Method for synthesizing nitrogen-containing compounds including cyanine compounds, and methine dyes containing cyanine compounds.
By extending polymethine chains with aldehyde groups and substituting them with nitrogen-containing heterocyclic groups, the synthesis of cyanine compounds is simplified, enabling controlled absorption and fluorescence wavelengths for improved near-infrared imaging.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2024-08-30
- Publication Date
- 2026-03-13
AI Technical Summary
Existing methods for synthesizing cyanine compounds with extended polymethine chains are complex and limited in controlling absorption and fluorescence wavelengths, particularly for near-infrared imaging, and there is a need for simpler and more effective synthesis methods to enhance biological penetration.
The method involves extending polymethine chains with aldehyde groups at their termini and substituting these with nitrogen-containing heterocyclic groups, allowing for controlled synthesis of cyanine compounds and polymethine dyes with adjustable absorption and fluorescence wavelengths.
This approach enables the synthesis of cyanine compounds that can be easily converted into polymethine dyes, facilitating deeper biological penetration through longer wavelengths, enhancing molecular imaging techniques.
Smart Images
Figure 2026045769000044 
Figure 2026045769000045 
Figure 2026045769000046
Abstract
Description
Technical Field
[0001] The present invention relates to a method for synthesizing a nitrogen-containing compound containing a cyanine compound that extends a polymethine chain having an aldehyde group at the terminal and further substitutes a heterocyclic ring containing nitrogen for the aldehyde terminal of the extended polymethine chain, an intermediate in the synthesis thereof, and a polymethine dye containing such a cyanine compound.
Background Art
[0002] As a means for clarifying the mechanism of life in the field of life science and medical research, molecular imaging technology that directly captures bioactive substances (bioactive small substances such as enzymes, receptors, DNAs, sugars, NO, etc.) in living cells, biological tissues or in vivo, and specifies and detects and visualizes their activities, change amounts, time and location is becoming increasingly important. As bioimaging methods for directly observing cells and biological tissues, PET, X-ray CT, MRI, ultrasonic examination, fluorescence probe method, etc. are widely used in clinical practice, but each has its advantages and disadvantages, so these methods are used appropriately in clinical practice according to their respective characteristics. Regarding spatial resolution, MRI is excellent, but on the surface layer, the resolution equivalent to that of the fluorescence probe method and MRI can be obtained. On the other hand, in terms of time resolution, PET and the fluorescence probe method are excellent. The detection sensitivity is 10
[0003] , , , -9 , -9 , -12 ~10 -12 mol / kg, and in fluorescence analysis it is 10 -9 mol / L, which is more sensitive than MRI. In particular, for detecting enzymes in blood by fluorescence analysis, the detection sensitivity and the wavelength of the light to be examined are important. Currently, most commercially available fluorescence probes emit fluorescence in the visible light region (400 to 700 nm). Since such short-wavelength light has high light scattering properties, it is extremely difficult to observe deep inside the body.
[0003] Near-infrared light (wavelengths approximately 700-2500 nm) is attracting attention as a light source that can visualize the structure and information deep within living organisms. Near-infrared light is a wavelength range that is attracting attention as a "window to living organisms" because it has higher biological penetration than ultraviolet light and visible light. In particular, the 650-950 nm range, which has been conventionally used for observing deep within living organisms, is called the "first window to living organisms," and the near-infrared region with wavelengths exceeding 1000 nm (OTN: over 1000 nanometers) is called the "second and third windows to living organisms." A schematic diagram of the wavelength ranges of visible light, near-infrared light, and OTN near-infrared light and their respective biological penetration is shown in Figure 1.
[0004] Indocyanine green (pharmaceutical name: Diagnogreen) (ICG: excitation light 774 nm, fluorescence wavelength 805 nm) is the only near-infrared fluorescent dye currently approved for human use by the U.S. Food and Drug Administration (FDA). However, this fluorescence wavelength does not penetrate biological tissue sufficiently, limiting the observation depth to approximately 2-3 mm. Therefore, molecular imaging techniques utilizing longer wavelength light are needed to increase this observation depth.
[0005] Cyanine dyes, including indocyanine green, are a type of polymethine dye that has a polymethine chain. The polymethine chain has nitrogen-containing heterocycles at both ends. One nitrogen atom is an ammonium compound with a cationic structure, acting as an electron acceptor, while the other nitrogen atom has a tertiary amine structure, acting as an electron donor. Cyanine dyes absorb through charge transfer via the polymethine chain in this way. Compounds that have a nitrogen-containing heterocycle at only one end of the polymethine chain are sometimes called hemicyanins, and in this invention, cyanine compounds are defined as those containing hemicyanins. Therefore, attempts have been made to extend the polymethine chain to shift the absorption and fluorescence wavelengths to longer wavelengths, and to control the absorption wavelength depending on the type of nitrogen-containing heterocycle.
