FORM 2 THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)


AN IMPROVED PROCESS FOR AMINOADAMANTANES AND INTERMEDIATES
THEREOF
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BAHVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.


An Improved Process for Aminoadamantanes and Intermediates
Thereof.
Technical Field of the Invention:
The present invention relates to an improved process for the preparation 1-aminoadamantanes and acid addition salts thereof. In particular, it relates to an improved process for the preparation of memantine hydrochloride. The present invention further provides an improved process for the preparation of intermediates for 1 -aminoadamantanes.
Background of the Invention:
Aminoadamantanes are long known to possess an activity on the central nervous system and more specific for the treatment of Parkinson's disease. Among these, Memantine hydrochloride or l-amino-3, 5-dimethyladamantane hydrochloride (R1 = R2 = Me, R3 -H) is a well known Tricyclic Antiviral (TAV's), which provides good and persistent activation of the central nervous system. Memantine is a proven orally active NMDA (N-methyl-D-aspartate) receptor antagonist, which works by blocking the NMDA receptors in the brain, thus blocking the excessive activity of the glutamate, but allowing the normal activation of the NMDA receptors that occurs when the brain forms a memory. Memantine, which may therefore improve the brain functioning in Alzheimer's disease, has been licensed to treat moderately severe to severe Alzheimer's disease. Studies have demonstrated that Memantine causes a small improvement or stabilization in the cognitive thinking, i.e. thinking, learning, memory and daily functioning of the Alzheimer's patients.
US Patent 3,391,142 (Jack Mills et al., Feb., 1966), discloses the synthesis of Memantine hydrochloride and its precursors according to the following Scheme-I.
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In the first step, 1,3-dimethyl adamantane is reacted with excess bromine at reflux temperatures to give the l-bromo-3,5-dimethyl adamantane, which after the work-up is distilled under reduced pressure. In the second step, the reaction between l-bromo-3,5-dimethyl adamantane and a large excess of both acetonitrile and concentrated sulphuric acid, afforded l-acetamido-3,5-dimethyl adamantane by way of the so called Ritter reaction. This reaction, which proceeds via the attack of acetonitrile on the carbocation that forms in an acid environment followed by formation of an amide, is strongly exothermic. This consequently posses scale-up problems due to the extreme heat release peaks caused by the potential reagent accumulations in the systems. As a result of this, alternate strategies such as use of glacial acetic acid-sulphuric acid as disclosed in EP1721888 (Vigano' Enrico et al., May, 2006), and use of phosphoric acid as disclosed in WO 2006/076562 (Merli Valeriano et al., Jan., 2006) were developed. In such cases however the reaction is exothermic and hence requires careful and controlled addition of the acid catalyst. Further, the use of these acid catalysts have led to the polymerization of acetonitrile, resulting in viscous reaction mass, which consequently leads to the generation of heat peaks, which are difficult to dissipate. In the third step, hydrolysis of the l-acetamido-3, 5-dimethyl adamantane is carried out in the presence of sodium hydroxide in diethylene glycol heated under reflux, i.e. at temperatures exceeding 240 °C to 250 °C. These conditions, with such high temperatures needed, not only require special set-ups, but also pose a constant danger of impurity formation, which must then be removed by laborious purifications. Hence, such reactions are not commonly used in the
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synthesis of pharmaceutical drugs and their intermediates. Further referring to US 3,391,142 (Jack Mills et al., Feb., 1966), the free base obtained following the hydrolysis is extracted with benzene, taken up in ether, treated with HC1 to provide an addition salt, which is then re crystallized from a mixture of alcohol-ether.
US 5,061,703 (Joachim Bormann et al., April 1990) discloses a method of prevention or treatment of cerebral ischemia using admanatane derivatives and salts thereof, which includes memantine. Also disclosed is the preparation of these compounds. The said method for the synthesis of Memantine hydrochloride starts from l-halo-3, 5-dimethyl adamantane. The innovators propose the formation of N-formyl derivatives of different alkyl adamantanes by the reaction between formamide and the respective halogen derivative under formamide reflux conditions. The conditions employed here are so severe that it may require considerable plant investments and expidents while carrying the process on an industrial scale. The temperatures required for formamide reflux are above 200 °C.
US 4,122,193 (Arthur Scherm et al, April 1973) discloses the synthesis of Memantine hydrochloride starting from l-chloro-3, 5-dimethyladamantane and urea. The reaction is carried out in a pressure vessel at 220 °C. Hereto the conditions are very severe and further that these conditions employed may lead to the insitu degradation of urea, whose thermal decomposition has been observed at above 132°C, leading to the formation of biuret, ammonia and hydrocyanic acid. This may inturn lead to the generation of undesired impurities, which may pose difficulties in meeting the tight specifications imposed by either by the pharmacopoeia or by the health authorities and the quality directives, since the acceptable maxima for known impurities is 0.1 %. Consequently the product prepared by the process mentioned above might need further purification, which could be done by several recrystallization steps, thereby lowering the overall yield.
CZ 282398 (Kysilka Vladimir RNDR CSC) discloses the hydrolysis of the acetamidoadamantanes in alcoholic solvents at 110-140 °C under pressure, thus leading to the corresponding aminoadamantanes e.g. memantine.
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Japanese Patent Publication JP2002 275142 (Ishii Yasutaka et aJ., Mar,, 2001) discloses the synthesis of n-acetyl memantine according to the following scheme-II with a yield of 45 %.

