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.

Synthesis of Nororipavine and Noroxymorphone via N- and O-Demethylation of Iron Tricarbonyl Complex of Thebaine

“…Both of the protective operations were easily reversible; iron decomplexation or the retro-cycloaddition restores the C ring with dienol ether function intact. 33 In addition, we found that the thebaine-iron complex is very stable even under extremely acidic conditions. However, after O-demethylation a phenolic iron complex was formed that proved quite sensitive to basic conditions, especially to the presence of ammonia and amines.…”

Direct Synthesis of Noroxymorph­one from Thebaine: Unusual CeIV Oxidation of a Methoxydiene‐Iron Complex to an Enone‐γ‐Nitrate

“…In 2014 we published the conversion of thebaine to oripavine and to hydromorphone7 via the O‐demethylation of the iron carbonyl complex 6 and hydrolysis. Realizing that the best common starting material for the synthesis of the various antagonists would be either noroxymorphone ( 5 ) or nororipavine ( 10 ) we set out this time to explore the conversion of thebaine to nororipavine as shown in Scheme .…”

The Local Anesthetic and Pain Relief Activity of Alkaloids

“…Even though oripavine is a strong pain reliever with comparable analgesic potency to morphine, it does not have clinical use. It is used as convenient source for the production of several synthetic opioid pharmaceuticals [97].…”