title: Aminolysis of ezetimibe.
abstract: The aminolysis of ezetimibe (1) and the structurally similar (3R*,4S*)-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-methylazetidin-2-one (4a) giving the corresponding β-aminoamides 2a-d and 5a-c was studied spectrophotometrically under pseudo-first order conditions in aqueous butylamine, 3-methoxypropylamine, 2-methoxyethylamine and 2-hydroxyethylamine buffer solutions at 39°C. It was found that the reaction mechanism involves uncatalyzed nucleophilic attack of an amine on the azetidinone carbonyl group as the rate-limiting step. On the basis of the Brønsted β(Nuc) value (0.58 and 0.55 respectively) an early transition state was proposed in which the extent of C-N(amine) bond formation is low and the C-N(lactam) bond remains almost intact. It was also found that the presence of the phenolic group has a crucial role in the aminolysis because the analogous O-methyl derivative 4b does not react with amines at all. This observation would explain the fact that aminolysis of ezetimibe was not observed in human serum albumins where faster glucuronidation which blocks the phenolic hydroxide group occurs.
authors: Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, The Czech Republic.
authors: Jana
authors: J
authors: Baťová
authors: Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, The Czech Republic.
authors: Aleš
authors: A
authors: Imramovský
authors: Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, The Czech Republic. Electronic address: Jiri.Hanusek@upce.cz.
authors: Jiří
authors: J
authors: Hanusek
mesh_terms: D000588:Amines / Q000737:chemistry*; D000069438:Ezetimibe / Q000737:chemistry*; D006868:Hydrolysis; D007700:Kinetics; D011437:Propylamines / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D000588:Amines; D011437:Propylamines; D014867:Water; D000069438:Ezetimibe; C547846:3-methoxypropylamine
keywords: Aminolysis; Azetidinone; Ezetimibe; Kinetics