title: Kinetics and mechanism of the base-catalyzed rearrangement and hydrolysis of ezetimibe.
abstract: The pH-rate profile of the pseudo-first-order rate constants for the rearrangement and hydrolysis of Ezetimibe giving (2R,3R,6S)-N,6-bis(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxamide (2) as the main product at pH of less than 12.5 and the mixture of 2 and 5-(4-fluorophenyl)-5-hydroxy-2-[(4-fluorophenylamino)-(4-hydroxyphenyl)methyl]-pentanoic acid (3) at pH of more than 12.5 in aqueous tertiary amine buffers and in sodium hydroxide solutions at ionic strength I = 0.1 mol L(-1) (KCl) and at 39 °C is reported. No buffer catalysis was observed and only specific base catalysis is involved. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple β-lactams and it contains several breaks. Up to pH 9, the log k(obs) linearly increases with pH, but between pH 9 and 11 a distinct break downwards occurs and the values of log k(obs) slightly decrease with increasing pH of the medium. At pH of approximately 13, another break upwards occurs that corresponds to the formation of compound 3 that is slowly converted to (2R,3R,6S)-6-(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxylic acid (4). The kinetics of base-catalyzed hydrolysis of structurally similar azetidinone is also discussed.
authors.affiliation: Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Pardubice, 532 10, The Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Baťová
authors.forename: Aleš
authors.initials: A
authors.lastname: Imramovský
authors.forename: Josef
authors.initials: J
authors.lastname: HájÍček
authors.forename: Ludmila
authors.initials: L
authors.lastname: Hejtmánková
authors.forename: Jiří
authors.initials: J
authors.lastname: Hanusek
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry*; D001384:Azetidines / Q000737:chemistry*; D002021:Buffers; D002384:Catalysis; D004355:Drug Stability; D000069438:Ezetimibe; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D009994:Osmolar Concentration
chemical_list: C116379:2-azetidinone; D000924:Anticholesteremic Agents; D001384:Azetidines; D002021:Buffers; D000069438:Ezetimibe
keywords: Liquid chromatography; NMR; UV-VIS spectroscopy; acid-base catalysis; azetidinone; chemical stability; degradation products; ezetimibe; kinetics; pH rate profile; rearrangement