The Development of a Robust Process for a CRF 1 Receptor Antagonist

A scalable and robust process was developed for the preparation of pexacerfont (2), a pyrazolotriazine corticotropin-releasing factor receptor 1 antagonist (CRF1). The formation of the core hydroxypyrazolotriazine moiety was achieved through two consecutive cyclizations of a semicarbazide, employing reaction conditions that are significantly milder than those reported in the literature. Further conversion to the key chloropyrazolotriazine intermediate was accomplished through a novel catalytic process using phosphorous oxychloride as the chlorinating agent. The active pharmaceutical ingredient 2 was obtained in > 99.5% purity with a 68% overall yield for the six synthetic steps.