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Dolutegravir is a fluorine containing antiretroviral drug prescribed for the treatment of HIV infection in combination with other HIV medicines in adults. Its chemical synthesis is associated with the formation of several impurities including the Enantiomer (4S, 12a R ), Impurity B, and Ethoxy acetamide the synthesis of which are presented here. The synthesis and characterization of critical impurities that may emerge during the synthesis of a particular API is a challenging as well as important task in the area of process research. Thus we report new, simple and efficient two-step strategies for the synthesis of Enantiomer (4S, 12a R ) and Ethoxy acetamide for the first time and an alternative environmentally friendly route for the existing synthesis of Impurity B. Two of these impurities were prepared from ethyl-5-((2,4-difluorobenzyl)carbamoyl)-3-ethoxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine–2-carboxylate and the third one was prepared from (2,4-difluorophenyl)methanamine. The synthesized impurities were characterized by IR,  1 H,  13 C and  19 F NMR and Mass spectral data as well as HPLC and HRMS analysis. The developed methodologies are convenient, economical and appeared to be suitable for laboratory as well as large scale preparations. Due to the potential importance of these impurities as reference standards the outcome of the current study would be of immense interest to researchers engaged in the process development for accessing chemically pure dolutegravir.

Synthesis of Three Key Impurities of Drug Dolutegravir: An Inhibitor of HIV-1 Integrase