Iridium Complexes

Abstract

To provide an iridium that has an N-hydroxysuccinimide ester group, which responds to a wavelength region called a biological window and is a site of binding to a biological substance.SOLUTION: Provided is a compound that is represented by the following formula (1). [In the formula (1), a ring A and a ring C, each independently represent a benzene ring which may have a substituent. A ring B and a ring D, each independently represent any one of a pyridine ring, a pyrazine ring, a pyrimidine ring, an imidazole ring, an oxazole ring, and a thiazole ring, each of which may have a substituent. X1 represents a nitrogen atom or CR2.].SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention provides an irradiated ion exchange membrane that can be easily introduced into biological materials such as nucleic acids, proteins, and polysaccharides. This relates to Zn complexes. [Background technology]

[0002] Various electronic devices using organic electroluminescent elements, such as lighting and displays, have been put to practical use. The company is now efficiently producing organic electroluminescent devices that can be used for large displays and lighting. The coating method is being researched as a manufacturing process. The coating method is more stable than the vacuum deposition method. This has the advantage that the layers can be easily formed, making it suitable for mass production of displays and lighting devices and for large-scale devices. In order to manufacture organic electroluminescent devices by the coating method, a light-emitting dopant is required. All materials, including the paint, must be able to be dissolved and used as ink.

[0003] As for the light-emitting dopants, red, green, and blue emission colors are required according to the application. For red, arylquinoline derivatives or arylisoquinoline derivatives are used as ligands. In addition, iridium complexes that can adjust the emission wavelength and improve solubility are used. For the purpose of this study, arylquinoxaline derivatives and arylquinazoline derivatives having two N atoms were synthesized. Iridium complexes with arylnaphthyridine derivatives such as aryl cations as ligands have also been proposed. (For example, Patent Document 1).

[0004] In recent years, it has been reported that iridium complexes exhibit intersystem crossing from the excited singlet state to the excited triplet state. The triplet excited state is easily oxidized, has a relatively long decay life, and emits light. Attempts have been made to apply the property of being easily inactivated by iridium to biochemical applications. When administering iridium complexes to the body, nuclear It is effective to bind iridium complexes to biological materials such as acids, proteins, and polysaccharides. The N-hydroxysuccinimide ester group is used as the binding site for these biological substances. It has been reported that this is the case (for example, Non-Patent Documents 1 and 2). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2015-83587 A [Non-patent literature]

[0006] [Non-Patent Document 1] Bioorganic & Medical Chemistry, 2018, vol. 26, pp. 4804-4816 [Non-Patent Document 2] Analytical Chemistry, 2016, Vol. 88, pp. 1892-1899 Summary of the Invention [Problem to be solved by the invention]

[0007] However, in the above-mentioned prior art, the wavelength of emission or absorption is short, which is called the biological window. It does not support the 650-1000 nm wavelength range, which is not easily absorbed by substances and water in the body. However, when iridium complexes were used in biochemical applications, sufficient performance could not be obtained. Therefore, it is an iridium complex that can be easily introduced into biological materials in the 650-1000 nm wavelength range. What was required was...

[0008] The present invention is directed to a wavelength range called the biological window, and is capable of detecting N-hydroxylase, which is a binding site for biological substances. The present invention provides an iridium complex having an iridium ester group. [Means for solving the problem]

[0009] As a result of intensive research in view of the above problems, the present inventors have discovered an N-hydroxysuccinimide ester. The dipyrromethene and boron atom are connected via a spacer (BODIPY skeleton). The iridium complex linked to a ligand having a BODIPY or aza-BODIPY skeleton shifts the absorption wavelength to the red. The wavelengths range from red to infrared, which corresponds to the wavelength range known as the biological window, and can be easily introduced into biological materials. Based on this finding, the present invention has been completed.

[0010] That is, the gist of the present invention is as follows. [1] A compound represented by the following formula (1):

[0011] [ka]

[0012] In formula (1), ring A and ring C each independently represent a benzene ring which may have a substituent. Ring B and ring D each independently represent a pyridine ring, a pyrazine ring, or a pyrimidine ring which may have a substituent. It represents any one of an aryl ring, an imidazole ring, an oxazole ring, and a thiazole ring. X 1 is a nitrogen atom or CR 2 Represents. R 2 is a hydrogen atom or a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. It represents a aryl group.

[0013] Ar 1 represents a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Ar 2is a hydrogen atom or a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. It represents a alkyl group. Rings A~D, R 2 , Ar 1 and Ar 2 The substituent that may be present is a C1-20 substituent. Alkyl groups, alkenyl groups with 2 to 20 carbon atoms, alkoxy groups with 1 to 20 carbon atoms, (Hetero)aryloxy group having 2 to 20 carbon atoms, alkylcarbonyl group having 2 to 20 carbon atoms, Arylcarbonyl groups having 7 to 20 carbon atoms, alkylamino groups having 2 to 20 carbon atoms, arylamino groups, (hetero)aryl groups having 3 to 20 carbon atoms, polyaryl groups having 4 to 16 carbon atoms alkyl ether group, quaternary ammonium group, sulfonic acid group, or sodium sulfonate groups, or a combination of these. The substituents may further be bonded to each other to form a ring.

