CN112939942B - 含喹啉结构的杂环酯类化合物及其制备方法与应用 - Google Patents
含喹啉结构的杂环酯类化合物及其制备方法与应用 Download PDFInfo
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- CN112939942B CN112939942B CN202110170394.5A CN202110170394A CN112939942B CN 112939942 B CN112939942 B CN 112939942B CN 202110170394 A CN202110170394 A CN 202110170394A CN 112939942 B CN112939942 B CN 112939942B
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- -1 Heterocyclic ester compound Chemical class 0.000 title claims abstract description 50
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims description 20
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
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- 150000004982 aromatic amines Chemical class 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
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- 238000000034 method Methods 0.000 claims description 3
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- 125000003545 alkoxy group Chemical group 0.000 claims 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 abstract description 21
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- XNXCINUKGNQCEZ-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxamide Chemical group CN1C=C(C(N)=O)C(C(F)F)=N1 XNXCINUKGNQCEZ-UHFFFAOYSA-N 0.000 abstract description 4
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 10
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
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- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
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- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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- WXWCDTXEKCVRRO-UHFFFAOYSA-N para-Cresidine Chemical compound COC1=CC=C(C)C=C1N WXWCDTXEKCVRRO-UHFFFAOYSA-N 0.000 description 4
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- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 3
