4-氨基二氢喹啉酮类化合物的合成方法及抗癌活性

文档序号：354363 发布日期：2021-12-07 浏览：35次 >En<

阅读说明：本技术 4-氨基二氢喹啉酮类化合物的合成方法及抗癌活性 (Synthesis method and anticancer activity of 4-aminodihydroquinolinone compounds ) 是由张新迎沈檬洋徐园双赵杰范学森于 2021-09-10 设计创作，主要内容包括：本发明公开了一种4-氨基二氢喹啉酮类化合物的合成方法及抗癌活性,属于有机合成和药物发现技术领域。以2-(三甲基甲硅烷基)芳基三氟甲磺酸酯1和1-取代吡唑烷酮类化合物2为原料,在催化剂和氟化铯存在下,有机溶剂中反应,得到4-氨基二氢喹啉酮类化合物3,该类化合物对REC-1和Ramos等癌细胞显示出显著的抗增殖活性。本发明合成方法具有底物范围广、反应条件温和、官能团耐受性好等优点,所得到产物具有潜在的药用价值。(The invention discloses a synthesis method and anticancer activity of a 4-aminodihydroquinolinone compound, belonging to the technical field of organic synthesis and drug discovery. 2- (trimethylsilyl) aryl triflate 1 and 1-substituted pyrazolidinone compounds 2 are used as raw materials and react in an organic solvent in the presence of a catalyst and cesium fluoride to obtain 4-amino dihydroquinolinone compounds 3, and the compounds show obvious antiproliferative activity on cancer cells such as REC-1 and Ramos. The synthetic method has the advantages of wide substrate range, mild reaction conditions, good functional group tolerance and the like, and the obtained product has potential medicinal value.)

技术领域

本发明属于有机合成和药物发现技术领域，具体涉及一种4-氨基二氢喹啉酮类化合物的合成方法及抗癌活性。

背景技术

4-氨基二氢喹啉酮是一类重要的含氮杂环化合物，具有显著的抗精神抑郁、阻断β-肾上腺素受体、抑制CYP11B2、抗炎以及抑制磷酸二酯酶等活性，在新药开发方面有着十分广泛的应用。此外，该类化合物还具有多样的反应性能，常用于制备生物碱、染料、农药和荧光增强剂等精细化学品。

尽管4-氨基二氢喹啉酮具有重要的应用价值，但目前该类化合物的合成方法却很有限，而且这些文献方法尚存在原料不易得到、合成路线长、反应条件苛刻、官能团耐受性差等问题。

因此，研究并开发从价廉易得的原料出发、在相对温和反应条件下合成4-氨基二氢喹啉酮类化合物的新方法，然后利用该方法合成多种不同取代4-氨基二氢喹啉酮类化合物，对其体外抗癌活性进行考察，以筛选出具有良好生物活性的药物前体，具有重要研究意义。

发明内容

本发明首先提供了一类4-氨基二氢喹啉酮类化合物，并研究了其抗癌活性。其次，还提供了4-氨基二氢喹啉酮类化合物的合成方法，通过2-(三甲基甲硅烷基)芳基三氟甲磺酸酯与1-取代吡唑烷酮之间发生的一锅串联反应，合成了4-氨基二氢喹啉酮类化合物。该合成方法具有底物范围广、反应条件温和、官能团耐受性好等优点。其中一些产品在人类癌细胞系中显示出显著的抗增殖活性，因此具有潜在的药用价值。

本发明所提供的具有抗癌活性4-氨基二氢喹啉酮类化合物，其结构通式为：

其中，R¹为C_1-4烷基、C_1-4烷氧基、甲叉二氧基或卤素，R¹为单取代或双取代，R²为萘基、苯基或取代苯基，取代苯基苯环上的取代基为C_1-4烷基、C_1-4烷氧基、苄氧基或卤素中的一个或多个。

本发明还提供了上述结构3化合物及其药学上可接受的盐在制备抗癌活性药物中的应用。

本发明中药学上可接受的盐包括4-氨基二氢喹啉酮类化合物与有机酸或无机酸形成的盐。有机酸选自苹果酸、乳酸、樟脑磺酸、枸橼酸、富马酸或草酸中的一种或多种，无机酸选自磷酸、氢卤酸、硫酸或硝酸中一种或多种。

进一步地，在上述技术方案中，所述抗癌活性是指抗REC-1和Ramos等癌细胞活性。

本发明还提供了上述4-氨基二氢喹啉酮类化合物的合成方法，采用的技术方案为：

4-氨基二氢喹啉酮类化合物的合成方法，包括如下操作：以2-(三甲基甲硅烷基)芳基三氟甲磺酸酯1和1-取代吡唑烷酮类化合物2为原料，在催化剂和氟化铯存在下，有机溶剂中反应，得到4-氨基二氢喹啉酮类化合物3，反应方程式为：

其中，R¹为氢、C_1-4烷基、C_1-4烷氧基、甲叉二氧基或卤素，R¹为单取代或双取代，R²为萘基、苯基或取代苯基，取代苯基苯环上的取代基为C_1-4烷基、C_1-4烷氧基、苄氧基或卤素中的一个或多个。

