Indian Patents. 268394:"PROCESS FOR THE PREPARATION OF HIGHLY PURE DONEPEZIL"

Title of Invention	"PROCESS FOR THE PREPARATION OF HIGHLY PURE DONEPEZIL"
Abstract	The present invention relates to the preparation of highly pure donepezil of Formula I or salt thereof,by hydrogenating indanonylidenyl compound of using platinum catalysts.

Full Text	FIELD OF THE INVENTION The field of the invention relates to the preparation of highly pure Donepezil or its salts in high yields. BACKGROUND OF THE INVENTION Donepezil of Formula I, is a cholinesterase inhibitor used in the treatment of mild to moderate cases of Alzheimer's diseases and is chemically known as l-benzyl-4-[(5,6-dimethoxy-1 -indanon)-2-ylidenyl] methylpiperidine. (Figure-Removed) MeO Donepezil was first disclosed in US Patent 4,895,841. Thereafter, several processes for the preparation of Donepezil and its salts have published. In US patent 4,895,841, 5,6-dimethoxy-l-indanone is condensed with l-benzylpiperidine-4-carboxaldehyde in the presence of strong base, such as lithium diisopropylamide (LDA) to prepare a indanonylidenyl compound of Formula II, which on reduction in the presence of palladium on carbon in tetrahydrofuran yield Donepezil. There are significant drawbacks to this method as the catalytic hydrogenation of the indanonylidenyl compound of Formula II (Figure-Removed) to the corresponding compound of Formula I, results in the debenzylation leading in the formation of following impurity of Formula III, in substantial amounts, (Figure-Removed) which is difficult to remove. This above impurity is further carried into Donepezil hydrochloride. The generation of significant quantity of debenzylated product during hydrogenation makes the process uneconomical. In the exemplified process given in US Patent 4,895,841, column chromatography is utilized to purify the product which is not amenable on industrial scale. Japanese Patent Application No.JP-A-H11-171861 discloses the preparation of indanoylidenyl compound of formula II by the aldol condensation of 5,6-dimethoxy-1-indanone with l-benzylpiperidine-4-carboxaldehyde in the presence of alkali-metal alkoxide such as sodium methoxide. PCT Publication WO 97/22584 discloses preparation of Donepezil hydrochloride by reacting pyridine-4-aldehyde with malonic acid. The resulting 3-(pyridin-4-yl)-2-propionic acid was reduced with rhodium on carbon under hydrogen atmosphere to give 3-(piperidin-4-yl)-2-propionic acid which on reaction with methyl chlorocarbonate gave 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid. On reacting 3-[N-(methoxycarbonyl) piperidin-4-yl] propionic acid with oxalyl chloride, methyl 4-(2-chlorocarbonylethyl) piperidin-1-carboxylate is obtained which on reaction with 1,2-dimethoxy benzene in the presence of aluminum chloride afforded 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-l-carboxylate. On reacting 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl] piperidin-1-carboxylate with tetramethyl diamino methane, 4-[2-(3,4-dimethoxy benzoyl) allyl] piperidin-1-carboxylate is obtained which on treatment with sulphuric acid gave methyl 4-(5,6-dimethoxy-l-indanon-2-yl methyl )piperidin-l-carboxylate. On decarboxylation of 4-(5,6-dimethoxy-l-indanon-2-yl methyl) piperidin-1-carboxylate gave 5,6-dimethoxy-2-(piperidin-4-yl methyl)-1-indanone which on treatment with benzyl bromide afforded Donepezil hydrochloride. US Patent 5,606,064 discloses another process for the preparation of Donepezil, which involves reacting 5,6-dimethoxy-1-indanone and pyridine-4-carboxaldehyde to yield 5,6 dimethoxy-2-(pyridin-4-yl)-methylene-indan-l-one, which upon treatment with benzyl bromide followed by reduction yields the required compound. US Patent 6,492,522 discloses an alternative process for the preparation of Donepezil hydrochloride which comprises the steps of carrying out the intramolecular cyclization of N-benzyl-2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionic acid of Formula IV, (Figure-Removed) to yield crude Donepezil and isolating the pure Donepezil by chromatography or crystallization. US Patent 6,252,081 discloses an additional process for production of Donepezil hydrochloride which involves the reaction of Donepezil intermediate of Formula V, (Figure-Removed) with halogenated benzyl to obtain a quaternary ammonium salt, hydrogenation of the quaternary ammonium salt to produce Donepezil base, followed by hydrohalogenation to produce Donepezil hydrochloride. The prior art processes employs reaction of l-benzylpiperidine-4-carboxaldehyde with 5,6-dimethoxy-l-indanone involves use of lithium diisopropylamide. Lithium diisopropylamide is toxic and needs to be carefully handled. Use of oxalyl chloride chemistry is difficult for scale up. Besides the oxalyl reaction also involves many protection deprotection chemistry and the overall yield is very low. Raw materials like methyl chlorocarbonate or tetramethyl diaminomethyl are expensive and difficult to source commercially. In view of the above, the prior