Method for producing indocyanine compound and indocyanine compound

Abstract

To provide a method for producing an indocyanine compound in which a side chain including a bulky benzene ring or pyridine ring is introduced into a polymethine chain that connects rings containing a nitrogen atom on both ends in an indocyanine dye.SOLUTION: A method for producing an indocyanine compound comprises a step of introducing a side chain including a benzene ring or a pyridine ring into an indocyanine compound represented by the following formula (1) by a mechanochemical process. (n represents an integer of 1 or more. The polymethine chain in formula (1) has a side chain including a benzene ring or a pyridine ring as a substituent. R1 and R2 each independently represent any substituent.)SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing an indocyanine-based compound using a mechanochemical method. The present invention also relates to a novel indocyanine-based compound produced by the method for producing an indocyanine-based compound. The indocyanine-based compound of the present invention has absorption and emission characteristics in the near-infrared region or more, and can be suitably used, for example, as a member for near-infrared light-emitting markers, indicators, bioimaging, sensors, wavelength-converting films, light-emitting transistors, OLEDs, electrochemiluminescence cells, photodynamic therapy, light beauty, night vision displays, security, anti-counterfeiting applications, and the like.

Background Art

[0002] Conventionally, as near-infrared light-emitting dyes, indocyanine-based dyes, particularly indocyanine-based dyes in which a tertiary amino group-containing structure and a quaternary ammonium cation-containing structure are bonded by a polymethine chain, are known. By changing the conjugation length of the polymethine chain, this dye can emit fluorescence from visible light to near-infrared light, and particularly in the heptamethine structure, fluorescence emission in the near-infrared region becomes possible.

[0003] As such indocyanine-based dyes, compounds having a structure improved by changing the conjugation length based on indocyanine green are known (Non-Patent Document 1). Further, as those having a similar structure, heptamethine cyanine dyes represented by the following structural formula (A) are known.

[0004]

Chemical Formula

[0005] As a method for producing such an indocyanine-based compound, a solution method is known (Non-Patent Document 2).

Prior Art Documents

Non-Patent Documents

[0006] [Non-Patent Document 1] RIKEN and Hokkaido University, "Short-Wave Infrared Fluorescent Dyes for in Vivo Fluorescent Imaging - Expected for Medical Applications such as Photo-Diagnosis of Breast Cancer -", August 2, 2021, Internet <URL:https: / / www.riken.jp / press / 2021 / 20210802_2 / index.html> [Non-Patent Document 2] Bioorganic & Medicinal Chemistry Letters (2018), 28(3), 509-514 [Summary of the Invention] [Problems to be Solved by the Invention]

[0007] Due to the large interaction between dipoles, these dye compounds tend to aggregate, resulting in problems such as a decrease in solubility, quenching due to non-radiative deactivation also known as concentration quenching, quenching due to electron transfer from anions, and particularly, due to the freedom of rotation at the portion connecting the rings containing nitrogen atoms on both sides, quenching due to vibrational relaxation easily occurs.

[0008] In order to solve these problems, it is conceivable to introduce a bulky side chain such as a benzene ring or a pyridine ring into the polymethine chain portion connecting the rings containing nitrogen atoms. However, in reality, since the ring structures containing nitrogen atoms on both sides are also bulky, these become interfering factors, and it is not easy to introduce a side chain containing a bulky benzene ring or pyridine ring into the polymethine chain portion connecting the rings containing nitrogen atoms on both sides. In addition, in the production of indocyanine-based compounds by the conventional solution method, when introducing a basic substituent such as pyridine, a decomposition reaction also proceeds, and there is a drawback of very poor yield. For example, in the above Non-Patent Document 2, the yield is as low as 25%.

[0009] The present invention has been made in view of the actual state of the above-mentioned prior art, and an indocyanine-based compound in which a side chain containing a bulky benzene ring or pyridine ring is introduced into a polymethine chain connecting rings containing nitrogen atoms on both sides in an indocyanine-based dye is produced at a higher yield than the conventional solution method. Another object is to provide a method and a novel indocyanine-based compound produced by this method.

Means for Solving the Problems

[0010] As a result of intensive studies, the present inventors have found that by using the mechanochemical method, a side chain containing a bulky benzene ring or pyridine ring can be easily introduced into a polymethine chain connecting rings containing nitrogen atoms on both sides of an indocyanine-based dye. That is, the gist of the present invention is as follows.

[0011] [1] A method for producing an indocyanine-based compound, comprising a step of introducing a side chain containing a benzene ring or a pyridine ring into an indocyanine-based compound represented by the following formula (1) by a mechanochemical method.

[0012] [Chemical formula]

[0013] (In formula (1), n represents an integer of 1 or more. The polymethine chain in formula (1) has a side chain containing a benzene ring or a pyridine ring as a substituent, and the polymethine chain may have any substituent other than the side chain containing the benzene ring or the pyridine ring. The arbitrary substituents may be bonded to each other to form a ring containing the methine chain. R 1 ,R 2 each independently represents an arbitrary substituent. M - represents a counteranion. -N + R 1 -containing ring and -NR 2The rings containing - may each have any substituent other than a dimethyl group, and these substituents may be bonded to each other to form a condensed ring condensed to each ring. Further, the condensed ring may have any substituent, and the substituents may be bonded to each other to form a further condensed ring.)

[0014] [2] The method for producing an indocyanine compound according to [1], wherein the step of introducing a side chain containing the benzene ring or pyridine ring is carried out without heating.)

[0015] [3] The method for producing an indocyanine compound according to [1] or [2], wherein the indocyanine compound is represented by the following formula (2).

[0016] [Chemical formula]

[0017] (In formula (2), R 1 , R 2 , M - have the same meanings as in formula (1) respectively.) X represents a direct bond or a carbon atom, and the carbon atom may have any substituent.) Ar represents a substituent containing a benzene ring or a pyridine ring.) The benzene ring condensed to the ring containing -N + R 1 - and the benzene ring condensed to the ring containing -NR 2 - may each have any substituent, and these substituents may be bonded to each other to form a condensed ring condensed to each benzene ring.)

[0018] [4] The method for producing an indocyanine compound according to [3], wherein the indocyanine compound is represented by the following formula (2A).

