WO2017071398A1 - 化合物i和化合物ii及其制备方法和应用 - Google Patents

化合物i和化合物ii及其制备方法和应用 Download PDF

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WO2017071398A1
WO2017071398A1 PCT/CN2016/097319 CN2016097319W WO2017071398A1 WO 2017071398 A1 WO2017071398 A1 WO 2017071398A1 CN 2016097319 W CN2016097319 W CN 2016097319W WO 2017071398 A1 WO2017071398 A1 WO 2017071398A1
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compound
aromatic
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唐本忠
王志明
赵祖金
秦安军
张晓娟
于大伟
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香港科技大学深圳研究院
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    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
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    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms

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  • This invention relates to the field of analytical and detection techniques, and more particularly to Compound I and Compound II and methods for their preparation and use.
  • the key technology of fluorescence imaging technology is the choice of fluorescent materials as labeling probes (or stains).
  • the ideal probe molecule is specifically adsorbed on specific cells and tissues by physical or chemical action, and realizes two-dimensional or three-dimensional imaging under low-energy optical irradiation, and judges cells or cells by fluorescence color, intensity and distribution.
  • the health of the organization Compared to ordinary chemical staining, the sensitivity of fluorescent staining is 100-1000 times higher, and online analysis of living organisms can be achieved by appropriate functional modification.
  • fluorescent probe structures are composed of 2-3 parts, ie, luminescent elements, linking motifs (optional), and recognition motifs.
  • the illuminating primitive is mainly responsible for achieving high-efficiency illuminating in the external environment (light, electricity or magnetic action), and then detected by the external signal detecting device becomes Visualization information;
  • the recognition primitive is mainly to identify the target target in the cell or the body to improve the positioning ability of the probe;
  • the link primitive is mainly to link the two to make the illuminating position and the detected structure stable. The correspondence ensures the accuracy of the detection process.
  • the recognition element and the luminescent core of the fluorescent probe can also be served by the same chemical structure in the probe molecule, but this has the luminescence mechanism and recognition function of the compound.
  • a large relationship which can not interfere with each other, but also to achieve rapid response and high resolution, which will be the mainstream direction of the future development of fluorescent probes.
  • phenamimidazole As a new type of luminescent material, phenamimidazole has high luminous efficiency, excellent photothermal stability, and relatively balanced carrier injection/transportability, showing great application potential in the field of luminescent materials. Meanwhile, phenanthrene Imidazole is also the parent structure of a class of anticancer drugs, indicating that it has certain molecular recognition and localization ability. Although the combination of the above two advantages makes phenamimidazole meet the requirements of a class of ideal fluorescent probe building blocks, the highly aromatic fused ring such as phenamimidazole has poor biocompatibility and better recognition and localization ability. Poor, it can not be applied as a fluorescent probe, and it is necessary to introduce other groups to adjust its performance.
  • the object of the present invention is to provide a compound of the formula I and formula II and a preparation method and application thereof, namely, a compound I and a compound II, and a preparation method and application thereof, in particular to provide a kind of carboxy group based on phenanthroline N1 substitution.
  • the acid and the carboxylic acid derivative solve the problem that the phenanthrene imidazole compound in the prior art cannot be realized as a fluorescent probe.
  • Ar represents an aromatic group or a derivative thereof
  • Ar is selected from the group consisting of phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolyl, decyl, carbazole One of a group, an anilino group, a triphenylethylene group, a tetraphenylethylene group, and a corresponding derivatized structure thereof
  • R is selected from the group consisting of a hydroxyl group, a halogen, an alkoxy group, an aromatic phenol group, an amine group, and an aromatic amine group, and their corresponding One of the derivatives
  • G1 and G2 represent an arbitrary substituent group at any position on the phenanthrene ring, respectively.
  • G1 and G2 represent hydrogen, respectively.
  • the invention also provides a preparation method of the compound of the above formula I, comprising the following steps:
  • Ar is selected from the group consisting of phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolyl, indolyl, oxazolyl, anilino, triphenylethylene, One of tetraphenylethylene and its corresponding derivatized structure; G1 and G2 each represent an arbitrary substituent group at any position on the phenanthrene ring, respectively.
  • Step S2 is further included after step S1:
  • the organic solvent is preferably selected from the group consisting of acetic acid, tetrahydrofuran, toluene, Any one or more of benzene, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, most preferably acetic acid and a mixed system of acetic acid and other solvents, namely acetic acid A mixed system with any one or more of tetrahydrofuran, toluene, benzene, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.
  • step S3 may be further included between step S1 and step S2: the step obtained in step S1
  • recrystallization and column chromatography may be employed, wherein the recrystallization solvent is preferably tetrahydrofuran, ethanol, toluene or N,N-dimethylformamide, more preferably N,N-dimethylformamide.
  • the invention also provides another compound of formula II having the following structural formula:
  • Ar represents an aromatic group or a derivative thereof
  • Ar is selected from the group consisting of phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolyl, decyl, carbazole
  • R and R 1 is independently selected from the group consisting of a hydroxyl group, a halogen, an alkoxy group, an aromatic phenol group, an amine group, and an aromatic group.
  • G1 and G2 represents an arbitrary substituent group at any position on the phenanthrene ring.
  • G1 and G2 represent hydrogen, respectively.
  • the invention also provides a preparation method of the compound of the above formula II, comprising the following steps:
  • Ar is selected from the group consisting of phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl
  • a pyridyl group a pyranyl group, a quinolyl group, a decyl group, a carbazolyl group, an anilino group, a triphenylethylene group, a tetraphenylethylene group, and a corresponding derivatized structure thereof; each of G1 and G2 represents a phenanthrene ring Any substituent group at any position above.
