FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"IMPROVED PROCESS FOR PREPARATION OF DONEPEZIL
INTERMEDIATE"
Emcure Pharmaceuticals Limited.,
an Indian company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF INVENTION
The present invention relates to a novel and cost effective process for the preparation of Donepezil hydrochloride. This invention particularly relates to an improved process for the preparation of l-benzyl-4-(5,6-dimemoxy-l-indanon)-2-ylidenyl methyl piperidine, an intermediate for the preparation of Donepezil hydrochloride.
BACKGROUND OF THE INVENTION
Donepezil hydrochloride of formula (I), chemically known as (±) 2,3-dihydro-5,6-dimethoxy 2-[[l-(phenylmethy])-4-piperidinyl]methyl]-lH-inden-l-one hydrochloride is a reversible inhibitor of the enzyme acetylcholinesterase, first approved in the USA in 1997 for the treatment of dementia of the Alzheimer's type.

Donepezil was first disclosed in US Patent 4,895,841 and thereafter, several processes for the preparation of Donepezil and its salts have been published. The process disclosed in US 4,895,841 for the preparation of l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine comprises condensation of 5,6-dimethoxy-l-indanone with 1-benzyl-piperidine-4-carboxaldehyde in the presence of a strong base such as lithium diisopropylamide to obtain an indanonylidenyl compound intermediate, which upon catalytic reduction using palladium on carbon in tetrahydrofuran, followed by treatment with hydrochloric acid gives Donepezil hydrochloride. The preparation of lithium diisopropylamide from diisopropylamine and n-butyllithium requires stringent anhydrous conditions. Further, n-butyllithium on a commercial scale requires careful handling as it is highly flammable with a flash point of -21°C.

WO 2009/084030 discloses another process for preparation of Donepezil hydrochloride, in which 5,6-dimethoxy-l-indanone is condensed with l-benzyl-piperidine-4-carboxaldehyde in methylene chloride, using a base selected from a group consisting of metal -hydroxides or metal carbonates or metal alkoxides, at 0-5°C to give indanonylidenyl intermediate.
The present inventors had also tried out sodium hydroxide as a base for the condensation but the yield obtained was only 66%. Further, the isolation procedure involving initial quenching with water followed by extraction with methylene chloride, washing with water, concentration of the organic layer followed by final isolation involving addition of acetone is quite tedious and cumbersome since there is a tendency for formation of a large amount of emulsion during extraction with methylene chloride. The formation of emulsion requires careful layer separation and hence increases the average time for a batch run. These factors thereby, exponentially raise the average cost for commercial production.
The same disadvantages were observed in the method disclosed in WO 2007/108011 utilizing an alkali metal alkoxide for the condensation of 5,6-dimethoxy-l-indanone and 1-benzyl-piperidine-4-carboxaldehyde.
WO 2010/070511 discloses a process for the preparation of the indanonylidenyl intermediate comprising reaction of 5,6-dimethoxy-l-indanone with N-benzyl-4-carboxaldehyde pyridine bromide salt for 17-18 hours. The lengthy reaction time even at a temperature of 80-85°C, dissuades commercialization of such a process in view of its increased occupancy of the reactor and the time taken for each batch run. Further, long reaction times generally have a tendency to give rise to associated impurities, which result in an additional step of purification thereby resulting in decreased yields and increased cost.
It would be quite evident from the foregoing, that prior art processes contain the following drawbacks:

i) utilize a base which requires flammable and hazardous reagents like n-butyllithium
and careful handling on a commercial scale, ii) utilize processes which have lengthy and tedious work-up procedures, which
increases time taken for each batch run and increases the cost exorbitantly, iii) lengthy reaction times and tendency to generate associated impurities which
eventually increases the reactor occupancy, decreases the yield due to an additional
purification step, hence making the processes commercially unviable due to increased
cost of production.
Therefore, there is a continuing need for developing a new process for the manufacture of Donepezil and its pharmaceutically acceptable salts which is simple, cost-effective and industrially feasible.
OBJECT OF THE INVENTION
An object of the present invention is to provide an efficient and environment friendly process for the preparation of Donepezil hydrochloride of formula (I) without requiring hazardous and flammable reagents.
Another object of the present invention is to provide a simple, efficient and cost effective process for preparation of Donepezil hydrochloride (I), which does not result in long reaction times and lengthy work up procedures for isolation of l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine of formula (II) having desired purity.
Yet another object of the invention is to provide a convenient process for the preparation of l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine of formula (II) which further provides Donepezil hydrochloride of formula (I) conforming to regulatory specifications.

SUMMARY OF THE INVENTION
The present invention relates to a novel process for the preparation of l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine of formula (II) by overcoming the limitations faced in prior art.
An aspect of the present invention relates to a novel, improved and cost-effective process for the preparation of Donepezil hydrochloride of formula (I), comprising reaction of 5,6-dimethoxy-l-indanone (III) with l-benzyl-piperidine-4-carboxaldehyde (IV) in an organic solvent and in presence of sodium hexamethyldisilazane and isolating to obtain l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine of formula (II), which is further catalytically hydrogenated and reacted with hydrochloric acid to yield Donepezil hydrochloride (I).
These objectives of the present invention will become fully apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors in their quest for finding a convenient and cost-effective process had tried out several bases like sodium hydroxide, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), triethyl amine (TEA) etc. as base for the reaction between 5,6-dimethoxy-l-indanone (HI) and l-benzyl-piperidine-4-carboxaldehyde (IV). However, with inorganic bases, the yield was found to be lower while with DBU and TEA as base, there was no conversion.
The inventors have surprisingly found out that the compound of formula (II) could be synthesized in a facile manner by utilizing bases like the sodium salt of hexamethyl disilazane. Further, the isolation was quite convenient with absence of any emulsion during work-up. The condensation of 5,6-dimethoxy-I-indanone (III) and I-benzyl-piperidine-4-carboxaldehyde (IV) in the presence of sodium hexamethyldisilazane was found to proceed to completion in 45-90 minutes, with associated impurities within the desired regulatory limits.

