Abstract
Midazolam, a potent benzodiazepine derivative and a typical substrate of CYP3A4/3A5, is essentially metabolized in human into 1′-hydroxymidazolam, then eliminated as the corresponding phase II metabolite, the 1′-O-β-d-glucuronide derivative.
A high yield alternative to the current multistep synthesis of 1′-hydroxymidazolam is described, using a biotransformation of midazolam by a fungal microorganism, Beauveria bassiana.
The corresponding phase II metabolite, 1′-hydroxymidazolam-1′-O-β-d-glucuronide, has been then prepared by chemical synthesis (3 steps, 20% yield), or by microbial glucuronidation (one step, 20% yield) using a Streptomyces sp. strain.
The use of the same Streptomyces strain allows a direct and expeditive synthesis of the same glucuronide conjugate from midazolam itself in an advantageous 17% yield.