Deuterium-enriched composition, method for producing deuterium-substituted carboxylic acid, reaction promoter and use of compound for converting carboxylic acid to acid anhydride

Abstract

Provided is a deuterium-enriched composition comprising a deuterium-substituted carboxylic acid or a salt thereof, wherein the carboxylic acid or the salt thereof includes an α hydrogen of a carboxy group and a hydrogen other than the α hydrogen bonded to a carbon, the deuterium substitution rate of the α hydrogen is not less than 5%, the deuterium substitution rate of the hydrogen other than the α hydrogen is not more than 3%, and when the carboxylic acid or the salt thereof comprises, in the molecule thereof, a group having a carbonyl group other than the carboxy group, the α hydrogen of the carbonyl group is not included in hydrogen other than the α hydrogen.

Description

[Technical Field]

[0001] The present disclosure relates to deuterium-enriched compositions, methods for producing deuterium-substituted carboxylic acids, reaction promoters, and the use of compounds to convert carboxylic acids to acid anhydrides. [Background technology]

[0002] Introducing deuterium into functional molecules can improve their stability and durability while minimizing the impact on molecular function (Non-Patent Document 1). Furthermore, because deuterium-substituted compounds are easily analyzed by mass spectrometry and other methods, they are also used in research to track the in vivo fate of deuterium-labeled drugs (Non-Patent Documents 4-6). In recent years, the number of deuterated drugs on the market has increased (the world's first deuterated drug, deutetrabenazine, was approved by the FDA in 2017), and they have attracted attention as a patent strategy (Non-Patent Document 2). Furthermore, deuterium is widely used in organic synthesis for purposes such as improving the stability of protecting groups and analyzing reaction mechanisms (Non-Patent Document 3). As described above, deuterated compounds are widely used in basic and applied research, engineering, and medicinal chemistry, and their demand is increasing year by year (Patent Documents 1-3). However, deuterium-labeled compounds generally require multi-step synthesis from small deuterated raw materials, and innovative and practical synthetic methods for deuterium-labeled compounds with complex carbon skeletons and diverse functional groups are desired (Patent Documents 1-4, Non-Patent Documents 7-9). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2016-222590 [Patent Document 2] International Publication No. 2004 / 060831 [Patent Document 3] International Publication No. 2009 / 005069 [Patent Document 4] International Publication No. 2005 / 070853 [Non-patent literature]

[0004] [Non-Patent Document 1] Chemical Physics Letters, 2010, 491, p.199-202 [Non-Patent Document 2] Nature, 2009, Vol. 458, p.269 [Non-Patent Document 3] Science, 2004, Vol. 305, p.495-499 [Non-Patent Document 4] Science, 1935, Vol. 82, p.156-157 [Non-Patent Document 5] Science Advances, 2018, 4, eaat7314 [Non-Patent Document 6] Nature Biomedical Engineering 2019, 3, p.402-413 [Non-Patent Document 7] Chemistry A European Journal, 2007, Vol. 13, p.4052-4063 [Non-Patent Document 8] Advanced Synthesis and Catalysis, 2016, vol. 3584, p.3277-3282 [Non-Patent Document 9] Journal of The American Chemistry Society, 2021, 143, p.10895-10901 [Summary of the Invention] [Problems to be Solved by the Invention]

[0005] Carboxylic acids are readily available as biomass resources, with any structural unit. Furthermore, alkyl radicals can be generated by one-electron oxidation and reduction, making them suitable for use as raw materials for a wide variety of deuterium-labeled compounds. Therefore, deuteration of carboxylic acids has been studied extensively. However, conventional deuteration methods have not yet developed a practical method, due in part to the fact that deuteration proceeds randomly, not just at the α-position of the carboxylic acid.

[0006] The present disclosure has been made in view of the above circumstances, and aims to provide a deuterium-enriched composition containing a carboxylic acid in which an α-hydrogen is substituted with deuterium with high selectivity. The present disclosure also aims to provide a method for producing a deuterium-substituted carboxylic acid in which an α-hydrogen can be substituted with deuterium with high selectivity, a reaction promoter that can be used in such a method, and the use of a compound that converts a carboxylic acid to an acid anhydride. [Means for solving the problem]

[0007] The deuterium-enriched composition of the present disclosure is a deuterium-enriched composition comprising a deuterium-substituted carboxylic acid or a salt thereof, wherein the carboxylic acid or salt thereof comprises an α-hydrogen of a carboxy group and hydrogens other than the α-hydrogen bonded to carbon, the deuterium substitution rate of the α-hydrogen being 5% or more, and the deuterium substitution rate of the hydrogens other than the α-hydrogen being 3% or less, provided that if the carboxylic acid or salt thereof has a group containing a carbonyl group other than the carboxy group in the molecule, the α-hydrogen of the carbonyl group is not included in the hydrogens other than the α-hydrogen.

[0008] The carboxylic acid or salt thereof is preferably a compound in which at least one carboxylic acid or salt thereof selected from the following formulae (1) to (21) and (38) to (47) is deuterium-substituted. [ka] [ka] [ka]

[0009] The method for producing a deuterium-substituted carboxylic acid or a salt thereof according to the present disclosure includes a reaction step of converting a carboxylic acid or a salt thereof having an α-hydrogen into an acid anhydride, and substituting a hydrogen corresponding to the α-hydrogen in the acid anhydride with deuterium in the presence of a deuteration source.

[0010] The reaction step is preferably carried out in the presence of at least one of the following components (A) and (B): (A) A compound that undergoes a dehydration condensation reaction with the above carboxylic acid or a salt thereof to form an acid anhydride. (B) A compound that accelerates the reaction between the carboxylic acid or its salt and an oxoacid to form an acid anhydride of the carboxylic acid and the oxoacid.

[0011] The component (A) preferably contains an acid anhydride.

[0012] The component (B) preferably contains a condensing agent.

[0013] The condensing agent is preferably a carbodiimide or carbodiimide hydrochloride.

[0014] The above reaction step is preferably carried out in the presence of at least one of the following components (C) and (D): (C) Nucleophilic activators. (D) A salt of a strong base and an acid having an acidity lower than that of the carboxy group of the above carboxylic acid.

[0015] The component (C) is preferably at least one selected from the group consisting of quinuclidine, 1,4-diazabicyclo[2.2.2]octane, and 4-dimethylaminopyridine.

[0016] The component (D) is preferably at least one selected from the group consisting of carbonates, phosphates, and carboxylates.

[0017] Preferably, the deuterium source is a deuterated solvent.

[0018] The reaction step is preferably carried out in the presence of a co-solvent.

[0019] The reaction accelerator of the present disclosure is a reaction accelerator for accelerating the reaction of substituting the alpha hydrogen of a carboxylic acid or a salt thereof with deuterium, and includes a compound that converts the carboxylic acid or a salt thereof into an acid anhydride.

[0020] The use of the compound of the present disclosure for converting a carboxylic acid or a salt thereof to an acid anhydride is its use as a catalyst in a reaction for substituting the α-hydrogen of a compound having a carboxy group with deuterium. [Effects of the Invention]

[0021] According to the present disclosure, it is possible to provide a deuterium-enriched composition containing a carboxylic acid in which an α-hydrogen is substituted with deuterium with high selectivity. Also, according to the present disclosure, it is possible to provide a method for producing a deuterium-substituted carboxylic acid in which an α-hydrogen can be substituted with deuterium with high selectivity, a reaction promoter that can be used in such a method, and the use of a compound that converts a carboxylic acid to an acid anhydride. DETAILED DESCRIPTION OF THE INVENTION

[0022] (Method of producing deuterium-substituted carboxylic acid or its salt) The method for producing a deuterium-substituted carboxylic acid or a salt thereof of this embodiment includes a reaction step of converting a carboxylic acid or a salt thereof having an α-hydrogen into an acid anhydride and then substituting the hydrogen (protium) corresponding to the α-hydrogen in the acid anhydride with deuterium in the presence of a deuteration source. According to the production method of this embodiment, by converting a carboxylic acid or a salt thereof into an acid anhydride, the acidity of the α-hydrogen in the carboxylic acid or its salt is increased, allowing for efficient deuterium substitution of the α-hydrogen, thereby increasing the selectivity of the α-hydrogen for the deuterium substitution reaction. Furthermore, while conventional deuteration methods require expensive substances such as catalysts (e.g., noble metals) and deuterium gas, the production method of this embodiment allows for the deuterium substitution reaction to be carried out using relatively inexpensive compounds. Furthermore, while conventional deuteration methods require harsh conditions, such as the use of a strong base and extremely high temperatures, the production method of this embodiment can be carried out under relatively mild conditions.

[0023] The carboxylic acid used in the production method of this embodiment is not particularly limited as long as it has an α-hydrogen. In this specification, unless otherwise specified, the term "α-hydrogen" in relation to a carboxylic acid refers to a hydrogen atom bonded to a carbon atom (α-carbon) directly bonded to a carbon atom of a carboxy group of the carboxylic acid. In other words, the carboxylic acid has an α-carbon and an α-hydrogen. Hereinafter, the carboxylic acid used for the purpose of undergoing deuterium substitution in the method of this embodiment will also be simply referred to as a "substrate."

[0024] A carboxylic acid is a compound having a carboxy group, and may have one or more carboxy groups in the molecule. When a molecule has multiple carboxy groups, the hydrogen atom bonded to the α-carbon of one of the carboxy groups is considered to be the α-hydrogen of the carboxy group. Hereinafter, a carboxylic acid to be deuterium-substituted using the production method of this embodiment will also be referred to as a carboxylic acid to be deuterium-substituted. In this specification, a carboxy group refers to both a -COOH group and a salt of a -COOH group, depending on the context.

[0025] The carboxylic acid that can be used in the production method of this embodiment can be represented by the following general formula (A). [ka] (In formula (A), R is an organic group containing an α-hydrogen.)

[0026] The carboxylic acid may be acetic acid, but the carboxylic acid other than acetic acid may be at least one of the compounds represented by the following chemical formula (A1) and the compounds represented by the chemical formula (A2). [ka]

[0027] In formula (A1), R 1 is a monovalent organic group. More specifically, R 1 may be any one of the following groups (1) to (5): The number of carbon atoms in the monovalent organic group may be 1 to 50, 2 to 40, or 5 to 30. (1) A straight-chain or branched-chain hydrocarbon group (2) A group having a carbocyclic ring (the carbocyclic ring may be aliphatic or aromatic). (3) Groups containing heterocycles (4) (1) where the hydrogen bonded to the carbon is replaced with a substituent (excluding hydrocarbon groups) (5)-XR 5 A group represented by

[0028] Regarding group (1), the hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group. In the case of an unsaturated hydrocarbon group, it may have 1 to 6 unsaturated groups. Examples of groups having group (1) include fatty acids. Note that group (1) does not contain a carbon ring.

[0029] The carbocyclic ring in group (2) is a ring containing only carbon as ring members. A group having a carbocyclic ring may have one or more carbocyclic ring moieties within group (2). Two or more carbocyclic rings may form a fused ring, or may be linked by a single bond or a divalent or higher organic group. Furthermore, group (2) may have a linear or branched, substituted or unsubstituted aliphatic hydrocarbon moiety other than the carbocyclic ring, such as an alkyl group. The carbocyclic ring may be either aliphatic or aromatic. Examples of group (2) include groups containing a cyclopentane ring, a cyclohexane ring, an adamantyl ring, a tetrahydronaphthyl ring, a benzene ring, a biphenyl ring, an indene ring, and hexadecahydro-1H-cyclopenta[a]phenanthrene. The hydrogen atoms bonded to the carbon atoms that are ring members may be substituted with a substituent.

[0030] The heterocycle in group (3) may contain heteroatoms such as nitrogen, oxygen, and sulfur as ring members. The heterocycle may be either aliphatic or aromatic. Two or more heterocycles may form a fused ring or may be linked by a single bond or a divalent or higher organic group. Group (3) may also contain a carbocycle. The carbocycle may be fused with another ring or may be linked to another ring by a single bond or a divalent or higher organic group. Group (3) may also have a linear or branched, substituted or unsubstituted aliphatic hydrocarbon moiety other than the carbocycle, such as an alkyl group. A hydrogen atom bonded to a carbon atom that is a ring member of the heterocycle or carbocycle may be substituted with a substituent. A substituted or unsubstituted hydrocarbon group such as an alkyl group may be bonded to the nitrogen that is a ring member of the heterocycle (i.e., it may be an N-substituted form). Examples of the group (3) include groups containing a ring such as an oxazole ring, an N-phthalimide ring, a tetrahydropyran ring, an azetidine ring, a pyrrole ring, an indole ring (which may be an N-substituted indole ring), an indazole ring, an oxepin ring, etc. The oxepin ring having a substituent may be an oxoxepin ring, and the oxoxepin ring may be 11-oxo-6,11-dihydrodibenzo[b,e]oxepin or a substituted derivative thereof.

[0031] Examples of the substituent of the group (4) include a halogen atom, a methylsulfinyl group, an alkoxy group, a polyoxyalkylene group, etc. The group (4) does not include a carbocyclic ring or a heterocyclic ring.

