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CN110698380B - 一种内酰胺衍生物及其制备方法与应用 - Google Patents

一种内酰胺衍生物及其制备方法与应用 Download PDF

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CN110698380B
CN110698380B CN201911018651.2A CN201911018651A CN110698380B CN 110698380 B CN110698380 B CN 110698380B CN 201911018651 A CN201911018651 A CN 201911018651A CN 110698380 B CN110698380 B CN 110698380B
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王佳毅
宋恭华
张娟
夏琦
赵心蕾
张阳
张萍
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East China University of Science and Technology
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Abstract

本发明涉及一种内酰胺衍生物及其制备方法与应用。与现有技术相比，本发明提供了一类结构新颖的内酰胺类化合物，且该类化合物以及其组合物具有显著的抑制癌细胞增殖活性(包括但不限于：肝癌细胞系HepG2和肺癌细胞系A549)，多个化合物与商品化药物阿霉素的活性在同一数量级，或优于阿霉素的活性；本发明中的化合物可由N‑取代吡咯化合物反应制备而成，制备方法便捷、快速、高效。

Description

一种内酰胺衍生物及其制备方法与应用
技术领域
本发明属于医药技术领域，涉及一种具有细胞毒性作用的内酰胺衍生物及其制备方法与应用。
背景技术
恶性肿瘤是影响人类健康的最危险的疾病之一。手术治疗根治性切除是目前最基本和常用的癌症治疗方法，但是手术切除创伤性大、易造成组织损伤，不适合老年人或身体素质差的患者。近年来，随着癌症患者的不断增多、科学对于癌症理解的不断加深，癌症制药领域正快速发展。尽管市场上已经存在多种治疗癌症的药物，但是或多或少都存在着缺陷，例如生物利用度不高、毒副作用大等问题。因此，发现具有抗癌活性的新型化合物先导结构，探索新的作用靶标，进而通过结构改造和优化，快速发现高活性化合物，对于新抗癌药的发现有着重要的意义。
γ-丁内酰胺结构在天然产物中广泛存在，研究发现含有γ-丁内酰胺结构的化合物具有一系列生物活性，包括：抗菌、抗氧化、抗惊厥和抗抑郁等。因此，如何从种类众多的γ-丁内酰胺中筛选出具有显著的抑制癌细胞增殖活性的化合物，将具有很好的实用意义和价值。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种内酰胺衍生物及其制备方法与应用。本发明基于结构进行设计，得到一种结构新颖的具有抗癌活性的内酰胺类化合物，且合成路线简单、有效，在抗癌药物上具有较好的应用前景。
本发明的目的可以通过以下技术方案来实现：
一种内酰胺衍生物，所述的衍生物为式I化合物、式I化合物的光学异构体、式I化合物的顺反异构体或式I化合物药学上可接受的盐：
Figure BDA0002246490020000021
其中：
Ra为取代的或未取代的芳基、取代的或未取代的杂环芳基、取代的或未取代的芳基甲酰基、取代的或未取代的9,10-二氢菲基、取代的或未取代的C1～C15烷基中的一种；
Rb、Rc分别独立地选自氰基、酯基或酰基，所述的酯基的通式为COOR，所述的酰基的通式为COR’，所述的R及R’分别独立地选自取代的或未取代的C1～C15烷基、取代的或未取代的芳基、取代的或未取代的杂环芳基中的一种。
进一步地，所述的Ra中，取代的芳基为一个或多个取代基取代的芳基，取代的杂环芳基为一个或多个取代基取代的杂环芳基，取代的芳基甲酰基为一个或多个取代基取代的芳基甲酰基，取代的9,10-二氢菲基为一个或多个取代基取代的9,10-二氢菲基，取代的C1～C15烷基为一个或多个取代基取代的C1～C15烷基；所述的R及R’中，取代的C1～C15烷基为一个或多个取代基取代的C1～C15烷基，取代的芳基为一个或多个取代基取代的芳基，取代的杂环芳基为一个或多个取代基取代的杂环芳基；所述的取代基选自羟基、卤素、氰基、硝基、三氟甲基、芳基、取代芳基、杂环芳基、取代杂环芳基、C1～C6烷基、C1～C6烷氧基、C1～C6卤代烷基、C1～C6卤代烷氧基、-C1～C6亚烷基-O-C1～C6亚烷基-或-C1～C6亚烷基-S-C1～C6亚烷基-。
进一步地，所述的取代芳基为一个或多个取代基取代的芳基，所述的取代芳基中的取代基选自卤素、氰基、硝基、三氟甲基、C1～C6烷基、C1～C6烷氧基、C1～C6卤代烷基、C1～C6卤代烷氧基、-C1～C6亚烷基-O-C1～C6亚烷基-或-C1～C6亚烷基-S-C1～C6亚烷基-；所述的取代杂环芳基为一个或多个取代基取代的杂环芳基，所述的取代杂环芳基中的取代基选自卤素、氰基、硝基、三氟甲基、C1～C6烷基、C1～C6烷氧基、C1～C6卤代烷基、C1～C6卤代烷氧基、-C1～C6亚烷基-O-C1～C6亚烷基-或-C1～C6亚烷基-S-C1～C6亚烷基-。
进一步地，所述的芳基选自苯基、萘基或菲基中的一种，所述的杂环芳基选自呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基或哒嗪基中的一种。杂环芳基还可选自其他的含氮杂环芳基。
一种内酰胺衍生物的制备方法，该方法为：在惰性酸溶剂中，以
Figure BDA0002246490020000031
为原料，以二水合醋酸锰(Mn(OAc)3 .2H2O)为催化剂，在30-110℃下反应4-72小时，反应结束后，经分离后即得到所述的内酰胺衍生物。
反应式如下：
Figure BDA0002246490020000032
进一步地，所述的
Figure BDA0002246490020000033
及二水合醋酸锰的摩尔比1:(1.0-6.0):(3.0-6.0)。
一种内酰胺衍生物的应用，所述的内酰胺衍生物用于制备抗肿瘤药物。
一种组合物，该组合物含有所述的内酰胺衍生物。
进一步地，该组合物包括一种或更多种内酰胺衍生物，以及药学上可接受的载体介质和/或赋形剂。该组合物可以只包含一种内酰胺衍生物，也可以将多种含有不同Ra、Rb、Rc的内酰胺衍生物组合成混合物。组合物中还含有药学上可接受的载体介质和/或赋形剂。
所述的内酰胺衍生物在组合物中的质量百分含量为0.001-99.99％。
一种组合物的应用，所述的组合物用于制备抗肿瘤药物。
所述的肿瘤选自：鼻咽癌、食管癌、胃癌、肝癌、乳腺癌、结肠癌、前列腺癌、肺癌、宫颈癌、白血病、口腔癌、唾液腺肿瘤、鼻腔与鼻旁窦恶性肿瘤、喉癌、耳部肿瘤、眼部肿瘤、甲状腺肿瘤、纵隔肿瘤、胸壁、胸膜肿瘤、小肠肿瘤、胆道肿瘤、胰腺与壶腹周围肿瘤、肠系膜与腹膜后肿瘤、肾脏肿瘤、肾上腺肿瘤、膀胱肿瘤、前列腺癌、睾丸肿瘤、阴茎癌、子宫内膜癌、卵巢恶性肿瘤、恶性滋养细胞肿瘤、外阴癌与阴道癌、恶性淋巴瘤、多发性骨髓瘤、软组织肿瘤、骨肿瘤、皮肤及附件肿瘤、恶性黑色素瘤或神经系统肿瘤。
采用本发明中内酰胺衍生物或组合物进行肿瘤治疗的方法，包括如下步骤：给需要的患者施用本发明中式I化合物、式I化合物的光学异构体、式I化合物的顺反异构体、式I化合物药学上可接受的盐或其组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
与现有技术相比，本发明具有以下特点：
1)本发明提供了一类结构新颖的内酰胺类化合物，且该类化合物以及其组合物具有显著的抑制癌细胞增殖活性(包括但不限于：肝癌细胞系HepG2和肺癌细胞系A549)，多个化合物与商品化药物阿霉素的活性在同一数量级，或优于阿霉素的活性；
2)本发明中的化合物可由N-取代吡咯化合物反应制备而成，制备方法便捷、快速、高效。
具体实施方式
本发明中合成的一系列结构新型的、具有显著抗癌活性的内酰胺类化合物，经MTT法测试后，显示出显著的抑制肝癌细胞系HepG2和肺癌细胞系A549的增殖活性。
基团定义：
术语“烷基”是指烷烃分子中少掉一个氢原子而成的基团；术语“亚烷基”是指烷烃分子中少掉两个氢原子而成的基团。
术语“卤素”指氟、氯、溴、或碘。术语“卤代的”指被相同或不同的一个或多个上述卤原子取代的基团，例如三氟甲基、五氟乙基、七氟异丙基、或类似基团。
术语“惰性酸溶剂”指的是不与原料发生反应的各种酸性溶剂，包括各种直链、支链或环状的烷基或芳基羧酸，如甲酸、乙酸、丙酸、异丙酸、丁酸、苯甲酸、苯乙酸等。
术语“药学上可接受的盐”指本发明的式I化合物与药学上可接受的无机酸和有机酸所形成的盐，其中，优选的无机酸包括(但并不限于)：盐酸、氢溴酸、磷酸、硝酸、硫酸；优选的有机酸包括(但并不限于)：甲酸、乙酸、丙酸、丁二酸、1,5-萘二磺酸、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸，以及氨基酸。
术语“光学异构体”指本发明化合物所涉及手性碳原子可以为R构型，也可以为S构型，或其组合。发明的化合物可以含有一个或多个不对称中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物和纯或部分纯的化合物包括在本发明的范围之内。本发明包括化合物的所有异构形式。
药物组合物和施用方法：
本发明中所用的“组合物”指任何混合物。可以是溶液、混合液、液体、粉末、油膏、水性的、非水性的或他们的任何组合。
本发明化合物及其药学上可接受的盐或含有它的组合物可以单位剂量形式给药，给药突进可分为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括O/W、W/O型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物及其药学上可接受的盐可以制成普通制剂、也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物及其药学上可接受的盐制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、驻留剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等：粘合剂可以是淀粉剂、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。为了将给药单元制成胶囊剂，可以将有效成分本发明化合物及其药学上可接受的盐与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物及其药学上可接受的盐先与稀释剂、粘合剂、崩解剂制成颗粒或微丸，在置于硬胶囊或软胶囊中。用于制备本发明化合物及其药学上可接受的盐片剂的各稀释剂、粘合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物及其药学上可接受的盐的胶囊剂。
为将本发明化合物及其药学上可接受的盐制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等，pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
下面结合具体实施例，进一步阐述对本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
除非另行定义，本发明中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。本发明中所述的较佳实施方法与材料仅做示范之用。
实施例1：
1-(3-甲氧基苯基)-1H-吡咯的合成
Figure BDA0002246490020000061
在25mL的圆底烧瓶中加入3mmol的甲醇钠，3mL的DMSO溶液，然后加入10mol％的CuI(0.2mmol，38mg)和10mol％的N-羟基邻苯二甲酰亚胺(L1，0.2mmol，33mg)，室温搅拌30分钟。然后向反应液中滴加已经溶解在DMSO(2mL)中的碘苯(2mmol，408mg)和吡咯(2mmol，134mg)，3分钟内滴加完毕。油浴升温至90℃后搅拌反应12h。反应结束后加入饱和食盐水10mL，用乙酸乙酯萃取(3×10mL)，合并萃取液，旋蒸脱除溶剂后的粗产物经柱层析纯化分离得到白色固体0.243g，产率85％。
m.p.61.5-62.0℃。1H NMR(400MHz,CDCl3)δ7.44–7.37(m,4H),7.27–7.22(m,1H),7.09(t,J＝2.2Hz,2H),6.35(t,J＝2.2Hz,2H)；13C NMR(101MHz,CDCl3)δ129.6(2C),125.7(2C),120.6(2C),119.4(2C),110.4(2C)；MS(GC-MS):m/z 143.1(M+).
