CN106497136A - A kind of nir dye of half flower cyanines structure and its preparation method and application - Google Patents

Abstract

The invention provides a near-infrared dye with a semi-cyanine structure and its preparation method and application. The structural formula of the dye is shown in formula I, R ₁ is a linear, branched or cyclic alkyl group with 1 to 32 carbon atoms; R ₂ is hydrogen, bromine, methoxy, N,N dimethylamino, ethoxy, hydroxyl, carboxymethoxy Or one of acetomethoxy. The dye is prepared by reacting Cy7 cyanine dye with resorcinol with benzimidazole. The invention introduces a benzimidazole group into a dye with a half cyanine structure, and the obtained dye not only absorbs and emits in the near-infrared region, but also responds to the pH value of the environment.

Description

A kind of near-infrared dye with semi-cyanine structure and its preparation method and application

technical field

The invention belongs to the technical field of organic near-infrared fluorescent dyes, and in particular relates to a near-infrared dye with a semicyanine structure and a preparation method and application thereof.

Background technique

Near-infrared fluorescent dyes are a kind of functional dyes. Because of their good absorption in the near-infrared region, near-infrared technology is widely used in solar cells, tumor treatment, radio frequency identification systems, and anti-counterfeiting printing.

As a class of near-infrared dyes, cyanine dyes have been used in practice, and new types are constantly emerging. The absorption and emission spectra of near-infrared methine cyanine dyes are located in the near-infrared region (>650nm). Compared with the detection in the visible fluorescence region (<650nm), in the near-infrared fluorescence region, the fluorescence absorption and fluorescence intensity of the biological sample matrix are very small. Therefore, the background interference is greatly reduced, and because the scattered light intensity is inversely proportional to the fourth power of the wavelength, as the wavelength increases, the Raman scattering decreases rapidly, so that the scattering interference is also greatly reduced. Qijiachuan, as a kind of Jiachuan cyanine dye, has a longer absorption wavelength and less background interference. Compared with conventional fluorescence detection, Qijiachuan has a deeper tissue penetration depth and less damage to biological tissues when applied to biological samples. Small, so its application prospects are also broader.

The semi-cyanine structure dye synthesized based on heptamethine indocyanine dye has strong absorption and emission properties in the near-infrared region, and can be used in the fields of photothermal therapy and photoacoustic imaging; and it has a response effect to the pH value of the environment, which can be It is used as a fluorescent probe in the near-infrared region; in addition, the photothermal and chemical stability of the dye have also been greatly improved compared with the heptamethanine dye.

Contents of the invention

Technical problem solved: the object of the present invention is to provide a near-infrared dye with a semi-cyanine structure of benzimidazole and a preparation method thereof, the dye has near-infrared absorption and emission properties, good photothermal and chemical stability .

Technical solution: On the one hand, the present invention provides a near-infrared dye with a semi-cyanine structure, the structural formula of which is shown in Formula I:

Wherein, R ₁ is a linear, branched or cyclic alkyl group with 1 to 32 carbon atoms; R ₂ is hydrogen, bromine, methoxy, N,N dimethylamino, ethoxy, hydroxyl, carboxymethyl One of oxy or acetylmethoxy.

The preparation method of the near-infrared dye of above-mentioned half cyanine structure, comprises the following steps:

First, the 2,3,3-trimethyl-1-H-indole ethylated compound was reacted with formylated cyclohexanone at 100°C to obtain a cyanine dye with a Cy7 structure; Resorcinol with benzimidazole was obtained by reacting amine with 2,4-dihydroxybenzaldehyde at 160°C; finally at 50°C, using N,N-dimethylformamide as solvent, using Cy7 cyanine The dyestuff reacts with the resorcinol with benzimidazole and is separated by column chromatography to obtain the near-infrared dyestuff with the half-cyanine structure.

The present invention also provides a dye with a boron-coordinated semicyanine structure, the structural formula of which is shown in Formula II:

Wherein, R ₁ is a linear, branched or cyclic alkyl group with 1 to 32 carbon atoms; R ₂ is hydrogen, bromine, methoxy, N,N dimethylamino, ethoxy, hydroxyl, carboxymethyl One of oxy or acetylmethoxy.

The preparation method of the above-mentioned semi-cyanine structure dye with boron coordination is to react the near-infrared dye of the semi-cyanine structure with boron trifluoride ether, and the specific process is as follows:

The application of the near-infrared dye with the above semi-cyanine structure in the field of photoacoustic imaging.

