CN108191902A - Glimmering analog derivative of a kind of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron and its preparation method and application - Google Patents

Glimmering analog derivative of a kind of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron and its preparation method and application Download PDF

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CN108191902A
CN108191902A CN201810125816.5A CN201810125816A CN108191902A CN 108191902 A CN108191902 A CN 108191902A CN 201810125816 A CN201810125816 A CN 201810125816A CN 108191902 A CN108191902 A CN 108191902A
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glimmering
fluorine boron
thienyl
analog derivative
base
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吴迪
章华星
兰静波
杨宇东
杨修光
梁文博
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Sichuan University
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages
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    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
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    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
    • C09K2211/1055—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms with other heteroatoms
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom

Abstract

The present invention provides a kind of 3,5 bisbenzimidazole base the 8 glimmering analog derivative of thienyl fluorine boron, belongs to the glimmering derivative technical field of fluorine boron.The glimmering analog derivative of fluorine boron has structure shown in following formula I：

Description

A kind of glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron and its preparation Methods and applications
Technical field
The invention belongs to the glimmering derivative technical fields of fluorine boron, specially 3,5- of one kind bisbenzimidazoles base -8- thienyl fluorine Glimmering analog derivative of boron and its preparation method and application.
Background technology
Endoplasmic reticulum is that very important multi-functional organelle, the synthesis of intracellular protein are folded, repaiied in eukaryocyte Decorations, lipid and sterol synthesis are carried out by place of endoplasmic reticulum.While these basic physiological functions are completed, endoplasmic reticulum Become the hinge platform for coordinating signal transduction by its huge membrane structure, maintain the stabilization of intracellular environment.When heredity or ring Border damage causes er stress, and er stress is too strong or the duration can cause Apoptosis too long, so as to cause Row disease [referring to：J.E.Vance, Traffic, 2015,16,1.], the form of the intracellular endoplasmic reticulum of specificity tracing detection And be distributed with conducive to understand in depth and study many relevant physiological activities [referring to：Z.Yang,Y.He,J.H.Lee,W.- S.Chae,W.X.Ren,J.H.Lee,C.Kang and J.S.Kim,Chem.Commun.,2014,50,11672.]。
In recent years, there are some reports for the targeting agent for marking endoplasmic reticulum, but the mechanism of specific targeting telltale mark is simultaneously Not very clearly.We need more to study the endoplasmic reticulum marker targeting agent of reliable design, and currently used is by target Be combined to group with fluorogen construct novel endoplasmic reticulum targeting agent [referring to：W.Xu,Z.Zeng,J.-H.Jiang, Y.-T.Chang and L.Yuan,Angew.Chem.,Int.Ed.2016,55,13658]。
In numerous fluorescent dyes, the dipyrrylmethanes fluorochrome of fluorine boron complexing be also known as fluorine boron it is glimmering have higher rub Spectral quality, high photo-thermal and chemical stability, the molecular weight that extinction coefficient, fluorescence quantum yield are high, stablize are small and relatively low Cytotoxicity the advantages that, extensively should as the fluorescence probes such as biomolecule, ion and organelle imaging fluorescent reagent etc. With [referring to：(a)S.Arai,S.-C.Lee,D.Zhai,M.Suzuki and Chang,Y.T.Sci.Rep.2014,4,6701； (b)X.Kong,F.Su,L.Zhang,J.Yaron,F.Lee,Z.Shi,Y.Tian and Meldrum, D.R.Angew.Chem.,Int.Ed.2015,54,12053；(c)L.Yang,Y.-J.Ji,J.-F.Yin,Y.Wu,H.Fan, Y.Zhang and G.-C.Kuang,Soft Matter,2016,12,8581.].There is the label much based on the glimmering skeleton of fluorine boron Molecule is circulated on the market by the standard labelled reagent extensively as organelle, such as LysoTrackerTM Red、 LysoTrackerTM Green、ER-TrackerTMRed and ER-TrackerTMGreen [referring to：I.Johnson, M.T.Z.Spence,The Molecular Probes Handbook,A Guide to Fluorescent Probes and Labeling Technologies,11th Ed.；Molecular Probes:Eugene,OR,2010.].But these are often The commercially available endoplasmic reticulum targeting agent seen is complicated, and synthesis is inconvenient, expensive.
Therefore it provides a kind of fluorescent molecular for endoplasmic reticulum marker, simple in structure, convieniently synthesized, production cost is low, Become those skilled in the art's urgent problem to be solved.
