CN113004294B - 一种四氢呋喃并1,4-二氢喹啉类化合物及其制备方法和应用 - Google Patents
一种四氢呋喃并1,4-二氢喹啉类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种四氢呋喃并1,4‑二氢喹啉类化合物及其制备方法与应用，通过以具有氧杂环丁烷结构的炔胺类化合物为起始原料，在室温及金催化剂存在条件下进行1,1‑碳烷氧基化外环化反应，生成环外金卡宾，随后1,2‑N迁移到金卡宾中，制备获得了一系列四氢呋喃并1,4‑二氢喹啉类化合物，反应条件温和、操作简单、效率高、目标产物收率高。对示例性化合物2a～2t的抗肿瘤细胞毒性测试结果表明，这些化合物对多种肿瘤细胞表现出一定的抑制活性。
Description
技术领域
本申请属于有机合成技术领域，具体涉及一种四氢呋喃并1,4-二氢喹啉类化合物及其制备方法和应用。
背景技术
呋喃并喹啉结构单元广泛地存在于天然产物及药物活性分子结构中，例如现有技术报道的
等呋喃并喹啉类化合物已经呈现出多种生物活性，而对于四氢呋喃并1,4-二氢喹啉类化合物的研究则较少，开发更多种结构新颖的化合物并研究其生物活性具有十分重要的现实意义。
过渡金属催化的炔烃分子内碳烷氧基化反应在过去的几十年中倍受关注，因为它在功能化环状化合物的快速组装中具有很高的键形成效率和原子经济性。该反应通常涉及通过外环化或内环化进行的分子内碳烷氧基化反应，然后内部或外部迁移，导致炔烃双官能化。但是，与Fürstner，Yamamoto，Toste等人建立的炔烃1,2-碳烷氧基化相比，相关的1,1-碳烷氧基化的开发利用程度要低得多，其中值得一提的是，炔烃的1,1-碳烷氧基化反应可能涉及金属卡宾的形成。在2002年，Yamamoto及其同事报道了一种钯催化的邻炔基苯甲醛二烷基缩醛的钯催化碳烷氧基化反应，形成了茚满醚，这是第一个炔烃1,1-碳烷氧基化反应(Angew.Chem.,Int.Ed.2002,41,4328–4331)。2014年，Liu和他的同事展示了一种精巧的方案金可催化2-乙炔基苄基醚的1,1-碳烷氧基化反应以控制茚满酮的合成(Adv.Synth.Catal.2014,356,144–152)。几乎在同一时间，Davies等人公开了金-催化炔胺的1,1-碳烷氧基化反应，涉及1,2-N-迁移，得到官能化的茚类化合物(Chem.-Eur.J.2014,20,7262–7266.)。尽管取得了这些成就，但这些1,1-碳烷氧基化反应仅限于内环化，最终导致内部迁移后环内金属卡宾的形成。特别地，提出了在这些1,1-碳烷氧基化反应中生成碳阳离子中间产物。
受这些发现以及发明人课题组对开发用于杂环合成的炔胺化学的最新研究的启发，发明人预见到，外环卡宾的生成可以通过过渡金属催化具有氧杂环丁烷结构单元的炔胺的碳烷氧基化反应，通过氧杂环丁烷环的扩环反应来进行。值得注意的是，据发明人所知，只有一个例子涉及氧杂环丁烷与炔烃通过扩环的催化反应，其中涉及典型的炔烃1,2-碳烷氧基化反应(Adv.Synth.Catal.2014,356,2411–2416)。在本发明中，发明人描述了在室温下进行外环化反应，金-催化炔胺的1,1-碳烷氧基化反应，生成环外金卡宾，随后1,2-N迁移到金卡宾中，导致各种四氢呋喃并1,4-二氢喹啉类化合物的原子经济合成。
发明内容
本发明的目的在于提供一种四氢呋喃并1,4-二氢喹啉类化合物及其制备方法与应用，本发明的制备方法以具有氧杂环丁烷结构的炔胺类化合物为起始原料，在室温及金催化剂存在条件下进行1,1-碳烷氧基化外环化反应，生成环外金卡宾，随后1,2-N迁移到金卡宾中，制备获得了一系列四氢呋喃并1,4-二氢喹啉类化合物，反应条件温和、操作简单、效率高、目标产物收率高。对示例性化合物2a～2t的抗肿瘤细胞毒性测试结果表明，这些化合物对癌细胞，包括乳腺癌细胞MDA-MB-231和MCF-7，骨肉瘤癌细胞U2OS，白血病细胞HL-60，淋巴瘤细胞JeKo-1，HepG2细胞和黑色素瘤细胞A375等具有一定的抑制活性。
本发明的第一个方面在于提供一种具有式2所示结构的四氢呋喃并1,4-二氢喹啉类化合物：
其中，R1表示所连接苯环上的取代基；n表示R1取代基的数量，选自1,2,3或4；各个R1相同或不同，彼此独立地选自氢、卤素、C1-6烷基、C1-6烷氧基。
