CN107266457A - 一种2,3′‑螺二吲哚啉‑2‑酮类化合物及其制备方法 - Google Patents

一种2,3′‑螺二吲哚啉‑2‑酮类化合物及其制备方法 Download PDF

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CN107266457A
CN107266457A CN201710592870.6A CN201710592870A CN107266457A CN 107266457 A CN107266457 A CN 107266457A CN 201710592870 A CN201710592870 A CN 201710592870A CN 107266457 A CN107266457 A CN 107266457A
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spiral shells
indole
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崔宝东
陈羽
单静
陈永正
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Zunyi Medical University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

本方案公开了一种2,3'‑螺二吲哚啉‑2‑酮类化合物，结构通式为：制备时，将3‑氨基氧化吲哚、2‑溴甲基芳基溴化物、一价铜盐催化剂和无机碱加入到有机溶剂中进行反应，反应完毕后经萃取、干燥、柱层析或重结晶处理得到2,3'‑螺二吲哚啉‑2‑酮类化合物，合成路线如下所示：本发明以3‑氨基氧化吲哚、2‑溴甲基芳基溴化物作为底物，再以一价铜盐催化底物的亲核取代/C(sp2)‑N交叉偶联一锅串联反应，合成结构多样性的2,3'‑螺二吲哚啉‑2‑酮类化合物，具有反应进行完全，易于纯化，产率高、操作简单等优点。

Description

一种2,3′-螺二吲哚啉-2-酮类化合物及其制备方法
技术领域
本发明涉及螺环杂环化合物和有机化学合成领域，特别涉及一种2,3'-螺二吲哚啉-2-酮类化合物及其制备方法。
背景技术
螺环氧化吲哚是构成许多药物和生物活性天然产物的核心结构单元。其中，螺吡咯烷-3,2'-氧化吲哚类化合物，其含有吡咯烷单元和氮杂原子与螺季碳中心相毗连的独特结构，广泛存在于药物活性分子与天然生物碱中。因此，螺吡咯烷-3,2'-氧化吲哚类化合物的合成一直是有机化学与药物化学界研究的热点。
目前，螺吡咯烷-3,2'-氧化吲哚类化合物的合成主要通过以下几类反应实现：(1)利用靛红衍生的硝酮与缺电子炔烃的[3+2]环加成反应来制备；(2)利用3-氨基氧化吲哚或靛红衍生的甲亚胺叶立德与缺电子烯烃的[3+2]环加成反应来制备；(3)利用卡宾催化的肉桂醛与靛红亚胺的加成/环化串联反应来制备等。尽管当前螺吡咯烷-3,2'-氧化吲哚类化合物的合成研究已经取得了较大进展，但是现有技术合成获得的此类化合物结构类型还不够广泛。因此，发展更加直接、高效、可供替代的合成技术实现螺吡咯烷-3,2'-氧化吲哚类化合物的结构多样性合成仍具有重要意义。
发明内容
本发明的目的在于提供一种以一价铜盐催化3-氨基氧化吲哚和2-溴甲基芳基溴化物的亲核取代/C(sp2)-N交叉偶联一锅串联反应，高产率合成系列结构多样化的2,3'-螺二吲哚啉-2-酮类化合物的方法。
本方案中的一种2,3'-螺二吲哚啉-2-酮类化合物，结构通式为：
结构通式中：R1选自5-Me、5-OMe、5-F、5-OCF3、7-F、7-CF3或7-OCF3；
R2选自Me、Et、nPr、nBu、iPr、Ph或Bn；
R3选自H和叔丁氧羰基(-Boc)；
R选自Me、Et、Ph；
Ar选自苯基、甲氧基取代苯基、[1,3]二氧戊烷并苯基、氟取代苯基、三氟甲基取代苯基、氯取代苯基、萘基或噻吩基。
本发明的2,3'-螺二吲哚啉-2-酮类化合物是一种新型的化合物，具有吲哚类化合物类似的特点，同时还可以作为抗肿瘤和抗菌类药物的活性分子使用。此外，本发明涉及2,3'-螺二吲哚啉-2-酮类化合物的制备方法与其他方法相比，是一种全新的方法，效率相对较高。
2,3'-螺二吲哚啉-2-酮类化合物的制备方法，包括以下步骤：将3-氨基氧化吲哚、2-溴甲基芳基溴化物、一价铜盐催化剂和无机碱加入到有机溶剂中进行反应，反应完毕后经萃取、干燥、柱层析或重结晶处理得到2,3'-螺二吲哚啉-2-酮类化合物，合成路线如下所示：
本发明的工作原理及有益效果：本发明以3-氨基氧化吲哚、2-溴甲基芳基溴化物作为底物，再以一价铜盐催化底物的亲核取代/C(sp2)-N交叉偶联一锅串联反应，合成结构多样性的2,3'-螺二吲哚啉-2-酮类化合物，是对2,3'-螺二吲哚啉-2-酮类化合物合成方法的重要补充；对利用3-氨基氧化吲哚参与的新的串联反应，用于合成其他新结构的螺环氧化吲哚类化合物具有重要的启示作用，而且本方法具有反应进行完全，易于纯化，产率高、操作简单等优点。
