JP2019178128A - Oxygen isotope-labeled compound, method for producing oxygen isotope-labeled compound, oxygen isotope-labeled urea derivative compound, and method for producing oxygen isotope-labeled urea derivative compound - Google Patents

Abstract

To provide a novel oxygen isotope-labeled compound in which a carbonyl site is substituted with heavy oxygen, and a method for producing the same.SOLUTION: The present invention provides a method for producing an oxygen isotope-labeled compound represented by formula (1), including reacting dichloromethylenedimethylammonium chloride and a compound represented by R-OH, and oxygen isotope-labeled water (HY). (Ris an aryl group substituted with a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group, a C1-C4 fluoroalkyl group or the like, or an unsubstituted aryl group; a heteroaryl group substituted with a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group, a C1-C4 fluoroalkyl group or the like, or an unsubstituted heteroaryl group; Y isO orO).SELECTED DRAWING: None

Description

  The present invention relates to an oxygen isotope labeled compound, a method for producing an oxygen isotope labeled compound, an oxygen isotope labeled urea derivative compound, and a method for producing an oxygen isotope labeled urea derivative compound.

  A stable isotope compound is often used as an internal standard substance of a mass spectrometer or a tracer of internal metabolism. Conventionally, deuterium is often used as a stable isotope element, but there are problems such as when deuterium substitution is difficult depending on the compound, or when the number of isotope labels is insufficient by deuterium substitution alone. Therefore, the above-described problem has been solved by introducing a deuterium-labeled carbonyl group and utilizing it.

Here, the technique of patent documents 1-3 is known regarding the labeled compound containing an oxygen isotope.
Specifically, Patent Document 1 discloses a deoxygenated compound that synthesizes an oxygen isotope-labeled organic carbonyl compound by reacting water labeled with an oxygen isotope with an amine compound in the presence of a dehydrogenation catalyst. A method for producing a carbonyl compound is disclosed.
Patent Document 2 discloses an oxygen isotope labeling method in which an active ester of a carboxyl group-containing compound (carboxylic acid) is reacted with H ₂ ¹⁷ O or H ₂ ¹⁸ O in the presence of an active agent. ing.
Furthermore, Patent Document 3 discloses an oxygen isotope substitution method for an oxide material in which oxygen in an oxide material that is an inorganic compound is substituted with heavy oxygen in a heavy oxygen gas atmosphere at a high temperature.

JP 2006-008591 A JP 2006-008666 A Japanese Patent No. 4444131

However, in the hydrolysis methods disclosed in Patent Documents 1 and 2 described above, the oxygen isotope ¹⁸ O ( ¹⁷ O is used ^under the condition of “raw material compound: water ( ¹⁸ O ( ¹⁷ O) labeled compound) = 1: 1”. ) Is difficult to proceed. Further, in the hydrolysis method, light water in the atmosphere is mixed, and there is a possibility that the concentration of ¹⁸ O ( ¹⁷ O) in the target compound is lowered. Moreover, as a method for preventing this, a reaction in an apparatus replaced with an inert gas can be considered. However, there is a problem that a large-scale apparatus is required and labor is required. In addition, the hydrolysis methods disclosed in Patent Documents 1 and 2 have a problem that the raw material compounds are limited.

Furthermore, in the methods disclosed in Patent Documents 1 to 3, since a large amount of oxygen isotope raw material serving as a labeling raw material is required, production cost has been a problem.
Furthermore, many of pharmaceuticals, agricultural chemicals and metabolites in the body have a carbonyl moiety, but there are few kinds of commercially available ¹⁸ O-labeled compounds in which the carbonyl moiety is substituted with deuterium, and more labeled compounds are desired. It was.

  This invention is made | formed in view of the said situation, Comprising: It makes it a subject to provide the novel oxygen isotope labeling compound by which the carbonyl site | part was substituted with deuterium, and its manufacturing method.

  Furthermore, this invention makes it a subject to provide the oxygen isotope labeled urea derivative compound using the said oxygen isotope labeled compound, and its manufacturing method.

In order to solve the above problems, the present invention comprises the following arrangement.
[1] An oxygen isotope labeled compound represented by the following formula (1).
In the above formula (1), Y is ¹⁷ O or ¹⁸ O.
Further, the above formula (1), _{R 1,} (A) an aryl group, (B) heteroaryl, (C) a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms , A nitro group, a fluoroalkyl group having 1 to 4 carbon atoms, a halogen, a cyano group, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, an aryl group substituted with a dialkylamino group having 2 to 8 carbon atoms, or (D) The hydrogen atom is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a fluoroalkyl group having 1 to 4 carbon atoms, a halogen, a cyano group, an amino group, or 1 to 1 carbon atom. 4 is a heteroaryl group substituted by a monoalkylamino group having 4 carbon atoms and a dialkylamino group having 2 to 8 carbon atoms.
[2] An oxygen isotope labeled compound represented by the following formula (2).
In the above formula (2), Y is ¹⁷ O or ¹⁸ O.
Further, the formula (2), _{R 2} is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a cyano group, an amino group, 1 to carbon atoms 4 monoalkylamino groups or C2-8 dialkylamino groups.
[3] The oxygen isotope labeled compound according to [1] or [2], wherein the oxygen isotope enrichment is not less than a natural abundance ratio.
[4] A method for producing an oxygen isotope-labeled compound according to [1],
A compound represented by the following formula _(3), a compound represented by R 1 -OH, oxygen isotope labeled water _(H 2 Y; Y ^is a is ¹⁷ O or ¹⁸ O) is reacted with an oxygen isotope labeled Compound production method.
In the above formula (3), _{R 3} is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
[5] A method for producing an oxygen isotope-labeled compound according to [2],
Oxygen isotope labeling in which a compound represented by the following formula (3), a compound represented by the following formula (4), and oxygen isotope labeled water (H ₂ Y; Y is ¹⁷ O or ¹⁸ O) are reacted. Compound production method.
In the above formula (3), _{R 3} is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
In the above formula (4), _{R 2} is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a cyano group, an amino group, having 1 to 4 carbon atoms Either a monoalkylamino group or a dialkylamino group having 2 to 8 carbon atoms.
[6] An oxygen isotope-labeled urea derivative compound represented by the following formula (5).
In the above formula (5), Y is ¹⁷ O or ¹⁸ O.
In the above formula (5), R ₄ and R ₅ are a hydrogen atom or an organic group.
[7] A method for producing an oxygen isotope-labeled urea derivative compound according to claim 6,
A method for producing an oxygen isotope-labeled urea derivative compound, wherein the oxygen isotope-labeled compound according to claim 1 or 2 is reacted with an amine compound represented by the following formula (6).
In the above formula (6), _{R 4} and _{R 5} are hydrogen atom or an organic group.

  According to the oxygen isotope labeled compound of the present invention and the method for producing the same, a novel oxygen isotope labeled compound in which the carbonyl moiety is substituted with deuterium and a method for producing the same can be provided.

  Moreover, according to this invention, the oxygen isotope labeled urea derivative compound using the said oxygen isotope labeled compound and its manufacturing method can be provided.

1 represents the ¹ H-NMR spectrum of diphenyl carbonate ¹⁸ O obtained in Example 1. The ¹³ C-NMR spectrum of diphenyl carbonate ¹⁸ O obtained in Example 1 is shown. The upper part represents the mass spectrum of diphenyl carbonate 18O obtained in Example 1, and the lower part represents the mass spectrum of unlabeled diphenyl carbonate.

<First Embodiment>
First, the configuration of the oxygen isotope labeled compound according to the first embodiment to which the present invention is applied will be described.
The oxygen isotope labeled compound (I) of this embodiment is represented by the following formula (1).

In the above formula (1), Y is ¹⁷ O or ¹⁸ O.
Further, in the above formula (1), R ₁ is an aryl group or a heteroaryl group. Specifically, R ₁ is (A) an aryl group, (B) a heteroaryl group, (C) a hydrogen atom is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, C1-C4 fluoroalkyl group, halogen, cyano group, amino group, C1-C4 monoalkylamino group, aryl group substituted with C2-C8 dialkylamino group, or (D) hydrogen An atom is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a fluoroalkyl group having 1 to 4 carbon atoms, a halogen, a cyano group, an amino group, or a monoalkyl having 1 to 4 carbon atoms. An amino group is a heteroaryl group substituted with a dialkylamino group having 2 to 8 carbon atoms.

  The aryl group is not particularly limited as long as it does not impede the effects of the present invention. For example, a phenyl group, a methoxyphenyl group, a nitrophenyl group, a cyanophenyl group, an aminophenyl group, a tolyl group, t- Examples thereof include those having one aromatic ring such as butylphenyl group and fluorophenyl group, and those having two or more aromatic rings such as naphthalene, anthracene and phenanthrene. Among these, those having one aromatic ring are preferable.

  The heteroaryl group is not particularly limited as long as it does not hinder the effects of the present invention, and examples thereof include pyridine, pyrrole, and thiophene.

Aryl or heteroaryl group R ₁ and R ₂ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a fluoroalkyl group having 1 to 4 carbon atoms, halogen , A cyano group, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, and a dialkylamino group having 2 to 8 carbon atoms.

That is, R ₁ is any _one of the following (A) to (D).
(A) aryl group (B) heteroaryl group (C) a hydrogen atom is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a fluoroalkyl group having 1 to 4 carbon atoms, a halogen , A cyano group, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, an aryl group (D) substituted with a dialkylamino group having 2 to 8 carbon atoms, an alkyl group having 1 to 4 carbon atoms, carbon An alkoxy group having 1 to 4 carbon atoms, a nitro group, a fluoroalkyl group having 1 to 4 carbon atoms, a halogen, a cyano group, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, and a dialkylamino group having 2 to 8 carbon atoms. Substituted heteroaryl groups

In the present specification, the “oxygen isotope-labeled compound” means the abundance ratio of the oxygen isotope ( ¹⁷ O or ¹⁸ O) in the oxygen atom at the site represented by “Y” in the formula (1). It means that the natural abundance ratio is exceeded. Note that the abundance ratios of the oxygen isotope ¹⁷ O or ¹⁸ O in nature are 0.037 atom% and 0.204 atom%, respectively.

  The oxygen isotope-labeled compound (I) of the present embodiment provides the target compound at a high oxygen isotope enrichment when used as an oxygen isotope labeling reagent, so that the oxygen isotope enrichment is 5 atom% or more. It is preferably 50 atom% or more, more preferably 90 atom% or more.

  Specific structures of the oxygen isotope labeled compound (I) of the present embodiment include the following formulas (7) to (11).

Next, a method for producing the oxygen isotope labeled compound (I) of this embodiment will be described.
The method for producing the oxygen isotope labeled compound (I) of the present embodiment includes a compound represented by the following formula (3), a compound represented by R ₁ —OH, oxygen isotope labeled water (H ₂ Y; Y is ¹⁷ O or ¹⁸ O) as raw materials, and these raw materials are reacted in an organic solvent.

In the above formula (3), _{R 3} is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Moreover, as a C1-C4 alkyl group, a methyl group and an ethyl group are mentioned, for example.

  Moreover, the manufacturing method of oxygen isotope labeled compound (I) of this embodiment can be shown like following Reaction formula (A).

  The organic solvent is not particularly limited as long as it can completely or partially dissolve the compound of the above formula (3). Examples of such an organic solvent include nonpolar solvents such as dichloromethane and chloroform.

Although the order in which the raw materials are charged into the organic solvent is not particularly limited, it is preferable that the compound represented by R ₁ —OH, the compound represented by the above formula (3), and oxygen isotope-labeled water be used in this order. Moreover, all the raw materials may be charged simultaneously into the organic solvent.

The amount of the compound represented by the above formula (3) with respect to the total amount of the compound represented by R ₁ —OH is not particularly limited as long as it is a stoichiometric amount or more, but a range of 1.0 to 2.0 times is preferable, A range of 1.05 to 1.5 times is more preferable. Within the preferable range, the yield of the oxygen isotope labeled compound (I) of the present embodiment can be improved without wasting raw materials.

The amount of oxygen isotope-labeled water used relative to the total amount of the compound represented by R ₁ -OH is not particularly limited as long as it is a stoichiometric amount or more, but is preferably in the range of 1.0 to 2.0 times. A range of 0.05 to 1.5 times is more preferable. Within the preferable range, the yield of the oxygen isotope labeled compound (I) of the present embodiment can be improved without wasting raw materials.

  In the method for producing the oxygen isotope labeled compound (I) of the present embodiment, the reaction conditions are not particularly limited, but the temperature range is 20 to 100 ° C., the reaction time is 30 minutes to 5 hours. be able to.

<Second Embodiment>
Next, the configuration of the oxygen isotope labeled compound according to the second embodiment to which the present invention is applied will be described.
The oxygen isotope labeled compound (II) of this embodiment is represented by the following formula (2).

In the formula (2), Y ^{is 17} O or ¹⁸ O.
Further, the formula (2), _{R 2} is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a cyano group, an amino group, 1 to carbon atoms 4 monoalkylamino groups or C2-8 dialkylamino groups.

  Specific examples of the halogen atom include chlorine, bromine, fluorine, and iodine atoms.

  The alkyl group is preferably a linear or branched chain having 1 to 4 carbon atoms, specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, A sec-butyl group and a tert-butyl group are mentioned.

  As the alkoxy group, those having 1 to 4 carbon atoms are preferable, and specifically, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, t-butoxy group. Is mentioned.

  The alkylamino group is preferably a monoalkyl quino group having 1 to 4 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms, specifically, a monomethylamino group, a dimethylamino group, a monoethylamino group, a diethylamino group. And diisopropylamino group.

  When the oxygen isotope labeled compound (II) of this embodiment is used as an oxygen isotope labeling reagent, the target compound can be obtained with a high oxygen isotope enrichment, so that the oxygen isotope enrichment is 5 atom% or more. It is preferably 50 atom% or more, more preferably 90 atom% or more.

  Specific structures of the oxygen isotope labeled compound (II) of the present embodiment include the following formulas (12) to (15).

Next, a method for producing the oxygen isotope labeled compound (II) of this embodiment will be described.
The method for producing the oxygen isotope-labeled compound (II) of the present embodiment includes the compound represented by the above formula (3), the compound represented by the following formula (4), the oxygen isotope labeled water ( H ₂ Y; Y is ¹⁷ O or ¹⁸ O), and these raw materials are reacted in an organic solvent.

In the formula (4), _{R 2,} like the _{R 2} in the formula (2), a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group , A cyano group, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, or a dialkylamino group having 2 to 8 carbon atoms.

  Moreover, the manufacturing method of oxygen isotope labeled compound (II) of this embodiment can be shown like following Reaction formula (B).

  The organic solvent is not particularly limited as long as it can completely or partially dissolve the compound of the above formula (3). Examples of such an organic solvent include nonpolar solvents such as dichloromethane and chloroform.

  The order in which the raw materials are introduced into the organic solvent is not particularly limited, but it is preferable that the compound represented by the above formula (4), the compound represented by the above formula (3), and oxygen isotope-labeled water be used in this order. Moreover, all the raw materials may be charged simultaneously into the organic solvent.

  Although the usage-amount of the compound shown to the said Formula (3) with respect to the compound shown to the said Formula (4) will not be specifically limited if it is more than a stoichiometric amount, the range of 1.0-2.0 times is preferable, and 1. The range of 05 to 1.5 times is more preferable. Within the above preferred range, the yield of the oxygen isotope labeled compound (II) of the present embodiment can be improved without wasting raw materials.

  The amount of oxygen isotope-labeled water used for the compound represented by the above formula (4) is not particularly limited as long as it is a stoichiometric amount or more, but is preferably in the range of 1.0 to 2.0 times, 1.05 The range of -1.5 times is more preferable. Within the above preferred range, the yield of the oxygen isotope labeled compound (II) of the present embodiment can be improved without wasting raw materials.

  Moreover, in the manufacturing method of oxygen isotope labeled compound (II) of this embodiment, although it does not specifically limit as reaction conditions, It is set as temperature range: 20-100 degreeC, reaction time: 30 minutes-5 hours. be able to.

<Third Embodiment>
Next, the configuration of the oxygen isotope labeled urea derivative compound oxygen isotope labeled compound according to the third embodiment to which the present invention is applied will be described.
The oxygen isotope labeled urea derivative compound of the present embodiment is represented by the following formula (5).

In the above formula (5), Y is ¹⁷ O or ¹⁸ O.
Further, in the above formula (5), _{R 4} and _{R 5} are hydrogen atom, or an organic group.
The organic group is not particularly limited, and can be appropriately selected according to a target compound into which an oxygen isotope ( ¹⁷ O or ¹⁸ O) is to be introduced. Specific examples of the organic group include a hydrocarbon group and a hetero atom-containing group. Furthermore, one or more hydrogen atoms contained in the above-described hydrocarbon group and heteroatom-containing group may be substituted with an arbitrary hydrocarbon group, heteroatom-containing group, halogen atom or the like.

  The oxygen isotope-labeled urea derivative compound of the present embodiment provides the target compound with a high oxygen isotope enrichment when used as an oxygen isotope labeling reagent. Therefore, the oxygen isotope enrichment is 5 atom% or more. It is preferably 50 atom% or more, more preferably 90 atom% or more.

  Specific examples of the oxygen isotope-labeled urea derivative compound of the present embodiment include the following formulas (16) to (17).

Next, the manufacturing method of the oxygen isotope labeled urea derivative compound of this embodiment is demonstrated.
The method for producing an oxygen isotope-labeled urea derivative compound of the present embodiment uses the oxygen isotope-labeled compound (I) of the first embodiment or the oxygen isotope compound (II) of the second embodiment as an oxygen isotope labeling reagent. Is. Specifically, the compound represented by the above formula (1) or the compound represented by the above formula (2) and the amine compound represented by the following formula (6) are reacted in a solvent in the presence of a base to obtain the above formula. The oxygen isotope labeled urea derivative compound shown in (5) is synthesized.

In the above formula (6), _{R 4} and _{R 5} are hydrogen atom, or an organic group. As said organic group, the same thing as shown to said Formula (5) can be used.

  In the method for producing an oxygen isotope labeled urea derivative compound of the present embodiment, when the oxygen isotope labeled compound (I) of the first embodiment is used as an oxygen isotope labeling reagent, It can be shown as the following reaction formula (C).

  In the method for producing an oxygen isotope-labeled urea derivative compound of the present embodiment, the oxygen isotope-labeled urea derivative compound is produced using the oxygen isotope-labeled compound (II) of the second embodiment as an oxygen isotope labeling reagent. In this case, it can be represented by the following reaction formula (D).

  The base is not particularly limited, and general organic bases and inorganic bases can be used. Among these bases, it is preferable to use a base that is more basic than the amine compound represented by the above formula (6). Specifically, sodium methoxide (NaOMe), potassium tertiary butoxide (tBuOK), sodium It is more preferable to use tertiary butoxide (tBuONa), diazabicycloundecene (DBU) or the like.

  The solvent is not particularly limited, and a general organic solvent can be used. As the organic solvent, it is preferable to use an aprotic polar solvent such as N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide or the like.

  The order in which the raw materials are added to the solvent is not particularly limited, but the order of the compound represented by the above formula (1) or (2), the amine compound represented by the above formula (6), and the base is preferable. Moreover, all the raw materials may be charged simultaneously into the organic solvent.

  Although the total usage-amount of the amine compound shown to the said Formula (6) with respect to the compound shown to the said Formula (1) or the said Formula (2) is more than a stoichiometric amount, it will not specifically limit, 1.0-1. A range of 5 times is preferable, and a range of 1.05 to 1.2 times is more preferable. Within the preferable range, the yield of the oxygen isotope-labeled urea derivative compound of the present embodiment is improved without wasting the compound represented by the above formula (1) or the above formula (2) as a raw material. Can do.

  The amount of the base used for the compound represented by the formula (1) or the formula (2) is not particularly limited as long as it is in the range of 0.01 to 100 times the stoichiometric amount, and is 0.05 to A range of 10 times is preferable, and a range of 0.05 to 2 times is more preferable. Within the preferable range, the yield of the oxygen isotope-labeled urea derivative compound of the present embodiment is improved without wasting the compound represented by the above formula (1) or the above formula (2) as a raw material. Can do.

  In the method for producing an oxygen isotope-labeled urea derivative compound of the present embodiment, the reaction conditions are not particularly limited, but the temperature range is 20 to 100 ° C. and the reaction time is 1 to 10 hours. it can.

  As described above, according to the oxygen isotope labeled compound (I) of the first embodiment and the oxygen isotope labeled compound (II) of the second embodiment, the novel oxygen isotope in which the carbonyl moiety is substituted with deuterium. Body labeled compounds can be provided.

  In addition, since the oxygen isotope labeled compound (I) of the first embodiment and the oxygen isotope labeled compound (II) of the second embodiment can be used as an oxygen isotope labeling reagent, pharmaceuticals, agricultural chemicals, body metabolites A compound having a carbonyl moiety such as can be easily labeled.

According to the production methods of the first and second embodiments, the oxygen isotope labeled compound (I) and the oxygen isotope labeled compound (II) can be produced by a simple method.
Moreover, according to the manufacturing method of 1st and 2nd embodiment, since it is the structure which reacts the compound used as a raw material, and oxygen isotope labeled water in an organic solvent, dilution of the concentration by mixing of light water arises Hateful.
Furthermore, according to the production methods of the first and second embodiments, the oxygen isotope enrichment of the oxygen isotope labeled compound (I) and the oxygen isotope labeled compound (II) can be appropriately selected.

Moreover, according to the manufacturing method of 1st and 2nd embodiment, it becomes possible to provide ¹⁸ O labeling compound with few commercial items easily.

  According to the oxygen isotope-labeled urea derivative compound of the third embodiment, many urea derivative compounds in which the carbonyl moiety is substituted with heavy oxygen can be provided.

  According to the method for producing an oxygen isotope-labeled urea derivative compound of the third embodiment, the oxygen isotope-labeled compound (I) of the first embodiment and the oxygen isotope-labeled compound (II) of the second embodiment are converted into oxygen isotopes. Since it is used as a labeling reagent, many compounds such as pharmaceuticals, agricultural chemicals, and in vivo metabolites can be easily labeled without requiring an excessive amount of heavy oxygen labeling compound.

  The technical scope of the present invention is not limited to the above embodiment, and various modifications can be made without departing from the spirit of the present invention.

Hereinafter, the effects of the present invention will be described in detail using specific examples.
Example 1
Dichloromethylenedimethyliminium chloride 1.62 g (10 mmol), phenol 1.88 g (20 mmol), H ₂ ¹⁸ O (98 atom% ¹⁸ O) 0.200 g (10 mmol) were added to a 50 mL eggplant flask and stirred. ) And then refluxed for reaction (see the following reaction formula (E)).
After the liquid obtained by the reaction was separated treatment, by solvent was concentrated under reduced pressure purified diphenyl carbonate ^{- 18} O (Yield: 1.55 g, yield: 72%, enrichment: ^{97.9atom% 18} O )

The obtained compound was subjected to NMR analysis. ^{The 1} H-NMR spectrum is shown in FIG. 1, and the ¹³ C-NMR spectrum is shown in FIG. As a result of mass spectrometry, the mass spectrum of diphenyl carbonate ¹⁸ O obtained in Example 1 is shown in the upper part of FIG. 3, and the mass spectrum of unlabeled diphenyl carbonate is shown in the lower part of FIG.

(Example 2)
Dichloromethylenedimethyliminium chloride 1.62 g (10 mmol), 4-methoxyphenol 2.49 g (20 mmol), H ₂ ¹⁸ O (98 atom% ¹⁸ O) 0. After adding 200 g (10 mmol), the reaction was carried out under reflux (see the following reaction formula (F)).
After separation processing liquid obtained by the reaction, by solvent was concentrated under reduced pressure Purification carbonate, bis (4-methoxyphenyl) ^{- 18} O (Yield: 2.15 g, yield: 78%, enrichment: 97.8 atom% ¹⁸ O) was obtained.

(Example 3)
Dichloromethylenedimethyliminium chloride 1.62 g (10 mmol), p-cresol 2.16 g (20 mmol), H ₂ ¹⁸ O (98 atom% ¹⁸ O) 0.200 g were added to a 50 mL eggplant flask and stirred. (10 mmol) was added, and the reaction was performed under reflux (see the following reaction formula (G)).
After separation processing liquid obtained by the reaction, by solvent was concentrated under reduced pressure Purification carbonate, bis (4-methylphenyl) ^{- 18} O (Yield: 1.81 g, yield: 74%, enrichment: 98.0 atom% ¹⁸ O) was obtained.

Example 4
Dichloromethylenedimethyliminium chloride 1.62 g (10 mmol), 4-nitrophenol 2.78 g (20 mmol), H ₂ ¹⁸ O (98 atom% ¹⁸ O) 0. After adding 200 g (10 mmol), the reaction was carried out under reflux (see the following reaction formula (H)).
After separation processing liquid obtained by the reaction, by solvent was concentrated under reduced pressure Purification carbonate, bis (4-nitrophenyl) ^{- 18} O (Yield: 1.68 g, yield: 55%, enrichment: 97.7 atom% ¹⁸ O) was obtained.

(Example 5)
Dichloromethylenedimethyliminium chloride 1.62 g (10 mmol), 3- (trifluoromethyl) phenol 3.24 g (20 mmol), H ₂ ¹⁸ O (98 atom% ¹⁸ ) were added to the 50 mL eggplant flask and stirred. O) 0.200 g (10 mmol) was added, and the reaction was performed under reflux (see the following reaction formula (I)).
After the liquid obtained by the reaction was separated treatment, by solvent was concentrated under reduced pressure Purification carbonate, bis (3- (trifluoromethyl) phenyl) ^{- 18} O (Yield: 2.14 g, yield: 61% Concentration: 97.7 atom% ¹⁸ O).

