Preparative chiral chromatography and chiroptical characterization of enantiomers of omeprazole and related benzimidazoles.
To chiroptically characterize the enantiomers of omeprazole and some structurally related benzimidazoles with circular dichroism (CD), preparative chiral liquid chromatography was utilized for the isolation of the pure enantiomers. A limited analytical column screen was performed identifying Kromasil-CHI-TBB and the amylose-based phases Chiralpak AD and AS as possible chiral stationary phases (CSPs) for the preparative scale separation of the enantiomers of the different benzimidazoles. Optimization of the chromatographic conditions with respect to retention, enantioseparation, and resolution was achieved by variation of the mobile phase constituents as well as of temperature. Because of the lability of the compound in slightly acidic media, supercritical fluid chromatography (SFC) could not be applied for a preparative scale separation of the enantiomers. The separation of omeprazole was optimized to give high throughput (2.6 kg racemate/kg CSP/day) and high enantiomeric excess of the obtained isomers. The absolute configurations of the pure enantiomers of rabeprazole, lansoprazole, and pantoprazole were determined from the strong correlation to the CD spectrum of (+)-(R)-omeprazole. For all the compounds, the (+)-enantiomers displayed similar chiroptical features as (+)-(R)-omeprazole and were thus assigned the (R)- configuration. Elution order of the optical isomers was monitored by injecting racemic solutions spiked with one of the isomers and also by an on-line laser polarimeter. Both the type of CSP and also the mobile phase constituents had a strong effect on elution order of the enantiomers.
Andersson
Shalini
S
Medicinal Chemistry, AstraZeneca R&D Mölndal, S-431 83, Mölndal, Sweden. shalini.andersson@astrazeneca.com
Nelander
Hanna
H
Ohlén
Kristina
K
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000032:analysis / Q000737:chemistry*; D001562:Benzimidazoles / Q000032:analysis / Q000737:chemistry*; D002845:Chromatography / Q000379:methods; D025924:Chromatography, Supercritical Fluid / Q000379:methods*; D002942:Circular Dichroism; D004791:Enzyme Inhibitors / Q000737:chemistry*; D064747:Lansoprazole; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D009853:Omeprazole / Q000032:analysis / Q000737:chemistry*; D000077402:Pantoprazole; D064750:Rabeprazole; D013237:Stereoisomerism
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D064747:Lansoprazole; D064750:Rabeprazole; D000077402:Pantoprazole; D009853:Omeprazole