CN109232557A - 一种9-o-芳基取代小檗碱衍生物的合成和用途 - Google Patents

一种9-o-芳基取代小檗碱衍生物的合成和用途 Download PDF

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CN109232557A
CN109232557A CN201811352564.6A CN201811352564A CN109232557A CN 109232557 A CN109232557 A CN 109232557A CN 201811352564 A CN201811352564 A CN 201811352564A CN 109232557 A CN109232557 A CN 109232557A
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滕巧巧
孟启
朱信辉
蒋卫华
缪春宝
杨海涛
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Changzhou University
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Abstract

本发明提供了一种新型9‑O‑芳基取代小檗碱衍生物5和9‑O‑苯基桥连小檗碱二聚体7的合成方法。以小檗碱1为原料，脱去9号位上的甲基得到小檗红碱2，将2质子化并还原制得四氢小檗红碱3。3和碘代芳烃在氮气保护下进行C‑O交叉偶联反应得到产物4，然后经氧化得到目标9‑O‑芳基取代小檗碱衍生物5。小檗碱二聚体7则是通过3和4o的偶联，氧化得到。本发明的小檗碱衍生物具有脂溶性好、制备方法简单，产率高等优点。通过体外实验发现，此类小檗碱衍生物对金黄色葡萄球菌有较好的抑制作用，因此在抗菌药物领域有着潜在的应用价值。

Description

一种9-O-芳基取代小檗碱衍生物的合成和用途
技术领域
本发明属于有机合成和药物领域，具体涉及9-O-芳基取代小檗碱衍生物的合成方法及其在抗菌方面的应用。
背景技术
小檗碱(BBR)，又名黄连素，常温下为淡黄色粉末。小檗碱是从毛茛科，芸香科和小檗科中提取出的天然生物碱，具有四环异喹啉核心单元，显示出丰富的治疗效力，包括：抗菌[Clin.Microbial.2014,3,150-153]，肿瘤细胞抑制[(a)J.Ethnopharmacol.2015,176,35-48,(b)Mini-Rev.Med.Chem.2016,16,104-119]和各种慢性疾病的治疗[Adv.Exp.Med.Biol.2016,928,27-45]。在大多数情况下，季铵结构被证明是核心功能组分，然而，这种结构却导致BBR的疏脂性增强，使其难以吸收。因此，高剂量BBR的摄入往往为治疗所需，这不但不经济，从长远来看，高剂量给药可能引起不良反应。
为了改善小檗碱的溶解性和生物利用率以提高其生理活性，学者们对小檗碱结构进行了修饰。已有修饰主要集中在N(7)、C(8)、C(9)、C(12)和C(13)等位置，其中，又以C(9)位的修饰最为成熟。因为C(9)修饰可以通过小檗碱脱甲基的产物小檗红碱经亲核取代反应方便制得。通过这种方法，Wu等[Bioorg.Med.Chem.Lett.2013,23,305-309]合成了一系列9-O-烷基或9-O-萜烯基取代的小檗碱衍生物，并评价对了它们对人类癌症细胞HepG2和HT-29的抑制作用。相比于小檗碱，衍生物I对HT-29细胞显示出108倍的抗增值活性，对HepG2细胞则是83倍；衍生物II对HepG2细胞显示出104倍的抗增值活性，对HT-29细胞则是32倍。Mistry等[Res.Chem.Intermediat.2016,42,3241-3256]合成了一系列吲哚修饰的小檗碱衍生物并测试了这些化合物的抗氧化特性，与母体小檗碱相比，III-IV抑制DPPH和ABTS两种自由基氧化的效力大幅度增强。
芳基是一类具有高亲脂性的取代基，然而，它们却很少用于BBR的修饰。据我们所知，迄今只有两个课题组将芳基与C(8)和C12)位偶联。Jiang和Bai等[RSC Adv.2017,7,26921-26929]首先通过小檗碱与液溴反应生成12-溴代小檗碱，然后经钯催化的Suzuki交叉偶联反应合成了一系列12-芳基小檗碱衍生物并研究了他们的生物活性。相比小檗碱母体本身，这些化合物对缺氧诱导因子HIF-1的抑制作用增强，而后者已被证明是众多抗癌剂的靶目标。Iwasa等[J.Nat.Prod.1998,61,1150-1153]合成了8-芳基取代的小檗碱衍生物，它们对金黄色葡萄球菌、枯草芽孢杆菌和肠炎沙门氏菌等的抗菌活性明显高于小檗碱母体。
发明内容
目前，通过在C(9)位引入亲脂性基团是提高小檗碱抗菌活性的较有效的方法之一，主要包括长链的烷烃和氮杂环取代基等。芳烃是另一族已知的亲脂性基团，却从未用于小檗碱的C(9)位结构修饰，原因之一可能是小檗碱结构中的季铵基团使得酚氧阴离子的亲核性减弱，同时卤代芳烃中的C-X键活性较低阻碍了C-O键的生成。本发明通过预先将小檗红碱还原，再通过Cu催化的Ullmann交叉偶联反应实现了C-O键的构建，经温和I2氧化，首次制得了9-O-芳基取代小檗碱衍生物。
本发明合成方法为：以四氢小檗红碱(3)与碘代芳烃为原料，在Cu催化剂、配体、碱存在的条件下，N2保护加热(80-100℃)反应24-48小时，合成9-O-芳基取代四氢小檗碱(4)，再经氧化生成9-O-芳基取代小檗碱(5)，合成路线如下：
其中，芳基包括Ph,2-Me-Ph,3-Me-Ph,4-Me-Ph,3,5-Me-Ph,4-tBu-Ph,4-Ph-Ph,4-OMe-Ph,4-CF3-Ph,4-OCF3-Ph,3-F-Ph,4-F-Ph,4-NO2-Ph,4-COOEt-Ph,4-I-Ph；
4-I-Ph取代的四氢小檗红碱还可与四氢小檗红碱进一步反应生成9-O-苯基桥连四氢小檗碱二聚体(6)，并经氧化制得9-O-苯基桥连小檗碱二聚体(7)，合成路线如下：
四氢小檗红碱的合成方法如下：
(1)、以盐酸小檗碱1为原料，在高温，减压条件下，脱去小檗碱C9-位上的-CH3得到小檗红碱2；
(2)、小檗红碱2先在盐酸/乙醇条件下质子化，再经硼氢化钠还原得到四氢小檗红碱3。
本发明还提供了所述小檗碱衍生物对金黄色葡萄球菌的抑制用途，结果显示，芳基取代基的引入使得该类小檗碱衍生物的抗菌活性普遍提高，其中，4-F-Ph取代小檗碱的最低抑菌浓度低达16μg/ml，与小檗碱母体相比，降低了24μg/ml。
本发明的有益效果：本发明采用还原-偶联-氧化的间接方法首次制得了具有潜在药物活性的9-O-芳基取代小檗碱和9-O-苯基桥连小檗碱二聚体，该方法效率高、底物适用性广，所合成的小檗碱衍生物的抗菌活性明显优于小檗碱母体化合物。基于卤代芳烃的结构多样性和该方法优良的底物适用性，将有望得到生理活性更为优异、药效范围更广的小檗碱衍生物。
附图说明
图1、图2为化合物4a的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图3、图4为化合物4b的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图5、图6为化合物4c的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图7、图8为化合物4d的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图9、图10为化合物4e的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图11、图12为化合物4f的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图13、图14为化合物4g的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图15、图16为化合物4h的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图17、图18为化合物4i的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图19、图20为化合物4j的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图21、图22为化合物4k的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图23、图24为化合物4l的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图25、图26为化合物4m的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图27、图28为化合物4n的1H-NMR(500MHz,CDCl3)谱图和13C-NMR(125MHz,CDCl3)谱图；