(Example 6)
Dichloromethylenedimethyliminium chloride 1.62 g (10 mmol), catechol 1.10 g (10 mmol), H ₂ ¹⁸ O (98 atom% ¹⁸ O) 0.200 g (10 mmol) were added to a 50 mL eggplant flask and stirred. ) And then refluxed for reaction (see the following reaction formula (J)).
After the liquid obtained by the reaction was separated treatment, by solvent was concentrated under reduced pressure Purification, catechol carbonate ^{- 18} O (Yield: 0.73 g, yield: 53%, enrichment: ^{98.1atom% 18} O )

(Example 7)
In a 10 mL eggplant flask, 1.08 g (5 mmol) of diphenyl carbonate ¹⁸ O, 0.98 g (5 mmol) of 5-amino-2-chlorobenzotrifluoride, 1,8-diazabicyclo [5.4.0] -7 -0.76 g (5 mmol) of undecene and 5 mL of dimethylformamide were added, and the mixture was stirred for 1 hour at 50 ° C. (see the following reaction formula (K)).
Thereafter, 0.64 g (5 mmol) of 4-chloroaniline and 0.76 g (5 mmol) of 1,8-diazabicyclo [5.4.0] -7-undecene were further added and stirred at 50 ° C. for 12 hours for reaction. (See reaction formula (L) below)
The liquid obtained by the reaction separation processes and solvent was concentrated in vacuum, black full Calvin ^{- 18} O containing (yield: ^{97.4atom% 18} O 0.61g, yield: 35% enrichment) A mixture was obtained.

  The method for producing an oxygen isotope-labeled compound and an oxygen isotope-labeled compound of the present invention is highly applicable as an oxygen isotope reagent for introducing an oxygen isotope-labeled carbonyl moiety into an organic compound.

Claims (7)

An oxygen isotope labeled compound represented by the following formula (1).
In the above formula (1), Y is ¹⁷ O or ¹⁸ O.
Further, the above formula (1), _{R 1,} (A) an aryl group, (B) heteroaryl, (C) a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms , A nitro group, a fluoroalkyl group having 1 to 4 carbon atoms, a halogen, a cyano group, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, an aryl group substituted with a dialkylamino group having 2 to 8 carbon atoms, or (D) The hydrogen atom is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a fluoroalkyl group having 1 to 4 carbon atoms, a halogen, a cyano group, an amino group, or 1 to 1 carbon atom. 4 is a heteroaryl group substituted by a monoalkylamino group having 4 carbon atoms and a dialkylamino group having 2 to 8 carbon atoms. An oxygen isotope-labeled compound represented by the following formula (2).
In the above formula (2), Y is ¹⁷ O or ¹⁸ O.
Further, the formula (2), _{R 2} is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a cyano group, an amino group, 1 to carbon atoms 4 monoalkylamino groups or C2-8 dialkylamino groups.   The oxygen isotope labeled compound according to claim 1 or 2, wherein the oxygen isotope enrichment is not less than a natural abundance ratio. A method for producing an oxygen isotope-labeled compound according to claim 1,
A compound represented by the following formula _(3), a compound represented by R 1 -OH, oxygen isotope labeled water _(H 2 Y; Y ^is a is ¹⁷ O or ¹⁸ O) is reacted with an oxygen isotope labeled Compound production method.
In the above formula (3), _{R 3} is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. A method for producing the oxygen isotope labeled compound according to claim 2,
Oxygen isotope labeling in which a compound represented by the following formula (3), a compound represented by the following formula (4), and oxygen isotope labeled water (H ₂ Y; Y is ¹⁷ O or ¹⁸ O) are reacted. Compound production method.
In the above formula (3), _{R 3} is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
In the above formula (4), _{R 2} is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a cyano group, an amino group, having 1 to 4 carbon atoms Either a monoalkylamino group or a dialkylamino group having 2 to 8 carbon atoms. An oxygen isotope-labeled urea derivative compound represented by the following formula (5).
In the above formula (5), Y ^{is 17} O or ¹⁸ O.
Further, in the above formula (5), _{R 4} and _{R 5} are hydrogen atom, or an organic group. A method for producing the oxygen isotope-labeled urea derivative compound according to claim 6,
A method for producing an oxygen isotope-labeled urea derivative compound, wherein the oxygen isotope-labeled compound according to claim 1 or 2 is reacted with an amine compound represented by the following formula (6).
In the above formula (6), _{R 4} and _{R 5} are hydrogen atom or an organic group.