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Development of a Commercial Manufacturing Route to 2-Fluoroadenine, The Key Unnatural Nucleobase of Islatravir

2020; American Chemical Society; Volume: 25; Issue: 3 Linguagem: Inglês

10.1021/acs.oprd.0c00304

1520-586X

Cynthia Hong, Yingju Xu, John Y. L. Chung, Danielle M. Schultz, Mark Weisel, Richard J. Varsolona, Yong‐Li Zhong, Akasha K. Purohit, Cyndi Qixin He, Donald R. Gauthier, Guy R. Humphrey, Kevin M. Maloney, François Lévesque, Zhixun Wang, Aaron M. Whittaker, E. B. Sirota, Jonathan P. McMullen,

HIV Research and Treatment

We report the practical synthesis of a key fragment of islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently under investigation for treatment and pre-exposure prophylaxis (PrEP) against HIV infection. The fragment, the unnatural nucleobase 2-fluoroadenine, is incorporated into MK-8591 via a biocatalytic aldol-glycosylation cascade, which imposes stringent requirements for its synthesis and isolation. Presented herein is the development work leading to a practical, scalable route from guanine, featuring a dual fluorination approach to a novel 9-THP-2,6-difluoropurine intermediate that enables a mild, highly selective, direct amination. This one-pot fluorination/amination sequence utilizes a direct isolation to deliver high purity 9-THP-2-fluoroadenine, which features ideal properties with respect to reactivity, solubility, and crystallinity. An acid-catalyzed liberation of 2-fluoroadenine in aqueous buffer delivers the appropriate purity profile to facilitate the enzymatic cascade to access MK-8591.