Scheme-II
The innovators of US 5,599,998 (George Kraus et al., Oct., 1994) describe the synthesis of Memantine hydrochloride via an electrophilic ammination reaction (scheme-Ill), with a yield of 48%. Thus, in addition to the low yield, the disclosed method is cumbersome on an industrial scale with the use of metallic lithium and chloramine, which can be hazardous if not handled properly.

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A recent synthesis of Memantine hydrochloride as disclosed in WO 2007/ 096124 (Schickander Christian, Feb., 2007) employs chloroacetonitrile for the Ritter reaction (scheme-IV). This reagent is lachrymatory and its use on a large scale requires special handling precautions.


WO2006/122238 (Sanjay S. et al., May, 2006) discloses the synthesis of Memantine hydrochloride, via the N-formyl derivative formation using formamide at 150-160°C. The method describes the bromination of 1,3-dimethyladamantane using excess bromine wherein, after the reaction; the bulk of the bromine is removed by distillation. This however is very difficult on an industrial scale and requires special reactor assemblies and isolated plant to handle the escape of the toxic bromine vapors during the distillation.
WO2005/062724 (Periyandi N. et al., Dec, 2004) describes a process for the preparation of Memantine hydrochloride. The process essentially proceeds through the basic bromination step, however instead of isolating the not very stable bromoadamantane, the product was insitu hydrolyzed to the stable hydroxyadamantane, which was isolated and used further for the Ritter reaction with acetonitrile using concentrated sulphuric acid.
WO 2006/076560 (Merli V. et al., Jan., 2006) mentions the methods for preparing the polymorphic forms of Memantine hydrochloride. The innovators of this application disclose Form-II of Memantine hydrochloride and also describe its method of preparation. It has been mentioned in this patent that Form-II is a hydrate, more specifically a monohydrate of Memantine hydrochloride.
From the afore mentioned approaches, it thus appears that, in the current state of the art there stands no synthetic approach free from the afore mentioned disadvantages i.e. a process which can be undertaken on an industrial scale under milder conditions and without the need of any special equipment. Thus there exists a need for an improved process for the preparation of 1 -aminoadamantanes and its intermediates thereof, which eliminates the disadvantages of the prior art reported process and which is safe, cost effective and industrially advantageous.
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Object of the Invention:
An object of the present invention is to provide an improved, simple, efficient and high yielding process for the preparation of aminoadamantanes and their salts such as Memantine hydrochloride and the intermediates thereof.
Another object of the present invention is to provide a cost effective process for the preparation of aminoadamantanes; intermediates thereof and the acid addition salts thereof, which involve reduced number of stages.
Yet another object of the present invention is to provide an industrially scalable process for the preparation of aminoadamantanes; intermediates thereof and acid addition salts thereof.
Further object of the present invention is to provide an improved process for the preparation of aminoadamantanes and acid addition salts thereof in one-pot manner, thus eliminating the steps such as isolation and purification of the intermediates.
Summary of the Invention:
According to one aspect of the present invention, there is provided a process for the preparation of 1-aminoadamantanes of formula (I) and acid addition salts thereof,

