WO2011125062A1

WO2011125062A1 - Process for the preparation of memantine hydrochloride

Info

Publication number: WO2011125062A1
Application number: PCT/IN2010/000230
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Rapolu Raji Reddy; Matta Ramakrishna Reddy; Bandi Vamsi Krishna
Original assignee: Hetero Research Foundation
Priority date: 2010-04-08
Filing date: 2010-04-08
Publication date: 2011-10-13
Also published as: EP2555616A1; EP2555616A4

Abstract

The present invention provides an improved process for the preparation of 1-bromo-3,5-dimethyladamantane. The present invention also provides a process for preparing free flowing solid of 1-acetamido-3,5-dimethyladamantane. The present invention further provides a process for the preparation of memantine hydrochloride substantially free of 1-amino-3,5,7-trimethyladamantane hydrochloride and/or 1-amino-3-methyladamantane hydrochloride impurity.

Description

PROCESS FOR THE PREPARATION OF MEMANTINE HYDROCHLORIDE

Field of the Invention

The present invention provides an improved process for the preparation of 1- bromo-3,5-dimethyladamantane. The present invention also provides a process for preparing free flowing solid of l-acetamido-3,5-dimethyladamantane. The present invention further provides a process for the preparation of memantine hydrochloride substantially free of l-amino-3,5,7-trimethyladamantane hydrochloride and/or 1- amino-3-methyladamantane hydrochloride impurity.

Background of the Invention

Memantine, its pharmaceutically acceptable salts thereof and process for their preparation were first disclosed in U.S. Patent No. 3,391 ,142. Memantine hydrochloride is chemically, 3,5-dimethyltricyclo-[3.3.1.1³'⁷]decan-l-amine hydrochloride and has the structural formula:

Memantine hydrochloride is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement the drug produces in Alzheimer's disease. Memantine hydrochloride is marketed under the brand name Namenda^® by Forest Labs.

U.S. Patent No. 3,391,142 disclosed process comprises of reacting 1-bromo- 3,5-dimethyladamantane with sulphuric acid in acetonitrile gives l-acetamido-3,5- dimethyl adamantine, followed by deacetylation in diethylene glycol with sodium hydroxide at reflux temperature which gives memantine. The obtained memantine is converted into its hydrochloride salt by treating with anhydrous hydrogen chloride and recrystallized 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- dimethy ladamantane .

PCT Publication no. WO 2006/122238 disclosed a process for the preparation of memantine hydrochloride, which comprises reacting l-bromo-3,5-dimethyl adamantane with formamide to form l-N-formyl-3, 5 -dimethyl adamantine, converting

1- N-formyl-3,5-dimethyl adamantine to memantine hydrochloride by reacting with an organic or inorganic acid such as hydrochloric acid.

U.S. Patent application no. 2006/0173215 disclosed a process for the preparation of n-acetamido-3,5-dimethyladamantane by reacting l-bromo-3,5- dimethyladamantane and a nitrile, the presence of phosphoric acid at about 50 to 100°C and for a period of time sufficient to produce n-acetamido-3,5- dimethy ladamantane. According to the patent also disclosed a process for the preparation of memantine hydrochloride by dissolving n-acetamido-3,5- dimethyladamantane in a solvent selected from the group consisting of C_3-6 alcohols such as n-butanol in the presence of a strong inorganic base such as potassium hydroxide or sodium hydroxide for a sufficient period of time to obtain memantine and reacting the memantine with hydrogen chloride or hydrochloric acid to obtain memantine hydrochloride.

U.S. Patent application no. 2006/0258885 disclosed a process for the preparation of l -acetamido-3,5-dimethyl-adamantane, which comprising the 1-chloro- 3, 5 -dimethy ladamantane, 5-10 equivalents of acetonitrile and 5-20 equivalents of glacial acetic acid, to provide a reaction mixture, the reaction mixture 3-10 equivalents of concentrated sulfuric acid, to provide l-acetamido-3,5-dimethyl-adamantane. According to the patent also disclosed a process for the preparation of memantine hydrochloride, which comprising the l-acetamido-3,5-dimethyl-adamantane, 5-20 equivalents of an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide and a solvent chosen from the group consisting of l-methoxy-2-propanol,

2- methoxy-l-propanol, 3-methoxy-l-propanol, 2-ethoxyethanol, 2-methoxyethanol and mixtures thereof, to provide a hydrolysis mixture, heating the hydrolysis mixture under reflux for a time sufficient and isolating the memantine, preferably by conversion into memantine hydrochloride.