The application of the near-infrared dye with the above-mentioned semi-cyanine structure in the field of photothermal therapy.

The application of the near-infrared dye with the above half cyanine structure in the field of fluorescence sensing.

Beneficial effect: the present invention introduces benzimidazole group into the dye with half cyanine structure, and the obtained dye not only absorbs and emits in the near-infrared region, but also responds to the pH value of the environment. The boron-coordinated hemicyanine dye not only absorbs and emits in the near-infrared region, but also responds to the pH value of the environment, and its photothermal and chemical stability has been improved.

Description of drawings

Fig. 1 is the ultraviolet-visible absorption spectrum of the near-infrared dye of the half cyanine structure of embodiment 1 under acidic and alkaline conditions;

Fig. 2 is the emission spectrum of the near-infrared dye of the semi-cyanine structure of Example 1 under acidic and alkaline conditions.

detailed description

In order to better understand the content of the patent of the present invention, the technical solution of the present invention will be further illustrated through specific examples below. Specifically, it includes synthesis and property determination. However, these examples do not limit the present invention.

Example 1

Preparation of a semicyanine dye with a benzimidazole structure, R ₁ is ethyl, R ₂ is H.

Synthesis of compound C1:

Add solid raw material 2,3,3-trimethylindole (478mg, 3mmol) into the two-necked bottle, seal it, vacuumize it, and fill it with nitrogen three times; then inject 10 mL of solvent anhydrous acetonitrile and liquid raw material into the two-necked bottle Ethyl iodide (515mg, 3.3mmol) was stirred at 70°C for 15h. Post-processing: the reaction mixture was cooled to room temperature, and 20 mL of petroleum ether was added with stirring. After stirring for 2 hours, it was filtered with suction to obtain 567 mg of pink solid powder with a yield of 60%. ¹ H NMR (400MHz, DMSO) δ8.00–7.91(m,1H),7.89–7.77(m,1H),7.66–7.56(m,2H),4.47(q,J=7.3Hz,2H),2.81 (s, 3H), 1.51 (s, 6H), 1.42 (t, J=7.3Hz, 3H).

Synthesis of compound C2:

Add N,N-dimethylformamide (1.14 g, 13.1 mmol) and dichloromethane (3 mL) into a two-necked flask, and cool in an ice-water bath for 10 min. Then, a mixed solution of phosphorus oxychloride (2 g, 13.1 mmol) and dichloromethane (3 mL) was added dropwise to the above cooled mixed solution, and stirred for 10 min. A mixed solution of cyclohexanone (430 mg, 4.38 mmol) and dichloromethane (3 mL) was injected into the above mixture, and stirred for 10 min. The reaction was stirred under N ₂ environment at 80 °C for 6 h. Post-processing: after the reaction mixture was cooled to room temperature, it was slowly poured into 160 g of ice water, a yellow solid was precipitated, and left to stand overnight. Suction filtration gave 613 mg of yellow powder, yield 80%. It was directly put into the next reaction without further processing.

Synthesis of Compound C3:

Add raw materials C1 (315 mg, 1 mmol), C2 (87.3 mg, 0.5 mmol), and potassium acetate (45 mg) into a two-necked bottle, seal it, vacuumize it and fill it with nitrogen three times. The solvent acetic anhydride 8Ml was injected, and the reaction was stirred at 100°C for 2h. Post-processing: the reacted mixture was cooled to room temperature, suction filtered, and washed with a small amount of acetic anhydride to obtain 287.6 mg of a green powder with metallic luster, with a yield of 90%. ¹ H NMR (400MHz, DMSO) δ8.25 (d, J = 14.1Hz, 1H), 7.62 (d, J = 7.4Hz, 1H), 7.47–7.39 (m, 2H), 7.32–7.22 (m, 1H ),6.30(d,J=14.2Hz,1H),4.23(q,J=7.0Hz,2H),2.69(dd,J=15.1,9.0Hz,2H),1.88–1.79(m,1H),1.68 (d, J=22.1 Hz, 6H), 1.29 (t, J=7.1 Hz, 3H).

