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

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Development of a Commercial Manufacturing Route to 2-Fluoroadenine, The Key Unnatural Nucleobase of Islatravir
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-07-31 , DOI: 10.1021/acs.oprd.0c00304
Cynthia M. Hong ₁ , Yingju Xu ₁ , John Y. L. Chung ₁ , Danielle M. Schultz ₁ , Mark Weisel ₁ , Richard J. Varsolona ₁ , Yong-Li Zhong ₁ , Akasha K. Purohit ₁ , Cyndi Q. He ₁ , Donald R. Gauthier ₁ , Guy R. Humphrey ₁ , Kevin M. Maloney ₁ , François Lévesque ₁ , Zhixun Wang ₁ , Aaron M. Whittaker ₁ , Eric Sirota ₁ , Jonathan P. McMullen ₁

Affiliation

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.

中文翻译：

开发一条商业化生产路线，以2-氟丁烯酸为基础，这是Islatravir的关键非天然核碱基

我们报告了islatravir（MK-8591），一种新型的核苷逆转录酶易位抑制剂（NRTTI）的关键片段的实际合成，该抑制剂目前正在研究中，针对HIV感染的治疗和暴露前预防（PrEP）。该片段（非天然核碱基2-氟腺嘌呤）通过生物催化的羟醛糖基化级联反应并入MK-8591，这对其合成和分离提出了严格的要求。本文介绍的是开发从鸟嘌呤到实用，可扩展路线的开发工作，其特征在于采用双氟化方法开发新颖的9-THP-2,6-二氟嘌呤中间体，从而实现温和，高度选择性的直接胺化。这种一锅式氟化/胺化步骤利用直接分离来提供高纯度的9-THP-2-氟腺嘌呤，在反应性，溶解性和结晶度方面具有理想的特性。在水性缓冲液中酸催化的2-氟腺嘌呤释放可提供适当的纯度，以利于酶联级联反应进入MK-8591。

更新日期：2020-07-31

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