WO2020114025A1 - β-内酰胺衍生物的制备方法 - Google Patents

β-内酰胺衍生物的制备方法 Download PDF

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WO2020114025A1
WO2020114025A1 PCT/CN2019/104403 CN2019104403W WO2020114025A1 WO 2020114025 A1 WO2020114025 A1 WO 2020114025A1 CN 2019104403 W CN2019104403 W CN 2019104403W WO 2020114025 A1 WO2020114025 A1 WO 2020114025A1
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曾润生
施鹏
赵应声
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Abstract

一种β-内酰胺衍生物的制备方法：以取代N-喹啉-3-丁烯酰胺衍生物为底物，与甲苯衍生物或杂环衍生物在DTBP和铜盐催化剂的作用下，在90-150℃下反应，制得β-内酰胺衍生物。按照此方法可以高收率的得到多个β-内酰胺衍生物，反应条件较温和、反应操作和后处理过程简单，适合于规模化生产。

Description

β-内酰胺衍生物的制备方法 技术领域
本发明涉及有机化合物的制备技术领域，尤其涉及一种β-内酰胺衍生物的制备方法。
背景技术
β-内酰胺衍生物通常具有显著的生物活性和药理活性，如抗病毒、抗革兰氏阴性杆菌，因此合成β-内酰胺衍生物具有重要的价值。
至今，β-内酰胺衍生物的合成方法主要有以下几种：
β-内酰胺衍生物的合成方法在文献J.Am.Chem.Soc，1982,104,3233中有所披露，该方法通过氧化关环。文献J.Org.Chem.1995,60,1276上披露了一种还原法关环反应制备β-内酰胺衍生物的方法。
利用C-H键活化和金属催化合成β-内酰胺的方法，分别在文献Angewandte Chemie，2013,52,13588、Angewandte Chemie 2014,53,3496和Chem.Eur.J,2014,20,9530上公开。但以上方法反应条件较苛刻，需要使用贵金属催化剂，成本高。且利用活化基团或者定位基团的反应并不符合原子经济性和环境友好性的要求。
发明内容
为了克服现有技术制备β-内酰胺衍生物收率较低，使用昂贵原料，反应条件苛刻和对环境不友好的不足，本发明提供一种β-内酰胺衍生物的制备方法，该方法原料易得、高收率、反应条件较温和、普适性好，且绿色环保。
本发明提供了一种β-内酰胺衍生物的制备方法，包括以下步骤：
将式(1)的取代N-喹啉-3-丁烯酰胺衍生物与甲苯或式(2)的甲苯衍生物在二叔丁基过氧化物(DTBP)以及铜盐催化剂的作用下于90-150℃下反应，得到式(4)的β-内酰胺衍生物；反应路线如下：
Figure PCTCN2019104403-appb-000001
或者将式(1)的取代N-喹啉-3-丁烯酰胺衍生物与式(3)的杂环衍生物在二叔丁基过氧化物以及铜盐催化剂的作用下于90-150℃下反应，得到式(5)的β-内酰胺衍生物；反应路线如下：
Figure PCTCN2019104403-appb-000002
其中，式(1)-(5)中，Y为氧原子或硫原子；
R 1、R 2、R 3的选择采取以下方案：
R 2、R 3为氢，R 1为氢、甲基、卤素或三氟甲基；
或R 1、R 2为氢，R 3为C1-C6烷基或苯甲基；
或R 1、R 3为氢，R 2为C1-C6烷基、烯丙基、苯甲基、苯乙基、环丙基甲基或环丁基甲基。
在以上制备方法中，式(2)的甲苯衍生物和式(3)的杂环衍生物在不存在其他有机溶剂的条件下，既作为反应底物又同时作为反应溶剂。
进一步地，当式(1)的取代N-喹啉-3-丁烯酰胺衍生物与式(3)的杂环衍生物反应时，R 2、R 3为氢，R 1为氢、甲基、卤素或三氟甲基。优选地，R 1为氢。
进一步地，铜盐催化剂为溴化亚铜(CuBr)、醋酸铜(Cu(OAc) 2)、氯化亚铜(CuCl)、四乙腈六氟磷酸铜(Cu(CH 3CN) 4PF 6)、三氟甲磺酸铜、氧化铜和溴化铜(CuBr 2)中的一种或几种。
进一步地，按摩尔比，取代N-喹啉-3-丁烯酰胺衍生物：二叔丁基过氧化物：铜盐催化剂＝1:1-3:0.05-0.2。
优选地，铜盐催化剂为四乙腈六氟磷酸铜。
优选地，按摩尔比，取代N-喹啉-3-丁烯酰胺衍生物：二叔丁基过氧化物：铜盐催化剂＝1:3:0.05-0.2。更优选地，按摩尔比，取代N-喹啉-3-丁烯酰胺衍生物：二叔丁基过氧化物：铜盐催化剂＝1:3:0.1。
进一步地，反应温度为130-150℃。优选地，反应温度为130℃。
进一步地，反应体系中还包括除甲苯、式(2)的甲苯衍生物或式(3)的杂环衍生物的其他有机溶剂。
进一步地，有机溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺和异丙醇中的一种或几种。
进一步地，反应时间为8-10h。
发明人通过深入细致的研究发现通过引发自由基串联成环反应，可以高效率合成β-内酰胺衍生物。本发明属于铜盐催化下自由基引发成环反应，条件较温和、适用范围广泛、符合绿色化学要求。
借由上述方案，本发明至少具有以下优点：
1、本发明提供了一个全新的体系，利用自由基反应实现了β-内酰胺衍生物的合成。
2、本发明使用取代N-喹啉-3-丁烯酰胺衍生物为起始物，原料易得、种类很多；利用本发明的方法得到的产物类型多样，既可以直接使用，又可以用于其他进一步的反应。
3、本发明反应新颖、反应操作和后处理过程简单，产率很高，适合于规模生产。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合详细说明如后。
具体实施方式
下面结合实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例一：4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000003
(1)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。将上述混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2a。分离产率为92％。
(2)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到110℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2a。分离产率为80％。
(3)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到140℃反应，TLC 跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2a。分离产率为90％。
(4)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到90℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2a。分离产率为22％。
(5)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol)，CuBr 2(0.005g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2a。分离产率为56％。
(6)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol)，Cu(OAc) 2(0.004g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2a。分离产率为18％。
(7)称取N-(8-喹啉基)-3-丁烯酰胺1a(0.042g,0.2mmol)，CuBr(0.003g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2a。分离产率为20％。
2a: 1H NMR(400MHz,CDCl 3)δ8.78(dd,J＝4.1,1.8Hz,1H),8.27(dd,J＝7.5,1.4Hz,1H),8.11(dd,J＝8.3,1.7Hz,1H),7.57(dd,J＝8.2,1.4Hz,1H),7.54–7.47(m,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.29–7.21(m,2H),7.20–7.15(m,1H),7.14–7.10(m,2H),5.20(ddd,J＝11.8,5.6,2.9Hz,1H),3.32(dd,J＝15.0,5.3Hz,1H),2.82(dd,J＝15.0,2.6Hz,1H),2.74–2.62(m,2H),2.37(tdd,J＝9.1,7.2,3.3Hz,1H),1.84(dtd,J＝13.3,8.7,6.4Hz,1H)； 13C NMR(101MHz,CDCl 3)δ166.46(s),148.92(s),141.10(s),140.65(s),136.03(s),133.61(s),128.99(s),128.38(s),128.29(s),126.70(s),126.02(s),124.01(s),121.63(s),121.32(s),56.11(s),43.12(s),35.24(s),31.63(s).HRMS(ESI-TOF)Calcd for C 20H 19N 2O[M+H] +:303.1497，found:303.1512。
