Application of Se-deuterated methylation or Se-13C methylation reagent

Abstract

The invention discloses an application of a Se-deuterated methylation or Se-13C methylation reagent, a compound shown in a formula (1) is placed in an organic solvent and reacts with a Se-deuterated methylation reagent shown in a formula (2) in an alkaline environment to obtain a Se-deuterated methylation compound shown in a formula (3), the reaction process is as follows: # imgabs0 #, A is CD3 or 13CH3, X is selected from halogen, OMs or OTs, and X is selected from halogen, OMs or OTs. R1 is selected from aromatic alkyl, phenylalkyl, phenylalkynyl, naphthyl methyl, substituted phenyl, adamantyl, 2-(2, 4-difluorophenyl)-1, 2, 4-triazolo [3, 4- The compound is selected from the group consisting of 2, 3-dihydrobenzofuran) ethyl, 2-indolyl ethyl, mono-substituted or poly-substituted phenoxyethyl, phenoxypropyl, mono-substituted or poly-substituted phenoxybutyl, mono-substituted thiophenyl ethyl, poly-substituted thiophenyl butyl, poly-substituted cyclopentyldioxacyclopentyl or a halogen alkyl group derived from D-glucose, vitamin E, estradiol or phenacetin, or a halogen alkyl group derived from D-glucose, vitamin E, estradiol or phenacetin, or a halogen alkyl group derived from D-glucose, vitamin E, or a halogen alkyl group derived from D-glucose, vitamin E, or a halogen alkyl group derived from D-glucose, vitamin E, or a halogen alkyl group derived from D-glucose; r2 is selected from substituted phenyl, benzyloxy or polysubstituted alkoxy. The method is mild in reaction condition, economical, practical and environment-friendly; the efficiency is high after reaction amplification.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a Se-deuterated methylation or Se- 13 Application of C methylating agents. Background Art

[0002] As the simplest functional group, methyl is commonly found in many natural products and drugs, and plays a vital role in improving the physical properties and biological activities of compounds. Natural products containing selenomethyl structures account for a large proportion and have extensive medicinal potential and other applications. Among them, there are L-selenomethionine with anticancer and antioxidant activities, allicin with anticancer activity, nutritional enhancer L-selenomethylselenocysteine, human bioactive metabolite MeSeGalNAc, and compound 5 with antitumor activity and compound 6 with anticancer and antioxidant activities.

[0003]

[0004] In addition, deuterium atoms, as bioisosteres of hydrogen atoms, can be used as tracer atoms to study the metabolic pathways of drugs in the human body. Since the bond dissociation energy of the carbon-deuterium bond is higher than the dissociation energy of the carbon-hydrogen bond, the introduction of deuterium atoms to replace hydrogen atoms at the metabolic sites of some drugs may have a significant effect on their pharmacokinetic properties. In the past few decades, a variety of deuterated drug candidates have entered the clinical trial stage. In 2017, the FDA approved the marketing of the first deuterated drug, Antaetan. In addition to its use in medicinal chemistry, deuterium-labeled compounds are widely used as a tool in the study of the mechanism of chemical reactions and the identification of products. In view of the importance of deuterated compounds, it is very necessary to develop a practical and versatile preparation method.

[0005]

[0006] In summary, the deuterated selenomethyl structure with a selenomethyl skeleton and deuterium hydrogen is a group with certain drug potential. Due to the presence of deuterium atoms, and for molecules containing selenomethyl deuterides, the difficulty and challenge in this field is to obtain an excellent deuteration rate (>99%) while preparing such compounds in high yield. At present, only deuterated thiomethyl reagents have been studied more. The synthesis of organic molecules containing thiomethyl deuterides is mainly through the reaction of highly toxic and foul-smelling thiophenol or thiol substrates with electrophilic deuterated methylation. This strategy often requires special substrates and has poor functional group compatibility. At the same time, the lack of deuterated methylation reagents also restricts the further application of this method (Wang, MY; Zhao, YF; Zhao.Y.; Shi, ZZ Science Adv, 2020, 6, 1-7). The direct thiomethyl deuteration method overcomes the above shortcomings, and the universality of the substrate is greatly enhanced. In this strategy, the development and application of nucleophilic deuterated thiomethylation reagents is an effective method. However, in the prior art, the traditional method for constructing a deuterated selenomethyl skeleton in a drug structure is mainly to introduce deuterated selenomethyl through DMSO-d6, which requires the use of a large amount of deuterated reagents as substrates or solvents, which is costly and limits its application on an industrial scale. Summary of the invention

[0007] The present invention overcomes many shortcomings of the traditional reaction for constructing deuterated selenomethyl skeletons, and innovatively develops a deuterated selenomethyl or Se- 13 Application of C methylating agents. They have the characteristics of wide substrate universality and high reactivity in nucleophilic coupling reactions and Michael addition reactions.

[0008] A Se-deuterated methyl or Se- 13 The application of C methylation reagent includes the following steps:

[0009] The compound represented by formula (1) is placed in an organic solvent and reacted with Se-deuterated methyl or Se- 13 C methylation reagent reacts in an alkaline environment to obtain Se-deuterated methylated compound or Se- 13 C methylation compound, the reaction process is as follows:

[0010]

[0011] Where A is CD3 or 13 CH3, X is selected from halogen, OMs or OTs, R 1R is selected from aromatic alkyl, phenylpropenyl, phenylpropynyl, naphthylmethyl, substituted phenyl, adamantyl, 2-(2,3-dihydrobenzofuran)ethyl, 2-indoleethyl, mono- or poly-substituted phenoxyethyl, phenoxypropyl, mono- or poly-substituted phenoxybutyl, mono-substituted phenylthioethyl, poly-substituted phenylthiobutyl, poly-substituted cyclopentadioxolyl or halogen alkyl derived from D-glucose, vitamin E, estradiol or phenacetin; 2 Selected from substituted phenyl, benzyloxy or polysubstituted alkoxy.

[0012] Furthermore, the base is DBU, DABCO, cesium carbonate or potassium carbonate, and the amount of the base used is 0.5-5.0 equivalents of the substrate represented by formula (1).

