WO2009153806A2

WO2009153806A2 - Process for preparing memantine hydrochloride substantially free of !mpurities

Info

Publication number: WO2009153806A2
Application number: PCT/IN2009/000274
Authority: WO
Inventors: Pradeep Kumar Jauhari
Original assignee: PHARMACEUTICAL SOLUTIONS FZCO; SAIRAM ORGANICS PVT Ltd
Current assignee: PHARMACEUTICAL SOLUTIONS FZCO; SAIRAM ORGANICS PVT Ltd
Priority date: 2008-05-09
Filing date: 2009-05-08
Publication date: 2009-12-23
Anticipated expiration: 2010-11-09
Also published as: WO2009153806A3

Abstract

A process for preparing memantine hydrochloride free from impurities comprises (a) reacting 1,3-dimethyladamantane with acetonitrile and sulphuric acid to produce 1 - acetamido-3,5- dimethyl adamantane; (b) treating 1-acetamido-3,5-dimethyl adamantane with base in the presence of solvent to produce memantine; (c) reacting memantine with alcoholic HCI in the presence of solvents to produce memantine hydrochloride; and purification of memantine hydrochloride using aliphatic solvents.

Description

PROCESS FOR PREPARING MEMANTINE HYDROCHLORIDE SUBSTANTIALLY FREE OF IMPURITIES

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Indian Provisional Patent Application No. 1143/CHE/2008, filed on May 9, 2008.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of l-amino-3,5- dimethyladamantane hydrochloride (hereinafter referred to by the officially adopted name "Memantine hydrochloride"), substantially free of impurities.

BACKGROUND OF THE INVENTION

Memantine hydrochloride is chemically known as l-amino-3,5- dimethyladamantane hydrochloride and it is represented by the structural formula 1

Formula 1

It belongs to the group of tricyclic antiviral drugs (TAV). It provides persistent activation of N-methyl-D-aspartate (NMDA) receptors, and thus, can be used in the treatment of Parkinson's disease and Alzheimer's disease. Memantine hydrochloride is commercially available in the market under the trademark Namenda®. Namenda® is available for oral administration as capsule-shaped, film- coated tablets containing 5 mg and 10 mg of memantine hydrochloride.

Different strategies for the preparation of Memantine hydrochloride are disclosed in the prior art:

U.S. Patent No. 3,391,142 discloses the synthesis of memantine hydrochloride and its precursors, l-acetamido-3,5-dimethyl-adamantane, by treating l-bromo-3,5- dimethyl adamantane, with a mixture of acetonitrile and sulphuric acid to give the crude intermediate product in 100 percent yield. 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 six hours. The hydrolyzed product is diluted with water, followed by several benzene extractions, and the memantine free base is recovered by solvent distillation. The free base is then diluted with ether, and the addition of hydrogen chloride gas provides crude memantine hydrochloride. Crystallization of the hydrochloride from an ethanol of ethanol and ether gives pure memantine hydrochloride in 69.8 %yield.

U.S. Patent No. 4,122,193 & Chinese patent CN 1400207A, discloses pharmacological compositions and methods for treating living mammals suffering from hyperkinesias, as well as memantine hydrochloride, hydrobromide, and sulphate synthesis, where in the memantine hydrochloride is prepared by treating l-halo-3,5- dimethyl adamantane with urea at high temperature, and thermally decomposing the resulting urea intermediate.

U.S. Patent No. 5,599,998 exhibited electrophilic substitution on metallated 3,5-dimethyl-adamantane by chloramine. Czech Patent No. 282398B6 discloses the synthesis of memantine hydrochloride by basic hydrolysis of l-acetamido-3,5-dimethyl adamantane at high pressure.

Japanese Patent Publication No. 2002275142 discloses the use of N-hydroxy phthalimide to prepare l-acetamido-3,5-dimethyl adamantane with low yield.

