CN115160331B - 一种氧化吲哚螺烯丙基取代色满骨架及其制备方法 - Google Patents
一种氧化吲哚螺烯丙基取代色满骨架及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种氧化吲哚螺烯丙基取代色满骨架及其合成方法和应用。本发明提供了氧化吲哚螺烯丙基取代色满类结构。本发明提供了其合成方法，包括以下步骤：将含有氧化吲哚骨架的四元合成子与(E)‑1,4‑二溴‑2‑丁烯在溶剂中混合均匀，碱性条件下，在50～90℃条件下反应，制得氧化吲哚螺烯丙基取代色满类化合物。本发明提供了一种药物组合物。本发明还提供了氧化吲哚螺烯丙基取代色满类骨架在制备治疗癌症等药物中的应用。本发明提供的一种高效合成氧化吲哚螺烯丙基取代色满类化合物的方法，通过(E)‑1,4‑二溴‑2‑丁烯参与的[4+2]环化反应实现了氧化吲哚螺烯丙基取代色满类骨架的高效构建。
Description
技术领域
本发明涉及药物中间体及化学合成技术领域，特别涉及一种氧化吲哚螺烯丙基取代色满结构及其合成方法和应用。
背景技术
氧化吲哚螺色满结构广泛存在于许多天然产物及药物分子中，在医药、农药方面具有重要的应用价值，例如分子p38α抑制剂是治疗前列腺癌药物，分子C是具有良好的抑菌活性。因此，氧化吲哚螺色满结构的高效构建对药物开发具有重要意义，近年来发展了一些方法来高效构建氧化吲哚螺色满结构。
例如，2019年，青岛农业大学的肖建教授团队报道了含有氧化吲哚的四元合成子与2,5-二甲基呋喃的[4+2]环化反应，并进一步发生呋喃的开环反应，高效合成了多取代的氧化吲哚螺色满结构(Adv.Synth.Catal.,2019,361,1453-1458)。
2020年，青岛农业大学的李帅帅教授团队报道了含有氧化吲哚的四元合成子与α-溴代苯乙酮的[4+2]环化反应，合成了含有多个取代基的氧化吲哚螺色满结构(Org.Chem.Front.,2020,7,747–755)。
烯丙基是有机合成转化中最重要的官能团，可进行化合物分子的多种修饰，对化合物基于活性的修饰与改造具有重要作用。因此，在化合物分子，尤其是在具有一定药用价值的潜在活性分子中引入烯丙基，具有极其重要的意义。上述已报道方法可高效合成氧化吲哚螺色满结构，但是氧化吲哚螺烯丙基取代色满结构却未有报道。因此，开发一种高效的合成氧化吲哚螺烯丙基取代色满类化合物的方法，对开发新型药物，尤其是治疗肿瘤、疼痛等疾病的药物具有重要意义。
发明内容
本发明的目的旨在针对现有技术的不足，提供了一种具有生物活性的氧化吲哚螺烯丙基取代色满类结构及其合成方法和应用。本发明提供的氧化吲哚螺烯丙基取代色满类骨架将为药物开发提供新的模型分子。本发明提供的氧化吲哚螺烯丙基取代色满类骨架的合成方法，首次通过(E)-1,4-二溴-2-丁烯参与的[4+2]环化反应一步高效合成该骨架，操作简单、高效实用，且所构建骨架中含有多种官能团，利于该骨架的后期合成应用。
本发明的技术方案是这样实现的：
氧化吲哚螺烯丙基取代色满类骨架，其结构式如式1所示：
式1中，R1为烷基、苄基、烯丙基、炔丙基中任意一种，式1所示的R1中所述烷基优选为碳原子数目为1～3的烷基；R2为烷基、烷氧基、卤素中任意一种，式1所示的R2中所述烷基优选为碳原子数目为1～3的烷基；R3为烷氧基、芳基，式1所示的R3中所述烷氧基优选为碳原子数目为1～3的烷氧基；优选的，式1中，R1为甲基、苄基、烯丙基、炔丙基中任意一种；R2为甲基、甲氧基、氟原子、氯原子、溴原子中任意一种；R3为甲氧基、苯环中任意一种；其中，R1、R2、R3彼此相同或者不同，各自独立地表示取代基。
