CN108640919A - 含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及其制备方法 - Google Patents

含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及其制备方法 Download PDF

Info

Publication number
CN108640919A
CN108640919A CN201810232086.9A CN201810232086A CN108640919A CN 108640919 A CN108640919 A CN 108640919A CN 201810232086 A CN201810232086 A CN 201810232086A CN 108640919 A CN108640919 A CN 108640919A
Authority
CN
China
Prior art keywords
sophoridine
matrine
solution
nmr
dichloromethane
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
CN201810232086.9A
Other languages
English (en)
Other versions
CN108640919B (zh
Inventor
王立升
敬德旺
王浩东
许亦明
吴黎川
刘旭
江俊
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 CN201810232086.9A priority Critical patent/CN108640919B/zh
Publication of CN108640919A publication Critical patent/CN108640919A/zh
Application granted granted Critical
Publication of CN108640919B publication Critical patent/CN108640919B/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

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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及其制备方法。这些化合物由苦参碱或槐定碱作为起始原料，经过催化加热后与芳胺发生脱水反应成为含芳基脒结构的亚胺类衍生物，并由含有2‑氰基苯基的亚胺类衍生物通过碱催化自身环合为氨基喹啉类衍生物，最后通过体外药理活性实验对得到的化合物进行活性筛选和评估。本发明具有原料易得、操作简单、反应条件温和、产率较高的优点，通过体外药理实验表明氨基喹啉类衍生物对多种癌细胞增殖具有较强的抑制作用，有适用于临床肿瘤研究的潜力。