优选的，所述一价铜盐催化剂为碘化亚铜、溴化亚铜、氯化亚铜、氰化亚铜或硫酸亚铜。选用这些催化剂，反应的副产物较少，产率较高。
优选的，所述有机溶剂为甲苯、氯苯、氟苯、三氟甲苯、均三甲苯、二甲基亚砜、特戊醇、N,N-二甲基甲酰胺(DMF)、1,4-二氧六环或乙腈。选用这些溶剂，反应的产率较高。
优选的，所述无机碱为碳酸锂、碳酸钠、碳酸钾、碳酸铯、特戊酸钠、磷酸钾、叔丁醇钠、叔丁醇钾或叔丁醇锂。选用这些无机碱，反应的副产物较少，产率较高。
优选的，反应温度为80～170℃，反应时间为6～24h。针对不同的反应物，其反应的活性有所差异，所需反应时间也不同。
进一步优选的，反应完毕后采用柱层析分离方法处理。在生成的产物中，部分不是固体，通过柱层析分离纯化，更为实用。
附图说明
图1为本发明化合物3a的1H NMR谱图；
图2为本发明化合物3a的13C NMR谱图；
图3为本发明化合物3b的1H NMR谱图；
图4为本发明化合物3b的13C NMR谱图；
图5为本发明化合物3c的1H NMR谱图；
图6为本发明手性化合物3c的13C NMR谱图。
具体实施方式
下面通过具体实施方式对本发明作进一步详细的说明，但具体实施例并不对本发明作任何限定。除非特别说明，实施例中所涉及的试剂、方法均为本领域常用的试剂和方法。
本发明一种2,3'-螺二吲哚啉-2-酮类化合物及其制备方法，合成的化合物3a～c'，结构式如下：
制备方法的具体步骤如下：
合成代表性化合物3a的操作步骤：
实施例1：
称取3-氨基氧化吲哚1a(52.5mg,0.2mmol)、2-溴苄溴2a(55.0mg,0.22mmol)、tBuONa(0.8mmol,76.8mg,4.0equiv.)、CuBr(0.01mmol,1.4mg)于硬质反应管中，然后加入2.0mL DMF。反应液在100℃下搅拌反应12h。TLC监测反应进行完全后，向反应液中加入10.0mL水，并用乙酸乙酯萃取(6×5mL)。合并所得的有机相用饱和的食盐水洗涤、无水硫酸钠干燥、过滤和浓缩。最后所得的残留物经柱层析(石油醚/乙酸乙酯＝5:1)分离纯化得目标化合物3a(yield 86％)。
实施例2：
称取3-氨基氧化吲哚1a(52.5mg,0.2mmol)、2-溴苄溴2a(55.0mg,0.22mmol)、Cs2CO3(0.8mmol,260.7mg,4.0equiv.)、CuI(0.01mmol,1.9mg)于硬质反应管中，然后加入2.0mL DMF。反应液在100℃下搅拌反应24h。TLC监测反应进行完全后，向反应液中加入10.0mL水，并用乙酸乙酯萃取(6×5mL)。合并所得的有机相用饱和的食盐水洗涤、无水硫酸钠干燥、过滤和浓缩。最后所得的残留物经柱层析(石油醚/乙酸乙酯＝5:1)分离纯化得目标化合物3a(yield 76％)。
实施例3：
称取3-氨基氧化吲哚1a(52.5mg,0.2mmol)、2-溴苄溴2a(55.0mg,0.22mmol)、tBuOK(0.8mmol,89.8mg,4.0equiv.)、CuBr(0.01mmol,1.4mg)于硬质反应管中，然后加入2.0mL DMF。反应液在100℃下搅拌反应12h。TLC监测反应进行完全后，向反应液中加入10.0mL水，并用乙酸乙酯萃取(6×5mL)。合并所得的有机相用饱和的食盐水洗涤、无水硫酸钠干燥、过滤和浓缩。最后所得的残留物经柱层析(石油醚/乙酸乙酯＝5:1)分离纯化得目标化合物3a(yield 77％)。
实施例4：
称取3-氨基氧化吲哚1a(52.5mg,0.2mmol)、2-溴苄溴2a(55.0mg,0.22mmol)、Cs2CO3(0.8mmol,260.7mg,4.0equiv.)、CuBr(0.01mmol,1.4mg)于硬质反应管中，然后加入2.0mL均三甲苯。反应液在100℃下搅拌反应24h。TLC监测反应进行完全后，向反应液中加入10.0mL水，并用乙酸乙酯萃取(6×5mL)。合并所得的有机相用饱和的食盐水洗涤、无水硫酸钠干燥、过滤和浓缩。最后所得的残留物经柱层析(石油醚/乙酸乙酯＝5:1)分离纯化得目标化合物3a(yield 74％)。
化合物3b～c'的制备：在本实施例中，使用与制备化合物3a相同的反应条件，可分别得到化合物3b～c'。
化合物3a～c'的数据表征如下：
3a:Yellow oil；60.3mg,yield 86％.1H NMR(400MHz,CDCl3):δ1.12(s,9H),3.21(d,J＝16.7Hz,1H),3.25(s,3H),3.65(d,J＝16.1Hz,1H),6.85(d,J＝7.7Hz,1H),6.98-7.03(m,2H),7.10-7.15(m,2H),7.24-7.27(m,1H),7.30-7.34(m,1H),7.98(d,J＝8.1Hz,1H)；13C NMR(100MHz,CDCl3):δ26.6,27.9,41.6,68.8,81.5,108.1,115.1,121.8,123.0,123.2,124.5,127.0,128.1,129.2,132.6,142.7,143.3,151.1,176.7.HRMS(ESI-TOF)calcd.for C21H22N2NaO3[M+Na]+373.1523；found:373.1523.