[0014] Y 1 represents a fluorine atom or a trifluoromethyl group. Z 1 represents a direct bond or a divalent aromatic linking group. R 1 is connected to Z via three or more single bonds. 1 and N-hydroxysuccinimide ester group Represents a linking group. [2] The compound according to [1], wherein the formula (1) is a compound represented by formula (2).

[0015] [ka]

[0016] [In the above formula, ring A, ring B, Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , Z1 , R 1 is expressed as (1) In the ring A, ring B, and Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , Z 1 , R 1 is equivalent to.] [3] The compound according to [2], wherein the formula (2) is a compound represented by the formula (3) or the formula (4): .

[0017] [ka]

[0018] [In formula (3), ring A, ring B, Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , Z 1 , R 1 is expressed as (2 ) in ring A, ring B, Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , Z 1 , R 1 is synonymous with. ]

[0019] [ka]

[0020] [In formula (4), ring A, ring B, Ar 1 , Ar 2 , Y 1 , Z 1 , Z 1 , R 1 In equation (2), Ring A, ring B, Ar 1 , Ar 2 , Y 1 , Z 1 , Z 1 , R 1is equivalent to.] Effect of the Invention

[0021] The present invention has enabled the development of a method for detecting N-, which is a binding site for biological substances and corresponds to a wavelength range called the biological window. Iridium having a hydroxysuccinimide ester group could be provided. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the results of measuring the absorption spectrum. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The embodiments of the present invention will be described in detail below, but the present invention is not limited to the following embodiments. The present invention is not limited to the above, and can be practiced in various modified forms within the scope of the spirit thereof. In this specification, the (hetero)aryloxy group and the (hetero)aryl group are an aryloxy group which may contain a heteroatom, each of which may contain a heteroatom; "Optionally, a heteroatom may be contained in the aryl group." The term "aryl group" refers to one or more carbon atoms forming the main skeleton of an aryl group or an aryloxy group. The carbon atom above is replaced with a heteroatom, such as a nitrogen atom, Examples of the atoms include oxygen atoms, sulfur atoms, phosphorus atoms, and silicon atoms. Among these, nitrogen atoms are preferred from the viewpoint of durability. Atoms are preferred. The iridium complex of the present invention is a compound represented by the following formula (1).

[0024] [ka]

[0025] In formula (1), ring A and ring C each independently represent a benzene ring which may have a substituent. Ring B and ring D each independently represent a pyridine ring, a pyrazine ring, or a pyrimidine ring which may have a substituent. It represents any one of an aryl ring, an imidazole ring, an oxazole ring, and a thiazole ring. X 1 is a nitrogen atom or CR 2 Represents. R 2 is a hydrogen atom or a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. It represents a aryl group. Ar 1 represents a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Ar 2 is a hydrogen atom or a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. It represents a alkyl group.

[0026] Rings A~D, R 2 , Ar 1 and Ar 2 The substituent that may be present is a C1-20 substituent. Alkyl groups, alkenyl groups with 2 to 20 carbon atoms, alkoxy groups with 1 to 20 carbon atoms, (Hetero)aryloxy group having 2 to 20 carbon atoms, alkylcarbonyl group having 2 to 20 carbon atoms, Arylcarbonyl groups having 7 to 20 carbon atoms, alkylamino groups having 2 to 20 carbon atoms, arylamino groups, (hetero)aryl groups having 3 to 20 carbon atoms, polyaryl groups having 4 to 16 carbon atoms alkyl ether group, quaternary ammonium group, sulfonic acid group, or sodium sulfonate groups, or a combination of these. The substituents may further be bonded to each other to form a ring. Y 1 represents a fluorine atom or a trifluoromethyl group. Z 1 represents a direct bond or a divalent aromatic linking group. R 1 is connected to Z via three or more single bonds. 1 and N-hydroxysuccinimide ester group Represents a linking group.

[0027] The iridium complex of formula (1) has a structure consisting of dipyrromethene and a boron atom (BODIPY Since it has a BODIPY skeleton or aza-BODIPY skeleton, it absorbs light at relatively long wavelengths from red to infrared. Furthermore, the corresponding iridium complex excited by irradiation with light disseminates its energy to the surroundings. In addition, the iridium molecule of formula (1) can transfer energy to the iridium The complex is a complex of iridium metal and ligand with N-hydroxysuccinimide ester group. Since it has one at a position away from the chain structure, it can bind one ion to the primary amine in the biological material. It is possible to easily introduce a rhodium complex while maintaining the above-mentioned excellent optical properties.

[0028] <Ring A~D> Ring A and ring C each independently represent a benzene ring which may have a substituent. Adjacent substituents may be bonded to each other to form a ring. In this case, the benzene rings of rings A and C are combined to form a naphthalene ring, anthracene ring, or phenanthane ring. A thylene ring, a pyrene ring, a perylene ring, a fluorene ring, a carbazole ring, a dibenzofuran ring, It forms a condensed ring with a benzene ring structure such as a dibenzothiophene ring.

[0029] From the viewpoint of solubility, it is preferable that the substituents of rings A and C do not bond to each other to form a ring. As the condensed ring including ring A and ring C, from the viewpoint of solubility, a naphthalene ring, an aliphatic ring, anthracene ring, phenanthrene ring, pyrene ring, perylene ring, fluorene ring, carbazole A ring, a dibenzofuran ring, or a dibenzothiophene ring is preferred, and a naphthalene ring or a fluorene ring is preferred. is more preferred.

