CN113234097A - tBu-azaBODIPY photo-thermal dye and preparation method thereof - Google Patents

Abstract

A tBu-azaBODIPY photo-thermal dye and a preparation method thereof relate to a photo-thermal dye and a preparation method thereof, and the general formula of the dye is shown as formula I:

Description

tBu-azaBODIPY photo-thermal dye and preparation method thereof

Technical Field

The invention relates to a photothermal dye and a preparation method thereof, in particular to a tBu-azaBODIPY photothermal dye and a preparation method thereof.

Background

Among the numerous dyes, azafluorodipyrromethene (BF)₂Azadipyrromethene, azaBODIPY for short) dyes have been used in recent yearsThe absorption and emission wavelengths of the novel near-infrared fluorescent dye are positioned in a visible-near infrared region, and the novel near-infrared fluorescent dye is easy to regulate and control and is widely researched. The quantum dot has the characteristics of narrow half-peak width, high quantum yield, large molar extinction coefficient and the like, has wide application prospect in the fields of biology, medicine, materials and the like, and has become a hotspot of research in recent years. However, the modification of the molecule is difficult, and the molecular structure is single.

In recent years, azafluorodipyrromethene has been extensively developed, and systematic studies by O' shear group, Jiano group and Jiang group have been carried out ((R))Chem. Soc. Rev., 2016, 45, 3846-3864). However, the 1, 7-positions in the parent nucleus structure of azaBODIPY are all aryl substituted (Chem. Soc. Rev., 2020, 49, 7533-7567）。

To date, there has been no report on the structure of 1, 7-tert-butyl substituted azafluorodipyrromethene.

Disclosure of Invention

The invention aims to provide a tBu-azaBODIPY photothermal dye and a preparation method thereof, and the invention develops a novel 1, 7-tert-butyl substituted dye tBu--azaBODIPY. The tBu-azaBODIPY dye is further applied to the development of biological and material research, provides a novel dye and enriches the phyla of dye families. As a novel tBu-azaBODIPY dye, the non-radiative transition is beneficial to photothermal conversion, and the photothermal conversion and singlet oxygen generation are higher in efficiency, good in water solubility and good in stability than those of the traditional Ar-azaBODIPY dye in addition to the advantages of the spectral performance of the classical traditional Ar-azaBODIPY dye and the like.

The purpose of the invention is realized by the following technical scheme:

a tBu-azaBODIPY photothermal dye, which has a general formula shown in formula I:

in formula I, Ar is selected from Ar₁、Ar₂、Ar₃、Ar₄、Ar₅、Ar₆、Ar₇、Ar₈、Ar₉And Ar₁₀An aryl group;

。

a preparation method of tBu-azaBODIPY photo-thermal dye comprises the following preparation steps:

(1) compound M3: adding arylethanone M2 and potassium hydroxide into a single-neck round-bottom flask, adding an ethanol/water solution into the system, adding trimethylacetaldehyde M1, and stirring at room temperature for 24 hours; after the reaction is finished, filtering, and recrystallizing the obtained solid by using ethanol to obtain a light white solid compound M3;

ar in M2 is selected from Ar₁-Ar₁₀A group; ar in M3 is selected from Ar₁-Ar₁₀A group;

(2) compound M4: adding a compound M3 into a reaction bottle, adding dry methanol to dissolve the compound, adding nitromethane and triethylamine into the system, and heating and refluxing for 6 hours; after the reaction is finished, cooling and standing the reaction system to room temperature, acidifying the reaction system to weak acidity by using hydrochloric acid, extracting the reaction system by using dichloromethane/distilled water, drying an organic phase by using anhydrous MgSO4, filtering out solids, and removing the solvent from the filtrate by using a rotary evaporator through rotary evaporation to obtain a crude product; recrystallizing with dichloromethane and anhydrous ether, filtering, and washing with cold ether to obtain white solid compound M4;

ar in M4 is selected from Ar₁-Ar₁₀A group;

(3) compound M5: the compound M4 and ammonium acetate were added to a reaction flask, and ethanol was added to dissolve it, followed by heating and refluxing for 48 hours. Cooling the system to room temperature, performing suction filtration, and washing with ethanol to obtain mauve solid compound M5;

ar in M5 is selected from Ar₁-Ar₁₀A group;

(4) dissolving the solid M5 obtained in the step (3) in dichloromethane, then adding triethylamine, and reacting for 0.5 h; finally, adding boron trifluoride diethyl etherate to react for 3 hours; and quenching the reaction mixed solution by using ice, extracting by using dichloromethane, distilling under reduced pressure, purifying the residue by using a silica gel column, wherein a developing agent is dichloromethane/n-hexane, and obtaining a dark blue solid I.

