hexynyl group, 5-hydroxy-5-methyl-2-hexynyl group, 6-hydroxy- 5-methyl-2-hexynyl group, 4,5-dihydroxy-5-methyl-2-hexynyl group, 4,6-dihydroxy-5-methyl-2-hexynyl group, 5,6-dihydroxy-5-methyl-2 -Hexynyl group, 5-ethyl-4-hydroxy-2-heptynyl group, 5-ethyl-5-hydroxy-2-heptynyl group, 5-ethyl-6-hydroxy-2-heptynyl group, 5-ethyl-4,5 -Dihydroxy-2-heptynyl group, 5-ethyl-4,6-dihydroxy-2-heptynyl group, 5-ethyl-5,6-dihydroxy-2-heptynyl group, 4-hydroxy -5- (n-propyl) -2-octynyl group, 5-hydroxy-5- (n-propyl) -2-octynyl group, 6-hydroxy-5- (n-propyl) -2-octynyl group, 4, 5-dihydroxy-5- (n-propyl) -2-octynyl group, 4,6-dihydroxy-5- (n-propyl) -2-octynyl group, 5,6-dihydroxy-5- (n-propyl)- 2-octynyl group, 6-hydroxy-6-methyl-4-heptynyl group, 7-hydroxy-6-methyl-4-heptynyl group, 6,7-dihydroxy-6-methyl-4-heptynyl group, 6-ethyl- 6-hydroxy-4-octynyl group, 6-ethyl-7-hydroxy-4-octynyl group, 6-ethyl-6, 7-dihydroxy-4-octynyl group, 6-hydroxy-6- (n-propyl)- 4-noninyl group, 7-hydroxy-6- (n-propyl) -4-noninyl group, 6,7-dihydroxy-6- (n-propyl) -4-noninyl group, 5-hydroxy-6-methyl-3 -Heptynyl group, 6-hydroxy-6-methyl-3-heptynyl group, 7-hydroxy-6-methyl-3-heptynyl group, 5,6-dihydroxy-6-methyl-3-heptynyl group, 5,7-dihydroxy -6-methyl-3-heptynyl group, 6,7-dihydroxy-6-methyl-3-heptynyl group, 6-ethyl-5-hydroxy-3-octynyl group, 6-ethyl-6-hydroxy-3-octynyl group 6-ethyl-7-hydroxy-3-octynyl group, 6-ethyl-5, 6-dihydroxy-3-octynyl group, 6-ethyl-5, 7-dihydroxy-3-octynyl group, -Ethyl-6,7-dihydroxy-3-octynyl group, 5-hydroxy-6- (n-propyl) -3-noninyl group, 6-hydroxy-6- (n-propyl) -3-noninyl group, 7- Hydroxy-6- (n-propyl) -3-noninyl group, 5,6-dihydroxy-6- (n-propyl) -3-noninyl group, 5,7-dihydroxy-6- (n-propyl) -3- Noninyl group, 6,7-dihydroxy-6- (n-propyl) -3-noninyl group, 5-hydroxy-6-methyl-2-heptynyl group, 6-hydroxy-6-methyl-2-heptynyl group, 7- Hydroxy-6-methyl-2-heptynyl group, 5,6-dihydroxy-6-methyl-2-heptynyl group, 5,7-dihydroxy-6-methyl-2-heptynyl group, 6,7-dihydroxy-6-methyl 2-heptynyl group, 6-ethyl-5-hydroxy-2-octynyl group, 6-ethyl-6-hydroxy-2-octynyl group, 6-ethyl-7-hydroxy-2-octynyl group, 6-ethyl-5 6-dihydroxy-2-octynyl group, 6-ethyl-5, 7-dihydroxy-2-octynyl group, 6-ethyl-6, 7-dihydroxy-2-octynyl group, 5-hydroxy-6- (n-propyl) ) -2-noninyl group, 6-hydroxy-6- (n-propyl) -2-noninyl group, 7-hydroxy-6- (n-propyl) -2-noninyl group, 5,6-dihydroxy-6- ( n-propyl) -2-noninyl group, 5,7-dihydroxy-6- (n-propyl) -2-noninyl group, 6,7-dihydroxy-6- (n-propyl) -2-noninyl group and the like. Is Preferably 3-hydroxy-3-methylbutyl group, 4-hydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl group, 3-ethyl-3-hydroxypentyl group, 3-ethyl-4-hydroxypentyl Group, 3-ethyl-3,4-dihydroxypentyl group, 4-hydroxy-4-methylpentyl group, 5-hydroxy-4-methylpentyl group, 4,5-dihydroxy-4-methylpentyl group, 4-ethyl- 4-hydroxyhexyl group, 4-ethyl-5-hydroxyhexyl group, 4-ethyl-4, 5-dihydroxyhexyl group, 4-hydroxy-4-methyl-2-pentenyl group, 5-hydroxy-4-methyl-2 -Pentenyl group, 4,5-dihydroxy-4-methyl-2-pentenyl group, 4-ethyl-4-hydroxy-2-hex Nyl group, 4-ethyl-5-hydroxy-2-hexenyl group, 4-ethyl-4, 5-dihydroxy-2-hexenyl group, 4-hydroxy-4-methyl-2-pentynyl group, 5-hydroxy-4- Methyl-2-pentynyl group, 4,5-dihydroxy-4-methyl-2-pentynyl group, 4-ethyl-4-hydroxy-2-hexynyl group, 4-ethyl-5-hydroxy-2-hexynyl group, 4- Examples include an ethyl-4,5-dihydroxy-2-hexynyl group.
[0022]
In the present specification, an alkyl group generally means a linear or branched alkyl group having 1 to 15 carbon atoms, preferably 1 to 8 carbon atoms, and an aryl group generally means carbon. Means an aryl group having 6 to 20 carbon atoms, preferably 6 to 14 carbon atoms, and the alkoxy group is generally a linear or branched alkoxy group having 1 to 15 carbon atoms, preferably 1 to 8 carbon atoms. Means.
[0023]
Examples of the protecting group include an acyl group, a substituted silyl group, and a substituted alkyl group, and an acyl group and a substituted silyl group are preferable.
The acyl group means a substituted carbonyl group. The substituent of the carbonyl group here is a hydrogen atom, an optionally substituted lower alkyl group, or an optionally substituted group. An aryl group, a lower alkyloxy group which may have a substituent, an aryloxy group which may have a substituent, an aralkyloxy group which may have a substituent, and the like are meant. The acyl group is preferably a formyl group, a lower alkylcarbonyl group, an optionally substituted phenylcarbonyl group, a lower alkyloxycarbonyl group, an optionally substituted phenylalkyloxycarbonyl group or the like. More preferably, a formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group and the like are shown.
[0024]
The substituted silyl group means a silyl group substituted with a lower alkyl group which may have one or more substituents or an aryl group which may have a substituent, preferably trisubstituted. A silyl group is shown. Preferable examples of the substituted silyl group include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldiphenylsilyl group, t-butyldimethylsilyl group and the like.
[0025]
The substituted alkyl group refers to an alkyl group that is substituted with one or more substituents, and preferred examples of the substituent include an alkyloxy group that may have a substituent and a substituent. And an aryloxy group which may have a substituent. Examples of the substituted alkyl group substituted with an alkyloxy group which may have a substituent such as an alkyloxy group include a tetrahydropyran-2-yl group in addition to a methoxymethyl group and a 2-methoxyethoxymethyl group. Can be mentioned. Examples of the substituent include a halogen atom, cyano group, nitro group, amino group, hydroxyl group, alkyl group, alkyloxy group, acyloxy group, sulfonyl group and the like.
[0026]
Among the compounds represented by the general formula (1) of the present invention, a compound in which X is a sulfur atom is represented by the formula (8) described in JP-A-7-330714, for example, as shown below. It can be produced from the compound represented.
Embedded image
(In the formula, TBS means t-butyldimethylsilyl group, R12Represents an alkyl group, an aryl group or an alkoxy group, R1aRepresents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted with a hydroxyl group or a protected hydroxyl group, and R1bRepresents a saturated or unsaturated aliphatic hydrocarbon group substituted with a hydroxyl group)
[0027]
In the above formula, an alkylhalothioformate or aryl in the presence of a base in a suitable solvent from a compound represented by the formula (8) obtained in the same manner as in the method described in JP-A-7-330714 By reacting with halothioformate, a compound represented by the general formula (9) can be obtained via O-alkylthiocarbonate or alkyldithiocarbonate (Step 1).
[0028]
Examples of the alkylhalothioformate or arylhalothioformate used in Step 1 above include phenylchlorothionoformate, tolylchlorothionoformate, 4-tert-butylphenylchlorothionoformate, 4-fluoro. Phenylchlorothionoformate, 3-chlorophenylchlorothionoformate, 4-chlorophenylchlorothionoformate, 3,4-dichlorophenylchlorothionoformate, 2,4,6-trichlorophenylchlorothionoformate, Pentafluorophenylchlorothionoformate, methylchlorodithioformate, ethylchlorodithioformate, isopropylchlorodithioformate, phenylchlorodithioformate, tolylchlorodithioformate, 2,4,6-trimethyl Phenylchlorodithioformate, 4-fluorophenylchlorodithioformate, pentafluorophenylchlorodithioformate, 2-chlorophenylchlorodithioformate, 3-chlorophenylchlorodithioformate, 4-chlorophenylchlorodithioformate, 2,4 , 5-trichlorophenylchlorodithioformate, pentachlorochlorodithioformate, 4-methoxyphenylchlorodithioformate, 4-cyanophenylchlorodithioformate, 4-nitrophenylchlorodithioformate, etc., preferably Phenylchlorothionoformate, tolylchlorothionoformate, 4-tert-butylphenylchlorothionoformate, 4-fluorophenylchlorothionoformate, 4-chlorophenyl Examples include rothionoformate, 2,4,6-trichlorophenylchlorothionoformate, pentafluorophenylchlorothionoformate, phenylchlorodithioformate, and more preferably phenylchlorothionoformate. .
[0029]
Examples of the solvent used in Step 1 include hydrocarbon solvents, ether solvents, halogen solvents, and the like, such as benzene, toluene, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane, chloroform, carbon tetrachloride, and the like. Preferably, dichloromethane, toluene, etc. are mentioned, More preferably, a dichloromethane can be used.
[0030]
Examples of the base used in Step 1 include pyridine compounds, amine compounds, imidazole compounds, alkali metal hydroxides, metal hydrides, alkali metal compounds, metal amides, and the like, such as pyridine, collidine, lutidine, 2 , 6-Di-tert-butylpyridine, 4-methyl-2,6-di-tert-butylpyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, imidazole, sodium hydroxide, potassium hydroxide, sodium hydride, Examples include potassium hydride, methyllithium, n-butyllithium, ethylmagnesium bromide, lithium diisopropylamide, lithium bistrimethylsilylamide, and the like, preferably pyridine, collidine, lutidine, 2,6-di-tert-butylpyridine. Emissions, 4-methyl-2,6-di -tert- butyl pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine and the like, more preferably pyridine are used.
[0031]
The reaction temperature in step 1 is not particularly limited as long as it proceeds, but it proceeds in the range of 0 to 100 ° C., preferably at room temperature. In this reaction, a thiol carbonate having a 20S steric form can be selectively synthesized from the 16α-OH form, and a thiol carbonate having a 20R steric form can be selectively synthesized from the 16β-OH form.
The compound represented by the general formula (9) constitutes a part of the intermediate represented by the general formula (4).
[0032]
From the compound represented by the general formula (9), a compound represented by the general formula (10) having a side chain introduced can be obtained by performing S-alkylation simultaneously with alkali solvolysis (step 2). .
[0033]
Examples of the base used for the alkali solvolysis and S-alkylation in Step 2 above include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, etc., preferably sodium hydroxide Potassium hydroxide, sodium methoxide and the like are used. The reaction may be water or an alcohol solvent such as methanol, ethanol, propanol, butanol or the like alone or a mixed solvent system with an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diglyme, etc. Can be done.
[0034]
Moreover, as an alkylating agent to be used, general formula (13) corresponding to a side chain:
Y-R1a (13)
Wherein Y represents a leaving group such as a halogen atom, mesyloxy group, tosyloxy group, trifluoromethanesulfonyloxy group, R1aRepresents the same meaning as described above) or epoxides such as isobutylene oxide, 1,2-epoxy-2-ethylbutane, 1,2-epoxy-3-methylbutane, 1,2-epoxy-3-ethylpentane, and the like. .
The compound represented by the general formula (10) constitutes a part of the intermediate represented by the general formula (4).
[0035]
Examples of the compound represented by the general formula (13) include 4-bromo-2-methyl-2-butanol, 1-bromo-4-methyl-4-triethylsilyloxypentane, 6-bromo-2-methyl-2- R of the compound of the present invention represented by the general formula (1) such as hexanol, 5-bromo-3-ethyl-3-pentanol, 6-bromo-3-ethyl-3-hexanol, etc.1An alkylating agent corresponding to is used.
The reaction in the above step 2 is performed at −40 to 100 ° C., preferably 0 to 50 ° C., more preferably at room temperature.
[0036]
The compound represented by the general formula (10) can be converted to the compound represented by the general formula (11) by a conventional deprotection (step 3).
Examples of the reagent used in the reaction in Step 3 above include hydrochloric acid, acidic ion exchange resin, tetrabutylammonium fluoride, hydrogen fluoride / pyridine, hydrogen fluoride / triethylamine, and hydrofluoric acid, preferably tetrabutylammonium fluoride. Ride is used.
[0037]
As the solvent used in Step 3, an ether solvent is usually used, and tetrahydrofuran is preferably used.
While the reaction temperature varies depending on the substrate, it is carried out in the range of room temperature to 65 ° C.
This deprotected compound of the general formula (11) also constitutes a part of the intermediate represented by the general formula (4).
[0038]
By subjecting the compound represented by the general formula (11) to photoreaction and thermal isomerization, among the compounds represented by the general formula (1) of the present invention, X is a sulfur atom, and R1(12) which is a saturated aliphatic hydrocarbon group optionally substituted with a hydroxyl group can be produced (Step 4). The photoreaction and thermal isomerization reaction performed here can be performed by conventional methods.
[0039]
Moreover, the compound shown by General formula (1) by which the hydroxyl group was protected can be obtained by giving to the compound of General formula (9) before deprotecting photoreaction and thermal isomerization reaction. Further, the order of performing steps 1, 2, 3, and 4 is not particularly limited, but step 2 is not performed before step 1. Further, it is not performed in the order of steps 4 → 3 → 1 → 2. Furthermore, when it has a protecting group in the side chain, step 3 can be performed as necessary.
[0040]
Of the compounds represented by the general formula (1) of the present invention, a compound in which X is an oxygen atom is represented by the following formula from a known compound (14) described in, for example, JP-A-7-330714. Can be obtained.
Embedded image
(In the formula, TBS means t-butyldimethylsilyl group)
[0041]
In the above formula, the compound represented by the formula (15) can be obtained by oxidizing the compound represented by the formula (14) obtained in the same manner as described in JP-A-7-330714. (Step 1).
Examples of the oxidizing agent used in Step 1 include m-chloroperbenzoic acid, magnesium monoperoxyphthalate, hydrogen peroxide, and the like. Preferably, m-chloroperbenzoic acid is suitable.
[0042]
Examples of the solvent in Step 1 include toluene, benzene, dichloromethane, chloroform, carbon tetrachloride and the like, and preferably toluene or dichloromethane is used. Further, the reaction may be carried out in the presence of a neutralizing agent such as sodium hydrogen carbonate or sodium dihydrogen phosphate in the reaction system.
The reaction temperature in Step 1 is −78 to 110 ° C., preferably −40 ° C. to room temperature.
[0043]
The compound represented by the formula (15) is subjected to a deprotection reaction according to a conventional method described in, for example, Journal of Organic Chemistry, 57, 5019 (1992). 16) can be obtained (Step 2).
The compound represented by the formula (15) or the formula (16) constitutes a part of the compound represented by the general formula (5).
[0044]
The step of obtaining the 20S-allyl alcohol intermediate represented by the formula (17) from the compound represented by the formula (16) (step 3) can be performed by a simple metal amide such as lithium diethylamide, but in the deprotonation reaction. Since the regioselectivity is not good, the target compound can be obtained in good yield when the reaction is carried out using a dialkylaluminum dialkylamide prepared from the corresponding metal amide and dialkylaluminum halide in an inert solvent.
[0045]
Examples of the metal amide used in Step 3 include lithium diethylamide, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, lithium-2,2,6,6-tetramethylpiperidide, and the like. Preferably, lithium diisopropylamide, lithium bistrimethylsilylamide, and more preferably lithium diisopropylamide is used. Examples of the dialkylaluminum halide include dimethylaluminum chloride, diethylaluminum chloride, diisobutylaluminum chloride, and diethylaluminum iodide, preferably dimethylaluminum chloride, diethylaluminum chloride, diisobutylaluminum chloride, and more preferably diethylaluminum chloride.
[0046]
Examples of the solvent used in Step 3 include hydrocarbon solvents, halogen solvents, and the like, such as hexane, benzene, toluene, dichloromethane, chloroform, and preferably benzene and toluene. The reaction temperature is −40 to 50 ° C., preferably 0 ° C. to room temperature, more preferably 0 ° C.
[0047]
The 20S-allyl alcohol intermediate represented by the formula (17) undergoes a reduction reaction through a compound represented by the formula (18) by oxidation reaction (step 4), whereby the 20R- represented by the formula (19) An allyl alcohol intermediate can be produced (step 5).
The compounds represented by the formula (17) and the formula (19) constitute a part of the compound represented by the general formula (6), and the compound represented by the formula (18) is one of the compounds represented by the general formula (7). Parts.
[0048]
In the oxidation reaction of the above step 4, as oxidation conditions, a method using a metal oxidizer such as a chromium compound, a manganese compound, an osmium compound, a ruthenium compound, a method using dimethyl sulfoxide, a method using a carbonyl compound (Openopener oxidation), a quinone Examples include a method using a compound. Specifically, pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, osmium tetroxide, ruthenium trichloride, tetrapropylammonium perruthenate, oxalyl chloride / dimethyl sulfoxide, triphosgene / dimethyl sulfoxide, sulfur trioxide pyridine complex / dimethyl sulfoxide , Acetone / aluminum triisopropoxide, cyclohexanone / aluminum triisopropoxide, and the like, and preferably pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, tetrapropylammonium perruthenate (catalyst) / 4-methylmorpholine N- And oxide, oxalyl chloride / dimethyl sulfoxide, and the like.
[0049]
Moreover, in the reduction reaction of the said process 5, metal hydride, a metal hydrogen complex compound, etc. are mentioned as reduction conditions. Specifically, borane, texylborane, 9-borabicyclo [3,3,1] nonane, catecholborane, diisobutylaluminum hydride, lithium borohydride, zinc borohydride, sodium borohydride, sodium trimethoxyborohydride, hydrocyanation Sodium borohydride, sodium triacetoxyborohydride, lithium hydrogenated tri-s-butylborohydride, potassium hydrogenated tri-s-butylborohydride, lithium triciamylborohydride, potassium triciamylborohydride, lithium lithium triethylborohydride, Potassium triphenylborohydride, lithium n-butylborohydride, lithium aluminum hydride, lithium trimethoxyaluminum hydride, lithium tri-t-butoxyaluminum hydride, bis (2- Toxiethoxy) aluminum sodium and the like, preferably diisobutylaluminum hydride, sodium borohydride / cerium chloride, lithium n-butylborohydride, lithium triethylborohydride, tri-t-butoxyaluminum lithium hydride and the like. More preferably, sodium borohydride / cerium chloride, lithium n-butylborohydride, lithium triethylborohydride can be mentioned.
[0050]
By introducing a side chain corresponding to the compound represented by the general formula (1) or the general formula (4) into the 20S- and 20R-allyl alcohol intermediate thus obtained, and subjecting to a series of reactions, As shown below, the compound of the present invention represented by the general formula (23) can be obtained.
Embedded image
(In the formula, TBS means t-butyldimethylsilyl group, R1aRepresents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted with a hydroxyl group or a protected hydroxyl group, and R1bRepresents a saturated or unsaturated aliphatic hydrocarbon group substituted with a hydroxyl group)
[0051]
A compound represented by the general formula (21) can be obtained by introducing a side chain into the 20S- or 20R-allyl alcohol represented by the general formula (20) (step 6). As a side chain introduction method, the general formula (13) corresponding to the side chain: R1a-Y (wherein R1aAnd Y have the same meaning as described above) can be achieved by reacting with the above-mentioned allyl alcohol intermediate in the presence of a base.
[0052]
Examples of the base used in Step 6 include alkali metal hydrides, alkali metal alkoxides, metal dialkylamides, and alkyl metals, preferably sodium hydride, potassium hydride, t-butoxypotassium, lithium diisopropylamide, lithium bistrimethylsilyl. Amide, methyllithium, n-butyllithium, ethylmagnesium bromide, etc. are mentioned, More preferably, sodium hydride and potassium hydride are mentioned. In addition, this reaction may be performed in the presence of a catalytic amount of crown ether. Examples of the crown ether include 15-crown-5, 18-crown-6, dibenzo-18-crown-6, and preferably 15-crown-5.
[0053]
Examples of the solvent used in the above step 6 include hydrocarbon-based, ether-based and amide-based solvents. For example, benzene, toluene, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N, N- And dimethylacetamide, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, and the like are preferable. Examples include tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide, and 1,3-dimethyl-2-imidazolidinone, and more preferably tetrahydrofuran.
The reaction temperature in the above step 6 is 0 ° C. to the boiling point or decomposition point of the solvent used, preferably room temperature to 100 ° C., more preferably about 50 to 80 ° C.
[0054]
When introducing the side chain, in addition to the above method, for example, 1-bromo-2,3-epoxy-3-methylbutane is used as the alkyl halide and alkylation is carried out in the presence of the base, followed by a reducing agent such as lithium hydride. It can also be carried out by opening the epoxide with aluminum hydride, lithium borohydride, tri-s-butylborohydride lithium, lithium triethylborohydride or the like. This method may be performed in two stages or in one stage.
When introducing the side chain, instead of alkyl halide, epoxide such as isobutylene oxide, 1,2-epoxy-2-ethylbutane, 1,2-epoxy-3-methylbutane, 1,2-epoxy-3-ethylpentane, etc. It may be used. As the reaction conditions, for example, the conditions described in JP-A-6-80626 (Japanese Patent Application No. 4-158383) can be used. Preferably, potassium t-butoxide is used as a base, and dibenzo-18- The reaction can be performed at 100 to 110 ° C. in toluene in the presence of crown-6.
[0055]
The compound represented by the general formula (21) is also included in the compound of the present invention, but can be converted to the compound represented by the general formula (22) by further deprotection (Step 7). The removal of the t-butyldimethylsilyl group is performed by a conventional method. That is, hydrochloric acid, acidic ion exchange resin, tetrabutylammonium fluoride, hydrogen fluoride / pyridine, hydrogen fluoride / triethylamine, and hydrofluoric acid are used as reagents used in the reaction, preferably tetrabutylammonium fluoride is used. It is done. As the solvent, an ether solvent is usually used, and preferably tetrahydrofuran is used. While the reaction temperature varies depending on the substrate, it is generally carried out in the range of room temperature to 65 ° C.
