CN105732399B - A kind of triphenylamine base amine derivant with living cell developing function and preparation method thereof - Google Patents

A kind of triphenylamine base amine derivant with living cell developing function and preparation method thereof Download PDF

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CN105732399B
CN105732399B CN201610102500.5A CN201610102500A CN105732399B CN 105732399 B CN105732399 B CN 105732399B CN 201610102500 A CN201610102500 A CN 201610102500A CN 105732399 B CN105732399 B CN 105732399B
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triphenylamine
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CN105732399A (en
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周虹屏
刘丹
甘小平
李伟
吴志超
吴杰颖
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Anhui University
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Abstract

The invention discloses a kind of triphenylamine base amine derivant with living cell developing function and preparation method thereof, wherein the triphenylamine base amine derivant with living cell developing function is 4,4 two (adjacent aminostyryl) triphenylamines or 4,4 two (adjacent aminophenethyl) triphenylamines.The present invention has synthesized the formylated derivative of triphenylamine two by parent of triphenylamine by Vilsmeier Haack reactions; by preparing 4 into alkene; 4 two (ortho-nitrophenyl vinyl) triphenylamine intermediates; control reaction condition; obtained triphenylamine base amine derivant is reduced under Pd/C, hydrazine hydrate effect; i.e. 4; 4 two (adjacent aminostyryl) triphenylamines or 4; 4 two (adjacent aminophenethyl) triphenylamines, and measure it there is the characteristic of relatively low bio-toxicity and biopsy cell's imaging.

Description

It is a kind of with the triphenylamine base amine derivant of living cell developing function and its preparation Method
First, technical field
It is specifically a kind of aobvious with active somatic cell the present invention relates to a kind of one-photon optical material and preparation method thereof Triphenylamine base amine derivant of shadow function and preparation method thereof.
2nd, background technology
The functional study of cell and gene is carried out using living cells imaging workstation, be biomedical research it is newest become Gesture.Fixed cell observation is only capable of providing the static information of fixed moment cell, it is impossible to reflect cell in normal physiological biochemical condition Under the observation of state living cells, whole scanning and record are carried out to the cell under normal physiological condition, it is obtained continuous, complete Face, dynamic process.Due to the dynamic active procedure of normal cell of its display, it is easy to find and determine cell-cell interaction With the interaction between the process of signal transduction, and biomolecule in living cells level, can not only solve for a long time with The problem of not solved to hang, it is more following the problem of researching and proposing new, it is indicated that new direction.
Fluorescence probe greatly improves people and explores eucaryotic cell structure and the ability of cell processes.It is to refer to inhale Receive the light of some specific wavelength and launch the chemical group of the light (fluorescence) of longer wavelength.Living cells imaging technique is exactly utilized These fluorescence probes, such as small molecule organic dyestuff or quantum dot carry out specific mark molecule interested.
Triphenylamine derivative has the features such as structural rigidity, coplanarity are strong, luminous efficiency is high, attracts people's always Extensive concern.All shown in terms of photic, electroluminescent material and biomarker potential application prospect (J.Kido, Y.Okamoto,Chem.Rev.,2002,102,2357-2368).In recent years, people are for living cell developing function Triphenylamine derivative shows larger interest.
Inventor has made following retrieval to the related content of the application：
1、http://scholar.glgoo.com/ net retrieval results：(2016/1/26)
2nd, middle National IP Network's retrieval result：(2016/1/26)
Retrieval mode one：
Piece name --- -- conjugation with active somatic cell imaging function/non-conjugated triphenylamine base amine derivant and preparation side Method 0.
Piece name --- -- conjugation/non-conjugated triphenylamine base amine derivant and preparation method 0.
Piece name ----conjugation triphenylamine base amine derivant and preparation method 0.
Name ----non-conjugated triphenylamine base amine derivant and preparation method 0.
Retrieval mode two：
The conjugation of --- -- with active somatic cell imaging function/non-conjugated triphenylamine base amine derivant and preparation side in full Method 90, it is unrelated with target compound.
--- -- conjugation/non-conjugated triphenylamine base amine derivant and preparation method 246 in full, and target compound It is unrelated.