The invention has the advantages and effects that:

1. the invention introduces a novel strategic design, and develops a novel 1, 7-tertiary butyl substituted dye tBu--azaBODIPY. The tBu-azaBODIPY dye is further applied to the development of biological and material research, provides a novel dye and enriches the phyla of dye families. As a novel tBu-azaBODIPY dye, the non-radiative transition is beneficial to photothermal conversion, and the photothermal conversion and singlet oxygen generation are higher in efficiency, good in water solubility and good in stability than those of the traditional Ar-azaBODIPY dye in addition to the advantages of the spectral performance of the classical traditional Ar-azaBODIPY dye and the like.

2. The dye has high photo-thermal conversion efficiency and can be applied to the field of photo-thermal treatment. Meanwhile, the dye has excellent water solubility, high singlet oxygen generation efficiency and cell membrane permeability, and can be applied to research on tumor photothermal-photodynamic therapy.

3. The tBu-azaBODIPY photothermal dye has the following characteristics:

the compound is mainly characterized in that the 1, 7-tert-butyl substituted aza-fluoro-boron dipyrromethene azaBODIPY dye structure is a breakthrough of the traditional classical Ar-azaBODIPY structure.

The compound of the invention has non-radiative transition, which is beneficial to photo-thermal conversion, and has high photo-thermal conversion and singlet oxygen generation efficiency, good water solubility and good stability.

The compound of the invention has the advantages of easily obtained raw materials, novel structure, easy preparation and easy industrialization, and can obtain the target compound through 4 steps of reaction.

Drawings

FIG. 1 is a structural formula I-1 of the novel photothermal dye of the present invention;

FIG. 2 is a hydrogen spectrum of structural formula I-1 of the novel photothermal dye of the present invention;

FIG. 3 is a carbon spectrum of structural formula I-1 of the novel photothermal dye of the present invention;

FIG. 4 shows the absorption spectrum of structural formula I-1 of the novel photothermal dye of the present invention: (λ _abs = 620 nm in CH₂Cl₂）；

FIG. 5 shows fluorescence spectra of structural formula I-1 of the novel photothermal dye of the present invention: (λ _em = 650 nm in CH₂Cl₂）；

FIG. 6 shows the photothermal dye I-1 in CH according to the present invention₂Cl₂Color in solution;

FIG. 7 is a crystal structure of the novel photothermal dye I-2 of the present invention;

FIG. 8 is a comparative photo-thermal conversion plot of the novel photo-thermal dyes of the present invention I-2, I-3 and the conventional aza-BODIPY.

Detailed Description

The present invention will be described in detail with reference to the embodiments shown in the drawings.

Unless otherwise indicated, the terms used herein have the following meanings.

Wherein, in the general formula I of the invention, Ar is selected from the Ar₁-Ar₁₀The radical, preferably Ph.

The invention provides a method for preparing the photothermal dye, which comprises the steps of firstly preparing M3, secondly preparing M4, then preparing a precursor M5, and finally complexing boron trifluoride diethyl etherate to obtain the novel 1, 7-tert-butyl substituted tBu-aza BODIPY. The specific embodiment is as follows:

(1) compound M3: arylethanone M2 and potassium hydroxide were added to a single-neck round-bottom flask, and an ethanol/water solution was added to the system, followed by trimethylacetaldehyde M1, followed by stirring at room temperature overnight. In the reaction process, a product is precipitated from the mixed solution, after the reaction is finished, the product is filtered, and the solid obtained by filtering is recrystallized by ethanol to obtain a light white solid compound M3;

the reaction time is 3-24 hours. The molar ratio of the corresponding aldehyde to the corresponding ketone charged was 1.2: 1.

