A method for achieving deuterated methylation of nucleophiles

Abstract

This invention belongs to the field of chemical synthesis and relates to a method for achieving deuterated methylation of a nucleophile. The invention provides a deuterated methylating reagent, which is obtained by reacting formic acid with deuterated methanol under acidic conditions, followed by a second reaction with thiaanthracite and trifluoromethanesulfonic acid. The nucleophile is then reacted with the deuterated methylating reagent described in claim 1, a base, and a solvent to obtain the deuterated methylated product. This invention also provides a method for achieving deuterated methylation of a nucleophile, which involves dissolving the nucleophile and 5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate in a suitable solvent, adding a base, and then performing the deuterated methylation reaction at room temperature. In the method provided by this invention, the yield of the product after nucleophile methylation can reach 52% to 95%.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis and relates to a method for achieving deuterated methylation of nucleophiles. Background Technology

[0002] In pharmaceutical and pesticide development, introducing alkyl groups, especially methyl groups, into candidate drug molecules can significantly modulate their physiological activity, improve half-life, solubility, and target selectivity. This effect is often referred to as the "magic methyl effect." Therefore, methylation modification of potentially bioactive organic molecules has become one of the most common strategies in new drug development. Due to the "magic methyl" effect, methyl groups are present in various building blocks and commercial drugs, making them one of the simplest organic substituents in drug development. Incorporating methyl groups into candidate drugs can significantly improve their biological activity, pharmacokinetic properties, and physical properties by modulating their solubility, hydrophilicity, and conformation. Deuterated drugs are obtained by replacing hydrogen atoms at specific sites on a drug molecule with deuterium atoms; the most widely used method is replacing carbon-hydrogen bonds with carbon-deuterium bonds. This substitution can improve the pharmacokinetics and / or toxicity of the drug. In April 2017, the U.S. Food and Drug Administration (FDA) approved the world's first deuterated drug, deuterabenazine (Antetane) from Auspex Pharmaceuticals, for the treatment of Huntington's disease, a rare autosomal dominant genetic disorder. In 2022, the FDA approved another novel deuterated drug, deucravacitinib, which is widely used to treat various autoimmune diseases, including classic Sjögren's syndrome, rheumatoid arthritis, and psoriasis.

[0003] In recent years, thioanthrayl chemistry has received increasing attention as a powerful toolbox for synthetic chemists. Arylthiaanthracene salts have emerged as efficient aryl radical precursors in photoredox reactions and have behaved as well as electrophiles in cross-coupling reactions. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for achieving deuterated methylation of nucleophiles based on microfluidic field reaction technology, which addresses the shortcomings of the prior art.

[0005] Invention concept: By incorporating deuterated methyl groups into the thiaanthra skeleton, deuterated methyl trifluorothiaanthra (TT-CD3) was developed. + OTf − This structure has been confirmed by X-ray analysis. Compared to other sulfur-containing deuterated methyl reagents, TT-CD3... + OTf −It is readily available from inexpensive starting materials (i.e., thioanthracene (TT) and CD3OD) and can be prepared on a large scale with a yield of 92%. The deuterated methyltrifluorothiathracene of this invention exhibits good stability and can be stored in solid form for extended periods at ambient temperature in the dark without significant reaction. In this invention, the nucleophile and deuterated methyltrifluorothiathracene (5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate) are dissolved in a suitable solvent, and then a base is added. The deuteration methylation reaction of the nucleophile can be achieved at room temperature.

[0006] To address the aforementioned technical problems, this invention discloses a deuterated methylating agent, the structure of which is shown below:

[0007] .

[0008] In some embodiments, formic acid and deuterated methanol undergo a first reaction under the action of acid, followed by a second reaction with thiaanthracene and trifluoromethanesulfonic acid to obtain the product.

[0009] In some embodiments, the acid is concentrated sulfuric acid, concentrated hydrochloric acid, or concentrated phosphoric acid; the molar ratio of formic acid to deuterated methanol, acid, thiamethoxam, and trifluoromethanesulfonic acid is 3~5:8~10:3~5:1~3:4~9; the first reaction is carried out at a temperature of 50~80°C. o C, the reaction time is 3~5 h; the second reaction, the reaction temperature is 20~40 °C. o C.

[0010] In some embodiments, preferably, the acid is concentrated sulfuric acid; the molar ratio of formic acid to deuterated methanol, acid, thiazoline, and trifluoromethanesulfonic acid is 3~4:8~9:3~4:1~2:5~7, more preferably 3.5:8.2:3.1:1:6; the first reaction is carried out at a reaction temperature of 50~70°C. o C, further preferably 60 o C, the reaction time is 4 h; the second reaction, the reaction temperature is 30 °C. o C.

[0011] The application of the aforementioned deuterated methylating agents in deuterated methylation reactions is also within the scope of protection of this invention.

[0012] Furthermore, this invention discloses a method for achieving deuteromethylation of nucleophiles based on microfluidic reaction technology, wherein the nucleophile is mixed with the above-mentioned deuteromethylating reagent, base, and solvent and reacted to obtain the deuteromethylated product.

[0013] in,

[0014] The nucleophile is a thiol-containing compound, an amine compound, a hydroxyl-containing compound, or a carboxyl-containing compound;

[0015] The structural formula of the thiol-containing compound is as follows: The structural formula of the amine compound is as follows: The structural formula of the hydroxyl-containing compound is as follows: The structural formula of the carboxyl-containing compound is as follows: ;

[0016] The structural formula of the deuterated methylated product is as follows: , , or ;

[0017] R 1 Selected from C5-C6 cycloalkyl, substituted or unsubstituted oxygen-containing heterocyclic groups, or substituted or unsubstituted aryl groups; wherein the substitution is substituted by one or more identical or different substituents, wherein the substitution is selected from any one or more groups substituted by C1-C3 alkoxy, C1-C3 alkoxy, and C1-C3 alkoxy-C1-C3 alkyl;

[0018] R 2 R 3 The group is independently selected from hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted benzenesulfonyl, or substituted or unsubstituted heterocyclic group; wherein the substitution is substituted by one or more identical or different substituents, and the substitution is selected from those substituted by C1-C3 alkoxy, amino or C1-C3 alkyl groups.

[0019] R 4 Selected from substituted or unsubstituted phenyl groups; the substitution is selected from those substituted by C1-C3 alkylamino or (tert-butoxycarbonylamino) (C1-C3 alkoxyC1-C3 alkylyl)C1-C3 alkyl groups;

[0020] R 5 Selected from substituted or unsubstituted C1-C3 alkyl groups, or substituted or unsubstituted aryl-C1-C3 alkyl groups; wherein the substitution is made by one or more identical or different substituents, the substitution being selected from (C1-C3 alkyl) (C1-C3 alkoxyaryl), (tert-butoxycarbonylamino) (aryl C1-C3 alkyl), C1-C3 alkoxy, halobenzoyl or C1-C3 alkyl groups by any substitution.

[0021] In some embodiments, preferably

[0022] The structural formula of the thiol-containing compound is as follows: Among them, R 1Selected from C5-C6 cycloalkyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted phenyl; wherein the substitution is substituted by one or more identical or different substituents, wherein the substitution is selected from any one or more groups substituted by C1-C2 alkoxy, C1-C2 alkoxy and C1-C2 alkoxy-C1-C2 alkyl;

[0023] The structural formula of the amine compound is as follows: Among them, R 2 R 3 The substituted group is independently selected from hydrogen, substituted phenyl, substituted benzenesulfonyl, substituted 5-isooxazolyl or substituted pyrimidinyl; wherein the substituted group is substituted by one or more of the same or different substituents, and the substituted group is selected from those substituted by C1-C2 alkoxy, amino or C1-C2 alkyl groups.

[0024] The structural formula of the hydroxyl-containing compound is: Among them, R 4 Selected from substituted phenyl groups; the substitution is selected from those substituted by C1-C2 alkylamino or (tert-butoxycarbonylamino) (C1-C2 alkoxyC1-C2 alkyl)C1-C2 alkyl groups;

[0025] The structural formula of the carboxyl compound is as follows: Among them, R 5 Selected from substituted C1-C2 alkyl groups, or substituted or unsubstituted aryl-C1-C2 alkyl groups; wherein the substitution is made by one or more identical or different substituents, the substitution being selected from (C1-C2 alkyl), (C1-C2 alkoxynaphthyl), (tert-butoxycarbonylamino), (indolyl C1-C2 alkyl), C1-C2 alkoxy, chlorobenzoyl, or any substitution by (C1-C2 alkyl), (C1-C2 alkoxy), (chlorobenzoyl), or (C1-C2 alkyl).

[0026] In some embodiments, more preferably

[0027] The structural formula of the thiol-containing compound is as follows: Among them, R 1 Selected from substituted tetrahydropyranyl or substituted phenyl; said substitution is substituted by one or more identical or different substituents, said substitution is selected from any one or more groups selected from methoxy, acetoxy and acetoxymethyl;

[0028] The structural formula of the amine compound is as follows: Among them, R 2 R 3 The substituted group is independently selected from hydrogen, substituted phenyl, substituted benzenesulfonyl, substituted 5-isooxazolyl or substituted pyrimidinyl; wherein the substituted group is substituted by one or more of the same or different substituents, and the substituted group is selected from those substituted by methoxy, amino or methyl in any way;

[0029] The structural formula of the hydroxyl-containing compound is: Among them, R 4 The substituted phenyl group is selected from substituted phenyl groups; the substituted phenyl group is selected from those substituted with acetamido or (tert-butoxycarbonylamino)(methoxyformyl)ethyl groups in any way;

[0030] The structural formula of the carboxyl compound is as follows: Among them, R 5 Selected from substituted methyl or substituted indolylmethyl; wherein the substitution is substituted by one or more identical or different substituents, the substitution being selected from (methyl) (methoxynaphthyl), or (tert-butoxycarbonylamino) (3-indolylmethyl), methoxy, 4-chlorobenzoyl or methyl in any substitution.

[0031] In some embodiments, the thiol-containing compound is selected from any one of the following structures:

[0032] ;

[0033] The amine compound is selected from any one of the following structures:

[0034] ;

[0035] The hydroxyl-containing compound is selected from any one of the following structures:

[0036] ;

[0037] The carboxyl compound is selected from any one of the following structures:

[0038] .

[0039] Wherein, when the structural formula of the thiol-containing compound is The structural formula of the obtained deuterated methylated product is as follows: .

[0040] Wherein, when the structural formula of the amine compound is The structural formula of the obtained deuterated methylated product is as follows: .

[0041] Wherein, when the structural formula of the hydroxyl-containing compound is The structural formula of the obtained deuterated methylated product is as follows: .

[0042] Wherein, when the structural formula of the carboxyl-containing compound is The structural formula of the obtained deuterated methylated product is as follows: .

[0043] The deuterated methylating agent, namely 5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate, is abbreviated as TT-CD3. + OTf ‒ .

[0044] In some embodiments, the base is any one or more combinations of triethylamine, 4-dimethylaminopyridine, 1,8-diazobisspirocyclo[5.4.0]undecyl-7-ene, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, and 2,6-dimethylpyridine; and the solvent is any one or more combinations of acetonitrile, methanol, ethyl acetate, dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, chloroform, and acetone.

