Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil.
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 x 10(-5) s(-1)) of these two atropisomers was determined by proton NMR analysis of a diastereoisomer-enriched sample in aqueous solution at 25 degrees C, and the corresponding Gibbs free energy DeltaG(#) of rotation barrier (97.4 kJ mol(-1)) was calculated using the Eyring equation. The diastereoisomer half-life at physiological temperature (37 degrees C) in aqueous media was estimated to be about 46 min.
Tucci
Fabio C
FC
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., San Diego, CA 92130, USA.
Hu
Tao
T
Mesleh
Michael F
MF
Bokser
Allan
A
Allsopp
Eric
E
Gross
Timothy D
TD
Guo
Zhiqiang
Z
Zhu
Yun-Fei
YF
Struthers
R Scott
RS
Ling
Nicholas
N
Chen
Chen
C
D002851:Chromatography, High Pressure Liquid; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013941:Thymine / Q000031:analogs & derivatives* / Q000737:chemistry; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry
C498569:3-(2-amino-2-phenylethyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione; D011966:Receptors, LHRH; D014498:Uracil; C008378:6-methyluracil; D013941:Thymine