进一步地，在上述技术方案中，所述反应有机溶剂为起到溶解原料的作用，优选甲醇、四氢呋喃或乙腈。

进一步地，在上述技术方案中，所述催化剂为钯催化剂、银催化剂、铜催化剂中的至少一种。

进一步地，在上述技术方案中，所述钯催化剂为醋酸钯、二氯化钯或双三苯基膦二氯化钯；银催化剂为碳酸银、氧化银或醋酸银；铜催化剂为氧化铜或醋酸铜。

进一步地，在上述技术方案中，所述反应还包括添加剂，添加剂为羧酸类添加剂，优选自醋酸、2,4,6-三甲基苯甲酸、1-金刚烷甲酸或特戊酸。

进一步地，在上述技术方案中，所述2-(三甲基甲硅烷基)芳基三氟甲磺酸酯类化合物1、1-取代吡唑烷酮2与添加剂摩尔比为1-1.5:1-1.5:0-2。

进一步地，在上述技术方案中，所述2-(三甲基甲硅烷基)芳基三氟甲磺酸酯类化合物1与催化剂摩尔比为1:0.05-1.1。

进一步地，在上述技术方案中，所述反应温度为80-120℃。

发明有益效果：

本发明与现有技术相比具有以下优点：(1)合成过程简单，反应条件温和，通过2-(三甲基甲硅烷基)芳基三氟甲磺酸酯类化合物与1-取代吡唑烷酮的一锅串联反应，即可合成4-氨基二氢喹啉酮类化合物；(2)原料廉价易得、底物范围广和官能团耐受性好；(3)4-氨基二氢喹啉酮类化合物具有显著的抗癌活性，因此具有潜在药用价值。

说明书附图

图1为实施例1-3中化合物3a的X-射线单晶衍射图。

具体实施方式

以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。

实施例1

向15mL反应管中，依次加入化合物2a、催化剂1、催化剂2、添加剂、分子筛和有机溶剂，在室温下搅拌5分钟，然后依次加入化合物1a和氟化铯，在空气条件下将反应管密封，并置于加热模块中升温搅拌反应。待反应结束后，冷却至室温，加入饱和碳酸氢钠溶液淬灭反应，用硅藻土过滤，滤液用乙酸乙酯萃取，有机相干燥后，抽滤、旋干，过硅胶柱分离(石油醚/乙酸乙酯＝3/1)得到白色固体产物3a。

通过改变反应的溶剂、催化剂1、催化剂2、添加剂、反应温度和物料比等反应条件，得到一系列的结果，见表1。

表1不同条件下3a的合成^a

实施例2

向15mL耐压管中，依次加入2a(38mg,0.2mmol)、醋酸钯(2.2mg,0.01mmol)、碳酸银(27.6mg,0.1mmol)、分子筛(40mg)、1-金刚烷甲酸(36.0mg,0.2mmol)和乙腈(2mL)，在室温下搅拌5分钟，随后依次加入1a(59.7mg,0.2mmol)和氟化铯(60.8mg,0.4mmol)，然后将反应管密封，置于100℃油浴中反应10h。反应结束后，将反应体系冷却至室温，加入饱和碳酸氢钠溶液淬灭反应，用硅藻土过滤，滤液用乙酸乙酯萃取，有机相干燥后，抽滤、旋干，过硅胶柱分离(石油醚/乙酸乙酯＝3/1)得到白色固体产物3a(29.3mg,55％)。该化合物的表征数据为：¹H NMR(400MHz,CDCl₃):δ9.47(s,1H),7.24(d,J＝7.6Hz,1H),7.20-7.16(m,3H),6.97-6.93(m,1H),6.90(d,J＝8.0Hz,1H),6.74-6.68(m,3H),4.50(d,J＝9.2Hz,1H),3.87(d,J＝9.6Hz,1H),1.32(s,3H),1.21(s,3H).¹³C{¹H}NMR(100MHz,CDCl₃):δ176.6,147.9,135.7,129.5,128.6,127.2,125.9,123.4,118.0,115.6,113.4,59.3,43.3,23.0,19.1.HRMS(ESI)m/z:[M+H]⁺Calcd for C₁₇H₁₉N₂O 267.1492；Found 267.1487.

实施例3

依照实施例2的方法和步骤^a,b，通过改变反应物1和反应物2，可以合成出各种4-氨基二氢喹啉酮类化合物3，具体结果如下：

代表性产物表征数据如下：

3,3-Dimethyl-4-(p-tolylamino)-3,4-dihydroquinolin-2(1H)-one(3b)

¹H NMR(400MHz,CDCl₃):δ8.97(s,1H),7.26-7.24(m,1H),7.21(t,J＝7.6Hz,1H),7.00-6.94(m,3H),6.86(d,J＝7.6Hz,1H),6.61(d,J＝8.4Hz,2H),4.46(s,1H),3.70(br s,1H),2.24(s,3H),1.32(s,3H),1.21(s,3H).¹³C NMR(100MHz,CDCl₃):δ176.4,145.6,135.5,130.0,128.5,127.3,127.2,126.2,123.4,115.3,113.5,59.6,43.3,22.9,20.4,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₂₀N₂NaO 303.1468；Found 303.1459.

4-((4-Ethylphenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3c)

¹H NMR(600MHz,CDCl₃):δ8.86(s,1H),7.26(d,J＝7.8Hz,1H),7.21(td,J₁＝7.8Hz,J₂＝1.2Hz,1H),7.02(d,J＝8.4Hz,2H),6.97(td,J₁＝7.8Hz,J₂＝1.2Hz,1H),6.85(d,J＝7.8Hz,1H),6.63(d,J＝8.4Hz,2H),4.47(s,1H),3.71(br s,1H),2.55(q,J＝7.8Hz,2H),1.32(s,3H),1.21(s,3H),1.20(t,J＝7.8Hz,3H).¹³C NMR(150MHz,CDCl₃):δ176.3,145.7,135.5,133.9,128.8,128.5,127.2,126.2,123.4,115.3,113.4,59.6,43.3,27.9,22.9,19.1,15.9.HRMS(ESI)m/z:[M+H]⁺Calcd for C₁₉H₂₂N₂NaO 317.1624；Found317.1611.

4-((4-Isopropylphenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3d)

¹H NMR(400MHz,CDCl₃):δ8.53(s,1H),7.28(d,J＝7.6Hz,1H),7.22(t,J＝6.8Hz,1H),7.06(d,J＝8.4Hz,2H),6.98(t,J＝7.2Hz,1H),6.83(d,J＝8.0Hz,1H),6.64(d,J＝8.4Hz,2H),4.48(s,1H),3.71(br s,1H),2.85-2.78(m,1H),1.33(s,3H),1.23-1.21(m,9H).¹³C NMR(150MHz,CDCl₃):δ176.1,145.7,138.5,135.5,128.5,127.34,127.26,126.2,123.4,115.2,113.3,59.5,43.3,33.1,24.2,22.8,19.0.HRMS(ESI)m/z:[M+Na]⁺Calcd forC₂₀H₂₄N₂NaO 331.1781；Found 331.1773.