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明公开了一种含喹啉结构的杂环酯类化合物及其制备方法与应用，属于小分子化合物技术领域。具体的以Waltherione F生物碱为先导结构，结合前期工作中发现的具有优异杀菌活性的1‑甲基‑3‑二氟甲基吡唑‑4‑酰胺基团，首次设计合成了系列结构新颖的含喹啉结构的杂环酯类化合物，生物活性测试发现目标化合物的杀菌活性对梨黑斑病菌和链格菌显示出较其他测试病原菌更好的抑制率，荧光特性研究发现化合物I‑3在二氯甲烷溶液中的绝对量子产率高达99％，该结果对于探索新型的荧光材料具有重要的指导意义。
Description
技术领域
本发明涉及一种杂环酯类化合物，属于小分子化合物技术领域，具体地涉及一种含喹啉结构的杂环酯类化合物及其制备方法与应用。
背景技术
基于天然产物为先导结构的分子优化是新药研发的重要手段。Newman和Cragg综述了近39年天然产物用于新药研发的现状，发现24％的药物分子来源于天然产物及其衍生物，26％的化学合成药物涉及天然产物药效团及其结构类似物(Newman,D.J.；Cragg,G.M.J.Nat.Prod.,2020,83,770-803)。基于天然产物的结构优化已成为开发新型绿色杀菌剂的重要途径，对于践行新发展理念、推动农药绿色发展具有重要的指导意义，例如基于天然产物Strobilurin A成功开发的甲氧基丙烯酸酯类杀菌剂已占据杀菌剂市场的榜首，沈阳化工研究院刘长令教授团队基于天然产物香豆素和甲氧基丙烯酸酯结构成功开发了具有自主知识产权的高效、广谱、安全的绿色杀菌剂丁香菌酯，刘长令教授团队基于天然产物肉桂酸及烯酰吗啉成功开发了具有自主知识产权的杀菌剂氟吗啉，中国农业大学覃兆海教授团队基于天然产物肉桂酸成功开发了自主创新的新型杀菌剂丁吡吗啉等(刘长令,关爱莹,李正名,等.ZL 200310105079.6,2007-04-18；覃兆海,慕长炜,毛淑芬,等.ZL03148340.2,2006-02-08)。
先导化合物的发现和作用靶标的探索是创新杀菌剂研究的关键。植物源中药蕴含宝贵的天然药物活性分子，是新型绿色农药研发重要的先导化合物来源。Waltheriones生物碱是从梧桐科(Sterculiaceae)中药植物蛇婆子(Waltheria indica L.)中分离得到的4-喹诺酮类化合物，目前已报道成功分离得到Waltherione A-Q、antidesmone、8-deoxoantidesmone和vanessine共计20个Waltheriones生物碱，并相继发现其具有抗病毒、抗肿瘤、抗锥体虫、杀菌、杀线虫等生物活性(Hoelzel et al.Phytochemistry,2005,66,1163；Gressler et al.Phytochemistry,2008,69,994；Dhiman et al.Bioorg.Chem.,2019,92,103291；Jang et al.Pest Manag.Sci.,2019,75,2264)。
因此，如何基于天然产物结构并对其进行进一步优选开发出新型绿色杀菌剂是目前需要解决的技术问题。
为了开发基于天然产物结构优化的新型绿色杀菌剂，以Waltherione F生物碱为先导结构，结合前期工作中发现的具有优异杀菌活性的1-甲基-3-二氟甲基吡唑-4-酰胺基团(Hua et al.Engineering,2020,6,553；Hua et al.Pest Manag.Sci.,2020,76,2368)，首次设计合成了系列结构新颖的含喹啉结构的杂环酯类化合物，生物活性测试发现目标化合物的杀菌活性对梨黑斑病菌和链格菌显示出较其他测试病原菌更好的抑制率。
发明内容
为解决上述技术问题，本发明公开了一种含喹啉结构的杂环酯类化合物及其制备方法与应用，以Waltherione F生物碱为先导结构，结合前期工作中发现的具有优异杀菌活性的1-甲基-3-二氟甲基吡唑-4-酰胺基团首次设计合成了系列结构新颖的含喹啉结构的杂环酯类化合物，生物活性测试发现目标化合物的杀菌活性对梨黑斑病菌和链格菌显示出较其他测试病原菌更好的抑制率。
其中，1-甲基-3-二氟甲基吡唑-4-酰胺基团如Hua et al.Engineering,2020,6,553；Hua et al.Pest Manag.Sci.,2020,76,2368中记载。
为实现上述技术目的，一种含喹啉结构的杂环酯类化合物，其特征在于，它具备如下化学结构式：
