SYNTHESIS AND BIOLOGICAL IDENTIFICATION OF THE ACYL GLUCURONIDE OF THE ANTIINFLAMMATORY DRUG ML-3000

The synthesis and identification in biological samples of the 1-O-acyl glucuronide 6 of the antiinflammatory drug ML-3000 is described. Star ting with D-glucuronic acid gamma-lactone, 2,3,4-tris(tert.-butyldimet hysilyl) glucuronic acid trichloroethylester 4 was prepared (in seven steps) and subsequently coupled with 1 under Mitsunobu conditions. Dep rotection, i. e. removal of the trichloroethoxy group with zinc dust a nd desilylation with hydrofluoric acid in acetonitrile afforded a mixt ure of alpha- and beta-6 which could be separated by preparative HPLC. The abundance of 6 in bile and plasma samples obtained from animal st udies with the cynomolgus monkey and the rabbit following repeated adm inistration of 1 could be demonstrated by LC-electrospray MS analysis. (C) 1997 Elsevier Science Ltd.