CN117510496A - 一种环丙烷拼接吡咯喹啉并四环类衍生物的制备方法 - Google Patents
一种环丙烷拼接吡咯喹啉并四环类衍生物的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- ZIUYHTQZEPDUCZ-UHFFFAOYSA-N 7h-pyrrolo[2,3-h]quinoline Chemical compound C1=CN=C2C(C=CN3)=C3C=CC2=C1 ZIUYHTQZEPDUCZ-UHFFFAOYSA-N 0.000 title claims abstract description 8
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
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- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 4
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- 238000005888 cyclopropanation reaction Methods 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- YDUWCKHQORLZSO-UHFFFAOYSA-N murrayamine-E Natural products C1CC2C(C)(C)N3C4=CC(O)=CC=C4C(C=C4C)=C3C3=C4OC1(C)CC23 YDUWCKHQORLZSO-UHFFFAOYSA-N 0.000 description 1
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- VJMRKWPMFQGIPI-UHFFFAOYSA-N n-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1-[2-[[3-(trifluoromethyl)phenyl]methyl]-1-benzothiophen-7-yl]pyrazole-4-carboxamide Chemical compound OCC1=C(C(=O)NCCO)C(C)=NN1C1=CC=CC2=C1SC(CC=1C=C(C=CC=1)C(F)(F)F)=C2 VJMRKWPMFQGIPI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 229930014626 natural product Natural products 0.000 description 1
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- LZMMZBXPCWKECN-UHFFFAOYSA-N pyrano[3,2-a]carbazole Chemical class O1C=CC=C2C3=NC4=CC=CC=C4C3=CC=C21 LZMMZBXPCWKECN-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
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- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical class CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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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
- C07D471/02—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 system contains two hetero rings
- C07D471/06—Peri-condensed systems
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种环丙烷拼接吡咯喹啉并四环类衍生物的制备方法,涉及化合物合成技术领域,以化合物Ⅰ与化合物Ⅱ为原料,在有机溶剂、碱性催化剂和相转移催化剂环境中,发生氮杂Michael/环丙烷化串联反应,得到衍生物Ⅲ。本发明通过一锅反应一步构建两个环,解决了1,7‑并环吲哚的合成问题,为吡咯喹啉化合物的合成提供了一种新思路,可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值。本发明操作简单易行,起始原料便宜易得,得到的产物具有较好的空气稳定性,合成方法表现出宽广的底物适应范围,对于合成前体含有的各种取代基都有很好的兼容性。
Description
技术领域
本发明涉及化学合成技术领域,特别是涉及一种环丙烷拼接吡咯喹啉并四环类衍生物的制备方法。
背景技术
一个具有生物活性的环状骨架和另外一个或几个具有不同生物活性的环状结构拼接到一个化合物中后,新形成的分子不仅具有这些结构单元的生物活性,同时还可能拓展出这些基本单元不具有的生物活性。因此,将几个具有生物活性的结构单元糅合成一个分子骨架,是有机合成和药物化学中极其重要的研究领域。
吡咯喹啉类化合物也广泛分布于各种不同结构的天然产物、药物分子和功能材料中,并且表现出显著的生物活性。例如:吡喃并咔唑类生物碱Murrayamine E,在PC-12细胞中有效加速神经突增生;KC11404有望被开发为预防哮喘的药物;从石蒜鳞茎中提取出的石蒜科生物碱lycoranine A和lycoranine B也含有吡咯喹啉类结构,这种植物在中药中被用来治疗喉部不适和细菌感染性皮肤病痈和疖。此外,DCQTB因为独特的光物理性质,被作为有机发光二极管的掺杂物而广泛运用。另一方面,环丙烷并环化合物广泛分布在结构复杂的生物活性分子中,受到了合成工作者和药物化学团队的持续关注。如倍林达(Brilinta)是一种口服抗血小板药物,一般用于心血管类疾病、心肌梗塞等疾病;安立泽(Onglyza)能有效治疗II型糖尿病;GSK1360707是一种前景看好的三重吸收抑制剂,在目前的临床实验中表现出优异的生物有效性和药代动力学参数;喹啉酮类化合物有望被开发为HIV-1非核苷类逆转录酶抑制剂。
上述活性化合物的结构式如下所示:
其中R选自甲基、乙基、正丙基、正丁基。
