CN111849196B - Near-infrared two-region dye and synthetic method thereof - Google Patents
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Abstract
The invention discloses a novel near-infrared two-region organic fluorescent dye and a synthesis method thereof, the structural formula of the dye is shown as a formula I,
the invention provides a novel fluorescent dye based on a structural formula I and a synthesis method thereof for the first time, the emission wavelength of the dye reaches a near-infrared two-region, and the dye has the advantages of excellent chemical stability, light stability, better anti-solvation quenching capability, larger Stokes shift and the like, and the dye has adjustable sites, thereby providing a new platform for the design of a fluorescent probe emitted in the near-infrared two-region.
Description
Technical Field
The invention belongs to the technical field of fluorescence imaging, and particularly relates to a near-infrared two-region organic fluorescent dye and a synthetic method thereof.
Background
Fluorescence imaging has been widely used to study biological systems due to its non-invasiveness, excellent sensitivity, and exceptional ability to visualize invisible structures or processes. Therefore, fluorescence imaging in combination with appropriate molecular probes has become a convenient and powerful tool for detecting biologically relevant species. In order to meet the increasing demand for fluorescent probes, various fluorophores with unique photophysical properties have been developed in succession in recent years. Fluorescence imaging in the second near infrared (NIR-II, 900-1700nm) window has unique advantages over visible (400-700nm) and first near infrared (NIR-I, 700-900nm) fluorescence imaging, such as reduced background autofluorescence, reduced photon scattering and deeper penetration, which makes it possible to image tissue at cm depths and achieve micron-scale resolution at mm depths, and therefore NIR-II imaging has received increasing attention in the past decade. Unfortunately, most of the current NIR-II organic dyes have poor brightness, poor stability and quenching phenomena due to solvent lyotropic discoloration, resulting in poor signal to noise ratio and spurious signal distortions in biological systems. In addition, the uncontrolled fluorescence of current NIR-II organic dyes further hinders their biological applications. Therefore, the development of the near-infrared two-region fluorescent dye with excellent luminous performance and adjustable sites has great significance.
Disclosure of Invention
The invention aims to provide a near-infrared two-region dye with high brightness, high stability and controllable fluorescence and a synthetic method thereof
The structural general formula of the NIR-II fluorescent dye is shown as the formula I:
wherein: m and n have values of 1,2 or 3; r1And R2One of alkyl groups from H, C1 to 20; r3Is one of H, alkyl, substituted alkyl, aryl and substituted aryl; r4Is one of H, alkyl, substituted alkyl, cycloalkyl and aryl.
Preferably, the NIR-II fluorescent dye has one of the structural general formulas II or III:
the preparation method of the NIR-II fluorescent dye comprises the following steps:
dissolving the intermediate c, alkali and the intermediate d in an organic solvent, then reacting at a set temperature, adding water for suction filtration after the reaction is finished, and separating and purifying the obtained substance by column chromatography to obtain the novel near-infrared two-region dye (I);
the synthetic route is as follows:
the molar ratio of the intermediate c to the intermediate d is (0.5-1.5) to (0.5-1.5), the molar ratio of the intermediate c to the alkali is 1 (1.5-2), and the molar volume ratio of the intermediate c to the organic solvent is 1 (4-15) mol/L; the alkali is one of potassium acetate and potassium carbonate, the organic solvent is acetic anhydride, the set temperature is 110-130 ℃, and the reaction time is 2-3 h; n is 1,2 or 3, n1＝n-1。
A method for synthesizing an intermediate c, comprising the following steps:
dissolving a compound a and a compound b in acetonitrile, reacting at a set temperature, concentrating after the reaction is finished, and separating by using column chromatography to obtain an intermediate c;
the synthetic route is as follows:
the molar ratio of the compound a to the compound b is 1 (1.5-2), and the molar ratio of the compound a to acetonitrile is 1 (1.2-2.5) mol/L; the set temperature is 70-90 ℃, and the reaction time is 3-6 h.