4-((4-Methoxyphenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3e)

¹H NMR(400MHz,CDCl₃):δ8.92(s,1H),7.23-7.19(m,2H),6.98-6.94(m,1H),6.86(d,J＝7.2Hz,1H),6.79-6.76(m,2H),6.65-6.62(m,2H),4.35(s,1H),3.74(s,3H),3.54(brs,1H),1.31(s,3H),1.24(s,3H).¹³C NMR(100MHz,CDCl₃):δ176.3,152.5,141.9,135.5,128.5,127.2,126.2,123.3,115.3,115.1,115.0,60.9,55.8,43.3,23.0,19.2.HRMS(ESI)m/z:[M+H]⁺Calcd for C₁₈H₂₁N₂O₂ 297.1598；Found 297.1593.

4-((4-(Benzyloxy)phenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3f)

¹H NMR(600MHz,CDCl₃):δ8.41(s,1H),7.42(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,1H),7.23-7.20(m,2H),6.97(t,J＝7.2Hz,1H),6.86-6.84(m,2H),6.82(d,J＝7.8Hz,1H),6.65-6.63(m,2H),4.99(s,2H),4.36(s,1H),3.54(br s,1H),1.31(s,3H),1.23(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.9,151.8,142.1,137.5,135.4,128.6,128.5,127.9,127.5,127.3,126.2,123.4,116.2,115.1,115.0,70.8,60.7,43.3,23.0,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₄H₂₄N₂NaO₂ 395.1730；Found 395.1731.

4-((4-Fluorophenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3g)

¹H NMR(400MHz,CDCl₃):δ8.84(s,1H),7.24-7.20(m,2H),6.98(t,J＝7.2Hz,1H),6.91-6.85(m,3H),6.64-6.60(m,2H),4.37(s,1H),3.69(br s,1H),1.30(s,3H),1.23(s,3H).¹³C NMR(100MHz,CDCl₃):δ176.0,156.1(d,¹J_C-F＝234.8Hz),144.1(d,⁴J_C-F＝1.7Hz),135.5,128.6,127.1,125.8,123.4,115.9(d,²J_C-F＝22.5Hz),115.4,114.6(d,³J_C-F＝7.0Hz),60.6,43.3,23.0,19.2.¹⁹F NMR(376MHz,CDCl₃):δ-127.09–-127.15(m).HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₇H₁₇FN₂NaO 307.1217；Found 307.1212.

4-((4-Chlorophenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3h)

¹H NMR(400MHz,CDCl₃):δ8.92(s,1H),7.23-7.20(m,2H),7.14-7.10(m,2H),6.98(t,J＝7.6Hz,1H),6.87(d,J＝8.0Hz,1H),6.63-6.60(m,2H),4.43(d,J＝9.2Hz,1H),3.85(d,J＝9.6Hz,1H),1.30(s,3H),1.21(s,3H).¹³C NMR(100MHz,CDCl₃):δ176.0,146.4,135.5,129.3,128.7,127.1,125.5,123.5,122.6,115.5,114.5,59.7,43.3,22.9,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₇H₁₇ClN₂NaO 323.0922；Found 323.0924.

4-((4-Bromophenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3i)

¹H NMR(400MHz,CDCl₃):δ8.78(s,1H),7.27-7.20(m,4H),6.98(t,J＝7.6Hz,1H),6.86(d,J＝8.0Hz,1H),6.57(d,J＝8.8Hz,2H),4.43(d,J＝8.8Hz,1H),3.86(d,J＝9.2Hz,1H),1.30(s,3H),1.20(s,3H).¹³C NMR(100MHz,CDCl₃):δ175.8,146.8,135.5,132.2,128.7,127.1,125.4,123.5,115.4,114.9,109.6,59.5,43.3,22.9,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₇H₁₇BrN₂NaO 367.0416；Found 367.0414.

3,3-Dimethyl-4-(m-tolylamino)-3,4-dihydroquinolin-2(1H)-one(3j)

¹H NMR(400MHz,CDCl₃):δ8.95(s,1H),7.27(d,J＝7.2Hz,1H),7.21(t,J＝7.6Hz,1H),7.08(t,J＝7.2Hz,1H),6.98(t,J＝7.2Hz,1H),6.86(d,J＝8.0Hz,1H),6.56(d,J＝7.6Hz,1H),6.52-6.50(m,2H),4.52(s,1H),3.78(br s,1H),2.27(s,3H),1.33(s,3H),1.21(s,3H).¹³C NMR(150MHz,CDCl₃):δ176.3,147.9,139.3,135.6,129.4,128.5,127.2,126.1,123.4,119.0,115.3,114.1,110.3,59.1,43.3,22.8,21.7,19.0.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₂₀N₂NaO 303.1468；Found 303.1470.

4-((3-Methoxyphenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3k)

¹H NMR(400MHz,CDCl₃):δ8.37(s,1H),7.28(d,J＝7.6Hz,1H),7.22(td,J₁＝7.6Hz,J₂＝0.8Hz,1H),7.09(t,J＝8.0Hz,1H),6.99(td,J₁＝7.6Hz,J₂＝0.8Hz,1H),6.82(d,J＝8.0Hz,1H),6.31-6.24(m,3H),4.50(d,J＝7.6 Hz,1H),3.81(d,J＝9.6Hz,1H),3.77(s,3H),1.32(s,3H),1.21(s,3H).¹³C NMR(150MHz,CDCl₃):δ176.0,161.0,149.2,135.5,130.3,128.6,127.3,125.9,123.5,115.2,106.3,103.0,99.4,59.1,55.2,43.3,22.8,19.0.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₂₀N₂NaO₂ 319.1417；Found 319.1422.