[0056]
Furthermore, the compound represented by the general formula (22) can be obtained by subjecting the compound represented by the general formula (23) to conventional photoreaction and thermal isomerization (step 8).
Steps 6, 7, and 8 may be performed in the order described above, or may be performed in the order of step 6 → step 8 → step 7 or step 8 → step 6 → step 7 (that is, the order is particularly limited). (However, step 7 is not performed before step 6).
[0057]
In the production process described above, each intermediate and final substance can be purified and isolated by usual means such as silica gel column chromatography, thin layer chromatography, recrystallization and the like.
The compound of the general formula (1) thus obtained is a useful compound as a medicine such as an antitumor agent and an antirheumatic agent having a low calcium-elevating action as shown in Examples below.
[0058]
In the compound represented by the general formula (1) of the present invention, any compound in which the steric configuration at the 20-position and the steric configuration of the hydroxyl group are R, S or α, β are included in the present invention. Further, R in the general formula (1)1Is an unsaturated aliphatic hydrocarbon group which may be substituted with a hydroxyl group, and when it contains a double bond, the resulting cis and trans geometric isomers are also included in the present invention. Conceivable optical isomers and geometric isomers are also included in the present invention.
[0059]
Among the compounds represented by the general formula (1) of the present invention, more preferable compound is R.1Is an alkyl group substituted with a hydroxyl group, particularly a 3-hydroxy-3-methylbutyl group. The 1-position is preferably substituted with a hydroxyl group, and the hydroxyl group is more preferably α-coordinate. Furthermore, a compound having an R configuration at the 20th position is also preferable because it exhibits a strong differentiation-inducing action. Furthermore, a compound in which X is a sulfur atom is also mentioned as one of preferred embodiments.
[0060]
Specific compounds included in the compound represented by the general formula (1) of the present invention include 1,3-dihydroxy-20- (3-hydroxy-3-methylbutylthio) -9,10-secopregna-5. , 7,10 (19), 16-tetraene, 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene, 1α, 3β-dihydroxy-20 (R)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene and the like are more preferred compounds Included as
A more preferable specific compound represented by the general formula (1) of the present invention is 1α, 3β-dihydroxy-20 (R)-((E) -4-hydroxy-4-methyl-2-pentenylthio). -9,10-secopregna-5,7,10 (19), 16-tetraene and 1α, 3β-dihydroxy-20 (R)-((E) -4-ethyl-4-hydroxy-2-hexenylthio)- 9,10-secopregna-5,7,10 (19), 16-tetraene, 1α, 3β-dihydroxy-20 (S)-(2-hydroxy-2-methylpropylthio) -9,10-secopregna-5 7,10 (19), 16-tetraene, 1α, 3β-dihydroxy-20 (R)-(2-hydroxy-2-methylpropylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene, 1α, 3β-dihydroxy-20 (S)-{2 (S) -hydroxy-3-methylbutyloxy} -9,10-secopregna-5,7,10 (19), 16-tetraene, 1α , 3β-dihydroxy-20 (S)-{2 (R) -hydroxy-3-methylbutyloxy} -9,10-secopregna-5,7,10 (19), 16-tetraene, 1α, 3β-dihydroxy- 20 (S)-(2-Ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene, 1α, 3β-dihydroxy-20 (R)-(2- And ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene.
[0061]
The compounds represented by the general formulas (4) to (7) for producing these preferable compounds can be said to be more preferable useful compounds as synthetic intermediates.
[0062]
The compound of the present invention is preferably formulated into an appropriate dosage form and used together with a pharmaceutically acceptable carrier, excipient, disintegrant, lubricant, binder, fragrance, colorant, and the like. Examples of the mold include tablets, granules, fine granules, capsules, powders, injections, solutions, suspensions, emulsions, transdermal absorption agents, suppositories, and the like.
[0063]
The dose of the compound of the present invention can be appropriately selected depending on the target disease, patient condition, body type, constitution, age, sex, administration route, dosage form, etc. The upper limit of the dose can be selected in the range of 001 μg to 0.1 μg, preferably around 0.01 μg, and can be selected in the range of 100 μg to 10,000 μg per day, preferably in the range of 200 μg to 1000 μg. Can be administered.
[0064]
【Example】
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.
In this example, the infrared absorption spectrum (IR) was measured with HITACHI 270-30.1H NMR was measured with JEOL FX-200 (200 MHz) or JEOL EX-270 (270 MHz), and CDClThreeTetramethylsilane was used as an internal standard in the solvent. Mass spectrum (MS) was measured with SHIMADZU GCMS-QP 1000 in EI mode and ionization voltage of 70 eV. The ultraviolet absorption spectrum (UV) was measured in ethanol using SHIMADZU UV-240.
[0065]
Example 1
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -phenoxycarbonylthiopregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -16α-hydroxypregna-5,7,17 (E) -triene (150 mg, 0.27 mmol) in dichloromethane (5 ml) in pyridine (0.13 ml, 1.61 mmol) and phenylchlorothionoformate (0.11 ml, 0.81 mmol) were added, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was diluted with hexane, washed with ice-cold 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and the organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (0.5 mm × 4, hexane: ethyl acetate = 9: 1, developed once) to give the title compound as a colorless solid. Obtained (160 mg, 85%).
[0066]
IR (KBr): 2920, 2850, 1720, 1490, 1460, 1370, 1245, 1180, 1155, 1095, 1000cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.89 (s, 21H), 0.95 (s, 3H), 1.60 (d,J = 7.3Hz, 3H), 3.72 (brs, 1H), 3.94-4.24 (m, 2H), 5.41 (brs, 1H), 5.61 (d,J = 5.4Hz, 1H), 5.77 (brs, 1H), 7.09-7.44 (m, 5H) .MS m / z: 694 (M+), 505 (100%). UV λmax nm: 205, 270, 282, 293.
[0067]
Example 2
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -16α-hydroxypregna-5,7,17 (E) -triene (1.50 g, 2.68 mmol), pyridine (1.30 ml, 16.1 mmol) , Phenylthionochloroformate (1.11 ml, 8.04 mmol) and dichloromethane (50 ml) were reacted and worked up in the same manner as in Example 1, and then dissolved in tetrahydrofuran (50 ml) without purification. 15 (3.00 g) was added and stirred at room temperature for 36 hours. The resin was filtered and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure and purified by column chromatography (hexane: ethyl acetate = 7: 1 → 5: 1) to give the title compound (1.07 g, 69%) as a colorless oil. )
[0068]
IR (neat): 3250, 2920, 2850, 1720, 1490, 1460, 1370, 1260, 1190, 1165, 1100cm-1.1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.95 (s, 3H), 0.96 (s, 3H), 1.60 (d,J = 6.8Hz, 3H), 3.76 (brs, 1H), 3.99-4.24 (m, 2H), 5.37-5.46 (m, 1H), 5.60-5.68 (m, 1H), 5.78 (brs, 1H), 7.12- 7.45 (m, 5H) .MS m / z: 580 (M+), 277 (100%). UV λmax nm: 205, 270, 282, 293.
[0069]
Example 3
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (81.6 mg, 0.140 mmol), 4-bromo-2-methyl To a solution of 2-butanol (117 mg, 0.700 mmol) in tetrahydrofuran (1 ml) was added 1M-KOH methanol solution (1 ml), and the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was diluted with hexane, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography (0.5 mm × 2 pieces, dichloromethane: ethyl acetate = 8: 1, developed once) to give the title compound (60.3 mg, 79%) as a colorless oil. Obtained.
[0070]
IR (neat): 3400, 2950, 2850, 1460, 1370, 1250, 1200, 1150, 1060cm-1.1H NMR δ: 0.08 (s, 3H), 0.13 (s, 3H), 0.88 (s, 9H), 0.93 (s, 3H), 0.94 (s, 3H), 1.22 (s, 6H), 1.43 (d,J = 6.9Hz, 3H), 3.51 (q,J = 6.9Hz, 1H), 3.75 (brs, 1H), 3.95-4.17 (m, 1H), 5.37-5.45 (br, 1H), 5.59-5.69 (br, 2H). MS m / z: 546 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
[0071]
Example 4
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-methyl-4-triethylsilyloxypentylthio) -pregna-5,7,16-triene
1α- (tert-Butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (82.4 mg, 0.142 mmol), 1-bromo-4-methyl -4-triethylsilyloxypentane (209 mg, 0.709 mmol), tetrahydrofuran (1 ml), 1M-KOH methanol solution (1 ml) were reacted under the same conditions as in Example 3, after the workup, preparative thin layer chromatography ( Purification by 0.5 mm × 2 sheets, hexane: ethyl acetate = 3: 2, developed once) gave the title compound (56.1 mg, 59%) as a colorless oil.
[0072]
IR (neat): 3350, 2950, 2850, 1460, 1365, 1255, 1150, 1050cm-1.1H NMR δ: 0.08 (s, 3H), 0.13 (s, 3H), 0.56 (q,J = 7.7Hz, 6H), 0.81-1.03 (m, 24H), 1.19 (s, 6H), 1.42 (d,J = 6.9Hz, 3H), 3.46 (q,J = 6.9Hz, 1H), 3.76 (brs, 1H), 4.00-4.16 (m, 1H), 5.39-5.47 (m, 1H), 5.59-5.71 (m, 2H). MS m / z: 674 (M+), 277 (100%). UV λmax nm: 270, 281, 293.
[0073]
Example 5
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(5-hydroxy-5-methylhexylthio) pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (82.6 mg, 0.142 mmol), 6-bromo-2-methyl 2-Hexanol (139 mg, 0.710 mmol), tetrahydrofuran (1 ml), 1M-KOH methanol solution (1 ml) were reacted under the same conditions as in Example 3, after the post-treatment, preparative thin layer chromatography (0.5 mm × 2 sheets, dichloromethane: ethyl acetate = 8: 1, developed once) to obtain 87.2 mg of product, but separation from 6-bromo-2-methyl-2-hexanol was difficult. Therefore, it was used for the next reaction as it was.
[0074]
Example 6
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(2-hydroxy-2-methylpropylthio) pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (83.0 mg, 0.143 mmol), isobutylene oxide (113 mg, 1. 56 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3, and after workup, preparative thin layer chromatography (0.5 mm × 2, hexane) The title compound (62.3 mg, 82%) was obtained as a colorless oil.
[0075]
IR (neat): 3400, 2950, 2850, 1460, 1370, 1250, 1200, 1150, 1060cm-1.1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.94 (s, 6H), 1.26 (s, 3H), 1.27 (s, 3H), 1.44 (d,J = 6.9Hz, 3H), 3.49 (q,J = 6.9Hz, 1H), 3.76 (brs, 1H), 4.00-4.17 (m, 1H), 5.36-5.47 (m, 1H), 5.59-5.69 (m, 2H). MS m / z: 532 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
[0076]
Example 7
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(3-ethyl-3-hydroxypentylthio) pregna-5,7,16-triene
1α- (tert-Butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (82.8 mg, 0.143 mmol), 5-bromo-3-ethyl -3-Pentanol (139 mg, 0.715 mmol), tetrahydrofuran (1 ml), 1M-KOH methanol solution (1 ml) were reacted under the same conditions as in Example 3, and after workup, preparative thin layer chromatography (0. 5 mm × 2 sheets, dichloromethane: ethyl acetate = 8: 1, developed once) to obtain 99.6 mg of product, but difficult to separate from 5-bromo-3-ethyl-3-pentanol Therefore, it was used in the next reaction as it was.
[0077]
Example 8
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-ethyl-4-hydroxyhexylthio) pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (84.3 mg, 0.145 mmol), 6-bromo-3-ethyl -3-Hexanol (152 mg, 0.725 mmol), tetrahydrofuran (1 ml), 1M-KOH methanol solution (1 ml) were reacted under the same conditions as in Example 3, and after workup, preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 2: 1, developed twice) to obtain 76.4 mg of product, but separation from 6-bromo-3-ethyl-3-hexanol was difficult. Therefore, it was used for the next reaction as it was.
[0078]
Example 9
Preparation of 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) pregna-5,7,16-triene
Of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) pregna-5,7,16-triene (58.5 mg, 0.107 mmol) To a tetrahydrofuran (3 ml) solution was added 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml), and the mixture was heated to reflux for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed in order with ice-cold 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (0.5 mm × 2 sheets, dichloromethane: ethanol = 7: 1, developed once) to give the title compound as a pale yellow oil ( 41.8 mg, 90%) was obtained.
[0079]
IR (neat): 3400, 2950, 1460, 1370, 1210, 1150, 1060cm-1.1H NMR δ: 0.93 (s, 3H), 0.96 (s, 3H), 1.22 (s, 6H), 1.42 (d,J = 6.8Hz, 3H), 3.52 (q,J = 6.8Hz, 1H), 3.77 (brs, 1H), 3.96-4.16 (m, 1H), 5.38-5.48 (m, 1H), 5.59-5.65 (brs, 1H), 5.66-5.76 (m, 1H). MS m / z: 432 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
[0080]
Example 10
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-hydroxy-4-methylpentylthio) pregna-5,7,16-triene
1α- (tert-Butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-methyl-4-triethylsilyloxypentylthio) -pregna-5,7,16-triene (55.7 mg, 0. 5). 0825 mmol), tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted under the same conditions as in Example 9 and after workup, preparative thin layer chromatography (0.5 mm × 2 Sheet, dichloromethane: ethanol = 7: 1, developed once) to give the title compound (34.1 mg, 92%) as a colorless oil.
[0081]
IR (neat): 3400, 2950, 2850, 1460, 1370, 1200, 1150, 1100, 1160cm-1.1H NMR δ: 0.92 (s, 3H), 0.97 (s, 3H), 1.21 (s, 6H), 1.42 (d,J = 6.9Hz, 3H), 3.47 (q,J = 6.9Hz, 1H), 3.77 (brs, 1H), 3.98-4.16 (m, 1H), 5.39-5.50 (m, 1H), 5.62 (brs, 1H), 5.69-5.77 (m, 1H). MS m / z: 446 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
[0082]
Example 11
Preparation of 1α, 3β-dihydroxy-20 (S)-(5-hydroxy-5-methylhexylthio) pregna-5,7,16-triene
Crude 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(5-hydroxy-5-methylhexylthio) pregna-5,7,16-triene (73) obtained in Example 5 .2 mg), tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted under the same conditions as in Example 9, after the workup, preparative thin layer chromatography (0.5 mm × The resulting product was purified by two pieces, dichloromethane: ethanol = 7: 1, developed once) to obtain the title compound (36.1 mg, 55%, two steps) as a pale yellow oil.
[0083]
IR (neat): 3400, 2950, 1460, 1370, 1200, 1145, 1050cm-1.1H NMR δ: 0.93 (s, 3H), 0.98 (s, 3H), 1.08 (s, 6H), 1.42 (d,J = 6.9Hz, 3H), 3.46 (q,J = 6.9Hz, 1H), 3.78 (brs, 1H), 3.98-4.16 (m, 1H), 5.41-5.50 (m, 1H), 5.61 (brs, 1H), 5.69-5.78 (m, 1H). MS m / z: 460 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
[0084]
Example 12
Preparation of 1α, 3β-dihydroxy-20 (S)-(2-hydroxy-2-methylpropylthio) pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(5-hydroxy-5-methylhexylthio) pregna-5,7,16-triene (60.1 mg, 0.113 mmol), Tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted under the same conditions as in Example 9, after workup, preparative thin-layer chromatography (0.5 mm × 2 sheets, dichloromethane) : Ethanol = 7: 1, developed once) to give the title compound (36.3 mg, 77%) as a colorless oil.
[0085]
IR (neat): 3400, 2950, 1460, 1370, 1250, 1210, 1150, 1060cm-1.1H NMR δ: 0.94 (s, 3H), 0.97 (s, 3H), 1.26 (s, 3H), 1.27 (s, 3H), 1.43 (d,J = 6.8Hz, 3H), 3.50 (q,J = 6.8Hz, 1H), 3.77 (brs, 1H), 3.96-4.16 (m, 1H), 5.40-5.51 (m, 1H), 5.64 (brs, 1H), 5.68-5.98 (m, 1H). MS m / z: 418 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
[0086]
Example 13
Preparation of 1α, 3β-dihydroxy-20 (S)-(3-ethyl-3-hydroxypentylthio) pregna-5,7,16-triene
Crude 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(3-ethyl-3-hydroxypentylthio) pregna-5,7,16-triene obtained in Example 7, tetrahydrofuran (2 ml) 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted under the same conditions as in Example 9 and after workup, preparative thin layer chromatography (0.5 mm × 2 sheets, dichloromethane: Purification with ethanol = 7: 1, developed once) gave the title compound (42.0 mg, 64%, 2 steps) as a colorless oil.
[0087]
IR (neat): 3400, 2950, 1460, 1370, 1150, 1060cm-1.1H NMR δ: 0.85 (t,J = 7.3Hz, 6H), 0.94 (s, 3H), 0.96 (s, 3H), 1.43 (d,J = 6.8Hz, 3H), 1.46 (q,J = 7.3Hz, 4H), 3.51 (q,J = 6.8Hz, 1H), 3.78 (brs, 1H), 3.90-4.09 (m, 1H), 5.38-5.49 (m, 1H), 5.63 (brs, 1H), 5.66-5.78 (m, 1H). MS m / z: 460 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
[0088]
Example 14
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-ethyl-4-hydroxyhexylthio) pregna-5,7,16-triene
Crude 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-ethyl-4-hydroxyhexylthio) pregna-5,7,16-triene (71) obtained in Example 8 .4 mg), tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted under the same conditions as in Example 9 and after workup, preparative thin layer chromatography (0.5 mm × The product was purified by two pieces, dichloromethane: ethanol = 7: 1, developed once) to obtain the title compound (45.8 mg, 67%, two steps) as a colorless oil.
[0089]
IR (neat): 3400, 2950, 1450, 1370, 1050cm-1.1H NMR δ: 0.85 (t,J = 7.3Hz, 6H), 0.94 (s, 3H), 0.98 (s, 3H), 3.51 (q,J = 6.8Hz, 1H), 3.78 (brs, 1H), 3.98-4.16 (m, 1H), 5.38-5.50 (m, 1H), 5.63 (brs, 1H), 5.69-5.78 (m, 1H). MS m / z: 474 (M+), 312 (100%). UV λmax nm: 270, 281, 293.
[0090]
Example 15
Preparation of 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) pregna-5,7,16-triene (40.2 mg, 0.0929 mmol) was dissolved in ethanol (200 ml) and 0 While bubbling argon with stirring at 0 ° C., light was irradiated for 3.5 minutes with 400 W high pressure mercury lamp Vycor filter transmitted light, and then heated under reflux for 1.5 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the resulting residue was subjected to preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethanol = 7: 1, developed once, and further 0.5 mm × 1). Sheet, hexane: ethyl acetate: ethanol = 10: 10: 1, developed three times) to give the title compound (3.66 mg, 9.1%) as a colorless oil.
[0091]
IR (neat): 3400, 2920, 1440, 1365, 1200, 1140, 1060cm-1.1H NMR δ: 0.83 (s, 3H), 1.23 (s, 6H), 1.42 (d,J = 7.3Hz, 3H), 3.49 (q,J = 7.3Hz, 1H), 4.18-4.32 (m, 1H), 4.39-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 432 (M+), 312 (100%). UV λmax nm: 263.
[0092]
Example 16
Production of 1α, 3β-dihydroxy-20 (S)-(4-hydroxy-4-methylpentylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
Example using 1α, 3β-dihydroxy-20 (S)-(4-hydroxy-4-methylpentylthio) pregna-5,7,16-triene (33.4 mg, 0.0748 mmol), ethanol (200 ml) After performing the reaction in the same manner as 15 (light irradiation for 2 minutes, heating under reflux for 2 hours), preparative thin layer chromatography (0.5 mm × 2 pieces, dichloromethane: ethanol = 7: 1, developed once, Purification by 0.5 mm × 1 sheet, hexane: ethyl acetate: ethanol = 10: 10: 1, developed three times) gave the title compound as a colorless oil (3.10 mg, 9.3%).
[0093]
IR (neat): 3400, 2930, 1450, 1370, 1220, 1150, 1060cm-1.1H NMR δ: 0.83 (s, 3H), 1.21 (s, 6H), 1.41 (d,J = 6.8Hz, 3H), 3.44 (q,J = 6.8Hz, 1H), 4.18-4.32 (m, 1H), 4.40-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 446 (M+), 312 (100%). UV λmax nm: 263.
[0094]
Example 17
Preparation of 1α, 3β-dihydroxy-20 (S)-(5-hydroxy-5-methylhexylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
Example using 1α, 3β-dihydroxy-20 (S)-(5-hydroxy-5-methylhexylthio) pregna-5,7,16-triene (35.7 mg, 0.0749 mmol), ethanol (200 ml) After performing the reaction in the same manner as 15 (light irradiation 2.75 minutes, heating under reflux 2 hours), preparative thin-layer chromatography (0.5 mm × 2 pieces, dichloromethane: ethanol = 8: 1, developed once) The product was further purified by 0.5 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) to obtain the title compound (2.94 mg, 8.2%) as a colorless oil.
[0095]
IR (neat): 3400, 2930, 1460, 1370, 1200, 1140, 1050cm-1.1H NMR δ: 0.83 (s, 3H), 1.21 (s, 6H), 1.41 (d,J = 6.8Hz, 3H), 3.44 (q,J = 6.8Hz, 1H), 4.18-4.32 (m, 1H), 4.40-4.52 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 460 (M+), 312 (100%). UV λmax nm: 263.
[0096]
Example 18
Preparation of 1α, 3β-dihydroxy-20 (S)-(2-hydroxy-2-methylpropylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
Example using 1α, 3β-dihydroxy-20 (S)-(2-hydroxy-2-methylpropylthio) pregna-5,7,16-triene (36.0 mg, 0.0860 mmol), ethanol (200 ml) After performing the reaction in the same manner as 15 (light irradiation 2.75 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethanol = 7: 1, developed once) The product was further purified by 0.5 mm × 1 sheet, hexane: ethyl acetate: ethanol = 10: 10: 1, developed three times) to obtain the title compound (2.60 mg, 7.2%) as a colorless oil.
[0097]
IR (neat): 3400, 2930, 1460, 1370, 1200, 1140, 1060cm-1.1H NMR δ: 0.84 (s, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.43 (d,J = 6.9Hz, 3H), 3.47 (q,J = 6.9Hz, 1H), 4.16-4.30 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H), 6.11 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 418 (M+), 312 (100%). UV λmax nm: 263.
[0098]
Example 19
Preparation of 1α, 3β-dihydroxy-20 (S)-(3-ethyl-3-hydroxypentylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
Example using 1α, 3β-dihydroxy-20 (S)-(3-ethyl-3-hydroxypentylthio) pregna-5,7,16-triene (41.7 mg, 0.0905 mmol), ethanol (200 ml) After performing the same operation as 15 (light irradiation 2.25 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethanol = 7: 1, developed once) Further, 0.5 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times, and further 0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 28: 12: 1) The title compound (3.78 mg, 9.1%) was obtained as a colorless oil.
