Sila-venlafaxine, a Sila-Analogue of the Serotonin/Noradrenaline Reuptake Inhibitor Venlafaxine: Synthesis, Crystal Structure Analysis, and Pharmacological Characterization

The serotonin/noradrenaline reuptake inhibitor rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol (rac-venlafaxine, rac-1a) is in clinical use as an antidepressant. The silicon analogue, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol (rac-sila-venlafaxine, rac-1b), was synthesized in multistep syntheses, starting from tetrachlorosilane or tetramethoxysilane. The corresponding 1-silacyclopentan-1-ol derivative rac-2 was prepared analogously. The sila-venlafaxine enantiomers (R)-1b and (S)-1b were obtained by resolution of rac-1b, using (+)- or (−)-10-camphorsulfonic acid as the resolving agent. Compounds rac-1b, (R)-1b, (S)-1b, rac-1b·HCl, (R)-1b·HCl, (S)-1b·HCl, (R)-1b·HBr, rac-2, and rac-2·HCl were characterized by multinuclear NMR studies and elemental analyses, and rac-1b·HCl, (R)-1b·HBr, and rac-2 were additionally characterized by crystal structure analyses. Compounds rac-1a, rac-1b, rac-2, (R)-1a, (S)-1a, (R)-1b, and (S)-1b were tested as their hydrochlorides...