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Publication detail

Aminolysis of ezetimibe
Authors: Baťová Jana | Imramovský Aleš | Hanusek Jiří
Year: 2015
Type of publication: článek v odborném periodiku
Name of source: Journal of Pharmaceutical and Biomedical Analysis
Publisher name: Pergamon-Elsevier Science Ltd.
Place: Oxford
Page from-to: 495-500
Titles:
Language Name Abstract Keywords
cze Aminolýza ezetimibu Byla studována aminolýza ezetimibu a strukturně podobného (3R*,4S*)-(4-fluorfeny1)-4-(4-hydroxyfenyl)-3-methylazetidin-2-onu poskytující odpovídající beta-aminoamidy. Reakce byla studována spektrofotometricky za podmínek pseudoprvního řádu ve vodných butylaminových, 3-methoxypropylaminových, 2-methoxyethylaminových a 2-hydroxyethylaminových pufrech při 39 C. Bylo zjištěno, že mechanismus zahrnuje nekatalyzovaný rychlost-určující nukleofilní atak aminu na azetidinonovou karbonylovou skupinu. Na základě Bronstedova beta koeficientu (0.58 a 0.55) byl navržen ranný transitní stav. Aminolýza;ezetimib;kinetika;azetidinon
eng Aminolysis of ezetimibe The aminolysis of ezetimibe (1) and the structurally similar (3R*,4S*)-(4-fluoropheny1)-4-(4-hydroxyphenyl)-3-methylazetidin-2-one (4a) giving the corresponding beta-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 degrees 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 Bronsted beta(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. Ezetimibe;Aminolysis;Azetidinone;Kinetics

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