CN110437227A - 一种具有多环桥环骨架的多取代四氢异喹啉及其制备方法 - Google Patents
一种具有多环桥环骨架的多取代四氢异喹啉及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有多环桥环的多取代四氢异喹啉及其制备方法,属于有机合成技术领域。本发明通过将烯胺酮和N‑苄基异喹啉盐加在乙腈溶剂中,以DBU为碱,在60℃的温度下发生1,2‑加成“诱导”的多级环化串联反应来制备桥环多取代四氢异喹啉。本发明开辟了N‑烷基异喹啉盐新的反应模式,能有效地利用其C1‑、C3‑和C4‑反应位点,用于合成结构复杂的多环桥环四氢异喹啉。本发明避免分离中间体,反应完全后,通过简单的过滤或者柱色谱即可拿到纯品。本发明具有反应时间短、反应条件温和、操作简便、底物耐受性好等优点。
Description
技术领域
本发明属于有机合成领域,具体涉及一种具有多环桥环骨架的多取代四氢异喹啉及其制备方法。
背景技术
多环(桥环)四氢异喹啉是一类重要的结构单元,是很多药物分子和具有生理活性天然产物的活性骨架,具有广泛的生理活性(图1)。因此发展更加高效的方法来合成结构多样的这类化合物具有十分重要的研究意义和应用价值。通过文献调研发现,异喹啉盐的去芳构化反应是制备四氢异喹啉最直接、最有效的方法之一。异喹啉盐通过与一系列亲核试剂发生加成反应,得到氢化的异喹啉。但是,这些反应通常发生在C1-位,反应相对简单,而C3-和C4-位还没有被有效利用,这将大大影响产物的复杂性和多样性(图2)。因此,开发异喹啉盐新的更多的反应位点用以合成结构新型的具有多环桥环复杂结构的多取代桥环四氢异喹啉具有很重要的意义。
发明内容
针对现有技术中存在的问题,本发明提供一种结构新型具有桥环多环复杂骨架的多取代四氢异喹啉及其制备方法,开辟了异喹啉盐新的反应位点,操作简单、反应条件温和、且目标产物容易分离。
为解决上述技术问题,本发明采用以下技术方案:
一种复杂桥环多环多取代四氢异喹啉,其结构式如下:
其中,R1为烷基、卤素或氢;R2为甲基或氢,R3为烷基、卤素或氢。
所述的结构新型具有桥环多环复杂骨架的多取代四氢异喹啉的制备方法,将烯胺酮和N-苄基异喹啉盐,在有机溶剂中,碱的存在下,25-80℃反应5分钟至24小时,薄层色谱跟踪反应至完全,反应结束后,通过用布氏漏斗过滤或柱色谱分离纯化,得到目标产物,其反应通式如下:
其中,R1为烷基、卤素或氢;R2为甲基或氢,R3为烷基、卤素或氢。
进一步,所述的碱为无机碱或有机碱。
进一步,所述无机碱为碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、醋酸钠;有机碱为三乙胺、吡啶、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、三乙烯二胺(DBU)、四甲基胍(TMG);所述的碱优选为三乙烯二胺(DBU)。
进一步,所述的碱的物质的量为烯胺酮的物质的量的3.6倍。
进一步,所述烯胺酮与N-苄基异喹啉盐的摩尔比为1:1-1:4,优选为1:2.2。
进一步,所述的有机溶剂为二甲亚砜、N,N-二甲基甲酰胺、乙腈、甲醇、乙醇、甲苯、氯仿、二氯甲烷、1,2-二氯乙烷、乙醚、四氢呋喃、1,4-二氧六环或乙酸乙酯,优选为乙腈。
进一步,所述的反应温度优选为60℃。
本发明的有益效果:本发明通过将烯胺酮和N-苄基异喹啉溴盐加在乙腈溶剂中,以DBU为碱,在60℃的温度下发生1,2-加成“诱导”的环化串联反应来制备具有多环桥环复杂结构的多取代四氢异喹啉。本发明开辟了N-烷基异喹啉盐新的反应模式,通过和烯胺酮反应,使其氮杂芳香环的C1-、C3-和C4-位均可有效地利用起来,生成了一种结构新型、具有多环桥环复杂结构的多取代四氢异喹啉化合物。本发明中间产物不需分离纯化,且目标产物容易分离;操作简单、反应条件温和、反应时间短,底物耐受性好,收率高达97%。
附图说明
图1为实施例1化合物3a的1H NMR图;
图2为实施例1化合物3a的13C NMR图;
图3为实施例1化合物3g的X-射线单晶衍射图;
图4为具有四氢异喹啉多环骨架的活性分子;
图5为文献报道的异喹啉盐的反应性。
具体实施方式
下面结合具体实施例,对本发明做进一步说明。应理解,以下实施例仅用于说明本发明而非用于限制本发明的范围,该领域的技术熟练人员可以根据上述发明的内容作出一些非本质的改进和调整。
