General Method of Synthesis for Naloxone, Naltrexone, Nalbuphone, and Nalbuphine by the Reaction of Grignard Reagents with an Oxazolidine Derived from Oxymorphone

Abstract

Abstract The N ‐oxide of O ‐acyloxymorphone, when treated with the Burgess reagent, provides the corresponding oxazolidine in a one‐pot sequence and in excellent yield. The oxazolidine derived from oxymorphone, temporarily protected at O‐3 and C‐6, reacts with Grignard reagents to provide directly N ‐allyl, N ‐cyclopropylmethyl, and N ‐cyclobutylmethyl derivatives that are further converted to the title compounds, namely naltrexone, naloxone, nalbuphone, and nalbuphine in excellent yields. Each of these medicinal agents is obtained from the oxazolidine in a one‐pot sequence. Complete spectral and experimental data are provided for all compounds.