Description

含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及 其制备方法
技术领域
本发明涉及苦参碱亚胺和氨基喹啉衍生物的合成以及槐定碱亚胺和氨基喹啉衍生物的合成，以及这些化合物在抗肿瘤研究中的应用。
背景技术
苦参碱(matrine)和槐定碱(sophoridine)是苦参、苦豆子和山豆根等豆科的干燥根、植株、果实经乙醇等有机溶剂提取制成的生物总碱中两种重要单体。除了苦参碱和槐定碱之外生物总碱中还含有槐果碱、氧化槐果碱等多种生物碱。苦参碱和槐定碱是具有四环的喹喏里西啶类生物碱，其结构区别是苦参碱C-5位氢原子为S构型，而槐定碱C-5位氢原子为R构型。苦参碱纯品外观为白色粉末，槐定碱纯品外观为白色粗针状结晶或大棱柱状结晶，在溶解性上两者均难溶于石油醚，槐定碱比苦参碱更易溶于水、乙醇、二氯甲烷等溶剂。
恶性肿瘤现已成为危害人类健康的最严重疾病之一，抗肿瘤药物是当今医药科学研究的一个重要领域。处方药复方苦参注射液功能主治清热利湿，凉血解毒，散结止痛，用于癌肿疼痛、出血。然而在对复方苦参注射液中重要单体研究中发现，苦参碱、槐定碱等单个化合物本身并没有太多的活性，多种化合物的组合，可能是有效的，并也意味着很少的副作用。因此，通过结构改造的方法提高苦参碱或槐定碱的抗肿瘤活性是非常有前景的。
发明内容
本发明目的在于克服现有技术的不足，提供一类具有较强抗肿瘤活性的苦参碱或槐定碱衍生物。
本发明技术方案为通过结构改造得到一类含有苯环、喹啉环等芳环的苦参碱和槐定碱衍生物。
为了实现上述目的，本发明采用了以下技术方案：
本发明提供以上化合物的合成方法，采用以下反应路线：
与现有技术相比较，本发明具备的有益效果：
实验数据表明，本发明中氨基喹啉类化合物对癌细胞增殖有较强抑制作用，具有较高的抗肿瘤活性。
具体实施方式
下面通过实施例对本发明的技术方案作进一步阐述。
实施例1
化合物JM-01的制备方法，步骤如下：
(1)将5mmol(1.24g)苦参碱溶于30ml二氯甲烷(DCM)中，室温搅拌下滴加2eq(10mmol)的三氯氧磷(POCl3)，待溶液由无色变为浅黄后置于60℃油浴锅中搅拌回流1～3h直至溶液变为棕红色。
(2)恢复溶液至室温，并向其边搅拌边滴加1～1.5eq(5～7.5mmol)苯胺的DCM溶液，滴毕后继续将溶液置于60℃油浴锅中搅拌回流12h。
(3)待反应完毕后，将溶液恢复至室温，搅拌下缓慢滴加冷的NaOH溶液或者NaHCO3饱和溶液，中和反应液pH至8～9后搅拌10min，用水和DCM萃取三次，合并有机相。
(4)将有机溶液浓缩，上硅胶柱，
用石油醚(PE)：DCM：乙酸乙酯(EA)＝5：1：1到DCM：EA＝1：1梯度洗脱，
得到洗脱液经浓缩后重结晶，得到JM-01。
JM-01:(E)-15-(N-苯基)苦参碱，浅黄色粉末，收率73％,熔点116.8～117.6℃。
1H NMR(600MHz,Chloroform-d)δ7.25–7.16(m,2H),6.96–6.87(m,1H),6.73–6.67(m,2H),4.39(dd,J＝12.9,4.5Hz,1H),3.70(m,1H),3.16(t,J＝12.7Hz,1H),2.86–2.79(m,2H),2.40(m,1H),2.10(t,J＝3.1Hz,1H),2.09–2.00(m,2H),1.99–1.89(m,3H),1.89–1.76(m,2H),1.73–1.61(m,3H),1.52(m,2H),1.50–1.25(m,5H).13C NMR(151MHz,CDCl3)δ157.78,151.89,128.60,122.33,121.15,64.14,57.44,57.33,53.78,43.78,42.94,34.68,27.99,27.79,27.38,26.70,21.37,20.99,19.98.
化合物JM-02～JM-29的制备参考化合物JM-01的技术方案，以苦参碱和相应的芳胺为原料，并根据薄层色谱(TLC)中展开剂和产物点比移值选择适当的洗脱剂。
JM-02:(E)-15-(N-4-甲基苯基)苦参碱，浅黄色晶体，收率68％,熔点92.5～95.1℃。
1H NMR(600MHz,Chloroform-d)δ7.03(d,J＝7.8Hz,2H),6.61(d,J＝7.9Hz,2H),4.40(dd,J＝12.9,4.5Hz,1H),3.70(m,1H),3.15(t,J＝12.7Hz,1H),2.84(m,2H),2.50–2.37(m,1H),2.29(s,3H),2.11(d,J＝3.1Hz,1H),2.10–2.00(m,2H),2.00–1.87(m,3H),1.94–1.78(m,2H),1.76–1.60(m,3H),1.53(m,2H),1.48–1.35(m,5H).13C NMR(151MHz,CDCl3)δ158.03,149.24,130.27,129.22,122.13,64.19,57.46,57.35,53.81,43.75,42.95,34.69,27.98,27.83,27.32,26.72,21.38,21.00,20.77,20.02.
JM-03:(E)-15-(N-4-乙基苯基)苦参碱,白色固体，收率75％，熔点103.7～104.8℃。
1H NMR(600MHz,Chloroform-d)δ7.08–7.01(m,2H),6.66–6.58(m,2H),4.39(dd,J＝12.9,4.5Hz,1H),3.74–3.60(m,1H),3.15(t,J＝12.7Hz,1H),2.88–2.80(m,2H),2.59(q,J＝7.6Hz,2H),2.43(m,1H),2.11(t,J＝3.1Hz,1H),2.10–2.04(m,2H),2.03–1.92(m,3H),1.92–1.78(m,2H),1.75–1.61(m,3H),1.56–1.49(m,2H),1.47–1.32(m,5H),1.21(t,J＝7.6Hz,3H).13C NMR(151MHz,CDCl3)δ157.99,149.34,136.85,127.96,122.13,64.20,57.45,57.34,53.81,43.79,42.95,34.68,28.19,27.98,27.83,27.36,26.71,21.38,20.99,20.01,15.79.
JM-04:(E)-15-(N-4-异丙基苯基)苦参碱，黄色固体，收率69％,熔点134.1～135.6℃。
1H NMR(600MHz,Chloroform-d)δ7.20–6.94(m,2H),6.78–6.33(m,2H),4.39(dd,J＝12.9,4.5Hz,1H),3.70(m,1H),3.15(t,J＝12.7Hz,1H),2.90–2.79(m,3H),2.45(m,1H),2.12(t,J＝3.1Hz,1H),2.11–2.00(m,2H),2.00–1.91(m,3H),1.91–1.75(m,2H),1.76–1.58(m,3H),1.54(m,2H),1.42(m,5H),1.23(d,J＝6.9Hz,6H).13C NMR(151MHz,CDCl3)δ157.96,149.30,141.55,126.50,122.04,64.21,57.45,57.35,53.82,43.82,42.94,34.67,33.39,27.98,27.83,27.38,26.71,24.23,24.21,21.38,20.99,20.01.
JM-05:(E)-15-(N-4-叔丁基苯基)苦参碱，白色粉末，收率77％,熔点161.9～162.3℃。
1H NMR(600MHz,Chloroform-d)δ7.26–7.16(m,2H),6.68–6.60(m,2H),4.40(dd,J＝12.9,4.5Hz,1H),3.83–3.63(m,1H),3.16(t,J＝12.7Hz,1H),2.84(m,2H),2.46(m,1H),2.12(d,J＝3.1Hz,1H),2.12–2.06(m,2H),2.03–1.91(m,3H),1.88(m,2H),1.75–1.65(m,3H),1.59–1.51(m,2H),1.47–1.37(m,5H),1.30(s,9H).13C NMR(151MHz,CDCl3)δ157.91,148.94,143.78,125.39,121.72,64.22,57.46,57.35,53.81,43.82,42.93,34.66,34.07,31.57,27.99,27.84,27.39,26.71,21.39,21.00,20.03.
JM-06:(E)-15-(N-4-甲氧基苯基)苦参碱，棕黄色油状液体，收率45％。
1H NMR(600MHz,Chloroform-d)δ6.85–6.77(m,2H),6.67–6.54(m,2H),4.39(dd,J＝12.9,4.5Hz,1H),3.78(s,3H),3.73–3.67(m,1H),3.15(t,J＝12.7Hz,1H),2.84(m,2H),2.42(m,1H),2.12(d,J＝3.1Hz,1H),2.11–2.03(m,2H),2.02–1.94(m,3H),1.94–1.80(m,2H),1.81–1.54(m,3H),1.54–1.46(m,2H),1.46–1.22(m,5H).13C NMR(151MHz,CDCl3)δ158.50,154.47,145.15,122.99,114.01,64.17,57.44,57.34,55.47,53.82,43.75,42.96,34.69,27.97,27.82,27.32,26.71,21.37,20.99,20.01.
JM-07:(E)-15-(N-4-乙氧基苯基)苦参碱，浅棕色固体，收率55％,熔点107.2～110.2℃。
1H NMR(600MHz,Chloroform-d)δ6.79–6.74(m,2H),6.67–6.56(m,2H),4.38(dd,J＝12.9,4.5Hz,1H),3.98(q,J＝7.0Hz,2H),3.75–3.61(m,1H),3.14(t,J＝12.7Hz,1H),2.83(m,2H),2.41(m,1H),2.10(t,J＝3.1Hz,1H),2.09–1.99(m,2H),1.99–1.88(m,3H),1.88–1.72(m,2H),1.72–1.57(m,3H),1.52(m,2H),1.45–1.34(m,8H).13C NMR(151MHz,CDCl3)δ158.55,153.82,144.99,122.99,114.76,64.16,63.64,57.43,57.32,53.81,43.78,42.95,34.68,27.95,27.80,27.33,26.69,21.36,20.97,19.97,15.00.
JM-08:(E)-15-(N-4-甲硫基苯基)苦参碱，灰黑色粉末，收率49％,熔点：106.1～107.1℃。
1H NMR(600MHz,Chloroform-d)δ7.24–7.09(m,2H),6.71–6.53(m,2H),4.37(dd,J＝12.9,4.5Hz,1H),3.70(td,J＝9.6,5.1Hz,1H),3.14(t,J＝12.7Hz,1H),2.82(m,2H),2.43(d,J＝1.6Hz,3H),2.39(m,1H),2.10(t,J＝3.0Hz,1H),2.08–2.01(m,2H),2.00–1.88(m,4H),1.88–1.74(m,2H),1.75–1.58(m,3H),1.52(m,2H),1.47–1.24(m,4H).13C NMR(151MHz,CDCl3)δ157.98,150.07,129.12,129.02,123.02,64.10,57.40,57.30,53.74,43.76,42.97,34.69,27.95,27.73,27.42,26.66,21.35,20.95,19.85,17.72.
JM-09:(E)-15-(N-3,4亚甲二氧基苯基)苦参碱，粉色粉末，收率71％,熔点96.9～97.4℃。
1H NMR(600MHz,Chloroform-d)δ6.60(d,J＝8.1Hz,1H),6.20(d,J＝2.1Hz,1H),6.07(dd,J＝8.1,2.1Hz,1H),5.81(s,2H),4.29(dd,J＝12.9,4.5Hz,1H),3.74–3.58(m,1H),3.07(t,J＝12.7Hz,1H),2.82–2.69(m,2H),2.37(m,1H),2.04(t,J＝3.0Hz,1H),2.02–1.93(m,2H),1.92–1.82(m,3H),1.76(m,2H),1.72–1.58(m,3H),1.58–1.44(m,2H),1.44–1.16(m,5H).13C NMR(151MHz,CDCl3)δ158.47,147.58,146.61,141.98,114.04,107.95,103.87,100.54,64.05,57.36,57.25,53.70,43.68,42.88,34.62,27.93,27.70,27.19,26.63,21.31,20.91,19.89.
JM-10:(E)-15-(N-3,4,5-三甲氧基苯基)苦参碱，白色粉末，收率53％,熔点137.2～138.3℃。
1H NMR(600MHz,Chloroform-d)δ5.91(s,2H),4.34(dd,J＝12.9,4.2Hz,1H),3.91–3.61(m,10H),3.11(t,J＝12.8Hz,1H),2.79(dd,J＝32.4,11.2Hz,2H),2.43(d,J＝16.2Hz,1H),2.06(d,J＝18.6Hz,3H),1.92(m,3H),1.85–1.56(m,5H),1.55–1.45(m,2H),1.37(m,5H).13C NMR(151MHz,CDCl3)δ158.13,153.15,148.16,132.62,99.36,64.06,60.93,57.37,57.26,55.89,53.71,43.69,42.95,34.68,27.93,27.72,27.33,26.63,21.31,20.92,19.90.
JM-11:(E)-15-(N-4-氟苯基)苦参碱，浅黄色晶体粉末，收率66％,熔点122.7～122.9℃。
1H NMR(600MHz,Chloroform-d)δ7.01–6.84(m,2H),6.69–6.55(m,2H),4.38(dd,J＝12.9,4.5Hz,1H),3.71(m,1H),3.15(t,J＝12.7Hz,1H),2.83(m,2H),2.38(m,1H),2.11(t,J＝3.1Hz,1H),2.10–1.89(m,5H),1.82(m,2H),1.76–1.59(m,3H),1.53(m,2H),1.42(m,5H).13C NMR(151MHz,CDCl3)δ159.03,158.36,157.45,147.89,123.21,123.15,115.17,115.02,64.10,57.41,57.30,53.76,43.73,42.96,34.69,27.95,27.72,27.33,26.67,21.34,20.95,19.85.19F NMR(565MHz,CDCl3)δ-124.11.
JM-12:(E)-15-(N-4-氯苯基)苦参碱，白色粉末，收率57％,熔点106.4～107.9℃。
1H NMR(600MHz,Chloroform-d)δ7.21–7.14(m,2H),6.72–6.61(m,2H),4.38(dd,J＝12.8,4.5Hz,1H),3.72(m,1H),3.16(t,J＝12.7Hz,1H),2.84(m,2H),2.38(m,1H),2.12(t,J＝3.1Hz,1H),2.11–2.01(m,2H),2.01–1.91(m,3H),1.90–1.74(m,2H),1.75–1.61(m,3H),1.54(m,2H),1.50–1.21(m,5H).13C NMR(151MHz,CDCl3)δ158.00,150.57,128.59,126.19,123.66,64.08,57.41,57.30,53.73,43.74,42.99,34.71,27.95,27.70,27.40,26.66,21.34,20.95,19.79.
JM-13:(E)-15-(N-4-溴苯基)苦参碱，白色粉末，收率63％,熔点115.0～115.5℃。
1H NMR(600MHz,Chloroform-d)δ7.39–7.22(m,2H),6.68–6.51(m,2H),4.37(dd,J＝12.9,4.5Hz,1H),3.71(m,1H),3.15(t,J＝12.7Hz,1H),2.83(m,2H),2.36(m,1H),2.11(t,J＝3.1Hz,1H),2.10–1.97(m,2H),1.97–1.84(m,3H),1.84–1.71(m,2H),1.70–1.53(m,3H),1.53–1.44(m,2H),1.45–1.20(m,5H).13CNMR(151MHz,CDCl3)δ157.90,151.06,131.51,124.20,113.78,64.06,57.39,57.29,53.71,43.73,42.99,34.71,27.94,27.68,27.41,26.65,21.33,20.94,19.75.
JM-14:(E)-15-(N-4-硝基苯基)苦参碱，黄色粉末，收率69％,熔点167.2～167.9℃。