[0006] Regarding the polymethine chain in indocyanine green, an indocyanine green derivative dye (ICG-C11) with an extended polymethine chain, having four additional methine groups, has been developed. It has been reported that it is excited at 975 nm and fluoresces at 1100 nm, shifting to a longer wavelength than indocyanine green (ICG) (Non-Patent Literature 1). However, the synthesis of indocyanine green derivative dyes is not a simple method, as the intermediates used in the synthesis are unstable and the synthesis requires seven steps.
[0007] Furthermore, in the case of polymethine dyes, attempts have been made to shift the absorption and fluorescence wavelengths to longer wavelengths by introducing cyclic compounds such as aromatic compounds between the polymethine chains, rather than extending the polymethine chains (Non-Patent Documents 2-8). However, in all of the prior art, the methine groups are limited to a maximum of two on one side of the introduced cyclic compound, and no compounds with three or more methine groups on both sides of the cyclic compound have been synthesized. Nor is there any description of introducing cyclic compounds between polymethine chains while extending the polymethine chains. In addition, in Non-Patent Documents 2-8, the maximum fluorescence wavelength is 700 nm when the maximum absorption wavelength is 578 nm (Non-Patent Document 3). [Prior art documents] [Non-patent literature]
[0008] [Non-Patent Document 1] T. Jin, et al., Bioconjugate Chem., 32(8), 1541-1547 (2021) [Non-Patent Document 2] J. Am. Chem. Soc., 133, 10960-10965 (2011) [Non-Patent Document 3] J. Phys. Chem. A, 116, 85-92 (2012) [Non-Patent Document 4] Angew. Chem. Int. Ed., 57, 12830-12834 (2018) [Non-Patent Document 5] J. Am. Chem. Soc., 141, 19151-19160 (2019) [Non-Patent Document 6] Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy, 213, 416-422 (2019) [Non-Patent Document 7] J. Phys. Chem. C, 123, 11823-11832 (2019) [Non-Patent Document 8] J. Phys. Chem. B, 125, 3918-3931 (2021) [Overview of the Initiative] [Problems that the invention aims to solve]
[0009] The present invention provides cyanine compounds that allow for easy control of absorption and fluorescence wavelengths and can be converted into polymethine dyes, as well as a simpler method for synthesizing these cyanine compounds, and polymethine dyes containing these cyanine compounds. [Means for solving the problem]
[0010] The present inventors have discovered that polymethine chains having aldehyde groups at their termini can be easily extended in aliphatic, aromatic, or heterocyclic compounds substituted with such chains. Furthermore, they have found that by substituting the terminal aldehyde groups with nitrogen-containing heterocyclic groups, nitrogen-containing compounds including cyanine compounds with controlled polymethylene chain lengths can be obtained. They have also discovered the usefulness of such cyanine compounds as polymethine dyes, thus completing the present invention.
[0011] In other words, the present invention relates to what is specified below. [1] A method for synthesizing a nitrogen-containing compound containing a cyanine compound, which comprises extending a polymethine chain having an aldehyde group at the terminal in the compound represented by the following formula (1), and further substituting the aldehyde terminal of the extended polymethine chain with a heterocyclic group containing nitrogen. [Chemical formula] In the formula, A represents an optionally substituted aliphatic ring, aromatic ring or heterocyclic ring, n represents an integer of 1 to 20, and m represents an integer of 1 to 4. [2] An intermediate compound of a nitrogen-containing compound represented by the following formula (2). [Chemical formula] [3] A nitrogen-containing compound represented by the following formula (4). [Chemical formula] In the formula, n represents an integer of 1 to 20, and R1 to R5 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group. [4] A cyanine compound represented by the following formula (5). [Chemical formula] In the formula, A represents an optionally substituted aliphatic ring, aromatic ring or heterocyclic ring, and n represents an integer of 1 to 20. [5] The cyanine compound according to [4], represented by the following formula (6). [Chemical formula] In the formula, R1 and R2 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group. [6] The cyanine compound according to [4], represented by the following formula (7). [Chemical formula] In the formula, R independently represents a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group, and q represents an integer from 0 to 4. [7] A polymethine dye containing a cyanine compound, represented by the following formula (5). [ka] In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, and n represents an integer from 1 to 20. [8] The polymethine dye according to [7], comprising a cyanine compound represented by the following formula (6). [ka] In the formula, R1 and R2 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group. [Effects of the Invention]
[0012] According to the present invention, by using an aliphatic, aromatic, or heterocyclic compound substituted with a polymethine chain having an aldehyde group at its terminus as a starting compound, the polymethine chain can be easily extended. Furthermore, by substituting the aldehyde terminus of the extended polymethine chain with a nitrogen-containing heterocyclic group, a cyanine compound can be easily synthesized. In addition, the synthesized cyanine compound can be converted into a polymethine dye by controlling the extension of the polymethine chain and by selecting an aliphatic, aromatic, or heterocyclic group to control the absorption and fluorescence wavelengths. [Brief explanation of the drawing]
[0013] [Figure 1] This shows the wavelength ranges for visible light, near-infrared light, and OTN near-infrared light, and their respective bio-penetration properties. [Figure 2] The absorption wavelengths of BDPhBDI, BDPhHTI, and BDPhOTI are shown. [Figure 3] The fluorescence wavelengths of BDPhBDI, BDPhHTI, and BDPhOTI are shown. [Figure 4] The absorption wavelengths of PhBBBDI and PyDDBBBDI are shown. [Figure 5] The fluorescence wavelengths of PhBBBDI and PyDDBBBDI are shown. [Modes for carrying out the invention]
[0014] The present invention relates to a method for synthesizing nitrogen-containing compounds including cyanine compounds by extending a polymethine chain having an aldehyde group at its terminus in a compound represented by the following formula (1), and further substituting the aldehyde terminus of the extended polymethine chain with a nitrogen-containing heterocyclic group; intermediate compounds of nitrogen-containing compounds represented by the following formulas (2) and (3); and nitrogen-containing compounds including cyanine compounds represented by the following formulas (4), (5), (6) and (7). [ka] In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, n is an integer from 1 to 20, and m is an integer from 1 to 4. [ka] In the formula, n represents an integer from 1 to 20, and R1 to R5 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group. [ka] In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, and n represents an integer from 1 to 20. [ka] In the formula, R1 and R2 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group. [ka] In the formula, R independently represents a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group, and q represents an integer from 0 to 4.
