Efficient and improved 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.


Introduction
Telmisartan (1) is an angiotensin II receptor antagonist useful in the treatment of hypertension, heart diseases, heart attack, and bladder diseases [1][2][3]. Telmisartan is currently available in the market as an antihypertensive drug [4] under the brand name of Micardis ® . Essential hypertension is a major risk factor in cardiovascular diseases and is responsible for one-third of global deaths. Most antihypertensive drugs interact with the renin-angiotensin system (RAS), which is the central regulator of blood pressure and electrolyte homeostasis. Renin transforms angiotensinogen into the decapeptide angiotensin I, which is converted by the angiotensin conversion enzyme (ACE) into the octapeptide angiotensin II. The latter binds to its angiotensin receptor (AT 1 ) and, thereby, becomes a powerful vasoconstrictor. In the early 1990s, Merck introduced the non-peptidic orally active angiotensin II receptor antagonist losartan (Lozaar) as the first member of a new class of antihypertensive drugs called sartans, all of which contain a characteristic ortho functionalized biaryl moiety. Telmisartan (1, Boehringer Ingelheim, Micardis ® ) ( Figure 1) is an important member of this class of top-selling drugs because it has the strongest binding affinity to the AT 1 receptor, an excellent bioavailability, and a once-per-day dosage.
The first total synthesis of Telmisartan as introduced by Ries et al. (Scheme 1) 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-benzimida-  zole 4, which is then alkylated with the 4′-(bromomethyl)-2biphenylcarboxylic 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 [5].
Several improvements to the above reaction sequence have been reported, e.g., the use of KOH instead of potassium tert-butoxide in the penultimate step and the use of methanolic HCl solution instead of trifluoroacetic acid in the final step [6]. However, the main shortcomings of the synthesis remained, namely, the unsatisfactory regioselectivity in the alkylation of 8 with 4 and the intricate synthesis of the biaryl intermediate 7.
In the original protocol, the latter was synthesized via an Ullmann coupling of the aryl iodides 5 and 6 using 5 equiv of copper [7]. Modern syntheses of 7 involve cross-couplings of sensitive aryl magnesium [8], zinc [9], or boron [10,11] compounds with alkyl 2-halobenzoates. Since the commercialization of Telmisartan, 7 has become readily available at low cost, so that most subsequent published procedures start from this compound.
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.

Conclusion
In conclusion, a concise and selective synthesis of the antihypertensive drug Telmisartan has been developed, featuring a Suzuki cross-coupling for the construction of the biaryl moiety and a regiospecific reductive amination-condensation sequence for the synthesis of the central benzimidazole.

Experimental
All solvents and reagents were purchased from the commercial suppliers and used without further purification. All non-aqueous reactions were performed in dry glassware under an atmosphere of dry nitrogen. Organic solutions were concentrated under reduced pressure. Thin layer chromatography was performed on Merck precoated Silica-gel 60F 254 plates. 1 H and 13 C NMR spectra were recorded in DMSO-d 6 and CDCl 3 using 400 MHz, on a Varian Gemini 400 MHz FT NMR spectrometer. The chemical shifts were reported in δ ppm relative to TMS (tetramethylsilane). The IR spectra were recorded in the solid state as KBr dispersion using Perkin Elmer FT-IR spectrophotometer. The mass spectra were recorded on Shimadzu LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS/MS. Melting points were obtained by using the open capillary method and are uncorrected.