实施例二：4-(3-甲基苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000004
称取N-(8-喹啉基)-3-丁烯酰胺1b(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL间二甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2b。分离产率为86％。
2b: 1H NMR(400MHz,CDCl 3)δ8.80(dd,J＝4.1,1.8Hz,1H),8.28(dd,J＝7.5,1.4Hz,1H),8.11(dd,J＝8.3,1.8Hz,1H),7.57(dd,J＝8.2,1.4Hz,1H),7.54–7.46(m,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.18–7.12(m,1H),7.00(d,J＝7.6Hz,1H),6.93(d,J＝6.5Hz,2H),5.21(ddd,J＝11.7,5.7,3.0Hz,1H),3.33(dd,J＝15.0,5.3Hz,1H),2.84(dd,J＝15.0,2.6Hz,1H),2.69–2.63(m,2H),2.41–2.34(m,1H),2.31(s,2H),1.93–1.78(m,1H)； 13C NMR(101MHz,CDCl 3)δ166.05(s),148.48(s),140.59(s),140.22(s),137.45(s),135.56(s),133.18(s),128.62(s),128.53(s),127.83(s),126.28(s),126.23(s),124.83(s),123.58(s),121.19(s),120.86(s),55.70(s),42.65(s),34.78(s),31.05(s),20.92(s)；HRMS Calcd for C 21H 21N 2O[M+H] +:317.1654,Found:317.1669。
实施例三：4-(4-甲基苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000005
称取N-(8-喹啉基)-3-丁烯酰胺1c(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL对二甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2c。分离产率为62％。
2c: 1H NMR(400MHz,CDCl 3)δ8.80(dd,J＝4.1,1.8Hz,1H),8.26(dd,J＝7.5,1.4Hz,1H),8.12(dd,J＝8.3,1.7Hz,1H),7.58(dd,J＝8.2,1.4Hz,1H),7.54–7.47(m,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.07(d,J＝7.9Hz,2H),7.01(d,J＝8.1Hz,2H),5.19(ddd,J＝11.8,5.7,3.0 Hz,1H),3.32(dd,J＝15.0,5.3Hz,1H),2.82(dd,J＝15.0,2.6Hz,1H),2.69–2.60(m,2H),2.45–2.32(m,1H),2.30(s,3H),1.90–1.76(m,1H)； 13C NMR(101MHz,CDCl 3)δ166.55(s),148.95(s),140.68(s),138.00(s),136.04(s),135.47(s),133.64(s),129.06(s),129.00(s),128.15(s),126.70(s),124.04(s),121.67(s),121.33(s),56.18(s),43.09(s),35.30(s),31.15(s),21.00(s)；HRMS Calcd for C 21H 21N 2O[M+H] +:317.1654,Found:317.1668。
实施例四：4-(2-甲基苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000006
称取N-(8-喹啉基)-3-丁烯酰胺1d(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL邻二甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2d。分离产率为80％。
2d: 1H NMR(400MHz,CDCl 3)δ8.79(dd,J＝4.1,1.8Hz,1H),8.30(dd,J＝7.5,1.5Hz,1H),8.11(dd,J＝8.3,1.8Hz,1H),7.57(dd,J＝8.2,1.4Hz,1H),7.54–7.49(m,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.11–7.05(m,4H),5.25(ddd,J＝11.6,5.7,3.0Hz,1H),3.37(dd,J＝15.0,5.3Hz,1H),2.88(dd,J＝15.0,2.6Hz,1H),2.66(t,J＝8.0Hz,2H),2.36–2.28(m,1H),2.17(s,3H),1.85–1.75(m,1H). 13C NMR(101MHz,CDCl 3)δ166.02(s),148.43(s),140.12(s),138.84(s),135.59(s),135.24(s),133.21(s),129.75(s),128.53(s),128.17(s),126.26(s),125.70(s),125.54(s),123.54(s),121.08(s),120.86(s),55.80(s),42.66(s),33.70(s),28.45(s),18.60(s).43.09(s),35.30(s),31.15(s),21.00(s)；HRMS Calcd for C 21H 21N 2O[M+H] +:317.1654,Found:317.1693。
实施例五：4-(2-氯苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000007
称取N-(8-喹啉基)-3-丁烯酰胺1e(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL邻氯甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应， TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2e。分离产率为83％。
2e: 1H NMR(400MHz,CDCl 3)δ8.77(dd,J＝4.1,1.8Hz,1H),8.28(dd,J＝7.5,1.4Hz,1H),8.11(dd,J＝8.3,1.7Hz,1H),7.57(dd,J＝8.1,1.4Hz,1H),7.52–7.47(m,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.31–7.28(m,1H),7.15–7.08(m,3H),5.23(ddd,J＝11.8,5.6,2.9Hz,1H),3.36(dd,J＝15.0,5.3Hz,1H),2.88(dd,J＝15.0,2.6Hz,1H),2.79(dd,J＝8.7,6.8Hz,2H),2.36(dtd,J＝11.0,8.0,3.3Hz,1H),1.90–1.78(m,1H). 13C NMR(101MHz,CDCl 3)δ165.94(s),148.42(s),140.08(s),138.30(s),135.52(s),133.36(s),133.18(s),129.78(s),129.02(s),128.50(s),127.07(s),126.33(s),126.22(s),123.46(s),120.99(s),120.83(s),55.58(s),42.68(s),33.30(s),28.99(s)；HRMS Calcd for C 20H 18ClN 2O[M+H] +:337.1108,Found:317.1122。
实施例六：4-(3-氯苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000008