1H NMR(600MHz,Chloroform-d)δ8.10(d,J＝8.8Hz,2H),6.76(d,J＝8.8Hz,2H),4.41(dd,J＝12.9,4.5Hz,1H),3.79(m,1H),3.20(t,J＝12.7Hz,1H),2.91–2.79(m,2H),2.44–2.31(m,1H),2.21–2.08(m,3H),2.04–1.90(m,3H),1.89–1.63(m,5H),1.61–1.40(m,7H).13C NMR(151MHz,CDCl3)δ158.97,157.15,141.66,124.92,122.45,63.89,57.32,57.23,53.69,43.96,43.13,34.85,27.89,27.50,26.55,21.27,21.05,20.87,19.42.
JM-15:(E)-15-(N-4-三氟甲基苯基)苦参碱，白色晶体，收率68％,熔点144.7～145.7℃。
4-CF3:1H NMR(600MHz,Chloroform-d)δ7.45(d,J＝8.3Hz,2H),6.77(d,J＝8.2Hz,2H),4.40(dd,J＝12.9,4.5Hz,1H),3.74(m,,1H),3.17(t,J＝12.7Hz,1H),2.87–2.79(m,2H),2.35(m,1H),2.12(t,J＝3.1Hz,1H),2.11–2.03(m,2H),2.00–1.90(m,3H),1.83(m,2H),1.76–1.61(m,3H),1.54(m,2H),1.49–1.36(m,5H).13C NMR(151MHz,CDCl3)δ157.54,155.37,125.83,125.80,125.78,125.76,123.99,123.04,122.82,122.39,64.02,57.37,57.27,53.68,43.79,43.02,34.74,27.94,27.61,27.55,26.61,21.31,20.91,19.64.
JM-16:(E)-15-(N-4-三氟甲氧基苯基)苦参碱，白色粉末，收率76％,熔点147.6～148.1℃。
4OCF3:1H NMR(600MHz,Chloroform-d)δ7.11–7.02(m,2H),6.71–6.64(m,2H),4.38(dd,J＝12.9,4.5Hz,1H),3.76–3.69(m,1H),3.16(t,J＝12.7Hz,1H),2.83(m,2H),2.38(m,1H),2.12(t,J＝3.1Hz,1H),2.11–2.00(m,2H),2.00–1.89(m,3H),1.89–1.77(m,2H),1.76–1.61(m,3H),1.54(m,2H),1.50–1.35(m,5H).13C NMR(151MHz,CDCl3)δ157.98,150.75,143.57,143.56,123.08,121.47,119.78,64.07,57.39,57.29,53.72,43.75,42.98,34.70,27.95,27.67,27.41,26.64,21.33,20.93,19.76.19F NMR(565MHz,CDCl3)δ-58.18.
JM-17:(E)-15-(N-4-甲磺酰基苯基)苦参碱，白色粉末，收率66％,熔点188.2～188.7℃。
1H NMR(600MHz,Chloroform-d)δ7.75–7.51(m,2H),6.94–6.59(m,2H),4.30(dd,J＝12.8,4.4Hz,1H),3.83–3.59(m,1H),3.08(t,J＝12.7Hz,1H),2.93(s,3H),2.73(m,2H),2.26(m,1H),2.07–1.92(m,3H),1.92–1.79(m,3H),1.79–1.50(m,5H),1.49–1.40(m,2H),1.40–1.27(m,5H).13C NMR(151MHz,CDCl3)δ157.48,157.26,131.88,128.19,122.83,63.82,57.24,57.14,53.57,44.80,43.77,42.96,34.70,27.86,27.65,27.41,26.47,21.22,20.79,19.36.
JM-18:(E)-15-(N-2-甲基-3-硝基苯基)苦参碱，黄色晶体，收率84％,熔点124.0～124.9℃。
1H NMR(600MHz,Chloroform-d)δ7.40(dd,J＝8.1,1.2Hz,1H),7.14(t,J＝8.0Hz,1H),6.84(dd,J＝7.9,1.2Hz,1H),4.42(dd,J＝12.9,4.5Hz,1H),3.78(m,1H),3.22(t,J＝12.7Hz,1H),2.90–2.81(m,2H),2.23(s,3H),2.19(m,1H),2.15(d,J＝3.1Hz,1H),2.12–1.91(m,5H),1.90–1.60(m,5H),1.60–1.52(m,2H),1.51–1.20(m,5H).13C NMR(151MHz,CDCl3)δ157.67,152.58,151.21,126.00,125.97,124.35,116.95,64.08,57.38,57.29,53.76,43.95,42.86,34.77,27.94,27.58,27.43,26.63,21.31,20.91,19.51,13.86.
JM-19:(E)-15-(N-2,6-二溴-4-甲基苯基)苦参碱，白色粉末，收率51％,熔点163.2～163.7℃。
1H NMR(600MHz,Chloroform-d)δ7.40–7.23(m,2H),4.49(dd,J＝12.8,4.4Hz,1H),3.86(m,1H),3.27(t,J＝12.6Hz,1H),2.86(m,2H),2.25(s,3H),2.16(t,J＝3.1Hz,1H),2.16–1.89(m,6H),1.93–1.65(m,5H),1.58(m,2H),1.54–1.18(m,5H).13C NMR(151MHz,CDCl3)δ159.03,145.97,132.88,132.14,132.11,117.85,117.58,64.38,57.46,57.38,53.50,44.31,42.77,34.65,27.92,27.64,26.88,26.69,21.33,20.96,20.05,18.77.
JM-20:(E)-15-(N-4-联苯基)苦参碱，棕色油状液体，收率49％。
1H NMR(600MHz,Chloroform-d)δ7.64–7.59(m,2H),7.52–7.47(m,2H),7.42(t,J＝7.7Hz,2H),7.33–7.24(m,1H),6.81(d,J＝8.1Hz,2H),4.45(dd,J＝12.9,4.5Hz,1H),3.76(m,1H),3.21(t,J＝12.7Hz,1H),2.95–2.81(m,2H),2.50(m,1H),2.19–2.08(m,3H),2.06–1.80(m,5H),1.80–1.63(m,3H),1.61–1.52(m,2H),1.52–1.25(m,5H).13C NMR(151MHz,CDCl3)δ157.92,141.31,134.01,128.60,127.32,126.58,126.36,122.80,118.43,64.16,57.43,57.34,53.84,43.89,43.01,34.75,27.96,27.77,27.54,26.69,21.36,20.98,19.88.
JM-21:(E)-15-(N-4-苯氧基苯基)苦参碱，白色粉末，收率58％,熔点132.0～132.3℃。
1H NMR(600MHz,Chloroform-d)δ7.34–7.24(m,2H),7.09–7.01(m,1H),7.00–6.95(m,2H),6.95–6.86(m,2H),6.74–6.66(m,2H),4.41(dd,J＝12.9,4.5Hz,1H),3.73(m,1H),3.18(t,J＝12.7Hz,1H),2.86(m,2H),2.47(m,1H),2.11(m,3H),2.05–1.92(m,3H),1.85(m,2H),1.76–1.68(m,3H),1.54(m,2H),1.51–1.22(m,5H).13C NMR(151MHz,CDCl3)δ158.72,158.27,150.81,147.95,129.49,123.35,122.12,120.26,117.52,64.15,57.44,57.33,53.81,43.80,42.98,34.70,27.97,27.78,27.40,26.69,21.36,20.98,19.94.
JM-22:(E)-15-(N-2-氰基苯基)苦参碱，无色晶体，收率79％,熔点135.9～136.6℃。
1H NMR(600MHz,Chloroform-d)δ7.36(t,J＝6.1Hz,1H),7.27(t,J＝7.6Hz,1H),6.80(m,1H),6.68(dd,J＝8.7,3.7Hz,1H),4.36(m,1H),3.73(m,1H),3.11(m,1H),2.83–2.54(m,2H),2.17(m,1H),2.03(m,2H),1.98–1.91(m,1H),1.91–1.78(m,3H),1.78–1.53(m,4H),1.53–1.40(m,2H),1.32(m,6H).13C NMR(151MHz,CDCl3)δ157.63,155.78,133.01,132.52,123.14,120.86,118.51,105.58,63.97,57.25,57.18,53.40,44.02,42.72,34.50,27.88,27.41,26.93,26.48,21.23,20.81,18.85.
JM-23:(E)-15-(N-2-甲酸甲酯苯基)苦参碱，白色晶体，收率76％,熔点152.0～152.7℃。
1H NMR(600MHz,Chloroform-d)δ7.79(dd,J＝7.8,1.6Hz,1H),7.34(m,1H),6.94(m,1H),6.74(dd,J＝8.0,1.2Hz,1H),4.38(dd,J＝12.8,4.4Hz,1H),3.81(s,3H),3.21(t,J＝12.6Hz,1H),2.85(m,2H),2.26(m,1H),2.15(t,J＝3.0Hz,1H),2.12–2.04(m,1H),2.03–1.92(m,5H),1.92–1.62(m,5H),1.61–1.52(m,2H),1.52–1.23(m,5H).13C NMR(151MHz,CDCl3)δ167.91,156.98,153.15,132.38,130.77,124.20,122.51,120.73,64.33,57.48,57.37,53.59,51.62,43.97,42.82,34.64,27.99,27.74,27.46,26.70,21.37,20.99,19.40.
JM-24:(E)-15-(N-2-吡啶基)苦参碱，灰白色粉末，收率55％,熔点131.2～132.2℃。
1H NMR(600MHz,Chloroform-d)δ8.25(dd,J＝5.0,2.0Hz,1H),7.47(m,1H),6.75(m,1H),6.72–6.62(m,1H),4.55(dd,J＝12.8,4.4Hz,1H),3.80–3.71(m,1H),3.15(t,J＝12.7Hz,1H),2.79(m,2H),2.38(m,1H),2.28(m,1H),2.12–2.00(m,2H),1.96–1.81(m,4H),1.80–1.56(m,4H),1.53–1.34(m,7H).13C NMR(151MHz,CDCl3)δ163.69,158.80,148.39,137.11,117.67,116.38,64.01,57.33,57.24,53.39,43.70,43.19,34.77,28.08,27.87,27.50,26.53,21.28,20.89,19.25.
JM-25:(E)-15-(N-1-萘基)苦参碱，浅粉色固体，收率46％,熔点146.3～146.7℃。
1H NMR(600MHz,Chloroform-d)δ7.92(dd,J＝8.2,1.3Hz,1H),7.80(dd,J＝7.9,1.4Hz,1H),7.48–7.35(m,4H),6.76(dd,J＝7.2,1.1Hz,1H),4.61(dd,J＝12.9,4.5Hz,1H),3.85–3.72(m,1H),3.33(t,J＝12.7Hz,1H),2.94–2.85(m,2H),2.31(m,1H),2.20(t,J＝3.1Hz,1H),2.10(m,1H),2.08–1.94(m,4H),1.90(m,1H),1.83–1.74(m,2H),1.65(m,4H),1.53–1.23(m,5H).13C NMR(151MHz,CDCl3)δ158.21,148.23,134.45,128.59,127.78,126.13,125.55,124.69,124.08,121.20,116.34,64.28,57.49,57.39,53.98,44.10,42.89,34.83,28.02,27.68,27.36,26.73,21.41,21.01,19.94.
JM-26:(E)-15-(N-2-萘基)苦参碱，灰白色粉末，收率57％,熔点175.8～177.6℃。
1H NMR(600MHz,Chloroform-d)δ7.76(dd,J＝8.2,1.1Hz,1H),7.72(d,J＝8.6Hz,1H),7.69(dd,J＝8.4,1.1Hz,1H),7.40(m,1H),7.31(m,1H),7.10(d,J＝1.9Hz,1H),6.99(dd,J＝8.5,2.1Hz,1H),4.49(dd,J＝12.9,4.5Hz,1H),3.84–3.68(m,1H),3.23(t,J＝12.7Hz,1H),2.87(m,2H),2.46(m,1H),2.24–2.02(m,4H),2.02–1.81(m,5H),1.81–1.67(m,3H),1.67–1.22(m,6H).13C NMR(151MHz,CDCl3)δ158.05,149.70,134.59,129.56,128.22,127.57,126.72,125.70,124.30,123.29,117.58,64.17,57.45,57.35,53.81,43.84,43.04,34.78,28.00,27.79,27.70,26.70,21.39,21.00,19.91.
JM-27:(E)-15-(N-4-溴-1-萘基)苦参碱，灰色粉末，收率39％,熔点138.7～141.4℃。
1H NMR(600MHz,Chloroform-d)δ8.17(m,1H),7.95(dd,J＝8.5,1.3Hz,1H),7.64(d,J＝7.9Hz,1H),7.56(m,1H),7.45(m,1H),6.62(d,J＝7.9Hz,1H),4.60(dd,J＝12.9,4.5Hz,1H),3.87–3.71(m,1H),3.32(t,J＝12.7Hz,1H),2.88(m,2H),2.28(m,1H),2.18(t,J＝3.0Hz,1H),2.13–2.06(m,1H),2.05–1.81(m,6H),1.77(m,1H),1.74–1.55(m,4H),1.52–1.24(m,5H).13C NMR(151MHz,CDCl3)δ158.19,148.47,132.47,129.98,126.99,125.43,124.67,116.87,114.25,64.17,57.45,57.35,53.92,44.05,42.93,34.87,28.00,27.59,27.42,26.69,21.38,20.98,19.79.
JM-28:(E)-15-(N-4-硝基-1-萘基)苦参碱，棕红色油状液体，收率83％。
1H NMR(600MHz,Chloroform-d)δ8.86(dt,J＝8.7,0.9Hz,1H),8.38(d,J＝8.4Hz,1H),8.17–8.03(m,1H),7.70(m,1H),7.52(m,1H),6.71(d,J＝8.3Hz,1H),4.60(dd,J＝12.9,4.4Hz,1H),3.99–3.85(m,1H),3.36(t,J＝12.7Hz,1H),2.94–2.86(m,2H),2.37–2.28(m,1H),2.21(t,J＝3.0Hz,1H),2.14(m,2H),2.08–2.02(m,2H),2.01–1.93(m,2H),1.86(m,1H),1.80–1.68(m,3H),1.67–1.56(m,2H),1.54–1.31(m,5H).13C NMR(151MHz,CDCl3)δ157.30,156.27,139.03,129.53,128.84,127.22,127.21,125.83,125.15,123.70,114.16,64.00,57.36,57.28,53.87,44.27,43.09,35.03,27.95,27.43,26.59,21.31,20.89,19.43.
JM-29:(E)-15-(N-5-甲基-2-噻唑基)苦参碱，灰白色粉末，收率39％,熔点182.1～184.5℃。
