Method for producing deuterated compound

Abstract

This method for producing a deuterated compound involves reacting an amide or an ester with a deuterium source in the presence of a base and a Lewis acid selected from a metal triflate and a metal triflyl imide, and thereby deuterating the α-hydrogen of the amide or ester.

Description

Method for producing deuterated compounds

[0001] The present invention relates to a method for deuterizing the alpha hydrogen of an amide or ester to produce a deuterated compound.

[0002] It has been shown that the introduction of deuterium into pharmaceuticals improves pharmacokinetics by increasing metabolic stability, etc. In 2017, deutetonabenazine was approved by the FDA as the world's first deuterated pharmaceutical, and on September 26, 2022, deuclavacitinib was approved in Japan as the first deuterated pharmaceutical for the treatment of psoriasis. Against this background, deuterium substitution has been attracting attention in drug discovery research in recent years.

[0003] Furthermore, deuterium-labeled compounds can be analyzed by NMR, MS, D-MRI, and Raman dispersive imaging, and are used as tools for monitoring pharmacokinetics and elucidating metabolites. Furthermore, deuterium is used in organic synthetic chemistry to improve the stability of protecting groups and analyze reaction mechanisms. In this way, expanding the chemical space of deuterium-substituted compounds can serve as the foundation for innovation in various fields, including drug discovery research and organic synthetic chemistry, and demand for such compounds is increasing year by year (see Patent Document 1).

[0004] On the other hand, amides occupy an important position as synthetic building blocks, and in recent years, the conversion of amides with electron-withdrawing groups and distorted amides such as azetidinamides has been reported, enabling molecular conversion to a variety of structures. Therefore, the development of a simple method for synthesizing deuterated amides is expected to enable the synthesis of various deuterated molecules. Research on the deuteration of amides and esters has been reported (Non-Patent Documents 1-3).

[0005] JP 2010-195755 A

[0006] Deslongchamps, P.; Barlet, R.; Taillefer, RJ Hydrolysis and Carbonyl-Oxygen Exchange in Tertiary Amides. Estimation of the Free Energy Changes for Breakdown and Conformational Changes of Tetrahedral Intermediates. Can. J. Chem. 1980, 58, 2167.Galka, PW; Ambrose, SJ; Ross, ARS; Abrams, SR Syntheses of deuterated jasmonates for mass spectrometry and metabolism studies. J. Label Compd. Radiopharm. 2005, 48, 797.Porte, V.; Zhang, H.; Kaiser, D.; Maulide, N. Harnessing ynamide activation to access deuterated carbonyls. Tetrahedron. 2021, 90, 18, 132211.

[0007] However, conventional methods for introducing deuterium into amides and the like have had problems such as the need for harsh conditions, such as high reaction temperatures and the use of strong bases, and are therefore not efficient.

[0008] An object of the present invention is to provide a method for producing (synthesizing) various deuterated amide or ester compounds directly and efficiently under mild conditions.

[0009] The present inventors have conducted extensive research to eliminate the various limitations imposed on conventional methods for producing deuterated amides or esters and to enable the direct and efficient synthesis of various deuterated amides and esters under mild conditions. As a result, they have found that this can be achieved by reacting an amide or ester with a deuterium source in the presence of a Lewis acid selected from metal triflates and metal triflyl imides and a base to deuterate the α-hydrogen of the amide or ester, thereby completing the present invention.

[0010] That is, the present invention is as follows: [1] A method for producing a deuterated compound, comprising reacting an amide or an ester with a deuterium source in the presence of a Lewis acid selected from a metal triflate and a metal triflyl imide, and a base, to deuterate the α-hydrogen of the amide or ester. [2] A method for producing a deuterated compound according to the above [1], wherein the amide is a compound represented by the following formula (1): (In the formula, R １ ~R ５ each represents a hydrogen atom or an organic group, R １ ~R ３ At least one of R is a hydrogen atom; １ ~R ５ may be linked to each other to form a ring. [3] The method for producing a deuterated compound according to the above [1] or [2], wherein the ester is a compound represented by the following formula (2): (In the formula, R ６ ~R ９ X represents an oxygen atom or a sulfur atom, each of which represents a hydrogen atom or an organic group; R ６ ~R ８ At least one of R is a hydrogen atom; ６ ~R ９ may be linked to each other to form a ring.)

[0011] [4] A method for producing a deuterated compound according to any one of [1] to [3] above, wherein the metal triflate is a compound selected from the group consisting of silyl triflate, scandium(III) triflate, and hafnium(IV) triflate. [5] A method for producing a deuterated compound according to any one of [1] to [4] above, wherein the metal triflate is a trialkylsilyl triflate. [6] A method for producing a deuterated compound according to [5] above, wherein the trialkylsilyl triflate is at least one trialkylsilyl triflate selected from the group consisting of trimethylsilyl triflate, triethylsilyl triflate, triisopropylsilyl triflate, and tert-butyldimethylsilyl triflate. [7] A method for producing a deuterated compound according to any one of [1] to [6] above, wherein the metal triflyl imide is silyl triflyl imide. [8] A method for producing a deuterated compound according to any one of [1] to [7] above, wherein the base is a tertiary amine. [9] The method for producing a deuterated compound according to [8] above, wherein the tertiary amine is at least one selected from the group consisting of 1-methylpiperidine, triethylamine, quinuclidine, 1,4-diazabicyclo[2.2.2]octane, diazabicycloundecene, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[10] The method for producing a deuterated compound according to any one of [1] to [9] above, wherein the deuterium source is at least one selected from the group consisting of acetonitrile-d3, acetone-d6, and chloroform-d.

[0012] According to the production method of the present invention, various deuterated amide or ester compounds can be produced directly and efficiently under mild conditions.

[0013] The method for producing a deuterated compound of the present invention is characterized in that an amide or an ester (hereinafter sometimes referred to as a substrate) is reacted with a deuterium source in the presence of a Lewis acid selected from a metal triflate and a metal triflyl imide, and a base, to deuterate the α-hydrogen of the amide or ester.

[0014] The production method of the present invention can deuterate the α-hydrogen of an amide or ester under milder conditions than conventional production methods. Furthermore, compared with conventional production methods, the method has a wider range of substrate selection, allowing the α-hydrogen of various amides or esters to be directly deuterated.

[0015] For example, the present invention makes it possible to directly deuterate amides or esters in the late stages of synthesis (final products or products close to final products) of natural products, pharmaceuticals, etc., which was difficult to achieve with conventional production methods, thereby enabling efficient production and development of pharmaceuticals. That is, conventional methods, which can only deuterate amides or esters with specific structures, can only deuterate pharmaceuticals and the like in the early or middle stages of synthesis, resulting in a low yield of the final deuterated compound and being inefficient. However, the present invention makes it possible to deuterate pharmaceuticals and the like in the late stages of synthesis, as described above, and therefore deuterated compounds can be obtained efficiently, making the method extremely effective in the production and development of pharmaceuticals, etc.

[0016] Here, the "α hydrogen" of an amide or ester in the production method of the present invention refers to a hydrogen atom bonded to the carbon atom (α carbon) adjacent to the carbonyl group of the amide or ester, although the production method of the present invention does not exclude cases in which other hydrogen atoms in addition to the α hydrogen atom are deuterated.

[0017] [Lewis Acid Selected from Metal Triflates and Metal Triflyl Imides] The production (synthesis) of the deuterated compound of the present invention is carried out in the presence of a Lewis acid selected from metal triflates and metal triflyl imides (hereinafter sometimes simply referred to as Lewis acid).

[0018] It is preferable to add metal triflate or metal triflyl imide itself to the reaction system, but any mode may be used as long as metal triflate or metal triflyl imide is formed in the reaction system. For example, a mode in which silyl triflate, which is an example of metal triflate, is formed in the reaction system can be exemplified by a method in which triisopropylsilyl chloride (TIPSCl) and silver trifluoromethanesulfonate (AgOTf) are added. Furthermore, a mode in which silyl triflyl imide, which is an example of metal triflyl imide, is formed can be exemplified by a method in which triisopropylsilyl chloride (TIPSCl) and silver bis(trifluoromethanesulfonyl)imide (AgNTf ２ ) and a method of adding the same.

[0019] Examples of metal triflates include silyl triflate, scandium (III) triflate, and hafnium (IV) triflate, with silyl triflate being preferred.

[0020] A preferred example of the silyl triflate is trialkylsilyl triflate. The number of carbon atoms in the alkyl group is preferably 1 to 6, and more preferably 1 to 4. Specific examples of the silyl triflate include trimethylsilyl triflate (TMSOTf), triethylsilyl triflate (TESOTf), triisopropylsilyl triflate (TIPSOTf), and tert-butyldimethylsilyl triflate (TBSOTf), with triethylsilyl triflate (TESOTf), triisopropylsilyl triflate (TIPSOTf), and tert-butyldimethylsilyl triflate (TBSOTf) being preferred.

[0021] Examples of metal triflyl imide include silyl triflyl imide, scandium (III) triflyl imide, and hafnium (IV) triflyl imide, with silyl triflyl imide being preferred.

[0022] Silyl triflic imide includes trimethylsilyl triflic imide (TMSNTf ２), triethylsilyl triflyl imide (TESNTf ２ ), triisopropylsilyl triflyl imide (TIPSNTf ２ ), tert-butyldimethylsilyl triflyl imide (TBSNTf ２ ), triethylsilyl triflylimide (TESNTf ２ ), triisopropylsilyl triflyl imide (TIPSNTf ２ ), tert-butyldimethylsilyl triflyl imide (TBSNTf ２ ) is preferred.

[0023] In the production method of the present invention, the amount of Lewis acid can be appropriately adjusted so that the reaction proceeds appropriately. For example, the amount of Lewis acid is about 0.001 to 5.0 mol, preferably 0.005 to 3.0 mol, more preferably 0.008 to 1.5 mol, and even more preferably 0.01 to 0.6 mol, relative to 1 mol of the amide or ester substrate.

[0024] [Base] The base used in the production method of the present invention is not particularly limited as long as it is an organic base, and examples thereof include tertiary amines, secondary amines, and primary amines, with tertiary amines being preferred. Also, it is preferred that the steric structure is not large.

[0025] Examples of tertiary amines include 1-methylpiperidine, triethylamine, quinuclidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), diazabicycloundecene (DBU), and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD). Quinuclidine or 1,4-diazabicyclo[2.2.2]octane (DABCO) is preferred, and 1,4-diazabicyclo[2.2.2]octane (DABCO) is more preferred.

[0026] In the production method of the present invention, the amount of base can be appropriately adjusted so that the reaction proceeds appropriately. For example, the amount of base is about 0.001 to 5.0 mol, preferably 0.005 to 3.0 mol, more preferably 0.008 to 1.5 mol, and even more preferably 0.01 to 1.2 mol, relative to 1 mol of the amide or ester substrate.

[0027] [Substrate] In the production method of the present invention, an amide or an ester is used as the substrate. The amide or ester is not particularly limited as long as it has an α-hydrogen.

[0028] Specifically, the amide may be a compound represented by the following formula (1):

[0029]

[0030] R １ ~R ５ each represents a hydrogen atom or an organic group, R １ ~R ３ At least one of R is a hydrogen atom. Specific examples of the organic group include an aliphatic group and an aromatic group. １ ~R ５ may be linked to each other to form a ring, R １ ~R ３ and R ４ ~R ５ are linked to each other to form a ring, or R １ ~R ５ are linked to each other to form a ring.

[0031] The aliphatic group may be linear, branched, or cyclic, and may be saturated or unsaturated. The aliphatic group may be interrupted by a heteroatom (a heteroatom may be present between carbon bonds). The number of carbon atoms in the aliphatic group may be, for example, about 1 to 30, and preferably about 1 to 10. Specific examples include alkyl groups such as methyl, ethyl, propyl, isopropyl, pentyl, and hexyl, and alkenyl groups such as vinyl and allyl.

