GB2557867A — New synthetic path to vortioxetine salts

USPTO Abstract

The preparation of vortioxetine free base 4 and pharmaceutically acceptable vortioxetine salts, is achieved by one of: oxidation of a 1-{2-[(2,4-dimethylphenyl)sulfanyl]cyclohexyl}piperazine derivative of formula 21 (where the cyclohexyl moiety is mono- or di-unsaturated); activation of 1-phenylpiperazine by oxidisation to give compound (10) and reacting (10) with 2,4-dimethylbenzensulfenyl chloride, before reduction to vortioxetine 4; or reaction of (2-(piperazin-1-yl)aniline) 2 with tert-butyl nitrite and tetrafluoroboric acid to give (2-piperazin-1-yl)benzenediazonium tetrafluoroborate salt 3 and then reacting compound 3 in the presence of alkali 2,4-dimethylbenzenethiolate and a metal catalyst to give vortioxetine 4. A process for the preparation of a particular polymorphic form of vortioxetine hydrobromide with an X-ray powder diffraction pattern with peaks at 2 theta (±0.2º 2-theta): 7.9, 14.8, 17.8 and 26.8 is also disclosed comprising cooling crystallisation using chloroform (CHCl3) as a solvent over various cooling cycles. The invention also relates to pharmaceutical compositions comprising the polymorph of vortioxetine hydrobromide for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).