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 βNuc value (0.58 and 0.55 respectively) an early transition state was proposed in which the extent of C–Namine bond formation is low and the C–Nlactam 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.
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