(I) in which R1, R2 and R3 are identical or different and are either 'H' or a straight or
branched C1 to C6 alkyl groups,
wherein the said process comprises the steps of
a) Halogenating the adamantane of formula (II) using a halogenating agent to
form 1-haloadamantane of formula (III)
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b) Reacting 1-haloadamantane (III) with an acid and a nitrile to give 1 amidoadamantane of formula (IV)

c) Hydrolyzing 1-amidoadamantane (IV) to give 1-amino-adamantane of formula (I);
d) Converting the 1-amino-adamantane (I) into its pharmaceutically acceptable salts.
According another aspect of the present invention, there is provided a process for the preparation of 1-aminoadamantanes of formula (I) and acid addition salts thereof

(I)
in which R1, R2 and R3 are identical or different and are either 'H' or a straight or branched C1 to C6 alkyl groups,

wherein the said process comprises the steps of
a) Reacting the adamantane of formula (II) with an acid and a nitrile to give 1 -amidoadamantane of formula (IV)

(II) (IV)
b) Hydrolyzing 1-amidoadamantane (IV) to give 1-amino-adamantane of
formula (I).
c) Converting 1-amino-adamantane (I) into its pharmaceutically acceptable
salts.
According to yet another aspect of the present invention, these is provided a process for the preparation of 1-aminoadamantanes of formula (I) and acid addition salts thereof

(I) in which R1, R2 and R3 are identical or different and are either 'H' or a straight or
branched C1 to C6 alkyl groups,
wherein the said process comprises the steps of
a) Reacting 1-hydroxyadamantane of formula (V) with formic acid to form

(V) (VI)
b) Reacting (VI) with nitrile to give 1-amidoadamantane of formula (IV)
formate ester of formula (VI)
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(IV)
c) Hydrolyzing 1-amidoadamantane (IV) to give 1-amino-adamantane of formula (I).
d) Converting 1-amino-adamantane (I) into its pharmaceutically acceptable salts.
According to further aspect of the present invention, the aminoadamantanes of formula (1) obtained by any of the above mentioned process are purified by recrystallization from acetic acid.
Detailed description of the Invention:
The present invention relates to an improved process for the preparation of aminoadamantanes of formula (I) and acid addition salts thereof, in particular Memantine hydrochloride and its intermediates and salts thereof.

(I) in which R1, R2 and R3 are identical or different and are either 'H' or a straight or
branched C1 to C6 alkyl groups
The said process comprises the steps of
a) Halogenating the adamantane of formula (II) using a halogenating agent to
form 1-haloadamantanes of formula (III)
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(II) (III)
in which, X is Br, C1 and R1, R2 and R3 have the meaning as defined above; b) Reacting 1-haloadamantane (III) with an acid and a nitrile to give I-amidoadamantane of formula (IV)

(IV)
c) Hydrolyzing 1-amidoadamantane (IV) to give 1-amino-adamantane of formula (I);
d) Converting 1-amino-adamantane (I) into its pharmaceutically acceptable salts.

Scheme-V
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The said process according to present invention for the preparation of 1-aminoadamantanes, in particular Memantine Hydrochloride (R1=R2=CH3; R3=H) of formula (I), is depicted in scheme-V;