PCT Publication no. WO 2007/132476 disclosed a process for the preparation of memantine hydrochloride, which comprises 3,5-Dimethyladamantane is reacted with bromine to form l-bromo-3,5,- dimethyladamantane at reflux, it is reacted with acetonitrile in the presence of sulphuric acid to form l-acetamido-3,5- dimethyladamantane. Optionally l-acetamido-3,5-dimethyladamantane is treated with an organic acid such as p-toulene sulfonic acid or benzene sulfonic acid to form 1- acetamido-3,5-dimethyladamantane p-toluene sulfonate, which is setting free of salt in the presence of base such as ammonia to get the pure l-acetamido-3,5- dimethyladamantane. l-acetamido-3,5-dimethyladamantane is subjected to hydrolysis followed by in-situ reaction with hydrochloric acid to form memantine hydrochloride.

PCT Publication no. WO 2008/040560 disclosed a process for the preparation of memantine, which comprises reacting N-chloro-acetyamino-3,5- dimethyladamantane with thiourea in the presence of an organic solvent such as isopropanol, and optionally recovering memantine and its hydrochloride acid salt form from reaction mixture. According to the patent publication also disclosed N-chloro- acetyamino-3,5-dimethyladamantane.

U.S. Patent application no. 2008/0033054 disclosed a process for preparing memantine hydrochloride containing less than about 0.15% of at least one of 1-amino- 3-methyladamantane hydrochloride or l-amino-3,5,7-trimethyladamantane hydrochloride.

PCT Publication no. WO 2008/062472 disclosed a process for the preparation of memantine hydrochloride, which comprises reacting 1,3 -dimethyl adamantane with bromine in methylene chloride to provide l-bromo-3,5-dimethyl adamantine which is reacted with acetamide in presence of anhydrous sodium sulfate to provide 1- acetamido-3,5-dimethyl adamantine and treated with sodium hydroxide in presence of toluene to obtain memantine. Optionally converting memantine to memantine hydrochloride by treating memantine with hydrochloride in isopropyl alcohol. PCT Publication no. WO 2009/057140 disclosed a process for the preparation of memantine hydrochloride which comprises reacting a 1,3 -dimethyl adamantane with acetonitrile in presence of sulphuric acid at a temperature of about 50 to 70°C for a sufficient period of time about 2 to 15 hours to provide l-acetamido-3,5- dimethyladamantane in absence of any solvent, hydrolysis with a sodium hydroxide in polyethylene glycol at a temperature of about 120 to 180°C for a sufficient period of time about 2 to 25 hours provides mamantine which on subsequent treatment with hydrochloric acid in isopropyl alcohol followed by adding ethyl acetate to obtain memantine hydrchloride.

PCT Publication no. WO 2010/007351 disclosed 2-(3,5-dimethyladamantan-l- yl)-isoindole-l ,3-dione can be prepared by condensing a l-bromo-3,5- dimethyladamantane with an alkali metal phthalimide such as potassium phthalimide. According to the patent also disclosed a process for the preparation of memantine, which comprising hydrolyzing 2-(3,5-dimethyladamantan-l-yl)-isoindole-l,3-dione to produce memantine and optionally converting the memantine to the pharmaceutically acceptable acid addition salt thereof.

It has been found that the l-bromo-3,5-dimethyladamantane produced according to the prior art procedures results in the formation of impurities along with the desired product. A novel process has now been found by the inventors which process yields l-bromo-3,5-dimethyladamantane in a better purity when compared with that obtained by the prior art procedures.

We have also discovered a process for preparing free flowing solid of 1- acetamido-3,5-dimethyladamantane.

The common impurities of the memantine hydrochloride are l-amino-3,5,7- trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride.

We have found a simple and effective process for the reduction of 1-amino- 3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity in the memantine hydrochloride. The process of the invention ensures the preparation of memantine hydrochloride substantially free of 1-amino- 3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity. Thus, one object of the present invention is to provide an improved process for the preparation of l-bromo-3,5-dimethyladamantane.

Another object of the present invention is to provide a process for preparing free flowing solid of l-acetamido-3,5-dimethyladamantane.

Yet another object of the present invention is to provide a process for the preparation of memantine hydrochloride substantially free of l-amino-3,5,7- trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.

Detailed description of the Invention

According to one aspect of the present invention, there is provided an improved process for the preparation of l-bromo-3,5-dimethyladamantane, which comprises reacting dimethyladamantane with bromine at 15 to 35°C to obtain 1- bromo-3 ,5-dimethyladamantane.

The reaction may preferably be carried out in the presence or absence of a solvent.

According to another aspect of the present invention, there is provided a process for preparing free flowing solid of l -acetamido-3,5-dimethyladamantane, which comprises stirring l-acetamido-3,5-dimethyladamantane with water at above 35°C and isolating the free flowing solid of l-acetamido-3,5-dimethyladamantane.

The l-acetamido-3, 5 -dimethyladamantane used in the process can be obtained by previously known methods.

Preferably the stirring may be carried out at 40 to 80°C and more preferably at 45 to 60°C.

Isolation of free flowing solid of l-acetamido-3, 5 -dimethyladamantane may preferably be carried out by the methods known such as filtration or centrifugation.

According to another aspect of the present invention, there is provided a process for the preparation of memantine hydrochloride substantially free of 1-amino- 3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity, which comprises: a) dissolving memantine hydrochloride containing l-amino-3, 5,7- trimethyladamantane hydrochloride and l-amino-3 -methyladamantane hydrochloride impurity in an alcohol solvent;

b) heating the solution obtained in step (a) at reflux;

c) adding ketonic solvent to the solution obtained in step (b);

d) maintaining the solution obtained in step (c) at below 50°C; and

e) isolating the memantine hydrochloride substantially free of l-amino-3, 5,7- trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.

The term "memantine hydrochloride substantially free of l-amino-3, 5,7- trimethyladamantane hydrochloride and/or l-amino-3 -methyladamantane hydrochloride impurity" refers to memantine hydrochloride having the content of either or both of l-amino-3, 5,7-trimethyladamantane hydrochloride and l-amino-3- methyladamantane hydrochloride impurity in equal to or less than about 0.2% by weight, preferably equal to or less than about 0.1% by weight, more preferably equal to or less than about 0.05% by weight and still more preferably not detected. The contents of memantine hydrochloride and the impurities are determined by Gas chromatography (GC).

GC conditions for analysis are:

GC System Shimadzu GC-2010

Column Rtx-35 Amine

Length 30 mts

ID 0.32mm

Film Thickness 1.5 μπι

Carrier Gas Nitrogen

Injection volume 1.0 μΐ

Linear velocity 37.4 cm/sec (Column flow-2.0 ml)

Injection Mode Split (1 :0)

Run time 60 minutes

Sample Concentration 25 mg. The chemical formula of l-amino-3,5,7-trimethyladamantane hydrochloride represented as:

The chemical formula of l-amino-3-methyladamantane hydrochloride represented as:

Preferable alcohol solvent used in step (a) may be selected from methanol, ethanol or isopropyl alcohol and more preferable alcohol solvent is methanol.

Preferable ketonic solvent used in step (c) may be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone and more preferable ketonic solvent is acetone.

The maintenance in step (d) may preferably be carried out at 0 to 35°C and more preferably at 0 to 5°C. Isolation of memantine hydrochloride substantially free of l-amino-3,5,7- trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity in step (e) may preferably be carried out by the methods known such as filtration or centrifugation.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples

Example 1 :

Preparation of l-acetamido-3,5-dimethyladamantane

Bromide (500 gm) was added to dimethyladamantane (100 gm) under stirring for 1 hour 30 minutes at 25 to 30°C. The reaction mass maintained for 12 hours at 25 to 30°C and the reaction mass was poured in water and methylene chloride under stirring at 5 to 10°C. To the reaction mass was added sodium sulfite (20%, 1000 ml) at 0 to 5°C and stirred for 30 minutes at 0 to 5°C. The layers were separated and the organic layer was distilled off completely under vacuum at below 45°C to obtain a residue. The residue was dissolved in acetonitrile (600 ml). The solution was cooled to 0 to 5°C and then added concentrated sulfuric acid (300 ml) drop wise for 2 hours at 0 to 5°C. Then, the contents were maintained for 14 hours at 25 to 30°C and the reaction mass was poured into a mixture of water and methylene chloride under stirring at 0 to 5°C. The layers were separated and the organic layer was distilled off completely under vacuum at below 45°C to obtain a residue. To the residue was added water (500 ml) at 35 to 40°C and stirred for 30 minutes at 50°C. The reaction mass was cooled to 25 to 30°C and maintained for 2 hours at 25 to 30°C, filtered. The solid obtained was dried at 45°C for 6 hours to obtain 130 gm of l-acetamido-3, 5 -dimethyl adamantane.

Example 2:

Preparation of memantine hydrochloride

l-Acetamido-3,5-dimethyladamantane (44 gm) as obtained in example 1, sodium hydroxide and diethylene glycol are added, and heated to reflux. Then, the contents were maintained for 6 hours at reflux and water (1 175 ml) was added under stirring. The reaction mass was cooled to below 20 C and then added methylene chloride (750 ml), and stirred for 15 minutes at 20°C. The layers were separated and the organic layer was distilled off completely under vacuum at below 45°C to obtain a residue. The residue was dissolved in ethyl acetate (700 ml). Ethyl acetate hydrochloride (160 ml) was added to the reaction mass and stirred for 5 hours at 25 to 30°C. The reaction mass was cooled to 0 to 5°C and stirred for 1 hour at 0 to 5 °C. The separated solid was filtered and dried at 50°C for 2 hours to obtain 87 gm of memantine hydrochloride containing l-amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity.

Memantine hydrochloride: 99.3%;

The combined contents of l-amino-3,5,7-trimethyladamantane hydrochloride and 1- amino-3-methyladamantane hydrochloride impurity: 0.5%.

Example 3 :

Preparation of purification of memantine hydrochloride

Memantine hydrochloride containing l -amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity (87 gm) as obtained in example 2 was dissolved in methanol (175 ml) at 25 to 30°C and stirred to obtain a solution. The solution was heated to reflux and maintained for 20 minutes. The reaction mass was cooled to 50 to 55°C and then added acetone (525 ml), and stirred for 1 hour at 50 to 55°C. The reaction mass was cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C. The separated solid was filtered and dried at 50 to 55°C for 4 hours to obtain 74 gm of memantine hydrochloride substantially free of 1-amino- 3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.

Memantine hydrochloride: 99.9%;

The combined contents of l-amino-3,5,7-trimethyladamantane hydrochloride and 1- amino-3-methyladamantane hydrochloride impurity: 0.07%.

Example 4:

Preparation of purification of memantine hydrochloride Memantine hydrochloride containing l-amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity (87 gm) was dissolved in methanol (350 ml) and stirred to obtain a solution. The solution was heated to reflux and maintained for 20 minutes. The reaction mass was cooled to 50 to 55°C and then added acetone (1000 ml), and stirred for 1 hour at 50 to 55°C. The reaction mass was cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C, filtered. The solid obtained was dried at 50 to 55°C for 4 hours to obtain 78 gm of memantine hydrochloride substantially free of l-amino-3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.

Memantine hydrochloride: 99.95%;

The combined contents of l-amino-3,5,7-trimethyladamantane hydrochloride and 1- amino-3-methyladamantane hydrochloride impurity: 0.03%.

Example 5:

Preparation of purification of memantine hydrochloride

Memantine hydrochloride containing l-amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity (44 gm) was dissolved in ethanol (90 ml) and stirred to obtain a solution. The solution was heated to reflux and maintained for 20 minutes. The reaction mass was cooled to 50 to 55°C and then added acetone (260 ml), and stirred for 1 hour at 50 to 55°C. The reaction mass was cooled to 0 to 5°C and stirred for 1 hour 0 to 5°C. The separated solid was filtered and dried at 50 to 55°C for 4 hours to obtain 35 gm of memantine hydrochloride substantially free of l-amino-3,5,7-trimethyladamantane hydrochloride and/or l-amino-3-methyladamantane hydrochloride impurity.

Memantine hydrochloride: 99.85%;

The combined contents of l-amino-3,5,7-trimethyladamantane hydrochloride and 1- amino-3-methyladamantane hydrochloride impurity: 0.1%.

Claims

We claim:

1. An improved process for the preparation of l-bromo-3,5-dimethyladamantane, which comprises reacting dimethyladamantane with bromine at 15 to 35°C to obtain 1- bromo-3,5-dimethyladamantane.

2. The process according to claim 1, wherein the reaction is carried out in the presence or absence of a solvent.

3. A process for preparing free flowing solid of l -acetamido-3, 5 -dimethyladamantane, which comprises stirring l-acetamido-3, 5 -dimethyladamantane with water at above 35°C and isolating the free flowing solid of l-acetamido-3, 5 -dimethyladamantane.

4. The process according to claim 3, wherein the stirring is carried out at 40 to 80°C.

5. The process according to claim 4, wherein the stirring is carried out at 45 to 60°C.

6. A process for the preparation of memantine hydrochloride substantially free of 1- amino-3,5,7-trimethyladamantane hydrochloride and/or l -amino-3- methyladamantane hydrochloride impurity, which comprises:

a) dissolving memantine hydrochloride containing l-amino-3,5,7- trimethyladamantane hydrochloride and l-amino-3 -methyl adamantane hydrochloride impurity in an alcohol solvent;

b) heating the solution obtained in step (a) at reflux;

c) adding ketonic solvent to the solution obtained in step (b);

d) maintaining the solution obtained in step (c) at below 50°C; and

e) isolating the memantine hydrochloride substantially free of l-amino-3, 5,7- trimethyladamantane hydrochloride and/or l-amino-3 -methyladamantane hydrochloride impurity.

7. The process according to claim 6, wherein the alcohol solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol or isopropyl alcohol.

8. The process according to claim 7, wherein the alcohol solvent is methanol.

9. The process according to claim 6, wherein the ketonic solvent used in step (c) is a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone.

10. The process according to claim 9, wherein the ketonic solvent is acetone.

1 1. The process according to claim 6, wherein the maintenance in step (d) is carried out at 0 to 35°C.

12. The process according to claim 1 1 , wherein the maintenance is carried out at 0 to 5°C.