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

摘要

A 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 Friedl?nder 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 c-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%.