Química de fluxo contínuo aplicada à síntese de insumos farmacêuticos ativos (IFAs): buclizina

Abstract

The development of novel synthetic routes for the production of Active Pharmaceutical Ingredients (APIs) is pivotal not only for establishing more sustainable and competitive manufacturing processes but also for the training of new professionals seeking to enter this sector. Among modern synthetic technologies offering significant advantages for API manufacturing, continuous flow synthesis stands out. This approach contributes to enhancing synthetic systems by improving scalability and productivity, reducing solvent consumption, increasing automation levels, and ensuring greater process safety. In this work, the synthesis of the API buclizine is presented comprising four steps, all performed under continuous flow conditions. Initially, a continuous flow photocatalyzed reductive amination between piperazine and 4-tert-butylbenzaldehyde was carried out, scaled up to the gram scale with a productivity of 10.7 g/day. Subsequently, the electrochemical reduction of 4- chlorobenzophenone was performed, also on a gram scale, achieving a productivity of 6.6 g/day. The resulting product then reacted with hydrochloric acid to convert the alcohol into its corresponding chloride, reaching a productivity of 86 g/day due to the short residence time and high concentration of the reaction mixture. Finally, the chloride intermediate was reacted with the product from the photocatalytic step via a nucleophilic substitution reaction, yielding buclizine. This step produced 1.5 g of the API with a productivity of 9.4 g/day, representing a gram-scale proof-of-concept for the continuous synthesis of this pharmaceutical ingredient.