R2为氨基保护基。
R3选自取代或未取代的C6-20芳基、取代或未取代的C2-20杂芳基。其中，所述“取代或未取代的”中的取代基选自卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基。所述杂芳基的杂原子选自O,S或N。
优选地，n选自1；R1选自氢、氯、氟、溴、甲基、甲氧基。
R2选自Ts(对甲苯磺酰基),MBS(对甲氧基苯磺酰基),SO2Ph(苯磺酰基),Bs(4-溴苯磺酰基),Ms(甲磺酰基)中的任意一种。
R3选自取代或未取代的苯基；噻吩基、呋喃基，其中，所述“取代或未取代的”中的取代基选自氯、氟、溴、三氟甲基、甲基、甲氧基。
进一步优选地，式2化合物选自如下式2a～2t的化合物：
本发明的第二个方面在于提供一种具有式2所示结构的四氢呋喃并1,4-二氢喹啉类化合物，包括如下步骤：
在室温下，将式1所示的炔胺溶于有机溶剂中，随后加入金催化剂，于室温下搅拌反应，经TLC监测反应完全，随后将反应液浓缩，残余物经硅胶柱层析分离得到式2所示的四氢呋喃并1,4-二氢喹啉类化合物。反应式如下：
其中，式1中R1-R3,n具有如本文前述所定义。
根据本发明的制备方法，其中所述的金催化剂选自IPrAuNTf2、Ph3PAuNTf2、Cy-JohnPhosAuNTf2、XPhosAuNTf2、BrettPhosAuNTf2中的任意一种。最优选为IPrAuNTf2。金催化剂与式1化合物的投料摩尔比为0.01～0.2:1，优选为0.05～0.1:1，最优选为0.05:1。
根据本发明的制备方法，其中所述的有机溶剂选自二氯甲烷、二氯乙烷、氯苯、甲苯、乙腈中的任意一种。优选为二氯甲烷或二氯乙烷，最优选为二氯甲烷。
根据本发明的制备方法，其中经TLC监测反应完全所需要的时间为0.5～24小时，最优选为1小时。
根据本发明的制备方法，其中，硅胶柱层析分离的洗脱溶剂为正己烷/乙酸乙酯的混合溶剂。
作为本发明的第三个方面，本发明提供了所示式2化合物的应用。对化合物2a～2t的抗肿瘤细胞毒性测试结果表明，这些化合物对癌细胞，包括乳腺癌细胞MDA-MB-231和MCF-7，骨肉瘤癌细胞U2OS，白血病细胞HL-60，淋巴瘤细胞JeKo-1，HepG2细胞和黑色素瘤细胞A375等具有一定的抑制活性。总体而言，本发明的化合物较之四氢呋喃并喹啉、或者呋喃并喹啉类化合物而言，对上述肿瘤细胞的抑制效果更好。值得一提的是，化合物2a～2b,2d,2f～2l,2n～2t对于淋巴瘤细胞JeKo-1，化合物2a～2b,2f对于白血病细胞HL-60，化合物2a～2b,2f～2g,2j,2n对于HepG2细胞的抑制效果非常显著，表明本发明的化合物可以应用于制备抗癌药物。
附图说明
图1为化合物2aa的单晶结构衍射图
具体实施方式
以下结合具体实施例，对本发明作进一步的详述。在下文中，如无特殊说明，所使用的方法均为本领域的常规方法，所使用的试剂均由常规的商业途径购买获得且未经进一步的纯化。
反应底物1a～1t的合成路线如下：
实施例1-12反应条件优化试验
以式1a所示的炔胺为起始原料，探讨了催化剂、溶剂等因素对反应的影响，以核磁内标法(内标为邻苯二甲酸二乙酯)计算产物中目标产物及原料的核磁产率，结果如表1所示。反应式如下：
表1：
其中，表1中，a反应条件:1a(0.1mmol),催化剂(0.005mmol),溶剂(2mL),rt,0.5–24h。b通过1H NMR测定；c催化剂使用量为10mol％。
实施例13化合物2a的合成
在室温下，将式1a所示的炔胺(0.2mmol)溶于二氯甲烷(4mL)中，随后加入金催化剂IPrAuNTf2(0.01mmol，8.7mg)，于室温下搅拌反应1小时，经TLC监测反应完全，随后将反应液浓缩，残余物经硅胶柱层析分离(洗脱溶剂为正己烷/乙酸乙酯)得到式Ia所示的目标产物77.5mg。产率：96％。