鉴于吡咯喹啉骨架和并环环丙烷类化合物丰富的药物活性,将吡咯并喹啉单元和环丙烷骨架拼接成并四环衍生物,有望构建一系列结构重要并具有重要生物活性的功能化合物,从而为生物活性筛选和新药开发提供化合物源。
此外,尽管1,2-、2,3-、3,4-吲哚并环化合物的制备技术已经较为成熟,但1,7-吲哚并环化合物的构建还处于起步阶段,是有机合成中的一个挑战性课题。
发明内容
本发明的目的在于提供一种环丙烷拼接吡咯喹啉并四环类衍生物的制备方法,以经济便捷的构建方法合成一类重要的药物中间体和药物类似物,可以为生物活性筛选提供化合物源,对药物筛选和制药行业具有重要的应用价值。
为了解决上述的技术问题,本发明所采用的技术方案是:
一种环丙烷拼接吡咯喹啉并四环类衍生物的制备方法,以化合物Ⅰ与化合物Ⅱ为原料,在有机溶剂、碱性催化剂和相转移催化剂环境中,发生氮杂Michael/环丙烷化串联反应,得到衍生物Ⅲ,反应通式如下:
其中,R1独立选自氢、卤素、甲氧基;R2独立选自氢、卤素、三氟乙酰基;R3独立选自芳杂环、C1-C6环烷基;Ar为取代或非取代苯基;X选自四取代硼酸根、三取代甲磺酸根或卤素;R4选自C1-C10烷基。
进一步地,R1独立选自氢、氟、氯、溴、甲氧基;R2独立选自氢、氯、溴、三氟乙酰基;R3独立选自噻吩、呋喃、萘、环丙烷基,R独立选自氢、甲氧基、卤素;Ar独立选自苯、甲苯、卤代苯,X选自四苯基硼酸根、四氟硼酸根、三氟甲磺酸根氟、氯、溴;R4选自C1-C10烷基。
通过采用上述技术方案,在有机溶剂中,在碱性催化剂和相转移催化剂的作用下,吲哚7-位衍生的查尔酮或苄叉丙酮类化合物(化合物Ⅰ)与α-芳基取代的烯基硫鎓盐(化合物Ⅱ)发生氮杂Michael/环丙烷化串联反应,获得环丙烷拼接吡咯喹啉并四环类衍生物III,该骨架化合物是第一例环丙烷拼接吡咯喹啉衍生物,可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值。
本发明获得的环丙烷中的三个碳上都有取代基,其中一个碳为全碳的季碳中心。由于环丙烷本身体积较小,同时也很容易开环,因此在狭小的立体空间引入密集的取代基和季碳中心无疑是一个挑战性课题。在研究中发现,当采用当量的碱时,目标产物的产率不高,这可能是在当量的碱作用下环丙烷单元容易发生开环所致。当在相转移催化剂作用下,加入催化量的碱时,在这种技术方案下反应产率明显提高。
进一步地,所述的有机溶剂选自四氢呋喃、乙醚、1,4-二氧六环、乙二醇二甲醚、乙酸乙酯、二氯甲烷、氯仿、甲苯、乙腈、甲醇、乙醇、丙醇、异丙醇、N,N’-二甲基甲酰胺或二甲亚砜中的一种或几种。
进一步地,所述的碱性催化剂选自有机碱或无机碱;
进一步地,所述有机碱选自DBU、DMAP、DABCO或Et3N中的一种或几种;
进一步地,所述无机碱选自无机碱性催化剂氢氧化钠、氢氧化钾、氢氧化铯、碳酸铯或叔丁醇钾中的一种或几种。
进一步地,所述的相转移催化剂选自季铵盐或冠醚;
进一步地,所述的相转移催化剂选自四丁基溴化铵、四丁基氯化铵、四丁基碘化铵、四丁基氢氧化铵、18-冠醚-6和十六烷基三甲基溴化铵中的一种或几种。
进一步地,反应中,化合物Ⅰ与化合物Ⅱ的摩尔比为0.2~5:1。
进一步地,反应中,所述碱性催化剂与化合物Ⅰ的摩尔比为的1~500:100。
进一步地,所述氮杂Michael/环丙烷化串联反应的反应温度为25~100℃,反应时间为1~120h。
衍生物Ⅲ在制备防治肿瘤疾病药物中的应用。
所述衍生物Ⅲ选自如下化合物:
DBU:1,8-二氮杂双环[5.4.0]十一碳-7-烯;
DMAP:4-二甲氨基吡啶;
DABCO:三亚乙基二胺;
Et3N:三乙胺。
本发明的有益效果是:
本发明用简单易得的原料通过一锅反应一步构建两个环,解决了1,7-并环吲哚的合成问题,为吡咯喹啉化合物的合成提供了一种新思路。同时,除吡咯喹啉结构外,该技术方案构建的产物还含有环丙烷单元,因此该方法进一步丰富了并环吲哚化合物结构的结构多样性和复杂性。本发明操作简单易行,原料合成便宜易得,可以在各种有机溶剂中进行,也具有较好的空气稳定性,适用性广,对于各种取代基都有很好的兼容性。
附图说明
图1衍生物1的X衍生晶体结构图。
具体实施方式
以下对本发明的技术方案进行清晰、完整地描述,显然,此处所描述的实施例仅是本发明中的一部分,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明的保护范围。
衍生物III的合成,反应通式如下所示:
实施例1
衍生物1的制备反应式如下所示:
在4毫升反应瓶中,依次加入3-三氟乙酰基吲哚7-位衍生的查尔酮0.1mmol(34.3mg),α-苯基-乙烯基四苯基硼酸硫鎓盐0.12mmol(58.1mg),碳酸铯16.3mg(50mmol%),四丁基溴化铵3.2mg(10mmol%),再加入1.0mL四氢呋喃,充分搅拌,在室温下反应3小时。
减压蒸馏除溶剂,然后向反应液中加5mL二氯甲烷,加入5mL水洗涤有机相,继续用二氯甲烷萃取水相,合并有机相,用无水硫酸钠干燥后浓缩。残留油状物硅胶柱层析(300-400目)分离(石油醚/乙酸乙酯=20:1,v/v),得到黄色固体43.7毫克,收率为98%。
衍生物1的结构式如下:
衍生物1的核磁共振和高分辨质谱测试结果如下:
1H NMR(400MHz,CDCl3)δ(ppm):8.17(d,J=8.0Hz,1H),7.96(s,1H),7.91(d,J=8.0Hz,2H),7.58(t,J=7.4Hz,1H),7.48-7.42(m,3H),7.35(t,J=7.8Hz,1H),7.31-7.26(m,5H),5.02(d,J=13.6Hz,1H),4.41(d,J=13.6Hz,1H),3.84(d,J=4.8Hz,1H),3.37(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):193.4,175.0(q,J=35.0Hz),137.8,137.0,135.4(q,J=4.7Hz),133.3,131.4,129.0,128.9,128.7,128.3,128.1,124.8,124.7,122.1,121.5,120.5,117.0(q,J=289.2Hz),111.6,49.0,41.9,40.4,26.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H19F3NO2 +446.1362,found446.1363。
衍生物2~33的制备方法同衍生物1,投料比与衍生物1相同,投入对应的原料可制备得到衍生物2~33,衍生物1~33结构式、反应产率和熔点见表1,但需强调的是本发明的化合物不限于表1所表示的内容。
表1衍生物1~33的化学结构式、熔点及产率
衍生物2-33的核磁共振和高分辨质谱测试结果如下:
衍生物2:黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.15(d,J=8.0Hz,1H),7.95(s,1H),7.94-7.92(m,2H),7.43(d,J=6.8Hz,1H),7.36-7.30(m,4H),7.26-7.24(m,2H),7.12(t,J=8.4Hz,2H),5.01(d,J=13.6Hz,1H),4.41(d,J=13.6Hz,1H),3.84(d,J=4.8Hz,1H),3.32(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):191.8,175.0(q,J=34.7Hz)165.8(d,J1=254.2Hz),136.9,135.3(q,J=4.7Hz),134.2(d,J4=3.3Hz),131.3,130.8(d,J3=9.2Hz),129.1,128.9,128.3,124.8,124.7,122.1,121.3,120.6,115.9(d,J2=21.8Hz),111.6,49.0,42.0,40.1,26.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.5,-104.5;ESI-HRMS:[M+H]+calcd.for[M+H]+calcd.forC27H18F4NO2 +464.1268,found 464.1268.
衍生物3:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):1H NMR(400MHz,CDCl3)δ(ppm):8.16(d,J=7.6Hz,1H),7.96(s,1H),7.85(d,J=8.4Hz,2H),7.43(d,J=8.0Hz,3H),7.35(t,J=7.8Hz,1H),7.32-7.31(m,3H),7.26-7.24(m,2H),5.01(d,J=13.6Hz,1H),4.41(d,J=13.6Hz,1H),3.84(d,J=4.4Hz,1H),3.32(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):191.8,167.1,136.9,135.29(dd,J=9.1,5.0Hz),134.2,131.4,130.76(d,J=9.4Hz),129.1,128.9,128.3,124.76(d,J=10.9Hz),122.1,121.3,120.6,116.0,115.8,111.7,49.0,42.0,40.1,26.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H18ClF3NO2 +480.0973,found480.0972.
衍生物4:白色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.17(d,J=8.0Hz,1H),7.96(s,1H),7.78–7.75(m,2H),7.67–7.58(m,2H),7.43(d,J=7.2Hz,1H),7.35(t,J=8.4Hz,1H),7.32-7.29(m,2H),7.26-7.23(m,3H),5.00(d,J=13.6Hz,1H),4.41(d,J=13.6Hz,1H),3.84(d,J=4.8Hz,1H),3.31(d,J=4.8Hz,1H);13CNMR(100MHz,CDCl3)δ(ppm):189.0,143.9,143.8,138.0(t,J=17.2Hz),136.0,135.3(d,J=6.5Hz),134.5,131.1,130.9(q,J=1.5Hz),130.6,129.7,129.0,128.5,128.0(t,J=3.6Hz),127.6,127.2,127.1,127.0,124.6,21.4;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H18BrF3NO2 +524.0468,found 524.0464.
衍生物5:黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(CDCl3,400MHz)δ:2.97(s,3H),3.64(d,J=13.6Hz,1H),3.91(d,J=13.6Hz,1H),5.99(s,1H),6.51(d,J=7.6Hz,1H),6.64-6.67(m,3H),6.71(d,J=6.4Hz,1H),6.92(d,J=8.4Hz,2H),7.01-7.04(m,1H),7.60(d,J=7.6Hz,1H),7.73-7.77(m,1H),7.85-7.88(m,1H),8.09(d,J=7.6Hz,1H);13C NMR(CDCl3,100MHz)δ:25.9,35.5,55.4,108.9,122.3,123.5,123.6,124.5,127.7,129.2,131.3,132.5,133.2,136.5,136.6,140.6,141.4,144.0,177.0,196.2,198.0.HRMS(ESI)Calcd.for C25H18ClNNaO4[M+Na]+:454.0822;Found:454.0823。
衍生物6:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.17(d,J=8.0Hz,1H),7.96(s,1H),7.78-7.75(m,2H),7.67-7.58(m,2H),7.43(d,J=7.2Hz,1H),7.35(t,J=8.4Hz,1H),7.32-7.29(m,2H),7.26-7.23(m,3H),5.00(d,J=13.6Hz,1H),4.41(d,J=13.6Hz,1H),3.84(d,J=4.8Hz,1H),3.31(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):192.6,175.0(q,J=34.9Hz),1430.3,136.7,135.3(q,J=5.0Hz),134.5(q,J=32.7Hz),131.3,129.1,128.9,128.5,128.4,125.8(q,J=3.4Hz),124.8,124.7,122.2,121.0,120.8,119.8(q,J=288.6Hz),111.7,110.1(q,J=276.3Hz),48.9,42.6,40.4,27.2;19F NMR(376MHz,CDCl3)δ(ppm):-63.1,-72.5;ESI-HRMS:[M+H]+calcd.for C28H18F6NO2 +514.1236,found 514.1234.