The said halogenating agent used in step a is usually liquid bromine though chlorine gas can sometimes be used.
The said halogenation reaction is carried out at temperatures ranging from 20°C to 40°C; preferably at 30 °C to 35 °C and for 8 - 15 hrs; preferably for 10 - 12 hrs.
In a preferred embodiment, the process of brominating the 1,3-dimethyladamantane (1,3-DMA) is carried out at temperatures ranging from 20°C to 40 °C, preferably at 30-35 °C. Addition of bromine to 1,3-DMA is often accompanied by a mild exotherm. The reaction is usually carried out using excess bromine and in the absence of any added solvent, thus bromine it self acting as a medium for the reaction. Usually bromine is used in 3 to 8 mol excess of 1,3-DMA, preferably 4 to 6 mol excess of 1,3-DMA.
After completion of the reaction, the reaction mixture is diluted with dichloromethane and quenched by slow addition of an aqueous solution of sodium bisulphite in order to destroy the excess bromine present. Quenching is conducted usually at lower temperatures of 0° to 25 °C. preferably in the range of 5° to 10°C. It has been observed that if the reaction mixture is not diluted with solvent before quenching, a considerable amount of the l-hydroxy-3,5-dimethyladamantane is obtained instead of the desired 1-bromo-3,5-dimethyladamantane. It has also been observed that the bromo intermediate is stable, if stored with proper care and does not hydrolyze readily and considerably by mere contacting with water. However, at plant scale varying amount of the hydroxy impurity may be formed, in which case the crude product is as such taken forward for the further reaction, without affecting the quality and/ or yield of the subsequent stages.
In the further process of converting the halo derivative to the acetamido derivative, the reaction essentially involves treating the halo derivative with acetonitrile in the presence of formic acid.
The problems reported in the prior art for the use of other acid catalysts for the said reaction (Ritter reaction) are eliminated by the use of formic acid. The said reaction can
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safely be run on industrial scale without the risk of developing any rapid heat peaks as against the prior art processes.
Starting from l-halo-3,5-dimethyl adamantane, 3 to 8 equivalents, preferably 5-6 equivalents of acetonitrile and 3 to 10 equivalents, preferably 5 to 8 equivalents of formic acid are employed. The reactants are added in one lot and the reaction is continued at 50°C -90 °C, preferably between 75 °C - 90 °C and more preferably between 85 °C - 90°C. The formic acid employed is usually as an aqueous solution of 80 to 98 % strength, preferably of 85 to 90 % strength. After completion of the reaction, the mixture is poured into ice cold water and the product of the reaction is extracted using commonly used organic solvents such as dichloromethane, toluene, ethylacetate and the like; or optionally, the solid so obtained after quenching the reaction mixture in water, is directly filtered under suction. In the first case however, the solvent is distilled till the residual stage, optionally swapping the residue with water miscible solvents like methanol, ethanol, isopropanol, acetone, ethyl methyl ketone, acetonitrile and the like and finally crystallizing the amide by addition of water. In yet another variation of the process, the solvent was distilled till residual stage and the product so obtained was dried under reduced pressure or in air tray-driers. The product obtained by all the above variants revealed a similar DSC and XRPD pattern.
In the next step of converting the l-acetamido-3,5-dialkyladamantane to the corresponding aminoadamantane i.e. hydrolysis of 1-acetamidoadamantanes, the reaction is carried out in the presence of solvent and a strong inorganic base. The reaction is run at 125° to 170 °C, preferably 130° to 140 °C.
The said inorganic base is an alkali metal hydroxide like sodium hydroxide or potassium hydroxide. The said solvent used in hydrolysis step is selected from the group consisting of diethylene glycol or polyethylene glycol.
The solvent used is in the range of 4 to 12 v/w, preferably 5 to 8 v/w and the base employed is in the range of 6 to 14 moles, preferably 8 to 10 moles. Reaction times may vary from 6 to 18 hrs.
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After completion of the reaction, the dark reaction mixture is poured into ice-cold water and the product amine is extracted in an organic solvent such as toluene or diisopropyl ether. The product is optionally isolated as oil upon evaporation of the solvent, or is directly converted to the acid addition salt commonly the hydrochloride. The amine so obtained is dissolved in an alcohol, preferably methanol and the acid is added slowly as either an alcoholic solution or an aqueous solution. Upon evaporation of the alcohol and optionally slurring in a solvent selected from ethers, ketones, esters and hydrocarbons, the amino-adamantane salt is filtered under suction and dried at 50 °C to 90 °C, preferably between 70 °C - 80 °C, optionally employing reduced pressures.
The 1-aminoadamantane salts so formed by the process according to the present invention are optionally purified by way of recrystallization from glacial acetic acid.
According to another aspect of the present invention, there is provided an improved process for the preparation of 1-aminoadamantanes and acid addition salts thereof.
The said process according to the second aspect of the invention comprises the steps of a) Reacting the adamantane of formula (II) with an acid and a nitrile to give 1 -amidoadamantane of formula (IV)

