CN104860974A - Pyrromethene-boron difluoride complex derivative and preparation method thereof - Google Patents
Pyrromethene-boron difluoride complex derivative and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 238000000926 separation method Methods 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 56
- 150000003233 pyrroles Chemical class 0.000 claims description 50
- 238000003756 stirring Methods 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- 230000006837 decompression Effects 0.000 claims description 20
- 239000003480 eluent Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 230000005526 G1 to G0 transition Effects 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000004440 column chromatography Methods 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- -1 alkyl amine compound Chemical class 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 2
- 150000003851 azoles Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 230000009257 reactivity Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- MFFMQGGZCLEMCI-UHFFFAOYSA-N 2,4-dimethyl-1h-pyrrole Chemical compound CC1=CNC(C)=C1 MFFMQGGZCLEMCI-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- PAPNRQCYSFBWDI-UHFFFAOYSA-N DMP Natural products CC1=CC=C(C)N1 PAPNRQCYSFBWDI-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000012650 click reaction Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 0 CC(*1*2(N)N)=CC(C)=C1C(c(cc1)ccc1OC=C)=C1*2=C(C)C=C1C Chemical compound CC(*1*2(N)N)=CC(C)=C1C(c(cc1)ccc1OC=C)=C1*2=C(C)C=C1C 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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 Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention provides a pyrromethene-boron difluoride complex derivative. A 1,3,5,7-tetramethyl-8-(4-allyloxy phenyl) pyrromethene-boron difluoride complex is formed by substituting allyloxy phenyl for a group on C8 of the pyrromethene-boron difluoride complex, the derivative contains specific 4-allyloxy phenyl group, so that the compound reactivity is improved greatly, and introduction of the 1,3,5,7-tetramethyl-8-(4-allyloxy phenyl) pyrromethene-boron difluoride complex as a group to a to-be-detected matter molecule is facilitated. The invention further provides a preparation method of the pyrromethene-boron difluoride complex derivative. The synthetic method is simple, intermediate separation is not required, and multiple steps of reactions are finished in one pot.
Description
Technical field
The present invention relates to technical field of organic synthesis.More particularly, the present invention relates to derivative of a kind of pyrroles methine-boron difluoride complex compound and preparation method thereof.
Background technology
The mother nucleus structure of pyrroles's methine-boron difluoride complex compound is as follows:
Two pyrrole rings are wherein connected with a boron atom by a methine bridged bond, and form the rigidity conjugate planes structure as shown in above formula, dyestuff has obvious fluorescent characteristic, and its fluorescence quantum yield is high, in physiological conditions can stable existence.Modification is carried out to its structure and can well improve its fluorescence property, pyrroles's methine-boron difluoride complex compound class is as fluorescence dye, be used as biosensor, ion probe, photodynamic therapy, biomarker and photosensitizers etc. widely, demonstrated diversity and the using value widely of pyrroles's methine-boron difluoride complex compound family.Certainly, in the last few years also shortcoming and defect was existed to this kind of thing Quality Research, such as optical property is unstable, easy generation photobleaching etc., trace it to its cause be current existing pyrroles's methine-boron difluoride complex structure and function more single, molecular diversity is inadequate, and thus some application is restricted.Therefore, on this basis, its structure is modified, obviously will improve the shortcoming and defect that existing pyrroles methine-boron difluoride complex compound exists, improve the actual application value of pyrroles's methine-boron difluoride complex compound, make it be widely used in the field such as environmental monitoring and life science.
Application number is 01126813.1 1,3,5,7-tetramethyl--2,6-dimethyl-8-(4-p-methoxy-phenyl) pyrroles methine-boron difluoride complex compound solves the higher triplet state of fluorescence dye and absorbs, the defects such as narrower laser tunable range and lower lasing efficiency, but its p-methoxy-phenyl chemical property introduced is more stable, when being used as fluorescence dye, be difficult to pyrroles's methine-boron difluoride complex compound to modify on the compound that need detect.