[0013] Furthermore, the organic solvent is methanol or THF, and the concentration of the substrate represented by formula (1) in the organic solvent is 0.1-1.0M.

[0014] Furthermore, the molar ratio of the compound represented by formula (1) to the Se-deuterated methylation agent represented by formula (2) is 1.0:1.0-1.0:5.0.

[0015] Furthermore, the reaction temperature is 20-100°C.

[0016] Furthermore, the reaction time is 1-24h.

[0017] The Se-deuterated methylated compound represented by formula (4) is placed in an organic solvent, and reacted with the meta-chloroperbenzoic acid represented by formula (5) in the organic solvent to obtain the selenosulfoxide compound represented by formula (6). The reaction process is as follows:

[0018]

[0019] R 1 The group is selected from aromatic alkyl, phenylpropenyl, phenylpropynyl, naphthylmethyl, substituted phenyl, adamantyl, 2-(2,3-dihydrobenzofuran)ethyl, 2-indoleethyl, mono-substituted or poly-substituted phenoxyethyl, phenoxypropyl, mono-substituted or poly-substituted phenoxybutyl, mono-substituted phenylthioethyl, poly-substituted phenylthiobutyl, poly-substituted cyclopentadioxolyl or halogen alkyl derived from D-glucose, vitamin E, estradiol or phenacetin.

[0020] Furthermore, the amount of m-chloroperbenzoic acid used is 2.0 equivalents of the compound (4).

[0021] Furthermore, the organic solvent used is dichloromethane, and the concentration of the substrate represented by formula (4) in the organic solvent is 0.1M.

[0022] Furthermore, the reaction temperature is -40°C and the reaction time is 1 hour.

[0023] The beneficial effects of the present invention are:

[0024] 1) Using Se-deuterated methylation or Se- 13 C methylation reagent, without nitrogen protection and water removal, can react with easily prepared halogenated hydrocarbon substrates in one pot, overcoming the previous unfavorable conditions such as harsh reaction conditions and the need to use a large amount of deuterium source, and developing a more efficient, green and convenient application of deuterated selenium methylation reagent;

[0025] 2) Using Se-deuterated methylation or Se- 13 C methylation reagent, without nitrogen protection and water removal, reacts with easily available α,β-unsaturated ketones in one pot to complete the Michael addition reaction to prepare selenide deuterated methyl compounds in high yield;

[0026] 3) The compound preparation of the present invention realizes a gram-scale reaction, is practical, has broad application prospects, and is suitable for industrial-scale production;

[0027] 4) The present invention has high reaction efficiency, high yield, simple and stable preparation, no irritating odor, and mild reaction conditions. DETAILED DESCRIPTION

[0028] The present invention is further described in detail below in conjunction with the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include specific operations and reaction conditions and products. The purity of the product is identified by nuclear magnetic resonance.

[0029] A Se-deuterated methyl or Se- 13 Application of C methylation reagent, the reaction process is as follows:

[0030]

[0031] Example 1

[0032] Synthesis of (methyl-d3)(3-phenylpropyl)selenane:

[0033]

[0034] 1-Chloro-3-phenylpropane (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to the Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3a (yield 51%, deuterated rate> 99%).

[0035] 1 H NMR (400MHz, CDCl3) δ7.28(q,J=5.7,3.8Hz,2H),7.19(d,J=7.9Hz,3H),2.60(dt,J=31.7,6.4Hz,4H),1.80-1.66(m,4H). 13 C NMR (100MHz, CDCl3) δ142.3,128.5,128.4,125.8,35.5,31.6,29.8,25.2.

[0036] Example 2

[0037] Synthesis of (methyl-d3)(3-phenylpropyl)selenane:

[0038]

[0039] Except for using 1-bromo-3-phenylpropane instead of 1-chloro-3-phenylpropane, the other steps were the same as in Example 1, and the product 3a was purified by column chromatography (yield 76%, deuteration rate>99%).

[0040] 1 H NMR (400MHz, CDCl3) δ7.28(q,J=5.7,3.8Hz,2H),7.19(d,J=7.9Hz,3H),2.60(dt,J=31.7,6.4Hz,4H),1.80-1.66(m,4H). 13 C NMR (100MHz, CDCl3) δ142.3,128.5,128.4,125.8,35.5,31.6,29.8,25.2.

[0041] Example 3

[0042] Synthesis of (methyl-d3)(3-phenylpropyl)selenane:

[0043]

[0044] Except for using 1-iodo-3-phenylpropane instead of 1-chloro-3-phenylpropane, the remaining steps were the same as in Example 1, and the product 3a was purified by column chromatography (yield 81%, deuteration rate>99%).

[0045] 1 H NMR (400MHz, CDCl3) δ7.28(q,J=5.7,3.8Hz,2H),7.19(d,J=7.9Hz,3H),2.60(dt,J=31.7,6.4Hz,4H),1.80-1.66(m,4H). 13 C NMR (100MHz, CDCl3) δ142.3,128.5,128.4,125.8,35.5,31.6,29.8,25.2.

[0046] Example 4

[0047] Synthesis of (methyl-d3)(3-phenylpropyl)selenane:

[0048]

[0049] Except for using 1-OTs-3-phenylpropane instead of 1-chloro-3-phenylpropane, the other steps were the same as in Example 1, and the product 3a was purified by column chromatography (yield 63%, deuteration rate>99%).

[0050] 1 H NMR (400MHz, CDCl3) δ7.28(q,J=5.7,3.8Hz,2H),7.19(d,J=7.9Hz,3H),2.60(dt,J=31.7,6.4Hz,4H),1.80-1.66(m,4H). 13 C NMR (100MHz, CDCl3) δ142.3,128.5,128.4,125.8,35.5,31.6,29.8,25.2.

[0051] Example 5

[0052] Synthesis of (methyl-d3)(3-phenylpropyl)selenane:

[0053]

[0054] Except for using 1-OMs-3-phenylpropane instead of 1-chloro-3-phenylpropane, the other steps were the same as in Example 1, and the product 3a was purified by column chromatography (yield 65%, deuteration rate>99%).

