Synthesis Of Antihypertensive Drug Valsartan

The Rennin-Angiotensin System(RAS) plays a fundamental role in bloodpressure regulation and fluid/electrolyte homeostasis. AngiotensinⅡ(AⅡ), themost potent hormone of RAS leads to a series of action through binding with AⅡreceptor, which results in vasoconstriction and aldosterone release that leadsto increase in blood pressure. Nonpeptide angiotensinⅡreceptor antagonistwere developed as antihypertensive agents, which bind specially to AⅡreceptor. Because it diplays the profile of good oral bioavailability and potentactivity with a long duration of action, it has become prime product in a fewyears after listed.Valsartan, which listed in 1998, is the first Nonpeptide AⅡReceptor Antagonistwithout imidazole link. It is paid attension because of its potent activity and longduration of action. Therefore it has a wild potentialin the market.(1) By reference to the synthetic methods of Valsartan, a s ynthesis routewas established. 2-Cyano-4'-bromomethybiphenyl was synthesized from startingmaterial neighbouring chlorobenzene nitrile and parachlorotoluene, which isthen converted into 4'-bromomethyl-2-(2N-trityl-tetrazole-5-yl) biphenyl. TheTetrazole reaction,introduction of the protecting group and Bromide are proceeded in the process. It was reacted with amino acid ester then with alkylcarboxylic acid chloride. In the end, the protecting group was removed to givethe terget products.(2)Intermediates including 2-cyano-4'-methylbiphenyl, 2-[(trimethyl)tetrazole]-4'-methylbiphenyl,2-[(triphenylmethyl)tetrazole]-4'-bromomethylbiphenyl, N-[[2'-(2N-trityl-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valinme ethyl-ester hydrochlorate, N-pentanoyl-N-[[2'-(2N-trityl-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine methylester and the terget products valsartan were pre pared,meanwhile,each product were attributed.(3)Improved the process of tetrazole reaction, using triflumethanesulfonicacid zinc as catalyst, reaction tempreture was redused to about 100℃from140℃, reaction time was reduced to 6.5hours from more than 30 hours, greatlyreduced the risk which the reactant sodium azide explodes, using water assolvent, greatly reduced the pollution and saves the cost.(4) On the basis of investigating effects of themole ratio of raw material,amount of catalyst, reaction temperature and time, optimized reaction conditionsof tetrazole reaction by using uniform design. Under the optimum conditions,the yield of 2-[(trimethyl)tetrazole]-4'-methylbiphenyl was 91.6%.(5) Based on lots of literatures,we studied removing protection group bymeans of experiments, the protection group of carboxyl-carbomethoxy andprotection group of tetrazole-triphenylmethyl were removed at the optimum condition.The problem of economic and environmental protection ancientlyliteratures was overcome.It is a process that can be operated easily, reaction condationmoderate,higher yield and more suitable for industrial production.