CN113861717A - Water-soluble indocyanine green dye for fluorescent labeling and synthetic method thereof - Google Patents
Water-soluble indocyanine green dye for fluorescent labeling and synthetic method thereof Download PDFInfo
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Abstract
The invention discloses a water-soluble indocyanine green dye for fluorescence labeling and a synthesis method thereof2) Preliminary cell labeling experiments show that the compound can be used for metabolic labeling of cell membranes by azide-sugar with high quality.
Description
Technical Field
The invention belongs to the technical field of synthesis of fluorescent dyes, and particularly relates to a water-soluble indocyanine green dye and a synthesis method thereof.
Background
Indocyanine green (ICG), a cyanine dye discovered in the early 1990 s by Alan waggon and colleagues at the university of capto-metron, is less toxic, has higher safety and better photostability than CY series cyanine dyes, and is a near-infrared imaging agent approved by the U.S. Food and Drug Administration (FDA) for clinical use. ICG dyes have mainly the following advantages: (1) ICG is a cyanine dye with a near-infrared characteristic absorption peak, the absorption wave of the ICG is 800-835 nm in the near-infrared range, the penetration depth of near-infrared light in tissues is large, the ICG is slightly influenced by the background of biological tissues, and the ICG can be used as an excellent in-vivo tissue penetrating agent due to the characteristics of near-infrared absorption and fluorescence emission. (2) ICG can be almost completely bound to plasma proteins in plasma and whole blood, remains almost completely in blood vessels and is not easily diffused out, and thus is used as a commonly used angiographic contrast agent. (3) ICG is also commonly used for determining cardiac output, liver function, hepatic blood flow and ophthalmic angiography. It has a maximum absorption spectrum around 800nm and these infrared bands can pass through the retinal layers, allowing access to deeper blood circulation than fluorescein angiographic ICG angiographic images. (4) ICG has a half-life of 150 to 180 seconds, is devoid of any known metabolites, is excreted only through the liver and bile ducts, and is completely withdrawn from circulation by the liver bile, since it is not absorbed by the intestinal mucosa, and can be classified as low-toxic. (5) ICG also absorbs light energy strongly to convert it into thermal energy or to generate singlet oxygen, and can be used for photothermal therapy (PTT) or photodynamic therapy (PDT). There are also reports in the literature that fluorescence imaging with ICG during surgery allows localization of certain in situ and metastatic tumors and their sentinel nodes. In summary, ICG has been widely used clinically.
However, because the two carbon chain ends in the ICG molecule are sulfonic acid and have no carboxyl, the carboxyl and the amino can not be reacted to mark the dye on nucleic acid and polypeptide small molecules containing amine, aiming at the problem, in the research and exploration of the structure and the application of the small molecules, C on one side in the ICG molecule has been developed4ICG-carboxylic acid (CAS: 181934-0908) with sulfonic acid replaced by hexanoic acid, and on this basis many other derivatives have been developed, the most common commercially valuable compounds being:
ICG-COOH (CAS: 181934-09-8) isA representative amine reactive group. Since it is to primary amine (-NH)2) Has rapid and high-specificity reaction, and can mark amine (-NH) in short time2) The protein, antibody and amine modified oligonucleotide can be combined with various biological molecular substrates (such as peptide, enzyme and the like) and small molecules containing amino functional groups to realize fluorescent labeling. Meanwhile, the method is also an important intermediate for synthesizing various ICG derivatives and probes with specific functions. The Ji Young Park team reports that a hepatocyte imaging agent probe (HIA for short, lambda em is 817nm) synthesized by ICG-COOH is used for living body near infrared imaging, can directly display and track the source hepatocyte which is transplanted in liver injury animals and is rich in human multifunctional stem cells, and is expected to become an effective tool for the source hepatocyte which is rich in human multifunctional stem cells and is used for drug screening and cell replacement therapy.
The Xiao-Guiang Yang team combines monoamine oxidase A inhibitor Isoniazid (INH) and tumor-targeted near-infrared heptamethiocarpine dye to synthesize a series of antitumor compounds, and evaluation shows that the antitumor compounds almost have moderate antitumor curative effects, and the antitumor compounds are tools with great development prospects in the aspect of treatment of advanced prostate cancer, wherein one antitumor compound is directly synthesized by taking ICG-COOH as a raw material.
