CN113563340A - 一种苦参碱并嘧啶衍生物及其制备方法和应用 - Google Patents

一种苦参碱并嘧啶衍生物及其制备方法和应用 Download PDF

Info

Publication number
CN113563340A
CN113563340A CN202110896510.1A CN202110896510A CN113563340A CN 113563340 A CN113563340 A CN 113563340A CN 202110896510 A CN202110896510 A CN 202110896510A CN 113563340 A CN113563340 A CN 113563340A
Authority
CN
China
Prior art keywords
matrine
general formula
pyrimidine derivative
cdcl
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202110896510.1A
Other languages
English (en)
Other versions
CN113563340B (zh
Inventor
王立升
姜文泰
王兴东
刘旭
江俊
吴黎川
张淇淞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangxi University
Original Assignee
Guangxi University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangxi University filed Critical Guangxi University
Priority to CN202110896510.1A priority Critical patent/CN113563340B/zh
Publication of CN113563340A publication Critical patent/CN113563340A/zh
Application granted granted Critical
Publication of CN113563340B publication Critical patent/CN113563340B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种苦参碱并嘧啶衍生物及其制备方法和应用，属于药物化学技术领域，所述苦参碱并嘧啶衍生物为
Figure DDA0003198147190000011
或通式(Ⅰ)所代表的化合物，或通式(II)所代表的化合物：

