Labeling method, oxidant for labeling, ruthenium complex, catalyst, labeling compound, and compound

Abstract

The present invention provides a labeling method that comprises a step for labeling a substrate, which has a carbon-hydrogen bond, with an oxygen isotope with use of a catalyst and an oxidant that is produced from a hypervalent iodine compound having an ester structure and labeled water which is labeled with at least one oxygen isotope that is selected from the group consisting of 17O and 18O. The present invention also provides an oxidant for labeling, said oxidant being produced from a hypervalent iodine compound having an ester structure and labeled water which is labeled with at least one oxygen isotope that is selected from the group consisting of 17O and 18O. This oxidant for labeling labels a substrate, which has a carbon-hydrogen bond, with an oxygen isotope in the coexistence of a catalyst.

Description

Labeling method, oxidizing agent for labeling, ruthenium complex, catalyst, labeled compound, and compound

[0001] The present disclosure relates to methods for labeling with oxygen isotopes, oxidizing agents for labeling with oxygen isotopes, ruthenium complexes, catalysts, oxygen isotope-labeled compounds, and novel compounds.

[0002] It has been attempted to obtain knowledge about metabolic pathways and distribution of substances in the body by administering labeled compounds in which some of the elements constituting a chemical substance are labeled with isotopes. Many biologically active compounds contain oxygen functional groups such as hydroxyl groups or carbonyl groups. With the recent advances in measurement equipment and methods, stable isotopes of oxygen atoms, １７ O and １８ It is expected that O will be utilized for in vivo imaging. １７ O and １８ Known methods for introducing O include using a hydration reaction with an alkene or carbonyl group, or converting coordinated water in a metal complex into a metal-oxo species using electrolysis or an oxidizing agent. Patent Document 1 also proposes using an oxygen-isotope-labeled carboxylate compound as a supply source of oxygen isotopes.

[0003] Japanese Patent Application Laid-Open No. 2020-37545

[0004] However, conventional methods using oxygen-isotope-labeled water require the use of a large excess of oxygen-isotope-labeled water. From the perspective of preserving scarce oxygen-isotope-labeled water resources, it is desirable to improve such conventional methods. Furthermore, the method of Patent Document 1 requires the synthesis of an oxygen-isotope-labeled carboxylate compound to label the substrate. Therefore, there is a demand for a technology that enables easy labeling with oxygen isotopes without consuming large amounts of oxygen-isotope-labeled water.

[0005] Therefore, the present disclosure provides a labeling method using oxygen isotopes that can produce labeled compounds in high yield without using excess oxygen-isotope-labeled water. It also provides a labeling oxidizing agent, a ruthenium complex, and a catalyst that can be suitably used in such a labeling method. It also provides labeled compounds labeled with oxygen isotopes. It also provides novel compounds that are useful as reagents.

[0006] In one aspect, the present disclosure provides a method for producing a methacrylic acid ester comprising: １７ O and １８ The present invention provides a labeling method comprising the step of labeling a substrate having a carbon-hydrogen bond with an oxygen isotope using labeled water labeled with at least one oxygen isotope selected from the group consisting of O, an oxidizing agent generated from the labeled water, and a catalyst.

[0007] In the above step of the labeling method, the carbon-hydrogen bond of the substrate is oxidized with high regioselectivity using an oxidizing agent and a catalyst. The oxidizing agent is generated from a hypervalent iodine compound having an ester structure and labeled water, so the substrate can be labeled with oxygen isotopes. Therefore, labeled compounds can be obtained in high yields without using large amounts of oxygen isotope-labeled water.

[0008] The catalyst may contain a ruthenium complex. The catalyst may contain at least one ruthenium complex selected from the group consisting of the following general formulas (1), (2), and (3):

[0009]

[0010] In the above general formulas (1), (2) and (3), R １ represents a hydrogen atom, a phenyl group, or a monovalent group in which at least one hydrogen atom of a phenyl group is substituted with an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy group; R ２ represents a hydrogen atom, a phenyl group, or an alkyl group; L １ represents a halogen atom or a water molecule, and L ２ represents triphenylphosphine, pyridine, imidazole, or dimethyl sulfoxide, X represents a halogen atom, and n represents 1 or 2. In the above general formula (2), R ９and R １０ each independently represents a hydrogen atom, a halogen atom or an alkyl group.

[0011] The catalyst containing the ruthenium complex has excellent activity and regioselectivity in the oxidation reaction of carbon-hydrogen bonds, and therefore can produce the desired oxygen isotope-labeled compounds in high yield from various substrates having carbon-hydrogen bonds.

[0012] The hypervalent iodine compound used in the labeling method may include a compound represented by the following general formula (4):

[0013]

[0014] In the above general formula (4), R ３ and R ４ each independently represents a hydrogen atom, an alkyl group, or a monovalent group having an aromatic ring, and R ５ represents a monovalent group having an aromatic ring.

[0015] In the above step, the compound represented by the general formula (4) activates labeled water and promotes the reaction between the substrate and labeled water, thereby enabling the production of the desired oxygen isotope-labeled compound in high yield.

[0016] In the above step, the substrate may be oxidized to obtain a hydroxy compound or oxo compound labeled with an oxygen isotope. Such a hydroxy compound or oxo compound can be used for various purposes.

[0017] In the above step, the oxygen atom of the hexose contained in the substrate may be substituted with an oxygen isotope to label the hexose. The oxygen-isotope-labeled hexose thus obtained can be used, for example, as an oxygen-isotope-labeled molecular probe for in vivo imaging, such as the observation of cellular tissues.

[0018] In one aspect, the present disclosure provides a method for producing a methacrylic acid ester comprising: １７ O and １８The present invention provides an oxidizing agent for labeling, which is generated from labeled water labeled with at least one oxygen isotope selected from the group consisting of O and O, and which labels a substrate having a carbon-hydrogen bond with an oxygen isotope in the presence of a catalyst. This labeling oxidizing agent oxidizes the carbon-hydrogen bond of the substrate with high regioselectivity in the presence of a catalyst, thereby labeling the substrate with an oxygen isotope. Therefore, a labeled compound can be obtained in high yield without using a large amount of oxygen-isotope-labeled water.

[0019] The hypervalent iodine compound used in the labeling method may include a compound represented by the following general formula (4): １７ O or １８ It may be O.

[0020]

[0021] In the above general formula (4), R ３ and R ４ each independently represents a hydrogen atom, an alkyl group, or a monovalent group having an aromatic ring, and R ５ represents a monovalent group having an aromatic ring.

[0022] By using a hypervalent iodine compound containing the compound represented by the above general formula (4), a substrate and an oxidizing agent can be reacted stably, and the desired oxygen isotope-labeled compound can be obtained in high yield.

[0023] In one aspect, the present disclosure provides a ruthenium complex represented by the following general formula (2) or (3):

[0024] In the above general formulas (2) and (3), R １ represents a hydrogen atom, a phenyl group, or a monovalent group in which at least one hydrogen atom of a phenyl group is substituted with an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy group; R ２ represents a hydrogen atom, a phenyl group, or an alkyl group; L １ represents a halogen atom or a water molecule, and L ２represents triphenylphosphine, pyridine, imidazole, or dimethyl sulfoxide, X represents a halogen atom, and n represents 1 or 2. In the above general formula (2), R ９ and R １０ each independently represents a hydrogen atom, a halogen atom or an alkyl group.

[0025] The ruthenium complex has high catalytic activity in the oxidation of carbon-hydrogen bonds. Such a ruthenium complex can be used as a catalyst for various applications. For example, it can oxidize a substrate having a carbon-hydrogen bond with high regioselectivity. Therefore, in the presence of an oxidizing agent generated from a hypervalent iodine compound having an ester structure and labeled water labeled with an oxygen isotope, the ruthenium complex acts as an oxidation catalyst to oxidize the carbon-hydrogen bond of the substrate with high regioselectivity. １７ O or １８ The ruthenium complex can label a substrate with O. That is, it is useful as a catalyst for oxygen isotope labeling. However, the uses of the ruthenium complex are not limited to the above. For example, it may be used as an oxidation catalyst for oxidizing a substrate without labeling.

[0026] In one aspect, the present disclosure provides a catalyst comprising at least one selected from the group consisting of a ruthenium complex represented by the general formula (2) above and a ruthenium complex represented by the general formula (3) above. Such a catalyst has high activity in a reaction for oxidizing a carbon-hydrogen bond. The catalyst may be an oxidation catalyst that oxidizes a substrate having a carbon-hydrogen bond, or may be an oxidation catalyst that hydroxylates a substrate.

[0027] In one aspect, the present disclosure provides a compound represented by the following formula (5), (6), or (7): １７ O and １８ The present invention provides a labeled compound labeled with at least one oxygen isotope selected from the group consisting of O. Such a labeled compound can be used for various purposes. For example, it can be used as a molecular probe for in vivo imaging.

[0028]

[0029] In the above formulas (5), (6) and (7), A is １７ O or１８ The labeled compound is １７ O or １８ The compound is labeled with O. Such a labeled compound can be used for various purposes. For example, it can be used as a molecular probe for in vivo imaging.

[0030] In one aspect, the present disclosure provides a compound (novel compound) represented by the following formula (8): In formula (8), Me represents a methyl group.

[0031] The above compound can be easily labeled with an oxygen isotope. For example, it is useful as an intermediate for obtaining mannose labeled with an oxygen isotope. For example, this novel compound can be used as an intermediate for producing mannose labeled with an oxygen isotope from mannose.

[0032] According to the present disclosure, it is possible to provide a labeling method using an oxygen isotope that can produce a labeled compound in high yield without using excess oxygen-isotope-labeled water. It is also possible to provide a labeling oxidizing agent, a ruthenium complex, and a catalyst that can be suitably used in such a labeling method. It is also possible to provide a labeled compound labeled with an oxygen isotope. It is also possible to provide a novel compound that is useful as a reagent.