[0015] Furthermore, the present invention relates to methine dyes containing a cyanine compound represented by formula (5) of the present invention, and polymethine dyes containing a specific cyanine compound represented by the following formula (6) of the present invention. [ka] In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, and n represents an integer from 1 to 20. [ka] In the formula, R1 and R2 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group.
[0016] The present invention provides a method for synthesizing nitrogen-containing compounds, including cyanine compounds, using a compound represented by the following formula (1), which has an aldehyde group at its terminus, as a starting material. [ka] In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, n is an integer from 1 to 20, and m is an integer from 1 to 4.
[0017] Examples of aliphatic rings as A include cyclohexane, cyclohexanone, and hydroxycyclohexene; examples of aromatic rings include benzene, naphthalene, and anthracene; examples of heterocycles include five-membered aromatic heterocycles such as pyrrole, furan, thiophene, imidazole, pyrazole, oxazar, isoxazole, thiazole, and isothiazole; examples of six-membered aromatic heterocycles include pyridine, pyrimidine, pyridazine, pyrazine, and 1,2,3-triazine; examples of aliphatic heterocycles include piperidine, piperazine, morpholine, quinuclidine, and pyrrolidine; and examples of polycyclic aromatic heterocycles include quinoline, isoquinoline, quinazoline, phthalazine, pteridine, coumarin, chromone, 1,4-benzodiazepine, indole, benzimidazole, benzofuran, purine, acridine, phenoxazine, and phenothiazine. When these cyclic compounds are heterocyclic, pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, piperidine, piperazine, morpholine, quinuclidine, pyrrolidine, phthalazine, acridine, phenoxazine, and phenothiazine are preferred because they can strongly donate electrons, with pyrrole rings being more preferred. Among five-membered and six-membered aliphatic rings and aromatic ring compounds, electron-donating compounds that easily push electrons are preferred, and aromatic rings such as benzene rings are preferred. Furthermore, substituents on ring A may include hydroxyl groups, alkyl groups, cycloalkyl groups, alkoxy groups, ester groups, etc., in addition to hydrogen, and the strength of electron-donating and electron-withdrawing properties of ring A can be controlled by selecting the substituents.
[0018] n is an integer from 1 to 20, and m is an integer from 1 to 4, depending on the number of elements constituting ring A. From the viewpoint of the synthesis efficiency of the compound shown in formula (1), n is preferably from 1 to 10, and m is not particularly limited, but 1 or 2 is preferred because it is easy to synthesize and can impart electron-donating properties. In addition, in the compound shown in formula (1), the polymethine chain having an aldehyde at the terminal may be attached to any of the ortho, meta, or para positions when ring A is a six-membered ring, but the meta or para position is preferred in order to enhance electron-donating properties. Furthermore, when ring A is a five-membered heterocycle such as a pyrrole ring, the polymethine chain can be attached to any two of the four carbon atoms constituting the ring, but attaching it to the positions adjacent to the heteroatom is preferred in order to enhance electron-donating properties.
[0019] In the present invention's method for synthesizing nitrogen-containing compounds including cyanine compounds, the length of the polymethine chains in the starting compound can be easily controlled by repeatedly reacting the starting compound with (1,3-dioxolan-2-yl)methyltriphenylphosphonium bromide in a solvent, if necessary.