[0099]
IR (neat): 3400, 2930, 1450, 1370, 1060cm-1.1H NMR δ: 0.83 (s, 3H), 0.86 (t,J = 7.3Hz, 6H), 1.42 (d,J = 6.8Hz, 3H), 1.47 (q,J = 7.3Hz, 4H), 3.49 (q,J = 6.8Hz, 1H), 4.27-4.32 (m, 1H), 4.38-4.52 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 460 (M+), 312 (100%). UV λmax nm: 263.
[0100]
Example 20
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-ethyl-4-hydroxyhexylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
Example using 1α, 3β-dihydroxy-20 (S)-(4-ethyl-4-hydroxyhexylthio) pregna-5,7,16-triene (44.7 mg, 0.0942 mmol), ethanol (200 ml) After carrying out the reaction in the same manner as in No. 15 (light irradiation 2.25 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 2 pieces, dichloromethane: ethyl acetate: ethanol = 14: 6: 1 and 3 developments, further 0.5 mm x 1 plate, hexane: ethyl acetate: ethanol = 12: 8: 1, 3 developments) and purified as a colorless oily title compound (3.62 mg, 8.1%) Got.
[0101]
IR (neat): 3400, 2930, 1450, 1370, 1050cm-1.1H NMR δ: 0.83 (s, 3H), 0.91 (t,J = 7.3Hz, 6H), 3.48 (q,J = 6.8Hz, 1H), 4.18-4.36 (m, 1H), 4.38-4.53 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 474 (M+), 312 (100%). UV λmax nm: 263.
[0102]
Example 21
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-hydroxy-4-methyl-2-pentynylthio) pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (59.4 mg, 0.102 mmol), 5-bromo-2-methyl -3-Pentyn-2-ol (90.5 mg, 0.511 mmol), tetrahydrofuran (1 ml), 1 M-KOH methanol solution (1 ml) were reacted under the same conditions as in Example 3, after treatment, and a preparative thin layer. Purification by chromatography (0.5 mm × 2 sheets, dichloromethane: ethyl acetate = 5: 1, developed twice) gave the title compound (41.6 mg, 73%) as a colorless oil.
[0103]
IR (neat): 3400, 2950, 2850, 1460, 1370, 1250, 1150, 1060cm-1.1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.93 (s, 3H), 0.94 (s, 3H), 1.46 (d,J = 7.3Hz, 3H), 1.51 (s, 6H), 3.18 (d,J = 16.6Hz, 1H), 3.22 (d,J = 16.6Hz, 1H), 3.67 (q,J = 7.3Hz, 1H), 3.76 (brs, 1H), 3.96-4.10 (m, 1H), 5.32-5.44 (m, 1H), 5.56-5.71 (m, 2H). MS m / z: 556 (M+), 188 (100%). UV λmax nm: 270, 281, 293.
[0104]
Example 22
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(E) -4-hydroxy-4-methyl-2-pentenylthio} -pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (33.5 mg, 0.0577 mmol), (E) -5-bromo 2-Methyl-3-penten-2-ol (41.2 mg, 0.230 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3, followed by After the treatment, purification by preparative thin-layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate = 5: 1, developed twice) gave 26.2 mg of product. Since separation from 5-bromo-2-methyl-3-penten-2-ol was difficult, the product was directly used in the next reaction.
[0105]
Example 23
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)- Preparation of {(Z) -4-methyl-4-triethylsilyloxy-2-pentenylthio} -pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (91.2 mg, 0.131 mmol), (Z) -1-bromo- 4-Methyl-4-triethylsilyloxy-2-pentene (192 mg, 0.655 mmol), tetrahydrofuran (1.5 ml), 1M-KOH methanol solution (1.5 ml) were reacted under the same conditions as in Example 3 and worked up. After purification by preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: dichloromethane: ethyl acetate = 160: 40: 1, developed once), the title compound (66.3 mg, 64%) as a colorless oil was obtained. Got.
[0106]
IR (neat): 2950, 2850, 1460, 1170, 1250, 1160, 1080cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.60 (q,J = 7.3Hz, 6H), 0.89 (s, 18H), 0.90-1.04 (m, 15H), 1.37 (s, 6H), 1.44 (d,J = 6.8Hz, 3H), 3.33 (dd,J = 13.0, 6.8Hz, 1H), 3.41-3.60 (m, 2H), 3.72 (brs, 1H), 3.96-4.16 (m, 1H), 5.23-5.52 (m, 3H), 5.55-5.68 (m, 2H MS m / z: 786 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
[0107]
Example 24
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-ethyl-4-hydroxy-2-hexynylthio) pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (60.8 mg, 0.105 mmol), 6-bromo-3-ethyl -4-Hexin-3-ol (108 mg, 0.525 mmol), tetrahydrofuran (1 ml), 1M-KOH methanol solution (1 ml) were reacted under the same conditions as in Example 3, after treatment, and preparative thin layer chromatography. Purification by (0.5 mm × 2 sheets, dichloromethane: ethyl acetate = 5: 1, developed twice) gave the title compound (38.4 mg, 63%) as a colorless oil.
[0108]
IR (neat): 3400, 2950, 2850, 1460, 1370, 1250, 1150, 1060cm-1.1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.88 (s, 9H), 0.92 (s, 3H), 0.94 (s, 3H), 1.03 (t,J = 7.3Hz, 6H), 1.46 (d,J = 6.8Hz, 3H), 1.66 (q,J = 7.3Hz, 4H), 3.20 (d,J = 16.6Hz, 1H), 3.24 (d,J = 16.6Hz, 1H), 3.68 (q,J = 6.8Hz, 1H), 3.75 (brs, 1H), 3.96-4.12 (m, 1H), 5.35-5.44 (m, 1H), 5.57-5.71 (m, 2H). MS m / z: 566 (M+-H2O), 187 (100%). UV λmax nm: 270, 281, 293.
[0109]
Example 25
Preparation of 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(E) -4-ethyl-4-hydroxy-2-hexenylthio} -pregna-5,7,16-triene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (33.1 mg, 0.0570 mmol), (E) -6-bromo -3-Ethyl-4-hexen-3-ol (47.4 mg, 0.229 mmol), tetrahydrofuran (0.5 ml), and 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3, followed by After the treatment, purification by preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate = 5: 1, developed twice) gave the title compound (28.2 mg, 84%) as a colorless oil. .
[0110]
IR (neat): 3400, 2920, 2850, 1460, 1370, 1250, 1150, 1060cm-1.1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.87 (t,J = 7.3Hz, 6H), 0.88 (s, 9H), 1.42 (d,J = 6.8Hz, 3H), 1.54 (q,J = 7.3Hz, 4H), 3.10 (dd,J = 12.6, 5.5Hz, 1H), 3.12 (dd,J = 12.6, 5.5Hz, 1H), 3.45 (q,J = 6.8Hz, 1H), 3.75 (brs, 1H), 3.96-4.15 (m, 1H), 5.35-5.44 (m, 1H), 5.45-5.73 (m, 4H). MS m / z: 586 (M+), 277 (100%). UV λmax nm: 270, 281, 293.
[0111]
Example 26
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(Z) -4-ethyl-4-triethylsilyloxy-2-hexenylthio} pregna-5,7,16-triene Manufacturing
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S) -phenoxycarbonylthiopregna-5,7,16-triene (33.0 mg, 0.0568 mmol), (Z) -1-bromo -4-Ethyl-4-triethylsilyloxy-2-hexene (91.0 mg, 0.284 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3. After the workup, the product was purified by preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate = 2: 1, developed once), and the title compound (23.8 mg, 60%) as a pale yellow oil Got.
[0112]
IR (neat): 3400, 2950, 2850, 1460, 1350, 1250, 1140, 1060cm-1.1H NMR δ: 0.08 (s, 3H), 0.12 (s, 3H), 0.62 (q,J = 7.5Hz, 6H), 0.80-1.05 (m, 30H), 1.44 (d,J = 6.8Hz, 3H), 1.57 (q,J = 7.3Hz, 4H), 3.28-3.59 (m, 3H), 3.76 (brs, 1H), 3.97-4.28 (m, 1H), 5.23 (d,J = 11.2Hz, 1H), 5.35-5.53 (m, 2H), 5.56-5.72 (m, 2H). MS m / z: 700 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
[0113]
Example 27
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-hydroxy-4-methyl-2-pentynylthio) -9,10-secopregna-5,7,10 (19), 16 -Production of tetraene
1α- (tert-Butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-hydroxy-4-methyl-2-pentynylthio) pregna-5,7,16-triene (41.6 mg, 0.0747 mmol) ), Ethanol (200 ml) was used and the reaction was carried out in the same manner as in Example 15 (light irradiation for 2 minutes, heating under reflux for 1.5 hours), followed by preparative thin layer chromatography (0.5 mm × 1, Purification by dichloromethane: ethyl acetate = 6: 1, developed three times, 0.5 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed three times), and the title compound (3.8 mg, 9. 1%) was obtained.
[0114]
IR (neat): 3400, 2930, 2850, 1460, 1360, 1245, 1160, 1060cm-1.1H NMR δ: 0.09 (s, 6H), 0.82 (s, 3H), 0.90 (s, 9H), 1.45 (d,J = 7.3Hz, 3H), 1.51 (s, 6H), 3.18 (d,J = 16.6Hz, 1H), 3.21 (d,J = 16.6Hz, 1H), 3.66 (q,J = 7.3Hz, 1H), 4.16-4.28 (m, 1H), 4.34-4.43 (m, 1H), 4.92 (brs, 1H), 5.27 (brs, 1H), 5.64 (brs, 1H), 6.11 (d,J = 11.2Hz, 1H), 6.32 (d,J = 11.2Hz, 1H) .MS m / z: 556 (M+), 248 (100%). UV λmax nm: 264.
[0115]
Example 28
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(E) -4-hydroxy-4-methyl-2-pentenylthio} -9,10-secopregna-5,7,10 (19), Production of 16-tetraene
Crude 1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(E) -4-hydroxy-4-methyl-2-pentenylthio} -pregna-5 obtained in Example 22 , 7,16-triene (25.8 mg) and ethanol (200 ml) were reacted in the same manner as in Example 15 (light irradiation for 2 minutes, heating under reflux for 2 hours), followed by preparative thin layer chromatography. (0.5 mm × 1 sheet, dichloromethane: ethyl acetate = 6: 1, developed four times) gave a crude product (3.1 mg) and raw material recovery (10.5 mg). The recovered raw material (10.5 mg) is reacted again for 2 minutes with light irradiation and heated for 2 hours under reflux, and preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate = 6: 1, developed four times) ) Gave a crude product (1.8 mg). Purified by preparative thin-layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate = 4: 1, developed four times) together with the previously obtained product, the title compound (2.0 mg, colorless oil) , 6.2%, 2 steps).
[0116]
IR (neat): 3400, 2930, 1460, 1370, 1250, 1060cm-1.1H NMR δ: 0.09 (s, 6H), 0.82 (s, 3H), 0.90 (s, 9H), 1.32 (s, 6H), 1.41 (d,J = 6.8Hz, 3H), 2.99-3.19 (m, 2H), 3.41 (q,J = 6.8Hz, 1H), 4.16-4.28 (m, 1H), 4.32-4.43 (m, 1H), 4.93 (brs, 1H), 5.27 (brs, 1H), 5.58 (brs, 1H), 5.10-5.78 ( m, 2H), 6.10 (d,J = 11.2Hz, 1H), 6.33 (d,J = 11.2Hz, 1H) .MS m / z: 558 (M+), 160 (100%). UV λmax nm: 263.
[0117]
Example 29
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(Z) -4-methyl-4-triethylsilyloxy-2-pentenylthio} -9,10-secopregna-5,7, 10 (19), Production of 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(Z) -4-methyl-4-triethylsilyloxy-2-pentenylthio} -pregna-5,7,16-triene ( (66.1 mg, 0.0839 mmol) and ethanol (200 ml) were used, and the reaction was carried out in the same manner as in Example 15 (light irradiation for 3 minutes, heating under reflux for 2 hours), followed by preparative thin layer chromatography (0. The resulting product was purified by 5 mm × 3 sheets, hexane: dichloromethane = 4: 1, developed twice) to obtain 20.9 mg of the compound, but it was difficult to separate from the raw material, so it was directly used in the next reaction.
[0118]
Example 30
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-ethyl-4-hydroxy-2-hexynylthio) -9,10-secopregna-5,7,10 (19), 16 -Production of tetraene
1α- (tert-Butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-ethyl-4-hydroxy-2-hexynylthio) pregna-5,7,16-triene (21.9 mg, 0.0374 mmol) ), Ethanol (200 ml) was used, and the reaction was carried out in the same manner as in Example 15 (light irradiation 3.45 minutes, heating under reflux 1.5 hours), followed by preparative thin layer chromatography (0.5 mm × 1). Sheet, dichloromethane: ethyl acetate = 6: 1, developed twice, further 0.5 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed four times) to give the title compound (1.8 mg, 1.8 mg, 8.2%).
[0119]
IR (neat): 3400, 2930, 2850, 1460, 1370, 1250, 1060cm-1.1H NMR δ: 0.09 (s, 3H), 0.81 (s, 3H), 0.89 (s, 9H), 1.03 (t,J = 7.3Hz, 6H), 1.45 (d,J = 6.8Hz, 3H), 1.67 (q,J = 7.3Hz, 4H), 3.20 (d,J = 16.8Hz, 1H), 3.23 (d,J = 16.8Hz, 1H), 3.67 (q,J = 6.8Hz, 1H), 4.14-4.28 (m, 1H), 4.32-4.43 (m, 1H), 4.93 (brs, 1H), 5.27 (brs, 1H), 5.63 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.32 (d,J = 11.2Hz, 1H) .MS m / z: 584 (M+), 248 (100%). UV λmax nm: 264.
[0120]
Example 31
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(E) -4-ethyl-4-hydroxy-2-hexenylthio} -9,10-secopregna-5,7,10 (19), Production of 16-tetraene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(E) -4-ethyl-4-hydroxy-2-hexenylthio} -pregna-5,7,16-triene (26 .3 mg, 0.0448 mmol) and ethanol (200 ml) were used, and the reaction was carried out in the same manner as in Example 15 (light irradiation 3 minutes, heating under reflux 1.5 hours), followed by preparative thin layer chromatography (0 .5 mm × 1 sheet, dichloromethane: ethyl acetate = 6: 1, developed 3 times, and further 0.5 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed 3 times) to give the title compound ( 2.1 mg, 8.0%) was obtained.
[0121]
IR (neat): 3400, 2930, 2850, 1460, 1375, 1255, 1060cm-1.1H NMR δ: 0.09 (s, 6H), 0.82 (s, 3H), 0.84-0.98 (m, 15H), 1.41 (d,J = 6.8Hz, 3H), 1.54 (q,J = 7.3Hz, 4H), 3.07-3.18 (m, 2H), 3.42 (q,J = 6.8Hz, 1H), 4.15-4.29 (m, 1H), 4.33-4.44 (m, 1H), 4.93 (brs, 1H), 5.27 (brs, 1H), 5.44-5.76 (m, 3H), 6.10 ( d,J = 11.2Hz, 1H), 6.32 (d,J = 11.2Hz, 1H) .MS m / z: 586 (M+), 426 (100%). UV λmax nm: 263.
[0122]
Example 32
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(Z) -4-ethyl-4-triethylsilyloxy-2-hexenylthio} -9,10-secopregna-5,7 , 10 (19), 16-tetraene production
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(Z) -4-ethyl-4-triethylsilyloxy-2-hexenylthio} pregna-5,7,16-triene ( 23.7 mg, 0.0338 mmol) and ethanol (200 ml) were used, and the reaction was carried out in the same manner as in Example 15 (light irradiation for 3.5 minutes, heating under reflux for 1.5 hours), followed by preparative thin-layer chromatography. Purification by chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate = 6: 1, developed three times) gave the title compound (1.3 mg, 5.5%) as a colorless oil.
[0123]
IR (neat): 3400, 2925, 2850, 1460, 1370, 1250, 1050cm-1.1H NMR δ: 0.09 (s, 6H), 0.62 (q,J = 7.5Hz, 6H), 0.76-1.05 (m, 27H), 1.43 (d,J = 6.8Hz, 3H), 1.56 (q,J = 7.5Hz, 4H), 3.28-3.60 (m, 3H), 4.16-4.29 (m, 1H), 4.32-4.43 (m, 1H), 4.93 (brs, 1H), 5.18-5.30 (m, 2H), 5.32-5.55 (m, 1H), 5.59 (brs, 1H), 6.11 (d,J = 11.2Hz, 1H), 6.32 (d,J = 11.2Hz, 1H) .MS m / z: 700 (M+), 202 (100%). UV λmax nm: 263.
[0124]
Example 33
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-hydroxy-4-methyl-2-pentynylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-hydroxy-4-methyl-2-pentynylthio) -9,10-secopregna-5,7,10 (19), 16 -To a solution of tetraene (3.4 mg, 0.00611 mmol) in tetrahydrofuran (2 ml) was added 1M-tetra-n-butylammonium fluoride in tetrahydrofuran (1 ml), and the mixture was reacted at room temperature for 13 hours. The reaction solution was diluted with ethyl acetate, washed successively with ice-cold 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) to give the title compound (0.653 mg, colorless oil). , 24%).
[0125]
IR (neat): 3400, 2930, 1450, 1370, 1250, 1160, 1050cm-1.1H NMR δ: 0.84 (s, 3H), 1.45 (d,J = 7.3Hz, 3H), 1.51 (s, 6H), 3.17 (d,J = 16.6Hz, 1H), 3.20 (d,J = 16.6Hz, 1H), 3.66 (q,J = 7.3Hz, 1H), 4.28-4.31 (m, 1H), 4.38-4.49 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.65 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 442 (M+), 311 (100%). UV λmax nm: 263.
[0126]
Example 34
Preparation of 1α, 3β-dihydroxy-20 (S)-{(E) -4-hydroxy-4-methyl-2-pentenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(E) -4-hydroxy-4-methyl-2-pentenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene (2.0 mg, 0.00358 mmol), tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.5 ml) was reacted in the same manner as in Example 33 (3 Day), and after purification, purified by preparative thin-layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) to give the title compound as a colorless oil ( 0.744 mg, 47%) was obtained.
[0127]
IR (neat): 3400, 2920, 1460, 1370, 1060cm-1.1H NMR δ: 0.88 (s, 3H), 1.32 (s, 6H), 1.41 (d,J = 6.8Hz, 3H), 2.96-3.20 (m, 2H), 3.40 (d,J = 6.8Hz, 1H), 4.17-4.32 (m, 1H), 4.39-4.49 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.60-5.77 (m, 2H), 6.10 ( d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 426 (M+-H2O), 105 (100%). UV λmax nm: 264.
[0128]
Example 35
Preparation of 1α, 3β-dihydroxy-20 (S)-{(Z) -4-hydroxy-4-methyl-2-pentenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
Crude 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(Z) -4-methyl-4-triethylsilyloxy-2-pentenylthio} -9, obtained in Example 29, 10-secopregna-5,7,10 (19), 16-tetraene (20.9 mg), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) were treated in the same manner as in Example 33. Reaction (40 hours), post-treatment, purification by preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed 5 times) gave colorless oil The title compound (1.67 mg, 14%, 2 steps) was obtained.
[0129]
IR (neat): 3400, 2930, 1450, 1370, 1210, 1150, 1060cm-1.1H NMR δ: 0.84 (s, 3H), 1.36 (s, 6H), 1.44 (d,J = 7.3Hz, 3H), 3.34 (dd,J = 12.2, 6.8Hz, 1H), 3.62-3.77 (m, 2H), 4.17-4.32 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.35-5.58 (m, 2H), 5.60 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 444 (M+), 312 (100%). UV λmax nm: 264.
[0130]
Example 36
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-ethyl-4-hydroxy-2-hexynylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-(4-ethyl-4-hydroxy-2-hexynylthio) -9,10-secopregna-5,7,10 (19), 16 -Tetraene (1.8 mg, 0.00308 mmol), tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted in the same manner as in Example 33 (40 hours), followed by post-treatment. , Purified by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times), and the title compound (0.699 mg, 48%) as a colorless oil Got.
[0131]
IR (neat): 3400, 2930, 1450, 1370, 1230, 1150, 1060cm-1.1H NMR δ: 0.82 (s, 3H), 1.02 (t,J = 7.3Hz, 6H), 1.44 (d,J = 6.8Hz, 3H), 1.65 (q,J = 7.3Hz, 4H), 3.28 (d,J = 16.7Hz, 1H), 3.32 (d,J = 16.7Hz, 1H), 3.66 (q,J = 6.8Hz, 1H), 4.16-4.31 (m, 1H), 4.36-4.52 (m, 1H), 4.99 (brs, 1H), 5.32 (brs, 1H), 5.61 (brs, 1H), 6.07 (d,J = 11.2Hz, 1H), 6.35 (d,J = 11.2Hz, 1H) .MS m / z: 452 (M+-H2O), 91 (100%). UV λmax nm: 264.
[0132]
Example 37
Preparation of 1α, 3β-dihydroxy-20 (S)-{(E) -4-ethyl-4-hydroxy-2-hexenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(E) -4-ethyl-4-hydroxy-2-hexenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene (1.9 mg, 0.00324 mmol), tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted in the same manner as in Example 33 (40 hours). Work up and purify by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) to give the title compound (0. 748 mg, 49%).
[0133]
IR (neat): 3400, 2920, 1450, 1370, 1270, 1050cm-1.1H NMR δ: 0.86 (t,J = 7.3Hz, 6H), 0.88 (s, 3H), 1.41 (d,J = 6.8Hz, 3H), 1.53 (q,J = 7.3Hz, 4H), 3.07-3.17 (m, 2H), 3.42 (q,J = 6.8Hz, 1H), 4.17-4.29 (m, 1H), 4.38-4.50 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.43-5.80 (m, 3H), 6.10 ( d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 454 (M+-H2O), 161 (100%). UV λmax nm: 264.
[0134]
Example 38
Preparation of 1α, 3β-dihydroxy-20 (S)-{(Z) -4-ethyl-4-hydroxy-2-hexenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α- (tert-butyldimethylsilyloxy) -3β-hydroxy-20 (S)-{(Z) -4-ethyl-4-triethylsilyloxy-2-hexenylthio} -9,10-secopregna-5,7 , 10 (19), 16-tetraene (1.2 mg, 0.00171 mmol), tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted in the same manner as in Example 33 (40 Time), worked up, and purified by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed twice) to give the title compound as a colorless oil ( 0.357 mg, 44%).
[0135]
IR (neat): 3400, 2920, 1450, 1370, 1060cm-1.1H NMR δ: 0.84 (s, 3H), 0.91 (t,J = 7.5Hz, 6H), 1.44 (d,J = 6.8Hz, 3H), 1.57 (q,J = 7.5Hz, 4H), 3.27-3.58 (m, 3H), 4.17-4.31 (m, 1H), 4.40-4.52 (m, 1H), 5.01 (brs, 1H), 5.23-5.37 (m, 2H), 5.44-5.70 (m, 2H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 454 (M+-H2O), 312 (100%). UV λmax nm: 263.
