FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(see section 10 and rule 13)
Benzylation process in aqueous medium for controlling donepezil benzyl chloride impurity in manufacture of donepezil hydrochloride
PIRAMAL ENTERPRISES LIMITED, a company incorporated under the Companies Act 1956, of Piramal Tower, Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400 013, States of Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed

Field of the invention
The present invention relates to a process for the preparation of 2,3-dihydro-5,6-
dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]-lH-inden-l-one
hydrochloride, which is known as "donepezil hydrochloride" and represented herein
by Formula I. More particularly, the present invention provides a green process for
the preparation of donepezil hydrochloride controlling a donepezil benzyl chloride
impurity, 4-[(2,3-dihydro-5,6-dimethoxy-1 -oxo-1 H-inden-2-yl)methyl]-1,1-
bis(phenylmethyl) piperidinium chloride to < 0.02%.
Background of the invention
Donepezil hydrochloride is chemically known as 2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]-lH-inden-l-one hydrochloride and it is structurally represented by the following formula I (wherein X is HC1). It is an active ingredient of Aricept®, which is available in the market for oral administration as film-coated tablets.

wherein X is as defined herein
Donepezil is developed for the treatment of Alzheimer's disease, which is an age-related and progressive neurodegenerative disease, characterized by deficits in memory and cognitive function. Remarkable dysfunction of the cholinergic system has been observed in several brain regions of patients suffering from Alzheimer's

disease [Bowen et al., 1976], [Davis and Maloney, 1976], [Perry et al., 1977] and [Whitehouse et al, 1982], and was shown to be correlated with the severity of cognitive impairment (Perry et al., 1978). These pathological findings, in addition to the fact that the cholinergic system plays a role in memory functions (Drachman, 1977), have led to the hypothesis that enhancing cholinergic neurotransmission with cholinergic agents may ameliorate the cognitive impairment in Alzheimer's disease. Although many attempts have been made to reverse the cognitive impairment by using cholinergic agents, cholinesterase inhibitors are the only class of drugs currently approved for the treatment of Alzheimer's disease in Europe and by the US Food and Drug Administration (FDA). Thus, the piperidine-based, acetylcholinesterase inhibitor, donepezil hydrochloride was approved by the US FDA in 1996, and is now being prescribed worldwide.. Donepezil is a well-tolerated drug that improves cognitive performance and global function in patients with mild to moderate Alzheimer's disease.
The prior arts references provide an enormous literature for the preparation of donepezil or its pharmaceutically acceptable salts such as the hydrochloride salt represented by formula I. Generally, the process for the preparation of donepezil or its pharmaceutically acceptable -salts involves benzylation of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyI)-lH-inden-l-one or its salts represented by formula II (hereinafter referred to as compounds of Formula II) using benzyl halide in the presence of a base and an organic solvent or biphasic solvents and optionally, in the presence of a phase transfer catalyst to yield donepezil or its pharmaceutically acceptable salts. The process disclosed in the prior arts references mainly involves use of large volume of organic solvents or biphasic solvents thereby rendering the process expensive and industrially disadvantageous, as the organic solvents such as ethanol, dimethylformamide, methylene dichloride or toluene, etc. used in the industry being volatile in nature, use of which inevitably leads to environmental damage through pollution, risks to human health and to resource depletion.
Also, benzylation of the compound of formula II using benzyl halide generates a donepezil benzyl chloride impurity, 4-[(2,3-dihydro-5,6-dimethoxy-l-oxo-lH-inden-2-yl)methyl]-l,l-bis(phenylmethyl)piperidinium chloride represented by

formula IV. The processes disclosed in prior arts for the removal of donepezil benzyl chloride impurity of formula IV involves use of ethyl acetate as a solvent. However the inventors of the present invention observed that, the donepezil obtained after treatment with ethyl acetate does not qualify the required pharmaceutically acceptable grade of donepezil hydrochloride. According to the US Pharmacopeia USP 35 the limit of the donepezil benzyl chloride impurity of formula IV, present in donepezil hydrochloride is not more than 0.15% (<0.15%).