4-((3-Fluorophenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3l)

¹H NMR(600MHz,CDCl₃):δ8.72(s,1H),7.24-7.21(m,2H),7.12-7.08(m,1H),7.00(td,J₁＝7.8Hz,J₂＝1.2Hz 1H),6.86(d,J＝7.8Hz,1H),6.45-6.38(m,3H),4.46(d,J＝9.6Hz,1H),3.97(d,J＝9.6Hz,1H),1.31(s,3H),1.21(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.8,164.2(d,¹J_C-F＝242.1Hz),149.6(d,³J_C-F＝10.2Hz),135.5,130.6(d,³J_C-F＝10.5Hz),128.8,127.2,125.4,123.6,115.4,109.1(d,⁴J_C-F＝2.0Hz),104.5(d,²J_C-F＝21.0Hz),100.0(d,²J_C-F＝26.0Hz),59.3,43.3,22.9,19.1.¹⁹F NMR(376MHz,CDCl₃):δ-122.3–-122.4(m).HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₇H₁₇FN₂NaO 307.1217；Found307.1222.

4-((3-Chlorophenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3m)

¹H NMR(600MHz,CDCl₃):δ8.06(s,1H),7.25-7.23(m,2H),7.09(t,J＝7.8Hz,1H),7.02-7.00(m,1H),6.81(d,J＝7.2Hz,1H),6.71-6.68(m,2H),6.55(dd,J₁＝8.4Hz,J₂＝2.4Hz,1H),4.48(s,1H),3.88(br s,1H),1.31(s,3H),1.20(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.5,148.9,135.4,135.3,130.5,128.8,127.2,125.3,123.6,118.0,115.2,113.0,111.5,59.2,43.4,22.8,19.0.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₇H₁₇ClN₂NaO323.0922；Found 323.0918.

4-((3-Bromophenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3n)

¹H NMR(400MHz,CDCl₃):δ8.58(s,1H),7.25-7.21(m,2H),7.04-6.99(m,2H),6.85-6.83(m,3H),6.61-6.58(m,1H),4.46(d,J＝10.0Hz,1H),3.91(d,J＝10.0Hz,1H),1.31(s,3H),1.20(s,3H).¹³C NMR(100MHz,CDCl₃):δ175.6,149.0,135.5,130.8,128.8,127.1,125.3,123.6,123.5,120.9,115.9,115.4,111.9,59.2,43.3,22.9,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₇H₁₇BrN₂NaO 367.0416；Found 367.0412.

3,3-Dimethyl-4-(o-tolylamino)-3,4-dihydroquinolin-2(1H)-one(3o)

¹H NMR(600MHz,CDCl₃):δ8.36(s,1H),7.24-7.21(m,2H),7.12-7.09(m,2H),6.98(td,J₁＝7.2Hz,J₂＝1.2Hz,1H),6.83(d,J＝7.8Hz,1H),6.72-6.68(m,2H),4.62(s,1H),3.70(br s,1H),2.18(s,3H),1.34(s,3H),1.21(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.8,145.6,135.5,130.6,128.5,127.3,127.1,126.0,123.5,122.0,117.6,115.1,110.7,58.8,43.3,22.6,18.9,17.6.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₂₀N₂NaO 303.1468；Found303.1474.

4-((2-Methoxyphenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3p)

¹H NMR(600MHz,CDCl₃):δ8.17(s,1H),7.27(d,J＝7.8Hz,1H),7.22(td,J₁＝7.8Hz,J₂＝1.2Hz,1H),6.99(t,J＝7.2.Hz,1H),6.87-6.84(m,1H),6.82-6.79(m,2H),6.71-6.68(m,2H),4.55(br s,2H),3.87(s,3H),1.34(s,3H),1.18(s,3H).¹³C NMR(100MHz,CDCl₃):δ176.0,146.6,137.8,135.5,128.4,127.1,126.2,123.4,121.3,116.9,115.0,110.3,109.9,58.7,55.6,43.4,22.5,18.8.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₂₀N₂NaO₂319.1417；Found 319.1413.

4-((2-Fluorophenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3q)

¹H NMR(400MHz,CDCl₃):δ8.13(s,1H),7.27-7.22(m,2H),7.04-6.97(m,3H),6.83-6.78(m,2H),6.69-6.64(m,1H),4.54(s,1H),4.08(br s,1H),1.34(s,3H),1.20(s,3H).¹³CNMR(CDCl₃,150MHz):δ175.5,151.5(d,¹J_C-F＝236.3Hz),136.2(d,²J_C-F＝11.0Hz),135.4,128.7,126.9,125.5,124.7(d,³J_C-F＝3.3Hz),123.5,117.4(d,³J_C-F＝6.6Hz),115.1,114.9(d,²J_C-F＝18.6Hz),112.8(d,⁴J_C-F＝3.2Hz),59.0,43.4,22.6,18.8.¹⁹F NMR(565MHz,CDCl₃):δ-136.1–-136.2(m).HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₇H₁₇FN₂NaO 307.1217；Found 307.1213.

4-((3,5-Dimethylphenyl)amino)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one(3r)

¹H NMR(600MHz,CDCl₃):δ9.35(s,1H),7.27(d,J＝7.8Hz,1H),7.20(t,J＝7.8Hz,1H),6.97(t,J＝7.8Hz,1H),6.89(d,J＝7.8Hz,1H),6.39(s,1H),6.34(s,2H),4.52(d,J＝7.8Hz,1H),3.75(d,J＝8.4Hz,1H),2.23(s,6H),1.33(s,3H),1.20(s,3H).¹³C NMR(150MHz,CDCl₃):δ176.6,148.0,139.2,135.7,128.5,127.1,126.2,123.4,120.0,115.4,111.2,59.0,43.3,22.8,21.6,19.0.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₉H₂₂N₂NaO 317.1624；Found 317.1611.

