WO2023038093A1 - Deuterium-enriched composition, deuterium-substituted carboxylic acid production method, reaction accelerator, and use of compound for converting carboxylic acid to acid anhydride - Google Patents

Deuterium-enriched composition, deuterium-substituted carboxylic acid production method, reaction accelerator, and use of compound for converting carboxylic acid to acid anhydride Download PDF

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WO2023038093A1
WO2023038093A1 PCT/JP2022/033782 JP2022033782W WO2023038093A1 WO 2023038093 A1 WO2023038093 A1 WO 2023038093A1 JP 2022033782 W JP2022033782 W JP 2022033782W WO 2023038093 A1 WO2023038093 A1 WO 2023038093A1
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carboxylic acid
hydrogen
deuterium
acid
group
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PCT/JP2022/033782
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French (fr)
Japanese (ja)
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孝志 大嶋
亮 矢崎
津久志 田中
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国立大学法人九州大学
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    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the present disclosure relates to the use of deuterium-enriched compositions, methods for producing deuterium-substituted carboxylic acids, reaction accelerators, and compounds that convert carboxylic acids to acid anhydrides.
  • Non-Patent Document 1 By introducing deuterium into functional molecules, it is possible to improve stability and durability while minimizing the impact on molecular functions (Non-Patent Document 1).
  • deuterium-substituted compounds can be easily analyzed by mass spectrometry, they are also used in pharmacokinetic studies using deuterium-labeled drugs (Non-Patent Documents 4 to 6).
  • Non-Patent Documents 4 to 6 the number of deuterated drugs on the market has also increased (in 2017, the world's first deuterated drug, deutetrabenazine, was approved by the FDA), and is attracting attention as one of the patent strategies (non-patent literature). 2).
  • Non-Patent Document 3 deuterium is widely used in organic synthesis for the purpose of improving the stability of protecting groups and analyzing reaction mechanisms.
  • deuterated compounds are widely used in basic research, applied research, engineering fields, and medicinal chemistry fields, and their demand is increasing year by year (Patent Documents 1 to 3).
  • Patent Documents 1 to 3 deuterium-labeled compounds need to be synthesized from low-molecular-weight deuterated raw materials in multiple steps. Synthetic methods are desired (Patent Documents 1 to 4, Non-Patent Documents 7 to 9).
  • Carboxylic acids with any structural unit are readily available as biomass resources. Furthermore, it is possible to generate alkyl radicals by one-electron oxidation and reduction, and it can be used as a raw material for various deuterium-labeled compounds. Deuteration of carboxylic acids is therefore classically studied. However, in the conventional deuteration method, a practical method has not been developed because deuteration proceeds randomly at positions other than the ⁇ -position of the carboxylic acid.
  • the present disclosure has been made in view of the circumstances described above, and aims to provide a deuterium-enriched composition containing a carboxylic acid in which ⁇ -hydrogen has been substituted with deuterium with high selectivity.
  • the present disclosure also provides methods for producing deuterated carboxylic acids capable of replacing alpha hydrogen with deuterium with high selectivity, reaction accelerators that can be used in such methods, and conversion of carboxylic acids to acid anhydrides. It is intended to provide uses for the compounds.
  • the deuterium-enriched composition of the present disclosure is a deuterium-enriched composition comprising a deuterated carboxylic acid or salt thereof, wherein the carboxylic acid or salt thereof is the alpha hydrogen of the carboxy group and a carbon-bonded
  • the deuterium substitution rate of the ⁇ hydrogen is 5% or more, and the deuterium substitution rate of the hydrogen other than the ⁇ hydrogen is 3% or less, provided that the carboxylic acid or When the salt has a group having a carbonyl group other than the carboxy group in the molecule, the ⁇ -hydrogen of the carbonyl group is not included in hydrogen other than the ⁇ -hydrogen.
  • the carboxylic acid or salt thereof is preferably a compound obtained by deuterium-substituting at least one carboxylic acid or salt thereof selected from the following formulas (1) to (21) and (38) to (47).
  • a method for producing a deuterated carboxylic acid or a salt thereof of the present disclosure converts a carboxylic acid having an ⁇ hydrogen or a salt thereof to an acid anhydride, and converts the ⁇ hydrogen in the anhydride in the presence of a deuteration source and replacing the hydrogen corresponding to with deuterium.
  • the above reaction step is carried out in the presence of at least one of the following components (A) and (B).
  • B A compound that promotes the reaction between the carboxylic acid or its salt and an oxoacid to form an acid anhydride of the carboxylic acid and the oxoacid.
  • the component (A) contains an acid anhydride.
  • the component (B) contains a condensing agent.
  • the condensing agent is preferably carbodiimide or carbodiimide hydrochloride.
  • 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 an acid having a lower acidity than the carboxy group of the carboxylic acid and a strong base.
  • the above component (C) is preferably at least one selected from the group consisting of quinuclidine, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine.
  • the component (D) is at least one selected from the group consisting of carbonates, phosphates, and carboxylates.
  • the deuterium source is preferably a deuterated solvent.
  • the above reaction step is preferably carried out in the presence of a co-solvent.
  • the reaction accelerator of the present disclosure is a reaction accelerator for promoting the reaction of substituting ⁇ hydrogen of a carboxylic acid or a salt thereof with deuterium, and is a compound that converts the carboxylic acid or a salt thereof into an acid anhydride.
  • the use of the compound that converts a carboxylic acid or a salt thereof of the present disclosure to an acid anhydride is use as a catalyst in a reaction in which the ⁇ -hydrogen of a compound having a carboxy group is replaced with deuterium.
  • a deuterium-enriched composition containing a carboxylic acid in which ⁇ -hydrogen has been substituted with deuterium with high selectivity it is possible to provide a deuterium-enriched composition containing a carboxylic acid in which ⁇ -hydrogen has been substituted with deuterium with high selectivity. Further, according to the present disclosure, a method for producing a deuterated carboxylic acid capable of substituting deuterium for ⁇ hydrogen with high selectivity, a reaction accelerator that can be used in such a method, and a carboxylic acid to an acid anhydride A use of the converting compound can be provided.
  • a carboxylic acid having an ⁇ hydrogen or a salt thereof is converted to an acid anhydride, and ⁇ A reaction step including substituting deuterium for hydrogen corresponding to hydrogen (protium).
  • ⁇ A reaction step including substituting deuterium for hydrogen corresponding to hydrogen (protium) According to the production method of the present embodiment, by converting a carboxylic acid or a salt thereof into an acid anhydride, the acidity of ⁇ -hydrogen in the carboxylic acid or a salt thereof is increased, and deuterium substitution of the ⁇ -hydrogen proceeds efficiently. can increase the selectivity of ⁇ -hydrogens for deuterium substitution reactions.
  • the carboxylic acid used in the production method of the present embodiment is not particularly limited as long as it is a carboxylic acid having ⁇ -hydrogen.
  • ⁇ hydrogen for a carboxylic acid refers to a hydrogen atom that bonds to the carbon atom ( ⁇ carbon) that is directly bonded to the carbon atom of the carboxy group of the carboxylic acid. Point.
  • the carboxylic acid has an alpha carbon and an alpha hydrogen.
  • the carboxylic acid used for the purpose of undergoing deuterium substitution in the method of the present embodiment is also simply referred to as "substrate".
  • a carboxylic acid is a compound having a carboxy group, and may have one or more carboxy groups in the molecule.
  • the hydrogen atom bonded to the ⁇ carbon of any carboxy group is considered to be the ⁇ hydrogen of the carboxy group.
  • the carboxylic acid to be deuterated by applying the production method of the present embodiment is also referred to as the carboxylic acid to be deuterated.
  • a carboxy group refers to both a --COOH group and a salt of --COOH group depending on the context.
  • a carboxylic acid that can be used in the production method of the present embodiment can be represented by the following general formula (A).
  • R is an organic group containing ⁇ -hydrogen.
  • the carboxylic acid may be acetic acid, and the carboxylic acid other than acetic acid may be at least one of compounds represented by the following chemical formula (A1) and chemical formula (A2). .
  • 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 or branched chain hydrocarbon group; (2) a group having a carbocyclic ring (the carbocyclic ring may be aliphatic or aromatic); (3) A group having a heterocyclic ring (4) A group represented by -X-R 5 in which the hydrogen bonded to the carbon of (1) is replaced with a substituent (excluding a hydrocarbon group)
  • the hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group.
  • Unsaturated hydrocarbon groups may have from 1 to 6 unsaturated groups.
  • Those having group (1) include fatty acids.
  • Group (1) does not contain a carbocyclic ring.
  • the carbocyclic ring in group (2) is a ring containing only carbon as a ring member.
  • a group having a carbocyclic ring may have one or more carbocyclic moieties in the group (2).
  • Two or more carbocyclic rings may form a condensed ring, or may be linked by a single bond or a divalent or higher valent organic group.
  • Group (2) may also have a linear or branched substituted or unsubstituted aliphatic hydrocarbon moiety other than the carbocyclic ring, such as an alkyl group.
  • Carbocycles may be either aliphatic or aromatic.
  • Group (2) includes groups containing cyclopentane ring, cyclohexane ring, adamantyl ring, tetrahydronaphthyl ring, benzene ring, biphenyl ring, indene ring, hexadecahydro-1H-cyclopenta[a]phenanthrene and the like.
  • a hydrogen atom bonded to a carbon atom that is a ring member may be substituted with a substituent.
  • the heterocyclic ring in group (3) may contain heteroatoms such as nitrogen, oxygen and sulfur as ring members. Heterocycles may be either aliphatic or aromatic. Two or more heterocyclic rings may form a condensed ring, or may be linked by a single bond or a divalent or higher valent organic group. Group (3) may also contain a carbocyclic ring. The carbocyclic ring may be condensed with another ring, or may be linked to another ring via 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, such as an alkyl group, in addition to the carbocyclic ring.
  • a hydrogen atom bonded to a carbon atom that is a ring member of a heterocycle or carbocycle may be substituted by a substituent.
  • a substituted or unsubstituted hydrocarbon group such as an alkyl group may be bonded to nitrogen, which is a ring member of the heterocyclic ring (that is, it may be N-substituted).
  • Group (3) includes groups containing rings such as oxazole ring, N-phthalimide ring, tetrahydropyran ring, azetidine ring, pyrrole ring, indole ring (which may be N-substituted indole ring), indazole ring, oxepin ring, etc.
  • a substituted oxepine ring may be an oxo-oxepine ring, and the oxo-oxepine ring may be 11-oxo-6,11-dihydrodibenzo[b,e]oxepine or a substituted product thereof.
  • substituents for group (4) include halogen atoms, methylsulfinyl groups, alkoxy groups, and polyoxyalkylene groups.
  • Group (4) does not contain a carbocyclic or heterocyclic ring.
  • X is a divalent group such as an ether bond (-O-), a thioether bond (-S-), an amino group and the like.
  • R 5 may be those exemplified as groups (1) to (4).
  • X is -S-, it is preferably not directly bonded to an atom (eg, carbon atom) that is a ring member of an aromatic ring (eg, benzene ring).
  • R 5 is bonded to X through the carbon atom of R 5 .
  • R 2 and R 3 are each a monovalent organic group or together 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.
  • Groups (1) to (5) include those exemplified for groups (1) to (5) in formula (A1).
  • R 2 and R 3 may be the same or different.
  • R2 and R3 When R2 and R3 together form a ring, R2 and R3 form a ring containing the alpha carbon.
  • R 2 and R 3 together form a divalent organic group with both of the two attachment sites of the divalent organic group attached to the alpha carbon.
  • examples of such rings include the azetidine ring of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid and the adamantyl group of adamantane-2-carboxylic acid.
  • a hydrogen atom attached to a carbon atom that is a ring member may be replaced by a substituent.
  • the number of carbon atoms in the divalent organic group may be 1 to 50, 2 to 40, or 5 to 30.
  • Carboxylic acid or its derivatives baclofen or its derivatives, oxaprozin or its derivatives, gabapentin or its derivatives, etodolac or its derivatives, isoxepac or its derivatives, indomethacin or its derivatives, sulindac or its derivatives, zomepirac or its derivatives, Loxoprofen or derivatives thereof, sarcosine or derivatives thereof, amino acids such as alanine or derivatives thereof, bendazac or derivatives thereof, phenylacetic acid or derivatives thereof, fats having a 2-(1,3-dioxoisoindolin-2-yl) group group carboxylic acid or the like.
  • amino acid refers to compounds generally having an amino group and a carboxy group in the molecule, and specifically, 20 kinds of amino acids (valine, isoleucine, leucine, methionine, valine, isoleucine, leucine, methionine, , lysine, phenylalanine, tryptophan, threonine, histidine, arginine, glycine, alanine, serine, tyrosine, cysteine, asparagine, glutamine, proline, aspartic acid, and glutamic acid).
  • amino acids valine, isoleucine, leucine, methionine, valine, isoleucine, leucine, methionine, , lysine, phenylalanine, tryptophan, threonine, histidine, arginine, glycine, alanine, serine, tyrosine, cysteine, asparagine, glutamine, proline,
  • Substituents possessed by the phenylacetic acid derivative include a fluorinated alkyl group having 1 to 3 carbon atoms (may be a perfluoroalkyl group) such as —CF 3 group, 4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl group, NHBoc group and the like.
  • 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, It may be an aliphatic carboxylic acid having carbon atoms.
  • the aliphatic carboxylic acid may be a straight or branched chain aliphatic carboxylic acid and may be a straight chain carboxylic acid.
  • the aliphatic carboxylic acid may have a substituent, and the substituent may be an alkylthioether group (the alkyl group may be a linear or branched alkyl group. may have carbon atoms and may have 1 to 3 alkyl groups), alkoxy group (the alkyl group possessed by the alkoxy group may be a linear or branched alkyl group.
  • the groups may have from 1 to 6 carbon atoms and may have from 1 to 3 alkyl groups.), amino groups, and the like.
  • the amino groups as substituents may be secondary or tertiary amino groups.
  • the amino group may also have 2 to 8 carbon atoms and may have 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 attached 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 in the aliphatic carboxylic acid having a 2-(1,3-dioxoisoindolin-2-yl) group is 1 to 3. , 1 or 2, or 1.
  • the carboxylic acid may be a carboxylate.
  • the counter cation of the carboxylate is not particularly limited, and 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 a mixture of a carboxylic acid and a salt (for example, a partially neutralized carboxylic acid). good.
  • R in general formula (A) may have a carboxy group
  • the carboxylic acid may have a carbon-bonded hydrogen other than the ⁇ -hydrogen of the carboxy group.
  • Such hydrogen atoms include hydrogen bonded to carbon in the aliphatic portion of the carboxylic acid, hydrogen bonded to carbon that is a ring member of the aromatic ring, and the like.
  • the ⁇ -hydrogen selectivity for deuterium substitution is high, even if the carboxylic acid to be deuterated has hydrogen other than the ⁇ -hydrogen of the carboxy group in the molecule, , the deuterium substitution rate of hydrogen other than the ⁇ -hydrogen of the carboxy group is low.
  • the carboxylic acid has a group containing a carbonyl group other than the carboxy group in the molecule, the ⁇ hydrogen of the carbonyl group is not included in the above "hydrogen other than the ⁇ hydrogen of the carboxy group”.
  • the production method of the present embodiment can be used to remove the ⁇ -hydrogen of the carbonyl group. May be deuterated.
  • the method of the present embodiment is useful because the deuterium substitution rate of the hydrogen other than the ⁇ -hydrogen of neither the carboxy group nor the carbonyl group in the carboxylic acid is low.
  • the deuterium substitution rate of the ⁇ hydrogen of the carbonyl group when the carbon of the aliphatic portion of Y is bonded to the oxygen atom of the ester portion tends to decline.
  • carboxylic acid examples 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, only one type of carboxylic acid may be subjected to the deuterium substitution reaction as the carboxylic acid to be deuterated. you can go
  • the production method of the present embodiment can of course also be applied to carboxylic acids (such as acetic acid) that do not have carbon-bonded hydrogen other than the ⁇ -hydrogen of the carboxy group.
  • carboxylic acids such as acetic acid
  • the term "acid anhydride” refers not only to compounds obtained by dehydration condensation of carboxylic acids, but also to general compounds obtained by dehydration condensation of oxo acids.
  • the term “obtained by dehydration condensation” formally refers to the chemical structure of a compound obtained by such a reaction, and does not limit the actual method of synthesizing the compound.
  • Oxoacids include carboxylic acids, sulfonic acids, phosphinic acids and the like.
  • Examples of the method for converting the carboxylic acid to be deuterated into an acid anhydride include the following components (A) and (B), and at least one of the components (A) and (B) may be used.
  • can 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 of the carboxylic acid to be deuterated with the oxoacid to form an anhydride of the carboxylic acid and the oxoacid.
  • the formed acid anhydride includes 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. It may be a compound represented by (X).
  • X is a monovalent group and is a group represented by any of the following formulas (B1), (B2), and (B3).
  • R 11 is an organic group, in formula (B2)
  • R 21 is an organic group, in formula (B3)
  • R 31 and R 32 are organic groups, in formulas (B1) to (B3)
  • * is , represents the bonding position between the oxygen atom and X in formula (B).
  • R 11 is not particularly limited 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 1-30.
  • Examples of organic groups include substituted or unsubstituted hydrocarbon groups, groups having a heterocyclic ring, and the like.
  • R 11 and R may be the same or different.
  • R 11 can be an organic group having 1 to 10 carbon atoms and can be an organic group having 1 to 8 carbon atoms.
  • the organic group include, but are not particularly limited to, a hydrocarbon group and a halogenated hydrocarbon group in which some or all of the hydrogen atoms of a hydrocarbon group are substituted with halogen.
  • the halogenated hydrocarbon group includes a fluorinated hydrocarbon group, preferably a wholly fluorinated hydrocarbon group.
  • the component (A) is preferably a carboxylic acid derivative having a structure corresponding to formula (B1).
  • Such carboxylic acid derivatives may be acid anhydrides, acid chlorides, ester compounds and the like, with acid anhydrides being preferred.
  • the carboxylic acid derivative preferably does not have an ⁇ -hydrogen for the carbonyl group of the carboxylic acid derivative.
  • R 11 has the same meaning as R 11 in formula (B1).
  • R 12 is an organic group and may be the same as or different from R 11 .
  • Specific examples of R 12 include those given as specific examples of R 11 .
  • At least one of R 11 and R 12 may have a quaternary carbon.
  • At least one of R 11 and R 12 preferably does not have an alpha hydrogen in terms of the acid anhydride group.
  • the acid anhydride includes acetic anhydride, pivalic anhydride, trifluoromethylacetic anhydride, benzoic anhydride, phthalic anhydride, diphenic anhydride and the like. At least one selected from the group consisting of trifluoromethylacetic acid 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.
  • R 11 has the same meaning as R 11 in formula (B1).
  • Acid chlorides include acetic acid chloride, pivalic acid chloride, trifluoromethyl acetic acid chloride, benzoic acid chloride and the like.
  • R 11 has the same meaning as R 11 in formula (B1).
  • Ar is a group having an aromatic ring.
  • the group having an aromatic ring may be a group having a hydrocarbon ring such as a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a group having a heterocyclic ring such as a pyridyl group.
  • Acid chlorides include phenyl acetate, phenyl pivalate, phenyl trifluoromethylacetate, and phenyl benzoate.
  • R 21 is not particularly limited and may be, for example, an organic group having 1 to 30 carbon atoms.
  • organic groups include substituted or unsubstituted hydrocarbon groups, —OR 22 groups (R 22 is a substituted or unsubstituted hydrocarbon group), groups having a heterocyclic ring, and the like.
  • the component (A) may be a compound represented by the general formula R 21 --SO 2 Cl, or a compound represented by the general formula R 21 --SO 2 --O--SO 2 --R 22 and the like compounds represented.
  • R 21 in these formulas has the same meaning as R 21 in formula (B2).
  • R 22 is an organic group and may be the same as or different from R 21 . Specific examples of R 22 include those given as specific examples of R 21 .
  • examples of the component (A) include compounds represented by the general formula R 31 R 32 POCl.
  • R 31 and R 32 in this general formula have the same meanings as R 31 R 32 in formula (B3).
  • the amount of component (A) to be used is not particularly limited, but it is preferably 1 to 200 mol%, more preferably 5 to 150 mol%, more preferably 10 to 100 mol% of the carboxylic acid to be deuterated. More preferably, it is 120 mol %.
  • the amount of component (A) used is preferably 0.01 to 2 equivalents, more preferably 0.05 to 1.5 equivalents, relative to the carboxy group of the carboxylic acid to be deuterated. 0.1 to 1.2 equivalents are preferred.
  • the component (B) there is no particular problem as long as it is a compound that has the effect of promoting the reaction between the carboxylic acid to be deuterated and the oxo acid. It may be a compound or a catalyst for a dehydration condensation reaction.
  • the oxoacid may be a compound different from the carboxylic acid to be deuterated, or may be the carboxylic acid itself to be deuterated. That is, under the action of the component (B), the carboxylic acid to be deuterated may undergo a dehydration condensation reaction with an added oxoacid to form an acid anhydride. They may react with each other to form an acid anhydride.
  • the condensing agent is not particularly limited, and includes carbodiimide or carbodiimide hydrochloride.
  • carbodiimides include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N,N'-dicyclohexylcarbodiimide (DCC).
  • the amount of the condensing agent to be used is not particularly limited, and is preferably 1 to 100 mol%, more preferably 3 to 80 mol%, more preferably 5 to 50 mol%, relative to 100 mol% of the carboxylic acid to be deuterated. It is more preferably mol %, and particularly preferably 5 to 30 mol %.
  • deuterium sources include deuterated solvents (heavy solvents).
  • the heavy solvent is not particularly limited, and is preferably a compound having a carbonyl group.
  • a compound having a carbonyl group is preferably a compound having an ⁇ -hydrogen of the carbonyl group, and examples thereof include deuterated acetone.
  • the amount of deuterium source to be used is preferably an excess amount (that is, more than 1 equivalent) relative to the carboxy group of the carboxylic acid to be deuterated, more preferably 2 equivalents or more, and 5 to 80 equivalents. It is more preferable to have 10 to 50 equivalents, and particularly preferably 10 to 50 equivalents.
  • the above reaction step may be carried out in the presence of at least one of the following components (C) and (D).
  • C a nucleophilic activator.
  • D Salts of acids and strong bases having an acidity lower than the carboxy group of the carboxylic acid to be deuterated.
  • Component (C) is a compound that acts as a catalyst that promotes elimination of carboxylic acid by nucleophilically attacking the carbonyl carbon of the acid anhydride. 2] octane (DABCO), 4-dimethylaminopyridine (DMAP) and the like. (C) Component may use 1 type(s) or 2 or more types.
  • the amount of component (C) used is not particularly limited, and is preferably 1 to 100 mol%, more preferably 3 to 80 mol%, based on 100 mol% of the carboxylic acid to be deuterated. It is more preferably up to 50 mol %, particularly preferably 5 to 30 mol %.
  • the component (D) includes carbonates, phosphates, and carboxylates.
  • Component may use 1 type(s) or 2 or more types.
  • Examples of carbonates include salts of carbonate ions with cations such as alkali metals and quaternary ammonium ions such as tetramethylammonium, and sodium carbonate, potassium carbonate, rubidium carbonate, or cesium carbonate is preferable. Rubidium or cesium carbonate are more preferred.
  • Phosphates include salts of phosphate ions with cations such as alkali metals and quaternary ammonium ions such as tetramethylammonium, and potassium phosphate is preferred.
  • the carboxylate ion contained in the carboxylate is not particularly limited, but is preferably a carboxylate ion having no ⁇ -hydrogen.
  • carboxylate ions include pivalate ions.
  • cations contained in the carboxylate include alkali metals and quaternary ammonium ions such as tetramethylammonium.
  • Carboxylate includes potassium pivalate, cesium pivalate, tetramethylammonium pivalate and the like.
  • component (D) Since the anion contained in component (D) is a conjugate base of an acid having a lower acidity than the carboxy group of the carboxylic acid to be deuterated, the carboxylic acid to be deuterated by liberation of the weak acid is added to component (D). It is thought to form a salt with the contained cation and promote the formation of acid anhydride.
  • the amount of component (D) to be used is not particularly limited, and is preferably 1 to 100 mol%, more preferably 3 to 80 mol%, based on 100 mol% of the carboxylic acid to be deuterated. It is more preferably up to 50 mol %, particularly preferably 5 to 30 mol %.
  • the reaction step may be performed in the presence of a co-solvent.
  • a co-solvent When the carboxylic acid to be deuterated, components (A) to (D), etc. are difficult to dissolve in the heavy solvent, it is effective to use a solvent that dissolves the components that are difficult to dissolve as a co-solvent.
  • the co-solvent is not particularly limited and is preferably an aprotic solvent such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), toluene, 1,2-dichloroethane (DCE), tetrahydrofuran (THF), acetonitrile and the like. be done.
  • the reaction temperature in the reaction step is not particularly limited, and may be 100°C or lower, or 80°C or lower.
  • the reaction time is also not particularly limited, and may be, for example, 0.5 to 72 hours.
  • a deuterium-enriched composition containing a carboxylic acid in which the ⁇ -hydrogen is deuterated can be produced by the above production method. That is, the deuterium-enriched composition of the present embodiment comprises a deuterium-substituted carboxylic acid, the carboxylic acid comprising an ⁇ -hydrogen of a carboxy group and hydrogen other than the ⁇ -hydrogen bonded to a carbon;
  • the deuterium substitution rate of hydrogen is 5% or more, and the deuterium substitution rate of hydrogen other than ⁇ hydrogen is 3% or less, provided that the carboxylic acid contains a group having a carbonyl group other than the carboxy group in the molecule.
  • the ⁇ -hydrogen of the carbonyl group is not included in hydrogen other than the ⁇ -hydrogen.
  • the deuterium-enriched means that the content of deuterium is higher than the natural abundance.
  • Deuterium-enriched compositions contain deuterated carboxylic acids and may contain unreacted carboxylic acids and incidental impurities.
  • the deuterium-enriched composition of the present embodiment is a composition in which the alpha hydrogen of the contained carboxylic acid is enriched with deuterium.
  • Deuterium substitution rate in the case of the alpha hydrogen of a carboxy group, refers to the percentage of hydrogens bound to the alpha carbon of the carboxy group of the carboxylic acid in the deuterium-enriched composition that are deuterated. In other words, it is the ratio of deuterium to total hydrogen (total of hydrogen and deuterium) bonded to the alpha carbon.
  • the deuteration rate can be calculated from the integrated intensity of the 1 H NMR spectrum. If there are multiple ⁇ -hydrogens in the molecule of the carboxylic acid, the calculation of the deuterium substitution rate shall be the deuterium substitution rate for each equivalent carbon in the molecule.