In summary, ICG-COOH has been developed for many applications, but it has a significant disadvantage of poor solubility in water, which is not favorable for in vivo applications, such as direct labeling and staining of cells under the condition of water as solvent, thus preventing its application and popularization.
Disclosure of Invention
In order to solve the problem of poor water solubility of ICG-COOH, the invention provides a water-soluble indocyanine green dye and a synthesis method for the dye.
The synthesis method of the water-soluble indocyanine green provided by the invention comprises the following steps:
(1) dissolving 6-aminonaphthalene-2-sulfonic acid in water, adding a sodium hydroxide aqueous solution, stirring for 10-15 minutes at 0 ℃, dropwise adding a sulfuric acid aqueous solution, continuing to stir at 0 ℃ after dropwise adding is finished, adding a sodium nitrite aqueous solution, stirring for 2-3 hours after adding is finished, filtering while the solution is cold to obtain diazonium salt, then adding the diazonium salt into a stannous chloride aqueous solution in hydrochloric acid at 0 ℃ under the stirring condition, reacting for 8-10 hours, and filtering to obtain a solid, namely an intermediate 1;
(2) adding the intermediate 1, sodium acetate and 3-methyl-2-butanone into acetic anhydride, reacting for 8-10 hours at 140-160 ℃, pouring reaction liquid into petroleum ether after the reaction is finished, separating out solids, filtering, and drying the solids to obtain an intermediate 2;
(3) dissolving the intermediate 2 with 1, 4-butane sultone, heating to 70-90 ℃ for reaction for 8-10 hours, adding into a mixed solution of petroleum ether and diethyl ether after the reaction is finished, separating out a solid, and filtering the solid to obtain an intermediate 3;
(4) adding the intermediate 2 and 6-bromohexanoic acid into o-dichlorobenzene, reacting at 110-130 ℃ for 8-12 hours, cooling after the reaction is finished, adding a methanol dissolved product, adding the methanol dissolved product into petroleum ether to separate out solids, and filtering the solids to obtain an intermediate 4;
(5) adding the intermediate 4 and glutaral aldehyde diphenylamine hydrochloride into acetic acid, heating to 140-160 ℃ for reaction for 10-15 hours, pouring reaction liquid into methyl tert-butyl ether after the reaction is finished, pouring out supernatant, dissolving solid by using mixed liquid of dichloromethane and methanol, dripping the dissolved solid into the methyl tert-butyl ether to separate out the solid, and filtering to obtain an intermediate 5;
(6) adding the intermediate 5 and the intermediate 3 into DMSO, adding pyridine, reacting at room temperature for 10-12 hours, adding a reaction solution into methyl tert-butyl ether after the reaction is finished, dissolving precipitated solid with dichloromethane, and purifying by column chromatography to obtain a water-soluble indocyanine green dye;
in the step (1), 6-aminonaphthalene-2-sulfonic acid, sodium hydroxide and H are preferably used2SO4The molar ratio of the sodium nitrite to the stannous chloride is 1: 2.5-4: 0.5-1: 2.5-4: 1.5-3.
In the step (2), the molar ratio of the intermediate 1 to the sodium acetate and the 3-methyl-2-butanone is preferably 1: 3.5-5: 2.5-4.
In the step (3), the molar ratio of the intermediate 2 to the 1, 4-butane sultone is preferably 1: 18-22.
In the step (4), the molar ratio of the intermediate 2 to the 6-bromohexanoic acid is preferably 1:1 to 1.5.
In the step (5), the molar ratio of the intermediate 4 to the glutarenal anilide hydrochloride is preferably 1: 1.5-2.5.
In the step (6), the molar ratio of the intermediate 5 to the intermediate 3 to pyridine is preferably 1:1 to 1.5:18 to 25.
The invention has the following beneficial effects:
the ICG-COOH molecule is further modified, two sulfonic acid groups are added on an aromatic ring, and finally the water-soluble indocyanine green dye with good solubility in water is obtained.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of a water-soluble indocyanine green dye of example 1.
Detailed Description
The invention will be further described in detail with reference to the following figures and examples, but the scope of the invention is not limited to these examples.
Example 1
1. 150g (0.67mol) of 6-aminonaphthalene-2-sulfonic acid was dissolved in 1L of water, an aqueous sodium hydroxide solution (80.4g (2.01mol) of sodium hydroxide was added in 160mL of water), and the mixture was stirred at 0 ℃ for 10min, and then an aqueous sulfuric acid solution (17.73mL (0.335mol) of sulfuric acid was added dropwise to 134mL of water, an aqueous sodium nitrite solution (137.98g (2.01mol) was added dropwise to 280mL of water) at 0 ℃, and after completion of the addition, the mixture was stirred at 0 ℃ for 2h, and then filtered while it was cold to obtain a diazonium salt. Dissolving 254g (1.34mol) of stannous chloride in 500mL of hydrochloric acid aqueous solution (250mL of hydrochloric acid is added into 250mL of water), stirring for 10min at 0 ℃, adding diazonium salt into the solution one by one under a stirring state, reacting for 8h, directly filtering after the reaction is finished, and drying at 80 ℃ to obtain 157g of intermediate 1.
2. Mixing 50g (0.21mol) of the intermediate 1, 68g (0.84mol) of sodium acetate and 54.26g (0.63mol) of 3-methyl-2-butanone, adding 800mL of acetic anhydride, heating at 150 ℃ for reaction for 8h, pouring the reaction liquid into petroleum ether after the reaction is finished, separating out solids, filtering, and drying the solids to obtain 45.8g of an intermediate 2.
3. Dissolving 10g (0.032mol) of intermediate 2 in 50mL (0.64mol) of 1, 4-butane sultone, reacting for 8h at 80 ℃, cooling the reaction after the reaction is finished, adding ethanol to dissolve reactants, and adding petroleum ether: in a mixed solution of 1:1 with ethyl ether, a solid was precipitated, and the solid was filtered to obtain 18g of intermediate 3.
4. Mixing 10g (0.032mol) of the intermediate 2 with 6.71g (0.032mol) of 6-bromohexanoic acid, adding 100mL of o-dichlorobenzene, reacting at 120 ℃ for 10h, cooling the reaction after the reaction is finished, adding a methanol dissolved product, adding the methanol dissolved product into petroleum ether to separate out a solid, and filtering the solid to obtain 11.6g of the intermediate 4.
5. 10g (0.022mol) of intermediate 4 and 12.7g (0.044mol) of glutarenal anilide hydrochloride are mixed and added into 50mL of acetic acid to react at 150 ℃ for 8h, after the reaction is finished, the reaction liquid is poured into methyl tert-butyl ether, after a supernatant is poured out, a solid is dissolved by a mixed liquid with a volume ratio of dichloromethane to methanol being 1:1, after the dissolution, the solid is dripped into the methyl tert-butyl ether to precipitate the solid, and 15.1g of intermediate 5 is obtained by filtration.
6. Dissolving 13.5g (0.021mol) of intermediate 5 and 10.6g (0.021mol) of intermediate 3 in 50mL of DMSO, adding 10mL of pyridine, reacting at room temperature for 12h, adding reaction liquid into methyl tert-butyl ether after the reaction is finished, dissolving precipitated solid in dichloromethane, purifying by column chromatography, preparing a developing agent by using dichloromethane in a volume ratio of 10:1 when the product passes through a column, adding water accounting for 1% of the volume of the developing agent, stirring and mixing uniformly to obtain a column-passing solvent, gradually increasing the proportion of methanol in the column-passing solvent according to the monitoring condition of a point plate, basically completing the product when the volume ratio of dichloromethane to methanol is increased to 4:1, and removing the solvent by reduced pressure distillation to obtain the water-soluble indocyanine green dye.
The nuclear magnetic hydrogen spectrum of the obtained water-soluble indocyanine green dye is shown in a figure 1:1H NMR(600MHz,MeOD)δ8.33(s,2H),8.18(d,J＝8.9Hz,2H),7.94(m,4H),7.55(m,3H),6.55(t,J＝12Hz,2H),6.26(d,J＝13.7Hz,2H),5.81-5.75(m,1H),4.10(t,J＝7.4Hz,4H),2.10(t,J＝7.1Hz,2H),1.88(s,12H),1.80-1.74(m,4H),1.61(m,4H),1.46-1.39(m,4H).
water solubility test experiment: putting 500mg of the prepared water-soluble indocyanine green dye into a clean 25mL pear-shaped bottle, adding 1mL of purified water, putting the pear-shaped bottle into an ultrasonic cleaning machine, carrying out ultrasonic treatment at room temperature for 1-2 min, completely dissolving the dye, and obtaining dark green clear liquid in the bottle, which shows that the indocyanine green dye prepared by the invention has good water solubility.
Claims (8)
1. A water-soluble indocyanine green dye for fluorescent labeling is characterized in that the structural formula of the water-soluble indocyanine green dye is as follows:
2. a method for synthesizing a water-soluble indocyanine green dye according to claim 1, which comprises the following steps:
(1) dissolving 6-aminonaphthalene-2-sulfonic acid in water, adding a sodium hydroxide aqueous solution, stirring for 10-15 minutes at 0 ℃, dropwise adding a sulfuric acid aqueous solution, continuing to stir at 0 ℃ after dropwise adding is finished, adding a sodium nitrite aqueous solution, stirring for 2-3 hours after adding is finished, filtering while the solution is cold to obtain diazonium salt, then adding the diazonium salt into a stannous chloride aqueous solution in hydrochloric acid at 0 ℃ under the stirring condition, reacting for 8-10 hours, and filtering to obtain a solid, namely an intermediate 1;
(2) adding the intermediate 1, sodium acetate and 3-methyl-2-butanone into acetic anhydride, reacting for 8-10 hours at 140-160 ℃, pouring reaction liquid into petroleum ether after the reaction is finished, separating out solids, filtering, and drying the solids to obtain an intermediate 2;
(3) dissolving the intermediate 2 with 1, 4-butane sultone, heating to 70-90 ℃ for reaction for 8-10 hours, adding into a mixed solution of petroleum ether and diethyl ether after the reaction is finished, separating out a solid, and filtering the solid to obtain an intermediate 3;
(4) adding the intermediate 2 and 6-bromohexanoic acid into o-dichlorobenzene, reacting at 110-130 ℃ for 8-12 hours, cooling after the reaction is finished, adding a methanol dissolved product, adding the methanol dissolved product into petroleum ether to separate out solids, and filtering the solids to obtain an intermediate 4;
(5) adding the intermediate 4 and glutaral aldehyde diphenylamine hydrochloride into acetic acid, heating to 140-160 ℃ for reaction for 10-15 hours, pouring reaction liquid into methyl tert-butyl ether after the reaction is finished, pouring out supernatant, dissolving solid by using mixed liquid of dichloromethane and methanol, dripping the dissolved solid into the methyl tert-butyl ether to separate out the solid, and filtering to obtain an intermediate 5;
(6) adding the intermediate 5 and the intermediate 3 into DMSO, adding pyridine, reacting at room temperature for 10-12 hours, adding a reaction solution into methyl tert-butyl ether after the reaction is finished, dissolving precipitated solid with dichloromethane, and purifying by column chromatography to obtain a water-soluble indocyanine green dye;
3. the process for the synthesis of a water-soluble indocyanine green dye according to claim 2, characterized in that: in the step (1), the 6-aminonaphthalene-2-sulfonic acid, sodium hydroxide and H2SO4The molar ratio of the sodium nitrite to the stannous chloride is 1: 2.5-4: 0.5-1: 2.5-4: 1.5-3.
4. The process for the synthesis of a water-soluble indocyanine green dye according to claim 2, characterized in that: in the step (2), the molar ratio of the intermediate 1 to sodium acetate to 3-methyl-2-butanone is 1: 3.5-5: 2.5-4.
5. The process for the synthesis of a water-soluble indocyanine green dye according to claim 2, characterized in that: in the step (3), the molar ratio of the intermediate 2 to the 1, 4-butane sultone is 1: 18-22.
6. The process for the synthesis of a water-soluble indocyanine green dye according to claim 2, characterized in that: in the step (4), the molar ratio of the intermediate 2 to the 6-bromohexanoic acid is 1: 1-1.5.
7. The process for the synthesis of a water-soluble indocyanine green dye according to claim 2, characterized in that: in the step (5), the molar ratio of the intermediate 4 to the glutarenal anilide hydrochloride is 1: 1.5-2.5.
8. The process for the synthesis of a water-soluble indocyanine green dye according to claim 2, characterized in that: in the step (6), the molar ratio of the intermediate 5 to the intermediate 3 to pyridine is 1: 1-1.5: 18-25.
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| CN115724787A (en) * | 2022-12-13 | 2023-03-03 | 沈阳思拓新材料技术有限公司 | Synthetic method of dye intermediate |
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