[0019] [Chemical formula]

[0020] (In formula (2A), R 1 , R 2 , M - have the same meanings as in formula (1), respectively.) R 3 represents a hydrogen atom or an arbitrary substituent.) Ar a represents a substituent containing a benzene ring.) The benzene ring condensed with the ring containing -N + R 1 - and the benzene ring condensed with the ring containing -NR 2 - may each have an arbitrary substituent, and these substituents may be bonded to each other to form a condensed ring condensed with each benzene ring.)

[0021] [5] The method for producing an indocyanine compound according to [3], wherein Ar in the formula (2) is a pyridyloxy group which may have a substituent.)

[0022] [6] The method for producing an indocyanine compound according to [4], wherein Ar in the formula (2A) is a phenoxy group which may have a substituent.) a

[0023] [7] An indocyanine compound represented by the following formula (3).

[0024] [Chemical formula]

[0025] (In formula (3), R 1 , R 2 each represent an arbitrary substituent.) R 3 , R 4 each independently represent a hydrogen atom or an arbitrary substituent.) M - represents a counter anion.) The benzene ring condensed with the ring containing -N + R 1 - and the benzene ring condensed with the ring containing -NR 2 ​The benzene rings fused to the ring containing - may each have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.)

[0026] [8] An indocyanine compound represented by the following formula (4).

[0027]

Chemical formula

[0028] (In formula (4), R 1 , R 2 each represent any substituent.) R 3 , R 4 each independently represent a hydrogen atom or any substituent.) M - represents a counteranion.) The benzene ring fused to the ring containing -N + R 1 - and the benzene ring fused to the ring containing -NR 2 - may each have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.)

[0029] In the case of the method for producing an indocyanine compound into which a side chain containing a benzene ring is introduced, the method for producing the indocyanine compound of the present invention is as follows in [1-1] to [1-4].

[0030] [1-1] A method for producing an indocyanine compound including a step of introducing a side chain containing a benzene ring into an indocyanine compound represented by the following formula (1) by a mechanochemical method.)

[0031]

Chemical formula

[0032] (In formula (1), n represents an integer of 1 or more.) In formula (1), the polymethine chain has a side chain containing a benzene ring as a substituent, and the polymethine chain may have any substituent other than the side chain containing the benzene ring. The any substituents may be bonded to each other to form a ring containing the methine chain. R 1 ,R 2 each independently represents any substituent. M - represents a counter anion. The ring containing -N + R 1 - and the ring containing -NR 2 - may each have any substituent other than a dimethyl group, and these substituents may be bonded to each other to form a condensed ring that condenses to each ring, and the condensed ring may have any substituent, and the substituents may be bonded to each other to form a further condensed ring.

[0033] [1-2] The method for producing an indocyanine-based compound according to [1-1], wherein the step of introducing the side chain containing the benzene ring is carried out without heating.

[0034] [1-3] The method for producing an indocyanine-based compound according to [1-1] or [1-2], wherein the indocyanine-based compound is represented by the following formula (2).

[0035]

Chemical formula

[0036] (In formula (2), R 1 , R 2 , M - have the same meanings as in formula (1), respectively. R 3 represents a hydrogen atom or any substituent. Ar represents a substituent containing a benzene ring. The benzene ring condensed to the ring containing -N + R 1 - and the benzene ring and -NR 2The benzene rings fused to the ring containing - may each optionally have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.)

[0037] [1-4] The method for producing an indocyanine compound according to [1-3], wherein Ar in the formula (2) is a phenoxy group which may have a substituent.) [Advantages of the Invention]

[0038] According to the method for producing an indocyanine compound of the present invention, a bulky side chain containing a benzene ring or a pyridine ring can be easily introduced into the polymethine chain connecting the rings containing nitrogen atoms on both sides of the indocyanine dye. By having a bulky side chain containing a benzene ring or a pyridine ring in the polymethine chain portion, (1) The interaction between dipoles is small and it is difficult to aggregate.) (2) From the above (1), problems such as a decrease in solubility, quenching due to non-radiative deactivation also called concentration quenching, and quenching due to electron transfer from anions are less likely to occur.) (3) Since the rotation at the portion of the ring containing nitrogen atoms on both sides is restricted, quenching due to vibrational relaxation is less likely to occur.) It is possible to present an indocyanine compound having excellent effects such as this, particularly a novel indocyanine compound not found in the prior art.) Further, according to the present invention, such a novel indocyanine compound can be produced in a high yield by a mechanochemical method.) [Embodiments for Carrying Out the Invention]

[0039] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments and can be variously modified and implemented within the scope of the gist.)

[0040] The method for producing an indocyanine compound of the present invention includes a step of introducing a side chain containing a benzene ring or a pyridine ring in an indocyanine compound represented by the following formula (1) (hereinafter, may be referred to as "compound (1)") by a mechanochemical method.

[0041]

Chemical formula

[0042] (In formula (1), n represents an integer of 1 or more. The polymethine chain in formula (1) has a side chain containing a benzene ring or a pyridine ring as a substituent, and the polymethine chain may have any substituent other than the side chain containing the benzene ring or the pyridine ring. The any substituents may be bonded to each other to form a ring containing the methine chain. R 1 ,R 2 each independently represents an arbitrary substituent. M - represents a counter anion. The ring containing -N + R 1 - and the ring containing -NR 2 - may each have any substituent other than a dimethyl group, and these substituents may be bonded to each other to form a condensed ring condensed to each ring, and the condensed ring may have any substituent, and the substituents may be bonded to each other to form a further condensed ring.)

[0043] <Any substituent> In the present invention, the optional substituent is not particularly limited, and examples thereof include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an alkoxy group, an aryloxy group, a heteroaryloxy group, an alkylthio group, an arylthio group, a heteroarylthio group, an amino group, an acyl group, an aminoacyl group, a ureido group, a sulfonamide group, a carbamoyl group, a sulfamoyl group, a sulfamoylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryloxycarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an imide group, and a silyl group.

