THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
A PROCESS FOR PREPARATION OF ACETYLCHOLINESTERASE
INHIBITOR
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA. ANDHERI-KURLA ROAD, ANDHERl (E), MUMBAI-400059, MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this nvention and the manner in which it is to be performed.
677/MUM/2006
2 8 APR 2006

The present invention relates to a process for the preparation of an acetylcholinesterase inhibitor. Particularly the present invention provides a process for preparation of I-benzyI-4-[(5,6-dimethoxy-I-indanon)-2-yl]-methylpiperidine, a compound of formula I, known as donepezil or pharmaceutical acceptable salt thereof.

Formula I
Donepezil is an effective acetylcholinesterase inhibitor, the racemic form of which is marketed for use in the treatment of dementia of the Alzheimer's type.
United States Patent No. 4895841 (equivalent Indian reference not available) discloses process for the preparation of the compound of formula I. by catalytic hydrogenation of a compound of formula II,

Formula II
with 10% palladium on charcoal in tetrahydrofuran. The compound of formula I thus obtained is isolated by column chromatography and then converted to the hydrochloride
salt.
The major disadvantage of '841 patent is that the method requires use of palladium as catalyst which is highly expensive and its potential pyrophoric nature makes it difficult to handle. Additionally catalytic hydrogenation requires high-pressure devices such as autoclaves or bomb-reactors which are restrictive by being expensive to install. Also the compound of formula 1 is purified by column chromatography, which is impractical on
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an industrial scale and then converted to the hydrochloride salt, the purity of which is not disclosed. There is a potential for the formation of byproducts viz debenzylation, carbony 1 reduction to form diastereomeric mixture of compounds. The byproducts formed initially may further degrade under acidic or basic conditions to form complex mixture of impurities like olefin impurity, amine addition product etc. When we followed the catalytic hydrogenation we observed that in addition to the desired product formation, a side reaction leading to reduction of carbonyl group to yield corresponding secondary alcohol, took place. This compound eventually underwent dehydration during hydrochloride salt preparation to give corresponding olefinic impurity, a compound of formula III leading to the reduction in the yield of compound of formula I.

Formula III
Japanese patent Publication Number JP04187674A2 discloses hydrogenation of compound of formula II using optically active ruthenium phosphine complex catalyst in a solvent such as methylene chloride at 25-75°C under 4-100 kg/cm2 pressure for 24-168 hours by passing hydrogen. This process relates to asymmetric hydrogenation of compound of formula II leading to the formation of single enantiomer of compound of formula I.
There is need in the state of art for a process to prepare compound of formula I, from compound of formula II which circumvents the use of catalytic hydrogenation and avoids the difficulties associated with it.
We have now developed a process for preparing a compound of formula I from a compound of formula II which does not require catalytic hydrogenation. The present invention provides a convenient preparation of the compound of formula I by reacting the compound of formula II with sodium dithionite in presence of a phase transfer catalyst, to
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obtain the compound of formula 1 and optionally converting the compound of formula I to a pharmaceutical acceptable salt.
The reaction of sodium dithionite with a compound of formula II is selective and does not produce any side reactions unlike catalytic hydrogenation which may reduce the carbonyl group of compound of formula II in addition to the double bond leading to the formation of impurities. Also the process of the present invention is advantageous, as it does not require specialized equipment required for catalytic hydrogenation and the compound of formula I prepared by the process of present invention can be isolated without the need to use column chromatography.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of an acetylcholinesterase inhibitor. l-benzyl-4-[(5,6-dimetho\y-l-indanon)-2-yi)-methylpiperidine. a compound of formula 1 or pharmaceutically acceptable salt thereof, comprising

Formula I
reacting 1 -benzyl-4-[(5,6-dimethoxy-1 -indanon)-2-ylidenyl]-methylpiperidine, a compound of formula II,

