CN111303017A - 一类含9,10-二氢菲骨架的化合物及其制备方法和用途 - Google Patents
一类含9,10-二氢菲骨架的化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一类含9,10‑二氢菲骨架的化合物及其制备方法和用途，所述化合物具有式3A或式3B所示结构：
使式1化合物在铑催化剂、金属盐添加剂的存在下，与式2化合物和乙酸发生反应，即可制得式3A化合物；再使式3A化合物水解，可制得式3B化合物；具体反应式如下所示：
Description
技术领域
本发明是涉及一类含9,10-二氢菲骨架的化合物及其制备方法和用途，属于医药领域。
背景技术
9,10-二氢菲骨架是天然产物中常见的结构单元，具有该骨架结构的天然产物或化合物很多具有良好的生物活性，例如：灯心草酚具有良好的抗癌和抗菌活性，石斛兰具有良好的抗癌活性，截叶金石斛具有良好的抗自由基活性，红门兰醇具有良好的抗真菌活性，Cedrelin A具有良好的抗菌活性，Paralycolin A具有良好的抗癌活性等。因此，采用高效便捷的化学合成方法对具有该骨架的化合物进行合成，并进一步开展生物活性评价，将具有重要意义。
发明内容
针对现有技术存在的上述问题和需求，本发明的目的是提供一类含9,10-二氢菲骨架的化合物及其制备方法和用途，以促进该类化合物在医药领域的广泛应用。
本发明所述的含9,10-二氢菲骨架的化合物是具有式3A或式3B所示结构的化合物：
其中：
R1、R2、R3、R分别独立选自氢、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的烷氧基、取代或未取代的芳基、取代或未取代的杂环基、取代或未取代的氰基、卤素中的任意一种；或者，相邻的R1、R2、R3之间独立的通过共价键形成饱和或不饱和的碳环(包括芳环、稠环)或杂环(包括烷基杂环、芳杂环、稠杂环)；
DG为具有式A所述结构的取代或未取代的含氮杂环基：
作为优选方案，R1、R2、R3、R分别独立选自氢、C1～C6烷基(包括支链烷基、支链烷基、环烷基)、Ra取代的C1～C6烷基、C2～C6烯基、C1～C6烷氧基、OCORb取代的C1～C6烷氧基、C3～C20芳基、卤素取代的C3～C20芳基、氰基取代的C3～C20芳基、烷基取代的C3～C20芳基、C3～C20杂环基、卤素取代的C3～C20杂环基、氰基取代的C3～C20杂环基、烷基取代的C3～C20杂环基、C1～C4氰基、卤素中的任意一种；
Ra选自卤素、C3～C20芳基、C3～C20杂环基、ORc、OCORc中的任意一种；
Rb为C1～C6烷基；
Rc选自C1～C6烷基、C3～C20碳环基(包括芳环基、稠环基)、C3～C20杂环基(包括烷基杂环及、芳杂环基、稠杂环基)中的任意一种；或者，相邻的R1、R2、R3之间独立的通过共价键形成饱和的碳环；
DG选自如下所述结构的取代或未取代的含氮杂环基：
作为进一步优选方案，R1、R2、R3、R分别独立选自氢、C1～C6烷基(例如：甲基、乙基、丙基、异丙基、甲基环丙烷基、环已基、)、
C2～C6烯基(例如：丙烯基)、C1～C6烷氧基(例如：甲氧基、乙氧基、丙氧基等)、
苯基、苄基、卤素或氰基取代的苯基(例如：4-氟-苯基、4-氯-苯基、4-溴-苯基、4-氰基-苯基等)、C1～C4氰基(例如：甲腈基、乙腈基等)、卤素(例如：氟、氯、溴等)中的任意一种，或者，相邻的R1、R2、R3之间独立的通过共价键形成六元碳环；
DG选自如下所述结构的取代或未取代的含氮杂环基：
作为优选方案，所述的含9,10-二氢菲骨架的化合物具有如下任意一种结构式：
一种本发明所述的含9,10-二氢菲骨架的化合物的制备方法，是使式1化合物在铑催化剂、金属盐添加剂的存在下，与式2化合物和乙酸发生反应，制得式3A化合物；再使式3A化合物水解，制得式3B化合物；具体反应式如下所示：
作为优选方案，所述式1化合物选自如下化合物：
作为优选方案，所述的式2化合物选自如下化合物：
作为优选方案，所述铑催化剂为三价铑催化剂，所述三价铑催化剂包括但不限于[Cp*RhCl2]2、[RhCp*(MeCN)3](SbF6)2、[RhCp*(MeCN)3](PF6)2、[RhCp*(MeCN)3](BF4)2。
作为优选方案，所述金属盐添加剂包括但不限于NaBArF、AgSbF6、AgOAc、Cu(OAc)2、ZnCl2。
作为优选方案，反应溶剂为乙酸或乙酸与水的混合溶剂，反应温度为90～110℃。
作为优选方案，式1化合物与式2化合物的摩尔比为2：1。
本发明所述的含9,10-二氢菲骨架的化合物的用途，是指以具有式3A或3B结构的化合物中的至少一种作为活性成分用于制备抗肿瘤的药物。
作为优选方案，以具有式3A或3B结构的化合物中的至少一种作为活性成分用于制备抗肝癌或乳腺癌的药物。
本发明所述的药物可以各种给药途径给予患者，包括但不限于口服、透皮、肌肉、皮下和静脉注射。
本发明所述的药物的剂型不限，只要是能够使活性成分有效地到达体内的剂型都可以，包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂等；优选口服剂型，如：胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。
本发明所述的药物可以单独使用，也可以以药物组合物的形式使用，所述的药物组合物是指在药物中，除了含有主要活性成分之外，还可含有少量的且不影响有效成分的次要成分和/或药学上可接受的载体以及各种制剂所必要的辅料等。例如，所述药物为口服剂型时，可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。适宜的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂；适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠；适宜的润滑剂包括，例如硬脂酸镁；适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
本发明所述活性成分的有效施用剂量可随所用的药物组合物、药物制剂、给药的模式和待治疗的疾病的严重程度而变化。
与现有技术相比，本发明具有如下显著性有益效果：
本发明的研究结果显示：本发明所述的一类含9,10-二氢菲骨架的化合物具有抑制肿瘤细胞增殖的作用，可望作为活性成分用于制备抗肿瘤的药物，尤其可望作为活性成分用于制备抗肝癌或乳腺癌的药物，具有广泛药用前景；另外，本发明所述制备方法，具有操作简单、成本低廉、安全环保、反应条件温和等优点，尤其适合规模化生产，因而本发明可促进该类化合物在医药领域的广泛应用。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：
(3aa)的制备
将2mmol的化合物1a、1mmol的化合物2a、0.05mmol的[Cp*RhCl2]2、0.24mmol的NaBArF加入反应器中，然后加入5ml乙酸，加料完毕后，在氮气保护下，于100℃搅拌反应8小时，结束反应，反应液降温至室温，加入碳酸氢钠水溶液淬灭反应，然后用二氯甲烷萃取，合并有机相，合并的有机相用无水硫酸钠干燥，抽滤，减压浓缩除去溶剂，柱层析(PE/EA＝3/1)，得到白色固体，即化合物3aa(收率：75％)。
经测试：1H NMR(600MHz,CDCl3)δ8.75(dd,J＝4.9,0.7Hz,1H),8.17(dd,J＝7.7,1.2Hz,1H),7.80(td,J＝7.7,1.8Hz,1H),7.44(d,J＝7.8Hz,1H),7.35-7.31(m,1H),7.28(dd,J＝7.6,1.4Hz,1H),7.24(d,J＝7.6Hz,1H),7.09(s,1H),6.89(d,J＝8.3Hz,1H),6.64(d,J＝8.2Hz,1H),3.92(dd,J＝10.9,5.8Hz,1H),3.47(t,J＝10.5Hz,1H),3.33-3.27(m,1H),2.90(dd,J＝15.5,2.1Hz,1H),2.81(dd,J＝15.5,4.8Hz,1H),2.27(s,3H),1.79(s,3H)；
13C NMR(150MHz,CDCl3)δ170.71,159.80,151.84,148.77,140.04,136.88,136.39,132.86,132.78,130.08,128.33,127.70,126.98,126.03,124.56,121.92,115.91,62.91,34.14,28.00,20.71,18.71；
HRMS(ESI):[M+H]+calcd for C23H22NO3 +360.1594,found 360.1595。
实施例2：
(3ab)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ab(收率：75％)。
经测试：1H NMR(600MHz,CDCl3)δ8.75(dd,J＝4.9,0.8Hz,1H),8.14(dd,J＝7.4,1.6Hz,1H),7.79(td,J＝7.7,1.8Hz,1H),7.44(d,J＝7.8Hz,1H),7.36–7.30(m,3H),7.00(d,J＝8.3Hz,1H),6.77(d,J＝8.3Hz,1H),6.26(s,1H),3.94(dd,J＝10.9,5.5Hz,1H),3.46(t,J＝10.6Hz,1H),3.40-3.33(m,1H),2.96(dd,J＝15.5,2.2Hz,1H),2.80(dd,J＝15.5,4.6Hz,1H),2.72(dq,J＝14.9,7.5Hz,1H),2.56(dq,J＝15.0,7.6Hz,1H),1.78(s,3H),1.20(t,J＝7.5Hz,3H)；
13C NMR(150MHz,CDCl3)δ170.64,159.66,151.38,148.98,140.51,136.32,136.23,133.56,132.94,132.91,128.63,128.52,127.30,126.25,124.47,121.87,121.78,116.16,63.19,33.54,28.10,24.82,20.68,15.77；
HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1744。
实施例3：
(3ac)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ac(收率：55％)。
经测试：1H NMR(600MHz,CDCl3)δ8.74(dd,J＝4.8,0.7Hz,1H),8.11(dd,J＝7.5,1.2Hz,1H),7.79(td,J＝7.7,1.8Hz,1H),7.45(d,J＝7.8Hz,1H),7.39–7.33(m,2H),7.31(ddd,J＝7.4,4.9,0.9Hz,1H),7.12(d,J＝8.5Hz,1H),6.84(d,J＝8.5Hz,1H),5.95(s,1H),3.95–3.87(m,1H),3.51–3.43(m,2H),3.23-3.14(m,1H),3.04–2.97(m,1H),2.81(dd,J＝15.3,3.5Hz,1H),1.79(s,3H),1.27(d,J＝6.8Hz,3H),1.18(d,J＝6.8Hz,3H)；
13C NMR(150MHz,CDCl3)δ170.71,159.75,151.43,148.80,140.01,138.04,136.37,135.51,133.10,132.78,128.31,127.65,126.05,125.42,124.55,121.91,121.55,116.47,63.53,33.07,28.15,28.13,25.15,23.35,20.68；
HRMS(ESI):[M+H]+calcd for C25H26NO3 +388.1907,found 388.1898。
实施例4：
(3ad)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ad(收率：69％)。
经测试：1H NMR(600MHz,CDCl3)δ8.75–8.73(m,1H),8.10(dd,J＝7.6,1.1Hz,1H),7.78(td,J＝7.7,1.8Hz,1H),7.45(d,J＝7.8Hz,1H),7.37–7.29(m,3H),7.08(d,J＝8.5Hz,1H),6.80(d,J＝8.5Hz,1H),6.16(s,1H),3.93–3.86(m,1H),3.49–3.42(m,2H),2.97(d,J＝15.5Hz,1H),2.81–2.73(m,2H),1.86(d,J＝13.3Hz,1H),1.80(s,3H),1.74(t,J＝14.5Hz,4H),1.55(dd,J＝12.4,3.3Hz,1H),1.46–1.35(m,2H),1.34–1.22(m,2H)；
13C NMR(150MHz,CDCl3)δ170.65,159.63,151.11,149.05,140.54,137.60,136.14,135.94,133.06,132.98,128.50,127.19,126.35,126.28,124.45,121.83,121.57,116.20,63.64,39.04,35.86,33.68,33.15,28.27,27.12,27.11,26.25,20.67；
HRMS(ESI):[M+Na]+calcd for C28H29NO3Na+450.2040,found 450.2051。
实施例5：
(3ae)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ae(收率：42％)。
经测试：1H NMR(600MHz,CDCl3)δ8.71(d,J＝4.2Hz,1H),8.19–8.15(m,1H),7.76(td,J＝7.7,1.7Hz,1H),7.41(d,J＝7.8Hz,1H),7.35–7.31(m,2H),7.30–7.26(m,3H),7.18(t,J＝7.3Hz,1H),7.10(d,J＝7.4Hz,2H),6.93(d,J＝8.3Hz,1H),6.75(d,J＝8.3Hz,1H),6.34(s,1H),4.14(d,J＝16.2Hz,1H),3.93(d,J＝16.2Hz,1H),3.83(dd,J＝10.9,5.7Hz,1H),3.44(t,J＝10.5Hz,1H),3.32-3.25(m,1H),2.85(dd,J＝15.6,2.2Hz,1H),2.75(dd,J＝15.6,4.6Hz,1H),1.75(s,3H)；
13C NMR(150MHz,CDCl3)δ170.66,159.81,152.15,149.11,141.23,140.73,137.65,136.38,133.22,132.93,130.97,130.04,128.76,128.57,128.52,127.39,126.39,126.14,124.54,122.31,122.00,116.29,63.33,38.21,34.14,28.22,20.79；
HRMS(ESI):[M+H]+calcd for C29H26NO3 +436.1907,found 436.1892。
实施例6：
(3af)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3af(收率：68％)。
经测试：1H NMR(600MHz,CDCl3)δ8.74(d,J＝4.7Hz,1H),8.23(dd,J＝5.9,3.2Hz,1H),7.92(s,1H),7.79(t,J＝7.3Hz,1H),7.41(d,J＝7.8Hz,1H),7.36(t,J＝7.4Hz,2H),7.34–7.29(m,2H),7.24(d,J＝5.7Hz,4H),6.91(d,J＝8.3Hz,1H),6.70(d,J＝8.3Hz,1H),3.69(dd,J＝10.8,5.8Hz,1H),3.46(t,J＝10.4Hz,1H),3.21-3.15(m,1H),2.85(dd,J＝15.5,4.4Hz,1H),2.74(d,J＝14.0Hz,1H),1.62(s,3H)；
13C NMR(150MHz,CDCl3)δ170.37,159.67,152.69,148.86,141.38,140.38,136.63,136.30,134.20,133.23,132.80,130.07,129.52,128.68,128.08,127.47,126.85,126.18,124.42,121.91,121.67,115.86,63.59,34.04,28.37,20.57,0.00；
HRMS(ESI):[M+Na]+calcd for C28H23NO3Na+444.1570,found 444.1559。
实施例7：
(3ag)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ag(收率：72％)。
经测试：1H NMR(600MHz,CDCl3)δ8.76–8.72(m,1H),8.24–8.19(m,1H),7.80(td,J＝7.7,1.8Hz,1H),7.73(s,1H),7.49(d,J＝8.3Hz,2H),7.41(d,J＝7.8Hz,1H),7.33(ddd,J＝7.5,5.0,1.0Hz,1H),7.26–7.23(m,2H),7.11(d,J＝8.3Hz,2H),6.87(d,J＝8.3Hz,1H),6.71(d,J＝8.3Hz,1H),3.66(dd,J＝10.9,5.8Hz,1H),3.46(t,J＝10.4Hz,1H),3.15–3.10(m,1H),2.85(dd,J＝15.5,4.5Hz,1H),2.76(dd,J＝15.5,2.3Hz,1H),1.65(s,3H)；
13C NMR(150MHz,CDCl3)δ170.38,159.77,153.28,148.58,140.43,139.85,136.61,136.33,133.05,132.69,132.49,131.23,131.19,129.72,128.56,127.86,125.93,124.50,122.06,121.83,120.97,116.12,63.52,34.06,28.30,20.59；
HRMS(ESI):[M+H]+calcd for C28H23BrNO3 +500.0856,found 500.0833。
实施例8：
(3ah)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ah(收率：66％)。
经测试：1H NMR(600MHz,CDCl3)δ8.74(d,J＝4.9Hz,1H),8.26–8.21(m,1H),7.81(td,J＝7.7,1.5Hz,1H),7.79(d,J＝10.9Hz,1H),7.67(d,J＝8.0Hz,2H),7.43(d,J＝7.8Hz,1H),7.37(d,J＝8.0Hz,2H),7.36–7.33(m,1H),7.25(dd,J＝6.7,3.7Hz,2H),6.87(d,J＝8.3Hz,1H),6.73(d,J＝8.3Hz,1H),3.67(dd,J＝11.0,6.0Hz,1H),3.44(t,J＝10.4Hz,1H),3.11-3.05(m,1H),2.90(dd,J＝15.5,4.5Hz,1H),2.76(dd,J＝15.6,2.1Hz,1H),1.64(s,3H)；
13C NMR(150MHz,CDCl3)δ170.45,160.07,154.38,148.34,146.86,139.25,137.18,136.06,133.07,132.71,132.04,131.64,130.54,129.33,128.53,125.70,124.78,122.41,122.12,119.09,116.61,110.78,63.73,34.18,28.42,20.70；
HRMS(ESI):[M+H]+calcd for C29H23N2O3 +447.1703,found 447.1707。
实施例9：
(3ai)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ai(收率：55％)。