Invention content
The purpose of the present invention is to provide a kind of glimmering analog derivative small molecules of the fluorine boron that can be used for endoplasmic reticulum marker, incite somebody to action this The glimmering analog derivative of invention fluorine boron is used for endoplasmic reticulum fluorescent marker, can effectively solve endoplasmic reticulum targeting agent structure in the prior art Complexity, synthesis is inconvenient, it is expensive the problem of.
The present invention also provides the preparation method and applications of the glimmering analog derivative of fluorine boron.
The object of the invention is achieved through the following technical solutions：
The glimmering analog derivative of one kind 3,5- bisbenzimidazole base -8- thienyl fluorine boron has structure shown in following formula I：
Wherein：R1,R2,R3For in hydrogen, deuterium, alkyl, alkoxy, carbonyl, ester group, halogen, substituted aryl or substituted heteroaryl One or two.Further, the carbochain of the alkyl, alkoxy, ester group or carbonyl be carbon number be 0~40 straight chain, branch Chain or loop chain.
Further, the substituent group in the substituted aryl and substituted heteroaryl is one in alkyl, alkoxy or carbonyl Kind is several.Further, the carbochain of the alkyl, alkoxy or carbonyl is straight chain, branch or the ring that carbon number is 0~40 Chain.
One as a kind of glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron of the present invention is specific real Example is applied, there is structure shown in following formula II：
The preparation method of the glimmering analog derivative of one kind 3,5- bisbenzimidazole base -8- thienyl fluorine boron, including：
1) by 8- thienyl fluorine boron is glimmering and benzimidazoles derivative, oxidant and solvent are uniformly mixed, then anhydrous It is reacted under oxygen free condition, reaction equation is as follows：
2) it after the completion of reacting, is cooled to room temperature, addition dichloromethane dissolves reaction system, then through diatom after removing solvent Soil filtering, and washed with dichloromethane, merging filtrate, solvent, residue silica gel column chromatography separating purification, vacuum are removed in decompression Drying can be prepared by type I compound.
Further, above-mentioned steps 1) in, the anhydrous and oxygen-free condition can take the mode of inert gas shielding, more into one Step can be preferably to be reacted under nitrogen atmosphere.
Synthetic route used in preparation method of the present invention is C-H/N-H direct oxidation coupling reactions, with traditional glimmering ammonia of fluorine boron Change technology of preparing to compare, shorten more interminable organic synthesis step, avoid the preactivated complicated processes of substrate, improve The compatibility of reaction, increases synthetic reaction gross production rate.
Preparation method as a kind of one's duty invention glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron A specific embodiment, the oxidant for copper acetate monohydrate, copper acetate, copper chloride, copper bromide, trifluoroacetic acid ketone, three Fluoromethane sulfonic acid copper (II), acetylacetone copper, silver carbonate, silver oxide, silver acetate, silver nitrate, silver hexafluoroantimonate, oxygen, acetic acid In iodobenzene, benzoquinones, dichlorodicyanobenzoquinone, sodium persulfate, ammonium peroxydisulfate, potassium persulfate, di-tert-butyl peroxide It is one or more.
Preparation method as a kind of one's duty invention glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron A specific embodiment, the solvent is methanol, ethyl alcohol, tetrahydrofuran, dichloromethane, chloroform, ether, dimethyl are sub- Sulfone, benzene, o-dichlorohenzene, chlorine benzene,toluene,xylene, mesitylene, hexamethylene, petroleum ether, tert-pentyl alcohol, 1,4- dioxane, 1, It is one or more in 2- dichloroethanes, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
Preparation method as a kind of one's duty invention glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron A specific embodiment, the glimmering reaction density of the 8- thienyls fluorine boron be 0.0001~10mol/L.Further preferably 0.1~8mol/L, 0.5~5mol/L, 1~3mol/L.
Preparation method as a kind of one's duty invention glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron A specific embodiment, the 8- thienyls fluorine boron is glimmering, benzimidazoles derivative, and the molar ratio of oxidant is 1:(0.01 ~50):(0.01~100).Further preferably 1:(0.1~40):(10~80), 1:(5~30):(20~60).
Preparation method as a kind of one's duty invention glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron A specific embodiment, the reaction temperature of the step 1) is -40~160 DEG C, further preferably 20~100 DEG C, 40~ 80℃；Time is 0.1~720h, further preferably 10~30h.