(2) Compound M4: adding the compound M3 into a reaction bottle, adding dry methanol to dissolve the compound, adding nitromethane and diethylamine into the system, and heating and refluxing for 6 h. After the reaction is finished, cooling and standing the reaction system to room temperature, acidifying with hydrochloric acid to weak acidity, extracting the mixed solution with dichloromethane/distilled water, drying the organic phase with anhydrous MgSO4, filtering to remove solids, removing the solvent from the filtrate by rotary evaporation with a rotary evaporator to obtain a crude product, recrystallizing with dichloromethane and anhydrous ether, performing suction filtration, and washing with cold ether to obtain a white solid compound M4;

in a preferred embodiment, the reaction temperature is 80 ℃. The reaction time is 4-8 hours.

(3) Compound M5: adding the compound M4 and ammonium acetate into a reaction bottle, adding ethanol for dissolving, heating and refluxing for 24 h, cooling the system to room temperature, performing suction filtration, and washing with ethanol to obtain a mauve solid compound M5.

The molar ratio of M4 to ammonium acetate fed was 1: 20. It is important to emphasize that the ammonium acetate must be in excess or not reacted.

(4) The solid M5 obtained in step (3) was dissolved in dichloromethane, and triethylamine was added thereto to react for half an hour. Finally, boron trifluoride ethyl ether was added to the reaction mixture to react for 3 hours. The mixture was quenched with ice. Extracting with dichloromethane, distilling under reduced pressure, and purifying the residue with silica gel column to obtain solid I of black blue.

For the above compounds of the invention, NMR spectra were taken including¹H， ¹³C NMR nuclear magnetic spectrum, absorption spectrum, fluorescence spectrum, mass spectrum, etc.

Example 1

Preparation of novel 1, 7-tert-butyl substituted tBu-aza-BODIPY photothermal dye I-1

(1) And (3) synthesizing 1, 7-tert-butyl substituted tBu-azaBODIPY photothermal dye I-1.

(2) Compound M3-1: acetophenone M2-1 (1.00 g, 8.3 mmol) and potassium hydroxide (0.93 g, 16.6 mmol) were added to a single-neck round-bottom flask, an ethanol/water solution (85: 15= v/v, 100 mL) was added to the system, and trimethylacetaldehyde M1-1 (1.43 g, 16.6 mmol) was added thereto, and stirred at room temperature for 24 hours, during which the product precipitated from the mixed solution, after completion of the reaction, the mixed solution was filtered, and the resulting solid was filtered and recrystallized from ethanol to give compound M3-1 (1.02 mg, 65%) as a pale white solid.

(3) Compound M4-1: compound M3-1 (1.02 g, 5.4 mmol) was weighed into a reaction flask, 100 mL of dry methanol was added to dissolve it, nitromethane (659.2 mg, 10.8 mmol) and triethylamine (2.19 g, 21.6 mmol) were added to the system, and the mixture was refluxed for 24 hours. After the reaction was completed, the reaction system was cooled and allowed to stand at room temperature, acidified to weak acidity with 1 mol/L hydrochloric acid, the mixture was extracted with dichloromethane/distilled water, the organic phase was dried over anhydrous MgSO4, the solid was filtered off by filtration, the filtrate was subjected to rotary evaporation with a rotary evaporator to remove most of the solvent to give a crude product, which was recrystallized with dichloromethane and anhydrous ether, subjected to suction filtration and washed with cold ether to give compound M4-1 (783 mg, 58%) as a white solid.

(4) Compound M4-1 (783 mg, 3.14 mmol) and ammonium acetate (4.8 g, 62.8 mmol) were weighed into a reaction flask, 60 mL of evaporated ethanol was added to dissolve, heated under reflux for 48 h, after the starting materials had reacted completely, the system was cooled to room temperature, filtered under suction, and washed with cold ethanol to give a magenta solid compound M5-1 (0.20 g, 31%).

