CN112876873A - Near-infrared two-region heptamethine cyanine dye and preparation method thereof - Google Patents

Near-infrared two-region heptamethine cyanine dye and preparation method thereof Download PDF

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CN112876873A
CN112876873A CN202110150077.7A CN202110150077A CN112876873A CN 112876873 A CN112876873 A CN 112876873A CN 202110150077 A CN202110150077 A CN 202110150077A CN 112876873 A CN112876873 A CN 112876873A
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闫立峰
钱红云
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University of Science and Technology of China USTC
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
    • C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
    • C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
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Abstract

The invention discloses a near-infrared two-region heptamethine cyanine dye QHS-Cy and a preparation method thereof, belonging to the field of organic dye synthesis. The near-infrared two-region heptamethine cyanine dye QHS-Cy prepared by the invention has the advantages that the ultraviolet absorption wavelength in dichloromethane is 983nm, the fluorescence emission wavelength is 1018nm, the light stability is good, the photo-thermal efficiency is high, the biological background fluorescence interference can be effectively avoided, the synthetic steps are short, and the near-infrared two-region heptamethine cyanine dye QHS-Cy has important significance in the aspect of application research of the heptamethine cyanine dye.

Description

Near-infrared two-region heptamethine cyanine dye and preparation method thereof
Technical Field
The invention relates to the technical field of organic dye synthesis, in particular to a near-infrared two-region heptamethine cyanine dye and a preparation method thereof.
Background
The near-infrared fluorescent dye has great application value in the aspects of analytical chemistry, life science, environmental science, optical materials and the like. In the fields of medicine and biology, a near-infrared fluorescent probe, particularly a near-infrared two-region fluorescent probe is a non-invasive detection method with good safety and high precision. The design and synthesis of novel near-infrared two-region fluorescent dyes have become a hot problem in recent years.
Although the heptamethine cyanine dye has the characteristics of long absorption wavelength, small background interference, small Raman scattering interference and the like, the heptamethine cyanine dye is easy to gather, low in quantum yield, complex in synthesis process and poor in stability.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a near-infrared two-region heptamethine cyanine dye and a preparation method thereof,
in order to achieve the purpose, the invention provides a near-infrared two-region heptamethine cyanine dye QHS-Cy which has a structure shown in a formula I:
Figure BDA0002931965110000011
in some embodiments of the invention, the near-infrared two-region heptamethine cyanine dye QHS-Cy has a structure represented by formula I-a:
Figure BDA0002931965110000021
the QHS-Cy prepared by the method has a symmetrical chemical structure, and is a purple to black solid in appearance. The method has the advantages of good light stability, high photo-thermal efficiency, short synthesis steps and great significance in the application research of the heptamethine cyanine dye, and can effectively avoid the interference of biological background fluorescence.
The invention also provides a preparation method of the near-infrared two-region heptamethine cyanine dye QHS-Cy, which comprises the following reaction route:
Figure BDA0002931965110000022
reacting a compound of formula I-1 with a compound of formula I-2 to obtain a compound of formula I-3; then reacting with a compound shown in a formula II-1 to obtain a compound shown in a formula II-2; then carrying out Grignard reaction with methyl magnesium chloride to obtain a compound shown in a formula III-2; then reacting with a compound shown in a formula IV-3 to obtain the near-infrared two-region heptamethine cyanine dye QHS-Cy.