--- --- conjugation triphenylamine base amine derivant and preparation method 1386, unrelated with target compound in full.
--- --- non-conjugated triphenylamine base amine derivant and preparation method 336 in full, with target compound without Close.
Retrieval mode three：
Keyword ----conjugation/non-conjugated triphenylamine base amine derivant and preparation method are without pertinent literature
Keyword ----conjugation/non-conjugated triphenylamine base amine derivant and preparation method are without pertinent literature.
Keyword --- -- is conjugated triphenylamine base amine derivant and preparation method without pertinent literature.
The non-conjugated triphenylamine base amine derivant of keyword --- -- and preparation method are without pertinent literature.
3rd, the content of the invention
The present invention is intended to provide a kind of with the triphenylamine base amine derivant of living cell developing function and its preparation side Method, technical problem to be solved is：Control synthesis is conjugated/non-conjugated triphenylamine base amine derivant, and possesses it Hypotoxicity and good optical property, so that suitable for biological applications cell imaging.
Triphenylamine is the compound with hub-and-spoke configuration centered on nitrogen-atoms.Because it has unique free mafic Matter, larger steric hindrance, hyperconjugation electronic effect and higher hole mobility, thus it is widely used in photoelectric material And hole mobile material.In fluorine-triphenylamine structure unit, three phenyl ring being connected with nitrogen-atoms have many compared with high activity, structure Sample and the characteristic for easily cutting modification, therefore can be by the appropriate external different group in position on phenyl ring, obtaining one is Triphen amine luminescent material of the row with specific function.And triphenylamine intermediate the setting for photoelectric material after functionalized modification Meter is very important.
The present invention has synthesized the formylated derivative of triphenylamine two by parent of triphenylamine by Vilsmeier-Haack reactions Thing, by preparing 4,4- bis- (ortho-nitrophenyl vinyl) triphenylamine intermediate into alkene, controls reaction condition, in Pd/C, hydration Hydrazine effect reduces down obtained triphenylamine base amine derivant, i.e. (adjacent aminostyryl) triphenylamines of 4,4- bis- or 4,4- bis- (adjacent aminophenethyl) triphenylamine, and measure it there is the characteristic of relatively low bio-toxicity and biopsy cell's imaging.
Triphenylamine base amine derivant of the present invention with living cell developing function is (the adjacent aminostyryls of 4,4- bis- Base) triphenylamine or 4,4- bis- (adjacent aminophenethyl) triphenylamine, structural formula is as follows：
Wherein 4,4- bis- (adjacent aminostyryl) triphenylamine is conjugated structure, 4,4- bis- (adjacent aminophenethyl) triphenylamines For non-conjugated structure.
The preparation method of triphenylamine base amine derivant of the present invention with living cell developing function, including following step Suddenly：
(1) solvent DMF 32mL is added under ice bath into round-bottomed flask, then to POCl3 is added dropwise in round-bottomed flask 50mL, control time for adding is no more than 60min, and 10g triphenylamines are added after dripping off, 80-100 DEG C is warming up to, dark solution is obtained, Continue to react 6-10h；Reaction adds reaction solution in 500mL frozen water after terminating, and adjusts pH value to be 7-8 with NaOH saturated solutions, uses Solid 2-3 time that ethyl acetate extraction is separated out, merging organic phase, then with organic phase 2-3 times described in saturated common salt water washing, plus nothing Water MgSO4Dry, suction filtration, be spin-dried for solvent, (eluant, eluent is molten for the mixing of petroleum ether and ethyl acetate through chromatogram post separation for residue Liquid, petroleum ether：Ethyl acetate=25:1, v/v) intermediate 1, is obtained, is faint yellow solid；The structural formula of intermediate 1 is：
Reaction temperature is preferably 90 DEG C in step (1), and the reaction time is 7 hours.
