Compound

Abstract

To provide a compound having an N-hydroxy succinimide ester group as a binding site to a biological substance, and absorbs and excites light in the wavelength region called "biological window" to produce singlet oxygen.SOLUTION: The present invention provides a compound represented by the formula (1). [X1 is halogen; Ar1 is a substituted / unsubstituted C3-C20 (hetero) aryl group; Ar2 is H or a substituted / unsubstituted C3-C20 (hetero) aryl group; Y1 is F or a trifluoromethyl group; Z1 is a direct bond or a divalent aromatic linking group; R1 is a group linking Z1 to an N-hydroxy succinimide ester group through three or more single bonds].SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a novel near-infrared light absorbing dye compound that can be easily introduced into biological materials such as nucleic acids, proteins, and polysaccharides. [Background technology]

[0002] Dyes that absorb or emit near-infrared light have attracted great interest for applications in novel sensors and in vitro and in vivo imaging. For example, near-infrared fluorescence can be used as a non-destructive method to track or analyze many different molecules, which are labeled with fluorescent dyes and the fluorescence of the dyes can be detected. Labeling of biological materials such as nucleic acids, proteins, and polysaccharides with dyes is generally achieved by introducing an N-hydroxysuccinimide ester group or the like into the dye molecule and using it as a binding site for the biological material.

[0003] Among light in the near-infrared region, examples of dyes that absorb and emit light in the wavelength region of 650 to 1000 nm (near-infrared region), which is called the biological window and is not easily absorbed by substances and water in the body, include cyanine dyes (e.g., Patent Document 1). Among the cyanine dyes, indocyanine green (ICG) has been approved for clinical use, but it has drawbacks such as low photostability and a long synthetic route.

[0004] Furthermore, the introduction of heavy atoms into appropriate positions in the skeleton of a fluorescent dye can promote intersystem crossing from the excited singlet state to the excited triplet state. It has been reported that the excited triplet state energy of the fluorescent dye is transferred to an oxygen molecule to generate singlet oxygen. Therefore, in recent years, there has been interest in applying the characteristics of such fluorescent dyes to the field of photodynamic therapy (e.g., Non-Patent Document 1). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2007 / 005222 [Non-patent literature]

[0006] [Non-Patent Document 1] Chem. Soc. Rev., 2013, 42, 77-88 Summary of the Invention [Problem to be solved by the invention]

[0007] However, although the above-mentioned prior art dyes have absorption in the near-infrared light region, they do not have a binding site with biological substances such as antibodies, and therefore are not necessarily effective compounds for application in the field of photodynamic therapy, and there has been a demand for the development of new dyes.

[0008] The present invention provides a near-infrared light-absorbing dye compound that has an N-hydroxysuccinimide ester group, which is a binding site for biological substances, and that generates singlet oxygen when excited by absorbing light in a wavelength range known as the biological window. [Means for solving the problem]

[0009] The present inventors have conducted intensive research in light of the above-mentioned problems and have found that a dye compound in which an N-hydroxysuccinimide ester group is linked via a spacer to a skeleton having a structure consisting of an azadipyrromethene substituted with a halogen atom and a boron atom (azaBODIPY skeleton) has an absorption wavelength of 650 nm or more, which corresponds to the wavelength range known as the biological window, and can be easily introduced into biological materials, thereby completing the present invention.

[0010] That is, the gist of the present invention is as follows.

[0011] [1] A compound represented by the following formula (1):

[0012] [ka]

[0013] [In formula (1), X 1 represents a halogen atom. 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. However, Ar 1 or Ar 2 is Z 1 may be bonded to Ar 1 or Ar 2 has a substituent Z 1 It may be combined with. Ar 1 and Ar 2 The substituent that may be possessed by the formula (I) is 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, an alkylamide group having 2 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, or a salt of sulfonic acid, or a combination thereof. 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 the N-hydroxysuccinimide ester group.]

