Chemo-Enzymatic Synthesis, Structural and Stereochemical Characterization, and Intrinsic Degradation Kinetics of Diastereomers of 1-β--Acyl Glucuronides Derived from Racemic 2-{4-[(2-Methylprop-2-en-1-yl)amino]phenyl}propanoic Acid.

Alminoprofen, ()-2-{4-[(2-methylprop-2-en-1-yl)amino]phenyl}propanoic acid (ALP) , is a racemic drug categorized as a 2-arylpropanoic acid-class nonsteroidal anti-inflammatory drug. Pharmacokinetic studies of in patients have revealed that the corresponding acyl glucuronide is a major urinary metabolite, but little is known about the structure and stereochemistry of . The present work describes the synthesis of a diastereomeric mixture of 1-β--acyl glucuronides (2)- from and methyl 2,3,4-tri--acetyl-1-bromo-1-deoxy-α-d-glucopyranuronate using our chemo-enzymatic method that has complete specificity for the β-configuration. The structure of (2)- was characterized by H and C NMR spectroscopy and high-resolution mass spectrometry as well as by complete hydrolysis by β-glucuronidase. The absolute stereochemistry of (2)- was determined by comparison with (2)- synthesized alternatively from (2)- and . Compound (2)- was prepared in two steps starting from chiral ()-2-(4-nitrophenyl)propanoic acid (2)-. Chiral resolution of (2)- was achieved using a chiral high-performance liquid chromatography column, and its stereochemistry was determined by comparison with (2)-. The intrinsic degradation rate constant of (2)- was 0.405 ± 0.002 h, which is approximately twice that of (2)- (the value was 0.226 ± 0.002 h) under physiological conditions (pH 7.40, 37 °C).