[0032] In the group (5), X is a divalent group, and examples thereof include an ether bond (—O—), a thioether bond (—S—), and an amino group. 5 may be any of the groups (1) to (4). When X is -S-, it is preferable that it is not directly bonded to an atom (e.g., a carbon atom) that is a member of an aromatic ring (e.g., a benzene ring). 5 is R 5 is bonded to X through a carbon atom.

[0033] In formula (A2), R 2 and R 3 are each a monovalent organic group, or are joined together to form a ring. More specifically, the monovalent organic group may be any one of the following groups (1) to (5). The number of carbon atoms in the monovalent organic group may be 1 to 50, 2 to 40, or 5 to 30. (1) A straight-chain or branched-chain hydrocarbon group (2) A group having a carbocyclic ring (the carbocyclic ring may be aliphatic or aromatic). (3)-XR 5 A group represented by (4) Groups containing heterocycles (5) (1) to (4) in which the hydrogen bonded to the carbon atom is replaced with a substituent (excluding hydrocarbon groups) Examples of the groups (1) to (5) include those exemplified as the groups (1) to (5) in formula (A1). 2 and R 3 may be the same or different.

[0034] R 2 and R 3 are joined together to form a ring, R 2 and R 3 forms a ring containing the α carbon. In other words, R2 and R 3 are bonded together to form a divalent organic group, and both of the two bonding sites of the divalent organic group are bonded to the α-carbon. Examples of such a ring include the azetidine ring of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid and the adamantyl group of adamantane-2-carboxylic acid. The hydrogen atoms bonded to the carbon atoms that are ring members may be replaced by substituents. The number of carbon atoms in the divalent organic group may be 1 to 50, 2 to 40, or 5 to 30.

[0035] The carboxylic acid may be lithocholic acid or a derivative thereof, baclofen or a derivative thereof, oxaprozin or a derivative thereof, gabapentin or a derivative thereof, etodolac or a derivative thereof, isoxepac or a derivative thereof, indomethacin or a derivative thereof, sulindac or a derivative thereof, zomepirac or a derivative thereof, loxoprofen or a derivative thereof, sarcosine or a derivative thereof, an amino acid or a derivative thereof such as alanine, bendazac or a derivative thereof, phenylacetic acid or a derivative thereof, an aliphatic carboxylic acid having a 2-(1,3-dioxoisoindolin-2-yl) group, or the like. In this specification, the term "amino acid" generally refers to a compound having an amino group and a carboxy group in the molecule. Specifically, it may be any of the 20 amino acids (valine, isoleucine, leucine, methionine, lysine, phenylalanine, tryptophan, threonine, histidine, arginine, glycine, alanine, serine, tyrosine, cysteine, asparagine, glutamine, proline, aspartic acid, and glutamic acid) that are the building blocks of proteins in the body. Examples of substituents that phenylacetic acid derivatives have include fluorinated alkyl groups (which may be perfluoroalkyl groups) having 1 to 3 carbon atoms, such as -CF3, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, and NHBoc. The carboxylic acid of the aliphatic carboxylic acid having a 2-(1,3-dioxoisoindolin-2-yl) group may be an aliphatic carboxylic acid having 2 to 8 carbon atoms or an aliphatic carboxylic acid having 3 to 6 carbon atoms. The aliphatic carboxylic acid may be a linear or branched aliphatic carboxylic acid, or may be a linear carboxylic acid. The aliphatic carboxylic acid may have a substituent, and examples of the substituent include an alkylthioether group (the alkyl group may be a linear or branched alkyl group. The alkyl group may have 1 to 6 carbon atoms and may have 1 to 3 alkyl groups), an alkoxy group (the alkyl group in the alkoxy group may be a linear or branched alkyl group. The alkyl group may have 1 to 6 carbon atoms and may have 1 to 3 alkyl groups), and an amino group. The amino group as a substituent may be a secondary or tertiary amino group.The amino group may have 2 to 8 carbon atoms, or 4 to 6 carbon atoms. The amino group may have a cyclic structure containing the nitrogen atom of the amino group as a ring member. The 2-(1,3-dioxoisoindolin-2-yl) group may be bonded to a carbon atom other than the carbon atom of the carboxy group of the aliphatic carboxylic acid. The number of 2-(1,3-dioxoisoindolin-2-yl) groups contained in the aliphatic carboxylic acid having a 2-(1,3-dioxoisoindolin-2-yl) group may be 1 to 3, or may be 1 or 2, or may be 1.

[0036] The carboxylic acid may be a carboxylate. The counter cation of the carboxylate is not particularly limited, but may be a monovalent cation such as an alkali metal ion. The carboxylic acid used in the production method of the present embodiment may be either a carboxylic acid or a salt thereof, or may be a mixture of a carboxylic acid and a salt (for example, a partially neutralized carboxylic acid).

[0037] The carboxylic acid may have one or more carboxy groups (i.e., R in general formula (A) may have a carboxy group). In addition to the carboxy group, the carboxylic acid may have a group containing a carbonyl group (—C(═O)—), such as a keto group, a formyl group, or an ester group.

[0038] The carboxylic acid may have a hydrogen atom bonded to a carbon other than the α-hydrogen of the carboxy group. Examples of such a hydrogen atom include a hydrogen atom bonded to a carbon in the aliphatic portion of the carboxylic acid and a hydrogen atom bonded to a carbon that is a member of an aromatic ring. The production method of this embodiment has high selectivity for α-hydrogens with respect to deuterium substitution, and therefore, even if the carboxylic acid to be deuterium-substituted has hydrogen atoms other than the α-hydrogen of the carboxy group in the molecule, the deuterium substitution rate for hydrogens other than the α-hydrogen of the carboxy group is low. Note that, in considering selectivity, if the carboxylic acid has a group containing a carbonyl group other than a carboxy group in the molecule, the α-hydrogen of the carbonyl group is not included in the above-mentioned "hydrogens other than the α-hydrogen of the carboxy group."

[0039] When the carboxylic acid contains, in addition to the carboxy group, a group containing a carbonyl group, such as a keto group, formyl group, or ester group, particularly when the carboxylic acid contains a keto group, the α-hydrogen of the carbonyl group may also be substituted with deuterium by the production method of this embodiment. If deuterium substitution of the α-hydrogen of the carbonyl group (except when the α-hydrogen of the carbonyl group also serves as the α-hydrogen of the carboxylic acid) is not desired, the reactivity of the α-hydrogen of the carbonyl group can be easily reduced by protection such as acetalization or ketalization of the carbonyl group, or by transesterification. Therefore, the method of this embodiment is useful because it provides a low deuterium substitution rate for hydrogens that are not α-hydrogens of either the carboxy group or the carbonyl group in the carboxylic acid. Note that when the carbonyl group is an ester -C(═O)—OY, the deuterium substitution rate of the α-hydrogen of the carbonyl group tends to decrease when the carbon in the aliphatic portion of Y is bonded to the oxygen atom in the ester portion.

[0040] Specific examples of carboxylic acids include compounds represented by the above formulas (1) to (21) and (38) to (47). Specific examples of carboxylic acids also include compounds represented by the following formulas (31) to (37). In the above production method, the deuteration reaction may be performed on only one type of carboxylic acid to be deuterated, or the deuteration reaction may be performed on a carboxylic acid mixture containing multiple types of carboxylic acids. [ka]

[0041] The production method of this embodiment can naturally be applied to carboxylic acids (acetic acid, etc.) that do not have hydrogen atoms bonded to carbon atoms other than the α-hydrogen atom of the carboxy group.

[0042] In this specification, the term "acid anhydride" is not limited to compounds obtained by dehydration condensation between carboxylic acids, but generally refers to all compounds obtained by dehydration condensation between oxo acids. Note that the phrase "obtained by dehydration condensation" refers to the chemical structure of a compound formally obtained by such a reaction, and does not limit the actual synthesis method of the compound. Examples of oxo acids include carboxylic acids, sulfonic acids, and phosphinic acids.

[0043] As a method for converting a carboxylic acid to be deuterium-substituted into an acid anhydride, for example, the following components (A) and (B) can be mentioned, and at least one of components (A) and (B) can be used. (A) A compound that undergoes a dehydration condensation reaction with the carboxylic acid to be deuterated to form an acid anhydride. (B) A compound that promotes the reaction between a carboxylic acid to be deuterated and an oxoacid to form an acid anhydride of the carboxylic acid and the oxoacid.

[0044] Examples of the acid anhydride formed include an acid anhydride between carboxylic acids, an acid anhydride between a carboxylic acid and a sulfonic acid, and an acid anhydride between a carboxylic acid and a phosphinic acid. Specifically, the acid anhydride may be a compound represented by the following structural formula (X): [ka] (In formula (B), X is a monovalent group represented by any one of the following formulas (B1), (B2), and (B3). In formula (B1), R 11 is an organic group. In formula (B2), R 21 is an organic group. In formula (B3), R 31 and R 32 is an organic group. In formulas (B1) to (B3), * represents the bonding position between the oxygen atom and X in formula (B).

[0045] [ka]

[0046] R 11There are no particular limitations on R, as long as it is an organic group that forms a carbon-carbon bond with the carbonyl carbon atom of formula (B1). The number of carbon atoms in the organic group may be 1 to 30. Examples of the organic group include substituted or unsubstituted hydrocarbon groups and groups having a heterocycle. 11 and R may be the same or different.

[0047] R 11 may be an organic group having 1 to 10 carbon atoms, or may be an organic group having 1 to 8 carbon atoms. The organic group is not particularly limited, but examples thereof include hydrocarbon groups and halogenated hydrocarbon groups in which some or all of the hydrogen atoms in a hydrocarbon group have been substituted with halogen. Examples of halogenated hydrocarbon groups include fluorinated hydrocarbon groups, and perfluorinated hydrocarbon groups are preferred.

[0048] When X is a group represented by (B1), the component (A) is preferably a carboxylic acid derivative having a structure corresponding to formula (B1). Such a carboxylic acid derivative may be an acid anhydride, an acid chloride, an ester compound, or the like, with an acid anhydride being preferred. The carboxylic acid derivative preferably does not have an α-hydrogen atom for the carbonyl group of the carboxylic acid derivative.

[0049] The acid anhydride is not particularly limited and may be a compound represented by the general formula R 11 -C(=O)-OC(=O)-R 12 In this case, R 11 is R in formula (B1) 11 It has the same meaning as R 12 is an organic group, and R 11 R may be the same as or different from 12 A specific example of this is R 11 Examples of specific examples include: R 11 and R 12 At least one of R may have a quaternary carbon. 11 and R 12 At least one of the above preferably has no α-hydrogen when viewed from the acid anhydride group.

[0050] Specific examples of acid anhydrides include acetic anhydride, pivalic anhydride, trifluoromethylacetic anhydride, benzoic anhydride, phthalic anhydride, and diphenic anhydride. At least one selected from the group consisting of acetic anhydride, pivalic anhydride, trifluoromethylacetic anhydride, and benzoic anhydride is preferred, and at least one selected from the group consisting of pivalic anhydride, trifluoromethylacetic anhydride, and benzoic anhydride is more preferred.

[0051] The acid chlorides include those represented by the general formula R 11 -C(=O)Cl, where R 11 is R in formula (B1) 11 The acid chloride includes acetic acid chloride, pivalic acid chloride, trifluoromethylacetic acid chloride, benzoic acid chloride, and the like.

[0052] The ester compound is represented by the general formula R 11 -C(=O)-OAr, where R 11 is R in formula (B1) 11 has the same meaning as above. Ar is a group having an aromatic ring. In the ester compound, it is preferable that a carbon atom that is a member of the aromatic ring is directly bonded to the oxygen atom of the ester. The group having an aromatic ring may be a group having a hydrocarbon ring such as a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group, or a group having a heterocycle such as a pyridyl group. Examples of acid chlorides include phenyl acetate, phenyl pivalate, phenyl trifluoromethylacetate, and phenyl benzoate.

[0053] R 21 is not particularly limited, and may be, for example, an organic group having 1 to 30 carbon atoms. The organic group may be a substituted or unsubstituted hydrocarbon group, -OR 22 Group(R 22 is a substituted or unsubstituted hydrocarbon group), a group having a heterocycle, and the like.

[0054] When X is a group represented by (B2), the component (A) is a group represented by the general formula R 21 -SO2Cl, a compound represented by the general formula R 21 -SO2-O-SO2-R 22 In these formulas, R 21 is R in formula (B2) 21 It has the same meaning as R 22 is an organic group, and R 21 R may be the same as or different from 22 A specific example of this is R 21 The following are specific examples:

[0055] When X is a group represented by (B3), the component (A) is a group represented by the general formula R 31 R 32 POCl. In this general formula, R 31 and R 32 is R in formula (B3) 31 R 32 It has the same meaning.

