SYNTHESIS OF MONTELUKAST (MK-0476) METABOLIC OXIDATION-PRODUCTS

We report the chemical synthesis of six oxidized derivatives of MK-047 6 (Montelukast, L-706631), which have been key tools in the identifica tion of its metabolites. We have prepared three diastereoisomeric pair s of potential oxidative metabolites of MK-0476, starting from the (S) -hydroxy ester 7 in 10 and five steps, and starting from MK-0476 itsel f in one step. The key benzylic hydroxyl of 1 and 2 was introduced by a bromination and saponification reaction sequence. In the case of the hydroxyl of 3 and 4, the key step was the addition of a hydroxymethyl carbanion equivalent on ketone 20. The two sulfoxide 5 and 6 were pre pared by a direct oxidation of MK-0476 with m-chloroperbenzoic acid.