Description

一种苦参碱并嘧啶衍生物及其制备方法和应用
技术领域
本发明属于药物化学技术领域，具体涉及一种苦参碱并嘧啶衍生物及其制备方法和应用。
背景技术
苦参碱是早期从苦参中提取分离得到的主要活性成分之一，是一种生物碱。苦参碱及其衍生物具有多种活性，例如：抗癌、抗病毒、抗炎、杀虫等。实验证明苦参碱在治疗癌症方面具有一定的活性，但是它的效果仅仅只是中等，推测这可能是由于它结合位点较多、选择性比较低导致的。因此，提高苦参碱抗肿瘤靶点的敏感性和选择性，将有效提升苦参碱的抗癌效果。嘧啶及其衍生物是非常重要的具有生物活性的化学成分。一些嘧啶类衍生物具有抗病毒、抗癌、抗炎、抗细菌、抗真菌等生物活性。嘧啶及其衍生物作为核酸DNA和RNA的组成部分，广泛分布于生命体内，在生命科学中有着重要作用。含嘧啶的分子使杂芳族化学研究领域不断扩大，因为它们独特的结构和良好的生物相容性，在制药及农用化学研究的不同领域提供了多种应用。现有技术中未有苦参碱并嘧啶类化合物的相关药物的研究。
发明内容
为解决现有技术中的上述问题，本发明提供了一种苦参碱并嘧啶衍生物及其制备方法和应用。
为实现上述目的，本发明提供了如下技术方案：
本发明的技术方案之一：一种苦参碱并嘧啶衍生物，为
Figure BDA0003198147180000011
或通式(Ⅰ)所代表的化合物；
Figure BDA0003198147180000012
或通式(II)所代表的化合物：
Figure BDA0003198147180000021
所述通式(Ⅰ)中，R为A01～A28中的一种：
Figure BDA0003198147180000031
所述通式(II)中，R1为B01～B06中的一种：
Figure BDA0003198147180000041
本发明的技术方案之二：一种上述所述的苦参碱并嘧啶衍生物的制备方法，所述结构式为
Figure BDA0003198147180000042
的苦参碱并嘧啶衍生物及所述通式(Ⅰ)所代表的苦参碱并嘧啶衍生物的制备方法，包括以下步骤：以苦参碱为原料，经过氯代甲酰化反应得到中间产物，之后经成环反应，得到所述结构式为
Figure BDA0003198147180000043
的苦参碱并嘧啶衍生物；继续进行酰化反应得到通式(Ⅰ)所代表的苦参碱并嘧啶衍生物；
反应方程式如式(Ⅰ)所示：
Figure BDA0003198147180000051
所述通式(II)所代表的苦参碱并嘧啶衍生物的制备方法，包括以下步骤：
在LDA的作用下苦参碱形成十四位的碳负离子，该碳负离子活性中间体再与取代苯甲腈进行亲核加成反应，脱去一分子水得到通式(II)所代表的苦参碱并嘧啶衍生物；反应方程式如式(II)所示：
Figure BDA0003198147180000052
本发明的技术方案之三：上述所述的苦参碱并嘧啶衍生物在制备抗癌药物中的应用。
进一步地，所述抗癌药物为抗人前列腺癌细胞、人非小细胞肺癌细胞、人结直肠腺癌细胞和人宫颈癌细胞的药物。
与现有技术相比，本发明具有以下有益效果：
(1)本发明的苦参碱并嘧啶衍生物将苦参碱与嘧啶类化合物有效结合，使其能够在抗肿瘤活性方面发挥协同增效作用，通过对此类化合物进行体外抗肿瘤活性测定，证实本发明公开的苦参碱并嘧啶衍生物对人体肿瘤细胞(人前列腺癌细胞DU-145、人非小细胞肺癌细胞A549、人结直肠腺癌细胞HCT15和人宫颈癌细胞HeLa)具有一定的抑制活性，从而可以抑制肿瘤细胞的增殖与分化，为抗肿瘤药物的研发提供新的思路。
(2)本发明的制备方法简便、可控，所得产物收率高且具有极高的纯度。
具体实施方式
现详细说明本发明的多种示例性实施方式，该详细说明不应认为是对本发明的限制，而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。应理解本发明中所述的术语仅仅是为描述特别的实施方式，并非用于限制本发明。
另外，对于本发明中的数值范围，应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明，否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料，但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入，用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时，以本说明书的内容为准。
在不背离本发明的范围或精神的情况下，可对本发明说明书的具体实施方式做多种改进和变化，这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见的。本发明说明书和实施例仅是示例性的。
苦参碱的结构式和原子序号如下：
Figure BDA0003198147180000071
以下结合实施例具体说明在苦参碱结构基础上发明的苦参碱并嘧啶衍生物及其制备方法。
实施例1
(1)中间体14-甲酰基-15-氯苦参碱的合成
称取20g(80mml，1eq)的苦参碱置于150ml干燥的烧杯中，加入120ml的二氯甲烷搅拌并充分溶解苦参碱，溶解后置于干燥环境备用。准备500ml干燥的三口烧瓶密封后抽真空并氮气保护，在冰浴下对三口烧瓶预降温。称取17.52g的DMF，将DMF注射到三口烧瓶中。再称取36.8g的三氯氧磷并缓慢滴加到DMF中，滴加完毕后，0摄氏度反应1h，最后将溶解好的苦参碱加入到反应液中，此时反应液从无色液体变为红棕色，撤去冰浴，让反应液缓慢升至常温并反应24h终止反应。反应后首先通过旋转蒸发仪除去DCM和部分三氯氧磷，将剩余反应液缓慢倒入过量冰水混合物中并不断搅拌20min，缓慢加入质量分数20％NaOH溶液调节pH至9～10，该过程可用pH试纸持续观测，最后反应液会从红棕色澄清溶液变为白色浑浊液。再将调节好pH的浑浊液置于60℃的水锅之中水解2h，水解完毕后有大量淡黄色固体析出，冷却至室温并自然沉淀，再用布氏漏斗抽滤同时用适量去离子水洗涤滤饼三次，将滤饼置于50℃的真空干燥箱中干燥5h，得到淡黄色粉末状的14-甲酰基-15-氯苦参碱粗产物。该粗产物用氯仿和石油醚的混合溶剂进行重结晶，在室温下缓慢挥发溶剂培养晶体，最后得到浅黄色的14-甲酰基-15-氯苦参碱晶体。
14-甲酰基-15-氯苦参碱：14-甲酰基-15-氯苦参碱，淡黄色晶体，收率91％，熔点123.9～124.1℃；1H NMR(500MHz,CDCl3)δ:9.68(s,1H,CHO-H),4.26～3.89(m,2H,11-H,5-H),3.63(t,J＝12.8Hz,1H,6-H),3.00～2.71(m,2H),2.42(dtd,J＝15.8,5.4,1.2Hz,1H),2.31(ddd,J＝15.6,9.8,5.1Hz,1H),2.01(tdd,J＝12.3,9.6,3.1Hz,2H),1.95～1.73(m,5H),1.73～1.53(m,5H),1.52～1.42(m,2H),1.37(tt,J＝14.0,4.3Hz,1H)；13C NMR(126MHz,CDCl3)δ:187.37,150.78,107.95,63.56,57.18,57.00,56.61,49.55,39.44,36.77,27.61,26.04,22.37,21.22,20.61,17.80；HRMS(+ESI):calcd for C16H23ClN2O m/z＝294.1499,[M+H]+found 295.1580.
(2)19-氨基嘧啶并苦参碱(WJ-01)的合成
分别称取10g(34mmol，1eq)14-甲酰基-15-氯苦参碱和14.1g(102mmol，3eq)无水碳酸钾于干燥的500mL的三口烧瓶中，向其加入约100mL的甲醇使14-甲醛基-15-氯苦参碱完全溶解，再缓慢加入3.25g(34mmol，leq)盐酸胍甲醇溶液，加毕，将三口烧瓶置于70℃的油浴锅中，搅拌回流8h并停止反应。加水溶解反应液底部过量的的碳酸钾和反应生成的盐，待反应液变成黄色均相溶液之后，用二氯甲烷萃取三次，合并有机相，饱和食盐水洗涤有机相两次，无水硫酸钠干燥，抽滤，直至黄色油状物变成黄色固体，该黄色固体即为19-氨基嘧啶并苦参碱粗产物，干燥后可直接用于下一步反应。
19-氨基嘧啶并苦参碱的精制方法：由于该化合物的极性较大，用(DCM/MeOH＝50/1，V/V)进行柱层析分离，浓缩收集到的纯品，此时仍为亮黄色油状物，加入乙醚，30℃加热溶解油状物直至乙醚溶液澄清，再让其在室温下慢速挥发生长晶体，最后得到浅黄色针状19-氨基嘧啶并苦参碱晶体。
WJ-01：19-氨基嘧啶并苦参碱，浅黄色针状晶体，收率73％，熔点128.9～129.7℃；1H NMR(500MHz,CDCl3)1H NMR(500MHz,CDCl3)δ:9.50(s,1H),3.89(dt,J＝10.9,5.6Hz,1H),3.60(dd,J＝12.8,4.4Hz,1H),3.41(t,J＝12.6Hz,1H),2.83(dd,J＝22.7,11.4Hz,2H),2.39～2.24(m,2H),2.16(s,1H),2.07～1.85(m,5H),1.83～1.58(m,7H),1.57～1.32(m,4H)；13C NMR(126MHz,CDCl3)δ:184.11,168.54,98.91,63.90,63.56,57.29,57.09,53.56,44.96,40.03,36.51,27.77,26.29,23.67,21.21,20.64,16.02；HRMS(+ESI):calcdfor C17H25N5m/z＝299.2110,[M+H]+found 300.1910。
(3)酰胺基嘧啶并苦参碱衍生物(WJ-02～WJ-29)的合成
称取1.5g(5mmol，1eq)19-氨基嘧啶并苦参碱于100mL干燥的三口烧瓶中，在氮气保护下将三口烧瓶置于冰浴之中。加入20ml无水DCM溶解原料，再加入0.7ml(6mmol，1.2eq)三乙胺，最后在冰浴下缓慢滴加6mmol(1.2eq)酰氯，滴加完毕后，撤去冰浴，缓慢升至室温并在室温下反应9～24h，反应终止的时间随酰氯的不同而变化，利用薄层色谱持续监测反应进程，至原料反应完全，终止反应，加入50mLDCM稀释反应液，先用饱和NaCO3洗涤反应液2～3次，收集有机相，再用饱和食盐水洗涤有机相2～3次，用无水硫酸钠干燥有机相。旋转蒸发仪浓缩有机相，最后用EA/PE体系为洗脱剂进行柱层析分离，洗脱剂的极性在EA/PE＝1.7/1(V/V)到EA/PE＝5/1(V/V)之间，合并柱层析得到的纯目标点溶液并减压浓缩，用乙醚重结晶得到酰胺基嘧啶并苦参碱系列衍生物WJ-02～WJ-29。
WJ-02：19-苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率87％，熔点100.1℃；1HNMR(500MHz,CDCl3)δ:8.45(s,1H),8.20～8.06(m,2H),7.68～7.59(m,1H),7.50(t,J＝7.8Hz,2H),4.48(dd,J＝12.8,4.5Hz,1H),3.98(ddd,J＝10.9,7.6,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),2.92～2.75(m,3H),2.48(dddd,J＝14.9,10.2,4.1,2.0Hz,1H),2.16(d,J＝10.2Hz,2H),2.05～1.86(m,4H),1.83～1.60(m,5H),1.60～1.40(m,5H),1.27(s,1H)；13CNMR(126MHz,CDCl3)δ:163.55,162.64,140.66,133.88,130.10,129.77,128.70,128.65,128.05,116.66,63.79,57.22,57.18,52.85,42.34,35.57,31.24,29.70,27.70,26.49,24.83,21.12,20.75,19.82；HRMS(+ESI):calcd for C24H29N5O m/z＝403.2372,[M+H]+found 404.2023。