称取N-(8-喹啉基)-3-丁烯酰胺1f(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL间氯甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2f。分离产率为82％。
2f: 1H NMR(400MHz,CDCl 3)δ8.79(dd,J＝4.1,1.8Hz,1H),8.26(dd,J＝7.5,1.4Hz,1H),8.13(dd,J＝8.3,1.8Hz,1H),7.58(dd,J＝8.2,1.4Hz,1H),7.54–7.47(m,1H),7.41(dd,J＝8.3,4.1Hz,1H),7.17(dd,J＝12.3,5.0Hz,2H),7.12(s,1H),7.01–6.97(m,1H),5.19(ddd,J＝11.8,5.7,3.0Hz,1H),3.33(dd,J＝15.0,5.3Hz,1H),2.82(dd,J＝15.0,2.6Hz,1H),2.75–2.59(m,2H),2.42–2.31(m,1H),1.84(dtd,J＝13.4,8.8,6.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ166.24(s),149.00(s),143.08(s),140.56(s),136.07(s),134.15(s),133.53(s),129.61(s),129.00(s),128.35(s),126.72(s),126.58(s),126.23(s),124.05(s),121.57(s),121.38(s),55.81(s),43.09(s),34.84(s),31.28(s)；HRMS Calcd for C20H17ClN2ONa[M+Na] +:359.0927,Found:359.0939。
实施例七：4-(4-氯苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000009
称取N-(8-喹啉基)-3-丁烯酰胺1g(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL对氯甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2g。分离产率为83％。
2g: 1H NMR(400MHz,CDCl 3)δ8.76(dd,J＝4.1,1.8Hz,1H),8.24(dd,J＝7.5,1.4Hz,1H),8.12(dd,J＝8.3,1.7Hz,1H),7.58(dd,J＝8.2,1.3Hz,1H),7.52–7.47(m,1H),7.40(dd,J＝8.3,4.1Hz,1H),7.22–7.18(m,2H),7.03(d,J＝8.4Hz,2H),5.18(ddd,J＝11.7,5.7,3.0Hz,1H),3.32(dd,J＝15.0,5.3Hz,1H),2.81(dd,J＝15.0,2.6Hz,1H),2.69–2.58(m,2H),2.33(tdd,J＝9.2,7.3,3.3Hz,1H),1.83(dtd,J＝13.4,8.7,6.3Hz,2H). 13C NMR(101MHz,CDCl 3)δ165.82(s),148.44(s),140.12(s),139.04(s),135.60(s),133.05(s),131.25(s),129.14(s),128.52(s),127.97(s),126.24(s),123.59(s),121.14(s),120.88(s),55.42(s),42.57(s),34.58(s),30.46(s)；HRMS Calcd for C 20H 18ClN 2O[M+H] +:337.1108,Found:337.1118。
实施例八：4-(2-呋喃乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000010
称取N-(8-喹啉基)-3-丁烯酰胺1h(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL 2-甲基呋喃中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2h。分离产率为80％。
2h: 1H NMR(400MHz,CDCl 3)δ8.82(dd,J＝4.1,1.8Hz,1H),8.25(dd,J＝7.5,1.4Hz,1H),8.13(dd,J＝8.3,1.8Hz,1H),7.58(dd,J＝8.2,1.4Hz,1H),7.54–7.48(m,1H),7.40(dd,J＝8.3,4.1Hz,1H),7.27(dd,J＝1.8,0.7Hz,1H),6.26(dd,J＝3.1,1.9Hz,1H),5.98(dd,J＝3.1,0.8Hz,1H),5.23(ddd,J＝11.7,5.7,3.0Hz,1H),3.31(dd,J＝15.1,5.3Hz,1H),2.76(dd,J＝ 15.1,2.6Hz,1H),2.70(t,J＝7.5Hz,2H),2.41–2.33(m,1H),1.93–1.83(m,1H). 13C NMR(101MHz,CDCl 3)δ165.89(s),154.26(s),148.50(s),140.48(s),140.18(s),135.56(s),133.08(s),128.53(s),126.22(s),123.57(s),121.15(s),120.86(s),109.73(s),104.73(s),55.47(s),42.56(s),31.62(s),23.51(s)；HRMS Calcd for C 18H 17N 2O 2[M+H +]:293.1290,Found:293.1300。
实施例九：4-(2-噻吩乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000011
称取N-(8-喹啉基)-3-丁烯酰胺1i(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL 2-甲基噻吩中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2i。分离产率为65％。
2i: 1H NMR(400MHz,CDCl 3)δ8.81(dd,J＝4.1,1.7Hz,1H),8.26(dd,J＝7.5,1.4Hz,1H),8.13(dd,J＝8.3,1.7Hz,1H),7.58(dd,J＝8.2,1.3Hz,1H),7.54–7.48(m,1H),7.40(dd,J＝8.3,4.1Hz,1H),7.10(dd,J＝5.1,1.1Hz,1H),6.89(dd,J＝5.1,3.4Hz,1H),6.76(dd,J＝2.3,1.0Hz,1H),5.25(ddd,J＝11.7,5.7,3.0Hz,1H),3.33(dd,J＝15.0,5.3Hz,1H),2.91(t,J＝7.6Hz,2H),2.83(dd,J＝15.0,2.6Hz,1H),2.43(dtd,J＝11.5,8.0,3.4Hz,1H),1.92(ddt,J＝13.4,9.1,7.3Hz,1H). 13C NMR(101MHz,CDCl 3)δ8.81(dd,J＝4.1,1.7Hz,1H),8.26(dd,J＝7.5,1.4Hz,1H),8.13(dd,J＝8.3,1.7Hz,1H),7.58(dd,J＝8.2,1.3Hz,1H),7.54–7.48(m,1H),7.40(dd,J＝8.3,4.1Hz,1H),7.10(dd,J＝5.1,1.1Hz,1H),6.89(dd,J＝5.1,3.4Hz,1H),6.76(dd,J＝2.3,1.0Hz,1H),5.25(ddd,J＝11.7,5.7,3.0Hz,1H),3.33(dd,J＝15.0,5.3Hz,1H),2.91(t,J＝7.6Hz,2H),2.83(dd,J＝15.0,2.6Hz,1H),2.43(dtd,J＝11.5,8.0,3.4Hz,1H),1.92(ddt,J＝13.4,9.1,7.3Hz,1H).23.51；HRMS Calcd for C 18H 17N 2OS[M+H] +:309.1062,Found:309.1077。
实施例十：4-(3-氟苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000012
称取N-(8-喹啉基)-3-丁烯酰胺1j(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL间氟甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2j。分离产率为64％。
