JP6372880B2 - Oxygen isotope labeled compound - Google Patents

Description

  The present invention relates to an oxygen isotope-labeled compound, a stable isotope-labeled acylating reagent, an oxygen isotope-labeled intermediate compound, an oxygen isotope-labeled intermediate compound, a method for producing an oxygen isotope-labeled acetyl group-containing compound, and a stable isotope label The present invention relates to a method for producing a carbamoylation reagent, an oxygen isotope-labeled isocyanate compound, and an oxygen isotope-labeled carbamoyl group-containing compound.

In the natural world, oxygen isotopes are present in a proportion of 99.759% for ¹⁶ O (atomic%, the same applies hereinafter), 0.037% for ¹⁷ O, and 0.204% for ¹⁸ O. Among these oxygen isotopes, isotope-labeled compounds deoxygenated with ¹⁸ O, which is an isotopic component, are internal standard substances for quantitative analysis by mass spectrometry in the fields of medicine, agricultural chemicals, biochemistry and the like. Useful as. Similarly, an isotope-labeled compound deoxygenated by ¹⁷ O has a nuclear magnetic moment and is used for structural analysis studies by nuclear magnetic resonance (NMR).

By the way, the ratio (atomic%) in which specific or all oxygen atoms constituting the compound are composed of oxygen isotopes ¹⁸ O and / or ¹⁷ O may be referred to as “oxygen isotope ( ¹⁸ O + ¹⁷ O) enrichment”. The ratio (atomic%) of specific or all oxygen atoms constituting the compound consisting of oxygen isotopes ( ¹⁸ O) is referred to as “oxygen isotope ( ¹⁸ O) enrichment” or simply “oxygen isotope enrichment”. Sometimes. As a synonym, it may be expressed as “oxygen isotope ratio” or “oxygen isotope concentration”.

The deoxygenated oxygen isotope-labeled compound can be obtained, for example, as oxygen 18 ( ¹⁸ O) by increasing the mass number per label, or by carbon 13 (which is a carbon isotope) it like it is inexpensive as compared with ^{13 C)} and nitrogen 15 which is an isotope of nitrogen (15 ^N), and has a number of advantages.

  However, in reality, there are not many kinds of deuterated oxygen isotope-labeled compounds on the market compared with deuterium-labeled compounds, carbon isotope-labeled compounds and nitrogen isotope-labeled compounds. For this reason, a person who intends to perform analysis using a deoxygenated oxygen isotope-labeled compound may have to synthesize the target oxygen isotope-labeled compound by himself / herself, for example.

Generally, as a method for obtaining a deoxygenated oxygen isotope-labeled compound, “H ₂ ¹⁷ O” or “H ₂ ¹⁸ O” (hereinafter sometimes referred to as “oxygen isotope-labeled water”) is oxygenated. Examples of the isotope source include a method of transferring the oxygen isotope ¹⁷ O or ¹⁸ O to a target compound. Specifically, for example, Patent Document 1 discloses a method of synthesizing an oxygen isotope-labeled organic carbonyl compound by reacting oxygen isotope-labeled water with an amine compound in the presence of a dehydrogenation catalyst. . Patent Document 2 discloses a labeled carboxyl group in which oxygen isotope-labeled water is reacted with a carboxyl group-containing compound such as an amino acid in the presence of an activator, and the oxygen of the carboxyl group is the oxygen isotope ¹⁷ O or ¹⁸ O. A method for obtaining a containing compound is disclosed.

JP 2006-008591 A JP 2006-008666 A

However, the conventional methods disclosed in Patent Documents 1 and 2 have a problem that when the oxygen isotope-labeled water and the carboxyl group-containing compound are reacted at a molar ratio of 1: 1, the reaction hardly proceeds. Further, in the methods disclosed in Patent Documents 1 and 2, there is a possibility that light water (H ₂ ¹⁶ O) in the atmosphere may be mixed, and there is a possibility that the oxygen isotope enrichment may be lowered. Here, in order to prevent a decrease in oxygen isotope enrichment, a synthesis reaction in an apparatus substituted with an inert gas may be performed. However, other problems such as a large apparatus and complicated operation are caused. It will occur. Furthermore, there are problems that the types of oxygen isotope-labeled compounds to be obtained are limited and that a large amount of oxygen isotope-labeled water as a raw material is required, leading to an increase in cost.

