CN106977463A - 一种联苯取代哌嗪衍生物的合成方法 - Google Patents
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Abstract
本发明公开了一种联苯取代哌嗪衍生物4‑(N‑Boc‑哌嗪‑3‑基)联苯的合成方法，以4‑乙酰基联苯为起始原料，经过氧化、环合、上Boc得到目标产物，该化合物是重要的医药中间体。
Description
技术领域
本发明涉及一种医药中间体的新型制备方法，特别涉及一种联苯取代哌嗪衍生物4-(N-Boc-哌嗪-3-基)联苯的一种合成工艺。
技术背景
联苯取代哌嗪衍生物4-(N-Boc-哌嗪-3-基)联苯，结构式为：
抗微生物药物是目前临床应用较广、用量较大的一类药物，在控制与治疗疾病方面发挥着重要作用。目前临床使用的抗微生物药物品种众多，但随着抗微生物药物的大量而广泛使用，特别是在临床上的不合理应用，甚至滥用，最后导致多重耐药。因此,如何克服多重耐药成为目前国内外抗微生物药物研究的重要课题。解决耐药性的方法众多,其中新型结构抗微生物药物的研发是解决耐药性的重要途径之一，已成为当今药物化学十分活跃的领域。
哌嗪环是药物化学研究中常用的一类碱性基团，其毒性小，易形成多个氢键或离子键，常能有效地调节药物的脂水分配系数和酸碱平衡常数。将其引入分子，能有效地增加分子的碱性和水溶性，从而增强分子的活性。因此,在一定程度上，哌嗪基团是一个增效基团，常在许多药物的设计和开发中引入。研究表明，含哌嗪且N-取代的化合物常显示出广泛的生物活性，如抗微生物、抗高血压、抗癌、消炎和止痛等，尤其作为抗微生物药物，其研究活跃且发展迅速，显示出宽广的发展潜力。
本发明涉及的一类哌嗪衍生物中间体对于新药研发具有重要作用。
发明内容
本发明公开了一种联苯取代哌嗪衍生物4-(N-Boc-哌嗪-3-基)联苯的合成方法，以4-乙酰基联苯为起始原料，经过氧化、环合、上Boc得到目标产物，合成步骤如下：
(1)以4-乙酰基联苯为起始原料，经氧化反应得到2；
(2)把3与乙二胺发生环合反应，得到3；
(3)把3与Boc2O反应得到4；
在一优选的实施方式中，所述的氧化反应制备化合物2所用的氧化试剂选自二氧化硒；所述的环合反应制备化合物3所用的还原剂选自硼氢化钠；所述的氨基保护反应所用的碱选自碳酸氢钠。
在一优选的实施方式中，所述的氧化反应制备化合物2所用的溶剂选自四氢呋喃；所述的环合反应制备化合物3所用的溶剂选自乙醇；所述的氨基保护反应所用的溶剂选自二氯甲烷。
在一优选的实施方式中，所述的氧化反应制备化合物2所用的反应温度是溶剂的回流温度；所述的环合反应制备化合物3所用的温度是溶剂的回流温度；所述的氨基保护反应所用的温度是室温。
本发明涉及联苯取代哌嗪衍生物4-(N-Boc-哌嗪-3-基)联苯的合成工艺，目前没有其他相关专利文献报道。
下面通过实施例对本发明作进一步的描述，这些描述并不是对本发明内容作进一步的限定。本领域的技术人员应理解，对本发明的技术特征所作的等同替换，或相应的改进，仍属于本发明的保护范围之内。
具体实施例方式
实施例1
(1)4-(二乙二醛基)联苯的合成
把20g 4-乙酰基联苯加入到150ml四氢呋喃中，加入45g二氧化硒，加热搅拌回流12小时,冷却至室温，过滤，再加入水和乙酸乙酯进行萃取，分液、干燥、浓缩即得到粗品二乙二醛对溴苯，重结晶得到11g 4-(二乙二醛基)联苯。
(2)4-哌嗪联苯的合成
把10g 4-(二乙二醛基)联苯加入到130ml乙醇中，再加入8.5g乙二胺，加热回流6小时，冷却至室温，分批加入3.8g硼氢化钠，室温搅拌4小时，加入1N盐酸，再加入乙酸乙酯，萃取分液，收集有机相，分液、干燥、浓缩，剩余物上硅胶柱分离得9.5g 4-哌嗪联苯。
(3)4-(N-Boc-哌嗪-3-基)联苯的合成
把9g 4-哌嗪联苯加入到100ml二氯甲烷中，再加入9.8g二碳酸二叔丁酯、3ml三乙胺，室温搅拌24小时，加入水，萃取分液，收集有机相，分液、干燥、浓缩，剩余物上硅胶柱分离得12.4g 4-(N-Boc-哌嗪-3-基)联苯。
Claims (6)
1.一种联苯取代哌嗪衍生物4-(N-Boc-哌嗪-3-基)联苯的合成方法，其特征是以4-乙酰基联苯为起始原料，经过氧化、环合、上Boc得到目标产物4，合成路线如下：
2.根据权利要求1的方法，其特征为所述的3步反应是，
(1)以4-乙酰基联苯为起始原料，经氧化反应得到2；
(2)把3与乙二胺发生环合反应，得到3；
(3)把3与Boc2O反应得到4；
3.根据权利要求1的方法，其特征在于,所述的氧化反应制备化合物2所用的氧化试剂选自二氧化锰、二氧化硒、氯铬酸吡啶、重铬酸吡啶盐、三氧化铬中的一种或几种的混合物；所述的环合反应制备化合物3所用的还原剂选自硼氢化锂、硼氢化钠、硼氢化钾、四氢铝锂、氰基硼氢化钠、三乙酰氧基硼氢化钠中的一种或几种的混合物；所述的氨基保护反应所用的碱选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、三乙胺、碳酸氢钠、吡啶、三异丙基胺、碳酸氢钾中的一种或几种的混合物。
4.根据权利要求1的方法，其特征在于，所述的氧化反应制备化合物2所用的溶剂选自甲醇、乙醇、正丙醇、异丙醇、四氢呋喃、甲苯、邻二甲苯、对二甲苯、间二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或几种的混合物；所述的环合反应制备化合物3所用的溶剂选自甲醇、乙醇、异丙醇、二氯甲烷、三氯甲烷、乙酸乙酯、四氢呋喃、甲苯、四氢呋喃、甲苯、邻二甲苯、对二甲苯、间二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或几种的混合物；所述的氨基保护反应所用的溶剂选自甲醇、乙醇、正丙醇、异丙醇、四氢呋喃、二氯甲烷、三氯甲烷、乙酸乙酯、甲苯、邻二甲苯、对二甲苯、间二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中的一种或几种的混合物。
5.根据权利要求1的方法，其特征在于,所述的氧化反应制备化合物2所用的反应温度是0℃～溶剂的回流温度；所述的环合反应制备化合物3所用的温度是0℃-溶剂的回流温度；所述的氨基保护反应所用的温度是0℃-溶剂的回流温度。
6.根据权利要求1的方法，其特征在于,所述的氧化反应制备化合物2所用的反应温度是室温；所述的环合反应制备化合物3所用的温度是溶剂的回流温度；所述的氨基保护反应所用的温度是室温。
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