[0033] Fig. 1 shows an example of the mechanism of alcohol production when a ruthenium complex is used as a catalyst. Fig. 2 shows the mechanism of alcohol production when a ruthenium complex of formula [III] (trans type), a ruthenium complex of formula [IV] (cis type), and a mixture thereof are used. １FIG. 3 shows the results of H-NMR measurement. FIG. 3 shows the results of single crystal structure analysis of the ruthenium complex of formula [III]. FIG. 4 shows the results of single crystal structure analysis of the ruthenium complex of formula [III] viewed from an angle different from that of FIG. 3. FIG. 5 shows the results of single crystal structure analysis of the ruthenium complex of formula [IV]. FIG. 6 shows the results of single crystal structure analysis of the ruthenium complex of formula [IV] viewed from an angle different from that of FIG. 5. FIG. 7 shows the results of single crystal structure analysis of the ruthenium complex of formula (V). FIG. 8 shows the results of single crystal structure analysis of the ruthenium complex of formula (V) viewed from an angle different from that of FIG. 7. FIG. 9 shows the results of time-of-flight mass spectrometry of oxygen isotope-labeled adamantan-1-ol in Example 2-1. FIG. 10 shows the results of time-of-flight mass spectrometry of oxygen isotope-labeled 7-hydroxy-3,7-dimethyloctyl acetate in Example 2-2. FIG. 11 shows the results of time-of-flight mass spectrometry of oxygen isotope-labeled 7-hydroxy-3,7-dimethyloctyl acetate in Example 2-3. FIG. 12 shows the results of time-of-flight mass spectrometry of oxygen isotope-labeled 4-hydroxy-4-methylpentyl benzoate in Example 2-4. FIG. 13 shows the results of time-of-flight mass spectrometry of oxygen-18 isotope-labeled (1R,2R,4R,5R)-4-hydroxy-2-methoxy-6,8-dioxabicyclo[3.2.1]octan-3-one in Example 3-1. FIG. 14 shows the results of time-of-flight mass spectrometry of oxygen-18 isotope-labeled (1R,2R,4R,5R)-4-hydroxy-2-methoxy-6,8-dioxabicyclo[3.2.1]octan-3-one in Example 3-1. １ 1H-NMR analysis results. FIG. 15 shows the results of two-dimensional NMR analysis of (1R,2R,4R,5R)-4-hydroxy-2-methoxy-6,8-dioxabicyclo[3.2.1]octan-3-one labeled with oxygen-18 isotopes in Example 3-1. FIG. 16 shows the results of two-dimensional NMR analysis of (1R,2R,4R,5R)-4-hydroxy-2-methoxy-6,8-dioxabicyclo[3.2.1]octan-3-one labeled with oxygen-18 isotopes in Example 3-1. １３17 shows the results of C-NMR analysis by BCM. １３ Figure 18 shows the results of time-of-flight mass spectrometry of 1,6-anhydro-4-O-methyl-β-D-mannopyranose labeled with oxygen-18 isotopes in Example 3-2. Figure 19 shows the results of time-of-flight mass spectrometry of 1,6-anhydro-4-O-methyl-β-D-mannopyranose labeled with oxygen-18 isotopes in Example 3-2. １ 20 shows the substituents of the ruthenium complexes used in Examples 4-2 to 4-8 and the amine compounds used to obtain the ruthenium complexes. １ 22 shows the results of H-NMR analysis of Ligand 2 obtained in Example 5-1. １３ Figure 23 shows the results of time-of-flight mass spectrometry of the ligand 2 obtained in Example 5-1. Figure 24 shows the results of time-of-flight mass spectrometry of the ruthenium complex obtained in Example 5-1. １ 25 shows the results of time-of-flight mass spectrometry of the ruthenium complex obtained in Example 5-1. FIG. 26 shows the results of time-of-flight mass spectrometry of the ligand 3 obtained in Example 5-2. １ 27 shows the results of H-NMR analysis of Ligand 3 obtained in Example 5-2. １３ Figure 28 shows the results of time-of-flight mass spectrometry of the ligand 3 obtained in Example 5-2. Figure 29 shows the results of time-of-flight mass spectrometry of the ruthenium complex obtained in Example 5-2. １ 30 shows the results of time-of-flight mass spectrometry of the ruthenium complex obtained in Example 5-2. FIG. 31 shows the relationship between the substrate concentration [S] calculated from the conversion efficiency at each reaction time and the initial concentration of the substrate [S ０ ] is a graph showing the change over time in the natural logarithm of the relative ratio to

[0034] Hereinafter, embodiments of the present disclosure will be described. However, the following embodiments are merely examples for explaining the present disclosure, and are not intended to limit the present disclosure to the following contents.

[0035] The labeling method according to one embodiment includes: a hypervalent iodine compound having an ester structure; １７ O and １８ The method includes a step of labeling a substrate having a carbon-hydrogen bond with an oxygen isotope using an oxidizing agent and a catalyst produced from labeled water labeled with at least one oxygen isotope selected from the group consisting of O. According to this labeling method, the substrate having a carbon-hydrogen bond is oxidized with an oxygen-17 isotope ( １７ O) and oxygen-18 isotope ( １８ O) can be labeled with at least one isotope selected from the group consisting of oxygen-17 isotope ( １７ O) and oxygen-18 isotope ( １８ In other words, this labeling method is a labeling method using oxygen isotopes.

[0036] The oxygen isotope labeling in this disclosure is an oxygen-17 isotope ( １７ O) and / or oxygen-18 isotope ( １８ In the present disclosure, the labeling rate (enrichment rate) is the rate at which a specific oxygen atom constituting a compound is １７ O and / or １８ The labeling rate of the labeled compound obtained by the labeling method may be 100% or less. １７ O and / or １８ The ratio of O is the natural abundance ratio of oxygen isotopes ( １６ O: １７ O: １８ The labeling rate in the present disclosure is determined by comparing the spectrum of a compound in which the isotope ratio of oxygen atoms measured using a time-of-flight mass spectrometer is at natural abundance with the spectrum of a compound in which all of the oxygen atoms are at natural abundance. １８ O and / or １７ The calculated spectrum of the compound is calculated by comparing it with the calculated spectrum of the compound when the compound is O.

[0037] The catalyst can be an oxidation catalyst. Examples of such catalysts include metal complexes and enzymes. Examples of metal complexes include porphyrin metal complexes and salen metal complexes. The enzyme may be an oxidase, specifically, a non-heme iron enzyme such as cytochrome P450 and lipoxygenase. Among these, the catalyst preferably contains a metal complex, more preferably a ruthenium complex, and even more preferably at least one ruthenium complex selected from the group consisting of the following general formulas (1), (2), and (3). A catalyst containing such a ruthenium complex exhibits excellent activity in the oxidation reaction of carbon-hydrogen bonds and also excellent regioselectivity. Therefore, it is possible to obtain the desired oxygen isotope-labeled compound in high yield from various substrates having carbon-hydrogen bonds.

[0038]

[0039] In the above general formulas (1), (2) and (3), R １ represents a hydrogen atom, a phenyl group, or a monovalent group in which at least one hydrogen atom of a phenyl group has been substituted with an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy group. Among these, from the viewpoint of sufficiently increasing the activity and selectivity as a catalyst, R １ is preferably a phenyl group or a monovalent group in which at least one hydrogen atom of a phenyl group (a hydrogen atom in a benzene ring) is substituted with an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy group. A monovalent group in which at least one hydrogen atom of a phenyl group is substituted with an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy group can also be called a substituted phenyl group.

[0040] R １When is a substituted phenyl group, the substituents substituting multiple hydrogen atoms in the phenyl group may be different from each other or the same. The alkyl group substituting at least one hydrogen atom in the phenyl group may be a methyl group, an ethyl group, or a propyl group. The halogen atom substituting at least one hydrogen atom in the phenyl group may be a chlorine atom. The alkoxy group substituting at least one hydrogen atom in the phenyl group may be a methoxy group, an ethoxy group, or a propoxy group.

[0041] In the above general formulas (1), (2) and (3), R ２ represents a hydrogen atom, a phenyl group, or an alkyl group. ２ When R is an alkyl group, the alkyl group may be a methyl group, an ethyl group, or a propyl group. ２ is preferably a hydrogen atom.

[0042] In the above general formula (3), R ９ and R １０ may each independently be a hydrogen atom, a halogen atom, or an alkyl group. The alkyl group may have 1 to 4 carbon atoms, or may have 1 to 3 carbon atoms. Among these, from the viewpoint of sufficiently increasing the activity and selectivity of the catalyst, R ９ and R １０ may each independently be a halogen atom or an alkyl group, and R ９ and R １０ may be a halogen atom. The halogen atom may be a chlorine atom or a bromine atom. ９ and R １０ When is a halogen atom, it may be the same halogen atom as X or may be a halogen atom different from X.

[0043] In the above general formulas (1), (2) and (3), L １ represents a halogen atom or a water molecule. Among these, from the viewpoint of sufficiently increasing the activity and selectivity as a catalyst, L １ In the above general formulas (1), (2) and (3), L is preferably a halogen atom. ２represents triphenylphosphine, pyridine, imidazole, or dimethyl sulfoxide. Among these, from the viewpoint of sufficiently increasing the activity and selectivity as a catalyst, L ２ is preferably triphenylphosphine. In the above general formulas (1), (2), and (3), X represents a halogen atom. This halogen atom constitutes a ruthenium complex as an ion. X is, for example, a chlorine atom. In the above general formulas (1), (2), and (3), n represents 1 or 2. The oxidation number of Ru in the above general formulas (1), (2), and (3) is +2.

[0044] The above ruthenium complexes are useful, for example, as catalysts for oxidizing carbon-hydrogen bonds. That is, these ruthenium complexes function as catalysts for oxidizing, for example, substrates having carbon-hydrogen bonds. For example, oxygen-containing compounds can be produced by oxidizing substrates having such bonds. Examples of oxygen-containing compounds include hydroxy compounds and oxo compounds. In hydroxy compounds, the oxygen atom in the hydroxy group is １７ O or １８ In oxo compounds, the oxygen atom of the oxo group is １７ O or １８ The oxygen-containing compound may be a carbonyl compound having a carbonyl group, or a ketone compound having a ketone group. In these cases, the oxygen atom in the carbonyl group or the ketone group may be １７ O or １８ It may be labeled with O.

