Vernakalant is an investigational drug under regulatory review for the acute conversion of atrial
fibrillation. The drug was initially developed by Cardiome Pharma under the trade names Kynapid ®
and Brinavess ® and its intravenous formulation was further developed by Merck in April 2009. Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby
prolonging repolarization. It differs from typical class III agents by blocking the cardiac
transient outward potassium current, with increased potency as the heart rate increases. It also slightly
blocks the hERG potassium channel, leading to a prolonged QT interval, which may theoretically
increase the risk of ventricular tachycardia.
The preparation of vernakalant entails the union of a
prolinol derivative 150 with a 3,4-dimethoxyphenethyl alcohol (148) across a cyclohexanyl lynchpin
152 and is described in the scheme. Decarboxylation of commercially available (2S,4R)-4-
hydroxyprolinol (150) was effected using cyclohexanol and cyclohexanone at elevated temperatures.
Subsequent protection of the nitrogen atom and the oxygen atom within this system resulted in
carbamate 151. Acid-mediated removal of the N-protective functionality preceded nucleophilic attack on epoxide 152 in hot water, and the ensuing mixture of diastereomers was separated by classical
resolution via the tartrate salt. O-Benzylated vernakalant 154 was obtained when enantiomerically pure
alcohol 153 was subjected to trichloroacetimidate 149 (which arose from the corresponding alcohol 148
under modified Williamson conditions. Acidic hydrogenolysis, which the authors report as
separate steps, furnished vernakalant hydrochloride (XIV) in excellent overall yield.
