SYNTHESIS OF 7-BENZYLIDENEOCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZINES, BICYCLIC ANALOGS OF THE CALCIUM-ANTAGONIST FLUNARIZINE

The bicyclic amino ketone 4 (2-benzyloctahydro-2H-pyrido[1,2-a]pyrazin -7-one) has been converted in four steps into the pharmacologically in teresting (Z)- and )-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 im proved (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 t he 2-amino group with (4-FC6H4)(2)CHCl gave the geometric isomers 2a ( Z) and 2b (E) in 53% overall yield.