图29、图30为化合物4o的1H-NMR(500MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图31、图32为化合物6的1H-NMR(300MHz,CDCl3)谱图和13C-NMR(75MHz,CDCl3)谱图；
图33、图34为化合物5a的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图35、图36为化合物5b的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图37、图38为化合物5c的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图39、图40为化合物5d的1H-NMR(500MHz,DMSO-d6)谱图和13C-NMR(125MHz,DMSO-d6)谱图；
图41、图42为化合物5e的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图43、图44为化合物5f的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图45、图46为化合物5g的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图47、图48为化合物5h的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图49、图50为化合物5i的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图51、图52为化合物5j的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图53、图54为化合物5k的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图55、图56为化合物5l的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图57、图58为化合物5m的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图59、图60为化合物5n的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图61、图62为化合物5o的1H-NMR(300MHz,DMSO-d6)谱图和13C-NMR(75MHz,DMSO-d6)谱图；
图63为化合物4a的1H-NMR(300MHz,DMSO-d6)谱图；
具体实施方式
本发明下面结合实施例作进一步详述：
实施例1
(1)小檗红碱的合成
取5.4mmol的小檗碱，置于圆底烧瓶中，在真空20-30mmHg，190℃条件下加热1h，反应结束冷却至室温，得到4.8mmol小檗红碱2，产率90％，无需纯化直接进行下一步反应。
(2)四氢小檗红碱的合成
取6.0mmol的小檗红碱，置于圆底烧瓶中，加HCl/EtOH(1:10)溶液常温下搅拌1h，反应结束，过滤，烘干，得质子化的四氢小檗红碱，产率95％。取质子化的四氢小檗红碱2.0mmol，置于圆底烧瓶中，加入甲醇使其溶解，然后在水浴下分批加入10.0mmol的NaBH4，加毕，50℃下搅拌过夜，反应结束，过滤，用甲醇洗，乙酸乙酯溶解，减压旋去乙酸乙酯得到灰白色固体3，产率62％。
(3)苯取代四氢小檗碱的合成
取四氢小檗红碱0.7mmol，加入0.7mmol的K2CO3，10％mol的CuI,20％mol的吡啶甲酸和1.4mmol的碘苯，在DMSO，100℃，N2保护下反应24h,反应结束，硅胶柱层析分离得到产物4a。
对所得产物进行表征和测试，所用仪器为：AVANCE 300MHz型核磁共振仪(Bruker公司，TMS为内标)；日本岛津LCMS-2020型质谱仪；SGW X-4显微熔点仪(温度计未经校正)。以下实施例测试方法与本实施例相同。
4a：淡黄色固体，产率72％，mp 144-146℃。1H NMR(300MHz,CDCl3):δ7.28-7.23(m,2H,Ar-H),7.04-6.96(m,2H,Ar-H),6.88-6.84(m,3H,Ar-H),6.73(s,1H,H-1),6.57(s,1H,H-4),5.91(q,2H,J＝1.4Hz,-OCH2O-),4.07(d,1H,J＝15.9Hz,H-8),3.73(s,3H,H-10),3.56-3.51(m,1H,H-14),3.43(d,1H,J＝15.9Hz,H-8),3.31-3.24(m,1H,H-13),3.11-2.98(m,2H,H-6&H-5),2.91-2.82(m,1H,H-5),2.63-2.48(m,2H,H-6&H-13)；13C{1H}NMR(75MHz,CDCl3):δ157.9,150.3,146.2,146.0,139.1,129.5,128.1,127.8,125.7,121.6,114.7,111.1,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.1(10-OCH3),53.7(C-8),51.2(C-6),36.4(C-13),29.5(C-5)；HRMS(ESI):m/z for C25H24NO4 +[M+1]+calcd 402.1700,found402.1704.
(4)9-O-苯基小檗碱的合成
取苯取代四氢小檗碱0.2mmol，加入0.6mmol I2，在DMSO中60℃反应7h，反应结束后抽干溶剂，NaHSO3水溶液(15ml*3)萃取三次，再用蒸馏水萃取三次，干燥，过滤，减压旋去有机溶剂，得到产物5a。以下实施例合成方法与本实施例相同。
5a：黄色固体，产率97％,mp 242-244℃。1H NMR(300MHz,DMSO-d6):δ9.81(s,1H,H-8),9.06(s,1H,H-13),8.31(d,1H,J＝9.2Hz,H-12),8.20(d,1H,J＝9.2Hz,H-11),7.83(s,1H,H-1),7.38-7.33(m,2H,Ar-H),7.13-7.08(m,2H,H-4&Ar-H),6.97-6.94(m,2H,Ar-H),6.18(s,2H,-OCH2O-),4.91(t,2H,J＝6.0Hz,H-6),3.92(s,3H,H-10),3.18(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ158.1,151.3,150.4,148.2,145.1,138.6,137.4,133.9,131.3,130.2,127.2,126.3,123.3,122.4,121.1,120.9,115.9,108.9,105.9,102.6(-OCH2O-),57.5(10-OCH3),55.7(C-6),26.7(C-5)；HRMS(ESI):m/z forC25H20NO4 +[M-I]+calcd 398.1387,found 398.1392.
实施例2
4b：淡黄色固体，产率69％，mp 153-155℃。1H NMR(300MHz,CDCl3):δ7.20(dd,1H,J＝0.8Hz,J＝7.3Hz,Ar-H),7.03-6.96(m,2H,Ar-H),6.91-6.85(m,2H,Ar-H),6.74(s,1H,H-1),6.57(s,1H,H-4),6.44-6.41(m,1H,Ar-H),5.92(q,2H,J＝1.4Hz,-OCH2O-),4.05(d,1H,J＝15.8Hz,H-8),3.72(s,3H,H-10),3.56-3.52(m,1H,H-14),3.43(d,1H,J＝15.8Hz,H-8),3.30-3.24(m,1H,H-13),3.12-3.03(m,2H,H-6&H-5),2.91-2.82(m,1H,H-5),2.64-2.48(m,2H,H-6&H-13)；13C{1H}NMR(75MHz,CDCl3):δ156.0,150.3,146.2,146.0,139.8,130.9,130.7,129.3,128.1,127.8,126.7,126.1,125.4,121.3,112.3,111.3,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.2(10-OCH3),53.6(C-8),51.2(C-6),36.3(C-13),29.4(C-5),16.3(-CH3)；HRMS(ESI):m/z for C26H26NO4 +[M+1]+calcd 416.1856,found 416.1861.
