Intramolecular continuous-flow strategy towards methylphenidate (Ritalin) hydrochloride

threo-Methylphenidate hydrochloride is the most widely prescribed drug to treat attention deficit hyperactivity disorder (ADHD). Herein we present the batch-to-flow translation of a carbene-based intramolecular strategy for the diastereoselective preparation of this active pharmaceutical ingredient. The process relies on the thermal generation and decomposition of a hazardous diazospecies, its thermal intramolecular C-H insertion reaction yielding an intermediate β-lactam, and its subsequent acidic methanolysis, giving enriched threo-methylphenidate hydrochloride in 70% isolated yield. The automated microfluidic setup telescopes 2 chemical transformations, 1 intermediate in-line purification and sustains a daily productivity of 20.4 g/day of methylphenidate hydrochloride. The preparation of the β-lactam is implemented on mesoscale in a pilot-scale continuous-flow reactor, providing 4.25 kg of this key intermediate per day.