WJ-03：19-邻甲基苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率81％，熔点102.8～103.9℃；1H NMR(500MHz,CDCl3)δ:8.44(s,1H),8.03(dd,J＝8.1,1.5Hz,1H),7.47(td,J＝7.6,1.4Hz,1H),7.31(d,J＝7.4Hz,2H),4.48(dd,J＝12.7,4.4Hz,1H),3.96(ddd,J＝10.9,7.7,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),2.91～2.74(m,3H),2.66(s,3H),2.44(dddd,J＝14.9,10.3,4.1,2.0Hz,1H),2.19～2.10(m,2H),2.06～1.87(m,5H),1.83～1.50(m,7H),1.48(s,1H),1.27(s,1H)；13C NMR(126MHz,CDCl3)δ:163.64,163.07,141.52,140.74,132.95,132.02,130.98,127.77,125.89,116.30,63.78,57.28,57.23,52.87,42.37,42.34,35.60,29.70,27.74,26.53,24.82,21.96,21.18,20.80,19.93；HRMS(+ESI):calcdfor C25H31N5O m/z＝417.2529,[M+H]+found 418.2354。
WJ-04：19-间甲基苯甲酰胺基嘧啶并苦参碱，红褐色固体，收率85％，熔点98.1～99.2℃；1H NMR(500MHz,CDCl3)δ:8.50～8.35(m,1H),7.92(dd,J＝7.0,1.5Hz,2H),7.44(d,J＝7.5Hz,1H),7.40～7.35(m,1H),4.48(dd,J＝12.8,4.4Hz,1H),3.98(ddd,J＝10.8,7.7,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),2.93～2.79(m,3H),2.44(s,4H),2.15(d,J＝7.8Hz,2H),2.09～1.86(m,3H),1.86～1.60(m,5H),1.59～1.51(m,2H),1.48(s,1H),1.46(t,J＝5.4Hz,1H),1.26(s,1H)；13C NMR(126MHz,CDCl3)δ:163.57,162.81,140.71,138.51,134.68,130.61,128.59,128.51,127.22,116.56,63.79,57.25,57.21,52.86,42.35,42.32,35.58,29.70,27.72,26.51,24.82,21.30,21.15,20.77,19.83；HRMS(+ESI):calcdfor C25H31N5O m/z＝417.2529,[M+H]+found 418.2192。
WJ-05：19-对甲基苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率80％，熔点146.5～146.6℃；1H NMR(500MHz,CDCl3)δ:8.44(s,1H),8.08～7.97(m,2H),7.30(s,2H),4.48(dd,J＝12.7,4.5Hz,1H),3.97(ddd,J＝10.9,7.7,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),2.98～2.75(m,3H),2.45(s,4H),2.21～2.10(m,2H),2.09～1.83(m,4H),1.82～1.60(m,5H),1.60～1.37(m,5H),1.27(d,J＝2.0Hz,1H)；13C NMR(126MHz,CDCl3)δ:163.59,162.67,144.81,140.72,130.14,129.36,125.92,116.39,63.79,57.29,57.25,52.87,42.36,42.33,38.15,35.60,31.25,29.70,27.75,26.55,24.82,21.79,21.20,20.82,19.82；HRMS(+ESI):calcdfor C25H31N5Om/z＝417.2529,[M+H]+found 418.2191。
WJ-06：19-(3，5-二甲基苯甲酰胺基)嘧啶并苦参碱，淡黄色固体，收率76％，熔点121.9℃；1H NMR(500MHz,CDCl3)δ:8.43(s,1H),7.73(d,J＝1.6Hz,2H),7.26(s,1H),4.49(dd,J＝12.8,4.5Hz,1H),3.99(ddd,J＝10.9,7.6,5.1Hz,1H),3.20(t,J＝12.7Hz,1H),2.87(dd,J＝28.1,11.2Hz,3H),2.48(dddd,J＝14.9,10.3,4.1,2.0Hz,1H),2.40(s,6H),2.17(s,3H),2.07～1.95(m,2H),1.92(d,J＝14.0Hz,1H),1.84～1.75(m,2H),1.75～1.69(m,2H),1.68～1.60(m,2H),1.60～1.52(m,2H),1.49(d,J＝6.0Hz,1H),1.27(s,1H)；13CNMR(126MHz,CDCl3)δ:163.62,162.98,140.79,138.34,135.59,128.52,127.79,127.55,116.46,63.81,57.24,57.21,52.86,42.34,42.32,38.15,35.58,31.24,29.70,27.72,26.52,24.83,21.19,21.15,20.77,19.84；HRMS(+ESI):calcd for C26H33N5O m/z＝431.2685,[M+H]+found 432.2318。
WJ-07：19-对甲氧基苯甲酰胺基嘧啶并苦参碱，白色晶体，收率91％，熔点159.0～159.5℃；1H NMR(500MHz,CDCl3)δ:8.43(s,1H),8.12～8.02(m,2H),7.05～6.92(m,2H),4.48(dd,J＝12.8,4.4Hz,1H),3.97(ddd,J＝11.0,7.6,5.1Hz,1H),3.90(s,3H),3.18(t,J＝12.7Hz,1H),2.92～2.76(m,3H),2.46(dddd,J＝15.0,10.2,4.2,2.0Hz,1H),2.14(s,2H),2.07～1.88(m,3H),1.84(s,1H),1.81～1.60(m,5H),1.55(d,J＝4.5Hz,2H),1.48(d,J＝3.3Hz,1H),1.46(s,1H),1.27(s,1H)；13C NMR(126MHz,CDCl3)δ:164.12,163.66,162.31,140.79,132.26,120.93,116.12,113.94,63.79,57.30,57.25,55.54,52.86,42.35,42.32,38.15,35.60,31.24,29.70,27.75,26.55,24.83,21.20,20.82,19.80；HRMS(+ESI):calcdfor C25H31N5O2m/z＝433.2478,[M+H]+found 434.2302。
WJ-08：19-间氟苯甲酰胺基嘧啶并苦参碱，白色固体，收率77％，熔点127.6℃；1HNMR(500MHz,CDCl3)δ:8.42(t,J＝1.7Hz,1H),7.93(dt,J＝7.8,1.3Hz,1H),7.79(ddd,J＝9.1,2.7,1.5Hz,1H),7.49(td,J＝8.0,5.5Hz,1H),7.34(tdd,J＝8.3,2.7,1.0Hz,1H),4.47(dd,J＝12.7,4.5Hz,1H),3.98(ddd,J＝10.9,7.6,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),2.95～2.74(m,3H),2.47(dddd,J＝15.0,10.3,4.1,2.0Hz,1H),2.23～2.09(m,2H),2.07～1.83(m,4H),1.83～1.60(m,5H),1.60～1.39(m,5H)；13C NMR(126MHz,CDCl3)δ:163.29,161.57,140.37,130.39,130.32,125.89,125.86,121.08,120.91,117.14,63.74,57.27,57.23,52.87,42.38,42.34,35.59,35.59,27.73,26.53,24.75,21.18,20.80,19.85；HRMS(+ESI):calcd for C24H28FN5O m/z＝421.2278,[M+H]+found 422.1913。
WJ-09：19-邻氯苯甲酰胺基嘧啶，淡黄色晶体，收率71％，熔点139.8℃；1H NMR(500MHz,CDCl3)δ:8.42(s,1H),8.05～7.90(m,1H),7.57～7.45(m,2H),7.38(ddd,J＝8.4,6.3,2.3Hz,1H),4.47(dd,J＝12.8,4.4Hz,1H),3.96(ddd,J＝10.9,7.7,5.1Hz,1H),3.18(t,J＝12.7Hz,1H),2.95～2.72(m,3H),2.43(dddd,J＝15.1,10.4,4.1,2.1Hz,1H),2.23～2.08(m,2H),1.99(qd,J＝12.3,2.8Hz,2H),1.87(s,3H),1.74(dd,J＝22.4,12.7Hz,3H),1.69～1.58(m,2H),1.57～1.50(m,2H),1.47(d,J＝2.7Hz,1H),1.46～1.43(m,1H)；13C NMR(126MHz,CDCl3)δ:163.37,161.62,140.45,134.55,133.52,132.20,131.49,128.34,126.76,117.27,63.74,57.27,57.23,52.90,42.37,35.59,27.73,26.52,24.79,21.18,20.79,19.96；HRMS(+ESI):calcd for C24H28ClN5O m/z＝437.1982,[M+H]+found438.1568。
WJ-10：19-间氯苯甲酰胺基嘧啶并苦参碱，红褐色固体，收率73％，熔点130.1℃；1H NMR(500MHz,CDCl3)δ:8.42(t,J＝1.8Hz,1H),8.09(t,J＝1.9Hz,1H),8.02(dt,J＝7.8,1.4Hz,1H),7.61(ddd,J＝8.1,2.2,1.1Hz,1H),7.45(t,J＝7.9Hz,1H),4.48(dd,J＝12.8,4.5Hz,1H),3.99(ddd,J＝10.8,7.7,5.1Hz,1H),3.20(t,J＝12.8Hz,1H),2.92～2.79(m,3H),2.48(dddd,J＝15.0,10.3,4.1,2.0Hz,1H),2.18(d,J＝13.9Hz,3H),2.10～1.83(m,4H),1.77(dd,J＝13.0,3.9Hz,2H),1.75～1.68(m,2H),1.68～1.55(m,3H),1.51(d,J＝20.7Hz,1H),1.34～1.22(m,1H)；13C NMR(126MHz,CDCl3)δ:163.29,161.52,140.38,134.82,133.90,130.46,130.02,129.99,128.24,117.20,63.75,57.24,57.20,52.85,42.36,42.33,35.58,29.70,27.71,26.51,24.76,21.14,20.76,19.88；HRMS(+ESI):calcdfor C24H28ClN5O m/z＝437.1982,[M+H]+found 438.1828。
WJ-11：19-对氯苯甲酰胺基嘧啶并苦参碱，白色固体，收率82％，熔点149.3～149.4℃；1H NMR(500MHz,CDCl3)δ:8.42(s,1H),8.15～8.02(m,2H),7.56～7.42(m,2H),4.47(dd,J＝12.8,4.5Hz,1H),3.98(ddd,J＝10.8,7.7,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),2.92～2.73(m,3H),2.46(dddd,J＝14.9,10.3,4.2,2.1Hz,1H),2.24～2.08(m,2H),2.07～1.87(m,3H),1.87～1.49(m,8H),1.45(qd,J＝9.6,4.3Hz,3H)；13C NMR(126MHz,CDCl3)δ:163.32,161.83,140.46,140.43,131.42,129.05,127.16,116.97,63.75,57.28,57.24,52.86,42.37,42.34,35.59,27.74,26.54,24.76,21.18,20.81,19.86；HRMS(+ESI):calcd for C24H28ClN5O m/z＝437.1982,[M+H]+found 438.1862。
