Method for producing deuterated compound

Abstract

To provide a method for producing deuterated compounds of various amides or esters directly and efficiently under mild conditions.SOLUTION: 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, thereby deuterating the α-hydrogen of the amide or ester.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] It has been shown that the introduction of deuterium into pharmaceuticals improves pharmacokinetics by improving metabolic stability, etc. In 2017, deutetonabenazine was approved by the FDA as the world's first deuterium-containing 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 recently attracted attention in drug discovery research.

[0003] In addition, deuterium-labeled compounds can be analyzed by NMR, MS, D-MRI, and Raman dispersion 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, the expansion of the chemical space of deuterium-substituted compounds can be the foundation for innovation in various fields, including drug discovery research and organic synthetic chemistry, and the demand for deuterium-substituted compounds is increasing year by year (see Patent Document 1).

[0004] On the other hand, amides occupy an important position as synthetic elements, and in recent years, the conversion of distorted amides such as amides having electron-withdrawing groups and azetidinamides has been reported, making it possible to convert molecules into a variety of structures. Therefore, it is expected that the development of a simple method for synthesizing deuterated amides will enable the synthesis of various deuterium-substituted molecules. Research on the deuteration of amides and esters has been reported so far (Non-Patent Documents 1 to 3). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2010-195755 A [Non-patent literature]

[0006] [Non-Patent Document 1] 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. [Non-Patent Document 2] 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. [Non-Patent Document 3] Porte, V.; Zhang, H.; Kaiser, D.; Maulide, N. Harnessing ynamide activation to access deuterated carbonyls. Tetrahedron. 2021, 90, 18, 132211. Summary of the Invention [Problem to be solved by the invention]

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

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

[0009] The present inventors have conducted intensive research to enable the direct and efficient synthesis of various deuterated amides and esters under mild conditions, while eliminating the various limitations imposed on conventional methods for producing deuterated amides or esters. 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 a metal triflate and a metal triflyl imide, 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] In the presence of a Lewis acid selected from a metal triflate and a metal triflyl imide, and a base, A method for producing a deuterated compound, comprising reacting an amide or an ester with a deuterium source to deuterate the α-hydrogen of the amide or ester. [2] The method for producing a deuterated compound according to the above [1], wherein the amide is a compound represented by the following formula (1): [ka] (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): [ka] (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] The method for producing a deuterated compound according to any one of the above [1] to [3], 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 any one of the above [1] to [4], wherein the metal triflate is a trialkylsilyl triflate. [6] The method for producing a deuterated compound according to the above [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 any one of the above [1] to [6], wherein the metal triflyl imide is a silyl triflyl imide. [8] The method for producing a deuterated compound according to any one of the above [1] to [7], wherein the base is a tertiary amine. [9] The method for producing a deuterated compound according to the above [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 any one of [1] to [9] above, wherein the deuterium source is at least one selected from acetonitrile-d3, acetone-d6, and chloroform-d. Effect of the Invention

[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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The method for producing a deuterated compound of the present invention is characterized in that an amide or 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 the conventional production methods. In addition, the range of substrates to be selected is wider than that of the conventional production methods, and the α-hydrogen of various amides or esters can be directly deuterated.

[0015] For example, it is possible to directly deuterate amides or esters in the late stages of synthesis (final products or products close to final products) of natural products or pharmaceuticals, which was difficult to do with conventional manufacturing methods, and thus it is possible to efficiently manufacture and develop pharmaceuticals. That is, in conventional methods that can only deuterate amides or esters of specific structures, deuteration can only be performed in the early to middle stages of synthesis of pharmaceuticals, etc., and the yield of the final deuterated compound was low, making it inefficient. However, in the method of the present invention, deuteration can be performed in the late stages of synthesis as described above, so that deuterated compounds can be obtained efficiently, and it is very effective in the manufacture 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, however, the production method of the present invention does not exclude cases in which other hydrogens are deuterated in addition to the α hydrogen.

[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 a metal triflate and a metal triflyl imide (hereinafter sometimes simply referred to as Lewis acid).

[0018] It is preferable to add metal triflate and metal triflyl imide themselves 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 may include a method of adding triisopropylsilyl chloride (TIPSCl) and silver trifluoromethanesulfonate (AgOTf). Also, a mode in which silyl triflyl imide, which is an example of metal triflyl imide, is formed may include a method of adding triisopropylsilyl chloride (TIPSCl) and silver bis(trifluoromethanesulfonyl)imide (AgNTf2).