[0020] According to the method for synthesizing nitrogen-containing compounds including the cyanine compound of the present invention, intermediate compounds of the nitrogen-containing compound represented by the following formula (2) or (3) of the present invention can be synthesized. These compounds are useful as intermediates for cyanine compounds as polymethine dyes because, according to the synthesis method of the present invention, the length of the polymethine chain can be controlled and substitution with a nitrogen-containing heterocyclic group. [ka]
[0021] The present invention provides a method for synthesizing cyanine compounds by substituting the aldehyde terminus of an extended polymethine chain with a nitrogen-containing heterocyclic group, in accordance with the present invention. The nitrogen-containing heterocyclic group is not particularly limited as long as it is used as a nitrogen-containing heterocyclic group at the terminus of the cyanine compound; for example, 1-butyl-2,3,3-trimethyl-3H-indolinium bromide can be used. The substitution reaction can be carried out according to standard procedures, as shown in the following examples.
[0022] According to the present invention's method for synthesizing nitrogen-containing compounds, including cyanine compounds, by substituting the aldehyde terminus of an extended polymethine chain with a nitrogen-containing heterocycle, compounds represented by the following formulas (8), (4), (5), (6), and (7) can be synthesized, and these compounds are useful as intermediates or polymethine dyes for polymethine dyes. [ka] In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, and n represents an integer from 1 to 20. In formula (8), n is preferably 1 to 10 from the viewpoint of synthesis efficiency, and preferably 2 or more from the viewpoint of increasing the control range of absorption and fluorescence wavelengths towards longer wavelengths. [ka] In the formula, n is an integer from 1 to 20, and R1 to R5 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group. In formula (4), n is preferably 1 to 10 from the viewpoint of synthesis efficiency, and preferably 2 or more from the viewpoint of increasing the control range of absorption wavelength and fluorescence wavelength towards longer wavelengths. [ka] In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, and n represents an integer from 1 to 20. In formula (5), n is preferably 1 to 10 from the viewpoint of synthesis efficiency. [ka] In the formula, R1 and R2 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group. [ka] In the formula, R independently represents a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group, and q represents an integer from 0 to 4.
[0023] The cyanine compound represented by the following formula (5) of the present invention can have its absorption and fluorescence wavelengths lengthened by controlling the length of the polymethine chain and interposing a ring structure within the polymethine chain, and is useful as a polymethine dye or an intermediate for polymethine dyes. [ka] In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, and n represents an integer from 1 to 20. A specific example of the cyanine compound represented by formula (5) of the present invention is the cyanine compound represented by formula (6) below. Since such a cyanine compound has an fluorescence wavelength in the near-infrared wavelength range, as described in the following examples, it is effective as a near-infrared fluorescent dye. [ka] In the formula, R1 and R2 each independently represent a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group.
[0024] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the description of the examples. [Examples]
[0025] [Synthesis Example 1: Synthesis of 1-butyl-2,3,3-trimethyl-3H-indolium bromide (1:1) (BTMI)] 1-butyl-2,3,3-trimethyl-3H-indolium bromide (1:1) (BTMI) was synthesized according to the following chemical reaction equation. [ka] A 5 mL C2H5CN solution of 2,3,3-trimethylindolenine (1.5 mL, 9.33 mmol) and 2-bromobutane (1.53 mL, 14.2 mmol) was prepared in a 50 mL round-bottom flask. This solution was heated and stirred at 90°C for 24 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. Subsequently, the organic solvent was removed by evaporation, and 2-bromobutane was removed by vacuum. Furthermore, the product was purified by distillation using a Kugelrohor apparatus to obtain 1-Butyl-2,3,3-trimethyl-3H-indolium bromide (1:1) (BTMI: 1.49 g, 5.03 mmol). Purple solid, yield: 1.49 g (5.03 mmol), yield: 54.0% 1H-NMR (CDCl3) δ (ppm from TMS): 1.01 (3H, t, J = 7.4 Hz, -CH3), 1.46-1.54 (2H, m, -CH2-), 1.64 (6H, s, -CH3), 1.87-1.94 (2H, m, -CH2-), 3.13 (3H, s, -CH3), 4.75 (2H, t, J = 7.4 Hz, -CH2-),7.52-7.64 (4H, m, Aromatic protons)
