Preparation method of deuterated methylamine hydrochloride and solid-phase continuous flow synthesis system

Abstract

The invention discloses a preparation method of deuterated methylamine hydrochloride and a solid-phase continuous flow synthesis system, and relates to the technical field of deuterated synthesis. The preparation method comprises the following steps: adding out-of-phase polykadexide into methyl trifluoromethanesulfonate and 1, 2-dichloroethane for heating reaction, then adding methanol for quenching reaction, washing and drying to obtain an out-of-phase polykadexide type methyl reagent; the method comprises the following steps: adding a heterophase polysulfide-type methyl reagent into a mixed solvent of a polar solvent and heavy water, and carrying out alkali treatment to complete deuteration conversion, so as to obtain a heterophase polysulfide-type deuterated methyl reagent; the preparation method comprises the following steps: dissolving o-phenylsuccinimide in acetonitrile, and adding a heterophase polysulfide deuterium methyl reagent and inorganic alkali to react, so as to obtain N-(1, 1, 1-trideuterium methyl) benzo-succinimide; the preparation method comprises the following steps: hydrolyzing N-(1, 1, 1-trideuterium methyl) benzo-succinimide and hydrochloric acid in an aqueous solvent to obtain deuterated methylamine hydrochloride. The preparation method is simple, the deuterium source is cheap, the atom utilization rate is high, the deuteration rate is high, and the production cost is low.

Description

Technical Field

[0001] The present invention relates to the technical field of deuterated synthesis, and in particular to a preparation method of deuterated methylamine hydrochloride and a solid-phase continuous flow synthesis system. Background Art

[0002] Deuteration technology is a hot field in current drug research and development. Deuterated methylamine hydrochloride (CD3NH2·HCl, CAS: 7436-22-8), as an important building block for the synthesis of deuterated drugs, plays a key role in improving the metabolic stability and pharmacokinetic properties of drugs. It is an important synthetic precursor of deucravacitinib and sorafenib and is widely used in the synthesis of N-deuterated methyl anti-tumor and antiviral drugs. However, the existing preparation processes of deuterated methylamine hydrochloride generally have problems such as complex steps, high costs, and insufficient deuteration rate, which seriously restrict its industrial application.

[0003] The existing preparation methods of deuterated methylamine hydrochloride mainly include the phthalimide method, the deuterated reduction method of nitromethane, the photocatalytic debenzylation method, and the electrochemical reduction method. Among them, the phthalimide method generates an intermediate by reacting phthalimide with deuterated iodomethane or methyl trifluoromethanesulfonate-d3, and then obtains the target product through acidolysis. This route requires the use of highly active deuterated reagents (such as CD3OTf), is prone to generate multi-substituted by-products, has a large purification difficulty, and a low yield; the deuterated reduction method of nitromethane is to perform a deuteration reaction on nitromethane and deuterated water and then catalytic reduction. This process requires deuteration and reduction to be carried out step by step, with a reaction period of up to 48 hours, and there are safety hazards in catalytic hydrogenation; the photocatalytic debenzylation method uses a semiconductor photocatalyst (such as C3N4, Pd@TiO2) to catalyze the reaction of benzylamine compounds with deuterated methanol, and then undergoes hydrogenation deprotection. Although the deuteration rate can reach 98%, the catalyst recovery is difficult, the industrial cost is high, and there is a risk of high-pressure hydrogenation; the electrochemical reduction method directly electrolyzes and reduces deuterated nitromethane with deuterated water, but requires a specific electrode material (such as copper nanorods), and is prone to generate N-deuterated methylhydroxylamine by-products under acidic conditions.

[0004] In addition, the existing deuterated methylamine hydrochloride is batch-synthesized using a batch synthesis process, with low reaction efficiency, difficult-to-control reaction conditions, and potential safety risks.