Preferably, the preparation method comprises the following steps:
(1) dissolving 1, 8-naphthalimide and an alkaline compound shown in a formula (I-1) in an organic solvent, adding 1, 4-butyl sultone (shown in a formula I-2), reacting, cooling, adding acetone for crystallization to obtain a benzoindole derivative 1- (4-sulfonyl butyl) -1, 2-dihydrobenzoindole potassium salt (shown in a formula I-3);
(2) dissolving 1- (4-sulfonylbutyl) -1, 2-dihydrobenzazole potassium salt and tetrabutylammonium chloride (shown in a formula II-1) obtained in the step 1 in an organic solvent for reaction, adding dichloromethane to remove KCl, and performing rotary evaporation on the obtained product to obtain 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole tetrabutylammonium salt (shown in a formula II-2);
(3) dissolving the tetrabutylammonium 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole salt obtained in the step 2 and methyl magnesium chloride in tetrahydrofuran for reaction, adding hydrochloric acid after the reaction is finished to adjust the solution to be neutral, adding diethyl ether and ethanol for recrystallization to obtain 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indole inner salt (shown in a formula III-2);
(4) and (2) mixing the 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indole inner salt obtained in the step (3) and a solution of (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridine-1-onium (shown as a formula IV-3) in a closed environment for reaction to obtain the near-infrared two-region heptamethine cyanine dye QHS-Cy.
In the present invention, in the step 1, the molar ratio of the 1, 8-naphthoylimine to the basic compound is preferably 0.4 to 0.5: 1.
the mol ratio of the 1, 8-naphthalimide to the 1, 4-butanesultone is preferably 1.1-1.2: 1.
the basic compound is preferably KOH.
The organic solvent is preferably N-methylpyrrolidone.
The reaction temperature is preferably 60-100 ℃, and more preferably 80-90 ℃; the reaction time is preferably 5 to 60min, and more preferably 10 to 30 min.
In the preferred embodiment of the present invention, in the step (1), the 1, 8-naphthoylimine represented by the formula (I-1) and the basic compound are dissolved in an organic solvent, and after the reaction, 1, 4-butanesultone is added to carry out the reaction.
In the preferred embodiment of the present invention, in the step (2), the molar ratio of the 1- (4-sulfonylbutyl) -1, 2-dihydrobenzazole potassium salt to the tetrabutylammonium chloride is 1.1 to 1.2: 1.
the organic solvent is preferably acetic acid.
The reaction temperature is preferably 70-100 ℃, and more preferably 80-95 ℃; the reaction time is preferably 0.5-2 h, and more preferably 1-2 h.
Preferably, in the step (3), the molar ratio of the 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole tetrabutyl ammonium salt to the methyl magnesium chloride is 4-8: 1; more preferably 5: 1.
The reaction temperature is preferably 50-75 ℃, and more preferably 55-65 ℃; the reaction time is preferably 2-5 h, and more preferably 2-4 h.
Preferably, the reaction is carried out under a nitrogen atmosphere.
In a preferred embodiment of the present invention, the (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium is prepared by the following method:
a) dissolving 1-methyl-4-piperidone (shown in a formula IV-1) and methyl iodide in acetone for reaction, and recrystallizing the acetone to obtain an ammonium salt compound;
b) reacting DMF with POCl3Mixing and stirring, mixing with the ammonium salt compound, reacting the mixed solution, adding hydrochloric acid to adjust the pH of the solution after the reaction is finished, and then cooling and crystallizing the mixture solution to obtain a dark yellow solid (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridine-1-onium;
Figure BDA0002931965110000041
in the invention, the preferable molar ratio of the methyl iodide to the 1-methyl-4-piperidone is 2-2.2: 1;
the temperature of the reaction in step a) is preferably room temperature; the reaction time is preferably 2-5 h, and more preferably 3-4 h.
The DMF and POCl3The molar ratio of (A) to (B) is preferably 2-2.5: 1; more preferably 2: 1.
The DMF and POCl3The mixing and stirring temperature is preferably-5 ℃, and more preferably-5-0 ℃; while the mixing and stirring are carried outThe time is preferably 20-40 min.
The reaction temperature in the step b) is preferably 75-95 ℃, and more preferably 75-85 ℃; the reaction time is preferably 2-7 h, and more preferably 2-4 h.
The POCl3And (E) -4-chloro-5-formyl-3- (hydroxymethyl) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium in a molar ratio of 2-4: 1; more preferably 3: 1.
