Nucleophilic radiofluorination of aryl halides with K18F mediated by well-defined copper complexes
2020
583 Objectives: Identifying novel methods for the synthesis of 18F aryl fluorides is of importance in the development and synthesis of radiotracers for Positron Emission Tomography. Accessing 18F aryl fluorides through halogen exchange of aryl halides is attractive because of the stability and synthetic accessibility of aryl halides. Nevertheless, radiofluorination of aryl halides is currently limited to SNAr-type reactivity, which generally requires electron deficient substrates and forcing conditions and gives poor yields. We report a new procedure for the synthesis of 18F aryl fluorides from the corresponding aryl halides (-Br, -Cl or -I) using K18F and a well-defined organometallic copper complex. Our method is compatible with electron-rich substrates, in contrast to most SNAr methods, and has been applied to the synthesis of pharmaceutically relevant radiolabeled products.
Methods: Fluorine-18 was prepared using a PETTrace cyclotron via the 18O(p, n)18F nuclear reaction, and K[18F]F was prepared and azeotropically dried using a TRACERLab FXFN automated radiochemistry synthesis module (General Electric, GE)according to our previously reported procedure (Org. Lett. 2016, 18, 5440−5443). A solution of the CuI complex and aryl halide substrate in anhydrous, air-free DMF was transferred to the reaction vial, heated, and analyzed by radio-TLC and radio-HPLC to determine product identity and radiochemical conversion (RCC). Reactions were run and analyzed manually or automated using a TRACERLab FXFN synthesis module.
Results: The appropriate selection of L in L-Cu-OTf facilitates the radiofluorination of a variety of electron-rich and -poor aryl halide substrates with R = various directing groups. Modest to good yields (9-74% RCC) are obtained in 30 min at 140 °C. This system has been successfully applied to the radiofluorination of pharmaceutically relevant substrates, including the anti-cancer pharmaceutical Vismodegib and MK-2 inhibitor PH-089. Automation of the method for model substrate 2-(2-bromophenyl)pyridine resulted in 18F incorporation with good molar activity (1614 ± 353 Ci/mmol, n=2) and modest isolated yield (56.1 mCi ± 13; 6.7 ± 1.5% yield, n=2).
Conclusions: The use of a copper organometallic complex has enabled the nucleophilic fluorination of aryl halides using K[18F]F. This method is tolerant of electron-rich substrates not generally amenable to traditional SNAr reactivity, and ongoing work is focused on leveraging it in the preparation of novel radiotracers from readily accessible and stable aryl halide precursors.
Acknowledgments. Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number F32GM136022 (LSS) and the National Institutes of Health under award number R01EB021155 (MSS and PJHS).
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