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DOI: 10.1055/s-0030-1259212
Synthesis of Telcagepant
Contributor(s):Philip KocienskiMerck Research Laboratories, Rahway, USA
Asymmetric Synthesis of Telcagepant, a CGRP Receptor Antagonist for the Treatment of Migraine
J. Org. Chem. 2010, 75: 7829-7841
Publication History
Publication Date:
19 January 2011 (online)
Key words
telcagepant - CGRP receptors - iminium organocatalysis - asymmetric conjugate addition - crystallization-induced diastereoselection - Doebner-Knoevenagel condensation
Significance
Telcagepant is a selective antagonist of calcitonin gene related peptide (CGRP) that is in phase clinical trials for the treatment of migraine. The synthesis featured an enantioselective 1,4-addition of nitromethane, which is the first application of iminium organocatalysis (B ♦ D) on an industrial scale and a highly stereoselective Doebner-Knoevenagel condensation that created the enamide F.
Comment
The formation of desfluoro impurities that accompanied the hydrogenation of F was minimized by conducting the reaction in the presence of LiCl. The mixture of caprolactams I and J (2:1) was converted into pure J by crystallization-induced diastereoselection. The synthesis was accomplished in 27% overall yield and involved only three isolated crystalline intermediates (F, J and K).