Synthesis of 15N‑Pyridines and Higher Mass Isotopologs via Zincke Imine Intermediates

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-labe...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Chemical Society 2024-02, Vol.146 (5), p.2944-2949
Main Authors: Nguyen, Hillary M. H., Thomas, David C., Hart, Marie A., Steenback, Kaila R., Levy, Jeffrey N., McNally, Andrew
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.3c12445