[0056] The amount of component (A) used is not particularly limited, but is preferably 1 to 200 mol %, more preferably 5 to 150 mol %, and even more preferably 10 to 120 mol %, relative to 100 mol % of the carboxylic acid to be deuterated. The amount of component (A) used is preferably 0.01 to 2 equivalents, more preferably 0.05 to 1.5 equivalents, and preferably 0.1 to 1.2 equivalents, relative to the carboxy groups of the carboxylic acid to be deuterated.

[0057] Other examples of the component (A) include dicarbonate compounds (compounds having an -OC(=O)-OC(=O)-O- group) such as di-tert-butyl dicarbonate (Boc2O).

[0058] Component (B) can be any compound that promotes the reaction between the carboxylic acid to be deuterated and the oxoacid. It may be a compound such as a condensing agent that promotes the dehydration condensation reaction by, for example, abstracting water molecules, or it may be a catalyst for the dehydration condensation reaction. The oxoacid may be a compound different from the carboxylic acid to be deuterated, or it may be the carboxylic acid to be deuterated itself. That is, under the action of component (B), a compound other than the carboxylic acid to be deuterated may undergo a dehydration condensation reaction with another oxoacid that has been added to form an acid anhydride, or the carboxylic acids to be deuterated may react with each other to form an acid anhydride.

[0059] The condensing agent is not particularly limited, and examples thereof include carbodiimides and carbodiimide hydrochlorides, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N,N'-dicyclohexylcarbodiimide (DCC).

[0060] The amount of the condensing agent used is not particularly limited, and is preferably 1 to 100 mol %, more preferably 3 to 80 mol %, even more preferably 5 to 50 mol %, and particularly preferably 5 to 30 mol %, relative to 100 mol % of the carboxylic acid to be deuterated.

[0061] Examples of heavy hydrogen sources include deuterated solvents (deuterated solvents). The deuterated solvent is not particularly limited, but is preferably a compound having a carbonyl group. The compound having a carbonyl group is preferably a compound having an α-hydrogen atom of the carbonyl group, such as deuterated acetone.

[0062] The amount of the deuterium source used is preferably an excess (i.e., more than 1 equivalent) relative to the carboxy group of the carboxylic acid to be deuterated, more preferably 2 equivalents or more, even more preferably 5 to 80 equivalents, and particularly preferably 10 to 50 equivalents.

[0063] The reaction step may be carried out in the presence of at least one of the following components (C) and (D): (C) Nucleophilic activators. (D) A salt of a strong base and an acid having a lower acidity than the carboxy group of the carboxylic acid to be deuterated.

[0064] Component (C) is a compound that acts as a catalyst to promote elimination of carboxylic acid by nucleophilically attacking the carbonyl carbon of the acid anhydride, and examples of component (C) include quinuclidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), etc. One or more types of component (C) may be used.

[0065] The amount of component (C) used is not particularly limited, and is preferably 1 to 100 mol %, more preferably 3 to 80 mol %, even more preferably 5 to 50 mol %, and particularly preferably 5 to 30 mol %, relative to 100 mol % of the carboxylic acid to be deuterated.

[0066] Examples of component (D) include carbonates, phosphates, and carboxylates. One or more types of component (D) may be used. Examples of carbonates include salts of carbonate ions with cations such as alkali metals, quaternary ammonium ions such as tetramethylammonium, etc., with sodium carbonate, potassium carbonate, rubidium carbonate, or cesium carbonate being preferred, and potassium carbonate, rubidium carbonate, or cesium carbonate being more preferred. Examples of phosphates include salts of phosphate ions with cations such as alkali metals, quaternary ammonium ions such as tetramethylammonium, etc., with potassium phosphate being preferred.

[0067] The carboxylate ion contained in the carboxylate salt is not particularly limited, but is preferably a carboxylate ion without an α-hydrogen. Examples of such a carboxylate ion include a pivalate ion. Examples of the cation contained in the carboxylate salt include alkali metals and quaternary ammonium ions such as tetramethylammonium. Examples of the carboxylate salt include potassium pivalate, cesium pivalate, and tetramethylammonium pivalate.

[0068] The anion contained in component (D) is the conjugate base of an acid that has a lower acidity than the carboxy group of the carboxylic acid to be deuterated. Therefore, it is thought that the release of the weak acid causes the carboxylic acid to be deuterated to form a salt with the cation contained in component (D), promoting the formation of an acid anhydride.

[0069] The amount of component (D) used is not particularly limited, but is preferably 1 to 100 mol %, more preferably 3 to 80 mol %, even more preferably 5 to 50 mol %, and particularly preferably 5 to 30 mol %, relative to 100 mol % of the carboxylic acid to be deuterated.

[0070] Furthermore, the reaction step may be carried out in the presence of a co-solvent. When the carboxylic acid to be deuterated, components (A) to (D), etc. are poorly soluble in a deuterated solvent, it is effective to use a solvent that dissolves the poorly soluble components as a co-solvent. The co-solvent is not particularly limited, and is preferably an aprotic solvent, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), toluene, 1,2-dichloroethane (DCE), tetrahydrofuran (THF), or acetonitrile.

[0071] The reaction temperature in the reaction step is not particularly limited, and may be not more than 100° C., or may be not more than 80° C. The reaction time is also not particularly limited, and may be, for example, 0.5 to 72 hours.

[0072] By the above production method, a deuterium-enriched composition containing a carboxylic acid in which the α-hydrogen has been substituted with deuterium can be produced. That is, the deuterium-enriched composition of this embodiment comprises a deuterium-substituted carboxylic acid, the carboxylic acid comprising the α-hydrogen of a carboxy group and hydrogens other than the α-hydrogen bonded to carbon, the deuterium substitution rate of the α-hydrogen being 5% or more, and the deuterium substitution rate of hydrogens other than the α-hydrogen being 3% or less, provided that if the carboxylic acid comprises a group having a carbonyl group other than the carboxy group in the molecule, the α-hydrogen of the carbonyl group is not included in the hydrogens other than the α-hydrogen.

[0073] As used herein, "deuterium enriched" refers to a composition in which the content of deuterium is increased relative to its natural abundance. The deuterium-enriched composition contains a deuterated carboxylic acid and may contain unreacted carboxylic acid and unavoidable impurities. The deuterium-enriched composition of this embodiment is a composition in which the α-hydrogen of the carboxylic acid contained therein is enriched with deuterium.

[0074] The deuterium substitution rate, in the case of the α-hydrogen of a carboxy group, refers to the ratio of deuterated hydrogen to the hydrogen bonded to the α-carbon of the carboxy group of the carboxylic acid in the deuterium-enriched composition. In other words, it is the ratio of deuterium to the total hydrogen (the sum of protium and deuterium) bonded to the α-carbon. The deuteration rate is 1 It can be calculated from the integrated intensity of the HNMR spectrum. When there are multiple α-hydrogens in a carboxylic acid molecule, the deuterium substitution rate is calculated as the deuterium substitution rate per equivalent carbon in the molecule. For example, succinic acid (HOOC-C A H2-C B H2-COOH) with two α-carbons C A and C B are equivalent, so C A and C B The ratio of deuterium to all hydrogen atoms (irrespective of isotope) bonded to the molecule is called the deuterium substitution rate. A H(CH3)-C B H2-COOH) with two α-carbons C A and C B are not equivalent, so the deuterium substitution rate is C A and C B Calculate separately for each of the above.

[0075] There is no problem with the deuterium substitution rate of α hydrogen being 5% or more, but it may be 10% or more, 20% or more, 30% or more, 50% or more, or 70% or more.

[0076] The deuterium substitution rate for hydrogens other than α-hydrogens is the ratio of deuterium to all hydrogens bonded to all carbons other than α-carbons (excluding the α-carbon of a carbonyl group in cases where the carboxylic acid has a group with a carbonyl group other than a carboxy group). The deuterium substitution rate may be 1% or less, 0.1% or less, or even approximately 0% (i.e., almost the same as the natural abundance rate).

[0077] The reaction accelerator of this embodiment is a reaction accelerator for accelerating the reaction of substituting the α-hydrogen of a carboxylic acid with deuterium, and contains a compound that converts the carboxylic acid to an acid anhydride. The reaction accelerator preferably contains at least one of component (A) and component (B), and more preferably contains at least one of component (A) and component (B), component (C), and component (D). [Example]

[0078] The present disclosure will be further described below using examples, but the present disclosure is not limited to the following examples.

[0079] <Deuteration of 4-(4-methoxyphenyl)butyric acid> [Example 1] The deuteration experiment of 4-(4-methoxyphenyl)butyric acid is described below. 4-(4-Methoxyphenyl)butyric acid (7.0 mmol) was added to a vial, along with 10 mol% potassium carbonate and 10 mol% DMAP relative to 100 mol% 4-(4-methoxyphenyl)butyric acid. Subsequently, deuterated acetone (acetone-d6) and 20 mol% pivalic anhydride (8 μL, 0.04 mmol) relative to 100 mol% 4-(4-methoxyphenyl)butyric acid were added. The amount of acetone-d6 was 19.4 equivalents (0.70 M) relative to 4-(4-methoxyphenyl)butyric acid. After stirring at 40 °C for 48 h, the reaction was quenched by adding DO (0.10 mL) and stirring at room temperature (25 °C) for 1 h. 1 M aqueous hydrochloric acid was added to the reaction solution, which was then extracted with CHCl, and the solvent was removed under reduced pressure. To remove pivalic acid, 2 mL of CHCl:formic acid (volume ratio: 4:1) was added to the residue and the solvent was distilled off. This azeotropic distillation was repeated three times. The residue was then purified by silica gel column chromatography. Regarding the obtained product 1 H NMR, 13 C NMR, infrared spectroscopy (IR), and accurate mass spectroscopy (HRMS (electrospray ionization, ESI)) confirmed that the product was a deuterium-enriched version of 4-(4-methoxyphenyl)butyric acid. The NMR measurements were performed using an Avance III (Bruker).

[0080] 1 The deuterium substitution rate of α-hydrogen in the product was calculated from the integrated intensity of HNMR. The deuterium substitution rate was 94%. The deuterium substitution rate of α-hydrogen is the ratio of the number of deuterium-substituted α-hydrogens to the total number of α-hydrogens in 4-(4-methoxyphenyl)butyric acid contained in the product (i.e., the total number of Ds at the α-position divided by the sum of D and H at the α-position). The deuterium substitution rate is 1 It was calculated from the ratio of the number of α-hydrogen atoms to the number of hydrogen atoms other than α-hydrogen atoms from the HNMR spectrum. The yield of 4-(4-methoxyphenyl)butyric acid was 82%. The yield is the ratio of 4-(4-methoxyphenyl)butyric acid (including both α-deuterium-substituted and non-α-deuterium-substituted) contained in the product to the amount of 4-(4-methoxyphenyl)butyric acid used as the substrate. The yield was calculated using the following method. (1) The weight of an empty 50 mL recovery flask was measured in advance, the purified product solution was added, the solvent was distilled off, and the recovery flask was reweighed. The yield (mg) of the product was calculated from the difference in weight. (2) Next, calculate the molecular weight with a deuteration rate of 0% and the molecular weight with a 100% α-deuteration rate using chemdraw. 1 The molecular weight was calculated based on the measured deuteration rate calculated from the H NMR spectrum. (Example: 4-(4-methoxyphenyl)butyric acid: d0 molecular weight 194.2300, d2 molecular weight 196.2422. When the deuteration rate is 94%, the molecular weight is 196.2422 x 0.94 + 194.2300 x 0.06 = 196.1215.) (3) The yield (mg) was divided by the calculated molecular weight to calculate the yield (mmol), and the yield (mmol) was divided by the amount (mmol) of carboxylic acid added as a substrate to calculate the yield (%). The obtained product 1-d2 weighed 1.12 g, and production on a gram scale was also possible.

[0081] 4-(4-Methoxyphenyl)butyric acid has 11 hydrogen atoms bonded to carbons other than the alpha carbon, including two beta and gamma hydrogens of the carboxyl group, four hydrogens bonded to the benzene ring, and three hydrogens bonded to the methyl group. 1 When the integrated intensity of 1H NMR was examined, deuterium substitution was not observed for hydrogens bonded to carbons other than the α-carbon of 4-(4-methoxyphenyl)butyric acid (i.e., it was below the detection limit).

[0082] In all of the following examples, deuterium substitution of hydrogen other than the α-hydrogen (excluding the α-hydrogen of carbonyl groups other than carboxy groups) was not detected. 1This can be seen from the fact that the integrated intensities of the peaks of hydrogens other than α-hydrogens in HNMR match within the error range compared to the intensities of each peak before deuterium substitution. Furthermore, as will be described later, the measured and calculated values ​​of the mass spectrum agree well, and the spectrum itself is sharp, which negates the possibility that deuterium substitution has occurred evenly throughout the molecule.

[0083] On the other hand, in conventional methods, for example, the method of International Publication No. 2005 / 070853, deuteration occurs indiscriminately for hydrogens other than the α-hydrogen. Furthermore, referring to page 4054 of Non-Patent Document 7, page 3279 of Non-Patent Document 8, and page 10897 of Non-Patent Document 9, deuterium substitution also occurs for hydrogens other than the α-hydrogen of carboxylic acid. The method of the present embodiment does not use a strong reagent such as a strong base or a reagent that strongly catalyzes the hydrogen abstraction reaction such as a metal catalyst, but instead utilizes the acidity of the hydrogen corresponding to the α-hydrogen of the carboxy group in the acid anhydride. Therefore, it is considered that the difference in reactivity between the α-hydrogen and hydrogens other than the α-hydrogen is large, resulting in high selectivity.

[0084] The proposed reaction mechanism for the catalytic deuterium substitution reaction of 4-(4-methoxyphenyl)butyric acid is believed to be as follows: [ka]

[0085] First, the addition of potassium carbonate, a weak Brønsted base, abstracts the proton from the carboxyl group of the carboxylic acid present in the system, generating a carboxylate ion and forming an acid anhydride mixture (I). The acid anhydride mixture (I) and DMAP then generate an acylpyridinium species (II). The carboxylate ion, a weak Brønsted base, abstracts a hydrogen atom, generating a carboxylic acid by-product and an enolate (III) derived from the acylpyridinium species (II). The enolate (III) reacts with an R'COOD (right-handed cycle) generated from the deuterated acetone to generate an α-deuterated acylpyridinium species (IV). An acyl exchange reaction then occurs, generating a deuterated carboxylic acid.

[0086] [Example 2] 4-(4-Methoxyphenyl)butyric acid (0.20 mmol) and 1.0 equivalent of potassium acetate (2.8 mg, 0.02 mmol) relative to the 4-(4-methoxyphenyl)butyric acid were added to a 4 mL vial containing a stir bar. Subsequently, acetone-d6 and 1.0 equivalent of acetic anhydride relative to the 4-(4-methoxyphenyl)butyric acid were added. The amount of acetone-d6 used was 34 equivalents (0.40 M) relative to the 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 70 °C for 16 hours, the product was separated by preparative thin-layer chromatography (PTLC) to determine the deuterium substitution rate, which was 95%.

[0087] [Example 3] Deuteration tests were carried out by changing the type of acid anhydride. Specifically, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol% potassium carbonate relative to the 4-(4-methoxyphenyl)butyric acid were added to a 4 mL vial containing a stir bar. Subsequently, acetone-d6 and 1.0 equivalent of an acid anhydride (Table 1) relative to the 4-(4-methoxyphenyl)butyric acid were added. The amount of acetone-d6 used was 34 equivalents (0.40 M) relative to the 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 60 °C for 16 hours, the product was separated by PTLC to determine the deuterium substitution rate. The results are shown in Table 1. [Table 1]

[0088] [Example 4] Deuteration tests were carried out using a condensing agent (DCC) instead of an acid anhydride. Specifically, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and the amounts of cesium carbonate, DCC, and DMAP shown in Table 2 were added to a 4 mL vial containing a stir bar. Subsequently, acetone-d6 was added. The amount of acetone-d6 used was 34 equivalents (0.40 M) relative to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 40°C for 6 hours, the product was separated by PTLC to determine the deuterium substitution rate. The results are shown in Table 2. The amount of each component used in Table 2 is the amount (mol %) relative to 100 mol % of 4-(4-methoxyphenyl)butyric acid. [Table 2]

[0089] [Example 5] 4-(4-Methoxyphenyl)butyric acid (0.20 mmol), 10 mol% potassium carbonate (2.8 mg, 0.02 mmol), 20 mol% DCC, and 10 mol% DMAP were added to a 4 mL vial containing a stir bar. A mixed solvent of acetone-d6 and dimethyl sulfoxide (volume ratio 1:1) was added. The amount of acetone-d6 used was 34 equivalents (0.20 M (mixed solvent of acetone-d6 and dimethyl sulfoxide)) relative to 4-(4-methoxyphenyl)butyric acid. After stirring at 40 °C for 24 hours, the product was separated by PTLC to determine the deuterium substitution rate. The deuterium substitution rate was 66%.

[0090] [Example 6] Deuteration tests were carried out by changing the type of acid anhydride. 4-(4-Methoxyphenyl)butyric acid (0.20 mmol) was added to a 4 mL vial containing a stir bar. 20 mol % potassium carbonate and 10 mol % DMAP were added relative to 100 mol % 4-(4-methoxyphenyl)butyric acid. Subsequently, acetone-d6 and the acid anhydrides shown in Table 3 were added. The amount of acetone-d6 used was 34 equivalents (0.40 M) relative to 4-(4-methoxyphenyl)butyric acid. The reaction solution was stirred at 60 °C for 24 hours, after which the product was separated by PTLC to determine the deuterium substitution rate. The results are shown in Table 3. The amount of acid anhydride used was 100 mol % relative to 100 mol % 4-(4-methoxyphenyl)butyric acid. [Table 3]

[0091] [Example 7] Deuteration tests were carried out by changing the type of nucleophilic activator. Specifically, 4-(4-methoxyphenyl)butyric acid, 10 mol% potassium carbonate, and 10 mol% of the nucleophilic activator shown in Table 4 were added to a 4 mL vial containing a stir bar. Subsequently, acetone-d6 and 20 mol% pivalic anhydride were added to 100 mol% 4-(4-methoxyphenyl)butyric acid. The amount of acetone-d6 used was 34 equivalents (0.40 M) relative to 4-(4-methoxyphenyl)butyric acid. The reaction solution was stirred at 40 °C for 12 hours, and the product was separated by PTLC to determine the deuterium substitution rate. The results are shown in Table 4. [Table 4]

[0092] [Example 8] Deuteration tests were carried out using different salt types. Specifically, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol % of the salt shown in Table 5 relative to 100 mol % of 4-(4-methoxyphenyl)butyric acid were added to a 4 mL vial containing a stir bar. Subsequently, acetone-d6 and 100 mol % of pivalic anhydride relative to 100 mol % of 4-(4-methoxyphenyl)butyric acid were added. The amount of acetone-d6 used was 34 equivalents (0.40 M) relative to 4-(4-methoxyphenyl)butyric acid. The reaction solution was stirred at 60 °C for 4 hours, and the product was separated by PTLC to determine the deuterium substitution rate. The results are shown in Table 5. OPiv represents pivalate ion. [Table 5]

[0093] [Example 9] 4-(4-Methoxyphenyl)butyric acid (0.20 mmol) was added to a 4 mL vial containing a stir bar. 20 mol % potassium carbonate and 10 mol % DMAP (Experiment 4 only) were added to 100 mol % 4-(4-methoxyphenyl)butyric acid. Subsequently, acetone-d6 and 100 mol % pivalic anhydride (8 μL, 0.04 mmol) were added to 100 mol % 4-(4-methoxyphenyl)butyric acid. The amount of acetone-d6 used was 34 equivalents (0.40 M) relative to 4-(4-methoxyphenyl)butyric acid. The reaction was carried out at the reaction temperature and time shown in Table 6. After the reaction, the product was separated by PTLC to determine the deuterium substitution rate. The results are shown in Table 6. [Table 6]

[0094] [Example 10] 4-(4-Methoxyphenyl)butyric acid (0.20 mmol) was added to a 4 mL vial containing a stir bar. 10 mol % potassium carbonate and 10 mol % DMAP were added to 100 mol % 4-(4-methoxyphenyl)butyric acid. A 1:1 volumetric mixture of acetone-d6 and the cosolvents listed in Table 7 was then added, along with 20 mol % pivalic anhydride (8 μL, 0.04 mmol) to 100 mol % 4-(4-methoxyphenyl)butyric acid. The amount of acetone-d6 used was 34 equivalents relative to 4-(4-methoxyphenyl)butyric acid. After stirring at 60 °C for 4 hours, the product was separated by PTLC to determine the deuterium substitution rate. The results are shown in Table 7. [Table 7]

[0095] [Example 11] Below, we performed deuterium substitution experiments (1) to (21) and (31) to (37) using various carboxylic acids as substrates. In each experiment, 10 mol % of potassium carbonate, 20 mol % of pivalic anhydride, and 10 mol % of DMAP were used relative to 100 mol % of carboxylic acid. Unless otherwise specified below, the amount of acetone-d6 used is 34 equivalents (0.40 M) relative to the carboxylic acid when no cosolvent is used, and 34 equivalents (0.20 M (mixed solvent of acetone-d6 and cosolvent)) relative to the carboxylic acid when a cosolvent is used. Unless otherwise specified below, the reaction solution in each experiment was stirred at 40°C for 48 hours to carry out the reaction. After the reaction in each experiment, D2O (0.10 mL) was added to the reaction solution and stirred at room temperature for 1 hour to quench the reaction. Unless otherwise stated below, 1 HNMR and 13 CNMR peak positions are expressed in ppm, and IR peak positions are expressed in cm. -1 Also, 1 The peak of the non-deuterated solvent contained in the deuterated solvent was used as the reference for the H NMR chemical shifts. That is, when CDCl3 was used as the deuterated solvent, the H peak of CHCl3 (δ 7.26 ppm) was used, and when methanol-d4 was used as the deuterated solvent, the hydrogen peak of the methyl group (δ 3.31 ppm) was used. 13 The peak of the deuterated solvent was used as the reference for the chemical shifts in CNMR.

[0096] [ka] (1) 4-(4-methoxyphenyl)butyric acid 4-(4-Methoxyphenyl)butyric acid (compound (1), 38.8 mg, 0.20 mmol) was used as the substrate. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate: 94%, yield: 98%, 38.5 mg). 1 HNMR (500MHz, CDCl3): δ7.10 (d, J=9.0Hz, 2H, ArH), 6.83 (d, J=9.0Hz, 2H, ArH), 3.79 (s, 3H, ArOCH3) ), 2.62(t, J=7.5Hz, 2H, ArCH2), 2.33(m, 0.12H, CH2COOH, 94%D), 1.92(t, J=7.5Hz, 2H, CH2CD2COOH) 13 CNMR (125MHz, CDCl3): δ180.0, 157.9, 133.3, 129.4, 113.8, 55.3, 34.0, 32.7, 26.3 IR (NEAT): 1695, 1510, 1412, 1300, 1277, 1242, 1182, 1175, 1026, 947, 831, 814, 557, 525, 403 HRMS(ESI)m / z:C 11 H 12 D2NaO3(M+Na) + Calculated value: 219.0961, measured value: 219.0978

[0097] (1)'4-(4-methoxyphenyl)butyric acid The deuterium substitution experiment was carried out in the same manner as in (1), except that pivalic anhydride was replaced with di-tert-butyl dicarbonate (BocO). The deuterium substitution rate was 97%, and the yield was 86%.

[0098] [ka] (2) 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (compound (2), 43.0 mg, 0.20 mmol) was used as the substrate. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate: 98%, yield: 90%, 38.9 mg). 1 HNMR (500MHz, CDCl3): δ4.09(dd, J=8.5, 8.5Hz, 2H, N(CH2)2), 3.63(dd, J=8.5, 5.5Hz, 2H, N(CH 2)2), 2.89-2.84(m, 1H, CHCD2COOH), 2.65(m, 0.05H, CH2COOH, 98%D), 1.43(s, 9H, NCOOC(CH3)3) 13 CNMR (125MHz, CDCl3): δ176.5, 156.5, 79.7, 54.2, 38.0, 28.4, 24.9 IR (NEAT): 1721, 1641, 1422, 1396, 1366, 1341, 1254, 1221, 1063, 968, 856, 818, 768, 635, 561 HRMS(ESI)m / z:C 10 H 15 D2NNaO4(M+Na) + Calculated value: 240.1175, Measured value: 240.1170

[0099] [ka] (3) 6-ethoxy-6-oxohexanoic acid 6-Ethoxy-6-oxohexanoic acid (compound (3), 32.0 μL, 0.20 mmol) was used as the substrate. The product was obtained without silica gel flash column chromatography (colorless liquid, deuterium substitution rate 96%, yield: 88%, 31.1 mg). 1 HNMR (500MHz, CDCl3): δ4.13(q, J=7.0Hz, 2H, COOCH2CH3), 2.34-2.31(m, 2.08H, CH2COO H+CH2COOEt, 96%D), 1.68-1.67(m, 4H, CD2CH2CH2CH2), 1.26(t, J=7.0Hz, 3H, COOCH2CH3) 13 CNMR (125MHz, CDCl3): δ179.5, 173.4, 60.4, 33.9, 33.1, 24.3, 24.0, 14.2 IR (NEAT): 411, 438, 451, 746, 945, 1028, 1086, 1117, 1167, 1252, 1344, 1373, 1703, 1730, 2938 HRMS(ESI)m / z:C8H 12 D2NaO4(M+Na) + Calculated value: 199.0910, Measured value: 199.0915 In addition, 1 HNMR showed no deuterium substitution on the α hydrogen of the ester group (-C(=O)OEt).

[0100] [ka] (4) 5-oxo-5-phenylpentanoic acid 5-Oxo-5-phenylpentanoic acid (compound (4), 38.4 mg, 0.20 mmol) was used as the substrate. The product was obtained without silica gel flash column chromatography. (White solid, D a : Deuterium substitution rate 93%, D b Deuterium substitution rate: 96%, yield: 76%, 30.0 mg) 1 HNMR (500MHz, CDCl3): δ7.96(d, J=7.0Hz, 2H, ArH), 7.57(t, J=7.0Hz, 1H, ArH), 7.46(t, J=7.0Hz, 2 H, ArH), 3.08(m, 0.08H, CH2COPh, 96%D), 2.49(m, 0.14H, CH2COOH, 93%D), 2.07(s, 2H, CH2CD2COOH) 13 CNMR (125MHz, CDCl3): δ199.5, 179.4, 136.8, 133.2, 128.6, 128.0, 36.6, 32.5, 18.8 IR (NEAT): 1690, 1668, 1304, 1273, 1126, 991, 947, 910, 837, 766, 756, 723, 691, 665, 652 HRMS(ESI)m / z:C 11 H8D4NaO3(M+Na) + Calculated value: 219.0930, Measured value: 219.0942

[0101] [ka] (5) (R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-acetoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-acetoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (compound (5), 83.7 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) afforded the product (white solid, deuterium substitution rate 90%, yield: 91%, 76.6 mg). 1 HNMR (500MHz, CDCl3): δ4.75-4.69(m, 1H, AcOCH), 2.40-2.23(m, 0.19H, CH2COOH, 90%D), 2.03(s, 3H, OCOCH3), 1.98-1.95(m, 1H, Alkyl), 1.87-1.8 0(m, 5H, Alkyl), 1.69-1.67(m, 1H, Alkyl), 1.58-1.53(m, 1H, Alkyl), 1.43-1.00(m, 18H, Alkyl), 0.93-0.92(m, 6H, CCH3+CHCH3), 0.65(s, 3H, CCH3) 13 CNMR (125MHz, CDCl3): δ180.5, 170.8, 74.5, 56.5, 56.0, 42.8, 41.9, 40.4, 40.2, 35.8, 35. 3, 35.0, 34.6, 32.2, 30.7, 30.5, 28.2, 27.0, 26.6, 26.3, 24.2, 23.3, 21.5, 20.8, 18.3, 12.1 IR (NEAT): 2359, 1734, 1707, 1412, 1294, 1254, 1026, 669, 617, 426, 419 HRMS(ESI)m / z:C 26 H 40 D2NaO4(M+Na) + Calculated value: 443.3101, Measured value: 443.3101

[0102] [ka] (6) 3-(4-chlorophenyl)-4-(1,3-dioxoisoindolin-2-yl)butanoic acid 3-(4-Chlorophenyl)-4-(1,3-dioxoisoindolin-2-yl)butanoic acid (compound (6), 72.2 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) was performed to obtain the product (white solid, deuterium substitution rate 98%, yield: 93%, 67.5 mg). 1 HNMR (500MHz, CDCl3): δ7.81-7.79(m, 2H, ArH), 7.70-7.69(m, 2H, ArH), 7.25(d, J=8.0Hz, 2H, ArH), 7.20( d, J=8.0Hz, 2H, ArH), 3.91-3.83(m, 2H, NCH2), 3.69(t, J=8.0Hz, 1H, ArCH), 2.70(m, 0.04H, CH2COOH, 98%D) 13 CNMR (125MHz, CDCl3): δ176.4, 168.1, 138.5, 134.1, 133.2, 131.7, 129.1, 128.9, 123.4, 42.8, 39.8, 37.3 IR (NEAT): 1728, 1688, 1398, 1358, 1229, 1053, 997, 887, 835, 816, 721, 710, 650, 552, 530 HRMS(ESI)m / z:C 18 H 12 D2ClNNaO4(M+Na) + Calculated value: 368.0629, Measured value: 368.0625

[0103] [ka] (7) 3-(4,5-diphenyloxazol-2-yl)propanoic acid 3-(4,5-Diphenyloxazol-2-yl)propanoic acid (compound (7), 58.7 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 2% methanol to CHCl) was performed to obtain the product (white solid, deuterium substitution rate 99%, yield: 96%, 56.6 mg). 1 HNMR (500MHz, CDCl3): δ7.63-7.61(m, 2H, ArH), 7.58-7.56(m, 2H, ArH), 7.38-7.31(m, 6H, ArH), 3.19(s, 2H, ArCH2), 2.96-2.93(m, 0.03H, CH2COOH, 99%D) 13 CNMR (125MHz, CDCl3): δ176.6, 161.9, 145.6, 134.9, 132.1, 128.8, 128.7, 128.6, 128.6, 128.2, 128.0, 126.5, 30.4, 23.1 IR (NEAT): 1717, 1308, 1256, 1219, 1206, 1059, 966, 922, 766, 756, 727, 704, 694, 675, 523 HRMS(ESI)m / z:C 18 H 13 D2NNaO3(M+Na) + Calculated value: 318.1070, Measured value: 318.1079

[0104] [ka] (8) Gabapentin N-phthalimide Gabapentin N-phthalimide (compound (8), 63.7 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 60 °C. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) afforded the product (white solid, deuterium substitution rate 97%, yield: 93%, 59.5 mg). 1 HNMR (500MHz, CDCl3): δ7.88-7.86(m, 2H, ArH), 7.76-7.74(m, 2H, ArH), 3.80(s, 2H, NCH2), 2.44(m, 0.05H, CH2COOH, 97%D), 1.66-1.33(m, 10H, Alkyl) 13 CNMR (125MHz, CDCl3): δ176.6, 169.5, 134.1, 131.9, 123.4, 46.1, 39.2, 38.0, 33.6, 25.7, 21.4 IR (NEAT): 2359, 2340, 1709, 1686, 1402, 1391, 1373, 1362, 1346, 1288, 1229, 718, 710, 669, 530 HRMS(ESI)m / z:C 17 H 17 D2NNaO4(M+Na) + Calculated value: 326.1332, Measured value: 326.1332

[0105] [ka] (9) 2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid (compound (9), 57.5 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 60 °C. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) afforded the product (white solid, deuterium substitution rate 92%, yield: 88%, 50.9 mg). 1HNMR (500MHz, CDCl3): δ8.56 (br, 1H, NH), 7.36 (d, J=7.5Hz, 1H, ArH), 7.07 (dd, J=7.5, 7.5Hz, 1 H, ArH), 7.00(d, J=7.5Hz, 1H, ArH), 4.14-4.09(m, 1H, OCH2), 4.07-4.02(m, 1H, OCH2), 3.05-3. 02(m, 0.15H, CH2COOH, 92%D), 2.86-2.78(m, 4H, ArCH2CH2+ArCH2CH3), 2.17-2.09(m, 1H, CCH2C H3), 2.07-2.00(m, 1H, CCH2CH3), 1.32(t, J=7.5Hz, 3H, CH2CH3), 0.88(t, J=7.5Hz, 3H, CH2CH3) 13 CNMR (125MHz, CDCl3): δ175.7, 134.7, 134.6, 126.7, 126.1, 120.7, 119.9, 116.0, 108.6, 75.1, 60.9, 42.2, 30.9, 24.0, 22.2, 13.7, 7.7 IR (NEAT): 1744, 1701, 1302, 1250, 1227, 1072, 1036, 905, 783, 746, 739, 590, 556, 519, 484 HRMS(ESI)m / z:C 17 H 19 D2NNaO3(M+Na) + Calculated value: 312.1539, Measured value: 312.1552

[0106] [ka] (10) 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid The reaction using 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (compound (10), 40.2 mg, 0.20 mmol) as the substrate was carried out at 60°C. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate 99%, yield: 83%, 33.7 mg). 1HNMR (500MHz, CDCl3): δ4.13(s, 4H, N(CH2)2), 3.38(m, 0.01H, CHCOOH, 99%D), 1.44(s, 9H, NCOOC(CH3)3) 13 CNMR (125MHz, CDCl3): δ177.1, 156.3, 80.3, 51.5, 31.7, 28.3 IR (NEAT): 1719, 1638, 1477, 1458, 1395, 1366, 1250, 1153, 1130, 895, 870, 854, 768, 694, 563 HRMS(ESI)m / z:C9H 14 DNNaO4(M+Na) + Calculated value: 225.0956, Measured value: 225.0950

[0107] [ka] (11) (1R,3S,5r,7r)-Adamantane-2-carboxylic acid (1R,3S,5r,7r)-Adamantane-2-carboxylic acid (compound (11), 36.0 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 80°C. The product was obtained by repeating the azeotropic distillation with toluene three times without silica gel flash column chromatography (white solid, deuterium substitution rate: 80%, yield: 90%, 32.7 mg). 1 HNMR (500MHz, CDCl3): δ2.68(s, 0.20H, CHCOOH, 80%D), 2.35(br, 2H, Alkyl), 1.94-1.85(m, 6H, Alkyl), 1.78-1.75(m, 4H, Alkyl), 1.66-1.64(m, 2H, Alkyl) 13 CNMR (125MHz, CDCl3): δ181.2, 49.0, 38.0, 37.3, 33.5, 29.3, 27.4, IR (NEAT): 2916, 2897, 2849, 1682, 1454, 1414, 1292, 1279, 1105, 949, 939, 766, 735, 511, 407 HRMS(ESI)m / z:C 11 H 15 DNaO2(M+Na) + Calculated value: 204.1105, Measured value: 204.1105

[0108] [ka] (12) 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (compound (12), 53.7 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 60 °C. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) afforded the product (white solid, deuterium substitution rate 90%, yield: 88%, 47.6 mg). 1 HNMR (500MHz, CDCl3): δ8.13 (d, J=2.5Hz, 1H, ArH), 7.89 (d, J=7.5Hz, 1H, ArH), 7.56 (t, J=7.5Hz, 1H, ArH), 7.47 (t, J=7.5Hz, 1H, ArH), 7.4 2(dd, J=8.5, 2.5Hz, 1H, ArH), 7.36(d, J=7.5Hz, 1H, ArH), 7.04(d, J=8.5Hz, 1H, ArH), 5.19(s, 2H, ArOCH2), 3.66(m, 0.21H, CH2COOH, 90%D) 13 CNMR (125MHz, CDCl3): δ190.9, 177.4, 160.6, 140.4, 136.3, 135.5, 132.8, 132.6, 129.5, 129.3, 127.8, 127.0, 125.2, 121.2, 73.6, 39.5 IR (NEAT): 1709, 1641, 1493, 1402, 1300, 1287, 1223, 1204, 1142, 1123, 1018, 827, 756, 669, 638 HRMS(ESI)m / z:C 16 H 10 D2NaO4(M+Na) + Calculated value: 293.0753, Measured value: 293.0757

[0109] [ka] (13) 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (compound (13), 71.6 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the co-solvent. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) was performed to obtain the product (white solid, deuterium substitution rate: 94%, yield: 84%, 60.7 mg). 1 HNMR (500MHz, CDCl3): δ7.66 (d, J=8.0Hz, 2H, ArH), 7.47 (d, J=8.0Hz, 2H, ArH), 6.95 (d, J=2.5Hz, 1H, ArH), 6.85 (d, J=9. 0Hz, 1H, ArH), 6.67(dd, J=9.0, 2.5Hz, 1H, ArH), 3.83(s, 3H, ArOCH3), 3.68(m, 0.12H, CH2COOH, 94%D), 2.39(s, 3H, ArCH3) 13 CNMR (125MHz, CDCl3): δ176.6, 168.3, 156.1, 139.3, 136.3, 133.8, 131.2, 130.8, 130.4, 129.1, 115.0, 111.8, 111.7, 101.3, 55.7, 29.5, 13.3 IR (NEAT): 1674, 1477, 1352, 1329, 1300, 1287, 1225, 1213, 1163, 1094, 1038, 999, 847, 810, 733 HRMS(ESI)m / z:C 19 H 14 D2ClNNaO4(M+Na) + Calculated value: 382.0786, Measured value: 382.0800

[0110] [ka] (14) (Z)-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetic acid (Z)-2-(5-Fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetic acid (compound (14), 71.3 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the co-solvent. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 5% methanol to CHCl) was performed to obtain the product (yellow solid, deuterium substitution rate 98%, yield: 72%, 51.8 mg). 1 HNMR (500MHz, CDCl3): δ7.71 (d, J=8.5Hz, 2H, ArH), 7.64 (d, J=8.5Hz, 2H, ArH), 7.15 (s, 1H, C=CH), 7.11 (dd, J=8.5, 5.0Hz, 1H, ArH), 6.8 9(dd, J=8.5, 2.5Hz, 1H, ArH), 6.54(dt, J=9.0, 2.5Hz, 1H, ArH), 3.57(m, 0.03H, CH2COOH, 98%D), 2.83(s, 3H, SOCH3), 2.21(s, 3H, ArCH3) 13CNMR (125MHz, CDCl3): δ174.5, 163.3 (d, J=246.7Hz), 146.7 (d, J=8.7Hz), 144.4, 141.7, 139.9, 138.3, 131.6, 130.3 , 129.5(d, J=2.8Hz), 128.1, 124.0, 123.6(d, J=8.9Hz), 110.8(d, J=22.8Hz), 106.2(d, J=23.8Hz), 43.4, 31.0, 10.5 IR (NEAT): 1713, 1599, 1464, 1246, 1184, 1022, 1005, 959, 881, 851, 814, 727, 577, 538, 438 HRMS(ESI)m / z:C 20 H 15 D2FNaO3S(M+Na) + Calculated value: 381.0900, Measured value: 381.0901