WJ-12：19-间溴苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率78％，熔点109.0℃；1H NMR(500MHz,CDCl3)δ:8.41(s,1H),8.24(t,J＝1.8Hz,1H),8.06(dt,J＝7.8,1.4Hz,1H),7.76(dq,J＝8.0,1.1Hz,1H),7.39(t,J＝7.9Hz,1H),4.47(dd,J＝12.8,4.4Hz,1H),3.98(ddd,J＝10.8,7.6,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),2.92～2.76(m,3H),2.47(dddd,J＝15.0,10.4,4.2,2.1Hz,1H),2.24～2.08(m,2H),2.08～1.83(m,5H),1.83～1.78(m,1H),1.77～1.72(m,1H),1.72～1.67(m,1H),1.67～1.63(m,1H),1.57(d,J＝4.5Hz,1H),1.56～1.51(m,1H),1.49(d,J＝3.3Hz,1H),1.46(d,J＝5.5Hz,1H),1.43～1.19(m,1H)；13C NMR(126MHz,CDCl3)δ:163.29,161.40,140.37,136.81,132.94,130.64,130.23,128.68,122.70,117.22,63.74,57.27,57.23,52.88,42.40,42.34,35.59,27.73,26.53,24.74,21.17,20.79,19.87；HRMS(+ESI):calcd for C24H28BrN5O m/z＝481.1477,[M+H]+found482.1094。
WJ-13：19-对三氟甲基苯甲酰胺基嘧啶并苦参碱，淡黄色晶体，收率61％，熔点153.5℃；1H NMR(500MHz,CDCl3)δ:8.44(s,1H),8.24(d,J＝8.1Hz,2H),7.77(d,J＝8.2Hz,2H),4.48(dd,J＝12.8,4.4Hz,1H),3.99(ddd,J＝10.9,7.7,5.1Hz,1H),3.20(t,J＝12.7Hz,1H),3.05～2.64(m,3H),2.48(dddd,J＝14.9,10.3,4.1,2.1Hz,1H),2.32～2.08(m,2H),2.08～1.85(m,3H),1.84～1.60(m,6H),1.60～1.40(m,5H)；13C NMR(126MHz,CDCl3)δ:163.18,161.53,140.29,135.37,135.11,131.99,130.46,125.73,125.71,125.68,125.65,117.46,63.73,57.27,57.23,52.87,42.39,42.36,35.59,27.73,26.54,24.74,21.18,20.80,19.90；HRMS(+ESI):calcd for C25H28F3N5O m/z＝471.2246,[M+H]+found 472.2191。
WJ-14：19-间三氟甲基苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率66％，熔点119.8℃；1H NMR(500MHz,CDCl3)δ:8.43(t,J＝1.8Hz,1H),8.37(d,J＝1.8Hz,1H),8.32(dt,J＝7.8,1.4Hz,1H),7.94～7.86(m,1H),7.66(t,J＝7.8Hz,1H),4.48(dd,J＝12.8,4.5Hz,1H),3.99(ddd,J＝10.8,7.7,5.1Hz,1H),3.20(t,J＝12.7Hz,1H),2.99～2.70(m,3H),2.49(dddd,J＝15.0,10.3,4.1,2.1Hz,1H),2.29～2.09(m,2H),2.06～1.90(m,3H),1.86(s,2H),1.78(ddd,J＝17.1,8.8,3.9Hz,2H),1.74～1.62(m,3H),1.60～1.52(m,2H),1.49(s,1H),1.46(d,J＝3.8Hz,1H)；13C NMR(126MHz,CDCl3)δ163.23,161.46,140.29,133.26,131.53,130.37,130.34,129.64,129.41,124.57,122.40,117.43,63.73,57.26,57.22,52.88,42.40,42.35,35.59,27.72,26.53,24.74,21.16,20.78,19.88；HRMS(+ESI):calcdfor C25H28F3N5Om/z＝471.2246,[M+H]+found 472.2151。
WJ-15：19-对叔丁基苯甲酰胺基嘧啶并苦参碱，淡黄色晶体，收率85％，熔点150.2℃；1H NMR(500MHz,CDCl3)δ:8.45(s,1H),8.06(d,J＝8.6Hz,2H),7.51(d,J＝8.6Hz,2H),4.48(dd,J＝12.8,4.4Hz,1H),3.97(ddd,J＝11.0,7.7,5.3Hz,1H),3.19(t,J＝12.7Hz,1H),3.01～2.73(m,3H),2.47(dddd,J＝15.0,10.3,4.1,2.0Hz,1H),2.28～2.09(m,2H),2.09～1.83(m,4H),1.83～1.61(m,5H),1.61～1.53(m,2H),1.53～1.43(m,3H),1.36(s,9H)；13C NMR(126MHz,CDCl3)δ:164.12,163.66,162.31,140.79,132.26,120.93,116.12,113.94,63.79,57.30,57.25,55.54,52.86,42.35,42.32,38.15,35.60,31.93,31.24,29.70,27.75,26.55,24.83,21.20,20.82,19.80；HRMS(+ESI):calcd for C28H37N5O m/z＝459.2998,[M+H]+found 460.2657。
WJ-16：19-对溴苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率78％，熔点163.1℃；1H NMR(500MHz,CDCl3)δ:8.42(s,1H),7.99(d,J＝8.6Hz,2H),7.65(d,J＝8.6Hz,2H),4.48(dd,J＝12.8,4.4Hz,1H),4.06～3.93(m,1H),3.20(t,J＝12.7Hz,1H),2.85(dt,J＝25.3,12.1Hz,3H),2.54～2.41(m,1H),2.16(s,2H),2.05～1.88(m,3H),1.79(s,2H),1.73～1.59(m,3H),1.59～1.20(m,6H)；13C NMR(126MHz,CDCl3)δ:163.32,161.99,140.43,132.06,131.52,129.19,127.62,117.00,63.76,57.26,57.22,52.84,42.35,42.33,35.58,27.72,26.53,24.78,21.16,20.79,19.87；HRMS(+ESI):calcd for C24H28BrN5O m/z＝481.1477,[M+H]+found482.0722。
WJ-17：19-(1-萘甲酰胺基)嘧啶并苦参碱，淡黄色固体，收率83％，熔点152.1～152.2℃；1H NMR(500MHz,CDCl3)δ:9.01(d,J＝8.7Hz,1H),8.57(s,1H),8.34(dd,J＝7.3,1.2Hz,1H),8.11(d,J＝8.2Hz,1H),7.93(d,J＝8.1Hz,1H),7.79～7.63(m,1H),7.63～7.49(m,2H),4.51(dd,J＝12.7,4.4Hz,1H),3.99(ddd,J＝11.0,7.6,5.3Hz,1H),3.21(t,J＝12.7Hz,1H),2.96～2.77(m,3H),2.49(dddd,J＝15.0,10.3,4.1,2.0Hz,1H),2.35～2.09(m,2H),2.08～1.95(m,2H),1.95～1.77(m,3H),1.77～1.68(m,2H),1.68～1.58(m,2H),1.58～1.55(m,1H),1.55～1.44(m,3H),1.44～1.20(m,1H)；13C NMR(126MHz,CDCl3)δ:163.59,162.97,140.78,134.61,133.88,131.67,131.07,128.69,128.36,126.55,125.70,125.06,124.41,116.53,63.79,57.30,57.26,52.89,42.38,42.36,35.62,27.77,26.55,24.85,21.21,20.82,19.98；HRMS(+ESI):calcd for C28H31N5O m/z＝453.2529,[M+H]+found454.2375。
WJ-18：19-对乙基苯甲酰胺基嘧啶并苦参碱，淡黄色粉末，收率69％，熔点154.6～154.9℃；1H NMR(500MHz,CDCl3)δ:8.45(s,1H),8.10～7.98(m,2H),7.37～7.30(m,2H),4.48(dd,J＝12.7,4.4Hz,1H),3.97(ddd,J＝10.9,7.7,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),3.01～2.65(m,5H),2.47(dddd,J＝15.0,10.3,4.1,2.0Hz,1H),2.25～2.10(m,2H),2.08～1.80(m,4H),1.80～1.68(m,3H),1.68～1.36(m,7H),1.28(t,J＝7.6Hz,3H)；13C NMR(126MHz,CDCl3)δ:163.58,162.67,150.96,140.72,130.26,128.18,126.14,116.41,63.80,57.30,57.25,52.87,42.35,42.33,35.60,29.05,27.75,26.55,24.82,21.20,20.82,19.82,15.18；HRMS(+ESI):calcd for C26H33N5O m/z＝431.2685,[M+H]+found432.2543。
WJ-19：19-邻溴苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率74％，熔点115.3℃；1H NMR(500MHz,CDCl3)δ:8.42(s,1H),7.98～7.89(m,1H),7.79～7.68(m,1H),7.48～7.36(m,2H),4.48(dd,J＝12.8,4.4Hz,1H),3.98(ddd,J＝11.0,7.7,5.4Hz,1H),3.20(t,J＝12.7Hz,1H),2.94～2.77(m,3H),2.44(dddd,J＝15.1,10.4,4.1,2.0Hz,1H),2.22～2.10(m,2H),2.01(qd,J＝12.3,2.8Hz,2H),1.91(d,J＝13.8Hz,1H),1.84～1.47(m,9H),1.47～1.41(m,2H)；13C NMR(126MHz,CDCl3)δ:163.33,162.05,140.45,134.79,133.45,132.12,130.47,127.32,122.41,117.32,63.77,57.23,57.19,52.86,42.37,42.31,35.56,27.69,26.48,24.85,21.40,21.13,20.74,20.01；HRMS(+ESI):calcd for C24H28BrN5O m/z＝481.1477,[M+H]+found 482.1285。