[0032] The aromatic group may be a group containing an aromatic ring or a group containing a heterocyclic ring. Examples of the aromatic ring of the aromatic group include benzene and naphthalene. Examples of the heterocyclic ring include pyrrole, pyridine, pyrazine, and quinoline.

[0033] Furthermore, it may be a group in which an aliphatic group and an aromatic group are combined, and examples thereof include aralkyl groups such as a benzyl group.

[0034] The aliphatic group and aromatic group may have a substituent, and examples of the substituent include aliphatic groups such as a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group, aromatic groups having a benzene ring or a heterocycle, and substituents having a heteroatom such as an alkoxy group and an amino group.

[0035] Specifically, for example, R １ ~R ３ Examples of the above include the following: １ represents the bond position with the α carbon, and * ２ represents the bonding position to the carbonyl carbon atom.

[0036]

[0037] Specifically, R ４ and R ５ Examples of the amine moiety containing * include the following: ３ represents the bonding position to the carbonyl carbon atom.

[0038]

[0039] Specific examples of the amide of the present invention are shown below. For example, the following compounds can be mentioned as amides substituted with alkyl at the α-position.

[0040]

[0041] Furthermore, examples of amides substituted with an aryl at the α-position include the following compounds:

[0042]

[0043] Furthermore, examples of amides with α-nitrogen substitution, α-oxygen substitution, α-sulfur substitution, etc. include the following compounds.

[0044]

[0045] Furthermore, examples of amides in which a ketone group or an ester group coexists include the following compounds:

[0046]

[0047] Furthermore, examples of amides derived from fatty acids include the following compounds:

[0048]

[0049] Furthermore, other examples of amides having various functional groups in the final stage of synthesis of natural products, pharmaceuticals, etc. include dihydroquinolinone, aniracetam, chlormezanone, sophoridine, brucine, melatonin, ramelteon, ketoconazole, aripiprazole, dipeptides such as glycylglycine, acetaminophen, and capsaicin, as shown below.

[0050]

[0051] Next, the ester as the substrate of the present invention will be described. Examples of the ester of the present invention include the compound represented by the following formula (2).

[0052]

[0053] X represents an oxygen atom or a sulfur atom, R ６ ~R ９ each represents a hydrogen atom or an organic group, R ６ ~R ８ At least one of the above is a hydrogen atom. １ ~R ５ is the same as R １ ~R ５ Similarly, R ６ ~R ９ may be linked to form a ring.

[0054] The ester of the present invention is not particularly limited, and examples thereof include the following esters.

[0055]

[0056] [Deuterium Source] The deuterium source of the present invention is not particularly limited as long as it serves as a source of deuterium, and examples thereof include deuterated compounds of substances that function as solvents (deuterated solvents). Specific examples include acetonitrile-d3, acetone-d6, and chloroform-d, with acetonitrile-d3 being preferred.

[0057] The amount of the deuterium source used can be adjusted as appropriate, but is, for example, 5 to 150 equivalents relative to the substrate amide or ester. From the viewpoint of obtaining a deuterated product with a higher deuterium substitution rate of α-hydrogen and / or a higher yield, the amount is preferably 10 equivalents or more, more preferably 20 equivalents or more, even more preferably 30 equivalents or more, and particularly preferably 66 equivalents or more.

[0058] In the production method of the present invention, a deuterated product having a higher deuterium substitution rate may be finally obtained by carrying out the reaction multiple times using a small amount of a deuterium source, or a deuterated product having a higher deuterium substitution rate may be finally obtained by carrying out the reaction fewer times, such as once or twice, using a relatively large amount of a deuterium source. When the amount of the deuterium source functioning as a solvent is small, an organic solvent such as toluene can be used as a co-solvent.

[0059] [Other Conditions] (Reaction Temperature) The reaction temperature in the production method of the present invention can be appropriately selected depending on the types of Lewis acid, base, amide or ester, and deuterium source, and is, for example, 10 to 100° C., more preferably about 15 to 80° C., and even more preferably about 20 to 60° C. Since the reaction of the present invention proceeds at room temperature, extreme temperature or pressure adjustment is not required, and production costs are low.

[0060] (Reaction Time) The reaction time varies depending on other conditions such as the reaction temperature, but is, for example, about 0.5 to 120 hours, preferably about 0.5 to 72 hours, and more preferably about 1 to 48 hours.

[0061] (Purification Method) The deuterated compound synthesized by the synthesis method of the present invention can be purified by column purification or the like.

[0062] Specific examples of the present invention will be described below, but the scope of the present invention is not limited to these examples.

[0063] Example 1 Deuteration Experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (30.0 mmol) and 6 mol % DABCO (202 mg) based on 100 mol % of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a vial. ３ ), toluene (1.0 M), and 3 mol % TIPSOTf (244 μL) based on 100 mol % of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. ３ The amount of was 10 equivalents relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. The reaction solution was stirred at 25° C. for 72 hours, and then purified by silica gel column chromatography.

[0064] The resulting product: １ H NMR, １３ CNMR, infrared spectroscopy (IR), and accurate mass spectrometry (HRMS (DART)) were performed to confirm that the compound was a deuterated compound of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. NMR measurements were performed using an Avance III (manufactured by Bruker).

[0065] １ ​The deuterium substitution rate of α-hydrogens in the product was determined from the integrated intensity of H NMR. The deuterium substitution rate was 93%. The deuterium substitution rate of α-hydrogens is the ratio of the number of deuterium-substituted α-hydrogens to the total number of α-hydrogens in 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one contained in the product (i.e., the total number of Ds at the α-position divided by the sum of D and H at the α-position). The deuterium substitution rate is １ It was calculated from the ratio of the number of α-hydrogen atoms to the number of hydrogen atoms other than α-hydrogen atoms from the H NMR spectrum.

[0066] The yield of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one was 99%. The yield is the ratio of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (including both α-deuterium-substituted and non-α-deuterium-substituted) contained in the product to the 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one used as the substrate. The yield was calculated by the following method.

[0067] (1) The weight of an empty 300 mL recovery flask was measured in advance, the purified product solution was added, the solvent was removed, and the recovery flask was reweighed. The yield (mg) of the product was calculated from the difference in weight. (2) Next, the molecular weights of the product with a deuteration rate of 0% and the product with a 100% α-deuteration rate were calculated using ChemDraw. １ The molecular weight was calculated based on the deuteration rate of the substrate using the measured deuteration rate calculated from the H NMR spectrum. (Example of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one: d ０ Molecular weight: 247.1572, d ２ (3) The yield (mg) was divided by the calculated molecular weight to calculate the yield (mmol), and the yield (mmol) was then divided by the amount (mmol) of the amide or ester (carbonyl compound) added as the substrate to calculate the yield (%). ２ The weight is 7.44 g, and production on a gram scale is also possible.

[0068] 4-(4-Methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one has, as hydrogen atoms other than the α-carbon, a total of 19 hydrogen atoms bonded to carbon atoms other than the α-carbon, including two β- and two γ-position hydrogen atoms of the carboxyl group, four hydrogen atoms bonded to the benzene ring, eight hydrogen atoms bonded to the pyrrolidine ring, and three hydrogen atoms bonded to the methyl group. １ When the integrated intensity of H NMR was examined, deuterium substitution was not observed for hydrogens bonded to carbons other than the α-carbon of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (i.e., below the detection limit).

[0069] In all of the following examples, deuterium substitution of hydrogens other than α-hydrogens (excluding α-hydrogens of carbonyl groups and α-hydrogens of sulfonyl groups) was not observed. １ This is clearly evident from the fact that the integrated intensities of the peaks of hydrogens other than α-hydrogens in H NMR match within the error range compared to the intensities of each peak before deuterium substitution. Furthermore, as will be described later, the measured and calculated values ​​of the mass spectrum agree well, and the spectrum itself is sharp, which negates the possibility that deuterium substitution has occurred evenly throughout the molecule.

[0070] The proposed reaction mechanism for the catalytic deuterium substitution reaction of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one is believed to be as shown in the following scheme.

[0071]

[0072] First, the addition of TIPSOTf and DABCO forms a silyl enolate of an amide or ester (carbonyl compound). At the same time, a triflate salt of the base is generated. Under similar conditions, deuterated acetonitrile, a deuterium source (deuteration agent), also becomes a silyl enolate, producing a triflate salt containing deuterium. The silyl enolate of the amide or ester abstracts deuterium from the salt, producing a deuterated amide or ester.

[0073] Example 2: Deuteration experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one using a different base and deuterium source from Example 1. 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 40 mol % DBU (6.0 μL) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stir bar. Subsequently, chloroform-d and 20 mol % TIPSOTf (5.4 μL) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. The amount of chloroform-d used was 96 equivalents (0.20 M) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. The reaction solution was stirred at 70°C for 15 hours, and then 1M hydrochloric acid was added to the reaction solution to obtain CHCl ３ The solvent was distilled off under reduced pressure, and the deuterium substitution rate was then determined, which was found to be 83%.

[0074] Example 3 Deuteration Experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one Using Various Metal Triflates 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 40 mol % DBU (6.0 μL) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stir bar. Subsequently, chloroform-d and 20 mol % of a metal triflate shown in Table 1 based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. The amount of chloroform-d used was 62 equivalents (0.20 M) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. The reaction solution was stirred at 70°C for 15 hours, and then ethyl acetate was added to the reaction solution, followed by short pad filtration. The solvent was then distilled off under reduced pressure. The deuterium substitution rate was then determined. The results are shown in Table 1.

[0075]

[0076] Example 4 Deuteration Experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one Using Different Deuterium Sources 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 40 mol % DBU (6.0 μL) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stir bar. Subsequently, the deuterium source (0.20 M) shown in Table 2 and 20 mol % TIPSOTf (5.4 μL) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. The reaction solution was stirred at 70° C. for 15 hours, and then 1 M hydrochloric acid was added to the reaction solution, followed by the addition of CHCl . ３ The solvent was removed under reduced pressure, and the deuterium substitution rate was then determined. The results are shown in Table 2.

[0077]

[0078] [Example 5] <Deuteration experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one using different types of base> Specifically, 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 20 mol % of a base shown in Table 3 relative to the 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stirrer. ３ and 10 mol% TIPSOTf (2.7 μL) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. ３ The amount of the compound used was 96 equivalents (0.20 M) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. The reaction solution was stirred at 25°C for 15 hours, after which 1 M hydrochloric acid was added to the reaction solution and CHCl ３ The solvent was removed under reduced pressure, and the deuterium substitution rate was then determined. The results are shown in Table 3.

[0079]

[0080] Example 6 Deuteration Experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one Using Different Types of Lewis Acid (Silicon Counter Anion) 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 20 mol % of DABCO (2.2 mg) and 10 mol % of the additives shown in Table 4 relative to the 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stirrer. ３ and 10 mol% TIPSCl (2.1 μL) based on 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. ３ The amount of was 96 equivalents (0.20 M) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. After stirring the reaction solution at 25°C for 15 hours, ethyl acetate was added to the reaction solution, which was then filtered through a short pad, and the solvent was distilled off under reduced pressure. The deuterium substitution rate was then determined. The results are shown in Table 4.

[0081]

[0082] [Example 7] Deuterium substitution experiments (1) to (46) were carried out using various amides and esters as substrates. In each experiment, unless otherwise specified, 10 mol % of TIPSOTf and 20 mol % of DABCO were used relative to 100 mol % of the amide or ester (carbonyl compound). Unless otherwise specified, acetonitrile-d ３ When no cosolvent is used, the amount used is 96 equivalents (0.20 M) relative to the amide or ester. Unless otherwise specified, the reaction solution in each experiment was stirred at 25°C for 48 hours. １ H NMR and １３ CNMR peak positions are expressed in ppm, and IR peak positions are expressed in cm ‐１ Also, １ The chemical shifts of H NMR were referenced to the non-deuterated peak contained in the deuterated solvent. ３When using CHCl ３ When methanol was used as the deuterated solvent, the peak of hydrogen in the methyl group (δ 3.31 ppm) was used. １３ The peak of the deuterated solvent was used as the reference for the chemical shifts in CNMR.

