7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

Angewandte Chemie
Robert E ZieglerTimothy F Jamison

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.

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Citations

Oct 10, 2020·Chemistry : a European Journal·Jiao JiaoPengfei Li
Jan 30, 2019·Reaction Chemistry & Engineering·Cameron T ArmstrongThomas D Roper
Jun 2, 2021·The Journal of Organic Chemistry·Cloudius R SagandiraPaul Watts
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jiahui KongYongping Yu
Feb 23, 2019·Journal of Medicinal Chemistry·Andrew R Bogdan, Amanda W Dombrowski
Apr 19, 2019·The Journal of Organic Chemistry·Dmitrii L ObydennovVyacheslav Y Sosnovskikh

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Methods Mentioned

BETA
amidation
silica gel chromatography

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