Convergent syntheses of carbon-13 labeled midazolam and 1′-hydroxymidazolam

For the purpose of drug interaction studies, the stable-isotope labeled [13C3]midazolam and its metabolite, 1′-hydroxy-[13C3]midazolam were synthesized in four and five steps in overall yields of 25.5% and 14.2%, from 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine, respectively, by a convergent synthesis, in which a key imidazoline ring formation was achieved by the facile reaction of [13C]2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine with varying ethyl imidate hydrochlorides. The scrambling of C-3 and C-4 labeling in intermediate diamine, and consequently in the final products, as well as the formation of a Δ4,5 isomer of 1′-hydroxy-[13C3]midazolam was observed and explained.