CN114605421A - 螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架及其合成方法和应用 - Google Patents
螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架及其合成方法和应用 Download PDFInfo
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- dihydrocoumarin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
技术领域
本发明涉及化学合成技术领域,具体涉及一种螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架及其合成方法和应用。
背景技术
螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素及其衍生物一类重要杂环化合物,兼具2,3-二氢喹啉-4-酮和3,4-二氢香豆素的特性,具有良好的生物活性,在医药领域的应用广泛,在抗疟疾、抗癌、镇痛、消炎、杀菌、TEMβ-内酰胺酶抑制剂等领域中发挥着重要作用。例如,2011年,韩国化学技术研究所Chul Min Park课题组发现1-(芳香基磺酰基)-2,3-二氢喹啉-4-酮类衍生物对5-HT6表现出高的结合亲和力(IC50=8nM)对血清素和多巴胺具有较好的选择性,显示其优异的抗癌活性。2014年,南京农业大学的张克云课题组发现4-芳香基-7,8-二羟基香豆素具有显著的抗肿瘤活性,IC50为29.1±1.3μM,而62.5mg/L的浓度几乎完全杀死所有的BGC-823细胞。2013年,北京大学的蔡少青课题组发现4-芳香基-3-氢香豆素对白色念珠菌的最低抑菌浓度(MIC)值为0.146mM,显示了杰出的抗菌活性。鉴于2,3-二氢喹啉-4-酮和3,4-二氢香豆素骨架在医药领域的重要性,对螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素骨架的高效合成将成为有机合成领域新的研究热点。
2015年,日本学习院大学TakahikoAkiyama课题组报道了用手性磷酸催化的不对称合成2,3-二氢喹啉-4-酮骨架的方法(Org.Lett.2015,17,3202-3205),手性磷酸价格昂贵,并且反应时间长。
2017年,中科院上海有机化学研究所的游书力课题组用酚类和烯醛通过N杂环卡宾催化苯酚与烯醛环化不对称合成4-芳基-3,4-二氢香豆素(Org.Lett.2017,19,1318-1321),该方法只能用于合成芳基取代的3,4-二氢香豆素。
2018年,南开大学的李鑫课题组开发了一种手性方酰胺催化的方法,通过1-四氢萘酮-2甲醛和邻羟基苯基取代的对醌甲基化物的对映选择性1,6-加成/缩醛反应,然后氧化来构建螺-3,4-二氢香豆素衍生物的方法,该方法需要两步才能得到螺-3,4-二氢香豆素且手性方酰胺催化剂价格昂贵。
上述反应虽然可以高效地合成2,3-二氢喹啉-4-酮或3,4-二氢香豆素骨架,但是昂贵的催化剂、底物普适性差、路线长大大限制这些反应的应用,而螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素及其衍生物,更是兼具2,3-二氢喹啉-4-酮和3,4-二氢香豆素的特性,到目前为止,未发现关于螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素及其衍生物的文献报道。
因此,如何利用廉价易得的原料,绿色温和的反应条件,高效构建螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素骨架,解决目前有机合成方法中存在的问题,合成一系列螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素及其衍生物是目前急需解决的问题。
发明内容
本发明要解决的技术问题是:克服现有技术的不足,提供一种螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架及其合成方法和应用,本发明具有反应条件温和、底物普适性好、步骤经济性、原子经济性、立体选择性和化学选择性好、副产物少、产率高、原料低廉等优点,便于将来工业化应用。
本发明的技术方案为:
第一方面,本发明提供了一种螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架,结构式如下:
式中,R1为氮杂环、甲基、乙基中任意一种;R2为氮杂环、甲基、苯基中任意一种;R3为氢原子、甲氧基中任意一种。
第二方面,如图1所示,本发明还提供了一种上述螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架的合成方法,包括以下步骤:
将2-氨基苯甲酰乙酸甲酯类化合物与水杨醛以1:1.2-1:1.5的摩尔比在溶剂中混合均匀,在80-120℃条件下反应,制得螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素化合物;
其中,上述2-氨基苯甲酰乙酸甲酯类化合物的结构式如下:
其中,R1为氮杂环、甲基、乙基中任意一种;R2为氮杂环、甲基、苯基中任意一种;R3为氢原子、甲氧基中任意一种;
其中,上述水杨醛的结构式如下:
可通过薄层色谱法检测上述反应情况,待反应完毕进行纯化,得到螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素化合物的纯化产物。
上述反应过程具体为:
2-氨基苯甲酰乙酸甲酯类化合物与水杨醛通过Knoevenagel缩合反应形成中间产物缺电子烯烃,缺电子烯烃作为驱动力引发分子内[1,7]-氢迁移/环化反应生成2,3-二氢喹啉-4-酮中间体,经过酯交换反应得到最终产物螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素化合物。合成路线具体如下(2-氨基苯甲酰乙酸甲酯类化合物以为例):
优选地,所述溶剂为乙醇或1,2-二氯乙烷;优选地,所述溶剂为1,2-二氯乙烷。
优选地,所述溶剂的用量为:每0.1毫摩尔2-氨基苯甲酰乙酸甲酯类化合物添加0.5-2.0mL溶剂;优选地,每0.1毫摩尔2-氨基苯甲酰乙酸甲酯类化合物添加1mL溶剂。
优选地,反应前加入催化剂,催化剂为布朗斯特酸和路易斯酸;优选地,催化剂为Sc(OTf)3。
优选地,所述催化剂的用量为10-20mol%。
优选地,所述催化剂载体的用量为甲醛类化合物质量的6-7倍。
优选地,反应前加入碱,碱为哌啶,用量为4-6mol%。
本发明涉及的化合物可以以一种或者多种立体异构体的形式存在。各种异构体包括对映异构体、非对映异构体、几何异构体。这些异构体包括这些异构体的混合物均在本发明的保护范围内。
第三方面,本发明还提供了一种利用上述合成方法合成出的螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架在抗癌药物中的应用。
本发明与现有技术相比,具有以下有益效果:
1.本反应在温和的反应条件下,实现了中性的氧化还原串联Knoevenagel缩合/[1,7]-氢迁移/环化/酯交换反应构建螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架化合物,提供了一种高效构建新型结构螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架的合成方法。
2.本发明的合成方法具有良好的立体选择性,可以直接构建全碳季碳中心的手性螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架化合物。
3.本发明的合成方法反应路线短,副产物只有水,符合步骤经济性、原子经济性和绿色环保的原则,实现了绿色高效地合成螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架。
附图说明
图1是本发明的合成工艺路线图。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。除非另有定义,本说明书所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本说明书所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
下面实施例中所使用的实验方法如无特殊说明,均为常规方法;下述实施例中所用的试剂、材料、仪器等,如无特殊说明,均可从商业途径得到。
实施例1:
1、本实施例提供一种螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架的合成方法,包括以下步骤:
取0.1mmol邻氨基苯甲酰乙酸甲酯类化合物于反应瓶中,依次加入1mL溶剂、0.15mmol水杨醛、催化剂。控制体系的反应温度,持续搅拌,通过薄层色谱板点样跟踪反应至原料反应完全。待反应完成后,使用硅胶柱进行分离纯化,将纯化后的产品旋蒸得目标产物。反应式如下:
2、按照上述方法,设立9组平行试验组,分别采用不同的催化剂、溶剂。催化剂分别为醋酸/醋酸铵Ac(OH)/NH4OAc、哌啶Piperidine、三氟甲磺酸钪Sc(OTf)3、三氟甲磺酸铜Cu(OTf)2、三氟甲磺酸镱Yb(OTf)3、三溴化铟InBr3、三氯化铁FeCl3、三氟化硼乙醚BF3.Et2O、三氟甲磺酸TfOH;溶剂分别为甲苯、乙醇和1,2-二氯乙烷。试验组具体使用的催化剂、溶剂种类及对应产率如表1所示:
表1不同催化剂条件下邻氨基苯甲酰乙酸甲酯类化合物与水杨醛反应产率表
注:上述产率为分离产率。制备不同目标物,上述催化剂的催化效果都表现为:三氟甲磺酸钪>三氟化硼乙醚>三氯化铁>三溴化铟>三氟甲磺酸>三氟甲磺酸镱>哌啶;上述碱的效果表现为哌啶>三乙胺>碳酸铯>碳酸钾>氢氧化钠;催化剂载体效果表现为加入分子筛>不加入分子筛。
根据以上平行试验结果分析可知:本发明的合成反应在以乙醇作为溶剂时,加入哌啶反应也可进行,只是产物收率稍低;而采用布朗斯特酸和路易斯酸作催化剂时,反应都可进行且三氟甲磺酸钪的催化效果最好;以甲苯作为溶剂时,反应不可进行;乙醇作为反应溶剂收率稍低;以1,2-二氯乙烷为溶剂时,通过筛选催化剂,最高收率可达到78%。对碱进行筛选时发现有机碱要比无机碱更有利于该反应,且哌啶作为碱时效果最好。不加入分子筛反应很差,加入分子筛后有利于该反应。
3、按照上述方法,设置以下9组平行试验组,分别采用不同的反应条件,如:不同的原料比例、不同的反应温度。催化剂统一采用三氟甲磺酸钪(20mol%)。溶剂为1,2-二氯乙烷。不同试验组的具体设置见表2:
表2不同反应条件下邻氨基苯甲酰乙酸甲酯类化合物与水杨醛反应产率表
根据以上平行试验结果分析可知:本发明的合成反应在以1,2-二氯乙烷作为溶剂时,每0.1毫摩尔邻胺基苯甲酰乙酸甲酯化合物添加0.5-2.0mL溶剂,反应都可进行;当每0.1毫摩尔邻胺基苯甲酰乙酸甲酯化合物添加1mL溶剂时,收率最高;在80-120℃条件下反应都可进行,其中100℃的转化效果最好。
下列实施例2-7中,按照实施例1的操作步骤进行反应;反应体系中,原料邻胺基苯甲酰乙酸甲酯化合物与甲醛类化合物分别为0.1mmol、0.15mmol,在20mol%Sc(OTf)3(三氟甲磺酸钪)催化下,以1mL 1,2-二氯乙烷作溶剂,在100℃温度下持续搅拌反应至原料反应完全,分别得到相应的目标产物。
实施例2
原料:2-四氢吡咯苯甲酰乙酸甲酯,水杨醛
产物:化学式C20H17NO3
分子量:319.3600
产率:42%
1H NMR(500MHz,CDCl3)δ7.69(d,J=7.9Hz,1H),7.44(dd,J=17.1,9.3Hz,1H),7.30–7.23(m,3H),7.14(t,J=10.9Hz,1H),7.05–6.94(m,2H),6.68(dd,J=13.9,7.9Hz,2H),4.40(dd,J=9.3,6.5Hz,1H),3.61(dd,J=16.8,7.8Hz,1H),3.46(tt,J=13.6,6.7Hz,1H),3.27(d,J=16.5Hz,1H),2.83(d,J=16.5Hz,1H),2.45–2.32(m,1H),2.27–2.14(m,1H),2.14–1.96(m,3H),1.56(s,1H).13C NMR(126MHz,CDCl3)δ189.67(s),167.37(s),151.46(s),148.69(s),135.98(s),129.53(s),128.78(s),128.34(s),124.53(s),118.90(s),117.00(s),116.51(s),115.41(s),112.86(s),77.26(d,J=6.2Hz),77.03(s),76.78(s),61.70(s),54.38(s),47.06(s),26.27(s),25.61(s),23.11(s).HRMS(ESI):calcd forC20H17NO3Na[M+Na]+:342.3492,found:342.3496。
实施例3
原料:4-甲氧基-2-四氢吡咯苯甲酰乙酸甲酯,水杨醛
产物:化学式C21H19NO4
分子量:349.3860
产率:58%
