(1S-cis)-Milnacipran Hydrochloride

Description

Levomilnacipran (Fetzima®) is a dual serotonin–norepinephrine reuptake inhibitor (SNRI) approved by the FDA in 2013 for the treatment of major depressive disorders (MDD). Levomilnacipran is the most active enantiomer of the racemate Milnacipran, which is currently used to treat pain associated with fibromyalgia. The drug was developed by Forest Laboratories and the Pierre Fabre group.

The Uses of (1S-cis)-Milnacipran Hydrochloride

The S-enatiomer of Milnacipran (M344600).

The Uses of (1S-cis)-Milnacipran Hydrochloride

The (1S-cis)-enatiomer of Milnacipran (M344600). A selective norepinephrine and serotonin reuptake inhibitor approved for the management of fibromyalgia.

Synthesis

Reaction of phenylacetonitrile (100) and commercially available (R)-epichlorohydrin (101) with NaNH2 led to chloride displacement and intramolecular cyclopropanation, yielding lactone 102 after a one-pot nitrile hydrolysis and acid-promoted lactonization (75% yield over 3 steps). Lactone ring-opening with Et2NH¨CAlCl3 complex provided amido-alcohol 103, which was converted to its phthalimido derivative 104 by sequential treatment with thionyl chloride and potassium phthalimide in 80% over three steps. Finally, levomilnacipran hydrochloride (XIII) was obtained in >95% optical purity after phthalimide cleavage, HCl salt formation, and crystallization from HCl/i-PrOH/i-PrAc. This sequence represents a highly efficient route to levomilnacipran, requiring no isolation of intermediates, resulting in >40% overall yield, and allowing use of the same solvent solution (toluene) for all steps.