[0030] Ring B and ring D each independently represent a pyridine ring, a pyrazine ring, or a pyrimidinium ring which may have a substituent. Ring B and Ring D represent one of the following rings: diphenyl ring, imidazole ring, oxazole ring, and thiazole ring. Adjacent substituents bonded to may be bonded to each other to form a ring. In this case, together with ring B and ring D, it forms a quinoline ring, an isoquinoline ring, a quinoxaline ring, or a quina ring. Forms a zoline ring, a benzimidazole ring, a benzoxazole ring, or a benzothiazole ring From the viewpoint of solubility, the condensed rings including rings B and D are preferably an azaanthracene ring, a diazaanthracene ring, Anthracene ring, azaphenanthrene ring, diazaphenanthrene ring, azatriphenylene A diazatriphenylene ring is preferable, and a benzothiazole ring is more preferable.

[0031] The substituents that the rings A to D may have are an alkyl group having 1 to 20 carbon atoms, a cyclic group having 2 to 20 carbon atoms, alkenyl groups, alkoxy groups having 1 to 20 carbon atoms, (hetero)aryl groups having 3 to 20 carbon atoms Oxy group, alkylcarbonyl group having 2 to 20 carbon atoms, arylcarbonyl group having 7 to 20 carbon atoms C2-20 alkylamino group, C6-20 arylamino group, C1-20 arylamino group, (Hetero)aryl groups having 3 to 20 carbon atoms, polyalkyl ether groups having 4 to 16 carbon atoms, quaternary aryl Either an ammonium group, a sulfonic acid group, or a sodium sulfonate group, or It is a combination of:

[0032] The substituents that the rings A to D may have are, from the viewpoint of solubility, alkyl groups having 1 to 20 carbon atoms, carbonyl groups, etc. Alkoxy groups having 1 to 20 carbon atoms, (hetero)aryl groups having 3 to 20 carbon atoms, and groups having 4 to 10 carbon atoms. polyalkyl ether group, quaternary ammonium group, sulfonic acid group, or sodium sulfonate group Preferably, the fluorine-containing amine is either a fluorine-containing amine or a thorium-containing amine, or a combination thereof. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. propyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n- Pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl , 1-methylpentyl group, 4-methyl-2-pentyl group, 3,3-dimethylbutyl group, 2 -Ethylbutyl group, n-heptyl group, 1-methylhexyl group, n-octyl group, tert -octyl group.

[0033] Specific examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, and an isopropyl group. isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group Si group, pentyloxy group, hexyloxy group, heptyloxy group, octyloxy group, etc. Examples include: Specific examples of the (hetero)aryl group include a phenyl group, a naphthyl group, a biphenyl group, and a tert-butyl group. Examples of the alkyl group include a phenyl group and a pyridyl group. The polyalkyl ether group can be a group represented by the following formula (5).

[0034] [ka]

[0035] [In formula (5), U represents a hydrogen atom, a methyl group, or an ethyl group; n represents an integer of 2 to 7. * represents the bonding position to rings A to D or to a substituent.] Among these, from the viewpoint of solubility, U is preferably a methyl group and n is preferably 4 or more. is preferred. As the quaternary ammonium group, a group represented by the following formula (6) can be used.

[0036] [ka]

[0037] [In formula (6), R 11 ~R 13 each independently represents an alkyl group having 1 to 4 carbon atoms, and T represents ion. * indicates the bonding position to rings A to D or to a substituent.] R 11 ~R 13 is preferably a methyl group or an ethyl group from the viewpoint of solubility. . Specific examples of T include chlorine atom, bromine atom, iodine atom, and tetrafluoroboric acid (BF 4), hexafluorophosphate (PF6), etc., among which, from the viewpoint of compound stability, Of these, a chlorine atom, a bromine atom, and an iodine atom are preferred.

[0038] <X 1 > X 1 is a nitrogen atom or CR 2 Represents R 2 may have a hydrogen atom or a substituent. R represents a (hetero)aryl group having 3 to 20 carbon atoms. 2 From the viewpoint of photostability of the compound, Therefore, a phenyl group which may have a substituent is preferred. 1 But if C, C is Z 1 And Z may be bonded to C via a substituent. 1 It may be combined with. R 2 The substituents which may be possessed by the rings A to D are the same as those which may be possessed by the rings A to D. From the viewpoint of solubility, an alkyl group having 1 to 20 carbon atoms and an alkoxy group having 1 to 20 carbon atoms are preferred. preferable.

[0039] <Y 1 > Y 1 represents a fluorine atom or a trifluoromethyl group. 1 is easy to manufacture, A fluorine atom is preferable. On the other hand, from the viewpoint of photostability, a trifluoromethyl group is preferable. It is preferable that there is.

[0040] <Ar 1 > Ar 1 represents a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Ar 1 is, in terms of absorption wavelength, X 1 When is a nitrogen atom, it may have a substituent. Preferably, X is a phenyl group. 1 CR 2 In the case of A thiophene group is preferred. 1 The substituents which may be possessed by the rings A to D are In terms of solubility, the alkyl group having 1 to 20 carbon atoms is preferably used. , an alkoxy group having 1 to 20 carbon atoms, a polyalkyl ether group having 4 to 10 carbon atoms, a quaternary aryl group, Either an ammonium group, a sulfonic acid group, or a sodium sulfonate group, or It is preferable that the combination of Ar 1 is Z 1 may be bonded to Ar 1 has The substituent is Z 1 It may be combined with.

