Preparation of Shortened Norbelladine Analogs 英文参考文献.docVIP

Molecules 2002, 7, 743-750 molecules ISSN 1420-3049 Preparation of Shortened Norbelladine Analogs Matthias Treu, Johannes Fr?hlich and Ulrich Jordis* Institute of Applied Synthetic Chemistry, Vienna University of Technology, A-1060 Vienna, Getreidemarkt 9/163, Austria; Tel. +43 (1) 58801.15460, Fax +43(1)58801.15499, * Author to whom correspondence should be addressed; email: ujordis@pop.tuwien.ac.at. Received: 1 November 2001; in revised form 23 September 2002 / Accepted: 30 September 2002 / Published: 31 October 2002 Abstract: The preparation of N-[(2-bromo-5-hydroxy-4-methoxyphenyl)methyl]-N-[(4- hydroxyphenyl)methyl]formamide (5) and 2-bromo-5-hydroxy-α-[(4-hydroxyphenyl)- methyl]-4-methoxypropaneamide (10) is reported. Keywords: O-dealkylation, norbelladine analogs. Introduction One of the key steps of the industrial synthesis [1] of the anti-Alzheimer drug galanthamine (Reminyl?, Nivalin?) [2] comprises a K3[Fe(CN)6] induced phenol oxidation tandem cyclization [3]. In this reaction the 5-6-6-7 ring system is formed in one step starting from a suitable norbelladine derivative. We tried to extend this cyclization reaction towards the construction of 5-6-6-6 ring systems and prepared both N-[(2-bromo-5-hydroxy-4-methoxyphenyl)methyl]-N-[(4-hydroxyphenyl)methyl]- formamide (5) and 2-bromo-5-hydroxy-α-[(4-hydroxyphenyl)methyl]-4-methoxypropaneamide (10) as necessary intermediates. These intermediates were subjected to the conditions of the tandem cyclization [1], however the desired ring contracted galanthamine analog could not be obtained.  Molecules, 2002, 7 744 OH OH H O OH H O HO HO MeO N H MeO G N Me norbelladine (-)-galanthamine desired galanthamine analogs G = NMe, CHCONH2 The synthesized open chained norbelladine analogs 3 – 5, which retain the partial structure of substituted benzylamines and thus are of potential pharmaceutical interest prompted this publication. Results and Disc