[0055] 1H NMR (400MHz, CDCl3) δ7.28(q,J=5.7,3.8Hz,2H),7.19(d,J=7.9Hz,3H),2.60(dt,J=31.7,6.4Hz,4H),1.80-1.66(m,4H). 13 C NMR (100MHz, CDCl3) δ142.3,128.5,128.4,125.8,35.5,31.6,29.8,25.2.

[0056] Example 6

[0057] Synthesis of cinnamyl (methyl-d3) selenane:

[0058]

[0059] Cinnamyl chloride (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain product 3b (yield 87%, deuterated rate> 99%).

[0060] 1 H NMR (400MHz, CDCl3) δ7.39(dd,J=8.4,1.4Hz,2H),7.32(dd,J=8.4,6.8Hz,2H),7.26-7.20(m,1H),6.42-6.21(m,2H),3.32(d,J=7.4Hz,2H). 13 C NMR (100MHz, CDCl3) δ136.7,131.3,128.5,127.4,126.3,126.2,26.6.

[0061] Example 7

[0062] Synthesis of cinnamyl (methyl-d3) selenane:

[0063]

[0064] Except for using cinnamyl bromide instead of cinnamyl chloride, the remaining steps were the same as in Example 6, and the product 3b was purified by column chromatography (yield 91%, deuteration rate>99%).

[0065] 1H NMR (400MHz, CDCl3) δ7.39(dd,J=8.4,1.4Hz,2H),7.32(dd,J=8.4,6.8Hz,2H),7.26-7.20(m,1H),6.42-6.21(m,2H),3.32(d,J=7.4Hz,2H). 13 C NMR (100MHz, CDCl3) δ136.7,131.3,128.5,127.4,126.3,126.2,26.6.

[0066] Example 8

[0067] Synthesis of cinnamyl (methyl-d3) selenane:

[0068]

[0069] Except for using 1-cinnamyloxysulfonyl-4-methylbenzene instead of cinnamyl chloride, the remaining steps were the same as in Example 6, and the product 3b was purified by column chromatography (yield 87%, deuteration rate>99%).

[0070] 1 H NMR (400MHz, CDCl3) δ7.39(dd,J=8.4,1.4Hz,2H),7.32(dd,J=8.4,6.8Hz,2H),7.26-7.20(m,1H),6.42-6.21(m,2H),3.32(d,J=7.4Hz,2H). 13 C NMR (100MHz, CDCl3) δ136.7,131.3,128.5,127.4,126.3,126.2,26.6.

[0071] Example 9

[0072] Synthesis of cinnamyl (methyl-d3) selenane:

[0073]

[0074] Except for using 3-phenyl-1-propene-1-methanesulfonate instead of cinnamyl chloride, the remaining steps were the same as in Example 6, and the product 3b was purified by column chromatography (yield 80%, deuteration rate>99%).

[0075] 1 H NMR (400MHz, CDCl3) δ7.39(dd,J=8.4,1.4Hz,2H),7.32(dd,J=8.4,6.8Hz,2H),7.26-7.20(m,1H),6.42-6.21(m,2H),3.32(d,J=7.4Hz,2H).13 C NMR (100MHz, CDCl3) δ136.7,131.3,128.5,127.4,126.3,126.2,26.6.

[0076] Example 10

[0077] Synthesis of (methyl-d3)(3-phenyl-2-propyn-1-yl)selenane:

[0078]

[0079] 1-Phenyl-3-chloro-1-propyne (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3c (yield 80%, deuterated rate> 99%).

[0080] 1 H NMR (400MHz, CDCl3) δ7.46-7.39 (m, 2H), 7.30 (dp, J = 4.8, 1.7Hz, 3H), 3.43 (s, 2H). 13 C NMR (100MHz, CDCl3) δ131.8,128.4,128.2,123.4,86.3,83.3,9.3.

[0081] Embodiment 11

[0082] Synthesis of (methyl-d3)(3-phenyl-2-propyn-1-yl)selenane:

[0083]

[0084] Except for using 1-phenyl-3-bromo-1-propyne instead of 1-phenyl-3-chloro-1-propyne, the remaining steps were the same as Example 10, and the product 3c was purified by column chromatography (yield 95%, deuteration rate>99%).

[0085] 1 H NMR (400MHz, CDCl3) δ7.46-7.39 (m, 2H), 7.30 (dp, J = 4.8, 1.7Hz, 3H), 3.43 (s, 2H). 13C NMR (100MHz, CDCl3) δ131.8,128.4,128.2,123.4,86.3,83.3,9.3.

[0086] Example 12

[0087] Synthesis of (methyl-d3)(3-phenyl-2-propyn-1-yl)selenane:

[0088]

[0089] Except for using 1-(p-toluenesulfonyloxy)-3-phenyl-2-propyne instead of 1-phenyl-3-chloro-1-propyne, the remaining steps were the same as Example 10, and the product 3c was purified by column chromatography (yield 85%, deuteration rate>99%).

[0090] 1 H NMR (400MHz, CDCl3) δ7.46-7.39 (m, 2H), 7.30 (dp, J = 4.8, 1.7Hz, 3H), 3.43 (s, 2H). 13 C NMR (100MHz, CDCl3) δ131.8,128.4,128.2,123.4,86.3,83.3,9.3.

[0091] Example 13

[0092] Synthesis of (methyl-d3)(3-phenyl-2-propyn-1-yl)selenane:

[0093]

[0094] Except for using 3-phenyl-2-propyn-1-ol methanesulfonate instead of 1-phenyl-3-chloro-1-propyne, the remaining steps were the same as Example 10, and the product 3c was purified by column chromatography (yield 82%, deuteration rate>99%).

[0095] 1 H NMR (400MHz, CDCl3) δ7.46-7.39 (m, 2H), 7.30 (dp, J = 4.8, 1.7Hz, 3H), 3.43 (s, 2H). 13 C NMR (100MHz, CDCl3) δ131.8,128.4,128.2,123.4,86.3,83.3,9.3.