[0041] <Ar 2 > Ar 2is a hydrogen atom or a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Represents a aryl group. 2 is a phenyl group which may have a substituent from the viewpoint of absorption wavelength. It is preferable that Ar 2 The substituents which may be possessed by the rings A to D are From the viewpoint of solubility, alkyl groups with 1 to 20 carbon atoms and alkyl groups with 1 to 2 0 alkoxy group, a polyalkyl ether group having 4 to 10 carbon atoms, a quaternary ammonium group, Sulfonic acid groups or sodium sulfonate groups, or a combination of these It is preferable that Ar 2 is Z 1 may be bonded to Ar 2 The substituent of 1 It may be combined with.

[0042] <Z 1 > Z 1 represents a direct bond or a divalent aromatic linking group. 1 is easy to manufacture and directly A bond is preferred. 1 The N-hydroxysuccinimide ester group is converted to iridic A divalent aromatic linking group is preferred because it can keep the linking group away from the aluminum metal. In order to prevent the absorption wavelength from becoming shorter, a phenylene group, a biphenylene group, a terphenylene group, a fluoro group, Any of the orangeyl groups is preferred.

[0043] <R 1 > R 1 is connected to Z via three or more single bonds. 1 and N-hydroxysuccinimide ester group Represents the connecting group. R 1 is preferably represented by the following formula (7).

[0044] [ka]

[0045] [In the formula, Q is selected from the group consisting of —CH2—, —O—, —CO—, —NH—, and —S—. n is an integer of 2 to 30. Q is preferably excellent in chemical durability, and may be different from the above. It is preferred that it contains —CH2—.

[0046] <Z 1 Binding point of > Z 1 may be bonded to any one of the dipyrromethene structures. 1 is expressed as in equation (3) below. It may be bonded to the 4-position of the dipyrromethene structure (β-position of the pyrrole ring) as shown in formula (4). The carbon atom between the pyrrole rings (meso position) may be bonded to the dipyrromethene structure. 2 , A r 1 From the viewpoint of ease of production, it is preferable to use the bond at the position of formula (3) or (4). It is preferable to do so. The iridium complex of the present invention is a compound represented by the formula (1), in which ring D is a pyridine ring and A structure consisting of a fluorine atom and a boron atom is attached to a benzene ring that coordinates with the iridium metal. That is, it is preferable that the compound is represented by the formula (2).

[0047] [ka]

[0048] [In formula (2), ring A, ring B, Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , Z1 , R 1 is expressed as (1 ) in ring A, ring B, Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , Z 1 , R 1 is synonymous with. ] In phenyl-pyridines coordinated to iridium metals, the phenyl moiety (benzene Since the HOMO (highest occupied molecular orbital) is largely distributed on the dimer ring, as shown in formula (2), A structure consisting of pyrromethene and boron atoms is bonded to a benzene ring that coordinates with the iridium metal. This effectively enables the dipyrromethene and boron atom to be π-conjugated with the iridium metal. Therefore, when the compound of the present invention is irradiated with light having a wavelength corresponding to the absorption wavelength, the singlet The compound of the present invention excited to the triplet state is excited by the heavy atom effect of the iridium metal. It is speculated that intersystem crossing occurs easily when irradiated with light. When oxygen molecules coexist under irradiation, singlet oxygen is generated (oxygen molecules are released from the compound of the present invention). Energy is transferred to the oxygen molecule, exciting it to singlet oxygen. For example, it is believed to be effective in inactivating cancer cells in the body. By binding the compound to an antibody, for example, and generating singlet oxygen in vivo, It is believed that this can effectively inactivate cancer cells. The iridium complex of the present invention is preferably represented by formula (3) or formula (4).

[0049] [ka]

[0050] [In formula (3), ring A, ring B, Ar1 , Ar 2 , X 1 , Y 1 , Z 1 , Z 1 , R 1 is expressed as (2 ) in ring A, ring B, Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , Z 1 , R 1 is synonymous with. ]

[0051] [ka]

[0052] [In formula (4), ring A, ring B, Ar 1 , Ar 2 , Y 1 , Z 1 , Z 1 , R 1 In equation (2), Ring A, ring B, Ar 1 , Ar 2 , Y 1 , Z 1 , Z 1 , R 1 is equivalent to.] As shown in formulas (3) and (4), the structure consisting of dipyrromethene and a boron atom is By bonding to the iridium metal at the para position in the ring, the dipyrromethene is bonded to the boron atom. The interaction between the structure and the iridium metal (heavy atom effect due to iridium metal) is the most important. Therefore, intersystem crossing from the excited singlet state to the excited triplet state is most likely to occur. Therefore, for example, singlet oxygen generation will occur efficiently. . Preferred specific examples of the iridium complex of the present invention are shown below, but the present invention is not limited to these. It is not something that can be done.

