一种二苯并环庚烷衍生物的制备方法与流程

文档序号:11103833

本发明属于有机合成领域,具体涉及一种二苯并环庚烷衍生物及其制备方法。



背景技术:

秋水仙碱(colchicine)能够与微管蛋白二聚体结合,阻止微管蛋白转换,使细胞停止于有丝分裂中期,从而导致细胞死亡,因此,可以用于地中海热综合征、急性通风等疾病的治疗;而且,它具有很好的抗肿瘤活性,在化疗中具有良好的效果,但是,临床研究表明,秋水仙碱具有较大的毒性不能高剂量的使用。幸运的是,二苯并环庚烷衍生物,包括别秋水仙碱(allocolchicine)、N-acetylcolchinol等许多具有生理活性的药物分子或天然产物,则表现出了比秋水仙碱更强的微管蛋白结合活性和更小的毒副作用(S.Larsson and N.Curr.Top.Med.Chem.,2014,14,274),是一种更有前景的抗肿瘤候选药物之一,因此,二苯并环庚烷衍生物的合成非常重要。

近几年来,二苯并环庚烷的合成研究愈来愈多,比较典型的方法是利用过渡金属MoCl5/TiCl4、Tl(OCOCF3)3、Pb(OAc)4或PhI(OCOCF3)2催化1,3-二芳基丙烷或1,3-二芳基丙烯氧化二芳基偶联反应合成:

但是,上述反应所用的试剂往往具有较强的毒性或者过量的使用强氧化剂,导致难以用于药物分子的合成或者造成反应的适用范围不够理想。其他的一些合成途径则往往需要较多的反应步骤,导致总产率偏低,合成成本较高。鉴于二苯并环庚烷衍生物的优良药用价值,发展简单、高效的二苯并环庚烷合成路线,开发新的抗癌活性药物分子迫在眉睫。



技术实现要素:

本发明要解决的技术问题是提供了一种反应收率良好,绿色环保且具有良好适用范围的二苯并环庚烷衍生物制备方法。

为解决该技术问题,本发明采用的技术方案为:

一种二苯并环庚烷衍生物的制备方法,其特征在于包括如下步骤:

将铜催化剂、碱和配体溶解在有机溶剂中,加入结构式Ⅱ所示的联苯乙炔类化合物和结构式Ⅲ所示α-溴代烯丙基丙二酸二乙酯形成反应体系,体系在110℃下反应12小时后,经淬灭、萃取、洗涤、干燥和柱层析处理得到结构式I所示的二苯并环庚烷衍生物;

其中,R1为氢、甲基、甲氧基、氟、氯、乙酰基、甲酸甲酯基、三氟甲基、苯基或苯乙炔基。

所述的铜催化剂、碱、配体、结构式Ⅱ所示化合物和结构式Ⅲ所示化合物的摩尔比为0.1:2:0.2:1:1.2。

所述的铜催化剂为六氟磷酸四乙腈铜,所述的碱为碳酸钠,所述的配体为联吡啶,所述有机溶剂为甲苯。

所述的萃取可采用乙酸乙酯作为萃取剂。

所述的洗涤可采用饱和食盐水洗。

所述的柱层析分离的条件为:硅胶300-400目,洗脱液:石油醚/乙酸乙酯的体积比为10/1。

同现有技术相比,本发明具有如下优点:1、首次采用铜催化完成α-溴代烯丙基丙二酸二乙酯与联苯乙炔的环化反应;2、实现了一系列二苯并环庚烷衍生物的合成,底物适用范围广,官能团兼容性好;3、反应操作简单,绿色环保,具有良好应用前景。故本发明具有较大的理论创新价值以及实施价值。

具体实施方式

实施例1

取一支干燥的反应管,称入六氟磷酸四乙腈铜(9.0mg,0.025mmol)、碳酸钠(53.0mg,0.5mmol)、联吡啶(7.8mg,0.05mmol),然后加入溶于5mL甲苯的联苯乙炔1a(44.5mg,0.25mmol)和α-溴代烯丙基丙二酸二乙酯2a(83.4mg,0.3mmol)。体系在110℃下反应12h后,加10mL水淬灭,用乙酸乙酯(10mL)萃取三次,合并后用饱和食用水洗涤有机相,无水硫酸钠干燥。有机相浓缩后用硅胶(300-400目)柱层析分离(洗脱液:石油醚/乙酸乙酯的体积比为10/1)得到77mg白色固体3aa,熔点86–88℃,收率82%。产物核磁分析1H NMR(600MHz,CDCl3):δ7.46–7.40(m,2H),7.34–7.28(m,4H),7.25–7.21(m,1H),7.18–7.14(m,1H),5.67–5.64(m,1H),4.24–4.17(m,2H),4.09–4.02(m,2H),3.81–3.74(m,1H),3.04–2.98(m,1H),2.75–2.71(m,1H),2.53–2.48(m,1H),2.13–2.07(m,1H),1.27(t,J=7.1Hz,3H),1.12(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ170.9,170.5,151.3,140.9,139.7,136.1,135.9,130.3,130.0,128.6,128.5,127.4,127.2,127.0,127.0,125.5,65.3,61.4,61.2,53.9,37.4,35.2,14.0,13.8;HRMS(ESI)calcd for C24H25O4(M+H)+377.1753,found 377.1745.

