Continuous flow reactions in the preparation of active pharmaceutical ingredients and fine chemicals.

Herein, we present an overview of continuous flow chemistry, including photoflow and electroflow technologies in the preparation of active pharmaceutical ingredients (APIs) and fine chemical intermediates. Examples highlighting the benefits and challenges associated with continuous flow processes, mainly involving continuous thermal, photo- and electrochemical transformations, are drawn from the relevant literature, especially our experience and collaborations in this area, with emphasis on the synthesis and prospective scale-up.

Synthesis of Fentanyl under Continuous Photoflow Conditions.

An advantageous and original synthesis of fentanyl is described. This new approach includes two efficient continuous flow reductive aminations achieved via photoredox catalysis and a final batch acylation. A telescoped protocol for the two photocatalyzed steps is also presented, and overall, this protocol provides improved sustainability, significant efficiency, reduced temperatures and reaction times, and is functional for scaling up this relevant active pharmaceutical ingredient (API).

One-Pot Synthesis of Indoles and Pyrazoles via Pd-Catalyzed Couplings/Cyclizations Enabled by Aqueous Micellar Catalysis.

An effective one-pot synthesis of either indoles or pyrazoles can be achieved via Pd-catalyzed aminations followed by subsequent cyclizations facilitated by aqueous micellar catalysis. This new technology includes efficient couplings with low loadings of palladium, a more stable source of the required hydrazine moiety, greater atom economy for the initial coupling, and reduced reaction temperatures, all leading to environmentally responsible processes.

Sustainable Palladium-Catalyzed Tsuji-Trost Reactions Enabled by Aqueous Micellar Catalysis.

Palladium-catalyzed allylic substitution, or "Tsuji-Trost" reactions, can be run under micellar catalysis conditions featuring not only chemistry in water but also numerous combinations of reaction partners that require low levels of palladium, typically on the order of 1000 ppm (0.1 mol %). These couplings are further characterized by especially mild conditions, leading to a number of cases not previously reported in an aqueous micellar medium. Inclusion of diverse nucleophiles, such as N-H heterocycles, alcohols, dicarbonyl compounds, and sulfonamides is described. Intramolecular cyclizations further illustrate the broad utility of this process. In addition to recycling studies, a multigram scale example is reported, indicative of the prospects for scale up.