  As described above, the method for synthesizing an oxygen isotope-labeled compound using oxygen isotope-labeled water, which is an existing oxygen supply source, has the above-described problems, so that the target compound can be obtained efficiently and easily. In fact, new compounds are desired.

  This invention is made | formed in view of the said situation, Comprising: It aims at providing the novel oxygen isotope labeling compound useful as a supply source of an oxygen isotope.

  The present invention also provides a stable isotope-labeled acylating reagent useful as an oxygen isotope source, a method for producing an oxygen isotope-labeled acetyl group-containing compound using the same, and an oxygen isotope-labeled intermediate produced at that time It is an object to provide a body compound.

  Furthermore, the present invention relates to a stable isotope-labeled carbamoylation reagent useful as an oxygen isotope source, a method for producing an oxygen isotope-labeled carbamoyl group-containing compound using the same, and an oxygen isotope-labeled isocyanate produced at that time It is an object to provide a compound.

ここで、上記一般式（１）中、Ｄは、重水素原子である。 The invention according to claim 1 is an oxygen isotope labeled compound characterized by being a compound represented by the following general formula (1) or a salt thereof.

Here, in said general formula (1), D is a deuterium atom .

The invention according to claim 2, oxygen isotope enrichment is oxygen isotopic labeling compound according to claim 1, characterized in that 90 at% or more.

The invention according to claim 3 is a stable isotope-labeled acylating reagent which is the oxygen isotope-labeled compound according to claim 1 or 2 .

ここで、上記一般式（２）中、Ｘは、^１７Ｏ又は^１８Ｏである。
また、上記一般式（２）中、Ｒ^１は、水素原子、炭素数１〜５のアルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜４のアルケニル基、炭素数２〜４のアルキニル基、又はアリール基である。なお、Ｒ^１を構成する炭素原子は^１３Ｃであってもよく、水素原子は重水素原子であってもよい。また、Ｒ^１上の水素原子は、ハロゲン原子で置換されていてもよい。 The invention according to claim 4 is an oxygen isotope-labeled intermediate compound, which is a compound represented by the following general formula ( 2 ).

Here, in the general formula ( 2 ), X is ¹⁷ O or ¹⁸ O.
Further, in the above general formula (2), ^{R 1} is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, C2-4 An alkynyl group or an aryl group. Note that the carbon atom constituting R ¹ may be ¹³ C, and the hydrogen atom may be a deuterium atom. The hydrogen atom on R ¹ may be substituted with a halogen atom.

The oxygen isotope labeled compound of the present invention is a novel compound useful as an oxygen isotope source. By using the oxygen isotope labeled compound of the present invention as an oxygen isotope supply source, the target oxygen isotope labeled compound can be obtained efficiently and simply.
Moreover, the oxygen isotope labeled compound of the present invention can be used as a stable isotope labeled acylating reagent and a stable isotope labeled carbamoylating reagent.

Since the stable isotope-labeled acylating reagent of the present invention is the above-mentioned oxygen isotope-labeled compound, it is useful as a source of oxygen isotopes when synthesizing an oxygen isotope-labeled acetyl group-containing compound.
Further, according to the method for producing an oxygen isotope-labeled acetyl group-containing compound of the present invention, equimolar reaction is possible because acylation is performed using the above-mentioned stable isotope-labeled acylating reagent. Thereby, an oxygen isotope can be efficiently introduced into the acetyl group-containing compound while maintaining high enrichment.
Furthermore, the oxygen isotope-labeled intermediate compound of the present invention is a novel compound produced during the above-described method for producing an oxygen isotope-labeled acetyl group-containing compound.

Since the stable isotope labeled carbamoylation reagent of the present invention is the above-mentioned oxygen isotope labeled compound, it is useful as a source of oxygen isotopes when synthesizing an oxygen isotope labeled carbamoyl group-containing compound.
Furthermore, according to the method for producing an oxygen isotope-labeled carbamoyl group-containing compound of the present invention, equimolar reaction is possible because carbamoylation is performed using the above-mentioned stable isotope-labeled carbamoylation reagent. Thereby, the oxygen isotope can be introduced into the carbamoyl group-containing compound while maintaining high enrichment efficiently.
Furthermore, the oxygen isotope-labeled isocyanate compound of the present invention is a novel compound produced during the above-described method for producing an oxygen isotope-labeled carbamoyl group-containing compound.

  Hereinafter, an oxygen isotope-labeled compound, a method for producing an oxygen isotope-labeled acetyl group-containing compound, and a method for producing an oxygen isotope-labeled carbamoyl group-containing compound according to an embodiment to which the present invention is applied will be described. The oxygen isotope labeled intermediate compound, the stable isotope labeled carbamoylation reagent, and the oxygen isotope labeled isocyanate compound will be described in detail.

<Oxygen isotope labeled compound>
First, an oxygen isotope labeled compound as an embodiment to which the present invention is applied will be described.
The oxygen isotope labeled compound of the present embodiment is a compound represented by the following general formula (11) or a salt thereof.

In the general formula (11), X is oxygen 17 ( ¹⁷ O) or oxygen 18 ( ¹⁸ O).
In the general formula (11), R ¹ is a hydrogen atom (H), an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or a carbon number. It is a 2-4 alkynyl group or an aryl group. The carbon atom constituting R ¹ may be carbon 13 ( ¹³ C), and the hydrogen atom may be a deuterium atom (D). The hydrogen atom on R ¹ may be substituted with a halogen atom.

Here, the alkyl group having 1 to 5 carbon atoms is not particularly limited, and may be a linear alkyl group or a branched alkyl group. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and an n-pentyl group.
Among these, those having 1 to 3 carbon atoms are preferred, methyl groups are more preferred, and “ ¹³ CD ₃ ” is particularly preferred.

  Specific examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Among these, those having 5 to 7 carbon atoms are more preferable.

Specific examples of the alkenyl group having 2 to 4 carbon atoms include a vinyl group, an allyl group, a 1-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, and a butadienyl group. .
Specific examples of the alkynyl group having 2 to 4 carbon atoms include ethynyl group, propargyl group, and 2-butynyl group.

The aryl group as R ¹ in the above formula (11) may be monocyclic or polycyclic, but is preferably monocyclic, particularly preferably a phenyl group or a tolyl group.
Further, the hydrogen atoms constituting R ¹ in the above formula (11), chlorine atom (Cl), it is preferably substituted with a halogen atom such as a bromine atom (Br) or iodine (I).

  The oxygen isotope labeled compound of the present embodiment may be a salt of the compound represented by the general formula (11). Specific examples include hydrochloride, sulfate, hydrobromide, acetate, and the like.

By the way, the oxygen isotope labeled compound of the present embodiment means that the abundance ratio of the oxygen isotope ( ¹⁷ O or ¹⁸ O) in the oxygen atom at the site represented by X in the above formula (11) is the natural abundance ratio. The one that exceeds. The abundance ratios of oxygen isotopes “ ¹⁷ O” and “ ¹⁸ O” in the natural world are 0.037% (atomic%, the same applies hereinafter) and 0.204%, respectively.

  Here, in the oxygen isotope labeled compound of the present embodiment, the oxygen isotope enrichment is preferably 90 atomic% or more, more preferably 95 atomic% or more, and further 98 atomic% or more. preferable. By using an oxygen isotope-labeled compound having an oxygen isotope enrichment of 90 atomic% or more as an oxygen isotope source, the target compound can be highly labeled.

Specifically, the oxygen isotope labeled compound of the present embodiment can be used for stable isotope labeled acylation of a required compound as described later. That is, the oxygen isotope labeled compound of the present embodiment can be used as a stable isotope labeled acylating reagent.
Moreover, the oxygen isotope labeled compound of this embodiment can be used for stable isotope labeled carbamoylation of a required compound, as will be described later. That is, the oxygen isotope labeled compound of the present embodiment can be used as a stable isotope labeled carbamoylation reagent.

Next, a synthesis method (manufacturing method) of the oxygen isotope labeled compound of the present embodiment will be described.
The compound represented by the general formula (11) is obtained by combining a compound represented by the chemical formula (R ¹ COOR ⁴ ) and hydrazine hydrate (H ₂ NN ₂ H · H ₂ O) with ethyl acetate or methyl acetate. In an organic solvent such as a reaction temperature of 0 to 100 ° C. and a reaction time of 30 to 360 minutes. After completion of the reaction, the organic solvent is distilled off.

Here, in the chemical formula (R ¹ COOR ⁴ ), R ⁴ represents an organic group and is not particularly limited. Specific examples of R ⁴ include an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, and an alkynyl group having 2 to 4 carbon atoms, Or an aryl group etc. are mentioned. In addition, the hydrogen atom constituting R ⁴ may be substituted with a halogen atom.

Note that the oxygen isotope labeled compound of the present embodiment is preferably a compound represented by the following general formula (12) or a salt thereof.

In the following description, the case where the oxygen isotope is oxygen 18 ( ¹⁸ O) may be exemplified, but the same applies to the case where oxygen 17 ( ¹⁷ O) is used. Shall be omitted.

<Method for producing oxygen-isotope-labeled acetyl group-containing compound>
Next, a method for producing an oxygen isotope-labeled acetyl group-containing compound as an embodiment to which the present invention is applied will be described.
In the method for producing an oxygen isotope-labeled acetyl group-containing compound of the present embodiment, the above-mentioned oxygen isotope-labeled compound (that is, the compound described in the above formula (11) or a salt thereof) is used as a stable isotope-labeled acylating reagent. The stable isotope-labeled acylating reagent is oxidized to produce an intermediate compound represented by the following general formula (13), and then this intermediate compound and the following general formula (14) are represented. The compound is reacted. Thereby, an oxygen isotope labeled acetyl group-containing compound represented by the following general formula (15) is obtained.

  A nitrous acid compound can be used for the oxidation of the stable isotope-labeled acylating reagent. Although it does not specifically limit as a nitrite compound, Specifically, nitrites, such as sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, nitrous acid, etc. can be used, for example.

Here, in the general formulas (13) and (15), X is ¹⁷ O or ¹⁸ O.
Further, in the general formula (13) and (15), ^{R 1} represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, carbon It is an alkynyl group having 2 to 4 or an aryl group. Note that the carbon atom constituting R ¹ may be ¹³ C, and the hydrogen atom may be a deuterium atom. The hydrogen atom on R ¹ may be substituted with a halogen atom.
In the general formulas (14) and (15), R ² and R ³ are each independently a cyclic structure composed of a hydrogen atom, a methyl group or a methoxy group, or a piperidyl group or a morpholyl group bonded within the molecule. Is exemplified.

  More specifically, first, the compound of the above general formula (11) is dissolved in a solvent, and is reacted with, for example, sodium nitrite at a reaction temperature of −10 to 10 ° C. for a reaction time of 30 to 90 minutes for oxidation. Thereby, the intermediate compound represented by the general formula (13) is generated as an intermediate.

  The solvent is not particularly limited as long as the reaction proceeds. Specifically, for example, aromatic hydrocarbons such as toluene, alcohols such as ethanol, ethers such as tetrahydrofuran, water, mixed solvents thereof can be used, and inorganic acids such as hydrochloric acid and organic acids such as acetic acid are mixed. May be.

  Next, the compound represented by the general formula (14) is added to the generated intermediate compound represented by the general formula (13), and the reaction is performed at a reaction temperature of 10 to 50 ° C. and a reaction time of 30 to 360 minutes. . At this time, a base such as triethylamine may be added as necessary.

By the above reaction, an oxygen isotope-labeled acetyl group-containing compound represented by the general formula (15) obtained by labeling the compound represented by the general formula (14) with oxygen 18 ( ¹⁸ O) can be obtained. .

By the way, the compound represented by the general formula (13), which is an intermediate obtained in the above-described synthesis (production) process, is dissolved in a solution under an appropriate condition as an oxygen isotope-labeled intermediate compound. It can be isolated.
This oxygen isotope labeled compound is a novel compound labeled with oxygen 18 ( ¹⁸ O).

  Examples of the isolation operation of the oxygen isotope-labeled intermediate compound include a method of extracting from the reaction solution with an organic solvent such as ether, benzene, toluene, and drying with magnesium sulfate or the like.

<Method for producing oxygen isotope-labeled carbamoyl group-containing compound>
Next, a method for producing an oxygen isotope-labeled carbamoyl group-containing compound, which is an embodiment to which the present invention is applied, will be described.
The method for producing an oxygen isotope-labeled carbamoyl group-containing compound of the present embodiment uses the above-mentioned oxygen isotope-labeled compound (that is, the compound described in the above formula (11) or a salt thereof) as a stable isotope-labeled carbamoylation reagent. The stable isotope-labeled carbamoylation reagent is heated to produce an isocyanate compound represented by the following general formula (16) (Curtius transfer reaction), and then the isocyanate compound and the following general formula (17) The compound represented by these is made to react. Thereby, an oxygen isotope labeled carbamoyl group-containing compound represented by the following general formula (18) is obtained.

Here, in the general formulas (16) and (18), X is ¹⁷ O or ¹⁸ O.
In the general formulas (16) and (18), R ¹ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or carbon. It is an alkynyl group having 2 to 4 or an aryl group. Note that the carbon atom constituting R ¹ may be ¹³ C, and the hydrogen atom may be a deuterium atom. The hydrogen atom on R ¹ may be substituted with a halogen atom.
In the general formulas (17) and (18), R ² and R ³ are each independently a cyclic structure composed of a hydrogen atom, a methyl group or a methoxy group, or a piperidyl group or a morpholyl group bonded within the molecule. Is exemplified.

In order to obtain the isocyanate compound represented by the general formula (16) by the Curtius rearrangement reaction, first, the compound represented by the general formula (11) is dissolved in a solvent, and the reaction temperature is −10 to 10 ° C. The reaction is performed for 30 to 90 minutes with the nitrite compound. Here, the solvent is not particularly limited, and a mixed solvent of an inorganic acid such as hydrochloric acid or sulfuric acid and water, a solvent obtained by adding an organic solvent such as toluene, benzene, or diphenyl ether to the mixed solvent can be used. Although it does not specifically limit as a nitrite compound, For example, nitrites, such as sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, nitrous acid, etc. can be used. Next, the obtained reaction solution is heated. The temperature condition at that time can be arbitrarily set as long as the Curtius transition occurs, but can be heated to 50 to 100 ° C., for example. Moreover, when the organic solvent is not contained in the prior mixed solvent, for example, an organic solvent such as toluene, benzene, or diphenyl ether may be added to the mixed solvent.
Thereby, the isocyanate compound represented with the said General formula (16) produces | generates as an intermediate body.

  Next, the compound represented by the general formula (17) is added to the generated isocyanate compound represented by the general formula (16), and the reaction is performed at a reaction temperature of 10 to 50 ° C. and a reaction time of 30 to 360 minutes.

By the above reaction, an oxygen isotope-labeled carbamoyl group-containing compound represented by the above general formula (18) can be obtained by converting the compound represented by the above general formula (17) into an oxygen 18 ( ¹⁸ O) labeled carbamoyl. it can.

By the way, the compound represented by the above general formula (16), which is an intermediate obtained in the above-described synthesis (manufacturing) process, is dissolved as an oxygen isotope-labeled isocyanate compound in a solution in an appropriate condition. Can be separated.
This oxygen isotope-labeled isocyanate compound is a novel compound labeled with oxygen 18 ( ¹⁸ O).

  Examples of the operation for isolating the oxygen isotope-labeled isocyanate compound include extraction with organic solvents such as ether, benzene, and toluene, and distillation.

As described above, the oxygen isotope labeled compound of the present embodiment is a novel compound useful as a source of oxygen isotopes. By using the oxygen isotope labeled compound of the present embodiment as an oxygen isotope supply source, the target oxygen isotope labeled compound can be obtained efficiently and simply.
In addition, the oxygen isotope labeled compound of the present embodiment can be used as a stable isotope labeled acylating reagent and a stable isotope labeled carbamoylating reagent.

According to the method for producing an oxygen isotope-labeled acetyl group-containing compound of the present embodiment, equimolar reaction is possible because acylation is performed using the above-mentioned stable isotope-labeled acylating reagent. Thereby, an oxygen isotope can be efficiently introduced into the acetyl group-containing compound while maintaining high enrichment.
Moreover, the oxygen isotope labeled intermediate compound obtained in the method for producing the oxygen isotope labeled acetyl group-containing compound of the present embodiment is a novel compound labeled with an oxygen isotope.

According to the method for producing an oxygen isotope-labeled carbamoyl group-containing compound of this embodiment, equimolar reaction is possible because carbamoylation is performed using the above-mentioned stable isotope-labeled carbamoylation reagent. Thereby, the oxygen isotope can be introduced into the carbamoyl group-containing compound while maintaining high enrichment efficiently.
Further, the oxygen isotope-labeled isocyanate compound obtained in the production method of the oxygen isotope-labeled carbamoyl group-containing compound of the present embodiment is a novel compound labeled with an oxygen isotope.

  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.

Specific examples are shown below.
Example 1
The reaction shown in the following formula (19), acetyl hydrazine hydrochloride ^- were synthesized ¹⁸ O.
Specifically, first, 9.0 g (0.1 mol) of ethyl acetate- ¹⁸ O (97.1 atom% ¹⁸ O), 5 g (0.1 mol) of ethanol and hydrazine monohydrate were placed in a 100 ml eggplant flask. Next, the reaction solution was heated at 50 ° C. to complete the reaction. After the reaction, the solvent was distilled off, added 8.3ml of hydrochloric acid (0.1 mol), white solid (acetyl hydrazine hydrochloride ^{- 18} O) was obtained (yield: 711 mg, yield: 9.3%, oxygen Isotope enrichment: 95.9 atom% ¹⁸ O).

(Example 2)
Acetyl hydrazine hydrochloride- ¹³ C, d ₃ , ¹⁸ O was synthesized by the reaction shown in the following formula (20).
Specifically, first, ethyl acetate- ¹³ C, d ₃ , ¹⁸ O (isotope enrichment: 99 atom% ¹³ C, 99.5 atom% D, 97.1 atom% ¹⁸ O) 950 mg (10 mmol) was added to a 100 ml eggplant flask. , 500 mg (10 mmol) of ethanol and hydrazine monohydrate were added. Next, the reaction solution was heated at 50 ° C. to complete the reaction. After the reaction, the solvent was distilled off, and 0.83 ml (10 mmol) of hydrochloric acid was added to obtain a white solid (acetylhydrazine hydrochloride- ¹³ C, d ₃ , ¹⁸ O) (yield: 80 mg, yield: 6. 8%, isotope enrichment: 99 atom% ¹³ C, 99.5 atom% D, 95.9 atom% ¹⁸ O).