5b：黄色固体，产率84％，mp 252-254℃。1H NMR(300MHz,DMSO-d6):δ9.78(s,1H,H-8),9.07(s,1H,H-13),8.30(d,1H,J＝9.2Hz,H-12),8.20(d,1H,J＝9.2Hz,H-11),7.82(s,1H,H-1),7.35-7.32(m,1H,Ar-H),7.08(s,1H,H-4),7.07-6.97(m,2H,Ar-H),6.44-6.41(m,1H,Ar-H),6.18(s,2H,-OCH2O-),4.93(t,2H,J＝6.0Hz,H-6),3.89(s,3H,H-10),3.20(t,2H,J＝6.0Hz,H-5),2.50(s,3H,-CH3)；13C{1H}NMR(75MHz,DMSO-d6):δ156.0,150.6,149.9,147.7,144.6,138.0,137.5,133.4,131.0,130.8,126.9,126.7,126.3,125.5,122.6,122.0,120.6,120.4,113.2,108.4,105.4,102.1(-OCH2O-),57.1(10-OCH3),55.2(C-6),26.2(C-5),16.2(-CH3)；HRMS(ESI):m/z for C26H22NO4 +[M-I]+calcd 412.1543,found412.1550.
实施例3
4c：淡黄色固体，产率90％，mp 158-160℃。1H NMR(300MHz,CDCl3):δ7.12(t,1H,J＝7.8Hz,Ar-H),7.02(d,1H,J＝8.4Hz,H-11),6.87(d,1H,J＝8.4Hz,H-12),6.80(d,1H,J＝7.5Hz,Ar-H),6.73(s,1H,H-1),6.70-6.69(m,1H,Ar-H),6.62(dd,1H,J＝2.4Hz,J＝8.2Hz,Ar-H),6.57(s,1H,H-4),5.92(q,2H,J＝1.4Hz,-OCH2O-),4.06(d,1H,J＝15.9Hz,H-8),3.74(s,3H,H-10),3.56-3.51(m,1H,H-14),3.43(d,1H,J＝15.9Hz,H-8),3.30-3.24(m,1H,H-13),3.11-2.99(m,2H,H-6&H-5),2.91-2.81(m,1H,H-5),2.62-2.49(m,2H,H-6&H-13)；13C{1H}NMR(75MHz,CDCl3):δ157.9,150.3,146.2,145.9,139.6,139.2,130.7,129.6,129.2,128.1,127.8,125.6,122.4,115.4,111.5,111.2,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.1(10-OCH3),53.7(C-8),51.2(C-6),36.4(C-13),29.5(C-5),21.5(-CH3)；HRMS(ESI):m/z for C26H26NO4 +[M+1]+calcd 416.1856,found 416.1862.
5c：黄色固体，产率93％，mp 239-241℃。1H NMR(300MHz,DMSO-d6):δ9.77(s,1H,H-8),9.07(s,1H,H-13),8.31(d,1H,J＝9.2Hz,H-12),8.21(d,1H,J＝9.2Hz,H-11),7.82(s,1H,H-1),7.21(t,1H,J＝15.8Hz,Ar-H),7.08(s,1H,H-4),6.91(d,1H,J＝7.5Hz,Ar-H),6.80(s,1H,Ar-H),6.70(dd,1H,J＝2.5Hz,J＝8.2Hz,Ar-H),6.18(s,2H,-OCH2O-),4.92(t,2H,J＝6.0Hz,H-6),3.92(s,3H,H-10),3.19(t,2H,J＝6.0Hz,H-5),2.27(s,3H,-CH3)；13C{1H}NMR(75MHz,DMSO-d6):δ157.7,150.8,149.9,147.7,144.5,139.4,138.0,136.9,133.3,130.8,129.4,126.7,125.7,123.5,122.0,120.6,120.3,115.9,112.3,108.4,105.4,102.1(-OCH2O-),57.0(10-OCH3),55.2(C-6),26.2(C-5),21.0(-CH3)；HRMS(ESI):m/z forC26H22NO4 +[M-I]+calcd 412.1543,found 412.1548.
实施例4
4d：淡黄色固体，产率88％，mp 142-144℃。1H NMR(300MHz,CDCl3):δ7.06-7.00(m,3H,H-11&Ar-H),6.86(d,1H,J＝8.4,H-12),6.75-6.73(m,3H,H-1&Ar-H),6.57(s,1H,H-4),5.91(q,2H,J＝1.4Hz,-OCH2O-),4.07(d,1H,J＝15.9Hz,H-8),3.73(s,3H,H-10),3.55-3.50(m,1H,H-14),3.42(d,1H,J＝15.9Hz,H-8),3.30-3.23(m,1H,H-13),3.12-3.02(m,2H,H-6&H-5),2.90-2.81(m,1H,H-5),2.63-2.48(m,2H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ155.9,150.4,146.1,146.0,139.4,130.8,130.7,129.9,129.6,128.1,127.8,125.6,114.4,111.2,108.4,105.5,100.8(-OCH2O-),59.6(C-14),56.1(10-OCH3),53.7(C-8),51.2(C-6),36.4(C-13),29.5(C-5),20.6(-CH3)；HRMS(ESI):m/z for C26H26NO4 +[M+1]+calcd416.1856,found 416.1859.
5d：黄色固体，产率98％，mp 257-259℃。1H NMR(500MHz,DMSO-d6):δ9.77(s,1H,H-8),9.05(s,1H,H-13),8.30(d,1H,J＝9.2Hz,H-12),8.19(d,1H,J＝9.2Hz,H-11),7.83(s,1H,H-1),7.14(d,2H,J＝8.4Hz,Ar-H),7.08(s,1H,H-4),6.84(d,2H,J＝8.6Hz),6.18(s,2H,-OCH2O-),4.91(t,2H,J＝6.0Hz,H-6),3.92(s,3H,H-10),3.18(t,2H,J＝6.0Hz,H-5),2.27(s,3H,-CH3)；13C{1H}NMR(125MHz,DMSO-d6):δ155.6,150.8,149.8,147.6,144.5,138.0,137.1,133.3,131.6,130.7,129.9,126.6,125.6,121,9,120.5,120.3,115.2,108.3,105.4,102.0(-OCH2O-),56.9(10-OCH3),55.1(C-6),26.1(C-5),20.0(-CH3)；HRMS(ESI):m/z for C26H22NO4 +[M-I]+calcd 412.1543,found 412.1552.
