Development of a Multikilogram-Scale One-Pot Albright–Goldman Oxidation/Dienol Acetate Formation Sequence for the Synthesis of Noroxymorphone from Morphine

Abstract

The syntheses of therapeutically important μ-opioid receptor antagonists such as naloxone and naltrexone use noroxymorphone as a key late-stage intermediate, which is manufactured from the poppy-derived alkaloids oripavine or thebaine. However, it would be advantageous to instead use morphine as the starting material, which is cheaper and more abundant. In this paper, we describe the conversion of morphine into a dienol acetate required for installation of the C14 hydroxyl group of noroxymorphone. Our approach is more efficient than previously described approaches and uses a one-pot Albright–Goldman oxidation/dienol acetate formation sequence of an allylic alcohol as the key feature. This synthesis has been successfully applied on multikilogram scales. A brief investigation of the scope of the one-pot Albright–Goldman oxidation/dienol ester formation on other substrates is also described.