[0136]
Example 39
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -16α-hydroxy-9,10-secopregna-5,7,10 (19), 17 (E) -tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -16α-hydroxypregna-5,7,17 (E) -triene (103 mg, 0.184 mmol) and ethanol (200 ml) were used as in Example 15. After reaction by operation (light irradiation for 5 minutes, heating under reflux for 2 hours), preparative thin layer chromatography (0.5 mm × 3 sheets, hexane: ethyl acetate = 9: 1, developed four times, and further 0. Purification by 5 mm × 2 sheets, hexane: ethyl acetate = 9: 1, developed 4 times) gave the title compound (24.1 mg, 23%) as a colorless oil.
[0137]
IR (neat): 3350, 2930, 2855, 1460, 1380, 1255, 1080cm-1.1H NMR δ: 0.06 (s, 12H), 0.74 (s, 3H), 0.88 (s, 18H), 1.74 (d,J = 7.3Hz, 3H), 4.12-4.28 (m, 1H), 4.32-4.52 (m, 2H), 4.86 (d,J = 2.0Hz, 1H), 5.19 (d,J = 2.0Hz, 1H), 5.64 (q,J = 7.3Hz, 1H), 6.00 (d,J = 11.2Hz, 1H), 6.23 (d,J = 11.2Hz, 1H) .MS m / z: 558 (M+), 248 (100%). UV λmax nm: 262.
[0138]
Example 40
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -16α-hydroxy-9,10-secopregna-5,7,10 (19), 17 (E) -tetraene (24.0 mg, 0.0430 mmol), dichloromethane (2.5 ml), pyridine (0.0209 ml, 0.258 mmol), and phenylchlorothionoformate (0.0178 ml, 0.129 mmol) were reacted under the same conditions as in Example 1 and after the post-treatment, a preparative thin film was obtained. Purification by layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate = 9: 1, developed once) gave the title compound (17.9 mg, 60%) as a colorless oil.
[0139]
IR (neat): 2925, 2850, 1730, 1490, 1470, 1255, 1190, 1160, 1100cm-1.1H NMR δ: 0.07 (s, 12H), 0.85 (s, 3H), 0.88 (s, 18H), 1.59 (d,J = 6.8Hz, 3H), 4.04-4.28 (m, 2H), 4.39 (t,J = 4.9Hz, 1H), 4.88 (d,J = 2.0Hz, 1H), 5.19 (d,J = 2.0Hz, 1H), 5.74 (brs, 1H), 6.09 (d,J = 11.2Hz, 1H), 6.24 (d,J = 11.2Hz, 1H), 7.12-7.44 (m, 5H) .MS m / z: 694 (M+), 248 (100%). UV λmax nm: 210, 263.
[0140]
Example 41
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (2.0 mg, 0.00288 mmol) 4-bromo-2-methyl-2-butanol (2.4 mg, 0.0144 mmol), tetrahydrofuran (0.25 ml), 1M-KOH in methanol (0.25 ml) under the same conditions as in Example 3, After the treatment, purification by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once) gave the title compound (1.5 mg, 79%) as a colorless oil. .
[0141]
IR (neat): 3400, 2920, 2850, 1460, 1360, 1250, 1080cm-1.1H NMR δ: 0.07 (s, 12H), 0.81 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.23 (s, 6H), 1.42 (d,J = 6.8Hz, 3H), 3.49 (q,J = 6.8Hz, 1H), 4.11-4.24 (m, 1H), 4.26-4.31 (m, 1H), 4.84 (brs, 1H), 5.19 (brs, 1H), 5.60 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.24 (d,J = 11.2Hz, 1H) .MS m / z: 660 (M+), 248 (100%). UV λmax nm: 263.
[0142]
Example 42
Preparation of 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene ( 1.5 mg, 0.00227 mmol), tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.5 ml) was reacted in the same manner as in Example 9 (1.5 hours), after post-treatment , Purified by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) to give the title compound as a colorless oil (0.511 mg, 52% ) Each spectrum of the compound obtained here was in agreement with that of the compound obtained in Example 15.
[0143]
Example 43
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -16-oxopregna-5,7,17 (E) -triene
Manganese dioxide (40 g) was added to a solution of 1α, 3β-bis (tert-butyldimethylsilyloxy) -16α-hydroxypregna-5,7,17 (E) -triene (2.01 g, 3.60 mmol) in chloroform (150 ml). ) And reacted for 2 hours under ultrasonic irradiation. The reaction solution was filtered, concentrated, and purified by column chromatography (hexane: dichloromethane: ethyl acetate = 18: 2: 1) to give the title compound (1.45 g, 73%) as a colorless solid.
[0144]
IR (KBr): 2950, 2850, 1730, 1650, 1460, 1380, 1255, 1100cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 3H), 0.08 (s, 3H), 0.12 (s, 3H), 0.89 (s, 18H), 0.97 (s, 3H), 0.99 (s, 3H), 1.88 (d,J = 7.3Hz, 3H), 3.73 (brs, 1H), 3.96-4.16 (m, 1H), 5.30-5.39 (m, 1H), 5.56-5.65 (m, 1H), 6.56 (q,J = 7.3Hz, 1H) .MS m / z: 556 (M+), 367 (100%). UV λmax nm: 242, 258, 270, 281, 293.
[0145]
Example 44
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -16β-hydroxypregna-5,7,17 (E) -triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -16-oxopregna-5,7,17 (E) -triene (1.45 g, 2.60 mmol) and cerium (III) chloride heptahydrate (1 .45 g, 3.90 mmol) in methanol (20 ml) and tetrahydrofuran (80 ml) were cooled to 0 ° C., and sodium borohydride (490 mg, 13.0 mmol) was added little by little. The reaction solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a colorless solid (1.29 g, 89%) and 1α, 3β-bis (tert-butyldimethylsilyloxy)- 16α-hydroxypregna-5,7,17 (E) -triene (85 mg, 5.8%) was obtained.
[0146]
Title Compound IR (KBr): 3300, 2950, 2850, 1460, 1370, 1245, 1100, 1000cm-1.1H NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.88 (s, 18H), 0.93 (s, 3H), 1.00 (s, 3H), 1.76 (dd,J = 7.3, 2.0Hz, 3H), 3.71 (brs, 1H), 3.93-4.16 (m, 1H), 4.49 (t,J = 7.8Hz, 1H), 5.33-5.42 (m, 1H), 5.47-5.64 (m, 2H). MS m / z: 558 (M+), 369 (100%). UV λmax nm: 270, 281, 293.
[0147]
Example 45
Production of 1α, 3β-bis (tert-butyldimethylsilyloxy) -16β-hydroxy-9,10-secopregna-5,7,10 (19), 17 (E) -tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -16β-hydroxypregna-5,7,17 (E) -triene (115 mg, 0.205 mmol) and ethanol (200 ml) were used as in Example 15. After reaction by operation (light irradiation 5.5 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 3, hexane: ethyl acetate = 8: 1, developed three times) Purification gave the title compound (27.0 mg, 23%) as a colorless oil.
[0148]
IR (neat): 3400, 2950, 2850, 1470, 1370, 1250, 1075cm-1.1H NMR δ: 0.06 (s, 6H), 0.07 (s, 6H), 0.88 (s, 18H), 0.91 (s, 3H), 1.74 (dd,J = 6.8, 1.5Hz, 3H), 4.13-4.29 (m, 1H), 4.32-4.55 (m, 2H), 4.87 (d,J = 1.9Hz, 1H), 5.20 (d,J = 1.9Hz, 1H), 5.57 (dq,J = 6.8, 1.5Hz, 1H), 6.04 (d,J = 11.2Hz, 1H), 6.21 (d,J = 11.2Hz, 1H) .MS m / z: 558 (M+), 427 (100%). UV λmax nm: 263.
[0149]
Example 46
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -16β-hydroxy-9,10-secopregna-5,7,10 (19), 17 (E) -tetraene (53.1 mg, 0.0950 mmol), dichloromethane (5 ml), pyridine (0.0461 ml, 0.570 mmol) and phenylchlorothionoformate (0.0394 ml, 0.285 mmol) were reacted under the same conditions as in Example 1, after the workup, and preparative thin-layer chromatography. Purification by chromatography (0.5 mm x 2 sheets, hexane: ethyl acetate = 8: 1, developed once) gave the title compound (55.4 mg, 84%) as a colorless oil.
[0150]
IR (neat): 2930, 2850, 1730, 1490, 1470, 1370, 1255, 1190, 1160, 1100, 1010cm-1.1H NMR δ: 0.06 (s, 12H), 0.73 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.61 (d,J = 6.8Hz, 3H), 4.08 (q,J = 6.8Hz, 1H), 4.12-4.28 (m, 1H), 4.32-4.44 (m, 1H), 4.88 (d,J = 1.9Hz, 1H), 5.19 (d,J = 1.9Hz, 1H), 5.72 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.24 (d,J = 11.2Hz, 1H), 7.07-7.48 (m, 5H) .MS m / z: 694 (M+), 248 (100%). UV λmax nm: 215, 263.
[0151]
Example 47
Preparation of 1α, 3β-dihydroxy-20 (R)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (3.3 mg, 0.00475 mmol) 4-bromo-2-methyl-2-butanol (4.0 mg, 0.0238 mmol), tetrahydrofuran (0.5 ml) and 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3, followed by After the treatment, purification was performed by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once) to obtain 3.6 mg of a product. Tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) was added thereto, and the reaction was carried out in the same manner as in Example 9 (1.5 hours). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.15 mg, 56%) as a colorless oil.
[0152]
IR (neat): 3400, 2920, 1450, 1370, 1200, 1060cm-1.1H NMR δ: 0.74 (s, 3H), 1.24 (s, 6H), 1.47 (d,J = 6.8Hz, 3H), 3.40 (q,J = 6.8Hz, 1H), 4.14-4.29 (m, 1H), 4.34-4.48 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.29 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 432 (M+), 312 (100%). UV λmax nm: 263.
[0153]
Example 48
Preparation of 1α, 3β-dihydroxy-20 (R)-(4-hydroxy-4-methylpentylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (3.9 mg, 0.00561 mmol) 1-bromo-4-methyl-4-triethylsilyloxypentane (8.3 mg, 0.0281 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) under the same conditions as in Example 3. After reaction and post-treatment, purification by preparative thin-layer chromatography (0.25 mm × 1 sheet, hexane: dichloromethane: ethyl acetate = 160: 40: 1, developed once) gave 3.1 mg of product. It was. Tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.5 ml) was added thereto, and the reaction was carried out in the same manner as in Example 9 (1.5 hours). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed twice) gave the title compound (0.614 mg, 24%) as a colorless oil.
[0154]
IR (neat): 3400, 2920, 1450, 1370, 1270, 1200, 1050cm-1.1H NMR δ: 0.74 (s, 3H), 1.22 (s, 6H), 1.45 (d,J = 6.9Hz, 3H), 3.36 (q,J = 6.9Hz, 1H), 4.18-4.30 (m, 1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.57 (brs, 1H), 6.11 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 428 (M+-H2O), 312 (100%). UV λmax nm: 264.
[0155]
Example 49
Preparation of 1α, 3β-dihydroxy-20 (R)-(5-hydroxy-5-methylhexylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (3.8 mg, 0.00547 mmol) , 6-bromo-2-methyl-2-hexanol (5.3 mg, 0.0274 mmol), tetrahydrofuran (0.5 ml) and 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3, followed by After the treatment, purification was performed by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once) to obtain 3.1 mg of the product. Tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) was added thereto, and the reaction was carried out in the same manner as in Example 9 (1.5 hours). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.34 mg, 60%) as a colorless oil.
[0156]
IR (neat): 3400, 2920, 1450, 1370, 1200, 1060cm-1.1H NMR δ: 0.73 (s, 3H), 1.21 (s, 6H), 1.45 (d,J = 6.8Hz, 3H), 3.34 (q,J = 6.8Hz, 1H), 4.28-4.32 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.56 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 442 (M+-H2O), 312 (100%). UV λmax nm: 264.
[0157]
Example 50
Production of 1α, 3β-dihydroxy-20 (R)-(2-hydroxy-2-methylpropylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (3.9 mg, 0.00561 mmol) , Isobutylene oxide (2.0 mg, 0.0281 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3, and after workup, preparative thin-layer chromatography. Purification by chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once) gave 2.2 mg of product. Tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) was added thereto, and the reaction was carried out in the same manner as in Example 9 (1.5 hours). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (0.929 mg, 40%) as a colorless oil.
[0158]
IR (neat): 3400, 2920, 1450, 1370, 1200, 1145, 1055cm-1.1H NMR δ: 0.73 (s, 3H), 1.26 (s, 3H), 1.27 (s, 3H), 1.46 (d,J = 6.9Hz, 3H), 3.39 (q,J = 6.9Hz, 1H), 4.18-4.29 (m, 1H), 4.41-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 418 (M+), 91 (100%). UV λmax nm: 264.
[0159]
Example 51
Preparation of 1α, 3β-dihydroxy-20 (R)-(3-ethyl-3-hydroxypentylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (4.0 mg, 0.00575 mmol) 5-bromo-3-ethyl-3-pentanol (5.6 mg, 0.0288 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3. After the post-treatment, the product was purified by preparative thin-layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once) to obtain 3.0 mg of the product. Tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) was added thereto, and the reaction was carried out in the same manner as in Example 9 (1.5 hours). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.48 mg, 56%) as a colorless oil.
[0160]
IR (neat): 3400, 2920, 1465, 1370, 1200, 1060cm-1.1H NMR δ: 0.74 (s, 3H), 0.86 (t,J = 7.4Hz, 6H), 1.40-1.53 (m, 7H), 3.39 (q,J = 6.9Hz, 1H), 4.18-4.30 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 460 (M+), 312 (100%). UV λmax nm: 264.
[0161]
Example 52
Preparation of 1α, 3β-dihydroxy-20 (R)-(4-ethyl-4-hydroxyhexylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (5.0 mg, 0.00719 mmol) , 6-bromo-3-ethyl-3-hexanol (7.5 mg, 0.0360 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3, followed by After the treatment, purification was performed by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once) to obtain 4.2 mg of the product. Tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) was added thereto, and reacted in the same manner as in Example 9 (1.5 hours). Purification by thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) to give the title compound (1.14 mg, 33%) as a colorless oil. .
[0162]
IR (neat): 3400, 2920, 1455, 1370, 1250, 1140, 1050cm-1.1H NMR δ: 0.74 (s, 3H), 0.92 (t,J = 6.9Hz, 6H), 3.39 (q,J = 6.8Hz, 1H), 4.18-4.32 (m, 1H), 4.39-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.11 (d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 456 (M+-H2O), 312 (100%). UV λmax nm: 264.
[0163]
Example 53
Preparation of 1α, 3β-dihydroxy-20 (R)-(4-hydroxy-4-methyl-2-pentynylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (4.3 mg, 0.00619 mmol) , 5-bromo-2-methyl-3-pentyn-2-ol (5.5 mg, 0.0309 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) under the same conditions as in Example 3. After reaction and after-treatment, purification was performed by preparative thin-layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once) to obtain 3.3 mg of the product. To this was added tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml), and the reaction was carried out in the same manner as in Example 33 (2 days). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.17 mg, 43%) as a colorless oil.
[0164]
IR (neat): 3400, 2920, 1455, 1370, 1250, 1170, 1055cm-1.1H NMR δ: 0.74 (s, 3H), 1.45 (d,J = 6.8Hz, 3H), 1.48 (s, 6H), 3.20 (d,J = 16.6Hz, 1H), 3.30 (d,J = 16.6Hz, 1H), 3.56 (q,J = 6.8Hz, 1H), 4.18-4.32 (m, 1H), 4.37-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.10 (d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 442 (M+), 312 (100%). UV λmax nm: 264.
[0165]
Example 54
Preparation of 1α, 3β-dihydroxy-20 (R)-{(E) -4-hydroxy-4-methyl-2-pentenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (5.0 mg, 0.00719 mmol) (E) -5-bromo-2-methyl-3-penten-2-ol (6.4 mg, 0.0360 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) 3. After reaction and post-treatment under the same conditions as in No. 3, purify by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once), Obtained. To this was added tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml), and the reaction was carried out in the same manner as in Example 33 (2 days). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed twice) gave the title compound (1.88 mg, 59%) as a colorless oil.
[0166]
IR (neat): 3400, 2920, 1450, 1370, 1205, 1140, 1050cm-1.1H NMR δ: 0.73 (s, 3H), 1.33 (s, 6H), 1.44 (d,J = 6.8Hz, 3H), 3.02-3.22 (m, 2H), 3.33 (q,J = 6.8Hz, 1H), 4.16-4.31 (m, 1H), 4.39-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 5.63-5.79 ( m, 2H), 6.10 (d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 426 (M+-H2O), 352 (100%). UV λmax nm: 264.
[0167]
Example 55
Preparation of 1α, 3β-dihydroxy-20 (R)-{(Z) -4-hydroxy-4-methyl-2-pentenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (4.8 mg, 0.00690 mmol) (Z) -1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (10.1 mg, 0.0345 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml). After the reaction and post-treatment under the same conditions as in Example 3, purification was performed by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: dichloromethane: ethyl acetate = 160: 40: 1, developed once), 4.2 mg of product was obtained. To this was added tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml), and the reaction was carried out in the same manner as in Example 33 (2 days). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed twice) gave the title compound (1.87 mg, 61%) as a colorless oil.
[0168]
IR (neat): 3400, 2920, 1450, 1370, 1200, 1140, 1055cm-1.1H NMR δ: 0.73 (s, 3H), 1.36 (s, 6H), 1.48 (d,J = 6.9Hz, 3H), 3.32-3.61 (m, 3H), 4.17-4.33 (m, 1H), 4.37-4.52 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.37- 5.63 (m, 3H), 6.10 (d,J = 11.2Hz, 1H), 6.37 (d,J = 11.2Hz, 1H) .MS m / z: 444 (M+), 294 (100%). UV λmax nm: 264.
[0169]
Example 56
Preparation of 1α, 3β-dihydroxy-20 (R)-(4-ethyl-4-hydroxy-2-hexynylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (4.3 mg, 0.00619 mmol) 6-Bromo-3-ethyl-4-hexyn-3-ol (6.4 mg, 0.0309 mmol), tetrahydrofuran (0.5 ml), 1 M-KOH methanol solution (0.5 ml) under the same conditions as in Example 3. After reaction and after-treatment, purification was performed by preparative thin-layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once) to obtain 4.2 mg of the product. To this was added tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml), and the reaction was carried out in the same manner as in Example 33 (2 days). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.17 mg, 43%) as a colorless oil.
[0170]
IR (neat): 3400, 2920, 1455, 1370, 1240, 1150, 1055cm-1.1H NMR δ: 0.74 (s, 3H), 1.03 (t,J = 7.3Hz, 6H), 1.49 (d,J = 6.8Hz, 3H), 1.66 (q,J = 7.3Hz, 4H), 3.23 (d,J = 16.6Hz, 1H), 3.29 (d,J = 16.6Hz, 1H), 3.59 (q,J = 6.8Hz, 1H), 4.18-4.33 (m, 1H), 4.39-4.53 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.11 (d,J = 11.2Hz, 1H), 6.34 (d,J = 11.2Hz, 1H) .MS m / z: 470 (M+), 312 (100%). UV λmax nm: 264.
[0171]
Example 57
Preparation of 1α, 3β-dihydroxy-20 (R)-{(E) -4-ethyl-4-hydroxy-2-hexenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (5.0 mg, 0.00719 mmol) (E) -6-Bromo-3-ethyl-4-hexen-3-ol (7.5 mg, 0.0360 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) 3. After reaction and post-treatment under the same conditions as in No. 3, purification was performed by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once), and 4.6 mg of product was obtained. Obtained. To this was added tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml), and the reaction was carried out in the same manner as in Example 33 (2 days). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed twice) gave the title compound (2.40 mg, 71%) as a colorless oil.
[0172]
IR (neat): 3400, 2920, 1450, 1370, 1220, 1140, 1055cm-1.1H NMR δ: 0.73 (s, 3H), 0.87 (t,J = 7.3Hz, 6H), 1.44 (d,J = 6.8Hz, 3H), 1.54 (q,J = 7.3Hz, 4H), 3.04-3.27 (m, 2H), 3.35 (q,J = 6.8Hz, 1H), 4.26-4.32 (m, 1H), 4.39-4.53 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.45-5.78 (m, 3H), 6.10 ( d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 454 (M+-H2O), 380 (100%). UV λmax nm: 264.
[0173]
Example 58
Preparation of 1α, 3β-dihydroxy-20 (R)-{(Z) -4-ethyl-4-hydroxy-2-hexenylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (5.0 mg, 0.00719 mmol) (Z) -1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (11.6 mg, 0.0360 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml). After reaction and post-treatment under the same conditions as in Example 3, purification was performed by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: dichloromethane: ethyl acetate = 160: 40: 1, developed once), 4 Obtained 2 mg of product. To this was added tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml), and the reaction was carried out in the same manner as in Example 33 (2 days). Purification by layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.74 mg, 51%) as a colorless oil.
[0174]
IR (neat): 3400, 2925, 1450, 1365, 1210, 1055cm-1.1H NMR δ: 0.72 (s, 3H), 0.91 (t,J = 7.3Hz, 6H), 1.48 (d,J = 6.8Hz, 3H), 1.52 (q,J = 7.3Hz, 4H), 3.32-3.64 (m, 3H), 4.16-4.32 (m, 1H), 4.39-4.51 (m, 1H), 5.01 (brs, 1H), 5.25-5.37 (m, 2H), 5.50-5.69 (m, 2H), 6.10 (d,J = 11.2Hz, 1H), 6.38 (d,J = 11.2Hz, 1H) .MS m / z: 454 (M+-H2O), 312 (100%). UV λmax nm: 263.
[0175]
Example 59
Production of 1α, 3β-bis (tert-butyldimethylsilyloxy) -17α, 20α-epoxypregna-5,7-diene PTAD adduct
1α, 3β-bis (tert-butyldimethylsilyloxy) pregna-5,7,17 (Z) -triene PTAD adduct (1.00 g, 1.39 mmol) and sodium bicarbonate (290 mg, 3.48 mmol) in dichloromethane (20 ml) The mixture was cooled to 0 ° C. and 70% -m-chloroperbenzoic acid (412 mg, 1.67 mmol) was added. The reaction mixture was stirred at the same temperature for 0.5 hour, diluted with dichloromethane, washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous sodium hydrogen sulfite solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in that order, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (920 mg, 90%) as a colorless solid.
[0176]
1H-NMR δ: 0.08 (s, 3H), 0.09 (s, 3H), 0.11 (s, 3H), 0.15 (s, 3H), 0.89 (s, 9H), 0.91 (s, 12H), 1.01 (s , 3H), 1.41 (d, 3H,J= 5.6Hz), 3.00 (q, 1H,J= 5.6Hz), 3.11-3.28 (m, 1H), 3.85 (brs, 1H), 4.69-4.85 (m, 1H), 6.13 (d, 1H,J= 8.3Hz), 6.28 (d, 1H,J= 7.9Hz), 7.15 (dd, 1H,J= 7.3, 7.6Hz), 7.28 (dd, 2H,J= 7.6, 7.9Hz), 7.38 (d, 2H,J= 7.6Hz). UV λmaxnm: 260.
