SYNTHESIS OF THE SELECTIVE D-2 RECEPTOR AGONIST PNU-95666E FROM D-PHENYLALANINE USING A SEQUENTIAL OXIDATIVE CYCLIZATION STRATEGY

Compound 1 (PNU-95666E) is a selective and high-affinity agonist at th e dopamine D-2 receptor subtype and is of interest as a potential agen t for the treatment of Parkinson's disease. Requiring a synthetic rout e amenable to scale-up, a synthesis of this enantiomerically pure tric yclic compound was developed, starting from D-phenylalanine. Critical to the success of this synthesis were two oxidative nitrogen annulatio ns to provide the tricyclic ring system. A highly efficient reduction with borane-methyl sulfide was used to reduce three different function al groups, a total of six hydrides transferred, with no concomitant ra cemization, contributing to the synthesis of 1 in eight steps with an overall yield of 26%. The utility of this synthetic route has been dem onstrated by the completion this synthesis on multikilogram scale.