Synthesis of Rovafovir Etalafenamide (Part III): Evolution of the Synthetic Process to the Phosphonamidate Fragment

• DOI: 10.1021/acs.oprd.0c00428
• Publication Date: 2021-05-06T02:27:34Z
• Authors: Andrea Ambrosi; Dustin A. Bringley; Selcuk Calimsiz; Jeffrey A. O. Garber; Huy Huynh; Sankar Mohan; Keshab Sarma; Jinyu Shen; Jonah Curl; Bernard Kwong; Olga Lapina; Edmund Leung; Lennie Lin; Andrew Martins; Teague McGinitie; Jaspal Phull; Ben Roberts; Mary Rosario; Bing Shi; Eric A. Standley; Li Wang; Xueqing Wang; Guojun Yu
• Keywords: Diastereomer; Epimer; Fragment (logic)

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