A method for synthesizing an intermediate D, comprising the steps of:
1) dissolving 4-methoxy o-phenylenediamine and 1, 2-cyclohexanedione in ethanol, reacting at a set temperature, concentrating after the reaction is finished, and separating by using column chromatography to obtain a light yellow solid compound 1;
2) dissolving the compound 1 in the step 1) and sodium borohydride in toluene, and dropwise adding R in an ice bath environment4-COOH, stirring in an ice bath after the dropwise addition is finished, and then continuing the reaction at the set temperature; after the reaction, water was added to quench the reaction, extracted with ethyl acetate, and the resulting organic phase was concentrated and separated by column chromatography to obtain brownCompound 2 in a yellow viscous state;
3) dissolving the compound 2 and the 1-phenyl-1, 3-butanedione in the step 2) in methanesulfonic acid, stirring for reaction at a set temperature, pouring the reaction liquid into ice water after the reaction is finished, adding inorganic acid while stirring to separate out a solid, and further purifying the solid obtained after filtering by using column chromatography to obtain a red-black solid intermediate d;
the synthetic route is as follows:
in the step (1), the molar ratio of 4-methoxy o-phenylenediamine to 1, 2-cyclohexanedione is 1 (0.4-1.5); the molar volume ratio of the 4-methoxy o-phenylenediamine to the ethanol is 3 (7-25) mol/L; the set temperature is 50-70 ℃, and the reaction time is 2-4 h.
In the step (2), the compound 1 and R4The molar volume ratio of-COOH is 5 (8-12) mol/L, and the molar volume ratio of the compound 1 to toluene is 1 (2.5-3.0) mol/L; the stirring time is 0.5-2 h, the set temperature is 100-120 ℃, and the continuous reaction time is 8-24 h.
In the step (3), the molar ratio of the compound 2 to the 1-phenyl-1, 3-butanedione is 1 (1-2); the molar volume ratio of the compound 2 to the methanesulfonic acid is 1 (10-25) mol/L; the inorganic acid is one of sulfuric acid, methanesulfonic acid, perchloric acid and p-toluenesulfonic acid.
In the steps (1) - (3), the stationary phase used for the column chromatography is preferably 100-200 mesh silica gel; the mobile phase of the column chromatography used for separating and purifying the compound 1 and the compound 2 is a petroleum ether-dichloromethane mixed solution, and the volume ratio is (1-30): 1; the mobile phase of the column chromatography used for separating and purifying the intermediate d is a dichloromethane-ethanol mixed solution, and the volume ratio is (20-200): 1.
The invention has the beneficial effects that the novel fluorescent dye based on the structural formula I and the synthesis method thereof are provided for the first time, the emission wavelength of the dye reaches a near-infrared two-region, and the dye has the advantages of stronger tissue penetration depth, better anti-scattering capability, larger Stokes shift and the like, has adjustable sites, and provides a new platform for the design of a fluorescent probe emitted in the near-infrared two-region.
Drawings
FIG. 1 is a mass spectrum of the near infrared two-region dye NIRII-RT1 of example I;
FIG. 2 is a NMR spectrum of a near infrared two-region dye NIRII-RT1 according to example I;
FIG. 3 is a mass spectrum of the near infrared two-region dye NIRII-RT2 of example II;
FIG. 4 is a NMR spectrum of a near infrared two-region dye NIRII-RT2 of example II;
FIG. 5 shows an absorption/emission spectrum (a) and a solvent effect study (b) of the near infrared two-region dye NIRII-RT2 in example II;
FIG. 6 shows a stability study of the near infrared two-region dye NIRII-RT2 of example two; (a) chemical stability; (b) and (3) light stability.
Detailed Description
The synthesis route of the novel near infrared two-region dye NIRII-RT1 with m being 1 and n being 1:
(1) intermediate c1The preparation of (1):
reacting the compound a1With compounds b1Dissolving in acetonitrile, reacting for 3-6h at 70-90 ℃ under stirring, concentrating to remove the solvent after the reaction is finished, and separating by using column chromatography to obtain an intermediate c1。
Wherein, the structure of the related compound is shown as a synthetic route, R1R2 and R3 are independently selected from hydrogen atom, unsubstituted alkyl, phenyl substituted alkyl or alkane sulfonic group. Compound a1With compounds b1The molar ratio of (a) to (b) is 1 (1.5-2), and the compound a1The mol ratio of the acetonitrile to the acetonitrile is 1 (1.2-2.5) mol/L.
(2) Preparation of dye:
reacting the intermediate c1Dissolving the alkali and the intermediate d in an organic solvent, wherein the used alkali can be organic and inorganic alkali such as potassium acetate, potassium carbonate and the like, the organic solvent is preferably acetic anhydride, the reaction temperature is 110-130 ℃, water is added for suction filtration after 2-3 h of reaction, and the obtained solid is separated and purified by column chromatography to obtain the novel near-infrared two-region dye NIRII-RT 1.