(2) 13.7g ortho-methylnitrobenzenes and 21.4g N- bromo-succinimides (NBS) are dissolved in 150mL benzene, it is another to add 0.5g benzoyl peroxides (BPO), are warming up to 80 DEG C of reaction 6-10h, and reaction is cooled to room temperature after terminating, filtered, into filtrate Add at 31.5g triphenylphosphines, 60-100 DEG C and react 2-5 hours, reaction is cooled to room temperature after terminating, filter, obtain intermediate 2, it is yellow solid；The structural formula of intermediate 2 is：
Preferred scheme is：
13.7g ortho-methylnitrobenzenes and 21.4g N- bromo-succinimides (NBS) are dissolved in 150mL benzene, it is another to add 0.5g benzoyl peroxides (BPO), are warming up to 80 DEG C of reaction 8h, and reaction is cooled to room temperature after terminating, filtered, added into filtrate 31.5g triphenylphosphines, react 3 hours at 70 DEG C, and reaction is cooled to room temperature after terminating, and filter, obtain intermediate 2, are that yellow is consolidated Body；
(3) by 1.0g intermediates 1,4.75g intermediates 2,8.0g K2CO3With 0.2g trioctylmethylammonium chlorides (allignit 336) it is dissolved in 20mL DMAs (DMA), N2In 120-160 DEG C of stirring reaction 18-26h under protection, add 30mL water, adds CH after cooling2Cl2Extraction, adds anhydrous MgSO4Dry, solvent is evaporated off, be dried in vacuo, obtain intermediate M, be red Solid；Intermediate M structural formula is：
Reaction temperature is preferably 140 DEG C in step (3), and the reaction time is 22 hours.
(4) nitrogen protection under, by intermediate M 0.2g, palladium carbon 0.02g, 85wt% hydrazine hydrate 0.35mL be dissolved in solvent without In water-ethanol, back flow reaction 0.5-6 hours at 40-100 DEG C, suction filtration while hot after reaction terminates is spin-dried for filtrate, obtains target production Thing.
Reaction temperature when preparing 4,4- bis- (adjacent aminostyryl) triphenylamine in step (4) is 40-60 DEG C, during reaction Between be 0.5-2 hours；Reaction temperature when preparing 4,4- bis- (adjacent aminophenethyl) triphenylamine in step (4) is 60-100 DEG C, Reaction time is 2-6 hours.
Preferred scheme is：
Reaction temperature when preparing 4,4- bis- (adjacent aminostyryl) triphenylamine in step (4) is 60 DEG C, reaction time For 1 hour；Reaction temperature when preparing 4,4- bis- (adjacent aminophenethyl) triphenylamine in step (4) is 85 DEG C, and the reaction time is 4 Hour.
The present invention is succinct efficient using the trianilino group with compared with high reaction activity and good biocompatibility as main body Ground is prepared for triphenylamine nitro-derivative, by controlling reaction condition, is conjugated/non-conjugated triphenylamine base amine derivant, The research of single photon cell imaging has been carried out to it.
Found through experiment, conjugation/non-conjugated triphenylamine base amine derivant prepared by the present invention has in 450,375nm or so There is good single photon fluorescence property (Fig. 2 and Fig. 3).After HepG2 cells are dyed by target product, it can be clearly observed organic Material has high recognition capability to HepG2 cell matter.The discovery of this result of study, design for organic dyestuff, Prepare and life science is significant.
Compared with the prior art, beneficial effects of the present invention are embodied in：
1st, conjugation/non-conjugated triphenylamine base amine derivant that the present invention is synthesized is the list that a class has cell imaging function Photonic optical material.To cell not damaged, available for active somatic cell detection, with obvious application value.
2nd, after HepG2 cells are dyed by target product, can be clearly observed the composite have to cytoplasm it is high Recognition capability；
3rd, raw material is easy to get, and cost is low, and synthesis step is simple, it is easy to operate.
4th, illustrate
Fig. 1 is the syntheti c route figure of the present invention.
Fig. 2 a are fluorescent emission figure of the triphenylamine base amine derivant of the invention being conjugated in different solvents, Fig. 2 b columns Figure is maximum emission intensity figure of the unconjugated triphenylamine base amine derivant in different solvents.