art processes are time consuming and difficult to carry out as they involve many steps. Most of the prior art approaches are not suitable from commercial point of view because the desired product is not obtained in high purity and requires purification by tedious and cumbersome purification processes.The inventors have observed that during the condensation reaction of 5,6-dimethoxy-l-indanone of Formula-VI, (Figure-Removed) with l-benzylpiperidine-4-carboxaldehyde of Formula-VII, (Figure-Removed) for the preparation of indanonylidenyl compound of Formula II (Figure-Removed) formation of a hydroxyl impurity of compound of Formula VIII, (Figure-Removed) occurs upto 20%. The amount of impurity formation varies depending upon reaction conditions, amount of solvent, nature of solvent used. It is advantageous to remove hydroxyl impurity at this stage; otherwise it converts to indanonylidenyl compound of Formula II during preparation of Donepezil hydrochloride in the presence of hydrochloric acid, hence difficult to remove. An additional step of hydrogenation is required. Further hydrogenation is required to reduce the double bond, which is an additional step leading to increase in cost As discussed above, the inventors have further found that during hydrogenation of indanonylidenyl compound of Formula II in the presence of palladium catalyst debenzylation occurs to the extent of 10%.. Once the debenzylated product is formed in reaction mixture it is difficult to remove. An additional step of benzylation is required to convert the debenzylated product to desired compound. To achieve a high efficiency of the reaction for industrial synthesis of Donepezil, it is necessary to minimize the formation of the impurities and improve the yields. Thus, the present invention provides an efficient and industrially advantageous process for the preparation of highly pure Donepezil hydrochloride in high yields. SUMMARY OF THE INVENTION Accordingly, in one aspect, present invention provides an improved process for the preparation of highly pure Donepezil of Formula I (Figure-Removed) or its salts which comprises: hydrogenating indanonylidenyl compound of Formula II; (Figure-Removed) using platinum catalyst in an organic solvent at a temperature of 0-50°C; preparing Donepezil base and converting to pharmaceutically acceptable salts. In another aspect, present invention provides a process for the preparation of indanonylidenyl compound of Formula II which comprises: condensing 5,6-dimethoxy-l-indanone of Formula-VI, (Figure-Removed) and l-benzylpiperidine-4-carboxaldehyde of Formula-VII, (Figure-Removed) in the presence of alkali metal alkoxide in methanol as solvent. In another aspect, present invention provides a process for the purification of indanonylidenyl compound of Formula II to remove hydroxy impurity of Formula VIII, (Figure-Removed) by converting compound of formula VIII into indanonylidenyl compound of Formula II by using acid base treatment or protection /deprotection of hydroxy group. DETAILED DESCRIPTION OF THE INVENTION The instant invention relates to an improved, efficient and industrially advantageous process for the preparation of highly pure Donepezil of Formula-1 or salt thereof. According to an embodiment, there is provided a process for the preparation of indanonylidenyl compound of Formula-II in high purity and better yields by the condensation of 5,6-dimethoxy-l-indanone of Formula-VI, (Figure-Removed) and l-benzylpiperidine-4-carboxaldehyde of Formula-VII, (Figure-Removed) in the presence of alkali metal alkoxide in a solvent. Specifically the reaction is conducted at 30 -65°C in methanol and it takes about 2-7 hours for completion of reaction. The indanonylidenyl compound of Formula-II may be further purified by several ways such as by using acid base treatment; by protecting deprotecting hydroxyl group, to remove the hydroxyl impurity of Formula VIII, by converting (Figure-Removed) compound of formula VIII into indanonylidenyl compound of Formula II. Generally, the crude indanonylidenyl compound of Formula-II, having hydroxy impurity is treated with organic or inorganic acid in the presence of solvent such as ethers, alcohols, ketones, hydrocarbons, polar aprotic solvents. Specifically the compound of Formula-II is treated with methanolic-hydrochloric acid in methanol. After work up, pure hydrochloride of indanonylidenyl compound of Formula-II is isolated, which is then basified to get pure indanonylideny compound of Formula II. Alternatively the hydroxy impurity of Formula VIII can be removed by converting hydroxy compound of formula VIII to compound of Formula IX by protecting the hydroxyl group with suitable hydroxyl protecting group, and in situ converting compound of Formula IX to compound of Formula II by dehydration using conventional methods. The protecting hydroxy group for the compound of Formula-IX can be selected from acetates, benzoates, sulfonates and the like which are prepared by using suitable reagents known in prior art. In one