Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2 R )‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil

1‐(2,6‐Difluorobenzyl)‐3‐[(2 R )‐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 Δ G # 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.