Optimized and Scalable Synthesis of Nalbuphine from Noroxymorphone: A Comparative Study of Organic Solvent and Ionic Liquid Media

Abstract Nalbuphine is a clinically important semi‑synthetic opioid analgesic that offers effective pain relief with a lower incidence of respiratory depression and pruritus than morphine. In the present work, a two‑step route to nalbuphine, starting from noroxymorphone, was developed and optimized. The first step consisted of selective N‑alkylation of noroxymorphone with cyclobutylmethyl bromide, and the second step involved reduction of the C6 carbonyl group of the resulting nalbuphone. Solvent, base, temperature, reaction time, and molar ratio were varied systematically to identify the optimal conditions. Three n‑butyl‑substituted ionic liquids—1‑butylpyridinium bromide, 1‑butyl‑3‑methylimidazolium bromide, and diethyldibutylammonium bromide—were prepared and tested as alternative reaction media. Although these ionic liquids displayed high thermal stability and could be recycled for up to three runs with > 93% recovery, their high viscosity led to mass‑transfer limitations and gave lower isolated yields (up to 74%). Under the optimized conditions, N‑alkylation in N‑methyl‑2‑pyrrolidone (NMP) with triethylamine as base at 80°C for 12 h produced nalbuphone in 79% yield. Reduction of nalbuphone with NaBH 4 /I 2 in tetrahydrofuran (THF) under reflux for 12 h afforded nalbuphine in 80% yield with an α:β epimer ratio of 75:25. The structures of all compounds were confirmed by FT‑IR, 1 H‑NMR, 13 C‑NMR, and GC‑MS. Green chemistry metrics, including E‑factor, Process Mass Intensity (PMI), Atom Economy (AE), and Reaction Mass Efficiency (RME) were calculated and compared for both the NMP and ionic liquid routes; the IL route showed a lower E‑factor (513 vs. 667) and PMI (514 vs. 668), while the NMP route gave a slightly higher overall yield (63% vs. 59%). The comparison of NMP and ionic liquid media highlights the trade‑offs between synthetic efficiency, reaction kinetics, and environmental impact, and provides a scalable basis for greener pharmaceutical synthesis, as demonstrated by a 10 mmol scale experiment (63% overall yield for the NMP route and 59% for the IL route). A complete mass balance was constructed for both steps, with an overall closure of 99.8%, confirming that essentially all input materials are accounted for in the product and waste streams.