CN 1335299 discloses the process of synthesis of memantine hydrochloride In the said process l-bromo-3,5-dimethyl adamantane, acetonitrile and sulfuric acid are made to produce acetamination reaction, and the product collected in water is made to produce alcoholysis reaction with sodium other and polyalcohol containing no ether linkage. Memantine is then obtained through chloroform extraction and is finally acidified with hydrochloric acid and chloroform recrystallized to obtain memantine hydrochloride. The said process employs the use of harsh basic conditions in the hydrolysis step.

CN 1488622 discloses the process of preparing memantine hydrochloride by treating 1, 3 -dimethyl adamantine with t-butyl-chloride & AlCl₃ to prepare 1-chloro- 3,5-dimethyl adamantane which is then amidated with acetamide and subjected to basic hydrolysis in the presence of sodium hydroxide in ethanediol or glycerin solvent to provide memantine base which is then subjected to dry HCl gas to obtain crude Memantine hydrochloride which is further purified by recrystallization.

W02005023753 discloses the process of preparing memantine hydrochloride by using bromine to get the bromo derivative (l-bromo-3,5 dimethyladamantane) which is then reacted with urea / HCOOH to give 1-acetamido analogue & then hydrolysis & acidification with HCl to obtain memantine hydrochloride. The deficiencies of the prior art include harsh reaction condition, undesirable by products such as bromine, very high temperatures, the need for high pressures, and the use of dangerous reactants.

Hence, there is a need for an improved process for preparing memantine hydrochloride that can take care of prior art deficiencies, improvement in yields, replacement of solvents like ether and reaction kinetics.

SUMMARY OF THE INVENTION

An aspect of the invention includes a process for preparing memantine hydrochloride starting from 1,3 -dimethyl adamantane and there by eliminating the impurities arising out from l-halo-3,5-dimethyl-adamantane. In another aspect hydrolysis of l-acetamido-3,5-dimethyl adamantane step is directed to synthesize 1- amino-3,5-dimethyl adamantane in very shorter duration of time with more purity and as such high temperature, degradation impurities that may arise due to longer time, are minimized. Further in another aspect, the Memantine HCl salt is obtained by using eco-friendly solvents. Memantine hydrochloride is then subjected to purification process to further eliminate any undesired impurity to give desired product in better quality and purity.

Another aspect of the invention includes a process for preparing memantine hydrochloride that avoids the halo intermediates which are obtained by corrosive processes.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention there is provided a process for the preparation of memantine hydrochloride which comprises a) reacting 1,3-dimethyladamantane with acetontitrile and sulphuric acid to produce l-acetamido-3,5-dimethyl adamantane; b) reacting l-acetamido-3,5-dimethyl adamantane with base in the presence of solvent to produce memantine; c) reacting memantine with alcoholic HCl in the presence of solvents to produce memantine hydrochloride; d) purification of memantine hydrochloride using aliphatic solvents.

In one embodiment, the present invention provides a process for the preparation of memantine hydrochloride, which involves, reacting 1,3-dimethyladamantane with acetontitrile and sulphuric acid catalyzed by long chain carbinol in a solvent like chlorinated solvent at about 50 to 80⁰C, for about 2-5 hours to from l-acetamido-3,5- dimethyladamantane. Carbinol used in the reaction may be selected from isopropyl alcohol, butanol, isoamyl alcohol and tertiary butyl alcohol.

Further in another aspect l-acetamido-3,5-dimethyladamantane is deacetylated by subjecting it to basic hydrolysis in the presence of solvent at about 150 to 18O⁰C, for about 2-3 hours to from memantine base. The bases used in the hydrolysis step are selected from potassium hydroxide, Sodium hydroxide, lithium hydroxide, and carbonates such as Barium carbonate and Cesium carbonate. The molar ratio of base can be varying from 2-10 moles per mole. The deacetylation of acetamido compound is carried out in a solvent selected from the group of polyethylene glycols H(OCH2- CH2)n OH where is greater than 4, monoethylene glycol, diethylene glycol along with chlorinated solvents such as dichloromethane, dichloroethane, carbon tetrachloride and chloroform.