[0045] The oxidizing agent comprises a hypervalent iodine compound having an ester structure as an oxidizing agent raw material, １７ O or １８ O and labeled water labeled with at least one oxygen isotope selected from the group consisting of O. Such an oxidizing agent can also be called an oxygen isotope labeling oxidizing agent. By using such a labeling oxidizing agent, an oxygen-containing compound obtained by oxidizing a substrate having a carbon-hydrogen bond can be produced by: １７ O and １８The oxidizing agent is labeled with at least one oxygen isotope selected from the group consisting of O. A method for producing the labeling oxidizing agent may include a step of reacting the hypervalent iodine compound with the labeled water.

[0046] The labeling with oxygen isotopes proceeds in the presence of the catalyst and an oxidizing agent generated from a hypervalent iodine compound having an ester structure and labeled water. The hypervalent iodine compound having an ester structure can activate labeled water in the reaction system. Therefore, in the presence of the catalyst, １７ O or １８ The hypervalent iodine compound having an ester structure has a function of promoting the oxidation of a substrate by O. From the viewpoint of further promoting this function, the hypervalent iodine compound having an ester structure may have one or more aromatic rings. Such hypervalent iodine compounds have strong electron-donating properties and can promote the oxidation of a substrate having electron-withdrawing properties. The hypervalent iodine compound having an ester structure, which is an oxidizing agent raw material, may include a compound represented by the following general formula (4):

[0047]

[0048] In the above general formula (4), R ３ and R ４ R each independently represents a hydrogen atom, an alkyl group, or a monovalent group having an aromatic ring. ５ represents a monovalent group having an aromatic ring. ３ and R ４ When R is an alkyl group, at least one hydrogen atom of the alkyl group may be substituted with a functional group. ３ , R ４ and R ５ may each have a benzene ring. ３ , R ４ and R ５ may each independently be an unsubstituted phenyl group or a substituted phenyl group in which at least one hydrogen atom is substituted. Examples of the substituted phenyl group include a phenyl group (benzene ring) in which at least one hydrogen atom is substituted with a heteroatom, a halogen atom, a hydroxy group, a nitro group, or an organic group other than these. ３ , R４ and R ５ In order to sufficiently increase the labeling rate with oxygen isotopes, for example, the hypervalent iodine compound may include a compound represented by the following general formula (5):

[0049]

[0050] In the above general formula (5), R ６、 R ７ and R ８ represents a heteroatom, and k1, k2, and k3 represent integers of 0 to 5. ６、 R ７ and R ８ The bond end indicated by * is bonded to a carbon atom constituting the benzene ring, replacing a hydrogen atom in the benzene ring. ６ If there are multiple R ６ may be the same as or different from each other. ７ If there are multiple R ７ may be the same as or different from each other. ８ If there are multiple R ８ may be the same as or different from each other. ６、 R ７ and R ８ may be the same as or different from each other. k1, k2, and k3 may be the same as or different from each other. From the viewpoint of sufficiently increasing the labeling rate with oxygen isotopes, R ６ and R ７ may be a halogeno group. ６ and R ７ The halogeno groups in may each independently be a fluoro group (-F) or a chloro group (-Cl). In this case, k1 and k2 may each independently be 1 to 5, 2 to 5, or 3 to 5. Furthermore, k3 may be 0.

[0051] In the above process, an oxidizing agent generated in situ from a hypervalent iodine compound having an ester structure and labeled water in the presence of a catalyst containing, for example, a ruthenium complex, oxidizes a carbon-hydrogen bond in the substrate to obtain an oxygen-containing compound having a hydroxyl group or an oxo group bonded to a carbon atom. The oxygen-containing compound may include at least one of an alcohol, a ketone, and an aldehyde. The reaction mechanism involves the oxidation of a carbon atom in the substrate by the generated oxidizing agent, resulting in: １７ O or １８ It is assumed that the compound is labeled with O. １７ O or １８ A labeled compound labeled with O (labeled oxygen-containing compound) can be obtained. Commercially available oxygen-17 labeled water or oxygen-18 labeled water can be used as labeled water. If necessary, a mixture of oxygen-17 labeled water and oxygen-18 labeled water can be used to １７ O and １８ The amount of labeled water used may be 1 to 10 equivalents, or 1 to 4 equivalents, relative to the substrate. Even if the amount of labeled water used is reduced in this way, the labeling rate can be sufficiently high. １７ O and １８ The labeling rate with at least one element selected from the group consisting of O may be 60 atom % or more, 80 atom % or more, or 90 atom % or more.

[0052] Fig. 1 shows an example of a mechanism for producing an alcohol, a type of hydroxy compound, from a substrate containing a tertiary carbon atom using the above-mentioned ruthenium complex as an oxidation catalyst. However, the mechanism for producing the alcohol is not limited to this example.

[0053] In step I of FIG. 1, an oxidizing agent generated from a hypervalent iodine compound having an ester structure and labeled water is reacted with a ruthenium complex (LM ｎ(where L is a ligand, M is ruthenium, and n is 1 or 2.) come into contact with each other to form a ruthenium-oxo bond. Tetrachloroethane can be used as the solvent. From the viewpoint of improving catalytic activity and selectivity (regioselectivity) of the oxidation position in the substrate, an acid may be used together with the oxidizing agent. Examples of the acid include acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, and pentafluorobenzoic acid.

[0054] In step II, the ruthenium-oxo bond comes into contact with a substrate containing a tertiary carbon atom, resulting in the elimination of a hydrogen atom from the substrate, forming a substrate radical and a ruthenium-hydroxy bond ( １８ O) is produced. １ , R ２ and R ３ may be different from each other or may be the same. １ , R ２ and R ３ At least two selected from the group consisting of may be bonded to form a ring.

[0055] The substrate may be a hydrocarbon, oxygenated hydrocarbon, or sugar having 5 to 30 carbon atoms, in which at least one hydrogen atom may be substituted with a functional group. The hydrocarbon may be a chain (straight or branched) hydrocarbon, an alicyclic hydrocarbon, or an aromatic hydrocarbon. Examples of the functional group include a hydroxyl group, a halogen atom, an alkoxy group, an aldehyde group, an acyl group, a carboxyl group, an allyl group, an amino group, a nitro group, an acetyl group, an oxo group, and an ester group. The substrate may also be a prohormone.

[0056] In step III, the hydroxy group ( １８ The ruthenium complex is then used again as a catalyst. １８ Although O is shown, it is calculated using oxygen-17 labeled water. １７ It may be labeled with O. Using a mixture of oxygen-17 labeled water and oxygen-18 labeled water, １７ O and １８Alternatively, the compound may be labeled with both O and O. In this example, a hydroxy compound is obtained, but other compounds (for example, oxo compounds) may be obtained by changing the substrate or adjusting the reaction conditions.

[0057] The reaction mechanism in the oxygen isotope labeling step of this embodiment is not limited to that shown in FIG. 1 . For example, when the substrate contains a sugar, the sugar may be any of monosaccharides, disaccharides, and polysaccharides. Monosaccharides include trioses, tetraoses, pentoses, and hexoses (hexoses). Hexoses may be aldohexoses or ketohexoses. Examples include allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, and tagatose. Each sugar may be any stereoisomer or optical isomer. The labeling method of this embodiment can label a substrate containing any of these.

[0058] For example, D-mannose can be synthesized by the following scheme, as shown in the examples: １８ In the following scheme, the hydroxy group at the 3-position can be labeled with O. １８ In this example, D-mannose is labeled with 0. １７ O, or １７ O and １８ O may be labeled.

[0059]

[0060] Mannose derivatives derived from D-mannose include compounds (A), (B), and (C) in the above scheme. Compound (A) (1,6-anhydro-4-O-methyl-2,3-O-isopropylidene-β-D-mannopyranose), compound (B) (1R,2R,4R,5R)-4-hydroxy-2-methoxy-6,8-dioxabicyclo[3.2.1]octan-3-one), and compound (C) (1,6-anhydro-4-O-methyl-β-D-mannopyranose) all contain oxygen isotopes (O １７ O or １８The compound (C) is a useful compound for obtaining D-mannose labeled with oxygen isotopes. Compound (C) is more stable than compound (B). Therefore, by synthesizing mannose derivative (C) from mannose derivative (A) in one pot, the labeling rate of D-mannose with oxygen isotopes can be increased.

[0061] Of the above-mentioned mannose derivatives (A), (B), and (C), compound (B) does not need to be labeled with an oxygen isotope. The compound not labeled with an oxygen isotope [(1R,2R,4R,5R)-4-hydroxy-2-methoxy-6,8-dioxabicyclo[3.2.1]octan-3-one)] is represented by the following formula (8) (Me represents a methyl group). This compound can be used, for example, as a reagent. D-mannose may also be synthesized using this compound. The compound of formula (8) can be synthesized from derivative (A) using ordinary water instead of labeled water.

[0062]

[0063] According to the labeling method (labeling method) of this embodiment, the desired oxygen isotope-labeled compound can be obtained in high yield while reducing the amount of labeled water used. Therefore, scarce labeled water can be effectively utilized. The labeled compound thus obtained can be used as a labeled molecular probe. For example, the labeled compound is １７ The present invention can be used for measurements using O nuclear magnetic resonance spectroscopy (NMR) and imaging (MRI). Such measurements can visualize objects such as cells. Furthermore, if sugars labeled with oxygen isotopes are used, cell tissues can be observed using an isotope microscope or the like. Thus, the labeling method (oxygen isotope labeling method) and labeled compound (oxygen isotope-labeled compound) of this embodiment can significantly expand the scope of application of labeling techniques.

[0064] Next, an example of a method for producing the above-mentioned ruthenium complex will be described below. This production method includes a first step of synthesizing a ligand by reacting an amino acid ester compound represented by general formula (iii), a methylpyridine compound represented by general formula (iv), and an amine compound represented by general formula (v).