白色固体(mp155–156℃).1H NMR(500MHz,CDCl3)δ7.94–7.80(m,3H),7.41–7.33(m,3H),7.32–7.25(m,3H),7.22–7.17(m,1H),7.12(d,J＝8.0Hz,2H),6.95(d,J＝7.5Hz,1H),4.27(t,J＝8.5Hz,1H),4.15–4.05(m,1H),2.46–2.31(m,4H),2.23–2.11(m,1H),1.81–1.69(m,1H)；13C NMR(125MHz,CDCl3)δ156.0,144.0,137.5,137.1,136.0,133.4,129.1,128.3,127.7,127.5,127.2,127.0,126.4,126.2,125.4,111.6,71.1,39.3,29.8,21.6；IR(neat):3063,2960,1660,1598,1493,1356,1168,673,589；HRESIMS Calcdfor[C24H21NNaO3S]+(M+Na+)426.1134,found426.1135。
实施例14-32化合物2b～2t的合成
替换式1的反应底物种类，根据实施例13的方法进行反应操作并根据TLC监测结果调整反应时间，制备获得目标化合物2b～2t并计算分离产率，结果如下：
其中,b表示基于分离回收的反应底物1o的量，根据实际反应的反应底物1o的量来计算目标产物2o分离产率则为98％，反应时间为24小时。
目标产物结构表征：
化合物2b:白色固体(mp 171–172℃).1HNMR(400MHz,CDCl3)δ7.91–7.81(m,3H),7.40–7.29(m,5H),7.28–7.22(m,1H),7.22–7.15(m,1H),6.94(d,J＝7.6Hz,1H),6.78(d,J＝8.8Hz,2H),4.26(t,J＝8.8Hz,1H),4.15–4.05(m,1H),3.78(s,3H),2.46–2.34(m,1H),2.28–2.20(m,1H),1.84–1.67(m,1H)；13C NMR(100MHz,CDCl3)δ163.4,156.0,137.5,137.0,136.1,130.2,127.9,127.6,127.5,127.2,126.9,126.4,126.1,125.3,113.7,111.6,71.1,55.6,39.4,29.8；IR(neat):3006,2989,1656,1593,1355,1275,1261,750；HRESIMS Calcdfor[C24H21NNaO4S]+(M+Na+)442.1083,found 442.1083。
化合物2c:白色固体(mp 153–154℃).1H NMR(400MHz,CDCl3)δ7.93–7.82(m,3H),7.58–7.50(m,1H),7.45–7.29(m,7H),7.28–7.17(m,2H),6.93(d,J＝7.6Hz,1H),4.26(t,J＝8.4Hz,1H),4.12–4.02(m,1H),2.40–2.30(m,1H),2.11–2.00(m,1H),1.81–1.66(m,1H)；13C NMR(100MHz,CDCl3)δ156.1,137.4,137.0,136.1,136.0,133.1,128.5,128.3,127.7,127.5,127.3,127.0,126.5,126.3,125.3,111.6,71.2,39.3,29.8；IR(neat):3063,2898,1660,1600,1446,1357,1171,723,599；HRESIMS Calcd for[C23H19NNaO3S]+(M+Na+)412.0978,found412.0979。
化合物2d:白色固体(mp 169–170℃).1H NMR(400MHz,CDCl3)δ7.89(d,J＝7.6Hz,1H),7.83(d,J＝7.2Hz,2H),7.49(d,J＝8.4Hz,2H),7.44–7.34(m,3H),7.33–7.26(m,3H),7.24–7.18(m,1H),6.99(d,J＝7.6Hz,1H),4.32(t,J＝8.4Hz,1H),4.24–4.10(m,1H),2.54–2.41(m,1H),2.37–2.23(m,1H),1.89–1.73(m,1H)；13C NMR(100MHz,CDCl3)δ155.9,137.1,136.8,135.7,135.6,131.8,129.8,128.3,127.8,127.5(4),127.4(6),127.3,126.5,125.6,111.7,71.2,39.5,29.9；IR(neat):3092,2928,1660,1573,1484,1360,1171,738,611；HRESIMS Calcd for[C23H18BrNNaO3S]+(M+Na+)490.0083,found490.0084。