In the preferred embodiment of the present invention, in the step (4), the molar ratio of the 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indolium salt to the (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium is 2 to 5: 1; more preferably 3-4: 1; further preferably 4: 1.
The reaction temperature is preferably 60-80 ℃; more preferably 70 deg.c. The reaction time is preferably 8-24 hours; more preferably 12 hours.
Compared with the prior art, the invention provides a near-infrared two-region heptamethine cyanine dye QHS-Cy which has a structure shown in a formula I.
The invention has the following beneficial effects:
(1) the near-infrared two-region heptamethine cyanine dye QHS-Cy dye provided by the invention has the ultraviolet absorption wavelength of 983nm in dichloromethane and the fluorescence emission wavelength of 1018nm, so that the dye is more widely applied.
(2) The near-infrared two-region heptamethine cyanine dye QHS-Cy dye prepared by the invention has an emission spectrum in the near-infrared two region and has large Stokes shift (Stokes shift in dichloromethane is 35nm), and the dye has the most obvious characteristics of strong absorption in the near-infrared two region and excellent penetrability to biological tissues.
(3) The near-infrared two-region heptamethine cyanine dye QHS-Cy dye prepared by the invention has good light stability and high molar extinction coefficient, and can effectively avoid biological background fluorescence interference; the fluorescent material can emit near-infrared fluorescence with the maximum wavelength of 980-1020nm in organic solvents such as dichloromethane, methanol and DMF, has mild synthesis conditions and higher yield, and provides good application prospects for the fields of biomolecular labeling, solar cells, fluorescence imaging and the like.
Drawings
FIG. 1 shows the UV spectrum of the heptamethine cyanine dye QHS-Cy prepared in example 1 of the present invention in dichloromethane;
FIG. 2 is a fluorescence spectrum of a heptamethine cyanine dye QHS-Cy prepared in example 1 of the present invention in dichloromethane;
FIG. 3 shows the penetration depth of the heptamethine cyanine dye QHS-Cy prepared by the present invention under 915nm excitation light under different thicknesses of chicken breast tissue;
FIG. 4 shows the photostability of the heptamethine cyanine dye QHS-Cy prepared in the example of the present invention in methanol solution at room temperature under natural light;
FIG. 5 shows the absorption spectra and standard curves of the heptamethine cyanine dye QHS-Cy prepared in the example of the present invention in methanol solution at different concentrations.
Detailed Description
In order to further illustrate the present invention, the near infrared two-region heptamethine cyanine dye and the preparation method thereof provided by the present invention are described in detail below with reference to the examples.
Example 1
(1) 0.85 g of 1, 8-naphthalimide and 0.56 g of KOH are weighed into a 100 ml flask, 10 ml of N-methylpyrrolidone is added, the mixture is stirred for 30min at 90 ℃, then 0.75 g of 1, 4-butyl sultone is weighed into the mixture, the mixture is stirred for 10h at 90 ℃, after the reaction is finished, the mixture is cooled, 35 ml of acetone is added, and yellow solid is precipitated. Filtering, adding acetone into the filter cake, washing for 3 times, and vacuum drying to obtain pure and pure 1- (4-sulfonyl butyl) -1, 2-dihydrobenzazole potassium salt of the benzazole derivative with the yield of 90%.
(2) 1.5 g of 1- (4-sulfonylbutyl) -1, 2-dihydrobenzazole potassium salt obtained in step 1 and 1.51 g of tetrabutylammonium chloride were weighed out and dissolved in 8 ml of acetic acid, stirred at 90 ℃ for 1 hour, after the reaction was completed, dichloromethane was added dropwise thereto, the precipitate was removed by filtration, and the obtained solvent was concentrated by rotary evaporation to obtain 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole tetrabutylammonium salt with a yield of 94%.
