A kind of electrochemical synthesis method of amantadine or memantane

Abstract

The present invention discloses an electrochemical synthesis method for amantadine or memantane. The method comprises the following steps: mixing adamantane or memantane with a solvent and an alcohol in a single-chamber electrolytic cell, applying electricity for a constant current electrochemical reaction to produce an iminoether intermediate; and then hydrolyzing the iminoether intermediate to produce amantadine or memantane. The method operates under simple and mild conditions, avoiding the hydrolysis conditions of high temperature and strong acid or base.

Description

Technical Field

[0001] The invention relates to an electrochemical synthesis method of amantadine or memantane, and belongs to the field of electrochemical synthesis. Background Art

[0002] Amantadine hydrochloride, an amino derivative of a saturated tricyclodecane, exhibits antiviral properties and is used for the prevention and early treatment of Asian influenza A virus. It is currently widely used against influenza viruses. Memantine hydrochloride, a low-to-moderate affinity, noncompetitive NMDA receptor antagonist, delays the release of excitatory neurotransmitters. Compared to other receptor antagonists, it requires a lower dosage and has fewer side effects in clinical practice. It is currently widely used in the treatment of Alzheimer's disease. Amantadine hydrochloride and memantane hydrochloride can be conveniently prepared by reacting the corresponding amantadine and memantane with hydrochloric acid. Amantadine and memantane are typically prepared from the corresponding adamantane and memantane via a Ritter reaction.

[0003] At present, the traditional synthesis of adamantane and memantane is prepared from the corresponding adamantane and memantane through the Ritter reaction. Su Xu et al. reported the synthesis of memantane by the acetonitrile method (Su Xu, Yan Han, et al. Improved synthesis of memantine hydrochloride [J]. Shandong Chemical Industry, 2020, 49 (22): 9-12.). This method uses 1,3-dimethyladamantane as the starting material, and undergoes a Ritter reaction with acetonitrile under the action of concentrated sulfuric acid to produce acetyl memantane, which is then alkaline hydrolyzed at a high temperature of 160°C to produce memantane. This method has the following disadvantages: First, a large amount of concentrated sulfuric acid is used as a solvent, and a large amount of high-concentration waste acid water is generated during the post-treatment process, which is difficult to handle and environmentally unfriendly; second, hydrolysis must be performed under high temperature conditions, the reaction conditions are relatively harsh, and strong base sodium hydroxide is used.

[0004] Wang Shaozhong et al. have provided a method for synthesizing memantane. (Wang Shaozhong, Li Jianxin, et al. Method for Synthesizing Memantane Hydrochloride, CN200410013859.2[P]. 2004-12-22.) The raw materials are reacted with bromine and acetonitrile in a one-pot halogenation and Ritter reaction. Alcohol is added to the reaction to form an iminoether intermediate, which is hydrolyzed under alkaline conditions to yield memantane. However, this reaction requires the addition of a large amount of bromine, 10 times the equivalent of the raw materials, which is highly corrosive to equipment and environmentally harmful. Toluene-based solvents are used for post-processing, which poses significant risks to humans and the environment.

[0005] Therefore, there is an urgent need for an environmentally friendly synthesis method of amantadine and memantane that is suitable for industrial production. Summary of the Invention

[0006] The present invention aims to provide an electrochemical synthesis method for amantadine or memantane. The method has simple and mild conditions and avoids the hydrolysis conditions of high temperature and strong acid or strong base.

[0007] The present invention provides an electrochemical synthesis method of amantadine or memantane, comprising the following steps: in a single-chamber electrolytic cell, mixing adamantane or memantane represented by Formula I with a solvent and an alcohol, and applying electricity to carry out a constant current electrochemical reaction to obtain an iminoether intermediate represented by Formula II; then, hydrolyzing the iminoether intermediate to obtain amantadine or memantane represented by Formula III;

[0008]

[0009] In formula I, when R is H, it represents adamantane, and when R is CH3, it represents memantane (also known as 1,3-dimethyladamantane);

[0010] In formula II, R is H or CH3, and R′ is methyl or ethyl;

[0011] In formula III, when R is H, it represents adamantane (also known as 1-adamantane), and when R is CH3, it represents memantane.

[0012] In the above method, the constant current electrochemical reaction is carried out in the presence of a protonic acid;

[0013] The molar ratio of the adamantane or memantane represented by Formula I to the protonic acid may be 1:0.2-3, specifically 1:0.5, 1:1, 1:1.5, or 1:3;

[0014] The protonic acid includes at least one of methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, formic acid, sulfuric acid and nitric acid.

[0015] In the above method, the molar ratio of the adamantane or memantane represented by Formula I to the alcohol may be 1:2 to 10, specifically 1:4;

[0016] The alcohol includes at least one of methanol, ethanol, propanol and isopropanol.

[0017] In the above method, the solvent includes acetonitrile and / or propionitrile.

[0018] In the above method, the conditions of the constant current electrochemical reaction are as follows:

[0019] The current density can be 10~60mA / cm 2 ;

[0020] The amount of electricity passed can be 2 to 4 F / mol;

[0021] The reaction temperature may be 10-60°C.

[0022] In the above method, the conditions of the constant current electrochemical reaction are specifically as follows:

[0023] The current density can be 10~40mA / cm 2 , specifically 10mA / cm 2 , 15mA / cm 2 , 25mA / cm 2 , 35 mA / cm 2 or 10~35mA / cm 2 ;

[0024] The amount of electricity passed can be 2 to 4 F / mol, specifically 2.5 F / mol, 3.0 F / mol, and 3.5 F / mol;

[0025] The reaction temperature may be 20 to 45°C, more preferably 25°C, 35°C, 45°C or 25 to 45°C.

[0026] In the above method, the anode of the constant current electrochemical reaction is platinum and / or graphite, and the cathode is nickel and / or graphite; the electrode combination is preferably anode platinum mesh / cathode nickel sheet, anode graphite / cathode nickel sheet or anode platinum mesh / cathode graphite.

[0027] In the above method, the hydrolysis temperature may be 10-50°C, specifically 10°C, 40°C, 50°C, 10-40°C or 40-50°C, and the time may be 1-12h, specifically 1h, 3h or 12h.

[0028] In the above method, the hydrolysis is carried out in the presence of a base or an acid;

[0029] The base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium phosphate;

[0030] The acid is selected from at least one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid and formic acid.

[0031] In the above method, the method further includes the step of adding the alcohol to the reaction system to continue the reaction after the power supply is completed, so as to make the reaction more complete.

[0032] The present invention has the following advantages:

[0033] (1) The constant current electrolysis method is adopted, and electrons are used as clean oxidants. There is no need to use oxidants such as bromine and concentrated sulfuric acid, which is green and environmentally friendly.

[0034] (2) The present invention uses a protonic acid (specifically, methanesulfonic acid or trifluoromethanesulfonic acid) to support constant current electrolysis, without the need to add a large amount of expensive supporting electrolytes such as perchlorate or tetrafluoroborate, and the protonic acid of the present invention can be recycled.

[0035] (3) The generated iminoether intermediate can be hydrolyzed under simple and mild conditions, avoiding harsh hydrolysis conditions such as high temperature and high pressure. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Schematic diagram of the reaction mechanism of the present invention. DETAILED DESCRIPTION

[0037] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0038] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0039] Example 1: Electrochemical synthesis of memantane

[0040] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (0.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 15 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 2.5 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL, and saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantane (3,5-dimethyl-1-aminoadamantane), a yellow oil with a gas phase yield of 31%.

[0041] The structure was confirmed as follows:

[0042] The post-treatment of the imino ether intermediate is to remove the organic phase by vacuum distillation, add 100 mL of water, extract three times with methyl tert-butyl ether, then extract the aqueous phase multiple times with chloroform, dry the organic phase with anhydrous sodium sulfate, remove the solvent, and finally treat to obtain the perchlorate of the imino ether.

[0043] The perchlorate salt of ethyl (E)-N-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)acetimidate, an iminoether intermediate, has a structure as shown below:

[0044]

[0045] 1H NMR (400MHz, CDCl3) δ4.59 (q, J=7.1Hz, 2H), 2.61 (d, J=1.1Hz, 3H), 2.23-2.20(m,1H),2.01-1.85(m,2H),1.75-1.66(m,4H),1.53(dd,J=7.6,6.5Hz,3H),1.40-1.29(m,4H),1.22-1.12(m,2H),0.88(s,6H). 13 C NMR (100MHz, CDCl3) δ175.9, 70.7,60.1,50.0,45.9,42.0,38.6,32.5,29.8,18.1,14.4.

[0046] Memantane (English name: 3,5-dimethyl-1-aminoadamantane) has a structure as shown below:

[0047]

[0048] 1 H NMR (400MHz, DMSO-d6) δ2.06-2.02(m,1H),1.36-1.29(m,2H),1.22-1.20(m,4H),1.19-1.07(m,4H),1.07-0.98(m,2H),0.79(s,6H).

[0049] Example 2: Electrochemical synthesis of memantane

[0050] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 25 mA / cm 2 Electrolysis was performed at a constant current with stirring at 60°C. When the current reached 2.5 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile, and the solution was adjusted to a pH of 8-9 by adding saturated sodium carbonate solution. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The gas phase yield was 35%.

[0051] Example 3: Electrochemical synthesis of memantane

[0052] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (0.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed under constant current with stirring at 45°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 28%.

