CN104844601A - 一种合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法 - Google Patents

一种合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法 Download PDF

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CN104844601A
CN104844601A CN201510229284.6A CN201510229284A CN104844601A CN 104844601 A CN104844601 A CN 104844601A CN 201510229284 A CN201510229284 A CN 201510229284A CN 104844601 A CN104844601 A CN 104844601A
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tetrahydroquinoline derivative
optical activity
tolylene
spiro
oxindole
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毛侦军
莫凡
林旭锋
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Zhejiang University ZJU
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract

本发明公开了一种合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法。它是以3-（2-吡咯烷-1-基）苯亚甲基-2-吲哚酮类或3-（2-哌啶-1-基）苯亚甲基-2-吲哚酮类化合物为原料，以手性螺环磷酸和无水氯化镁为催化剂，在氮气保护，分子筛存在下，在有机溶剂中，于70－90oC反应3～10小时，经纯化分离获得光学活性螺环氧化吲哚四氢喹啉衍生物。本发明反应条件温和，工艺简单，操作便捷；所得光学活性螺环氧化吲哚四氢喹啉衍生物有潜在的良好的生物活性，并可以作为药物合成的中间体及活性成分使用。

Description

一种合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法
技术领域
本发明涉及一种手性螺环磷酸和路易斯酸共催化合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法。
背景技术
大量手性的含螺环氧化吲哚骨架的化合物广泛存在于天然产物和药物中，它们含有重要生物活性而越来越受到人们的关注,参见【(a)M.Rottmann,C.McNamara,etc.,Science,2010,329,1175-1180；(b)Y.Huang,C.Zheng,G.Zhao,RSC Adv,2013,3,16999-17002；(c)L.Hong,R.Wang,Adv.Synth.Catal.,2013,355,1023-1052；(d)D.Cheng,Y.Ishihara,B.Tan,C.F.Barbas,III,ACS Catalysis,2014,4,743-762。含有螺环氧化吲哚骨架的天然产物和手性药物有，比如天然产物生物碱(Gelsemine)，肿瘤抑制因子p53抑制剂(MI209)，抗疟药物(NITD609)，植物保护素((S)-Spirobrassinin)等，参见【(a)Lin,H.；Danishefsky,S.J.Angew.Chem.,Int.Ed.2003,42,36-51；(b)Shangary,S.；Qin,D.；McEachern,D.；et al.Proc.Natl.Acad.Sci.U.S.A.2008,105,3933-3938；(c)Rottmann,M.；McNamara,C.；Yeung,B.K.S.；et al.Science.2010,329,1175-1180；(d)Pedras M.S.C.；Sarwar M.G.；Suchy M.；et al.Phytohemistry,2006,67,1503-1509】。有关非手性的合成方法是氯化铁催化，比如Org.Lett.2012,14,4054。不对称催化也已经有报道，比如Chem.Eur.J.,2014，21:1632–1636，但是底物范围仍然有限。
发明内容
本发明的目的是提供一种反应温和、操作简便、对映选择性高的合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法。
本发明的合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法，是以3-(2-吡咯烷-1-基)苯亚甲基-2-吲哚酮类或3-(2-哌啶-1-基)苯亚甲基-2-吲哚酮类化合物为原料，以手性螺环磷酸和无水氯化镁为催化剂，在氮气保护，分子筛存在下，在有机溶剂中，于70－90℃反应3～10小时，经纯化分离获得光学活性螺环氧化吲哚四氢喹啉衍生物；所述的手性螺环磷酸催化剂和3-(2-吡咯烷-1-基)苯亚甲基-2-吲哚酮类或3-(2-哌啶-1-基)苯亚甲基-2-吲哚酮类化合物的摩尔比为1～10：100；所述的无水氯化镁和手性螺环磷酸的摩尔比为1：4；
反应式为：
式中：R1选自氢、C1～C4的烷基或烷氧基、卤素、硝基；R2选自甲基、乙基、苄基；
所述的手性螺环磷酸催化剂是具有结构式(1)的左旋或右旋的光学活性化合物：
本发明中，所述的有机溶剂是1,2-二氯乙烷、四氯化碳、氯仿、甲苯、二甲苯或苯。
本发明与已有的合成方法相比，具有以下优点：
1)反应条件温和、操作简便；
2)反应通用性强，产物具有良好的生物活性，可以作为药物合成的中间体及活性成分使用；
3)对映选择性高。
具体实施方法
以下实施例将有助于理解本发明，但不限于本发明的内容：
实施例1
在氮气保护下，向一反应瓶中加入式(1)的(S)-O,O’-{7,7’-[6,6’-二-(9-菲基)-1,1’-螺双二氢茚]}磷酸催化剂催化剂(0.1mmol)和无水氯化镁(0.025mmol),以及5毫升甲苯，100毫克的分子筛粉末，室温搅拌0.5小时，再加入2-氧代-3(-(2-吡咯烷-1基)苯亚甲基)二氢吲哚-1-羧酸甲酯(1.0mmol)，控制反应温度在80度。在TLC下检测反应过程，3小时反应完毕。反应结束后直接用硅胶柱层析，得到光学活性(3S,3a'S)-2-氧代-1',2',3',3a'-四氢-5'H-螺[二氢吲哚-3,4'-吡咯并[1,2-a]喹啉]-1-羧酸甲酯，产率82％。产物光学纯度用HPLC测定是90％ee。HPLCanalysis:Chiralpak AD-H(hexane/i-PrOH＝90/10,0.8mL/min),tR(major)＝12.4min,tR(minor)＝16.8min；[α]D 20＝42.9(c＝1.2,CH2Cl2)；1H NMR(400MHz,CDCl3):δ＝7.96(d,J＝8.0Hz,1H),7.29-7.20(m,2H),7.02(d,J＝7.6Hz,1H),6.96-6.92(m,1H),6.67-6.63(m,1H),6.59(d,J＝8.0Hz,1H),6.45(dd,J＝7.6,1.2Hz,1H),4.05(s,3H)3.77(q,J＝9.6Hz,1H),3.54-3.44(m,1H),3.26-3.20(m,1H),2.75(d,J＝15.6Hz,1H),1.92-1.81(m,3H),0.93-0.88(m,1H)；13C NMR(100MHz,CDCl3):δ＝177.26,151.34,143.46,139.02,129.64,128.39,128.11,127.99,124.95,124.51,117.83,115.90,114.51,110.26,62.88,53.94,47.09,46.79,37.76,27.04,23.24；IR(film):γ＝2965,1760,1738,1604,1479,1462,1360,1287,1243,1160,1072,746cm-1；HRMS(EI-TOF):calcd forC21H20N2O3348.1474,found 348.1476.
产物结构是：
实施例2～3
如实施例1投料过程，其中改变有机溶剂的种类，可以得到以下实验结果：
1,2-二氯乙烷溶剂中反应，得到产物的产率90％，产物光学纯度71％。
四氯化碳溶剂中反应，得到产物的产率80％，产物光学纯度85％。
实施例4
在氮气保护下，向一反应瓶中加入式(1)的(S)-O,O’-{7,7’-[6,6’-二-(9-菲基)-1,1’-螺双二氢茚]}磷酸催化剂催化剂(0.1mmol)和无水氯化镁(0.025mmol),以及5毫升甲苯，100毫克的分子筛粉末，室温搅拌0.5小时，再加入2-氧代-5-硝基-3(-(2-吡咯烷-1基)苯亚甲基)二氢吲哚-1-羧酸甲酯(1.0mmol)，控制反应温度在80度。在TLC下检测反应过程，6小时反应完毕。反应结束后直接用硅胶柱层析，得到光学活性(3S,3a'S)-2-氧代-5硝基-1',2',3',3a'-四氢-5'H-螺[二氢吲哚-3,4'-吡咯并[1,2-a]喹啉]-1-羧酸甲酯，产率85％。产物光学纯度用HPLC测定是97％ee。HPLC analysis:Chiralpak OD-H(hexane/i-PrOH＝70/30,0.8mL/min),tR(major)＝19.9min,tR(minor)＝38.2min；[α]D 20＝15.2(c＝0.7,CH2Cl2)；1H NMR(400MHz,CDCl3):δ＝8.21(dd,J＝9.2,2.4Hz,1H),8.14(d,J＝9.2Hz,1H),7.30-7.26(m,2H),7.03(d,J＝7.2Hz,1H),6.70(q,J＝12.8Hz,1H),4.09(s,3H)3.90(q,J＝9.6Hz,1H),3.56-3.49(m,1H),3.34-3.28(m,1H),2.78(d,J＝15.6Hz,1H),1.97-1.85(m,3H),0.87-0.82(m,1H)；13C NMR(100MHz,CDCl3):δ＝176.13,150.97,145.04,144.14,143.03,129.66,129.50,128.77,124.58,120.12,116.77,116.62,114.66,110.89,62.77,54.49,47.04,46.93,37.73,27.08,23.09；IR(film):γ＝2959,1770,1743,1604,1525,1305,1249,1155,1030,739cm-1；HRMS(EI-TOF):calcd for C21H19N3O5393.1325,found393.1326.
产物结构是：
实施例5
在氮气保护下，向一反应瓶中加入式(1)的(S)-O,O’-{7,7’-[6,6’-二-(9-菲基)-1,1’-螺双二氢茚]}磷酸催化剂催化剂(0.1mmol)和无水氯化镁(0.025mmol),以及5毫升甲苯，100毫克的分子筛粉末，室温搅拌0.5小时，再加入2-氧代-3(-(2-哌啶-1基)苯亚甲基)二氢吲哚-1-羧酸甲酯(1.0mmol)，控制反应温度在80度。在TLC下检测反应过程，8小时反应完毕。反应结束后直接用硅胶柱层析，得到光学活性(3S,4a'S)-2-氧代-2',3',4',4a'-四氢-1'H,6'H-螺[二氢吲哚-3,5'-吡啶并[1,2-a]喹啉]-1-羧酸甲酯，产率90％。产物光学纯度用HPLC测定是90％ee；HPLCanalysis:Chiralpak AD-H(hexane/i-PrOH＝95/5,1.0mL/min),tR(minor)＝13.5min,tR(major)＝17.9min；[α]D 20＝-77.0(c＝1.2,CH2Cl2)；1H NMR(400MHz,CDCl3):δ＝7.95(d,J＝8.4,1H),7.31-7.27(m,1H),7.21(t,J＝7.6Hz,1H),7.01-6.98(m,1H),6.91(d,J＝7.6Hz,1H),6.82-6.81(m,1H),6.72(t,J＝7.2Hz,1H),4.10(d,J＝12.4Hz,1H),4.05(s,3H),3.50(d,J＝15.6Hz,1H),3.36(dd,J＝11.6,2.4Hz,1H),2.83-2.76(m,1H),2.63(d,J＝15.6Hz,1H),1.77-1.74(m,1H),1.65-1.62(m,1H),1.52-1.31(m,3H),0.74-0.70(m,1H)；13C NMR(100MHz,CDCl3):δ＝177.25,151.33,146.21,138.85,130.09,129.33,128.11,127.78,125.35,124.91,120.00,118.18,114.36,113.27,60.54,53.96,48.33,37.90,27.18,25.53,23.17；IR(film):γ＝2938,1764,1738,1604,1494,1479,1437,1285,1196,1078,751cm-1；HRMS(EI-TOF):calcd for C22H22N2O3362.1630,found 362.1635.
产物结构是：