1H NMR(600MHz,Chloroform-d)δ6.95(q,J＝1.3Hz,1H),4.67(dd,J＝12.8,4.3Hz,1H),3.89–3.77(m,1H),3.17(t,J＝12.7Hz,1H),2.88–2.76(m,3H),2.49(m,1H),2.33(d,J＝1.4Hz,3H),2.14–2.06(m,2H),2.06–1.89(m,3H),1.89–1.68(m,3H),1.68–1.58(m,1H),1.56–1.25(m,8H).13C NMR(151MHz,CDCl3)δ172.05,160.92,136.34,127.19,63.83,57.27,57.19,53.48,43.87,43.46,35.04,28.25,27.82,27.15,26.49,21.24,20.84,18.64,12.46.
化合物JS-01～JS-29的制备参考化合物JM-01的技术方案，以槐定碱和相应的芳胺(JS-29使用2-(N-Boc-氨基)噻吩)为反应原料，并根据薄层色谱(TLC)中展开剂和产物点比移值选择适当的洗脱剂。重要的，JS类化合物加热时反应温度约为65℃～70℃，洗脱剂中石油醚比例适当减少，二氯甲烷和乙酸乙酯比例适当增加，必要时加适量甲醇提高洗脱剂极性。
JS-01:(E)-15-(N-苯基)槐定碱，浅黄色油状液体，收率61％。
1H NMR(600MHz,Chloroform-d)δ7.25–7.17(m,2H),6.93(m,1H),6.77–6.67(m,2H),3.62(dd,J＝13.3,5.2Hz,1H),3.37(m,1H),3.27(dd,J＝13.2,11.7Hz,1H),2.89(m,1H),2.79(m,1H),2.36(m,1H),2.22(m,1H),2.19–2.11(m,2H),2.11–1.93(m,3H),1.92–1.78(m,2H),1.77–1.65(m,2H),1.65–1.41(m,5H),1.40–1.00(m,3H).13C NMR(151MHz,CDCl3)δ156.93,151.98,128.63,122.62,121.26,63.80,55.95,55.38,50.43,50.02,41.97,31.45,30.29,29.09,27.41,23.99,21.68,21.02,19.19.
JS-02:(E)-15-(N-4-甲基苯基)槐定碱，浅黄色油状液体，收率59％。
1H NMR(600MHz,Chloroform-d)δ7.01(d,J＝8.0Hz,2H),6.71–6.42(m,2H),3.60(dd,J＝13.3,5.2Hz,1H),3.41–3.29(m,1H),3.24(dd,J＝13.3,11.6Hz,1H),2.86(m,1H),2.76(m,1H),2.34(m,1H),2.27(s,3H),2.23–2.07(m,3H),2.07–1.90(m,3H),1.90–1.63(m,5H),1.62–1.39(m,4H),1.38–0.85(m,3H).13CNMR(151MHz,CDCl3)δ157.07,149.31,130.29,129.21,122.36,63.83,55.96,55.35,50.45,50.00,42.01,31.48,30.32,29.12,27.35,24.04,21.71,20.99,20.77,19.21.
JS-03:(E)-15-(N-4-乙基苯基)槐定碱，黄色油状液体，收率54％。
1H NMR(600MHz,Chloroform-d)δ7.02(m,2H),6.66(m,2H),3.61(m,1H),3.45–3.19(m,2H),3.01–2.70(m,2H),2.56(m,2H),2.33(m,1H),2.28–2.07(m,4H),2.06–1.77(m,5H),1.76–1.27(m,7H),1.32–1.16(m,3H),1.16–0.96(m,2H).13C NMR(151MHz,CDCl3)δ157.56,147.99,137.52,128.03,122.71,63.32,55.75,55.61,50.14,50.11,41.60,31.05,30.07,28.85,28.17,27.36,23.53,21.50,21.06,18.96,15.70.
JS-04:(E)-15-(N-4-异丙基苯基)槐定碱，黄色油状液体，收率71％。
1H NMR(600MHz,Chloroform-d)δ7.10–6.93(m,2H),6.70–6.57(m,2H),3.61(dd,J＝13.3,5.3Hz,1H),3.45–3.31(m,1H),3.25(dd,J＝13.3,11.7Hz,1H),2.94–2.82(m,2H),2.78(m,1H),2.38(m,1H),2.24–2.10(m,4H),2.09–1.92(m,3H),1.92–1.77(m,3H),1.77–1.65(m,2H),1.64–1.41(m,4H),1.39–1.26(m,1H),1.23(d,J＝6.9Hz,6H),1.10(m,1H).13CNMR(151MHz,CDCl3)δ157.04,149.43,141.57,126.49,122.26,63.78,55.96,55.42,50.41,49.99,42.02,33.37,31.41,30.33,29.18,27.39,24.21,23.99,21.73,21.04,19.27.
JS-05:(E)-15-(N-4-叔丁基苯基)槐定碱，浅黄色油状液体，收率39％。
1H NMR(600MHz,Chloroform-d)δ7.25–7.10(m,2H),6.78–6.48(m,2H),3.62(dd,J＝13.3,5.3Hz,1H),3.36(m,1H),3.26(dd,J＝13.3,11.8Hz,1H),2.88(m,1H),2.79(m,1H),2.40(m,1H),2.26–2.11(m,3H),2.11–1.78(m,7H),1.71(m,1H),1.64–1.42(m,4H),1.42–1.32(m,1H),1.30(s,9H),1.28–1.17(m,1H),1.16–0.86(m,1H).13C NMR(151MHz,CDCl3)δ157.05,149.01,143.87,125.39,121.96,63.76,55.96,55.44,50.40,49.99,42.03,34.08,31.57,31.39,30.33,29.19,27.41,23.97,21.74,21.06,19.28.
JS-06:(E)-15-(N-4-甲氧基苯基)槐定碱，浅灰色粉末，收率49％，熔点125.4～125.8℃。
1H NMR(600MHz,Chloroform-d)δ6.86–6.74(m,2H),6.70–6.54(m,2H),3.77(s,3H),3.60(dd,J＝13.3,5.1Hz,1H),3.35(m,1H),3.24(dd,J＝13.2,11.6Hz,1H),2.87(m,1H),2.77(m,1H),2.35(m,1H),2.29–2.08(m,4H),2.09–1.92(m,3H),1.92–1.75(m,2H),1.77–1.64(m,2H),1.62–1.41(m,4H),1.40–0.78(m,3H).13C NMR(151MHz,CDCl3)δ157.55,154.47,145.25,123.21,113.99,63.83,55.96,55.44,55.36,50.45,50.03,42.01,31.48,30.31,29.12,27.38,24.03,21.70,20.99,19.23.
JS-07:(E)-15-(N-4-乙氧基苯基)槐定碱，黄色油状液体，收率43％。
1H NMR(600MHz,Chloroform-d)δ6.86–6.71(m,2H),6.68–6.61(m,2H),3.97(q,J＝7.0Hz,2H),3.59(dd,J＝13.3,5.2Hz,1H),3.34(m,1H),3.24(dd,J＝13.2,11.7Hz,1H),2.86(m,1H),2.76(m,1H),2.38–2.28(m,2H),2.19(m,1H),2.16–2.10(m,2H),2.10–1.90(m,3H),1.91–1.75(m,2H),1.75–1.64(m,2H),1.62–1.40(m,4H),1.38(t,J＝7.0Hz,3H),1.36–0.96(m,3H).13C NMR(151MHz,CDCl3)δ157.54,153.80,145.12,123.19,114.72,63.80,63.61,55.95,55.36,50.43,50.02,41.99,31.45,30.31,29.11,27.37,24.01,21.69,21.00,19.22,15.00.
JS-08:(E)-15-(N-4-甲硫基苯基)槐定碱，棕色粉末，收率53％，熔点93～95.5℃。
1H NMR(600MHz,Chloroform-d)δ7.25–7.10(m,2H),6.68(dd,J＝8.6,2.1Hz,2H),3.59(m,1H),3.35(m,1H),3.23(dd,J＝13.2,11.6Hz,1H),2.87(m,1H),2.77(m,1H),2.44(d,J＝2.2Hz,3H),2.37–2.32(m,1H),2.32–2.09(m,4H),2.09–1.92(m,3H),1.91–1.75(m,2H),1.76–1.64(m,2H),1.63–1.42(m,4H),1.40–0.83(m,3H).13C NMR(151MHz,CDCl3)δ157.12,150.19,129.21,128.95,123.24,63.80,55.95,55.35,50.44,50.03,41.96,31.46,30.28,29.04,27.42,24.01,21.67,20.99,19.15,17.65.
JS-09:(E)-15-(N-3,4亚甲二氧基苯基)槐定碱，棕黄色油状液体，收率69％。
1H NMR(600MHz,Chloroform-d)δ6.65(d,J＝8.1Hz,1H),6.27(d,J＝2.0Hz,1H),6.14(dd,J＝8.2,2.1Hz,1H),5.86(s,2H),3.55(dd,J＝13.3,5.1Hz,1H),3.32(m,1H),3.19(m,1H),2.84(m,1H),2.74(m,1H),2.41–2.28(m,1H),2.24–2.05(m,3H),2.06–1.89(m,3H),1.89–1.62(m,5H),1.61–1.37(m,4H),1.36–0.91(m,3H).13C NMR(151MHz,CDCl3)δ157.63,147.58,146.73,142.04,114.37,108.00,104.13,100.58,63.78,55.92,55.31,50.42,49.98,41.94,31.43,30.27,29.04,27.22,24.00,21.65,20.96,19.16.
JS-10:(E)-15-(N-3,4,5-三甲氧基苯基)槐定碱，浅黄色固体，收率56％，熔点125.1～126.4℃。
1H NMR(600MHz,Chloroform-d)δ5.95(s,2H),3.77(s,6H),3.76(s,3H),3.55(dd,J＝13.3,5.2Hz,1H),3.32(m,1H),3.20(dd,J＝13.3,11.7Hz,1H),2.84(m,1H),2.74(m,1H),2.47–2.13(m,4H),2.10–1.88(m,4H),1.89–1.74(m,2H),1.68(m,2H),1.61–1.42(m,4H),1.42–0.76(m,3H).13C NMR(151MHz,CDCl3)δ157.32,153.15,148.23,132.69,99.60,63.74,60.96,55.90,55.35,50.39,50.02,41.97,31.40,30.26,29.06,27.18,23.95,21.65,20.98,19.19.
JS-11:(E)-15-(N-4-氟苯基)槐定碱，浅黄色晶体，收率65％，熔点124.2～125.4℃。
1H NMR(600MHz,Chloroform-d)δ6.95–6.83(m,2H),6.69–6.56(m,2H),3.58(dd,J＝13.2,5.0Hz,1H),3.35(m,1H),3.22(dd,J＝13.2,11.5Hz,1H),2.87(m,1H),2.77(m,1H),2.38–2.26(m,2H),2.19(m,1H),2.15–1.94(m,5H),1.94–1.80(m,2H),1.80–1.60(m,3H),1.59–1.45(m,3H),1.45–0.96(m,3H).13CNMR(151MHz,CDCl3)δ159.05,157.47,157.41,148.03,148.01,123.42,123.37,115.17,115.03,63.84,55.95,55.31,50.46,50.02,41.95,31.49,30.27,29.01,27.35,24.04,21.65,20.96,19.13.19F NMR(565MHz,CDCl3)δ-124.04.
JS-12:(E)-15-(N-4-氯苯基)槐定碱，黄色固体，收率75％，熔点100.0～101.9℃。
1H NMR(600MHz,Chloroform-d)δ7.15(d,J＝8.3Hz,2H),6.65(d,J＝8.4Hz,2H),3.57(dd,J＝13.3,5.1Hz,1H),3.35(m,1H),3.22(t,J＝12.4Hz,1H),2.97–2.81(m,1H),2.77(m,1H),2.32–2.26(m,1H),2.20(m,1H),2.12(m,2H),2.10–1.91(m,3H),1.90–1.81(m,2H),1.81–1.65(m,3H),1.65–1.44(m,4H),1.44–0.81(m,3H).13C NMR(151MHz,CDCl3)δ157.14,150.65,128.60,126.28,123.87,63.75,55.91,55.33,50.41,50.01,41.88,31.41,30.24,28.95,27.37,23.95,21.61,20.98,19.07.
JS-13:(E)-15-(N-4-溴苯基)槐定碱，黄色固体，收率59％，熔点96.7～99.2℃。
1H NMR(600MHz,Chloroform-d)δ7.35–7.23(m,2H),6.60(d,J＝429.1Hz,2H),3.57(dd,J＝13.3,5.0Hz,1H),3.35(m,1H),3.21(dd,J＝13.2,11.5Hz,1H),2.86(m,1H),2.76(m,1H),2.45–2.26(m,2H),2.19(m,1H),2.11(m,2H),2.08–1.91(m,3H),1.90–1.84(m,1H),1.83–1.65(m,3H),1.63–1.44(m,4H),1.44–0.93(m,3H).13C NMR(151MHz,CDCl3)δ157.03,151.18,131.52,124.41,113.87,63.79,55.93,55.31,50.44,50.03,41.91,31.46,30.25,28.95,27.39,24.01,21.63,20.96,19.07.
JS-14:(E)-15-(N-4-硝基苯基)槐定碱，黄色油状液体，收率44％。
1H NMR(600MHz,Chloroform-d)δ8.09(dd,J＝8.9,1.8Hz,2H),6.77(dd,J＝8.7,1.5Hz,2H),3.58(dd,J＝13.5,5.5Hz,1H),3.41(m,1H),3.28(t,J＝12.6Hz,1H),3.05–2.93(m,1H),2.88(m,1H),2.44–2.16(m,5H),2.10(m,2H),2.02–1.87(m,3H),1.86–1.70(m,2H),1.69–1.47(m,5H),1.45–1.06(m,2H).13C NMR(151MHz,CDCl3)δ158.97,156.45,141.89,124.92,122.60,63.15,55.65,55.53,50.03,49.88,41.40,30.82,29.93,28.64,27.62,23.19,21.26,21.06,18.81.
JS-15:(E)-15-(N-4-三氟甲基苯基)槐定碱，黄色固体，收率65％，熔点77.2～80.2℃。
1H NMR(600MHz,Chloroform-d)δ7.44(d,J＝8.3Hz,2H),6.79(d,J＝8.2Hz,2H),3.58(dd,J＝13.3,5.0Hz,1H),3.37(m,1H),3.23(dd,J＝13.2,11.5Hz,1H),2.87(m,1H),2.77(m,1H),2.29(m,1H),2.24–2.08(m,4H),2.07–1.91(m,3H),1.91–1.77(m,2H),1.70(m,2H),1.63–1.42(m,5H),1.40–0.94(m,2H).13CNMR(151MHz,CDCl3)δ156.74,155.51,125.84,125.82,125.79,125.77,123.97,123.17,122.95,122.60,63.76,55.90,55.32,50.41,50.03,41.87,31.42,30.22,28.89,27.46,23.96,21.58,20.95,18.99.
JS-16:(E)-15-(N-4-三氟甲氧基苯基)槐定碱，浅黄色油状液体，收率65％。