[0083] (1) 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one

[0084]

[0085] 4-(4-Methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (compound (1), 49.5 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 3), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 95%, 47.5 mg).

[0086] 1 H NMR (500 MHz, CDCl3) δ 7.12-7.09 (m, 2H, ArH), 6.83-6.80 (m, 2H, ArH), 3.78 (s, 3H, ArOCH3), 3.45 (t, J = 7. 0 Hz, 2H, NCH2), 3.32 (t, J = 7.0 Hz, 2H, NCH2), 2.62 (t, J = 7.5 Hz, 2H, ArCH2), 2.23 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.96-1.88 (m, 4H, ArCH2CH2 + NCH2CH2), 1. 83 (quin, J = 6.5 H, 2H, NCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 171.4, 157.8, 133.9, 129.4, 113.7, 55.2, 46.5, 45.6, 34.4, 33.2, 26.4, 26.1, 24.4 IR (neat) 2949, 2932, 2868, 1632, 1612, 1510, 1418, 1300, 1242, 1177, 1109, 1032, 831, 513 cm -1HRMS (DART-MS) m / z: C 15 H 20 D2NO2 (M+H) + Calculated value: 250.1771, Measured value: 250.1774.

[0087] (2) 1-(azetidin-1-yl)-4-(4-methoxyphenyl)butan-1-one

[0088]

[0089] 1-(azetidin-1-yl)-4-(4-methoxyphenyl)butan-1-one (compound (2), 46.7 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 5), the product was obtained (white solid, deuterium substitution rate: 98%, yield: 86%, 40.5 mg).

[0090] 1 H NMR (500 MHz, CDCl3) δ 7.10-7.09 (m, 2H, ArH), 6.83-6.81 (m, 2H, ArH), 4.03 (t, J = 7.5 Hz, 2H, NCH2), 4.00 (t, J = 7.5 Hz, 2H, NCH2), 3.78 (s, 3H, ArOCH3), 2.59 (t, J = 7.5 Hz, 2H, ArCH2), 2.23 (q, J = 7.5 Hz, 2H, NCH2CH2), 2.03 (t, J = 7.5 Hz, COCH2), 1.90 (t, J = 7.5 H, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 173.0, 157.8, 133.7, 129.4, 113.7, 55.3, 50.0, 47.7, 34.3, 29.6, 26.3, 15.0 IR (neat) 2953, 2882, 2866, 1614, 1584, 1512, 1454, 1433, 1300, 1242, 1175, 1111, 1030, 837, 814, 534, 525 cm -1 HRMS (DART-MS) m / z: C 14 H18 D2NO 2 (M+H) + Calculated value: 236.1614, measured value: 236.1615.

[0091] (3) 4-(4-methoxyphenyl)-1-(piperidin-1-yl)butan-1-one

[0092]

[0093] 4-(4-Methoxyphenyl)-1-(piperidin-1-yl)butan-1-one (compound (3), 52.3 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=1 / 3), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 88%, 46.1 mg).

[0094] 1 H NMR (500 MHz, CDCl3) δ 7.12-7.09 (m, 2H, ArH), 6.84-6.81 (m, 2H, ArH), 3.78 (s, 3H, ArOCH3), 3.54 (t, J = 5.5 Hz, 2H, NCH2), 3.31 (t, J = 5.5 Hz, 2H, NCH2), 2.61 (t, J = 7.5 Hz, 2H, ArCH2), 2.28 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.91 (t, J = 7.5 Hz, 2H, ArCH2CH2), 1.64-1.60 (m, 2H, NCH2CH2CH2), 1.54-1.49 (m, 4H, NCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 171.1, 157.8, 133.9, 129.4, 113.8, 55.2, 46.6, 42.6, 34.5, 31.9, 27.0, 26.6, 25.6, 24.6 IR (neat) 2940, 2853, 1628, 1508, 1460, 1429, 1263, 1234, 1177, 1109, 1028, 997, 833, 816, 799, 525 cm -1 HRMS (DART-MS) m / z: C16 H 22 D2NO 2 (M+H) + Calculated value: 264.1927, measured value: 264.1931.

[0095] (4) 1-(azepan-1-yl)-4-(4-methoxyphenyl)butan-1-one

[0096]

[0097] 1-(azepan-1-yl)-4-(4-methoxyphenyl)butan-1-one (compound (4), 53.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=1 / 3), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 102%, 56.5 mg).

[0098] 1 H NMR (500 MHz, CDCl3) δ 7.12-7.10 (m, 2H, ArH), 6.83-6.81 (m, 2H, ArH), 3.78 (s, 3H, ArOCH3), 3.51 (t, J = 6.0 Hz, 2H, NCH2), 3.35 (t, J = 6.0 Hz, 2H, NCH2), 2.62 (t, J = 7.5 Hz, 2H, ArCH2), 2.28 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.94 (t, J = 7.5 Hz, 2H, ArCH2CH2), 1.71-1.63 (m, 4H, NCH2CH2), 1.57-1.51 (m, 4H, NCH2CH2CH2) 13 C NMR (125 MHz, CDCl3) δ 172.4, 157.8, 134.0, 129.4, 113.7, 55.3, 47.8, 45.9, 34.4, 31.7, 29.1, 27.6, 27.1, 26.9, 26.9 IR (neat) 2928, 2857, 1630, 1510, 1441, 1422, 1300, 1242, 1175, 1107, 1034, 829, 554 cm -1 HRMS (DART-MS) m / z: C17 H 24 D2NO 2 (M+H) + Calculated value: 278.2084, measured value: 276.2088.

[0099] (5) 4-(4-methoxyphenyl)-N,N-dimethylbutanamide

[0100]

[0101] 4-(4-Methoxyphenyl)-N,N-dimethylbutanamide (compound (5), 44.3 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 3), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 95%, 42.5 mg).

[0102] 1 H NMR (500 MHz, CDCl3) δ 7.12-7.09 (m, 2H, ArH), 6.84-6.81 (m, 2H, ArH), 3.78 (s, 3H, ArOCH3), 2.93 (s, 6H, NCH3), 2.62 (t, J = 7.5 Hz, 2H, ArCH2), 2.27 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.93 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 172.9, 157.8, 133.9, 129.4, 113.8, 55.2, 37.2, 35.3, 34.4, 31.8, 26.6 IR (neat) 2932, 2911, 2858, 2835, 2158, 1634, 1609, 1510, 1244, 1179, 1030, 835, 793, 565 cm -1 HRMS (DART-MS) m / z: C 13 H 18 D2NO 2 (M+H) + Calculated value: 224.1614, measured value: 224.1615.

[0103] (6) N-benzyl-4-(4-methoxyphenyl)-N-methylbutanamide

[0104]

[0105] N-benzyl-4-(4-methoxyphenyl)-N-methylbutanamide (compound (6), 55.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 2), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 93%, 56.0 mg).

[0106] 1 H NMR (500 MHz, CDCl3) δ 7.35-7.21 (m, 4H, ArH), 7.12-7.05 (m, 3H, ArH), 6.83-6.78 (m, 2H, ArH), 4.58 (s, 2H, NCH2, major rotamer), 4.45 (s, ,2H, NCH2, minor rotamer), 3.77 (s, 3H, ArOCH3, major rotamer), 3.76 (s, 3H, ArOCH3, minor rotamer), 2.94 (s, 3H, NCH3, minor rotamer), 2.84 (s, 3H, NCH3, major rotamer), 2.65 (t, J = 7.5 Hz, 2H, ArCH2, major rotamer), 2.59 (t, J = 7.5 Hz, 2H, ArCH2, minor rotamer), 2.34 (t, J =7.5 Hz, 0.02H, COCH2, 99% D), 2.00-1.93 (m, 2H, ArCH2CH2) 13C NMR (125 MHz, CDCl3) δ 173.2, 172.9, 157.8, 157.8, 137.5, 136.8, 133.8, 133.8, 129.4, 129.3, 128.9, 128.5, 128.0, 127.5, 127.3, 126.3, 113.8, 113.7, 55.2, 53.3, 50.7, 34.7, 34.4, 34.3, 33.9, 32.6, 31.7, 26.9, 26.7 IR (neat) 2922, 2849, 2166, 1965, 1634, 1510, 1452, 1396, 1242, 1177, 1034, 831, 729, 698 cm -1 HRMS (DART-MS) m / z: C 19 H 22 D2NO 2 (M+H) + Calculated value: 300.1927, measured value: 300.1933.

[0107] (7) N,N-diallyl-4-(4-methoxyphenyl)butanamide

[0108]

[0109] N,N-diallyl-4-(4-methoxyphenyl)butanamide (compound (7), 54.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 2), the product was obtained (light yellow liquid, deuterium substitution rate: 99%, yield: 99%, 54.5 mg).

[0110] 1H NMR (500 MHz, CDCl3) δ 7.10-7.09 (m, 2H, ArH), 6.83-6.81 (m, 2H, ArH), 5.79-5.67 (m, 2H, NCH2CH), 5.17-5.07 (m, 4H, NCH2CHCH2), 3.98 (d, J = 6.0 Hz, 2H, NCH2), 3.79 (d, J = 4.5 Hz, 2H, NCH2), 3.78 (s, 3H, ArOCH3), 2.60 (t, J = 7.5 Hz, 2H, ArCH2), 2.28 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.94 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 172.8, 157.8, 133.9, 133.4, 133.0, 129.4, 117.1, 116.5, 113.8, 55.2, 49.2, 47.8, 34.3, 31.5, 26.9 IR (neat) 2982, 2835, 1636, 1464, 1435, 1408, 1300, 1244, 1177, 1111, 1036, 989, 920, 831, 729, cm -1 HRMS (DART-MS) m / z: C 17 H 22 D2NO 2 (M+H) + Calculated value: 276.1927, measured value: 276.1931.

[0111] (8) 4-(4-methoxyphenyl)-N-methyl-N-phenylbutanamide

[0112]

[0113] 4-(4-Methoxyphenyl)-N-methyl-N-phenylbutanamide (compound (8), 56.7 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 2), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 93%, 53.3 mg).

[0114] 1H NMR (500 MHz, CDCl3) δ 7.40-7.36 (m, 2H, ArH), 7.33-7.30 (m, 2H, ArH), 7.13 (d, J = 7.5 Hz, 2H, ArH), 6.99 (d, J = 8.0 Hz, 2H, ArH), 6.76 (d, J = 8.5 Hz, 2H, ArH), 3.76 (s, 3H, ArOCH3), 3.26 (s, 3H, NCH3), 2.46 (t, J = 7.5 Hz, 2H, ArCH2), 2.03 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.85 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 172.9, 157.7, 144.2, 133.8, 129.7, 129.2, 127.6, 127.3, 113.7, 55.2, 37.3, 34.3, 32.8, 27.1 IR (neat) 2949, 2920, 2862, 1649, 1595, 1510, 1495, 1371, 1300, 1238, 1180, 1032, 835, 706, 559, 515, 409 cm -1 HRMS (DART-MS) m / z: C 18 H 20 D2NO 2 (M+H) + Calculated value: 286.177, Measured value: 286.1773.

[0115] (9) 4-(4-methoxyphenyl)-1-morpholinobutan-1-one

[0116]

[0117] 4-(4-Methoxyphenyl)-1-morpholinobutan-1-one (compound (9), 47.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=1 / 3), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 99%, 51.3 mg).

