Continuous-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds

Abstract

The efficacy, safety, and scale-up of several chemical rearrangements remain unsolved problems due to the associated handling of hazardous, toxic, and pollutant chemicals and high-risk intermediates. For many years batch processes have been considered the only possibility to drive these reactions, but continuous-flow technology has emerged, for both academic laboratories and pharmaceutical companies, as a powerful tool for easy, controlled, and safer chemistry protocols, helping to minimize the formation of side products and increase reaction yields. This Technology Note summarizes recently reported chemical rearrangements using continuous-flow approaches, with a focus on Curtius, Hofmann, and Schmidt reactions. Flow protocols, general advantages and safety aspects, and reaction scope for the generation of both privileged scaffolds and active pharmaceutical ingredients will be showcased.

Photochemistry in Medicinal Chemistry and Chemical Biology

“…Indeed, this has recently been reported for the most common photochemical rearrangements for the generation of privileged scaffolds and APIs with generally good yields and short reaction times. 160,161 The scale up of photochemical reactions is of high priority to enable their application to the pharmaceutical industry. Typically, continuous flow approaches with small channel diameters are ideally suited since the penetration of photons decreases exponentially with the Beer−Lambert's Law.…”

Unified and green oxidation of amides and aldehydes for the Hofmann and Curtius rearrangements

“…The Hofmann and Curtius rearrangements [1][2][3] have found wide applications in organic synthesis because they offer a convenient and reliable way to convert carboxylic acid derivatives (amides and acyl azides) into synthetically valuable amines or protected amines (carbamates and ureas) through a common isocyanate intermediate as a result of formal insertion of nitrogen into C-C bond (Scheme 1a). Notably, both the Hofmann and Curtius rearrangements have been used for (continuous flow) industrial production of pharmaceutically relevant amines/carbamates: 4 (a) the Hofmann rearrangement using (diacetoxyiodo)benzene as the oxidant has been applied to the industrial degradation (100 kg quantities) of asparagine derivatives; 5 (b) a continuous flow Hofmann rearrangement using trichloroisocyanuric acid (TCCA) has been developed for the massive production of highly medicinally valuable 2-benzoxazolinone (23 g h −1 ) from inexpensive salicylamide; 6 and (c) a continuous flow Curtius rearrangement 4,7,8 typically using diphenylphosphoryl azide (DPPA) 9,10 as an activating reagent for carboxylic acids has been rigorously studied for the largescale preparation of the medicine-relevant carbamate intermediates including the carbamate (5.97-kg scale) of AZD7648 (a selective inhibitor of DNA-dependent protein kinase for anticancer treatment) 11 and p-methoxybenzyl carbamate (0.8 kg h −1 , 40 kg scale) for the synthesis of a CCR1 antagonist. 12 An in situ generation of the unstable rearrangement substrates, N-halo amides and acyl azides, is generally conducive to the overall efficiency of both the Hofmann and Curtius rearrangements, which can be readily achieved by the halogenation of primary amides and the azidation of carboxylic acid derivatives (i.e., acid chloride), respectively.…”

Monolithic Catalysts Supported by Emulsion-Templated Porous Polydivinylbenzene for Continuous Reduction of 4-Nitrophenol

“…Continuous flow chemistry has garnered increasing attention in the modern chemical industry for its extensive applicability to both small-scale and large-scale syntheses. − A continuous flow reactor offers fine chemical engineering with numerous advantages including cost-effectiveness, efficiency, and environmental friendliness. Catalysts, particularly heterogeneous catalysts, play a crucial role in continuous flow reactors .…”