衍生物7:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.18(d,J=8.0Hz,1H),7.99(d,J=8.4Hz,2H),7.98(s,1H)7.68(d,J=8.4Hz,2H),7.61(d,J=7.2Hz,2H),7.49-7.41(m,4H),7.38-7.30(m,6H),5.04(d,J=13.6Hz,1H),4.42(d,J=13.6Hz,1H),3.87(d,J=4.8Hz,1H),3.41(d,J=4.8Hz,1H);13CNMR(100MHz,CDCl3)δ(ppm):193.4,175.0(q,J=34.1Hz),137.8,137.0,135.3(q,J=4.3Hz),133.3,131.4,1290,128.9,128.7,128.3,128.1,124.8,124.7,122.1,121.5,120.5,117.2(q,J=239.9Hz),111.6,49.0,41.9,40.3,26.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+Na]+calcd.for C33H22F3NNaO2 +544.1495,found 544.1497.
衍生物8:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.15(d,J=7.6Hz,1H),7.96(s,1H),7.70(d,J=7.6Hz,1H),7.55(d,J=9.6Hz,1H),7.47-7.41(m,2H),7.36-7.29(m,4H),7.27-7.24(m,3H),5.02(d,J=13.6Hz,1H),4.41(d,J=13.6Hz,1H),3.84(d,J=4.4Hz,1H),3.32(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):192.2,175.2(q,J=36.7Hz),162.8(q,J=247.2Hz),139.8,136.8,135.3,131.3,130.44(q,J=7.6Hz),129.1,128.9,128.4,124.8,124.7,123.8,122.1,121.1,120.7,120.4,120.2,115.0,114.8,111.6,48.9,42.3,40.3,26.9;19F NMR(376MHz,CDCl3)δ(ppm):-72.6,-111.4;ESI-HRMS:[M+H]+calcd.for C27H18F4NO2 +464.1268,found 464.1272.
衍生物9:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.16(d,J=8.0Hz,1H),7.95(s,1H),7.89(d,J=7.6Hz,2H),7.58(t,J=7.4Hz,1H),7.49-7.42(m,3H),7.35(t,J=7.6Hz,1H),7.29-7.22(m,3H),7.13(d,J=7.2Hz,1H),4.99(d,J=13.6Hz,1H),4.39(d,J=13.6Hz,1H),3.81(d,J=4.8Hz,1H),3.38(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):193.3,172.4(q,J=31.9Hz),139.1,137.6,135.6(q,J=5.1Hz),134.8,133.5,131.2,130.3,129.3,128.8,128.6,128.1,127.1,124.8,124.7,122.2,120.9,120.7,116.9(q,J=289.4Hz),111.7,48.7,41.2,40.1,26.9;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H18ClF3NO2 +480.0973,found 480.0974.
衍生物10:淡黄色固体,核磁共振和高分辨质谱测试结果如下:8.17(d,J=8.0Hz,1H),7.99(d,J=11.2Hz,2H),7.83(d,J=7.6Hz,1H),7.70(d,J=8.0Hz,1H),7.42(d,J=7.2Hz,1H),7.37-7.32(m,5H),7.26-7.25(s,3H),5.02(d,J=13.6Hz,1H),4.42(d,J=13.6Hz,1H),3.84(d,J=4.8Hz,1H),3.31(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):192.1,139.4,136.8,136.2,135.35(q,J=4.8Hz),131.3,131.1,130.3,129.1,128.9,128.4,126.7,124.8,124.7,123.1,122.2,121.1,120.7,48.9,42.5,40.2,27.2;19FNMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H18BrF3NO2 +524.0468,found 524.0470.
衍生物11:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.16(d,J=8.0Hz,1H),7.96(s,1H),7.53(d,J=7.6Hz,1H),7.42(d,J=7.2Hz,1H),7.39-7.34(m,3H),7.32-7.38(m,5H),7.12(d,J=8.0Hz,1H),5.01(d,J=13.6Hz,1H),4.40(d,J=13.6Hz,1H),3.83(d,J=4.8Hz,1H),3.81(s,3H),3.35(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):193.2,175.0(d,J=35.2Hz),159.9,139.1,137.0,135.4(q,J=4.3Hz),131.3,129.7,129.0,128.9,128.3,124.8,124.6,122.1,121.4,120.7,120.5,119.5,114.2(q,J=289.3Hz),112.7,111.6,55.5,49.0,41.9,40.4,26.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C28H21F3NO3 +476.1468,found 476.1468.
衍生物12:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.15(d,J=8.0Hz,1H),7.9(s,1H),7.48-7.43(m,3H),7.41-7.38(m,5H),7.36-7.28(m,3H),5.05(d,J=13.6Hz,1H),4.39(d,J=13.6Hz,1H),3.76(d,J=4.8Hz,1H),3.34(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):195.4,175.0(d,J=34.8Hz),138.7,137.0,135.4(q,J=4.6Hz),132.7,131.6,131.3,130.6,130.5,129.3,129.0,128.2,127.2,124.7,124.5,122.0,121.1,120.6,116.9(q,J=289.2Hz),111.5,48.8,44.3,42.8,28.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.forC27H18ClF3NO2 +480.0973,found 480.0974.