(II) (IV),
in which R1, R2 and R3 are identical or different and are either 'H' or straight or branched C1 to C6 alkyl groups,
b) Hydrolyzing 1-amidoadamantane (IV) to give 1-amino-adamantane of
formula (I).
c) Converting 1-amino-adamantane (I) into its pharmaceutically acceptable
salts.
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The said process according to second aspect of the present invention is as depicted in scheme-VI below;
Scheme-VI
In the said process according to the second aspect of the present invention as depicted in scheme-VI, the adamantane and the nitrile are directly treated with an acid catalyst such as sulphuric acid to yield the acetamidoadamantane (IV). The reaction is carried out between 30° to 70 °C, preferably between 40° to 70 °C and more preferably between 50-60 °C. The reaction is carried out in a neat condition, without employing any other added solvent and / or reagents.
In a preferred embodiment of the present invention, the concentrated sulphuric acid is. added to a solution of 1,3-dimethyladamantane in acetonitrile. The exothermicity of the reaction is carefully controlled by controlling the rate of addition of sulphuric acid. The molar ratio of DMA: Acetonitrile: Sulphuric acid is preferably kept at 1: 5: 12; although definite modifications in the molar ratios can be made by skilled artisans in order to suit the process simplicity.
After completion of the reaction, the reaction mixture is poured in ice and the isolation of product is carried out as mentioned earlier.
Further the present invention relates to an improved process for the preparation of 1-aminoadamantanes of formula (I) or acid addition salts thereof, wherein the said 1-aminoadamantanes are prepared according to any one of the above mentioned process, but without isolating the intermediates formed. Thus 1-aminoadamantanes formed in
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such one-pot process advantageously avoids the steps like isolation or purification of intermediates, and thus making it cost-effective and operationally advantageous.
According to the third aspect of the present invention there is provided another improved process for the preparation of 1-aminoadamantanes and pharmaceutically acceptable salts thereof starting from 1 -hydroxyadamantanes.
The said process according to the third aspect of the present invention comprises the steps of
a) Reacting 1 -hydroxyadamantane of formula (V) with formic acid to form
formate ester of formula (VI)

(V) (VI);
b) Optionally isolating the said formate ester (VI);
c) Reacting it with nitrile to give 1 -amidoadamantane of formula (IV)