[0053] [ka] EXAMPLES

[0054] The present invention will be described in more detail below with reference to the following examples. The present invention is not limited to the above, and can be modified and implemented as desired without departing from the spirit of the invention. . <Synthesis of Compound 1> [Reaction 1]

[0055] [ka]

[0056] In a 1L eggplant flask, add 4'-hydroxychalcone (25.5 g) and 1-bromohexane. (24.3g), potassium carbonate (31.4g), N,N-dimethylformamide (100 The mixture was stirred at 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, water (20 mL) was added. 0 mL) and a hexane / ethyl acetate (4 / 1) mixed solvent (400 mL) were added and washed. The oil phase was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. (neutral silica gel, dichloromethane / hexane = 1 / 1) gave a pale yellow solid As a result, 29.3 g of intermediate 1 was obtained.

[0057] [Reaction 2] [ka]

[0058] In a 500 mL eggplant flask, add intermediate 1 (15.4 g), dimethyl sulfoxide (80 mL), and Add 11 mL of nitromethane and diazabicyclo[4.2.1]diaminetetraacetate (11 mL) and stir at room temperature under a nitrogen atmosphere. Cycloundecene (12 mL) was added little by little, and the mixture was then stirred at 60°C for 10 hours. After cooling to room temperature, the mixture was dissolved in 1M hydrochloric acid (100 mL) and hexane / ethyl acetate (4 / 1). The oil phase was collected and concentrated under reduced pressure, and the residue was washed with silane. Column chromatography (neutral silica gel, dichloromethane / hexane = 1 / 1 ) to give 14.1 g of intermediate 2 as a pale brown oil.

[0059] [Reaction 3] [ka]

[0060] In a 500 mL eggplant flask, add intermediate 2 (10.1 g), ammonium acetate (75.8 g ) was added and stirred at 180°C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, dichloromethane (600 mL) and water (300 mL) were added for separation and washing. The oil phase was collected and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (neutral silica gel, dichloromethane When purified with a solvent mixture of hexane / hexane = 1 / 3 → 2 / 3), it was found to be a metallic glossy green-brown solid. 2.2 g of intermediate 3 was obtained.

[0061] [Reaction 4] [ka]

[0062] In a 500 mL eggplant flask, add intermediate 3 (2.2 g) and dichloromethane (250 mL). Add N-bromosuccinimide (0.56 g) while stirring at room temperature, and then stir at room temperature for 1 The mixture was stirred for 1.5 hours. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. When purified with neutral silica gel (dichloromethane / hexane = 3 / 7 → 5 / 5), This gave 2.4 g of intermediate 4 as a dark blue solid with metallic luster.

[0063] [Reaction 5] [ka]

[0064] Place intermediate 4 (2.4 g) and dichloromethane (250 mL) in a 1 L eggplant flask. N,N-diisopropylethylamine (5.6 mL) was added to the flask while stirring at room temperature under a nitrogen atmosphere. Add boron trifluoride diethyl ether complex (6.1 mL) little by little and stir at 50°C for 2 hours. After cooling to room temperature, dichloromethane (100 mL) and water (250 mL) were added. The oil phase was collected and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The mixture was purified using neutral silica gel (dichloromethane / hexane = 3 / 7 → 4 / 6). As a result, 2.4 g of intermediate 5 was obtained as a dark blue solid.

[0065] [Reaction 6] [ka]

[0066] In a 500 mL eggplant flask, add 4-(4-bromophenyl)butyric acid (10.6 g), Add concentrated sulfuric acid (2.5 mL) dropwise while stirring, and then heat at 90°C. The mixture was stirred for 3 hours. After cooling to room temperature, water (200 mL) and dichloromethane (150 mL) were added. The oil phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. This gave 11.2 g of intermediate 6 as a colorless oil.

[0067] [Reaction 7] [ka]

[0068] In a 500 mL flask, add intermediate 6 (11.2 g), bis(pinacolato)diboron (1 2.7g), potassium acetate (12.8g), dichloro(1,1'-bis(diphenylphos) (Phino)ferrocene)palladium·dichloromethane adduct (1.1g) and dimethylsulfate The mixture was stirred at 85°C for 5 hours. After cooling to room temperature, water (300 1 mL) and dichloromethane (150 mL) were added for separation and washing, and further dichloromethane was added The oil phase was collected and concentrated under reduced pressure, and the residue was extracted with a silica gel column. Purified by chromatography (neutral silica gel, ethyl acetate / hexane = 1 / 4) As a result, 11.9 g of intermediate 7 was obtained as a colorless oil.

[0069] [Reaction 8] [ka]

[0070] Under a nitrogen atmosphere, a 500 mL flask was charged with Intermediate 5 (3.07 g), Intermediate 7 (1.39 g), toluene (100 mL), tetrahydrofuran (20 mL) and 2 mol / L An aqueous solution of tripotassium phosphate (11 mL) was added and stirred. Palladium acetate (86 mg), 2-dicyclohexylphosphino-2',6'-di Methoxy-1,1'-biphenyl (313 mg) and tetrahydrofuran (10 mL) were The catalyst solution was added after stirring at 80°C for 10 minutes, and the mixture was stirred at 80°C for 7 hours. The aqueous phase was then removed, and the remaining liquid was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The mixture was purified using neutral silica gel (dichloromethane / hexane = 5 / 5 → 6 / 4). As a result, 2.81 g of intermediate 8 was obtained as a dark blue solid.

[0071] [Reaction 9] [ka]

[0072] In a 500 mL recovery flask, place intermediate 8 (2.8 g) and dichloromethane (60 mL). While stirring at room temperature, add N-bromosuccinimide (0.59 g) and mix at room temperature for 1. The mixture was stirred for 5 hours. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. - (neutral silica gel, dichloromethane / hexane = 6 / 4) purification, metallic luster 2.9 g of intermediate 9 was obtained as a copper-colored solid with a yellow tint.