[0014] [2] The compound according to [1], wherein the compound represented by formula (1) is a compound represented by the following formula (2):

[0015] [ka]

[0016] [In formula (2), Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , R 1 represents Ar in the formula (1). 1 , Ar 2 , X 1 , Y 1 , Z 1 , R 1 is equivalent to.]

[0017] [3] The compound according to [2], wherein the compound represented by formula (2) is a compound represented by the following formula (3):

[0018] [ka]

[0019] [In formula (3), Ar 1 , Ar 2 , Y 1 , Z 1 , R 1 represents Ar in the formula (1). 1 , Ar 2 , Y 1 , Z 1 , R 1 is equivalent to.] Effect of the Invention

[0020] The present invention provides a dye compound which corresponds to a wavelength range known as the biological window and has an N-hydroxysuccinimide ester group, which is a binding site for a biological substance. [Brief description of the drawings]

[0021] [Figure 1] 1 is a chart showing absorption spectrum measurement of Compound 1, Compound 2, and Intermediate 15. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The following describes in detail the embodiments of the present invention, but the present invention is not limited to the following embodiments and can be modified in various ways within the scope of the invention.

[0023] In this specification, the terms "(hetero)aryloxy group" and "(hetero)aryl group" refer to an aryloxy group which may contain a heteroatom and an aryl group which may contain a heteroatom, respectively. The term "may contain a heteroatom" refers to one or more carbon atoms among the carbon atoms forming the main skeleton of the aryl group or aryloxy group being substituted with a heteroatom, and examples of the heteroatom include a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus atom, and a silicon atom. Among these, a nitrogen atom is preferred from the viewpoint of durability.

[0024] The compound of the present invention is a compound represented by the following formula (1) (hereinafter, may be referred to as "dye of formula (1)").

[0025] [ka]

[0026] [In formula (1), X 1 represents a halogen atom. 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. However, Ar 1 or Ar 2 Z 1 may be bonded to Ar 1 or Ar 2 has a substituent Z 1 It may be combined with. Ar 1 and Ar 2The substituent that may be possessed by the formula (I) is 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, an alkylamide group having 2 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, or a salt of sulfonic acid, or a combination thereof. 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 the N-hydroxysuccinimide ester group.]

[0027] The dye of formula (1) has a structure consisting of azadipyrromethene and boron atoms (azaBODIPY skeleton), and therefore absorbs light at relatively long wavelengths from red to infrared. Furthermore, when excited by the corresponding light, the dye can transfer its energy to surrounding molecules. In addition, the dye of formula (1) has one N-hydroxysuccinimide ester group at a position away from the π-conjugated structure of the dye skeleton, so that it is possible to easily introduce one dye molecule to a primary amine in a biological material while maintaining the excellent optical properties described above.

[0028] The dye of formula (1) is X 1One of the characteristics of the azaBODIPY skeleton is that a halogen atom (halogen atom) is bonded to the 4th position (β-position of the pyrrole ring). In the azaBODIPY skeleton, the HOMO (highest occupied molecular orbital) is widely distributed at the 4th position, so by directly bonding a halogen atom to that position, the interaction between the azaBODIPY skeleton and the halogen atom becomes the strongest. Therefore, when light corresponding to the absorption wavelength of the dye of formula (1) is irradiated, it is presumed that the dye of formula (1) excited to the singlet state is likely to undergo intersystem crossing to the excited triplet state due to the heavy atom effect of the halogen atom. Because of such optical properties, singlet oxygen is generated when oxygen molecules coexist under light irradiation (energy transfer from the dye of formula (1) to the oxygen molecule, and the oxygen molecule is excited to singlet oxygen). Singlet oxygen can, for example, inactivate cancer cells in a living body, so it is considered that cancer cells can be inactivated more effectively by binding the compound of the present invention, which is the dye of formula (1), to, for example, an antibody to generate singlet oxygen in a living body.

