Practical and scalable synthesis of beclomethasone dipropionate

Abstract

Beclomethasone dipropionate (1) is a synthetic corticosteroid with anti-inflammatory, antipruritic, and anti-allergy properties. It is widely used to treat asthma, allergic rhinitis, and dermatoses. However, existing synthetic routes to this active pharmaceutical ingredient (API) contain steps resulting in low and/or inconsistent yields, and use obsolete reagents. Such inconsistencies coupled with a lack of reliable experimental data makes laboratory-scale and large-scale synthesis of this API difficult and time-consuming. In this paper, we report a practical and scalable approach to synthesize 1 from the readily available steroidal intermediate, 16β-methyl epoxide (3, DB-11). A gram-scale to kilogram-scale synthesis of 1 was achieved with 82% yield, using a cost-effective and scalable methodology. Selective propionylation of the hydroxyl groups at C₁₇ and C₂₁ demonstrate the fact that this approach can be conveniently implemented in fine chemical industries.

Keywords: Beclomethasone; Beclomethasone dipropionate; DB-11; Glucocorticoids; Propionic anhydride; Triethyl orthopropionate.