Synthesis of 14 C‐ and 3 H‐labeled fluoxetine, a selective serotonin uptake inhibitor

Fluoxetine (N‐methyl‐γ‐(4‐(trifluoromethyl)phenoxy)benzenepropanamine) is a potent, highly selective serotonin uptake inhibitor that is useful in treating a variety of major psychiatric derangements. We have synthesized this compound in 14 C‐ and 3 H‐labeled forms. The tritium label was introduced in the final step by catalytic dehalogenation of the brominated fluoxetine precursor 6 . Reaction conditions could be controlled such that catalytic hydrogenolysis of the labile C‐O benzylic bond was minimized. Following HPLC purification, [ 3 H]‐fluoxetine was obtained in a state of high radiochemical purity (98%) and specific activity (20.4 Ci/mmol). The 14 C‐label was introduced in the final step via a nucleophilic aromatic substitution reaction between the sodium salt of α‐(2‐(methylamino)ethyl)benzenemethanol and uniformly ring‐labeled p‐chlorobenzotrifluoride. Following purification by flash chromatography, [ 14 C]‐fluoxetine was obtained in 98.3% radiochemical purity with a specific activity of 5.52 mCi/mmol.