The general process for the preparation of donepezil or its pharmaceutically acceptable salts, the compound of formula I from the compound of formula II is depicted herein below:


wherein in the compound of formula II, X© = 4-methylbenzenesulfonate, chloride,
sulfate
in the compound of formula I, X is a phosphate, a sulfate, 4-
methylbenzenesulfonate or hydrochloride
US Patent No. 7,148,354 discloses a process for the preparation of donepezil comprising benzylation of solution of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-l-one (free base of the compound of formula II) in ethanol with benzyl bromide in the presence of sodium carbonate as a base at a

temperature of 55° C to 60°C with stirring for 6 hours. The reaction mixture was then cooled to room temperature and then filtered. To the filtrate then added water and the resulting aqueous solution was extracted with toluene. The separated toluene layer was then concentrated to yield donepezil after treatment with petroleum ether. The process disclosed in said patent describes use of 15 volume of organic solvent for the benzylation of free base of the compound of formula II.
US Patent Application Publication No. 2007/0072905 discloses a process for the preparation of donepezil and its pharmaceutically acceptable salts comprising benzylation of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-l-one p-toluenesulfonate salt (the compound of formula II) with benzyl bromide in the presence of potassium carbonate as a base and dimethylformamide as a solvent with stirring till completion of the reaction. To the resulting reaction mixture then added water and extracted four times each with 30ml of ethyl acetate. The extracted ethyl acetate layers combined and dried under vacuum to yield donepezil. The above disclosed benzylation process involves use of 55.5 volume of dimethylformamide.
PCT Application Publication No. 2004/082685 discloses a process for the preparation of donepezil hydrochloride comprising the steps of: (i) benzylation of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-l-one hydrochloride (the compound of formula II) with benzyl bromide using tetrabutyl ammonium bromide as a phase transfer catalyst and potassium carbonate as a base in the presence of a mixture of water and dichloromethane as a solvent at a temperature of 20°C to 25°C for 30 minutes to obtain the reaction mixture containing organic and aqueous layer, (ii) the resulting organic layer was separated and stirred with a mixture of water and hydrochloric acid at a temperature of 20°C to 25°C for 15 minutes, (iii) the organic layer formed was separated and concentrated to obtain the residue, (iv) the residue obtained was dissolved in water and the resulting solution was extracted with ethyl acetate; the pH of the reaction mixture was adjusted to 9.5 with aqueous ammonia solution, (v) the reaction mixture was then extracted with ethyl acetate and the separated ethyl acetate layer was washed with water, (vi) the ethyl acetate layer was then concentrated to obtain the residue. The obtained residue

was then treated with hydrochloric acid in the presence of methanol followed by treatment with diisopropyl ether to yield donepezil hydrochloride. The process disclosed in said patent application teaches use of a biphasic solvent system, that is mixture of water and methylene dichloride as a solvent. Also, the process involves use of phase transfer catalyst for the benzylation of compound of formula II.
US Patent Application Publication No. 2007/0135644 discloses a process for the preparation of donepezil comprising benzylation of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-l-one (free base of the compound of formula II) with benzyl chloride in the presence of sodium bicarbonate as a base and 12.5 volumes of toluene as a solvent at a bath temperature of 145°C for 8 hours. The resulting reaction mixture was then cooled and filtered. The filtrate washed with demineralised water and toluene and the obtained toluene phase evaporated to yield donepezil.
The donepezil obtained using above said process is then treated with ethyl acetate over 12 hours to remove the donepezil benzyl chloride impurity of formula IV. The obtained donepezil further converted to the donepezil hydrochloride using hydrochloric acid in the presence of ethyl acetate.
However, the inventors of the present invention carried out reaction of donepezil with ethyl acetate as described in the US patent appln. and observed that, the donepezil obtained after the treatment with ethyl acetate contains > 0.2% of donepezil benzyl chloride impurity of formula IV, which does not qualify required criteria for the impurity of formula IV, <0.15%.
The process for the preparation of donepezil or its pharmaceutically acceptable salts (compound of formula I) can be improved particularly in terms of industrial applicability by providing cost-effective and efficient process for the preparation of product, that would also result in obtaining said product in good yield and purity. The process for the preparation of donepezil or its pharmaceutically suitable salts disclosed in the prior art references involves use of large volume of organic solvents.
Thus, there is a need to develop an improved process for the preparation of donepezil or its pharmaceutically acceptable salts (the compound of Formula I) from the