The present invention also provides a kind of application of the glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron, Application in matter net specificity fluorography and fluorescent marker in the cell.
One of application as a kind of glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron of the present invention Specific embodiment includes the following steps：
Step 1：Cell is cultivated in culture medium；
Step 2：Cell after culture is removed into culture medium, adds in the glimmering class of 3,5- bisbenzimidazole base -8- thienyl fluorine boron The buffer solution of derivative, culture；
Step 3：After step 2 is cultivated, culture glass bottom ware is imaged through confocal microscope.
One of application as a kind of glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron of the present invention Specific embodiment, the cell are HepG2 cells.
One of application as a kind of glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron of the present invention Specific embodiment, the culture medium are DMEM (H) culture medium containing 10% fetal calf serum.
One of application as a kind of glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron of the present invention Specific embodiment, the buffer concentration of the glimmering analog derivative of 3, the 5- bisbenzimidazoles base -8- thienyl fluorine boron are 2.5 μM of phosphorus Phthalate buffer.
One of application as a kind of glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron of the present invention Specific embodiment, the condition of culture in step 1 are to be cultivated 24 hours at 37 DEG C.
One of application as a kind of glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron of the present invention Specific embodiment includes the following steps：
5%CO is passed through into DMEM (H) culture medium containing 10% fetal calf serum2, HepG2 cells are cultivated at 37 DEG C 24 hours；Culture medium is removed, adds in 2.5 μM of compounds 3, the glimmering phosphate of 5- bisbenzimidazole base -8- thienyl fluorine boron delays Fliud flushing is cultivated 30 minutes；It waits after cultivating, takes out culture glass bottom ware, after cleaning 2~3 times with phosphate buffer, will cultivate Glass bottom ware is imaged through confocal microscope.
Compared with prior art, the invention has the advantages that：
Compared with existing commercially available endoplasmic reticulum fluorescent labeling reagent, the present invention 3,5- bisbenzimidazole base -8- thienyl fluorine The glimmering analog derivative of boron, synthetic route is more succinct, efficient, environmental-friendly, and product is cheap, easily a large amount of acquisitions.Specific table It is now:
1st, synthetic route used in the present invention is C-H/N-H direct oxidation coupling reactions, is prepared with traditional glimmering ammonification of fluorine boron Technology compares, and shortens more interminable organic synthesis step, avoids the preactivated complicated processes of substrate, improve reaction Compatibility, increase synthetic reaction gross production rate.
2nd, compared with commercially available endoplasmic reticulum marker reagent E R-Tracker Red and ER-Tracker Green, the present inventionization It is simple to close object synthesis, it is cheap.The price of ER-Tracker Red and ER-Tracker Green are up to 4863 yuan/100 μ g (Thermo Fisher Scientific companies), and our product then it is opposite it is cheap very much, in synthesis material, even Oxidant AgOAc the most expensive, cost price also just 289 yuan/25g (An Naiji companies), and other synthesis materials are all It is compound cheap and easily-available in the market, the glimmering analog derivative price of the application fluorine boron is probably in 3000~8000 yuan/1g.Exist simultaneously Under the reaction condition of the present invention, yield can reach more than 20%.So using the glimmering analog derivative of fluorine boron of the present invention as endoplasm The cost of net fluorescent marker will be far below commercially available labelled reagent.
Description of the drawings
Fig. 1 is the general structure of the glimmering analog derivative of 3,5- bisbenzimidazole base -8- thienyl fluorine boron.
Fig. 2 is the glimmering nuclear magnetic spectrum H spectrums of 3,5- bisbenzimidazole base -8- thienyl fluorine boron.
Fig. 3 is the glimmering nuclear magnetic spectrum C spectrums of 3,5- bisbenzimidazole base -8- thienyl fluorine boron.
Fig. 4 is the glimmering UV-vis absorption spectrum of 3,5- bisbenzimidazole base -8- thienyl fluorine boron and fluorescence emission Spectrum.
Fig. 5 is the cell imaging figure of the glimmering label endocytoplasmic reticulum of 3,5- bisbenzimidazole base -8- thienyl fluorine boron.
Fig. 6 is the glimmering CCK8 cytotoxicity experiment knots in HepG2 cells of 3,5- bisbenzimidazole base -8- thienyl fluorine boron Fruit.
Specific embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to the accompanying drawings and embodiments, it is right The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and It is not used in the restriction present invention.