1H NMR(600MHz,Chloroform-d)δ7.15–6.94(m,2H),6.79–6.62(m,2H),3.58(dd,J＝13.3,4.9Hz,1H),3.36(m,1H),3.22(dd,J＝13.2,11.5Hz,1H),2.87(m,1H),2.77(m,1H),2.33(m,1H),2.22–1.92(m,7H),1.91–1.77(m,2H),1.71(m,2H),1.63–1.43(m,4H),1.42–1.21(m,2H),1.08(m,1H).13C NMR(151MHz,CDCl3)δ157.11,150.86,143.65,143.63,123.30,121.47,119.77,63.84,55.94,55.31,50.46,50.02,41.95,31.48,30.25,28.98,27.39,24.03,21.63,20.96,19.08.19F NMR(565MHz,CDCl3)δ-58.18.
JS-17:(E)-15-(N-4-甲磺酰基苯基)槐定碱，棕黄色油状液体，收率59％。
1H NMR(600MHz,Chloroform-d)δ7.84–7.49(m,2H),6.87–6.64(m,2H),3.52(dd,J＝13.4,5.2Hz,1H),3.33(m,1H),3.17(dd,J＝13.4,11.6Hz,1H),2.97(s,3H),2.83(m,1H),2.73(m,1H),2.25(m,1H),2.20–2.00(m,5H),2.00–1.85(m,2H),1.83–1.77(m,2H),1.76–1.43(m,6H),1.43–0.67(m,3H).13C NMR(151MHz,CDCl3)δ157.69,156.56,132.13,128.26,123.05,63.56,55.80,55.32,50.30,50.01,44.82,41.69,31.23,30.13,28.72,27.54,23.79,21.49,20.94,18.86.
JS-18:(E)-15-(N-2-甲基-3-硝基苯基)槐定碱，黄色粉末，收率69％，熔点111.2～113.1℃。
1H NMR(600MHz,Chloroform-d)δ7.36(dd,J＝8.1,1.3Hz,1H),7.11(t,J＝8.0Hz,1H),6.85(dd,J＝7.9,1.3Hz,1H),3.59(dd,J＝13.3,4.7Hz,1H),3.36(m,1H),3.27(dd,J＝13.2,11.3Hz,1H),2.85(m,1H),2.75(m,1H),2.21(s,3H),2.17(dd,J＝11.6,7.7Hz,1H),2.15–2.08(m,3H),2.08–2.01(m,1H),1.99(m,2H),1.88–1.75(m,2H),1.68(m 2H),1.60–1.41(m,5H),1.38–1.00(m,3H).13C NMR(151MHz,CDCl3)δ156.70,152.72,151.17,126.38,126.01,124.38,117.00,63.73,55.89,55.38,50.37,50.05,41.88,31.30,30.27,28.86,27.57,23.94,21.63,20.99,18.92,13.86.
JS-19:(E)-15-(N-2,6-二溴-4-甲基苯基)槐定碱，白色粉末，收率79％，熔点135.5～137.2℃。
1H NMR(600MHz,Chloroform-d)δ7.28–7.23(m,2H),3.60(dd,J＝13.3,5.5Hz,1H),3.48–3.25(m,2H),2.91–2.68(m,2H),2.20(s,3H),2.20–2.10(m,3H),2.10–1.96(m,4H),1.96–1.75(m,3H),1.73–1.60(m,3H),1.61–1.15(m,5H),1.10(m,1H).13C NMR(151MHz,CDCl3)δ157.55,154.47,145.25,123.21,113.99,63.83,55.96,55.44,55.36,50.45,50.03,42.01,31.48,30.31,29.12,27.38,24.03,21.70,20.99,19.23.
JS-20:(E)-15-(N-4-联苯基)槐定碱，黄色粉末，收率56％，熔点116.9～117.7℃。
1H NMR(600MHz,Chloroform-d)δ7.60(dd,J＝8.2,1.3Hz,2H),7.54–7.46(m,2H),7.41(t,J＝7.7Hz,2H),7.33–7.24(m,1H),6.87–6.77(m,2H),3.64(dd,J＝13.3,5.1Hz,1H),3.37(m,1H),3.29(dd,J＝13.2,11.6Hz,1H),2.88(m,1H),2.78(m,1H),2.47–2.41(m,1H),2.28–2.17(m,2H),2.14(m,1H),2.09–1.77(m,5H),1.72(m,2H),1.66–1.42(m,4H),1.41–1.24(m,2H),1.18–0.86(m,2H).13C NMR(151MHz,CDCl3)δ156.96,151.47,141.30,133.93,128.61,127.29,126.55,126.35,122.97,63.83,55.97,55.39,50.46,50.07,42.01,31.49,30.33,29.11,27.50,24.06,21.71,21.02,19.22.
JS-21:(E)-15-(N-4-苯氧基苯基)槐定碱，白色粉末，收率85％，熔点115.8～121.7℃。
1H NMR(600MHz,Chloroform-d)δ7.33–7.26(m,2H),7.03(m,1H),6.99–6.95(m,2H),6.94–6.89(m,2H),6.76–6.68(m,2H),3.62(dd,J＝13.2,5.1Hz,1H),3.38(m,1H),3.26(dd,J＝13.2,11.6Hz,1H),2.89(m,1H),2.79(m,1H),2.41(m,1H),2.27–2.10(m,3H),2.09–1.93(m,4H),1.93–1.79(m,2H),1.73(m,2H),1.65–1.43(m,4H),1.41–0.84(m,3H).13C NMR(151MHz,CDCl3)δ158.72,157.32,150.82,148.05,129.49,123.55,122.12,120.26,117.52,63.82,55.96,55.37,50.45,50.06,41.99,31.46,30.30,29.09,27.41,24.01,21.68,21.01,19.21.
JS-22:(E)-15-(N-2-氰基苯基)槐定碱，白色晶体，收率79％，熔点167.0～167.6℃。
1H NMR(600MHz,Chloroform-d)δ7.50(dd,J＝7.7,1.5Hz,1H),7.39(m,1H),6.95(t,J＝7.5Hz,1H),6.83(d,J＝8.1Hz,1H),3.65(dd,J＝13.4,5.1Hz,1H),3.42(m,1H),3.32(t,J＝12.5Hz,1H),2.89(m,1H),2.80(m,1H),2.35–1.80(m,9H),1.73(m,2H),1.67–1.44(m,5H),1.44–0.76(m,3H).13C NMR(151MHz,CDCl3)δ157.24,155.91,133.12,132.77,123.43,121.19,118.64,105.97,63.66,55.88,55.34,50.39,50.09,41.76,31.36,30.07,28.73,27.40,23.93,21.51,20.94,18.79.
JS-23:(E)-15-(N-2-甲酸甲酯基苯基)槐定碱，白色粉末，收率55％，熔点103.4～106.9℃。
1H NMR(600MHz,Chloroform-d)δ7.79(m,1H),7.38–7.30(m,1H),6.94(m,1H),6.76(m,1H),3.80(d,J＝2.2Hz,3H),3.60(m,1H),3.44–3.36(m,1H),3.30(dd,J＝13.1,11.5Hz,1H),2.88(m,1H),2.82–2.69(m,1H),2.30–1.92(m,10H),1.91–1.64(m,3H),1.63–1.41(m,3H),1.41–0.71(m,3H).13C NMR(151MHz,CDCl3)δ167.69,156.31,153.46,132.46,130.80,124.49,122.51,120.82,63.74,55.94,55.36,51.57,50.36,49.97,41.93,31.25,30.33,28.98,27.67,23.88,21.73,21.09,18.93.
JS-24:(E)-15-(N-2-吡啶基)槐定碱，黄色固体，45％，熔点68.7～72.2℃。
1H NMR(600MHz,Methanol-d4)δ8.22(dd,J＝5.1,1.9Hz,1H),7.70(m,1H),6.99(dd,J＝7.2,5.2Hz,1H),6.84(d,J＝8.1Hz,1H),3.55(dd,J＝13.3,5.8Hz,1H),3.49–3.41(m,1H),3.42–3.34(m,1H),2.95(m,1H),2.89(m,1H),2.42–2.24(m,5H),2.10(m,2H),1.99–1.86(m,4H),1.86–1.70(m,2H),1.69–1.58(m,3H),1.60–1.40(m,2H),1.17(m,1H).13C NMR(151MHz,MeOD)δ163.20,159.51,147.22,138.32,118.34,117.41,62.56,55.75,55.25,49.91,49.32,41.05,29.94,29.77,27.92,27.36,22.29,21.25,21.03,18.07.
JS-25：(E)-15-(N-1-萘基)槐定碱，白色粉末，收率55％，熔点105.3～109.6℃。
1H NMR(600MHz,Chloroform-d)δ7.95(dd,J＝8.3,1.4Hz,1H),7.80(dd,J＝7.9,1.4Hz,1H),7.49–7.34(m,4H),6.80(dd,J＝7.2,1.1Hz,1H),3.81(dd,J＝13.3,5.2Hz,1H),3.56–3.30(m,2H),2.92(m,1H),2.82(m,1H),2.29–2.04(m,7H),2.04–1.83(m,3H),1.76(m,1H),1.67–1.49(m,5H),1.49–1.33(m,2H),1.31–1.08(m,1H).13C NMR(151MHz,CDCl3)δ157.13,148.45,134.49,128.63,127.83,126.15,125.50,124.67,124.00,121.22,116.81,63.86,56.00,55.54,50.43,50.20,42.08,31.44,30.41,29.12,27.26,24.01,21.77,21.09,19.20.
JS-26：(E)-15-(N-2-萘基)槐定碱，浅粉色粉末，收率48％，熔点137.3～138.0℃。
1H NMR(600MHz,Chloroform-d)δ7.76(dd,J＝8.2,1.2Hz,1H),7.72(d,J＝8.6Hz,1H),7.69(dd,J＝8.4,1.1Hz,1H),7.39(m,1H),7.31(m,1H),7.13(d,J＝2.0Hz,1H),7.00(dd,J＝8.6,2.1Hz,1H),3.68(dd,J＝13.3,5.1Hz,1H),3.40(m,1H),3.33(dd,J＝13.3,11.6Hz,1H),2.89(m,1H),2.80(m,1H),2.39(m,1H),2.31–1.94(m,7H),1.94–1.66(m,4H),1.65–1.43(m,4H),1.43–1.05(m,3H).13C NMR(151MHz,CDCl3)δ157.21,149.79,134.59,129.60,128.23,127.56,126.73,125.67,124.46,123.32,117.91,63.83,55.97,55.41,50.45,50.11,42.00,31.49,30.33,29.07,27.69,24.03,21.70,21.03,19.19.
JS-27：(E)-15-(N-4-溴-1-萘基)槐定碱，白色粉末，收率64％，熔点82.6～86.8℃。
1H NMR(600MHz,Chloroform-d)δ8.86(m,1H),8.38(d,J＝8.3Hz,1H),8.27–8.06(m,1H),7.70(m,1H),7.53(m,1H),6.76(d,J＝8.4Hz,1H),3.80(dd,J＝13.4,4.6Hz,1H),3.56–3.28(m,2H),2.93(m,1H),2.83(m,1H),2.35–2.05(m,6H),2.05–1.69(m,5H),1.63–1.39(m,4H),1.38–0.84(m,4H).13C NMR(151MHz,CDCl3)δ156.56,156.45,139.21,129.51,128.81,127.19,127.14,125.88,125.03,123.74,114.58,63.82,55.95,55.55,50.45,50.39,41.96,31.48,30.26,28.87,27.67,24.00,21.61,21.02,18.95.
JS-28：(E)-15-(N-4-硝基-1-萘基)槐定碱，橙黄色粉末，收率83％，熔点碳化。
1H NMR(600MHz,Chloroform-d)δ8.86(m,1H),8.38(d,J＝8.4Hz,1H),8.13(m,1H),7.70(m,1H),7.53(m,1H),6.76(d,J＝8.4Hz,1H),3.79(dd,J＝13.5,4.4Hz,1H),3.54–3.34(m,2H),2.93(m,1H),2.83(m,1H),2.35–2.06(m,8H),1.92(m,2H),1.77–1.63(m,3H),1.62–1.39(m,4H),1.36–1.11(m,2H).13C NMR(151MHz,CDCl3)δ156.54,156.46,139.20,129.51,128.81,127.19,127.14,125.87,125.04,123.74,114.57,63.86,55.96,55.54,50.48,50.40,41.98,31.52,30.26,28.87,27.67,24.05,21.62,21.00,18.96.
JS-29：(E)-15-(N-2-噻吩基)槐定碱，浅黄色油状液体，收率29％。
1H NMR(600MHz,Chloroform-d)δ6.79(dd,J＝5.6,3.6Hz,1H),6.73(dd,J＝5.6,1.3Hz,1H),6.18(dd,J＝3.5,1.3Hz,1H),3.59(dd,J＝13.5,4.6Hz,1H),3.38(m,1H),3.28(dd,J＝13.4,11.5Hz,1H),2.87(m,1H),2.77(m,1H),2.69(m,1H),2.38(m,1H),2.26–1.94(m,6H),1.93–1.70(m,3H),1.69–1.42(m,5H),1.41–0.80(m,3H).13C NMR(151MHz,CDCl3)δ159.61,155.94,125.90,116.21,113.79,63.82,55.95,55.31,50.52,50.07,41.71,31.59,30.13,28.64,27.17,24.09,21.56,20.95,18.80.
通过本发明制备的苦参碱和槐定碱亚胺类衍生物，其构成纯度在99％以上。
以下表中给出了亚胺类衍生物的结构式：
实施例2
化合物JM-30的制备方法，步骤如下：
(1)将5mmol(1.24g)苦参碱溶于30ml二氯甲烷(DCM)中，室温搅拌下滴加2eq(10mmol)的三氯氧磷(POCl3)，待溶液由无色变为浅黄后置于60℃油浴锅中搅拌回流1～3h直至溶液变为棕红色。
(2)恢复溶液至室温，并向其边搅拌边滴加1～1.5eq(5～7.5mmol)2-氰基苯胺的DCM溶液，滴毕后继续将溶液置于60℃油浴锅中搅拌回流12h。
(3)待反应完毕后，将溶液恢复至室温，搅拌下缓慢滴加冷的NaOH溶液或者NaHCO3饱和溶液，中和反应液PH至8～9后搅拌10min，用水和DCM萃取三次，合并有机相。
(4)将有机溶液浓缩，上硅胶柱，用石油醚(PE)：DCM：乙酸乙酯(EA)＝5：1：1到DCM：EA＝1：1梯度洗脱，得到洗脱液经浓缩后重结晶，得到中间产物亚胺。
(5)氮气保护、冰浴下，将中间产物亚胺溶于30ml无水四氢呋喃(THF)中，搅拌下分次用干燥注射器缓慢注入3eq～9eq的二异丙基氨基锂(LDA)，并定时取用少量反应液用TLC监测反应进度。
(6)待反应完全后，用水或者饱和氯化铵溶液淬灭反应，分液漏斗中适量DCM三次萃取，合并萃取液，浓缩后用硅胶或者氧化铝柱层析分离出目标产物，并在低温下密封保存。
值得注意的，此反应要控制水和LDA的量以防止副产物过多，并且硅胶柱层析可能会破坏最终目标产物结构。
JM-30，黄色粉末，最终收率53％,熔点197.0～197.2℃。