(3) 2.5 g of tetrabutylammonium 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole salt obtained in step 2 are weighed out, 7.5 ml of methylmagnesium chloride are dissolved in 20 ml of tetrahydrofuran in a measuring cylinder and stirred for 3h at 60 ℃ under nitrogen. After the reaction, hydrochloric acid was added to adjust the solution to neutrality, 15 ml of diethyl ether and 15 ml of ethanol were added, and the mixture was cooled at 0 ℃ overnight to be recrystallized to obtain 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indolium salt with a yield of 85%.
(4) Weighing 5 g of 1-methyl-4-piperidone and dissolving in 70 ml of acetone, cooling the mixed solution to 0 ℃, dropwise adding 6 ml of methyl iodide under the condition of ice-water bath, stirring the mixture at room temperature for 4h, filtering to obtain white precipitate after the reaction is finished, drying to obtain an ammonium salt compound, measuring 9 ml of DMF by using a measuring cylinder, and dropwise adding 5.5 ml of POCl at 0 DEG3The reaction was stirred at 0 ℃ for 30min, 5 g of ammonium salt compound was added, the mixture was stirred at 80 ℃ for 3h, after cooling, 30 ml of a 20% by volume hydrochloric acid solution was added dropwise to adjust the pH, the mixture was placed in a refrigerator at-20 ℃ to cool and crystallize, after sufficient crystallization, the yellow to black precipitate (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium was obtained by suction filtration in a yield of 72%.
(5) 606 mg of the 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indolium salt obtained in step (3) and 202 mg of the (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium salt obtained in step (4) were dissolved in 40 ml of acetic anhydride and reacted at 65 ℃ for 12 hours, after completion of the reaction, the solvent was evaporated, and the product was purified by column chromatography (dichloromethane: methanol ═ 8: 1), to obtain a pure near-infrared di-regio heptamethine cyanine dye QHS-Cy dye in a yield of 42%.
As shown in FIG. 1 and FIG. 2, the near-infrared two-region heptamethine cyanine dye QHS-Cy dye prepared in this example has a maximum ultraviolet absorption peak wavelength of 983nm in dichloromethane, and a maximum fluorescence emission wavelength of 1018 nm.
Example 2
(1) 0.68 g of 1, 8-naphthalimide and 0.56 g of KOH are weighed into a 100 ml flask, 10 ml of N-methylpyrrolidone is added, the mixture is stirred for 30min at 90 ℃, then 0.82 g of 1, 4-butyl sultone is weighed into the mixture, the mixture is stirred for 10h at 90 ℃, after the reaction is finished, the mixture is cooled, 35 ml of acetone is added, and yellow solid is precipitated. Filtering, adding acetone into the filter cake, washing for 3 times, and vacuum drying to obtain pure and pure 1- (4-sulfonyl butyl) -1, 2-dihydrobenzazole potassium salt of the benzazole derivative with the yield of 95%.
(2) 1.5 g of 1- (4-sulfonylbutyl) -1, 2-dihydrobenzazole potassium salt obtained in step 1 and 1.64 g of tetrabutylammonium chloride were weighed out and dissolved in 8 ml of acetic acid, stirred at 90 ℃ for 1 hour, after the reaction was completed, dichloromethane was added dropwise thereto, the precipitate was removed by filtration, and the obtained solvent was concentrated by rotary evaporation to obtain 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole tetrabutylammonium salt with a yield of 95%.
(3) 2.5 g of tetrabutylammonium 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole salt obtained in step 2 are weighed out, 6 ml of methylmagnesium chloride are dissolved in 20 ml of tetrahydrofuran in a measuring cylinder and stirred for 3h at 60 ℃ under nitrogen. After the reaction, the solution was neutralized by adding hydrochloric acid, and then 15 ml of diethyl ether and 15 ml of ethanol were added, and the mixture was cooled at 0 ℃ overnight to recrystallize to obtain 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indolium salt with a yield of 87%.
