Research On The Synthesis Of Deuterium Labeling 5-carboxylic Acid Losartan And Temisartan

Losartan and Temisartan are novel antihypertensive drugs, well known nonpeptide angiotensin II receptor AT1 antagonist. The two drugs belong to sartan antihypertensive drugs. They can combine selectively and durably with the AT1 receptor, and can not combined AT2 receptor and AT receptor. Losartan was reseached by DuPount/Merck in 1994 and marketed in Sweden. Temisartan was reseached by Boehringer Ingelheim of Germany, and was granted Germany patent in 1991 . It was marketed in the United States in 1998. The two antihypertensive drugs are characteristics of specific receptor, medication safety, well-tolerated, significant antihypertensive effect, lower side effect.5-carboxylic acid Losartan(EXP-3174) is the active metabolite of Losartan. Losartan undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part , to an active metabolite 5-carboxylic acid Losartan. It has more longer half-life and lower side effect than Losartan and lowers the blood-brain barrier penetration, therefore, it has more significant antihypertensive effect.In this thesis, the total synthesis 5-carboxylic acid Losartan-[d4] and Timisatran-d3 were investigated. They are used by the important internal standards for bioavailability and bioequivalent studies of drugs.5-carboxylic acid Losartan-[d4] was synthesized by total seven steps.The reaction of 4,4-dimethyl-2-(2'-methyloxyphenyl) oxazoline (1) with 4-methyl-[d4] phenyl magnesium boromide afforded the 4,4-dimethyl-2-(4'-methyl-[2H4]biphenyl-2-yl) oxazoline (compound 2). The compound 2 was treated with Phosphorus oxychloride in pyridine to furnish 2-cyano- 4'-methyl- [d4] biphenyl (compound 3).The bromination of compound 3 with N-bromosuccinimide (NBS) gave 2-cyano-4'-bromidemethyl-[d4]biphenyl (compound 4). The reaction of compound 4 and intermediate 2-butyl-4- chloro-5-formyl imidazole, followed by the reduction using Sodium boro-hydride (NaBH4) afforded 2-butyl-4-chloro-1-[(2'-cyano[d4]biphenyl-4-yl)methyl]-5(hydroxy methyl) imidazole (compound 5). Compound 5 and sodium azide underwent cyclization at 110℃to give losartan-[d4] (compound 6).Oxidation of compound 6 with TBA-permangnate yielded 5-carboxylic acid losartan-[d4](compound 8).Timisatran-[d3] was synthesis by total seven steps. 2-Nitroaniline was protected by 4-methyl -benzene sulfonyl chloride to give 4-methyl-N-(2-nitro-phenyl)-benzenesulfonamide (compound 11) and subsequent N-methylation with iodomethane-[d3] to afford 4,N-dimethyl-[d3]-N-(2-nitro-phenyl) benzenesulfonamide (compound 12), which in turn was deprotected with concentrated sulfuric acid to produce N-methyl-[d3]-2-nitrobenzenamide (compound 13). A efficient reduction of compound 13 using 10% Pd/C catalyst at hydrogen to yield N-methyl-[d3]-1,2-benzenediamine (compound 14). Compound 14 and 2-propyl-4-methyl-benzimidazole-6-carboxylic acid underwent cyclization under polyphosphoric condition to give 2-propyl-4-methyl-6-(1-methyl-[d3]-benzimidazole-2-yl)benzimida -zole (compound 15). The N-alkylation of compound 15 and 4'-bromomethylbiphenyl-2-carboxylate produce 4'-[[2-propyl-4-methyl-6-(1-methyl-[d3]-benzimidazole-2-yl)benzimidazole-1-yl]methyl] biphenyl-2-carboxylate (compound 16).Compound 16 was ydrolysised with Sodium hydroxide/Methanol to yield temisartan-[d3](Compound 17).