compound of formula II, that avoids use of large volume of organic solvent and provides a green process for the industrial manufacturing of donepezil or its pharmaceutically acceptable salts containing a donepezil benzyl chloride impurity represented by formula IV to < 0.02%, which is efficient, cost-effective and industrially viable process for the preparation of donepezil hydrochloride.
Objects of the invention
An object of the present invention is to provide an improved process for the
preparation of 2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-
piperidinyl]methyl]-lH-inden-l-one hydrochloride (donepezil hydrochloride) represented by formula I of pharmaceutically acceptable grade from 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-l-one, 4-methylbenzenesulfonate salt represented by formula II.
Another object of the present invention is to provide a process for the preparation of donepezil hydrochloride represented by formula I wherein, the benzylation of the compound of formula II is carried out using an aqueous medium thereby avoiding use of large volume of organic solvent and controlling the donepezil benzyl chloride impurity of formula IV < 3%.
Another object of the present invention is to provide a process for the preparation of donepezil hydrochloride represented by formula I wherein, the donepezil benzyl chloride impurity of formula IV contained in donepezil is controlled to < 0.02% using a mixture of ethyl acetate and hexane in the molar ratio of 1:1.
Still another object of the present invention is to provide a process for the preparation of donepezil hydrochloride represented by formula I which is eco-friendly, efficient and industrially applicable.

Summary of the invention
In accordance with the aspect of the present invention, there is provided an improved
process for the preparation of 2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-
piperidinyl]methyl]-lH-inden-l-one hydrochloride (donepezil hydrochloride)
represented by formula I comprising the steps of: (i) benzylation of 2,3-dihydro-5,6-
dimethoxy-2-(4-piperidinylmethyl)-lH-inden-l-one 4-methylbenzenesulfonate
represented by formula II with benzyl halide using a base in the presence of an aqueous medium to yield donepezil of formula la having controlled donepezil benzyl chloride impurity represented by formula IV, (ii) treating the donepezil obtained in step (i) with a mixture of ethyl acetate and hexanes to obtain a reaction mixture containing donepezil with controlled donepezil benzyl chloride impurity of formula IV, (iii) converting the donepezil contained in the reaction mixture obtained in step (ii) to donepezil hydrochloride of formula I of pharmaceutically acceptable grade.
The process of the present invention is depicted in the following scheme:


In accordance with another aspect of the present invention, the process of the present invention overcomes the disadvantageous associated with the processes described in the prior art, which mainly concerns with the use of large volume of organic solvents. The process of the present invention utilizes an aqueous medium in the

reaction step involving benzylation of the compound of formula II, thereby making the instant process industrially applicable and eco-friendly. Accordingly, the process of the present invention is referred to as green process.
In accordance with yet another aspect of the present invention, the process of the present invention provides donepezil of formula la, wherein the donepezil benzyl chloride impurity of formula IV is controlled to < 0.02%, thereby making the process industrially applicable.
In accordance with further aspect of the present invention, the process of the present invention provides a green chemistry for the preparation of donepezil hydrochloride represented by formula I containing < 3% of donepezil benzyl chloride impurity of formula IV from the 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-1-one 4-methylbenzene sulfonate, of formula II. The basic idea of green chemistry is to increase production efficiency while at the same time eliminating or at least minimizing wastes and emissions at their source rather than treating them at the end of the reaction after they have been generated. Green chemistry is considered an essential part of a comprehensive program to protect human health and the environment.
Detailed description of the invention
The present invention relates to a process for preparation of 2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]-lH-inden-l-one hydrochloride (donepezil hydrochloride) represented by the following formula I


