Optimized Synthesis of the Key Intermediate of Telmisartan via the Cyclization of 2-Bromoarylamine with n-Butyronitrile

Herein, a facile and sustainable synthesis method of bis-benzimidazole compound 5, which is the key intermediate of telmisartan, is realized using commercially available 3-methyl-4-nitrobenzoic acid and 2-chloronitrobenzene as starting materials. Aniline 10 was produced in 98% isolated yield using a one-pot reduction/cyclization procedure. Subsequently, 2-bromoarylamine 11 was prepared in 96% isolated yield via the bromination of aniline 10 with bromine. Finally, bis-benzimidazole 5 synthesis was completed via the cyclization of 2-bromoarylamine 11 with n-butyronitrile; the isolated yield of bis-benzimidazole 5 was 95%, and its high-performance liquid chromatography purity based on area was 99.8%. Each reaction step was optimized to achieve high yields, and the optimal conditions were identified in the final step via the design of experiments. The developed process provides an alternative sustainable route for synthesizing bis-benzimidazole 5; this route avoids undesired nitration using nitric/sulfuric acid and cyclization in polyphosphoric acid, which are used in the current methods.