Radiosynthesis of α-[¹⁸F]Fluoroamides with [¹⁸F]AgF

Abstract

A silver-promoted nucleophilic radiofluorination of α-bromoamides has been developed for the radiosynthesis of α-[¹⁸F]fluoroamides. The reaction conditions are straightforward and compatible with primary, secondary, and tertiary α-bromoamides. Furthermore, the methodology has been successfully applied to the synthesis of bioactive radiotracers with good radiochemical conversion (RCC) and radiochemical yield (RCY).

Keywords

silver - radiofluorination - α-bromoamides - α-[¹⁸F]fluoroamides - nucleophilic reactions

Publikationsverlauf

Eingereicht: 06. Oktober 2023

Angenommen nach Revision: 27. November 2023

Artikel online veröffentlicht:
15. Januar 2024

• References and Notes

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• 14 General procedure for the synthesis of α-fluoroamides: α-Bromoamide 1 (2 mmol, 1 equiv), AgF (2 equiv), and MeCN (20 mL) were consecutively added to a 100 mL round-bottomed flask equipped with a magnetic stirring bar. The resulting mixture was stirred at room temperature for 12 h. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction mixture was extracted with brine and EtOAc. The crude product was further purified by column chromatography on silica gel to give the corresponding product. 2-Fluoro-2-methyl-N-phenylpropanamide (2g): White solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.10 (br s, 1 H), 7.58 (d, J = 7.9 Hz, 2 H), 7.35 (t, J = 7.8 Hz, 2 H), 7.15 (t, J = 7.1 Hz, 1 H), 1.67 (d, J = 22.4 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.0 (d, J = 19.5 Hz), 137.0, 129.0, 124.7, 119.8, 96.5 (d, J = 182.7 Hz), 25.0 (d, J = 24.0 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –144.72 to –145.32 (m, 1 F). HRMS: (EI⁺): m/z calcd for C₁₀H₁₂FNO [M]⁺: 181.0898; found: 181.0903.
• 15 General procedure for radiosynthesis of α-[¹⁸F]fluoroamides: α-Bromoamide 1 (6 mg, about 25–35 μmol) and acetonitrile (850 μL) were added to a reaction vial. [¹⁸F]AgF/K₂.₂.₂ solution (0.2–0.3 GBq, 150 μL) was then transferred to the reaction vial. The reaction was kept at 110 °C for 30 min. The reaction mixture was then cooled and subjected to HPLC for further analysis.