CN108164535A - 三氟甲基化的苯氮卓并吲哚衍生物及其催化合成方法 - Google Patents

三氟甲基化的苯氮卓并吲哚衍生物及其催化合成方法 Download PDF

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CN108164535A
CN108164535A CN201810072995.0A CN201810072995A CN108164535A CN 108164535 A CN108164535 A CN 108164535A CN 201810072995 A CN201810072995 A CN 201810072995A CN 108164535 A CN108164535 A CN 108164535A
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trifluoromethylation
diindyl
nitrogen zhuo
benzene
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林旭锋
阿卜杜勒·拉赫曼
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Zhejiang University ZJU
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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

本发明公开的三氟甲基化的苯氮卓并吲哚衍生物是具有如下结构式的消旋体、左旋或右旋的光学活性体；

Description

三氟甲基化的苯氮卓并吲哚衍生物及其催化合成方法
技术领域
本发明属于杂环合成技术领域，具体涉及三氟甲基化的苯氮卓并吲哚衍生物及其催化合成方法。
背景技术
苯氮卓并吲哚衍生物是一类重要的含氮杂环化合物，也是一些药物活性分子的重要骨架，具有作为酶抑制剂、抗癌/抗肿瘤等药理活性(Heterocycles,1975,3,931；Int.J.Antimicrob.Agents,2000,14,193；Curr.Org.Chem.,2001,5,519；J.Med.Chem.,1999,42,2909；J.Med.Chem.,1996,39,3547；Drugs,2000,60,1095；Exp.Opin.Invest.Drugs,2000,9,2393)。因此，研究合成苯氮卓并吲哚衍生物受到了人们的关注(Synthesis,2010,4087；Heterocycl.Chem.1992,29,241；Bioorg.Med.Chem.Lett.1999,9,1737；J.Org.Chem.2011,76,1239.Org.Lett.,2012,14,3890；J.Org.Chem.,2014,79,11759)。另外吡咯与吲哚及其衍生物也具有重要的药理活性(Chem.Rev.,2006,106,2875；Angew.Chem.,Int.Ed.,2009,48,9608；Chem.Rev.2004,104,2481；Tetrahedron,2006,62,7213)。此外，大量含有三氟甲基的化合物表现出重要的生物活性而引起人们的极大关注和广泛研究(Chem.Rev.,1997,97,757；Science,2007,317,1881；Chem.Soc.Rev.,2008,37,320；Future Med.Chem.,2009,1,1189)。化合物分子中含有三氟甲基基团能够增强分子的化学、代谢稳定性，亲酯性和膜通透性。众所周知，含三氟甲基的一些环状手性药物分子中大多都包含三氟甲基季立体中心，比如HIV逆转录酶抑制剂依非韦伦(Efavirenz)，孕激素受体抑制剂(Progesterone receptor antagonist)，NK-1受体抑制剂(CJ-17493)，抗疟药物青蒿素(Fluoroartemisinin)，抗风湿剂(Antirheumaticagent)等。那么可以预期组装成含有三氟甲基，苯氮卓并吲哚基和吡咯基或吲哚基等多种高药理活性结构的三氟甲基化的苯氮卓并吲哚衍生物的分子很可能也具有较高生物活性。
发明内容
本发明的目的是提供三氟甲基化的苯氮卓并吲哚衍生物及其催化合成方法。
本发明的三氟甲基化的苯氮卓并吲哚衍生物,它是具有如下结构式的消旋体、左旋或右旋的光学活性体:
式中：R1～R8，R9 1～R9 5选自H、卤素、硝基、三氟甲基、二氟甲基、环丙基、环丁基、环戊基、环己基、苄氧基、苯氧基、C1～C4烷基或C1～C4烷氧基。
所述的三氟甲基化的苯氮卓并吲哚衍生物的制备方法，是以三氟甲基化的二氢苯氮卓并吲哚类化合物和亲核试剂为原料，以螺环磷酸为催化剂，以分子筛为添加剂，在有机溶剂中于20～80℃，反应12～48小时，纯化得到三氟甲基化的苯氮卓并吲哚衍生物，所述的三氟甲基化的二氢苯氮卓并吲哚类化合物和亲核试剂的摩尔比为1：1～1.2，螺环磷酸催化剂和三氟甲基化的二氢苯氮卓并吲哚类化合物的摩尔比为5～20：100；
所述的螺环磷酸催化剂为具有结构式(1)的化合物，可以是消旋体、左旋或右旋的光学活性体：
所述的三氟甲基化的二氢苯氮卓并吲哚类化合物结构如下式(2)所示：
该化合物可以采用如下方法获得：
以邻氨基苯甲醇类化合物和吲哚类化合物为起始原料，依次经三氟乙酸催化的傅克烷基化反应、三氟乙酰化反应和多聚磷酸催化的氮杂傅克环化反应得到。
所述的亲核试剂为吡咯类化合物或吲哚类化合物，结构分别如下式(3)和式(4)所示：
式中：R1～R8，R9 1～R9 5选自H、卤素、硝基、三氟甲基、二氟甲基、环丙基、环丁基、环戊基、环己基、苄氧基、苯氧基、C1～C4烷基或C1～C4烷氧基。
所述的有机溶剂为甲苯、二甲苯、苯、二氯甲烷、氯仿、1,2-二氯乙烷、氟苯、氯苯或乙基苯。
与现有技术相比，本发明具有以下优点：
1)无需金属催化，反应可在温和条件下进行；
2)含有取代基的吡咯或吲哚能直接作为反应底物，其来源十分广泛，这些降低了最终产品的制备成本；
3)可以获得高光学活性的含三氟甲基季立体中心的苯氮卓并吲哚衍生物。
综上所述，本发明利用催化氮杂傅克烷基化反应方法合成三氟甲基化的苯氮卓并吲哚衍生物，反应条件温和，工艺简单，操作便捷，所得产物有潜在的良好的生物活性，这将对新药筛选有重要意义。
具体实施方式
以下实施例将有助于理解本发明，但不限于本发明的内容。
本发明中原料三氟甲基化的二氢苯氮卓并吲哚类化合物可以采用如下的技术路线合成：
其中，反应步骤1中的溶剂可以采用氯仿或1,2-二氯乙烷，反应温度为40～80℃，反应时间为6～24小时；反应步骤2中的溶剂可以采用二氯甲烷、氯仿或1,2-二氯乙烷，反应温度为室温，反应时间为2～12小时；反应步骤3的反应温度为回流温度，反应时间为4～12小时。
实施例1
反应瓶中依次加入三氟甲基化的二氢苯氮卓并吲哚类化合物1a(0.05mmol)和吡咯2a(0.06mmol)，4°A分子筛(100mg)和二氯甲烷(1mL)，最后加入螺环磷酸催化剂(R)-6a(0.004mmol)；室温搅拌反应24小时，反应完毕，直接柱层析纯化得到三氟甲基化的苯氮卓并吲哚衍生物3a，产率80％；产物表征如下：
6-(2-pyrrolyl)-6-trifluoromethyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(3a).
Colorless oil,80％yield,85％ee,determined by HPLC[Daicel ChiralcelOD-H column(250×4.6mm),n-hexane/i-PrOH＝45/55,0.8mL/min,254nm；tmajor＝6.652min,tminor＝8.401min；1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.79–7.69(m,2H),7.26(d,J＝7.3Hz,1H),7.22–7.14(m,3H),7.09(td,J＝7.6,1.5Hz,1H),7.01(td,J＝7.4,1.2Hz,1H),6.80(d,J＝6.9Hz,1H),6.60(td,J＝2.7,1.5Hz,1H),6.46(s,1H),6.18(dd,J＝6.2,2.7Hz,1H),4.19(s,2H),4.04(s,1H)；13C NMR(101MHz,CDCl3)δ142.55,137.50,135.31,129.71,128.46,128.33,127.32,126.87,126.82,126.60,124.25,124.06,123.95,123.19,121.07(q,j＝239Hz),119.82,119.01,118.71,114.78,111.06,108.45,107.00,106.97,65.30,65.03,64.76,64.56(q,j＝27Hz),28.29；19F NMR(376MHz,CDCl3)δ-71.43(s)；HRMS(EI-TOF):calcd for C21H16F3N3 367.1296found367.1296.
