Patent ID: 8604241

Claim:
A method for synthesizing a pharmaceutically acceptable acid addition salt of (1S,2R)-milnacipran of the following formula (I): said method comprising the following successive steps: (a) reaction of phenylacetonitrile and of (R)-epichlorhydrin in the presence of a base containing an alkaline metal, followed by a basic treatment, and then by an acid treatment in order to obtain the lactone of the following formula (II): (b) reaction of the lactone (II) obtained in the previous step (a) with MNEt 2 , wherein M represents an alkaline metal, or with NHEt 2 in the presence of a Lewis acid-amine complex wherein the amine is selected from diethylamine, triethylamine, diisopropylethylamine, N,N-diethylaniline, N,N-dimethylbenzylamine, N-methylpiperidine, N-methylmorpholine, N,N′-dimethylpiperazine and hexamethylene tetramine, in order to obtain the amide-alcohol of the following formula (III): (c) reaction of the amide-alcohol of formula (III) obtained in the previous step (b) with thionyl chloride in order to obtain the chlorinated amide of the following formula (IV): (d) reaction of the chlorinated amide of formula (IV) obtained in the previous step (c) with a phthalimide salt, in order to obtain the phthalimide derivative of the following formula (V): (e) hydrolysis of the phthalimide group of the phthalimide derivative of formula (V) obtained in the previous step (d), in order to obtain (1S,2R)-milnacipran; and (f) salification of the (1S,2R)-milnacipran obtained in the previous step (e) in a suitable system of solvents, in the presence of a pharmaceutically acceptable acid, wherein steps (a) to (e) are carried out in a reaction medium comprising a same and single toluene solvent.