1H NMR(600MHz,Chloroform-d)δ7.61(d,J＝8.3Hz,1H),7.49(dd,J＝8.2,1.4Hz,1H),7.43(m,1H),7.19–6.99(m,1H),4.92(dd,J＝12.7,4.5Hz,1H),4.33(s,2H),3.94(m,1H),3.34(t,J＝12.6Hz,1H),2.86(m,2H),2.65–2.45(m,2H),2.31–2.10(m,2H),2.05–1.72(m,8H),1.61(m,1H),1.58–1.35(m,4H).13C NMR(151MHz,CDCl3)δ155.78,147.16,144.76,128.32,126.74,120.44,119.40,115.07,99.18,64.45,57.56,57.46,51.56,45.01,39.68,34.98,28.10,26.59,23.24,21.54,21.14,19.47.
化合物JM-31～JM37和JS-30～JS-32的制备参考化合物JM-30的技术方案，以苦参碱或者槐定碱和相应的芳胺为原料，并根据薄层色谱(TLC)中展开剂和产物点比移值选择适当的洗脱剂。
JM-31，黄色粉末，最终收率55％,熔点182.1～184.5℃。
1H NMR(600MHz,Chloroform-d)δ7.53(d,J＝8.9Hz,1H),7.35–7.06(m,2H),4.89(dd,J＝12.8,4.5Hz,1H),4.30(s,2H),3.92(m,1H),3.33(t,J＝12.6Hz,1H),2.86(m,2H),2.56(m,2H),2.45(s,3H),2.26–2.12(m,2H),2.02–1.69(m,8H),1.64–1.35(m,5H).13C NMR(151MHz,CDCl3)δ155.40,145.37,144.38,130.21,129.77,126.62,118.75,114.83,99.31,64.47,57.58,57.47,51.57,45.02,39.70,34.91,28.11,26.62,23.40,21.55,21.48,21.16,19.61.
JM-32，棕色固体，最终收率35％,熔点103.2～105.3℃。
1H NMR(600MHz,Chloroform-d)δ7.58(d,J＝9.1Hz,1H),7.13(dd,J＝9.1,2.7Hz,1H),6.86(d,J＝2.8Hz,1H),4.83(dd,J＝12.8,4.4Hz,1H),4.29(s,2H),3.90(m,1H),3.88(s,3H),3.33(t,J＝12.6Hz,1H),2.86(m,2H),2.56(m,2H),2.34–2.10(m,2H),2.05–1.69(m,8H),1.68–1.35(m,5H).13C NMR(151MHz,CDCl3)δ154.58,154.04,144.28,142.33,128.14,119.05,115.00,100.12,99.82,64.43,57.56,57.46,55.67,51.59,45.10,39.69,34.85,28.10,26.62,23.45,21.54,21.15,19.72.
JM-33，棕色固体，最终收率33％,熔点199.3～202.8℃。
1H NMR(600MHz,Chloroform-d)δ7.58(dd,J＝9.1,5.4Hz,1H),7.20(t,J＝8.9Hz,1H),7.14(d,J＝9.8Hz,1H),4.85(dd,J＝12.7,4.4Hz,1H),4.24(s,2H),3.94(m,1H),3.34(t,J＝12.6Hz,1H),2.87(dd,J＝32.8,11.2Hz,2H),2.57(m,2H),2.29–2.12(m,2H),2.03–1.73(m,8H),1.63–1.36(m,5H).13C NMR(151MHz,CDCl3)δ158.21,156.62,155.39,144.32,144.29,143.97,128.58,128.53,117.51,117.35,114.97,114.92,103.84,103.69,100.07,64.40,57.53,57.43,51.53,44.97,39.73,34.93,28.09,26.58,23.24,21.51,21.11,19.58.19F NMR(565MHz,CDCl3)δ-121.80.
JM-34，棕色固体，最终收率39％,熔点碳化。
1H NMR(600MHz,Chloroform-d)δ7.53(d,J＝8.9Hz,1H),7.46(d,J＝2.3Hz,1H),7.35(dd,J＝8.9,2.3Hz,1H),4.87(dd,J＝12.8,4.5Hz,1H),4.27(s,2H),3.95(m,1H),3.34(t,J＝12.6Hz,1H),2.87(m,2H),2.72–2.48(m,2H),2.29–2.10(m,2H),2.02–1.72(m,8H),1.64–1.39(m,5H).13C NMR(151MHz,CDCl3)δ155.86,145.68,143.93,128.77,128.23,125.47,118.89,115.78,99.93,64.36,57.52,57.42,51.53,44.94,39.77,35.03,28.07,26.56,23.11,21.50,21.09,19.46.
JM-35，灰白色粉末，最终收率41％,熔点碳化。
1H NMR(600MHz,Chloroform-d)δ7.61–7.50(m,1H),7.27(dd,J＝8.9,2.4Hz,1H),7.09(d,J＝2.3Hz,1H),4.90(dd,J＝12.8,4.4Hz,1H),4.33(s,2H),3.93(m,1H),3.34(t,J＝12.6Hz,1H),2.86(m,2H),2.57(m,2H),2.30–2.09(m,2H),2.08–1.93(m,3H),1.94–1.67(m,5H),1.66–1.38(m,5H).13C NMR(151MHz,CDCl3)δ155.02,154.78,144.48,140.42,128.23,125.97,116.19,114.58,99.12,64.47,57.57,57.46,51.67,48.56,39.75,34.97,28.08,26.62,23.39,21.54,21.46,21.43,21.15,19.59.
JM-36，棕红色粉末，最终收率39％,熔点碳化。
1H NMR(600MHz,Chloroform-d)δ8.54(d,J＝2.5Hz,1H),8.19(dd,J＝9.2,2.5Hz,1H),7.51(d,J＝9.3Hz,1H),4.96(dd,J＝12.8,4.5Hz,1H),4.57(s,2H),4.10–3.96(m,1H),3.39(t,J＝12.6Hz,1H),2.87(m,2H),2.66–2.44(m,2H),2.22–2.13(m,2H),2.08–1.70(m,8H),1.67–1.39(m,5H).13C NMR(151MHz,CDCl3)δ157.44,151.32,145.64,140.09,126.84,122.77,117.71,113.63,99.68,64.17,57.42,57.34,51.78,45.07,40.01,35.58,27.99,26.45,22.45,21.41,20.97,18.97.
JM-37，浅黄色粉末，最终收率65％,熔点碳化。
1H NMR(600MHz,Chloroform-d)δ7.77(d,J＝1.9Hz,1H),7.63(d,J＝8.8Hz,1H),7.59(dd,J＝8.8,1.9Hz,1H),4.93(dd,J＝12.8,4.5Hz,1H),4.40(s,2H),3.99(m,1H),3.36(t,J＝12.6Hz,1H),2.86(m,2H),2.69–2.46(m,2H),2.30–2.11(m,2H),2.03–1.69(m,8H),1.66–1.37(m,5H).13C NMR(151MHz,CDCl3)δ156.81,144.96,127.16,125.85,124.23,124.21,124.06,121.73,121.52,117.60,117.57,114.07,99.84,64.30,57.49,57.39,51.57,44.97,39.80,35.20,28.05,26.51,22.85,21.47,21.05,19.26.19F NMR(565MHz,CDCl3)δ-61.10.
JS-30，白色粉末，最终收率66％，熔点150.0～152.2℃。
1H NMR(600MHz,Chloroform-d)δ7.65(dd,J＝8.4,1.2Hz,1H),7.52(dd,J＝8.3,1.3Hz,1H),7.45(m,1H),7.14(m,1H),4.33(s,2H),3.80(dd,J＝12.7,5.3Hz,1H),3.59(dd,J＝12.7,11.3Hz,1H),3.52–3.28(m,1H),2.90(m,1H),2.83(m 1H),2.71–2.49(m,2H),2.24(m,2H),2.20–2.13(m,2H),2.09(m,1H),1.99–1.87(m,2H),1.83–1.70(m,2H),1.63–1.56(m,4H),1.44–0.87(m,2H).13C NMR(151MHz,CDCl3)δ155.71,147.31,143.90,128.37,126.73,120.47,119.51,115.21,99.40,63.34,55.97,54.84,50.16,49.64,40.40,31.89,30.49,25.71,23.58,22.23,22.06,20.18.
JS-31，深棕色固体，最终收率45％，熔点162.9～166.2℃。
1H NMR(600MHz,Chloroform-d)δ7.62(d,J＝9.1Hz,1H),7.15(dd,J＝9.1,2.7Hz,1H),6.88(d,J＝2.8Hz,1H),4.28(s,2H),3.90(s,3H),3.77(dd,J＝12.6,5.3Hz,1H),3.61–3.45(m,1H),3.43m,1H),2.91(m,1H),2.84(m,1H),2.70–2.52(m,2H),2.31–2.10(m,4H),1.99–1.76(m,5H),1.67–1.52(m,4H),1.39–1.13(m,2H).13C NMR(151MHz,CDCl3)δ160.05,154.81,154.07,143.59,128.14,118.96,115.21,100.36,100.17,63.12,55.87,55.67,55.13,49.95,49.87,40.47,31.53,30.43,25.61,23.30,22.40,22.22,20.51.
JS-32，深棕色粉末，最终收率32％，熔点碳化。
1H NMR(600MHz,Chloroform-d)δ7.80(d,J＝2.0Hz,1H),7.67(d,J＝8.8Hz,1H),7.61(dd,J＝8.8,1.9Hz,1H),4.42(s,2H),3.79(dd,J＝12.9,5.6Hz,1H),3.66(dd,J＝12.9,11.1Hz,1H),3.49(M,1H),3.13–2.82(m,2H),2.69–2.52(m,2H),2.43–2.26(m,3H),2.06–1.91(m,3H),1.86–1.71(m,2H),1.66–1.58(m,3H),1.35–1.17(m,4H).13C NMR(151MHz,CDCl3)δ156.56,149.01,144.27,127.12,125.81,124.33,124.31,124.01,121.89,121.68,117.79,117.76,114.29,99.92,62.66,55.51,54.96,49.67,49.41,39.99,31.42,30.31,25.31,22.97,22.09,21.85,19.88.19F NMR(565MHz,CDCl3)δ-61.13.
通过本发明制备的苦参碱和槐定碱氨基喹啉类衍生物，其构成纯度在99％以上。
以下表中给出了氨基喹啉类衍生物的结构式：
实施例3
本发明还包括，所述亚胺和氨基喹啉衍生物在制备抗肿瘤药物中的应用。优选地，所述肿瘤为肝癌(HepG2)和宫颈癌(HeLa)。
实验方法：将上述亚胺和氨基喹啉衍生物用二甲基亚砜(DMSO)溶解稀释成100um的母液。实验时，用培养基将母液稀释成所需测试的浓度。取对数期生长的细胞一瓶，加入胰蛋白酶消化、离心、重悬后显微镜下计数。根据计数结果将细胞按每孔5000个细胞(100ul培养基)的密度接种于96孔板中，置于培养箱中24小时。待细胞贴壁后，小心吸走培养基，加入含有不同浓度待测药品的培养基培养44小时。在每孔中加入5mg/ml的噻唑蓝(MTT)试剂，放入培养箱中培养染色4小时。去除MTT和培养基，在每孔中加入150ul DMSO，振摇5min，用酶标仪在490nm波长下测试每孔的吸光值(OD)计算细胞抑制率。
增殖抑制率％＝(OD对照孔-OD测试孔)*100％/(OD对照孔-OD空白孔)
并用IBM SPSS Statistics 22软件计算出IC50参考数值，即为抑制率为50％的参考数值。每次测试设置对照孔和空白孔，每个药品浓度用三个孔测试，总共测试三次取平均数值。
实验结果如下表所示：
实验数据表明，本发明中氨基喹啉类化合物对癌细胞增殖有较强抑制作用，具有较高的抗肿瘤活性。
附：对应化合物的芳胺指芳环上含伯胺的原料药，不同试剂销售公司可能对某一种药品存在有不同的命名，但是都指的是同一种物质(有统一的CAS号)。
附表芳胺与对应产物编号
实施例4
所述的苦参碱亚胺类衍生物JM-01～JM-29的制备方法，步骤如下：
(1)将5mmol苦参碱溶于25ml二氯甲烷中，室温搅拌下滴加2eq的三氯氧磷，待溶液由无色变为浅黄后置于55℃油浴锅中搅拌回流1h直至溶液变为棕红色；
(2)恢复溶液至室温，并向其边搅拌边滴加含有1eq芳胺或N-Boc保护的芳胺的二氯甲烷溶液，滴毕后继续将溶液置于55℃油浴锅中搅拌回流8h；
(3)待反应完毕后，将溶液恢复至室温，搅拌下缓慢滴加冷的NaOH溶液或者NaHCO3饱和溶液，中和反应液pH至8后搅拌5min，用水和二氯甲烷萃取三次，合并有机相；
(4)将有机溶液浓缩，上硅胶柱，用石油醚：二氯甲烷：乙酸乙酯＝5：1：1到二氯甲烷：乙酸乙酯＝1：1梯度洗脱，得到洗脱液经浓缩后重结晶，得到目标产物。
实施例5
所述的槐定碱亚胺类衍生物JS1～JS29的制备方法，步骤如下：
(1)将5mmol槐定碱溶于35ml二氯甲烷中，室温搅拌下滴加2.5eq的三氯氧磷，待溶液由无色变为浅黄后置于65℃油浴锅中搅拌回流3h直至溶液变为棕红色；
(2)恢复溶液至室温，并向其边搅拌边滴加含有1.5eq芳胺或N-Boc保护的芳胺的二氯甲烷溶液，滴毕后继续将溶液置于65℃油浴锅中搅拌回流12h；
(3)待反应完毕后，将溶液恢复至室温，搅拌下缓慢滴加冷的NaOH溶液或者NaHCO3饱和溶液，中和反应液pH至9后搅拌10min，用水和二氯甲烷萃取三次，合并有机相；
(4)将有机溶液浓缩，上硅胶柱，用石油醚：二氯甲烷：乙酸乙酯＝5：1：1到二氯甲烷：乙酸乙酯＝1：1梯度洗脱，得到洗脱液经浓缩后重结晶，得到目标产物。
实施例5
所述的槐定碱氨基喹啉类衍生物JS-30～JS-32的制备方法，其特征在于，具体步骤如下：
(1)将5mmol苦参碱溶于25ml二氯甲烷中，室温搅拌下滴加2eq的三氯氧磷，待溶液由无色变为浅黄后置于55℃油浴锅中搅拌回流1h直至溶液变为棕红色；
(2)恢复溶液至室温，并向其边搅拌边滴加含有1.5eq邻氰基苯胺类化合物的二氯甲烷溶液，滴毕后继续将溶液置于65℃油浴锅中搅拌回流12h；
(3)待反应完毕后，将溶液恢复至室温，搅拌下缓慢滴加冷的NaOH溶液或者NaHCO3饱和溶液，中和反应液PH至9后搅拌10min，用水和二氯甲烷萃取三次，合并有机相；
(4)将有机溶液浓缩，上硅胶柱，用石油醚：二氯甲烷：乙酸乙酯＝5：1：1到二氯甲烷：乙酸乙酯＝1：1梯度洗脱，得到洗脱液经浓缩后重结晶，得到中间产物亚胺；
(5)氮气保护、冰浴下，将中间产物亚胺溶于35ml无水四氢呋喃中，搅拌下分次用干燥注射器缓慢注入3eq的二异丙基氨基锂；
(6)待反应完全后，用水或者饱和氯化铵溶液淬灭反应，分液漏斗中二氯甲烷三次萃取，合并萃取液，浓缩后用硅胶或者氧化铝柱层析分离出目标产物，并在低温下密封保存。
实施例6
所述的苦参碱氨基喹啉类衍生物JM-30～JM-37的制备方法，其特征在于，具体步骤如下：
(1)将5mmol槐定碱溶于35ml二氯甲烷中，室温搅拌下滴加2.5eq的三氯氧磷，待溶液由无色变为浅黄后置于65℃油浴锅中搅拌回流3h直至溶液变为棕红色；
(2)恢复溶液至室温，并向其边搅拌边滴加含有1.5eq邻氰基苯胺类化合物的二氯甲烷溶液，滴毕后继续将溶液置于65℃油浴锅中搅拌回流12h；
(3)待反应完毕后，将溶液恢复至室温，搅拌下缓慢滴加冷的NaOH溶液或者NaHCO3饱和溶液，中和反应液PH至9后搅拌10min，用水和二氯甲烷萃取三次，合并有机相；
(4)将有机溶液浓缩，上硅胶柱，用石油醚：二氯甲烷：乙酸乙酯＝5：1：1到二氯甲烷：乙酸乙酯＝1：1梯度洗脱，得到洗脱液经浓缩后重结晶，得到中间产物亚胺；
(5)氮气保护、冰浴下，将中间产物亚胺溶于35ml无水四氢呋喃中，搅拌下分次用干燥注射器缓慢注入9eq的二异丙基氨基锂；
(6)待反应完全后，用水或者饱和氯化铵溶液淬灭反应，分液漏斗中二氯甲烷三次萃取，合并萃取液，浓缩后用硅胶或者氧化铝柱层析分离出目标产物，并在低温下密封保存。