  • the deuterium substitution rate of ⁇ hydrogen is 5% or more, but it may be 10% or more, 20% or more, 30% or more, or 50% or more. Well, it can be 70% or more.
  • the deuterium substitution rate of hydrogen other than ⁇ hydrogen is all carbons other than ⁇ carbon (however, if the carboxylic acid has a group with a carbonyl group other than a carboxyl group, the ⁇ carbon of the carbonyl group is excluded). It is the ratio of deuterium to hydrogen.
  • the deuterium substitution rate may be 1% or less, 0.1% or less, or approximately 0% (that is, substantially the same as the natural abundance).
  • the reaction accelerator of the present embodiment is a reaction accelerator for promoting the reaction of substituting deuterium for the ⁇ -hydrogen of the carboxylic acid, and includes a compound that converts the carboxylic acid into an acid anhydride.
  • the reaction accelerator preferably contains at least one of the components (A) and (B), and contains at least one of the components (A) and (B), the component (C), and the component (D). is preferred.
  • Deuterium substitution rate of ⁇ -hydrogen in the product was obtained from the integrated intensity of 1 HNMR. Deuterium substitution rate was 94%.
  • the deuterium substitution rate of ⁇ -hydrogen is the ratio of the number of deuterated ⁇ -hydrogens to the total number of ⁇ -hydrogens in 4-(4-methoxyphenyl)butyric acid contained in the product (that is, the number of ⁇ -position D the total number divided by the sum of D and H at the ⁇ -position).
  • the deuterium substitution rate was calculated from the ratio of the number of hydrogen atoms of ⁇ -hydrogen and hydrogen other than ⁇ -hydrogen from the 1 HNMR spectrum. Also, the yield of 4-(4-methoxyphenyl)butyric acid was 82%.
  • the yield is calculated based on the 4-(4-methoxyphenyl)butyric acid used as a substrate, and the 4-(4-methoxyphenyl)butyric acid contained in the product ( ⁇ -deuterium-substituted and ⁇ -deuterium-substituted (including both without). Yield was calculated by the following method. (1) An empty 50 mL eggplant flask is weighed in advance, the purified product solution is added, the solvent is distilled off, the eggplant flask is weighed again, and the difference in weight is used to generate The yield (mg) of the product was calculated.
  • 4-(4-methoxyphenyl)butyric acid has, as hydrogen other than ⁇ -hydrogen, ⁇ -hydrogen and ⁇ -hydrogen of the carboxy group (two each), hydrogen bonding to the benzene ring (4 hydrogens), and hydrogen bonding to the methyl group. (3) have a total of 11 hydrogen atoms bonded to carbons other than the ⁇ -carbons. When the integrated intensity of 1 H NMR was examined, no deuterium substitution was observed for hydrogens bonded to carbons other than the ⁇ carbon of 4-(4-methoxyphenyl)butyric acid (that is, below the detection limit).
  • the enolate (III) reacts with R'COOD (clockwise cycle) generated from the deuteration agent deuterated acetone to give the ⁇ -deuterated acylpyridinium species (IV).
  • An acyl exchange reaction then occurs to produce a deuterated carboxylic acid.
  • Example 2 In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and potassium acetate (2.8 mg, 0.02 mmol) was added. Acetic anhydride was then added in an amount of 1.0 equivalents relative to acetone-d 6 and 4-(4-methoxyphenyl)butyric acid. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 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) and the deuterium substitution rate was determined to be 95%.
  • PTLC preparative thin layer chromatography
  • Example 3 A deuteration test was performed by changing the type of acid anhydride. Specifically, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol % potassium carbonate relative to 4-(4-methoxyphenyl)butyric acid were added to a 4 mL vial containing a stir bar. rice field. Subsequently, acetone-d 6 and 1.0 equivalent of the acid anhydride shown in Table 1 relative to 4-(4-methoxyphenyl)butyric acid were added. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 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. Table 1 shows the results.
  • Example 4 A deuteration test was performed using a condensing agent (DCC) in place of the 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. Acetone-d 6 was then added. The amount of acetone- d6 used was 34 equivalents (0.40M) 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. Table 2 shows the results. The amount of each component used in Table 2 is the amount (mol %) relative to 100 mol % of 4-(4-methoxyphenyl)butyric acid.
  • DCC condensing agent
  • Example 5 In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and potassium carbonate (2.8 mg, 0.02 mmol), 20 mol % DCC, and 10 mol % DMAP were added. A mixed solvent of acetone- d6 and dimethylsulfoxide (1:1 volume ratio) was added. The amount of acetone- d6 used was 34 equivalents (0.20 M (mixed solvent of acetone- d6 and dimethylsulfoxide)) relative to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 40° C. for 24 hours, the product was separated by PTLC to determine the deuterium substitution rate. Deuterium substitution rate was 66%.
  • Example 6 A deuteration test was performed by changing the type of acid anhydride.
  • 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol % potassium carbonate and 10 mol % DMAP was added.
  • Acetone-d 6 and the anhydrides shown in Table 3 were then added.
  • the amount of acetone- d6 used was 34 equivalents (0.40M) relative to 4-(4-methoxyphenyl)butyric acid.
  • the product was separated by PTLC to determine the deuterium substitution rate. Table 3 shows the results.
  • the amount of acid anhydride used was 100 mol % with respect to 100 mol % of 4-(4-methoxyphenyl)butyric acid.
  • Example 7 Deuteration tests were performed with different types of nucleophilic activators. Specifically, 4-(4-methoxyphenyl)butyric acid and 10 mol% potassium carbonate and 10 mol % of the nucleophilic activator shown in Table 4 was added. Acetone-d 6 and 20 mol % of pivalic anhydride with respect to 100 mol % of 4-(4-methoxyphenyl)butyric acid were then added. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 40° C. for 12 hours, the product was separated by PTLC to determine the deuterium substitution rate. Table 4 shows the results.
  • Example 8 A deuteration test was performed by changing the type of salt. Specifically, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol% of 4-(4-methoxyphenyl)butyric acid per 100 mol% were added to a 4 mL vial containing a stir bar. The salts shown in Table 5 were added. Acetone-d 6 and 100 mol % of pivalic anhydride with respect to 100 mol % of 4-(4-methoxyphenyl)butyric acid were then added. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 60° C. for 4 hours, the product was separated by PTLC to determine the deuterium substitution rate. Table 5 shows the results. OPiv represents a pivalate ion.
  • Example 9 In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol % potassium carbonate and 10 mol % of DMAP (experiment number 4 only) was added. Acetone-d 6 and 100 mol % pivalic anhydride (8 ⁇ L, 0.04 mmol) with respect to 100 mol % 4-(4-methoxyphenyl)butyric acid were then added. The amount of acetone- d6 used was 34 equivalents (0.40M) 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 obtain the deuterium substitution rate. Table 6 shows the results.
  • Example 10 In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 10 mol % potassium carbonate and 10 mol % DMAP was added. Subsequently, a mixed solvent (1:1 by volume) of acetone-d 6 and a co-solvent shown in Table 7, and 20 mol% of pivalic anhydride with respect to 100 mol% of 4-(4-methoxyphenyl)butyric acid (8 ⁇ L, 0.04 mmol) was added. The amount of acetone- d6 used was 34 equivalents to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 60° C. for 4 hours, the product was separated by PTLC to determine the deuterium substitution rate. Table 7 shows the results.
  • Example 11 Deuterium substitution experiments (1) to (21) and (31) to (37) were performed using various carboxylic acids as substrates.
  • the amount of acetone-d 6 used is 34 equivalents (0.40 M) with respect to the carboxylic acid when no co-solvent is used, and when using a co-solvent, the carboxylic acid (0.20 M (mixture of acetone- d6 and co-solvent)).
  • the reaction solution was stirred at 40° C. for 48 hours to carry out the reaction, unless otherwise specified.
  • 6-ethoxy-6-oxohexanoic acid 6-ethoxy-6-oxohexanoic acid (compound (3), 32.0 ⁇ L, 0.20 mmol) was used as substrate.
  • the product was obtained without silica gel flash column chromatography.
  • N-phthalimide of gabapentin N-phthalimide of gabapentin (compound (8), 63.7 mg, 0.20 mmol) was used as substrate and DMSO (0.50 mL) was used as co-solvent. .
  • the reaction was carried out at 60°C.
  • Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate 97%, yield: 93%, 59.5 mg)
  • 1 H NMR (500 MHz, CDCl 3 ): ⁇ 7.88-7.86 (m, 2H, ArH), 7.76-7.74 (m, 2H, ArH), 3.80 (s, 2H, NCH 2 ).
  • a deuterium-enriched composition comprising a deuterated carboxylic acid or salt thereof,
  • the carboxylic acid or its salt contains ⁇ -hydrogen of the carboxy group and hydrogen other than the ⁇ -hydrogen bonded to carbon,
  • the deuterium substitution rate of the ⁇ hydrogen is 5% or more
  • the deuterium substitution rate of hydrogen other than the ⁇ -hydrogen is 3% or less,
  • the carboxylic acid or its salt has a group having a carbonyl group other than the carboxy group in the molecule, the ⁇ -hydrogen of the carbonyl group is not included in hydrogen other than the ⁇ -hydrogen, deuterium-rich composition thing.
  • carboxylic acid or its salt is a compound in which at least one carboxylic acid or its salt selected from the following formulas (1) to (21) and (38) to (47) is deuterated; A deuterium-enriched composition.
  • a method for producing a deuterated carboxylic acid or a salt thereof A production method comprising a reaction step of converting a carboxylic acid having an ⁇ -hydrogen or a salt thereof into an acid anhydride, and substituting deuterium for the hydrogen corresponding to the ⁇ -hydrogen in the acid anhydride in the presence of a deuteration source. .
  • [4] The production method of [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 its salt to form an acid anhydride.
  • (B) A compound that promotes the reaction between the carboxylic acid or its salt and the oxoacid to form an acid anhydride of the carboxylic acid or its salt and the oxoacid.
  • [5] The production method of [4], wherein the component (A) contains an acid anhydride.
  • [6] The production method of [4] or [5], wherein the component (B) contains a condensing agent.

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

重水素富化組成物、重水素置換されたカルボン酸の製造方法、反応促進剤及びカルボン酸を酸無水物に変換する化合物の使用Deuterium-enriched compositions, methods of making deuterated carboxylic acids, use of reaction accelerators and compounds to convert carboxylic acids to anhydrides
　本開示は、重水素富化組成物、重水素置換されたカルボン酸の製造方法、反応促進剤及びカルボン酸を酸無水物に変換する化合物の使用に関する。 The present disclosure relates to the use of deuterium-enriched compositions, methods for producing deuterium-substituted carboxylic acids, reaction accelerators, and compounds that convert carboxylic acids to acid anhydrides.
　機能性分子への重水素導入によって、分子機能への影響を最小限に抑えた安定性・耐久性の向上が可能である（非特許文献１）。また、重水素置換された化合物は質量分析などによって解析が容易であることから、重水素標識された医薬品を用いた体内動態追跡の研究にも利用されている（非特許文献４～６）。近年では重水素化医薬品の上市数も増加しており（２０１７年に世界初の重水素化医薬品デューテトラベナジンがＦＤＡにより承認）、特許戦略の一つとして注目を集めている（非特許文献２）。さらに、重水素は、保護基の安定性向上や反応機構解析といった目的で有機合成にも広く利用されている（非特許文献３）。以上のように、重水素化化合物は基礎研究から応用研究、工学分野や創薬化学分野まで幅広く用いられており、その需要は年々高まっている（特許文献１～３）。しかし、一般に重水素標識された化合物は、低分子の重水素化原料から多段階をかけて合成する必要があり、複雑な炭素骨格や多様な官能基を有する重水素標識化合物の革新的かつ実用的な合成手法が望まれている（特許文献１～４、非特許文献７～９）。 By introducing deuterium into functional molecules, it is possible to improve stability and durability while minimizing the impact on molecular functions (Non-Patent Document 1). In addition, since deuterium-substituted compounds can be easily analyzed by mass spectrometry, they are also used in pharmacokinetic studies using deuterium-labeled drugs (Non-Patent Documents 4 to 6). In recent years, the number of deuterated drugs on the market has also increased (in 2017, the world's first deuterated drug, deutetrabenazine, was approved by the FDA), and is attracting attention as one of the patent strategies (non-patent literature). 2). Furthermore, deuterium is widely used in organic synthesis for the purpose of improving the stability of protecting groups and analyzing reaction mechanisms (Non-Patent Document 3). As described above, deuterated compounds are widely used in basic research, applied research, engineering fields, and medicinal chemistry fields, and their demand is increasing year by year (Patent Documents 1 to 3). However, in general, deuterium-labeled compounds need to be synthesized from low-molecular-weight deuterated raw materials in multiple steps. Synthetic methods are desired (Patent Documents 1 to 4, Non-Patent Documents 7 to 9).
特開２０１６－２２２５９０号公報JP 2016-222590 A 国際公開第２００４／０６０８３１号WO2004/060831 国際公開第２００９／００５０６９号WO2009/005069 国際公開第２００５／０７０８５３号公報International Publication No. 2005/070853
　カルボン酸はバイオマス資源として、任意の構造ユニットを有するカルボン酸が容易に入手可能である。さらに１電子酸化、還元的にアルキルラジカルを生成させることが可能であり、多彩な重水素標識化合物の原料となり得る。そのため、カルボン酸の重水素化は古典的に研究されている。しかし、従来の重水素化方法では、カルボン酸のα位以外にもランダムに重水素化が進行する点などおいて、実用的な手法が開発されていない。 Carboxylic acids with any structural unit are readily available as biomass resources. Furthermore, it is possible to generate alkyl radicals by one-electron oxidation and reduction, and it can be used as a raw material for various deuterium-labeled compounds. Deuteration of carboxylic acids is therefore classically studied. However, in the conventional deuteration method, a practical method has not been developed because deuteration proceeds randomly at positions other than the α-position of the carboxylic acid.
　本開示は、上述の事情に鑑みてなされたものであり、α水素が高い選択性で重水素に置換されたカルボン酸を含む重水素富化組成物を提供することを目的とする。また、本開示は、α水素を高い選択性で重水素に置換できる重水素置換されたカルボン酸の製造方法、そのような方法に使用できる反応促進剤、並びにカルボン酸を酸無水物に変換する化合物の使用を提供することを目的とする。 The present disclosure has been made in view of the circumstances described above, and aims to provide a deuterium-enriched composition containing a carboxylic acid in which α-hydrogen has been substituted with deuterium with high selectivity. The present disclosure also provides methods for producing deuterated carboxylic acids capable of replacing alpha hydrogen with deuterium with high selectivity, reaction accelerators that can be used in such methods, and conversion of carboxylic acids to acid anhydrides. It is intended to provide uses for the compounds.
　本開示の重水素富化組成物は、重水素置換されたカルボン酸又はその塩を含む重水素富化組成物であって、上記カルボン酸又はその塩はカルボキシ基のα水素と、炭素に結合した当該α水素以外の水素とを含み、上記α水素の重水素置換率は５％以上であり、上記α水素以外の水素の重水素置換率が３％以下であり、ただし、上記カルボン酸又はその塩が分子内に前記カルボキシ基以外のカルボニル基を有する基を備える場合、当該カルボニル基のα水素は上記α水素以外の水素には含まれない。 The deuterium-enriched composition of the present disclosure is a deuterium-enriched composition comprising a deuterated carboxylic acid or salt thereof, wherein the carboxylic acid or salt thereof is the alpha hydrogen of the carboxy group and a carbon-bonded The deuterium substitution rate of the α hydrogen is 5% or more, and the deuterium substitution rate of the hydrogen other than the α hydrogen is 3% or less, provided that the carboxylic acid or When the salt 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 hydrogen other than the α-hydrogen.
　上記カルボン酸又はその塩が、下記式（１）～（２１）及び（３８）～（４７）から選択される少なくとも一種のカルボン酸又はその塩を重水素置換した化合物であると好ましい。
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000006
 The carboxylic acid or salt thereof is preferably a compound obtained by deuterium-substituting at least one carboxylic acid or salt thereof selected from the following formulas (1) to (21) and (38) to (47).
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000006
　本開示の重水素置換されたカルボン酸又はその塩の製造方法は、α水素を有するカルボン酸又はその塩を酸無水物に変換し、重水素化源の存在下で当該酸無水物におけるα水素に対応する水素を重水素に置換する反応工程を備える。 A method for producing a deuterated carboxylic acid or a salt thereof of the present disclosure converts a carboxylic acid having an α hydrogen or a salt thereof to an acid anhydride, and converts the α hydrogen in the anhydride in the presence of a deuteration source and replacing the hydrogen corresponding to with deuterium.
　上記反応工程が、以下の（Ａ）及び（Ｂ）成分の少なくとも一方の存在下で行われると好ましい。
（Ａ）上記カルボン酸又はその塩と脱水縮合反応をして酸無水物を形成する化合物。
（Ｂ）上記カルボン酸又はその塩とオキソ酸との反応を促進させて当該カルボン酸とオキソ酸との酸無水物を形成する化合物。 It is preferable that the above 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 its salt to form an acid anhydride.
(B) A compound that promotes the reaction between the carboxylic acid or its salt and an oxoacid to form an acid anhydride of the carboxylic acid and the oxoacid.
　上記（Ａ）成分が、酸無水物を含むと好ましい。 It is preferable that the component (A) contains an acid anhydride.
　上記（Ｂ）成分が、縮合剤を含むと好ましい。 It is preferable that the component (B) contains a condensing agent.
　上記縮合剤が、カルボジイミド又はカルボジイミド塩酸塩であると好ましい。 The condensing agent is preferably carbodiimide or carbodiimide hydrochloride.
　上記反応工程が、以下の（Ｃ）及び（Ｄ）成分の少なくとも一方の成分の存在下で行われると好ましい。
（Ｃ）求核的活性化剤。
（Ｄ）上記カルボン酸のカルボキシ基よりも低い酸性度を有する酸と強塩基との塩。 It is preferable that 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 an acid having a lower acidity than the carboxy group of the carboxylic acid and a strong base.
　上記（Ｃ）成分が、キヌクリジン、１，４－ジアザビシクロ［２．２．２］オクタン及び４－ジメチルアミノピリジンからなる群から選択される少なくとも一種であると好ましい。 The above component (C) is preferably at least one selected from the group consisting of quinuclidine, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine.
　上記（Ｄ）成分が炭酸塩、リン酸塩、及びカルボン酸塩からなる群から選択される少なくとも一種であると好ましい。 It is preferable that the component (D) is at least one selected from the group consisting of carbonates, phosphates, and carboxylates.
　上記重水素源が重水素化された溶媒であると好ましい。 The deuterium source is preferably a deuterated solvent.
　上記反応工程が、共溶媒の存在下で行われると好ましい。 The above reaction step is preferably carried out in the presence of a co-solvent.
　本開示の反応促進剤は、カルボン酸又はその塩のα水素を重水素に置換する反応を促進するための反応促進剤であって、上記カルボン酸又はその塩を酸無水物に変換する化合物を含む。 The reaction accelerator of the present disclosure is a reaction accelerator for promoting the reaction of substituting α hydrogen of a carboxylic acid or a salt thereof with deuterium, and is a compound that converts the carboxylic acid or a salt thereof into an acid anhydride. include.
　本開示のカルボン酸又はその塩を酸無水物に変換する化合物の使用は、カルボキシ基を有する化合物のα水素を重水素に置換する反応における触媒としての使用である。 The use of the compound that converts a carboxylic acid or a salt thereof of the present disclosure to an acid anhydride is use as a catalyst in a reaction in which the α-hydrogen of a compound having a carboxy group is replaced with deuterium.
　本開示によれば、α水素が高い選択性で重水素に置換されたカルボン酸を含む重水素富化組成物を提供することができる。また、本開示によれば、α水素を高い選択性で重水素に置換できる重水素置換されたカルボン酸の製造方法、そのような方法に使用できる反応促進剤、並びにカルボン酸を酸無水物に変換する化合物の使用を提供することができる。 According to the present disclosure, it is possible to provide a deuterium-enriched composition containing a carboxylic acid in which α-hydrogen has been substituted with deuterium with high selectivity. Further, according to the present disclosure, a method for producing a deuterated carboxylic acid capable of substituting deuterium for α hydrogen with high selectivity, a reaction accelerator that can be used in such a method, and a carboxylic acid to an acid anhydride A use of the converting compound can be provided.
（重水素置換されたカルボン酸又はその塩の製造方法）
　本実施形態の重水素置換されたカルボン酸又はその塩の製造方法は、α水素を有するカルボン酸又はその塩を酸無水物に変換し、重水素化源の存在下で当該酸無水物におけるα水素に対応する水素（軽水素）を重水素に置換することを含む反応工程を備える。本実施形態の製造方法によれば、カルボン酸又はその塩を酸無水物に変換することにより、カルボン酸又はその塩におけるα水素の酸性度を高め、効率よく当該α水素の重水素置換を進めることができ、重水素置換反応に対するα水素の選択性を高めることができる。また、従来の重水素化方法では、貴金属等の触媒、重水素ガスなど、高価な物質が必要であったが、本実施形態の製造方法では、比較的安価な化合物を使用して重水素置換反応を行うことができる。また、従来の重水素化方法では、強塩基を用いる、極めて高温の条件が必要であるなど、過酷な条件が必須であったが、本実施形態の製造方法は、比較的温和な条件で実施することができる。 (Method for producing deuterium-substituted carboxylic acid or salt thereof)
In the method for producing a deuterated carboxylic acid or a salt thereof of the present embodiment, a carboxylic acid having an α hydrogen or a salt thereof is converted to an acid anhydride, and α A reaction step including substituting deuterium for hydrogen corresponding to hydrogen (protium). According to the production method of the present embodiment, by converting a carboxylic acid or a salt thereof into an acid anhydride, the acidity of α-hydrogen in the carboxylic acid or a salt thereof is increased, and deuterium substitution of the α-hydrogen proceeds efficiently. can increase the selectivity of α-hydrogens for deuterium substitution reactions. In addition, in the conventional deuteration method, expensive substances such as catalysts such as noble metals and deuterium gas were required, but in the production method of the present embodiment, relatively inexpensive compounds are used to replace deuterium. reactions can be carried out. In addition, in the conventional deuteration method, harsh conditions were essential, such as using a strong base and requiring extremely high temperature conditions, but the production method of the present embodiment is performed under relatively mild conditions. can do.
　本実施形態の製造方法において使用するカルボン酸としては、α水素を有するカルボン酸であれば特に制限はない。なお、本明細書において、特に断らない限り、カルボン酸について「α水素」というときは、当該カルボン酸のカルボキシ基の炭素原子と直接結合している炭素原子（α炭素）に結合する水素原子を指す。言い換えれば、上記カルボン酸は、α炭素及びα水素を有するものである。なお、以下、本実施形態の方法において重水素置換を受けること目的として使用されるカルボン酸を単に「基質」とも呼ぶ。 The carboxylic acid used in the production method of the present embodiment is not particularly limited as long as it is a carboxylic acid having α-hydrogen. In the present specification, unless otherwise specified, the term "α hydrogen" for a carboxylic acid refers to a hydrogen atom that bonds to the carbon atom (α carbon) that is directly bonded to the carbon atom of the carboxy group of the carboxylic acid. Point. In other words, the carboxylic acid has an alpha carbon and an alpha hydrogen. In addition, hereinafter, the carboxylic acid used for the purpose of undergoing deuterium substitution in the method of the present embodiment is also simply referred to as "substrate".
　カルボン酸は、カルボキシ基を有する化合物であり、分子内に一つ又は複数のカルボキシ基を有していてよい。分子内に複数のカルボキシ基を有する場合、いずれかのカルボキシ基のα炭素に結合した水素原子はカルボキシ基のα水素であるとみなす。なお、以下では、本実施形態の製造方法を適用して重水素置換しようとするカルボン酸を重水素置換すべきカルボン酸とも呼ぶ。なお、本明細書においてカルボキシ基とは文脈に応じて－ＣＯＯＨ基及び－ＣＯＯＨ基の塩のいずれをも指す。 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 any carboxy group is considered to be the α hydrogen of the carboxy group. In addition, hereinafter, the carboxylic acid to be deuterated by applying the production method of the present embodiment is also referred to as the carboxylic acid to be deuterated. In this specification, a carboxy group refers to both a --COOH group and a salt of --COOH group depending on the context.
　本実施形態の製造方法において使用可能なカルボン酸は、以下の一般式（Ａ）で表すことができる。
Figure JPOXMLDOC01-appb-C000007
 （式（Ａ）中、Ｒは、α水素を含む有機基である。） A carboxylic acid that can be used in the production method of the present embodiment can be represented by the following general formula (A).
Figure JPOXMLDOC01-appb-C000007
 (In formula (A), R is an organic group containing α-hydrogen.)
　上記カルボン酸は、酢酸であってよいが、酢酸以外のカルボン酸としては、以下の化学式（Ａ１）で表される化合物及び化学式（Ａ２）で表される化合物のうち、少なくとも一種であってよい。
Figure JPOXMLDOC01-appb-C000008
 The carboxylic acid may be acetic acid, and the carboxylic acid other than acetic acid may be at least one of compounds represented by the following chemical formula (A1) and chemical formula (A2). .
Figure JPOXMLDOC01-appb-C000008
　式（Ａ１）中、Ｒ１は、１価の有機基である。より具体的には、Ｒ１は、以下の（１）～（５）の基のいずれかひとつであってよい。１価の有機基が有する炭素の個数は、１～５０個であってよく、２～４０個であってよく、５～３０個であってよい。
（１）直鎖状若しくは分岐鎖状の炭化水素基
（２）炭素環を有する基（当該炭素環は脂肪族であっても芳香族であってもよい。）
（３）複素環を有する基
（４）（１）の炭素に結合する水素を置換基（炭化水素基を除く）に置き換えたもの
（５）－Ｘ－Ｒ５で表される基 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 or branched chain hydrocarbon group; (2) a group having a carbocyclic ring (the carbocyclic ring may be aliphatic or aromatic);
(3) A group having a heterocyclic ring (4) A group represented by -X-R 5 in which the hydrogen bonded to the carbon of (1) is replaced with a substituent (excluding a hydrocarbon group)
　基（１）について、炭化水素基は、飽和炭化水素基であっても不飽和炭化水素基であってもよい。不飽和炭化水素基の場合、１～６個の不飽和基を有していてよい。基（１）を有するものとしては、脂肪酸が挙げられる。なお、基（１）は炭素環を含まない。 Regarding group (1), the hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group. Unsaturated hydrocarbon groups may have from 1 to 6 unsaturated groups. Those having group (1) include fatty acids. Group (1) does not contain a carbocyclic ring.
