Synthesis of the Selective D 2 Receptor Agonist PNU-95666E from d -Phenylalanine Using a Sequential Oxidative Cyclization Strategy

  • 10.1021/jo970526a
  • The Journal of Organic Chemistry
  • p 6582-6587, Volume 62, Issue 19,
  • journal-article
Compound 1 (PNU-95666E) is a selective and high-affinity agonist at the dopamine D 2 receptor subtype and is of interest as a potential agent for the treatment of Parkinson's disease. Requiring a synthetic route amenable to scale-up, a synthesis of this enantiomerically pure tricyclic compound was developed, starting from d-phenylalanine. Critical to the success of this synthesis were two oxidative nitrogen annulations to provide the tricyclic ring system. A highly efficient reduction with borane−methyl sulfide was used to reduce three different functional groups, a total of six hydrides transferred, with no concomitant racemization, contributing to the synthesis of 1 in eight steps with an overall yield of 26%. The utility of this synthetic route has been demonstrated by the completion this synthesis on multikilogram scale.


Good synthesis of enantiomerically pure (R)-sumanirole

PNU-95666E (sumanirole) was reported to be a highly selective D2 receptor full agonist. It was originally developed for the treatment of Parkinson’s disease. An eight steps synthesis was developed for the scale up of enantiomerically pure (R)-sumanirole with an overall yield of...