Chromatographic separation of the interconverting enantiomers of imidazo- and triazole-fused benzodiazepines

The toolbox of medicinal chemists includes the 1,4-benzodiazepine scaffold as a “privileged scaffold” in drug discovery. Several biologically active small molecules containing have been approved by FDA for treatment various diseases, with most them being used their psychotropic effects. therapeutic potential 1,4-benzodiazepines has stimulated interest synthetic developing new strategies to range substituted analogues biological evaluation. A structural variation classical benzodiazepine skeleton is observed e.g. alprazolam, midazolam, and related benzodiazepines, which contain 1,2,4-triazole or an imidazole ring fused core. Irrespective presence heterocyclic ring, seven-membered diazepine far from planar, its shape resembles twist chair. Then, unsymmetrical substitution pattern around seven membered cycle renders these chiral, they lack any reflection-type symmetry element. However, chirality this labile at room temperature, becausea simple flipping process converts one enantiomer into other, exist mixture rapidly interconverting conformational enantiomers solution near temperature. Physical separation diazepam other 1,4-benzodiazepin-2-ones can be accomplished low temperature HPLC on chiral stationary phases (CSPs). If column cooled down temperatures where interconversion rate sufficiently low, compared chromatographic rate, distinct separated peaks observed, provided CSP enantioselctive. apparent constants on-column enantiomerization corresponding free energy activation barriers were obtained simulation exchange-deformed profiles using computer program based stochastic model. Here we report dynamic investigations carried out set imidazo triazolo-benzodiazepines (alprazolam, triazolam estazolam) experimental chromatograms reported paper show that third increase barrier 2 kcal/mol.