[0177]
Example 60
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -17α, 20α-epoxypregna-5,7-diene
1α, 3β-bis (tert-butyldimethylsilyloxy) -17α, 20α-epoxypregna-5,7-diene PTAD adduct (613 mg, 0.835 mmol) was converted to 1,3-dimethyl-2-imidazolidinone ( 60 ml) and stirred with heating at 140 ° C. for 5 hours. This was poured into water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 20: 1) to obtain the title compound (328 mg, 70%) as a colorless solid.
[0178]
1H-NMR δ: 0.04 (s, 9H), 0.08 (s, 3H), 0.81 (s, 3H), 0.86 (s, 18H), 0.88 (s, 3H), 1.36 (d, 3H,J= 5.6Hz), 2.95 (q, 1H,J= 5.6Hz), 3.67 (brs, 1H), 3.95-4.10 (m, 1H), 5.33-5.44 (m, 1H), 5.57 (d, 1H,J= 5.3Hz). UV λmaxnm: 269, 281, 293.
[0179]
Example 61
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene
A solution of 1.5M-lithium diisopropylamide in cyclohexane (4.7 ml, 7.05 mmol) in toluene (3 ml) was cooled to 0 ° C., and 0.95 M-diethylaluminum chloride in hexane (4.95 ml, 4.70 mmol) was added. added. After stirring the reaction solution at the same temperature for 0.5 hour, 1α, 3β-bis (tert-butyldimethylsilyloxy) -17α, 20α-epoxypregna-5,7-diene (328 mg, 0.587 mmol) in toluene. (5 ml) was added, and the mixture was further stirred at the same temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the mixture was filtered through Celite. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the residue obtained after evaporation of the solvent under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (277 mg) as a colorless solid. 84%).
[0180]
1H-NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.88 (s, 21H), 0.95 (s, 3H), 1.36 (d, 3H,J= 6.3Hz), 3.71 (brs, 1H), 3.97-4.12 (m, 1H), 4.39 (q, 1H,J= 6.3Hz), 5.35-5.44 (m, 1H), 5.61 (d, 1H,J= 5.3Hz), 5.67 (s, 1H). UV λmaxnm: 270, 281, 293.
[0181]
Example 62
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-(3-hydroxy-3-methylbutyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (97 mg, 0.175 mmol), sodium hydride (50 mg, 2.08 mmol) and 4 -A solution of bromo-2,3-epoxy-2-methylbutane (145 mg, 0.877 mmol) in tetrahydrofuran (2 ml) was heated under reflux for 12 hours, and then 1M-hydrogenated tri-s-butylboron lithium tetrahydrofuran solution (1.8 ml, 1.80 mmol) was added and heated to reflux for 45 minutes. 3N-aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide were added to the reaction solution, stirred at room temperature for 30 minutes, diluted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound (113 mg, 100%) as a colorless oil.
[0182]
IR (neat): 3500, 2960, 2860, 1463, 1375, 1260, 1105cm-1.1H-NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.88 (s, 21H), 0.94 (s, 3H), 1.23 (s, 3H), 1.24 (s , 3H), 1.31 (d, 3H,J= 6.6Hz), 3.47-3.59 (m, 1H), 3.59-3.78 (m, 1H), 3.70 (brs, 1H), 3.93 (q, 1H,J= 6.6Hz), 3.98-4.12 (m, 1H), 5.34-5.45 (m, 1H), 5.57-5.70 (m, 2H). UV λmaxnm: 269, 281, 293.
[0183]
Example 63
Preparation of 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-(3-hydroxy-3-methylbutyloxy) pregna-5,7,16-triene (27 mg, 0.0419 mmol) in tetrahydrofuran (1 ml) ) To the solution was added 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.25 ml, 0.25 mmol), and the mixture was stirred at room temperature for 20 hours and heated under reflux for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer chromatography (0.5 mm × 1 and 0.25 mm × 1, dichloromethane: ethanol = 20: 1, developed twice), The title compound (17.3 mg, 99%) was obtained as a colorless oil.
[0184]
IR (neat): 3420, 2940, 1735, 1660, 1460, 1365, 1270, 1150, 1055cm-1.1H-NMR δ: 0.88 (s, 3H), 0.96 (s, 3H), 1.22 (s, 3H), 1.23 (s, 3H), 1.30 (d, 3H,J= 6.6Hz), 3.45-3.58 (m, 1H), 3.58-3.72 (m, 2H), 3.76 (brs, 1H), 3.94 (q, 1H,J= 6.6Hz), 3.98-4.14 (m, 1H), 5.37-5.48 (m, 1H), 5.62 (s, 1H), 5.72 (d, 1H,J= 3.6Hz). UV λmaxnm: 270, 281, 293.
[0185]
Example 64
Preparation of 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19), 16-tetraene
Example 1 using 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutyloxy) pregna-5,7,16-triene (11 mg, 0.0264 mmol), ethanol (200 ml) and After performing the reaction by the same operation (light irradiation 1 minute 50 seconds, heating under reflux 2 hours), the solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative thin layer chromatography (0.25 mm × 1, Purification by dichloromethane: ethyl acetate = 20: 1, developed twice, further 0.25 mm × 0.5 sheets, hexane: ethyl acetate: ethanol = 10: 5: 1, developed three times) to give the title compound as a colorless oil ( 0.890 mg, 8.1%).
[0186]
IR (neat): 3400, 2980, 2940, 1450, 1370, 1160, 1060cm-1.1H-NMR δ: 0.78 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.31 (d, 3H,J= 6.6Hz), 3.47-3.58 (m, 1H), 3.63 (s, 1H), 3.61-3.73 (m, 1H), 3.91 (q, 1H,J= 6.6Hz), 4.18-4.30 (m, 1H), 4.39-4.51 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.59 (brs, 1H), 6.10 (d, 1H,J= 11.6Hz), 6.37 (d, 1H,J= 11.6Hz). UV λmaxnm: 263.
[0187]
Example 65
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20-oxopregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (600 mg, 1.07 mmol), pyridinium dichromate (610 mg, 1.61 mmol) and florisil A suspension of (3 g) in dichloromethane (10 ml) was stirred for 1.5 hours at room temperature and then subjected to ultrasonic irradiation for 2.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with diethyl ether and filtered through celite. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (hexane: ethyl acetate = 15: 1) to obtain the title compound (343 mg, 57%) as a colorless solid.
[0188]
IR (KBr): 2920, 2850, 1655, 1585, 1460, 1370, 1250, 1225, 1100, 1075, 1060cm-1.1H-NMR δ: 0.06 (s, 6H), 0.07 (s, 3H), 0.11 (s, 3H), 0.87 (s, 9H), 0.89 (s, 12H), 0.95 (s, 3H), 2.28 (s , 3H), 3.72 (brs, 1H), 3.95-4.15 (m, 1H), 5.36-5.44 (m, 1H), 5.57-5.67 (m, 1H), 6.74 (brs, 1H). MS m / z: 556 (M+), 367 (100%). UV λmaxnm: 238, 270, 281, 293.
[0189]
Example 66
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20-oxopregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (50.0 mg, 0.0894 mmol) and 4-methylmorpholine-N-oxide (15 (7 mg, 0.134 mmol) in dichloromethane (1 ml) was added powdered molecular sieve 4A and stirred at room temperature for 10 minutes. To this, tetra-n-butylammonium perruthenate (1.6 mg, 0.00447 mmol) was added and stirred at room temperature for 30 minutes. The reaction solution was filtered, diluted with dichloromethane, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution, a saturated saline solution and a saturated copper sulfate aqueous solution in this order, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate = 5: 1, developed once) to give the title compound as a colorless solid ( 37.1 mg, 74%).
[0190]
Example 67
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20-oxopregna-5,7,16-triene (93 mg, 0.167 mmol) and cerium (III) chloride heptahydrate (93 mg, 0.251 mmol) Of methanol (1.5 ml) and tetrahydrofuran (6 ml) was cooled to 0 ° C., and sodium borohydride (32 mg, 0.835 mmol) was gradually added. The reaction solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 10: 1, developed three times) to give the title compound (68.2 mg, 73%) as a colorless solid. And 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (17.0 mg, 18%).
[0191]
Title compound1H-NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.85 (s, 3H), 0.89 (s, 18H), 0.95 (s, 3H), 1.37 (d , 3H,J= 6.6Hz), 3.70 (brs, 1H), 3.96-4.12 (m, 1H), 4.31-4.44 (m, 1H), 5.31-5.43 (m, 1H), 5.61 (d, 1H,J= 5.3Hz), 5.66 (brs, 1H). UV λmaxnm: 270, 281, 293.
[0192]
Example 68
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-(3-hydroxy-3-methylbutyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (51 mg, 0.0911 mmol), sodium hydride (50 mg, 2.08 mmol) and 4 -A solution of bromo-2,3-epoxy-2-methylbutane (75 mg, 0.455 mmol) in tetrahydrofuran (2 ml) was heated to reflux for 1.5 hours, and 1M-hydrogenated tri-s-butylboron lithium tetrahydrofuran solution (0. 9 ml, 0.900 mmol) was added and the mixture was heated to reflux for 20 minutes. 3N-aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide were added to the reaction solution, stirred at room temperature for 30 minutes, diluted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate = 10: 1, developed twice) to give the title compound as a colorless oil ( 48.6 mg, 83%).
[0193]
IR (neat): 3500, 2950, 2870, 1470, 1380, 1260cm-1.1H-NMR δ: 0.05 (s, 3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.11 (s, 3H), 0.85 (s, 3H), 0.88 (s, 18H), 0.94 (s , 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.32 (d, 3H,J= 6.6Hz), 1.73 (t, 2H,J= 5.6Hz), 3.53 (s, 1H), 3.57-3.70 (m, 2H), 3.70 (brs, 1H), 3.93-4.11 (m, 2H), 5.31-5.42 (m, 1H), 5.60 (d, 1H,J= 5.6Hz), 5.64 (s, 1H). UV λmaxnm: 270, 281, 293.
[0194]
Example 69
Preparation of 1α, 3β-dihydroxy-20 (R)-(3-hydroxy-3-methylbutyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-(3-hydroxy-3-methylbutyloxy) pregna-5,7,16-triene (50 mg, 0.0775 mmol) in tetrahydrofuran (1 ml) ) To the solution was added 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.5 ml), and the mixture was stirred at room temperature for 12 hours and heated under reflux for 5 hours. The reaction solution was diluted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (0.5 mm × 2 pieces, dichloromethane: ethanol = 20: 1, developed twice) to give the title compound (23 .8 mg, 74%) and raw material recovery (6 mg, 12%).
[0195]
IR (neat): 3420, 2970, 2940, 1460, 1370, 1160, 1088, 1060cm-1.1H-NMR δ: 0.84 (s, 3H), 0.97 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.73 (d, 3H,J= 6.6Hz), 3.59-3.72 (m, 3H), 3.77 (brs, 1H), 4.00 (q, 1HJ= 6.6Hz), 4.06-4.20 (m, 1H), 5.41-5.51 (m, 1H), 5.65 (s, 1H), 5.73 (d, 1H,J= 4.0Hz). UV λmaxnm: 270, 281, 292.
[0196]
Example 70
Preparation of 1α, 3β-dihydroxy-20 (R)-(3-hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10 (19), 16-tetraene
Example using 1α, 3β-dihydroxy-20 (R)-(3-hydroxy-3-methylbutyloxy) pregna-5,7,16-triene (12.2 mg, 0.0293 mmol), ethanol (200 ml) The reaction was carried out in the same manner as in No. 15 (light irradiation 1 minute 30 seconds, heating under reflux 2 hours), the reduced-pressure solvent was distilled off, and the resulting residue was subjected to preparative thin-layer chromatography (0.25 mm × 1 , Dichloromethane: ethanol = 10: 1, developed once, further 0.25 mm × 0.5, hexane: ethyl acetate: ethanol = 10: 5: 1, developed three times) to give the title compound as a colorless oil (1.11 mg, 9.1%) was obtained.
[0197]
IR (neat): 3380, 2940, 2850, 1370, 1160, 1055cm-1.1H-NMR δ: 0.75 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H), 1.32 (d, 3H,J= 6.6Hz), 1.75 (t, 2H,J= 5.9Hz), 3.58 (s, 1H), 3.65 (t, 2H,J= 5.9Hz), 3.97 (q, 1H,J= 6.6Hz), 4.20-4.25 (m, 1H), 4.40-4.51 (m, 1H), 5.00 (s, 1H), 5.33 (s, 1H), 5.62 (s, 1H), 6.10 (d, 1H,J= 11.6Hz), 6.37 (d, 1H,J= 11.6Hz). UV λmaxnm: 264.
[0198]
Example 71
Preparation of 1α, 3β-dihydroxy-20 (S)-(2-ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (6.8 mg, 0.00978 mmol) , 1,2-epoxy-2-ethylbutane (9.8 mg, 0.0978 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) were reacted under the same conditions as in Example 3 and then under reduced pressure. Concentrated. The residue was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 4: 1, developed once), and 1α, 3β-bis ( A fraction containing tert-butyldimethylsilyloxy) -20 (S)-(2-ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene was obtained. . This and tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (1 ml) were reacted in the same manner as in Example 9 (60 ° C., 1.5 hours), after the post-treatment, a thin layer for preparative treatment Purification by chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (2.05 mg, 47%) as a colorless oil.
[0199]
IR (neat): 3369, 2964, 2929, 2879, 2848, 1446, 1369, 1055cm-1.1H NMR δ: 0.84 (s, 3H), 1.42 (d, J = 7.3Hz, 3H), 2.76-2.87 (m, 1H), 3.43 (q, J = 6.8Hz, 1H), 4.18-4.30 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
[0200]
Example 72
Production of 1α, 3β-dihydroxy-20 (R)-(2-ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (6.9 mg, 0.00993 mmol) 1,2-epoxy-2-ethylbutane (9.9 mg, 0.0993 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) under the same conditions as in Example 71, after After the treatment, it was purified by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 4: 1, developed once), and 1α, 3β-bis (tert-butyldimethylsilyloxy) -20. (R)-(2-Ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetrae To give a fraction containing. This and tetrahydrofuran (2 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (1 ml) were reacted in the same manner as in Example 9 (60 ° C., 1.5 hours), after the post-treatment, a thin layer for preparative treatment Purification by chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (2.64 mg, 59%) as a colorless oil.
[0201]
IR (neat): 3369, 2929, 2909, 2879, 2848, 1446, 1371, 1055cm-1.1H NMR δ: 0.73 (s, 3H), 0.87 (t, J = 7.4Hz, 3H), 0.88 (t, J = 7.4Hz, 3H), 1.46 (d, J = 6.9Hz, 3H), 2.77-2.87 (m, 1H), 3.35 (q, J = 6.9Hz, 1H), 4.18-4.31 (m, 1H), 4.39-4.01 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
[0202]
Example 73
Preparation of 1α, 3β-dihydroxy-20 (S)-{2 (S) -hydroxy-3-methylbutylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (5.7 mg, 0.00820 mmol) (S)-(+)-1,2-epoxy-3-methylbutane (3.53 mg, 0.0410 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) After the alkylation reaction and post-treatment under the same conditions, purification was performed by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once), and 1α, 3β-bis (tert -Butyldimethylsilyloxy) -20 (S)-{2 (S) -hydroxy-3-methylbutylthio} -9,10-secopregna-5,7,10 19), to obtain a fraction containing 16-tetraene. This was reacted with tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) in the same manner as in Example 9 (60 ° C., 2 hours), after workup, for fractionation. Purification by thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.36 mg, 38%) as a colorless oil.
[0203]
IR (neat): 3400, 2950, 2920, 2860, 2845, 1450, 1370, 1050cm-1.1H NMR δ: 0.85 (s, 3H), 0.93 (d, J = 7.4Hz, 3H), 0.96 (d, J = 7.4Hz, 3H), 1.43 (d, J = 6.9Hz, 3H), 2.53-2.66 (m, 1H), 2.73 (dd, J = 13.4, 3.2Hz, 1H), 2.76-2.88 (m, 1H), 3.32-3.54 (m, 2H), 4.16-4.30 (m, 1H), 4.38-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H) UV λmax nm: 263.
[0204]
Example 74
Production of 1α, 3β-dihydroxy-20 (S)-{2 (R) -hydroxy-3-methylbutylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (5.1 mg, 0.00734 mmol) (R)-(−)-1,2-epoxy-3-methylbutane (3.16 mg, 0.0367 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) After the alkylation reaction and post-treatment under the same conditions, purification was performed by preparative thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate = 3: 1, developed once), and 1α, 3β-bis (tert -Butyldimethylsilyloxy) -20 (S)-{2 (R) -hydroxy-3-methylbutylthio} -9,10-secopregna-5,7,10 19), to obtain a fraction containing 16-tetraene. This was reacted with tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) in the same manner as in Example 9 (60 ° C., 2 hours), after workup, for fractionation. Purification by thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.34 mg, 42%) as a colorless oil.
[0205]
IR (neat): 3400, 2958, 2929, 2850, 1446, 1369, 1254, 1213, 1053cm-1.1H NMR δ: 0.81 (s, 3H), 0.92 (d, J = 6.8Hz, 3H), 0.96 (d, J = 6.8Hz, 3H), 1.41 (d, J = 6.8Hz, 3H), 2.56-2.66 (m, 1H), 2.70 (dd, J = 13.4, 2.8Hz, 1H), 2.76-2.88 (m, 1H), 3.31-3.42 (m, 1H), 3.51 (q, J = 6.8Hz, 1H), 4.18-4.30 (m, 1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H) , 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 264.
[0206]
Example 75
Production of 1α, 3β-dihydroxy-20 (R)-{2 (S) -hydroxy-3-methylbutylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (7.1 mg, 0.0102 mmol) (S)-(+)-1,2-epoxy-3-methylbutane (4.4 mg, 0.0510 mmol), tetrahydrofuran (0.5 ml), 1 M-KOH methanol solution (0.5 ml) and After the alkylation reaction and post-treatment under the same conditions, purification was performed by preparative thin layer chromatography (0.25 mm × 1 plate, hexane: ethyl acetate = 4: 1, developed once), and 1α, 3β-bis (tert -Butyldimethylsilyloxy) -20 (R)-{2 (S) -hydroxy-3-methylbutylthio} -9,10-secopregna-5,7,10 (1 ), To obtain a fraction containing 16-tetraene. This was reacted with tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) in the same manner as in Example 9 (60 ° C., 2 hours), after workup, for fractionation. Purification by thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (1.24 mg, 28%) as a colorless oil.
[0207]
IR (neat): 3367, 2956, 2929, 2850, 1446, 1369, 1215, 1055cm-1.1H NMR δ: 0.75 (s, 3H), 0.93 (d, J = 6.9Hz, 3H), 0.96 (d, J = 6.9Hz, 3H), 1.46 (d, J = 6.9Hz, 3H), 2.56-2.66 (m, 1H), 2.74 (dd, J = 13.2, 3.0Hz, 1H), 2.78-2.88 (m, 1H), 3.32-3.48 (m, 2H), 4.16-4.29 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H) UV λmax nm: 263.
[0208]
Example 76
Production of 1α, 3β-dihydroxy-20 (R)-{2 (R) -hydroxy-3-methylbutylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (6.7 mg, 0.00964 mmol) , (R)-(−)-1,2-epoxy-3-methylbutane (4.2 mg, 0.0482 mmol), tetrahydrofuran (0.5 ml), 1M-KOH methanol solution (0.5 ml) and After the alkylation reaction and post-treatment under the same conditions, purification was performed by preparative thin layer chromatography (0.25 mm × 1 plate, hexane: ethyl acetate = 4: 1, developed once), and 1α, 3β-bis (tert -Butyldimethylsilyloxy) -20 (R)-{2 (R) -hydroxy-3-methylbutylthio} -9,10-secopregna-5,7,10 ( 9) to give a fraction containing the 16-tetraene. This was reacted with tetrahydrofuran (0.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml) in the same manner as in Example 9 (60 ° C., 2 hours), after workup, for fractionation. Purification by thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) gave the title compound (0.754 mg, 18%) as a colorless oil.
[0209]
IR (neat): 3340, 2922, 2846, 1456, 1369, 1290, 1238, 1043cm-1.1H NMR δ: 0.72 (s, 3H), 0.94 (d, J = 6.9Hz, 3H), 0.97 (d, J = 6.9Hz, 3H), 1.47 (d, J = 6.9Hz, 3H), 2.56-2.68 (m, 1H), 2.75-2.88 (m, 2H), 3.32-3.45 (m, 2H), 4.18-4.30 (m, 1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H).max nm: 263.
[0210]
Example 77
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{3-ethyl-2 (S) -hydroxypentylthio} pregna-5,7,16-triene and 1α, 3β-bis (tert -Butyldimethylsilyloxy) -20 (S)-{3-ethyl-2 (R) -hydroxypentylthio} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (151.7 mg, 0.220 mmol) , 1,2-epoxy-3-ethylpentane (503 mg, 4.40 mmol), tetrahydrofuran (1 ml), 1M-KOH methanol solution (1 ml) under the same conditions as in Example 71, post-treatment, fractionation Purified by thin layer chromatography (0.5 mm × 3, hexane: ethyl acetate = 4: 1, developed once), 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-( 3-Ethyl-2-hydroxypentylthio) pregna-5,7,16-triene (diastereomer mixture) was obtained. This was dissolved in dichloromethane (2 ml), 4-dimethylaminopyridine (117 mg, 0.956 mmol) and (1R)-(+)-camphanic chloride (104 mg, 0.478 mmol) were added, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed with ice-cold 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over magnesium sulfate. Remove the solvent under reduced pressure and purify by preparative thin-layer chromatography (0.5 mm x 4 plates, hexane: benzene: ethyl acetate = 10: 20: 1, developed 3 times). Separated. Next, each was dissolved in tetrahydrofuran (3 ml), 1M-sodium methoxide methanol solution (1 ml) was added, the mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 4: 1, developed once), and 1α, 3β- Bis (tert-butyldimethylsilyloxy) -20 (S)-{3-ethyl-2 (S) -hydroxypentylthio} pregna-5,7,16-triene (57.9 mg, 44%) and colorless oil 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{3-ethyl-2 (R) -hydroxypentylthio} pregna-5,7,16-triene (56.7 mg, 43%) Got.
[0211]
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{3-ethyl-2 (S) -hydroxypentylthio} pregna-5,7,16-triene:
IR (neat): 2897, 2856, 1462, 1371, 1254, 1099, 1082cm-1.1H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.88 (s, 18H), 1.44 (d, J = 6.9Hz, 3H), 2.47 (dd, J = 13.4, 9.6Hz, 1H), 2.72 (dd, J = 13.4, 3.0Hz, 1H), 2.79-2.91 (m, 1H), 3.49 (q, J = 6.7Hz, 1H), 3.60-3.73 (m, 2H ), 3.95-4.13 (m, 1H), 5.34-5.42 (m, 1H), 5.56-5.62 (m, 1H), 5.66 (brs, 1H) .MS m / z: 557 (M+-OSitBuMe2), 500 (100%). UV λmax nm: 270, 281, 293.
