Simplifying the access to FLYRCADOTM: A shorter route for preparing [18F]Flurpiridaz precursors under mild conditions

We report a novel and efficient three-step synthesis of flurpiridaz precursors and reference compounds. Central to this strategy is the mild and operationally simple AgOTf-mediated etherification of the benzyl bromide intermediate with hydroxyethyl sulfonates. The tosylate-bearing precursor was obtained in a 64% yield, a two-fold improvement over previous routes. DFT calculations showed that the presence of electron-donating groups on the benzensulfonyl ring decreases the electrophilic character of the sp3-hybridized carbon bonded to the sulfonate leaving group. We expect this approach to become widely employed for the preparation of both precursors and reference compounds, crucial for the FDA-approved FLYRCADOTM GMP manufacturing.