2j: 1H NMR(400MHz,CDCl 3)δ8.79(dd,J＝4.1,1.8Hz,1H),8.26(dd,J＝7.5,1.4Hz,1H),8.12(dd,J＝8.4,1.7Hz,1H),7.58(dd,J＝8.2,1.3Hz,1H),7.53–7.47(m,1H),7.40(dd,J＝8.3,4.1Hz,1H),7.20(td,J＝7.8,6.2Hz,1H),6.91–6.82(m,3H),5.19(ddd,J＝11.8,5.6,3.0Hz,1H),3.32(dd,J＝15.0,5.3Hz,1H),2.81(dd,J＝15.0,2.6Hz,1H),2.75–2.62(m,2H),2.45–2.31(m,1H),1.90–1.77(m,1H). 19F NMR(376MHz,CDCl 3)δ-113.64(s). 13C NMR(101MHz,CDCl 3)δ165.81(s),163.64(s),161.20(s),148.49(s),143.14(d,J＝7.2Hz),140.10(s),135.60(s),133.07(s),129.30(d,J＝8.4Hz),128.53(s),126.24(s),123.73–123.07(m),121.09(s),120.90(s),114.61(d,J＝21.0Hz),112.42(d,J＝20.9Hz),55.38(s),42.59(s),34.33(s),30.84(s)；HRMS Calcd for C 20H 18FN 2O[M+H] +:321.1403,Found:321.1400。
实施例十一：4-(2-氟苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000013
称取N-(8-喹啉基)-3-丁烯酰胺1k(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL邻氟甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2k。分离产率为82％。
2k: 1H NMR(400MHz,CDCl 3)δ8.73(dd,J＝4.1,1.8Hz,1H),8.27(dd,J＝7.5,1.4Hz,1H),8.10(dd,J＝8.3,1.8Hz,1H),7.55(dd,J＝8.2,1.4Hz,1H),7.52–7.45(m,1H),7.37(dd,J ＝8.3,4.1Hz,1H),7.19–7.08(m,2H),7.04–6.92(m,2H),5.19(ddd,J＝12.1,5.5,2.9Hz,1H),3.33(dd,J＝15.0,5.3Hz,1H),2.83(dd,J＝15.1,2.6Hz,1H),2.71(t,J＝7.7Hz,2H),2.37(dtd,J＝11.3,8.0,3.2Hz,1H),1.89–1.73(m,2H). 19F NMR(376MHz,CDCl 3)δ-118.68(s).. 13C NMR(101MHz,CDCl 3)δ165.94(s),161.79(s),159.36(s),148.40(s),140.07(s),135.52(s),133.13(s),129.98(d,J＝4.9Hz),128.49(s),127.60(s),127.45(s),127.32(d,J＝8.1Hz),126.20(s),123.50(d,J＝4.0Hz),120.92(d,J＝16.5Hz),114.74(d,J＝22.1Hz),55.56(s),42.67(s),33.57(s),24.46(d,J＝2.6Hz)；HRMS Calcd for C 20H 18FN 2O[M+H] +:321.1403,Found:321.1398。
实施例十二：4-(2-溴苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000014
称取N-(8-喹啉基)-3-丁烯酰胺1l(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL邻溴甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2l。分离产率为82％。
2l: 1H NMR(400MHz,CDCl 3)δ8.77(dd,J＝4.1,1.8Hz,1H),8.28(dd,J＝7.5,1.5Hz,1H),8.10(dd,J＝8.3,1.8Hz,1H),7.56(dd,J＝8.2,1.4Hz,1H),7.52–7.45(m,2H),7.38(dd,J＝8.3,4.1Hz,1H),7.15(ddd,J＝9.6,7.4,1.5Hz,2H),7.05–6.99(m,1H),5.24(ddd,J＝11.7,5.6,2.9Hz,1H),3.36(dd,J＝15.0,5.3Hz,1H),2.90(dd,J＝15.0,2.6Hz,1H),2.78(dd,J＝9.1,7.1Hz,2H),2.34(dtd,J＝9.0,7.9,3.3Hz,1H),1.87–1.80(m,1H). 13C NMR(101MHz,CDCl 3)δ165.95(s),148.46(s),140.09(s),140.00(s),135.53(s),133.19(s),132.34(s),129.77(s),128.50(s),127.33(s),127.00(s),126.22(s),123.83(s),123.49(s),121.01(s),120.84(s),55.53(s),42.68(s),33.48(s),31.55(s)；HRMS Calcd for C 20H 18BrN 2O[M+H] +:381.0603,Found:381.0607.
实施例十三：4-(2-碘苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000015
称取N-(8-喹啉基)-3-丁烯酰胺1m(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL邻碘甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2m。分离产率为80％。
2m: 1H NMR(400MHz,CDCl 3)δ8.79(dt,J＝12.6,6.3Hz,1H),8.29(dd,J＝7.5,1.4Hz,1H),8.10(dd,J＝8.3,1.7Hz,1H),7.75(dd,J＝7.9,1.1Hz,1H),7.56(dd,J＝8.1,1.4Hz,1H),7.52–7.45(m,1H),7.38(dd,J＝8.3,4.1Hz,1H),7.21(td,J＝7.5,1.1Hz,1H),7.12(dd,J＝7.6,1.6Hz,1H),6.84(td,J＝7.7,1.7Hz,1H),5.26(ddd,J＝11.6,5.7,3.0Hz,1H),3.37(dd,J＝15.0,5.3Hz,1H),2.94(dd,J＝15.0,2.6Hz,1H),2.83–2.65(m,1H),2.41–2.17(m,1H),1.89–1.73(m,1H).1 3C NMR(101MHz,CDCl 3)δ165.93(s),148.53(s),143.25(s),140.13(s),139.03(s),135.54(s),133.21(s),128.82(s),128.53(s),127.92(s),127.46(s),126.24(s),123.50(s),121.05(s),120.85(s),99.84(s),55.46(s),42.71(s),36.20(s),33.83(s)；HRMS Calcd for C 20H 18BrN 2O[M+H] +:429.0464,Found:429.0474。
实施例十四：4-(3-碘苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000016
称取N-(8-喹啉基)-3-丁烯酰胺1n(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL间碘甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2n。分离产率为62％。
2n: 1H NMR(400MHz,CDCl 3)δ8.79(dd,J＝4.1,1.8Hz,1H),8.24(dd,J＝7.5,1.4Hz,1H),8.13(dd,J＝8.4,1.7Hz,1H),7.58(dd,J＝8.2,1.4Hz,1H),7.54–7.46(m,3H),7.41(dd,J＝8.3,4.1Hz,1H),7.07(d,J＝8.0Hz,1H),6.98(t,J＝7.7Hz,1H),5.18(ddd,J＝11.8,5.7,3.0Hz,1H),3.32(dd,J＝15.0,5.3Hz,1H),2.81(dd,J＝15.0,2.6Hz,1H),2.70–2.52(m,2H),2.34(dddd,J＝12.7,9.2,7.2,3.3Hz,1H),1.82(dtd,J＝13.4,8.8,5.9Hz,1H). 13C NMR(101MHz,CDCl 3)δ166.26(s),149.06(s),143.53(s),140.57(s),137.23(s),136.08(s),135.13(s),133.50(s),130.11(s),129.00(s),127.68(s),126.71(s),124.09(s),121.59(s),121.40(s),94.51(s),55.82(s),43.09(s),34.91(s),31.17(s)；HRMS Calcd for C 20H 18BrN 2O[M+H] +:429.0464,Found: 429.0472.
