Application of In Situ FTIR for the Preparation of 17-α-Estradiol via Mitsunobu Reaction

An efficient synthesis of 17-alpha-estradiol 1 is described. Utilization of in situ IR allowed for an online monitoring of the key Mitsunobu reaction and development of a safe and reliable synthesis of 17-alpha-estradiol 1 in 78% overall yield over three steps. Benzoylation of 17-beta-estradiol 2 is conducted at high regioselectivity under phase-transfer catalysis (PTC) conditions, followed by a Mitsunobu reaction to invert the chiral center at C-17 and provide intermediate 5, containing the core structure of 17-alpha-estradiol 1. Finally, the desired active pharmaceutical ingredient (API) is prepared by saponification of the remaining esters.