Pierre Fabre Medicament

Commissariat a L'energie Atomique

Commissariat a L'energie Atomique Et Aux Energies Alternatives

Paul Hellier

Eric Doris

Marc Nicolas

Bernard Rousseau

Laurent Subra

Emerson Giovanelli

Catherine Diard

Lionel Moisan

Sébastien Comesse

The present invention relates to a method for synthesizing a pharmaceutically acceptable acid addition salt of (1S, 2R)-milnacipran 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 a lactone; (b) reaction of said lactone with MNEt, wherein M represents an alkaline metal, or with NHEtin the presence of a Lewis acid-amine complex, in order to obtain an amide-alcohol; (c) reaction of said amide-alcohol with thionyl chloride in order to obtain a chlorinated amide; (d) reaction of said chlorinated amide with a phthalimide salt in order to obtain a phthalimide derivative; (e) hydrolysis of the phthalimide group of said phthalimide derivative in order to obtain (1S, 2R)-milnacipran, and (f) salification of (1S, 2R)-milnacipran in a suitable solvent system in the presence of a pharmaceutically acceptable acid.

Method for synthesis of (1S, 2R)-milnacipran

The fluorinated derivatives of catharanthine according to the invention respond to the general formula I: in which:

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Castelnau de Montmiral, France

Paul Hellier