按照上述一样的反应过程，改变反应底物，可以得到以下三氟甲基化的苯氮卓并吲哚衍生物3b-3g：
6-(2-pyrrolyl)-6-trifluoromethyl-4-methyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(3b).
White solid,85％yield,m.p.158-159℃,93％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝90/10,0.8mL/min,254nm；tmajor＝10.778min,tminor＝12.881min；1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.67(s,1H),7.59(d,J＝8.0Hz,1H),7.25(dd,J＝7.3,1.1Hz,1H),7.09(ddd,J＝9.9,9.1,4.4Hz,2H),7.00(ddd,J＝8.7,5.1,1.1Hz,2H),6.83–6.77(m,1H),6.64(td,J＝2.7,1.5Hz,1H),6.47(s,1H),6.21(dd,J＝6.2,2.7Hz,1H),4.18(s,2H),4.04(s,1H),2.35(s,3H)；13C NMR(101MHz,CDCl3)δ142.52,137.71,134.99,129.79,128.37,127.28,126.91,126.41,126.22,124.27,124.10,124.03,123.76,122.61(q,j＝288Hz),120.40,120.13,118.96,116.42,115.58,108.58,107.00,106.97,65.39,65.12,64.85,64.58(q,j＝27Hz),28.45,16.59；19F NMR(376MHz,CDCl3)δ-71.40(s)；HRMS(EI-TOF):calcd for C22H18F3N3 381.1453found 381.1456.
6-(2-pyrrolyl)-6-trifluoromethyl-1-methyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(3c).
White solid,92％yield,m.p.115-116℃,91％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝90/10,0.8mL/min,254nm；tmajor＝10.388min,tminor＝19.982min；1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.76(s,1H),7.24(d,J＝1.2Hz,1H),7.09(td,J＝7.5,1.5Hz,1H),7.05–6.98(m,3H),6.86(dd,J＝8.3,4.4Hz,1H),6.81–6.76(m,1H),6.63(dt,J＝4.1,2.1Hz,1H),6.46(s,1H),6.19(dd,J＝6.2,2.8Hz,1H),4.49(dd,J＝39.6,15.2Hz,2H),4.03(s,1H),2.90(s,3H)；13C NMR(101MHz,CDCl3)δ142.31,138.29,135.34,130.92,129.70,128.66,128.23,127.21,126.75,126.07,124.68,124.06,123.88,123.61,122.93,122.04,121.81(q,j＝295Hz),118.92,116.18,109.18,108.32,106.79,65.44,65.29,65.02,64.75(q,j＝15Hz),29.57,21.63；19FNMR(376MHz,CDCl3)δ-71.90(s)；HRMS(EI-TOF):calcd for C22H18F3N3 381.1453found 381.1448.
6-(2-pyrrolyl)-6-trifluoromethyl-2-methyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(3d).
Colorless oil,81％yield,85％ee,determined by HPLC[Daicel ChiralcelOD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tmajor＝6.993min,tminor＝21.066min；1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.63(s,1H),7.51(s,1H),7.26(d,J＝7.4Hz,1H),7.12–7.05(m,1H),7.04–6.96(m,3H),6.78(d,J＝7.6Hz,1H),6.57(dd,J＝4.0,2.6Hz,1H),6.45(s,1H),6.17(dd,J＝6.1,2.8Hz,1H),4.16(s,2H),4.01(s,1H),2.48(s,3H)；13C NMR(101MHz,CDCl3)δ141.49,136.57,132.54,128.63,128.09,127.37,127.34,126.19,125.75,125.71,123.74,123.13,122.98,122.88(q,j＝126Hz),117.87,117.21,113.29,109.66,107.31,105.83,64.24,63.97,63.70,63.43(q,j＝27Hz),27.18,20.48；19F NMR(376MHz,CDCl3)δ-71.51；HRMS(EI-TOF):calcd forC22H18F3N3381.1453 found 381.1448.
