5. DATE AND SIGNATURE (to be given at the end of last page of specification)
6, ABSTRACT OF THE INVENTION (to be given along with complete specification
on separate page)

IMPROVED PROCESS FOR MEMANTINE HYDROCHLORIDE Filed of the Invention:
The present invention relates to an improved eco-friendly process for the preparation of memantine hydrochloride. Memantine hydrochloride is chemically known as l-amino-3,5-dimethyl adamantane hydrochloride, which is represented by the compound of formula-1.

Memantine is an orally active NMDA (N-methyl-D-aspartate) receptor antagonist which works by blocking the NMDA receptors in the brain. It blocks the excessive activity of glutamate, but still allows the normal activation of these receptors that occurs when the brain forms a memory. Therefore it improves the brain functioning in Alzheimer's disease, and may also block the glutamate activity that could cause further damage to the brain cells. Memantine is commercially available in the form of hydrochloride salt under the brand name NAMENDA. NAMEMDA is available for oral administration as capsule shaped film-coated tablets containing 5 mg and 10 mg of memantine hydrochloride.
Background of the Invention:
Memantine, its pharmaceutically acceptable salts thereof and process for their preparation are first disclosed in US patent 3391142. The disclosed process comprises of reacting l-bromo-3,5-dimethyladamantane with sulphuric acid in acetonitrile gives l-acetamido-3,5-dimethyl adamantane followed by deacetylation in diethylene glycol

with sodium hydroxide at reflux temperature gives memantine which was converted into its hydrochloride salt by treating with anhydrous hydrogen chloride followed by recrystallising memantine hydrochloride from a mixture of alcohol and ether. This process involves the addition of bromine at reflux condition for the preparation of starting compound l-bromo-3,5-dimethyladamantane, which leads to the generation of toxic bromine vapours and also producing excess of effluent Hence this process is not suitable for the commercial purpose as well as it is not environment friendly.
Tetrahedron letters 56, page number. 5833-5835, 1968 discloses a process for the preparation of l-amino-3,5-dimethyl adamantane without bromination reaction. The disclosed process comprise of amination of 1,3-dimethyl adamantane with trichloroamine and aluminium chloride give l-amino-3,5-dimethyl adamantane with 40% yield.
The Japanese patent publication number JP 2002/275142 disclosed alternate process for the preparation of l-acetamido-3,5-dimethyl adamantane directly from 1,3-dimethyl adamantane with out converting into l-halo-3,5-dimethyl adamantane as shown by the following scheme with a yield of 45%.

Even though the above two references disclosed a process for the preparation of memantine hydrochloride without involving the usage of bromine, but the overall yield of less than 45% and involve the usage of expensive and dangerous reagents. Hence the above said processes are commercially not suitable. Still there is a need in the art for the environment friendly process for the preparation of memantine and its pharmaceutically acceptable salts.
It will be appreciable to have an environment friendly process which avoids/eliminates/reduces the usage of solvent or toxic reagents which affects the

environment or reduces number of stages thereby saving the production cost, time and effluent formation to safeguard the environment.
The main aim of the present inventors is to provide an eco-friendly process over the prior art processes. This aim of present inventors is attained by two ways, one is by providing an improved eco-friendly process for the preparation of l-acetamido-3,5-dimethyl adamantane from 1,3-dimethyl adamantane without using any solvents in the reaction and without converting into l-bromo-3,5 -dimethyl adamantane there by avoiding the toxic vapours and effluent caused by the usage of bromine. The non-usage of solvent leads to the reduction of production cost and effluent formation and make the process eco-friendly as well as economic.
The second way attained by providing one-pot process for the preparation of memantine hydrochloride without isolating any intermediates and there by reducing the excess time and solvent usage and material wastage.
Brief Description of the Invention:
The present invention relates to an improved eco-friendly process for the preparation of memantine and its pharmaceutically acceptable salts thereof especially hydrochloride salt over the prior art. Memantine hydrochloride is chemically known as l-amino-3,5-dimethyl adamantane hydrochloride, which is represented by the compound of formula-1.