  • step Sb is further included after the step Sa:
  • the organic solvent is preferably selected from the group consisting of acetic acid, tetrahydrofuran, toluene, Any one or more of benzene, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, most preferably acetic acid and a mixed system of acetic acid and other solvents, namely acetic acid A mixed system with any one or more of tetrahydrofuran, toluene, benzene, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.
  • step Sc may be further included between step Sa and step Sb: obtained by the step Sa
  • recrystallization and column chromatography may be employed, wherein the recrystallization solvent is preferably tetrahydrofuran, ethanol, toluene or N,N-dimethylformamide, more preferably N,N-dimethylformamide.
  • the compounds of the above formula I and formula II are each used for the preparation of fluorescent probes, in particular for the preparation of bioluminescent probes.
  • the compounds of Formulas I and II of the present invention have the beneficial effects that the compounds of Formulas I and II of the present invention introduce different substituent structures at Ar (C2 substituent position), To achieve the adjustment of the luminescent color and efficiency of the above compounds; focus on the loss of the efficiency of the compound in the solid state by introducing the structure of triphenylethylene or tetraphenylvinylene and its derivatives, thereby achieving high water system conditions. Fluorescence quantum yield; by selecting different aminocarboxylic acid structures as reactants, introducing different carboxylic acid structures at the N1 benzene ring, and preparing various carboxylic acid-derived structures, such as acid halides, aromatic acid alkyl groups, by a suitable method.
  • 1A is a graph showing the relative fluorescence intensity of TPE-PA in a fluorescence ratio at different ratios of tetrahydrofuran to water;
  • Figure 1B is a graph showing the relative fluorescence intensity of TPE-PAC in different ratios of tetrahydrofuran and water;
  • Figure 2 is a graph of pH value of TPE-PAC in water as a function of time
  • Figure 3A is a bright field photograph of TPE-PAC stained HeLa cells under a fluorescence microscope
  • Figure 3B is a fluorescent photograph of TPE-PAC stained HeLa cells under a fluorescence microscope
  • Figure 4 is a graph showing the fluorescence spectrum of TPE-P2A at different ratios of tetrahydrofuran to water;
  • Figure 5A is a bright field photograph of TPE-P2A stained HeLa cells under a fluorescence microscope
  • Figure 5B is a fluorescent photograph of TPE-P2A stained HeLa cells under a fluorescence microscope.
  • the invention provides a compound of the formula I and the formula II which can be used as a novel fluorescent probe material, that is, the compound I and the compound II, the material is a phenymidazole carboxylic acid and a carboxylic acid derivative structure, and the structure has the following structure.
  • the above structure has 9,10-phenanthroimidazole as a core structure
  • Ar represents an aromatic group or a derivative structure thereof, which are respectively selected from a phenyl group, a tolyl group, a naphthyl group, a furyl group, a thienyl group, a pyrrolyl group, a pyridyl group, a pyran group.
  • One of the corresponding derivatized structures a quinolyl group, a decyl group, a carbazolyl group, an anilino group, a triphenylethylene group, a tetraphenylethylene group, and the like.
  • R and R 1 respectively represent a carbonyl linking substituent structure at an arbitrary substitution position on the N1-substituted benzene ring in imidazole, and are respectively selected from a hydroxyl group, a halogen, an alkoxy group or an aromatic phenol group, an amine group and an aromatic amine group.
  • G1 and G2 represent an arbitrary substituent group at any position on the phenanthrene ring.
  • the derivative structures of aromatic aldehydes and phenanthrenequinones are obtained by various coupling, substitution and condensation reactions.
  • the aromatic aldehyde and the phenanthrenequinone derivatives are all existing compounds, and the synthesis process thereof is a prior art, and the specific preparation process will not be described herein.
  • aromatic aldehyde derivative, phenanthrenequinone derivative, ammonium acetate and aminobenzoic acid (or aminophthalic acid) are prepared in a "one-pot method" in an appropriate solvent and temperature to prepare an important carboxylic acid structure.
  • the aromatic aldehyde derivative, phenanthrenequinone derivative, ammonium acetate and aminobenzoic acid (or amino phthalic acid) are heated to an appropriate temperature in an organic solvent, reacted for a while, cooled to room temperature, and filtered to obtain a carboxylic acid structure ( Further purification was carried out by recrystallization and column chromatography).
  • the organic solvent is preferably acetic acid, tetrahydrofuran, toluene, benzene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), or the like.
  • a mixed system of the three most preferably acetic acid and its mixed system with other solvents;
  • the temperature is preferably 80 ° C to 180 ° C, most preferably 100 ° C to 120 ° C;
  • the reaction time is preferably 1 hour to 24 hours, of which the most preferred 2 hours to 4 hours; recrystallization solvent, preferably tetrahydrofuran, ethanol, toluene, DMF, etc., most preferably DMF.
  • the above carboxylic acid structure is obtained by a corresponding method to obtain a substituted acyl halide of an phenamimidazole N1 benzene ring, an alkyl aryl acid ester, an aryl aryl aryl ester, an aromatic acid alkyl amide or an aromatic aryl amide. It should be noted that the specific substitution reaction process is the prior art, and details are not described herein again.
  • G1 and G2 represent hydrogen, respectively.
  • X is one of F, Cl, Br and I
  • R 2 - R 5 are each independently hydrogen, alkyl, hydroxy, alkoxy, nitro, cyano, amino, fluorenyl, halogen atom, etc.