6-(2-pyrrolyl)-6-trifluoromethyl-3-fluoro-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(3e).
Colorless oil,72％yield,76％ee,determined by HPLC[Daicel ChiralcelOD-H column(250×4.6mm),n-hexane/i-PrOH＝90/10,0.8mL/min,254nm；tminor＝7.659min,tmajor＝9.555min；1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.74(s,1H),7.62(dd,J＝8.7,5.2Hz,1H),7.26(d,J＝7.4Hz,1H),7.10(td,J＝7.6,1.4Hz,1H),7.02(td,J＝7.4,1.1Hz,1H),6.98–6.89(m,1H),6.87(dd,J＝9.5,2.1Hz,1H),6.82(d,J＝7.6Hz,1H),6.64(dt,J＝4.1,2.1Hz,1H),6.46(s,1H),6.19(dd,J＝6.2,2.8Hz,1H),4.27–4.08(m,2H),4.04(s,1H)；13C NMR(101MHz,CDCl3)δ161.70,159.32,142.51,137.15,135.29,135.16,129.13,128.48,128.11,127.44,127.17,127.13(q,j＝13Hz),126.78,124.29,124.08,123.90,123.26,121.02(q,j＝235Hz),119.67,119.57,119.13,114.75,108.85,108.60,108.52,107.15,107.12,97.53,97.27,65.21,64.94,64.67,64.40(q,j＝27Hz),28.31；19F NMR(376MHz,CDCl3)δ-71.42(s),-108.39–-123.93(m)；HRMS(EI-TOF):calcd for C21H15F4N3385.1202,found 385.1202.
6-(2-pyrrolyl)-6-trifluoromethyl-3-chloro-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(3f).
White solid,75％yield,m.p.115-116℃,75％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝85/15,0.8mL/min,254nm；；tminor＝10.430min,tmajor＝12.456min；1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.77(s,1H),7.62(d,J＝8.5Hz,1H),7.27(s,1H),7.19(d,J＝1.6Hz,1H),7.18–7.08(m,2H),7.03(td,J＝7.4,1.2Hz,1H),6.87–6.77(m,1H),6.66(td,J＝2.7,1.5Hz,1H),6.46(s,1H),6.20(dd,J＝6.3,2.7Hz,1H),4.15(q,J＝15.5Hz,2H),4.06(s,1H)；13C NMR(101MHz,CDCl3)δ142.46,137.06,135.58,129.09,128.81,128.50,127.98,127.65,127.48,126.72,125.24,124.35,124.10,123.84,120.74(q,j＝209Hz),120.63,119.66,119.21,114.78,110.99,108.55,107.22,65.21,64.95,64.68,64.40(q,j＝26Hz),28.27；19F NMR(376MHz,CDCl3)δ-71.35(s)；HRMS(EI-TOF):calcd for C21H15ClF3N3401.0907,found 401.0906.
6-(2-pyrrolyl)-6-trifluoromethyl-2-bromo-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(3g).
Colorless oil,78％yield,70％ee,determined by HPLC[Daicel ChiralcelOD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tmajor＝8.102min,tminor＝17.432min；1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.85(d,J＝1.5Hz,2H),7.28(dd,J＝6.2,2.4Hz,2H),7.15–7.08(m,2H),7.04(t,J＝7.4Hz,1H),6.84(d,J＝7.6Hz,1H),6.69(d,J＝1.3Hz,1H),6.45(s,1H),6.20(dd,J＝6.0,2.9Hz,1H),4.13(q,J＝15.5Hz,2H),4.07(s,1H)；13C NMR(101MHz,CDCl3)δ142.46,137.06,135.58,129.09,128.81,128.50,127.98,127.65,127.48,126.72,125.24,124.35,124.10,123.84,120.74(q,j＝209Hz),120.63,119.66,119.21,114.78,110.99,108.55,107.22,65.21,64.95,64.68,64.40(q,j＝26Hz),28.27；19F NMR(376MHz,CDCl3)δ-71.35(s)；HRMS(EI-TOF):calcd forC21H15BrF3N3445.0401found 445.099.