(Example 3)
The reaction shown in the following formula (21), benzoyl hydrazine ^- was synthesized ¹⁸ O.
Specifically, first, methyl benzoate in 50ml eggplant type flask ^{- 18} O (oxygen isotope ^{enrichment: 99.2atom% 18 O) 1.38g (} 10mmol), ethanol 10 ml, hydrazine monohydrate was placed, 60 The reaction was stirred at ° C. After completion of the reaction, the mixture was concentrated to dryness with an evaporator to obtain a white solid. Furthermore, by recrystallizing the crystals from ethanol, acicular crystals (benzoyl hydrazine ^{- 18} O) was obtained (yield: 0.90 g, Yield: 65.3%, oxygen isotope enrichment: 99.0Atom% ¹⁸ O).

Example 4
The reaction shown in the following formula (22), formylhydrazine ^- was synthesized ¹⁸ O.
Specifically, first, formic acid methyl 100ml round-bottomed flask ^{- 18} O (oxygen isotope ^{enrichment: 99.0atom% 18 O) 6.2g (} 0.1mol), ethanol, hydrazine monohydrate 5 g (0. 1 mol) was added. Next, the reaction solution was stirred at room temperature to complete the reaction. After the reaction, the solvent was distilled off, red-brown solid (formylhydrazine ^{- 18} O) was obtained (yield: 3.1 g, Yield: 50.0%, oxygen isotope enrichment: ^98.6atom% 18 O).

(Example 5)
As shown in the following reaction formula (23), acetylation of aniline was performed using acetylhydrazine- ¹³ C, d ₃ , ¹⁸ O obtained by the synthesis method of Example 2.
Specifically, first, acetyl hydrazine hydrochloride 50ml eggplant type flask _{^{- 13 C, d 3, 18}} O ( isotopic ^{enrichment: 99atom% 13 C, 99.5atom%} D, 95.9atom% 18 O) 583mg ( 5 mmol), 2.5 ml of water and 5 ml of toluene were added and dissolved. Next, 345 mg (5 mmol) of sodium nitrite was added while stirring under ice cooling. Thereafter, liquid separation was performed, the toluene phase was separated, dehydrated with magnesium sulfate, and filtered. Next, 465 mg (5 mmol) of aniline and 505 mg (5 mmol) of triethylamine were added to the obtained filtrate. After completion of the reaction, the mixture was separated with toluene and water, and the toluene phase was distilled off to obtain a transparent liquid (acetylaniline- ¹³ C, d ₃ , ¹⁸ O) (yield: 76 mg, yield: 11%, isotopic enrichment). Degree: 99.0 atom% ¹³ C, 99.5 atom% D, 95.8 atom% ¹⁸ O).

(Example 6)
As shown in the following reaction formula (24), benzoyl hydrazine obtained in the synthesis of Example 3 - with ^{18 O,} it was benzoylated morpholine.
Specifically, first, benzoyl hydrazine in 10ml eggplant type flask ^{- 18} O (oxygen isotope ^{enrichment: 99atom% 18 O) 138mg (} 1mmol), 1N hydrochloric acid 1.2 ml, was dissolved a mixture of toluene 3 ml. Subsequently, 70 mg of sodium nitrite was added while stirring under ice cooling. Next, 174 mg (2 mmol) of morpholine was added while cooling the reaction solution with ice. After completion of the reaction, was separated with ethyl acetate and water, transparent liquid was distilled off ethyl acetate phase ^- was obtained (benzoyl morpholine ¹⁸ O) (Yield: 135 mg, Yield: 70%, oxygen isotope enrichment: 98 .1 atom% ¹⁸ O).

