The Synthesis Of Losartan

This paper briefly described the current situation of hypertension and the development state of the antihypertensive drug, introduced with emphasis effect characteristic and step-down mechanism of Losartan, and to the synthesis process carried out a detailed research. Losartan was an efficient oral antihypertensive drug that producted by the United States DuPont-Merck pharmaceutical company in 1994. It was the first non-peptide angiotensinâ…¡receptor blockers which can be easily accepted by patients with safe and effective. Because of the better drug action, long action time, few side effects and easy use, Losartan can be considered as an ideal drug for treatment of hypertension and congestive heart failure that had a widely market prospects.In this paper, the synthetic route of Losartan was divided into two parts. The first part was synthesis research of the key intermediate 2-butyl-4-chloro-3H-imidazole-5-carbaldehyde. Route one was starting from dimethyl malonate and pentanenitrile as raw materials, which has gained dimethyl 2-aminomalonate and methyl pentanimidate respectively at first, and then direct reacted to get methyl 2-butyl-4-hydroxy-1H-imidazole-5-carboxylate, finally has gained 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde by the system of phosphorus oxychloride and N,N-dimethylformamide. This route was synthesized via six-steps with the yield of 68%. Route two was staring from pentanoyl chloride and methyl 2-aminoacetate as raw materials, which has gained methyl 2-butyl-4-hydroxy-1H-imidazole-5-carboxylate via two-steps at first, and then has gained 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde by the system of phosphorus oxychloride and N,N-dimethylformamide. This route was synthesized via four-steps with the yield of 43%. The second part was synthesis research of Losartan, 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde was reacted with another key intermediate 5-(4-(bromomethyl)biphenyl-2-yl)-1-trityl-1H-tetrazole by N-alkylation, reduction reaction and deprotection of triphenylmethyl group to gain the product 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-1H-imidazole-5-methanol finally, which was Losartan. The structure of the key intermediate 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde, final product Losartan and most intermediates were established by spectral data 1H-NMR, MS.The overall yields of two routes were 37.4% and 23.8% respectively.In this paper, 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde as a key intermediate of Losartan had a very important reference value, for the novelty design route, cheap raw materials, convenient post-processing and the route of synthesis had not reported in domestic and abroad references. Then, the route provided a mature experience for avoid patent and scaling-up.