comprising the steps of:
(i) benzylation of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-1-one 4-methylbenzenesulfonate represented by the following formula II

with benzyl halide using a base in the presence of an aqueous medium to yield donepezil of formula la


having controlled donepezil benzyl chloride impurity, 4-[(2,3-dihydro-5,6-dimethoxy-1 -oxo-1 H-inden-2-yl)methyl]-1,1 -bis(phenylmethy])piperidinium chloride < 3% and represented by formula IV,

(ii) treating the donepezil obtained in step (i) with a mixture of ethyl acetate and hexanes to yield donepezil having controlled donepezil benzyl chloride impurity < 0.02%,
(iii) converting the donepezil obtained in step (ii) to donepezil hydrochloride represented by formula I of pharmaceutically acceptable grade.

In an embodiment of the present invention, in the step (i) of the process said benzylation of compound of formula II with benzyl halide is carried out using a base in the presence of an aqueous medium to yield donepezil of formula la, wherein the donepezil benzyl chloride impurity represented by formula IV is controlled to < 3%.
In accordance with the embodiment of the present invention, in the step (i) of the process said benzylation of the compound of formula II with benzyl halide is carried out in the presence of demineralised water as an aqueous medium.
In accordance with the embodiment of the present invention, in the step (i) of the process benzyl halide used for the benzylation of compound of formula II is selected from benzyl chloride or benzyl bromide.
In accordance with the embodiment of the present invention, in the step (i) of the process said benzylation of compound of formula II using benzyl halide is carried out using 0.8 to 2.0 mole equivalent of benzyl halide based on the compound of formula II.
In accordance with the embodiment of the present invention, in the step (i) of the process benzylation of compound of formula II is carried out in the presence a mixture of potassium carbonate and sodium hydroxide as the base.
In accordance with the embodiment of the present invention, in the step (i) of the process benzylation of compound of formula II is carried out using 1.5 to 3.0 mole equivalent of potassium carbonate based on the compound of formula II.
In accordance with the embodiment of the present invention, in the step (i) of the process, benzylation of compound of formula II is carried out using 5.0 to 8.0 mole equivalent of sodium hydroxide based on the compound of formula II.
In accordance with the embodiment of the present invention, the benzylation of compound of formula II is carried out using benzyl halide in the presence of an

aqueous medium at a temperature of 40°C to 45°C for 4 to 6 hours to obtain donepezil of formula la having controlled donepezil benzyl chloride impurity < 3%.
It is observed that when benzylation of compound of formula II is carried out using
an organic solvent, the compound, donepezil formed in the reaction mixture gets
further benzylated to form a donepezil benzyl chloride impurity, 4-[(2,3-dihydro-5,6-
dimethoxy-1-oxo-1 H-inden-2-yl)methyl]-l,l-bis(phenylmethyl) piperidinium
chloride, represented by formula IV, which renders decrease in the yield of compound of formula la. In accordance with the process of the present invention, the use of aqueous medium for the benzylation of compound of formula II, avoiding use of organic solvents, reduces the generation of donepezil benzyl chloride impurity of formula IV to < 3%. It is observed that when the benzylation of compound of formula II is carried out using aqueous medium such as demineralised water as a solvent, the generation of donepezil benzyl chloride impurity of formula IV is controlled to < 3%.

In accordance with the embodiment of the present invention, the inventors of the present invention further improvised on the process to reduce the donepezil benzyl chloride impurity of formula IV controlled in the reaction mixture containing donepezil to < 0.02%.

In accordance with the embodiment of the present invention, the donepezil obtained in step (i) is further treated with a mixture of ethyl acetate and hexanes at a temperature of 20°C to 55°C for 20 minutes to 60 minutes to yield donepezil with controlled donepezil benzyl chloride impurity of formula IV to < 0.02%.
In accordance with the embodiment of the present invention, the mixture of ethyl acetate and hexane is used in the mole ratio of 1:1.
In accordance with the embodiment of the present invention, donepezil treated with mixture of ethyl acetate and hexane using 5 volumes, based on the compound of formula la.
In accordance with the embodiment of the present invention, the process further comprises treatment with charcoal at a temperature of 20°C to 55°C to yield donepezil of formula la.
In an another embodiment of the present invention, in step (iii) of the process the donepezil of formula la obtained in step (ii) is converted to its hydrochloride salt represented by formula I.
In accordance with the embodiment of the present invention, in the step (iii) of the process the obtained donepezil of formula la treated with concentrated hydrochloric acid in the presence of ethanol as a solvent at a temperature of 10°C to 15°C to yield donepezil hydrochloride represented by formula I of pharmaceutically acceptable grade.
In accordance with the embodiment of the present invention, in the step (ii) of the process the pH of the reaction mixture is 2.
In accordance with the embodiment of the present invention, the term, "pharmaceutically acceptable grade" refers to the donepezil hydrochloride of formula I obtained using the process of the present invention, which contains the donepezil

benzyl chloride impurity of formula IV not more than 0.15% and total organic impurities not more than 0.5%, as disclosed in U.S. Pharmacopeia USP 35.
In accordance with the embodiment of the present invention, the term, "controlled donepezil benzyl chloride impurity represented by formula IV" refers to the donepezil hydrochloride of formula I obtained using the process of the present invention, which contains the donepezil benzyl chloride impurity of formula IV not more than 0.15%, as disclosed in U.S. Pharmacopeia USP 35.
According to the present invention, the starting material, 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-l-one 4-methylbenzenesulfonate (the compound of formula II), charged to the reaction flask containing aqueous medium such as demineralised water . To the reaction mixture then charged a solution of base such as mixture of potassium carbonate and sodium hydroxide solution in demineralised water and heated the reaction mixture at a temperature of 40°C to 45°C. To the reaction mixture then added benzyl chloride lot wise at a temperature of 40°C to 45°C. The resulting reaction mixture heated at a temperature of 40°C to 45°C for 2 hours (at this stage the reaction mixture monitored for the consumption of compound of formula II). The obtained reaction mixture is allowed to cool to 20°C to 25°C. To the reaction mixture then charged dichloromethane and allowed to stir the reaction mixture for 30 minutes, the two layers formed were separated. The aqueous layer extracted twice with dichloromethane. The dichloromethane layers combined and distilled under vacuum at a temperature of 35°C to 40°C under vacuum (at this stage donepezil obtained contains < 3% of donepezil benzyl chloride impurity of formula IV). The resulting reaction mixture then heated at a temperature of 50°C to 55°C under vacuum for 1 hour. To the reaction mixture then charged ethyl acetate and hexanes and heated the reaction mixture at a temperature of 25°C to 55°C for 20 minutes to 60 minutes. The obtained reaction mixture is allowed to cool to 20°C to 25°C and then filtered. The filtrate obtained is then treated with charcoal and distilled under vacuum at a temperature of 50°C to 55°C under vacuum to yield donepezil containing < 0.08% of donepezil benzyl chloride impurity represented by formula IV.