3b:White solid；40.1mg,yield 55％；mp 206.7-207.9℃.1H NMR(400MHz,CDCl3):δ1.11(s,9H),1.33(t,J＝7.2Hz,3H),3.23(d,J＝16.0Hz,1H),3.44-3.50(m,1H),3.63(d,J＝16.1Hz,1H),4.05-4.12(m,1H),6.87(d,J＝7.8Hz,1H),6.97-7.02(m,2H),7.10-7.14(m,2H),7.23(d,J＝7.7Hz,1H),7.28-7.32(m,1H),7.98(d,J＝7.9Hz,1H)；13CNMR(100MHz,CDCl3):δ13.1,27.9,35.2,41.7,68.8,81.6,108.2,115.1,121.9,123.0,124.4,127.0,128.1,129.1,132.8,142.0,143.5,151.1,176.2.HRMS(ESI-TOF)calcd.forC22H25N2O3[M+H]+365.1860；found:365.1869.
3c:White solid；42.1mg,yield 51％；mp 202.4-203.6℃.1H NMR(400MHz,CDCl3):δ1.17(s,9H),3.39(d,J＝16.1Hz,1H),3.75(d,J＝16.1Hz,1H),7.02-7.09(m,3H),7.16-7.22(m,3H),7.28(s,1H),7.39-7.42(m,1H),7.55-7.56(m,4H),8.04(d,J＝7.8Hz,1H)；13C NMR(100MHz,CDCl3):δ28.1,42.5,69.0,82.0,109.7,115.2,122.2,123.1,123.8,124.5,125.6,126.8,127.8,128.2,129.0,129.6,132.7,134.5,142.2,143.5,151.2,175.8.HRMS(ESI-TOF)calcd.for C26H24N2NaO3[M+Na]+435.1679；found:435.1686.
3d:Yellow oil；40.1mg,yield 47％.1H NMR(400MHz,CDCl3):δ1.12(s,9H),3.31(d,J＝16.0Hz,1H),3.73(d,J＝16.0Hz,1H),4.41(d,J＝15.4Hz,1H),5.42(d,J＝15.4Hz,1H),6.78(d,J＝7.1Hz,1H),6.96-7.01(m,1H),7.03(d,J＝7.3Hz,1H),7.12-7.17(m,2H),7.21(d,J＝7.2Hz,1H),7.28(d,J＝10.0Hz,2H),7.36(s,4H),8.02(d,J＝7.4Hz,1H)；13CNMR(100MHz,CDCl3):δ27.8,41.8,44.1,68.8,81.7,109.0,115.1,121.8,123.0,123.2,124.5,126.9,127.6,127.9,128.1,129.0,129.1,132.7,135.9,141.9,143.5,151.1,176.8.HRMS(ESI-TOF)calcd.for C27H26N2NaO3[M+Na]+449.1836；found:449.1851.
3e:Colourless oil；51.0 mg,yield 70％.1H NMR(400 MHz,CDCl3):δ1.13(s,9H),2.24(s,3H),3.19(d,J＝16.1 Hz,1H),3.22(s,3H),3.63(d,J＝16.1 Hz,1H),6.73(d,J＝7.8 Hz,1H),6.91(s,1H),6.99-7.03(m,1H),7.10(d,J＝7.7 Hz,1H),7.14(d,J＝7.4Hz,1H),7.23-7.27(m,1H),7.98(d,J＝8.1 Hz,1H)；13C NMR(100MHz,CDCl3):δ21.1,26.6,27.9,41.6,68.9,81.5,107.9,115.1,122.5,123.0,124.5,127.2,128.1,129.4,132.6,132.9,140.3,143.4,151.2,176.6.HRMS(ESI-TOF)calcd.for C22H24N2NaO3[M+Na]+387.1679；found:387.1686.
3f:White solid；54.0 mg,yield 71％；mp 163.2-164.5 ℃.1H NMR(400 MHz,CDCl3):δ1.14(s,9H),3.20(d,J＝16.2 Hz,1H),3.22(s,3H),3.64(d,J＝16.2 Hz,1H),3.70(s,3H),6.71(d,J＝1.9 Hz,1H),6.74(d,J＝8.5Hz,1H),6.82-6.84(m,1H),6.98-7.02(m,1H),7.13(d,J＝7.3 Hz,1H),7.23(d,J＝7.7 Hz,1H),7.97(d,J＝8.1Hz,1H)；13C NMR(100 MHz,CDCl3):δ26.6,27.9,41.6,56.0,69.1,81.5,108.6,109.0,113.6,115.1,123.0,124.5,127.0,128.1,133.7,136.2,143.3,151.0,156.6,176.4.HRMS(ESI-TOF)calcd.forC22H24N2NaO4[M+Na]+403.1628；found:403.1626.