  • Ar' and Ar" are each independently selected from the group consisting of phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridyl
  • One of the corresponding derivatized structures such as decyl, quinolyl, decyl, oxazolyl, anilino, triphenylethylene, tetraphenylethylene, and the like.
  • Ar is limited to a benzene ring or a benzene ring derivative, a naphthalene ring or a naphthalene ring derivative, an anthracene ring or an anthracene ring derivative substituent, and the compound formula and preferred compound structure are as follows, and A carboxylic acid group-derived structure represented by a hydroxyl group, a halogen, an alkoxy group or an aromatic phenol group, an amine group, an aromatic amine group, or the like on the N1 benzene ring:
  • each of A 1 -A 9 is hydrogen, alkyl, hydroxy, alkoxy, nitro, cyano, amino, fluorenyl, halogen atom, phenyl, tolyl, naphthyl, furyl, thienyl, pyrrole
  • a pyridyl group a pyridyl group, a pyranyl group, a quinolyl group, a decyl group, a carboxylic acid or a carboxylic acid derivative, a carbazolyl group or an anilino group, and a corresponding derivatized structure (further, wherein an alkyl group or an alkoxy group)
  • the number of carbon atoms in the group is 1 to 12).
  • Ar is limited to triphenylethylene and triphenylethylene derivatives, and the compound formula and preferred compound structure are as follows, and A carboxylic acid group-derived structure represented by a hydroxyl group, a halogen, an alkoxy group or an aromatic phenol group, an amine group, an aromatic amine group, or the like on the N1 benzene ring:
  • Ar"' is selected from the group consisting of phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolyl, indolyl, oxazolyl, anilino, benzothiazide
  • B 1 -B 15 are each hydrogen, alkyl, hydroxy, alkoxy, nitro, cyano, amino, Sulfhydryl, halogen atom, phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolyl, decyl, carboxylic or carboxylic acid derivatives, carbazolyl or One of an anilino group or a corresponding derivative or the like (further, wherein the alkyl group or the alkyl group or the alkyl group or the alkyl group or the alkyl group or the alkyl group
  • Ar is limited to tetraphenylethylene and tetraphenylethylene derivatives, and the compound formula and preferred compound structure are as follows, and A carboxylic acid group-derived structure represented by a hydroxyl group, a halogen, an alkoxy group or an aromatic phenol group, an amine group, an aromatic amine group, or the like on the N1 benzene ring:
  • Ar"' is selected from the group consisting of phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolyl, indolyl, oxazolyl, anilino, benzothiazide
  • B 1 -B 15 are each hydrogen, alkyl, hydroxy, alkoxy, nitro, cyano, amino, Sulfhydryl, halogen atom, phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolyl, decyl, carboxylic or carboxylic acid derivatives, carbazolyl or One of an anilino group or a corresponding derivative or the like (further, wherein the alkyl group or the alkyl group or the alkyl group or the alkyl group or the alkyl group or the alkyl group
  • Ar is furan, thiophene, pyrrole, pyridine, pyran, quinoline (containing isoquinoline), hydrazine, carbazole, anilino, benzothiadiazole and their corresponding derivatized structures, or any two One of the new aromatic groups consisting of the compound formula and the preferred compound structure as follows, and A carboxylic acid group-derived structure represented by a hydroxyl group, a halogen, an alkoxy group or an aromatic phenol group, an amine group, an aromatic amine group, or the like on the N1 benzene ring:
  • the preferred structure of the aryl group and the alkyl group may be selected from one of the 29 species shown in the following formula or a hydrogen atom:
  • Example 5 Aggregation-Induced Luminescence (AIE) Properties of TPE-PA and TPE-PAC
  • the pH of the TPE-PAC in water is a function of time.
  • the acid chloride will be rapidly hydrolyzed in water to the corresponding carboxylic acid and hydrogen chloride, which will lose high. Reactivity, but TPE-PAC can exhibit significant stability in aqueous conditions due to the specificity of imidazole.
  • the decomposition rate is estimated to be only 25% by pH change within 1500 minutes, which is a stable acid chloride structure under a series of water systems.
  • the acid chloride structure can be subjected to extraction and column chromatography as it is, indicating that it can serve as a fluorescent molecular probe motif under aqueous conditions.
  • TPE-PAC was formulated into a certain concentration of DMSO solution, it was dropped into the cell culture medium, and Hela cells were selected as the research object. After the culture for a period of time, the polarity was observed by a fluorescence microscope, as shown in FIGS. 3A and 3B, and TPE was found.
  • -PAC can smoothly pass through the cell wall and is directed to enrich in the cytoplasm, thereby showing blue fluorescence, indicating that the acid chloride structure can be used as a fluorescent probe under water conditions.
  • Example 8 Synthesis of tetraphenylethylene-phenanthroimidazole-N1-carboxylic acid derivative TPE-P2A
  • Example 9 Study on the aggregation-induced luminescence (AIE) properties of TPE-P2A
  • TPE-P2A was formulated into a certain concentration of DMSO solution, it was dropped into the cell culture medium, and Hela cells were selected as the research object. After a period of culture, the polarity was observed by fluorescence microscope, as shown in Figures 5A and 5B, TPE was found.
  • -P2A can smoothly pass through the cell wall and is directed to enrich in the cytoplasm, thereby showing blue fluorescence, indicating that the dicarboxylic acid structure has self-activation properties and can be used as a fluorescent probe.

