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See detailExpedient Prepararation of Active Pharmaceutical Ingredient Ketamine under Sustainable Continuous Flow Conditions
Kassin, Victor-Emmanuel ULiege; Gerardy, Romaric ULiege; Toupy, Thomas ULiege et al

Poster (2019, February 26)

According to the World Health Organization, depression has become one of the most challenging health issue. With most current antidepressant medications, weeks, if not months, are typically required for ... [more ▼]

According to the World Health Organization, depression has become one of the most challenging health issue. With most current antidepressant medications, weeks, if not months, are typically required for improving patient conditions. By contrast, ketamine (1a), is effective within the first intake. Recent Phase III clinical studies demonstrated the ability of ketamine to rapidly reduce the most severe symptoms of depression. However, current synthetic routes for the preparation of 1a require the use of toxic reagents, FDA class 1-2 solvents and are low atom economy processes. In this work, we describe an effective continuous flow procedure for the expedient and sustainable preparation of 1a and analogs. This procedure involves commercially available low-toxicity chemicals and a FDA class 3 solvent (ethanol). The continuous flow procedure (Figure 1) features 3 steps, including a unique hydroxylation step with molecular oxygen, an iminiation relying on triisopropyl borate and a thermal rearrangement catalyzed by Montmorillonite K10. Each continuousflow step can be performed individually or can be concatenated, thus providing a compact yet robust process for the manufacture of ketamine and analogs (1a-c). The scalability of the critical hydroxylation step was assessed in a commercial pilot continuous-flow reactor. [less ▲]

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See detailExpedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditions
Kassin, Victor-Emmanuel ULiege; Gerardy, Romaric ULiege; Toupy, Thomas ULiege et al

in Green Chemistry (2019)

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 ... [more ▼]

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. [less ▲]

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See detailContinuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges
Gerardy, Romaric ULiege; Emmanuel, Noémie ULiege; Toupy, Thomas ULiege et al

in European Journal of Organic Chemistry (2018)

This review intends to provide the reader with a clear and concise overview of how preparative continuous flow organic chemistry could potentially impact on current important societal challenges. These ... [more ▼]

This review intends to provide the reader with a clear and concise overview of how preparative continuous flow organic chemistry could potentially impact on current important societal challenges. These societal challenges include health/well-being and sustainable development. Continuous flow chemistry has enabled significant advances for the manufacturing of pharmaceuticals, as well as for biomass valorization toward a biosourced chemical industry. Examples related to pharmaceutical production are herein focused on (a) the implementation of flow chemistry to reduce the occurrence of drug shortages, (b) continuous flow manufacturing of orphan drugs, (c) continuous flow preparation of active pharmaceuticals listed on the WHO list of essential medicines and (d) perspectives for the manufacturing of peptide-based pharmaceuticals. Examples related to sustainable development are focused on the valorization of biosourced platform molecules. Besides positive impacts on societal challenges, this review also illustrates some of the potentially most threatening perspectives of continuous flow technology within the actual context of terrorism and drug abuse. [less ▲]

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