实施例5
4e：淡黄色固体，产率87％，mp 193-195℃。1H NMR(300MHz,CDCl3):δ7.02(d,1H,J＝8.4Hz,H-11),6.87(d,1H,J＝8.4Hz,H-12),6.74(s,1H,H-1),6.63(s,1H,Ar-H),6.57(s,1H,H-4),6.47(s,2H,Ar-H),5.92(q,2H,J＝1.4Hz,-OCH2O-),4.07(d,1H,J＝15.9Hz,H-8),3.74(s,3H,H-10),3.57-3.52(m,1H,H-14),3.45(d,1H,J＝15.9Hz,H-8),3.31-3.25(m,1H,H-13),3.12-2.98(m,2H,H-6&H-5),2.92-2.83(m,1H,H-5),2.64-2.49(m,2H,H-13&H-6),2.25(s,6H,-CH3)；13C{1H}NMR(75MHz,CDCl3):δ157.9,150.4,146.2,146.0,139.3,139.2,130.7,129.6,128.0,127,8,125,5,123.5,112.3,111.2,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.2(10-OCH3),53.7(C-8),51.2(C-6),36.4(C-13),29.4(C-5),21.4(-CH3)；HRMS(ESI):m/z for C27H28NO4 +[M+1]+calcd 430.2013,found 430.2017.
5e：黄色固体，产率99％，mp 251-253℃。1H NMR(300MHz,DMSO-d6):δ9.74(s,1H,H-8),9.06(s,1H,H-13),8.31(d,1H,J＝9.2Hz,H-12),8.20(d,1H,J＝9.2Hz,H-11),7.82(s,1H,H-1),7.08(s,1H,H-4),6.73(s,1H,Ar-H),6.54(s,1H,Ar-H),6.18(s,2H,-OCH2O-),4.91(t,2H,J＝6.0Hz,H-6),3.93(s,3H,H-10),3.18(t,2H,J＝6.0Hz,H-5),2.21(s,6H,-CH3)；13C{1H}NMR(75MHz,DMSO-d6):δ157.8,150.9,149.9,147.7,144.6,139.0,138.0,137.0,133.4,130.9,126.8,125.7,124.4,122.0,120.7,120.4,112.9,108.4,105.5,102.2(-OCH2O-),57.0(10-OCH3),55.3(C-6),26.2(C-5),20.9(-CH3)；HRMS(ESI):m/z forC27H24NO4 +[M-I]+calcd 426.1700,found 426.1708.
实施例6
4f：黄色固体，产率86％，mp 153-155℃。1H NMR(300MHz,CDCl3):δ7.27-7.22(m,2H,Ar-H),7.01(d,1H,J＝8.4Hz,H-11),6.86(d,1H,J＝8.4Hz,H-12),6.79-6.75(m,2H,Ar-H),6.73(s,1H,H-1),6.57(s,1H,H-4),6.47(s,2H,Ar-H),5.91(q,2H,J＝1.4Hz,-OCH2O-),4.07(d,1H,J＝15.9Hz,H-8),3.74(s,3H,H-10),3.56-3.51(m,1H,H-14),3.43(d,1H,J＝15.9Hz,H-8),3.30-3.23(m,1H,H-13),3.11-3.03(m,2H,H-6&H-5),2.90-2.81(m,1H,H-5),2.63-2.47(m,2H,H-13&H-6),1.29(s,9H,-CH3)；13C{1H}NMR(75MHz,CDCl3):δ155.6,150.4,146.1,145.9,144.1,139.5,130.7,129.6,128.0,127.8,126.2,125.5,114.0,111.2,108.4,105.5,100.8(-OCH2O-,59.5(C-14),56.2(10-OCH3),53.7(C-8),51.2(C-6),36.4(C-13),34.1(-C(CH3)3),31.6(-CH3),29.5(C-5)；HRMS(ESI):m/z for C29H32NO4 +[M+1]+calcd458.2326,found 458.2332.
5f：为黄色固体，产率99％，mp 236-238℃。1H NMR(300MHz,DMSO-d6):δ9.77(s,1H,H-8),9.06(s,1H,H-13),8.31(d,1H,J＝9.2Hz,H-12),8.21(d,1H,J＝9.2Hz,H-11),7.82(s,1H,H-1),7.35(d,2H,J＝8.7Hz,Ar-H),7.07(s,1H,H-4),6.86(d,2H,J＝8.7Hz,Ar-H),6.18(s,2H,-OCH2O-),4.91(t,2H,J＝6.0Hz,H-6),3.94(s,3H,H-10),3.18(t,2H,J＝6.0Hz,H-5),1.26(s,9H,-CH3)；13C{1H}NMR(75MHz,DMSO-d6):δ155.5,151.0,149.9,147.7,144.9,144.6,138.1,137.0,133.4,130.9,126.6,126.4,125.8,122.1,120.6,120.4,114.8,108.4,105.5,102.1(-OCH2O-),57.1(10-OCH3),55.3(C-6),34.0(-C(CH3)3),31.3(-CH3),26.2(C-5)；HRMS(ESI):m/z for C29H28NO4 +[M-I]+calcd 454.2013,found 454.2020.
实施例7
4g：淡黄色固体，产率58％，mp 169-171℃。1H NMR(300MHz,CDCl3):δ7.56-7.53(m,2H,Ar-H),7.50-7.47(m,2H,Ar-H),7.40-7.38(m,2H,Ar-H),7.32-7.29(m,1H,Ar-H),7.05(d,1H,J＝8.4Hz,H-11),6.93-6.88(m,3H,H-12&Ar-H),6.74(s,1H,H-1),6.57(s,1H,H-4),5.92(q,2H,-OCH2O-),4.10(d,1H,J＝15.9Hz,H-8),3.76(s,3H,H-10),3.57-3.53(m,1H,H-14),3.47(d,1H,J＝15.9Hz,H-8),3.32-3.26(m,1H,H-13),3.12-3.00(m,2H,H-6&H-5),2.92-2.83(m,1H,H-5),2.65-2.49(m,2H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ157.6,150.3,146.2,146.0,140.7,139.2,134.7,130.6,129.5,128.7,128.2,128.1,127.8,126.8,126.7,125.8,115.0,111.2,108.4,105.5,100.8(-OCH2O-),59.6(C-14),56.2(10-OCH3),53.8(C-8),51.3(C-6),36.5(C-13),29.6(C-5)；HRMS(ESI):m/z for C31H28NO4 +[M+1]+calcd 478.2013,found 478.2016.
