Reference : Intramolecular continuous-flow strategy towards methylphenidate (Ritalin) hydrochloride
Scientific congresses and symposiums : Poster
Physical, chemical, mathematical & earth Sciences : Chemistry
Intramolecular continuous-flow strategy towards methylphenidate (Ritalin) hydrochloride
Gerardy, Romaric mailto [Université de Liège > Département de chimie (sciences) > Chimie organométallique et catalyse homogène >]
Winter, Marc []
Vizza, Alessandra []
Monbaliu, Jean-Christophe mailto [Université de Liège > Département de chimie (sciences) > Chimie organométallique et catalyse homogène >]
20th SIGMA-ALDRICH Organic Synthesis Meeting
du 08 décembre 2016 au 09 décembre 2016
[en] Flow Chemistry ; Active Pharmaceutical Ingredient ; C-H insertion
[en] 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.
Center for Integrated Technology and Organic Synthesis
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS
Researchers ; Professionals ; Students

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