实施例1
具有多环桥环复杂结构的多取代四氢异喹啉3a的制备:往10mL硬质玻璃反应试管中,加入烯胺酮1a(0.15mmol,34.4mg),N-苄基异喹啉溴盐2a(0.33mmol,99.1mg),0.8mL乙腈,然后加入34.6mg四甲基胍(0.30mmol),混合物在60℃搅拌5min。反应完全后,过滤,滤饼即为目标化合物3a(白色固体,93.9mg,收率94%,>20:1dr,)。
所得化合物3a的核磁共振氢谱、碳谱、红外以及高分辨质谱数据如下:
1H NMR(400MHz,CDCl3),δ7.50(d,J=4.0Hz,1H),7.21-7.12(m,12H),6.95-6.86(m,5H),6.70-6.49(m,4H),6.18(d,J=4.0Hz,1H),5.25(t,J=8.0Hz,3H),4.66(s,1H),4.30(d,J=8.0Hz,1H),3.81(d,J=16.0Hz,1H),3.67(d,J=16.0Hz,1H),3.55(d,J=12.0Hz,1H),3.33(d,J=16.0Hz,1H),2.93(d,J=16.0Hz,1H),2.26(s,3H),2.12(d,J=12.0Hz,2H),1.77(d,J=16.0Hz,1H),1.02(s,3H),0.81(s,3H);13C NMR(100MHz,CDCl3)δ192.1,154.5,141.0,138.3,138.2,137.8,136.7,136.6,132.5,131.1,129.7,129.4,128.4,128.3,127.5,127.3,127.1,126.8,126.7,126.5,126.0,125.4,125.3,123.5,122.2,105.8,99.8,96.4,74.9,61.5,58.0,57.2,52.2,49.8,45.7,41.0,33.1,29.6,27.4,20.9.IR(KBr)ν3441,1611,1565,1391,756cm-1.HRMS(ESI)calcd for C47H46N3O[M+H]+668.3635,found668.3635.
化合物3b-o的制备方法同化合物3a,投料比与化合物3a相同,可得到化合物3b-o,反应产率见表1,但需要强调的是本发明的化合物并不局限于表1中所示化合物。
表1:含有不同取代基的多环桥环多取代四氢异喹啉的制备结果
化合物3b(白色固体,92%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.51(d,J=8.0Hz,1H),7.24-7.13(m,11H),6.97-6.84(m,5H),6.68-6.48(m,4H),6.19(d,J=8.0Hz,1H),5.25(d,J=8.0Hz,2H),5.19(d,J=8.0Hz,1H),4.64(s,1H),4.26(d,J=8.0Hz,1H),3.82(d,J=16.0Hz,1H),3.67(d,J=16.0Hz,1H),3.55(d,J=12.0Hz,1H),3.32(d,J=16.0Hz,1H),2.90(d,J=8.0Hz,1H),2.55(q,J=8.0Hz,2H),2.13(d,J=12.0Hz,3H),1.79(d,J=16.0Hz,1H),1.18(t,J=8.0Hz,3H),1.03(s,3H),0.81(s,3H);13CNMR(100MHz,CDCl3)δ192.1,154.5,142.9,141.0,138.3(2C),137.9,136.7,132.5,131.2,129.8,129.4,128.4(2C),127.5,127.3,127.1,126.8,126.6,126.5,126.0,125.4,125.3,123.5,122.2,105.7,96.4,74.8,61.5,58.1,57.2,52.3,49.9,45.6,41.0,33.1,29.6,28.3,27.4,15.6,one carbon missing in the aromatic region.IR(KBr)ν3445,2953,1616,1558,1389,760cm-1.HRMS(ESI)calcd for C48H48N3O[M+H]+682.3792,found682.3786.