实施例2：
1-(菲-9-基)-1H-吡咯的合成
Figure BDA0002246490020000071
在100mL圆底烧瓶中加入邻溴苯甲醛(1.84g，10mmol)、2-甲酰基苯硼酸(0.164g，1.1mmol)、双(二亚苄基丙酮)钯(0.060g，0.1mmol)、三环己基膦(0.003g，0.12mmol)和二水合氟化钾(3.10g，33mmol)，2mL四氢呋喃作为溶剂，油浴中回流温度下进行反应，8h反应结束。待反应溶液温度降到室温后，减压除去溶剂，加入去离子水(100mL)洗涤，用二氯甲烷萃取(3×50mL)，合并有机相后用饱和氯化钠溶液洗涤，再用无水硫酸镁进行干燥，抽滤后旋干滤液得粗产物。经柱层析纯化分离得到黄色固体[1,1′-联苯]-2,2′-二甲醛1.9g，产率90％。
Yellow oil；1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.06(s,1H),7.68(td,J＝7.5,1.4Hz,1H),7.60(t,J＝7.5Hz,1H),7.40–7.32(m,1H).13C NMR(101MHz,CDCl3)δ191.07(2C),141.25(2C),134.59(2C),133.46(2C),131.73(2C),128.85(2C),128.59(2C).MS(GC-MS):m/z 210.0(M+).
在10mL圆底烧瓶中加入[1,1′-联苯]-2,2′-二甲醛(0.105g，0.5mmol)、反式-4-羟基-L-脯氨酸(0.098g，0.75mmol)，以1.5mL二甲基亚砜为溶剂，油浴温度140℃下进行反应，30min反应结束。待反应溶液温度降到室温后，加入去离子水(10mL)洗涤，用乙酸乙酯萃取三次，合并乙酸乙酯萃取液。用饱和氯化钠溶液洗涤萃取液，再用无水硫酸镁进行干燥，抽滤后旋干滤液得粗产物。经柱层析纯化分离得到10-(1H-吡咯-1-基)-9,10-二氢菲-9-醇的固体。白色固体；trans/cis＝87:13；HRMS(EI)calcd for C18H15NO[M]+261.1154,found2261.1153.
将10-(1H-吡咯-1-基)-9,10-二氢菲-9-醇(2mmol，522mg)，五氧化二磷(6mmol，852mg)和苯(10mL)加入到25mL的圆底烧瓶中，回流条件下搅拌6h。反应结束后加入饱和食盐水10mL，用乙酸乙酯萃取(3×10mL)，合并萃取液，旋蒸脱除溶剂后的粗产物经柱层析纯化分离得到0.403g 1-(菲-9-基)-1H-吡咯的白色固体，产率83％。
m.p.108.2-108.9℃。1H NMR(400MHz,CDCl3)δ8.70(dd,J＝17.4,8.3Hz,2H),7.90–7.83(m,1H),7.76–7.53(m,6H),7.03(t,J＝2.1Hz,2H),6.43(t,J＝2.1Hz,2H)；13C NMR(101MHz,CDCl3)δ136.8,131.2,131.2,129.9,129.5,128.8,127.3,127.29,127.28,127.2,124.1,123.9,123.3(2C),122.9,122.7,109.1(2C)；MS(GC-MS):m/z 243.1(M+).
实施例3：
1-(4-硝基苄基)-1H-吡咯的合成
Figure BDA0002246490020000081
在25mL两颈圆底烧瓶中加入反式-4-羟基-L-脯氨酸(0.983g，7.5mmol)，10mol％乙酸(0.03mL，0.5mmol)和DMF(10mL)，然后加热到回流。将4-硝基苯甲醛(5.0mmol，755mg)溶解在DMF(5mL)中并在30分钟内滴加到上述反应混合物中，反应10分钟。反应结束后加入饱和食盐水10mL，用乙酸乙酯萃取(3×10mL)，合并萃取液，旋蒸脱除溶剂后的粗产物经柱层析纯化分离得到淡黄色固体0.909g，产率90％。
m.p.61.0-61.4℃。1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.7Hz,2H),7.19(d,J＝8.6Hz,2H),6.69(t,J＝2.0Hz,2H),6.24(t,J＝2.0Hz,2H),5.18(s,2H)；13C NMR(101MHz,CDCl3)δ147.5,145.8,127.4(2C),124.0(2C),121.3(2C),109.4(2C),52.6；MS(GC-MS):m/z202.1(M+).
实施例4：
1-苄基-1H-吡咯的合成
Figure BDA0002246490020000082
将吡咯(2mmol，134mg)，氢氧化钠(6mmol，240mg)和DMSO(10mL)加入到25mL的圆底烧瓶中，室温条件下搅拌20-30分钟，然后缓慢加入氯苄。将混合物在室温下搅拌3小时。反应结束后加入饱和食盐水10mL，用乙酸乙酯萃取(3×10mL)，合并萃取液，旋蒸脱除溶剂后的粗产物经柱层析纯化分离得到无色液体0.266g，产率85％。
1H NMR(400MHz,CDCl3)δ7.37–7.22(m,3H),7.10(d,J＝7.2Hz,2H),6.68(t,J＝2.0Hz,2H),6.19(t,J＝2.0Hz,2H),5.05(s,2H)；13C NMR(101MHz,CDCl3)δ138.2,128.8(2C),127.7,127.0(2C),121.2(2C),108.5(2C),53.4；MS(GC-MS):m/z157.1(M+).
实施例5：
1-苄基-1H-吡咯的合成
Figure BDA0002246490020000091
在10mL的微波反应瓶中加入3-硝基苯甲醛(0.151g,1.00mmol)、反式-4-羟基-L-脯氨酸(0.098g,0.75mmol)，1.5mL二甲基亚砜(DMSO)作为溶剂，加盖密闭，油浴温度110℃下进行反应，24h后反应结束。待反应溶液降至室温后，加入10mL去离子水，产生大量絮状固体，抽滤，保留滤饼。滤液用乙酸乙酯(EA)萃取三次，合并有机层。有机相先用饱和食盐水洗涤，再用无水硫酸镁干燥，抽滤后将滤液旋干得到粗产物。粗产物和滤饼合并后经快速液相色谱仪分离(流动相为石油醚:乙酸乙酯(PE:EA)＝10:1)得到淡黄色固体0.168g，分离产率95％。
M.p.137–145℃。dr＝66:34,major isomer:1H NMR(400MHz,CDCl3)δ8.14–8.06(m,4H),7.50–7.37(m,4H),6.66–6.58(m,2H),6.06(t,J＝2.1Hz,2H),5.60(d,J＝7.9Hz,1H),5.23(d,J＝7.7Hz,1H),2.99(s,1H)；13C NMR(100MHz,CDCl3)δ148.28,148.19,142.79,139.31,134.80,132.27,129.70,129.43,123.39,123.26,121.17,120.84,119.86(2C),109.46(2C),74.56,68.11；HRMS(EI)calcd for C18H15N3O5[M]+353.1012,found 353.1015.
按照上述实施例1-5所述方法，采用不同的起始原料制备如下所示的N-取代吡咯类化合物。
Figure BDA0002246490020000092
:1H NMR(400MHz,CDCl3)δ7.30(t,J＝8.1Hz,1H),7.12–7.04(m,2H),7.01–6.90(m,2H),6.82–6.72(m,1H),6.42–6.26(m,2H),3.82(s,3H)；13C NMR(101MHz,CDCl3)δ160.6,142.0,130.4,119.4(2C),112.9,110.9,110.4(2C),106.8,55.5；MS(GC-MS):m/z 173.1(M+).
Figure BDA0002246490020000101
:M.p.112.5-113.3℃。1H NMR(400MHz,CDCl3)δ7.35–7.25(m,2H),7.03–6.88(m,4H),6.31(t,J＝2.1Hz,2H),3.81(s,3H)；13C NMR(101MHz,CDCl3)δ157.7,134.5,122.2(2C),119.7(2C),114.7(2C),109.9(2C),55.6；MS(GC-MS):m/z 173.1(M+).
Figure BDA0002246490020000102
:1H NMR(400MHz,CDCl3)δ7.63(s,1H),7.53(dt,J＝23.0,7.6Hz,3H),7.10(s,2H),6.38(s,2H)；13C NMR(101MHz,CDCl3)δ141.1,132.1(q,JCF＝32.7Hz),130.2,123.7(q,JCF＝272.5Hz),123.4,122.1(q,JCF＝3.8Hz),119.2(2C),117.2(q,JCF＝3.8Hz),111.3(2C)；MS(GC-MS):m/z 211.1(M+).
Figure BDA0002246490020000103
:1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),7.20–7.04(m,2H),6.49–6.31(m,2H)；13C NMR(101MHz,CDCl3)δ143.2,127.45(d,JCF＝33.0Hz),126.90(q,JCF＝3.7Hz,2C),124.03(d,JCF＝271.7Hz),120.0(2C),119.1(2C),111.5(2C)；MS(GC-MS):m/z 211.1(M+).
