A method for electrochemical synthesis of 3-aryl-3-deuteriopropylamines from azetidinium salts and heavy water

Abstract

The application belongs to the field of organic synthesis and deuterated compound preparation, and discloses a method for electrochemically synthesizing 3-aryl-3-deuterated propylamine by using azetidinium salt and heavy water. The method comprises the following steps: electrolysis is performed by using an integrated electrolytic cell, reaction substrates, heavy water and a solvent are added under an argon atmosphere, and the system is sealed after inserting an electrode sheet. Constant current electrolysis is performed under a current of 3-10 mA, and the reaction time is 4-10 hours. After post-treatment of the reaction solution, 3-aryl-3-deuterated propylamine is obtained through silica gel column chromatography. The application realizes highly specific benzyl ring-opening deuterium substitution through an electrochemical strategy, and the method has the advantages of mild reaction conditions, good functional group compatibility and the like without the need for additional supporting electrolyte and transition metal catalysts. The target product synthesized has a high separation yield, and the deuterium substitution rate can reach 99% at most, and the method is suitable for large-scale synthesis of 3-aryl-3-deuterated propylamine intermediates.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and preparation of deuterated compounds, and relates to a method for the electrochemical synthesis of 3-aryl-3-deuterated propylamine from nitrogen-containing heterocyclic butane salts and heavy water. Background Technology

[0002] 3-aryl-3-deuterated propylamine compounds containing deuterated labels have significant scientific and industrial application value in pharmacokinetic studies and the development of targeted molecules. However, how to achieve efficient construction of such core frameworks while maintaining high site selectivity, high conversion rate, and cost-effectiveness has always been a technical challenge that needs to be overcome in related fields.

[0003] Currently, the preparation of these deuterated compounds mainly relies on traditional thermochemical routes, typically requiring a high-pressure deuterium (D2) environment, the introduction of expensive noble metal catalysts (such as platinum and palladium), or the use of strong acids or bases. These methods not only involve large equipment investments and high safety risks, but also suffer from inherent defects such as poor chemoselectivity. When transforming substrates containing complex and sensitive functional groups, they are highly susceptible to side reactions such as dehalogenation and hydrolysis, making it difficult to meet the stringent requirements of modern pharmaceutical industry for targeted specificity.

[0004] In recent years, organic electrochemical synthesis, with its advantages of being green and operating under mild conditions, combined with inexpensive heavy water (D2O) as a direct deuterium source, has provided a highly promising alternative strategy for the preparation of deuterated molecules. However, existing electrochemical deuteration techniques are mainly limited to the reduction transformation of unsaturated chemical bonds such as C=N double bonds and C=C double bonds. Org. Lett. 2023 25 , 2, 432–437、 Angew. Chem. Int. Ed. 2023, 62 (e202312803.). Technical solutions for directly inducing ring opening and selectively introducing deuterium atoms using an electrocatalytic strategy to address saturated carbon-nitrogen bonds (CN bonds) with extremely high dissociation energies are rarely reported in existing technologies. This is mainly attributed to the fact that, under conventional electrolysis systems, the breaking of saturated CN bonds often involves highly reactive free radical or carbanion intermediate processes (e202312803.). Org. Lett. 2019, 21 The intermediates mentioned above (e.g., 22, 9262–9267) have extremely short lifetimes, making them difficult to capture precisely by deuterium sources. This can easily lead to substrate degradation or trigger numerous uncontrollable side reactions. Therefore, effectively overcoming this reaction energy barrier and achieving highly site-selective ring-opening deuteration remains a challenge in current organic electrochemical synthesis.

[0005] Furthermore, publicly available organic electrochemical synthesis schemes generally suffer from process bottlenecks due to their high dependence on supporting electrolytes. To maintain the conductivity of organic solvents, existing systems require the addition of large amounts of supporting electrolytes such as perchlorate and tetrafluoroborate. This not only increases reagent costs but also significantly increases the technical difficulty of separating and purifying the target product after the reaction, and inevitably generates large amounts of saline industrial waste liquid, severely restricting the large-scale mass production and commercial application prospects of electrochemical deuteration technology. In summary, existing technologies have not yet achieved efficient ring-opening and specific deuteration of saturated CN bonds under mild conditions, and are overly dependent on noble metal catalysts and large amounts of supporting electrolytes. Therefore, there is an urgent need in the field to provide a novel electrochemical ring-opening synthesis method for deuterated compounds that does not require transition metal catalysis, does not require the addition of additional supporting electrolytes, and can overcome the activation barrier of saturated CN bonds. Summary of the Invention

[0006] This invention addresses the technical problem of how to synthesize 3-aryl-3-deuterated propylamine under mild conditions, with high selectivity, without the need for transition metal catalysis and without the need for additional supporting electrolytes.