化合物3c(白色固体,97%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.51(d,J=8.0Hz,1H),7.24-7.13(m,11H),6.92-6.86(m,3H),6.68(dd,J1=J2=8.0Hz,4H),6.50(t,J=8.0Hz,2H),6.21(d,J=8.0Hz,1H),5.28(d,J=8.0Hz,1H),5.25(s,1H),5.20(d,J=8.0Hz,1H),4.59(s,1H),4.28(d,J=8.0Hz,1H),3.81(d,J=12.0Hz,1H),3.73(s,3H),3.70(d,J=16.0Hz,1H),3.55(d,J=12.0Hz,1H),3.33(d,J=16.0Hz,1H),2.93(d,J=8.0Hz,1H),2.14(s,2H),2.07(d,J=16.0Hz,1H),1.77(d,J=16.0Hz,1H),1.03(s,3H),0.80(s,3H);13C NMR(100MHz,CDCl3)δ192.0,158.0,154.7,141.0,138.3,137.8,136.7,133.5,132.5,131.2,129.7,129.4,128.5,128.3,127.5,127.3,127.1,126.8,126.7,126.5,125.9,125.3(2C),123.5,122.3,105.7,96.5,74.8,61.5,58.1,57.2,55.4,52.4,49.8,45.6,40.9,33.0,29.5,27.5,one carbon missing in the aromaticregion.IR(KBr)ν3442,2951,1611,1563,1504,1247,756cm-1.HRMS(ESI)calcd forC47H45N3NaO2[M+Na]+706.3404,found 706.3410.
化合物3d(白色固体,97%收率,>20:1dr,通过柱色谱分离纯化(石油醚:乙酸乙酯=5:1)):1H NMR(400MHz,CDCl3),δ7.50(d,J=4.0Hz,1H),7.24-7.13(m,14H),6.92-6.86(m,3H),6.68(d,J=8.0Hz,3H),6.51(t,J=8.0Hz,1H),6.19(d,J=8.0Hz,1H),5.24(q,J=8.0Hz,3H),4.71(s,1H),4.30(d,J=8.0Hz,1H),3.82(d,J=16.0Hz,1H),3.67(d,J=16.0Hz,1H),3.57(d,J=16.0Hz,1H),3.31(d,J=16.0Hz,1H),2.91(d,J=8.0Hz,1H),2.15(s,2H),1.90(s,1H),1.76(d,J=16.0Hz,1H),1.03(s,3H),0.81(s,3H);13C NMR(100MHz,CDCl3)δ192.2,154.2,140.8(2C),138.2,137.7,136.6,132.5,131.1,129.7,129.6,129.3,128.4,128.3,127.5,127.3,127.0,126.7,126.6(2C),126.5,125.9,125.3(2C),123.5,122.2,106.0,96.4,74.8,61.4,58.0,57.2,52.2,49.8,45.6,41.0,33.1,29.5,27.3.IR(KBr)ν3438,2949,1615,1557,1387,759cm-1.HRMS(ESI)calcd for C46H44N3O[M+H]+654.3479,found 654.3488.
化合物3e(白色固体,95%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.51(d,J=8.0Hz,1H),7.29-7.16(m,11H),6.90(dd,J1=4.0Hz,J2=8.0Hz,3H),6.81(t,J=8.0Hz,2H),6.72-6.48(m,4H),6.23(d,J=8.0Hz,1H),5.30(d,J=8.0Hz,2H),5.15(d,J=8.0Hz,1H),4.55(s,1H),4.23(d,J=8.0Hz,1H),3.83(d,J=12.0Hz,1H),3.73(d,J=16.0Hz,1H),3.53(d,J=12.0Hz,1H),3.30(d,J=16.0Hz,1H),2.85(d,J=8.0Hz,1H),2.29-2.05(m,3H),1.73(d,J=16.0Hz,1H),1.03(s,3H),0.81(s,3H);13C NMR(100MHz,CDCl3)δ192.3,160.8(d,J=246.0Hz,1C),154.1,140.7,138.2,137.7,136.9,136.8,136.7,132.5,131.4,129.8,129.1,128.6,128.4,127.7,127.3,127.1,126.8,126.7,126.6,125.9,125.4,125.3,123.5,122.2,106.4,96.6,74.7,61.3,58.4,57.3,52.6,49.8,45.2,41.0,33.1,29.5,27.5.IR(KBr)ν3440,2953,1611,1566,1502,1220,757cm-1.HRMS(ESI)calcd for C46H42FN3NaO[M+Na]+694.3204,found 694.3190.