5g：黄色固体，产率95％，mp 222-224℃。1H NMR(300MHz,DMSO-d6):δ9.83(s,1H,H-8),9.08(s,1H,H-13),8.34(d,1H,J＝9.2Hz,H-12),8.23(d,1H,J＝9.2Hz,H-11),7.83(s,1H,H-1),7.63(t,4H,J＝14.7Hz,Ar-H),7.45(t,2H,J＝7.5Hz,Ar-H),7.34(t,1H,J＝7.3Hz,Ar-H),7.05(t,3H,J＝8.7Hz,H-4&Ar-H),6.18(s,2H,-OCH2O-),4.93(t,2H,J＝6.0Hz,H-6),3.96(s,3H,H-10),3.19(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ157.3,150.9,150.0,147.7,144.6,139.5,138.2,136.8,134.9,133.4,133.4,130.9,128.9,128.0,127.1,126.6,126.4,126.0,122.0,120.7,120.4,115.9,108.4,105.5,102.2(-OCH2O-),57.1(10-OCH3),55.3(C-6),26.2(C-5)；HRMS(ESI):m/z for C31H24NO4 +[M-I]+calcd 474.1700,found 474.1708.
实施例8
4h：淡黄色固体，产率86％，mp 136-138℃。1H NMR(300MHz,CDCl3):δ7.01(d,1H,J＝8.4,H-11),6.86(d,1H,J＝8.4Hz,H-12),6.78(s,4H,Ar-H),6.73(s,1H,H-1),6.57(s,1H,H-4),5.91(q,2H,-OCH2O-),4.08(d,1H,J＝15.9Hz,H-8),3.76(s,3H,H-10),3.74(s,3H,-OCH3),3.56-3.51(m,1H,H-14),3.42(d,1H,J＝15.9Hz,H-8),3.30-3.23(m,1H,H-13),3.12-2.98(m,2H,H-6&H-5),2.90-2.81(m,1H,H-5),2.63-2.48(m,2H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ154.3,152.1,150.4,146.2,146.0,139.7,130.6,129.6,128.1,127.8,125.5,115.4,114.6,111.2,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.1(10-OCH3),55.7(-OCH3),53.7(C-8),51.2(C-6),36.3(C-13),29.4(C-5)；HRMS(ESI):m/z forC26H26NO5 +[M+1]+calcd 432.1805,found 432.1812.
5h：黄色固体，产率95％，mp 226-228℃。1H NMR(300MHz,DMSO-d6):δ9.80(s,1H,H-8),9.05(s,1H,H-13),8.30(d,1H,J＝9.2Hz,H-12),8.18(d,1H,J＝9.2Hz,H-11),7.82(s,1H,H-1),7.08(s,1H,H-4),6.90(s,4H,Ar-H),6.18(s,2H,-OCH2O-),4.92(t,2H,J＝6.0Hz,H-6),3.91(s,3H,H-10),3.72(s,3H,-OCH3),3.19(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ155.3,152.2,151.3,150.4,148.2,145.2,138.5,138.3,133.8,131.3,127.2,126.0,122.5,121.1,120.9,117.0,115.1,108.9,105.9,102.6(-OCH2O-),57.5(10-OCH3),56.0(-OCH3),55.7(C-6),26.7(C-5)；HRMS(ESI):m/z for C26H22NO5 +[M-I]+calcd428.1492,found 428.1495.
实施例9
4i：黄色固体，产率92％，mp 161-163℃。1H NMR(300MHz,CDCl3):δ7.51(d,2H,J＝8.5Hz,Ar-H),7.06(d,1H,J＝8.4Hz,H-11),6.93-6.87(m,3H,H-12&Ar-H),6.73(s,1H,H-1),6.57(s,1H,H-4),5.91(q,2H,-OCH2O-),4.02(d,1H,J＝15.9Hz,H-8),3.73(s,3H,H-10),3.56-3.51(m,1H,H-14),3.42(d,1H,J＝15.9Hz,H-8),3.31-3.24(m,1H,H-13),3.12-3.02(m,2H,H-6&H-5),2.90-2.82(m,1H,H-5),2.64-2.50(m,2H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ160.4,149.9,146.2,146.2,138.4,130.5,129.3,128.3,127.7,127.0,127.0,126.2,114.8,111.1,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.0(10-OCH3),53.6(C-8),51.2(C-6),36.3(C-13),29.4(C-5)；HRMS(ESI):m/z for C26H23F3NO4 +[M+1]+calcd 470.1574,found 470.1588.
5i：黄色固体，产率96％，mp 273-275℃。1H NMR(300MHz,DMSO-d6):δ9.83(s,1H,H-8),9.09(s,1H,H-13),8.35(d,1H,J＝9.2Hz,H-12),8.25(d,1H,J＝9.2Hz,H-11),7.82(s,1H,H-1),7.73(d,2H,J＝8.6Hz,Ar-H),7.16(d,2H,J＝8.46Hz,Ar-H),7.08(s,2H,H-4),6.18(s,2H,-OCH2O-),4.91(t,2H,J＝6.0Hz,H-6),3.95(s,3H,H-10),3.19(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ160.1,150.7,150.0,147.7,144.4,138.2,135.8,133.4,130.8,127.22,127.17,126.5,126.4,121.6,120.6,120.3,116.2,108.4,105.5,102.1(-OCH2O-),57.1(10-OCH3),55.3(C-6),26.1(C-5)；HRMS(ESI):m/z forC26H19F3NO4 +[M-I]+calcd 466.1261,found 466.1273.
实施例10
4j：淡黄色固体，产率82％，mp 119-121℃。1H NMR(300MHz,CDCl3):δ7.11-7.02(m,3H,H-11&Ar-H),6.88-6.82(m,3H,H-12&Ar-H),6.73(s,1H,H-1),6.57(s,1H,H-4),5.91(q,2H,J＝1.4Hz,-OCH2O-),4.03(d,1H,J＝15.9Hz,H-8),3.74(s,3H,H-10),3.56-3.51(m,1H,H-14),3.43(d,1H,J＝15.9Hz,H-8),3.30-3.24(m,1H,H-13),3.10-2.99(m,2H,H-6&H-5),2.90-2.81(m,1H,H-5),2.64-2.49(m,2H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ156.3,150.0,146.2,146.0,143.4,138.9,130.5,129.4,128.2,127.7,126.0,122.4,122.2,115.5,111.1,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.0(10-OCH3),53.6(C-8),51.2(C-6),36.3(C-13),29.4(C-5)；HRMS(ESI):m/z for C26H23F3NO5 +[M+1]+calcd 486.1523,found 486.1531.
5j：黄色固体，产率98％，mp 246-248℃。1H NMR(300MHz,DMSO-d6):δ9.84(s,1H,H-8),9.07(s,1H,H-13),8.33(d,1H,J＝9.2Hz,H-12),8.23(d,1H,J＝9.2Hz,H-11),7.83(s,1H,H-1),7.37(d,2H,J＝8.0Hz,Ar-H),7.07(d,3H,J＝8.0Hz,Ar-H),6.18(s,2H,-OCH2O-),4.91(t,2H,J＝6.0Hz,H-6),3.94(s,3H,H-10),3.19(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ156.2,150.7,150.0,147.7,144.6,143.3,138.2,136.5,133.4,130.9,126.6,126.2,122.7,121.8,120.6,120.3,117.0,108.4,105.5,102.2(-OCH2O-),57.1(10-OCH3),55.3(C-6),26.2(C-5)；HRMS(ESI):m/z for C26H19F3NO5 +[M-I]+calcd 482.1210,found 482.1221.
