3‑((Hetera)cyclobutyl)azetidines, “Stretched” Analogues of Piperidine, Piperazine, and Morpholine: Advanced Building Blocks for Drug Discovery

Four 3-((hetera)­cyclobutyl)­azetidine-based isosteres of piperidine, piperazine, and morpholine were designed and synthesized on up to gram scale. The key step of the synthetic sequence included cyclization of N-protected 2-(azetidin-3-yl)­propane-1,3-diol or the corresponding 1,3-dibromide. X-ray...

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Bibliographic Details
Published in:Journal of organic chemistry 2019-02, Vol.84 (3), p.1363-1371
Main Authors: Feskov, Illia O, Chernykh, Anton V, Kuchkovska, Yuliya O, Daniliuc, Constantin G, Kondratov, Ivan S, Grygorenko, Oleksandr O
Format: Article
Language:English
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Summary:Four 3-((hetera)­cyclobutyl)­azetidine-based isosteres of piperidine, piperazine, and morpholine were designed and synthesized on up to gram scale. The key step of the synthetic sequence included cyclization of N-protected 2-(azetidin-3-yl)­propane-1,3-diol or the corresponding 1,3-dibromide. X-ray diffraction studies of the products obtained, followed by exit vector plot analysis of their molecular geometry, demonstrated their larger size and increased conformational flexibility as compared to the parent heterocycles and confirmed their potential utility as building blocks for lead optimization programs.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.8b02822