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Dolutegravir_Dietz_et_al.pdf (2.15 MB)

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

preprint
submitted on 12.04.2021, 16:33 and posted on 13.04.2021, 13:01 by Jule-Phillip Dietz, Tobias Lucas, Jonathan Groß, Sebastian Seitel, Jan Brauer, Dorota Ferenc, B. Frank Gupton, Till Opatz
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 linear steps.

Funding

The Medicines4All Initiative of the Bill and Melinda Gates Foundation

History

Email Address of Submitting Author

opatz@uni-mainz.de

Institution

Johannes Gutenberg University Mainz

Country

Germany

ORCID For Submitting Author

0000-0002-3266-4050

Declaration of Conflict of Interest

No conflict of interest to declare

Version Notes

Version 1 of April 12, 2021

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