Research On The Synthesis Of High Optical Purity Valsartan

Valsartan is the first nonpeptide A II receptor antagonist without imidazole link. It has paid much attention due to its antagonistic activity and long duration of action and thus has a very broad potential of application in the market. From these points of view, it is significant to develop an effective technique with safety, convenience, high yield, environmentally friendly, suitable for industrial production for the synthesis of high optical purified valsartan.This paper is aimed to use o-chlorobenzonitrile as raw material, anhydrous nickel chloride as a catalyst to synthesize 4-methyl-2-cyanobiphenyl through coupling reaction in THF. Then in the presence of free radical initiator, oxidants, and bromine, 4-bromomethyl-2-cyanobiphenyl could be synthesized, after which can give N-[(2'-cyano[1,1'biphenyl]-4-yl)methyl]-methyl ester L-valine monohydrochloride with L-Valine methyl ester hydrochloride through condensation reaction. Finally valsartan was got through N-acylation reaction, tetrazole reaction, the hydrolysis reaction.This paper defines the best synthesis technical of 4-bromomethyl-2-cyanobiphenyl: it can be prepared through reflux in chloroform by using 4-methyl-2-cyanobiphenyl(OBTN)as raw material,0.55mol bromine as brominating agent, AIBN as free radical initiator, and using sodium bromate as Oxidants. This technical avoids the inhibition of hydrogen bromide on the main reaction, and also enhances the utilization rate of bromine atoms. Using the best synthesis technical, the yield of bromination can be reached 75.4%, and the purity of target product checked by HPLC can be more than 99.0%.The second part studies the synthesis technical of N-[(2'-cyano[1,1'biphenyl]-4-yl)methyl]-methyl ester L-valine monohydrochloride: it can be prepared by using potassium carbonate as the base, 3-5% water as cosolvent, and the molar ratio of 4-bromomethyl-2-cyanobiphenyl with L-Valine methyl ester hydrochloride is 1:1. The product can be prepared through salt-forming reaction by refluxing in ethyl acetate for 4h. The yield of the product can be reached 75.4%, and its HPLC purity can be more than 99.0%.A new method for the synthesis of (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate via solid acid catalysis was introduced in third part. Under the optimum conditions, the reaction was conducted using sodium azide and (S)-methyl 2-(N-((2'-cyanobiphenyl-4-yl) methyl)pentanamido)-3-methylbutanoate at the molar ratio of 1.8:1 in the presence of 20 mol% of NaHSO₄/ZnO(20wt% of NaHSO₄) as catalyst with refluxing 48 hours in xylene, and the yield of 2-[(trimethyl)tetrazole]-4-methyl biphenyl was 79.5%.This process has the advantage of easily operated, higher yield and more suitable for industrial production.