Studies On Synthesis Of The Antihypertensive Drug:Candesartan Cilexetil And Telmisartan

This research briefly described the current situation of hypertension and the development state of the antihypertensive drug, introduced action system, action mechanism and action characteristic of the new type antihypertensive drug, angiotensin receptor blocker (ARB). Introduced with emphasis step-down mechanism and action characteristic of candesartan cilexetil and telmisartan of angiotensin receptor blockers, and detailed researches were carried out to the synthesis process. A novel and effective route for synthesis of candesartan cilexetil and telmisartan was designed respectively.Candesartan cilexetil, a prodrug, is rapidly and completely hydrolyzed to candesartan during absorption by the gastrointestinal tract. Because of the better drug action, longer action time, fewer side effects and easier use, candesartan cilexetil can be considered as an ideal drug for treatment of hypertension and congestive heart failure that had a widely market prospects. This research described a novel, efficient and avoid patent synthetic route for the preparation of candesartan cilexetil from methyl2-amino-3-nitrobenzoate. First, methyl2-amino-3-nitrobenzoate was converted to2-bromide-3-nitrobenzoate via a Sandmeyer reaction. After reduction, converting to methyl2-bromo-3-(diethoxymethyleneamino)benzoate via reacting with tetraethoxymethane, which obtained a serious of new intermediate compounds avoid patent rather than benzimidazole according to literatures. Then, reacted with (2’-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methanamine to afford methyl2-bromo-3-(ethoxy((2’-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl)methylamino)methyleneamino)benzoate. After that, esterified with1-chloroethyl cyclohexyl carbonate to obtain (±)-1-(cyclohexyloxycarbonyloxy)ethyl2-bromo-3-(ethoxy((2’-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl) methylamino)methyleneamino)benzoate. Finally, intramolecular N-arylation was accomplished in the presence of copper(Ⅰ) iodide, potassium carbonate and L-proline to afford the substituted2-ethoxy benzimidazole, then to afford the target compound candesartan cilexetil after deprotection. Furthermore, a Cu-catalyzed intramolecular N-arylation process to synthesize substituted2-ethoxy benzimidazole was used firstly. It is expected that other2-substituted benzimidazoles may also be prepared by this strategy.Telmisartan, a new type antihypertensive angiotensin receptor blocker, has the advantages of advanced action mechanism, equable pressure release, no bounce, prolonged action and high performance, good tolerance, target selection, little side-effect, high bioavailability, good adaptability, etc. It especially suitable for the high blood pressure patient allergic or intolerance to other antihypertensive agents. Moreover, telmisartan also affects selectively to peroxisome proliferator activate acceptor γ (PPAR-γ), so it can be used in the therapy of diabetes mellitus and cardiovascular diseases. This research described a novel and cost-efficient synthetic route for the preparation of telmisartan from o-cresol. First, starting material o-cresol was converted to4-hydroxy-3-methyl-5-nitrobenzaldehyde after nitration. After the phenolic hydroxyl group being protected with dimethyl sulfate, reacted with o-phenylenediamine to form noncentral benzimidazole. Followed by N-methylation with dimethyl sulfate could afford2-(4-methoxy-3-methyl-5-nitrophenyl)-1-methyl-1H-benzimidazole. Subsequently, conversion of methoxy group into the amino group obtained2-methyl-4-(1-methyl-1H-benzimidazol-2-yl)-6-nitrobenzenamine via treatment with concentrated ammonia solution. In the presence of sodium dithionite,2-methyl-4-(1-methyl-lH-benzimidazol-2-yl)-6-nitrobenzenamine was reacted with butyl aldehyde directly to afford key intermediate1,7’-dimethyl-2’-propyl-2,5’-bi(1H-benzimidazole). Finally, the N-alkylation with methyl4’-(bromomethyl)biphenyl-2-carboxylate to afford the target compound telmishatan after saponification. The reaction conditions for synthesis of telmisartan has been optimizatied by amount of parallel experiments, which established the optimum reaction conditions, workup and Purification methods, etc. Finally, the synthesis route has been scaled up and made stability test before semi-works production. The simple operation and workup procedure, along with the low production costs, make it suitable for industrial production.Currently, Ca-antagonist and ACEI still remain predominance of antihypertensive drug market in China, but "sartans" drugs can be considered as ideal drugs to market, because of the better drug action and few side effects of angiotensin receptor blocker. In the offing, new type "sartans" drug will possess a crucial position in antihypertensive market. Clinical trial shows, the effect of pressure release and tolerance of candesartan and telmisartan are better than that of the others, which makes these have strong market competition. The research suggested a novel and effective route for synthesis of candesartan cilexetil and telmisartan respectively. The strategy had cheap raw materials, convenient test-processing and the route of synthesis have no report in domestic and abroad references. Especially to telmisartan, which have made stability test before semi-works production and ready for industrial production. Therefore, the research has great academic value and economic value.