反应式如下:

实施例2

除用结构式1b所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:65%,无色液体。1H NMR(600MHz,CDCl3):δ7.44–7.39(m,2H),7.32–7.26(m,2H),7.21–7.18(m,1H),7.12–7.09(m,1H),6.99–6.96(m,1H),5.68–5.63(m,1H),4.24–4.18(m,2H),4.12–4.04(m,2H),3.79–3.73(m,1H),3.02–2.97(m,1H),2.74–2.70(m,1H),2.49–2.45(m,1H),2.35(s,3H),2.14–2.08(m,1H),1.27(t,J=7.1Hz,3H),1.14(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ171.0,170.6,151.5,139.7,138.0,136.9,136.0,135.9,131.1,129.9,128.6,128.5,127.7,127.1,127.0,125.3,65.3,61.5,61.2,53.7,37.5,35.2,21.1,14.1,13.9;HRMS(ESI)calcd for C25H27O4(M+H)+391.1909,found 391.1905.

反应式如下:

实施例3

除用结构式1c所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:73%,白色固体,熔点为102–104℃。1H NMR(600MHz,CDCl3):δ7.41–7.38(m,2H),7.30–7.26(m,2H),7.24–7.20(m,1H),6.85–6.81(m,1H),6.74–6.71(m,1H),5.67–5.65(m,1H),4.24–4.18(m,2H),4.12–4.05(m,2H),3.82(s,3H),3.78–3.74(m,1H),3.03–2.98(m,1H),2.76–2.71(m,1H),2.50–2.45(m,1H),2.13–2.07(m,1H),1.27(t,J=7.1Hz,3H),1.15(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ170.9,170.5,158.6,151.4,139.4,137.6,135.7,133.5,131.1,128.5,128.4,127.0,126.9,125.2,116.1,111.7,65.2,61.4,61.2,55.2,53.5,37.6,35.4,14.0,13.8;HRMS(ESI)calcd for C25H27O5(M+H)+407.1858,found 407.1850.

反应式如下:

实施例4

除用结构式1d所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:71%,无色液体。1H NMR(600MHz,CDCl3):δ7.44–7.39(m,2H),7.34–7.31(m,1H),7.29–7.26(m,2H),7.01–6.97(m,1H),6.92–6.89(m,1H),5.68–5.65(m,1H),4.25–4.18(m,2H),4.13–4.06(m,2H),3.81–3.73(m,1H),3.02–2.97(m,1H),2.77–2.73(m,1H),2.52–2.46(m,1H),2.10–2.04(m,1H),1.27(t,J=7.1Hz,3H),1.15(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ170.8,170.4,161.2(d,J=246.7Hz),150.9,138.8,138.4(d,J=7.6Hz),137.0(d,J=3.1Hz),135.8,131.5(d,J=8.2Hz),128.6,128.6,127.5,127.1,125.7,117.0(d,J=21.1Hz),113.7(d,J=20.9Hz),65.3,61.5,61.3,53.6,37.4,35.2,14.1,13.9;19F NMR(565MHz,CDCl3):δ-115.9;HRMS(ESI)calcd for C24H24O4F(M+H)+395.1659,found 395.1649.

反应式如下:

实施例5

除用结构式1e所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:73%,白色固体,熔点为100–102℃。1H NMR(600MHz,CDCl3):δ7.45–7.39(m,2H),7.36–7.33(m,1H),7.29–7.27(m,2H),7.24–7.21(m,1H),7.19–7.15(m,1H),5.70–5.65(m,1H),4.26–4.18(m,2H),4.15–4.05(m,2H),3.83–3.76(m,1H),3.01–2.95(m,1H),2.79–2.74(m,1H),2.51–2.46(m,1H),2.09–2.03(m,1H),1.27(t,J=7.1Hz,3H),1.16(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ170.7,170.3,150.7,139.4,138.5,138.0,135.8,132.7,131.2,130.0,128.6,128.5,127.7,127.1,127.0,125.8,65.2,61.5,61.3,53.6,37.3,35.0,14.0,13.8;HRMS(ESI)calcd for C24H24O4Cl(M+H)+411.1363,found 411.1358.