To the another reaction flask charged donepezil of formula la and ethanol and heated the reaction mixture at a temperature of 50°C for 30 minutes. The resulting reaction mixture is then cooled at a temperature of 10°C to 15°C. To the reaction mixture then dropwise added concentrated hydrochloric acid and stirred at a temperature of 10°C to 15°C for 30 minutes, at this stage the pH of the reaction mixture is 2. The resulting reaction mixture then treated with diisopropylether at a temperature of 20°C to 25°C to precipitate the product, donepezil hydrochloride. The precipitated product is then filtered and washed with diisopropylether and dried under vacuum to yield donepezil hydrochloride.
The starting material of the process, 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-l-one, 4-methylbenzenesulfonate (the compound of formula II) is a known compound and can be prepared by a person skilled in the art by following the processes known in the art. For example the compound of formula II can be prepared by following the process disclosed in the US Patent No. 2007/0072905, which is incorporated herein by reference. The process involves reaction of 2,3-dihydro-5,6-dimethoxy-2-(4-pyridinylmethylene)-lH-inden-l-one 4-methylbenzenesulfonate with platinum dioxide (PtO2) in the presence of methanol as a solvent at a room temperature at 1 atmosphere for 7 hours to obtain the residue. The residue obtained was then filtered and concentrated under vacuum to yield the compound of formula II.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be considered in anyway to limit the scope of the present invention.
Examples
Example 1:
To the reaction flask charge compound of formula II (l00g), demineralised water (1000ml), and a solution of mixture of potassium carbonate (68.9g) and sodium hydroxide (58.9g) in demineralised water and heated the reaction mixture at a

temperature of 40°C to 45°C. Then benzyl chloride added to the reaction mixture lot wise at a temperature of 40°C to 45°C. The resulting reaction mixture heated at a temperature of 40°C to 45°C for 2 hours and then cooled to 20°C to 25°C. To the reaction mixture then charged dichloromethane and allowed to stir the reaction mixture for 30 minutes, the two layers formed were separated. The aqueous layer extracted twice with dichloromethane. The dichloromethane layers combined and distilled under vacuum at a temperature of 35°C to 40°C under vacuum. The resulting reaction mixture is then heated at a temperature of 50°C to 55°C under vacuum for 1 hour. To the reaction mixture then charged ethyl acetate and hexanes and heated the reaction mixture at a temperature of 25°C to 55°C for 20 minutes to 60 minutes. The obtained reaction mixture is allowed to cool to 20°C to 25°C and then filtered. The filtrate obtained is then treated with charcoal and distilled under vacuum at a temperature of 50°C to 55°C under vacuum to yield donepezil.
To another reaction flask charged obtained donepezil of formula Ia and ethanol and heated the reaction mixture at a temperature of 50°C for 30 minutes. The resulting reaction mixture is then cooled at a temperature of 10°C to 15°C. To the reaction mixture then dropwise added concentrated hydrochloric acid and stirred at a temperature of 10°C to 15°C for 30 minutes, at this stage the pH of the reaction mixture is 2. The resulting reaction mixture then treated with diisopropylether at a temperature of 20°C to 25°C to precipitate the product, donepezil hydrochloride. The precipitated product is then filtered and washed with diisopropylether and dried under vacuum to yield donepezil hydrochloride. Yield 63%, purity 99.85% and donepezil benzyl chloride impurity represented by formula IV 0.07%.
Example 2:
To the reactor charge compound of formula II (22Kg), demineralised water (220L), and a solution of mixture of potassium carbonate (15.1Kg) and sodium hydroxide (12.98Kg) in demineralised water and heated the reaction mixture at a temperature of 40°C to 45°C. Then benzyl chloride added to the reaction mixture lot wise at a temperature of 40°C to 45°C. The resulting reaction mixture heated at a temperature of 40°C to 45°C for 10 hours and then cooled to 20°C to 25°C. To the reaction mixture then charged dichloromethane and allowed to stir the reaction mixture for 30