Wherein the structure of the related compound is shown as a synthetic route, R4Is one of H, alkyl, substituted alkyl, cycloalkyl, aryl and the like, and an intermediate c1The molar ratio of the intermediate to the intermediate d is 1:1, the molar ratio of the intermediate c to the base is 1: 1.5-2, and the intermediate c1The mol volume ratio of the organic solvent to the organic solvent is 1 (4-15) mol/L.
The synthesis route of the novel near infrared two-region dye NIRII-RT2 is that m is 2 and n is 1:
(1) intermediate c2The preparation of (1):
reacting the compound a2With compounds b1Dissolving in acetonitrile, reacting at 70-90 ℃ for 3-6h, concentrating after the reaction is finished, and separating by using column chromatography to obtain an intermediate c2。
The structure of the related compound is shown in a synthetic route, and R1, R2 and R3 are respectively and independently selected from a hydrogen atom, unsubstituted alkyl, phenyl substituted alkyl or alkane sulfonic group. Compound a2With compounds b1The molar ratio of (a) to (b) is 1 (1.5-2), and the compound a2The mol ratio of the acetonitrile to the acetonitrile is 1 (1.2-2.5) mol/L.
(2) Preparation of dye:
and dissolving the intermediate c2, alkali and the intermediate d in an organic solvent, wherein the used alkali can be potassium acetate, potassium carbonate organic and inorganic alkali, the organic solvent is preferably acetic anhydride, the reaction temperature is 110-130 ℃, the reaction time is 2-3 h, water is added for suction filtration after the reaction is finished, and the obtained substance is separated and purified by column chromatography to obtain the target compound.
Wherein the structure of the related compound is shown as a synthetic route, R4Is one of H, alkyl, substituted alkyl, cycloalkyl, aryl and the like, and an intermediate c2The molar ratio of the intermediate d to the intermediate d is 1:1, the molar ratio of the intermediate c to the potassium acetate is 1: 1.5-2, and the molar ratio of the intermediate c2 to the acetic anhydride is 1 (4-15) mol/L.
Example 1: synthesis of a novel near-infrared two-region dye, NIRII-RT1 (m 1, n 1, R)1，R2，R4Are all ethyl radicals, R3Is H)
(1) Synthesis of intermediate C
After dissolving compound a (3.62g, 0.01mol) and compound B (3.92g, 0.02mol) in acetonitrile (20ml), heating to 90 ℃ and stirring, reacting for 3 hours, concentrating the reaction solution to remove the solvent, and performing column chromatography using a polar condition of 20:1 in dichloromethane/ethanol to obtain 2.5g of the target intermediate C.
(2) Synthesis of intermediate D
Weighing 4-methoxy o-phenylenediamine (4.38g, 35.0mmol) and 1, 2-cyclohexanedione (2.24g, 20.0mmol), dissolving the two in 100mL ethanol, stirring at 60 ℃ for 4h, and separating and purifying by silica gel column chromatography (eluent is petroleum ether and dichloromethane with the volume ratio of 1:1) to obtain 3g (7-methoxy-1, 2,3, 4-tetrahydrophenazine) of a light yellow solid compound; dissolving a compound 1(1.4g, 6.5mmol) in 150mL of anhydrous toluene, adding sodium borohydride (3.8g, 100.0mmol) in an ice bath environment, stirring for 30min, slowly dropwise adding 12mL of glacial acetic acid into the reaction solution in batches, maintaining the ice bath for reaction for 30min after the glacial acetic acid is completely dripped, heating the reaction solution to 110 ℃, reacting for 8h under a reflux condition, slowly adding 200mL of water to quench redundant sodium borohydride after the reaction is completed, extracting the mixed solution with ethyl acetate, washing an organic phase with a saturated sodium carbonate solution, drying with anhydrous sodium sulfate, concentrating, separating and purifying by silica gel column chromatography (an eluent is petroleum ether and dichloromethane with a volume ratio of 7:3) to obtain a brown yellow viscous liquid compound 2(750mg) (5, 10-diethyl-7-methoxy-1, 2,3,4,4 a), 5,10,10 a-octahydrophenazine). Compound 2(54.8mg, 0.2mmol) and 1-phenyl-1, 3-butanedione (48.6mg, 0.3mmol) were dissolved in 4mL of methanesulfonic acid and stirred at 90 ℃ for 4h, after the reaction was stopped, the reaction solution was poured into crushed ice, 1mL of perchloric acid was slowly added with stirring to precipitate a solid, which was filtered with suction and washed 3 times with 20mL of petroleum ether, and the solid was separated and purified by silica gel column chromatography (eluent: dichloromethane: ethanol ═ 20:1, v/v) to give intermediate D as a blackish red solid.
