CN113121433B - 一种n-8-喹啉基-2-胺基苯甲酰胺类化合物的合成方法 - Google Patents

一种n-8-喹啉基-2-胺基苯甲酰胺类化合物的合成方法 Download PDF

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CN113121433B
CN113121433B CN202110606099.XA CN202110606099A CN113121433B CN 113121433 B CN113121433 B CN 113121433B CN 202110606099 A CN202110606099 A CN 202110606099A CN 113121433 B CN113121433 B CN 113121433B
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饶伟浩
李琪
蒋莉莉
邓雪婉
许盼
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    • C07—ORGANIC CHEMISTRY
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明公开了一种N‑8‑喹啉基‑2‑胺基苯甲酰胺类化合物的合成方法，属于有机合成技术领域。以N‑8‑喹啉基芳基酰胺为反应原料，以碘化亚铜为催化剂，以O‑苯甲酰基羟胺为胺化试剂，在无机碱存在下有机溶剂中加热反应，得到N‑8‑喹啉基‑2‑胺基苯甲酰胺类化合物。该发明合成方法操作方便，条件温和、工艺简单，底物官能团适用范围广泛，胺基化反应区域选择性好，收率高。

Description

一种N-8-喹啉基-2-胺基苯甲酰胺类化合物的合成方法
技术领域
本发明涉及一种N-8-喹啉基-2-胺基苯甲酰胺类化合物的高效便捷合成方法，属于有机合成技术领域。
背景技术
芳胺类化合物是有机合成领域中一类重要的精细化工原料，广泛应用于医药、农药和染料等领域。利用导向碳氢键活化策略实现芳胺类化合物的合成，不仅能有效提高底物的反应活性，而且可以获得优秀的区域选择性。
目前，已报道N-8-喹啉基-芳基酰胺的芳基邻位碳氢键直接胺化反应主要局限于具有良好亲核性有机胺，并且需要贵金属盐碳酸银(Angew.Chem.Int.Ed.2013,52,6043；Org.Lett.2015,17,2482；Adv.Synth.Catal.2016,358,2707)或空气作为氧化剂在难闻吡啶溶剂中进行反应(J.Am.Chem.Soc.2016,138,4601)，这些方法不环保不经济。
电化学方法具有绿色环保的优势，但同样使用亲核性的有机胺，在有机溶剂中通入电流具有操作不便性，且具有安全隐患，难以进行工业放大(Org.Biomol.Chem.2020,18,4802；Org.Lett.2019,21,1968；Chem.Eur.J.2018,24,19166；J.Am.Chem.Soc.2018,140,4195)。采用亲电性N-氯代胺类化合物进行胺化反应(J.Am.Chem.Soc.2014,136,646)，反应时需要价格昂贵且难以获取双膦配体和活性高苯基溴化镁格氏试剂的使用，相对反应官能团容忍性差，反应底物范围较窄。
基于以上方法的不足，本发明以亲电性O-苯甲酰基羟胺类化合物为胺源通过铜盐催化的碳氢键活化反应实现N-8-喹啉基-2-胺基苯甲酰胺类化合物的高效便捷合成。
发明内容
为了解决现有合成方法的不足，本发明提供了一种操作简便、产率高以及区域选择性高的N-8-喹啉基-2-胺基苯甲酰胺类化合物的模块化合成方法。以N-8-喹啉基芳基酰胺为反应原料，以亚铜盐为催化剂，以O-苯甲酰基羟胺以胺化试剂，在无机碱存在下有机溶剂中加热反应，得到N-8-喹啉基-2-胺基苯甲酰胺类化合物。该发明合成方法操作方便，条件温和、工艺简单，底物官能团适用范围广泛，胺基化反应区域选择性好，收率高。
一种N-8-喹啉基-2-胺基苯甲酰胺类化合物的合成方法，包括以下步骤：以亚铜盐为催化剂，在无机碱存在下，N-8-喹啉基芳基酰胺与O-苯甲酰基羟胺在有机溶剂中加热反应，得到N-8-喹啉基-2-胺基苯甲酰胺类化合物。反应方程式如下：
Figure BDA0003089081260000021
其中：R选自氢、卤素、硝基、腈基、三氟甲基、酯基、C1-C4烷氧基、C1-C6烷基或芳基；R取代基团为一个或者多个，取代位置为邻位、间位或对位。R1和R2均选自C1-C8烷基。
进一步地，在上述技术方案中，所述有机溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮中的一种。
进一步地，在上述技术方案中，所述无机碱选自碳酸锂、碳酸钠、碳酸钾、磷酸氢二钾、磷酸钾中的至少一种。
进一步地，在上述技术方案中，所述无机碱与原料N-8-喹啉基-芳基酰胺摩尔比为1-3:1。
进一步地，在上述技术方案中，加热反应温度为80-100℃。
进一步地，在上述技术方案中，所述亚铜盐催化剂为碘化亚铜或醋酸亚铜。
进一步地，在上述技术方案中，所述无机碱与N-8-喹啉基苯甲酰胺摩尔比为1-3:1；所述亚铜盐催化剂与N-8-喹啉基苯甲酰胺摩尔比为0.05-0.25:1；所述O-苯甲酰基羟胺与N-8-喹啉基苯甲酰胺摩尔比为1-2:1。