[0029] <X 1 > X 1 represents a halogen atom. X 1 is preferably a bromine atom or an iodine atom from the viewpoint of the heavy atom effect, and more preferably a bromine atom from the viewpoint of the photostability of the compound.

[0030] <Y 1 > Y 1 represents a fluorine atom or a trifluoromethyl group. Y 1 is preferably a fluorine atom in terms of ease of production, whereas is preferably a trifluoromethyl group in terms of photostability. In addition, the two Y in formula (1) 1 may be the same as each other or may be different.

[0031] <Ar 1 > Ar 1represents a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Ar 1 From the viewpoint of absorption wavelength, it is preferable that is a phenyl group which may have a substituent.

[0032] Ar 1 The substituents which may be included in the aryloxy group are 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, an alkylamide group having 2 to 20 carbon atoms, a (hetero)aryl group having 3 to 20 carbon atoms, a polyalkylether group having 4 to 16 carbon atoms, a quaternary ammonium group, a sulfonic acid group, and a salt of sulfonic acid, or a combination thereof. Among these substituents, from the viewpoint of solubility, an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a polyalkylether group having 4 to 10 carbon atoms, a quaternary ammonium group, a sulfonic acid group, and a salt of sulfonic acid, or a combination thereof, is preferable.

[0033] Ar 1 is Z 1 may be bonded to Ar 1 The substituent of 1 It may be combined with. The two Ar in formula (1) 1 may be the same as each other or may be different.

[0034] <Substituent> Ar 1 and Ar 2 Specific examples of the substituent that may be possessed by are as follows.

[0035] Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, an n-hexyl group, a 1-methylpentyl group, a 4-methyl-2-pentyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group, an n-heptyl group, a 1-methylhexyl group, an n-octyl group, and a tert-octyl group.

[0036] Specific examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, a heptyloxy group, and an octyloxy group.

[0037] Specific examples of the (hetero)aryl group include a phenyl group, a naphthyl group, a biphenyl group, a terphenyl group, and a pyridyl group.

[0038] The polyalkyl ether group can be a group represented by the following formula (5).

[0039] [ka]

[0040] In formula (5), U represents a hydrogen atom, a methyl group, or an ethyl group, and n represents an integer of 2 to 7. * represents Ar 1 or Ar 2 represents the bond position with

[0041] Among these, from the viewpoint of solubility, U is preferably a methyl group, and n is preferably 4 or more.

[0042] As the quaternary ammonium group, a group represented by the following formula (6) can be used.

[0043] [ka]

[0044] [In formula (6), R 11 ~R 13 each independently represents an alkyl group having 1 to 4 carbon atoms, and T represents a counter ion. 1 or Ar 2 represents the bond position with

[0045] R 11 ~R 13 From the viewpoint of solubility, is preferably a methyl group or an ethyl group. Specific examples of T include a chlorine atom, a bromine atom, an iodine atom, tetrafluoroboric acid (BF4), and hexafluorophosphoric acid (PF6). Among these, from the viewpoint of the stability of the compound, a chlorine atom, a bromine atom, and an iodine atom are preferred.

[0046] Examples of the salts of sulfonic acid include sodium salts, potassium salts, and cesium salts.

[0047] <Ar 2 > Ar 2 represents a hydrogen atom or a (hetero)aryl group having 3 to 20 carbon atoms which may have a substituent. Ar 2 From the viewpoint of absorption wavelength, it is preferable that is a phenyl group which may have a substituent. Ar 2 The substituent that may be possessed by Ar 1 From the viewpoint of solubility, it is preferable that the substituent is any one of an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, a polyalkyl ether group having 4 to 10 carbon atoms, a quaternary ammonium group, a sulfonic acid group, or a salt of sulfonic acid, or a combination of these.

[0048] Ar 2 is Z 1 may be bonded to Ar 2 The substituent of 1 It may be combined with. The two Ar in formula (1) 2 may be the same as each other or may be different.