Formula II
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with sodium dithionite in presence of a phase transfer catalyst, to obtain a compound of formula I and optionally converting the compound of formula I to a pharmaceuticaly acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparation of an acetylcholinesterase inhibitor, l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl]-methylptperidine, a compound of formula I or pharmaceuticaly acceptable salt thereof, comprising reacting l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-ylidenyl]-methylpiperidine, a compound of formula II. with sodium dithionite in presence of a phase transfer catalyst, to obtain a compound of formula I and optionally converting the compound of formula J to a pharmaceutically acceptable salt thereof.
The phase transfer catalyst that may be used in the process of the present invention may be selected from quaternary ammonium salt such as for example tetrabutylammonium hydrogen sulfate, tetrabutyl-ammonium bromide, benzyltriethylammonium chloride. cetyltrialkylammonium salts and the like or quaternary phosphonium salts such as for example Benzyl triphenyl phosphonium bromide, n-Butyl triphenyl phosphonium chloride and the like. The amount of the phase transfer catalyst that may be conveniently used is about 0.01 to 0. 25 mole equivalent, preferably 0.04 to 0.05 mole equivalent with reference to compound of formula II.
The reaction of a compound of formula II with sodium dithionite may be advantageously carried out in a biphasic system comprising water and organic solvent. The biphasic system can be formed by using water and a water-immiscible organic solvent. The water-immiscible organic solvent for forming the biphasic system may be selected from ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate and the like; ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether;
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hydrocarbon or halogenated hydrocarbon solvents such as benzene, toluene, chlorobenzene, methylene chloride, ethylene dichloride, chloroform and the like.
The reaction of a compound of formula II with sodium dithionite in presence of phase transfer catalyst may be carried out at pH greater than 7.5. The desired pH may be obtained by using any suitable inorganic or organic base. For example, inorganic base such as hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals such as sodium hydroxide, sodium carbonate and sodium bicarbonate and the like and organic base such as tertiary amines, for example triethyl amine, diisopropyl ethyl amine and the like.
The reaction of a compound of formula II with sodium dithionite may be carried out at a temperature between the range of about 20 °C to about 100°C, preferably at about 35°C to about 90°C for a suitable reaction time, generally for about 20 to about 30 hours.
The compound of formula I obtained by following the process of the present invention may be converted to a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of compound of formula I may be selected from hydrochloride, hydrobromide. sulfate, nitrate, acetate, fumarate, maleate, citrate and the like.
In a preferred embodiment, the compound of formula II is reacted with sodium dithionite in a biphasic system comprising water and methylene dichloride in presence of tetrabutyl-ammonium bromide and sodium bicarbonate.
In a typical work up. after completion of reaction the organic layer is separated. The product enriched organic layer is treated with an acid to obtain a salt of compound of formula I, for example, with aqueous hydrochloric acid to obtain the hydrochloride salt of compound of formula I. The isolated salt of compound of formula I if desired, can be recrvstallized from a suitable solvent(s).
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The starting compound of formula II may be prepared by any process known in the art such as United States Patent Number 4895841 or Japanese Patent Publication Number 11-171861 incorporated herein by reference only.
The compound of formula II, if desired may be converted to an acid addition salt thereof by treatment with acid in suitable solvent. For example the acid addition salt of compound of formula I may be oxalate, maleate or succinate. Before subjecting it to treatment with sodium dithionite the acid addition salt of compound of formula II can be converted to the compound of formula II by treatment with a suitable base. This way the purity of compound of formula II can be increased.
In one embodiment the compound of formula II is treated with oxalic acid in methanol and dichoromethane to obtain the oxalate salt thereof. The resultant oxalate salt is converted to the compound of formula II by treatment with aqueous inorganic bases like ammonia, sodium bicarbonate, sodium hydroxide etc. in chlorinated solvents like chloroform, dichloromethane to obtain compound of formula II with HPLC purity greater than 99.90 %
The present invention is illustrated by examples and not to be construed as limiting.
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EXAMPLES