Claims (8)

1.苦参碱或槐定碱的亚胺类化合物，其特征在于，所述化合物具有以下结构：
2.根据权利要求1所述的苦参碱亚胺类衍生物JM-01～JM-29和槐定碱亚胺类衍生物JS1～JS29的制备方法，其特征在于，以苦参碱或槐定碱为原料，经过加热和三氯氧磷催化形成氯代苦参碱或氯代槐定碱中间体，然后再与芳胺或N-Boc保护的芳胺加热反应得到目标产物。
3.根据权利要求2所述的苦参碱亚胺类衍生物JM-01～JM-29和槐定碱亚胺类衍生物JS1～JS29的制备方法，其特征在于，具体步骤如下：
(1)将5mmol苦参碱或槐定碱溶于25～35ml二氯甲烷中，室温搅拌下滴加2～2.5eq的三氯氧磷，待溶液由无色变为浅黄后置于55～65℃油浴锅中搅拌回流1～3h直至溶液变为棕红色；
(2)恢复溶液至室温，并向其边搅拌边滴加含有1～1.5eq芳胺或N-Boc保护的芳胺的二氯甲烷溶液，滴毕后继续将溶液置于55～65℃油浴锅中搅拌回流8～12h；
(3)待反应完毕后，将溶液恢复至室温，搅拌下缓慢滴加冷的NaOH溶液或者NaHCO3饱和溶液，中和反应液pH至8～9后搅拌5～10min，用水和二氯甲烷萃取三次，合并有机相；
(4)将有机溶液浓缩，上硅胶柱，用石油醚∶二氯甲烷∶乙酸乙酯＝5∶1∶1到二氯甲烷∶乙酸乙酯＝1∶1梯度洗脱，得到洗脱液经浓缩后重结晶，得到目标产物。
4.根据权利要求2或3所述的苦参碱亚胺类衍生物JM-01～JM-29和槐定碱亚胺类衍生物JS1～JS29的制备方法，其特征在于，
所述芳胺为苯胺、对甲苯胺、4-乙基苯胺、4-异丙基苯胺、4-叔丁基苯胺、对甲氧基苯胺、4-氨基苯乙醚、4-氨基茴香硫醚、3，4-亚甲二氧基苯胺、3，4，5-三甲氧基苯胺、4-氟苯胺、对氯苯胺、4-溴苯胺、4-硝基苯胺、对三氟甲基苯胺、对三氟氧甲基苯胺、4-甲磺酰基苯胺、2-甲基-3-硝基苯胺、2，6-二溴-4-甲基苯胺、4-氨基联苯、4-氨基二苯醚、2-氨基苯甲腈、胺茴酸甲酯、2-氨基吡啶、1-萘胺、2-萘胺、4-溴-1-萘胺、4-硝基-1-萘胺或2-氨基-5-甲基噻唑；
所述N-Boc保护的芳胺为2-(N-Boc-氨基)噻吩。
5.苦参碱或槐定碱氨基喹啉类化合物，其特征在于，所述化合物具有以下结构：
6.根据权利要求5所述的苦参碱氨基喹啉类衍生物JM-30～JM-37和槐定碱氨基喹啉类衍生物JS-30～JS-32的制备方法，其特征在于，以苦参碱或槐定碱为原料，经过加热和三氯氧磷催化形成氯代苦参碱或氯代槐定碱中间体，然后再与邻氰基苯胺类化合物加热反应得到含有氰基的芳基亚胺类衍生物；在冰浴条件和氮气保护下向所述含有氰基的芳基亚胺类衍生物中缓慢滴加二异丙基氨基锂，滴加完毕后恢复温度到室温，得到目标产物。
7.根据权利要求6所述的苦参碱氨基喹啉类衍生物JM-30～JM-37和槐定碱氨基喹啉类衍生物JS-30～JS-32的制备方法，其特征在于，具体步骤如下：
(1)将5mmol苦参碱或槐定碱溶于25～35ml二氯甲烷中，室温搅拌下滴加2～2.5eq的三氯氧磷，待溶液由无色变为浅黄后置于55～65℃油浴锅中搅拌回流1～3h直至溶液变为棕红色；
(2)恢复溶液至室温，并向其边搅拌边滴加含有1～1.5eq邻氰基苯胺类化合物的二氯甲烷溶液，滴毕后继续将溶液置于55～65℃油浴锅中搅拌回流8～12h；
(3)待反应完毕后，将溶液恢复至室温，搅拌下缓慢滴加冷的NaOH溶液或者NaHCO3饱和溶液，中和反应液PH至8～9后搅拌8～1Omin，用水和二氯甲烷萃取三次，合并有机相；
(4)将有机溶液浓缩，上硅胶柱，用石油醚∶二氯甲烷∶乙酸乙酯＝5∶1∶1到二氯甲烷∶乙酸乙酯＝1∶1梯度洗脱，得到洗脱液经浓缩后重结晶，得到中间产物亚胺；
(5)氮气保护、冰浴下，将中间产物亚胺溶于25～35ml无水四氢呋喃中，搅拌下分次用干燥注射器缓慢注入3eq～9eq的二异丙基氨基锂；
(6)待反应完全后，用水或者饱和氯化铵溶液淬灭反应，分液漏斗中二氯甲烷三次萃取，合并萃取液，浓缩后用硅胶或者氧化铝柱层析分离出目标产物，并在低温下密封保存。
8.根据权利要求6或7所述的苦参碱氨基喹啉类衍生物JM-30～JM-37和槐定碱氨基喹啉类衍生物JS-30～JS-32的制备方法，其特征在于，
所述邻氰基苯胺类化合物为2-氨基苯甲腈、2-氨基-5-甲基苯甲腈、2-氨基-5-甲氧基苯甲腈、2-氨基-5-氟苯腈、2-氨基-5-氯苯甲腈、2-氨基-5-溴苯腈、2-氨基-4-硝基苯胺或2-氨基-5-三氟甲基苯腈。
CN201810232086.9A 2018-03-20 2018-03-20 含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及其制备方法 Active CN108640919B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810232086.9A CN108640919B (zh) 2018-03-20 2018-03-20 含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810232086.9A CN108640919B (zh) 2018-03-20 2018-03-20 含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及其制备方法

