CN115478284A - Electrochemical synthesis method of amantadine or memantine - Google Patents

Abstract

The invention discloses an electrochemical synthesis method of amantadine or memantine. The method comprises the following steps: mixing adamantane or memantine and a solvent with alcohol in a single-chamber electrolytic cell, electrifying to perform constant-current electrochemical reaction to obtain an imine ether intermediate; and hydrolyzing the imino ether intermediate to obtain amantadine or memantine. The method has simple and mild conditions, and avoids the hydrolysis conditions of high temperature and strong acid or strong base.

Description

Electrochemical synthesis method of amantadine or memantine

Technical Field

The invention relates to an electrochemical synthesis method of amantadine or memantine, belonging to the field of electrochemical synthesis.

Background

Amantadine hydrochloride is an amino derivative of saturated tricyclodecane, has an antiviral effect, can be used for preventing and early treating Asia influenza A virus, and is widely applied to anti-influenza virus at present; memantine hydrochloride is used as a low-affinity, moderate and noncompetitive NMDA receptor antagonist, can delay the release of excitatory neurotransmitters, is clinically less in dosage and less in side effect compared with other receptor antagonists, and is widely used for treating senile dementia at present. Amantadine hydrochloride and memantine hydrochloride may be conveniently prepared by reacting the corresponding amantadine and memantine with hydrochloric acid. While amantadine and memantine are generally prepared from the corresponding adamantane and memantine via the Ritter reaction.

Currently, the traditional syntheses of amantadine and memantine are prepared from the corresponding adamantane and memantine via the Ritter reaction. Suasa et al reported the synthesis of memantine amine by the acetonitrile method (Suasa, yan break, et al. Memantine hydrochloride synthesis improvement [ J ]. Shandong chemical, 2020,49 (22): 9-12.) starting from 1, 3-dimethyladamantane, which undergoes a Ritter reaction with acetonitrile under the action of concentrated sulfuric acid to form acetylmemantine, which is then hydrolyzed under alkaline conditions at a high temperature of 160 ℃ to form memantine amine. This method has the following disadvantages: firstly, a large amount of concentrated sulfuric acid is used as a solvent, a large amount of high-concentration waste acid water is generated in the post-treatment process, the treatment difficulty is high, and the environment is not friendly; secondly, hydrolysis must be carried out at high temperature, the reaction conditions are harsh, and strong alkali sodium hydroxide is used.

Wang Shaosheng et al provide a method for synthesizing memantine. (Wang Shaoshan, li Jian Xin, etc. the method for synthesizing memantine hydrochloride, CN200410013859.2[ P ]. 2004-12-22.) raw material and bromine and acetonitrile complete halogenation and Ritter reaction by one-pot method, alcohol is added into the reaction to generate imine ether intermediate, and the intermediate is hydrolyzed under alkaline condition to obtain memantine hydrochloride. However, the reaction needs to add a large amount of bromine which is 10 times of the equivalent of the raw material, so that the method has high corrosion to equipment and large environmental pollution. Toluene solvent is selected for post-treatment, so that the method has great harm to human bodies and environment.

Therefore, there is a need for an environmentally friendly method for synthesizing amantadine and memantine that is suitable for industrial production.

Disclosure of Invention

The invention aims to provide an electrochemical synthesis method of amantadine or memantine, which has simple and mild conditions and avoids hydrolysis conditions of high temperature and strong acid or strong base.

The invention provides an electrochemical synthesis method of amantadine or memantine, which comprises the following steps: mixing adamantane or memantine shown in a formula I and a solvent with alcohol in a single-chamber electrolytic cell, electrifying to perform constant-current electrochemical reaction to obtain an imine ether intermediate shown in a formula II; then hydrolyzing the imino ether intermediate to obtain amantadine or memantine shown in a formula III;

in the formula I, when R is H, the adamantane is shown, and R is CH ₃ When used, it means memantine (also referred to as 1, 3-dimethyladamantane);

in the formula II; r is H or CH ₃ R' is methyl or ethyl;

in the formula III, when R is H, amantadine (also known as 1-amantadine) is represented, and R is CH ₃ When represents memantine.

In the above method, the galvanostatic electrochemical reaction is carried out in the presence of a protonic acid;

the molar ratio of the adamantane or memantine of formula i to the protic acid may be 1:0.2 to 3, specifically 1.5, 1, 1.5, 1;

the protic acid comprises at least one of methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, formic acid, sulfuric acid, and nitric acid.

In the above method, the molar ratio of the adamantane or memantine represented by the formula i to the alcohol may be 1:2 to 10, specifically 1:4;

the alcohol includes at least one of methanol, ethanol, propanol, and isopropanol.

In the above process, the solvent comprises acetonitrile and/or propionitrile.

In the above method, the conditions of the galvanostatic electrochemical reaction are as follows:

the current density can be 10-60 mA/cm ² ；

The electrification amount can be 2-4F/mol;

the reaction temperature may be 10-60 ℃.

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

the current density can be 10-40 mA/cm ² Specifically, it may be 10mA/cm ² 、15mA/cm ² 、25mA/cm ² 、35 mA/cm ² Or 10 to 35mA/cm ² ；

The electrification amount can be 2-4F/mol, specifically 2.5F/mol, 3.0F/mol and 3.5F/mol;

the reaction temperature may be 20 to 45 deg.C, more preferably 25 deg.C, 35 deg.C, 45 deg.C or 25 to 45 deg.C.

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 an anode platinum mesh/cathode nickel sheet, an anode graphite/cathode nickel sheet or an anode platinum mesh/cathode graphite.

In the above method, the hydrolysis temperature may be 10-50 ℃, specifically 10 ℃, 40 ℃, 50 ℃, 10-40 ℃ or 40-50 ℃, and the time may be 1-12 hours, specifically 1 hour, 3 hours, 12 hours.

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

the alkali 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.

In the above method, the method further comprises a step of adding the alcohol to the reaction system after the completion of the energization to continue the reaction, so that the reaction is more sufficient.

The invention has the following advantages:

(1) The constant current electrolysis method is adopted, electrons are used as clean oxidants, and oxidants such as bromine and concentrated sulfuric acid are not needed, so that the method is green and environment-friendly.

(2) The invention adopts protonic acid (such as methanesulfonic acid or trifluoromethanesulfonic acid specifically) to support constant current electrolysis, does not need to add a large amount of expensive supporting electrolytes such as perchlorate or tetrafluoroborate, and the protonic acid can be recycled.

(3) The generated imine ether intermediate can be hydrolyzed under simple and mild conditions, and harsh hydrolysis conditions such as high temperature and high pressure are avoided.

Drawings

FIG. 1 is a diagram showing the reaction mechanism of the present invention.

Detailed Description

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

Example 1: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (0.5 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode and nickel plate as the cathode at 15mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrifying amount reaches 2.5F/mol, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h in water bath at 40 ℃ to convert the reaction intermediate into a product memantine (British name is 3, 5-dimethyl-1-aminoadamantane), yellow oil and gas phase yield: 31 percent.

The structure was confirmed as follows:

and the aftertreatment of the imine ether intermediate is to remove an organic phase by reduced pressure distillation, add 100mL of water, extract the organic phase by methyl tert-butyl ether for three times, extract the aqueous phase by chloroform for multiple times, dry the organic phase by anhydrous sodium sulfate, remove a solvent and finally treat the organic phase to obtain the perchlorate of the imine ether.

The perchlorate salt of the imine ether intermediate (the british name of the perchlorrate salt of ethyl (E) -N- ((1r, 3r,5s, 7r) -3, 5-dimethylladamantan-1-yl) acetimidate) has the structure shown below:

¹ H NMR(400MHz,CDCl ₃ )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,CDCl ₃ )δ175.9, 70.7,60.1,50.0,45.9,42.0,38.6,32.5,29.8,18.1,14.4.

memantine (British name 3, 5-dimethyl-1-aminoadamantane) having the following structure:

¹ H NMR(400MHz,DMSO-d ₆ )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).

example 2: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 25mA/cm ² Electrolyzing under constant current, stirring at 60 ℃, stopping electrolyzing when the electrified amount reaches 2.5F/mol, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 35 percent.

Example 3: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (0.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 35mA/cm ² Electrolyzing under constant current, stirring at 45 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 28 percent.

Example 4: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.0 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode and nickel plate as the cathode at 25mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 62 percent.

Example 5: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.0 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 25mA/cm ² Electrolyzing under constant current, stirring at 10 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 51 percent.

Example 6: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 35mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Distilling the organic phase of the reaction under reduced pressure to remove acetonitrile to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, stirring for 1h in water bath at 50 ℃ to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 65 percent.