1H NMR(500MHz,CDCl3)δ7.61–7.52(m,1H),7.21–7.14(m,1H),7.08–7.01(m,1H),6.99–6.88(m,2H),6.21(dd,J=8.9,2.3Hz,1H),5.98(d,J=2.2Hz,1H),4.33(dd,J=9.5,6.4Hz,1H),3.78(s,3H),3.50(t,J=8.5Hz,1H),3.43–3.33(m,1H),3.18(d,J=16.4Hz,1H),2.75(d,J=16.5Hz,1H),2.34–2.25(m,1H),2.11(ddd,J=15.3,7.8,4.0Hz,1H),2.07–1.85(m,2H),1.37(d,J=11.8Hz,1H).13C NMR(126MHz,CDCl3)δ188.36(s),167.60(s),166.09(s),151.50(s),150.45(s),131.74(s),128.71(s),128.31(s),124.47(s),119.09(s),116.44(s),109.68(s),105.34(s),95.95(s),77.30(s),77.05(s),76.79(s),61.89(s),55.45(s),54.28(s),47.12(s),26.37(s),25.87(s),23.10(s).HRMS(ESI):calcd forC21H19NO4Na[M+Na]+:372.3752,found:372.3756。
实施例4
原料:2-四氢异喹啉苯甲酰乙酸甲酯,水杨醛
产物:化学式C25H19NO3
分子量:381.4310
产率:48%
1H NMR(500MHz,CDCl3)δ7.92(dd,J=7.9,1.5Hz,1H),7.46–7.39(m,2H),7.09–6.94(m,4H),6.90(dd,J=7.1,4.8Hz,3H),6.84(dd,J=7.4,6.7Hz,1H),6.78(t,J=7.4Hz,1H),6.73(d,J=8.1Hz,1H),5.54(s,1H),3.99(ddd,J=10.9,4.6,2.1Hz,1H),3.22–3.11(m,1H),3.08–2.91(m,4H),2.80(d,J=15.4Hz,1H),1.51(s,3H).13C NMR(126MHz,CDCl3)δ191.51(s),167.78(s),151.35(s),150.84(s),136.25(d,J=6.8Hz),131.16(s),129.75(s),128.23(d,J=7.9Hz),127.98(s),127.80(s),127.28(s),127.09(s),124.38(s),119.10(s),118.39(s),117.74(s),116.16(s),113.33(s),77.32(s),77.06(s),76.81(s),62.94(s),61.39(s),42.36(s),30.68(s),26.10(s).HRMS(ESI):calcd for C25H19NO3Na[M+Na]+:404.4202,found:404.4206。
实施例5
原料:2-环己亚胺苯甲酰乙酸甲酯,水杨醛
产物:化学式:C22H21NO3
分子量:347.4140
产率:62%
1HNMR(500MHz,CDCl3)δ7.93(d,J=7.8Hz,1H),7.39(t,J=7.7Hz,1H),7.32(t,J=7.7Hz,1H),7.22(d,J=7.3Hz,1H),7.15(t,J=7.4Hz,1H),7.10(d,J=8.1Hz,1H),6.72(t,J=7.5Hz,1H),6.68(d,J=8.5Hz,1H),4.05–3.93(m,1H),3.77(t,J=16.1Hz,1H),3.60–3.47(m,1H),3.09(t,J=11.1Hz,1H),2.78(d,J=17.0Hz,1H),2.01(t,J=24.0Hz,1H),1.90–1.81(m,1H),1.68–1.43(m,6H),1.34(s,2H).13C NMR(126MHz,CDCl3)δ189.44(s),166.55(s),151.30(s),149.35(s),136.31(s),128.81–128.47(m),124.87(s),120.45(s),119.01(s),116.85(s),116.08(s),112.84(s),77.31(s),77.06(s),76.80(s),62.45(s),53.92(s),51.18(s),27.37(d,J=9.7Hz),25.37(d,J=15.3Hz).HRMS(ESI):calcd forC22H21NO3Na[M+Na]+:370.4032,found:370.4034。
实施例6
原料:N,N-二乙基苯甲酰乙酸甲酯,水杨醛
产物:化学式:C20H19NO3
分子量:321.3760
产率:55%