[0044] Specifically, the following substituents can be mentioned. A halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; An alkyl group having about 1 to 15 carbon atoms such as a methyl group or an ethyl group; An alkenyl group having about 2 to 10 carbon atoms such as an ethynyl group or a propylenyl group; An alkynyl group having about 2 to 10 carbon atoms such as an acetylenyl group; An aryl group having about 6 to 20 carbon atoms such as a phenyl group or a naphthyl group; A heteroaryl group having about 3 to 20 carbon atoms such as a thienyl group, a furyl group, or a pyridyl group; An alkoxy group having about 1 to 15 carbon atoms such as a methoxy group, an ethoxy group, or a propoxy group; An aryloxy group having about 6 to 20 carbon atoms such as a phenoxy group or a naphthoxy group; A heteroaryloxy group having about 3 to 20 carbon atoms such as a pyridyloxy group or a thienyloxy group; An alkylthio group having about 1 to 15 carbon atoms such as a methylthio group or an ethylthio group; An arylthio group having about 6 to 20 carbon atoms such as a phenylthio group or a naphthylthio group; A heteroarylthio group having about 3 to 20 carbon atoms such as a pyridylthio group or a thienylthio group; An amino group which may have a substituent having about 1 to 20 carbon atoms such as a dimethylamino group or a diphenylamino group; An acyl group having about 2 to 20 carbon atoms such as an acetyl group or a pivaloyl group; An acylamino group having about 2 to 20 carbon atoms such as an acetylamino group or a propionylamino group; A ureido group having about 2 to 20 carbon atoms such as a 3-methylureido group; A sulfonamide group having about 1 to 20 carbon atoms such as a methanesulfonamide group or a benzenesulfonamide group; A carbamoyl group having about 1 to 20 carbon atoms such as a dimethylcarbamoyl group or an ethylcarbamoyl group; A sulfamoyl group having about 1 to 20 carbon atoms such as an ethylsulfamoyl group; A sulfamoylamino group having about 1 to 20 carbon atoms such as a dimethylsulfamoylamino group; An alkoxycarbonyl group having about 2 to 6 carbon atoms such as a methoxycarbonyl group or an ethoxycarbonyl group; An aromatic hydrocarbon oxycarbonyl group having about 7 to 20 carbon atoms such as a phenoxycarbonyl group or a naphthoxycarbonyl group; An aromatic heterocyclic hydrocarbon oxycarbonyl group having about 6 to 20 carbon atoms such as a pyridyloxycarbonyl group; An alkylsulfonyl group having about 1 to 6 carbon atoms such as a methanesulfonyl group, an ethanesulfonyl group, or a trifluoromethanesulfonyl group; An arylsulfonyl group having about 6 to 20 carbon atoms such as a benzenesulfonyl group or a monofluorobenzenesulfonyl group; A heteroaryloxysulfonyl group having about 3 to 20 carbon atoms such as a thienylsulfonyl group; An imide group having about 4 to 20 carbon atoms such as phthalimide; A silyl group trisubstituted with a substituent selected from the group consisting of an alkyl group and an aryl group;

[0045] <Compound (1)> According to the present invention, the compound (1) produced by introducing a side chain containing a benzene ring or a pyridine ring by a mechanochemical method will be described below.

[0046] In the formula (1) representing the compound (1), n is an integer of 1 or more. Since it is particularly difficult to introduce a side chain when n is 4 or less, and the effects of the present invention are more effectively exhibited, n is preferably 2 to 4, and most preferably 3.

[0047] The polymethine chain in formula (1) has a side chain containing a benzene ring or a pyridine ring. Usually, the side chain containing a benzene ring or a pyridine ring has a larger intermolecular interaction and is more likely to cause fluorescence deactivation as the overlap of the conjugated system increases during aggregation. Therefore, it is preferable that there is a side chain containing a benzene ring or a pyridine ring at the polymethine moiety (the position of the double bond). Further, the side chain containing a benzene ring or a pyridine ring is preferably introduced at the position farthest from the ring containing nitrogen atoms on both sides.

[0048] The polymethine chain in formula (1) may have an arbitrary substituent other than the side chain containing a benzene ring or a pyridine ring, and the arbitrary substituents may be bonded to each other to form a ring containing a methine chain. Examples of such a ring include a cyclohexene ring (when X in formula (2) below is a carbon atom) or a cyclopentene ring (when X in formula (2) is a direct bond) as shown in formula (2) below, and a cycloheptene ring and the like. Preferably, a cyclohexene ring or a cyclopentene ring bonded to the methine chain at the meta position from the viewpoint of synthesis, and more preferably a cyclohexene ring. Thus, when a ring structure is introduced into the polymethine chain, it is preferable from the viewpoint of synthesis that the side chain containing a benzene ring or a pyridine ring is introduced at the ortho position with respect to the methine chain in this ring. Here, in the case of a side chain containing a benzene ring, various substituents can be easily introduced, which is suitable for imparting compatibility, adjusting the wavelength, supporting on a metal oxide, etc., and is preferable. On the other hand, in the case of a side chain containing a pyridine ring, the emission wavelength can be adjusted by the electron-withdrawing effect, and in addition, N of the pyridine ring is effectively coordinated to a metal as a linking group, which is suitable for arranging on a substrate or forming a complex, and is preferable.

[0049] In formula (1), R 1 , R 2Each independently represents an arbitrary substituent. Specific examples of the arbitrary substituent are as described above. R 1 ,R 2 From the viewpoint of solubility, each independently, a linear or branched alkyl group having 1 to 12 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group is preferable, and particularly a linear alkyl group having 1 to 6 carbon atoms is preferable. Further, these alkyl groups may be substituted with a sulfonic acid group, a carboxylic acid group, a hydroxyl group, an alkoxy group, a phenyl group, an amino group, or the like. R 1 and R 2 may be the same or different, but are preferably the same in the synthesis of the compound (1).

[0050] M - is a counter anion, and examples thereof include halogen ions such as chloride ion, bromide ion, iodide ion, and fluoride ion; inorganic anions such as perchlorate ion, chlorate ion, thiocyanate ion, hexafluorophosphate anion, and tetrafluoroborate anion; and organic sulfonic acid anions such as benzenesulfonate ion, p-toluenesulfonate ion, and trifluoromethanesulfonate ion. Although not particularly limited, halogen ions such as chloride ion are preferable.

[0051] -N + R 1 -containing ring and -NR 2 -containing ring may each have an arbitrary substituent other than a dimethyl group, and these substituents may be bonded to each other to form a condensed ring condensed to each ring. Further, the condensed ring may further have an arbitrary substituent, and the substituents may be bonded to each other to form a further condensed ring. Examples of the ring forming such a condensed ring include aromatic hydrocarbon rings such as a benzene ring and a naphthalene ring. From the viewpoint of high luminous efficiency, a benzene ring is preferable, and from the viewpoint of wavelength elongation, a naphthalene ring is preferable.

[0052] As the compound (1), from the viewpoint of ease of photoexcitation at a wavelength of 780 nm, an indocyanine compound represented by the following formula (2) (hereinafter, may be referred to as "compound (2)") can be mentioned.