其中，式I-1中基团R1，R2，R3，R4均选自氢、卤素、硝基、氰基、三氟甲基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、C1-C6烷氧基羰基、卤代C3-C6环烷基或N,N-(C1-C6烷基)氨基甲酰基中任意一种；
基团R5选自氢、卤素、硝基、氰基、三氟甲基、羰基取代基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基或卤代C3-C6环烷基中任意一种；
其中，所述羰基取代基包括酮羰基、羧基、酯基或酰胺基中任意一种；
基团R6选自氢、卤素、硝基、氰基、三氟甲基、酯基、酰胺基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基或卤代C1-C6烷硫基中任意一种；
基团Het选自取代或非取代的五元含氧或硫或氮芳香杂环，或取代或非取代的六元含氧或硫或氮芳香杂环。
进一步地，C1-C6烷基为直链或支链烷基；卤代C1-C6烷基为直链或支链烷基，其中，卤代C1-C6烷基中的氢原子被部分或全部的卤原子取代。
进一步地，所述卤素和/或卤原子包括氟、氯、溴或碘中任意一种。
进一步地，基团Het中的取代或非取代的五元含氧或硫或氮芳香杂环包括吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、三氮唑、恶唑环、异恶唑环、恶二唑环、噻唑环、异噻唑环、噻二唑环或吲哚环中任意一种；取代或非取代六元含氧或硫或氮芳香杂环包括吡啶环、嘧啶环、三嗪环或嘌呤环中任意一种，其中所述的取代基为甲基、乙基、丙基、氟甲基、氯甲基、二氯甲基、二氟甲基、三氟甲基或三氯甲基中的一种或多种。
进一步地，所述基团R5中酯基选自C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、芳香基氧基羰基、C1-C6烷硫基羰基、卤代C1-C6烷硫基羰基或芳香基硫基羰基中任意一种；酰胺基选自C1-C6烷氨基甲酰基、卤代C1-C6烷氨基甲酰基或芳香基氨基甲酰基中任意一种，且各基团中的卤代包括氢原子被部分或全部的卤原子取代，所述卤原子包括氟、氯、溴或碘中任意一种。
为更好的实现本发明技术目的，本发明还公开了一种含喹啉结构的杂环酯类化合物的制备方法，其特征在于，它包括如下步骤：
(1)杂环羧酸化合物1溶解到第一溶剂中，加热回流一段时间，制备杂环酰氯化合物2；其中，化合物1和化合物2的化学结构式如下：
(2)喹诺酮中间体II和三乙胺、4-二甲氨基吡啶溶解到第二溶剂中，室温条件下滴加上述环酰氯化合物2，制备目标化合物I；其中，喹诺酮中间体II和目标化合物I的化学结构式如下：
其中，式I-1中基团R1，R2，R3，R4均选自氢、卤素、硝基、氰基、三氟甲基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基、C1-C6烷氧基羰基、卤代C3-C6环烷基或N,N-(C1-C6烷基)氨基甲酰基中任意一种；
基团R5选自氢、卤素、硝基、氰基、三氟甲基、羰基取代基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基或卤代C3-C6环烷基中任意一种；
其中，所述羰基取代基包括酮羰基、羧基、酯基或酰胺基中任意一种；
基团R6选自氢、卤素、硝基、氰基、三氟甲基、酯基、酰胺基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基或卤代C1-C6烷硫基中任意一种；
基团Het选自取代或非取代的五元含氧或硫或氮芳香杂环，或取代或非取代的六元含氧或硫或氮芳香杂环。
定义：如在说明书和权利要求书中使用的，除非相反地指明，否则以下术语具有下文指示的含义。
C1-C6烷基包含1-6个碳原子(例如C1-C6)、1-5个碳原子(例如C1-C5)、1-4个碳原子(例如C1-C4)、1-3个碳原子(例如C1-C3)、1-2个碳原子(例如C1-C2)的烷基，例如为：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正己基等。
卤素或卤原子指的是氟原子、溴原子、氯原子和碘原子。
基团R1选自甲基、乙基、丙基、异丙基、正丁基、叔丁基；基团R2和R3为氢；基团R4为甲氧基、乙氧基、丙氧基、丁氧基；基团R5为氢、甲基、-COOCH3、甲基、-COOC2H5、-COOPh、COOAr、CONHCH3、CONHC2H5、CONHPh、CONHAr，其中Ar为苯环、萘环、吡啶环等；基团R6为氢、-COOC2H5、Br。