3g:White solid；59.0 mg,yield 80％；mp 190.3-192.1 ℃.1H NMR(400 MHz,CDCl3):δ1.15(s,9H),3.19(d,J＝16.5 Hz,1H),3.24(s,3H),3.65(d,J＝16.0 Hz,1H),6.76-6.78(m,1H),6.87(d,J＝6.5 Hz,1H),7.00-7.04(m,2H),7.14(d,J＝7.0 Hz,1H),7.24-7.27(m,1H),7.97(d,J＝7.8 Hz,1H)；13C NMR(100 MHz,CDCl3):δ26.8,27.9,41.6,68.9,81.8,108.7(d,J＝7.6 Hz,1C),110.1(d,J＝24.8 Hz,1C),115.2,115.4(d,J＝23.4Hz,1C),123.2,124.5,126.6,128.3,134.0,138.7,143.2,150.8,159.6(d,J＝240.9 Hz,1C),176.4.HRMS(ESI-TOF)calcd.for C21H21FN2NaO3[M+Na]+391.1428；found:391.1436.
3h:Yellow solid；41.3 mg,yield 56％；mp 161.2-162.7 ℃.1H NMR(400 MHz,CDCl3):δ1.18(s,9H),3.20(d,J＝16.1 Hz,1H),3.46(s,3H),3.64(d,J＝16.0 Hz,1H),6.88-6.94(m,2H),6.99-7.07(m,2H),7.13(d,J＝7.4 Hz,1H),7.23-7.27(m,1H),7.97(d,J＝8.1 Hz,1H)；13C NMR(100 MHz,CDCl3):δ27.9,28.4,41.7,68.8,81.8,115.1,117.1(d,J＝19.2 Hz,1C),117.7,123.1,123.9(d,J＝6.2 Hz,1C),124.5,126.7,128.2,129.8,135.4,143.2,147.7(d,J＝242.3 Hz,1C),150.9,176.3.HRMS(ESI-TOF)calcd.forC21H21FN2NaO3[M+Na]+391.1428；found:391.1424.
3i:Yellow oil；49.4 mg,yield 59％.1H NMR(400 MHz,CDCl3):δ1.14(s,9H),3.19(d,J＝16.1 Hz,1H),3.47(s,3H),3.65(d,J＝15.9 Hz,1H),7.03-7.08(m,2H),7.15(d,J＝6.3 Hz,1H),7.28(s,2H),7.61(d,J＝7.4Hz,1H),7.98(d,J＝7.5 Hz,1H)；13C NMR(100 MHz,CDCl3):δ27.8,28.4,42.1,67.1,82.1,112.6(q,J＝33.2Hz,1C),115.1,122.3,122.6,123.3,124.6,125.2,126.5,127.0(q,J＝5.9 Hz,1C),128.4,135.2,140.5,143.2,150.7,176.3.HRMS(ESI-TOF)calcd.for C22H21F3N2NaO3[M+Na]+441.1397；found:441.1401.
3j:Yellow solid；31.0 mg,yield 62％；mp 259.9-262.1 ℃.1H NMR(400 MHz,CDCl3):δ3.23(s,3H),3.25(d,J＝15.8 Hz,1H),3.61(d,J＝15.8 Hz,1H),4.18(s,1H),6.71(d,J＝7.6 Hz,1H),6.79-6.86(m,2H),6.99-7.02(m,1H),7.08-7.14(m,2H),7.24(d,J＝7.7 Hz,1H),7.29-7.33(m,1H)；13C NMR(100 MHz,CDCl3):δ26.6,41.9,68.3,108.5,110.0,119.8,122.8,123.4,124.7,126.7,127.9,129.6,133.1,142.6,149.9,178.5.HRMS(ESI-TOF)calcd.for C16H15N2O[M+H]+251.1179；found:251.1182.
3k:Yellow solid；44.9 mg,yield 85％；mp 252.1-253.2 ℃.1H NMR(400 MHz,CDCl3):δ1.30(t,J＝7.1Hz,3H),3.25(d,J＝15.7 Hz,1H),3.62(d,J＝15.8 Hz,1H),3.78-3.81(m,2H),4.19(s,1H),6.71(d,J＝7.6 Hz,1H),6.78-6.83(m,1H),6.88(d,J＝7.6 Hz,1H),6.98-7.01(m,1H),7.09-7.14(m,2H),7.25(d,J＝7.4 Hz,1H),7.29-7.32(m,1H)；13CNMR(100 MHz,CDCl3):δ12.8,35.1,42.0,68.3,108.6,110.1,119.8,123.0,123.2,124.7,126.8,127.9,129.5,133.4,141.7,149.9,178.1.HRMS(ESI-TOF)calcd.for C17H17N2O[M+H]+265.1335；found:265.1339.
3l:White solid；29.4 mg,yield 47％；mp 223.8-224.6 ℃.1H NMR(400 MHz,CDCl3):δ3.39(d,J＝15.8Hz,1H),3.75(d,J＝15.7 Hz,1H),4.35(s,1H),6.75(d,J＝7.5Hz,1H),6.82-6.88(m,2H),7.03-7.07(m,1H),7.11-7.17(m,2H),7.23(d,J＝7.6 Hz,1H),7.33(d,J＝7.4 Hz,1H),7.40-7.47(m,3H),7.52-7.55(m,2H)；13CNMR(100 MHz,CDCl3):δ42.6,68.4,109.8,110.1,119.9,123.2,123.9,124.8,126.5,126.6,128.0,128.2,129.5,129.8,133.0,134.4,142.4,149.9,177.9.HRMS(ESI-TOF)calcd.for C21H17N2O[M+H]+313.1335；found:313.1347.
