METHOD FOR (1S,2R)-MILNACIPRAN SYNTHESIS Russian patent published in 2014 - IPC C07C231/18 C07C233/58 C07C237/24 

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for synthesis of a pharmaceutically acceptable salt of (1S,2R)-milnacipran of formula . The method involves the following sequential stages. At the stage (a), phenylacetonitrile and (R)-epichlorohydrin are reacted in the presence of a base containing an alkaline metal, then processed with the same base and an acid to prepare lactone of formula (II). At the stage (b), lactone of formula reacts with MNEt₂, wherein M represents an alkaline metal, or with NHEt₂ in the presence of a complex of Lewis acid and amine to prepare amide alcohol of formula (III). At the stage (c), amide alcohol of formula reacts with thionyl chloride to prepare chlorine amide of formula . At the stage (d) chlorine amide of formula (IV) reacts with phthalimide salt, such as potassium salt to prepare a phthalimide derivative of formula . The stage (e) involves hydrolysis of the phthalimide group of the phthalimide derivative of formula (V) to prepare (1S,2R)-milnacipran. The stage (f) provides preparing a (1S,2R)-milnacipran salt in the applicable solvent system in the presence of a pharmaceutically acceptable acid. The stages (a)-(e) are performed in a reaction medium containing the same solvent representing toluene. The invention also refers to a compound of formula (IV) in its (1S,1R) enantiomer form.

EFFECT: using the same solvent at all the stages, except for the last one, enables making the procedure free from the recovery of intermediate products, and simplifying the process.

9 cl, 9 ex