Triethylamine → Sufentanil

Participants

Reaction Conditions

Reaction Steps

To a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities was charged 4-[(1-oxopropyl)phenylamino]-4-methoxymethyl piperidine nosylate (100.0 g, 21 mmol), 2-(2-thiophenylethyl) 4-nitro-benzene sulfonate (71.9 g, 23 mmol), tert-butyl methyl ether (MTBE, 222 g, 300 mL), and triethylamine (TEA, 436 g, 4.3 mol). The reaction mixture was warmed to 60±5° C. As the reaction progressed, a slurry was formed. After 5 hours, the system was cooled and charged with MTBE (296 g, 400 mL). This diluted system was washed sequentially with water (400 mL), 5% aqueous sodium bicarbonate (400 mL), water (400 mL), and water (400 mL). The solvent was removed by distillation and replaced with iso-propanol (394 g, 500 mL). The system was warmed to give a clear solution at 45° C. Water (800 g, 800 mL) was added to give a turbid system at 45° C. The hazy slurry was cooled slowly to ambient temperature, then further cooled to 5° C., and held at that temperature for approximately 15 hours. The resultant slurry was filtered and washed with 40% aqueous iso-propanol to provide white crystals. The solids were dried to constant weight under vacuum at 55° C. This process provided 67.5 g (84 mol %) of sufentanil as a white solid, purity over 99% by HPLC.

Provenance & Evidence