本发明涉及的化合物可以以一种或者多种立体异构体的形式存在。各种异构体包括互变异构体、几何异构体、对映异构体、非对映异构体等。这些异构体以及这些异构体的混合物均在本发明的保护范围内。
基于同一个发明构思，本发明还提供了氧化吲哚螺烯丙基取代色满类骨架的合成方法，本发明的合成工艺路线图如图1所示，包括以下步骤：
将含有氧化吲哚骨架的四元合成子与(E)-1,4-二溴-2-丁烯在溶剂中混合均匀，碱性条件下，在50～90℃条件下反应，制得氧化吲哚螺烯丙基取代色满类化合物；
其中，上述含有氧化吲哚骨架的四元合成子的结构式如式2所示：
式2中，R1为烷基、苄基、烯丙基、炔丙基中任意一种，式2所示的R1中所述烷基优选为碳原子数目为1～3的烷基；R2为烷基、烷氧基、卤素中任意一种，式2所示的R2中所述烷基优选为碳原子数目为1～3的烷基；R3为烷氧基、芳基，式2所示的R3中所述烷氧基优选为碳原子数目为1～3的烷氧基；优选的，式2中，R1为甲基、苄基、烯丙基、炔丙基中任意一种；R2为甲基、甲氧基、氟原子、氯原子、溴原子中任意一种；R3为甲氧基、苯环中任意一种；其中，R1、R2、R3彼此相同或者不同，各自独立地表示取代基。
其中，上述(E)-1,4-二溴-2-丁烯的结构式如式3所示：
可通过薄层色谱法检测上述反应情况，待反应完毕进行纯化，得到氧化吲哚螺烯丙基取代色满类化合物的纯化产物。
上述反应过程具体为：
含有氧化吲哚骨架的四元合成子在碱性条件下对(E)-1,4-二溴-2-丁烯进行亲核取代反应，生成中间体I，然后在碱性条件性发生碳溴键的异裂，得到碳正离子中间体II，紧接着发生分子内的单分子亲核取代反应，生成六元环结构，得到氧化吲哚螺烯丙基取代色满类化合物。合成原理路线具体如下：
优选的，如上所述的合成方法，在80℃条件下反应。
如上所述的合成方法，所述含有氧化吲哚骨架的四元合成子与(E)-1,4-二溴-2-丁烯的摩尔比为1：(1～3)。优选的，所述含有氧化吲哚骨架的四元合成子与(E)-1,4-二溴-2-丁烯的摩尔比为1：1.1。
如上所述的合成方法，所述溶剂为乙腈或乙醇。优选的，所述溶剂为乙腈。
如上所述的合成方法，所述溶剂的用量为：每摩尔含有氧化吲哚骨架的四元合成子添加10～25L溶剂。优选的，所述溶剂的用量为：每摩尔含有氧化吲哚骨架的四元合成子添加10L溶剂。
如上所述的合成方法，所述碱性催化剂在反应前加入，所述催化剂为无机碱。优选的，所述催化剂为氢氧化钠、磷酸钾中任意一种。
如上所述的合成方法，所述碱性催化剂的用量为200～300mol％。优选的，所述催化剂的用量为300mol％。
基于同一个发明构思，本发明还提供了一种药物组合物，其包含如上所述的氧化吲哚螺烯丙基取代色满类骨架及其药学上可接受的盐、溶剂化物、水合物、多晶体、共晶体、互变异构体、几何异构体、对映异构体、非对映异构体或它们的混合物或前药，和药学上可接受的载体、稀释剂、赋形剂或它们的组合。本发明对所述载体、稀释剂、赋形剂并无特殊限定，可以为本领域技术人员熟知的适用于药物组合物的载体、稀释剂、赋形剂。
基于同一个发明构思，本发明还提供了氧化吲哚螺烯丙基取代色满类骨架在制备治疗癌症、动脉粥样硬化、结核、心血管疾病、癫痫、精神类疾病、帕金森、阿尔茨海默症的药物中的应用。
本发明的有益效果是：
1、本发明在温和的条件下，通过多步连续反应，高效合成了氧化吲哚螺烯丙基取代色满类骨架，本发明的技术方案为氧化吲哚螺烯丙基取代色满类骨架提供了方便、简洁的合成方法，首次通过[4+2]环化反应实现了氧化吲哚螺烯丙基取代色满类骨架的高效构建。
2、本发明发展了一种高效合成含有多个官能团的氧化吲哚螺烯丙基取代色满类化合物的方法，提供了氧化吲哚螺烯丙基取代色满类骨架的化合物库，为药物开发提供了新的模型分子。