[0111] [ka] (15) 2-(5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl)acetic acid Sodium 2-(5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl)acetate (compound (15), 62.7 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the co-solvent. Potassium carbonate was not used in this reaction. The reaction was carried out at 60°C. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 2% methanol to CHCl) was performed to obtain the product (white solid, deuterium substitution rate 98%, yield: 83%, 48.9 mg). 1 HNMR (500MHz, CDCl3): δ7.66(d, J=9.0Hz, 2H, ArH), 7.42(d, J=9.0Hz, 2H, ArH), 5.97(s, 1H, ArH), 3.75(m, 3.03H, NCH3+CH2COOH, 98%D), 1.75(s, 3H, ArCH3) 13CNMR (125MHz, CDCl3): δ186.6, 174.3, 139.1, 138.1, 132.2, 130.6, 129.9, 129.1, 128.7, 112.7, 33.1, 31.8, 14.4 IR (NEAT): 1611, 1593, 1449, 1396, 1379, 1265, 1184, 1169, 1088, 934, 791, 754, 735, 698, 652 HRMS(ESI)m / z:C 15 H 12 D2ClNNaO3(M+Na) + Calculated value: 316.0680, Measured value: 316.0692

[0112] [ka] (16) 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoic acid 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoic acid (compound (16), 49.3 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) was performed to obtain product 2, 2-d2 (colorless liquid, deuterium substitution ratio: D). a (98%), D b (78%), D c (83%), Yield: 96%, 47.9mg) 1HNMR (500MHz, CDCl3): δ7.23 (d, J=8.5Hz, 2H, ArH), 7.12 (d, J=8.5Hz, 2H, ArH), 3.71 (q, J= 7.0Hz, 0.03H, CHCOOH, 98%D), 3.11(d, J=14.0Hz, 1H, ArCH2), 2.50(d, J=14.0Hz, 1H, ArCH2) , 2.32-2.30(m, 0.33H, COCH2, 83%D), 2.09-2.06(m, 1.22H, CH2CH2+COCH, 78%D), 1.96-1.9 2(m, 1H, CH2CH2), 1.75-1.69(m, 1H, CH2CH2), 1.57-1.50(m, 1H, CH2CH2), 1.49(s, 3HCDCH3) 13 CNMR (125MHz, CDCl3): δ180.6, 139.2, 137.6, 129.2, 127.6, 50.5, 44.6, 37.7, 35.1, 29.1, 20.3, 18.0 IR (NEAT): 1730, 1701, 1512, 1287, 1209, 1130, 1092, 939, 910, 864, 837, 731, 569, 509, 405 HRMS(ESI)m / z:C 15 H 14 D4NaO3(M+Na) + Calculated value: 273.1399, Measured value: 273.1406

[0113] [ka] (17) 1,2,3,4-Tetrahydronaphthalene-1-carboxylic acid 1,2,3,4-Tetrahydronaphthalene-1-carboxylic acid (compound (17), 35.2 mg, 0.20 mmol) was used as the substrate. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate: 99%, yield: 100%, 35.6 mg). 1HNMR (500MHz, CDCl3): δ7.23-7.10(m, 4H, ArH), 3.85(t, J=6.0Hz, 0.01H, CHCOOH, 99%D), 2.87-2.81(m, 1H, Ar CH2), 2.79-2.73(m, 1H, ArCH2), 2.21-2.17(m, 1H, Alkyl), 2.05-1.94(m, 2H, Alkyl), 1.83-1.75(m, 1H, Alkyl) 13 CNMR (125MHz, CDCl3): δ181.5, 137.3, 132.4, 129.6, 129.5, 127.1, 125.8, 44.1, 29.1, 26.4, 20.4 IR (NEAT): 2357, 1684, 1495, 1402, 1290, 1279, 1219, 1184, 951, 926, 735, 702, 677, 484, 434 HRMS(ESI)m / z:C 11 H 11 DNaO2(M+Na) + Calculated value: 200.0792, Measured value: 200.0792

[0114] [ka] (18) N-(tert-butoxycarbonyl)-N-methylglycine (24-d2) N-(tert-butoxycarbonyl)-N-methylglycine (compound (18), 37.8 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate: 91%, yield: 68%, 26.1 mg). 1 H NMR (500 MHz, CDCl3) (mixture of rotamers): δ 2.94 (s, 3H, NCH3), 2.68 (m, 0.18H, CH2COOH, 91% D), 1.47-1.44 (m, 9H, NCOOC(CH3)3) 13CNMR (125 MHz, CDCl3) (mixture of rotamers): δ 175.1, 174.6, 156.5, 155.5, 80.6, 80.5, 50.2, 35.6, 35.4, 28.3, 28.2 IR (NEAT): 1744, 1638, 1449, 1396, 1368, 1223, 1159, 1092, 1049, 1020, 853, 831, 822, 766, 673 HRMS(ESI)m / z:C8H 13 D2NNaO4(M+Na) + Calculated value: 214.1019, Measured value: 214.1026

[0115] [ka] (19) 2-(1,3-dioxoisoindolin-2-yl)propanoic acid 2-(1,3-Dioxoisoindolin-2-yl)propanoic acid (compound (19), 43.8 mg, 0.20 mmol) was used as the substrate. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate: 98%, yield: 93%, 40.7 mg). 1 HNMR (500MHz, CDCl3): δ7.87-7.86(m, 2H, ArH), 7.74-7.73(m, 2H, ArH), 5.04(q, J=7.5Hz, 0.02H, CHCOOH, 98%D), 1.72(s, 3H, CDCH3) 13 CNMR (125MHz, CDCl3): δ175.6, 167.4, 134.2, 131.8, 123.6, 47.0, 14.9 IR (NEET): 2359, 2342, 1707, 1389, 1306, 1190, 961, 916, 745, 718, 706, 692, 669, 625, 529 HRMS(ESI)m / z:C 11 H8DNNaO4(M+Na) + Calculated value: 243.0487, Measured value: 243.0493

[0116] [ka] (20) 2-((1-benzyl-1H-indazol-3-yl)oxy)acetic acid 2-((1-benzyl-1H-indazol-3-yl)oxy)acetic acid (compound (20), 56.5 mg, 0.20 mmol) was used as the substrate, and DMF (0.50 mL) was used as the co-solvent. The reaction was carried out at 60 °C. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 2% methanol to CHCl) gave the product (white solid, deuterium substitution rate: 91%, yield: 82%, 46.6 mg). 1 HNMR (500MHz, methanol-d4): δ7.71 (d, J=8.0Hz, 1H, ArH), 7.38-7.33 (m, 2H, ArH), 7.29-7.26 (m, 2H, ArH), 7.24-7.21 (m, 1H, ArH), 7.18 (d, J=7.5Hz, 2H, ArH), 7.09-7.06 (m, 1H, ArH), 5.43 (s, 2H, NCH2Ph), 4.95 (m, 0.19H, CH2COOH, 91%D) 13 CNMR (125MHz, methanol-d4): δ171.1, 154.8, 141.9, 137.6, 128.1, 127.3, 127.1, 126.7, 119.4, 119.2, 112.3, 108.9, 64.3, 51.5 IR (NEAT): 2361, 1719, 1707, 1701, 1522, 1352, 1190, 1128, 748, 741, 700, 669, 656, 648, 623 HRMS(ESI)m / z:C 16 H 12 D2N2NaO3(M+Na) + Calculated value: 307.1022, Measured value: 307.1022

[0117] [ka] 2-((2,4-dichlorophenyl)thio)acetic acid 2-((2,4-Dichlorophenyl)thio)acetic acid (compound (21), 47.4 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate: 97%, yield: 98%, 47.0 mg). 1 HNMR (500MHz, CDCl3): δ7.37(d, J=2.0Hz, 1H, ArH), 7.32(d, J=8.5Hz, 1H, ArH), 7.15(dd, J=8.5, 2.0Hz, 1H, ArH), 3.93(m, 0.06H, CH2COOH, 97%D) 13 CNMR (125MHz, CDCl3): δ174.3, 135.6, 133.2, 132.2, 130.7, 129.0, 127.8, 34.2 IR (NEAT): 2361, 1701, 1447, 1283, 1101, 1034, 1016, 885, 841, 804, 681, 644, 575, 544, 407 HRMS(ESI)m / z:C8H4D2Cl2NaO2S(M+Na) + Calculated value: 260.9483, Measured value: 260.9483

[0118] [ka] (31)(9Z,12Z)-Octadeca-9,12-dienoic acid (9Z,12Z)-octadeca-9,12-dienoic acid (compound (31), 62.5 μL, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. The product was obtained without silica gel flash column chromatography (colorless liquid, deuterium substitution rate: 97%, yield: 103%, 58.2 mg). 1HNMR (500MHz, CDCl3): δ5.41-5.30(m, 4H, vinyl), 2.77(t, J=6.5Hz, 2H, CH=CHCH2CH=CH), 2.35-2.32(m, 0.06H, CH2COOH, 97%D ), 2.07-2.03(m, 4H, CH=CHCH2CH2), 1.64-1.61(m, 2H, CH2CD2COOH), 1.39-1.27(m, 14H, Alkyl), 0.89(t, J=7.0Hz, 3H, CH2CH3) 13 CNMR (125MHz, CDCl3): δ180.3, 130.2, 130.0, 128.1, 127.9, 33.5, 31.5, 29.6, 29.4, 29.2, 29.1, 29.0, 27.2, 27.2, 25.6, 24.6, 22.6, 14.1 IR (NEAT): 3007, 2924, 2855, 1705, 1464, 1410, 1377, 1294, 1171, 1125, 945, 723, 436, 415, 409 HRMS(ESI)m / z:C 18 H 30 D2NaO2(M+Na) + Calculated value: 305.2420, Measured value: 305.2420

[0119] [ka] (32) 4-(4-(bis(2-chloroethyl)amino)phenyl)butanoic acid 4-(4-(bis(2-chloroethyl)amino)phenyl)butanoic acid (compound (32), 60.8 mg, 0.20 mmol) was used as the substrate. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate: 95%, yield: 97%, 59.3 mg). 1HNMR (500MHz, CDCl3): δ7.07(d, J=8.5Hz, 2H, ArH), 6.63(d, J=8.5Hz, 2H, ArH), 3.71-3.69(m, 4H, CH2CH2), 3.63-3 .60(m, 4H, CH2CH2), 2.58(t, J=7.5Hz, 2H, ArCH2), 2.35(m, 0.11H, CH2COOH, 95%D), 1.91(t, J=7.5Hz, 2H, ArCH2CH2) 13 CNMR (125MHz, CDCl3): δ180.0, 144.4, 130.4, 129.7, 112.2, 53.6, 40.5, 33.8, 32.7, 26.3 IR (NEAT): 1713, 1614, 1520, 1358, 1292, 1275, 1244, 1177, 1140, 947, 804, 741, 725, 557, 544 HRMS(ESI)m / z:C 14 H 18 D2Cl2NO2(M+H) + Calculated value: 306.0991, Measured value: 306.0998

[0120] [ka] (33) 2-Methyl-3-propanoic acid 2-Methyl-3-propanoic acid (compound (33), 32.8 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 80°C. The product was obtained without silica gel flash column chromatography (white solid, deuterium substitution rate: 83%, yield: 92%, 30.4 mg). 1 HNMR (500MHz, CDCl3): δ7.29(t, J=7.5Hz, 2H, ArH), 7.23-7.18(m, 3H, ArH), 3.07(d, J=14.0Hz, 1H , PhCH2), 2.81-2.74(m, 0.17H, CHCOOH, 83%D), 2.67(d, J=14.0Hz, 1H, PhCH2), 1.18(s, 3H, CDCH3) 13CNMR (125MHz, CDCl3): δ182.5, 139.0, 129.0, 128.4, 126.4, 40.9, 39.2, 16.4 IR (NEAT): 1686, 1450, 1310, 1288, 1217, 1092, 962, 910, 781, 739, 725, 702, 604, 515, 474 HRMS(ESI)m / z:C 10 H 11 DNaO2(M+Na) + Calculated value: 188.0792, Measured value: 188.0792

