Efficient synthesis and reaction pathway studies of novel fused morpholine oxadiazolines for use as gamma secretase modulators
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- 作者：Xianhai Huang ; xianhai.huang@merck.com ; Dmitri Pissarnitski ; Hongmei Li ; Theodros Asberom ; Hubert Josien ; Xiaohong Zhu ; Monica Vicarel ; Zhiqiang Zhao ; Murali Rajagopalan ; Anandan Palani ; Robert Aslanian ; Zhaoning Zhu ; William Greenlee ; Alexei Buevich
- 关键词：Morpholine ; Oxadiazoline ; Cyclization ; Heterocycles ; Gamma secretase modulator ; Alzheimer&rsquo ; s disease
- 刊名：Tetrahedron Letters
- 出版年：2012
- 出版时间：21 November, 2012
- 年：2012
- 卷：53
- 期：47
- 页码：6451-6455
- 全文大小：588 K
文摘
An efficient synthesis of fused morpholine oxadiazoline core structures was accomplished in an effort to identify optimum gamma secretase modulator leads in the treatment of Alzheimer¡¯s disease. Reaction pathways were proposed for the key intramolecular cyclization reaction, and chemistry was designed to probe these hypotheses. A highly diastereoselective synthesis of potent GSM 27 was achieved. To further improve the synthesis, a second route was developed which successfully addressed the formation of a fused seven-member ring by-product, and provided opportunities to accelerate future SAR studies.