衍生物13:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.13(d,J=8.0Hz,1H),7.94(s,1H),7.53(d,J=7.6Hz,1H),7.46(t,J=7.6Hz,1H),7.41-7.37(m,3H),7.35-7.28(m,4H),6.98(t,J=8.0Hz,1H),6.97(d,J=8.8Hz,1H),4.97(d,J=13.6Hz,1H),4.41(d,J=13.2Hz,1H),3.99(s,3H),3.78(d,J=5.2Hz,1H),3.40(d,J=5.2Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):195.1,158.5,137.7,135.0(q,J=5.2Hz),133.9,131.4,130.7,129.4,129.0,128.6,128.0,124.7,124.6,122.00,121.96,121.0,120.2,117.2(d,J=241.6Hz),111.53,111.48,56.0,49.3,45.4,41.5,26.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C28H21F3NO3 +476.1468,found 476.1469.
衍生物14:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.47(s,1H),8.18(d,J=8.0Hz,1H),8.01(s,1H),7.94(t,J=8.0Hz,2H),7.87(d,J=8.4Hz,2H),7.61(t,J=7.6Hz,1H),7.57(d,J=7.4Hz,1H),7.46(d,J=7.2Hz,1H),7.36(t,J=7.6Hz,1H),7.30-7.26(m,5H),5.08(d,J=13.6Hz,1H),4.43(d,J=13.6Hz,1H),3.91(d,J=4.8Hz,1H),3.55(d,J=4.8Hz,1H);13CNMR(100MHz,CDCl3)δ(ppm):193.2,175.0(q,J=34.8Hz),137.1,135.6,135.4(q,J=4.8Hz),135.1,132.4,131.4,129.7,129.5,129.0,128.9,128.7,128.2,127.8,126.9,124.8,124.7,123.8,122.1,121.5,120.9,120.5,117.0(d,J=289.4Hz),111.6,49.0,41.9,40.3,26.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.4;ESI-HRMS:[M+H]+calcd.for C31H21F3NO2 +496.1519,found496.1516.
衍生物15:棕色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.17(d,J=7.6Hz,1H),7.95(s,1H),7.57(s,1H),7.41-7.26(m,9H),7.15(s,1H),6.54(s,1H),4.98(d,J=13.6Hz,1H),4.37(d,J=13.6Hz,1H),3.77(d,J=2.8Hz,1H),3.33(d,J=2.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):182.3,153.6,146.4,136.9,135.3(q,J=5.3Hz),129.0,128.3,124.6,122.1,120.6,116.9,112.6,49.1,39.9,29.7,26.5;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C25H17F3NO3 +436.1155,found 436.1152.
衍生物16:棕色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):)8.17(d,J=7.9Hz,1H),7.95(s,1H),7.76(d,J=2.9Hz,1H),7.64(d,J=4.6Hz,1H),7.42(d,J=7.2Hz,1H),7.38-7.25(m,7H),7.15-7.11(m,1H),4.97(d,J=13.6Hz,1H),4.38(d,J=13.6Hz,1H),3.80(d,J=4.4Hz,1H),3.24(d,J=4.4Hz,1H);13CNMR(100MHz,CDCl3)δ(ppm):185.6,175.0(q,J=35.0Hz),145.1,137.0,135.3(q,J=5.0Hz),134.1,131.9,131.3,129.0,128.8,128.30,128.25,124.8,124.7,122.2,121.3,120.6,116.9(q,J=289.6Hz),111.6,49.1,41.5,40.9,26.7;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C25H17F3NO2S+452.0927,found 452.0931.
衍生物17:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.14(d,J=8.0Hz,1H),7.90(s,1H),7.40-7.37(m,2H),7.35-7.31(m,5H),4.95(d,J=13.6Hz,1H),4.32(d,J=13.6Hz,1H),3.60(d,J=4.8Hz,1H),2.83(d,J=4.8Hz,1H),2.05-1.99(m,1H),1.04-0.99(m,1H),0.93-0.82(m,3H);13C NMR(100MHz,CDCl3)δ(ppm):203.5,174.8,137.3,135.27(q,J=4.8Hz),131.3,129.0,128.9,128.2,124.7,124.6,121.9,121.5,120.4,116.9(q,J=289.9Hz),111.5,49.0,43.9,41.2,26.4,22.4,11.7,11.0;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.forC24H19F3NO2 +410.1362,found 410.1364.
衍生物18:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):)7.95–7.90(m,2H),7.56(d,J=7.4Hz,1H),7.45(t,J=7.6Hz,2H),7.32-7.26(m,4H),7.18-7.12(m,2H),7.05(dd,J=9.4,1.8Hz,1H),6.55(d,J=2.9Hz,1H),4.89(d,J=12.4Hz,1H),4.20(d,J=12.8Hz,1H),3.74(d,J=4.8Hz,1H),3.57(d,J=4.4Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):194.0,158.5(d,J=233.5Hz),138.0,137.7,133.1,129.0,128.8,128.6,128.1,127.9,125.9(d,J=10.8Hz),121.61(d,J=10.4Hz),108.1,107.8,103.8,103.5,103.24,103.19,48.42(s),43.7,39.1,27.41(d,J=2.0Hz);19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H17F4NO2 +464.1268,found464.1270
衍生物19:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.14(s,1H),7.95(s,1H),7.90(d,J=7.4Hz,2H),7.59(t,J=7.4Hz,1H),7.47(t,J=7.6Hz,2H),7.40(s,1H),7.31-7.30(m,3H),7.26-7.24(m,2H),5.00(d,J=13.6Hz,1H),4.41(d,J=13.6Hz,1H),3.80(d,J=4.8Hz,1H),3.35(d,J=4.8Hz,1H);13CNMR(100MHz,CDCl3)δ(ppm):193.0,137.6,136.6,135.7(q,J=4.9Hz),133.4,130.5,129.1,128.8,128.7,128.4,128.1,125.5,122.8,122.7,120.1,115.2,111.1,49.0,41.7,40.3,26.2;19F NMR(376MHz,CDCl3)δ(ppm):-72.7;ESI-HRMS:[M+H]+calcd.forC27H17ClF3NO2 +480.0973,found 480.0976.
