Synthesis of Rovafovir Etalafenamide (Part IV): Evolution of the Synthetic Process to the Fluorinated Nucleoside Fragment

Fluorinated
nucleoside 1 is a key starting material
in the synthesis of rovafovir etalafenamide (2), a novel
nucleotide reverse transcriptase inhibitor under development at Gilead
Sciences for the treatment of HIV. While an initial manufacturing
route enabled the production of 1 to support clinical
development, alternative approaches were explored to further enhance
manufacturing effectiveness, improve processing time, reduce cost,
and minimize the environmental impact. Toward this end, two new routes
were developed to a key synthetic intermediate, which was converted
to 1 using a new protecting group strategy. The new chemistry
led to improvements in the manufacturing process while reducing the
overall process mass intensity (PMI).