同现有技术相比，本发明的有益效果体现在：本发明的反应条件温和，反应通用性强，可以适用于各种取代基取代的底物，同时反应的区域选择性高；避免了外加氧化剂。
具体实施方式
实施例1
Figure BDA0003089081260000031
在50mL反应瓶中，加入0.5毫摩尔N-8-喹啉基-苯甲酰胺、0.125毫摩尔碘化亚铜催化剂、0.75毫摩尔O-苯甲酰基吗啉氧化物、1毫摩尔碳酸钠和5毫升N,N-二甲基乙酰胺，80℃反应2小时，反应结束后处理，硅胶柱层析得到N-8-喹啉基-2-(N-吗啉基)苯甲酰胺化合物1a，产率为74％。白色固体，1H NMR(600MHz,CDCl3)δ12.67(s,1H),9.13(d,J＝7.8Hz,1H),8.82(dd,J＝3.6,1.8Hz,1H),8.19(dd,J＝7.8,1.8Hz,1H),8.11(dd,J＝8.4,1.2Hz,1H),7.55(t,J＝7.8Hz,1H),7.49(d,J＝7.8Hz,1H),7.46(td,J＝7.8,1.2Hz,1H),7.41(dd,J＝8.4,4.2Hz,1H),7.23(d,J＝7.2Hz,1H),7.20(d,J＝8.4Hz,1H),3.93(t,J＝4.2Hz,4H),3.10(t,J＝4.2Hz,4H).13C NMR(150MHz,CDCl3)δ165.6,151.1,148.1,138.7,136.3,135.5,132.3,132.1,128.8,128.2,127.5,124.2,121.7,121.6,119.2,117.7,66.0,53.8.
实施例2
按照实施例1中反应条件，仅仅改变反应底物，反应结果如下：
Figure BDA0003089081260000041
Figure BDA0003089081260000051
代表性化合物表征数据如下：
化合物1b，产率为70％。白色固体，1H NMR(600MHz,CDCl3)δ12.69(s,1H),9.13(dd,J＝7.8,1.2Hz,1H),8.86(dd,J＝4.2,1.8Hz,1H),8.16(dd,J＝8.4,1.2Hz,1H),8.09(d,J＝7.8Hz,1H),7.58(t,J＝7.8Hz,1H),7.52(d,J＝7.8Hz,1H),7.46(dd,J＝8.4,4.2Hz,1H),7.10-6.98(m,2H),3.97(t,J＝4.2Hz,4H),3.13(t,J＝4.2Hz,4H),2.41(s,3H).13C NMR(150MHz,CDCl3)δ165.9,151.2,148.2,143.0,138.9,136.5,135.8,132.3,128.4,127.7,126.1,125.2,121.7,121.7,120.1,117.8,66.2,54.0,21.7.
化合物1c，产率为53％。白色固体，1H NMR(600MHz,CDCl3)δ12.71(s,1H),9.13(d,J＝7.8Hz,1H),8.87(dd,J＝4.2,1.2Hz,1H),8.19(d,J＝7.8Hz,1H),8.13(d,J＝7.8Hz,1H),7.60(t,J＝7.8Hz,1H),7.54(d,J＝7.8Hz,1H),7.48(dd,J＝8.4,4.2Hz,1H),7.32-7.27(m,2H),3.99(t,J＝4.2Hz,4H),3.18(t,J＝4.2Hz,4H),1.37(s,9H).13C NMR(150MHz,CDCl3)δ165.9,156.1,151.0,148.2,139.0,136.5,135.9,132.0,128.4,127.7,126.1,121.7,121.6,121.5,117.9,116.3,66.3,54.1,35.3,31.3.
化合物1d，产率为68％。白色固体，1H NMR(600MHz,CDCl3)δ12.62(s,1H),9.12(dd,J＝7.8,1.2Hz,1H),8.86(dd,J＝4.2,1.8Hz,1H),8.23-8.10(m,2H),7.58(t,J＝7.8Hz,1H),7.51(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,4.2Hz,1H),6.77-6.75(m,2H),3.97(t,J＝4.2Hz,4H),3.87(s,3H),3.12(t,J＝4.2Hz,4H).13C NMR(150MHz,CDCl3)δ165.5,163.0,153.1,148.1,138.9,136.5,135.9,134.1,128.4,127.7,121.7,121.6,121.6,117.8,108.4,106.2,66.2,55.6,54.0.