3m:Yellow solid；48.3 mg,yield 74％；mp 211.9-213.4 ℃.1H NMR(400 MHz,CDCl3):δ3.32(d,J＝15.7Hz,1H),3.69(d,J＝15.8 Hz,1H),4.26(s,1H),4.89(d,J＝15.5Hz,1H),4.96(d,J＝15.6 Hz,1H),6.73-6.76(m,2H),6.81-6.85(m,1H),6.95-6.99(m,1H),7.10-7.21(m,3H),7.25-7.29(m,2H),7.33(s,4H)；13C NMR(100MHz,CDCl3):δ42.2,44.1,68.3,109.5,110.1,119.9,123.0,123.4,124.8,126.7,127.5,127.9,128.0,129.0,129.5,133.1,135.8,141.7,149.9,178.7.HRMS(ESI-TOF)calcd.for C22H18N2NaO[M+Na]+349.1311；found:349.1323.
3n:Yellow solid；40.2 mg,yield 76％；mp 251.8-252.4 ℃.1H NMR(400 MHz,CDCl3):δ2.26(s,3H),3.21(s,3H),3.24(d,J＝15.8 Hz,1H),3.61(d,J＝15.8 Hz,1H),4.17(s,1H),6.70-6.75(m,2H),6.80-6.83(m,1H),7.06(s,1H),7.09-7.12(m,3H)；13C NMR(100 MHz,CDCl3):δ21.1,26.6,42.0,68.3,108.2,110.0,119.8,123.6,124.7,126.8,127.9,129.8,133.1,133.2,140.2,149.9,178.5.HRMS(ESI-TOF)calcd.for C17H17N2O[M+H]+265.1335；found:265.1339.
3o:White solid；39.2 mg,yield 73％；mp 190.9-192.8 ℃.1H NMR(400 MHz,CDCl3):δ3.22(s,3H),3.23(d,J＝15.8 Hz,1H),3.61(d,J＝15.8 Hz,1H),4.21(s,1H),6.71(d,J＝7.6 Hz,1H),6.76-6.83(m,2H),6.98-7.02(m,2H),7.08-7.13(m,2H)；13C NMR(100 MHz,CDCl3):δ26.7,42.0,68.5,109.1(d,J＝7.9 Hz,1C),110.1,111.1(d,J＝24.7Hz,1C),115.7(d,J＝23.4 Hz,1C),120.0,124.8,126.3,128.1,134.6(d,J＝7.6 Hz,1C),138.4,149.6,159.7(d,J＝240.9 Hz,1C),178.2.HRMS(ESI-TOF)calcd.for C16H13FN2NaO[M+Na]+291.0904；found:291.0911.
3p:Yellow solid；50.2 mg,yield 66％；mp 168.7-169.5 ℃.1H NMR(400 MHz,CDCl3):δ1.11(s,9H),3.16(d,J＝16.2 Hz,1H),3.24(s,3H),3.61(d,J＝16.1 Hz,1H),3.78(s,3H),6.72(s,1H),6.78(d,J＝8.5 Hz,1H),6.83(d,J＝7.6 Hz,1H),6.98-7.01(m,1H),7.10(d,J＝7.0 Hz,1H),7.29-7.33(m,1H),7.87(d,J＝8.6 Hz,1H)；13C NMR(100 MHz,CDCl3):δ26.6,27.9,41.6,55.8,68.9,81.3,108.1,110.9,112.7,115.5,121.8,123.2,128.4,129.2,132.6,137.0,142.8,151.1,156.0,176.6.HRMS(ESI-TOF)calcd.forC22H24N2NaO4[M+Na]+403.1628；found:403.1636.
3q:Yellow solid；51.3 mg,yield 65％；mp 228.0-229.6 ℃.1H NMR(400 MHz,CDCl3):δ1.10(s,9H),3.09(d,J＝15.8 Hz,1H),3.23(s,3H),3.54(d,J＝15.7 Hz,1H),5.93(d,J＝7.6 Hz,2H),6.61(s,1H),6.83(d,J＝7.4Hz,1H),7.00-7.02(m,1H),7.13(d,J＝6.8 Hz,1H),7.29-7.31(m,1H),7.63(s,1H)；13C NMR(100 MHz,CDCl3):δ26.6,27.9,41.3,69.4,81.4,98.4,101.4,104.9,108.1,118.7,121.7,123.2,129.3,132.5,137.6,142.7,143.5,147.5,151.0,176.5.HRMS(ESI-TOF)calcd.for C22H22N2NaO5[M+Na]+417.1421；found:417.1428.
3r:White solid；48.0 mg,yield 65％；mp 162.8-164.0 ℃.1H NMR(400 MHz,CDCl3):δ1.12(s,9H),3.23(d,J＝16.4 Hz,1H),3.25(s,3H),3.62(d,J＝16.4 Hz,1H),6.71-6.75(m,1H),6.85(d,J＝7.7 Hz,1H),7.01-7.05(m,1H),7.14(d,J＝7.6 Hz,1H),7.20-7.24(m,1H),7.31-7.35(m,1H),7.76(d,J＝8.0 Hz,1H)；13CNMR(100 MHz,CDCl3):δ26.7,27.8,42.8,69.3,82.0,108.3,109.9(d,J＝19.4 Hz,1C),111.0,113.9,121.9,123.4,125.8,129.5,130.1(d,J＝7.6 Hz,1C),132.2,142.8,150.9,158.9(d,J＝245.1Hz,1C),176.2.HRMS(ESI-TOF)calcd.for C21H21FN2NaO3[M+Na]+391.1428；found:391.1436.