3,3-Dimethyl-4-(naphthalen-2-ylamino)-3,4-dihydroquinolin-2(1H)-one(3s)

¹H NMR(600MHz,CDCl₃):δ8.36(s,1H),7.69-7.65(m,2H),7.59(d,J＝8.4Hz,1H),7.36(td,J₁＝7.2Hz,J₂＝1.2Hz,1H),7.30(d,J＝7.2Hz,1H),7.24-7.20(m,2H),6.99-6.94(m,3H),6.84(d,J＝7.8Hz,1H),4.69(s,1H),4.02(br s,1H),1.37(s,3H),1.26(s,3H).¹³CNMR(150MHz,CDCl₃):δ175.6,145.4,135.5,135.1,129.4,128.6,127.8,127.7,127.3,126.6,125.9,125.7,123.5,122.4,117.8,115.2,105.3,59.1,43.4,22.8,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₁H₂₀N₂NaO 339.1468；Found 339.1465.

3,3,6,7-Tetramethyl-4-(phenylamino)-3,4-dihydroquinolin-2(1H)-one(3t)

¹H NMR(400MHz,CDCl₃):δ8.55(s,1H),7.18(t,J＝8.4Hz,2H),7.00(s,1H),6.73-6.68(m,3H),6.61(s,1H),4.44(d,J＝8.4Hz,1H),3.82(d,J＝7.6Hz,1H),2.18(s,3H),2.14(s,3H),1.29(s,3H),1.22(s,3H).¹³C NMR(100MHz,CDCl₃):δ176.0,147.9,137.0,133.2,131.5,129.5,128.3,123.2,117.7,116.5,113.2,59.1,43.6,23.1,19.5,19.3,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₉H₂₂N₂NaO 317.1624；Found 317.1622.

3,3,6,7-Tetramethyl-4-(p-tolylamino)-3,4-dihydroquinolin-2(1H)-one(3u)

¹H NMR(400MHz,CDCl₃):δ8.18(s,1H),7.00-6.98(m,3H),6.61-6.59(m,3H),4.39(d,J＝8.0Hz,1H),3.63(d,J＝8.4Hz,1H),2.24(s,3H),2.20(s,3H),2.14(s,3H),1.28(s,3H),1.21(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.9,145.7,136.9,133.1,131.5,130.0,128.4,127.0,123.4,116.4,113.3,59.5,43.7,23.0,20.4,19.5,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₀H₂₄N₂NaO 331.1781；Found 331.1785.

4-((4-Methoxyphenyl)amino)-3,3,6,7-tetramethyl-3,4-dihydroquinolin-2(1H)-one(3v)

¹H NMR(600MHz,CDCl₃):δ8.18(s,1H),6.97(s,1H),6.79-6.76(m,2H),6.64-6.62(m,2H),6.59(s,1H),4.28(s,1H),3.75(s,3H),3.49(br s,1H),2.20(s,3H),2.14(s,3H),1.27(s,3H),1.23(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.9,152.3,142.1,136.9,133.1,131.5,128.4,123.5,116.4,115.0,114.8,60.6,55.8,43.6,23.1,19.5,19.3,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₀H₂₄N₂NaO₂ 347.1730；Found 347.1727.

4-((4-Fluorophenyl)amino)-3,3,6,7-tetramethyl-3,4-dihydroquinolin-2(1H)-one(3w)

¹H NMR(600MHz,CDCl₃):δ8.27(s,1H),6.96(s,1H),6.90-6.87(m,2H),6.62-6.59(m,3H),4.30(d,J＝6.6Hz,1H),3.67(br s,1H),2.20(s,3H),2.15(s,3H),1.27(s,3H),1.23(s,3H).¹³C NMR(CDCl₃,150MHz):δ175.8,155.9(d,¹J_C-F＝234.2Hz),144.2,137.1,133.1,131.6,128.3,123.1,116.5,115.9(d,²J_C-F＝21.9Hz),114.3(d,³J_C-F＝6.6Hz),60.3,43.6,23.1,19.5,19.3,19.2.¹⁹F NMR(565MHz,CDCl₃):δ-127.44–-127.47(m).HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₉H₂₁FN₂NaO 335.1530；Found 335.1525.

4-((4-Chlorophenyl)amino)-3,3,6,7-tetramethyl-3,4-dihydroquinolin-2(1H)-one(3x)

¹H NMR(400MHz,CDCl₃):δ8.22(s,1H),7.12(d,J＝8.8Hz,2H),6.95(s,1H),6.62-6.58(m,3H),4.35(s,1H),3.82(br s,1H),2.19(s,3H),2.15(s,3H),1.26(s,3H),1.21(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.6,146.5,137.2,133.1,131.7,129.3,128.2,122.7,122.3,116.5,114.3,59.5,43.6,23.1,19.5,19.25,19.22.HRMS(ESI)m/z:[M+Na]⁺Calcdfor C₁₉H₂₁ClN₂NaO 351.1235；Found 351.1243.

4-((4-Bromophenyl)amino)-3,3,6,7-tetramethyl-3,4-dihydroquinolin-2(1H)-one(3y)

¹H NMR(600MHz,CDCl₃):δ7.84(s,1H),7.27-7.24(m,2H),6.96(s,1H),6.57-6.55(m,3H),4.36(s,1H),3.80(br s,1H),2.21(s,3H),2.16(s,3H),1.26(s,3H),1.20(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.3,146.9,137.2,133.1,132.2,131.8,128.3,122.7,116.4,114.7,109.3,59.3,43.7,23.0,19.6,19.24,19.21.HRMS(ESI)m/z:[M+Na]⁺Calcd forC₁₉H₂₁BrN₂NaO 395.0729；Found 395.0732.

