Method for preparing deuterium methylation reagent from deuterium water, obtained deuterium methylation reagent and application

Abstract

The invention discloses a method for preparing a deuterium methylation reagent from deuterium water, the obtained deuterium methylation reagent and application, and belongs to the technical field of preparation of deuterated chemicals. The preparation method comprises the following steps: reacting a diaryl sulfide compound with a cross-linking agent in the presence of Lewis acid and a solvent I to obtain a diaryl sulfide porous polymer; reacting the diaryl sulfide porous polymer with methyl trifluoromethanesulfonate in a solvent II to obtain a methylation reagent; and reacting the methylation reagent with deuterium water at 15-35 DEG C in the presence of alkali for 5-12 hours to obtain the deuterium deuterium. The deuterium methylation reagent has the advantages of simple synthesis steps, high efficiency, low cost, avoiding of the use of expensive reagents, and mild preparation conditions; the obtained deuterium methylation reagent can realize controllable deuterization of different functional groups and site drug molecules, and the reaction process has the advantages of low energy consumption, high product selectivity, simple separation and less pollutant discharge.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of deuterated chemicals, and in particular to a method for preparing a deuterated methylation reagent from deuterated water, and the obtained deuterated methylation reagent and application thereof. Background Art

[0002] The information disclosed in the background of the invention is only intended to enhance the understanding of the overall background of the invention and should not be necessarily regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Deuterium (D) is a non-radioactive and stable isotope of hydrogen (H), and compounds containing deuterium (D) are widely used in various scientific applications, such as elucidating reaction mechanisms in organic chemistry and tracers to reveal metabolic pathways in medicinal chemistry, functional enhancement of drugs and organic light-emitting diodes, etc. The deuterium kinetic isotope effect (KIE), which arises from the much higher dissociation energy of carbon-deuterium (CD) bonds than that of carbon-hydrogen (CH) bonds, has attracted much attention in drug discovery research. This is because most drugs undergo cytochrome P450 (CYP)-mediated oxidative metabolism, and replacing CH bonds with more stable CD bonds at the metabolic site of the drug, especially at the position alpha to the heteroatom (i.e., deuterium switch), can improve its pharmacokinetics or the toxicity characteristics of the drug.

[0004] Heavy isotopes of hydrogen (deuterium or tritium) are usually introduced into target compounds through multi-step synthesis. Commonly used hydrogen-deuterium exchange reactions mostly rely on transition metal catalysis. However, this method has problems with the D content of the product and the regioselectivity of the deuterated position, and the reaction conditions involved are relatively harsh, the reaction energy consumption is high, and the reaction purification is complicated. Another method is to use a stable deuterium source to achieve a high deuteration rate and high regioselectivity. For example, some commercial d3-methyl sources (such as CD3I, CD3OD, and CD3NH2·HCl, etc.) are often used to synthesize deuterated drugs, including the approved drugs deuterated tetrabenazine and deuterated colestipol. However, these deuterated methyl reagents either require multi-step synthesis and harsh synthesis conditions that are difficult to operate (such as using methyl metal reagents and methyl boron reagents), or the corresponding deuterated methyl reagents are relatively expensive. Therefore, it is urgent to develop an efficient, convenient and economical deuterated methylation reagent. Summary of the invention

[0005] In view of this, the present invention provides a method for preparing a deuterium methylation reagent from deuterium water, the obtained deuterium methylation reagent and its application, which is synthesized using cheap and readily available deuterium water as a deuterium source, thereby solving the problems of the existing deuterium methylation reagent being complicated in synthesis, demanding in conditions and expensive in raw materials.

[0006] In a first aspect, the present invention provides a method for preparing a deuterated methylation reagent from deuterated water, comprising the following steps:

[0007] S1, a diaryl sulfide compound and a cross-linking agent react in the presence of a Lewis acid and a solvent to obtain a diaryl sulfide porous polymer;

[0008] S2, reacting the diaryl sulfide porous polymer and methyl trifluoromethanesulfonate in solvent 2 to obtain a methylating agent;

[0009] S3. The methylation reagent is reacted with deuterated water in the presence of a base at 15 to 35° C. for 5 to 12 hours to obtain a deuterated methylation reagent.

