Two carbene-based strategies for the diastereoselective preparation of the active pharmaceutical ingredient threo-methylphenidate hydrochloride are adapted from batch to continuous-flow conditions. These strategies rely either on the inter- or intramolecular reactivity of hazardous diazospecies that are generated and consumed in situ, thus minimizing safety issues. The intermolecular strategy combines several steps including the generation of an organic azide, a diazo transfer reaction, and a Rh(II)-catalyzed C-H insertion. Isolated yields of 38 or 19% in enriched threo-N-Boc methylphenidate are obtained according to sequential or telescoped processes, respectively. Boc deprotection is quantitatively carried out off-line. The intramolecular strategy relies on the thermal generation and decomposition of a diazo compound, 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. An alternative photochemical process is presented as well. Scale-out of the critical intramolecular thermal C-H insertion reaction is demonstrated in a pilot-scale mesofluidic reactor.

Assessing inter- and intramolecular continuous-flow strategies towards methylphenidate hydrochloride

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.