The reactions were carried out under moderate conditions and moreover, did not require hazardous or costly raw materials as reported in the prior art processes. The desired compound, 1-benzyl-4-(5,6-dimethoxy-1-indanon)-2-ylidenyl methyl piperidine of formula (II) thus obtained, on catalytic hydrogenation and subsequent treatment with hydrochloric acid yielded Donepezil hydrochloride of formula (I) having the purity > 99% and with associated impurities within regulatory limits.

Scheme 1: Method embodied in the present invention for the preparation of Donepezil hydrochloride
In an embodiment, 5,6-dimethoxy-l-indanone (III) was reacted with 1-benzyl-piperidine-4-carboxaldehyde (IV) in an organic solvent, in presence of sodium hexamethyldisilazane to get l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenylmethyl piperidine (II).
The solvent was selected from the group comprising of water-miscible organic solvents such as tetrahydrofuran, 1,2-dimethoxyethane etc.
The reaction was carried out in the temperature range of 25 °C to 55 °C and was found to proceed towards completion within 45-90 minutes.

The reaction mass was then concentrated and treated further with an organic solvent selected from methanol, ethanol, isopropyl alcohol etc. The reaction mass was then filtered, washed with water and dried to obtain the compound of formula (II) having purity >99% and with associated impurities within regulatory limits.
It is pertinent to note that the reaction was quite facile and proceeded towards completion with minimal formation of associated impurities.
Further, the isolation of the compound of formula is quite simple as it involves removal of the organic solvent and addition of an organic solvent like methanol as compared to prior art methods, which require extraction with a solvent, repeated washings, concentration of the solvent, which makes the process lengthy and tedious.
l-Benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine (H), thus obtained, was then subjected to catalytic hydrogenation to yield Donepezil base, which was then treated with hydrochloric acid in a biphasic mixture of an organic solvent and water to give Donepezil hydrochloride of formula (I).
Donepezil hydrochloride (I) thus isolated had purity > 99% with the level of associated impurities conforming to regulatory specifications.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

Example 1
Preparation of l-Benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine
Tetrahydrofuran (400ml) was added to a mixture of 5,6-dimethoxy-l-indanone (25gm) and l-benzyl-piperidine-4-carboxaldehyde (37gm) in a flask, followed by addition of 1.0M solution of sodium hexamethyldisilazane in THF (50ml). The reaction mixture was stirred for 1 hr at temperature between 40° C and 45° C. After completion of reaction, the reaction mass was concentrated, and the solid obtained was treated with methanol.
The reaction mass was then filtered, washed with DM water followed by methanol and dried at 50-55°C to obtain l-benzyl-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine (44.6 gm). Yield: 91%. purity>99%.
Example 2
Preparation of Donepezil hydrochloride
The autoclave was charged with tetrahydrofuran, (125ml), methylene chloride (125ml),l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-ylidenyl methyl piperidine (25.0g) and 10% Palladium on carbon (2.5g). The reaction mass was cooled to 0-5°C and hydrogen pressure of around 3-4 Kg/cm was applied to the reactor. The reaction was continued for four hours. After completion of the reaction, catalyst was filtered off and the filtrate was concentrated. The obtained residue was mixed with methylene chloride (100ml) and water (25ml) followed by addition of hydrochloric acid (30ml). The organic layer was separated, washed with hydrochloric acid solution ( 12.5 ml water and 12.5 ml conc HC1), and water. The organic layer was concentrated under vacuum. The concentrated mass was diluted with toluene (100ml) and 25 ml water, and basifled to pH 9-10 using aqueous ammonia. The Organic layer was separated and concentrated. The residue was dissolved in aqueous isopropanol and heated to 45-50°C. The pH of the reaction mass was adjusted to 2-3 using concentrated HC1. Reprecipitation of the compound was done using methyl tertiary butyl ether .The solid was filtered and dried. Yield: 25gms. Purity: >99%.

We Claim;
1. A process for the preparation of l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-
ylidenylmethyl piperidine (II), comprising reaction of 5,6-dimethoxy-l-indanone (HI)
with l-benzyl-piperidine-4-carboxaldehyde (IV) in an organic solvent in presence of
sodium hexamethyldisilazane and isolating the compound of formula (II).
2. A process according to claim 1 wherein the organic solvent is selected from
tetrahydrofuran and 1,2 dimethoxyethane.
3. A process according to Claim 1, wherein the compound of formula (II) is isolated by concentrating the reaction mixture and adding a second organic solvent.
4. A process according to claim 3, wherein the second organic solvent is selected from the group comprising of methanol, ethanol and isopropanol.