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Issue 2, 2017
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Assessing inter- and intramolecular continuous-flow strategies towards methylphenidate (Ritalin) hydrochloride

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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

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Publication details

The article was received on 07 Oct 2016, accepted on 03 Nov 2016 and first published on 24 Nov 2016


Article type: Paper
DOI: 10.1039/C6RE00184J
Citation: React. Chem. Eng., 2017,2, 149-158
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    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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