3s:White solid；58.2 mg,yield 79％；mp 191.8-192.8 ℃.1H NMR(400 MHz,CDCl3):δ1.11(s,9H),3.18(d,J＝16.4 Hz,1H),3.24(s,3H),3.62(d,J＝16.4 Hz,1H),6.84-6.87(m,2H),6.92-6.96(m,1H),7.00-7.04(m,1H),7.11(d,J＝7.2 Hz,1H),7.31-7.35(m,1H),7.91-7.94(m,1H)；13C NMR(100 MHz,CDCl3):δ26.6,27.9,41.3,69.1,81.7,108.2,111.8(d,J＝24.4 Hz,1C),114.3(d,J＝22.7 Hz,1C),115.7(d,J＝8.1 Hz,1C),121.8,123.3,128.8(d,J＝8.6 Hz,1C),129.4,132.2,139.4,142.7,151.0,159.2(d,J＝239.3 Hz,1C),176.4.HRMS(ESI-TOF)calcd.for C21H21FN2NaO3[M+Na]+391.1428；found:391.1441.
3t:Yellow oil；58.2 mg,yield 79％.1H NMR(400 MHz,CDCl3):δ1.11(s,9H),3.16(d,J＝15.9 Hz,1H),3.24(s,3H),3.58(d,J＝15.9 Hz,1H),6.67-6.72(m,1H),6.85(d,J＝7.7 Hz,1H),7.00-7.06(m,2H),7.11(d,J＝7.2 Hz,1H),7.31-7.34(m,1H),7.74(d,J＝10.2 Hz,1H)；13C NMR(100 MHz,CDCl3):δ26.6,27.8,40.8,69.6,82.0,103.5(d,J＝29.6 Hz,1C),108.2,109.4(d,J＝22.8 Hz,1C),121.8,122.3,123.3,124.8(d,J＝9.9 Hz,1C),129.4,132.2,142.7,144.7(d,J＝12.3 Hz,1C),150.9,163.1(d,J＝241.0 Hz,1C),176.3.HRMS(ESI-TOF)calcd.for C21H21FN2NaO3[M+Na]+391.1428；found:391.1437.
3u:Yellow solid；52.0 mg,yield 62％；mp 169.7-170.8 ℃.1H NMR(400 MHz,CDCl3):δ1.13(s,9H),3.26(s,3H),3.26(d,J＝16.4 Hz,1H),3.67(d,J＝16.4 Hz,1H),6.87(d,J＝7.7 Hz,1H),7.01-7.05(m,1H),7.11(d,J＝7.1 Hz,1H),7.32-7.36(m,1H),7.39(s,1H),7.53(d,J＝8.4 Hz,1H),8.06(d,J＝8.2 Hz,1H)；13C NMR(100MHz,CDCl3):δ26.6,27.8,41.1,69.1,82.3,108.4,114.8,121.6,121.7,123.4,124.5(q,J＝270.0 Hz,1C),125.0(q,J＝32.0 Hz,1C),125.8(q,J＝4.0 Hz,1C),127.9,129.6,131.9,142.8,146.3,150.8,176.1.HRMS(ESI-TOF)calcd.for C22H22F3N2O3[M+H]+419.1577；found:419.1573.
3v:White solid；56.5 mg,yield 74％；mp 190.9-192.8 ℃.1H NMR(400 MHz,CDCl3):δ1.11(s,9H),3.18(d,J＝16.4 Hz,1H),3.24(s,3H),3.62(d,J＝16.3 Hz,1H),6.85(d,J＝7.7 Hz,1H),7.00-7.04(m,1H),7.09-7.12(m,2H),7.22(d,J＝8.7 Hz,1H),7.31-7.35(m,1H),7.91(d,J＝8.6 Hz,1H)；13C NMR(100 MHz,CDCl3):δ26.7,27.9,41.2,69.0,81.9,108.3,116.0,121.8,123.4,124.6,128.0,128.1,129.0,129.5,132.1,142.1,142.8,150.9,176.3.HRMS(ESI-TOF)calcd.for C21H21ClN2NaO3[M+Na]+407.1133；found:407.1141.
3w:Yellow oil；44.1 mg,yield 55％.1H NMR(400 MHz,CDCl3):δ1.28(s,9H),3.27(d,J＝16.0 Hz,1H),3.31(s,3H),3.92(d,J＝16.0 Hz,1H),6.88(d,J＝7.8 Hz,1H),6.94-6.98(m,1H),7.06(d,J＝7.4 Hz,1H),7.29-7.34(m,2H),7.43-7.48(m,2H),7.64(d,J＝8.2 Hz,1H),7.84(d,J＝7.4 Hz,1H),8.04(d,J＝7.6 Hz,1H)；13C NMR(100 MHz,CDCl3):δ26.7,27.8,43.0,70.6,82.0,108.2,122.1,123.2,123.3,124.9,125.2,125.3,125.5,125.6,128.4,129.4,132.6,134.6,138.4,142.5,152.0,176.3.HRMS(ESI-TOF)calcd.forC25H24N2NaO3[M+Na]+423.1679；found:423.1697.