(S)-6-(2-pyrrolyl-5`-methyl)-6-trifluoromethyl-4-methyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(3i).
Colorless oil,93％yield；75％ee,determined by HPLC[Daicel ChiralcelOD-H column(250×4.6mm),n-hexane/i-PrOH＝90/10,0.8mL/min,254nm；tmajor＝6.171min,tminor＝7.250min；1H NMR(400MHz,CDCl3)δ7.68(s,2H),7.60(d,J＝8.0Hz,1H),7.25(d,J＝7.3Hz,1H),7.10(dt,J＝9.1,4.3Hz,2H),7.01(dd,J＝13.4,6.8Hz,2H),6.84(d,J＝7.6Hz,1H),6.34(s,1H),5.86(t,J＝2.9Hz,1H),4.19(dd,J＝34.6,15.4Hz,2H),4.03(s,1H),2.37(s,3H),2.11(s,3H).；13C NMR(101MHz,CDCl3)δ142.72,137.40,134.93,129.20,129.00,128.41,128.15,127.22,127.14,126.78,126.75,126.48(q,j＝85Hz),126.28,124.16,124.01,123.65,120.47,120.07,116.37,115.19,107.21,106.27,65.25,65.07,64.81,64.69,28.50,16.64(q,j＝18Hz),12.92；19F NMR(376MHz,CDCl3)δ-71.06(s)；HRMS(EI-TOF):calcd for C23H20F3N3 395.1609,found395.1612.
实施例2
反应瓶中依次加入三氟甲基化的二氢苯氮卓并吲哚类化合物1a(0.05mmol)和吲哚4a(0.06mmol)，4°A分子筛(100mg)和二氯甲烷(1mL)，最后加入螺环磷酸催化剂(R)-6a(0.004mmol)；室温搅拌反应24小时，反应完毕，直接柱层析纯化得到三氟甲基化的苯氮卓并吲哚衍生物5a，产率75％；产物表征如下：
(S)-6-(3-indolyl-)-6-trifluoromethyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(5a).
Yellow solid,75％yield,m.p.115-116℃,69％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tminor＝8.304min,tmajor＝11.361min；1HNMR(400MHz,CDCl3)δ8.17(s,1H),7.78(d,J＝7.0Hz,1H),7.67(s,1H),7.39(s,1H),7.31(d,J＝7.2Hz,1H),7.27(d,J＝8.1Hz,1H),7.20–7.02(m,6H),6.99(dd,J＝10.4,4.2Hz,1H),6.80(dd,J＝13.4,7.1Hz,2H),4.35(dd,J＝74.2,15.7Hz,2H),4.04(s,1H)；13C NMR(101MHz,CDCl3)δ143.82,136.42,136.07,135.37,130.36,128.82,128.27,127.46,127.21,126.86,125.66,124.56,123.76,123.67,122.78,122.62,122.33,121.66(q,j＝290Hz),121.13,120.47,119.51,118.70,113.64,113.54,111.10,65.42,65.16,64.89,64.64(q,j＝26Hz),29.05,14.25；19F NMR(376MHz,CDCl3)δ-70.23(s)；HRMS(EI-TOF):calcd forC25H18F3N3 417.1453,found 417.1454.
(S)-6-(3-indolyl-)-6-trifluoromethyl-3-fluoro-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(5b).
Light yellow solid,70％yield,m.p.120-121℃,72％ee,determined by HPLC[Daicel Chiralcel OD-Hcolumn(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tminor＝7.973min,tmajor＝10.150min；1H NMR(400MHz,CDCl3)δ8.22(s,1H),7.66(dd,J＝8.6,5.1Hz,2H),7.47–7.40(m,1H),7.29(dd,J＝10.3,8.0Hz,2H),7.11(d,J＝7.7Hz,2H),7.06(td,J＝7.5,2.1Hz,1H),7.00(td,J＝7.4,1.0Hz,1H),6.91(td,J＝9.5,2.2Hz,1H),6.82(dd,J＝16.2,7.9Hz,2H),6.75(dd,J＝9.6,2.2Hz,1H),4.31(dd,J＝88.9,15.8Hz,2H),4.03(s,1H).13C NMR(101MHz,CDCl3)δ161.43,159.06,143.78,136.07,135.30,135.17,130.30,128.83,128.56,128.52(q,j＝13Hz),127.40,127.32,125.65,124.49,123.77,123.71,123.47,122.87,122.32,122.28,121.59,121.01(q,j＝290Hz),120.51,119.60,119.50,113.67,113.39,111.15,108.44,108.20,97.48,97.22,65.30,65.04,64.78,64.52(q,j＝26Hz),29.07；19F NMR(376MHz,CDCl3)δ-70.24,-120.17,-120.18,-120.19,-120.21；HRMS(EI-TOF):calcd for C25H17F4N3 435.1359found,435.1356.
(S)-6-(3-indolyl-)-6-trifluoromethyl-3-chloro-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(5c).
Red solid,72％yield,m.p.124-125℃,61％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tminor＝8.176min,tmajor＝10.645min；1H NMR(400MHz,CDCl3)δ8.27(s,1H),7.75–7.56(m,2H),7.41(s,1H),7.29(t,J＝7.9Hz,2H),7.13–7.03(m,5H),7.00(t,J＝7.0Hz,1H),6.85–6.72(m,2H),4.30(dd,J＝88.1,15.8Hz,2H),4.03(s,1H)；13C NMR(101MHz,CDCl3)δ143.68,136.05,135.97,135.57,128.98,128.80,128.44,127.30,125.57,125.43,123.75,123.71,122.93,122.25,122.22,122.18,122.15(q,j＝4Hz),120.93,120.56,120.27,119.64,113.78,113.37,111.12,110.93,65.28,65.02,64.76,64.49(q,j＝26Hz),28.99；19F NMR(376MHz,CDCl3)δ-70.29(s)；HRMS(EI-TOF):calcd for C25H17ClF3N3 451.1063,found451.1064.
(S)-6-(3-indolyl-)-6-trifluoromethyl-2-methyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(5d).
Red solid,88％yield,m.p.116-117℃,58％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tminor＝7.681min,tmajor＝10.521min；1HNMR(400MHz,CDCl3)δ8.15(s,1H),7.57(d,J＝7.1Hz,2H),7.35–7.28(m,2H),7.21(d,J＝3.2Hz,1H),7.12–7.05(m,2H),7.05–7.01(m,1H),7.00–6.92(m,2H),6.77(td,J＝7.6,0.7Hz,2H),4.32(dd,J＝68.3,15.7Hz,2H),4.01(s,1H),2.49(s,3H)；13C NMR(101MHz,CDCl3)δ143.42,136.61,136.12,135.01,130.39,128.72,127.94,127.49,127.12,126.45,125.64,124.58,123.74,123.66,123.24,122.76,122.31,122.28,121.26,120.45,120.16,119.75,119.09(q,j＝290Hz),116.39,114.14,113.64,111.06,65.47,65.21,64.95,64.68(q,j＝26Hz),29.21,16.53；19F NMR(376MHz,CDCl3)δ-70.32(s)；HRMS(EI-TOF):calcd for C26H20F3N3 431.1609,found 431.1614.
(S)-6-(3-indolyl-)-6-trifluoromethyl-4-methyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(5e).
