7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. Issue 24 (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 international edition. Volume 57:Issue 24(2018)
• Page Start: 7181
• Page End: 7185
• Publication Date: 2018-05-14
• Subjects: amidation -- continuous flow -- HIV -- multistep synthesis -- pyridone; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201802256
• Languages: English
• ISSNs: 1433-7851

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. Abstract : It's easy as D‐T‐G : We report a strategy for the flow synthesis of the anti‐HIV pharmaceutical drug Dolutegravir in 7 steps with three discrete flow operations. This resulted in a short synthesis of the active pharmaceutical ingredient and two examples of three‐step telescoped flow sequences.