FIELD OF INVENTION

The present invention relates to the novel bisulfite adduct of 1-benzyl piperidine-4-aldehyde and process for preparing the same. The novel bisulfite adduct is a useful intermediate in the preparation of piperidylmethyl-indanones, more particularly donepezil or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions that include the donepezil or a pharmaceutically acceptable salt thereof.
BACKGROUND OF INVENTION
Benzyl-piperidylmethyl-indanones such as donepezil have excellent pharmacological action as prophylactic or medicament for senile dementia, especially for Alzheimer disease. Several processes have been reported for the preparation of benzyl-piperidylmethyl-indanones for example, in U.S. Pat. Nos. 4,895,841; 5,606,064; 6,252,081; WO 97/22584 and J. Med. Chem. 1995, 38(24), 4821-4829. These processes require multiple steps such as purification processes and chromatography and therefore inevitably lead to poorer yields and purity.
OBJECT OF THE INVENTION
One of the object of the present invention is to provide a novel, stable bisulfite adduct of 1 -benzyl piperidine-4-aldehyde.
Another object of the present invention is to provide a bisulfite adduct of 1-benzyl piperidine-4-aldehyde having purity of more than 99.5%.
One another object of the present invention is to provide a process for preparing the bisulfite adduct of 1 -benzyl piperidine-4-aldehyde.

Another object of the present invention is to provide a commercial viable synthetic process for donepezil hydrochloride using the bisulfite adduct of 1-benzyl piperidine-4-aldehyde.
SUMMARY OF THE INVENTION
The present invention describes a novel, stable bisulfite adduct of 1-benzyl piperidine-4-aldehyde of formula I.

Further the present invention describes a process for preparing the bisulfite adduct of 1-benzyl piperidine-4-aldehyde of formula I, having purity more than 99.5%.
Further the present invention describes a process for preparing donepezil hydrochloride from the said adduct of 1-benzyl piperidine-4-aldehyde and 5,6-dimethoxy indanone.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention there is provided a novel, stable bisulfite adduct of 1-benzyl piperidine-4-aldehyde and process of preparation thereof.
Further, invention provides a process for the preparation of donepezil hydrochloride comprising reacting the said adduct of 1-benzyl piperidine-4-aldehyde having purity more than 99.5% and 5,6-dimethoxy indanone. The resultant product 1-beirzyl-4-(5,6-dimethoxy-l-oxoindan-2-ylindenemethyl)-piperidine is hydrogenated with

a noble metal catalyst in an organic solvent at 20 to 50 °C and 4 to 5 Kg/cm2 pressure to provide donepezil.
The preparation of donepezil hydrochloride comprises reacting the donepezil and hydrochloric acid in one organic solvent or more than one organic solvent, further the donepezil hydrochloride is recrystallized by one organic solvent or more than one organic solvent.
The organic solvent used in the hydrogenation of l-benzyl-4-(5,6-dimethoxy-l-oxoindan-2-ylindenemethyl)-piperidine may be tetrahydrofuran, methanol or acetic acid or combination thereof preferably methanol.
The noble metal oxide catalyst used in hydrogenation may be platinum on carbon or palladium on carbon or palladium oxide, preferably platinum on carbon.
Preferably hydrogenation is carried out at 25 to 45 °C and 4.0 to 4.5 Kg/cm2 hydrogen pressure.
The organic solvent used for donepezil hydrochloride may be methanol, ethanol, tetrahydrofuran or mixtures thereof preferably methanol and ethanol.
The organic solvent used for recrystallization of donepezil hydrochloride may be methanol, ethanol, diethyl ether, diisopropyl ether, methyl tert.butyl ether or mixtures thereof preferably methanol and diisopropyl ether, or methyl tert butyl ether.
The process of the invention eliminates formation of byproducts and gives high yield of the product (about 99%). The process of the invention is efficient, economical, and industrially applicable. Since, the process involves few steps; it is therefore, less time consuming, easy, and convenient to carryout. For the above reasons, it is also suitable for industrial scale up.

The following examples are illustrative of the invention but not limitative to the scope of the invention.
EXAMPLE
Step-I: Preparation of bisulfite adduct of l-benzyl-piperidine-4-carboxaldehyde:
In a reactor, 10L of acetonitrile, 1 kg of l-benzyl-piperidine-4-carboxaldehyde was charged. The 563gm of sodium bisulfite was dissolved in 1.2L DM water in another flask at room temperature. The sodium bisulfite solution was charged in above reaction mass. The total reaction mass was stirred for 3 to 4 hours, white solid was formed. The solid was filtered and dried under vacuo at 60-65 °C. Dried wt. 1.45 kg.
Step-II: Preparation of l-benzyl-4-(5,6-dimethoxy-l-oxoindan-2-yIindenemethyl) -piperidine:
In a 5L flask, 230gm of 1-benzyl piperidine-4-carbaldehyde adduct was dissolved in 1150ml of DM water and pH was adjusted to 11.5 to 12 with 10% 470ml of potassium hydroxide solution. The total reaction solution was extracted with 400ml of toluene. This toluene layer was added to solution of 14.6gm of potassium hydroxide in 600ml of methanol followed by l00gm of 5,6-dimethoxyindanone and methanol. The reaction mass was heated to 55-60°C and stirred till completion of the reaction under nitrogen atmosphere. The reaction mass was cooled to room temperature and isolated the product by filtration. This wet product was added to methanol and stirred at 60-65°C for 30-45 mins. The reaction mass was cooled to 20-25 °C and stirred for 30-45 mins. The product was isolated by filtration and further dried at 50-60°C. The obtained weight of product as 196gm.
Step-Ill: Preparation of Donepezil Hydrochloride:
In a 5L flask, 900ml of ethyl acetate was charged followed by l00gm of l-benzyl-4-(5,6-dimethoxy-l-oxoindan-2-ylindenemethyl)-piperidine. The reaction was stirred till dissolution. The 5% (i.e. 5gm) Platinum on carbon was charged in above reaction mass and hydrogen pressure was applied at 4 to 5 Kg/cm2 pressure of hydrogen at 40 to 50°C. The catalyst was filtered off and extracted in to DM water by adding DM Water. The

400ml of DM water was added to ethyl acetate layer followed by 31ml of concentrated hydrochloric acid. The reaction solution was stirred. The layers were separated. The aqueous layer was extracted with dichloromethane. After charcoalisation, the donepezil hydrochloride was recrystalized in methanol and methyl tert.butyl ether and isolated as solid. The weight obtained as product: 110gm.

We claim:
1) A bisulfite adduct of 1 -benzyl piperidine-4-carboxaldehyde.
2) The bisulfite adduct according to claim 1, which has purity grater than 99.5%.
3) The process for preparation of bisulfite adduct of l-benzylpiperidine-4-carboxaldehyd comprising reacting of l-benzyl-piperidine-4-carboxaldehyde with sodium bisulfite.
4) Use of the bisulfite adduct in preparation of donepezil hydrochloride.