化合物3f(白色固体,95%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.50(d,J=8.0Hz,1H),7.25-7.17(m,11H),7.08(d,J=8.0Hz,2H),6.92(t,J=8.0Hz,3H),6.73(d,J=8.0Hz,1H),6.53(q,J=8.0Hz,3H),6.23(d,J=8.0Hz,1H),5.29(t,J=8.0Hz,2H),5.16(d,J=8.0Hz,1H),4.60(s,1H),4.23(d,J=8.0Hz,1H),3.82(d,J=12.0Hz,1H),3.72(d,J=12.0Hz,1H),3.52(d,J=12.0Hz,1H),3.31(d,J=16.0Hz,1H),2.83(d,J=8.0Hz,1H),2.28-2.09(m,3H),1.73(d,J=16.0Hz,1H),1.03(s,3H),0.82(s,3H);13C NMR(100MHz,CDCl3)δ192.4,153.7,140.6,139.4,138.2,137.7,136.6,132.6,132.2,131.4,129.8,129.3,129.1,128.6,128.3,127.7,127.3,127.1,126.8,126.6(2C),125.9,125.4,125.3,123.5,122.4,106.9,96.6,74.6,61.4,58.4,57.2,52.5,49.8,45.2,41.1,33.2,29.6,27.4.IR(KBr)ν3440,2929,1614,1564,1387,762cm-1.HRMS(ESI)calcdfor C46H43ClN3O[M+H]+688.3089,found 688.3077.
化合物3g(白色固体,89%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.42(d,J=8.0Hz,1H),7.23-7.07(m,13H),6.87-6.81(m,3H),6.66(d,J=8.0Hz,1H),6.45(t,J=8.0Hz,3H),6.15(d,J=8.0Hz,1H),5.22(t,J=8.0Hz,2H),5.08(d,J=8.0Hz,1H),4.53(s,1H),4.15(d,J=8.0Hz,1H),3.75(d,J=12.0Hz,1H),3.65(d,J=16.0Hz,1H),3.45(d,J=12.0Hz,1H),3.24(d,J=16.0Hz,1H),2.74(d,J=8.0Hz,1H),2.05(d,J=8.0Hz,3H),1.66(d,J=16.0Hz,1H),0.95(s,3H),0.75(s,3H);13C NMR(100MHz,CDCl3)δ192.5,153.6,140.6,140.0,138.2,137.7,136.6,132.6,132.3,131.4,129.8,129.1,128.6,128.4,127.7,127.3,127.1,126.8,126.6,125.9,125.4,125.3,123.5,122.4,120.1,106.9,96.7,74.6,61.4,58.4,57.3,52.5,49.8,45.2,41.1,33.3,29.7,27.4,one carbon missing in the aromatic region.IR(KBr)ν3426,2950,1615,1563,1387,762cm-1.HRMS(ESI)calcd for C46H43BrN3O[M+H]+732.2584,found 732.2587.
化合物3h(黄色固体,95%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.88(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,1H),7.34-7.20(m,11H),6.96(t,J=8.0Hz,1H),6.86(s,2H),6.70(d,J=8.0Hz,1H),6.61(q,J=8.0Hz,3H),6.26(d,J=8.0Hz,1H),5.37(s,1H),5.28(d,J=4.0Hz,1H),5.11(d,J=8.0Hz,1H),4.77(s,1H),4.17(d,J=8.0Hz,1H),3.86(d,J=12.0Hz,1H),3.76(d,J=12.0Hz,1H),3.54(d,J=12.0Hz,1H),3.25(d,J=16.0Hz,1H),2.67(d,J=8.0Hz,1H),2.30(d,J=16.0Hz,1H),2.21(s,2H),1.75(d,J=16.0Hz,1H),1.05(s,3H),0.88(s,3H);13C NMR(100MHz,CDCl3)δ193.1,152.3,147.0,144.6,139.9,138.0,137.4,136.5,132.7,131.6,129.8,128.7,128.6,128.3,127.9,127.2,127.1,127.0,126.8,126.4,125.7,125.6,125.3,124.4,123.5,122.4,109.5,96.7,74.2,61.1,58.6,57.3,52.9,49.9,44.9,41.6,33.7,29.8,27.0.IR(KBr)ν3421,2930,1618,1556,1340,760cm-1.HRMS(ESI)calcd for C46H42N4NaO3[M+Na]+721.3149,found721.3165.
