175131-60-9

Usage

Uses

Used in Pharmaceutical Industry:
(1S-cis)-Milnacipran Hydrochloride is used as an antidepressant for the treatment of major depressive disorders (MDD) due to its dual action as a serotonin-norepinephrine reuptake inhibitor, which helps to increase the levels of these neurotransmitters in the brain and alleviate depressive symptoms.
Used in Pain Management:
(1S-cis)-Milnacipran Hydrochloride is used as an analgesic for the management of pain associated with fibromyalgia. As a selective norepinephrine and serotonin reuptake inhibitor, it helps to regulate the levels of these neurotransmitters, which play a role in pain perception and modulation, thus providing relief from the chronic pain experienced by fibromyalgia patients.

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–AlCl3 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.