[0118] 1H NMR (500 MHz, CDCl3) δ 7.10 (d, J = 9.0 Hz, 2H, ArH), 6.83 (d, J = 8.5 Hz, 2H, ArH), 3.78 (s, 3H, ArOCH3), 3.66-3.59 (m, 6H, NCH2+NCH2CH2), 3.37 (t, J = 5.0 Hz, 2H, NCH2), 2.62 (t, J = 7.5 Hz, 2H, ArCH2), 2.27 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.93 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 171.5, 157.9, 133.6, 129.3, 113.8, 66.9, 66.6, 55.2, 45.9, 41.8, 34.3, 31.4, 26.7 IR (neat) 2951, 2851, 1634, 1611, 1510, 1425, 1275, 1242, 1177, 1113, 1030, 831, 569 cm -1 HRMS (DART-MS) m / z: C 15 H 20 D2NO 3 (M+H) + Calculated value: 266.1720, measured value: 266.1722.

[0119] (10) 4-(4-methoxyphenyl)-1-thiomorpholinobutan-1-one

[0120]

[0121] 4-(4-Methoxyphenyl)-1-thiomorpholinobutan-1-one (compound (10), 49.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=1 / 3), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 98%, 55.6 mg).

[0122] 1H NMR (500 MHz, CDCl3) δ 7.09 (d, J = 8.5 Hz, 2H, ArH), 6.83 (d, J = 9.0 Hz, 2H, ArH), 3.86 (t, J = 5.0 Hz, 2H, NCH2), 3.78 (s, 3H, ArOCH3), 3.64 (t, J = 5.0 Hz, 2H, NCH2), 2.62 (t, J = 7.5 Hz, 2H, ArCH2), 2.59-2.54 (m, 4H, NCH2CH2), 2.26 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.92 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 171.2, 157.9, 133.6, 129.3, 113.8, 55.3, 48.2, 44.1, 34.3, 31.7, 27.9, 27.4, 26.7 IR (neat) 2949, 2203, 1632, 1510, 1460, 1420, 1300, 1288, 1244, 1177, 1032, 957, 910, 831, 729 cm -1 HRMS (DART-MS) m / z: C 15 H 20 D2NO2S (M+H) + Calculated value: 282.1491, measured value: 282.1495.

[0123] (11) 1-(4-benzoylpiperazin-1-yl)-4-(4-methoxyphenyl)butan-1-one

[0124]

[0125] 1-(4-benzoylpiperazin-1-yl)-4-(4-methoxyphenyl)butan-1-one (compound (11), 73.3 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 2), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 96%, 70.4 mg).

[0126] 1H NMR (500 MHz, CDCl3) δ 7.45-7.38 (m, 5H, ArH), 7.09 (d, J = 8.5 Hz, 2H, ArH), 6.82 (d, J = 8.5 Hz, 2H, ArH), 3.78 (s, 3H, ArOCH3), 3.43 (br, 8H, NCH2), 2.62 (t, J = 7.5 Hz, 2H, ArCH2), 2.30 (br, 0.02H, COCH2, 99% D), 1.94 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 171.6, 170.6, 157.9, 135.2, 133.5, 130.1, 129.3, 128.6, 127.1, 113.8, 55.2, 47.4 (br), 45.3 (br), 42.2 (br), 41.6 (br), 34.2, 31.6, 26.6 IR (NEET) 2928, 2149, 1626, 1510, 1456, 1420, 1285, 1242, 1175, 1030, 1003, 833, 787, 731, 708, 523cm -1 HRMS (DART-MS) m / z: C 22 H 25 D2N2O 3 (M+H) + Calculated value: 369.2142, measured value: 369.2144.

[0127] (12) N-benzyl-4-(4-methoxyphenyl)butanamide

[0128]

[0129] N-benzyl-4-(4-methoxyphenyl)butanamide (compound (12), 56.7 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 1), the product was obtained (white solid, deuterium substitution rate: 99%, yield 94%, 53.6 mg).

[0130] 1H NMR (500 MHz, CDCl3) δ 7.33-7.24 (m, 5H, ArH), 7.05 (d, J = 8.5 Hz, 2H, ArH), 6.80 (d, J = 8.5 Hz, 2H, ArH), 5.88 (br, 1H, NH), 4.39 (d, J = 5.5 Hz, 2H, NHCH2), 3.76 (s, 3H, ArOCH3), 2.58 (t, J = 7.5 Hz, 2H, ArCH2), 2.16 (t, J = 7.5 Hz, 0.03H, COCH2, 99% D), 1.93 (t, J = 7.5 Hz, 2H, ArCH2CH2); 13 C NMR (125 MHz, CDCl3) δ 172.7, 157.9, 138.4, 133.5, 129.4, 128.7, 127.8, 127.5, 113.8, 55.2, 43.5, 35.2, 34.2, 27.2 IR (neat) 3283, 2941, 2833, 1624, 1551, 1512, 1452, 1248, 1175, 1028, 818, 812, 721, 692, 598, 515 cm -1 HRMS (DART-MS) m / z: C 18 H 20 D2NO 2 (M+H) + Calculated value: 286.1771, measured value: 286.1777.

[0131] (13) 4-(4-methoxyphenyl)-N-phenylbutanamide

[0132]

[0133] 4-(4-Methoxyphenyl)-N-phenylbutanamide (compound (13), 53.9 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. 3.0 equivalents of TIPSOTf and 6.0 equivalents of DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate = 4 / 1), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 97%, 53.0 mg).

[0134] 1H NMR (500 MHz, CDCl3) δ 7.50-7.48 (m, 2H, ArH), 7.32-7.29 (m, 2H, ArH), 7.19 (br, 1H, NH), 7.11-7.08 (m, 3H, ArH), 6.84-6.82 (m, 2H, ArH), 3.78 (s, 3H, ArOCH3), 2.64 (t, J = 7.5 Hz, 2H, ArCH2), 2.31 (t, J = 7.5 Hz, 0.03H, 99% D), 2.02 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 171.1, 157.9, 137.9, 133.4, 129.4, 129.0, 124.2, 119.8, 113.9, 55.3, 36.1, 34.1, 27.0 IR (neat) 3327, 3314, 2932, 2912, 2149, 1659, 1599, 1528, 1510, 1437, 1321, 1302, 1238, 1180, 1032, 762, 696, 673 cm -1 HRMS (DART-MS) m / z: C 17 H 18 D2NO 2 (M+H) + Calculated value: 272.1614, measured value: 2721616.

[0135] (14) 4-(4-methoxyphenyl)butanamide

[0136]

[0137] 4-(4-Methoxyphenyl)butanamide (compound (14), 38.7 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. 3.0 equivalents of TIPSOTf and 6.0 equivalents of DABCO were used. 3.3 equivalents of CsF were added to the reaction mixture, which was then stirred at room temperature for 1 hour. Silica gel flash chromatography (CH ２ Cl ２ After filtration (MeOH = 97 / 3), the product was obtained (white solid, deuterium substitution rate: 98%, yield: 78%, 30.4 mg).

[0138] 1 H NMR (500 MHz, CDCl3) δ 7.11-7.08 (m, 2H, ArH), 6.84-6.81 (m, 2H, ArH), 5.64-5.44 (br, 2H, NH2), 3.78 (s, 3H, ArOCH3), 2.61 (t, J = 7.5 Hz, 2H, ArCH2), 2.19 (t, J = 7.5 Hz, 0.03H, 98% D), 1.93 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 175.4, 157.9, 133.5, 129.4, 113.8, 55.3, 34.3, 34.1, 27.0 IR (neat) 3368, 3356, 3215, 3167, 1659, 1632, 1612, 1512, 1396, 1304, 1240, 1177, 1030, 837, 818, 694, 673, 523 cm -1 HRMS (DART-MS) m / z: C 11 H 14 D2NO 2 (M+H) + Calculated value: 196.1301, measured value: 196.1305.

[0139] (15) 2-phenyl-1-(pyrrolidin-1-yl)ethan-1-one

[0140]

[0141] 2-phenyl-1-(pyrrolidin-1-yl)ethan-1-one (compound (15), 37.9 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 2), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 95%, 36.3 mg).

[0142] 1H NMR (500 MHz, CDCl3) δ 7.33-7.22 (m, 5H, ArH), 3.64-3.63 (m, 0.03H, COCH2, 98% D), 3.49 (t, J = 7.0 Hz, 2H, NCH2), 3.42 (t, J = 7.0 Hz, 2H, NCH2), 1.91 (quin, J = 6.5 Hz, 2H, NCH2CH2), 1.83 (quin, J = 6.5 Hz, 2H, NCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 169.5, 134.9, 128.9, 128.6, 126.7, 46.8, 45.9, 41.7, 26.1, 24.3 IR (neat) 2968, 2876, 1612, 1601, 1491, 1416, 1337, 1200, 741, 716, 692, 583, 569, 515, 503 cm -1 HRMS (DART-MS) m / z: C 12 H 14 D2NO (M+H) + Calculated value: 192.1352, measured value: 192.1353.

[0143] (16) 2-(1H-indol-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one

[0144]

[0145] 2-(1H-indol-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one (compound (16), 45.7 mg, 0.20 mmol) was used as the substrate, and THF (0.25 mL) was used as the co-solvent. ２ Cl ２ After filtration (MeOH = 30 / 1), the product was obtained (brown solid, deuterium substitution rate: 98%, yield: 101%, 46.3 mg).

[0146] 1H NMR (500 MHz, CDCl3) δ 8.75 (br, 1H, NH), 7.63 (d, J = 8.0 Hz, 1H, ArH), 7.29 (d, J = 8.0 Hz, 1H, ArH), 7.16-7.13 (m, 1H, ArH), 7.11-7.07 (m, 2H, ArH), 7.00 (d, J = 2.5 Hz, 1H, ArH), 3.73 (s, 0.03H, COCH2, 98% D), 3.50 (t, J = 7.0 Hz, NCH2), 3.44 (t, J = 7.0 Hz, NCH2), 1.86 (quin, J = 6.5 Hz, 2H, NCH2CH2), 1.80 (quin, J = 6.5 Hz, 2H, NCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 170.3, 136.3, 127.4, 123.0, 121.8, 119.3, 118.7, 111.3, 108.5, 46.9, 45.9, 31.8, 26.1, 24.3 IR (neat) 3273, 2970, 2870, 2170, 2048, 1622, 1423, 1335, 1242, 1005, 816, 789, 737, 704, 602, 567, 426 cm -1 HRMS (DART-MS) m / z: C 14 H 15 D2N2O (M+H) + Calculated value: 231.1461, measured value: 231.1459.

[0147] (17) Pyrrolidin-1-yl(1,2,3,4-tetrahydronaphthalen-1-yl)methanone

[0148]

[0149] Pyrrolidin-1-yl(1,2,3,4-tetrahydronaphthalen-1-yl)methanone (compound (17), 45.9 mg, 0.20 mmol) was used as the substrate. 20 mol % TESOTf and 40 mol % DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 2), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 96%, 44.0 mg).

[0150] 1 H NMR (500 MHz, CDCl3) δ 7.13-7.07 (m, 3H, ArH), 6.95-6.93 (m, 1H, ArH), 3.97-3.94 (m, 0.007H, COCH, 99% D), 3.62-3.50 (m, 3H, NCH2), 3.47-3.43 (m, 1H, NCH2), 2.91-2.85 (m, 1H, ArCH2), 2.79-2.73 (m, 1H, ArCH2), 2.09-1.85 (m, 7H, Alkyl), 1.76-1.68 (m, 1H, Alkyl) 13 C NMR (125 MHz, CDCl3) δ 173.8, 137.5, 135.0, 129.4, 127.9, 126.4, 125.9, 46.9, 46.0, 44.5, 29.3, 26.6, 26.3, 24.3, 21.4 IR (neat) 2972, 2928, 2872, 2830, 1618, 1449, 1406, 1260, 1223, 1196, 1161, 1028, 754, 739, 679, 610, 500, 434 cm -1 HRMS (DART-MS) m / z: C 15 H 19 DNO (M+H) + Calculated value: 231.1602, measured value: 231.1602.

