Enantiomeric separation of substituted 2-arylindoles on derivatised polysaccharide chiral stationary phases.
The enantiomeric separation of a series of 2-arylindoles, developed as 5HT(2A) receptor antagonists for the treatment of schizophrenia, was investigated. Evaluation of a number of chiral stationary phases (CSPs) suggested that Chiralcel OD-H and Chiralpak AD were the most versatile for these compounds, and were employed for more detailed studies. A degree of complementarity between the CSPs was observed, such that Chiralcel OD-H was more effective for piperidine-containing molecules and Chiralpak AD for piperazine- and morpholine-containing molecules. The presence of a basic secondary amine was detrimental chromatographically, but resolution was improved substantially by employing diethylamine (DEA) in the mobile phase. All separations were either enthalpy-controlled or showed no temperature dependence. Differential temperature effects between series highlighted the possibility of multiple binding modes on these CSPs. Based on this study, it is possible to make a more rational selection of chromatographic conditions for future novel analogues.
Watt
Alan P
AP
Department of Medicinal Chemistry, Drug Metabolism and Pharmacokinetics Section, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. alan_watt@merck.com
Hitzel
Laure
L
Mortishire-Smith
Russell J
RJ
D000688:Amylose / Q000031:analogs & derivatives*; D002219:Carbamates; D002482:Cellulose / Q000031:analogs & derivatives*; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation / Q000379:methods*; D007211:Indoles / Q000032:analysis / Q000737:chemistry / Q000302:isolation & purification* / Q000627:therapeutic use; D048448:Phenylcarbamates; D011134:Polysaccharides; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000188:drug therapy; D012680:Sensitivity and Specificity; D013194:Staining and Labeling / Q000379:methods; D013237:Stereoisomerism; D013696:Temperature
D002219:Carbamates; D007211:Indoles; D048448:Phenylcarbamates; D011134:Polysaccharides; C065943:cellulose tris-3,5-dimethylphenyl-carbamate; C080033:Chiralpak AD; D002482:Cellulose; D000688:Amylose