(3) NIRII-RT1 Synthesis of Compounds
Intermediate C (1.5g, 3mmol) and Compound D (1.2g, 3mmol), potassium acetate (0.6g, 6mmol) were dissolved in acetic anhydride (15mL), stirred and heated to 130 ℃. After reacting for 3 hours, pouring the reaction solution into a beaker filled with 300mL of water, and performing suction filtration, wherein the stationary phase in column chromatography is silica gel, and the mobile phase is dichloromethane to dichloromethane: and (3) carrying out polar gradient elution with ethanol of 20:1 to obtain a dark green solid product of 500mg, namely the target compound NIRII-RT1, and characterizing the obtained target compound by mass spectrum (figure 1) and nuclear magnetic characterization (figure 2), wherein a characteristic absorption peak is completely consistent with the structural formula of NIRII-RT 1.
Example 2: synthesis of novel near infrared two-region dye NIRII-RT2 (m 2, n 1, R)1，R2，R4Are all ethyl radicals, R3H) and study of luminescence properties
(1) Synthesis of intermediate C2
After compound a2(3.76g, 0.01mol) and compound B (3.92g, 0.02mol) were dissolved in acetonitrile (25ml), stirred and heated to 90 ℃ for reaction for 3 hours, the solvent was distilled off from the reaction mixture under reduced pressure, and the target intermediate 2.8g was obtained by column chromatography using a polar condition of 20:1 dichloromethane to ethanol.
(2) NIRII-RT2 Synthesis of Compounds
Intermediate C2(1g, 2mmol) and Compound D (0.8g, 2mmol), potassium acetate (0.4g, 4mmol) were dissolved in acetic anhydride (10mL), stirred and heated to 130 ℃. After reacting for 3 hours, pouring the reaction solution into a beaker filled with 250ml of water, and performing suction filtration, wherein the stationary phase in column chromatography is silica gel, and the mobile phase is dichloromethane to dichloromethane: and (3) carrying out polar gradient elution with ethanol of 20:1 to obtain a solid product which is 300mg of dark green, namely the target compound NIRII-RT2, wherein the mass spectrum and nuclear magnetic characterization diagrams are shown in figures 3 and 4, and the characteristic absorption peaks in figures 3 and 4 are completely consistent with the structural formula of the target compound NIRII-RT 2.
(3) Absorption and emission spectra of the NIRII-RT2 dye
FIG. 5 shows a plot of absorption versus emission spectra for the NIRII-RT2 dye. When in test, the dye NIRII-RT2 is dissolved in dichloromethane, a solution with the dye concentration of 5uM is prepared, the absorption wavelength of the solution is measured to be 856nm, and the solution is excited by a laser with the wavelength of 808nm, as shown in figure 5, the emission wavelength of the NIRII-RT2 dye is 929/989nm, and the Stokes shift value of the dye is 62/139 nm.
(4) Stability Studies of the NIRII-RT2 dye
NIRII-RT2 was dissolved in PBS buffer (10mM, pH 7.4, containing 20% organic solvent and 1% tween) to make a solution at a concentration of 5 μ M, followed by addition of various bioactive molecules (e.g., ONOO)-,5μM；HOCl,50μM；H2O2,100μM；H2S,100 mu M; GSH,1 mM; cys,100 μ M) whose absorption spectrum was tested and compared with the commercial NIR-II dyes ICG and IR1061, the results of which are shown in fig. 6 a. The experimental results show that the NIRII-RT2 dye has better chemical stability than the commercial dye, and is helpful for accurate imaging analysis in organisms. In addition, photostability experiments showed that the NIRII-RT2 dye also showed better photostability than the commercial NIR-II dyes ICG and IR1061 at the same laser power (fig. 6b), indicating its ability to image NIR-II better for long periods of time.
Claims (10)
1. A near-infrared two-region dye is characterized in that the structural general formula is shown as formula I:
Ⅰ
wherein: m is 1 or 2; n is 1; r1、R2And R4Is ethyl; r3Is H.