In the embodiment of the present invention, HepG2 cell strains are purchased in ATCC (American Type Culture Collection) company, 10% fetal calf serum are purchased in Hyclone companies, DMEM (H) (Dulbecco ' s modified Essential medium) culture medium buying in U.S. Gibco.Endoplasmic reticulum dyestuff ER-TrackerTMGreen buying in Thermo Fisher Scientific companies.
Embodiment 1
The glimmering synthesis of 3,5- bisbenzimidazole base -8- thienyl fluorine boron
Glimmering (13.7mg, 0.05mmol), benzimidazole (23.6mg, 0.20mmol), AgOAc by 8- thienyl fluorine boron (33.4mg, 4.0equiv), dimethyl sulfoxide (DMSO) (1.0mL) add in reaction tube, 80 are heated to after stirring evenly under a nitrogen atmosphere DEG C, it reacts 12 hours；Specific reaction equation is as follows：
After the completion of reaction, reaction tube is cooled to room temperature, addition 10mL dichloromethane is molten by reaction system after removing solvent Solution, then filter and washed with the dichloromethane of 10~20mL, merging filtrate through diatomite, solvent, residue silicon are removed in decompression Plastic column chromatography (dichloromethane/petrol ether/ethyl acetate=10:10:1, v/v/v) it isolates and purifies, black is obtained after vacuum drying Solid target compound 3, the 5- bisbenzimidazole base -8- thienyl glimmering 5.1mg of fluorine boron, yield 20%.
The glimmering nuclear magnetic spectrum H spectrums of the present embodiment product bisbenzimidazole base -8- thienyl fluorine boron and C spectrums are respectively such as Fig. 2 and Fig. 3 Shown, structured data is characterized as below：
1H NMR(400MHz,DMSO-d6) δ=7.13 (d, J=4.4Hz, 2H), 7.33-7.39 (m, 4H), 7.50-7.53 (m, 3H), 7.68 (d, J=2.0Hz, 2H), 7.76-7.79 (m, 2H), 7.96 (s, 1H), 8.30 (d, J=4.4Hz, 1H), 8.42(s,2H).13C NMR(100MHz,DMSO-d6) δ=111.4,115.9,120.1,123.5,124.4,129.5, 131.7,132.6,133.2,133.8,134.8,135.4,138.6,142.9,143.7,145.8.HRMS(ESI+):Calculated value C27H18BF2N6S[M+H]+:507.1369 measured value 507.1367.
Embodiment 2
The glimmering ultraviolet-visible of compound 3,5- bisbenzimidazole base -8- thienyl fluorine boron that embodiment 1 is prepared-near Infrared absorpting light spectra and fluorescent emission spectrogram
By compound 3,5- bisbenzimidazole base -8- thienyl fluorine boron is glimmering to be dissolved in dichloromethane, is made into 1 × 10-5mol/ L takes 2.5mL to be put into cuvette, measures ultraviolet-visible-near infrared absorption and fluorescence emission spectrum.
Fig. 4 is the glimmering UV-vis absorption spectrum and fluorescence of compound 3,5- bisbenzimidazole base -8- thienyl fluorine boron Emission spectrum, wherein solid black lines represent UV-vis absorption spectrum, and black dotted lines represent fluorescence emission spectrum.From Fig. 4 Compound 3 is can be seen that, the glimmering absorption spectrum maximum absorption band of 5- bisbenzimidazole base -8- thienyl fluorine boron is located at 559nm； Fluorescence emission spectrum maximum absorption band is located at 590nm, Stokes shift 31nm.
Embodiment 3
The compound 3,5- bisbenzimidazole base -8- thienyl fluorine boron that embodiment 1 is prepared is glimmering and commercially available endoplasmic reticulum contaminates Toner ER-TrackerTMFluorescence co-focusings of the Green in HepG2 cells is imaged altogether
First, it is passed through 5%CO into DMEM (H) culture medium containing 10% fetal calf serum2, by HepG2 cells in 37 DEG C Lower culture 24 hours.Culture medium is removed, adds in 2.5 μM of compounds 3, the glimmering phosphorus of 5- bisbenzimidazole base -8- thienyl fluorine boron Phthalate buffer then adds in 1 μM of commercially available endoplasmic reticulum coloring agent ER-TrackerTMGreen co-incubations 30 at 37 DEG C are divided Clock.It waits after cultivating, takes out culture glass bottom ware, after cleaning 2~3 times with phosphate buffer, by culture glass bottom ware through fluorescence Laser Scanning Confocal Microscope is imaged.