4-((3,5-Dimethylphenyl)amino)-3,3,6,7-tetramethyl-3,4-dihydroquinolin-2(1H)-one(3z)

¹H NMR(400MHz,CDCl₃):δ7.90(s,1H),7.02(s,1H),6.57(s,1H),6.39(s,1H),6.32(s,2H),4.45(s,1H),3.67(br s,1H),2.24(s,6H),2.21(s,3H),2.15(s,3H),1.28(s,3H),1.18(s,3H).¹³C NMR(100MHz,CDCl₃):δ175.7,148.0,139.2,136.9,133.1,131.6,128.4,123.4,119.8,116.3,111.0,58.8,43.7,22.9,21.5,19.5,19.2,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₁H₂₆N₂NaO 345.1937；Found 345.1933.

6,7-Dimethoxy-3,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-2(1H)-one(3aa)

¹H NMR(600MHz,DMSO-d₆):δ9.89(s,1H),7.06(t,J＝7.8Hz,2H),6.81(d,J＝8.4Hz,2H),6.78(s,1H),6.58(s,1H),6.52(t,J＝7.2Hz,1H),5.67(d,J＝9.6Hz,1H),4.50(d,J＝9.6Hz,1H),3.71(s,3H),3.59(s,3H),1.12(s,3H),1.01(s,3H).¹³C NMR(150MHz,DMSO-d₆):δ174.7,149.6,149.0,144.2,130.8,129.4,117.8,116.3,113.0,112.3,100.7,57.7,56.6,56.0,43.1,23.1,19.4.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₉H₂₂N₂NaO₃349.1523；Found 349.1527.

6,7-Dimethoxy-3,3-dimethyl-4-(p-tolylamino)-3,4-dihydroquinolin-2(1H)-one(3bb)

¹H NMR(400MHz,CDCl₃):δ9.07(s,1H),6.99(d,J＝8.4Hz,2H),6.77(s,1H),6.62(d,J＝8.4Hz,2H),6.44(s,1H),4.36(s,1H),3.82(s,3H),3.73(s,3H),3.71(brs,1H),2.24(s,3H),1.29(s,3H),1.23(s,3H).¹³C NMR(100MHz,CDCl₃):δ176.3,149.1,145.7,145.0,130.0,129.0,127.2,117.6,113.6,111.1,100.2,60.0,56.4,56.1,43.6,23.1,20.4,19.3.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₀H₂₄N₂NaO₃ 363.1679；Found 363.1680.

6,7-Difluoro-3,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-2(1H)-one(3cc)

¹H NMR(600MHz,CDCl₃):δ9.04(s,1H),7.22-7.20(m,2H),7.13-7.10(m,1H),6.78(t,J＝7.8Hz,1H),6.75-6.72(m,1H),6.68(d,J＝7.8Hz,2H),4.48(s,1H),3.76(br s,1H),1.33(s,3H),1.19(s,3H).¹³C NMR(100MHz,CDCl₃):δ176.0,149.9(dd,¹J_C-F＝247.4Hz,²J_C-F＝13.9Hz),147.2,146.4(dd,¹J_C-F＝243.4Hz,²J_C-F＝13.6Hz),131.8(dd,³J_C-F＝8.3Hz,⁴J_C-F＝2.7Hz),129.7,122.4(dd,³J_C-F＝3.9Hz,⁴J_C-F＝3.7Hz),118.7,116.2(d,²J_C-F＝19.4Hz),113.3,104.8(d,²J_C-F＝21.4Hz),58.6,43.0,22.5,18.7.¹⁹F NMR(565MHz,CDCl₃):δ-137.28–-137.35(m),-143.68–-143.75(m).HRMS(ESI)m/z:[M+Na]⁺Calcd forC₁₇H₁₆F₂N₂NaO 325.1123；Found 325.1129.

7,7-Dimethyl-8-(phenylamino)-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one(3dd)

¹H NMR(600MHz,DMSO-d₆):δ9.96(s,1H),7.06(s,2H),6.80-6.79(m,2H),6.67(s,1H),6.53-6.52(m,2H),5.92(d,J＝9.0Hz,2H),5.71(d,J＝7.8Hz,1H),4.47(d,J＝6.6Hz,1H),1.13(s,3H),1.01(s,3H).¹³C NMR(150MHz,DMSO-d₆):δ174.7,149.4,146.9,142.5,131.5,129.5,119.0,116.4,112.9,107.5,101.4,97.4,57.7,42.6,22.9,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₁₈N₂NaO₃ 333.1210；Found 333.1206.

7,7-Dimethyl-8-(p-tolylamino)-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one(3ee)

¹H NMR(600MHz,CDCl₃):δ8.72(s,1H),6.99(d,J＝7.8Hz,2H),6.73(s,1H),6.59(d,J＝8.4Hz,2H),6.42(s,1H),5.89(d,J＝1.2Hz,2H),4.32(s,1H),3.61(br s,1H),2.24(s,3H),1.29(s,3H),1.21(s,3H).¹³C NMR(150MHz,CDCl₃):δ176.0,147.5,145.4,143.6,130.0,129.7,127.3,118.9,113.5,107.6,101.3,97.6,59.8,43.1,22.9,20.4,19.0.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₉H₂₀N₂NaO₃ 347.1366；Found 347.1361.

8-((4-Methoxyphenyl)amino)-7,7-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one(3ff)

¹H NMR(600MHz,DMSO-d₆):δ9.92(s,1H),6.74-6.68(m,4H),6.65(s,1H),6.50(s,1H),5.91(d,J＝12.0Hz,2H),5.28(d,J＝9.6Hz,1H),4.33(d,J＝9.6Hz,1H),3.63(s,3H),1.12(s,3H),1.00(s,3H).¹³C NMR(150MHz,DMSO-d₆):δ174.8,151.3,146.8,143.5,142.5,131.4,119.4,115.1,114.2,107.5,101.3,97.4,58.8,55.7,42.6,22.9,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₉H₂₀N₂NaO₄ 363.1315；Found 363.1311.