[0005] Therefore, based on the problems of low atomic utilization rate, high cost, complex steps, and certain safety hazards of homogeneous (deuterated) methylation reagents in the existing processes, there is an urgent need to develop a preparation method of deuterated methylamine hydrochloride with a cheap deuterium source, which is simple, efficient, and a continuous flow synthesis system suitable for this preparation scheme. Summary of the Invention

[0006] To solve the problems existing in the above-mentioned prior art, the purpose of the present invention is to provide a preparation method of deuterated methylamine hydrochloride and a solid-phase continuous flow synthesis system, which can use a cheap deuterium source, be simple, efficient, and meet the requirements of continuous flow synthesis production.

[0007] The present invention provides the following technical solutions:

[0008] The present invention provides a preparation method of deuterated methylamine hydrochloride, which comprises the following steps:

[0009] S1. Add hetero-poly(thiophene) to methyl trifluoromethanesulfonate and 1,2-dichloroethane, and react at 50 - 100 °C for 12 - 24 hours; after the reaction is completed, cool to room temperature, add methanol to quench the reaction, wash and dry to obtain a hetero-poly(thiophene)-type methylation reagent.

[0010] S2. Add the hetero-poly(thiophene)-type methyl reagent to a mixed solvent of a polar solvent and heavy water, and then add a base to react for 24 - 48 hours, filter, wash and dry to obtain a hetero-poly(thiophene)-type deuterated methyl reagent.

[0011] S3. Dissolve the substrate molecule phthalimide in acetonitrile, add the hetero-poly(thiophene)-type deuterated methyl reagent and an inorganic base, and react at room temperature for 12 - 24 hours. After the reaction is completed, centrifuge and take the supernatant for extraction and concentration to obtain N-(1,1,1-trideuteromethyl)phthalimide.

[0012] S4. React N-(1,1,1-trideuteromethyl)phthalimide with hydrochloric acid in an aqueous solvent to prepare deuterated methylamine hydrochloride.

[0013] Preferably, in step S3, the precipitate after centrifugation is hetero-poly(thiophene), and the recovered hetero-poly(thiophene) can be recycled and used for methylation in step S1 after drying.

[0014] Further, the molar equivalent ratio of the hetero-poly(thiophene) to methyl trifluoromethanesulfonate is 1:(1.5 - 3).

[0015] Preferably, the molar concentration of the 1,2-dichloroethane is 0.4 M.

[0016] Further, the polar solvent is selected from at least one of acetonitrile, dimethyl sulfoxide, 1,4-dioxane, and N,N-dimethylformamide.

[0017] Preferably, in the mixed solvent, the volume ratio of the polar solvent to heavy water is 1:(1 - 5).

[0018] Preferably, the molar concentration of the hetero-poly(thiophene)-type methyl reagent in the mixed solvent is 0.1 - 0.8 M.

[0019] Preferably, the base is selected from at least one of the organic bases DBU, LDA (lithium diisopropylamide), inorganic base carbonates, and hydroxides.

[0020] Preferably, the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0021] Preferably, the molar equivalent ratio of the phthalimide, the heterogeneous (deuterated) methylation reagent, and the inorganic base is 1:(1.5 - 3):(1.5 - 3).

[0022] Preferably, the molar equivalent ratio of the N-(1,1,1-trideuteriomethyl)phthalimide and hydrochloric acid is 1:(5 - 20).

[0023] The present invention also provides a solid-phase continuous flow synthesis system for preparing deuterated methylamine hydrochloride by using the preparation method of deuterated methylamine hydrochloride described above, which includes a sampling system, a first switching valve, a fixed-bed reactor, a second switching valve, and a collection system connected in sequence. The sampling system includes a first pipeline with one end connected to methyl trifluoromethanesulfonate, a second pipeline connected to phthalimide, a third pipeline connected to a mixed solvent, and a fourth pipeline connected to acetonitrile. The other ends of the first pipeline, the second pipeline, the third pipeline, and the fourth pipeline are respectively connected to the switching valve; conveying pumps are provided on the first pipeline, the second pipeline, the third pipeline, and the fourth pipeline; the fixed-bed reactor is connected with a temperature controller, and the fixed-bed reactor is filled with heterogeneous polythiophene.

[0024] Further, the collection system includes a recovery pipeline, a product pipeline, and a waste liquid pipeline. One ends of the recovery pipeline, the product pipeline, and the waste liquid pipeline are all connected to the second switching valve.

[0025] Further, the collection system corresponds to the sampling system. Among them, the recovery pipeline corresponds to the first pipeline; the product pipeline corresponds to the fourth pipeline; the waste liquid pipeline corresponds to the second pipeline and the third pipeline.

[0026] Preferably, the fixed-bed reactor is designed with a temperature-controlled sandwich layer, and a water bath or an oil bath can be passed through the sandwich layer for temperature control as needed.

[0027] Further, the collection system further includes a circulation pipeline. One end of the circulation pipeline is connected to the second switching valve, and the other end is connected to the first pipeline.

[0028] Preferably, the continuous preparation system for deuterated methylamine hydrochloride further includes a control system for controlling the operation of the entire system.

[0029] The present invention has the following technical effects:

[0030] The preparation method of deuterated methylamine hydrochloride of the present invention uses hetero - poly(thiophene) as a methyl carrier, methyl trifluoromethanesulfonate as a methyl source, and inexpensive heavy water as the ultimate deuterium source. Through Friedel - Crafts alkylation reaction, hydrogen - deuterium exchange reaction and acidolysis steps, the efficient preparation of deuterated methylamine hydrochloride is realized, with high atom utilization rate, high deuteration rate and simple and reliable steps. Secondly, due to the recyclable characteristic of hetero - poly(thiophene), not only the consumption of raw materials is reduced, but also the production cost is further lowered. And poly(thiophene) has super - strong stability, which can provide reliable guarantee for the solid - phase continuous - flow synthesis process.

[0031] In addition, in the continuous - flow synthesis system of the present invention, since the reactants are transported in a flowing form, they can come into contact with the catalyst more fully, improving the reaction efficiency; and conditions such as temperature and catalyst concentration in the continuous - flow synthesis system are easier to control, making the reaction process more stable and controllable; the continuous - flow system has higher safety, and the smaller reaction volume in the system makes potential hazards easier to control; the continuous - flow synthesis technology has no amplification effect and can be industrially amplified by a number - increasing method, facilitating large - scale production; by controlling the operation of the entire continuous - flow synthesis system through a control system, the combination of flow chemistry technology and intelligent chemistry can meet a higher degree of automation and autonomous synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0033] Figure 1 It is the solid - phase continuous - flow synthesis process flowchart of deuterated methylamine hydrochloride provided in Embodiment 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0034] The following will combine the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the described embodiments are some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0035] It should be understood that when used in this specification and the appended claims, the terms "comprising" and "including" indicate the presence of the described features, wholes, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, wholes, steps, operations, elements, components and / or their combinations.

[0036] To better understand the technical content of the present invention, the technical solution of the present invention will be further introduced and described below in conjunction with specific embodiments.

[0037] Example 1

[0038] A preparation method of deuterated methylamine hydrochloride, which comprises the following steps:

[0039] S1. Methyl trifluoromethanesulfonate (5.0 mmol, 2.17 eq, 0.6 ml) was added to hetero-poly(thiophene) (2.3 mmol, 500 mg) and 1,2-dichloroethane (5.0 mL, 0.4 M), and the temperature was raised to 60 °C for reaction for 12 hours. The reaction formula is shown in Formula 1 below. After the reaction, it was cooled to room temperature, and methanol was added to quench the reaction. It was washed with methanol and ethyl acetate respectively until the filtrate was colorless, and the filter cake was dried to obtain 820 mg of a red-brown solid (hetero-poly(thiophene)-type methylation reagent);

[0040]

[0041] S2. The above-mentioned hetero-poly(thiophene)-type methyl reagent (820 mg, 2 mmol) was dispersed in a mixed solvent of dimethyl sulfoxide (3 mL) and heavy water (6 mL), and then potassium carbonate (552 mg, 4 mmol) was added. The reaction was stirred at room temperature for 24 hours. The reaction formula is shown in Formula 2 below. It was filtered, washed, and dried to obtain 818 mg of hetero-poly(thiophene)-type deuterated methyl reagent;

[0042]

[0043] S3. Phthalimide (147 mg, 1.0 mmol) was dissolved in acetonitrile (5 mL) solution, and hetero-poly(thiophene)-type deuterated methyl reagent (800 mg, 2 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added. The reaction was stirred at room temperature for 12 hours. The reaction formula is shown in Formula 3 below. After the reaction, it was centrifuged and the supernatant was taken and extracted with ethyl acetate. The organic phase was concentrated to obtain 157 mg of white solid N-(1,1,1-trideuteromethyl)phthalimide; the precipitate obtained by centrifugation (hetero-poly(thiophene)) was washed and dried and then recycled for methylation in step S1;

[0044]

[0045] S5. N-(1,1,1-trideuteriomethyl)phthalimide (164 mg, 1.0 mmol) was added to a mixed solution of concentrated hydrochloric acid (1 mL, about 12 mmol) and distilled water (1 mL) for reaction. The temperature was raised to 100 °C and refluxed overnight. After cooling to room temperature, it was stirred for half an hour, filtered, and the obtained solid was washed with distilled water. Deuterated methylamine hydrochloride was obtained by vacuum distillation, and then refluxed and washed with ethanol to obtain 58 mg of white solid deuterated methylamine hydrochloride.

[0046]

[0047] This example also provides a solid-phase continuous flow synthesis system for preparing deuterated methylamine hydrochloride by using the above preparation method of deuterated methylamine hydrochloride. It includes a control system for controlling the whole system, an injection system, a first switching valve, a fixed-bed reactor, a second switching valve, and a collection system connected in sequence. The injection system includes a first pipeline with one end connected to methyl trifluoromethanesulfonate, a second pipeline connected to phthalimide, a third pipeline connected to a mixed solvent, and a fourth pipeline connected to acetonitrile. The other ends of the first pipeline, the second pipeline, the third pipeline, and the fourth pipeline are respectively connected to the switching valve; conveying pumps are provided on the first pipeline, the second pipeline, the third pipeline, and the fourth pipeline; the fixed-bed reactor is connected with a temperature controller, and heteropoly thiophene is filled in the fixed-bed reactor; the collection system includes a recovery pipeline, a product pipeline, a waste liquid pipeline, and a circulation pipeline. The collection system corresponds to the injection system. Among them, the circulation pipeline and the recovery pipeline correspond to the first pipeline; the product pipeline corresponds to the fourth pipeline; the waste liquid pipeline corresponds to the second pipeline and the third pipeline.

[0048] Specifically, please refer to Figure 1 , and the specific process flow for preparing deuterated methylamine hydrochloride by using the solid-phase continuous flow synthesis system in this example is as follows:

[0049] (1) 40 g of polythiophene was loaded into a fixed-bed reactor. Through the first pipeline (line1), a 1,2-dichloroethane (DCE) solution of 200 mL, 30 mmol of methyl trifluoromethanesulfonate (CH3OTf) was pumped into the fixed-bed reactor filled with heteropoly thiophene at a flow rate of 10 mL / min by a conveying pump. At the same time, the reactor was heated to 60 °C and maintained under this reaction condition for 12 h to enable the relevant reactants to fully react.

[0050] (2) After the first-step reaction was completed, the second pipeline (line2) was opened, and a mixed solution containing 60 mmol of potassium carbonate, 100 mL of heavy water, and 50 mL of dimethyl sulfoxide (DMSO) was pumped into the fixed-bed reactor at a flow rate of 0.5 mL / min to initiate the hydrogen-deuterium exchange reaction.

[0051] (3) After the hydrogen-deuterium exchange reaction is completed, open the third pipeline (line3) and pump the MeCN solution into the fixed-bed reactor at a flow rate of 10 mL / min for 20 min continuously to wash the entire fixed-bed reactor and related channels, ensuring that there are no residual impurities in the system affecting the subsequent reaction. The waste liquid after washing is introduced into the waste liquid bottle through the waste liquid pipeline.

[0052] (4) Dissolve 20 mmol of phthalimide and 40 mmol of K2CO3 in a mixed solvent composed of 250 mL of MeCN and 50 mL of H2O, and pump it into the fixed-bed reactor through the fourth pipeline (line4) at a flow rate of 0.8 mL / min. Phthalimide stays in the reactor for 3 h for sufficient reaction. After the reaction is completed, the mixture flows into the product collection bottle through the product pipeline, and finally 3 g of N-(1,1,1-trideuteriomethyl)phthalimide is obtained through extraction and concentration, with a yield of 92%.

[0053] (5) N-(1,1,1-trideuteriomethyl)phthalimide can be hydrolyzed to obtain the final deuterated methylamine hydrochloride.

[0054] In this example, the process for preparing deuterated methylamine hydrochloride by the solid-phase continuous flow synthesis system is particularly suitable for large-scale intelligent production and can achieve continuous and efficient synthesis of deuterated methylamine. In the separation step, it has significant advantages. Only a simple extraction operation is required to effectively separate the deuterated methylamine precursor. This simple separation step greatly shortens the process flow, improves the synthesis efficiency, reduces the dependence on complex separation equipment and technologies compared with traditional methods, and thus further reduces the production cost.

[0055] Example 2

[0056] A method for preparing deuterated methylamine hydrochloride, which comprises the following steps:

[0057] S1. Add methyl trifluoromethanesulfonate (3.45 mmol, 1.5 eq, 0.8 ml) to hetero-poly(thiophene) (2.3 mmol, 500 mg) and 1,2-dichloroethane (5.0 mL, 0.4 M), heat to 50 °C and react for 24 hours. The reaction formula is shown in Formula 1 below; after the reaction is completed, cool to room temperature, add methanol to quench the reaction, wash with methanol and ethyl acetate respectively until the filtrate is colorless, and dry the filter cake to obtain the hetero-poly(thiophene)-type methylation reagent.

[0058] S2. Disperse the above-mentioned hetero-aggregated thienyl methyl reagent (800 mg, 1.6 mmol) in a mixed solvent of 1,4-dioxane (1 mL) and heavy water (1 mL), then add sodium hydroxide (552 mg, 4 mmol), and stir the reaction at room temperature for 36 hours. The reaction formula is shown in Formula 2 below. Filter by suction, wash, and dry to obtain the hetero-aggregated thienyl deuterated methyl reagent;

[0059] S3. Dissolve phthalimide (147 mg, 1.0 mmol) in acetonitrile (5 mL) solution, add the hetero-aggregated thienyl deuterated methyl reagent (615 mg, 1.5 mmol) and potassium carbonate (207 mg, 1.5 mmol), and stir the reaction at room temperature for 16 hours. The reaction formula is shown in Formula 3 below. After the reaction is completed, centrifuge and take the supernatant, add water and ethyl acetate for extraction. The organic phase is concentrated to obtain 157 mg of white solid N-(1,1,1-trideuteromethyl)phthalimide; the precipitate obtained by centrifugation (hetero-aggregated thienyl) is washed and dried and then recycled for methylation in Step S1;

[0060] S5. Add N-(1,1,1-trideuteromethyl)phthalimide (164 mg, 1.0 mmol) to a mixed solution of concentrated hydrochloric acid (0.42 mL, about 5 mmol) and distilled water (1 mL) for reaction, heat up to 100 °C and reflux overnight. After it cools to room temperature, stir for half an hour, filter, wash the obtained solid with distilled water, and obtain pale yellow solid deuterated methylamine hydrochloride by vacuum distillation. Then reflux and wash deuterated methylamine hydrochloride with ethanol.

[0061] Example 3

[0062] A preparation method of deuterated methylamine hydrochloride, which comprises the following steps:

[0063] S1. Add methyl trifluoromethanesulfonate (6.9 mmol, 3 eq, 1.6 ml) to hetero-aggregated thienyl (2.3 mmol, 500 mg) and 1,2-dichloroethane (5.0 mL), and heat up to 100 °C for reaction for 16 hours; after the reaction is completed, cool to room temperature, add methanol to quench the reaction, wash with methanol and ethyl acetate respectively until the filtrate is colorless, and dry the filter cake to obtain the hetero-aggregated thienyl methylation reagent;

[0064] S2. Disperse the above-mentioned hetero-aggregated thienyl methyl reagent (850 mg, 2.4 mmol) in a mixed solvent of dimethyl sulfoxide (4 mL) and heavy water (20 mL), then add potassium carbonate (828 mg, 6 mmol), and stir the reaction at room temperature for 48 hours. The reaction formula is shown in Formula 2 below. Filter by suction, wash, and dry to obtain 818 mg of hetero-aggregated thienyl deuterated methyl reagent;

[0065] S3. Dissolve phthalimide (147 mg, 1.0 mmol) in acetonitrile (5 mL) solution, add hetero - poly - thiophene - type deuteromethyl reagent (1230 mg, 3 mmol) and potassium carbonate (414 mg, 3.0 mmol), stir the reaction at room temperature for 24 hours. The reaction formula is shown in Formula 3 below. After the reaction, centrifuge and take the supernatant, add water and ethyl acetate for extraction. The organic phase is concentrated to obtain N-(1,1,1 - trideuteriomethyl)phthalimide; the precipitate obtained by centrifugation (hetero - poly - thiophene) is washed, dried and then recycled for methylation in step S1;

[0066] S5. Add N-(1,1,1 - trideuteriomethyl)phthalimide (164 mg, 1.0 mmol) to a mixed solution of concentrated hydrochloric acid (1.67 mL, about 20 mmol) and distilled water (2 mL) for reaction. Heat up to 100 °C and reflux overnight. After it cools to room temperature, stir for half an hour, filter. The obtained solid is washed with distilled water, and deuterated methylamine hydrochloride is obtained by vacuum distillation. Subsequently, reflux and wash with ethanol to obtain deuterated methylamine hydrochloride.

[0067] To illustrate the technical effect of the present invention, the yield of N-(1,1,1 - trideuteriomethyl)phthalimide obtained in step S3 of Example 1 was calculated and the nuclear magnetic resonance hydrogen spectrum was detected. The yield was 96%, and the nuclear magnetic resonance hydrogen spectrum data was as follows: 1 HNMR(600MHz,Chloroform - d)δ7.85 - 7.82(m,2H),7.72 - 7.69(m,2H),3.18 - 3.15(m,0.07H). 13 C NMR(151MHz,CDCl3)δ168.42,133.79,132.17,123.08ppm.HRMS(ESI)m / z calcd for[C9H5D3NO2] + (M + H + ):165.0738;found:165.0735.

[0068] To further illustrate the technical effect of the present invention, the following comparative examples were set on the basis of Example 1:

[0069] Comparative Example 1

[0070] The difference between this comparative example and Example 1 is only that the molar equivalent ratio of hetero - poly - thiophene and methyl trifluoromethanesulfonate is 1:1.

[0071] Comparative Example 2

[0072] The difference between this comparative example and Example 1 is only that the reaction temperature in step S1 is 40 °C.

[0073] The methyl loading amounts (percentage of the molar amount of methyl groups loaded on 1.0 mmol of hetero - poly - thiophene) of the hetero - poly - thiophene - type methylation reagents in Example 1, Comparative Example 1, and Comparative Example 2 were tested, and the results are shown in Table 1 below.

[0074] Table 1 Methyl loading amounts of hetero - poly - thiophene - type methylation reagents

[0075]

[0076]

[0077] As shown in Table 1, in the solution of the present invention, the molar amount of methyl groups loaded on 1.0 mmol of hetero - poly - thiophene can reach 0.9 mmol. When the reaction parameters or proportional relationships of the present invention are changed, it is easy to cause insufficient methyl loading amount in the product, thereby further affecting the yield of the final product.

[0078] As described above, the above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention can easily think of various equivalent modifications or substitutions, and these modifications or substitutions should be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A method for preparing deuterated methylamine hydrochloride, characterized in that: The following steps are involved: S1. Adding heterogeneous polythiophene to methyl trifluoromethanesulfonate and 1,2-dichloroethane, reacting at 50-100° C. for 12-24 hours; cooling to room temperature after the reaction, adding methanol to quench the reaction, washing and drying to obtain a heterogeneous polythiophene methylation reagent; S2, adding a heterogeneous polythiophene-type methyl reagent to a mixed solvent of a polar solvent and heavy water, and then adding a base to react for 24-48 hours, filtering, washing, and drying to obtain a heterogeneous polythiophene-type deuterated methyl reagent; S3, dissolving the substrate molecule o-phthalimide in acetonitrile, adding a heterogeneous polythiophene type deuterated methyl reagent and an inorganic base, reacting at room temperature for 12-24 hours, centrifuging after the reaction, extracting and concentrating the supernatant to obtain N-(1,1,1-trideuterated methyl) benzosuccinimide; S4. Reacting N-(1,1,1-trideuteriomethyl)benzosuccinimide with hydrochloric acid in an aqueous solvent to prepare deuterated methylamine hydrochloride.

2. The method for preparing deuterated methylamine hydrochloride according to claim 1, characterized in that: The molar equivalent ratio of the heterogeneous polythiophene and methyl trifluoromethanesulfonate is 1:(1.5-3).

3. The method for preparing deuterated methylamine hydrochloride according to claim 1, characterized in that: The molar concentration of the 1,2-dichloroethane is 0.4M.

4. The method for preparing deuterated methylamine hydrochloride according to claim 1, characterized in that: The polar solvent is selected from at least one of acetonitrile, dimethyl sulfoxide, 1,4-dioxane and dimethylformamide.

5. The method for preparing deuterated methylamine hydrochloride according to claim 1, characterized in that: In the mixed solvent, the volume ratio of the polar solvent to heavy water is 1:(1-5).

6. The method for preparing deuterated methylamine hydrochloride according to claim 1, characterized in that: The molar concentration of the heterogeneous polythiophene-type methyl reagent in the mixed solvent is 0.1-0.8M.

7. The method for preparing deuterated methylamine hydrochloride according to claim 1, characterized in that: The base is selected from at least one of an organic base, lithium diisopropylamide, an inorganic base carbonate and a hydroxide.

8. The method for preparing deuterated methylamine hydrochloride according to claim 1, characterized in that: The molar equivalent ratio of the o-phthalimide, the heterogeneous polythienyl deuterated methyl reagent and the inorganic base is 1:(1.5-3):(1.5-3).

9. The method for preparing deuterated methylamine hydrochloride according to claim 1, characterized in that: The molar equivalent ratio of the N-(1,1,1-trideuteriomethyl)benzosuccinimide to hydrochloric acid is 1:(5-20).

10. A solid phase continuous flow synthesis system for deuterated methylamine hydrochloride, which is prepared by the method for preparing deuterated methylamine hydrochloride according to any one of claims 1 to 9, characterized in that: The invention comprises an injection system, a first switching valve, a fixed reaction bed, a second switching valve and a collection system which are connected in sequence. The injection system comprises a first pipeline connected to methyl trifluoromethanesulfonate at one end, a second pipeline connected to phthalimide, a third pipeline connected to a mixed solvent and a fourth pipeline connected to acetonitrile. The other ends of the first pipeline, the second pipeline, the third pipeline and the fourth pipeline are respectively connected to the first switching valve; the first pipeline, the second pipeline, the third pipeline and the fourth pipeline are all provided with a delivery pump; the fixed reactor is connected to a temperature controller, and the fixed reactor is filled with heterogeneous polythione.

Images