2018
DOI: 10.1002/anie.201802256
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7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

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 mu… Show more

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Cited by 86 publications
(60 citation statements)
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“…Dual therapies have begun to replace other cARTs as a maintenance strategy for improving adherence and safety. A number of dual therapies that combine ETR or RPV with an INSTI are [42,[66][67][68]. Important single bonds with broad rotational flexibility are shown in red or with partial flexibility in blue.…”
Section: Dapy/insti Dual Therapiesmentioning
confidence: 99%
See 1 more Smart Citation
“…Dual therapies have begun to replace other cARTs as a maintenance strategy for improving adherence and safety. A number of dual therapies that combine ETR or RPV with an INSTI are [42,[66][67][68]. Important single bonds with broad rotational flexibility are shown in red or with partial flexibility in blue.…”
Section: Dapy/insti Dual Therapiesmentioning
confidence: 99%
“…The virologic failure of patients on ETR, RPV, and cARTs has been attributed in part to regimen non-adherence [40,41,50,60,64,65]. [42,[66][67][68]. Important single bonds with broad rotational flexibility are shown in red or with partial flexibility in blue.…”
Section: Introductionmentioning
confidence: 99%
“…The development of flow chemistry over the past few decades has led to improvements in synthesis, [1][2][3][4][5][6][7][8] catalysis, [9][10][11][12][13] reaction screening, 14 scale up, 15,16 and quality control. [17][18][19] Flow syntheses applied to bulk polymerizations have shown better control in reaction kinetics and have improved product quality.…”
Section: Introductionmentioning
confidence: 99%
“…Compared with the first generation of integrase inhibitors, raltegravir and elvitegravir, dolutegravir possesses a higher barrier for developing resistance, as well as that the clinical efficacy for AIDS treatment is better than raltegravir . Recently, there is a great need for process research for the forthcoming industrial manufacture. Hence, an efficient synthetic route of dolutegravir is urgently needed.…”
Section: Introductionmentioning
confidence: 99%