Abstract

提供化合物I和化合物II及其制备方法和应用，通过在Ar处引入不同的取代基结构，实现对上述化合物的发光颜色、效率的调节；有效的遏制化合物在固态下效率的损失，实现其水系条件下高的荧光量子产率；通过选择不同的氨基羧酸结构作为反应物，在N1苯环处引入不同的羧酸结构，并通过适当的方法制备各种羧酸衍生结构，以提高上述化合物结构的分子相容性、识别能力等。化合物I和化合物II作为一类新型的探针结构，菲并咪唑羧酸和羧酸衍生物能够自由的进出细胞，并对特定结构进行选择性识别与成像，使其在生物、医疗、健康和监测领域，具有极其广阔的应用前景。

Description

化合物I和化合物II及其制备方法和应用 技术领域
本发明涉及分析和检测技术领域，更具体地说，涉及化合物I和化合物II及其制备方法和应用。
背景技术
随着国家经济的快速发展和人民生活水平的不断提高，个人身体健康的实时监测、疾病的预防和治疗逐渐成为人们更加关注的民生问题。相对于传统的体外化学检验的延迟性和放射线在线检测的危害性，荧光在线显像技术以其高效、绿色、实时性强的优势渐渐走入人们的视野，被广泛应用于细胞免疫学、微生物学、分子生物学、遗传学、神经生物学、病理学、肿瘤学、临床检验学、医学、植物学等方面的科研和民生等领域。
荧光显像技术的关键技术就是荧光物质作为标记探针(或染色剂)的选择。理想的探针分子通过物理或化学作用，特异性吸附在特定的细胞和组织上，在低能量光学辐照下实现二维或三维的成像，通过与荧光颜色、强度和分布情况来判断细胞或组织的健康情况。与普通的化学染色相比，荧光染色的灵敏度要高出100-1000倍，而且通过适当的功能修饰即可实现对活体的在线分析。
通常，荧光探针结构有2-3部分组成，即发光基元、链接基元(可选)和识别基元。其中，发光基元主要负责在外界环境刺激(光、电或磁作用)实现高效率的发光，进而被外界信号检测设备检出变成可 视化信息；识别基元主要是对细胞或体内的靶向目标起到识别作用，以提高探针的定位能力；链接基元主要是将二者链接起来，使发光位置与被探测结构具有稳定的对应关系，保证检测过程的准确性。在实际应用中，为了简化荧光探针结构制备过程和降低成本，荧光探针的识别基元和发光核心也可由探针分子中的同一化学结构担任，但是这与化合物的发光机理和识别作用有很大关系，既不能相互干扰，又要实现快速响应和高度分辨，这将是荧光探针未来发展的主流方向。
菲并咪唑作为一类新型发光材料，具有较高的发光效率、优异的光热稳定性、相对平衡的载流子注入\传输能力，在发光材料领域展现了较大的应用潜力；同时，菲并咪唑也是一类抗癌型药物的母体结构，说明其具有一定的分子识别和定位能力。虽然上述两种优势的结合使菲并咪唑满足了一类理想的荧光探针构筑基元的要求，但是菲并咪唑这类高芳香性稠环的生物相容性较差，且识别定位能力较差，还无法作为荧光探针进行应用，需要引入其它基团对其性能进行调节。
发明内容
本发明的目的在于提供结构通式为式I和式II的化合物及其制备方法和应用，即化合物I和化合物II及其制备方法和应用，具体是提供一类基于菲并咪唑N1取代的羧酸及羧酸衍生物，解决了现有技术中的菲并咪唑类化合物尚无法实现作为荧光探针应用的问题。
本发明解决技术问题所采用的技术方案是：一种式I的化合物，具有如下结构通式：
Figure PCTCN2016097319-appb-000001
其中，Ar表示芳香基团或其衍生结构，Ar选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯及其相应的衍生结构中的一种；R选自羟基、卤素、烷氧基、芳香酚基团、胺基及芳香胺基及其相应的衍生物中的一种；G1和G2分别表示菲环上任意位置的任意取代基团。
在本发明式I的化合物中，G1和G2分别表示氢。
本发明还提供了上述式I的化合物的制备方法，包括如下步骤：
S1、将芳香醛衍生物
Figure PCTCN2016097319-appb-000002
菲醌衍生物
Figure PCTCN2016097319-appb-000003
乙酸铵和氨基苯甲酸
Figure PCTCN2016097319-appb-000004
在有机溶剂中加热至80℃-180℃，反应1-24小时后冷却至室温，过滤，得到
Figure PCTCN2016097319-appb-000005
其中，Ar选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、 四苯基乙烯及其相应的衍生结构中的一种；G1和G2各自分别表示菲环上任意位置的任意取代基团。
在步骤S1后还包括步骤S2：
S2、将S1步骤中制备得到的
Figure PCTCN2016097319-appb-000006
中的羟基分别进行相对应的取代反应得到由R取代的式I的化合物，其中R选自卤素、烷氧基、芳香酚基团、胺基及芳香胺基及其相应的衍生物中的一种。
在本发明式I的化合物的制备方法中，在步骤S1中，优选加热至100℃-120℃；优选反应2-4小时后冷却至室温；所述有机溶剂优选选自乙酸、四氢呋喃、甲苯、苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和N-甲基吡咯烷酮中的任意一种或多种，最优选乙酸以及乙酸与其它溶剂的混合体系，即乙酸与四氢呋喃、甲苯、苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和N-甲基吡咯烷酮中的任意一种或多种的混合体系。
进一步地，在步骤S1与步骤S2之间还可包括步骤S3：对S1步骤得到的
Figure PCTCN2016097319-appb-000007
进一步提纯，可采用重结晶和柱层析法，其中重结晶溶剂优选四氢呋喃、乙醇、甲苯或N,N-二甲基甲酰胺，更优选N,N-二甲基甲酰胺。
本发明还提供另外一种式II的化合物，具有如下结构通式：