[0065]

[0066] In general formula (iii), R ２ represents R in the general formulas (1), (2) and (3) of the ruthenium complexes described above. ２ In general formula (iii), R ３ represents an alkyl group having 1 to 3 carbon atoms. ３ is, for example, a methyl group. In general formula (iv), Z is a halogen atom. An example of a methylpyridine compound is chloromethylpyridine. In general formula (v), R １ represents R in the general formulas (1), (2) and (3) of the ruthenium complexes described above. １ is the same as

[0067] In the first step, an amino acid ester (general formula (iii)) is N-alkylated with a methylpyridine compound (general formula (iv)), followed by hydrolysis of the amino acid ester and amidation with an amine (general formula (v)) to obtain a ligand represented by the following general formula (vi):

[0068]

[0069] After the first step, a second step is carried out in which the ligand is reacted with a ruthenium compound to obtain a ruthenium complex containing at least one selected from the group consisting of a trans-type ruthenium complex represented by general formula (1) and a cis-type ruthenium complex represented by general formula (2).

[0070] Examples of ruthenium compounds include ruthenium(II) chloride and complexes having dimethyl sulfoxide or triphenylphosphine as a ligand. Examples of such complexes include dichlorotetrakis(dimethyl sulfoxide)ruthenium(II) and tris(triphenylphosphine)ruthenium(II) dichloride. The second step may be carried out under reflux using an alcohol such as ethanol as a solvent. Ruthenium complexes represented by general formulas (1) and (2) are obtained by these steps.

[0071] After the second step, a step of separating the trans-ruthenium complex represented by general formula (1) and the cis-ruthenium complex represented by general formula (2) may be carried out. This step may be carried out, for example, by column chromatography. This allows the trans-ruthenium complex represented by general formula (1) and the cis-ruthenium complex represented by general formula (2) to be obtained. The ruthenium complex represented by general formula (3) may be synthesized by the same method as for the ruthenium complexes of general formulas (1) and (2), or may be synthesized by the method described in the Examples. The method described in the Examples may be modified as appropriate based on the above explanation.

[0072] Although the embodiments of the present disclosure have been described above, the present disclosure is not limited to the above-described embodiments.

[0073] The present disclosure will be described in more detail with reference to examples, but the present disclosure is not limited to the following examples.

[0074] Example 1-1 Synthesis of Ligand 1 The reaction of reaction formula (1a) was carried out by the following procedure to N-alkylate an amino acid ester, where Me represents a methyl group.

[0075]

[0076] A recovery flask was charged with 2.76 g (20 mmol) of potassium carbonate, 332 mg (2 mmol) of potassium iodide, and 10 mL of acetonitrile. To this was added 251 mg (2 mmol) of glycine methyl ester hydrochloride and 820 mg (5 mmol) of 2-(chloromethyl)pyridine hydrochloride. The mixture was maintained under reflux at 95°C for 24 hours to obtain a reaction solution. After cooling to room temperature, the light components were distilled off using a rotary evaporator to obtain a product. 50 g of ethyl acetate was added to this product, and the product was filtered to remove solids (salts). The filtrate was washed with an aqueous solution of sodium carbonate and sodium chloride, and sodium sulfate was added to the washings to remove moisture, after which the light components were distilled off using a rotary evaporator. The obtained liquid product was separated and purified by column chromatography using basic silica gel (dichloromethane / methanol = 100:1), and the light components were again distilled off using a rotary evaporator to obtain a product. This product was １ As a result of H-NMR analysis, it was found that the product of formula (I) shown in reaction formula (1a) (bis(pyridin-2-ylmethyl)glycine methyl ester, 0.4634 g, 1.71 mmol, yield 85%) was obtained.

[0077] Next, the above product was hydrolyzed as shown in reaction formula (1b). The detailed procedure is as follows:

[0078]

[0079] A solution was obtained by adding 8.3 mL of a mixed solvent of acetonitrile and water in a 1:1 mass ratio and 282.14 mg (1.04 mmol) of the product of reaction formula (1a) to a recovery flask. 52.36 mg (1.25 mmol) of lithium hydroxide monohydrate was added to this solution and stirred at room temperature for 4 hours. Then, 20 mL of dichloromethane was added, and the aqueous phase was collected. Hydrochloric acid was added to this aqueous phase to neutralize it and adjust the pH to 6. Then, a mixed solvent of trichloromethane and methanol in a 9:1 mass ratio was added to obtain an extract. Magnesium sulfate was added to this extract to dehydrate it. Light components were then removed using a rotary evaporator to obtain a liquid product. This liquid product was then mixed with 20 mL of dichloromethane and methanol to neutralize it and adjust the pH to 6. １ H-NMR and １３Analysis by C-NMR confirmed that the compound was the compound represented by formula (II) in reaction formula (1b) above (bis(pyridin-2-ylmethyl)glycine). The amount of this compound produced was 401.55 mg (1.561 mmol), and the yield was 94%.

[0080] A ligand was synthesized according to the following reaction formula (1c) at room temperature under an atmospheric atmosphere. 678.7 mg (2.638 mmol) of bis(pyridin-2-ylmethyl)glycine obtained in the above reaction formula (1b), 10 ml of 2-propanol, 270.2 mg (2.902 mmol) of aniline, and 762.2 mg (2.902 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride were placed in a round-bottom flask. The mixture was then stirred at room temperature for 20 hours. The resulting mixture was filtered, and the light components were removed by distillation using a rotary evaporator to obtain the product.

[0081] The product was purified by column chromatography (basic silica gel, hexane / ethyl acetate=4:1 to 0:1) to obtain a purified product. １ H-NMR and １３ As a result of structural analysis by C-NMR, it was confirmed that 2-(bis(pyridin-2-ylmethyl)amino)-N-phenylacetamide represented by formula (E) in reaction formula (1c) was obtained (yield: 652.6 mg, 1.963 mmol, yield: 74.42%).

[0082]

[0083] <Synthesis of Metal Complex> A ruthenium complex was synthesized in air under heating conditions at 95°C according to the following reaction formula (2): 33.2 mg (0.100 mmol) of 2-(bis(pyridin-2-ylmethyl)amino)-N-phenylacetamide synthesized according to the above reaction formula (1), 4 mL of ethanol, RuCl ２ (PPh ３ ) ３105 mg (110 μmol) of methyl methyl ketone was added. The reaction was carried out under reflux conditions at 95° C. for 4 hours to obtain a reaction mixture. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to obtain a concentrate. The concentrate was then separated by two-stage column chromatography. １ The results of H-NMR measurement are shown at the bottom of FIG.

[0084] In the first step, a mixture of trans- and cis-ruthenium complexes was obtained using a neutral silica gel column (dichloromethane / methanol = 19 / 1 to 4 / 1). In the second step, the trans- and cis-ruthenium complexes were separated using chromatography (chloroform / methanol = 14 / 1 to 4 / 1) using neutral silica gel.

[0085] The two products obtained １ H-NMR and １３ As a result of C-NMR measurement and single crystal X-ray structural analysis, a trans-type ruthenium complex represented by formula [III] in the following reaction formula (2) and a cis-type ruthenium complex represented by formula [IV] were obtained (R = C ６ H ５ ).

[0086] trans-type ruthenium complex １ The results of H-NMR measurement are shown at the top of Figure 2. １ The results of H-NMR measurement are as shown in the center of Figure 2. Figure 3 shows the results of single crystal structure analysis of a trans-ruthenium complex. Figure 4 shows the results of single crystal structure analysis of a trans-ruthenium complex viewed from an angle different from that of Figure 3. Figure 5 shows the results of single crystal structure analysis of a cis-ruthenium complex. Figure 6 shows the results of single crystal structure analysis of a cis-ruthenium complex viewed from an angle different from that of Figure 5.

[0087] The yield of the trans-ruthenium complex (MW: 766.09690) was 17.6 mg (23.0 μmol), representing a yield of 23.0%, while the yield of the cis-ruthenium complex (MW: 766.09690) was 28.8 mg (37.6 μmol), representing a yield of 37.6%.

[0088]

[0089] Example 1-2 Synthesis of N-2,6-dimethylphenyl-2-chloroacetamide Chloroacetic acid (1.42 g, 15 mmol), 2,6-dimethylaniline (2.0 mL, 16.5 mmol), and 4-dimethylaminopyridine (183 mg, 1.5 mmol) were placed in dichloromethane (60 mL) in a vessel, and the mixture was cooled to 0°C using an ice bath. After cooling, dicyclohexylcarbodiimide (3.43 g, 16.5 mmol) was added to the vessel, and then the ice bath was removed and the mixture was stirred for 3 hours while being returned to room temperature. The resulting reaction solution was eluted with basic silica gel (ethyl acetate) to obtain a solution. The solvent was distilled off from the solution using a rotary evaporator to obtain a crude product.

[0090] The crude product was purified by column chromatography using basic silica gel (hexane / ether=4 / 1), and the solvent was removed by distillation using a rotary evaporator. １ Analysis by H-NMR confirmed that N-2,6-dimethylphenyl-2-chloroacetamide (1.75 g, 8.85 mmol, yield: 59%) was produced.

[0091] <Synthesis of 2-(2-pyridyl)-N-(2-pyridylmethyl)ethyl-1-amine> 1.22 g (10 mmol) of 2-(2-pyridyl)ethylamine and 1.07 g (10 mmol) of 2-pyridylcarboxylaldehyde were dissolved in 10 mL of ethanol, and 45.4 mg (12 mmol) of sodium borohydride was added to the solution. The mixture was then stirred for 3 hours under heating and reflux. After that, the mixture was cooled to room temperature, and 15 mL of saturated aqueous sodium bicarbonate solution was added to obtain a solution. The solution was extracted three times with 5 mL of ethyl acetate, and then concentrated under reduced pressure using a rotary evaporator to obtain a reaction mixture. The reaction mixture was purified by column chromatography using basic silica gel (hexane / ethyl acetate = 1 / 1 mixed solution), and the solvent was then distilled off using a rotary evaporator. The obtained product was １ Analysis by H-NMR confirmed that the product was 2-(2-pyridyl)-N-(2-pyridylmethyl)ethyl-1-amine (1.58 g, 7.42 mmol, yield: 74%) (see J. Am. Chem. Soc. 2018, 140, 1, 58-61).

