Telmisartan synthesis

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. 

The presence of bi(hetero)aryl substructures in various biologically active natural products as well as in other complex structures has aroused great interest towards the synthesis of such important molecules. This has been demonstrated over the years through the development of new synthetic strategies for constructing such important intermediates that are found to occur in economically valuable pharmaceuticals such as Valsartan 1 and Telmisartan 2, the agrochemical Boscalid 3, and liquid crystal 4 for LCD screens (Fig. 1). 

GooBen, L. J., Knauber, T. (2008). Concise synthesis of telmisartan via decarboxylative cross-coupling. The Journal of Organic Chemistry, 73, 8631-8634. 

The DoM C—C cross-coupling was notably employed in the synthesis of telmisartan 75, an angiotensin II receptor antagonist [173]. The reaction pathway is based on a one-pot protocol employing sequential metalation, transmetalation to zincate, and Negishi transition metal-catalyzed cross-coupling. At final step, the oxazoline DMG is removed by hydrolysis to afford the expected carboxylic acid product 75 (Scheme 26.22). 

SCHEME 26.22 Synthesis of telmisartan (angiotensin II receptor antagonist). 

The applicability of the decarboxylative biaryl synthesis was rapidly extended to a broad range of aryl electrophiles with the help of new catalyst generations, including not only aryl iodides, bromides, and triflates but also the inexpensive but unreactive aryl chlorides and tosylates [46, 47]. Its preparative utility was demonstrated, e.g., in the synthesis of telmisartan and valsartan [48, 49]. The key factor in these advances was the identification of ligands that strongly activate the palladium catalysts toward oxidative addition steps while not interfering with the decarboxylation activity of the copper cocatalysts (Scheme 14). 

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