实施例十五：4-(4-碘苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000017
称取N-(8-喹啉基)-3-丁烯酰胺1o(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL对碘甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2o。分离产率为52％。
2o: 1H NMR(400MHz,CDCl 3)δ8.76(dd,J＝4.1,1.8Hz,1H),8.23(dd,J＝7.5,1.3Hz,1H),8.12(dd,J＝8.3,1.7Hz,1H),7.58(dd,J＝8.2,1.3Hz,1H),7.56–7.52(m,2H),7.50(t,J＝7.8Hz,1H),7.40(dd,J＝8.3,4.1Hz,1H),6.85(d,J＝8.3Hz,2H),5.18(ddd,J＝11.6,5.6,3.0Hz,1H),3.32(dd,J＝15.0,5.3Hz,1H),2.81(dd,J＝15.0,2.6Hz,1H),2.68–2.54(m,2H),2.32(tdd,J＝9.1,7.2,3.3Hz,1H),1.83(dtd,J＝13.5,8.7,6.3Hz,1H). 13C NMR(101MHz,CDCl 3)δ166.29(s),148.92(s),140.72(s),140.58(s),137.37(s),136.09(s),133.51(s),130.38(s),128.99(s),126.73(s),124.08(s),121.62(s),121.37(s),91.01(s),55.89(s),43.04(s),34.93(s),31.09(s)；HRMS Calcd for C 20H 18BrN 2O[M+H] +:429.0464,Found:429.0472。
实施例十六：4-(2-三氟甲基苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000018
称取N-(8-喹啉基)-3-丁烯酰胺1p(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL邻三氟甲基甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2p。分离产率为76％。
2p: 1H NMR(400MHz,CDCl 3)δ8.81(dd,J＝4.1,1.7Hz,1H),8.28(dd,J＝7.5,1.3Hz,1H),8.11(dd,J＝8.3,1.7Hz,1H),7.60–7.54(m,2H),7.50(t,J＝7.8Hz,1H),7.40(dd,J＝8.3, 4.3Hz,2H),7.23(dd,J＝13.9,7.4Hz,2H),5.26(ddd,J＝11.7,5.6,3.0Hz,1H),3.38(dd,J＝15.0,5.3Hz,1H),2.88(dd,J＝15.0,2.6Hz,1H),2.86–2.75(m,2H),2.44–2.30(m,1H),1.92–1.76(m,1H). 19F NMR(376MHz,CDCl 3)δ-59.65(s). 13C NMR(101MHz,CDCl 3)δ166.33(s),148.93(s),140.54(s),140.01(s),136.03(s),133.58(s),131.73(s),130.90(s),128.99(s),128.29(dd,J＝50.2,20.6Hz),126.69(s),126.12(s),125.96(q,J＝272.0Hz),125.96(d,J＝5.7Hz),123.99(s),121.49(s),121.34(s),56.12(s),43.15(s),35.93(s),28.44(s)；HRMS Calcd for C 21H 17F 3N 2ONa[M+Na] +:393.1191,Found:393.1196。
实施例十七：4-(3-三氟甲基苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000019
称取N-(8-喹啉基)-3-丁烯酰胺1q(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL间三氟甲基甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2q。分离产率为64％。
2q: 1H NMR(400MHz,CDCl 3)δ8.75(dd,J＝4.1,1.8Hz,1H),8.25(dd,J＝7.5,1.4Hz,1H),8.12(dd,J＝8.4,1.7Hz,1H),7.58(dd,J＝8.2,1.4Hz,1H),7.54–7.47(m,1H),7.43(d,J＝7.8Hz,1H),7.40(dd,J＝8.4,4.2Hz,1H),7.35(d,J＝7.2Hz,2H),7.29(d,J＝7.4Hz,1H),5.21(ddd,J＝11.7,5.7,3.1Hz,1H),3.34(dd,J＝15.0,5.3Hz,1H),2.83(dd,J＝15.0,2.6Hz,1H),2.78–2.67(m,2H),2.45–2.33(m,1H),1.89(dtd,J＝13.4,8.8,6.2Hz,1H). 19F NMR(376MHz,CDCl 3)δ-62.54(s). 13C NMR(101MHz,CDCl 3)δ166.22(s),148.95(s),141.98(s),140.57(s),136.10(s),133.47(s),131.74(s),130.70(q,J＝33.3Hz),129.01(s),128.80(s),126.71(s),125.35(q,J＝241.0Hz),124.92(q,J＝3.7Hz),124.13(s),122.94(dd,J＝7.5,3.6Hz),121.64(s),121.39(s),55.81(s),43.07(s),34.98(s),31.44(s)；HRMS Calcd for C 21H 17F 3N 2ONa[M+Na +]:393.1191,Found:393.1198。
实施例十八：4-(4-三氟甲基苯乙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000020
称取N-(8-喹啉基)-3-丁烯酰胺1r(0.042g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL对三氟甲基甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物2r。分离产率为48％。
2r: 1H NMR(400MHz,CDCl 3)δ8.75(dd,J＝4.1,1.7Hz,1H),8.24(dd,J＝7.5,1.4Hz,1H),8.12(dd,J＝8.3,1.7Hz,1H),7.58(dd,J＝8.1,1.3Hz,1H),7.50(t,J＝8.0Hz,3H),7.40(dd,J＝8.3,4.1Hz,1H),7.21(d,J＝8.1Hz,2H),5.21(ddd,J＝11.6,5.6,3.0Hz,1H),3.34(dd,J＝15.0,5.3Hz,1H),2.84(dd,J＝15.0,2.6Hz,1H),2.74(dt,J＝14.0,6.1Hz,2H),2.43–2.32(m,1H),1.90(dtd,J＝13.5,8.8,6.3Hz,1H). 19F NMR(376MHz,CDCl 3)δ-62.36(s). 13C NMR(101MHz,CDCl 3)δ166.21(s),148.89(s),145.24(s),140.56(s),136.12(s),133.48(s),129.00(s),128.59(s),126.73(s),125.58(q,J＝268.7Hz),125.41(d,J＝4.0Hz),125.27(dd,J＝7.6,3.8Hz),124.11(s),121.61(s),121.37(s),55.83(s),43.02(s),34.88(s),31.40(s)；HRMS Calcd for C 21H 18F 3N2O[M+H +]:371.1371,Found:371.1382。
实施例十九：3-甲基-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000021
称取N-(8-喹啉基)-2-甲基-3-丁烯酰胺3a(0.045g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4a。分离产率为85％。