[0049] <Z 1 > Z 1 represents a direct bond or a divalent aromatic linking group. Z 1 is preferably a direct bond in terms of ease of production. 1 is preferably a divalent aromatic linking group in that it can distance the N-hydroxysuccinimide ester group from the dye skeleton, and is preferably any one of a phenylene group, a biphenylene group, a terphenylene group, and a fluorenediyl group in that it can prevent the absorption wavelength from being shortened.

[0050] <R 1 > R 1 is connected to Z via three or more single bonds. 1 R represents the group connecting the N-hydroxysuccinimide ester group. 1 is preferably represented by the following formula (7).

[0051] [ka]

[0052] [In the formula, Q represents any group selected from the group consisting of -CH2-, -O-, -CO-, -NH-, and -S-, and m represents an integer of 2 to 30. The m number of Qs may be the same or different.]

[0053] Among these, Q preferably contains -CH2- or -O- because of its excellent chemical durability.

[0054] <Z 1 Binding point of > Z 1 may be bonded to any part of the azadipyrromethene structure. 1 Ar 2 , Ar 1Alternatively, as shown in formula (2) below, the bond may be at the 4-position of the azadipyrromethene structure (the β-position of the pyrrole ring). From the viewpoint of ease of production, the bond at the position shown in formula (2) is preferred.

[0055] <Suitable dyes> The dye of formula (1) is 1 The substitution position of is preferably the 4-position of the azadipyrromethene structure (β-position of the pyrrole ring). That is, it is preferably a compound represented by the following formula (2), and particularly preferably a compound represented by the following formula (2): 1 is preferably a compound represented by the following formula (3), in which

[0056] [ka]

[0057] [In formula (2), Ar 1 , Ar 2 , X 1 , Y 1 , Z 1 , R 1 represents Ar in the formula (1). 1 , Ar 2 , X 1 , Y 1 , Z 1 , R 1 is equivalent to.]

[0058] [ka]

[0059] [In formula (3), Ar 1 , Ar 2 , Y 1 , Z 1 , R 1 represents Ar in the formula (1). 1 , Ar 2 , Y 1 , Z 1 , R 1 is equivalent to.]

[0060] <Example> Preferred specific examples of the dye of formula (1), which is the compound of the present invention, are shown below, but the present invention is not limited to these.

[0061] [ka]

[0062] <Synthesis method> As shown in the reaction formula below, the compound of the present invention can be synthesized by synthesizing an intermediate in which a halogen atom and a protected carboxylic acid are substituted on a structure consisting of an azadipyrromethene and a boron atom, deprotecting the protecting group of the carboxylic acid to convert it into a carboxylic acid intermediate or a carboxylate intermediate, and then converting the carboxylic acid intermediate or the carboxylate intermediate into an N-hydroxysuccinimide ester group. A specific synthesis method is as shown in the synthesis example of compound 1 described in the Examples section below.

[0063] [ka]

[0064] (In the above reaction scheme, X 1 ,Ar 1 ,Ar 2 ,Y 1 ,Z 1 ,R 1 has the same meaning as in the above formula (1). EXAMPLES

[0065] The present invention will be described in more detail below with reference to examples. The present invention is not limited to the following examples, and the present invention can be practiced with any modifications without departing from the gist of the present invention.

[0066] <Synthesis of Compound 1> [ka]

[0067] Intermediate 1 (1.69 g, synthesized according to the method described in Org. Lett. 2009, 11, 23, 5386-5389) and N,N-dimethylformamide (75 mL) were placed in a 200 mL eggplant flask and cooled in an ice bath under a nitrogen atmosphere. Imidazole (1.76 g) and tert-butyldimethylsilyl chloride (1.93 g) were added thereto and stirred at room temperature for 3 hours. Water (200 mL) and ethyl acetate (500 mL) were further added for separation and washing. The oil phase was collected and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (neutral silica gel, dichloromethane / hexane = 1 / 2), obtaining 1.87 g of intermediate 2 as a black-green solid.