Fig. 3 is conjugation/non-conjugated triphenylamine base amine derivant to HepG2 cell fluorescence confocal microscopic images：(a) altogether Yoke target product 4, the fluorescence co-focusing microphoto of the HepG2 cells of 4- bis- (adjacent aminostyryl) triphenylamine coloring；(b) Light field action diagram；(c) photo of overlapping；(d) non-conjugated target product 4, the coloring of 4- bis- (adjacent aminophenethyl) triphenylamine The fluorescence co-focusing microphoto of HepG2 cells；(e) light field action diagram；(f) photo of overlapping.Can be clearly from Fig. 3 Arrive, target product has passed through the cell membrane of HepG2 cells, into cytoplasm, and to the coloring of its substantially uniformity, illustrate that target is produced Thing has very high recognition capability to HepG2 cytoplasm.The preparation of this organic material for the selecting of cell developing material, make It is standby, for suffering from important meaning in terms of life science, material science.
5th, embodiment
1st, the preparation of intermediate 1
DMF 31.73mL (0.41mol) are added under ice bath into 250mL round-bottomed flasks, are leaked while stirring with constant pressure addition Trichlorine phosphine oxide 49.25mL (0.55mol) is slowly added dropwise in bucket, continues stirring to white jelly salt and occurs, adds 10g (0.041mol) 90 DEG C are warming up under triphenylamine, stirring, dark solution is obtained, continues to react 8h, after thin-layered chromatography tracking reaction completely, will react Liquid is poured slowly into 500mL frozen water, and pH is adjusted to 8 with NaOH saturated solutions, obtains black solid, and suction filtration, washing obtains primiparity Thing；Column chromatography carries out separating-purifying, and eluant, eluent is the mixed solution (petroleum ether of petroleum ether and ethyl acetate：Ethyl acetate= 25:1, v/v) 6.92g intermediates 1, yield 56.4.%, are obtained.
2nd, the preparation of intermediate 2
13.7g (0.1mol) ortho-methylnitrobenzenes and 21.4g (0.12mol) N- bromo-succinimides (NBS) are weighed respectively It is added in 500mL round-bottomed flask, takes 150mL benzene to be dissolved, separately takes 0.5g benzoyl peroxide (BPO) to add instead Answer in system, be warming up to 80 DEG C, be stirred at reflux, TLC tracking, 8h reactions are complete, are cooled to room temperature, there is white solid (succinyl Imines) separate out, suction filtration, filtrate is then heated to 80 DEG C, 31.5g (0.12mol) triphenylphosphine is added, stirring is reacted for 8 hours Completely, being cooled to room temperature has substantial amounts of solid to separate out, and suction filtration obtains 39.0g yellow solids, is intermediate 2, and yield is 81.6%.
1H NMR:((CD3)2CO,400Hz),δ(ppm):5.98 (d, J=8.00,2H), 7.47 (d, J=8.40Hz, 2H), 7.57-7.62 (m, 6H), 7.75 (t, J=7.60Hz, 3H), 7.82 (q, 8H).
3rd, intermediate M preparation
Weigh 1.0g triphenylamines dialdehyde (3.32mmol), 4.75g brominations (4- nitrobenzene methyl) triphenylphosphine (10.0mmol), 8.0gK2CO3(26.56mmol), 20mLN, N- dimethyl acetamides (DMA), 0.2g trioctylmethylammonium chlorides (allignit 336), N2Lower 140 DEG C of heating stirrings are protected to flow back, TLC points plate tracking, 22h reactions are complete；Added into system 30mL water stops reaction, and CH is added after cooling down completely2Cl2And water extraction, repeatedly extraction, takes organic layer, silica gel mixed sample, column chromatography Analysis, eluant, eluent is the mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate is by 50 during elution:1 Ratio is adjusted to 5:1, absolute ethyl alcohol/dichloromethane (EtOH:CH2Cl2=20:1, v/v) 0.28g red solids are recrystallized to obtain, in being Mesosome M, yield is 45.5%.