化合物3i(白色固体,90%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.51(d,J=8.0Hz,1H),7.21-7.12(m,12H),7.01(t,J=8.0Hz,1H),6.89(t,J=8.0Hz,4H),6.70(d,J=8.0Hz,1H),6.42(q,J=8.0Hz,3H),6.19(d,J=12.0Hz,1H),5.24(q,J=8.0Hz,3H),4.68(s,1H),4.29(d,J=8.0Hz,1H),3.83(d,J=16.0Hz,1H),3.68(d,J=24.0Hz,1H),3.56(d,J=16.0Hz,1H),3.28(d,J=20.0Hz,1H),2.90(dd,J1=J2=8.0Hz,1H),2.20(s,3H),2.15(s,2H),1.77(d,J=12.0Hz,1H),1.04(s,3H),0.83(s,3H);13C NMR(100MHz,CDCl3)δ192.2,154.3,140.9,140.7,139.5,138.3,137.8,136.7,132.6,131.3,129.8,129.3,128.8,128.5,128.4,127.6,127.5,127.3,127.1,126.8,126.7,126.5,126.0,125.5,125.3,123.5,123.2,122.3,106.1,96.4,74.6,61.4,58.2,57.2,52.4,49.9,45.4,41.1,33.2,29.7,27.3,21.2.IR(KBr)ν3438,2952,1609,1562,1396,753cm-1.HRMS(ESI)calcd for C47H46N3O[M+H]+668.3635,found 668.3635.
化合物3j(白色固体,97%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.50(d,J=8.0Hz,1H),7.29-7.13(m,11H),7.04(q,J=12.0Hz,2H),6.91(d,J=8.0Hz,3H),6.72(d,J=8.0Hz,2H),6.57(s,2H),6.23(d,J=8.0Hz,1H),5.28(t,J=8.0Hz,2H),5.20(d,J=12.0Hz,1H),4.67(s,1H),4.25(d,J=8.0Hz,1H),3.82(d,J=16.0Hz,1H),3.72(d,J=20.0Hz,1H),3.53(d,J=16.0Hz,1H),3.31(d,J=20.0Hz,1H),2.83(d,J=12.0Hz,1H),2.16(d,J=12.0Hz,3H),1.73(d,J=12.0Hz,1H),1.04(s,3H),0.85(s,3H);13CNMR(100MHz,CDCl3)δ192.6,153.4,142.1,140.5(2C),138.2,137.5,136.6,132.4,131.3,129.7,129.0,128.6,128.3,127.7,127.3,127.2,127.1,126.9,126.8,126.7,126.6,126.5,125.9,125.4,125.3,123.5,122.3,107.0,96.6,74.7,61.3,58.2,57.2,52.3,49.8,45.6,41.1,33.3,29.8,27.2.IR(KBr)ν3427,2952,1611,1564,1394,759cm-1.HRMS(ESI)calcd for C46H42ClN3NaO[M+Na]+710.2909,found 710.2905.
化合物3k(白色固体,93%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.49(d,J=12.0Hz,1H),7.22-7.15(m,12H),7.01-6.82(m,5H),6.73(d,J=12.0Hz,1H),6.58(d,J=16.0Hz,2H),6.23(d,J=8.0Hz,1H),5.30(d,J=8.0Hz,1H),5.25(s,1H),5.21(d,J=12.0Hz,1H),4.67(s,1H),4.26(s,1H),3.82(d,J=16.0Hz,1H),3.72(d,J=20.0Hz,1H),3.53(d,J=16.0Hz,1H),3.30(d,J=20.0Hz,1H),2.84(s,1H),2.16(d,J=12.0Hz,3H),1.71(t,J=20.0Hz,1H),1.04(s,3H),0.85(s,3H);13C NMR(100MHz,CDCl3)δ192.5,153.3,142.3,142.2,140.5,138.1,137.5,136.6,131.3,130.1,130.0,129.7,129.6,129.1,128.5,128.3,127.7,127.3,127.1,126.8,126.5,125.9,125.4,125.3,123.6,123.5,122.3(2C),106.8,96.6,74.8,61.3,58.2,57.2,52.2,49.8,45.7,41.1,33.3,29.8,27.2.IR(KBr)ν3444,2952,1612,1562,1395,759cm-1.HRMS(ESI)calcd forC46H42BrN3NaO[M+Na]+754.2403,found 754.2398.