Figure BDA0002246490020000104
:1H NMR(400MHz,CDCl3)δ7.69–7.59(m,2H),7.57–7.48(m,2H),7.15–7.01(m,2H),6.49–6.27(m,2H)；13C NMR(101MHz,CDCl3)δ141.3,130.6,128.9,124.4,123.4,119.0(2C),118.1,113.8,111.8(2C)；MS(GC-MS):m/z 168.1(M+).
Figure BDA0002246490020000105
:1H NMR(400MHz,CDCl3)δ8.21(ddt,J＝9.3,8.2,2.0Hz,2H),7.77–7.46(m,2H),7.23–7.07(m,2H),6.53–6.32(m,2H)；13C NMR(101MHz,CDCl3)δ130.5,125.6,125.6,120.0,119.4,119.2,119.1,114.9,112.6,111.9；MS(GC-MS):m/z 188.1(M+).
Figure BDA0002246490020000106
:1H NMR(400MHz,CDCl3)δ7.28(t,J＝7.7Hz,1H),7.23–7.14(m,2H),7.13–6.98(m,3H),6.45–6.25(m,2H),2.39(s,3H)；13C NMR(101MHz,CDCl3)δ140.8,139.6,129.4,126.4,121.4,119.4(2C),117.7,110.3(2C),21.5；MS(GC-MS):m/z 157.1(M+).
Figure BDA0002246490020000107
:1H NMR(400MHz,CDCl3)δ7.75–7.67(m,2H),7.52–7.44(m,2H),7.19–7.10(m,2H),6.45–6.36(m,2H)；13C NMR(101MHz,CDCl3)δ143.7,133.9(2C),120.0(2C),118.9(2C),118.5,112.2(2C),108.6；MS(GC-MS):m/z 168.1(M+).
Figure BDA0002246490020000111
:1H NMR(400MHz,CDCl3)δ7.30–7.24(m,2H),7.20(d,J＝8.2Hz,2H),7.04(t,J＝2.2Hz,2H),6.32(t,J＝2.1Hz,2H),2.36(s,3H)；13C NMR(101MHz,CDCl3)δ138.5,135.4,130.1(2C),120.6(2C),119.4(2C),110.1(2C),20.9；MS(GC-MS):m/z 157.1(M+).
Figure BDA0002246490020000112
:1H NMR(400MHz,CDCl3)δ7.44–7.37(m,4H),7.27–7.22(m,1H),7.09(t,J＝2.2Hz,2H),6.35(t,J＝2.2Hz,2H)；13C NMR(101MHz,CDCl3)δ138.2,134.3,129.9,128.2,127.9,127.0,126.6,125.3,123.3,123.3,123.3(2C),109.1(2C)；MS(GC-MS):m/z 193.2(M+).
Figure BDA0002246490020000113
:1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.7Hz,2H),7.19(d,J＝8.6Hz,2H),6.69(t,J＝2.0Hz,2H),6.24(t,J＝2.0Hz,2H),5.18(s,2H)；13C NMR(101MHz,CDCl3)δ147.5,145.8,127.4(2C),124.0(2C),121.3(2C),109.4(2C),52.6；MS(GC-MS):m/z202.1(M+).
Figure BDA0002246490020000114
:1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.1Hz,2H),7.17(d,J＝8.0Hz,2H),6.67(t,J＝2.1Hz,2H),6.21(t,J＝2.1Hz,2H),5.11(s,2H),13C NMR(101MHz,CDCl3)δ142.4(d,JCF＝1.2Hz,2C),130.0(q,JCF＝32.6Hz),127.1(2C),125.7(q,JCF＝3.8Hz,2C),124.1(q,JCF＝272.1Hz),121.2,109.1(2C),52.8；MS(GC-MS):m/z 225.1(M+).
Figure BDA0002246490020000115
:1H NMR(400MHz,CDCl3)δ8.12(dd,J＝8.2,1.6Hz,1H),7.97(s,1H),7.48(t,J＝7.9Hz,1H),7.36(d,J＝8.3Hz,1H),6.70(t,J＝2.1Hz,2H),6.23(t,J＝2.1Hz,2H),5.16(s,2H).13C NMR(101MHz,CDCl3)δ148.6,140.5,132.8,129.8,122.7,121.8,121.1(2C),109.4(2C),52.5；MS(GC-MS):m/z 202.1(M+).
Figure BDA0002246490020000116
:1H NMR(400MHz,CDCl3)δ7.55(d,J＝7.7Hz,1H),7.42(t,J＝7.7Hz,1H),7.34(s,1H),7.32–7.27(m,1H),6.67(t,J＝2.1Hz,2H),6.22(t,J＝2.1Hz,2H),5.10(s,2H)；13C NMR(101MHz,CDCl3)δ140.0,131.4,131.1,130.3,129.6,121.1(2C),118.5,112.9,109.3(2C),52.4；MS(GC-MS):m/z 182.1(M+).
Figure BDA0002246490020000117
:1H NMR(400MHz,CDCl3)δ8.53(dd,J＝4.8,1.3Hz,1H),8.46(d,J＝1.8Hz,1H),7.38–7.33(m,1H),7.23(dd,J＝7.9,4.8Hz,1H),6.68(t,J＝2.1Hz,2H),6.20(t,J＝2.1Hz,2H),5.07(s,2H).13C NMR(101MHz,CDCl3)δ149.2,148.5,134.7,133.7,123.7,121.0(2C),109.1(2C),50.8；MS(GC-MS):m/z 158.1(M+).
Figure BDA0002246490020000121
:1H NMR(400MHz,CDCl3)δ7.53(d,J＝7.8Hz,1H),7.42(t,J＝7.8Hz,1H),7.38(s,1H),7.26–7.20(m,1H),6.68(t,J＝2.1Hz,2H),6.21(t,J＝2.0Hz,2H),5.11(s,2H)；13C NMR(101MHz,CDCl3)δ139.4,131.1(q,JCF＝32.4Hz),130.2(d,JCF＝0.7Hz),129.3,121.2(2C),124.6(q,JCF＝3.8Hz),124.0(q,JCF＝272.3Hz),123.7(q,JCF＝3.8Hz).109.1(2C),52.8；MS(GC-MS):m/z 225.1(M+).
Figure BDA0002246490020000122
:1H NMR(400MHz,CDCl3)δ7.07(ddd,J＝8.1,5.3,2.4Hz,2H),7.03–6.95(m,2H),6.66(t,J＝2.0Hz,2H),6.18(t,J＝1.8Hz,2H),5.01(s,2H)；13C NMR(101MHz,CDCl3)δ162.3(d,JCF＝246.0Hz),134.0(d,JCF＝3.2Hz),128.7(d,JCF＝8.2Hz,2C),121.0(2C),115.6(d,JCF＝21.6Hz,2C),108.7(2C),52.6；MS(GC-MS):m/z 175.1(M+).
Figure BDA0002246490020000123
:1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.3Hz,2H),7.14(d,J＝8.5Hz,2H),6.67(t,J＝2.1Hz,2H),6.22(t,J＝2.1Hz,2H),5.13(s,2H).13C NMR(101MHz,CDCl3)δ143.8,132.6(2C),127.3(2C),121.3(2C),118.6,111.6,109.3(2C),52.8；MS(GC-MS):m/z 182.1(M+).
Figure BDA0002246490020000124
:1H NMR(400MHz,CDCl3)δ7.25–7.19(m,1H),6.99–6.89(m,2H),6.71(t,J＝1.9Hz,2H),6.17(d,J＝1.7Hz,2H),5.19(s,2H).13C NMR(101MHz,CDCl3)δ140.64,126.94,126.01,125.59,120.72,108.74,48.07.
Figure BDA0002246490020000125
:1H NMR(400MHz,CDCl3)δ7.35(d,J＝1.1Hz,1H),6.69(t,J＝1.8Hz,2H),6.31(dd,J＝3.1,1.9Hz,1H),6.23(d,J＝3.0Hz,1H),6.16(s,2H),5.00(s,2H).13C NMR(101MHz,CDCl3)δ150.83,142.72,120.74,110.43,108.58,108.15,46.10.
Figure BDA0002246490020000126
:1H NMR(400MHz,CDCl3)δ7.30–7.24(m,2H),7.22(ddd,J＝7.3,3.5,1.3Hz,1H),7.14–7.05(m,2H),6.58(s,2H),6.12(s,2H),4.15–4.04(m,2H),3.09–2.96(m,2H).13C NMR(101MHz,CDCl3)δ138.51,128.72,128.60,126.65,120.52,108.07,51.20,38.43.
Figure BDA0002246490020000127
:1H NMR(400MHz,CDCl3)δ7.73(dd,J＝5.2,3.3Hz,2H),7.63–7.56(m,1H),7.49(dd,J＝10.4,4.7Hz,2H),7.34–7.26(m,2H),6.40–6.29(m,2H).13C NMR(101MHz,CDCl3)δ167.71,133.28,132.27,129.50,128.48,121.30,113.15.
Figure BDA0002246490020000131
:白色固体；trans/cis＝96:4；HRMS(EI)calcd for C18H13F2NO[M]+297.0965,found 297.0963.
Figure BDA0002246490020000132
:白色固体；trans/cis＝60:40；1H NMR(400MHz,CDCl3)δ8.06(s,0.6H),8.00(dd,J＝15.8,8.2Hz,0.8H),7.91(dd,J＝13.2,8.2Hz,1.2H),7.80(d,J＝3.8Hz,0.4H),7.74(d,J＝10.0Hz,1.2H),7.71–7.66(m,0.8H),7.48(s,0.4H),6.90(s,0.6H),6.80(t,J＝2.1Hz,1.2H),6.52(t,J＝2.1Hz,0.8H),6.34(t,J＝2.0Hz,1.2H),6.11(t,J＝2.1Hz,0.8H),5.36(d,J＝4.8Hz,0.4H),5.20(q,J＝11.6Hz,1.2H),5.11(d,J＝4.7Hz,0.4H),2.59(s,0.4H),2.04(s,0.6H).HRMS(EI)calcd for C20H13F6NO[M]+297.0901,found 297.0900.
Figure BDA0002246490020000133
:白色固体,m.p.＝141-149℃；trans isomer:1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.91(dd,J＝13.2,8.2Hz,2H),7.70(dd,J＝16.1,8.2Hz,2H),6.90(s,1H),6.81(t,J＝2.1Hz,2H),6.36(t,J＝2.1Hz,2H),5.23(d,J＝11.7Hz,1H),5.18(d,J＝11.6Hz,1H),2.60(s,1H)；13C NMR(100MHz,DMSO)δ148.05,147.99,141.46,139.30,136.59,136.26,126.66,126.52,123.62,123.35,121.32,121.16,120.54(2C),108.70(2C),68.58,62.83.HRMS(EI)calcd for C18H13N3O5[M]+351.0855,found 351.0871.
