A NOVEL METHOD FOR PREPARATION OF DONEPEZIL HYDROCHLORIDE POLYMORPH-I
FIELD OF INVENTION
The present invention relates to a simple and novel method for the preparation of 'PURE DONEPEZIL HYDROCHLORIDE POLYMORPH -F Donepezil Hydrochloride is the drug useful in the treatment of Alzheimer's Disease, and the drug is introduced by Japanese Pharmaceutical Company 'EISAI.'
The chemical name of Donepezil hydrochloride is l-benzyl-4-[(5,6-dimethoxy -1- indanone)-2-yl]-methyl piperidine hydrochloride of formula -I and the structural formula is as follows

The present invention describes the method of preparation of Donepezil hydrochloride polymorph-I, starting from the intermediate compound l-benzyl-4-[(5,6-dimethoxy -1-indanone)-2-ylidenyl]-methyl piperidine or its hydrochloride salt of formula-II

The polymorphism of Donepezil hydrochloride is disclosed in the patents US 5985864 and US 6140321.

BACKGROUND OF INVENTION:
Donepezil.Hydrochloride is a memory enhancer drug useful in the treatment of Alzheimer's disease introduced by Japanese Pharmaceutical Company 'Eisai'.
Donepezil.Hydrochloride shows the acetyl choline esterase inhibiting action and is useful for treatment of all kinds of senile dementia.
Alzheimer's disease is the commonest cause of dementia and is characterized by degeneration of specific nerve cells presence of neurotic plaques and neurofibrillary tangles.
Definitive diagnosis of Alzheimer's disease requires demonstration of these characteristic pathological features in brain tissue although in vast majority of cases diagnosis is made on clinical grounds alone, where it is more correctly called 'Senile Dementia'
Donepezil is a new drug treatment for use in mild to moderate dementia due to 'SDAT' (SDAT: SENILE DEMENTIA OF THE ALZHEIMER TYPE] Donepezil acts by inhibiting acetyl choline esterase the enzyme responsible for metabolising acetyl choline, there by enhancing neurotransmitter levels.
Donepezil.Hydrochloride is administered orally as usual and it may be placed for distribution and storage in a period of time before the administration. The stability of this medical substance against heat and humidity during the storage period is very important.
The process for the isolation of Donepezil hydrochloride described in the patent US 4895841 (1988) is as follows.
Hydrogenation of formula-II is carried out in THF solvent using 10% palladium carbon at room temperature under atmospheric pressure. The catalyst is filtered off and the solvent is evaporated

under vacuum. The resulting residue is purified by column chromatography employing silica gel (methylene chloride : methanol = 50:1). The eluate is concentrated in vacuo to yield Donepezil base as crude product.
The above crude product is dissolved in methylene chloride, a 10% solution of hydrogen chloride in ethyl acetate is added to the resulting solution followed by concentration in vacuo to obtain crystals which are recrystallized from methanol : isopropyl ether to get pure Donepezil hydrochloride of formula-I
In the patents US 5985864, US 6140321 the polymorphism of Donepezil.Hydrochloride is discribed. Different methods of preparation are disclosed for six polymorphic forms.
Disadvantages of the above processes.
1. The isolation of Donpezil baseinvolves column chromatography which is time consuming and limits the batch size. The process is uneconomical andyields are considerably low .
2. The described methods for preparation of Donepezil.Hydrochloride polymorph-I could not be reproduced,
SUMMARY OF THE INVENTION:
The present invention describes a simple novel and economically viable process to prepare high purity of Donepezil hydrochloride polymorph -I in good yields.
The first step of the process is the hydrogenation of the intermediate product l-benzyl-4-[(5,6-dimethoxy -1- indanone)-2-ylidenyl] -methyl piperidine as free base or hydrochloride salt whose structural formula is as follows:

Scheme-A
1) After completion of hydrogenation of free base of formula-II, the obtained Donepezil crude base is treated with dil hydrochloric acid and is extracted with chloroform. Organic layer is washed with water dried over sodium sulphate and evaporated. The crude .Hydrochloride salt of Donepezil. is recrystallized in Methanol : isopropyl ether. The distillation of chloroform is carried out at a temperature in the range of 40-50 ° C, and reduced pressure in the range of 25-50 mmHg.
Purity of product : >99.8% by HPLC
Scheme-B
The intermediate of formula-II can also be used as its hydrochloride salt, in this case, the solvent after hydrogenation is distilled off to get the crude hydrochloride salt of Donepezil. This is taken in CHCI3 washed with water to remove impurities. The solvent is removed under vacuum and recrystallized from methanol: Isopropyl ether. Donepezil.Hydrochloride obtained is indentified as polymorph-I in both the cases and is characterized by IR, DSC and XRD data in comparison with the reported data in the patent US 5985864.
By the above schemes of process, Donepezil Hydrochloride Polymorphic Form 1 in very high purity >99.8% could be achieved. The distillation of chloroform is carried out at a temperature in the range of 40-50 ° C, and reduced pressure in the range of 25-50 mmHg.
The invention is described in details in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention.