[0096] Embodiment 14

[0097] Synthesis of (methyl-d3)(naphthalen-2-ylmethyl)selenane:

[0098]

[0099] 2-(Chloromethyl)naphthalene (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to a Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain product 3d (yield 81%, deuterated rate>99%).

[0100] 1 H NMR (400MHz, CDCl3) δ7.81 (dt, J = 9.2, 5.1Hz, 3H), 7.66 (d, J = 1.8Hz, 1H), 7.54-7.40 (m, 3H), 3.90 (s, 2H). 13 C NMR (100MHz, CDCl3) δ136.7,133.3,132.4,128.5,127.8,127.7,127.4,127.0,126.3,125.77,28.6.

[0101] Embodiment 15

[0102] Synthesis of (methyl-d3)(naphthalen-2-ylmethyl)selenane:

[0103]

[0104] Except for using 2-(bromomethyl)naphthalene instead of 2-(chloromethyl)naphthalene, the remaining steps were the same as Example 14, and the product 3d was purified by column chromatography (yield 82%, deuteration rate>99%).

[0105] 1 H NMR (400MHz, CDCl3) δ7.81 (dt, J = 9.2, 5.1Hz, 3H), 7.66 (d, J = 1.8Hz, 1H), 7.54-7.40 (m, 3H), 3.90 (s, 2H). 13 C NMR (100MHz, CDCl3) δ136.7,133.3,132.4,128.5,127.8,127.7,127.4,127.0,126.3,125.77,28.6.

[0106] Example 16

[0107] Synthesis of (methyl-d3)(naphthalen-2-ylmethyl)selenane:

[0108]

[0109] Except for using 2-naphthalenemethanol-2-toluenesulfonate instead of 2-(chloromethyl)naphthalene, the remaining steps were the same as Example 14, and the product 3d was purified by column chromatography (yield 78%, deuteration rate>99%).

[0110] 1 H NMR (400MHz, CDCl3) δ7.81 (dt, J = 9.2, 5.1Hz, 3H), 7.66 (d, J = 1.8Hz, 1H), 7.54-7.40 (m, 3H), 3.90 (s, 2H). 13 C NMR (100MHz, CDCl3) δ136.7,133.3,132.4,128.5,127.8,127.7,127.4,127.0,126.3,125.77,28.6.

[0111] Embodiment 17

[0112] Synthesis of (methyl-d3)(naphthalen-2-ylmethyl)selenane:

[0113]

[0114] Except for using 2-naphthalenemethanol-2-methanesulfonate instead of 2-(chloromethyl)naphthalene, the remaining steps were the same as Example 14, and the product 3d was purified by column chromatography (yield 70%, deuteration rate>99%).

[0115] 1 H NMR (400MHz, CDCl3) δ7.81 (dt, J = 9.2, 5.1Hz, 3H), 7.66 (d, J = 1.8Hz, 1H), 7.54-7.40 (m, 3H), 3.90 (s, 2H). 13 C NMR (100MHz, CDCl3) δ136.7,133.3,132.4,128.5,127.8,127.7,127.4,127.0,126.3,125.77,28.6.

[0116] Embodiment 18

[0117] Synthesis of methyl 4-(((methyl-d3)selenoalkyl)methyl)benzoate:

[0118]

[0119] Methyl 4-bromomethylbenzoate (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3e (yield 85%, deuterated rate> 99%).

[0120] 1 H NMR (400MHz, CDCl3) δ7.90 (d, J = 8.3Hz, 2H), 7.26 (d, J = 8.3Hz, 2H), 3.83 (s, 3H), 3.68 (s, 2H). 13 C NMR (100MHz, CDCl3) δ166.8,144.8,129.8,128.8,128.4,52.0,27.6.

[0121] Embodiment 19

[0122] Synthesis of ((3S,5S,7S)-adamantan-1-yl)(methyl-d3)selenane:

[0123]

[0124] 1-Bromoadamantane (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3f (yield 74%, deuterated rate> 99%).

[0125] 1 H NMR (400MHz, CDCl3) δ2.36 (d, J = 2.9Hz, 6H), 2.10 (t, J = 3.9Hz, 3H), 1.72 (t, J = 3.1Hz, 6H). 13 C NMR (100MHz, CDCl3) δ66.9, 49.3, 35.5, 32.6.

[0126] Embodiment 20

[0127] Synthesis of 5-(2-((methyl-d3)selenoalkyl)ethyl)-2,3-dihydrobenzofuran:

[0128]

[0129] 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to the Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate, and the organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 3 g of the product (yield 73%, deuterated rate> 99%).

[0130] 1 H NMR(400MHz, CDCl3) δ7.04(d,J=1.9Hz,2H),6.94(dd,J=8.1,2.0Hz,2H),6.71(d,J=8.1Hz ,2H),4.55(t,J=8.7Hz,4H),3.19(t,J=8.7Hz,4H),2.93-2.86(m,4H),2.78-2.70(m,4H). 13 C NMR (100MHz, CDCl3) δ158.6,133.3,127.8,127.1,124.9,124.8,109.0,71.2,36.2,29.7,26.9.

[0131] Embodiment 21

[0132] Synthesis of 3-(2-((methyl-d3)selenoalkyl)ethyl)-1H-indole:

[0133]

[0134] 3-(2-bromoethyl)indole (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to the Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate, and the organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3h (yield 90%, deuterated rate>99%).

[0135] 1 H NMR (400MHz, CDCl3) δ7.97(s,1H),7.62(d,J=7.8Hz,1H),7.37(d,J=8.1Hz,1H),7.25-7.18(m,1 H),7.18-7.11(m,1H),7.05(d,J=2.3Hz,1H),3.16(t,J=7.9Hz,2H),2.90(dd,J=8.6,7.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ136.4,127.2,122.2,121.6,121.6,119.4,118.8,115.9,111.3,26.6,25.7.