[0045] In some embodiments, preferably, the base is triethylamine; and the solvent is acetonitrile.

[0046] Acetonitrile is abbreviated as MeCN, methanol as MeOH, ethyl acetate as EA, dichloromethane as DCM, tetrahydrofuran as THF, 1,4-dioxane as Dioxane, dimethyl sulfoxide as DMSO, N,N-dimethylformamide as DMF, and N,N-dimethylacetamide as DMA.

[0047] In some embodiments, the molar ratio of the nucleophile to the deuterated methylating agent and the base is 1:1 to 5:1 to 2.

[0048] In some embodiments, preferably, the molar ratio of the nucleophile to the deuterated methylating agent and the base is 1:1~2:1~2.

[0049] In some embodiments, more preferably, the molar ratio of the nucleophile to deuterated methyltrifluorothiane and the base is 1:1.2:1.5.

[0050] In some embodiments, the reaction is carried out at a temperature of 20-30°C.

[0051] In some embodiments, preferably, the reaction is carried out at a temperature of 25°C.

[0052] In some embodiments, the reaction is carried out in a conventional reactor or in a microfluidic reaction device.

[0053] In some embodiments, preferably, when the reaction is carried out in a microfluidic reaction device, it includes the following steps:

[0054] The above-mentioned deuterated methylating reagent is mixed with a solvent to obtain a first mixture; the nucleophile reagent, base and solvent are mixed to obtain a second mixture; the first mixture and the second mixture are simultaneously pumped into the microfluidic reactor of the microfluidic reaction device to react, thereby obtaining the deuterated methylation product.

[0055] In some embodiments, the concentration of the deuterated methylating agent in the first mixture is 0.05~1 mmol / mL; the concentration of the nucleophile in the second mixture is 0.05~1 mmol / mL; the flow rate of the first mixture pumped into the microfluidic reactor of the microfluidic reaction device is 0.05 mL / min~0.1 mL / min; and the flow rate of the second mixture pumped into the microfluidic reactor of the microfluidic reaction device is 0.05 mL / min~0.1 mL / min.

[0056] In some embodiments, preferably, the concentration of the deuterated methylating agent in the first mixture is 0.1~0.5 mmol / mL, more preferably 0.24 mmol / mL.

[0057] In some embodiments, preferably, the concentration of the nucleophile in the second mixture is 0.1 to 0.5 mmol / mL, more preferably 0.2 mmol / mL.

[0058] In some embodiments, preferably, the flow rate of the first mixture pumped into the microfluidic reactor of the microfluidic reaction device is 0.08 mL / min to 0.1 mL / min, more preferably 0.1 mL / min; the flow rate of the second mixture pumped into the microfluidic reactor of the microfluidic reaction device is 0.08 mL / min to 0.1 mL / min, more preferably 0.1 mL / min.

[0059] In some embodiments, the microflow reactor has a porous structure, is made of perfluoroalkoxyalkane, has an inner diameter of 0.5~2.0 mm, and a volume of 0.3~20.0 mL; the residence time of the material in the microflow reactor is 30 s~2.6 h.

[0060] In some embodiments, preferably, the microflow reactor has a porous structure, is made of perfluoroalkoxyalkane, and has an inner diameter of 0.5~1.0 mm, more preferably 0.6 mm, and a volume of 0.3~10.0 mL, more preferably 0.3~5.0 mL, even more preferably 0.3~2.0 mL, and most preferably 1.0 mL.

[0061] In some embodiments, preferably, the residence time of the material in the microflow reactor is 30 s to 1.0 h, more preferably 30 s to 30 min, even more preferably 1 min to 10 min, and most preferably 5 min.

[0062] The aforementioned microfluidic reaction device includes two injection pumps, a Y-type micromixer, a microfluidic reactor, and a product receiver. The two injection pumps are connected in parallel to the micromixer via connecting pipes, and the micromixer, microfluidic reactor, and product receiver are connected in series via connecting pipes.

[0063] In the above method, no metal catalyst is required, and the nucleophile deuteration methylation can be achieved under alkaline conditions. The method of the present invention fully meets the concept of green chemistry and achieves nucleophile deuteration methylation with an ideal yield.

[0064] Beneficial effects:

[0065] (1) This invention provides a novel method for realizing the deuteration methylation of nucleophiles. By dissolving the nucleophile and 5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate in a suitable solvent, and then adding triethylamine (Et3N), the deuteration methylation reaction of the nucleophile can be realized at room temperature.

[0066] (2) The raw materials in the system designed in this invention are readily available, and the system is easy to operate, safe, and improves the selectivity of the product while increasing the apparent reaction rate, which is conducive to large-scale continuous production.

[0067] (3) The method of the present invention does not require the use of expensive transition metal catalysts, which greatly reduces the reaction cost and solves the environmental pollution problem caused by post-processing.

[0068] (4) The 5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate used in this invention can be synthesized from inexpensive and readily available raw materials through simple steps, avoiding the complex deuterated methylation reagents used in the original method.

[0069] (5) In the method provided by the present invention, the yield of the product after methylation by the nucleophile can reach 52% to 95%. Attached Figure Description

[0070] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0071] Figure 1 This is a schematic diagram of the reaction process of the present invention.

[0072] Figure 2This is a diagram of the microfluidic reaction device used in the embodiments of the present invention.

[0073] Figure 3 The compound (4-methoxyphenyl) (methyl-) prepared in Example 2 d 3 (1H NMR spectrum of thioalkylene)

[0074] Figure 4 The compound (4-methoxyphenyl) (methyl-) prepared in Example 2 d 3 ) Carbon spectrum of thioanes.