Memantine free base obtained is dissolved in ketonic solvents such as MIBK, cyclohexanone, cyclopentanone or acetone and then alcoholic HCl is added to adjust the pH of the solution to 2-4. The reaction mixture is then cooled preferably to a temperature of about O⁰C to room temperature to obtain crude memantine hydrochloride.

The present further provides a process for purification of memantine hydrochloride which comprises of treating memantine hydrochloride with aliphatic solvents selected from hexane, cyclopentane, & cyclohexane at 30°- 80°c preferably between 45-50°c and time between 2 to 20 hrs, preferably 6-8 hrs. The reaction mass is filtered and washed with the solvent (2-5 times of the material taken). The filtered mass is dried to a constant wt. that gives GC purity more than 99.6%.

The present invention will now be described in more detail by the way of examples which should not construed as limiting the invention thereto The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples

Example 1

Preparation of l-Acetamido-3,5-dimethyl adamantane

A mixture of 1,3-dimethyl adamantane, acetonitrile and t-butanol heat to 50 to 80⁰C and add cone, sulphuric acid slowly within 3 hours. Maintain at 70 - 80°C for 3 hours. The reaction mixture product was poured in to ice and extracted with dichloromethane and wash the dichloromethane layer with water and sodium bicarbonate solution. Wash with water and dry with sodium sulphate. Distilled the dichloromethane and concentrated of organic layer and add n-Hexane and reflux. Cool to 0°C and filter the compound and wash with chilled n-Hexane and dry the compound l-Acetamido-3,5-dimethyl adamantane.

Example 2

Preparation of Memantine base

A mixture of l-acetamido-3,5-dimethyl adamantane, sodium hydroxide in Poly ethylene glycol-400 was heated to 170 -18O⁰C and maintain for a period of 2-3 hours. The reaction product mixture was cooled to RT and poured water thus obtained was extracted 3 times with 10 ml portion of dichloromethane. Distill dichloromethane completely; to obtained memantine base. Product is obtained in 90% yield.

Example 3

Preparation of Memantine Hydrochloride

Memantine free base obtained is dissolved in acetone and then alcoholic HCl is added to adjust the pH of the solution to 2-4. The reaction mixture is then cooled preferably to a temperature of about O⁰C to room temperature to obtain crude memantine hydrochloride.

Example 4

Purification of Memantine Hydrochloride

Impure Memantine HCl is taken and to cyclohexane is added and the reaction is heated at a temp., ranging from 45-5OfC and time between 6-8 hrs. The reaction mass is filtered and washed with the solvent (2-5 times of the material taken). The filtered mass is dried to a constant wt. that gives GC purity more than 99.6%. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only with a true scope and spirit of the invention being indicated by the following claims.

Claims

We Claim:

1. A process for preparing memantine hydrochloride comprising the steps of :

e) reacting 1,3-dimethyladamantane with acetontitrile and sulphuric acid to produce l-acetamido-3,5-dimethyl adamantane; f) reacting l-acetarnido-3,5-dimethyl adamantane with base in the presence of solvent to produce memantine; g) reacting memantine with alcoholic HCl in the presence of solvents to produce memantine hydrochloride; h) purification of memantine hydrochloride using aliphatic solvents.

2. A process as claimed in claim 1, wherein the said base in step (b) is selected from the group comprising of potassium hydroxide, Sodium hydroxide, lithium hydroxide, and carbonates such as Barium carbonate and Cesium carbonate

3. A process as claimed in claim 1, wherein the said solvent in step (b) is selected from the group of polyethylene glycols, monoethylene glycol, diethylene glycol dichloromethane, dichloroethane, carbon tetrachloride and chloroform.

4. A process as claimed in claim 1, where in the said alcohol in step (c) is selected from the group comprising of methanol, ethanol, isopropanol or butanol.

5. A process as claimed in claim 1, where in the said solvent in step (c) is selected from the group comprising of MIBK, cyclohexanone, cyclopentanone or acetone.

6. A process as claimed in claim 1, where in the said aliphatic solvent in step (d) is selected from the group comprising of hexane, cyclopentane or cyclohexane.