[0136] Embodiment 22

[0137] Synthesis of (methyl-d3)(2-phenoxyethyl)selenane:

[0138]

[0139] 2-Phenoxyethyl bromide (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to the Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate, and the organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3i (yield 85%, deuterated rate>99%). 1H NMR (400MHz, CDCl3) δ7.33-7.26(m,2H),6.96(tt,J=7.3,1.1Hz,1H),6.93-6.86(m,2H),4.22(t,J=7.1Hz,2H),2.89(t,J=7.1Hz,2H); 13 C NMR (100MHz, CDCl3) δ158.5,129.6,121.1,114.7,68.2,23.4.

[0140] Embodiment 23

[0141] Synthesis of (methyl-d3)(3-phenoxypropyl)selenane:

[0142]

[0143] 2-Phenoxypropyl bromide (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain product 3j (yield 76%, deuterated rate> 99%).

[0144] 1 H NMR (400MHz, CDCl3) δ7.34 (d, J = 3.1Hz, 4H), 7.31-7.25 (m, 1H), 4.51 (s, 2H), 3. 56(t,J=6.2Hz,2H), 2.64(t,J=7.3Hz,2H), 1.97(ddd,J=13.5,7.5,6.2Hz,2H). 13 C NMR (100MHz, CDCl3) δ138.5,128.5,127.8,127.7,73.1,69.7,30.4,21.9.

[0145] Embodiment 24

[0146] Synthesis of (methyl-d3)(4-(naphthalen-1-ylmethoxy)butyl)selenane:

[0147]

[0148] 1-Naphthylmethyl-4-bromobutyl ether (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to the Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate, and the organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3k (yield 81%, deuterated rate>99%).

[0149] 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.7Hz,1H),7.88(dd,J=7.9,1.6Hz,1H),7.85-7.75(m,1H),7.58-7.49(m,3H ),7.48-7.42(m,1H),4.96(s,2H),3.58(t,J=5.7Hz,2H),2.53(t,J=6.8Hz,2H),1.76(dd,J=6.6,3.5Hz,4H). 13 C NMR (100MHz, CDCl3) δ134.0,133.8,131.8,128.6,128.6,126.4,126.2,125.9,125.3,124.2,71.6,69.9,30.0,27.0,25.0,3.4.

[0150] Embodiment 25

[0151] Synthesis of (4-(4-methoxyphenoxy)butyl)(methyl-d3)selenane:

[0152]

[0153] 4-Methoxyphenyl-4-bromobutyl ether (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3l (yield 79%, deuterated rate> 99%).

[0154] 1H NMR (400MHz, CDCl3) δ6.83 (s, 4H), 3.93 (t, J = 5.6Hz, 2H), 3.76 (s, 3H), 2.71-2.50 (m, 2H), 1.85 (dt, J = 6.1, 3.0Hz, 4H). 13 C NMR (100MHz, CDCl3) δ153.8,153.2,115.4,114.6,67.9,55.8,29.6,26.8,24.9.

[0155] Embodiment 26

[0156] Synthesis of (4-(s-triphenylsulfonyl)butyl)(methyl-d3)selenane:

[0157]

[0158] In a Schlenk tube, mesitylene-4-bromobutyl ether (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylating agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3m (yield 76%, deuterated rate> 99%).

[0159] 1 H NMR (400MHz, CDCl3) δ6.84(s,2H),3.77(t,J=5.7Hz,2H),2.64(t,J=6.9Hz,2H),2.26(s,9H),1.93(tt,J=6.3,2.8Hz,4H). 13 C NMR (100MHz, CDCl3) δ153.7,133.0,130.6,129.4,71.7,30.7,27.0,25.1,20.8,16.3.

[0160] Embodiment 27

[0161] Synthesis of (4-(2-ethoxyphenoxy)butyl)(methyl-d3)selenane:

[0162]

[0163] 2-(2-ethoxyphenoxy)ethyl bromide (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3n (yield 76%, deuterated rate> 99%).

[0164] 1 H NMR (400MHz, CDCl3) δ6.98-6.81(m,4H),4.26(t,J=7.3Hz,2H),4.08(q,J=7.0Hz,2H),2.92(t,J=7.3Hz,2H),1.44(t,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ149.0,148.3,121.7,121.0,114.2,113.5,69.7,64.5,23.3,15.0.

[0165] Embodiment 28

[0166] Synthesis of (4-(2,4-difluorophenoxy)butyl)(methyl-d3)selenane:

[0167]

[0168] 2,4-Difluorophenyl-4-bromobutyl ether (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to a Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3o (yield 86%, deuterated rate>99%).

[0169] 1H NMR (400MHz, CDCl3) δ6.99 (ddd, J=10.8, 9.0, 5.3Hz, 1H), 6.67 (ddd, J=9.9, 6.7, 3.0Hz, 1H), 6.55(tt,J=8.4,3.2Hz,1H),4.01(t,J=6.0Hz,2H),2.60(t,J=7.0Hz,2H),1.99-1.76(m,4H). 13 C NMR(100MHz,CDCl3)δ160.0(d,J C-F =3Hz),157.6(d,J C-F =3Hz),150.2(d,J C-F =3Hz),147.9,147.8,147.8,147.8,147.7,147.6,116.2(q,J C-F =10Hz),106.4(dd,J C-F =24,7Hz),102.6(d,J C-F =28Hz),68.9,29.2,26.6,24.8,3.8,3.5. 19 F NMR (376MHz, CDCl3) δ -116.78 (d, J = 15.0Hz), -140.45 (d, J = 15.0Hz).

[0170] Embodiment 29

[0171] Synthesis of (2-(4-bromophenoxy)ethyl)(methyl-d3)selenane:

[0172]

[0173] 4-Bromo-2-phenoxyethyl bromide (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to the Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate, and the organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3p (yield 79%, deuterated rate>99%).

[0174] 1H NMR (400MHz, CDCl3) δ7.39-7.35(m,2H),6.80-6.76(m,2H),4.17(t,J=7.1Hz,2H),2.87(t,J=7.1Hz,2H). 13 C NMR (100MHz, CDCl3) δ157.7,132.4,116.5,113.2,68.5,23.2.