[0073] [Response 10] [ka]

[0074] In a 500 mL flask, intermediate 10 (prepared according to the method described in WO2016194784A) was added. 3.6g), bis(pinacolato)diboron (6.1g), potassium acetate (5 .5g), dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium Add dichloromethane adduct (0.33 g) and dimethyl sulfoxide (100 mL) The mixture was stirred at 105° C. for 14.5 hours. After cooling to room temperature, water (200 mL) and dichloromethane were added. Add methane (300 mL) for separation and washing, then extract with dichloromethane (150 mL). The oil phase was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( Neutral silica gel, dichloromethane / hexane = 85 / 15 → dichloromethane / ethyl acetate The crude product was dissolved in dichloromethane (15 mL) and purified with 1:1 hexane / hexane. Hexane (200 mL) was added to the liquid at room temperature in small portions, and the resulting solid was filtered and dried. Obtained 1.7 g of intermediate 11 as a yellow solid.

[0075] [Response 11] [ka]

[0076] Under a nitrogen atmosphere, a 100 mL flask was charged with Intermediate 9 (0.80 g), Intermediate 11 (0.8 7g), tetrahydrofuran (50mL) and 2mol / L tripotassium phosphate aqueous solution ( The solution was stirred at 55°C and then added with 2.5 mL of paraacetic acid in a 30 mL Schlenk flask. 19mg, 2-dicyclohexylphosphino-2',6'-dimethoxy-1, 1'-Biphenyl (69 mg) and tetrahydrofuran (10 mL) were stirred at room temperature for 10 minutes. The catalyst solution prepared by the above procedure was added and stirred at 80°C for 3.5 hours. After cooling to room temperature, the solvent was reduced. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (neutral silica gel, dichloromethane). Purified with chloromethane / hexane / ethyl acetate = 4 / 6 / 0.5 → 4.5 / 5 / 0.5 As a result, 0.23 g of intermediate 12 was obtained as a dark blue solid.

[0077] [Response 12] [ka]

[0078] In a 100 mL eggplant flask, add 4-bromocatechol (1.66 g), triethylene glycol Coal 2-bromoethyl methyl ether (5.24 g), potassium carbonate (4.85 g), Add N,N-dimethylformamide (10 mL) and stir at 70°C for 6 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was dissolved in water (180 mL) and hexane / ethyl acetate (1 / 1). The solvent (300 mL) was added and the mixture was separated and washed. The oil phase was collected and concentrated under reduced pressure to give a pale yellow oil. As a result, 3.79 g of intermediate 13 was obtained as the product. This was used in the next reaction without further purification.

[0079] [Response 13] [ka]

[0080] Under a nitrogen atmosphere, a 200 mL flask was charged with Intermediate 12 (0.23 g), Intermediate 13 (0. 29 g), tetrahydrofuran (20 mL) and 2 mol / L aqueous potassium phosphate solution (0.38 mL) was added and stirred at room temperature. Radium (5.7 mg), 2-dicyclohexylphosphino-2',6'-dimethoxy 1,1'-biphenyl (21 mg) and tetrahydrofuran (3 mL) were stirred at room temperature for 10 minutes. The catalyst solution prepared by stirring was added and stirred at 70°C for 18 hours. After cooling to room temperature, the solvent was reduced. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (neutral silica gel, dichloromethane). Purify with dichloromethane / ethyl acetate = 3 / 7 → dichloromethane / methanol = 100 / 4) As a result, 0.10 g of intermediate 13 was obtained as a dark blue solid.

[0081] [Response 14] [ka]

[0082] In a 100 mL eggplant flask, intermediate 13 (80 mg), tetrahydrofuran (25 mL ), distilled water (10 mL), and phosphoric acid (8 mL) were added, and the mixture was stirred for 14 hours in an oil bath at 80°C. After cooling to room temperature, water (150 mL) and dichloromethane (200 mL) were added. The mixture was separated and washed, and then extracted with dichloromethane (200 mL). Saturated saline (100 mL) was added to the mixture for separation and washing. The solvent was concentrated under reduced pressure to give a residue. Silica gel column chromatography (neutral silica gel, dichloromethane / methanol = Purification by elution with 30 / 1→4 / 1 afforded 57 mg of intermediate 14 as a dark blue solid.

[0083] [Reaction 15] [ka]

[0084] In a 100 mL eggplant flask, add intermediate 14 (57 mg), N-hydroxysuccinimide (5.4 mg) and dry dichloromethane (10 mL), and 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.9 mg) was administered. The reaction solution was stirred at room temperature for 5 hours. Then, water (100 mL) and dichloromethane were added to the reaction solution. The oil phase was collected and concentrated under reduced pressure to give a residue. Silica gel column chromatography (neutral silica gel, dichloromethane / methanol = 9 5 / 5) to obtain 27 mg of compound 1 as a dark blue solid.

