Synthesis of Deuterium-Labelled (±)-Duloxetine-d5 as an Internal Standard

Abstract

The synthesis of (±)-duloxetine- d6, which is needed for metabolism studies, has been achieved in four steps. The product of a Mannich reaction of 2-acetylthiophene, dimethylamine- d6 hydrochloride and paraformaldehyde- d2 was reduced with NaBH4 to yield an octadeuterated aminoalcohol that was etherified with 1-fluoronaphalene/NaH. The final step was a demethylation (removal of a CD3 group) using PhOCOCI/ethyldiisopropylamine. The pentadeuterated product was formed in 51% overall yield and with a chemical purity of 99.3%.