Figure PCTCN2016097319-appb-000008
其中，Ar表示芳香基团或其衍生结构，Ar选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯及其相应的衍生结构中的一种；R和R1各自分别选自羟基、卤素、烷氧基、芳香酚基团、胺基及芳香胺基及其相应的衍生物中的一种；G1和G2各自分别表示菲环上任意位置的任意取代基团。
在本发明的式II的化合物中，G1和G2分别表示氢。
本发明还提供了上述式II的化合物的制备方法，包括如下步骤：
Sa、将芳香醛衍生物
Figure PCTCN2016097319-appb-000009
菲醌衍生物
Figure PCTCN2016097319-appb-000010
乙酸铵和氨基苯二甲酸
Figure PCTCN2016097319-appb-000011
在有机溶剂中加热至80℃-180℃，反应1-24小时后冷却至室温，过滤，得到
Figure PCTCN2016097319-appb-000012
其中，Ar选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡 啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯及其相应的衍生结构中的一种；G1和G2各自分别表示菲环上任意位置的任意取代基团。
在式II的化合物的制备方法中，在步骤Sa后还包括步骤Sb：
Sb、将Sa步骤中制备得到的
Figure PCTCN2016097319-appb-000013
中的两个羟基各自分别进行相对应的取代反应得到分别由R和R1取代的式II的化合物，其中R和R1各自分别选自卤素、烷氧基、芳香酚基团、胺基及芳香胺基及其相应的衍生物中的一种。
在本发明式II的化合物的制备方法中，在步骤Sa中，优选加热至100℃-120℃；优选反应2-4小时后冷却至室温；所述有机溶剂优选选自乙酸、四氢呋喃、甲苯、苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和N-甲基吡咯烷酮中的任意一种或多种，最优选乙酸以及乙酸与其它溶剂的混合体系，即乙酸与四氢呋喃、甲苯、苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和N-甲基吡咯烷酮中的任意一种或多种的混合体系。
进一步地，在步骤Sa与步骤Sb之间还可包括步骤Sc：对Sa步骤得到的
Figure PCTCN2016097319-appb-000014
进一步提纯，可采用重结晶和柱层析法，其中重结晶溶剂优选四氢呋喃、乙醇、甲苯或N,N-二甲基甲酰胺，更优选N,N-二甲基甲酰胺。
上述式I和式II的化合物均分别用于制备荧光探针的用途，特别是用于制备生物荧光探针的用途。
实施本发明的式I和式II的化合物及其制备方法和应用，具有以下有益效果：本发明的式I和式II的化合物通过在Ar处(C2取代基位置)引入不同的取代基结构，实现对上述化合物的发光颜色、效率的调节；重点通过引入三苯基乙烯或四苯基乙烯基元及其衍生物结构，有效的遏制化合物在固态下效率的损失，实现其水系条件下高的荧光量子产率；通过选择不同的氨基羧酸结构作为反应物，在N1苯环处引入不同的羧酸结构，并通过适当的方法制备各种羧酸衍生结构，如酰卤、芳酸烷基酯、芳酸芳基酯、芳酸烷基酰胺或芳酸芳基酰胺等，以提高上述化合物结构的分子相容性、识别能力等；重点强调通过简单的卤化反应得到了一类水系稳定的酰氯结构，并通过晶体结构证明分子内电荷分离可能是稳定此类结构的关键因素；式I和式II化合物作为一类新型的探针结构，菲并咪唑羧酸和羧酸衍生物能够自由的进出细胞，并对特定结构进行选择性识别与成像，使其在生物、 医疗、健康和监测领域，具有极其广阔的应用前景。
附图说明
图1A为TPE-PA在四氢呋喃与水的不同比例下的荧光光谱相对荧光强度变化曲线图；
图1B为TPE-PAC在四氢呋喃与水的不同比例下的荧光光谱相对荧光强度变化曲线图；
图2为TPE-PAC在水中pH值随时间变化的曲线图；
图3A为TPE-PAC染色的Hela细胞在荧光显微镜下的明场照片；
图3B为TPE-PAC染色的Hela细胞在荧光显微镜下的荧光照片；
图4为TPE-P2A在四氢呋喃与水的不同比例下的荧光光谱变化曲线图；
图5A为TPE-P2A染色的Hela细胞在荧光显微镜下的明场照片；
图5B为TPE-P2A染色的Hela细胞在荧光显微镜下的荧光照片。
具体实施方式
下面结合附图和实施例，对本发明的化合物I和化合物II及其制备方法和应用作进一步说明：
本发明提供的一类可以作为新型荧光探针材料的式I和式II的化合物，即化合物I和化合物II，该材料为菲并咪唑羧酸及羧酸衍生物结构，其结构具有以下结构通式：
Figure PCTCN2016097319-appb-000015
上述结构以9,10-菲并咪唑为核心结构，Ar表示芳香基团或其衍生结构，分别选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯等及相应的衍生结构中的一种。R和R1分别表示在咪唑中N1取代苯环上的任意取代位置的羰基链接取代基结构，分别选自羟基、卤素、烷氧基或芳香酚基团、胺基及芳香胺基等构筑的羧酸基团衍生结构。G1和G2表示菲环上任意位置的任意取代基团。
具体合成过程：
(1)
Figure PCTCN2016097319-appb-000016
通过各种耦联、取代和缩合等反应得到芳香醛和菲醌的衍生物结构。芳香醛和菲醌的衍生物均为现有化合物，其合成过程为现有技术，这里不再赘述具体制备过程。
(2)
Figure PCTCN2016097319-appb-000017
将上述芳香醛衍生物、菲醌衍生物、乙酸铵和氨基苯甲酸(或氨基苯二甲酸)采用“一锅法”在适当的溶剂和温度制备重要的羧酸结构。
