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研究生： 郭俊偉
Chun-Wei Kuo
論文名稱： 壹、N-溴代丁二醯亞胺作為催化劑在有機合成上的應用; 貳、磷化物在有機合成上之應用；參、合成含有1,2,4-噁二唑之吡唑類衍生物在CB1受體拮抗劑之生物活性研究
(I) Novel synthetic strategy for the synthesis of biologically active N-heterocycles catalyted by N-bromosuccinimide (II) Application of phosphous reagent in organic synthesis (III) SAR study on novel series of oxadiazoles as CB1 cannabinoid receptor antagonists
指導教授： 姚清發
Yao, Ching-Fa
夏克山
Shia, Kak-Shan
學位類別： 博士
Doctor
系所名稱： 化學系
Department of Chemistry
論文出版年： 2008
畢業學年度： 96
語文別： 中文
論文頁數： 370
中文關鍵詞： N-溴代丁二醯亞胺 、催化劑 、磷化物 、1,2,4-噁二唑 、吡唑 、CB1受體拮抗劑
英文關鍵詞： N-bromosuccinimide, catalyst, phosphorus reagent, 1,2,4-oxadiazole, pyrazole, CB1 receptor antagonist
論文種類： 學術論文
相關次數： 點閱：214  下載：0 
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    • 本論文共分成三部分
    第一部分以便宜易取得之N-溴代丁二醯亞胺 (NBS) 試劑，分別催化合成具生物活性1,5-benzodiazepines衍生物以及吲哚基硝基烷化合物，此高效催化效率皆可使反應順利進行，並得到高產率的產物。
    第二部分以磷化物試劑，二氯化磷酸乙酯 (ethyl dichlorophosphate)或是二氯化磷酸苯酯 (phenyl dichlorophosphate)進行官能基的轉變及Beckmann 重排反應，反應順利可在室溫下進行並且得到高產率的產物。
    第三部分為探討含1,2,4-噁二唑為新型CB1受體拮抗劑之抗肥胖藥物的開發研究，以Rimonabant（SR141716A, Acomplia™）作為先導化合物進行pyrazole-C3位置的官能基修飾，依生物同質性概念成功引入1,2,4-噁二唑取代之新型化合物並顯現高度之CB1受體親和力、功能活性與CB2/1選擇性。發現具高度CB1親和力與CB2/1選擇性的化合物如11g, 11h等，將適合針對減重機制與抗肥胖藥物的特性進一步深入研究動物體內活性（in vivo efficacy）、藥物動力學（pharmacokinetics）及毒理試驗（toxicology）期能獲得具有潛力治療肥胖症的先導藥物或候選藥物。

    In the first part of this dissertation, we have focused on the use of relatively low toxic, inexpensive reagents such as N-bromosuccinimide for carrying out the catalytic synthetic methodology. Various biologically important 1,5-benzodiazepine derivatives were efficiently synthesized in excellent yields. Furthermore, 3-indolyl-nitroalkane derivatives can be synthesized utilizing this newly development catalytic system as well.

    The second part is focused on ethyl dichlorophosphate mediates functional group transormation from primary amides into nitriles under mild condition. However, phenyl dichlorophosphate also promotes Beckmann rearrangement at room temperature with highly efficiently to afford products in good to high yields.

    Finally, a novel series of 1,2,4-oxadiazole as potent and selective CB1 cannabinoid receptor antagonists has been developed. Replacing the conventional pyrazole 3-aryl substituent of rimonabant with the 1,2,4-oxadiazole moiety, a novel class of 1,2,4-oxadiazole-pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB2/1 selectivity, was discovered.

    目 錄 中文摘要……………………………………………………………I 英文摘要……………………………………………………………II 縮寫對照表........................................III 第一章 N-溴代丁二醯亞胺作為催化劑在有機合成上的應用………1 1 緒論……………………………………………………………………1 1.1 NBS作為催化劑………………………………………………1 1.2 NBS作為氧化劑………………………………………………4 1.3 NBS在綠色化學的應用………………………………………7 1.4 NBS對酮的羰基鄰位氫取代的研究…………………………9 第一節 N-溴代丁二醯亞胺催化合成1,5-benzodiazepines衍生物…11 1 前言…………………………………………………………………11 1.1 合成1,5-benzodiazepines衍生物的方法……………………13 1.2 研究構想……………………………………………………20 1.3 實驗結果與討論……………………………………………21 1.4 結論……………..……………………………………………29 第二節 N-溴代丁二醯亞胺催化合成β-吲哚硝基烷化合物………31 1 前言…………………………………………………………………31 1.1 共軛硝基化合物……………………………………………….32 1.2 吲哚基硝基烷化合物的合成研究構想……………………34 1.3 實驗結果與討論……………………………………………37 1.3.1 共軛硝基苯乙烯衍生物的製備……………………………37 1.3.2 N-溴代丁二醯亞胺催化吲哚與共軛硝基苯乙烯衍生物的反 應…………………………………………………………37 1.4 結論……………………………………………………………46 第二章 磷化物在有機合成上之應用……………………………48 1 緒論…………..……………………………………………………48 1.1 磷化物試劑應用於有機合成之文獻介紹………………… 49 1.2 研究構想……………………………………………………55 1.3 實驗結果與討論………………………………………………55 1.4 結論……………………………………………………………61 第一節 磷化物試劑應用在Beckmann 重排反應之研究…………62 1 緒論…………………………………………………………………62 1.1氣、液相Beckmann 重排中的催化劑………………………63 1.1.1酸性試劑用於Beckmann 重排反應的研究……………64 1.2 離子液體用於Beckmann 重排反應的研究………………69 1.3 磷化物試劑用於Beckmann 重排反應的研究………………72 1.4 實驗結果與討論……………………………………………74 1.5 結論…………………………………………………………83 第三章 合成含有1,2,4-噁二唑之吡唑類衍生物在CB1受體拮抗劑之生物活性研究…………………………………………………………84 1 前言………………………………………………………………84 1.1 肥胖症（obesity）………………………………………84 1.2 抗肥胖藥物的分類…………………………………………88 1.2.1 抑制食慾的藥物（Anorexic drugs）…………………88 1.2.2 阻礙營養素吸收的藥物………………………………91 1.2.3 增加熱量消耗的藥物…………………………………92 1.3 類大麻素受體拮抗劑的抗肥胖藥物………………………93 1.3.1 內生性類大麻素系統（endogenous cannabinoids）…93 1.3.2 以CB1受體為標靶的抗肥胖藥物..............96 1.4 研究構想…………………………………………………101 2 結果與討論………………………………………………………103 2.1 oxadiazole衍生物之合成…………………………………103 2.2 生物活性評估與討論 ………………………………108 3 結論………………………………………………………………111

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