[0121] [ka] (34) 2-(1H-indol-3-yl)acetic acid 2-(1H-indol-3-yl)acetic acid (compound (34), 35.0 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) was performed to obtain the product (white solid, deuterium substitution rate: 98%, yield: 71%, 25.0 mg). 1 HNMR (500MHz, methanol-d4): δ7.44 (d, J=7.5Hz, 1H, ArH), 7.24 (d, J=8.0Hz, 1H, ArH), 7.06 (s, 1H, ArH), 7.01-6.97(m, 1H, ArH), 6.92-6.89(m, 1H, ArH), 3.61(m, 0.04H, CH2COOH, 98%D) 13 CNMR (125MHz, methanol-d4): δ175.1, 136.6, 127.3, 123.2, 121.0, 118.4, 118.1, 110.8, 107.4, 30.0 IR (NEAT): 2513, 1452, 1342, 1331, 1312, 1190, 1001, 947, 922, 741, 664, 610, 575, 426, 419 HRMS(ESI)m / z:C 10 H7D2NNaO2(M+Na)+ Calculated value: 200.0651, Measured value: 200.0651

[0122] [ka] (35) 2-([1,1'-biphenyl]-4-yl)acetic acid 2-([1,1'-biphenyl]-4-yl)acetic acid (compound (35), 42.4 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 60 °C. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) afforded the product (white solid, deuterium substitution rate: 97%, yield: 84%, 36.1 mg). 1 HNMR (500MHz, CDCl3): δ7.58-7.56(m, 4H, ArH), 7.43(t, J=7.5Hz, 2H, ArH), 7.38-7.33(m, 3H, ArH), 3.69(m, 0.06H, CH2COOH, 97%D) 13 CNMR (125MHz, CDCl3): δ177.7, 140.7, 140.4, 132.2, 129.8, 128.8, 127.4, 127.3, 127.1, 40.1 IR (NEAT): 1684, 1487, 1406, 1323, 1242, 1049, 1007, 928, 858, 760, 739, 696, 660, 432, 419 HRMS(ESI)m / z:C 14 H 10 D2NaO2(M+Na) + Calculated value: 237.0855, Measured value: 237.0855

[0123] [ka] (36) 2-(3-benzoylphenyl)propanoic acid 2-(3-Benzoylphenyl)propanoic acid (compound (36), 50.9 mg, 0.20 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 1% methanol to CHCl) was performed to obtain the product (white solid, deuterium substitution rate: 98%, yield: 99%, 50.5 mg). 1 HNMR (500MHz, CDCl3): δ7.80-7.78(m, 3H, ArH), 7.70-7.68(m, 1H, ArH), 7.60-7.56(m, 2H, ArH), 7.49-7.43(m, 3H, ArH), 3.83(q, J=7.0Hz, 0.02H, CHCOOH, 98%D), 1.55(s, 3H, CDCH3) 13 CNMR (125MHz, CDCl3): δ196.5, 180.1, 140.0, 137.9, 137.4, 132.5, 131.6, 130.1, 129.3, 129.3, 128.6, 128.3, 44.8, 18.0 IR (NEAT): 2361, 2342, 1651, 1283, 1138, 962, 937, 924, 716, 700, 689, 669, 642, 602, 438 HRMS(ESI)m / z:C 16 H 13 DNaO3(M+Na) + Calculated value: 278.0898, Measured value: 278.0909

[0124] [ka] (37) 2-(2,4-Dichlorophenoxy)acetic acid 2-(2,4-Dichlorophenoxy)acetic acid (compound (37), 44.2 mg, 0.20 mmol) was used as the substrate, and DMF (0.50 mL) was used as the co-solvent. The reaction was carried out at 60 °C. Silica gel flash column chromatography (mobile phase: a mixed solvent obtained by adding 5% methanol to CHCl) afforded the product (white solid, deuterium substitution rate: 87%, yield: 93%, 41.4 mg). 1 HNMR (500MHz, CDCl3): δ7.41 (d, J=2.5Hz, 1H, ArH), 7.19 (dd, J=9.0, 2.5Hz, 1H, ArH), 6.82 (d, J=9.0Hz, 1H, ArH), 4.72 (m, 0.27H, CH2COOH, 87%D) 13 CNMR (125MHz, CDCl3): δ172.4, 152.0, 130.5, 127.7, 127.6, 124.3, 114.9, 65.5 IR (NEAT): 1722, 1477, 1288, 1248, 1233, 1130, 1103, 1057, 872, 827, 793, 708, 677, 638, 438 HRMS(ESI)m / z:C8H4D2Cl2NaO3(M+Na) + Calculated value: 244.9712, Measured value: 244.9715

[0125] [Example 12] <General method and product identification> A general procedure for the anhydride-mediated alpha-deuteration of carboxylic acids. Acetone-d6 (0.50 mL, 6.8 mmol, 0.40 M) and pivalic anhydride (8 μL, 0.04 mmol) were added to a 4 mL vial equipped with a magnetic stir bar, followed by the carboxylic acid (0.20 mmol), K2CO3 (2.8 mg, 0.02 mmol), and DMAP (2.4 mg, 0.02 mmol). The reaction mixture was stirred at 40 °C for 48 h under an argon atmosphere. DO (0.10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. 1 M aqueous HCl was added to the reaction mixture, which was then extracted with CHCl2, and the solvent was removed under reduced pressure. Next, 2.0 mL of CHCl2 / formic acid (4 / 1 by volume) was added to the residue, and the mixture was evaporated to remove the pivalic acid. This azeotropic procedure was repeated three times. If necessary, the residue was purified by silica gel column flash chromatography. For some compounds, the solvent was difficult to remove. Using this method, the following deuterium substitution experiments (38)-(46) were carried out.

[0126] [ka] (38) 2-(4-(trifluoromethyl)phenyl)acetic acid 2-(4-(trifluoromethyl)phenyl)acetic acid (40.8 mg, 0.2 mmol) was used as the substrate. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution rate: 92%, yield: 86%, 35.4 mg). 1 HNMR (500MHz, CDCl3): δ7.60(d, J=8.0Hz, 2H, ArH), 7.41(d, J=8.0Hz, 2H, ArH), 3.71(d, 0.15H, CH2COOH, 92%D) 13 CNMR (125MHz, CDCl3) δ177.1, 137.0, 129.8 (q, JC-F=32Hz), 129.8, 125.6 (q, J C-F =4Hz), 124.1(q, J C-F =270Hz), 40.3 IR (NEAT): 3014, 2920, 1693, 1622, 1411, 1319, 1292, 1233, 1165, 1109, 1069, 1016, 941, 858, 799, 673 cm -1 HRMS(ESI)m / z:C9H4D2F3Na2O2(M+2Na-H) + Calculated value: 251.0235, measured value: 251.0242.

[0127] [ka] (39) 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (26.2 mg, 0.1 mmol) was used as the substrate. The reaction was carried out at 60 °C. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution rate: 98%, yield: 72%, 19.0 mg). 1 HNMR (500MHz, CDCl3): δ7.76(d, J=8.0Hz, 2H, ArH), 7.28(d, J=8.0Hz, 2H, ArH), 3.60(s, 0.03H, CH2COOH, 98%D), 1.33(s, 12H, CH3) 13 CNMR (125MHz, CDCl3): δ177.0, 136.3, 135.1, 128.7, 83.8, 49.3, 40.6, 24.8 IR (NEAT): 2978, 2926, 1707, 1610, 1517, 1398, 1355, 1323, 1294, 1267, 1140, 1090, 961, 856, 651 cm -1 HRMS(ESI)m / z:C 14 H 16 D2BNa2O4 + (M+2Na-H) + Calculated value: 309.1214, Measured value: 309.1219

[0128] [ka] (40) 2-(4-((tert-butoxycarbonyl)amino)phenyl)acetic acid 2-(4-((tert-Butoxycarbonyl)amino)phenyl)acetic acid (50.3 mg, 0.2 mmol) was used as the substrate. The reaction was carried out at 60 °C. After silica gel flash chromatography (mobile phase: a mixed solvent obtained by adding 2% MeOH to CHCl), the product was obtained (colorless solid, deuterium substitution rate: 98%, yield: 67%, 34.5 mg). 1HNMR (500MHz, CDCl3): δ7.30(d, J=7.5Hz, 2H, ArH), 7.19(d, J=8.5Hz, 2H, ArH), 6.59(s, 1H, NH), 3.57(s, 0.03H, CH2COOH, 98%D)1.51(s, 9H, C(CH3)3) 13 CNMR (125MHz, CDCl3): δ177.3, 153.0, 137.5, 129.9, 127.8, 118.8, 80.8, 39.8, 28.3 IR (NEAT): 3375, 2976, 1697, 1593, 1526, 1510, 1410, 1294, 1234, 1155, 1057, 947, 827, 775, 746, 662, 604, 511 cm -1 HRMS(ESI)m / z:C 13 H 15 D2NNaO4(M+Na) + Calculated value: 276.1175, Measured value: 276.1199

[0129] [ka] (41) 4-(1,3-dioxoisoindolin-2-yl)butanoic acid 4-(1,3-Dioxoisoindolin-2-yl)butanoic acid (46.6 mg, 0.2 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution rate: 95%, yield: 75%, 34.9 mg). 1 HNMR (500MHz, CDCl3): δ7.87-7.83(m, 2H, ArH), 7.74-7.70(m, 2H, ArH), 3.77(t, J=7.0Hz, 2H, CH2), 2.42-2.37(m, 0.05H, CH2COOH, 95%D), 2.01(t, 7.0Hz, 2H, CH2) 13 CNMR (125MHz, CDCl3): δ178.5, 168.4, 134.0, 132.0, 123.3, 37.1, 30.7 IR (NEAT): 2970, 2538, 1771, 1694, 1437, 1395, 1354, 1306, 1142, 1042, 947, 880, 719, 527, 446 cm -1 HRMS(ESI)m / z:C 12 H9D2NNaO4(M+Na) + Calculated value: 258.0706, measured value: 258.0707

[0130] [ka] (42) 2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoic acid 2-(1,3-Dioxoisoindolin-2-yl)-3-methylbutanoic acid (49.5 mg, 0.2 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 60 °C. 30 mol% K2CO3, 60 mol% Piv2O, and 30 mol% DMAP were used. After silica gel flash chromatography (mobile phase: a mixed solvent obtained by adding 2% MeOH to CHCl2), the product was obtained (colorless solid, deuterium substitution rate: 99%, yield: 95%, 47.3 mg). 1 HNMR (500MHz, CDCl3): δ7.89-7.85(m, 2H, ArH), 7.76-7.73(m, 2H, ArH), 4.63(d, J=8.5Hz, 0.01H, CHC OOH, 99%D), 2.75(sep, J=6.8Hz, 1H, CH(CH3)2), 1.16(d, J=6.7Hz, 3H, CH3), 0.92(d, J=6.8Hz, 3H, CH3) 13 CNMR (125MHz, CDCl3): δ174.4, 167.8, 134.3, 131.6, 123.7, 57.3, 28.3, 20.8, 19.5. IR (NEAT): 2961, 2930, 2874, 1778, 1722, 1709, 1470, 1385, 1285, 1188, 1123, 1072, 907, 714, 642, 529 cm -1 HRMS (DART-MS) m / z: C13 H 13 DNO4(M+H) + Calculated value: 249.0980, measured value: 249.0981.

[0131] [ka] (43) 3-(tert-butoxy)-2-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)propanoic acid 3-(tert-Butoxy)-2-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)propanoic acid (58.3 mg, 0.2 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 60 °C. 30 mol% K2CO3, 60 mol% Piv2O, and 30 mol% DMAP were used. After silica gel flash chromatography (mobile phase: a mixed solvent obtained by adding 2% MeOH to CHCl2), the product was obtained (colorless solid, deuterium substitution rate: 99%, yield: 40%, 23.2 mg). 1 HNMR (500MHz, CDCl3): δ7.89-7.87(m, 2H, ArH), 7.75-7.74(m, 2H, ArH), 5.06(t, J=15.6Hz, 0.0 1H, CHCOOH, 99%D), 4.22(d, J=9.1Hz, 1H, CH2), 3.89(d, J=9.1Hz, 1H, CH2), 1.21(s, 9H, C(CH3)3) 13 CNMR (125MHz, CDCl3): δ170.1, 167.4, 134.3, 131.8, 123.7, 75.5, 58.8, 51.3, 27.3 IR (NEAT): 2978, 2924, 1775, 1711, 1385, 1288, 1267, 1182, 1078, 932, 914, 856, 764, 716, 625, 529 cm -1 HRMS(ESI)m / z:C 15 H 16 DNNaO5(M+Na) + Calculated value: 315.1062, measured value: 315.1054.

