Synthesis of radiolabeled racemic and enantiomeric antiarrhythmic agents

Ibutilide fumarate, racemic N‐[4‐[4‐(ethyl‐n‐heptylamino)‐1‐hydroxybutyl]phenyl]methanesulfonamide hemifumarate, and artilide, the R‐(+)‐enantiomer of N‐[4‐[4‐(di‐n‐butylalmino)‐1‐hydroxybutyl]‐phenyl]methanesulfonamide hemifumerate, are under clinical investigation as Class III antiarrhythmic agents. For conducting drug disposition studies, we synthesized carbon‐14 labeled ibutilide, as well as its two enantiomeric forms. In addition, high specific activity tritium labeled ibutilide was also prepared to facilitate development of a radioimmunoassay and for studying receptor site characteristics of this agent. Results of metabolism studies with [ 14 C]ibutilide led us to prepare tritium labeled artilide, which is more readily accessible than the C‐14 labeled drug. The optical antipode of artilide was also labeled with tritium for comparative drug disposition investigations on the two enantiomers.