Publications (2)

Publication Number Publication Date
CN108640919A true CN108640919A (zh) 2018-10-12
CN108640919B CN108640919B (zh) 2020-09-08

Family

ID=63744454

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810232086.9A Active CN108640919B (zh) 2018-03-20 2018-03-20 含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及其制备方法

Country Status (1)

Country Link
CN (1) CN108640919B (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101704817A (zh) * 2009-11-23 2010-05-12 中国人民解放军第二军医大学 新的苦参碱类化合物及其制备方法与应用
CN101863887A (zh) * 2010-06-01 2010-10-20 广西大学 苦参碱衍生物及其制备方法
CN104230932A (zh) * 2013-06-19 2014-12-24 天士力控股集团有限公司 苦参碱衍生物及其制备方法与应用
CN104926814A (zh) * 2015-06-14 2015-09-23 广西大学 苦参碱衍生物及其应用
CN107629053A (zh) * 2017-10-09 2018-01-26 广西大学 烷基、芳基、杂环类槐定碱衍生物制备方法和用途
CN107793416A (zh) * 2017-10-30 2018-03-13 广西大学 硫代苦参碱衍生物及其制备方法与应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101704817A (zh) * 2009-11-23 2010-05-12 中国人民解放军第二军医大学 新的苦参碱类化合物及其制备方法与应用
CN101863887A (zh) * 2010-06-01 2010-10-20 广西大学 苦参碱衍生物及其制备方法
CN104230932A (zh) * 2013-06-19 2014-12-24 天士力控股集团有限公司 苦参碱衍生物及其制备方法与应用
CN104926814A (zh) * 2015-06-14 2015-09-23 广西大学 苦参碱衍生物及其应用
CN107629053A (zh) * 2017-10-09 2018-01-26 广西大学 烷基、芳基、杂环类槐定碱衍生物制备方法和用途
CN107793416A (zh) * 2017-10-30 2018-03-13 广西大学 硫代苦参碱衍生物及其制备方法与应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIHE JIANG ET AL.: "Synthesis, biological evaluation and mechanism studies of matrine derivatives as anticancer agents", 《ONCOLOGY LETTERS》 *
胡会平 等: "苦参碱及衍生物的生物活性和合成研究进展", 《鲁东大学学报(自然科学版)》 *

Also Published As

Publication number Publication date
CN108640919B (zh) 2020-09-08

Similar Documents

Publication Publication Date Title
JP7026196B2 (ja) Ｒｅｔの阻害剤
CN107709320B (zh) 一种吡啶并氮杂环化合物及其制备方法和用途
CN102015693B (zh) 作为erk抑制剂的化合物
JP2022506887A (ja) 窒素含有縮合複素環系ｓｈｐ２阻害剤化合物、製造方法及び使用
AU2013251804A1 (en) DNA-PK inhibitors
MX2008012818A (es) Novedosas bi-aril-aminas.
CN104926788B (zh) 取代哌啶类衍生物、含其的药物组合物及其在抗肿瘤中的应用
CN112979679B (zh) 具有大环结构的含氟并杂环衍生物及其用途
Martínez-Urbina et al. 6-Substituted 2-(N-trifluoroacetylamino) imidazopyridines induce cell cycle arrest and apoptosis in SK-LU-1 human cancer cell line
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
CN108947996A (zh) 二氢嘧啶-磺酰胺类衍生物及其制备方法与应用
JP2023527242A (ja) Ａｘｌ阻害剤であるピリミジン系化合物
JP7420403B2 (ja) キナーゼ阻害剤として使用される化合物およびその応用
EP1869036B1 (en) Substituted 1,5-naphthyridine azolidinones as cdk inhibitors
CN104926814B (zh) 苦参碱衍生物及其应用
CN114516832A (zh) 一种微管蛋白抑制剂及其制备方法与应用
CA3021185C (en) Fused heterocyclic compound
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
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
CN108373462A (zh) 6-（吡啶-4-基）-4-取代氨基的喹唑啉或喹啉类化合物及其应用
CN108640919A (zh) 含芳基脒或氨基喹啉结构的苦参碱衍生物和槐定碱衍生物及其制备方法
CN113461661B (zh) 6-(吡啶-3-基)喹唑啉-4(3h)-酮类衍生物及其制备和应用
CN110256465B (zh) 一种含二氢吡喃并噻唑的2,4-二氨基嘧啶及其应用
CS et al. Synthesis and antiproliferative activity of substituted diazaspiro hydantoins: a structure–activity relationship study
CN111606888B (zh) 吡咯类衍生物及其制备方法与应用

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