[0053] Example 4: Electrochemical Synthesis of Memantane

[0054] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.0 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 25 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 62%.

[0055] Example 5: Electrochemical Synthesis of Memantane

[0056] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.0 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 25 mA / cm 2 Electrolysis was performed under constant current with stirring at 10°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 51%.

[0057] Example 6: Electrochemical Synthesis of Memantane

[0058] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL, and saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was stirred in a water bath at 50°C for 1 hour to convert the reaction intermediate into the product, memantaneamine. The gas phase yield was 65%.

[0059] Example 7: Electrochemical Synthesis of Memantane

[0060] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. Graphite was used as the anode and nickel sheet was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile, and the solution was adjusted to pH 8-9 by adding saturated sodium carbonate solution. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 36%.

[0061] Example 8: Electrochemical Synthesis of Memantane

[0062] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and graphite was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 54%.

[0063] Example 9: Electrochemical Synthesis of Memantane

[0064] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and methanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.5 F / mol, electrolysis was stopped, 4.0 mmol of methanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 68%.

[0065] The structure was confirmed as follows:

[0066] The structure of the iminoether intermediate (methyl(E)-N-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)acetimidate) is shown below:

[0067]

[0068] 1 H NMR (400MHz, CDCl3) δ3.50(s,3H),1.97(s,3H),1.66(s,2H),1.53-1.39(m,4H),1.39-1.26(m,5H),1.15(s,2H),0.86(s,6H). 13 C NMR (100MHz, CDCl3) δ169.2, 62.6,52.6,50.7,49.1,47.5,42.8,32.3,30.6,29.9,24.2.

[0069] Example 10: Electrochemical Synthesis of Memantane

[0070] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 15 mA / cm 2 Electrolysis was performed at a constant current with stirring at 35°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes. The organic phase was distilled under reduced pressure to remove acetonitrile, and the solution was adjusted to approximately 5 mL by adding saturated sodium carbonate solution to a pH of 8-9. The solution was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate to the product, memantaneamine. The vapor phase yield was 70%.

[0071] Example 11: Electrochemical Synthesis of Memantane

[0072] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.5 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 72%.

[0073] Example 12: Electrochemical Synthesis of Memantane

[0074] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL, and saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was stirred in a water bath at 10°C for 12 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 63%.

[0075] Example 13: Electrochemical Synthesis of Memantane

[0076] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium bicarbonate solution was added to adjust the solution to pH 8-9. The reaction was stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate to the product, memantaneamine. The gas phase yield was 68%.

[0077] Example 14: Electrochemical Synthesis of Memantane

[0078] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 10 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 59%.

[0079] Example 15: Electrochemical Synthesis of Memantane

[0080] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 60 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 58%.

[0081] Example 16: Electrochemical Synthesis of Memantane

[0082] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), methanesulfonic acid (3.0 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 15 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution to pH 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The gas phase yield was 32%.

[0083] Example 17: Electrochemical Synthesis of Memantane

[0084] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (0.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 25 mA / cm 2 Electrolysis was performed at a constant current with stirring at 35°C. When the current reached 3.5 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 26%.

[0085] Example 18: Electrochemical Synthesis of Memantane

[0086] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.0 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 35 mA / cm 2 Electrolysis was performed at a constant current with stirring at 35°C. When the current reached 2.5 F / mol, the electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 55%.

[0087] Example 19: Electrochemical Synthesis of Memantane

[0088] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.0 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 15 mA / cm 2 Electrolysis was performed under constant current with stirring at 45°C. When the current reached 3.5 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL, and saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 47%.

[0089] Example 20: Electrochemical Synthesis of Memantane

[0090] In a 50 ml single-chamber electrolytic cell, 1,3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) and ethanol (4.0 mmol) were added to 10 ml of acetonitrile. A platinum mesh was used as the anode and a nickel sheet was used as the cathode. The electrolysis was carried out at 25 mA / cm 2 Electrolysis was performed under constant current with stirring at 45°C. When the current reached 2.5 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL. Saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 40°C for 3 hours to convert the reaction intermediate into the product, memantaneamine. The vapor phase yield was 66%.

[0091] Example 21: Electrochemical Synthesis of Amantadine

[0092] In a 50 ml single-chamber electrolytic cell, adamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol), and methanol (4.0 mmol) were added to 10 ml of acetonitrile, with a platinum mesh as the anode and a nickel sheet as the cathode. The electrolysis was carried out at 15 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of methanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile to approximately 5 mL, and saturated sodium carbonate solution was added to adjust the solution pH to 8-9. The reaction was heated and stirred in a water bath at 50°C for 3 hours to convert the reaction intermediate into the product, 1-adamantanamine (English name: 1-Adamantanamine), with a gas phase yield of 43% and a white solid.

