(R)-Sila-venlafaxine: A selective noradrenaline reuptake inhibitor for the treatment of emesis

Hydroaminoalkylation of Allylsilanes and a One‐Pot Procedure for the Synthesis of 1,5‐Benzoazasilepines

“…For that purpose, ah ydroaminoalkylation reaction mixture of allylsilane 21 and N-methylaniline (1)i nt oluene was initially heatedt o1 40 8Cf or 24 hi nt he presence of 10 mol %o fc atalyst IV.A fterwards, 2.5 mol %P d 2 (dba) 3 ,7mol %R uPhos, sodium tert-butoxide and additional toluene were added and the resulting reactionm ixture was heatedt o1 10 8Cf or additional 24 h. The yield of 83 % in which 1,5-benzoazasilepine 23 was obtained after chromatographic purification ( Table 5, entry 1) again underlines the wellestablished fact that the Buchwald-Hartwig amination tolerates the presence of the reagents used in hydroaminoalkyla-tion reactions. To finally investigate the scope of the onepot procedure, we then reacteda dditional ortho-, meta-, and para-substituted N-methylanilines with allylsilane 21.A se xpecteda nd in good agreement with the results obtained for the hydroaminoalkylation of simple allylsilanes presented in Ta ble 2, it was found that para-o rmeta-substituted N-methylanilinesu ndergo smooth reactiont og ive the desired 1,5-benzoazasilepines in good yields between 66 and 84 %( Ta ble 5, entries [3][4][5][6][7][8][9][10][11]. To finally investigate the scope of the onepot procedure, we then reacteda dditional ortho-, meta-, and para-substituted N-methylanilines with allylsilane 21.A se xpecteda nd in good agreement with the results obtained for the hydroaminoalkylation of simple allylsilanes presented in Ta ble 2, it was found that para-o rmeta-substituted N-methylanilinesu ndergo smooth reactiont og ive the desired 1,5-benzoazasilepines in good yields between 66 and 84 %( Ta ble 5, entries [3][4][5][6][7][8][9][10][11].…”

“…[1] However,s ince this opinionh ad been changed through the investigation of the unusualh igh toxicityo fs ilatranes by Voronkove tal., [2] organosiliconc hemistry has become more and more populari nt he pharmaceutical sectoro ver the past decades. [3,4] The feasibility of the latter approach, whichw as pioneeredb yt he Ta cke group, [4a-c, e-k] hass trongly been underlined by al arge number of examples in which sila-substitution significantly affects the features of ad rug. [3,4] The feasibility of the latter approach, whichw as pioneeredb yt he Ta cke group, [4a-c, e-k] hass trongly been underlined by al arge number of examples in which sila-substitution significantly affects the features of ad rug.…”

Silicon Switches of Marketed Drugs

“…However, the reuptake inhibition of serotonin was significantly reduced. Hence, the pharmacological profile has been altered by the introduction of silicon into the core of venlafaxine with silavenlafaxine being a selective noradrenaline reuptake inhibitor [19,20]. …”

Molecular Variations Based on Isosteric Replacements

“…The application of this isosterism remains, however, limited. Figure 8.68 shows a silicon-containing hypocholesterolemic squalene epoxidase inhibitor; [228,229] the silicon analog of the α 2 -adrenergic antagonist atipamezole; [230] a highly potent, stable, and CNS-penetrating silatecan; [231] some ACE inhibitors; [232] HIV protease inhibitors; [233] the (R)-sila-analog of the antidepressant venlafaxine; [234] and a trimethylsilylpyrazole as novel inhibitor of p38 MAP kinase [235] (mitogen-activating protein). Silicon is more electropositive than carbon (and even more if compared to oxygen and nitrogen) and the covalent siliconÀcarbon bonds in the sp 3 hybridization state are 20 percent longer than the corresponding carbonÀcarbon bond.…”