[0151] (18) 2-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)isoindoline-1,3-dione

[0152]

[0153] 2-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)isoindoline-1,3-dione (compound (18), 54.5 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 2), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 97%, 52.9 mg).

[0154] 1 H NMR (500 MHz, CDCl3) δ 7.87-7.84 (m, 2H, ArH), 7.75-7.72 (m, 2H, ArH), 5.00 (q, J = 7.0 Hz, 0.004H, COCH, 99% D), 3.52-3.49 (m, 2H, NCH2), 3.48-3.43 (m, 2H, NCH2), 3.29-3.24 (m, 2H, NCH2), 1.95-1.74 (m, 4H, NCH2CH2), 1.71 (s, 3H, CDCH3) 13 C NMR (125 MHz, CDCl3) δ 167.7, 167.5, 134.1, 131.8, 123.5, 48.2, 46.6, 46.4, 26.4, 23.9, 15.1 IR (neat) 2994, 2982, 2949, 2878, 1709, 1634, 1427, 1377, 1337, 1179, 1061, 972, 916, 872, 804, 718, 604, 544, 529 cm -1 HRMS (DART-MS) m / z: C 15 H 16 DN2O 3 (M+H) + Calculated value: 274.1296, measured value: 274.1305.

[0155] (19) 2-(2,4-dichlorophenoxy)-1-(pyrrolidin-1-yl)ethan-1-one

[0156]

[0157] 2-(2,4-Dichlorophenoxy)-1-(pyrrolidin-1-yl)ethan-1-one (compound (19) 54.8 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 3), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 88%, 48.8 mg).

[0158] 1 H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 2.5 Hz, 1H, ArH), 7.16 (dd, J = 2.5 Hz, 9.0 Hz, 1H, ArH), 6.94 (d, J = 9.0 Hz, 1H, ArH), 4.67 (s, 0.02H, COCH 2, 99% D), 3.56 (t, J = 7.0 Hz, 2H, NCH2), 3.50 (t, J = 7.0 Hz, 2H, NCH2), 1.97 (quin, J = 7.0 Hz, 2H, NCH2CH2), 1.85 (quin, J = 7.0 Hz, 2H, NCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 165.6, 152.4, 130.1, 127.7, 126.6, 123.7, 114.7, 68.6, 46.3, 46.1, 26.3, 23.8 IR (neat) 2872, 2363, 1645, 1477, 1437, 1287, 1134, 1107, 1059, 880, 802, 706, 691, 638, 565, 505 cm -1 HRMS (DART-MS) m / z: C 12 H 12 D2Cl2NO 2 (M+H) + Calculated value: 276.0522, measured value: 276.0525.

[0159] (20) 2-((2,5-dichlorophenyl)thio)-1-(pyrrolidin-1-yl)ethan-1-one

[0160]

[0161] 2-((2,5-dichlorophenyl)thio)-1-(pyrrolidin-1-yl)ethan-1-one 20 (compound (20), 58.0 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 3), the product was obtained (white solid, deuterium substitution rate: 96%, yield: 95%, 55.6 mg).

[0162] 1 H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 2.5 Hz, 1H, ArH), 7.27 (d, J = 8.5 Hz, 1H, ArH), 7.10 (dd, J = 2.0 Hz, 8.5 Hz, 1H, ArH), 3.70 (s, 0.07H, COCH2, 96% D), 3.54 (t, J = 7.0 Hz, 2H, NCH2), 3.49 (t, J = 7.0 Hz, 2H, NCH2), 1.99 (quin, J = 7.0 Hz, 2H, NCH2CH2), 1.88 (quin, J = 7.0 Hz, 2H, NCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 165.7, 136.9, 133.1, 131.6, 130.4, 128.8, 127.1, 47.0, 46.3, 35.8, 26.2, 24.3 IR (neat) 2974, 2945, 2874, 2027, 1624, 1429, 1364, 1090, 1030, 1020, 858, 851, 826, 802, 571, 556, 511, 436 cm -1 HRMS (DART-MS) m / z: C 12 H 12 D2Cl2NOS (M+H) + Calculated value: 292.0293, measured value: 292.0297.

[0163] (21) 1-phenyl-5-(pyrrolidin-1-yl)pentane-1,5-dione

[0164]

[0165] 1-phenyl-5-(pyrrolidin-1-yl)pentane-1,5-dione (compound (21), 49.1 mg, 0.20 mmol) was used as the substrate. 20 mol % quinuclidine was used as the base instead of DABCO. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 3), the product was obtained (colorless liquid, D ａ Deuterium substitution rate: 96%, D ｂ Deuterium substitution rate: 40%, yield: 95%, 47.6 mg)

[0166] 1 H NMR (500 MHz, CDCl3) δ 8.00-7.98 (m, 2H, ArH), 7,56-7.53 (m, 1H, ArH), 7.47-7.44 (m, 2H, ArH), 3.46 (t, J = 7.0 Hz, 2H, NCH2), 3.41 (t, J = 2.08 (t, J = 7.0 Hz, 2H, NCOCD2CH2), 1.94 (quin, J = 7.0 Hz, NCH2CH2), 1.84 (quin, J = 7.0 Hz, NCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 200.3, 171.1, 136.9, 133.0, 128.6, 128.1, 46.5, 45.6, 37.7, 33.1, 26.1, 24.4, 19.3 IR (neat) 2872, 2166, 1680, 1626, 1597, 1422, 1271, 1254, 1209, 849, 750, 739, 691, 511 cm -1 HRMS (DART-MS) m / z: C 15 H 16 D4NO 2 (M+H) + Calculated value: 250.1740, measured value: 250.1726.

[0167] (22) Ethyl 6-oxo-6-(pyrrolidin-1-yl)hexanoate

[0168]

[0169] Ethyl 6-oxo-6-(pyrrolidin-1-yl)hexanoate (compound (22), 43.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=1 / 3), the product was obtained (colorless liquid, D ａ Deuterium substitution rate: 98%, D ｂ Deuterium substitution rate: 73%, yield: 89%, 41.4 mg)

[0170] 1 H NMR (500 MHz, CDCl3) δ 4.12 (q, J = 7.0 Hz, 2H, COOCH2), 3.46 (t, J = 7.0 Hz, 2H, NCH2), 3.41 (t, J = 7.0 Hz, 2H, NCH2), 2.35-2.29 (m, 0.55H, CH2COOEt, 73% D), 2.26 (br, 0.03H, CH2CONR2, 98% D), 1.95 (quin, J = 7.0 Hz, 2H, NCH2CH2), 1.85 (quin, J = 7.0 Hz, 2H, NCH2CH2), 1.68-1.67 (m, 4H, Alkyl), 1.25 (t, J = 7.0 Hz) 13 C NMR (125 MHz, CDCl3) δ 173.6, 171.2, 60.2, 46.6, 45.6, 34.2, 33.7, 26.1, 24.7, 24.4, 24.2, 14.3 IR (neat) 2920, 2853, 1728, 1634, 1422, 1368, 1341, 1254, 1225, 1169, 1121, 1026, 851, 800 cm -1 HRMS (DART-MS) m / z: C 12 H 18 D4NO 3 (M+H) + Calculated value: 232.1845, measured value: 232.1846.

[0171] (23) (9Z,12Z)-1-(pyrrolidin-1-yl)octadeca-9,12-dien-1-one

[0172]

[0173] (9Z,12Z)-1-(pyrrolidin-1-yl)octadeca-9,12-dien-1-one (compound (23), 74.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=1 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 90%, 60.4 mg).

[0174] 1 H NMR (500 MHz, CDCl3) δ 5.41-5.30 (m, 4H, vinyl), 3.46 (t, J = 7.0 Hz, 2H, NCH2), 3.41 (t, J = 7.0 Hz, 2H, NCH2), 2.77 (t, J = 6.5 Hz, 2H, CH=CHCH2CH=CH), 2.23 (t, J = 7.5 Hz, 0.03H, COCH2, 99% D) 2.07-2.03 (m, 4H, CH=CHCH2CH2), 1.95 (quin, J = 7.0 Hz, 2H, NCH2CH2), 1.85 (quin, J = 7.0 Hz, 2H, NCH2CH2), 1.63-1.62 (m, 2H, COCD2CH2), 1.39-1.26 (m, 14H, Alkyl), 0.89 (t, J = 7.0 Hz, 3H, CH2CH3) 13 C NMR (125 MHz, CDCl3) δ 171.9, 130.2, 130.1, 128.0, 127.9, 46.6, 45.6, 34.2, 31.5, 29.7, 29.5, 29.4, 29.4, 29.2, 27.2, 27.2, 26.2, 25.6, 24.8, 24.4, 22.6, 14.1 IR (neat) 3007, 2924, 2853, 1634, 1418, 1341, 1252, 1227, 1194, 1167, 922, 847, 729, 644 cm -1 HRMS (DART-MS) m / z: C22 H 38 D2NO (M+H) + Calculated value: 336.3230, measured value: 336.3230.

[0175] (24) 1-methyl-3,4-dihydroquinolin-2(1H)-one

[0176]

[0177] 1-Methyl-3,4-dihydroquinolin-2(1H)-one (compound (24), 28.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=3 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 94%, 30.7 mg).

[0178] 1 H NMR (500 MHz, CDCl3) δ 7.27-7.24 (m, 1H, ArH), 7.16 (d, J = 7.5 Hz, 1H, ArH), 7.03-6.97 (m, 2H, ArH), 3.36 (s, 3H, NCH3), 2.89 (s, 2H, ArCH2), 2.63 (t, J = 7.5 Hz, 2H, COCH2) 13 C NMR (125 MHz, CDCl3) δ 170.5, 140.6, 127.7, 127.4, 126.2, 122.8, 114.6, 31.1, 29.5, 25.2 IR (neat) 2889, 2843, 1663, 1601, 1470, 1460, 1358, 1331, 1287, 1271, 1115, 752, 725, 654, 490, 463, 420 cm -1 HRMS (DART-MS) m / z: C 10 H 10 D2NO (M+H) + Calculated value: 164.1039, Measured value: 164.1039.

[0179] (25) 1-(4-methoxybenzoyl)pyrrolidin-2-one

[0180]

[0181] 1-(4-Methoxybenzoyl)pyrrolidin-2-one (compound (25), 43.8 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 1), the product was obtained (white solid, deuterium substitution rate: 97%, yield: 101%, 44.8 mg).

[0182] 1 H NMR (500 MHz, CDCl3) δ 7.66-7.63 (m, 2H, ArH), 6.91-6.88 (m, 2H, ArH), 3.93 (t, J = 12.0 Hz, 2H, NCH2), 3.85 (s, 3H, ArOCH3), 2.58 (t, J = 8.5 Hz, 0.07H, COCH2, 97% D), 2.11 (t, J = 7.0 Hz, 2H, CD2CH2) 13 C NMR (125 MHz, CDCl3) δ 174.7, 170.0, 162.9, 131.7, 126.2, 113.1, 55.4, 46.8, 32.9, 17.5 IR (neat) 3869, 3848, 2999, 2164, 1967, 1724, 1658, 1601, 1512, 1360, 1315, 1296, 1240, 1177, 1115, 856, 822, 768, 577, 532 cm -1 HRMS (DART-MS) m / z: C 12 H 12 D2NO 3 (M+H) + Calculated value: 222.1094, measured value: 222.1094.