经测试：1H NMR(600MHz,CDCl3)δ8.78(d,J＝4.3Hz,1H),8.25(s,1H),8.19-8.15(m,1H),7.86(td,J＝7.7,1.7Hz,1H),7.47(d,J＝7.8Hz,1H),7.39(dd,J＝6.8,5.1Hz,1H),7.19(d,J＝4.5Hz,2H),7.07(d,J＝8.4Hz,1H),6.65(d,J＝8.4Hz,1H),3.84(dd,J＝11.1,6.7Hz,1H),3.81(d,J＝18.3Hz,1H),3.67(d,J＝18.3Hz,1H),3.47(dd,J＝11.0,8.9Hz,1H),3.20–3.14(m,1H),2.85(dd,J＝15.7,4.8Hz,1H),2.81–2.74(m,1H),1.83(s,3H)；
13C NMR(150MHz,DMSO-d6)δ170.34,159.21,155.11,149.50,140.52,137.55,136.92,132.88,132.26,129.59,128.84,128.78,126.09,124.73,122.52,121.99,120.06,119.91,116.47,62.83,33.43,28.04,20.76,20.33；
HRMS(ESI):[M+H]+calcd for C24H21N2O3 +385.1547,found 385.1545。
实施例10：
(3aj)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3aj(收率：69％)。
经测试：1H NMR(600MHz,CDCl3)δ8.75(d,J＝4.2Hz,1H),8.17(dd,J＝7.3,1.7Hz,1H),7.82(td,J＝7.7,1.8Hz,1H),7.44(d,J＝7.8Hz,1H),7.36-7.32(m,1H),7.29(s,1H),7.28-7.23(m,2H),6.92(d,J＝8.4Hz,1H),6.66(d,J＝8.3Hz,1H),4.21(t,J＝7.4Hz,2H),3.91(dd,J＝10.9,5.9Hz,1H),3.46(t,J＝10.5Hz,1H),3.39-3.33(m,1H),3.04(dt,J＝14.4,7.3Hz,1H),2.90(dd,J＝15.6,2.1Hz,1H),2.86–2.79(m,2H),2.04(s,3H),1.79(s,3H)。
13C NMR(150MHz,CDCl3)δ171.24,170.67,159.92,152.93,148.47,139.34,137.06,136.72,132.91,132.58,129.49,128.32,128.15,126.05,125.71,124.64,122.06,122.01,116.42,65.07,63.43,33.61,30.89,28.06,21.04,20.69。
HRMS(ESI):[M+H]+calcd for C26H26NO5 +432.1805,found 432.1786。
实施例11：
(3ak)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ak(收率：76％)。
经测试：1H NMR(600MHz,CDCl3)δ8.77(d,J＝4.4Hz,1H),8.16(d,J＝7.7Hz,1H),7.82(t,J＝7.2Hz,1H),7.80(d,J＝14.9Hz,1H),7.62(d,J＝7.8Hz,1H),7.43(d,J＝7.7Hz,1H),7.36(dd,J＝6.8,5.4Hz,1H),7.31(d,J＝8.2Hz,1H),7.23–7.14(m,3H),7.12–7.06(m,2H),6.78(d,J＝8.3Hz,1H),6.57(d,J＝8.3Hz,1H),6.48(d,J＝2.8Hz,1H),4.19–4.10(m,2H),3.82(dd,J＝10.9,5.6Hz,1H),3.35(t,J＝10.5Hz,1H),3.15-3.09(m,1H),2.78–2.69(m,2H),2.67(dd,J＝14.7,7.3Hz,1H),2.50–2.43(m,1H),2.11–2.03(m,2H),1.75(s,3H)；
13C NMR(150MHz,CDCl3)δ170.67,159.89,152.35,148.53,139.56,136.66,136.39,135.98,132.94,132.69,129.79,128.84,128.63,128.17,128.10,127.74,125.80,124.65,122.07,122.05,121.39,120.97,119.24,116.35,109.42,101.11,63.30,45.93,33.52,31.83,29.03,28.02,20.70；
HRMS(ESI):[M+H]+calcd for C33H31N2O3 +503.2329,found 503.2321。
实施例12：
(3al)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3al(收率：74％)。
经测试：1H NMR(600MHz,CDCl3)δ8.76(d,J＝4.7Hz,1H),8.13(d,J＝7.7Hz,1H),8.07(d,J＝7.7Hz,2H),7.81(td,J＝7.7,1.6Hz,1H),7.56(s,1H),7.42(dd,J＝16.8,8.5Hz,3H),7.37-7.33(m,3H),7.23–7.14(m,4H),6.77(d,J＝8.4Hz,1H),6.57(d,J＝8.4Hz,1H),4.32(t,J＝7.2Hz,2H),3.77(dd,J＝10.9,5.8Hz,1H),3.30(t,J＝10.4Hz,1H),3.13–3.05(m,1H),2.78–2.64(m,3H),2.58–2.46(m,1H),2.12–2.03(m,2H),1.71(s,3H)；
13C NMR(150MHz,CDCl3)δ170.77,159.95,152.34,148.71,140.49,139.78,136.71,136.57,133.00,132.82,130.10,128.85,128.31,128.10,125.98,125.77,124.71,122.97,122.14,120.47,118.92,116.39,108.81,63.46,42.72,33.59,30.51,29.36,28.16,20.78；
HRMS(ESI):[M+H]+calcd for C37H33N2O3 +553.2486,found 553.2512。
实施例13：
(3am)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3am(收率：74％)。
经测试：1H NMR(600MHz,CDCl3)δ8.75(d,J＝4.3Hz,1H),8.18(d,J＝7.4Hz,1H),7.86–7.77(m,3H),7.72-7.67(m,2H),7.43(d,J＝7.7Hz,2H),7.35–7.31(m,1H),7.26-7.19(m,2H),6.91(d,J＝8.2Hz,1H),6.62(d,J＝8.2Hz,1H),3.85(dd,J＝10.8,5.6Hz,1H),3.76(t,J＝6.7Hz,2H),3.43(t,J＝10.5Hz,1H),3.27(s,1H),2.89–2.73(m,3H),2.58–2.50(m,1H),2.01–1.87(m,2H),1.73(s,3H)；
13C NMR(150MHz,CDCl3)δ170.55,168.50,159.69,151.92,148.89,136.57,136.34,133.88,132.87,132.19,130.28,129.12,128.43,127.60,126.08,124.51,123.20,121.92,121.88,116.22,63.37,38.02,33.64,30.19,29.25,28.14,20.62；
HRMS(ESI):[M+Na]+calcd for C33H28N2O5Na+555.1890,found 555.1881。
实施例14：
(3an)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3an(收率：52％)。
经测试：1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.62(d,J＝4.0Hz,1H),8.39(dd,J＝7.5,1.1Hz,1H),7.83(td,J＝7.7,1.7Hz,1H),7.60(d,J＝9.3Hz,1H),7.42(d,J＝7.8Hz,1H),7.38–7.23(m,3H),7.03(d,J＝8.4Hz,1H),6.95–6.85(m,3H),6.22–6.16(m,1H),4.13–3.98(m,2H),3.76(d,J＝5.3Hz,1H),3.38–3.29(m,2H),2.90–2.76(m,2H),2.70–2.53(m,2H),2.35(s,3H),2.06–1.92(m,2H),1.72(s,3H)；
13C NMR(100MHz,DMSO-d6)δ169.81,161.62,160.14,158.91,154.70,153.29,153.20,148.97,140.01,136.56,136.20,133.15,131.84,129.38,129.09,128.31,127.81,126.32,125.41,124.10,121.88,120.75,115.77,113.05,112.21,111.14,101.27,67.28,62.59,32.71,30.40,27.64,27.13,20.28,18.10；
HRMS(ESI):[M+H]+calcd for C35H32NO6 +562.2224,found 562.2224。
实施例15：
(3ao)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ao(收率：70％)。