3x:Yellow oil；48.1 mg,yield 66％,dr 4:1.1H NMR(400 MHz,CDCl3):δ(major)0.93(d,J＝7.1 Hz,3H),1.13(s,9H),3.25(s,3H),3.90(q,J＝6.9 Hz,1H),6.84-6.95(m,3H),7.01-7.10(m,2H),7.20-7.23(m,1H),7.28-7.32(m,1H),7.97(d,J＝7.8 Hz,1H)；13CNMR(100 MHz,CDCl3):δ(major)13.3,26.7,27.8,45.1,74.3,81.4,108.0,114.8,122.6,122.8,123.0,123.3,128.9,129.4,131.0,132.7,142.8,143.2,151.2,177.1.HRMS(ESI-TOF)calcd.for C22H24N2NaO3[M+Na]+387.1679；found:387.1681.
3y:Yellow solid；39.8 mg,yield 52％,dr 2:1；mp 108.7-110.2 ℃.1H NMR(400 MHz,CDCl3):δ(major+minor)0.91(d,J＝7.0 Hz,3H),1.12(s,9H),3.21(s,1H),3.25(s,2H),3.84(q,J＝7.1 Hz,1H),6.69-6.73(m,1H),6.82-6.90(m,2H),6.94-7.01(m,2H),7.30-7.34(m,1H),7.74(d,J＝10.2 Hz,1H)；13C NMR(100 MHz,CDCl3):δ(major+minor)13.5,14.5,26.7,27.8,44.6,74.2,74.9,82.0,103.2(d,J＝29.5 Hz,1C),103.3(d,J＝29.4 Hz,1C),108.1,109.3(d,J＝22.8 Hz,1C),122.1,122.7,123.2,123.3,123.4,127.5,128.1,129.1,129.6,143.2,143.4,144.1,144.2,151.0,151.2,163.2(d,J＝241.2 Hz,1C),173.9,176.7.HRMS(ESI-TOF)calcd.forC22H23FN2NaO3[M+Na]+405.1585；found:405.1592.
3z:White solid；55.8 mg,yield 70％,dr 3:1；mp 79.3-81.2 ℃.1H NMR(400MHz,CDCl3):δ(major+minor)0.91(d,J＝7.1 Hz,3H),1.12(s,9H),3.20(s,0.75H),3.25(s,2.25H),3.84(q,J＝7.0 Hz,1H),6.84-6.89(m,2H),6.93-6.99(m,3H),7.30-7.33(m,1H),8.02(s,1H)；13C NMR(100 MHz,CDCl3):δ(major+minor)13.4,14.3,26.7,27.8,44.7,74.0,74.6,82.0,108.2,115.2,115.3,122.0,122.7,122.9,123.0,123.2,123.3,123.6,127.4,129.2,129.6,131.3,134.0,143.2,143.4,143.9,151.0,173.8,176.7.HRMS(ESI-TOF)calcd.forC22H23ClN2NaO3[M+Na]+421.1289；found:421.1297.
3a':Yellow solid；52.2 mg,yield 69％,dr 3:1；mp 86.6-88.1 ℃.1H NMR(400MHz,CDCl3):δ(major+minor)0.93(d,J＝7.0 Hz,3H),1.13(s,9H),2.20(s,2.25H),2.29(s,0.75H),3.18(s,0.75H),3.23(s,2.25H),3.89(q,J＝6.8 Hz,1H),6.68(s,1H),6.73(d,J＝8.0 Hz,1H),7.04(d,J＝9.0 Hz,1H),7.10(d,J＝6.7 Hz,2H),7.23(d,J＝7.4 Hz,1H),7.98(d,J＝7.6 Hz,1H)；13C NMR(100 MHz,CDCl3):δ(major+minor)13.3,14.7,21.0,26.7,27.8,45.1,73.5,74.4,81.4,107.8,114.6,114.8,122.7,122.8,123.0,123.9,127.8,128.2,129.0,129.6,132.2,132.8,140.8,141.0,142.9,151.3,174.0,177.1.HRMS(ESI-TOF)calcd.for C23H26N2NaO3[M+Na]+401.1836；found:401.1842.
3b':Yellow oil；49.7 mg,yield 63％,dr 4:1.1H NMR(400 MHz,CDCl3):δ(major)0.95(d,J＝7.3 Hz,3H),1.15(s,9H),3.23(s,3H),3.67(s,3H),3.90(q,J＝6.8Hz,1H),6.49(s,1H),6.75(d,J＝8.9 Hz,1H),6.83(d,J＝9.7 Hz,1H),7.03(d,J＝7.1 Hz,1H),7.09(d,J＝7.0 Hz,1H),7.23(d,J＝7.5 Hz,1H),7.96(d,J＝7.6 Hz,1H)；13C NMR(100MHz,CDCl3):δ(major)13.3,26.7,27.9,45.1,56.0,74.6,81.5,108.3,110.9,113.4,114.8,122.9,123.1,128.3,128.9,131.0,136.8,142.8,151.2,156.0,176.8.HRMS(ESI-TOF)calcd.for C23H26N2NaO4[M+Na]+417.1785；found:417.1779.
