CN107353209B - 与Aβ斑块具有高亲和力的二苯氧基柔性分子及其制备方法和应用 - Google Patents
与Aβ斑块具有高亲和力的二苯氧基柔性分子及其制备方法和应用 Download PDFInfo
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- CN107353209B CN107353209B CN201710474957.3A CN201710474957A CN107353209B CN 107353209 B CN107353209 B CN 107353209B CN 201710474957 A CN201710474957 A CN 201710474957A CN 107353209 B CN107353209 B CN 107353209B
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Abstract
本发明公开了一类与Aβ斑块具有高亲和力的二苯氧基柔性分子及其制备方法和应用，该类分子被放射性核素标记后作为Aβ斑块显像剂用于阿尔兹海默症的诊断，其结构式如下所示；此类分子的化学结构不同于现有技术所公开的化合物，属于诊断阿尔茨海默症的全新分子；经过放射性核素标记后得到的Aβ斑块显像剂，体内稳定性好，脂溶性低、脑清除速率快，具有巨大的应用前景和市场价值。
Description
技术领域
本发明涉及放射性药物化学和临床核医学技术领域，具体地说，涉及一类与Aβ斑块具有高亲和力的二苯氧基柔性分子及其制备方法和应用，
背景技术
阿尔茨海默症(Alzheimer's Disease，AD)是一种进行性发展的致死性神经退行性疾病，临床表现为认知和记忆功能下降，日常生活能力减退，并伴有各种神经精神症状和行为障碍。AD多发于老年人群，统计资料显示，全球目前有3600万人患有AD,而且每隔二十年AD病患翻两倍，即到2030年将有6600万人遭受AD的折磨，而到2050年，这一数字将达到11500万。目前我国正在快速步入老龄化社会，AD已成为继肿瘤、心脏病和中风之后，严重威胁老年人身心健康的主要疾病。可见，AD的防治工作任务艰巨，研究AD的早期诊断方法及治疗药物具有极其重要社会意义和实际价值。研究表明，AD脑内沉积在神经细胞外的老年斑(SPs)和神经细胞内的神经纤维缠结(NFTs)是AD的两大主要病理特征。利用脑内的Aβ斑块为靶点，开发与之具有高亲和性和选择性的分子探针，通过单光子计算机扫描(SPECT)或正电子发射断层扫描(PET)等核医学影像技术，可以无创伤的从分子水平上早期诊断AD。
在过去的研究里，用于核医学PET显像的Aβ斑块显像剂发展迅速，通过对硫磺素-T(ThT)和刚果红(CR)这两种染料进行修饰，已经有不少分子进入了临床试验阶段。如2-苯基苯并噻唑类的代表化合物[11C]PIB是目前使用最为广泛的Aβ斑块显像剂，它的类似物[18F]GE-067获得美国FDA批准；二苯乙烯衍生物[18F]AV-45、[18F]BAY94-9172也获得美国FDA批准。然而，用于SPECT显像的Aβ斑块显像剂还没有获得突破性进展，其中123I标记的2-苯基咪唑并吡啶衍生物[123I]IMPY是第一个进入临床阶段的SPECT显像剂，但由于其体内稳定性差而宣告失败。纵观以往发展的Aβ斑块分子探针，均具有共轭的平面结构，而我组最近研究表明柔性结构的苯基苄基醚类衍生物与Aβ斑块具有高亲和性，有发展为Aβ斑块显像剂的潜力。在此基础上，试图进一步增加分子柔性，从而得到一系列二苯氧基柔性分子。该类分子是一类全新的与脑内Aβ斑块具有高亲和力的化合物，对其进行放射性核素标记，可以得到一种能够用于AD的早期诊断的Aβ斑块显像剂，势必将会有巨大的应用前景和经济价值。同时，具有不同柔性linker二苯氧基柔性分子化合物与Aβ蛋白结合模式的探究为继续开发新型柔性结构Aβ斑块分子探针的研究奠定理论基础。
发明内容
本发明的目的之一在于，提供一类二苯氧基柔性分子化合物。该类化合物与AD病人脑内Aβ斑块具有高亲和力，属于诊断和治疗AD的全新化合物。
本发明的另一目的在于，提供所述二苯氧基柔性分子化合物的制备方法。
本发明的另一目的在于，提供一种利用所述二苯氧基柔性分子化合物制备得到的Aβ斑块显像剂。
本发明的另一目的在于，提供所述Aβ斑块显像剂在诊断淀粉样病变疾病的药物中的应用，包括AD的早期诊断。
为了实现上述目的，本发明提供的二苯氧基柔性分子化合物，其结构式如下所示：
其中，化合物(Ⅰ)，n为1–11的整数，R1为I或NMe2,R2为氢、卤素、羟基、巯基、烷氧基、烷基、硝基、氨基、烷氨基、氰基、羧基、-Sn(烷基)3、-(OCH2CH2)m-F(m为1-3的整数)；化合物(Ⅱ)，n为2–5的整数，R1为NMe2，R2为I或-(OCH2CH2)m-F(m为1-3的整数)；化合物(III)，n为1–5的整数，R1为NMe2，R2为I或-(OCH2CH2)m-F(m为1-3的整数)。
其中，Me表示甲基。
本发明提供的二苯氧基柔性分子化合物，进一步地，其结构式如式(I)所示：
其中，n为1–11的整数，R1为I或NMe2，R2为氢、卤素、羟基、巯基、烷氧基、烷基、硝基、氨基、烷氨基、氰基、羧基、-Sn(Bu)3、-(OCH2CH2)m-F(m为1-3的整数)，R1和R2均为邻位、间位或对位取代基。
进一步，优选地，n＝2或6，R1和R2分别为：
本发明提供的二苯氧基柔性分子化合物，进一步地，其结构式如式(Ⅱ)所示：
其中，n为2–5的整数，R1为NMe2，R2为I、-Sn(Bu)3、(OCH2CH2)m-F(m为1-3的整数)。
本发明提供的二苯氧基柔性分子化合物，进一步地，其结构式如式(III)所示：
其中，n为2–5的整数，R1为NMe2，R2为I或-(OCH2CH2)m-F(m为1-3的整数)。
本发明提供的上述任意一项二苯氧基柔性分子化合物，进一步地，当其中含有氟原子时，F为18F或19F；当其中含有碘原子时，I为123I、124I、125I、127I或131I；当其中含有甲基、甲氧基、N-甲氨基或二甲氨基时，-CH3为-11CH3、-OCH3为-O11CH3、-NHCH3为-NH11CH3或-N(CH3)2为-N(11CH3)2或-N(CH3)(11CH3)。
更进一步地，当F为18F或I为124I时，得到的二苯氧基柔性分子化合物可作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
更进一步地，当-CH3为-11CH3、-OCH3为-O11CH3、-NHCH3为-NH11CH3或-N(CH3)2为-N(11CH3)2或-N(CH3)(11CH3)时，得到的二苯氧基柔性分子化合物可作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
更进一步地，当I为125I，123I或131I时，得到的二苯氧基柔性分子化合物可作为Aβ斑块显像剂，尤其作为SPECT类Aβ斑块显像剂。
本发明所述二苯氧基柔性分子化合物(I)，可按照下述反应方程式制备所述化合物：
其中，R1、R2、n与式(I)所示化合物具有相应的定义。
其制备方法包括以下步骤(以n为2，R1为p-NMe2，R2为p-I为例，其他均采用类似方法制备)：
(1)将化合物对硝基苯酚(1396.0mg,10.0mmol)、化合物1,2-二溴乙烷(3758.2mg,20.0mmol)和K2CO3(4142.8mg,30.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色粉末中间体(Ⅴ-a)。
(2)将化合物(Ⅴ-a)(738.2mg,3.0mmol)、化合物4-碘苯酚(660.1mg,3.0mmol)和K2CO3(1242.8mg,9.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色粉末中间体(Ⅰ-a)。
(3)将化合物(Ⅰ-a)(385.2mg,1.0mmol)和二水合二氯亚锡(902.8mg,4.0mmol)溶于适量乙醇中，向溶液中滴加5mL浓盐酸，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，抽滤，除去干燥剂，旋蒸，除去溶剂，即得中间体(Ⅰ-b)。
(4)将化合物(Ⅰ-b)(269.6mg,0.7mmol)和多聚甲醛(210.2mg,7.0mmol)溶于适量冰醋酸中，在冰浴条件下，向溶液中缓慢分批加入氰基硼氢化钠(219.9mg,3.5mmol)，室温反应过夜，反应结束后，向溶液中加入氨水调pH至弱碱性，CH2Cl2萃取，MgSO4干燥，柱色谱分离得白色粉末的终产物(Ⅰ-c)。
本发明所述二苯氧基柔性分子化合物(Ⅱ)，可按照下述反应方程式制备所述化合物：
其中，R1、R2、n与式(Ⅱ)所示化合物具有相应的定义。
其制备方法包括以下步骤(以n为2，R1为NMe2，R2为I为例，其他均采用类似方法制备)：
(1)将化合物对硝基苯酚(1396.0mg,10.0mmol)、化合物2-氯乙氧基乙醇(1246.2mg,10.0mmol)和K2CO3(4142.8mg,30.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色蜡状中间体。将该中间体(1136.5mg,5.0mmol)和对甲苯磺酰氯(1143.8mg,6.0mmol)溶于适量的无水二氯甲烷中，再向溶液中滴加5mL的三乙胺，室温反应6h，旋蒸，除掉溶剂，柱色谱分离得淡黄色粉末的中间体(Ⅶ-a)。
(2)将化合物(Ⅶ-a)(1144.2mg,3.0mmol)、化合物4-碘苯酚(660.1mg,3.0mmol)和K2CO3(1242.8mg,9.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色粉末中间体(Ⅱ-a)。
(3)将化合物(Ⅱ-a)(429.2mg,1.0mmol)和二水合二氯亚锡(902.8mg,4.0mmol)溶于适量乙醇中，向溶液中滴加5mL浓盐酸，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，抽滤，除去干燥剂，旋蒸，除去溶剂，即得中间体(Ⅱ-b)。
(4)将化合物(Ⅱ-b)(360.0mg,0.9mmol)和多聚甲醛(270.9mg,9.0mmol)溶于适量冰醋酸中，冰浴下，向溶液中缓慢分批加入氰基硼氢化钠(282.9mg,4.5mmol)，室温反应过夜，反应结束后，向溶液中加入氨水调pH至弱碱性，CH2Cl2萃取，MgSO4干燥，柱色谱分离得白色粉末的终产物(Ⅱ-c)。
本发明所述二苯氧基柔性分子化合物(III)，可按照下述反应方程式制备所述化合物：
其中，R1、R2、n与式(III)所示化合物具有相应的定义。
其制备方法包括以下步骤(以n为2，R1为NMe2，R2为I为例，其他均采用类似方法制备)：
(1)取3mL溴化氢溶液(40％)加入溶有化合物哌嗪(516.8mg,6.0mmol)的乙醇溶液中，然后将溶有化合物(Ⅴ-a)(738.2mg,3.0mmol)的乙醇溶液加入上述溶液中，90℃回流反应48h，反应结束后，旋蒸，除去溶剂，加水酸化(10％HCl,pH＝5-6)，CH2Cl2洗涤，收集水相，碱化(50％NaOH,pH>9),CH2Cl2萃取，得到黄色固体中间体(VIII-a)。
(2)将化合物(VIII-a)(152.9mg,0.6mmol)、化合物1-(2-溴乙醇)-4-碘苯(199.0mg,0.6mmol)和K2CO3(248.8mg,1.8mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色粉末中间体(III-a)。
(3)III-b，III-c的合成方法同Ⅱ-b，Ⅱ-c的合成。
本发明还提供利用所述二苯氧基柔性分子化合物制备得到的Aβ斑块显像剂。
其中，当上述任意一项二苯氧基柔性分子化合物中含有氟原子时，制备得到含有放射性核素18F的化合物，即作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
或者，当上述任意一项二苯氧基柔性分子化合物中含有碘原子时，制备得到含有放射性核素124I的化合物，即作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
或者，当上述任意一项二苯氧基柔性分子化合物中含有甲基、甲氧基、N-甲氨基或二甲氨基时，制备得到含有放射性核素11C(-11CH3、-O11CH3、-NH11CH3、-N(11CH3)2或-N(CH3)(11CH3))的化合物，即作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
或者，当上述任意一项二苯氧基柔性分子化合物中含有碘原子时，制备得到含有放射性核素123I、125I或131I的化合物，即作为Aβ斑块显像剂，尤其作为SPECT类Aβ斑块显像剂。
其中，所述Aβ斑块显像剂为单光子或正电子Aβ斑块显像剂。
其中，所述Aβ斑块显像剂可用于PET显像或SPECT显像。
本发明提供的Aβ斑块显像剂可用于AD中淀粉样病变的早期诊断。
本发明还提供所述二苯氧基柔性分子化合物或所述Aβ斑块显像剂在制备和治疗诊断淀粉样病变疾病(包括阿尔茨海默症)的药物中的应用。
本发明首次公开了一类全新结构的二苯氧基柔性分子化合物化合物，体外竞争结合实验表明，该类分子与Aβ1-42聚集体的亲和力很高；体外放射自显影实验表明I-125的该类分子可以特异性地与AD人脑切片或AD转基因小鼠脑内的Aβ斑块结合；正常小鼠体内生物分布实验表明，部分I-125标记的显像剂具有初始脑摄取高，清除快的优点；有望成为一种新的用于临床显像的单光子Aβ斑块显像剂。
本发明提供一类全新的与AD病人脑内Aβ斑块具有高亲和力的苯基苄基醚衍生物，化学结构不同于现有技术所公开的化合物，尤其是硫磺素-T和刚果红，属于诊断和治疗阿尔茨海默症的全新化合物；利用该化合物制备的Aβ斑块显像剂，体内稳定性好，具有巨大的应用前景和市场价值。同时，具有不同柔性linker二苯氧基柔性分子化合物与Aβ蛋白结合模式的探究，为继续开发新型柔性结构Aβ斑块分子探针的研究奠定理论基础。
附图说明
图1和图2为本发明实施例1中碘代化合物(Ⅰ)的合成反应路线。
图3为本发明实施例2中碘代化合物(Ⅱ)合成反应路线。
图4为本发明实施例3中碘代化合物(III)合成反应路线。
图5为本发明实施例4中部分二苯氧基柔性分子与AD转基因小鼠及AD病人脑切片中的斑块结合的放射自显影实验结果。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段，所用原料均为市售商品。
实施例1：碘代化合物(Ⅰ)的合成
合成反应路线如图1，图2所示，本实施例中的化合物编号均与该图反应路线中的编号统一。
在图1所示的合成路线中，试剂与条件如下：(a)1，n-二溴烷烃(n＝2-11)，K2CO3,DMF,90℃；(b)n-碘苯酚(n＝2,3或4)，K2CO3,DMF,90℃；(c)SnCl2·2H2O,EtOH,HCl,回流；(d)(CH2O)n,NaBH3CN,HAc,室温(e)(Bu3Sn)2,(PPh3)4Pd,甲苯,Et3N,回流；(f)[125I]NaI,HCl(1M),H2O2(3％)。
在图2所示的合成路线中，试剂与条件如下：(a)1，n-二溴烷烃(n＝2，6)，K2CO3,丙酮,90℃；(b)4-R-苯酚(R＝OCH3,F,Cl,Br,I,t-Bu)，K2CO3,DMF,90℃。
1)1-(2-溴乙醇基)-4-硝基苯(1-(2-bromoethoxy)-4-nitrobenzene，化合物1.1)的合成
将对硝基苯酚(1396.0mg,10.0mmol)、1,2-二溴乙烷(3758.2mg,20.0mmol)和K2CO3(4142.8mg,30.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色粉末1.1。1H NMR(400MHz,CDCl3)δ8.22(d,J＝8.9Hz,2H),6.98(d,J＝9.1Hz,2H),4.39(t,J＝6.1Hz,2H),3.68(t,J＝6.1Hz,2H).
2)1-(2-溴乙醇基)-2-硝基苯(1-(2-bromoethoxy)-2-nitrobenzene，化合物1.1a)的合成
按照化合物1.1)的方法制备(反应物用邻硝基苯酚代替对硝基苯酚)，得到淡黄色固体1.1a。1H NMR(400MHz,CDCl3)δ7.84(dd,J＝8.3,1.7Hz,1H),7.54(td,J＝8.5,1.7Hz,1H),7.12–7.06(m,2H),4.42(t,J＝6.5Hz,2H),3.68(t,J＝6.5Hz,2H).
3)1-(2-溴乙醇基)-3-硝基苯(1-(2-bromoethoxy)-3-nitrobenzene，化合物1.1b)的合成
按照化合物1.1)的方法制备(反应物用间硝基苯酚代替对硝基苯酚)，得到淡黄色固体1.1b。1H NMR(400MHz,CDCl3)δ7.88(ddd,J＝8.1,2.1,0.8Hz,1H),7.76(t,J＝2.3Hz,1H),7.47(t,J＝8.2Hz,1H),7.27(ddd,J＝8.1,2.1,0.8Hz,1H),4.39(t,J＝6.1Hz,2H),3.69(t,J＝6.1Hz,2H).
4)1-(3-溴丙醇基)-4-硝基苯(1-(3-bromopropoxy)-4-nitrobenzene，化合物1.2)的合成
按照化合物1.1)的方法制备(反应物用1,3-二溴丙烷代替1,2-二溴乙烷)，得到淡黄色固体1.2。1H NMR(400MHz,CDCl3)δ8.21(d,J＝9.1Hz,2H),6.97(d,J＝9.1Hz,2H),4.22(t,J＝5.8Hz,2H),3.61(t,J＝6.2Hz,2H),2.39–2.36(m,2H).
5)1-(4-溴丁醇基)-4-硝基苯(1-(4-bromobutoxy)-4-nitrobenzene，化合物1.3)的合成
按照化合物1.1)的方法制备(反应物用1,4-二溴丁烷代替1,2-二溴乙烷)，得到淡黄色固体1.3。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.1Hz,2H),6.95(d,J＝9.1Hz,2H),4.10(t,J＝5.8Hz,2H),3.50(t,J＝6.2Hz,2H),2.10–1.99(m,4H).
6)1-(5-溴戊醇基)-4-硝基苯(1-((5-bromopentyl)oxy)-4-nitrobenzene，化合物1.4)的合成
按照化合物1.1)的方法制备(反应物用1,5-二溴戊烷代替1,2-二溴乙烷)，得到淡黄色固体1.4。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.1Hz,2H),6.94(d,J＝9.1Hz,2H),4.07(t,J＝6.2Hz,2H),3.47–3.40(m,2H),1.99–1.83(m,4H),1.69–1.59(m,2H).
7)1-(6-溴己醇基)-4-硝基苯(1-((6-bromohexyl)oxy)-4-nitrobenzene，化合物1.5)的合成
按照化合物1.1)的方法制备(反应物用1,6-二溴己烷代替1,2-二溴乙烷)，得到淡黄色固体1.5。1H NMR(400MHz,CDCl3)δ8.20(d,J＝8.9Hz,2H),6.94(d,J＝8.9Hz,2H),4.06(t,J＝6.2Hz,1H),3.45–3.40(m,2H),1.91–1.85(m,4H),1.54–1.48(m,4H).
8)1-(7-溴庚醇基)-4-硝基苯(1-((7-bromoheptyl)oxy)-4-nitrobenzene，化合物1.6)的合成
按照化合物1.1)的方法制备(反应物用1,7-二溴庚烷代替1,2-二溴乙烷)，得到淡黄色固体1.6。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,2H),8.19(d,J＝9.2Hz,2H),4.05(t,J＝6.4Hz,2H),3.42(t,J＝6.4Hz,2H),1.90–1.80(m,4H),1.49–1.43(m,4H),1.42–1.35(m,2H).
9)1-(8-溴辛醇基)-4-硝基苯(1-((8-bromooctyl)oxy)-4-nitrobenzene，化合物1.7)的合成
按照化合物1.1)的方法制备(反应物用1,8-二溴辛烷代替1,2-二溴乙烷)，得到淡黄色固体1.7。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,2H),6.94(d,J＝9.2Hz,2H),4.05(t,J＝6.5Hz,2H),3.41(t,J＝6.8Hz,2H),1.87–1.79(m,4H),1.49–1.44(m,4H),1.44–1.36(m,4H).
10)1-(10-溴癸醇基)-4-硝基苯(1-((10-bromodecyl)oxy)-4-nitrobenzene，化合物1.9)的合成
按照化合物1.1)的方法制备(反应物用1,10-二溴癸烷代替1,2-二溴乙烷)，得到淡黄色固体1.9。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,2H),6.94(d,J＝9.2Hz,2H),4.05(t,J＝6.5Hz,1H),3.41(t,J＝6.8Hz,1H),1.89–1.78(m,4H),1.48–1.40(m,4H),1.40–1.32(m,8H).
11)1-(12-溴十二醇基)-4-硝基苯(1-((12-bromododecyl)oxy)-4-nitrobenzene，化合物1.11)的合成
按照化合物1.1)的方法制备(反应物用1,12-二溴辛烷代替1,2-二溴乙烷)，得到淡黄色固体1.11。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,2H),6.94(d,J＝9.3Hz,2H),4.04(t,J＝6.5Hz,2H),3.40(t,J＝6.8,2H),1.89–1.78(m,4H),1.50–1.39(m,4H),1.29(s,12H).
12)1-碘-4-(2-(4-硝基苯氧基)乙氧基)苯(1-iodo-4-(2-(4-nitrophenoxy)ethoxy)benzene,化合
物1.12)的合成
将化合物1.1(738.2mg,3.0mmol)、4-碘苯酚(660.1mg,3.0mmol)和K2CO3(1242.8mg,9.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色粉末。1H NMR(400MHz,CDCl3)δ8.23(d,J＝9.0Hz,2H),7.59(d,J＝8.6Hz,2H),7.01(d,J＝9.1Hz,2H),6.73(d,J＝8.7Hz,2H),4.41(s,2H),4.33(s,2H).
13)1-(2-(4-碘苯氧基)乙氧基)-2-硝基苯(1-(2-(4-iodophenoxy)ethoxy)-2-nitrobenzene,化合
物1.12a)的合成
按照化合物1.12)的方法制备(反应物用1.1a代替1.1)，得到淡黄色固体1.12a。1HNMR(400MHz,CDCl3)δ7.84(dd,J＝8.1,1.7Hz,1H),7.57(d,J＝9.0Hz,2H),7.55–7.52(m,1H),7.16(dd,J＝8.4,0.8Hz,1H),7.10–7.06(m,1H),6.73(d,J＝9.0Hz,2H),4.47–4.44(m,2H),4.35–4.33(m,2H).
14)1-(2-(4-碘苯氧基)乙氧基)-3-硝基苯(1-(2-(4-iodophenoxy)ethoxy)-3-nitrobenzene,化合
物1.12b)的合成
按照化合物1.12)的方法制备(反应物用1.1b代替1.1)，得到淡黄色固体1.12b。1HNMR(400MHz,CDCl3)δ7.86(ddd,J＝8.1,2.1,0.8Hz,1H),7.80(t,J＝2.3Hz,1H),7.58(d,J＝9.0Hz,2H),7.45(t,J＝8.2Hz,1H),7.28(ddd,J＝8.5,2.6,0.9Hz,1H),6.73(d,J＝9.0Hz,2H),4.41–4.39(m,2H),4.34–4.32(m,2H).
15)1-碘-2-(2-(4-硝基苯氧基)乙氧基)苯(1-iodo-2-(2-(4-nitrophenoxy)ethoxy)benzene,化合物
1.12c)的合成
按照化合物1.12)的方法制备(反应物用1-碘苯酚代替4-碘苯酚)，得到淡黄色固体1.12c。1H NMR(400MHz,CDCl3)δ8.22(dt,J＝9.28,3.4Hz,2H),7.79(dd,J＝7.8,1.6Hz,1H),7.32(ddd,J＝8.2,7.5,1.6Hz,1H),7.06(dt,J＝9.24,3.4Hz,2H),6.90(dd,J＝8.2,1.3Hz,1H),6.76(td,J＝7.6,1.3Hz,1H),4.53–4.47(m,2H),4.41(dd,J＝5.8,3.7Hz,2H).
16)1-碘-3-(2-(4-硝基苯氧基)乙氧基)苯(1-iodo-3-(2-(4-nitrophenoxy)ethoxy)benzene,化合物
1.12d)的合成
按照化合物1.12)的方法制备(反应物用3-碘苯酚代替4-碘苯酚)，得到淡黄色固体1.12d。1H NMR(400MHz,CDCl3)δ8.23(d,J＝9.3Hz,2H),7.34–7.30(m,2H),7.04–7.00(m,3H),6.93–6.90(m,1H),4.42–4.39(m,1H),4.36–4.33(m,1H).
17)1-氟-4-(2-(4-硝基苯氧基)乙氧基)苯(1-fluoro-4-(2-(4-nitrophenoxy)ethoxy)benzene,化合
物1.12e)的合成
按照化合物1.12)的方法制备(反应物用4-氟苯酚代替4-碘苯酚)，得到淡黄色固体1.12e。1H NMR(400MHz,CDCl3)δ8.23(d,J＝9.3Hz,2H),7.03–6.98(m,4H),6.91–6.87(m,2H),4.42–4.40(m,2H),4.34–4.32(m,2H).
18)1-氯-4-(2-(4-硝基苯氧基)乙氧基)苯(1-chloro-4-(2-(4-nitrophenoxy)ethoxy)benzene,化合
物1.12f)的合成
按照化合物1.12)的方法制备(反应物用4-氯苯酚代替4-碘苯酚)，得到淡黄色固体1.12f。1H NMR(400MHz,CDCl3)δ8.22(d,J＝9.3Hz,2H),7.26(d,J＝9.0Hz,2H),7.02(d,J＝9.3Hz,2H),6.88(d,J＝9.0Hz,2H),4.43–4.39(m,2H),4.36–4.32(m,2H).
19)1-溴-4-(2-(4-硝基苯氧基)乙氧基)苯(1-bromo-4-(2-(4-nitrophenoxy)ethoxy)benzene,化合
物1.12g)的合成
按照化合物1.12)的方法制备(反应物用4-溴苯酚代替4-碘苯酚)，得到淡黄色固体1.12g。1H NMR(400MHz,CDCl3)δ8.22(d,J＝9.0Hz,2H),7.40(d,J＝8.7Hz,2H),7.01(d,J＝9.1Hz,2H),6.83(d,J＝8.6Hz,2H),4.41–4.40(m,2H),4.34–4.33(m,2H).
20)1-碘-4-(3-(4-硝基苯氧基)丙氧基)苯(1-iodo-4-(3-(4-nitrophenoxy)propoxy)benzene,化合
物1.13)的合成
按照化合物1.12)的方法制备(反应物用化合物1.2代替化合物1.1)，得到淡黄色固体1.13。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.2Hz,2H),7.55(d,J＝8.8Hz,2H),6.94(d,J＝9.2Hz,2H),6.67(d,J＝8.8Hz,2H),4.12(d,J＝5.7Hz,2H),4.01(d,J＝5.8Hz,2H),2.32–2.27(m,2H).
21)1-碘-4-(4-(4-硝基苯氧基)丁氧基)苯(1-iodo-4-(4-(4-nitrophenoxy)butoxy)benzene,化合物
1.14)的合成
按照化合物1.12)的方法制备(反应物用化合物1.3代替化合物1.1)，得到淡黄色固体1.14。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.2Hz,2H),7.55(d,J＝8.8Hz,2H),6.94(d,J＝9.2Hz,2H),6.67(d,J＝8.8Hz,2H),4.13(d,J＝5.7Hz,2H),4.01(d,J＝5.8Hz,2H),1.99(s,4H).
22)1-碘-4-(5-(4-硝基苯氧基)戊氧基)苯(1-iodo-4-((5-(4-nitrophenoxy)pentyl)oxy)benzene,化
合物1.15)的合成
按照化合物1.12)的方法制备(反应物用化合物1.4代替化合物1.1)，得到淡黄色固体1.15。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,2H),7.55(d,J＝8.8Hz,2H),6.94(d,J＝9.2Hz,2H),6.67(d,J＝8.8Hz,2H),4.08(d,J＝6.3Hz,2H),3.96(d,J＝6.3Hz,2H),1.94–1.83(m,4H),1.70–1.62(m,2H).
23)1-碘-4-(6-(4-硝基苯氧基)己氧基)苯(1-iodo-4-((6-(4-nitrophenoxy)hexyl)oxy)benzene,化
合物1.16)的合成
按照化合物1.12)的方法制备(反应物用化合物1.5代替化合物1.1)，得到淡黄色固体1.16。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,2H),7.53(d,J＝8.8Hz,2H),6.93(d,J＝9.2Hz,2H),6.66(d,J＝8.8Hz,2H),4.06(t,J＝6.4Hz,1H),3.93(t,J＝6.4Hz,1H),1.87–1.80(m,4H),1.56–1.53(m,4H).
24)1-氟-4-(6-(4-硝基苯氧基)己氧基)苯(1-fluoro-4-((6-(4-nitrophenoxy)hexyl)oxy)benzene,化
合物1.16a)的合成
按照化合物1.12)的方法制备(反应物用化合物4-氟苯酚代替4-碘苯酚)，得到淡黄色固体1.16a。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.3Hz,2H),7.22(d,J＝9.0Hz,2H),6.94(d,J＝9.3Hz,2H),6.81(d,J＝9.0Hz,2H),4.06(t,J＝6.4Hz,2H),3.94(t,J＝6.4Hz,2H),1.88–1.78(m,4H),1.57–1.53(m,4H).
25)1-氯-4-(6-(4-硝基苯氧基)己氧基)苯(1-chloro-4-((6-(4-nitrophenoxy)hexyl)oxy)benzene,化
合物1.16b)的合成
按照化合物1.12)的方法制备(反应物用化合物4-氯苯酚代替4-碘苯酚)，得到淡黄色固体1.16b。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.3Hz,2H),6.98–6.93(m,4H),6.85–6.79(m,2H),4.06(t,J＝6.4Hz,2H),3.93(t,J＝6.4Hz,2H),1.88–1.78(m,4H),1.57–1.54(m,4H).
26)1-溴-4-(6-(4-硝基苯氧基)己氧基)苯(1-bromo-4-((6-(4-nitrophenoxy)hexyl)oxy)benzene,化
合物1.16b)的合成
按照化合物1.12)的方法制备(反应物用化合物4-溴苯酚代替4-碘苯酚)，得到淡黄色固体1.16c。1H NMR(400MHz,CDCl3)δ8.19(dd,J＝9.3,2.2Hz,2H),7.39–7.33(m,2H),6.97–6.91(m,2H),6.77(dd,J＝8.9,2.1Hz,2H),4.06(t,J＝6.4Hz,2H),3.94(t,J＝6.3Hz,2H),1.93–1.77(m,4H),1.56–1.53(m,4H).
27)1-碘-4-(7-(4-硝基苯氧基)庚氧基)苯(1-iodo-4-((7-(4-nitrophenoxy)heptyl)oxy)benzene,化
合物1.17)的合成
按照化合物1.12)的方法制备(反应物用化合物1.6代替化合物1.1)，得到淡黄色固体1.17。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,2H),7.54(d,J＝8.9Hz,2H),6.93(d,J＝9.2Hz,2H),6.66(d,J＝8.8Hz,2H),4.05(t,J＝6.5Hz,1H),3.92(t,J＝6.5Hz,1H),1.87–1.76(m,4H),1.51–1.43(m,6H).
28)1-碘-4-(8-(4-硝基苯氧基)辛氧基)苯(1-iodo-4-((8-(4-nitrophenoxy)octyl)oxy)benzene,化
合物1.18)的合成
按照化合物1.12)的方法制备(反应物用化合物1.7代替化合物1.1)，得到淡黄色固体1.18。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,1H),7.54(d,J＝8.9Hz,1H),6.94(d,J＝9.3Hz,1H),6.67(d,J＝8.9Hz,1H),4.04(t,J＝6.5Hz,1H),3.91(t,J＝6.5Hz,1H),1.86–1.74(m,4H),1.50–1.43(m,4H),1.41–1.38(m,4H).
29)1-碘-4-(10-(4-硝基苯氧基)葵氧基)苯(1-iodo-4-((10-(4-nitrophenoxy)decyl)oxy)benzene,化
合物1.20)的合成
按照化合物1.12)的方法制备(反应物用化合物1.9代替化合物1.1)，得到淡黄色固体1.20。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.2Hz,2H),7.54(d,J＝8.9Hz,2H),6.94(d,J＝9.3Hz,2H),6.67(d,J＝8.9Hz,2H),4.04(t,J＝6.5Hz,2H),3.91(t,J＝6.5Hz,2H),1.89–1.73(m,4H),1.51–1.39(m,4H),1.33(s,8H).
30)1-碘-4-(12-(4-硝基苯氧基)十二烷氧基)苯
(1-iodo-4-((12-(4-nitrophenoxy)dodecyl)oxy)benzene,化合物1.22)的合成
按照化合物1.12)的方法制备(反应物用化合物1.11代替化合物1.1)，得到淡黄色固体1.22。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.3Hz,2H),7.53(d,J＝8.9Hz,2H),6.94(d,J＝9.3Hz,2H),6.67(d,J＝9.0Hz,2H),4.04(t,J＝6.5Hz,2H),3.91(t,J＝6.5Hz,2H),1.87–1.71(m,4H),1.52–1.38(m,4H),1.29(s,12H).