Synthesis of compound C4:

The raw material o-phenylenediamine (216mg, 2mmol), 2,4-dihydroxybenzaldehyde (276mg, 2.2mmol) and sodium metabisulfite (190mg, 2mmol) were loaded into a two-necked bottle, and then injected into the solvent N,N-dimethyl 15 mL of formamide was stirred at 160°C for 4 hours. Post-treatment: After the reaction mixture was cooled to room temperature, 50 mL of deionized water was added, and a yellow powdery solid was obtained by suction filtration. The obtained solid was dissolved in ethyl acetate, added with silica gel powder, spin-dried and purified by column to obtain 295 mg of light yellow powder with a yield of 65%. ¹ H NMR (400MHz, DMSO) δ13.17(s, 1H), 12.90(s, 1H), 9.97(s, 1H), 7.82(d, J=8.4Hz, 1H), 7.57(d, J=30.2 Hz, 2H), 7.21 (s, 2H), 6.42 (d, J=7.7Hz, 1H), 6.38 (s, 1H).

Synthesis of compound C5:

The raw material C4 (160 mg, 0.7 mmol) was put into a two-necked bottle, sealed, evacuated and filled with nitrogen three times. 5 mL of solvent N,N-dimethylformamide and triethylamine (70.7 mg, 0.7 mmol) were injected, and stirred at room temperature for 10 minutes. Starting material C3 (150 mg, 0.23 mmol) was dissolved in 5 mL of DMF and injected into the reaction vial. The reaction was stirred at 50°C for 4 hours. Post-treatment: 50 mL of dichloromethane was poured into the reaction mixture, and the organic phase was washed 3 times with 20 mL of deionized water. The obtained organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by column to obtain 62 mg of blue-black powder with a yield of 42%. ¹ H NMR (400MHz, DMSO) δ8.40(s, 1H), 8.22(d, J=13.2Hz, 1H), 7.77(s, 1H), 7.62(s, 2H), 7.52(d, J=6.6 Hz,1H),7.35(d,J=6.7Hz,1H),7.29(s,1H),7.17(s,1H),7.13-7.17(2H),6.55(s,1H),6.00(d,J =13.0Hz, 1H), 4.09(q, J=8.9Hz, 2H), 3.58(t, J=7.0Hz, 2H), 2.69(t, J=7.2Hz, 2H), 2.59(t, J=7.0 Hz, 2H), 1.77(s, 3H), 1.67(s, 6H).

Synthesis of compound C6:

The raw material C5 (100mg, 0.16mmol) was put into a two-necked bottle, sealed, vacuumed and filled with nitrogen three times. A mixed solution of solvent tetrahydrofuran (5 mL) and boron trifluoride diethyl ether (0.1 mL, excess) was injected, and stirred at room temperature for 15 hours. Post-processing: the reaction mixture was directly purified by column to obtain 55 mg of blue-black powder with a yield of 52%. ¹ H NMR (400MHz,DMSO)δ13.20(s,1H),8.47(s,1H),8.19(d,J=13.6Hz,1H),7.89(s,1H),7.67–7.64(m,1H ),7.57(d,J=6.8Hz,1H),7.49(d,J=7.6Hz,1H),7.31(d,J=7.6Hz,1H),7.19(d,J=7.9Hz,1H), 7.12(dd, J=8.6,4.6Hz,3H),6.43(s,1H),5.92(d,J=13.9Hz,1H),4.03(d,J=6.8Hz,2H),2.72–2.68(m , 2H), 2.64 (d, J=6.0Hz, 2H), 1.81 (t, J=12.6Hz, 3H), 1.76 (d, J=4.0Hz, 2H), 1.67 (s, 6H).

UV-visible spectrum test of the semicyanine structure dye C5 with benzimidazole: dilute solutions of the two compounds (10 ^-5 M, the solvents are respectively PBS buffer at pH=3.0 and pH=9.0), pipette Put 2mL of compound solution in a fluorescent cuvette, and then test the absorption and emission spectra, as shown in Figure 1 and Figure 2. The test data shows that the compound has good absorption and emission properties in the near-infrared fluorescence region, and under alkaline conditions, the absorption and emission peaks of the compound are red-shifted compared with those under acidic conditions.

Example 2

Preparation of a semicyanine dye with a benzimidazole structure, R ₁ is ethyl, R ₂ is hydroxyl.

The synthesis of compounds C1, C2, and C3 is the same as in Example 1.