[0132] [ka] (44) 2,6-bis(1,3-dioxoisoindolin-2-yl)hexanoic acid 2,6-Bis(1,3-dioxoisoindolin-2-yl)hexanoic acid (81.3 mg, 0.2 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 60 °C. 30 mol% K2CO3, 60 mol% Piv2O, and 30 mol% DMAP were used. After silica gel flash chromatography (mobile phase: a mixed solvent obtained by adding 2% MeOH to CHCl2), the product was obtained (colorless solid, deuterium substitution rate: 99%, yield: 76%, 61.6 mg). 1 HNMR (500MHz, CDCl3): δ7.84-7.83(m, 2H, ArH), 7.79-7.77(m, 2H, ArH), 7.74-7.72(m, 2H, ArH), 7.69-7.67(m, 2H, ArH), 4.87(dd, J=1 0.4, 5.1Hz, 0.01H, CHCOOH, 99%D), 3.64(t, J=7.3Hz, 2H, CH2), 2.35-2.23(m, 2H, CH2), 1.80-1.63(m, 2H, CH2), 1.42-1.33(m, 2H, CH2) 13 CNMR (125MHz, CDCl3): δ174.2, 168.4, 167.6, 134.2, 133.9, 132.1, 131.7, 123.6, 123.2, 51.4, 37.5, 27.9, 27.8, 23.6 IR (NEAT): 3333, 2957, 2930, 2857, 1759, 1694, 1389, 1317, 1179, 1144, 1022, 922, 893, 874, 729, 714, 615, 527 cm -1 HRMS(ESI)m / z:C 22 H 17 DN2NaO6(M+Na) + Calculated value: 430.1120, measured value: 430.1109.

[0133] [ka] (45) 2-(1,3-dioxoisoindolin-2-yl)-4-(methylthio)butanoic acid 2-(1,3-Dioxoisoindolin-2-yl)-4-(methylthio)butanoic acid (55.9 mg, 0.2 mmol) was used as the substrate. The reaction was carried out at 60 °C. 30 mol% K2CO3, 60 mol% Piv2O, and 30 mol% DMAP were used. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution rate: 99%, yield: 98%, 54.7 mg). 1 HNMR (500MHz, CDCl3): δ7.89-7.85(m, 2H, ArH), 7.76-7.73(m, 2H, ArH), 5.17(dd , J=9.0, 5.0Hz, 0.01H, CHCOOH, 99%D), 2.62-2.44(m, 4H, CH2), 2.07(s, 3H, SCH3) 13 CNMR (125MHz, CDCl3): δ175.0, 167.6, 134.4, 131.7, 123.7, 50.4, 30.8, 27.7, 15.3 IR (NEAT): 3318, 2916, 1759, 1694, 1387, 1192, 1171, 1078, 1030, 916, 876, 797, 725, 714, 613, 557, 529, 438 cm -1 HRMS(ESI)m / z:C 13 H 12 DNNaO4S(M+Na) + Calculated value: 303.0520, Measured value: 303.0534

[0134] [ka] (46) 2-(1,3-dioxoisoindolin-2-yl)-5-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-5-oxopentanoic acid 2-(1,3-Dioxoisoindolin-2-yl)-5-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-5-oxopentanoic acid (77.7 mg, 0.2 mmol) was used as the substrate. The reaction was carried out at 60 °C. 30 mol% K2CO3, 60 mol% Piv2O, and 30 mol% DMAP were used. The product was obtained (colorless solid, deuterium substitution rate: 99%, yield: 68%, dr = 1 / 1.4, 55.7 mg). 1 HNMR (500MHz, CDCl3) (mixture of rotamers and diastereomers): δ7.86-7.82(m, 2H, ArH), 7.74-7.71(m, 2H, ArH), 4.94-4.92(m, 0.01H, CHCOOH, 99 %D), 4.49-4.31(m, 1H, CHCOOCH3), 3.69-3.59(m, 3H, COOCH3), 3.59-3.21(m, 2H, NCH2), 2.70-1.79(m, 8H, CH2CH2CONCH2CH2CH2) 13 CNMR (125 MHz, CDCl3) (mixture of rotamers and diastereomers): δ 172.8, 172.7, 172.3, 171.7, 171.7, 171.4, 171.2, 171.1, 167.6, 167.6, 167.5, 134.2, 134.2, 131.8, 123.5, 123.5, 123.5, 59.5, 5 9.4, 58.8, 58.8, 53.5, 52.7, 52.5, 52.3, 51.2, 47.1, 47.1, 46.7, 46.5, 31.9, 31.3, 31.2, 31.2, 31.0, 30.0, 29.7, 29.3, 29.1, 24.9, 24.6, 24.6, 24.5, 24.2, 24.1, 22.7, 22.5, 22.5 IR (NEAT): 2953, 1771, 1736, 1707, 1597, 1466, 1437, 1383, 1196, 1175, 1115, 1070, 995, 920, 856, 797, 718, 617, 529, 419, 409 cm -1 HRMS (DART-MS) m / z: C 19 H 20 DN2O7 + (M+H) +Calculated value: 390.1406, Measured value: 390.14149

[0135] [ka] (47) 2-(1,3-dioxoisoindolin-2-yl)-5-(((S)-1-methoxy-3-methoxy-1-oxobutan-2-yl)amino)-5-oxopentanoic acid (S)-2-(1,3-Dioxoisoindolin-2-yl)-5-(((S)-1-methoxy-3-methoxy-1-oxobutan-2-yl)amino)-5-oxopentanoic acid (78.1 mg, 0.2 mmol) was used as the substrate, and DMSO (0.50 mL) was used as the cosolvent. The reaction was carried out at 60 °C. 30 mol% K2CO3, 60 mol% Piv2O, and 30 mol% DMAP were used. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution: 96%, yield: 43%, dr = 1 / 1.5, 34.0 mg). 1 H NMR (500 Hz, DMSO) (mixture of rotamers and diastereomers): δ 8.06-8.03 (m, 1H, NH), 7.94-7.88 (m, 4H, ArH), 4.70 (dd, J = 23.5 Hz and 9 Hz, 0.06H, CHCOOH, 94% D), 4.12-4.03 (m, 1H, CHCOOCH), 3.61 (s, 1.2H, COOCH), 3.59 (s, 1.8H, COOCH), 2.42-2.18 (m, 4H, CHCH), 1.99-1.88 (m, 1H, CH(CH)), 0.84-0.75 (m, 6H, CH(CH)). 13 CNMR (125 Hz, DMSO) (mixture of rotamers and diastereomers) δ 172.5, 172.5, 172.0, 171.9, 170.9, 170.8, 167.9, 167.8, 135.4, 135.3, 131.7, 131.7, 124.0, 123.8, 57.8, 52.0, 51.4, 32.0, 31.6, 30.3, 30.3, 24.6, 24.4, 19.3, 19.3, 18.7, 18.7 IR (NEAT): 3308, 2963, 1771, 1732, 1703, 1620, 1537, 1469, 1435, 1385, 1246, 1200, 1152, 1115, 1086, 1043, 993, 970, 928, 854, 737, 716, 685, 629, 529 cm -1 HRMS (DART-MS) m / z: C 19 H 21 DN2O7 + (M+H) + Calculated value: 392.1563, Measured value: 392.14568

[0136] The present disclosure includes the following embodiments [1] to

[14] . [1] 1. A deuterium-enriched composition comprising a deuterium-substituted carboxylic acid or a salt thereof, the carboxylic acid or salt thereof contains an α-hydrogen of a carboxyl group and a hydrogen atom other than the α-hydrogen bonded to a carbon atom, The deuterium substitution rate of the α hydrogen is 5% or more, The deuterium substitution rate of hydrogen other than the α hydrogen is 3% or less, However, when the carboxylic acid or salt thereof has a group having a carbonyl group other than the carboxy group in the molecule, the α-hydrogen of the carbonyl group is not included in the hydrogens other than the α-hydrogen. [2] The deuterium-enriched composition according to [1], wherein the carboxylic acid or salt thereof is a compound in which at least one carboxylic acid or salt thereof selected from the following formulae (1) to (21) and (38) to (47) is deuterium-substituted: [ka] [ka] [ka] [3] A method for producing a deuterium-substituted carboxylic acid or a salt thereof, comprising the steps of: A production method comprising a reaction step of converting a carboxylic acid or a salt thereof having an α-hydrogen into an acid anhydride, and substituting a hydrogen atom corresponding to the α-hydrogen in the acid anhydride with deuterium in the presence of a deuteration source. [4] The production method according to [3], wherein the reaction step is carried out in the presence of at least one of the following components (A) and (B): (A) A compound that undergoes a dehydration condensation reaction with the carboxylic acid or a salt thereof to form an acid anhydride. (B) A compound that accelerates the reaction between the carboxylic acid or its salt and an oxoacid to form an acid anhydride of the carboxylic acid or its salt and the oxoacid. [5] The production method according to [4], wherein the component (A) contains an acid anhydride. [6] The method according to [4] or [5], wherein the component (B) contains a condensing agent. [7] The method according to [6], wherein the condensing agent is a carbodiimide or a carbodiimide hydrochloride. [8] The production method according to any one of [3] to [7], wherein the reaction step is carried out in the presence of at least one of the following components (C) and (D): (C) Nucleophilic activators. (D) A salt of a strong base and an acid having an acidity lower than that of the carboxy group of the carboxylic acid. [9] The method according to [8], wherein the component (C) is at least one selected from the group consisting of quinuclidine, 1,4-diazabicyclo[2.2.2]octane, and 4-dimethylaminopyridine.

[10] The method according to [8] or [9], wherein the component (D) is at least one selected from the group consisting of carbonates, phosphates, and carboxylates.

[11] The method according to any one of [3] to

[10] , wherein the heavy hydrogen source is a deuterated solvent.

[12] The method according to any one of [3] to

[11] , wherein the reaction step is carried out in the presence of a co-solvent.

[13] A reaction promoter for promoting a reaction of substituting an α-hydrogen atom of a carboxylic acid or a salt thereof with a deuterium atom, A reaction accelerator comprising a compound that converts the carboxylic acid or a salt thereof into an acid anhydride.

[14] Use of a compound that converts a carboxylic acid or a salt thereof into an acid anhydride as a catalyst in a reaction that substitutes alpha hydrogen for deuterium in a compound having a carboxy group.

Claims

1. 1. A deuterium-enriched composition comprising a deuterium-substituted carboxylic acid or a salt thereof, the carboxylic acid or salt thereof contains an α-hydrogen of a carboxyl group and a hydrogen atom other than the α-hydrogen bonded to a carbon; The deuterium substitution rate of the α hydrogen is 5% or more, the deuterium substitution rate of hydrogen other than the α hydrogen is 3% or less, However, when the carboxylic acid or salt thereof has a group having a carbonyl group other than the carboxy group in the molecule, the α-hydrogen of the carbonyl group is not included in the hydrogens other than the α-hydrogen, and the carboxylic acid or salt thereof is a compound in which at least one carboxylic acid or salt thereof selected from the following formulas (2) to (8), (10) to (18), (20), (21), and (39) to (47) is deuterium-enriched. 【Chemical 1】 【Chemistry 2】 【Chemistry 3】

2. A method for producing a deuterium-substituted carboxylic acid or a salt thereof, comprising the steps of: a reaction step of converting a carboxylic acid or a salt thereof having an α-hydrogen into an acid anhydride, and substituting a hydrogen atom corresponding to the α-hydrogen atom in the acid anhydride with a deuterium atom in the presence of a deuteration source, the deuteration source is a deuterated solvent; The method for producing a deuterated solvent is a compound having a carbonyl group and an alpha hydrogen of the carbonyl group.

3. The method according to claim 2, wherein the reaction step is carried out in the presence of at least one of the following components (A) and (B): (A) A compound that undergoes a dehydration condensation reaction with the carboxylic acid or a salt thereof to form an acid anhydride. (B) A compound that accelerates the reaction between the carboxylic acid or its salt and an oxoacid to form an acid anhydride of the carboxylic acid or its salt and the oxoacid.

4. The method according to claim 3 , wherein the component (A) comprises an acid anhydride.

5. The method according to claim 3 or 4, wherein the component (B) includes a condensing agent.

6. The method according to claim 5 , wherein the condensing agent is a carbodiimide or carbodiimide hydrochloride.

7. The method according to claim 2 or 3, wherein the reaction step is carried out in the presence of at least one of the following components (C) and (D): (C) A nucleophilic activator. (D) A salt of a strong base and an acid having an acidity lower than that of the carboxy group of the carboxylic acid.

8. The method according to claim 7, wherein the component (C) is at least one selected from the group consisting of quinuclidine, 1,4-diazabicyclo[2.2.2]octane, and 4-dimethylaminopyridine.

9. The method according to claim 7, wherein the component (D) is at least one selected from the group consisting of carbonates, phosphates, and carboxylates.

10. The process according to claim 2 or 3, wherein the reaction step is carried out in the presence of a co-solvent.

11. A reaction promoter for promoting a reaction of substituting an α-hydrogen atom of a carboxylic acid or a salt thereof with a deuterium atom, A reaction accelerator comprising a compound that converts the carboxylic acid or a salt thereof into an acid anhydride, a nucleophilic activator, and a salt of a strong base and an acid having an acidity lower than that of the carboxy group of the carboxylic acid.

12. 1. Use of a compound that converts a carboxylic acid or a salt thereof into an acid anhydride as a catalyst in a reaction for substituting an alpha hydrogen atom of a compound having a carboxy group with deuterium, comprising: The compound for converting a carboxylic acid or a salt thereof into an acid anhydride is acetic anhydride or pivalic anhydride.

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