(IV); d) Hydrolyzing 1-amidoadamantane (IV) to give 1 -amino-adamantane of
formula (I), f) Converting 1-amino-adamantane (I) into its pharmaceutic ally acceptable
salts.
The said process according to the third aspect of the present invention is as depicted in scheme-VII below.
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Scheme-VII
According to the third aspect (scheme-VII) of the present invention, the hydroxyadamantane and the nitrile are treated with formic acid to give the acetamidoadamantane. As per a preferred embodiment of the present invention, the 1-hydroxy-3;5-dimethyladamantane is treated with formic acid to give the corresponding formate ester, which is optionally isolated. The said in-situ formed formate ester is converted to the l-acetamido-3,5-dimethyI adamantane, in presence of Acetonitrile-formic acid.
According to further aspect, the present invention relates to the purification of aminoadamantanes or pharmaceutically acceptable salts thereof, wherein the said purification is carried out via recrystallization from glacial acetic acid.
In a particular embodiment of the present invention, it relates to the purification of the Memantine HC1 salt. Memantine HC1 normally contains impurities arising either from degradation of the product or the intermediates used therein, or the carry over of the intermediate, or related impurities arising from the impurities present in the starting material viz the 1,3-dimethyl adamantane. Impurities arising from the carry over of the intermediates can be taken care of by mere washing the acid addition salt of the amino-
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adamantane with a suitable organic solvent selected from a group of ketones, ethers, esters, aromatic or aliphatic hydrocarbons and chloro-hydrocarbons and mixtures thereof, which are capable of dissolving the intermediates preferentially w.r.t. the said salt. 1,3-Dimethyl adamantane, may contain impurities such as 1-methyl adamantane and 1,3,5-trimethyl adamantane, which impurities are generally carry forwarded to the final stage. It has however been observed that these impurities need to be controlled at the raw-material stage itself in order to avoid for losses during final purification. Contrary to this, purification of the hydrochloride salt from acetic acid reduces the level of one of the impurities viz; 1 amino-3-methyl adamantane hydrochloride, to a considerable extent. It thus resolves the problems of laborious purifications, which are often accompanied by a huge yield loss, which would be necessary in order to achieve a material passing as per the quality directives of the ICH- Q7A guidelines. Usually crystallization of the hydrochloride may be performed in 4 -10 v/w of glacial acetic acid depending on the level of impurity present.
In a particular embodiment of the present invention, the Memantine hydrochloride is purified via recrystallization from glacial acetic acid comprising the steps of suspending memantine hydrochloride in glacial acetic acid; heating to 70 °C to 75 °C till complete dissolution; gradually cooling the solution to 25 °C to 30 °C; filtering the solid precipitate; and finally washing with an organic solvent. The said organic solvent is selected from the group consisting of ketones, esters or ethers; preferably the solvent used is ethyl acetate. The Memantine hydrochloride obtained by process according to present invention has purity of greater than 98%, preferably greater than 99.5%.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the said invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as defined herein above and as exemplified and claimed herein below.
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Examples:
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
1) l-Bromo-3,5-dimethvl adamantane:
To 1,3-dimethyladamantane (200 g) at 20-25 °C is added liquid bromine(315 mL) slowly over a period of 15-20 mins. The reaction mixture is then stirred at ambient temperature for further 8-12 hrs monitoring the progress of the reaction on GC. After completion of the reaction the reaction mixture is diluted with dichloromethane (1.6 L) and cooled to 0-5 °C. Excess bromine is decomposed by slow addition of 5-10 % solution of sodium bisulphite, maintaining the temperature of the reaction mixture below 10 °C. The phases are allowed to settle and the organic phase is separated, washed with water and the solvent MDC evaporated under atmospheric pressure, finally degassing under reduced pressure, to give l-bromo-3,5-dimethyladamantane as yellowish colored oil (280-290 g).
2) 1 -Acetamido-3,5-dimethyl adamantane from l-Bromo-3,5-dimethyl adamantane:
To l-Bromo-3,5-dimethyl adamantane (280 g) is added acetonitile (336 mL) and formic acid (about 85%; 336 mL) in one lot at 25-30 °C. The biphasic reaction mixture is stirred and gradually heated to 85-90 °C. In almost an hour at 85-90 °C, the reaction mixture becomes homogenous. The reaction is maintained at this temperature for further 3 hrs. After completion of the reaction as monitored on GC, the contents are cooled to 50-55 °C. The clear reaction mass is quenched in an ice cold water in a thin stream. Agitation is continued for 15-20 mins. The solid product so obtained is filtered under suction, washed with water and dried in air oven at 50-55 °C. Yield: 240-245 g
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3) 1- Amino-3,5-dimethyl adamantane:
To a suspension of l-Acetamido-3,5-dimethyl adamantane (200 g) in diethyleneglycol (1.2 L) is added sodium hydroxide (435 g) in one lot. The reaction mixture is stirred while heating to 130-135 °C. Reaction is maintained at this temperature for further 8-12 hrs. Progress of the reaction is monitored by GC. After completion of the reaction, the contents are quenched in ice cold water. Product is extracted in toluene (1 L). The toluene layer washed with water and solvent evaporated under reduced pressure below 70 °C. The product is obtained as brown oil (150-160 g)
4) 1- Amino-3,5-dimethyl adamantane hydrochloride:
To a solution of 1- Amino-3,5-dimethyl adamantane (140 g) in methanol (700 mL) at 15-20 °C is added slowly concentrated HC1 till pH 2-3. The clear solution is warmed to 45-50 °C, charcoalized. The filtrate is evaporated under atmospheric pressure, till residual stage. The solid thus obtained is slurried in acetone, stirred for lhr, before cooling to 10-15 °C. The product is filtered under suction and washed with acetone and dried at 75-80 °C for 8-10 hrs.
