Potassium fluoride as additive in nucleophilic aromatic substitution with chloroheteroaromatic partners
In the kilogram scale synthesis of the drug candidate CVN424, a selective GPR6 (G Protein-Coupled Receptor 6) inverse agonist, treatment of (R)-tetrahydrofuran-3-amine 1 with chloroheteroaromatic 2, in presence of potassium fluoride and triethylamine in DMSO at 60°C provided the desired pyrido[3,4-b]pyrazine intermediate 3 in 70.2% yield (13.86 kg) as outlined in Scheme below. [1]
To avoid harsh thermal conditions, potassium fluoride was added to facilitate the nucleophilic aromatic amination reaction, via the in situ formation of a more reactive aryl fluoride derivative, by halide exchange reaction. [2]
[1] C. Mu, X. Li, Y. Yang, Y. Zhou, C. Wang, K. J. Doyle, N. Ye, A. Mistry, R. W. Bürli, Org. Process Res. Dev. 2023, 27, 256-261.
[2] D. Kase, R. Haraguchi, Org. Lett. 2022, 24, 90-94.