1H NMR(400MHz,DMSO-d6)δ(ppm):9.52 (s, 1H), 8.93-8.91 (d, 1H, J=8Hz), 8.49- 8.48 (d, 1H, J=4Hz), 8.32 (s, 1H), 8.16-8.13 (q, 1H, J=4Hz), 8.05-8.03 (d, 1H, J=8Hz), 7.52 (s, 1H), 7.19-7.15 (t, 1H, J=8Hz), 6.84-6.80 (t, 1H, J=8Hz), 5.88 (s, 1H), 5.60-5.58 (d, 1H, J=8Hz), 4.11-4.08 (t, 2H, J=6Hz), 3.43 (s, 10H), 1.38-1.34 (t, 4H, J=8Hz)
4th, target product A preparation
Intermediate M (0.2g, 0.37mmol) is dissolved in 20mL absolute ethyl alcohols, 80 DEG C are warming up under the protection of nitrogen Backflow, palladium carbon (0.02g) is added into system, 85wt% hydrazine hydrates (0.35mL is dissolved in a small amount of ethanol), TLC is slowly added dropwise Point plate tracking, reacts about 1 hour and completes；Palladium carbon is filtered while hot, filtrate is spin-dried for, and obtains yellow solid 0.12g as target products A, yield 67.5%.
1H NMR(400MHz,DMSO-d6)δ(ppm):7.57-7.55 (d, 4H, J=8Hz), 7.42-7.40 (d, 2H, J= 8Hz), 7.33-7.27 (m, 4H), 7.07-7.05 (d, 4H, J=8Hz), 7.01-6.92 (m, 8H), 6.66-6.64 (d, 2H, J =8Hz), 6.57-6.53 (t, 2H, J=8Hz), 5.29 (s, 3H)
5th, target product B preparation
Intermediate M (0.2g, 0.37mmol) is dissolved in 20mL absolute ethyl alcohols, 90 DEG C are warming up under the protection of nitrogen Backflow, palladium carbon (0.05g) is added into system, 85% hydrazine hydrate (0.35mL is dissolved in a small amount of ethanol), TLC points is slowly added dropwise Plate is tracked, and reaction reacts incomplete after about 24 hours, then adds palladium carbon (0.02g), 85% hydrazine hydrate (0.2mL).About 48 hours Reaction is complete.Palladium carbon is filtered while hot, filtrate is spin-dried for, and obtains yellow oily material, Al2O3Sample dress post is mixed, eluant, eluent polarity is oil Ether：Ethyl acetate=5:1 (v/v), it is target product B, yield 44.64% to obtain yellow solid 0.08g.
1H NMR(400MHz,DMSO-d6)δ(ppm):7.28-7.22(m,6H),6.96-6.87(m,11H),6.63- 6.61 (d, 2H, J=8Hz), 6.51-6.47 (t, 2H, J=8Hz), 4.87 (s, 4H), 2.77-2.68 (m, 8H)
6th, the test of target product A, B single photons cell developing effect
The cover glass for cleaning up and sterilizing is put into 6 hole tissue culturing plates, liver cancer tissue cell (HepG2 cells) 5 ×105The density in individual/hole is seeded in diameter 35mm 6 orifice plate culture dishes, and carries out cell as cell culture medium with DMEM Contain hyclone (10%), penicillin (100 μ g/mL) and streptomysin (100ug/mL) in culture, cell culture medium.Cell is trained Foster ware is placed in containing 5%CO2And 95%O2Incubator in maintain 37 DEG C of temperature progress cell culture 24h, with PBS (phosphoric acid buffers Liquid, pH=7.4, the production of Gibco Reagent Companies) wash HepG2 cells three times, wash away culture medium.It is then respectively adding 4 μ L targets Compound A or B DMSO solution (1mM), cultivate 0.5h, and cover glass is rinsed 6~7 times with PBS cushioning liquid (pH=7.4), drop 4% paraformaldehydes of 1mL/PBS solution fixes cell 10min, distilled water flushing cover glass 6~7 times.Cover glass is stuck in cleaning On slide, observation cellular morphology and fluorescence intake feelings under laser confocal microscope (LSM-710, Zeiss, Germany) are placed in Condition, is as a result shown in Fig. 3.
It is clear from fig. 3 that, target product A, B pass through the cell membrane of HepG2 cells, into cytoplasm, and Coloring to its substantially uniformity, it is very high to the uptake ratio of target product, illustrate that target product has to HepG2 cytoplasm very high Recognition capability.The preparation of this organic material for the selecting of cell developing material, prepare, for life science, material science In terms of suffer from important meaning.

