title: Liquid chromatographic enantioseparation of three beta-adrenolytics using new derivatizing reagents synthesized from (S)-ketoprofen and confirmation of configuration of diastereomers.
abstract: Diastereomers of racemic β-adrenolytic drugs [namely (RS)-propranolol, (RS)-metoprolol and (RS)-atenolol] were synthesized under microwave irradiation with (S)-ketoprofen based chiral derivatization reagents (CDRs) newly synthesized for this purpose. (S)-Ketoprofen was chosen for its high molar absorptivity (εo~ 40,000) and its availability as a pure (S)-enantiomer. Its -COOH group was activated with N-hydroxysuccinimide and N-hydroxybenzotriazole; these were easily introduced and also acted as good leaving groups during nucleophilic substitution by the amino group of the racemic β-adrenolytics. The CDRs were characterized by UV, IR,1H-NMR, HRMS and CHNS. Separation of diastereomers was achieved by RP HPLC and open column chromatography. Absolute configuration of the diastereomers was established with the help of1HNMR supported by developing their optimized lowest energy structures using Gaussian 09 Rev. A.02 program and hybrid density functional B3LYP with 6-31G* basis set (based on density functional theory), and elution order was established. RP HPLC conditions for separation were optimized and the separation method was validated. The limit of detection values were 0.308 and 0.302 ng mL-1. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee, 247667, India.
authors.forename: Shiv
authors.initials: S
authors.lastname: Alwera
authors.affiliation: Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee, 247667, India. rbushfcy54@gmail.com.
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhushan
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000302:isolation & purification*; D001262:Atenolol / Q000737:chemistry / Q000302:isolation & purification*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D056148:Chromatography, Reverse-Phase / Q000379:methods*; D007660:Ketoprofen; D057230:Limit of Detection; D008790:Metoprolol / Q000737:chemistry / Q000302:isolation & purification*; D008958:Models, Molecular; D008968:Molecular Conformation; D011433:Propranolol / Q000737:chemistry / Q000302:isolation & purification*; D013237:Stereoisomerism
chemical_list: D000319:Adrenergic beta-Antagonists; D001262:Atenolol; D007660:Ketoprofen; D011433:Propranolol; D008790:Metoprolol
keywords: (S)-(+)-ketoprofen; diastereomers; enantioseparation; liquid chromatography; molecular configuration; β-adrenolytics