[0075] Figure 5 The compound (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((methyl-) prepared in Example 3 d 3 Carbon spectrum of tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (THO-2H-pyran-3,4,5-trimethyltriacetate).

[0076] Figure 6 The compound (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((methyl-) prepared in Example 3 d 3 Carbon spectrum of tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (THO-2H-pyran-3,4,5-trimethyltriacetate).

[0077] Figure 7 The compound 4-methoxy-N-(methyl-) prepared in Example 4 d 3) The hydrogen spectrum of aniline.

[0078] Figure 8 The compound 4-methoxy-N-(methyl-) prepared in Example 4 d 3) Carbon spectrum of aniline.

[0079] Figure 9 The hydrogen spectrum of compound 4-amino-N-(methyl-d3)-N-(5-methylisoxazol-3-yl)benzenesulfonamide prepared in Example 5.

[0080] Figure 10 The carbon spectrum of compound 4-amino-N-(methyl-d3)-N-(5-methylisoxazol-3-yl)benzenesulfonamide prepared in Example 5.

[0081] Figure 11 The photon spectrum of compound 4-amino-N-(2,6-dimethylpyrimidin-4-yl)-N-(methyl-d3)benzenesulfonamide prepared in Example 6.

[0082] Figure 12The carbon spectrum of compound 4-amino-N-(2,6-dimethylpyrimidin-4-yl)-N-(methyl-d3)benzenesulfonamide prepared in Example 6.

[0083] Figure 13 The hydrogen spectrum of N-(4-(methoxy-d3)phenyl)acetamide, the compound prepared in Example 7.

[0084] Figure 14 The carbon spectrum of N-(4-(methoxy-d3)phenyl)acetamide, the compound prepared in Example 7.

[0085] Figure 15 The compound (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(methoxy-) prepared in Example 8 d 3 The hydrogen spectrum of methyl phenylpropionate.

[0086] Figure 16 The compound (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(methoxy-) prepared in Example 8 d 3 Carbon spectrum of methyl phenyl propionate.

[0087] Figure 17 The compound methyl- prepared in Example 9 d The hydrogen spectrum of methyl 3(S)-2-(6-methoxynaphthalene-2-yl)propionate.

[0088] Figure 18 The compound methyl- prepared in Example 9 d Carbon spectrum of methyl 3(S)-2-(6-methoxynaphthalene-2-yl)propionate.

[0089] Figure 19 The compound methyl- prepared in Example 10 d The hydrogen spectrum of 3(tert-butoxycarbonyl)-L-tryptophan methyl ester.

[0090] Figure 20 The compound methyl- prepared in Example 10 d Carbon spectrum of 3-(tert-butoxycarbonyl)-L-tryptophan methyl ester.

[0091] Figure 21 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)methyl acetate, prepared in Example 11 d The hydrogen spectrum of 3.

[0092] Figure 22 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)methyl acetate, prepared in Example 11d Carbon spectrum of 3.

[0093] Figure 23 The compound is a trideuteryl reagent TT-CD3 + OTf ‒ The hydrogen spectrum.

[0094] Figure 24 The compound is a trideuteryl reagent TT-CD3 + OTf ‒ The carbon spectrum. Detailed Implementation

[0095] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0096] The raw materials used in the embodiments of this invention are all existing compounds.

[0097] The reaction process diagram of the present invention is shown below. Figure 1 As shown.

[0098] The microfluidic field reaction device used in the embodiments of the present invention is shown in the figure below. Figure 2 As shown, the system includes two injection pumps, a Y-type micromixer, a microfluidic reactor, and a product receiver. The two injection pumps are connected in parallel to the micromixer via connecting pipes. The micromixer, microfluidic reactor, and product receiver are connected in series via connecting pipes. The microfluidic reactor has a porous structure and is made of perfluoroalkoxyalkane. The inner diameter of the microfluidic reactor is 0.5~2.0 mm; in this embodiment, a pipe with an inner diameter of 0.6 mm is preferred.

[0099] Example 1

[0100]

[0101] Add formic acid (4.0 mL, 106 mmol) and CD3OD (10.0 mL, 247 mmol, 99% D) to a 50 mL round flask. Next, add sulfuric acid (5.0 mL, 94 mmol, 98%) dropwise to the above solution while stirring. Incubate the mixture at 60 °C. o The reaction was heated at C for 4 hours. After the reaction was complete, the formic acid-d3 formate containing a small amount of deuterated methanol was directly distilled at atmospheric pressure (33-38℃) to obtain formic acid-d3, which did not require further purification.

[0102] Thianthracene (TT, 30 mmol, 1.0 equivalent) and distilled formic acid-d3 formate were added to a 100 mL round flask. The mixture was stirred at 0 °C, and TfOH (16.0 mL, 180 mmol, 6.0 equivalent) was added dropwise while stirring. The reaction was then heated to 30 °C and stirred overnight. After the reaction was complete, the reactants were poured into water (50 mL), extracted with CH2Cl2 (50 mL × 3), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was washed with Et2O (25 mL × 3) and dried under vacuum to give the trideuterium methyl reagent TT-CD3. + OTf ‒ (10.6 g, 92%, 99% D).

[0103] Product: Trideuterium Methyl Reagent TT-CD3 + OTf ‒ The characterization data are as follows (e.g.) Figure 23 , Figure 24 (as shown) 1 H NMR (400MHz, CDCl3) δ 8.37 (dd, J = 7.8, 1.3 Hz, 2H), 7.84 (dd, J = 7.9, 1.2 Hz, 2H), 7.75 (td, J = 7.7, 1.4 Hz, 2H), 7.68 (td, J = 7.7, 1.4 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 135.6, 134.4, 134.2, 130.2, 130.0, 118.8. 19 F NMR (376 MHz, CDCl3) δ78.25. HRMS (ESI) m / z: calcd for C 13 H8D3S2 + [M–OTf] + : 234.0484, found: 234.0487.