[0007] The technical solution of this invention: A method for the electrochemical synthesis of 3-aryl-3-deuterated propylamine from azacyclobutane salt and heavy water comprises the following steps: The electrolytic cell is purged with argon three times and then filled with argon. Under an argon atmosphere, azacyclobutane salt, heavy water, and a solvent are added to the electrolytic cell. The electrolytic cell is sealed using a polytetrafluoroethylene stopcock equipped with a cathode and an anode. Electrolysis is performed at a constant current at 25°C. After the reaction is complete, the reaction solution is treated with sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. 3-aryl-3-deuterated propylamine is then purified by column chromatography.

[0008] The above reaction is shown in the following equation: Wherein, Ar is naphth-2-yl, naphth-1-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, [1,1'-biphenyl]-4-yl, o-tolyl, m-tolyl, p-tolyl, 4-(tert-butyl)phenyl, etc.; R 1 R 2 Methyl, ethyl, n-propyl, isopropyl, or butyl, etc.; X - For I - Cl - ,Br - or OTf - wait; In the above method, the cathode sheet is a foamed copper sheet, a foamed nickel sheet, a glassy carbon sheet, carbon cloth, carbon paper, a mesh glassy carbon sheet, a platinum sheet, a stainless steel sheet, or a graphite felt sheet.

[0009] In the above method, the anode sheet is a magnesium sheet, aluminum sheet, iron sheet, stainless steel sheet, or zinc sheet.

[0010] In the above method, the solvent is N , N -Dimethylformamide, N , N - One or more of the following solvents: dimethylacetamide, N-methylpyrrolidone, acetonitrile, and dimethyl sulfoxide.

[0011] In the above method, the argon atmosphere is at atmospheric pressure.

[0012] In the above method, the concentration of the azacyclobutane salt in the reaction system is 0.5-1 mol / L.

[0013] In the above method, the constant current is 3-10 mA and the reaction time is 4-10 hours.

[0014] The beneficial effects of this invention are as follows: This invention constructs a green, efficient, and economical electrochemical ring-opening deuteration system. This method uses safe and inexpensive heavy water (D₂O) as the direct deuterium source, carried out in a membrane-free electrolytic cell at ambient temperature and pressure. By utilizing the substrate itself as the electrolyte, it eliminates the dependence on high-pressure deuterium gas, strong acids and bases, expensive transition metal catalysts, and additional supporting electrolytes found in traditional methods, thus reducing the overall production and subsequent separation and purification costs. Simultaneously, thanks to the electrochemical-chemical-electrochemical-chemical ring-opening mechanism, this reaction achieves high site specificity; the introduction of deuterium atoms into the benzylic position effectively accommodates multiple sensitive functional groups, with the benzylic deuteration rate reaching up to 99%. Furthermore, this process is simple to operate, safe, and controllable, and has been successfully scaled up to gram-scale, providing an innovative technical route with promising industrial applications for the large-scale preparation of high-value-added deuterium-containing drug intermediates and metabolic tracer materials. Detailed Implementation

[0015] The specific embodiments of the present invention will be further described below in conjunction with the technical solution.

[0016] Example 1: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. oThe sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(naphth-2-yl)azacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N- Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved. A PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a magnesium anode (20 mm × 10 mm × 0.5 mm) was then placed in the solution. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 5 mA, and electrolysis was continued for 5 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the final product, with a yield of 70% and a deuteration rate of 99%.

[0017] Example 2: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(naphth-2-yl)azacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N-Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved, and then placed in a PTFE stopcock connected to a graphite felt cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm). The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was carried out in constant current mode with stirring at 1000 RPM. The current was set to 5 mA and electrolysis was continued for 5 hours. After the reaction was completed, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the product, with a yield of 88% and a deuteration rate of 99%.

[0018] Example 3: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(naphth-2-yl)azacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N- Dimethylacetamide and heavy water (1.5 mmol) were stirred until completely dissolved. A PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm) was then placed inside. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 5 mA, and electrolysis was continued for 5 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the final product, with a yield of 86% and a deuteration rate of 92%.

[0019] Example 4: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(naphth-2-yl)azacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N- Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved. A PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm) was then placed in the solution. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 10 mA, and electrolysis was continued for 5 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the final product, with a yield of 86% and a deuteration rate of 92%.

[0020] Example 5: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(naphth-2-yl)azacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N-Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved. A PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm) was then placed inside. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 3 mA, and electrolysis was continued for 5 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the product, with a yield of 90% and a deuteration rate of 94%.

[0021] Example 6: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(naphth-2-yl)azacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N- Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved. A PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm) was then placed inside. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 5 mA, and electrolysis was continued for 4 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the final product, with a yield of 75% and a deuteration rate of 99%.

[0022] Example 7: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(naphth-2-yl)azacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N- Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved. A PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm) was then placed in the solution. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 5 mA, and electrolysis was continued for 10 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the final product, with a yield of 95% and a deuteration rate of 99%.

[0023] Example 8: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 100 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(naphth-2-yl)azacyclobutane-1-onium trifluoromethanesulfonate (3 mmol) was added under a continuously flowing argon atmosphere. Then, 40 mL of ultra-dry solution was added to the electrolytic cell under argon gas flow protection. N,NDimethylformamide was stirred until completely dissolved and then placed in a PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm). The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was carried out in constant current mode with stirring at 1000 RPM. The current was set to 5 mA and electrolysis was continued for 50 hours. After the reaction was completed, 50 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.1) to obtain the final product. The yield was 69%, and the deuteration rate was 99%.

[0024] The structural characterization data of the products obtained in Examples 1-8 are shown below: 1 H NMR (500 MHz, Chloroform- d ) δ 7.82 – 7.73 (m,3H), 7.61 (s, 1H), 7.48 – 7.36 (m, 2H), 7.33 (dd, J = 8.3, 1.8 Hz, 1H), 2.78(q, J = 9.2, 8.6 Hz, 0.96H), 2.31 (t, J = 7.5 Hz, 2H), 2.22 (s, 6H), 1.87 (q, J =7.6 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 139.80, 133.66, 132.02, 127.88,127.64, 127.45, 127.36, 126.38, 125.90, 125.12, 59.28, 45.57, 33.83, 29.26. Example 9: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. oThe sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-phenylazacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved, and then placed in a PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm). The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was carried out in constant current mode with stirring at 1000 RPM. The current was set to 5 mA and electrolysis was continued for 5 hours. After the reaction was completed, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the product, with a yield of 91% and a deuteration rate of 91%.

[0025] The structural characterization data of the product obtained in Example 9 are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.24 – 7.07 (m, 5H), 2.56(q, J = 7.7 Hz, 1.09H), 2.22 (t, 2H), 2.15 (s, 6H), 1.77 – 1.67 (m, 2H)., 13 C NMR (101 MHz, Chloroform- d ) d 142.27, 128.36 (d, J = 7.2 Hz), 125.75, 59.30, 45.51,33.69, 29.44. Example 10: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. oThe sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the vacuuming and purging process was repeated at least three times to ensure complete removal of air from the system. The substrate 2-(4-bromophenyl)-1,1-dimethylazirmonobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultradry N,N-dimethylformamide and heavy water (1.5 mmol) were added to the electrolytic cell under argon protection, stirred until completely dissolved, and a PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm) was placed in the cell. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 5 mA, and electrolysis was continued for 5 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the product, with a yield of 57% and a deuteration rate of 99%.

[0026] The structural characterization data of the product obtained in Example 10 are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.31 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 2.51 (q, J = 7.7 Hz, 0.9H), 2.19 (t, 2H), 2.14 (s,6H), 1.67 (q, J = 7.4 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d ) d 141.20, 131.36, 130.18, 119.46, 59.00, 45.47, 33.00, 29.21. Example 11: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 2-(4-chlorophenyl)-1,1-dimethylazacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry gel was added to the electrolytic cell under argon gas flow protection. N,N- Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved. A PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm) was then placed inside. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 5 mA, and electrolysis was continued for 5 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the final product, with a yield of 72% and a deuteration rate of 99%.

[0027] The structural characterization data of the product obtained in Example 11 are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 7.20 – 7.13 (m,2H), 7.08 – 7.00 (m, 2H), 2.52 (q, J = 7.6 Hz, 0.92H), 2.19 (t, 2H), 2.14 (s,6H), 1.67 (q, J = 6.9 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 140.68, 131.43,129.75, 128.39, 59.03, 45.51, 32.95, 29.30. Example 12: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 2-([1,1'-biphenyl]-4-yl)-1,1-dimethylazacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry gel was added to the electrolytic cell under argon gas flow protection. N,N Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved, and then placed in a PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm). The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was carried out in constant current mode with stirring at 1000 RPM. The current was set to 5 mA and electrolysis was continued for 5 hours. After the reaction was completed, sodium hydroxide aqueous solution (15 mL, 1 M) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the product, with a yield of 97% and a deuteration rate of 99%.

[0028] The structural characterization data of the product obtained in Example 12 are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 7.53 – 7.46 (m,2H), 7.46 – 7.39 (m, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.27 – 7.20 (m, 1H), 7.21 –7.13 (m, 2H), 2.58 (q, J = 7.7 Hz, 0.83H), 2.23 (t, J = 7.4 Hz, 2H), 2.15 (s,6H), 1.73 (q, J = 7.4 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d) δ 141.39, 141.15,138.78, 128.81, 127.70 – 126.58 (m), 59.30, 45.54, 33.33, 29.39. Example 13: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-(o-tolyl)azacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry powder was added to the electrolytic cell under argon gas flow protection. N,N- Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved. A PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm) was then placed inside. The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was performed in constant current mode with stirring at 1000 RPM. The current was set to 5 mA, and electrolysis was continued for 5 hours. After the reaction was complete, 15 mL of sodium hydroxide aqueous solution (1 M) was added to the reaction solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the final product, with a yield of 88% and a deuteration rate of 97%.

[0029] The structural characterization data of the product obtained in Example 13 are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.11 – 6.98 (m, 4H), 2.60 – 2.46 (m, 1.03H), 2.30 – 2.21 (m, 4H), 2.16 (s, 6H), 1.66 (q, J = 7.7 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d ) d139.37, 134.84, 129.11, 124.87, 58.53, 44.42, 27.18, 18.25. Example 14: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 2-(4-(tert-butyl)phenyl)-1,1-dimethylazacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry gel was added to the electrolytic cell under argon gas flow protection. N,N Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved, and then placed in a PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm). The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was carried out in constant current mode with stirring at 1000 RPM. The current was set to 5 mA and electrolysis was continued for 5 hours. After the reaction was completed, sodium hydroxide aqueous solution (15 mL, 1 M) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the product, with a yield of 52% and a deuteration rate of 61%.

[0030] The structural characterization data of the product obtained in Example 14 are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.26 – 7.20 (m, 2H),7.09 – 7.02 (m, 2H), 2.52 (m, J = 7.7 Hz, 1.39H), 2.26 – 2.20 (m, 2H), 2.15 (s,6H), 1.70 (q, J = 7.5 Hz, 2H), 1.24 (s, 9H). 13 C NMR (101 MHz, Chloroform-d ) d 148.51, 139.22, 128.02, 125.20, 59.48, 45.54, 34.36, 33.15, 31.44, 29.44. Example 15: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1,1-dimethyl-2-phenylazacyclobutane-1-iodide (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry material was added to the electrolytic cell under argon protection. N,N Dimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved and placed in a PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm). The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was carried out in constant current mode with stirring at 1000 RPM. The current was set to 5 mA and electrolysis was continued for 5 hours. After the reaction was completed, sodium hydroxide aqueous solution (15 mL, 1 M) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the product, with a yield of 75% and a deuteration rate of 92%.