[0092] <Synthesis of Metal Complex> N-2,6-dimethylphenyl-2-chloroacetamide (593 mg, 3 mmol), 2-(2-pyridyl)-N-(2-pyridylmethyl)ethyl-1-amine (640 mg, 3 mmol), potassium carbonate (622 mg, 4.5 mmol), and potassium iodide (598 mg, 3 mmol) prepared as described above were added to 20 mL of acetonitrile, and the mixture was stirred under heating and reflux for 3 hours to obtain a reaction solution. The solvent was distilled off from the reaction solution using a rotary evaporator, dichloromethane was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated aqueous sodium chloride solution (20 mL). The resulting solution was dried using sodium sulfate, and the solvent was distilled off using a rotary evaporator to obtain a reaction mixture. The reaction mixture was purified by column chromatography (basic silica gel, hexane / ethyl acetate = 2 / 1), and the solvent was distilled off using a rotary evaporator to obtain a product. １H-NMR analysis confirmed that the product was N'-2,6-dimethylphenyl N-2-(2-pyridyl)ethyl, N-2-(2-pyridyl)methylacetamide (1.03 g, 2.8 mmol, yield: 92%).

[0093] The resulting N'-2,6-dimethylphenyl N-2-(2-pyridyl)ethyl, N-2-(2-pyridyl)methylacetamide (820 mg, 2.2 mmol) and RuCl ２ (PPh ３ ) ３ (2.3 g, 2.41 mmol) was added to 90 mL of ethanol and stirred for 12 hours under heating and reflux to obtain a reaction solution. This reaction solution was filtered through Celite to remove solid components, and then concentrated under reduced pressure using a rotary evaporator to obtain a reaction mixture. The reaction mixture was purified by column chromatography (neutral silica gel, chloroform / methanol = 12 / 1-4 / 1), and the solvent was distilled off using a rotary evaporator. Single crystal X-ray structural analysis confirmed that the obtained product was a ruthenium complex of the following formula (V) (290 mg, 0.36 mmol, yield: 16.4%).

[0094]

[0095] Fig. 7 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of formula (V) above. Fig. 8 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of formula (V) above viewed from an angle different from that of Fig. 7.

[0096] (Example 1-3) <Synthesis of Oxidant Raw Material> With reference to a known synthesis method (Angew. Chem. Int. Ed. 2014, 53, 11060-11064), the reaction of the following formula (1-3) was carried out under air at 45°C. Specifically, 3.22 g (10.0 mmol, 1.0 equivalent) of (diacetoxyiodo)benzene, 4.24 g (20.0 mmol, 2.0 equivalents) of pentafluorobenzoic acid, 100 mL of dichloromethane, and 100 mL of toluene were placed in a 300 mL eggplant-shaped flask. The resulting reaction solution was concentrated under reduced pressure at 45°C using a rotary evaporator to distill off the solvent. 50 mL of toluene was added to the resulting reaction mixture, and the operation of concentrating under reduced pressure using a rotary evaporator was repeated four times to obtain a mixture. The mixture was recrystallized using hexane / dichloromethane, and the resulting crystals were collected by filtration, washed with hexane, and dried under reduced pressure. １ H-NMR and １３ The obtained product was analyzed using C-NMR, and it was confirmed that 5.20 g (8.30 mmol) of [bis(pentafluorobenzoyloxy)iodo]benzene (yield: 83.0%, (VI) of the following formula (1-3)) was obtained.

[0097]

[0098] Example 2-1 <Hydroxylation> Using the ruthenium complex of formula [IV] (R in formula [IV] is a 2,6-dimethylphenyl group) obtained in accordance with Example 1-1 as a catalyst, adamantane represented by the following formula (2-1) was hydroxylated under a nitrogen stream at a reaction temperature of 35°C. Specifically, 27.2 mg (0.20 mmol) of adamantane and 3.18 mg (4.0 μmol) of the ruthenium complex of formula [IV] were placed in a 5 mL Schlenk tube. After the atmosphere in this Schlenk tube was replaced with nitrogen, 0.5 mL of 1,1,2,2-tetrachloroethane and １８ O-labeled water (oxygen 18 isotope labeled water, ≥ 98 atom%) １８ To the mixture was added 8.0 mg (7.2 μL, 0.40 mmol, 2 equivalents relative to the substrate) of oxidizing agent (VI) obtained in Example 1-3 (250 mg, 0.40 mmol), and the mixture was stirred at 35° C. for 0.5 hours.

[0099]

[0100] After stirring was completed, the carboxylic acid and catalyst were removed from the reaction mixture using short column chromatography (basic silica gel, developing solvent: ethyl acetate), and then the solvent was distilled off using a rotary evaporator. The resulting mixture was purified using column chromatography (neutral silica gel, developing solvent: hexane / ethyl acetate = 9 / 1-2 / 1), and then the solvent was distilled off using a rotary evaporator. The resulting product was １ Analysis by H-NMR confirmed that the target product, adamantan-1-ol (21.9 mg, yield: 71%), was obtained. Analysis by time-of-flight mass spectrometry (ESI-TOF-MS) revealed that the oxygen-18 isotope ( １８ It was confirmed that the labeling rate (concentration rate) of 1,2-dichloro-2,4-trimethylsilyl-1, ...

[0101] Example 2-2 <Hydroxylation> Using the ruthenium complex of formula [IV] (R in formula [IV] is a 2,6-dimethylphenyl group) obtained in accordance with Example 1-1 as a catalyst, 3,7-dimethyloctyl acetate was hydroxylated according to the following formula (2-2) under conditions of a nitrogen stream and a reaction temperature of 35° C. Specifically, the ruthenium complex of formula [IV] (3.18 mg, 4.0 μmol) was placed in a 5 mL Schlenk tube, and the atmosphere in the Schlenk tube was replaced with nitrogen. Then, 0.5 mL of 1,1,2,2-tetrachloroethane, 40.1 mg (0.20 mmol) of 3,7-dimethyloctyl acetate, and １８ 8.0 mg (7.2 μL, 0.40 mmol, 2 equivalents relative to the substrate) of O-labeled water (≧98 atom%) was added, and 250 mg (0.40 mmol) of the oxidizing agent raw material of formula (VI) obtained in Example 1-3 was added, followed by stirring at 35° C. for 12 hours.

[0102]

[0103] After the stirring was completed, the carboxylic acid and catalyst were removed using short column chromatography (basic silica gel, developing solvent: ethyl acetate), and then the solvent was distilled off using a rotary evaporator. The resulting mixture was purified using column chromatography (neutral silica gel, developing solvent: hexane / ethyl acetate = 9 / 1-2 / 1), and then the solvent was distilled off using a rotary evaporator. The resulting product was １ Analysis by H-NMR confirmed that the target product, 7-hydroxy-3,7-dimethyloctyl acetate (30.1 mg, yield: 69%), was obtained. Analysis by time-of-flight mass spectrometry (ESI-TOF-MS) revealed that the oxygen-18 isotope ( １８ It was confirmed that the labeling rate (concentration rate) of 1,2-dichloro-2,4-trimethylsilyl-1, ...

[0104] (Example 2-3) <Hydroxylation> The reaction and purification were carried out in the same manner as in Example 2-2, except that the ruthenium complex of formula (V) obtained in Example 1-2 was used as a catalyst instead of the ruthenium complex of formula [IV] obtained in Example 1-1. １ Analysis by H-NMR confirmed that the target product, 7-hydroxy-3,7-dimethyloctyl acetate (28.4 mg, yield: 65%), was obtained. Analysis by time-of-flight mass spectrometry (ESI-TOF-MS) revealed that the oxygen-18 isotope ( １８ It was confirmed that the labeling rate (concentration rate) of 1,2-dichloro-2,4-trimethylsilyl ...

[0105] Example 2-4 Hydroxylation Using the ruthenium complex of formula [IV] (R in formula [IV] is a 2,6-dimethylphenyl group) obtained in accordance with Example 1-1 as a catalyst, hydroxylation of 4-methylpentyl benzoate represented by the following formula (2-4) was carried out under a nitrogen stream at a reaction temperature of 35° C. Specifically, 3.18 mg (4.0 μmol) of the ruthenium complex of formula [IV] was added to a 5 mL Schlenk tube, and the atmosphere in the Schlenk tube was replaced with nitrogen. Then, 0.5 mL of 1,1,2,2-tetrachloroethane, 41.3 mg (0.20 mmol) of 4-methylpentyl benzoate, and １８ 8.0 mg (7.2 μL, 0.40 mmol) of O-labeled water (≧98 atom%) was added, and 250 mg (0.40 mmol) of the oxidizing agent raw material of formula (VI) obtained in Example 1-3 was further added, followed by stirring at 35° C. for 24 hours.

[0106]

[0107] After stirring was completed, the reaction mixture was subjected to short column chromatography (basic silica gel, developing solvent: ethyl acetate) to remove the carboxylic acid and catalyst, and then the solvent was removed using a rotary evaporator. The resulting mixture was purified by column chromatography (neutral silica gel, developing solvent: hexane / ethyl acetate = 4 / 1-2 / 1), and then the solvent was removed using a rotary evaporator. The resulting product was １ Analysis by H-NMR confirmed that the target product, 4-hydroxy-4-methylpentyl benzoate (34.5 mg, yield: 77%), was obtained. Analysis by time-of-flight mass spectrometry (ESI-TOF-MS) revealed that the oxygen-18 isotope ( １８ It was confirmed that the labeling rate (concentration rate) of 1,2-dichloro-2,4-trimethylsilyl-1, ...