3、本发明为具有良好生物活性的氧化吲哚螺烯丙基取代色满类骨架的高效构建提供了实验依据，具有很好的实践意义和应用价值。
附图说明
图1为本发明的合成工艺路线图。
具体实施方式
下面将结合本发明实施例中的内容，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
除非另有定义，本说明书所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。在本发明的说明书中所使用的术语只是为了描述具体的实施方式的目的，不是用于限制本发明。本说明书所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法；下述实施例中所用的试剂、材料、仪器等，如无特殊说明，均可从商业途径得到；下述实施例中所用的反应容器为25mL的厚壁耐压管。
实施例1
1、本实施例提供一种氧化吲哚螺烯丙基取代色满类骨架的合成方法，其包括以下步骤：
取0.1mmol含有氧化吲哚骨架的四元合成子于反应瓶中，依次加入1mL溶剂、0.11mmol(E)-1,4-二溴-2-丁烯，最后再加入0.3mmol碱。控制体系的反应温度，持续搅拌，通过薄层色谱板点样跟踪反应至原料反应完全。待反应完成后，使用硅胶柱进行分离纯化，将纯化后的产品旋蒸得目标产物A。反应式如下：
2、按照上述方法，设立6组平行试验组，分别采用不同的碱性催化剂、反应温度。催化剂分别为氢氧化钠NaOH、碳酸钾K2CO3、碳酸钠Na2CO3、磷酸钾K3PO4。试验组具体使用的碱性催化剂、反应温度及对应产率如表1所示：
表1不同碱性催化剂、反应温度下对应产率表
| 序号 | 碱性催化剂 | 溶剂 | 温度(℃) | 产物A产率(％) |
| 1 | NaOH | CH3CN | 50 | 30 |
| 2 | K2CO3 | CH3CN | 50 | 28 |
| 3 | Cs2CO3 | CH3CN | 50 | 34 |
| 4 | K3PO4 | CH3CN | 50 | 38 |
| 5 | K3PO4 | CH3CN | 80 | 58 |
| 6 | K3PO4 | CH3CN | 100 | 52 |
注：含有氧化吲哚骨架的四元合成子(0.1mmol)，溶剂(1mL)、(E)-1，4-二溴-2-丁烯(0.11mmol)，碱用量(0.3mmol)；上述产率为分离产率。根据以上平行试验结果分析可知：采用无机碱均可催化本发明的合成反应；磷酸钾K3PO4为碱性催化剂时产物A的产率最高。反应温度为80℃时，产物A的产率最高。
3、按照上述方法，设置以下9组平行试验组，分别采用不同的反应条件，如：不同溶剂、不同原料比例、不同碱性催化剂用量。不同试验组的具体设置见表2：
表2不同溶剂、不同原料比例、不同碱性催化剂用量条件下反应产率表
注：溶剂(1mL)、反应温度为80℃；上述产率为分离产率Dioxane＝1,4-二氧六环；上述产率为分离产率。
根据以上平行试验结果分析可知：本发明的合成反应在以乙腈CH3CN(1mL)作为溶剂，含有氧化吲哚骨架的四元合成子(0.1mmol)，(E)-1,4-二溴-2-丁烯(0.11mmol)，K3PO4(0.3mmol)，80℃条件下反应，产物A的产率最高。
下列实施例2-13中，按照实施例1的操作步骤进行反应；取0.1mmol含有氧化吲哚骨架的四元合成子于反应瓶中，依次加入1mL乙腈、0.11mmol(E)-1,4-二溴-2-丁烯，最后再加入0.3mmol磷酸钾。控制体系的反应温度为80℃，持续搅拌，通过薄层色谱板点样跟踪反应至原料反应完全。待反应完成后，使用硅胶柱进行分离纯化，将纯化后的产品旋蒸得目标产物。
实施例2
原料：
产物：化学式：C20H17NO4
结构式：