[0175] Embodiment 30

[0176] Synthesis of (2-((methyl-d3)selenophenyl)ethyl)(4-(trifluoromethyl)phenyl)sulfane:

[0177]

[0178] In a Schlenk tube, p-trifluoromethylphenyl-2-bromo-ethylsulfide (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylating agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added and reacted at 50° C. for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3q (yield 86%, deuterated rate>99%).

[0179] 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 3.36-3.17 (m, 2H), 2.92-2.61 (m, 2H). 13 C NMR(100MHz,CDCl3)δ141.2(d,J C-F =1Hz),128.1,127.8,126.0(dd,J C-F =7,4Hz),125.6,122.8,33.3,23.4. 19 F NMR (376 MHz, CDCl3) δ 62.44.

[0180] Embodiment 31

[0181] Synthesis of (3,5-difluorophenyl)(4-((methyl-d3)selenoalkyl)butyl)sulfane:

[0182]

[0183] 3,5-Difluorophenyl-4-bromobutylsulfide (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to a Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain product 3r (yield 68%, deuterated rate>99%).

[0184] 1 H NMR (400MHz, CDCl3) δ6.78(h,J=4.8Hz,2H),6.58(tt,J=8.9,2.4Hz,1H),2.95(t,J=6.6Hz,2H),2.55(t,J=6.6Hz,2H),1.80(dq,J=7.4,4.7,3.9Hz,4H). 13 C NMR(100MHz,CDCl3)δ164.4(d,J C-F =14Hz),161.9(d,J C-F =13Hz),141.3,141.2,110.3(dd,J C-F =19,7Hz),101.2(dd,J C-F =25,25Hz),32.3,29.2,28.8,24.5. 19 F NMR (376MHz, CDCl3) δ -116.78 (d, J = 15.0Hz), -140.45 (d, J = 15.0Hz).

[0185] Embodiment 32

[0186] Synthesis of (3aS, 4S, 5R, 6aS)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-4-(4-((methyl-d3)selenoalkyl)butoxy)tetrahydro-4H-cyclopenta[d][1,3]dioxole:

[0187]

[0188] (3aS, 4S, 5R, 6aS)-4-(4-bromobutyloxy)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3s (yield 72%, deuterated rate> 99%).

[0189] 1 H NMR (400MHz, CDCl3) δ5.84(d,J=3.7Hz,1H),4.50(d,J=3.7Hz,1H),4.26(dt,J=8.0,6 .1Hz,1H),4.11-4.01(m,2H),3.95(dd,J=8.6,5.7Hz,1H),3.82(d,J=3.0Hz,1H),3.61 (dt,J=9.1,5.9Hz,1H),3.51(dt,J=9.1,5.9Hz,1H),2.51(t,J=7.1Hz,2H),1.68(ddd d,J=19.3,13.6,8.9,5.1Hz,4H),1.46(s,3H),1.39(s,3H),1.32(s,3H),1.28(s,3H). 13 C NMR (100MHz, CDCl3) δ111.8,109.0,105.3,82.5,82.1,81.2,72.5,70.0.,67.3,29.9,26.9,26.9,26.7,26.3,25.5,24.9,3.5,3.2.

[0190] Embodiment 33

[0191] Synthesis of (4-(5-chloro-2-(2,4-dichlorophenoxy)phenoxy)butyl)(methyl-d3)selenane:

[0192]

[0193] 2-(4-bromobutoxy)-4-chloro-1-(2,4-dichlorophenoxy)benzene (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 3t (yield 68%, deuterated rate> 99%).

[0194] 1 H NMR (400MHz, CDCl3) δ7.43(d,J=2.6Hz,1H),7.08(dd,J=8.8,2.5Hz,1H),7.01-6.87(m,3H),6.62(d,J=8.8Hz ,1H),3.93(t,J=6.0Hz,2H),2.46(t,J=7.3Hz,2H),1.73(dq,J=8.4,6.2Hz,2H),1.59(dt,J=10.3,6.2Hz,2H). 13 C NMR (100MHz, CDCl3) δ152.7,151.0,142.9,130.8,130.3,127.8,127.7,124.3,122.4,121.1,117.7,114.7,68.5,29.1,26.3,24.7,3.5.

[0195] Embodiment 34

[0196] Synthesis of N-(4-ethoxyphenyl)-N-(4-((methyl-d3)selenoalkyl)butyl)acetamide:

[0197]

[0198] N-(4-bromobutyl)-N-(4-ethoxyphenyl)acetamide (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to the Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate, and the organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3u (yield 75%, deuteration rate>99%).

[0199] 1 H NMR (400MHz, CDCl3) δ7.05(d,J=8.7Hz,2H),6.90(d,J=8.8Hz,2H),4.03(q,J=7.0Hz,2H),3.66(t,J=7.3Hz,2H),2.51 (t,J=7.2Hz,2H),1.80(s,3H),1.65(dd,J=11.3,4.9Hz,2H),1.58(td,J=8.5,8.1,3.9Hz,2H),1.43(t,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ170.8,158.4,135.6,129.2,115.3,63.8,48.4,28.0,27.5,24.9,22.9,14.9.

[0200] Embodiment 35

[0201] Synthesis of (8R, 9S, 13S, 14S, 17S)-13-methyl-17-((methyl-d3)selenoalkyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl 4-methylbenzenesulfonate:

[0202]

[0203] In a Schlenk tube, (8R,9S,13S,14S,17S)-17-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl 4-methylbenzenesulfonate (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were added and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting, and water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate, and the organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3v (yield 75%, deuterated rate>99%).