[0085] <Synthesis example of compound 2> [ka]

[0086] Under a nitrogen atmosphere, intermediate 15 (WO2016194784A It was synthesized by the method described in. 13.3 g), 2-(3-bromophenyl)pyridine (3.5 g ), diglyme (50 mL), and stirred at 100°C. Silver sulfonate (3.8 g) and 2,6-di-tert-butylpyridine (2.8 g) were added. The mixture was immediately heated to 130°C and stirred for 3 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (neutral silica gel, dichloromethane When purified with a solvent mixture of toluene / hexane (5 / 5 to toluene / hexane (6 / 4)), a yellow solid was obtained. As a result, 4.7 g of intermediate 16 was obtained.

[0087] [ka]

[0088] In a 200 mL flask, add intermediate 16 (1.1 g), bis(pinacolato)diboron (0 .3g), potassium acetate (0.5g), dichloro(1,1'-bis(diphenylphosphine) Ferrocene palladium dichloromethane adduct (75 mg) and dimethylsulfoxide Cinnamon (50 mL) was added and the mixture was stirred at 95° C. for 6 hours. After cooling to room temperature, water (150 mL) was added. A mixed solvent of hexane / ethyl acetate (1 / 2) (700 mL) was added and the mixture was separated and washed. The oil phase was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (neutral silica gel). Rikagel, dichloromethane / hexane = 4 / 6 → dichloromethane / hexane / ethyl acetate =2.5 / 2.5 / 1) to give 0.56 g of intermediate 17 as a yellow solid. .

[0089] [ka]

[0090] Under a nitrogen atmosphere, a 100 mL flask was charged with Intermediate 5 (0.15 g), Intermediate 17 (0.2 3g), toluene (5mL), tetrahydrofuran (2mL) and 2mol / L phosphorus A 30 mL aqueous solution of potassium triphosphate (0.6 mL) was added and stirred at room temperature. In a Lenk tube, palladium acetate (8 mg) and 2-dicyclohexylphosphino-2',6'- Dimethoxy-1,1'-biphenyl (30 mg) and tetrahydrofuran (4 mL) were heated at room temperature. The catalyst solution prepared by stirring at 80°C for 10 minutes was added and stirred at 80°C for 8 hours. After cooling to room temperature, The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (neutral silica gel When purified with dichloromethane / hexane (3 / 7 → 5 / 5), a dark green solid was obtained. Compound 2 was obtained in an amount of 0.12 g by the addition of N-hydroxysuccinimide ester. Although the ester group does not have a structure with a carboxyl group, the N-hydroxysuccinimide ester group is This group is necessary for binding with , and it is considered that the effect on the confirmation of absorption wavelength and singlet oxygen generation ability is small. It is possible.

[0091] <Synthesis example of compound 3> [ka]

[0092] In a 500 mL flask, add 4-n-octyloxybenzaldehyde (1 Add 4.0 g), pyrrole (100 mL), and trifluoroacetic acid (0.5 mL) and heat at room temperature. The mixture was stirred for 1 hour. Dichloromethane (250 mL) and 0.1 mol / L sodium hydroxide were added. The oil phase was collected and concentrated under reduced pressure to give a residue. Column chromatography on silica gel (neutral silica gel, ethyl acetate / hexane = 5 / 95) to give 14.6 g of intermediate 18 as a yellow solid.

[0093] [ka]

[0094] In a 500 mL flask under a nitrogen atmosphere, intermediate 18 (7.5 g) and tetrahydrofuran were added. (100 mL) was added and cooled to -78°C. N-Bromosuccinimide (11.4 g) The solution was stirred at -78°C for 40 minutes. No-p-benzoquinone (5.3 g) was added and the mixture was stirred while being cooled to room temperature. The solvent was concentrated under reduced pressure. The residue obtained by condensation was purified by silica gel column chromatography (neutral silica gel, dichloromethane The mixture was purified using methane only to obtain 12 g of crude intermediate 19 as a red solid. The product was subjected to the next reaction without further purification.

[0095] [ka]

[0096] Under a nitrogen atmosphere, a 500 mL recovery flask was charged with the crude intermediate 19 (12 g), dichloromethane, and 100 mL of ethyl acetate. Add 100 mL of ethanol and 10 mL of triethylamine, and add 10 mL of trifluoride at room temperature while stirring. Boron chloride diethyl ether complex (13.5 mL) was added in small portions and stirred at room temperature for 1 hour. 0.1 mol / L sodium hydroxide aqueous solution (150 mL) was added and the mixture was separated and washed. The residue was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (neutral silica When purified with hexane / hexane (dichloromethane / hexane = 35 / 65), a dark red solid was obtained. 4.2 g of intermediate mass 20 was obtained.

[0097] [ka]

[0098] In a 100 mL flask under a nitrogen atmosphere, intermediate 20 (1.1 g), benzo[b]thiophene phenyl-2-boronic acid (0.60 g), tri-tert-butylphosphonium tetrafluoro Borate (196 mg), tris(dibenzylideneacetone)dipalladium (180 mg ), cesium carbonate (2.2 g), and tetrahydrofuran (40 mL) were added and the mixture was heated at 80°C for 2 hours. After cooling to room temperature, activated clay was added and the mixture was filtered. The solvent was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (neutral silica gel, dichloromethane / hexane =3 / 7) to obtain 0.16 g of intermediate 21 as a copper-colored solid.