(4) Weighing 5 g of 1-methyl-4-piperidone and dissolving in 70 ml of acetone, cooling the mixed solution to 0 ℃, dropwise adding 6 ml of methyl iodide under the condition of ice-water bath, stirring the mixture at room temperature for 4h, filtering to obtain white precipitate after the reaction is finished, drying to obtain an ammonium salt compound, measuring 12 ml of DMF by using a measuring cylinder, and dropwise adding 5.5 ml of POCl at 0 DEG3The reaction was stirred at 0 ℃ for 30min, 5 g of ammonium salt compound was added, the mixture was stirred at 80 ℃ for 3h, after cooling, 30 ml of a 20% by volume hydrochloric acid solution was added dropwise to adjust the pH, the mixture was placed in a refrigerator at-20 ℃ to cool and crystallize, after sufficient crystallization, the yellow to black precipitate (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium was obtained by suction filtration in a yield of 72%.
(5) 606 mg of 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indolium salt obtained in step (3) and 150 mg of (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium obtained in step (4) were dissolved in 40 ml of acetic anhydride and reacted at 65 ℃ for 12 hours, after completion of the reaction, the solvent was evaporated, and the product was purified by column chromatography (dichloromethane: methanol ═ 8: 1), to obtain a pure near-infrared di-regio heptamethine cyanine dye QHS-Cy dye with a yield of 60%.
Example 3
(1) 0.75 g of 1, 8-naphthalimide and 0.56 g of KOH are weighed into a 100 ml flask, 10 ml of N-methylpyrrolidone is added, the mixture is stirred for 30min at 90 ℃, then 0.75 g of 1, 4-butyl sultone is weighed into the mixture, the mixture is stirred for 10h at 90 ℃, after the reaction is finished, the mixture is cooled, 35 ml of acetone is added, and yellow solid is precipitated. Filtering, adding acetone into the filter cake, washing for 3 times, and vacuum drying to obtain pure 1- (4-sulfonyl butyl) -1, 2-dihydrobenzazole potassium salt of the benzazole derivative with the yield of 92%.
(2) 1.5 g of 1- (4-sulfonylbutyl) -1, 2-dihydrobenzazole potassium salt obtained in step 1 and 1.55 g of tetrabutylammonium chloride were weighed out and dissolved in 8 ml of acetic acid, stirred at 90 ℃ for 1 hour, after the reaction was completed, dichloromethane was added dropwise thereto, the precipitate was removed by filtration, and the obtained solvent was concentrated by rotary evaporation to obtain 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole tetrabutylammonium salt with a yield of 93%.
(3) 2.5 g of tetrabutylammonium 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole salt obtained in step 2 are weighed out, 5 ml of methylmagnesium chloride are dissolved in 20 ml of tetrahydrofuran in a measuring cylinder and stirred for 3h at 60 ℃ under nitrogen. After the reaction, hydrochloric acid was added to adjust the solution to neutrality, 15 ml of diethyl ether and 15 ml of ethanol were added, and the mixture was cooled at 0 ℃ overnight to be recrystallized to obtain 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indolium salt with a yield of 85%.
(4) Weighing 5 g of 1-methyl-4-piperidone, dissolving in 70 ml of acetone, cooling the mixed solution to 0 ℃, dropwise adding 6 ml of methyl iodide under the condition of ice-water bath, stirring the mixture at room temperature for 4 hours, filtering to obtain white precipitate after the reaction is finished, drying to obtain an ammonium salt compound, measuring 1 by using a measuring cylinder, and obtaining the ammonium salt compound0 ml of DMF, 5.5 ml of POCl was added dropwise at 0 deg.C3The reaction was stirred at 0 ℃ for 30min, 5 g of ammonium salt compound was added, the mixture was stirred at 80 ℃ for 3h, after cooling, 30 ml of a 20% by volume hydrochloric acid solution was added dropwise to adjust the pH, the mixture was placed in a refrigerator at-20 ℃ to cool and crystallize, after sufficient crystallization, yellow to black precipitate (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium was obtained by suction filtration in 74% yield.
