CN109796779A - A kind of preparation method of seven methines benzindole cyanine dye - Google Patents
A kind of preparation method of seven methines benzindole cyanine dye Download PDFInfo
- Publication number
- CN109796779A CN109796779A CN201711147066.3A CN201711147066A CN109796779A CN 109796779 A CN109796779 A CN 109796779A CN 201711147066 A CN201711147066 A CN 201711147066A CN 109796779 A CN109796779 A CN 109796779A
- Authority
- CN
- China
- Prior art keywords
- formula
- hydrogen
- benzindole
- hours
- methine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- HIYWOHBEPVGIQN-UHFFFAOYSA-N 1h-benzo[g]indole Chemical compound C1=CC=CC2=C(NC=C3)C3=CC=C21 HIYWOHBEPVGIQN-UHFFFAOYSA-N 0.000 title claims abstract description 37
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 title claims abstract description 36
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000000975 dye Substances 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 24
- MRUOEOGYSDTCDK-UHFFFAOYSA-N 1h-cyclopenta[c]quinoline Chemical class C1=CC=CC2=C3CC=CC3=CN=C21 MRUOEOGYSDTCDK-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 18
- -1 methine benzindoles Chemical class 0.000 claims abstract description 18
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 15
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 14
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 14
- 239000001632 sodium acetate Substances 0.000 claims abstract description 14
- 125000000596 cyclohexenyl group Chemical class C1(=CCCCC1)* 0.000 claims abstract description 13
- 238000006073 displacement reaction Methods 0.000 claims abstract description 13
- 238000000605 extraction Methods 0.000 claims abstract description 11
- 150000002222 fluorine compounds Chemical class 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 150000002170 ethers Chemical class 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 235000019441 ethanol Nutrition 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 125000004185 ester group Chemical group 0.000 claims description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 239000011630 iodine Chemical group 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 229910052708 sodium Chemical group 0.000 claims description 11
- 239000011734 sodium Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 239000000523 sample Substances 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Chemical group 0.000 claims description 6
- 239000000460 chlorine Chemical group 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012752 auxiliary agent Substances 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 11
- 238000000926 separation method Methods 0.000 abstract description 9
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000010970 precious metal Substances 0.000 abstract description 4
- 238000010923 batch production Methods 0.000 abstract description 3
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 19
- 238000004458 analytical method Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- JWUQFQYYMGMPKE-UHFFFAOYSA-N 2-chloro-3-(hydroxymethylidene)cyclohexene-1-carbaldehyde Chemical compound OC=C1CCCC(C=O)=C1Cl JWUQFQYYMGMPKE-UHFFFAOYSA-N 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000000862 absorption spectrum Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 2
- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical compound OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 2
- 229960004657 indocyanine green Drugs 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 238000007626 photothermal therapy Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- RANIQVAJHXBIAY-UHFFFAOYSA-M sodium;4-[(2e)-2-[(2e)-2-[2-chloro-3-[(e)-2-[1,1-dimethyl-3-(4-sulfonatobutyl)benzo[e]indol-3-ium-2-yl]ethenyl]cyclohex-2-en-1-ylidene]ethylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=C\C=C/1C(Cl)=C(\C=C\C=2C(C3=C4C=CC=CC4=CC=C3[N+]=2CCCCS([O-])(=O)=O)(C)C)CCC\1 RANIQVAJHXBIAY-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- CHJQJBNHNFXMEZ-UHFFFAOYSA-N (2e)-2-[(2e)-2-[2-chloro-3-[(e)-2-(1,3,3-trimethylindol-1-ium-2-yl)ethenyl]cyclohex-2-en-1-ylidene]ethylidene]-1,3,3-trimethylindole;tetrafluoroborate Chemical compound F[B-](F)(F)F.CC1(C)C2=CC=CC=C2N(C)\C1=C\C=C/1C(Cl)=C(\C=C\C=2C(C3=CC=CC=C3[N+]=2C)(C)C)CCC\1 CHJQJBNHNFXMEZ-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000002194 fatty esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Abstract
This application discloses a kind of preparation methods of seven methine benzindole cyanine dyes, include at least following steps: 2,3,3- trimethyl -4,5- benzindole derivatives are reacted with nucleophilic displacement of fluorine compound, recrystallize, obtain organic ammonium salt；By organic ammonium salt, cyclohexene derivative, sodium acetate solution reaction, product is mixed with pure and mild ethers, repeatedly extraction to get the seven methines benzindole cyanine dye.The method synthetic route is short, simple process, the catalysis without precious metal, yield is high, method of purification is simply not necessarily to chromatograph post separation and consumed solvent is few, greatly improves the preparation efficiency of such dyestuff, it can be achieved that low cost batch production.Important meaning is all had in terms of the production and application study of seven methine benzindoles flower cyanines；Seven methine benzindole cyanine dyes being prepared contain aliphatic chain and replace N structure, have or individually have near-infrared absorption, fluorography.
Description
Technical field
This application involves a kind of preparation methods of seven methine benzindole cyanine dyes, belong to polymethine benzindole flower cyanines
The preparation field of dyestuff.
Background technique
Indocyanine green in heptamethine cyanine is uniquely to can be used for facing by U.S. Food and Drug Administration's approval
The nir dye of bed development photo-thermal therapy.The new indocyanine green of its derivative belongs to one in seven methine benzindole cyanine dyes
Kind.Near-infrared region of this kind of dyestuffs near 808nm has stronger assimilation effect, can be used as other medical consultations sides
The complementary imaging technique of method (such as MRI, PET, SPECT, ultrasonic echo scanning technique, radiography or tomography), together
When be also used as the photosensitizer of photo-thermal therapy, with important researching value and apply valence in life science and biomedical research
Value.
Seven methine benzindole cyanine dyes may modify site with multiple, can expand such dyestuff and small molecule medicine significantly
Object etc. is used in combination.Currently, the seven methine benzindoles that market is sold spend cyanines, only new indocyanine green (IR-820) is a kind of and pure
It spends low (80%), price height (1324 yuan/1g).Its different derivative production purification process needs to carry out a large amount of conditional filterings simultaneously
And a large amount of organic solvents of consuming, therefore this field needs to develop new industrialized seven methine that is suitable for of one kind and spends cyanines benzindole
Dyestuff and its prepare purification process.
Summary of the invention
According to the one aspect of the application, a kind of preparation method of seven methine benzindole cyanine dyes, the party are provided
Method synthetic route is short, simple process, the catalysis without precious metal, yield are high, the big method of purification of single reacting dose is simply not necessarily to
It chromatographs post separation and consumed solvent is few, greatly improve the preparation efficiency of such dyestuff.Low cost batch production can be achieved.?
Important meaning is all had in terms of the production and application study of seven methine benzindoles flower cyanines.
The preparation method of the seven methines benzindole cyanine dye includes at least following steps:
(1) by 2,3,3- trimethyl -4,5- benzindole derivatives and nucleophilic displacement of fluorine compound under enclosed environment, 70~
150 DEG C it is melt and dissolved reaction 4~24 hours, recrystallization, obtain organic ammonium salt；
Wherein, shown in the structural formula such as formula (I-1) of described 2,3,3- trimethyl -4,5- benzindole derivatives, nucleophilic is taken
Shown in structural formula such as formula (I-2) or formula (I-3) for compound, the structural formula of organic ammonium salt such as formula (I-4) or formula (I-5) institute
Show:
In formula (I-1), R2Selected from hydrogen, C1~C4One of alkyl；B is selected from 0,1,2,3 or 4；
In formula (I-2), R " is selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, amide groups, sulfonic group or ester group；N be selected from 0 to
Any positive integer between 14；X is selected from fluorine, bromine, iodine or chlorine；
In formula (I-3), R " ' is selected fromN is selected from any just whole between 0 to 14
Number；
In formula (I-4), R4Selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, sulfonic group or ester group；M=1；In formula (I-5),
R5Selected from carboxylate radical or sulfonate radical；
(2) solution of organic ammonium salt obtained in step (1), cyclohexene derivative, sodium acetate will be contained in enclosed environment
Under, 50~80 DEG C are reacted 8~48 hours, volatilize completely to solvent, product is mixed with pure and mild ethers, and repeatedly extraction is to get institute
State seven methine benzindole cyanine dyes；
Wherein, shown in the structural formula of the cyclohexene derivative such as formula (I-6):
In formula (I-6), R3Selected from hydrogen, C1~C4One of alkyl；C is selected from 0,1,2 or 3.
Preferably, shown in the structural formula of nucleophilic displacement of fluorine compound such as formula (I-2) or selected from one of heterocyclic compound；Its
In, the heterocyclic compound is selected from In
One kind, R " ' are selected from
Optionally, sodium acetate described in step (2) is used as catalyst.
Preferably, shown in the structural formula such as formula (II) for seven methine benzindole cyanine dyes being prepared in step (2):
Wherein, R' is selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, amide groups, sulfonic group or ester group；N be selected from 0 to 14 it
Between any positive integer；X is selected from fluorine, bromine, iodine or chlorine；M=1；P=0；R2, R3Independently selected from hydrogen, C1~C4One in alkyl
Kind；B is selected from 0,1,2,3 or 4；C is selected from 0,1,2 or 3；Or
R' is selected from carboxylate radical or sulfonate radical；N is selected from any positive integer between 0 to 14；Y is selected from hydrogen or sodium；M=0；P=
1；R2, R3Independently selected from hydrogen, C1~C4One of alkyl；B is selected from 0,1,2,3 or 4；C is selected from 0,1,2 or 3.
Preferably, R' is selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, amide groups, sulfonic group or ester group in formula (II)；N choosing
Any positive integer between from 0 to 14；X is selected from bromine or iodine；M=1；P=0；R2, R3Independently selected from one of hydrogen, methyl；b
Selected from 0,1,2,3 or 4；C is selected from 0,1,2 or 3；Or
R' is selected from carboxylate radical or sulfonate radical；N is selected from any positive integer between 0 to 14；Y is selected from hydrogen or sodium；M=0；P=
1；R2, R3Independently selected from one of hydrogen, methyl；B is selected from 0,1,2,3 or 4；C is selected from 0,1,2 or 3.
Preferably, R' is selected from sulfonic group or ester group in formula (II)；N is selected from 2,4 or 6；X is selected from bromine or iodine；M=1；P=0；
R2, R3It is hydrogen；B, c are 1；Or
R' is selected from carboxylate radical or sulfonate radical；N is selected from 3,5 or 7；Y is sodium；M=0；P=1；R2, R3It is hydrogen；B, c are 1.
Preferably, n is selected from 0,1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 in formula (II).
Preferably, shown in the structural formula such as formula (III) of seven methine benzindole cyanine dyes:
Wherein, R is selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, amide groups, sulfonic group or ester group；Q is selected between 0 to 14
Any positive integer；X1Selected from fluorine, bromine, iodine or chlorine；K=1；J=0；Or
R is selected from carboxylate radical or sulfonate radical；Q is selected from any positive integer between 0 to 14；Y1Selected from hydrogen or sodium；K=0；J=
1。
Preferably, in formula (III), R is selected from sulfonic group or ethoxycarbonyl；Q is selected from 2,4 or 6；X1Selected from bromine or iodine；K=1；j
=0；Or
R is sulfonate radical；Q is selected from 3,5 or 7；Y1For sodium；K=0；J=1.
Preferably, q is selected from 0,1,2,3,4,5,6,7,8,9,10,11,12,13 or 14 in formula (III).
As specific embodiment, seven methine benzindole cyanine dyes in the application, which are selected from, has the following structure formula
Compound represented:
(1) when R is ethoxycarbonyl, when q=2,4 or 6, X1When for bromine, structural formula is compound 1, compound 2, compound
3；
(2) when R is carboxyl, when q=2,4 or 6, X1When for bromine, structural formula is compound 4, compound 5, compound 6；
(3) when R is sulfonate radical, when q=3,5 or 7, Y1When for sodium, structural formula is compound 7, compound 8, compound
9；
One kind fatty ester containing N- involved in the application, seven methine benzindoles of N- fatty acid amide or N- fat chain hydrocarbon side chain
The synthesis of cyanine dye and purification process.The seven methines benzindole cyanine dye has or individually there is near infrared light to inhale
It receives, fluorography.This method synthetic route is short, simple process, the catalysis without precious metal, yield is high, method of purification is simple
Without chromatographing post separation and consumed solvent is few, the preparation efficiency of such dyestuff is greatly improved.It is raw that low cost batch can be achieved
It produces.Important meaning is all had in terms of the production and application study of seven methine benzindoles flower cyanines.
Preferably, 2,3,3- trimethyl -4,5- benzindole derivatives described in step (1) rub with nucleophilic displacement of fluorine compound
You are than being 1:1~12；Recrystallization described in step (1) is acetone recrystallization.
Preferably, 2,3,3- trimethyl -4,5- benzindole derivatives described in step (1) rub with nucleophilic displacement of fluorine compound
You are selected from 1:1.5,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9,1:10,1:11 or 1:12 than the upper limit；Lower limit is selected from 1:
1,1:1.5,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9,1:10 or 1:11.
Preferably, the reaction temperature upper limit described in step (1) is selected from 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130
DEG C, 140 DEG C or 150 DEG C；Lower limit is selected from 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130 DEG C or 140 DEG C.
Preferably, the reaction time upper limit described in step (1) be selected from 5 hours, 10 hours, 12 hours, 14 hours, it is 15 small
When, 16 hours, 18 hours, 20 hours, 22 hours, 23 hours or 24 hours；Lower limit be selected from 4 hours, 5 hours, 10 hours, it is 12 small
When, 14 hours, 15 hours, 16 hours, 18 hours, 20 hours, 22 hours or 23 hours.
Preferably, 2,3,3- trimethyl -4,5- benzindole derivatives described in step (1) rub with nucleophilic displacement of fluorine compound
You are than being 1:1~2；The reaction condition is 80~150 DEG C and reacts 5~20 hours.
Preferably, 2,3,3- trimethyl -4,5- benzindole derivatives described in step (1) rub with nucleophilic displacement of fluorine compound
You are than being 1:1~2；The reaction condition is 100~150 DEG C and reacts 5~20 hours.
It is further preferred that 2,3,3- trimethyl -4,5- benzindole derivatives described in step (1) and nucleophilic displacement of fluorine
Conjunction object molar ratio is 1:1.5；The reaction condition is 120 DEG C and reacts 10 hours.
Preferably, the molar ratio upper limit of cyclohexene derivative described in step (2) and organic ammonium salt is selected from 1:2.1,1:
2.2,1:2.4,1:2.5,1:2.8,1:3,1:3.2,1:3.4,1:3.6,1:3.8 or 1:4；Lower limit is selected from 1:2,1:2.1,1:
2.2,1:2.4,1:2.5,1:2.8,1:3,1:3.2,1:3.4,1:3.6 or 1:3.8.
Preferably, the molar ratio upper limit of cyclohexene derivative described in step (2) and sodium acetate be selected from 1:1.5,1:1.8,
1:2,1:2.5,1:3,1:3.5,1:4,1:4.5,1:4.8 or 1:5；Lower limit choosing: 1:1,1:1.5,1:1.8,1:2,1:2.5,1:
3,1:3.5,1:4,1:4.5,1:4.8.
Preferably, reaction temperature described in step (2) is selected from 55 DEG C, 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C or 80 DEG C；Lower limit choosing
From 50 DEG C, 55 DEG C, 60 DEG C, 65 DEG C, 70 DEG C or 75 DEG C.
Preferably, the reaction time upper limit described in step (2) be selected from 10 hours, 15 hours, 18 hours, 20 hours, it is 24 small
When, 28 hours, 30 hours, 32 hours, 35 hours or 48 hours；Lower limit is selected from 8 hours, 10 hours, 15 hours, 18 hours, 20
Hour, 24 hours, 28 hours, 30 hours, 32 hours, 35 hours or 38 hours.
Preferably, the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate described in step (2) be 1:2~4:1~
5。
Preferably, the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate described in step (2) is 1:2~3:1.5
~2.5, reaction condition is 70~80 DEG C and reacts 20~30 hours.
It is further preferred that the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate described in step (2) is 1:
2.5:2, reaction condition are 75 DEG C and react 24 hours.
Preferably, alcohol described in step (1) and step (2) in methanol, ethyl alcohol, propyl alcohol, ethylene glycol, glycerine extremely
Few one kind；
The ethers is selected from least one of methyl ether, ether, butyl ether, propyl ether, petroleum ether；
The number of the extraction is 3~12.
Preferably, the number of the extraction is 3,4,5,6,7,8,9,10,11 or 12.
Preferably, the mode that product described in step (2) is mixed with pure and mild ethers are as follows: product is dissolved in alcohol first,
Then it is mixed with ether.
Preferably, the purity of seven methine benzindole cyanine dyes described in step (2) is 98% or more.
As a kind of specific embodiment, the preparation method of the seven methines benzindole cyanine dye presses following route
It carries out:
X is selected from one of halogen, preferably bromine；N is selected from any positive integer between 0 to 14, and R is selected from hydrogen, methyl, first
Oxygroup, hydroxyl, carboxyl, amide groups, sulfonic group or ester group；
Wherein, the molar ratio of 2,3,3- trimethyl -4,5- benzindoles shown in formula 12 and bromine substituent is 1:1~12,
Heating temperature is 80~150 degrees Celsius, preferably 1:1.5,120 degrees Celsius, the chloro- 1- formyl -3- hydroxymethylenecyclohexene of 2-,
The molar ratio of N- substituent and sodium acetate shown in formula 13 is 1:2~4:1~5, and heating temperature is 50~80 degrees Celsius, preferably
1:2.5:2 75 degrees Celsius.
As a kind of specific embodiment, the preparation method of seven methine benzindole cyanine dyes includes at least step:
(1) after mixing 2,3,3- trimethyl -4,5- benzindoles shown in formula 12 and bromine substituent, under enclosed environment
Heat it is melt and dissolved after to fully reacting, with after acetone recrystallization N- substituent shown in formula 13, wherein 2,3,3- trimethyls -4,5-
The molar ratio of benzindole and bromine substituent is 1:1~12, and heating temperature is 70~150 degrees Celsius, and preferably 1:1.5,120 is Celsius
Degree.
(2) N- substituent shown in the chloro- 1- formyl -3- hydroxymethylenecyclohexene of 2- and formula 13 and sodium acetate are dissolved in second
After alcohol, ethyl alcohol is volatilized after being heated to fully reacting at reflux, is mixed after being dissolved product with polyalcohol with ethers solution
With obtain product after rear multiple extraction liquid separation, N- substituent shown in the chloro- 1- formyl -3- hydroxymethylenecyclohexene of 2- and formula 13
And it is 50~80 degrees Celsius, preferably 1:2.5:2 that the molar ratio of sodium acetate, which is the heating temperature of 1:2~4:1~5,75 degrees Celsius.
Seven methine benzindole cyanine dyes are used to prepare probe auxiliary agent described in step (2) and/or near-infrared fluorescent is received
Rice probe.
This application provides the applications of the seven methine benzindole cyanine dyes, receive applied to near-infrared fluorescent is prepared
Rice probe.
Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art
Justice is identical.
In the application, C1~C4Etc. the carbon atom number for referring both to group and being included.
In the application, " alkyl " refers to the group formed by losing any one hydrogen atom on alkane compound molecule.Alkane
Hydrocarbon compound includes cycloalkane, linear paraffin, branched paraffin.
The condition of related to numberical range can be independently selected from any point value in the numberical range in the application.
The beneficial effect that the application can generate includes:
1) the seven methine benzindole cyanine dyes that the present processes are prepared, having can near-infrared absorption, glimmering
The advantage of photodevelopment.
2) preparation method provided herein, synthetic route is short, simple process, the catalysis without precious metal, yield
Height, method of purification is simply not necessarily to chromatograph post separation and consumed solvent is few, greatly improves the preparation efficiency of such dyestuff, can be real
Existing low cost batch production.
3) seven methine benzindole cyanine dye purity is highs being prepared in the application, purity are higher than 90%.
Detailed description of the invention
Fig. 1 is the seven methine benzindole cyanine dye flight mass spectrum figures that embodiment 1 provides.
Fig. 2 is the seven methine benzindole cyanine dye high-efficient liquid phase chromatograms that embodiment 1 provides.
Fig. 3 is the seven methine benzindole cyanine dye uv absorption spectras that embodiment 1 provides.
Fig. 4 is the seven methine benzindole cyanine dye flight mass spectrum figures that embodiment 2 provides.
Fig. 5 is the seven methine benzindole cyanine dye high-efficient liquid phase chromatograms that embodiment 2 provides.
Fig. 6 is the seven methine benzindole cyanine dye uv absorption spectras that embodiment 2 provides.
Fig. 7 is that 2 mouse of embodiment passes through in-vivo imaging effect after intravenous injection 48 hours.
Specific embodiment
The application is described in detail below with reference to embodiment, but the application is not limited to these embodiments.
Unless otherwise instructed, the raw material in embodiments herein is bought by commercial sources.
Analysis method is as follows in embodiments herein:
It is analyzed by mass spectrometry using 4600 type time of-flight mass spectrometer of AB Sciex Triple TOF.
Infrared absorption analysis is carried out using 6700 type infrared spectrometer of Thermo Nciolet.
Ultraviolet absorption spectroscopy is carried out using 950 type ultraviolet specrophotometer of PerkinElmer Lambda.
Fluorimetric analysis is carried out using PerkinElmer IVIS Lumina LT type small animal imaging instrument.
Embodiment 1 synthesizes compound 1
The present embodiment synthesizes compound 1 by following route:
The synthesis of (1) 2,3,3- trimethyl -1- (ethyl butyrate) -4,5- benzindole
2,3,3- trimethyl -4,5- benzindoles and 4- bromobutyrate that molar ratio is 1:1.5 are added in the reactor,
It stirs 10 hours, is cooled to room temperature after being heated to 120 DEG C of meltings under enclosed environment.It is dried in vacuo after being recrystallized with acetone 4 times,
Yield is 85.9%, can be used for reacting in next step without being further purified.
(2) synthesis and purification of compound 1
The chloro- 1- formyl -3- hydroxymethylenecyclohexene of 2- that addition molar ratio is 1:2.5:2 in the reactor, 2,3,3-
Trimethyl -1- (ethyl butyrate) -4,5- benzindole and anhydrous sodium acetate, and be added after ethyl alcohol is completely dissolved, in enclosed environment
Under at reflux reaction (75 DEG C react 24 hours) be added after methanol dissolution and petroleum to ethyl alcohol volatilizing completely after completely
Ether mixing, 12 extraction liquid separations, until lenticular product is obtained, product vacuum is dry, yield 87.2%.
Embodiment 2 synthesizes compound 7
The present embodiment synthesizes compound 7 by following route:
The synthesis of (1) 2,3,3- trimethyl -1- (fourth sulfonic acid) -4,5- benzindole
It is in 2,3,3- trimethyl -4, the 5- benzindoles and Isosorbide-5-Nitrae-fourth sulfonic acid of 1:1.5 that molar ratio is added in the reactor
Ester is stirred 10 hours after being heated to 120 DEG C of meltings under enclosed environment, is cooled to room temperature.It is dry with vacuum after acetone 4 times recrystallizations
Dry, yield 83.7% can be used for reacting in next step without being further purified.
(2) synthesis and purification of compound 7
The chloro- 1- formyl -3- hydroxymethylenecyclohexene of 2- that addition molar ratio is 1:2.5:2 in the reactor, 2,3,3-
Trimethyl -1- (fourth sulfonic acid) -4,5- benzindole and anhydrous sodium acetate, and be added after ethyl alcohol is completely dissolved, under enclosed environment
Reaction (75 DEG C react 24 hours) is to volatilizing ethyl alcohol after completely completely at reflux, is added after methanol dissolution and petroleum ether
Mixing, 12 extraction liquid separations, until lenticular product is obtained, product vacuum is dry, yield 84.2%.
Embodiment 3 synthesizes compound C1
The present embodiment synthesizes compound C1 by following route:
The synthesis of (1) 2,3,3- trimethyl -1- (butyramide) -4,5- benzindole
2,3,3- trimethyl -4,5- benzindoles and 4- bromine butyramide that molar ratio is 1:1.5, envelope are added in the reactor
Closed loop border is stirred 10 hours after being heated to 120 DEG C of meltings, is cooled to room temperature.With being dried in vacuo after acetone 4 times recrystallizations, yield is
85.7%, it can be used for reacting in next step without being further purified.
(2) synthesis and purification of compound C1
The chloro- 1- formyl -3- hydroxymethylenecyclohexene of 2- that addition molar ratio is 1:2.5:2 in the reactor, 2,3,3-
Trimethyl -1- (butyramide) -4,5- benzindole and anhydrous sodium acetate, and be added after ethyl alcohol is completely dissolved, under enclosed environment
Reaction (75 DEG C react 24 hours) is to volatilizing ethyl alcohol after completely completely at reflux, is added after methanol dissolution and petroleum
Ether, 12 extraction liquid separations, until lenticular product is obtained, product vacuum is dry, yield 87.0%.
Embodiment 4 synthesizes compound C2
The present embodiment synthesizes compound C2 by following route:
The synthesis of (1) 2,3,3- trimethyl -1- (butane) -4,5- benzindole
2,3,3- trimethyl -4,5- benzindoles and 4- bromobutyrate that molar ratio is 1:1.5 are added in the reactor,
It stirs 10 hours, is cooled to room temperature after being heated to 120 DEG C of meltings under enclosed environment.It is dried in vacuo after being recrystallized with acetone 5 times,
Yield is 85.9%, can be used for reacting in next step without being further purified.
(2) synthesis and purification of compound C2
The chloro- 1- formyl -3- hydroxymethylenecyclohexene of 2- that addition molar ratio is 1:2.5:2 in the reactor, 2,3,3-
Trimethyl -1- (butane) -4,5- benzindole and anhydrous sodium acetate, and be added after ethyl alcohol is completely dissolved, under enclosed environment
Reaction (75 DEG C react 24 hours) is to volatilizing ethyl alcohol after completely completely under reflux state, is added after methanol dissolution and petroleum ether 12
Secondary extraction liquid separation, until lenticular product is obtained, product vacuum is dry, yield 87.8%.
Embodiment 5 synthesizes compound C3~C9
Compound C3~C9 is synthesized in the present embodiment, specific reaction condition is as shown in table 1, other conditions and specific
It operates same as Example 1.
The yield for the C3~C10 being prepared in the present embodiment is greater than 85%.
The analysis of 6 structure of matter of embodiment
Phase structure analysis is carried out to the product that embodiment 1 to embodiment 5 is prepared.Wherein, embodiment 1 and embodiment
The product mass spectrogram and liquid chromatogram that are prepared in 2 as shown in Figure 1, Figure 2, shown in Fig. 4 and Fig. 5.Wherein, Fig. 1 show implementation
The mass spectrogram of compound 1 in example 1, theoretical molecular weight 783.39, mass spectrum acquired results are 783.40；In infrared spectrum: red
Outer ester bond (1724 (C=O), 1391 (C-O-C)).Fig. 2 show the high-efficient liquid phase chromatogram of compound 1, because in test process
Ester bond hydrolyzes, therefore peak value there are two it, respectively 18.059 and 18.482min, area ratio 98.9%, therefore gained chemical combination
The purity of object 1 is 98.9%.Fig. 4 show the mass spectrogram of compound 7 in embodiment 2, theoretical molecular weight 825.3, mass spectrum
Acquired results are 825.26；Infrared analysis sulfonic group (1396,1167,1042 (- SO in infrared spectrum3H)).Fig. 5 show reality
The high-efficient liquid phase chromatogram of compound 7 in example 2 is applied, appearance time 15.368min, area ratio is 98.5% in addition to the solvents, therefore
The purity of gained compound 7 is 98.5%.From the foregoing, corresponding product has been obtained in embodiment 1 and embodiment 2.Implement
Product C1~C9 test result of the example 3 into embodiment 5 is similar with embodiment 1 and embodiment 2, has obtained corresponding product,
Purity is 98% or more.Wherein, the purity of C10 is lower than 90%.
7 ultra-violet analysis of embodiment
Ultra-violet analysis is carried out to product of the embodiment 1 into embodiment 5, it is typical as shown in Figure 3 and Figure 6.Fig. 3 is corresponding real
Apply compound 1 in example 1 can be seen that its maximum absorption band in 815nm using methanol as the uv absorption spectra of solvent from figure.Figure
In 6 corresponding embodiments 2 compound 7 using methanol as the uv absorption spectra of solvent, can be seen that its maximum absorption band from figure
In 820nm.The uv absorption spectra of product into embodiment 5 of embodiment 3 is similar with embodiment 1 and embodiment 2.Embodiment 3
Into embodiment 5, the maximum absorption wavelength of product C1~C9 is in 800~830nm.
The analysis of 8 fluorography of embodiment
The product that embodiment 2 is prepared is dissolved in PBS liquid, and concentration dilution is obtained into 0.2mg/mL with PBS water
Near-infrared targeted probes preparation.
The above-mentioned near-infrared targeted probes preparation that concentration is 0.2mg/mL is injected into the nude mouse with breast cancer, 48
Fluorescence detection is carried out after hour, as a result as shown in Figure 7.The near-infrared fluorescent signal peak of the near-infrared fluorescent nano-probe and nude mice
The background signal peak of itself separates fine, and the contrast of tumor region and tumour normal surrounding tissue is up to more than 10 times, in this way
Background interference can provide the knub position and accurate tumor boundaries of cleaning to patient, improve the verification and measurement ratio of tumour, cut with regard to small
Except rate.
Meanwhile embodiment 1, product of the embodiment 3 into embodiment 5 have fluorography effect.
The above is only several embodiments of the application, not does any type of limitation to the application, although this Shen
Please disclosed as above with preferred embodiment, however not to limit the application, any person skilled in the art is not taking off
In the range of technical scheme, a little variation or modification are made using the technology contents of the disclosure above and is equal to
Case study on implementation is imitated, is belonged in technical proposal scope.
Claims (10)
1. a kind of preparation method of seven methine benzindole cyanine dyes, which is characterized in that include at least following steps:
(1) by 2,3,3- trimethyl -4,5- benzindole derivatives and nucleophilic displacement of fluorine compound under enclosed environment, 70~150
DEG C melt and dissolved reaction 4~24 hours, recrystallization obtain organic ammonium salt；
Wherein, shown in the structural formula such as formula (I-1) of described 2,3,3- trimethyl -4,5- benzindole derivatives, nucleophilic displacement of fluorine
It closes shown in the structural formula such as formula (I-2) or formula (I-3) of object, shown in the structural formula of organic ammonium salt such as formula (I-4) or formula (I-5):
In formula (I-1), R2Selected from hydrogen, C1~C4One of alkyl；B is selected from 0,1,2,3 or 4；
In formula (I-2), R " is selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, amide groups, sulfonic group or ester group；N be selected from 0 to 14 it
Between any positive integer；X is selected from fluorine, bromine, iodine or chlorine；
In formula (I-3), R " ' is selected fromN is selected from any positive integer between 0 to 14；
In formula (I-4), R4Selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, sulfonic group or ester group；M=1；In formula (I-5), R5Choosing
From carboxylate radical or sulfonate radical；
(2) solution of organic ammonium salt obtained in step (1), cyclohexene derivative, sodium acetate will be contained under enclosed environment, 50
~80 DEG C are reacted 8~48 hours, volatilize completely to solvent, product is mixed with pure and mild ethers, and repeatedly extraction is to get seven first
River benzindole cyanine dye；
Wherein, shown in the structural formula of the cyclohexene derivative such as formula (I-6):
In formula (I-6), R3Selected from hydrogen, C1~C4One of alkyl；C is selected from 0,1,2 or 3.
2. the method according to claim 1, wherein the seven methine benzindoles flower being prepared in step (2)
Shown in the structural formula of cyanine dyes such as formula (II):
Wherein, R' is selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, amide groups, sulfonic group or ester group；N is selected between 0 to 14
Any positive integer；X is selected from fluorine, bromine, iodine or chlorine；M=1；P=0；R2, R3Independently selected from hydrogen, C1~C4One of alkyl；b
Selected from 0,1,2,3 or 4；C is selected from 0,1,2 or 3；Or
R' is selected from carboxylate radical or sulfonate radical；N is selected from any positive integer between 0 to 14；Y is selected from hydrogen or sodium；M=0；P=1；R2,
R3Independently selected from hydrogen, C1~C4One of alkyl；B is selected from 0,1,2,3 or 4；C is selected from 0,1,2 or 3.
3. according to the method described in claim 2, it is characterized in that, R' is selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxylic in formula (II)
Base, amide groups, sulfonic group or ester group；N is selected from any positive integer between 0 to 14；X is selected from bromine or iodine；M=1；P=0；R2, R3
Independently selected from one of hydrogen, methyl；B is selected from 0,1,2,3 or 4；C is selected from 0,1,2 or 3；Or
R' is selected from carboxylate radical or sulfonate radical；N is selected from any positive integer between 0 to 14；Y is selected from hydrogen or sodium；M=0；P=1；R2,
R3Independently selected from one of hydrogen, methyl；B is selected from 0,1,2,3 or 4；C is selected from 0,1,2 or 3；
Preferably, R' is selected from sulfonic group or ester group in formula (II)；N is selected from 2,4 or 6；X is selected from bromine or iodine；M=1；P=0；R2, R3
It is hydrogen；B, c are 1；Or
R' is selected from carboxylate radical or sulfonate radical；N is selected from 3,5 or 7；Y is sodium；M=0；P=1；R2, R3It is hydrogen；B, c are 1.
4. seven methines benzindole cyanine dye according to claim 2, which is characterized in that the seven methines benzindole
Shown in the structural formula of cyanine dye such as formula (III):
Wherein, R is selected from hydrogen, methyl, methoxyl group, hydroxyl, carboxyl, amide groups, sulfonic group or ester group；Q is selected from appointing between 0 to 14
One positive integer；X1Selected from fluorine, bromine, iodine or chlorine；K=1；J=0；Or
R is selected from carboxylate radical or sulfonate radical；Q is selected from any positive integer between 0 to 14；Y1Selected from hydrogen or sodium；K=0；J=1；
Preferably, in formula (III), R is selected from sulfonic group or ethoxycarbonyl；Q is selected from 2,4 or 6；X1Selected from bromine or iodine；K=1；J=0；Or
R is sulfonate radical；Q is selected from 3,5 or 7；Y1For sodium；K=0；J=1.
5. the method according to claim 1, wherein 2,3,3- trimethyl -4,5- benzo Yin described in step (1)
Diindyl derivative and nucleophilic displacement of fluorine compound mole ratio are 1:1~12；
Recrystallization described in step (1) is acetone recrystallization；
Preferably, 2,3,3- trimethyl -4,5- benzindole derivatives described in step (1) and nucleophilic displacement of fluorine compound mole ratio
For 1:1~2；The reaction condition is 100~150 DEG C and reacts 5~20 hours；
It is further preferred that 2,3,3- trimethyl -4,5- benzindole derivatives described in step (1) and nucleophilic displacement of fluorine compound
Molar ratio is 1:1.5；The reaction condition is 120 DEG C and reacts 10 hours.
6. the method according to claim 1, wherein cyclohexene derivative described in step (2), organic ammonium salt and
The molar ratio of sodium acetate is 1:2~4:1~5；
Preferably, the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate described in step (2) be 1:2~3:1.5~
2.5, reaction condition is 70~80 DEG C and reacts 20~30 hours；
It is further preferred that the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate described in step (2) is 1:2.5:2,
Reaction condition is 75 DEG C and reacts 24 hours.
7. the method according to claim 1, wherein alcohol described in step (2) is selected from methanol, ethyl alcohol, propyl alcohol, second
At least one of glycol, glycerine；
The ethers is selected from least one of methyl ether, ether, butyl ether, propyl ether, petroleum ether；
The number of the extraction is 3~12.
8. the method according to claim 1, wherein the side that product described in step (2) is mixed with pure and mild ethers
Formula are as follows: product is dissolved in alcohol first, is then mixed with ether.
9. the method according to claim 1, wherein seven methine benzindole cyanine dye described in step (2)
Purity be 98% or more.
10. the method according to claim 1, wherein seven methine benzindole cyanine dye described in step (2)
It is used to prepare probe auxiliary agent and/or near-infrared fluorescent nano-probe.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711147066.3A CN109796779B (en) | 2017-11-17 | 2017-11-17 | Preparation method of heptamethine benzindole cyanine dye |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711147066.3A CN109796779B (en) | 2017-11-17 | 2017-11-17 | Preparation method of heptamethine benzindole cyanine dye |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109796779A true CN109796779A (en) | 2019-05-24 |
| CN109796779B CN109796779B (en) | 2024-05-07 |
Family
ID=66556088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711147066.3A Active CN109796779B (en) | 2017-11-17 | 2017-11-17 | Preparation method of heptamethine benzindole cyanine dye |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109796779B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020181929A1 (en) * | 2019-03-08 | 2020-09-17 | 中国科学院宁波工业技术研究院慈溪生物医学工程研究所 | Preparation method for heptamethylbenzylindole cyanine dye and application thereof |
| CN111704570A (en) * | 2020-06-17 | 2020-09-25 | 河南大学 | Near-infrared reaction type fluorescent probe with heptamethine cyanine structure and preparation method and application thereof |
| CN113248940A (en) * | 2021-05-12 | 2021-08-13 | 上海戎科特种装备有限公司 | Heptamethine cyanine dye with high-selectivity red light absorption, and synthesis method and application thereof |
| CN113979917A (en) * | 2021-09-24 | 2022-01-28 | 南京大学 | Trimethine cyanine dye, synthesis method and application |
| CN114685348A (en) * | 2022-04-14 | 2022-07-01 | 华南理工大学 | Near-infrared cyanine photosensitizer with AIE (aluminum-doped zinc oxide) property and preparation method and application thereof |
| CN114874638A (en) * | 2022-06-23 | 2022-08-09 | 西安建筑科技大学 | Meso-position substituted pentamethine cyanine dye, preparation method and application thereof, and fluorescent probe |
| CN115304539A (en) * | 2022-09-13 | 2022-11-08 | 中国科学技术大学 | Bromoheptamethine cyanine dye with near-infrared two-region absorption and fluorescence emission, and preparation method and application thereof |
| CN117169182A (en) * | 2023-08-30 | 2023-12-05 | 广州沙艾生物科技有限公司 | In-vitro efficacy detection method for stem cell therapeutic preparation and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5808044A (en) * | 1993-01-22 | 1998-09-15 | Pharmacia Biotech Inc. | Indocarbocyanine and benzindocarbocyanine phosphoramidites |
| CN102268191A (en) * | 2010-06-06 | 2011-12-07 | 史春梦 | Heptamethine indocyanine dye, synthetic method thereof and applications thereof |
| CN102532933A (en) * | 2010-12-10 | 2012-07-04 | 江南大学 | Synthetic and purifying method of near-infrared indole hepatmethine cyanine dye |
| CN106883637A (en) * | 2017-03-10 | 2017-06-23 | 中国人民解放军第三军医大学 | The methine cyanine dyes of indoles seven and preparation method and application of uracil |
-
2017
- 2017-11-17 CN CN201711147066.3A patent/CN109796779B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5808044A (en) * | 1993-01-22 | 1998-09-15 | Pharmacia Biotech Inc. | Indocarbocyanine and benzindocarbocyanine phosphoramidites |
| CN102268191A (en) * | 2010-06-06 | 2011-12-07 | 史春梦 | Heptamethine indocyanine dye, synthetic method thereof and applications thereof |
| CN102532933A (en) * | 2010-12-10 | 2012-07-04 | 江南大学 | Synthetic and purifying method of near-infrared indole hepatmethine cyanine dye |
| CN106883637A (en) * | 2017-03-10 | 2017-06-23 | 中国人民解放军第三军医大学 | The methine cyanine dyes of indoles seven and preparation method and application of uracil |
Non-Patent Citations (1)
| Title |
|---|
| YIHUI CHEN等: ""A Novel Approach to a Bifunctional Photosensitizer for Tumor Imaging and Pphototherapy"", 《BIOCONJUGATE CHEM.》 * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020181929A1 (en) * | 2019-03-08 | 2020-09-17 | 中国科学院宁波工业技术研究院慈溪生物医学工程研究所 | Preparation method for heptamethylbenzylindole cyanine dye and application thereof |
| CN111704570A (en) * | 2020-06-17 | 2020-09-25 | 河南大学 | Near-infrared reaction type fluorescent probe with heptamethine cyanine structure and preparation method and application thereof |
| CN111704570B (en) * | 2020-06-17 | 2022-05-06 | 河南大学 | Near-infrared reaction type fluorescent probe with heptamethine cyanine structure and preparation method and application thereof |
| CN113248940A (en) * | 2021-05-12 | 2021-08-13 | 上海戎科特种装备有限公司 | Heptamethine cyanine dye with high-selectivity red light absorption, and synthesis method and application thereof |
| CN113979917B (en) * | 2021-09-24 | 2023-11-17 | 南京大学 | Trimethyl cyanine dye, synthesis method and application |
| CN113979917A (en) * | 2021-09-24 | 2022-01-28 | 南京大学 | Trimethine cyanine dye, synthesis method and application |
| CN114685348A (en) * | 2022-04-14 | 2022-07-01 | 华南理工大学 | Near-infrared cyanine photosensitizer with AIE (aluminum-doped zinc oxide) property and preparation method and application thereof |
| CN114874638A (en) * | 2022-06-23 | 2022-08-09 | 西安建筑科技大学 | Meso-position substituted pentamethine cyanine dye, preparation method and application thereof, and fluorescent probe |
| CN114874638B (en) * | 2022-06-23 | 2024-01-19 | 西安建筑科技大学 | Meso-position substituted pentamethine cyanine dye, preparation method and application thereof, and fluorescent probe |
| CN115304539A (en) * | 2022-09-13 | 2022-11-08 | 中国科学技术大学 | Bromoheptamethine cyanine dye with near-infrared two-region absorption and fluorescence emission, and preparation method and application thereof |
| CN115304539B (en) * | 2022-09-13 | 2024-02-13 | 中国科学技术大学 | Bromide heptamethine cyanine dye with near infrared two-region absorption and fluorescence emission, and preparation method and application thereof |
| CN117169182A (en) * | 2023-08-30 | 2023-12-05 | 广州沙艾生物科技有限公司 | In-vitro efficacy detection method for stem cell therapeutic preparation and application thereof |
| CN117169182B (en) * | 2023-08-30 | 2024-03-15 | 广州沙艾生物科技有限公司 | In-vitro efficacy detection method for stem cell therapeutic preparation and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109796779B (en) | 2024-05-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109796779A (en) | A kind of preparation method of seven methines benzindole cyanine dye | |
| CN109180680B (en) | Ultraviolet light triggered crosslinking near-infrared molecular probe and preparation method and application thereof | |
| CN108102408B (en) | A kind of preparation and application of the nir dye based on azepine fluorine borine | |
| CN110684017B (en) | High-stability near-infrared two-region small-molecule fluorescent probe and preparation method and application thereof | |
| CN109796780A (en) | Seven methine benzindole cyanine dyes of one kind and its preparation method and application | |
| CN103911017B (en) | Cyanine dye compound and preparation method thereof, for dual-use function agent of photodynamic therapy and preparation method thereof | |
| CN108795088A (en) | It is a kind of that there is the nir dye for enhancing light power and photo-thermal effect and its preparation and application | |
| WO2020181931A1 (en) | Heptamethine carboxylindole cyanine dye and preparation method and application therefor | |
| CN106317018B (en) | A kind of tumor-targeting lipophilic cation-Chlorambucil compound and preparation method and the application in albumin nano drug | |
| CN106631979A (en) | Indocyanine green, and preparation method and application thereof | |
| CN113683602B (en) | Heptamethine cyanine micromolecule for multi-modal treatment of hypoxic tumors, and preparation method and application thereof | |
| Chen et al. | Photostability investigation of a near-infrared-II heptamethine cyanine dye | |
| CN114790215A (en) | Quinoxaline-based D-A-D near-infrared two-region fluorescent molecule and preparation method and application thereof | |
| CN111662568B (en) | Preparation method of heptamethine indole cyanine dye and application of dye | |
| CN114685348B (en) | Near-infrared cyanine photosensitizer with AIE (AIE) property and preparation method and application thereof | |
| CN112358493A (en) | Micromolecular photothermal reagent based on boron-fluorine complex and preparation method and application thereof | |
| CN108503673B (en) | Near-infrared azapyrrolidine dye and preparation method and application thereof | |
| CN102030765B (en) | Ether-linked porphyrin dimer salt and preparation method thereof | |
| CN106083872B (en) | Purpurin 18 ether derivative and its preparation method and application | |
| CN1736987A (en) | Bipyridine methyl sulfonamide derivatives and inner complex thereof and their preparation method | |
| WO2020181929A1 (en) | Preparation method for heptamethylbenzylindole cyanine dye and application thereof | |
| CN111662565B (en) | Heptamethine nitroindole cyanine dye and preparation method and application thereof | |
| CN108624080A (en) | A kind of nir dye | |
| CN108250125B (en) | Tumor targeting probe compound and synthesis and application thereof | |
| CN111662566A (en) | Heptamethine hydroxyindole cyanine dye, and synthesis method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |