【作者】 王平；

【导师】 王相晶；

【作者基本信息】 东北农业大学 ， 生物化学与分子生物学， 2012， 博士

【摘要】 本论文简述了高血压的现状以及抗高血压药物的发展状况,介绍了新型抗高血压药物血管紧张素Ⅱ受体AT1拮抗剂(ARB)的作用体系,作用机制以及作用特点。重点介绍了血管紧张素Ⅱ受体AT1拮抗剂类药物坎地沙坦酯和替米沙坦的降压机制和作用特点,并对其合成工艺进行了详细研究,分别设计并完成了一条新颖而且高效的合成路线。坎地沙坦酯为一前体药物,在体内经肠道吸收,完全水解为高活性的去酯坎地沙坦。具有药效强,作用时间长、毒副作用少,服用方便等特点,是治疗高血压、充血性心力衰竭的理想药物,拥有很广泛的市场前景。本论文以2-氨基-3-硝基苯甲酸甲酯为起始原料,设计并完成了一条新颖而且高效的坎地沙坦酯避专利合成路线。首先2-氨基-3-硝基苯甲酸甲酯经过Sandmeyer反应得到2-溴-3-硝基苯甲酸甲酯,经还原后与原碳酸四乙酯反应得到2-溴-3-(二乙氧基亚甲基氨基)苯甲酸甲酯,而没有以文献方式形成苯并咪唑环,得到了全新的中间体化合物,避开了专利。随后与2’-(卜三苯甲基-卜氢-四唑-5-基)联苯-4-基)苄胺发生置换反应得到2-溴-3-[乙氧基[[2’-(卜三苯甲基-1H-四唑-5-基)联苯-4-基]胺甲基]亚甲基氨基]苯甲酸甲酯。再与卜氯乙基环己基碳酸酯发生酯化反应得到2-溴-3-[乙氧基[[2’-(1-三苯甲基-1H-四唑-5-基)联苯-4-基]胺甲基]亚甲基氨基]苯甲酸-1-[[(环己基氧基)羰基]氧基]乙基酯。最后在碘化亚铜、碳酸钾和脯氨酸的作用下发生分子内N-芳基化反应,形成2-乙氧基苯并咪唑化合物再脱保护得到目标产物坎地沙坦酯。此外,Cu催化分子内N-芳基化反应首次在合成2-乙氧基苯并咪唑中使用,为其他2-取代苯并咪唑的合成提供了一种方法。替米沙坦作为一类新型血管紧张素Ⅱ受体拮抗剂降压药,具有先进的作用机理,平稳降压,不反弹,长效高效,耐受性好,靶向选择,副作用小,生物利用度高,适应性好等诸多优势,尤其适用于对其它降压药不能耐受或过敏的各种高血压患者。此外,替米沙坦也能对过氧化物酶体增殖物活化受体Y(PPAR-γ)发生选择性作用,因而也能用于糖尿病和心血管疾病的治疗。本论文以邻甲基苯酚为起始原料,设计并完成了一条新颖的替米沙坦合成路线。首先,邻甲苯酚经过常规方法上醛基,然后再经发烟硝酸硝化得到2-甲基-4-甲酰基-6-硝基苯酚,酚羟基被硫酸二甲酯保护后与邻苯二胺环合形成非核心苯并咪唑,再利用硫酸二甲酯进行N-甲基化得到2-(4-甲氧基-3-甲基-5-硝基苯)-1-甲基-1H-苯并咪唑。然后在浓氨水的作用下,甲氧基转化为氨基得到2-甲基-4-(1-甲基苯并咪唑-2-基)-6-硝基苯胺。在保险粉的作用下,2-甲基-4-(1-甲基苯并咪唑-2-基)-6-硝基苯胺直接与正丁醛环合得到关键中间体2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑。最后与4’-溴甲基联苯-2-甲酸甲酯发生N-烷基化反应后,再皂化得到目标产物替米沙坦。通过大量的平行实验,确定最佳反应条件,以及后处理,纯化方法等对替米沙坦的合成工艺进行优化。最后对合成工艺进行放大实验,并且进行中试前批量的稳定性试验。整个工艺原料廉价,操作简单,尤其是简洁的后处理,纯化,非常适合工业化生产。目前,中国抗高血压药物市场虽然仍以钙拮抗剂和ACEI占主导地位,但由于ARB类药物具有显著的降压效果,且副作用小,使得“沙坦”类药物有较好的市场准入点。在不久的将来,“沙坦”类新药在抗高血压药市场中将占有十分重要的位置。临床试验表明,坎地沙坦和替米沙坦的降压效果和耐受性优于其他沙坦,具有很强的市场竞争力。本研究提出一条全新的,有效的坎地沙坦酯避专利合成路线和一条新颖的,高效的替米沙坦的合成路线。整个试验中所使用的原料均廉价易得,试验操作简单方便。两条路线设计新颖,在国外内参考文献中未见报道,特别是替米沙坦,已经通过中试前稳定性试验,即将准备中试,并投入生产。因此本研究内容及成果具有较大的科研参考价值和经济价值。更多还原

【Abstract】 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.更多还原