The first aspect of the present invention is to provide an improved eco-friendly process for the preparation of memantine hydrochloride compound of formula-1, which comprises of reacting the 1,3-dimethyl adamantane compound of formula-2 with nitrile in presence of a suitable strong acid at a temperature of about 50-85°C and for a period of time sufficient to produce n-acetamido-3,5-dimethyl adamantane compound of formula-3 followed by isolation of n-acetamido-3,5-dimethyladamantane compound of formula-3.
Hydrolyzing the n-acetamido-3,5-dimethyladamantane with a suitable alkali metal hydroxide in a suitable alcoholic solvents or aqueous alcoholic solvent or mixtures thereof for a sufficient period of time to obtain l-amino-3,5-dimethyladamantane compound of formula-4 followed by in-situ treating with hydrochloric acid in a suitable alcohol solvents followed by the addition of suitable anti-solvents like ester solvents to provide memantine hydrochloride compound of formula-1.
The second aspect of the present invention is to provide an eco-friendly one-pot process for the preparation of memantine hydrochloride compound of formula-1 from l,3-dimethyl adamantane compound of formula-2 without isolating any intermediates, which comprises of reacting 1,3 -dimethyl adamantane compound of formula-2 with nitrile in presence of a suitable strong acid at a temperature of about 50-85°C and for a period of time sufficient to produce n-acetamido-3,5-dimethyl adamantane compound of formula-3 and hydrolyzing it with suitable alkali metal hydroxide in a suitable alcoholic solvent or aqueous alcoholic solvent or mixtures thereof gives memantine compound of formula-4 which on subsequent treatment with hydrochloric acid in a suitable solvent and addition of suitable anti-solvent such as ester solvents gives memantine hydrochloride compound of formula-1.
Advantages of the present Invention:
• Provides eco-friendly and industrially feasible process for the preparation of memantine hydrochloride which avoids the usage of bromine.

• Provides the cost effective and eco-friendly process for the preparation of l-acetamido-3,5-dimethyl adamantane from 1,3-dimethyl adamantane compound of formula-2 without using a solvent thereby reducing the solvent consumption and reduces the formation of effluent.
• Provides eco-friendly and economic one-pot process for the preparation of memantine hydrochloride which avoids unnecessary isolation and excess solvent usage and minimizes time cycle and the wastage of material by transformation.
• Provides the process which gives high yield and high purity without any further purification.
Brief Description of Drawing:
Figure-1: Illustrates the X-ray powder diffraction pattern of memantine hydrochloride
compound of formula-1.
Detailed Description of the Invention:
Accordingly the present invention provides an improved eco-friendly process for the preparation of memantine and its pharmaceuticallly acceptable salts thereof especially hydrochloride salt over the prior art processes. Memantine hydrochloride is chemically known as l-amino-3,5-dimethyl adamantane hydrochloride, which is represented by the compound of formula-1.
The first aspect of the present invention is to provide an improved eco-friendly process for the preparation of memantine hydrochloride compound of formula-1, which comprises of reacting 1,3-dimethyladamantane compound of formula-2,

with suitable nitrile selected trom a group consisting of propionitrile, butyronitrile, valeronitrile, phenylacetonitrile and acetonitrile, preferably acetonitrile in presence of a suitable acid selected from sulphuric acid and/or phosphoric acid and/or acetic acid or mixtures thereof, preferably sulphuric acid at a temperature of about 50-70°C preferably 60-65 °C and for a period of time sufficient preferably 2 to 15 hours, most preferably 2 to 10 hours to produce n-acetamido-3,5-dimethyl adamantane compound of formula-3 in the absence of any solvent and recovering n-acetamido-3,5-dimethyl adamantane compound of formula-3 by the method known in the art or by extracting the n-acetamido-3,5-dimethyladamantane compound using methylene chloride or toluene and concentrating the organic layer to obtain the n-acetamido-3,5-dimethyladamantane compound of formula-3,
Hydrolyzing the n-acetamido-3,5-dimethyl adamantane compound of formula-3
Formula-3 with suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide, preferably sodium hydroxide in a suitable alcoholic solvent selected from polyethylene glycol or diethylene glycol or aqueous alcoholic solvents or mixtures thereof preferably polyethylene glycol or aqueous polyethylene glycol at a temperature of about 110-200°C

preferably 120-160°C for a sufficient period of time preferably about 2 to 25 hours, most preferably 2 to 20 hours to obtain l-amino-3,5-dimethyladamantane compound of formula-4,

followed by treating compound of formula-4 in-situ with hydrochloric acid in a suitable alcoholic solvent like isopropyl alcohol, methanol and the like preferably isopropyl alcohol followed by the addition of suitable ester solvents like ethyl acetate provides memantine hydrochloride compound of formula-1.

The second aspect of the present invention is to provide an eco-ftiendly and cost effective one pot process for the preparation of memantine hydrochloride compound of formula-1 from 1,3-dimethyladmantane compound of formula-2 without isolating any intermediate, which comprises of reacting 1,3-dimethyladamantane compound of formula-2

with suitable nitrile selected from a group consisting of propionitrile, butyronitrile, valeronitrile, phenylacetonitrile and acetonitrile, preferably acetonitrile in presence of a suitable acid selected from sulphuric acid and/or phosphoric acid and/or acetic acid or mixtures thereof, preferably sulphuric acid like sulphuric acid at about 50-70°C preferably 60-70°C and for a period of time sufficient preferably is about 2 to 15 hours, most preferably 2 to 10 hours to produce n-acetamido-3,5-dimethyladamantane compound of formula-3, in absence of any solvent,

Which on hydrolysis in-situ with a suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide preferably sodium hydroxide in a suitable alcoholic solvents selected from diethylene glycol, polyethylene glycol or aqueous alcoholic solvent or mixtures thereof at a temperature of about 110-200°C preferably 120-160°C for a sufficient period of time preferably 2 to 25 hours most preferably 2 to 20 hours provides the l-amino-3,5-dimethyl adamantane compound of formula-4,

Which on subsequent treatment in-situ with hydrochloric acid in a suitable alcoholic solvent like isopropyl alcohol, methanol and the like preferably isopropyl alcohol followed by the addition of suitable ester solvents like ethyl acetate provides memantine hydrochloride compound of formula-1.

Preferably the aqueous alcoholic solvent refers to the mixture of particular alcoholic solvent with water for example a mixture of polyethylene glycol and water or diethylene glycol and water. Preferably water content of the aqueous alcoholic solvent according to the present invention is 0.2 to 5% v/v.
The memantine hydrochloride compound of formula-1 prepared according to the present invention is characterized by the X-ray powder diffraction (as shown in figure-1) is similar to the prior art form i.e., Form-I of memantine hydrochloride.
The present invention schematically represented as follows: Scheme-1:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1:
Preparation of l-acetamido-3,5-dimethyl adamantane :
A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-65°C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 80°C. The reaction mixture was stirred for 10 hours at 65-70°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with methylene chloride. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene chloride and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C to get the title compound. Yield: 12.5 grams. Purity by GC: 99.47%
Example-2:
Preparation of l-acetamido-3,5-dimethyl adamantane :
A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-65 °C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 80°C. The reaction mixture was stirred for 10 hours at 65-70°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with toluene. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 70°C to get the title compound. Yield: 12.3 grams:

Example-3:
Preparation of memantine hydrochloride from l-acetamido-3,5-dimethyl
adamantane:
A mixture of l-acetamido-3,5-dimethyl adamantane (10 grams), polyethylene glycol (60 ml) and sodium hydroxide (14.5 grams) was heated to 120°C. The reaction mixture was stirred for 20 hours at 120°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with toluene. The reaction mixture was stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 70°C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-5°C. Isopropyl alcohol hydrochloric acid (10 ml) was added to the above mixture at 0-5°C. The reaction mixture was heated to 80-85°C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-80°C. The reaction mixture was cooled to 0-5°C. The separated solid was filtered and dried at 50°C for 5 hours to get the title compound. Yield: 7.5 grams Purity by GC: 99.90%
Example-4:
Preparation of memantine hydrochloride from l-acetamido-3,5-dimethyl
adamantane:
A mixture of l-acetamido-3,5-dimethyl adamantane (10 grams), polyethylene glycol (60 ml) and sodium hydroxide (14.5 grams) was heated to 120°C. The reaction mixture was stirred for 20 hours at 120°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with methylene chloride. The reaction mixture was stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene chloride. The organic layer was dried with sodium sulphate. Methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-5°C. Isopropyl alcohol hydrochloric acid (10 ml) was added to the above

mixture at 0-5°C. The reaction mixture was heated to 80-85°C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-80°C. The reaction mixture was cooled to 0-5°C. The separated solid was filtered dried at 50°C for 5 hours to get the title compound. Yield: 7.3 grams Purity by GC: 99.92%
Example-5:
Preparation of memantine hydrochloride from l-acetamido-3,5-dimethyl
adamantane:
A mixture of l-acetamido-3,5-dimethyl adamantane (10 grams), polyethylene glycol (60 ml) and water (3 ml) and sodium hydroxide (14.5 grams) was heated to 120°C. The reaction mixture was stirred for 20 hours at 120°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with toluene. The reaction mixture was stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 70°C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-5°C. Isopropyl alcohol hydrochloric acid (10 ml) was added to the above mixture at 0-5°C. The reaction mixture was heated to 80-85°C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-80°C. The reaction mixture was cooled to 0-5°C. The separated solid was filtered dried at 50°C for 5 hours to get the title compound. Yield: 7 grams
Example-6:
One-pot preparation of memantine hydrochloride:
A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-65°C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 80°C. The reaction mixture was stirred for 10 hours at 65-70°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with

methylene chloride. The organic and aqueous layers were separated. The aqueous layer was extracted with water and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C and added polyethylene glycol (60 ml) and sodium hydroxide (14.5 grams). The reaction mixture was heated to 120°C. The reaction mixture was stirred for 20 hours at 120°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with toluene. The reaction mixture was stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 70°C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-5°C. Isopropyl alcohol hydrochloric acid (10 ml) was added to the above mixture at 0-5°C. The reaction mixture was heated to 80-85°C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-80°C. The reaction mixture was cooled to 0-5°C. The separated solid was filtered dried at 50°C for 5 hours to get the title compound. Yield: 9.5 grams Purity by GC: 99.90%
Example-7:
One-pot preparation of memantine hydrochloride:
A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-65°C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 80°C. The reaction mixture was stirred for 10 hours at 65-70°C. The reaction mixture was quenched with the ice water. The reaction mixture was extracted with toluene. The organic and aqueous layers were separated. The aqueous layer was extracted with water and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off completely under reduced pressure at below 70°C and added polyethylene glycol (60 ml) and sodium hydroxide (14.5 grams). The reaction mixture was heated to 120°C. The reaction mixture was stirred for 20 hours at 120°C. The reaction mixture was quenched

with ice water. The reaction mixture was extracted with methylene chloride. The reaction mixture was stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with methylene chloride. The organic layer was dried with sodium sulphate. The methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-5°C. Isopropyl alcohol hydrochloric acid (10 ml) was added to the above mixture at 0-5°C. The reaction mixture was heated to 80-85°C and stirred for 30 minutes. Ethyl acetate (20 ml) was added to the above reaction mixture at 75-80°C. The reaction mixture was cooled to 0-5°C. The separated solid was filtered dried at 50°C for 5 hours to get the title compound. Yield: 9.6 grams.
Example-8:
One-pot preparation of memantine hydrochloride:
A mixture of 1,3-dimethyl adamantane (10 grams) and acetonitrile (36.8 ml) was heated to 60-65°C. Sulphuric acid (75 ml) was slowly added to the above reaction mixture at below 80°C. The reaction mixture was stirred for 10 hours at 65-70°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with methylene chloride. The organic and aqueous layers were separated. The aqueous layer was extracted with water and the organic layer was washed with water. The organic layer was dried with sodium sulphate. The methylene chloride from the organic layer was distilled off under reduced pressure at below 40°C and added polyethylene glycol (60 ml), water (2.8 ml) and sodium hydroxide (14.5 grams). The reaction mixture was heated to 120°C. The reaction mixture was stirred for 20 hours at 120°C. The reaction mixture was quenched with ice water. The reaction mixture was extracted with toluene. The reaction mixture was stirred for 15 minutes. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layer was dried with sodium sulphate. The toluene from the organic layer was distilled off under reduced pressure at below 70°C. The residue was dissolved in isopropyl alcohol (20 ml) and cooled to 0-5°C. Isopropyl alcohol hydrochloric acid (10 ml) was added to the above mixture at 0-5°C. The reaction mixture was heated to 80-85°C and stirred for 30 minutes.

Ethyl acetate (20 ml) was added to the above reaction mixture at 75-80°C. The reaction mixture was cooled to 0-5°C. The separated solid was filtered dried at 50°C for 5 hours to get the title compound. Yield: 7.8 grams

We claim:
1. An improved process for the preparation of memantine hydrochloride compound of formula-1
Which comprises of the following steps,
a) reacting the 1,3 -dimethyl adamantane compound of formula-2

with acetonitrile in presence of a suitable acid like sulphuric acid at a temperature of about 50-70°C for a sufficient period of time about 2 to 15 hours to obtain n-acetamido-3,5-dimethyladamantane compound of formula-3, in absence of any solvent,
b) hydrolyzing the n-acetamido-3,5-dimethyl adamantane compound of formula-3
with a suitable alkali metal hydroxide like sodium hydroxide or potassium
hydroxide in a suitable alcoholic solvent like polyethylene glycol at a temperature
of about 120°C to 180°C for a sufficient period of time about 2-25 hours to obtain
memantine compound of formula-4,


c) treating the memantine compound of formula-4 with hydrochloric acid in a suitable alcoholic solvent like isopropyl alcohol,
d) isolating memantine hydrochloride compound of formula-1 by adding suitable ester solvent like ethyl acetate.
2. An improved process for the preparation of memantine hydrochloride compound of formula-1,
Which comprises of the following steps,
a) reacting the 1,3-dimethyl adamantane compound of formula-2
with acetonitrile in presence of a suitable acid like sulphuric acid at a temperature of about 50-70°C for a sufficient period of time about 2 to 15 hours to obtain n-acetamido-3,5-dimethyladamantane compound of formula-3, in absence of any solvent,


b) hydrolyzing the n-acetamido-3,5-dimethyl adamantane compound of formula-3
with a suitable alkali metal hydroxide like sodium hydroxide or potassium
hydroxide in a suitable aqueous alcoholic solvent like aqueous polyethylene
glycol at a temperature of about 120°C to 180°C for a sufficient period of time
about 2- 25 hours to obtain memantine compound of formula-4,

c) treating the memantine compound of formula-4 with hydrochloric acid in a suitable alcoholic solvent like isopropyl alcohol,
d) isolating memantine hydrochloride compound of formula-1 by adding suitable ester solvent like ethyl acetate.

3. The process according to claim 2 b), wherein the aqueous alcoholic solvent contains 0.2 to 5% v/v of water.
4. One-pot process for the preparation of memantine hydrochloride compound of formula-1 from 1,3 -dimethyl adamantane with out isolating any intermediates,


which comprises of reacting the 1,3-dimethyl adamantane compound of formula-2,

with acetonitrile in presence of a suitable acid like sulphuric acid at a temperature of about 50-70°C for a sufficient period of time about 2-15 hours to obtain n-acetamido-3,5-dimethyladamantane compound of formula-3? in absence of any solvent,

Which on hydrolysis in-situ with a suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide in a suitable alcoholic solvent like polyethylene glycol at a temperature of about 120-180°C for a sufficient period of time about 2 to 25 hours provides memantine compound of formula-4,

Which on subsequent treatment in-situ with hydrochloric acid in a suitable alcoholic solvent like isopropyl alcohol followed by adding suitable ester solvents like ethyl acetate provides mementine hydrochloride compound of formula-1.

5. One-pot process for the preparation of memantine hydrochloride compound of formula-1 from 1,3-dimethyl adamantane with out isolating any intermediates ,

which comprises of reacting the 1,3-dimethyl adamantane compound of formula-2

with acetonitrile in presence of a suitable acid like sulphuric acid at a temperature of about 50-70°C for a sufficient period of time about 2-15 hours to obtain n-acetamido-3,5-dimethyladamantane compound of formula-3, in the absence of any solvent,

Which on hydrolysis in-situ with a suitable alkali metal hydroxide like sodium hydroxide or potassium hydroxide in a suitable aqueous alcoholic solvent like aqueous polyethylene glycol at a temperature of about 120-180°C for a sufficient period of time about 2 to 25 hours provides memantine compound of formula-4,

Which on subsequent treatment in-situ with hydrochloric acid in a suitable alcoholic solvent like isopropyl alcohol followed by adding suitable ester solvent like ethyl acetate provides memantine hydrochloride compound of formula-1.
I. The process according to claim 5, wherein the aqueous alcoholic solvent contains 0.2 to 5 % v/v of water.
r. The process according to claim 5, wherein the intermediates n-acetamido-3,5-dimethyladamantane compound of formula-3 and memantine compound of formula-4 are not isolated.
Dated this day 29th of October 2007