经测试：1H NMR(600MHz,CDCl3)δ8.74(d,J＝4.3Hz,1H),8.19(d,J＝7.6Hz,1H),7.96(s,1H),7.81(t,J＝7.4Hz,1H),7.42(d,J＝7.7Hz,1H),7.37–7.31(m,1H),7.21–7.12(m,3H),6.88(d,J＝8.3Hz,1H),6.70(d,J＝8.1Hz,1H),6.64(s,1H),6.60(d,J＝8.3Hz,1H),3.94(t,J＝6.0Hz,2H),3.88(dd,J＝10.8,5.6Hz,1H),3.46(t,J＝10.5Hz,1H),3.35(s,1H),2.90–2.76(m,5H),2.68–2.60(m,1H),2.50(dd,J＝19.1,8.7Hz,1H),2.38(d,J＝10.1Hz,1H),2.24(t,J＝9.5Hz,1H),2.19–2.11(m,1H),2.08-1.93(m,5H),1.77(s,3H),1.64–1.41(m,6H),0.91(s,3H)；
13C NMR(150MHz,CDCl3)δ221.15,170.64,160.01,157.02,152.38,148.48,139.47,137.68,136.62,133.09,132.71,131.93,130.16,129.20,128.09,126.29,125.72,124.65,121.99,116.35,114.64,112.30,66.86,63.49,50.45,48.07,44.02,38.40,35.91,33.49,31.62,31.04,29.66,28.12,28.05,26.60,25.94,21.62,20.72,13.89；
HRMS(ESI):[M+H]+calcd for C43H46NO5 +656.3371,found 656.3387。
实施例16：
(3ap)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ap(收率：76％)。
经测试：1H NMR(400MHz,CDCl3)δ8.75(d,J＝3.2Hz,1H),8.22(d,J＝7.1Hz,1H),7.95(s,1H),7.81(t,J＝7.4Hz,1H),7.44(d,J＝7.3Hz,1H),7.38–7.30(m,1H),7.25–7.13(m,2H),6.85(d,J＝8.2Hz,1H),6.62(d,J＝8.2Hz,1H),4.10(t,J＝5.6Hz,2H),3.89(dd,J＝10.6,5.2Hz,1H),3.44(t,J＝10.4Hz,1H),3.30(s,1H),2.96–2.69(m,6H),2.59–2.47(m,1H),2.39–2.17(m,7H),2.18–2.07(m,2H),2.08–1.81(m,8H),1.77(s,3H),1.68–1.54(m,2H),1.38(s,4H),1.34–1.21(m,3H),1.09–0.97(m,3H),0.84(d,J＝6.2Hz,3H)；
13C NMR(100MHz,CDCl3)δ212.18,209.21,208.81,174.27,170.60,159.92,152.49,148.62,139.63,136.62,136.41,133.08,132.60,129.93,129.15,128.29,125.79,124.67,122.04,116.39,63.88,63.38,56.95,51.82,49.01,46.87,45.72,45.68,45.61,45.01,42.82,38.67,36.51,36.05,35.53,35.30,33.58,31.54,30.48,28.23,28.07,27.66,25.18,21.93,20.72,18.68,11.90；
HRMS(ESI):[M+H]+calcd for C49H58NO8 +788.4157,found 788.4157。
实施例17：
(3aq)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3aq(收率：63％)。
经测试：1H NMR(600MHz,CDCl3)δ8.73(dd,J＝4.8,0.7Hz,1H),8.11(dd,J＝6.8,2.3Hz,1H),7.78(td,J＝7.7,1.8Hz,1H),7.44(d,J＝7.8Hz,1H),7.39–7.34(m,2H),7.32–7.28(m,1H),6.69(s,1H),5.74(s,1H),4.00–3.92(m,1H),3.49–3.41(m,2H),3.05–2.99(m,1H),2.80(dd,J＝15.6,4.0Hz,1H),2.26(s,3H),2.21(s,3H),1.79(s,3H)；
13C NMR(150MHz,CDCl3)δ170.72,159.60,150.77,149.16,140.76,137.73,137.08,136.08,133.05,132.61,128.33,126.87,126.40,126.25,124.43,121.80,119.60,117.52,62.86,34.47,28.15,20.76,20.72,14.48；
HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1745。
实施例18：
(3ar)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ar(收率：45％)。
经测试：1H NMR(600MHz,CDCl3)δ8.72(d,J＝4.2Hz,1H),8.09(dd,J＝6.7,2.3Hz,1H),7.77(td,J＝7.7,1.7Hz,1H),7.45–7.38(m,3H),7.31–7.27(m,1H),6.93(s,1H),5.49(s,1H),3.93(dd,J＝10.9,5.9Hz,1H),3.45(t,J＝10.5Hz,1H),3.35–3.29(m,1H),3.00(dd,J＝15.5,1.9Hz,1H),2.80(dd,J＝15.5,4.8Hz,1H),2.29(s,3H),2.28(s,3H)；
13C NMR(150MHz,CDCl3)δ170.78,159.57,149.53,149.40,141.45,136.16,134.77,133.57,133.14,132.26,128.83,127.08,126.74,126.48,124.47,123.78,121.96,121.57,63.04,34.36,28.45,20.84,18.61,16.22；
HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1735。
实施例19：
(3as)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3as(收率：55％)。
经测试：1H NMR(600MHz,CDCl3)δ8.73(d,J＝4.3Hz,1H),8.18(d,J＝7.6Hz,1H),7.78(t,J＝7.5Hz,1H),7.43(d,J＝7.8Hz,1H),7.32–7.26(m,3H),7.14(s,1H),6.47(s,1H),3.96(dd,J＝10.8,5.1Hz,1H),3.42(t,J＝10.7Hz,1H),3.35-3.29(m,1H),2.93(d,J＝15.4Hz,1H),2.79(dd,J＝15.5,4.4Hz,1H),2.72–2.61(m,4H),1.90–1.83(m,1H),1.78(s,3H),1.76–1.59(m,3H)；
13C NMR(150MHz,CDCl3)δ170.78,159.80,151.39,148.82,140.03,138.10,136.86,136.30,133.18,132.44,127.99,127.70,126.07,124.60,121.84,119.94,116.47,62.63,33.21,30.15,27.92,25.65,23.59,22.72,20.70；
HRMS(ESI):[M+H]+calcd for C26H26NO3 +400.1907,found 400.1920。
实施例20：
(3ba)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ba(收率：42％)。
经测试：1H NMR(600MHz,CDCl3)δ8.70(d,J＝4.7Hz,1H),7.76(td,J＝7.7,1.6Hz,1H),7.43(d,J＝7.8Hz,1H),7.40(d,J＝7.9Hz,1H),7.30–7.26(m,2H),7.04(d,J＝8.3Hz,1H),6.81(d,J＝8.3Hz,1H),5.31(s,1H),3.91(dd,J＝10.9,6.3Hz,1H),3.46–3.40(m,1H),3.36–3.29(m,1H),2.96(dd,J＝15.5,2.1Hz,1H),2.76(dd,J＝15.5,4.5Hz,1H),2.39(s,3H),2.33(s,3H),1.80(s,3H)；
13C NMR(150MHz,CDCl3)δ170.65,159.38,150.80,149.25,138.49,138.33,136.12,135.23,134.88,131.80,130.49,129.71,128.53,126.64,124.34,121.98,121.73,114.83,62.88,35.03,30.12,21.05,20.70,18.52；
HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1764。
实施例21：
(3ca)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ca(收率：83％)。
经测试：1H NMR(600MHz,CDCl3)δ8.72(dd,J＝4.8,0.8Hz,1H),7.75(td,J＝7.7,1.8Hz,1H),7.54(d,J＝8.5Hz,1H),7.50(s,1H),7.39(d,J＝7.8Hz,1H),7.29–7.26(m,1H),7.12(dd,J＝8.4,2.4Hz,2H),6.95(d,J＝8.3Hz,1H),4.01(s,3H),3.93(dd,J＝10.9,6.3Hz,1H),3.53–3.47(m,1H),3.42–3.36(m,1H),3.03(dd,J＝15.5,2.3Hz,1H),2.79(dd,J＝15.5,4.6Hz,1H),2.34(s,3H),1.80(s,3H)；