[0104] Example 2

[0105]

[0106] Weigh out TT-CD3 + OTf ‒(0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, 4-methoxythiophenol (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor of the microfluidic reaction apparatus (coil inner diameter 0.6 mm, volume 1.0 mL) for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC and the reaction solution was collected. After the reaction was complete, the reaction was quenched and the final product (4-methoxyphenyl) (methyl-) was obtained by column chromatography (eluent: petroleum ether: ethyl acetate). d 3 55.2 mg of thionine, yield 88%.

[0107] Product (4-methoxyphenyl) (methyl- d 3 The characterization data for thioanes are as follows (e.g.) Figure 3 , Figure 4 (as shown) 1 H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.78 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.2, 130.2, 128.7, 114.6, 55.4. HRMS (ESI) m / z: calcd for C8H7D3OSNa [M+Na] + : 180.0533, found: 180.0530.

[0108] Example 3

[0109]

[0110] Weigh out TT-CD3 + OTf ‒(0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(thio)tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor of the microfluidic reaction apparatus (coil inner diameter 0.6 mm, volume 1.0 mL) for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC, with the reaction solution collected. After the reaction was completed, the reaction was quenched and the final product (2R, 3R, 4S, 5R, 6S)-2-(acetoxymethyl)-6-((methyl- d 3 137.6 mg of tetrahydro-2H-pyran-3,4,5-trimethyltriacetate (thiolated) was obtained, with a yield of 90%.

[0111] Product (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((methyl- d 3 The characterization data of thiotetrahydro-2H-pyran-3,4,5-trimethyltriacetate are as follows (e.g.) Figure 5 , Figure 6 (as shown) 1 H NMR (400 MHz, CDCl3) δ 5.00– 4.93 (m, 1H), 4.85 – 4.76 (m, 2H), 4.17 – 4.11 (m, 1H), 4.02 – 3.95 (m,1H), 3.90 – 3.84 (m, 1H), 3.52 – 3.45 (m, 1H), 1.83 – 1.78 (m, 6H), 1.77 –1.71 (m, 6H). 13 C NMR (100 MHz, CDCl3) δ 170.5, 170.0, 169.3, 82.6, 75.8, 73.7,69.0, 68.2, 62.0, 20.7, 20.6, 20.5. HRMS (ESI) m / z: calcd for C 15 H 19D3O9SNa [M+Na] + : 404.1065, found: 404.1089.

[0112] Example 4

[0113]

[0114] Weigh out TT-CD3 + OTf ‒ (0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, 4-methoxyaniline (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC and the reaction solution was collected. After the reaction was complete, the reaction was quenched and the final product 4-methoxy-N-(methyl-) ... d 3) Aniline 28.9 mg, yield 52%.

[0115] Product 4-methoxy-N-(methyl- d 3) The characterization data of aniline are as follows (e.g.) Figure 7 , Figure 8 ): 1 H NMR (400 MHz, CDCl3) δ 6.80 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H), 3.17 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 152.1, 143.7, 114.9, 113.7, 55.9. HRMS(ESI) m / z: calcd for C8H9D3NO [M+H] + : 141.1102, found: 141.1101.

[0116] Example 5

[0117]

[0118] Weigh out TT-CD3 + OTf ‒ (0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, 4-amino-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzenesulfonamide (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus for reaction, with the pump flow rate for both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC, with the reaction solution collected. After the reaction was completed, the reaction was quenched and the final product 102.8 mg of 4-amino-N-(methyl-d3)-N-(5-methylisoxazol-3-yl)benzenesulfonamide was obtained by column chromatography (eluent: petroleum ether: ethyl acetate), with a yield of 95%.

[0119] The characterization data of the product 4-amino-N-(methyl-d3)-N-(5-methylisoxazol-3-yl)benzenesulfonamide are as follows (e.g.) Figure 9 , Figure 10 ): 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 8.7 Hz, 2H), 6.39 (s, 1H), 4.19 (s, 2H), 2.28 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ170.2, 161.1, 151.6, 129.3, 124.3, 114.0, 97.6, 12.7. HRMS (ESI) m / z: calcdfor C 11 H 10 D3N3O3SNa [M+Na] + : 293.0758, found: 293.0768.

[0120] Example 6

[0121]

[0122] Weigh out TT-CD3 + OTf ‒ (0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, 4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamide (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC, with the reaction solution collected. After the reaction was completed, the reaction was quenched and the final product 4-amino-N-(2,6-dimethylpyrimidin-4-yl)-N-(methyl-d3)benzenesulfonamide 92.3 mg was obtained by column chromatography (eluent: petroleum ether: ethyl acetate), with a yield of 78%.

[0123] The characterization data of the product 4-amino-N-(2,6-dimethylpyrimidin-4-yl)-N-(methyl-d3)benzenesulfonamide are as follows (e.g.) Figure 11 , Figure 12 (as shown) 1 H NMR (400 MHz, CDCl3) δ 7.82 – 7.78 (m, 2H), 6.57 – 6.53(m, 2H), 6.48 (s, 1H), 3.78 (s, 2H), 2.25 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ167.1, 158.3, 150.5, 131.2, 128.8, 114.1, 113.1, 23.7. HRMS (ESI) m / z: calcdfor C 13 H 13 D3N4O2SNa [M+Na] + : 318.1074, found: 318.1081.

[0124] Example 7

[0125]

[0126] Weigh out TT-CD3 + OTf ‒(0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, N-(4-(hydroxy)phenyl)acetamide (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC, with the reaction solution collected. After the reaction was completed, the reaction was quenched and separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain the final product N-(4-(methoxy-d3)phenyl)acetamide 60.3 mg, yield 90%.

[0127] The characterization data of the product N-(4-(methoxy-d3)phenyl)acetamide are as follows (e.g.) Figure 13 , Figure 14 (as shown) 1 H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.41 – 7.35 (m, 2H), 6.84 – 6.78 (m, 2H), 2.10 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.8, 156.4, 131.2, 122.1, 114.0,24.2. HRMS (ESI) m / z: calcd for C9H8D3NO2Na [M+Na] + : 191.0870, found: 191.0868.

[0128] Example 8

[0129]

[0130] Weigh out TT-CD3 + OTf ‒(0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, (S)-2-((tert-butyloxycarbonyl)amino)-3-(4-hydroxyphenyl)propionate methyl ester (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC, with the reaction solution collected. After the reaction was completed, the reaction was quenched and the final product (S)-2-((tert-butyloxycarbonyl)amino)-3-(4-(methoxy-) d 3 Methyl phenyl propionate 107.4 mg, yield 86%.

[0131] Product (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(methoxy- d 3 The characterization data of methyl phenyl propionate are as follows (e.g.) Figure 15 , Figure 16 ): 1 H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 8.4 Hz, 2H), 6.75 (d, J =8.5 Hz, 2H), 4.90 (d, J = 7.6 Hz, 1H), 4.52 – 4.42 (m, 1H), 3.64 (s, 3H), 3.01 – 2.89 (m, 2H), 1.35 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 172.5, 158.7, 155.1,130.3, 127.9, 114.0, 79.9, 54.5, 52.2, 37.5, 28.3. HRMS (ESI) m / z: calcd forC 16 H 20 D3NO5Na [M+Na] + : 335.1657, found: 335.1659.

[0132] Example 9

[0133]

[0134] Weigh out TT-CD3 + OTf ‒ (0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, (S)-2-(6-methoxynaphthyl-2-yl)propionic acid (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC and the reaction solution was collected. After the reaction was complete, the reaction was quenched and the final product methyl- was obtained by column chromatography (eluent: petroleum ether: ethyl acetate). d 89.4 mg of methyl 3(S)-2-(6-methoxynaphthyl-2-yl)propionate, yield 90%.

[0135] Product methyl- d The characterization data of methyl 3(S)-2-(6-methoxynaphthyl-2-yl)propionate are as follows (e.g.) Figure 17 , Figure 18 (as shown) 1 H NMR (400 MHz, CDCl3) δ 7.71 – 7.62 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H),7.15 – 7.07 (m, 2H), 3.87 (s, 3H), 3.86 – 3.81 (m, 1H), 1.57 (d, J = 7.2 Hz, 3H). 13 HRMS (ESI) m / z: calcdfor C 15 H 13 D3O3Na [M+Na]+ : 270.1180, found: 270.1181.

[0136] Example 10

[0137]

[0138] Weigh out TT-CD3 + OTf ‒ (0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, (tert-butyloxycarbonyl)-L-tryptophan (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC and the reaction solution was collected. After the reaction was complete, the reaction was quenched and the final product methyl- was obtained by column chromatography (eluent: petroleum ether: ethyl acetate). d 114.6 mg of 3-(tert-butyloxycarbonyl)-L-tryptophan methyl ester, yield 89%.

[0139] Product methyl- d The characterization data of 3-(tert-butyloxycarbonyl)-L-tryptophan methyl ester are as follows (e.g.) Figure 19 , Figure 20 (as shown) 1 HNMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.0Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.94 (s, 1H), 5.12(d, J = 7.7 Hz, 1H), 4.70 – 4.57 (m, 1H), 3.35 – 3.18 (m, 2H), 1.42 (s, 9H). 13CNMR (100 MHz, CDCl3) δ 172.9, 155.4, 136.2, 127.7, 122.9, 122.1, 119.5,118.7, 111.3, 109.9, 80.0, 54.3, 28.4, 28.0. HRMS (ESI) m / z: calcd forC 17 H 19 D3N2O4Na [M+Na] + : 344.1660, found: 344.1661.

[0140] Example 11

[0141]

[0142] Weigh out TT-CD3 + OTf ‒ (0.48 mmol, 1.2 equiv.) was dissolved in 2 mL of acetonitrile to prepare the first mixture; separately, 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (0.4 mmol, 1.0 equiv.) and triethylamine (0.6 mmol, 1.5 equiv.) were dissolved in 2 mL of acetonitrile to prepare the second mixture. The first and second mixtures were drawn into syringes and placed on syringe pumps for later use. The first and second mixtures were simultaneously pumped into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus for reaction, with the pump flow rate of both mixtures set at 0.1 mL / min. The reaction was carried out at 25 °C for 5 min, and the reaction was monitored by TLC, with the reaction solution collected. After the reaction was completed, the reaction was quenched and separated by column chromatography (eluent: petroleum ether: ethyl acetate) to obtain the final product methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetate. d 3130.4 mg, yield 87%.

[0143] Product 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)methyl acetate- d The characterization data for 3 are as follows (e.g.) Figure 21 , Figure 22 ): 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.2 Hz, 2H), 7.44(d, J= 8.2 Hz, 2H), 6.98 – 6.92 (m, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.69 – 6.62(m, 1H), 3.81 (s, 3H), 3.65 (s, 2H), 2.37 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ171.4, 168.2, 156.1, 139.2, 136.0, 134.0, 131.2, 130.8, 130.7, 129.1, 115.0,112.5, 111.6, 101.3, 55.7, 30.1, 13.4. HRMS (ESI) m / z: calcd forC 20 H 15 D3ClNO4Na [M+Na] + : 397.1005, found: 397.1015.