衍生物20:淡黄色固体,核磁共振和高分辨质谱测试结果如下:The product wasobtained as a yellow solid(41.4mg,87%yield)via flash chromatography on asilica gel(petroleum ether/ethyl acetate=20:1,v/v);1H NMR(400MHz,CDCl3)δ(ppm):7.91(d,J=8.4Hz,2H),7.90(s,1H),7.61(s,1H),7.57(t,J=7.4Hz,1H),7.46(t,J=7.6Hz,2H),7.30-7.25(m,5H),7.07(s,1H),4.98(d,J=13.6Hz,1H),4.38(d,J=13.6Hz,1H),3.89(s,3H),3.78(d,J=4.4Hz,1H),3.36(d,J=4.4Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):193.3,175.1,158.2,137.7,136.9,134.78(q,J=4.8Hz),133.3,129.0,128.9,128.7,128.2,128.1,126.2 125.5,122.4,118.4,115.5,112.6,111.2,102.0,55.9,49.0,41.8,40.1,26.6;19F NMR(376MHz,CDCl3)δ(ppm):-72.4;ESI-HRMS:[M+H]+calcd.forC28H21F3NO3 +476.1468,found 476.1469.
衍生物21:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):)7.92(d,J=7.6Hz,2H),7.55(d,J=7.2Hz,1H),7.45(t,J=7.6Hz,2H),7.29-7.26(m,4H),7.18(d,J=7.6Hz,2H),7.08(d,J=7.6Hz,1H),6.67(d,J=2.3Hz,1H),4.90(d,J=12.8Hz,1H),4.22(d,J=12.8Hz,1H),3.77(d,J=4.6Hz,1H),3.50(d,J=4.6Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):194.1,138.0,137.7,133.0,132.1,128.9,128.8,128.6,128.0,127.9,127.1,124.9,124.0,119.8,119.7,119.4,101.9,48.43(s),43.2,39.3,27.3;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.forC27H18F3NO2 +480.0973,found 480.0971
衍生物22:白色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):7.91(d,J=8.0Hz,2H),7.55(d,J=7.4Hz,1H),7.45(t,J=7.4Hz,2H),7.28-7.24(m,5H),7.18-7.17(m,1H),7.13(d,J=7.6Hz,1H),6.61-6.60(m,1H),4.90(d,J=12.8Hz,1H),4.22(d,J=12.8Hz,1H),3.76(d,J=4.4Hz,1H),3.51(d,J=4.4Hz,1H);13CNMR(100MHz,CDCl3)δ(ppm):194.0,138.0,137.7,133.0,131.7,128.9,128.8,128.6,128.0,127.9,127.1,126.9,123.0,120.0,119.9,112.2,103.4,48.5,43.2,39.3,27.3;19FNMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H18BrF3NO2 +524.0468,found 524.0469.
衍生物23:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.16(d,J=8.0Hz,1H),7.95(s,1H),7.89(d,J=7.6Hz,2H),7.58(t,J=7.4Hz,1H),7.49-7.42(m,3H),7.35(t,J=7.6Hz,1H),7.29-7.22(m,3H),7.13(d,J=7.2Hz,1H),4.99(d,J=13.6Hz,1H),4.39(d,J=13.6Hz,1H),3.81(d,J=4.8Hz,1H),3.38(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):193.3,172.4(q,J=31.9Hz),139.1,137.6,135.6(q,J=5.1Hz),134.8,133.5,131.2,130.3,129.3,128.8,128.6,128.1,127.1,124.7,122.2,120.9,120.7,118.4,115.5,111.7,48.7,41.2,40.1,26.9;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H18ClF3NO2 +480.0973,found480.0974.
衍生物24:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):)7.92(d,J=7.6Hz,2H),7.55(d,J=7.2Hz,1H),7.45(t,J=7.6Hz,2H),7.29-7.26(m,4H),7.18(d,J=7.6Hz,2H),7.08(d,J=7.6Hz,1H),6.67(d,J=2.3Hz,1H),4.90(d,J=12.8Hz,1H),4.22(d,J=12.8Hz,1H),3.77(d,J=4.6Hz,1H),3.50(d,J=4.6Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):194.1,138.0,137.7,133.0,132.1,128.9,128.8,128.6,128.0,127.9,127.1,124.9,124.0,119.8,119.7,119.4,101.9,48.43(s),43.2,39.3,27.3;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;[M+H]+calcd.for C25H19BrNO+428.0645,found 428.0648.
