Furlan, Borut, Grdadolnik, Simona Golič, Hočevar, Stanko, Kocjan, Darko, Levec, Janez, Maskill, Howard, Navrátilová, Hana, Pospíšil, Jiří, Potáček, Milan, Urleb, Uroš and Žmitek, Janko (2009) Amlodipine Benzenesulfonate: A Mechanistic Investigation of Its Industrial Preparation via Detritylation of N-tritylamlodipine and Related NMR Studies. Croatica Chemica Acta, 82 (1). pp. 299-309. ISSN 0011-1643
Kinetics and product analysis of detritylation of N-tritylamlodipine by benzenesulfonic acid in methanol, methanol-chloroform (volume ratio 9:1), ethanol, 2-propanol, and methanol/2-propanol (mole ratio 1:1) have been investigated by HPLC; amongst these reaction conditions are ones closely similar to those of one method of manufacturing amlodipine benzenesulfonate. Kinetics of detritylation of Ntritylamlodipine have also been investigated in methanol-d4 by 1H NMR spectroscopy and the agreement with the results by HPLC is good. The rate of detritylation increases with increasing concentrations of benzenesulfonic acid, and p-methoxy-substituents in the trityl group have been shown to lead to faster reactions. In methanol, the rate is hardly affected by 10 % (vol. fraction) chloroform. These studies relate to mechanistic investigations of acid-catalysed deaminations of methoxy-substituted tritylalkylamines, and Arrhenius activation parameters (Ea and A) are similar indicating a common generic mechanism. Acid-catalysed trans-esterification has been shown by HPLC to accompany detritylation in methanol, and attendant protium-deuterium exchange in the methyl at C6 by reversible acid-catalysed iminium ion formation in the 4-aryl-1,4-dihydropyridine moiety of both N-tritylamlodipine and amlodipine has been investigated in deuteriated methanol by 1H, 13C, and 15N NMR spectroscopy.
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