Figure BDA0002246490020000134
:白色固体；trans/cis＝58:42；1H NMR(400MHz,CDCl3)δ7.79–7.63(m,2.65H),7.44–7.32(m,2H),7.19(ddd,J＝8.6,5.1,1.1Hz,0.39H),7.11–6.98(m,1H),6.75(t,J＝2.1Hz,0.83H),6.73(t,J＝2.1Hz,1.16H),6.60(d,J＝7.6Hz,0.39H),6.34(ddd,J＝9.3,2.6,0.8Hz,0.57H),6.29–6.22(m,2H),5.12–5.03(m,2H),2.43(s,1H).HRMS(EI)calcd for C18H14FNO[M]+279.1059,found 279.1033.
Figure BDA0002246490020000135
:白色固体；trans/cis＝69:31；1H NMR(400MHz,CDCl3)δ7.80–7.66(m,3H),7.45–7.32(m,2.42H),7.23(ddd,J＝7.6,3.7,1.2Hz,0.77H),6.78(t,J＝2.1Hz,1.39H),6.76(t,J＝2.1Hz,0.61H),6.70–6.61(m,1H),6.33–6.26(m,2H),5.16–5.07(m,2H),2.31(s,1H).HRMS(EI)calcd for C18H14 35ClNO[M]+295.0764,found 295.0762,calcdfor C18H14 37ClNO[M]+297.0734,found 297.0733.
Figure BDA0002246490020000141
:白色固体；trans:cis＝33:67；1H NMR(400MHz,CDCl3)δ8.01(s,0.41H),7.90–7.77(m,2H),7.75–7.70(m,0.6H),7.64(dd,J＝13.9,8.4Hz,1H),7.48–7.38(m,1.59H),7.28(t,J＝7.5Hz,0.41H),6.92(s,0.58H),6.80(s,0.82H),6.76(s,1.17H),6.65(d,J＝7.7Hz,0.42H),6.36–6.25(m,2H),5.21–5.12(m,2H),2.34(s,1H).HRMS(EI)calcd for C19H14F3NO[M]+329.1027,found 329.1021.
Figure BDA0002246490020000142
:白色固体；trans/cis＝57:43；HRMS(EI)calcd for C19H17NO2[M]+291.1259,found 291.1254.
通过进一步分离获得反式(trans)异构体:m.p.131-134℃；1H NMR(400MHz,CDCl3)δ7.75(t,J＝8.7Hz,2H),7.70–7.64(m,1H),7.38(dtd,J＝15.2,7.6,1.7Hz,3H),7.19(td,J＝7.6,1.0Hz,1H),6.75(t,J＝2.1Hz,2H),6.65(d,J＝7.7Hz,1H),6.24(t,J＝2.1Hz,2H),5.20–5.03(m,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ160.08,137.60,133.69,133.14,128.71,127.52,126.43,125.26,124.85,122.97,120.41(2C),114.49,110.43,109.31(2C),72.13,65.94,55.44.HRMS(EI)calcd for C19H17NO2[M]+291.1259,found 291.1260.
Figure BDA0002246490020000143
:白色固体,m.p.＝142-146℃；trans isomer:1H NMR(400MHz,CDCl3)δ8.64(d,J＝1.4Hz,1H),8.29(dd,J＝8.5,2.2Hz,1H),7.91(d,J＝8.6Hz,1H),7.85(d,J＝7.7Hz,1H),7.46(t,J＝7.6Hz,1H),7.35(t,J＝7.6Hz,1H),6.85(t,J＝2.0Hz,2H),6.70(d,J＝7.7Hz,1H),6.37(t,J＝2.0Hz,2H),5.24(dd,J＝26.0,11.7Hz,2H),2.45(s,1H)；13C NMR(100MHz,CDCl3)δ135.91,134.51,133.12,132.12,128.78,128.57,128.54,128.50,126.59,125.58,123.77,123.66,120.45(2C),109.26(2C),72.02,65.80；HRMS(EI)calcd for C18H14N2O3[M]+306.1004,found 306.1023.
Figure BDA0002246490020000144
:白色固体,m.p.＝141-149℃；trans isomer:1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.91(dd,J＝13.2,8.2Hz,2H),7.70(dd,J＝16.1,8.2Hz,2H),6.90(s,1H),6.81(t,J＝2.1Hz,2H),6.36(t,J＝2.1Hz,2H),5.23(d,J＝11.7Hz,1H),5.18(d,J＝11.6Hz,1H),2.60(s,1H)；13C NMR(100MHz,DMSO)δ148.05,147.99,141.46,139.30,136.59,136.26,126.66,126.52,123.62,123.35,121.32,121.16,120.54(2C),108.70(2C),68.58,62.83.HRMS(EI)calcd for C18H13N3O5[M]+351.0855,found 351.0871.
Figure BDA0002246490020000151
:白色固体；trans/cis＝60:40；1H NMR(400MHz,CDCl3)δ8.06(s,0.6H),8.00(dd,J＝15.8,8.2Hz,0.8H),7.91(dd,J＝13.2,8.2Hz,1.2H),7.80(d,J＝3.8Hz,0.4H),7.74(d,J＝10.0Hz,1.2H),7.71–7.66(m,0.8H),7.48(s,0.4H),6.90(s,0.6H),6.80(t,J＝2.1Hz,1.2H),6.52(t,J＝2.1Hz,0.8H),6.34(t,J＝2.0Hz,1.2H),6.11(t,J＝2.1Hz,0.8H),5.36(d,J＝4.8Hz,0.4H),5.20(q,J＝11.6Hz,1.2H),5.11(d,J＝4.7Hz,0.4H),2.59(s,0.4H),2.04(s,0.6H).HRMS(EI)calcd for C20H13F6NO[M]+297.0901,found 297.0900.
Figure BDA0002246490020000152
:白色固体；trans/cis＝96:4；HRMS(EI)calcd for C18H13F2NO[M]+297.0965,found 297.0963.
通过进一步分离获得反式(trans)异构体:m.p.143-148℃；1H NMR(400MHz,CDCl3)δ7.71–7.64(m,2H),7.46(ddd,J＝9.4,2.7,0.8Hz,1H),7.14–7.03(m,2H),6.82(t,J＝2.1Hz,2H),6.42–6.28(m,3H),5.14(q,J＝11.7Hz,2H),2.34(s,1H).13C NMR(101MHz,CDCl3)δ162.95(d,JCF＝248.4Hz),162.86(d,JCF＝248.3Hz),138.10(d,JCF＝7.3Hz),136.86(d,JCF＝6.8Hz),128.63(d,JCF＝3.3Hz),127.56(d,JCF＝3.3Hz),125.45(d,JCF＝8.1Hz),125.37(d,JCF＝7.9Hz),120.24,115.79(d,JCF＝21.8Hz),115.41(d,JCF＝21.9Hz),113.45(d,JCF＝23.6Hz),112.66(d,JCF＝23.7Hz),109.98,71.51,65.70.
Figure BDA0002246490020000153
:1H NMR(400MHz,CDCl3)δ8.84(dd,J＝20.3,8.7Hz,2H),8.20(s,1H),8.12(s,1H),8.00–7.85(m,3H),7.04(t,J＝2.1Hz,2H),6.49(t,J＝2.1Hz,2H)；13CNMR(101MHz,CDCl3)δ137.9,132.5,131.4,130.9,130.2(qd,JCF＝33.0,3.5Hz,2C),129.6,126.1(q,JCF＝4.1Hz),124.7,124.4,124.1,124.0(qd,JCF＝272.6,3.9Hz,2C),123.8(dd,JCF＝6.4,3.1Hz),123.5(q,JCF＝3.2Hz),123.1(2C),121.9(q,JCF＝4.2Hz),110.3(2C)；HRMS(EI)calcd for C20H11F6N[M]+379.0796,found 379.0797.
Figure BDA0002246490020000154
:1H NMR(400MHz,CDCl3)δ8.66–8.52(m,2H),7.68(s,1H),7.49(dd,J＝9.1,2.7Hz,1H),7.45–7.35(m,3H),6.99(t,J＝2.1Hz,2H),6.44(t,J＝2.1Hz,2H)；13C NMR(101MHz,CDCl3)δ161.8(dd,JCF＝247.1,0.8Hz),161.5(dd,JCF＝248.8,1.7Hz),137.4(d,JCF＝3.8Hz),132.1(dd,JCF＝9.0,1.0Hz),130.5(dd,JCF＝8.6,1.2Hz),127.6(d,JCF＝1.7Hz),126.1(d,JCF＝1.3Hz),125.2(d,JCF＝8.6Hz),124.9(d,JCF＝8.9Hz),124.3(d,JCF＝3.8Hz),123.0,116.8(d,JCF＝20.5Hz),116.6(d,JCF＝20.3Hz),112.9(d,JCF＝20.9Hz),109.7,109.1(d,JCF＝23.1Hz)；HRMS(EI)calcd for C18H11F2N[M]+279.0860,found279.0863.
Figure BDA0002246490020000161
:1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ8.87(d,J＝8.8Hz,1H),8.82(d,J＝8.7Hz,1H),8.20(s,1H),8.12(s,1H),7.94(td,J＝8.7,1.7Hz,2H),7.87(s,1H),7.04(t,J＝2.1Hz,2H),6.49(t,J＝2.1Hz,2H),3.91(s,3H),3.78(s,3H)；13CNMR(101MHz,CDCl3)δ158.2,158.0,136.9,131.4,129.7,125.7,124.4,124.1,124.0,123.8,123.0(2C),117.9,117.9,109.1(2C),108.5,104.4,55.5,55.3；HRMS(EI)calcd forC20H17NO2[M]+303.1259,found 303.1262.
Figure BDA0002246490020000162
:1H NMR(400MHz,CDCl3)δ8.85(d,J＝9.2Hz,1H),8.78–8.62(m,2H),8.45(dd,J＝9.1,2.4Hz,1H),8.01–7.72(m,4H),7.04(t,J＝2.1Hz,2H),6.49(t,J＝2.1Hz,2H)；13C NMR(101MHz,CDCl3)δ146.6,136.7,134.9,132.5,129.3,129.2,129.1,128.7,128.1,125.9,124.6,123.6,123.3(2C),121.0,120.4,110.2(2C)；HRMS(EI)calcdfor C18H12N2O2[M]+288.0899,found 288.0897.