[0026] [Synthesis Example 2: Synthesis of 1-butyl-3,3-dimethyl-2-(4-phenyl-1,3-butadiene-1-yl)-3H-indolium bromide (1:1) (BDPhBDI)] 1-butyl-3,3-dimethyl-2-(4-phenyl-1,3-butadiene-1-yl)-3H-indolium bromide (1:1) (BDPhBDI) was synthesized according to the following chemical reaction equation. [ka] In a 50 mL round-bottom flask, 1-butyl-2,3,3-trimethyl-3H-indolium bromide (1:1) (BTMI: 0.30 g, 1.01 mmol) and trans-cinnamaldehyde (Cin-ald: 0.16 g, 1.21 mmol) were dissolved in 10 mL of EtOH solution under a nitrogen atmosphere, and one drop of CH3SO3H was added as a catalyst. This solution was heated and stirred at 75°C for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the organic solvent was removed by vacuum distillation. Subsequently, it was washed with Et2O to obtain 1-Butyl-3,3-dimethyl-2-(4-phenyl-1,3-butadien-1-yl)-3H-indolium bromide (1:1) (BDPhBDI). Brown solid, mp: 160 - 162 ℃ 1H-NMR (CDCl3) δ (ppm from TMS): 1.00 (3H, t, J = 7.4 Hz, -CH3), 1.57-1.66 (2H, m, -CH2-), 1.80 (6H, s, -CH3), 1.90-1.99 (2H, m, -CH2-), 4.86 (2H, t, J = 7.4 Hz, -CH2-), 7.39-8.24 (13H, m, Aromatic protons, -CH=)
[0027] "Synthesis Example 3: Synthesis of (2E, 4E)-5-phenyl-2,4-pentadienal (PhPDE)" (2E,4E)-5-phenyl-2,4-pentadienal (PhPDE) was synthesized according to the following chemical reaction equation. [ka] A tetrahydrofuran (THF) solution (45 mL) containing trans-cinnamaldehyde (Cin-ald: 1.59 g, 11.9 mmol), (1,3-Dioxolan2-yl)methyltriphenylphosphonium bromide (Doxl-MeTPPBr: 5.85 g, 13.6 mmol), and 18-crown-6 (0.041 g, 0.155 mmol) was prepared in a 100 mL round-bottom flask. This solution was cooled with stirring in a salt ice bath, and a THF (6 mL) suspension of NaH (0.96 g, 24.0 mmol in 60% oil), from which the oil had been removed with n-hexane, was added all at once. The reaction mixture was raised to room temperature and stirred at that temperature for 2 hours. Subsequently, a suspension of NaH (1.03 g, 25.8 mmol in 60% oil) with oil removed using n-hexane was added in THF (6 mL), and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 20 hours. The reaction mixture was cooled again on ice, and water (30 mL) was slowly added to stop the reaction. Further, concentrated hydrochloric acid (9.6 mL, 46.5 mmol) was added to the reaction mixture while stirring to deprotect it (hydrolysis of 1,3-dioxolane). After 2 hours at room temperature, the deprotected mixture was cooled again on ice and carefully neutralized by adding aqueous NaOH solution. The target product was extracted with diethyl ether (30 mL three times), and the collected diethyl ether layer was washed with Sat. NaCl aq. (15 mL three times). The organic layer was dried over anhydrous Na2SO4, and the organic solvent was removed by distillation using an evaporator. The residue was purified by silica gel chromatography (n-hexane : siRNA = 10 : 1, v / v, Rf = 0.23) to obtain (2E, 4E)-5-phenyl-2,4-pentadienal (PhPDE: 1.06 g, 6.67 mmol). Orange viscous liquid, yield: 1.06 g (6.67 mmol), yield: 55.4% 1H-NMR (CDCl3) δ (ppm from TMS): 6.26 (1H, dd, J = 8.0, 14.9 Hz, -CH=), 6.96-7.04 (2H, m, HC=HC), 7.23-7.51 (6H, m, Aromatic protons, -CH=), 9.61 (1H, d, J = 8.0 Hz, -CHO)
[0028] [Synthesis Example 4: Synthesis of 1-butyl-3,3-dimethyl-2-(6-phenyl-1,3,5-hexatrien-1-yl)-3H-indolium bromide (1:1) (BDPhHTI)] 7 1-butyl-3,3-dimethyl-2-(6-phenyl-1,3,5-hexatrien-1-yl)-3H-indolium bromide (1:1) (BDPhHTI) was synthesized according to the following chemical reaction equation. [ka] In a 50 mL round-bottom flask, 1-butyl-2,3,3-trimethyl-3H-indolium bromide (1:1) (BTMI: 0.12 g, 0.41 mmol) and (2E,4E)-5-phenyl-2,4-pentadienal (PhPDE: 0.092 g, 0.58 mmol) were dissolved in 5 mL of EtOH solution under a nitrogen atmosphere, and one drop of CH3SO3H was added as a catalyst. This solution was heated and stirred at 75°C for 7 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the organic solvent was removed by vacuum distillation. Subsequently, it was washed with Et2O to obtain 1-butyl-3,3-dimethyl-2-(6-phenyl-1,3,5-hexatrien-1-yl)-3H-indolium bromide (1:1) (BDPhHTI: 0.077 g, 0.18 mmol). Reddish-brown solid, yield: 0.077 g (0.18 mmol), yield: 44.5%, mp: 165 ℃ 1H-NMR (CDCl3) δ (ppm from TMS): 1.00 (3H, t, J = 7.4 Hz, -CH3), 1.57-1.65 (2H, m, -CH2-), 1.78 (6H, s, -CH3), 1.89-1.97 (2H, m, -CH2-), 4.82 (2H, t, J = 7.4 Hz, -CH2-), 7.00-8.03 (15H, m, Aromatic protons, -CH=)