　基（２）における炭素環は、環員として炭素のみを含む環である。炭素環を有する基とは、基（２）内に炭素環部分を一つ以上有していればよい。二つ以上の炭素環は、縮合環を形成していてもよく、単結合又は２価以上の有機基により連結されていてもよい。また、基（２）は、アルキル基等、炭素環以外に直鎖状若しくは分岐鎖状の置換又は未置換の脂肪族炭化水素部分を有していてもよい。炭素環は脂肪族及び芳香族のいずれであってもよい。基（２）としては、シクロペンタン環、シクロヘキサン環、アダマンチル環、テトラヒドロナフチル環、ベンゼン環、ビフェニル環、インデン環、ヘキサデカヒドロ－１Ｈ－シクロペンタ［ａ］フェナントレン等を含む基が挙げられる。なお、環員である炭素原子に結合する水素原子は、置換基により置換されていてもよい。 The carbocyclic ring in group (2) is a ring containing only carbon as a ring member. A group having a carbocyclic ring may have one or more carbocyclic moieties in the group (2). Two or more carbocyclic rings may form a condensed ring, or may be linked by a single bond or a divalent or higher valent organic group. Group (2) may also have a linear or branched substituted or unsubstituted aliphatic hydrocarbon moiety other than the carbocyclic ring, such as an alkyl group. Carbocycles may be either aliphatic or aromatic. Group (2) includes groups containing cyclopentane ring, cyclohexane ring, adamantyl ring, tetrahydronaphthyl ring, benzene ring, biphenyl ring, indene ring, hexadecahydro-1H-cyclopenta[a]phenanthrene and the like. A hydrogen atom bonded to a carbon atom that is a ring member may be substituted with a substituent.
　基（３）における複素環は環員として窒素、酸素、硫黄等のヘテロ原子を含んでいてよい。複素環は、脂肪族及び芳香族のいずれであってもよい。二つ以上の複素環は、縮合環を形成していてもよく、単結合又は２価以上の有機基により連結されていてもよい。また、基（３）は炭素環を含んでいてもよい。当該炭素環は他の環と縮合していてもよく、単結合又は２価以上の有機基により他の環に連結されていてもよい。また、基（３）は、アルキル基等、炭素環以外に直鎖状若しくは分岐鎖状の置換又は未置換の脂肪族炭化水素部分を有していてもよい。複素環又は炭素環の環員である炭素原子に結合する水素原子は、置換基により置換されていてもよい。なお、複素環の環員である窒素には、アルキル基等の置換又は未置換の炭化水素基が結合していてもよい（つまり、Ｎ置換体であってよい。）。基（３）としては、オキサゾール環、Ｎ－フタルイミド環、テトラヒドロピラン環、アゼチジン環、ピロール環、インドール環（Ｎ置換インドール環であってよい。）、インダゾール環、オキセピン環等の環を含む基が挙げられる。置換基を有するオキセピン環は、オキソオキセピン環であってよく、当該オキソオキセピン環は、１１－オキソ－６，１１－ジヒドロジベンゾ［ｂ，ｅ］オキセピン又はその置換体であってよい。 The heterocyclic ring in group (3) may contain heteroatoms such as nitrogen, oxygen and sulfur as ring members. Heterocycles may be either aliphatic or aromatic. Two or more heterocyclic rings may form a condensed ring, or may be linked by a single bond or a divalent or higher valent organic group. Group (3) may also contain a carbocyclic ring. The carbocyclic ring may be condensed with another ring, or may be linked to another ring via 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, such as an alkyl group, in addition to the carbocyclic ring. A hydrogen atom bonded to a carbon atom that is a ring member of a heterocycle or carbocycle may be substituted by a substituent. In addition, a substituted or unsubstituted hydrocarbon group such as an alkyl group may be bonded to nitrogen, which is a ring member of the heterocyclic ring (that is, it may be N-substituted). Group (3) includes groups containing rings such as oxazole ring, N-phthalimide ring, tetrahydropyran ring, azetidine ring, pyrrole ring, indole ring (which may be N-substituted indole ring), indazole ring, oxepin ring, etc. is mentioned. A substituted oxepine ring may be an oxo-oxepine ring, and the oxo-oxepine ring may be 11-oxo-6,11-dihydrodibenzo[b,e]oxepine or a substituted product thereof.
　基（４）の置換基としては、例えば、ハロゲン原子、メチルスルフィニル基、アルコキシ基、ポリオキシアルキレン基等が挙げられる。なお、基（４）は炭素環又は複素環を含まない。 Examples of substituents for group (4) include halogen atoms, methylsulfinyl groups, alkoxy groups, and polyoxyalkylene groups. Group (4) does not contain a carbocyclic or heterocyclic ring.
　基（５）について、Ｘは、二価の基であり、エーテル結合（－Ｏ－）、チオエーテル結合（－Ｓ－）、アミノ基等が挙げられる。Ｒ５は、基（１）～基（４）として例示したものであってよい。なお、Ｘが－Ｓ－である場合、芳香環（例えば、ベンゼン環）の環員である原子（例えば炭素原子）に直接結合していないことが好ましい。なお、Ｒ５は、Ｒ５が有する炭素原子によりＸと結合している。 Regarding the group (5), X is a divalent group such as an ether bond (-O-), a thioether bond (-S-), an amino group and the like. R 5 may be those exemplified as groups (1) to (4). When X is -S-, it is preferably not directly bonded to an atom (eg, carbon atom) that is a ring member of an aromatic ring (eg, benzene ring). R 5 is bonded to X through the carbon atom of R 5 .
　式（Ａ２）中、Ｒ２及びＲ３は、それぞれ１価の有機基である、又は一緒になって環を形成している。より具体的には、１価の有機基は、以下の（１）～（５）の基のいずれかひとつであってよい。１価の有機基が有する炭素の個数は、１～５０個であってよく、２～４０個であってよく、５～３０個であってよい。
（１）直鎖状若しくは分岐鎖状の炭化水素基
（２）炭素環を有する基（当該炭素環は脂肪族であっても芳香族であってもよい。）
（３）－Ｘ－Ｒ５で表される基
（４）複素環を有する基
（５）（１）～（４）の炭素に結合する水素を置換基（炭化水素基を除く）に置き換えたもの
　基（１）～（５）としては、式（Ａ１）における基（１）～（５）で例示したものが挙げられる。Ｒ２及びＲ３は、同じであってもよく、異なっていてもよい。 In formula (A2), R 2 and R 3 are each a monovalent organic group or together 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 or branched chain hydrocarbon group; (2) a group having a carbocyclic ring (the carbocyclic ring may be aliphatic or aromatic);
(3) A group represented by -X-R 5 (4) A group having a heterocyclic ring (5) (1) to (4) in which the hydrogen bonded to the carbon was replaced with a substituent (excluding a hydrocarbon group) Groups (1) to (5) include those exemplified for groups (1) to (5) in formula (A1). R 2 and R 3 may be the same or different.
　Ｒ２及びＲ３が一緒になって環を形成している場合、Ｒ２及びＲ３はα炭素を含む環を形成する。言い換えれば、Ｒ２及びＲ３は一緒になって二価の有機基を形成し、当該二価の有機基の２つの結合部位がいずれもα炭素に結合している。このような環としては、２－（１－（ｔｅｒｔ－ブトキシカルボニル）アゼチジン－３－イル）酢酸のアゼチジン環、アダマンタン－２－カルボン酸のアダマンチル基等が挙げられる。環員である炭素原子に結合する水素原子は置換基に置き換えられていてもよい。二価の有機基が有する炭素の個数は、１～５０個であってよく、２～４０個であってよく、５～３０個であってよい。 When R2 and R3 together form a ring, R2 and R3 form a ring containing the alpha carbon. In other words, R 2 and R 3 together form a divalent organic group with both of the two attachment sites of the divalent organic group attached to the alpha carbon. Examples of such rings include the azetidine ring of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid and the adamantyl group of adamantane-2-carboxylic acid. A hydrogen atom attached to a carbon atom that is a ring member may be replaced by a substituent. The number of carbon atoms in the divalent organic group may be 1 to 50, 2 to 40, or 5 to 30.
　カルボン酸は、リトコール酸又はその誘導体、バクロフェン又はその誘導体、オキサプロジン又はその誘導体、ガバペンチン又はその誘導体、エトドラク又はその誘導体、イソキセパック又はその誘導体、インドメタシン又はその誘導体、スリンダク又はその誘導体、ゾメピラク又はその誘導体、ロキソプロフェン又はその誘導体、サルコシン又はその誘導体、アラニン等のアミノ酸又はその誘導体、ベンダザック又はその誘導体、フェニル酢酸又はその誘導体、２－（１，３－ジオキソイソインドリン－２－イル）基を有する脂肪族カルボン酸等であってもよい。なお、本明細書においてアミノ酸は、分子内にアミノ基とカルボキシ基を有する化合物一般を指し、具体的には、生体内でタンパク質の構成単位となる２０種類のアミノ酸（バリン、イソロイシン、ロイシン、メチオニン、リジン、フェニルアラニン、トリプトファン、スレオニン、ヒスチジン、アルギニン、グリシン、アラニン、セリン、チロシン、システイン、アスパラギン、グルタミン、プロリン、アスパラギン酸、及びグルタミン酸）であってよい。フェニル酢酸誘導体が有する置換基としては、－ＣＦ３基等の１～３の炭素原子を有するフッ素化アルキル基（パーフルオロアルキル基であってよい。）、４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル基、ＮＨＢｏｃ基等が挙げられる。２－（１，３－ジオキソイソインドリン－２－イル）基を有する脂肪族カルボン酸のカルボン酸としては、２～８の炭素原子を有する脂肪族カルボン酸であってよく、３～６の炭素原子を有する脂肪族カルボン酸であってよい。脂肪族カルボン酸は、直鎖又は分岐鎖脂肪族カルボン酸であってよく、直鎖カルボン酸であってよい。脂肪族カルボン酸は、置換基を有していてもよく、置換基としては、アルキルチオエーテル基（アルキル基は、直鎖又は分岐鎖のアルキル基であってよい。アルキル基は、１～６の炭素原子を有していてよく、１～３個のアルキル基を有していてよい。）、アルコキシ基（アルコキシ基が有するアルキル基は、直鎖又は分岐鎖のアルキル基であってよい。アルキル基は、１～６の炭素原子を有していてよく、１～３個のアルキル基を有していてよい。）、アミノ基等が挙げられる。置換基としての当該アミノ基は、２級又は３級アミノ基であってよい。また、当該アミノ基は、２～８個の炭素原子を有していてよく、４～６個の炭素原子を有していてよい。当該アミノ基は、アミノ基の窒素原子を環員として含む環状構造を有していてもよい。２－（１，３－ジオキソイソインドリン－２－イル）基は、脂肪族カルボン酸のカルボキシ基の炭素原子以外の炭素原子に結合していてよい。２－（１，３－ジオキソイソインドリン－２－イル）基を有する脂肪族カルボン酸が有する２－（１，３－ジオキソイソインドリン－２－イル）基の個数は、１～３個であってよく、１又は２個であってよく、１個であってよい。 Carboxylic acid or its derivatives, baclofen or its derivatives, oxaprozin or its derivatives, gabapentin or its derivatives, etodolac or its derivatives, isoxepac or its derivatives, indomethacin or its derivatives, sulindac or its derivatives, zomepirac or its derivatives, Loxoprofen or derivatives thereof, sarcosine or derivatives thereof, amino acids such as alanine or derivatives thereof, bendazac or derivatives thereof, phenylacetic acid or derivatives thereof, fats having a 2-(1,3-dioxoisoindolin-2-yl) group group carboxylic acid or the like. In the present specification, amino acid refers to compounds generally having an amino group and a carboxy group in the molecule, and specifically, 20 kinds of amino acids (valine, isoleucine, leucine, methionine, valine, isoleucine, leucine, methionine, , lysine, phenylalanine, tryptophan, threonine, histidine, arginine, glycine, alanine, serine, tyrosine, cysteine, asparagine, glutamine, proline, aspartic acid, and glutamic acid). Substituents possessed by the phenylacetic acid derivative include a fluorinated alkyl group having 1 to 3 carbon atoms (may be a perfluoroalkyl group) such as —CF 3 group, 4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl group, NHBoc group and the like. 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, It may be an aliphatic carboxylic acid having carbon atoms. The aliphatic carboxylic acid may be a straight or branched chain aliphatic carboxylic acid and may be a straight chain carboxylic acid. The aliphatic carboxylic acid may have a substituent, and the substituent may be an alkylthioether group (the alkyl group may be a linear or branched alkyl group. may have carbon atoms and may have 1 to 3 alkyl groups), alkoxy group (the alkyl group possessed by the alkoxy group may be a linear or branched alkyl group. The groups may have from 1 to 6 carbon atoms and may have from 1 to 3 alkyl groups.), amino groups, and the like. The amino groups as substituents may be secondary or tertiary amino groups. The amino group may also have 2 to 8 carbon atoms and may have 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 attached 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 in the aliphatic carboxylic acid having a 2-(1,3-dioxoisoindolin-2-yl) group is 1 to 3. , 1 or 2, or 1.
　上記カルボン酸は、カルボン酸塩であってもよい。カルボン酸塩が有する対カチオンとしては、特に制限はないが、アルカリ金属イオン等の一価のカチオンであってよい。本実施形態の製造方法で使用するカルボン酸は、カルボン酸及びその塩のいずれか一方でよいが、カルボン酸と塩の混合物（例えば、カルボン酸を部分的に中和したもの）であってもよい。 The carboxylic acid may be a carboxylate. The counter cation of the carboxylate is not particularly limited, and 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 a mixture of a carboxylic acid and a salt (for example, a partially neutralized carboxylic acid). good.
　カルボン酸は、一つ又は複数のカルボキシ基を有していてよい（つまり、一般式（Ａ）におけるＲがカルボキシ基を有していてもよい。）。また、カルボン酸は、カルボキシ基以外に、ケト基、ホルミル基、エステル基等のカルボニル基（－Ｃ（＝Ｏ）－）を含む基を有していてよい。 The carboxylic acid may have one or more carboxy groups (that is, R in general formula (A) may have a carboxy group). Moreover, the carboxylic acid may have a group containing a carbonyl group (--C(=O)--) such as a keto group, a formyl group, an ester group, etc., in addition to the carboxy group.
　上記カルボン酸は、カルボキシ基のα水素以外の、炭素に結合した水素を有していてもよい。このような水素原子としては、カルボン酸の脂肪族部分における炭素に結合している水素、芳香環の環員である炭素に結合している水素等が挙げられる。本実施形態の製造方法は、重水素置換に関するα水素の選択性が高いため、重水素置換すべきカルボン酸が分子内にカルボキシ基のα水素以外の水素を有している場合であっても、カルボキシ基のα水素以外の水素の重水素置換率が低い。なお、選択性の検討においてカルボン酸が分子内にカルボキシ基以外のカルボニル基を含む基を有する場合、当該カルボニル基のα水素は上記「カルボキシ基のα水素以外の水素」には含まれないものとする。 The carboxylic acid may have a carbon-bonded hydrogen other than the α-hydrogen of the carboxy group. Such hydrogen atoms include hydrogen bonded to carbon in the aliphatic portion of the carboxylic acid, hydrogen bonded to carbon that is a ring member of the aromatic ring, and the like. In the production method of the present embodiment, since the α-hydrogen selectivity for deuterium substitution is high, even if the carboxylic acid to be deuterated has hydrogen other than the α-hydrogen of the carboxy group in the molecule, , the deuterium substitution rate of hydrogen other than the α-hydrogen of the carboxy group is low. In the study of selectivity, if the carboxylic acid 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 above "hydrogen other than the α hydrogen of the carboxy group". and
　カルボン酸が、カルボキシ基以外に、ケト基、ホルミル基、エステル基等のカルボニル基を含む基を有する場合、特にケト基を有する場合、本実施形態の製造方法により、当該カルボニル基のα水素も重水素置換される場合がある。カルボニル基のα水素（カルボニル基のα水素がカルボン酸のα水素にもなっている場合を除く）が重水素置換されることを望まない場合、カルボニル基のアセタール化、ケタール化等の保護、又はエステル交換等によりカルボニル基のα水素の反応性を低下させることが容易である。そのため、カルボン酸におけるカルボキシ基及び上記カルボニル基のいずれのα水素でもない水素の重水素置換率が低い本実施形態の方法は有用である。なお、カルボニル基がエステル－Ｃ（＝Ｏ）－Ｏ－Ｙである場合、Ｙの脂肪族部分の炭素がエステル部分の酸素原子と結合している場合にカルボニル基のα水素の重水素置換率が低下する傾向にある。 When the carboxylic acid has a group containing a carbonyl group such as a keto group, a formyl group, an ester group, etc., in addition to the carboxy group, particularly when it has a keto group, the production method of the present embodiment can be used to remove the α-hydrogen of the carbonyl group. May be deuterated. If you do not want the α-hydrogen of the carbonyl group (excluding the case where the α-hydrogen of the carbonyl group is also the α-hydrogen of the carboxylic acid) to be deuterated, protection such as acetalization or ketalization of the carbonyl group, Alternatively, it is easy to reduce the reactivity of the α-hydrogen of the carbonyl group by transesterification or the like. Therefore, the method of the present embodiment is useful because the deuterium substitution rate of the hydrogen other than the α-hydrogen of neither the carboxy group nor the carbonyl group in the carboxylic acid is low. Incidentally, when the carbonyl group is an ester -C (= O) -O-Y, the deuterium substitution rate of the α hydrogen of the carbonyl group when the carbon of the aliphatic portion of Y is bonded to the oxygen atom of the ester portion tends to decline.
　カルボン酸の具体例としては、上記式（１）～（２１）、（３８）～（４７）で表される化合物等が挙げられる。また、カルボン酸の具体例としては、以下の式（３１）～（３７）で表される化合物も挙げられる。上記製造方法では、重水素化すべきカルボン酸として、一種のカルボン酸のみに対して重水素置換反応を行ってもよいが、複数種のカルボン酸を含むカルボン酸混合物に対して重水素化反応を行ってもよい。
Figure JPOXMLDOC01-appb-C000009
 Specific examples of the carboxylic acid 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, only one type of carboxylic acid may be subjected to the deuterium substitution reaction as the carboxylic acid to be deuterated. you can go
Figure JPOXMLDOC01-appb-C000009
　本実施形態の製造方法は、カルボキシ基のα水素以外に炭素に結合した水素を有しないカルボン酸（酢酸等）にも当然、適用可能である。 The production method of the present embodiment can of course also be applied to carboxylic acids (such as acetic acid) that do not have carbon-bonded hydrogen other than the α-hydrogen of the carboxy group.
　本明細書において、「酸無水物」という用語は、カルボン酸同士を脱水縮合させて得られる化合物に限らず、一般にオキソ酸同士が脱水縮合して得られる化合物全般を指すものとする。なお、「脱水縮合させて得られる」とは、形式的にそのような反応により得られる化合物の化学構造を指し、当該化合物の実際の合成方法を限定するものではない。オキソ酸としては、カルボン酸、スルホン酸、ホスフィン酸等が挙げられる。 In this specification, the term "acid anhydride" refers not only to compounds obtained by dehydration condensation of carboxylic acids, but also to general compounds obtained by dehydration condensation of oxo acids. The term "obtained by dehydration condensation" formally refers to the chemical structure of a compound obtained by such a reaction, and does not limit the actual method of synthesizing the compound. Oxoacids include carboxylic acids, sulfonic acids, phosphinic acids and the like.
　重水素置換すべきカルボン酸を酸無水物に変換する方法としては、例えば、以下の（Ａ）及び（Ｂ）成分が挙げられ、（Ａ）及び（Ｂ）成分の少なくとも一方を使用することができる。
（Ａ）重水素化すべきカルボン酸と脱水縮合反応をして酸無水物を形成する化合物。
（Ｂ）重水素化すべきカルボン酸とオキソ酸との反応を促進させて当該カルボン酸とオキソ酸との酸無水物を形成する化合物。 Examples of the method for converting the carboxylic acid to be deuterated into an acid anhydride include the following components (A) and (B), and at least one of the components (A) and (B) may be used. can.
(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 of the carboxylic acid to be deuterated with the oxoacid to form an anhydride of the carboxylic acid and the oxoacid.
　形成された酸無水物は、カルボン酸同士の酸無水物、カルボン酸とスルホン酸との酸無水物、カルボン酸とホスフィン酸との酸無水物等が挙げられ、具体的には以下の構造式（Ｘ）で表される化合物であってよい。
Figure JPOXMLDOC01-appb-C000010
 （式（Ｂ）中、Ｘは、一価基であり、下記式（Ｂ１）、式（Ｂ２）、及び式（Ｂ３）のいずれかで表される基である。式（Ｂ１）中、Ｒ１１は有機基である。式（Ｂ２）中、Ｒ２１は有機基である。式（Ｂ３）中、Ｒ３１及びＲ３２は有機基である。式（Ｂ１）～（Ｂ３）中、＊は、式（Ｂ）における酸素原子とＸとの結合位置を表す。） The formed acid anhydride includes 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. It may be a compound represented by (X).
Figure JPOXMLDOC01-appb-C000010
 (In formula (B), X is a monovalent group and is a group represented by any 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 are organic groups, in formulas (B1) to (B3), * is , represents the bonding position between the oxygen atom and X in formula (B).)
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　Ｒ１１としては特に制限はなく、式（Ｂ１）のカルボニル炭素原子と炭素－炭素結合を形成する有機基であればよい。有機基が有する炭素原子の数としては、１～３０個であってよい。有機基としては、置換又は未置換の炭化水素基、複素環を有する基等が挙げられる。なお、Ｒ１１とＲは同じであってもよく、異なっていてもよい。 R 11 is not particularly limited 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 1-30. Examples of organic groups include substituted or unsubstituted hydrocarbon groups, groups having a heterocyclic ring, and the like. R 11 and R may be the same or different.
　Ｒ１１は、１～１０個の炭素原子を有する有機基であってよく、１～８個の炭素原子を有する有機基であってよい。有機基としては、特に制限はないが、炭化水素基、炭化水素基が有する水素原子の一部または全部がハロゲンに置換されたハロゲン化炭化水素基等が挙げられる。ハロゲン化炭化水素基としては、フッ素化炭化水素基が挙げられ、全フッ素化炭化水素基が好ましい。 R 11 can be an organic group having 1 to 10 carbon atoms and can be an organic group having 1 to 8 carbon atoms. Examples of the organic group include, but are not particularly limited to, a hydrocarbon group and a halogenated hydrocarbon group in which some or all of the hydrogen atoms of a hydrocarbon group are substituted with halogen. The halogenated hydrocarbon group includes a fluorinated hydrocarbon group, preferably a wholly fluorinated hydrocarbon group.
　Ｘが（Ｂ１）で表される基の場合、（Ａ）成分としては、式（Ｂ１）に対応する構造を有するカルボン酸誘導体が好ましい。そのようなカルボン酸誘導体としては、酸無水物、酸塩化物、エステル化合物等であってよく、酸無水物が好ましい。カルボン酸誘導体は、当該カルボン酸誘導体が有するカルボニル基についてのα水素を有しないことが好ましい。 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 carboxylic acid derivatives may be acid anhydrides, acid chlorides, ester compounds and the like, with acid anhydrides being preferred. The carboxylic acid derivative preferably does not have an α-hydrogen for the carbonyl group of the carboxylic acid derivative.
　酸無水物としては、特に制限はなく、一般式Ｒ１１－Ｃ（＝Ｏ）－Ｏ－Ｃ（＝Ｏ）－Ｒ１２で表される化合物が挙げられる。ここで、Ｒ１１は、式（Ｂ１）におけるＲ１１と同じ意味である。Ｒ１２は、有機基であり、Ｒ１１と同じであってもよく、異なっていてもよい。Ｒ１２の具体例としては、Ｒ１１の具体例として挙げられたものが挙げられる。Ｒ１１及びＲ１２の少なくとも一方は、第４級炭素を有していてよい。Ｒ１１及びＲ１２の少なくとも一方は、酸無水物基から見た場合のα水素を有しないと好ましい。 The acid anhydride is not particularly limited and includes compounds represented by the general formula R 11 -C(=O)-OC(=O)-R 12 . Here, R 11 has the same meaning as R 11 in formula (B1). R 12 is an organic group and may be the same as or different from R 11 . Specific examples of R 12 include those given as specific examples of R 11 . At least one of R 11 and R 12 may have a quaternary carbon. At least one of R 11 and R 12 preferably does not have an alpha hydrogen in terms of the acid anhydride group.
　具体的には、酸無水物としては、無水酢酸、無水ピバル酸、無水トリフルオロメチル酢酸、無水安息香酸、フタル酸無水物、ジフェン酸無水物等が挙げられ、無水酢酸、無水ピバル酸、無水トリフルオロメチル酢酸及び無水安息香酸からなる群から選択される少なくとも一種が好ましく、無水ピバル酸、無水トリフルオロメチル酢酸及び無水安息香酸からなる群から選択される少なくとも一種がより好ましい。 Specifically, the acid anhydride includes acetic anhydride, pivalic anhydride, trifluoromethylacetic anhydride, benzoic anhydride, phthalic anhydride, diphenic anhydride and the like. At least one selected from the group consisting of trifluoromethylacetic acid 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.
　酸塩化物としては、一般式Ｒ１１－Ｃ（＝Ｏ）Ｃｌで表される化合物が挙げられる。ここで、Ｒ１１は、式（Ｂ１）におけるＲ１１と同じ意味である。酸塩化物としては、酢酸クロリド、ピバル酸クロリド、トリフルオロメチル酢酸クロリド、安息香酸クロリド等が挙げられる。 Acid chlorides include compounds represented by the general formula R 11 -C(=O)Cl. Here, R 11 has the same meaning as R 11 in formula (B1). Acid chlorides include acetic acid chloride, pivalic acid chloride, trifluoromethyl acetic acid chloride, benzoic acid chloride and the like.
　エステル化合物としては、一般式Ｒ１１－Ｃ（＝Ｏ）－ＯＡｒで表される化合物が挙げられる。ここで、Ｒ１１は、式（Ｂ１）におけるＲ１１と同じ意味である。Ａｒは、芳香環を有する基である。エステル化合物において、当該芳香環の環員である炭素原子とエステルの酸素原子とが直接結合していると好ましい。芳香環を有する基は、置換若しくは未置換のフェニル基、置換若しくは未置換のナフチル基等の炭化水素環を有する基、ピリジル基等の複素環を有する基などであってもよい。酸塩化物としては、酢酸フェニル、ピバル酸フェニル、トリフルオロメチル酢酸フェニル、安息香酸フェニル等が挙げられる。 Ester compounds include compounds represented by the general formula R 11 -C(=O)-OAr. Here, R 11 has the same meaning as R 11 in formula (B1). Ar is a group having an aromatic ring. In the ester compound, it is preferred that the carbon atom, which is a ring member of the aromatic ring, and the oxygen atom of the ester are directly bonded. The group having an aromatic ring may be a group having a hydrocarbon ring such as a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a group having a heterocyclic ring such as a pyridyl group. Acid chlorides include phenyl acetate, phenyl pivalate, phenyl trifluoromethylacetate, and phenyl benzoate.
