CN109970746B - N-hybrid porphyrin-dipyrrolene photoacoustic developer and synthesis method thereof - Google Patents
N-hybrid porphyrin-dipyrrolene photoacoustic developer and synthesis method thereof Download PDFInfo
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- CN109970746B CN109970746B CN201910345060.XA CN201910345060A CN109970746B CN 109970746 B CN109970746 B CN 109970746B CN 201910345060 A CN201910345060 A CN 201910345060A CN 109970746 B CN109970746 B CN 109970746B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Abstract
The invention belongs to the technical field of organic chemical industry, in particular to synthesis and application of an N-hybrid porphyrin-dipyrrolene photoacoustic developer, wherein the chemical structural formula is as follows:
the synthesis method is to obtain the N-hybrid porphyrin-dipyrrole photoacoustic developer by condensation reaction of 5-methoxy-2, 3, 3-trimethylindole and tetraphenyl N-hybrid porphyrin with high yield. The key point is that the methoxy-containing N-hybrid porphyrin-dipyrrole conjugated structure is simply and efficiently obtained, so that the developing agent with a good photoacoustic developing effect is obtained, the photoacoustic conversion rate is high, and the developing resolution is high.
Description
Technical Field
The invention relates to the technical field of organic fine chemical engineering, in particular to synthesis and application of an N-hybrid porphyrin-dipyrrolene photoacoustic developer.
Background
Cancer has become one of the major diseases threatening human life and health, and the in vivo, accurate and noninvasive diagnosis of cancer at cellular level has become the hot spot of scientific research. The photoacoustic imaging is a nondestructive biophoton imaging method based on optical absorption difference in biological tissues and using ultrasound as a medium, and has the advantages of high resolution, high contrast, deep penetration depth (up to 7cm), non-invasiveness and the like. The photoacoustic developer is a key component of photoacoustic imaging technology, and achieves the purpose of accurate diagnosis by accurately positioning the focus position. Therefore, people have important social benefits and scientific research values for early accurate and noninvasive diagnosis of cancers by increasingly extensive research on the photoacoustic probe. At present, the existing photoacoustic developer comprises N-hybrid porphyrin, and the main problems are that the compound does not reach the absorption range of near infrared light, the molar extinction coefficient is low, and the photoacoustic imaging resolution ratio is low. Therefore, the improvement of the N-hybrid porphyrin compound, so that the N-hybrid porphyrin compound can be applied to the photoacoustic developer, which is a research difficulty and a hotspot of current scientific research work.
Disclosure of Invention
The invention mainly aims to provide a simple synthesis method for obtaining an N-hybrid porphyrin-dipyrrolene photoacoustic developer.
The technical scheme of the invention is as follows:
the synthesis and application of N-hybrid porphyrin-dipyrrolene photoacoustic developer have the chemical structural formula:
the synthesis method of the N-hybrid porphyrin-dipyrrolene photoacoustic developer comprises the following synthesis paths:
1) adding the compound 5-methoxy-2, 3, 3-trimethylindole (1), 5,10,15, 20-tetraphenyl-N-hybrid porphyrin (2) and tetrahydrofuran into a reaction bottle at room temperature, and stirring to dissolve;
2) heating and refluxing the step 1) under the condition of no acid catalysis to obtain a dark red mixed solution;
3) purifying the solid compound in the step 2) to obtain a deep red solid compound I;
the synthesis of the large conjugated dipyrrole dye is completed.
The feeding ratio of the compound 1 to the compound 2 in the step 1) is 1.2-6: 1.
The compound 1 in the step 2) has high reaction activity, and can react without an acid catalyst.
The reflux temperature of the reaction solvent tetrahydrofuran in the step 2) is 75-85 ℃, and the reaction time is 0.5-3 hours.
The separation method in the step 3) is to separate the target product 3 by utilizing a diatomite column chromatography.
The invention has the following beneficial effects:
1. the invention obtains an N-hybrid porphyrin-dipyrrole conjugated structure by simply and efficiently using a 5-methoxy-2, 3, 3-trimethylindole derivative and 5,10,15, 20-tetraphenyl-N-hybrid porphyrin, particularly, methoxy is introduced by modifying the peripheral ring of the derivative, and the methoxy is a stronger power supply group, so that the electronegativity of the methyl group at the 3-position of the indole is higher, the 3-carbon point in the N-hybrid porphyrin is favorably supplied only, the condensation reaction is easier to occur, and the reaction yield is higher.
2. The N-hybrid porphyrin-dipyrromethene (specifically, the products synthesized in examples 1-7) of the invention is a larger conjugated system, which is larger than the conjugated system of pure N-hybrid porphyrin, and the introduction of the chromophore methoxyl group enables the spectrum of the developer to generate a red shift of 20-50nm, and the extinction coefficient is larger than 104-106L·mol-1·cm-1In the range, the photoacoustic conversion rate is higher, and the compound can be used as a photoacoustic imaging developer, is beneficial to imaging of tumor cells and has important application in photoacoustic imaging technology.
3. The invention synthesizes the N-hybrid porphyrin-dipyrromethene photoacoustic developer, and the compound has the advantages of absorption at 700nm, good imaging effect and high resolution.
Drawings
FIG. 1 Compound of example 1 in CDCl3Nuclear magnetic hydrogen spectrum of (1).
Figure 2 high resolution mass spectrum of the compound of example 1.
FIG. 3 UV-VIS absorption spectrum of the compound of example 1 in acetone.
FIG. 4 fluorescence spectrum of example 1 compound in acetone.
Detailed Description
The invention is further illustrated by the following examples, but the scope of the invention as claimed is not limited to the scope of the examples.