产率：56％
1H NMR(500MHz,CDCl3)δ7.25(t,J＝7.7Hz,1H),7.15(d,J＝7.4Hz,1H),6.98(t,J＝7.5Hz,1H),6.87(d,J＝7.8Hz,1H),6.42(s,1H),5.97–5.88(m,1H),5.86(s,1H),5.74(s,2H),5.37(d,J＝17.3Hz,1H),5.21(d,J＝10.6Hz,1H),4.74(dd,J＝11.8,5.7Hz,1H),3.25(s,3H),2.39–2.27(m,1H),1.79(dd,J＝13.5,1.9Hz,1H).13C NMR(125MHz,CDCl3)δ179.3,150.3,147.9,142.5,142.4,136.7,136.4,128.4,124.2,123.0,117.3,111.8,108.5,106.0,101.1,99.1,72.9,49.9,37.9,26.8.HRMS(ESI)m/z:[M+H]+calcd.for C20H18NO4:336.1230,found:336.1212.
实施例3
原料：
产物：化学式：C26H21NO4
结构式：
产率：58％
1H NMR(500MHz,CDCl3)δ7.35(d,J＝4.3Hz,4H),7.29(dd,J＝8.5,4.3Hz,1H),7.20(dd,J＝10.1,7.7Hz,2H),7.01(t,J＝7.5Hz,1H),6.84(d,J＝7.8Hz,1H),6.51(s,1H),6.06–5.97(m,1H),5.96(s,1H),5.82(d,J＝3.7Hz,2H),5.46(d,J＝17.2Hz,1H),5.29(d,J＝10.6Hz,1H),5.00(q,J＝15.5Hz,2H),4.82(dd,J＝11.9,5.8Hz,1H),2.48(t,J＝12.8Hz,1H),1.91(d,J＝13.5Hz,1H).13C NMR(125MHz,CDCl3)δ179.4,150.3,148.0,142.4,141.5,136.6,136.4,135.8,128.9,128.3,127.8,127.4,124.3,122.9,117.4,111.8,109.5,106.1,101.1,99.2,72.9,49.8,44.2,38.1.HRMS(ESI)m/z:[M+H]+calcd.for C26H22NO4:412.1543,found:412.1539.
实施例4
原料：
产物：化学式：C22H19NO4
结构式：
产率：55％
1H NMR(500MHz,CDCl3)δ7.22(d,J＝7.7Hz,1H),7.15(d,J＝7.4Hz,1H),6.97(t,J＝7.5Hz,1H),6.86(d,J＝7.8Hz,1H),6.42(s,1H),5.98–5.88(m,1H),5.88(s,1H),5.86–5.78(m,1H),5.75(s,2H),5.38(d,J＝17.2Hz,1H),5.29–5.12(m,3H),4.75(dd,J＝11.7,5.7Hz,1H),4.36(d,J＝15.9Hz,2H),2.35(t,J＝12.8Hz,1H),1.80(dd,J＝13.5,1.7Hz,1H).13C NMR(125MHz,CDCl3)δ178.9,150.3,147.9,142.4,141.6,136.6,136.4,131.3,128.3,124.3,122.9,117.9,117.4,111.8,109.4,106.0,101.2,99.2,72.9,49.8,42.7,38.1.HRMS(ESI)m/z:[M+H]+calcd.for C22H20NO4:362.1387,found:362.1370.