WJ-20：19-邻氟苯甲酰胺基嘧啶并苦参碱，淡黄色晶体，收率70％，熔点111.0～111.3℃；1H NMR(500MHz,CDCl3)δ:8.45(s,1H),8.05(td,J＝7.6,1.8Hz,1H),7.66～7.55(m,1H),7.30～7.24(m,1H),7.19(ddd,J＝10.8,8.4,0.8Hz,1H),4.48(dd,J＝12.8,4.4Hz,1H),3.97(ddd,J＝11.0,7.6,5.3Hz,1H),3.19(t,J＝12.7Hz,1H),2.96～2.75(m,3H),2.45(dddd,J＝15.2,10.3,4.1,2.0Hz,1H),2.21～2.11(m,2H),2.05～1.88(m,3H),1.88～1.66(m,4H),1.66～1.44(m,6H),1.43～1.20(m,1H)；13C NMR(126MHz,CDCl3)δ:163.40,161.24,160.55,160.52,140.29,135.58,135.50,132.64,124.26,124.23,117.35,117.23,63.77,57.25,57.21,52.90,42.32,35.58,27.72,26.51,24.78,21.15,20.77,19.83；HRMS(+ESI):calcd for C24H28BrN5O m/z＝421.2278,[M+H]+found 482.2134。
WJ-21：19-(2-氯-4-氟苯甲酰胺基)嘧啶并苦参碱，黄色粉末，收率63％，熔点113.5℃；1H NMR(500MHz,CDCl3)δ:8.40(s,1H),8.04(dd,J＝8.8,6.1Hz,1H),7.33～7.22(m,1H),7.10(ddd,J＝8.9,7.6,2.5Hz,1H),4.47(dd,J＝12.8,4.4Hz,1H),3.97(ddd,J＝11.0,7.7,5.3Hz,1H),3.19(t,J＝12.7Hz,1H),2.94～2.71(m,3H),2.43(dddd,J＝15.1,10.4,4.0,2.0Hz,1H),2.31～2.10(m,3H),2.09～1.97(m,2H),1.97～1.76(m,3H),1.76～1.67(m,2H),1.67～1.47(m,5H),1.43～1.20(m,1H)；13C NMR(126MHz,CDCl3)δ:165.70,163.27,160.66,140.36,136.70,134.43,124.47,119.18,118.98,117.33,114.47,114.29,63.74,57.19,52.86,42.35,42.33,35.56,27.69,26.48,24.79,21.12,20.74,20.01；HRMS(+ESI):calcd for C24H28BrN5O m/z＝455.1888,[M+H]+found 456.1710.
WJ-22：19-(2,4,6-三氯苯甲酰胺基)嘧啶并苦参碱，白色晶体，收率57％，熔点158.9～159.2℃；1H NMR(500MHz,CDCl3)δ:8.35(s,1H),7.41(s,2H),4.47(dd,J＝12.7,4.3Hz,1H),4.08～3.78(m,1H),3.19(t,J＝12.7Hz,1H),3.02～2.54(m,3H),2.34(dddd,J＝15.1,10.5,4.0,2.0Hz,1H),2.23～2.05(m,2H),2.00(q,J＝11.2Hz,2H),1.93～1.75(m,3H),1.75～1.65(m,2H),1.59(ddd,J＝20.9,14.8,10.7Hz,3H),1.52～1.41(m,3H),1.33～1.20(m,1H)；13C NMR(126MHz,CDCl3)δ:162.92,160.24,140.07,136.99,133.20,130.69,128.26,118.60,65.85,63.71,57.24,57.20,52.88,42.41,42.33,35.56,27.70,26.47,24.74,21.14,20.75,19.74,15.28；HRMS(+ESI):calcd for C24H26Cl3N5O m/z＝5051203,[M+H]+found506.1039。
WJ-23：19-对碘苯甲酰胺基嘧啶并苦参碱，白色晶体，收率84％，熔点127.4℃；1HNMR(500MHz,CDCl3)δ:8.43(s,1H),8.07～7.91(m,1H),7.61～7.44(m,2H),7.38(ddd,J＝8.5,6.5,2.2Hz,1H),4.48(dd,J＝12.7,4.4Hz,1H),3.96(ddd,J＝10.9,7.7,5.3Hz,1H),3.19(t,J＝12.7Hz,1H),2.94～2.71(m,3H),2.44(dddd,J＝15.1,10.4,4.0,2.0Hz,1H),2.24～2.07(m,2H),2.04～1.87(m,3H),1.86～1.53(m,8H),1.52～1.42(m,3H)；13C NMR(126MHz,CDCl3)δ:163.34,161.62,140.43,134.55,133.50,132.21,131.49,128.37,126.76,117.29,63.76,57.28,57.24,52.90,42.36,35.59,27.74,26.53,24.80,21.19,20.80,19.98；HRMS(+ESI):calcd for C24H28IN5O m/z＝529.1339,[M+H]+found 530.1484。
WJ-24：19-(3,5-二氯苯甲酰胺基)嘧啶并苦参碱，淡黄色固体，收率68％，熔点157.0～158.1℃；1H NMR(500MHz,CDCl3)δ:8.38(s,1H),7.97(d,J＝1.9Hz,2H),7.62(t,J＝1.9Hz,1H),4.47(dd,J＝12.8,4.4Hz,1H),4.03～3.94(m,1H),3.20(t,J＝12.7Hz,1H),2.85(dd,J＝28.7,12.3Hz,4H),2.47(dddd,J＝12.3,10.3,4.1,2.0Hz,1H),2.15(s,3H),2.10～2.02(m,1H),1.99(d,J＝2.8Hz,2H),1.91(d,J＝13.5Hz,1H),1.75(d,J＝19.1Hz,3H),1.66(s,2H),1.55(s,2H),1.48(s,2H)；13CNMR(126MHz,CDCl3)δ:163.06,160.49,140.15,135.61,133.67,131.55,128.37,117.69,63.71,57.25,57.21,52.86,42.39,42.33,41.32,35.58,27.71,26.52,25.69,24.69,21.40,21.15,20.77,19.92；HRMS(+ESI):calcd for C24H27Cl2N5O m/z＝471.1593,[M+H]+found 472.1214。
WJ-25：19-对氰基苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率79％，熔点141.5～142.5℃；1H NMR(500MHz,CDCl3)δ:8.44(s,1H),7.94(dd,J＝7.9,1.8Hz,1H),7.64～7.49(m,1H),7.14～6.97(m,2H),4.48(dd,J＝12.7,4.4Hz,1H),3.94(s,4H),3.18(t,J＝12.7Hz,1H),2.95～2.69(m,3H),2.42(dddd,J＝15.0,10.3,4.0,2.0Hz,1H),2.14(s,2H),2.06～1.82(m,4H),1.82～1.59(m,5H),1.59～1.52(m,2H)；13C NMR(126MHz,CDCl3)δ:163.07,161.15,156.98,140.18,132.45,130.52,117.71,117.25,63.71,57.22,57.19,52.84,42.38,42.35,41.31,35.57,27.69,26.50,25.70,24.73,21.40,21.12,20.75,19.91；HRMS(+ESI):calcd for C25H28N6Om/z＝428.2325,[M+H]+found 429.2152。
WJ-26：19-邻甲氧基苯甲酰胺基嘧啶并苦参碱，淡黄色固体，收率85％，熔点141.5～142.5℃；1H NMR(500MHz,CDCl3)δ:8.44(s,1H),7.94(dd,J＝7.9,1.8Hz,1H),7.64～7.43(m,1H),7.13～6.91(m,2H),4.48(dd,J＝12.7,4.4Hz,1H),3.94(s,4H),3.18(t,J＝12.7Hz,1H),2.95～2.69(m,3H),2.42(dddd,J＝15.0,10.3,4.0,2.0Hz,1H),2.14(s,2H),2.06～1.82(m,4H),1.80～1.39(m,10H)；13C NMR(126MHz,CDCl3)δ:163.68,161.71,160.15,140.81,134.73,132.33,120.18,117.96,116.29,112.21,99.99,63.81,57.30,57.26,55.98,52.89,42.35,42.31,35.58,27.76,26.54,24.89,21.21,20.82,19.84；HRMS(+ESI):calcd for C25H31N5O2m/z＝433.2478,[M+H]+found 434.2122。
WJ-27：19-(2,6-二氯苯甲酰胺基)嘧啶并苦参碱，淡黄色粉末，收率61％，熔点166.7℃；1H NMR(500MHz,CDCl3)δ:8.36(s,1H),7.47～7.30(m,3H),4.47(dd,J＝12.7,4.4Hz,1H),3.94(ddd,J＝10.8,7.8,5.3Hz,1H),3.18(t,J＝12.7Hz,1H),2.93～2.59(m,3H),2.34(dddd,J＝15.1,10.5,4.0,2.0Hz,1H),2.21～2.06(m,2H),2.05～1.92(m,2H),1.92～1.35(m,12H)；13C NMR(126MHz,CDCl3)δ:163.03,160.91,140.20,132.40,132.17,131.54,128.05,118.43,63.71,57.26,57.22,52.90,42.41,42.34,35.58,27.73,26.49,24.75,21.18,20.78,19.73；HRMS(+ESI):calcd for C24H27Cl2N5O m/z＝471.1593,[M+H]+found 472.1419。
WJ-28：19-(2,4-二氯苯甲酰胺基)嘧啶并苦参碱，淡黄色固体，收率63％，熔点130.4～130.6℃；1H NMR(500MHz,CDCl3)δ:8.40(s,1H),7.94(d,J＝8.5Hz,1H),7.54(d,J＝2.0Hz,1H),7.37(dd,J＝8.5,2.0Hz,1H),4.47(dd,J＝12.8,4.4Hz,1H),3.97(ddd,J＝11.0,7.7,5.3Hz,1H),3.19(t,J＝12.7Hz,1H),2.91～2.73(m,3H),2.43(dddd,J＝15.1,10.4,4.0,2.0Hz,1H),2.21～2.09(m,2H),2.09～1.96(m,2H),1.90(d,J＝13.7Hz,1H),1.87～1.64(m,7H),1.58(ddt,J＝18.6,9.7,5.5Hz,3H),1.46(s,1H)；13C NMR(126MHz,CDCl3)δ:163.24,160.82,140.31,139.47,135.67,133.22,131.44,127.25,126.64,117.50,63.73,57.26,57.22,52.89,42.37,35.58,27.72,26.51,24.77,21.16,20.78,20.01；HRMS(+ESI):calcd for C24H27Cl2N5O m/z＝471.1593,[M+H]+found 472.1424。
