A method for preparing deuterated methylating reagents from deuterium water, and the resulting deuterated methylating reagents and applications

Abstract

This invention discloses a method for preparing a deuterated methylating agent from deuterium water, the obtained deuterated methylating agent, and its applications, belonging to the field of deuterated chemical preparation technology. The preparation method of this invention includes the following steps: a diaryl sulfide compound and a crosslinking agent react in the presence of a Lewis acid and solvent one to obtain a diaryl sulfide porous polymer; the diaryl sulfide porous polymer and methyl trifluoromethanesulfonate react in solvent two to obtain a methylating agent; the methylating agent reacts with deuterium water in the presence of a base at 15–35°C for 5–12 h to obtain the final product. The synthesis steps of the deuterated methylating agent of this invention are simple, efficient, and low-cost, avoiding the use of expensive reagents, and the preparation conditions are mild; the obtained deuterated methylating agent can achieve controllable deuteration of drug molecules with different functional groups and sites, and the reaction process has low energy consumption, high product selectivity, simple separation, and low pollutant emissions.

Description

Technical Field

[0001] This invention relates to the field of deuterated chemical preparation technology, and more particularly to a method for preparing deuterated methylating reagents from deuterium water, the resulting deuterated methylating reagents, and their applications. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Deuterium (D) is a non-radioactive and stable isotope of hydrogen (H). Compounds containing deuterium (D) are widely used in various scientific applications, such as elucidating reaction mechanisms in organic chemistry, using it as a tracer to reveal metabolic pathways in medicinal chemistry, enhancing drug function, and in organic light-emitting diodes (OLEDs). The deuterokinetic isotope effect (KIE), arising from the much higher dissociation energy of the carbon-deuterium (CD) bond compared to the carbon-hydrogen (CH) bond, has attracted significant 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 drug metabolic sites, particularly at heteroatom α positions (i.e., deuterium switches), can improve their pharmacokinetics or toxicity profile.

[0004] Heavy isotopes of hydrogen (deuterium or tritium) are typically introduced into target compounds through multi-step synthesis. Common hydrogen-deuterium exchange reactions often rely on transition metal catalysis. However, this method suffers from limitations in the D content and regioselectivity of the deuterated position of the product, and involves harsh reaction conditions, high energy consumption, and complex purification processes. Another approach utilizes stable deuterium sources to achieve high deuteration rates and regioselectivity. For example, commercially available d3-methyl sources (such as CD3I, CD3OD, and CD3NH2·HCl) are frequently used to synthesize deuterated drugs, including the approved drugs deuterated buphenazine and deuterated colexitinib. However, these deuterated methylating agents either require multi-step synthesis under harsh and difficult-to-operate conditions (e.g., using methyl metal reagents or methyl boron reagents), or the corresponding deuterated methylating agents are expensive. Therefore, the development of an efficient, convenient, and economical deuteration methylation reagent is urgently needed. Summary of the Invention

[0005] In view of this, the present invention provides a method for preparing deuterated methylating reagents from deuterium water, the obtained deuterated methylating reagents and their applications, which are synthesized using inexpensive and readily available deuterium water as the deuterium source, solving the problems of cumbersome synthesis, harsh conditions and expensive raw materials of existing deuterated methylating reagents.

[0006] In a first aspect, the present invention provides a method for preparing a deuterium methylating agent from deuterium water, comprising the following steps:

[0007] S1, a diaryl sulfide compound and a crosslinking agent were reacted in the presence of a Lewis acid and solvent one to obtain a diaryl sulfide porous polymer;

[0008] S2. The diaryl sulfide porous polymer and methyl trifluoromethanesulfonate react in solvent two to obtain a methylating agent;

[0009] S3. The methylating agent is reacted with deuterium water in the presence of an alkali at 15–35°C for 5–12 h to obtain the deuterium methylating agent.

[0010] Preferably, the diaryl sulfide compound is selected from one or more of thiaanthracene, diarylthiophene, diphenyl sulfide, 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 in step S1 is 70–100°C, and the reaction time is 10–20 h.

[0016] Preferably, the 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 in step S2 is 50–70°C, and the reaction time is 3–10 h.

[0019] Preferably, the alkali 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; and the volume ratio of the methylating agent to deuterium water is (0.4-0.6) g: (1-5) mL.

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

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

[0023] Thirdly, the present invention provides the application of the above-mentioned deuterium methylating agent in the deuterium methylation of drug molecules.

[0024] Fourthly, the present invention provides a method for deuterylation of a drug molecule, comprising the following steps:

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

[0026] Preferably, the mass ratio of the deuterium methylating agent 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) In this invention, a diaryl sulfide porous polymer is used to activate methyl groups, and then deuterium water, which is inexpensive and readily available, is used to undergo efficient hydrogen-deuterium exchange with methyl groups at room temperature under alkaline catalysis to obtain a deuterated methylating agent. The deuterated methylating agent of this invention has a simple and efficient synthesis step, avoids the use of expensive reagents, and has mild preparation conditions.

[0030] (2) The deuterium methylating 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, reducing the preparation cost of deuterated chemicals, and making them widely used in exploring drug metabolism, revealing organic reaction mechanisms and improving material properties; moreover, the reaction process has low energy consumption, high product selectivity, simple separation and low pollutant emissions. The deuterium methylating reagent after separation can be reused in steps S2 and S3, and has broad industrial application prospects. Attached Figure Description

[0031] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention and do not constitute an undue limitation thereof. Obviously, those skilled in the art can obtain other drawings based on these drawings without any inventive effort.

[0032] Figure 1 The thermogravimetric curve and thermogravimetric differential curve of the deuterated methylating agent POP-1-CD3 in Example 1 of this invention are shown. Detailed Implementation

[0033] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0034] This invention provides a method for preparing a deuterium methylating reagent from deuterium water, comprising the following steps:

[0035] S1, a diaryl sulfide compound and a crosslinking agent were reacted in the presence of a Lewis acid and solvent one to obtain a diaryl sulfide porous polymer;

[0036] S2. The diaryl sulfide porous polymer and methyl trifluoromethanesulfonate react in solvent two to obtain a methylating agent;

[0037] S3. The methylating agent is reacted with deuterium water in the presence of an alkali at 15–35°C for 5–12 h to obtain the deuterium methylating agent.

[0038] This invention first synthesizes an organic porous polymer based on aryl sulfides. The sulfur in this organic porous polymer reacts with methyl trifluoromethanesulfonate to yield a thiomethyl group. The resulting sulfonium ylide induces a positive charge at the sulfur ring, which can induce acidity at the α-position hydrogen. A deuterylation catalyst can then be obtained through a simple pH-dependent hydrogen isotope exchange (HIE) process. Specifically, the base anion attacks the hydrogen atom adjacent to the sulfur atom, forming a carbanion. The deuterium hydrogen produced from deuterium water undergoes electrophilic addition, thus yielding the deuterylation catalyst. This process is mild, requires no metal catalyst, and can be completed at room temperature. It can also be recycled after subsequent modification of drug molecules (by repeating steps S2 and S3).

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

[0040] In this 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 this invention, the Lewis acid is selected from one or more of aluminum chloride, ferric chloride, or boron trifluoride.

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

[0043] In this invention, the mass ratio of the diaryl sulfide compound, the crosslinking agent, and the Lewis acid is 1:(3-10):(3-10). This invention does not impose any special restrictions on the amount of solvent one, as long as it ensures sufficient dissolution or dispersion of the reactants.

[0044] In this invention, the reaction temperature in step S1 is 70-100°C and the reaction time is 10-20 h.

[0045] This invention does not impose special limitations on the purification steps after the reaction in step S1; commonly used purification methods for organic porous polymers in the art can be employed. Preferably, the method involves vacuum filtration, followed by washing with hydrochloric acid solution until the filtrate is colorless, then washing with an organic solvent, and finally drying to obtain the final product.

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

[0047] In this 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. This invention does not impose any special limitations on the amount of the first solvent, as long as it ensures sufficient dissolution or dispersion of the reactants.

[0048] In this invention, the reaction temperature in step S2 is 50-70°C and the reaction time is 3-10 hours.

[0049] In this 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. This invention has found that inorganic bases have superior catalytic activity compared to organic bases (such as triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene), enabling the reaction yield and deuteration rate of step S3 to remain at a high level.

[0050] In this invention, the mass ratio of the methylating agent to the base is (1-20):1, more preferably (5-15):1; the volume ratio of the methylating agent to deuterated water is (0.4-0.6) g:(1-5) mL. This invention uses deuterated water as the deuterium source, which exhibits 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, both the reaction yield and the deuteration rate decrease significantly.

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

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

[0053] The present invention also provides the application of the above-mentioned deuterium methylating agent in the deuterium methylation of drug molecules.

[0054] This invention also provides a method for deuterium methylation of a drug molecule, comprising the following steps:

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

[0056] This invention does not impose any special restrictions on the types of drug molecules mentioned above, such as carboxylic acids, phenols, benzenethiols, primary amines, or secondary amine compounds.

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

[0058] In this 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 deuteration reaction of the drug molecule is completed, the deuterated deuterated reagent can be repeated in steps S2 and S3 to prepare a new deuterated reagent, so it can be recycled.

[0060] The technical solution of the present invention will be further described below with reference to specific embodiments. In the following embodiments, room temperature refers to 25±3℃.

[0061] Example 1

[0062] This embodiment provides a method for preparing a deuterium methylating agent, and the reaction route is shown in the following formula:

[0063]

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

[0065] (2) Place 500 mg of dried POP-1 in a 50 mL round-bottom flask, add 10 mL of 1,2-dichloroethane and 0.5 mL of methyl trifluoromethanesulfonate (CH3OTf) while stirring, and heat to 60 °C for 5 hours. After the reaction is complete, cool to room temperature, add methanol to quench the reaction, wash with methanol and ethyl acetate until the filtrate is colorless, dry, and obtain 650 mg of methylating agent POP-1-CH3.

[0066] (3) Take 500 mg of POP-1-CH3 and place it in a 50 mL round bottom flask. Add 2 mL of deuterium water and 2 mL of acetonitrile. Add 50 mg of potassium carbonate while stirring. Stir at room temperature for 8 h. After the reaction is complete, filter with methanol and wash with ethyl acetate. Dry to obtain 480 mg of deuterated methylation reagent POP-1-CD3. The yield is 96% and the deuteration rate is 98%.

[0067] Figure 1 The thermogravimetric curves and thermogravimetric differential curves of the deuterated methylating agent POP-1-CD3 prepared in this embodiment are shown. As can be seen from the figure, there are two sets of weight loss peaks. Around 250℃ corresponds to the shedding of deuterated methyl groups, and 500℃ corresponds to the decomposition of the material, which indicates that it has good heat resistance.

[0068] Example 2

[0069] This embodiment provides a method for preparing a deuterium methylating agent, and the reaction route is shown in the following formula:

[0070]

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

[0072] (2) Place 500 mg of dried POP-2 in a 250 mL round-bottom flask, add 10 mL of 1,2-dichloroethane and 0.5 mL of methyl trifluoromethanesulfonate while stirring, and heat to 60 °C for 5 hours. After the reaction is complete, cool to room temperature, add methanol to quench the reaction, wash with methanol and ethyl acetate until the filtrate is colorless, dry, and obtain 670 mg of methylating agent POP-2-CH3.

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

[0074] Example 3

[0075] Compared with Example 1, in step (3) of this example, 4 mL of deuterium water is added, but acetonitrile is not added.

[0076] Example 4

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

[0078] Comparative Example 1

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

[0080] Comparative Example 2

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

[0082] Comparative Example 3

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

[0084] Comparative Example 4

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

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

[0087] Table 1. Yields and deuteration rates of step (3) in Examples 1-4 and Comparative Examples 1-4.

[0088]

[0089]

[0090] As shown in Table 1, when the base was changed to potassium hydroxide, the reaction yield and deuteration rate decreased slightly. When the base was changed to organic bases Et3N and DBU, both the reaction yield and deuteration rate decreased significantly. When other deuteration sources (deuterated DMSO and deuterated methanol) were used, the reaction yield and deuteration rate also decreased significantly. Changing the solvent from deuterated water to a mixed solvent of deuterated water and acetonitrile did not result in a significant decrease in yield and deuteration rate.

[0091] Application Example 1

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

[0093]

[0094] Fenofibrate acid (0.5 mmol, 159 mg), potassium carbonate (0.2 mmol), and deuterated methylation reagent POP-1-CD3 were weighed and added to a 5 mL reaction flask, along with 5 mL of acetonitrile solution. The mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was filtered. The filter cake was POP-1 obtained after deuteration methylation, which could be reacted again to obtain POP-1-CD3 for further use. The filtrate was extracted with 5 mL of water and 10.0 mL of CH2Cl2. The extract was dried over anhydrous sodium sulfate and concentrated to give 160 mg (95%) of a white solid. NMR and HR-MS analyses were performed to identify 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 deuteration methylation catalyst POP-1-CD3 prepared in Example 1 is used for the deuteration methylation reaction of deuterated nimesulide. The reaction route is shown in the following formula:

[0097]

[0098] Nimesulide (0.5 mmol, 154 mg), 0.2 mmol potassium carbonate, and 300 mg of deuterated methyl catalyst POP-1-CD3 were weighed and added to a 5 mL reaction flask, along with 5 mL of acetonitrile solution. The mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was filtered. The filter cake was POP-1 obtained after deuteration, which could be reacted again to obtain POP-1-CD3 for use. The filtrate was extracted with 5 mL of water and 10.0 mL of CH2Cl2. The extract was dried over anhydrous sodium sulfate and concentrated to give 130 mg (92%) of a white solid. NMR and HR-MS analyses were performed to identify 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 merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a deuterated methylating agent from deuterium water, characterized in that, Includes the following steps: S1, a diaryl sulfide compound and a crosslinking agent were reacted in the presence of a Lewis acid and solvent one to obtain a diaryl sulfide porous polymer; S2. The diaryl sulfide porous polymer and methyl trifluoromethanesulfonate are reacted in solvent two to obtain a methylating agent; the reaction temperature of step S2 is 50~70℃ and the reaction time is 3~10h. S3. The methylating agent is reacted with deuterium water in the presence of an alkali at 15-35°C for 5-12 h to obtain a deuterium methylating agent; the alkali in step S3 is selected from one or two of potassium carbonate and potassium hydroxide. The mass ratio of the methylating agent to the base is (1~20):1; the volume ratio of the methylating agent to deuterium water is (0.4~0.6)g: (1~5)mL.

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

3. The method as described in claim 1, characterized in that, The mass ratio of the diaryl sulfide compound, the crosslinking agent, and the Lewis acid is 1:(3~10):(3~10); the reaction temperature of step S1 is 70~100℃, and the reaction time is 10~20h.

4. The method as described in claim 1, characterized in that, The ratio of the diaryl sulfide porous polymer to methyl trifluoromethanesulfonate is 1 g: (0.8~2) mL; The solvent is selected from one or more of 1,2-dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, or nitrobenzene.

5. The method as described in claim 1, characterized in that, The reaction in step S3 also includes solvent three, which is selected from acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the volume ratio of deuterium water to solvent three is 1:(0~2).

6. The deuterium methylating agent prepared by the method according to any one of claims 1 to 5.

7. The use of the deuterium methylating agent as described in claim 6 in the deuterium methylation of drug molecules.

8. A method for deuterylation of a drug molecule, characterized in that, Includes the following steps: The deuterium methylating reagent and the drug molecule substrate described in claim 6 are placed in solvent four and reacted at 15-35°C for 5-10 hours. After the reaction is completed, the mixture is filtered, and the filtrate is the deuterium methylated drug.

9. The method as described in claim 8, characterized in that, The mass ratio of the deuterium methylating agent 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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