Original scientific paper

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

Borut Furlan ; Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
Simona Golič Grdadolnik ; National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
Stanko Hočevar ; National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
Darko Kocjan ; Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
Janez Levec ; National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
Howard Maskill ; Department of Chemical and Biological Sciences, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield, UK
Hana Navrátilová ; Department of Organic Chemistry, Masaryk University of Brno, Kotlářská 2, CZ-61137 Brno, The Czech Republic
Jiří Pospíšil ; Department of Organic Chemistry, Masaryk University of Brno, Kotlářská 2, CZ-61137 Brno, The Czech Republic
Milan Potáček ; Department of Organic Chemistry, Masaryk University of Brno, Kotlářská 2, CZ-61137 Brno, The Czech Republic
Uroš Urleb ; Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia
Janko Žmitek ; National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia

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 (E_a 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.

Keywords

kinetics; detritylation; mechanism; acid-catalysed deaminations

Hrčak ID:

38639

URI

https://hrcak.srce.hr/38639

Publication date:

30.6.2009.

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