[0019] Examples of the metal triflate 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. Specifically, the silyl triflate may include trimethylsilyl triflate (TMSOTf), triethylsilyl triflate (TESOTf), triisopropylsilyl triflate (TIPSOTf), tert-butyldimethylsilyl triflate (TBSOTf), and the like, 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] Examples of the silyl triflyl imide include trimethylsilyl triflyl imide (TMSNTf2), triethylsilyl triflyl imide (TESNTf2), triisopropylsilyl triflyl imide (TIPSNTf2), and tert-butyldimethylsilyl triflyl imide (TBSNTf2). Of these, triethylsilyl triflyl imide (TESNTf2), triisopropylsilyl triflyl imide (TIPSNTf2), and tert-butyldimethylsilyl triflyl imide (TBSNTf2) are 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, per 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, per 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 a 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] [ka]

[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 together to form a ring, R 1 ~R 3 or R 4 ~R5 are linked together to form a ring, or R 1 ~R 5 are linked to each other to form a ring.

[0031] The aliphatic group may be any of linear, branched, and cyclic aliphatic groups, and may be either saturated or unsaturated. The aliphatic group may be interrupted by a heteroatom (a heteroatom may exist 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 groups, and alkenyl groups such as vinyl and allyl groups.

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

[0033] Furthermore, it may be a group in which an aliphatic group and an aromatic group are combined, for example, an aralkyl group such as a benzyl group.

[0034] The aliphatic group and aromatic group may have a substituent. 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 or 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] [ka]

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

[0038] [ka]

[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] [ka]

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

[0042] [ka]

[0043] Examples of amides having α-position nitrogen substitution, α-position oxygen substitution, α-position sulfur substitution, etc. include the following compounds.

[0044] [ka]

[0045] Further, for example, the following compounds can be mentioned as amides containing a ketone group or an ester group.

[0046] [ka]

[0047] Further, for example, the following compounds can be mentioned as amides derived from fatty acids.

[0048] [ka]

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

[0050] [ka]

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

[0052] [ka]

[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 R 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] [ka]

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

[0057] The amount of the deuterium source used can be appropriately adjusted, 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 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 small amount of a deuterium source may be used to carry out the reaction multiple times to finally obtain a deuterium compound having a higher deuterium substitution ratio, or a relatively large amount of a deuterium source may be used to carry out the reaction fewer times, such as one or two times, to obtain a deuterium compound having a high deuterium substitution ratio. 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 further preferably about 20 to 60° C. Since the reaction of the present invention proceeds at room temperature, extreme temperature adjustment or pressure adjustment is not required, and the production cost is 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. EXAMPLES

[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) were added to the vial relative to 100 mol% 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. Then, deuterated acetonitrile (acetonitrile-d3), toluene (1.0 M), and 3 mol% TIPSOTf (244 μL) relative to 100 mol% 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. The amount of acetonitrile-d3 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] For the obtained product, 1 HNMR, 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. The NMR measurements were performed using an AvanceIII (Bruker).

[0065] 1 The deuterium substitution rate of α-hydrogen in the product was calculated from the integrated intensity of HNMR. The deuterium substitution rate was 93%. The deuterium substitution rate of α-hydrogen is the ratio of the number of deuterium-substituted α-hydrogens to the total number of α-hydrogens in 4-(4-methoxyphenyl)-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 light hydrogen atoms of α-hydrogen to non-α-hydrogen from the HNMR 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 then weighed again. The product yield (mg) was calculated from the difference in weight. (2) Next, calculate the molecular weight with 0% deuteration and the molecular weight with 100% α-deuteration using chemdraw. 1 The molecular weight was calculated based on the deuteration rate of the substrate using the measured deuteration rate calculated from the HNMR spectrum. (Example of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one: molecular weight of d0: 247.1572, molecular weight of d2: 249.1698, molecular weight at deuteration rate of 93%: 249.1698 x 0.93 + 247.1572 x 0.07 = 249.0289) (3) The yield (mmol) was calculated by dividing the yield (mg) by the calculated molecular weight, and the yield (mmol) was divided by the amount (mmol) of amide or ester (carbonyl compound) added as a substrate to calculate the yield (%). The obtained product 1-d2 weighed 7.44 g, and production on a gram scale was also possible.

[0068] 4-(4-Methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one has 19 hydrogen atoms bonded to carbons other than the α carbon, including the β- and γ-position hydrogens of the carboxyl group (2 each), the hydrogens bonded to the benzene ring (4), the hydrogens bonded to the pyrrolidine ring (8), and the hydrogens bonded to the methyl group (3). 1When the integrated intensity of 1H NMR was examined, deuterium substitution was not observed for hydrogens bonded to carbons other than the α-carbon of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (i.e., it was below the detection limit).

[0069] In all of the following examples, deuterium substitution of hydrogen other than α hydrogen (excluding α hydrogen of carbonyl group and α hydrogen of sulfonyl group) was not observed. 1 This is evident from the fact that the integrated intensities of the peaks of hydrogens other than α-hydrogens in HNMR match within the error range compared to the intensities of each peak before and after deuterium substitution. In addition, as described later, the measured and calculated values ​​of the mass spectrum match well, and the spectrum itself is sharp, so the possibility that deuterium substitution has occurred evenly throughout the molecule is denied.

[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] [ka]

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

[0073] [Example 2] <Deuteration experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one with different base and deuterium source in Example 1> 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 40 mol% DBU (6.0 μL) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stir bar. Then, chloroform-d and 20 mol% TIPSOTf (5.4 μL) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. The amount of chloroform-d used was 96 equivalents (0.20 M) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. After stirring the reaction solution at 70° C. for 15 hours, 1 M hydrochloric acid was added to the reaction solution, which was extracted with CHCl3, and the solvent was distilled off under reduced pressure. The deuterium substitution rate was then determined and was found to be 83%.

[0074] [Example 3] <Deuteration experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one with different metal triflates> 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 40 mol% DBU (6.0 μL) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stirrer. Chloroform-d and 20 mol% of the metal triflate shown in Table 1 relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were then added. The amount of chloroform-d used was 62 equivalents (0.20 M) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one. After stirring the reaction solution at 70°C for 15 hours, ethyl acetate was added to the reaction solution, which was then filtered by short pad filtration, and the solvent was distilled off under reduced pressure. The deuterium substitution rate was then determined. The results are shown in Table 1.

[0075] [Table 1]

[0076] [Example 4] <Deuteration experiments of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one using different types of deuterium sources> 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 40 mol% DBU (6.0 μL) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stirrer. Then, the deuterium source (0.20 M) shown in Table 2 and 20 mol% TIPSOTf (5.4 μL) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. After stirring the reaction solution at 70°C for 15 hours, 1 M hydrochloric acid was added to the reaction solution, which was extracted with CHCl3, and the solvent was distilled off under reduced pressure. The deuterium substitution rate was then determined. The results are shown in Table 2.

[0077] [Table 2]

[0078] [Example 5] <Deuteration experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one with different bases> Specifically, 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol) and 20 mol% of the base shown in Table 3 relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added to a 4 mL vial containing a stirrer. Then, acetonitrile-d3 and 10 mol% of TIPSOTf (2.7 μL) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. The amount of acetonitrile-d3 used 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, 1 M hydrochloric acid was added to the reaction solution, which was extracted with CHCl3, and the solvent was distilled off under reduced pressure. The deuterium substitution rate was then determined. The results are shown in Table 3.

[0079] [Table 3]

[0080] [Example 6] <Deuteration experiment of 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one with different Lewis acids (silicon counter anions)> In a 4 mL vial containing a stirrer, 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one (0.10 mmol), 20 mol % DABCO (2.2 mg) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one, and 10 mol % of the additives shown in Table 4 were added. Then, acetonitrile-d3 and 10 mol % TIPSCl (2.1 μL) relative to 4-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)butan-1-one were added. The amount of acetonitrile-d3 used 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 by short pad filtration, and the solvent was distilled off under reduced pressure. The deuterium substitution rate was then determined. The results are shown in Table 4.

[0081] [Table 4]

[0082] [Example 7] Below, we carried out deuterium substitution experiments (1)-(46) 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). Furthermore, unless otherwise specified, the amount of acetonitrile-d3 used is 96 equivalents (0.20 M) relative to the amide or ester when no cosolvent is used. Unless otherwise specified, the reaction solution in each experiment was stirred at 25° C. for 48 hours to carry out the reaction. Unless otherwise stated, 1 HNMR and 13 CNMR peak positions are expressed in ppm, and IR peak positions are expressed in cm. ‐1 Also, 1 The chemical shifts of HNMR were based on the non-deuterated peak in the deuterated solvent: when CDCl3 was used as the deuterated solvent, the H peak of CHCl3 (δ 7.26 ppm) was used, and when methanol was used as the deuterated solvent, the hydrogen peak of the methyl group (δ 3.31 ppm) was used. 13 The peak of the deuterated solvent was used as the reference for the chemical shifts in CNMR.

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

[0084] [ka]

[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] 1H 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 -1 HRMS (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] [ka]

[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 H 18 D2NO2(M+H) + Calculated value: 236.1614, Measured value: 236.1615.

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

[0092] [ka]

[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: C 16 H 22 D2NO2(M+H) + Calculated value: 264.1927, measured value: 264.1931.

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

[0096] [ka]

[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: C 17 H 24 D2NO2(M+H) + Calculated value: 278.2084, measured value: 276.2088.

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

[0100] [ka]

[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: C13 H 18 D2NO2(M+H) + Calculated value: 224.1614, Measured value: 224.1615.

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

[0104] [ka]

[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 D2NO2(M+H) + Calculated value: 300.1927, measured value: 300.1933.

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

[0108] [ka]

[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 D2NO2(M+H) + Calculated value: 276.1927, measured value: 276.1931.

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

[0112] [ka]

[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] 1 H 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 D2NO2(M+H) + Calculated value: 286.177, Measured value: 286.1773.

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

[0116] [ka]

[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] 1 H 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 D2NO3(M+H) + Calculated value: 266.1720, Measured value: 266.1722.

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

[0120] [ka]

[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] 1 H 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] [ka]

[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] 1 H 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 (NEAT) 2928, 2149, 1626, 1510, 1456, 1420, 1285, 1242, 1175, 1030, 1003, 833, 787, 731, 708, 523 cm -1 HRMS (DART-MS) m / z:C 22 H 25 D2N2O3(M+H) + Calculated value: 369.2142, Measured value: 369.2144.

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

[0128] [ka]

[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] 1 H 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); 13C 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 D2NO2(M+H) + Calculated value: 286.1771, Measured value: 286.1777.

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

[0132] [ka]

[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 (ニート) 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 D2NO2(M+H) + について calculated value: 272.1614, measured value: 2721616.

[0135] (14)4-(4-メトキシフェニル)ブタンアミド

[0136]

change

[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 h. The product was obtained after silica gel flash chromatography (CH2Cl2 / MeOH=97 / 3) (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 D2NO2(M+H) + Calculated value: 196.1301, Measured value: 196.1305.

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

[0140] [ka]

[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] 1 H 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] [ka]

[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. After silica gel flash chromatography (CH2Cl2 / MeOH=30 / 1), the product was obtained (brown solid, deuterium substitution rate: 98%, yield: 101%, 46.3 mg).

[0146] 1 H 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] [ka]

[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] [ka]

[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) 13C NMR (125 MHz, CDCl3) δ167.7, 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 DN2O3(M+H) + Calculated value: 274.1296, measured value: 274.1305.

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

[0156] [ka]

[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 D2Cl2NO2(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] [ka]

[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] 1H 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] [ka]

[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%, 47.6mg)

[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 D4NO2(M+H) + Calculated value: 250.1740, measured value: 250.1726.

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

[0168] [ka]

[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 D4NO3(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] [ka]

[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) 13C 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:C 22 H 38 D2NO (M+H) + Calculated value: 336.3230, Measured value: 336.3230.

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

[0176] [ka]

[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) 13C 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] [ka]

[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) 13C 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 D2NO3(M+H) + Calculated value: 222.1094, measured value 222.1094.

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

[0184] [ka]

[0185] 2-(4-Chlorophenyl)-3-methyl-1,3-thiazinane-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%, 46.8mg)

[0186] 1H 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] [ka]

[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). After silica gel flash chromatography (CH2Cl2 / 2MNH3inMeOH=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] [ka]

[0193] The substrate used 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 the co-solvent. After silica gel flash chromatography (CH2Cl2 / MeOH / NEt3=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, IR (No.) 2855, 2833, 2166, 1979, 1651, 1497, 1445, 1402, 1281, 1207, 1117, 746, 420 cm -1 HRMS (DART-MS) m / z:C 23 H 25 D2N2O4(M+H) + Note: 397.2091.

