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).

Phosphonamidate 1 is a key fragment in the assembly of rovafovir etalafenamide, a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV infection.An early manufacturing route, relying on simulated moving bed (SMB) chromatog. for the separation of phosphorus diastereomers, was executed on scale to produce multiple batches of 1.However, developing alternative synthetic conditions became desirable in consideration of the high production cost, long lead time, and high process mass intensity (PMI) associated with SMB.Several strategies to improve these factors are described herein, including epimerization and recycling of the undesired (R)-phosphorus diastereomer, design of stereoselective approaches to establish the desired (S)-configuration at phosphorus, and identification of conditions or derivatives to allow for selective crystallizationUltimately, a second-generation route to 1 was developed and demonstrated on scale.The new route achieves the separation of phosphorus diastereomers by means of selective crystallization, does not require SMB, and offers lower PMI, cost, and lead time.