化合物2e:白色固体(mp 148–149℃).1H NMR(500MHz,CDCl3)δ7.79(dd,J＝8.5,1.5Hz,2H),7.75(dd,J＝8.0,1.5Hz,1H),7.39–7.29(m,4H),7.24–7.16(m,2H),4.50–4.40(m,2H),4.10–4.04(m,1H),2.85–2.71(m,4H),2.14–2.04(m,1H)；13C NMR(125MHz,CDCl3)δ155.5,137.4,136.3,135.5,127.9,127.5,127.3,127.0,126.4,126.3,126.0,112.0,71.6,40.8,36.8,30.0；IR(neat):2919,2850,1660,1482,1348,1194,1162,1127,744,544；HRESIMS Calcd for[C18H17NNaO3S]+(M+Na+)350.0821,found 350.0822。
化合物2f:白色固体(mp 166–167℃).1H NMR(400MHz,CDCl3)δ7.90–7.79(m,3H),7.39–7.32(m,1H),7.30–7.21(m,3H),7.11(d,J＝8.0Hz,2H),7.08–7.01(m,2H),6.94(d,J＝7.6Hz,1H),4.26(t,J＝8.4Hz,1H),4.14–4.04(m,1H),2.44–2.33(m,4H),2.20–2.11(m,1H),1.83–1.68(m,1H)；13C NMR(100MHz,CDCl3)δ161.1(d,J＝244.0Hz),155.8,144.1,137.3,137.0,133.2,132.2(d,J＝3.0Hz),129.1,128.2,128.1(d,J＝7.0Hz),127.4,127.3,127.0,125.4,114.5(d,J＝21.0Hz),110.8,71.2,39.2,29.8,21.5；IR(neat):2927,1651,1507,1356,1192,1166,672,585；HRESIMS Calcd for[C24H20FNNaO3S]+(M+Na+)444.1040,found444.1041。
化合物2g:白色固体(mp 180–181℃).1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.0Hz,1H),7.80(d,J＝8.8Hz,2H),7.40–7.30(m,3H),7.29–7.22(m,3H),7.12(d,J＝8.0Hz,2H),6.95(d,J＝7.6Hz,1H),4.29(t,J＝8.4Hz,1H),4.17–4.07(m,1H),2.47–2.32(m,4H),2.23–2.11(m,1H),1.85–1.70(m,1H)；13C NMR(100MHz,CDCl3)δ156.6,144.2,137.2,136.9,134.7,133.2,131.5,129.2,128.2,127.8,127.7,127.4(1),127.3(9),127.1,125.4,110.8,71.4,39.4,29.7,21.6；IR(neat):2925,1660,1489,1454,1357,1168,1089,673,583；HRESIMS Calcd for[C24H20ClNNaO3S]+(M+Na+)460.0745,found460.0749
化合物2h:白色固体(mp 100–101℃).1H NMR(400MHz,CDCl3)δ7.86(dd,J＝8.0,1.2Hz,1H),7.75(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),7.41–7.32(m,1H),7.31–7.21(m,3H),7.12(d,J＝8.0Hz,2H),6.95(d,J＝7.6Hz,1H),4.29(t,J＝8.8Hz,1H),4.17–4.07(m,1H),2.51–2.30(m,4H),2.22–2.07(m,1H),1.86–1.69(m,1H)；13C NMR(100MHz,CDCl3)δ156.7,144.2,137.2,136.8,135.1,133.2,130.8,129.2,128.3,128.1,127.5,127.4,127.1,125.4,119.7,110.8,71.4,39.4,29.7,21.6；IR(neat):2923,1659,1596,1488,1356,1168,1007,673；HRESIMS Calcd for[C24H20BrNNaO3S]+(M+Na+)504.0239,found504.02340。
化合物2i:白色固体(mp 185–186℃).1H NMR(500MHz,CDCl3)δ7.98(d,J＝8.0Hz,2H),7.90(dd,J＝8.0,1.0Hz,1H),7.61(d,J＝8.0Hz,2H),7.42–7.35(m,1H),7.32–7.26(m,3H),7.14(d,J＝8.0Hz,2H),6.97(d,J＝7.5Hz,1H),4.34(t,J＝8.5Hz,1H),4.23–4.13(m,1H),2.49–2.36(m,4H),2.25–2.17(m,1H),1.87–1.75(m,1H)；13C NMR(125MHz,CDCl3)δ158.0,144.3,139.6(q,J＝1.3Hz),137.2,136.6,133.2,129.2,128.3,127.7(q,J＝31.3Hz),127.5(2),127.5(0),127.3,126.5,125.5,124.7(q,J＝3.8Hz),124.4(q,J＝270.0Hz),110.7,71.7,39.7,29.7,21.67；IR(neat):2925,2851,1652,1615,1455,1359,1324,1167,672,585；HRESIMS Calcd for[C25H20F3NNaO3S]+(M+Na+)494.1008,found494.1006。
化合物2j:白色固体(mp 95–96℃).1H NMR(400MHz,CDCl3)δ7.87(dd,J＝8.0,1.2Hz,1H),7.74(d,J＝8.4Hz,2H),7.38–7.31(m,1H),7.31–7.23(m,3H),7.18(d,J＝8.0Hz,2H),7.11(d,J＝8.0Hz,2H),6.93(d,J＝7.6Hz,1H),4.24(t,J＝8.8Hz,1H),4.14–4.01(m,1H),2.44–2.28(m,7H),2.19–2.09(m,1H),1.81–1.65(m,1H)；13C NMR(100MHz,CDCl3)δ155.3,143.9,137.5,137.1,135.8,133.4,133.2,129.0,128.4,128.2,127.4,127.2,126.9,126.4,125.3,111.6,71.0,39.2,29.8,21.6,21.2；IR(neat):2988,1662,1482,1455,1355,1275,1167,749；HRESIMS Calcd for[C25H23NNaO3S]+(M+Na+)440.1291,found440.1296。
化合物2k:白色固体(mp 90–91℃).1H NMR(400MHz,CDCl3)δ7.86(dd,J＝8.0,1.2Hz,1H),7.80(d,J＝8.8Hz,2H),7.39–7.31(m,1H),7.31–7.21(m,3H),7.11(d,J＝8.0Hz,2H),6.97–6.89(m,3H),4.24(t,J＝8.8Hz,1H),4.13–4.02(m,1H),3.80(s,3H),2.44–2.30(m,4H),2.19–2.08(m,1H),1.82–1.66(m,1H)；13C NMR(100MHz,CDCl3)δ157.9,154.6,143.9,137.4,137.2,133.4,129.1,128.8,128.3,127.7,127.5,127.2,126.9,125.3,113.2,111.4,70.9,55.1,39.1,29.9,21.6；IR(neat):2960,2922,1748,1653,1605,1509,1250,1177,753；HRESIMS Calcd for[C25H23NNaO4S]+(M+Na+)456.1240,found456.1241。