反应式如下:

实施例6

除用结构式1f所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:70%,白色固体,熔点为111–113℃。1H NMR(600MHz,CDCl3):δ7.92–7.86(m,1H),7.81–7.72(m,1H),7.49–7.44(m,2H),7.41–7.37(m,2H),7.32–7.29(m,1H),5.71–5.67(m,1H),4.26–4.20(m,2H),4.13–4.01(m,2H),3.88–3.77(m,1H),3.07–3.00(m,1H),2.79–2.72(m,1H),2.63(s,3H),2.63–2.59(m,1H),2.10–2.03(m,1H),1.27(t,J=7.1Hz,3H),1.13(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ198.0,170.7,170.3,150.6,146.1,138.6,136.7,136.0,135.7,130.3,129.9,128.8,128.7,128.3,127.4,127.2,126.2,65.2,61.5,61.3,53.7,37.4,35.2,26.7,14.1,13.9;HRMS(ESI)calcd for C26H27O5(M+H)+419.1858,found 419.1844.

反应式如下:

实施例7

除用结构式1g所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:70%,白色固体,熔点为96–98℃。1H NMR(600MHz,CDCl3):δ7.99–7.95(m,1H),7.86–7.84(m,1H),7.47–7.44(m,2H),7.38–7.36(m,2H),7.31–7.29(m,1H),5.69–5.67(m,1H),4.24–4.19(m,2H),4.10–4.02(m,2H),3.93(s,3H),3.83–3.79(m,1H),3.05–3.01(m,1H),2.77–2.73(m,1H),2.62–2.59(m,1H),2.05–2.10(m,1H),1.27(t,J=7.1Hz,3H),1.13(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ170.7,170.4,167.0,150.7,145.8,138.6,136.4,136.0,131.3,130.1,128.8,128.7,128.6,128.3,128.2,127.2,126.1,65.2,61.5,61.3,53.7,52.1,37.3,35.1,14.0,13.8;HRMS(ESI)calcd for C26H27O6(M+H)+435.1808,found 435.1804.

反应式如下:

实施例8

除用结构式1h所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:76%,无色液体。1H NMR(600MHz,CDCl3):δ7.57–7.54(m,1H),7.47–7.44(m,2H),7.43–7.37(m,3H),7.32–7.30(m,1H),5.72–5.65(m,1H),4.26–4.18(m,2H),4.11–4.03(m,2H),3.85–3.79(m,1H),3.06–3.02(m,1H),2.82–2.77(m,1H),2.61–2.57(m,1H),2.07–2.01(m,1H),1.28(t,J=7.1Hz,3H),1.11(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ170.7,170.3,150.3,144.7,138.3,137.1,136.0,130.3,129.1(q,J=32.3Hz),128.8,128.7,128.3,127.2,126.8(q,J=4.0Hz),126.2,124.1(q,J=272.2Hz),123.9(q,J=4.2Hz),65.3,61.6,61.3,53.7,37.3,35.2,14.0,13.8;19F NMR(565MHz,CDCl3):δ-62.2;HRMS(ESI)calcd for C25H24O4F3(M+H)+445.1627,found 445.1624.

反应式如下:

实施例9

除用结构式1i所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:77%,白色固体,熔点为153–155℃。1H NMR(600MHz,CDCl3):δ7.66–7.60(m,2H),7.56–7.52(m,1H),7.51–7.47(m,1H),7.47–7.42(m,3H),7.42–7.32(m,4H),7.32–7.28(m,1H),5.72–5.65(m,1H),4.27–4.17(m,2H),4.10–4.00(m,2H),3.85–3.78(m,1H),3.11–3.02(m,1H),2.79–2.73(m,1H),2.65–2.55(m,1H),2.17–2.10(m,1H),1.27(t,J=7.1Hz,3H),1.10(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ170.9,170.5,151.2,140.7,140.0,140.0,139.3,136.6,136.0,130.5,128.9,128.7,128.7,128.6,127.5,127.3,127.1,127.1,125.7,125.6,65.3,61.5,61.2,53.8,37.5,35.5,14.1,13.8;HRMS(ESI)calcd for C30H29O4(M+H)+453.2066,found 453.2062.

反应式如下:

实施例10

除用结构式1j所示的联苯乙炔类化合物代替实施事例1中结构式1a所示的联苯乙炔外,其余操作步骤同实施例1,产率:52%,白色固体,熔点为152–154℃。1H NMR(600MHz,CDCl3):δ7.56–7.54(m,2H),7.48–7.43(m,3H),7.37–7.34(m,5H),7.30–7.28(m,2H),5.70–5.67(m,1H),4.24–4.18(m,2H),4.12–4.04(m,2H),3.83–3.78(m,1H),3.03–2.98(m,1H),2.80–2.73(m,1H),2.56–2.51(m,1H),2.14–2.07(m,1H),1.27(t,J=7.1Hz,3H),1.15(t,J=7.1Hz,3H);13C NMR(151MHz,CDCl3):δ170.8,170.5,150.9,141.2,139.0,136.4,136.0,133.3,131.6,130.3,130.1,128.7,128.6,128.3,128.2,127.8,127.1,125.9,123.3,122.0,89.7,89.4,65.3,61.5,61.3,53.7,37.5,35.1,14.1,13.9;HRMS(ESI)calcd for C32H29O4(M+H)+477.2066,found 477.2043.

反应式如下:

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