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

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.