　Ｒ２１としては特に制限はなく、例えば、１～３０個の炭素原子を有する有機基であってよい。有機基としては、置換又は未置換の炭化水素基、－ＯＲ２２基（Ｒ２２は、置換又は未置換の炭化水素基である）、複素環を有する基等が挙げられる。 R 21 is not particularly limited and may be, for example, an organic group having 1 to 30 carbon atoms. Examples of organic groups include substituted or unsubstituted hydrocarbon groups, —OR 22 groups (R 22 is a substituted or unsubstituted hydrocarbon group), groups having a heterocyclic ring, and the like.
　Ｘが（Ｂ２）で表される基の場合、（Ａ）成分としては、一般式Ｒ２１－ＳＯ２Ｃｌで表される化合物、一般式Ｒ２１－ＳＯ２－Ｏ－ＳＯ２－Ｒ２２で表される化合物等が挙げられる。これらの式においてＲ２１は、式（Ｂ２）におけるＲ２１と同じ意味である。Ｒ２２は、有機基であり、Ｒ２１と同じであってもよく、異なっていてもよい。Ｒ２２の具体例としては、Ｒ２１の具体例として挙げられたものが挙げられる。 When X is a group represented by (B2), the component (A) may be a compound represented by the general formula R 21 --SO 2 Cl, or a compound represented by the general formula R 21 --SO 2 --O--SO 2 --R 22 and the like compounds represented. R 21 in these formulas has the same meaning as R 21 in formula (B2). R 22 is an organic group and may be the same as or different from R 21 . Specific examples of R 22 include those given as specific examples of R 21 .
　Ｘが（Ｂ３）で表される基の場合、（Ａ）成分としては、一般式Ｒ３１Ｒ３２ＰＯＣｌで表される化合物等が挙げられる。かかる一般式においてＲ３１及びＲ３２は、式（Ｂ３）におけるＲ３１Ｒ３２と同じ意味である。 When X is a group represented by (B3), examples of the component (A) include compounds represented by the general formula R 31 R 32 POCl. R 31 and R 32 in this general formula have the same meanings as R 31 R 32 in formula (B3).
　（Ａ）成分の使用量は、特に限定されないが、重水素化すべきカルボン酸１００モル％に対して、１～２００モル％であると好ましく、５～１５０モル％であるとより好ましく、１０～１２０モル％であると更に好ましい。また、（Ａ）成分の使用量は、重水素化すべきカルボン酸が有するカルボキシ基に対して、０．０１～２当量であると好ましく、０．０５～１．５当量であるとより好ましく、０．１～１．２当量であると好ましい。 The amount of component (A) to be used is not particularly limited, but it is preferably 1 to 200 mol%, more preferably 5 to 150 mol%, more preferably 10 to 100 mol% of the carboxylic acid to be deuterated. More preferably, it is 120 mol %. The amount of component (A) used is preferably 0.01 to 2 equivalents, more preferably 0.05 to 1.5 equivalents, relative to the carboxy group of the carboxylic acid to be deuterated. 0.1 to 1.2 equivalents are preferred.
　（Ａ）成分としては、他にも二炭酸ジ－ｔｅｒｔ－ブチル（Ｂｏｃ２Ｏ）等の二炭酸化合物（－Ｏ－Ｃ（＝Ｏ）－Ｏ－Ｃ（＝Ｏ）－Ｏ－基を有する化合物）が挙げられる。 As the component (A), there are other dicarbonic compounds (-OC(=O)-OC(=O)-O- groups such as di-tert-butyl dicarbonate (Boc 2 O) compound).
　（Ｂ）成分としては、重水素化すべきカルボン酸とオキソ酸との反応を促進させる作用がある化合物であれば特に問題はなく、水分子を引き抜くなどにより脱水縮合反応を促進させる縮合剤等の化合物であってもよく、脱水縮合反応の触媒であってもよい。なお、オキソ酸は、重水素化すべきカルボン酸と異なる化合物であってもよいが、重水素化すべきカルボン酸自体であってもよい。すなわち、（Ｂ）成分の作用の下、重水素化すべきカルボン酸以外は添加された他のオキソ酸と脱水縮合反応を行って酸無水物を形成してもよいが、重水素化すべきカルボン酸同士が反応して酸無水物を形成してもよい。 As the component (B), there is no particular problem as long as it is a compound that has the effect of promoting the reaction between the carboxylic acid to be deuterated and the oxo acid. It may be a compound or a catalyst for a dehydration condensation reaction. The oxoacid may be a compound different from the carboxylic acid to be deuterated, or may be the carboxylic acid itself to be deuterated. That is, under the action of the component (B), the carboxylic acid to be deuterated may undergo a dehydration condensation reaction with an added oxoacid to form an acid anhydride. They may react with each other to form an acid anhydride.
　縮合剤としては、特に限定されず、カルボジイミド又はカルボジイミドの塩酸塩が挙げられる。カルボジイミドとしては具体的には、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ）等が挙げられる。 The condensing agent is not particularly limited, and includes carbodiimide or carbodiimide hydrochloride. Specific examples of carbodiimides include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N,N'-dicyclohexylcarbodiimide (DCC).
　縮合剤の使用量としては、特に限定されず、重水素化すべきカルボン酸１００モル％に対して、１～１００モル％であると好ましく、３～８０モル％であるとより好ましく、５～５０モル％であると更に好ましく、５～３０モル％であると特に好ましい。 The amount of the condensing agent to be used is not particularly limited, and is preferably 1 to 100 mol%, more preferably 3 to 80 mol%, more preferably 5 to 50 mol%, relative to 100 mol% of the carboxylic acid to be deuterated. It is more preferably mol %, and particularly preferably 5 to 30 mol %.
　重水素源としては、重水素化された溶媒（重溶媒）等が挙げられる。重溶媒としては特に限定されず、カルボニル基を有する化合物であると好ましい。カルボニル基を有する化合物は、当該カルボニル基のα水素を有する化合物であると好ましく、例えば、重アセトン等が挙げられる。 Examples of deuterium sources include deuterated solvents (heavy solvents). The heavy solvent is not particularly limited, and is preferably a compound having a carbonyl group. A compound having a carbonyl group is preferably a compound having an α-hydrogen of the carbonyl group, and examples thereof include deuterated acetone.
　重水素源の使用量としては、重水素化すべきカルボン酸のカルボキシ基に対して過剰量（つまり、１当量より大きい）であると好ましく、２当量以上であるとより好ましく、５～８０当量であると更に好ましく、１０～５０当量であると特に好ましい。 The amount of deuterium source to be used is preferably an excess amount (that is, more than 1 equivalent) relative to the carboxy group of the carboxylic acid to be deuterated, more preferably 2 equivalents or more, and 5 to 80 equivalents. It is more preferable to have 10 to 50 equivalents, and particularly preferably 10 to 50 equivalents.
　上記反応工程は、以下の（Ｃ）及び（Ｄ）成分の少なくとも一方の成分の存在下で行われてもよい。
（Ｃ）求核的活性化剤。
（Ｄ）重水素化すべきカルボン酸のカルボキシ基よりも低い酸性度を有する酸と強塩基との塩。 The above reaction step may be carried out in the presence of at least one of the following components (C) and (D).
(C) a nucleophilic activator.
(D) Salts of acids and strong bases having an acidity lower than the carboxy group of the carboxylic acid to be deuterated.
　（Ｃ）成分は、酸無水物のカルボニル炭素に求核的に攻撃することにより、カルボン酸の脱離を促進する触媒として作用する化合物であり、キヌクリジン、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、４－ジメチルアミノピリジン（ＤＭＡＰ）等が挙げられる。（Ｃ）成分は、１種又は２種以上を使用してよい。 Component (C) is a compound that acts as a catalyst that promotes elimination of carboxylic acid by nucleophilically attacking the carbonyl carbon of the acid anhydride. 2] octane (DABCO), 4-dimethylaminopyridine (DMAP) and the like. (C) Component may use 1 type(s) or 2 or more types.
　（Ｃ）成分の使用量としては、特に限定されず、重水素化すべきカルボン酸１００モル％に対して、１～１００モル％であると好ましく、３～８０モル％であるとより好ましく、５～５０モル％であると更に好ましく、５～３０モル％であると特に好ましい。 The amount of component (C) used is not particularly limited, and is preferably 1 to 100 mol%, more preferably 3 to 80 mol%, based on 100 mol% of the carboxylic acid to be deuterated. It is more preferably up to 50 mol %, particularly preferably 5 to 30 mol %.
　（Ｄ）成分としては、炭酸塩、リン酸塩、及びカルボン酸塩が挙げられる。（Ｄ）成分は、１種又は２種以上を使用してよい。炭酸塩としては、アルカリ金属、テトラメチルアンモニウム等の第４級アンモニウムイオンなどのカチオンと炭酸イオンとの塩が挙げられ、炭酸ナトリウム、炭酸カリウム、炭酸ルビジウム、又は炭酸セシウムが好ましく、炭酸カリウム、炭酸ルビジウム、又は炭酸セシウムがより好ましい。リン酸塩としては、アルカリ金属、テトラメチルアンモニウム等の第４級アンモニウムイオンなどのカチオンとリン酸イオンとの塩が挙げられ、リン酸カリウムが好ましい。 The component (D) includes carbonates, phosphates, and carboxylates. (D) Component may use 1 type(s) or 2 or more types. Examples of carbonates include salts of carbonate ions with cations such as alkali metals and quaternary ammonium ions such as tetramethylammonium, and sodium carbonate, potassium carbonate, rubidium carbonate, or cesium carbonate is preferable. Rubidium or cesium carbonate are more preferred. Phosphates include salts of phosphate ions with cations such as alkali metals and quaternary ammonium ions such as tetramethylammonium, and potassium phosphate is preferred.
　カルボン酸塩に含まれるカルボン酸イオンとしては、特に制限はないが、α水素を有しないカルボン酸イオンであると好ましい。このようなカルボン酸イオンとしては、ピバル酸イオン等が挙げられる。カルボン酸塩に含まれるカチオンとしては、アルカリ金属、テトラメチルアンモニウム等の第４級アンモニウムイオンなどが挙げられる。カルボン酸塩としては、ピバル酸カリウム、ピバル酸セシウム、ピバル酸テトラメチルアンモニウム等が挙げられる。 The carboxylate ion contained in the carboxylate is not particularly limited, but is preferably a carboxylate ion having no α-hydrogen. Examples of such carboxylate ions include pivalate ions. Examples of cations contained in the carboxylate include alkali metals and quaternary ammonium ions such as tetramethylammonium. Carboxylate includes potassium pivalate, cesium pivalate, tetramethylammonium pivalate and the like.
　（Ｄ）成分に含まれるアニオンは、重水素化すべきカルボン酸のカルボキシ基よりも低い酸性度を有する酸の共役塩基であるため、弱酸の遊離により重水素化すべきカルボン酸が（Ｄ）成分に含まれるカチオンと塩を形成し、酸無水物の形成を促進するものと考えられる。 Since the anion contained in component (D) is a conjugate base of an acid having a lower acidity than the carboxy group of the carboxylic acid to be deuterated, the carboxylic acid to be deuterated by liberation of the weak acid is added to component (D). It is thought to form a salt with the contained cation and promote the formation of acid anhydride.
　（Ｄ）成分の使用量としては、特に限定されず、重水素化すべきカルボン酸１００モル％に対して、１～１００モル％であると好ましく、３～８０モル％であるとより好ましく、５～５０モル％であると更に好ましく、５～３０モル％であると特に好ましい。 The amount of component (D) to be used is not particularly limited, and is preferably 1 to 100 mol%, more preferably 3 to 80 mol%, based on 100 mol% of the carboxylic acid to be deuterated. It is more preferably up to 50 mol %, particularly preferably 5 to 30 mol %.
　更に、反応工程は、共溶媒の存在下で行ってもよい。重水素化すべきカルボン酸、（Ａ）～（Ｄ）成分等が重溶媒に溶解しにくい場合に、溶解しにくい成分を溶解させる溶媒を共溶媒として使用すると有効である。共溶媒は、特に限定されず、非プロトン性溶媒であると好ましく、ジメチルスルホキシド（ＤＭＳＯ）、ジメチルホルムアミド（ＤＭＦ）、トルエン、１，２－ジクロロエタン（ＤＣＥ）、テトラヒドロフラン（ＴＨＦ）、アセトニトリル等が挙げられる。 Furthermore, the reaction step may be performed in the presence of a co-solvent. When the carboxylic acid to be deuterated, components (A) to (D), etc. are difficult to dissolve in the heavy solvent, it is effective to use a solvent that dissolves the components that are difficult to dissolve as a co-solvent. The co-solvent is not particularly limited and is preferably an aprotic solvent such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), toluene, 1,2-dichloroethane (DCE), tetrahydrofuran (THF), acetonitrile and the like. be done.
　反応工程における反応温度は特に限定されず、１００℃以下であってよく、８０℃以下であってよい。反応時間も特に限定されず、例えば、０．５～７２時間であってよい。 The reaction temperature in the reaction step is not particularly limited, and may be 100°C or lower, or 80°C or lower. The reaction time is also not particularly limited, and may be, for example, 0.5 to 72 hours.
　上記製造方法によってα水素が重水素置換されたカルボン酸を含む重水素富化組成物を製造することができる。
　すなわち、本実施形態の重水素富化組成物は、重水素置換されたカルボン酸を含み、上記カルボン酸はカルボキシ基のα水素と、炭素に結合した当該α水素以外の水素とを含み、α水素の重水素置換率は５％以上であり、α水素以外の水素の重水素置換率が３％以下であり、ただし、上記カルボン酸が分子内に前記カルボキシ基以外のカルボニル基を有する基を備える場合、当該カルボニル基のα水素は前記α水素以外の水素には含まれない。 A deuterium-enriched composition containing a carboxylic acid in which the α-hydrogen is deuterated can be produced by the above production method.
That is, the deuterium-enriched composition of the present embodiment comprises a deuterium-substituted carboxylic acid, the carboxylic acid comprising an α-hydrogen of a carboxy group and hydrogen other than the α-hydrogen bonded to a carbon; The deuterium substitution rate of hydrogen is 5% or more, and the deuterium substitution rate of hydrogen other than α hydrogen is 3% or less, provided that the carboxylic acid contains a group having a carbonyl group other than the carboxy group in the molecule. When provided, the α-hydrogen of the carbonyl group is not included in hydrogen other than the α-hydrogen.
　本明細書において重水素富化とは、天然存在比よりも重水素の含有率が高められたことを言う。重水素富化組成物は、重水素化されたカルボン酸を含み、未反応のカルボン酸及び不可避不純物を含む場合があってもよい。本実施形態の重水素富化組成物は、含まれるカルボン酸のα水素が重水素富化された組成物である。 In this specification, the deuterium-enriched means that the content of deuterium is higher than the natural abundance. Deuterium-enriched compositions contain deuterated carboxylic acids and may contain unreacted carboxylic acids and incidental impurities. The deuterium-enriched composition of the present embodiment is a composition in which the alpha hydrogen of the contained carboxylic acid is enriched with deuterium.
　重水素置換率は、カルボキシ基のα水素の場合、重水素富化組成物において上記カルボン酸のカルボキシ基のα炭素に結合する水素のうち重水素化された水素の割合を言う。つまり、つまり、α炭素に結合する全水素（軽水素及び重水素の合計）に対する重水素の割合である。重水素化率は、１ＨＮＭＲスペクトルの積分強度から計算することができる。カルボン酸の分子内に複数のα水素がある場合、重水素置換率の計算は分子内の等価な炭素毎の重水素置換率であるものとする。例えば、コハク酸（ＨＯＯＣ－ＣＡＨ２－ＣＢＨ２－ＣＯＯＨ）の２つのα炭素ＣＡ及びＣＢは等価であるため、ＣＡ及びＣＢに結合する全水素（同位体の区別をしない全水素）に対する、重水素の割合を重水素置換率とする。一方、例えば、メチルコハク酸（ＨＯＯＣ－ＣＡＨ（ＣＨ３）－ＣＢＨ２－ＣＯＯＨ）の２つのα炭素ＣＡ及びＣＢは等価ではないため、重水素置換率はＣＡ及びＣＢのそれぞれについて別々に算出する。 Deuterium substitution rate, in the case of the alpha hydrogen of a carboxy group, refers to the percentage of hydrogens bound to the alpha carbon of the carboxy group of the carboxylic acid in the deuterium-enriched composition that are deuterated. In other words, it is the ratio of deuterium to total hydrogen (total of hydrogen and deuterium) bonded to the alpha carbon. The deuteration rate can be calculated from the integrated intensity of the 1 H NMR spectrum. If there are multiple α-hydrogens in the molecule of the carboxylic acid, the calculation of the deuterium substitution rate shall be the deuterium substitution rate for each equivalent carbon in the molecule. For example, since the two α-carbons C A and C B of succinic acid (HOOC-C A H 2 -C B H 2 -COOH) are equivalent, all hydrogens attached to C A and C B (isotopic distinction Deuterium replacement rate is the ratio of deuterium to total hydrogen that does not On the other hand, for example, the two alpha carbons C A and C B of methylsuccinic acid (HOOC-C A H(CH 3 )-C B H 2 -COOH) are not equivalent, so the deuterium substitution ratios are C A and C B are calculated separately for each of the
　α水素の重水素置換率は、５％以上であれば問題はないが、１０％以上であってよく、２０％以上であってよく、３０％以上であってよく、５０％以上であってよく、７０％以上であってよい。 There is no problem if the deuterium substitution rate of α hydrogen is 5% or more, but it may be 10% or more, 20% or more, 30% or more, or 50% or more. Well, it can be 70% or more.
　α水素以外の水素の重水素置換率は、α炭素以外の全炭素（ただし、カルボン酸がカルボキシ基以外のカルボニル基を有する基を備える場合、当該カルボニル基のα炭素は除く）に結合する全水素に対する重水素の割合である。重水素置換率は、１％以下であってよく、０．１％以下であってよく、略０％であってもよい（すなわち、天然存在比とほぼ変わらない）。 The deuterium substitution rate of hydrogen other than α hydrogen is all carbons other than α carbon (however, if the carboxylic acid has a group with a carbonyl group other than a carboxyl group, the α carbon of the carbonyl group is excluded). It is the ratio of deuterium to hydrogen. The deuterium substitution rate may be 1% or less, 0.1% or less, or approximately 0% (that is, substantially the same as the natural abundance).
　本実施形態の反応促進剤は、カルボン酸のα水素を重水素に置換する反応を促進するための反応促進剤であって、カルボン酸を酸無水物に変換する化合物を含む。反応促進剤は、（Ａ）成分及び（Ｂ）成分の少なくとも一方を含むことが好ましく、（Ａ）成分及び（Ｂ）成分の少なくとも一方と、（Ｃ）成分と、（Ｄ）成分とを含むことが好ましい。 The reaction accelerator of the present embodiment is a reaction accelerator for promoting the reaction of substituting deuterium for the α-hydrogen of the carboxylic acid, and includes a compound that converts the carboxylic acid into an acid anhydride. The reaction accelerator preferably contains at least one of the components (A) and (B), and contains at least one of the components (A) and (B), the component (C), and the component (D). is preferred.
　以下、実施例を用いて本開示を更に説明するが、本開示は以下の実施例に限定されるものではない。 The present disclosure will be further described below using examples, but the present disclosure is not limited to the following examples.
＜４－（４－メトキシフェニル）酪酸の重水素化＞
［実施例１］
　４－（４－メトキシフェニル）酪酸の重水素化実験について、以下に説明する。
　バイアルに４－（４－メトキシフェニル）酪酸（７．０ｍｍｏｌ）と、４－（４－メトキシフェニル）酪酸１００モル％に対してそれぞれ１０モル％の炭酸カリウム及び１０モル％のＤＭＡＰとを加えた。続いて重アセトン（アセトン－ｄ６）と４－（４－メトキシフェニル）酪酸１００モル％に対して２０モル％無水ピバル酸（８μＬ、０．０４ｍｍｏｌ）とを加えた。なお、アセトン－ｄ６の量は、４－（４－メトキシフェニル）酪酸に対して１９．４当量（０．７０Ｍ）であった。反応溶液を４０℃で４８時間撹拌した後、反応溶液にＤ２Ｏ（０．１０ｍＬ）を加えて室温（２５℃）で１時間撹拌して反応をクエンチした。反応溶液に１Ｍの塩酸水溶液を加えてＣＨ２Ｃｌ２で抽出し、溶媒を減圧下で留去した。ピバル酸を除くために、残渣に２ｍＬのＣＨ２Ｃｌ２：ギ酸＝４：１（体積比）を添加して溶媒留去を行った。この共沸操作を３回行った。その後、シリカゲルカラムクロマトグラフィーによって精製を行った。
　得られた生成物について１ＨＮＭＲ、１３ＣＮＭＲ、赤外分光スペクトル（ＩＲ）、及び精密質量分析（ＨＲＭＳ（エレクトロスプレーイオン化、ＥＳＩ））を行い、生成物が４－（４－メトキシフェニル）酪酸の重水素富化組成物であることを確認した。なお、ＮＭＲの測定に使用した装置はＡｖａｎｃｅ　ＩＩＩ（Ｂｒｕｋｅｒ社製）であった。 <Deuteration of 4-(4-methoxyphenyl)butyric acid>
[Example 1]
Deuteration experiments for 4-(4-methoxyphenyl)butyric acid are described below.
To the vial was added 4-(4-methoxyphenyl)butyric acid (7.0 mmol) and 10 mol% potassium carbonate and 10 mol% DMAP for each 100 mol% of 4-(4-methoxyphenyl)butyric acid. . Subsequently, deuterated acetone (acetone-d 6 ) and 20 mol % pivalic anhydride (8 μL, 0.04 mmol) with respect to 100 mol % 4-(4-methoxyphenyl)butyric acid were added. Note that the amount of acetone- d6 was 19.4 equivalents (0.70M) with respect to 4-(4-methoxyphenyl)butyric acid. After the reaction solution was stirred at 40° C. for 48 hours, D 2 O (0.10 mL) was added to the reaction solution and stirred at room temperature (25° C.) for 1 hour to quench the reaction. A 1 M hydrochloric acid aqueous solution was added to the reaction solution, extracted with CH 2 Cl 2 , and the solvent was distilled off under reduced pressure. To remove pivalic acid, 2 mL of CH 2 Cl 2 :formic acid=4:1 (volume ratio) was added to the residue and the solvent was distilled off. This azeotropic operation was performed three times. After that, purification was performed by silica gel column chromatography.
The obtained product was subjected to 1 H NMR, 13 C NMR, infrared spectroscopy (IR), and accurate mass spectrometry (HRMS (electrospray ionization, ESI)), and the product was 4-(4-methoxyphenyl)butyric acid. It was confirmed to be a deuterium-enriched composition. The apparatus used for NMR measurement was Avance III (manufactured by Bruker).
　１ＨＮＭＲの積分強度から生成物におけるα水素の重水素置換率を求めた。重水素置換率は９４％であった。なお、α水素の重水素置換率は、生成物に含まれる４－（４－メトキシフェニル）酪酸のα水素の総数に対する重水素置換されたα水素の数の比（すなわち、α位のＤの総数をα位のＤとＨの合計で除したもの）である。重水素置換率は、１ＨＮＭＲスペクトルから、α水素とα水素以外の水素の軽水素の原子数の比から算出した。
　また、４－（４－メトキシフェニル）酪酸の収率は８２％であった。なお、収率は、基質として使用した４－（４－メトキシフェニル）酪酸に対する、生成物に含まれる４－（４－メトキシフェニル）酪酸（α重水素置換されたものとα重水素置換されていないものの両方を含む）の割合である。収率は、以下の方法により算出した。
（１）空の状態の５０ｍＬナスフラスコの重さをあらかじめ量っておき、精製後の生成物溶液を入れて溶媒を留去し、再度ナスフラスコの重さを量り、重さの差から生成物の収量（ｍｇ）を算出した。
（２）次に、重水素化率０％の分子量とα重水素化率１００％の分子量をｃｈｅｍｄｒａｗにて算出し、１ＨＮＭＲスペクトルから算出した実測の重水素化率を用いて基質の重水素化率に合わせた分子量を算出した。（※４－（４－メトキシフェニル）酪酸での例：ｄ０の分子量１９４．２３００、ｄ２の分子量１９６．２４２２、重水素化率９４％の場合の分子量１９６．２４２２×０．９４＋１９４．２３００×０．０６＝１９６．１２１５）
（３）収量（ｍｇ）を、算出した分子量で除して収量（ｍｍｏｌ）を計算し、収量（ｍｍｏｌ）を基質として加えたカルボン酸の量（ｍｍｏｌ）で除して収率（％）を算出した。
　得られた生成物１－ｄ２は１．１２ｇであり、グラムスケールでの製造も可能である。 Deuterium substitution rate of α-hydrogen in the product was obtained from the integrated intensity of 1 HNMR. Deuterium substitution rate was 94%. The deuterium substitution rate of α-hydrogen is the ratio of the number of deuterated α-hydrogens to the total number of α-hydrogens in 4-(4-methoxyphenyl)butyric acid contained in the product (that is, the number of α-position D the total number divided by the sum of D and H at the α-position). The deuterium substitution rate was calculated from the ratio of the number of hydrogen atoms of α-hydrogen and hydrogen other than α-hydrogen from the 1 HNMR spectrum.
Also, the yield of 4-(4-methoxyphenyl)butyric acid was 82%. The yield is calculated based on the 4-(4-methoxyphenyl)butyric acid used as a substrate, and the 4-(4-methoxyphenyl)butyric acid contained in the product (α-deuterium-substituted and α-deuterium-substituted (including both without). Yield was calculated by the following method.
(1) An empty 50 mL eggplant flask is weighed in advance, the purified product solution is added, the solvent is distilled off, the eggplant flask is weighed again, and the difference in weight is used to generate The yield (mg) of the product was calculated.
(2) Next, the molecular weight at a deuteration rate of 0% and the molecular weight at an α-deuteration rate of 100% were calculated by chemdraw, and the deuterium of the substrate was calculated using the actually measured deuteration rate calculated from the 1 H NMR spectrum. The molecular weight was calculated according to the conversion rate. (*Example with 4-(4-methoxyphenyl)butyric acid: d 0 molecular weight 194.2300, d 2 molecular weight 196.2422, molecular weight 196.2422 × 0.94 + 194.2300 when deuteration rate is 94% × 0.06 = 196.1215)
(3) Calculate the yield (mmol) by dividing the yield (mg) by the calculated molecular weight, and divide the yield (mmol) by the amount (mmol) of carboxylic acid added as a substrate to obtain the yield (%). Calculated.
The product 1- d2 obtained is 1.12 g, and gram-scale production is also possible.
　４－（４－メトキシフェニル）酪酸は、α水素以外の水素として、カルボキシ基のβ水素及びγ水素（それぞれ２個）、ベンゼン環に結合する水素（４個）、及びメチル基に結合する水素（３個）の合計１１個のα炭素以外の炭素に結合した水素原子を有する。１ＨＮＭＲの積分強度を検討したところ、４－（４－メトキシフェニル）酪酸のα炭素以外の炭素に結合する水素について重水素置換は観測されなかった（つまり、検出限界以下であった。）。 4-(4-methoxyphenyl)butyric acid has, as hydrogen other than α-hydrogen, β-hydrogen and γ-hydrogen of the carboxy group (two each), hydrogen bonding to the benzene ring (4 hydrogens), and hydrogen bonding to the methyl group. (3) have a total of 11 hydrogen atoms bonded to carbons other than the α-carbons. When the integrated intensity of 1 H NMR was examined, no deuterium substitution was observed for hydrogens bonded to carbons other than the α carbon of 4-(4-methoxyphenyl)butyric acid (that is, below the detection limit).
　なお、以下のすべての実施例において、α水素以外の水素（カルボキシ基以外のカルボニル基のα水素を除く）の重水素置換は検出されなかった。このことは、１ＨＮＭＲのα水素以外の水素のピークの積分強度が重水素置換を行う前の各ピークの強度と比較して誤差範囲で一致することからわかる。また、後述のとおり、マススペクトルの測定値と計算値がよく合っており、また、スペクトル自体もシャープであることから、分子全体として均等に重水素置換が起こっている可能性が否定される。 In all of the following examples, deuterium substitution of hydrogen other than α-hydrogen (excluding α-hydrogen of carbonyl groups other than carboxy groups) was not detected. This can be seen from the fact that the integrated intensities of the peaks of hydrogen other than α-hydrogen in 1 H NMR agree with the intensities of the respective peaks before deuterium substitution within an error range. In addition, as will be described later, the measured and calculated values of the mass spectrum are in good agreement, and the spectrum itself is sharp.
　一方、従来の方法、例えば、国際公開第２００５／０７０８５３号公報の方法では、α水素以外の水素についても無差別に重水素化が起こってしまう。また、非特許文献７の第４０５４頁、非特許文献８の第３２７９頁、及び非特許文献９の第１０８９７頁を参照しても、同様にカルボン酸のα水素以外の水素にも重水素置換が起こってしまう。本実施形態の方法では、強塩基等の強力な試薬、金属触媒等の水素引き抜き反応を強く触媒する試薬などを用いておらず、酸無水物におけるカルボキシ基のα水素に対応する水素の酸性を利用しているため、α水素以外の水素との反応性の差が大きく、選択性が高いと考えられる。 On the other hand, in the conventional method, for example, the method of International Publication No. 2005/070853, hydrogen other than α-hydrogen is indiscriminately deuterated. Also, referring to page 4054 of Non-Patent Document 7, page 3279 of Non-Patent Document 8, and page 10897 of Non-Patent Document 9, hydrogens other than the α-hydrogen of the carboxylic acid are similarly substituted with deuterium. will happen. In the method of the present embodiment, strong reagents such as strong bases and reagents that strongly catalyze hydrogen abstraction reactions such as metal catalysts are not used. Since it is used, it is thought that the difference in reactivity with hydrogen other than α-hydrogen is large and the selectivity is high.
　４－（４－メトキシフェニル）酪酸の触媒的重水素置換反応について提案される反応機構は以下のスキームのとおりであると考えられる。
Figure JPOXMLDOC01-appb-C000012
 The proposed reaction mechanism for the catalytic deuterium substitution reaction of 4-(4-methoxyphenyl)butyric acid is believed to be as shown in the scheme below.
Figure JPOXMLDOC01-appb-C000012
　まず、弱いブレンステッド塩基である炭酸カリウムの添加により系内に存在するカルボン酸におけるカルボキシ基のプロトンが引き抜かれ、カルボン酸イオンが生じると共に、酸無水物の混合物（Ｉ）が形成される。形成された酸無水物の混合物（Ｉ）とＤＭＡＰからアシルピリジニウム種（ＩＩ）が生成し、弱いブレンステッド塩基である上記カルボン酸イオンにより水素が引き抜かれ、副生物であるカルボン酸が生じると共にアシルピリジニウム種（ＩＩ）に由来するエノラート（ＩＩＩ）が生じる。エノラート（ＩＩＩ）は、重水素化剤である重アセトンから生じるＲ’ＣＯＯＤ（右回りのサイクル）と反応し、α重水素化されたアシルピリジニウム種（ＩＶ）が生じる。そして、アシル交換反応が起こり、重水素化されたカルボン酸が生じる。 First, by adding potassium carbonate, which is a weak Bronsted base, the proton of the carboxy group in the carboxylic acid present in the system is withdrawn to generate carboxylic acid ions and form the acid anhydride mixture (I). An acylpyridinium species (II) is produced from the formed acid anhydride mixture (I) and DMAP, and hydrogen is abstracted by the carboxylic acid ion, which is a weak Bronsted base, to produce a by-product carboxylic acid and acyl Enolate (III) derived from pyridinium species (II) is produced. The enolate (III) reacts with R'COOD (clockwise cycle) generated from the deuteration agent deuterated acetone to give the α-deuterated acylpyridinium species (IV). An acyl exchange reaction then occurs to produce a deuterated carboxylic acid.
［実施例２］
　撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸（０．２０ｍｍｏｌ）と、４－（４－メトキシフェニル）酪酸に対して１．０当量の酢酸カリウム（２．８ｍｇ、０．０２ｍｍｏｌ）とを加えた。続いてアセトン－ｄ６と４－（４－メトキシフェニル）酪酸に対して１．０当量の無水酢酸を加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量（０．４０Ｍ）であった。反応溶液を７０℃で１６時間撹拌した後、生成物を分取薄層クロマトグラフィー（ＰＴＬＣ）により分離して重水素置換率を求めたところ、重水素置換率は９５％であった。 [Example 2]
In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and potassium acetate (2.8 mg, 0.02 mmol) was added. Acetic anhydride was then added in an amount of 1.0 equivalents relative to acetone-d 6 and 4-(4-methoxyphenyl)butyric acid. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 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) and the deuterium substitution rate was determined to be 95%.
［実施例３］
　酸無水物の種類を変更して重水素化試験を行った。
　具体的には、撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸（０．２０ｍｍｏｌ）と４－（４－メトキシフェニル）酪酸に対して２０モル％の炭酸カリウムを加えた。続いてアセトン－ｄ６と、４－（４－メトキシフェニル）酪酸に対して１．０当量の表１に示す酸無水物を加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量（０．４０Ｍ）であった。反応溶液を６０℃で１６時間撹拌した後、生成物をＰＴＬＣにより分離して重水素置換率を求めた。結果を表１に示す。
Figure JPOXMLDOC01-appb-T000013
 [Example 3]
A deuteration test was performed by changing the type of acid anhydride.
Specifically, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol % potassium carbonate relative to 4-(4-methoxyphenyl)butyric acid were added to a 4 mL vial containing a stir bar. rice field. Subsequently, acetone-d 6 and 1.0 equivalent of the acid anhydride shown in Table 1 relative to 4-(4-methoxyphenyl)butyric acid were added. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 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. Table 1 shows the results.
Figure JPOXMLDOC01-appb-T000013
［実施例４］
　酸無水物に代えて縮合剤（ＤＣＣ）を使用して重水素化試験を行った。
　具体的には、撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸（０．２０ｍｍｏｌ）と、表２に示す量の炭酸セシウム、ＤＣＣ及びＤＭＡＰとを加えた。続いて、アセトン－ｄ６を加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量（０．４０Ｍ）であった。反応溶液を４０℃で６時間撹拌した後、生成物をＰＴＬＣにより分離して重水素置換率を求めた。結果を表２に示す。なお、表２における各成分の使用量は、４－（４－メトキシフェニル）酪酸１００モル％に対する量（モル％）である。
Figure JPOXMLDOC01-appb-T000014
 [Example 4]
A deuteration test was performed using a condensing agent (DCC) in place of the 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. Acetone-d 6 was then added. The amount of acetone- d6 used was 34 equivalents (0.40M) 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. Table 2 shows the results. The amount of each component used in Table 2 is the amount (mol %) relative to 100 mol % of 4-(4-methoxyphenyl)butyric acid.
Figure JPOXMLDOC01-appb-T000014
［実施例５］
　撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸（０．２０ｍｍｏｌ）と、４－（４－メトキシフェニル）酪酸に対してそれぞれ１０モル％の炭酸カリウム（２．８ｍｇ、０．０２ｍｍｏｌ）、２０モル％のＤＣＣ、及び１０モル％のＤＭＡＰを加えた。アセトン－ｄ６とジメチルスルホキシドとの混合溶媒（体積比１：１）を加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量（０．２０Ｍ（アセトン－ｄ６とジメチルスルホキシドとの混合溶媒））であった。反応溶液を４０℃で２４時間撹拌した後、生成物をＰＴＬＣにより分離して重水素置換率を求めた。重水素置換率は６６％であった。 [Example 5]
In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and potassium carbonate (2.8 mg, 0.02 mmol), 20 mol % DCC, and 10 mol % DMAP were added. A mixed solvent of acetone- d6 and dimethylsulfoxide (1:1 volume ratio) was added. The amount of acetone- d6 used was 34 equivalents (0.20 M (mixed solvent of acetone- d6 and dimethylsulfoxide)) relative to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 40° C. for 24 hours, the product was separated by PTLC to determine the deuterium substitution rate. Deuterium substitution rate was 66%.
［実施例６］
　酸無水物の種類を変更して重水素化試験を行った。
　撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸（０．２０ｍｍｏｌ）と、４－（４－メトキシフェニル）酪酸１００モル％に対してそれぞれ２０モル％の炭酸カリウム及び１０モル％のＤＭＡＰを加えた。続いてアセトン－ｄ６と表３に示す酸無水物を加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量（０．４０Ｍ）であった。反応溶液を６０℃で２４時間撹拌した後、生成物をＰＴＬＣにより分離して重水素置換率を求めた。結果を表３に示す。なお、酸無水物の使用量は、４－（４－メトキシフェニル）酪酸１００モル％に対して１００モル％のであった。
Figure JPOXMLDOC01-appb-T000015
 [Example 6]
A deuteration test was performed by changing the type of acid anhydride.
In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol % potassium carbonate and 10 mol % DMAP was added. Acetone-d 6 and the anhydrides shown in Table 3 were then added. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 60° C. for 24 hours, the product was separated by PTLC to determine the deuterium substitution rate. Table 3 shows the results. The amount of acid anhydride used was 100 mol % with respect to 100 mol % of 4-(4-methoxyphenyl)butyric acid.
Figure JPOXMLDOC01-appb-T000015
［実施例７］
　求核的活性化剤の種類を変更して重水素化試験を行った。
　具体的には、撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸と、４－（４－メトキシフェニル）酪酸１００モル％に対してそれぞれ１０モル％の炭酸カリウム及び１０モル％の表４に示す求核的活性化剤とを加えた。続いてアセトン－ｄ６と４－（４－メトキシフェニル）酪酸１００モル％に対して２０モル％のピバル酸無水物とを加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量（０．４０Ｍ）であった。反応溶液を４０℃で１２時間撹拌した後、生成物をＰＴＬＣにより分離して重水素置換率を求めた。結果を表４に示す。
Figure JPOXMLDOC01-appb-T000016
 [Example 7]
Deuteration tests were performed with different types of nucleophilic activators.
Specifically, 4-(4-methoxyphenyl)butyric acid and 10 mol% potassium carbonate and 10 mol % of the nucleophilic activator shown in Table 4 was added. Acetone-d 6 and 20 mol % of pivalic anhydride with respect to 100 mol % of 4-(4-methoxyphenyl)butyric acid were then added. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 40° C. for 12 hours, the product was separated by PTLC to determine the deuterium substitution rate. Table 4 shows the results.
Figure JPOXMLDOC01-appb-T000016
［実施例８］
　塩の種類を変更して重水素化試験を行った。
　具体的には、撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸（０．２０ｍｍｏｌ）と、４－（４－メトキシフェニル）酪酸１００モル％に対して２０モル％の表５に示す塩を加えた。続いてアセトン－ｄ６と４－（４－メトキシフェニル）酪酸１００モル％に対して１００モル％のピバル酸無水物とを加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量（０．４０Ｍ）であった。反応溶液を６０℃で４時間撹拌した後、生成物をＰＴＬＣにより分離して重水素置換率を求めた。結果を表５に示す。なお、ＯＰｉｖはピバル酸イオンを表す。
Figure JPOXMLDOC01-appb-T000017
 [Example 8]
A deuteration test was performed by changing the type of salt.
Specifically, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol% of 4-(4-methoxyphenyl)butyric acid per 100 mol% were added to a 4 mL vial containing a stir bar. The salts shown in Table 5 were added. Acetone-d 6 and 100 mol % of pivalic anhydride with respect to 100 mol % of 4-(4-methoxyphenyl)butyric acid were then added. The amount of acetone- d6 used was 34 equivalents (0.40M) relative to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 60° C. for 4 hours, the product was separated by PTLC to determine the deuterium substitution rate. Table 5 shows the results. OPiv represents a pivalate ion.
Figure JPOXMLDOC01-appb-T000017
［実施例９］
　撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸（０．２０ｍｍｏｌ）と、４－（４－メトキシフェニル）酪酸１００モル％に対してそれぞれ２０モル％の炭酸カリウム及び１０モル％のＤＭＡＰ（実験番号４のみ）とを加えた。続いてアセトン－ｄ６と４－（４－メトキシフェニル）酪酸１００モル％に対して１００モル％のピバル酸無水物（８μＬ、０．０４ｍｍｏｌ）とを加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量（０．４０Ｍ）であった。表６に示す反応温度及び時間で反応を行った。反応後、生成物をＰＴＬＣにより分離して重水素置換率を求めた。結果を表６に示す。
Figure JPOXMLDOC01-appb-T000018
 [Example 9]
In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 20 mol % potassium carbonate and 10 mol % of DMAP (experiment number 4 only) was added. Acetone-d 6 and 100 mol % pivalic anhydride (8 μL, 0.04 mmol) with respect to 100 mol % 4-(4-methoxyphenyl)butyric acid were then added. The amount of acetone- d6 used was 34 equivalents (0.40M) 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 obtain the deuterium substitution rate. Table 6 shows the results.
Figure JPOXMLDOC01-appb-T000018
［実施例１０］
　撹拌子を入れた４ｍＬのバイアルに、４－（４－メトキシフェニル）酪酸（０．２０ｍｍｏｌ）と、４－（４－メトキシフェニル）酪酸１００モル％に対してそれぞれ１０モル％の炭酸カリウム及び１０モル％のＤＭＡＰを加えた。続いてアセトン－ｄ６と表７に示す共溶媒との混合溶媒（体積比で１：１）と、４－（４－メトキシフェニル）酪酸１００モル％に対して２０モル％のピバル酸無水物（８μＬ、０．０４ｍｍｏｌ）とを加えた。アセトン－ｄ６の使用量は４－（４－メトキシフェニル）酪酸に対して３４当量であった。反応溶液を６０℃で４時間撹拌した後、生成物をＰＴＬＣにより分離して重水素置換率を求めた。結果を表７に示す。
Figure JPOXMLDOC01-appb-T000019
 [Example 10]
In a 4 mL vial containing a stir bar, 4-(4-methoxyphenyl)butyric acid (0.20 mmol) and 10 mol % potassium carbonate and 10 mol % DMAP was added. Subsequently, a mixed solvent (1:1 by volume) of acetone-d 6 and a co-solvent shown in Table 7, and 20 mol% of pivalic anhydride with respect to 100 mol% of 4-(4-methoxyphenyl)butyric acid (8 μL, 0.04 mmol) was added. The amount of acetone- d6 used was 34 equivalents to 4-(4-methoxyphenyl)butyric acid. After stirring the reaction solution at 60° C. for 4 hours, the product was separated by PTLC to determine the deuterium substitution rate. Table 7 shows the results.
Figure JPOXMLDOC01-appb-T000019
［実施例１１］
　以下、基質として種々のカルボン酸を用い、重水素置換実験（１）～（２１）及び（３１）～（３７）を行った。
　各実験において、カルボン酸１００モル％に対してそれぞれ１０モル％の炭酸カリウム、２０モル％の無水ピバル酸及び１０モル％のＤＭＡＰを使用した。
　なお、以下、特に記載がない場合、アセトン－ｄ６の使用量は、共溶媒を使用しない場合、カルボン酸に対して３４当量（０．４０Ｍ）であり、共溶媒を使用する場合、カルボン酸に対して３４当量（０．２０Ｍ（アセトン－ｄ６と共溶媒の混合溶媒））である。
　また、以下、特に記載がない場合、各実験において反応溶液を４０℃で４８時間撹拌して反応を行った。
　各実験において反応後、反応溶液にＤ２Ｏ（０．１０ｍＬ）を加えて室温で１時間撹拌して反応をクエンチした。
　なお、以下、断らない限り、１ＨＮＭＲ及び１３ＣＮＭＲのピーク位置は、単位ｐｐｍで表し、ＩＲのピーク位置は単位ｃｍ－１で表す。また、１ＨＮＭＲの化学シフトの基準は、重溶媒中に含まれる重水素化されていない溶媒のピークを使用した。すなわち、重溶媒としてＣＤＣｌ３を使用した場合は、ＣＨＣｌ３のＨのピーク（δ７．２６ｐｐｍ）を使用し、重溶媒としてメタノール－ｄ４のメチル基の水素のピーク（δ３．３１ｐｐｍ）を使用した。１３ＣＮＭＲの化学シフトの基準は、重溶媒のピークを使用した。 [Example 11]
Deuterium substitution experiments (1) to (21) and (31) to (37) were performed using various carboxylic acids as substrates.
In each experiment, 10 mol % potassium carbonate, 20 mol % pivalic anhydride and 10 mol % DMAP were used for each 100 mol % carboxylic acid.
In the following, unless otherwise specified, the amount of acetone-d 6 used is 34 equivalents (0.40 M) with respect to the carboxylic acid when no co-solvent is used, and when using a co-solvent, the carboxylic acid (0.20 M (mixture of acetone- d6 and co-solvent)).
Further, in each experiment, the reaction solution was stirred at 40° C. for 48 hours to carry out the reaction, unless otherwise specified.
After the reaction in each experiment, D 2 O (0.10 mL) was added to the reaction solution and stirred at room temperature for 1 hour to quench the reaction.
In the following, unless otherwise specified, peak positions of 1 HNMR and 13 CNMR are expressed in units of ppm, and IR peak positions are expressed in units of cm −1 . Also, the 1 H NMR chemical shift reference used the undeuterated solvent peak contained in the deuterated solvent. That is, when CDCl 3 was used as the deuterated solvent, the H peak of CHCl 3 (δ 7.26 ppm) was used, and the hydrogen peak of the methyl group of methanol-d 4 (δ 3.31 ppm) was used as the deuterated solvent. . The deuterated solvent peak was used as the reference for 13 C NMR chemical shifts.
Figure JPOXMLDOC01-appb-C000020
 （１）４－（４－メトキシフェニル）酪酸
　４－（４－メトキシフェニル）酪酸（化合物（１）、３８．８ｍｇ、０．２０ｍｍｏｌ）を基質として用いた。生成物は、シリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率：９４％、収率：９８％、３８．５ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１８０．０、１５７．９、１３３．３、１２９．４、１１３．８、５５．３、３４．０、３２．７、２６．３
ＩＲ（ニート）：１６９５、１５１０、１４１２、１３００、１２７７、１２４２、１１８２、１１７５、１０２６、９４７、８３１、８１４、５５７、５２５、４０３
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１１Ｈ１２Ｄ２ＮａＯ３（Ｍ＋Ｎａ）＋について計算値：２１９．０９６１、実測値２１９．０９７８
Figure JPOXMLDOC01-appb-C000020
 (1) 4-(4-methoxyphenyl)butyric acid 4-(4-methoxyphenyl)butyric acid (compound (1), 38.8 mg, 0.20 mmol) was used as a substrate. The product was obtained without silica gel flash column chromatography. (white solid, deuterium substitution rate: 94%, yield: 98%, 38.5 mg)
1 H NMR (500 MHz, CDCl3 ): δ 7.10 (d, J = 9.0 Hz, 2H, ArH), 6.83 (d, J = 9.0 Hz, 2H, ArH), 3.79 (s, 3H , ArOCH3 ), 2.62 (t, J = 7.5 Hz, 2H, ArCH2 ), 2.33 (m, 0.12H, CH2COOH , 94% D), 1.92 (t, J = 7.5Hz, 2H , CH2CD2COOH )
13 C NMR (125 MHz, CDCl3 ): δ 180.0, 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: calcd for C11H12D2NaO3 ( M+Na) + : 219.0961 , found 219.0978.
（１）’４－（４－メトキシフェニル）酪酸
　無水ピバル酸を二炭酸ジ－ｔｅｒｔ－ブチル（Ｂｏｃ２Ｏ）に変更したこと以外は重水素置換実験（１）と同様に実験を行った。重水素置換率は９７％、収率は８６％であった。 (1) '4-(4-Methoxyphenyl)butyric acid An experiment was conducted in the same manner as in deuterium substitution experiment (1) except that pivalic anhydride was changed to di-tert-butyl dicarbonate (Boc 2 O). The deuterium substitution rate was 97% and the yield was 86%.
Figure JPOXMLDOC01-appb-C000021
 （２）２－（１－（ｔｅｒｔ－ブトキシカルボニル）アゼチジン－３－イル）酢酸
　２－（１－（ｔｅｒｔ－ブトキシカルボニル）アゼチジン－３－イル）酢酸（化合物（２）、４３．０ｍｇ、０．２０ｍｍｏｌ）を基質として使用した。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率：９８％、収率：９０％、３８．９ｍｇ）
１ＨＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３）：δ４．０９（ｄｄ、Ｊ＝８．５、８．５Ｈｚ、２Ｈ、Ｎ（ＣＨ２）２）、３．６３（ｄｄ、Ｊ＝８．５、５．５Ｈｚ、２Ｈ、Ｎ（ＣＨ２）２）、２．８９－２．８４（ｍ、１Ｈ、ＣＨＣＤ２ＣＯＯＨ）、２．６５（ｍ、０．０５Ｈ、ＣＨ２ＣＯＯＨ、９８％Ｄ）、１．４３（ｓ、９Ｈ、ＮＣＯＯＣ（ＣＨ３）３）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７６．５、１５６．５、７９．７、５４．２、３８．０、２８．４、２４．９
ＩＲ（ニート）：１７２１、１６４１、１４２２、１３９６、１３６６、１３４１、１２５４、１２２１、１０６３、９６８、８５６、８１８、７６８、６３５、５６１
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１０Ｈ１５Ｄ２ＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値：２４０．１１７５、実測値：２４０．１１７０
Figure JPOXMLDOC01-appb-C000021
 (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 substrate. The product was obtained without silica gel flash column chromatography. (white solid, deuterium substitution rate: 98%, yield: 90%, 38.9 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 4.09 (dd, J=8.5, 8.5 Hz, 2H, N(CH 2 ) 2 ), 3.63 (dd, J=8.5, 5.5 Hz , 2H, N(CH 2 ) 2 ), 2.89-2.84 (m, 1H, CHCD 2 COOH), 2.65 (m, 0.05H, CH 2 COOH, 98% D), 1.43 (s, 9H, NCOOC(CH3) 3 )
13 C NMR (125 MHz, CDCl3 ): δ 176.5, 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: calcd for C10H15D2NNaO4 (M+Na) + : 240.1175 , found: 240.1170.
Figure JPOXMLDOC01-appb-C000022
 （３）６－エトキシ－６－オキソヘキサン酸
　６－エトキシ－６－オキソヘキサン酸（化合物（３）、３２．０μＬ、０．２０ｍｍｏｌ）を基質として使用した。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（無色の液体、重水素置換率９６％、収率：８８％、３１．１ｍｇ）
１ＨＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３）：δ４．１３（ｑ、Ｊ＝７．０Ｈｚ、２Ｈ、ＣＯＯＣＨ２ＣＨ３）、２．３４－２．３１（ｍ、２．０８Ｈ、ＣＨ２ＣＯＯＨ＋ＣＨ２ＣＯＯＥｔ、９６％Ｄ）、１．６８－１．６７（ｍ、４Ｈ、ＣＤ２ＣＨ２ＣＨ２ＣＨ２）、１．２６（ｔ、Ｊ＝７．０Ｈｚ、３Ｈ、ＣＯＯＣＨ２ＣＨ３）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７９．５、１７３．４、６０．４、３３．９、３３．１、２４．３、２４．０、１４．２
ＩＲ（ニート）：４１１、４３８、４５１、７４６、９４５、１０２８、１０８６、１１１７、１１６７、１２５２、１３４４、１３７３、１７０３、１７３０、２９３８
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ８Ｈ１２Ｄ２ＮａＯ４（Ｍ＋Ｎａ）＋について計算値：１９９．０９１０、実測値：１９９．０９１５
　なお、１ＨＮＭＲによれば、エステル基（－Ｃ（＝Ｏ）ＯＥｔ）のα水素については重水素置換は観測されなかった。
Figure JPOXMLDOC01-appb-C000022
 (3) 6-ethoxy-6-oxohexanoic acid 6-ethoxy-6-oxohexanoic acid (compound (3), 32.0 μL, 0.20 mmol) was used as substrate. The product was obtained without silica gel flash column chromatography. (colorless liquid, deuterium substitution rate 96%, yield: 88%, 31.1 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 4.13 (q, J=7.0 Hz, 2H, COOCH 2 CH 3 ), 2.34-2.31 (m, 2.08 H, CH 2 COOH + CH 2 COOEt, 96 % D ) , 1.68-1.67 (m, 4H, CD2CH2CH2CH2 ), 1.26 ( t, J = 7.0 Hz, 3H, COOCH2CH3 ) .
13 C NMR (125 MHz, CDCl3 ): δ 179.5, 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: calcd for C8H12D2NaO4 (M+Na) + : 199.0910 , found: 199.0915.
According to 1 HNMR, deuterium substitution was not observed for the α hydrogen of the ester group (-C(=O)OEt).
