CN109796779B - Preparation method of heptamethine benzindole cyanine dye - Google Patents
Preparation method of heptamethine benzindole cyanine dye Download PDFInfo
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- 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 29
- 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 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- MRUOEOGYSDTCDK-UHFFFAOYSA-N 1h-cyclopenta[c]quinoline Chemical class C1=CC=CC2=C3CC=CC3=CN=C21 MRUOEOGYSDTCDK-UHFFFAOYSA-N 0.000 claims abstract description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 28
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 18
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 15
- 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
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- -1 methoxy, hydroxyl Chemical group 0.000 claims description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 12
- 238000007336 electrophilic substitution reaction Methods 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 239000011630 iodine Chemical group 0.000 claims description 12
- 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
- 229910052708 sodium Chemical group 0.000 claims description 11
- 239000011734 sodium Chemical group 0.000 claims description 11
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 11
- 125000001246 bromo group Chemical group Br* 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 150000007942 carboxylates Chemical class 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 239000000523 sample Substances 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-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
- 125000004185 ester group Chemical group 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 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
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims 4
- 150000001408 amides Chemical class 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 15
- 238000000926 separation method Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000011161 development Methods 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 5
- 238000010923 batch production Methods 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229910000510 noble metal Inorganic materials 0.000 abstract description 4
- 230000031700 light absorption Effects 0.000 abstract description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract 1
- 239000000975 dye Substances 0.000 description 34
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 229940125904 compound 1 Drugs 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 238000001819 mass spectrum Methods 0.000 description 7
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical group OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- DZWDRAPWMQNNNM-UHFFFAOYSA-N 2-chloro-3-(hydroxymethyl)cyclohexene-1-carbaldehyde Chemical compound OCC1CCCC(C=O)=C1Cl DZWDRAPWMQNNNM-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 4
- 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
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- GDIYMWAMJKRXRE-UHFFFAOYSA-N (2z)-2-[(2e)-2-[2-chloro-3-[(z)-2-(1,3,3-trimethylindol-1-ium-2-yl)ethenyl]cyclohex-2-en-1-ylidene]ethylidene]-1,3,3-trimethylindole Chemical compound CC1(C)C2=CC=CC=C2N(C)C1=CC=C1C(Cl)=C(C=CC=2C(C3=CC=CC=C3[N+]=2C)(C)C)CCC1 GDIYMWAMJKRXRE-UHFFFAOYSA-N 0.000 description 2
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 2
- JWUQFQYYMGMPKE-UHFFFAOYSA-N 2-chloro-3-(hydroxymethylidene)cyclohexene-1-carbaldehyde Chemical compound OC=C1CCCC(C=O)=C1Cl JWUQFQYYMGMPKE-UHFFFAOYSA-N 0.000 description 2
- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical compound OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 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
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 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
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001917 fluorescence detection Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 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
- 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
- 230000035484 reaction time Effects 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
- 230000008685 targeting Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XYHHQIWETDSNOP-UHFFFAOYSA-N 4-bromobutanamide Chemical compound NC(=O)CCCBr XYHHQIWETDSNOP-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 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
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009472 formulation 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
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004949 mass spectrometry 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
- MHYFEEDKONKGEB-UHFFFAOYSA-N oxathiane 2,2-dioxide Chemical compound O=S1(=O)CCCCO1 MHYFEEDKONKGEB-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 238000007626 photothermal therapy Methods 0.000 description 1
- 238000002601 radiography 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
- 239000007858 starting material Substances 0.000 description 1
- 238000012916 structural analysis Methods 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Indole Compounds (AREA)
Abstract
The application discloses a preparation method of heptamethine benzindole cyanine dye, which at least comprises the following steps: reacting 2, 3-trimethyl-4, 5-benzindole derivative with nucleophilic substitution compound, and recrystallizing to obtain organic ammonium salt; and (3) reacting the solution of the organic ammonium salt, cyclohexene derivative and sodium acetate, mixing the product with alcohol and ether, and extracting for multiple times to obtain the heptamethine benzindole cyanine dye. The method has the advantages of short synthetic route, simple process, no need of noble metal catalysis, high yield, simple purification method, no need of chromatographic column separation and less solvent consumption, greatly improves the preparation efficiency of the dye, and can realize low-cost batch production. Has great significance in the production and application research of heptamethine benzoindole cyanine; the prepared heptamethine benzoindocyanine dye contains a fatty chain substituted N structure, and has or independently has near infrared light absorption and fluorescence development.
Description
Technical Field
The application relates to a preparation method of a heptamethine benzindole cyanine dye, belonging to the field of preparation of polymethine benzindole cyanine dyes.
Background
Indocyanine green in heptamethine cyanine dyes is the only near infrared dye approved by the U.S. food and drug administration for clinical development photothermal therapy. The derivative of the new indocyanine green belongs to one of the heptamethine benzoindocyanine dyes. The dye has a strong absorption effect in a near infrared region near 808nm, can be used as a complementary imaging technology of other medical diagnosis and treatment methods (such as MRI, PET, SPECT, an ultrasonic echo scanning technology, a radiography or a tomography), and also can be used as a photosensitizer for photothermal treatment, and has important research value and application value in life science and biomedical research.
The heptamethine benzoindole cyanine dye has a plurality of modifiable sites, and can greatly expand the combined use of the dye and small molecule medicines and the like. Currently, the commercially available heptamethine benzindole cyanines are only one of the new indocyanine green (IR-820) and have low purity (80%) and high selling price (1324 yuan/1 g). Meanwhile, the production and purification processes of different derivatives need to be screened under a large amount of conditions and consume a large amount of organic solvents, so that the field needs to develop a novel heptamethine cyanine benzindole dye suitable for industrialization and a preparation and purification method thereof.
Disclosure of Invention
According to one aspect of the application, a preparation method of the heptamethine benzindole cyanine dye is provided, and the preparation method has the advantages of short synthetic route, simple process, no need of noble metal catalysis, high yield, large single reaction amount, simple purification method, no need of chromatographic column separation, less solvent consumption and great improvement of the preparation efficiency of the dye. Can realize low-cost batch production. Has great significance in the production, application and research of heptamethine benzoindole cyanine.
The preparation method of the heptamethine benzoindole cyanine dye at least comprises the following steps:
(1) Melting 2, 3-trimethyl-4, 5-benzindole derivative and electrophilic substitution compound in a closed environment at 70-150 ℃ for 4-24 hours, and recrystallizing to obtain organic ammonium salt;
Wherein the structural formula of the 2, 3-trimethyl-4, 5-benzindole derivative is shown as a formula (I-1), the structural formula of the electrophilic substitution compound is shown as a formula (I-2) or a formula (I-3), and the structural formula of the organic ammonium salt is shown as a formula (I-4) or a formula (I-5):
In the formula (I-1), R 2 is selected from one of hydrogen and C 1～C4 alkyl; b is selected from 0, 1, 2, 3 or 4;
In the formula (I-2), R' is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amido, sulfonic acid or ester; n is selected from any positive integer between 0 and 14; x is selected from fluorine, bromine, iodine or chlorine;
in the formula (I-3), R' "is selected from N is selected from any positive integer between 0 and 14;
In the formula (I-4), R 4 is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, sulfonic acid or ester; m=1; in formula (I-5), R 5 is selected from carboxylate or sulfonate;
(2) Reacting the solution containing the organic ammonium salt, cyclohexene derivative and sodium acetate obtained in the step (1) for 8-48 hours at 50-80 ℃ in a closed environment, mixing the product with alcohol and ethers after the solvent is completely volatilized, and extracting for multiple times to obtain the heptamethine benzoindole cyanine dye;
The structural formula of the cyclohexene derivative is shown as a formula (I-6):
In the formula (I-6), R 3 is selected from one of hydrogen and C 1～C4 alkyl; c is selected from 0, 1,2 or 3.
Preferably, the electrophilic substituted compound has a structural formula shown in formula (I-2) or is selected from one of heterocyclic compounds; wherein the heterocyclic compound is selected from R' "is selected from/>
Optionally, the sodium acetate in step (2) is used as a catalyst.
Preferably, the structural formula of the heptamethine benzindole cyanine dye prepared in the step (2) is shown as a formula (II):
Wherein R' is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amido, sulfonic acid or ester; n is selected from any positive integer between 0 and 14; x is selected from fluorine, bromine, iodine or chlorine; m=1; p=0; r 2,R3 is independently selected from one of hydrogen and C 1～C4 alkyl; b is selected from 0,1, 2, 3 or 4; c is selected from 0,1, 2 or 3; or (b)
R' is selected from carboxylate or sulfonate; n is selected from any positive integer between 0 and 14; y is selected from hydrogen or sodium; m=0; p=1; r 2,R3 is independently selected from one of hydrogen and C 1～C4 alkyl; b is selected from 0,1,2,3 or 4; c is selected from 0,1,2 or 3.
Preferably, R' in formula (II) is selected from hydrogen, methyl, methoxy, hydroxy, carboxyl, amido, sulfonic acid or ester groups; n is selected from any positive integer between 0 and 14; x is selected from bromine or iodine; m=1; p=0; r 2,R3 is independently selected from one of hydrogen and methyl; b is selected from 0,1,2, 3 or 4; c is selected from 0,1,2 or 3; or (b)
R' is selected from carboxylate or sulfonate; n is selected from any positive integer between 0 and 14; y is selected from hydrogen or sodium; m=0; p=1; r 2,R3 is independently selected from one of hydrogen and methyl; b is selected from 0,1, 2,3 or 4; c is selected from 0,1, 2 or 3.
Preferably, R' in formula (II) is selected from a sulfonic acid group or an ester group; n is selected from 2, 4 or 6; x is selected from bromine or iodine; m=1; p=0; r 2,R3 are hydrogen; b and c are 1; or (b)
R' is selected from carboxylate or sulfonate; n is selected from 3, 5 or 7; y is sodium; m=0; p=1; r 2,R3 are hydrogen; b and c are 1.
Preferably, n in formula (II) is selected from 0, 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 or 14.
Preferably, the structural formula of the heptamethine benzindole cyanine dye is shown as a formula (III):
wherein R is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amido, sulfonic acid or ester; q is selected from any positive integer between 0 and 14; x 1 is selected from fluorine, bromine, iodine or chlorine; k=1; j=0; or (b)
R is selected from carboxylate or sulfonate; q is selected from any positive integer between 0 and 14; y 1 is selected from hydrogen or sodium; k=0; j=1.
Preferably, in formula (III), R is selected from a sulfonic acid group or an ethyl ester group; q is selected from 2,4 or 6; x 1 is selected from bromine or iodine; k=1; j=0; or (b)
R is sulfonate; q is selected from 3, 5 or 7; y 1 is sodium; k=0; j=1.
Preferably, q in formula (III) is selected from 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14.
As a specific embodiment, the heptamethine benzindole cyanine dye in the present application is selected from compounds having the following structural formula:
(1) When R is ethyl, q=2, 4 or 6, X 1 is bromo, the structural formulae are compound 1, compound 2, compound 3;
(2) When R is carboxyl, q=2, 4 or 6, X 1 is bromine, the structural formula is compound 4, compound 5, compound 6;
(3) When R is sulfonate, q=3, 5 or 7, Y 1 is sodium, the structural formula is compound 7, compound 8, compound 9;
the application relates to a synthesis and purification method of heptamethine benzindole cyanine dye containing N-fatty ester, N-fatty amide or N-fatty chain hydrocarbon side chain. The heptamethine benzoindocyanine dye has near infrared light absorption or singly has fluorescence development. The method has the advantages of short synthetic route, simple process, no need of noble metal catalysis, high yield, simple purification method, no need of chromatographic column separation and less solvent consumption, and greatly improves the preparation efficiency of the dye. Can realize low-cost batch production. Has great significance in the production, application and research of heptamethine benzoindole cyanine.
Preferably, the molar ratio of the 2, 3-trimethyl-4, 5-benzindole derivative to the electrophilic substitution compound in step (1) is 1:1 to 12; the recrystallization in step (1) is acetone recrystallization.
Preferably, the upper limit of the molar ratio of the 2, 3-trimethyl-4, 5-benzindole derivative to the electrophilic substitution compound in step (1) is 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; the 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 upper limit of the reaction temperature in step (1) is selected from 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃ or 150 ℃; the lower limit is selected from 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃ or 140 ℃.
Preferably, the upper limit of the reaction time in step (1) is selected from 5 hours, 10 hours, 12 hours, 14 hours, 15 hours, 16 hours, 18 hours, 20 hours, 22 hours, 23 hours or 24 hours; the lower limit is selected from 4 hours, 5 hours, 10 hours, 12 hours, 14 hours, 15 hours, 16 hours, 18 hours, 20 hours, 22 hours or 23 hours.
Preferably, the molar ratio of the 2, 3-trimethyl-4, 5-benzindole derivative to the electrophilic substitution compound in step (1) is 1:1 to 2; the reaction condition is that the reaction is carried out for 5 to 20 hours at the temperature of 80 to 150 ℃.
Preferably, the molar ratio of the 2, 3-trimethyl-4, 5-benzindole derivative to the electrophilic substitution compound in step (1) is 1:1 to 2; the reaction condition is 100-150 ℃ for 5-20 hours.
Further preferably, the molar ratio of the 2, 3-trimethyl-4, 5-benzindole derivative to the electrophilic substitution compound in step (1) is 1:1.5; the reaction conditions were 120℃for 10 hours.
Preferably, the upper limit of the molar ratio of cyclohexene derivative to organic ammonium salt in step (2) 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, a step of; the 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 upper limit of the molar ratio of cyclohexene derivative to sodium acetate in step (2) is 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, a step of; and the lower limit is selected from 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, the reaction temperature in step (2) is selected from 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃ or 80 ℃; the lower limit is selected from 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃ or 75 ℃.
Preferably, the upper limit of the reaction time in step (2) is selected from 10 hours, 15 hours, 18 hours, 20 hours, 24 hours, 28 hours, 30 hours, 32 hours, 35 hours or 48 hours; the lower limit is selected from 8 hours, 10 hours, 15 hours, 18 hours, 20 hours, 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 in step (2) is 1:2 to 4:1 to 5.
Preferably, the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate in step (2) is 1: 2-3: 1.5 to 2.5, and the reaction condition is 70 to 80 ℃ for 20 to 30 hours.
Further preferably, the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate in step (2) is 1:2.5:2, the reaction condition is 75 ℃ for 24 hours.
Preferably, the alcohol in step (1) and step (2) is at least one selected from methanol, ethanol, propanol, ethylene glycol, glycerol;
The ethers are at least one selected from methyl ether, diethyl ether, butyl ether, propyl ether and petroleum ether;
the extraction times are 3-12.
Preferably, the number of extractions is 3,4,5, 6, 7, 8, 9, 10, 11 or 12.
Preferably, the product of step (2) is mixed with the alcohol and the ether in such a way that: the product is first dissolved in alcohol and then mixed with ether.
Preferably, the purity of the heptamethine benzindole cyanine dye in the step (2) is more than 98%.
As a specific embodiment, the preparation method of the heptamethine benzindole cyanine dye is carried out according to the following route:
X is selected from one of halogens, preferably bromine; n is selected from any positive integer between 0 and 14, and R is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amido, sulfonic acid or ester;
Wherein the molar ratio of 2, 3-trimethyl-4, 5-benzindole to bromine substituent shown in formula 12 is 1: 1-12, heating temperature is 80-150 ℃, preferably 1:1.5, 120 ℃, 2-chloro-1-formyl-3-hydroxymethylcyclohexene, wherein the molar ratio of the N-substituent shown in the formula 13 to sodium acetate is 1:2 to 4: 1-5, heating temperature is 50-80 ℃, preferably 1:2.5:2,75 degrees celsius.
As a specific embodiment, the preparation method of the heptamethine benzoindocyanine dye at least comprises the following steps:
(1) Mixing 2, 3-trimethyl-4, 5-benzindole and bromine substituent shown in formula 12, heating and melting in a closed environment until the reaction is complete, and recrystallizing with acetone to obtain N-substituent shown in formula 13, wherein the molar ratio of 2, 3-trimethyl-4, 5-benzindole to bromine substituent is 1: 1-12, heating temperature 70-150 degrees celsius, preferably 1:1.5, 120 degrees celsius.
(2) Dissolving 2-chloro-1-formyl-3-hydroxymethylene cyclohexene, an N-substituent shown in a formula 13 and sodium acetate in ethanol, heating in a reflux state until the reaction is complete, volatilizing the ethanol, dissolving a product by using polyalcohol, mixing the product with an ether solution, and extracting and separating the mixture for multiple times to obtain the product, wherein the molar ratio of the 2-chloro-1-formyl-3-hydroxymethylene cyclohexene to the N-substituent shown in the formula 13 and sodium acetate is 1:2 to 4: the heating temperature of 1-5 is 50-80 ℃, and is preferably 1:2.5:2,75 degrees celsius.
The heptamethine benzindole cyanine dye in the step (2) is used for preparing a probe auxiliary agent and/or a near infrared fluorescent nano probe.
The application provides application of the heptamethine benzindole cyanine dye in preparation of near infrared fluorescent nano probes.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
In the present application, C 1～C4 and the like refer to the number of carbon atoms contained in the group.
In the present application, "alkyl" refers to a group formed by losing any one of hydrogen atoms on an alkane compound molecule. The alkane compounds include cycloalkanes, straight-chain alkanes, branched alkanes.
All conditions in the present application that relate to a numerical range can be independently selected from any point value within the numerical range.
The application has the beneficial effects that:
1) The heptamethine benzindole cyanine dye prepared by the method has the advantage of near infrared light absorption and fluorescence development.
2) The preparation method provided by the application has the advantages of short synthetic route, simple process, no need of noble metal catalysis, high yield, simple purification method, no need of chromatographic column separation and less solvent consumption, greatly improves the preparation efficiency of the dye, and can realize low-cost batch production.
3) The heptamethine benzindole cyanine dye prepared by the method has high purity which is higher than 90 percent.
Drawings
FIG. 1 is a mass spectrum of the heptamethine benzoindocyanine dye provided in example 1.
Fig. 2 is a high performance liquid chromatogram of the heptamethine benzindole cyanine dye provided in example 1.
FIG. 3 is an ultraviolet absorption spectrum of the heptamethine benzoindocyanine dye provided in example 1.
Fig. 4 is a mass spectrum of the heptamethine benzoindocyanine dye provided in example 2.
Fig. 5 is a high performance liquid chromatogram of the heptamethine benzindole cyanine dye provided in example 2.
FIG. 6 is an ultraviolet absorption spectrum of the heptamethine benzoindocyanine dye provided in example 2.
Fig. 7 shows in vivo imaging effects of the mice of example 2 after 48 hours by intravenous injection.
Detailed Description
The present application is described in detail below with reference to examples, but the present application is not limited to these examples.
Unless otherwise indicated, all starting materials in the examples of the present application were purchased commercially.
The analysis method in the embodiment of the application is as follows:
Mass spectrometry was performed using a AB Sciex Triple TOF 4600 model time-of-flight mass spectrometer.
Infrared absorption analysis was performed using a Thermo Nciolet 6700 model infrared spectrometer.
Ultraviolet absorption spectroscopy was performed using a PERKINELMER LAMBDA model 950 ultraviolet spectrophotometer.
Fluorescence detection analysis was performed using a PERKINELMER IVIS luminea LT-type small animal imager.
EXAMPLE 1 Synthesis of Compound 1
Compound 1 was synthesized in this example as follows:
(1) Synthesis of 2, 3-trimethyl-1- (ethyl butyrate) -4, 5-benzoindole
The molar ratio of the added materials in the reactor is 1:1.5 ethyl 2, 3-trimethyl-4, 5-benzoindole and 4-bromobutyrate are heated to 120 ℃ in a closed environment, melted and stirred for 10 hours, and cooled to room temperature. After 4 recrystallisations with acetone, the product was dried in vacuo to give 85.9% yield, which was used in the next reaction without further purification.
(2) Synthesis and purification of Compound 1
The molar ratio of the added materials in the reactor is 1:2.5: 2-chloro-1-formyl-3-hydroxymethylcyclohexene, 2, 3-trimethyl-1- (ethyl butyrate) -4, 5-benzindole and anhydrous sodium acetate are added, ethanol is fully dissolved and then reacted in a reflux state (reaction is carried out for 24 hours at 75 ℃ C.) in a closed environment until the ethanol is fully volatilized, methanol is added for dissolution and then mixed with petroleum ether, and extraction and liquid separation are carried out for 12 times until a crystalline product is obtained, and the product is dried in vacuum with the yield of 87.2 percent.
EXAMPLE 2 Synthesis of Compound 7
Compound 7 was synthesized in this example as follows:
(1) Synthesis of 2, 3-trimethyl-1- (butanesulfonic acid) -4, 5-benzoindole
The molar ratio of the added materials in the reactor is 1:1.5 2, 3-trimethyl-4, 5-benzoindole and 1, 4-butanesultone are heated to 120℃in a closed environment, melted and stirred for 10 hours, cooled to room temperature. After 4 recrystallisations with acetone, the product was dried in vacuo to give 83.7% yield, which was used in the next reaction without further purification.
(2) Synthesis and purification of Compound 7
The molar ratio of the added materials in the reactor is 1:2.5: 2-chloro-1-formyl-3-hydroxymethylcyclohexene, 2, 3-trimethyl-1- (butanesulfonic acid) -4, 5-benzoindole and anhydrous sodium acetate are added, ethanol is completely dissolved and then reacted in a reflux state (reaction is carried out for 24 hours at 75 ℃ C.) in a closed environment until the ethanol is completely volatilized, methanol is added for dissolution and then mixed with petroleum ether, and extraction and liquid separation are carried out for 12 times until a crystalline product is obtained, and the product is dried in vacuum with the yield of 84.2%.
EXAMPLE 3 Synthesis of Compound C1
This example synthesizes compound C1 as follows:
(1) Synthesis of 2, 3-trimethyl-1- (butyramide) -4, 5-benzoindole
The molar ratio of the added materials in the reactor is 1:1.5 2, 3-trimethyl-4, 5-benzoindole and 4-bromobutanamide, and the mixture is heated to 120 ℃ in a closed environment, melted and stirred for 10 hours, and cooled to room temperature. After 4 recrystallisations with acetone, the product was dried in vacuo to give 85.7% yield, which was used in the next reaction without further purification.
(2) Synthesis and purification of Compound C1
The molar ratio of the added materials in the reactor is 1:2.5: 2-chloro-1-formyl-3-hydroxymethylcyclohexene, 2, 3-trimethyl-1- (butyramide) -4, 5-benzindole and anhydrous sodium acetate are added, ethanol is completely dissolved and then reacted in a reflux state (reaction is carried out for 24 hours at 75 ℃ C.) in a closed environment until the ethanol is completely volatilized, methanol is added and dissolved, petroleum ether is added, and the mixture is extracted and separated for 12 times until a crystalline product is obtained, and the product is dried in vacuum, wherein the yield is 87.0%.
EXAMPLE 4 Synthesis of Compound C2
This example synthesizes compound C2 as follows:
(1) Synthesis of 2, 3-trimethyl-1- (butane) -4, 5-benzoindole
The molar ratio of the added materials in the reactor is 1:1.5 ethyl 2, 3-trimethyl-4, 5-benzoindole and 4-bromobutyrate are heated to 120 ℃ in a closed environment, melted and stirred for 10 hours, and cooled to room temperature. After 5 recrystallisations with acetone, the product was dried in vacuo to give 85.9% yield, which was used in the next reaction without further purification.
(2) Synthesis and purification of compound C2
The molar ratio of the added materials in the reactor is 1:2.5: 2-chloro-1-formyl-3-hydroxymethylcyclohexene, 2, 3-trimethyl-1- (butane) -4, 5-benzoindole and anhydrous sodium acetate are added, after ethanol is completely dissolved, the ethanol is reacted in a reflux state (75 ℃ for 24 hours) under a closed environment until the ethanol is completely volatilized, methanol is added for dissolution, and then the mixture is extracted and separated with petroleum ether for 12 times until a crystalline product is obtained, and the product is dried in vacuum, wherein the yield is 87.8%.
EXAMPLE 5 Synthesis of Compounds C3 to C9
In this example, the synthesis of compounds C3 to C9 was carried out under the conditions shown in Table 1, and the other conditions and the specific procedures were the same as in example 1.
Table 1:
The yields of C3 to C10 prepared in this example were greater than 85%.
EXAMPLE 6 structural analysis of substances
The products prepared in examples 1 to 5 were subjected to phase structure analysis. Wherein mass spectra and liquid phase chromatograms of the products prepared in example 1 and example 2 are shown in fig. 1, fig. 2, fig. 4 and fig. 5. Wherein, FIG. 1 shows a mass spectrum of compound 1 of example 1, which has a theoretical molecular weight of 783.39 and a mass spectrum of 783.40; in the infrared spectrogram: infrared ester bond (1724 (c=o), 1391 (C-O-C)). FIG. 2 shows a high performance liquid chromatogram of Compound 1, which shows that there are two peaks, 18.059 and 18.482min, respectively, due to hydrolysis of ester bond during the test, with an area ratio of 98.9%, and thus the purity of Compound 1 obtained was 98.9%. FIG. 4 is a mass spectrum of compound 7 of example 2 with a theoretical molecular weight of 825.3 and a mass spectrum of 825.26; the sulfonic groups (1396, 1167, 1042 (-SO 3 H)) were analyzed by infrared in the infrared spectrum. FIG. 5 shows a high performance liquid chromatogram of Compound 7 in example 2, showing a peak time of 15.368min and an area ratio excluding the solvent of 98.5%, so that the purity of the obtained Compound 7 was 98.5%. From the above, the corresponding products were obtained in examples 1 and 2. The results of testing the products C1 to C9 in examples 3 to 5 are similar to those in examples 1 and 2, and the corresponding products are obtained with the purity of more than 98%. Wherein the purity of C10 is lower than 90%.
EXAMPLE 7 ultraviolet analysis
The products of examples 1 to 5 were subjected to UV analysis, typically as shown in FIGS. 3 and 6. FIG. 3 is a graph showing the ultraviolet absorption spectrum of compound 1 in example 1 using methanol as a solvent, and the maximum absorption peak is 815nm. FIG. 6 is a graph of the ultraviolet absorption spectrum of compound 7 of example 2 using methanol as a solvent, showing that the maximum absorption peak is 820nm. The ultraviolet absorption spectra of the products in examples 3 to 5 are similar to those of examples 1 and 2. The maximum absorption wavelength of the products C1 to C9 in examples 3 to 5 is 800 to 830nm.
Example 8 fluorescent development analysis
The product prepared in example 2 was dissolved in PBS and the concentration was diluted with PBS water to give a near infrared targeting probe formulation of 0.2 mg/mL.
The near infrared targeting probe preparation with the concentration of 0.2mg/mL is injected into a nude mouse with breast cancer, and fluorescence detection is carried out after 48 hours, and the result is shown in FIG. 7. The near infrared fluorescence signal peak of the near infrared fluorescence nano probe is well separated from the background signal peak of the nude mouse, the contrast ratio of a tumor area and normal tissues around the tumor is up to more than 10 times, so that the background interference is small, the cleaned tumor position and accurate tumor boundary can be provided for an operator, and the detection rate and the excision rate of the tumor are improved.
Meanwhile, the products in examples 1, 3 to 5 have a fluorescent developing effect.
While the application has been described in terms of preferred embodiments, it will be understood by those skilled in the art that various changes and modifications can be made without departing from the scope of the application, and it is intended that the application is not limited to the specific embodiments disclosed.
Claims (13)
1. A preparation method of heptamethine benzoindole cyanine dye, which is characterized by at least comprising the following steps:
(1) Melting 2, 3-trimethyl-4, 5-benzindole derivative and electrophilic substitution compound in a closed environment at 70-150 ℃ for 4-24 hours, and recrystallizing to obtain organic ammonium salt;
Wherein the structural formula of the 2, 3-trimethyl-4, 5-benzindole derivative is shown as a formula (I-1), the structural formula of the electrophilic substitution compound is shown as a formula (I-2) or a formula (I-3), and the structural formula of the organic ammonium salt is shown as a formula (I-4) or a formula (I-5):
Formula (I-1);
Formula (I-2); /(I) Formula (I-3);
formula (I-4); /(I) Formula (I-5);
in the formula (I-1), R 2 is selected from one of hydrogen and C 1~C4 alkyl; b is selected from 0, 1, 2, 3 or 4;
In the formula (I-2), R '' is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amido, sulfonic acid or ester; n is selected from any positive integer between 0 and 14; x is selected from bromine, iodine or chlorine;
in the formula (I-3), R ' ' ' is selected from Or/>; N is selected from any positive integer between 0 and 14;
in the formula (I-4), R 4 is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amido, sulfonic acid group or ester group; m=1; in formula (I-5), R 5 is selected from carboxylate or sulfonate;
The recrystallization is acetone recrystallization;
the molar ratio of the 2, 3-trimethyl-4, 5-benzindole derivative to the electrophilic substitution compound in the step (1) is 1: 1-12;
(2) Reacting a solution containing the organic ammonium salt, cyclohexene derivative and sodium acetate obtained in the step (1) for 8-48 hours at 50-80 ℃ in a closed environment, mixing a product with alcohol and ethers after the solvent is completely volatilized, and extracting for multiple times to obtain the heptamethine benzoindole cyanine dye;
The structural formula of the cyclohexene derivative is shown as a formula (I-6):
formula (I-6);
In the formula (I-6), R 3 is selected from one of hydrogen and C 1~C4 alkyl; c is selected from 0, 1,2 or 3;
the product is mixed with alcohol and ethers in the following way: firstly, dissolving a product in alcohol, and then mixing with ether;
The alcohol is at least one selected from methanol, ethanol, propanol, ethylene glycol and glycerol;
The ethers are at least one selected from methyl ether, diethyl ether, butyl ether, propyl ether and petroleum ether;
The extraction times are 3-12.
2. The method according to claim 1, wherein the structural formula of the heptamethine benzoindocyanine dye prepared in the step (2) is shown as formula (II):
Formula (II);
Wherein R' is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amido, sulfonic acid or ester; n is selected from any positive integer between 0 and 14; x is selected from bromine, iodine or chlorine; m=1; p=0; r 2,R3 is independently selected from one of hydrogen and C 1~C4 alkyl; b is selected from 0, 1,2, 3 or 4; c is selected from 0, 1,2 or 3; or (b)
R' is selected from carboxylate or sulfonate; n is selected from any positive integer between 0 and 14; y is selected from hydrogen or sodium; m=0; p=1; r 2,R3 is independently selected from one of hydrogen and C 1~C4 alkyl; b is selected from 0,1,2,3 or 4; c is selected from 0,1,2 or 3.
3. The method according to claim 2, wherein R' in formula (II) is selected from hydrogen, methyl, methoxy, hydroxy, carboxyl, amide, sulfonate or ester groups; n is selected from any positive integer between 0 and 14; x is selected from bromine or iodine; m=1; p=0; r 2,R3 is independently selected from one of hydrogen and methyl; b is selected from 0,1, 2, 3 or 4; c is selected from 0,1, 2 or 3; or (b)
R' is selected from carboxylate or sulfonate; n is selected from any positive integer between 0 and 14; y is selected from hydrogen or sodium; m=0; p=1; r 2,R3 is independently selected from one of hydrogen and methyl; b is selected from 0,1, 2,3 or 4; c is selected from 0,1, 2 or 3.
4. A process according to claim 3, wherein R' in formula (II) is selected from a sulphonic acid group or an ester group; n is selected from 2,4 or 6; x is selected from bromine or iodine; m=1; p=0; r 2,R3 are hydrogen; b and c are 1; or (b)
R' is selected from carboxylate or sulfonate; n is selected from 3, 5 or 7; y is sodium; m=0; p=1; r 2,R3 are hydrogen; b and c are 1.
5. The method according to claim 2, wherein the heptamethine benzoindocyanine dye has a structural formula as shown in formula (III):
Formula (III);
wherein R is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amido, sulfonic acid or ester; q is selected from any positive integer between 0 and 14; x 1 is selected from bromine, iodine or chlorine; k=1; j=0; or (b)
R is selected from carboxylate or sulfonate; q is selected from any positive integer between 0 and 14; y 1 is selected from hydrogen or sodium; k=0; j=1.
6. The process according to claim 5, wherein in formula (III), R is selected from the group consisting of sulfonic acid groups or ethyl ester groups; q is selected from 2,4 or 6; x 1 is selected from bromine or iodine; k=1; j=0; or (b)
R is sulfonate; q is selected from 3, 5 or 7; y 1 is sodium; k=0; j=1.
7. The method of claim 1, wherein the molar ratio of 2, 3-trimethyl-4, 5-benzindole derivative to electrophilic substitution compound in step (1) is 1: 1-2; the reaction condition is that the reaction is carried out for 5-20 hours at the temperature of 100-150 ℃.
8. The method of claim 7, wherein the molar ratio of 2, 3-trimethyl-4, 5-benzindole derivative to electrophilic substitution compound in step (1) is 1:1.5; the reaction conditions were 120℃for 10 hours.
9. The method according to claim 1, wherein the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate in step (2) is 1: 2-4: 1-5.
10. The method according to claim 1, wherein the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate in step (2) is 1: 2-3: 1.5-2.5, and reacting for 20-30 hours at the temperature of 70-80 ℃.
11. The method according to claim 10, wherein the molar ratio of cyclohexene derivative, organic ammonium salt and sodium acetate in step (2) is 1:2.5:2, the reaction condition is 75 ℃ for 24 hours.
12. The process according to claim 1, wherein the purity of the heptamethine benzoindocyanine dye in step (2) is 98% or more.
13. The method according to claim 1, characterized in that the heptamethine benzoindocyanine dye in step (2) is used for the preparation of probe aids and/or near infrared fluorescent nanoprobes.
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