31)4-(2-(4-碘苯氧基)乙氧基)苯胺(4-(2-(4-iodophenoxy)ethoxy)aniline,化合物1.23)的合成
将化合物1.12)(385.2mg,1.0mmol)和二水合二氯亚锡(902.8mg,4.0mmol)溶于适量乙醇中，向溶液中滴加5mL浓盐酸，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，抽滤，除去干燥剂，旋蒸，除去溶剂，即得化合物1.23。1H NMR(400MHz,CDCl3)δ7.56(dd,J＝8.8,2.8Hz,2H),6.79(d,J＝8.9Hz,2H),6.73(d,J＝8.6Hz,2H),6.64(d,J＝8.6Hz,2H),4.24(s,4H),3.44(s,2H).
32)2-(2-(4-碘苯氧基)乙氧基)苯胺(2-(2-(4-iodophenoxy)ethoxy)aniline,化合物1.23a)的合成
按照化合物1.23)的方法制备(反应物用化合物1.12a代替化合物1.12)，得到淡黄色固体1.23a.1H NMR(400MHz,CDCl3)δ7.57(d,J＝9.0Hz,2H),6.83–6.81(m,2H),6.74–6.71(m,4H),4.34–4.28(m,4H),3.79(s,2H).
33)3-(2-(4-碘苯氧基)乙氧基)苯胺(3-(2-(4-iodophenoxy)ethoxy)aniline,化合物1.23b)的合成
按照化合物1.23)的方法制备(反应物用化合物1.12b代替化合物1.12)，得到淡黄色固体1.23b.1H NMR(400MHz,CDCl3)δ7.56(d,J＝9.0Hz,2H),7.07(t,J＝8.0Hz,1H),6.73(d,J＝9.0Hz,2H),6.37–6.30(m,2H),6.28(t,J＝2.2Hz,1H),4.27(s,4H),3.68(s,2H).
34)4-(2-(2-碘苯氧基)乙氧基)苯胺(4-(2-(2-iodophenoxy)ethoxy)aniline,化合物1.23c)的合成
按照化合物1.23)的方法制备(反应物用化合物1.12c代替化合物1.12)，得到淡黄色固体1.23c.1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.8Hz,2H),7.28(m,1H),6.86(m,3H),6.72(m,3H),4.33(s,4H).
35)4-(2-(3-碘苯氧基)乙氧基)苯胺(4-(2-(3-iodophenoxy)ethoxy)aniline,化合物1.23d)的合成
按照化合物1.23)的方法制备(反应物用化合物1.12d代替化合物1.12)，得到淡黄色固体1.23d.1H NMR(400MHz,CDCl3)δ7.30–7.29(m,2H),6.98(t,J＝8.0Hz,1H),6.93–6.90(m,1H),6.79(d,J＝8.9Hz,2H),6.65(d,J＝8.8Hz,2H),4.24(s,4H).
36)4-(2-(4-氟苯氧基)乙氧基)苯胺(4-(2-(4-fluorophenoxy)ethoxy)aniline,化合物1.23e)的合成
按照化合物1.23)的方法制备(反应物用化合物1.12e代替化合物1.12)，得到淡黄色固体1.23e.1H NMR(400MHz,CDCl3)δ6.98(t,J＝8.0Hz,2H),6.90(s,1H),6.80(d,J＝7.7Hz,2H),6.65(d,J＝7.6Hz,2H),4.24(s,4H),3.47(s,2H).
37)4-(2-(4-氯苯氧基)乙氧基)苯胺(4-(2-(4-chlorophenoxy)ethoxy)aniline,化合物1.23f)的合成
按照化合物1.23)的方法制备(反应物用化合物1.12f代替化合物1.12)，得到淡黄色固体1.23f.1H NMR(400MHz,CDCl3)δ7.24(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),6.79(d,J＝8.8Hz,2H),6.65(d,J＝8.8Hz,2H),4.25(s,4H),3.45(s,2H).
38)4-(2-(4-溴苯氧基)乙氧基)苯胺(4-(2-(4-bromophenoxy)ethoxy)aniline,化合物1.23f)的合成
按照化合物1.23)的方法制备(反应物用化合物1.12g代替化合物1.12)，得到淡黄色固体1.23g.1H NMR(400MHz,CDCl3)δ7.30(d,J＝7.5Hz,2H),6.95(d,J＝7.9Hz,2H),6.80(d,J＝8.3Hz,2H),6.64(d,J＝8.4Hz,2H),4.27(s,4H),3.42(s,2H).
39)4-(3-(4-碘苯氧基)丙氧基)苯胺(4-(3-(4-iodophenoxy)propoxy)aniline,化合物1.24)的合成
按照化合物1.23)的方法制备(反应物用化合物1.13代替化合物1.12)，得到淡黄色固体1.24。1H NMR(400MHz,CDCl3)δ7.54(d,J＝9.0Hz,2H),6.76(d,J＝8.9Hz,2H),6.70(d,J＝8.9Hz,2H),6.68(d,J＝8.9Hz,2H),4.11(t,J＝6.2Hz,2H),4.07(t,J＝6.1Hz,2H),2.24–2.18(m,2H).
40)4-(4-(4-碘苯氧基)丁氧基)苯胺(4-(4-(4-iodophenoxy)butoxy)aniline,化合物1.25)的合成
按照化合物1.23)的方法制备(反应物用化合物1.14代替化合物1.12)，得到淡黄色固体1.25。1H NMR(400MHz,CDCl3)δ7.54(dd,J＝8.9,2.2Hz,2H),6.74(d,J＝8.8Hz,2H),6.67(d,J＝8.7Hz,2H),6.64(d,J＝8.7Hz,2H),3.98–3.95(m,4H),3.48(s,2H),1.93–1.84(m,4H).
41)4-(5-(4-碘苯氧基)戊氧基)苯胺(4-((5-(4-iodophenoxy)pentyl)oxy)aniline,化合物1.26)的合成
按照化合物1.23)的方法制备(反应物用化合物1.15代替化合物1.12)，得到淡黄色固体1.26。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.9Hz,2H),6.73(d,J＝8.7Hz,2H),6.66(d,J＝8.9Hz,1H),6.63(d,J＝8.7Hz,2H),3.95–3.89(m,4H),3.41(s,2H),1.88–1.77(m,4H),1.65–1.58(m,2H).
42)4-(6-(4-碘苯氧基)己氧基)苯胺(4-((6-(4-iodophenoxy)hexyl)oxy)aniline,化合物1.27)的合成
按照化合物1.23)的方法制备(反应物用化合物1.16代替化合物1.12)，得到淡黄色固体1.27。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.9Hz,2H),6.73(d,J＝8.7Hz,2H),6.66(d,J＝8.9Hz,1H),6.63(d,J＝8.7Hz,2H),3.93–3.87(m,4H),3.51(s,2H),1.83–1.74(m,4H),1.55–1.49(m,4H).
43)4-(6-(4-氟苯氧基)己氧基)苯胺(4-((6-(4-fluorophenoxy)hexyl)oxy)aniline,化合物1.27a)的合成
按照化合物1.23)的方法制备(反应物用化合物1.16a代替化合物1.12)，得到淡黄色固体1.27a。1H NMR(400MHz,CDCl3)δ6.98–6.94(m,2H),6.85–6.80(m,2H),6.74(d,J＝8.8Hz,2H),6.65(d,J＝8.8Hz,2H),3.93–3.88(m,4H),1.81–1.75(m,4H),1.54–1.50(m,4H).
44)4-(6-(4-氯苯氧基)己氧基)苯胺(4-((6-(4-chlorophenoxy)hexyl)oxy)aniline,化合物1.27b)的合成
按照化合物1.23)的方法制备(反应物用化合物1.16b代替化合物1.12)，得到淡黄色固体1.27b。1H NMR(400MHz,CDCl3)δ6.99–6.93(m,2H),6.85–6.79(m,2H),6.74(d,J＝8.7Hz,2H),6.65(d,J＝8.7Hz,2H),3.93–3.88(m,4H),1.80–1.75(m,4H),1.54–1.50(m,4H).
45)4-(6-(4-溴苯氧基)己氧基)苯胺(4-((6-(4-bromophenoxy)hexyl)oxy)aniline,化合物1.27c)的合成
按照化合物1.23)的方法制备(反应物用化合物1.16c代替化合物1.12)，得到淡黄色固体1.27c。1H NMR(400MHz,CDCl3)δ7.36(d,J＝7.7Hz,1H),7.29(d,J＝1.6Hz,1H),6.90(d,J＝8.2Hz,1H),6.78–6.73(m,3H),6.64(d,J＝8.7Hz,2H),3.98–3.88(m,4H),3.31(s,2H),1.83–1.76(m,4H),1.53–1.50(m,4H).
46)4-(7-(4-碘苯氧基)庚氧基)苯胺(4-((7-(4-iodophenoxy)heptyl)oxy)aniline,化合物1.28)的合成
按照化合物1.23)的方法制备(反应物用化合物1.17代替化合物1.12)，得到淡黄色固体1.28。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.7Hz,2H),6.73(d,J＝8.8Hz,2H),6.66(d,J＝8.8Hz,2H),6.63(d,J＝8.8Hz,2H),3.92–3.86(m,4H),3.40(s,2H),1.77–1.71(m,4H),1.51–1.35(m,6H).
47)4-(8-(4-碘苯氧基)辛氧基)苯胺(4-((8-(4-iodophenoxy)octyl)oxy)aniline,化合物1.29)的合成
按照化合物1.23)的方法制备(反应物用化合物1.18代替化合物1.12)，得到淡黄色固体1.29。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),6.74(d,J＝8.8Hz,2H),6.67(d,J＝8.9Hz,2H),6.64(d,J＝8.8Hz,2H),3.92–3.86(m,4H),3.51(s,2H),1.80–1.70(m,4H),1.48–1.43(m,4H),1.42–1.36(m,4H).
48)4-(10-(4-碘苯氧基)葵氧基)苯胺(4-((10-(4-iodophenoxy)decyl)oxy)aniline,化合物1.31)的合成
按照化合物1.23)的方法制备(反应物用化合物1.20代替化合物1.12)，得到淡黄色固体1.31。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.9Hz,2H),6.74(d,J＝8.8Hz,2H),6.67(d,J＝9.0Hz,2H),6.63(d,J＝8.8Hz,2H),3.92–3.86(m,4H),3.41(s,2H),1.79–1.70(m,4H),1.46–1.40(m,4H),1.32(m,8H).
49)4-(12-(4-碘苯氧基)十二烷氧基)苯胺(4-((12-(4-iodophenoxy)dodecyl)oxy)aniline,化合物1.33)的合成
按照化合物1.23)的方法制备(反应物用化合物1.22代替化合物1.12)，得到淡黄色固体1.33。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.8Hz,2H),6.74(d,J＝8.6Hz,2H),6.67(d,J＝8.9Hz,2H),6.64(d,J＝8.6Hz,2H),3.92–3.86(m,4H),1.79–1.70(m,4H),1.43–1.39(m,4H),1.28(s,12H).
50)4-(2-(4-碘苯氧基)乙氧基)-氮，氮-二甲苯胺(4-(2-(4-iodophenoxy)ethoxy)-N,N-dimethylaniline,化合物1.34)的合成
将化合物1.23(269.6mg,0.7mmol)和多聚甲醛(210.2mg,7.0mmol)溶于适量冰醋酸中，在冰浴条件下，向溶液中缓慢分批加入氰基硼氢化钠(219.9mg,3.5mmol)，室温反应过夜，反应结束后，向溶液中加入氨水调pH至弱碱性，CH2Cl2萃取，MgSO4干燥，柱色谱分离得白色粉末的终产物1.34。1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.9Hz,2H),7.02–6.82(m,4H),6.73(d,J＝8.9Hz,2H),4.26(s,4H),2.91(s,6H).