具体操作：将芳香醛衍生物、菲醌衍生物、乙酸铵和氨基苯甲酸(或氨基苯二甲酸)在有机溶剂中加热至适当温度，反应一段时间后冷却至室温，过滤得到羧酸结构(进一步提纯采用重结晶和柱层析法)。其中，有机溶剂优选乙酸、四氢呋喃、甲苯、苯、N,N-二甲基甲酰胺(DMF)，N,N-二甲基乙酰胺(DMAC)和N-甲基吡咯烷酮(NMP)等或二者、三者的混合体系，最优选乙酸及其与其他溶剂的混合体系；温度优选80℃至180℃，其中最优选为100℃至120℃；反应时间优选1小时至24小时，其中最优选2小时至4小时；重结晶溶剂，优选四氢呋喃、乙醇、甲苯、DMF等，最优选DMF。
(3)
Figure PCTCN2016097319-appb-000018
将上述羧酸结构采用对应方法，分别得到菲并咪唑N1苯环的取代的酰卤、芳酸烷基酯、芳酸芳基酯、芳酸烷基酰胺或芳酸芳基酰胺等。需要说明的是，其具体的取代反应过程均为现有技术，这里不再进行详细赘述。
进一步地，G1和G2分别表示氢。
进一步地，Ar为任意芳基结构，取代基R和R1为羟基、卤素、烷氧基或芳香酚基团、胺基及芳香胺基及其衍生物时，其优选化合物结构为：
Figure PCTCN2016097319-appb-000019
其中，X为F、Cl、Br和I中的一种，R2-R5各自分别为氢、烷基、羟基、烷氧基、硝基、氰基、氨基、巯基、卤素原子等(进一步地，其中烷基或烷氧基的碳原子数为1～12)，Ar’和Ar”各自分别选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯等及相应的衍生结构中的一种。
进一步地，Ar被限制为苯环或苯环衍生物、萘环或萘环衍生物、蒽环或蒽环衍生物取代基，其化合物通式及优选化合物结构如下，且用
Figure PCTCN2016097319-appb-000020
表示N1苯环上由羟基、卤素、烷氧基或芳香酚基团、胺基及芳香胺基等所构筑的羧酸基团衍生结构：
Figure PCTCN2016097319-appb-000021
其中，A1-A9各自分别为氢、烷基、羟基、烷氧基、硝基、氰基、氨基、巯基、卤素原子、苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、羧酸或羧酸衍生物、咔唑基或苯胺基及相应的衍生结构中的一种(进一步地，其中烷基或烷氧基的碳原子数为1～12)。
进一步地，Ar被限制为三苯基乙烯及三苯基乙烯衍生物，其化合物通式及优选化合物结构如下，且用
Figure PCTCN2016097319-appb-000022
表示N1苯环上由羟基、卤素、烷氧基或芳香酚基团、胺基及芳香胺基等所构筑的羧酸基团衍生结构：
Figure PCTCN2016097319-appb-000023
其中，Ar”’选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、苯并噻二唑及相应的衍生结构或者是任意二者组成的新的芳香基团的一种；B1-B15各自分别为氢、烷基、羟基、烷氧基、硝基、氰基、氨基、巯基、卤素原子、苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、羧酸或羧酸衍生物、咔唑基或苯胺基中的一种或相应衍生物等中的一种(进一步地，其中烷基或烷氧基的碳原子数为1～12)。
进一步地，Ar被限制为四苯基乙烯及四苯基乙烯衍生物，其化合物通式及优选化合物结构如下，且用
Figure PCTCN2016097319-appb-000024
表示N1苯环上由羟基、卤素、烷氧基或芳香酚基团、胺基及芳香胺基等所构筑的羧酸基团衍生结构：
Figure PCTCN2016097319-appb-000025
其中，Ar”’选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、苯并噻二唑及相应的衍生结构或者是任意二者组成的新的芳香基团的一种；B1-B15各自分别为氢、烷基、羟基、烷氧基、硝基、氰基、氨基、巯基、卤素原子、苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、羧酸或羧酸衍生物、咔唑基或苯胺基中的一种或相应衍生物等中的一种(进一步地，其中烷基或烷氧基的碳原子数为1～12)。
进一步地，Ar为呋喃、噻吩、吡咯、吡啶、吡喃、喹啉(含异喹啉)、吲哚、咔唑、苯胺基、苯并噻二唑及其相应的衍生结构，或者是任意二者组成的新的芳香基团的一种，其化合物通式及优选化合物结构如下，且用
Figure PCTCN2016097319-appb-000026
表示N1苯环上由羟基、卤素、烷氧基或芳香酚基团、胺基及芳香胺基等所构筑的羧酸基团衍生结构：
Figure PCTCN2016097319-appb-000027
上述所有结构式中，其中芳基和烷基优选结构可以选自下式中所示29种中的一种或氢原子：
Figure PCTCN2016097319-appb-000028
实施例1：苯基-菲并咪唑-N1-羧酸及衍生物的合成
Figure PCTCN2016097319-appb-000029
将适量苯甲醛、菲醌、对氨基苯甲酸和过量的乙酸铵在冰醋酸中120℃反应3小时后冷却至室温，过滤得到羧酸衍生物。将其溶解于N，N-二甲基甲酰胺和二氯亚砜的混合溶剂中，80℃反应4小时后旋走未反应的二氯亚砜。加入过量的苯胺回流4小时，色谱柱分离得到目标化合物结构。1H NMR(DMSO,500MHz):δ:10.6(s,1H),8.96(d,1H),8.90(d,1H),8.70(d,1H),8.21(d,2H),7.85(d,2H),7.79(t,1H),7.71(t,1H),7.60-7.56(m,5H),7.40-7.37(m,7H),7.11(d,1H).MALDI-TOF(m/z):[M+]calcd.C34H23N3O,489.5659；found,490.59.
