Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist
Organic Process Research & Development2012Vol. 17(1), pp. 61–68
Citations Over TimeTop 10% of 2012 papers
Mélina Girardin, Stéphane G. Ouellet, Danny Gauvreau, Jeffrey C. Moore, G. Hughes, Paul N. Devine, Paul O’Shea, Louis‐Charles Campeau
Abstract
MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselective O-alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.
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