Methods to incorporate stable radioisotopes are integral to pharmaceutical and agrochemical development. However, despite the prevalence of pyridines in candidate compounds, methods to incorporate ¹⁵N atoms within their structures are limited. Here, we present a general approach to pyridine ¹⁵N-labeling that proceeds via ring-opening to NTf-Zincke imines and then ring-closure with commercially available ¹⁵NH₄Cl salts. This process functions on a range of substituted pyridines, from simple building block-type compounds to late-stage labeling of complex pharmaceuticals, and ¹⁵N-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.

中文翻译：

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通过锌亚胺中间体合成 15N-吡啶和更高质量的同位素异构体

掺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，但在其结构中掺入^{15 个}N 原子的方法仍然有限。^{在这里，我们提出了吡啶15} N-标记的一般方法，该方法通过开环为N Tf-Zincke 亚胺，然后用市售的¹⁵ NH ₄ Cl 盐闭环。该过程适用于一系列取代的吡啶，从简单的结构单元型化合物到复杂药物的后期标记，并且在大多数情况下¹⁵ N-掺入率 >95%。Zincke 亚胺中间体的反应活性还可以使吡啶 C3 和 C5 位发生氘化，从而产生药物开发过程中生物液体 LCMS 分析所需的更高质量的同位素同位素。