[0093] The structure is confirmed as follows:

[0094] The perchlorate salt of the iminoether intermediate (the perchlorate salt of methyl (E)-N-((3s,5s,7s)-adamantan-1-yl)acetimidate) is prepared by the same method as in Example 1 of the present invention, and has the following structural formula:

[0095]

[0096] 1 H NMR (400MHz, CDCl3) δ4.27 (s, 3H), 2.65 (s, 3H), 2.22-2.14 (m, 3H), 2.08 (d, J = 3.0Hz, 6H), 1.71-1.69 (m, 6H). 13 C NMR (100MHz, CDCl3) δ176.9, 60.1, 58.9, 40.0, 35.6, 29.1, 17.8.

[0097] 1-Adamantanamine (English name: 1-Adamantanamine) has the following structural formula:

[0098]

[0099] 1 H NMR (400MHz, DMSO-d6) δ1.97 (d, J = 3.0Hz, 3H), 1.63-1.49 (m, 6H), 1.49-1.45 (m, 6H).

[0100] Example 22: Electrochemical Synthesis of Amantadine

[0101] In a 50 ml single-chamber electrolytic cell, adamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol), and ethanol (4.0 mmol) were added to 10 ml of acetonitrile, with a platinum mesh as the anode and a nickel sheet as the cathode. The electrolysis was carried out at 15 mA / cm 2 Electrolysis was performed under constant current with stirring at 25°C. When the current reached 3.0 F / mol, electrolysis was stopped, 4.0 mmol of ethanol was added, and stirring was continued for 30 minutes to obtain the iminoether intermediate. The organic phase was distilled under reduced pressure to remove acetonitrile, and the solution was adjusted to a pH of 8-9 by adding saturated sodium carbonate solution. The reaction was heated and stirred in a water bath at 50°C for 3 hours to convert the reaction intermediate into the product, 1-adamantine. The gas phase yield was 45%.

[0102] The structure is confirmed as follows:

[0103] Imine ether intermediate (ethyl(E)-N-((3s,5s,7s)-adamantan-1-yl)acetimidate), the structural formula is shown below:

[0104]

[0105] 1 H NMR (400MHz, DMSO-d6) δ3.83 (q, J = 7.1Hz, 2H), 2.04-1.98 (m, 3H), 1.91 (s, 3H), 1. 85-1.79(m,1H),1.74(d,J=2.9Hz,6H),1.64-1.60(m,6H),1.12(t,J=7.1Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ155.6,59.3,52.1,43.6,36.5,29.7,19.3,14.6.

Claims

1. A method for electrochemically synthesizing amantadine or memantane, comprising the following steps: mixing adamantane or memantane represented by Formula I with a solvent and an alcohol in a single-chamber electrolytic cell, applying electricity to conduct a constant current electrochemical reaction to obtain an iminoether intermediate represented by Formula II; then hydrolyzing the iminoether intermediate to obtain amantadine or memantane represented by Formula III; In formula I, when R is H, it represents adamantane, and when R is CH3, it represents memantane; In formula II, R is H or CH3, and R′ is methyl or ethyl; In formula III, when R is H, it represents amantadine, and when R is CH3, it represents memantane; The alcohol is at least one of methanol and ethanol; The constant current electrochemical reaction is carried out in the presence of a protonic acid; the protonic acid is at least one of methanesulfonic acid and trifluoromethanesulfonic acid; The solvent is acetonitrile; The conditions of the constant current electrochemical reaction are as follows: Current density is 10~60 mA / cm 2 ; The amount of electricity passed is 2~4 F / mol; The reaction temperature is 10~60℃.

2. The method according to claim 1, wherein: The molar ratio of the adamantane or memantane represented by formula I to the protonic acid is 1:0.2-3.

3. The method according to claim 1 or 2, characterized in that: The molar ratio of the adamantane or memantane represented by formula I to the alcohol is 1:2-10.

4. The method according to claim 1 or 2, characterized in that: The conditions of the constant current electrochemical reaction are as follows: Current density is 10~40 mA / cm 2 , The amount of electricity passed can be 2~4 F / mol; The reaction temperature is 20~45℃.

5. The method according to claim 1 or 2, characterized in that: The anode of the constant current electrochemical reaction is platinum and / or graphite, and the cathode is nickel and / or graphite.

6. The method according to claim 1 or 2, characterized in that: The hydrolysis temperature is 10-50° C., and the time is 1-12 h.

7. The method according to claim 1 or 2, characterized in that: The hydrolysis is carried out in the presence of a base or an acid; The base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium phosphate; The acid is selected from at least one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid and formic acid.

8. The method according to claim 1 or 2, characterized in that: The method further includes the step of adding the alcohol to the reaction system to continue the reaction after the power supply is completed.

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