In designing an alternative synthesis of Telmisartan our goal was to minimize the use of expensive and hazardous metals, circumvent the bromination step, and increase the overall efficiency of the synthesis. This was accomplished by reversing the order of the major bond disconnections. We realized biaryl synthesis and reductive amination are the key steps, and have the potential to overcome both of these weaknesses.
The first total synthesis of Telmisartan as introduced by Ries et al. () starts with the acylation of 4-amino-3-methylbenzoic acid methyl ester (2) with butyryl chloride, followed by nitration, reduction of the nitro group, and subsequent cyclization of the resulting amine to the benzimidazole derivative 3. After saponification, the free carboxyl group is condensed with N-methyl-1,2-phenylenediamine to afford the bis-benzimidazole 4, which is then alkylated with the 4′-(bromomethyl)-2-biphenylcarboxylic acid tert-butyl ester (8) to give, after hydrolysis of the ester group, Telmisartan (1) in 21% overall yield and with eight steps as the longest sequence .
A modification to the synthesis of Telmisartan ..
An efficient synthesis of the angiotensin II receptor antagonist Telmisartan (1) is presented involving a cross coupling of 4-formylphenylboronic acid 10 with 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline (11) as the key step (90% yield). The benzimidazole moiety 15 was constructed regioselectively via a reductive amination-condensation sequence, replacing the alkylation of the preformed benzimidazole step in the previously published route. This methodology overcomes many of drawbacks associated with previously reported syntheses.