Method and device for producing deuterium-labeled compound

Abstract

This method for producing a deuterium-labeled compound is characterized by comprising: supplying a proton supply source and heavy water to the anode side of a membrane electrode assembly including an electrode and a proton conductive membrane; supplying a compound to be deuterated to the cathode side of the membrane electrode assembly; and energizing the membrane electrode assembly to deuterate the compound on the cathode side.

Description

Method and apparatus for producing deuterium-labeled compounds

[0001] The present invention relates to a method and an apparatus for producing a deuterium-labeled compound using a proton conductor.

[0002] Deuterium-labeled compounds, labeled with deuterium (D) atoms, play important roles in the fields of chemistry, the environment, and biology. For example, deuterium-labeled amino acids and fatty acids are used to track metabolic pathways in animals. Because the reaction rate of C-D bonds is 6 to 10 times slower than that of C-H bonds, deuterium-incorporated molecules are frequently used in a variety of applications, including elucidating the reaction mechanisms of organic synthesis, structural analysis of biopolymers, and quantitative analysis of environmental pollutants. Furthermore, by replacing hydrogen atoms in pharmaceuticals with deuterium, drugs that are less likely to be metabolized can be developed. Furthermore, molecules in which C-H bonds are replaced with C-D bonds have improved durability, which can lead to longer device life and lower energy consumption in functional materials where stability is important, such as organic electroluminescent (EL) compounds. The development of these functional deuterium compounds has a significant impact.

[0003] With the increasing demand for deuterium-labeled compounds, their synthesis methods have been actively researched. Conventional deuterium labeling methods include (1) a total synthetic method for preparing compounds from small molecular weight deuterium-labeled compounds, (2) a method for converting reducing functional groups into deuterium gas (D ２ gas) and lithium aluminum deuterium (LiAlD ４ ), and (3) direct deuterium labeling of the target compound by the H-D exchange reaction. The H-D exchange reaction is cost-effective and simple, and reactions using acid-base catalysts or transition metal catalysts, high-temperature and high-pressure conditions, microwaves, or enzymes have been reported. In addition, a small amount of hydrogen gas (H ２ gas) and a heterogeneous catalyst, palladium on carbon (Pd / C), in the presence of heavy water (D ２ It has been reported that the H-D exchange reaction proceeds selectively at the benzylic position by stirring in a 2,4-dichloro-2,6-dichloro-1,6 ...

[0004] A method has been proposed for deuterizing the β-position of a fatty acid amide by stirring in a solvent such as toluene at room temperature to 130°C for 1 to 24 hours using 0.02 to 4 equivalents of a base such as cesium pivalate and a platinum group metal catalyst such as palladium (Patent Document 1).

[0005] A method for deuterizing an aromatic compound has been proposed, in which the aromatic compound is contacted with a heavy hydrogen source selected from heavy water and a deuterated solvent in the coexistence of at least one solvent selected from 2-propanol, 2-butanol, and 3-pentanol and a platinum catalyst (Patent Document 2).

[0006] WO-A-2022 / 019336 JP 2014-111561 A

[0007] "Deuterium Labeling Reactions Using Heterogeneous Platinum Catalysts," Hiroyoshi Ezaki et al., Journal of the Society of Synthetic Organic Chemistry, Vol. 65, No. 12, 2007. "Deuterium Labeling Compounds for Pharmaceutical and Industrial Applications and Development of Efficient Synthesis Methods," Hironao Sajiki et al., MEDCHEM NEWS 32(1) 41-46 (2022).

[0008] Conventional deuteration methods, as exemplified by Non-Patent Documents 1 and 2 and Patent Documents 1 and 2, are all batch-type deuteration methods using organic synthesis. The organic synthesis of deuterium-labeled compounds requires hydrogen and an active catalyst, and it is not easy to replace only C-H bonds with C-D bonds while suppressing the reduction of highly reactive sites. Furthermore, the labeling reaction is often carried out batch-wise using a homogeneous base catalyst under high-temperature and high-pressure conditions, which poses a problem of complicated manufacturing processes. Therefore, the more complex the structure of a deuterium-labeled compound, the more expensive it becomes.

[0009] Therefore, an object of the present invention is to provide a method and apparatus for inexpensively and simply synthesizing deuterium-labeled compounds on demand using heavy water as a raw material without relying on organic synthesis methods and without discharging large amounts of waste.

[0010] According to the present invention, a membrane reactor having electrodes attached to a proton conductive membrane is used, and heavy water (D ２O) and a proton supply source are supplied, a compound to be deuterized is supplied to the cathode side of the proton conductive membrane, and a current is passed through the proton conductive membrane, whereby the proton supply source and heavy water are electrochemically oxidized to produce H ＋ or D ＋ As a result, D passes through the proton conductive membrane and passes to the cathode side. ＋ or D ２ and a compound to be deuterated.

[0011] Specifically, the following methods for producing a deuterium-labeled compound are provided: [1] A method for producing a deuterium-labeled compound, comprising supplying a proton source and heavy water to the anode side of a membrane electrode assembly including an electrode and a proton-conductive membrane, supplying a compound to be deuterated to the cathode side of the membrane electrode assembly, and applying current to the membrane electrode assembly to deuterate the compound on the cathode side. [2] A method for producing a deuterium-labeled compound according to [1], wherein the proton source is one or more selected from hydrogen gas, alcohol, sugar solution, organic acid, and amine compound. [3] A method for producing a deuterium-labeled compound according to [1] or [2], wherein a base is supplied to the cathode side together with the compound to be deuterated. [4] A method for producing a deuterium-labeled compound according to any one of [1] to [3], wherein excess deuterium is recovered from the cathode side, mixed with oxygen, and combusted to produce heavy water, and the resulting heavy water is supplied to the anode side. [5] The method for producing a deuterium-labeled compound according to any one of [1] to [4], wherein a noble metal catalyst is supported on the anode side and / or cathode side surface of the membrane electrode assembly.

[0012] The synthesis method of the present invention uses a membrane reactor equipped with electrodes on a proton-conducting membrane to generate D electrochemically from a proton source and deuterium. ＋ The present invention also provides the following apparatus for producing a deuterated compound.

[0013] [6] An apparatus for producing a deuterium-labeled compound, comprising: a membrane electrode assembly having a proton-conducting membrane and an electrode catalyst supported on the surface of the proton-conducting membrane; a proton supply source and heavy water supply chamber provided on the anode side of the membrane electrode assembly; a deuteration reaction chamber provided on the cathode side of the membrane electrode assembly; and an energizer for energizing the anode side surface and the cathode side surface of the membrane electrode assembly. [7] The apparatus for producing a deuterium-labeled compound according to [6], wherein the proton supply source and heavy water supply chamber include inlets for the proton supply source and heavy water, and an outlet for discharging unnecessary components. [8] The apparatus for producing a deuterium-labeled compound according to [6] or [7], further comprising a gas diffusion layer and a separator provided between the membrane electrode assembly and the proton supply source and heavy water supply chamber, and between the membrane electrode assembly and the deuteration reaction chamber, respectively. [9] The apparatus for producing a deuterium-labeled compound according to any one of [6] to [8], further comprising a catalytic combustor that recovers deuterium gas generated in the deuteration reaction chamber, mixes it with oxygen, and combusts it to produce heavy water, and the apparatus has a circulation type configuration in which the heavy water from the catalytic combustor is supplied to the proton supply source and the heavy water supply chamber.

[10] The apparatus for producing a deuterium-labeled compound according to any one of [6] to [9], characterized in that the electrode catalyst is a noble metal catalyst.

[0014] The method for producing a deuterium-labeled compound of the present invention uses clean electrical energy, so no unnecessary waste is generated. Furthermore, the reaction can proceed at normal pressure and room temperature, so that a deuterium-labeled compound can be produced inexpensively and simply.

[0015] In the method for producing a deuterium-labeled compound of the present invention, when an alcohol or a sugar solution is used as a proton source, it is not necessary to use hydrogen gas, which is difficult to handle, and a deuterium-labeled compound can be produced inexpensively and simply. In addition, waste materials such as wastewater from food factories can be used as the proton source for the alcohol or sugar solution.

[0016] In the method for producing a deuterium-labeled compound of the present invention, when no base is added, aldehydes, alkynes, and benzylic hydrogens can be preferentially deuterized, whereas when a base is added, aromatic rings can be preferentially deuterized. By using a base appropriately, substitution of H and D can be selectively carried out without destroying functional groups.

[0017] Since the deuterium-labeled compound production apparatus of the present invention is a membrane reactor, it is easy to separate the product from the catalyst and raw materials, and deuterium-labeled compounds can be produced inexpensively.

[0018] The deuterium-labeled compound production apparatus of the present invention can be easily assembled as a small membrane reactor even in a laboratory, and can produce deuterium-labeled compounds on demand.

[0019] The circulating deuterium-labeled compound production apparatus reuses excess deuterium gas generated in the deuteration reaction chamber to produce heavy water, which is used as a raw material for producing deuterium-labeled compounds. This reduces the amount of expensive heavy water required and reduces the cost of producing deuterium-labeled compounds.

[0020] A side view showing the schematic configuration of a reaction apparatus using hydrogen gas as a proton supply source. An exploded perspective view showing the schematic configuration of a reaction apparatus using hydrogen gas as a proton supply source. An enlarged view of a diaphragm portion of a reaction apparatus using hydrogen gas as a proton supply source. A side view showing the schematic configuration of a reaction apparatus using methanol as a proton supply source. An exploded perspective view showing the schematic configuration of a reaction apparatus using methanol as a proton supply source. An enlarged view of a diaphragm portion of a reaction apparatus using methanol as a proton supply source. A schematic explanatory diagram showing the structure of a membrane electrode assembly. A schematic diagram of a circulatory deuterium-labeled compound production apparatus. １ H NMR and ２ H NMR spectrum of 4-methylbenzaldehyde in Example 1 １ H NMR and ２ H NMR spectrum of benzaldehyde in Example 1 １ H NMR and ２ H NMR spectrum of the chloroform of Example 1 ２ H NMR spectrum of methanol in Example 1 ２1H NMR spectrum. Graph showing the relationship between reaction time and D introduction rate in Example 2. ２ Graph showing the change in potential over time when a current of 1000 kJ / cm2 is applied. １ H NMR and ２ H NMR spectrum of 1-ethynyl-4-methylbenzene in Example 3 １ H NMR and ２ H NMR spectrum of 1-ethynyl-4-methoxybenzene in Example 4 １ H NMR and ２ H NMR spectrum of ibuprofen in Example 5 １ H NMR and ２ H NMR spectrum of biphenyl in Example 6 １ H NMR and ２ H NMR spectrum of the phenol of Example 6 １ H NMR and ２ H NMR spectrum of naphthalene in Example 7 １ H NMR and ２ H NMR spectrum of 2,3-dihydroxynaphthalene in Example 7 １ H NMR and ２ H NMR spectrum of 2-methylquinoline in Example 7 １ H NMR and ２ H NMR spectrum of 6-methoxyquinoline in Example 7 １ H NMR and ２ H NMR spectrum of the xanthine of Example 7 １ H NMR and ２ H NMR spectrum of theophylline in Example 7 １ H NMR and ２ H NMR spectrum of caffeine in Example 7 １ H NMR and ２ H NMR spectrum of Vitamin D3 in Example 7 １ H NMR and ２ H NMR spectrum of ketoprofen in Example 7 １ H NMR and ２ H NMR spectrum.

[0021] The present invention will be described in detail with reference to the accompanying drawings. The method for producing a deuterium-labeled compound of the present invention is characterized by supplying a proton source and heavy water to the anode side of a membrane electrode assembly including an electrode and a proton-conductive membrane, supplying a compound to be deuterated to the cathode side of the membrane electrode assembly, and applying electricity to the membrane electrode assembly to deuterate the compound on the cathode side.

[0022] The proton conductive membrane is not particularly limited as long as it can selectively transmit and diffuse protons, but Nafion (registered trademark), which is a perfluoroalkylsulfonic acid polymer, or a proton conductive graphene oxide membrane (hereinafter also referred to as "GO membrane") can be preferably used.

[0023] The GO membrane can be a thin GO film doped with hydroxymethanesulfonic acid or a polyvalent metal cation, which can improve proton conductivity, and the polyvalent metal cation can expand the interlayer space of the GO nanosheets, promoting proton diffusion.

[0024] In particular, it is believed that the use of an asymmetric proton-conducting membrane in which a dense GO thin film and a porous membrane are bonded can dramatically improve the proton permeation rate while maintaining strength. The asymmetric proton-conducting membrane is preferably a bonded membrane in which a porous support membrane, a catalyst layer, a proton-conducting membrane (GO membrane), and a catalyst layer are laminated in this order. The proton-conducting membrane can be formed by densely laminating an anode oxidation catalyst-supporting graphene oxide nanosheet and a graphene oxide nanosheet in this order on a porous support membrane, and then coating the surface of the graphene oxide nanosheet with carbon nanotubes or nanorods supporting a noble metal catalyst as an electrode catalyst.

[0025] Since the proton permeation rate through a proton conductive membrane is inversely proportional to the membrane thickness, the deuterium permeation rate at the cathode can be significantly improved by thinning the proton conductive membrane. Conventional proton conductive membranes have a thickness of 250 to 300 μm and a deuterium permeation rate of 0.1 mL / min cm. ３ (Applied voltage 2V), but by thinning the membrane thickness to about 1 / 1000, the deuterium permeation rate was increased to 1.0 ml / min cm３ It is expected that the proton conductivity can be improved to as high as 1000 keV. Although the mechanical strength of a proton conductive membrane decreases as the membrane becomes thinner, mechanical strength can be maintained by forming a proton conductive membrane with an asymmetric structure in which a dense thin film and a porous support film are bonded. Carbon paper, which has high conductivity and high strength, can be used as the porous support film. Carbon paper with a hydrophilic surface is particularly preferred because it facilitates the diffusion of alcohol or sugar solutions as proton sources. Furthermore, to promote the oxidation of the proton source at the anode, it is preferable to insert an anodic oxidation catalyst between the porous support film and the GO thin film. A platinum carbon catalyst can be preferably used as the anodic oxidation catalyst.

[0026] It is preferable to coat the surface of the GO thin film (GO nanosheet) of the asymmetric proton conductive membrane with carbon nanotubes or nanorods carrying a noble metal catalyst as an electrode catalyst. Examples of the noble metal catalyst include Pt, Pd, Ru, Rh, Ag, and Au, as well as noble metal alloy catalysts such as Pt—Ni, Pt—Co, Ru—Ni, and Pd—Mo. The carbon nanotubes or nanorods carrying these catalysts preferably have an anisotropic shape to increase the surface area and have high electronic conductivity.

[0027] The proton supply source supplied to the anode side of the membrane electrode assembly is protons H ＋ Preferred examples of proton sources that produce hydrogen include hydrogen gas, alcohols, sugar solutions, organic acids such as formic acid, and amine compounds. Proton sources other than hydrogen gas, such as alcohols and sugar solutions, are particularly preferred because they allow the deuteration reaction to proceed without using hydrogen gas, which is difficult to handle. Examples of alcohols that can be used include lower alcohols such as methanol and ethanol, as well as glycerin, a by-product of biodiesel fuel. Examples of sugar solutions that can be used include sake lees and other sugar solutions that are waste products from food manufacturing plants, etc.

[0028] The amount of the proton source to be supplied must be in excess of the amount of the organic compound to be deuterated, preferably at a molar ratio of 10 or more. Continuous operation can be achieved even when a large amount of organic compound to be deuterated is used by continuously supplying a heavy water solution containing a proton source other than hydrogen gas to the anode side using a pump.

[0029] A wide range of organic compounds can be used as the compound to be deuterated and supplied to the cathode side of the membrane electrode assembly, including alcohols, halomethanes, hydrocarbons, aldehydes, alkynes, and pharmaceuticals. Preferred examples of alcohols include methanol and ethanol; halomethanes include chloromethane and chloroform; hydrocarbons include aromatic hydrocarbons such as toluene and styrene; alkynes include terminal aromatic alkynes such as ethynylbenzene, 1-ethynyl-4-methylbenzene, and 1-ethynyl-4-methoxybenzene; and aldehydes include aromatic aldehydes such as benzaldehyde, 4-methylbenzaldehyde, and 4-methoxybenzaldehyde. In particular, it has been confirmed that hydrogen atoms in terminal aromatic alkynes and aromatic aldehydes can be regioselectively substituted with hydrogen atoms without destroying the structure of the alkynes or aldehydes.

[0030] A constant voltage can be applied to the membrane electrode assembly by passing electricity through it. ２ 2A / cm or more ２ Preferably, 100 mA / cm or less ２ 1A / cm or more ２ By passing the following current, it is possible to apply a constant voltage of 0.5 V or more and 5 V or less, preferably 1 V or more and 3.5 V or less, more preferably 1.5 V or more and 3 V or less. If the passing current or applied voltage is within the above range, side reactions can be suppressed and a deuterium compound can be obtained in a shorter time.

[0031] The deuteration reaction is preferably carried out within a temperature range in which H at a position that is easily deuterized can be stabilized, and can be carried out at a temperature of 5° C. to 80° C., preferably 25° C. to 80° C., and more preferably 25° C. to 60° C. Conventional organic chemical synthesis methods require a high temperature of about 100° C., but in the present invention, the deuteration reaction can proceed even in a low temperature range, eliminating the need for thermal energy and suppressing the generation of by-products.

[0032] First, the deuteration reaction of a compound when hydrogen gas is used as a proton source will be described.

[0033]

[0034] Heavy water D on the anode side of the membrane electrode assembly ２ O vapor and hydrogen gas H ２ When a compound to be deuterated is supplied to the cathode side of the membrane electrode assembly and a voltage is applied to the anode and cathode of the membrane electrode assembly, hydrogen is oxidized at the anode to produce protons H ＋ is generated, and the protons diffuse from the anode to the cathode inside the proton conductive membrane of the membrane electrode assembly.

[0035]

[0036] Heavy water D ２ O passes through the inside of the proton conductive membrane. Inside the proton conductive membrane, protons H generated by voltage application ＋ and heavy water D ２ An H-D exchange reaction occurs between O and D ＋ is generated. ２ Direct oxidation of O also produces D ＋ is generated.

[0037]

[0038] On the cathode side surface of the proton conductive membrane, electrons e injected into the cathode by applying a voltage － and D ＋ recombines to form deuterium gas D ２ is generated.

[0039]

[0040] On the cathode surface of the proton conducting membrane, D ＋ Or the generated D ２ The gas reacts with the compound supplied to the cathode to produce a deuterium-labeled compound, which can be catalyzed by a metal catalyst such as platinum, palladium, or rhodium.

[0041] For example, if the compound to be deuterated is an alkyne, the deuteration reaction can be represented as follows:

[0042] For example, if the compound to be deuterated is an aldehyde, the deuteration reaction can be expressed as follows:

[0043] Next, the deuteration reaction of a compound when an alcohol is used as a proton source will be described.

[0044]

[0045] Heavy water D on the anode side of the membrane electrode assembly ２ O and alcohol R—OH are supplied, and the compound to be deuterated is supplied to the cathode side of the membrane electrode assembly. When a voltage is applied to the anode and cathode of the membrane electrode assembly, the alcohol is oxidized at the anode to generate protons, which diffuse inside the proton conductive membrane of the membrane electrode assembly from the anode to the cathode.

[0046] The reaction on the anode side of the proton conductive membrane will be explained using methanol as an example. Methanol (MeOH) supplied to the anode side is oxidized to formaldehyde (HCOH) by applying a voltage at the anode, and protons (H ＋ Generates proton H ＋ passes through the proton conducting membrane and diffuses into the interior of the proton conducting membrane.

[0047]

[0048] On the anode side of the proton conducting membrane, the generated HCOH is converted into heavy water D ２ It reacts with O to form HCOOD and proton H ＋ and D ＋ Generates proton H ＋ and D ＋passes through the proton conducting membrane and diffuses into the interior of the proton conducting membrane.

[0049]

[0050] Furthermore, on the anode side of the proton conductive membrane, the generated HCOOD is further oxidized by applying voltage to produce CO ２ and proton H ＋ and D ＋ Generates proton H ＋ and D ＋ passes through the proton conducting membrane and diffuses into the interior of the proton conducting membrane.

[0051]

[0052] CO produced ultimately by the oxidation of alcohol ２ does not pass through the proton conductive membrane, remains on the anode side, and is discharged to the outside.

[0053] Heavy water D ２ O passes through the inside of the proton conductive membrane. Inside the proton conductive membrane, protons H generated by the oxidation of alcohol due to the application of voltage ＋ and heavy water D ２ An H-D exchange reaction occurs between O and D ＋ is generated. ２ Direct oxidation of O also produces D ＋ is generated.

[0054]

[0055] On the cathode side surface of the proton conductive membrane, electrons e injected into the cathode by applying a voltage － and D ＋ recombines to form deuterium gas D ２ is generated.

[0056]

[0057] On the cathode surface of the proton conducting membrane, D ＋ Or the generated D ２ The gas reacts with the compound supplied to the cathode to produce a deuterium-labeled compound, which can be catalyzed by a metal catalyst such as platinum, palladium, or rhodium.

[0058] When a platinum catalyst is supported on the anode and cathode surfaces of a proton conductive membrane, the reaction is believed to occur as follows.

[0059]

[0060] (A) Methanol CH supplied to the anode side ３ OH and heavy water D ２ O is converted to CO by applying a voltage to the anode. ２ is oxidized to deuterium ions D ＋ and proton H ＋ Heavy water D supplied to the anode side ２ O is oxygen ２ and deuterium ions D ＋ Heavy water D ２ O, deuterium ion D ＋ , proton H ＋ passes through the proton conducting membrane and diffuses into the interior of the proton conducting membrane. CO is ultimately produced by the oxidation of alcohol. ２ and O ２ does not pass through the proton conductive membrane, remains on the anode side, and is discharged to the outside.

[0061] (B) Inside the proton conductive membrane, protons H generated by the oxidation of alcohol due to the application of voltage ＋ and heavy water D ２ An H-D exchange reaction occurs between O and D ＋ is further generated. ２ Direct oxidation of O also produces D ＋ is generated.

[0062] (B') D reaching the cathode side ２ O and H ＋ reacts, D ＋ and H ２ O becomes H ２ O returns to the inside of the proton conductive membrane, and D ＋ is present on the cathode surface.

[0063] (C) and (C') D reaching the cathode side of the proton conducting membrane ＋ is adsorbed onto the platinum catalyst on the cathode surface by applying a voltage (D ads ).

[0064] (D) The compound to be deuterated (RCHO) supplied to the cathode side of the proton conductive membrane is adsorbed onto the platinum catalyst on the cathode surface (RCHO ads ), deuterium ions D adsorbed on the platinum catalyst ads A deuterium-labeled compound (RCDO) is produced by an H-D exchange reaction between the proton H and the platinum catalyst (H ads ).

[0065] When alcohol is used as a proton source, D produced by direct oxidation of heavy water ＋ In addition, protons H ＋ is generated and an H-D exchange reaction occurs between the heavy water and the D that diffuses into the proton conductive membrane. ＋ is enriched, and the yield of the deuteration reaction on the cathode side can be improved.

[0066] Furthermore, the deuteration reaction of a compound when a sugar solution is used as a proton source will be explained. ６ H １２ O ６ By applying a voltage to the anode, gluconic acid (C ６ H １２ O ７ ) and proton H ＋ Generates proton H ＋ passes through the proton conducting membrane and diffuses into the interior of the proton conducting membrane.

[0067]

[0068] Heavy water D ２ O passes through the inside of the proton conductive membrane. Inside the proton conductive membrane, protons H generated by the oxidation of glucose due to the application of voltage ＋ and heavy water D ２ An H-D exchange reaction occurs between O and D ＋ is generated. ２ Direct oxidation of O also produces D ＋ is generated.

[0069]

[0070] On the cathode side surface of the proton conductive membrane, electrons e injected into the cathode by applying a voltage － and D ＋ recombines to form deuterium gas D ２ is generated.

[0071]

[0072] On the cathode surface of the proton conducting membrane, D ads Or the generated D ２ The gas reacts with the compound supplied to the cathode to produce a deuterium-labeled compound, which can be catalyzed by a metal catalyst such as platinum, palladium, or rhodium.

[0073] Furthermore, when a base is present together with the compound on the cathode side, hydrogen in the compound is activated, and deuteration can be promoted. The hydrogen activation reaction by the base is thought to occur on the surface of the proton conductive membrane, and the base may be supplied together with the compound to be deuterated, or may be applied to the cathode side surface of the proton conductive membrane. The amount of base added is 10 mol% to 80 mol%, preferably 20 mol% to 50 mol%, based on the compound to be deuterated. Usable bases include NaOH, Ca(OH) ２ metal hydroxides such as LiH and NaH, metal hydrides such as Cs ２ CO ３ , Na ２ CO ３ , K. ２ CO ３ Metal carbonates such as NaHCO ３ , K. ２ CO ３ metal bicarbonates such as sodium methoxide and potassium tert-butoxide; metal alkoxides such as NaNH ２ Suitable examples of the alkylamine include metal amides such as lithium diisopropylamide, n-butyllithium, and trimethylaluminum; alkylamines such as triethylamine, tetramethylethylenediamine, piperidine, and 1,4-diazabicyclo[2.2.2]octane; and heterocyclic amines such as diazabicycloundecene, pyridine, and imidazole.

[0074] When no base is added, aldehydes, alkynes, and benzyl hydrogens are preferentially deuterated, while when a base is added, aromatic rings can be deuterated. The base abstracts hydrogen, and the active D species reacts with the abstracted site. Because C-D bonds are stronger than C-H bonds, it is thought that abstraction of hydrogen H takes precedence, allowing for deuteration. It is thought that appropriate use of a base can improve substitution selectivity without destroying functional groups.

[0075] Next, the deuterium-labeled compound production apparatus of the present invention will be described with reference to the drawings. Figures 1 to 3 show an embodiment in which hydrogen gas is used as a proton source, and Figures 4 to 6 show an embodiment in which an alcohol or sugar solution is used as a proton source.

[0076] The deuterium-labeled compound manufacturing apparatus 1 of the present invention is characterized by comprising: a membrane electrode assembly 10 having an electrode catalyst 12 supported on the surface of a proton conductive membrane 14; a proton supply source and heavy water supply chamber 20 provided on the anode side of the membrane electrode assembly 10; a deuteration reaction chamber 30 provided on the cathode side of the membrane electrode assembly 10; and an electric current applying means 40 for applying electric current to the anode side surface and the cathode side surface of the membrane electrode assembly 10.

[0077] Fig. 1 is a side view of an apparatus for producing deuterium-labeled compounds that uses hydrogen gas as a proton source, and Fig. 2 is an exploded perspective view of Fig. 1. As shown in Figs. 1 and 2, a supply chamber 20 for the proton source and heavy water is provided with a supply port 22 for the proton source and heavy water and an outlet 24 for discharging unnecessary components produced by oxidation of the proton source, and a deuteration reaction chamber 30 is provided with an outlet 32 ​​for removing the deuterium-labeled compound. The supply port 22 is provided on a lower side of the supply chamber 20, and the outlet 24 is provided on an upper side of the supply chamber 20. Hydrogen gas, which serves as a proton source, is introduced into the heavy water and then sent to the supply chamber 20 via the supply port 22.

[0078] 2, it is preferable that the membrane electrode assembly 10 further includes carbon paper 16a and a carbon separator 18a as gas diffusion layers provided between the anode side surface of the membrane electrode assembly 10 and the supply chamber 20, and carbon paper 16c and a carbon separator 18c as gas diffusion layers provided between the cathode side surface of the membrane electrode assembly 10 and the deuteration reaction chamber 30. The carbon separator 18a has a plurality of through-holes, which allow the proton supply source and heavy water from the supply chamber 20 to pass through the carbon paper 16a and the proton conductive membrane 14. The carbon separator 18c has a plurality of through-holes, which allow the proton supply source and heavy water from the supply chamber 20 to pass through the carbon paper 16a and the proton conductive membrane 14. ＋ is passed through the deuterium conversion reaction chamber 30.

[0079] 3 is an enlarged view of a portion centered on the membrane electrode assembly 10. As shown in Fig. 3, an electrode catalyst 12 is provided on each of the anode side surface and the cathode side surface of the proton conductive membrane 14. A voltage can be applied to the membrane electrode assembly 10 via a current-carrying means 40 on the anode side surface and the cathode side surface of the membrane electrode assembly 10.

[0080] The supply chamber 20 and the deuteration reaction chamber 30 can be cells made of acrylic or Teflon (registered trademark). Since the deuteration method of the present invention can proceed at approximately room temperature, an acrylic cell with low heat resistance can be used. On the other hand, since a Teflon (registered trademark) cell is heat resistant, the reaction temperature can be increased to approximately 50°C.

[0081] Fig. 4 is a side view of a deuterium-labeled compound production apparatus that uses alcohol or a sugar solution as a proton source, and Fig. 5 is an exploded perspective view of Fig. 4. As shown in Figs. 4 and 5, the proton source and heavy water supply chamber 120 is provided with a proton source and heavy water supply inlet 122 and an outlet 124 for discharging unnecessary components generated by oxidation of the proton source, and the deuteration reaction chamber 130 is provided with an outlet 132 for removing the deuterium-labeled compound. The supply inlet 122 and the outlet 124 are provided on the upper surface of the supply chamber 120. The alcohol or sugar solution serving as the proton source is introduced into the supply chamber 120 via the supply inlet 122.

[0082] 5, it is preferable to further include carbon paper 116a and carbon separator 118a provided between the anode side surface of the membrane electrode assembly 110 and the supply chamber 120, and carbon paper 116c and carbon separator 118c provided between the cathode side surface of the membrane electrode assembly 110 and the deuteration reaction chamber 130. The carbon separator 118a has a plurality of through-holes, which allow the proton supply source and heavy water from the supply chamber 120 to pass through the carbon paper 116a and the proton conductive membrane 114. The carbon separator 118c has a plurality of through-holes, which allow the proton supply source and heavy water from the supply chamber 120 to pass through the carbon paper 116a and the proton conductive membrane 114. ＋ is passed through the deuterium conversion reaction chamber 130.

[0083] 6 is an enlarged view of a portion centered on the membrane electrode assembly. As shown in Fig. 6, an electrode catalyst 112 is provided on each of the anode side and cathode side of a proton conductive membrane 114. The anode side and cathode side surfaces of the membrane electrode assembly 110 are configured so that a voltage can be applied to the membrane electrode assembly 110 via a current-carrying means 140.

[0084] FIG. 7 is a schematic diagram illustrating the configuration of an asymmetric membrane electrode assembly. The asymmetric membrane electrode assembly 1 comprises a proton conductive membrane 4 carrying an electrode catalyst on the cathode side, a proton source (e.g., methanol, sugar) oxidation catalyst 21 on the anode side, and a porous support 41 beneath the oxidation catalyst 21. In the illustrated example, a graphene oxide nanosheet is used as the proton conductive membrane 4, precious metal nanoparticle-supported conductive carbon or oxide nanotubes are used as the electrode catalyst 2, Pt nanoparticle-supported graphene oxide nanosheets are used as the oxidation catalyst 21, and carbon paper is used as the porous support 41. The use of graphene oxide nanosheets allows for the fabrication of a dense, pinhole-free thin film, enabling the design of a junction interface suitable for proton transport in a multi-junction structure consisting of a porous support / catalyst layer / proton conductive membrane / catalyst layer. Although not shown, the proton conductive membrane 4 may be doped with hydroxymethanesulfonic acid, which is expected to improve proton conductivity. Furthermore, the proton conductive membrane 4 may be doped with polyvalent metal cations, which is expected to increase the interlayer space and improve the diffusibility of protons.

[0085] 8 is a schematic diagram of a circulating deuterium-labeled compound production apparatus that utilizes excess deuterium after a deuterium labeling reaction as heavy water. The circulating deuterium-labeled compound production apparatus comprises a proton supply source and heavy water supply chamber 20 provided on the anode side of a proton conductive membrane 10, a deuteration reaction chamber 30 provided on the cathode side of the proton conductive membrane 10, and a deuterium gas (D ２ ) to oxygen gas (O ２ ) and burn it to produce heavy water (D ２ The deuteration reaction chamber 30 has a catalytic combustor 40 for producing excess deuterium gas (D ２ The deuterium gas outlet 34 is provided to discharge deuterium gas (D ２ The deuterium gas supply line 42 is connected to a deuterium gas supply line 42 that carries oxygen gas (O ２ ) is supplied, and deuterium gas (D ２ ) and oxygen gas (O ２The mixture of deuterium gas (D) is introduced into the catalytic combustor 40. ２ ) to oxygen gas (O ２ ) in the presence of heavy water (D ２ O), such as Pt / C or Pt / Al ２ O ３ The heavy water (D) produced in the catalytic combustor 40 is ２ O) is supplied to the supply chamber 20 via the supply port 22. The circulation-type deuterium-labeled compound production apparatus reuses excess deuterium gas generated in the deuteration reaction chamber 30 to produce heavy water, which is used as a raw material for producing deuterium-labeled compounds, thereby reducing the amount of expensive heavy water required and suppressing the cost of producing deuterium-labeled compounds.

[0086] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these. [Example 1]

[0087] 1 to 3 was assembled, and a deuterium-labeled compound was electrochemically synthesized. An electrode catalyst 12 was supported on the surface of a proton-conductive membrane 14 to form a membrane electrode assembly 10. Carbon paper 16a, a carbon separator 18a, and a Teflon® cell serving as a gas diffusion layer and a supply chamber 20 were installed on the anode side of the membrane electrode assembly 10, and carbon paper 16c, a carbon separator 18c, and a Teflon® cell serving as a gas diffusion layer and a deuteration reaction chamber 30 were installed on the cathode side of the membrane electrode assembly 10. Teflon® cells measuring 60 mm x 60 mm x 30 mm were used for the supply chamber 20 and the deuteration reaction chamber 30. The proton conductive membrane 14 of the membrane electrode assembly 10 was a Pd particle-supported graphene oxide membrane (thickness: 220 μm, proton conductivity: 0.001 S / cm) or a Nafion 117 membrane (thickness: 117 μm, proton conductivity: 0.1 S / cm), and the electrode catalyst 12 was conductive carbon (Rh / C) supporting 20 wt % Rh for both the anode and cathode. The electrode area was 32 mm × 32 mm (10 cm ２ )

[0088] A mixed hydrogen gas of 5 vol% wet hydrogen and 95 vol% argon was used as a proton source, and 0.5 M D was supplied at 100 mL / min.２ SO ４ / D ２ O solution, and heavy water containing hydrogen gas was supplied to the supply chamber 20 from the supply port 22. Alkyne, aldehyde, chloroform, or methanol was used as the compound to be deuterized and supplied to the deuteration reaction chamber 30. A current of 10 mA / cm was applied to the membrane electrode assembly 10. ２ A current of 1000 kJ / cm was passed through the deuteration reaction chamber 30, and a voltage of 3 V was applied. The reaction temperature in the deuteration reaction chamber 30 was set to 25°C.

[0089] (Pd particle-supported graphene oxide membrane) Table 1 shows the results of deuterizing various alkynes and aldehydes using a Pd particle-supported graphene oxide membrane as the proton conductive membrane 14. The D incorporation rate (%) is the rate at which H is replaced with D, and the yield (%) is the rate at which deuterium-labeled compounds are synthesized (the same applies to the following tables). The D incorporation rate is １ H NMR and ２ It was calculated from the abundance of H and D measured by H NMR.

[0090]

[0091] 4-Methoxybenzaldehyde １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, CDCl3): δ [ppm] 9.80 (s, 0.03H), 7.75-7.79 (d, 2H), 6.92-6.95 (d, 2H), 3.82 (s, 2.94H); 2 H NMR (61 MHz, CHCl3): δ [ppm] 9.83 (s, 1D). The NMR spectrum is shown in Figure 9. It was confirmed that H in the aldehyde group was selectively replaced with D (4-Methoxybenzaldehyde-d1).

[0092] 4-methylbenzaldehyde １ H NMR and ２ The results of H NMR measurement are as follows: 1H NMR (400 MHz, CDCl3): δ [ppm] 9.94 (s, 0.23H), 7.73-7.76 (d, 2H), 7.29-7.32 (d, 2H), 2.41 (s, 3H); 2 H NMR (61 MHz, CHCl3): δ [ppm] 9.93 (s, 1D). The NMR spectrum is shown in Figure 10. It was confirmed that H in the aldehyde group was selectively replaced with D (4-Methylbenzaldehyde-d1).

[0093] Benzaldehyde １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, CDCl3): δ [ppm] 9.93 (s, 0.03H), 7.75-7.81 (m, 2H), 7.51-7.55 (m, 1H), 7.41-7.45 (m, 2H); 2 H NMR (61 MHz, CHCl3): δ [ppm] 9.93 (s, 1D). The NMR spectrum is shown in Figure 11. It was confirmed that H in the aldehyde group was selectively substituted with D (Benzaldehyde-α-d1).

[0094] Table 2 shows the results of deuteration of chloroform and methanol using a Pd particle-supported graphene oxide film as the proton conductive film 14.

[0095]

[0096] of chloroform ２ The results of H NMR measurement are as follows: 2 H NMR (61 MHz): δ [ppm] 7.26 (s, 1D). The NMR spectrum is shown in Figure 12. It was confirmed that H was replaced by D (Chloroform-d1).

[0097] of methanol ２ The results of H NMR measurement are as follows: 2H NMR (61 MHz): δ [ppm] 4.80 (s, 1D), 3.50 (s, 3D). The NMR spectrum is shown in Figure 13. It was confirmed that all H was replaced with D (methanol-d4).

[0098] With the exception of 4-methylbenzaldehyde, the D incorporation rate and yield for alkynes and aldehydes were both 90% or higher. Methanol and chloroform had an extremely high D incorporation rate of 99%, with almost all H being replaced by D, but the yield was low at 50% or less. Because the deuteration reaction is catalyzed by palladium, platinum, or the like, it is believed that the yield can be improved by optimizing the catalyst, reaction temperature, applied voltage, applied current, and other factors.

[0099] (Nafion 117 Membrane) Table 3 shows the results of deuteration of various alkynes and aldehydes using Nafion 117 membrane as the proton conductive membrane 14.

[0100]

[0101] Comparing the Pd particle-supported graphene oxide membrane used as the proton conductive membrane with the Nafion 117 membrane, it can be seen that the D incorporation rate and yield were similar except for ethynylbenzene, and the Nafion 117 membrane enabled a shorter reaction time. For ethynylbenzene, when the Nafion 117 membrane was used, both the D incorporation rate and yield decreased after a reaction time of 8 hours, indicating a high dependency on reaction time.

[0102] Example 2 For ethynylbenzene, a deuteration reaction was carried out in the same manner as in Example 1, using a Pd particle-supported graphene oxide membrane as the proton conductive membrane 14, with the reaction time increased in 2-hour increments from 2 hours to 24 hours. The results of confirming the progress of the deuteration reaction depending on the reaction time are shown in Figure 14. The D incorporation rate increases as the reaction time is increased, reaching an incorporation rate of 90% or more at approximately 22 hours. When using a Nafion 117 membrane, the D incorporation rate was 87% after a reaction time of 8 hours, so it is predicted that a D incorporation rate of 90% or more can be achieved by extending the reaction time to approximately 10 hours.

[0103] Example 3 The reaction apparatus shown in Figures 4 to 6 was assembled, and a deuterium-labeled compound was electrochemically synthesized. An electrode catalyst 112 was supported on the surface of a proton-conductive membrane 114 to form a membrane electrode assembly 110. A carbon paper 116a serving as a gas diffusion layer, a carbon separator 118a, and a Teflon (registered trademark) cell serving as a supply chamber 120 were installed on the anode side of the membrane electrode assembly 110. A carbon paper 116c serving as a gas diffusion layer, a carbon separator 118c, and a Teflon (registered trademark) cell serving as a deuteration reaction chamber 130 were installed on the cathode side of the membrane electrode assembly 110. A Nafion (117) membrane was used as the proton-conductive membrane 114 of the membrane electrode assembly 110, and conductive carbon (Rh / C) supporting 20 wt% Rh was used as the electrode catalyst 112 for both the anode and cathode. The electrode area was 32 mm x 32 mm (10 cm) for both the anode and cathode. ２ )

[0104] Methanol was used as a proton source, and heavy water was used in a 1M methanol / D ２ The O solution was supplied to the supply chamber 120 through the supply port 122. Alkyne was used as the compound to be deuterated and supplied to the deuteration reaction chamber 130. A current of 10 mA / cm was applied to the membrane electrode assembly 110. ２ A current of 1000 kJ / cm was passed through the electrode, and a voltage of 3.5 V was applied. The potential after passing the current is shown in Figure 15. The potential reached 3.5 V about 7 minutes after passing the current, and thereafter stabilized at 3.5 V. The reaction temperature in the deuteration reaction chamber 30 was set to 25°C. The results of deuteration are shown in Table 4.

[0105]

[0106] Ethynylbenzene １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR(400 MHz, CDCl3-d1): δ [ppm] 7.43-7.46 (m, 2H), 7.25-7.29 (m, 3H), 3.05 (s, 0.13H), 2.82 (s, Internal Standard=DMSO2, 6H). 2H NMR (61 MHz, CHCl3): δ [ppm] 3.06 (s, 1D), 4.33 (s, DO). The NMR spectrum is shown in Figure 16. It was confirmed that H of the ethynyl group was selectively replaced by D (Ethynylbenzene-d1).

[0107] 1-ethynyl-4-methylbenzene １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR(400 MHz, CDCl3): δ [ppm] 7.31-7.34 (d, 2H), 7.05-7.05 (d, 2H), 3.09 (s, 0.07H), 2.99 (s, Internal Standard=DMSO2, 6H), 2.29 (s, 3.02H); 2 H NMR (61 MHz, CHCl3): δ [ppm] 3.09 (s, 1D) The NMR spectrum is shown in Figure 17. It was confirmed that H of the ethynyl group was selectively substituted with D (1-ethynyl-4-methylbenzene-d1).

[0108] Example 4 The reaction apparatus shown in Figures 4 to 6 was assembled, and a deuterium-labeled compound was electrochemically synthesized. A membrane electrode assembly 110 was formed by supporting an electrode catalyst 112 on the surface of a proton-conductive membrane 114. A carbon paper 116a serving as a gas diffusion layer, a carbon separator 118a, and a Teflon (registered trademark) cell serving as a supply chamber 120 were installed on the anode side of the membrane electrode assembly 10, and a carbon paper 116c serving as a gas diffusion layer, a carbon separator 118c, and a Teflon (registered trademark) cell serving as a deuteration reaction chamber 130 were installed on the cathode side of the membrane electrode assembly 110. A Nafion (registered trademark) membrane was used as the proton-conductive membrane 114 of the membrane electrode assembly 110, and an Al (registered trademark) membrane supporting 5 wt% Ru was used as the electrode catalyst 112 for both the anode and cathode. ２ O ３ (Ru / Al ２ O ３ The electrode area was 32 mm × 32 mm (10 cm) for both the anode and cathode. ２ )

[0109] Methanol was used as a proton source, and heavy water was used in a 1M methanol / D ２ The O solution was supplied to the supply chamber 120 through the supply port 122. Alkyne was used as the compound to be deuterated and supplied to the deuteration reaction chamber 130. A current of 10 mA / cm was applied to the membrane electrode assembly 110. ２ A current of 1000 kJ / cm was passed through the reaction chamber 30, and a voltage of 3.5 V was applied. The reaction temperature in the deuteration reaction chamber 30 was set to 25° C. The results of deuteration are shown in Table 5.

[0110]

[0111] 1-ethynyl-4-methoxybenzene １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR(400 MHz, CDCl3): δ [ppm] 7.43-7.46 (m, 2H), 7.25-7.29 (m, 2H), 4.83 (s, D2O), 3.97 (s, 1H), 3.06 (s, 0.09H), 2.95 (s, Internal Standard=DMSO2, 6H); 2 H NMR (61 MHz, CHCl3): δ [ppm] 4.80 (s, DO), 3.92 (s, 2D). The NMR spectrum is shown in Figure 18. It was confirmed that the H of the ethynyl group and the H of the methoxy group were selectively replaced by D (1-ethynyl-4-methoxybenzene-d4).

[0112] 4 to 6 were assembled, and a deuterium-labeled compound was electrochemically synthesized. A membrane electrode assembly 110 was formed, with an electrode catalyst 112 supported on the surface of a proton-conductive membrane 114. A carbon paper 116a serving as a gas diffusion layer, a carbon separator 118a, and a Teflon® cell serving as a supply chamber 120 were installed on the anode side of the membrane electrode assembly 110. A carbon paper 116c serving as a gas diffusion layer, a carbon separator 118c, and a Teflon® cell serving as a deuteration reaction chamber 130 were installed on the cathode side of the membrane electrode assembly 110. A Nafion® membrane was used as the proton-conductive membrane 114 of the membrane electrode assembly 110. Conductive carbon (Pt / C) carrying 38 wt % Pt was used as the electrode catalyst 112 for the anode, and conductive carbon (Pd / C) carrying 5 wt % Pd was used for the cathode. The electrode area of ​​both the anode and cathode is 32 mm x 32 mm (10 cm ２ )

[0113] Methanol was used as a proton source, and heavy water was used in a 1M methanol / D ２ The O solution was supplied to the supply chamber 120 from the supply port 122. The compound to be deuterated was ibuprofen (or 4-isobutyl-α-methylbenzeneacetic acid), which is a pharmaceutical product, and supplied to the deuteration reaction chamber 130. The membrane electrode assembly 110 was supplied with a current of 10 mA / cm ２ A current of 1000 kJ / s was passed through the reaction chamber 30, and a voltage of 3.5 V was applied. The reaction temperature in the deuteration reaction chamber 30 was 25°C. The results of deuteration are shown in Table 6. In this example, the D incorporation rates d1 and d2 of two H atoms in the methyl group were 99%, and the D incorporation rate d3 of one H atom was 31%, both of which were low, after a reaction time of 12 hours. However, it is expected that d3 will also reach 99% if the reaction time is extended.

[0114]

[0115] Ibuprofen １ H NMR and ２ The results of H NMR measurement are as follows: 1H NMR(400 MHz, CDCl3): δ [ppm] 7.25-7.26 (m, 2H), 6.99-7.01 (m, 2H), 4.61 (m, 1H), 2.36 (s, 2H), 1.74 (s, 1H), 1.39 (d, 0.66H), 0.80 (d, 6H); 2 H NMR (61 MHz, CHCl): δ [ppm] 1.39 (s, 2.34D). The NMR spectrum is shown in Figure 19.

[0116] It can be confirmed that of the three methyl groups in ibuprofen, the methyl groups adjacent to each other are not deuterated, while the methyl groups at sites without adjacent methyl groups are deuterated, indicating that there is stereoselectivity for H, which is easily deuterated.

[0117] The structural formulas of the deuterium-labeled compounds produced by the deuteration reactions in Examples 1 to 5 are shown below. Deuterium-labeled compounds could be synthesized for aromatic terminal alkynes, aromatic aldehydes, chloroform, and methanol, and partial deuteration was achieved for ibuprofen.

[0118]

[0119] Example 6 The reactor shown in Figures 4 to 6 was assembled, and a deuterium-labeled compound was electrochemically synthesized. A membrane electrode assembly 110 was formed, with an electrode catalyst 112 supported on the surface of a proton-conductive membrane 114. A carbon paper 116a serving as a gas diffusion layer, a carbon separator 118a, and a Teflon cell serving as a supply chamber 120 were installed on the anode side of the membrane electrode assembly 110. A carbon paper 116c serving as a gas diffusion layer, a carbon separator 118c, and a Teflon cell serving as a deuteration reaction chamber 130 were installed on the cathode side of the membrane electrode assembly 110. A graphene oxide membrane was used as the proton-conductive membrane 114 of the membrane electrode assembly 110. Conductive carbon (Pt / C) carrying 38 wt% Pt was used as the electrode catalyst 112 for the anode, and conductive carbon (Pt / C) carrying 38 wt% Pt was used for the cathode. The electrode area of ​​both the anode and cathode is 32 mm x 32 mm (10 cm ２ )

[0120] Methanol was used as a proton source, and biphenyl or phenyl was used as a compound to be deuterated. ２ 0.7 mL of O solution was supplied to the supply chamber 120 through the supply port 122, and 7 mL of ethyl acetate containing biphenyl (0.5 mmol) or phenol (0.5 mmol) and cesium carbonate (39.09 mg, 0.12 mmol, 24 mol% relative to the raw material) as a catalyst were supplied to the deuteration reaction chamber 130. A current shown in Table 7 was passed through the membrane electrode assembly 110, and a voltage of 3 V was applied. The reaction temperature in the deuteration reaction chamber 30 was 25°C, and the reaction time was 24 hours. After completion of the reaction, the product in the ethyl acetate was concentrated in vacuo to obtain a pure white solid product. The results of deuteration are shown in Table 7.

[0121]

[0122] Biphenyl １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, CDCl3-d1): δ [ppm] 7.50-7.52 (m, 0.04H), 7.34-7.35 (m, 0.04H), 7.27-7.33(m, 0.02H), 3.61 (s, Internal Standard=1,4-dioxane, 8H). 2 H NMR (61 MHz, CHCl3): δ [ppm] 7.31-7.70 (m, 10D), 4.80 (s, DO). The NMR spectrum is shown in Figure 20. It was confirmed that all H in the benzene ring was deuterated with a high D introduction rate of 99% (Biphenyl-d 10 ).

[0123]

[0124] Phenol １ H NMR and ２ The results of H NMR measurement are as follows: 1H NMR (400 MHz, CDCl3-d1): δ [ppm] 7.22-7.26 (m, 0.22H), 7.12-7.16 (m, 0.24H), 2.97 (s, Internal Standard=DMSO2, 6H). 2 H NMR (61 MHz, CHCl3): δ [ppm] 7.36-7.83 (m, 5D), 5.09 (s, 1D), 4.80 (s, DO). The NMR spectrum is shown in Figure 21. It was confirmed that all H in the benzene rings were deuterated with a high D introduction rate of 91.54% on average, and that H in the OH groups was deuterated with a D introduction rate of 100% (Phenol-d6).

[0125]

[0126] By supplying the compound to be deuterized and cesium carbonate to the deuteration reaction chamber on the cathode side, all H in the benzene ring was replaced with D. From this, it is thought that cesium carbonate (base) activated the hydrogen in the benzene ring and promoted deuteration.

[0127]

[0128] 4 to 6 were assembled, and a deuterium-labeled compound was electrochemically synthesized. A membrane electrode assembly 110 was formed, with an electrode catalyst 112 supported on the surface of a proton-conductive membrane 114. A carbon paper 116a serving as a gas diffusion layer, a carbon separator 118a, and a Teflon® cell serving as a supply chamber 120 were installed on the anode side of the membrane electrode assembly 110. A carbon paper 116c serving as a gas diffusion layer, a carbon separator 118c, and a Teflon® cell serving as a deuteration reaction chamber 130 were installed on the cathode side of the membrane electrode assembly 110. A graphene oxide membrane was used as the proton-conductive membrane 114 of the membrane electrode assembly 110. Conductive carbon (Pt / C) carrying 38 wt % Pt was used as the electrode catalyst 112 for the anode, and conductive carbon (Pt / C) carrying 38 wt % Pt was used for the cathode. The electrode area of ​​both the anode and cathode is 32 mm x 32 mm (10 cm ２ )

[0129] Methanol was used as a proton source, and naphthalene, 2,3-dihydroxynaphthalene, 2-methylquinoline, 6-methoxyquinoline, xanthine, theophylline, caffeine, vitamin D3 (cholecalciferol), or ketoprofen was used as a compound to be deuterated. ２ 0.7 mL of O solution was supplied to the supply chamber 120 through the supply port 122, and 7 mL of ethyl acetate containing the compound to be deuterated (1 mmol) and cesium carbonate (39.09 mg, 0.12 mmol, 24 mol% relative to the raw material) as a catalyst were supplied to the deuteration reaction chamber 130. A current shown in Table 8 was applied to the membrane electrode assembly 110, and a voltage of 3 V was applied. The reaction temperature in the deuteration reaction chamber 30 was 25°C, and the reaction time was 24 hours. After completion of the reaction, the product in the ethyl acetate was concentrated in vacuo to obtain a solid product. The results of deuteration are shown in Table 8.

[0130]

[0131] Naphthalene (C 10 H8) １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, DMSO-d6): δ [ppm] 7.76-7.81 (m, 1H), 7.40-7.43 (m, 2H), 7.12 (s, 0.03H) 2 H NMR (67 MHz, CHCl3): δ [ppm] 7.67 (s, 4D), 7.40 (s, 4D). The NMR spectrum is shown in Figure 22. It was confirmed that all H atoms in the naphthalene ring were deuterated with a high D introduction rate of 75% (Naphtalene-D8).

[0132]

[0133] 2,3-dihydroxynaphthalene (C 10 H ８ O2) １ H NMR and ２ The results of H NMR measurement are as follows: 1H NMR (400 MHz, DMSO-d6): δ [ppm] 7.67-7.77 (m, 2H), 7.30-7.33 (m, 2H), 7.12 (s, 0.03H). 2 H NMR (67 MHz, CHCl3): δ [ppm] 9.00 (s, 2D), 7.81 (s, 2D). The NMR spectrum is shown in Figure 23. It was confirmed that the H of the hydroxy group bonded to the aromatic ring and the H bonded to the C adjacent to the C bonded to the hydroxy group were selectively deuterated with a D introduction rate of 99% (C 10 H4O2-D4).

[0134]

[0135] 2-methylquinoline (C 10 H9N) １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, DMSO-d6): δ [ppm] 8.15-8.19 (d, 1H), 7.87-7.89 (d, 1H),7.64-7.68 (d, 1H), 7.60-7.63 (m, 1H), 7.40-7.43 (m, 1H), 7.35 (s, 0.1H), 1,4-dioxane internal standard (s, 1H), 2.61 (s, 3H). 2 H NMR (67 MHz, CHCl3): δ [ppm] 8.07 (s, 1D), 7.30 (s, 1D). The NMR spectrum is shown in Figure 24. It was confirmed that the H of the CH group adjacent to the C of the heterocycle to which a methyl group is bonded and the H of the CH group adjacent to the CH group were selectively deuterated with a D introduction rate of 95% (2-methyl quinolone C 10 H7N-D2).