[0099] [ka]

[0100] Under a nitrogen atmosphere, a 100 mL flask was charged with Intermediate 21 (0.14 g), Intermediate 17 (0. 23 g), toluene (10 mL), tetrahydrofuran (2 mL) and 2 mol / L Aqueous tripotassium phosphate solution (0.6 mL) was added and stirred at room temperature. In a Jurenk flask, palladium acetate (8.5 mg), 2-dicyclohexylphosphino-2', 6'-Dimethoxy-1,1'-biphenyl (31 mg) and tetrahydrofuran (4 mL) The catalyst solution was added and stirred at room temperature for 10 minutes, and the mixture was stirred at 80°C for 5 hours. After cooling, the solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (neutral When purified with silica gel and dichloromethane / hexane = 4 / 6 → 5 / 5), a dark green solid was obtained. As a result, 0.17 g of compound 3 was obtained as a solid. In addition, compound 3 does not have a structure having an N-hydroxysuccinimide ester group. However, the N-hydroxysuccinimide ester group is necessary for binding to biomolecules. It is believed that the effect on confirmation of absorption wavelength and singlet oxygen generation ability is small.

[0101] <Evaluation of Absorption Spectrum> [Measurement method] Using a Hitachi U-3900H spectrophotometer, -5 mol / L of dichloro A fluoromethane solution was prepared and measured. The measurement wavelength range was 400 nm to 900 nm.

[0102] (Reference example 1) The absorption spectrum of the obtained compound 2 was measured, and the measurement results are shown in FIG. Compound 2 had a maximum absorption wavelength of 684 nm.

[0103] (Reference example 2) The absorption spectrum of the obtained compound 3 was measured, and the measurement results are shown in FIG. Compound 3 had a maximum absorption wavelength of 650 nm.

[0104] Comparative Example 1 The absorption spectrum of the comparative compound 1 was measured. The measurement results are shown in FIG. Compound 1 showed no absorption in the wavelength region of 620 nm or more.

[0105] [ka]

[0106] <Evaluation of singlet oxygen generation ability> [Measurement method] The singlet oxygen generating ability was measured by detecting the emission of singlet oxygen. The solvent used for the measurement was toluene. The concentration was adjusted so that the absorbance at the excitation wavelength in a 1 cm square cell was 2. Actes, CSM-330) was used, and the detector was a photomultiplier tube (Hamamatsu Photonics, R5509-43) was used. Measurements were performed at an excitation wavelength of 660 nm.

[0107] (Reference example 3) The singlet oxygen generation of the obtained compound 2 was measured. From the results, emission of singlet oxygen was clearly observed at 1270 nm.

[0108] (Reference example 4) The absorption spectrum of the obtained compound 3 was measured. From the results, emission of singlet oxygen was clearly observed at 1270 nm.

Claims

1. A compound represented by the following formula (1): 【Chemistry 1】 In formula (1), ring A and ring C each independently represent a benzene ring which may have a substituent. Ring B and ring D each independently represent a pyridine ring, a pyrazine ring, a pyrimidine ring, an imidazole ring, an oxazole ring, or a thiazole ring which may have a substituent. X １ is a nitrogen atom or CR ２ Represents. R ２ represents a hydrogen atom or a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Ar １ represents a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Ar ２ represents a hydrogen atom or a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Rings A to D, R ２ , Ar １ and Ar ２ The substituents which may be possessed by the rings A to D include any one of an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a (hetero)aryloxy group having 3 to 20 carbon atoms, an alkylcarbonyl group having 2 to 20 carbon atoms, an arylcarbonyl group having 7 to 20 carbon atoms, an alkylamino group having 2 to 20 carbon atoms, an arylamino group having 6 to 20 carbon atoms, a (hetero)aryl group having 3 to 20 carbon atoms, a polyalkyl ether group having 4 to 16 carbon atoms, a quaternary ammonium group, a sulfonic acid group, and a sodium sulfonate group, or a combination thereof. Adjacent substituents bonded to the rings A to D may be bonded to each other to form a further ring. Y １ represents a fluorine atom or a trifluoromethyl group. Z １ represents a direct bond or a divalent aromatic linking group. R １ is a group represented by the following formula (7). 【Chemistry 8】 (In formula (7), Q represents any group selected from the group consisting of -CH 2 -, -O-, -CO-, -NH-, and -S-, and n represents an integer of 2 to 30. The n Qs may be the same or different.)

2. The compound according to claim 1, wherein the formula (1) is a compound represented by formula (2). 【Chemistry 2】 [In the above formula, ring A, ring B, Ar １ , Ar ２ , X １ , Y １ , Z １ , Z １ , R １ is expressed by the formula (1). In the formula (I), ring A, ring B, and Ar １ , Ar ２ , X １ , Y １ , Z １ , Z １ , R １ is equivalent to.]

3. The compound according to claim 2, wherein the formula (2) is a compound represented by formula (3) or formula (4). 【Chemistry 3】 [In formula (3), ring A, ring B, Ar １ , Ar ２ , X １ , Y １ , Z １ , Z １ , R １ is expressed by the formula (2 ) in which ring A, ring B, Ar １ , Ar ２ , X １ , Y １ , Z １ , Z １ , R １ is synonymous with. ］ 【Chemistry 4】 [In formula (4), ring A, ring B, Ar １ , Ar ２ , Y １ , Z １ , Z １ , R １ In equation (2), Ring A, ring B, Ar １ , Ar ２ , Y １ , Z １ , Z １ , R １ is equivalent to.]

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