质子泵抑制剂的合成工艺研究

【作者】 王庆河；

【导师】 程卯生；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2008， 硕士

【摘要】 消化性溃疡(peptic ulcer)是一种常见病和多发病,发病率约占人口的15%左右。胃溃疡的发病主要与胃酸分泌过多有关,因此,抑制胃酸分泌的药物一直是抗消化性溃疡药物开发的热点之一。本文详细叙述了胃溃疡的发病机制,以及抗胃溃疡药物的发展现状。着重介绍了质子泵抑制剂奥美拉唑和兰索拉唑的药理作用、药代动力学、临床应用等情况。在参考有关文献的基础上,总结出四条奥美拉唑和兰索拉唑的合成路线,在对生产中普遍采用的路线一进行研究的基础上,对其合成路线进行了改进。新的合成路线以2,3,5-三甲基吡啶为原料,经一锅法氧化、硝化,烷氧基取代,与邻硝基苯磺酰氯反应转化为2-氯甲基吡啶,再与5-甲氧基-2-巯基-1H-苯并咪唑缩合,经过硼酸钠氧化,以较高的收率得到奥美拉唑(1a),总收率36.6%。采用相同的方法,以2,3-二甲基吡啶为原料,合成了兰索拉唑(1b),总收率41.3%。各步中间体及最终产物经1H-NMR、MS等测试,结构均得到确证。该合成工艺路线,仅4步反应,操作简单,收率高,原料价廉易得,适合工业化生产。更多还原

【Abstract】 Peptic ulcer is a common and frequently encountered disease with a morbidity rate of 15%in the whole population. This kind of disease is mainly caused by the over-secretion of gastric acid. Therefore, drugs with inhibitory activities of gastric acid secretion are still one of hotspot in the field of drug research and development. In this thesis, the pharmacological mechanism of the peptic ulcer and the progress of the anti-peptic ulcer drugs were briefly summarized. The action mechanism, pharmacokinetic characters, clinical applications of omeprazole and lansoprazole were also introduced.According to the literatures, four synthetic routes of omeprazole and lansoprazole were summarized. The 1th route, one representative industrial synthetic route, was deeply studied and further improved. Starting from 2,3,5-trimethylpyridine,2-chloromethylpyridine was synthesized after oxidation and nitration in one pot, substitution, rearrangement with o-nitrylbenzenesulfonyl chloride. Then omeprazole(la) was synthesized by condensation between 2-chloromethylpyridine and 5-mehtoxy-2-mercapto-1H-benzimidazole, then oxidation with sodium perborate with a total yield of 36.6%. Lansoprazole(lb) was synthesized by similar process with high yield (41.3%) from 2,3-dimethylpyridine. The structures of the intermediates and the final product were identified by 1H-NMR and MS.The four-step synthetic process of the two drugs,is convenient to operate with lower cost and high yield, and suitable for scale-up manufacture.更多还原