WJ-29：19-间碘苯甲酰胺基嘧啶并苦参碱，白色粉末，收率75％，熔点132.4℃；1HNMR(500MHz,CDCl3)δ:8.42(dt,J＝17.2,1.7Hz,2H),8.09(dt,J＝7.8,1.4Hz,1H),7.96(ddd,J＝7.8,1.9,1.1Hz,1H),7.25(t,J＝7.9Hz,1H),4.47(dd,J＝12.8,4.4Hz,1H),3.98(ddd,J＝10.7,7.6,5.1Hz,1H),3.19(t,J＝12.7Hz,1H),2.92～2.71(m,3H),2.47(dddd,J＝15.0,10.3,4.1,2.0Hz,1H),2.22～2.12(m,2H),2.05～1.89(m,3H),1.85～1.60(m,7H),1.59～1.51(m,2H),1.49(d,J＝3.3Hz,1H),1.46(d,J＝5.0Hz,1H)；13C NMR(126MHz,CDCl3)δ:163.29,161.23,142.68,140.38,138.83,130.60,130.30,129.24,117.20,93.95,63.75,57.28,57.24,52.88,42.39,42.34,41.32,35.59,27.74,26.55,24.75,21.18,20.80,19.88；HRMS(+ESI):calcd for C24H28IN5O m/z＝529.1339,[M+H]+found 530.0988。
(4)二苯基嘧啶并苦参碱衍生物(WJ-30～WJ-35)的合成
称取苦参碱于反应瓶中，加入甲苯溶解固体粉末，在氮气保护的状态下，冰浴滴加LDA溶液(2eq)，滴毕后，冰浴中搅拌三十分钟。然后向其边搅拌边滴加邻甲基苯甲腈，滴毕，置于120℃油浴锅中搅拌回流12h。待反应完成后，升至室温，加入冰的稀盐酸调节pH至酸性，减压除去多余的有机溶剂，随后用DCM萃取三次，取水相。将水相用冰的氢氧化钠溶液调节pH至7～8，用DCM萃取三次，合并有机相，加入无水硫酸钠干燥，将有机溶液浓缩，上硅胶层析柱，EA/PE＝1.8/1(V/V)至EA/PE＝2.5/1(V/V)，得到洗脱液经浓缩后用正己烷重结晶，得到固体产物(WJ-30～WJ-35)。
WJ-30：19，21-二苯基嘧啶并苦参碱，红褐色固体，收率39％，熔点120.1℃；1H NMR(500MHz,CDCl3)δ:8.53～8.46(m,2H),7.51～7.39(m,8H),3.52～3.24(m,3H),2.84～2.73(m,3H),2.59(dt,J＝14.7,4.1Hz,1H),1.96～1.17(m,15H)；13C NMR(126MHz,CDCl3)δ:167.10,164.65,155.00,138.56,132.06,131.51,129.17,128.74(d,J＝5.0Hz),128.53,127.84,120.70,77.41,62.05,56.83,50.93,44.25,38.42,31.90,30.94,27.48,26.23,21.00,20.69,20.11；HRMS(+ESI):calcd for C29H32N4m/z＝436.2627,[M+H]+found437.2066。
WJ-31：19，21-二(间二甲氧苯基)嘧啶并苦参碱，淡黄色固体，收率28％，熔点164.2℃；1H NMR(500MHz,CDCl3)δ:8.35(ddd,J＝7.9,3.5,1.9Hz,1H),7.46(ddt,J＝9.1,7.3,1.9Hz,1H),7.36(tt,J＝8.0,1.7Hz,1H),7.14(d,J＝7.4Hz,1H),7.07～6.93(m,4H),4.03(t,J＝2.0Hz,3H),3.73(s,3H),3.22(tdd,J＝10.0,6.0,2.2Hz,2H),3.13～3.00(m,1H),2.88(dd,J＝11.8,4.1Hz,1H),2.70(s,2H),2.45(d,J＝14.1Hz,1H),1.90～1.80(m,3H),1.67(s,1H),1.61(d,J＝13.4Hz,2H),1.54～1.48(m,2H),1.41～1.35(m,2H),1.25～1.19(m,3H),1.08(tt,J＝7.3,1.9Hz,2H)；13C NMR(126MHz,CDCl3)δ:170.19,157.88,152.92,133.56,131.73,130.30,123.09,121.77,120.75,119.13,111.77,111.35,63.05,57.17,57.13,56.26,55.51,51.40,44.50,34.41,27.44,26.09,23.26,21.03,20.52；HRMS(+ESI):calcd for C31H36N4O2m/z＝496.2838,[M+H]+found 497.2633。
WJ-32：19,21-二(间二甲苯基)嘧啶并苦参碱，淡黄色固体，收率41％，熔点196.9℃；1H NMR(500MHz,CDCl3)δ:8.16～8.03(m,2H),7.26(d,J＝15.3Hz,2H),7.20～7.11(m,4H),3.50～3.40(m,1H),3.30～3.13(m,2H),2.74(d,J＝11.2Hz,2H),2.62(s,2H),2.37(s,3H),2.34(s,3H),1.91(dt,J＝19.8,9.3Hz,3H),1.66(d,J＝30.5Hz,5H),1.45～1.35(m,4H),1.08(d,J＝76.5Hz,3H)；13C NMR(126MHz,CDCl3δ:165.19,140.33,137.75,137.62,130.54,128.93,128.84,128.71,128.11,128.08,125.36,125.11,77.41,62.68,57.04,57.01,43.62,33.48,32.06,31.72,29.86,29.83,29.49,27.62,26.39,22.82,22.78,21.63,21.57,20.87,20.26；HRMS(+ESI):calcd for C31H36N4m/z＝464.2940,[M+H]+found465.2881。
WJ-33：19,21-二(邻二溴苯基)嘧啶并苦参碱，红褐色固体，收率26％，熔点178.3～179.1℃；1HNMR(500MHz,CDCl3)δ:7.69～7.60(m,2H),7.57(ddd,J＝8.1,3.1,1.1Hz,1H),7.40～7.31(m,2H),7.27(t,J＝2.7Hz,1H),7.25～7.18(m,2H),3.54(q,J＝7.3Hz,1H),3.46～3.30(m,2H),2.76(d,J＝12.3Hz,1H),2.70(d,J＝12.0Hz,1H),2.56～2.39(m,1H),2.37(s,1H),1.90(s,1H),1.71(s,1H),1.55(s,3H),1.45～1.33(m,4H),1.31～1.23(m,6H).；13C NMR(126MHz,CDCl3)δ:170.16,139.38,133.39,133.18,131.15,130.17,129.70,129.42,127.75,127.35,121.87(d,J＝15.8Hz),77.41,63.39,62.21,58.62,56.87,53.01,50.77,45.72,43.57,38.83,34.56,32.35,30.23,29.79,27.35,25.87,23.41,20.71,20.56,20.17,14.93；HRMS(+ESI):calcd for C29H30Br2N4m/z＝592.0837,[M+H]+found593.0355。
WJ-34：19,21-二(间二氯苯基)嘧啶并苦参碱，红褐色固体，收率34％，熔点108.8～109.1℃；1H NMR(500MHz,CDCl3)δ:8.29(s,1H),8.25(d,J＝7.7Hz,1H),7.39～7.32(m,5H),7.23(d,J＝6.2Hz,1H),3.20(d,J＝12.3Hz,1H),2.89(q,J＝7.3Hz,1H),2.75(d,J＝44.9Hz,3H),2.50(s,2H),1.67(s,1H),1.37(d,J＝6.2Hz,6H),1.36～1.22(m,8H)；13C NMR(126MHz,CDCl3)δ:134.48,134.33,129.77,129.73,129.13,128.66,128.46,128.32,128.23,126.42,126.23,125.39,62.24,56.82,46.05,43.77,32.84,31.99,27.32,26.20,25.72,22.80,21.61,20.72,20.21；HRMS(+ESI):calcd for C29H30Cl2N4m/z＝504.1848,[M+H]+found505.1515。
WJ-35：19,21-二(邻二甲氧苯基)嘧啶并苦参碱，红棕色固体，收率21％，熔点119.8～121.1℃；1H NMR(500MHz,CDCl3)δ:7.69～7.60(m,2H),7.57(ddd,J＝8.1,3.1,1.1Hz,1H),7.40～7.31(m,2H),7.27(t,J＝2.7Hz,1H),7.25～7.18(m,2H),3.54(q,J＝7.3Hz,1H),3.46～3.30(m,2H),2.76(d,J＝12.3Hz,1H),2.70(d,J＝12.0Hz,1H),2.56～2.39(m,5H),2.37(s,1H),1.90(s,1H),1.71(s,1H),1.55(s,3H),1.45～1.33(m,6H),1.31～1.23(m,6H)；13C NMR(126MHz,CDCl3)δ:158.02,133.77,131.91,130.45,129.32,123.22,121.95,118.91,111.85,111.44,77.41,77.16,63.08,57.26,57.23,56.37,55.60,51.48,44.51,34.57,33.50,31.77,29.77,27.48,26.17,23.43,21.10,20.59；HRMS(+ESI):calcdfor C31H36N4O2m/z＝496.2838,[M+H]+found 497.2198。
通过本发明制备的上述嘧啶并苦参碱衍生物(WJ-01～WJ-35)，其构成纯度在99％以上。
实施例1制备得到的化合物WJ-01～WJ-35的分子式和结构式如表1所示：
表1并嘧啶类苦参碱衍生物一览
Figure BDA0003198147180000211
Figure BDA0003198147180000221
Figure BDA0003198147180000231
药理实验：体外抗肿瘤活性研究
选取所有合成的目标化合物，以苦参碱为阳性对照药，选择人前列腺癌细胞DU-145、人非小细胞肺癌细胞A549、人结直肠腺癌细胞HCT15和人宫颈癌细胞HeLa为测试细胞株，采用MTT法进行了抑制细胞活性实验，具体方法为：
用DMSO将待测化合物溶解为10mmol/L的母液，苦参碱直接用培养基溶解，置于冰箱中0℃至4℃保存，测定时用培养基稀释为所需的浓度。将96孔板培养基抽离，吸取0.01mL含有不同浓度测试药品的培养基于细胞计数板中记数，计算细胞总量。向96孔板中每孔加入0.2mL细胞悬液，大约1000个细胞。12h细胞贴壁后，每孔加入20μL(5mg/mL)的MTT试剂，轻晃混匀后置于培养箱培养4h。移去上层清液每孔避光加入0.2mL DMSO，脱色摇床轻摇10min，最后用酶标仪(490nm波长)测每孔OD值。
抑制率(％)＝(OD对照组-OD实验组)*100％/(OD阴性对照组-OD空白对照组)
使用IBM SPSS Statistics软件计算出抑制率为50％的参考数值，即为IC50参考数值。每个96孔板测定时设置5个接种细胞但不加待测化合物的对照孔和5个既不接种细胞也不加待测化合物的空白孔，待测化合物每个浓度用3个孔测试，总共测试三次取平均值。结果如表2所示。
表2目标化合物的体外抗肿瘤活性
Figure BDA0003198147180000241
Figure BDA0003198147180000251
由表2可得，本发明的苦参碱并嘧啶衍生物对人前列腺癌细胞DU-145、人非小细胞肺癌细胞A549、人结直肠腺癌细胞HCT15和人宫颈癌细胞HeLa具有良好的抑制活性，均高于苦参碱的活性。
以上所述，仅为本发明较佳的具体实施方式，本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明披露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围内。