基团Het中的取代或非取代的五元含氧或硫或氮芳香杂环为吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、三氮唑、恶唑环、异恶唑环、恶二唑环、噻唑环、异噻唑环、噻二唑环或吲哚环中任意一种；取代或非取代六元含氧或硫或氮芳香杂环包括吡啶环、嘧啶环、三嗪环或嘌呤环中任意一种，其中所述的取代基为甲基、乙基、丙基、氟甲基、氯甲基、二氯甲基、二氟甲基、三氟甲基或三氯甲基中的一种或多种。
进一步的Het为1-甲基-3-二氟甲基吡唑-4-基。
进一步的，羰基取代基包括酮羰基、羧基、酯基或酰胺基中的一种，其中酮羰基指代C1-C6CO-、C1-C5CO-、C1-C4CO-、C1-C3CO-、C1-C2CO-、CH3CO-、C2H5CO-、C3H7CO-、C4H9CO-。其中羧基为-COOH。其中酯基为-COOC1-C6、-COOC1-C5、-COOC1-C4、-COOC1-C3、-COOC1-C2、-COOCH3、-COOC2H5、-COOC3H7、-COOC4H9、COOPh、COOAr等。其中酰胺基为-CONHCH3、-CONHC2H5、-CONHPh、-CONHAr。
进一步地，所述第一溶剂为二氯亚砜；所述第二溶剂为二氯甲烷。进一步地，所述喹诺酮中间体II的制备过程包括：首先，取代芳香胺分别与乙酰乙酸乙酯、丁炔二酸二甲酯或者乙氧基甲叉丙二酸二乙酯反应，制备含芳香胺的取代酯类化合物；然后，在多聚磷酸(PPA)作用下，通过Conrad-Limpach反应，制备喹诺酮中间体；随后，喹诺酮中间体与N-氯代丁二酰亚胺(NCS)、N-溴代丁二酰亚胺(NBS)或者N-碘代丁二酰亚胺(NIS)反应，进而与甲醇钠等亲核试剂反应，可制备不同取代的喹诺酮中间体II。
此外，本发明还公开了上述含喹啉结构的杂环酯类化合物在制备植物抗菌剂或荧光剂中的应用。
发明还公开了上述含喹啉结构的杂环酯类化合物在制备植物抗菌剂和荧光剂中的应用。
有益效果：
本发明提供了一种含喹啉结构的杂环酯类化合物，该化合物具备一定杀菌性，并显示出对梨黑斑病菌和链格菌较好的抑制率。
附图说明
图1为化合物I-3的谱图，其中，图1A为紫外吸收光谱；图1B为激发光360nm下荧光发射光谱；图1C为荧光激发光谱；图1D为激发光265nm下荧光发射光谱；
图2为化合物I-3在不同极性溶剂中的光谱特性研究；其中，图2A为不同溶液在波长为254nm紫外灯下的图片；图2B为不同溶液在波长为365nm紫外灯下的图片；图2C为不同溶液的紫外吸收光谱；图2D为激发光为360nm下不同溶液的荧光发射光谱；图2E为激发光为265nm下不同溶液的荧光发射光谱；
图3为化合物I-3在乙腈-PEG混合溶剂中的紫外吸收光谱；其中，图3A为激发光为360nm的荧光发射光谱；图3B为激发光为265nm的荧光发射光谱；图3C为PEG含量为0—75％，每15％为一个梯度，蓝色箭头和红色箭头显示PEG含量增加方向。
具体实施方式
本发明还公开了所述喹诺酮中间体II的制备过程包括：首先，取代芳香胺分别与乙酰乙酸乙酯、丁炔二酸二甲酯或者乙氧基甲叉丙二酸二乙酯反应，制备含芳香胺的取代酯类化合物；然后，在多聚磷酸(PPA)作用下，通过Conrad-Limpach反应，制备喹诺酮中间体；随后，喹诺酮中间体与N-氯代丁二酰亚胺(NCS)、N-溴代丁二酰亚胺(NBS)或者N-碘代丁二酰亚胺(NIS)反应，进而与甲醇钠等亲核试剂反应，可制备不同取代的喹诺酮中间体II。
以下公开了部分喹诺酮中间体II的合成路线：
具体的，起始原料2-甲氧基-5-甲基苯胺3分别与乙酰乙酸乙酯反应制备化合物4，与丁炔二酸二甲酯反应制备化合物5，与乙氧基甲叉丙二酸二乙酯反应制备化合物6；在多聚磷酸(PPA)加热到130℃条件下，化合物4、5、6分别环合得到喹诺酮中间体II-1、II-3、II-5和II-6，其中，II-1、II-3分别与N-溴代丁二酰亚胺(NBS)反应制备中间体II-2和II-4。
以下结合实施例来进一步说明本发明，其目的是能更好的理解本发明的内容及体现本发明的实质性特点，因此所举之例不应视为对本发明保护范围的限制。
实施例1
(E)-3-((2-甲氧基-5-甲基苯基)氨基)丁-2-烯酸甲酯(4)的合成：