Figure JPOXMLDOC01-appb-C000023
 （４）５－オキソ－５－フェニルペンタン酸
　５－オキソ－５－フェニルペンタン酸（化合物（４）、３８．４ｍｇ、０．２０ｍｍｏｌ）を基質として使用した。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、Ｄａ：重水素置換率９３％、Ｄｂ：重水素置換率９６％、収率：７６％、３０．０ｍｇ）
１ＨＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３）：δ７．９６（ｄ、Ｊ＝７．０Ｈｚ、２Ｈ、ＡｒＨ）、７．５７（ｔ、Ｊ＝７．０Ｈｚ、１Ｈ、ＡｒＨ）、７．４６（ｔ、Ｊ＝７．０Ｈｚ、２Ｈ、ＡｒＨ）、３．０８（ｍ、０．０８Ｈ、ＣＨ２ＣＯＰｈ、９６％Ｄ）、２．４９（ｍ、０．１４Ｈ、ＣＨ２ＣＯＯＨ、９３％Ｄ）、２．０７（ｓ、２Ｈ、ＣＨ２ＣＤ２ＣＯＯＨ）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１９９．５、１７９．４、１３６．８、１３３．２、１２８．６、１２８．０、３６．６、３２．５、１８．８
ＩＲ（ニート）：１６９０、１６６８、１３０４、１２７３、１１２６、９９１、９４７、９１０、８３７、７６６、７５６、７２３、６９１、６６５、６５２
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１１Ｈ８Ｄ４ＮａＯ３（Ｍ＋Ｎａ）＋について計算値：２１９．０９３０、実測値：２１９．０９４２
Figure JPOXMLDOC01-appb-C000023
 (4) 5-oxo-5-phenylpentanoic acid 5-oxo-5-phenylpentanoic acid (compound (4), 38.4 mg, 0.20 mmol) was used as 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 H NMR (500 MHz, CDCl 3 ): δ 7.96 (d, J = 7.0 Hz, 2H, ArH), 7.57 (t, J = 7.0 Hz, 1H, ArH), 7.46 (t, J = 7.0 Hz, 2H, ArH), 3.08 (m, 0.08H, CH2COPh, 96%D), 2.49 (m, 0.14H, CH2COOH , 93 % D), 2. 07 ( s , 2H, CH2CD2COOH )
13 C NMR (125 MHz, CDCl3 ): δ 199.5, 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: calcd for C11H8D4NaO3 (M+Na) + : 219.0930, found : 219.0942.
Figure JPOXMLDOC01-appb-C000024
 （５）（Ｒ）－４－（（３Ｒ，５Ｒ，８Ｒ，９Ｓ，１０Ｓ，１３Ｒ，１４Ｓ，１７Ｒ）－３－アセトキシ－１０，１３－ジメチルヘキサデカヒドロ－１Ｈ－シクロペンタ［ａ］フェナントレン－１７－イル）ペンタン酸
（Ｒ）－４－（（３Ｒ，５Ｒ，８Ｒ，９Ｓ，１０Ｓ，１３Ｒ，１４Ｓ，１７Ｒ）－３－アセトキシ－１０，１３－ジメチルヘキサデカヒドロ－１Ｈ－シクロペンタ［ａ］フェナントレン－１７－イル）ペンタン酸（化合物（５）、８３．７ｍｇ、０．２０ｍｍｏｌ）を基質として使用しすると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率９０％、収率：９１％、７６．６ｍｇ）
１ＨＮＭＲ（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）、１．８７－１．８０（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）
１３ＣＮＭＲ（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（ニート）：２３５９、１７３４、１７０７、１４１２、１２９４、１２５４、１０２６、６６９、６１７、４２６、４１９
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ２６Ｈ４０Ｄ２ＮａＯ４（Ｍ＋Ｎａ）＋について計算値：４４３．３１０１、実測値：４４３．３１０１
Figure JPOXMLDOC01-appb-C000024
 (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 substrate and DMSO (0.50 mL) was used as co-solvent. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate 90%, yield: 91%, 76.6 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 4.75-4.69 (m, 1 H, AcOCH), 2.40-2.23 (m, 0.19 H, CH 2 COOH, 90% D), 2.03. (s, 3H, OCOCH 3 ), 1.98-1.95 (m, 1H, Alkyl), 1.87-1.80 (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, CCH 3 +CHCH 3 ), 0.65 (s, 3H, CCH3 )
13 C NMR (125 MHz, CDCl3 ): δ 180.5, 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: calcd for C26H40D2NaO4 ( M+Na) + : 443.3101, found : 443.3101 .
Figure JPOXMLDOC01-appb-C000025
 （６）３－（４－クロロフェニル）－４－（１，３－ジオキソイソインドリン－２－イル）ブタン酸
　３－（４－クロロフェニル）－４－（１、３－ジオキソイソインドリン－２－イル）ブタン酸（化合物（６）、７２．２ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率９８％、収率：９３％、６７．５ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（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（ニート）：１７２８、１６８８、１３９８、１３５８、１２２９、１０５３、９９７、８８７、８３５、８１６、７２１、７１０、６５０、５５２、５３０
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１８Ｈ１２Ｄ２ＣｌＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値：３６８．０６２９、実測値：３６８．０６２５
Figure JPOXMLDOC01-appb-C000025
 (6) 3-(4-chlorophenyl)-4-(1,3-dioxoisoindolin-2-yl)butanoic acid 3-(4-chlorophenyl)-4-(1,3-dioxoisoindoline-2 -yl)butanoic acid (compound (6), 72.2 mg, 0.20 mmol) was used as substrate and DMSO (0.50 mL) was used as co-solvent. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate 98%, yield: 93%, 67.5 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.81-7.79 (m, 2H, ArH), 7.70-7.69 (m, 2H, ArH), 7.25 (d, J = 8.0 Hz , 2H, ArH), 7.20 (d, J = 8.0 Hz, 2H, ArH), 3.91-3.83 (m, 2H, NCH2 ), 3.69 (t, J = 8.0 Hz , 1H, ArCH), 2.70 (m, 0.04H, CH2COOH , 98% D)
13 C NMR (125 MHz, CDCl3 ): δ 176.4, 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: calcd for C18H12D2ClNNaO4 (M+Na) + : 368.0629 , found : 368.0625.
Figure JPOXMLDOC01-appb-C000026
 （７）３－（４，５－ジフェニルオキサゾール－２－イル）プロパン酸
　３－（４，５－ジフェニルオキサゾール－２－イル）プロパン酸（化合物（７）、５８．７ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に２％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率９９％、収率：９６％、５６．６ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（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（ニート）：１７１７、１３０８、１２５６、１２１９、１２０６、１０５９、９６６、９２２、７６６、７５６、７２７、７０４、６９４、６７５、５２３
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１８Ｈ１３Ｄ２ＮＮａＯ３（Ｍ＋Ｎａ）＋について計算値：３１８．１０７０、実測値：３１８．１０７９
Figure JPOXMLDOC01-appb-C000026
 (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 substrate and DMSO (0.50 mL) as co-solvent. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 2% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate 99%, yield: 96%, 56.6 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.63-7.61 (m, 2H, ArH), 7.58-7.56 (m, 2H, ArH), 7.38-7.31 (m, 6H , ArH), 3.19 (s, 2H, ArCH 2 ), 2.96-2.93 (m, 0.03H, CH 2 COOH, 99% D)
13 C NMR (125 MHz, CDCl3 ): δ 176.6, 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: calcd for C18H13D2NNaO3 ( M+Na) + : 318.1070 , found : 318.1079.
Figure JPOXMLDOC01-appb-C000027
 （８）ガバペンチンのＮ-フタル酸イミド
　ガバペンチンのＮ-フタル酸イミド（化合物（８）、６３．７ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で行われた。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率９７％、収率：９３％、５９．５ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（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（ニート）：２３５９、２３４０、１７０９、１６８６、１４０２、１３９１、１３７３、１３６２、１３４６、１２８８、１２２９、７１８、７１０、６６９、５３０
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１７Ｈ１７Ｄ２ＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値：３２６．１３３２、実測値：３２６．１３３２
Figure JPOXMLDOC01-appb-C000027
 (8) N-phthalimide of gabapentin N-phthalimide of gabapentin (compound (8), 63.7 mg, 0.20 mmol) was used as substrate and DMSO (0.50 mL) was used as co-solvent. . The reaction was carried out at 60°C. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate 97%, yield: 93%, 59.5 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.88-7.86 (m, 2H, ArH), 7.76-7.74 (m, 2H, ArH), 3.80 (s, 2H, NCH 2 ). , 2.44 (m, 0.05H, CH 2 COOH, 97% D), 1.66-1.33 (m, 10H, Alkyl)
13 C NMR (125 MHz, CDCl3 ): δ 176.6, 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: calcd for C17H17D2NNaO4 (M+Na) + : 326.1332 , found: 326.1332.
Figure JPOXMLDOC01-appb-C000028
 （９）２－（１，８－ジエチル－１，３，４，９－テトラヒドロピラノ［３，４－ｂ］インドール－１－イル）酢酸
　２－（１，８－ジエチル－１，３，４，９－テトラヒドロピラノ［３，４－ｂ］インドール－１－イル）酢酸（化合物（９）、５７．５ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で行われた。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率９２％、収率：８８％、５０．９ｍｇ）
１ＨＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３）：δ８．５６（ｂｒ、１Ｈ、ＮＨ）、７．３６（ｄ、Ｊ＝７．５Ｈｚ、１Ｈ、ＡｒＨ）、７．０７（ｄｄ、Ｊ＝７．５、７．５Ｈｚ、１Ｈ、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、ＣＣＨ２ＣＨ３）、２．０７－２．００（ｍ、１Ｈ、ＣＣＨ２ＣＨ３）、１．３２（ｔ、Ｊ＝７．５Ｈｚ、３Ｈ、ＣＨ２ＣＨ３）、０．８８（ｔ、Ｊ＝７．５Ｈｚ、３Ｈ、ＣＨ２ＣＨ３）
１３ＣＮＭＲ（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（ニート）：１７４４、１７０１、１３０２、１２５０、１２２７、１０７２、１０３６、９０５、７８３、７４６、７３９、５９０、５５６、５１９、４８４
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１７Ｈ１９Ｄ２ＮＮａＯ３（Ｍ＋Ｎａ）＋について計算値：３１２．１５３９、実測値：３１２．１５５２
Figure JPOXMLDOC01-appb-C000028
 (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 substrate, and DMSO (0.50 mL) was co-existed. used as solvent. The reaction was carried out at 60°C. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate 92%, yield: 88%, 50.9 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 8.56 (br, 1 H, NH), 7.36 (d, J = 7.5 Hz, 1 H, ArH), 7.07 (dd, J = 7.5, 7 .5Hz, 1H, ArH), 7.00 (d, J = 7.5Hz, 1H, ArH), 4.14-4.09 (m, 1H, OCH2 ), 4.07-4.02 (m , 1H, OCH 2 ), 3.05-3.02 (m, 0.15H, CH 2 COOH, 92% D), 2.86-2.78 (m, 4H, ArCH 2 CH 2 +ArCH 2 CH 3 ), 2.17-2.09 (m, 1H, CCH 2 CH 3 ), 2.07-2.00 (m, 1H, CCH 2 CH 3 ), 1.32 (t, J=7.5 Hz, 3H, CH2CH3 ), 0.88 (t, J = 7.5 Hz, 3H , CH2CH3 )
13 C NMR (125 MHz, CDCl3 ): δ 175.7, 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: calcd for C17H19D2NNaO3 (M+Na) + : 312.1539 , found : 312.1552.
Figure JPOXMLDOC01-appb-C000029
 （１０）１－（ｔｅｒｔ－ブトキシカルボニル）アゼチジン－３－カルボン酸
　１－（ｔｅｒｔ－ブトキシカルボニル）アゼチジン－３－カルボン酸（化合物（１０）、４０．２ｍｇ、０．２０ｍｍｏｌ）を基質として用いた反応は６０℃で行われた。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率９９％、収率：８３％、３３．７ｍｇ）
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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７７．１、１５６．３、８０．３、５１．５、３１．７、２８．３
ＩＲ（ニート）：１７１９、１６３８、１４７７、１４５８、１３９５、１３６６、１２５０、１１５３、１１３０、８９５、８７０、８５４、７６８、６９４、５６３
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ９Ｈ１４ＤＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値：２２５．０９５６、実測値：２２５．０９５０
Figure JPOXMLDOC01-appb-C000029
 (10) 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (compound (10), 40.2 mg, 0.20 mmol) was used as a substrate. The reaction 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)
1 H NMR (500 MHz, CDCl 3 ): δ 4.13 (s, 4H, N(CH 2 ) 2 ), 3.38 (m, 0.01 H, CHCOOH, 99% D), 1.44 (s, 9H, NCOOC( CH3 ) 3 )
13 C NMR (125 MHz, CDCl3 ): δ 177.1, 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: calcd for C9H14DNNaO4 (M+Na) + : 225.0956 , found : 225.0950.
Figure JPOXMLDOC01-appb-C000030
 （１１）（１Ｒ，３Ｓ，５ｒ，７ｒ）－アダマンタン－２－カルボン酸
　（１Ｒ，３Ｓ，５ｒ，７ｒ）－アダマンタン－２－カルボン酸（化合物（１１）３６．０ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は８０℃で行われた。生成物は、トルエンを添加した共沸操作を３度繰り返すことにより、シリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率：８０％、収率：９０％、３２．７ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１８１．２、４９．０、３８．０、３７．３、３３．５、２９．３、２７．４、
ＩＲ（ニート）：２９１６、２８９７、２８４９、１６８２、１４５４、１４１４、１２９２、１２７９、１１０５、９４９、９３９、７６６、７３５、５１１、４０７
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１１Ｈ１５ＤＮａＯ２（Ｍ＋Ｎａ）＋について計算値：２０４．１１０５、実測値：２０４．１１０５
Figure JPOXMLDOC01-appb-C000030
 (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) and DMSO (0.50 mL) was used as a co-solvent. The reaction was carried out at 80°C. The product was obtained without silica gel flash column chromatography by repeating the azeotropic run three times with the addition of toluene. (white solid, deuterium substitution rate: 80%, yield: 90%, 32.7 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 2.68 (s, 0.20 H, 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 C NMR (125 MHz, CDCl3 ): δ 181.2, 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: calcd for C11H15DNaO2 (M+Na) + : 204.1105, found : 204.1105 .
Figure JPOXMLDOC01-appb-C000031
 （１２）２－（１１－オキソ－６，１１－ジヒドロジベンゾ［ｂ，ｅ］オキセピン－２－イル）酢酸
　２－（１１－オキソ－６，１１－ジヒドロジベンゾ［ｂ，ｅ］オキセピン－２－イル）酢酸（化合物（１２）、５３．７ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で行われた。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率９０％、収率：８８％、４７．６ｍｇ）
１ＨＮＭＲ（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）、７．４２（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）
１３ＣＮＭＲ（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（ニート）：１７０９、１６４１、１４９３、１４０２、１３００、１２８７、１２２３、１２０４、１１４２、１１２３、１０１８、８２７、７５６、６６９、６３８
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１６Ｈ１０Ｄ２ＮａＯ４（Ｍ＋Ｎａ）＋について計算値：２９３．０７５３、実測値：２９３．０７５７
Figure JPOXMLDOC01-appb-C000031
 (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 substrate and DMSO (0.50 mL) was used as co-solvent. The reaction was carried out at 60°C. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate 90%, yield: 88%, 47.6 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 8.13 (d, J = 2.5 Hz, 1 H, ArH), 7.89 (d, J = 7.5 Hz, 1 H, ArH), 7.56 (t, J = 7.5 Hz, 1 H, ArH), 7.47 (t, J = 7.5 Hz, 1 H, ArH), 7.42 (dd, J = 8.5, 2.5 Hz, 1 H, ArH), 7. 36 (d, J=7.5 Hz, 1 H, ArH), 7.04 (d, J=8.5 Hz, 1 H, ArH), 5.19 (s, 2 H, ArOCH2 ), 3.66 (m, 0.21 H, CH2COOH , 90% D)
13 C NMR (125 MHz, CDCl3 ): δ 190.9, 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: calcd for C16H10D2NaO4 ( M+Na) + : 293.0753 , found : 293.0757.
Figure JPOXMLDOC01-appb-C000032
 （１３）２－（１－（４－クロロベンゾイル）－５－メトキシ－２－メチル－１Ｈ－インドール－３－ｙｌ）酢酸
　２－（１－（４－クロロベンゾイル）－５－メトキシ－２－メチル－１Ｈ－インドール－３－ｙｌ）酢酸（化合物（１３）、７１．６ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率：９４％、収率：８４％、６０．７ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（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（ニート）：１６７４、１４７７、１３５２、１３２９、１３００、１２８７、１２２５、１２１３、１１６３、１０９４、１０３８、９９９、８４７、８１０、７３３
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１９Ｈ１４Ｄ２ＣｌＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値：３８２．０７８６、実測値：３８２．０８００
Figure JPOXMLDOC01-appb-C000032
 (13) 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetic acid 2-(1-(4-chlorobenzoyl)-5-methoxy-2- Methyl-1H-indole-3-yl)acetic acid (compound (13), 71.6 mg, 0.20 mmol) was used as substrate and DMSO (0.50 mL) was used as co-solvent. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (White solid, deuterium substitution rate: 94%, yield: 84%, 60.7 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.66 (d, J = 8.0 Hz, 2H, ArH), 7.47 (d, J = 8.0 Hz, 2H, ArH), 6.95 (d, J = 2.5 Hz, 1 H, ArH), 6.85 (d, J = 9.0 Hz, 1 H, ArH), 6.67 (dd, J = 9.0, 2.5 Hz, 1 H, ArH), 3. 83 (s, 3H, ArOCH3 ), 3.68 (m, 0.12H, CH2COOH , 94% D), 2.39 (s, 3H, ArCH3 )
13 C NMR (125 MHz, CDCl3 ): δ 176.6, 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: calcd for C19H14D2ClNNaO4 ( M+Na) + : 382.0786, found : 382.0800 .
Figure JPOXMLDOC01-appb-C000033
 （１４）（Ｚ）－２－（５－フルオロ－２－メチル－１－（４－（メチルスルフィニル）ベンジリデン）－１Ｈ－インデン－３－イル）酢酸
　（Ｚ）－２－（５－フルオロ－２－メチル－１－（４－（メチルスルフィニル）ベンジリデン）－１Ｈ－インデン－３－イル）酢酸（化合物（１４）、７１．３ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に５％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（黄色固体、重水素置換率９８％、収率：７２％、５１．８ｍｇ）
１ＨＮＭＲ（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）、６．８９（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（ニート）：１７１３、１５９９、１４６４、１２４６、１１８４、１０２２、１００５、９５９、８８１、８５１、８１４、７２７、５７７、５３８、４３８
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ２０Ｈ１５Ｄ２ＦＮａＯ３Ｓ（Ｍ＋Ｎａ）＋について計算値：３８１．０９００、実測値：３８１．０９０１
Figure JPOXMLDOC01-appb-C000033
 (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 substrate and DMSO (0.20 mmol) was used. 50 mL) was used as a co-solvent. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 5% methanol mixed solvent) was performed to give the product. (yellow solid, deuterium substitution rate 98%, yield: 72%, 51.8 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.71 (d, J = 8.5 Hz, 2H, ArH), 7.64 (d, J = 8.5 Hz, 2H, ArH), 7.15 (s, 1H , C=CH), 7.11 (dd, J=8.5, 5.0 Hz, 1 H, ArH), 6.89 (dd, J=8.5, 2.5 Hz, 1 H, 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 )
13 C NMR (125 MHz, CDCl3 ): δ 174.5, 163.3 (d, J = 246.7 Hz), 146.7 (d, J = 8.7 Hz), 144.4, 141.7, 139.9 , 138.3, 131.6, 130.3, 129.5 (d, J = 2.8 Hz), 128.1, 124.0, 123.6 (d, J = 8.9 Hz), 110.8 (d, J = 22.8 Hz), 106.2 (d, J = 23.8 Hz), 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: calcd for C20H15D2FNaO3S (M+Na) + : 381.0900 , found : 381.0901
Figure JPOXMLDOC01-appb-C000034
 （１５）２－（５－（４－クロロベンゾイル）－１，４－ジメチル－１Ｈ－ピロール－２－イル）酢酸
　２－（５－（４－クロロベンゾイル）－１，４－ジメチル－１Ｈ－ピロール－２－イル）酢酸ナトリウム（化合物（１５）、６２．７ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。なお、本反応では炭酸カリウムを使用しなかった。反応は６０℃で行われた。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に２％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率９８％、収率：８３％、４８．９ｍｇ）
１ＨＮＭＲ（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（ニート）：１６１１、１５９３、１４４９、１３９６、１３７９、１２６５、１１８４、１１６９、１０８８、９３４、７９１、７５４、７３５、６９８、６５２
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１５Ｈ１２Ｄ２ＣｌＮＮａＯ３（Ｍ＋Ｎａ）＋について計算値：３１６．０６８０、実測値：３１６．０６９２
Figure JPOXMLDOC01-appb-C000034
 (15) 2-(5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl)acetic acid 2-(5-(4-chlorobenzoyl)-1,4-dimethyl-1H- Sodium pyrrol-2-yl)acetate (compound (15), 62.7 mg, 0.20 mmol) was used as substrate and DMSO (0.50 mL) was used as co-solvent. Note that potassium carbonate was not used in this reaction. The reaction was carried out at 60°C. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 2% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate 98%, yield: 83%, 48.9 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.66 (d, J = 9.0 Hz, 2H, ArH), 7.42 (d, J = 9.0 Hz, 2H, ArH), 5.97 (s, 1H , ArH), 3.75 (m, 3.03H, NCH3 + CH2COOH , 98% D), 1.75 (s, 3H, ArCH3 )
13 C NMR (125 MHz, CDCl3 ): δ 186.6, 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: calcd for C15H12D2ClNNaO3 (M+Na) + : 316.0680, found : 316.0692 .
Figure JPOXMLDOC01-appb-C000035
 （１６）２－（４－（（２－オキソシクロペンチル）メチル）フェニル）プロパン酸
　２－（４－（（２－オキソシクロペンチル）メチル）フェニル）プロパン酸（化合物（１６）、４９．３ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物２、２－ｄ２が得られた。（無色の液体、重水素置換率：Ｄａ（９８％）、Ｄｂ（７８％）、Ｄｃ（８３％）、収率：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）、１．９６－１．９２（ｍ、１Ｈ、ＣＨ２ＣＨ２）、１．７５－１．６９（ｍ、１Ｈ、ＣＨ２ＣＨ２）、１．５７－１．５０（ｍ、１Ｈ、ＣＨ２ＣＨ２）、１．４９（ｓ、３ＨＣＤＣＨ３）
１３ＣＮＭＲ（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（ニート）：１７３０、１７０１、１５１２、１２８７、１２０９、１１３０、１０９２、９３９、９１０、８６４、８３７、７３１、５６９、５０９、４０５
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１５Ｈ１４Ｄ４ＮａＯ３（Ｍ＋Ｎａ）＋について計算値：２７３．１３９９、実測値：２７３．１４０６
Figure JPOXMLDOC01-appb-C000035
 (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 substrate and DMSO (0.50 mL) was used as co-solvent. Silica gel flash column chromatography (mobile phase: mixed solvent obtained by adding 1% methanol to CH 2 Cl 2 ) gave product 2, 2- d2 . (Colorless liquid, deuterium substitution rate: D a (98%), D b (78%), D c (83%), Yield: 96%, 47.9 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.23 (d, J = 8.5 Hz, 2H, ArH), 7.12 (d, J = 8.5 Hz, 2H, ArH), 3.71 (q, J = 7.0 Hz, 0.03 H, CHCOOH, 98% D), 3.11 (d, J = 14.0 Hz, 1 H, ArCH2 ), 2.50 (d, J = 14.0 Hz, 1 H, ArCH2 ), 2.32-2.30 (m, 0.33 H, COCH 2 , 83% D), 2.09-2.06 (m, 1.22 H, CH 2 CH 2 +COCH, 78% D), 1 .96-1.92 (m, 1H, CH 2 CH 2 ), 1.75-1.69 (m, 1H, CH 2 CH 2 ), 1.57-1.50 (m, 1H, CH 2 CH 2 ), 1.49 (s, 3HCDCH3 )
13 C NMR (125 MHz, CDCl3 ): δ 180.6, 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: calcd for C15H14D4NaO3 (M+Na) + : 273.1399, found : 273.1406 .
Figure JPOXMLDOC01-appb-C000036
 （１７）１，２，３，４－テトラヒドロナフタレン－１－カルボン酸
　１，２，３，４－テトラヒドロナフタレン－１－カルボン酸（化合物（１７）、３５．２ｍｇ、０．２０ｍｍｏｌ）を基質として使用した。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率：９９％、収率：１００％、３５．６ｍｇ）
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、ＡｒＣＨ２）、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）
１３ＣＮＭＲ（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（ニート）：２３５７、１６８４、１４９５、１４０２、１２９０、１２７９、１２１９、１１８４、９５１、９２６、７３５、７０２、６７７、４８４、４３４
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１１Ｈ１１ＤＮａＯ２（Ｍ＋Ｎａ）＋について計算値：２００．０７９２、実測値：２００．０７９２
Figure JPOXMLDOC01-appb-C000036
 (17) 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid Using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (compound (17), 35.2 mg, 0.20 mmol) as a substrate used. The product was obtained without silica gel flash column chromatography. (white solid, deuterium substitution rate: 99%, yield: 100%, 35.6 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.23-7.10 (m, 4H, ArH), 3.85 (t, J=6.0 Hz, 0.01 H, CHCOOH, 99% D), 2.87. -2.81 (m, 1H, ArCH 2 ), 2.79-2.73 (m, 1H, ArCH 2 ), 2.21-2.17 (m, 1H, Alkyl), 2.05-1. 94 (m, 2H, Alkyl), 1.83-1.75 (m, 1H, Alkyl)
13 C NMR (125 MHz, CDCl3 ): δ 181.5, 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: calcd for C11H11DNaO2 (M+Na) + : 200.0792, found : 200.0792 .