[0010] Preferably, the diaryl sulfide compound is selected from one or more of thianthrene, diarylthiophene, diphenyl sulfide, phenoxathiol, phenothiazine or 10-methylphenothiazine.

[0011] Preferably, the crosslinking agent is selected from one or more of 1,4-dichlorobenzyl, dimethoxymethane, acetaldehyde dimethyl acetal, 2,2-dimethoxypropane, 1,4-dimethoxybenzene or 9,10-dimethoxyanthracene.

[0012] Preferably, the Lewis acid is selected from one or more of aluminum chloride, ferric chloride or boron trifluoride.

[0013] Preferably, the solvent is selected from one or more of 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene or nitrobenzene.

[0014] Preferably, the mass ratio of the diaryl sulfide compound, the crosslinking agent and the Lewis acid is 1:(3-10):(3-10).

[0015] Preferably, the reaction temperature of step S1 is 70-100° C., and the reaction time is 10-20 h.

[0016] Preferably, the usage ratio of the diaryl sulfide porous polymer to methyl trifluoromethanesulfonate is 1 g: (0.8-2) mL.

[0017] Preferably, the solvent is selected from one or more of 1,2-dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene or nitrobenzene.

[0018] Preferably, the reaction temperature of step S2 is 50-70° C., and the reaction time is 3-10 h.

[0019] Preferably, the base in step S3 is selected from one or more of potassium carbonate, sodium carbonate, lithium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0020] Preferably, the mass ratio of the methylating agent to the base is (1-20):1; the dosage ratio of the methylating agent to deuterated water is (0.4-0.6) g:(1-5) mL.

[0021] Preferably, the reaction in step S3 further comprises solvent three, and the solvent three is selected from acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the volume ratio of deuterated water to solvent three is 1:(0-2).

[0022] In a second aspect, the present invention provides a deuterated methylation reagent prepared by the above method.

[0023] In a third aspect, the present invention provides the use of the above-mentioned deuterium methylation reagent in the deuterium methylation of drug molecules.

[0024] In a fourth aspect, the present invention provides a method for deuterated methylation of a drug molecule, comprising the following steps:

[0025] The above-mentioned deuterated methylation reagent and drug molecule substrate are placed in solvent four, and reacted at 15-35° C. for 5-10 hours. After the reaction is completed, the filtrate is filtered and the filtrate is the deuterated methylation drug.

[0026] Preferably, the mass ratio of the deuterated methylation reagent to the drug molecule substrate is (1-10):1.

[0027] Preferably, the solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, methyl tert-butyl ether or ethanol.

[0028] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0029] (1) The present invention uses a porous diaryl sulfide polymer to activate the methyl group, and then uses cheap and easily available deuterated water to efficiently exchange hydrogen and deuterium with the methyl group at room temperature under base catalysis to obtain a deuterated methylation reagent; the deuterated methylation reagent of the present invention has simple and efficient synthesis steps, avoids the use of expensive reagents, and has mild preparation conditions;

[0030] (2) The deuterated methylation reagent prepared by the present invention is a heterogeneous reagent, which can realize the controllable deuteration of drug molecules with different functional groups and sites, thereby obtaining a series of deuterated chemicals with high added value, which can reduce the preparation cost of deuterated chemicals and make them widely used in exploring drug metabolism, revealing organic reaction mechanisms and improving material properties. In addition, the reaction process has low energy consumption, high product selectivity, simple separation and low pollutant emissions. The separated deuterated methylation reagent can be re-processed for the reactions of steps S2 and S3 and then reused, which has broad industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The drawings constituting part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute an improper limitation of the present invention. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative work.

[0032] Figure 1 It is the thermogravimetric curve and thermogravimetric differential curve of the deuterated methylation reagent POP-1-CD3 of Example 1 of the present invention. DETAILED DESCRIPTION

[0033] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0034] The present invention provides a method for preparing a deuterium methylation reagent from deuterium water, comprising the following steps:

[0035] S1, a diaryl sulfide compound and a cross-linking agent react in the presence of a Lewis acid and a solvent to obtain a diaryl sulfide porous polymer;

[0036] S2, reacting the diaryl sulfide porous polymer and methyl trifluoromethanesulfonate in solvent 2 to obtain a methylating agent;

[0037] S3. The methylation reagent is reacted with deuterated water in the presence of a base at 15 to 35° C. for 5 to 12 hours to obtain a deuterated methylation reagent.

