Synthesis 2021; 53(15): 2689-2692
DOI: 10.1055/a-1472-0925
paper

Convergent Synthesis of Angiotensin II Receptor Blockers through C–H Arylation of 1-Benzyl-5-phenyl-1H-tetrazole with Functionalized Aryl Bromides

Masahiko Seki
,
Yusuke Takahashi


Abstract

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.

Supporting Information



Publication History

Received: 12 March 2021

Accepted after revision: 31 March 2021

Accepted Manuscript online:
31 March 2021

Article published online:
14 April 2021

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