Synthesis of fluorine-18-labelled 5- and 6-fluoro-2-pyridinamine

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 49; no. 4; pp. 345 - 356
• Main Authors: Abrahim, Aiman, Angelberger, Peter, Kletter, Kurt, Müller, Markus, Joukhadar, Christian, Erker, Thomas, Langer, Oliver
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 30-03-2006; Wiley
• Subjects: Chemistry; Exact sciences and technology; fluorine-18; fluoropyridine; Hofmann rearrangement; Labelled compounds chemistry; meta-position; no-carrier-added nucleophilic aromatic substitution; Organic chemistry; Reactivity and mechanisms; Fluorine Isotopes; Nitrile; Fluorine 18; Radiolabelling; Nitrogen heterocycle; Hofmann rearrangement; fluoropyridine; fluorine-18; Position isomer; Six membered ring; no-carrier-added nucleophilic aromatic substitution; Carboxamide; Hofmann reaction; Fluorination; Chemical synthesis; SNAr mechanism; meta-position
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.1049

A one‐pot radiosynthesis method to prepare the new fluorine‐18‐labelled fluoropyridine derivatives 5‐[18F]fluoro‐2‐pyridinamine and 6‐[18F]fluoro‐2‐pyridinamine in two to three reaction steps was developed. The first step consisted of no‐carrier‐added nucleophilic aromatic substitution of commercially available halogen‐substituted 2‐pyridinecarboxamide or 2‐pyridinecarbonitrile derivatives with K[18F]F‐K222 in DMSO at 150–180°C. The [18F]fluoride incorporation yields ranged from 67 to 98% for all studied precursor molecules. It is remarkable that 5‐bromo‐2‐pyridinecarbonitrile gave almost quantitative [18F]fluoride incorporation at the meta‐position (5‐position) of the pyridine ring after only 5 min of heating at 150°C. After base‐catalysed hydrolysis of the [18F]fluorinated pyridinecarbonitriles into their corresponding carboxamides, the latter were transformed in a Hofmann‐type rearrangement reaction into the respective amines by treatment of crude reaction mixtures with bromine and aqueous base (20–30% conversion yield). Reaction mixtures were purified by reversed‐phase semipreparative HPLC followed by strong cation exchange solid‐phase extraction to afford 5‐[18F]fluoro‐2‐pyridinamine and 6‐[18F]fluoro‐2‐pyridinamine in non‐decay‐corrected radiochemical yields of 6–10% in a total synthesis time of 83–112 min. The preparation of 5‐[18F]fluoro‐2‐pyridinamine is one of very few examples demonstrating the feasibility of nucleophilic meta‐[18F]fluorination of a pyridine derivative. Both 5‐[18F]fluoro‐2‐pyridinamine and 6‐[18F]fluoro‐2‐pyridinamine are new potentially useful radiolabelled synthons for radiopharmaceutical chemistry. Copyright © 2006 John Wiley & Sons, Ltd.