Synthesis of compound C4:

The raw material o-phenylenediamine (216mg, 2mmol), 2,4,6-trihydroxybenzaldehyde (311mg, 2.2mmol) and sodium metabisulfite (190mg, 2mmol) were loaded into a two-necked bottle, and then the solvent N,N-di Methylformamide 15mL was stirred at 160°C for 4 hours. Post-treatment: After the reaction mixture was cooled to room temperature, 50 mL of deionized water was added, and a yellow powdery solid was obtained by suction filtration. The obtained solid was dissolved in ethyl acetate, added silica gel powder, spin-dried and purified by column to obtain 290 mg of light yellow powder with a yield of 60%. ¹ H NMR (400MHz, Chloroform) δ9.07(s, 1H), 7.57(d, J=5.6Hz, 2H), 7.25(d, J=2.9Hz, 2H), 6.36(d, J=11.4Hz, 3H), 6.04–5.99 (m, 2H).

Synthesis of compound C5:

The raw material C4 (170mg, 0.7mmol) was put into a two-necked bottle, sealed, evacuated and filled with nitrogen three times. 5 mL of solvent N,N-dimethylformamide and triethylamine (70.7 mg, 0.7 mmol) were injected, and stirred at room temperature for 10 minutes. Starting material C3 (150 mg, 0.23 mmol) was dissolved in 5 mL of DMF and injected into the reaction vial. The reaction was stirred at 50°C for 4 hours. Post-treatment: 50 mL of dichloromethane was poured into the reaction mixture, and the organic phase was washed 3 times with 20 mL of deionized water. The obtained organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by column to obtain 46 mg of blue-black powder with a yield of 40%. ¹ H NMR (400MHz, Chloroform) δ9.10(s, 1H), 8.09(s, 1H), 7.69(s, 1H), 7.63–7.56(m, 3H), 7.24(d, J=2.4Hz, 2H ),7.16(s,1H),6.99(s,1H),6.81(s,1H),6.69(s,1H),6.43(s,1H),5.58(s,1H),5.26(s,1H) ,3.73(s,1H),3.47(s,1H),2.86(s,2H),2.19(s,2H),1.70(s,2H),1.47(s,3H),1.39(s,6H).

Synthesis of compound C6:

The raw material C5 (100mg, 0.15mmol) was put into a two-necked bottle, sealed, vacuumed and filled with nitrogen three times. A mixed solution of solvent tetrahydrofuran (5 mL) and boron trifluoride diethyl ether (0.1 mL, excess) was injected, and stirred at room temperature for 15 hours. Post-processing: the reaction mixture was directly purified by column to obtain 45 mg of blue-black powder with a yield of 42%. ¹ H NMR (400MHz, Chloroform) δ9.80(s, 1H), 8.12(s, 1H), 7.69(s, 1H), 7.66–7.58(m, 3H), 7.23(d, J=2.4Hz, 2H ),7.11(s,1H),6.93(s,1H),6.60(s,1H),6.41(s,1H),5.57(s,1H),5.21(s,1H),3.73(s,1H) ,3.41(s,1H),2.85(s,2H),2.11(s,2H),1.72(s,2H),1.50(s,3H),1.32(s,6H).

Claims (7)

1. a kind of half the nir dye of cyanines structure is spent, it is characterised in that：Its structural formula is as shown in formula I：

Wherein, R₁It is straight chain with 1 to 32 carbon atom, side chain or cyclic alkyl；R₂For hydrogen, bromine, methoxyl group, N, N diformazans One kind in amino, ethyoxyl, hydroxyl, Carboxvmethoxv or acetyl methoxyl group.

2. half described in claim 1 spends the preparation method of the nir dye of cyanines structure, it is characterised in that：Including following step Suddenly：

3. a kind of half the nir dye of cyanines structure is spent, it is characterised in that：Its structural formula is as shown in formula II：

Wherein, R₁It is straight chain with 1 to 32 carbon atom, side chain or cyclic alkyl；R₂For hydrogen, bromine, methoxyl group, N, N diformazans One kind in amino, ethyoxyl, hydroxyl, Carboxvmethoxv or acetyl methoxyl group.

4. half described in claim 3 spends the preparation method of the nir dye of cyanines structure, it is characterised in that：Including following step Suddenly：

5. application of the nir dye of half flower cyanines structure described in claim 1 or 3 in photoacoustic imaging field.

6. application of the nir dye of half flower cyanines structure described in claim 1 or 3 in photo-thermal therapy field.

7. application of the nir dye of half flower cyanines structure described in claim 1 or 3 in fluorescence sense field.