Synthesis Of Losartan

Losartan is the first non-peptide angiotensin II receptor blocker drug in clinical. Losartan and itsactive metabolite-EXP3174both act on the AT1receptor. It is competitive for the angiotensin II toact with AT1receptor. So the blood vessels will dilate and blood pressure will reduce. The patentprotection of Losartan has expired, but its application prospect is still very wide and marketpotential is very great.Losartan was synthesized with5-(4’-Bromomethyl-biphenyl-2-yl)-2-trityl-2H-tetrazole and5-Chloro-2-propyl-3H-imidazole-4-carbaldehyde through deoxididation and detritylation.5-(4’-Bromomethyl-biphenyl-2-yl)-2-trityl-2H-tetrazole is derived from4’-Methyl-biphenyl-2-carbonitrile. And this process is consist of dipolar cyclization, N-alkylation and bromination.5-Chloro-2-propyl-3H-imidazole-4-carbaldehyde could be obtained through the following process:the synthesis of amyl imino acid methyl ester with Pinner amidine as the raw materials, theamination with amino acid, and Chloriding formylating under the presence of Vilsmeier reagent.And a lot of experiments have been carried out to investigated the effect of the craft parameters onthe yield of5-Chloro-2-propyl-3H-imidazole-4-carbaldehyde.Another Intermediate,4’-Methyl-biphenyl-2-carbonitrile’s was also prepared through couple reaction between1-Chloro-4-methyl-benzene’s Grignard reagent and2-Chloro-benzonitrile under the catalysis of the MnCl2.The following conclusions can be obtained: Losartan can be successfully synthesized throughthe method mentioned above; The optimum conditions for the synthesis of5-Chloro-2-propyl-3H-imidazole-4-carbaldehyde: the molar ratio of N-carboxymethyl pentamidine to phosphorusoxychloride to N,N-dimethyl formamide was1.0:3.5:3.0. N-carboxymethyl pentamidine, tolueneand phosphorus oxychloride were first added in the reactor and then they were heated to70℃.After keeping stirring for1hour, the reactor was heated to90℃. And N, N-dimethyl formamidewas added in during1.5hours. Then temperature was raised to105℃, and the this situation waskeeping for3hours. After some separation process,5-Chloro-2-propyl-3H-imidazole-4-carbaldehyde can be obtained. the yield is76.80%,2.77%higher than the literature (74.03%).