[0183] (26) 2-(4-chlorophenyl)-3-methyl-1,3-thiazinan-4-one 1,1-dioxide

[0184]

[0185] 2-(4-chlorophenyl)-3-methyl-1,3-thiazinan-4-one 1,1-dioxide (compound (26), 54.7 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=1 / 3), the product was obtained (white solid, D ａ Deuterium substitution rate: 98%, D ｂ Deuterium substitution rate: 46%, yield: 85%, 46.8 mg)

[0186] 1 H NMR (500 MHz, CDCl3) δ 7.49-7.46 (m, 2H, ArH), 7.36-7.33 (m, 2H, ArH), 5.30 (d, J = 2.5 Hz, 0.54H, ArCH, 54% D), 3.33-3.18 (m, 2.04H, COCH2 + COCD2CH2, 98% D), 2.95 (d, J = 1.5 Hz, 3H, NCH3) 13 C NMR (125 MHz, CDCl3) δ 166.1, 136.8, 129.6, 129.5, 128.5, 128.4, 80.0, 79.8, 79.6, 79.4, 43.5, 43.5, 36.1, 36.0, 30.0 IR (neat) 2164, 2156, 2151, 1643, 1593, 1489, 1379, 1317, 1130, 1090, 827, 538, 527, 436 cm -1 HRMS (DART-MS) m / z: C 11 H 10 D3ClNO3S (M+H) + Calculated value: 277.0487, measured value: 277.0482.

[0187] (27) (41R,7aS,13aS,13bS)-dodecahydro-1H,5H,10H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10-one

[0188]

[0189] The substrate used was (41R,7aS,13aS,13bS)-dodecahydro-1H,5H,10H-dipyrido[2,1-f:3',2',1'-ij][1,6]naphthyridin-10-one (compound (27), 49.7 mg, 0.20 mmol). ２ Cl ２ / 2MNH ３ After filtration (MeOH = 97 / 3), the product was obtained (light orange solid, deuterium substitution rate: 99%, yield: 94%, 46.8 mg).

[0190] 1 H NMR (500 MHz, MeOD) δ 3.32-3.24 (m, 2H, NCH2+NCH), 3.19-3.14 (m, 1H, NCH2), 2.81-2.77 (m, 1H, NCH2), 2.75-2.70 (m, 1H, NCH2), 2.21-2.15 (m, 2.01H, COCH2+NCH2, 99% D), 2.04-2.00 (m, 1H, NCH), 1.99-1.29 (m, 13H, Alkyl), 1.05-0.96 (m, 1H, Alkyl) 13 C NMR (125 MHz, MeOD) δ 171.2, 62.2, 56.1, 55.3, 49.2, 47.3, 40.3, 30.9, 30.0, 29.2, 27.2, 22.2, 21.5, 21.4, 17.9 IR (neat) 2924, 2866, 2851, 2361, 1614, 1458, 1441, 1354, 1217, 1130, 1113, 1198, 905, 652, 469, 444, 415 cm -1 HRMS (DART-MS) m / z: C 15 H 23 D2N2O (M+H) + Calculated value: 251.2087, measured value: 251.2088.

[0191] (28) (4aR,4a1R,5aS,8aR,8a1S,15aS)-10,11-dimethoxy-2,4a,4a1,5,5a,7,8,8a1,15,15a-decahydro-14H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one

[0192]

[0193] The substrate was (4aR,4a1R,5aS,8aR,8a1S,15aS)-10,11-dimethoxy-2,4a,4a1,5,5a,7,8,8a1,15,15a-decahydro-14H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinolin-14-one (compound (28), 78.9 mg, 0.20 mmol), and THF (0.25 mL) was used as a co-solvent. Silica gel flash chromatography (CH ２ Cl ２ / MeOH / NEt ３ After filtration (mixture of 40 / 1 / 1), the product was obtained (white solid, deuterium substitution rate: 98%, yield: 94%, 74.2 mg).

[0194] 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H, ArH), 6.68 (s, 1H, ArH), 5.90 (t, J = 5.5 Hz, 2H, vinyl), 4.28 (d, J = 3.5 Hz, 1H, CD2CH), 4.16-4.04 (m, 2H, CH=CH2O), 3.90 (m, 8H, ArCOH3 + NR2CH), 3.71 (d, J = 15.0 Hz, 1H, NCH'2CR=CH), 3.21-3.14 (m, 2.02H, NCH'2CH2 + CHCR2CH + COCH'2, 98% D), 2.88-2.82 (m, 1H, NCH”2CH2), 2.73 (d, J = 15.0 Hz, 1H, NCH"2CR=CH), 2.64 (d, J = 3.5 Hz, 0.02H, COCH"2, 98% D), 2.38-2.33 (m, 1H, NCHCH'2), 1.93-1.83 (m, 2H, NCH2CH2), 1.48-1.45 (m, 1H, NCHCH”2), 1.28-1.24 (m, 1H, CR3H) 13 C NMR (125 MHz, CDCl3) δ 169.0, 149.2, 146.2, 140.4, 136.0, 127.4, 123.4, 105.6, 101.0, 77.6, 64.6, 60.4, 60.0, 56.5, 56.2, 52.7, 51.9, 50.2, 48.3, 42.4, 41.8, 31.5, 26.8 IR (neat) 2855, 2833, 2166, 1979, 1651, 1497, 1445, 1402, 1281, 1207, 1117, 746, 420 cm -1 HRMS (DART-MS) m / z: C 23 H 25 D2N2O 4 (M+H) + Calculated value: 397.2091, measured value: 397.2092.

[0195] (29) N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide

[0196]

[0197] N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide (compound (29), 46.5 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 5), the product was obtained (white solid, deuterium substitution rate: 98%, yield: 100%, 47.0 mg).

[0198] 1 H NMR (500 MHz, CDCl3) δ 8.16 (br, 1H, NH), 7.26 (d, J = 8.5 Hz, 2H, ArH), 7.02 (dd, J = 2.5 Hz, 15 Hz, 2H, ArH), 6.87 (dd, J = 2.5 Hz, 8.5 Hz, 1H, ArH), 5.60 (br, 1H, NH), 3.86 (s, 3H, OCH3), 3.59 (q, J = 6.5 Hz, 2H, ArCH2CH2), 2.94 (t, J = 6.5 Hz, 2H, ArCH2), 1.90 (q, J = 7.0 Hz, 0.06H, COCH2, 98% D) 13 C NMR (125 MHz, CDCl3) δ 170.2, 154.1, 131.6, 127.8, 122.8, 112.6, 112.4, 112.1, 100.5, 56.0, 39.7, 25.3, 22.7 IR (neat) 3273, 2369, 2359, 1611, 1547, 1487, 1339, 1209, 1175, 1101, 1036, 928, 824, 795, 650, 623, 565, 529 cm -1 HRMS (DART-MS) m / z: C 13 H 14 D3N2O 2 (M+H) + Calculated value: 236.1473, measured value: 236.1466.

[0199] (30) (S)—N-(2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl)propionamide

[0200]

[0201] (S)—N-(2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl)propionamide (compound (30), 51.9 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. After silica gel flash chromatography (n-hexane / ethyl acetate = 1 / 2), the product was obtained (white solid, deuterium substitution rate: 98%, yield: 95%, 49.8 mg).

[0202] 1 H NMR (500 MHz, CDCl3) δ 6.94 (d, J = 8.0 Hz, 1H, ArH), 6.60 (d, J = 8.0 Hz, 1H, ArH), 5.63 (br, 1H, NH), 4.59-4.47 (m, 2H, OCH2), 3.35-3.31 (m, 2H, NHCH2), 3.27-3.15 (m, 2H, ArCH+OCH2CH2), 3.12-3.06 (m, 1H, OCH2CH2), 2.91-2.73 (m, 2H, ArCH2), 2.30-2.23 (m, 1H, ArCH2CH2), 2.19-2.12 (m, 0.05H, COCH2, 98% D), 2.05-1.97 (m, 1H, NHCH2CH2), 1.85-1.78 (m, 1H, ArCH2CH2), 1.66-1.59 (m, 1H, NHCH2CH2), 1.12 (s, 3H, CH3) 13 C NMR (125 MHz, CDCl3) δ 173.8, 159.4, 143.1, 135.8, 123.4, 122.2, 107.4, 71.2, 42.2, 38.0, 33.5, 31.7, 30.7, 29.1, 28.6, 9.7 IR (neat) 3316, 2934, 2860, 2843, 2158, 1636, 1535, 1458, 1315, 1229, 1209, 991, 808, 692, 403 cm -1 HRMS (DART-MS) m / z: C 16 H 20 D2NO2 (M+H) + Calculated value: 262.1771, measured value: 262.1772.

[0203] (31) 1-(4-(((2R,4S)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethan-1-one

[0204]

[0205] The substrate used was 1-(4-(((2R,4S)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethan-1-one (compound (31), 106.3 mg, 0.20 mmol), and the co-solvent was chlorobenzene (1.0 mL). The reaction was carried out at 60°C. 30 mol% TIPSOTf and 60 mol% DABCO were used. Silica gel flash chromatography (CH ２ Cl ２ After filtration (MeOH = 30 / 1), the product was obtained (white solid, deuterium substitution rate: 98%, yield: 94%, 100.3 mg).

[0206] 1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.5 Hz, 1H, ArH), 7.51 (s, 1H, ArH), 7.46 (d, J = 2.0 Hz, 1H, ArH), 7.25 (dd, J = 2.0 Hz, 8.5 Hz, 1H, ArH), 6.99 (s, 1H, ArH), 6.97 (s, 1H, ArH), 6.88 (d, J = 9.0 Hz, 2H, ArH), 6.77 (d, J = 9.0 Hz, 2H, ArH), 4.50 (d, J gem = 14.5, 1H, ArCH2), 4.40 (d, J gem= 14.5, 1H, ArCH2), 4.34 (m, 1H, OCH), 3.87 (dd, J = 6.5 Hz, 8.5 Hz, 1H, OCH2), 3.76-3.70 (m, 4H, NCH2+OCH2+ArOCH2), 3.61-3.59 (m, 2H, NCH2), 3.28 (dd, J = 6.5 Hz, 9.5 Hz, 1H, ArOCH2), 3.06-3.01 (m, 4H, NCH2), 2.10 (br, 0.06H, COCH3, 98% D) 13 C NMR (125 MHz, CDCl3) δ 169.0, 152.9, 145.7, 138.8, 135.8, 134.6, 133.0, 131.3, 129.5, 128.5, 127.2, 121.2, 118.8, 115.2, 108.0, 74.8, 67.6, 67.5, 51.2, 51.0, 50.7, 46.3, 41.4, 20.7 IR (neat) 2369, 2357, 1636, 1510, 1462, 1437, 1242, 1200, 1018, 1007, 812, 737, 664, cm -1 HRMS (DART-MS) m / z: C 26 H 26 D3Cl2N4O 4 (M+H) + Calculated value: 534.1749, measured value: 534.1760.

[0207] (32) 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one

[0208]

[0209] The substrate used was 7-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (compound (32), 89.7 mg, 0.20 mmol), and the co-solvent was chlorobenzene (1.0 mL). The reaction was carried out at 60°C. 3.0 equivalents of TIPSOTf and 6.0 equivalents of DABCO were used. Silica gel flash chromatography (CH２ Cl ２ / MeOH=30 / 1), the product was obtained. (White solid, deuterium replacement rate: 99%, yield: 94%, 84.5mg)

[0210] 1 H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H, NH), 7.16-7.12 (m, 2H, ArH), 7.04 (d, J = 8.5 Hz, 1H, ArH), 6.96 (dd, J = 2.5 Hz, 7.0 Hz, 1H, ArH), 6.52 (dd, J = 2.5 Hz, 8.5 Hz, 1H, ArH), 6.37 (d, J = 2.5 Hz, 1H, ArH), 3.97 (t, J = 6.25 Hz, ArOCH2, 2H), 3.08 (br, 4H, NCH2), 2.88 (s, 2H, ArCH2), 2.66 (br, 4.01H, NCH2+COCH2, 99% D), 2.49 (t, J = 7.5 Hz, 2H, NCH2), 1.85-1.79 (m, 2H, OCH2CH2), 1.74-1.68 (m, 2H, NCH2CH2) 13 C NMR (125 MHz, CDCl3) δ 172.2, 158.7, 151.3, 138.2, 134.0, 128.6, 127.5, 127.5, 124.6, 118.6, 115.7, 108.7, 102.3, 67.9, 58.2, 53.3, 51.3, 30.5, 27.3, 24.4, 23.4 IR (ニート) 2945, 2868, 2835, 1678, 1626, 1593, 1576, 1447, 1371, 1290, 1240, 1175, 1140, 1028, 860, 822, 773, 710, 675 cm -1 HRMS (DART-MS) m / z: C 23 H 26 D2Cl2N3O 2 (M+NH4) + について calculated value: 450.1679, measured value: 450.1672.