[0053]

Chemical formula

[0054] (In formula (2), R 1 , R 2 , M - are synonymous with those in formula (1), respectively. X represents a direct bond or a carbon atom, and the carbon atom may have any substituent. Ar represents a substituent containing a benzene ring or a pyridine ring. In formula (2), the benzene ring condensed to the ring containing -N + R 1 - and the benzene ring condensed to the ring containing -NR 2 - may each have any substituent, and these substituents may be bonded to each other to form a condensed ring condensed to each benzene ring. )

[0055] In the above formula (2), when X is a direct bond, the ring containing X becomes a five-membered ring (cyclopentene ring). When X is a carbon atom, the ring containing X becomes a six-membered ring (cyclohexene ring). From the viewpoint of synthesis, X is preferably a carbon atom which may have any of the aforementioned substituents, and from the viewpoint of synthesis, it is preferably a carbon atom having no substituent or having an alkyl group having 1 to 6 carbon atoms as a substituent.

[0056] Examples of the substituent containing a benzene ring of Ar in formula (2) include aryl groups such as phenyl group, aryloxy groups such as phenoxy group, benzyl group, thiophenyl group, anilino group, etc. From the viewpoint of stability against light, aryl groups such as phenyl group and aryloxy groups such as phenoxy group are preferable. The substituent containing a benzene ring of Ar may further have an arbitrary substituent. In this case, examples of the arbitrary substituent preferably include an alkyl group and an aryl group.

[0057] Examples of the substituent containing a pyridine ring of Ar include pyridyl group, pyridyloxy group, pyridylmethyl group, thiopyridyl group, pyridinylamino group, etc. From the viewpoint of stability against light, pyridinylamino group and pyridyloxy group are preferable. The substituent containing a pyridine ring of Ar may further have an arbitrary substituent. In this case, examples of the arbitrary substituent preferably include an alkyl group and an aryl group.

[0058] From the viewpoint of synthesis, as compound (2), it is preferable that X in the above formula (2) is a carbon atom which may have a substituent, and Ar is a substituent containing a benzene ring. That is, as compound (2), a compound represented by the following formula (2A) (hereinafter, may be referred to as "compound (2A)") is preferable.

[0059]

Chemical formula

[0060] (In formula (2A), R 1 , R 2 , M - have the same meanings as in formula (1) respectively. R 3 represents a hydrogen atom or an arbitrary substituent. Ar a represents a substituent containing a benzene ring and has the same meaning as the case where Ar in formula (2) is a substituent containing a benzene ring. The benzene ring condensed to the ring containing -N + R 1 - and -NR 2The benzene rings fused to the ring containing - may each have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.)

[0061] In the above formula (2A), R 3 Specific examples of any substituent of are as described above, but from the viewpoint of synthesis, preferably R 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

[0062] More specifically, as the compound (2), the indocyanine compound of the present invention represented by the following formula (3) (hereinafter, may be referred to as "compound (3)") or the indocyanine compound of the present invention represented by the following formula (4) (hereinafter, may be referred to as "compound (4)") can be mentioned, and these compounds (3) and compound (4) are novel compounds first produced by the present inventors.

[0063]

Chemical formula

[0064] (In formula (3), R 1 , R 2 each represent any substituent. R 3 , R 4 each independently represent a hydrogen atom or any substituent. M - represents a counter anion. The benzene ring fused to the ring containing -N + R 1 - and the benzene ring fused to the ring containing -NR 2 - may each have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.)

[0065]

Chemical formula

[0066] (In formula (4), R 1 , R 2 each represents an arbitrary substituent.) R 3 , R 4 each independently represents a hydrogen atom or an arbitrary substituent.) M - represents a counter anion.) The benzene ring condensed to the ring containing -N + R 1 - and the benzene ring condensed to the ring containing -NR 2 - may each have an arbitrary substituent, and these substituents may be bonded to each other to form a condensed ring condensed to each benzene ring.)

[0067] In the above formulas (3) and (4), R 1 , R 2 , R 3 have the same meanings as in the above formulas (2) and (2A), and the preferred ones are also the same.) Examples of the arbitrary substituent of R 4 include an alkyl group, an alkoxy group, an aryl group, a halogen atom, a sulfonic acid group, a carboxylic acid group, etc. From the viewpoint of aggregation inhibition, R 4 is preferably a hydrogen atom or an alkyl group or aryl group having 1 to 12 carbon atoms. When coordinating to a metal, R 4 is preferably a carboxylic acid group or a sulfonic acid group.)

[0068] <Compound before introducing a side chain containing a benzene ring or a pyridine ring> In the present invention, as the compound (hereinafter sometimes referred to as "pre-modification compound") used for introducing a side chain containing a benzene ring or a pyridine ring into a polymethine chain by a mechanochemical method, it is preferable to introduce a group that facilitates the introduction of the side chain, or a halogen atom, preferably a chlorine atom or a bromine atom, into the side chain introduction part of the polymethine chain part of formula (1). For example, a compound represented by the following formula (5) can be mentioned. However, the pre-modification compound according to the present invention is not limited to the compound represented by the following formula (5).)

[0069] [Chemical formula] (In formula (5), R is the same as R in formula (1) 1 , R 2 corresponds to. R 3 is synonymous with R in formula (2A) 3 . Cl of the counter anion - may be the aforementioned M - and is not limited to Cl - .)

[0070] The above pre-modification compound can be produced by the following method according to the following scheme, following the methods described in Org. Chem. 2008, 73, 723 - 725 and Chem. Eur. J. 2017, 23, 9306 - 9312.

[0071] [Chemical formula]

[0072] That is, as a general production method, aniline hydrochloride is added to the intermediate (b) formed by adding the cyclohexanone compound (a) into the Vilsmeier reagent (POCl 3 + DMF) to synthesize the chloro-substituted iminium salt (c). By reacting this compound (c) with the indolium salt compound (d) at a ratio of 1:2, the symmetric indocyanine compound (pre-modification compound) represented by the above formula (5) can be synthesized. In addition, when forming an asymmetric indocyanine compound in the same way, the indolium salt compound (d) may be reacted with a different one. However, in terms of purity, it is preferable to use a single indolium salt compound. In addition, the above scheme is an example of the production method of the pre-modification compound according to the present invention and does not limit the present invention in any way. However, any pre-modification compound can be produced in the same manner as above.