化合物2l:白色固体(mp 156–157℃).1H NMR(400MHz,CDCl3)δ7.86(dd,J＝8.0,1.2Hz,1H),7.52–7.41(m,2H),7.39–7.20(m,5H),7.11(d,J＝8.0Hz,2H),6.97–6.91(m,1H),6.78–6.73(m,1H),4.26(t,J＝8.4Hz,1H),4.15–4.05(m,1H),3.84(s,3H),2.45–2.30(m,4H),2.20–2.11(m,1H),1.82–1.66(m,1H)；13C NMR(100MHz,CDCl3)δ159.1,156.4,144.0,137.4(0),137.3(7),137.0,133.3,129.1,128.6,128.2,127.4,127.2,126.9,125.3,119.1,112.5,111.5,111.4,71.2,55.1,39.3,29.7,21.6；IR(neat):3066,2957,2933,1660,1598,1483,1356,1190,1163,1124,807,669,580；HRESIMS Calcd for[C25H23NNaO4S]+(M+Na+)456.1240,found456.1241。
化合物2m:白色固体(mp 188–189℃).1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.0Hz,1H),7.54–7.44(m,1H),7.41–7.31(m,3H),7.30–7.24(m,1H),7.22–7.10(m,5H),6.99(d,J＝7.2Hz,1H),4.17(t,J＝8.4Hz,1H),4.08–3.97(m,1H),2.49–2.23(m,8H),1.88–1.72(m,1H)；13C NMR(100MHz,CDCl3)δ143.8,137.5,137.2,136.3,134.0,130.3,129.1,128.0,127.1(3),127.1(0),127.0,125.5,125.1,70.8,38.8,30.2,21.6,20.7；IR(neat):2960,2927,1677,1483,1456,1356,1275,1261,1168,750,671；HRESIMS Calcd for[C25H23NNaO3S]+(M+Na+)440.1291,found408.1300。
化合物2n:白色固体(mp 92–93℃).1H NMR(400MHz,CDCl3)δ7.81(dd,J＝8.0,1.2Hz,1H),7.50–7.45(m,1H),7.36–7.30(m,1H),7.29–7.21(m,3H),7.19(dd,J＝5.2,1.2Hz,1H),7.10(d,J＝8.0Hz,2H),7.03(dd,J＝5.2,3.6Hz,1H),6.96–6.90(m,1H),4.36(t,J＝8.8Hz,1H),4.21–4.06(m,1H),2.49–2.31(m,4H),2.16–2.06(m,1H),1.86–1.71(m,1H)；13C NMR(100MHz,CDCl3)δ154.9,144.2,139.4,137.3,137.0,132.9,129.1,128.5,127.6,127.4,127.0,126.5,125.4,123.6,123.0,108.3,71.6,39.0,30.2,21.6；IR(neat):2923,1663,1481,1454,1357,1276,1167,754；HRESIMS Calcd for[C22H19NNaO3S2]+(M+Na+)432.0699,found432.0698。