实施例5
原料：
产物：化学式：C22H17NO4
结构式：
产率：54％
1H NMR(500MHz,CDCl3)δ7.25(t,J＝7.7Hz,1H),7.15(d,J＝7.4Hz,1H),6.98(t,J＝7.5Hz,1H),6.87(d,J＝7.8Hz,1H),6.42(s,1H),5.97–5.88(m,1H),5.86(s,1H),5.74(s,2H),5.37(d,J＝17.3Hz,1H),5.21(d,J＝10.6Hz,1H),4.74(dd,J＝11.8,5.7Hz,1H),3.25(s,3H),2.39–2.27(m,1H),1.79(dd,J＝13.5,1.9Hz,1H).13C NMR(125MHz,CDCl3)δ179.3,150.3,147.9,142.5,142.4,136.7,136.4,128.4,124.2,123.0,117.3,111.8,108.5,106.0,101.1,99.1,72.9,49.9,37.9,26.8.HRMS(ESI)m/z:[M+H]+calcd.for C20H18NO4:336.1230,found:336.1212.
实施例6
原料：
产物：化学式：C27H23NO4
结构式：
产率：54％
1H NMR(500MHz,CDCl3)δ7.26(dd,J＝10.1,2.9Hz,4H),7.21(m,1H),6.94(s,1H),6.92(d,J＝8.0Hz,1H),6.64(d,J＝7.9Hz,1H),6.43(s,1H),5.94(m,1H),5.89(s,1H),5.75(dd,J＝2.4,1.4Hz,2H),5.40(m,1H),5.23(m,1H),4.91(q,J＝15.5Hz,2H),4.79–4.71(m,1H),2.39(dd,J＝13.4,12.3Hz,1H),2.19(s,3H),1.83(dd,J＝13.5,2.0Hz,1H).13C NMR(125MHz,CDCl3)δ179.4,150.3,147.9,142.4,139.1,136.7,136.5,135.9,132.6,128.9,128.6,127.8,127.4,125.2,117.3,112.0,109.3,106.2,101.2,99.1,72.9,49.9,44.2,38.1,21.1.HRMS(ESI)m/z:[M+H]+calcd.for C27H24NO4:426.1700,found:426.1680.
实施例7
原料：
产物：化学式：C27H23NO5
结构式：
产率：61％
1H NMR(500MHz,CDCl3)δ7.38–7.32(m,4H),7.32–7.27(m,1H),6.81(d,J＝1.9Hz,1H),6.72(t,J＝6.0Hz,2H),6.50(s,1H),6.06–5.98(m,1H),5.97(s,1H),5.83(d,J＝1.2Hz,2H),5.46(d,J＝17.3Hz,1H),5.30(d,J＝10.6Hz,1H),4.98(q,J＝15.5Hz,2H),4.80(dd,J＝11.5,5.8Hz,1H),3.71(s,3H),2.55–2.42(m,1H),1.91(dd,J＝13.5,2.0Hz,1H).13CNMR(125MHz,CDCl3)δ179.1,156.2,150.3,148.0,142.4,137.7,136.6,135.9,134.9,128.9,127.8,127.4,117.4,112.2,112.1,111.8,109.8,106.1,101.1,99.2,72.9,55.8,50.2,44.3,38.1.HRMS(ESI)m/z:[M+H]+calcd.for C27H24NO5:442.1649,found:442.1622.
实施例8
原料：
产物：化学式：C26H20BrNO4
结构式：
产率：60％
1H NMR(500MHz,CDCl3)δ7.38–7.34(m,2H),7.31(d,J＝8.0Hz,5H),6.70(d,J＝8.1Hz,1H),6.52(d,J＝9.3Hz,1H),6.01(m,1H),5.93(s,1H),5.86(d,J＝10.1Hz,2H),5.49(d,J＝17.2Hz,1H),5.32(d,J＝10.4Hz,1H),4.98(q,J＝15.5Hz,2H),4.75(dd,J＝11.9,5.6Hz,1H),2.47(t,J＝12.9Hz,1H),1.91(d,J＝13.4Hz,1H).13C NMR(125MHz,CDCl3)δ178.8,150.4,148.3,142.5,140.6,138.3,136.4,135.4,131.2,129.0,128.0,127.5,127.3,117.5,115.8,111.0,110.9,105.9,101.2,99.3,72.7,49.9,44.3,38.0.HRMS(ESI)m/z:[M+H]+calcd.for C26H21BrNO4:492.0628,found:492.0626.