(5) Compound I-1 Compound M5-1 (0.20 g, 0.49 mmol) was weighed into a reaction flask, vacuum-pumped, nitrogen-replaced, 50 mL of methylene chloride was added as a solvent, triethylamine (98.8 mg, 0.98 mmol) was added thereto and stirred for 30 min, boron trifluoride diethyl etherate (277.2 mg, 1.95 mmol) was added thereto and stirred for 12 h. Extracting the mixture with dichloromethane/distilled water, and extracting the organic phase with anhydrous MgSO₄Drying, filtration to remove the solid, rotary evaporation of the filtrate with a rotary evaporator to remove most of the solvent to give the crude product, recrystallization with dichloromethane and anhydrous ether, suction filtration, and washing with cold ether to give a blue-green solid (134.5 mg, 60.2%).¹H NMR (500 MHz, CDCl₃):δ(ppm) 7.46 (d, ³J = 7.5 Hz, 4H)， 7.35 (t, ³J = 7.5 Hz, 4H)， 7.19 (t, ³J = 7.5 Hz, 2H)， 6.65 (s, 2H)， 1.31 (s, 18H)。 ¹³C NMR (125 MHz, CDCl₃): δ 137.5, 133.1, 131.9, 128.9, 126.1, 123.7, 113.9, 104.2, 31.8, 30.7. HRMS (ESI) m/z calcd for C₂₈H₃₀BF₂N₃Na⁺ (M+Na)⁺ 480.23931, found 480.23944.

The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to the specific details set forth herein. For those skilled in the art to which the invention pertains, a number of simple deductions and substitutions can be made on the premise of the core concept of the invention, and all should be considered as belonging to the protection scope of the invention. As a person of ordinary skill in the art to which the invention pertains, numerous and simple inferences can be made based on the present invention to find other applications of the compounds of the present invention, which are considered to fall within the scope of the present invention.

Claims (2)

1. A tBu-azaBODIPY photothermal dye is characterized in that the dye has a general formula shown in a formula I:

in formula I, Ar is selected from Ar₁、Ar₂、Ar₃、Ar₄、Ar₅、Ar₆、Ar₇、Ar₈、Ar₉And Ar₁₀An aryl group;

。

2. a preparation method of tBu-azaBODIPY photo-thermal dye is characterized by comprising the following preparation steps:

(1) compound M3: adding arylethanone M2 and potassium hydroxide into a single-neck round-bottom flask, adding an ethanol/water solution into the system, adding trimethylacetaldehyde M1, and stirring at room temperature for 24 hours; after the reaction is finished, filtering, and recrystallizing the obtained solid by using ethanol to obtain a light white solid compound M3;

ar in M2 is selected from Ar₁-Ar₁₀A group; ar in M3 is selected from Ar₁-Ar₁₀A group;

(2) compound M4: adding a compound M3 into a reaction bottle, adding dry methanol to dissolve the compound, adding nitromethane and triethylamine into the system, and heating and refluxing for 6 hours; after the reaction is finished, cooling and standing the reaction system to room temperature, acidifying the reaction system to weak acidity by using hydrochloric acid, extracting the reaction system by using dichloromethane/distilled water, drying an organic phase by using anhydrous MgSO4, filtering out solids, and removing the solvent from the filtrate by using a rotary evaporator through rotary evaporation to obtain a crude product; recrystallizing with dichloromethane and anhydrous ether, filtering, and washing with cold ether to obtain white solid compound M4;

ar in M4 is selected from Ar₁-Ar₁₀A group;

(3) compound M5: adding the compound M4 and ammonium acetate into a reaction bottle, adding ethanol for dissolving, and heating and refluxing for 48 h;

cooling the system to room temperature, performing suction filtration, and washing with ethanol to obtain mauve solid compound M5;

ar in M5 is selected from Ar₁-Ar₁₀A group;

(4) dissolving the solid M5 obtained in the step (3) in dichloromethane, then adding triethylamine, and reacting for 0.5 h; finally, adding boron trifluoride diethyl etherate to react for 3 hours; and quenching the reaction mixed solution by using ice, extracting by using dichloromethane, distilling under reduced pressure, purifying the residue by using a silica gel column, wherein a developing agent is dichloromethane/n-hexane, and obtaining a dark blue solid I.

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