Asymmetric Synthesis of Enantiomerically Pure Milnacipran Analogs

Abstract

There are currently no antidepressant drugs available with the desired efficacy, onset of action, or absence of side effects. Milnacipran is a commercially available antidepressant drug that shows affinity for the serotonin and norepinephrine transporters. During the present work it has been used as a lead compound in the development of a series of analogs.

A three-step synthesis was employed in the preparation of eleven 2-(aminomethyl)-1-aryl-N,N-diethylcyclopropanecarboxamide hydrochlorides from the corresponding 1-aryl-3-oxa-bicyclo[3.1.0]hexane-2-ones. The bicyclic lactone building blocks were prepared by two different methods, these being an asymmetric synthesis in a reaction of arylacetonitrile with epichlorohydrin, and an intramolecular cyclopropanation reaction of a diazocompound. Yields range from moderate to excellent, and high enantiomeric excess is achieved in all cases. Sizty-nine new compounds were prepared and identified during the project.

IC50-values show that (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-(naphthalen-2-yl)cyclopropanecarboxamide has a higher affinity for the serotonin and dopamine transporters than milnacipran, and an equivalent affinity for the norepinephrine transporter.