(5) 606 mg of 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indolium salt obtained in step (3) and 100 mg of (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium obtained in step (4) were dissolved in 40 ml of acetic anhydride and reacted at 65 ℃ for 12 hours, after completion of the reaction, the solvent was evaporated, and the product was purified by column chromatography (dichloromethane: methanol ═ 8: 1), to obtain a pure near-infrared dicarballylcyanine dye QHS-Cy dye in 52% yield.
Example 4 fluorescent penetration depth test of Probe QHS-Cy into biological tissue
The probe QHS-Cy prepared in example 3 was dissolved in analytically pure Dichloromethane (DCM), 500. mu.L of the probe was sealed in a 1cm long tube, placed in sequence under the chicken breast with a thickness of 0, 1,2,3, 4, 5, 6mm, excited with a laser of 915nm, and recorded as an image under a filter of 1000LP, 1100LP, 1200LP, as shown in FIG. 3, in a section with a wavelength greater than 1000nm, when the thickness of the chicken breast reached 6mm, an NIR-II signal was still obtained, indicating that the biological tissue penetration of QHS-Cy was strong.
EXAMPLE 5 stability test of Probe QHS-Cy
The probe QHS-Cy prepared in example 3 was dissolved in analytically pure methanol (MeOH) and stored for 20 days at room temperature under natural light storage conditions, and the change in absorbance of the probe was measured at intervals. As shown in FIG. 4, the absorbance of the probe was substantially maintained for 20 days, indicating that the stability of the probe was good.
EXAMPLE 6 molar absorptivity test of Probe QHS-Cy
2mg of the probe QHS-Cy prepared in example 3 was dissolved in analytically pure AStock solutions were prepared in alcohol (MeOH), then diluted to solutions of 20, 15, 10, 5, 2.5 μ g/mL, respectively, and the absorbance of the solutions at the maximum absorption wavelength was measured and recorded, respectively, as shown in fig. 5, by the molar absorption coefficient formula a ═ lg (I) as shown in fig. 50Calculated as the molar absorption coefficient of the dye in methanol was 34354L mol-1*cm-1。
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (9)

1. A near-infrared two-region heptamethine cyanine dye QHS-Cy has a structure shown in formula I:
Figure FDA0002931965100000011
2. the method for preparing the near-infrared two-region heptamethine cyanine dye QHS-Cy as claimed in claim 1, which comprises the following reaction route:
Figure FDA0002931965100000012
3. the method of claim 2, comprising the steps of:
(1) dissolving 1, 8-naphthalimide and an alkaline compound shown in a formula (I-1) in an organic solvent, adding 1, 4-butyl sultone (shown in a formula I-2), reacting, cooling, adding acetone for crystallization to obtain a benzoindole derivative 1- (4-sulfonyl butyl) -1, 2-dihydrobenzoindole potassium salt (shown in a formula I-3);
(2) dissolving 1- (4-sulfonylbutyl) -1, 2-dihydrobenzazole potassium salt and tetrabutylammonium chloride (shown in a formula II-1) obtained in the step 1 in an organic solvent for reaction, adding dichloromethane to remove KCl, and performing rotary evaporation on the obtained product to obtain 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole tetrabutylammonium salt (shown in a formula II-2);
(3) dissolving the tetrabutylammonium 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole salt obtained in the step 2 and methyl magnesium chloride in tetrahydrofuran for reaction, adding hydrochloric acid after the reaction is finished to adjust the solution to be neutral, adding diethyl ether and ethanol for recrystallization to obtain 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indole inner salt (shown in a formula III-2);
(4) and (2) mixing the 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indole inner salt obtained in the step (3) and a solution of (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridine-1-onium (shown as a formula IV-3) in a closed environment for reaction to obtain the near-infrared two-region heptamethine cyanine dye QHS-Cy.
