WO2022138748A1 - 標識方法、標識用酸化剤、ルテニウム錯体、触媒、標識化合物、及び、化合物 - Google Patents

標識方法、標識用酸化剤、ルテニウム錯体、触媒、標識化合物、及び、化合物 Download PDF

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WO2022138748A1
WO2022138748A1 PCT/JP2021/047658 JP2021047658W WO2022138748A1 WO 2022138748 A1 WO2022138748 A1 WO 2022138748A1 JP 2021047658 W JP2021047658 W JP 2021047658W WO 2022138748 A1 WO2022138748 A1 WO 2022138748A1
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group
labeled
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labeling
hydrogen atom
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竜也 内田
大樹 土居内
達也 中村
奈々子 下田
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Kyushu University NUC
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    • A61K51/04—Organic compounds
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
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    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by oxidation reactions with formation of hydroxy groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
    • C07C35/37—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with a hydroxy group on a condensed system having three rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0046—Ruthenium compounds
    • C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • C07H3/10—Anhydrosugars, e.g. epoxides
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present disclosure relates to a labeling method using an oxygen isotope, an oxidizing agent for labeling with an oxygen isotope, a ruthenium complex, a catalyst, a labeling compound with an oxygen isotope, and a novel compound.
  • Patent Document 1 proposes to use an oxygen isotope-labeled carboxylate compound as a source of oxygen isotopes.
  • the present disclosure provides a labeling method using an oxygen isotope, which can obtain a labeled compound in a high yield without using excess oxygen isotope-labeled water. Also provided are an oxidizing agent for labeling, a ruthenium complex and a catalyst that can be suitably used for such a labeling method. Also provided are labeled compounds labeled with oxygen isotopes. It also provides a novel compound useful as a reagent.
  • the present disclosure in one aspect, is an oxidizing agent produced from a superatomic iodine compound having an ester structure and labeled water labeled with at least one oxygen isotope selected from the group consisting of 17 O and 18 O. And, a labeling method comprising the step of labeling a substrate having a carbon-hydrogen bond with an oxygen isotope using a catalyst is provided.
  • the carbon-hydrogen bond of the substrate is oxidized with high regioselectivity using an oxidizing agent and a catalyst. Since an oxidizing agent produced from a hypervalent iodine compound having an ester structure and labeled water is used, the substrate can be labeled with isotope oxygen. Therefore, the labeled compound can be obtained in a high yield without using a large amount of oxygen isotope-labeled water.
  • 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).
  • R 1 at least one hydrogen atom of a hydrogen atom, a phenyl group, or a phenyl group is an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy.
  • a monovalent group substituted with a group R 2 indicates a hydrogen atom, a phenyl group, or an alkyl group
  • L 1 indicates a halogen atom or a water molecule
  • L 2 indicates a triphenylphosphine, pyridine
  • X indicates a halogen atom
  • n indicates 1 or 2.
  • R 9 and R 10 each independently represent a hydrogen atom, a halogen atom or an alkyl group.
  • the catalyst containing the ruthenium complex is excellent in the activity of the carbon-hydrogen bond oxidation reaction and also in the regioselectivity. Therefore, a labeled compound with a target oxygen isotope can be obtained in high yield from various substrates having a carbon-hydrogen bond.
  • the hypervalent iodine compound used in the above labeling method may contain a compound represented by the following general formula (4).
  • R 3 and R 4 each independently represent a monovalent group having a hydrogen atom, an alkyl group, or an aromatic ring
  • R 5 represents a monovalent group having an aromatic ring. show.
  • the compound represented by the above general formula (4) can activate the labeled water and promote the reaction between the substrate and the labeled water. Thereby, the desired oxygen isotope-labeled compound can be obtained in a high yield.
  • the substrate may be oxidized to obtain a hydroxy compound or an oxo compound labeled with an oxygen isotope.
  • hydroxy compounds or oxo compounds can be used for various purposes.
  • the oxygen atom of the hexacarbonate contained in the substrate may be replaced with an oxygen isotope to label the hexacarbonate.
  • the oxygen isotope-labeled hexacarbonate sugar thus obtained can be utilized for in vivo imaging such as observation of cell tissue as a molecular probe labeled with oxygen isotope, for example.
  • the present disclosure in one aspect, is produced and catalyzed from a superatomic iodine compound having an ester structure and labeled water labeled with at least one oxygen isotope selected from the group consisting of 17 O and 18 O.
  • a superatomic iodine compound having an ester structure and labeled water labeled with at least one oxygen isotope selected from the group consisting of 17 O and 18 O.
  • an oxidizing agent for labeling in which a substrate having a carbon-hydrogen bond is labeled with an oxygen isotope in the coexistence.
  • This labeling oxidant can oxidize the carbon-hydrogen bond of the substrate with high regioselectivity in the presence of a catalyst and label the substrate with isotope oxygen. Therefore, the labeled compound can be obtained in a high yield without using a large amount of oxygen isotope-labeled water.
  • the hypervalent iodine compound used in the above labeling method may contain a compound represented by the following general formula (4). At least one of the oxygen atoms in the following general formula (4) may be 17 O or 18 O.
  • R 3 and R 4 each independently represent a monovalent group having a hydrogen atom, an alkyl group, or an aromatic ring
  • R 5 represents a monovalent group having an aromatic ring. show.
  • the substrate and the oxidizing agent can be stably reacted to obtain the desired oxygen isotope-labeled compound in high yield. Can be done.
  • the present disclosure provides, in one aspect, a ruthenium complex represented by the following general formula (2) or (3).
  • R 1 at least one hydrogen atom of a hydrogen atom, a phenyl group, or a phenyl group is replaced 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. It represents sulfoxide, where X is a halogen atom and n is 1 or 2.
  • R 9 and R 10 each independently represent a hydrogen atom, a halogen atom or an alkyl group.
  • the ruthenium complex has high activity as a catalyst in a reaction for oxidizing a carbon-hydrogen bond.
  • a ruthenium complex can be used for various purposes as a catalyst.
  • substrates with carbon-hydrogen bonds can be oxidized with high regioselectivity. Therefore, in the coexistence of an oxidizing agent generated from a superatomic iodine compound having an ester structure and labeled water labeled with an oxygen isotope, the carbon-hydrogen bond of the substrate is oxidized with high position selectivity as an oxidation catalyst. , 17 O or 18 O can be labeled with the substrate. That is, it is useful as a catalyst for oxygen isotope labeling.
  • the use of the ruthenium complex is not limited to the above. For example, it may be an oxidation catalyst that oxidizes the substrate without labeling.
  • the present disclosure provides, in one aspect, a catalyst comprising at least one selected from the group consisting of the ruthenium complex represented by the general formula (2) and the ruthenium complex represented by the general formula (3). do.
  • Such catalysts have high activity in the reaction of oxidizing carbon-hydrogen bonds.
  • the catalyst may be an oxidation catalyst that oxidizes a substrate having a carbon-hydrogen bond, or may be an oxidation catalyst that hydroxyizes the substrate.
  • the present disclosure in one aspect, is a labeled compound labeled with at least one oxygen isotope selected from the group consisting of 17 O and 18 O represented by the following formulas (5), (6) or (7). I will provide a.
  • labeled compounds can be used for various purposes. For example, it can be used for in vivo imaging as a molecular probe.
  • A represents 17 O or 18 O.
  • the labeled compound is labeled with 17 O or 18 O.
  • Such labeled compounds can be used for various purposes. For example, it can be used for in vivo imaging as a molecular probe.
  • the present disclosure provides a compound (new compound) represented by the following formula (8) in one aspect.
  • Me in the formula (8) represents a methyl group.
  • the above compounds can be easily labeled with oxygen isotopes.
  • it is useful as an intermediate for obtaining isotope oxygen-labeled mannose.
  • This novel compound can be used, for example, as an intermediate for producing isotope oxygen-labeled mannose from mannose.
  • a labeling method using an oxygen isotope which can obtain a labeled compound in a high yield without using excess oxygen isotope-labeled water.
  • an oxidizing agent for labeling a ruthenium complex, and a catalyst that can be suitably used for such a labeling method.
  • labeled compounds labeled with oxygen isotopes can be provided.
  • FIG. 1 is a diagram showing an example of an alcohol production mechanism when a ruthenium complex is used as a catalyst.
  • FIG. 2 is a diagram showing 1 H-NMR measurement results of a ruthenium complex of formula [III] (trans type), a ruthenium complex of formula [IV] (cis type), and a mixture thereof.
  • FIG. 3 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of the formula [III].
  • FIG. 4 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of the formula [III] when viewed from an angle different from that of FIG.
  • FIG. 5 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of the formula [IV].
  • FIG. 1 is a diagram showing an example of an alcohol production mechanism when a ruthenium complex is used as a catalyst.
  • FIG. 2 is a diagram showing 1 H-NMR measurement results of a ruthenium complex of formula [III] (trans type
  • FIG. 6 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of the formula [IV] viewed from an angle different from that of FIG.
  • FIG. 7 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of the formula (V).
  • FIG. 8 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of the formula (V) viewed from an angle different from that of FIG. 7.
  • FIG. 9 is the result of time-of-flight mass spectrometry of oxygen isotope-labeled adamantane-1-ol in Example 2-1.
  • FIG. 9 is the result of time-of-flight mass spectrometry of oxygen isotope-labeled adamantane-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-methylpentylbenzoate in Example 2-4.
  • FIG. 13 shows the oxygen-18 isotope-labeled (1R, 2R, 4R, 5R) -4-hydroxy-2-methoxy-6,8-dioxabicyclo [3.2.1] octane in Example 3-1. It is the result of time-of-flight mass spectrometry of -3-on.
  • FIG. 14 shows an oxygen-18 isotope-labeled (1R, 2R, 4R, 5R) -4-hydroxy-2-methoxy-6,8-dioxabicyclo [3.2.1] octane in Example 3-1. It is the analysis result of 1 H-NMR of -3-on.
  • FIG. 15 shows an oxygen-18 isotope-labeled (1R, 2R, 4R, 5R) -4-hydroxy-2-methoxy-6,8-dioxabicyclo [3.2.1] octane in Example 3-1. It is an analysis result of -3-on two-dimensional NMR.
  • FIG. 16 shows an oxygen-18 isotope-labeled (1R, 2R, 4R, 5R) -4-hydroxy-2-methoxy-6,8-dioxabicyclo [3.2.1] octane in Example 3-1. It is the analysis result by BCM of 13 C-NMR of -3-on.
  • FIG. 17 shows an oxygen-18 isotope-labeled (1R, 2R, 4R, 5R) -4-hydroxy-2-methoxy-6,8-dioxabicyclo [3.2.1] octane in Example 3-1. It is the analysis result by the DEPT method of 13 C-NMR of -3-one.
  • FIG. 18 is the result of time-of-flight mass spectrometry of oxygen-18 isotope-labeled 1,6-anhydro-4-O-methyl- ⁇ -D-mannopyranose in Example 3-2.
  • FIG. 19 shows 1 H-NMR analysis results of oxygen-18 isotope-labeled 1,6-anhydro-4-O-methyl- ⁇ -D-mannopyranose in Example 3-2.
  • FIG. 20 is a diagram showing a substituent of the ruthenium complex used in Examples 4-2 to 4-8 and an amine compound used for obtaining the ruthenium complex.
  • FIG. 21 is the analysis result of 1 H-NMR of the ligand 2 obtained in Example 5-1.
  • FIG. 22 shows the analysis result of 13 C-NMR of the ligand 2 obtained in Example 5-1.
  • FIG. 23 is the result of time-of-flight mass spectrometry of the ligand 2 obtained in Example 5-1.
  • FIG. 24 is the analysis result of 1 H-NMR of the ruthenium complex obtained in Example 5-1.
  • FIG. 25 is the result of time-of-flight mass spectrometry of the ruthenium complex obtained in Example 5-1.
  • FIG. 21 is the analysis result of 1 H-NMR of the ligand 2 obtained in Example 5-1.
  • FIG. 22 shows the analysis result of 13 C-NMR of the ligand 2 obtained in Example 5-1.
  • FIG. 23 is the result of time
  • FIG. 26 is the analysis result of 1 H-NMR of the ligand 3 obtained in Example 5-2.
  • FIG. 27 is the analysis result of 13 C-NMR of the ligand 3 obtained in Example 5-2.
  • FIG. 28 is the result of time-of-flight mass spectrometry of the ligand 3 obtained in Example 5-2.
  • FIG. 29 is the analysis result of 1 H-NMR of the ruthenium complex obtained in Example 5-2.
  • FIG. 30 is the result of time-of-flight mass spectrometry of the ruthenium complex obtained in Example 5-2.
  • FIG. 31 is a graph showing the change over time in the natural logarithm of the relative ratio between the substrate concentration [S] obtained from the conversion efficiency at each reaction time and the initial concentration [S 0 ] of the substrate.
  • the labeling method is an oxidizing agent produced from a superatomic iodine compound having an ester structure and labeled water labeled with at least one oxygen isotope selected from the group consisting of 17 O and 18 O. And, using a catalyst, there is a step of labeling a substrate having a carbon-hydrogen bond with an oxygen isotope.
  • a substrate having a carbon-hydrogen bond can be labeled with at least one selected from the group consisting of oxygen 17 isotope ( 17 O) and oxygen 18 isotope ( 18 O). It may be labeled with either oxygen 17 isotope ( 17 O) or oxygen 18 isotope ( 18 O). That is, this labeling method is a labeling method using oxygen isotopes.
  • Labeling with oxygen isotopes in the present disclosure is carried out by oxygen 17 isotopes ( 17 O) and / or oxygen 18 isotopes ( 18 O).
  • the labeling rate (concentration) in the present disclosure is a ratio in which the specific oxygen atom constituting the compound is 17 O and / or 18 O.
  • the labeling rate of the labeled compound obtained by this labeling method may be 100% or less.
  • the labeling rates in the present disclosure are the spectra of compounds in which the isotope ratio of oxygen atoms is the natural abundance ratio measured using a time-of-flight mass analyzer, and all oxygen atoms are 18 O and / or 17 O. It is calculated by comparing with the calculated value of the spectrum of the compound in a certain case.
  • an oxidation catalyst can be used.
  • catalysts include metal complexes and enzymes.
  • the metal complex include a porphyrin metal complex and a salen metal complex.
  • the enzyme may be an oxidase, and specific examples thereof include cytochrome P450 and non-heme iron enzymes such as lipoxygenase.
  • the catalyst preferably contains a metal complex, more preferably contains a ruthenium complex, and at least one ruthenium complex selected from the group consisting of the following general formulas (1), (2) and (3). It is more preferable to include it.
  • a catalyst containing such a ruthenium complex is excellent in the activity of the oxidation reaction of the carbon-hydrogen bond and also in the regioselectivity. Therefore, a labeled compound with a target oxygen isotope can be obtained in high yield from various substrates having a carbon-hydrogen bond.
  • R 1 at least one hydrogen atom of a hydrogen atom, a phenyl group, or a phenyl group is an alkyl group, a hydroxy group, a phenyl group, a halogen atom, or an alkoxy. Indicates a monovalent group substituted with a group.
  • R 1 preferably has a phenyl group or at least one hydrogen atom of the phenyl group (hydrogen atom in the benzene ring) having an alkyl group or a hydroxy group.
  • a monovalent group substituted with a phenyl group, a halogen atom, or an alkoxy group is a monovalent group substituted with 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 referred to as a substituted phenyl group.
  • R 1 is a substituted phenyl group
  • the substituents substituting a plurality of hydrogen atoms in the phenyl group may be different from each other or may be the same.
  • the alkyl group that replaces at least one hydrogen atom of the phenyl group may be a methyl group, an ethyl group, or a propyl group.
  • the halogen atom that replaces at least one hydrogen atom of the phenyl group may be a chlorine atom.
  • the alkoxy group that substitutes at least one hydrogen atom of the phenyl group may be a methoxy group, an ethoxy group, or a propoxy group.
  • R 2 represents a hydrogen atom, a phenyl group, or an alkyl group.
  • the alkyl group may be a methyl group, an ethyl group, or a propyl group.
  • R 2 is preferably a hydrogen atom from the viewpoint of sufficiently increasing the activity and selectivity as a catalyst.
  • 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 and may have 1 to 3 carbon atoms.
  • R 9 and R 10 may be independently halogen atoms or alkyl groups, and R 9 and R 10 are halogen atoms. There may be.
  • the halogen atom may be a chlorine atom or a bromine atom.
  • R 9 and R 10 are halogen atoms, they may be the same halogen atom as X, or may be a halogen atom different from X.
  • L 1 represents a halogen atom or a water molecule. Of these, L 1 is preferably a halogen atom from the viewpoint of sufficiently increasing the activity and selectivity as a catalyst.
  • L 2 represents triphenylphosphine, pyridine, imidazole or dimethyl sulfoxide. Of these, L2 is preferably triphenylphosphine from the viewpoint of sufficiently increasing the activity and selectivity as a catalyst.
  • X represents a halogen atom. This halogen atom constitutes a ruthenium complex as an ion. X is, for example, a chlorine atom.
  • n represents 1 or 2. The oxidation number of Ru in the above general formulas (1), (2) and (3) is +2.
  • the ruthenium complex is useful, for example, as a catalyst for oxidizing a carbon-hydrogen bond. That is, these ruthenium complexes function as, for example, a catalyst for oxidizing a substrate having a carbon atom-hydrogen atom bond.
  • the substrate having the above bond can be oxidized to produce an oxygen-containing compound.
  • the oxygen-containing compound include a hydroxy compound and an oxo compound. In hydroxy compounds, the oxygen atom in the hydroxy group may be labeled with 17 O or 18 O. In oxo compounds, the oxygen atom of the oxo group may be labeled with 17 O or 18 O.
  • the oxygen-containing compound may be a carbonyl compound having a carbonyl group, or may be a ketone compound having a ketone group. Again, the oxygen atoms in the carbonyl and ketone groups may be labeled with 17 O or 18 O.
  • the oxidant is produced by using a hypervalent iodine compound having an ester structure and labeled water labeled with at least one oxygen isotope selected from the group consisting of 17 O or 18 O as a raw material for the oxidant. ..
  • a hypervalent iodine compound having an ester structure and labeled water labeled with at least one oxygen isotope selected from the group consisting of 17 O or 18 O as a raw material for the oxidant. ..
  • Such an oxidizing agent can also be referred to as an oxidizing agent for labeling with an oxygen isotope.
  • the oxygen-containing compound obtained by oxidizing a substrate having a carbon atom-hydrogen atom bond is at least one oxygen isotope selected from the group consisting of 17 O and 18 O. Will be labeled.
  • the method for producing an oxidizing agent for labeling may include a step of reacting the hypervalent iodine compound with the labeled water.
  • Labeling with an oxygen isotope proceeds by the coexistence of the catalyst and an oxidizing agent produced from a hypervalent iodine compound having an ester structure and labeled water.
  • the hypervalent iodine compound having an ester structure can activate the labeled water in the reaction system. Therefore, it has a function of promoting oxidation of the substrate by 17 O or 18 O in the coexistence of a catalyst. From the viewpoint of further promoting such a function, the hypervalent iodine compound having an ester structure may have one or more aromatic rings. Since such a hypervalent iodine compound has a strong electron-donating property, it can promote the oxidation of a substrate having an electron-withdrawing property.
  • the hypervalent iodine compound having an ester structure which is a raw material for an oxidizing agent, may contain a compound represented by the following general formula (4).
  • R 3 and R 4 each independently represent a monovalent group having a hydrogen atom, an alkyl group, or an aromatic ring.
  • R 5 represents a monovalent group having an aromatic ring.
  • R 3 and R 4 are alkyl groups, at least one hydrogen atom of the alkyl group may be substituted with a functional group.
  • R 3 , R 4 and R 5 may each have a benzene ring.
  • R 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.
  • the substituted phenyl group examples include those in which at least one hydrogen atom in the phenyl group (benzene ring) is substituted with a hetero atom, a halogen atom, a hydroxy group, a nitro group, or an organic group different from these. At least one hydrogen on the aromatic ring in at least one of R 3 , R 4 and R 5 in the above general formula (4) may be substituted with a halogen atom.
  • the hypervalent iodine compound may contain a compound represented by the following general formula (5).
  • R6 , R7 and R8 represent heteroatoms, and k1, k2 and k3 represent integers of 0 to 5.
  • the bond ends indicated by * in R6 , R7 and R8 are bonded to carbon atoms constituting the benzene ring and replace hydrogen atoms in the benzene ring.
  • the plurality of R6s may be the same as each other or may be different from each other.
  • the plurality of R7s may be the same as each other or may be different from each other.
  • the plurality of R8s may be the same as each other or may be different from each other.
  • R6 , R7 and R8 may be the same as each other or may be different from each other.
  • k1, k2 and k3 may be the same as each other or may be different from each other.
  • R 6 and R 7 may be halogeno groups.
  • the halogeno group in R 6 and R 7 may be a fluoro group (—F) or a chloro group (—Cl) independently of each other.
  • k1 and k2 may be independently 1 to 5, may be 2 to 5, and may be 3 to 5. Further, k3 may be 0.
  • an oxidizing agent generated in the system from a superatomic iodine compound having an ester structure and labeled water oxidizes a carbon-hydrogen bond in the substrate to hydroxy to a carbon atom.
  • An oxygen-containing compound to which a group or an oxo group is bonded is obtained.
  • the oxygen-containing compound may contain at least one of an alcohol, a ketone, and an aldehyde. The mechanism of the reaction is presumed to be labeled with 17 O or 18 O by oxidizing the carbon atom of the substrate with the generated oxidizing agent.
  • a labeled compound labeled with 17 O or 18 O (labeled oxygen-containing compound) can be obtained.
  • the labeled water commercially available oxygen 17 labeled water or oxygen 18 labeled water can be used. Further, if necessary, oxygen 17-labeled water and mixed labeled water of oxygen 18-labeled water may be used to label with both 17 O and 18 O.
  • the amount of labeled water used may be 1 to 10 equivalents or 1 to 4 equivalents with respect to the substrate. Even if the amount of labeled water used is reduced in this way, the labeling rate can be sufficiently increased.
  • the labeling rate by at least one selected from the group consisting of 17 O and 18 O may be 60 atom% or more, 80 atom% or more, and 90 atom% or more.
  • FIG. 1 shows an example of a mechanism for producing an alcohol, which is a kind of hydroxy compound, from a substrate containing a tertiary carbon atom by using the above-mentioned ruthenium complex as an oxidation catalyst.
  • the mechanism of alcohol production is not limited to this example.
  • an oxidizing agent produced from a hypervalent iodine compound having an ester structure and labeled water, and a ruthenium complex (LM n : L is a ligand, M is ruthenium, and n is 1 or 2).
  • a ruthenium complex (LM n : L is a ligand, M is ruthenium, and n is 1 or 2).
  • tetrachloroethane can be used as the solvent.
  • an acid may be used together with the above-mentioned oxidizing agent. Examples of the acid include acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, pentafluorobenzoic acid and the like.
  • step II the ruthenium-oxo bond and the substrate containing the tertiary carbon atom come into contact with each other to desorb a hydrogen atom from the substrate, and a ruthenium-hydroxy bond (including 18 O) is generated with the substrate radical.
  • R 1 , R 2 and R 3 in the substrate may be different from each other or may be the same. At least two selected from the group consisting of R 1 , R 2 and R 3 may be combined to form a ring.
  • the substrate may be a hydrocarbon having 5 to 30 carbon atoms, an oxygen-containing hydrocarbon, or a sugar 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 or an aromatic.
  • the functional group include a hydroxy 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, an ester group and the like.
  • the substrate may be a prohormone.
  • step III the hydroxy group (including 18 O) bonded to ruthenium is bonded to the substrate radical to obtain a labeled compound.
  • the ruthenium complex is then used again as a catalyst.
  • 18 O is shown as an oxygen isotope in FIG. 1, it may be labeled with 17 O using oxygen 17-labeled water. Both 17 O and 18 O may be labeled with mixed labeled water of oxygen 17 labeled water and oxygen 18 labeled water.
  • the hydroxy compound is obtained, but another compound (for example, an oxo compound) may be obtained by changing the substrate or adjusting the reaction conditions.
  • the sugar when the substrate contains a sugar, the sugar may be any of monosaccharides, disaccharides, and polysaccharides.
  • monosaccharides include triose sugar, four-carbon sugar, five-carbon sugar, and six-carbon sugar (hexose).
  • the six charcoal sugar may be aldohexose or ketohexose. 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 the present embodiment can label a substrate containing any of these.
  • D-mannose can be labeled with 18 O by the following scheme, as shown in the examples.
  • the following scheme shows an example of labeling the hydroxy group at the 3-position with 18 O, but D-mannose may be labeled with 17 O, or both 17 O and 18 O in the same manner.
  • Examples of the mannose derivative derived from D-mannose include the compounds (A), (B) and (C) in the above scheme.
  • Compound (A) (1,6-anhydro-4-O-methyl-2,3-O-isopropylidene- ⁇ -D-mannopyranose)
  • compound (B) (1R, 2R, 4R, 5R) -4-Hydroxy-2-methoxy-6,8-dioxabicyclo [3.2.1] octane-3-one) and the compound of (C) (1,6-anhydro-4-O-methyl-).
  • ( ⁇ -D-mannopyranose) are all useful compounds for obtaining D-mannose labeled with an oxygen isotope (O 17 O or 18 O).
  • the compound (C) is more stable than the compound (B). Therefore, by synthesizing the mannose derivative (C) from the mannose derivative (A) in one pot, the labeling rate of D-mannose with an oxygen isotope can be increased
  • the compound (B) does not have to be labeled with an oxygen isotope.
  • Compounds not labeled with oxygen isotopes [(1R, 2R, 4R, 5R) -4-hydroxy-2-methoxy-6,8-dioxabicyclo [3.2.1] octane-3-one)] Is as shown in the following formula (8) (Me represents a methyl group).
  • This compound can be used, for example, as a reagent.
  • This compound may be used to synthesize D-mannose.
  • the compound of the formula (8) can be synthesized from the derivative (A) using ordinary water instead of labeled water.
  • the target oxygen isotope-labeled compound can be obtained in a high yield while reducing the amount of labeled water used. Therefore, the rare labeled water can be effectively used.
  • the labeled compound thus obtained can be used as a labeled molecular probe.
  • the labeled compound can be used for measurements by 17 O Nuclear Magnetic Resonance Spectrum (NMR) and Imaging (MRI). By such measurement, an object such as a cell can be visualized. Further, if a sugar labeled with an oxygen isotope is used, the cell tissue can be observed with an isotope microscope or the like.
  • the labeling method (oxygen isotope labeling method) and the labeling compound (oxygen isotope labeling compound) of the present embodiment can greatly expand the application range of the labeling utilization technique.
  • the amino acid ester compound represented by the general formula (iii) is reacted with the methylpyridine compound represented by the general formula (iv) and the amine compound represented by the general formula (v). It has a first step of synthesizing a ligand.
  • R 2 is the same as R 2 in the general formulas (1), (2) and (3) of the ruthenium complex described above.
  • R 3 represents an alkyl group having 1 to 3 carbon atoms.
  • R3 is , for example, a methyl group.
  • Z is a halogen atom.
  • the methylpyridine compound is, for example, chloromethylpyridine.
  • R 1 is the same as R 1 in the general formulas (1), (2) and (3) of the ruthenium complex described above.
  • the ligand is reacted with the ruthenium compound to form a trans-type ruthenium complex represented by the general formula (1) and a cis-type ruthenium complex represented by the general formula (2).
  • a second step is performed to obtain a ruthenium complex containing at least one selected from the group.
  • Examples of the ruthenium compound include ruthenium (II) chloride and a complex having dimethyl sulfoxide or triphenylphosphine as a ligand.
  • Examples of such a complex include dichlorotetrakis (dimethyl sulfoxide) ruthenium (II) and tris (triphenylphosphine) ruthenium (II) dichloride.
  • the second step may be carried out under heating and reflux using an alcohol such as ethanol as a solvent.
  • a step of separating the trans-type ruthenium complex represented by the general formula (1) and the cis-type ruthenium complex represented by the general formula (2) may be performed.
  • This step may be performed, for example, by column chromatography.
  • a trans-type ruthenium complex represented by the general formula (1) and a cis-type ruthenium complex represented by the general formula (2) can be obtained.
  • the ruthenium complex represented by the general formula (3) may be synthesized by the same method as the ruthenium complex of the general formulas (1) and (2), or may be synthesized by the method described in Examples. The method described in the examples may be appropriately modified based on the above-mentioned description.
  • the ligand was synthesized by the following reaction formula (1c) under an atmospheric atmosphere at room temperature.
  • 678.7 mg (2.638 mmol) of bis (pyridine-2-ylmethyl) glycine obtained by the above reaction formula (1b) 10 ml of 2-propanol, 270.2 mg (2.902 mmol) of aniline, and 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride 762.22 mg (2.902 mmol) was added. Then, the mixture was stirred at room temperature for 20 hours. After filtering the obtained mixed solution, the light component was distilled off with a rotary evaporator to obtain a product.
  • 2- (bis (pyridin-2-ylmethyl) amino) -N-phenylacetamide represented by the formula (E) of the reaction formula (1c) was found. It was confirmed that it was obtained (yield: 652.6 mg, 1.963 mmol, yield: 74.42%).
  • FIG. 3 is a diagram showing the results of single crystal structure analysis of a trans-type ruthenium complex.
  • FIG. 4 is a diagram showing the results of single crystal structure analysis of a trans-type ruthenium complex viewed from an angle different from that of FIG.
  • FIG. 5 is a diagram showing the results of single crystal structure analysis of a cis-type ruthenium complex.
  • FIG. 6 is a diagram showing the results of single crystal structure analysis of a cis-type ruthenium complex viewed from an angle different from that of FIG.
  • the yield of the trans-type ruthenium complex (MW: 766.09690) was 17.6 mg (23.0 ⁇ mol), and the yield was 23.0%.
  • the yield of the cis-type ruthenium complex (MW: 766.09690) was 28.8 mg (37.6 ⁇ mol), and the yield was 37.6%.
  • 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 hydrogen carbonate solution (20 mL) and saturated aqueous sodium chloride solution (20 mL). The obtained solution was dried using sodium sulfate, and the solvent was distilled off using a rotary evaporator to obtain a reaction mixture.
  • FIG. 7 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of the above formula (V).
  • FIG. 8 is a diagram showing the results of single crystal structure analysis of the ruthenium complex of the above formula (V) when viewed from an angle different from that of FIG. 7.
  • Example 2-1 ⁇ Hydroxylation>
  • R of the formula [IV] is a 2,6-dimethylphenyl group
  • the reaction temperature is 35 ° C. under a nitrogen stream.
  • hydroxyalysis of adamantane represented by the following formula (2-1) was carried out. Specifically, 27.2 mg (0.20 mmol) of adamantane and 3.18 mg (4.0 ⁇ mol) of the ruthenium complex of the formula [IV] were added to a 5 mL Schlenk tube.
  • the carboxylic acid and the 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 obtained product was analyzed by 1 H-NMR, it was confirmed that the target product, adamantane-1-ol (21.9 mg, yield: 71%) was obtained.
  • FIG. 9 is an analysis result by a time-of-flight mass spectrometer.
  • Example 2-2 ⁇ Hydroxylation> Using the ruthenium complex of the formula [IV] obtained according to Example 1-1 (R of the formula [IV] is a 2,6-dimethylphenyl group) as a catalyst, the reaction temperature is 35 ° C. under a nitrogen stream. Then, hydroxylation of 3,7-dimethyloctyl acetate was carried out according to the following formula (2-2). Specifically, a ruthenium complex (3.18 mg, 4.0 ⁇ mol) of the formula [IV] was added to a 5 mL Schlenk tube, the inside of the Schlenk tube was replaced with nitrogen, and then 1,1,2,2-tetrachloroethane was added to 0.
  • FIG. 10 is an analysis result by a time-of-flight mass spectrometer.
  • Example 2-3 ⁇ Hydroxylation> Example 2-2, except that the ruthenium complex of the formula (V) obtained in Example 1-2 was used as a catalyst instead of the ruthenium complex of the formula [IV] obtained according to Example 1-1.
  • the reaction and purification were carried out in the same manner.
  • the product obtained in the same manner as in Example 2-2 was analyzed by 1 H-NMR, the target product, 7-hydroxy-3,7-dimethyloctyl acetate (28.4 mg, yield: 65%) was analyzed. ) Was obtained.
  • FIG. 11 is an analysis result by a time-of-flight mass spectrometer.
  • Example 2-4 ⁇ Hydroxylation> Using the ruthenium complex of the formula [IV] obtained according to Example 1-1 (R of the formula [IV] is a 2,6-dimethylphenyl group) as a catalyst, the reaction temperature was 35 ° C. under a nitrogen stream. Hydroxylation of 4-methylpentylbenzoate represented by the following formula (2-4) was performed. Specifically, 3.18 mg (4.0 ⁇ mol) of the ruthenium complex of the formula [IV] was added to a 5 mL Schlenk tube, nitrogen was substituted in the Schlenk tube, and then 1,1,2,2-tetrachloroethane was added to 0.
  • the reaction mixture was subjected to short column chromatography (basic silica gel, developing solvent: ethyl acetate) to remove the carboxylic acid and the catalyst, and then the solvent was distilled off using a rotary evaporator.
  • the obtained product was analyzed by 1 H-NMR, it was confirmed that the target product 4-hydroxy-4-methylpentylbenzoate (34.5 mg, yield: 77%) was obtained.
  • FIG. 12 is an analysis result by a time-of-flight mass spectrometer.
  • 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 attached to the flask, and 5.50 g (28) of p-toluenesulfonyl chloride was added to the dropping funnel. .9 mmol, 1.3 equivalents) was added and nitrogen substitution was performed. 40 mL of pyridine was added to the flask and 8 mL of pyridine was added to the dropping funnel to dissolve each of them, and then the flask was immersed in an ice water bath and cooled to 0 ° C.
  • the mixture dried under reduced pressure was suspended in 100 mL of ethanol, filtered, and the remaining solid was washed 3 times with 30 mL of ethanol.
  • the solvent was distilled off from the obtained filtrate using a rotary evaporator, and the mixture was dried under reduced pressure.
  • the mixture thus obtained contained 1,6-anhydro- ⁇ -D-mannopyranose represented by the formula (VII) of the following reaction formula (3-0). This mixture was used in the next reaction without purification.
  • the obtained product was analyzed by 1 H-NMR, it was the target product (1R, 2R, 4R, 5R) -4-hydroxy-2-methoxy-6,8-dioxabicyclo [3.2. 1] It was confirmed that octane-3-one (11.3 mg, yield: 32%) was obtained.
  • FIG. 13 is an analysis result by a time-of-flight mass spectrometer.
  • FIG. 14 is the analysis result of 1 H-NMR, and
  • FIG. 15 is the analysis result of two-dimensional NMR.
  • FIG. 16 shows the analysis result by BCM of 13 C-NMR, and
  • FIG. 17 shows the analysis result by the DEPT method of 13 C-NMR.
  • Example 3-2 ⁇ Oxolation ⁇ Hydroformylation>
  • One-pot synthesis represented by the following formula (3-2) was performed.
  • the reaction temperature was 35 ° C. under a nitrogen stream.
  • oxidative deprotection of 1,6-anhydro-4-O-methyl-2,3-O-isopropyridene- ⁇ -D-mannopyranose was performed.
  • 1,6-anhydro-4-O-methyl- ⁇ -D-mannopyranose (4.1 mg, yield: 12%) was obtained.