化合物3l(白色固体,90%收率,1.6:1dr,通过柱色谱分离纯化(石油醚:乙酸乙酯=4:1)):1H NMR(400MHz,CDCl3),δ7.49(dd,J1=J2=8.0Hz,1H),7.25-7.14(m,12H),6.96-6.84(m,5H),6.68(t,J=8.0Hz,2H),6.49(t,J=8.0Hz,1H),6.24(d,J=8.0Hz,1H),5.33-5.20(m,3H),4.52(s,1H),4.27(d,J=8.0Hz,1H),3.86-3.54(m,3H),3.34(t,J=16.0Hz,1H),2.95(d,J=8.0Hz,1H),2.21-1.96(m,3H),1.77(dd,J1=J2=16.0Hz,1H),1.04(s,3H),0.80(s,3H);13C NMR(100MHz,CDCl3)δ192.5,159.1,156.6,154.6,140.8,138.4,138.1,136.7,132.4,131.3(d,J=36.0Hz,1C),129.9,129.4,129.3,128.6,128.5,128.3,127.6,127.3,127.3,127.1,126.8,126.6,126.5,125.9,125.4,125.3,125.1,122.8(d,J=144.0Hz,1C),116.7(d,J=20.0Hz,1C),106.8,96.6,73.9,61.4,58.4,56.9,52.5,49.8,45.9,40.6,32.9,29.2.IR(KBr)ν3430,1620,1562,1390,757cm-1.HRMS(ESI)calcd forC46H43FN3O[M+H]+672.3385,found 672.3366.
化合物3m(白色固体,89%收率,>20:1dr,通过过滤分离纯化):1H NMR(400MHz,CDCl3),δ7.53(d,J=8.0Hz,1H),7.25-7.12(m,11H),6.94-6.5(m,5H),6.69-6.47(m,4H),6.19(d,J=8.0Hz,1H),5.27(d,J=12.0Hz,2H),5.18(d,J=8.0Hz,1H),4.63(s,1H),4.28(d,J=8.0Hz,1H),3.79(d,J=12.0Hz,1H),3.67(d,J=16.0Hz,1H),3.53(d,J=12.0Hz,1H),3.32(d,J=16.0Hz,1H),2.93(d,J=4.0Hz,1H),2.34-2.15(m,6H),1.97(d,J=16.0Hz,1H),1.83-1.74(m,2H);13C NMR(100MHz,CDCl3)δ192.5,156.3,141.0,138.3,138.2,137.9,136.7,136.6,132.5,131.2,130.8,129.7,129.5,128.4,128.3,128.1,127.4,127.3,127.0,126.8,126.6,126.4,126.1,125.3,125.3,123.5,122.2,106.6,96.4,74.6,61.4,58.0,57.0,52.3,45.9,36.3,27.3,22.4,20.8.IR(KBr)ν3436,2932,1612,1558,1446,751cm-1.HRMS(ESI)calcd for C45H42N3O[M+H]+640.3322,found 640.3323.
化合物3n(白色固体,88%收率,>20:1dr,通过柱色谱分离纯化(石油醚:乙酸乙酯=4:1)):1H NMR(400MHz,CDCl3),δ7.37(dd,J1=J2=8.0Hz,3H),7.25-7.20(m,9H),7.03(d,J=4.0Hz,2H),6.97(t,J=8.0Hz,2H),6.83(t,J=4.0Hz,2H),6.40(t,J=8.0Hz,1H),6.13(d,J=4.0Hz,1H),5.51(dd,J1=J2=4.0Hz,3H),5.43(d,J=4.0Hz,1H),4.62(s,1H),4.01(d,J=16.0Hz,1H),3.79(d,J=12.0Hz,1H),3.71(d,J=4.0Hz,1H),3.59(d,J=4.0Hz,1H),3.56(s,1H),2.50(s,3H),2.14(d,J=16.0Hz,1H),2.04(s,2H),1.77(d,J=20.0Hz,1H),1.03(s,3H),0.83(s,3H);13C NMR(100MHz,CDCl3)δ191.8,154.1,144.3,139.3,138.4,137.7,137.6,136.3,133.0,131.0,131.0,130.4,130.2,129.4,129.1,128.7,128.7,128.6,128.0,127.5,127.4,127.1,126.3,125.7,124.8,124.0,118.9,104.3,95.1,78.0,60.5,56.7,55.1,49.8,48.7,48.2,40.8,32.9,27.5,21.2.IR(KBr)ν3440,2925,1630,794cm-1.HRMS(ESI)calcd for C47H44Br2N3O[M+H]+824.1846,found824.1834.
