Deprotection of N-Boc Groups Under Continuous Flow High Temperature Conditions

    • Bryan Li
    • Ruizhi Li
    • Peter Dorff
    • James Christopher McWilliams
    • Robert M Guinn
    • Steven M. Guinness
    • Lu Han
    • Ke Wang
    • Shu Yu
    • Medicinal Science, Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States

    The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.

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