实施例2：1-萘基-菲并咪唑-N1-羧酸及衍生物的合成
Figure PCTCN2016097319-appb-000030
将适量1-萘甲醛、菲醌、对氨基苯甲酸和过量的乙酸铵在冰醋酸中120℃反应3小时后冷却至室温，过滤得到羧酸衍生物。将其溶解于N，N-二甲基甲酰胺和二氯亚砜的混合溶剂中，80℃反应4小时后旋走未反应的二氯亚砜。加入过量的苯胺回流4小时，色谱柱分离得到目标化合物结构。1H NMR(500MHz,DMSO-d6)δ13.27(s,1H),9.02-8.97(m,1H),8.94(d,J＝8.3Hz,1H),8.67(dd,J＝7.9,1.4Hz,1H), 8.02-7.93(m,4H),7.91(dd,J＝8.2,1.4Hz,1H),7.83-7.65(m,5H),7.61(ddd,J＝8.4,7.0,1.4Hz,1H),7.60-7.45(m,3H),7.41(ddd,J＝8.1,6.9,1.1Hz,1H),7.14(dd,J＝8.3,1.2Hz,1H).MALDI-TOF(m/z):[M+]calcd.C38H25N3O,539.6246；found,540.77.
实施例3：2-萘基-菲并咪唑-N1-羧酸及衍生物的合成
Figure PCTCN2016097319-appb-000031
将适量2-萘甲醛、菲醌、对氨基苯甲酸和过量的乙酸铵在冰醋酸中120℃反应3小时后冷却至室温，过滤得到羧酸衍生物。将其溶解于N，N-二甲基甲酰胺和二氯亚砜的混合溶剂中，80℃反应4小时后旋走未反应的二氯亚砜。加入过量的苯胺回流4小时，色谱柱分离得到目标化合物结构。1HNMR(500MHz,DMSO-d6)δ10.36(s,1H),8.98(dd,J＝28.1,8.4Hz,2H),8.67(dd,J＝8.0,1.4Hz,1H),8.04-7.90(m,5H),7.83-7.69(m,7H),7.66-7.49(m,4H),7.43(ddd,J＝8.2,7.0,1.1Hz,1H),7.35(t,J＝7.9Hz,2H),7.18(dd,J＝8.4,1.2Hz,1H),7.11(dd,J＝8.0,6.7Hz,1H).MALDI-TOF(m/z):[M+]calcd.C38H25N3O,539.6246；found,540.45.
实施例4：四苯基乙烯-菲并咪唑-N1-羧酸及衍生物的合成
Figure PCTCN2016097319-appb-000032
将适量四苯乙烯基甲醛、菲醌、对氨基苯甲酸和过量的乙酸铵在冰醋酸中120℃反应3小时后冷却至室温，过滤，柱层析得到羧酸衍生物TPE-PA。MALDI-TOF(m/z):[M+]calcd.C48H32N2O2,668.7799；found,668.8732.Anal Calc.for C48H32N2O2:C,86.20；H,4.82；N,4.19；O,4.78.Found:C,86.12；H,4.77；N,4.20；O,4.74.
将TPE-PA溶解于N，N-二甲基甲酰胺(少量)和二氯亚砜的混合溶剂中，80℃反应4小时后旋走未反应的二氯亚砜，用水和二氯甲烷萃取后干燥，色谱柱分离得到酰氯化合物结构TPE-PAC。MALDI-TOF(m/z):[M+]calcd.C48H31ClN2O,687.2255；found,687.2345.Anal Calc.for C48H31ClN2O:C,83.89；H,4.55；Cl,5.16；N,4.08；O,2.33Found:C,83.87；H,4.53；N,4.09；O,2.32。
实施例5：TPE-PA和TPE-PAC的聚集诱导发光(AIE)性质研究
如图1A和1B所示，分别为TPE-PA和TPE-PAC在四氢呋喃与水的不同比例下的荧光光谱相对荧光强度变化曲线，随着水含量的增加，二者的荧光强度明显增加，具有明显的聚集诱导发光现象，是一类潜在的荧光分子探针。
实施例6：TPE-PAC水系稳定性研究
如图2所示，为TPE-PAC在水中pH值随时间变化曲线。通常条件下，酰氯在水中会快速水解为对应的羧酸和氯化氢，进而失去高 的反应活性，但是TPE-PAC由于咪唑的特殊性在水系条件可以表现出显著的稳定性。在搅拌条件下，1500分钟内通过pH值变化估计其分解率仅为25％，是一类水系下稳定的酰氯结构。而且，该酰氯结构可以正常的进行萃取和柱层析，表明其可以作为水系条件下的荧光分子探针基元。
实施例7：TPE-PAC细胞染色实验
将TPE-PAC配成一定浓度的DMSO溶液后，滴入细胞培养液中，选择Hela细胞作为研究对象，培养一段时间后采用荧光显微镜对其极性观察，如图3A和3B所示，发现TPE-PAC可以顺利的透过细胞壁，并定向的在细胞质处富集，从而显示出蓝色荧光，说明该类酰氯结构在水系条件下可以作为荧光探针使用。
实施例8：四苯基乙烯-菲并咪唑-N1-羧酸衍生物TPE-P2A的合成
Figure PCTCN2016097319-appb-000033
将适量四苯乙烯基甲醛、菲醌、对氨基苯二酸和过量的乙酸铵在冰醋酸中120℃反应3小时后冷却至室温，过滤，柱层析得到羧酸衍生物TPE-P2A。MALDI-TOF(m/z):[M+]calcd.C49H32N2O4,712.7894；found,712.7902.Anal Calc.for C49H32N2O4:C,82.57；H,4.53；N,3.93；O,8.98.Found:C,82.48；H,4.45；N,3.9387；O,8.68.