[0144] Example 12

[0145] (1) Different nucleophiles were reacted with 5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate in a conventional reactor under the action of a base. The specific reaction conditions [a] are as follows.

[0146] [a] Reaction conditions: 0.48 mmol (1.2 equiv) of 5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate was added to a dry Schlenk reaction tube, and the tube was purged with argon three times. A nucleophile (0.4 mmol (1 equiv)) and triethylamine (0.6 mmol (1.5 equiv) were dissolved in 4 mL of acetonitrile and injected into the Schlenk reaction tube using a syringe. The deuteration methylation reaction was carried out at 25 °C for 8 h. The reaction was monitored by TLC, and the reaction solution was collected. After the reaction was complete, the product was obtained by column chromatography. The specific yields are shown in Table 1.

[0147] (2) Different nucleophiles were reacted with 5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate in a flow field reactor under the action of alkali. The specific reaction conditions are as follows [b].

[0148] [b]Reaction conditions: Weigh 0.48 mmol (1.2 equiv) of 5-deuterated methyl-5H-thiophene-5-onium trifluoromethanesulfonate and dissolve it in 2 mL of acetonitrile to prepare the first mixture. Separately, dissolve 0.4 mmol (1 equiv) of nucleophile and 0.6 mmol (1.5 equiv) of triethylamine in 2 mL of acetonitrile to prepare the second mixture. After complete dissolution, load the first and second mixtures into syringes. Simultaneously pump the first and second mixtures into the microfluidic reactor (coil inner diameter 0.6 mm, volume 1.0 mL) of the flow field reaction apparatus using a syringe pump. Set the pump flow rate for both mixtures to 0.1 mL / min. The reaction was carried out at 25 °C for 5 min. The reaction was monitored by TLC, and the reaction solution was collected. After the reaction was completed, the product was obtained by column chromatography. The specific yields are shown in Table 1.

[0149] Table 1

[0150]

[0151] This invention provides a concept and method for achieving deuterated methylation of nucleophiles. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A deuterated methylation reagent characterized in that, The structure of the deuterated methylating reagent is shown as follows: 。 2. The method of producing the deuterated methylating reagent according to claim 1, characterized by, After the first reaction of formic acid and deuterated methanol under the action of acid, and the second reaction with thianthrene and trifluoromethanesulfonic acid, the deuterated methylated product is obtained.

3. The production method according to claim 2, characterized by, The acid is concentrated sulfuric acid, concentrated hydrochloric acid or concentrated phosphoric acid; the molar ratio of formic acid, deuterated methanol, acid, thianthrene, trifluoromethanesulfonic acid is 3-5:8-10:3-5:1-3:4-9; the first reaction, the reaction temperature is 50-80 o C, the reaction time is 3-5 h; the second reaction, the reaction temperature is 20-40 o C.

4. Use of the deuterated methylating reagent according to claim 1 in a deuterated methylation reaction, characterized in that, The deuterated methylated product is prepared by using a thiol compound, an amine compound, a hydroxyl compound or a carboxyl compound as a nucleophilic reagent, and performing a deuterated methylation reaction of the nucleophilic reagent and the deuterated methylating reagent of claim 1. The thiol-containing compound has a structural formula of ; the amine compound has a structural formula of ; and the hydroxyl-containing compound has a structural formula of ; The carboxyl group-containing compound has a structural formula of ; The structural formula of the deuterated methylation product is 、 、 or ; R 1 is selected from C5-C6cycloalkyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted phenyl; said substitution is selected from one or more, identical or different, substituents selected from any one or several of C1-C3alkoxy, C1-C3alkanoyloxy and C1-C3alkanoyloxy-C1-C3alkyl; R 2 , R 3 is independently selected from hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted phenylsulfonyl, substituted 5-isoxazolyl or substituted pyrimidinyl; wherein said substitution is selected from substitution with one or more substituents which are the same or different and selected from C1-C3alkoxy, amino or C1-C3alkyl optionally substituted; R 4 is selected from substituted or unsubstituted phenyl; said substitution is selected from optional substitution with C1-C3alkanoylamino or (tert-butoxycarbonylamino) (C1-C3alkoxyC1-C3alkanoyl)C1-C3alkyl; R 5 substituted or unsubstituted C1-C3alkyl, or substituted indolylmethyl; wherein said substitution is selected from substitution with one or more substituents which are the same or different and are selected from (C1-C2alkyl)(C1-C2alkyloxy naphthyl), (tert-butoxycarbonylamino)(indolyl C1-C2alkyl), C1-C3alkoxy, halobenzoyl, or C1-C3alkyl.