[0038] The present invention first synthesizes an organic porous polymer based on aryl sulfide, and the sulfur of the organic porous polymer can react with methyl trifluoromethanesulfonate to obtain a thiomethyl group. The formed sulfonium ylide causes the sulfur ring to have a positive charge, which can induce the hydrogen at the α position to have acidity. Through a simple pH-dependent hydrogen isotope exchange (HIE) process, a deuterated methylation catalyst can be obtained. The specific principle is: the anion of the base attacks the hydrogen at the adjacent position of sulfur to form a carbon anion, and the deuterated hydrogen produced by deuterated water undergoes electrophilic addition to obtain a deuterated methyl catalyst. The process is mild, does not require a metal catalyst, and the reaction can be completed at room temperature. The drug molecules can be subsequently modified and recycled (the reactions of steps S2 and S3 are repeated).

[0039] In the present invention, the diaryl sulfide compound is selected from one or more of thianthrene, diarylthiophene, diphenyl sulfide, phenoxathiol, phenothiazine or 10-methylphenothiazine.

[0040] In the present invention, the crosslinking agent is selected from one or more of 1,4-dichlorobenzyl, dimethoxymethane, acetaldehyde dimethyl acetal, 2,2-dimethoxypropane, 1,4-dimethoxybenzene or 9,10-dimethoxyanthracene.

[0041] In the present invention, the Lewis acid is selected from one or more of aluminum chloride, ferric chloride or boron trifluoride.

[0042] In the present invention, the solvent one is selected from one or more of 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene or nitrobenzene.

[0043] In the present invention, the mass ratio of the diaryl sulfide compound, the crosslinking agent and the Lewis acid is 1:(3-10):(3-10). The present invention does not impose any particular limitation on the amount of solvent 1, as long as the reactants can be fully dissolved or dispersed.

[0044] In the present invention, the reaction temperature of step S1 is 70-100° C., and the reaction time is 10-20 hours.

[0045] The present invention does not impose any special restrictions on the purification step after the reaction in step S1 is completed, and the purification method of the organic porous polymer commonly used in the art can be used. The present invention preferably performs suction filtration, then washes with a hydrochloric acid solution until the filtrate is colorless, then washes with an organic solvent, and then dries to obtain the product.

[0046] In the present invention, the usage ratio of the diaryl sulfide porous polymer and methyl trifluoromethanesulfonate is 1 g: (0.8-2) mL.

[0047] In the present invention, the second solvent is selected from one or more of 1,2-dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene or nitrobenzene. The present invention does not impose any particular restriction on the amount of the first solvent, as long as the reactants can be fully dissolved or dispersed.

[0048] In the present invention, the reaction temperature of step S2 is 50-70° C., and the reaction time is 3-10 h.

[0049] In the present invention, the base in step S3 is selected from one or more of potassium carbonate, sodium carbonate, lithium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide or lithium hydroxide. The present invention finds that inorganic bases have better reaction catalytic ability than organic bases (such as triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene), and can keep the reaction yield and deuteration rate of step S3 at a high level.

[0050] In the present invention, the mass ratio of the methylating agent to the base is (1-20):1, more preferably (5-15):1; the amount ratio of the methylating agent to deuterated water is (0.4-0.6) g:(1-5) mL. The present invention uses deuterated water as a deuterium source, which has good reactivity with the methylating agent, and the reaction can occur at room temperature. If the deuterium source is replaced with deuterated dimethyl sulfoxide or deuterated methanol, the reaction yield and the deuteration rate are significantly reduced.

[0051] In the present invention, the reaction of step S3 further includes solvent three, and the solvent three is selected from acetonitrile, tetrahydrofuran or N,N-dimethylformamide, preferably acetonitrile; the volume ratio of deuterated water to solvent three is 1:(0-2). Step S3 can use deuterated water alone as a solvent, or a mixed solvent can be used. When a mixed solvent is used, the reaction yield and deuteration rate are not significantly reduced, but the cost can be significantly reduced, so it is preferred to use a mixed solvent.

[0052] The present invention also provides a deuterated methylation reagent prepared by the above method, which is a solid reagent and has good stability, separability and reusability.

[0053] The present invention also provides application of the deuterium methylation reagent in deuterium methylation of drug molecules.

[0054] The present invention also provides a method for deuterated methylation of drug molecules, comprising the following steps:

[0055] The above-mentioned deuterated methylation reagent and drug molecule substrate are placed in solvent four, and reacted at 15-35° C. for 5-10 hours. After the reaction is completed, the filtrate is filtered and the filtrate is the deuterated methylation drug.

[0056] The present invention does not impose any particular limitation on the types of drug molecules mentioned above, and may be, for example, carboxylic acids, phenols, benzenethiols, primary amines or secondary amine compounds.

[0057] In the present invention, the mass ratio of the deuterated methylation reagent to the drug molecule substrate is (1-10):1, more preferably (1-4):1.

[0058] In the present invention, the solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, methyl tert-butyl ether or ethanol.

[0059] After the deuterated methylation reaction of the drug molecule is completed, the deuterated deuterated methylation reagent can be subjected to step S2 and step S3 again to prepare the deuterated methylation reagent, so it can be recycled.

[0060] The technical solution of the present invention is further described below in conjunction with specific embodiments. The room temperature in the following embodiments refers to 25±3°C.

[0061] Example 1

[0062] This embodiment provides a method for preparing a deuterated methylation reagent, and the reaction route is shown in the following formula:

[0063]

[0064] (1) Diphenyl sulfide (5 g, 26.8 mmol) and ferric chloride (22.5 g) were placed in a 500 mL round-bottom flask. The replacement system was an argon atmosphere. During the argon introduction process, 250 mL of 1,2-dichloroethane (DCE) was added. 1,4-dichlorobenzyl (23.5 g) was added under full stirring. The temperature was raised to 80°C for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature. 50 mL of methanol was added to precipitate a solid. After filtration, the solid was repeatedly washed with a 3M hydrochloric acid solution until the filtrate was colorless. Finally, it was washed with ethyl acetate and methanol and dried to obtain a total of 7.1 g (142%) of a diphenyl sulfide porous polymer POP-1.

[0065] (2) 500 mg of dried POP-1 was placed in a 50 mL round-bottom flask, 10 mL of 1,2-dichloroethane and 0.5 mL of methyl trifluoromethanesulfonate (CH3OTf) were added under stirring, and the temperature was raised to 60°C for reaction for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, methanol was added to quench the reaction, and the filtrate was washed with methanol and ethyl acetate until the filtrate was colorless, and dried to obtain a total of 650 mg of the methylation reagent POP-1-CH3.

[0066] (3) 500 mg of POP-1-CH3 was placed in a 50 mL round-bottom flask, 2 mL of deuterated water and 2 mL of acetonitrile were added, and 50 mg of potassium carbonate was added under stirring. The mixture was stirred at room temperature for 8 h. After the reaction was completed, methanol and ethyl acetate were filtered out for washing, and the mixture was dried to obtain 480 mg of the deuterated methylation reagent POP-1-CD3, with a yield of 96% and a deuteration rate of 98%.

[0067] Figure 1 It is the thermogravimetric curve and thermogravimetric differential curve of the deuterated methylation reagent POP-1-CD3 prepared in this example. It can be seen from the figure that there are two groups of weight loss peaks. About 250°C corresponds to the shedding of deuterated methyl, and 500°C corresponds to the decomposition of the material, which can be explained that it has good heat resistance.

[0068] Example 2

[0069] This embodiment provides a method for preparing a deuterated methylation reagent, and the reaction route is shown in the following formula:

[0070]

[0071] (1) Dibenzothiophene (5 g, 26.8 mmol) and ferric chloride (22.5 g) were placed in a 500 mL round-bottom flask. The replacement system was an argon atmosphere. During the introduction of argon, 250 mL of 1,2-dichloroethane was added. 1,4-dichlorobenzyl (23.5 g) was added under full stirring. The temperature was raised to 80°C for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature. 50 mL of methanol was added to precipitate solids. After filtration, the solids were repeatedly washed with 3 M hydrochloric acid solution until the filtrate was colorless. Finally, the solids were washed with ethyl acetate and methanol and dried to obtain 7.6 g (152%) of organic porous polymer POP-2.

[0072] (2) 500 mg of dried POP-2 was placed in a 250 mL round-bottom flask, 10 mL of 1,2-dichloroethane and 0.5 mL of methyl trifluoromethanesulfonate were added under stirring, and the temperature was raised to 60°C for reaction for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, methanol was added to quench the reaction, and the filtrate was washed with methanol and ethyl acetate until the filtrate was colorless and dried to obtain 670 mg of the methylation reagent POP-2-CH3.

[0073] (3) 500 mg of POP-2-CH3 was placed in a 250 mL round-bottom flask, 2 mL of deuterated water and 2 mL of acetonitrile were added, and 50 mg of potassium carbonate was added under stirring. The mixture was stirred at room temperature for 8 h. After the reaction, methanol and ethyl acetate were filtered and washed, and dried to obtain 460 mg of the deuterated methylation reagent POP-2-CD3. The yield was 92% and the deuteration rate was 98%.

[0074] Example 3

[0075] Compared with Example 1, 4 mL of deuterated water was added in step (3) of this example, and acetonitrile was not added.

[0076] Example 4

[0077] Compared with Example 1, potassium hydroxide is used to replace potassium carbonate in step (3) of this example.

[0078] Comparative Example 1

[0079] Compared with Example 3, in step (3) of this comparative example, triethylamine (Et3N) is used to replace potassium carbonate.

[0080] Comparative Example 2

[0081] Compared with Example 3, in step (3) of this comparative example, potassium carbonate was replaced by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0082] Comparative Example 3

[0083] Compared with Example 3, deuterated water is replaced by deuterated dimethyl sulfoxide (DMSO-D6) in step (3) of this comparative example.

[0084] Comparative Example 4

[0085] Compared with Example 3, deuterated water is replaced by deuterated methanol (CD3OD) in step (3) of this comparative example.

[0086] The yield and deuteration rate of step (3) of Examples 1 to 4 and Comparative Examples 1 to 4 are shown in Table 1.

[0087] Table 1 Yield and deuteration rate of step (3) of Examples 1 to 4 and Comparative Examples 1 to 4

[0088]

[0089]

[0090] As can be seen from Table 1, when the base is replaced by potassium hydroxide, the reaction yield and deuteration rate are slightly reduced, and when the base is replaced by organic bases Et3N and DBU, the reaction yield and deuteration rate are significantly reduced. When replaced by other deuterated sources (deuterated DMSO and deuterated methanol), the reaction yield and deuteration rate also decrease by a large margin. When the solvent is replaced by a mixed solvent of deuterated water and acetonitrile from deuterated water, the yield and deuteration rate do not significantly decrease.

[0091] Application Example 1

[0092] In this application example, the deuterium methylation catalyst POP-1-CD3 prepared in Example 1 is used for the deuterium methylation reaction of fenofibric acid, and the reaction route is shown in the following formula:

[0093]

[0094] Weigh fenofibric acid (0.5mmol, 159mg), 0.2mmol potassium carbonate, 300mg deuterated methylation reagent POP-1-CD3 respectively and add them to a 5mL reaction bottle, and add 5mL acetonitrile solution, stir and react at room temperature for 6 hours, and filter after the reaction. The filter cake is POP-1 obtained after deuterated methylation, which can be reacted again to obtain POP-1-CD3 and put into use. Add 5mL water to the filtrate and extract with 10.0mL CH2Cl2, dry the extract with anhydrous sodium sulfate, and concentrate to obtain 160mg (95%) of white solid. Perform NMR test and HR-MS analysis to determine the product. 1 H NMR(500MHz, CDCl3)δ:7.77-7.68(m,4H),7.45(d,2H),6.86(d,2H),1.68(s,2H); 13C NMR(125MHz, CDCl3)δ:194.24,174.24,159.58,138.40,136.34,132.07,131.19,130.45,128.55,117.31,79.35,25.41; HRMS(ESI-TOF)(m / z)calculated for C 18 H 15 D3ClO4[M+H] + :336.1076,Found:336.1073.

[0095] Application Example 2

[0096] In this application example, the deuterium methylation catalyst POP-1-CD3 prepared in Example 1 is used for the deuterium methylation reaction of deuterated nimesulide, and the reaction route is shown in the following formula:

[0097]

[0098] Weigh nimesulide (0.5mmol, 154mg), 0.2mmol potassium carbonate, 300mg deuterated methyl catalyst POP-1-CD3 respectively and add them to a 5mL reaction bottle, and add 5mL acetonitrile solution, stir and react at room temperature for 6 hours, and filter after the reaction. The filter cake is POP-1 obtained after deuterated methylation, which can be reacted again to obtain POP-1-CD3 and put into use. Add 5mL water to the filtrate and extract with 10.0mL CH2Cl2, dry the extract with anhydrous sodium sulfate, and concentrate to obtain 130mg (92%) of white solid. Perform NMR test and HR-MS analysis to determine the product. 1 H NMR(500MHz, CDCl3)δ:7.94-7.89(dd,1H),7.65-7.60(m,2H),7.47(t,2H),7.30(t,1H),7.12(d,2H),3.01(s,3H); 13 C NMR (125MHz, CDCl3) δ: 194.24, 174.24, 159.58, 138.40, 136.34, 132.07, 131.19, 130.45, 128.55, 117.31, 79.35, 25.41; 13 CNMR(151MHz, CDCl3)δ:154.94,154.44,147.74,136.79,132.63,130.74,125.80,119.79,118.09,112.75,38.63; HRMS(ESI-TOF)(m / z)calculated for C 14 H 12D3N2O5S[M+H] + :326.0884,Found:326.0881.

[0099] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a deuterium methylation reagent from deuterium water, characterized in that: The steps include: S1, a diaryl sulfide compound and a cross-linking agent react in the presence of a Lewis acid and a solvent to obtain a diaryl sulfide porous polymer; S2, reacting the diaryl sulfide porous polymer and methyl trifluoromethanesulfonate in solvent 2 to obtain a methylating agent; S3. The methylation reagent is reacted with deuterated water in the presence of a base at 15 to 35° C. for 5 to 12 hours to obtain a deuterated methylation reagent.

2. The method according to claim 1, characterized in that The diaryl sulfide compound is selected from one or more of thianthrene, diarylthiophene, diphenyl sulfide, phenoxathiol, phenothiazine or 10-methylphenothiazine; The Lewis acid is selected from one or more of aluminum chloride, ferric chloride or boron trifluoride; The solvent one is selected from one or more of 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene or nitrobenzene.

3. The method according to claim 1, characterized in that The mass ratio of the diaryl sulfide compound, the cross-linking agent and the Lewis acid is 1:(3-10):(3-10); the reaction temperature of step S1 is 70-100° C., and the reaction time is 10-20 hours.

4. The method according to claim 1, characterized in that The diaryl sulfide porous polymer and methyl trifluoromethanesulfonate are used in a ratio of 1 g: (0.8-2) mL; The second solvent is selected from one or more of 1,2-dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene or nitrobenzene; The reaction temperature of step S2 is 50-70° C., and the reaction time is 3-10 h.

5. The method according to claim 1, characterized in that The base in step S3 is selected from one or more of potassium carbonate, sodium carbonate, lithium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide or lithium hydroxide; The mass ratio of the methylating agent to the base is (1-20):1; the dosage ratio of the methylating agent to deuterated water is (0.4-0.6) g:(1-5) mL.

6. The method according to claim 1, characterized in that The reaction in step S3 further includes solvent three, and the solvent three is selected from acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the volume ratio of deuterated water to solvent three is 1:(0-2).

7. A deuterated methylation reagent prepared by the method according to any one of claims 1 to 6.

8. Use of the deuterium methylation reagent as claimed in claim 7 in the deuterium methylation of drug molecules.

9. A method for deuterated methylation of drug molecules, characterized in that: The steps include: The deuterated methylation reagent and the drug molecule substrate described in claim 7 are placed in solvent 4, reacted at 15-35° C. for 5-10 hours, and filtered after the reaction is completed. The filtrate is the deuterated methylation drug.

10. The method according to claim 8, characterized in that The mass ratio of the deuterated methylation reagent to the drug molecule substrate is (1-10):1; the solvent is selected from one or more of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, methyl tert-butyl ether or ethanol.

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