Synthesis of Benzimidazoles Classical Approaches

Angiotensin (ATi) Receptor Antagonists for Hypertension and Heart Failure 8.7 Synthesis of Benzimidazoles Classical Approaches 

In one of the reported syntheses of pimobendan, cyclization to form the benzimidazole is achieved as the final step. In this case, dehydrative cyclization of the functionalized 2-aminoanilide intermediate in refluxing acetic acid provides pimobendan efficiently.  

A similar approach has been used in the preparation of rivoglitazone, a PPARy agonist which proceeded to Phase III clinical trials for the treatment of diabetes. One of the reported protocols for preparation of rivoglitazone involves reductive cyclization by catalytic hydrogenation in the presence of acid to induce benzimidazole formation. 

A recent patent for candesartan cilexetil describes the formation of the benzimidazole at a relatively late stage of the synthesis by cyclization of the highly functionalized diaminobenzene core under modified Phillips conditions with tetraethyl orthocarbonate at 90 Alternative syntheses of candesartan cilexetil use similar condensation conditions on variously elaborated benzimidazole precursors.  

Numerous syntheses have been reported of the AT i receptor antagonist telmisartan, which contains two benzimidazoles/ Although typical reductive cyclization conditions are used in most of the reported syntheses, one patent describes unique cyclization conditions for formation of the second benzimidazole ring system/ In this one-pot protocol, the 2-propyl-4-methyl-l//-benzimidazole-6-carboxylic acid is first activated with 2-chloro-4,6-dimethoxy-l,3,5-triazine in A-methyl morpholine (NMM) and methanol, then treated with A-methyl-o-phenylenediamine and heated to reflux to provide the cyclized product. This protocol allow for synthesis of the benzimidazole system under nonacidic conditions and moderate temperatures. 

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