Figure JPOXMLDOC01-appb-C000037
 （１８）Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－メチルグリシン（２４－ｄ２）
　Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｎ－メチルグリシン（化合物（１８）、３７．８　ｍｇ、　０．２０　ｍｍｏｌ）を基質として使用した。反応は６０℃で行われた。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、　重水素置換率：９１％、収率：６８％、２６．１ｍｇ）
１ＨＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３）（回転異性体混合物）：δ２．９４（ｓ、３Ｈ、ＮＣＨ３）、２．６８（ｍ、０．１８Ｈ、ＣＨ２ＣＯＯＨ、９１％Ｄ）、１．４７－１．４４（ｍ、９Ｈ、ＮＣＯＯＣ（ＣＨ３）３）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）（回転異性体混合物）：δ１７５．１、１７４．６、１５６．５、１５５．５、８０．６、８０．５、５０．２、３５．６、３５．４、２８．３、２８．２
ＩＲ（ニート）：１７４４、１６３８、１４４９、１３９６、１３６８、１２２３、１１５９、１０９２、１０４９、１０２０、８５３、８３１、８２２、７６６、６７３
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ８Ｈ１３Ｄ２ＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値：２１４．１０１９、実測値：２１４．１０２６
Figure JPOXMLDOC01-appb-C000037
 (18) N-(tert-butoxycarbonyl)-N-methylglycine (24-d 2 )
N-(tert-butoxycarbonyl)-N-methylglycine (compound (18), 37.8 mg, 0.20 mmol) was used as 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, CDCl 3 ) (rotamer mixture): δ 2.94 (s, 3H, NCH 3 ), 2.68 (m, 0.18H, CH 2 COOH, 91% D), 1.47- 1.44 (m, 9H, NCOOC(CH3) 3 )
13 CNMR (125 MHz, CDCl 3 ) (rotamer mixture): 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: calcd for C8H13D2NNaO4 (M+Na) + : 214.1019 , found : 214.1026.
Figure JPOXMLDOC01-appb-C000038
 （１９）２－（１，３－ジオキソイソインドリン－２－イル）プロパン酸
　２－（１，３－ジオキソイソインドリン－２－イル）プロパン酸（化合物（１９）、４３．８ｍｇ、０．２０ｍｍｏｌ）を基質として使用した。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率：９８％、収率：９３％、４０．７ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７５．６、１６７．４、１３４．２、１３１．８、１２３．６、４７．０、１４．９
ＩＲ（ニート）：２３５９、２３４２、１７０７、１３８９、１３０６、１１９０、９６１、９１６、７４５、７１８、７０６、６９２、６６９、６２５、５２９
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１１Ｈ８ＤＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値：２４３．０４８７、実測値：２４３．０４９３
Figure JPOXMLDOC01-appb-C000038
 (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 substrate. The product was obtained without silica gel flash column chromatography. (white solid, deuterium substitution rate: 98%, yield: 93%, 40.7 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.87-7.86 (m, 2H, ArH), 7.74-7.73 (m, 2H, ArH), 5.04 (q, J = 7.5 Hz , 0.02H, CHCOOH, 98% D), 1.72 (s, 3H, CDCH3 )
13 C NMR (125 MHz, CDCl3 ): δ 175.6, 167.4, 134.2, 131.8, 123.6, 47.0, 14.9
IR (neat): 2359, 2342, 1707, 1389, 1306, 1190, 961, 916, 745, 718, 706, 692, 669, 625, 529
HRMS (ESI) m/z: calcd for C11H8DNNaO4 (M+Na) + : 243.0487 , found: 243.0493.
Figure JPOXMLDOC01-appb-C000039
 （２０）２－（（１－ベンジル－１Ｈ－インダゾール－３－イル）オキシ）酢酸
　２－（（１－ベンジル－１Ｈ－インダゾール－３－イル）オキシ）酢酸（化合物（２０）、５６．５ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＦ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で行われた。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に２％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率：９１％、収率：８２％、４６．６ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（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（ニート）：２３６１、１７１９、１７０７、１７０１、１５２２、１３５２、１１９０、１１２８、７４８、７４１、７００、６６９、６５６、６４８、６２３
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１６Ｈ１２Ｄ２Ｎ２ＮａＯ３（Ｍ＋Ｎａ）＋について計算値：３０７．１０２２、実測値：３０７．１０２２
Figure JPOXMLDOC01-appb-C000039
 (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 substrate and DMF (0.50 mL) was used as co-solvent. The reaction was carried out at 60°C. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 2% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate: 91%, yield: 82%, 46.6 mg)
1 H NMR (500 MHz, methanol-d 4 ): δ 7.71 (d, J = 8.0 Hz, 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 = 7.5 Hz, 2H, ArH), 7.09-7.06 (m, 1H, ArH), 5.43 (s, 2H, NCH2Ph ), 4.95 (m, 0.19H, CH2COOH , 91% D)
13 C NMR (125 MHz, methanol-d 4 ): δ 171.1, 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 : calcd for C16H12D2N2NaO3 (M+Na) + : 307.1022 , found: 307.1022.
Figure JPOXMLDOC01-appb-C000040
 ２－（（２，４－ジクロロフェニル）チオ）酢酸
　２－（（２，４－ジクロロフェニル）チオ）酢酸（化合物（２１）、４７．４ｍｇ、０．２０ｍｍｏｌ）を基質として使用した。反応は６０℃で行われた。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率：９７％、収率：９８％、４７．０ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７４．３、１３５．６、１３３．２、１３２．２、１３０．７、１２９．０、１２７．８、３４．２
ＩＲ（ニート）：２３６１、１７０１、１４４７、１２８３、１１０１、１０３４、１０１６、８８５、８４１、８０４、６８１、６４４、５７５、５４４、４０７
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ８Ｈ４Ｄ２Ｃｌ２ＮａＯ２Ｓ（Ｍ＋Ｎａ）＋について計算値：２６０．９４８３、実測値：２６０．９４８３
Figure JPOXMLDOC01-appb-C000040
 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 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 H NMR (500 MHz, CDCl 3 ): δ 7.37 (d, J=2.0 Hz, 1 H, ArH), 7.32 (d, J=8.5 Hz, 1 H, ArH), 7.15 (dd, J = 8.5, 2.0 Hz, 1 H, ArH), 3.93 (m, 0.06 H, CH2COOH , 97% D)
13 C NMR (125 MHz, CDCl3 ): δ 174.3, 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: calcd for C8H4D2Cl2NaO2S (M+Na) + : 260.9483 , found : 260.9483 .
Figure JPOXMLDOC01-appb-C000041
 （３１）（９Ｚ，１２Ｚ）－オクタデカ－９，１２－ジエン酸　
　（９Ｚ，１２Ｚ）－オクタデカ－９，１２－ジエン酸（化合物（３１）、６２．５μＬ、０．２０ｍｍｏｌ）を基質として使用した。反応は６０℃で行われた。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（無色の液体、重水素置換率：９７％、収率：１０３％、５８．２ｍｇ）
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）
１３ＣＮＭＲ（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（ニート）：３００７、２９２４、２８５５、１７０５、１４６４、１４１０、１３７７、１２９４、１１７１、１１２５、９４５、７２３、４３６、４１５、４０９
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１８Ｈ３０Ｄ２ＮａＯ２（Ｍ＋Ｎａ）＋について計算値：３０５．２４２０、実測値：３０５．２４２０
Figure JPOXMLDOC01-appb-C000041
 (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 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)
1 H NMR (500 MHz, CDCl 3 ): δ 5.41-5.30 (m, 4H, vinyl), 2.77 (t, J=6.5 Hz, 2H, CH=CHCH 2 CH=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, CH 2 CD 2 COOH), 1.39-1.27 (m, 14H, Alkyl), 0.89 (t, J=7.0 Hz, 3H, CH 2 CH 3 ).
13 C NMR (125 MHz, CDCl3 ): δ 180.3, 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: calcd for C18H30D2NaO2 (M+Na) + : 305.2420, found : 305.2420 .
Figure JPOXMLDOC01-appb-C000042
 （３２）４－（４－（ビス（２－クロロエチル）アミノ）フェニル）ブタン酸　
　４－（４－（ビス（２－クロロエチル）アミノ）フェニル）ブタン酸（化合物（３２）、６０．８ｍｇ、０．２０ｍｍｏｌ）を基質として使用した。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率：９５％、収率：９７％、５９．３ｍｇ）
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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１８０．０、１４４．４、１３０．４、１２９．７、１１２．２、５３．６、４０．５、３３．８、３２．７、２６．３
ＩＲ（ニート）：１７１３、１６１４、１５２０、１３５８、１２９２、１２７５、１２４４、１１７７、１１４０、９４７、８０４、７４１、７２５、５５７、５４４
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１４Ｈ１８Ｄ２Ｃｌ２ＮＯ２（Ｍ＋Ｈ）＋について計算値：３０６．０９９１、実測値：３０６．０９９８
Figure JPOXMLDOC01-appb-C000042
 (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 substrate. The product was obtained without silica gel flash column chromatography. (white solid, deuterium substitution rate: 95%, yield: 97%, 59.3 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.07 (d, J=8.5 Hz, 2H, ArH), 6.63 (d, J=8.5 Hz, 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, 0.11 H, CH2COOH , 95 % D), 1.91 (t, J = 7.5 Hz, 2H, ArCH2CH2 )
13 C NMR (125 MHz, CDCl3 ): δ 180.0, 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: calcd for C14H18D2Cl2NO2 (M+H ) + : 306.0991, found : 306.0998.
Figure JPOXMLDOC01-appb-C000043
 （３３）２－メチル－３－プロパン酸
　２－メチル－３－プロパン酸（化合物（３３）、３２．８ｍｇ、０．２０ｍｍｏｌ）を基質として使用した。反応は８０℃で行われた。生成物はシリカゲルフラッシュカラムクロマトグラフィーを行わずに得られた。（白色固体、重水素置換率：８３％、収率：９２％、３０．４ｍｇ）
１ＨＮＭＲ（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（ニート）：１６８６、１４５０、１３１０、１２８８、１２１７、１０９２、９６２、９１０、７８１、７３９、７２５、７０２、６０４、５１５、４７４
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１０Ｈ１１ＤＮａＯ２（Ｍ＋Ｎａ）＋について計算値：１８８．０７９２、実測値：１８８．０７９２
Figure JPOXMLDOC01-appb-C000043
 (33) 2-methyl-3-propanoic acid 2-methyl-3-propanoic acid (compound (33), 32.8 mg, 0.20 mmol) was used as 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 H NMR (500 MHz, CDCl 3 ): δ 7.29 (t, J=7.5 Hz, 2H, ArH), 7.23-7.18 (m, 3H, ArH), 3.07 (d, J=14 .0 Hz, 1 H, PhCH 2 ), 2.81-2.74 (m, 0.17 H, CHCOOH, 83% D), 2.67 (d, J=14.0 Hz, 1 H, PhCH 2 ), 1. 18(s, 3H, CDCH3 )
13 C NMR (125 MHz, CDCl3 ): δ 182.5, 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: calcd for C10H11DNaO2 (M+Na) + : 188.0792, found : 188.0792 .
Figure JPOXMLDOC01-appb-C000044
 （３４）２－（１Ｈ－インドール－３－イル）酢酸
　２－（１Ｈ－インドール－３－イル）酢酸（化合物（３４）、３５．０ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率：９８％、収率：７１％、２５．０ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ｍｅｔｈａｎｏｌ－ｄ４）：δ１７５．１、１３６．６、１２７．３、１２３．２、１２１．０、１１８．４、１１８．１、１１０．８、１０７．４、３０．０
ＩＲ（ニート）：２５１３、１４５２、１３４２、１３３１、１３１２、１１９０、１００１、９４７、９２２、７４１、６６４、６１０、５７５、４２６、４１９
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１０Ｈ７Ｄ２ＮＮａＯ２（Ｍ＋Ｎａ）＋について計算値：２００．０６５１、実測値：２００．０６５１
Figure JPOXMLDOC01-appb-C000044
 (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 a substrate and DMSO ( 0.50 mL) was used as a co-solvent. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate: 98%, yield: 71%, 25.0 mg)
1 H NMR (500 MHz, methanol-d 4 ): δ 7.44 (d, J = 7.5 Hz, 1 H, ArH), 7.24 (d, J = 8.0 Hz, 1 H, 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 C NMR (125 MHz, methanol-d 4 ): δ 175.1, 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: calcd for C10H7D2NNaO2 (M+Na) + : 200.0651, found : 200.0651 .
Figure JPOXMLDOC01-appb-C000045
 （３５）２－（［１，１’－ビフェニル］－４－イル）酢酸
　２－（［１，１’－ビフェニル］－４－イル）酢酸（化合物（３５）、４２．４ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で行われた。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率：９７％、収率：８４％、３６．１ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７７．７、１４０．７、１４０．４、１３２．２、１２９．８、１２８．８、１２７．４、１２７．３、１２７．１、４０．１
ＩＲ（ニート）：１６８４、１４８７、１４０６、１３２３、１２４２、１０４９、１００７、９２８、８５８、７６０、７３９、６９６、６６０、４３２、４１９
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１４Ｈ１０Ｄ２ＮａＯ２（Ｍ＋Ｎａ）＋について計算値：２３７．０８５５、実測値：２３７．０８５５
Figure JPOXMLDOC01-appb-C000045
 (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 substrate and DMSO (0.50 mL) was used as co-solvent. The reaction was carried out at 60°C. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate: 97%, yield: 84%, 36.1 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.58-7.56 (m, 4H, ArH), 7.43 (t, J = 7.5 Hz, 2H, ArH), 7.38-7.33 (m , 3H, ArH), 3.69 (m, 0.06H, CH2COOH , 97% D)
13 C NMR (125 MHz, CDCl3 ): δ 177.7, 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: calcd for C14H10D2NaO2 ( M+Na) + : 237.0855, found : 237.0855 .
Figure JPOXMLDOC01-appb-C000046
 （３６）２－（３－ベンゾイルフェニル）プロパン酸
　２－（３－ベンゾイルフェニル）プロパン酸（化合物（３６）、５０．９ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に１％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率：９８％、収率：９９％、５０．５ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（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（ニート）：２３６１、２３４２、１６５１、１２８３、１１３８、９６２、９３７、９２４、７１６、７００、６８９、６６９、６４２、６０２、４３８
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１６Ｈ１３ＤＮａＯ３（Ｍ＋Ｎａ）＋について計算値：２７８．０８９８、実測値：２７８．０９０９
Figure JPOXMLDOC01-appb-C000046
 (36) 2-(3-benzoylphenyl)propanoic acid 2-(3-benzoylphenyl)propanoic acid (compound (36), 50.9 mg, 0.20 mmol) was used as substrate and DMSO (0.50 mL) was used as a co-solvent. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 1% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate: 98%, yield: 99%, 50.5 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.80-7.78 (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 = 7.0 Hz, 0.02H, CHCOOH, 98% D), 1.55 (s, 3H, CDCH3 )
13 C NMR (125 MHz, CDCl3 ): δ 196.5, 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: calcd for C16H13DNaO3 (M+Na) + : 278.0898 , found : 278.0909.
Figure JPOXMLDOC01-appb-C000047
 （３７）２－（２，４－ジクロロフェノキシ）酢酸
　２－（２，４－ジクロロフェノキシ）酢酸（化合物（３７）、４４．２ｍｇ、０．２０ｍｍｏｌ）を基質として使用すると共に、ＤＭＦ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で行われた。シリカゲルフラッシュカラムクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に５％のメタノールを添加して得られた混合溶媒）を行い、生成物が得られた。（白色固体、重水素置換率：８７％、収率：９３％、４１．４ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７２．４、１５２．０、１３０．５、１２７．７、１２７．６、１２４．３、１１４．９、６５．５
ＩＲ（ニート）：１７２２、１４７７、１２８８、１２４８、１２３３、１１３０、１１０３、１０５７、８７２、８２７、７９３、７０８、６７７、６３８、４３８
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ８Ｈ４Ｄ２Ｃｌ２ＮａＯ３（Ｍ＋Ｎａ）＋について計算値：２４４．９７１２、実測値：２４４．９７１５
Figure JPOXMLDOC01-appb-C000047
 (37) 2-(2,4-dichlorophenoxy)acetic acid 2-(2,4-dichlorophenoxy)acetic acid (compound (37), 44.2 mg, 0.20 mmol) was used as substrate and DMF (0.20 mmol) was used. 50 mL) was used as a co-solvent. The reaction was carried out at 60°C. Silica gel flash column chromatography (mobile phase: CH 2 Cl 2 with 5% methanol mixed solvent) was performed to give the product. (white solid, deuterium substitution rate: 87%, yield: 93%, 41.4 mg)
1 H NMR (500 MHz, CDCl 3 ): δ 7.41 (d, J=2.5 Hz, 1 H, ArH), 7.19 (dd, J=9.0, 2.5 Hz, 1 H, ArH), 6.82. (d, J=9.0 Hz, 1 H, ArH), 4.72 (m, 0.27 H, CH2COOH , 87% D)
13 C NMR (125 MHz, CDCl3 ): δ 172.4, 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: calcd for C8H4D2Cl2NaO3 (M+Na) + : 244.9712, found : 244.9715.
［実施例１２］
＜一般的な手法と生成物の同定＞
酸無水物により媒介されたカルボン酸のα重水素化の一般的な手順
　磁器撹拌子を備える４ｍＬのバイアルに、アセトン－ｄ６（０．５０ｍＬ、６．８ｍｍｏｌ、０．４０Ｍ）及びピバル酸無水物（８μＬ、０．０４ｍｍｏｌ）の添加に続いてカルボン酸（０．２０ｍｍｏｌ）、Ｋ２ＣＯ３（２．８ｍｇ、０．０２ｍｍｏｌ）及びＤＭＡＰ（２．４ｍｇ、０．０２ｍｍｏｌ）が添加された。反応混合物は、アルゴン雰囲気下で４０℃、４８時間、撹拌された。反応混合物にＤ２Ｏ(0.10 mL)を添加し、室温で１時間撹拌した。反応混合物には１ＭのＨＣｌ水溶液が添加され、ＣＨ２Ｃｌ２により抽出され、溶媒は減圧下で除去された。次に、２．０ｍＬのＣＨ２Ｃｌ２／ギ酸＝４／１（体積比）が残渣に添加され、ピバル酸を除去するためエバポレーションが行われた。この共沸操作は３回行われた。必要に応じ、シリカゲルカラムフラッシュクロマトグラフィーにより残渣は精製された。化合物の中には、溶媒を除去することが困難なものもあった。
　このような方法により、以下の重水素置換実験（３８）～（４６）が行われた。 [Example 12]
<General method and product identification>
General Procedure for Anhydride-Mediated α-Deuteration of Carboxylic Acids Acetone-d 6 (0.50 mL, 6.8 mmol, 0.40 M) and pivalic anhydride were added to a 4 mL vial equipped with a magnetic stirrer. (8 μL, 0.04 mmol) was followed by carboxylic acid (0.20 mmol), K 2 CO 3 (2.8 mg, 0.02 mmol) and DMAP (2.4 mg, 0.02 mmol). The reaction mixture was stirred at 40° C. for 48 hours under an argon atmosphere. D2O (0.10 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was added 1 M aqueous HCl, extracted with CH 2 Cl 2 and the solvent was removed under reduced pressure. Then 2.0 mL of CH 2 Cl 2 /formic acid=4/1 (volume ratio) was added to the residue and evaporated to remove pivalic acid. This azeotropic operation was performed three times. The residue was purified by silica gel column flash chromatography if necessary. For some compounds it was difficult to remove the solvent.
The following deuterium replacement experiments (38) to (46) were carried out by such a method.
Figure JPOXMLDOC01-appb-C000048
 （３８）２－（４－（トリフルオロメチル）フェニル）酢酸
　２－（４－（トリフルオロメチル）フェニル）酢酸（４０．８ｍｇ、０．２ｍｍｏｌ）を基質として使用した。シリカゲルフラッシュクロマトグラフィーを使用せず、生成物が得られた（無色固体、重水素置換率：９２％、収率：８６％、３５．４ｍｇ）。
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）δ１７７．１、１３７．０、１２９．８（ｑ、ＪＣ－Ｆ＝３２Ｈｚ）、１２９．８、１２５．６（ｑ、ＪＣ－Ｆ＝４Ｈｚ）、１２４．１（ｑ、ＪＣ－Ｆ＝２７０Ｈｚ）、４０．３
ＩＲ（ニート）：３０１４、２９２０、１６９３、１６２２、１４１１、１３１９、１２９２、１２３３、１１６５、１１０９、１０６９、１０１６、９４１、８５８、７９９、６７３ｃｍ－１
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ９Ｈ４Ｄ２Ｆ３Ｎａ２Ｏ２（Ｍ＋２Ｎａ－Ｈ）＋について計算値：２５１．０２３５、実測値２５１．０２４２．
Figure JPOXMLDOC01-appb-C000048
 (38) 2-(4-(trifluoromethyl)phenyl)acetic acid 2-(4-(trifluoromethyl)phenyl)acetic acid (40.8 mg, 0.2 mmol) was used as substrate. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution: 92%, yield: 86%, 35.4 mg).
1 H NMR (500 MHz, CDCl 3 ): δ 7.60 (d, J = 8.0 Hz, 2H, ArH), 7.41 (d, J = 8.0 Hz, 2H, ArH), 3.71 (d, 0 .15H, CH2COOH , 92% D)
13 CNMR (125 MHz, CDCl 3 ) δ 177.1, 137.0, 129.8 (q, JC-F = 32 Hz), 129.8, 125.6 (q, JC -F = 4 Hz), 124.1 (q, JCF = 270 Hz), 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: calcd for C9H4D2F3Na2O2 ( M + 2Na-H ) + : 251.0235 , found 251.0242.
Figure JPOXMLDOC01-appb-C000049
 （３９）２－（４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル）酢酸
　２－（４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル）酢酸（２６．２ｍｇ、０．１ｍｍｏｌ）を基質として使用した。反応は６０°Ｃで行われた。シリカゲルフラッシュクロマトグラフィーを使用せず、生成物が得られた（無色固体、重水素置換率：９８％収率：７２％、１９．０ｍｇ）。
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７７．０、１３６．３、１３５．１、１２８．７、８３．８、４９．３、４０．６、２４．８
ＩＲ（ニート）：２９７８、２９２６、１７０７、１６１０、１５１７、１３９８、１３５５、１３２３、１２９４、１２６７、１１４０、１０９０、９６１、８５６、６５１ｃｍ－１
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１４Ｈ１６Ｄ２ＢＮａ２Ｏ４ ＋（Ｍ＋２Ｎａ－Ｈ）＋について計算値：３０９．１２１４、実測値：３０９．１２１９
Figure JPOXMLDOC01-appb-C000049
 (39) 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid 2-(4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (26.2 mg, 0.1 mmol) was used as substrate. The reaction was carried out at 60°C. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution: 98% yield: 72%, 19.0 mg).
1 H NMR (500 MHz, CDCl 3 ): δ 7.76 (d, J = 8.0 Hz, 2H, ArH), 7.28 (d, J = 8.0 Hz, 2H, ArH), 3.60 (s, 0 .03H, CH2COOH , 98% D), 1.33 (s, 12H, CH3 )
13 C NMR (125 MHz, CDCl3 ): δ 177.0, 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: calculated for C14H16D2BNa2O4 + (M+2Na-H) + : 309.1214, found: 309.1219 .
Figure JPOXMLDOC01-appb-C000050
 （４０）２－（４－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）フェニル）酢酸
　２－（４－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）フェニル）酢酸（５０．３ｍｇ、０．２ｍｍｏｌ）を基質として用いた。反応は６０℃で行われた。シリカゲルフラッシュクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に２％ＭｅＯＨを添加して得られた混合溶媒）の後、生成物が得られた（無色固体、重水素置換率：９８％収率：６７％、３４．５ｍｇ）。
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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７７．３、１５３．０、１３７．５、１２９．９、１２７．８、１１８．８、８０．８、３９．８、２８．３
ＩＲ（ニート）：３３７５、２９７６、１６９７、１５９３、１５２６、１５１０、１４１０、１２９４、１２３４、１１５５、１０５７、９４７、８２７、７７５、７４６、６６２、６０４、５１１ｃｍ－１
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１３Ｈ１５Ｄ２ＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値：２７６．１１７５、実測値：２７６．１１９９
Figure JPOXMLDOC01-appb-C000050
 (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 substrate. board. The reaction was carried out at 60°C. The product was obtained after silica gel flash chromatography (mobile phase: mixed solvent obtained by adding 2% MeOH in CH 2 Cl 2 ) (colorless solid, deuterium substitution: 98% yield: 67 %, 34.5 mg).
1 H NMR (500 MHz, CDCl 3 ): δ 7.30 (d, J = 7.5 Hz, 2H, ArH), 7.19 (d, J = 8.5 Hz, 2H, ArH), 6.59 (s, 1H , NH), 3.57 (s, 0.03H, CH2COOH , 98% D) 1.51 (s, 9H, C(CH3) 3 )
13 C NMR (125 MHz, CDCl3 ): δ 177.3, 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 : calcd for C13H15D2NNaO4 (M+Na) + : 276.1175 , found: 276.1199.
Figure JPOXMLDOC01-appb-C000051
 （４１）４－（１，３－ジオキソイソインドリン－２－イル）ブタン酸
４－（１，３－ジオキソイソインドリン－２－イル）ブタン酸（４６．６ｍｇ，０．２ｍｍｏｌ）を基質として使用し、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。シリカゲルフラッシュクロマトグラフィーを使用せず、生成物が得られた（無色固体、重水素置換率：９５％、収率：７５％、３４．９ｍｇ）
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７８．５、１６８．４、１３４．０、１３２．０、１２３．３、３７．１、３０．７
ＩＲ（ニート）：２９７０、２５３８、１７７１、１６９４、１４３７、１３９５、１３５４、１３０６、１１４２、１０４２、９４７、８８０、７１９、５２７、４４６ｃｍ－１
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１２Ｈ９Ｄ２ＮＮａＯ４（Ｍ＋Ｎａ）＋について計算値２５８．０７０６、実測値：２５８．０７０７
Figure JPOXMLDOC01-appb-C000051
 (41) 4-(1,3-dioxoisoindolin-2-yl)butanoic acid 4-(1,3-dioxoisoindolin-2-yl)butanoic acid (46.6 mg, 0.2 mmol) was and DMSO (0.50 mL) was used as a co-solvent. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution: 95%, yield: 75%, 34.9 mg).
1 H NMR (500 MHz, CDCl 3 ): δ 7.87-7.83 (m, 2H, ArH), 7.74-7.70 (m, 2H, ArH), 3.77 (t, J=7.0 Hz , 2H, CH 2 ), 2.42-2.37 (m, 0.05H, CH 2 COOH, 95% D), 2.01 (t, 7.0 Hz, 2H, CH 2 )
13 C NMR (125 MHz, CDCl3 ): δ 178.5, 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: calcd for C12H9D2NNaO4 (M+Na) + 258.0706 , found: 258.0707.