3c':Yellow solid；41.8mg,yield 49％,dr 3:1；mp 107.3-108.8℃.1H NMR(400MHz,CDCl3):δ(major)1.06(d,J＝7.0Hz,3H),1.19(s,9H),3.99(q,J＝7.0Hz,1H),6.94-6.98(m,1H),7.02-7.08(m,2H),7.09-7.14(m,2H),7.40-7.41(m,1H),7.48-7.57(m,6H),8.01-8.05(m,1H)；13C NMR(100MHz,CDCl3):δ(major)13.8,28.1,46.2,74.5,82.0,109.4,109.7,114.7,114.9,122.9,123.6,125.5,127.9,128.7,129.2,129.6,129.7,132.4,133.1,142.5,143.0,151.4,176.2.HRMS(ESI-TOF)calcd.for C27H26N2NaO3[M+Na]+449.1836；found:449.1839.
抽取化合物3a、3b、3c进行谱图分析，NMR谱图如图1～6所示。
以上所述的仅是本发明的实施例，方案中公知的具体结构及特性等常识在此未作过多描述。应当指出，对于本领域的技术人员来说，在不脱离本发明结构的前提下，还可以作出若干变形和改进，这些也应该视为本发明的保护范围，这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准，说明书中的具体实施方式等记载可以用于解释权利要求的内容。

Claims (7)

1.一种2,3'-螺二吲哚啉-2-酮类化合物，其特征在于，结构通式为：
结构通式中：R1选自5-Me、5-OMe、5-F、5-OCF3、7-F、7-CF3或7-OCF3；
R2选自Me、Et、nPr、nBu、iPr、Ph或Bn；
R3选自H和叔丁氧羰基；
R选自Me、Et、Ph；
Ar选自苯基、甲氧基取代苯基、[1,3]二氧戊烷并苯基、氟取代苯基、三氟甲基取代苯基、氯取代苯基、萘基或噻吩基。
2.根据权利要求1所述的2,3'-螺二吲哚啉-2-酮类化合物的制备方法，其特征在于：包括以下步骤：将3-氨基氧化吲哚、2-溴甲基芳基溴化物、一价铜盐催化剂和无机碱加入到有机溶剂中进行反应，反应完毕后经萃取、干燥、柱层析或重结晶处理得到2,3'-螺二吲哚啉-2-酮类化合物，合成路线如下所示：
3.根据权利要求2所述的2,3'-螺二吲哚啉-2-酮类化合物的制备方法，其特征在于：所述一价铜盐催化剂为碘化亚铜、溴化亚铜、氯化亚铜、氰化亚铜或硫酸亚铜。
4.根据权利要求2或3所述的2,3'-螺二吲哚啉-2-酮类化合物的制备方法，其特征在于：所述有机溶剂为甲苯、氯苯、氟苯、三氟甲苯、均三甲苯、二甲基亚砜、特戊醇、N,N-二甲基甲酰胺、1,4-二氧六环或乙腈。
5.根据权利要求4所述的2,3'-螺二吲哚啉-2-酮类化合物的制备方法，其特征在于：所述无机碱为碳酸锂、碳酸钠、碳酸钾、碳酸铯、特戊酸钠、磷酸钾、叔丁醇钠、叔丁醇钾或叔丁醇锂。
6.根据权利要求5所述的2,3'-螺二吲哚啉-2-酮类化合物的制备方法，其特征在于：所述反应温度为80～170℃，反应时间为6～24h。
7.根据权利要求6所述的2,3'-螺二吲哚啉-2-酮类化合物的制备方法，其特征在于：反应完毕后采用柱层析分离方法处理。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111892608A (zh) * 2020-08-27 2020-11-06 遵义医科大学 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用
CN111961060A (zh) * 2020-08-27 2020-11-20 遵义医科大学 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物的制备方法
CN112300178A (zh) * 2020-11-03 2021-02-02 合肥工业大学 一种5-溴喹唑啉衍生物的制备及用途
CN114057756A (zh) * 2021-12-10 2022-02-18 山东第一医科大学(山东省医学科学院) 一种抗肿瘤活性的吡咯烷基螺氧化吲哚类化合物及其合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAODONG CUI，等: "Synthesis of 2,3"-spirobi[indolin]-2-ones enabled by a tandem nucleophilic benzylation/C(sp2)-N ross-coupling reaction sequence", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 *

Cited By (6)

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Publication number Priority date Publication date Assignee Title
CN111892608A (zh) * 2020-08-27 2020-11-06 遵义医科大学 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用
CN111961060A (zh) * 2020-08-27 2020-11-20 遵义医科大学 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物的制备方法
CN111892608B (zh) * 2020-08-27 2021-07-06 遵义医科大学 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用
CN112300178A (zh) * 2020-11-03 2021-02-02 合肥工业大学 一种5-溴喹唑啉衍生物的制备及用途
CN114057756A (zh) * 2021-12-10 2022-02-18 山东第一医科大学(山东省医学科学院) 一种抗肿瘤活性的吡咯烷基螺氧化吲哚类化合物及其合成方法
CN114057756B (zh) * 2021-12-10 2022-12-09 山东第一医科大学(山东省医学科学院) 一种抗肿瘤活性的吡咯烷基螺氧化吲哚类化合物及其合成方法

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