51)2-(2-(4-碘苯氧基)乙氧基)-氮-甲苯胺(2-(2-(4-iodophenoxy)ethoxy)-N-methylaniline,化合物1.34a)的合成
按照化合物1.34)的方法制备(反应物用化合物1.23a代替化合物1.23)，得到白色固体1.34a。52)3-(2-(4-碘苯氧基)乙氧基)-氮，氮-二甲苯胺(3-(2-(4-iodophenoxy)ethoxy)-N,N-dimethylaniline,化合物1.34b)的合成
按照化合物1.34)的方法制备(反应物用化合物1.23b代替化合物1.23)，得到白色固体1.34b。1H NMR(400MHz,CDCl3)δ7.56(d,J＝9.0Hz,2H),7.16(t,J＝8.0Hz,1H),6.73(d,J＝9.0Hz,2H),6.39(d,J＝6.5Hz,1H),6.33(s,2H),4.33–4.30(m,2H),4.29–4.26(m,2H),2.94(s,6H).
53)4-(2-(2-碘苯氧基)乙氧基)-氮，氮-二甲苯胺(4-(2-(2-iodophenoxy)ethoxy)-N,N-dimethylaniline,化合物1.34c)的合成
按照化合物1.34)的方法制备(反应物用化合物1.23c代替化合物1.23)，得到白色固体1.34c。1H NMR(400MHz,CDCl3)δ7.78(dd,J＝7.8,1.6Hz,1H),7.30(td,J＝8.2,1.6Hz,1H),6.94(d,J＝9.0Hz,2H),6.89(dd,J＝8.2,1.3Hz,1H),6.82–6.69(m,3H),4.34(s,4H),2.89(s,6H).
54)4-(2-(3-碘苯氧基)乙氧基)-氮，氮-二甲苯胺(4-(2-(3-iodophenoxy)ethoxy)-N,N-dimethylaniline,化合物1.34d)的合成
按照化合物1.34)的方法制备(反应物用化合物1.23d代替化合物1.23)，得到白色固体1.34d。1H NMR(400MHz,CDCl3)δ7.31–7.29(m,2H),7.01(t,J＝8.1Hz,1H),6.93–6.89(m,3H),6.75(s,2H),4.26(s,4H),2.89(s,6H).
55)4-(2-(4-氟苯氧基)乙氧基)-氮，氮-二甲苯胺(4-(2-(4-fluorophenoxy)ethoxy)-N,N-dimethylaniline,化合物1.34e)的合成
按照化合物1.34)的方法制备(反应物用化合物1.23e代替化合物1.23)，得到白色固体1.34e。1H NMR(400MHz,CDCl3)δ7.02–6.95(m,2H),6.94–6.86(m,4H),6.77(s,2H),4.26(s,4H),2.90(s,6H).
56)4-(2-(4-氯苯氧基)乙氧基)-氮，氮-二甲苯胺(4-(2-(4-chlorophenoxy)ethoxy)-N,N-dimethylaniline,化合物1.34f)的合成
按照化合物1.34)的方法制备(反应物用化合物1.23f代替化合物1.23)，得到白色固体1.34f。1H NMR(400MHz,CDCl3)δ7.24(d,J＝9.0Hz,2H),6.91–6.86(m,4H),6.76(s,2H),4.26(s,4H),2.89(s,6H).
57)4-(2-(4-溴苯氧基)乙氧基)-氮，氮-二甲苯胺(4-(2-(4-bromophenoxy)ethoxy)-N,N-dimethylaniline(化合物1.34g)的合成
按照化合物1.34)的方法制备(反应物用化合物1.23g代替化合物1.23)，得到白色固体1.34g。1H NMR(400MHz,CDCl3)δ7.31–7.27(m,2H),6.98–6.90(m,6H),4.29(s,4H),2.90(s,6H).
58)4-(3-(4-碘苯氧基)丙氧基)-氮，氮-二甲苯胺(4-(3-(4-iodophenoxy)propoxy)-N,N-dimethylaniline(化合物1.35)的合成
按照化合物1.34)的方法制备(反应物用化合物1.24代替化合物1.23)，得到白色固体1.35。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),6.85(d,J＝8.7Hz,2H),6.75(s,2H),6.69(d,J＝8.9Hz,2H),4.13–4.08(m,4H),2.88(s,6H),2.26–2.17(m,2H).
59)4-(4-(4-碘苯氧基)丁氧基)-氮，氮-二甲苯胺(4-(4-(4-iodophenoxy)butoxy)-N,N-dimethylaniline,化合物1.36)的合成
按照化合物1.34)的方法制备(反应物用化合物1.25代替化合物1.23)，得到白色固体1.36。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),6.84(d,J＝8.5Hz,2H),6.78(s,2H),6.67(d,J＝8.9Hz,2H),4.00–3.96(m,4H),2.89(s,6H),1.97–1.90(m,4H).
60)4-(5-(4-碘苯氧基)戊氧基)-氮，氮-二甲苯胺(4-((5-(4-iodophenoxy)pentyl)oxy)-N,N-dimethylaniline,化合物1.37)的合成
按照化合物1.34)的方法制备(反应物用化合物1.26代替化合物1.23)，得到白色固体1.37。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),6.84(d,J＝8.5Hz,2H),6.76(s,2H),6.67(d,J＝8.9Hz,2H),3.96–3.92(m,4H),2.88(s,6H),1.86–1.79(m,4H),1.66–1.60(m,2H).
61)4-(6-(4-碘苯氧基)己氧基)-氮，氮-二甲苯胺(4-((6-(4-iodophenoxy)hexyl)oxy)-N,N-dimethylaniline,化合物1.38)的合成
按照化合物1.34)的方法制备(反应物用化合物1.27代替化合物1.23)，得到白色固体1.38。1H NMR(400MHz,CDCl3)δ7.53(d,J＝9.0Hz,2H),6.83(d,J＝9.0Hz,2H),6.75(s,2H),6.66(d,J＝8.9Hz,2H),3.94–3.90(m,4H),2.87(s,6H),1.81–1.74(m,4H),1.53–1.50(m,4H).
62)4-(6-(4-氟苯氧基)己氧基)-氮，氮-二甲苯胺(4-((6-(4-fluorophenoxy)hexyl)oxy)-N,N-dimethylaniline,化合物1.38a)的合成
按照化合物1.34)的方法制备(反应物用化合物1.27a代替化合物1.23)，得到白色固体1.38a。1H NMR(400MHz,CDCl3)δ6.98–6.94(m,2H),6.85–6.77(m,6H),3.92(t,J＝6.5Hz,4H),2.87(s,6H),1.80–1.75(m,4H),1.56–1.49(m,4H).
63)4-(6-(4-氯苯氧基)己氧基)-氮，氮-二甲苯胺(4-((6-(4-chlorophenoxy)hexyl)oxy)-N,N-dimethylaniline,化合物1.38b)的合成
按照化合物1.34)的方法制备(反应物用化合物1.27b代替化合物1.23)，得到白色固体1.38b。1H NMR(400MHz,CDCl3)δ7.22(d,J＝8.9Hz,2H),6.85–6.79(m,4H),6.77–6.70(m,2H),3.94–3.90(m,4H),2.87(s,6H),1.82–1.74(m,4H),1.54–1.50(m,4H).
64)4-(6-(4-溴苯氧基)己氧基)-氮，氮-二甲苯胺(4-((6-(4-bromophenoxy)hexyl)oxy)-N,N-dimethylaniline(化合物1.38c)的合成
按照化合物1.34)的方法制备(反应物用化合物1.27c代替化合物1.23)，得到白色固体1.38c。1H NMR(400MHz,CDCl3)δ7.35(d,J＝9.0Hz,1H),7.29–7.27(m,1H),6.94–6.83(m,4H),6.77(d,J＝9.0Hz,2H),3.98–8.91(m,4H),2.88(s,6H),1.81–1.78(m,4H),1.55–1.50(m,4H).
65)4-(7-(4-碘苯氧基)庚氧基)-氮，氮-二甲苯胺(4-((7-(4-iodophenoxy)heptyl)oxy)-N,N-dimethylaniline,化合物1.39)的合成
按照化合物1.34)的方法制备(反应物用化合物1.28代替化合物1.23)，得到白色固体1.39。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.9Hz,2H),6.83(d,J＝8.8Hz,2H),6.75(s,2H),6.66(d,J＝8.9Hz,2H),3.93–3.89(m,4H),2.87(s,6H),1.79–1.74(m,4H),1.49–1.41(m,6H).
66)4-(8-(4-碘苯氧基)辛氧基)-氮，氮-二甲苯胺(4-((8-(4-iodophenoxy)octyl)oxy)-N,N-dimethylaniline,化合物1.40)的合成
按照化合物1.34)的方法制备(反应物用化合物1.29代替化合物1.23)，得到白色固体1.40。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.9Hz,2H),6.84(d,J＝8.2Hz,2H),6.76(s,2H),6.66(d,J＝8.9Hz,2H),3.91(t,J＝6.5Hz,4H),2.89(s,6H),1.80–1.72(m,4H),1.47–1.43(m,4H),1.39–1.37(m,4H).
67)4-(10-(4-碘苯氧基)葵氧基)-氮，氮-二甲苯胺(4-((10-(4-iodophenoxy)decyl)oxy)-N,N-dimethylaniline,化合物1.42)的合成
按照化合物1.34)的方法制备(反应物用化合物1.31代替化合物1.23)，得到白色固体1.42。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.9Hz,2H),6.84(d,J＝8.9Hz,2H),6.78(s,2H),6.67(d,J＝8.9Hz,2H),3.92–3.88(m,4H),2.87(s,6H),1.79–1.71(m,4H),1.45–1.40(m,4H),,1.32(s,8H).
68)4-(12-(4-碘苯氧基)十二烷氧基)-氮，氮-二甲苯胺(4-((12-(4-iodophenoxy)dodecyl)oxy)-N,N-dimethylaniline,化合物1.44)的合成
按照化合物1.34)的方法制备(反应物用化合物1.33代替化合物1.23)，得到白色固体1.44。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.9Hz,2H),6.84(d,J＝9.1Hz,2H),6.75(d,J＝8.0Hz,2H),6.67(d,J＝8.9Hz,2H),3.92–3.88(m,4H),2.86(s,6H),1.78–1.71(m,4H),1.45–1.38(m,4H),1.35–1.28(m,12H).
69)氮，氮-二甲基-4-(2-(4-(三叔丁基锡)苯氧基)乙氧基)苯胺(N,N-dimethyl-4-(2-(4-(tributylstannyl)phenoxy)ethoxy)aniline,化合物1.45)的合成
将化合物1.34(93.8mg,0.24mmol)、六正丁基二锡(417.7mg,0.72mmol)和四(三苯基磷)钯(23.1mg,0.02mmol)溶于10mL甲苯中(含1mL三乙胺)，回流搅拌反应过夜。减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝15/1)得无色油状化合物1.45(67.5mg,51.5％)。1H NMR(400MHz,CDCl3)δ7.36(d,J＝8.4Hz,2H),6.94(d,J＝8.5Hz,2H),6.90(d,J＝9.1Hz,2H),6.77(d,J＝8.7Hz,2H),4.28(t,J＝2.7Hz,4H),2.88(s,6H),1.57–1.50(m,6H),1.37–1.30(m,12H),0.88(t,J＝7.3Hz,9H).
