Cite this paper: Vietnam J. Chem., 2019, 57(3), 343-346 Article DOI: 10.1002/vjch.201900038 343 Wiley Online Library © 2019 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Synthesis of Valsartan as drug for the treatment of hypertension Tran Van Chien 1,2* , Nguyen The Anh 1 , Tran Thi Phuong Thao 1,2 Le Dac Phuong 3 , Pham Thi Tham 3 , Nguyen Quang Tung 3 , Tran Van Loc 1,2 1 Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, Viet Nam 2 Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay, Hanoi, Viet Nam 3 Hanoi University of industry, No 298 Cau Dien street, Bac Tu Liem District, Hanoi, Viet Nam Received May 15, 2019; Accepted for publication May 30, 2019 Abstract The synthesis of valsartan (1), one of the most currently used pharmaceutical agent in antihypertensive therapy, was described through five steps in an overall yield of 54 % starting from 4’-methyl-2-cyanobiphenyl (2). The key step involved tetrazole ring formation catalyzed by Lewis acid. The structures of synthesized compounds were confirmed by means of NMR and MS spectroscopíe. Keywords. Valsartan, antihypertension, biphenyltetrazole, Lewis acid. 1. INTRODUCTION The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure as well as electrolyte balance. [1] This system acts by producing angiotensin I that is converted into octapeptide angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II is regarded as the key regulator in stimulation of angiotensin II type 1 receptor (AT1), which mainly located in the heart, blood vessels and kidneys, and thus triggers further downstream effects and leads to vasoconstriction. Currently, two major therapeutic approaches in the treatment of hypertension target on angiotensin II either by inhibition of angiotensin-converting enzyme (ACE) or by blocking the action of angiotensin II on its AT1 receptor. [2] Sartan drugs such as telmisartan, candesartan, olmesartan, irbesartan and valsartan are effectively used in the clinic for the regulation of high blood pressure. [3,4] They are biphenyl-tetrazole derivatives and specific angiotensin II antagonists, binding to the AT1 receptor subtype. Among these, valsartan has been prescribed for the treatment of hypertension since 1996. It is commercially available in the market under the brand name DIOVAN™ and is a generic medication. In 2016, it was on the top 100 most prescribed drugs in the United States of America, with more than 8 million prescriptions. Herein, we describe a simple synthetic procedure of valsartan in order to develop in large pilot plant. 2. MATERIALS AND METHODS All chemicals and solvents were purchased from commercial suppliers and used without further purification. Column chromatography was performed using silica gel (60 Å, particle size 40-60 µm). NMR spectra were recorded on a Bruker Avance 500 MHz spectrometer. Chemical shifts (δ) are given in parts per million (ppm) and coupling constants (J) in hertz (Hz). ESI-MS was carried out on an Agilent 1100 mass spectrometer (Canton, Massachusetts, USA). Synthesis of 5-(4'-methyl-[1,1’-biphenyl-2-yl]-1H- tetrazole (3) A solution of 4’-methyl-2-cyanobiphenyl (2) (2.4 g, 12.44 mmol) in DMF (50 mL) was added Et3N*HCl (3.43 g, 25 mmol) and NaN3 (2.02 g, 31 mmol). The reaction mixture was then warmed up to 120 o C for 54 h. The solvent was evaporated under reduced vacuum to dryness. The residue was dissolved in water and added aqueous solution 4 % K2CO3. The starting material was precipitated and collected by filtration. The filtrate was acidified with 5 % HCl. The resulting solid was collected and dried at 65 o C for 4 h to obtain a white product 3 (2.8 g, 96.4 %).