[0073] [Mechanochemical method] The mechanochemical method refers to a reaction method in which mechanical energy such as friction and compression is applied to particles of a plurality of different materials, and the locally generated high energy is utilized to bond the particles to each other at the molecular level to create composite fine particles.

[0074] (Reaction method · Reaction vessel) The reaction method of the mechanochemical method is not particularly limited, and examples include a compression shear treatment method, a high-speed impact treatment method, a mixing shear friction method, etc. Among them, the high-speed impact treatment method is preferable. Examples of the high-speed impact treatment method include a method using a ball mill. In a ball mill, the container used for the reaction of the raw materials has a hardness that can withstand impacts and is not particularly limited as long as it is inert to the reaction, but a ceramic container is preferable, and a zirconia container is particularly preferable. By using a ceramic container, especially a zirconia container, it is easy to manufacture a high-purity indocyanine-based compound by suppressing the mixing of impurities derived from the container. Also, when the solubility of the product is high and it can be filtered, from the viewpoint of reducing the manufacturing cost of the container, it is also preferable to use a stainless steel container. The capacity of the container is preferably sufficiently large with respect to the amount of the raw materials. The internal volume of the container is usually 5 times or more, preferably 10 times or more, more preferably 20 times or more the volume of the raw materials, and on the other hand, usually 300 times or less, preferably 100 times or less, more preferably 50 times or less.

[0075] The material of the balls used in the reaction is not particularly limited, but ceramic balls are preferable, and zirconia balls are preferably used. When using zirconia balls, since the specific gravity is large and hard, the impact on the raw materials is large, and the reaction can proceed in a short time. As the zirconia balls, usually stabilized YSZ, YTZ manufactured by Nikkato, etc. can be used. Also, when the solubility of the product is high and it can be filtered, from the viewpoint of reducing the manufacturing cost of the container, it is also preferable to use stainless steel balls. The size of the balls is usually 30 mm or less in diameter, preferably 20 mm or less, more preferably 15 mm or less. On the other hand, it is usually 1 mm or more, preferably 5 mm or more. When the size of the balls is within the above range, sufficient energy for the reaction can be efficiently applied, and the target indocyanine compound can be obtained in a short time. The ratio of the total volume of the balls to the volume of the container is usually 3% by volume or more, preferably 5% by volume or more, more preferably 8% by volume or more, even more preferably 10% by volume or more. On the other hand, it is usually 50% by volume or less, preferably 30% by volume or less, more preferably 20% by volume or less, even more preferably 15% by volume or less. When the total volume of the balls used is within the above range, the impact energy of the balls is efficiently transmitted to the raw materials, and the target indocyanine compound can be produced by efficiently introducing a side chain containing a benzene ring or a pyridine ring.

[0076] Examples of the rotation method of the ball mill include uniaxial rotation and planetary rotation. Planetary rotation is preferred because the energy of the balls can be efficiently applied to the entire raw material mixture. The rotation speed in a planetary ball mill is usually 50 rpm or more, preferably 100 rpm or more. On the other hand, it is usually 300 rpm or less, preferably 200 rpm or less. When the rotation speed is within this range, the target indocyanine compound can be stably produced without breaking the produced indocyanine compound.

[0077] The inside of the ball mill container may be filled with a gas. Usually, an inert gas such as nitrogen or air is preferred, and air is particularly preferred for simplicity.

[0078] (Reaction time and reaction temperature) The reaction time by the mechanochemical method is usually 5 minutes or more, preferably 0.5 hours or more, more preferably 1 hour or more. On the other hand, it is usually 9 hours or less, preferably 6 hours or less, more preferably 3 hours or less. When the treatment time is within this range, the target compound can be efficiently synthesized without breaking the produced indocyanine compound.

[0079] The reaction temperature by the mechanochemical method is usually 100 °C or lower, preferably 90 °C or lower, more preferably 80 °C or lower. On the other hand, it is usually 0 °C or higher, preferably 10 °C or higher, particularly 15 to 40 °C under non-heating conditions. When in this temperature range, side reactions are less likely to occur, and high-purity indocyanine-based compounds can be efficiently synthesized.

[0080] <Introduction of a side chain containing a benzene ring or a pyridine ring by the mechanochemical method> The introduction of an aryloxy group into the pre-modification compound by the mechanochemical method as described above can be carried out, for example, according to the following scheme.

[0081] [Chemical formula]

[0082] (In the above scheme, R, R 3 are synonymous with R, R in the formula (5) above, and Ar’ is a benzene ring having R 3 in the formula (3) or a pyridine ring having R 4 in the formula (4).) 4

[0083] In the above scheme, for the pre-modification compound (5), the aryloxy (Ar’-O) group is preferably at a molar ratio of 1.0 or more, and considering the cost, preferably 15 or less. As the base (Base), an organic base is desirable, and examples include triethylamine, tributylamine, pyridine, diazabicycloundecene, diazabicyclononene, etc. The usage amount of Base is preferably at a molar ratio of 1.5 or more with respect to the pre-modification compound (5), and considering the suppression of side reactions, a molar ratio of 2 or less is preferable. The molar ratio of the pre-modification compound (5): Ar’-OH: Base is preferably 1: 1.0 to 10: 1.5 to 20.

[0084] ​When introducing an aryl group, a catalyst such as a palladium catalyst, a ligand, and a base (Base) are required, and the following scheme can be mentioned.

[0085]

Chemical formula

[0086] (In the above scheme, R, R 3 is synonymous with R, R in formula (5), and Ar is synonymous with Ar in the above formula (2). Q represents the following.) 3

[0087]

Chemical formula

[0088] Examples of the palladium catalyst include divalent palladium compounds such as palladium(II) acetate, palladium(II) chloride, palladium(II) bromide, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorotetraamminepalladium(II), dichloro(cycloocta-1,5-diene)palladium(II), palladium(II) trifluoroacetate, etc., and zero-valent palladium compounds such as tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone)dipalladium chloroform complex(0), tetrakis(triphenylphosphine)palladium(0), etc. The palladium catalysts can be used individually or in combination. The amount of the palladium catalyst used is preferably 5 mol% or more and 10 mol% or less based on the pre-modification compound (5).

[0089] ​Examples of the ligand include arylphosphines such as triphenylphosphine, tri(o-tolyl)phosphine, and tri(mesityl)phosphine, and alkylphosphines such as tri(tert-butyl)phosphine, tri(cyclohexyl)phosphine, and tri(isopropyl)phosphine. The amount of the ligand used is preferably 0.1 to 10 molar equivalents relative to the catalyst.

