Palladium-Catalyzed C–O Cross-Coupling as a Replacement for a Mitsunobu Reaction in the Development of an Androgen Receptor Antagonist

A scalable and efficient synthesis of N-{trans-4-[(8-cyanoquinolin-4-yl)oxy]cyclohexyl}-3-fluorobenzamide (BAY 1161116), an androgen receptor antagonist, is reported. The original synthesis included a low-yielding Mitsunobu reaction and employed cis-aminocyclohexanol, which is accessible only via a troublesome synthesis, as a key building block. The novel synthetic pathway starts from readily available trans-aminocyclohexanol and features a palladium-catalyzed etherification reaction in place of the Mitsunobu reaction as the key step. This four-step synthesis can be performed reliably on a multikilogram scale, and purification of all intermediates as well as the final product can be achieved by simple extraction and crystallization procedures.