specific embodiment of the present invention sulfonates derivatives of Formula IX are prepared. Sufonates can be methanesulfonate, 4-toluenesulfonate, benzenesulfonate and the like. The compound of Formula VIII may be treated with sulfonyl chloride in the presence of an organic base and a solvent. The solvent comprises one or more of ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents. It is advantageous to remove impurity of Formula VIII before carrying out hydrogenation; otherwise it would carry forward. During hydrochloride preparation of Donepezil it is converting to compound of Formula II on dehydration, in the presence of hydrochloric acid. It is very difficult to remove indanonylidenyl compound of Formula-II from Donepezil hydrochloride and further hydrogenation is required to reduce the double bond, which is an additional step leading to increase in cost. After purification, the indanonylidenyl compound of Formula II is isolated in high purity greater than 98.5% preferably greater than 99.8%. According to another embodiment, there is provided a process for the preparation of Donepezil of Formula I which includes hydrogenating indanonylidenyl compound of Formula-II, in the presence of platinum catalyst to produce and isolating the substantially pure Donepezil or a salt thereof. Specifically hydrogenation of indanonylidenyl compound of Formula II is carried out using platinum catalyst in an organic solvent at 0-50°C preferably at 25-40°C under 1-5 atmospheric pressure preferably at 4 atmospheric pressure. The organic solvent can be selected from solvent comprises one or more of ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof and preferably ethyl acetate is used. We have carried out same reactions using palladium catalyst also and found that using palladium catalyst, impurity of Formula III is formed in substantial amount depending upon reaction time. The examples have been provided as comparative examples. Platinum catalysts are mild in nature therefore debenzylation is not observed using platinum catalysts. Platinum catalyst can be selected from platinum oxide, platinum on carbon and preferably platinum on carbon is used. The reaction can be accomplished at 0-50°C and preferably at 25-35°C. The progress of the reaction is monitored by high performance liquid chromatography (HPLC), and the reaction is stirred till the starting material i.e. compound of Formula II remains less than 0.15%, the reaction mixture is filtered to recover the catalyst. The filtrate is concentrated and crude Donepezil is dissolved in organic solvent. The organic solvent is selected from methylene chloride, ethyl acetate and preferably methylene chloride is used. The reaction mixture is treated with a solution of hydrochloric acid in ethyl acetate to obtain Donepezil hydrochloride. The resulting mixture is concentrated and the product obtained is recrystallized from methanol and isopropyl ether to obtain highly pure Donepezil hydrochloride having purity greater than 99.5% preferably greater than 99.8%. Major advantages realized in the present invention are high purity and high yields. The formation of impurity of Formula-Ill has been restricted by making use of platinum catalyst This avoids the use of tedious and cumbersome technique i.e. chromatographic purification, and additional step of benzylation of compound of Formula-Ill. The hydroxy impurity of Formula VIII is removed by acid base treatment or protection/ deprotection technique. The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to 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. EXAMPLES Preparation of l-Benzvl-4-[5,6-dimethoxv-l-indanon)-2-vlidenvl\|methyl piperidine Sodium hydroxide (1.46g) was added to methanol (150ml) followed by addition of 5,6-dimethoxy-l-indanone (5g) and l-benzylpiperidene-4-carboxaldehyde (6.8g) at 20-30°C.The temperature of the reaction mass was gradually raised to 62-66°C and was stirred for 6 hours. The reaction mass was concentrated under vacuum and 2/3 volume of the reaction mass was recovered. The remaining slurry was filtered and the product was washed with water followed by methanol to give 6.9 g of l-benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (yield=70%), having purity 98.5% by HPLC. Preparation of Benzyl-4-K5. 6-dimethoxy-l-indanon)-2-ylidenyll methyl piperidine A solution 9.8 g of sodium methoxide in 60 ml of methanol was added to a stirred solution of 25 g of 5,6-dimethoxy-l-indanone and 36.75 g 1-benzyl piperidene-4-carboxaldehyde in methanol (690ml) at 20-30°C. The temperature of the reaction mass was gradually raised to 60-65°C and stirred for 2 hours. The precipitated solid was filtered and the product was washed with water followed by methanol to give crude product which was converted to its hydrochloride salt using methanol. The hydrochloride salt was basified using sodium hydroxide to obtain 26.9 g of 1-benzyl- 4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (yield=60%) having purity 99.92% by HPLC. Purification of l-Benzyl-4-[(5. 