Issue 2, 2017

Assessing inter- and intramolecular continuous-flow strategies towards methylphenidate (Ritalin) hydrochloride

Abstract

The batch-to-flow translation of inter- and intramolecular strategies for the diastereoselective preparation of the active pharmaceutical ingredient threo-methylphenidate hydrochloride is presented. Both inter- and intramolecular strategies imply the telescoping of multiple processing steps and the generation of unstable diazo species under continuous-flow conditions. The intermolecular strategy relies on an unprecedented continuous-flow Rh-catalyzed intermolecular C–H carbene insertion, providing enriched threo-N-Boc methylphenidate in 38% or 19% isolated yield according to sequential or fully telescoped processes, respectively. Quantitative Boc-deprotection is carried out off-line. The intramolecular strategy relies on a continuous-flow thermal intramolecular C–H carbene insertion, providing enriched threo-methylphenidate hydrochloride in 70% isolated yield. A continuous-flow photochemical alternative is also presented. The critical step of the most promising intramolecular strategy is implemented on the mesoscale in a pilot-scale continuous-flow reactor.

Graphical abstract: Assessing inter- and intramolecular continuous-flow strategies towards methylphenidate (Ritalin) hydrochloride

Supplementary files

Article information

Article type
Paper
Submitted
07 okt 2016
Accepted
03 nov 2016
First published
24 nov 2016

React. Chem. Eng., 2017,2, 149-158

Assessing inter- and intramolecular continuous-flow strategies towards methylphenidate (Ritalin) hydrochloride

R. Gérardy, M. Winter, A. Vizza and J. M. Monbaliu, React. Chem. Eng., 2017, 2, 149 DOI: 10.1039/C6RE00184J

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