[0212]
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{3-ethyl-2 (R) -hydroxypentylthio} pregna-5,7,16-triene:
IR (neat): 2956, 2929, 2856, 1462, 1371, 1254, 1099, 1082cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.89 (s, 18H), 1.43 (d, J = 6.9Hz, 3H), 2.68 (dd, J = 13.2, 3.0Hz, 1H), 2.78-2.92 (m, 1H), 3.53 (q, J = 6.8Hz, 1H), 3.56-3.66 (m, 1H), 3.71 (brs, 1H), 3.95-4.12 (m , 1H), 5.31-5.44 (m, 1H), 5.52-5.68 (m, 2H) .MS m / z: 557 (M+-OSitBuMe2), 500 (100%). UV λmax nm: 270, 281, 293.
[0213]
Example 78
Preparation of 1α, 3β-dihydroxy-20 (S)-{3-ethyl-2 (S) -hydroxypentylthio} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{3-ethyl-2 (S) -hydroxypentylthio} pregna-5,7,16-triene (55.3 mg, 0.0802 mmol) ), Tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted in the same manner as in Example 9 (heated reflux, 5 hours), after workup, preparative thin layer chromatography (0.5 mm × 2 sheets, dichloromethane: ethanol = 9: 1, developed once) to obtain the title compound (35.5 mg, 96%) as a white solid.
[0214]
IR (KBr): 3390, 2950, 2920, 2870, 1460, 1365, 1045, 1030, 1020cm-1.1H NMR (CDClThree/ CDThreeOD) δ: 0.91 (t, J = 7.3Hz, 6H), 0.94 (s, 3H), 0.97 (s, 3H), 1.44 (d, J = 6.9Hz, 3H), 2.68 (dd, J = 13.4, 3.5Hz, 1H), 2.78-2.90 (m, 1H), 3.43-3.73 (m, 2H), 3.75 (brs, 1H), 3.92-4.08 (m, 1H), 5.40-5.49 (m, 1H), 5.66 (brs, 1H), 5.68-5.76 (m, 1H) .MS m / z: 460 (M+), 315 (100%). UV λmax nm: 270, 281, 293.
[0215]
Example 79
Preparation of 1α, 3β-dihydroxy-20 (S)-{3-ethyl-2 (R) -hydroxypentylthio} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{3-ethyl-2 (R) -hydroxypentylthio} pregna-5,7,16-triene (54.9 mg, 0.0797 mmol) ), Tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was reacted in the same manner as in Example 9 (heated reflux, 5 hours), after workup, preparative thin layer chromatography (0.5 mm × 2 sheets, dichloromethane: ethanol = 9: 1, developed once) to obtain the title compound (37.9 mg, 100%) as a colorless oil.
[0216]
IR (neat): 3400, 2962, 2929, 2873, 1460, 1369, 1055, 1030cm-1.1H NMR δ: 0.90 (t, J = 7.3Hz, 6H), 0.92 (s, 3H), 0.98 (s, 3H), 1.43 (d, J = 6.9Hz, 3H), 2.68 (dd, J = 13.5, 3.0Hz, 1H), 2.75-2.87 (m, 1H), 3.55 (q, J = 6.9Hz, 1H), 3.56-3.67 (m, 1H), 3.79 (brs, 1H), 3.99-4.16 (m, 1H ), 5.41-5.50 (m, 1H), 5.63 (brs, 1H), 5.70-5.79 (m, 1H) .MS m / z: 460 (M+), 313 (100%). UV λmax nm: 270, 281, 293.
[0217]
Example 80
Preparation of 1α, 3β-dihydroxy-20 (S)-{3-ethyl-2 (S) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-dihydroxy-20 (S)-{3-ethyl-2 (S) -hydroxypentylthio} pregna-5,7,16-triene (33.0 mg, 0.0716 mmol), ethanol (200 ml) was used. , Reaction in the same manner as in Example 15 (light irradiation 3.25 minutes, heating under reflux 2 hours), post-treatment, preparative thin-layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 14) : 6: 1, developed twice, and further purified by 0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 10: 10: 1, developed three times) to give the title compound (1.81 mg, 5. 5%).
[0218]
IR (neat): 3367, 2960, 2873, 1456, 1369, 1055cm-1.1H NMR δ: 0.85 (s, 3H), 0.90 (t, J = 7.3Hz, 6H), 1.43 (d, J = 6.9Hz, 3H), 2.47 (dd, J = 13.3, 9.6Hz, 1H), 2.55 -2.68 (m, 1H), 2.71 (dd, J = 13.3, 3.0Hz, 1H), 2.78-2.89 (m, 1H), 3.47 (q, J = 6.8Hz, 1H), 3.60-3.72 (m, 1H ), 4.19-4.31 (m, 1H), 4.40-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H) .MS m / z: 460 (M+), 312 (100%). UV λmax nm: 263.
[0219]
Example 81
Production of 1α, 3β-dihydroxy-20 (S)-{3-ethyl-2 (R) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-dihydroxy-20 (S)-{3-ethyl-2 (R) -hydroxypentylthio} pregna-5,7,16-triene (34.1 mg, 0.0740 mmol), ethanol (200 ml) was used. , Reaction in the same manner as in Example 15 (light irradiation 3.25 minutes, heating under reflux 2 hours), post-treatment, preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 10) : 10: 1, developed twice, further 0.25 mm × 1 piece, dichloromethane: ethanol = 18: 1, developed three times) to give the title compound (2.13 mg, 6.2%) as a colorless oil. It was.
[0220]
IR (neat): 3369, 2960, 2929, 2873, 1446, 1369, 1055cm-1.1H NMR δ: 0.82 (s, 3H), 0.90 (t, J = 7.1Hz, 6H), 1.42 (d, J = 6.9Hz, 3H), 2.75-2.89 (m, 1H), 3.51 (q, J = 6.9Hz, 1H), 3.57-3.68 (m, 1H), 4.18-4.31 (m, 1H), 4.39-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs , 1H), 6.11 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H) .MS m / z: 460 (M+), 312 (100%). UV λmax nm: 263.
[0221]
Example 82
1α, 3β-dihydroxy-20 (R)-{3-ethyl-2 (R) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene and 1α, 3β-dihydroxy Preparation of -20 (R)-{3-ethyl-2 (S) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -phenoxycarbonylthio-9,10-secopregna-5,7,10 (19), 16-tetraene (24.5 mg, 0.0352 mmol) 1,2-epoxy-3-ethylpentane (80.4 mg, 0.704 mmol), tetrahydrofuran (1 ml), 1M-KOH methanol solution (1 ml) in the same manner as in Example 71 (at room temperature, 1 hour) ), After workup, purified by preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate = 4: 1, developed once), and 1α, 3β-bis (tert-butyldimethylsilyloxy) ) -20 (R)-(3-ethyl-2-hydroxypentylthio) -9,10-secopregna-5,7,10 (19), 16 Tetraene (diastereomeric mixture, 18.5mg) was obtained. Of this, 17.2 mg was dissolved in dichloromethane (1 ml), and 4-dimethylaminopyridine (15.3 mg, 0.125 mmol) and (1S)-(−)-camphanic chloride (13.5 mg, 0.0625 mmol) were added. After stirring at room temperature for 15 minutes, the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed with ice-cold 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over magnesium sulfate. Remove the solvent under reduced pressure and purify by preparative thin-layer chromatography (0.5 mm x 1 plate, hexane: benzene: ethyl acetate = 10: 20: 1, developed twice), low polar component and high polar component Separated. Next, each was dissolved in tetrahydrofuran (1 ml), 1M-sodium methoxide methanol solution (0.5 ml) was added, and the mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate = 4: 1, developed once) to obtain 1α, 3β-bis (tert -Butyldimethylsilyloxy) -20 (R)-{3-ethyl-2 (R) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene and 1α, 3β- Bis (tert-butyldimethylsilyloxy) -20 (R)-{3-ethyl-2 (S) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene is obtained. It was. Each compound and tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.5 ml) were reacted in the same manner as in Example 9 (60 ° C., 2 hours). Purification by thin layer chromatography (0.25 mm × 1 sheet, hexane: ethyl acetate: ethanol = 12: 8: 1, developed three times) and 1α, 3β-dihydroxy-20 (R)-{3- Ethyl-2 (R) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene (3.09 mg, 20%) and colorless oily 1α, 3β-dihydroxy-20 ( R)-{3-Ethyl-2 (S) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene (2.95 mg) To obtain a 20%).
[0222]
1α, 3β-dihydroxy-20 (R)-{3-ethyl-2 (R) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene:
IR (neat): 3361, 2960, 2929, 2873, 1446, 1371, 1290, 1217, 1055cm-1.1H NMR δ: 0.72 (s, 3H), 0.91 (t, J = 7.1Hz, 6H), 1.47 (d, J = 6.9Hz, 3H), 2.54-2.67 (m, 1H), 2.72-2.90 (m, 2H), 3.37 (q, J = 6.9Hz, 1H), 3.58-3.70 (m, 1H), 4.18-4.29 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). MS m / z: 460 (M+), 312 (100%). UV λmax nm: 263.
[0223]
1α, 3β-dihydroxy-20 (R)-{3-ethyl-2 (S) -hydroxypentylthio} -9,10-secopregna-5,7,10 (19), 16-tetraene:
IR (neat): 3369, 2960, 2929, 2873, 1448, 1371, 1290, 1211, 1055cm-1.1H NMR δ: 0.75 (s, 3H), 0.90 (t, J = 7.1Hz, 6H), 1.46 (d, J = 6.9Hz, 3H), 2.48 (dd, J = 13.5, 9.6Hz, 1H), 2.55 -2.66 (m, 1H), 2.72 (dd, J = 13.5, 3.1Hz, 1H), 2.76-2.88 (m, 1H), 3.41 (q, J = 6.9Hz, 1H), 3.57-3.70 (m, 1H ), 4.18-4.30 (m, 1H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.60 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H) .MS m / z: 460 (M+), 312 (100%). UV λmax nm: 263.
[0224]
Example 83
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol) in tetrahydrofuran (1 ml) at 60 ° C. Stir for hours. After returning to room temperature, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 40: 1, developed once) to give the title compound (82.4 mg, 99%) as a colorless oil. Obtained.
[0225]
IR (neat): 2950, 2875, 1460, 1370, 1250, 1160, 1090, 1040cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.67 (q, J = 7.8Hz, 6H), 0.89 (s, 18H), 0.96 (t, J = 7.8Hz, 9H), 1.32 (d, J = 6.5Hz, 3H), 1.46 (s, 6H), 3.70 (brs, 1H), 3.76-3.83 (m, 1H), 3.94-4.39 (m, 3H), 5.35-5.44 (m, 1H), 5.56-5.66 (m, 2H). UV λmax nm: 270, 281, 293.
[0226]
Example 84
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)} pregna-5,7,16-triene Manufacturing of
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl) and (E) -1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol), tetrahydrofuran (1 ml) After reaction and post-treatment under the same conditions as in Example 83, purification by preparative thin-layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 40: 1, developed once) gave the title compound (85 .9 mg, 99%).
[0227]
IR (neat): 2950, 2850, 1460, 1370, 1250, 1150, 1040cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.57 (q, J = 7.8Hz, 6H), 0.89 (s, 18H), 0.94 (t, J = 7.8Hz, 9H), 1.31 (s, 6H), 3.72 (brs, 1H), 3.79-4.18 (m, 4H), 5.37-5.45 (m, 1H), 5.57-5.83 (m, 4H). UV λmax nm: 270, 281, 293.
[0228]
Example 85
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)} pregna-5,7,16-triene Manufacturing of
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl) and (Z) -1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol), tetrahydrofuran (1 ml) After reaction and post-treatment under the same conditions as in Example 83, purification by preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 30: 1, developed once) gave the title compound (80 0.7 mg, 98%).
[0229]
IR (neat): 2950, 2850, 1460, 1370, 1255, 1170, 1100, 1040cm-1.1H NMR δ: 0.05 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.58 (q, J = 7,8Hz, 6H), 0.88 (s, 18H), 0.94 (t, J = 7.8Hz, 9H), 1.32 (s, 6H), 3.71 (brs, 1H), 3.93-4.14 (m, 2H), 4.16-4.36 (m, 2H), 5.29-5.44 (m, 3H), 5.57- 5.66 (m, 2H). UV λmax nm: 270, 281, 293.
[0230]
Example 86
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 21.0 mg) , 0.525 mmol), 15-crown-5 (10 μl), 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol), tetrahydrofuran (1 ml) as in Example 83. After reaction under the conditions and after-treatment, the product was purified by preparative thin-layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 40: 1, developed once) to give the title compound as a colorless oil (79.0 mg, 92 %).
[0231]
IR (neat): 2950, 2850, 1460, 1375, 1255, 1080, 1010cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.67 (q, J = 7.8Hz, 6H), 0.89 (s, 18H), 1.32 (d, J = 6.4Hz, 3H), 3.72 (brs, 1H), 3.95-4.32 (m, 4H), 5.36-5.44 (m, 1H), 5.58-5.68 (m, 2H). MS m / z: 796 (M+), 278 (100%). UV λmax nm: 270, 281, 293.
[0232]
Example 87
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)} pregna-5,7,16-triene Manufacturing of
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl), (E) -1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (134 mg, 0.420 mmol), tetrahydrofuran (1 ml) After reaction and post-treatment under the same conditions as in Example 83, purification by preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 40: 1, developed once) gave the title compound (86 0.0 mg, 100%).
[0233]
IR (neat): 2950, 2850, 1460, 1375, 1255, 1100, 1000cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.58 (q, J = 7.8Hz, 6H), 0.89 (s, 18H), 1.31 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 3.70-4.19 (m, 4H), 5.37-5.45 (m, 1H), 5.49-5.76 (m, 4H). UV λmax nm: 270, 281, 293.
[0234]
Example 88
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)} pregna-5,7,16-triene Manufacturing of
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl), (Z) -1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol), tetrahydrofuran (1 ml) After reaction and post-treatment under the same conditions as in Example 83, purification by preparative thin-layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 40: 1, developed once) gave the title compound (83 .6 mg, 98%).
[0235]
IR (neat): 2950, 2850, 1460, 1370, 1250 1100 1000cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.60 (q, J = 7.5Hz, 6H), 0.89 (s, 18H), 1.32 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 3.89-4.47 (m, 4H), 5.09-5.20 (m, 1H), 5.35-5.66 (m, 4H) .MS m / z: 798 (M+), 277 (100%). UV λmax nm: 270, 281, 293.
[0236]
Example 89
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl), 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol), tetrahydrofuran (1 ml) as in Example 83. After reaction under the conditions and after-treatment, the product was purified by preparative thin-layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 40: 1, developed once) and purified as a colorless oil of the title compound (76.4 mg, 93 %).
[0237]
IR (neat): 2950, 2850, 1465, 1375, 1250, 1160, 1090, 1040cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.67 (q, J = 7.8Hz, 6H), 0.85 (s, 3H), 0.89 (s, 18H) , 0.95 (s, 3H), 0.96 (t, J = 7.8Hz, 9H), 1.33 (d, J = 6.6Hz, 3H), 1.48 (s, 6H), 3.71 (brs, 1H), 3.93-4.32 ( m, 4H), 5.36-5.45 (m, 1H), 5.58-5.66 (m, 1H), 5.60 (brs, 1H). UV λmax nm: 270, 281, 293.
[0238]
Example 90
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)} pregna-5,7,16-triene Manufacturing of
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl) and (E) -1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol), tetrahydrofuran (1 ml) After reaction and post-treatment under the same conditions as in Example 83, purification by preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 30: 1, developed once) gave the title compound (73 .4 mg, 89%).
[0239]
IR (neat): 2950, 2850, 1460, 1370, 1250, 1150, 1095, 1040cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.58 (q, J = 7.8Hz, 6H), 0.85 (s, 3H), 0.88 (s, 9H) , 0.89 (s, 9H), 0.94 (t, J = 7.8Hz, 9H), 0.94 (s, 3H), 1.30, (s, 6H), 1.33 (d, J = 5.1Hz, 3H), 3.71 (brs , 1H), 3.83-4.16 (m, 4H), 5.35-5.45 (m, 1H), 5.57-5.88 (m, 4H). UV λmax nm: 270, 281, 293.
[0240]
Example 91
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{(Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)} pregna-5,7,16-triene Manufacturing of
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl) and (Z) -1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol), tetrahydrofuran (1 ml) After reaction and post-treatment under the same conditions as in Example 83, purification by preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 30: 1, developed once) gave the title compound (70 .3 mg, 85%).
[0241]
IR (neat): 2950, 2850, 1460, 1375, 1255, 1170, 1100, 1040cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.59 (q, J = 7.9Hz, 6H), 0.86 (s, 3H), 0.88 (s, 9H) , 0.89 (s, 9H), 0.95 (t, J = 7.9Hz, 9H), 0.95 (s, 3H), 1.32 (s, 6H), 1.33 (d, J = 4.9Hz, 3H), 3.71 (brs, 1H), 3.96-4.13 (m, 2H), 4.23-4.38 (m, 2H), 5.29-5.47 (m, 3H), 5.58-5.68 (m, 2H). UV λmax nm: 270, 281, 293.
[0242]
Example 92
Preparation of 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (58.9 mg, 0.105 mmol), sodium hydride (60%, 21.0 mg) , 0.525 mmol), 15-crown-5 (10 μl), 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol), tetrahydrofuran (1 ml) as in Example 83. After reaction under the conditions and after-treatment, the product was purified by preparative thin-layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 19: 1, developed once) to give the title compound as a colorless oil (60.2 mg, 72 %).
[0243]
IR (neat): 2950, 2850, 1460, 1370, 1250, 1085cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.67 (q, J = 7.3Hz, 6H), 0.88 (s, 9H), 0.89 (s, 9H) , 1.33 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 3.97-4.35 (m, 4H), 5.35-5.44 (m, 1H), 5.58-5.64 (m, 1H), 5.67 (brs , 1H) .MS m / z: 796 (M+), 301 (100%). UV λmax nm: 270, 281, 293.
[0244]
Example 93
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)} pregna-5,7,16-triene Manufacturing of
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl), (E) -1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (134 mg, 0.420 mmol), tetrahydrofuran (1 ml) After reaction and post-treatment under the same conditions as in Example 83, purification by preparative thin-layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 40: 1, developed once) gave the title compound as a colorless oil (62 .4 mg, 73%).
[0245]
IR (neat): 2950, 2870, 1460, 1375, 1255, 1070cm-1.1H NMR δ: 0.06 (s, 3H), 0.07 (s, 6H), 0.11 (s, 3H), 0.58 (q, J = 7.8Hz, 6H), 0.88 (s, 9H), 0.89 (s, 9H) , 1.32 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 3.88-4.14 (m, 4H), 5.36-5.44 (m, 1H), 5.54-5.76 (m, 4H). MS m / z: 798 (M+), 609 (100%). UV λmax nm: 270, 281, 293.
[0246]
Example 94
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)} pregna-5,7,16-triene Manufacturing of
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg) , 0.428 mmol), 15-crown-5 (10 μl), (Z) -1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol), tetrahydrofuran (1 ml) After reaction and post-treatment under the same conditions as in Example 83, purification by preparative thin layer chromatography (0.5 mm × 2 sheets, hexane: ethyl acetate = 40: 1, developed once) gave the title compound (84 .6 mg, 99%).
[0247]
IR (neat): 2950, 2850, 1460, 1375, 1255, 1100, 1070cm-1.1H NMR δ: 0.05 (s, 3H), 0.06 (s, 6H), 0.11 (s, 3H), 0.61 (q, J = 7.8Hz, 6H), 0.88 (s, 9H), 0.89 (s, 9H) , 1.32 (d, J = 6.6Hz, 3H), 3.71 (brs, 1H), 4.15-4.24 (m, 2H), 4.23-4.38 (m, 2H), 5.13 (dt, J = 12.5, 2.2Hz, 1H ), 5.35-5.42 (m, 1H), 5.50 (dt, J = 12.2, 5.0Hz, 1H), 5.59-5.69 (m, 2H) .MS m / z: 798 (M+), 610 (100%). UV λmax nm: 270, 281, 293.
[0248]
Example 95
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-hydroxy-4-methyl-2-pentynyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy) pregna-5,7,16-triene (80.0 mg, 0.104 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml), and the reaction in the same manner as in Example 9 (heating under reflux, 5.5 hours), after the post-treatment, Purification by preparative thin layer chromatography (0.5 mm × 1, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) gave the title compound (14.0 mg, 32%) as a pale yellow oil. Obtained.
[0249]
IR (neat): 3400, 2980, 2940, 2850, 1450, 1370, 1230, 1170, 1060cm-1.1H NMR δ: 0.90 (s, 3H), 0.99 (s, 3H), 1.33 (d, J = 6.4Hz, 3H), 1.52 (s, 6H), 3.79 (brs, 1H), 3.98-4.23 (m, 4H), 5.43-5.50 (m, 1H), 5.66 (brs, 1H), 5.70-5.80 (m, 1H). UV λmax nm: 270, 281, 293.
[0250]
Example 96
Preparation of 1α, 3β-dihydroxy-20 (S)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)} pregna-5,7,16-triene (83.0 mg, 0.108 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride Tetrahydrofuran solution (2 ml) was used for the reaction in the same manner as in Example 9 (heating under reflux, 5.5 hours) After the workup, the product was purified by preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once), and the title compound (15.9 mg) developed as a pale yellow oil. 34%).
[0251]
IR (neat): 3400, 2950, 2850, 1460, 1370, 1230, 1150, 1050cm-1.1H NMR δ: 0.89 (s, 3H), 0.99 (s, 3H), 1.33 (s, 6H), 3.71-4.12 (m, 5H), 5.42-5.51 (m, 1H), 5.63 (brs, 1H), 5.66-5.92 (m, 3H). UV λmax nm: 270, 281, 293.
[0252]
Example 97
Preparation of 1α, 3β-dihydroxy-20 (S)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)} pregna-5,7,16-triene (78.0 mg, 0.101 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride Tetrahydrofuran solution (2 ml) was used for the reaction in the same manner as in Example 9 (heating under reflux, 5.5 hours). After the post-treatment, the product was purified by preparative thin-layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) to give the title compound as a colorless oil (32.0 mg, 74%).
[0253]
IR (neat): 3400, 2960, 2850, 1460, 1375, 1260, 1150, 1050cm-1.1H NMR δ: 0.89 (s, 3H), 0.97 (s, 3H), 1.34 (s, 6H), 3.76 (brs, 1H), 3.96-4.24 (m, 4H), 5.35-5.51 (m, 2H), 5.59-5.78 (m, 3H). UV λmax nm: 270, 281, 293.
[0254]
Example 98
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-ethyl-4-hydroxy-2-hexynyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy) pregna-5,7,16-triene (79.0 g, 0. 0991 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride in tetrahydrofuran (2 ml) and reacted in the same manner as in Example 9 (heated reflux, 5.5 hours), after workup, preparative Purification by thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) to obtain the title compound (43.5 mg, 96%) as a colorless oil.
[0255]
IR (neat): 3400, 2960, 2930, 2850, 1460, 1370, 1260, 1195, 1150, 1050cm-1.1H NMR δ: 0.90 (s, 3H), 0.99 (s, 3H), 1.03 (t, J = 7.8Hz, 6H), 1.33 (d, J = 6.6Hz, 3H), 3.79 (brs, 1H), 4.02 -4.31 (m, 4H), 5.43-5.52 (m, 1H), 5.66 (brs, 1H), 5.72-5.80 (m, 1H) .MS m / z: 454 (M+), 263 (100%). UV λmax nm: 270, 281, 293.