[0068] [ka]

[0069] In a 500 mL recovery flask, intermediate 2 (1.86 g) and dichloromethane (115 mL) were placed, and while stirring at room temperature, N-bromosuccinimide (0.44 g) was added and stirred at room temperature for 2 hours. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (neutral silica gel, dichloromethane / hexane = 35 / 65), and 2.05 g of intermediate 3 was obtained as a dark green solid with metallic luster.

[0070] [ka]

[0071] In a 100 mL recovery flask, 1-(tosyloxy)-3,6,9,12-tetraoxapentadecan-15-oic acid tert-butyl (4.99 g), 4-bromophenol (2.17 g), potassium carbonate (2.17 g), and N,N-dimethylformamide (20 mL) were placed and stirred under a nitrogen atmosphere at 70° C. for 5 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, ethyl acetate / hexane=5 / 5), yielding 4.32 g of intermediate 4 as a colorless, transparent oil.

[0072] [ka]

[0073] In a 200mL flask, intermediate 4 (4.32g), bis(pinacolato)diboron (2.76g), potassium acetate (4.44g), dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium·dichloromethane adduct (0.37g) and 1,4-dioxane (70mL) were placed and stirred at 100°C for 8 hours under a nitrogen atmosphere. After cooling to room temperature, water (200mL) and dichloromethane (300mL) were added for separation and washing. The oil phase was collected and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (neutral silica gel, ethyl acetate / hexane = 5 / 5) to obtain 4.57g of intermediate 5 as a pale yellow oil.

[0074] [ka]

[0075] Under a nitrogen atmosphere, intermediate 3 (1.0 g), intermediate 5 (0.88 g), toluene (35 mL), tetrahydrofuran (8 mL), and 2 mol / L tripotassium phosphate aqueous solution (3.6 mL) were placed in a 300 mL flask and stirred. A catalyst solution prepared by stirring palladium acetate (27 mg), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (99 mg), and tetrahydrofuran (7 mL) at room temperature for 10 minutes was added to the solution in a 30 mL Schlenk flask, and the mixture was stirred at 80°C for 1.5 hours. After cooling to room temperature, the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (neutral silica gel, dichloromethane / ethyl acetate / methanol = 5 / 5 / 0 → 2 / 2 / 1). The obtained crude product was placed in a 300 mL flask, and tetrahydrofuran (50 mL), acetic acid (32 mg), and 1 M tetra-n-butylammonium fluoride / tetrahydrofuran solution (0.54 mL) were added and stirred at room temperature for 30 minutes. The residue obtained by vacuum concentration was purified by silica gel column chromatography (neutral silica gel, ethyl acetate / dichloromethane = 4 / 6), and 1.02 g of intermediate 6 was obtained as a dark green solid.

[0076] [ka]

[0077] In a 300 mL eggplant flask, intermediate 6 (1.00 g), dichloromethane (50 mL) and tetrahydrofuran (30 mL) were placed, and N-bromosuccinimide (0.19 g) was added while stirring at room temperature, and the mixture was stirred at room temperature for 40 minutes. Water (100 mL) and ethyl acetate (200 mL) were added thereto for liquid separation and washing. The oil phase was collected and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (neutral silica gel, dichloromethane / ethyl acetate / methanol = 5 / 5 / 0 → 25 / 25 / 2), yielding 1.04 g of intermediate 7 as a dark green solid.

[0078] [ka]

[0079] In a 200 mL flask, intermediate 7 (0.25 g), 1,3-propane sultone (0.15 g), cesium carbonate (0.41 g) and tetrahydrofuran (40 mL) were placed and stirred at 80° C. for 2.5 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure, and acetone (20 mL) and diethyl ether (120 mL) were added and suction filtered. The resulting filtered product was purified by reversed-phase silica gel column chromatography (acetonitrile / water = 5 / 5), yielding 0.14 g of intermediate 8 as a black-blue solid.

[0080] [ka]

[0081] In a 200 mL flask, intermediate 8 (120 mg) and 4 M hydrogen chloride / 1,4-dioxane solution (40 mL) were placed and stirred at room temperature for 2.5 hours, and then concentrated under reduced pressure to obtain a crude intermediate 9. The crude product was used in the next reaction without purification. The crude intermediate 9 was placed in a 200 mL flask, water (30 mL) and sodium carbonate (60 mg) were added, and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed-phase silica gel column chromatography (acetonitrile / water = 5 / 5), yielding 109 mg of intermediate 10 as a black-blue solid.

[0082] [ka]

[0083] In a 200 mL flask, intermediate 10 (43 mg), N,N'-disuccinimidyl carbonate (28 mg), pyridine (0.2 mL) and dimethyl sulfoxide (7 mL) were placed and stirred at 55°C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, diethyl ether (80 mL) was added and the supernatant was removed. Methanol was added to the residue and concentrated under reduced pressure. The mixture was purified by reversed phase silica gel column chromatography (acetonitrile / water = 5 / 5) to obtain 45 mg of compound 1 as a black-blue solid.

[0084] <Synthesis example of compound 2> [ka]

[0085] In a 300 mL flask, intermediate 1 (1.20 g) and N,N-dimethylformamide (35 mL) were placed and stirred at 50 ° C under a nitrogen atmosphere. The solution was stirred at 50 ° C for 15.5 hours while gradually adding 2-(tert-butoxycarbonylamino)ethyl bromide (total 44.2 g) and potassium carbonate (total 28.3 g). After cooling to room temperature, water (250 mL) and a mixed solvent of hexane / ethyl acetate (1 / 3) (400 mL) were added for liquid separation and washing. The oil phase was recovered and concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (neutral silica gel, dichloromethane / ethyl acetate = 97 / 3 → 9 / 1), and 1.58 g of intermediate 11 was obtained as a dark green solid.

[0086] [ka]

[0087] In a 500 mL recovery flask, intermediate 11 (2.20 g) and dichloromethane (270 mL) were placed, and N-bromosuccinimide (0.48 g) was added while stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (neutral silica gel, dichloromethane / ethyl acetate = 95 / 5 → 9 / 1), and 2.40 g of intermediate 12 was obtained as a dark green solid.

[0088] [ka]

[0089] In a 500 mL recovery flask, 4-(4-bromophenyl)butyric acid (10.6 g) and methanol (200 mL) were placed, and concentrated sulfuric acid (2.5 mL) was added dropwise while stirring, followed by stirring at 90°C for 3 hours. After cooling to room temperature, water (200 mL) and dichloromethane (150 mL) were added for liquid separation and washing. The oil phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 11.2 g of intermediate 13 as a colorless oil.

[0090] [ka]

[0091] In a 500mL flask, intermediate 13 (11.2g), bis(pinacolato)diboron (12.7g), potassium acetate (12.8g), dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium·dichloromethane adduct (1.1g) and dimethylsulfoxide (100mL) were placed and stirred at 85°C for 5 hours. After cooling to room temperature, water (300mL) and dichloromethane (150mL) were added for separation and washing, and further extraction was performed with dichloromethane (100mL). The oil phase was collected and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (neutral silica gel, ethyl acetate / hexane = 1 / 4) to obtain 11.9g of intermediate 14 as a colorless oil.

[0092] [ka]

[0093] Under a nitrogen atmosphere, intermediate 12 (2.21 g), intermediate 14 (1.02 g), toluene (80 mL), tetrahydrofuran (27 mL), and 2 mol / L tripotassium phosphate aqueous solution (7.4 mL) were placed in a 300 mL flask and stirred. A catalyst solution prepared by stirring palladium acetate (55.5 mg), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (202 mg), and tetrahydrofuran (5 mL) at room temperature for 10 minutes was added to the solution in a 30 mL Schlenk flask, and the mixture was stirred at 80°C for 7.5 hours. After cooling to room temperature, the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (neutral silica gel, dichloromethane / ethyl acetate = 95 / 5 → 9 / 1), and 1.65 g of intermediate 15 was obtained as a dark green solid.

