7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

• Published in: Angewandte Chemie International Edition 2018-06, Vol.57 (24), p.7181-7185
• Main Authors: Ziegler, Robert E., Desai, Bimbisar K., Jee, Jo‐Ann, Gupton, B. Frank, Roper, Thomas D., Jamison, Timothy F.
• Format: Article
• Language: English
• Subjects: amidation; Amides - chemical synthesis; Amides - chemistry; Antiretroviral drugs; Chemical synthesis; Combinatorial Chemistry Techniques - economics; Combinatorial Chemistry Techniques - methods; Communication; Communications; Continuous flow; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; HIV; HIV Infections - drug therapy; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; Human immunodeficiency virus; Humans; Integrase; Intermediates; multistep synthesis; Organic chemistry; Oxazines; Piperazines; pyridone; Pyridones - chemical synthesis; Pyridones - chemistry; Rapid manufacturing; Telescoping; Time Factors
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201802256

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. 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.