4. The method according to claim 3, wherein in the step (1), the molar ratio of the 1, 8-naphthoylimide to the basic compound is 0.4 to 0.5: 1;
the molar ratio of the 1, 8-naphthalimide to the 1, 4-butanesultone is 1.1-1.2: 1;
the alkaline compound is KOH;
the organic solvent is N-methyl pyrrolidone;
the reaction temperature is 60-100 ℃; the reaction time is 5-60 min.
5. The preparation method according to claim 3, wherein in the step (2), the molar ratio of the 1- (4-sulfonylbutyl) -1, 2-dihydrobenzazole potassium salt to the tetrabutylammonium chloride is 1.1-1.2: 1;
the organic solvent is acetic acid;
the reaction temperature is 70-100 ℃; the reaction time is 0.5-2 h.
6. The method according to claim 3, wherein in the step (3), the molar ratio of the tetrabutylammonium 1- (4-sulfonylbutyl) -1, 2-dihydrobenzo [ c, d ] indole salt to the methylmagnesium chloride is 4-8: 1;
the reaction temperature is 50-75 ℃; the reaction time is 2-5 h;
the reaction was carried out under nitrogen atmosphere.
7. The process according to claim 3, wherein the (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium is produced by:
a) dissolving 1-methyl-4-piperidone (shown in a formula IV-1) and methyl iodide in acetone for reaction, and recrystallizing the acetone to obtain an ammonium salt compound (shown in a formula IV-2);
b) reacting DMF with POCl3Mixing and stirring, mixing with the ammonium salt compound, reacting the mixed solution, adding hydrochloric acid to adjust the pH of the solution after the reaction is finished, and then cooling and crystallizing the mixture solution to obtain a dark yellow solid (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridine-1-onium;
Figure FDA0002931965100000031
8. the method according to claim 7, wherein the molar ratio of methyl iodide to 1-methyl-4-piperidone is 2-2.2: 1;
the temperature of the reaction in the step a) is room temperature; the reaction time is 2-5 h;
the DMF and POCl3The molar ratio of (A) to (B) is 2-2.5: 1;
the DMF and POCl3The mixing and stirring temperature is-5 to 5 ℃; the mixing and stirring time is 20-40 min;
the reaction temperature in the step b) is 75-95 ℃; the reaction time is 2-7 h;
the POCl3And (E) -4-chloro-5-formyl-3- (hydroxymethyl) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium in a molar ratio of 2-4: 1.
9. the method according to claim 3, wherein in the step (4), the molar ratio of the 1- (4-sulfonylbutyl) -2-methylbenzo [ c, d ] indolium salt to the (E) -4-chloro-5-formyl-3- (hydroxymethylene) -1, 1-dimethyl-1, 2,3, 6-tetrahydropyridin-1-ium is 2 to 5: 1;
the reaction temperature is 60-80 ℃; the reaction time is 8-24 hours.
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CN108440986A (en) * 2018-03-06 2018-08-24 复旦大学 The fluorescent dye and its preparation method and application of near-infrared the second window excitation/emission
CN110003103A (en) * 2019-03-28 2019-07-12 南通大学 A kind of two area side's acid quinoline dye of near-infrared and preparation method thereof
CN110041723A (en) * 2019-04-22 2019-07-23 复旦大学 The fluorescent dye and preparation method thereof of near-infrared the second window excitation/emission
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Publication number Priority date Publication date Assignee Title
CN108440986A (en) * 2018-03-06 2018-08-24 复旦大学 The fluorescent dye and its preparation method and application of near-infrared the second window excitation/emission
CN110003103A (en) * 2019-03-28 2019-07-12 南通大学 A kind of two area side's acid quinoline dye of near-infrared and preparation method thereof
CN110041723A (en) * 2019-04-22 2019-07-23 复旦大学 The fluorescent dye and preparation method thereof of near-infrared the second window excitation/emission
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