实施例11
4k：淡黄色固体，产率84％，mp 106-108℃。1H NMR(300MHz,CDCl3):δ7.23-7.16(m,1H,Ar-H),7.04(d,1H,J＝8.4Hz,H-11),6.87(d,1H,J＝8.4Hz,H-12),6.73-6.64(m,3H,H-1&Ar-H),6.58-6.53(m,2H,H-4&Ar-H),5.92(q,2H,J＝1.4Hz,-OCH2O-),4.04(d,1H,J＝15.9Hz,H-8),3.75(s,3H,H-10),3.56-3.51(m,1H,H-14),3.42(d,1H,J＝15.9Hz,H-8),3.30-3.24(m,1H,H-13),3.12-2.99(m,2H,H-6&H-5),2.90-2.81(m,1H,H-5),2.64-2.48(m,2H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ,159.2(d,J＝10.7Hz),150.1,146.2,146.0,138.7,130.5,130.2(d,J＝9.8Hz),129.4,128.2,127.8,126.1,111.1,110.5(d,J＝2.9Hz),108.7,108.4(d,J＝4.3Hz),105.5,102.8,102.4,100.8(-OCH2O-),59.5(C-14),56.0(10-OCH3),53.6(C-8),51.2(C-6),36.3(C-13),29.4(C-5)；HRMS(ESI):m/z forC25H23FNO4 +[M+1]+calcd 420.1606,found 420.1613.
5k：黄色固体，产率99％，mp 220-222℃。1H NMR(300MHz,DMSO-d6):δ9.81(s,1H,H-8),9.07(s,1H,H-13),8.32(d,1H,J＝9.2Hz,H-12),8.23(d,1H,J＝9.2Hz,H-11),7.83(s,1H,H-1),7.43-7.35(m,1H,Ar-H),7.09(s,1H,H-4),7.00-6.92(m,1H,Ar-H),6.87-6.80(m,2H,Ar-H),6.18(s,2H,-OCH2O-),4.91(t,2H,J＝6.0Hz,H-6),3.95(s,3H,H-10),3.19(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ162.2,158.8(d,J＝10.9Hz),150.8,150.0,147.7,144.5,138.2,136.3,133.4,131.0(d,J＝16.0Hz),130.9,126.6,126.2,121.8,120.7,120.3,111.8,109.7(d,J＝20.9Hz),108.4,105.5,103.5(d,J＝25.3Hz),102.2(-OCH2O-),57.1(10-OCH3),55.3(C-6),26.2(C-5)；HRMS(ESI):m/z for C25H19FNO4 +[M-I]+calcd 416.1293,found 416.1296.
实施例12
4l：淡黄色固体，产率84％，mp 129-131℃。1H NMR(300MHz,CDCl3):δ7.02(d,1H,J＝8.4Hz,H-11),6.96-6.90(m,2H,Ar-H),6.86(d,1H,J＝8.4Hz,H-12),6.81(m,2H,Ar-H),6.73(s,1H,H-1),6.57(s,1H,H-4),5.92(q,2H,J＝1.4Hz,-OCH2O-),4.05(d,1H,J＝15.9Hz,H-8),3.73(s,3H,H-10),3.56-3.51(m,1H,H-14),3.42(d,1H,J＝15.9Hz,H-8),3.30-3.23(m,1H,H-13),3.12-2.98(m,2H,H-6&H-5),2.90-2.81(m,1H,H-6),2.64-2.48(m,2H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ154.0,150.2,146.2,146.0,139.4,130.6,129.5,128.2,127.8,125.8,116.0,115.7,115.6,111.2,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.1(10-OCH3),53.7(C-8),51.2(C-6),36.4(C-13),29.4(C-5)；HRMS(ESI):m/z for C25H23FNO4 +[M+1]+calcd 420.1606,found 420.1610.
5l：黄色固体，产率97％，mp 232-234℃。1H NMR(300MHz,DMSO-d6):δ9.83(s,1H,H-8),9.06(s,1H,H-13),8.31(d,1H,J＝9.2Hz,H-12),8.20(d,1H,J＝9.2Hz,H-11),7.83(s,1H,H-1),7.19(t,2H,J＝8.9Hz,Ar-H),7.09(s,1H,H-4),7.02-6.98(m,2H,Ar-H),6.18(s,2H,-OCH2O-),4.92(t,2H,J＝6.0Hz,H-6),3.92(s,3H,H-10),3.19(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ157.7(d,J＝236.5Hz),153.9,150.7,149.9,147.7,144.6,138.1,137.2,133.3,130.8,126.7,125.8,121.9,120.6,120.3,117.1(d,J＝8.2Hz),116.6(d,J＝23.3Hz),108.4,105.5,102.1(-OCH2O-),57.0(10-OCH3),55.2(C-6),26.2(C-5)；HRMS(ESI):m/z for C25H19FNO4 +[M-I]+calcd 416.1293,found 416.1299.
实施例13
4m：棕黄色固体，产率80％，mp 182-184℃。1H NMR(300MHz,CDCl3):δ8.20-8.14(m,2H,Ar-H),7.08(d,1H,J＝8.4Hz,H-11),6.94-6.88(m,3H,H-12&Ar-H),6.73(s,1H,H-1),6.57(s,1H,H-4),5.92(q,2H,J＝1.4Hz,-OCH2O-),3.99(d,1H,J＝15.8Hz,H-8),3.73(s,3H,H-10),3.57-3.52(m,1H,H-14),3.43(d,1H,J＝15.8Hz,H-8),3.32-3.25(m,1H,H-13),3.12-2.98(m,2H,H-6&H-5),2.91-2.82(m,1H,H-5),2.64-2.50(m,2H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ162.9,149.5,146.2,146.1,142.4,138.1,130.3,129.0,128.4,127.7,126.7,126.0,115.0,111.1,108.4,105.4,100.8(-OCH2O-),59.5(C-14),56.0(10-OCH3),53.5(C-8),51.3(C-6),36.3(C-13),29.4(C-5)；HRMS(ESI):m/z for C25H23N2O6 +[M+1]+calcd 447.1551,found 447.1557.
5m：棕黄色固体，产率80％，mp 245-247℃。1H NMR(300MHz,DMSO-d6):δ9.87(s,1H,H-8),9.10(s,1H,H-13),8.37(d,1H,J＝9.2Hz,H-12),8.29-8.24(m,3H,H-11&Ar-H),7.83(s,1H,H-1),7.23-7.17(m,2H,Ar-H),7.09(s,1H,H-4),6.18(s,2H,-OCH2O-),4.90(t,2H,J＝6.0Hz,H-6),3.96(s,3H,H-10),3.19(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ162.1,150.5,150.0,147.7,144.4,142.6,138.3,135.4,133.4,130.9,126.7,126.5,125.9,121.4,120.7,120.3,116.4,108.4,105.5,102.2(-OCH2O-),57.1(10-OCH3),55.3(C-6),26.1(C-5)；HRMS(ESI):m/z for C25H19N2O6 +[M-I]+calcd 443.1238,found 443.1247.
