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Early-Stage Flow Process Development of a Key Intermediate toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate

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    Early-Stage Flow Process Development of a Key Intermediate toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate
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    • Cameron T. Armstrong*
      Cameron T. Armstrong
      Chemical Research & Development, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
      *Email: [email protected]
      More by Cameron T. Armstrong
      Orcidhttps://orcid.org/0000-0001-6342-0860
    • Katharina Grohowalski
      Katharina Grohowalski
      Chemical Research & Development, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
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    • Grace Russell
      Grace Russell
      Snapdragon Chemistry, Waltham, Massachusetts 02451, United States
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    • Sara Mason
      Sara Mason
      Snapdragon Chemistry, Waltham, Massachusetts 02451, United States
      More by Sara Mason
    • Kakasaheb Y. Nandiwale
      Kakasaheb Y. Nandiwale
      Chemical Research & Development, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
      More by Kakasaheb Y. Nandiwale
      Orcidhttps://orcid.org/0000-0002-0754-7362
    • DaQuawn Edwards
      DaQuawn Edwards
      Snapdragon Chemistry, Waltham, Massachusetts 02451, United States
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    • Jillian Sheeran
      Jillian Sheeran
      Snapdragon Chemistry, Waltham, Massachusetts 02451, United States
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    • Talia J. Steiman
      Talia J. Steiman
      Snapdragon Chemistry, Waltham, Massachusetts 02451, United States
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    • Douglas J. Critcher
      Douglas J. Critcher
      Chemical Research and Development, Pfizer Worldwide Research & Development, Sandwich, Kent CT13 9NJ, United Kingdom
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      Orcidhttps://orcid.org/0009-0007-8197-1202
    • Christopher P. Ashcroft
      Christopher P. Ashcroft
      Chemical Research and Development, Pfizer Worldwide Research & Development, Sandwich, Kent CT13 9NJ, United Kingdom
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    • Angel R. Diaz
      Angel R. Diaz
      Chemical Research & Development, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
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    • Steven M. Guinness*
      Steven M. Guinness
      Chemical Research & Development, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
      *Email: [email protected]
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    Organic Process Research & Development

    Cite this: Org. Process Res. Dev. 2024, 28, 8, 3206–3216
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    https://doi.org/10.1021/acs.oprd.4c00112
    Published July 31, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    The application of continuous processing can afford certain advantages during development and scale-up, such as enhanced risk mitigation of hazardous compounds and reducing both manufacturing cycle time and solvent waste through telescoping steps and avoiding intermediate isolations. While telescoping is not unique to flow, the operating windows enabled by the process intensification only possible in flow are notable, and they often possess the additional benefit of accessing chemistries not feasible in a batch. In this work, we highlight efforts to translate an early-stage batch route for the AXL-MER inhibitor oncology candidate PF-07265807 into a viable continuous flow process. The route to the key intermediate of interest features two SNAr reactions, the latter utilizing aqueous hydrazine to enable an intramolecular cascade reaction, followed by a Boc deprotection. Efforts were made to assess and demonstrate the suitability of the process for telescoping steps in flow by finding a solvent/base system that maintained the solubility of all species and led to efficacious reactions. Additional studies were performed to reduce the concentration of aqueous hydrazine solution used as a feed in the continuous process to 5 wt % hydrazine, adding to the various safety advantages not amenable to a traditional batch process. Furthermore, an automated D-optimal design of experiment study was carried out for the aqueous hydrazine step to increase process understanding and screen effects during this early stage of development.

    Copyright © 2024 American Chemical Society

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    Organic Process Research & Development

    Cite this: Org. Process Res. Dev. 2024, 28, 8, 3206–3216
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.oprd.4c00112
    Published July 31, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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