[0256]
Example 99
Preparation of 1α, 3β-dihydroxy-20 (S)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)} pregna-5,7,16-triene (84.0 mg, 0.105 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride Tetrahydrofuran solution (2 ml) was used for the reaction in the same manner as in Example 9 (heating under reflux, 5.5 hours). After the post-treatment, the product was purified by preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once), and the title compound (37.3 mg, 78%) was obtained.
[0257]
IR (neat): 3400, 2960, 2925, 2850, 1460, 1371, 1255, 1200 1150, 1055cm-1.1H NMR δ: 0.87 (t, J = 7.4Hz, 6H), 0.89 (s, 3H), 0.98 (s, 3H), 1.32 (d, J = 6.6Hz, 3H), 1.55 (q, J = 7.4Hz , 4H), 3.78 (brs, 1H), 3.86 (dd, J = 12.6, 5.3Hz, 1H), 3.94-4.09 (m, 3H), 5.41-5.51 (m, 1H), 5.58-5.73 (m, 4H ). UV λmax nm: 270, 281, 293.
[0258]
Example 100
Preparation of 1α, 3β-dihydroxy-20 (S)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)} pregna-5,7,16-triene (81.3 mg, 0.102 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride Tetrahydrofuran solution (2 ml) was used for the reaction in the same manner as in Example 9 (heating under reflux, 5.5 hours) After the workup, the product was purified by preparative thin-layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) to give the title compound as a pale yellow oil (44.0 mg). 94%).
[0259]
IR (neat): 3400, 2965, 2930, 2850, 1460, 1370, 1275, 1150, 1050cm-1.1H NMR δ: 0.89 (s, 3H), 0.90 (t, J = 7.4Hz, 6H), 0.98 (s, 3H), 1.33 (d, J = 6.6Hz, 3H), 1.54 (q, J = 7.4Hz , 4H), 3.78 (brs, 1H), 3.98-4.24 (m, 4H), 5.37-5.49 (m, 2H), 5.54-5.68 (m, 2H), 5.71-5.78 (m, 1H). UV λmax nm: 270, 281, 293.
[0260]
Example 101
Preparation of 1α, 3β-dihydroxy-20 (R)-(4-hydroxy-4-methyl-2-pentynyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy) pregna-5,7,16-triene (74.1 mg, 0.0963 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml), and the reaction in the same manner as in Example 9 (heating under reflux, 5.5 hours), after the post-treatment, Purification by preparative thin layer chromatography (0.5 mm × 1, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) gave the title compound (21.0 mg, 51%) as a pale yellow oil. Obtained.
[0261]
IR (neat): 3400, 2970, 2920, 2850, 1450, 1370, 1230, 1160, 1050cm-1.1H NMR δ: 0.85 (s, 3H), 0.97 (s, 3H), 1.35 (d, J = 6.4Hz, 3H), 1.52 (s, 6H), 3.78 (m, 1H), 5.41-5.50 (m, 1H), 5.64-5.78 (m, 2H). UV λmax nm: 270, 281, 293.
[0262]
Example 102
Preparation of 1α, 3β-dihydroxy-20 (R)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)} pregna-5,7,16-triene (71.0 mg, 0.0920 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride Tetrahydrofuran solution (2 ml) was used for the reaction in the same manner as in Example 9 (heating under reflux, 5.5 hours) After the workup, the product was purified by preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) to give the title compound (34.0 mg, 86%).
[0263]
IR (neat): 3400, 2960, 2925, 2850, 1460, 1370, 1240, 1150, 1055cm-1.1H NMR δ: 0.85 (s, 3H), 0.97 (s, 3H), 1.32 (s, 6H), 3.77 (brs, 1H), 3.85-4.16 (m, 4H), 5.40-5.50 (m, 1H), 5.61-5.91 (m, 4H). UV λmax nm: 270, 281, 293.
[0264]
Example 103
Preparation of 1α, 3β-dihydroxy-20 (R)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{(Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)} pregna-5,7,16-triene (67.9 mg, 0.0880 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was used, and the reaction was carried out in the same manner as in Example 9 (heating under reflux, 5.5 hours). After the post-treatment, the product was purified by preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) to give the title compound as a white solid (32.0 mg, 85%).
[0265]
IR (KBr): 3400, 2960, 2920, 2850, 1460, 1370, 1200, 1170, 1135, 1080, 1060, 1035cm-1.1H NMR (CDClThree/ CDThreeOD) δ: 0.86 (s, 3H), 0.96 (s, 3H), 1.33 (s, 6H), 1.37 (d, J = 6.6Hz, 3H), 3.74 (brs, 1H), 3.90-4.27 (m, 4H), 5.36-5.50 (m, 2H), 5.55-5.76 (m, 3H). UV λmax nm: 270, 281, 293.
[0266]
Example 104
Preparation of 1α, 3β-dihydroxy-20 (R)-(4-ethyl-4-hydroxy-2-hexynyloxy) pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy) pregna-5,7,16-triene (58.2 mg,. 0730 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride in tetrahydrofuran (2 ml) and reacted in the same manner as in Example 9 (heated reflux, 5.5 hours). Purification by thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) to give the title compound (33.5 mg, 100%) as a colorless oil.
[0267]
IR (neat): 3400, 2960, 2930, 2850, 1460, 1370, 1325, 1260, 1195, 1150, 1060, 1035cm-1.1H NMR δ: 0.85 (s, 3H), 0.98 (s, 3H), 1.03 (t, J = 7.4Hz, 6H), 1.34 (d, J = 6.6Hz, 3H), 3.78 (brs, 1H), 4.00 -4.32 (m, 4H), 5.41-5.50 (m, 1H), 5.68 (brs, 1H), 5.71-5.80 (m, 1H). UV λmax nm: 270, 281, 293.
[0268]
Example 105
Preparation of 1α, 3β-dihydroxy-20 (R)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)} pregna-5,7,16-triene (60.3 mg, 0.0754 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride Tetrahydrofuran solution (2 ml) was used for the reaction in the same manner as in Example 9 (heating under reflux, 5.5 hours) After the post-treatment, the product was purified by preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) to give the title compound as a pale yellow oil (14.5 mg). 42%).
[0269]
IR (neat): 3400, 2960, 2930, 2850, 1460, 1375, 1330, 1270, 1150, 1060, 1035cm-1.1H NMR δ: 0.86 (s, 3H), 0.86 (t, J = 7.3Hz, 6H), 0.98 (s, 3H), 1.33 (d, J = 6.6Hz, 3H), 1.55 (q, J = 7.6Hz , 4H), 3.78 (brs, 1H), 3.91-4.20 (m, 4H), 5.42-5.52 (m, 1H), 5.58-5.82 (m, 4H). UV λmax nm: 270, 281, 293.
[0270]
Example 106
Preparation of 1α, 3β-dihydroxy-20 (R)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)} pregna-5,7,16-triene (82.0 mg, 0.103 mmol), tetrahydrofuran (3 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (2 ml) was used in the same manner as in Example 9 (heating under reflux, 5.5 hours). After working up, purification by preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 20: 80: 1, developed once) gave the title compound as a white solid (46.1 mg, 98%).
[0271]
IR (KBr): 3400, 2960, 2930, 2850, 1460, 1370, 1325, 1270, 1250, 1200, 1150, 1060cm-1.1H NMR δ: 0.86 (s, 3H), 0.90 (t, J = 7.4Hz, 6H), 0.98 (s, 3H), 1.36 (d, J = 6.4Hz, 3H), 1.54 (q, J = 7.4Hz , 4H), 3.77 (brs, 1H), 3.99-4.22 (m, 4H), 5.35-5.49 (m, 2H), 5.55-5.70 (m, 2H), 5.71-5.79 (m, 1H). UV λmax nm: 270, 281, 293.
[0272]
Example 107
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-hydroxy-4-methyl-2-pentynyloxy) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-dihydroxy-20 (S)-(4-hydroxy-4-methyl-2-pentynyloxy) pregna-5,7,16-triene (13.0 mg, 0.0305 mmol), ethanol (200 ml). And reaction in the same manner as in Example 15 (light irradiation for 2.5 minutes, heating under reflux for 1.5 hours), post-treatment, preparative thin-layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate: (Ethanol = 8: 12: 1, developed twice, 0.25 mm × 1 sheet, dichloromethane: ethyl acetate: ethanol = 10: 10: 1, developed twice, further dichloromethane: ethanol = 19: 1, developed three times)) Purification gave the title compound (0.758 mg, 5.8%) as a colorless oil.
[0273]
IR (neat): 3369, 2929, 2852, 1442, 1369, 1234, 1167, 1060cm-1.1H NMR δ: 0.79 (s, 3H), 1.33 (d, J = 6.6Hz, 3H), 1.52 (s, 6H), 4.03 (d, J = 15.4Hz, 1H), 4.14 (m, 1H), 4.15 (d, J = 15.4Hz, 1H), 4.19-4.30 (m, 1H), 4.41-4.51 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H) .MS m / z: 367 (M+-C (CHThree)2OH), 129 (100%). UV λmax nm: 264.
[0274]
Example 108
1α, 3β-dihydroxy-20 (S)-(E)-(4-hydroxy-4-methyl-2-pentenyloxy)}-9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing
1α, 3β-dihydroxy-20 (S)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)} pregna-5,7,16-triene (14.5 mg, 0.0338 mmol), After performing the reaction in the same manner as in Example 15 using ethanol (200 ml) (light irradiation for 2.5 minutes, heating under reflux for 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, dichloromethane: Purified with ethyl acetate: ethanol = 10: 10: 1, developed twice, further 0.25 mm × 1 sheet, dichloromethane: ethanol = 18: 1, developed three times) to give the title compound as a colorless oil (1.41 mg, 9 0.7%).
[0275]
IR (neat): 3400, 2929, 2850, 1446, 1369, 1220, 1153, 1101, 1055cm-1.1H NMR δ: 0.79 (s, 3H), 1.33 (s, 6H), 3.81 (dd, J = 6.3, 5.6Hz, 1H), 3.89-4.04 (m, 2H), 4.17-4.30 (m, 1H), 4.38-4.50 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.59 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.27 (d, J = 11.2Hz , 1H) .MS m / z: 410 (M+-H2O), 134 (100%). UV λmax nm: 264.
[0276]
Example 109
1α, 3β-dihydroxy-20 (S)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)}-9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing of
1α, 3β-dihydroxy-20 (S)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)} pregna-5,7,16-triene (30.0 mg, 0.0700 mmol), After reacting in the same manner as in Example 15 using ethanol (200 ml) (light irradiation 3.5 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: Purified by ethyl acetate: ethanol = 8: 12: 1, developed twice, further 0.25 mm × 1 sheet dichloromethane: ethanol = 16: 1, developed three times) to give the title compound as colorless oil (3.04 mg, 10%) )
[0277]
IR (neat): 3369, 2972, 2929, 2850, 1446, 1371, 1169, 1055cm-1.1H NMR δ: 0.78 (s, 3H), 1.34 (s, 6H), 2.54-2.68 (m, 1H), 2.75-2.88 (m, 1H), 3.95-4.30 (m, 4H), 4.38-4.50 (m , 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.44 (dt, J = 12.2, 5.6Hz, 1H), 5.58-5.70 (m, 2H), 6.11 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H) .UV λmax nm: 263.
[0278]
Example 110
Preparation of 1α, 3β-dihydroxy-20 (S)-(4-ethyl-4-hydroxy-2-hexynyloxy) -9,10-secopregna-5,7,10 (19), 16-tetraene
Using 1α, 3β-dihydroxy-20 (S)-(4-ethyl-4-hydroxy-2-hexynyloxy) pregna-5,7,16-triene (40.0 mg, 0.0880 mmol), ethanol (200 ml), After performing the reaction in the same manner as in Example 15 (light irradiation for 2.5 minutes, heating under reflux for 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate: ethanol = 8: 12: 1, developed twice, further 0.25 mm × 1 piece, dichloromethane: ethanol = 19: 1, developed three times) to give the title compound (2.76 mg, 6.9%) as a colorless oil. .
[0279]
IR (neat): 3369, 2970, 2931, 2850, 1442, 1369, 1263, 1182, 1146, 1057cm-1.1H NMR δ: 0.79 (s, 3H), 1.03 (t, J = 7.4Hz, 6H), 1.32 (d, J = 6.3Hz, 3H), 2.55-2.65 (m, 1H), 2.77-2.88 (m, 1H), 4.06 (d, J = 15.5Hz, 1H), 4.14-4.31 (m, 3H), 4.38-4.53 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.61 (brs , 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H) .UV λmax nm: 264.
[0280]
Example 111
1α, 3β-dihydroxy-20 (S)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)}-9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing of
1α, 3β-dihydroxy-20 (S)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)} pregna-5,7,16-triene (35.0 mg, 0.0766 mmol), After reacting in the same manner as in Example 15 using ethanol (200 ml) (light irradiation 3.5 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: Purified by ethyl acetate: ethanol = 8: 12: 1, developed twice, further 0.25 mm × 1 sheet, dichloromethane: ethanol = 16: 1, developed three times) to give the title compound as a colorless oil (3.94 mg, 11 %).
[0281]
IR (neat): 3400, 2968, 2931, 2850, 1446, 1369, 1101, 1055cm-1.1H NMR δ: 0.79 (s, 3H), 0.86 (t, J = 7.4Hz, 6H), 2.55-2.68 (m, 1H), 2.77-2.89 (m, 1H), 3.86 (dd, J = 12.4, 5.4 Hz, 1H), 3.93-4.06 (m, 2H), 4.18-4.31 (m, 1H), 4.39-4.52 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.58 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H) .MS m / z: 456 (M+), 134 (100%). UV λmax nm: 263.
[0282]
Example 112
1α, 3β-dihydroxy-20 (S)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)}-9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing of
1α, 3β-dihydroxy-20 (S)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)} pregna-5,7,16-triene (41.0 mg, 0.0898 mmol), After reacting in the same manner as in Example 15 using ethanol (200 ml) (light irradiation 3.75 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: Purified with ethyl acetate: ethanol = 8: 12: 1, developed twice, further 0.25 mm × 1 sheet, dichloromethane: ethanol = 16: 1, developed three times) to give the title compound as a colorless oil (1.58 mg, 3 0.9%).
[0283]
IR (neat): 3400, 2968, 2929, 2850, 1448, 1371, 1055cm-1.1H NMR δ: 0.78 (s, 3H), 0.90 (t, J = 7.4Hz, 3H), 0.91 (t, J = 7.4Hz, 3H), 1.34 (d, J = 6.3Hz, 3H), 2.55-2.65 (m, 1H), 2.78-2.88 (m, 1H), 3.95-4.31 (m, 4H), 4.39-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.42 (d , J = 12.5Hz, 1H), 5.55-5.69 (m, 2H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
[0284]
Example 113
Preparation of 1α, 3β-dihydroxy-20 (R)-(4-hydroxy-4-methyl-2-pentynyloxy) -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-dihydroxy-20 (R)-(4-hydroxy-4-methyl-2-pentynyloxy) pregna-5,7,16-triene (20.0 mg, 0.0469 mmol), ethanol (200 ml). And after carrying out the reaction in the same manner as in Example 15 (light irradiation for 3 minutes, heating under reflux for 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate: ethanol = 8: 12: 1, developed twice, 0.25 mm × 1 piece, dichloromethane: ethyl acetate: ethanol = 10: 10: 1, developed twice, further dichloromethane: ethanol = 19: 1, developed three times), colorless The title compound was obtained as an oil (1.19 mg, 5.9%).
[0285]
IR (neat): 3400, 2976, 2929, 2852, 1444, 1373, 1234, 1167, 1063cm-1.1H NMR δ: 0.75 (s, 3H), 1.33 (d, J = 6.3Hz, 3H), 1.52 (s, 6H), 2.55-2.66 (m, 1H), 2.76-2.86 (m, 1H), 4.03- 4.31 (m, 4H), 4.40-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.56 (brs, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 264.
[0286]
Example 114
1α, 3β-dihydroxy-20 (R)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)}-9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing of
1α, 3β-dihydroxy-20 (R)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)} pregna-5,7,16-triene (31.8 mg, 0.0742 mmol), After reacting in the same manner as in Example 15 using ethanol (200 ml) (light irradiation 3.5 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: Purified with ethyl acetate: ethanol = 10: 10: 1, developed twice, further 0.25 mm × 1 sheet, dichloromethane: ethanol = 18: 1, developed three times) to give the title compound as a colorless oil (3.03 mg, 9 .5%).
[0287]
IR (neat): 3390, 2972, 2931, 2850, 1448, 1371, 1217, 1153, 1095, 1057cm-1.1H NMR δ: 0.75 (s, 3H), 1.33 (s, 6H), 2.56-2.68 (m, 1H), 2.78-2.88 (m, 1H), 3.85-4.08 (m, 3H), 4.18-4.30 (m , 1H), 4.39-5.00 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.62 (brs, 1H), 5.73 (dt, J = 15.8, 5.3Hz, 1H), 5.85 ( d, J = 15.8Hz, 1H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H) .UV λmax nm: 263.
[0288]
Example 115
1α, 3β-dihydroxy-20 (R)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)}-9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing of
1α, 3β-dihydroxy-20 (R)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)} pregna-5,7,16-triene (30.0 mg, 0.0700 mmol), After reacting in the same manner as in Example 15 using ethanol (200 ml) (light irradiation 3.5 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: Purified by ethyl acetate: ethanol = 8: 12: 1, developed twice, further 0.25 mm × 1 sheet, dichloromethane: ethanol = 16: 1, developed three times) to give the title compound as a colorless oil (3.04 mg, 10 %).
[0289]
IR (neat): 3350, 2972, 2929, 2850, 1448, 1371, 1167, 1063cm-1.1H NMR δ: 0.75 (s, 3H), 1.34 (s, 6H), 2.55-2.67 (m, 1H), 2.75-2.87 (m, 1H), 4.06 (q, J = 6.3Hz, 1H), 4.11- 4.30 (m, 3H), 4.38-4.50 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.45 (dt, J = 12.5, 5.3Hz, 1H), 5.58 (m, 2H) , 6.01 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
[0290]
Example 116
Preparation of 1α, 3β-dihydroxy-20 (R)-(4-ethyl-4-hydroxy-2-hexynyloxy) -9,10-secopregna-5,7,10 (19), 16-tetraene
Using 1α, 3β-dihydroxy-20 (R)-(4-ethyl-4-hydroxy-2-hexynyloxy) pregna-5,7,16-triene (30.8 mg, 0.0677 mmol), ethanol (200 ml), After performing the reaction in the same manner as in Example 15 (light irradiation 3.5 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: ethyl acetate: ethanol = 8: 12: 1, developed twice, further 0.25 mm × 1 sheet, dichloromethane: ethanol = 19: 1, developed three times) to give the title compound (1.83 mg, 5.9%) as a colorless oil. .
[0291]
IR (neat): 3390, 2970, 2933, 2852, 1450, 1371, 1265, 1146, 1061cm-1. 1H NMR δ: 0.75 (s, 3H), 1.03 (t, J = 7.4Hz, 6H), 1.33 ( d, J = 6.6Hz, 3H), 2.56-2.65 (m, 1H), 2.75-2.85 (m, 1H), 4.08-4.29 (m, 4H), 4.39-4.53 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.64 (brs, 1H), 6.10 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H).max nm: 264.
[0292]
Example 117
1α, 3β-dihydroxy-20 (R)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)}-9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing of
1α, 3β-dihydroxy-20 (R)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)} pregna-5,7,16-triene (13.0 mg, 0.0285 mmol), After reacting in the same manner as in Example 15 using ethanol (200 ml) (light irradiation for 2.5 minutes, heating under reflux for 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: Purified with ethyl acetate: ethanol = 8: 12: 1, developed twice, further 0.25 mm × 1 sheet, dichloromethane: ethanol = 16: 1, developed three times) to give the title compound as a colorless oil (0.888 mg, 6 8%).
[0293]
IR (neat): 3378, 2964, 2925, 2852, 1452, 1385, 1057cm-1.1H NMR δ: 0.75 (s, 3H), 0.86 (t, J = 7.4Hz, 6H), 1.32 (d, J = 6.6Hz, 3H), 2.55-2.66 (m, 1H), 2.76-2.87 (m, 1H), 3.90-4.10 (m, 3H), 4.18-4.31 (m, 1H), 4.39-4.51 (m, 1H), 5.02 (brs, 1H), 5.34 (brs, 1H), 5.57-5.81 (m, 3H), 6.11 (d, J = 11.2Hz, 1H), 6.38 (d, J = 11.2Hz, 1H) .UV λmax nm: 263.
[0294]
Example 118
1α, 3β-dihydroxy-20 (R)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)}-9,10-secopregna-5,7,10 (19), 16-tetraene Manufacturing of
1α, 3β-dihydroxy-20 (R)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)} pregna-5,7,16-triene (42.1 mg, 0.0922 mmol), After reacting in the same manner as in Example 15 using ethanol (200 ml) (light irradiation 3.75 minutes, heating under reflux 2 hours), preparative thin layer chromatography (0.5 mm × 1 sheet, hexane: Purified with ethyl acetate: ethanol = 8: 12: 1, developed twice, further 0.25 mm × 1 sheet, dichloromethane: ethanol = 16: 1, developed three times) to give the title compound as a colorless oil (2.09 mg, 5 0.0%).
[0295]
IR (neat): 3400, 2968, 2931, 2852, 1456, 1371, 1059cm-1.1H NMR δ: 0.75 (s, 3H), 0.90 (t, J = 7.4Hz, 6H), 1.34 (d, J = 6.6Hz, 3H), 2.55-2.66 (m, 1H), 2.73-2.89 (m, 1H), 3.98-4.31 (m, 4H), 4.39-4.51 (m, 1H), 5.01 (brs, 1H), 5.34 (brs, 1H), 5.41 (d, J = 12.5Hz, 1H), 5.55-5.71 (m, 2H), 6.10 (d, J = 11.2Hz, 1H), 6.37 (d, J = 11.2Hz, 1H). UV λmax nm: 263.
[0296]
Example 119
Preparation of 1α, 3β-dihydroxy-20 (S)-{2 (S) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (97.9 mg, 0.175 mmol), potassium t-butoxide (230 mg, 2.05 mmol) ), Dibenzo-18-crown-6 (45.0 mg, 0.125 mmol) in toluene (6 ml) at room temperature under (S)-(+)-1,2-epoxy-3-methylbutane (0.18 ml). , 1.72 mmol), and stirred at 106 ° C. for 1 hour. The reaction solution was diluted with diethyl ether and washed with saturated brine, and then the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated by preparative thin layer chromatography (0.5 mm × 4, hexane: dichloromethane: ethyl acetate = 45: 5: 2, developed three times), and 1α , 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{2 (S) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene (67.5 mg) Got. Of this, 52.6 mg was dissolved in tetrahydrofuran (1.5 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.5 ml) was added, and the mixture was stirred at an external temperature of 71 ° C. for 10 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (0.25 mm × 2 pieces, dichloromethane: ethanol = 15: 1, developed twice) to give the title compound as a colorless oil ( 20.6 mg, 36%).