实施例14
4n：淡黄色固体，产率87％，mp 124-126℃。1H NMR(300MHz,CDCl3):δ7.99-7.94(m,2H,Ar-H),7.05(d,1H,J＝8.4Hz,H-11),6.89-6.86(m,3H,H-12&Ar-H),6.73(s,1H,H-1),6.56(s,1H,H-4),5.91(q,2H,J＝1.4Hz,-OCH2O-),4.33(q,2H,J＝7.1Hz,-CH2-),4.02(d,1H,J＝15.9Hz,H-8),3.72(s,3H,H-10),3.55-3.50(m,1H,H-14),3.41(d,1H,J＝15.9Hz,H-8),3.30-3.24(m,1H,H-13),3.11-2.98(m,2H,H-6&H-5),2.90-2.81(m,1H,H-5),2.63-2.48(m,2H,H-13&H-6),1.36(t,3H,J＝7.1Hz,-CH3)；13C{1H}NMR(75MHz,CDCl3):δ166.4,161.7,150.0,146.3,146.1,138.6,131.7,130.6,129.3,128.3,127.8,126.2,124.1,114.6,111.2,108.5,105.6,100.9(-OCH2O-),60.8(-CH2-),59.6(C-14),56.1(10-OCH3),53.7(C-8),51.3(C-6),36.4(C-13),29.8(-CH3),29.5(C-5),14.5；HRMS(ESI):m/z for C28H28NO6 +[M+1]+calcd 474.1911,found 474.1919.
5n：黄色固体，产率75％，mp 258-260℃。1H NMR(300MHz,DMSO-d6):δ9.84(s,1H,H-8),9.08(s,1H,H-13),8.34(d,1H,J＝9.2Hz,H-12),8.24(d,1H,J＝9.2Hz,H-11),7.96(d,2H,J＝8.7Hz,Ar-H),7.83(s,1H,H-1),7.08(s,2H,Ar-H),7.06(s,1H,H-4),6.18(s,2H,-OCH2O-),4.90(t,2H,J＝6.0Hz,H-6),4.30(q,2H,J＝6.9Hz,-CH2-),3.93(s,3H,H-10),3.19(t,2H,J＝6.0Hz,H-5),1.30(t,3H,J＝14.2Hz)；13C{1H}NMR(75MHz,DMSO-d6):δ165.1,161.0,150.6,150.0,147.7,144.5,138.2,136.0,133.4,131.2,130.9,126.6,126.3,124.5,121.6,120.6,120.3,115.7,108.4,105.5,102.1(-OCH2O-),60.6(-CH2-),57.0(10-OCH3),55.3(C-6),26.2(C-5),14.2(-CH3)；HRMS(ESI):m/z for C28H24NO6 +[M-I]+calcd470.1598,found 470.1605.
实施例15
4o：淡黄色固体，产率87％，mp 182-184℃。1H NMR(500MHz,CDCl3):δ7.53-7.50(m,2H,Ar-H),7.03(d,1H,J＝8.4Hz,H-11),6.86(d,1H,J＝8.4Hz,H-12),6.73(s,1H,H-1),6.64-6.61(m,2H,Ar-H),6.57(s,1H,H-4),5.92(q,2H,J＝1.4Hz,-OCH2O-),4.02(d,1H,J＝15.9Hz,H-8),3.73(s,3H,H-10),3.55-3.52(m,1H,H-14),3.41(d,1H,J＝15.9Hz,H-8),3.29-3.25(m,1H,H-13),3.10-3.03(m,2H,H-6&H-5),2.89-2.83(m,1H,H-5),2.63-2.51(m,2H,H-13&H-6)；13C{1H}NMR(125MHz,CDCl3):δ158.0,150.1,146.3,146.1,138.8,138.4,130.6,129.4,128.2,127.8,117.2,111.2,108.5,105.5,100.9(-OCH2O-),84.0,59.6(C-14),56.1(10-OCH3),53.6(C-8),51.3(C-6),36.4(C-13),29.5(C-5)；HRMS(ESI):m/z forC25H23INO4 +[M+1]+calcd 528.0666,found 528.0672.
5o：黄色固体，产率81％，mp 250-252℃。1H NMR(300MHz,DMSO-d6):δ9.79(s,1H,H-8),9.06(s,1H,H-13),8.31(d,1H,J＝9.2Hz,H-12),8.21(d,1H,J＝9.2Hz,H-11),7.82(s,1H,H-1),7.66(d,2H,J＝8.9Hz,Ar-H),7.08(s,1H,H-4),6.80(d,2H,J＝8.9Hz,Ar-H),6.18(s,2H,-OCH2O-),4.90(t,2H,J＝6.0Hz,H-6),3.93(s,3H,H-10),3.18(t,2H,J＝6.0Hz,H-5)；13C{1H}NMR(75MHz,DMSO-d6):δ157.6,150.7,150.0,147.7,144.5,138.2,136.4,133.4,130.9,126.6,126.1,121.7,120.6,120.3,118.2,108.4,105.5,102.2(-OCH2O-),86.2,57.1(10-OCH3),55.3(C-6),26.2(C-5)；HRMS(ESI):m/z for C25H19INO4 +[M-I]+calcd524.0353,found 524.0361.
实施例16
取0.75mmol四氢小檗红碱，0.5mmol化合物4o，10％mol的CuI,20％mol的吡啶甲酸，在DMSO，100℃，N2保护下反应60h,结束反应，硅胶柱层析分离得到产物6。
6：黄色固体，产率60％，mp 293-295℃。1H NMR(300MHz,CDCl3):δ6.99(d,2H,J＝8.4Hz,H-11),6.88-6.77(m,3H,H-12&Ar-H),6.73-6.72(m,5H,Ar-H),6.58(d,2H,J＝6.5Hz,Ar-H),5.91(s,4H,-OCH2O-),4.24,4.07(d,2H,0.5:1.5,H-8),3.85,3.74(s,6H,2.2:4.4,-OCH3),3.55-3.51(m,2H,H-14),3.45-3.39(m,2H,H-8),3.28-3.17(m,2H,H-13),3.12-3.03(m,4H,H-6&H-5),2.88-2.77(m,2H,H-5),2.68-2.49(m,4H,H-13&H-6)；13C{1H}NMR(75MHz,CDCl3):δ152.6,150.4,146.1,145.9,139.8,139.7,130.7,129.5,128.1,127.8,125.5,115.5,111.1,108.4,105.5,100.8(-OCH2O-),59.5(C-14),56.1(10-OCH3),53.8(C-8),51.3(C-6),36.4(C-13),29.5(C-5)；HRMS(ESI):m/z for C44H41N2O8 +[M+1]+calcd 725.2857,found 725.2861.
