Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2R)‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil
- 1 January 2005
- Vol. 17 (9) , 559-564
- https://doi.org/10.1002/chir.20198
Abstract
1-(2,6-Difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (6), a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor, exists as a pair of atropisomers in solution, which was detected by NMR spectroscopy, and separable by HPLC. In addition to a (R)-configured benzylamine, there is a second stereogenic element due to the presence of a chiral axis between the substituted 5-phenyl group and the uracil core. The rate constant of the interconversion (k = 5.07 × 10−5 s−1) of these two atropisomers was determined by proton NMR analysis of a diastereoisomer-enriched sample in aqueous solution at 25°C, and the corresponding Gibbs free energy ΔG# of rotation barrier (97.4 kJ mol−1) was calculated using the Eyring equation. The diastereoisomer half-life at physiological temperature (37°C) in aqueous media was estimated to be about 46 min. © 2005 Wiley-Liss, Inc. Chirality 17:559–564, 2005.Keywords
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