(Example 7)
As shown in the following reaction formula (25), formylhydrazine obtained in the synthesis of Example 4 - with ^{18 O,} was formylated aniline.
Specifically, first, 62 mg (1 mmol) of formylhydrazine- ¹⁸ O (oxygen isotope enrichment: 98.5 atom% ¹⁸ O), 1.2 ml of 1N hydrochloric acid, and 3 ml of toluene were mixed and dissolved in a 10 ml eggplant flask. . Subsequently, 70 mg of sodium nitrite was added while stirring under ice cooling. Next, 186 mg (2 mmol) of aniline was added while cooling the reaction solution with ice. After completion of the reaction, was separated with ethyl acetate and water, transparent liquid was distilled off ethyl acetate phase (N- formyl aniline ^{- 18} O) was obtained (yield: 92 mg, Yield: 75.0%, oxygen isotope Concentration: 98.1 atom% O).

(Example 8)
As shown in the following reaction formula (26), aniline was carbamoylated using acetylhydrazine hydrochloride- ¹⁸ O obtained by the synthesis method of Example 2.
Specifically, first, 583 mg (5 mmol) of acetylhydrazine hydrochloride- ¹⁸ O (isotope enrichment: 95.9 atom% ¹⁸ O), 2.5 ml of water and 5 ml of toluene were mixed and dissolved in a 50 ml eggplant flask. Next, 345 mg (5 mmol) of sodium nitrite was added while stirring under ice cooling. Then, liquid separation was performed, the toluene phase was separated, dehydrated with magnesium sulfate, and filtered. Then, the obtained filtrate by heating at 100 ° C., methyl isocyanate ^- to synthesize ¹⁸ O, cooled, added aniline 465 mg (5 mmol), were reacted at 50 ° C.. After completion of the reaction, was separated with toluene and water, evaporated and transparent liquid (1-methyl-3-urea-phenyl ^{- 18} O) The toluene phase was obtained (yield: 236 mg, yield: 30.2%, oxygen Isotope enrichment: 95.8 atom% ¹⁸ O).

Example 9
As shown in the following reaction formula (27), benzoyl hydrazine obtained in the synthesis of Example 3 - with ^{18 O,} ammonia and carbamoylation, (1-phenyl urea - ^{18 O)} was synthesized.
Specifically, first, benzoyl hydrazine in 10ml eggplant type flask ^{- 18} O (oxygen isotope ^{enrichment: 99.0atom% 18 O) 138mg (} 1mmol), 1N hydrochloric acid 1.2 ml, was dissolved a mixture of toluene 3ml . Subsequently, 70 mg of sodium nitrite was added while stirring under ice cooling. After completion of the reaction, the toluene phase was collected, dried over magnesium sulfate, and filtered. Next, the obtained filtrate was heated at 100 ° C. to synthesize benzoisocyanate- ¹⁸ O, and after cooling, 0.5 ml of aqueous ammonia was added. After completion of the reaction, the solution was distilled off white crystals (1-phenyl urea ^{- 18} O) was obtained (yield: 71.1 mg, yield 51.5% oxygen isotope enrichment: ^{97.5atom% 18} O ).

Claims (4)

An oxygen isotope-labeled compound, which is a compound represented by the following general formula (1) or a salt thereof.

Here, in said general formula (1), D is a deuterium atom . The oxygen isotope labeled compound according to claim 1 , wherein the oxygen isotope enrichment is 90 atomic% or more. Stable isotope-labeled acylating reagent, characterized in that an oxygen isotope-labeled compound according to claim 1 or 2. An oxygen isotope-labeled intermediate compound, which is a compound represented by the following general formula ( 2 ):

Here, in the general formula ( 2 ), X is ¹⁷ O or ¹⁸ O.
Further, in the above general formula (2), ^{R 1} is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, C2-4 An alkynyl group or an aryl group. Note that the carbon atom constituting R ¹ may be ¹³ C, and the hydrogen atom may be a deuterium atom. The hydrogen atom on R ¹ may be substituted with a halogen atom.