7：黄色固体，产率68％，mp＞300℃。1H NMR(300MHz,DMSO-d6):δ9.85(s,2H,H-8),9.06(s,2H,H-13),8.31(d,2H,J＝9.2Hz,H-12),8.22(d,2H,J＝9.2Hz,H-11),7.83(s,2H,H-1),7.10(s,2H,H-4),6.95(s,4H,Ar-H),6.18(s,4H,-OCH2O-),4.92(t,4H,J＝6.0Hz,H-6),3.93(s,6H,H-10),3.19(t,4H,J＝6.0Hz,H-5)；由于溶解性不佳，碳谱出峰不明显。HRMS(ESI):m/z for C44H34N2O8 2+[M-2I]2+calcd 359.1152,found 359.1159.
实施例17本发明部分化合物的抗菌活性研究
按照本发明实施例1的方法制备的9-O-芳基取代的小檗碱衍生物的体外抗菌药效评估如下：
(1)实验菌种
金黄色葡萄球菌(S.aureus)
(2)实验方法
挑选一个S.aureus菌落于10mL的TSB中，37℃，250rmp摇床中过夜培养，取上述菌液100μL置于新的5mL TSB中传代6小时(37℃，180rmp摇床)。传代后的菌液继续用TSB稀释50倍，测OD600大约为0.1，备用。将样品5a，5l，5i，7，BBR用去离子水分别稀释成20μg/mL-200μg/mL的溶液，间隔10μg/mL。取稀释后的菌液1mL与样品250μL共同孵育1小时(37℃，250rmp摇床)，对照为稀释后的菌液加水，孵育后将样品稀释103倍,取100μL均匀涂抹于TSA平板上，放置于生化培养箱中37℃，培养24小时。观察细菌生长情况，记录MIC和MBC值。
(3)实验结果
实验结果如下表所示：
由表可知：经过结构改造后的化合物5a，5l，5i，7的MIC和MBC值均低于小檗碱母体化合物，其中带有4-氟苯取代基的小檗碱衍生物5l的综合抗菌效果最好。

Claims (7)

1.一种9-O-芳基取代小檗碱衍生物的合成方法，其特征在于：所述合成方法包括以下步骤：
(1)以盐酸小檗碱1为原料，在高温，减压条件下，脱去小檗碱C9-位上的CH3得到小檗红碱2，无需纯化直接用于下一步反应：
(2)小檗红碱2先在盐酸/乙醇条件下质子化，再经硼氢化钠还原得到四氢小檗红碱3：
(3)四氢小檗红碱3在Ullmann反应条件下和碘代芳烃偶联得到四氢小檗碱的芳基衍生物4：
(4)9-O-芳基四氢小檗碱4在碘的氧化下，得到9-O-芳基取代的小檗碱衍生物5：
2.根据权利要求1所述的合成方法，特征在于：步骤(3)中所用的溶剂DMF、DMA、DMSO、1,4-二氧六环。
3.根据权利要求1所述的合成方法，特征在于：步骤(3)中所用的Cu催化剂为CuI、CuBr、CuCl、CuSO4、CuCl2·2H2O、CuCl2、Cu(OAc)2，用量为四氢小檗红碱的5％-15％。
4.根据权利要求1所述的合成方法，特征在于：步骤(3)中所用的配体为8-羟基喹啉、联吡啶、邻菲啰啉、吡啶甲酸、DL-脯氨酸、4-二甲氨基吡啶，用量为四氢小檗红碱的10％-20％。
5.根据权利要求1所述的合成方法，特征在于：步骤(3)中所用的碱为K3PO4·3H2O、K2CO3、CS2CO3，用量为四氢小檗红碱的1-1.5倍。
6.根据权利要求1所述的合成方法，特征在于：步骤(4)中碘的用量为1-5eq。
7.根据权利要求1所述的合成方法，特征在于：步骤(3)中的碘代芳烃若为4-I-Ph取代的四氢小檗碱，则产物为9-O-苯基桥连小檗碱二聚体，其结构式为：
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114028391A (zh) * 2021-09-30 2022-02-11 哈尔滨医科大学 四氢小檗红碱用于制备激活棕色脂肪活化和白色脂肪棕色化的药物的用途
CN114057723A (zh) * 2021-11-25 2022-02-18 四川大学 一种13-甲基小檗碱类生物碱的合成方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1827618A (zh) * 2005-03-04 2006-09-06 周桂华 一类异喹啉衍生物、制备方法及用途
WO2009002873A1 (en) * 2007-06-22 2008-12-31 Cvi Pharmaceuticals Limited Compounds, compositions and methods for reducing lipid levels
WO2011006000A1 (en) * 2009-07-08 2011-01-13 Haiyan Liu Berberine derivatives useful for modulating lipid levels and their methods of synthesis
CN102256973A (zh) * 2008-12-23 2011-11-23 Cvi制药有限公司 用于降低脂类水平的紫堇碱衍生物
CN104208061A (zh) * 2013-06-04 2014-12-17 中山大学 小檗碱衍生物的医药用途
EP3055307B1 (en) * 2013-10-04 2019-12-04 SpecGx LLC Substituted berbines and their synthesis

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1827618A (zh) * 2005-03-04 2006-09-06 周桂华 一类异喹啉衍生物、制备方法及用途
WO2009002873A1 (en) * 2007-06-22 2008-12-31 Cvi Pharmaceuticals Limited Compounds, compositions and methods for reducing lipid levels
CN102256973A (zh) * 2008-12-23 2011-11-23 Cvi制药有限公司 用于降低脂类水平的紫堇碱衍生物
WO2011006000A1 (en) * 2009-07-08 2011-01-13 Haiyan Liu Berberine derivatives useful for modulating lipid levels and their methods of synthesis
CN104208061A (zh) * 2013-06-04 2014-12-17 中山大学 小檗碱衍生物的医药用途
EP3055307B1 (en) * 2013-10-04 2019-12-04 SpecGx LLC Substituted berbines and their synthesis

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HAIXIA GE等: "Chemical and microbial semi-synthesis of tetrahydroprotoberberines as inhibitors on tissue factor procoagulant activity", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
JICHAO CHEN等: "Design, synthesis and biological evaluation of novel nitric oxidedonating protoberberine derivatives as antitumor agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
SADYKOV,YU.D.等: "Synthesis of esters and ethers from the alkaloid berberine", 《DOKLADY AKADEMII NAUK TADZHIKSKOI SSR》 *
WEI-WEI GAO等: "Discovery of 2-aminothiazolyl berberine derivatives as effectively antibacterial agents toward clinically drug-resistant Gram-negative Acinetobacter baumanii", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114028391A (zh) * 2021-09-30 2022-02-11 哈尔滨医科大学 四氢小檗红碱用于制备激活棕色脂肪活化和白色脂肪棕色化的药物的用途
CN114057723A (zh) * 2021-11-25 2022-02-18 四川大学 一种13-甲基小檗碱类生物碱的合成方法

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