[0090] Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium fluoride, and cesium fluoride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium methoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide; and organic bases such as triethylamine, tributylamine, pyridine, diazabicycloundecene, and diazabicyclononene. The amount of the base used is preferably 0.5 or more and 10 or less in molar ratio relative to the compound (5) before modification.

[0091] Ar in Ar-Q is a substituent containing a benzene ring or a substituent containing a pyridine ring, preferably within the following range. Exemplary preferred ones as Ar can be selected from an aryl group which may have a substituent and a heteroaryl group which may have a substituent. The aryl group which may have a substituent includes, for example, phenyl group, naphthyl group, anthracenyl group, phenanthrenyl group, biphenyl group, terphenyl group, pyrenyl group, perylenyl group, triphenylenyl group and the like. The heteroaryl group which may have a substituent includes, for example, sulfur-containing heteroaryl groups such as thiophenyl group, thienylenyl group, benzothienyl group, dibenzothienyl group, phenyldibenzothienylenyl group and dibenzothienylenylphenyl group; oxygen-containing heteroaryl groups such as furanyl group, benzofuranyl group, dibenzofuranyl group, phenyldibenzofuranyl group and dibenzofuranylphenyl group; pyridyl group, pyridylenyl group, pyrimidinyl group, pyrazyl group, quinolyl group, isoquinolyl group, carbazolyl group, 9-phenylcarbazolyl group, acridinyl group, quinazolinyl group, quinoxalinyl group, 1,6-naphthyridinyl group, 1,8-naphthyridinyl group.

[0092] As described above, the mechanochemical method is a reaction method that utilizes the locally generated high energy by applying mechanical energy such as friction and compression to particles of a plurality of different materials to bond the particles to each other at the molecular level and create composite fine particles. Usually, the reaction is carried out without using a solvent, but when the viscosity is high and it is difficult to adsorb and disperse in the container, a liquid may be used as necessary. In this case, the amount of the liquid used is 12 μL / mg or less, for example, about 0.001 to 12 μL / mg, which is a very small amount, and is distinguished from the solution method using a solvent exceeding 12 μL / mg with respect to the weight of the substrate. In addition, Adv. Synth. Catal. 2021, 363, 1246-1271 describes the definition of a solvent as follows. It is empirically characterized by the parameter η, based on how Mechanochemical reactivity is affected by the ratio of the liquid additive to the weight of reactants [η,η=V(liquid;μL) / m(reagents;mg)]

[14] (Scheme 2a). For example, η = 0 μL / mg refers to neat grinding, η>12 μL / mg refers to a typical solution reaction. While values of η in LAG lies in the range of 0 - 2 μL / mg When using a liquid, there is no particular limitation as long as it is a solvent in which the reaction substrate is dispersed. For example, polar solvents such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, ethanol, methanol, water, etc., and non-polar solvents such as toluene and hexane can be mentioned. These solvents may be used alone or in combination of two or more kinds.

Examples

[0093] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples and synthetic compounds as long as it does not exceed the gist. The various conditions and the values of the evaluation results in the following examples indicate the preferred ranges in the embodiments of the present invention. Similarly, the preferred range of the present invention can be determined in consideration of the preferred ranges in the above-described embodiments and the ranges indicated by the values in the following examples or the combinations of the values of the examples.

[0094] In the following, as the mechanochemical apparatus, “Mixer Mill MM400” manufactured by Retsch GmbH was used.

[0095] [Example 1] According to the following scheme, a side chain containing a benzene ring was introduced to produce the indocyanine compound of the present invention.

[0096]

Chem.

[0097] (In the above reaction formula, R a is a methyl group, and R b is a 1,1-dimethyl-3,3-dimethyl-butyl group.)

[0098] As the cyanine compound of the pre-modification compound, 0.30 g (0.58 mmol) of IR755 Chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 4-tert-octylphenol and triethylamine in amounts corresponding to the following molar ratios were placed in a zirconia grinding jar with a volume of 5 mL. One zirconia ball with a diameter of 10 mm was placed therein, and the container was sealed. This container was set in a mixer mill and shaken at a shaking frequency of 30 Hz (30 times / s) for 30 minutes to carry out a mechanochemical reaction. After the reaction, the container was opened, and the obtained reaction product was dissolved in deuterated chloroform and analyzed by NMR. By comparing the ratio of the integrated values of the hydrogen atoms of the methylene chain of the raw material and the product from the obtained NMR spectrum, the target ratio (the percentage of the integrated value of the target product with respect to the total integrated values of the raw material and the target product) and the raw material ratio (the percentage of the integrated value of the raw material with respect to the total integrated values of the raw material and the target product) of the target product were determined. Molar ratio (cyanine compound:phenol:amine) = 1:1.1:2 Reaction time: 30 minutes Reaction temperature: room temperature (about 23 °C) As a result, the target ratio was 45% and the raw material ratio was 55%.

[0099] [Comparative Examples 1, 2] Using 15 mL of N,N-dimethylformamide (DMF) as a solvent per 0.3 g of the cyanine dye, the raw materials and the solvent were put into a 30 mL Schlenk tube at the same ratio as in Example 1. The target indocyanine-based compound was produced by the same reaction scheme as in Example 1, except that the reaction was carried out by the solution method for 30 minutes at the reaction temperature shown in Table 1 under a nitrogen atmosphere. After sampling the reaction solution, the solvent was distilled off and vacuum dried, and then NMR measurement was carried out in the same manner to determine the ratio of the target product. The ratio of the target product is shown in Table 1 together with the ratio of the target product in Example 1.

[0100]

Table 1

[0101] As shown in Table 1, in the solution method, the reaction did not occur at room temperature, and even at a high temperature of 85 °C, the ratio of the target product was very low at 16%. In contrast, in the mechanochemical method, the introduction reaction of the side chain containing a benzene ring could be carried out at room temperature with a target product ratio of 45%.

[0102] [Examples 2, 3] In Example 1, the introduction of the side chain containing a benzene ring by the mechanochemical method was carried out in the same manner except that the reaction time was changed as shown in Table 2. The ratio of the target product and the raw material ratio as the reaction result are shown in Table 2 together with the results of Example 1. From this result, it can be seen that in the production method of the present invention, the reaction proceeds sufficiently in a short time of about 30 minutes.

