Synthesis of 14C- and 3H-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 14C‐ and 3H‐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, [3H]‐fluoxetine was obtained in a state of high radiochemical purity (98%) and specific activity (20.4 Ci/mmol). The 14C‐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, [14C]‐fluoxetine was obtained in 98.3% radiochemical purity with a specific activity of 5.52 mCi/mmol.