Claims (6)

1. a kind of triphenylamine base amine derivant with living cell developing function, it is characterised in that：It is described to have live body thin The triphenylamine base amine derivant of born of the same parents' developing function is (adjacent aminostyryl) triphenylamines of 4,4- bis- or (the adjacent aminobenzene of 4,4- bis- Ethyl) triphenylamine, structural formula is as follows：
2. a kind of preparation method of the triphenylamine base amine derivant with living cell developing function described in claim 1, It is characterized in that comprising the following steps：
(1) solvent DMF 32mL is added under ice bath into round-bottomed flask, then to POCl3 50mL is added dropwise in round-bottomed flask, is controlled Time for adding processed is no more than 60min, and 10g triphenylamines are added after dripping off, 80-100 DEG C is warming up to, and obtains dark solution, continues anti- Answer 6-10h；Reaction adds reaction solution in 500mL frozen water after terminating, and adjusts pH value to be 7-8 with NaOH saturated solutions, uses acetic acid second Solid 2-3 time that ester extraction is separated out, merging organic phase, then with organic phase 2-3 times described in saturated common salt water washing, plus it is anhydrous MgSO4Dry, suction filtration is spin-dried for solvent, and residue obtains intermediate 1 through chromatogram post separation, is that faint yellow solid is；Intermediate 1 Structural formula be：
(2) 13.7g ortho-methylnitrobenzenes and 21.4g N- bromo-succinimides are dissolved in 150mL benzene, it is another to add 0.5g peroxides Change benzoyl, be warming up to 80 DEG C of reaction 6-10h, reaction is cooled to room temperature after terminating, filtered, and 31.5g triphens are added into filtrate Base phosphine, reacts 2-5 hour at 60-100 DEG C, and reaction is cooled to room temperature after terminating, and filtering obtains intermediate 2；The knot of intermediate 2 Structure formula is：
(3) by 1.0g intermediates 1,4.75g intermediates 2,8.0g K2CO320mL N, N- bis- are dissolved in 0.2g trioctylmethylammonium chlorides In methylacetamide, N2In 120-160 DEG C of stirring reaction 18-26h under protection, 30mL water is added, CH is added after cooling2Cl2Extraction, Add anhydrous MgSO4Dry, solvent is evaporated off, be dried in vacuo, obtain intermediate M；Intermediate M structural formula is：
(4) under nitrogen protection, intermediate M 0.2g, palladium carbon 0.02g, 85wt% hydrazine hydrate 0.35mL are dissolved in the anhydrous second of solvent Reacted in alcohol, suction filtration while hot after reaction terminates is spin-dried for filtrate, obtains target product；
Reaction temperature when 4,4- bis- (adjacent aminostyryl) triphenylamine is prepared in step (4) in step (4) is 40-60 DEG C, Reaction time is 0.5-2 hours；Reaction temperature when preparing 4,4- bis- (adjacent aminophenethyl) triphenylamine in step (4) is 60- 100 DEG C, the reaction time is 2-6 hours.
3. preparation method according to claim 2, it is characterised in that：
Reaction temperature is 90 DEG C in step (1), and the reaction time is 7 hours.
4. preparation method according to claim 2, it is characterised in that the course of reaction of step (2) is as follows：
13.7g ortho-methylnitrobenzenes and 21.4g N- bromo-succinimides are dissolved in 150mL benzene, it is another to add 0.5g benzoyl peroxides Formyl, is warming up to 80 DEG C of reaction 8h, and reaction is cooled to room temperature after terminating, filtered, and 31.5g triphenylphosphines, 70 are added into filtrate Reacted 3 hours at DEG C, reaction is cooled to room temperature after terminating, filter, obtain intermediate 2.
5. preparation method according to claim 2, it is characterised in that：
Reaction temperature is 140 DEG C in step (3), and the reaction time is 22 hours.
6. preparation method according to claim 2, it is characterised in that：
Reaction temperature when step (4) prepares 4,4- bis- (adjacent aminostyryl) triphenylamine in step (4) is 60 DEG C, during reaction Between be 1 hour；Reaction temperature when preparing 4,4- bis- (adjacent aminophenethyl) triphenylamine in step (4) is 85 DEG C, reaction time For 4 hours.
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