[0103]

Table 2

[0104] [Examples 4, 5] In Example 1, the introduction of the side chain containing a benzene ring by the mechanochemical method was carried out in the same manner except that the molar ratio of the amine to the cyanine compound of the compound before modification was changed as shown in Table 3. The ratio of the target product and the raw material ratio are shown in Table 3 together with the results of Example 1.

[0105]

Table 3

[0106] From Table 3, it can be seen that the higher the molar ratio of amine, the higher the target product ratio and the lower the raw material ratio (the ratio of the raw materials remaining without reaction). In particular, a high yield has been obtained by setting the molar ratio of amine to 3 or more. Also, since the sum of the target product ratio and the raw material ratio is 100, it can be seen that almost no impurities are generated.

[0107] [Example 6] In Example 1, the side chain containing a benzene ring was introduced by the mechanochemical method in the same manner except that N-ethyldiisopropylamine (DIPEA) was used instead of triethylamine (Et 3 N). The target product ratio and the raw material ratio are shown in Table 4 together with the results of Example 1.

[0108]

Table 4

[0109] From Table 4, it can be seen that Et 3 N is more preferable as the amine.

[0110] [Examples 7 - 10] In Example 1, the molar ratios of phenol and amine to the cyanine compound of the compound before modification were changed as shown in Table 5. In Example 7, DIPEA was used as the amine and the amount of cyanine was set to 0.1 g. Also, in Examples 8 - 10, the reaction time was set to 60 minutes. The side chain containing a benzene ring was introduced by the mechanochemical method in the same manner except for these. The target product ratio and the raw material ratio are shown in Table 5 together with the results of Example 1.

[0111]

Table 5

[0112] From Table 5, it can be seen that the reaction performance is improved by increasing the molar ratios of phenol and amine. In particular, by setting both the molar ratio of phenol and amine to 3 or more, preferably 4 or more, it can be seen that a very excellent target product ratio (yield) can be obtained.

[0113] [Examples 11 to 15]

Chemical formula

[0114] The same cyanine compound used in Example 1, a phenol compound represented by R 11 ~R 15 described in Table 6, and triethylamine were charged at a molar ratio of (1:5:4), and in the same manner, a side chain containing a benzene ring was introduced by the mechanochemical method, and the target product ratio and the raw material ratio were determined. The results of Examples 11 to 15 are shown in Table 6. The phenol compounds used in Examples 11 to 15 are as follows.

[0115]

Chemical formula

[0116] [Example 16]

Chemical formula

[0117] Except for using ADS775PI (manufactured by American DyeSource) represented by the above structural formula as the cyanine compound of the raw material, in the same manner as in Example 12, a side chain containing a benzene ring was introduced by the mechanochemical method, and the target product ratio and the raw material ratio were determined in the same manner. The results of Example 16 are shown in Table 6.

[0118] [Example 17]

Chemical formula

[0119] Except for using NK-4680 (manufactured by Hayashibara Biochemical Laboratories, Inc.) represented by the above structural formula as the starting cyanine compound, the side chain containing a benzene ring was introduced by the mechanochemical method in the same manner as in Example 12, and the target product ratio and the raw material ratio were determined in the same way. The results of Example 17 are shown in Table 6.

[0120]

Table 6

[0121] From Table 6, it can be seen that side chains containing a benzene ring or a pyridine ring can be introduced using various phenolic compounds.

[0122] [Example 18]

Chemical formula

[0123] [Example 19] 0.20 g (0.39 mmol) of the same cyanine compound as used in Example 1, and R 13 =COOH, R 11 =R 12 =R 14 =R 150.27 g of 4-hydroxybenzoic acid represented by =H (molar ratio 5 to the cyanine compound), 0.35 g of triethylamine (molar ratio 9 to the cyanine compound), and 0.25 mL of DMF were placed in a 5 mL stainless steel grinding jar, and one 10 mm diameter stainless steel ball was placed therein and the container was sealed. This container was set in a mixer mill and subjected to a mechanochemical reaction by shaking at a shaking frequency of 30 Hz (30 times / s) for 90 minutes. After the reaction, the container was opened, and NMR measurement was performed in the same manner as in Example 1 to determine the target product ratio, which was 75%.

[0124] [Example 20] 0.15 g (0.29 mmol) of the same cyanine compound as used in Example 1, and R 13 =SO 3 H, R 11 =R 12 =R 14 =R 15 0.25 g of 4-hydroxybenzenesulfonic acid represented by =H (molar ratio 5 to the cyanine compound), 0.26 g of triethylamine (molar ratio 9 to the cyanine compound), and 0.4 mL of N-methyl-2-pyrrolidone were placed in a 5 mL stainless steel grinding jar, and one 10 mm diameter stainless steel ball was placed therein and the container was sealed. This container was set in a mixer mill and subjected to a mechanochemical reaction by shaking at a shaking frequency of 30 Hz (30 times / s) for 150 minutes. After the reaction, the container was opened, and NMR measurement was performed in the same manner as in Example 1 to determine the target product ratio, which was 40%.

[0125] [Example 21] 0.20 g (0.39 mmol) of the same cyanine compound as used in Example 1, and R 12 =R 13 =COOH, R 11 =R 14 =R 150.35 g of 4-hydroxyphthalic acid represented by =H (molar ratio 5 with respect to the cyanine compound), 0.35 g of triethylamine (molar ratio 9 with respect to the cyanine compound), and 0.5 mL of DMF were placed in a 5 mL stainless steel grinding jar, and one 10 mm diameter stainless steel ball was placed therein, and the container was sealed. This container was set in a mixer mill and subjected to a mechanochemical reaction by shaking at a shaking frequency of 30 Hz (30 times / s) for 90 minutes. After the reaction, the container was opened, and NMR measurement was performed in the same manner as in Example 1 to determine the target product ratio, which was 67%.

[0126] [Example 22] 0.20 g (0.39 mmol) of the same cyanine compound as used in Example 1, and R 12 =R 14 =COOH, R 11 =R 13 =R 15 0.35 g of 5-hydroxyisophthalic acid represented by =H (molar ratio 5 with respect to the cyanine compound), 0.35 g of triethylamine (molar ratio 9 with respect to the cyanine compound), and 0.5 mL of N-methyl-2-pyrrolidone were placed in a 5 mL stainless steel grinding jar, and one 10 mm diameter stainless steel ball was placed therein, and the container was sealed. This container was set in a mixer mill and subjected to a mechanochemical reaction by shaking at a shaking frequency of 30 Hz (30 times / s) for 150 minutes. After the reaction, the container was opened, and NMR measurement was performed in the same manner as in Example 1 to determine the target product ratio, which was 47%.

