Development of a Novel Process for the Preparation of the Anti-Inflammatory Drug Betamethasone Sodium Phosphate

In this paper, we report our efforts for the development of a novel and improved preparation of the anti-inflammatory steroidal active pharmaceutical ingredient, namely, betamethasone sodium phosphate. Starting from commercially available betamethasone, the synthetic strategy involved the mesylation of the hydroxyl group at C21 position, followed by the key phosphorylation reaction of the mesylate derivative with potassium di-tert-butyl phosphate, the hydrolysis of the di-tert-butyl ester intermediate under mild acidic conditions, and the final salification. The developed process allowed us to obtain the desired betamethasone sodium phosphate in 68% overall yield at multi-kg scale ≥ 99.9% HPLC purity. Cost-effectiveness of the process, impurity profiling, and material quality are also discussed.