minutes, the two layers formed were separated. The aqueous layer extracted twice with dichloromethane. The dichloromethane layers combined and distilled under vacuum at a temperature of 35°C to 40°C under vacuum. The resulting reaction mixture is then heated at a temperature of 50°C to 55°C under vacuum for 1 hour. To the reaction mixture then charged ethyl acetate and hexanes and heated the reaction mixture at a temperature of 25°C to 55°C for 20 minutes to 60 minutes. The obtained reaction mixture is allowed to cool to 20°C to 25°C and then filtered. The filtrate obtained is then treated with charcoal and distilled under vacuum at a temperature of 50°C to 55°C under vacuum to yield donepezil.
To another reaction tlask charged obtained donepezil of formula la and ethanol and heated the reaction mixture at a temperature of 50°C for 30 minutes. The resulting reaction mixture is then cooled at a temperature of 10°C to 15°C. To the reaction mixture then dropwise added concentrated hydrochloric acid and stirred at a temperature of 10°C to 15°C for 30 minutes, at this stage the pH of the reaction mixture is 2. The resulting reaction mixture then treated with diisopropylether at a temperature of 20°C to 25°C to precipitate the product, donepezil hydrochloride. The precipitated product is then filtered and washed with diisopropylether and dried under vacuum to yield donepezil hydrochloride. Yield 63%, purity 99.85% and donepezil benzyl Chloride impurity represented by formula IV 0.02%.

We Claim:
1. A process for preparation of 2)3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-
4-piperidinyl]methyl]-1 H-inden-1 -one, hydrochloride (donepezil
hydrochloride), of formula I

comprising the steps of: (i) benzylation of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinylmethyl)-lH-inden-1 -one 4-methylbenzenesulfonate represented by the following formula II

with benzyl halide using a base in the presence of an aqueous medium to yield donepezil of formula la


having donepezil benzyl chloride impurity, 4-[(2,3-dihydro-5,6-dimethoxy-1 -oxo-1 H-inden-2-yl)methyl]-1,1 -bis(phenylmethyl)piperidinium chloride < 3% and represented by formula IV,

(ii) treating the donepezil obtained in step (i) with a mixture of ethyl acetate and hexanes to yield donepezil having the donepezil benzyl chloride impurity represented by formula IV < 0.02%,
(iii) converting the donepezil obtained in step (ii) to donepezil hydrochloride represented by formula 1 of pharmaceutically acceptable grade.

2. The process as claimed in claim 1, wherein in the step (i) benzyl halide is selected from benzyl chloride or benzyl bromide.
3. The process as claimed in claim 2, wherein said benzyl halide is used in 0.8 to 2.0 mole equivalent based on the compound of formula II.
4. The process as claimed in claim 1, wherein said aqueous medium used is demineralised water.
5. The process as claimed in claim 1, wherein in the step (i) said base is mixture of potassium carbonate and sodium hydroxide.
6. The process as claimed in claim 5, wherein said potassium carbonate is used in 1.5 to 3.0 mole equivalent based on the compound of formula II.
7. The process as claimed in claim 5, wherein said sodium hydroxide is used in 5.0 to 8.0 mole equivalent based on the compound of formula II.
8. The process as claimed in claim 1, wherein in the step (ii) the molar ratio of ethyl acetate to hexane is 1:1
9. The process as claimed in claim 1, wherein in the step (ii) the obtained donepezil treated with mixture of ethyl acetate and hexanes at a temperature of 20°C to 55°C.
10. The process as claimed in claim 8, wherein said donepezil treated with mixture of ethyl acetate and hexanes at a temperature of 20°C to 55°C from 20 minutes to 60 minutes.
11. The process as claimed in claim 1, wherein in the step (iii) the obtained donepezil treated with hydrochloric acid in the presence of ethanol as a solvent to yield donepezil hydrochloride of formula I.

12. The process as claimed in claim 1, wherein in the step (iii) the pH of the reaction mixture is 2.
13. The process as claimed in claim 1, wherein in the step (ii) the donepezil obtained having donepezil benzyl chloride impurity of formula IV < 0.02%
14. A process for preparation of 2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinyl]methyl]-1 H-inden-1 -one, hydrochloride (donepezil hydrochloride), of formula I substantially as herein described with reference to examples 1 and 2.