[0094] [ka]

[0095] In a 500 mL recovery flask, intermediate 15 (1.60 g) and dichloromethane (150 mL) were placed, and N-bromosuccinimide (0.28 g) was added while stirring at room temperature, and the mixture was stirred at room temperature for 1.5 hours. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (neutral silica gel, dichloromethane / ethyl acetate = 9 / 1 → 85 / 15), and 1.66 g of compound 2 was obtained as a dark green solid. Although compound 2 does not have an N-hydroxysuccinimide ester group, the N-hydroxysuccinimide ester group is a group necessary for binding to a biomolecule, and the presence or absence of the N-hydroxysuccinimide ester group is considered to have little effect on the confirmation of the absorption wavelength and singlet oxygen generation ability.

[0096] <Evaluation of Absorption Spectrum> Using a Hitachi U-3900H spectrophotometer, 10 -5 A mol / L dichloromethane solution was prepared and the absorption spectrum was measured in the measurement wavelength range of 400 nm to 900 nm.

[0097] [ka]

[0098] Example 1 The absorption spectrum of the obtained compound 1 was measured using an acetonitrile-water (7 / 3) mixed solution. The measurement results are shown in Figure 1. The maximum absorption wavelength of compound 1 was 673 nm.

[0099] (Reference example 1) The absorption spectrum of compound 2 was measured using a toluene solution. The measurement results are shown in Figure 1. The maximum absorption wavelength of compound 2 was 685 nm.

[0100] (Reference example 2) The absorption spectrum of intermediate 15 was measured using a toluene solution. The measurement results are shown in Figure 1. The maximum absorption wavelength of intermediate 15 was 691 nm.

[0101] <Evaluation of singlet oxygen generation ability> The singlet oxygen generating ability was evaluated by detecting the emission of singlet oxygen. The measurement solvent was toluene, and the concentration of each compound was adjusted so that the absorbance at the excitation wavelength was 2 in a 1 cm square cell. A spectrometer (Actes, CSM-330) was used, and a photomultiplier tube (Hamamatsu Photonics, R5509-43) was used as the detector. Measurements were performed at an excitation wavelength of 660 nm.

[0102] (Reference example 3) Singlet oxygen generation was measured for the obtained compound 2. Light emission due to singlet oxygen was clearly observed at 1270 nm from a toluene solution of compound 2. From the measurement results of compound 2, it is presumed that compound 1 also has the ability to generate singlet oxygen.

[0103] (Reference Comparative Example 1) Singlet oxygen generation was measured for intermediate 15. No emission due to singlet oxygen was observed at 1270 nm from a toluene solution of intermediate 15.

Claims

1. A compound represented by the following formula (2): 【Chemistry 1】 [In formula (2), X １ represents a halogen atom. Ar １ represents a phenyl group 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. However, Ar １ Or Ar ２ Is Z １ Ar may be bonded to １ Or Ar ２ The substituent of １ It may be combined with. Ar １ and Ar ２ The substituent that may be possessed by the formula (I) is 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, an alkylamide group having 2 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, or a salt of sulfonic acid, or a combination thereof. Y １ represents a fluorine atom or a trifluoromethyl group. Z １ represents a phenylene group. R １ is connected to Z via three or more single bonds. １ and the N-hydroxysuccinimide ester group.

2. The compound according to claim 1, wherein the compound represented by formula (2) is a compound represented by the following formula (3): 【Chemistry 2】 [In formula (3), Ar １ , Ar ２ , Y １ , Z １ , R １ is Ar in the formula (2). １ , Ar ２ , Y １ , Z １ , R １ is equivalent to.]

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