[0029] [Synthesis Example 5: Synthesis of (2E, 4E, 6E)-7-phenyl-2,4,6-heptatrienal (PhHTE)] (2E,4E,6E)-7-phenyl-2,4,6-heptatrienal (PhHTE) was synthesized according to the following chemical reaction equation. [ka] A tetrahydrofuran (THF) solution (20 mL) containing PhPDE (0.81 g, 5.12 mmol), (1,3-Dioxolan-2-yl)methyltriphenylphosphonium bromide (Doxl-MeTPPBr: 2.53 g, 5.89 mmol), and 18-crown-6 (0.014 g, 0.058 mmol) was prepared in a 100 mL round-bottom flask. This solution was cooled with stirring in a salt ice bath, and a THF (4 mL) suspension of NaH (0.44 g, 11.0 mmol in 60% oil) from which the oil had been removed with n-hexane was added all at once. The reaction mixture was raised to room temperature and stirred at that temperature for 1.5 hours. Subsequently, a suspension of NaH (0.46 g, 11.5 mmol in 60% oil) with oil removed using n-hexane was added in THF (4 mL), and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 65 hours. The reaction mixture was cooled again on ice, and water (20 mL) was slowly added to stop the reaction. Further, concentrated hydrochloric acid (4.1 mL, 20.0 mmol) was added to the reaction mixture while stirring to deprotect it (hydrolysis of 1,3-dioxolane). After 2 hours at room temperature, the deprotected mixture was cooled again on ice and carefully neutralized by adding aqueous NaOH solution. The target product was extracted with diethyl ether (30 mL three times), and the collected diethyl ether layer was washed with Sat. NaCl aq. (15 mL three times). The organic layer was dried over anhydrous Na2SO4, and the organic solvent was removed by distillation using an evaporator. The residue was purified by silica gel chromatography (n-hexane : Depositphotos = 7 : 1, v / v, Rf = 0.18) to obtain (2E, 4E, 6E)-7-phenyl-2,4,6-heptatrienal (PhHTE: 0.45 g, 2.44 mmol). Orange solid, yield: 0.45 g (2.44 mmol), yield: 48.0%, mp: 112 - 114 ℃ 1H-NMR (CDCl3) δ (ppm from TMS): 6.19 (1H, dd, J = 8.0, 15.5 Hz, -CH=), 6.52-6.94 (4H, m, HC=CH), 7.14-7.47 (6H, m, Aromatic protons, -CH=), 9.58 (1H, d, J = 8.0 Hz, -CHO)
[0030] [Synthesis Example 6: Synthesis of 1-butyl-3,3-dimethyl-2-(8-phenyl-1,3,5,7-octatetraen-1-yl)-3H-indolium bromide (1:1) (BDPhOTI)] 1-butyl-3,3-dimethyl-2-(8-phenyl-1,3,5,7-octatetraen-1-yl)-3H-indolium bromide (1:1) (BDPhOTI) was synthesized according to the following chemical reaction equation. [ka] In a 50 mL round-bottom flask, 1-butyl-2,3,3-trimethyl-3H-indolium bromide (1:1) (BTMI: 0.056 g, 0.056 mmol) and (2E,4E,6E)-7-phenyl-2,4,6-heptatrienal (PhHTE: 0.043 g, 0.233 mmol) were dissolved in 5 mL of EtOH solution under a nitrogen atmosphere, and one drop of CH3SO3H was added as a catalyst. This solution was heated and stirred at 75 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the organic solvent was removed by vacuum distillation. Subsequently, it was washed with Et2O to obtain 1-Butyl-3,3-dimethyl-2-(8-phenyl-1,3,5,7-octatetraene-1-yl)-3H-indolium bromide (1:1) (BDPhOTI). black viscous liquid 1H-NMR (CDCl3) δ (ppm from TMS): 0.96-1.04 (3H, m, -CH3), 1.49-1.59 (2H, m, -CH2-), 1.78(6H, s, -CH3), 1.91 (2H, s, -CH2-), 4.64 (2H, s, -CH2-), 6.69-8.03 (17H, m, Aromatic protons, - CH=)
[0031] [Synthesis Example 7: Synthesis of (2E,2E')-3,3'-(1,4-phenylene)bis(2-propenal)(PhBPE)] (2E,2E')-3,3'-(1,4-phenylene)bis(2-propenal)(PhBPE) was synthesized according to the following chemical reaction equation. [ka] A tetrahydrofuran (THF) solution (20 mL) containing terephthalaldehyde (0.53 g, 3.96 mmol), (1,3-Dioxolan-2-yl)methyltriphenylphosphonium bromide (Doxl-MeTPPBr: 3.90 g, 9.08 mmol), and 18-crown-6 (0.025 g, 0.095 mmol) was prepared in a 100 mL round-bottom flask. This solution was cooled with stirring in a salt ice bath, and a THF (5 mL) suspension of NaH (0.65 g, 16.3 mmol in 60% oil) from which the oil had been removed with n-hexane was added all at once. The reaction mixture was raised to room temperature and stirred at that temperature for 2 hours. Subsequently, a suspension of NaH (0.68 g, 17.0 mmol in 60% oil) with oil removed using n-hexane was added in THF (5 mL), and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 23.5 hours. The reaction mixture was cooled again on ice, and water (30 mL) was slowly added to stop the reaction. Further, concentrated hydrochloric acid (6.4 mL, 31.0 mmol) was added to the reaction mixture while stirring to deprotect it (hydrolysis of 1,3-dioxolane). After 2 hours at room temperature, the deprotected mixture was cooled again on ice and carefully neutralized by adding aqueous NaOH solution. The target product was extracted with diethyl ether (30 mL three times), and the collected diethyl ether layer was washed with sat. NaCl aq. (15 mL three times). The organic layer was dried over anhydrous Na2SO4, and the organic solvent was removed by distillation using an evaporator. The residue was purified by silica gel chromatography (n-hexane : Depositphotos = 2 : 1, v / v, Rf = 0.23) to obtain (2E,2E')-3,3'-(1,4-phenylene)bis(2-propenal) (PhBPE: 0.40 g, 2.15 mmol)). Yellow solid, mp: 240 - 243 ℃ 1H NMR (Solv: CDCl3): 6.26 (1H, dd, J = 8.0, 14.9 Hz, -CH=), 6.96-7.04 (2H, m, HC=HC), 7.23-7.51 (6H, m, Aromatic protons, -CH=), 9.61 (1H, d, J = 8.0 Hz, -CHO).