Claims (4)

1.一种苦参碱并嘧啶衍生物，其特征在于，所述苦参碱并嘧啶衍生物为
Figure FDA0003198147170000011
或通式(Ⅰ)所代表的化合物，或通式(II)所代表的化合物：
Figure FDA0003198147170000012
所述通式(Ⅰ)中，R为A01～A28中的一种：
Figure FDA0003198147170000021
所述通式(II)中，R1为B01～B06中的一种：
Figure FDA0003198147170000031
2.一种权利要求1所述的苦参碱并嘧啶衍生物的制备方法，其特征在于，所述结构式为
Figure FDA0003198147170000032
的苦参碱并嘧啶衍生物及所述通式(Ⅰ)所代表的苦参碱并嘧啶衍生物的制备方法，包括以下步骤：以苦参碱为原料，经过氯代甲酰化反应得到中间产物，之后经成环反应，得到所述结构式为
Figure FDA0003198147170000033
的苦参碱并嘧啶衍生物；继续进行酰化反应得到通式(Ⅰ)所代表的苦参碱并嘧啶衍生物；
所述通式(II)所代表的苦参碱并嘧啶衍生物的制备方法，包括以下步骤：
在LDA的作用下苦参碱形成十四位的碳负离子，该碳负离子活性中间体再与取代苯甲腈进行亲核加成反应，脱去一分子水得到通式(II)所代表的苦参碱并嘧啶衍生物。
3.权利要求1所述的苦参碱并嘧啶衍生物在制备抗癌药物中的应用。
4.根据权利要求3所述的应用，其特征在于，所述抗癌药物为抗人前列腺癌细胞、人非小细胞肺癌细胞、人结直肠腺癌细胞和人宫颈癌细胞的药物。
CN202110896510.1A 2021-08-05 2021-08-05 一种苦参碱并嘧啶衍生物及其制备方法和应用 Active CN113563340B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110896510.1A CN113563340B (zh) 2021-08-05 2021-08-05 一种苦参碱并嘧啶衍生物及其制备方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110896510.1A CN113563340B (zh) 2021-08-05 2021-08-05 一种苦参碱并嘧啶衍生物及其制备方法和应用

Publications (2)

Publication Number Publication Date
CN113563340A true CN113563340A (zh) 2021-10-29
CN113563340B CN113563340B (zh) 2023-06-06

Family

ID=78170488

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110896510.1A Active CN113563340B (zh) 2021-08-05 2021-08-05 一种苦参碱并嘧啶衍生物及其制备方法和应用

Country Status (1)

Country Link
CN (1) CN113563340B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114621226A (zh) * 2022-04-21 2022-06-14 广西大学 一种苦参碱衍生物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
姜文泰等: "新型嘧啶并苦参碱衍生物的合成及抗肿瘤活性" *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114621226A (zh) * 2022-04-21 2022-06-14 广西大学 一种苦参碱衍生物及其制备方法和应用
CN114621226B (zh) * 2022-04-21 2023-06-06 广西大学 一种苦参碱衍生物及其制备方法和应用

Also Published As

Publication number Publication date
CN113563340B (zh) 2023-06-06

Similar Documents

Publication Publication Date Title
CN101323591A (zh) 一类5-位或6-位取代的萘酰亚胺化合物及抗肿瘤应用
CN112679549B (zh) 一种8-羟基喹啉衍生物铱(ⅲ)配合物及其制备方法、应用
CN112125911B (zh) Cdk9抑制剂及其制备方法与应用
WO2021008588A1 (zh) 一类嘧啶喹啉衍生物及其制备方法和应用
CN111039990B (zh) 低毒性的铱配合物及其合成方法和应用
CN108147995A (zh) 一种毒性低的1,8-萘二甲酰亚胺衍生物及其合成方法和应用
CN113061138A (zh) 一种三氮唑[5,4-d]嘧啶酮三环类化合物及制备方法和用途
CN110041310A (zh) 一种伊马替尼衍生物的制备方法和应用
CN110372703A (zh) 五元杂环并嘧啶类化合物及其用途
CN104072493A (zh) 一类含2-巯基苯并噻唑和三唑杂环的萘酰亚胺化合物，其制备方法及其应用
CN113563340B (zh) 一种苦参碱并嘧啶衍生物及其制备方法和应用
CN106810560B (zh) 一种8-氮杂香豆素的合成方法及其在抗肿瘤药物中的应用
CN110878046A (zh) 基于2-甲基-5,7-二氯-8-羟基喹啉构筑的稀土配合物及其制备方法和应用
CN108164463A (zh) 一种具有非小细胞肺癌选择性抑制作用的1,8-萘二甲酰亚胺衍生物及其合成方法和应用
CN102558042B (zh) 4-溴-6-甲基烟酸及其制备方法
CN110642740B (zh) 异斯特维醇酰胺衍生物及其制备方法
CN108997341B (zh) 酰胺-朝格尔碱衍生物及其合成方法与应用
CN103880890A (zh) 新型抗肿瘤药物钌（ⅱ）配合物及其制备方法
CN110156735A (zh) 芒柄花黄素衍生物及其制备方法和应用
CN108358927B (zh) 1,4-二取代1,2,3-三氮唑核苷类似物及其制备方法和应用
CN112608341B (zh) 一种混合喹啉衍生物铱(ⅲ)配合物及其制备方法、应用
CN105153027A (zh) 一种3-氰基-4-羟基-2-吡啶酮类化合物及其制备和应用
CN110156672B (zh) 一种氨基脲化合物制备方法以及制得化合物的应用
CN110016011B (zh) 酰胺衍生物及其医药用途
CN108864110B (zh) 萘醌并吡喃衍生物及其合成方法与应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant