Heterogeneous methylation reagent and method for its preparation

Abstract

The application discloses a kind of heterogeneous methylation reagent and preparation method thereof, it is related to organic synthesis technical field.The preparation method of heterogeneous methylation reagent provided by the application, the heterogeneous methylation reagent is heterogeneous aryl sulfide type methylation reagent or heterogeneous aryl sulfide type deuteromethylation reagent, this preparation method is based on the synthesis method of superhigh crosslinking polymer, by aryl sulfide compound with thianthrene as representative is polymerized, the reactivity of material obtained after polymerization still retains monomer, can repeatedly cycle and carry out methylation or deuteromethylation, reach almost 100% atomic utilization efficiency.The traditional homogeneous sulfur methyl methylation reagent such as (DMTT) will produce dibenzothiophene by-product after reaction, and it is very difficult to separate and purify methylated product, and the methylation reagent of heterogeneous of the application only needs simple centrifugation or suction filtration step to realize the separation of product and methylation reagent, greatly improve synthesis efficiency.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a heterogeneous methylation reagent and a preparation method thereof. BACKGROUND

[0002] Methyl is the smallest alkyl group, which is widely present in natural products and their drug molecules. In medicinal chemistry, the introduction of methyl into specific positions of drug molecules can significantly improve their biological activity and pharmacokinetic characteristics, which is known as the "magic methyl effect". Due to its special function, methyl is considered as a practical functional group with both chemical stability and improved molecular drug properties, and has been widely used in lead compound screening and structure modification optimization. On the other hand, deuterated drugs have attracted increasing attention in the pharmaceutical industry in recent years. Deuterated strategies are considered to prolong drug metabolic cycles, reduce the production of toxic metabolites and drug interactions, thereby reducing the dosage, improving safety and achieving better efficacy. Therefore, the combination of "magic methyl" and deuterated strategies will significantly improve the drug efficacy. Since 2008, two deuterated drugs approved for listing by the State Drug Administration are achieved by introducing deuterated methyl.

[0003] The commonly used methyl reagents can be divided into oxygen-methyl reagents (such as methyl p-toluenesulfonate (MeOTs), methyl p-nitrobenzenesulfonate (MeONs) and methyl triflate (MeOTf)), sulfur-methyl reagents (such as S-adenosyl methionine (SAM), diarylthiophene type (DMTT)), nitrogen-methyl reagents (diazomethane, nitrogen-nitrogen dimethylformamide), methyl metal reagents, methyl boron reagents and methyl-containing small molecules such as methyl iodide, methanol, dimethyl sulfoxide, methyl-containing peroxide and the like. The above methyl reagents either need multi-step synthesis and harsh synthesis conditions which are not easy to operate (such as methyl metal reagents, methyl boron reagents), or it is difficult to obtain the corresponding deuterated methyl reagent, or the corresponding deuterated methyl reagent is relatively expensive and seriously dependent on imports (such as methyl iodide, methyl-containing peroxide), and most importantly, the above methyl reagents are homogeneous methylating reagents, which means that these methyl reagents have poor atomic economy (atomic utilization rate).

[0004] Therefore, the development of a heterogeneous (deuterated) methylation reagent with simple preparation method, easy scale-up preparation and nearly 100% atomic economy not only has an urgent need and broad prospects in academic research but also in industrial applications. SUMMARY

[0005] The technical problem to be solved by the present application is to provide a heterogeneous methylation reagent with simple preparation method and low cost.

[0006] To solve the above problems, the present application proposes the following technical solutions:

[0007] The present application provides a preparation method of a heterogeneous methylation reagent, which is a heterogeneous aryl sulfide type methylation reagent or a heterogeneous aryl sulfide type deuteromethylation reagent, comprising the following steps:

[0008] S1, dissolve the aryl sulfide compound, Lewis acid and complexing agent in a solvent according to the stoichiometric ratio of 1:2-8:2-12, and react at 40-70℃ for 1-3 hours to preliminarily form a cross-linked structure, then continue to increase the temperature to 75-110℃ for reaction until the end, and then reduce to room temperature after the reaction is completed, filter, wash the filter cake with hydrochloric acid solution and organic solvent until the filtrate is colorless, and dry to obtain a heterogeneous aryl sulfide compound;

[0009] S2, add the heterogeneous aryl sulfide compound obtained in S1 to a reaction solvent at -5-4℃, add a methyl source under stirring, and react at 40-80℃, then reduce to room temperature after the reaction is completed, quench the reaction by adding methanol, filter, wash the filter cake with organic solvent until the filtrate is colorless, and dry to obtain the heterogeneous methylation reagent; the reaction solvent is a mixture of a buffer solvent and trifluoromethanesulfonic acid, and the mass ratio of the buffer solvent to trifluoromethanesulfonic acid is 0.01-5:0-1.

[0010] Further, the methyl source is selected from one or more combinations of methanol, deuterated methanol, methyl iodide, deuterated methyl iodide, methyl formate, deuterated methyl formate, methyl trifluoromethanesulfonate, and deuterated methyl trifluoromethanesulfonate.

[0011] It should be noted that when the methyl source is selected from methyl trifluoromethanesulfonate or deuterated methyl trifluoromethanesulfonate, the addition amount of trifluoromethanesulfonic acid is 0.

[0012] Further, the organic solvent for washing the filter cake includes methanol, ethanol, ethyl acetate, etc.

[0013] Further, in the step S1, the reaction time at 75-110℃ is more than 6 hours, for example, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, etc.

[0014] Further, the aryl sulfide compound is selected from one or more combinations of thianthrene, diaryl sulfide, diphenyl sulfide, phenoxathiine, phenothiazine, and 10-methylphenothiazine.

[0015] Further, the Lewis acid is selected from one or more combinations of aluminum chloride, iron chloride, boron trifluoride, and niobium pentachloride.

[0016] Further, the complexing agent is selected from a combination of one or more of dimethoxymethane, acetaldehyde dimethyl acetal, 2,2-dimethoxypropane, 1,4-dimethoxybenzene, 9,10-dimethoxyanthracene.

[0017] Further, in the step S1, the solvent is selected from a combination of one or more of 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, nitrobenzene.

[0018] Further, in the step S2, the buffer solvent is selected from a combination of one or more of dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, nitrobenzene.

[0019] Further, the preparation method of the heterogeneous methylation reagent also comprises a circulation step: dissolving a substrate molecule in a solvent, adding the heterogeneous aryl sulfide type methylation reagent obtained in S2, and reacting at room temperature under the action of an inorganic base to obtain a methylation product and a demethylated heterogeneous aryl sulfide compound; the demethylated heterogeneous aryl sulfide compound is extracted and concentrated and then used for the preparation of the heterogeneous methylation reagent in step S2; the amount ratio of the substrate molecule to the heterogeneous aryl sulfide type methylation reagent is 0.1 mmol: 200-400 mg; and the amount ratio of the substrate molecule to the inorganic base is 1:0.01-0.1.

[0020] It should be noted that, in the present application, "room temperature" refers to 0-50°C; in some embodiments, room temperature refers to 20-40°C, and in some embodiments, room temperature refers to 25-35°C.

[0021] Further, the substrate molecule comprises a carboxylic acid compound, a phenol compound, a benzene thiol primary amine compound, and a benzene thiol secondary amine compound.

[0022] Further, the inorganic base is selected from a combination of one or more of an alkali metal alcoholate, an alkali metal carbonate, and an alkali metal hydroxide.

[0023] Further, the inorganic base is selected from a combination of one or more of potassium carbonate, sodium carbonate, lithium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, and sodium methoxide.

[0024] Further, in the circulation step, the solvent is selected from a combination of one or more of acetonitrile, dichloromethane, ethyl acetate, 1,2-dichloroethane, methyl tert-butyl ether, and tetrahydrofuran.

[0025] The application also provides a heterogeneous methylation reagent prepared by the above-mentioned preparation method of a heterogeneous methylation reagent. The heterogeneous methylation reagent is a heterogeneous aryl sulfide type methylation reagent or a heterogeneous aryl sulfide type deuteromethylation reagent.

[0026] Compared with the prior art, the application can achieve the following technical effects:

[0027] The application provides a preparation method of a heterogeneous methylation reagent. The heterogeneous methylation reagent is a heterogeneous aryl sulfide type methylation reagent or a heterogeneous aryl sulfide type deuteromethylation reagent. The preparation method is based on a synthesis method of super-high cross-linked polymers. By polymerizing aryl sulfide compounds represented by thianthrene, the obtained material after polymerization still has the reactivity of monomers, and can be repeatedly cycled for methylation or deuteromethylation, achieving an atomic utilization efficiency of nearly 100%. Traditional homogeneous sulfur methylation reagents such as (DMTT) produce dibenzothiophene byproducts after reaction, and it is very difficult to separate and purify the methylation products. However, the heterogeneous methylation reagent of the application only needs simple centrifugation or suction filtration steps to realize the separation of the product and the methylation reagent, greatly improving the synthesis efficiency.

[0028] The preparation method of the heterogeneous methylation reagent provided by the application has the advantages of cheap and readily available raw materials, simple operation, low equipment requirements, large-scale preparation, and suitability for rapid preparation of new heterogeneous aryl sulfide type alkyl reagents or deuterated alkyl reagents. Meanwhile, the prepared alkylating reagent can be recycled for alkylation or deuterated alkylation and dealkylation or deuterated dealkylation reactions. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 The cycle results of the reaction yield and recovery rate of Example 7. DETAILED DESCRIPTION

[0030] The technical solutions in the embodiments will be clearly and completely described below with reference to the drawings in the embodiments of the application. Obviously, the embodiments to be described below are only a part of the embodiments of the application, rather than all the embodiments of the application. Based on the embodiments in the application, all other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the application.

[0031] It should be understood that, when used in the specification and the appended claims, the terms “comprise” and “include” indicate the presence of described features, integers, steps and / or operations, but do not exclude the presence or addition of one or more other features, integers, steps, operations and / or collections thereof.

[0032] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the embodiments will be defined by the claims. As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. Throughout this application, the term "about" when used before a

[0033] The term "room temperature" means 0-50 °C; in some embodiments, room temperature means 20-40 °C, and in some embodiments, room temperature means 25-35 °C.

[0034] The amount of solvent required for the reaction used herein is preferably an amount in which the reactants are completely dissolved, and is appropriately changed depending on the reactants. In some embodiments, the amount of solvent required for the reaction can also be appropriately more than the amount required for just dissolving the reactants.

[0035] General synthetic procedures

[0036] In general, the compounds of the present embodiments can be prepared by the methods described herein. The following reaction schemes and examples are intended to further illustrate the present embodiments.

[0037] Those skilled in the art will recognize that the chemical reactions described herein can be used to prepare many of the other compounds of the embodiments, and that other methods for preparing the compounds of the embodiments are also within the scope of the embodiments. For example, the synthesis of any of the non-exemplified compounds according to the embodiments can be successfully performed by modifying the methods described herein, by appropriate modification (e.g., by appropriate protection of interfering groups, by the use of other known reagents and reactions, or by making routine modifications), as appreciated by those skilled in the art. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for the preparation of other compounds of the embodiments.

[0038] The following examples are described herein, unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company, and were used without further purification, unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoguyu Chemicals Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haoyang Chemical Factory.

[0039] The solvents used in the present application, such as chlorobenzene, dichlorobenzene, p-methyl chlorobenzene, anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether, dichloromethane, chloroform, ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide, are dried in advance by the drying method suitable in the art.

[0040] Example 1

[0041] This embodiment provides a thianthrene-type heterogeneous deuteromethyl reagent and a preparation method thereof, and the reaction process is as follows:

[0042]

[0043] The specific operation is as follows: S1, thianthrene (5 g, 23.1 mmol) and iron chloride (6.0 equiv, 138.9 mmol, 22.5 g) are placed in a 500 ml round-bottom flask, and the replacement system is an argon atmosphere. During the argon gas inlet process, 250 ml of 1,2-dichloroethane is added, and dimethoxymethane (6.0 equiv, 138.9 mmol, 10.5 g) is added under sufficient stirring. The temperature is raised to 50°C, and the reaction is continued for 5 hours. Then the temperature is raised to 90°C, and the reaction is continued for 12 hours. After the reaction is completed, the temperature is lowered to room temperature, 50 ml of methanol is added to precipitate the solid, and the solid is extracted after filtration. The solid is repeatedly washed with 3 mol / L hydrochloric acid solution until the filtrate is colorless. Finally, the solid is washed with ethyl acetate and methanol and dried to obtain 5.1 g of solid heterogeneous thianthrene (yield 105%).

[0044] S2, 500 mg of the dried heterogeneous thianthrene is added to 2 ml of 1,2-dichloroethane and 2 ml of trifluoromethanesulfonic acid at 0°C. 0.5 ml of methyl deuteromethylate is added under stirring, and the temperature is raised to 60°C for reaction for 12 hours. After the reaction is completed, the temperature is cooled to room temperature, methanol is added to quench the reaction, and the solid is extracted after filtration. The solid is washed with methanol and ethyl acetate until the filtrate is colorless, and dried to obtain 520 mg of thianthrene-type heterogeneous deuteromethyl reagent.

[0045] Example 2

[0046] This embodiment provides a thianthrene-type heterogeneous deuteromethyl reagent and a preparation method thereof, and the reaction process is as follows:

[0047]

[0048] Specific operation is: the thianthrene (5g, 23.1mmmol) and iron chloride (6.0equiv, 138.9mmmol, 22.5g) are placed in a 500ml round bottom flask, the replacement system is argon atmosphere, 250ml 1,2-dichloroethane is added in the argon inlet process, dimethoxymethane (6.0equiv, 138.9mmmol, 10.5g) is added under sufficient stirring, the temperature is raised to 50 DEG C, and the reaction is carried out for 5 hours;Then raise the temperature to 90 DEG C, continue to react for 12 hours;After the reaction is completed, it is cooled to room temperature, 50ml methanol is added to precipitate the solid, and the solid is washed repeatedly with 3mol / L hydrochloric acid solution until the filtrate is colorless, finally washed with ethyl acetate and methanol and dried to obtain solid heterophase thianthrene 5.1g (yield 105%).

[0049] Take 500mg of the dried heterophase thianthrene, add 5ml 1,2-dichloroethane and 0.5ml deuterated methyl triflate at room temperature, and react at 60 DEG C for 12 hours. After the reaction is completed, it is cooled to room temperature, methanol is added to quench the reaction, filtered, and the solid is washed with methanol and ethyl acetate until the filtrate is colorless, dried and obtained thianthrene type heterophase deuterated methyl reagent 520mg.

[0050] Example 3

[0051] This example provides a thianthrene type heterophase deuterated methyl reagent and a preparation method thereof, and the reaction process is as follows:

[0052]

[0053] Specific operation is: the thianthrene (5g, 23.1mmmol) and iron chloride (6.0equiv, 138.9mmmol, 22.5g) are placed in a 500ml round bottom flask, the replacement system is argon atmosphere, 250ml 1,2-dichloroethane is added in the argon inlet process, dimethoxymethane (6.0equiv, 138.9mmmol, 10.5g) is added under sufficient stirring, the temperature is raised to 50 DEG C, and the reaction is carried out for 5 hours;Then raise the temperature to 90 DEG C, continue to react for 12 hours;After the reaction is completed, it is cooled to room temperature, 50ml methanol is added to precipitate the solid, and the solid is washed repeatedly with 3mol / L hydrochloric acid solution until the filtrate is colorless, finally washed with ethyl acetate and methanol and dried to obtain solid heterophase thianthrene 5.1g (yield 105%).

[0054] Take 500mg of the dried heterophase thianthrene, add 5ml 1,2-dichloroethane and 2ml trifluoromethanesulfonic acid at 0 DEG C, add 0.5ml deuterated methyl formate under stirring, and react at 60 DEG C for 12 hours. After the reaction is completed, it is cooled to room temperature, methanol is added to quench the reaction, filtered, and the solid is washed with methanol and ethyl acetate until the filtrate is colorless, dried and obtained thianthrene type heterophase deuterated methyl reagent 520mg.

[0055] Example 4

[0056] This embodiment provides thioxanthene type heterogeneous deuteromethyl reagent and its preparation method, and the reaction process is as follows:

[0057]

[0058] The specific operation is as follows: thioxanthene (5 g, 25.2 mmol) and iron chloride (6.0 equiv, 138.9 mmol, 22.5 g) are placed in a 500 ml round bottom flask, the replacement system is argon atmosphere, 250 ml 1,2-dichloroethane is added during argon gas inlet, dimethoxymethane (6.0 equiv, 138.9 mmol, 10.5 g) is added under sufficient stirring, the temperature is raised to 50°C, and the reaction is carried out for 5 hours, then the temperature is raised to 90°C, and the reaction is continued for 12 hours, after the reaction is completed, the temperature is lowered to room temperature, 50 ml of methanol is added to precipitate the solid, the solid is filtered, and then the solid is repeatedly washed with 3 mol / L hydrochloric acid solution until the filtrate is colorless, finally the solid is washed with ethyl acetate and methanol and dried to obtain 5.1 g of solid heterogeneous thioxanthene (yield 105%).

[0059] 500 mg of the dried heterogeneous thioxanthene is taken, 5 ml of 1,2-dichloroethane and 2 ml of trifluoromethanesulfonic acid are added at 0°C, 0.5 ml of deuterated methyl formate is added under stirring, the temperature is raised to 60°C, and the reaction is carried out for 12 hours. After the reaction is completed, the temperature is lowered to room temperature, methanol is added to quench the reaction, the solid is filtered, the solid is washed with methanol and ethyl acetate until the filtrate is colorless, and the solid is dried to obtain 520 mg of thioxanthene type heterogeneous deuteromethyl reagent.

[0060] Example 5

[0061] This embodiment provides thioxanthene type heterogeneous deuteromethyl reagent and its preparation method, and the reaction process is as follows:

[0062]

[0063] The specific operation is as follows: thioxanthene (5 g, 25.2 mmol) and iron chloride (6.0 equiv, 138.9 mmol, 22.5 g) are placed in a 500 ml round bottom flask, the replacement system is argon atmosphere, 250 ml 1,2-dichloroethane is added during argon gas inlet, dimethoxymethane (6.0 equiv, 138.9 mmol, 10.5 g) is added under sufficient stirring, the temperature is raised to 50°C, and the reaction is carried out for 5 hours, then the temperature is raised to 90°C, and the reaction is continued for 12 hours, after the reaction is completed, the temperature is lowered to room temperature, 50 ml of methanol is added to precipitate the solid, the solid is filtered, and then the solid is repeatedly washed with 3 mol / L hydrochloric acid solution until the filtrate is colorless, finally the solid is washed with ethyl acetate and methanol and dried to obtain 5.1 g of solid heterogeneous thioxanthene (yield 105%).

[0064] Take 500 mg of the dried hetero-thiaxanthene, add 2 ml of 1,2-dichloroethane and 2 ml of trifluoromethanesulfonic acid at 0°C, add 0.5 ml of deuterated methyl formate under stirring, and heat to 60°C for 12 hours. After the reaction is completed, cool to room temperature, add methanol to quench the reaction, and filter. Wash the solid with methanol and ethyl acetate until the filtrate is colorless, dry, and obtain 520 mg of the hetero-thiaxanthene-type hetero-methyl reagent.

[0065] Example 6

[0066] This example provides a hetero-thiaxanthene-type hetero-deuterated methyl reagent and a preparation method thereof, and the reaction process is as follows:

[0067]

[0068] Specific operation: Place dibenzothiophene (5 g, 25.0 mmol) and iron chloride (6.0 equiv, 138.9 mmol, 22.5 g) in a 500 ml round-bottom flask, and replace the system with an argon atmosphere. Add 250 ml of 1,2-dichloroethane during argon introduction, and add dimethoxymethane (6.0 equiv, 138.9 mmol, 10.5 g) under sufficient stirring. Heat to 50°C, react for 5 hours, then heat to 90°C, and continue to react for 12 hours. After the reaction is completed, cool to room temperature, add 50 ml of methanol to precipitate the solid, filter, and then wash the solid with 3 mol / L hydrochloric acid solution until the filtrate is colorless. Finally, dry the solid after washing with ethyl acetate and methanol, and obtain 5.1 g of the solid hetero-thiaxanthene (yield 105%).

[0069] Take 500 mg of the dried hetero-thiaxanthene, add 2 ml of 1,2-dichloroethane and 2 ml of trifluoromethanesulfonic acid at 0°C, add 0.5 ml of deuterated methyl formate under stirring, and heat to 60°C for 12 hours. After the reaction is completed, cool to room temperature, add methanol to quench the reaction, and filter. Wash the solid with methanol and ethyl acetate until the filtrate is colorless, dry, and obtain 520 mg of the hetero-thiaxanthene-type hetero-methyl reagent.

[0070] Example 7

[0071] This example is based on the hetero-thiaxanthene-type hetero-deuterated methyl reagent prepared in Example 1, and tests the recycling performance of the hetero-thiaxanthene-type hetero-deuterated methyl reagent after methylating reaction with a substrate molecule, and the reaction process is as follows:

[0072]

[0073] The specific operation is: 106 mg (1.0 mmol) of N-methylaniline is dissolved in 10 ml of acetonitrile solution, 3 g of thianthrene type heterogeneous deuteromethylating reagent prepared in Example 1 and 280 mg (2.0 mmol) of potassium carbonate are added, and stirring is carried out at room temperature for 12 hours. After the reaction is completed, centrifugation is carried out, the supernatant is taken, water and ethyl acetate are added for extraction of the organic phase, and concentration is carried out to obtain N,N-dimethylaniline (denoted as the first reaction yield). The precipitate obtained by centrifugation is the demethylated heterogeneous thianthrene, which is dried and weighed, which is the first cycle.

[0074] The collected demethylated heterogeneous thianthrene is subjected to deuteromethylation again (refer to step S2 of Example 1), and the thianthrene type heterogeneous deuteromethylating reagent is prepared again. It is reacted with 1.0 mmol of N-methylaniline to obtain the second reaction yield, and the precipitate is dried and weighed (compared with the initial weight, and recorded as the recovery rate of the methylation reagent), and the cycle is repeated for five cycles. The results are as follows: Figure 1 It can be seen that the yield of N,N-dimethylaniline and the methylation reagent remains stable during the cycle.

[0075] Example 8

[0076] Scale-up test

[0077] Thianthrene (30 g, 138.9 mmol) and iron chloride (6.0 equiv, 833.3 mmol, 135 g) are placed in a 2 L round-bottom flask, and the system is replaced with an argon atmosphere. During the argon introduction, 1 L of 1,2-dichloroethane is added, and dimethoxymethane (6.0 equiv, 833.3 mmol, 63.3 g) is added with sufficient stirring. The temperature is raised to 50°C, and after 5 hours of reaction, the temperature is raised to 90°C, and the reaction is continued for 12 hours. After the reaction is completed, the temperature is lowered to room temperature, 250 ml of methanol is added to precipitate the solid, and after suction filtration, the solid is repeatedly washed with 3 mol / L hydrochloric acid solution until the filtrate is colorless. Finally, the solid is washed with ethyl acetate and methanol and dried to obtain 31.5 g of solid, with a yield of 105%.

[0078] The dried heterogeneous thianthrene is added to 100 ml of 1,2-dichloroethane and 50 ml of trifluoromethanesulfonic acid at 0°C, and 30 ml of methyl deuterate formate is added with stirring. The temperature is raised to 60°C, and the reaction is carried out for 12 hours. After the reaction is completed, the temperature is cooled to room temperature, methanol is added to quench the reaction, filtration is carried out, the solid is washed with methanol and ethyl acetate until the filtrate is colorless, and drying is carried out to obtain 34.6 mg of solid thianthrene type heterogeneous deuteromethylating reagent.

[0079] In the above examples, the description of each example has its own focus, and the parts not described in detail in a certain example can be referred to the relevant description of other examples.

[0080] The above is a specific embodiment of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can easily think of various equivalent modifications or replacements within the technical scope disclosed by the present application, and these modifications or replacements should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A method for preparing a heteromorphic methylation reagent, characterized by, The heterogeneous methylation reagent is a heterogeneous aryl sulfide type methylation reagent or a heterogeneous aryl sulfide type deuteromethylation reagent, and a preparation method thereof comprises the following steps: S1, dissolving an aryl sulfide compound, a Lewis acid, and a complexing agent in a solvent according to a stoichiometric ratio of 1:2-8:2-12, and reacting at 40-70°C for 1-3 hours to preliminarily form a crosslinked structure, and then continuing to increase the temperature to 75-110°C until the reaction is completed, and then reducing the temperature to room temperature, filtering, washing the filter cake with a hydrochloric acid solution and an organic solvent until the filtrate is colorless, and drying to obtain a heterogeneous aryl sulfide compound; S2, adding the heterogeneous aryl sulfide compound obtained in S1 into a reaction solvent at -5-4°C, adding a methyl source under stirring, and reacting at 40-80°C, and then reducing the temperature to room temperature, adding methanol to quench the reaction, filtering, washing the filter cake with an organic solvent until the filtrate is colorless, and drying to obtain the heterogeneous methylation reagent; the reaction solvent is a mixture of a buffer solvent and trifluoromethanesulfonic acid, and the mass ratio of the buffer solvent to trifluoromethanesulfonic acid is 0.01-5:0-1; The aryl sulfide compound is selected from one or more combinations of thianthrene, diaryl bithiophene, diphenyl sulfide, phenoxathiin, phenothiazine, and 10-methylphenothiazine; The complexing agent is selected from one or more combinations of dimethoxymethane, acetaldehyde dimethyl acetal, 2,2-dimethoxypropane, 1,4-dimethoxybenzene, and 9,10-dimethoxyanthracene.

2. The method of preparing a heteromorphic methylation reagent according to claim 1, wherein, The methyl source is selected from one or more combinations of methanol, deuterated methanol, iodomethane, deuterated iodomethane, methyl formate, deuterated methyl formate, methyl trifluoromethanesulfonate, and deuterated methyl trifluoromethanesulfonate.

3. The method of preparing a heteromorphic methylation reagent according to claim 1, wherein, The Lewis acid is selected from one or more combinations of aluminum chloride, iron chloride, boron trifluoride, and niobium pentachloride.

4. The method of preparing a heteromorphic methylation reagent according to claim 1, wherein In S1, the solvent is selected from one or more combinations of 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, and nitrobenzene.

5. The method of preparing a heteromorphic methylation reagent according to claim 1, wherein In S2, the buffer solvent is selected from one or more combinations of dichloromethane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, toluene, chlorobenzene, and nitrobenzene.

6. A method of preparing a heteromorphic methylation reagent according to any one of claims 1 to 5, wherein, Further comprising a circulation step: dissolving a substrate molecule in a solvent, adding the heterogeneous aryl sulfide type methylation reagent obtained in S2, and reacting under the action of an inorganic base to obtain a methylation product and a demethylated heterogeneous aryl sulfide compound; and after extraction and concentration, the demethylated heterogeneous aryl sulfide compound is used for the preparation of the heterogeneous methylation reagent in step S2; the use amount ratio of the substrate molecule to the heterogeneous aryl sulfide type methylation reagent is 0.1 mmol:200-400 mg.

7. The method of preparing a heteromorphic methylation reagent according to claim 6, wherein, The substrate molecule includes carboxylic acid compounds, phenol compounds, benzene thiol primary amine compounds, and benzene thiol secondary amine compounds.

8. A heteromorphic methylation reagent, characterized in that, The heterogeneous methylation reagent is prepared by the preparation method in any one of claims 1-7.

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