实施例6：
2-(5-氧代-1-苯基-1,5-二氢-2H-吡咯-2-亚基)丙二酸二甲酯的合成
Figure BDA0002246490020000163
在25mL的圆底烧瓶中加入1-苯基-1H-吡咯(2mmol，286mg)，丙二酸二甲酯(4mmol，528mg)，二水合醋酸锰(6mmol，1608mg)和15mL的乙酸。70℃油浴搅拌12h。反应结束后加入饱和食盐水10mL，用乙酸乙酯萃取(3×10mL)，合并萃取液，旋蒸脱除溶剂后的粗产物经柱层析纯化分离得到淡黄色固体0.287g，产率50％，m.p.133.7-134.7℃。1H NMR(400MHz,CDCl3)δ8.34(d,J＝6.1Hz,1H),7.50–7.37(m,3H),7.20(d,J＝7.4Hz,2H),6.46(d,J＝6.1Hz,1H),3.79(s,3H),3.07(s,3H)；13C NMR(101MHz,CDCl3)δ170.4,163.9,149.1,138.5(2C),133.4,129.1(2C),128.9(2C),126.2(2C),108.0,52.8,52.2；HRMS(EI)calcd forC15H13NO5[M]+287.0794,found 287.0792.
按照上述实施例6所述方法，采用不同的起始原料制备如下所示的内酰胺类化合物。
Figure BDA0002246490020000171
:1H NMR(400MHz,CDCl3)δ8.33(d,J＝6.1Hz,1H),7.33(t,J＝7.7Hz,1H),7.20(d,J＝7.5Hz,1H),7.00(dd,J＝8.1,0.5Hz,2H),6.45(d,J＝6.1Hz,1H),3.79(s,3H),3.08(s,3H),2.38(s,3H)；13C NMR(101MHz,CDCl3)δ170.4,163.9(2C),149.2,139.0,138.4,133.3,129.6,129.4,128.8,126.2,125.9,107.9,52.7,52.0,21.2；HRMS(EI)calcd for C16H15NO5[M]+301.0950,found 301.0949.
Figure BDA0002246490020000172
:1H NMR(400MHz,CDCl3)δ8.37(d,J＝6.1Hz,1H),8.30–8.26(m,1H),8.09(t,J＝2.1Hz,1H),7.65(t,J＝8.1Hz,1H),7.57(ddd,J＝7.9,1.9,1.1Hz,1H),6.50(dd,J＝6.1,2.4Hz,1H),3.81(s,3H),3.13(s,3H)；13C NMR(101MHz,CDCl3)δ169.7,163.6,163.5,148.3,139.0,134.8(3C),129.9,126.0,123.9,123.5,108.6,52.9,52.2；HRMS(EI)calcd for C16H12N2O5[M]+332.0645,found 332.0647.
Figure BDA0002246490020000173
:1H NMR(400MHz,CDCl3)δ8.34(d,J＝6.1Hz,1H),7.72(d,J＝8.3Hz,2H),7.34(d,J＝8.2Hz,2H),6.48(d,J＝6.1Hz,1H),3.80(s,3H),3.08(s,3H)；13CNMR(101MHz,CDCl3)δ169.8,163.70,163.66,148.6,138.9(2C),136.9,130.8(q,JCF＝33.1Hz),129.1(2C),126.1(dd,JCF＝6.5,2.6Hz,2C),123.6(q,JCF＝272.4Hz),108.5,52.9,52.1；HRMS(EI)calcd for C16H12F3NO5[M]+355.0668,found355.0670.
Figure BDA0002246490020000174
:1H NMR(400MHz,CDCl3)δ8.34(d,J＝6.1Hz,1H),7.15–7.08(m,2H),6.97–6.92(m,2H),6.45(d,J＝6.1Hz,1H),3.83(s,3H),3.78(s,3H),3.16(s,3H)；13CNMR(101MHz,CDCl3)δ170.7,164.0,163.9,159.8,149.2,138.3,130.4(2C),126.2,125.6,114.3(2C),107.8,55.5,52.7,52.3；HRMS(EI)calcd for C16H15NO6[M]+317.0899,found317.0900.
Figure BDA0002246490020000175
:1H NMR(400MHz,CDCl3)δ8.35(d,J＝6.1Hz,1H),7.70(dt,J＝7.8,1.3Hz,1H),7.58(dd,J＝10.4,5.4Hz,1H),7.52(t,J＝1.6Hz,1H),7.46(ddd,J＝8.0,2.0,1.1Hz,1H),6.49(d,J＝6.1Hz,1H),3.81(s,3H),3.18(s,3H)；13C NMR(101MHz,CDCl3)δ169.7,163.6,163.5,148.3,139.0,134.6,133.3,132.2,132.2,130.1,126.1,117.4,113.3,108.5,53.0,52.3；HRMS(EI)calcd for C16H12N2O5[M]+312.0746,found 312.0745.
Figure BDA0002246490020000181
:1H NMR(400MHz,CDCl3)δ8.36(d,J＝6.1Hz,1H),7.68(d,J＝7.9Hz,1H),7.60(t,J＝7.8Hz,1H),7.52–7.38(m,2H),6.48(d,J＝6.1Hz,1H),3.80(s,3H),3.10(s,3H)；13C NMR(101MHz,CDCl3)δ169.9,163.7,163.6,148.6,138.8,134.2,132.6,131.5(q,JCF＝33.1Hz),129.8,126.1,125.63,125.61,123.4(d,JCF＝272.6Hz),108.4,52.9,52.2；HRMS(EI)calcd for C16H12F3NO5[M]+355.0668,found 355.0670.
Figure BDA0002246490020000182
:1H NMR(400MHz,CDCl3)δ8.33(d,J＝6.1Hz,1H),7.75(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),6.49(d,J＝6.1Hz,1H),3.82(s,3H),3.14(s,3H)；13CNMR(101MHz,CDCl3)δ169.5,163.6,163.6,148.4,139.1,137.9,132.8(2C),129.2(2C),126.0,117.8,112.4,108.6,53.0,52.3；HRMS(EI)calcd forC16H12N2O5[M]+312.0746,found312.0748.
Figure BDA0002246490020000183
:1H NMR(400MHz,CDCl3)δ8.33(d,J＝6.1Hz,1H),7.24(d,J＝8.1Hz,2H),7.07(d,J＝8.2Hz,2H),6.45(d,J＝6.1Hz,1H),3.78(s,3H),3.09(s,3H),2.38(s,3H)；13C NMR(101MHz,CDCl3)δ170.6,164.0,163.9,149.2,139.0,138.4,130.6,129.7(2C),128.8(2C),126.2,107.8,52.7,52.1,21.2；HRMS(EI)calcd for C16H15NO5[M]+301.0950,found 301.0951.
Figure BDA0002246490020000184
:1H NMR(400MHz,CDCl3)δ8.33(d,J＝6.1Hz,1H),7.34(t,J＝8.1Hz,1H),6.94(dd,J＝8.4,2.4Hz,1H),6.83–6.76(m,1H),6.71(t,J＝2.1Hz,1H),6.45(d,J＝6.1Hz,1H),3.80(d,J＝6.7Hz,6H),3.14(s,3H)；13C NMR(101MHz,CDCl3)δ170.2,163.9(2C),159.9,149.0,138.5,134.4,129.6,126.1,121.0,115.2,114.0,108.1,55.4,5.7,52.1；HRMS(EI)calcd for C16H15NO6[M]+317.0899,found 317.0897.
Figure BDA0002246490020000191
:1H NMR(400MHz,CDCl3)δ8.51(d,J＝6.1Hz,1H),7.98–7.86(m,2H),7.60–7.47(m,4H),7.36(d,J＝7.1Hz,1H),6.57(d,J＝6.1Hz,1H),3.74(s,3H),2.53(s,3H)；13C NMR(101MHz,CDCl3)δ170.6,163.7,163.6,149.3,138.6,134.1,131.3,130.1,129.9,128.3,128.3,127.4,126.7,126.4,125.2,122.7,108.4,52.7,51.5；HRMS(EI)calcd for C19H15NO5[M]+337.0950,found 337.0952.
Figure BDA0002246490020000192
:1H NMR(400MHz,CDCl3)δ8.71(dd,J＝13.9,8.3Hz,2H),8.55(d,J＝6.1Hz,1H),7.88(d,J＝7.3Hz,1H),7.75–7.57(m,6H),6.59(d,J＝6.1Hz,1H),3.74(s,3H),2.37(s,3H)；13C NMR(101MHz,CDCl3)δ170.6,163.7,163.7,149.3,138.7,131.0,130.7,130.7,129.5(2C),129.1,128.6,128.1,127.5(2C),127.3,126.5,123.5,123.0,122.7,108.5,52.7,51.6；HRMS(EI)calcd for C23H17NO5[M]+387.1107,found 387.1106.
Figure BDA0002246490020000193
:1H NMR(400MHz,CDCl3)δ8.83(d,J＝9.1Hz,1H),8.70(d,J＝8.2Hz,1H),8.58(d,J＝6.1Hz,1H),8.51(d,J＝2.3Hz,1H),8.45(dd,J＝9.1,2.3Hz,1H),7.93(dd,J＝7.7,0.9Hz,1H),7.84–7.72(m,3H),6.65(d,J＝6.1Hz,1H),3.77(s,3H),2.43(s,3H)；13C NMR(101MHz,CDCl3)δ170.5,163.6,163.4,149.0,146.5,139.2,134.8,131.9,131.2,129.7,129.5,129.3,129.3,129.2,129.1,126.5,124.7,123.8,121.2,119.8,108.9,52.9,51.7；HRMS(EI)calcd for C23H16N2O7[M]+432.0958,found 432.0957.
Figure BDA0002246490020000194
:1H NMR(400MHz,CDCl3)δ8.83(t,J＝9.4Hz,2H),8.58(d,J＝6.1Hz,1H),8.19(s,1H),8.00–7.92(m,3H),7.77(s,1H),6.64(d,J＝6.1Hz,1H),3.78(s,3H),2.38(s,3H)；13C NMR(101MHz,CDCl3)δ170.4,163.6,163.4,149.0,139.3,132.3,131.7,130.8,130.6,130.5,130.4,130.2,130.1,130.0,126.5,126.4,126.4,124.6(t,JCF＝4.7Hz),124.5,124.3,124.1(dd,JCF＝6.4,3.2Hz),121.5(d,JCF＝4.3Hz).108.9,52.9,51.6；HRMS(EI)calcd for C25H15F6NO5[M]+523.0854,found 523.0852.
