Scalable Synthesis of Antihistamines and Sensipar via Intensified Hydrogen Borrowing Methodology

<p dir="ltr">Borrowing hydrogen has gained much interest in academia and industry as a green method in converting simple alcohols to valuable amines in a waste-free manner. Despite the considerable efforts in its development, many challenges in this strategy still remain and prevent its application to the final stages of drug synthesis, such as the high loadings of heavy metal catalysts, harmful solvents, and cumbersome purification procedures needed to obtain purity profiles that comply with regulatory guidelines. In view of these problems, we have explored possible alternatives that emphasize atom economy and circumvent the use of toxic solvents while ensuring scalability and low heavy metal content in the final API. We report herein a high productivity hydrogen borrowing synthesis of a range of commercial drugs including Cinacalcet (Sensipar) and a selection of antihistamines: Meclizine, Buclizine, and Cyclizine. This scalable synthetic approach avoids the generation of stoichiometric waste and yields good to excellent PMI values thanks to the intensified nature of the developed process (e.g., space–time yield of 29.8 g L^–1 h^–1 for the synthesis of Sensipar). The use of low iridium catalyst loadings (0.15 mol %) and benign reaction media (e.g., solventless), coupled with the efficient salt precipitation of the amine salts resulting in low iridium detected in the final product (below 10 ppm), renders this work a realistic green alternative for synthetic application in Pharma.</p>