1H NMR(500MHz,CDCl3)δ7.97(dd,J=7.9,1.6Hz,1H),7.45–7.38(m,1H),7.35–7.29(m,1H),7.23(d,J=7.4Hz,1H),7.15(t,J=7.4Hz,1H),7.11(d,J=8.1Hz,1H),6.75(t,J=7.5Hz,1H),6.71(t,J=6.5Hz,1H),3.81(dd,J=16.7,9.4Hz,1H),3.61–3.49(m,2H),3.03(dq,J=14.5,7.2Hz,1H),2.80(d,J=17.1Hz,1H),1.58(s,1H),1.17(t,J=7.1Hz,3H),1.08(d,J=6.7Hz,3H).13C NMR(126MHz,CDCl3)δ189.01(s),166.51(s),151.28(s),148.58(s),136.19(s),128.61(d,J=8.4Hz),124.87(s),120.40(s),119.42(s),116.90(s),116.03(s),112.91(s),77.28(s),77.03(s),76.77(s),56.46(s),53.93(s),43.81(s),27.39(s),13.05(s),10.71(s).HRMS(ESI):calcd for C20H19NO3Na[M+Na]+:344.3652,found:344.3654。
实施例7
原料:N-甲基苄基苯甲酰乙酸甲酯,水杨醛
产物:化学式:C24H19NO3
分子量:369.4200
产率:56%
1H NMR(500MHz,CDCl3)δ7.92(dt,J=11.2,5.6Hz,1H),7.45–7.36(m,1H),7.27(t,J=7.6Hz,1H),7.21(d,J=7.4Hz,1H),7.12–7.05(m,4H),6.89(d,J=7.6Hz,1H),6.84–6.76(m,1H),6.73(t,J=8.8Hz,2H),6.60(d,J=8.5Hz,1H),4.34(d,J=8.3Hz,1H),3.71(d,J=17.0Hz,1H),2.76(d,J=17.1Hz,3H),2.32(d,J=17.1Hz,1H).13C NMR(126MHz,CDCl3)δ188.70(s),166.53(s),151.05(s),150.67(s),136.53(s),134.32(s),129.20(d,J=10.4Hz),128.86(s),128.55(s),128.06(s),127.89(s),124.88(s),120.37(d,J=11.0Hz),117.65(s),116.16(s),113.09(s),77.36(s),77.19(d,J=31.9Hz),76.80(s),69.04(s),53.67(s),38.60(s),28.24(s).HRMS(ESI):calcd for C24H19NO3Na[M+Na]+:392.4092,found:392.4093。
对本发明的化合物进行肿瘤细胞增殖抑制试验,试验方法采用常规的MTT法。细胞株选用肠癌细胞HCT-8、肝癌细胞BEL-7402和MGC-803(人胃癌细胞)。培养液为DMEM+15%NBS+双抗;以抗肿瘤药物5-氟尿嘧啶为对照。将细胞以4000cell/ml细胞悬液接种于96孔板,每孔总体积为192μL,培养24h后,加入化合物8μL,药物作用72h;弃掉含有药物的培养液,并以PBS洗涤孔板一次;再重新加入培养液100μL MTT溶液,继续培养4h后,去除培养液,加入DMSO,待完全溶解显色后,用MK-2全自动酶标仪检测570nm OD值,计算细胞存活率,并计算半数抑制浓度IC50。结果见表3。实验结果表明,本发明的化合物具有良好的抗肿瘤活性。
表3
尽管通过参考附图并结合优选实施例的方式对本发明进行了详细描述,但本发明并不限于此。在不脱离本发明的精神和实质的前提下,本领域普通技术人员可以对本发明的实施例进行各种等效的修改或替换,而这些修改或替换都应在本发明的涵盖范围内/任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应所述以权利要求的保护范围为准。
Claims (10)
3.如权利要求2所述的合成方法,其特征在于,所述溶剂为乙醇或1,2-二氯乙烷;优选地,所述溶剂为1,2-二氯乙烷。
4.如权利要求2所述的合成方法,其特征在于,所述溶剂的用量为:每0.1毫摩尔2-氨基苯甲酰乙酸甲酯类化合物添加0.5-2.0mL溶剂;优选地,每0.1毫摩尔2-氨基苯甲酰乙酸甲酯类化合物添加1mL溶剂。
5.如权利要求2所述的合成方法,其特征在于,反应前加入催化剂,催化剂为布朗斯特酸和路易斯酸;优选地,催化剂为Sc(OTf)3。
6.如权利要求5所述的合成方法,其特征在于,所述催化剂的用量为10-20mol%。
8.如权利要求7所述的合成方法,其特征在于,所述催化剂载体的用量为甲醛类化合物质量的6-7倍。
9.如权利要求2所述的合成方法,其特征在于,反应前加入碱,碱为哌啶,用量为4-6mol%。
10.如权利要求2-9任一项的合成方法合成出的螺-2,3-二氢喹啉-4-酮-3,4-二氢香豆素生物活性骨架在抗癌药物中的应用。
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