Kinetics of electrophilic fluorination of steroids and epimerisation of fluorosteroids

Fluorinated steroids, which are synthesised by electrophilic fluorination, form a significant proportion of marketed pharmaceuticals. To gain quantitative information on fluorination at the 6‐position of steroids, kinetics studies were conducted on enol ester derivatives of progesterone, testosterone, cholestenone and hydrocortisone with a series of electrophilic N−F reagents. The stereoselectivities of fluorination reactions of progesterone enol acetate and the kinetic effects of additives, including methanol and water, were investigated. The kinetics of epimerisation of 6β‐fluoroprogesterone to the more pharmacologically active 6α‐fluoroprogesterone isomer in HCl/acetic acid solutions are detailed.
Fluorosteroid pharmaceuticals are prepared industrially by electrophilic fluorination. Quantitative insights into the synthesis of 6‐fluorosteroids could lead to more efficient processes. Here, kinetic and analytical studies upon a range of fluorinations of steroid enol esters, and subsequent epimerisation towards the α‐epimer are described. X‐ray crystallography is exploited to deliver unambiguous assignments of absolute configurations.