Synthesis of 1-β-O-acyl glucuronides of diclofenac, mefenamic acid and (S)-naproxen by the chemo-selective enzymatic removal of protecting groups from the corresponding methyl acetyl derivatives

Abstract

Using a straightforward chemo-enzymatic procedure, 1-β-O-acyl glucuronides of three non-steroidal anti-inflammatory drugs, diclofenac (DF) 5, mefenamic acid (MF) 6 and (S)-naproxen (NP) 7, were prepared. Caesium salts of these carboxylic acid drugs reacted with commercially available methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-α-D-glucopyranuronate 4 to give exclusively the corresponding 1-β-O-acyl glucuronides 8–10 in moderate yields. The protecting acetyl (for –OH group) and methyl ester (for –CO₂H group) groups of each sugar moiety were easily removed to provide the corresponding free 1-β-O-acyl glucuronides 1–3 in high yields. Deprotection was achieved through effective enzyme-catalysed chemo-selective hydrolyses of the acetyl groups using lipase AS Amano (LAS), and of the methyl ester group using esterase from porcine liver (PLE).