6-dimethoxv-l-indanone)-2-ylidenyl] methylpiperidine To a stirred solution of l-benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (lOg, purity 93.38%)) in methylene chloride (200ml) was added methane sulfonyl chloride(0.2 ml) and triethylamine at 25-30°C.The reaction mixture was stirred at 20-30°C and after completion of reaction, the reaction mass was quenched with DM water. The organic layer was washed with aqueous sodium bicarbonate solution followed by concentration in vacuum to obtain the product which was filtered with methanol to obtain 7.7gm of l-benzyl-4-[(5, 6-dimethoxy-l-indanone)- 2-ylidenyl] methylpiperidine having a purity of 98.71 % by HPLC. Purification of Benzvl-4-K5. 6-dimethoxy-l-indanon)-2-ylidenyl1 methyl piperidine l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (80g, purity 98.85%) was taken in methanol (400ml) followed by addition of methaolic solution of hydrogen chloride (48ml) at!0-15°C. The product was filtered followed by addition in the mixture of DM water (400ml) and methylene chloride (640ml), the Ph of the mass was adjusted to ~9 with 10% caustic solution at 20-30°C. The organic layer was separated and concentration in vacuum to obtain the product which was filtered, washed with methanol to obtain 67gm of l-benzyl-4-[(5, 6-dimethoxy-l- indanone)-2-ylidenyl] methylpiperidine having a purity 99.67% by HPLC. Preparation of l-Benzyl-4-K5, 6-dimethoxy-l-indanone)-2-vll methylpiperidine hydrochloride (Donepezil Hydrochloride) l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (lOg) was taken in ethyl acetate (200ml) followed by addition of 5 % platinum-carbon (2g). The reaction mixture was hydrogenated at temperature 20-30°C and 2 atmospheric pressure for 2 hours. After completion of reaction, the catalyst was filtered off and the filtrate was concentrated in vacuum. The residue was dissolved in methylene chloride and a solution of hydrochloric acid in ethyl acetate was added to the resulting solution, followed by concentration in vacuum to obtain a crystal, which was recrystallized from methanol / isopropyl ether to obtain 10.6 g of l-benzyl-4-[(5, 6-dimethoxy-l-indanone)-2-yl]methylpiperidine hydrochloride having a purity of 99.55% by HPLC. Preparation of l-Benzyl-4-K5, 6-dimethoxy-l-indanone)-2-vll methvlpiperidine hydrochloride (Donepezil Hydrochloride) l-Benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyl]methyl piperidine (10g) was hydrogenated in ethyl acetate (100 ml) for 2 hours in presence of 5% platinum-carbon (2g) at 4 atmospheric pressure. The reaction mixture was filtered and concentrated under vacuum to give residue. The residue was dissolved in methylene chloride and further acidified with a solution ethyl acetate hydrochloric acid at 0-10°C followed by concentration in vacuum to obtain a solid which was recrystallized from methanol and isopropyl ether to obtain 7.4 g of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride(yield=67%) having a purity of 99.93% by HPLC Preparation of l-Benzyl-4-[(5, 6-dimethoxy-l-indanone)-2-yl1 methvlpiperidine hydrochloride (Donepezil Hvdrochloride) l-Benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyl]methyl piperidine (8g) was taken in ethyl acetate (160ml) followed by addition of 5% platinum-carbon (1.6g). The reaction mass was hydrogenated at 20-3 0°C under 2 atmospheric pressure for 2 hours and the progress of the reaction was monitored by HPLC analysis (debenzlated impurity is isopropyl ether to obtain 6.8 g of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride having purity of 99.56% by HPLC. Reference Examples Preparation of l-Benzvl-4-K5. 6-dimethoxy-l-indanone)-2-yl] methylpiperidine hydrochloride (Donepezil Hvdrochloride) l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine was taken in tetrahydrofuran (200ml) followed by addition of palladium-carbon (Ig). The mixture was hydrogenated at 20-30 °C under 1.5 atmospheric pressure for 8 hours, monitored by HPLC analysis and analysis shows ~ 38.5% of debenzylated impurity in the reaction mass. Preparation of l-Benzyl-4-K5. 6-dimethoxv-l-indanonc)-2-yll methvlpiperidine hydrochloride (Donepezil Hvdrochloride) l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine was taken in 200 ml THF followed by addition of 10% palladium-carbon (0.5g). The mixture was hydrogenated at 20-3 0°C under 1.5 atmospheric pressure for 8 hour and the progress of the reaction was monitored by HPLC analysis (the analysis showed ~22.4% of debenzylated impurity in the reaction mass after 4 hours and ~38% after 8 hours). Preparation of l-Benzyl-4-[(5, 6-dimethoxy-l-indanone)-2-yll methvlpiperidine hydrochloride (Donepezil Hvdrochloride) l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (5g) was taken in 100 ml of THF followed by addition of 10% palladium-carbon (0.5g). The reaction mixture was hydrogenated at temperature of 20-30°C at 0.3 atmospheric pressure for 2 hour and the progress of the reaction was monitored by HPLC analysis (the HPLC analysis showed the debenzylated impurity9%).

