Rovafovir etalafenamide (GS-9131, 1) is the phosphonamidate prodrug of a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV infection. In order to support pre-clinical and clinical studies, a process was needed to produce 1 on multi-kilogram scale. The novel structure of 1 presented a variety of synthetic challenges in order to retain the desired stereochemistry and integrity of the functional groups over numerous chemical transformations. This presentation will outline the strategies used to develop a robust, operationally-safe, and chromatography-free synthetic route to 1. Topics to be discussed will include the development of a decarboxylative elimination, the Design of Experiments study of an iodoetherification reaction, the development of an oxidative elimination, and dynamic strategies investigated for improving the synthesis of the phosphonamidate fragment.
The presentation will be followed by a pizza lunch/information session from 12:00pm – 1:30pm in D211.