  • a time-of-flight mass spectrometer (ESI-TOF-MS)
  • the oxygen-18 isotope ( 18O ) of 1,6-anhydro-4-O-methyl- ⁇ -D-mannopyranose was labeled.
  • the conversion rate (concentration rate) was 82 atom%.
  • FIG. 18 is an analysis result by a time-of-flight mass spectrometer.
  • FIG. 19 shows the analysis result of 1 H-NMR.
  • 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. These could be synthesized by treating the compound of the formula (I) of the reaction formula (1a) in Example 1-1 with aqueous ammonia.
  • Examples 4-2 to 4-8) A trans-type ruthenium complex and a cis-type ruthenium complex in which R in the general formulas (10) and (11) is a substituent shown in FIG. 20 were obtained, respectively. These were synthesized by using the amine compounds shown in FIG. 20 instead of the aniline of the formula (II) of the reaction formula (1c) in Example 1-1.
  • the wavy line in FIG. 20 shows the main body of the ruthenium complex to which R is bonded in the general formulas (10) and (11).
  • Me indicates a methyl group.
  • An eggplant-shaped flask was filled 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.
  • 771 mg (3.90 mmol, 1.3 equivalent) of 2-chloro-N- (2,6-dimethylphenyl) acetamide, 539 mg (3.90 mmol, 1.3 equivalent) of potassium carbonate, and 245 mg (1.50 mmol, 0.5 eq) of potassium iodide was added.
  • the reaction solution was obtained by stirring for 4 hours under heating and reflux.
  • FIG. 21 is the analysis result of 1 H-NMR of the ligand 2.
  • FIG. 22 shows the analysis result of 13 C-NMR of the ligand 2.
  • FIG. 23 shows the analysis result of the ligand 2 by the time-of-flight mass spectrometer.
  • the obtained product was analyzed by 1 H-NMR and a time-of-flight mass spectrometer. When these analysis results were collated with the structures of the ruthenium complexes obtained in Examples 1-1 and 1-2, the ruthenium complex of the following formula (X) (168 mg, 195 ⁇ mol, yield: 23.9%) was collated. It was confirmed that.
  • the reaction formula is as shown in the following formula (5-9).
  • FIG. 24 is the analysis result of 1 H-NMR of the ruthenium complex of the formula (X).
  • FIG. 25 shows the analysis result of the ruthenium complex of the formula (X) by the time-of-flight mass spectr
  • Examplementation 5-2 ⁇ Synthesis of ligand 3> Methyl 4-bromo-2-pyridinecarboxylate was used instead of methyl 4-chloro-2-pyridinecarboxylate in the same manner as in Example 5-1 by the reaction route represented by the following formula (5-10). -(Bis ((4-bromo-2-pyridyl) methyl) amino) -N- (2,6-dimethylphenyl) acetamide (ligand 3) was synthesized.
  • FIG. 26 is the analysis result of 1 H-NMR of the ligand 3.
  • FIG. 27 is the analysis result of 13 C-NMR of the ligand 3.
  • FIG. 28 shows the analysis result of the ligand 3 by the time-of-flight mass spectrometer.
  • FIG. 29 is the analysis result of 1 H-NMR of the ruthenium complex of the formula (XI).
  • FIG. 30 shows the analysis result of the ruthenium complex of the formula (XI) by the time-of-flight mass spectrometer.
  • Examplementation 6-1 ⁇ Hydroxylation>
  • iodobenzene (dipentafluorobenzoate) (123.3 mg, 0.2 mmol)
  • H2O 3.6 mg, 0. 2 mmol
  • tetrachloroethane (0.25 mL) was added and dissolved, and the temperature was adjusted to 35 ° C.
  • the cis-type ruthenium catalyst (2.0 ⁇ mol, 2 mol%) obtained in Example 4-8 was added to the solution thus obtained to carry out hydroxylation represented by the following formula (6-1). ..
  • Examplementation 6-2 The proportion of products was tracked in the same manner as in Example 6-1 except that the ruthenium catalyst of the above formula (X) was used in place of the cis-type ruthenium catalyst obtained in Example 4-8. The results are as shown in FIG. 31 and Table 1.
  • Examplementation 6-3 The proportions of products were tracked in the same manner as in Example 6-1 except that the ruthenium catalyst of the above formula (XI) was used in place of the cis-type ruthenium catalyst obtained in Example 4-8. The results are as shown in FIG. 31 and Table 1.
  • Table 1 shows the conversion of the substrate after 6 hours or 12 hours and the yield of each product.
  • the relative ratio ([S] / [S 0 ]) of the substrate concentration [S] obtained from the conversion efficiency at each reaction time and the initial concentration [S 0 ] of the substrate was calculated.
  • FIG. 31 is a graph showing the change over time in the natural logarithm of the relative ratio. The slope in this graph indicates the reaction rate. From the results shown in FIG. 31 and Table 1, the ruthenium compounds of the above formula (X) and the above formula (XI) have more than twice the catalytic activity of the cis-type ruthenium compound obtained in Example 4-8. It was confirmed that
  • a labeling method using an oxygen isotope which can obtain a labeled compound in a high yield without using excess oxygen isotope-labeled water.
  • an oxygen isotope-labeled oxidant, a ruthenium complex and a catalyst that can be suitably used for such a labeling method.
  • labeled compounds labeled with oxygen isotopes can be provided.

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