FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A PROCESS FOR THE PREPARATION OF DONEPEZIL HYDROCHLORIDE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of donepezil hydrochloride. Further the process of present invention provides donepezil hydrochloride substantially free of 2-((1-benzylpipehdin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1 -one hydrochloride.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides a process for the preparation of donepezil hydrochloride. Further the process of present invention provides donepezil hydrochloride substantially free of 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1 -one hydrochloride.
Donepezil is chemically known as 2,3-Dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one and is represented by following formula (I).

Donepezil, marketed under the name ARICEPT, is a reversible inhibitor of the enzyme acetylcholinesterase and is commonly referred to in the pharmacological literature as E2020. ARICEPT is indicated for the treatment of mild to moderate dementia of the Alzheimers type.
There are several patents and patent applications cited in the literature, which refer to process for the preparation of donepezil such as U.S. Patent No. 7,148,354, U.S. Patent No. 6,953,856, U.S. Patent No. 6,649,765, WO 2005/076749, WO 2007/108011 and WO 2007/057226. The polymorphs of donepezil are disclosed in U.S. Patent No. 5,985,864, U.S. Patent No. 6,140,321, U.S. Patent No. 7,186,842 and WO 2006/111983. Further, U.S. Patent No. 6,492,522 provides a process for preparing intermediates of donepezil.
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The present inventors have developed an industrially advantageous process for the preparation of donepezil hydrochloride. This involves reaction of 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1-one hydrochloride of formula (II) with a hydrogenation catalyst as depicted in scheme 1.

Hydrogenation catalyst

Donepezil Hydrochloride Scheme 1
Further the process of present invention provides donepezil hydrochloride substantially free of 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1 -one hydrochloride.
In one aspect of the present invention there is provided a process for the preparation of donepezil hydrochloride, wherein the process includes the steps of;
(a) reacting 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxy inden-1-one hydrochloride of formula (II) with a hydrogenation catalyst;

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(b) isolating donepezil hydrochloride from the reaction mixture thereof.
The process of present invention involves heating 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1-one hydrochloride of formula (II) in a solvent under stirring to get clear solution. The solution obtained thereof is cooled to 3-5 °C and hydrogenation catalyst is added to it. A slow stream of hydrogen gas is bubbled at about 5 °C under stirring. The product donepezil hydrochloride is isolated from the reaction mixture thereof. Donepezil hydrochloride obtained thereof is substantially free of 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1-one hydrochloride
The non-limiting examples of hydrogen catalyst include metal catalyst, metal oxide catalyst and the like. The non-limiting examples of metal catalysts include palladium, platinum, rhodium, ruthenium and the like. The non-limiting examples of metal oxide catalyst include platinum oxide, palladium oxide and the like. The catalyst can be supported on a carrier, such as carbon, calcium carbonate, barium sulphate, or alumina.
The non-limiting examples of solvent include polar protic and polar aprotic solvent. The non-limiting examples of polar protic solvent include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-methoxyethanol, or mixtures thereof. The non-limiting examples of polar aprotic solvent include tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide, N-methyl pyrrol idone, acetonitrile, acetone, ethylmethyl ketone, ethyl acetate, methyl acetate or mixtures thereof.
In another aspect of the present invention there is provided donepezil hydrochloride substantially free of 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1 -one hydrochloride.
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In this disclosure, donepezil hydrochloride having a content of 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1-one hydrochloride 0.5% or less.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE Preparation of donepezil hydrochloride
2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxy inden-1-one
hydrochloride (255 gm) was added to methanol (7.6 litre). The reaction mixture was heated under stirring to get clear solution. The reaction mixture was then cooled to 3-5 °C and to it added 5 % palladium on carbon (51 gm; 50 %). A slow stream of hydrogen gas is bubbled at about 5 °C under stirring. The catalyst was filtered and filtrate was concentrated to get donepezil hydrochloride. Yield: 247 gm. HPLC purity: 98.8%.
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We claim:
1. A process for the preparation of donepezil hydrochloride, wherein the process comprises the steps of;
(a) reacting 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxy inden-1-one hydrochloride of formula (II) with a hydrogenation catalyst;

(b) isolating donepezil hydrochloride from the reaction mixture thereof.
2. A process of claim 1, wherein hydrogen catalyst is metal catalyst.
3. A process of claim 2, wherein the metal catalyst palladium on carbon.

4. A process of claim 1, wherein 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxy inden-1-one hydrochloride of formula (II) is reacted with a hydrogen catalyst between temperature of 0-10 °C.
5. A process of claim 1, wherein 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxy inden-1-one hydrochloride of formula (II) is reacted with a hydrogen catalyst in presence of solvent.

6. A process of claim 5, wherein a solvent comprises of polar protic solvent, polar aprotic solvent or a mixture thereof.
7. A process of claim 6, wherein polar protic solvent is selected from the group of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-methoxyethanol, or mixtures thereof.
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8. A process of claim 6, wherein polar aprotic solvent is selected from the group
of tetrahydrofuran, dimethylsulfoxide, N.N-dimethylformamide, 1,4-dioxane, N,N-
dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, ethylmethyl
ketone, ethyl acetate, methyl acetate or mixtures thereof.
9. Donepezil hydrochloride having a content of 2-((1-benzylpiperidin-4-
yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1-one hydrochloride 0.5% or less.


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Abstract
The present invention provides a process for the preparation of donepezil hydrochloride. Further the process of present invention provides donepezil hydrochloride substantially free of 2-((1-benzylpiperidin-4-yl)methylene)-2,3-dihydro-5,6-dimethoxyinden-1 -one hydrochloride.
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