实施例9
原料：
产物：化学式：C26H20BrNO4
结构式：
产率：51％
1H NMR(500MHz,CDCl3)δ7.41–7.27(m,7H),7.19–7.13(m,1H),7.07(d,J＝7.9Hz,1H),6.93(dd,J＝22.9,15.8Hz,2H),6.51(d,J＝12.4Hz,1H),5.99(m,1H),5.92(s,1H),5.88–5.78(m,3H),5.48(dd,J＝24.2,17.3Hz,1H),5.40(dd,J＝10.0,6.1Hz,1H),5.30(d,J＝10.5Hz,1H),4.97(q,J＝15.6Hz,2H),4.83(d,J＝15.6Hz,1H),4.75(dd,J＝11.8,5.8Hz,1H),2.45(t,J＝12.8Hz,1H),2.15–2.02(m,1H),1.88(d,J＝13.4Hz,1H).13C NMR(125MHz,CDCl3)δ179.2,179.1,151.0,150.3,148.2,148.1,144.0,142.9,142.5,142.1,136.6,136.4,135.3,135.2,133.0,129.1,129.1,128.1,127.9,127.3,127.2,126.3,125.8,125.6,125.1,122.0,121.9,117.6,117.3,112.8,112.5,111.2,111.1,105.9,105.9,101.2,101.2,99.4,99.2,72.9,71.9,49.6,48.3,44.3,43.9,38.1,37.2.HRMS(ESI)m/z:[M+H]+calcd.for C26H21BrNO4:492.0628,found:492.0626.
实施例10
原料：
产物：化学式：C26H20ClNO4
结构式：
产率：58％
1H NMR(500MHz,CDCl3)δ7.27(d,J＝7.7Hz,1H),7.25–7.17(m,4H),7.12(d,J＝8.2Hz,1H),7.05(d,J＝7.4Hz,1H),6.89(t,J＝7.8Hz,1H),6.43(s,1H),5.98–5.90(m,1H),5.89(d,J＝4.0Hz,1H),5.76(s,2H),5.40(t,J＝15.4Hz,2H),5.33(d,J＝16.0Hz,1H),5.23(d,J＝10.5Hz,1H),4.71(dd,J＝11.6,5.8Hz,1H),2.39(t,J＝12.9Hz,1H),1.84(dd,J＝13.5,1.7Hz,1H).13C NMR(125MHz,CDCl3)δ180.1,150.4,148.2,142.5,139.2,137.8,137.6,136.4,130.9,128.7,127.4,126.7,123.9,123.1,117.6,115.8,111.3,106.0,101.3,99.2,72.7,49.6,45.3,38.6.HRMS(ESI)m/z:[M+H]+calcd.for C26H21ClNO4:446.1154,found:446.1131.
实施例11
原料：
产物：化学式：C26H20FNO4
结构式：
产率：60％
1H NMR(500MHz,CDCl3)δ7.33(d,J＝7.6Hz,2H),7.27(t,J＝7.4Hz,2H),7.21(dd,J＝13.9,6.6Hz,1H),6.95–6.83(m,3H),6.42(s,1H),5.98–5.88(m,1H),5.84(s,1H),5.76(dd,J＝5.4,1.1Hz,2H),5.38(d,J＝17.2Hz,1H),5.23(d,J＝10.6Hz,1H),5.12–5.02(m,2H),4.70(dd,J＝11.9,5.7Hz,1H),2.42–2.30(m,1H),1.82(dd,J＝13.5,2.0Hz,1H).13CNMR(125MHz,CDCl3)δ179.2,150.3,148.2,147.6(d,J＝245.0Hz),142.3,139.2,137.2,136.5,128.7,128.4(d,J＝7.5Hz),127.8,127.7,123.7(d,J＝6.3Hz),120.3,117.5,116.5(d,J＝20.0Hz),111.4,105.9,101.2,99.2,72.8,50.1,45.8,45.7,38.2.HRMS(ESI)m/z:[M+H]+calcd.for C26H21FNO4:430.1449,found:430.1422.