5. A method of effecting deuteromethylation of a nucleophile, characterized by, The deuterated methylated product is obtained by mixing the nucleophilic reagent, the deuterated methylating reagent of claim 1, a base and a solvent, and then performing a reaction. The nucleophilic reagent is a thiol compound, an amine compound, a hydroxyl compound or a carboxyl compound. When the reaction is performed in a microfluidic field reaction device, the following steps are included: The structure of the thiol-containing compound is ; the structure of the amine compound is ; the structure of the hydroxyl-containing compound is ; and the structure of the carboxyl-containing compound is ; The structural formula of the deuterated methylation product is , , or ; R 1 is selected from C5-C6cycloalkyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted phenyl; said substitution is selected from one or more, identical or different, substituents selected from any one or several of C1-C3alkoxy, C1-C3alkanoyloxy and C1-C3alkanoyloxy-C1-C3alkyl; R 2 , R 3 is independently selected from hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted phenylsulfonyl, substituted 5-isoxazolyl or substituted pyrimidinyl; wherein the substitution is selected from one or more of the same or different substituents selected from C1-C3alkoxy, amino or C1-C3alkyl optionally substituted; R 4 is selected from the group consisting of substituted or unsubstituted phenyl; said substitution is selected from the group consisting of being optionally substituted with C1-C3alkanoylamino or (tert-butoxycarbonylamino)(C1-C3alkoxyC1-C3alkanoyl)C1-C3alkyl; R 5 substituted or unsubstituted C1-C3alkyl, or substituted indolylmethyl; wherein said substitution is selected from substitution with one or more substituents which are the same or different and are selected from (C1-C2alkyl)(C1-C2alkyloxy naphthyl), (tert-butoxycarbonylamino)(indolyl C1-C2alkyl), C1-C3alkoxy, halobenzoyl, or C1-C3alkyl optionally substituted; The deuterated methylating reagent of claim 1 is mixed with a solvent to obtain a first mixed solution; the nucleophilic reagent, a base and a solvent are mixed to obtain a second mixed solution; the first mixed solution and the second mixed solution are simultaneously pumped into a microfluidic field reactor of a microfluidic field reaction device to perform a reaction, and the deuterated methylated product is obtained.

6. The method of claim 5, wherein 7. The method of claim 5, wherein said thiol-containing compound has the formula ; wherein R 1 is selected from C5-C6cycloalkyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted phenyl; said substitution is selected from one or more of the same or different substituents selected from any one or several of C1-C2alkoxy, C1-C2alkanoyloxy, and C1-C2alkanoyloxy-C1-C2alkyl; The amine compound has a structural formula of ; wherein R 2 , R 3 are independently selected from hydrogen, substituted phenyl, substituted phenylsulfonyl, substituted 5-isoxazolyl or substituted pyrimidinyl; wherein the substitution is selected from being substituted with one or more of the same or different substituents selected from C1-C2alkoxy, amino or C1-C2alkyl optionally substituted; The hydroxyl-containing compound has the formula ; wherein R 4 is selected from substituted phenyl; said substitution is selected from optional substitution with C1-C2alkanoylamino or (t-butoxycarbonylamino) (C1-C2alkoxyC1-C2alkanoyl)C1-C2alkyl; said carboxylic compound has the formula ; wherein R 5 is selected from substituted C1-C2alkyl, or substituted indolylmethyl; wherein said substitution is selected from being substituted with one or more of the same or different substituents selected from being optionally substituted with (C1-C2alkyl)(C1-C2alkyloxy naphthyl), (t-butoxycarbonylamino)(indolyl C1-C2alkyl), C1-C2alkoxy, chlorobenzoyl, or C1-C2alkyl.

8. The method of claim 7, wherein said thiol-containing compound has the formula ; wherein R 1 is selected from substituted tetrahydropyranyl, or substituted phenyl; said substitution is selected from substitution with one or more of the same or different substituents selected from any one or several of methoxy, acetoxy, and acetyloxymethyl groups; The amine compound has a structural formula of ; wherein R 2 , R 3 are independently selected from hydrogen, substituted phenyl, substituted phenylsulfonyl, substituted 5-isoxazolyl or substituted pyrimidinyl; wherein the substitution is selected from being substituted with one or more substituents which are the same or different and selected from methoxy, amino or methyl optionally substituted; The hydroxyl-containing compound has the formula ; wherein R 4 is selected from substituted phenyl; said substitution is selected from acetylamino or (t-butoxycarbonylamino) (methoxymethoxy) ethyl. The carboxylic compound has the formula ; wherein R 5 is selected from substituted methyl, or substituted indolylmethyl; wherein said substitution is selected from substitution with one or more of the same or different substituents selected from (methyl)(methoxynaphthyl), or (tert-butoxycarbonylamino)(3-indolylmethyl), methoxy, 4-chlorobenzoyl, or methyl. The thiol compound is selected from any one of the following structures: The amine compound is selected from any one of the following structures: ； The hydroxyl compound is selected from any one of the following structures: ； The carboxyl compound is selected from any one of the following structures: ； The base is any one or a combination of multiple of triethylamine, 4-dimethylaminopyridine, 1,8-diazobicyclo[5.4.0]undec-7-ene, N,N-diisopropylethylamine, N,N,N',N'-tetramethyl ethylenediamine and 2,6-dimethylpyridine; and the solvent is any one or a combination of multiple of acetonitrile, methanol, ethyl acetate, dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, chloroform and acetone. 。 9. The method of claim 5, wherein, The molar ratio of the nucleophilic reagent to the deuterated methylating reagent and the base is 1:1-5:1-2.

10. The method of claim 5, wherein, The reaction temperature is 20-30°C.

11. The method of claim 5, wherein, In the first mixed solution, the concentration of the deuterated methylating reagent is 0.05-1 mmol / mL; in the second mixed solution, the concentration of the nucleophilic reagent is 0.05-1 mmol / mL; the flow rate of the first mixed solution pumped into the microfluidic field reactor of the microfluidic field reaction device is 0.05 mL / min-0.1 mL / min; and the flow rate of the second mixed solution pumped into the microfluidic field reactor of the microfluidic field reaction device is 0.05 mL / min-0.1 mL / min.

12. The method of claim 5, wherein, The microfluidic field reactor has a pore structure and is made of perfluoroalkoxy alkane; the size of the microfluidic field reactor is an inner diameter of 0.5-2.0 mm and a volume of 0.3-20.0 mL; and the residence time of the material in the microfluidic field reactor is 30 s-2.6 h.

13. The method of claim 5, wherein, ​

Images