[0031] Example 16: Before conducting the electrochemical reaction, the reaction vessel must undergo rigorous pretreatment. First, a 50 mL three-necked electrochemical electrolytic cell containing a magnetic stirrer is placed in a 120°C environment. o The sample was dried in an oven at C for 1 hour to remove moisture adsorbed on the walls. After drying, it was allowed to cool naturally to room temperature under vacuum. Subsequently, the system was purged with argon, and the purging and priming process was repeated at least three times to ensure complete removal of air from the system. The substrate 1-ethyl-1-methyl-2-phenylazacyclobutane-1-onium trifluoromethanesulfonate (0.3 mmol) was added under a continuously flowing argon atmosphere. Then, 4 mL of ultra-dry gel was added to the electrolytic cell under argon gas flow protection. N,NDimethylformamide and heavy water (1.5 mmol) were stirred until completely dissolved, and then placed in a PTFE stopcock connected to a glassy carbon cathode (10 mm × 10 mm × 0.1 mm) and a zinc anode (20 mm × 10 mm × 0.5 mm). The assembled electrolytic cell was placed at room temperature and connected to a DC power supply. Electrolysis was carried out in constant current mode with stirring at 1000 RPM. The current was set to 5 mA and electrolysis was continued for 5 hours. After the reaction was completed, sodium hydroxide aqueous solution (15 mL, 1 M) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel column; developing solvent: petroleum ether / ethyl acetate / triethylamine = 3 / 1 / 0.01) to obtain the product, with a yield of 82% and a deuteration rate of 94%.

[0032] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for the electrochemical synthesis of 3-aryl-3-deuterated propylamine from a nitrogen-containing heterocyclic butane salt and heavy water, characterized in that, The steps are as follows: The electrolytic cell is purged with argon three times and then filled with argon. Under the protection of the argon atmosphere, nitrogen-containing heterocyclic butane salt, heavy water, and solvent are added to the electrolytic cell. The electrolytic cell is sealed using a polytetrafluoroethylene stopcock equipped with a cathode and an anode. Electrolysis is performed at a constant current at 25°C. After the reaction is completed, the reaction solution is treated with sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product is then purified by column chromatography to obtain 3-aryl-3-deuterated propylamine. The above reaction is shown in the following equation: Wherein, Ar is naphth-2-yl, naphth-1-yl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, [1,1'-biphenyl]-4-yl, o-tolyl, m-tolyl, p-tolyl, or 4-(tert-butyl)phenyl; R 1 R 2 It can be methyl, ethyl, n-propyl, isopropyl, or butyl, and the two may be the same or different; X - For I - Cl - ,Br - or OTf - .

2. The method for electrochemically synthesizing 3-aryl-3-deuterated propylamine from nitrogen-containing heterocyclic butane salts and heavy water according to claim 1, characterized in that, The cathode is made of copper foam, nickel foam, glass carbon, carbon cloth, carbon paper, mesh glass carbon, platinum sheet, stainless steel sheet, or graphite felt.

3. The method for electrochemically synthesizing 3-aryl-3-deuterated propylamine from nitrogen-containing heterocyclic butane salts and heavy water according to claim 1, characterized in that, The anode is a magnesium sheet, aluminum sheet, iron sheet, stainless steel sheet, or zinc sheet.

4. The method for electrochemically synthesizing 3-aryl-3-deuterated propylamine from nitrogen-containing heterocyclic butane salts and heavy water according to claim 1, characterized in that, The solvent is N , N -Dimethylformamide, N , N - One or more of the following solvents: dimethylacetamide, N-methylpyrrolidone, acetonitrile, and dimethyl sulfoxide.

5. The method for electrochemically synthesizing 3-aryl-3-deuterated propylamine from nitrogen-containing heterocyclic butane salts and heavy water according to claim 1, characterized in that, The argon atmosphere is at normal pressure.

6. The method for electrochemically synthesizing 3-aryl-3-deuterated propylamine from azacyclic butane salts and heavy water according to claim 1, characterized in that, The concentration of the nitrogen-containing heterocyclic butane salt in the reaction system is 0.5-1 mol / L.

7. The method for electrochemically synthesizing 3-aryl-3-deuterated propylamine from azacyclic butane salts and heavy water according to claim 1, characterized in that, The constant current is 3-10 mA, and the reaction time is 4-10 hours.

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