Convergent kilogram-scale synthesis of dual orexin receptor antagonist

…, G Hughes, PN Devine, PD O'Shea…

Index: Girardin, Melina; Ouellet, Stephane G.; Gauvreau, Danny; Moore, Jeffrey C.; Hughes, Greg; Devine, Paul N.; O'Shea, Paul D.; Campeau, Louis-Charles Organic Process Research and Development, 2013 , vol. 17, # 1 p. 61 - 68

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Citation Number: 24

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 ...