实施例9：TPE-P2A的聚集诱导发光(AIE)性质研究
如图4所示，为TPE-P2A在四氢呋喃与水的不同比例下的荧光光谱变化曲线，随着水含量的增加，二者的荧光强度明显增加，具有明显的聚集诱导发光现象，可以作为一类荧光分子探针。
实施例10：TPE-P2A细胞染色实验
将TPE-P2A配成一定浓度溶液DMSO溶液后，滴入细胞培养液中，选择Hela细胞作为研究对象，培养一段时间后采用荧光显微镜对其极性观察，如图5A和5B所示，发现TPE-P2A可以顺利的透过细胞壁，并定向的在细胞质处富集，从而显示出蓝色荧光，说明该类二羧酸结构具有自活化性能，可以作为荧光探针使用。
应当理解的是，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进或变换都应属于本发明所附权利要求的保护范围之内。

Claims (10)

  1. 一种式I的化合物，具有如下结构通式：
    Figure PCTCN2016097319-appb-100001
    其中，Ar表示芳香基团或其衍生结构，Ar选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯及其相应的衍生结构中的一种；R选自羟基、卤素、烷氧基、芳香酚基团、胺基及芳香胺基及其相应的衍生物中的一种；G1和G2分别表示菲环上任意位置的任意取代基团。
  2. 根据权利要求1所述的化合物，其特征在于，G1和G2分别表示氢。
  3. 一种式I的化合物的制备方法，其特征在于，包括如下步骤：
    S1、将芳香醛衍生物
    Figure PCTCN2016097319-appb-100002
    菲醌衍生物
    Figure PCTCN2016097319-appb-100003
    乙酸铵和氨基苯甲酸
    Figure PCTCN2016097319-appb-100004
    在有机溶剂中加热至80℃-180℃，反应1-24小时后冷却至室温，过滤，得到
    Figure PCTCN2016097319-appb-100005
    其中，Ar选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯及其相应的衍生结构中的一种；G1和G2各自分别表示菲环上任意位置的任意取代基团。
  4. 根据权利要求3所述的化合物的制备方法，其特征在于，在步骤S1后还包括步骤S2：
    S2、将S1步骤中制备得到的
    Figure PCTCN2016097319-appb-100006
    中的羟基分别进行相对应的取代反应得到由R取代的式I的化合物，其中R选自卤素、烷氧基、芳香酚基团、胺基及芳香胺基及其相应的衍生物中的一种。
  5. 根据权利要求3所述的化合物的制备方法，其特征在于，在步骤S1中，加热至100℃-120℃；反应2-4小时后冷却至室温；所述有机溶剂选自乙酸、四氢呋喃、甲苯、苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和N-甲基吡咯烷酮中的任意一种或多种。
  6. 一种式II的化合物，具有如下结构通式：
    Figure PCTCN2016097319-appb-100007
    其中，Ar表示芳香基团或其衍生结构，Ar选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯及其相应的衍生结构中的一种；R和R1各自分别选自羟基、卤素、烷氧基、芳香酚基团、胺基及芳香胺基及其相应的衍生物中的一种；G1和G2各自分别表示菲环上任意位置的任意取代基团。
  7. 根据权利要求6所述的化合物，其特征在于，G1和G2分别表示氢。
  8. 一种式II的化合物的制备方法，其特征在于，包括如下步骤：
    Sa、将芳香醛衍生物
    Figure PCTCN2016097319-appb-100008
    菲醌衍生物
    Figure PCTCN2016097319-appb-100009
    乙酸铵和氨基苯二甲酸
    Figure PCTCN2016097319-appb-100010
    在有机溶剂中加热至80℃-180℃，反应1-24小时后 冷却至室温，过滤，得到
    Figure PCTCN2016097319-appb-100011
    其中，Ar选自苯基、甲苯基、萘基、呋喃基、噻吩基、吡咯基、吡啶基、吡喃基、喹啉基、吲哚基、咔唑基、苯胺基、三苯基乙烯、四苯基乙烯及其相应的衍生结构中的一种；G1和G2各自分别表示菲环上任意位置的任意取代基团。
  9. 根据权利要求8所述的化合物的制备方法，其特征在于，在步骤Sa后还包括步骤Sb：
    Sb、将Sa步骤中制备得到的
    Figure PCTCN2016097319-appb-100012
    中的两个羟基各自分别进行相对应的取代反应得到分别由R和R1取代的式II的化合物，其中R和R1各自分别选自卤素、烷氧基、芳香酚基团、胺基及芳香胺基及其相应的衍生物中的一种。
  10. 权利要求1、2、6或7所述的化合物用于制备荧光探针的用途。
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