Synthesis of Rovafovir Etalafenamide (Part I): Active Pharmaceutical Ingredient Process Development, Scale-Up, and Impurity Control Strategy

• DOI: 10.1021/acs.oprd.1c00059
• Publication Date: 2021-05-09T12:05:48Z
• Authors: Eric A. Standley; Dustin A. Bringley; Selcuk Calimsiz; Jeffrey D. Ng; Keshab Sarma; Jinyu Shen; David A. Siler; Andrea Ambrosi; Wen-Tau T. Chang; Anna Chiu; Jason A. Davy; Ian J. Doxsee; Mihaela M. Esanu; Jeffrey A. O. Garber; Youri Kim; Bernard Kwong; Olga Lapina; Edmund Leung; Lennie Lin; Andrew Martins; Jenny Phoenix; Jaspal Phull; Benjamin J. Roberts; Bing Shi; Olivier St-Jean; Xiang Wang; Li Wang; Nande Wright; Guojun Yu
• Keywords: Process development

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