A Sustainable and Potentially Cost-Effective Approach to the Antimalarial Drug KAF156 (Ganaplacide)

Reported herein is a sustainable route to obtaining the prospective antimalarial KAF156 (ganaplacide). This sequence eliminates usage of environmentally irresponsible solvents such as DCM, DMF and 1,4-dioxane while improving the overall yields and reaction times of these reactions. Included is a 6-step telescoped process that provides high yields of an intermediate which eliminates egregious solvents and long reaction times. A reduction in palladium associated with the catalyst required for amination was achieved by utilizing an iodide (rather than the corresponding bromide), leading to comparable yields of the N-Boc-protected drug. The final step leads to an easily isolated and high yielding HCl salt of KAF156, this route outperforming the previously reported approach in terms of sustainability, reaction and workup time, and yield.