Rovafovir etalafenamide

Fluorinated nucleoside I is a key starting material in the synthesis of rovafovir etalafenamide, 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 I to support clin. 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 I using a new protecting group strategy.The new chem. led to improvements in the manufacturing process while reducing the overall process mass intensity (PMI).

This manuscript describes the chem. process development and multi-kilogram synthesis of rovafovir etalafenamide (GS-9131), a phosphonamidate prodrug nucleotide reverse transcriptase inhibitor under investigation for the treatment of HIV-1 infection.Rovafovir etalafenamide is assembled in a four-step sequence beginning from the nucleoside core and an elaborated phosphonamidate alc.The assembly starts with a decarboxylative elimination of a β-hydroxy acid to yield the corresponding cyclic enol ether, which is subsequently coupled to a functionalized phosphonamidate alc. in an iodoetherification reaction.Oxidative syn elimination then installs the required fluoroalkene, after which a final deprotection reaction yields the active pharmaceutical ingredient (API).Understanding the genesis, fate, and purge of the des-fluoro analog of the API, a mitochondrial toxin, proved to be a central driver in the development of the manufacturing route and impurity control strategy.Initial control strategies revolved around the use of silica gel chromatog. or simulated moving bed chromatog. to purge the des-fluoro impurity to an acceptable level but ultimately a chromatog.-free approach to mitigate the formation of this impurity was devised that expanded manufacturing flexibility.Design of experiments was used to improve the iodoetherification fragment coupling reaction and to reduce the level of the des-fluoro impurity formed in this step.Furthermore, several new crystalline intermediate forms were discovered and implemented as isolation points to bolster the overall impurity control strategy for standard, diastereomeric, and potentially mutagenic impurities as well as for the des-fluoro impurity.These processes were executed on the multi-kilogram scale to produce API for clin. studies.