[0297]
IR (neat): 3416, 2924, 1462, 1370, 1056, 1196cm-1.1H NMR δ: 0.88 (s, 3H), 0.90 (d, J = 6.9Hz, 3H), 0.97 (s, 3H), 1.31 (d, J = 6.6Hz, 3H), 2.72-2.86 (m, 1H) , 3.10-3.24 (m, 1H), 3.39-3.53 (m, 2H), 3.77 (brs, 1H), 3.96 (q, J = 6.6Hz, 1H), 4.00-4.16 (m, 1H), 5.40-5.49 (m, 1H), 5.60 (s, 1H), 5.68-5.80 (m, 1H). MS m / z: 312 (M+-HOCH2CH (OH)iPr), 223 (100%). UV λmax nm: 269, 281, 292.
[0298]
Example 120
Preparation of 1α, 3β-dihydroxy-20 (S)-{2 (R) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S) -hydroxypregna-5,7,16-triene (71.5 mg, 0.128 mmol), potassium t-butoxide (170 mg, 1.52 mmol) ), Dibenzo-18-crown-6 (32.0 mg, 0.0888 mmol), toluene (4.5 ml), (R)-(−)-1,2-epoxy-3-methylbutane (0.13 ml, 1. 24 mmol), and after the alkylation reaction (108 ° C., 1 hour) and post-treatment in the same manner as in Example 119, preparative thin layer chromatography (0.5 mm × 3, hexane: dichloromethane: acetic acid) Ethyl = 45: 5: 2, developed three times), and 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (S)-{2 ( ) - to give hydroxy-3 fraction containing methylbutyloxy} pregna -5,7,16- triene (26.8 mg). Using this and tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.4 ml), the deprotection reaction (reaction temperature: 74 ° C., reaction time: 12 hours) was carried out in the same manner as in Example 119. After the treatment, the product was purified by preparative thin layer chromatography (0.25 mm × 1 sheet, dichloromethane: ethanol = 15: 1, developed twice) to give the title compound as a colorless oil (12.0 mg, 23%) Got.
[0299]
IR (neat): 3420, 2924, 1460, 1368, 1056cm-1.1H NMR δ: 0.89 (s, 3H), 0.89 (d, J = 6.6Hz, 3H), 0.98 (s, 3H), 1.32 (d, J = 6.6Hz, 3H), 2.49-2.62 (m, 1H) , 2.72-2.87 (m, 1H), 3.26-3.54 (m, 3H), 3.77 (brs, 1H), 3.93-4.18 (m, 2H), 5.41-5.50 (m, 1H), 5.63 (s, 1H) , 5.70-5.80 (m, 1H) .MS m / z: 312 (M+-HOCH2CH (OH)iPr, 100%). UV λmax nm: 269, 280, 292.
[0300]
Example 121
Preparation of 1α, 3β-dihydroxy-20 (R)-{2 (S) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (79.0 mg, 0.141 mmol), potassium t-butoxide (190 mg, 1.69 mmol) ), Dibenzo-18-crown-6 (25.0 mg, 0.0694 mmol), toluene (4.5 ml), (S)-(+)-1,2-epoxy-3-methylbutane (0.15 ml, 1. 43 mmol), and after the alkylation reaction (108 ° C., 1 hour) and post-treatment in the same manner as in Example 119, preparative thin layer chromatography (0.5 mm × 3, hexane: dichloromethane: acetic acid) Ethyl = 45: 5: 2, developed three times), and 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{2 ( ) - to give hydroxy-3 fraction containing methylbutyloxy} pregna -5,7,16- triene (27.8 mg). Using this and tetrahydrofuran (1 ml), 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.25 ml), the deprotection reaction (reaction temperature: 76 ° C., reaction time: 13 hours) was carried out in the same manner as in Example 119. After the treatment, the product was purified by preparative thin layer chromatography (0.25 mm × 1 sheet, dichloromethane: ethanol = 15: 1, developed twice) to give the title compound as a colorless oil (11.0 mg, 19%) Got.
[0301]
IR (neat): 3416, 3036, 2928, 1462, 1370, 1270, 1196, 1056cm-1.1H NMR δ: 0.84 (s, 3H), 0.90 (d, J = 6.9Hz, 3H), 0.97 (s, 3H), 1.34 (d, J = 6.6Hz, 3H), 2.72-2.88 (m, 1H) , 3.19-3.34 (m, 1H), 3.40-3.60 (m, 2H), 3.77 (brs, 1H), 3.93-4.16 (m, 2H), 5.40-5.50 (m, 1H), 5.67 (s, 1H) , 5.71-5.80 (m, 1H) .MS m / z: 312 (M+-HOCH2CH (OH)iPr, 100%). UV λmax nm: 270, 281, 293.
[0302]
Example 122
Preparation of 1α, 3β-dihydroxy-20 (R)-{2 (R) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene
1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R) -hydroxypregna-5,7,16-triene (69.7 mg, 0.125 mmol), potassium t-butoxide (170 mg, 1.52 mmol) ), Dibenzo-18-crown-6 (22.0 mg, 0.0610 mmol), toluene (4 ml), (R)-(−)-1,2-epoxy-3-methylbutane (0.13 ml, 1.24 mmol) Was used for the alkylation reaction (109 ° C., 1 hour) and post-treatment in the same manner as in Example 119, followed by preparative thin layer chromatography (0.5 mm × 3, hexane: dichloromethane: ethyl acetate = 45: 5: 2, 3 developments), 1α, 3β-bis (tert-butyldimethylsilyloxy) -20 (R)-{2 (R) Fractions containing hydroxy-3-methylbutyloxy} pregna -5,7,16- triene (23.6 mg) was obtained. Of these, 21.1 mg, tetrahydrofuran (1 ml), and 1M-tetra-n-butylammonium fluoride tetrahydrofuran solution (0.2 ml) were used for the deprotection reaction (reaction temperature 76 ° C., reaction time 13) in the same manner as in Example 119. Time) and after-treatment, the product was purified by preparative thin-layer chromatography (0.25 mm × 1 sheet, dichloromethane: ethanol = 15: 1, developed twice) to give the title compound as a colorless oil (9.4 mg). 20%).
[0303]
IR (neat): 3404, 2960, 2928, 1462, 1370, 1272, 1196, 1056cm-1.1H NMR δ: 0.85 (s, 3H), 0.90 (d, J = 6.9Hz, 3H), 0.98 (s, 3H), 1.33 (d, J = 6.3Hz, 3H), 2.49-2.61 (m, 1H) , 2.74-2.87 (m, 1H), 3.21-3.35 (m, 1H), 3.39-3.56 (m, 2H), 3.78 (brs, 1H), 3.93-4.15 (m, 2H), 5.40-5.50 (m, 1H), 5.65 (s, 1H), 5.70-5.81 (m, 1H) .MS m / z: 312 (M+-HOCH2CH (OH)iPr, 100%). UV λmax nm: 269, 281, 293.
[0304]
Example 123
Preparation of 1α, 3β-dihydroxy-20 (S)-{2 (S) -hydroxy-3-methylbutyloxy} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-dihydroxy-20 (S)-{2 (S) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene (9.7 mg, 0.0233 mmol), ethanol (200 ml) was used. Then, after carrying out the reaction in the same manner as in Example 15 (light irradiation 1
[0305]
IR (neat): 3400, 2928, 1444, 1368, 1056cm-1.1H NMR δ: 0.78 (s, 3H), 0.90 (d, J = 6.9Hz, 3H), 0.96 (d, J = 6.9Hz, 3H), 1.31 (d, J = 6.6Hz, 3H), 2.53-2.68 (m, 1H), 2.76-2.90 (m, 1H), 3.09-3.24 (m, 1H), 3.40-3.55 (m, 2H), 3.88-4.01 (m, 1H), 4.18-4.30 (m, 1H) , 4.40-4.50 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.57 (s, 1H), 6.10 (d, J = 11.4Hz, 1H), 6.37 (d, J = 11.4 Hz, 1H) .MS m / z: 312 (M+-HOCH2CH (OH)iPr), 149 (100%). UV λmax nm: 262.
[0306]
Example 124
Production of 1α, 3β-dihydroxy-20 (S)-{2 (R) -hydroxy-3-methylbutyloxy} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-Dihydroxy-20 (S)-{2 (R) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene (12.0 mg, 0.0288 mmol) and ethanol (200 ml) were used. After performing the reaction in the same manner as in Example 15 (light irradiation 1
[0307]
IR (neat): 3400, 2928, 1444, 1370, 1056cm-1.1H NMR δ: 0.78 (s, 3H), 0.89 (d, J = 6.9Hz, 3H), 0.97 (d, J = 6.9Hz, 3H), 1.31 (d, J = 6.6Hz, 3H), 2.54-2.67 (m, 1H), 2.74-2.90 (m, 1H), 3.25-3.53 (m, 3H), 3.95 (q, J = 6.6Hz, 1H), 4.19-4.32 (m, 1H), 4.38-4.51 (m , 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.58 (s, 1H), 6.11 (d, J = 11.4Hz, 1H), 6.37 (d, J = 11.4Hz, 1H). m / z: 312 (M+-HOCH2CH (OH)iPr), 149 (100%). UV λmax nm: 263.
[0308]
Example 125
Preparation of 1α, 3β-dihydroxy-20 (R)-{2 (S) -hydroxy-3-methylbutyloxy} -9,10-secopregna-5,7,10 (19), 16-tetraene
Using 1α, 3β-dihydroxy-20 (R)-{2 (S) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene (9.9 mg, 0.0238 mmol) and ethanol (200 ml) After performing the reaction in the same manner as in Example 15 (light irradiation 1
[0309]
IR (neat): 3392, 2928, 1452, 1370, 1264, 1056cm-1.1H NMR δ: 0.74 (s, 3H), 0.90 (d, J = 6.6Hz, 3H), 0.97 (d, J = 6.6Hz, 3H), 1.33 (d, J = 6.3Hz, 3H), 2.55-2.68 (m, 1H), 2.77-2.90 (m, 1H), 3.21-3.34 (m, 1H), 3.41-3.56 (m, 2H), 3.98 (q, J = 6.3Hz, 1H), 4.18-4.31 (m , 1H), 4.38-4.51 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.63 (s, 1H), 6.10 (d, J = 11.4Hz, 1H), 6.37 (d, J = 11.4Hz, 1H) .MS m / z: 312 (M+-HOCH2CH (OH)iPr), 149 (100%). UV λmax nm: 262.
[0310]
Example 126
Preparation of 1α, 3β-dihydroxy-20 (R)-{2 (R) -hydroxy-3-methylbutyloxy} -9,10-secopregna-5,7,10 (19), 16-tetraene
1α, 3β-dihydroxy-20 (R)-{2 (R) -hydroxy-3-methylbutyloxy} pregna-5,7,16-triene (8.5 mg, 0.0204 mmol), ethanol (200 ml) was used. After performing the reaction in the same manner as in Example 15 (light irradiation 1
[0311]
IR (neat): 3416, 2924, 1452, 1370, 1262, 1066cm-1.1H NMR δ: 0.75 (s, 3H), 0.91 (d, J = 6.6Hz, 3H), 0.97 (d, J = 6.6Hz, 3H), 1.32 (d, J = 6.3Hz, 3H), 2.55-2.67 (m, 1H), 2.77-2.88 (m, 1H), 3.21-3.33 (m, 1H), 3.36-3.57 (m, 2H), 3.92-4.06 (m, 1H), 4.19-4.30 (m, 1H) , 4.40-4.50 (m, 1H), 5.01 (s, 1H), 5.34 (s, 1H), 5.60 (s, 1H), 6.10 (d, J = 11.4Hz, 1H), 6.37 (d, J = 11.4 Hz, 1H). UV λmax nm: 260.
[0312]
Compound 1 (1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene), Compound 2 (1α, 3β-dihydroxy-20 (R)-(3-hydroxy-3-methylbutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene), compound 3 (1α, 3β -Dihydroxy-20 (R)-(4-hydroxy-4-methyl-2-pentynylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene), compound 4 (1α, 3β-dihydroxy -20 (R)-(4-ethyl-4-hydroxy-2-hexynylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene), compound 5 (1α, 3β- Hydroxy-20 (R)-((E) -4-hydroxy-4-methyl-2-pentenylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene), compound 6 (1α , 3β-dihydroxy-20 (R)-((E) -4-ethyl-4-hydroxy-2-hexenylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene) An example of the test is shown.
[0313]
Test example 1
Active vitamin D dissolved in phosphate bufferThreeOr each vitamin DThreeThe derivative was intravenously administered to 8-week-old male ddY mice at a dose of 30 μg / kg, and then the ionized calcium level in blood was measured at 24 hours. The experiment was carried out with 5 cases in each group, and the results are shown as mean ± standard error. Active vitamin DThreeAnd each vitamin DThreeThe blood calcium-elevating activity of the derivatives was evaluated by comparison with a control group to which only the same amount of phosphate buffer was administered. The results are shown in FIGS. Dunnett's T test is used for the significant difference test. In the figure, * indicates a significant difference with a risk rate of 5%, ** is 1%, and *** is 0.1%.
[0314]
Test example 2
HL-60 cells were treated with 5% CO 2 in RPMI-1640 medium containing 10% fetal bovine serum and 20 μg / ml gentamicin.2Then, the cells were subcultured at 37 ° C. Differentiation inducing action was evaluated by the following method. First, add 10% of the culture solution containing various concentrations of test compound to a 24-well plate.FiveCells were seeded and cultured under the above culture conditions for 4 days. Next, the amount of superoxide produced by stimulation with phorbol myristate acetate (PMA) was measured as cytochrome C reducing ability. That is, after removing the culture supernatant by aspiration, cells treated with the test compound were suspended in 1.5 ml of a reaction mixture (80 μM ferritochrome C, 500 ng / ml PMA), cultured at 37 ° C. for 1 hour, and then cultured supernatant. Was measured at OD550-540 using a Hitachi dual wavelength spectrophotometer. The results are shown in FIGS. The concentration of reduced cytochrome C is a molecular extinction coefficient of 19.1 × 10Threecm-1Calculated using
[0315]
【The invention's effect】
The compound represented by the general formula (1) of the present invention is a useful compound as a medicament such as an antitumor agent and an antirheumatic agent having a low calcium-elevating action.
[Brief description of the drawings]
FIG. 1 shows active vitamin DThreeOr vitamin DThreeIt is the graph which showed the measurement result of the blood ionized calcium level after administration of a derivative.
FIG. 2 shows active vitamin DThreeOr vitamin DThreeIt is the graph which showed the measurement result of the blood ionized calcium level after administration of a derivative.
FIG. 3 shows active vitamin DThreeOr vitamin DThreeIt is the graph which showed the measurement result of the blood ionized calcium level after administration of a derivative.
FIG. 4 shows active vitamin DThreeOr vitamin DThreeIt is the graph which showed the result of the evaluation test of the differentiation induction effect of a derivative.
FIG. 5 shows active vitamin DThreeOr vitamin DThreeIt is the graph which showed the result of the evaluation test of the differentiation induction effect of a derivative.
FIG. 6 shows active vitamin DThreeOr vitamin DThreeIt is the graph which showed the result of the evaluation test of the differentiation induction effect of a derivative.
Claims (28)
Xは酸素原子またはイオウ原子を示し、
R11は、(i)水酸基で置換された炭素数1〜15の直鎖または分岐鎖状のアルキル基または炭素数2〜15の直鎖または分岐鎖状のアルケニル基またはアルキニル基、あるいは(ii)−COR12基(式中、R12は炭素数が6〜20のアリールオキシ基または炭素数が1〜15のアルコキシ基を示す)を意味し、
R2は−OR 9 を示し、
R9およびR10は同一または異なって水素原子または保護基を示す)
で表される化合物。General formula (1):
X represents an oxygen atom or a sulfur atom,
R 11 represents (i) a linear or branched alkyl group having 1 to 15 carbon atoms substituted with a hydroxyl group, a linear or branched alkenyl group or alkynyl group having 2 to 15 carbon atoms, or (ii) ) —COR 12 group (wherein R 12 represents an aryloxy group having 6 to 20 carbon atoms or an alkoxy group having 1 to 15 carbon atoms ) ,
R 2 represents —OR 9 ;
R 9 and R 10 are the same or different and each represents a hydrogen atom or a protecting group)
A compound represented by
キシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン。1α, 3β-dihydroxy-20 (S)-(2-ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene.
キシブチルチオ)−9,10−セコプレグナ−5,7,10(19),16−テトラエン。1α, 3β-dihydroxy-20 (R)-(2-ethyl-2-hydroxybutylthio) -9,10-secopregna-5,7,10 (19), 16-tetraene.
Xは酸素原子またはイオウ原子を示し、
R11は、(i)水酸基または保護された水酸基で置換された炭素数1〜15の直鎖または分岐鎖状のアルキル基または炭素数2〜15の直鎖または分岐鎖状のアルケニル基またはアルキニル基、あるいは(ii)−COR12基(式中、R12は炭素数が6〜20のアリールオキシ基または炭素数が1〜15のアルコキシ基を示す)を意味し、
R9およびR10は同一または異なって、水素原子または保護基を示す)
で表される化合物。General formula (4):
X represents an oxygen atom or a sulfur atom,
R 11 is (i) a linear or branched alkyl group having 1 to 15 carbon atoms or a linear or branched alkenyl group having 2 to 15 carbon atoms or alkynyl substituted with a hydroxyl group or a protected hydroxyl group. Group or (ii) -COR 12 group (wherein R 12 represents an aryloxy group having 6 to 20 carbon atoms or an alkoxy group having 1 to 15 carbon atoms ) ,
R 9 and R 10 are the same or different and represent a hydrogen atom or a protecting group)
A compound represented by
R5およびR6は水素原子または水酸基を示すが、R6はR3またはR4と同時に水酸基となることはない。mは1〜4の整数を示し、nは0〜2の整数を示す)または基(3):
R 5 and R 6 represent a hydrogen atom or a hydroxyl group, but R 6 does not become a hydroxyl group simultaneously with R 3 or R 4 . m represents an integer of 1 to 4 and n represents an integer of 0 to 2) or group (3):
R11は(i)水酸基で置換されていてもよい、炭素数1〜15の直鎖または分岐鎖状のアルキル基または炭素数2〜15の直鎖または分岐鎖状のアルケニル基またはアルキニル基、あるいは−COR12基(式中、R12は炭素数が6〜20のアリールオキシ基または炭素数が1〜15のアルコキシ基を示す)を意味し、
R2は−OR9または水素原子を示し、
R9およびR10は同一または異なって水素原子または保護基を示す)
で表される化合物の製造方法。General formula (4a):
R 11 is (i) a linear or branched alkyl group having 1 to 15 carbon atoms or a linear or branched alkenyl group or alkynyl group having 2 to 15 carbon atoms , which may be substituted with a hydroxyl group, Alternatively -COR 12 group (wherein, R 12 represents an alkoxy group having 1 to 15 is an aryloxy group or a carbon number of 6 to 20 carbon atoms) means,
R 2 represents —OR 9 or a hydrogen atom,
R 9 and R 10 are the same or different and each represents a hydrogen atom or a protecting group)
The manufacturing method of the compound represented by these.
Xは酸素原子またはイオウ原子を示し、
R11は、(i)水酸基で置換された炭素数1〜15の直鎖または分岐鎖状のアルキル基または炭素数2〜15の直鎖または分岐鎖状のアルケニル基またはアルキニル基、あるいは−COR12基(式中、R12は炭素数が6〜20のアリールオキシ基または炭素数が1〜15のアルコキシ基を示す)を意味し、
R2は−OR 9 を示し、
R9及びR10は水素原子を示す)
で表される化合物を含む、医薬。General formula (1):
X represents an oxygen atom or a sulfur atom,
R 11 represents (i) a linear or branched alkyl group having 1 to 15 carbon atoms substituted with a hydroxyl group, a linear or branched alkenyl group or alkynyl group having 2 to 15 carbon atoms, or —COR. 12 groups (wherein R 12 represents an aryloxy group having 6 to 20 carbon atoms or an alkoxy group having 1 to 15 carbon atoms ),
R 2 represents —OR 9 ;
R 9 and R 10 represent a hydrogen atom )
The pharmaceutical containing the compound represented by these.
Xは酸素原子またはイオウ原子を示し、 X represents an oxygen atom or a sulfur atom,
R R 1111 は、(i)水酸基で置換された炭素数1〜15の直鎖または分岐鎖状のアルキル基または炭素数2〜15の直鎖または分岐鎖状のアルケニル基またはアルキニル基、あるいは(ii)−COR(I) a linear or branched alkyl group having 1 to 15 carbon atoms substituted with a hydroxyl group, a linear or branched alkenyl group or alkynyl group having 2 to 15 carbon atoms, or (ii)- COR 1212 基(式中、RGroup (wherein R 1212 は炭素数が6〜20のアリールオキシ基または炭素数が1〜15のアルコキシ基を示す)を意味し、Represents an aryloxy group having 6 to 20 carbon atoms or an alkoxy group having 1 to 15 carbon atoms),
R R 22 は−ORIs -OR 99 を示し、Indicate
R R 99 およびRAnd R 10Ten は同一または異なって水素原子または保護基を示し、RAre the same or different and each represents a hydrogen atom or a protecting group, and R 99 およびRAnd R 10Ten の少なくとも一方は保護基を示す)At least one of them represents a protecting group)
で表される化合物。A compound represented by
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JP35093897A JP4012293B2 (en) | 1996-12-20 | 1997-12-19 | 16-ene-vitamin D derivative |
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JP34178696 | 1996-12-20 | ||
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JP35093897A JP4012293B2 (en) | 1996-12-20 | 1997-12-19 | 16-ene-vitamin D derivative |
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JP4012293B2 true JP4012293B2 (en) | 2007-11-21 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP35093897A Expired - Fee Related JP4012293B2 (en) | 1996-12-20 | 1997-12-19 | 16-ene-vitamin D derivative |
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JP (1) | JP4012293B2 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2001079166A1 (en) | 2000-04-19 | 2001-10-25 | Chugai Seiyaku Kabushiki Kaisha | Vitamin d derivatives |
DK1295871T3 (en) | 2000-06-15 | 2011-07-11 | Chugai Pharmaceutical Co Ltd | Vitamin D derivatives with a 22-oxa or 22-thia atom, a C17 side chain substituted with an acid, ester or amide group and a 16 (17) double bond |
JP4490262B2 (en) * | 2002-06-13 | 2010-06-23 | ジョンズ ホプキンス ユニバーシティ | 24-sulfoximine vitamin D3 compound |
WO2006093291A1 (en) * | 2005-03-04 | 2006-09-08 | Tokyo Medical And Dental University | 19-norvitamin d derivative |
JP5095413B2 (en) * | 2005-11-30 | 2012-12-12 | 中外製薬株式会社 | Preparation of vitamin D derivatives using photoreaction |
KR20150036717A (en) | 2006-06-02 | 2015-04-07 | 니뽄 신야쿠 가부시키가이샤 | 9,10-secopregnane derivative and pharmaceutical |
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1997
- 1997-12-19 JP JP35093897A patent/JP4012293B2/en not_active Expired - Fee Related
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JPH10231284A (en) | 1998-09-02 |
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