Synthesis of 7-benzylideneoctahydro-2H-pyrido[1,2-a]pyrazines, bicyclic analogues of the calcium antagonist flunarizine

Abstract

The bicyclic amino ketone 4(2-benzyloctahydro-2H-pyrido[1,2-a]pyrazin-7-one) has been converted in four steps into the pharmacologically interesting (Z)- and (E)-7-benzylideneoctahydro-2H-pyrido[1,2-a]pyrazines 2a, b, bicyclic analogues of the calcium antagonist flunarizine 1. In the key step, olefination of the ketone group, the yield was highly improved (15–20%→82–85%) by using (a) the phosphonate anion instead of the Wittig reagent and (b) the solvent 1,3-dimethylimidazolidin-2-one instead of tetrahydrofuran. Debenzylation and final substitution of the 2-amino group with (4-FCSH4)2CHCI gave the geometric isomers 2a(Z) and 2b(E) in 53% overall yield.