An Efficient Synthesis of (Fluoromethyl)pyridylamines for Labeling with Fluorine-18

We have described a two-step method for the preparation of (fluoromethyl)pyridyl-substituted amines. The sequence involves fluoride ion displacement of methanesulfonates (mesylates) of 6-chloro-α-hydroxy-2- and -3-picolines, followed by arylation of the amine by chloropicoline. We have called this sequence fluorination− N -arylation. 1-Phenylpiperazine has been used as a model amine. Two key precursors for this sequence are the mesylates of 6-chloro-α-hydroxy-2- and -3-picolines. The former was synthesized in four steps from 6-chloro-2-picoline in 78% yield and the latter in three steps from 6-chloronicotinic acid in 53% yield. This fluorination− N -arylation sequence is sufficiently rapid and efficient for the preparation of a variety of aryl-substituted amine compounds labeled with the short half-life ( t 1/2 = 110 min) positron-emitting radionuclide fluorine-18.