4a: 1H NMR(400MHz,CDCl 3)δ8.77(dd,J＝4.1,1.7Hz,1H),8.27(dd,J＝7.4,1.4Hz,1H),8.11(dd,J＝8.3,1.7Hz,1H),7.56(dd,J＝8.1,1.3Hz,1H),7.50(t,J＝7.8Hz,1H),7.38(dd, J＝8.3,4.1Hz,1H),7.26(dd,J＝8.2,6.6Hz,2H),7.22–7.12(m,3H),4.82(dt,J＝9.6,2.7Hz,1H),3.03(qd,J＝7.3,2.2Hz,1H),2.72(t,J＝7.7Hz,2H),2.44–2.32(m,1H),1.95–1.80(m,1H),1.44(d,J＝7.4Hz,3H). 13C NMR(101MHz,CDCl 3)δ169.54(s),148.37(s),140.71(s),140.15(s),135.50(s),133.09(s),128.53(s),127.90(s),127.85(s),126.23(s),125.55(s),123.33(s),121.20(s),120.78(s),63.98(s),50.68(s),34.45(s),31.33(s),13.26(s)；HRMS Calcd for C 21H 21N 2O[M+H +]:317.1654,Found:317.1645。
实施例二十：3-乙基-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000022
称取N-(8-喹啉基)-2-乙基-3-丁烯酰胺3b(0.048g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4b。分离产率为82％。
4b: 1H NMR(400MHz,CDCl 3)δ8.79(dd,J＝4.1,1.6Hz,1H),8.30(dd,J＝7.4,0.8Hz,1H),8.11(dd,J＝8.3,1.5Hz,1H),7.56(d,J＝7.9Hz,1H),7.50(t,J＝7.8Hz,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.25(dd,J＝9.0,5.9Hz,2H),7.20–7.11(m,3H),4.93(dt,J＝9.3,2.6Hz,1H),3.01(ddd,J＝8.2,6.2,2.1Hz,1H),2.71(dd,J＝8.6,5.9Hz,2H),2.46–2.28(m,1H),2.06–1.93(m,1H),1.91–1.80(m,2H),1.15(t,J＝7.4Hz,3H). 13C NMR(101MHz,CDCl 3)δ169.52(s),148.88(s),141.26(s),140.65(s),135.98(s),133.59(s),129.01(s),128.36(s),128.25(s),126.71(s),125.98(s),123.80(s),121.62(s),121.26(s),62.46(s),58.00(s),35.01(s),31.78(s),22.23(s),11.97(s)；HRMS Calcd for C 22H 22N 2ONa[M+Na] +:353.1630；Found:353.1632。
实施例二十一：3-丙基-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000023
称取N-(8-喹啉基)-2-丙基-3-丁烯酰胺3c(0.051g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4c。分离产率为75％。
4c: 1H NMR(400MHz,CDCl 3)δ8.79(dd,J＝4.1,1.8Hz,1H),8.30(dd,J＝7.4,1.1Hz,1H),8.11(dd,J＝8.4,1.7Hz,1H),7.56(dd,J＝8.2,1.5Hz,1H),7.53–7.46(m,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.26–7.23(m,2H),7.17(d,J＝7.3Hz,1H),7.12(d,J＝7.1Hz,2H),4.92(dt,J＝9.3,2.7Hz,1H),3.06(ddd,J＝8.4,6.2,2.2Hz,1H),2.70(t,J＝8.0Hz,2H),2.44–2.29(m,1H),2.02–1.87(m,2H),1.85–1.75(m,1H),1.66–1.49(m,2H),1.01(t,J＝7.3Hz,3H). 13C NMR(101MHz,CDCl 3)δ169.65(s),148.86(s),141.28(s),140.66(s),135.98(s),133.62(s),129.01(s),128.36(s),128.24(s),126.72(s),125.97(s),123.78(s),121.62(s),121.25(s),62.96(s),56.44(s),35.04(s),31.74(s),31.33(s),20.86(s),14.16(s)；HRMS Calcd for C 23H 25N 2O[M+H] +:345.1967,Found:345.1972.
实施例二十二：3-异丙基-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000024
称取N-(8-喹啉基)-2-异丙基-3-丁烯酰胺3d(0.051g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4d。分离产率为73％。
4d: 1H NMR(400MHz,CDCl 3)δ8.82(dd,J＝4.1,1.7Hz,1H),8.32(dd,J＝7.4,1.4Hz,1H),8.11(dd,J＝8.3,1.7Hz,1H),7.56(dd,J＝8.1,1.4Hz,1H),7.50(t,J＝7.8Hz,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.24(t,J＝7.4Hz,2H),7.18–7.10(m,3H),5.05–5.00(m,1H),2.91(dd,J＝7.8,2.2Hz,1H),2.70(t,J＝8.2Hz,2H),2.38–2.28(m,1H),2.22(dq,J＝13.7,6.8Hz,1H),1.95–1.83(m,1H),1.22(d,J＝6.7Hz,3H),1.15(d,J＝6.7Hz,3H). 13C NMR(101MHz,CDCl 3)δ169.03(s),148.91(s),141.36(s),140.76(s),135.98(s),133.59(s),129.02(s),128.35(s),128.19(s),126.71(s),125.94(s),123.82(s),121.64(s),121.26(s),63.29(s),60.70(s),35.13(s),31.75(s),28.48(s),20.97(s),20.45(s)；HRMS Calcd for C 23H 25N 2O[M+H] +:345.1967,Found:345.1977。
实施例二十三：3,3’-二甲基-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000025
称取N-(8-喹啉基)-2,2’-二甲基-3-丁烯酰胺3e(0.048g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4e。分离产率为52％。
4e: 1H NMR(400MHz,CDCl 3)δ8.75(dd,J＝4.1,1.8Hz,1H),8.17(dd,J＝7.5,1.4Hz,1H),8.09(dd,J＝8.3,1.7Hz,1H),7.56(dd,J＝8.2,1.4Hz,1H),7.54–7.44(m,1H),7.37(dd,J＝8.3,4.1Hz,1H),7.25(td,J＝6.9,1.8Hz,2H),7.22–7.16(m,1H),7.13–7.06(m,2H),4.91(dd,J＝9.8,3.7Hz,1H),2.74–2.55(m,2H),2.33–2.14(m,1H),1.98–1.80(m,1H),1.52(s,3H),1.38(s,3H). 13C NMR(101MHz,CDCl 3)δ172.83(s),148.48(s),141.01(s),140.66(s),135.50(s),132.83(s),128.57(s),127.91(s),127.90(s),126.17(s),125.54(s),123.75(s),122.21(s),120.80(s),67.26(s),52.59(s),32.31(s),31.17(s),23.03(s),16.64(s)；HRMS Calcd for C 22H 22N 2ONa[M+Na] +:353.1630,Found:353.1643。
实施例二十四：3-烯丙基-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000026
称取N-(8-喹啉基)-2-烯丙基-3-丁烯酰胺3f(0.051g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4f。分离产率为79％。
