Stereocontrolled Synthesis of Delgocitinib, a JAK Inhibitor for the Treatment of Atopic Dermatitis

• Published in: Organic process research & development Vol. 25; no. 2; pp. 342 - 348
• Main Authors: Takiguchi, Hiromu, Higashi, Akinobu, Watanabe, Takashi, Takeichi, Tsubasa, Shimazaki, Takahisa, Inaba, Takashi
• Format: Journal Article
• Language: English
• Published: American Chemical Society 19-02-2021
• Subjects: hydrazine-free dephthaloylation; intramolecular SN2 reaction; one-pot reduction of β- and γ-lactams; rigid transition state; delgocitinib; chiral spirodiamine
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.1c00031

Herein is reported the nine-step commercial synthesis of delgocitinib, a Janus kinase inhibitor approved for the treatment of atopic dermatitis in 2020. Its chiral spirodiamine core was selectively constructed by an intramolecular SN2 reaction of the suitably designed γ-lactone substrate and a few subsequent steps including a selective γ-lactone ring-opening reaction with potassium phthalimide, hydrazine-free mild dephthaloylation, and one-pot reduction of β- and γ-lactams. The route affords chemically and stereochemically pure delgocitinib in 39% yield.