8-((4-Chlorophenyl)amino)-7,7-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one(3gg)

¹H NMR(600MHz,DMSO-d₆):δ9.96(s,1H),7.07(d,J＝9.0Hz,2H),6.82(d,J＝8.4Hz,2H),6.66(s,1H),6.53(s,1H),5.95-5.92(m,3H),4.46(d,J＝9.6Hz,1H),1.11(s,3H),1.01(s,3H).¹³C NMR(150MHz,DMSO-d₆):δ174.5,148.3,147.0,142.6,131.5,129.1,119.5,118.5,114.3,107.4,101.4,97.4,57.8,42.6,23.0,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₁₇ClN₂NaO₃ 367.0820；Found 367.0815.8-((4-Bromophenyl)amino)-7,7-dimethyl-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one(3hh)

¹H NMR(600MHz,DMSO-d₆):δ9.97(s,1H),7.19-7.17(m,2H),6.79-6.76(m,2H),6.66(s,1H),6.53(s,1H),5.97(d,J＝9.6Hz,1H),5.92(dd,J₁＝7.8Hz,J₂＝0.6Hz,2H),4.46(d,J＝10.2Hz,1H),1.11(s,3H),1.01(s,3H).¹³C NMR(150MHz,DMSO-d₆):δ174.5,148.7,147.0,142.6,131.9,131.5,118.5,114.9,107.4,106.8,101.4,97.4,57.7,42.6,22.9,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₁₇BrN₂NaO₃ 411.0315；Found 411.0313.

7,7-Dimethyl-8-(m-tolylamino)-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one(3ii)

¹H NMR(600MHz,DMSO-d₆):δ9.95(s,1H),6.94(t,J＝7.8Hz,1H),6.66(s,1H),6.63(s,1H),6.59(d,J＝7.8Hz,1H),6.52(s,1H),6.35(d,J＝7.2Hz,1H),5.92(d,J＝9.0Hz,2H),5.60(d,J＝9.6Hz,1H),4.47(d,J＝9.6Hz,1H),2.17(s,3H),1.13(s,3H),1.00(s,3H).¹³C NMR(150MHz,DMSO-d₆):δ174.7,149.4,146.9,142.5,138.5,131.4,129.3,119.2,117.4,113.5,110.2,107.4,101.3,97.4,57.6,42.6,22.8,21.9,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₉H₂₀N₂NaO₃ 347.1366；Found 347.1370.

3,3-Dimethyl-4-(phenylamino)-3,4-dihydrobenzo[h]quinolin-2(1H)-one(3jj)

¹H NMR(600MHz,CDCl₃):δ9.12(s,1H),7.77(d,J＝7.8Hz,1H),7.74(d,J＝8.4Hz,1H),7.69(d,J＝8.4Hz,1H),7.41-7.38(m,1H),7.36-7.33(m,1H),7.20-7.18(m,2H),7.10(d,J＝9.0Hz,1H),6.73-6.70(m,3H),4.96(d,J＝6.6Hz,1H),3.76(d,J＝6.6Hz,1H),1.52(s,3H),1.25(s,3H).¹³C NMR(150MHz,CDCl₃):δ176.1,147.7,133.3,131.6,130.8,129.8,129.4,128.8,127.7,124.5,122.7,118.0,117.6,116.7,112.9,56.9,44.6,24.8,20.6.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₁H₂₀N₂NaO339.1468；Found 339.1470.

6-Methoxy-3,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-2(1H)-one(3kk)

¹H NMR(600MHz,CDCl₃):δ8.30(s,1H),7.19(t,J＝7.8Hz,2H),6.85(s,1H),6.75-6.72(m,3H),6.69(d,J＝8.4Hz,2H),4.48(s,1H),3.78(br s,1H),3.71(s,3H),1.31(s,3H),1.19(s,3H).¹³C NMR(150MHz,CDCl₃):δ175.4,156.0,147.7,129.5,128.8,127.5,118.1,116.1,113.4,113.24,113.20,59.4,55.6,43.2,22.8,18.9.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₂₀N₂NaO 319.1417；Found 319.1429.

7-Methoxy-3,3-dimethyl-4-(phenylamino)-3,4-dihydroquinolin-2(1H)-one(3ll)

¹H NMR(600MHz,CDCl₃):δ8.23(s,1H),7.19-7.15(m,3H),6.73(t,J＝7.2Hz,1H),6.68(d,J＝7.8Hz,2H),6.51(dd,J₁＝8.4Hz,J₂＝2.4Hz,1H),6.37(d,J＝2.4Hz,1H),4.45(s,1H),3.77(s,3H),3.74(br s,1H),1.30(s,3H),1.21(s,3H).¹³C NMR(150MHz,CDCl₃):δ176.0,160.0,147.8,136.5,129.5,128.4,118.3,117.9,113.3,108.2,101.5,58.8,55.4,43.6,22.9,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₂₀N₂NaO₂ 319.1417；Found319.1413.

实施例4

本发明所合成产物4-氨基二氢喹啉酮类化合物3进行一系列反应，合成多种衍生物。例如：

在25mL圆底烧瓶中将3a(26.6mg,0.1mmol)、四丁基碘化铵(2.6mg,0.007mmol)和氢氧化钾(14mg,0.25mmol)溶于甲苯和水(7:1)的混合溶液中，然后在室温下滴加碘甲烷(35.5mg,0.25mmol)，之后将反应体系升温至90℃反应24h。反应结束后冷却至室温，缓慢加入氯化铵溶液淬灭反应。乙酸乙酯萃取、水洗、干燥、过滤，将有机相浓缩过硅胶柱分离(石油醚/乙酸乙酯＝5/1)得黄色油状产物4(26.0mg,93％)。¹H NMR(400MHz,CDCl₃):δ7.32-7.28(m,2H),7.20-7.15(m,2H),7.04-7.00(m,2H),6.74-6.70(m,1H),6.69-6.67(m,2H),4.47(d,J＝8.0Hz,1H),3.77(d,J＝8.0Hz,1H),3.41(s,3H),1.30(s,3H),1.12(s,3H).¹³CNMR(100MHz,CDCl₃):δ174.4,147.8,138.9,129.5,128.4,127.6,126.8,123.3,117.9,114.5,113.2,58.6,43.4,30.2,23.3,19.2.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₁₈H₂₀N₂NaO303.1468；Found 303.1465.