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

[0196] [ka]

[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:C13 H 14 D3N2O2(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] [ka]

[0201] The substrate used was (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). 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) 13C 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] [ka]

[0205] The substrate 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. After silica gel flash chromatography (CH2Cl2 / MeOH=30 / 1), the product was obtained (white solid, deuterium substitution rate: 98%, yield: 94%, 100.3 mg).

[0206] 11H 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 13C 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 D3Cl2N4O4(M + H) + Calculated for: 534.1749, Found: 534.1760.

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

[0208] [ka]

[0209] 7-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (compound (32), 89.7 mg, 0.20 mmol) was used as the substrate, and chlorobenzene (1.0 mL) was used as the co-solvent. 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 (CH2Cl2 / MeOH=30 / 1), the product was obtained (white solid, deuterium substitution rate: 99%, yield: 94%, 84.5 mg).

[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) 13C 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 (NEAT) 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 D2Cl2N3O2(M+NH4) + 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] [ka]

[0213] 2-(1,3-dioxoindolin-2-yl)-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)acetamide (compound (33), 63.1 mg, 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 (CH2Cl2 / MeOH=30 / 1), the product was obtained (white solid, D a : Deuterium substitution rate 98%, D b Deuterium substitution rate: 98%, yield: 97%, 62.2mg)

[0214] 1H 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 (ニート) 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 H 14 D4N3O4(M+NH4) + について calculated value: 320.1543, measured value: 320.1541.

[0215] (34)N-(4-ヒドロキシフェニル)アセトアミド

[0216]

change

[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] [ka]

[0221] The substrate used was (E)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnona-6-enamide (compound (35), 61.1 mg, 0.20 mmol, 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) 13 C 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] [ka]

[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, CDCl3) 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 D2O3(M+H) + Calculated value: 211.1298, Measured value: 211.1297.

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

[0228] [ka]

[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 D2O3(M+H) + Calculated value: 225.1454, Measured value: 225.1457.

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

[0232] [ka]

[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] 1H 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) 13 C 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 D2O3(M+H) + Calculated value: 281.2080, measured value: 281.2075.

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

[0236] [ka]

[0237] Isopropyl 4-(4-methoxyphenyl)butanoate (compound (39), 50.0 μL, 0.2 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=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) 13 C 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 D2O3(M+H) + Calculated value: 239.1611, Measured value: 239.1607.

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

[0240] [ka]

[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) 13 C 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 O3(M+H) + Calculated value: 287.1611, Measured value: 287.1605.

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

[0244] [ka]

[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) 13 C 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 D2NO3(M+NH4) +Calculated value: 290.1720, measured value: 290.1719.

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

[0248] [ka]

[0249] Allyl 4-(4-methoxyphenyl)butanoate (compound (42), 45.0 μL, 0.2 mmol) was used as the substrate. 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) 13 C 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 D2O3(M+H) + Calculated value: 237.11454, Measured value: 237.1450.

[0251] (43) Chroman-2-one

[0252] [ka]

[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:C9H7D2O2(M+H) + Calculated value: 151.0723, Measured value: 151.0720.

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

[0256] [ka]

[0257] (9Z,12Z)-Ethyl octadeca-9,12-dienoate (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 -1 HRMS (DART-MS) m / z:C 20 H 35 D2O2(M+H) + Calculated value: 311.2914, Measured value: 311.2912.

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

[0260] [ka]

[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 30D2NO3(M+H) + Calculated value: 312.2502, measured value: 312.2504.

[0263] (46) Ethyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

[0264] [ka]

[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) 13C 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 -1 HRMS (DART-MS) m / z:C 21 H 18 D2ClNO4(M+H) + Calculated value: 388.1279, Measured value: 388.1286. [Industrial Applicability]

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

Claims

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

2. 2. The method for producing a deuterated compound according to claim 1, wherein the amide is a compound represented by the following formula (1): 【Chemistry 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. 2. The method for producing a deuterated compound according to claim 1, wherein the ester is a compound represented by the following formula (2): 【Chemistry 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. 2. 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. 2. The method for producing a deuterated compound according to claim 1, wherein the metal triflate is a trialkylsilyl triflate.

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

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

9. 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. 2. 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.

Images