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Pharmaceuticals 2019, 12(1), 21; https://doi.org/10.3390/ph12010021

On the Absolute Stereochemistry of Tolterodine: A Circular Dichroism Study

1
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Moruzzi 13, 56124 Pisa, Italy
2
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52 St., 01-224 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Received: 28 December 2018 / Revised: 18 January 2019 / Accepted: 22 January 2019 / Published: 26 January 2019
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Abstract

Tolterodine (1) is a potent muscarinic receptor antagonist used in the treatment of overactive urinary bladder (OAB) syndrome. Tolterodine is chiral and it was patented, and is currently marketed, as the l-tartrate salt of the (R)-enantiomer. However, the existing literature does not offer an ultimate proof of a stereoselective mode of action of 1. A second open stereochemical issue concerns the absolute configuration (AC) of 1. Neither the original patents nor subsequent studies have established the AC of 1 in an unambiguous way, although the AC of the l-tartrate salt of 1 was assigned by X-ray diffractometry. Finally, neither electronic nor vibrational circular dichroism (ECD and VCD) spectra of 1 are reported so far. We performed a thorough ECD/VCD study of 1 in different solvents and at variable temperatures. Solvent and temperature dependence highlighted the existence of moderate flexibility which was confirmed by molecular modelling. ECD calculations with time-dependent density functional theory (TDDFT) accurately reproduced the experimental spectra and allowed us to confirm the AC of 1 in an independent way. View Full-Text
Keywords: absolute configuration; drug enantiomers; circular dichroism calculations; conformational analysis; variable-temperature CD; solvent dependent CD absolute configuration; drug enantiomers; circular dichroism calculations; conformational analysis; variable-temperature CD; solvent dependent CD
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Górecki, M.; Zullo, V.; Iuliano, A.; Pescitelli, G. On the Absolute Stereochemistry of Tolterodine: A Circular Dichroism Study. Pharmaceuticals 2019, 12, 21.

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