13C NMR(150MHz,CDCl3)δ170.67,158.96,154.02,152.55,149.40,137.60,136.11,135.97,135.38,131.20,130.02,127.08,124.51,122.84,121.70,120.99,118.40,111.41,62.80,57.19,34.48,29.49,20.70,19.02；
HRMS(ESI):[M+H]+calcd for C24H24NO4 +390.1700,found 390.1699。
实施例22：
(3da)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3da(收率：37％)。
经测试：1H NMR(600MHz,CDCl3)δ8.75(d,J＝4.7Hz,1H),7.79(td,J＝7.7,1.4Hz,1H),7.46–7.40(m,2H),7.31(dd,J＝7.2,5.1Hz,1H),7.15–7.10(m,1H),7.08(d,J＝8.3Hz,1H),6.87(d,J＝8.3Hz,1H),6.10(t,J＝13.4Hz,1H),3.92(dd,J＝10.9,5.9Hz,1H),3.45(t,J＝10.4Hz,1H),3.39–3.34(m,1H),3.01(d,J＝15.6Hz,1H),2.75(dd,J＝15.6,4.4Hz,1H),2.32(s,3H),1.77(s,3H)；
13C NMR(150MHz,CDCl3)δ170.51,158.47,158.01,151.83,149.27,137.49,136.99,136.71,136.32,131.50,130.31,127.21,124.45,122.03,120.29,118.14,116.87,114.57,62.48,34.72,29.15,20.62,18.64；
HRMS(ESI):[M+Na]+calcd for C23H20FNO3Na+400.1319,found 400.1327。
实施例23：
(3ea)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ea(收率：51％)。
经测试：1H NMR(600MHz,CDCl3)δ8.75(d,J＝4.6Hz,1H),7.80(td,J＝7.7,1.6Hz,1H),7.46-7.38(m,3H),7.32(dd,J＝7.2,5.1Hz,1H),7.10(d,J＝8.3Hz,1H),6.86(d,J＝8.3Hz,1H),5.80(s,1H),3.93(dd,J＝11.0,6.1Hz,1H),3.44(t,J＝10.3Hz,1H),3.37-3.31(m,1H),2.97(dd,J＝15.6,2.0Hz,1H),2.75(dd,J＝15.6,4.5Hz,1H),2.32(s,3H),1.78(s,3H)；
13C NMR(150MHz,CDCl3)δ170.58,158.28,151.32,149.41,139.29,138.27,137.44,136.41,131.90,131.83,131.58,129.61,128.79,126.82,124.38,122.22,120.56,116.27,62.58,35.01,30.37,20.68,18.58；
HRMS(ESI):[M+Na]+calcd for C23H20ClNO3Na+416.1024,found 416.1031。
实施例24：
(3fa)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3fa(收率：57％)。
经测试：1H NMR(600MHz,CDCl3)δ8.74(d,J＝4.4Hz,1H),7.79(td,J＝7.7,1.5Hz,1H),7.64(d,J＝8.3Hz,1H),7.43(d,J＝7.8Hz,1H),7.34–7.29(m,2H),7.09(d,J＝8.3Hz,1H),6.83(d,J＝8.3Hz,1H),5.76(s,1H),3.95(dd,J＝11.0,6.1Hz,1H),3.50–3.42(m,1H),3.37-3.31(m,1H),2.96(dd,J＝15.6,1.9Hz,1H),2.77(dd,J＝15.6,4.5Hz,1H),2.32(s,3H),1.79(s,3H)；
13C NMR(150MHz,CDCl3)δ170.58,158.31,151.12,149.29,139.51,138.22,137.67,136.50,134.04,132.11,131.43,129.59,126.43,124.40,122.23,122.21,121.85,115.98,62.60,35.02,30.58,20.66,18.49；
HRMS(ESI):[M+Na]+calcd for C23H20BrNO3Na+460.0519,found 460.0502。
实施例25：
(3ga)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ga(收率：57％)。
经测试：1H NMR(400MHz,CDCl3)δ8.75–8.68(m,1H),7.75(td,J＝7.7,1.8Hz,1H),7.70(s,1H),7.47–7.35(m,2H),7.28–7.25(m,1H),7.11(d,J＝8.3Hz,1H),7.04(d,J＝8.5Hz,1H),6.95(d,J＝8.3Hz,1H),4.26(q,J＝7.1Hz,2H),3.97(dd,J＝10.8,6.2Hz,1H),3.51(t,J＝10.3Hz,1H),3.43–3.35(m,1H),3.03(dd,J＝15.5,2.2Hz,1H),2.76(dd,J＝15.5,4.5Hz,1H),2.34(s,3H),1.81(s,3H),1.55(s,3H),1.41(s,3H),1.30(t,J＝7.1Hz,3H)；
13C NMR(100MHz,CDCl3)δ173.13,170.57,158.63,152.38,150.20,149.37,137.37,136.38,136.13,135.97,131.23,129.41,126.87,126.26,124.48,121.80,121.37,118.36,118.06,82.47,62.47,61.99,34.51,29.47,27.01,22.50,20.70,19.00,14.05；
HRMS(ESI):[M+H]+calcd for C29H32NO6 +490.2224,found 490.2235。
实施例26：
(3ha)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ha(收率：64％)。
经测试：1H NMR(600MHz,CDCl3)δ8.74(d,J＝4.2Hz,1H),7.94(s,1H),7.77(td,J＝7.7,1.8Hz,1H),7.42(d,J＝7.8Hz,1H),7.29(dd,J＝7.1,5.3Hz,1H),7.22(s,1H),6.97(d,J＝8.3Hz,1H),6.76(d,J＝8.2Hz,1H),5.88(s,1H),3.94(dd,J＝10.9,5.8Hz,1H),3.47(t,J＝10.5Hz,1H),3.36-3.31(m,1H),2.96(dd,J＝15.4,2.0Hz,1H),2.78(dd,J＝15.4,4.6Hz,1H),2.39(s,3H),2.30(s,3H),1.79(s,3H)。
13C NMR(150MHz,CDCl3)δ170.67,159.56,151.27,149.16,140.76,137.18,136.02,135.92,132.62,130.24,129.93,129.41,127.49,124.41,121.91,121.77,115.72,62.81,34.35,27.72,21.42,20.69,18.72。
HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1755。
实施例27：
(3ia)的制备
反应条件及后处理参见实施例1，得到白色固体，即化合物3ia(收率：72％)。
经测试：1H NMR(600MHz,DMSO-d6)δ9.61(s,1H),8.71(s,1H),8.32(d,J＝7.5Hz,1H),7.92(d,J＝35.8Hz,1H),7.47–7.38(m,1H),7.28(s,1H),7.18(d,J＝7.6Hz,1H),6.93(d,J＝8.3Hz,1H),6.81(d,J＝8.2Hz,1H),3.77(d,J＝73.1Hz,1H),3.41(t,J＝10.6Hz,1H),3.23(d,J＝3.5Hz,1H),2.43(d,J＝40.6Hz,2H),2.21(s,3H),1.99(s,3H),1.88(d,J＝14.0Hz,3H)；
13C NMR(150MHz,DMSO-d6)δ170.52,159.47,153.51,149.96,140.59,136.80,136.45,133.92,132.24,130.72,130.28,128.26,127.63,125.91,124.80,122.49,121.34,115.79,62.19,33.74,28.05,21.03,20.36,18.75；
HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1754。
实施例28：
(3ja)的制备
将2mmol的化合物1j、1mmol的化合物2a、0.05mmol的[Cp*RhCl2]2、0.24mmol的NaBArF加入反应器中，然后加入5ml乙酸和水的混合溶剂(乙酸和水的体积比为3:2)，后续反应条件及后处理参见实施例1，得到白色固体，即化合物3ja(收率：70％)。
经测试：HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1761。