化合物2o:白色固体(mp 141–142℃).1H NMR(400MHz,CDCl3)δ7.82(dd,J＝8.4,1.2Hz,2H),7.75(d,J＝8.8Hz,1H),7.52–7.45(m,1H),7.40–7.28(m,4H),7.23–7.12(m,3H),7.10–7.07(m,1H),4.27(t,J＝8.4Hz,1H),4.15–4.04(m,1H),2.42–2.29(m,4H),2.19–2.09(m,1H),1.81–1.67(m,1H)；13C NMR(100MHz,CDCl3)δ155.4,144.2,139.1,136.8,135.6,133.1,130.1,129.3,129.1,128.4,128.3,127.7,126.4,120.9,111.6,71.1,39.2,29.6,21.6；IR(neat):2924,1662,1596,1474,1359,1168,587；HRESIMS Calcd for[C24H20BrNNaO3S]+(M+Na+)504.0239,found 504.0241。
化合物2p:白色固体(mp 111–112℃).1H NMR(400MHz,CDCl3)δ7.88–7.81(m,2H),7.74(d,J＝8.0Hz,1H),7.40–7.33(m,2H),7.30(d,J＝8.4Hz,2H),7.21–7.07(m,4H),6.74(s,1H),4.25(t,J＝8.4Hz,1H),4.13–4.02(m,1H),2.44–2.25(m,7H),2.18–2.05(m,1H),1.83–1.65(m,1H)；13C NMR(100MHz,CDCl3)δ156.1,143.9,137.1,136.8,136.1,134.9,133.4,129.0,128.3,127.7,127.6,127.1,126.5,126.1,125.9,111.7,71.1,39.3,29.7,21.6,21.0；IR(neat):2923,1656,1598,1492,1355,1167,677,590；HRESIMS Calcd for[C25H23NNaO3S]+(M+Na+)440.1291,found440.1293。
化合物2q:白色固体(mp 90–91℃).1HNMR(400MHz,CDCl3)δ7.85(d,J＝7.6Hz,2H),7.78(d,J＝8.8Hz,1H),7.41–7.33(m,2H),7.30(d,J＝8.0Hz,2H),7.22–7.16(m,1H),7.13(d,J＝8.0Hz,2H),6.87(dd,J＝8.8,2.8Hz,1H),6.45(d,J＝2.8Hz,1H),4.25(t,J＝8.8Hz,1H),4.15–4.02(m,1H),3.79(s,3H),2.42–2.27(m,4H),2.17–2.06(m,1H),1.81–1.66(m,1H)；13C NMR(100MHz,CDCl3)δ158.7,155.9,143.9,138.5,136.0,133.3,130.4,129.1,128.4,128.3,127.7,126.5,126.2,111.9,111.6,111.2,71.1,55.5,39.5,29.7,21.6；IR(neat):2929,1656,1599,1493,1354,1167,757,680,587；HRESIMS Calcd for[C25H23NNaO4S]+(M+Na+)456.1240,found456.1241。
化合物2r:白色固体(mp 174–175℃).1HNMR(400MHz,CDCl3)δ7.89(d,J＝2.0Hz,1H),7.82(d,J＝7.6Hz,2H),7.40–7.33(m,2H),7.31(d,J＝8.0Hz,2H),7.25–7.16(m,2H),7.13(d,J＝8.0Hz,2H),6.86(dd,J＝8.4,0.8Hz,1H),4.25(t,J＝8.8Hz,1H),4.14–4.04(m,1H),2.42–2.30(m,4H),2.17–2.08(m,1H),1.77–1.62(m,1H)；13CNMR(100MHz,CDCl3)δ155.8,144.3,138.6,135.7,135.6,133.1,132.5,129.2,128.2,127.7,127.5,127.4,126.4,126.3,111.4,71.1,39.1,29.7,21.6；IR(neat):2988,1653,1598,1474,1359,1275,1167,764,587；HRESIMS Calcdfor[C24H20ClNNaO3S]+(M+Na+)460.0745,found460.0748。
