Development of a Commercial Manufacturing Route to 2‑Fluoroadenine, The Key Unnatural Nucleobase of Islatravir
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-fluoro...
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| Veröffentlicht in: | Organic process research & development 2021-03, Vol.25 (3), p.395-404 |
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| creator | Hong, Cynthia M Xu, Yingju Chung, John Y. L Schultz, Danielle M Weisel, Mark Varsolona, Richard J Zhong, Yong-Li Purohit, Akasha K He, Cyndi Q Gauthier, Donald R Humphrey, Guy R Maloney, Kevin M Lévesque, François Wang, Zhixun Whittaker, Aaron M Sirota, Eric McMullen, Jonathan P |
| description | 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. |
| doi_str_mv | 10.1021/acs.oprd.0c00304 |
| format | Article |
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L ; Schultz, Danielle M ; Weisel, Mark ; Varsolona, Richard J ; Zhong, Yong-Li ; Purohit, Akasha K ; He, Cyndi Q ; Gauthier, Donald R ; Humphrey, Guy R ; Maloney, Kevin M ; Lévesque, François ; Wang, Zhixun ; Whittaker, Aaron M ; Sirota, Eric ; McMullen, Jonathan P</creator><creatorcontrib>Hong, Cynthia M ; Xu, Yingju ; Chung, John Y. L ; Schultz, Danielle M ; Weisel, Mark ; Varsolona, Richard J ; Zhong, Yong-Li ; Purohit, Akasha K ; He, Cyndi Q ; Gauthier, Donald R ; Humphrey, Guy R ; Maloney, Kevin M ; Lévesque, François ; Wang, Zhixun ; Whittaker, Aaron M ; Sirota, Eric ; McMullen, Jonathan P</creatorcontrib><description>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. 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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. 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| source | Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; American Chemical Society Journals |
| subjects | Chemistry Chemistry, Applied Chemistry, Organic Physical Sciences Science & Technology |
| title | Development of a Commercial Manufacturing Route to 2‑Fluoroadenine, The Key Unnatural Nucleobase of Islatravir |
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