Highly convergent synthesis of angiotensin II receptor blockers has been accomplished
by means of late-stage C–H arylation using functionalized aryl bromides. C–H arylation
of 1-benzyl-5-phenyl-1H-tetrazole with aryl bromides carrying methyl 2-ethoxybenzimidazole-7-carboxylate
unexpectedly provided coupling products where ethyl group was migrated from oxygen
to nitrogen atom. The O-to-N ethyl migration was completely suppressed by the use
of N-pivaloyl-l-valine rather than the combined use of triphenylphosphine and sodium mesitylenesulfonate
to result in the preferential formation of a key intermediate of candesartan cilexetil.
In contrast, when an aryl bromide having ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate
was employed, the C–H arylation proceeded smoothly to provide a late-stage intermediate,
which rapidly led to olmesartan medoxomil in 3 steps.
Key words
tetrazole - ruthenium - hypertensive drugs
