罗氟司特及其杂质的合成工艺研究-药学专业毕业论文.docx

万方数据 万方数据 摘 要 慢性阻塞性肺疾病是一种具有气流阻塞特征的 HYPERLINK /view/110229.htm 慢性支气管炎和（或） HYPERLINK /view/44433.htm 肺气肿， 该疾病作为一种严重的肺部疾病，正在逐渐成为一个全球性的公共健康问题。并 且预计到2030年，慢性阻塞性肺病的排名将跃升到第三位。现代药理学疗法在治 疗慢性阻塞性肺病上有一定的局限性，尤其是在减轻疾病进行性加重方面。 以磷酸二酯酶作为一种新型作用靶点的第二代选择性磷酸二酯酶4抑制剂正 逐渐引起大家的关注。而罗氟司特作为唯一上市的磷酸二酯酶4抑制剂，日趋成 为竞相仿制的焦点。 本文在传统的四种合成路径的基础上，筛选出一条合成罗氟司特的简便方 法。 在合成路线的优化过程中，前后共对七种杂质化合物进行了合成，并以此对 其结构进行了高效液相色谱、红外吸收光谱、紫外吸收光谱、氢核磁共振波谱、 碳核磁共振波谱以及质谱等表征。同时，本文还对七种杂质的来源进行了详尽的 分析，并以杂质含量降至最低为准线对工艺进行了系统优化。 最终，在所合成的罗氟司特产品中，罗氟司特的含量大于 99.96%，其中两 种杂质的单个杂质含量（0.01%和 0.02%）降至 0.1%以下，总杂质含量（0.04%） 在 0.3%以下。符合国家食品药品监督管理局颁布的《化学药物杂质研究的技术 指导原则》。并且，作为国家 3.1 类新药的罗氟司特片剂，其制备工艺通过天津 新药审评中心的审批。 关键词：慢性阻塞性肺病；磷酸二酯酶 4 抑制剂；新药；罗氟司特；杂质 ABSTRACT Chronic obstructive pulmonary disease is a kind of characteristic of airflow obstruction in chronic bronchitis and emphysema, as a kind of severe lung disease, the disease is gradually becoming a global public health problem. It is projected that by 2030 chronic obstructive pulmonary disease will rank jump to the third leading cause of death. Modern pharmacology therapy in the treatment of chronic obstructive pulmonary disease has certain limitations, especially in the area of reduce the disease progressive strengthening. Roflumilast, as a new type of targets of the second generation of selective phosphodiesterase 4 inhibitors, is gradually come to the attention of researchers. Meanwhile, roflumilast, as the only listed phosphodiesterase 4 inhibitor, gradually become the focus of competition to generic. In this paper, on the basis of the traditional four synthetic routes, we selected a simple method of synthesis of Roflumilast. In the optimization process of synthetic route, we found seven kinds of impurityies, and their structures were confirmed by high performance liquid chromatography, infrared absorption chromatography, ultraviolet absorption chromatography, nuclear magnetic resonance hydrogen spectrum, carbon nuclear magnetic resonance spectrum and mass spectrum characterization. At the same time