实施例29：
的制备
反应条件及后处理参见实施例28，得到白色固体，即化合物3ka(收率：53％)。
经测试：1H NMR(600MHz,CDCl3)δ8.59(d,J＝5.1Hz,1H),8.14(dd,J＝6.2,2.9Hz,1H),7.26–7.21(m,3H),7.15(d,J＝4.8Hz,1H),7.07(s,1H),6.89(d,J＝8.2Hz,1H),6.65(d,J＝8.2Hz,1H),3.90(dd,J＝10.9,5.9Hz,1H),3.48(t,J＝10.4Hz,1H),3.33–3.27(m,1H),2.88(dd,J＝15.5,2.0Hz,1H),2.79(dd,J＝15.5,4.8Hz,1H),2.44(s,3H),2.27(s,3H),1.80(s,3H)；
13C NMR(150MHz,CDCl3)δ170.68,159.64,151.81,148.45,147.56,140.16,136.90,132.85,132.76,130.01,128.27,127.44,126.93,125.94,125.34,122.90,121.96,115.93,63.03,34.13,28.03,21.19,20.70,18.73；
HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1754。
实施例30：
(3la)的制备
反应条件及后处理参见实施例28，得到白色固体，即化合物3la(收率：68％)。
经测试：1H NMR(600MHz,CDCl3)δ8.79(d,J＝5.1Hz,1H),8.20(d,J＝7.8Hz,1H),7.71(d,J＝7.4Hz,2H),7.66(s,1H),7.56(d,J＝4.2Hz,1H),7.51(t,J＝7.4Hz,2H),7.46(t,J＝7.2Hz,1H),7.32(d,J＝7.4Hz,1H),7.27(d,J＝9.3Hz,1H),7.21(s,1H),6.89(d,J＝8.2Hz,1H),6.66(d,J＝8.2Hz,1H),3.92(dd,J＝10.8,5.5Hz,1H),3.51(t,J＝10.5Hz,1H),3.33–3.27(m,1H),2.94(d,J＝14.8Hz,1H),2.84(dd,J＝15.5,4.5Hz,1H),2.27(s,3H),1.64(s,3H)；
13C NMR(150MHz,CDCl3)δ170.75,160.41,151.91,149.14,148.93,140.06,138.00,136.82,132.91,132.86,130.07,129.29,129.23,128.23,127.79,127.09,126.94,126.01,122.54,121.97,119.87,116.00,62.85,34.20,28.00,20.54,18.71；
HRMS(ESI):[M+H]+calcd for C29H26NO3 +436.1907,found 436.1905。
实施例31：
(3ma)的制备
反应条件及后处理参见实施例28，得到白色固体，即化合物3ma(收率：75％)。
经测试：1H NMR(600MHz,CDCl3)δ8.57(s,1H),8.13(dd,J＝7.1,1.8Hz,1H),7.60(dd,J＝7.9,1.8Hz,1H),7.33(d,J＝7.9Hz,1H),7.31-7.27(m,2H),6.92(d,J＝8.3Hz,1H),6.69(d,J＝8.2Hz,1H),6.58(s,1H),3.92(dd,J＝11.0,5.9Hz,1H),3.48(t,J＝10.4Hz,1H),3.34–3.28(m,1H),2.94(dd,J＝15.5,2.0Hz,1H),2.80(dd,J＝15.5,4.8Hz,1H),2.43(s,3H),2.29(s,3H),1.81(s,3H)；
13C NMR(150MHz,CDCl3)δ170.70,156.81,151.55,149.33,140.40,137.03,136.81,132.93,132.71,131.35,130.16,128.53,127.22,127.07,126.17,123.89,121.92,115.81,62.99,34.20,28.08,20.76,18.73,18.26；
HRMS(ESI):[M+H]+calcd for C24H24NO3 +374.1751,found 374.1754。
实施例32：
(3na)的制备
反应条件及后处理参见实施例28，得到白色固体，即化合物3na(收率：41％)。
经测试：1H NMR(600MHz,CDCl3)δ8.59(s,1H),8.16(d,J＝3.6Hz,1H),7.51(t,J＝8.1Hz,1H),7.47–7.43(m,1H),7.40-7.33(m,2H),6.99(d,J＝8.0Hz,1H),6.75(d,J＝8.1Hz,1H),5.59(s,1H),4.01–3.90(m,1H),3.49(t,J＝10.3Hz,1H),3.40-7.32(m,1H),2.97(d,J＝15.4Hz,1H),2.83(d,J＝15.5Hz,1H),2.32(s,3H),1.83(s,3H)；
13C NMR(150MHz,CDCl3)δ170.68,159.31,157.61,155.76,151.32,139.71,137.20,137.05,132.95,130.42,128.62,127.57,127.41,126.40,125.20,122.92,121.72,115.74,62.83,34.23,28.05,20.75,18.72；
HRMS(ESI):[M+H]+calcd for C23H21FNO3 +378.1500,found 378.1502。
实施例33：
(3oa)的制备
反应条件及后处理参见实施例28，得到白色固体，即化合物3oa(收率：38％)。
经测试：1H NMR(600MHz,CDCl3)δ8.69(d,J＝2.4Hz,1H),8.18(dd,J＝7.0,2.0Hz,1H),7.76(dd,J＝8.3,2.5Hz,1H),7.41(d,J＝8.3Hz,1H),7.39–7.36(m,2H),7.00(d,J＝8.2Hz,1H),6.76(d,J＝8.2Hz,1H),5.50(s,1H),3.96(dd,J＝11.0,5.7Hz,1H),3.49(t,J＝10.5Hz,1H),3.38-3.33(m,1H),2.99(dd,J＝15.6,2.0Hz,1H),2.84(dd,J＝15.6,4.8Hz,1H),2.32(s,3H),1.83(s,3H)；
13C NMR(150MHz,CDCl3)δ170.67,157.63,151.21,148.07,139.64,137.10,135.87,132.97,132.88,130.48,128.61,127.68,127.50,126.52,125.07,121.64,115.72,62.82,34.23,28.08,20.78,18.73；
HRMS(ESI):[M+H]+calcd for C23H21ClNO3 +394.1204,found 394.1208。
实施例34：
(3pa)的制备
反应条件及后处理参见实施例28，得到白色固体，即化合物3pa(收率：37％)。
经测试：1H NMR(600MHz,CDCl3)δ8.79(d,J＝2.2Hz,1H),8.18(dd,J＝6.0,3.0Hz,1H),7.91(dd,J＝8.3,2.2Hz,1H),7.37–7.33(m,3H),6.97(d,J＝8.2Hz,1H),6.72(d,J＝8.2Hz,1H),5.82(s,1H),3.95(dd,J＝11.0,5.7Hz,1H),3.49(t,J＝10.5Hz,1H),3.37–3.32(m,1H),2.97(dd,J＝15.5,1.6Hz,1H),2.83(dd,J＝15.6,4.8Hz,1H),2.31(s,3H),1.83(s,3H)；
13C NMR(150MHz,CDCl3)δ170.72,158.08,151.37,150.20,139.45,138.82,137.04,132.97,132.88,130.44,128.49,127.73,127.54,126.46,125.66,121.66,119.20,115.77,62.87,34.23,28.09,20.81,18.74；
HRMS(ESI):[M+H]+calcd for C23H21BrNO3 +438.0699,found 438.0692。
实施例35：
(3qa)的制备
将2mmol的化合物1q、1mmol的化合物2a、0.05mmol的[RhCp*(MeCN)3](SbF6)2、0.24mmol的AgSbF6加入反应器中，然后加入5ml乙酸，后续反应条件及后处理参见实施例1，得到白色固体，即化合物3qa(收率：31％)。
经测试：HRMS(ESI):[M+H]+calcd for C27H24NO3 +410.1751,found 410.1753。
实施例36：
(3ra)的制备
反应条件及后处理参见实施例35，得到白色固体，即化合物3ra(收率：75％)。
经测试：1H NMR(600MHz,CDCl3)δ9.39(s,1H),8.17(d,J＝7.7Hz,1H),8.07(d,J＝8.2Hz,1H),7.88(d,J＝8.2Hz,1H),7.78(s,1H),7.76(t,J＝7.5Hz,1H),7.66(t,J＝7.5Hz,1H),7.44(d,J＝7.5Hz,1H),7.35(t,J＝7.7Hz,1H),6.95(d,J＝8.3Hz,1H),6.74(d,J＝8.3Hz,1H),6.28(s,1H),3.93(dd,J＝10.9,5.8Hz,1H),3.53(t,J＝10.4Hz,1H),3.35-3.29(m,1H),3.00(dd,J＝15.6,1.8Hz,1H),2.90(dd,J＝15.6,4.8Hz,1H),2.29(s,3H),1.70(s,3H)；
