|Place of Conferral||北京|
|Keyword||丙型肝炎病毒 核糖核苷 磷酸酯前药 三氮唑类抗真菌药物 艾氟康 唑 绿色合成路线与工艺|
本论文研究内容分为两部分：第一部分为核苷类抗丙型肝炎病毒（HCV）化合物的合成与构效关系研究（第1，2，3章）；第二部分为三氮唑类抗真菌化合物的合成与构效关系研究（第4，5，6章）。第一部分开展了核苷类前药化合物抗丙型肝炎病毒活性的构效关系研究。本论文在已有研究基础上采用磷酸酯前药和碱基修饰策略，对核苷化合物的核糖和碱基片段进行结构改造，合成出了32个核苷类前药化合物，抗HCV活性测试结果显示多个目标化合物对HCV复制具有明显抑制作用。研究发现5'-氨基磷酸酯前药系列化合物的活性明显优于3,5'-环磷酸酯前药系列化合物，这在一定程度上说明环磷酸酯前药在体内不易被转为三磷酸活性形式。嘌呤的6位引入氨基酸酯或酰胺后没有增加抗HCV活性，而甲氧基、乙氧基等醚类取代基能够明显提高活性。本部分同时开展了2-Cl-2-Me-和2-F-4-Me两个C-甲基取代核糖的合成与应用研究。运用手性辅基诱导策略，发现并验证了合成2-氯-2-甲基核糖内酯的新路线，该路线符合“绿色合成路线与工艺”的工业与社会要求。完成了索非布韦原料药的合成，为在“一带一路”沿线的中亚国家开展索非布韦药品注册项目，提供了稳定可靠的药物活性成分来源。2-氟-4-甲基核糖是合成新型核苷类化合物的关键中间体，其合成方法尚未见文献报道。本论文设计、尝试了3条合成路线，其探索工作仍在进行中。 第二部分开展了三氮唑类化合物抑制表皮真菌活性的构效关系研究。本论文根据该类药物的作用机理和已有的构效关系，研究了C3位置环状胺基侧链对化合物分子抗真菌活性的影响，初步探讨了侧链体积、疏水性和碱性等化合物化合物结构特征与抗真菌活性之间的关系。测试了26个三氮唑类化合物的抗真菌活性。结果显示大多数目标化合物具有明显的抗真菌活性，其中F013、016、017、 018和 026的抑真菌活性与阳性对照艾氟康唑处于相同水平。结果还显示，N-苯基哌嗪结构片段取代哌啶烯片段的结构优化工作值得继续深入研究。该部分工作同时简要分析了各位置的取代基团，特别是侧链碱基的结构特征对目标化合物抑真菌活性的影响，进一步验证和丰富了三氮唑类抗真菌化合物的构效关系内容。本部分同时开展了艾氟康唑的合成研究。内容包括：合成路线评估与确认，4-亚甲基哌啶盐酸盐的合成研究，艾氟康唑合成的关键点及相关物质研究。（1）经过路线评估和实验室验证，确定了适于生产应用的合成路线。（2）设计了4-亚甲基哌啶盐酸盐的新合成路线，并进而开发优化了其合成工艺。三步化学反应的总收率高达83.5%，且HPLC纯度为99.9%。（3）发现了叔丁醇镁能够高效地促进三唑环氧和哌啶烯盐酸盐发生胺解反应。优化后的反应条件在实验室中制备艾氟康唑API的收率和HPLC纯度分别达到了91.5%和99.5%。把该反应系统和条件扩展应用到不同结构胺基物与三氮唑环氧反应，也取得了预期的良好结果，为三氮唑类抗真菌化合物的高效合成提供了一个行之有效的方法。（4）鉴定了艾氟康唑合成工艺中出现的6个杂质的化学结构，并设计合成路线予以合成、确认。同时分析了杂质产生的可能来源和过程，并在优化了的工艺过程中设置了相应的控制策略。该“绿色合成”技术方案，将在中科院“一带一路”国家科技合作框架下实施，向中亚国家提供药品注册所需的艾氟康唑原料药。核苷类化合物的磷酸酯和碱基修饰双前药策略表现出了优异的抗HCV活性，为核苷前药的进一步结构改造提供了依据；三氮唑类化合物的抑制表皮真菌活性构效关系研究显示C3位置的N-苯基哌嗪结构片段结构优化工作值得继续深入；氯甲基核糖与艾氟康唑的合成研究与工艺条件优化践行了“源头控制”入手的理念，研究开发了“简易、安全、清洁、低耗”的“绿色制药”技术。
The dissertation is divided into two parts：The first part consists of the synthesis and structure-activity relationship of nucleoside inhibitors of HCV NS5B; the second part consists of the synthesis and structure-activity relationship of triazole antifungal compounds.In the first part: the structure-activity relationship of nucleoside prodrugs against hepatitis C virus activity was studied. On the basis of previous studies, we adopted phosphate prodrug and base modification strategies to modify ribose and base fragment of nucleosides. Thirty two nucleoside prodrugs were synthesized and most of the target compounds had potent inhibitory effect on HCV replication. It is found that the activity of 5'-phosphamide prodrug compounds is obviously superior to 3,5'-cyclic phosphate, which reflects that the prodrug of the cyclic phosphate ester is harder converted to the active triphosphoric acid form. The introduction of amino acid esters or amides at 6-position of purine did not increase the anti-HCV activity, while methoxyl and ethoxyl substituents greatly improve biological activity. In this part, the synthesis of 2-Me-2-Cl ribose lactones were also studied. Firstly, a new synthetic route of 2-Cl-2-methyl ribose was developed by using the chiral auxiliary induction strategy. The synthetic route meets the requirements of "green chemistry". Then sofosbuvir was successfully synthesized. It is conducive to the registration of sofosbuvir in the Central Asia countrie along"The Belt and Road". Secondly, we studied the synthesis of 2-fluoro-4-methyl ribose lactone, which has not been reported in the literature searching. Three synthetic routes have been tried to prepare the compound and the study will be continued. In the second part: the structure activity relationship of three azole compounds inhibiting antifungal activity was studied. According to the action mechanism and existing structure-activity relationship, the effect of C3-cyclic amido side chain with the near plane structure on the antifungal activity of the molecules was studied in second round compounds, and the relationship between side chain volume, hydrophobicity, alkalinity and antifungal activity was further explored. The antifungal activity of 26 triazole antifungal compounds was tested. The results displayed that most of the compounds had obvious antifungal activity, and several compounds, such as F013, 016, 017, 018, 026, have similar inhibitory activity with efinaconazole. It is revealed that the remarks of N-phenyl piperazine substituted side chain is worth continuing to study in depth.The effect of the substituent groups in each position and the structure of side chain on the antibacterial activity were analyzed, and the structure-activity relationship of the antifungal compounds of three azoles was further verified and enriched.In this part, the synthetic study of efinaconazole is divided into four aspects: synthesis route evaluation and confirmation, the synthesis of the key intermediate 4-methylenepiperidine hydrochloride, the key reaction for preparing efinaconazole API and the study of related substances. (1) Through the route evaluation and preliminary verification, a synthetic route for the preparation of efinaconazole was identified. (2) A new synthetic route for the synthesis of 4-methylene piperidine hydrochloride was designed and developed. The target molecular was finally obtained in 3 steps with a total yield of 83.5% and HPLC purity 99.9%. (3) It was found that (t-BuO)2Mg was a novel and efficient method of triazole epoxide ring opening with 4-methylenepiperidine hydrochloride. Using the optimized conditions, efinaconazol was synthesized in 91.5% isolated yield, 99.5% HPLC purity, and > 99.9% ee. This method was demonstrated by applying it to the ring opening with a number of amines, including the synthesis of efinaconazole and will be contributed to synthesize new triazole compounds with potential antifungal activity. (4) Six impurities encountered in the proceess development of making efinaconazole were identified and synthesized. Based on the investigation of the root cause of their formation, the strategy for elimination or minimization of these impurities to the accepted level has been demonstrated. The "green synthesis" technical proposal will be implemented in the national science and technology cooperation framework of Chinese Academy of Sciences "the Belt and Road" to provide the efinaconazole API required by drug registration in Central Asian countries.The phosphoric acid esters of nucleoside compounds and base modified double prodrug strategies showed excellent anti HCV activity; the structure-activity relationship of triazoles antifungal activity showed that the structure optimization of N-phenyl piperazine structure fragment in the C3 position should be further developed; The concept of "source control" has been implemented by the synthesis of ribose lactone and efinaconazole and the "green pharmaceutical technology" embodied by "simple, safe, clean and low consumption" was developed.
|朱富强. 核苷类抗丙型肝炎病毒和三氮唑类抗真菌化合物的合成研究[D]. 北京. 中国科学院大学,2018.|
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