Example 7: electrochemical method for synthesizing memantine

In a 50ml single chamber cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, using graphite as anode, nickel plate as cathode, at 35mA/cm ² Electrolyzing under constant current, stirring at 25 deg.CAnd when the electrification amount reaches 3.0F/mol, stopping electrolysis, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 36 percent.

Example 8: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, using a platinum mesh as anode and graphite as cathode at 35mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 54 percent.

Example 9: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) methanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode and nickel plate as the cathode at 35mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.5F/mol, adding 4.0mmol of methanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 68 percent.

The structure was confirmed as follows:

the imine ether intermediate (English name: methyl (E) -N- ((1r, 3R,5S, 7r) -3, 5-dimethylladamantan-1-yl) acetimidate) has the following structure:

¹ H NMR(400MHz,CDCl ₃ )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,CDCl ₃ )δ169.2, 62.6,52.6,50.7,49.1,47.5,42.8,32.3,30.6,29.9,24.2.

example 10: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode and nickel plate as the cathode at 15mA/cm ² Electrolyzing under constant current, stirring at 35 deg.C, stopping electrolysis when the energization amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 70 percent.

Example 11: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 35mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.5F/mol, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: and 72 percent.

Example 12: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, using a platinum mesh as anode, a nickel plate as cathode, at 35mA/cm ² Electrolyzing under constant current, stirring at 25 deg.C, stopping electrolysis when the energization amount reaches 3.0F/mol, adding 4.0mmol ethanol, stirringAnd (3) obtaining an imine ether intermediate after 30min. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, stirring for 12h in water bath at 10 ℃ to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: and 63 percent.

Example 13: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 35mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Distilling the organic phase of the reaction under reduced pressure to remove acetonitrile to about 5mL, adding saturated sodium bicarbonate solution to adjust the pH of the solution to 8-9, stirring for 3h in water bath at 40 ℃ to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 68 percent.

Example 14: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 10mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Distilling the organic phase of the reaction under reduced pressure to remove acetonitrile to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h in water bath at 40 ℃ to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: and 59 percent of the total weight of the solution.

Example 15: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode and nickel plate as the cathode at 60mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Will reactRemoving acetonitrile to about 5mL by organic phase vacuum distillation, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at the temperature of 40 ℃ in water bath to convert a reaction intermediate into a product memantine, wherein the gas phase yield is as follows: 58 percent.

Example 16: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), methanesulfonic acid (3.0 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, with a platinum mesh as the anode, a nickel plate as the cathode, at 15mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrifying amount reaches 3.0F/mol, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 32 percent.

Example 17: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (0.5 mmol) ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 25mA/cm ² Electrolyzing under constant current, stirring at 35 ℃, stopping electrolyzing when the electrification amount reaches 3.5F/mol, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. Distilling the organic phase of the reaction under reduced pressure to remove acetonitrile to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h in water bath at 40 ℃ to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 26 percent.

Example 18: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.0 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, using a platinum mesh as anode, a nickel plate as cathode, at 35mA/cm ² Electrolyzing under constant current, stirring at 35 ℃, stopping electrolyzing when the electrification amount reaches 2.5F/mol, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. The organic phase of the reaction is decompressed and distilled to remove acetonitrile to about 5mLAnd (3) adding a saturated sodium carbonate solution to adjust the pH value of the solution to 8-9, heating and stirring for 3h in a water bath at 40 ℃ to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: and 55 percent.

Example 19: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.0 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode and nickel plate as the cathode at 15mA/cm ² Electrolyzing under constant current, stirring at 45 ℃, stopping electrolyzing when the electrification amount reaches 3.5F/mol, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: and 47 percent.

Example 20: electrochemical method for synthesizing memantine

In a 50ml single chamber electrolytic cell, 1, 3-dimethyladamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol), ethanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode and nickel plate as the cathode at 25mA/cm ² Electrolyzing under constant current, stirring at 45 ℃, stopping electrolyzing when the electrifying amount reaches 2.5F/mol, adding 4.0mmol of ethanol, and stirring for 30min to obtain the imine ether intermediate. Removing acetonitrile by vacuum distillation of the reaction organic phase to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring for 3h at 40 ℃ in water bath to convert the reaction intermediate into the product memantine, wherein the gas phase yield is as follows: 66 percent.

