A direct and highly efficient synthesis has been developed for telmisartan, the active ingredient in the widely prescribed antihypertensive drug Micardis®. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by a homogeneous palladium source or palladium on a solid support.
The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of a 2-bromo-1-methylbenzimidazole precursor. The method developed is the first reported selective bromination at the 2-position of a benzimidazole and produces the first major precursor in high yield (93%). The second precursor, potassium (4-methyl-2-propylbenzimidazol-6-yl) trifluoroborate, was prepared from commercially available 4-bromo-2-methyl-6-nitroaniline. An optimized preparation is described that provides a direct three-step process to prepare the benzimidazole and install the borate; this synthetic sequence yields the second precursor with a 90% yield and no isolated intermediates.
The two prepared precursors were combined with a third, commercially available methyl-4’-(bromomethyl)-[1,1’-biphenyl]-2-carboxylate, utilizing a short sequence of high yielding reactions to produce the telmisartan with an 83% yield from these advanced intermediates. This new convergent approach provides the active drug ingredient with an overall yield of 74% while circumventing many issues associated with the previously reported processes. Additionally, a flow-based synthesis of telmisartan was achieved with no intermediate purifications or solvent exchanges. The continuous process utilizes a tubular reactor system coupled with a plug flow cartridge, ultimately delivering telmisartan in an 86% isolated yield.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-4770 |
| Date | 01 January 2015 |
| Creators | Martin, Alex D |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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