Summary of the invention
As the result of various extensive and careful research and experiment, the present inventor has been found that, time in pyrroles's methine-boron difluoride complex compound containing specific 4-allyloxy phenyl, described compound reactive behavior improves greatly, contributes to pyrroles's methine-boron difluoride complex compound and is incorporated on tested substance molecule as group.Based on this discovery, complete the present invention.
In order to realize according to these objects of the present invention and other advantage, provide the derivative of a kind of pyrroles methine-boron difluoride complex compound, 1 is formed by the group on 8 carbon of allyloxy phenyl substituted azole methine-boron difluoride complex compound, 3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound, its molecular structural formula is as shown in [chemical formula 1]:
[chemical formula 1]
Object of the present invention also comprises the method for the derivative of preparation pyrroles methine-boron difluoride complex compound, and this synthetic method has that step is simple, intermediate is without the need to be separated and polystep reaction one pot such as to complete at the advantage.This method comprises the steps:
Step 1: under the condition of room temperature lucifuge and nitrogen protection, methylene chloride is added in the reactor that agitator is housed, add 4-allyloxy phenyl aldehyde and 2 again, turn on agitator after 4-dimethyl pyrrole, wherein 4-allyloxy phenyl aldehyde and 2, the mass ratio of 4-dimethyl pyrrole is 1:0.71 ~ 0.853, adds catalyst reaction afterwards 8 ~ 12 hours;
Step 2: by oxygenant 2,3-bis-chloro-5,6-dicyano-1,4-para benzoquinone is dissolved in methylene dichloride, is joined in reactor afterwards, stirring at room temperature 10 ~ 30min, wherein oxygenant 2, the mass ratio of chloro-5, the 6-dicyanos of 3-bis--Isosorbide-5-Nitrae-para benzoquinone and 4-allyloxy phenyl aldehyde is 0.8 ~ 0.85:1;
Step 3: add alkyl amine compound, stirring at room temperature 3 ~ 10min, slowly adds boron trifluoride diethyl etherate under ice bath, and continue stirring 0.5 ~ 8h, wherein the mass ratio of boron trifluoride diethyl etherate and 4-allyloxy phenyl aldehyde is 0.008 ~ 0.013:1;
Step 4: by the reactant of step 3 successively through washing, dry, the lower solvent evaporated of decompression, afterwards using normal hexane: ethyl acetate volume ratio is that the mixed solution of 10:1 preparation is as eluent, silica gel is that stationary phase carries out column chromatography for separation, the lower evaporate to dryness eluent of decompression obtains 1,3, the crystal of the red needle-like of 5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound.
Preferably, wherein, in described step 1 and step 2 methylene chloride through drying treatment.
Preferably, wherein, the reaction times of described step 1 is 10 hours.
Preferably, wherein, in described step 1, catalyzer is trifluoroacetic acid, and the mass ratio of itself and 4-allyloxy phenyl aldehyde is 0.00005:1.
Preferably, wherein, in described step 2, the mass ratio of oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone and 4-allyloxy phenyl aldehyde is 0.831:1.
Preferably, wherein, the churning time in described step 2 is 30min.
Preferably, wherein, the alkyl amine compound in described step 3 is the one in triethylamine, triisopropylamine and N, N-di-isopropyl second.
Preferably, wherein, described step 3 at room temperature stirs 10min after adding alkyl amine compound.
Preferably, wherein, in described step 3, the mass ratio of boron trifluoride diethyl etherate and 4-allyloxy phenyl aldehyde is 0.01:1.
The present invention at least comprises following beneficial effect:
Of the present invention 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound, sulfydryl-double bond Click reaction is easily there is by introducing 4-allyloxy phenyl group, the introducing carboxyl that can further facilitate, hydroxyl, amino waits functional group, also BODIPY dyestuff can be modified on other molecule simultaneously, as albumen, drug molecule etc., thus the diversity that pyrroles's methine-boron difluoride derivative molecular structure and function can be enriched; Provide the method that one prepares 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound, this synthetic method is simple simultaneously, and intermediate is without the need to being separated, and polystep reaction one pot completes.