在15mL反应管中，依次加入碘化亚铜(5.7mg,0.03mmol)、磷酸钾(32.5mg,0.23mmol)、2-碘吡啶(12.0μL,0.11mmol)、N,N-二甲基乙二胺(5.1μL,0.05mmol)、3a(26.6mg,0.1mmol)和1,4-二氧六环(1mL)，随后将体系抽真空充氩气三次，再置于80℃油浴中反应24h。冷却至室温，缓慢加入氯化铵溶液淬灭反应。有机相用乙酸乙酯萃取、水洗、干燥、过滤，将有机相浓缩过硅胶柱分离(石油醚/乙酸乙酯＝3/1)得到黄色油状产物5(22.6mg,66％)。¹H NMR(600MHz,CDCl₃):δ8.69-8.68(m,1H),7.91(td,J₁＝7.2Hz,J₂＝1.8Hz,1H),7.39-7.37(m,2H),7.34(d,J＝7.2Hz,1H),7.20(t,J＝7.8Hz,2H),7.10(td,J₁＝7.8Hz,J₂＝1.2Hz,1H),7.00(td,J₁＝7.2Hz,J₂＝0.6Hz,1H),6.76-6.74(m,3H),6.28(d,J＝7.8Hz,1H),4.68(s,1H),3.94(br s,1H),1.39(s,3H),1.28(s,3H).¹³C NMR(150MHz,CDCl₃):δ174.5,152.1,150.3,147.8,138.7,138.6,129.5,128.2,127.3,127.2,124.7,123.8,123.5,118.0,116.7,113.3,58.9,43.9,22.9,19.1.HRMS(ESI)m/z:[M+Na]⁺Calcdfor C₂₂H₂₁N₃NaO 366.1577；Found 366.1575.

将溶于四氢呋喃(4mL)3a(45mg,0.17mmol)置于25mL两颈瓶中，然后加入氢化锂铝(0.56mL,1M in THF)。将该体系在氩气条件下回流反应8h。反应结束后冷却至室温，向该体系中加入1mL水，搅拌10分钟后，再加入0.5mL 2M的氢氧化钠水溶液，继续搅拌5分钟，用乙酸乙酯萃取。有机相水洗、干燥、过滤、浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝20/1)得到黄色油状产物6(27.0mg,63％)。¹H NMR(600MHz,CDCl₃):δ7.19-7.16(m,2H),7.14(d,J＝7.2Hz,1H),7.03-7.01(m,1H),6.71-6.67(m,3H),6.58(td,J₁＝7.8Hz,J₂＝1.2Hz,1H),6.49(dd,J₁＝7.8Hz,J₂＝0.6Hz,1H),4.27(s,1H),3.97(br s,1H),3.65(br s,1H),3.08-3.03(m,2H),1.03(s,3H),1.02(s,3H).¹³C NMR(150MHz,CDCl₃):δ149.2,143.3,129.4,129.2,128.1,123.0,117.2,117.0,113.8,112.8,59.1,51.5,33.2,25.2,21.3.MS:m/z 252[M]⁺.

在15mL反应管中，依次加入3i(28.4mg,0.08mmol)、苯乙炔(13μL,0.12mmol)、三苯基膦(4.2mg,0.016mmol)、磷酸钾(20.4mg,0.096mmol)、醋酸钯(0.9mg,0.004mmol)和二甲基亚砜(1mL)，置于80℃油浴中于氩气条件下反应24h。反应结束后冷却至室温，缓慢加入碳酸氢钠溶液淬灭反应。用乙酸乙酯萃取，有机相水洗、干燥、过滤、浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝3/1)得到粉色固体7(20.8mg,71％)。

¹H NMR(400MHz,DMSO-d₆):δ10.17(s,1H),7.47-7.45(m,2H),7.40-7.34(m,3H),7.25(d,J＝8.8Hz,2H),7.21-7.15(m,2H),6.95-6.90(m,2H),6.86(d,J＝8.8Hz,2H),6.32(d,J＝10.0Hz,1H),4.72(d,J＝9.6Hz,1H),1.14(s,3H),1.02(s,3H).¹³C NMR(150MHz,DMSO-d₆):δ174.8,150.0,137.3,133.1,131.4,129.1,128.5,128.3,127.1,125.8,123.9,122.5,115.3,112.8,108.9,91.6,87.2,57.2,42.8,22.8,19.3.HRMS(ESI)m/z:[M+Na]⁺Calcd for C₂₅H₂₂N₂NaO 389.1624；Found 389.1621.

实施例6

化合物抗癌活性是利用CCK8分析，通过细胞抗增殖活性研究来评估的。首先，将细胞以每孔5000个细胞的密度接种到每孔装有100μL培养基的96孔板中，并在37℃和5％CO₂环境下孵育过夜。第二天，在每孔中加入100μL用培养基稀释的待测化合物(浓度为0.03nM-30μM)，接着，细胞在37℃和5％CO₂环境下孵育72小时。然后，向每个孔中加入10μL的CCK8，并将96孔板置于37℃孵育2小时。使用EnVision multilatelbel Reader(Perkinermer)在450nm处测量吸光度(用630nm作为参考波长)，并用GraphPad Prism 6.0软件计算出IC₅₀值。所有的实验均布施三个平行样品，并重复三次。选择REC-1和Ramos两种癌细胞作为研究对象，阿霉素(Adriamycin)被用作药物的阳性对照品。

部分化合物的抗癌活性结果如下：

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。

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4-氨基二氢喹啉酮类化合物的合成方法及抗癌活性

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