Full Text

FIELD OF THE INVENTION
The field of the invention relates to the preparation of highly pure Donepezil or its salts in high yields.
BACKGROUND OF THE INVENTION
Donepezil of Formula I, is a cholinesterase inhibitor used in the treatment of mild to moderate cases of Alzheimer's diseases and is chemically known as l-benzyl-4-[(5,6-dimethoxy-1 -indanon)-2-ylidenyl] methylpiperidine.
(Figure-Removed)
MeO
Donepezil was first disclosed in US Patent 4,895,841. Thereafter, several processes for the preparation of Donepezil and its salts have published. In US patent 4,895,841, 5,6-dimethoxy-l-indanone is condensed with l-benzylpiperidine-4-carboxaldehyde in the presence of strong base, such as lithium diisopropylamide (LDA) to prepare a indanonylidenyl compound of Formula II, which on reduction in the presence of palladium on carbon in tetrahydrofuran yield Donepezil.
There are significant drawbacks to this method as the catalytic hydrogenation of the indanonylidenyl compound of Formula II

(Figure-Removed)
to the corresponding compound of Formula I, results in the debenzylation leading in the formation of following impurity of Formula III, in substantial amounts,

(Figure-Removed)
which is difficult to remove. This above impurity is further carried into Donepezil hydrochloride. The generation of significant quantity of debenzylated product during hydrogenation makes the process uneconomical. In the exemplified process given in US Patent 4,895,841, column chromatography is utilized to purify the product which is not amenable on industrial scale.
Japanese Patent Application No.JP-A-H11-171861 discloses the preparation of indanoylidenyl compound of formula II by the aldol condensation of 5,6-dimethoxy-1-indanone with l-benzylpiperidine-4-carboxaldehyde in the presence of alkali-metal alkoxide such as sodium methoxide.
PCT Publication WO 97/22584 discloses preparation of Donepezil hydrochloride by reacting pyridine-4-aldehyde with malonic acid. The resulting 3-(pyridin-4-yl)-2-propionic acid was reduced with rhodium on carbon under hydrogen atmosphere to give 3-(piperidin-4-yl)-2-propionic acid which on reaction with methyl chlorocarbonate gave 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid. On reacting 3-[N-(methoxycarbonyl) piperidin-4-yl] propionic acid with oxalyl chloride, methyl 4-(2-chlorocarbonylethyl) piperidin-1-carboxylate is obtained which on reaction with 1,2-dimethoxy benzene in the presence of aluminum chloride afforded 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-l-carboxylate. On reacting 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl] piperidin-1-carboxylate with tetramethyl diamino methane, 4-[2-(3,4-dimethoxy benzoyl) allyl] piperidin-1-carboxylate is
obtained which on treatment with sulphuric acid gave methyl 4-(5,6-dimethoxy-l-indanon-2-yl methyl )piperidin-l-carboxylate. On decarboxylation of 4-(5,6-dimethoxy-l-indanon-2-yl methyl) piperidin-1-carboxylate gave 5,6-dimethoxy-2-(piperidin-4-yl methyl)-1-indanone which on treatment with benzyl bromide afforded Donepezil hydrochloride.
US Patent 5,606,064 discloses another process for the preparation of Donepezil, which involves reacting 5,6-dimethoxy-1-indanone and pyridine-4-carboxaldehyde to yield 5,6 dimethoxy-2-(pyridin-4-yl)-methylene-indan-l-one, which upon treatment with benzyl bromide followed by reduction yields the required compound. US Patent 6,492,522 discloses an alternative process for the preparation of Donepezil hydrochloride which comprises the steps of carrying out the intramolecular cyclization of N-benzyl-2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionic acid of Formula IV,
(Figure-Removed)

to yield crude Donepezil and isolating the pure Donepezil by chromatography or crystallization.
US Patent 6,252,081 discloses an additional process for production of Donepezil hydrochloride which involves the reaction of Donepezil intermediate of Formula V,
(Figure-Removed)
with halogenated benzyl to obtain a quaternary ammonium salt, hydrogenation of the quaternary ammonium salt to produce Donepezil base, followed by hydrohalogenation to produce Donepezil hydrochloride.

The prior art processes employs reaction of l-benzylpiperidine-4-carboxaldehyde with 5,6-dimethoxy-l-indanone involves use of lithium diisopropylamide. Lithium diisopropylamide is toxic and needs to be carefully handled. Use of oxalyl chloride chemistry is difficult for scale up. Besides the oxalyl reaction also involves many protection deprotection chemistry and the overall yield is very low. Raw materials like methyl chlorocarbonate or tetramethyl diaminomethyl are expensive and difficult to source commercially.
In view of the above, the prior art processes are time consuming and difficult to carry out as they involve many steps. Most of the prior art approaches are not suitable from commercial point of view because the desired product is not obtained in high purity and requires purification by tedious and cumbersome purification processes.The inventors have observed that during the condensation reaction of 5,6-dimethoxy-l-indanone of Formula-VI,
(Figure-Removed)

with l-benzylpiperidine-4-carboxaldehyde of Formula-VII,
(Figure-Removed)
for the preparation of indanonylidenyl compound of Formula II