Example I
Preparation of l-benzyl-4-f(5,6- dimethoxy-l-indanon)-2-yll-methvIpiperidine
hydrochloride , compound of formula I
In a round bottom flask containing 250 ml of methylene dichloride was added 25 g of 1 -benzyl-4-[(5;6- dimethoxy-l-indanon)-2-ylidenyl]-methylpiperidine, compound of formula II 1050 ml of water and 75g of sodium bicarbonate. The contents of the flask were stirred for 30 minutes and 2 g of tetrabutyl ammonium bromide were added and heated the contents of the flask to 42-45°C. 80 g of freshly prepared sodium dithionite in water was added slowly at 42-45°C over a period of 1.5-2 hours. The reaction mixture was maintained at 42-45 °C for 20 to 24 hours. The product enriched methylene dichloride layer was separated and washed with sodium bicarbonate followed by brine washins. The organic layer was washed with sodium iodide solution and water. The organic layer, was then treated with 1: 1 aqueous hydrochloric acid and stirred for 30 minutes. The organic layer was separated and solvent was distilled out to give a syrupy mass. Inprocess HPLC analysis of the crude product is given below % puriry: 99.1% % olefinic impurity (a compound of formula III): nil
To the residue was added methanol and charcoal and stirred for 15 minutes at 25-30 °C. The contents were filtered and the bed was washed with methanol. The contents of the flask were cooled to 0-2 °C and compound of formula 1 was allowed to crystallize out followed by addition of diisopropyi ether and stirring for 1 hour. The resultant product was filtered and washed with diisopropyi ether : methanol and dried to gel l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl]-methyIpiperidine hydrochloride.
% Yield: 75%
% puriry HPLC: 99.72 %
% impurity profile: any single impurity was <0.1%
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Example 2
Preparation of l-benzvl-4-f(5,6- dimethoxv-l-indanon)-2-ylidenyn-
methvlpiperidine, compound of formula II
To a round bottom flask under nitrogen atmosphere, was charged 450ml of dichloromethane, and 30 gm 5, 6-Dimethoxy-1-indanone at 25-30°C. The reaction mass was stirred. To above clear solution was added at 25-30°C, 35g of 1-benzylpiperidine carbaldehyde and the contents were cooled further to 15-20°C. A solution of 27g of sodium methoxide solution (-25 % w/w in methanol) was added by maintaining a temperature of 15-20 °C over a period of 20-30 minutes. The reaction temperature was maintained at 15-20°C for 1 hour. The temperature of the reaction mixture was raised to 25-30°C and the reaction mixture was stirred at 25-30°C for 1-1.5 hour. To the reaction mass was added 300ml of D M Water in single lot and stirred the content below 30°C. The organic layer was seperated. The organic layer was washed subsequently with D M Water and then with aqueous NaCl solution followed by charcoalizing and addition of anhydrous sodium sulphate was to the clear solution and stirring the content for 10-15 minutes. The charcoal was filtered off and the bed was washed with methylene dichloride. The solvents from filtrate were distilled out to obtain a thick syrupy mass. Methanol was added and the contents of the flask were heated to 50 - 55°C and temperature maintained for 30 - 45 minutes under stirring. The content of the fiask were cooled gradually to 20-25°C and maintained for 30-45 minutes filtered and the product was washed with methanol and dried.
To the reaction flask, 250ml dichloromethane, 50 g crude product and 100 ml Methanol in single lot was charged and the contents were stirred at 25-30°C. To above clear solution was added 15.86g of Oxalic acid dihydrated in a single lot and stirred the reaction mixture for 5-6 hours at 25-30°C. The suspension was cooled to 0 to 5°C and maintained at the same temperature for 1.0-1.5 hrs. The solid was filtered and the product cake was washed with methanol and dried to yield the oxalate salt. To the reaction fiask. was charged 300ml D M water, 75 ml aqueous ammonia; 200 ml dichloromethane and