[0032] [Synthesis Example 8: Synthesis of 2,2'-(1,4-phenylenedi-1,3-butadiene-1-yl)bis(1-butyl-3,3-dimethyl-3H-indrolium bromide)] 2,2'-(1,4-phenylenedi-1,3-butadiene-1-yl)bis(1-butyl-3,3-dimethyl-3H-indrolium bromide) was synthesized according to the following chemical reaction equation. [ka] In a 50 mL round-bottom flask, 1-butyl-2,3,3-trimethyl-3H-indolium bromide (1:1) (BTMI: 0.30 g, 1.01 mmol) and (2E,2E')-3,3'-(1,4-phenylene)bis(2-propenal) (PhBPE: 0.12 g, 0.64 mmol) were dissolved in 5 mL of EtOH solution under a nitrogen atmosphere, and one drop of CH3SO3H was added as a catalyst. This solution was heated and stirred at 75°C for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the organic solvent was removed by vacuum distillation. The residue was then washed with siRNA to obtain 2,2'-(1,4-phenylenedi-1,3-butadien-1-yl)bis(1-butyl-3,3-dimethyl-3H-indolium bromide (1:2) (PhBBBDI: 0.17 g, 0.26 mmol)). Black solid 1H NMR (Solv: CDCl3): 0.97-1.03 (6H, m, -CH3), 1.80 (2H, s, -CH3), 1.85 (10H, s, -CH3), 1.92-2.00 (4H, m, -CH2-), 4.87 (4H, q, J = 15.3 Hz, -CH2-), 7.48-8.39 (20H, m, Aromatic protons, -CH=).
[0033] [Synthesis Example 9: Synthesis of 1H-pyrrole-2,5-diacrylaldehyde (PyDAA)] (1H-pyrrole-2,5-diacrylaldehyde (PyDAA)) was synthesized according to the following chemical reaction equation. [ka] A 45 mL solution of pyrrole (0.84 mL, 12.2 mmol) and 3-dimethylaminoacrolein (4.1 mL, 4.09 mmol) in C2H4Cl2 was prepared in a 200 mL three-necked round-bottom flask. This solution was stirred at room temperature under a nitrogen atmosphere, and a 6 mL solution of phosphorus oxychloride (3.4 mL, 3.73 mmol) in C2H4Cl2 was added dropwise. The reaction mixture was heated under a nitrogen atmosphere at 80°C for 90 min and stirred. Then, 45 mL of 1 M sodium acetate solution was added, and the reaction mixture was heated under a nitrogen atmosphere at 80°C for 15 min and stirred. The reaction mixture was cooled to room temperature, and Sat. NaHCO3 aq. was slowly added. The reaction mixture was extracted with CHCl3 (4 times) and washed with water (4 times). The organic layer was dried over anhydrous Na2SO4, and the organic solvent was removed by vacuum distillation. EtOH (60 mL) was added to the residue, and the mixture was heated to dissolve the solids. The mixture was cooled to room temperature, the precipitated solid was filtered off, and the filtrate was concentrated using an evaporator. The residue was purified by silica gel chromatography (n-hexane : siRNA = 2 : 1, v / v, Rf = 0.28) to obtain 1H-pyrrole-2,5-diacrylaldehyde (PyDAA: 0.21 g, 1.2 mmol). Yellowish brown solid, mp:138~141℃ 1H NMR (Solv: DMSO): 6.67 (2H, dd, J = 8.0, 16.0 Hz, -CH=), 6.79 (2H, s, -CH=), 7.46 (2H, d, J = 16.0 Hz, -CH=), 9.53 (2H, d, J = 8.0 Hz, -CHO), 12.02 (1H, s, -NH).