化合物2s:白色固体(mp 178–179℃).1H NMR(400MHz,CDCl3)δ8.05(d,J＝2.0Hz,1H),7.85–7.78(m,2H),7.41–7.31(m,5H),7.24–7.18(m,1H),7.15(d,J＝8.0Hz,2H),6.82(dd,J＝8.0,0.8Hz,1H),4.28(t,J＝8.8Hz,1H),4.15–4.06(m,1H),2.44–2.33(m,4H),2.17–2.08(m,1H),1.80–1.66(m,1H)；13C NMR(100MHz,CDCl3)δ155.7,144.3,138.9,136.1,135.7,133.2,130.5,130.4,129.3,128.3,127.8,126.6,126.4,120.3,111.5,71.1,39.2,29.7,21.6；IR(neat):2925,1662,1594,1492,1476,1358,1167,765,586；HRESIMSCalcdfor[C24H20BrNNaO3S]+(M+Na+)504.0239,found 504.0240。
化合物2t:白色固体(mp 158–159℃).1H NMR(400MHz,CDCl3)δ7.72(d,J＝7.6Hz,1H),7.35–7.18(m,4H),7.10(d,J＝8.0Hz,2H),6.92(d,J＝7.6Hz,1H),4.20(t,J＝8.4Hz,1H),3.98–3.85(m,1H),2.42–2.28(m,4H),2.14(d,J＝2.0Hz,3H),1.99–1.88(m,1H),1.84–1.69(m,1H)；13C NMR(100MHz,CDCl3)δ154.4,143.7,137.5,136.8,133.3,129.0,128.1,127.3,126.9,126.7,125.5,107.6,69.9,37.4,30.6,21.6,16.3；IR(neat):2960,2923,2893,1711,1597,1482,1453,1352,1276,1165,764,579；HRESIMS Calcd for[C19H19NNaO3S]+(M+Na+)364.0978,found364.0980。
实施例33化合物2aa～2ab的制备
应用实施例
测试了新合成的化合物2a～2t,2aa～2ab作为抗肿瘤剂的生物活性。评估了这些化合物对一组癌细胞的细胞毒性作用，这些细胞包括乳腺癌细胞MDA-MB-231和MCF-7，骨肉瘤癌细胞U2OS，白血病细胞HL-60，淋巴瘤细胞JeKo-1，HepG2细胞和黑色素瘤细胞A375等，通过使用细胞活力测定法，使用市售增殖测定试剂盒(Promega,US)进行。简而言之，将细胞以合适的密度接种在96孔培养板中的培养基中，并使其附着过夜，在按指定的时间和浓度处理对照组(0.1％DMSO作为对照)或测试化合物后，加入20μLMTS反应溶液(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt；MTS(a)和100μg/mL吩嗪硫酸甲酯(phenazine methosulfate)；PES)添加到每个孔中,温育1-4小时后，用分光光度计(Varioskan Flash，Thermo，US)在490nm波长下读取吸光度值。细胞存活率计算为：细胞存活率＝(OD测试化合物-OD空白)/(OD对照-OD空白)*100％。相关结果汇总在表2中。
表2：
表2中所示测试结果为两次试验的平均值。
以上所述实施例仅为本发明的优选实施例，而并非本发明可行实施的穷举。对于本领域技术人员而言，在不背离本发明原理和精神的前提下，对其所作出的任何显而易见的改动，都应当被认为包含在本发明的权利要求保护范围之内。
Claims (1)
1.一种四氢呋喃并1,4-二氢喹啉类化合物在制备抗肿瘤药物中的应用，其特征在于，所述四氢呋喃并1,4-二氢喹啉类化合物具有如下结构：
所述肿瘤选自人胃腺癌细胞BGC-823、人食道癌肿瘤细胞SK-GT-4或人食管癌细胞KYSE450。
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