Part is embodied by explanation below by other advantage of the present invention, target and feature, part also will by research and practice of the present invention by those skilled in the art is understood.
Accompanying drawing explanation
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound.
Fig. 2 is 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound nuclear-magnetism carbon spectrogram.
Fig. 3 is the mass spectrum of 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound.
Embodiment
Below in conjunction with accompanying drawing, the present invention is described in further detail, can implement according to this with reference to specification sheets word to make those skilled in the art.
Should be appreciated that used hereinly such as " to have ", other element one or more do not allotted in " comprising " and " comprising " term or the existence of its combination or interpolation.
1,3,5,7-tetramethyl--8-of the present invention (4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound
By the double bond in this structure, utilize sulfydryl-double bond Click reaction, the introducing carboxyl that can further facilitate, hydroxyl, amino waits functional group, BODIPY dyestuff can be modified on other molecule simultaneously, as albumen, and drug molecule etc.The binding characteristic of 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound is illustrated below with r-sphaeroprotein.
< comparative example 1>
1, 3, 5, 7-tetramethyl--pyrroles's methine-boron difluoride complex compound is used as the probe detecting protein, its experiment is as follows: in No. 1 and No. 2 cuvettes, add concentration is the Tris-Hcl buffered soln of 0.5mol/L and the NaCl solution of 0.4mol/L, regulate pH value to 7.4, in No. 1 cuvette, add that concentration is 0.03mmol/L afterwards 1, 3, 5, 7-tetramethyl--pyrroles's methine-boron difluoride complex solution 2mL, at its absorption spectrum of 300-800nm wavelength region interscan, excitation wavelength is fixed near maximum absorption band wavelength, the r-globulin solution 2mL that concentration is 0.03mmol/L is added respectively in No. 1 and No. 2 cuvettes, measure No. 1 cuvette fluorescence intensity F
1, No. 2 cuvette fluorescence intensities are F
2, and the fluorescence intensity that 1,3,5,7-tetramethyl--pyrroles's methine-boron difluoride complex compound and the r-sphaeroprotein of identical mole combine is Δ F=F
1-F
2=68.
< comparative example 2>
1, 3, 5, 7-tetramethyl--8-(4-propyl group phenyl) pyrroles's methine-boron difluoride complex compound is used as the probe detecting protein, its experiment is as follows: in No. 1 and No. 2 cuvettes, add concentration is the Tris-Hcl buffered soln of 0.5mol/L and the NaCl solution of 0.4mol/L, regulate pH value to 7.4, in No. 1 cuvette, add that concentration is 0.03mmol/L afterwards 1, 3, 5, 7-tetramethyl--8-(4-propyl group phenyl) pyrroles's methine-boron difluoride complex solution 2mL, at its absorption spectrum of 300-800nm wavelength region interscan, excitation wavelength is fixed near maximum absorption band wavelength, the r-globulin solution 2mL that concentration is 0.03mmol/L is added respectively in No. 1 and No. 2 cuvettes, measure No. 1 cuvette fluorescence intensity F
1, No. 2 cuvette fluorescence intensities are F
2, and the fluorescence intensity that 1,3,5,7-tetramethyl--8-(4-propyl group phenyl) pyrroles's methine-boron difluoride complex compound and the r-sphaeroprotein of identical mole combine is Δ F=F
1-F
2=73.
< example >
1, 3, 5, 7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound is used as the probe detecting protein, its experiment is as follows: in No. 1 and No. 2 cuvettes, add concentration is the Tris-Hcl buffered soln of 0.5mol/L and the NaCl solution of 0.4mol/L, regulate pH value to 7.4, in No. 1 cuvette, add that concentration is 0.03mmol/L afterwards 1, 3, 5, 7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex solution 2mL, at its absorption spectrum of 300-800nm wavelength region interscan, excitation wavelength is fixed near maximum absorption band wavelength, the r-globulin solution 2mL that concentration is 0.03mmol/L is added respectively in No. 1 and No. 2 cuvettes, measure No. 1 cuvette fluorescence intensity F
1, No. 2 cuvette fluorescence intensities are F
2, and the fluorescence intensity that 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound and the r-sphaeroprotein of identical mole combine is Δ F=F
1-F
2=104.