5) l-Acetamido-3,5-dimethyl adamantane from 1,3-dimethyl adamantane:
To a mixture 1,3-dimethyl adamantane (200 g) and Acetonitrile (300 mL) maintained at 50-55 °C is added dropwise concentrated sulphuric acid (800 mL), maintaining the exotherm at 55 + 5 °C. After complete addition of the sulphuric acid, the reaction mixture is maintained at 55 °C till completion of the reaction (1-3 hrs). The reaction mixture is cooled to 35-40 °C and is slowly added to a biphasic mixture of ice-cold water and dichloromethane. The MDC layer separated, washed with water and distilled under atmospheric pressure till residual stage. Methanol added and distillation continued to remove the residual MDC. The reaction mixture is cooled to 30-35 °C and product precipitated by slow addition of water. The reaction mixture cooled to 15-20 °C and solid
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product so obtained is filtered under suction, washed with water and dried in air oven at 50-55 °C. Yield: 230-235 g.
6) l-Acetamido-3, 5-dimethvl adamantane from l-hydroxy-3, 5-dim ethyl
adamantane via l-formyl-3, 5-dimethvl adamantane:
To a suspension of l-hydroxy-3, 5-dimethyladamantane in 85-98 % formic acid, acetonitrile was added and heated to 90-95°C till completion of reaction. The reaction mixture is cooled to 35-40 °C and is slowly added to a biphasic mixture of ice-cold water and dichloromethane. The MDC layer separated, washed with water and distilled under atmospheric pressure till residual stage. Methanol added and distillation continued to remove the residual MDC. The reaction mixture is cooled to 30-35 °C and product precipitated by slow addition of water. The reaction mixture cooled to 15-20 °C and solid product so obtained is filtered under suction, washed with water and dried in air oven at 50-55 °C.
7) Purification of 1- Amino-3,5-dimethyl adamantane hydrochloride:
1- Amino-3,5-dimethyl adamantane hydrochloride (100 g) containing an impurity of 1-Amino-3-methyl adamantane hydrochloride (~0.30% by area) is suspended in glacial acetic acid (1L) and heated to 70-75 °C to obtain a clear solution. The solution is gradually cooled to 25-30 °C and the solid precipitated is filtered under suction, suck thoroughly and finally washed with ethyl acetate. The product is dried at 70-75 °C. Purity : 99.92% (by HPLC- area%). Yield : 78-82 gms
8) One pot process for Memantine HCl:
Method A: To 1,3-dimethyladamantane at 20-25 °C is added liquid bromine slowly over a period of 15-20 mins. The reaction mixture is then stirred at room temperature for further 8-12 hrs monitoring the progress of the reaction on GC. After completion of the
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reaction the reaction mixture is diluted with dichloromethane and cooled to 0-5 °C. Excess bromine is decomposed by slow addition of 5-10 % solution of sodium bisulphite, maintaining the temperature of the reaction mixture below 10 °C. The phases are allowed to settle and the organic phase is separated, washed with water and the solvent MDC evaporated under atmospheric pressure, finally degassing under reduced pressure, to give l-bromo-3,5-dirnethyladamantane as a yellowish colored oil. To this oil, is added acetonitile and formic acid (85% strength) in one lot at 25-30 °C. The biphasic reaction mixture is stirred and gradually heated to 85-90 °C. In almost an hour at 85-90 °C, the reaction mixture becomes homogenous. The reaction is maintained at this temperature for further 3 hrs. After completion of the reaction as monitored on GC, the contents are cooled to 50-55 °C. The clear reaction mass is quenched in an ice cold water in a thin stream and the product is extracted in toluene. Solvent toluene is distilled under reduced pressure below 60 °C, till the residual stage. To the residue is added diethylene glycol and sodium hydroxide. The contents are heated to around 120 °C, distilling the residual toluene and then raising the temperature of the reaction mass to 130-135 °C. The reaction is maintained at this temperature for 8-10 hrs. After completion of the reaction, the contents are cooled gradually to 85-90 °C and poured over ice-cold water. The reaction mixture is extracted with toluene and the toluene layer is distilled under reduced pressure below 70 °C till residual stage. The oil so obtained is diluted with methanol and cooled to 15-20 °C. To the methanolic solution is added slowly aqueous hydrochloric acid solution till pH 2-3. The clear solution is charcoalized and the filtrate evaporated atmospherically till residual stage. Acetone is added to the solid so obtained and the reaction mass is cooled to 15-20 °C and filtered under suction.
Method B:
To a mixture 1,3-dimethyl adamantane and acetonitrile maintained at 50-55 °C is added dropwise concentrated sulphuric acid, maintaining the exotherm at 55 + 5 °C. After complete addition of the sulphuric acid, the reaction mixture is maintained at 55 °C till completion of the reaction (1-3 hrs). The reaction mixture is cooled to 35-40 °C and is slowly added to a biphasic mixture of ice-cold water and dichloromethane. The MDC
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layer separated, washed with water and distilled under atmospheric pressure till residual stage. Toluene added and distillation continued to remove the residual MDC. To the residue is added diethylene glycol and sodium hydroxide. The contents are heated to around 120 °C, distilling the residual toluene and then raising the temperature of the reaction mass to 130-135 °C. The reaction is maintained at this temperature for 8-10 hrs. After completion of the reaction, the contents are cooled gradually to 85-90 °C and poured over ice-cold water. The reaction mixture is extracted with toluene and the toluene layer is distilled under reduced pressure below 70 °C till residual stage. The oil so obtained is diluted with methanol and cooled to 15-20 °C. To the methanolic solution is added slowly aqueous hydrochloric acid solution till pH 2-3. The clear solution is charcoalized and the filtrate is evaporated atmospherically till the residual stage. Acetone is added to the solid slurry so obtained and the reaction mass is cooled to 15-20 °C and filtered under suction.
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Claim:
A process for the preparation of 1-amino-adamantanes of formula (I) and pharmaceutically acceptable salts thereof