70)氮，氮-二甲基-4-(6-(4-(三叔丁基锡)苯氧基)乙氧基)苯胺(N,N-dimethyl-4-((6-(4-(tributylstannyl)phenoxy)hexyl)oxy)aniline,化合物1.46)的合成按照化合物1.45)的方法制备(反应物用化合物1.38代替化合物1.34)，得到无色油状化合物1.46。1HNMR(400MHz,CDCl3)δ7.35(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),6.84(d,J＝9.0Hz,2H),7.76–7.74(m,2H),3.96(t,J＝6.5Hz,2H),3.91(t,J＝6.5Hz,2H),2.87(s,6H),1.84–1.76(m,4H),1.56–1.49(m,10H),1.37–1.28(m,6H),1.06–0.98(m,6H),0.88(t,J＝7.3Hz,9H).
71)1-(2-溴乙氧基)-4-碘苯(1-(2-bromoethoxy)-4-iodobenzene,化合物2.1)的合成
将对碘苯酚(5000.0mg,22.7mmol)、1,2-二溴乙烷(12800.0mg,68.2mmol)和K2CO3(4700.0mg,34.1mmol)溶于适量丙酮中，90℃回流反应24h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得白色粉末2.1。1H NMR(400MHz,CDCl3)δ7.57(d,J＝9.0Hz,2H),6.69(d,J＝9.0Hz,2H),4.26(t,J＝6.2Hz,2H),3.62(t,J＝6.2Hz,2H).
72)1-(6-溴乙氧基)-4-碘苯(1-((6-bromohexyl)oxy)-4-iodobenzene,化合物2.2)的合成
按照化合物2.1)的方法制备(反应物用1,6-二溴己烷代替1,2-二溴乙烷)，得到白色固体化合物2.2。1H NMR(400MHz,CDCl3)δ7.53(d,J＝9.0Hz,2H),6.67(d,J＝9.0Hz,2H),3.91(t,J＝6.6Hz,2H),1.79–1.72(m,2H),1.48–1.40(m,2H),1.37–1.29(m,4H),0.90(t,J＝7.0Hz,2H).
73)1-碘-4-(2-(4-甲氧基苯氧基)乙氧基)苯(1-iodo-4-(2-(4-methoxyphenoxy)ethoxy)benzene,化合物2.3a)的合成
将化合物2.1(738.2mg,3.0mmol)、4-甲氧基苯酚(660.1mg,3.0mmol)和K2CO3(1242.8mg,9.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，重结晶得白色晶体2.3a。1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.9Hz,2H),6.90–6.83(m,4H),6.73(d,J＝8.9Hz,2H),4.26(s,4H),3.78(s,3H).
74)1-碘-4-(6-(4-甲氧基苯氧基)己氧基)苯(1-iodo-4-((6-(4-methoxyphenoxy)hexyl)oxy)benzene,
化合物2.3b)的合成
按照化合物2.3a)的方法制备(反应物用化合物2.2代替化合物2.1)，得到白色固体化合物2.3b。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),6.83(s,4H),6.67(d,J＝8.9Hz,2H),3.92(t,J＝6.4,4H),3.77(s,3H),1.83–1.76(m,4H),1.54–1.50(m,4H).
75)1-氟-4-(2-(4-碘苯氧基)乙氧基)苯(1-fluoro-4-(2-(4-iodophenoxy)ethoxy)benzene,化合物2.4a)的合成
按照化合物2.3a)的方法制备(反应物用4-氟苯酚代替4-甲氧基苯酚)，得到白色固体化合物2.4a。1H NMR(400MHz,CDCl3)δ7.57(d,J＝9.0Hz,2H),6.98–6.95(m,2H),6.91–6.87(m,2H),6.73(d,J＝9.0Hz,2H),4.27(s,4H).
76)1-氟-4-(6-(4-碘苯氧基)乙氧基)苯(1-fluoro-4-((6-(4-iodophenoxy)hexyl)oxy)benzene(化合物2.4b)的合成
按照化合物2.3a)的方法制备(反应物用4-氟苯酚代替4-甲氧基苯酚，化合物2.2代替化合物2.1)，得到白色固体化合物2.4b。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),6.98–6.94(m,2H),6.83–6.80(m,1H),6.67(d,J＝8.9Hz,2H),3.93(t,J＝6.4,2H),3.92(t,J＝6.4,2H),1.81–1.79(m,2H),1.54–1.51(m,2H).
77)1-氯-4-(2-(4-碘苯氧基)乙氧基)苯(1-chloro-4-(2-(4-iodophenoxy)ethoxy)benzene,化合物2.5a)的合成
按照化合物2.3a)的方法制备(反应物用化合物4-氯苯酚代替化合物4-甲氧基苯酚)，得到白色固体化合物2.5a。1H NMR(400MHz,CDCl3)δ7.57(d,J＝9.0Hz,2H),7.25(d,J＝9.0Hz,2H),6.87(d,J＝9.0Hz,2H),6.73(d,J＝9.0Hz,2H),4.28(s,4H).
78)1-氯-4-(6-(4-碘苯氧基)乙氧基)苯(1-chloro-4-((6-(4-iodophenoxy)hexyl)oxy)benzene,化合物2.5b)的合成
按照化合物2.3a)的方法制备(反应物用4-氯苯酚代替4-甲氧基苯酚，化合物2.2代替化合物2.1)，得到白色固体化合物2.5b。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),7.22(d,J＝9.0Hz,2H),6.81(d,J＝9.0Hz,2H),6.67(d,J＝8.9Hz,2H),3.93(t,J＝6.4,2H),3.92(t,J＝6.4,2H),1.82–1.77(m,4H),1.54–1.50(m,4H).
79)1-溴-4-(2-(4-碘苯氧基)乙氧基)苯(1-bromo-4-(2-(4-iodophenoxy)ethoxy)benzene,化合物2.6a)的合成
按照化合物2.3a)的方法制备(反应物用4-溴苯酚代替4-甲氧基苯酚)，得到白色固体化合物2.6a。1H NMR(400MHz,CDCl3)δ7.57(d,J＝9.0Hz,1H),7.39(d,J＝9.0Hz,1H),6.82(d,J＝9.1Hz,1H),6.72(d,J＝9.0Hz,1H),4.27(s,2H).
80)1-溴-4-(6-(4-碘苯氧基)乙氧基)苯(1-bromo-4-((6-(4-iodophenoxy)hexyl)oxy)benzene,化合物2.6b)的合成
按照化合物2.3a)的方法制备(反应物用4-溴苯酚代替4-甲氧基苯酚，化合物2.2代替化合物2.1)，得到白色固体化合物2.6b。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),7.36(d,J＝9.0Hz,2H),6.76(d,J＝9.0Hz,2H),6.66(d,J＝8.9Hz,2H),3.92(t,J＝6.4Hz,4H),1.83–1.77(m,4H),1.54–1.50(m,4H).
81)1,2-二(4-碘苯氧基)乙烷(1,2-bis(4-iodophenoxy)ethane,化合物2.7a)的合成
按照化合物2.3a)的方法制备(反应物用4-碘苯酚代替4-甲氧基苯酚)，得到白色固体化合物2.7a。1H NMR(400MHz,CDCl3)δ7.57(d,J＝9.0Hz,4H),6.72(d,J＝9.0Hz,4H),4.27(s,4H).
82)1,6-二(4-碘苯氧基)己烷(1,6-bis(4-iodophenoxy)hexane,化合物2.7b)的合成
按照化合物2.3a)的方法制备(反应物用4-溴苯酚代替4-甲氧基苯酚，化合物2.2代替化合物2.1)，得到白色固体化合物2.6b。1H NMR(400MHz,CDCl3)δ7.54(d,J＝9.0Hz,2H),6.66(d,J＝8.9Hz,2H),3.92(t,J＝6.4Hz,4H),1.81–1.77(m,4H),1.53–1.50(m,4H).
83)1-叔丁基-4-(2-(4-碘苯氧基)乙氧基)苯(1-(tert-butyl)-4-(2-(4-iodophenoxy)ethoxy)benzene,化合物2.8a)的合成
按照化合物2.3a)的方法制备(反应物用4-叔丁基苯酚代替4-甲氧基苯酚)，得到白色固体化合物2.8a。1H NMR(400MHz,CDCl3)δ7.56(d,J＝9.0Hz,2H),7.31(d,J＝8.9Hz,2H),6.88(d,J＝8.9Hz,2H),6.73(d,J＝9.0Hz,2H),4.31–4.26(m,4H),1.30(s,9H).
84)1-叔丁基-4-(6-(4-碘苯氧基)己氧基)苯(1-(tert-butyl)-4-((6-(4-iodophenoxy)hexyl)oxy)benzene,化合物2.8b)的合成
按照化合物2.3a)的方法制备(反应物用4-叔丁基苯酚代替4-甲氧基苯酚，化合物2.2代替化合物2.1)，得到白色固体化合物2.6b。1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.9Hz,2H),7.29(d,J＝8.8Hz,2H),6.83(d,J＝8.8Hz,2H),6.67(d,J＝8.9Hz,2H),3.95(t,J＝6.4Hz,2H),3.92(t,J＝6.4Hz,2H),1.83–1.77(m,4H),1.54–1.51(m,4H),1.30(s,9H).
实施例2：碘代化合物(Ⅱ)的合成
合成反应路线如图3所示，本实施例中的化合物编号均与该图反应路线中的编号统一。
在图3所示的合成路线中，试剂与条件如下：(a)(n＝1-4)，K2CO3,DMF,90℃；(b)TsCl,Et3N,CH2Cl2,0℃–室温；(c)4-碘苯酚，K2CO3,DMF,90℃；(d)SnCl2·2H2O,EtOH,HCl,回流；(e)(CH2O)n,NaBH3CN,HAc,室温(f)(Bu3Sn)2,(PPh3)4Pd,甲苯,Et3N,回流；(g)[125I]NaI,HCl(1M),H2O2(3％)。
1)2-(2-(4-硝基苯氧基)乙氧基)乙醇(2-(2-(4-nitrophenoxy)ethoxy)ethan-1-ol,化合物3.1)
的合成
将对硝基苯酚(1396.0mg,10.0mmol)、2-氯乙氧基乙醇(1246.2mg,10.0mmol)和K2CO3(4142.8mg,30.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色蜡状固体3.1。1H NMR(400MHz,CDCl3)δ8.21(d,J＝9.2Hz,2H),6.99(d,J＝9.2Hz,2H),4.25–4.23(m,2H),3.92–3.90(m,2H),3.79–3.78(m,2H),3.70–3.68(m,2H),1.96(s,1H).
2)2-(2-(2-(4-硝基苯氧基)乙氧基)乙氧基)乙醇
(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethan-1-ol,化合物3.2)的合成
按照化合物3.1)的方法制备(反应物用2-(2-(2-氯乙氧基)乙氧基乙醇代替2-氯乙氧基乙醇)，得到淡黄色蜡状固体3.2。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.1Hz,2H),6.99(d,J＝9.2Hz,2H),4.27–4.19(m,2H),3.95–3.87(m,2H),3.79–3.67(m,6H),3.66–3.59(m,2H),2.46(s,1H).
