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.