O-Glucuronide synthesis made easy - Being bio-reactive

Synthetic glucuronide metabolites are needed as reference substances in drug research.

Syntheses and Characterization of the Acyl Glucuronide …

In humans, metabolism of the commonly used nonsteroidal antiinflammatory drug diclofenac 1 yields principally the 4‘-hydroxy 2, 5-hydroxy 3, and acyl glucuronide 4 metabolites. All three metabolites have been implicated in rare idiosyncratic adverse reactions associated with this widely used drug. Therefore, for mechanistic toxicological studies of 1, substantial quantities of 24 are required and their syntheses and characterization are described here. Key steps were a convenient two-step preparation of aniline 5 from phenol, efficient and selective 6-iodination of amide 18, and high-yielding Ullmann couplings to generate diarylamines 11 and 21. The acyl glucuronide 4 was obtained by Mitsunobu reaction of 1 (free acid) with allyl glucuronate 23 followed by Pd(0) deprotection, using a modification of a published procedure. We report full characterization of 4 and note that this important metabolite has been made available pure and in quantity for the first time. We report also the metabolic fates of the synthetic metabolites: 2 and 3 were glucuronidated in rats, but only 3 formed glutathione adducts in vivo and by enzymatic synthesis via a quinoneimine intermediate. A previously undescribed glutathione adduct of 3 was obtained by enzymatic synthesis. Compound 4 formed an imine-linked protein conjugate as evinced by sodium cyanoborohydride trapping.

US6566510B1 - Morphine-6-glucuronide synthesis - …

Glucuronide isomers of dobutamine, losartan, candesartan, and zolarsartan were synthesized by enzyme-assisted methods whereas clenbuterol glucuronides were synthesized chemically using the Koenigs-Knorr reaction.

Acyl glucuronides are vital metabolites for many carboxylic acid containing drugs. We report an efficient new method for the chemical synthesis of these molecules by selective 1β-acylation of allyl glucuronate with carboxylic acids catalyzed by HATU and then mild deprotection through treatment with Pd(PPh3)4 and morpholine. The method is effective for a range of aryl and alkyl carboxylic acids, including important drugs.