7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

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...

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Bibliographic Details
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
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Summary: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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201802256