883223-10-7

Upstream product

• 852160-37-3 N-[[2'-(2N-trityl-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine methyl-ester hydrobromide 
• 638-29-9 n-valeryl chloride 
• 138500-85-3 4-bromomethylphenylboronic acid pinacol ester 
• 195062-57-8 p-tolylboronic pinacol ester 
• 73096-42-1 5-(2-bromophenyl)-2H-tetrazole 
• 5084-80-0 tri(4-tolyl)boroxine 
• 2042-37-7 o-cyanobromobenzene 
• 883223-08-3 (S)-methyl 3-methyl-2-((4-(4,4,5,5-tetramethyl-2,3,2-dioxaborolan-2-yl)benzyl)amino)butanoate 

Downstream Products

• 137863-17-3 N-pentanoyl-N-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine methyl-ester 
• 137862-53-4 N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine 
• 137863-17-3 methyl N-((2’-(1H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)methyl)-N-pentanoyl-L-valinate 

Relevant academic research and scientific papers

Efficient synthesis of valsartan, a nonpeptide angiotensin II receptor antagonist

A highly efficient and convergent approach to the synthesis of the angiotensin II receptor antagonist valsartan (1), one of the most important agents used in antihypertensive therapy today, is described. Directed ortho-metalation of 4-bromotoluene provides the key boronic acid intermediate 11 which was subjected to palladium-catalyzed Suzuki coupling. This method overcomes many of the drawbacks associated with the previously reported syntheses. The saponification of the methyl ester in valsartan was realized in a convenient and economical manner, which is more suitable for industrial production. Georg Thieme Verlag Stuttgart.

PROCESS FOR PRODUCTION OF (S) -N-PENTANOYL-N-[[2’-(1H-TETRAZOLE-5YL) [1,1’-BIPHENYL]-4-YL]METHYL]-L-VALINE

The patent relates to a new process of synthesis of an antihypertensive agent, N-pentanoyl-N-[[2'-(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine (1), also known under the generic name of valsartan, by selective reaction of N-pentanoyl-N-[[2'-(1H-tetrazole-5-yl) [1,1'-biphenyl]-4-yl]methyl]-L-valine methyl-ester (14) with metallic or quaternary ammonium trialkylsilanolates by SN2 reaction. The compound 14 was produced in four reaction steps starting from 2N-trityl-5-(4'-methylbiphenyl-2-yl)tetrazole (17) and L-valine methyl-ester (11). Free-radical bromination of the compound 17 with N-bromosuccinimide produced 2N-trityl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (7), which in the reaction with L-valine methyl-ester (11) results in N-[[2'-(2N-trityl-tetrazole-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine methyl-ester hydrobromide (15). Acylation of the compound 15 with pentanoyl chloride in the presence of trialkylamine bases results in N-pentanoyl-N-[[2'-(2N-trityl-tetrazole-5-yl)[1,1'-biphenyl] -4-yl]methyl]-L-valine methyl-ester (16). Removal of trityl protecting group by strong acids produces the key intermediary, compound 14.