Example;!
Preparation of Donepezil hydrochloride Polvmorph-I
To the suspension of l-benzyl-4-[(5,6-dimethoxy -1- indanon)-2-ylidenyl]-methyl piperidine (formula-II, 10.0 g, 0.026 moles) in methanol (200 ml) is added 10% pd/carbon (wet) (l.Og). The mixture is hydrogenated at atmospheric pressure for 2 hrs at room temperature, the catalyst is filtered and the filtrate is evaporated to yield Donepezil base as crude product.
The crude Donepezil base is treated with 3.5% aqueous hydrochloric acid (81.0ml) and this solution is washed with ethyl acetate (22 ml x2). The organic layer is separated, and the aqueous layer is extracted with chloroform (65 ml x 2). The combined chloroform layer is washed with water (65 ml x 2), organic layer is separated and dried over Na2SC>4. The solvent is distilled off to get Donepezil hydrochloride salt (9.1g).
Above product is recrystallized from methanol : isopropyl ether to yield Donepezil
hydrochloride polymorph-I
Weight of the product: 6.60 g (60%)
Mioisture content: 5.06%w/w
IR values (cm"1) Fig-I:
700, 750,1266,1316,1644,1685, 2925, 3004, 3074, 3388, 3589
DSC TO : Fig-II:
on set: 89.6; peak : 114.9
on set: 219.5; peak: 224.6
XRD data Fig-III:

Example:!!
Preparation of Donepezil hydrochloride Polvmorph-I
To the suspension of l-benzyl-4-[(5,6-dimethoxy -1- indanon)-2-ylidenyl]-methyl piperidine hydrochloride (formula-II ,35 g, 0.0845 moles) in methanol (700 ml) is added 10% pd/carbon (wet) (3.5 g), and the mixture is hydrogenated at atmospheric pressure for 2 hrs at room temperature, the catalyst is filtered. Filtrate is evaporated under reduced pressure to yield Donepezil hydrochloride as crude product.
The crude Donepezil hydrochloride product is taken in chloroform (420 ml), washed with water (420 mix 2), organic layer is separated dried over Na2S04. Aqueous layer is reextracted in chloroform (200ml x 2), and this organic layer is washed with water (200 ml) the separated organic layer is combined with previous organic layer dried over Na2SC>4 distilled off under vacuum to yield Donepezil hydrochloride salt.
Above crude product is recrystallized from methanol: isopropyl ether to get the pure Donepezil
hydrochloride polymorph-I
Weight of the product: 21.0 g (59.7%)
Mioisture content: 5.3%w/w
IR values (cm1): 700,750,1267,1316,1643,1684,2923, 3004,3073,3399,3588 DSC(°Q:
onset: 85.5; peak : 109.8
on set: 220.2; peak: 224.7

ADVANTAGES OF THIS INVENTION.
1) The method does not use column chromatography for purification of Donepezil.Base.
2) Simple extraction methods are involved.
3) Reproducble experimental conditions are employed.
4) The process is economically viable.

We Claim;
1) A process for the of preparation of Donepezil hydrochloride polymorph-I of formula-I (according to scheme -A) by

the hydrogenation of free base of l-benzyl-4-[(5,6-dimethoxy -1- indanon)-2-ylidenyl]-methyl piperidine of formula-II in methanol by using 5-10% palladium on carbon as catalyst

2) The process for isolating Donepezil hydrochloride in high purity and high yield (>99.8% ) by dissolving the crude product as in claim-1 in 3.5% aqueous hydrochloric acid, washing the aqueous layer with ethyl acetate, extracting the aqueous layer with chloform and distillating the chloroform to obtain Donepezil hydrochloride.
3) The process as claimed in claims 1 to 2 wherein the distillation of chloroform is carried out at a temperature in the range of 40-50 ° C, and reduced pressure in the range of 25-50 mmHg.
4) The process as claimed in claim 1 to 3 wherein solvents such as methanol: isopropyl ether are used for crystallization to obtain Donepezil hydrochloride polymorph-I

5) A process for the preparation of Donepezil hydrochloride polymorph-I of formula-I
(according to scheme-B) by the hydrogenation of hydrochloride salt of 1-benzyl-4-[(5,6-
dimethoxy -1- indanon)-2-ylidenyl]-methyl piperidine of formula-II in methanol by using 5-
10% palladium on carbon as catalyst

6) The process as claimed in claim 5 wherein Donepezil hydrochloride is isolated for obtaining
high purity and high yield ( >99.8% ) by dissolving crude product as in claim-4 in
chloroform, washing the organic layer with water, and by distillating the chloroform.
7) The process as claimed in claims 5 to 6 wherein the distillation of chloroform is carried out
at a temperature in the range of 40-50 ° C, and reduced pressure in the range of 25-50
mmHg.
8) The process as claimed in claim 5 to 7 wherein solvents such as methanol : Isopropyl ether
are used for crystallization to obtain Donepezil hydrochloride polymorph-I
9) The process for the preparation of Deonepezil Hydrochloride Polymorph-I of purity >99.8%
as herein described with reference to examples 1 & 2.