Yellow solid,80％yield,m.p.118-119℃,69％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tminor＝7.023min,tmajor＝9.372min；1HNMR(400MHz,CDCl3)δ8.24(s,1H),7.63(d,J＝8.0Hz,1H),7.51(s,1H),7.39(s,1H),7.29(t,J＝8.5Hz,2H),7.25–7.20(m,1H),7.13–7.06(m,2H),7.04(dd,J＝7.5,1.3Hz,1H),6.99(d,J＝6.4Hz,1H),6.95(t,J＝7.0Hz,1H),6.84(t,J＝7.6Hz,1H),6.79(d,J＝7.4Hz,1H),4.34(dd,J＝91.0,15.7Hz,2H),4.03(s,1H),2.24(s,3H)；13C NMR(101MHz,CDCl3)δ143.76,136.61,136.12,135.01,130.39,128.72,127.94,127.49,127.12,126.45,125.64,124.58,123.74,123.66,123.24,122.76,122.31,122.28,121.26,120.45,120.16,119.75,119.09(q,j＝290Hz),116.39,114.14,113.64,111.06,65.47,65.21,64.95,64.68(q,j＝26Hz),29.21,16.53；19F NMR(376MHz,CDCl3)δ-70.10(s)；HRMS(EI-TOF):calcd for C26H20F3N3 431.1609,found 431.1613.
(S)-6-(3-indolyl-5`-methoxy)-6-trifluoromethyl-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(5f).
Red solid,85％yield,m.p.209-210℃,62％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tminor＝9.004min,tmajor＝10.229min；1HNMR(400MHz,CDCl3)δ8.13(s,1H),7.75(s,2H),7.38(s,1H),7.31(d,J＝6.5Hz,1H),7.19–7.09(m,4H),7.08–6.96(m,3H),6.79(d,J＝7.0Hz,1H),6.69(dd,J＝8.8,2.3Hz,1H),6.26(d,J＝2.1Hz,1H),4.34(dd,J＝40.7,15.5Hz,2H),4.02(s,1H),3.18(s,3H)；13C NMR(101MHz,CDCl3)δ154.04,143.76,136.63,135.43,130.84,130.44,128.55,127.95,127.39,127.21,126.57,126.29,124.50,123.87,123.65,122.67,122.34,121.93,119.52(q,j＝305Hz),118.51,113.97,113.59,113.51,111.66,111.03,101.63,65.50,65.10,64.84,64.39(q,j＝40Hz),54.94,28.86.；19F NMR(376MHz,CDCl3)δ-70.73(s)；HRMS(EI-TOF):calcd for C26H20F3N3O 447.1558 found 447.1553.
(S)-6-(3-indolyl-5`-methyl)-6-trifluoromethyl-3-chloro-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(5g).Yellow solid,76％yield,m.p.170-171℃,81％ee,determined by HPLC[Daicel Chiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tminor＝7.337min,tmajor＝9.495min；1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.66(d,J＝8.1Hz,2H),7.40(d,J＝2.1Hz,1H),7.32(d,J＝7.2Hz,1H),7.22(d,J＝8.2Hz,1H),7.14–7.05(m,3H),7.01(td,J＝7.4,1.0Hz,1H),6.98–6.92(m,2H),6.82(d,J＝7.6Hz,1H),4.32(dd,J＝93.3,15.8Hz,2H),4.05(s,1H),2.15(s,3H)；13C NMR(101MHz,CDCl3)δ143.82,135.84,135.57,134.43,130.21,129.70,129.05,128.82,128.38,127.34,127.28,125.73,125.47,124.64,124.40,123.76,123.65,122.21,121.88(q,j＝287Hz),120.77,120.19,119.62(q,j＝27Hz),113.60,112.91,110.92,110.74,65.32,65.05,64.79,64.53(q,j＝27Hz),29.05,21.57；19F NMR(376MHz,CDCl3)δ-70.27(s)；HRMS(EI-TOF):calcd for C26H19ClF3N3 465.1220found,465.1216.
(S)-6-(3-indolyl-7`-methyl)-6-trifluoromethyl-3-chloro-5,6,7,12-tetrahydroindolo[2,3-c][1]benzazepine(5h).
Yellow solid,75％yield,m.p.125-125℃,77％ee,determined by HPLC[DaicelChiralcel OD-H column(250×4.6mm),n-hexane/i-PrOH＝80/20,0.8mL/min,254nm；tminor＝15.590min,tmajor＝17.884min；1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.66(d,J＝8.2Hz,2H),7.41(s,1H),7.31(d,J＝7.2Hz,1H),7.22(d,J＝8.2Hz,1H),7.14–7.06(m,3H),7.02(dd,J＝10.6,4.1Hz,1H),6.95(d,J＝11.0Hz,2H),6.82(d,J＝7.5Hz,1H),4.32(dd,J＝93.2,15.8Hz,2H),4.05(s,1H),2.15(s,3H)；13C NMR(101MHz,CDCl3)δ143.73,135.94,135.68,135.56,130.23,129.02,128.89,128.80,128.40,127.30,125.45,125.16,124.42,123.73,123.67,123.40,121.93,121.89,121.51(q,j＝191Hz),120.77,120.25,119.63,118.66,113.87,113.80,110.94,65.32,65.06,64.80,64.53(q,j＝26Hz),29.00,16.53.19FNMR(376MHz,CDCl3)δ-70.27(s)；HRMS(EI-TOF):calcd for C26H19ClF3N3 465.1220found,465.1216.
实施例3
反应瓶中依次加入三氟甲基化的二氢苯氮卓并吲哚类化合物1a(0.05mmol)和吡咯2a(0.06mmol)，4°A分子筛(100mg)和二氯甲烷(1mL)，最后加入螺环磷酸催化剂6a(0.004mmol，消旋体)；室温搅拌反应24小时，反应完毕，直接柱层析纯化得到三氟甲基化的苯氮卓并吲哚衍生物消旋体3a，产率82％。

Claims (5)

1.一种三氟甲基化的苯氮卓并吲哚衍生物,其特征在于，它是具有如下结构式的消旋体、左旋或右旋的光学活性体；
式中：R1～R8，R9 1～R9 5选自H、卤素、硝基、三氟甲基、二氟甲基、环丙基、环丁基、环戊基、环己基、苄氧基、苯氧基、C1～C4烷基或C1～C4烷氧基。
2.制备权利要求1所述的三氟甲基化的苯氮卓并吲哚衍生物的方法，其特征在于，以三氟甲基化的二氢苯氮卓并吲哚类化合物和亲核试剂为原料，以螺环磷酸为催化剂，以分子筛为添加剂，在有机溶剂中于20～80℃，反应12～48小时，纯化得到三氟甲基化的苯氮卓并吲哚衍生物，所述的三氟甲基化的二氢苯氮卓并吲哚类化合物和亲核试剂的摩尔比为1：1～1.2，螺环磷酸催化剂和三氟甲基化的二氢苯氮卓并吲哚类化合物的摩尔比为5～20：100。
3.根据权利要求2所述的三氟甲基化的苯氮卓并吲哚衍生物的制备方法，其特征在于，所述的螺环磷酸催化剂为具有结构式(1)的化合物，可以是消旋体、左旋或右旋的光学活性体：
4.根据权利要求2所述的三氟甲基化的苯氮卓并吲哚衍生物的制备方法，其特征在于，所述的三氟甲基化的二氢苯氮卓并吲哚类化合物结构如下式(2)所示：
所述的亲核试剂为吡咯类化合物或吲哚类化合物，结构如下式(3)和式(4)所示：
式中：R1～R8，R9 1～R9 5选自H、卤素、硝基、三氟甲基、二氟甲基、环丙基、环丁基、环戊基、环己基、苄氧基、苯氧基、C1～C4烷基或C1～C4烷氧基。
5.根据权利要求2所述的三氟甲基化的苯氮卓并吲哚衍生物的制备方法，其特征在于，所述的有机溶剂为甲苯、二甲苯、苯、二氯甲烷、氯仿、1,2-二氯乙烷、氟苯、氯苯或乙基苯。
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KR20230087741A (ko) * 2021-12-10 2023-06-19 원광대학교산학협력단 스피로[인돌린-3,2'-피페리딘] 유도체 및 이의 제조 방법
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