[0211] (33) 2-(1,3-dioxoisoindolin-2-yl)-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)acetamide

[0212]

[0213] The substrate used was 2-(1,3-dioxoindolin-2-yl)-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)acetamide (compound (33), 63.1 mg, 0.20 mmol). The reaction was carried out at 60°C. 30 mol% TIPSOTf and 60 mol% DABCO were used. Silica gel flash chromatography (CH ２ Cl ２ After filtration (MeOH = 30 / 1), the product was obtained (white solid, D ａ Deuterium substitution rate: 98%, D ｂ Deuterium substitution rate: 98%, yield: 97%, 62.2 mg)

[0214] 1 H NMR (500 MHz, CDCl3) δ 7.88-7.86 (m, 2H, ArH), 7.74-7.72 (m, 2H, ArH), 4.46 (s, 0.04H, NHCOCH2, 98% D), 3.98 (d, J = 3.5 Hz, 0.04H, NHCH2, 98% D), 3.48 (t, J = 7.0 Hz, 2H, NH2), 3.37 (t, J = 7.0 Hz, 2H, NCH2), 1.98 (quin, J = 7.0 Hz, 2H, NCH2CH2), 1.87 (quin, J = 7.0 Hz, quin, CH2CH2) 13 C NMR (125 MHz, CDCl3) δ 167.8, 166.2, 166.1, 134.1, 132.1, 123.5, 46.0, 45.5, 41.6, 40.0, 25.9, 24.1 IR (neat) 3294, 2367, 2357, 2145, 1717, 1661, 1649, 1628, 1400, 1188, 910, 748, 737, 710, 530, 523, 507 cm -1 HRMS (DART-MS) m / z: C 16 H14 D4N3O 4 (M+NH4) + Calculated value: 320.1543, measured value: 320.1541.

[0215] (34) N-(4-hydroxyphenyl)acetamide

[0216]

[0217] N-(4-hydroxyphenyl)acetamide (compound (34), 30.2 mg, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. 3.0 equivalents of TIPSOTf and 6.0 equivalents of DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate = 2 / 1), the product was obtained (white solid, deuterium substitution rate: 98%, yield: 98%, 60.6 mg).

[0218] 1 H NMR (500 MHz, CDCl3) δ 7.64 (br, 1H, NH), 7.34 (d, J = 8.5 Hz, 2H, ArH), 6.81 (d, J = 8.5 Hz, 2H, ArH), 2.09 (br, 0.06H, COCH3, 98% D), 1.23 (sep, J = 7.0 Hz, 3H, CH(CH3)2), 1.09 (d, J = 7.0 Hz, 18H, CH(CH3)2) 13 C NMR (125 MHz, CDCl3) δ 168.4, 152.7, 131.4, 121.6, 120.0, 23.6, 17.9, 12.6 IR (neat) 2955, 2943, 2889, 2866, 1647, 1506, 1327, 1256, 1227, 903, 881, 837, 702, 683, 664, 521 cm -1 HRMS (DART-MS) m / z: C 17 H 27 D3NO2Si (M+H) + Calculated value: 311.2229, Measured value: 311.2229.

[0219] (35) (E)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide

[0220]

[0221] The substrate used was (E)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnona-6-enamide (compound (35), 61.1 mg, 0.20 mmol, a mixture of capsaicinoids, capsaicin:dihydrocapsaicin=2:1). The reaction was carried out at 60°C. 1.1 equivalents of TIPSOTf and 2.2 equivalents of DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate=3:1→1:1), the product was obtained (colorless liquid, deuterium substitution rate: 96%, yield: 99%, 91.7 mg).

[0222] 1 H NMR (500 MHz, CDCl3) δ 6.81-6.79 (m, 1H, ArH), 6.75-6.75 (m, 1H, ArH), 6.69-6.67 (m, 1H, ArH), 5.80 (br, 1H, NH), 5.39-5.28 (m, 1.37H. Vinyl), 4.34 (d, 5.5 Hz, 2H, ArCH2), 3.77+3.77(s+s, 3H, ArOCH3), 2.25-2.18 (m, 0.73H, Allyl+COCH2, 96% D), 1.98 (q, J = 7.0 Hz, 1.38H, Vinyl), 1.65-1.62 (m, 2H, Alkyl), 1.54-1.35 (m, 2H, Alkyl), 1.30-1.20 (m, 5.67H, Alkyl), 1.08 (d, J = 7.0 Hz, 18H, CH(CH3)2), 0.95 (d, J = 6.5 Hz, 4H, CH(CH3)2), 0.86 (d, J = 6.5 Hz, 2H, CH(CH3)2) 13C NMR (125 MHz, CDCl3) δ 172.9, 172.8, 151.0, ; 144.9, 138.0, 131.5, 131.5, 126.5, 120.3, 120.0, 111.9, 55.4, 43.4, 39.0, 36.2, 32.2, 31.0, 29.7, 29.3, 29.2, 27.9, 27.3, 25.7, 25.2, 22.7, 22.6, 17.9, 12.9. IR (neat) 2928, 2866, 2365, 2153, 1638, 1543, 1512, 1464, 1418, 1283, 1233, 1159, 1126, 1040, 883, 814, 679 cm -1 HRMS (DART-MS) m / z: C 27 H 46 D2NO3Si (M+H) + Calculated value: 464.3524, measured value: 464.3517.

[0223] (36) Methyl 4-(4-methoxyphenyl)butanoate

[0224]

[0225] Methyl 4-(4-methoxyphenyl)butanoate (compound (36), 39.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=10 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 97%, yield: 63%, 26.2 mg).

[0226] 1 H NMR (500 MHz, CDCl3) δ 7.10-7.08 (m, 2H, ArH), 6.83-6.82 (m, 2H, ArH), 3.78 (s, 3H, ArOCH3), 3.66 (s, 3H, COOCH3), 2.59 (t, J = 7.5 Hz, 2H, ArCH2), 2.30 (t, J = 7.5 Hz, 0.05H, COCH2, 97% D), 1.91 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13C NMR (125 MHz, CDCl) δ 174.0, 157.9, 133.5, 129.4, 113.8, 55.3, 51.5, 34.2, 32.8, 26.6; IR (neat) 2835, 2172, 1732, 1611, 1510, 1458, 1435, 1242, 1177, 1123, 1034, 831, 556, 517 cm -1 HRMS (DART-MS) m / z: C 12 H 15 D2O 3 (M+H) + Calculated value: 211.1298, measured value: 211.1297.

[0227] (37) Ethyl 4-(4-methoxyphenyl)butanoate

[0228]

[0229] Ethyl 4-(4-methoxyphenyl)butanoate (compound (37), 44.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=10 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 82%, 36.4 mg).

[0230] 1 H NMR (500 MHz, CDCl3) δ 7.09 (d, J = 8.5 Hz, 2H, ArH), 6.82 (d, J = 8.5 Hz, 2H, ArH), 4.12 (q, J = 7.5 Hz, 2H, COOCH2), 3.78 (s, 3H, ArOCH3), 2.59 (t, J = 7.5 Hz, 2H, ArCH2), 2.28 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.91 (t, J = 7.5 Hz, 2H, ArCH2CH2), 1.25 (t, J = 7.0 Hz, COOCH2CH3) 13C NMR (125 MHz, CDCl3) δ 173.6, 157.9, 133.5, 129.4, 113.8, 60.2, 55.3, 34.2, 33.1, 26.7, 14.3 IR (neat) 2938, 2835, 2176, 2035, 2014, 1728, 1611, 1512, 1242, 1177, 1121, 1034, 910, 831, 731 cm -1 HRMS (DART-MS) m / z: C 13 H 17 D2O 3 (M+H) + Calculated value: 225.1454, measured value: 225.1457.

[0231] (38) Hexyl 4-(4-methoxyphenyl)butanoate

[0232]

[0233] Hexyl 4-(4-methoxyphenyl)butanoate (compound (38), 56.0 μL, 0.2 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=20 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 99%, 55.3 mg).

[0234] 1 H NMR (500 MHz, CDCl3) δ 7.10-7.07 (m, 2H, ArH), 6.84-6.81 (m, 2H, ArH), 4.06 (t, J = 7.0 Hz, 2H, COOCH2), 3.78 (s, 3H, ArOCH3), 2.59 (t, J = 7.5 Hz, 2H, ArCH2), 2.29 (t, J = 7.5 Hz, 0.01H, COCH2, 99% D), 1.90 (t, J = 7.5 Hz, 2H, ArCH2CH2), 1.61 (quin, J = 7.0 Hz, COOCH2CH2), 1.37-1.27 (m, 6H, Alkyl), 0.89 (t, J = 7.0 Hz, 3H, CH2CH3) 13C NMR (125 MHz, CDCl3) δ 173.7, 157.9, 133.5, 129.4, 113.8, 64.5, 55.2, 34.2, 33.1, 31.4, 28.6, 26.7, 25.6, 22.5, 14.0 IR (neat) 2949, 2930, 2857, 1971, 1730, 1611, 1512, 1300, 1244, 1177, 1119, 1036, 829, 557, 521 cm -1 HRMS (DART-MS) m / z: C 17 H 25 D2O 3 (M+H) + Calculated value: 281.2080, measured value: 281.2075.

[0235] (39) Isopropyl 4-(4-methoxyphenyl)butanoate

[0236]

[0237] The substrate used was isopropyl 4-(4-methoxyphenyl)butanoate (compound (39), 50.0 μL, 0.2 mmol). The reaction was carried out at 60°C. 30 mol% TIPSOTf and 60 mol% DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate = 20 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 100%, 50.6 mg).

[0238] 1 H NMR (500 MHz, CDCl3) δ 7.10-7.07 (m, 2H, ArH), 6.84-6.81 (m, 2H, ArH), 5.00 (sep, J = 6.5 Hz, 1H, COOCH), 3.78 (s, 3H, ArOCH3), 2.58 (t, J = 7.5 Hz, 2H, ArCH2), 2.25 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 1.89 (t, J = 7.5 Hz, 2H, ArCH2CH2), 1.22 (d, J = 6.0 Hz, 6H, COOCH(CH3)2) 13C NMR (125 MHz, CDCl3) δ 173.1, 157.9, 133.6, 129.4, 113.8, 67.4, 55.2, 34.2, 33.4, 26.8, 21.9 IR (neat) 2980, 2160, 2012, 1724, 1512, 1466, 1244, 1177, 1107, 1036, 937, 831, 754, 557, 517 cm -1 HRMS (DART-MS) m / z: C 14 H 19 D2O 3 (M+H) + Calculated value: 239.1611, measured value: 239.1607.

[0239] (40) Benzyl 4-(4-methoxyphenyl)butanoate

[0240]

[0241] Benzyl 4-(4-methoxyphenyl)butanoate (compound (40), 53.0 μL, 0.20 mmol) was used as the substrate. 30 mol % TIPSOTf and 60 mol % DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate = 10 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 96%, yield: 90%, 52.0 mg).

