Development of Synthetic Routes to Dolutegravir

Within the last decade, a new class of anti-HIV drugs, the so-called integrase inhibitors featuring a novel mode of action, became available as an additional treatment option. The design and discovery of integrase inhibitors were first focusing on targeting the catalytic site of HIV-1 integrase with a specific effect on strand transfer. This approach led to a first generation of 3′-processing and strand transfer inhibitors (INSTIs), from which raltegravir and elvitegravir have been promoted to market. These first-generation integrase inhibitors proved remarkably efficient at reducing viral load in treatment of naive patients’ viral strains. However, subsequent discovery of a low genetic barrier of resistance demonstrated the pressing need for the development of second-generation INSTIs that should be active against raltegravir-resistant and elvitegravir-resistant viral strains. Very recently, dolutegravir sodium, a molecule with a significantly improved resistance profile, received approval in major markets. Dolutegravir features a tricyclic carbamoyl pyridone core comprising two chiral carbon centres. This paper will summarise several synthetic routes disclosed for the preparation of dolutegravir as well as discuss their applicability at multi-ton scale.