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Issue 11, 2019
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Expedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditions

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Abstract

A robust three-step continuous flow procedure is presented for the efficient and sustainable preparation of active pharmaceutical ingredient ketamine. The procedure relies on the main assets of continuous flow processing, starts from commercially available chemicals, utilizes low toxicity reagents and a FDA class 3 solvent under intensified conditions. The procedure features a unique hydroxylation step with molecular oxygen, a fast imination relying on triisopropyl borate and a thermolysis employing Montmorillonite K10 as a heterogeneous catalyst, all three steps being performed in ethanol. The three individual steps can be run independently or can be concatenated, thus providing a compact yet efficient setup for the production of ketamine. The scalability of the critical hydroxylation step was assessed in a commercial pilot continuous flow reactor. The process can also be adapted for the preparation of ketamine analogs. A thorough computational study on the backbone rearrangement of the cyclopentylphenylketone scaffold under thermal stress rationalizes the experimental selectivity and the various experimental observations reported herein.

Graphical abstract: Expedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditions

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Publication details

The article was received on 28 Jan 2019, accepted on 19 Mar 2019 and first published on 19 Mar 2019


Article type: Paper
DOI: 10.1039/C9GC00336C
Green Chem., 2019,21, 2952-2966

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    Expedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditions

    V. H. Kassin, R. Gérardy, T. Toupy, D. Collin, E. Salvadeo, F. Toussaint, K. Van Hecke and J. M. Monbaliu, Green Chem., 2019, 21, 2952
    DOI: 10.1039/C9GC00336C

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