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) chromatography 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 crystallization. Ultimately, 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.