Nguyen Hillary M H, Thomas David C, Hart Marie A, Steenback Kaila R, Levy Jeffrey N, McNally Andrew
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
J Am Chem Soc. 2024 Feb 7;146(5):2944-2949. doi: 10.1021/jacs.3c12445. Epub 2024 Jan 16.
Methods to incorporate stable radioisotopes are integral to pharmaceutical and agrochemical development. However, despite the prevalence of pyridines in candidate compounds, methods to incorporate N atoms within their structures are limited. Here, we present a general approach to pyridine N-labeling that proceeds via ring-opening to Tf-Zincke imines and then ring-closure with commercially available NHCl salts. This process functions on a range of substituted pyridines, from simple building block-type compounds to late-stage labeling of complex pharmaceuticals, and N-incorporation is >95% in most cases. The reactivity of the Zincke imine intermediates also enables deuteration of the pyridine C3- and C5-positions, resulting in higher mass isotopologs required for LCMS analysis of biological fluids during drug development.
纳入稳定放射性同位素的方法是药物和农用化学品开发不可或缺的一部分。然而，尽管吡啶在候选化合物中普遍存在，但在其结构中纳入氮原子的方法却很有限。在此，我们提出了一种吡啶氮标记的通用方法，该方法通过开环生成三氟甲磺酸锌（Tf-Zincke）亚胺，然后与市售的氯化铵盐闭环。该过程适用于一系列取代吡啶，从简单的构建模块型化合物到复杂药物的后期标记，并且在大多数情况下，氮的纳入率>95%。锌亚胺中间体的反应性还能够使吡啶的C3和C5位氘代，从而产生药物开发过程中生物流体LCMS分析所需的更高质量的同位素异构体。
