7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

Abstract

Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapyf or the treatment of HIV,has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir,D TG was produced in 4.5 hi n sequential flowoperations from commercially available materials.Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of afunctionalized pyridone,and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.

Six-Step Gram Scale Synthesis of the HIV Integrase Inhibitor Dolutegravir Sodium

“…Oven-dried glass ware was dried in an oven at 150 °C overnight, assembled while still hot, cooled to room temperature and then purged with nitrogen. NMR spectra were recorded on a Bruker Avance-III HD instrument ( 1 H-NMR: 300 MHz, 13 C-NMR: 75 MHz) or a Bruker Avance-III HD instrument…”

“…( 1 H-NMR: 400 MHz, 13 C-NMR: 101 MHz, 19 F-NMR: 377 MHz) with a 5 mm BBFO probe. The chemical shifts δ were expressed in ppm downfield from tetramethylsilane ( 1 H-NMR, 13 C-NMR).…”

“…The aminolysis of an ethyl ester moiety with 2,4-difluorobenzylamine by heating in toluene in the presence of acetic acid has already been reported in literature for other dolutegravir building blocks. 7,13 The toluene/acetic conditions showed to be appropriate also for ester 18 and thus were optimized (for more details see supporting information). After heating overnight in the presence of an excess of amine and acetic acid (both 2.5 eq.…”

“…When the water was removed in vacuo and the salty residue was suspended in ethyl acetate, a further 40% of 26 could be isolated. Scheme 6: N-Acylation of 3-(R)-amino-1-butanol (13).…”

Continuous flow synthesis of N‑(2‑aminophenyl) benzamide with high selectivity and its kinetic study in a microreactor

“…The microreactor, also called micro structured reactor or micro channel reactor, has received extensive attention as an efficient and strong tool for continuous synthesis. [16][17][18][19] With its numerous advantages such as large surface area-to-volume ratios, high mixing efficiency, fast mass and heat transfer rates, inherent safety, and precise control over process parameters, this technology has been widely applied in drug synthesis, [20][21][22][23][24] organic chemistry methodology, [25][26][27][28] chemical engineering [29][30][31][32][33][34][35][36][37] and so on.…”