(Figure-Removed)
formation of a hydroxyl impurity of compound of Formula VIII,
(Figure-Removed)

occurs upto 20%. The amount of impurity formation varies depending upon reaction conditions, amount of solvent, nature of solvent used. It is advantageous to remove hydroxyl impurity at this stage; otherwise it converts to indanonylidenyl compound of Formula II during preparation of Donepezil hydrochloride in the presence of hydrochloric acid, hence difficult to remove. An additional step of hydrogenation is required. Further hydrogenation is required to reduce the double bond, which is an additional step leading to increase in cost As discussed above, the inventors have further found that during hydrogenation of indanonylidenyl compound of Formula II in the presence of palladium catalyst debenzylation occurs to the extent of 10%.. Once the debenzylated product is formed in reaction mixture it is difficult to remove. An additional step of benzylation is required to convert the debenzylated product to desired compound. To achieve a high efficiency of the reaction for industrial

synthesis of Donepezil, it is necessary to minimize the formation of the impurities and improve the yields.
Thus, the present invention provides an efficient and industrially advantageous process for the preparation of highly pure Donepezil hydrochloride in high yields.
SUMMARY OF THE INVENTION
Accordingly, in one aspect, present invention provides an improved process for the preparation of highly pure Donepezil of Formula I

(Figure-Removed)
or its salts which comprises:
hydrogenating indanonylidenyl compound of Formula II;

(Figure-Removed)
using platinum catalyst in an organic solvent at a temperature of 0-50°C;
preparing Donepezil base and converting to pharmaceutically acceptable salts.
In another aspect, present invention provides a process for the preparation of indanonylidenyl compound of Formula II which comprises:
condensing 5,6-dimethoxy-l-indanone of Formula-VI,

(Figure-Removed)

and l-benzylpiperidine-4-carboxaldehyde of Formula-VII,
(Figure-Removed)

in the presence of alkali metal alkoxide in methanol as solvent.
In another aspect, present invention provides a process for the purification of indanonylidenyl compound of Formula II to remove hydroxy impurity of Formula
VIII,

(Figure-Removed)
by converting compound of formula VIII into indanonylidenyl compound of Formula II by using acid base treatment or protection /deprotection of hydroxy group.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention relates to an improved, efficient and industrially advantageous process for the preparation of highly pure Donepezil of Formula-1 or salt thereof.
According to an embodiment, there is provided a process for the preparation of indanonylidenyl compound of Formula-II in high purity and better yields by the condensation of 5,6-dimethoxy-l-indanone of Formula-VI,

(Figure-Removed)
and l-benzylpiperidine-4-carboxaldehyde of Formula-VII,
(Figure-Removed)
in the presence of alkali metal alkoxide in a solvent. Specifically the reaction is conducted at 30 -65°C in methanol and it takes about 2-7 hours for completion of
reaction. The indanonylidenyl compound of Formula-II may be further purified by several ways such as by using acid base treatment; by protecting deprotecting hydroxyl group, to remove the hydroxyl impurity of Formula VIII, by converting

(Figure-Removed)
compound of formula VIII into indanonylidenyl compound of Formula II.
Generally, the crude indanonylidenyl compound of Formula-II, having hydroxy impurity is treated with organic or inorganic acid in the presence of solvent such as ethers, alcohols, ketones, hydrocarbons, polar aprotic solvents. Specifically the compound of Formula-II is treated with methanolic-hydrochloric acid in methanol. After work up, pure hydrochloride of indanonylidenyl compound of Formula-II is isolated, which is then basified to get pure indanonylideny compound of Formula II. Alternatively the hydroxy impurity of Formula VIII can be removed by converting hydroxy compound of formula VIII to compound of Formula IX by protecting the hydroxyl group with suitable hydroxyl protecting group, and in situ converting compound of Formula IX to compound of Formula II by dehydration using conventional methods. The protecting hydroxy group for the compound of Formula-IX can be selected from acetates, benzoates, sulfonates and the like which are prepared by using suitable reagents known in prior art.