实施例12
原料：
产物：化学式：C26H20BrNO4
结构式：
产率：58％
1H NMR(500MHz,CDCl3)δ7.31(dd,J＝8.2,1.0Hz,1H),7.29–7.24(m,2H),7.22–7.17(m,3H),7.12–7.07(m,1H),6.83(t,J＝7.8Hz,1H),6.43(s,1H),5.98–5.90(m,1H),5.89(s,1H),5.76(d,J＝1.5Hz,2H),5.47(d,J＝16.3Hz,1H),5.43–5.34(m,2H),5.23(d,J＝10.5Hz,1H),4.71(dd,J＝11.5,5.9Hz,1H),2.38(dd,J＝13.4,12.4Hz,1H),1.84(dd,J＝13.5,2.0Hz,1H).13C NMR(125MHz,CDCl3)δ180.3,150.4,148.2,142.5,139.5,139.3,137.5,136.4,134.3,128.7,127.3,126.5,124.2,123.7,117.6,111.2,106.1,102.9,101.3,99.2,72.6,49.5,44.9,38.7.HRMS(ESI)m/z:[M+H]+calcd.for C26H21BrNO4:492.0628,found:492.0615.
实施例13
原料：
产物：化学式：C29H23NO2
结构式：
产率：61％
1H NMR(500MHz,CDCl3)δ8.26(d,J＝8.0Hz,1H),7.64(d,J＝7.5Hz,1H),7.42(m,2H),7.35–7.27(m,4H),7.24(d,J＝6.8Hz,1H),7.18(s,1H),7.17–7.09(m,2H),6.91(t,J＝7.5Hz,1H),6.80(d,J＝7.8Hz,1H),6.54(d,J＝8.5Hz,1H),6.17–5.99(m,1H),5.55(d,J＝17.3Hz,1H),5.31(d,J＝10.6Hz,1H),5.06–4.90(m,3H),2.64–2.49(m,1H),2.00(dd,J＝13.4,2.0Hz,1H).13C NMR(125MHz,CDCl3)δ179.4,150.5,141.8,136.7,136.3,135.9,133.9,128.9,128.4,127.8,127.5,127.5,126.6,125.7,125.5,124.9,124.6,122.9,121.9,121.1,117.2,114.0,109.5,73.0,50.1,44.3,38.3.HRMS(ESI)m/z:[M+H]+calcd.for C29H24NO2:418.1802,found:418.1786.
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (5)
1.氧化吲哚螺烯丙基取代色满类化合物的合成方法，其特征在于，包括以下步骤：
将含有氧化吲哚骨架的四元合成子与（E）-1,4-二溴-2-丁烯在溶剂中混合均匀，碱性条件下，在50～90℃条件下反应，制得氧化吲哚螺烯丙基取代色满类化合物，其结构式如式1所示；所述溶剂为乙腈或乙醇；
其中，上述含有氧化吲哚骨架的四元合成子的结构式如式2所示：
式1和式2中，R1为甲基、苄基、烯丙基、炔丙基中任意一种；R2为甲基、甲氧基、氟原子、氯原子、溴原子中任意一种；R3为甲氧基、苯环中任意一种；其中，R1、R2、R3彼此相同或者不同，各自独立地表示取代基；
其中，上述（E）-1,4-二溴-2-丁烯的结构式如式3所示：
2.根据权利要求1所述的合成方法，其特征在于，所述含有氧化吲哚骨架的四元合成子与1,2-二(溴甲基)苯的摩尔比为1：（1～3）。
3.根据权利要求1所述的合成方法，其特征在于，所述溶剂的用量为：每摩尔含有氧化吲哚骨架的四元合成子添加10～25 L溶剂。
4.根据权利要求1所述的合成方法，其特征在于，催化剂在反应前加入，所述催化剂为无机碱。
5.根据权利要求4所述的方法，其特征在于，所述催化剂的摩尔用量为氧化吲哚骨架的四元合成子的200～300 %。
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