A Safe and Reliable Continuous-Flow System towards Methylphenidate Hydrochloride

The batch-to-flow translation of a carbene-based strategy for the diastereoselective preparation of the active pharmaceutical ingredient threo-methylphenidate hydrochloride is presented. The continuous-flow system implies the generation of an explosive organic azide, its consumption in a diazo transfer reaction, an intermediate purification step followed by a Rh(II)-catalyzed carbene C-H insertion reaction that produces threo-enriched N-Boc-methylphenidate. Boc-deprotection is carried out off-line and provides methylphenidate hydrochloride in 19% isolated yield (3 steps fully telescoped) or 38% isolated yield (sequential).