In one specific embodiment of the present invention sulfonates derivatives of Formula IX are prepared. Sufonates can be methanesulfonate, 4-toluenesulfonate, benzenesulfonate and the like. The compound of Formula VIII may be treated with sulfonyl chloride in the presence of an organic base and a solvent. The solvent comprises one or more of ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents. It is advantageous to remove impurity of Formula VIII before carrying out hydrogenation; otherwise it would carry forward. During hydrochloride preparation of Donepezil it is converting to compound of Formula II on dehydration, in the presence of hydrochloric acid. It is very difficult to remove indanonylidenyl compound of Formula-II from Donepezil hydrochloride and further hydrogenation is required to reduce the double bond, which is an additional step leading to increase in cost.
After purification, the indanonylidenyl compound of Formula II is isolated in high purity greater than 98.5% preferably greater than 99.8%.
According to another embodiment, there is provided a process for the preparation of Donepezil of Formula I which includes hydrogenating indanonylidenyl compound of
Formula-II, in the presence of platinum catalyst to produce and isolating the substantially pure Donepezil or a salt thereof. Specifically hydrogenation of indanonylidenyl compound of Formula II is carried out using platinum catalyst in an organic solvent at 0-50°C preferably at 25-40°C under 1-5 atmospheric pressure preferably at 4 atmospheric pressure. The organic solvent can be selected from solvent comprises one or more of ethers, alcohols, chlorinated hydrocarbons, esters, ketones, hydrocarbons, polar aprotic solvents, water and mixtures thereof and preferably ethyl acetate is used. We have carried out same reactions using palladium catalyst also and found that using palladium catalyst, impurity of Formula III is formed in substantial amount depending upon reaction time. The examples have been provided as comparative examples. Platinum catalysts are mild in nature therefore debenzylation is not observed using platinum catalysts. Platinum catalyst can be selected from platinum oxide, platinum on carbon and preferably platinum on carbon is used. The reaction can be accomplished at 0-50°C and preferably at 25-35°C. The progress of the reaction is monitored by high performance liquid chromatography (HPLC), and the reaction is stirred till the starting material i.e. compound of Formula II remains less than 0.15%, the reaction mixture is filtered to recover the catalyst. The filtrate is concentrated and crude Donepezil is dissolved in organic solvent. The organic solvent is selected from methylene chloride, ethyl acetate and preferably methylene chloride is used. The reaction mixture is treated with a solution of hydrochloric acid in ethyl acetate to obtain Donepezil hydrochloride.
The resulting mixture is concentrated and the product obtained is recrystallized from methanol and isopropyl ether to obtain highly pure Donepezil hydrochloride having purity greater than 99.5% preferably greater than 99.8%.
Major advantages realized in the present invention are high purity and high yields. The formation of impurity of Formula-Ill has been restricted by making use of
platinum catalyst This avoids the use of tedious and cumbersome technique i.e. chromatographic purification, and additional step of benzylation of compound of Formula-Ill. The hydroxy impurity of Formula VIII is removed by acid base treatment or protection/ deprotection technique.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to 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.
EXAMPLES
Preparation of l-Benzvl-4-[5,6-dimethoxv-l-indanon)-2-vlidenvl|methyl
piperidine
Sodium hydroxide (1.46g) was added to methanol (150ml) followed by addition of 5,6-dimethoxy-l-indanone (5g) and l-benzylpiperidene-4-carboxaldehyde (6.8g) at 20-30°C.The temperature of the reaction mass was gradually raised to 62-66°C and was stirred for 6 hours. The reaction mass was concentrated under vacuum and 2/3 volume of the reaction mass was recovered. The remaining slurry was filtered and the product was washed with water followed by methanol to give 6.9 g of l-benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (yield=70%), having purity 98.5% by HPLC.
Preparation of Benzyl-4-K5. 6-dimethoxy-l-indanon)-2-ylidenyll methyl piperidine
A solution 9.8 g of sodium methoxide in 60 ml of methanol was added to a stirred solution of 25 g of 5,6-dimethoxy-l-indanone and 36.75 g 1-benzyl piperidene-4-carboxaldehyde in methanol (690ml) at 20-30°C. The temperature of the reaction mass was gradually raised to 60-65°C and stirred for 2 hours. The precipitated solid was filtered and the product was washed with water followed by methanol to give
crude product which was converted to its hydrochloride salt using methanol. The
hydrochloride salt was basified using sodium hydroxide to obtain 26.9 g of 1-benzyl-
4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (yield=60%) having
purity 99.92% by HPLC.
Purification of l-Benzyl-4-[(5. 6-dimethoxv-l-indanone)-2-ylidenyl]
methylpiperidine
To a stirred solution of l-benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl
piperidine (lOg, purity 93.38%)) in methylene chloride (200ml) was added methane
sulfonyl chloride(0.2 ml) and triethylamine at 25-30°C.The reaction mixture was
stirred at 20-30°C and after completion of reaction, the reaction mass was quenched
with DM water. The organic layer was washed with aqueous sodium bicarbonate