将2-甲氧基-5-甲基苯胺(6.00g,43.7mmol)、乙酰乙酸乙酯(6.10g,52.5mmol)、无水硫酸镁(10.52g,87.5mmol)和催化量的乙酸(0.52g,8.7mmol)加入到乙醇(70mL)中，将体系加热回流24h，TLC监测反应。待反应完成后，过滤，滤液真空减压浓缩除去溶剂乙醇，剩余物通过柱层析纯化得到黄色黏稠液体，洗脱液为石油醚：乙酸乙酯，体积比为20：1，收率91％。1H NMR(500MHz,CDCl3)δ10.21(s,1H,NH),6.94–6.87(m,2H,,Ph-H),6.79(d,J＝8.8Hz,1H,Ph-H),4.70(s,1H,CH),3.83(s,3H,OCH3),3.68(s,3H,COOCH3),2.27(s,3H,Ph-CH3),1.99(s,3H,CH3)。
实施例2
2-((2-甲氧基-5-甲基苯基)氨基)马来酸二甲酯(5)的合成：
将2-甲氧基-5-甲基苯胺(5.00g,36.4mmol)溶解到甲醇(50mL)中，室温搅拌条件下，逐滴滴加丁炔二酸二甲酯(6.21g,43.7mmol)的甲醇(20mL)溶液。滴加完毕后，室温搅拌3小时，TLC监测反应进程。反应完成后，真空浓缩除去溶剂甲醇，剩余物通过柱层析纯化得到橙色黏稠液体，洗脱液为石油醚：乙酸乙酯，体积比10:1，收率93％。1H NMR(500MHz,CDCl3)δ9.63(s,1H,NH),6.83(d,J＝8.1Hz,1H,Ph-H),6.75(d,J＝8.3Hz,1H,Ph-H),6.61(s,1H,Ph-H),5.37(s,1H,CH),3.80(s,3H,OCH3),3.73(s,3H,COOCH3),3.72(s,3H,COOCH3),2.24(s,3H,Ph-CH3)。
实施例3
2-(((2-甲氧基-5-甲基苯基)氨基)亚甲基)丙二酸二乙酯(6)的合成：
将2-甲氧基-5-甲基苯胺(5.00g,36.4mmol)和乙氧基甲叉丙二酸二乙酯(8.67g,40.1mmol)溶解到乙醇(70mL)中，加热回流4小时。待反应完成后，真空减压浓缩除去溶剂乙醇，剩余物通过柱层析纯化得到黄色黏稠液体，室温放置冷却后变为黄色固体，洗脱液为石油醚：乙酸乙酯，体积比10:1，收率90％。1H NMR(500MHz,CDCl3)δ11.07(d,J＝14.0Hz,1H,NH),8.55(d,J＝14.1Hz,1H,CH),7.05(s,1H,Ph-H),6.89(d,J＝8.3Hz,1H,Ph-H),6.82(d,J＝8.3Hz,1H,Ph-H),4.33(q,J＝7.1Hz,2H,COOCH2 CH3),4.27(q,J＝7.1Hz,2H,COOCH2 CH3),3.90(s,3H,OCH3),2.33(s,3H,Ph-CH3),1.39(t,J＝7.1Hz,3H,COOCH2 CH3 ),1.34(t,J＝7.1Hz,3H,COOCH2 CH3 )。
实施例4
8-甲氧基-2,5-二甲基喹诺-4-酮(II-1)的合成：
首先，将多聚磷酸(PPA)加热，增加其流动性。然后，将3-((2-甲氧基-5-甲基苯基)氨基)丁-2-烯酸甲酯(20.0g,85.1mmol)加入到20mL PPA中，加热升温至130℃反应2小时。待反应完成后，将体系冷却至室温，加入冰水充分搅拌。用碳酸钠将体系的pH值调节至8左右，产生大量固体，抽滤、水洗、干燥得到黄色固体产物，收率57％。m.p.196–197℃.1H NMR(500MHz,DMSO)δ10.58(s,1H,NH),7.05(d,J＝8.0Hz,1H,Ph-H),6.87(d,J＝8.1Hz,1H,Ph-H),5.83(s,1H,quinolone-H),3.94(s,3H,OCH3),2.70(s,3H,Ph-CH3),2.32(s,3H,quinolone-CH3).13C NMR(126MHz,DMSO)δ179.7,148.5,146.7,132.8,130.1,124.5,123.8,111.4,110.9,56.5,22.9,19.6.HRMS(ESI)m/z:calcd 204.1019,found 204.1018[M+H]+。
实施例5
3-溴-8-甲氧基-2,5-二甲基喹诺-4-酮(II-2)的合成：
