A PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF l-AMINO-3, 5-DIMETHYL ADAMANTANE
Field of the invention
The present invention provides a process for the preparation of a pharmaceutically acceptable acid addition salt of l-amino-3, 5-dimethyladamantane of Formula-A.

Background and prior art
l-Amino-3, 5-dimethyl adamantane hydrochloride or memantine hydrochloride is a well known N-methyl-d-asparate (NMDA) receptor antagonist. It is used in the treatment of Parkinson's and Alzheimer's diseases. The chemical structure of l-amino-3, 5-dimethyl adamantane hydrochloride or memantine hydrochloride is represented by the Formula -I.

Several processes for the synthesis of memantine hydrochloride have been reported in the prior art.
US 3,391.142 discloses synthesis of memantine hydrochloride, as depicted in the following reaction Scheme 1.

Scheme 1:

In the first step, l-bromo-3, 5-dimethyladamantane reacts with acetonitrile in a large amount of sulphuric acid at room temperature to give the crude intermediate product. The intermediate product is subjected to alkaline hydrolysis with sodium hydroxide in diethylene glycol by refluxing at a temperature of greater than 190°C for 6 hours. The hydrolyzed product is diluted with water followed by extraction with benzene and the memantine free base is recovered by solvent distillation. The free base is then dissolved in ether and addition of hydrogen chloride gas to the free base in ether gives crude memantine hydrochloride. In this process bromine and sulphurdioxide are obtained as by-products, which are hazardous. Another disadvantage of this method is use of sulphuric acid which is a corrosive and hazardous chemical. Furthermore, it is difficult to hydrolyze the intermediate compound, N-acetamido-3, 5-dimethyladamantane, and the desired product gets badly discoloured due to its contact with alkaline reaction mixture for longer duration.
US 4,122,193 discloses a process for the preparation of memantine hydrochloride as depicted in the following reaction Scheme 2. Scheme 2:

In this method, l-chloro-3, 5-dimethyl adamantane reacts with urea for about 40 minutes at 220°C. The heating is carried out in a closed vessel on an oil bath with a thermostat. The product is mixed with water and then acidified to adjust pH between 3 and 5 and then the acidified solution is extracted with ether. The aqueous layer is basified to a pH between 12 and 13 and the basified aqueous layer is extracted with ether several times and the organic layers are combined, dried, salified by inletting HC1 gas to yield memantine hydrochloride. This method requires acidification and basification, to obtain memantine which requires exposure to HCL gas for making memantine hydrochloride. The additional steps make the process lengthy and inefficient.
US 5,599,998 discloses a synthetic route for memantine with a yield of 48%. The process steps are depicted in the following reaction Scheme 3. Scheme 3:

The process described in this patent comprises reacting the bridgehead halo polycyclic hydrocarbons with lithium metal under conditions of sonication and aminating the resultant lithio compounds. In addition to obtaining memantine in low yield, the disclosed method is cumbersome on an industrial scale. This process also uses metallic lithium and chloramine, which are hazardous chemicals.
WO 2006/076562A1 discloses three-step process for the preparation of memantine hydrochloride. The process steps are depicted in the following reaction scheme 4.

Scheme 4:

This process comprises reacting l-halo-3,5-dimethyladamantane with acetonitrile in presence of phosphoric acid at a temperature of about 50-100°C to obtain N-acetamido-3, 5-dimethyladamantane and solvolysing of N-acetamido-3, 5-dimethyladamantane with an inorganic base such as KOH or NaOH in the presence of C3-C6 alcohol to obtain memantine free base, which is then converted into its hydrochloride.
WO 2006/122238 A1 discloses the process for the preparation of memantine hydrochloride as depicted in the following reaction Scheme 5. Scheme 5:

Memantine hydrochloride obtained in this process is contaminated with l-hydroxy-3, 5-dimethyl adamantane, l-bromo-3, 5-dimethyl adamantane and l-formamido-3, 5-dimethyl adamantane as impurities. Although the impurities can be removed by washing with organic

solvents such as ketone, alcohols, DMSO, DMF to obtain substantially pure memantine hydrochloride, the process becomes lengthy and removal of the impurities formed requires substantial effort.
EP 1721888 Al discloses a process for the preparation of memantine as depicted in the following reaction Scheme 6. Scheme 6:

In the first step of the process, haloadamantane is reacted with acetonitrile, glacial acetic acid and Conc.H2S04 to obtain acetamidoadamantane. In the second step, isolated acetamidoadamantane is reacted with alkali metal or alkaline earth metal hydroxide in an organic solvent such as l-methoxy-2-propanol, 2-methoxy-l-propanol, 3-methoxy-l-propanol, 2-methoxyethanol, 2-ethoxyethanol and mixtures thereof to provide a hydrolysis mixture. The hydrolysis mixture is heated under reflux for sufficient time to obtain the corresponding aminoadamantane. This process uses corrosive reagents like sulphuric acid and glacial acetic acid.
WO 2005/062724 A2 discloses a process for the preparation of memantine, as depicted in the following reaction Scheme 7. Scheme 7


The first step involves brominating compound of formula IIa followed by hydrolyzing the brominated compound and isolating of compound of formula IIb. In the second step, isolated compound of formula-lib is reacted with acetonitrile in the presence of sulphuric acid to yield acetamido derivative of formula-IIc. In the third step, acetamido derivative is deacetylated to yield compound of formula-IId. This process for memantine hydrochloride is lengthy and not viable commercially. Objects of the invention
An object of the present invention is to provide a process for the preparation of pharmaceutically acceptable acid addition salt of l-amino-3, 5-dimethyl adamantane without using corrosive reagents such as sulphuric acid and phosphoric acid.
Another object of the present invention is to provide a process for the preparation of pharmaceutically acceptable acid addition salt of l-amino-3,5-dimethyl adamantane by using an organic acid. Summary of the invention
The present invention provides a process for the preparation of a pharmaceutically acceptable acid addition salt of l-amino-3,5-dimethyladamantane of Formula-A,

said process comprising the steps of reacting l-halo-3, 5- dimethyl adamantane with acetonitrile in presence of an organic acid to obtain N-acetamido-3,5-dimethyladamantane, and hydrolyzing N-acetamido-3,5-dimethyladamantane with a non-toxic inorganic base in presence of an organic solvent to obtain l-amino-3,5-dimethyladamantane of Formula-A and preparing corresponding pharmaceutically acceptable acid addition salt of l-amino-3,5-dimethyladamantane of Formula-A by using a suitable acid. Detailed description of the invention
Accordingly, the present invention provides a process for the preparation of a pharmaceutically acceptable acid addition salt of l-amino-3,5-dimethyladamantane of Formula-A,


said process comprising:
reacting l-halo-3, 5- dimethyl adamantane with acetonitrile in the presence of an organic acid to obtain N-acetamido-3, 5-dimethyladamantane,
hydrolyzing said N-acetamido-3, 5-dimethyladamantane with an inorganic base in the presence of an organic solvent to obtain l-amino-3, 5-dimethyladamantane of Formula-A, and
reacting said l-amino-3,5-dimethyladamantane of Formula-A with a non-toxic inorganic or organic acid to obtain a corresponding pharmaceutically acceptable acid addition salt ofl-amino-3,5-d:methyladamantane of Formula -A.
The present invention provides a process for the preparation of pharmaceutically acceptable acid addition salt of l-amino-3, 5-dimethyl adamantane of Formula-A, by using a suitable non-toxic organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as oxalic acid, maleic acid, benzenesulphonic acid, p-toluenesulphonic acid, methanesulphonic acid, ethanesulphonic acid and the like.
It is an embodiment of the present invention to provide a process, wherein the 1-halo-3, 5-dimethyl adamantane is l-chloro-3, 5-dimethyl adamantane or l-bromo-3, 5-dimethyl adamantane.
An embodiment of the present invention provides a process, wherein the molar ratio of organic acid and l-halo-3,5-dimethyladamantane is in the range of 1.5:1 to 7.5:1.
Another embodiment of the present invention provides a process, wherein the organic acid is carboxylic acid or sulphonic acid.
Yet another embodiment of the present invention provides a process, wherein the carboxylic acid is selected from a group consisting of formic acid, oxalic acid, and succinic acid.

Still another embodiment of the present invention provides a process, wherein the sulphonic acid is selected from a group consisting of methanesulphonic acid, cthanesulphonic acid and para-toluenesulphonic acid.
Further an embodiment of the present invention provides a process, wherein the reaction of l-halo-3, 5- dimethyl adamantane with acetonitrile in the presence of an organic acid to obtain N-acetamido-3, 5-dimethyladamantane is performed at a temperature in the range of 50°C to 100°C, preferably at a temperature in the range of 75°C to 85°C. The period of time sufficient to produce N-acetamido-3, 5-dimethyladamantane is about 8 tolO hours.
Another embodiment of the present invention provides a process wherein the inorganic base is an alkali metal hydroxide.
It is also an embodiment of the present invention to provide a process wherein the inorganic base is sodium hydroxide or potassium hydroxide.
Another embodiment of the present invention provides a process wherein the organic solvent is selected from the group consisting of an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, a high boiling alcohol, and mixtures thereof.
Yet another embodiment of the present invention provides a process wherein the aromatic hydrocarbon is toluene or xylene and the halogenated aromatic hydrocarbon is chlorobenzene.
Still another embodiment of the present invention provides a process wherein the high boiling alcohol is benzyl alcohol.
The process steps for the preparation of l-amino-3,5-dimethyladamantane hydrochloride, as an exemplary embodiment, are now described
Process for the preparation of l-amino-3, 5-dimcthyladamantane hydrochloride a) Preparation of N-acetamido-3,5-dimethyladamantane
N-acetamido-3, 5-dimethyladamantane of Formula-II is prepared by reacting 1-halo-3,5-dimethyl adamantane of Formula-Ill (where X represents a halogen) and acetonitrile in the presence of an organic acid, at a temperature in the range of 50°C to 100°C for a period of sufficient time to produce N-acetamido-3,5-dimethyladamantane. The reaction is depicted in the following reaction scheme-a


Scheme-a
b) Preparation of l-amino-3, 5-dimethyladamantane hydrochloride
Hydrolysis of N-acetamido-3, 5-dimethyladamantane is carried out with an inorganic base such as alkali metal or alkaline earth metal hydroxide in the presence of an organic solvent for an adequate period of time followed by the addition of conc, hydrochloric acid to obtain l-amino-3, 5-dimethyladamantane hydrochloride. The reaction is depicted in the following reaction scheme-b

Scheme-b
The process steps of the present invention are described in the following examples, which are only illustrative in nature and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES Example 1 Preparation of N-acetamido-3, 5-dimethyladamantane
At room temperature, 50g (0.2056 mole) of l-bromo-3, 5-dimethyladamantane and 50ml (0.9585mole) of acetonitrile are charged into a four necked round bottom flask

equipped with a thermometer, condenser and mechanical stirrer. Then 28.3g (0.6152 mole) of formic acid is added and the resulting mixture is heated to 80° ± 5°C and maintained at that temperature for 10 to 12 hours. The reaction mixture is cooled to room temperature, and then quenched into 750ml of ice water. The mass is stirred for 1 hour, filtered and washed twice with 50ml of water and 50ml of hexane to obtain N-acetamido-3, 5-dimethyladamantane (44g, 99%) with HPLC purity >99%.
Example 2 Preparation of N-acetamido-3, 5-dimcthyladamanrane
At room temperature, l00g (0.411 mole) of l-bromo-3, 5-dimethyladamantane and 100ml (1.9170 mole) of acetonitrile are charged into a four necked round bottom flask equipped with a thermometer, condenser and mechanical stirrer. Then 145.14g (1.1519 mole) of oxalic acid is added and the resulting mixture is heated to 80° ± 5°C and maintained at that temperature for 10 to 12 hours. The reaction mixture is cooled to room temperature, and then quenched into 1500ml of ice water. The mass is stirred for 1 hour, filtered and washed twice with 100ml of water and 100ml of hexane to obtain N-acetamido-3, 5-dimethyladamantane (88g, 99%) with HPLC purity >99%.
Example 3 Preparation of N-acetamido-3, 5-dimethyladamantane
At room temperature, 5g (0.0251 mole) of l-chloro-3, 5-dimethyladamantane and 10ml (0.1902 mole) of acetonitrile are charged into a four necked round bottom flask equipped with a thermometer, condenser and mechanical stirrer. Then 22g (0.1746 mole) of oxalic acid is added and the resulting mixture is heated to 80° ± 5°C and maintained at that temperature for 8 to 10 hours. The reaction mixture is cooled to room temperature, and then quenched into 75ml of ice water. The mass is stirred for 1 hour, filtered and washed twice with 5ml of water and 5ml of hexane to obtain N-acetamido-3, 5-dimethyladamantane (5g, 90%) with HPLC purity >99%.
Example 4 Preparation of N-acetamido-3, 5-dimethyladamantane
At room temperature, 5g (0.0205mole) of l-bromo-3, 5-dimethyladamantane and 10ml (0.1902 mole) of acetonitrile are charged into a four necked round bottom flask equipped with a thermometer, condenser and mechanical stirrer. Then 24. lg (0.123 mole) of

para-toluenesulphonic acid is added and the resulting mixture is heated to 80° ± 5°C and maintained at that temperature for 10 to 12 hours. The reaction mixture is cooled to room temperature, and then quenched into 75ml of ice water. The mass is stirred for 1 hour, filtered and washed twice with 5ml of water and 5ml of hexane to obtain N-acetamido-3, 5-dimethyladamantane (3.7g, 81.5%) with HPLC purity >99%.
Example 5 Preparation of l-amino-3, 5-dimcthyl adamantanc hydrochloride
50g of N-acetamido-3, 5-dimethyladamantane (0.2262 mole) and mixture of 500ml of xylene and 75ml of benzyl alcohol and 54.3g of NaOH (1.3574 mole) are charged into a four necked round bottom flask at room temperature. The reaction mixture is heated to 135° ± 5°C and the temperature is maintained for 14-15 hours. After completion of the reaction, the resulting solid mass is cooled to 50-60°C and 250ml of DM water is added. The resulting solution is stirred and the layers are separated, 250ml of water is added to the organic layer and pH is adjusted to 8.5-9.5 with 37% hydrochloric acid. After stirring, the resulting solution is separated into organic and aqueous layer. The organic layer is washed thrice with 250ml of DM water. After washing, the organic layer is filtered and 25ml of 37% HC1 is added to the filtrate. The resulting acidified solution is concentrated under reduced pressure to a residue at a temperature below 110°C. Then 350ml of ethyl acetate and 20ml of water are added to the residue at a temperature below 50°C. The resulting suspension is cooled to 0-5°C for 1 hour, filtered and washed thrice with 50 ml of ethyl acetate. The solid is dried under vacuum at 60° to 70°C for 10-15 hours to obtain 41.5g of memantine hydrochloride (85%) with >99.9%, purity.
Example 6 Preparation of l-amino-3, 5-dimethyl adamantane hydrochloride
lOg (0.0452 mole) of N-acetamido-3, 5-dimethyladamantane, 50ml of benzyl alcohol and 10.85g (0.2714 mole) of NaOH are charged into a four necked round bottom flask at room temperature. The reaction mixture is heated to 155° ± 5°C and the temperature maintained for 4-6 hours. After completion of the reaction, the resulting suspension is cooled to 50-60°C and 60ml of DM water is added. The resulting reaction mixture is stirred for 20 minutes and the layers are separated. 60ml of water is added to the organic layer and pH is adjusted to 8.5-9.5 with 37% hydrochloric acid. After stirring, the resulting solution is

separated into organic and aqueous layer. The organic layer is washed thrice with 50ml of DM water. After washing, the organic layer is filtered and 5ml of 37% HC1 is added to the filtrate. The resulting acidified solution is concentrated under reduced pressure to a residue at a temperature below 110°C. Then 70ml of ethyl acetate and 4ml of water are added to the residue at a temperature below 50°C. The resulting suspension is cooled to 0-5°C for 1 hour filtered and washed thrice with 10 ml of ethyl acetate. The solid is dried under vacuum at 60° to 70°C for 10-15 hours to obtain 8.3g of memantine hydrochloride (85%) with >99.9% purity.
Example 7 Preparation of l-amino-3, 5-dimcthyI adamantane hydrobromide 3g of N-acetamido-3, 5-dimethyladamantane (0.0135 mole) and mixture of 30ml of xylene and 4.5ml of benzyl alcohol and 3.3g of NaOH (0.0837 mole) are charged into a four necked round bottom flask at room temperature. The reaction mixture is heated to 135° ± 5°C and the temperature is maintained for 14-15 hours. After completion of the reaction, the resulting solid mass is cooled to 50-60°C and 15ml of DM water is added. The resulting solution is stirred and the layers are separated, 15ml of water is added to the organic layer and pH is adjusted to 8.5-9.5 with 37% hydrochloric acid. After stirring, the resulting solution is separated into organic and aqueous layer. The organic layer is washed thrice with 15ml of DM water. After washing, the organic layer is filtered and 1.5ml of aqueous HBr is added to the filtrate. The resulting acidified solution is concentrated under reduced pressure to a residue at a temperature below 110°C. Then 21ml of ethyl acetate and 1.2ml of water are added to the residue at a temperature below 50°C. The resulting suspension is cooled to 0-5°C for 1 hour, filtered and washed thrice with 3 ml of ethyl acetate. The solid is dried under vacuum at 60 to 70°C for 10-15 hours to obtain 2.8g of memantine hydrobromide (80%) with >99 % purity.
Example 8 Preparation of l-amino-3, 5-dimcthyl adamantane hydrogcnsulphate
3g of N-acetamido-3, 5-dimethyladamantanc (0.0135 mole) and mixture of 30ml of xylene and 4.5ml of benzyl alcohol and 3.3g of NaOH (0.0837 mole) are charged into a four necked round bottom flask at room temperature. The reaction mixture is heated to 135° ± 5°C and

the temperature is maintained for 14-15 hours. After completion of the reaction, the resulting solid mass is cooled to 50-60°C and 15ml of DM water is added. The resulting solution is stirred and the layers are separated, 15ml of water is added to the organic layer and pH is adjusted to 8.5-9.5 with 37% hydrochloric acid. After stirring, the resulting solution is separated into organic and aqueous layer. The organic layer is washed thrice with 15ml of DM water. After washing, the organic layer is filtered and 1ml of sulphuric acid is added to the filtrate. The resulting acidified solution is concentrated under reduced pressure to a residue at a temperature below 110°C. Then 21ml of ethyl acetate and 1.2ml of water are added to the residue at a temperature below 50°C. The resulting suspension is cooled to 0-5°C for 1 hour, filtered and washed thrice with 3 ml of ethyl acetate. The solid is dried under vacuum at 60 to 70°C for 10-15 hours to obtain 2.6g of memantine hydrogensulphate (70%) with >99 % purity.
Example 9 Preparation of l-amino-3, 5-dimethyl adamantane methanesulphonate
3g of N-acetamido-3, 5-dimethyladamantane (0.0135 mole) and mixture of 30ml of xylene and 4.5ml of benzyl alcohol and 3.3g of NaOH (0.0837 mole) are charged into a four necked round bottom flask at room temperature. The reaction mixture is heated to 135° ± 5°C and the temperature is maintained for 14-15 hours. After completion of the reaction, the resulting solid mass is cooled to 50-60°C and 15ml of DM water is added. The resulting solution is stirred and the layers are separated. 15ml of DM water is added to the organic layer and pH is adjusted to 8.5-9.5 with 37% hydrochloric acid. After stirring, the resulting solution is separated into organic and aqueous layer. The organic layer is washed thrice with 15ml of DM water. After washing, the organic layer is filtered and 1ml of methanesulfonic acid is added to the filtrate. The resulting acidified solution is concentrated under reduced pressure to a residue at a temperature below 110°C. Then 21ml of ethyl acetate and 1.2ml of water are added to the residue at a temperature below 50()C. The resulting suspension is cooled to 0-5°C for 1 hour, filtered and washed thrice with 3 ml of ethyl acetate. The solid is dried under vacuum at 60° to 70°C for 10-15 hours to obtain 2.6g of memantine hydrogensulphate (70%o) with >99 % purity.

Advantages of (he invention
The process of the present invention does not use corrosive reagents such as sulphuric acid and phosphoric acid.

NH2 Formula-A
We Claim:
1. A process for the preparation of a pharmaceutically acceptable acid addition salt of l-amino-3,5-dimethyladamantane of Formula-A,
NH2
Formula-A said process comprising:
reacting l-halo-3, 5- dimethyl adamantane with acetonitrile in the presence of an organic acid to obtain N-acetamido-3, 5-dimethyladamantane; hydrolyzing said N-acetamido-3, 5-dimethyladamantane with an inorganic base in the presence of an organic solvent to obtain l-amino-3, 5-dimethyladamantane of Formula-A; and
reacting said l-amino-3,5-dimethyladamantane of Formula-A with a non-toxic inorganic or organic acid to obtain a corresponding pharmaceutically acceptable acid addition salt of l-amino-3,5-dimethyladamantane of Formula-A.
2. The process as claimed in claim 1, wherein the l-halo-3, 5-dimethyl adamantane is l-chloro-3, 5-dimethyl adamantane or l-bromo-3, 5-dimethyl adamantane.
3. The process as claimed in claim 1, wherein the molar ratio of organic acid and 1-halo-3,5-dimethyladamantane is in the range of 1.5:1 to 7.5:1.
4. The process as claimed in claim 1, wherein the organic acid is carboxylic acid or sulphonic acid.
5. The process as claimed in claim 4, wherein the carboxylic acid is selected from a group consisting of formic acid, oxalic acid, and succinic acid.
6. The process as claimed in claim 4, wherein the sulphonic acid is selected from a group consisting of methanesulphonic acid, ethanesulphonic acid and para-toluenesulphonic acid.
7. The process as claimed in claim 1, wherein the reaction of l-halo-3, 5- dimethyl adamantane with acetonitrile in the presence of an organic acid to obtain N-acetamido-3, 5-dimethyladamantane is performed at a temperature in the range of 50°C to 100°C.

The process as claimed in claim 1, wherein the inorganic base is an alkali metal hydroxide.
9. The process as claimed in claim 8, wherein the alkali metal hydroxide is sodium
hydroxide or potassium hydroxide.
10. The process as claimed in claim 1, wherein the organic solvent is selected from the
group consisting of an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, a
high boiling alcohol, and mixtures thereof.
11. The process as claimed in claim 10, wherein the aromatic hydrocarbon is toluene, or
xylene.
12. The process as claimed in claim 10, wherein the halogenated aromatic hydrocarbon
is chlorobenzene.
13. The process as claimed in claim 10, wherein the high boiling alcohol is benzyl alcohol.
14. The process as claimed in claim 1, wherein the non-toxic inorganic acid is selected from a group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.
15. The process as claimed in claim 1, wherein the non-toxic organic acid is selected
from a group consisting of oxalic acid, maleic acid, benzenesulphonic acid, p-
toluenesulphonic acid, methanesulphonic acid, and ethanesulphonic acid.