[0127] [Example 23]

Chemical formula

[0128] As the starting cyanine compound, 0.15 g (0.19 mmol) of S0804 (manufactured by FEW Chemicals) represented by the above structural formula, and R 13 =COOH, R 11 =R 12 =R14 =R 15 0.13 g of 4-hydroxybenzoic acid represented by =H (molar ratio 5 to the cyanine compound), 0.17 g of triethylamine (molar ratio 9 to the cyanine compound), and 0.3 mL of DMF were placed in a 5 mL stainless steel grinding jar, and one 10 mm diameter stainless steel ball was placed therein, and the container was sealed. This container was set in a mixer mill and shaken for 90 minutes under the condition of a shaking frequency of 30 Hz (30 times / s) to carry out a mechanochemical reaction. After the reaction, the container was opened, and NMR measurement was carried out in the same manner as in Example 1 to determine the target substance ratio, and it was 87%.

[0129] [Example 24] [Chemical formula]

[0130] As the starting cyanine compound, 0.15 g (0.23 mmol) of S0337 (manufactured by FEW Chemicals) represented by the above structural formula and R 13 =COOH, R 11 =R 12 =R 14 =R 15 0.16 g of 4-hydroxybenzoic acid represented by =H (molar ratio 5 to the cyanine compound), 0.21 g of triethylamine (molar ratio 9 to the cyanine compound), and 0.3 mL of DMF were placed in a 5 mL stainless steel grinding jar, and one 10 mm diameter stainless steel ball was placed therein, and the container was sealed. This container was set in a mixer mill and shaken for 90 minutes under the condition of a shaking frequency of 30 Hz (30 times / s) to carry out a mechanochemical reaction. After the reaction, the container was opened, and NMR measurement was carried out in the same manner as in Example 1 to determine the target substance ratio, and it was 93%.

[0131] [Example 25] [Chemical formula]

[0132] 0.20 g (0.39 mmol) of the same cyanine compound as that used in Example 1, 0.18 g of 4-hydroxypyridine (molar ratio 5 to the cyanine compound), and 0.16 g of triethylamine (molar ratio 4 to the cyanine compound) were placed in a 5 mL stainless steel grinding jar, and one 10 mm diameter stainless steel ball was placed therein, and the container was sealed. This container was set in a mixer mill and subjected to a mechanochemical reaction by shaking at a shaking frequency of 30 Hz (30 times / s) for 150 minutes. After the reaction, the container was opened, and NMR measurement was performed in the same manner as in Example 1 to determine the ratio of the target product, and it was 100%.

[0133] From these results, by the mechanochemical method, since impurities were few at the position of Ar and a bulky group could be introduced, compared with the case where no substituent was present, it was less likely to aggregate. As a result, phenomena such as an increase in solubility, a decrease in quenching due to non-radiative deactivation also called concentration quenching, and quenching due to electron transfer from an anion were suppressed. In addition, particularly, rotation at the portion connecting the rings containing nitrogen atoms on both sides was suppressed, so quenching due to vibrational relaxation could also be suppressed, and it was found that an industrially useful indocyanine-based compound could be obtained in a high yield.

Claims

1. A method for producing an indocyanine compound, comprising the step of introducing a side chain containing a benzene ring or a pyridine ring into an indocyanine compound represented by the following formula (1) by a mechanochemical method: 【Chemistry 1】 (In formula (1), n ​​represents an integer of 1 or more. The polymethine chain in formula (1) has a side chain containing a benzene ring or a pyridine ring as a substituent, and the polymethine chain may have any substituent other than the side chain containing the benzene ring or the pyridine ring. The optional substituents may be bonded to each other to form a ring containing the methine chain. R １ , R ２ each independently represents an arbitrary substituent. M － represents a counter anion. -N in formula (1) ＋ R １ -containing ring and -NR ２ Each of the rings containing - may have any substituent other than a dimethyl group, and these substituents may be bonded to each other to form a fused ring fused to each ring, and the fused ring may have any substituent, and the substituents may be bonded to each other to form further fused rings.

2. 2. The method for producing an indocyanine compound according to claim 1, wherein the step of introducing a side chain containing a benzene ring or a pyridine ring is carried out without heating.

3. The method for producing an indocyanine compound according to claim 1 or 2, wherein the indocyanine compound is represented by the following formula (2): 【Chemistry 2】 (In formula (2), R １ , R ２ , M. － are the same as defined in formula (1). X represents a direct bond or a carbon atom, and the carbon atom may have an optional substituent. Ar represents a substituent containing a benzene ring or a pyridine ring. -N in formula (2) ＋ R １ A benzene ring fused to a ring containing - and -NR ２ The benzene rings fused to the ring containing - may each have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.)

4. The method for producing an indocyanine compound according to claim 3, wherein the indocyanine compound is represented by the following formula (2A): 【Chemistry 3】 (In formula (2A), R １ , R ２ , M. － are the same as defined in formula (1). R ３ represents a hydrogen atom or an arbitrary substituent. Ar ａ represents a substituent containing a benzene ring. -N in formula (2A) ＋ R １ A benzene ring fused to a ring containing - and -NR ２ The benzene rings fused to the ring containing - may each have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.

5. The method for producing an indocyanine compound according to claim 3, wherein Ar in the formula (2) is a pyridinyloxy group which may have a substituent.

6. Ar in the formula (2A) ａ The method for producing an indocyanine compound according to claim 4, wherein is a phenoxy group which may have a substituent.

7. An indocyanine compound represented by the following formula (3): 【Chemistry 4】 (In formula (3), R １ , R ２ represents an optional substituent. R ３ , R ４ each independently represents a hydrogen atom or an arbitrary substituent. M － represents a counter anion. -N in formula (3) ＋ R １ A benzene ring fused to a ring containing - and -NR ２ The benzene rings fused to the ring containing - may each have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.)

8. An indocyanine compound represented by the following formula (4): 【Chemistry 5】 (In formula (4), R １ , R ２ represents an optional substituent. R ３ , R ４ each independently represents a hydrogen atom or an arbitrary substituent. M － represents a counter anion. -N in formula (4) ＋ R １ A benzene ring fused to a ring containing - and -NR ２ The benzene rings fused to the ring containing - may each have any substituent, and these substituents may be bonded to each other to form a fused ring fused to each benzene ring.

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