Comparative example and comparative example 1-2 known, the present invention prepare 1,3,5, the protein probe of 7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound, the double bond of its end is easily combined with protein free group, thus causes 1,3,5, the accumulation of 7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride dyes on protein, makes fluorescence intensity reduce even cancellation further, shows that probe has good sensitivity.
For illustrating that the present invention prepares the method for 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound, provide following experiment:
< example 1>
Step 1: under the condition of room temperature lucifuge and nitrogen protection, 100mL anhydrous methylene chloride is added in the reactor that agitator is housed, add 2 again, 4-dimethyl pyrrole 419mg (4.4 mmol) and 4-allyloxy phenyl aldehyde 546mg (2.0mmol) turn on agitator afterwards, add catalyzer 20 μ L trifluoroacetic acid afterwards and react 10 hours;
Step 2: 454mg oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone is dissolved in 10mL methylene dichloride, is joined afterwards in reactor, stirring at room temperature 30min;
Step 3: add 3mL triethylamine, stirring at room temperature 10min, slowly add boron trifluoride diethyl etherate 5mL under ice bath, continues to stir 3h;
Step 4: successively through washing, dry, the lower solvent evaporated of decompression, with normal hexane: ethyl acetate=10:1 (volume ratio) is eluent, and silica gel is that stationary phase carries out column chromatography for separation, and the lower evaporate to dryness eluent of decompression obtains shiny red needle-like crystal 215mg.
Tested by product respectively, CDCl selected by solvent
3the nucleus magnetic hydrogen spectrum figure of products therefrom is shown in Fig. 1, and CDCl selected by solvent
3the nuclear-magnetism carbon spectrogram of products therefrom is shown in Fig. 2.
Mass spectrum is shown in Fig. 3, and the molecular weight of 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound is 380.19 as calculated, and the molecular weight that mass spectrometric measurement provides is 380.19, and both match.What in figure, the peak of 379.2 was corresponding is has used up by ionizer the result of a hydrogen atom in measuring process.
< example 2>
Step 1: under the condition of room temperature lucifuge and nitrogen protection, 100mL anhydrous methylene chloride is added in the reactor that agitator is housed, add 2 again, 4-dimethyl pyrrole 419mg (4.4mmol) and 4-allyloxy phenyl aldehyde 546mg (2.0mmol) turn on agitator afterwards, add catalyzer 20 μ L trifluoroacetic acid afterwards and react 10 hours;
Step 2: 454mg oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone is dissolved in 10mL methylene dichloride, is joined afterwards in reactor, stirring at room temperature 30min;
Step 3: add 3mL triisopropylamine, stirring at room temperature 10min, slowly add boron trifluoride diethyl etherate 5mL under ice bath, continues to stir 8h;
Step 4: successively through washing, dry, the lower solvent evaporated of decompression, with normal hexane: ethyl acetate=10:1 (volume ratio) is eluent, and silica gel is that stationary phase carries out column chromatography for separation, and the lower evaporate to dryness eluent of decompression obtains shiny red needle-like crystal 186mg.
< example 3>
Step 1: under the condition of room temperature lucifuge and nitrogen protection, 100mL anhydrous methylene chloride is added in the reactor that agitator is housed, add 2 again, 4-dimethyl pyrrole 439mg (4.6mmol) and 4-allyloxy phenyl aldehyde 546mg (2.0mmol) turn on agitator afterwards, add catalyzer 20 μ L trifluoroacetic acid afterwards and react 10 hours;
Step 2: 454mg oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone is dissolved in 10mL methylene dichloride, is joined afterwards in reactor, stirring at room temperature 30min;
Step 3: add 3mL DIPEA, stirring at room temperature 10min, slowly add boron trifluoride diethyl etherate 5mL under ice bath, continues to stir 6h;
Step 4: successively through washing, dry, the lower solvent evaporated of decompression, with normal hexane: ethyl acetate=10:1 (volume ratio) is eluent, and silica gel is that stationary phase carries out column chromatography for separation, and the lower evaporate to dryness eluent of decompression obtains shiny red needle-like crystal 192mg.