[0136]

[0137] 6-Methoxyquinoline １ H NMR and ２ The results of H NMR measurement are as follows: 1H NMR (400 MHz, DMSO-d6): δ [ppm] 8.80-8.82 (d, 1H), 8. 32-8.34 (d, 1H), 7.43-7.48 (d, 1H), 3.80 (s, 0.02H). 2 H NMR (67 MHz, CHCl3): δ [ppm] 7.37 (s, 1D), 4.90 (s, 1D), 3.72 (s, 3D). The NMR spectrum is shown in Figure 25. It was confirmed that the H of the methoxy group and the H of the CH groups adjacent to both sides of the C of the heterocycle to which the methoxy group is bonded were selectively deuterated with a high D introduction rate of 99% (6-meyhoxyquinoline-D5).

[0138]

[0139] Xanthine １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, DMSO-d6): δ [ppm] 7.85 (s, 0.15H), 3.52 (s, Internal Standard=1,4-dioxane, 8.00H). 2 H NMR (67 MHz, DMSO-d): δ [ppm] 7.87 (s, 1D) The NMR spectrum is shown in Figure 26. It was confirmed that the H of the CH group in the five-membered heterocyclic ring was selectively deuterated with a D introduction rate of 85% (Xanthine-D1).

[0140]

[0141] Theophylline １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, DMSO-d6): δ [ppm] 7.97 (s, 0.10H), 3.40-3.41 (s, 3.03H), 3.20-3.21(s, 3.03H), 3.53 (s, Internal Standard=1,4-dioxane, 8.00H). 2H NMR (67 MHz, CHCl): δ [ppm] 8.05 (s, 1D) The NMR spectrum is shown in Figure 27. It was confirmed that the H of the CH group in the five-membered heterocyclic ring was selectively deuterated with a D introduction rate of 90% (Throphylline-D1).

[0142]

[0143] Caffeine (C8H 10 N4O ２ )of １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, CDCl3): δ [ppm] 7.25 (s, CDCl3), 3.89 (s, 2.5H), 3.57 (s, Internal Standard=1,4-dioxane, 8.00H), 3.46-3.47(s, 3.03H), 3.32 (0.93H). 2 H NMR (67 MHz, CHCl3): δ [ppm] 7.48 (s, 1D), 3.32 (s, 3D). The NMR spectrum is shown in Figure 28. It was confirmed that the H of the methyl group sandwiched between the C=O groups of the six-membered heterocyclic ring and the H of the CH group of the five-membered heterocyclic ring were selectively deuterated with a D introduction rate of 77% (C8H ６ N4O ２ -D4).

[0144]

[0145] Vitamin D3 (cholecalciferol) １ H NMR and ２ The results of H NMR measurement are as follows: 1H NMR (400 MHz, CDCl3): δ [ppm] 6.20-6.23 (d, 1H), 6.0-6.03 (d, 1H), 5.03 (s, 1H), 4.80 (s, 1H), 3.90-3.92 (m, 1H), 3.57 (s, Internal Standard=1,4-dioxane, 8.00H), 2.53-2.54 (d. 1H), 2.15-2.29 (m, 4H), 1.98-1.99 (m, 1H), 1.66-1.68 (m, 3H), 1.50-1.52 (m, 3H), 1.45-1.49 (m, 7H), 1.29-1.34 (m, 5H), 1.12-1.29 (m, 3H), 1.04-1.12 (m, 3H), 0.89-0.99 (m, 3H), 0.52 (s, 3H). 2 H NMR (67 MHz, CHCl3): δ [ppm] 7.26 (CDCl3), 1.98 (s, 2D) NMR spectrum is shown in Figure 29. C=CH ２ It was confirmed that the H of the CH group adjacent to the group and the H of the CH group adjacent to the CH group were selectively deuterated with a D introduction rate of 97% (Vitamin D3 (cholecalciferol)-D2).

[0146]

[0147] Ketoprofen １ H NMR and ２ The results of H NMR measurement are as follows: 1 H NMR (400 MHz, CDCl3): δ [ppm] 7.77-7.80 (s, 2H), 7.75-7.76 (d, 1H), 7.57-7.59 (m, 2H), 7.44-7.47 (m, 2H), 7.25 (CDCl3), 3.69-3.71 (m, 0.07H), 3.57 (s, Internal Standard=1,4-dioxane, 8.00H), 1.15 (m, 3H). 2H NMR (67 MHz, CHCl3): δ [ppm] 7.54 (s, 1D), 3.86 (s, 1D) The NMR spectrum is shown in Figure 30. It was confirmed that the H of the CH group to which the methyl group is bonded and the H of the CH group at the meta position of the six-membered ring to which the CH group is bonded were selectively deuterated with a D introduction rate of 93% (Ketoprofen-D2).

[0148]

[0149] It was confirmed that by supplying the compound to be deuterated and cesium carbonate to the deuteration reaction chamber on the cathode side, not only the substituent but also the H of the heterocycle was substituted with D. From this, it is thought that the cesium carbonate (base) activated the hydrogen of the heterocycle and promoted deuteration. In addition, in the case of a heterocycle having a substituent, the H of the substituent or a CH group adjacent to the substituent tends to be preferentially deuterated, and the substituents are OH groups and CH ３ It was confirmed that groups tend to be preferentially deuterated.

[0150] Deuterium-labeled compounds are widely used in organic synthesis, but are expensive even in small quantities. The method and apparatus for producing deuterium-labeled compounds of the present invention provide a means for researchers to easily synthesize deuterium-labeled compounds in their own laboratories, which previously had to be purchased.

Claims

1. A method for producing a deuterium-labeled compound, comprising: supplying a proton source and heavy water to the anode side of a membrane electrode assembly including an electrode and a proton conductive membrane; supplying a compound to be deuterized to the cathode side of the membrane electrode assembly; and passing an electric current through the membrane electrode assembly to deuterize the compound on the cathode side.

2. The method for producing a deuterium-labeled compound according to claim 1, characterized in that the proton source is one or more selected from the group consisting of hydrogen gas, alcohol, sugar solution, organic acid, and amine compound.

3. The method for producing a deuterium-labeled compound according to claim 1 or 2, characterized in that a base is supplied to the cathode side together with the compound to be deuterized.

4. A method for producing a deuterium-labeled compound according to claim 1 or 2, characterized in that excess deuterium is recovered from the cathode side, mixed with oxygen and combusted to produce heavy water, and the resulting heavy water is supplied to the anode side.

5. The method for producing a deuterium-labeled compound according to claim 1 or 2, characterized in that a precious metal catalyst is supported on the surface of the anode side and / or the cathode side of the membrane electrode assembly.

6. An apparatus for producing a deuterium-labeled compound, comprising: a membrane electrode assembly having a proton conductive membrane and an electrode catalyst supported on the surface of the proton conductive membrane; a proton supply source and a heavy water supply chamber provided on the anode side of the membrane electrode assembly; a deuteration reaction chamber provided on the cathode side of the membrane electrode assembly; and an electric current supply means for supplying electric current to the anode side surface and the cathode side surface of the membrane electrode assembly.

7. The deuterium-labeled compound manufacturing apparatus according to claim 6, wherein the proton supply source and heavy water supply chamber includes a proton supply source and heavy water supply port, and an exhaust port for discharging unnecessary components.

8. The deuterium-labeled compound manufacturing apparatus as described in claim 6 or 7, further comprising a gas diffusion layer and a separator provided between the membrane electrode assembly and the proton supply source and heavy water supply chamber, and between the membrane electrode assembly and the deuteration reaction chamber, respectively.

9. The deuterium-labeled compound manufacturing apparatus according to claim 6 or 7, further comprising a catalytic combustor which recovers deuterium gas generated in the deuteration reaction chamber, mixes it with oxygen and combusts it to produce heavy water, and has a circulation type configuration in which the heavy water from the catalytic combustor is supplied to the proton supply source and the heavy water supply chamber.

10. The apparatus for producing a deuterium-labeled compound according to claim 6 or 7, characterized in that the electrode catalyst is a precious metal catalyst.

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