[0108] Example 3-1 Synthesis of 1,6-anhydro-4-O-methyl-2,3-O-isopropylidene-β-D-mannopyranose The synthesis represented by the following reaction scheme (3-0) was carried out by the following method, with reference to known synthesis methods (J. Org. Chem. 1989, 54, 6125-6127, J. Org. Chem. 1989, 54, 1346-1353). First, D-mannose was etherified under nitrogen at 0°C to room temperature according to the following procedure to obtain 1,6-anhydro-β-D-mannopyranose (Compound VII). Specifically, a 25 mL dropping funnel was attached to a 100 mL Schlenk flask, 4.00 g (22.2 mmol, 1.0 equivalent) of D-mannose was added to the flask, and 5.50 g (28.9 mmol, 1.3 equivalents) of p-toluenesulfonyl chloride was added to the dropping funnel, followed by nitrogen substitution. 40 mL of pyridine was added to the flask, and 8 mL of pyridine was added to the dropping funnel. After dissolving, the flask was immersed in an ice-water bath and cooled to 0°C.

[0109] Thereafter, while stirring the reaction solution in the flask at 0°C, the sulfonyl chloride solution was added dropwise over 10 minutes. After stirring at room temperature for 2 hours, the solution was cooled again to 0°C, and 12 mL (60 mmol, 2.7 equivalents) of a 5N aqueous sodium hydroxide solution was added dropwise from the dropping funnel over 10 minutes. After stirring at room temperature for 2 hours, the solution was cooled again to 0°C and neutralized to pH 7.0 with 2N hydrochloric acid. The resulting reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the solvent was distilled off. Furthermore, 20 mL of toluene was added, and the operation of concentrating under reduced pressure using a rotary evaporator was repeated twice.

[0110] The mixture dried under reduced pressure was suspended in 100 mL of ethanol and filtered, and the remaining solid was washed three times with 30 mL of ethanol. The solvent was removed from the filtrate using a rotary evaporator, and the residue was dried under reduced pressure. The mixture thus obtained contained 1,6-anhydro-β-D-mannopyranose represented by formula (VII) in reaction scheme (3-0) below. This mixture was used in the next reaction without purification.

[0111] Next, the above 1,6-anhydro-β-D-mannopyranose was subjected to isopropylidene protection under nitrogen at room temperature according to the following procedure to obtain 1,6-anhydro-2,3-O-isopropylidene-β-D-mannopyranose shown in formula (VIII) of reaction scheme (3-0) below. Specifically, the mixture obtained in the above reaction was placed in a 300 mL eggplant-shaped flask, and after purging with nitrogen, 70 mL of acetone was added and the mixture was stirred and suspended. Subsequently, 6.94 g (8.19 mL, 66.6 mmol, 3.0 equivalents) of 2,2-dimethoxypropane and 211 mg (1.11 mmol, 0.05 equivalents) of p-toluenesulfonic acid monohydrate were added, and the mixture was stirred at room temperature for 12 hours to obtain a reaction mixture.

[0112] This reaction mixture was neutralized by adding 112 mg (155 μL, 1.11 mmol, 0.05 equivalents) of triethylamine, and the salt was removed by short column chromatography (neutral silica gel, developing solvent: ethyl acetate), and then the solvent was distilled off using a rotary evaporator. The resulting mixture was purified by column chromatography (neutral silica gel, developing solvent: hexane / ethyl acetate = 1 / 1-1 / 2), and the solvent was distilled off using a rotary evaporator. The resulting product was １ H-NMR analysis confirmed that 2.32 g (11.5 mmol) of 1,6-anhydro-2,3-O-isopropylidene-β-D-mannopyranose (formula (VIII) below, two-stage yield: 51.8%) was obtained.

[0113] The above-mentioned 1,6-anhydro-2,3-O-isopropylidene-β-D-mannopyranose was methyl-etherified under nitrogen at 0°C to room temperature according to the following procedure to obtain 1,6-anhydro-4-O-methyl-2,3-O-isopropylidene-β-D-mannopyranose of formula (IX). Specifically, 1.01 g (5.00 mmol, 1.0 equivalent) of 1,6-anhydro-2,3-O-isopropylidene-β-D-mannopyranose of formula (VIII) was placed in a 100 mL Schlenk flask and purged with nitrogen. Then, 20 mL of tetrahydrofuran and 5 mL of N,N-dimethylformamide were added, and the mixture was cooled to 0°C. Subsequently, 300 mg (7.50 mmol, 1.5 equivalents) of sodium hydride (60%) was added, and the mixture was stirred at 0°C for 1 hour. Thereafter, 1.42 g (625 μL, 10.0 mmol, 2.0 equivalents) of iodomethane was added dropwise at 0° C. over 5 minutes.

[0114] After stirring at room temperature for 1.5 hours, 20 mL of saturated aqueous ammonium chloride solution was added at 0°C, and extraction was performed three times with 20 mL of ethyl acetate. The organic phases from the three times were combined, washed with 20 mL of saturated saline, and dried over sodium sulfate. Then, the solvent was distilled off using a rotary evaporator to obtain a mixture. The obtained mixture was purified using column chromatography (neutral silica gel, developing solvent: hexane / ethyl acetate = 9 / 1-2 / 1), and the solvent was distilled off using a rotary evaporator. The obtained product was １ H-NMR analysis confirmed that 1.02 g (4.72 mmol) of 1,6-anhydro-4-O-methyl-2,3-O-isopropylidene-β-D-mannopyranose (formula (IX) in the following reaction scheme (3-0)), yield: 94.4%) was obtained.

[0115]

[0116] <Oxo-reaction> Using the ruthenium complex of formula [IV] (R in formula [IV] is a 2,6-dimethylphenyl group) obtained in Example 1-1 as a catalyst, oxidative deprotection of 1,6-anhydro-4-O-methyl-2,3-O-isopropylidene-β-D-mannopyranose was carried out under a nitrogen atmosphere at a reaction temperature of 35°C, as shown in the following formula (3-1). Specifically, 43.2 mg (0.20 mmol) of 1,6-anhydro-4-O-methyl-2,3-O-isopropylidene-β-D-mannopyranose and 3.18 mg (4.0 µmol) of the ruthenium complex of formula [IV] were placed in a 5 mL Schlenk tube, and the atmosphere in the Schlenk tube was replaced with nitrogen. Then, 0.5 mL of 1,1,2,2-tetrachloroethane and 1.0 mL of methyl 2,3-O-isopropylidene-β-D-mannopyranose were added. １８ 8.0 mg (7.2 μL, 0.40 mmol) of O-labeled water (≧98 atom%) was added, and 250 mg (0.40 mmol) of the oxidizing agent raw material of formula (VI) obtained in Example 1-3 was added, followed by stirring at 35° C. for 3 hours.

[0117]

[0118] After stirring was completed, the reaction mixture was purified using column chromatography (neutral silica gel, developing solvent: hexane / ethyl acetate = 4 / 1-1 / 1). Then, the solvent was distilled off using a rotary evaporator. １ Analysis by H-NMR confirmed that the target product, (1R,2R,4R,5R)-4-hydroxy-2-methoxy-6,8-dioxabicyclo[3.2.1]octan-3-one (11.3 mg, yield: 32%), was obtained. Analysis by time-of-flight mass spectrometry (ESI-TOF-MS) revealed that the oxygen-18 isotope ( １８ It was confirmed that the labeling rate (concentration rate) of 1,000 sachets (C1, C2, C3, C4) was 34 atom %. Figure 13 shows the analysis results using a time-of-flight mass spectrometer. Figure 14 shows the results of the analysis using a time-of-flight mass spectrometer. １ 1H-NMR analysis results, and FIG. 15 shows the results of two-dimensional NMR analysis. １３ The results of the C-NMR analysis by BCM are shown in Figure 17. １３The results of the analysis using the DEPT method of C-NMR are shown below. The product (1R,2R,4R,5R)-4-hydroxy-2-methoxy-6,8-dioxabicyclo[3.2.1]octan-3-one is converted to oxygen-18 isotope ( １８ Therefore, the following one-pot synthesis was carried out.

[0119] Example 3-2 <Oxonation → Hydroxylation> A one-pot synthesis represented by the following formula (3-2) was carried out. Using the ruthenium complex of formula [IV] (R in formula [IV] is a 2,6-dimethylphenyl group) obtained in Example 1-1 as a catalyst, oxidative deprotection of 1,6-anhydro-4-O-methyl-2,3-O-isopropylidene-β-D-mannopyranose was carried out under a nitrogen stream at a reaction temperature of 35°C, as shown in the following formula (3-2). Specifically, 43.2 mg (0.20 mmol) of 1,6-anhydro-4-O-methyl-2,3-O-isopropylidene-β-D-mannopyranose and 3.18 mg (4.0 μmol) of the ruthenium complex of formula [IV] were added to a 5 mL Schlenk tube, and the Schlenk tube was purged with nitrogen. Then, 0.5 mL of 1,1,2,2-tetrachloroethane and 0.5 mL of 1,1,2,2-tetrachloroethane were added. １８ 8.0 mg (7.2 μL, 0.40 mmol) of O-labeled water (≧98 atom%) was added, and 250 mg (0.40 mmol) of the oxidizing agent raw material of formula (VI) obtained in Example 1-3 was added, followed by stirring at 35° C. for 3 hours.

[0120] Subsequently, 0.5 mL of methanol was added and the mixture was cooled to 0°C, after which sodium cyanoborohydride (44.0 mg, 0.70 mmol) was added and stirred at 0°C for 10 minutes to obtain a reaction mixture. After stirring was completed, the carboxylic acid, catalyst, and reducing agent were removed from the reaction mixture using short column chromatography (basic silica gel, developing solvent: dichloromethane / methanol = 9 / 1), and the solvent was then distilled off using a rotary evaporator. The resulting mixture was purified by column chromatography (neutral silica gel, developing solvent: dichloromethane / methanol = 9 / 1-4 / 1), and the solvent was distilled off using a rotary evaporator. The resulting product was １Analysis by H-NMR confirmed that 1,6-anhydro-4-O-methyl-β-D-mannopyranose (4.1 mg, yield: 12%) was obtained. Analysis by time-of-flight mass spectrometry (ESI-TOF-MS) revealed that the oxygen-18 isotope of 1,6-anhydro-4-O-methyl-β-D-mannopyranose ( １８ The labeling rate (concentration rate) of 1,000 sachets (C1, C2, C3, C4) was 82 atom %. Figure 18 shows the analysis results using a time-of-flight mass spectrometer. Figure 19 shows the results of the analysis using a time-of-flight mass spectrometer. １ 1H-NMR analysis results.