Figure JPOXMLDOC01-appb-C000052
 （４２）２－（１，３－ジオキソイソインドリン－２－イル）－３－メチルブタン酸
　２－（１，３－ジオキソイソインドリン－２－イル）－３－メチルブタン酸（４９．５ｍｇ、０．２ｍｍｏｌ）を基質として使用し、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で実施された。３０モル％のＫ２ＣＯ３、６０モル％のＰｉｖ２Ｏ、及び３０モル％のＤＭＡＰを使用した。シリカゲルフラッシュクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に２％ＭｅＯＨを添加して得られた混合溶媒）の後、生成物が得られた（無色固体、重水素置換率：９９％、収率：９５％、４７．３ｍｇ）。
１ＨＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３）：δ７．８９－７．８５（ｍ、２Ｈ、ＡｒＨ）、７．７６－７．７３（ｍ、２Ｈ、ＡｒＨ）、４．６３（ｄ、Ｊ＝８．５Ｈｚ、０．０１Ｈ、ＣＨＣＯＯＨ、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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７４．４、１６７．８、１３４．３、１３１．６、１２３．７、５７．３、２８．３、２０．８、１９．５．
ＩＲ（ニート）：２９６１、２９３０、２８７４、１７７８、１７２２、１７０９、１４７０、１３８５、１２８５、１１８８、１１２３、１０７２、９０７、７１４、６４２、５２９ｃｍ－１
ＨＲＭＳ（ＤＡＲＴ－ＭＳ）ｍ／ｚ：Ｃ１３Ｈ１３ＤＮＯ４（Ｍ＋Ｈ）＋について計算値：２４９．０９８０、実測値：２４９．０９８１．
Figure JPOXMLDOC01-appb-C000052
 (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 substrate and DMSO (0.50 mL) was used as co-solvent. The reaction was carried out at 60°C. 30 mol % K 2 CO 3 , 60 mol % Piv 2 O, and 30 mol % DMAP were used. After silica gel flash chromatography (mobile phase: mixed solvent obtained by adding 2% MeOH to CH 2 Cl 2 ), the product was obtained (colorless solid, deuterium substitution: 99%, yield: 95%, 47.3 mg).
1 H NMR (500 MHz, CDCl 3 ): δ 7.89-7.85 (m, 2H, ArH), 7.76-7.73 (m, 2H, ArH), 4.63 (d, J = 8.5 Hz , 0.01 H, CHCOOH, 99% D), 2.75 (sep, J=6.8 Hz, 1 H, CH( CH3 ) 2 ), 1.16 (d, J=6.7 Hz, 3H, CH3 ), 0.92 (d, J = 6.8 Hz, 3H, CH3 )
13 C NMR (125 MHz, CDCl 3 ): δ 174.4, 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: calcd for C13H13DNO4 (M+H) + : 249.0980 , found : 249.0981.
Figure JPOXMLDOC01-appb-C000053
 （４３）３－（ｔｅｒｔ－ブトキシ）－２－（１，３－ジオキソ－２，３－ジヒドロ－１Ｈ－インデン－２－イル）プロパン酸
　３－（ｔｅｒｔ－ブトキシ）－２－（１，３－ジオキソ－２，３－ジヒドロ－１Ｈ－インデン－２－イル）プロパン酸（５８．３ｍｇ、０．２ｍｍｏｌ）を基質として使用し、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で実施された。３０モル％のＫ２ＣＯ３、６０モル％のＰｉｖ２Ｏ、及び３０モル％のＤＭＡＰが使用された。シリカゲルフラッシュクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に２％ＭｅＯＨを添加して得られた混合溶媒）の後、生成物が得られた（無色固体、重水素置換率：９９％、収率：４０％、２３．２ｍｇ）。
１ＨＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３）：δ７．８９－７．８７（ｍ、２Ｈ、ＡｒＨ）、７．７５－７．７４（ｍ、２Ｈ、ＡｒＨ）、５．０６（ｔ、Ｊ＝１５．６Ｈｚ、０．０１Ｈ、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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７０．１、１６７．４、１３４．３、１３１．８、１２３．７、７５．５、５８．８、５１．３、２７．３
ＩＲ（ニート）：２９７８、２９２４、１７７５、１７１１、１３８５、１２８８、１２６７、１１８２、１０７８、９３２、９１４、８５６、７６４、７１６、６２５、５２９ｃｍ－１
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１５Ｈ１６ＤＮＮａＯ５（Ｍ＋Ｎａ）＋について計算値：３１５．１０６２、実測値：３１５．１０５４。
Figure JPOXMLDOC01-appb-C000053
 (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 substrate and DMSO (0.50 mL) was used as co-solvent. The reaction was carried out at 60°C. 30 mol % K 2 CO 3 , 60 mol % Piv 2 O, and 30 mol % DMAP were used. After silica gel flash chromatography (mobile phase: mixed solvent obtained by adding 2% MeOH to CH 2 Cl 2 ), the product was obtained (colorless solid, deuterium substitution: 99%, yield: 40%, 23.2 mg).
1 H NMR (500 MHz, CDCl 3 ): δ 7.89-7.87 (m, 2H, ArH), 7.75-7.74 (m, 2H, ArH), 5.06 (t, J=15.6 Hz , 0.01 H, CHCOOH, 99% D), 4.22 (d, J = 9.1 Hz, 1 H, CH2 ), 3.89 (d, J = 9.1 Hz, 1 H, CH2 ), 1. 21 (s, 9H, C(CH3) 3 )
13 C NMR (125 MHz, CDCl3 ): δ 170.1, 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: calcd for C15H16DNNaO5 (M+Na) + : 315.1062 , found: 315.1054 .
Figure JPOXMLDOC01-appb-C000054
 （４４）２，６－ビス（１，３－ジオキソイソインドリン－２－イル）ヘキサン酸
　２，６－ビス（１，３－ジオキソイソインドリン－２－イル）ヘキサン酸（８１．３ｍｇ、０．２ｍｍｏｌ）を基質として使用し、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で実施された。３０モル％のＫ２ＣＯ３、６０モル％のＰｉｖ２Ｏ、及び３０モル％のＤＭＡＰが使用された。シリカゲルフラッシュクロマトグラフィー（移動相：ＣＨ２Ｃｌ２に２％ＭｅＯＨを添加して得られた混合溶媒）の後、生成物が得られた（無色固体、重水素置換率：９９％、収率：７６％、６１．６ｍｇ）。
１ＨＮＭＲ（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＝１０．４、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）
１３ＣＮＭＲ（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（ニート）：３３３３、２９５７、２９３０、２８５７、１７５９、１６９４、１３８９、１３１７、１１７９、１１４４、１０２２、９２２、８９３、８７４、７２９、７１４、６１５、５２７ｃｍ－１
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ２２Ｈ１７ＤＮ２ＮａＯ６（Ｍ＋Ｎａ）＋について計算値：４３０．１１２０、実測値：４３０．１１０９．
Figure JPOXMLDOC01-appb-C000054
 (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 substrate and DMSO (0.50 mL) was used as co-solvent. The reaction was carried out at 60°C. 30 mol % K 2 CO 3 , 60 mol % Piv 2 O, and 30 mol % DMAP were used. After silica gel flash chromatography (mobile phase: mixed solvent obtained by adding 2% MeOH to CH 2 Cl 2 ), the product was obtained (colorless solid, deuterium substitution: 99%, yield: 76%, 61.6 mg).
1 H NMR (500 MHz, CDCl 3 ): δ 7.84-7.83 (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 = 10.4, 5.1 Hz, 0.01H, CHCOOH, 99% D), 3.64 ( t, J = 7.3 Hz, 2H, CH 2 ), 2.35-2.23 (m, 2H, CH 2 ), 1.80-1.63 (m, 2H, CH 2 ), 1.42- 1.33 (m, 2H, CH2 )
13 C NMR (125 MHz, CDCl3 ): δ 174.2, 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: calcd for C22H17DN2NaO6 (M+Na) + : 430.1120 , found: 430.1109.
Figure JPOXMLDOC01-appb-C000055
 （４５）２－（１，３－ジオキソイソインドリン－２－イル）－４－（メチルチオ）ブタン酸
　２－（１，３－ジオキソイソインドリン－２－イル）－４－（メチルチオ）ブタン酸（５５．９ｍｇ、０．２ｍｍｏｌ）を基質として使用した。反応は６０℃で実施された。３０モル％のＫ２ＣＯ３、６０モル％のＰｉｖ２Ｏ、及び３０モル％のＤＭＡＰを使用した。シリカゲルフラッシュクロマトグラフィーを使用せず、生成物が得られた（無色固体、重水素置換率：９９％、収率：９８％、５４．７ｍｇ）。
１ＨＮＭＲ（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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）：δ１７５．０、１６７．６、１３４．４、１３１．７、１２３．７、５０．４、３０．８、２７．７、１５．３
ＩＲ（ニート）：３３１８、２９１６、１７５９、１６９４、１３８７、１１９２、１１７１、１０７８、１０３０、９１６、８７６、７９７、７２５、７１４、６１３、５５７、５２９、４３８ｃｍ－１
ＨＲＭＳ（ＥＳＩ）ｍ／ｚ：Ｃ１３Ｈ１２ＤＮＮａＯ４Ｓ（Ｍ＋Ｎａ）＋について計算値：３０３．０５２０、実測値：３０３．０５３４
Figure JPOXMLDOC01-appb-C000055
 (45) 2-(1,3-dioxoisoindolin-2-yl)-4-(methylthio)butanoic acid 2-(1,3-dioxoisoindolin-2-yl)-4-(methylthio)butane Acid (55.9 mg, 0.2 mmol) was used as substrate. The reaction was carried out at 60°C. 30 mol % K 2 CO 3 , 60 mol % Piv 2 O, and 30 mol % DMAP were used. The product was obtained without silica gel flash chromatography (colorless solid, deuterium substitution: 99%, yield: 98%, 54.7 mg).
1 H NMR (500 MHz, CDCl 3 ): δ 7.89-7.85 (m, 2H, ArH), 7.76-7.73 (m, 2H, ArH), 5.17 (dd, J=9.0 , 5.0 Hz, 0.01 H, CHCOOH, 99% D), 2.62-2.44 (m, 4H, CH2 ), 2.07 (s, 3H, SCH3 )
13 C NMR (125 MHz, CDCl3 ): δ 175.0, 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: calcd for C13H12DNNaO4S (M+Na) + : 303.0520, found: 303.0534.
Figure JPOXMLDOC01-appb-C000056
 （４６）２－（１，３－ジオキソイソインドリン－２－イル）－５－（（Ｓ）－２－（メトキシカルボニル）ピロリジン－１－イル）－５－オキソペンタン酸
　２－（１，３－ジオキソイソインドリン－２－イル）－５－（（Ｓ）－２－（メトキシカルボニル）ピロリジン－１－イル）－５－オキソペンタン酸（７７．７ｍｇ、０．２ｍｍｏｌ）を基質として使用した。反応は６０℃で行われた。３０モル％のＫ２ＣＯ３、６０モル％のＰｉｖ２Ｏ、及び３０モル％のＤＭＡＰが使用された。生成物が得られた。（無色固体、重水素置換率：９９％、収率：６８％、ｄｒ＝１／１．４、５５．７ｍｇ）。
１ＨＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３）（回転異性体とジアステオマーの混合物）：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）
１３ＣＮＭＲ（１２５ＭＨｚ、ＣＤＣｌ３）（回転異性体とジアステオマーの混合物）：δ１７２．８、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、５９．４、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（ニート）：２９５３、１７７１、１７３６、１７０７、１５９７、１４６６、１４３７、１３８３、１１９６、１１７５、１１１５、１０７０、９９５、９２０、８５６、７９７、７１８、６１７、５２９、４１９、４０９ｃｍ－１
ＨＲＭＳ（ＤＡＲＴ－ＭＳ）ｍ／ｚ：Ｃ１９Ｈ２０ＤＮ２Ｏ７ ＋（Ｍ＋Ｈ）＋について計算値：３９０．１４０６、実測値：３９０．１４１４９
Figure JPOXMLDOC01-appb-C000056
 (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 substrate. bottom. The reaction was carried out at 60°C. 30 mol % K 2 CO 3 , 60 mol % Piv 2 O, and 30 mol % DMAP were used. A product was obtained. (colorless solid, deuterium substitution rate: 99%, yield: 68%, dr=1/1.4, 55.7 mg).
1 H NMR (500 MHz, CDCl 3 ) (mixture of rotamers and diastereomers): δ 7.86-7.82 (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, NCH 2 ), 2.70-1.79 (m, 8H, CH 2 CH 2 CONCH 2 CH 2 CH 2 ).
13 CNMR (125 MHz, CDCl 3 ) (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, 59.4, 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 : calculated for C19H20DN2O7 + (M+H) + : 390.1406, found : 390.14149.
Figure JPOXMLDOC01-appb-C000057
 （４７）２－（１，３－ジオキソイソインドリン－２－イル）－５－（（（Ｓ）－１－メトキシ－３－メトキシ－１－オキソブタン－２－イル）アミノ）－５－オキソペンタン酸
　（Ｓ）－２－（１，３－ジオキソイソインドリン－２－イル）－５－（（（Ｓ）－１－メトキシ－３－メトキシ－１－オキソブタン－２－イル）アミノ）－５－オキソペンタン酸（７８．１ｍｇ、０．２ｍｍｏｌ）を基質として使用し、ＤＭＳＯ（０．５０ｍＬ）を共溶媒として使用した。反応は６０℃で行われた。３０モル％のＫ２ＣＯ３、６０モル％のＰｉｖ２Ｏ、及び３０モル％のＤＭＡＰが使用された。シリカゲルフラッシュクロマトグラフィーを使用せず、生成物が得られた（無色固体、重水素置換率：９６％、収率：４３％、ｄｒ＝１／１．５、３４．０ｍｇ）。
１ＨＮＭＲ（５００Ｈｚ、ＤＭＳＯ）（回転異性体とジアステオマーの混合物）δ８．０６－８．０３（ｍ、１Ｈ、ＮＨ）、７．９４－７．８８（ｍ、４Ｈ、ＡｒＨ）、４．７０（ｄｄ、Ｊ＝２３．５Ｈｚ及び９Ｈｚ、０．０６Ｈ、ＣＨＣＯＯＨ、９４％Ｄ）、４．１２－４．０３（ｍ、１Ｈ、ＣＨＣＯＯＣＨ３）、３．６１（ｓ、１．２Ｈ、ＣＯＯＣＨ３）、３．５９（ｓ、１．８Ｈ、ＣＯＯＣＨ３）、２．４２－２．１８（ｍ、４Ｈ、ＣＨ２ＣＨ２）、１．９９－１．８８（ｍ、１Ｈ、ＣＨ（ＣＨ３）２）、０．８４－０．７５（ｍ、６Ｈ、ＣＨ（ＣＨ３）２）
１３ＣＮＭＲ（１２５Ｈｚ、ＤＭＳＯ）（回転異性体とジアステオマーの混合物）δ１７２．５、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（ニート）：３３０８、２９６３、１７７１、１７３２、１７０３、１６２０、１５３７、１４６９、１４３５、１３８５、１２４６、１２００、１１５２、１１１５、１０８６、１０４３、９９３、９７０、９２８、８５４、７３７、７１６、６８５、６２９、５２９ｃｍ－１
ＨＲＭＳ（ＤＡＲＴ－ＭＳ）ｍ／ｚ：Ｃ１９Ｈ２１ＤＮ２Ｏ７ ＋（Ｍ＋Ｈ）＋について計算値：３９２．１５６３、実測値：３９２．１４５６８
Figure JPOXMLDOC01-appb-C000057
 (47) 2-(1,3-dioxoisoindolin-2-yl)-5-(((S)-1-methoxy-3-methoxy-1-oxobutan-2-yl)amino)-5-oxo pentanoic 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 substrate and DMSO (0.50 mL) as co-solvent. The reaction was carried out at 60°C. 30 mol % K 2 CO 3 , 60 mol % Piv 2 O, 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, 0.06 H, CHCOOH, 94% D), 4.12-4.03 (m, 1 H, CHCOOCH3 ), 3.61 (s, 1.2 H, COOCH3 ) , 3.59 (s , 1.8H, COOCH3 ), 2.42-2.18 (m, 4H, CH2CH2 ), 1.99-1.88 (m, 1H, CH( CH3 ) 2 ), 0.84-0.75 (m, 6H, CH( CH3 ) 2 )
13 C NMR (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 : calculated for C19H21DN2O7 + (M+H) + : 392.1563, found : 392.14568.
　本開示は、以下の実施形態［１］～［１４］を含む。
［１］
　重水素置換されたカルボン酸又はその塩を含む重水素富化組成物であって、
　前記カルボン酸又はその塩はカルボキシ基のα水素と、炭素に結合した当該α水素以外の水素とを含み、
　前記α水素の重水素置換率は５％以上であり、
　前記α水素以外の水素の重水素置換率が３％以下であり、
　ただし、前記カルボン酸又はその塩が分子内に前記カルボキシ基以外のカルボニル基を有する基を備える場合、当該カルボニル基のα水素は前記α水素以外の水素には含まれない、重水素富化組成物。
［２］
　前記カルボン酸又はその塩が、下記式（１）～（２１）及び（３８）～（４７）から選択される少なくとも一種のカルボン酸又はその塩を重水素置換した化合物である、［１］の重水素富化組成物。
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000060
 ［３］
　重水素置換されたカルボン酸又はその塩の製造方法であって、
　α水素を有するカルボン酸又はその塩を酸無水物に変換し、重水素化源の存在下で当該酸無水物における前記α水素に対応する水素を重水素に置換する反応工程を備える、製造方法。
［４］
　前記反応工程が、以下の（Ａ）及び（Ｂ）成分の少なくとも一方の存在下で行われる、［３］の製造方法。
（Ａ）前記カルボン酸又はその塩と脱水縮合反応をして酸無水物を形成する化合物。
（Ｂ）前記カルボン酸又はその塩とオキソ酸との反応を促進させて当該カルボン酸又はその塩とオキソ酸との酸無水物を形成する化合物。
［５］
　前記（Ａ）成分が、酸無水物を含む、［４］の製造方法。
［６］
　前記（Ｂ）成分が、縮合剤を含む、［４］又は［５］の製造方法。
［７］
　前記縮合剤が、カルボジイミド又はカルボジイミド塩酸塩である、［６］の製造方法。
［８］
　前記反応工程が、以下の（Ｃ）及び（Ｄ）成分の少なくとも一方の成分の存在下で行われる、［３］～［７］のいずれか一つの製造方法。
（Ｃ）求核的活性化剤。
（Ｄ）前記カルボン酸のカルボキシ基よりも低い酸性度を有する酸と強塩基との塩。
［９］
　前記（Ｃ）成分が、キヌクリジン、１，４－ジアザビシクロ［２．２．２］オクタン及び４－ジメチルアミノピリジンからなる群から選択される少なくとも一種である、［８］の製造方法。
［１０］
　前記（Ｄ）成分が炭酸塩、リン酸塩、及びカルボン酸塩からなる群から選択される少なくとも一種である、［８］又は［９］に記載の製造方法。
［１１］
　前記重水素源が重水素化された溶媒である、［３］～［１０］のいずれか一つの製造方法。
［１２］
　前記反応工程が、共溶媒の存在下で行われる、［３］～［１１］のいずれか一つの製造方法。
［１３］
　カルボン酸又はその塩のα水素を重水素に置換する反応を促進するための反応促進剤であって、
　前記カルボン酸又はその塩を酸無水物に変換する化合物を含む、反応促進剤。
［１４］
　カルボン酸又はその塩を酸無水物に変換する化合物の、カルボキシ基を有する化合物のα水素を重水素に置換する反応における触媒としての、使用。 The present disclosure includes the following embodiments [1]-[14].
[1]
A deuterium-enriched composition comprising a deuterated carboxylic acid or salt thereof,
The carboxylic acid or its salt contains α-hydrogen of the carboxy group and hydrogen other than the α-hydrogen bonded to 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 its salt 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 hydrogen other than the α-hydrogen, deuterium-rich composition thing.
[2]
[1], wherein the carboxylic acid or its salt is a compound in which at least one carboxylic acid or its salt selected from the following formulas (1) to (21) and (38) to (47) is deuterated; A deuterium-enriched composition.
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000060
 [3]
A method for producing a deuterated carboxylic acid or a salt thereof,
A production method comprising a reaction step of converting a carboxylic acid having an α-hydrogen or a salt thereof into an acid anhydride, and substituting deuterium for the hydrogen corresponding to the α-hydrogen in the acid anhydride in the presence of a deuteration source. .
[4]
The production method of [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 its salt to form an acid anhydride.
(B) A compound that promotes the reaction between the carboxylic acid or its salt and the oxoacid to form an acid anhydride of the carboxylic acid or its salt and the oxoacid.
[5]
The production method of [4], wherein the component (A) contains an acid anhydride.
[6]
The production method of [4] or [5], wherein the component (B) contains a condensing agent.
[7]
The production method of [6], wherein the condensing agent is carbodiimide or 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) a nucleophilic activator.
(D) A salt of an acid having a lower acidity than the carboxy group of the carboxylic acid and a strong base.
[9]
The production method of [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 production 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 production method according to any one of [3] to [10], wherein the deuterium source is a deuterated solvent.
[12]
The production method according to any one of [3] to [11], wherein the reaction step is performed in the presence of a co-solvent.
[13]
A reaction accelerator for promoting the reaction of substituting deuterium for α-hydrogen of a carboxylic acid or a salt thereof,
A reaction accelerator containing a compound that converts the carboxylic acid or its salt into an acid anhydride.
[14]
Use of a compound that converts a carboxylic acid or a salt thereof to an acid anhydride, as a catalyst in a reaction in which the α-hydrogen of a compound having a carboxy group is replaced with deuterium.

Claims (14)

  1. 　重水素置換されたカルボン酸又はその塩を含む重水素富化組成物であって、
    　前記カルボン酸又はその塩はカルボキシ基のα水素と、炭素に結合した当該α水素以外の水素とを含み、
    　前記α水素の重水素置換率は５％以上であり、
    　前記α水素以外の水素の重水素置換率が３％以下であり、
    　ただし、前記カルボン酸又はその塩が分子内に前記カルボキシ基以外のカルボニル基を有する基を備える場合、当該カルボニル基のα水素は前記α水素以外の水素には含まれない、重水素富化組成物。     A deuterium-enriched composition comprising a deuterated carboxylic acid or salt thereof,
    The carboxylic acid or its salt contains α-hydrogen of the carboxy group and hydrogen other than the α-hydrogen bonded to 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 its salt 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 hydrogen other than the α-hydrogen, a deuterium-rich composition thing.
  2. 　前記カルボン酸又はその塩が、下記式（１）～（２１）及び（３８）～（４７）から選択される少なくとも一種のカルボン酸又はその塩を重水素置換した化合物である、請求項１に記載の重水素富化組成物。
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
         According to claim 1, wherein the carboxylic acid or a salt thereof is a compound obtained by deuterating at least one carboxylic acid or a salt thereof selected from the following formulas (1) to (21) and (38) to (47). A deuterium-enriched composition as described.
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
  3. 　重水素置換されたカルボン酸又はその塩の製造方法であって、
    　α水素を有するカルボン酸又はその塩を酸無水物に変換し、重水素化源の存在下で当該酸無水物における前記α水素に対応する水素を重水素に置換する反応工程を備える、製造方法。     A method for producing a deuterated carboxylic acid or a salt thereof, comprising:
    A production method comprising a reaction step of converting a carboxylic acid having an α-hydrogen or a salt thereof into an acid anhydride, and substituting deuterium for the hydrogen corresponding to the α-hydrogen in the acid anhydride in the presence of a deuteration source. .
  4. 　前記反応工程が、以下の（Ａ）及び（Ｂ）成分の少なくとも一方の存在下で行われる、請求項３に記載の製造方法。
    （Ａ）前記カルボン酸又はその塩と脱水縮合反応をして酸無水物を形成する化合物。
    （Ｂ）前記カルボン酸又はその塩とオキソ酸との反応を促進させて当該カルボン酸又はその塩とオキソ酸との酸無水物を形成する化合物。     4. The production method according to claim 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 its salt to form an acid anhydride.
    (B) A compound that promotes the reaction between the carboxylic acid or its salt and the oxoacid to form an acid anhydride of the carboxylic acid or its salt and the oxoacid.
  5. 　前記（Ａ）成分が、酸無水物を含む、請求項４に記載の製造方法。 The production method according to claim 4, wherein the component (A) contains an acid anhydride.
  6. 　前記（Ｂ）成分が、縮合剤を含む、請求項４又は５に記載の製造方法。 The production method according to claim 4 or 5, wherein the component (B) contains a condensing agent.
  7. 　前記縮合剤が、カルボジイミド又はカルボジイミド塩酸塩である、請求項６に記載の製造方法。 The production method according to claim 6, wherein the condensing agent is carbodiimide or carbodiimide hydrochloride.
  8. 　前記反応工程が、以下の（Ｃ）及び（Ｄ）成分の少なくとも一方の成分の存在下で行われる、請求項３又は４に記載の製造方法。
    （Ｃ）求核的活性化剤。
    （Ｄ）前記カルボン酸のカルボキシ基よりも低い酸性度を有する酸と強塩基との塩。     5. The production method according to claim 3 or 4, 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 an acid having a lower acidity than the carboxy group of the carboxylic acid and a strong base.
  9. 　前記（Ｃ）成分が、キヌクリジン、１，４－ジアザビシクロ［２．２．２］オクタン及び４－ジメチルアミノピリジンからなる群から選択される少なくとも一種である、請求項８に記載の製造方法。 The production method according to claim 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. 　前記（Ｄ）成分が炭酸塩、リン酸塩、及びカルボン酸塩からなる群から選択される少なくとも一種である、請求項８に記載の製造方法。 The production method according to claim 8, wherein the component (D) is at least one selected from the group consisting of carbonates, phosphates, and carboxylates.
  11. 　前記重水素源が重水素化された溶媒である、請求項３又は４に記載の製造方法。 The production method according to claim 3 or 4, wherein the deuterium source is a deuterated solvent.
  12. 　前記反応工程が、共溶媒の存在下で行われる、請求項３又は４に記載の製造方法。 The production method according to claim 3 or 4, wherein the reaction step is performed in the presence of a co-solvent.
  13. 　カルボン酸又はその塩のα水素を重水素に置換する反応を促進するための反応促進剤であって、
    　前記カルボン酸又はその塩を酸無水物に変換する化合物を含む、反応促進剤。     A reaction accelerator for promoting the reaction of substituting deuterium for α-hydrogen of a carboxylic acid or a salt thereof,
    A reaction accelerator containing a compound that converts the carboxylic acid or its salt into an acid anhydride.
  14. 　カルボン酸又はその塩を酸無水物に変換する化合物の、カルボキシ基を有する化合物のα水素を重水素に置換する反応における触媒としての、使用。 Use of a compound that converts a carboxylic acid or a salt thereof into an acid anhydride as a catalyst in a reaction in which the α-hydrogen of a compound having a carboxy group is replaced with deuterium.
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