化合物3o(白色固体,82%收率,>20:1dr,通过柱色谱分离纯化(石油醚:乙酸乙酯=4:1)):1H NMR(400MHz,CDCl3),δ7.44(d,J=8.0Hz,1H),7.34-7.23(m,8H),7.19(d,J=8.0Hz,2H),6.98(s,2H),6.90(d,J=4.0Hz,2H),6.78(d,J=4.0Hz,1H),6.56(dd,J1=J2=4.0Hz,2H),6.49(s,1H),6.30(d,J=8.0Hz,1H),5.24(t,J=8.0Hz,2H),4.78(d,J=8.0Hz,1H),4.43(s,1H),4.07(d,J=8.0Hz,1H),3.82(dd,J1=8.0Hz,J2=12.0Hz,2H),3.51(d,J=12.0Hz,1H),3.35(d,J=16.0Hz,1H),2.76(d,J=8.0Hz,1H),2.32(s,3H),2.13(d,J=16.0Hz,3H),1.80(d,J=20.0Hz,1H),1.02(s,3H),0.83(s,3H);13C NMR(100MHz,CDCl3)δ192.2,154.6,140.1,137.7,137.7,137.6,137.4,137.2,134.7,134.1,131.6,130.3,129.9,129.8,128.7,128.5,127.8,127.7,127.4,127.3,126.8,126.1,124.9,124.6,123.0,120.7,119.0,105.2,95.9,73.4,61.0,58.6,57.1,52.6,49.8,44.3,40.9,33.1,29.6,20.9.IR(KBr)ν3437,2924,1614,1566,1393,723cm-1.HRMS(ESI)calcd forC47H44Br2N3O[M+H]+824.1846,found 824.1854.
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.一种具有多环桥环骨架的多取代四氢异喹啉,其特征在于结构式如下:其中,R1为烷基、卤素或氢;R2为甲基或氢,R3为烷基、卤素或氢。
2.根据权利要求1所述的具有多环桥环骨架的多取代四氢异喹啉的制备方法,其特征在于步骤如下:将烯胺酮和N-苄基异喹啉溴盐,在有机溶剂中、碱的存在下,25-80℃反应5分钟至24小时,薄层色谱跟踪反应至完全,反应结束后,通过用布氏漏斗过滤或柱色谱分离纯化,得到目标产物,其反应通式如下:
其中,R1为烷基、卤素或氢;R2为甲基或氢,R3为烷基、卤素或氢。
3.根据权利要求2所述的多环桥环多取代四氢异喹啉的制备方法,其特征在于:所述的碱为无机碱或有机碱,所述的无机碱为碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾或醋酸钠;所述的有机碱为三乙胺、吡啶、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、三乙烯二胺(DABCO)或四甲基胍(TMG)。
4.根据权利要求3所述的具有多环桥环骨架的多取代四氢异喹啉的制备方法,其特征在于:所述的碱为1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)。
5.根据权利要求3或4所述的具有多环桥环骨架的多取代四氢异喹啉的制备方法,其特征在于:所述的碱的物质的量为烯胺酮物质的量的3.6倍。
6.根据权利要求2所述的具有多环桥环骨架的多取代四氢异喹啉的制备方法,其特征在于:所述的有机溶剂为二甲亚砜、N,N-二甲基甲酰胺、乙腈、甲醇、乙醇、甲苯、氯仿、二氯甲烷、1,2-二氯乙烷、乙醚、四氢呋喃、1,4-二氧六环或乙酸乙酯。
7.根据权利要求6所述的具有多环桥环骨架的多取代四氢异喹啉的制备方法,其特征在于:所述的有机溶剂为乙腈。
8.根据权利要求2所述的具有多环桥环骨架的多取代四氢异喹啉的制备方法,其特征在于:所述反应温度为60℃。
9.根据权利要求2所述的具有多环桥环骨架的多取代四氢异喹啉的制备方法,其特征在于:所述烯胺酮与N-苄基异喹啉溴盐的摩尔比为1:1-1:4。
10.根据权利要求9所述的具有多环桥环骨架的多取代四氢异喹啉的制备方法,其特征在于:所述烯胺酮与N-苄基异喹啉溴盐的摩尔比为1:2.2。
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