衍生物25:淡黄色固体,核磁共振和高分辨质谱测试结果如下:H NMR(400MHz,CDCl3)δ(ppm):7.94(d,J=7.4Hz,2H),7.56(t,J=7.2Hz,1H),7.53(d,J=8.4Hz,1H),7.45(t,J=7.6Hz,2H),7.32-7.25(m,6H),7.15-7.11(m,2H),6.61(d,J=2.7Hz,1H),4.91(d,J=12.6Hz,1H),4.22(d,J=12.6Hz,1H),3.81(d,J=4.4Hz,1H),3.60(d,J=4.8Hz,1H);13CNMR(100MHz,CDCl3)δ(ppm):194.4,138.1,138..0,132.9,131.6,129.0,128.7,128.6,128.1,127.8,126.7,126.1,120.6,120.3,118.9,118.8,103.2,48.4,43.8,39.0,27.8;ESI-HRMS:[M+Na]+calcd.for C25H19NNaO+372.1359,found 372.1356.
衍生物26:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):7.95(dd,J=8.0,6.0Hz,2H),7.52(d,J=8.0Hz,1H),7.33-7.24(m,6H),7.15-7.07(m,4H),6.60(d,J=3.2Hz,1H),4.89(d,J=12.6Hz,1H),4.21(d,J=12.6Hz,1H),3.78(d,J=4.8Hz,1H),3.54(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):192.8,166.9,164.4,138.0,134.6,131.6,130.72(d,J=9.3Hz),128.9(d,J=18.1Hz),127.8,126.7,126.1,120.40(d,J=9.7Hz),119.0,118.9,115.8,115.6,103.3,48.4,43.8,38.8,27.9;19F NMR(376MHz,CDCl3)δ(ppm):-105.3;ESI-HRMS:[M+H]+calcd.for C25H19FNO+368.1445,found 368.1443.
衍生物27:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):7.91(d,J=8.0Hz,2H),7.56(t,J=7.4Hz,1H),7.45(t,J=7.4Hz,2H),7.28-7.24(m,6H),7.17(d,J=2.0Hz,1H),7.13(d,J=7.6Hz,1H),6.61(d,J=2.0Hz,1H),4.90(d,J=12.8Hz,1H),4.22(d,J=12.8Hz,1H),3.76(d,J=4.4Hz,1H),3.51(d,J=4.4Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):194.0,138.0,137.7,133.0,131.7,129.0,128.8,128.6,128.1,127.9,127.1,126.9,123.0,120.1,120.0,112.2,103.4,48.5,43.2,39.3,27.3;ESI-HRMS:[M+H]+calcd.for C25H19BrNO+428.0645,found 428.0645.
衍生物28:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):7.91(d,J=8.8Hz,2H),7.49(d,J=8.0Hz,1H),7.26-7.24(m,6H),7.12(d,J=2.8Hz,1H),7.08(t,J=7.5Hz,1H),6.90(d,J=8.8Hz,2H),6.58(d,J=2.8Hz,1H),4.86(d,J=12.6Hz,1H),4.18(d,J=12.6Hz,1H),3.85(s,3H),3.75(d,J=4.8Hz,1H),3.52(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):192.7,163.4,138.3,131.7,131.3,130.4,129.0,128.7,127.7,126.7,126.0,120.8,120.3,118.9,118.8,113.7,103.2,55.5,48.5,43.2,38.7,27.3;ESI-HRMS:[M+H]+calcd.for C26H21NO+380.1645,found 380.1642.
衍生物29:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.17(d,J=8.0Hz,1H),7.96(s,1H),7.90(d,J=7.6Hz,2H),7.58(d,J=7.4Hz,1H),7.50-7.40(m,3H),7.35(t,J=7.4Hz,1H),7.26-7.23(m,3H),7.00(t,J=8.0Hz,2H),4.99(d,J=13.6Hz,1H),4.39(d,J=13.6Hz,1H),3.80(d,J=4.0Hz,1H),3.37(d,J=4.4Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):193.3,139.1,137.6,135.3,134.8,133.4,131.3,130.3,129.3,128.8,128.6,128.1,124.7,122.2,120.9,116.2,116.0,48.7,41.2,40.1,26.9.19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.forC27H17F4NO2 +464.1268,found 464.1273.
衍生物30:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.15(d,J=7.6Hz,1H),7.96(s,1H),7.89(d,J=7.6Hz,2H),7.58(t,J=7.4Hz,1H),7.48-7.41(m,3H),7.34(t,J=7.6Hz,1H),7.29-7.25(m,1H),7.05(d,J=7.6Hz,1H),7.00-6.97(m,2H),5.00(d,J=13.6Hz,1H),4.40(d,J=13.6Hz,1H),3.82(d,J=4.8Hz,1H),3.38(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):192.1,172.5,139.9,136.8,136.0,135.3(q,J=3.9Hz),131.3,129.5,129.1,128.9,128.4,127.6,124.8,124.7,122.2,121.2,120.7,120.0(q,J=288.9Hz),111.7,48.9,42.1,40.2,26.8;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+Na]+calcd.for C27H18BrF3NNaO2 +546.0287,found 546.0290.
衍生物31:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.16(d,J=8.0Hz,1H),7.96(s,1H),7.91(d,J=7.6Hz,2H),7.57(t,J=7.4Hz,1H),7.46(t,J=8.0Hz,2H),7.43(d,J=9.0Hz,1H),7.34(t,J=7.6Hz,1H),7.15(d,J=8.0Hz,2H),7.10(d,J=7.6Hz,2H),5.00(d,J=13.6Hz,1H),4.38(d,J=13.6Hz,1H),3.82(d,J=4.8Hz,1H),3.34(d,J=4.8Hz,1H),2.31(s,3H);13C NMR(100MHz,CDCl3)δ(ppm):193.5,138.0,137.9,135.3,134.0,133.2,131.4,129.8,128.7,128.6,128.1,124.7,127.0,122.1,121.6,120.5,111.5,49.1,41.7,40.4,26.7,21.2;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for ESI-HRMS:[M+H]+calcd.for C28H21F3NO3 +476.1468,found 476.1466.
