Conversion of Thebaine to Oripavine and Other Useful Intermediates for the Semisynthesis of Opiate-Derived Agents: Synthesis of Hydromorphone

Abstract

Thebaine was converted to oripavine in three steps by employing two different modes of protection of the diene moiety; as an iron tricarbonyl complex and as a Diels-Alder adduct with thioformyl cyanide. The two C-ring-protected thebaine derivatives were subjected to 3-O-demethylation by four different protocols, providing oripavine derivatives, which yielded oripavine after deprotection.

Oripavine was then converted to hydromorphone by a three-step process of ketalization, hydrogenation, and deprotection, without the isolation of intermediates.

Keywords

• alkaloids
• hetero-Diels-Alder cycloaddition
• hydromorphone synthesis
• iron-diene complexes
• natural products
• oripavine synthesis
• protecting groups
• thebaine O-demethylation