[0121]

[0122] (Example 3-3) <O １８ Synthesis of mannose labeled with > The synthesis shown in the following formula (3-3) was carried out. 17.6 mg (0.10 mmol) of 1,6-anhydro-4-O-methyl-β-D-mannopyranose was placed in a 5 mL Schlenk tube, and the atmosphere inside the Schlenk tube was replaced with nitrogen. 1 mL of dichloromethane was then added, and the mixture was cooled to 0°C. 0.30 mL (0.30 mmol) of boron tribromide (1 M dichloromethane solution) was added, and the mixture was stirred at 0°C for 30 minutes to obtain a reaction mixture.

[0123] To the reaction mixture, 1 mL of water was added, and 79.1 mg (1.0 mmol) of pyridine was added to neutralize the mixture. The solvent was removed using a rotary evaporator. １ H-NMR analysis confirmed that mannose was the main product.

[0124]

[0125] Example 4-1 Trans-type and cis-type ruthenium complexes in which R in the following general formulas (10) and (11) is H (hydrogen) were obtained by treating the compound of formula (I) in reaction formula (1a) in Example 1-1 with aqueous ammonia.

[0126]

[0127]

[0128] Examples 4-2 to 4-8 A trans-type ruthenium complex and a cis-type ruthenium complex were obtained in which R in the general formulas (10) and (11) was the substituent shown in Figure 20. These were synthesized by using the amine compound shown in Figure 20 instead of the aniline of formula (II) in reaction formula (1c) in Example 1-1. The wavy line in Figure 20 indicates the main body of the ruthenium complex to which R in the general formulas (10) and (11) is bonded. Furthermore, Me represents a methyl group. In this way, it was confirmed that various ruthenium complexes can be synthesized.

[0129] (Example 5-1) <Synthesis of Ligand 2> 9.55 g (55.7 mmol, 1.0 equivalent) of methyl 4-chloro-2-pyridinecarboxylate, 50 mL of methanol, 25 mL of tetrahydrofuran, and 42.7 g (223 mmol, 4.0 equivalents) of calcium chloride were placed in a recovery flask. The recovery flask was immersed in an ice-water bath and cooled to 0°C. Then, while stirring the suspension at 0°C, 4.21 g (111 mmol, 2.0 equivalents) of sodium borohydride was slowly added. After stirring at 0°C for 1 hour, 100 mL of water was added. This extraction operation, in which 100 mL of ethyl acetate was added, was then repeated three times. The extract obtained after the three extraction operations was washed with saturated saline. Sodium sulfate was added to the washings to remove water, and the light components were then distilled off using a rotary evaporator. The resulting mixture was purified by column chromatography (neutral silica gel, developing solvent: hexane / ethyl acetate = 2 / 1-1 / 2) to obtain 4-chloro-2-pyridinemethanol (7.73 g, 53.8 mmol, yield: 96.7%). The reaction formula is shown in formula (5-1) below.

[0130]

[0131] A recovery flask was charged with 1.44 g (10.0 mmol, 1.0 equivalent) of 4-chloro-2-pyridinemethanol and 20 mL of chloroform, followed by the addition of 10.4 g (120 mmol, 12 equivalents) of manganese dioxide. The mixture was stirred for 2 hours under heating and reflux to obtain a reaction solution. After cooling the reaction solution to room temperature, it was filtered through Celite to remove solid components, and the light components were distilled off using a rotary evaporator. The resulting mixture was purified by column chromatography (neutral silica gel, developing solvent: dichloromethane / methanol = 1 / 0-9 / 1) to obtain 4-chloro-2-pyridinecarboxaldehyde (947 mg, 6.69 mmol, yield: 66.9%). The reaction scheme is shown in formula (5-2) below.

[0132]

[0133] A recovery flask was charged with 1.72 g (12.0 mmol, 1.0 equivalent) of 4-chloro-2-pyridinemethanol, and the flask was purged with nitrogen. Then, 60 mL of dichloromethane was added, and the recovery flask was immersed in an ice-water bath and cooled to 0°C. Then, 2.14 g (1.31 mL, 18.0 mmol, 1.5 equivalents) of thionyl chloride was added dropwise at 0°C over 3 minutes. After the dropwise addition, the ice-water bath was removed, and the mixture was stirred for 2 hours while returning to room temperature. It was again cooled to 0°C, and 50 mL of saturated aqueous sodium bicarbonate solution was added. Then, 50 mL of dichloromethane was added and extraction was repeated three times. The extract obtained after three extractions was washed with saturated saline. Sodium sulfate was added to the washings to remove water, and the light components were then distilled off using a rotary evaporator. The resulting mixture was purified by column chromatography (neutral silica gel, developing solvent: hexane / ethyl acetate = 4 / 1) to obtain 4-chloro-2-(chloromethyl)pyridine (1.71 g, 10.5 mmol, yield: 87.8%). The reaction formula is shown in formula (5-3) below.

[0134]

[0135] A recovery flask was charged with 1.71 g (10.5 mmol, 1.0 equivalent) of 4-chloro-2-(chloromethyl)pyridine. The flask was then purged with nitrogen, and 21 mL of N,N-dimethylformamide and 2.15 g (11.6 mmol, 1.1 equivalent) of potassium phthalimide were added. The mixture was stirred at 100°C for 2 hours, cooled to room temperature, and 50 mL of saturated aqueous sodium bicarbonate solution was added. This mixture was then extracted with 50 mL of dichloromethane, and this procedure was repeated three times. The extract obtained after these three extractions was washed with saturated saline. Sodium sulfate was added to the washings to remove water, and the light components were then distilled off using a rotary evaporator. The mixture thus obtained contained 2-((4-chloro-2-pyridyl)methyl)isoindoline-1,3-dione. The reaction formula is shown in formula (5-4) below. This mixture was used in the next reaction without purification.

[0136]

[0137] The mixture obtained in the above reaction was placed in a recovery flask, and 100 mL of ethanol and 1.58 g (1.54 mL, 31.6 mmol, 3.0 equivalents) of hydrazine monohydrate were added. The mixture was then heated to reflux and stirred for 2 hours to obtain a reaction solution. After cooling the reaction solution to room temperature, it was filtered to remove solid components, and the light components were distilled off using a rotary evaporator. The resulting mixture was purified by column chromatography (basic silica gel, developing solvent: dichloromethane / methanol = 1 / 0-99 / 1) to obtain 4-chloro-2-pyridinemethanamine (1.22 g, 8.53 mmol, two-stage yield: 80.9%). The reaction formula is shown in formula (5-5) below.

[0138]

[0139] A recovery flask was charged with 713 mg (5.00 mmol, 1.0 equivalent) of 4-chloro-2-pyridinemethanamine, 10 mL of 1,2-dichloroethane, and 708 mg (5.00 mmol, 1.0 equivalent) of 4-chloro-2-pyridinecarboxaldehyde. The recovery flask was immersed in an ice-water bath and cooled to 0°C. Subsequently, 2.12 g (10.0 mmol, 2.0 equivalents) of sodium triacetoxyborohydride was slowly added while stirring the reaction solution at 0°C. The ice-water bath was removed, and the mixture was stirred for 3 hours while returning to room temperature. The mixture was again cooled to 0°C, and 20 mL of saturated aqueous sodium bicarbonate solution was added. This extraction procedure was repeated three times: the resulting extract was washed with saturated saline, and sodium sulfate was added to the washings to remove moisture, followed by distilling off light components using a rotary evaporator. The resulting mixture was purified by column chromatography (basic silica gel, developing solvent: hexane / ethyl acetate = 4 / 1-2 / 1) to obtain bis((4-chloro-2-pyridyl)methyl)amine (1.16 g, 4.34 mmol, yield: 86.8%). The reaction formula is shown in formula (5-6) below.

[0140]

[0141] After purging the atmosphere in the eggplant-shaped flask with nitrogen, 2.42 g (2.47 mL, 20.0 mmol, 1.0 equivalent) of 2,6-dimethylaniline, 40 mL of dichloromethane, and 2.23 g (3.07 mL, 22.0 mmol, 1.1 equivalent) of triethylamine were added, and the flask was immersed in an ice-water bath and cooled to 0°C. Subsequently, 2.48 g (1.75 mL, 22.0 mmol, 1.1 equivalent) of chloroacetyl chloride was added dropwise at 0°C over 3 minutes, the ice-water bath was removed, and the mixture was stirred for 1 hour while returning to room temperature. The mixture was again cooled to 0°C, and 40 mL of saturated aqueous sodium bicarbonate solution was added. This extraction procedure was repeated three times, followed by the addition of 40 mL of dichloromethane. The extract obtained after the three extraction procedures was washed with 1 N hydrochloric acid and saturated saline. Sodium sulfate was added to the washings to remove water, and the light components were then distilled off using a rotary evaporator. The resulting mixture was purified by column chromatography (neutral silica gel, developing solvent: dichloromethane / methanol=1 / 0-49 / 1) to obtain 2-chloro-N-(2,6-dimethylphenyl)acetamide (3.40 g, 17.2 mmol, yield: 86.0%). The reaction formula is shown in formula (5-7) below.

[0142]

[0143] A recovery flask was charged with 804 mg (3.00 mmol, 1.0 equivalent) of bis((4-chloro-2-pyridyl)methyl)amine, 27 mL of acetonitrile, and 3 mL of N,N-dimethylformamide. To this recovery flask, 771 mg (3.90 mmol, 1.3 equivalents) of 2-chloro-N-(2,6-dimethylphenyl)acetamide, 539 mg (3.90 mmol, 1.3 equivalents) of potassium carbonate, and 245 mg (1.50 mmol, 0.5 equivalents) of potassium iodide were further added. The mixture was stirred for 4 hours under reflux, yielding a reaction solution. After cooling the reaction solution to room temperature, solid components were removed using short column chromatography (basic silica gel, developing solvent: ethyl acetate), and light components were distilled off using a rotary evaporator to yield a mixture. This mixture was purified by column chromatography (basic silica gel, developing solvent: hexane / ethyl acetate = 4 / 1-1 / 2). The resulting product was １ H-NMR, １３Analysis by C-NMR and time-of-flight mass spectrometry confirmed that 2-(bis((4-chloro-2-pyridyl)methyl)amino)-N-(2,6-dimethylphenyl)acetamide (1.04 g, 2.43 mmol, yield: 80.8%, Ligand 2) was obtained. The reaction formula is shown in the following formula (5-8). Figure 21 shows the reaction of Ligand 2 １ 22 shows the results of H-NMR analysis of Ligand 2. １３ 23 shows the results of analysis of Ligand 2 by a time-of-flight mass spectrometer.