Figure BDA0002246490020000195
:1H NMR(400MHz,CDCl3)δ8.58(ddd,J＝19.3,9.6,5.7Hz,3H),7.63(s,1H),7.47(dtd,J＝17.5,9.1,2.6Hz,3H),7.24(dd,J＝9.6,2.5Hz,1H),6.60(d,J＝6.1Hz,1H),3.76(s,3H),2.46(s,3H)；13C NMR(101MHz,CDCl3)δ170.3,163.6,163.5,161.8(d,JCF＝247.3Hz),161.3(d,JCF＝248.1Hz),148.8,139.0,131.5(d,JCF＝8.2Hz),130.9(d,JCF＝9.7Hz),129.8(d,JCF＝3.8Hz),129.6(d,JCF＝3.9Hz),127.4,127.0,126.4,125.4(d,JCF＝8.6Hz),125.0(d,JCF＝8.9Hz),117.6(d,JCF＝23.8Hz),117.0(d,JCF＝23.9Hz),113.2(d,JCF＝21.0Hz),108.7,108.7(d,JCF＝22.6Hz),52.8,51.6；HRMS(EI)calcd forC23H15F2NO5[M]+423.0918,found 423.0922.
Figure BDA0002246490020000201
:1H NMR(400MHz,CDCl3)δ8.61–8.41(m,3H),7.56(s,1H),7.30(ddd,J＝8.9,5.3,2.6Hz,2H),7.20(d,J＝2.6Hz,1H),6.89(d,J＝2.6Hz,1H),6.59(d,J＝6.1Hz,1H),3.89(d,J＝26.6Hz,6H),3.75(s,3H),2.42(s,3H)；13C NMR(101MHz,CDCl3)δ170.5,163.7,163.6,158.2,157.9,149.2,138.7,131.0,129.9,129.5,128.6,126.5,125.6,125.2,124.2,123.8,119.0,117.7,108.7,108.6,104.2,55.4,55.4,52.7,51.6；HRMS(EI)calcd for C25H21NO7[M]+447.1318,found 447.1321.
Figure BDA0002246490020000202
:1H NMR(400MHz,CDCl3)δ8.25(d,J＝6.1Hz,1H),7.25(dt,J＝26.9,7.2Hz,3H),7.00(d,J＝7.3Hz,2H),6.45(d,J＝6.1Hz,1H),4.97(s,2H),3.76(s,3H),3.35(s,3H)；13C NMR(101MHz,CDCl3)δ171.0,165.0,164.0,147.8,138.8,135.9,128.6(2C),127.3,125.9,125.6(2C),108.1,52.8,52.6,43.7；HRMS(EI)calcdfor C16H15NO5[M]+301.0950,found 301.0949.
Figure BDA0002246490020000203
:1H NMR(400MHz,CDCl3)δ8.23(dd,J＝44.7,7.4Hz,3H),7.20(d,J＝8.6Hz,2H),6.49(d,J＝6.1Hz,1H),5.03(s,2H),3.78(s,3H),3.42(s,3H)；13C NMR(101MHz,CDCl3)δ170.7,164.8,163.6,147.3,147.3,143.7,139.2,126.7(2C),125.9,123.8(2C),108.3,52.9,52.8,43.5；HRMS(EI)calcd for C16H14N2O7[M]+346.0801,found346.0799.
Figure BDA0002246490020000204
:1H NMR(400MHz,CDCl3)δ8.27(d,J＝6.1Hz,1H),7.55(d,J＝7.7Hz,1H),7.43(t,J＝7.8Hz,1H),7.32(s,1H),7.28(d,J＝7.7Hz,1H),6.48(d,J＝6.1Hz,1H),4.97(s,2H),3.78(s,3H),3.43(s,3H)；13C NMR(101MHz,CDCl3)δ170.8,164.8,163.6,147.3,139.1,137.9,131.1,130.4,129.5,129.5,125.9,118.4,112.8,108.3,52.9,52.7,43.2；HRMS(EI)calcd for C17H14N2O5[M]+326.0903,found 326.0906.
Figure BDA0002246490020000211
:1H NMR(400MHz,CDCl3)δ8.28(d,J＝6.1Hz,1H),7.61(d,J＝8.2Hz,2H),7.14(d,J＝8.2Hz,2H),6.48(d,J＝6.1Hz,1H),4.99(s,2H),3.78(s,3H),3.39(s,3H).13C NMR(101MHz,CDCl3)δ170.7,164.8,163.6,147.3,141.7,139.1,132.4(2C),126.5(2C),125.9,118.5,111.4,108.3,52.9,52.7,43.6；HRMS(EI)calcd for C17H14N2O5[M]+326.0903,found 326.0905.
Figure BDA0002246490020000212
:E/Z＝81:19；major isomer:1H NMR(400MHz,CDCl3)δ8.55(d,J＝6.2Hz,1H),7.64(d,J＝8.4Hz,2H),7.31(d,J＝8.5Hz,2H),6.56(d,J＝6.2Hz,1H),5.37(s,2H),4.31(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H).HRMS(EI)calcd for C16H11N3O3[M]+293.0800,found 293.0802.
Figure BDA0002246490020000213
:1H NMR(400MHz,CDCl3)δ7.67–7.59(m,3H),7.40(dt,J＝16.3,8.2Hz,6H),7.31–7.26(m,2H),7.19(dd,J＝8.0,4.4Hz,2H),6.97(s,1H),6.84(d,J＝8.1Hz,1H),6.75(s,1H),4.72(s,1H),4.59(s,1H).HRMS(EI)calcd for C27H18N2O3[M]+418.1317,found 418.1318.
Figure BDA0002246490020000214
:E/Z＝63:37；major isomer:1H NMR(400MHz,CDCl3)δ8.19(d,J＝6.1Hz,1H),7.59(d,J＝8.1Hz,2H),7.09(d,J＝8.1Hz,2H),6.47(d,J＝6.1Hz,1H),4.95(s,2H),3.81(s,3H),1.69(ddd,J＝12.2,7.9,4.5Hz,1H),0.98–0.93(m,2H),0.76(dq,J＝7.4,3.7Hz,2H).HRMS(EI)calcd for C19H16N2O4[M]+336.1110,found 336.1110.
Figure BDA0002246490020000215
:E/Z＝66:34；major isomer:1H NMR(400MHz,CDCl3)δ8.14(d,J＝6.1Hz,1H),7.61(d,J＝8.0Hz,2H),7.10(d,J＝8.1Hz,2H),6.47(d,J＝6.2Hz,1H),4.95(s,2H),4.39–4.32(m,2H),3.64–3.55(m,2H),3.34(s,3H),1.72(s,3H).HRMS(EI)calcd forC19H18N2O5[M]+322.1216,found 322.1219.
Figure BDA0002246490020000221
:1H NMR(400MHz,CDCl3)δ8.26(d,J＝6.1Hz,1H),7.51(d,J＝7.8Hz,1H),7.43(t,J＝7.8Hz,1H),7.32(s,1H),7.17(d,J＝7.7Hz,1H),6.47(d,J＝6.1Hz,1H),5.01(s,2H),3.77(s,3H),3.37(s,3H)；13C NMR(101MHz,CDCl3)δ170.9,164.9,163.8,147.5,139.1,137.3,131.0(q,JCF＝32.4Hz),129.2,129.1,125.8,124.3(q,JCF＝3.8Hz),123.9(d,JCF＝272.3Hz),122.8(q,JCF＝3.8Hz),108.3,52.8,52.6,43.5；HRMS(EI)calcdfor C17H14F3NO5[M]+369.0842,found 369.0838.
Figure BDA0002246490020000222
:1H NMR(400MHz,CDCl3)δ8.28(d,J＝6.1Hz,1H),7.56(d,J＝8.2Hz,2H),7.14(d,J＝8.1Hz,2H),6.47(d,J＝6.1Hz,1H),5.01(s,2H),3.77(s,3H),3.35(s,3H)；13C NMR(101MHz,CDCl3)δ170.8,164.9,163.7,147.4,140.3,139.0(2C),129.7(d,JCF＝32.6Hz),126.1,125.9,125.5(q,JCF＝3.8Hz,2C),124.0(q,JCF＝272.0Hz),108.3,52.8,52.6,43.5；HRMS(EI)calcd for C17H14F3NO5[M]+369.0824,found 369.0827.
Figure BDA0002246490020000223
:1H NMR(400MHz,CDCl3)δ8.27(d,J＝6.1Hz,1H),8.12(dd,J＝8.1,1.3Hz,1H),7.92(s,1H),7.50(t,J＝7.9Hz,1H),7.37(dd,J＝7.7,0.4Hz,1H),6.49(d,J＝6.1Hz,1H),5.03(s,2H),3.78(s,3H),3.46(s,3H).13C NMR(101MHz,CDCl3)δ170.83,164.84,163.65,148.40,147.34,139.21,138.50,132.06,129.69,125.89,122.55,121.10,108.30,52.89,52.78,43.28；HRMS(EI)calcd for C16H14N2O7[M]+346.0801,found346.0799.
Figure BDA0002246490020000224
:1H NMR(400MHz,CDCl3)δ8.24(d,J＝6.1Hz,1H),6.99(d,J＝6.9Hz,4H),6.44(d,J＝6.1Hz,1H),4.92(s,2H),3.77(s,3H),3.44(s,3H)；13C NMR(101MHz,CDCl3)δ171.0,164.9,163.9,162.0(d,JCF＝245.7Hz),147.6,138.9,131.7(d,JCF＝3.1Hz),127.5(d,JCF＝8.1Hz,2C),125.9,115.5(d,JCF＝21.6Hz,2C),108.1,52.8,52.7,43.1；HRMS(EI)calcd for C16H14FNO5[M]+319.0856,found 319.0858.
Figure BDA0002246490020000225
:1H NMR(400MHz,CDCl3)δ8.57–8.46(m,1H),8.39(s,1H),8.24(d,J＝6.1Hz,1H),7.32(d,J＝7.8Hz,1H),7.24(dd,J＝7.6,4.3Hz,1H),6.46(d,J＝6.1Hz,1H),4.98(s,2H),3.77(s,3H),3.46(s,3H)；13C NMR(101MHz,CDCl3)δ170.9,164.9,163.7,148.7,147.8,147.3,139.1,133.7,131.8,125.8,123.5,108.3,52.8,52.7,41.6；HRMS(EI)calcd for C15H14N2O5[M]+302.0903,found 302.0906.
