Practical and scalable synthesis of beclomethasone dipropionate

• Published in: Steroids Vol. 177; pp. 108948 - 108953
• Main Authors: Welideniya, Dhanushi T., Jayathilaka, Adeesha S., Acharige, Anjana Delpe, Samanthi, K.A.U., Wanninayake, Umayangani K., Perera, Shashika S., Rajapaksha, Weranga, Fernando, Chamod C., Hewadikaram, Madhavi, Buddhika, Janani, Gunasekara, Pivini, Karunaratne, Veranja, Amaratunga, G.A.J., Gunasekera, Dinara S.
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 01.01.2022; Elsevier
• Subjects: Beclomethasone; Beclomethasone - chemical synthesis; Beclomethasone - chemistry; Beclomethasone dipropionate; Biochemistry & Molecular Biology; DB-11; Endocrinology & Metabolism; Glucocorticoids; Life Sciences & Biomedicine; Molecular Conformation; Propionic anhydride; Science & Technology; Stereoisomerism; Triethyl orthopropionate; Beclomethasone dipropionate; Triethyl orthopropionate; Beclomethasone; Propionic anhydride; DB-11; Glucocorticoids; THERAPEUTIC INDEX; INHALED CORTICOSTEROIDS; CHILDREN
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2021.108948

[Display omitted] •Practical and scalable approach to synthesize beclomethasone dipropionate.•Readily available and cost-effective intermediate DB-11 as the starting material.•Optimized consistent conversion of DB-11 to beclomethasone with high purity.•A one-pot conversion of beclomethasone to beclomethasone dipropionate. 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.