Highly Selective Catalysts in Reductive Alkylations and in Debenzylation in the Presence of Aromatic Chlorine

This chapter reports the first selective debenzylation of a tertiary amine in the presence of an aromatic halogen employing H₃PO₃ as a catalyst inhibitor. Bidisomide, -α-[2-[acetyl(l-methylethyl)ammo]ethyl]-α-(2-chlorophenyl)-l-piperidinebutanamide, is being developed by Searle to be used as a potential class la/lb antiarrhythmic agent. Bidisomide will be used to treat supravennicular and ventricular arrhythmias with few or none of the side effects frequently associated with drugs used to treat chronic ventricular arrhythmias. The process developed for the second hydrogenation step is a selective catalytic debenzylation in the presence of an aromatic halogen using palladium as a catalyst. Typically, palladium catalysts have been used to dehalogenate halogenated aromatic compounds. Two highly selective hydrogenations based on sequential reductive alkylations and debenzylation have been developed for the synthesis of bidisomide. The second hydrogenation step is the first reported debenzylation of a tertiary amine in the presence of an aromatic chlorine.