3)2-(2-(4-硝基苯氧基)乙氧基)乙基-4-甲苯磺酸盐2-(2-(4-nitrophenoxy)ethoxy)ethyl
4-methylbenzenesulfonate,化合物3.5)的合成
将3.1(1136.5mg,5.0mmol)和对甲苯磺酰氯(1143.8mg,6.0mmol)溶于适量的无水二氯甲烷中，再向溶液中滴加5mL的三乙胺，室温反应6h，旋蒸，除掉溶剂，柱色谱分离得淡黄色粉末3.5。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.3Hz,2H),7.79(d,J＝8.3Hz,2H),7.32(d,J＝8.0Hz,2H),6.96(d,J＝9.3Hz,2H),4.21–4.15(m,2H),3.86–3.83(m,2H),3.79–3.76(m,2H),3.67–3.63(m,2H),2.43(s,3H).
4)2-(2-(2-(4-硝基苯氧基)乙氧基)乙氧基)乙基-4-甲苯磺酸盐(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate,化合物3.6)的合成
按照化合物3.5)的方法制备(反应物用化合物3.2代替化合物3.1)，得到淡黄色粉末3.6。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.3Hz,2H),7.80(d,J＝8.3Hz,2H),7.34(d,J＝8.0Hz,2H),6.98(d,J＝9.3Hz,2H),4.23–4.20(m,2H),4.17–4.15(m,2H),3.89–3.87(m,2H),3.69–3.67(m,4H),3.64–3.62(m,2H),2.44(s,3H).
5)1-碘-4-(2-(2-(4-硝基苯氧基)乙氧基)乙氧基)苯(1-iodo-4-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)benzene,化合物3.9)的合成
将化合物3.5(1144.2mg,3.0mmol)、4-碘苯酚(660.1mg,3.0mmol)和K2CO3(1242.8mg,9.0mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色粉末粉末3.9。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.3Hz,2H),7.54(d,J＝9.0Hz,2H),6.97(d,J＝9.3Hz,2H),6.69(d,J＝9.0Hz,2H),4.25–4.23(m,2H),4.13–4.11(m,2H),3.97–3.94(m,2H),3.93–3.91(m,2H).
6)1-碘-4-(2-(2-(2-(4-硝基苯氧基)乙氧基)乙氧基)乙氧基)苯1-iodo-4-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)benzene,化合物3.10)的合成
按照化合物3.9)的方法制备(反应物用化合物3.6代替化合物3.5)，得到淡黄色粉末3.10。1H NMR(400MHz,CDCl3)δ8.19(d,J＝9.3Hz,2H),7.53(d,J＝9.0Hz,2H),6.96(d,J＝9.3Hz,2H),6.68(d,J＝9.0Hz,2H),4.21–4.19(m,2H),4.10–4.08(m,2H),3.90–3.88(m,2H),3.86–3.83(m,2H),3.74(s,4H).
7)4-(2-(2-(4-碘苯氧基)乙氧基)乙氧基)苯胺(4-(2-(2-(4-iodophenoxy)ethoxy)ethoxy)aniline,化合物3.13)的合成
将化合物3.9(429.2mg,1.0mmol)和二水合二氯亚锡(902.8mg,4.0mmol)溶于适量乙醇中，向溶液中滴加5mL浓盐酸，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，抽滤，除去干燥剂，旋蒸，除去溶剂，即得白色油状物3.13。1H NMR(400MHz,CDCl3)δ7.54(d,J＝9.0Hz,2H),6.76(d,J＝8.8Hz,2H),6.70(d,J＝9.0Hz,2H),6.63(d,J＝8.8Hz,2H),4.12–4.06(m,4H),3.93–3.85(m,4H).
8)4-(2-(2-(2-(4-碘苯氧基)乙氧基)乙氧基)乙氧基)苯胺(4-(2-(2-(2-(4-iodophenoxy)ethoxy)ethoxy)ethoxy)aniline,化合物3.14)的合成
按照化合物3.13)的方法制备(反应物用化合物3.10代替化合物3.9)，得到白色油状物3.14。1H NMR(400MHz,CDCl3)δ7.53(d,J＝9.0Hz,2H),6.75(d,J＝8.8Hz,2H),6.69(d,J＝9.0Hz,2H),6.62(d,J＝8.8Hz,2H),4.09–4.03(m,4H),3.85–3.82(m,4H),3.74(s,4H),3.41(s,2H).
9)4-(2-(2-(4-碘苯氧基)乙氧基)乙氧基)-氮，氮-二甲苯胺4-(2-(2-(4-iodophenoxy)ethoxy)ethoxy)-N,N-dimethylaniline,化合物3.17)的合成
将化合物3.13(360.0mg,0.9mmol)和多聚甲醛(270.9mg,9.0mmol)溶于适量冰醋酸中，冰浴下，向溶液中缓慢分批加入氰基硼氢化钠(282.9mg,4.5mmol)，室温反应过夜，反应结束后，向溶液中加入氨水调pH至弱碱性，CH2Cl2萃取，MgSO4干燥，柱色谱分离得白色粉末的终产物3.17。1H NMR(400MHz,CDCl3)δ7.54(d,J＝9.0Hz,2H),6.86(d,J＝9.1Hz,2H),6.76–6.68(m,4H),4.12–4.09(m,4H),3.90–3.87(m,4H),2.87(s,6H).
10)4-(2-(2-(2-(4-碘苯氧基)乙氧基)乙氧基)乙氧基)-氮，氮-二甲苯胺(4-(2-(2-(2-(4-iodophenoxy)ethoxy)ethoxy)ethoxy)-N,N-dimethylaniline,化合物3.18)的合成
按照化合物3.17)的方法制备(反应物用化合物3.14代替化合物3.13)，得到白色粉末3.18。1H NMR(400MHz,CDCl3)δ7.53(d,J＝9.0Hz,2H),6.85(d,J＝9.1Hz,2H),6.75–6.65(m,4H),4.09–4.06(m,4H),3.86–3.81(m,4H),3.74(s,4H),2.87(s,6H).
11)氮，氮-二甲基-4-(2-(2-(4-(三叔丁基锡)苯氧基)乙氧基)乙氧基)苯胺(N,N-dimethyl-4-(2-(2-(4-(tributylstannyl)phenoxy)ethoxy)ethoxy)aniline,化合物3.21)的合成
按照化合物1.45)的方法制备(反应物用化合物3.17代替化合物1.34)，得到无色油状化合物3.21。1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,2H),6.88(d,J＝9.1Hz,2H),6.80(d,J＝7.1Hz,2H),4.18–4.14(m,2H),4.13–4.09(m,2H),3.94–3.87(m,4H),2.88(s,6H),4.18–4.14(m,6H),4.18–4.14(m,12H),0.88(t,J＝7.3Hz,9H).
实施例3：碘代化合物(III)的合成
合成反应路线如图4所示，本实施例中的化合物编号均与该图反应路线中的编号统一。
在图3所示的合成路线中，试剂与条件如下：(a)溴化氢溶液(40％)，哌嗪,1-(n-溴R烷氧基)-4-硝基苯，乙醇,90℃；(b)4-碘苯酚，K2CO3,DMF,90℃；(c)SnCl2·2H2O,EtOH,HCl,回流；(d)(CH2O)n,NaBH3CN,HAc,室温。
1)1-(2-(4-硝基苯氧基)乙基)哌嗪(1-(2-(4-nitrophenoxy)ethyl)piperazine,化合物4.2)的合成
取3mL溴化氢溶液(40％)加入溶有哌嗪(516.8mg,6.0mmol)的乙醇溶液中，然后将溶有化合物1-(2-溴乙氧基)-4-硝基苯(738.2mg,3.0mmol)的乙醇溶液加入上述溶液中，90℃回流反应48h，反应结束后，旋蒸，除去溶剂，加水酸化(10％HCl,pH＝5-6)，CH2Cl2洗涤，收集水相，碱化(50％NaOH,pH>9),CH2Cl2萃取，得到黄色固体4.2。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.3Hz,2H),6.97(d,J＝9.3Hz,2H),4.20(t,J＝5.8Hz,2H),2.97–2.93(m,4H),2.84(t,J＝5.8Hz,2H),2.59(s,4H),2.45(s,1H).
2)1-(6-(4-硝基苯氧基)己基)哌嗪(1-(6-(4-nitrophenoxy)hexyl)piperazine,化合物4.6)的合成
按照化合物4.2)的方法制备(反应物用1-(6-溴己氧基)-4-硝基苯代替1-(2-溴乙氧基)-4-硝基苯)，得到黄色固体4.6。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.2Hz,2H),6.94(d,J＝9.2Hz,2H),5.75(s,1H),4.05(t,J＝6.4Hz,2H),3.12–3.10(m,4H),2.66–2.64(m,4H),2.43–2.39(m,2H),1.86–1.79(m,2H),1.57–1.46(m,4H),1.42–1.34(m,2H).
3)1-(2-(4-碘苯氧基)乙基)-4-(2-(4-硝基苯氧基)乙基)哌嗪
(1-(2-(4-iodophenoxy)ethyl)-4-(2-(4-nitrophenoxy)ethyl)piperazine,化合物4.8)的合成
将化合物4.2(152.9mg,0.6mmol)、1-(2-溴乙氧基)-4-碘苯(199.0mg,0.6mmol)和K2CO3(248.8mg,1.8mmol)溶于适量DMF中，90℃回流反应4h,反应结束后，旋蒸，除去溶剂，CH2Cl2萃取，MgSO4干燥，柱色谱分离得淡黄色粉末4.8。1H NMR(400MHz,CDCl3)δ8.21(d,J＝9.2Hz,2H),7.56(d,J＝8.9Hz,2H),6.96(d,J＝9.2Hz,2H),6.70(d,J＝9.0Hz,2H),4.44–4.41(m,2H),4.19–4.14(m,4H),3.50(s,4H),2.85(s,2H),2.53(s,4H).
4)1-(6-(4-碘苯氧基)己基)-4-(6-(4-硝基苯氧基)己基)哌嗪(1-(6-(4-iodophenoxy)hexyl)-4-(2-(4-nitrophenoxy)hexyl)piperazine,化合物4.12)的合成
按照化合物4.8)的方法制备(反应物用化合物4.3代替4.2，1-(6-溴己氧基)-4-碘苯代替1-(2-溴乙氧基)-4-碘苯)，得到黄色固体4.12。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.3Hz,2H),7.54(d,J＝9.0Hz,2H),6.93(d,J＝9.3Hz,2H),6.66(d,J＝9.0Hz,2H),4.04(t,J＝6.4Hz,2H),3.91(t,J＝6.4Hz,2H),2.57(s,8H),2.51(s,4H),1.86–1.80(m,2H),1.79–1.73(m,2H),1.69–1.56(m,4H),1.54–1.43(m,4H),1.40–1.33(m,4H).
5)4-(2-(4-(2-(4-碘苯氧基)乙基)哌嗪-1-基)乙氧基)苯胺(4-(2-(4-(2-(4-iodophenoxy)ethyl)piperazin-1-yl)ethoxy)aniline,化合物4.14)的合成
按照化合物3.13)的方法制备(反应物用化合物4.8代替3.9)，得到黄色固体4.14。1H NMR(400MHz,CDCl3)δ7.56(d,J＝9.0Hz,2H),6.73(d,J＝8.8Hz,2H),6.69(d,J＝8.9Hz,0H),6.63(d,J＝8.9Hz,2H),4.44–4.42(m,2H),4.25–4.11(m,4H),3.79–3.56(m,4H),3.11–2.64(m,6H).
