An Enantioselective Synthesis of CymbaltaTM

Abstract

Duloxetine or Cymbalta? is a potent antidepressant which targets neural serotonin channels, making it successful at treating patients with major depressive disorder, generalized anxiety disorder, diabetic neuropathy and fibromyalgia. Cymbalta? is an enantiopure molecule in which the (S)-enantiomer acts as the active antidepressant and the (R)-enantiomer has little biological activity. In the investigated alternative synthesis this enantiopurity is achieved in the first reaction step; the cyanation of crotonaldehyde by the enzyme oxynitrilase, which is extracted from raw almonds. In exploring this alternative route of synthesis of Cymbalta? the challenge lies in maintaining the enantiopurity; because after the cyanation 9 more reactions are required to obtain Cymbalta?. The allylic substitution catalyzed by a palladium(0) complex is one of those steps and the focus of my research was on this reaction. Enantiopurity was in the first phase monitored with a polarimeter and in the second phase by high-performance liquid chromatography.