[0204] 1H NMR (400MHz, CDCl3) δ7.77-7.71(m,2H),7.27(d,J=8.1Hz,2H),7.06-6.98(m,1H),6.54(dd, J=8.4,2.8Hz,1H),6.50-6.43(m,1H),4.77(s,1H),4.27(dd,J=9.1,7.7Hz,1H),2.81-2.61(m ,2H),2.39(s,3H),2.13(dq,J=13.3,3.9Hz,1H),2.03(td,J=11.2,4.3Hz,1H),1.90(dtd,J= 14.4,9.6,6.3Hz,1H),1.78-1.57(m,3H),1.39-1.21(m,4H),1.11-1.01(m,2H),0.75(s,3H). 13 C NMR (100MHz, CDCl3) δ153.5,144.6,138.2,134.3,132.3,129.8,128.0,126.6,115.4 ,112.8,90.0,49.1,43.7,43.4,38.5,36.2,29.6,27.8,27.1,26.1,23.1,21.8,11.9.

[0205] Embodiment 36

[0206] Synthesis of (R)-2,5,7,8-tetramethyl-6-(4-((methyl-d3)selenoalkyl)butoxy)-2-((4R,8R)-4,8,12-trimethyltridecyl)benzosaturated alkane:

[0207]

[0208] (R)-6-(4-bromobutoxy)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)benzodihydrogen (0.2mmol, 1.0equiv.), cesium carbonate (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.2mmol, 1.0equiv.) and MeOH (0.5mL) were added to a Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate, and the organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product 3w (yield 50%, deuteration rate>99%).

[0209] 1H NMR(400MHz, CDCl3)δ3.64(q,J=5.1,4.2Hz,2H),2.59(dt,J=25.2,6.7Hz,4H),2.23-2.03(m,9H),1.95-1.84(m,4H),1 .76(tt,J=13.3,6.7Hz,2H),1.54-1.48(m,2H),1.29-1.20(m,14H),1.18-0.98(m,8H),0.85(dd,J=10.0,6.7Hz,12H); 13 C NMR (100MHz, CDCl3) δ148.2,147.7,127.8,125.8,122.8,117.5,74.8,72.4,40.0,39.4,37.5,37.4,37. 3,32.8,32.7,31.2,30.6,28.0,24.8,24.5,23.9,22.8,22.7,21.1,20.7,19.8,19.7,12.8,11.9,11.8.

[0210] Embodiment 37

[0211] Synthesis of phenyl 3-((methyl-d3)selenoalkyl)propionate:

[0212]

[0213] Phenyl acrylate (0.2 mmol, 1.0 equiv.), DBU (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.3 mmol, 1.5 equiv.) and THF (2.0 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain product 5a (yield 81%, deuterated rate> 99%).

[0214] 1 H NMR (400MHz, CDCl3) δ7.44-7.34(m,2H),7.24(td,J=7.4,1.4Hz,1H),7.15-7.07(m,2H),3.04-2.94(m,2H),2.88(t,J=7.1Hz,2H); 13 C NMR (100MHz, CDCl3) δ170.9,150.6,129.5,126.0,121.6,35.6,18.7.

[0215] Embodiment 38

[0216] Synthesis of 3-((methyl-d3)selenoalkyl)benzyl propionate:

[0217]

[0218] Benzyl acrylate (0.2 mmol, 1.0 equiv.), DBU (0.2 mmol, 1.0 equiv.), Se-deuterated methylation agent 2 (0.3 mmol, 1.5 equiv.) and THF (2.0 mL) were added to a Schlenk tube and reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain product 5b (yield 82%, deuterated rate> 99%).

[0219] 1 H NMR (400MHz, CDCl3) δ7.37 (d, J = 3.7Hz, 5H), 5.15 (s, 2H), 2.78 (s, 4H). 13 C NMR (100MHz, CDCl3) δ172.2,135.8,128.7,128.4,128.4,66.6,35.5,18.8.

[0220] Embodiment 39

[0221] Synthesis of 3-((methyl-d3)selenoalkyl)propionic acid-4-ethylphenyl:

[0222]

[0223] 4-Ethylphenylacrylate (0.2mmol, 1.0equiv.), DBU (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.3mmol, 1.5equiv.) and THF (2.0mL) were added to a Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain product 5c (yield 78%, deuterated rate>99%).

[0224] 1H NMR(400MHz, CDCl3) δ7.20(d,J=8.1Hz,2H),7.01(d,J=8.5Hz,2H),3.04-2.9 3(m,2H),2.87(t,J=7.1Hz,2H),2.64(q,J=7.6Hz,2H),1.23(t,J=7.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ171.2,148.6,142.0,128.9,121.3,35.6,28.4,18.8,15.7.

[0225] Embodiment 40

[0226] Synthesis of (3aR, 4S, 6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl 3-((methyl-d3)selenoalkyl)propionate:

[0227]

[0228] (R)-6-(4-bromobutoxy)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)benzodihydrogen (0.2mmol, 1.0equiv.), DBU (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.3mmol, 1.5equiv.) and THF (2.0mL) were added to a Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain product 5d (yield 58%, deuteration rate>99%).

[0229] 1 H NMR (400MHz, CDCl3) δ5.88(d,J=3.7Hz,1H),5.27(d,J=2.4Hz,1H),4.54(d,J=3.6Hz,1H),4.21(d,J=2.6Hz,2H), 4.09(dd,J=8.6,5.5Hz,1H),4.05-4.00(m,1H),2.77(s,4H),1.52(s,3H),1.41(s,3H),1.32(s,3H),1.31(s,3H). 13C NMR (100MHz, CDCl3) δ171.1,112.5,109.5,105.2,83.4,79.9,76.5,72.5,67.4,35.4,27.0,26.9,26.3,25.4,18.7.

[0230] Embodiment 41

[0231] Synthesis of (1S, 2R, 5S)-2-isopropyl-5-methylcyclohexyl 3-((methyl-d3)selenoalkyl)propionate:

[0232]

[0233] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl acryloyl ester (0.2mmol, 1.0equiv.), DBU (0.2mmol, 1.0equiv.), Se-deuterated methylation agent 2 (0.3mmol, 1.5equiv.) and THF (2.0mL) were added to a Schlenk tube and reacted at 50°C for 12h. The reaction was monitored by TLC plate spot plate. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain product 5e (yield 71%, deuterated rate>99%).

[0234] 1 H NMR (400MHz, CDCl3) δ4.70 (td, J=10.9, 4.4Hz, 1H), 2.79-2.73 (m, 2H), 2.7 2-2.66(m,2H),1.99(dtd,J=11.9,4.1,3.5,2.0Hz,1H),1.90-1.83(m,1H), 1.70-1.64(m,2H),1.48(dddd,J=11.9,8.7,6.3,3.2Hz,1H),1.40-1.32(m, 1H),1.08-0.95(m,2H),0.89(dd,J=6.8,3.6Hz,7H),0.75(d,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ172.0,74.7,47.1,41.0,35.9,34.3,31.5,26.4,23.5,22.2,20.9,19.1,16.4.

[0235] Embodiment 42

[0236] (4-(5-chloro-2-(2,4-dichlorophenoxy)phenoxy-)butyl)-(methyl-13 C) Synthesis of silane:

[0237]

[0238] In a Schlenk tube, 2-(4-bromobutoxy)-4-chloro-1-(2,4-dichlorophenoxy)benzene (0.2 mmol, 1.0 equiv.), cesium carbonate (0.2 mmol, 1.0 equiv.), Se- 13 C methylating agent 9 (0.2 mmol, 1.0 equiv.) and MeOH (0.5 mL) were reacted at 50°C for 12 h. The reaction was monitored by TLC plate spotting. Water was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography to obtain product 8a (yield 71%).

[0239] Embodiment 43

[0240] Synthesis of (2-methyl-d3) selenosulfoxide naphthalene:

[0241]

[0242] (2-Methyl-d3)selenonaphthalene (0.2 mmol, 1.0 equiv.), m-chloroperbenzoic acid (0.4 mmol, 2.0 equiv.) and DCM (2 mL) were added to a Schlenk tube and reacted at -40°C for 1 h. The reaction was monitored by TLC plate spotting. A saturated aqueous sodium hydroxide solution was added to the Schlenk tube to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected and anhydrous sodium sulfate was added to the organic phase to dry the filtrate, which was concentrated under reduced pressure and purified by silica gel column chromatography (EA / MEOH=20:1) to obtain product 9b (yield 53%).

[0243] 1 H NMR (400MHz, CDCl3) δ7.89-7.79(m,3H),7.78(d,J=1.8Hz,1H),7.56-7.46(m,2 H),7.38(dd,J=8.4,1.8Hz,1H),4.39(d,J=11.7Hz,1H),4.19(d,J=11.7Hz,1H). 13 C NMR (100MHz, CDCl3) δ133.38,133.00,129.10,128.81,127.85,127.81,127.80,126.97,126.80,126.65,55.08.

Claims

1. A Se-deuterated methylation or Se- 13 The application of C methylating agent is characterized in that The steps include: The compound represented by formula (1) is placed in an organic solvent and reacted with Se-deuterated methyl or Se- 13 C methylation reagent reacts in an alkaline environment to obtain a Se-deuterated methylated compound or Se- 13 C methylation compound, the reaction process is as follows: Where A is CD3 or 13 CH3, X is selected from halogen, OMs or OTs, R 1 R is selected from aromatic alkyl, phenylpropenyl, phenylpropynyl, naphthylmethyl, substituted phenyl, adamantyl, 2-(2,3-dihydrobenzofuran)ethyl, 2-indoleethyl, mono- or poly-substituted phenoxyethyl, phenoxypropyl, mono- or poly-substituted phenoxybutyl, mono-substituted phenylthioethyl, poly-substituted phenylthiobutyl, poly-substituted cyclopentadioxolyl or halogen alkyl derived from D-glucose, vitamin E, estradiol or phenacetin; 2 Selected from substituted phenyl, benzyloxy or polysubstituted alkoxy.

2. A Se-deuterated methylated or Se- 13 The application of C methylating agent is characterized in that The base is DBU, DABCO, cesium carbonate or potassium carbonate, and the amount of the base used is 0.5-5.0 equivalents of the substrate represented by formula (1).

3. A Se-deuterated methylated or Se- 13 The application of C methylating agent is characterized in that The organic solvent is methanol or THF, and the concentration of the substrate represented by formula (1) in the organic solvent is 0.1-1.0M.

4. A Se-deuterated methylated or Se- 13 The application of C methylating agent is characterized in that The molar ratio of the compound represented by formula (1) to the Se-deuterated methylation agent represented by formula (2) is 1.0:1.0-1.0:5.

0.

5. A Se-deuterated methylated or Se- 13 The application of C methylating agent is characterized in that The reaction temperature is 20-100°C.

6. A Se-deuterated methylated or Se- 13 The application of C methylating agent is characterized in that The reaction time is 1-24h.

7. A Se-deuterated methylated or Se- 13 The application of C methylating agent is characterized in that The steps include: The Se-deuterated methylated compound represented by formula (4) is placed in an organic solvent, and reacted with the meta-chloroperbenzoic acid represented by formula (5) in the organic solvent to obtain the selenosulfoxide compound represented by formula (6). The reaction process is as follows: R 1 The group is selected from aromatic alkyl, phenylpropenyl, phenylpropynyl, naphthylmethyl, substituted phenyl, adamantyl, 2-(2,3-dihydrobenzofuran)ethyl, 2-indoleethyl, mono-substituted or poly-substituted phenoxyethyl, phenoxypropyl, mono-substituted or poly-substituted phenoxybutyl, mono-substituted phenylthioethyl, poly-substituted phenylthiobutyl, poly-substituted cyclopentadioxolyl or halogen alkyl derived from D-glucose, vitamin E, estradiol or phenacetin.

8. A Se-deuterated methylated or Se- 13 The application of C methylating agent is characterized in that The amount of m-chloroperbenzoic acid used is 2.0 equivalents of the compound (4) shown.

9. A Se-deuterated methylated or Se- 13 The application of C methylating agent is characterized in that The organic solvent used is dichloromethane, and the concentration of the substrate represented by formula (4) in the organic solvent is 0.1M.

10. A Se-deuterated methylated or Se- 13 The derivative application of C methylating agent is characterized in that The reaction temperature was -40°C and the reaction time was 1 hour.

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