[0242] 1 H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H, ArH), 7.05 (d, J = 8.5 Hz, 2H, ArH), 6.81 (d, J = 8.5 Hz, 2H, ArH), 5.10 (s, 2H, COOCH2), 3.76 (s, 3H, ArOCH3), 2.57 (t, J = 7.5 Hz, 2H, ArCH2), 2.34 (t, J = 7.5 Hz, 0.09H, COCH2, 96% D), 1.92 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13C NMR (125 MHz, CDCl3) δ 173.4, 157.9, 136.1, 133.4, 129.4, 128.5, 128.2, 113.8, 66.1, 55.2, 34.1, 33.0, 26.6 IR (neat) 2936, 1730, 1611, 1510, 1454, 1242, 1175, 1113, 1034, 974, 829, 735, 696, 554, 517 cm -1 HRMS (DART-MS) m / z: C 18 H 21 O 3 (M+H) + Calculated value: 287.1611, measured value: 287.1605.

[0243] (41) Phenyl 4-(4-methoxyphenyl)butanoate

[0244]

[0245] Phenyl 4-(4-methoxyphenyl)butanoate (compound (41), 49.0 μL, 0.20 mmol) was used as the substrate. The reaction was carried out at 60°C. 30 mol% TIPSOTf and 60 mol% DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate = 10 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 98%, yield: 98%, 52.9 mg).

[0246] 1 H NMR (500 MHz, CDCl3) δ 7.38-7.34 (m, 2H, ArH), 7.22-7.19 (m, 2H, ArH), 7.13 (d, J = 8.5 Hz, 2H, ArH), 7.05 (d, J = 7.5 Hz, 2H, ArH), 6.84 (d, J = 8.5 Hz, 2H, ArH), 3.78 (s, 3H, ArOCH3), 2.68 (t, J = 7.5 Hz, 2H, ArCH2), 2.54 (t, J = 7.5 Hz, 0.03H, COCH2, 98% D), 2.03 (quin, J = 7.5 Hz, 2H, ArCH2CH2) 13C NMR (125 MHz, CDCl3) δ 172.0, 158.0, 150.7, 133.3, 129.4, 129.4, 125.7, 121.5, 113.9, 55.2, 34.1, 33.0, 26.6 IR (neat) 2936, 2833, 2023, 1753, 1611, 1591, 1510, 1491, 1244, 1194, 1175, 1161, 1096, 1032, 829, 808, 745, 689, 494 cm -1 HRMS (DART-MS) m / z: C 17 H 20 D2NO 3 (M+NH4) + Calculated value: 290.1720, measured value: 290.1719.

[0247] (42) Allyl 4-(4-methoxyphenyl)butanoate

[0248]

[0249] The substrate used was allyl 4-(4-methoxyphenyl)butanoate (compound (42), 45.0 μL, 0.2 mmol). 30 mol % TIPSOTf and 60 mol % DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate = 20 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 98%, yield: 93%, 43.8 mg).

[0250] 1 H NMR (500 MHz, CDCl3) δ 7.10-7.07 (m, 2H, ArH), 6.84-6.81 (m, 2H, ArH), 5.95-5.87 (m, 1H, OCH2CH), 5.33-5.21 (m, 2H, OCH2CHCH2), 4.57-4.56 (m, 2H, COOCH2), 3.77 (s, 3H, ArOCH3), 2.59 (t, J = 7.5 Hz, 2H, ArCH2), 2.32 (t, J = 7.5 Hz, 0.03H, COCH2, 98% D), 1.92 (t, J = 7.5 Hz, 2H, ArCH2CH2) 13C NMR (125 MHz, CDCl3) δ 173.2, 157.9, 133.4, 132.3, 129.4, 118.2, 113.8, 65.0, 55.2, 34.2, 32.9, 26.6 IR (neat) 2936, 2833, 2164, 2081, 2050, 1994, 1730, 1611, 1510, 1242, 1177, 1117, 1034, 986, 932, 831, 517 cm -1 HRMS (DART-MS) m / z: C 14 H 17 D2O 3 (M+H) + Calculated value: 237.11454, measured value: 237.1450.

[0251] (43) Chroman-2-one

[0252]

[0253] Chroman-2-one (compound (43), 25.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate=9 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 98%, yield: 94%, 27.9 mg).

[0254] 1 H NMR (500 MHz, CDCl3) δ 7.27-7.24 (m, 1H, ArH), 7.20 (d, J = 7.0 Hz, 1H, ArH), 7.11-7.08 (m, 1H, ArH), 7.05 (d, J = 8.0 Hz, 1H, ArH), 2.99 (s, 2H, ArCH2) 2.79-2.75 (m, 0.05H, COCH2, 98% D) 13 C NMR (125 MHz, CDCl3) δ 168.6, 152.0, 128.3, 128.0, 124.4, 122.6, 116.9, 28.7, 23.5 IR (neat) 3319, 1763, 1742, 1489, 1458, 1250, 1225, 1150, 1125, 1103, 918, 833, 756, 733, 667, 494, 459 cm-1 HRMS (DART-MS) m / z: C9H7D2O 2 (M+H) + Calculated value: 151.0723, measured value: 151.0720.

[0255] (44) (9Z,12Z)-octadeca-9,12-dienoate ethyl

[0256]

[0257] (9Z,12Z)-octadeca-9,12-dienoate ethyl (compound (44), 70.0 μL, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 20 / 1), the product was obtained (colorless liquid, deuterium substitution rate: 99%, yield: 98%, 61.0 mg).

[0258] 1 H NMR (500 MHz, CDCl3) δ 5.41-5.30 (m, 4H, vinyl), 4.12 (q, J = 7.0 Hz, 2H, COOCH2), 2.77 (t, J = 7.0 Hz, 2H, CH=CHCH2CH=CH), 2.27 (t, J = 7.5 Hz, 0.02H, COCH2, 99% D), 2.07-2.03 (m, 4H, CH=CHCH2CH2), 1.61-1.59 (m, 2H, COCD2CH2), 1.40-1.27 (m, 14H, Alkyl), 1.25 (t, J = 7.5 Hz, 3H, COOCH2CH3) 0.89 (t, J = 7.0 Hz, 3H, CH2CH3) 13 C NMR (125 MHz, CDCl3) δ 173.9, 130.2, 130.1, 128.1, 127.9, 60.1, 33.8, 31.6, 29.6, 29.4, 29.2, 29.1, 29.1, 27.2, 27.2, 25.7, 24.9, 22.6, 14.3, 14.1 IR (neat) 3009, 2957, 2924, 2853, 2149, 1734, 1655, 1647, 1458, 1366, 1260, 1121, 1032, 725 cm -1HRMS (DART-MS) m / z: C 20 H 35 D2O 2 (M+H) + Calculated value: 311.2914, measured value: 311.2912.

[0259] (45) Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoate

[0260]

[0261] Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoate (compound (45), 58.5 mg, 0.20 mmol) was used as the substrate. After silica gel flash chromatography (n-hexane / ethyl acetate = 30 / 1), the product was obtained (white solid, deuterium substitution rate: 94%, yield: 94%, 55.2 mg).

[0262] 1 H NMR (500 MHz, CDCl3) δ 6.99 (s, 2H, ArH), 5.07 (s, 1H, OH), 3.69 (s, 3H, COOCH3), 2.86 (s, 2H, ArCH2), 2.59 (t, J = 7.0 Hz, 0.13H, COCH2, 94% D), 1.43 (s, 18H, C(CH3)3) 13 C NMR (125 MHz, CDCl3) δ 173.7, 152.2, 135.9, 131.1, 124.8, 51.6, 35.9, 34.3, 30.9, 30.3 IR (neat) 3638, 2951, 2872, 1732, 1433, 1362, 1258, 1234, 1211, 1155, 1117, 868, 770, 735, 430 cm -1 HRMS (DART-MS) m / z: C 18 H 30 D2NO3 (M+H) + Calculated value: 312.2502, measured value: 312.2504.

[0263] (46) 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid ethyl ester

[0264]

[0265] The substrate used was 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)ethyl acetate (compound (46), 77.2 mg, 0.20 mmol). The reaction was carried out at 60°C. 30 mol% TIPSOTf and 60 mol% DABCO were used. After silica gel flash chromatography (n-hexane / ethyl acetate = 8 / 1), the product was obtained (light yellow solid, deuterium substitution rate: 99%, yield: 97%, 75.5 mg).

[0266] 1 H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.5 Hz, 2H, ArH), 7.47 (d, J = 8.5 Hz, 2H, ArH), 6.98 (d, J = 2.5 Hz, 1H, ArH), 6.87 (d, J = 9.0 Hz, 1H, ArH), 6.80-6.66 (dd, J = 2.5 Hz, 9.0 Hz, 1H, ArH), 4.16 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.84 (s, 3H, OCH3), 3.63 (s, 0.02H, COCH2, 99% D), 2.38 (s, 3H, CCH3), 1.26 (t, J = 7.0 Hz, 3H, OCH2CH3) 13 C NMR (125 MHz, CDCl3) δ 170.9, 168.3, 156.1, 139.2, 135.9, 134.0, 131.2, 130.8, 130.7, 129.1, 114.9, 112.7, 111.7, 101.4, 61.0, 55.7, 14.3, 13.4 IR (neat) 2994, 2967, 2928, 1724, 1672, 1599, 1510, 1466, 1356, 1263, 1211, 1159, 1148, 1034, 845, 802, 746 600, 482 cm -1HRMS (DART-MS) m / z: C 21 H 18 D2ClNO4 (M+H) + Calculated value: 388.1279, measured value: 388.1286.

[0267] The production method of the present invention is industrially useful because it can produce deuterated amide or ester compounds.

Claims

1. A method for producing a deuterated compound, comprising reacting an amide or ester with a deuterium source in the presence of a Lewis acid selected from a metal triflate and a metal triflyl imide, and a base, to deuterate the α-hydrogen of the amide or ester.

2. The method for producing a deuterated compound according to claim 1, wherein the amide is a compound represented by the following formula (1): (In the formula, R １ ~R ５ each represents a hydrogen atom or an organic group; R １ ~R ３ At least one of R is a hydrogen atom; １ ~R ５ may be linked to each other to form a ring.) 3. The method for producing a deuterated compound according to claim 1, wherein the ester is a compound represented by the following formula (2): (In the formula, X represents an oxygen atom or a sulfur atom, R ６ ~R ９ each represents a hydrogen atom or an organic group; R ６ ~R ８ At least one of R is a hydrogen atom; ６ ~R ９ may be linked to each other to form a ring.) 4. The method for producing a deuterated compound according to claim 1, wherein the metal triflate is a compound selected from the group consisting of silyl triflate, scandium (III) triflate, and hafnium (IV) triflate.

5. The method for producing a deuterated compound according to claim 1, wherein the metal triflate is a trialkylsilyl triflate.

6. The method for producing a deuterated compound according to claim 5, wherein the trialkylsilyl triflate is at least one trialkylsilyl triflate selected from the group consisting of trimethylsilyl triflate, triethylsilyl triflate, triisopropylsilyl triflate, and tert-butyldimethylsilyl triflate.

7. The method for producing a deuterated compound according to claim 1, wherein the metal triflyl imide is silyl triflyl imide.

8. The method for producing a deuterated compound according to claim 1, wherein the base is a tertiary amine.

9. The method for producing a deuterated compound according to claim 8, wherein the tertiary amine is at least one selected from the group consisting of 1-methylpiperidine, triethylamine, quinuclidine, 1,4-diazabicyclo[2.2.2]octane, diazabicycloundecene, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

10. The method for producing a deuterated compound according to claim 1, wherein the deuterium source is at least one selected from the group consisting of acetonitrile-d3, acetone-d6, and chloroform-d.

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