化合物1e，产率为70％。白色固体，1H NMR(600MHz,CDCl3)δ12.73(s,1H),9.17(dd,J＝7.8,1.2Hz,1H),8.89(dd,J＝4.2,1.8Hz,1H),8.28(d,J＝7.8Hz,1H),8.19(dd,J＝8.4,1.8Hz,1H),7.68-7.64(m,2H),7.61(t,J＝7.8Hz,1H),7.55(d,J＝8.4Hz,1H),7.52-7.47(m,4H),7.46(d,J＝1.8Hz,1H),7.44-7.39(m,1H),4.00(t,J＝4.2Hz,4H),3.23(t,J＝4.2Hz,4H).13CNMR(150MHz,CDCl3)δ165.6,151.6,148.2,145.4,140.3,138.9,136.5,135.7,132.8,129.0,128.4,128.2,127.7,127.6,127.3,123.0,121.9,121.7,118.2,117.9,66.2,54.1.
实施例3
Figure BDA0003089081260000061
在50mL反应瓶中，加入0.5毫摩尔N-8-喹啉基-4-甲苯甲酰胺、0.125毫摩尔碘化亚铜催化剂、0.75毫摩尔O-苯甲酰基-4-乙氧羰基哌啶氧化物、1毫摩尔碳酸钠和5毫升N,N-二甲基乙酰胺，80℃反应2小时，反应结束后处理，硅胶柱层析得到N-8-喹啉基-2-(N-4-羧酸乙酯哌啶)-4-甲基苯甲酰胺化合物1Aa，产率为78％。白色固体，1HNMR(600MHz,1H),8.14(dd,J＝8.4,1.8Hz,1H),8.12(d,J＝7.8Hz,1H),7.57(t,J＝7.8Hz,1H),7.51(dd,J＝7.8,1.2Hz,1H),7.44(dd,J＝8.4,4.2Hz,1H),7.03(s,1H),7.04(d,J＝7.8Hz,1H),4.05(q,J＝7.2Hz,2H),3.40(d,J＝12.0Hz,2H),2.98-2.79(m,2H),2.43-2.38(m,1H),2.40(s,3H),2.32-2.22(m,2H),2.05-1.93(m,2H),1.15(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ174.9,165.9,152.1,148.3,142.8,139.1,136.3,136.1,132.2,128.4,127.5,126.1,125.0,121.6,121.5,120.4,117.9,60.4,54.0,41.0,27.7,21.7,14.3.
实施例4
按照实施例3中反应条件，仅仅改变反应底物，反应结果如下：
Figure BDA0003089081260000071
代表性化合物表征数据如下：
化合物1Bb，产率为68％。白色固体，1H NMR(600MHz,CDCl3)δ13.08(s,1H),9.16(dd,J＝7.8,1.2Hz,1H),8.93(dd,J＝4.2,1.8Hz,1H),8.21-8.10(m,2H),7.58(t,J＝7.8Hz,1H),7.52(dd,J＝8.4,1.2Hz,1H),7.47(dd,J＝8.4,4.2Hz,1H),7.15(s,1H),7.06(d,J＝7.8Hz,1H),3.96(s,4H),3.21(t,J＝5.4Hz,4H),2.40(s,3H),2.13(s,4H).13C NMR(150MHz,CDCl3)δ165.9,152.0,148.1,142.9,139.2,136.4,136.3,132.2,128.4,127.6,126.1,125.4,121.7,121.7,121.2,118.2,107.2,64.4,52.6,34.7,21.7.化合物1Cc，产率为60％。白色固体，1H NMR(600MHz,CDCl3)δ9.14(dd,J＝7.8,1.2Hz,1H),8.84(dd,J＝4.2,1.8Hz,1H),8.17(dd,J＝8.4,1.8Hz,1H),8.08(d,J＝8.4Hz,1H),7.59(t,J＝7.8Hz,1H),7.52(dd,J＝8.4,1.2Hz,1H),7.45(dd,J＝8.4,4.2Hz,1H),7.05(s,1H),7.03-6.97(m,1H),3.07(s,4H),2.40(s,3H),1.91-1.77(m,4H),1.50(d,J＝5.4Hz,2H).13CNMR(150MHz,CDCl3)δ166.3,153.0,147.9,142.7,139.2,136.3,136.2,132.0,128.4,127.7,126.0,124.5,121.6,121.5,120.3,118.0,55.5,25.4,24.2,21.8.
以上实施例描述了本发明的基本原理、主要特征及优点。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，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (1)

1.一种N-8-喹啉基-2-(N-4-Boc-1-哌嗪)-4-甲基苯甲酰胺化合物1Ee的合成方法，其特征在于，包括以下步骤：
Figure FDA0003683454770000011
在50mL反应瓶中，加入0.5毫摩尔N-8-喹啉基-4-甲苯甲酰胺、0.125毫摩尔碘化亚铜催化剂、0.75毫摩尔O-苯甲酰基-N-Boc-N-羟基哌嗪、1毫摩尔碳酸钠和5毫升N,N-二甲基乙酰胺，80℃反应2小时，反应结束后处理，硅胶柱层析得到N-8-喹啉基-2-(N-4-Boc-1-哌嗪)-4-甲基苯甲酰胺化合物1Ee，产率为75％。
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