solution followed by concentration in vacuum to obtain the product which was
filtered with methanol to obtain 7.7gm of l-benzyl-4-[(5, 6-dimethoxy-l-indanone)-
2-ylidenyl] methylpiperidine having a purity of 98.71 % by HPLC.
Purification of Benzvl-4-K5. 6-dimethoxy-l-indanon)-2-ylidenyl1 methyl
piperidine
l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (80g, purity
98.85%) was taken in methanol (400ml) followed by addition of methaolic solution
of hydrogen chloride (48ml) at!0-15°C. The product was filtered followed by
addition in the mixture of DM water (400ml) and methylene chloride (640ml), the Ph
of the mass was adjusted to ~9 with 10% caustic solution at 20-30°C. The organic
layer was separated and concentration in vacuum to obtain the product which was
filtered, washed with methanol to obtain 67gm of l-benzyl-4-[(5, 6-dimethoxy-l-
indanone)-2-ylidenyl] methylpiperidine having a purity 99.67% by HPLC.
Preparation of l-Benzyl-4-K5, 6-dimethoxy-l-indanone)-2-vll methylpiperidine
hydrochloride (Donepezil Hydrochloride)
l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (lOg) was taken in ethyl acetate (200ml) followed by addition of 5 % platinum-carbon (2g). The
reaction mixture was hydrogenated at temperature 20-30°C and 2 atmospheric pressure for 2 hours. After completion of reaction, the catalyst was filtered off and the filtrate was concentrated in vacuum. The residue was dissolved in methylene chloride and a solution of hydrochloric acid in ethyl acetate was added to the resulting solution, followed by concentration in vacuum to obtain a crystal, which was recrystallized from methanol / isopropyl ether to obtain 10.6 g of l-benzyl-4-[(5, 6-dimethoxy-l-indanone)-2-yl]methylpiperidine hydrochloride having a purity of 99.55% by HPLC.
Preparation of l-Benzyl-4-K5, 6-dimethoxy-l-indanone)-2-vll methvlpiperidine hydrochloride (Donepezil Hydrochloride)
l-Benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyl]methyl piperidine (10g) was hydrogenated in ethyl acetate (100 ml) for 2 hours in presence of 5% platinum-carbon (2g) at 4 atmospheric pressure. The reaction mixture was filtered and concentrated under vacuum to give residue. The residue was dissolved in methylene chloride and further acidified with a solution ethyl acetate hydrochloric acid at 0-10°C followed by concentration in vacuum to obtain a solid which was recrystallized from methanol and isopropyl ether to obtain 7.4 g of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl] methylpiperidine hydrochloride(yield=67%) having a purity of 99.93% by HPLC
Preparation of l-Benzyl-4-[(5, 6-dimethoxy-l-indanone)-2-yl1 methvlpiperidine hydrochloride (Donepezil Hvdrochloride)
l-Benzyl-4-[5,6-dimethoxy-l-indanon)-2-ylidenyl]methyl piperidine (8g) was taken in ethyl acetate (160ml) followed by addition of 5% platinum-carbon (1.6g). The reaction mass was hydrogenated at 20-3 0°C under 2 atmospheric pressure for 2 hours and the progress of the reaction was monitored by HPLC analysis (debenzlated impurity is
isopropyl ether to obtain 6.8 g of l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl]
methylpiperidine hydrochloride having purity of 99.56% by HPLC.
Reference Examples
Preparation of l-Benzvl-4-K5. 6-dimethoxy-l-indanone)-2-yl] methylpiperidine
hydrochloride (Donepezil Hvdrochloride)
l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine was taken in
tetrahydrofuran (200ml) followed by addition of palladium-carbon (Ig). The mixture
was hydrogenated at 20-30 °C under 1.5 atmospheric pressure for 8 hours, monitored
by HPLC analysis and analysis shows ~ 38.5% of debenzylated impurity in the
reaction mass.
Preparation of l-Benzyl-4-K5. 6-dimethoxv-l-indanonc)-2-yll methvlpiperidine hydrochloride (Donepezil Hvdrochloride)
l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine was taken in 200 ml THF followed by addition of 10% palladium-carbon (0.5g). The mixture was hydrogenated at 20-3 0°C under 1.5 atmospheric pressure for 8 hour and the progress of the reaction was monitored by HPLC analysis (the analysis showed ~22.4% of debenzylated impurity in the reaction mass after 4 hours and ~38% after 8 hours).
Preparation of l-Benzyl-4-[(5, 6-dimethoxy-l-indanone)-2-yll methvlpiperidine hydrochloride (Donepezil Hvdrochloride)
l-Benzyl-4-[5, 6-dimethoxy-l-indanon)-2-ylidenyl] methyl piperidine (5g) was taken in 100 ml of THF followed by addition of 10% palladium-carbon (0.5g). The reaction mixture was hydrogenated at temperature of 20-30°C at 0.3 atmospheric pressure for 2 hour and the progress of the reaction was monitored by HPLC analysis (the HPLC analysis showed the debenzylated impurity9%).

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=ntWoQm5f6FSf5hLDLfJdpQ==&loc=+mN2fYxnTC4l0fUd8W4CAA==

« Previous Patent

Next Patent »

Patent Number

268394

Indian Patent Application Number

936/DEL/2006

PG Journal Number

36/2015

Publication Date

04-Sep-2015

Grant Date

28-Aug-2015

Date of Filing

20-Mar-2006

Name of Patentee

IND-SWIFT LABORATORIES LIMITED

Applicant Address

S.C.O. NO. 850, SHIVALIK ENCLAVE, NAC MANIMAJRA, CHANDIGARH-160 101 INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	CHIDAMBARAM VENKATESWARAN SRINIVASAN	201 A, GH NO. 30, FAIRDEAL GROUP HOUSING SOCIETY, SECTOR 20, PANCHKULA - (HARYANA)
2	ASHVIN KUMAR AGGARWAL	413, LB ENCLAVE, 49-A, CHANDIGARH
3	LALIT WADHWA	408, SHAKTI APARTMENTS, SECTOR 14, PANCHKULA - (HARYANA)

PCT International Classification Number

A61K 31/445

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA