Carbon‐14 radiosynthesis of 4‐(5‐chloro‐2‐hydroxyphenyl)‐3‐(2‐hydroxyethyl)‐6‐(trifluoromethyl)‐[4‐14C]quinolin‐2(1H)‐one (XEN‐D0401), A novel BK channel activator

Abstract

AbstractA method has been developed for the carbon‐14 radiosynthesis of [14C]XEN‐D0401, a 4‐(2‐hydroxyphenyl)quinolin‐2(1H)‐one derivative. The radiosynthetic route involves a series of ortho‐lithiations directed by both 2‐methoxymethyl (MOM) and pivaloyl protecting groups. This is demonstrated in the first key radiochemical step between the reaction of 5‐chloro‐2‐methoxymethoxy‐[carboxyl‐14C]benzoic acid methyl ester [14C]‐3 and the ortho‐lithiated intermediate generated from 2,2‐dimethyl‐N‐(4‐trifluoromethylphenyl)‐propionamide (2) to afford the protected benzophenone [14C]‐4. The other key radiochemical step utilizes a variation of the Friedländer quinoline synthesis, which involves a base catalysed, one‐pot condensation process between (2‐amino‐5‐trifluoromethyl‐phenyl)‐(5‐chloro‐2‐methoxymethoxy‐phenyl)‐[14C]methanone [14C]‐5 and γ‐butyrolactone to give MOM‐protected [14C]‐6. On MOM deprotection, [14C]XEN‐D0401 was isolated with a radiochemical purity of >97%, with a specific activity of 55 mCi/mmol from seven radiochemical steps, starting from barium [14C]carbonate in a radiochemical yield of 10.5%. Copyright © 2010 John Wiley & Sons, Ltd.