Synthesis of deuterium labeled dabigatran etexilate

Dabigatran is a direct thrombin inhibitor widely applied in atrial fibrillation anticoagulation therapy. The stable isotope-labeled dabigatran etexilate were required. [²H₄] dabigatran etexilate was prepared from [²H₅] bromobenzene through nitration, cyanation, Pinner reaction, esterfication, reduction and alkylation. [²H₃] dabigatran etexilate was obtained after acylchlorination, acylamidation, alkylation, reduction, cyclization, alkylation. [²H₄] O-n-hexylacarbamate derivative was condensed with [²H₃] benzimidazole to afford [²H₇] dabigatran etexilate. Three versions of deuterium labelled dabigatran etexilate with excellent deuterium enrichment could be applied in LC/MS analysis.