in which R1, R2 and R3 are identical or different and are either 'H' or a straight or
branched C1 to C6 alkyl groups,
wherein the said process comprises the steps of
a. Halogenating the adamantane of formula (II) using a halogenating agent to give 1-haloadamantane of formula (III)

(II) (III)
in which, X is Br, CI and R1, R2 and R3 have the meaning same as above; b. Reacting 1-haloadamantane of formula (III) with an acid and a nitrile to give 1-amidoadamantane of formula (IV)

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c. Hydrolyzing 1-amidoadamantane (IV) to give I -amino-adamantane of
formula (I);
d. Converting 1-amino-adamantane (I) into its pharmaceutically
acceptable salts.
2. A process of claim la, wherein the intermediates viz. 1-bromoadamantane of formula (III) is optionally isolated or purified before further reaction.
3. A process of claim 1 and claim 2, wherein the 1-haloadamantane of formula (III) may contain an impurity of 1-hydroxy-adamantane of formula (V).

4. A process of claim 1-b), wherein the said acid used is formic acid; and the said nitrile used is acetonitrile.
5. A process of claim 1-c), wherein the hydrolysis of 1-amidoadamantane comprises, treating the amide with a base in the presence of a solvent at an elevated temperature.
6. A process as claimed in claim 5, wherein the said base employed is an alkali metal hydroxide selected from the group consisting of NaOH or KOH.
7. A process as claimed in claim 5, wherein the said solvent employed is selected from the group consisting of glycols or alcohols or mixtures thereof.
8. A process for the preparation of 1 -amino-adamantanes of formula (I) or pharmaceutically acceptable salts thereof
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in which R1, R2 and R3 are identical or different and are either 'H' or a straight or branched C1 to C6 alkyl groups, wherein the said process comprises the steps of
a. Reacting the adamantane of formula (II) with an acid and a nitrile to give 1-amidoadamantane of formula (IV)

wherein R1, R2 and R3 have the meaning same as above
b. Hydrolyzing 1-amidoadamantane (IV) to give 1-amino-adamantane of
formula (I).
c. Converting 1-amino-adamantane (I) into its pharmaceutically acceptable
salts.
9. A process of claim 8-a), wherein the said acid used is sulphuric acid and the said nitrile used is acetonitrile.
10. A process of claim 8-b). wherein the hydrolysis of 1-amidoadamantane comprises treating the amide with a base in the presence of a solvent at an elevated temperature.
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11. A process as claimed in claim 10, wherein the said base employed is an alkali metal hydroxide selected from the group consisting of NaOH or KOH.
12. A process as claimed in claim 10, wherein the said solvent employed is selected from the group consisting of glycols or alcohols or mixture thereof.
13. A process for the preparation of 1-amino-adamantanes of formula (I) comprising the steps as claimed claim 1 and 8, wherein the intermediates are not isolated before further reactions.
14. A process for the preparation of 1-amino-adamantanes of formula (I) or pharmaceutically acceptable salts thereof

in which R1, R2 and R3 are identical or different and are either 'H' or a straight or
branched C1 to C6 alkyl groups,
wherein the said process comprises the steps of
a. Reacting 1-hydroxyadamantane of formula (V) with formic acid to form
formate ester of formula (VI)

wherein R1, R2 and R3 have the meaning same as above
b. Reacting the in-situ formed formate ester (VI) with nitrile to form 1-
amidoadamantane of formula (IV)
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c. Hydrolyzing 1-amidoadamantane (IV) to give 1-amino-adamantane of
formula (I), and
d. Converting 1-amino-adamantane (I) into its pharmaceutically acceptable
salts.
15. A process of claim 14-b), wherein the said nitrile used is acetonitrile.
16. A process of claim 14-c), wherein the hydrolysis of 1-amidoadamantane comprises treating the amide with a base in the presence of a solvent at an elevated temperature.
17. A process as claimed in claim 16, wherein the said base employed is an alkali metal hydroxide selected from the group consisting of NaOH or KOH.
18. A process as claimed in claim 16, wherein the said solvent employed is selected from the group consisting of glycols or alcohols or mixtures thereof.
19. 1-Aminoadamantanes obtained in accordance with the claims 1, 8 and 14.
20. The 1 -Aminoadamantane as claimed in claim 19 is 1 -amino-3,5-dimethyl adamantane and the pharmaceutically acceptable salts thereof.
21. A process for purification of l-amino-3,5-dimethyl adamantane hydrochloride, comprising of recrystallization from acetic acid.
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22. A process according to any of the preceding claims as substantially herein described with reference to the examples.
Dated this 15th day of September, 2008
For Unichem Laboratories Limited

K. Subharaman
Head - Legal & Company Secretary
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