4f: 1H NMR(400MHz,CDCl 3)δ8.78(dd,J＝4.1,1.7Hz,1H),8.30(dd,J＝7.5,1.4Hz,1H),8.11(dd,J＝8.3,1.7Hz,1H),7.57(dd,J＝8.1,1.4Hz,1H),7.50(t,J＝7.8Hz,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.30–7.21(m,2H),7.18(d,J＝7.3Hz,1H),7.15–7.10(m,2H),5.96(ddt,J＝17.1,10.1,7.0Hz,1H),5.24(dd,J＝17.0,1.5Hz,1H),5.15(d,J＝10.1Hz,1H),4.95(dt,J＝9.3,2.8Hz,1H),3.27–2.87(m,1H),2.88–2.64(m,3H),2.63–2.49(m,1H),2.36(tdd,J＝9.3,7.2,3.2Hz,1H),1.88(dtd,J＝13.4,8.9,6.7Hz,1H). 13C NMR(101MHz,CDCl 3)δ168.75(s),148.93(s),141.26(s),140.63(s),135.98(s),134.99(s),133.52(s),129.01(s),128.36(s),128.29(s),126.69(s),125.99(s),123.92(s),121.65(s),121.29(s),117.38(s),62.41(s),56.00(s),34.91(s),33.31(s),31.78(s)；HRMS Calcd for C 23H 23N 2O[M+H] +:343.1810,Found:343.1810。
实施例二十五：3-苯甲基-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000027
称取N-(8-喹啉基)-2-苯甲基-3-丁烯酰胺3g(0.061g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4g。分离产率为84％。
4g: 1H NMR(400MHz,CDCl 3)δ8.68(dd,J＝4.1,1.8Hz,1H),8.20(dd,J＝7.5,1.5Hz,1H),8.00(dd,J＝8.3,1.7Hz,1H),7.47(dd,J＝8.1,1.3Hz,1H),7.43–7.37(m,1H),7.33–7.22(m,5H),7.20–7.13(m,1H),7.11–7.06(m,2H),7.03(dd,J＝4.9,3.5Hz,1H),6.85–6.74(m,2H),4.89(dt,J＝9.6,2.4Hz,1H),3.32–3.13(m,2H),2.94(dd,J＝13.3,9.4Hz,1H),2.24–2.17(m,1H),2.17–2.03(m,2H),1.66(ddt,J＝10.5,9.3,8.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ168.74(s),148.98(s),141.29(s),140.68(s),139.20(s),136.00(s),133.47(s),129.02(s),128.71(s),128.26(s),128.15(s),126.70(s),126.65(s),125.85(s),124.05(s),121.79(s),121.32(s),62.93(s),58.37(s),35.35(s),34.79(s),31.20(s)；HRMS Calcd for C 27H 25N 2O[M+H] +:393.1967,Found:393.1967。
实施例二十六：3,4-二苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000028
称取N-(8-喹啉基)-2-苯乙基-3-丁烯酰胺3h(0.063g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4h。分离产率为80％。
4h: 1H NMR(400MHz,CDCl 3)δ8.76(dd,J＝4.1,1.8Hz,1H),8.24(dd,J＝7.5,1.5Hz,1H),8.07(dd,J＝8.3,1.7Hz,1H),7.53(dd,J＝8.2,1.4Hz,1H),7.50–7.42(m,1H),7.35(dd,J＝8.3,4.1Hz,1H),7.26(d,J＝7.2Hz,2H),7.23(t,J＝2.2Hz,2H),7.21(d,J＝4.2Hz,2H),7.18(dd,J＝4.5,2.4Hz,1H),7.13(d,J＝7.3Hz,1H),7.08–7.04(m,2H),4.99–4.89(m,1H),3.03(td,J＝7.8,2.2Hz,1H),2.94–2.75(m,2H),2.63(t,J＝7.9Hz,2H),2.35–2.18(m,2H),2.15–2.03(m,1H),1.89–1.75(m,1H). 13C NMR(101MHz,CDCl 3)δ169.27(s),148.92(s),141.44(s),141.15(s),140.71(s),136.00(s),133.52(s),129.02(s),128.59(s),128.49(s),128.46(s),128.38(s),128.26(s),126.72(s),126.02(s),123.92(s),121.72(s),121.29(s),62.90(s),55.84(s),34.83(s),33.58(s),31.70(s),30.92(s)；HRMS Calcd for C 28H 27N 2O[M+H] +:407.2123,Found:407.2134。
实施例二十七：3-甲基环丙烷-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000029
称取N-(8-喹啉基)-2-甲基环丙烷-3-丁烯酰胺3i(0.053g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4i。分离产率为78％。
4i: 1H NMR(400MHz,CDCl 3)δ8.81(dd,J＝4.1,1.8Hz,1H),8.30(dd,J＝7.4,1.4Hz,1H),8.11(dd,J＝8.3,1.8Hz,1H),7.56(dd,J＝8.2,1.5Hz,1H),7.53–7.47(m,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.27–7.24(m,2H),7.20–7.11(m,3H),5.11–4.96(m,1H),3.15(ddd,J＝8.4,6.2,2.2Hz,1H),2.80–2.71(m,2H),2.45–2.33(m,1H),1.89(ddd,J＝13.1,6.5,3.3Hz,1H),1.82–1.77(m,2H),0.94(tdd,J＝7.6,5.0,2.6Hz,1H),0.54(dd,J＝8.1,1.4Hz,2H),0.20(ddd,J＝16.1,7.5,3.1Hz,2H). 13C NMR(101MHz,CDCl 3)δ169.47(s),148.89(s),141.34(s),140.68(s),135.99(s),133.62(s),129.03(s),128.37(s),128.23(s),126.72(s),125.98(s),123.82(s),121.65(s),121.27(s),62.77(s),56.96(s),35.10(s),34.00(s),31.79(s),9.25(s),5.11(s),4.55(s)；HRMS Calcd for C 24H 24N 2ONa[M+H] +:379.1786,Found:379.1769。
实施例二十八：3-甲基环丁烷-4-苯乙基-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000030
称取N-(8-喹啉基)-2-甲基环丁烷-3-丁烯酰胺3j(0.055g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸 乙酯＝10:1)提纯后得到化合物4j。分离产率为75％。
4j: 1H NMR(400MHz,CDCl 3)δ8.80(dd,J＝4.1,1.7Hz,1H),8.28(dd,J＝7.4,1.4Hz,1H),8.11(dd,J＝8.3,1.7Hz,1H),7.56(dd,J＝8.1,1.4Hz,1H),7.53–7.47(m,1H),7.39(dd,J＝8.3,4.1Hz,1H),7.25(dd,J＝9.0,5.7Hz,2H),7.19–7.11(m,3H),4.97–4.88(m,1H),2.97(ddd,J＝8.4,6.0,2.1Hz,1H),2.68(t,J＝8.0Hz,2H),2.57(dt,J＝15.4,7.8Hz,1H),2.33(dtd,J＝11.3,8.2,3.2Hz,1H),2.15(dtd,J＝11.5,7.6,3.6Hz,2H),2.05(ddd,J＝14.2,8.4,6.1Hz,1H),1.96–1.90(m,2H),1.89–1.83(m,2H),1.76–1.68(m,2H). 13C NMR(101MHz,CDCl 3)δ169.72(s),148.87(s),141.29(s),140.68(s),135.98(s),133.62(s),129.01(s),128.38(s),128.22(s),126.71(s),125.99(s),123.81(s),121.65(s),121.26(s),62.89(s),54.75(s),36.26(s),35.05(s),34.12(s),31.67(s),28.51(s),28.37(s),18.44(s)；HRMS Calcd for C 25H 27N 2O[M+H] +:371.2123,Found:371.2125。
