title: Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil.
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 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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., San Diego, CA 92130, USA.
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.forename: Michael F
authors.initials: MF
authors.lastname: Mesleh
authors.forename: Allan
authors.initials: A
authors.lastname: Bokser
authors.forename: Eric
authors.initials: E
authors.lastname: Allsopp
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Gross
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ling
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: 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
chemical_list: 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