Six-Step Gram Scale Synthesis of the HIV Integrase Inhibitor Dolutegravir Sodium
ChemRxiv(2021)
摘要
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.
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