Claims (2)

1.一种合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法，其特征是以3-(2-吡咯烷-1基)苯亚甲基-2-吲哚酮类或3-(2-哌啶-1基)苯亚甲基-2-吲哚酮类化合物为原料，以手性螺环磷酸和无水氯化镁为催化剂，在氮气保护，分子筛存在下，在有机溶剂中，于70－90℃反应3～10小时，经纯化分离获得光学活性螺环氧化吲哚四氢喹啉衍生物；所述的手性螺环磷酸催化剂和3-(2-吡咯烷-1基)苯亚甲基-2-吲哚酮类或3-(2-哌啶-1基)苯亚甲基-2-吲哚酮类化合物的摩尔比为1～10：100；所述的无水氯化镁和手性螺环磷酸的摩尔比为1：4；
反应式为：
式中：R1选自氢、C1～C4的烷基或烷氧基、卤素、硝基；R2选自甲基、乙基、苄基；
所述的手性螺环磷酸催化剂是具有结构式(1)的左旋或右旋的光学活性化合物：
2.根据权利要求1所述的合成光学活性螺环氧化吲哚四氢喹啉衍生物的方法，其特征是所述的有机溶剂是1,2-二氯乙烷、四氯化碳、氯仿、甲苯、二甲苯或苯。
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WO2022127827A1 (zh) * 2020-12-17 2022-06-23 上海维申医药有限公司 Kras g12c蛋白突变抑制剂、其制备方法、药物组合物及其应用

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