< example 4>
Step 1: under the condition of room temperature lucifuge and nitrogen protection, 100mL anhydrous methylene chloride is added in the reactor that agitator is housed, add 2 again, 4-dimethyl pyrrole 381mg (4.0mmol) and 4-allyloxy phenyl aldehyde 546mg (2.0mmol) turn on agitator afterwards, add catalyzer 20 μ L trifluoroacetic acid afterwards and react 10 hours;
Step 2: 454mg oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone is dissolved in 10mL methylene dichloride, is joined afterwards in reactor, stirring at room temperature 30min;
Step 3: add 3mL DIPEA, stirring at room temperature 10min, slowly add boron trifluoride diethyl etherate 5mL under ice bath, continues to stir 7h;
Step 4: successively through washing, dry, the lower solvent evaporated of decompression, with normal hexane: ethyl acetate=10:1 (volume ratio) is eluent, and silica gel is that stationary phase carries out column chromatography for separation, and the lower evaporate to dryness eluent of decompression obtains shiny red needle-like crystal 195mg.
< example 5>
Step 1: under the condition of room temperature lucifuge and nitrogen protection, 100mL anhydrous methylene chloride is added in the reactor that agitator is housed, add again and get 2,4-dimethyl pyrrole 400mg (4.2mmol) and 4-allyloxy phenyl aldehyde 546mg (2.0mmol) turn on agitator afterwards, add catalyzer 20 μ L trifluoroacetic acid afterwards and react 10 hours;
Step 2: 454mg oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone is dissolved in 10mL methylene dichloride, is joined afterwards in reactor, stirring at room temperature 30min;
Step 3: add 3mL triethylamine, stirring at room temperature 10min, slowly add boron trifluoride diethyl etherate 5mL under ice bath, continues to stir 5h;
Step 4: successively through washing, dry, the lower solvent evaporated of decompression, with normal hexane: ethyl acetate=10:1 (volume ratio) is eluent, and silica gel is that stationary phase carries out column chromatography for separation, and the lower evaporate to dryness eluent of decompression obtains shiny red needle-like crystal 206mg.
< example 6>
Step 1: under the condition of room temperature lucifuge and nitrogen protection, 100mL anhydrous methylene chloride is added in the reactor that agitator is housed, add again and get 2,4-dimethyl pyrrole 457mg (4.8 mmol) and 4-allyloxy phenyl aldehyde 546mg (2.0mmol) turn on agitator afterwards, add catalyzer 20 μ L trifluoroacetic acid afterwards and react 10 hours;
Step 2: 454mg oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone is dissolved in 10mL methylene dichloride, is joined afterwards in reactor, stirring at room temperature 30min;
Step 3: add 3mL triethylamine, stirring at room temperature 10min, slowly add boron trifluoride diethyl etherate 5mL under ice bath, continues to stir 8h;
Step 4: successively through washing, dry, the lower solvent evaporated of decompression, with normal hexane: ethyl acetate=10:1 (volume ratio) is eluent, and silica gel is that stationary phase carries out column chromatography for separation, and the lower evaporate to dryness eluent of decompression obtains shiny red needle-like crystal 162mg.
The embodiment 1-6 that will prepare 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound gathers and table 1.
[table 1]
| Raw materials quality ratio | Alkyl amine | Step 2 reaction times (h) | Output (mg) | |
| Example 1 | 2：4.4 | Triethylamine | 3 | 215 |
| Example 2 | 2：4.4 | Triisopropylamine | 8 | 186 |
| Example 3 | 2：4.6 | DIPEA | 6 | 192 |
| Example 4 | 2：4 | DIPEA | 6 | 195 |
| Example 5 | 2：4.2 | Triethylamine | 5 | 206 |
| Example 6 | 2：4.8 | Triethylamine | 8 | 162 |
As shown in table 1, comparative example 3 with 4 under the condition that other reaction conditionss are identical, by 2, the mol ratio of 4-dimethyl pyrrole and 4-allyloxy phenyl aldehyde is reduced to 2:4 from 2:4.6, and the output of product increases 3mg, illustrate that the feed ratio of raw material 2,4-dimethyl pyrrole and 4-allyloxy phenyl aldehyde is less to influential factors of yield; The comparing embodiment 2 and 6 when known feed ratio factor of influence is little, finds that alkyl amine catalyzer is less than feed ratio to this experiment factor of influence; Comparing embodiment 1,3,5 known, along with the growth output in reaction times reduces, and the reaction times to the factor of influence of experiment compared with feed ratio and catalyzer large.
For confirming the optimum way of reaction, is further discussed the reaction times.
< example 7>
Step 1: under the condition of room temperature lucifuge and nitrogen protection, 100mL anhydrous methylene chloride is added in the reactor that agitator is housed, add 2 again, 4-dimethyl pyrrole 419mg (4.4mmol) and 4-allyloxy phenyl aldehyde 546mg (2.0mmol) turn on agitator afterwards, add catalyzer 20 μ L trifluoroacetic acid afterwards and react 10 hours;
Step 2: 454mg oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone is dissolved in 10mL methylene dichloride, is joined afterwards in reactor, stirring at room temperature 30min;
Step 3: add 3mL triethylamine, stirring at room temperature 10min, slowly add boron trifluoride diethyl etherate 5mL under ice bath, continues to stir 2h;
Step 4: successively through washing, dry, the lower solvent evaporated of decompression, with normal hexane: ethyl acetate=10:1 (volume ratio) is eluent, and silica gel is that stationary phase carries out column chromatography for separation, and the lower evaporate to dryness eluent of decompression obtains shiny red needle-like crystal 245mg.
< example 8>
Step 1: under the condition of room temperature lucifuge and nitrogen protection, 100mL anhydrous methylene chloride is added in the reactor that agitator is housed, add 2 again, 4-dimethyl pyrrole 419mg (4.4mmol) and 4-allyloxy phenyl aldehyde 546mg (2.0mmol) turn on agitator afterwards, add catalyzer 20 μ L trifluoroacetic acid afterwards and react 10 hours;
Step 2: 454mg oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone is dissolved in 10mL methylene dichloride, is joined afterwards in reactor, stirring at room temperature 30min;
Step 3: add 3mL triethylamine, stirring at room temperature 10min, slowly add boron trifluoride diethyl etherate 5mL under ice bath, continues to stir 1h;
Step 4: successively through washing, dry, the lower solvent evaporated of decompression, with normal hexane: ethyl acetate=10:1 (volume ratio) is eluent, and silica gel is that stationary phase carries out column chromatography for separation, and the lower evaporate to dryness eluent of decompression obtains shiny red needle-like crystal 186mg.
Comparing embodiment 1,7 and 8 known, the reaction times is the highest in the output of 2 hours products.
Visible, of the present invention 1,3,5,, easily there is sulfydryl-double bond Click reaction by introducing 4-allyloxy phenyl group, the introducing carboxyl that can further facilitate in 7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound, hydroxyl, amino waits functional group, also BODIPY dyestuff can be modified on other molecule, as albumen simultaneously, drug molecule etc., thus the diversity that pyrroles's methine-boron difluoride derivative molecular structure and function can be enriched; Provide the method that one prepares 1,3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound, the output of product is higher simultaneously.
Although embodiment of the present invention are open as above, it is not restricted to listed in specification sheets and embodiment utilization.It can be applied to various applicable the field of the invention completely.For those skilled in the art, can easily realize other amendment.Therefore do not deviating under the universal that claim and equivalency range limit, the present invention is not limited to specific details and illustrates here and the legend described.
Claims (10)
1. the derivative of pyrroles's methine-boron difluoride complex compound, 1 is formed by the group on 8 carbon of allyloxy phenyl substituted azole methine-boron difluoride complex compound, 3,5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound, its molecular structural formula is as shown in [chemical formula 1]:
[chemical formula 1]
2. prepare a method for the derivative of pyrroles according to claim 1 methine-boron difluoride complex compound, comprise the steps:
Step 1: under the condition of room temperature lucifuge and nitrogen protection, methylene chloride is added in the reactor that agitator is housed, add 4-allyloxy phenyl aldehyde and 2 again, turn on agitator after 4-dimethyl pyrrole, wherein 4-allyloxy phenyl aldehyde and 2, the mass ratio of 4-dimethyl pyrrole is 1:0.71 ~ 0.853, adds catalyst reaction afterwards 8 ~ 12 hours;
Step 2: by oxygenant 2,3-bis-chloro-5,6-dicyano-1,4-para benzoquinone is dissolved in methylene dichloride, is joined in reactor afterwards, stirring at room temperature 10 ~ 30min, wherein oxygenant 2, the mass ratio of chloro-5, the 6-dicyanos of 3-bis--Isosorbide-5-Nitrae-para benzoquinone and 4-allyloxy phenyl aldehyde is 0.8 ~ 0.85:1;
Step 3: add alkyl amine compound, stirring at room temperature 3 ~ 10min, slowly adds boron trifluoride diethyl etherate under ice bath, and continue stirring 0.5 ~ 8h, wherein the mass ratio of boron trifluoride diethyl etherate and 4-allyloxy phenyl aldehyde is 0.008 ~ 0.013:1;
Step 4: by the reactant of step 3 successively through washing, dry, the lower solvent evaporated of decompression, afterwards using normal hexane: ethyl acetate volume ratio is that the mixed solution of 10:1 preparation is as eluent, silica gel is that stationary phase carries out column chromatography for separation, the lower evaporate to dryness eluent of decompression obtains 1,3, the crystal of the red needle-like of 5,7-tetramethyl--8-(4-allyloxy phenyl) pyrroles's methine-boron difluoride complex compound.
3. the method for the derivative of preparation pyrroles methine-boron difluoride complex compound as claimed in claim 2, in described step 1 and step 2, methylene chloride is through drying treatment.
4. the method for the derivative of preparation pyrroles methine-boron difluoride complex compound as claimed in claim 2, the reaction times of described step 1 is 10 hours.
5. the method for the derivative of preparation pyrroles methine-boron difluoride complex compound as claimed in claim 2, in described step 1, catalyzer is trifluoroacetic acid, and the mass ratio of itself and 4-allyloxy phenyl aldehyde is 0.00005:1.
6. the method for the derivative of preparation pyrroles methine-boron difluoride complex compound as claimed in claim 2, in described step 2, the mass ratio of oxygenant 2,3-bis-chloro-5,6-dicyanos-Isosorbide-5-Nitrae-para benzoquinone and 4-allyloxy phenyl aldehyde is 0.831:1.
7. the method for the derivative of preparation pyrroles methine-boron difluoride complex compound as claimed in claim 2, the churning time in described step 2 is 30min.
8. the method for the derivative of preparation pyrroles methine-boron difluoride complex compound as claimed in claim 2, the alkyl amine compound in described step 3 is the one in triethylamine, triisopropylamine and N, N-di-isopropyl second.
9. the method for the derivative of preparation pyrroles methine-boron difluoride complex compound as claimed in claim 2, described step 3 at room temperature stirs 10min after adding alkyl amine compound.
10. the method for the derivative of preparation pyrroles methine-boron difluoride complex compound as claimed in claim 2, in described step 3, the mass ratio of boron trifluoride diethyl etherate and 4-allyloxy phenyl aldehyde is 0.01:1.
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| CN111100153A (en) * | 2019-12-31 | 2020-05-05 | 华侨大学 | Boron dipyrromethene derivative dye ligand and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105566369A (en) * | 2016-03-07 | 2016-05-11 | 北京化工大学 | Isoindolinone formamide skeleton-containing boron bifluoride complex and preparing method thereof |
| CN111100153A (en) * | 2019-12-31 | 2020-05-05 | 华侨大学 | Boron dipyrromethene derivative dye ligand and preparation method thereof |
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