Premium
Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2 R )‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil
Author(s) -
Tucci Fabio C.,
Hu Tao,
Mesleh Michael F.,
Bokser Allan,
Allsopp Eric,
Gross Timothy D.,
Guo Zhiqiang,
Zhu YunFei,
Struthers R. Scott,
Ling Nicholas,
Chen Chen
Publication year - 2005
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20198
Subject(s) - chemistry , atropisomer , benzylamine , diastereomer , stereochemistry , proton nmr , stereocenter , aqueous solution , nuclear magnetic resonance spectroscopy , gibbs free energy , crystallography , medicinal chemistry , organic chemistry , enantioselective synthesis , physics , quantum mechanics , catalysis
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.