6)4-(6-(4-(6-(4-碘苯氧基)己基)哌嗪-1-基)己氧基)苯胺4-((6-(4-(6-(4-iodophenoxy)hexyl)piperazin-1-yl)hexyl)oxy)aniline,化合物4.18)的合成
按照化合物3.13)的方法制备(反应物用化合物4.12代替3.9)，得到黄色固体4.14。1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.7Hz,2H),6.73(d,J＝8.7Hz,2H),6.67–6.62(m,4H),3.92–3.5(m,4H),3.41(s,2H),2.51(s,8H),2.36–2.32(m,4H),1.80–1.70(m,4H),1.57–1.42(m,8H),1.39–1.34(m,4H).
7)4-(2-(4-(2-(4-碘苯氧基)乙基)哌嗪-1-基)乙氧基)-氮，氮-二甲苯胺(4-(2-(4-(2-(4-iodophenoxy)ethyl)piperazin-1-yl)ethoxy)-N,N-dimethylaniline,化合物4.20)的合成
按照化合物3.17)的方法制备(反应物用化合物4.14代替3.13)，得到黄色固体4.20。1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.9Hz,2H),6.84(d,J＝9.1Hz,2H),6.79–6.74(m,2H),6.70(d,J＝8.9Hz,2H),4.44–4.41(m,2H),4.16–4.10(m,4H),3.58(s,4H),2.87(s,8H),2.62(s,4H).
8)4-(6-(4-(6-(4-碘苯氧基)己基)哌嗪-1-基)己氧基)-氮，氮-二甲苯胺(4-((6-(4-(6-(4-iodophenoxy)hexyl)piperazin-1-yl)hexyl)oxy)-N,N-dimethylaniline,化合物4.24)的合成
按照化合物3.17)的方法制备(反应物用化合物4.18代替3.13)，得到黄色固体4.24。1H NMR(400MHz,CDCl3)δ7.53(d,J＝9.0Hz,2H),6.83(d,J＝9.2Hz,2H),6.73(d,J＝9.2Hz,2H),6.66(d,J＝9.0Hz,2H),3.92–3.88(m,4H),2.86(s,6H),2.53(s,8H),2.42–2.32(s,4H),1.80–1.71(m,4H),1.57–1.50(m,4H),1.48–1.43(m,4H),1.39–1.32(m,4H).
实施例4：125I标记配体的制备
一、实验步骤
化合物[125I]1.34、[125I]1.38和[125I]3.17的制备
合成反应路线见图1，称取0.1mg各相应锡前体(分别为化合物1.45、1.46和3.21)于玻璃反应瓶中，加入100μL乙醇溶解，再依次加入1μL[125]NaI溶液(200μCi，2200Ci/mmol)，100μL 1M盐酸和50μL H2O2水溶液(3％)。密闭后室温下反应15min，加入20μL饱和亚硫酸氢钠溶液终止反应，适量NaHCO3调节至中性。反应液经HPLC分离，[125I]1.34的分离条件：Venusil MP C18反向柱(5μm,4.6×250mm)；CH3CN:H2O＝85％:15％；流速1.0mL/min。[125I]1.38的分离条件为：Venusil MP C18反向柱(5μm,4.6×250mm)；CH3CN:H2O＝80％:20％；流速1.0mL/min。[125I]3.17的分离条件为：Venusil MP C18反向柱(5μm,4.6×250mm)；CH3CN:H2O＝70％:30％；流速1.0mL/min。并通过HPLC分析125I标记配体与参比化合物的保留时间。所得125I标记配体置于-20℃下储存待用。
二、实验结果
125I标记配体由经典的锡卤交换法制备。[125I]1.34、[125I]1.38和[125I]3.17的标记率依次为95.9％、98.1％和98.1％。经HPLC分离纯化后，放射性化学纯度都大于95％，且与稳定碘代配体的保留时间一致(表1)。
表1 125I标记配体及其稳定配体的保留时间和纯度
实验例1：生物评价
一、化合物1.34～1.44，2.3a～2.8b，3.17，3.18，4.20，4.24，IMPY与Aβ1-42聚集体体外竞争结合实验(Ki测定)
使一定浓度的Aβ1-42聚集体蛋白与一定浓度的放射性配基[125I]IMPY发生结合反应，反应系统中同时加入不同浓度的待测化合物(分别制备的化合物1.34～1.44，2.3a～2.8b，3.17，3.18，4.20和4.24)以及IMPY与[125I]IMPY发生竞争反应，平衡后分离复合物通过测定放射性来计算抑制常数(Ki)。
1、实验步骤
(1)配制10％乙醇溶液4L；
(2)放射配基[125I]IMPY按照已有方法制备；将[125I]IMPY配制成100000cpm/100μL的水溶液；
(3)将待测化合物配制成10-3至10-9mol/L连续稀释的乙醇溶液；
(4)受体Aβ1-42蛋白按照已有方法制备。将其稀释成约30nM的水溶液；
(5)在12mm×75mm高硼硅玻璃管中分别加入100μL不同浓度待测化合物溶液和100μL[125I]IMPY溶液、700μL PBS及100μL Aβ1-42溶液。用封口膜封好，涡旋；
(6)在37℃恒温水浴中振荡孵育3h；
(7)多头细胞收集器收集反应液，用10％乙醇溶液冲洗三遍，每次3mL；
(8)用γ计数仪测量计数；
(9)数据处理。
2、实验结果
由竞争结合实验得到的半抑制常数(IC50)以及进一步根据公式计算出的抑制常数Ki见表2。
表2稳定配体的抑制常数Ki值
通过上述的竞争结合实验可知，本发明的部分化合物具有与Aβ1-42聚集体较高的亲和力，比已知化合物IMPY和PIB要高。
实验例2：放射自显影实验
分别使一定浓度的[125I]1.34和[125I]3.17与AD转基因小鼠及AD病人脑切片中的斑块结合后，通过磷屏曝光，然后用储磷屏系统分析图像。
1、实验步骤
(1)预处理AD转基因小鼠脑切片和AD人脑切片；
(2)分别在AD转基因小鼠脑切片或AD人脑切片上覆盖5μCi的125I标记的化合物溶液100μL，室温下孵育60分钟；
(3)用40％乙醇溶液冲洗3分钟；
(4)晾干后，保鲜膜包覆置于磷屏下曝光3h，用储磷屏系统分析图像。
2、实验结果
实验结果如图5所示，充分说明本发明的化合物被放射性核素标记后，可以作为脑Aβ斑块的显像剂，在临床诊断中具有潜在的应用前景。
图5显示：[125I]1.34和[125I]3.17分别在AD人脑切片(A和G)，91岁，女性；转基因鼠脑切片(C和I)，APPswe/PSEN1，22月；正常鼠脑切片(E和K)，C57BL6(22月)的放射自显影结果。相同切片经过硫磺素-S染色加以对照，其中，B和H与A和G对应；D和J与C和I对应；F和L与E和K对应。
实验例3：正常小鼠体内生物分布实验
通过体内分布实验研究了[125I]1.34、[125I]1.38和[125I]3.17在小鼠体内的药代动力学性质，特别是初始脑摄取和脑清除情况。
1、实验步骤
将5-10μCi标记化合物(100μL生理盐水溶液，含5％乙醇)由尾静脉注射入正常小鼠(ICR，雄性，20-22g，5周龄)体内(n＝5)，分别于注射后2分钟、10分钟、30分钟和60分钟将其断头处死，解剖取出相关脏器，测量湿重及放射性计数。数据表示为脏器中放射性百分剂量(％ID/organ)和每克脏器中放射性百分剂量(％ID/g)。
2、实验结果
实验结果如表3所示，本发明所述的[125I]1.34可以顺利的通过血脑屏障，2分钟时脑部摄取达到峰值且在正常小鼠脑部清除很快，2分钟与60分钟脑摄取比值达到约为7。而化合物[125I]1.38和[125I]3.17的2分钟初始脑部摄取值较低，脑清除速率较低。
表3[125I]1.34、[125I]1.38及[125I]3.17在正常小鼠体内生物分布结果a
a表示为％ID/g，n＝4-5
b表示为％ID/organ(器官)
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
Claims (8)
1.二苯氧基柔性分子化合物，其特征在于，所述化合物为4-(2-(2-(4-碘苯氧基)乙氧基)乙氧基)-氮，氮-二甲苯胺或4-(2-(2-(2-(4-碘苯氧基)乙氧基)乙氧基)乙氧基)-氮，氮-二甲苯胺；
所述碘为123I、124I、125I、127I或131I。
2.二苯氧基柔性分子化合物，其特征在于，化合物的结构式如下：
其中，n为2–5的整数，R1为NMe2，R2为I或-(OCH2CH2)m-F，其中m为1-3的整数；当化合物中含有氟原子时，F为18F或19F；当化合物中含有碘原子时，I为123I、124I、125I、127I或131I；当化合物中含有-N(CH3)2时，-N(CH3)2为-N(11CH3)2。
3.权利要求2所述化合物的制备方法，按照下述反应方程式制备所述化合物：
其中，R1、R2、n与权利要求2中式(Ⅲ)所示化合物具有相应的定义。
4.利用权利要求1或2所述化合物制备得到的Aβ斑块显像剂，其特征在于，当所述化合物中含有氟原子时，制备得到含有放射性核素18F的化合物，作为Aβ斑块显像剂；或者，
当所述化合物中含有碘原子时，制备得到含有放射性核素124I的化合物，作为Aβ斑块显像剂；或者，
当所述化合物中含有二甲氨基时，制备得到含有放射性核素11C的化合物，作为Aβ斑块显像剂；或者，
当所述化合物中含有碘原子时，制备得到含有放射性核素123I、125I或131I的化合物，作为Aβ斑块显像剂。
5.根据权利要求4所述的Aβ斑块显像剂，其特征在于，当所述化合物中含有氟原子时，制备得到含有放射性核素18F的化合物，作为PET类Aβ斑块显像剂；或者，
当所述化合物中含有碘原子时，制备得到含有放射性核素124I的化合物，作为PET类Aβ斑块显像剂；或者，
当所述化合物中含有二甲氨基时，制备得到含有放射性核素11C的化合物，作为PET类Aβ斑块显像剂；或者，
当所述化合物中含有碘原子时，制备得到含有放射性核素123I、125I或131I的化合物，作为SPECT类Aβ斑块显像剂。
6.权利要求1或2所述化合物或权利要求4或5所述Aβ斑块显像剂在制备用于治疗或诊断阿尔茨海默症的药物中的应用。
7.二苯氧基柔性分子化合物在制备用于治疗或诊断阿尔茨海默症的药物中的应用；
所述二苯氧基柔性分子化合物的结构如下：
其中，n为1–11的整数，R1为I或NMe2，R2为氢、卤素、羟基、巯基、烷氧基、烷基、硝基、氨基、烷氨基、氰基、羧基、-Sn(Bu)3、-(OCH2CH2)m-F，其中m为1-3的整数，R1和R2均为邻位、间位或对位取代基；当化合物中含有氟原子时，F为18F或19F；当化合物中含有碘原子时，I为123I、124I、125I、127I或131I；当化合物中含有-CH3或-N(CH3)2时，-CH3为-11CH3、-N(CH3)2为-N(11CH3)2。
8.根据权利要求7所述的应用，其特征在于，所述二苯氧基柔性分子化合物的结构中，n＝2或6，R1和R2分别为：
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