Figure BDA0002246490020000231
:1H NMR(400MHz,CDCl3)δ8.11(d,J＝6.1Hz,1H),7.29(d,J＝1.1Hz,1H),6.39(d,J＝6.1Hz,1H),6.28(dd,J＝3.2,1.9Hz,1H),6.04(dd,J＝3.3,0.8Hz,1H),4.94(s,2H),3.79(s,3H),3.74(s,3H).13C NMR(101MHz,CDCl3)δ170.76,164.94,164.12,149.23,147.63,142.12,139.06,125.77,110.51,108.01,107.27,52.92,52.79,37.51.HRMS(EI)calcd for C14H13NO6[M]+291.0743,found 291.0742.
Figure BDA0002246490020000232
:1H NMR(400MHz,CDCl3)δ8.14(d,J＝6.1Hz,1H),7.18(dd,J＝5.1,1.2Hz,1H),6.90(dd,J＝5.1,3.5Hz,1H),6.81–6.76(m,1H),6.40(d,J＝6.1Hz,1H),5.10(d,J＝0.7Hz,2H),3.78(s,3H),3.67(s,3H).13C NMR(101MHz,CDCl3)δ170.75,165.00,164.02,147.46,139.13,138.83,126.77,125.82,125.21,125.01,108.11,52.98,52.81,39.48.HRMS(EI)calcd for C14H13NO5S[M]+307.0514,found 307.0508.
Figure BDA0002246490020000233
:1H NMR(400MHz,CDCl3)δ8.21(d,J＝6.1Hz,1H),7.32–7.27(m,2H),7.26–7.18(m,3H),6.32(d,J＝6.1Hz,1H),3.84(s,3H),3.83(s,3H),3.77–3.69(m,2H),2.80(dd,J＝9.3,7.2Hz,2H).13C NMR(101MHz,CDCl3)δ170.82,165.77,163.88,148.18,138.33,137.82,128.81,128.57,126.68,126.19,106.75,53.08,52.77,42.17,34.69.HRMS(EI)calcd for C17H17NO5[M]+315.1107,found 315.1109.
Figure BDA0002246490020000234
:1H NMR(400MHz,CDCl3)δ8.31(d,J＝6.1Hz,1H),7.78–7.63(m,3H),7.41–7.31(m,3H),7.25(t,J＝7.4Hz,1H),7.02(d,J＝7.6Hz,1H),6.38(d,J＝6.1Hz,1H),5.79(d,J＝11.3Hz,1H),4.84(d,J＝8.6Hz,1H),3.78(s,3H),3.27(s,3H),2.76(s,1H).13C NMR(101MHz,CDCl3)δ171.30,165.72,163.96,151.01,139.01,138.45,133.14,132.24,132.05,128.40,128.38,128.16,127.96,126.79,124.88,124.31,123.97,123.75,107.39,68.68,61.84,52.89,52.68.HRMS(EI)calcd for C23H19NO6[M]+405.1212,found405.1197.
Figure BDA0002246490020000241
:1H NMR(400MHz,DMSO-d6)δ8.26(d,J＝7.8Hz,1H，CH-C＝C),8.22–8.15(m,1H,PhH),8.12(s,1H,PhH),7.96(t,J＝12.2Hz,1H,PhH),7.90(s,1H,PhH),7.60(d,J＝24.5Hz,1H,PhH),7.56–7.36(m,2H,PhH),6.77(d,J＝5.3Hz,1H,-OH),6.35(s,1H,CO-CH),5.51(d,J＝6.0Hz,1H,OH-CH),4.66(s,1H,-N-CH),3.74(d,J＝29.3Hz,3H,-COOMe),3.17(s,3H,-COOMe)；13C NMR(101MHz,DMSO)δ171.17(1C,CO),164.45(1C,COOMe),163.81(1C,COOMe),146.58(1C,PhC),145.60(1C,-N-C＝C),140.02(1C,PhC),139.44(1C,PhC),139.13(1C,-CH-C＝C),134.65(1C,PhC),130.20(1C,PhC),129.54(1C,PhC),128.35(1C,PhC),127.34(1C,PhC),125.49(1C,CO-CH),125.15(1C,PhC),125.08(1C,PhC),123.45(1C,PhC),120.34(1C,PhC),107.22(1C,-N-C＝C),66.00(1C,OH-CH),61.42(1C,-N-CH),52.98(1C,COOMe),52.34.(1C,COOMe).HRMS(EI)calcd for C23H16N2O7[M-H2O]+432.0958,found 432.0956.
Figure BDA0002246490020000242
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.1Hz,1H,CH-C＝C),7.69(d,J＝8.6Hz,1H,PhH),7.66–7.58(m,2H,PhH),7.39–7.27(m,2H,PhH),6.89(dd,J＝8.6,2.6Hz,1H,PhH),6.61–6.48(m,1H,PhH),6.40(d,J＝6.1Hz,1H,CO-CH),5.77(d,J＝11.6Hz,1H,OH-CH),4.82(s,1H,-N-CH),3.79(s,3H,-COOMe),3.78(s,3H,-COOMe),3.32(s,3H,OMe),2.82–2.32(m,1H,-OH)；13C NMR(101MHz,CDCl3)δ165.74(1C,CO),163.92(1C,COOMe),159.55(1C,COOMe),151.10(1C,-N-C＝C),139.09,137.53(1C,-CH-C＝C),133.98(1C,PhC),132.05(1C,PhC),128.15(2C,PhC),127.46(1C,PhC),126.761C,CO-CH),125.94(1C,PhC),125.41(1C,PhC),124.19(1C,PhC),123.12(1C,PhC),113.01(1C,PhC),111.25(1C,PhC),107.41(1C,-N-C＝C),68.88(1C,OH-CH),61.80(1C,-N-CH),55.34(1C,-OMe),52.89(1C,COOMe),52.76(1C,COOMe).HRMS(EI)calcd for C24H19NO6[M-H2O]+417.1212,found417.1215.
Figure BDA0002246490020000243
:1H NMR(400MHz,CDCl3)δ8.31(d,J＝6.2Hz,1H,CH-C＝C),7.86(d,J＝8.2Hz,1H,PhH),7.75–7.70(m,1H,PhH),7.69–7.59(m,2H,PhH),7.45–7.36(m,2H,PhH),7.30(s,1H,PhH),6.39(d,J＝6.1Hz,1H,PhH),5.76(d,J＝11.2Hz,1H,OH-CH),4.85(s,1H,-N-CH),3.79(s,3H,-COOMe),3.25(s,3H,-COOMe),3.01(dd,J＝17.2,12.0Hz,1H,-OH)；13C NMR(101MHz,CDCl3)δ171.36,165.59,163.91,150.90,139.26,139.19,135.55,132.71,131.77,130.06(q,J＝32.5Hz),129.14,128.66,126.72,125.11,125.04(q,J＝3.8Hz),124.17(q,J＝272.2Hz),124.51,124.09,121.85(d,J＝2.9Hz),107.71,68.24,61.41,52.99,52.74.HRMS(EI)calcd for C24H16F3NO5[M-H2O]+455.0982,found 455.0979.
Figure BDA0002246490020000251
:1H NMR(400MHz,CDCl3)δ8.31(d,J＝6.2Hz,1H),7.75–7.61(m,3H),7.37(dd,J＝5.7,3.3Hz,2H),7.33(dd,J＝8.4,1.5Hz,1H),7.01(s,1H),6.40(d,J＝6.1Hz,1H),5.75(d,J＝11.6Hz,1H),4.80(s,1H),3.80(s,3H),3.30(s,3H),2.53(d,J＝123.3Hz,1H)；13CNMR(101MHz,CDCl3)δ171.20,165.52,163.84,150.89,139.23,138.18,134.19,133.85,131.73,131.09,128.73,128.58,128.32,126.78,125.39,125.18,124.45,123.73,107.62,68.45,61.42,52.98,52.75.HRMS(EI)calcdfor C23H16 35ClNO5[M-H2O]+421.0717,found 421.0713；calcd for C23H16 37ClNO5[M-H2O]+423.0688,found 423.0703.
Figure BDA0002246490020000252
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.2Hz,1H),7.99(s,1H),7.74(dd,J＝5.9,3.1Hz,1H),7.70–7.63(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.38(m,2H),7.17(d,J＝8.1Hz,1H),6.40(d,J＝6.1Hz,1H),5.77(dd,J＝10.5,7.3Hz,1H),4.85(s,1H),3.80(s,3H),3.31(s,3H),2.81(s,1H)；13C NMR(101MHz,CDCl3)δ171.28,165.58,163.85,162.58(d,J＝247.7Hz),150.88,139.19,137.89,134.97(d,J＝7.4Hz),131.29,129.31(d,J＝3.2Hz),128.28(2C),126.76,125.89(d,J＝8.2Hz),124.40,123.58,115.35(d,J＝21.7Hz),112.33(d,J＝23.7Hz),107.63,68.43,61.62,52.97,52.73.HRMS(EI)calcd forC23H16FNO5[M-H2O]+405.1013,found405.1014.
Figure BDA0002246490020000253
:1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝8.2Hz,1H),8.18(d,J＝8.2Hz,1H),8.11(d,J＝5.9Hz,1H),7.88(s,1H),7.83(t,J＝6.8Hz,2H),7.45(s,1H),6.76(d,J＝6.1Hz,1H),6.54(d,J＝6.5Hz,1H),5.58(dd,J＝10.7,6.5Hz,1H),4.70(d,J＝11.1Hz,1H),3.78(s,3H),3.16(s,3H)；13C NMR(101MHz,DMSO-d6)δ171.14,164.40,163.82,151.53,140.93,139.40,135.03,134.53,134.11,129.30(q,J＝32.1Hz),129.08(q,J＝31.9Hz),127.39,125.78,125.71,125.26,125.00(q,J＝3.3Hz),124.07(q,J＝272.3Hz),123.92(q,J＝274.3Hz),122.34(q,J＝4.0Hz),121.64(q,J＝4.6Hz),107.10,65.88,61.22,52.95,52.25.HRMS(EI)calcd forC25H15F6NO5[M-H2O]+523.0854,found 523.0853.