[0144]

[0145] <Synthesis of Metal Complex> In a recovery flask, 350 mg (815 μmol, 1.0 equivalent) of 2-(bis((4-chloro-2-pyridyl)methyl)amino)-N-(2,6-dimethylphenyl)acetamide (ligand 2), RuCl ２ (PPh ３ ) ３ 860 mg (897 μmol, 1.1 equivalents) of toluene and 32 mL of ethanol were added, and the mixture was stirred for 4 hours under heating and reflux to obtain a reaction solution. After that, light components were distilled off from the reaction solution using a rotary evaporator. The resulting mixture was purified by two column chromatography runs (first run: neutral silica gel (developing solvent: dichloromethane / methanol = 19 / 1-4 / 1), second run: neutral silica gel (developing solvent: chloroform / methanol = 19 / 1-4 / 1)). The resulting product was １ The product was analyzed by H-NMR and time-of-flight mass spectrometry. When these analytical results were compared with the structure of the ruthenium complexes obtained in Examples 1-1 and 1-2, it was confirmed that the product was a ruthenium complex of the following formula (X) (168 mg, 195 μmol, yield: 23.9%). The reaction formula is shown in the following formula (5-9). Figure 24 shows the reaction of the ruthenium complex of formula (X) １ 25 shows the results of analysis of the ruthenium complex of formula (X) by a time-of-flight mass spectrometer.

[0146]

[0147] (Example 5-2) <Synthesis of Ligand 3> 2-(bis((4-bromo-2-pyridyl)methyl)amino)-N-(2,6-dimethylphenyl)acetamide (ligand 3) was synthesized in the same manner as in Example 5-1, except that 4-bromo-2-pyridine methyl carboxylate was used instead of 4-chloro-2-pyridine methyl carboxylate, according to the reaction pathway shown in formula (5-10) below. Figure 26 shows the structure of Ligand 3. １ 27 shows the results of H-NMR analysis of Ligand 3. １３ 28 shows the results of analysis of Ligand 3 by a time-of-flight mass spectrometer.

[0148]

[0149] <Synthesis of Metal Complex> A ruthenium complex was synthesized in the same manner as in Example 5-1, except that 2-(bis((4-bromo-2-pyridyl)methyl)amino)-N-(2,6-dimethylphenyl)acetamide (ligand 3) was used instead of 2-(bis((4-chloro-2-pyridyl)methyl)amino)-N-(2,6-dimethylphenyl)acetamide (ligand 2). The resulting product was １ The ruthenium complex was analyzed by H-NMR and time-of-flight mass spectrometry. When these analytical results were compared with the structure of the ruthenium complex obtained in Examples 1-1 and 1-2, it was confirmed to be a ruthenium complex of the following formula (XI). The reaction formula is shown in the following formula (5-11). Figure 29 shows the reaction of the ruthenium complex of formula (XI). １ 30 shows the results of analysis of the ruthenium complex of formula (XI) by a time-of-flight mass spectrometer.

[0150]

[0151] (Example 6-1) <Hydroxylation> In a 5 mL glass sample bottle, 3,7-dimethyloctyl acetate (20 mg, 0.1 mmol), iodobenzene (dipentafluorobenzoate) (123.3 mg, 0.2 mmol), and H ２0 (3.6 mg, 0.2 mmol) was added to the solution. Tetrachloroethane (0.25 mL) was added to dissolve the solution, and the temperature was adjusted to 35°C. The cis-type ruthenium catalyst (2.0 μmol, 2 mol%) obtained in Example 4-8 was added to the solution obtained in this manner, and the hydroxylation shown in the following formula (6-1) was carried out. １ H-NMR analysis and １３ C-NMR analysis was performed to determine the conversion rate and the yield of each product. The product ratio was monitored up to 12 hours of reaction time. The results are shown in Figure 31 and Table 1.

[0152]

[0153] (Example 6-2) The proportion of the product was monitored in the same manner as in Example 6-1, except that the ruthenium catalyst of formula (X) above was used instead of the cis-type ruthenium catalyst obtained in Example 4-8. The results are shown in FIG. 31 and Table 1.

[0154] (Example 6-3) The proportion of the product was monitored in the same manner as in Example 6-1, except that the ruthenium catalyst of formula (XI) above was used instead of the cis-type ruthenium catalyst obtained in Example 4-8. The results are shown in FIG. 31 and Table 1.

[0155]

[0156] Table 1 shows the conversion rate of the substrate after 6 or 12 hours and the yield of each product. The substrate concentration [S] calculated from the conversion efficiency at each reaction time and the initial concentration of the substrate [S ０ ] relative ratio ([S] / [S ０ ]) was calculated. Figure 31 is a graph showing the change over time in the natural logarithm of the relative ratio. The slope of this graph indicates the reaction rate. From the results shown in Figure 31 and Table 1, it was confirmed that the ruthenium compounds of formula (X) and formula (XI) above have catalytic activity at least twice that of the cis-type ruthenium compound obtained in Example 4-8.

[0157] According to the present disclosure, it is possible to provide a labeling method using an oxygen isotope that can produce a labeled compound in high yield without using excess oxygen-isotope-labeled water. It is also possible to provide an oxygen-isotope-labeled oxidizing agent, a ruthenium complex, and a catalyst that can be suitably used in such a labeling method. It is also possible to provide a labeled compound labeled with an oxygen isotope. It is also possible to provide a novel compound that is useful as a reagent.

Claims

1. A hypervalent iodine compound having an ester structure, １７ O and １８ An oxidizing agent produced from labeled water labeled with at least one oxygen isotope selected from the group consisting of O, and a method for labeling a substrate having a carbon-hydrogen bond with the oxygen isotope, comprising the step of using a catalyst.

2. The labeling method according to claim 1, wherein the catalyst contains a ruthenium complex.

3. The labeling method according to claim 1, wherein the catalyst contains at least one ruthenium complex selected from the group consisting of the following general formulas (1), (2), and (3). [In the general formulas (1), (2), and (3), R １ represents a hydrogen atom, a phenyl group, or a monovalent group in which at least one hydrogen atom of the phenyl group is substituted with an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy group, R ２ represents a hydrogen atom, a phenyl group, or an alkyl group, L １ represents a halogen atom or a water molecule, L ２ represents triphenylphosphine, pyridine, imidazole, or dimethyl sulfoxide, X represents a halogen atom, n represents 1 or 2, and in the general formula (2), R ９ and R １０ each independently represent a hydrogen atom, a halogen atom, or an alkyl group. ] 4. The labeling method according to any one of claims 1 to 3, wherein the hypervalent iodine compound contains a compound represented by the following general formula (4). [In the general formula (4), R ３ and R ４ each independently represents a hydrogen atom, an alkyl group, or a monovalent group having an aromatic ring, and R ５ represents a monovalent group having an aromatic ring. ] 5. The labeling method according to any one of claims 1 to 4, wherein in the step, the substrate is oxidized to obtain a hydroxy compound or an oxo compound labeled with the oxygen isotope.

6. The labeling method according to any one of claims 1 to 4, wherein in the step, the oxygen atom of the hexose contained in the substrate is replaced with the oxygen isotope to label the hexose.

7. A hypervalent iodine compound having an ester structure, １７ O and １８ and labeled water labeled with at least one oxygen isotope selected from the group consisting of O, and a labeling oxidizing agent for labeling a substrate having a carbon-hydrogen bond with the oxygen isotope in the presence of a catalyst.

8. The labeling oxidizing agent according to claim 7, wherein the hypervalent iodine compound contains a compound represented by the following general formula (4). [In the general formula (4), R ３ and R ４ each independently represent a hydrogen atom, an alkyl group, or a monovalent group having an aromatic ring, and R ５ represents a monovalent group having an aromatic ring. ] 9. A ruthenium complex represented by the following general formula (2) or (3). [In the general formulas (2) and (3), R １ represents a hydrogen atom, a phenyl group, or a monovalent group in which at least one hydrogen atom of the phenyl group is substituted with an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy group, R ２ represents a hydrogen atom, a phenyl group, or an alkyl group, L １ represents a halogen atom or a water molecule, L ２ represents triphenylphosphine, pyridine, imidazole, or dimethyl sulfoxide, X represents a halogen atom, n represents 1 or 2, and in the general formula (2), R ９ and R １０ each independently represent a hydrogen atom, a halogen atom, or an alkyl group. ] 10. A catalyst comprising at least one selected from the group consisting of a ruthenium complex represented by the following general formula (2) and a ruthenium complex represented by the following general formula (3). [In the general formulas (2) and (3), R １ represents a hydrogen atom, a phenyl group, or a monovalent group in which at least one hydrogen atom of the phenyl group is substituted with an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy group, R ２ represents a hydrogen atom, a phenyl group, or an alkyl group, L ２ represents triphenylphosphine, pyridine, imidazole, or dimethyl sulfoxide, X represents a halogen atom, n represents 1 or 2, and in the general formula (2), R ９ and R １０ each independently represent a hydrogen atom, a halogen atom, or an alkyl group.] 11. The catalyst according to claim 10, which is an oxidation catalyst for oxidizing a substrate having a carbon-hydrogen bond.

12. A labeled compound labeled with at least one oxygen isotope selected from the group consisting of O and １７ and １８ and represented by the following formula (5), (6) or (7). １７ O and １８ O. [In the above formulas (5), (6) and (7), A represents １７ O or １８ O. ] １７ O or １８ O.

13. A compound represented by the following formula (8).

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