Publication details

Amlodipine Benzenesulfonate: A Mechanistic Investigation of Its Industrial Preparation via Detritylation of N-tritylamlodipine and Related NMR Studies

Authors

FURLAN Borut GRDADOLNIK Simona Golic HOCEVAR Stanko KOCJAN Darko LEVEC Janez MASKILL Howard NAVRÁTILOVÁ Hana POSPÍŠIL Jiří POTÁČEK Milan URLEB Uros ZMITEK Janko

Year of publication 2009
Type Article in Periodical
Magazine / Source CROATICA CHEMICA ACTA
MU Faculty or unit

Faculty of Science

Citation
Web https://hrcak.srce.hr/38639
Keywords kinetics; detritylation; mechanism; acid-catalysed deaminations
Description 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 N-tritylamlodipine have also been investigated in methanol-d(4) by (1)H 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 (E(a) and A) are similar indicating a common generic mechanism. Acid-catalysed traps-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 (1)H, (13)C, and (15)N NMR spectroscopy.

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