Recent advances in process development for opiate-derived pharmaceutical agents

Abstract

This short review summarizes our work on the process development for the synthesis of buprenorphine, naltrexone, naloxone, and nalbuphine from naturally occurring opiates such as thebaine and oripavine. Several new methods for N-demethylation of morphinans have been developed during the pursuit of this research. The article traces the evolution of various approaches and provides a comparison for overall efficiency.

The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

“…The knowledge acquired so far on the biosynthesis of medicinally important BIAs has of course allowed the transfer of partial or entire pathways into non-plant hosts. Strategies for chemical synthesis of morphinans (e.g., morphine, codeine, aka "opiates") have in fact been demonstrated not to be economically feasible; therefore, the licit cultivation of opium poppy is the only source of opiates, from which several semisynthetic derivatives ("opioids") can be also obtained through semisynthesis (e.g., hydrocodone, [52]). Synthesis of thebaine and hydrocodone, for example, has been obtained in yeast starting from common precursors of primary metabolism.…”

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

“…Furthermore, the above 10-keto opiates were also identified as purported intermediates in the decomposition of the parent opiates upon storage [6]. As part of our continuing program in the preparation of morphine alkaloids and related compounds [7,8], we recently had the opportunity to access a suitable intermediate that could potentially be converted to ent -10-keto-oxycodone.…”

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

“…We have recently reported several diverse methods for the N ‐demethylations of morphinans and their derivatives 1. These include the nucleophilic demethylation of quaternary salts,2 palladium‐catalyzed oxidative demethylation with intramolecular acyl transfer from C‐14,3 Burgess reagent demethylation of N ‐oxides,4 and fungal cytochrome oxidative demethylation of several morphine alkaloids to the corresponding secondary amines 5.…”