[0034] [Synthesis Example 10: Synthesis of 2,2'-(1H-pyrrole-2,5-diyludi-1,3-butadiene-1-yl)bis(1-butyl-3,3-dimethyl-3H-indrolium bromide (PyDDBBBDI)] 2,2'-(1H-pyrrole-2,5-diylyl-1,3-butadiene-1-yl)bis(1-butyl-3,3-dimethyl-3H-indrolium bromide (PyDDBBBDI)) was synthesized according to the following chemical reaction equation. [ka] In a 100 mL round-bottom flask, 1-butyl-2,3,3-trimethyl-3H-indolium bromide (1:1) (BTMI: 0.71 g, 2.4 mmol) and 1H-pyrrole-2,5-diacrylaldehyde (PyDAA: 0.21 g, 1.2 mmol) were dissolved in 15 mL of EtOH solution under a nitrogen atmosphere, and one drop of CH3SO3H was added as a catalyst. This solution was heated and stirred at 75°C for 22 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the organic solvent was removed by vacuum distillation. The residue was then purified by washing with Et2O to obtain 2,2'-(1H-Pyrrole-2,5-diyldi-1,3-butadien-1-yl)bis(1-butyl-3,3-dimethyl-3H-indolium bromide (1:2)) (PyDDBBBDI: 0.90 g, 1.2 mmol)). Black solid 1H NMR (Solv: DMSO): 0.89-0.94 (6H, m, -CH3), 4.38-4.48 (4H, m, -CH2-), 1.67-1.83 (16H, m, -CH2-, -CH3), 4.38-4.48 (4H, m, -CH2-), 6.98-8.37 (18H, m, aromatic protons). [Examples]
[0035] The optical properties of BDPhBDI synthesized in Synthesis Example 2, BDPhHTI synthesized in Synthesis Example 4, and BDPhOTI synthesized in Synthesis Example 6 were investigated. -5 UV, Visible, and Near-Infrared absorption spectra of moles / L and 1.0 × 10⁻¹⁰ in tetrahydrofuran -4 The fluorescence emission spectra were measured at moles / L. The ultraviolet, visible, and near-infrared absorption spectra are shown in Figure 2, and the fluorescence emission spectra are shown in Figure 3. It was confirmed that both the maximum absorption wavelength and the maximum fluorescence wavelength shifted to longer wavelengths as the polymethylene difference increased. [Examples]
[0036] The optical properties of PhBBBDI synthesized in Synthesis Example 8 and PyDDBBBDI synthesized in Synthesis Example 10 were investigated. -5 The ultraviolet, visible, and near-infrared absorption spectra and fluorescence emission spectra of mol / L PhBBBDI and PyDDBBBDI were measured. The ultraviolet, visible, and near-infrared absorption spectra are shown in Figure 4, and the fluorescence emission spectra are shown in Figure 5. The maximum absorption wavelength of PhBBBDI was 537.0 nm (excitation wavelength 539.5 nm), and the maximum fluorescence wavelength was 627.2 nm. On the other hand, the maximum absorption wavelength of PyDDBBBDI was 760.0 nm (excitation wavelength 779.0 nm), and the maximum fluorescence wavelength was 823.6 nm. By interposing a pyrrole ring in the polymethine chain, the maximum fluorescence wavelength was in the near-infrared region. [Industrial applicability]
[0037] The present invention makes it possible to easily extend polymethine chains and, by introducing electron-donating groups such as pyrrole rings into the polymethine chains, provides polymethine dyes having a cyanine skeleton that are effective even in the near-infrared region.
Claims
1. A method for synthesizing a nitrogen-containing compound including a cyanine compound, characterized by extending a polymethine chain having an aldehyde group at its terminus in a compound represented by the following formula (1), and further substituting the aldehyde terminus of the extended polymethine chain with a nitrogen-containing heterocyclic group. 【Chemistry 1】 In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, n represents an integer from 1 to 20, and m represents an integer from 1 to 4.
2. An intermediate compound of a nitrogen-containing compound represented by the following formula (2). 【Chemistry 2】
3. A nitrogen-containing compound represented by the following formula (4). 【Transformation 3】 In the formula, n represents an integer from 1 to 20, and R １ ~R ５ Each of these independently represents a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group.
4. A cyanine compound represented by the following formula (5). 【Chemistry 4】 In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, and n represents an integer from 1 to 20.
5. The cyanine compound according to claim 4, represented by the following formula (6). 【Transformation 5】 In the formula, R １ and R ２ Each of these independently represents a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group.
6. The cyanine compound according to claim 4, represented by the following formula (7). 【Transformation 6】 In the formula, R independently represents a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group, and q represents an integer from 0 to 4.
7. A polymethine dye containing a cyanine compound, as shown in formula (5) below. 【Transformation 7】 In the formula, A represents an optional aliphatic ring, aromatic ring, or heterocycle, and n represents an integer from 1 to 20.
8. The polymethine dye according to claim 7, comprising a cyanine compound represented by the following formula (6). 【Transformation 8】 In the formula, R １ and R ２ Each of these independently represents a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, or an ester group.