Example 1
Dissolving 0.23g (0.12mmol) of 5-methoxy-2, 3, 3-trimethylindole and 0.61g (0.10mmol) of N-hybrid porphyrin in tetrahydrofuran, stirring for 5 minutes, refluxing at 70 ℃ for 0.5 hour, after the reaction is finished, filtering and purifying column chromatography to obtain a purple compound with the yield of 90 percent after spin drying. The compound has high stability under the illumination of visible light and ultraviolet light, can stably exist for 40 days under natural light, is a macrocyclic porphyrin compound, is similar to a structural matrix of heme iron in vivo blood, and has extremely low toxicity.
Example 2
Dissolving 0.38g (0.2mmol) of 5-methoxy-2, 3, 3-trimethylindole and 0.61g (0.10mmol) of N-hybrid porphyrin in tetrahydrofuran, stirring for 5 minutes, refluxing at 70 ℃ for 0.5 hour, after the reaction is finished, filtering and purifying column chromatography to obtain a purple compound with the yield of 88 percent after spin drying.
Example 3
Dissolving 0.19g (0.1mmol) of 5-methoxy-2, 3, 3-trimethylindole and 0.61g (0.10mmol) of N-hybrid porphyrin in tetrahydrofuran, stirring for 5 minutes, refluxing at 70 ℃ for 0.5 hour, after the reaction is finished, filtering and purifying column chromatography to obtain a purple compound with the yield of 84 percent after spin drying.
Example 4
Dissolving 0.19g (0.1mmol) of 5-methoxy-2, 3, 3-trimethylindole and 0.61g (0.10mmol) of N-hybrid porphyrin in tetrahydrofuran, stirring for 5 minutes, refluxing at 70 ℃ for 0.5 hour, after the reaction is finished, filtering and purifying column chromatography to obtain a purple compound with the yield of 85 percent after spin drying.
Example 5
Dissolving 0.95g (0.5mmol) of 5-methoxy-2, 3, 3-trimethylindole and 0.61g (0.10mmol) of N-hybrid porphyrin in tetrahydrofuran, stirring for 5 minutes, refluxing at 70 ℃ for 0.5 hour, after the reaction is finished, filtering and purifying column chromatography to obtain a purple compound with the yield of 88 percent after spin drying.
Example 6
Dissolving 0.23g (0.12mmol) of 5-methoxy-2, 3, 3-trimethylindole and 0.61g (0.10mmol) of N-hybrid porphyrin in tetrahydrofuran, stirring for 5 minutes, refluxing at 70 ℃ for 2 hours, after the reaction is finished, filtering and purifying column chromatography to obtain a purple compound with the yield of 84 percent after spin-drying.
Example 7
Dissolving 0.23g (0.12mmol) of 5-methoxy-2, 3, 3-trimethylindole and 0.61g (0.10mmol) of N-hybrid porphyrin in tetrahydrofuran, stirring for 5 minutes, refluxing at 70 ℃ for 3 hours, after the reaction is finished, filtering and purifying column chromatography to obtain a purple compound with the yield of 75 percent after spin-drying.
Example 8
0.08g of the compound obtained in example 1 is weighed and dissolved in 10mL of acetone to prepare a mother solution of 10mmol/L, then 10 μ L of the mother solution is diluted into a dye solution of 10mL (10 μmol/L), and an ultraviolet visible spectrum and a fluorescence spectrum of the dye solution are tested by using an ultraviolet visible spectrophotometer and a fluorescence spectrophotometer, wherein the test results are shown in FIGS. 3 and 4, and the results show that the compound has near infrared light absorption and certain fluorescence emission and can be used as a photoacoustic developer.
The above-described embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and features in the embodiments and examples in the present application may be arbitrarily combined with each other without conflict. The protection scope of the present invention is defined by the claims, and includes equivalents of technical features of the claims. I.e., equivalent alterations and modifications within the scope hereof, are also intended to be within the scope of the invention.
Claims (4)
1. An N-hybrid porphyrin-dipyrrolene photoacoustic developer is characterized in that the chemical structural formula is as follows:
2. a method of synthesizing an N-hybrid porphyrin-dipyrroline-based photoacoustic imaging agent according to claim 1, comprising the steps of:
1) adding a compound 5-methoxy-2, 3, 3-trimethylindole, 5,10,15, 20-tetraphenyl-N-mixed porphyrin and tetrahydrofuran into a reaction bottle at room temperature, stirring for dissolving, and heating and refluxing to obtain a dark red mixed solution;
2) purifying the dark red mixed solution obtained in the step 1) to obtain a dark red solid compound I; thus obtaining the N-hybrid porphyrin-dipyrrolene photoacoustic developer.
3. The method for synthesizing N-hybrid porphyrin-dipyrroline-based photoacoustic imaging agent according to claim 2, wherein the molar ratio of the 5-methoxy-2, 3, 3-trimethylindole to the 5,10,15, 20-tetraphenyl-N-hybrid porphyrin in step 1) is 1-5: 1.
4. The method for synthesizing an N-hybrid porphyrin-dipyrromethene photoacoustic imaging agent according to claim 2, wherein the reflux reaction temperature in step 1) is 75-85 ℃ and the reflux reaction time is 0.5-3 hours.
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| L-Proline catalyzed reaction of N-confused porphyrin and active methylene compounds;Bin Liu et al.;《Org. Biomol. Chem.》;20130603;第11卷;第4831-4839页 * |
| Synthesis of N-Confused Porphyrin Derivatives with a Substituted 3-C Position;Xiaofang Li et al.;《J. Org. Chem.》;20110225;第76卷;第2345-2349页 * |
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