Organophotocatalytic N-Demethylation of Oxycodone Using Molecular Oxygen

Abstract

N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable organophotocatalytic procedure that accomplishes the N-demethylation step using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst. Optimization of the reaction conditions under continuous flow conditions using visible-light irradiation led to an efficient, reliable, and scalable process, producing noroxycodone hydrochloride in high isolated yield and purity after a simple workup.

Keywords: N-demethylation; continuous-flow; gas/liquid reaction; opioid; photocatalysis.

Scheme 1

Significance of N‐demethylation in the synthesis of semisynthetic opioids and common methods.

Figure 1

Stern–Volmer quenching experiment of RB using 2 (OC) as a quencher in different solvents (T=21 °C, [RB]=1 μmol L⁻¹). Viscosity of the solvents: η (MeOH)=0.5838 MPa s, η(EtOH)=1.170 MPa s and η(n‐PrOH)=2.125 MPa s.

Scheme 2

Suggested reaction mechanism.

Figure 2

Flow setup for the N‐demethylation of 2 and optimization of the residence time and relative irradiation power (P/P _max).

Figure 3

Influence of reaction temperature and catalyst loading in the continuous photochemical generation of 5.