常山酮中间体合成工艺及其中试研究-生物化工专业论文.docxVIP

摘要 摘要 万方数据 万方数据 摘 要 常山酮(Halofuginone)是中药常山的提取物常山碱（Febrifugine）的衍生物， 市场上销售的是 0.6%氢溴酸常山酮的预混剂商品名叫速丹（Stenorol）。目前常 山酮主要用于球虫病和疟疾等疾病预防和治疗，具有广谱高效、安全无毒、无交 叉耐药性、不可逆以及停药后不复发等优点。研究发现，常山酮可以用来预防和 治疗肝纤维化以及瘢痕和硬皮病等疾病，也可以用来治疗膀胱癌、乳腺癌等恶性 肿瘤。由于常山酮合成工艺比较复杂，国内尚无厂家生产，故价格比较昂贵。 本论文研究的主要内容分为两个部分： （1）间氯甲苯作为起始原料，经溴代、氧化、氨解、环化缩合四步反应得 到了 7-溴-6-氯-4(3H)-喹唑啉酮，总收率 50.61%，采用质谱、核磁共振对所得化 合物进行结构表征，化合物的纯度采用 HPLC 测定。在小试工艺的基础上，进行 了放大试验，并对中试过程中的问题进行了优化和改进，获取了中试生产的工艺 条件，总收率 50.52%。该工艺原料廉价易得，工艺简单，易于操作，适合工业 化生产。 （2）以 3-羟基吡啶为起始原料，经 Mannich 反应、乙酰化、氢溴酸水解得 到 2-溴甲基-3-羟基吡啶后，对羟基进行保护没有成功，通过对该工艺进行一系 列改进和优化后没有得到终产物，说明通过该工艺得到哌啶环部分的路线行不 通，需要进一步研究。 关键词：常山酮；常山碱；球虫病；合成；中试研究 II Abst Abstract ABSTRACT Halofuginone was a febrifugine derivative extracted from the Chinese herb ChangShan. The premixes of 0.6% halofuginone hydrobromide whose brand name is Stenorol were saled on the market. At present, halofuginone was mainly used as feed additives to treat and prevent diseases such as coccidiosis and malaria in domesticated poultry and livestock. It had many advantages such as broad-spectrum, non-toxic, no cross resistance, no reversibility and no recurrence after drug withdrawal. Some latest researchs indicated that halofuginone can be used for the treatment and prevention of human diseases such as liver fibrosis, pulmonary fibrosis, scar and scleroderma, and it can also be used to treat human malignant neoplasm of bladder cancer, breast cancer, prostate cancer, lung cancer, skin cancer. So halofuginone had a broad market prospects. However, nowadays halofuginone used in China mostly depended on import for its complex synthesis process, and there were no domestic manufacturers, so the price was relatively expensive. The main contents of this paper were divided into two parts: 7-bromo-6-chloro-4(3H)-quinazolinone was synthesized from M-chloroto- luene by substitution of bromine, oxidation, ammonolysis and then subjected to cyclization to afford the product. The total yield of four steps is 50.61%, the structures of all the intermedi