Figure BDA0002246490020000254
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.2Hz,1H),7.99(s,1H),7.74(dd,J＝5.9,3.1Hz,1H),7.70–7.63(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.38(m,2H),7.17(d,J＝8.1Hz,1H),6.40(d,J＝6.1Hz,1H),5.77(dd,J＝10.5,7.3Hz,1H),4.85(s,1H),3.80(s,3H),3.31(s,3H),2.81(s,1H)；13C NMR(101MHz,CDCl3)δ171.21,165.61,163.86(t,J＝20.1Hz),163.78,δ,161.44(d,J＝40.1Hz),150.64,140.62(d,J＝7.3Hz),139.29,134.48(d,J＝7.4Hz),128.57(d,J＝3.2Hz),127.47(d,J＝3.3Hz),126.71,125.72(d,J＝8.0Hz),125.55(d,J＝8.1Hz),115.42(d,J＝33.1Hz),115.20(d,J＝33.4Hz),112.34(d,J＝23.8Hz),111.92(d,J＝23.6Hz),107.78,68.24,61.25,53.02,52.82.HRMS(EI)calcdfor C23H15F2NO5[M-H2O]+423.0918,found 423.0917.
Figure BDA0002246490020000261
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.2Hz,1H),7.99(s,1H),7.74(m,3.1Hz,1H),7.70–7.63(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.38(m,2H),7.17(d,J＝8.1Hz,1H),6.40(d,J＝6.1Hz,1H),5.77(dd,J＝10.5,7.3Hz,1H),4.85(s,1H),3.80(s,3H),3.31(s,3H),2.81(s,1H)；13C NMR(101MHz,CDCl3)δ171.27,165.61,163.83,150.81,139.29,138.43,136.08(d,J＝0.9Hz),134.00,130.78(q,J＝32.4Hz),130.69,129.33,128.50,126.75,125.65,124.52(d,J＝3.2Hz),124.45(d,J＝3.6Hz),124.05(q,J＝272.4Hz),124.03,120.95(d,J＝3.1Hz),107.70,68.31,61.56,53.04,52.85.HRMS(EI)calcd for C23H15F3NO5[M-H2O]+455.0981,found 455.0979.
Figure BDA0002246490020000262
:1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝10.2Hz,1H),8.31–8.25(m,4H),8.09(t,J＝14.4Hz,1H),7.96(s,1H),6.79(d,J＝6.1Hz,1H),6.73(d,J＝6.5Hz,1H),5.61(dd,J＝11.3,6.6Hz,1H),4.78(d,J＝10.6Hz,1H),3.78(d,J＝12.3Hz,3H),3.23(s,3H)；13C NMR(101MHz,DMSO-d6)δ171.20,164.33,163.84,151.19,148.03,147.76,141.89,139.64,136.76,135.82,135.62,127.37,126.98,126.90,123.59,123.33,120.61,120.17,107.47,65.78,60.86,53.03,52.52.HRMS(EI)calcd for C23H15N3O9[M-H2O]+477.0808,found 477.0799.
Figure BDA0002246490020000263
:1H NMR(400MHz,CDCl3)δ8.32(d,J＝6.2Hz,1H),7.99(s,1H),7.74(dd,J＝5.9,3.1Hz,1H),7.70–7.63(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.38(m,2H),7.17(d,J＝8.1Hz,1H),6.40(d,J＝6.1Hz,1H),5.77(dd,J＝10.5,7.3Hz,1H),4.85(s,1H),3.80(s,3H),3.31(s,3H),2.81(s,1H)；13C NMR(101MHz,CDCl3)δ172.73,165.12,163.25,148.20,147.96,147.72,142.39,139.47,137.89,134.41,132.99,129.50,129.32,126.12,123.57,123.48,123.22,121.87,109.09,72.65,63.62,53.52,53.20.HRMS(EI)calcd for C23H17N3O9[M-H2O]+479.0808,found.479.2361.
Figure BDA0002246490020000271
:E/Z＝50:50；1H NMR(400MHz,CDCl3)δ8.25(d,J＝6.1Hz,0.5H),7.94(d,J＝6.1Hz,0.5H),7.69–7.60(m,2H),7.42–7.32(m,2H),7.12–7.01(m,1H),6.77(ddd,J＝9.3,2.6,1.1Hz,0.5H),6.71(ddd,J＝9.3,2.6,1.1Hz,0.5H),6.41(d,J＝6.1Hz,1H)5.79(d,J＝11.7Hz,1H),4.84(dd,J＝19.9,11.5Hz,1H),4.43–4.19(m,1H),3.98(dq,J＝14.2,7.0Hz,0.5H),3.75(dq,J＝10.8,7.1Hz,0.5H),2.31(s,3H),1.32(t,J＝7.1Hz,1.5H),0.91(t,J＝7.1Hz,1.5H).HRMS(EI)calcd forC24H18FNO4[M-H2O]+403.1220,found.403.1221.
Figure BDA0002246490020000272
:E/Z＝50:50；1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ8.22(d,J＝6.1Hz,0.5H),7.89(d,J＝6.1Hz,0.5H),7.70(d,J＝7.8Hz,1H),7.67–7.64(m,1H),7.62(d,J＝8.4Hz,1H),7.34(ddd,J＝10.4,8.3,4.4Hz,2H),7.30–7.21(m,1H),7.01(d,J＝7.7Hz,0.5H),6.96(d,J＝7.7Hz,0.5H),6.35(dd,J＝6.1,1.5Hz,1H),5.75(dd,J＝11.7,4.9Hz,1H),4.89(d,J＝11.3Hz,0.5H),4.81(d,J＝10.6Hz,0.5H),4.43–4.20(m,1H),3.96(d,J＝6.8Hz,0.5H),3.72(dq,J＝10.8,7.1Hz,0.5H),2.30(s,3H),1.30(t,J＝7.1Hz,1.5H),0.89(t,J＝7.1Hz,1.5H).HRMS(EI)calcd for C24H18 35ClNO4[M-H2O]+419.0924,found 419.0925；calcd for C24H18 37ClNO4[M-H2O]+421.0895,found 421.0905.
实施例7：
本发明化合物的抗肿瘤活性测试
1.实验原理
活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为不溶于水的蓝紫色结晶甲瓒(Formazan)并沉积在细胞中，而死细胞无此功能。二甲基亚砜(DMSO)，其作用是能够溶解细胞中甲瓒，用酶标仪测定其光吸收值就可反映活细胞数量。
2.抗肿瘤活性实验
试样：实施例化合物
细胞系：肝癌细胞系HepG2和肺癌细胞系A549
试剂：0.5％MTT溶液，RPMI 1640培养液、新生牛血清；胰酶；96孔培养板；二甲基亚砜；
仪器：超净台、培养箱、Perkin Elmer全自动多功能酶标仪
实验步骤：
1)将指数生长期的HepG2和A549细胞(2×10 5个/mL)接种到96孔板上培养过夜，然后用设定浓度的药物处理细胞。
2)药物处理24小时后，向每个孔中加入20μL MTT试剂(5mg/mL)。5％CO2，37℃孵育4小时后，吸出培养基的上清液，向每个孔中加入150μL DMSO溶解甲瓒晶体。
3)采用双波长法测定，通过酶标仪测定在492和630nm的吸光度。
3.抗肿瘤活性评价
1)细胞活力抑制率计算
细胞活力抑制率＝[1-加药(OD492-OD630)/对照(OD492-OD630)]×100(％)
2)IC50值计算
试样浓度与细胞抑制率线性回归，利用软件计算试样对细胞的半数抑制浓度IC50值。
表1细胞活力抑制IC50值
Figure BDA0002246490020000281
Figure BDA0002246490020000291
由表1可以看出，对于HepG2细胞，有33个化合物的IC50值低于10μM；对于A549细胞，有26个化合物的IC50值低于10μM。并且，对于HepG2细胞，有11个化合物表现出了优于阳性对照阿霉素的活性；对于A549细胞，有34个化合物表现出了优于阳性对照阿霉素的活性。可见，该类结构新颖的内酰胺化合物具有优异的抗癌活性。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。

Claims (7)

1.一种内酰胺衍生物，其特征在于，所述的衍生物为式I化合物或式I化合物药学上可接受的盐：
Figure FDA0002723764090000011
其中：
Ra为取代的或未取代的芳基、取代的或未取代的苯甲酰基、取代的或未取代的9,10-二氢菲基、取代的或未取代的C1～C15烷基中的一种；
Rb、Rc分别独立地选自酯基或酰基，所述的酯基的通式为COOR，所述的酰基的通式为COR’，所述的R及R’分别独立地选自取代的或未取代的C1～C15烷基；
所述的Ra中，取代的芳基为一个或多个取代基取代的芳基，取代的苯甲酰基为一个或多个取代基取代的苯甲酰基，取代的9,10-二氢菲基为一个或多个取代基取代的9,10-二氢菲基，取代的C1～C15烷基为一个或多个取代基取代的C1～C15烷基；所述的R及R’中，取代的C1～C15烷基为一个或多个取代基取代的C1～C15烷基；所述的取代基选自羟基、卤素、氰基、硝基、三氟甲基、芳基、取代芳基、杂环芳基、取代杂环芳基、C1～C6烷基或C1～C6烷氧基；
所述的取代芳基为一个或多个取代基取代的芳基，所述的取代芳基中的取代基选自卤素、氰基、硝基、三氟甲基、C1～C6烷基或C1～C6烷氧基；所述的取代杂环芳基为一个或多个取代基取代的杂环芳基，所述的取代杂环芳基中的取代基选自C1～C6烷基；
所述的芳基选自苯基、萘基或菲基中的一种；所述的杂环芳基选自呋喃基、噻吩基或吡啶基中的一种。
2.一种如权利要求1所述的内酰胺衍生物的制备方法，其特征在于，该方法为：在惰性酸溶剂中，以
Figure FDA0002723764090000012
为原料，以二水合醋酸锰为催化剂，在30-110℃下反应4-72小时，反应结束后，经分离后即得到所述的内酰胺衍生物。
3.根据权利要求2所述的一种内酰胺衍生物的制备方法，其特征在于，所述的
Figure FDA0002723764090000021
及二水合醋酸锰的摩尔比1:(1.0-6.0):(3.0-6.0)。
4.一种如权利要求1所述的内酰胺衍生物的应用，其特征在于，所述的内酰胺衍生物用于制备抗肿瘤药物。
5.一种组合物，该组合物含有如权利要求1所述的内酰胺衍生物。
6.根据权利要求5所述的一种组合物，其特征在于，该组合物包括一种或更多种所述的内酰胺衍生物，以及药学上可接受的载体介质和/或赋形剂。
7.一种如权利要求5所述的组合物的应用，其特征在于，所述的组合物用于制备抗肿瘤药物。
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