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60g oxalate salt and stir the content at 25-30°C for 15-30 minutes. Stirring was slopped and allowed the layers to settle for 10-15 minutes, and the organic layer was separated. The organic layers were pooled up and washed subsequently with D. M. Water followed by Aqueous NaCl solution. The organic layer was distilled out at atmospheric pressure and degassed to obtain a thick syrupy mass under vacuum at 40-45°C. To the syrupy mass was added Methanol and distill under vacuum at 40-45°C. Again add methanol at 40-45°C and stir it at same temperature for 15-20 minutes. The suspension was cooled to 25-30°C and the solid product was filtered, and washed with methanol and dried to obtain 33.5 g of l-benzyl-4-[(5,6- dimethoxy-l-indanon)-2-ylideny!]-methylpiperidine. compound of formula II. % purity HPLC: 99.96 %
Comparative Example
Preparation of l-benzvl-4-f(5,6- dimethoxv-l-indanon)-2-vll-methylpiperidine
hydrochloride , compound of formula I
In a 250 L autoclave containing 80L Tetrahydrofuran, added 2 Kg compound of formula
II and 0.225 Kg Platinum on carbon (5% [50% wet] ) at 27°C to 33°C. The content of
autoclave was stirred under 2.5-3.0 Kg/cm2 pressure of hydrogen gas. The reaction
mixture was maintained at 27°C to 33°C for 16 to 18 hours. After the completion of the
reaction the catalyst was filtered off and the filtrate was concentrated under vacuum to
obtain an oily mass. This oily mass was treated with 2 L 6N aqueous hydrochloric acid
in 200 L of dichloromethane. The product enriched organic layer was washed with 2 L of
water. The organic layer was separated and solvent was distilled out to give a syrupy
mass.
% Yield: 68%
% purity HPLC: 94.67 %
% impurity profile: 5.18 % of olefinic impurity
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To the residue was added methanol and charcoal and stirred for 15 minutes at 25-30 °C.
The contents were filtered and the bed was washed with methanol. The contents of the
flask were cooled to 0-2 °C and compound of formula 1 was allowed to crystallize out
followed by addition of diisopropyl ether and stirring for 1 hour. The resultant product
was filtered and washed with diisopropyl ether: methanol and dried to get l-benzyI-4-
[(5.6- dimethoxy-1 -indanon)-2-yl]-methylpiperidine hydrochloride.
Yield: 58%
% purity HPLC: 99.7 %
% impurity profile: < 0.1% of olefinic impurity
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We Claim:
A process for the preparation of acetylcholinesterase inhibitor, 1 -benzyI-4-[(5,6-dimethoxy-l-indanon)-2-yl]-methylpiperidine, a compound of formula 1 or pharmaceutically acceptable salt thereof, comprising

Formula I
reacting 1 -benzyl-4-[(5.6- dimethoxy-1 -indanon)-2-ylidenyl]-methylpiperidine. a compound of formula II,

Formula II
with sodium dithionite in presence of a phase transfer catalyst, to obtain a compound of formula I and optionally converting the compound of formula I to a pharmaceutically acceptable salt thereof.
2. The process as claimed in claim 1, wherein the reaction of compound of formula II with sodium dithionite is carried out in a biphasic system comprising water and organic solvent.
3. The process as claimed in claim 1, wherein the reaction of compound of formula II with sodium dithionite is carried out at pH greater than 7.5.
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4. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from the group consisting of quaternary ammonium salts, and quaternary phosphonium salts.
5. The process as claimed in claim 4, wherein the wherein the phase transfer catalyst is tetrabutyl ammonium halide.
6. The process as claimed in claim 2, wherein the biphasic system comprises water and methylene dichloride.
7. The process as claimed in claim 1, wherein the compound of formula II is prepared by reacting an oxalate salt of compound of formula II with aqueous ammonia.
Dated this 28TH day of April, 2007

DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR
SUN PHARMACEUTICAL INDUSTRIES LTD
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