Fig. 5 is the glimmering fluorescence imaging figure (excitation wavelength of compound 3,5- bisbenzimidazole base -8- thienyl fluorine boron： 553nm, launch wavelength capture range：550-650nm).By with commercially available endoplasmic reticulum coloring agent ER-TrackerTMGreen's is glimmering Light image (excitation wavelength：488nm, launch wavelength capture range：It 450-550nm) compares and can visually see, chemical combination The object 3,5- glimmering distributions in cell of bisbenzimidazole base -8- thienyl fluorine boron and commercially available endoplasmic reticulum coloring agent ER-TrackerTM Green is basically identical, and corresponding Pearson ' s coefficients reach 0.96, illustrates compound 3, and 5- bisbenzimidazoles base- 8- thienyl fluorine boron is glimmering to have excellent endoplasmic reticulum tracer effect, can the intracellular endoplasmic reticulum of specificity label.
Embodiment 4
The glimmering CCK8 cytotoxicities of compound 3,5- bisbenzimidazole base -8- thienyl fluorine boron that embodiment 1 is prepared Experiment
By the HepG2 cell inoculations in exponential phase in 96 well culture plates, 3000 cells are inoculated with per hole, 37 With being passed through 5%CO at DEG C2DMEM (H) culture medium containing 10% fetal calf serum in overnight incubation.After cell is completely adherent, The compound 3 of various concentration is added in thereto, and 5- bisbenzimidazole base -8- thienyl fluorine boron is glimmering, and every group of concentration separately sets 3 multiple holes And blank control wells.Continue to cultivate cell 24 hours after sample-adding, cell survival rate is detected using CCK8 detection methods.
Fig. 6 is the glimmering CCK8 cytotoxicity experiment knots in HepG2 cells of 3,5- bisbenzimidazole base -8- thienyl fluorine boron Fruit.As shown in fig. 6, in 0.25~4 μM of concentration range, compound 3,5- bisbenzimidazole base -8- thienyl fluorine boron is glimmering Cell survival rate is very high (survival rate is more than 90%), and at 8 μM, survival rate can just be substantially reduced (survival rate is less than 30%), Showing compound 3, the endotoxic glimmering markers work concentration at us of 5- bisbenzimidazole base -8- thienyl fluorine boron is very little, It can be ignored.
Embodiment 5
In the preparation method of embodiment 1, deuterium, alkyl, alkoxy, carbonyl, ester group, halogen, substituted aryl is respectively adopted Or substituted heteroaryl replaces R1, R2And R3In hydrogen.Other conditions are constant, and successfully having prepared a series of can realize cell endoplasm The glimmering analog derivative of 3,5- bisbenzimidazole base -8- thienyl fluorine boron of net specificity fluorography and fluorescent marker.Wherein with reality Applying the product prepared in example 1, matter net fluorography and fluorescent marker effect are best in the cell.
Embodiment 6
In the preparation method of embodiment 1 or 5, adjustment relevant parameter carries out serial experiment：
In step 1) respectively select -40 DEG C, -20 DEG C, 0 DEG C, 20 DEG C, 40 DEG C, 60 DEG C, 100 DEG C, 120 DEG C, 140 DEG C, 160 DEG C of 80 DEG C of replacements；Reaction time is controlled in 0.1~720h；
The glimmering analog derivative of 8- thienyl fluorine boron is controlled respectively, and benzimidazoles derivative, the molar ratio of oxidant is 1: (0.01~50):(0.01~100)；
With copper acetate monohydrate, copper acetate, copper chloride, copper bromide, trifluoroacetic acid ketone, trifluoromethayl sulfonic acid copper (II), second Acyl acetone copper, silver oxide, silver nitrate, silver hexafluoroantimonate, oxygen, iodobenzene acetate, benzoquinones, dichlorodicyanobenzoquinone, crosses two at silver carbonate Sodium sulphate, ammonium peroxydisulfate, potassium persulfate, di-tert-butyl peroxide replace silver acetate；
With methanol, ethyl alcohol, tetrahydrofuran, dichloromethane, chloroform, ether, benzene, o-dichlorohenzene, chlorobenzene, toluene, two Toluene, mesitylene, hexamethylene, petroleum ether, tert-pentyl alcohol, 1,4- dioxane, 1,2- dichloroethanes, N, N- dimethyl formyls Amine, DMAC N,N' dimethyl acetamide replace dimethyl sulfoxide (DMSO).
