可用於親核性芳香環氟化反應之不對稱雙苯基碘鹽的合成研究

Synthesis of Unsymmetric Diaryliodonium Salts for Nucleophilic Aromatic Fluorination

鄭惠文(Hui-Wen Cheng)

指導教授 ： 忻凌偉

國立臺灣大學/醫學院/藥學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201603126

摘要

為發展放射性核醫藥物，研究腦中多巴胺神經系統分佈及運作，合成出多巴胺轉運體配體 45。其於紋狀體有明顯選擇性吸收並有良好清除率，極具潛力發展為多巴胺轉運體之正子斷層造影劑。因進行放射標記氟化反應時，電子密度大的芳香環作親核性取代反應仍具挑戰性，故本研究採用具有缺電子、良好離去基性質之雙芳香環碘鹽作為前驅物，使氟離子能更有效率進行親核性取代反應。在製備氟化前驅物之反應途徑中，發現有機錫中間體純化不易且穩定性差，為優化合成策略，設計、合成出一系列的硼酸酯與硼酸化合物，以評估其製備雙芳香環碘鹽之可能性。經分析，選用硼酸化合物 31 取代錫化物為關鍵中間體，並與碘(III) 試劑反應，可合得碘鹽 34。在此反應條件下，可避免 piperazine 之鹼性氮原子與碘(III) 試劑有副反應發生，使得產物純度、產率皆得以提升。以立體阻礙較大 mesityl 基團做為配位體，使反應有更高的化學選擇性；並在銅催化的條件下進行氟化反應，克服原先氟化反應須高溫 (> 100oC)、且對於多電子起使物反應性不佳之問題，產率可提升至 24%。本研究成功建立由硼酸化合物合成碘鹽之條件，也將溫和的氟化反應條件應用於含鹼性氮原子的 GBR 結構中。期望此新的合成策略能有效、高產率地合成碘鹽，並多方應用於合成正子斷層掃描造影劑。

關鍵字

多巴胺轉運體 ； 正子斷層造影劑 ； 芳香環作親核性取代反應 ； 不對稱雙芳香環碘鹽 ； 有機錫 ； 硼酸酯 ； 硼酸 ； 銅催化氟化反應

並列摘要

In order to develop a potent radiopharmaceuticals for investigation of the distribution and function of dopaminergic system in the brain, a dopamine transporter (DAT) ligand, 45 was synthesized. Its selective uptake in stratum and good washout characteristics made it become a promising positron emission tomography (PET) radiotracer of DAT. Direct incorporation of a fluoride into the electron-rich arene via nucleophilic aromatic substitution is still a challenge. By using diaryliodonium salts, which possessed electron-deficient and good leaving group properties, allows nucleophilic substitution with fluoride proceeding more efficiently. Owing to the difficulty in purification and low stability of organotin intermediates, a series of boronated compounds were designed, synthesized and evaluated to optimize the synthetic strategy. By being used to prepare the novel diaryliodonium salts as precursors, the boronic acid 31 as an alternative of organostannane reacted with hypervalent iodine to form the diaryliodonium salt 34. Moreover, undesired side reaction between the basic nitrogen atoms in piperazine and hypervalent iodine can be avoided under this reaction condition, and both of the purity and chemical yield of the product have become higher. In addition, choosing the sterically hindered mesityl group as the ligand of diaryliodonium salts to proceed higher chemoselectivity. And the requirement for the high temperature (> 100oC) and poor reactivity of electron rich substrates of fluorination was overcome under Cu-catalyzed condition. The improved yield is up to 24%. An improved protocol for the preparation of diaryliodonium salts from boronic acid was established for mild fluorination condition with basic-nitrogen containing GBR structures. The new established synthetic methodology was efficient and high-yield for the preparation of diaryliodonium salts, making these precursors more feasible for applying in various PET imaging agents.

並列關鍵字

dopamine transporter ； promising positron emission tomography ； nucleophilic aromatic substitution ； diaryliodonium salts ； organotin ； boronic ester ； boronic acid ； Cu-catalyzed fluorination

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