将8-甲氧基-2,5-二甲基喹诺-4-酮(3.0g,14.8mmol)溶解到30mL乙腈中，冰浴条件下冷却到0℃，然后加入N-溴代丁二酰亚胺(2.63g,14.8mmol)。反应体系在0℃条件下搅拌1小时，TLC监测反应完成后，将体系倒入乙酸乙酯和水(100mL，v/v＝1/1)的混合溶液中，取有机层，用无水硫酸钠干燥，过滤，减压浓缩。剩余物经柱层析纯化得到黄色固体产物，洗脱剂为二氯甲烷，收率52％。m.p.218–219℃.1H NMR(500MHz,DMSO)δ11.13(s,1H,NH),7.10(d,J＝8.1Hz,1H,Ph-H),6.97(d,J＝8.0Hz,1H,Ph-H),3.96(s,3H,OCH3),2.71(s,3H,Ph-CH3),2.59(s,3H,quinolone-CH3).13C NMR(126MHz,DMSO)δ173.1,148.0,146.8,131.5,130.0,125.5,122.3,111.1,109.5,56.6,23.2,21.5.HRMS(ESI)m/z:calcd 282.0124,found 282.0122[M+H]+。
实施例6
(8-甲氧基-2,5-二甲基喹啉-4-基)-3-二氟甲基-1-甲基-1H-吡唑-4-羧酸酯的合成：
将3-二氟甲基-1-甲基-1H-吡唑-4-甲酸(1.30g,7.4mmol)加入到4mL二氯亚砜中，体系加热升温回流4小时，然后减压浓缩充分除去过量的二氯亚砜，剩余物溶解到无水二氯甲烷(2mL)中，室温条件下逐滴滴加到8-甲氧基-2,5-二甲基喹诺-4-酮(1.0g,4.9mmol)、4-二甲氨基吡啶(0.18g,1.5mmol)和三乙胺(1.49g,14.7mmol)的无水二氯甲烷溶液(20mL)中，反应体系搅拌过夜。待反应完成后，将体系倒入二氯甲烷和水(100mL,v/v＝1/1)的混合溶剂中，取有机层，依次经稀盐酸、碳酸钾水溶液洗涤，二氯甲烷层经无水硫酸钠干燥，过滤，减压浓缩。剩余物通过柱层析纯化得到白色固体，洗脱液为石油醚：乙酸乙酯，体积比为1:1，收率43％。
现将根据实施例1～6的制备方法而采用不同的原料制备的该类衍生物列入表1，部分衍生物1H NMR、13C NMR(Bruker AV-500spectrometer using tetramethylsilane asthe internal standard)、高分辨质谱、熔点数据列入表2。
表1目标化合物I的结构
表2部分目标化合物的核磁、高分辨质谱及熔点数据
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实施例7
利用本发明提供的衍生物进行杀菌活性测试，测试对象为小麦赤霉病菌(Gibberella zeae，GZ)、玉米纹枯病菌(Rhizoctonia solani，RS)、苹果轮纹病菌(Physalospora piricola，PP)、梨黑斑病菌(Alternaria kikuchiana Tanaka，AK)、桃褐斑病菌(Cercospora circumscissa Sacc.，CS)、辣椒炭疽病菌(Colletotrichum capsici，CC)、黄瓜灰霉病(Botrytis cinerea，BC)和链格菌(Alternaria sp.，AS)，测试方法为菌病直径抑制法。测试方法如下：
准确称取5.0mg的目标化合物置于1.5mL离心管中，加入2滴二甲基亚砜溶解，然后用0.1％的吐温80水溶液稀释至10mL，得到500μg/mL的待测母液。取1mL待测母液与9mL PDA培养基混合均匀，得到测试浓度为50μg/mL的含药培养基。用直径为7mm的打孔器取相应菌饼置于含药培养基中，25℃条件下培养72小时，根据菌落直径计算化合物的抑菌率，蒸馏水为阴性对照，氟吡菌酰胺和多菌灵为阳性对照。对离体初筛活性较好的化合物进行EC50测试，测试方法与离体初筛测试方法相同，化合物测试浓度范围为0.1μg/mL～200μg/mL，EC50值采用DPS软件进行计算。
上述离体杀菌活性的测试结果如表3所示，EC50值测试结果如表4所示：
表3部分目标化合物I的离体杀菌活性抑制率(％)
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表4部分目标化合物I的EC50值
离体杀菌活性初筛结果表明，目标化合物对梨黑斑病菌均表现出良好的杀菌活性，化合物I-4对苹果轮纹病菌显示出较其他化合物更好的抑菌率。EC50值测试结果表明，测试化合物对苹果轮纹病菌和梨黑斑病菌的EC50值均低于100μg/mL。
实施例8
本发明提供的衍生物的荧光特性研究包括紫外吸收光谱、荧光发射光谱、荧光激发光谱以及绝对量子产率的测定。具体测试方法和结果以I-3为例说明。
1)光谱测试
