7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. (14th May 2018)

• Record Type: Journal Article
• Authors: Ziegler, Robert E.; Desai, Bimbisar K.; Jee, Jo‐Ann; Gupton, B. Frank; Roper, Thomas D.; Jamison, Timothy F.
• Is Part Of: Angewandte Chemie. Volume 130:Number 24(2018)
• Page Start: 7299
• Page End: 7303
• Publication Date: 2018-05-14
• Subjects: Amidierungen -- Durchflussreaktoren -- HIV -- Mehrstufige Synthesen -- Pyridone; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201802256
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one‐step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.