Example 21: electrochemical method for synthesizing amantadine

In a 50ml single chamber cell, adamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol), methanol (4.0 mmol) were added to 10ml acetonitrile, with platinum gauze as the anode, nickel plate as the cathode, at 15mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol of methanol, and stirring for 30min to obtain the imine ether intermediate. Distilling the organic phase of the reaction under reduced pressure to remove acetonitrile to about 5mL, adding saturated sodium carbonate solution to adjust the pH of the solution to 8-9, heating and stirring in water bath at 50 ℃ for 3h to convert the reaction intermediate into the product 1-amantadine (english name 1-adamantamine), gas phase yield: 43% as a white solid.

The structure was confirmed as follows:

the perchlorate salt of the imine ether intermediate (the perchlorate salt of methyl (E) -N- ((3 s,5s,7 s) -adaman-1-yl) acetanidate) was prepared in the same manner as in example 1 of the present invention and has the formula:

¹ H NMR(400MHz,CDCl ₃ )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,CDCl ₃ )δ176.9,60.1,58.9,40.0, 35.6,29.1,17.8.

1-Adamantanamine (the name 1-Adamantanamine in England) having the formula:

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

example 22: electrochemical method for synthesizing amantadine

In a 50ml single chamber electrolytic cell, adamantane (1.0 mmol), trifluoromethanesulfonic acid (1.5 mmol), and ethanol (4.0 mmol) were added to 10ml acetonitrile, using a platinum mesh as the anode and a nickel plate as the cathode at 15mA/cm ² Electrolyzing under constant current, stirring at 25 ℃, stopping electrolyzing when the electrification amount reaches 3.0F/mol, adding 4.0mmol ethanol, and stirring for 30min to obtain the imine ether intermediate. Distilling the organic phase of the reaction under reduced pressure to remove acetonitrile to about 5mL, adding saturated sodium carbonate solution to adjust the pH value of the solution to 8-9, heating and stirring for 3h in water bath at 50 ℃ to convert the reaction intermediate into the product 1-amantadine, wherein the gas phase yield is as follows: 45 percent.

The structure was confirmed as follows:

the imine ether intermediate (ethyl (E) -N- ((3s, 5s, 7s) -adamantan-1-yl) acetimidate) has the formula:

¹ H NMR(400MHz,DMSO-d ₆ )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-d ₆ )δ155.6,59.3,52.1,43.6,36.5,29.7,19.3,14.6。

Claims (10)

1. an electrochemical synthesis method of amantadine or memantine comprises the following steps: mixing adamantane or memantine shown in a formula I and a solvent with alcohol in a single-chamber electrolytic cell, electrifying to perform constant-current electrochemical reaction to obtain an imine ether intermediate shown in a formula II; then hydrolyzing the imino ether intermediate to obtain amantadine or memantine shown in a formula III;

in the formula I, R represents adamantane when R is H, and R is CH ₃ When represents memantine;

in the formula II; r is H or CH ₃ R' is methyl or ethyl;

in the formula III, when R is H, the formula represents amantadine, and R is CH ₃ When represents memantine.

2. The method of claim 1, wherein: the constant current electrochemical reaction is carried out in the presence of protonic acid;

the molar ratio of the adamantane or memantine shown in the formula I to the protonic acid is 1:0.2 to 3;

the protonic acid includes at least one of methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, formic acid, sulfuric acid, and nitric acid.

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

the alcohol includes at least one of methanol, ethanol, propanol, and isopropanol.

4. The method according to any one of claims 1-3, wherein: the solvent comprises acetonitrile and/or propionitrile.

5. The method according to any one of claims 1-4, wherein: the conditions of the constant current electrochemical reaction are as follows:

the current density is 10-60 mA/cm ² ；

The electrification amount is 2-4F/mol;

the reaction temperature is 10-60 ℃.

6. The method according to any one of claims 1-5, wherein: the conditions of the galvanostatic electrochemical reaction are as follows:

the current density is 10-40 mA/cm ² ，

The electrification amount can be 2-4F/mol;

the reaction temperature is 20-45 ℃.

7. The method according to any one of claims 1-6, wherein: the anode of the constant current electrochemical reaction is platinum and/or graphite, and the cathode is nickel and/or graphite.

8. The method according to any one of claims 1-7, wherein: the hydrolysis temperature is 10-50 ℃, and the hydrolysis time is 1-12 h.

9. The method according to any one of claims 1-8, wherein: the hydrolysis is carried out in the presence of a base or an acid;

the alkali 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.

10. The method according to any one of claims 1-9, wherein: the method also comprises the step of adding the alcohol into the reaction system to continue the reaction after the electrification is finished.

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