衍生物32:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):)7.92(d,J=7.6Hz,2H),7.56(t,J=7.3Hz,1H),7.52-7.41(m,3H),7.29(dd,J=17.1,6.5Hz,7H),7.16(t,J=7.6Hz,1H),7.10(s,1H),4.82(d,J=12.5Hz,1H),4.15(d,J=12.5Hz,1H),3.78(d,J=4.7Hz,1H),3.58(d,J=4.7Hz,1H);13C NMR(100MHz,CDCl3)δ(ppm):194.1,128.0,123.7,123.3,121.0,120.0,116.5,107.3,48.12,43.3,39.0,27.2;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C27H18F3NO2 +480.0973,found 480.0970.
衍生物33:淡黄色固体,核磁共振和高分辨质谱测试结果如下:1H NMR(400MHz,CDCl3)δ(ppm):8.16(d,J=8.0Hz,1H),7.95(s,1H),7.91(d,J=7.6Hz,2H),7.58(s,1H),7.45(dd,J=16.2,7.8Hz,3H),7.36(d,J=7.8Hz,1H),7.16(d,J=7.5Hz,1H),7.09(d,J=8.2Hz,2H),7.02(d,J=7.4Hz,1H),5.00(d,J=13.6Hz,1H),4.39(d,J=13.6Hz,1H),3.83(d,J=4.8Hz,1H),3.35(d,J=4.8Hz,1H),2.28(s,3H);13CNMR(100MHz,CDCl3)δ(ppm):193.5,138.8,137.8,136.9,135.51(q,J=4.9Hz),133.2,131.4,129.7,129.1,128.8,128.7,128.1,125.9,124.7,124.8,122.1,121.6,120.5,111.5,49.0,41.9,40.4,26.7,21.4;19F NMR(376MHz,CDCl3)δ(ppm):-72.5;ESI-HRMS:[M+H]+calcd.for C28H21F3NO3 +476.1468,found 476.1464.
Claims (10)
1.一种环丙烷拼接吡咯喹啉并四环类衍生物的制备方法,其特征在于,以化合物Ⅰ与化合物Ⅱ为原料,在有机溶剂、碱性催化剂和相转移催化剂环境中,发生氮杂Michael/环丙烷化串联反应,得到衍生物Ⅲ,反应通式如下:
其中,R1独立选自氢、卤素、甲氧基;R2独立选自氢、卤素、三氟乙酰基,R3独立选自芳杂环、C1-C6环烷基,Ar为取代或非取代苯基,X选自四取代硼酸根、三取代甲磺酸根或卤素,R4选自C1-C10烷基。
2.根据权利要求1所述制备方法,其特征在于,R1独立选自氢、氟、氯、溴、甲氧基;R2独立选自氢、氯、溴、三氟乙酰基;R3独立选自噻吩、呋喃、萘基、环丙烷基,R独立选自氢、甲氧基、卤素;Ar独立选自苯、甲苯、卤代苯;X选自四苯基硼酸根、四氟硼酸根、三氟甲磺酸根氟、氯、溴;R4选自C1-C5烷基。
3.根据权利要求1所述的衍生物的制备方法,其特征在于,所述的有机溶剂选自四氢呋喃、乙醚、1,4-二氧六环、乙二醇二甲醚、乙酸乙酯、二氯甲烷、氯仿、甲苯、乙腈、甲醇、乙醇、丙醇、异丙醇、N,N’-二甲基甲酰胺或二甲亚砜中的一种或几种。
4.根据权利要求1所述的衍生物的制备方法,其特征在于,所述的碱性催化剂选自有机碱或无机碱;
进一步地,所述有机碱选自DBU、DMAP、DABCO或Et3N中的一种或几种;
进一步地,所述无机碱选自无机碱性催化剂氢氧化钠、氢氧化钾、氢氧化铯、碳酸铯或叔丁醇钾中的一种或几种。
5.根据权利要求1所述的衍生物的制备方法,其特征在于,所述的相转移催化剂选自季铵盐或冠醚;
进一步地,所述相转移催化剂选自四丁基溴化铵、四丁基氯化铵、四丁基碘化铵、四丁基氢氧化铵、18-冠醚-6或十六烷基三甲基溴化铵中的一种或几种。
6.根据权利要求1所述的衍生物的制备方法,其特征在于,反应中,化合物Ⅰ与化合物Ⅱ的摩尔比为0.2~5:1。
7.根据权利要求1所述的衍生物的制备方法,其特征在于,反应中,所述碱性催化剂与化合物Ⅰ的摩尔比为的1~500:100。
8.根据权利要求1所述的制备方法,其特征在于,所述氮杂Michael/环丙烷化串联反应的反应温度为25~100℃,反应时间为1~120h。
9.如权利要求1-8任一项所述的制备方法制备的衍生物Ⅲ在制备防治肿瘤疾病药物中的应用。
10.如权利要求1-9任一项所述的方法制备的衍生物Ⅲ,其特征在于,所述衍生物Ⅲ选自如下化合物:
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