实施例二十九：4-(2-苯丙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000031
称取N-(8-喹啉基)-3-戊烯酰胺3k(0.045g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4k。分离产率为40％。
4k: 1H NMR(400MHz,CDCl 3)δ8.86(dd,J＝4.1,1.7Hz,1H),8.14(ddd,J＝8.7,7.9,1.5Hz,2H),7.64(dd,J＝8.2,1.2Hz,1H),7.53(t,J＝7.8Hz,1H),7.42(dd,J＝8.3,4.2Hz,1H),7.08(t,J＝4.9Hz,3H),6.81–6.75(m,2H),5.24(td,J＝5.2,2.7Hz,1H),3.25(dd,J＝15.2,5.6Hz,1H),2.96(dd,J＝15.2,2.7Hz,1H),2.80(dd,J＝12.9,3.4Hz,1H),2.35–2.27(m,1H),2.22(dd,J＝12.9,10.3Hz,1H),0.82(d,J＝6.6Hz,3H). 13C NMR(101MHz,CDCl 3)δ166.69(s),149.18(s),141.52(s),140.25(s),136.09(s),133.92(s),129.03(s),128.83(s),128.13(s),126.71(s),125.81(s),124.68(s),122.84(s),121.40(s),60.38(s),39.40(s),37.52(s),36.87(s),15.66(s)；HRMS Calcd for C 21H 20N 2ONa[M+Na] +:339.1473,Found:339.1468。
实施例三十：4-(2-苯丁基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000032
称取N-(8-喹啉基)-3-己烯酰胺3l(0.048g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4l。分离产率为20％。
4l: 1H NMR(400MHz,CDCl 3)δ8.84(dd,J＝4.1,1.8Hz,1H),8.17–8.12(m,2H),7.62(dd,J＝8.2,1.3Hz,1H),7.50(dd,J＝10.3,5.4Hz,1H),7.42(dd,J＝8.3,4.1Hz,1H),7.05–7.00(m,3H),6.71–6.67(m,2H),5.45(td,J＝5.7,3.0Hz,1H),3.21(dd,J＝15.2,5.6Hz,1H),3.00(dd,J＝15.2,2.8Hz,1H),2.76(dd,J＝13.4,4.0Hz,1H),2.35(dd,J＝13.4,9.7Hz,1H),2.22(ddt,J＝12.3,8.4,4.1Hz,1H),1.42(dtd,J＝12.2,7.5,4.7Hz,1H),1.24–1.18(m,1H),0.93(t,J＝7.5Hz,3H). 13C NMR(101MHz,CDCl 3)δ166.19(s),148.55(s),140.65(s),140.10(s),135.60(s),133.25(s),128.48(s),128.31(s),127.59(s),126.30(s),125.19(s),123.82(s),121.87(s),120.90(s),57.72(s),41.94(s),38.23(s),33.56(s),23.04(s),11.03(s)；HRMS Calcd for C 22H 23N 2O[M+H +]:331.1810,Found:331.1813。
实施例三十一：4-(1.3-二苯丙基)-1-(8-喹啉基)丙内酰胺的合成
Figure PCTCN2019104403-appb-000033
称取化合物3m(0.060g,0.2mmol)，Cu(CH 3CN) 4PF 6(0.008g,0.02mmol)溶于1mL甲苯中，加入DTBP(0.088g,0.6mmol)。混合物加热到130℃反应，TLC跟踪反应直到反应完全结束。反应结束后粗产物经硅胶柱层析分离(石油醚:乙酸乙酯＝10:1)提纯后得到化合物4m。分离产率为20％。
4m: 1H NMR(400MHz,CDCl 3)δ8.54(dd,J＝4.1,1.8Hz,1H),8.12(ddd,J＝5.1,3.1,1.6Hz,2H),7.57(dd,J＝8.2,1.3Hz,1H),7.49–7.44(m,1H),7.37(dd,J＝8.3,4.1Hz,1H),7.33– 7.28(m,2H),7.22(dd,J＝5.9,3.5Hz,1H),7.10(d,J＝6.9Hz,2H),7.06–7.00(m,3H),6.71(dd,J＝7.0,2.4Hz,2H),5.27(dt,J＝5.7,3.0Hz,1H),3.15(dd,J＝15.2,5.6Hz,1H),3.01(dd,J＝15.2,2.9Hz,1H),2.87–2.79(m,2H),2.77(d,J＝4.1Hz,1H),2.45–2.36(m,2H). 13C NMR(101MHz,CDCl 3)δ166.30(s),148.74(s),140.65(s),140.13(s),139.82(s),135.96(s),133.72(s),129.01(s),128.83(s),128.74(s),128.29(s),128.20(s),126.79(s),126.15(s),125.84(s),123.95(s),121.67(s),121.27(s),57.88(s),42.61(s),38.28(s),37.34(s),34.08(s)；HRMS Calcd for C 27H 25N 2O[M+H +]:393.1967,Found:393.1972。
总之，本发明公开了一种β-内酰胺衍生物的制备方法，以取代N-喹啉-3-丁烯酰胺衍生物为底物，与甲苯、甲苯衍生物或杂环衍生物在DTBP和铜盐的作用下，在90-150℃下反应，高收率的制得多种β-内酰胺衍生物。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (8)

  1. 一种β-内酰胺衍生物的制备方法，其特征在于，包括以下步骤：
    将式(1)的取代N-喹啉-3-丁烯酰胺衍生物与式(2)的甲苯衍生物在二叔丁基过氧化物以及铜盐催化剂的作用下于90-150℃下反应，得到式(4)的β-内酰胺衍生物；反应路线如下：
    Figure PCTCN2019104403-appb-100001
    或者将式(1)的取代N-喹啉-3-丁烯酰胺衍生物与式(3)的杂环衍生物在二叔丁基过氧化物以及铜盐催化剂的作用下于90-150℃下反应，得到式(5)的β-内酰胺衍生物；反应路线如下：
    Figure PCTCN2019104403-appb-100002
    其中，式(1)-(5)中，Y为氧原子或硫原子；
    R 1、R 2、R 3的选择采取以下方案：
    R 2、R 3为氢，R 1为氢、甲基、卤素或三氟甲基；
    或R 1、R 2为氢，R 3为C1-C6烷基或苯甲基；
    或R 1、R 3为氢，R 2为C1-C6烷基、烯丙基、苯甲基、苯乙基、环丙基甲基或环丁基甲基。
  2. 根据权利要求1所述的方法，其特征在于：所述铜盐催化剂为溴化亚铜、醋酸铜、氯化亚铜、四乙腈六氟磷酸铜、三氟甲磺酸铜、氧化铜和溴化铜中的一种或几种。
  3. 根据权利要求1所述的方法，其特征在于：按摩尔比，取代N-喹啉-3-丁烯酰胺衍生物：二叔丁基过氧化物：铜盐催化剂＝1:1-3:0.05-0.2。
  4. 根据权利要求1-3中任一项所述的方法，其特征在于：所述铜盐催化剂为四乙腈六氟磷酸铜。
  5. 根据权利要求1-3中任一项所述的方法，其特征在于：按摩尔比，取代N-喹啉-3-丁烯酰胺衍生物：二叔丁基过氧化物：铜盐催化剂＝1:3:0.05-0.2。
  6. 根据权利要求1-3中任一项所述的方法，其特征在于：反应温度为130-150℃。
  7. 根据权利要求1-3中任一项所述的方法，其特征在于：反应体系中还包括除式(2)的甲苯衍生物或式(3)的杂环衍生物的其他有机溶剂。
  8. 根据权利要求7所述的方法，其特征在于：所述有机溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺和异丙醇中的一种或几种。
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