13C NMR(150MHz,CDCl3)δ170.72,153.22,151.70,151.50,140.74,137.10,136.22,133.34,132.78,130.77,130.22,129.02,127.67,127.34,127.31,127.01,126.67,126.27,121.96,120.47,115.80,63.01,34.29,28.27,20.71,18.74；
HRMS(ESI):[M+H]+calcd for C27H24NO3 +410.1751,found 410.1764。
实施例37：
(3sa)的制备
反应条件及后处理参见实施例35，得到白色固体，即化合物3sa(收率：75％)。
经测试：1H NMR(600MHz,CDCl3)δ8.29–8.21(m,3H),7.92(d,J＝8.1Hz,1H),7.79(t,J＝7.5Hz,1H),7.64–7.57(m,2H),7.36(d,J＝7.4Hz,1H),7.29(t,J＝7.7Hz,1H),7.03(s,1H),6.88(d,J＝8.3Hz,1H),6.65(d,J＝8.3Hz,1H),3.95(dd,J＝10.9,5.7Hz,1H),3.51(t,J＝10.5Hz,1H),3.30(dd,J＝10.6,7.1Hz,1H),2.97–2.90(m,2H),2.27(s,3H),1.73(s,3H)；
13C NMR(150MHz,CDCl3)δ170.71,160.17,151.88,147.51,140.39,136.90,136.34,133.07,133.06,130.11,129.98,129.21,128.34,127.86,127.62,127.00,126.86,126.65,126.11,122.65,121.86,115.92,63.02,34.18,28.22,20.74,18.71；
HRMS(ESI):[M+H]+calcd for C27H24NO3 +410.1751,found 410.1751。
实施例38：
(3ta)的制备
将2mmol的化合物1t、1mmol的化合物2a、0.05mmol的[RhCp*(MeCN)3](PF6)2、0.24mmol的AgOAc加入反应器中，然后加入5ml乙酸，后续反应条件及后处理参见实施例1，得到白色固体，即化合物3ta(收率：26％)。
经测试：1H NMR(600MHz,CDCl3)δ8.89(d,J＝4.9Hz,2H),8.21(d,J＝7.8Hz,1H),7.75(d,J＝7.6Hz,1H),7.41(t,J＝7.8Hz,1H),7.28(t,J＝4.9Hz,1H),7.00(d,J＝8.2Hz,1H),6.75(d,J＝8.2Hz,1H),5.55(s,1H),3.96(dd,J＝11.0,6.1Hz,1H),3.57–3.49(m,1H),3.42–3.32(m,2H),2.96(dd,J＝15.8,4.7Hz,1H),2.33(s,3H),1.80(s,3H)；
13C NMR(150MHz,CDCl3)δ170.69,167.44,156.89,151.20,138.88,137.46,134.40,133.00,130.38,129.55,128.26,127.63,126.39,121.67,118.65,115.67,63.30,34.25,28.33,20.72,18.73；
HRMS(ESI):[M+H]+calcd for C22H21N2O3 +361.1547,found 361.1552。
实施例39：
(3ua)的制备
反应条件及后处理参见实施例38，得到白色固体，即化合物3ua(收率：28％)。
经测试：1H NMR(600MHz,CDCl3)δ9.34(s,1H),8.82(d,J＝3.3Hz,1H),8.34–8.25(m,1H),7.50(s,1H),7.44(s,2H),7.02(d,J＝8.0Hz,1H),6.77(d,J＝8.1Hz,1H),5.58(s,1H),4.01–3.93(m,1H),3.49(t,J＝10.4Hz,1H),3.44–3.36(m,1H),3.10(d,J＝15.6Hz,1H),2.91(d,J＝15.3Hz,1H),2.34(s,3H),1.82(s,3H)；
13C NMR(150MHz,CDCl3)δ170.64,166.82,158.61,156.72,151.28,138.07,137.09,133.23,133.10,130.63,128.88,128.54,127.75,126.70,121.62,121.41,115.76,62.69,34.17,28.01,20.73,18.73；
HRMS(ESI):[M+H]+calcd for C22H21N2O3 +361.1547,found 361.1540。
实施例40：
(3va)的制备
将2mmol的化合物1v、1mmol的化合物2a、0.05mmol的[RhCp*(MeCN)3](BF4)2、0.24mmol的Cu(OAc)2加入反应器中，然后加入5ml乙酸，后续反应条件及后处理参见实施例1，得到白色固体，即化合物3ta(收率：24％)。
经测试：1H NMR(600MHz,CDCl3)δ8.22(d,J＝7.8Hz,1H),7.78(s,1H),7.62(d,J＝1.8Hz,1H),7.23(t,J＝7.8Hz,1H),7.19(d,J＝7.6Hz,1H),6.93(d,J＝8.2Hz,1H),6.68(d,J＝8.2Hz,1H),6.65(s,1H),6.48(s,1H),3.90(dd,J＝11.0,5.5Hz,1H),3.49(t,J＝10.7Hz,1H),3.37–3.29(m,1H),2.66(dd,J＝15.8,4.7Hz,1H),2.63–2.56(m,1H),2.29(s,3H),1.88(s,3H)；
13C NMR(150MHz,CDCl3)δ170.76,151.79,140.08,139.33,136.66,133.88,131.16,131.05,130.54,128.20,127.30,126.39,124.60,121.23,116.04,106.17,62.61,33.78,25.55,20.76,18.74；
HRMS(ESI):[M+H]+calcd for C21H21N2O3 +349.1547,found 349.1564。
实施例41：
(3wa)的制备
将2mmol的化合物1w、1mmol的化合物2a、0.05mmol的[Cp*RhCl2]2、0.24mmol的ZnCl2加入反应器中，然后加入5ml乙酸，后续反应条件及后处理参见实施例1，得到白色固体，即化合物3wa(收率：51％)。
经测试：1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),9.03(s,1H),8.66(s,1H),8.48(d,J＝8.0Hz,1H),7.55(d,J＝7.4Hz,1H),7.41(t,J＝7.8Hz,1H),6.98(d,J＝8.2Hz,1H),6.84(d,J＝8.3Hz,1H),4.25–4.13(m,2H),3.73(dd,J＝10.5,6.0Hz,1H),3.39(t,J＝10.0Hz,1H),3.31–3.27(m,1H),2.82(dt,J＝16.1,9.4Hz,2H),2.23(s,3H),1.59(s,3H),1.45–1.34(m,1H),0.61–0.49(m,4H)；
13C NMR(100MHz,DMSO-d6)δ169.93,157.05,153.17,151.68,151.60,146.46,137.04,135.08,133.32,132.04,130.41,129.52,129.01,125.66,125.47,120.60,115.43,62.79,47.81,33.13,28.45,20.29,18.54,11.42,4.05,4.01；
HRMS(ESI):[M+H]+calcd for C27H27N4O3 +455.2078,found 455.2081。
实施例42：
(3xa)的制备
反应条件及后处理参见实施例41，得到白色固体，即化合物3xa(收率：44％)。
经测试：1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.03(s,1H),8.59(s,1H),8.48(d,J＝7.8Hz,1H),7.57(d,J＝7.2Hz,1H),7.42(t,J＝7.8Hz,1H),6.98(d,J＝8.3Hz,1H),6.85(d,J＝8.3Hz,1H),6.21-6.09(m,1H),5.26(d,J＝10.2Hz,1H),5.14(d,J＝17.1Hz,1H),4.98(d,J＝5.5Hz,2H),3.74(dd,J＝10.6,6.1Hz,1H),3.41(d,J＝9.7Hz,1H),3.32–3.24(m,1H),2.92–2.76(m,2H),2.23(s,3H),1.61(s,3H)；
13C NMR(100MHz,DMSO-d6)δ169.82,157.06,153.10,151.45,136.97,134.96,133.31,133.26,132.98,131.91,130.32,128.96,125.57,125.37,120.54,118.11,115.39,62.77,45.37,33.13,28.40,20.24,18.43；
HRMS(ESI):[M+H]+calcd for C26H25N4O3 +441.1921,found 441.1930。
实施例43：
(3mg)的制备
反应条件及后处理参见实施例28，得到白色固体，即化合物3mg(收率：72.9％)。
经测试：1H NMR(600MHz,DMSO-d6)δ10.06(s,1H),8.50(s,1H),8.43(d,J＝7.6Hz,1H),7.69(d,J＝7.5Hz,1H),7.59(d,J＝6.7Hz,2H),7.36(d,J＝5.8Hz,2H),7.32(d,J＝7.3Hz,1H),7.27(d,J＝6.6Hz,2H),7.02–6.95(m,2H),3.49(d,J＝6.7Hz,1H),3.38(t,J＝10.3Hz,1H),3.18-3.12(m,1H),2.84(q,J＝15.5Hz,2H),2.35(s,3H),1.59(s,3H)；
