Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium
This is the accepted manuscript version of the work published in its final form as Dietz, Jule-Philipp; Lucas, Tobias; Groß, Jonathan; Seitel, Sebastian; Brauer, Jan; Ferenc, Dorota; Gupton, B. Frank; Opatz, Till. Organic Process Research & Development; Volume: 25; Issue: 11; Pages: 1898-1910; https://doi.org/10.1021/acs.oprd.1c00139. Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.
Nickel‐Mediated Photoreductive Cross Coupling of Carboxylic Acid Derivatives for Ketone Synthesis**
A simple photochemical, nickel-catalyzed synthesis of ketones starting from carboxylic acids is presented. Hantzsch-ester (HE) functions as a cheap, green and strong photoreductant upon visible-light excitation to facilitate radical generation and also engages in the Ni-catalytic cycle to restore the reactive species. With this dual role, HE allows for the coupling of a large variety of radicals (1°,2°, benzylic, α-oxy & α-amino) with aroyl and alkanoyl moieties, a new feature in the synthesis of ketones through dual nickel photoredox catalysis. With both precursors deriving from abundant carboxylic acids, this protocol is a welcome addition to the organic chemistry toolbox. The reactio…
Six-Step Gram Scale Synthesis of the HIV Integrase Inhibitor Dolutegravir Sodium
A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was investigated. The convergent strategy developed herein starts from 3-(R)-amino-1- butanol and builds up the BC ring system in 76% isolated yield over four steps. Ring A was constructed by a one-pot 1,4-addition to diethyl-(2E/Z)-2-(ethoxymethylidene)-3-oxobutandioate and subsequent MgBr2·OEt2-mediated regioselective cyclization. Amide formation with 2,4- difluorobenzylamine was either performed from the carboxylic acid or through aminolysis of the corresponding ester precursor. Final salt formation afforded dolutegravir sodium in 48–51% isolated yield (HPLC-purity: 99.7–99.9%) over six…