Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium

A short and practical synthesis for
preparing the active pharmaceutical
ingredient dolutegravir sodium was developed. The convergent strategy
starts from (R)-3-amino-1-butanol and establishes
the BC ring system in a 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 free carboxylic acid or through aminolysis of the corresponding
ethyl ester. Final salt formation afforded dolutegravir sodium in
a 48–51% isolated yield (HPLC purity of 99.7–99.9%)
over six linear steps.