13C NMR(150MHz,DMSO-d6)δ170.03,156.52,155.00,149.68,140.94,140.44,137.14,136.57,133.27,132.47,132.13,131.62,131.54,131.49,130.30,128.73,128.67,125.96,124.07,121.15,120.61,115.98,63.36,33.85,28.30,20.69,18.14；
HRMS(ESI):[M+H]+calcd for C29H25BrNO3 +514.1012,found 514.1022。
实施例44：
(3mh)的制备
反应条件及后处理参见实施例28，得到白色固体，即化合物3mh(收率：26.5％)。
经测试：1H NMR(600MHz,DMSO-d6)δ10.16(s,1H),8.50(s,1H),8.43(d,J＝7.8Hz,1H),7.88(d,J＝7.4Hz,2H),7.69(d,J＝7.8Hz,1H),7.53(d,J＝7.3Hz,2H),7.37(t,J＝7.1Hz,2H),7.33(d,J＝7.5Hz,1H),7.04-6.98(m,2H),3.50–3.45(m,1H),3.38(t,J＝10.3Hz,1H),3.18-3.12(m,1H),2.86(q,J＝15.5Hz,2H),2.35(s,3H),1.58(s,3H)；
13C NMR(150MHz,DMSO-d6)δ170.03,156.46,155.40,149.71,146.85,140.42,137.16,136.55,133.11,132.56,132.49,131.57,131.38,131.10,130.17,128.76,126.01,124.07,121.20,119.40,116.11,110.05,63.51,33.80,28.34,20.70,18.14；
HRMS(ESI):[M+H]+calcd for C30H25N2O3 +461.1860,found 461.1869。
实施例45：
(3mg-OH)的制备
将实施例43制备的化合物3mg溶于适量的甲醇，然后加入5ml、1M/L的氢氧化钠，室温搅拌反应2小时，结束反应，反应液加入1M/L盐酸调节pH值为2左右，然后用乙酸乙酯萃取，合并有机相，合并的有机相无水硫酸钠干燥，抽滤，减压浓缩除去溶剂，得到白色固体，即化合物3mg-OH(收率：95％)。
经测试：1H NMR(600MHz,CDCl3)δ8.37(s,1H),8.28(d,J＝7.9Hz,1H),7.66(dd,J＝7.9,1.5Hz,1H),7.50(d,J＝8.2Hz,2H),7.44(d,J＝7.9Hz,1H),7.39(t,J＝7.8Hz,1H),7.25(s,1H),7.17(d,J＝8.2Hz,2H),6.97(d,J＝8.2Hz,1H),6.82(d,J＝8.2Hz,1H),6.26(s,1H),3.52(dd,J＝14.6,2.6Hz,1H),3.41(dd,J＝11.6,5.1Hz,1H),3.27(t,J＝11.4Hz,1H),3.12-3.07(m,1H),2.50(dd,J＝14.6,3.4Hz,1H),2.37(s,3H)；
13C NMR(150MHz,CDCl3)δ156.68,152.91,148.35,140.22,139.70,138.89,138.34,133.82,133.18,133.15,131.82,131.26,131.14,130.06,129.11,127.19,126.43,123.76,121.78,121.20,115.17,60.75,38.11,26.96,18.19；
HRMS(ESI):[M+H]+calcd for C27H23BrNO2 +472.0907,found 474.0914。
实施例46：含9,10-二氢菲骨架的化合物抑制人肿瘤细胞增殖试验
1)试验材料
人肝癌细胞HepG2、人乳腺癌细胞MDA-MB-468和MDA-MB-231均购自中科院细胞库，培养基DMEM，培养基F12，胎牛血清FBS，青霉素和链霉素购自美国Invitrogen公司，0.25％胰蛋白酶购自Hyclone公司，CCK-8购自Apexbio公司。
2)试验方法
人肝癌细胞HepG2，培养基DMEM含10％FBS，100U/mL青霉素和100U/mL链霉素，培养于37℃，含5％CO2以及饱和湿度的培养箱中培养，传代消化使用0.25％胰蛋白酶消化，取对数生长期细胞用于CCK-8实验；人乳腺癌细胞MDA-MB-468和MDA-MB-231，培养DMEM+F12(1:1)含10％FBS，100U/mL青霉素和100U/mL链霉素，培养于37℃，含5％CO2以及饱和湿度的培养箱中培养，传代消化使用0.25％胰蛋白酶消化，取对数生长期细胞用于CCK-8实验；将HepG2细胞、MDA-MB-468细胞和MDA-MB-231细胞分别以1*104个/孔的密度接种于96孔板中，待细胞贴壁后加药；药物加入96孔板的终浓度分别为100μM，50μM，25μM，12.5μM，6.25μM，3.12μM，1.56μM，0.78μM和0.39μM；培养72小时后，吸除含药物的培养基，并加入含10％CCK-8的DMEM完全培养基，避光孵育1-4小时，使用酶标仪在450nm下检测吸光度，计算出不同浓度的生长抑制率，生长抑制率(％)＝(Control组的平均值-给药组的平均值)/Control组平均值*100％。细胞生长抑制率为50％的化合物浓度即为IC50值；实验数据用平均值±SD值表示，并使用Graphpad7.0进行数据分析。
3)试验结果
含9,10-二氢菲骨架的化合物对人肿瘤细胞的抑制活性结果分别如表1和表2所示。
表1含9,10-二氢菲骨架的化合物对人肝癌细胞HepG2的抑制活性(xˉ±s)
表2含9,10-二氢菲骨架的化合物对人乳腺癌细胞MDA-MB-468和MDA-MB-231的抑制活性(xˉ±s)
| 化合物 | MDA-MB-231/IC<sub>50</sub>(μM) | MDA-MB-468/IC<sub>50</sub>(μM) |
| 3mg | 2.82±0.44 | 1.87±0.17 |
| 3mh | 6.47±2.88 | 3.53±0.44 |
| 3mg-OH | 0.84±0.02 | 1.32±0.16 |
由表1和表2可见：本发明所述的含9,10-二氢菲骨架的化合物能明显抑制人肝癌细胞HepG2、人乳腺癌细胞MDA-MB-468和MDA-MB-231增殖，可见，本发明所述的含9,10-二氢菲骨架的化合物能抑制肿瘤细胞的增殖能力，具有潜在的抗肿瘤作用，可望作为活性成分用于制备抗肿瘤的药物，尤其可望作为活性成分用于制备抗肝癌或乳腺癌的药物，具有药用前景。
最后需要在此指出的是：以上仅是本发明的部分优选实施例，不能理解为对本发明保护范围的限制，本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
Claims (10)
1.一类含9,10-二氢菲骨架的化合物，其特征在于，所述化合物具有式3A或式3B所示结构：
其中：
R1、R2、R3、R分别独立选自氢、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的烷氧基、取代或未取代的芳基、取代或未取代的杂环基、取代或未取代的氰基、卤素中的任意一种；或者，相邻的R1、R2、R3之间独立的通过共价键形成饱和或不饱和的碳环或杂环；
DG为具有式A所述结构的取代或未取代的含氮杂环基：
2.根据权利要求1所述的含9,10-二氢菲骨架的化合物，其特征在于：R1、R2、R3、R分别独立选自氢、C1～C6烷基、Ra取代的C1～C6烷基、C2～C6烯基、C1～C6烷氧基、OCORb取代的C1～C6烷氧基、C3～C20芳基、卤素取代的C3～C20芳基、氰基取代的C3～C20芳基、烷基取代的C3～C20芳基、C3～C20杂环基、卤素取代的C3～C20杂环基、氰基取代的C3～C20杂环基、烷基取代的C3～C20杂环基、C1～C4氰基、卤素中的任意一种；Ra选自卤素、C3～C20芳基、C3～C20杂环基、ORc、OCORc中的任意一种；Rb为C1～C6烷基，Rc选自C1～C6烷基、C3～C20碳环基、C3～C20杂环基中的任意一种；或者，相邻的R1、R2、R3之间独立的通过共价键形成饱和的碳环；
DG选自如下所述结构的取代或未取代的含氮杂环基：
3.根据权利要求2所述的含9,10-二氢菲骨架的化合物，其特征在于：R1、R2、R3、R分别独立选自氢、C1～C6烷基、
C2～C6烯基、C1～C6烷氧基、
苯基、苄基、卤素或氰基取代的苯基、C1～C4氰基、卤素中的任意一种，或者，相邻的R1、R2、R3之间独立的通过共价键形成六元碳环；
DG选自如下所述结构的取代或未取代的含氮杂环基：
4.根据权利要求3所述的含9,10-二氢菲骨架的化合物，其特征在于，所述化合物具有如下任意一种结构式：
5.一种权利要求1所述的含9,10-二氢菲骨架的化合物的制备方法，其特征在于，使式1化合物在铑催化剂、金属盐添加剂的存在下，与式2化合物和乙酸发生反应，制得式3A化合物；再使式3A化合物水解，制得式3B化合物；具体反应式如下所示：
6.根据权利要求5所述的制备方法，其特征在于：所述铑催化剂为三价铑催化剂。
7.根据权利要求6所述的制备方法，其特征在于：所述三价铑催化剂包括但不限于[Cp*RhCl2]2、[RhCp*(MeCN)3](SbF6)2、[RhCp*(MeCN)3](PF6)2、[RhCp*(MeCN)3](BF4)2。
8.根据权利要求5所述的制备方法，其特征在于：所述金属盐添加剂包括但不限于NaBArF、AgSbF6、AgOAc、Cu(OAc)2、ZnCl2。
9.一种权利要求1所述的含9,10-二氢菲骨架的化合物的用途，其特征在于：以具有式3A或3B结构的化合物中的至少一种作为活性成分用于制备抗肿瘤的药物。
10.根据权利要求9所述的用途，其特征在于：用于制备抗肝癌或乳腺癌的药物。
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