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

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

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    Abstract

    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.

    Item Type: Article
    Uncontrolled Keywords: kinetics, detritylation, mechanism, acid-catalysed deaminations
    Subjects: Q Science > QD Chemistry
    Schools: School of Applied Sciences
    Related URLs:
    Depositing User: Graham Stone
    Date Deposited: 02 Sep 2009 15:40
    Last Modified: 28 Jul 2010 19:46
    URI: http://eprints.hud.ac.uk/id/eprint/5501

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