将化合物I-3溶解到甲醇中，定容制备摩尔浓度为25nM的待测溶液，依次进行紫外吸收光谱、荧光发射和激发光谱扫描，结果见图1。结合图1可知，化合物I-3具有两个最大吸收峰，其中，在265nm激发光下的荧光强度比在360nm激发光下的荧光强度强。
2)溶剂效应对化合物I-3荧光强度的影响
以标准化的Dimroth-Reichardt参数ETN值作为选择不同极性溶剂的参考依据，选取1,4-二氧六环、四氢呋喃(THF)、乙酸乙酯(EA)、二氯甲烷(DCM)、N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、乙腈、乙醇和甲醇作为研究溶剂。将化合物I-3分别溶解在不同溶剂中，定容制备摩尔浓度为25nM的待测溶液，分别测试紫外吸收光谱和荧光发射光谱，结果见图2。
结合图2可知，溶剂效应对化合物I-3荧光强度的影响结果显示，无论激发光为360nm还是265nm，化合物I-3在二氯甲烷溶剂中的荧光强度最强。此外，化合物I-3在1,4-二氧六环和N,N-二甲基甲酰胺(DMF)中的紫外最大吸收大大减弱，导致在激发光为265nm下，几乎无荧光强度，说明1,4-二氧六环和N,N-二甲基甲酰胺(DMF)会大大降低化合物I-3在265nm激发光下的荧光强度，而二氯甲烷溶剂却可以大大提高化合物I-3的荧光强度。
3)溶液的粘度效应对化合物I-3荧光强度的影响
按照聚乙二醇(PEG)在乙腈中的体积分数由0至75％配置不同粘度的混合溶剂，每15％为一个粘度梯度，然后将化合物I-3溶解到不同粘度的乙腈-PEG混合溶剂中，制备最终摩尔浓度为25nM的待测溶液，分别测试紫外吸收光谱和荧光发射光谱，结果见图3。
结合图3可知，溶液的粘度效应对化合物I-3荧光强度的影响结果显示，随着粘度的增加，紫外吸收变强，但在激发光为360nm处的荧光强度无明显差异，相反，在激发光为265nm处的荧光强度逐渐减小，说明溶液的粘度增加有利于增强紫外吸收，但不利于荧光强度的增加。
4)化合物I-3绝对量子产率的测定
为了进一步探索化合物I-3的荧光效能，在FLS1000(Edinburgh Instruments)光谱仪上测定化合物I-3的固体粉末的绝对量子产率以及在溶剂二氯甲烷、甲醇中的绝对量子产率，结果见表5。
表5化合物I-3的绝对量子产率(％)
绝对量子产率结果显示，化合物I-3显示出了优异的荧光特性，在二氯甲烷溶液中的量子产率高达99.41％，即使在不利于增强其荧光强度的甲醇溶液中，量子产率也达到84.31％，这对该类结构在荧光领域的研究具有重要指导意义。
Claims (6)
1.一种含喹啉结构的杂环酯类化合物，其特征在于，它具备如下化学结构式：
其中，式I-1中基团R1，R2，R3，R4独立地选自氢、C1-C6烷基、C1-C6烷氧基中任意一种；
基团R5选自氢、-COOC1-C2烷基中任意一种；
基团R6选自氢、卤素、-COOC1-C2烷基中任意一种；
基团Het选自1-甲基-3-二氟甲基吡唑-4-基。
2.根据权利要求1所述含喹啉结构的杂环酯类化合物，其特征在于，具体选自以下化合物：
3.一种权利要求1或2所述的含喹啉结构的杂环酯类化合物的制备方法，其特征在于，它包括如下步骤：
(1)杂环羧酸化合物1溶解到第一溶剂中，加热回流一段时间，制备杂环酰氯化合物2；其中，化合物1和化合物2的化学结构式如下：
(2)喹诺酮中间体II和三乙胺、4-二甲氨基吡啶溶解到第二溶剂中，室温条件下滴加上述杂环酰氯化合物2，制备目标化合物I；其中，喹诺酮中间体II和目标化合物I的化学结构式如下：
其中，目标化合物I、中间体II中基团R1，R2，R3，R4、R5、R6、Het定义与权利要求1或2的定义相同；所述第一溶剂为二氯亚砜；所述第二溶剂为二氯甲烷。
4.根据权利要求3所述含喹啉结构的杂环酯类化合物的制备方法，其特征在于，所述喹诺酮中间体II的制备过程包括：首先，取代芳香胺分别与乙酰乙酸甲酯、丁炔二酸二甲酯或者乙氧基甲叉丙二酸二乙酯反应，制备含芳香胺的取代酯类化合物；然后，在多聚磷酸PPA作用下，通过Conrad-Limpach反应，制备喹诺酮中间体；喹诺酮中间体可进一步与N-氯代丁二酰亚胺NCS、N-溴代丁二酰亚胺NBS或者N-碘代丁二酰亚胺NIS反应。
5.一种如权利要求1或2所述的含喹啉结构的杂环酯类化合物在制备植物抗菌剂或荧光剂中的应用。
6.一种如权利要求1或2所述的含喹啉结构的杂环酯类化合物在制备抗菌剂和荧光剂中的应用。
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