1. Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil.
- Author
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Tucci FC, Hu T, Mesleh MF, Bokser A, Allsopp E, Gross TD, Guo Z, Zhu YF, Struthers RS, Ling N, and Chen C
- Subjects
- Chromatography, High Pressure Liquid, Humans, Magnetic Resonance Spectroscopy, Molecular Structure, Receptors, LHRH antagonists & inhibitors, Stereoisomerism, Thymine chemistry, Uracil chemistry, Thymine analogs & derivatives, Uracil analogs & derivatives
- 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., (Copyright 2005 Wiley-Liss, Inc.)
- Published
- 2005
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