2. A near-infrared two-region dye according to claim 1, having one of the general structural formulae ii or iii:
3. the method of preparing a near-infrared two-region dye according to claim 1, comprising the steps of:
dissolving the intermediate c, alkali and the intermediate d in an organic solvent, then reacting at a set temperature, adding water for suction filtration after the reaction is finished, and separating and purifying the obtained substance by using column chromatography to obtain the near-infrared two-zone dye;
the synthetic route is as follows:
4. the method for preparing the near-infrared two-region dye according to claim 3, wherein the molar ratio of the intermediate c to the intermediate d is (0.5-1.5) - (0.5-1.5), the molar ratio of the intermediate c to the base is 1 (1.5-2), and the molar volume ratio of the intermediate c to the organic solvent is 1 (4-15) mol/L; the alkali is one of potassium acetate and potassium carbonate, the organic solvent is acetic anhydride, the set temperature is 110-130 ℃, and the reaction time is 2-3 h.
5. The method for preparing the near-infrared two-region dye according to claim 3, wherein the method for synthesizing the intermediate c comprises the following steps:
dissolving a compound a and a compound b in acetonitrile, reacting at a set temperature, concentrating after the reaction is finished, and separating by using column chromatography to obtain an intermediate c;
the synthetic route is as follows:
6. the preparation method of the near-infrared two-region dye according to claim 5, wherein the molar ratio of the compound a to the compound b is 1 (1.5-2), and the molar volume ratio of the compound a to acetonitrile is 1 (1.2-2.5) mol/L; the set temperature is 70-90 ℃, and the reaction time is 3-6 h.
7. A method of preparing a near-infrared two-region dye according to claim 3, comprising the steps of:
1) dissolving 4-methoxy o-phenylenediamine and 1, 2-cyclohexanedione in ethanol, reacting at a set temperature, concentrating after the reaction is finished, and separating by using column chromatography to obtain a light yellow solid compound 1;
2) dissolving the compound 1 in the step 1) and sodium borohydride in toluene, and dropwise adding R in an ice bath environment4-COOH, stirring in an ice bath after the dropwise addition is finished, and then continuing the reaction at the set temperature; after the reaction is finished, adding water to quench the reaction, extracting with ethyl acetate, concentrating the obtained organic phase, and separating by using column chromatography to obtain a brown yellow viscous compound 2;
3) dissolving the compound 2 and the 1-phenyl-1, 3-butanedione in the step 2) in methanesulfonic acid, stirring for reaction at a set temperature, pouring the reaction liquid into ice water after the reaction is finished, adding inorganic acid while stirring to separate out a solid, and further purifying the solid obtained after filtering by using column chromatography to obtain a red-black solid intermediate d;
the synthetic route is as follows:
8. the method for preparing the near-infrared two-region dye according to claim 7, wherein in the step (1), the molar ratio of 4-methoxy o-phenylenediamine to 1, 2-cyclohexanedione is 1 (0.4-1.5); the molar volume ratio of the 4-methoxy o-phenylenediamine to the ethanol is 3 (7-25) mol/L; setting the temperature to be 50-70 ℃ and the reaction time to be 2-4 h; the stationary phase used for the column chromatography is preferably 100-200 mesh silica gel; the mobile phase of the column chromatography for separating and purifying the compound 1 is a petroleum ether-dichloromethane mixed solution, and the volume ratio is (1-30): 1.
9. The process for preparing a near-infrared two-region dye according to claim 7, wherein in the step (2), the compound 1 and R4The molar volume ratio of-COOH is 5 (8-12) mol/L, and the molar volume ratio of the compound 1 to toluene is 1 (2.5-3.0) mol/L; stirring for 0.5-2 h, setting the temperature to be 110 ℃, and continuing to react for 8-24 h; the stationary phase used for the column chromatography is preferably 100-200 mesh silica gel; the mobile phase of the column chromatography used for separating and purifying the compound 2 is a petroleum ether-dichloromethane mixed solution, and the volume ratio is (1-30): 1.
10. The method for preparing the near-infrared two-region dye according to claim 7, wherein in the step (3), the molar ratio of the compound 2 to the 1-phenyl-1, 3-butanedione is 1 (1-2); the molar volume ratio of the compound 2 to the methanesulfonic acid is 1 (10-25) mol/L; the inorganic acid is one of sulfuric acid and perchloric acid; the stationary phase used for the column chromatography is preferably 100-200 mesh silica gel; the mobile phase of the column chromatography used for separating and purifying the intermediate d is a dichloromethane-ethanol mixed solution, and the volume ratio is (20-200): 1.
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