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

  • Eric A. Standley*
    Eric A. Standley
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
    *Email: [email protected]
  • Dustin A. Bringley
    Dustin A. Bringley
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
  • Selcuk Calimsiz
    Selcuk Calimsiz
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
  • Jeffrey D. Ng
    Jeffrey D. Ng
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
  • Keshab Sarma
    Keshab Sarma
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
    More by Keshab Sarma
  • Jinyu Shen
    Jinyu Shen
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
    More by Jinyu Shen
  • David A. Siler
    David A. Siler
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
  • Andrea Ambrosi
    Andrea Ambrosi
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
  • Wen-Tau T. Chang
    Wen-Tau T. Chang
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
  • Anna Chiu
    Anna Chiu
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
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  • Jason A. Davy
    Jason A. Davy
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
  • Ian J. Doxsee
    Ian J. Doxsee
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
  • Mihaela M. Esanu
    Mihaela M. Esanu
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
  • Jeffrey A. O. Garber
    Jeffrey A. O. Garber
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
  • Youri Kim
    Youri Kim
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
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  • Bernard Kwong
    Bernard Kwong
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
  • Olga Lapina
    Olga Lapina
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
    More by Olga Lapina
  • Edmund Leung
    Edmund Leung
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
    More by Edmund Leung
  • Lennie Lin
    Lennie Lin
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
    More by Lennie Lin
  • Andrew Martins
    Andrew Martins
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
  • Jenny Phoenix
    Jenny Phoenix
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
  • Jaspal Phull
    Jaspal Phull
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
    More by Jaspal Phull
  • Benjamin J. Roberts
    Benjamin J. Roberts
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
  • Bing Shi
    Bing Shi
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
    More by Bing Shi
  • Olivier St-Jean
    Olivier St-Jean
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
  • Xiang Wang
    Xiang Wang
    Gilead Sciences, Inc., Process Chemistry, 333 Lakeside Drive, Foster City, California 94404, United States
    More by Xiang Wang
  • Li Wang
    Li Wang
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
    More by Li Wang
  • Nande Wright
    Nande Wright
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
    More by Nande Wright
  • , and 
  • Guojun Yu
    Guojun Yu
    Gilead Alberta ULC, Process Development, 1021 Hayter Road NW, Edmonton, Alberta T6S 1A1, Canada
    More by Guojun Yu
Cite this: Org. Process Res. Dev. 2021, 25, 5, 1215–1236
Publication Date (Web):May 9, 2021
https://doi.org/10.1021/acs.oprd.1c00059
Copyright © 2021 American Chemical Society
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Abstract

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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 the treatment of HIV-1 infection. Rovafovir etalafenamide is assembled in a four-step sequence beginning from the nucleoside core and an elaborated phosphonamidate alcohol. The assembly starts with a decarboxylative elimination of a β-hydroxyacid to yield the corresponding cyclic enol ether, which is subsequently coupled to a functionalized phosphonamidate alcohol 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 chromatography or simulated moving bed chromatography to purge the des-fluoro impurity to an acceptable level, but ultimately a chromatography-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 multi-kilogram scale to produce API for clinical studies.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.1c00059.

  • A listing of the species flagged as potentially mutagenic impurities; raw data, analysis, and models for DOE studies; additional description of the development and use of the depth filtration process in the iodoetherification workup; and NMR spectra for all isolated compounds (PDF)

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Cited By

This article is cited by 8 publications.

  1. Daniel J. Griffin, Hsiao-Wu Hsieh, Nadide Hazal Avci, Nandini Sarkar, James D. Fostinis, Nicholas Klitzing, James I. Murray, Rasangi Wimalasinghe, Simone Spada, Alicia Zeng, Matthew G. Beaver. A Continuous Process for Manufacturing Apremilast. Part II: Process Characterization to Establish a Parametric Control Strategy. Organic Process Research & Development 2024, Article ASAP.
  2. Hsiao-Wu Hsieh, Carolyn M. Cohen, Daniel J. Griffin, Padmini Ananthoji, Nadide Hazal Avci, Derek B. Brown, Ari Ericson, James D. Fostinis, Muhammad Irfan, Neil Langille, Michael A. Lovette, James I. Murray, Simone Spada, Oliver R. Thiel, Frankie Aiello, Joseph Daou, Nicole Goudas-Salomon, Ende Pan, Nandini Sarkar, Rasangi Wimalasinghe, Zufan Steven Wu, Alicia Zeng, Matthew G. Beaver. A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles. Organic Process Research & Development 2024, Article ASAP.
  3. Paridhi Agrawal, Saurin H. Rawal, Venkata Ramana Reddy, Shekhar K. Viswanath, Jeremy M. Merritt. Case Studies in the Application of a Workflow-Based Crystallization Design for Optimized Impurity Rejection in Pharmaceutical Development. Organic Process Research & Development 2023, 27 (4) , 610-626. https://doi.org/10.1021/acs.oprd.2c00346
  4. 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. Synthesis of Rovafovir Etalafenamide (Part III): Evolution of the Synthetic Process to the Phosphonamidate Fragment. Organic Process Research & Development 2021, 25 (5) , 1247-1262. https://doi.org/10.1021/acs.oprd.0c00428
  5. Dustin A. Bringley, Benjamin J. Roberts, Selcuk Calimsiz, Brandon H. Brown, Jason A. Davy, Bernard Kwong, Detian Gao, Andrew Martins, Keshab Sarma, Elan Shao, Jinyu Shen, Mark V. Smith, Keiko Sujino, Alan S. Triman, Nande Wright. Synthesis of Rovafovir Etalafenamide (Part II): Dynamic Control for Successful Scale-Up of an Oxygen-Releasing Elimination Reaction Mediated by Oxone. Organic Process Research & Development 2021, 25 (5) , 1237-1246. https://doi.org/10.1021/acs.oprd.0c00439
  6. David A. Siler, Selcuk Calimsiz, Ian J. Doxsee, Bernard Kwong, Jeffrey D. Ng, Keshab Sarma, Jinyu Shen, Jonah W. Curl, Jason A. Davy, Jeffrey A. O. Garber, Sura Ha, Olga Lapina, Jisung Lee, Lennie Lin, Sangsun Park, Mary Rosario, Olivier St-Jean, Guojun Yu. Synthesis of Rovafovir Etalafenamide (Part IV): Evolution of the Synthetic Process to the Fluorinated Nucleoside Fragment. Organic Process Research & Development 2021, 25 (5) , 1263-1274. https://doi.org/10.1021/acs.oprd.1c00026
  7. Simon Backx, Andreas Dejaegere, Andreas Simoens, Jef Van de Poel, Dorota Krasowska, Christian V. Stevens, Sven Mangelinckx. Triethylamine‐Mediated Transformation of Phosphonates into Phosphonamidates. European Journal of Organic Chemistry 2023, 26 (26) https://doi.org/10.1002/ejoc.202300172
  8. . Synthesis of Rovafovir Etalafenamide. Synfacts 2021, 0843. https://doi.org/10.1055/s-0040-1719675

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