Process improvements in the synthesis of corticosteroid 9,11β-epoxides

Corticosteroid 9,11 beta -epoxides are key intermediates in the preparation of pharmaceutically important compounds such as betamethasone, mometasone, beclomethasone, and dexamethasone. A new process for the 9,11 beta -epoxide was developed using a PCl5-mediated regioselective dehydration of II alpha -hydroxysteroid to form the corresponding Delta (9,11) double bond. The olefin is then converted into 9 alpha ,11 beta -bromoformate by treatment with 1,3-dibromo-5, 5-dimethyl hydantoin (DBH) in DMF and subsequently cyclized to produce the desired 9,11 beta -epoxide upon treatment with NaOH. Major process-related impurities such as 21-OH-Delta (9,11)-triene, 21-OH-Delta (11,12)-triene, 21-Cl-Delta (9,11)-triene, and beta -epoxide-21-cathylate as well as 11 beta -Cl are all eliminated or minimized. This new process has been implemented in our manufacturing facility in full-scale production and proved to raise the overall yield and the quality of the product dramatically compared to the existing process.