By experiment parameter screening find it is above-mentioned it is each under the conditions of can successfully prepare and can realize endocytoplasmic reticulum specificity The glimmering analog derivative of 3,5- bisbenzimidazole base -8- thienyl fluorine boron of fluorography and fluorescent marker.Wherein to be made in embodiment 1 Matter net fluorography and fluorescent marker effect are best in the cell for standby product.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention All any modification, equivalent and improvement made within refreshing and principle etc., should all be included in the protection scope of the present invention.

Claims (9)

1. one kind 3, the glimmering analog derivative of 5- bisbenzimidazole base -8- thienyl fluorine boron, which is characterized in that have shown in following formula I Structure：
Wherein：R1,R2,R3For one in hydrogen, deuterium, alkyl, alkoxy, carbonyl, ester group, halogen, substituted aryl or substituted heteroaryl Kind or two kinds.
2. the glimmering analog derivative of one kind 3,5- bisbenzimidazole base -8- thienyl fluorine boron as described in claim 1, which is characterized in that With structure shown in following formula II：
3. a kind of preparation side of the glimmering analog derivative of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron as claimed in claim 1 or 2 Method, which is characterized in that include the following steps：
1) the glimmering analog derivative of 8- thienyl fluorine boron and benzimidazoles derivative, oxidant and solvent are uniformly mixed, then existed It is reacted under the conditions of anhydrous and oxygen-free, reaction equation is as follows：
2) it after the completion of reacting, is cooled to room temperature, addition dichloromethane dissolves reaction system, then through diatomite mistake after removing solvent Filter, and washed with dichloromethane, merging filtrate, solvent, residue silica gel column chromatography separating purification, vacuum drying are removed in decompression It can be prepared by type I compound.
4. the preparation method of the glimmering analog derivative of 3,5- of one kind bisbenzimidazoles base -8- thienyl fluorine boron as described in right wants 3, special Sign is that the oxidant is copper acetate monohydrate, copper acetate, copper chloride, copper bromide, trifluoroacetic acid ketone, trifluoromethayl sulfonic acid Copper (II), acetylacetone copper, silver carbonate, silver oxide, silver acetate, silver nitrate, silver hexafluoroantimonate, oxygen, iodobenzene acetate, benzoquinones, It is one or more in dichlorodicyanobenzoquinone, sodium persulfate, ammonium peroxydisulfate, potassium persulfate, di-tert-butyl peroxide.
5. the preparation method of the glimmering analog derivative of one kind 3,5- bisbenzimidazole base -8- thienyl fluorine boron as claimed in claim 3, It is characterized in that, the solvent is methanol, ethyl alcohol, tetrahydrofuran, dichloromethane, chloroform, ether, dimethyl sulfoxide (DMSO), benzene, neighbour Dichloro-benzenes, chlorine benzene,toluene,xylene, mesitylene, hexamethylene, petroleum ether, tert-pentyl alcohol, 1,4- dioxane, bis- chloroethenes of 1,2- It is one or more in alkane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
6. the preparation method of the glimmering analog derivative of one kind 3,5- bisbenzimidazole base -8- thienyl fluorine boron as claimed in claim 3, It is characterized in that, the glimmering reaction density of the 8- thienyls fluorine boron is 0.0001~10mol/L.
7. the preparation method of the glimmering analog derivative of one kind 3,5- bisbenzimidazole base -8- thienyl fluorine boron as claimed in claim 3, It is characterized in that, the glimmering analog derivative of the 8- thienyls fluorine boron, benzimidazoles derivative, the molar ratio of oxidant is 1:(0.01 ~50):(0.01~100).
8. the preparation method of the glimmering analog derivative of one kind 3,5- bisbenzimidazole base -8- thienyl fluorine boron as claimed in claim 3, It is characterized in that, the reaction temperature of the step 1) is -40~160 DEG C, and the time is 0.1~720h.
9. the application of the glimmering analog derivative of one kind 3,5- bisbenzimidazole base -8- thienyl fluorine boron as claimed in claim 1 or 2, It is characterized in that, in the cell the application in matter net specificity fluorography and fluorescent marker.
CN201810125816.5A 2018-02-07 2018-02-07 Glimmering analog derivative of a kind of 3,5- bisbenzimidazoles base -8- thienyl fluorine boron and its preparation method and application Pending CN108191902A (en)

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