Synthesis of ~(14)C-labeled piperidines and application to synthesis of (~(14)C)SCH 351125, a CCR5 receptor antagonist

摘要

l-Benzyl-4-hydroxy[2-~(14)C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [~(14)C]formaldehyde in high yield. The distribution pattern of ~(14)C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza-Cope rearrangement. These steps precede the rate-determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [~(14)C]SCH 351125, required for metabolism studies, was prepared from l-benzyl-4-hydroxy[2-~(14)C]piperidine in six steps. [~(14)C]SCH 351125 is a mixture of four atropisomers. Preparation of [~(14)C]SCH 351125 besylate salt of the desired atropisomer pair is also described.