A short and efficient synthesis of valsartan via a Negishi reaction

Summary An efficient synthesis of the angiotensin-II inhibitor valsartan (Diovan®) is presented. Directed ortho-metalation of 5-phenyl-1-trityl-1H-tetrazole (6) and its Negishi coupling with aryl bromide 5 are the key steps of the synthesis. This method overcomes many of the drawbacks associated with previously reported syntheses.


Introduction
Valsartan ( Figure 1) is a member of a class of compounds known as angiotensin II (AT-II) receptor antagonists. This class combines effective anti-hypertensive activity with an excellent profile of safety and tolerability. Activation of AT-II receptors in the outer membrane of vascular smooth muscle cells of the heart and arteries causes the tissues to constrict. AT-II receptors are activated by the octapeptide AT-II. AT-II helps to maintain constant blood pressure [1] despite fluctuations in a person's state of hydration, sodium intake and other physiological variables. AT-II also performs the regulatory tasks of inhibiting the excretion of sodium by the kidneys, inhibiting norephedrine re-uptake and stimulating aldosterone biosynthesis.
Valsartan [2] is therefore a non-peptide AT-II antagonist. By inhibiting the actions of AT-II on its receptors, valsartan prevents the increase of blood pressure produced by the hormone-receptor interactions. Hence, it is used in the treatment of cardiovascular complaints such as hypertension and heart failure. Comparative trial studies have shown that valsartan is as effective as angiotensin-converting enzyme (ACE) [3] inhibitors, calcium-channel blockers and α-blockers, and is generally better tolerated. Valsartan is marketed as the free acid under the trade name Diovan ® . In addition, in combination with diuretics such as hydrochlorothiazide, valsartan offers specific advantages as an anti-hypertensive agent.
The formation of the aryl-aryl bond represents the key step in the synthesis of sartans: whilst the synthesis of losartan [4] as described in the literature makes use of Negishi [5,6] and Ullmann [7] couplings, the published methods for the preparation of valsartan utilize Suzuki-Miyaura couplings [8]. Of these, Negishi reactions have proved to be very efficient. However, the use of organozinc compounds provides better transmetalation activity than that obtained by the use of organoboron reagents as well as good chemoselectivity since most common functional groups are not attacked by organozinc species. Although preparations of several biphenyl ring systems related to valsartan have been reported, a number of challenges and some disadvantages -such as tedious reaction conditions, low yields and multistep sequences -still exist. Therefore, developing an efficient synthetic strategy with fewer steps that provides diverse access to these bioactive compounds is an important goal. In this paper, we report a new, concise and efficient synthesis of valsartan via Negishi coupling.

Results and Discussion
From a retro-synthetic analysis (Scheme 1), compound 8 could be constructed via Negishi coupling from aryl bromide 5 and 5-phenyl-1-trityl-1H-tetrazole (6), which in turn could be obtained from commercially available benzonitrile. Aryl bromide 5 could be accessed by several discrete reactions of compound 3 and compound 4 via a nucleophilic substitution reaction.

Conclusion
In summary, a highly efficient approach to the biphenyltetrazole structure of the AT-II antagonists has been developed which involves Negishi coupling of metalated 5-phenyl-1-trityl-1H-tetrazole. The method is commercially viable and applicable to plant scale production. This approach provides an industrial viable procedure for the synthesis of valsartan.

Materials and instruments
All solvents and reagents were purchased from the suppliers and used without further purification. All non-aqueous reactions were performed in dry glassware under a dry nitrogen atmosphere. Organic solutions were concentrated under reduced pressure. Thin layer chromatography was performed on Merck precoated Silica-gel 60 F 254 plates. 1 H and 13 C NMR spectra were recorded on a Varian Gemini 400 MHz FT NMR spectrometer using CDCl 3 or DMSO-d 6 as solvent. Chemical shifts are reported in δ ppm relative to TMS. Mass spectra were recorded on a Shimadzu LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS/MS.

N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine (8).
To a solution of compound 7 (2 g, 2.89 mmol) in methanol (20 mL), 3 N NaOH (2.85 mL) was added and the mixture heated under reflux for 6 h. The progress of the reaction was monitored by TLC until the starting material was absent. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL) and distilled H 2 O (20 mL). Hydrochloric acid (2 N HCl) was added dropwise to the mixture until the pH reached 4.0. Then the organic phase was separated and the aqueous phase extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 . Evaporation of the solvent gave the crude product (1.12 g, 90%). Recrystallization from EtOAc afforded the anticipated product valsartan 8; mp 114-118 °C; 1